Hetero-[3.1.1]propellane compounds, synthesis and uses thereof

Abstract

Hetero-[3.1.1]propellanes and compounds useful in their synthesis are disclosed. The disclosure also relates to synthetic methods for preparing hetero-[3.1.1]propellanes, reactions of hetero-[3.1.1]propellanes to form hetero-bicyclo-[3.1.1]heptanes (hetBCHeps). The disclosure further relates to the use of the compounds and / or processes of the disclosure in the preparation of a pharmacologically active compound. Moreover the disclosure further relates to the use of 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety or N-substituted analogues thereof, or 3-thiabicyclo[3.1.1]heptane moiety in a pharmacologically active compound.

Description

HETERO-[3.1.1]PROPELLANE COMPOUNDS, SYNTHESIS AND USES THEREOFFIELD OF THE INVENTION

[0001] The invention relates to hetero-[3.1.1]propellanes and compounds useful in their synthesis. The invention also relates to synthetic methods for preparing hetero- [3.1.1]propellanes, reactions of hetero-[3.1.1]propellanes to form hetero-bicyclo- [3.1.1]heptanes (hetBCHeps). The invention further relates to the use of the compounds and / or processes of the invention in the preparation of a pharmacologically active compound. Moreover the invention further relates to the use of 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety or N-substituted analogues thereof, or 3-thiabicyclo[3.1.1]heptane moiety in a pharmacologically active compound.BACKGROUND

[0002] Arenes and heteroarenes are extremely prevalent moieties found in compounds showing biological activity, such as pharmaceutical candidates and drug molecules, owing in part to their ease of synthesis, structural rigidity and range of interactions they can have with biomolecules. Despite their prevalence, arenes and heteroarenes in bioactive molecules may be associated with a number of drawbacks such as instability to metabolism, poor potency and poor solubility, so are the target for bioisosteric replacement (see e.g. Subbaiah et al. J. Med. Chem. 2021, 64, 19, 14046-14128). Small caged hydrocarbons such as [1.1.1]-bicyclopentane (BCP) and cubanes have been proposed as analogues of arenes and heteroarenes (see Cuadros etal. Angew. Chem. Int. Ed. 2024, 63, e202317333, and Bethany R. Shire and Edward A. Anderson JACS Au 2023, 3, 1539-1553 discusses the synthesis and functionalisation of bicyclo[1.1.1]pentanes, as well as the utility of these structures as bioisosteres).

[0003] In particular, small caged hydrocarbons (such as bicyclo[1.1.1]pentanes) are commonly suitable as bioisosteres for para-substituted benzene rings due to the relative ease of producing structures with substituents which are oriented approximately 180 degrees apart in these scaffolds, however there remains a significant challenge to prepare bioisosteres for meta-substituted benzene rings owing to for example the difficulty in making rigid scaffolds that are of suitable size with substituents which are approximately 120 degrees apart and also are not arenes and heteroarenes (see e.g. Frank et al. Nature volume 611, pages 721-726 (2022)). Preparing bioisosteres for meta-substituted heteroaryl rings has similar difficulties to meta-substituted aryls but is even more challenging, as incorporation of heteroatoms into small molecule cages presents particular synthetic challenges.

[0004] A number of methods of preparing all carbon bicyclo-[3.1.1]heptanes (BCHeps) are known, however synthesis of bicyclo-[3.1.1]heptanes bearing heteroatoms within the bicyclic structure (hetBCHeps) are extremely challenging to synthesise. Known syntheses of hetBCHeps are very limited as to the structures that can be produced (e.g. the substituents present). Owing to the difficulty of synthesis, many hetBCHep structures have never before been synthesized.

[0005] In short, there is a need to provide methods of synthesis of hetBCHeps and compounds used in these methods of synthesis.SUMMARY OF THE INVENTION

[0006] A first aspect of the present invention relates to a compound having a structure selected from:wherein X1= O, NR1, S, SO, or SO2;each R1is each, independently, SO2R2, Bn, COCF3, COC(CH3)3, CO(1,3,5-trimethylphenyl), CO2OBn, C(C6H5)3, CO2OtBu, 2-pyridine or allyl;R2is Me, Ph, 4-methoxyphenyl, 2-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 2-nitrophenyl, or 2-trimethylsilylethanyl, C6-C10 aryl, 5 to 10 membered heteroaryl, C1-C10 alkyl, optionally substituted aryls, optionally substituted phenyl;R3is an acyl group, a C1-C10 acyl group, a benzoyl group or acetyl;R4is a C1-C10 alkyl group, C6-C10aryl group, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl or cyclohexyl;R5is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10cycloalkyl, C3-C10cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3,CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R5groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R6is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R6groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R7is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R7groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;X2is each, independently, Cl, Br, or I; andX3is each, independently, absent or =0.

[0007] Advantageously, it has been found that compounds of the first aspect may be useful in the synthesis of hetBCHeps, chemical structures which are desirable in the field of drug discovery but difficult to synthesise. The present disclosure relates to a new method of preparing hetBCHeps, and the compounds used in the method, which may be associated with numerous advantages. Suitably methods of the disclosure provide a synthetic route to hetBCHeps where substitution at both bridgehead atoms can be introduced in a single step, meaning that the structurally complex target compounds may be synthesised more easily than alternative methods. Further, using the process of the invention a wide range of chemical structures are tolerated for the bridgehead substituents of the hetBCHeps that may be prepared, so advantageously a broader range of hetBCHep products may be prepared than alternative methods. Advantageously, the synthetic methods disclosedherein to 3-oxa-[3.1.1]propellane, 3-aza-[3.1.1]propellane or N-substituted analogues thereof and 3-thia-[3.1.1]propellane all use a common precursor that is conveniently assembled on a large scale (a multigram scale) via a rhodium-catalyzed cyclopropanation, so bioisosteres with differing heteroatoms can be prepared easily due to the lower total number of synthetic steps than would otherwise be necessary. Advantageously hetBCHeps can be prepared for which no known synthetic procedure to them is known.

[0008] A second aspect of the invention relates to a process for the preparation of a compound of formula 1 according to the first aspect, wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi.

[0009] A third aspect of the invention relates to a process for the preparation of a compound of the structure:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III). Processes according to the third aspect use compound of formula 1 according to the first aspect.

[0010] A fourth aspect process for the preparation of a compound of formula 1 wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi, preferably wherein X2are each I or each Br, more preferably wherein X2are each I.

[0011] A fifth aspect relates to of the invention relates to the use of a compound according to the first aspect or a process according to the second aspect, third aspect or fourth aspect in the preparation of a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted aryl bioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

[0012] A sixth aspect relates to the use of a 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety, or 3-thiabicyclo[3.1.1]heptane moiety in a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted aryl bioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The invention is further described hereinafter with reference to the accompanying drawings.

[0014] Figure 1 shows a1H NMR (600 MHz, C6D6) spectrum for 3-oxa-[3.1.1]propellane prepared according to the disclosure.

[0015] Figure 2 shows a13C NMR (151 MHz, C6D6) spectrum for 3-oxa-[3.1.1]propellane prepared according to the disclosure.

[0016] Figure 3 shows a1H NMR (400 MHz, CDCl3) spectrum for 3-thia-[3.1.1]propellane prepared according to the disclosure.

[0017] Figure 4 shows a13C NMR (101 MHz, CDCl3) spectrum for 3-thia-[3.1.1]propellane prepared according to the disclosure.

[0018] Figure 5 shows a1H NMR (500 MHz, C6D6) spectrum for 3-(tosyl)aza-[3.1.1]propellane prepared according to the disclosure. This NMR spectrum includes some residual Et2O.

[0019] Figure 6 shows a13C NMR (126 MHz, C6D6) spectrum for 3-(tosyl)aza- [3.1.1]propellane prepared according to the disclosure. This NMR spectrum includes some residual Et2O.DETAILED DESCRIPTION

[0020] Dibchak et al. (Angew. Chem. Int. Ed. 2023, 62, e202304246) describes a synthesis of 3-azabicyclo-[3.1,1]heptanes by reduction of spirocyclic oxetanyl nitriles. The method of Dibchak et al. is limited in that it can only prepare 3-azabicyclo-[3.1.1]heptanes, i.e. it cannot be used to prepare bicyclo-[3.1.1]heptanes bearing heteroatoms other than nitrogen at the 3 position. Further, the method of Dibchak et al. is limited by the what particular 3-azabicyclo-[3.1.1]heptanes can be produced, as the product of their method always has a bridgehead carbon bearing a -CH2OH group, and the method does not product 3-azabicyclo-[3.1.1]heptane with substituents at positions other than the bridgehead carbons.

[0021] Dibchak et al. discusses the suitability of 3-azabicyclo-[3.1.1]heptanes as bioisosteres, in particular 3-azabicyclo-[3.1.1]heptanes as bioisosteres for a pyridine ring. In the synthesis of a Ruputadine analogue bearing a 3-azabicyclo-[3.1.1]heptane in place of the pyridine ring, finding that the replacement of pyridine a 3-azabicyclo-[3.1.1]heptane lead to an “dramatic improvement of all measured physicochemical parameters: solubility, metabolic stability, and lipophilicity” - specifically an increase in solubility in water, decreasein lipophilicity and increase in metabolic stability. The present disclosure is advantageous over the method of Dibchak et al. because a wide range of hetBCHeps can be prepared.

[0022] It has been reported in the prior art that BCHeps may be prepared by photocycloaddition reactions or by reaction with [3.1.1]propellane - see Cuadros et al. Angew. Chem. Int. Ed. 2024, 63, e202317333. Preparing BCHeps by reaction with [3.1.1]propellane (for example by photo-redox-catalysed ATRA reactions) is advantageous because the methods of the present disclosure introduce BCHep structure in a single step and products can be readily functionalised. The inventors believe that the present disclosure provides the first evidence that hetero-[3.1.1]propellanes can be reacted to form hetBCHeps.

[0023] Frank et al. reported the synthesis of the hydrocarbon molecule [3.1.1]propellane and its utility in the synthesis of BCHeps. The method of Frank et al. is associated with a number of advantages over other methods (e.g. ring expansion of BCPs and cyclization of cyclohexane dicarboxylates), including that the procedure is associated with high yielding, BCHeps can be installed with relatively few synthetic steps and the BCHep products can have broader scope of substituents. [3.1.1]propellane can be reacted under radical ring opening conditions to form BCHeps which are substituted at the bridgehead positions, lida et al. J. Am. Chem. Soc. 2022, 144, 21848-21852 also discloses a synthesis of [3.1.1]propellane from a diiodo precursor using lithium-halogen exchange, reactions of [3.1.1]propellane to form BCHeps. Frank et al. and lida et al. are limited in that they do not prepare heteroatom substituted [3.1.1]propellanes nor hetBCHeps.

[0024] The inventors have found that attempts to synthesize hetero-[3.1.1]propellanes (including 3-oxa-[3.1.1]propellane, 3-thia[3.1.1]propellane and a 3-aza-[3.1.1]propellane) using the conventional methods to prepare all carbon propellanes (e.g. [3.1.1]propellane and [1.1.1]propellane) were unsuccessful. Methods to prepare all carbon propellanes generally rely on the formation of a tetra-halogenated intermediate which is exposed to a lithium source such as MeLi. Without being bound by theory, the inventors hypothesise the unsuitability of this synthetic method as a way to prepare hetero-[3.1.1]propellanes may be due to the fragmentation of a partially lithiated intermediate as the heteroatoms may act as a leaving group, which is not possible in the corresponding all carbon structures.

[0025] Used herein [3.1.1]propellane is synonymous with tricyclo[3.1.1.01’5]heptane.[3.1.1]Propellanes are molecules featuring a carbon-carbon bond to which three rings are fused, two being cyclopropanes and the third a 5-membered ring. The present disclosure relates to 3-hetero-[3.1.1]propellanes, i.e. [3.1.1]propellanes with a heteroatom at theposition of the 5-membered ring which is not a bridgehead atom and not directly bonded to a bridgehead atom.

[0026] In recent years small-ring bridged bicyclic hydrocarbon moieties have emerged as important building blocks in contemporary drug design due to their rigid frameworks with associated well-defined substituent vectors. BCHeps and by extension hetBCHeps have this advantageous property of well-defined substituent vectors. BCHeps and by extension hetBCHeps have particularly advantageous substituent vectors where they are substituted at the bridgehead positions, as the dihedral angle is very close to 120 degrees. This makes them excellent candidates for bioisosteres of meta substituted aryl and / or heteroaryl rings.

[0027] The inventors believe that this application is the first disclosure of the synthesis of a family of heterocyclic [3.1.1]propellanes, featuring oxygen, nitrogen and sulfur heteroatoms in the three-carbon bridge. These heterocyclic [3.1.1]propellanes are strained structures, previously unknown to the scientific community. As such, it was unknown whether these compounds would be stable or whether it would be possible to synthesise them. The inventors have found that these hetero[3.1.1]propellanes are stable towards isolation and storage. Importantly, these hetero[3.1.1]propellanes are also readily amenable to radical ring-opening reactions under a variety of conditions, leading to diverse bridgehead-disubstituted hetero-bicyclo[3.1.1]heptanes that cannot be accessed using alternative approaches. The inventors expect these novel hetero-propellanes will be of highly useful in drug discovery programmes as they can be used to generate a wide structural range of hetero-bicyclo[3.1.1]heptane products - highly desirable targets for drug discovery. The hetero-bicyclo[3.1.1]heptane products are especially suitable as moieties within pharmaceutically active compounds because compounds containing heterocyclic scaffolds are often highly active in bioactive compounds and their rigid structure is particularly suitable for drug candidates because the conformational restriction is advantageous to the enthalpy of binding to a target relative to more flexible groups. Further, the inventors have surprisingly found that heterocyclic [3.1.1]propellanes can be sufficiently stable to be isolated as solids, whilst still being reactive enough to form hetBCHeps, specifically the inventors disclose herein that tosyl azapropellane compound 15 has been isolated in a solid form that has been characterised by X-ray crystallography. This X-ray crystal structure further confirms the presence of the [3.1.1]propellane structure in these compounds (in addition to the unambiguous NMR spectra and other characterisation techniques performed by the inventors).

[0028] A first aspect of the present invention provides a compound having a structure selected from:wherein X1= O, NR1, S, SO, or SO2;each R1is each, independently, SO2R2, Bn, COCF3, COC(CH3)3, CO(1,3,5-trimethylphenyl), CO2OBn, C(C6H5)3, CO2OtBu, 2-pyridine or allyl;R2is Me, Ph, 4-methoxyphenyl, 2-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 2-nitrophenyl, or 2-trimethylsilylethanyl, C6-C10 aryl, 5 to 10 membered heteroaryl, C1-C10 alkyl, optionally substituted aryls, optionally substituted phenyl;R3is an acyl group, a C1-C10 acyl group, a benzoyl group or acetyl;R4is a C1-C10 alkyl group, C6-C10aryl group, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl or cyclohexyl;R5is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10cycloalkyl, C3-C10cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CFWMe, or two R5groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R6is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R6groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R7is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R7groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;X2is each, independently, Cl, Br, or I; andX3is each, independently, absent or =0.

[0029] Suitably R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

[0030] Suitably R5is H. Suitably R6is H. Suitably R7is H. Suitably R5and R6are H. Suitably R5and R7are H. Suitably R6and R7are H. Preferably R5, R6and R7are H.

[0031] Suitably R4is Me.

[0032] Suitably X2is Br.

[0033] Preferably X1= NR1and R1is each, independently, (4-methylphenyl)sulfonyl, Bn, or CO2OtBu. More preferably X1= NR1and R1is (4-methylphenyl)sulfonyl. More preferably X1= NR1and R1is Bn.

[0034] Suitably X1is O.

[0035] Suitably X1is S.

[0036] Suitably a compound of the invention is selected from:

[0037] Suitably a compound of the invention is selected from:5

[0038] Suitably a compound of the invention is selected from:

[0039] Suitably a compound of the inventionSuitably a compound of theSuitably a compound of theSuitably a compound of the invention isSuitably a compound of the

[0040] Suitably a compound of the invention is selected from:Suitably a compound of the invention isSuitably a compound of the inventionSuitably a compound of the

[0041] A second aspect of the invention relates to a process for the preparation of a compound of formula 1:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi. Preferably the organolithium reagent (e.g. MeLi) is present as 1 equivalent, for example 1.0 equivalents. This may be advantageous as less quenching may be required. Preferably step (i) further comprises a quenching step comprising or consisting of addition of solid NaHCO3. More preferably the organolithium reagent (e.g. MeLi) is present as 1 equivalent, forexample 1.0 equivalents and step (i) further comprises a quenching step comprising or consisting of addition of solid NaHCO3. Methods of the second aspect may further comprise a purification step after step (i) comprising filtration, wherein the filtration is optionally through celite, or distillation, preferably wherein the purification step comprises filtration. Methods of the second aspect wherein X1= S or O may further comprise a purification step after step (i) comprising filtration, wherein the filtration is optionally through celite, or distillation, preferably wherein the purification step comprises filtration.

[0042] Suitably where X1is O or NR1, the process further comprises the step of:(ii) reactingoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine or CBr4 and triphenylphosphine, more preferably in the presence of N-bromo succinimide and triphenylphosphine where X1is O or CBr4and triphenylphosphine where X1is NR1.

[0043] Suitably where X1is O, the process further comprises the step of:optionally wherein the reaction occurs in the presence of a base, for example in the presence of a hydroxide source, preferably in the presence of potassium hydroxide.

[0044] Suitably where X1is O, the process further comprises the step of:optionally wherein the reaction occurs in the presence of a reducing agent, for example LiAlH4, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride.

[0045] Suitably where X1is NR1, the process further comprises the step of:preferably wherein the reaction occurs in the presence of sulfonyl chloride and an amine base, more preferably in the presence of tosyl chloride and an amine base, yet more preferably in the presence of tosyl chloride and triethylamine, or tosyl chloride and sodium carbonate.

[0046] Suitably where X1is NR1, the process further comprises the step of:preferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of sodium bis(2-methoxyethoxy)aluminium hydride.

[0047] Suitably where X1is NR1, the process further comprises the step of:(vii)preferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of a phosphine, even more preferably in the presence of PBU3.

[0048] Suitably where X1is NR1, the process further comprises the step of:preferably wherein the reaction occurs in the presence of a metal azide, more preferably in the presence of sodium azide.

[0049] Suitably where X1is NR1, the process further comprises the step of:(ix) reactingoptionally wherein the reaction occurs in the presence of a nitrogen deprotecting reagent, preferably in the presence of trifluoroacetic acid.

[0050] Suitably where X1is NR1, the process further comprises the step of:optionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.

[0051] Suitably where X1is NR1, the process further comprises the step of:(xi)optionally wherein the reaction occurs in the presence of a reducing agent, preferably in the presence of diisobutylaluminium hydride.

[0052] Suitably where X1is S, the process further comprises the step of:(xiii)formoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.

[0053] Suitably where X1is S, the process further comprises the step of:(xiv) reactingoptionally wherein the reaction occurs in the presence of an amine base, preferably in the presence of triethylamine, more preferably in the presence of potassium thioacetate, most preferably in the presence of potassium thioacetate and triethylamine.

[0054] Suitably where X1is S, the process further comprises the step of:(xv) reactingoptionally wherein the reaction occurs in the presence of a reducing agent, for example LiAIF, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride. In some embodiments step (xiv) occurs without a base present.

[0055] Suitably R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5, R6and R7are each,independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

[0056] Suitably R5is H. Suitably R6is H. Suitably R7is H. Suitably R5and R6are H. Suitably R5and R7are H. Suitably R6and R7are H.

[0057] Preferably R5, R6and R7are H.

[0058] Suitably R4is Me.

[0059] Suitably X2is Br.

[0060] Suitably X1= NR1and R1is each, independently, (4-methylphenyl)sulfonyl, Bn, or CO2OtBu. Suitably where X1= NR1and R1is (4-methylphenyl)sulfonyl.

[0061] Suitably X1= NR1and R1is Bn.

[0062] Suitably X1is O.

[0063] Suitably X1is S.

[0064] Suitably the process further comprises the step of:(xiv) reactingoptionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III), or 4CzIPN.

[0065] Suitably compound of formula 1 is obtained in step (i) in a purity of 85 mol% or higher, 90 mol% or higher, 95 mol% or higher, or 98 mol% or higher.

[0066] Suitably the yield of formula 1 in step (i) is 50 % or higher, 60 % or higher, or 70 % or higher.

[0067] In a third aspect, the disclosure provides process for the preparation of a compound of the structure:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III).

[0068] Suitably R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

[0069] Suitably R5is H. Suitably R6is H. Suitably R7is H. Suitably R5and R6are H. Suitably R5and R7are H. Suitably R6and R7are H. Preferably R5, R6and R7are H.

[0070] Suitably X1= NR1and R1is (4-methylphenyl)sulfonyl.

[0071] Suitably X1= NR1and R1is Bn.

[0072] Suitably X1is O.

[0073] Suitably X1is S.

[0074] In a fourth aspect, the disclosure provides a process for the preparation of a compound of formula 1:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi, preferably wherein X2are each I or are each Br. More preferably X2are each I. In some embodiments X2are each Br.

[0075] Suitably R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3,CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe. Suitably R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

[0076] Suitably R5is H. Suitably R6is H. Suitably R7is H. Suitably R5and R6are H. Suitably R5and R7are H. Suitably R6and R7are H. Preferably R5, R6and R7are H.

[0077] Suitably X1= NR1and R1is (4-methylphenyl)sulfonyl.

[0078] Suitably X1= NR1and R1is Bn.

[0079] Suitably X1is O.

[0080] Suitably X1is S.

[0081] A fifth aspect relates to of the invention relates to the use of a compound according to the first aspect or a process according to the second aspect, third aspect or fourth aspect in the preparation of a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted aryl bioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

[0082] A sixth aspect relates to the use of a 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety, or 3-thiabicyclo[3.1.1]heptane moiety in a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted aryl bioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

[0083] According to the present disclosure, hetero-[3.1.1]propellane formation steps occur in the presence of an organolithium reagent. Suitably the organolithium reagent is nBuLi or MeLi. nBuLi is advantageous as it enables a wide range of substituents on the 3-aza group of the 3-azabicyclo[3.1.1]heptane to be tolerated. MeLi is advantageous because it enables simple purification, as the byproduct of propellane formation, a methyl halide e.g. MeBr or Mel may be easily removed from the reaction vessel under reduced pressure.

[0084] Suitably the 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety, or 3-thiabicyclo[3.1.1]heptane moiety is covalently bonded to the rest of the pharmacologically active compound at one or both of the bridgehead atoms of the heterobicyclo[3.1.1 ]heptane moiety.

[0085] Suitably the use comprises reacting 3-oxatricyclo[3.1.1.01’5]heptane, 3-azatricyclo[3.1.1.01’5]heptane, a N-substituted analogue of 3-azatricyclo[3.1.1.01’5]heptane, or 3-thiatricyclo[3.1.1.01’5]heptane to form the 3-oxabicyclo[3.1.1]heptane moiety, 3-oxabicyclo[3.1.1]heptane moiety, or 3-oxabicyclo[3.1.1]heptane moiety.

[0086] According to some aspects of the invention compounds of the following structure may be obtained:Wherein R8is optionally substituted benzyl, benzyl, substituted amine, alkyl, aryl,R9is Br, I, H, 4-tetrahydropyranyl, boronic ester, BO2C2(CH3)4, BF3K, S(2-pyridyl)..0.Br

[0087] In some embodiments the process includes the step of reacting HO toform

[0088] In some embodiments the process includes the step of reactingform

[0089] In an embodiment the invention provides a compound having a structure selected from:

[0090] In an embodiment the invention provides a compound having the structure:

[0091] In an embodiment the invention provides a compound having the structure:

[0093] In an embodiment the invention provides a compound having a structure selected, , .5 Suitably methods of the disclosure may further comprise:adjusted to a pH of 5.0 to 9.0, more preferably a pH of 6.0 to 8.0, e.g. 8.0.ExamplesSynthesis

[0094] Starting materials were obtained from Merck and Fluorochem and used without further purification unless otherwise stated. Used herein rt refers to room temperature. Used herein THF refers to tetrahydrofuran. Used herein NBS means N-bromosuccinimide.NMR Spectroscopy: Proton (1H) and carbon (13C) NMR spectra were recorded on Bruker AVIII HD 400, NEO 600, AVIII HD 500, and AVII 500 spectrometers (University of Oxford).1H, and13C chemical shifts (5) are quoted in parts per million (ppm).1H NMR spectra were recorded using an internal deuterium lock for the residual protons in benzene-d (5 = 7.16) or chloroform-d (5 = 7.26).13C NMR spectra were recorded using an internal deuterium lock in benzene-d (5 = 128), chloroform-d (5 = 77.16). Assignments were determined either on the basis of unambiguous chemical shift or coupling patterns, COSY, HSQC, HMBC and / or NOESY experiments. Peak multiplicities are defined as s (singlet), d (doublet), t (triplet), q (quartet), quin, (quintet), m (multiplet) and br (broad). Coupling constants (J) are reported to the nearest 0.1 Hz.Mass Spectroscopy: High-resolution mass spectra (HRMS) were recorded by the Departmental Mass Spectrometry Service, University of Oxford on a Thermo Scientific Exactive Mass Spectrometer (Waters Equity autosampler and pump) for electrosprayionization (ESI) and an Agilent 7200 Accurate Mass QTOF GCMS (using a SIM Direct Insertion Probe) for electron ionization (El) and chemical ionization (Cl). HRMS (ESI) data were recorded on a Waters Xevo G2-XS Q-TOF instrument (IISC India). High-resolution values are calculated to 4 decimal places from the molecular formula, and all values are within a tolerance of 5 ppm.Infrared Spectroscopy: Infrared spectra were obtained on a Bruker Tensor 27 FT-IR spectrometer, as a thin film by evaporation of a solution onto a diamond ATR module. Wavelengths of maximum absorbance (Umax) are quoted in cm-1.Chromatography: Column chromatography refers to normal phase column chromatography and was performed on silica gel (Merck Si 60, 0.040-0.063 mm) under a positive pressure of nitrogen, using the stated solvent system. Analytical thin-layer chromatography was performed on pre-coated aluminium-backed plates (Merck Kieselgel 60 F254 plates) with visualization by ultraviolet light (254 nm) and / or by staining with potassium permanganate or vanillin. Retention factors (Rf) are reported with the solvent system in parentheses.Materials / procedures: All air- or moisture-sensitive reactions were carried out in anhydrous solvents under an inert atmosphere of argon or nitrogen. Light-sensitive reactions were carried out under aluminium foil protection. Heating was performed using a silicone oil bath. Dry tetrahydrofuran, CH2CI2, pyridine, triethylamine and diethyl ether were collected from an mBraun SPS-800 solvent purification system, having been passed through anhydrous alumina columns, "rt" refers to room (ambient) temperature, typically 23 °C.Photochemical setup: Photochemical reactions were carried out in an EvoluChem PhotoRedOx Box with an LED lamp (HCK1012-01-010 405 nm or HCK1012-01-002 450-455 nm or Kessil PR160, 456 nm) positioned 10 cm away from the vial, with fan cooling.Melting points: Recorded using a Gallenkamp melting point apparatus, and are uncorrected.

[0095] Safety note: all reactions involving diazo compounds or azides were carried out behind a blast shield, although no explosions have been observed.

[0096] Exemplary routes to hetero[3.1.1]propellanes are shown below in Scheme 1:

[0097] Exemplary substrate scope is provided below in Scheme 2:

[0098] Exemplary diversification on nitrogen is provided below in Scheme 3:Exemplary route to azapropellanes that may be used with General Procedure 4 is provided below in Scheme 4:Dimethyl 2-diazomalonate (1’)o oMeO2C-CO2MeN2Method 1: The product was prepared according to the literature procedure1. To a solution of dimethyl malonate (4.33 mL, 37.8 mmol, 1.0 eq.) and p-ABSA (10.9 g, 45.4 mmol, 1.2 eq.) in dry MeCN (30 mL) at 0 °C was added DBU (7.92 mL, 53.0 mmol, 1.4 eq.) dropwise over 10 min. The mixture was stirred at 0 °C for a further 10 min then warmed to rt and stirred for 3 h. The reaction was quenched with sat. NH4CI (5 mL), then the MeCN was removed under reduced pressure. Water (100 mL) was added and the mixture was extracted with Et20 (3 x 100 mL), then the combined organic layers were washed with brine (200 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, hexane / EtOAc 4:1) gave the product (5.25 g, 33.2 mmol, 88%) as a yellow oil.Method 2: The product was prepared according to a modified literature procedure1. To a solution of dimethyl malonate (17.3 mL, 151 mmol, 1.0 eq.) and p-ABSA (40.0 g, 167 mmol, 1.1 eq.) in dry MeCN (150 mL) at 0 °C was added DBU (24.9 mL, 167 mmol, 1.1 eq.) dropwise over 30 min, keeping the internal temperature below 20 °C. The mixture was then warmed to rt and stirred for 3 h. NH4CI sat. (20 mL) was added, then the solvent was removed under reduced pressure. Water (400 mL) was added and the mixture was extracted with Et20 (3 x 400 mL), then the combined organic layers were washed with brine (600 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The mixture was filtered through a silica plug and eluted with a 4:1 mixture of hexane / EtOAc until all of the yellowsubstance was removed from the silica. Concentration under reduced pressure gave the product (20.6 g, 130 mmol, 86%) as a yellow oil.Rf 0.20 (4:1 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H3.83 (6H, s, H1).13C NMR (101 MHz, CDCh) 6c 161.2, 52.7.Analytical data matches that previously recorded1.Note: For safety reasons, to avoid isolation of neat diazo compound, the product is not concentrated until completely free of solvent, but is taken forward to the next step with around 10% residual solvent remaining. The amount of product was determined by NMR spectroscopy.Dimethyl 2-bromo-2-(bromomethyl)cyclopropane-1,1 -dicarboxylate (2)o oMeO2C-CO2Me7Br BrMethod 1: To a solution of rhodium(ll) triphenylacetate dimer (38.0 mg, 26.4 pmol, 0.050 mol%) in dry CH2CI2 (50.0 mL) was added 2,3-dibromoprop-1-ene (10.3 mL, 106 mmol, 2.0 eq.). A solution of dimethyl 2-diazomalonate (8.35 g, 52.8 mmol, 1.0 eq.) in dry CH2CI2 (20.0 mL) was added via a syringe pump over 8 h at rt then the mixture was stirred at rt for an additional 8 h. The solvent was removed under reduced pressure, then purification by column chromatography (SiCh, pentane / Et2O 19:1) gave the product (12.4 g, 37.6 mmol, 71%) as a colourless oil.Method 2: To a solution of rhodium(ll) triphenylacetate dimer (93.8 mg, 65.1 pmol, 0.050 mol%) in dry CH2CI2 (100 mL) was added 2,3-dibromoprop-1-ene (25.5 mL, 80%, 208 mmol, 1.6 eq.). A solution of dimethyl 2-diazomalonate 1' (20.6 g, 130 mmol, 1.0 eq.) in dry CH2CI2 (20.0 mL) was added via a syringe pump over 8 h at rt then the mixture was stirred at rt for an additional 8 h. The solvent was removed under reduced pressure, then purification by column chromatography (SiO2, pentane / Et2O 19:1 → 8:2) gave the product (29.1 g, 88.2 mmol, 68%) as a colourless oil.Rf 0.26 (8:2 pentane / Et20).1H NMR (400 MHz, CDCh) 6H4.07 (2H, s, H8), 3.84 (3H, s, H1 or 5), 3.80 (3H, s, H1 or 5), 2.29 (1H, d, J= 7.2 Hz, H6), 2.06 (1 H, d, J= 7.2 Hz, H6).13C NMR (101 MHz, CDCh) 6c 166.9, 165.9, 53.6, 53.5, 42.3, 41.2, 38.3, 30.8. IR (thin film, Vmax / crn’1; selected peaks): 2955, 1743, 1438, 1345, 1258.HRMS (ES+) calc. for C8H11Br2O4[M+H]+328.9019, found 328.9006.Note: some product fractions contained traces of catalyst, giving them a blue colour, but this did not impact the following step.(5-Bromo-3-oxabicyclo[3.1.0]hexan-1-yl)methanol (4)1To a solution of 2 (15.0 g, 46.0 mmol, 1.0 eq.) in dry THF (150 mL) at -78 °C was added DIBALH (200 mL, 1.0 M solution in hexanes, 200 mmol, 4.3 eq.). The mixture was stirred at -78 °C for 2.5 h, allowed to warm slowly to rt and stirred for an additional 30 min. The mixture was cooled to 0 °C and Rochelle’s salt (250 mL, aq. sat.) was added slowly. The cloudy mixture was stirred at rt for 5 h until it became clear. THF was removed under reduced pressure, then the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford (2-Bromo-2-(bromomethyl)cyclopropane-1,1-diyl)dimethanol (3).The crude product 3 from the first step was dissolved in MeOH (100 mL) and added to a solution of KOH (4.50 g, 80.0 mmol, 1.8 eq.) in MeOH (150 mL). The mixture was heated to 60 °C for 1 h, then the solvent was removed under reduced pressure. Water (100 mL) was added and the mixture was extracted with Et20 (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product 4 (7.40 g, 38.0 mmol, 84%) as a yellow oil, which required no further purification.Rf 0.45 (4:6 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H4.09 (1 H, d, J = 8.2 Hz, H4 or H5), 4.00 (1 H, d, J = 8.7 Hz, H4 or H5), 3.98 (1 H, d, J = 12.5 Hz, H2), 3.88 (1 H, d, J = 8.3 Hz, H4 or H5),3.83 (1 H, d, J = 9.1 Hz, H 4 or H5), 3.82 (1H, d, J = 11.8 Hz, H2), 1.69 (1H, br s, H1), 1.33 (1H, d, J = 6.1 Hz, H7), 1.19 (1H, d, J= 6.1 Hz, H7).13C NMR (101 MHz, CDCl3) δC 75.1, 70.0, 63.5, 37.2, 34.0, 20.8.IR (thin film, Vmax / crn’1; selected peaks): 3422, 2870, 1074, 1040, 998.HRMS (ES+) Not found.If desired, the product 3 of the first step can be isolated by trituration. A representative procedure is as follows:(2-Bromo-2-(bromomethyl)cyclopropane-1,1-diyl)dimethanol (3)To a solution of 2 (6.69 g, 20.3 mmol, 1.0 eq.) in dry THF (50.0 mL) at -78 °C was added DIBALH (83.1 mL, 1.0 M solution in hexanes). The mixture was stirred at -78 °C for 2 h, then stirred at 0 °C for a further 1 h. Rochelle’s salt (100 mL, aq, sat.) was added and the cloudy mixture was stirred at rt for 3 h until it became clear. THF was removed under reduced pressure, then the aqueous layer was extracted with EtOAc (3x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. Trituration from a 7:3 mixture of pentane: Et2O gave the product (2.59 g, 9.45 mmol, 47%) as a white amorphous solid which was collected by filtration.Rf 0.24 (4:6 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H4.15 (1H, d, J = 11.9 Hz, H2), 4.08 (1H, d, J = 12.2 Hz, H4), 4.03 (1H, d, J= 12.0 Hz, H8), 3.93 (1H, d, J= 12.0 Hz, H8), 3.89 (1H, d, J = 12.0 Hz, H2), 3.76 (1H, d, J= 12.2 Hz, H4), 2.23 (2H, br s, H1 / H5), 1.36 (1H, d, J = 7.1 Hz, H6), 1.23 (1H, d, J= 7.1 Hz, H6).13C NMR (101 MHz, CDCh) 6C69.9, 64.1, 44.2, 42.6, 37.1, 26.7.IR (thin film, Vmax / cnr1; selected peaks): 3373, 2947, 1436, 1229, 1025.HRMS (ES+) calc, for C6HiiBr2O2 [M+H]+272.9120, found 272.9122.1-Bromo-5-(bromomethyl)-3-oxabicyclo[3.1.0]hexane (5)_ / 4Br V y5BrMethod 1: To a solution of 4 (2.00 g, 10.4 mmol, 1.0 eq.) in dry CH2CI2 (25 mL), was added NBS (2.21 g, 12.4 mmol, 1.2 eq.). PPhs (3.26 g, 12.4 mmol, 1.2 eq.) was then added in portions at 0 °C and the mixture was stirred at rt for 1.5 h. After complete consumption of the starting material, 150 mL of pentane was added to the reaction mixture and stirred for 10 minutes at room temperature. The reaction mixture was filtered through a short pad of celite, and the filtrate was concentrated. Purification by column chromatography (SiO2, pentane / Et2O 9:1) gave 5 (2.25 g, 8.81 mmol, 85%) as a pale yellow oil.Method 2: To a solution of 4 (7.59 g, 39.3 mmol, 1.0 eq.) in dry CH2CI2 (100 mL), was added NBS (8.40 g, 47.2 mmol, 1.2 eq.). PPhs (12.4 g, 47.2 mmol, 1.2 eq.) was then added in portions at 0 °C and the mixture was stirred at rt for 1 h. Pentane (150 mL) was added to the reaction mixture and stirred for 10 minutes at room temperature. The mixture was filtered through a celite pad, and the filtrate was concentrated. Purification by column chromatography (SiO2, pentane / Et2O 19:1) gave the product (7.43 g, 29.0 mmol, 74%) as a pale yellow oil.Rf 0.33 (19:1 pentane I Et20).Rf 0.40 (9:1 pentane I Et20).1H NMR (500 MHz, CDCI3) 6H3.99 (1H, d, J = 8.4 Hz, H2 / 3), 3.81 (1H, d, J = 8.6 Hz, H2 / 3), 3.77 (1H, d, J= 8.6 Hz, H2 / 3), 3.76 (1H, dd, J= 8.4, 1.2 Hz, H2 / 3), 3.54 (1H, d, J= 11.0 Hz, H6), 3.51 (1H, d, J= 11.0 Hz, H6), 1.42 (1H, d, = 6.3 Hz, H5), 1.14 (1H, d, = 6.3 Hz, H5).13C NMR (126 MHz, CDCI3) 6c 75.0, 71.4, 40.1, 34.2, 33.1, 23.6.IR (thin film, Vmax / cnr1; selected peaks): 2939, 2869, 1442, 1358, 1177, 948.HRMS (ES+) Not found.Note: the product is relatively volatile and must be concentrated carefully with pressure not lower than 250 mbar.3-Oxa-[3.1.1]propellane (6)Method 1 (filtration): MeLi (0.70 M solution in Et2O, 5.60 mL, 3.90 mmol, 1.0 eq.) was added dropwise to a stirred solution of 5 (1.00 g, 3.90 mmol, 1.0 eq.) in Et2O (20 mL) at -78 °C. After 15 minutes of stirring at this temperature, the reaction mixture was allowed to slowly warm up to ambient temperature and stirred under a nitrogen atmosphere for 6 h. MgSO4(1.50 g) was added to the reaction flask, and the mixture was stirred for an additional 10 minutes. The reaction mixture was then filtered through a celite pad, and the MgSO4residue was washed with Et20 (2 x 15 mL). The combined filtrate was partially concentrated under reduced pressure to give the product 6 as a solution in Et20 (9.20 mL, 0.28 M, 2.60 mmol, 66%), which was stored in an amber glass bottle fitted with a Sure / Seal™ PTFE cap under nitrogen at -20 °C.Method 2 (filtration): To a stirred solution of 5 (5.03 g, 15.7 mmol, 1.0 eq.) in dry Et20 (80 mL) at rt was added MeLi (12.1 mL, 1.3 M in Et20, 15.7 mmol, 1.0 eq.). The mixture was stirred at rt for 4 h, then NaHCO3(1.32 g, 15.7 mmol, 1.0 eq) was added. The mixture was cooled to 0 °C, then passed through a celite pad and eluted with Et20 (100 mL). The mixture was partially concentrated under reduced pressure to give the product as a solution in Et20 (72.0 mL, 0.16 M, 11.7 mmol, 74%), which was stored in an amber glass bottle with an AcroSeal under N2 at -20 °C. The concentration was determined by integrating the1H peak at 2.51 ppm relative to the Et20 peaks.Method 3 (distillation): To a stirred solution of 5 (1.02 g, 3.19 mmol, 1.0 eq.) in dry Et20 (16 mL) at rt was added MeLi (2.45 mL, 1.3 M in Et20, 3.19 mmol, 1.0 eq.). The mixture was stirred at rt for 4 h, then NaHCO3(268 mg, 3.19 mmol, 1.0 eq) was added. / 7BU2O (30 mL) was added and the mixture was distilled using a rotary evaporator (30 °C water bath) with a dry ice cold finger condenser and a receiving flask immersed in an acetone / dry ice bath. The Et20 fraction containing bromomethane was removed by slowly decreasing the pressure to 150 mbar and this fraction was discarded. The / 7BU2O fraction containing 3-oxa-[3.1.1]propellane was then distilled by slowly decreasing the pressure to <10 mbar. This gave the product as a solution in / 7BU2O (27.0 mL, 0.065 M, 1.76 mmol, 55%), which was stored in an amber bottle with an AcroSeal under N2 at -20 °C. The concentration was determined by integrating the1H peak at 2.42 ppm relative to a CH2CI2 internal standard.1H NMR (600 MHz, C6D6) 6H3.68 (4H, s, H2), 2.51 (2H, s, H3), 1.62 (2H, s, H3).13C NMR (151 MHz, C6D6) 6c 73.8 (C2), 53.9 (C3), 28.6 (C1).Note: the solution of product contains a white precipitate, presumed to be LiBr, which does not affect subsequent reactions.Caution: During the partial concentration process, bromomethane will be released.(1 -Bromo-2,2-bis(hydroxymethyl)cyclopropyl)methyl ethanethioate (7)To a solution of 2 (8.51 g, 25.8 mmol, 1.0 eq.) in dry THF (65 mL) at -78 °C was added DIBALH (106 mL, 1.0 M solution in hexanes, 106 mmol, 4.1 eq.). The mixture was stirred at -78 °C for 2 h, then 0 °C for 1 h, then rt for 1 h. Rochelle’s salt (100 mL, aq., sat.) was added and the cloudy mixture was stirred at rt for 16 h until it became clear. THF was removed under reduced pressure, then the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give the crude product 3.The crude product 3 was dissolved in MeOH (30 mL) and potassium thioacetate (2.95 g, 25.8 mmol, 1.0 eq.) was added. The mixture was stirred at rt for 3 h, then the solvent was removed under reduced pressure. Water (50 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, pentane / EtOAc 4:6) gave the product (3.75 g, 13.9 mmol, 54%) as a white solid.Rf 0.30 (4:6 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H4.18 (1H, d, J= 11.9 Hz, H7 / 9), 4.12 (1H, d, J= 12.0 Hz, H7 / 9), 3.85 (1H, dd, J= 12.0, 1.6 Hz, H7 / 9), 3.83 (1H, d, J= 14.8 Hz, H3), 3.73 (1H, dd, J= 12.0, 1.7 Hz, H7 / 9), 3.54 (1H, d, J= 14.7 Hz, H3), 2.39 (3H, s, H1), 1.14 (1H, d, J= 7.0 Hz, H5), 1.12 (1H, d, = 6.9 Hz, H5).13C NMR (101 MHz, CDCh) 6C195.2, 71.0, 65.6, 45.0, 39.7, 35.6, 30.6, 24.9.IR (thin film, vmax / cm-1; selected peaks): 3395, 2943, 1692, 1422, 1137, 1029. HRMS (ES+) calc, for C8Hi3BrO3SNa [M+Na]+290.9661, found 290.9664.m.p. 54 °C(1 -Bromo-2,2-bis(bromomethyl)cyclopropyl)methyl ethanethioate (8)To a stirred solution of 7 (3.16 g, 11.7 mmol, 1.0 eq.) and NBS (5.22 g, 29.4 mmol, 2.5 eq.) in dry CH2CI2 (120 mL) at 0 °C was added PPh3(7.70 g, 29.4 mmol, 2.5 eq.) portionwise. The mixture was stirred at rt for 10 min, then H2O2 (30%, 3.6 mL) and water (100 mL) were added. The organic layer was removed and mixture was extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with pentane I Et20 (9:1), filtered through a silica pad and concentrated under reduced pressure to give the product (2.70 g, 6.84 mmol, 58%) as a white solid.Rf 0.27 (19:1 pentane / Et20).1H NMR (400 MHz, CDCI3) 4.01 (1H, dd, J = 10.9, 1.0 Hz, H7 / 8), 3.85 (1H, d, J = 10.9 Hz, H7 / 8), 3.85 (1H, dd, J= 11.3, 0.9 Hz, H7 / 8), 3.82 (1H, d, J= 13.5 Hz, H3), 3.77 (1H, dd, J= 11.1, 1.0 Hz, H7 / 8), 3.50 (1H, d, J= 14.9 Hz, H3), 2.42 (3H, s, H1), l.43 (2H, s, H5).13C NMR (101 MHz, CDCI3) δC 194.8, 48.0, 40.0, 39.0, 35.2, 34.8, 30.8, 30.4. IR (thin film, vmax / cm-1; selected peaks): 2970, 1693, 1428, 1354, 1293, 1135. HRMS (ES+) Not found.m.p. 75 °C1 -Bromo-5-(bromomethyl)-3-thiabicyclo[3.1.0] hexane (9)To a suspension of 8 (2.70 g, 6.84 mmol, 1.0 eq.) in MeOH (35 mL) was added KOH (767 mg, 13.7 mmol, 2.0 eq.) and the mixture was stirred at 50 °C for 1 h. The solvent was removed under reduced pressure, then water (60 mL) was added and the mixture was extracted with Et20 (3 x 60 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product (1.77 g, 6.51 mmol, 95%) as a low melting point pale yellow solid. Rf 0.59 (19:1 pentane I Et20).1H NMR (400 MHz, CDCl3) 3.73 (1H, d, J= 10.8 Hz, H2 / 3), 3.63 (1H, d, J= 10.8 Hz, H2 / 3), 3.45 (1H, d, J= 11.2 Hz, H2 / 3), 3.31 (1H, d, J= 10.9 Hz, H2 / 3), 3.29 (1H, d, J = 11.3 Hz, H6), 2.89 (1H, d, J = 11.3 Hz, H6), 2.07 (1H, d, J = 6.6 Hz, H5), 1.13 (1H, d, = 6.6 Hz, H5).13C NMR (101 MHz, CDCl3) δC 44.3, 41.0, 38.7, 35.9, 34.6, 22.6.IR (thin film, Vmax / cnr1; selected peaks): 2927, 1432, 1343, 1224, 1105, 1018. HRMS (ES+) Not found.m.p. 33 °C3-Thia-[3.1.1]propellane (10)Method 1: To a solution of 9 (450 mg, 1.65 mmol, 1.0 eq.) in dry Et20 (17 mL) at O °C was added MeLi (2.45 mL, 1.35 M in Et20, 3.31 mmol, 2.0 eq.). The mixture was stirred at 0 °C for 5 min then at rt for 1 h. Mg2SC>4 (5.0 g) was added and the mixture was stirred for a further 30 min. The mixture was passed through a celite pad and eluted with Et20 (20 mL) then partially concentrated under reduced pressure to give the product as a solution in Et20 (10.0 mL, 0.12 M, 1.18 mmol, 71%). The concentration was determined by integrating the triplet at 2.79 ppm relative to the Et20 peaks.Method 2: To a stirred solution of 9 (0.961 g, 3.53 mmol, 1.0 eq.) in dry Et20 (18 mL) at rtwas added MeLi (2.72 mL, 1.3 M in Et20, 3.53 mmol, 1.0 eq.). The mixture was stirred at rt for 4 h, then NaHCO3(297 mg, 3.53 mmol, 1.0 eq) was added. The mixture was cooled to 0 °C, then passed through a celite pad and eluted with Et20 (50 mL). The mixture was partially concentrated under reduced pressure to give theproduct as a solution in Et2O (18.5 mL, 0.13 M, 2.41 mmol, 68%), which was stored in an amber glass bottle with an AcroSeal under N2 at -20 °C. The concentration was determined by integrating the1H peak at 2.79 ppm relative to the Et2O peaks.1H NMR (400 MHz, C6D6) bH1H NMR (400 MHz, C6D6) 5 2.78 (2H, t, J = 1.4 Hz, H3), 2.70 (4H, s, H2), 1.58 (2H, t, J= 1.4 Hz, H3).13C NMR (101 MHz, C6D6) be 52.4 (C2), 37.7 (C1), 37.7 (C3).Note: the solution of product contains a white precipitate of LiBr, which does not affect subsequent reactions.Caution: During the partial concentration process, bromomethane will be released.Dimethyl 2-(azidomethyl)-2-bromocyclopropane-1,1 -dicarboxylate (11)o oMeO^z^^QMe7Br N3Method 1: To a mixture of 2 (4.54 g, 13.8 mmol, 1.0 eq.) in dry DMF (25 mL) was added NaNs (984 mg, 15.1 mmol, 1.1 eq.) and the mixture was stirred at 40 °C for 4 h. Et20 (200 mL) was added and the mixture was washed with water (3 x 200 mL). Each water wash was back-extracted with Et20 (2 x 200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product (3.63 g, 12.4 mmol, 90%) as a yellow oil.Method 2: To a mixture of 2 (14.3 g, 43.3 mmol, 1.0 eq.) in dry DMF (70 mL) was added NaNs (2.82 g, 43.3 mmol, 1.0 eq.) and the mixture was stirred at 40 °C for 4 h. Et20 (500 mL) was added and the mixture was washed with water (3 x 500 mL). Each water wash was back-extracted with Et20 (2 x 500 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product (12.2 g, 41.8 mmol, 96%) as a yellow oil.Rf 0.40 (6:4 pentane I Et20).1H NMR (400 MHz, CDCI3)H4.03 (1H, d, J = 13.8 Hz, H8), 3.89 (1H, d, J = 13.8 Hz, H8), 3.83 (3H, s, H1 / 5), 3.79 (3H, s, H1 / 5), 2.16 (1H, d, J = 7.2 Hz, H6), 1.93 (1H, d, J= 7.2 Hz, H6).13C NMR (101 MHz, CDCl3) δC 167.3, 166.1, 56.4, 53.7, 53.4, 39.7, 39.6, 27.8. IR (thin film, Vmax / cnr1; selected peaks): 2956, 2109, 1731, 1436, 1250.HRMS (ES+) calc, for C8H10BrN3O4Na [M+Na]+313.9747, found 313.9747.Methyl 5-bromo-2-oxo-3-azabicyclo[3.1.0]hexane-1 -carboxylate (12)Method 1: To a stirred solution of PBu3(5.99 mL, 24.0 mmol, 1.0 eq.) and water (0.432 mL, 24.0 mmol, 1.0 eq.) in THF (60 mL) at 0 °C was added a solution of 11 (7.01 g, 24.0 mmol, 1.0 eq.) in THF (20 mL) dropwise over 1 h, keeping the internal temperature below 5 °C. The mixture was stirred at 0 °C for a further 1 h, then slowly warmed to rt over 30 min and stirred at rt for 1 h. The mixture was then concentrated under reduced pressure. Trituration from THF / pentane (1:5) gave the product (3.42 g, 14.6 mmol, 61%) as a white solid.Method 2: To a stirred solution of PBu3(11.2 mL, 44.8 mmol, 1.0 eq.) and water (0.808 mL, 44.8 mmol, 1.0 eq.) in THF (110 mL) at 0 °C was added a solution of 11 (13.1 g, 44.8 mmol, 1.0 eq.) in THF (20 mL) dropwise over 45 min, keeping the internal temperature below 5 °C. The mixture was stirred at 0 °C for a further 30 min, then slowly warmed to rt over 30 min and stirred at rt for 1 h. The mixture was then concentrated under reduced pressure. Trituration from THF / pentane (1:5) gave the product (6.01 g, 25.7 mmol, 57%) as a white solid.Rf 0.17 (3:7 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.07 (1H, s, H3), 3.85 (3H, s, H8), 3.82 (2H, d, J= 0.9 Hz, H2), 2.38 (1 H, d, J = 6.2 Hz, H6), 1.66 (1 H, d, J = 6.2 Hz, H6).13C NMR (101 MHz, CDCl3) δC 171.8, 165.4, 53.2, 51.8, 37.8, 34.4, 27.0.IR (thin film, vmax / crn'1; selected peaks): 3210, 1730, 1708, 1439, 1248.HRMS (ES+) calc, for C7H9BrNO3[M+H]+233.9760, found 233.9768.m.p. 109 °C (dec.)(5-bromo-3-tosyl-3-azabicyclo[3.1.0]hexan-1 -yl)methanol (13)To a stirred solution of 12 (3.10 g, 13.2 mmol, 1.0 eq.) in dry THF (125 mL) at 0 °C was added Red-AI (10.8 mL, 60%, 33.1 mmol, 2.5 eq.) and the mixture was stirred at rt for 5 h. Rochelle's salt (70 mL) was added slowly at 0 °C (note: vigorous quenching) and the mixture was stirred for 10 min at rt until it became clear. The mixture was diluted with water (50 mL), then Na2CO3(2.10 g, 19.8 mmol, 1.5 eq.) was added. The mixture was cooled to 0 °C and TsCI (2.52 g, 13.2 mmol, 1.0 eq.) was added. The mixture was stirred at 0 °C for another 5 min, then at rt for 1 h. The THF was removed under reduced pressure and the mixture was extracted with EtOAc (3 x 120 mL). The combined organic extractes were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (6:4 pentane I EtOAc) gave the product (1.82 g, 5.26 mmol, 40%) as a white solid.Rf 0.24 (6:4 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.68 (2H, d, J = 8.3 Hz, Ts), 7.35 (2H, d, J = 8.0 Hz, Ts), 3.95 (1 H, d, J= 9.2 Hz, H2 / 3), 3.90 (1 H, dd, J= 12.4, 7.6 Hz, H6), 3.66 (1H, dd, J= 12.4, 4.6 Hz, H6), 3.56 (1H, d, J= 9.4 Hz, H2 / 3), 3.32 (1H, d, J= 9.4 Hz, H2 / 3), 3.26 (1H, dd, J= 9.2, 1.2 Hz, H2 / 3), 2.45 (3H, s, Ts), 1.52 (1H, dd, J= 7.8, 4.9 Hz, H7), 1.38 (1H, d, J = 6.9 Hz, H5), 1.12 (1H, d, = 6.5 Hz, H5).13C NMR (101 MHz, CDCl3) δC 144.2, 133.2, 130.0, 127.7, 64.0, 56.6, 49.9, 35.2, 33.7, 21.7, 21.5.IR (thin film, Vmax / crn’1; selected peaks): 3535, 2924, 1346, 1167, 1030.HRMS (ES+) calc, for Ci3Hi7BrNO3S [M+H]+346.0107, found 346.0111.m.p. 130 °C1-Bromo-5-(bromomethyl)-3-tosyl-3-azabicyclo[3.1.0]hexane (14)To a stirred solution of 13 (5.80 g, 16.8 mmol, 1.0 eq.) and NBS (3.58 g, 20.1 mmol, l.2 eq.) in dry CH2CI2 (80 mL) at 0 °C was added a solution of PPhs (5.27 g, 20.1 mmol, 1.2 eq.) in CH2CI2 (10 mL) dropwise. The mixture was stirred at rt for 1 h, then concentrated under reduced pressure. Purification by column chromatography (8:2 pentane I Et20) gave the product (6.32 g, 15.4 mmol, 92%) as a white solid.Rf 0.21 (8:2 pentane I Et20).1H NMR (400 MHz, CDCI3) 6H7.68 (2H, d, J = 8.3 Hz, Ts), 7.36 (2H, d, J = 7.9 Hz, Ts), 3.95 (1H, d, J = 9.4 Hz, H2 / 3), 3.65 (1H, d, J= 9.5 Hz, H2 / 3), 3.52 (1H, d, J = 11.1 Hz, H6), 3.47 (1H, d, J = 11.1 Hz, H6), 3.24 (1H, d, J = 15.9 Hz, H2 / 3), 3.22 (1H, d, J = 16.2 Hz, H2 / 3), 2.45 (3H, s, Ts), 1.54 (1H, d, J= 6.7 Hz, H5), 1.19 (1H, d, J= 6.8 Hz, H5).13C NMR (101 MHz, CDCl3) δC 144.3, 133.2, 130.1, 127.6, 56.5, 51.7, 38.1, 34.8, 32.8, 24.5, 21.7.IR (thin film, Vmax / cm-1; selected peaks): 2923, 1351, 1166, 1100, 1013.HRMS (ES+) calc, for Ci3Hi6Br2NO2S [M+H]+407.9263, found 407.9251.m.p. 124 °C3-( / V-Tosyl)aza-[3.1.1]propellane (15)Method 1: To a stirred solution of 14 (3.00 g, 7.33 mmol, 1.0 eq.), in dry THF (60 mL) at -78 °C was added MeLi (5.64 mL, 1.3 M in Et20, 7.33 mmol, 1.0 eq.). The mixture was stirred at -78 °C for 10 min, then at rt for 1 h. MgSO4(5.0 g) was added to the reaction mixture and this was stirred for 10 min. Then the mixture was passed through a celite filter and eluted with THF (60 mL). The mixture was partially concentrated under reduced pressure (120 mbar) to remove MeBr and Et20, giving the product (48.1 mL, 0.15 M, 7.21 mmol, 98%) as a 0.15 M solution in THF, which was stored under nitrogen at -20 °C. The concentration was determined by integrating the singlet at 3.17 ppm relative to the THF peaks.Method 2: To a stirred solution of 14 (2.00 g, 4.89 mmol, 1.0 eq.) in dry THF (40 mL) at -78 °C was added MeLi (3.76 mL, 1.3 M in Et20, 4.89 mmol, 1.0 eq.). The mixture was stirred at -78 °C for 10 min then at rt for 1 h. NaHCO3(411 mg, 4.89mmol, 1.0 eq) was added, then the mixture was cooled to 0 °C, passed through a celite pad and eluted with THF (100 mL). The mixture was partially concentrated under reduced pressure to give the product as a solution in THF (26.0 mL, 0.18 M, 4.79 mmol, 98%), which was stored in an amber glass bottle with an AcroSeal under N2 at -20 °C. The concentration was determined by integrating the1H peak at 3.17 ppm relative to the THF peaks.1H NMR (500 MHz, C6D6) bH7.62 (2H, d, J = 8.2 Hz, Ts), 6.99 (2H, d, J = 8.0 Hz, Ts), 3.17 (4H, s, H2), 2.04 (3H, s, Ts), 2.03 (2H, t, J = 1.7 Hz, H3), 1.31 (2H, t, J = 1.7 Hz, H3).13C NMR (126 MHz, C6D6) bc143.3 (Ts), 135.0 (Ts), 129.8 (Ts), 127.9 (Ts), 53.6 (C2), 52.1 (C3), 22.4 (C1), 21.1 (Ts Me).HRMS (ES+) calc, for C13H16NO2S [M+H]+250.0896, found 250.0900.General procedure 1: Reaction with chalcogen (RXH) Hetero[3.1.1]propellane (1.0 eq.) was added dropwise to a solution of thiol / benzeneselenol (1.1 eq.) in anhydrous diethyl ether. The reaction mixture was stirred for 1 h at ambient temperature, then diluted with diethyl ether and washed with 1 M aqueous NaOH solution (x3), followed by brine. The organic layerwas dried over MgSO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography on silica gel.General procedure 2: BEt3-initiated atom transfer radical additionAn alkyl iodide (1 eq.) was added to a stirred diethyl ether solution of hetero[3.1.1]propellane (1.2-1.5 eq.) at 0 °C. Et3B (10 mol%, 1 M in hexane) was then added. The mixture was stirred until complete consumption of the alkyl iodide, as monitored by TLC. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel. General procedure 3: Photoredox-catalysed atom transfer radical addition To a 4 mL screw-capped vial equipped with a stirrer bar were added fac-lr(ppy)3(2.5 mol%), an alkyl or aryl halide (1.0 eq.), and t-BuCN (0.13 M). Hetero[3.1.1]propellane (1.5-2.0 eq.) was added and the mixture was degassed with N2for 5 minutes. The vial was placed in the photobox, and the stirred reaction mixture was irradiated with blue LEDs (HCK1012-01-002 450-455 nm or Kessil PR160, 456 nm) with fan cooling for the specified time. After the consumption of theiodides as monitored by TLC, the reaction mixture was concentrated, and the product was purified by column chromatography on silica gel.Ethyl 2-(5-iodo-3-oxabicyclo[3.1.1]heptan-1-yl)acetate (16a)Method 1: Synthesised in accordance with General Procedure 3 using iodomethyl propionate (43.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 1.5 eq, 0.25 M in Et2O) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 2 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column gel (SiO2, pentane / Et2O 8:2) to afford the title compound 16a (51.0 mg, 0.160 mmol, 82%) as a colourless oil.Method 2: Synthesised in accordance with General Procedure 2 using iodomethyl propionate (43.0 mg, 0.200 mmol, 1 eq.), oxa[3.1.1]propellane (1.2 mL, 0.300 mmol, 1.5 eq, 0.25 M in diethyl ether) and BEt3(20.0 µL, 1.0 M in hexane, 10 mol%). The reaction was stirred at ambient temperature for 45 min. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography (SiCh, pentane / Et2O 8:2) to afford the title compound 16a (43.0 mg, 0.140 mmol, 69%) as a colourless oil.Rf = 0.5 (8:2 pentane / Et2O).1H NMR (500 MHz, CDCh) 6H4.13-4.09 (4H, singlet from H1 / H2 and quartet from H8 overlapped), 3.80 (2H, s, H1 / H2), 2.60-2.58 (2H, m, H4b), 2.51-2.49 (2H, m, H4a), 2.36 (2H, s, H6), 1.25 (3H, t, J= 7.1 Hz, H9).13C NMR (126 MHz, CDCh) 6c 170.2, 77.8, 72.1, 60.8, 48.7, 44.6, 41.4, 27.6, 14.4.IR (thin film, vmax / cm-1): 2944, 2859, 1733, 1273, 1246, 1196, 1086.HRMS (ESI+) [M+H]+calculated for [C10H16IO3]+311.0139, found 311.0135.Ethyl 2-(5-iodo-3-tosyl-3-azabicyclo[3.1.1]heptan-1-yl)acetate (16b)Synthesised in accordance with General Procedure 2, using 3-( / V-tosyl)aza- [3.1.1]propellane (1.25 mL, 0.15 M in THF, 0.288 mmol, 2.0 eq.), ethyl 2-iodoacetate (17.4 pL, 0.147 mmol, 1.0 eq.) and BEt3(14.7 µL, 1.0 M solution in hexanes, 14.7 µmol, 0.1 eq). The mixture was stirred for 1 h. Purification by column chromatography (SiO2, pentane / EtOAc 8:2) gave the product 16b (58.7 mg, 0.127 mmol, 86%) as a colourless oil.Rf 0.29 (8:2 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.69 (2H, d, J = 8.3 Hz, Ts), 7.33 (2H, d, J = 7.7 Hz, Ts), 4.09 (2H, q, J = 7.1 Hz, H8), 3.84 (2H, s, H1 / 2), 3.36 (2H, s, H1 / 2), 2.51-2.46 (2H, m, H4b), 2.43 (3H, s, Ts), 2.40 (2H, s, H6), 2.18-2.10 (2H, m, H4a), 1.22 (3H, t, J= 7.2 Hz, H9).13C NMR (101 MHz, CDCh) 6c 169.9, 143.9, 134.3, 130.0, 127.4, 60.9, 59.2, 52.2, 48.7, 42.0, 41.5, 22.5, 21.7, 14.3.IR (thin film, Vmax / cnr1; selected peaks): 2943, 1731, 1345, 1160, 1094.HRMS (ES+) calc, for C17H23INO4S [M+H]+464.0387, found 464.0395.2-(5-lodo-3-oxabicyclo[3.1.1]heptan-1-yl)acetamide (16c)Synthesised in accordance with General Procedure 3 using 2-iodoacetamide (37.0 mg, 0.200 mmol, 1 eq.), oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 1.2 eq, 0.25 M in Et20) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 3 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography (SiCh, pentane / EtOAc 8:2) to afford 16c (35.0 mg, 0.120 mmol, 62%) as a white solid. Rf = 0.2 (8:2 pentane / EtOAc).1H NMR (500 MHz, CDCh) 6H5.49 (1 H, s, H8), 5.34 (1H, s, H8), 4.14 (2H, s, H1 / H2), 3.85 (2H, s, H1 / H2), 2.62-2.61 (2H, m, H4b), 2.55-2.52 (2H, m, H4a), 2.28 (2H, s, H6).13C NMR (126 MHz, CDCh, 298 K) 6C171.4, 77.8, 72.2, 48.7, 44.9, 42.6, 27.7. IR (thin film, vmax / cm-1): 3381, 2945, 2861, 1732, 1666, 1419, 1242, 1198, 1024.HRMS (ESI+) [M+Na]+calculated for [C8H12INO2Na]+303.9805, found 303.9805. m.p. 113-115 °C2-(5-lodo-3-tosyl-3-azabicyclo[3.1.1]heptan-1-yl)acetonitrile (16d)Synthesised in accordance with General Procedure 2, using 3-( / V-tosyl)aza-[3.1.1]propellane (2.13 mL, 0.15 M in THF, 0.320 mmol, 2.0 eq.), 2-iodoacetonitrile (11.6 pL, 0.160 mmol, 1.0 eq.) and BEt3(16.0 µL, 16.0 µmol, 10 mol%). The mixture was stirred for 1 h. Purification by column chromatography (SiO2, pentane / EtOAc 7:3) gave the product 16d (23.3 mg, 56.0 pmol, 35%) as a white solid.Rf 0.27 (7:3 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.71 (2H, d, J = 8.3 Hz, Ts), 7.36 (2H, d, J = 8.1 Hz, Ts), 3.86 (2H, s, H1 / 2), 3.36 (2H, s, H1 / 2), 2.59-2.50 (2H, m, H4b), 2.46 (2H, s, H6), 2.45 (3H, s, Ts), 2.18-2.09 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6c 144.3, 133.9, 130.2, 127.4, 115.8, 58.9,51.8, 47.5, 40.8, 25.5, 21.7, 19.6.IR (thin film, Vmax / cnr1; selected peaks): 2920, 1343, 1159, 1011.HRMS (ES+) calc, for C15H18IN2O2S [M+H]+417.0128, found 417.0126.m.p. 126 °C(5-lodo-3-oxabicyclo[3.1.1]heptan-1-yl)methyl pivalate (16e)Method 1: Synthesised in accordance with General Procedure 3 using iodomethyl pivalate (48.0 mg, 0.200 mmol, 1 eq.), oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 1.2 eq, 0.25 M in Et2O) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 5 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography (SiO2, pentane / Et2O 8:2) to give the product 16e (51.0 mg, 0.150 mmol, 75%) as a colourless oil.Method 2: Synthesised in accordance with General Procedure 2 using iodomethyl pivalate (48.0 mg, 0.200 mmol, 1 eq.), oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 1.5 eq, 0.25 M in diethyl ether) and BEts (20 pL, 1.0 M in hexane, 10 mol%). The reaction was stirred at ambient temperature for 8 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography (SiO2, pentane / Et2O 8:2) to give the product 16e (39.0 mg, 0.120 mmol, 58%) as a colourless oil.Rf = 0.3 (8:2 pentane I Et20)1H NMR (500 MHz, CDCh) bH4.16 (2H, s, H1 / 2 / 6), 3.92 (2H, s, H1 / 2 / 6), 3.81 (2H, s, H1 / 2 / 6), 2.59-2.55 (2H, m, H4b), 2.41-2.37 (2H, m, H4a), 1.20 (9H, s, H9).13C NMR (126 MHz, CDCh, 298 K) be 178.2, 78.2, 70.4, 66.1, 47.0, 46.2, 39.1, 27.4, 27.3.IR (thin film, vmax / cm’1): 2986, 2863, 1732, 1600, 1503, 1479, 1363, 1282, 1155, 1085.HRMS (ESI+) [M+H]+calculated for [C12H20IO3]+339.0452, found 339.0459.(5-lodo-3-tosyl-3-azabicyclo[3.1.1]heptan-1-yl)methyl pivalate (16f)Synthesised in accordance with General Procedure 3, using 3-( / V-tosyl)aza-[3.1.1]propellane (1.54 mL, 0.15 M in THF, 0.354 mmol, 2.0 eq.), iodomethyl pivalate (28.2 pL, 0.182 mmol, 1.0 eq) and fac-Ir(ppy)3(3.0 mg, 4.5 µmol, 2.5 mol%). The mixture was stirred and irradiated with blue LED (450-455 nm) for 4 h. Purification by column chromatography (SiCh, pentane / EtOAc 9:1) gave the product 16f (18.3 mg, 37.2 pmol, 21%) as a white solid.Rf 0.16 (9:1 pentane I EtOAc).1H NMR (500 MHz, CDCh) 6H7.71 (2H, d, J = 8.3 Hz, Ts), 7.34 (2H, d, J = 8.1 Hz, Ts), 3.93 (2H, s, H1 / 2), 3.89 (2H, s, H1 / 2), 3.33 (2H, s, H6), 2.50-2.45 (2H, m, H4b), 2.45 (3H, s, Ts), 2.03-1.97 (2H, m, H4a), 1.18 (9H, s, H9).13C NMR (101 MHz, CDCh) 6c 178.0, 144.0, 134.3, 130.0, 127.4, 66.3, 59.6, 50.3, 46.2, 44.0, 39.1, 27.3, 22.1, 21.7.IR (thin film, Vmax / cnr1; selected peaks): 2974, 1733, 1344, 1283, 1163.HRMS (ES+) calc, for C19H27INO4S [M+H]+492.0700, found 492.0686.m.p. 137 °C2-(5-lodo-3-oxabicyclo[3.1.1]heptan-1-yl)pyridine (16g)Synthesised in accordance with General Procedure 3 using 2-iodopyridine (41.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.30 mL, 0.240 mmol, 1.5 eq, 0.23 M in Et20) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 3 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiCh, pentane / Et2O 8:2) to give the product 16g (39.0 mg, 0.130 mmol, 65%) as a yellow oil.Rf = 0.3 (6:4 pentane I Et20).1H NMR (500 MHz, CDCh) 6H8.54 (1H, dd, J= 4.9, 1.9 Hz, ArH), 7.66 (1H, td, J = 7.7, 1.8 Hz, ArH), 7.17 (1H, ddd, J= 7.5, 4.9, 1.2 Hz, ArH), 7.07 (1H, dt, J= 7.9, 1.1 Hz, ArH), 4.26 (2H, s, H1 / H2), 4.06 (2H, s, H1 / H2), 3.01-2.97 (2H, m, H4b), 2.84-2.80 (2H, m, H4a).13C NMR (126 MHz, CDCh) 6c 161.0, 149.5, 136.9, 122.1, 120.0, 77.9, 72.8, 52.4, 48.3, 27.3.IR (thin film, vmax / cm-1): 2946, 2858, 1589, 1471, 1423, 1216, 1040.HRMS (ESI+) [M+H]+calculated for [C11H13INO]+302.0036, found 302.0039.tert-Butyl 3-(5-iodo-3-oxabicyclo[3.1.1]heptan-1-yl)azetidine-1 -carboxylate (16h)Synthesised in accordance with General Procedure 2 using tert-butyl 3-iodoazetidine-1 -carboxylate (57.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 1.5 eq, 0.25 M in Et20) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 4 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiCh, pentane / Et2O 8:2) to give the product 16h (49.0 mg, 0.130 mmol, 65%) as a light yellow oil.Rf = 0.3 (8:2 pentane I Et20).1H NMR (600 MHz, CDCh) 6H4.16 (2H, s, H1 / H2), 3.87 (2H, t, = 8.2 Hz, H7), 3.68-3.65 (4H, m, H1 / H2+H7), 2.58-2.55 (2H, m, H4b), 2.38-2.35 (1H, m, H6), 2.35-2.31 (2H, m, H4a), 1.43 (9H, s, Boc).13C NMR (151 MHz, CDCh) 6C156.3, 79.9, 78.3, 71.1, 50.0, 48.3, 44.4, 31.4, 28.5, 27.4.IR (thin film, vmax / crn-1): 2974, 2882, 1698, 1478, 1404, 1301, 1252, 1084.HRMS (ESI+) [M+Na]+calculated for [C14H22INO3Na]+402.0537, found 402.0538.tert-Butyl 4-(5-iodo-3-oxabicyclo[3.1.1]heptan-1-yl)piperidine-1 -carboxylate (16i)Synthesised in accordance with General Procedure 2 using terf-butyl 4-iodopiperidine-1 -carboxylate (62.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.40 mL, 0.300 mmol, 1.5 eq, 0.22 M in Et2O) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 4 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiCh, pentane / Et2O 8:2) to give the product 16i (52.0 mg, 0.130 mmol, 64%) as a crystalline solid.Rf = 0.5 (8:2 pentane / Et20).1H NMR (500 MHz, CDCh) 6H4.15 (2H, m, H8), 4.12 (2H, s, H1 / H2), 3.75 (2H, s, H1 / H2), 2.59-2.54 (2H, m, H8), 2.48-2.44 (2H, m, H4b), 2.38-2.35 (2H, m, H4a), 1.48-1.36 (3H, m, H6 / 7), 1.44 (9H, s, Boc), 1.11 (1H, dd, J= 12.6, 4.4 Hz, H7), 1.06 (1H, dd, J= 12.5, 4.4 Hz, H7).13C NMR (126 MHz, CDCh) 6c 154.8, 79.7, 78.3, 70.9, 50.3, 46.9, 42.7, 28.8, 28.6, 26.9.IR (thin film, vmax / cm-1): 2936, 2857, 1688, 1426, 1367, 1242, 1038.HRMS (ESI+) [M+Na]+calculated for [C16H26INO3Na]+430.0850, found 430.0862. m.p. 72-75 °C1-(3-Chlorobenzyl)-5-iodo-3-tosyl-3-azabicyclo[3.1.1]heptane (16j)Synthesised in accordance with General Procedure 2, using 3-( / V-tosyl)aza-[3.1.1]propellane (1.60 mL, 0.15 M in THF, 0.240 mmol, 1.2 eq.), 1-chloro-3-(iodomethyl)benzene (50.5 mg, 0.200 mmol, 1.0 eq.) and fac-lr(ppy)3(3.3 mg, 5.0 pmol, 2.5 mol%). The mixture was stirred and irradiated with 450-455 nm blue lightin a photobox with fan cooling for 4 h. Purification by column chromatography (SiO2, pentane / Et2O 8:2) gave the product 16j (25.2 mg, 50.2 pmol, 25%) as a yellow solid. Rf 0.17 (8:2 pentane / Et20).1H NMR (400 MHz, CDCh) 6H7.60 (2H, d, J = 8.3 Hz, Ts), 7.29 (2H, d, J = 8.0 Hz, Ts), 7.25-7.21 (2H, m, Ar H), 6.97 (1H, s, Ar H), 6.93-6.84 (1H, m, Ar H), 3.85 (2H, s, H1 / 2 / 6), 3.21 (2H, s, H1 / 2 / 6), 2.66 (2H, s, H1 / 2 / 6), 2.43 (3H, s, Ts), 2.42-2.37 (2H, m, H4b), 2.00-1.91 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6c 143.8, 138.4, 134.6, 134.3, 130.0, 130.0, 129.3, 127.7, 127.3, 127.2, 59.5, 52.2, 48.3, 44.7, 43.3, 23.2, 21.7.IR (thin film, Vmax / cnr1; selected peaks): 2943, 1597, 1342, 1160, 1094.HRMS (ES+) calc, for C20H22CIINO2S [M+H]+502.0099, found 502.0087.m.p. 156 °C2-(5-Bromo-3-oxabicyclo[3.1.1]heptan-1 -y I )-1 -(p-tolyl)ethan-l -one (16k)Synthesised in accordance with General Procedure 3 using 2-bromo-1-(p-tolyl)ethan-1-one (43.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.30 mL, 0.300 mmol, 1.5 eq, 0.23 M in diethyl ether) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 5 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography (SiCh, pentane / Et2O 9:1) to give the product 16k (32.0 mg, 0.100 mmol, 52%) as a crystalline solid.Rf = 0.5 (9:1 pentane I Et20).1H NMR (500 MHz, CDCh) 6H7.78 (2H, d, J = 8.3 Hz, ArH), 7.26 (2H, d, J = 7.9 Hz, ArH), 4.05 (2H, s, H1 / H2), 3.82 (2H, s, H1 / H2), 3.06 (2H, s, H6), 2.54-2.50 (2H, m, H4a), 2.45-2.42 (2H, m, H4b), 2.41 (3H, s, H8).13C NMR (126 MHz, CDCh) 6c 196.9, 144.5, 134.6, 129.6, 128.3, 75.5, 72.2, 52.2, 47.5, 44.6, 41.4, 21.8.IR (thin film, vmax / cm-1): 2949, 2859, 1681, 1606, 1572, 1406, 1180, 1036.HRMS (ESI+) [M+ H]+calculated for [C15H18BrO2]+309.0485, found 309.0482. m.p. 93-95 °CDimethyl 2-(5-bromo-3-oxabicyclo[3.1.1]heptan-1-yl)malonate (161)Synthesised in accordance with General Procedure 2 using dimethyl bromomalonate (42.0 mg, 0.200 mmol, 1.0 eq.), oxa[3.1.1]propellane (1.30 mL, 0.300 mmol, 1.5 eq, 0.24 M in diethyl ether) and fac-lr(ppy)3(3.0 mg, 2.5 mol%). The mixture was irradiated with 456 nm light at ambient temperature for 4 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified via column chromatography chromatography (SiO2, pentane / Et2O 8:2) to give the product 161 (33.0 mg, 0.110 mmol, 54%) as a colourless oil.Rf = 0.5 (8:2 pentane I Et2O)1H NMR (500 MHz, CDCh) 6H4.01 (2H, s, H1 / H2), 3.85 (2H, s, H1 / H2), 3.73 (6H, s, H8), 3.45 (1H, s, H6), 2.53-2.47 (4H, m, H4).13C NMR (126 MHz, CDCh, 298 K) 5C167.2, 75.4, 70.2, 56.9, 52.7, 50.9, 46.2, 42.4.IR (thin film, vmax / crn-1): 2955, 2867, 1740, 1437, 1332, 1239, 1087.HRMS (ESI+) [M+H]+calculated for [C11H16BrO5]+307.0176, found 307.0178.1-Bromo-3-tosyl-5-(trichloromethyl)-3-azabicyclo[3.1.1]heptane (16m)To a stirred solution of 3-( / V-tosyl)aza-[3.1.1]propellane (1.33 mL, 0.15 M in THF, 0.200 mmol, 1.0 eq.) at -78 °C was added CChBr (59.2 pL, 0.600 mmol, 3.0 eq.).The mixture was stirred at -78 °C for 15 min, then at rt for 1 h. The mixture was then concentrated under reduced pressure. Purification by column chromatography (SiCh, pentane / Et2O 9:1) gave the product 16m (37.7 mg, 84.2 pmol, 42%) as a white solid.Rf 0.31 (9:1 pentane / Et2O).1H NMR (400 MHz, CDCh) 6H7.74 (2H, d, J = 8.1 Hz, Ts), 7.37 (2H, d, J = 8.0 Hz, Ts), 3.77 (2H, s, H1 / 2), 3.75 (2H, s, H1 / 2), 2.92-2.82 (2H, m, H4b), 2.46 (3H, s, Ts), 2.14-2.04 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6c 144.3, 134.1, 130.2, 127.5, 101.6, 56.4, 55.5, 49.8, 44.6, 44.3, 21.7.IR (thin film, vmax / cm-1; selected peaks): 2872, 1344, 1162, 1035, 1014.HRMS (ES+) calc. for C14H16BrCl3NO2S [M+H]+445.9145, found 445.9130. m.p. 136 °C1-Bromo-5-(trichloromethyl)-3-thiabicyclo[3.1.1]heptane (16n)To a solution of 3-thia[3.1.1]propellane (1.00 mL, 0.12 M, 0.12 mmol, 1.0 eq.) in Et20 at -78 °C was added CChBr (59.2 pL, 0.60 mmol, 5.0 eq.), then BEts (12.0 pL, 1.0 M solution in hexanes, 12.0 pmol, 10 mol%). The mixture was stirred at -78 °C for 15 min then rt for 1 h. The mixture was concentrated under reduced pressure, then purification by column chromatography (SiCh, pentane 100%) gave the product 16n (11.9 mg, 38.3 pmol, 32%) as a white solid.Rf 0.29 (100% pentane).1H NMR (400 MHz, CDCh) 6H3.43 (2H, s, H1 / 2), 3.27 (2H, s, H1 / 2), 3.12-3.03 (2H, m, H4b), 2.69-2.60 (2H, m, H4a).13C NMR (126 MHz, CDCh) 6C104.2, 57.1, 49.3, 45.1, 40.3, 31.7.IR (thin film, vmax / cm-1; selected peaks): 2934, 1272, 1137, 775.HRMS (ES+) Not foundm.p. 77 °CN-allyl-N-(5-iodo-3-oxabicyclo[3.1.1]heptan-1-yl)-4-methylbenzene sulfonamide (16o)Prepared according to the procedure of Pickford et al3and in accordance with General Procedure 3, using 2-(iodomethyl)-1 -tosylaziridine (67.0 mg, 0.200 mmol, 1.0 eq.), fac-lr(ppy)3(3.0 mg, 2.5 mol%), t-BuCN (1.5 mL) and oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 0.25 M in Et2O, 1.5 eq.). The mixture was irradiated with 456 nm light for 4 h. The crude reaction mixture was purified via column chromatography (SiO2, pentane / Et2O 8:2) to give the product 16o (46.0 mg 0.110 mmol, 53%) as a colourless oil.Rf = 0.3 (8:2 pentane I Et20).1H NMR (500 MHz, CDCh) 6H7.69 (2H, d, J = 8.3 Hz, ArH), 7.31 (2H, d, J = 7.8 Hz, ArH), 5.75 (1H, ddt, J= 17.2, 10.1, 6.3 Hz, H7), 5.16 (1H, dd, J= 11.0, 1.3 Hz, H8), 5.13 (1H, dd, J= 10.5, 1.2 Hz, H8), 3.98 (2H, s, H1 / H2), 3.93 (2H, s, H1 / H2), 3.77 (2H, dt, J= 6.3, 1.4 Hz, H6), 2.83-2.80 (2H, m, H4b), 2.82-2.75 (2H, m, H4a), 2.44 (3H, s, H9).13C NMR (126 MHz, CDCh) 6c 143.8, 138.7, 135.3, 130.0, 127.3, 118.6, 76.8, 71.7, 62.7, 49.8, 49.3, 22.1, 21.7.IR (thin film, vmax / cm-1): 2954, 2862, 1437, 1335, 1238, 1087.HRMS (ESI+) [M+H]+calculated for [C16H21INO3S]+434.0281, found 434.0281.1-Bromo-5-(ethylsulfonyl)-3-oxabicyclo[3.1.1]heptane (16p)The reaction was carried out according to the procedure of Pickford et a / .4To an oven-dried vial, ethanesulfonyl bromide (35.0 mg, 0.200 mmol, 1.0 eq.) was added.The vial was sealed with a PTFE cap, and Et2O (1.50 mL) was added. The reaction mixture was degassed for 10 min, after which oxa[3.1.1]propellane (1.20 mL, 0.300 mmol, 0.24 M in Et20, 1.5 eq.) was added, and degassing was continued with argon for an additional 5 min. The reaction mixture was stirred at ambient temperature overnight. The solvent was then removed under reduced pressure, and the crude reaction mixture was treated with Et2O (5.0 mL) and cooled in an ice bath for 30 min. The resulting cloudy solution was filtered, and the solvent was removed under reduced pressure, to give the product 16p (35.0 mg 0.120 mmol, 62%) as a thick, colourless oil.Note: The product is not stable on silica gel.1H NMR (500 MHz, CDCh) 6H4.09 (2H, s, H1 / H2), 4.06 (2H, s, H1 / H2), 3.01-3.07 (2H, m, H4b), 2.86 (2H, q, J = 7.5 Hz, H6), 2.53-2.49 (2H, m, H4a), 1.39 (3H, t, J = 7.5 Hz, H7).13C NMR (151MHz, CDCh) 6c 75.0, 67.0, 60.6, 48.4, 44.0, 42.8, 5.7.IR (thin film, vmax / cm-1): 2953, 2866, 1599, 1436, 1312, 1237, 1040.HRMS not found.1-lodo-5-(phenylsulfonyl)-3-oxabicyclo[3.1.1]heptane (16q)The reaction was carried out according to the procedure of Pickford et al4A solution of sodium benzenesulfinate salt (0.50 mL, 0.500 mmol, 1.0 M in H2O, 2.5 eq.) was added dropwise to a suspension of 1,3-diiodo-5,5-dimethylhydantoin (76.0 mg, 0.200 mmol, 1.0 eq.) in CH2CI2(1.0 mL) at -5 °C (ice / NaCI). The mixture was stirred vigorously for 15 minutes, then a solution of oxa[3.1.1]propellane (0.8 mL, 0.20 mmol, 0.25 M in Et2O, 1.0 eq.) was added. The slurry was stirred at -5 °C for 10 minutes and then sonicated for a few seconds at ambient temperature to ensure complete mixing. The reaction was quenched at ambient temperature by addition of saturated aqueous Na2S2O3(0.50 mL). The biphasic mixture was poured into H2O (2 mL) and extracted with CH2CI2(3 x 2 mL). The combined organic phases were concentrated in vacuo. The crude reaction mixture was treated with Et2O (5 mL) and cooled in an ice bath for 30 minutes. The resulting cloudy solution was filtered, andthe solvent was removed under reduced pressure, yielding the product 16q (50.0 mg 0.140 mmol, 69%) as a thick colourless liquid.Note: The product is not stable on silica gel.1H NMR (600 MHz, C6D6) 6H7.46 (2H, dd, J= 8.3, 1.3 Hz, ArH), 6.94-6.86 (1H, m, ArH), 6.82 (2H, dd, J = 8.4, 7.2 Hz, ArH), 3.70 (2H, s, H1 / H2), 3.68 (2H, s, H1 / H2), 3.08-3.05 (2H, m, H4b), 1.94-1.91 (2H, m H4a).13C NMR (151MHz, C6D6) 6c 136.6, 133.7, 129.2, 129.1, 77.1, 66.7, 64.9, 44.3, 23.0.IR (thin film, vmax / cm-1): 2925, 2872, 1690, 1583, 1450, 1300, 1159, 1081.HRMS (ESI+) [M+H]+calculated for [C12H14IO3S]+364.9703, found 364.9685.1,5-Diiodo-3-tosyl-3-azabicyclo[3.1.1]heptane (16r) and 5,5'-Diiodo-3,3'-ditosyl-3,3'-diaza-1,1 '-bi(bicyclo[3.1.1]heptane) (16^)To a stirred solution of 3-( / V-tosyl)aza-[3.1.1]propellane (1.32 mL, 0.15 M in THF, 0.198 mmol, 1.1 eq.) was added iodine (45.7 mg, 0.180 mmol, 1.0 eq.) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure, then purification by column chromatography (SiO2, pentane / EtOAc 19:1) gave the inseparable products 16r and 16r' (58.1 mg) as a yellow solid in a 1.4: 1.0 ratio of 16r:16r’ as determined from the1H NMR spectrum, with 75% overall yield. Rf 0.20 (19:1 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.70 (6H, d, J = 8.3 Hz, Ts), 7.36 (6H, d, J = 8.1 Hz, Ts), 3.80 (4H, s, H1), 3.76 (4H, s, H4 / 5), 3.69 (4H, s, H4 / 5), 3.18-3.05 (2H, m, H3b), 3.04-2.96 (4H, m, H7b), 2.70-2.59 (2H, m, H3a), 2.58-2.50 (4H, m, H7a), 2.45 (9H, s, Ts).13C NMR (126 MHz, CDCh) 6C144.3, 144.3, 134.1, 130.2, 127.4, 127.4, 58.2, 58.0, 55.8, 55.6, 54.3, 47.2, 21.7, 19.4, 16.4.IR (thin film, Vmax / crn’1; selected peaks): 2869, 1344, 1160, 1012.HRMS (ES+) calc. for C13H15I2NO2SNa [M(16r)+Na]+525.8805, found 525.8807.m.p. 167 °C2-(3-Oxabicyclo[3.1.1]heptan-1 -y I )-1 -phenylpyrrolidine (16s)The reaction was carried out according to the procedure of Nugent et al2. To an oven-dried vial containing 1-(4-bromophenyl)pyrrolidine (450 mg, 0.200 mmol, 10.0 eq.) and 4CzlPN (4.0 mg, 2.5 mol%) was added anhydrous DMA (0.50 mL) and H2O (36.0 pL, 2.0 mmol, 10.0 eq.). The solution was deggased with argon for 15 minutes before adding oxa[3.1.1]propellane (0.80 mL, 0.300 mmol, 1.0 eq, 0.25 M in Et20). The vial was sealed and irradiated with a 440 nm Kessil PR160L LED lamp. After stirring at ambient temperature for 18 h, the solution was diluted with EtOAc (5.0 mL) and washed with 5% LiCI solution (10.0 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude reaction mixture was purified via column chromatography using silica gel to afford the product 16s (44.0 mg, 0.140 mmol, 68%) as a colourless crystalline solid. m.p. 88-90 °CRf = 0.5 (19:1 pentane I Et20).1H NMR (600 MHz, CDCI3) 6H7.22-7.20 (2H, m, ArH), 6.69 (1H, t, J = 7.3 Hz, ArH), 6.58 (2H, d, J= 8.1 Hz, ArH), 3.91-3.86 (4H, m, H1 / 2), 3.61 (1H, td, J= 8.7, 2.5 Hz, H10), 3.45 (1H, dd, J = 7.0, 3.5 Hz, H7), 3.18 (1H, td, J = 9.3, 7.4 Hz, H10), 2.18 (1H, tt, J = 6.5, 3.3 Hz, H3), 2.02-1.92 (4H, m, H4b / 5b / 9), 1.82-1.78 (2H, m, H8), 1.62 (1H, t, J= 8.2 Hz, H4a / 5a), 1.56 (1H, t, J = 8.4 Hz, H4a / 5a).13C NMR (151 MHz, CDCI3) 6c 149.4, 129.0, 116.1, 112.8, 73.8, 70.9, 61.2, 50.3, 48.7, 34.5, 32.5, 31.4, 28.0, 24.4.IR (thin film, vmax / cm-1): 2954, 2853, 1600, 1503, 1341, 1238, 1055.HRMS (ESI-) [M-H]-calculated for [C16H20NO]-242.1550, found 242.1539.1-(Phenylselenyl)-3-oxabicyclo[3.1.1]heptane (16t)Synthesised in accordance with General Procedure 1 using benzeneselenol (35.0 mg, 0.220 mmol, 1.1 eq.) and oxa[3.1.1]propellane (0.80 mL, 0.200 mmol, 1.0 eq, 0.24 M in Et20), stirred at ambient temperature for 1 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiCh, pentane / Et2O 9:1) to afford the product 16t (47.0 mg, 0.190 mmol, 93%) as a colorless solid.Rf = 0.2 (99:1 pentane I Et20)1H NMR (500 MHz, CDCh) 6H7.54-7.53 (2H, m, ArH), 7.35-7.27 (3H, m, ArH), 3.99 (2H, s, H1), 3.88 (2H, d, J= 2.1 Hz, H2), 2.52 (1H, tt, J= 6.8, 2.2 Hz, H3), 2.33-2.27 (2H, m, H4b), 1.98-1.94 (2H, m, H4a).13C NMR (126 MHz, CDCh) 6c 136.6, 129.1, 128.4, 126.9, 75.5, 69.9, 46.4, 39.1, 34.7.IR (thin film, vmax / cm-1): 2947, 2855, 1578, 1473, 1435, 1232, 1122, 1038.HRMS (ESI+) [M+H]+calculated for [C12H15OSe]+255.0283, found 255.0274.1-(Phenylthio)-3-oxabicyclo[3.1.1]heptane (16u)Synthesised in accordance with General Procedure 1 using thiophenol (24.0 mg, 0.220 mmol, 1.1 eq.) and oxa[3.1.1]propellane (0.80 mL, 0.200 mmol, 1.0 eq, 0.24 M in diethyl ether), stirred at ambient temperature for 1 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography chromatography (SiCh, pentane / Et2O 9:1) to afford the product 16u (38.0 mg, 0.180 mmol, 91%) as a colourless solid.Rf = 0.2 (99:1 pentane / Et20).1H NMR (500 MHz, CDCh) 6H7.42-7.40 (2H, m, ArH), 7.32 -7.30 (3H, m, ArH), 3.89 (2H, s, H1), 3.85 (2H, d, J= 2.2 Hz, H2), 2.46 (1 H, tt, J= 6.8, 2.2 Hz, H3), 2.22-2.19 (2H, m, H4b), 1.93-1.89 (2H, m, H4a).13C NMR (126 MHz, CDCh) 6c 134.9, 131.7, 129.0, 128.3, 74.6, 69.9, 50.4, 38.3, 32.9.IR (thin film, vmax / cm-1): 2951, 2858, 1474, 1233, 1124, 1024.HRMS (ESI+) [M+H]+calculated for [C12H15OS]+207.0838, found 207.0835.1-(Phenylthio)-3-thiabicyclo[3.1.1]heptane (16v)A solution of 3-thia[3.1.1]propellane (1.67 mL, 0.12 M, 0.200 mmol, 1.0 eq.) in Et2O was added dropwise to stirred neat PhSH (0.205 mL, 2.00 mmol, 10 eq.). The mixture was stirred at rt for 30 min then diluted with Et2O (2 mL), washed with 1 M aq NaOH (3 mLx 3), dried over anhydrous Na2SCU, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, pentane / Et2O 98:2) gave the product 16v (18.5 mg, 83.2 pmol, 42%) as a colourless oil.Rf 0.24 (98:2 pentane I Et2O).1H NMR (400 MHz, CDCh) 6H7.44-7.36 (2H, m, Ar H), 7.35-7.28 (3H, m, Ar H), 3.16 (2H, s, H1), 3.03 (2H, d, J = 3.3 Hz, H2), 2.77-2.70 (1H, m, H3), 2.40-2.29 (2H, m, H4b), 2.18-2.08 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6C134.8, 132.3, 129.0, 128.3, 50.0, 38.5, 37.9, 32.8, 31.0.IR (thin film, vmax / cm-1; selected peaks): 2933, 1583, 1438, 1202, 1097.HRMS (ES+) calc. for C12H15S2[M+H]+223.0610, found 223.0614.1-(Phenylthio)-3-tosyl-3-azabicyclo[3.1.1]heptane (16w)Synthesised in accordance with General Procedure 1, using 3-( / V-tosyl)aza-[,3.1.1]propellane (1.33 mL, 0.15 M in THF, 0.200 mmol, 1.0 eq.) and PhSH (20.5 pL 0.200 mmol, 1.0 eq.). Purification by column chromatography (SiO2, pentane / Et207:3) gave the product 16w (35 mg, 97 pmol, 48%) as a white solid. Rf 0.23 (7:3 pentane I Et20).1H NMR (400 MHz, CDCh) 6H7.61 (2H, d, J = 8.3 Hz, Ar H), 7.42-7.24 (7H, m, Ar H), 3.53 (2H, s, H1), 3.42 (2H, d, J = 2.6 Hz, H2), 2.49 (1H, tt, J= 6.5, 2.7 Hz, H3), 2.43 (3H, s, Ts), 2.16-2.05 (2H, m, H4b), 1.50-1.40 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6c 143.4, 135.1, 134.7, 131.2, 129.8, 129.1, 128.7, 127.3, 54.8, 49.6, 48.5, 38.0, 29.7, 21.7.IR (thin film, vmax / cm-1; selected peaks): 2943, 1340, 1164, 1123, 1012.HRMS (ES+) calc, for C19H22NO2S2 [M+H]+360.1087, found 360.1089.m.p. 99 °CMethyl S-(3-oxabicyclo[3.1]heptan-1-yl)-N-(tert-butoxycarbonyl) cysteinate (16x)Synthesised in accordance with General Procedure 1 using L-cysteine methyl ester (47.0 mg, 0.200 mmol, 1 eq.), oxa[3.1.1]propellane (1.00 mL, 0.260 mmol, 1.3 eq, 0.27 M in diethyl ether) and BEt3(20.0 pL, 1.0 M in hexane, 10 mol%). The reaction was stirred at ambient temperature for 2.5 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiCh, pentane / Et2O 8:2) to afford 16x (44.0 mg, 0.130 mmol, 67%) as a colourless oil.Scaled up synthesis:Synthesised in accordance with General Procedure 1 using L-cysteine methyl ester (240 mg, 1.00 mmol, 1 eq.), oxa[3.1.1]propellane (4.80 mL, 1.30 mmol, 1.3 eq, 0.27 M in diethyl ether) and BEt3(0.10 mL, 1.0 M in hexane, 10 mol%). The reaction was stirred at ambient temperature for 2.5 h. All volatiles were removed under vacuum, and the crude reaction mixture was purified by column chromatography (SiO2, pentane / Et2O 8:2) to afford 16x (200 mg, 0.610 mmol, 61%) as a light yellow oil. Rf = 0.3 (8:2 pentane I Et20)1H NMR (500 MHz, CDCh) 6H5.28 (1 H, d, J = 7.9 Hz, H9), 4.52 (1 H, d, J = 5.5 Hz, H8), 3.88 (2H, s, H1), 3.87 (2H, d, J= 2.2 Hz, H2), 3.77 (3H, s, H14), 2.95 (1H, dd, J = 13.4, 4.9 Hz, H7), 2.90 (1H, dd, J = 13.2, 5.3 Hz, H7), 2.50 (1H, tt, J= 6.9, 2.2 Hz, H3), 2.17 (2H, m, H4 / 5), 1.90 (2H, m, H4 / 5), 1.45 (9H, s, H12).13C NMR (126 MHz, CDCh) 6c 171.3, 155.2, 80.4, 74.8, 69.7, 53.5, 52.8, 48.0, 38.0, 37.9, 32.7, 31.2, 28.5.IR (thin film, vmax / cm’1): 3352, 2975, 2861, 1748, 1714, 1508, 1439, 1362, 1314, 1167, 1044.HRMS (ESI+) [M+H]+calculated for [C15H26NO5S]+332.1526, found 332.1520.1,5-Bis(phenylselanyl)-3-thiabicyclo[3.1.1]heptane (16y)To a solution of 3-thia[3.1.1]propellane (1.15 mL, 0.13 M, 0.150 mmol, 1.0 eq.) in Et2Owas added diphenyl diselenide (46.8 mg, 0.150 mmol, 1.0 eq.) and the mixture was stirred for 3 h at rt. The mixture was concentrated under reduced pressure, and the residue purified by column chromatography (SiCh, pentane / Et2O 98:2) to give the product 16y (43.4 mg, 0.102 mmol, 68% approx.) as a pale yellow oil, which contained a small unidentified impurity that co-eluted with the product. Trituration from pentane removed this impurity with some loss of yield to give the product (21.8 mg, 51.4 pmol, 34%) as a white crystalline solid.Rf 0.12 (98:2 pentane / Et20).1H NMR (400 MHz, CDCh) 6H7.49 (4H, d, J = 6.6 Hz, Ar H), 7.39-7.32 (2H, m, Ar H), 7.32-7.27 (4H, m, Ar H), 3.21 (4H, s, H1), 2.73-2.63 (2H, m, H3b), 2.61-2.52 (2H, m, H3a).13C NMR (101 MHz, CDCh) 6c 136.7, 129.3, 128.8, 127.2, 47.4, 43.9, 38.1.IR (thin film, vmax / cm-1; selected peaks): 3070, 2930, 1475, 1436, 1200, 1065. HRMS (ES+) calc. for C18H19SSe2[M+H]+426.9532, found 426.9544.m.p. 87 °C1-(Pyridin-2-ylthio)-3,5-ditosyl-3-azabicyclo[3.1.1]heptane (16z)To a solution of S-2-pyridyl tolylthiosulfonate (54.3 mg, 0.205 mmol, 1.0 eq.) in dry MeCN (1.5 mL) was added of 3-( / V-tosyl)aza-[3.1.1]propellane (2.05 mL, 0.15 M in THF, 0.307 mmol, 1.5 eq.) and the mixture was stirred at 60 °C for 16 h. The mixture was then cooled to rt, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, pentane / EtOAc 7:3) to give the product 16z (51.9 mg, 0.101 mmol, 49%) as a white solid.Rf 0.29 (7:3 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H8.29 (1H, ddd, J = 4.9, 1.9, 0.9 Hz, Ar H), 7.67 (2H, d, J = 8.3 Hz, Ts), 7.63 (2H, d, J = 8.3 Hz, Ts), 7.49 (1 H, td, J = 7.7, 1.9 Hz, Ar H), 7.37 (2H, d, J= 8.0 Hz, Ts), 7.29 (2H, d, J= 8.0 Hz, Ts), 7.11 (1H, d, J= 8.0 Hz, Ar H), 7.02 (1H, ddd, J= 7.4, 4.9, 1.1 Hz, Ar H), 3.82 (2H, s, H1 / 2), 3.55 (2H, s, H1 / 2), 2.81-2.71 (2H, m, H4b), 2.49 (3H, s, Ts), 2.45 (3H, s, Ts), 2.00-1.90 (2H, m, H4a).13C NMR (101 MHz, CDCh) 6C156.9, 149.7, 145.7, 143.9, 136.6, 134.4, 132.3, 130.3, 129.9, 129.3, 127.5, 123.7, 120.6, 60.6, 53.8, 48.0, 43.1, 39.0, 21.9, 21.7.IR (thin film, vmax / cm-1; selected peaks): 2926, 1578, 1416, 1317, 1160.HRMS (ES+) calc, for C25H27N2O4S3[M+H]+515.1128, found 515.1136.m.p. 164 °C1,5-Diiodo-3-oxabicyclo[3.1.1]heptane (16aa and S. S'-Diiodo-S. S'-dioxa-l.l'-bi(bicyclo[3.1.1]heptane) (16aa’)To a stirred solution of 3-oxa-[3.1.1]propellane (0.60 mL, 0.14 M in THF, 84.0 pmol, l.0 eq.) was added iodine (21.3 mg, 84.0 pmol, 1.0 eq.) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure, then purification by column chromatography (SiO2, pentane / Et2O 19:1) gave the inseparable products 16aa and 16aa' (17.3 mg) as a yellow solid in a 1.0:0.15 ratio of 16aa:16aa’ as determined from the1H NMR spectrum, with 64% overall yield.Rf 0.42 (19:1 pentane I Et20).1H NMR (400 MHz, CDCh) 6H4.12 (4H, s, H1), 4.05 (4H, s, H4 / 5), 4.03 (4H, s, H4 / 5), 3.25 - 3.15 (2H, m, H3b), 3.14 - 3.08 (4H, m, H7b), 3.04-2.95 (2H, m, H3a), 2.94-2.86 (4H, m, H7a)13C NMR (101 MHz, CDCh) 6c 76.5, 55.7, 24.6.IR (thin film, Vmax / crn’1; selected peaks): 2862, 1456, 1244, 1072, 976.HRMS (ES+) Not foundm.p. 43 °C1 -Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane (17)Method 1: To a solution of HBr in acetic acid (33%, 146 mmol, 30 eq.) was added phenol (4.60 g, 48.9 mmol, 10 eq.). 1-Bromo-5-(bromomethyl)-3-tosyl-3-azabicyclo[3.1.0]hexane 14 (2.00 g, 4.89 mmol, 1.0 eq.) was added and the mixture was stirred at 70 °C for 2 h. The mixture was then made alkaline with 1 M aq NaOH and extracted with Et20 (x3). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give thecrude product 17 (6.26 g, 16% w / w, 3.85 mmol, 79%) as a brown solid. The yield was determined by NMR; the doublet at 3.39 ppm was integrated relative to a DMSO internal standard. The crude product was taken forward without further purification to all subsequent amine functionalisation steps.Method 2: To a solution of HBr in acetic acid (33%, 12.1 mL, 73.3 mmol, 30 eq.) was added phenol (2.30 g, 24.4 mmol, 10 eq.). 1-Bromo-5-(bromomethyl)-3-tosyl-3-azabicyclo[3.1.0]hexane 14 (1.00 g, 2.44 mmol, 1.0 eq.) was added and the mixture was stirred at 70 °C for 2 h. The mixture was then made adjusted to pH 8 with 1 M aq NaOH (250 mL) and extracted with Et20 (3 x 200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the crude product 17 (2.45 g, 25% w / w, 2.40 mmol, 98%) as an orange oil. The yield was determined by NMR; the doublet at 3.39 ppm was integrated relative to a CH2CI2 internal standard. The crude product was taken forward without further purification to all subsequent amine functionalisation steps. Rf 0.19 (3:7 pentane I EtOAc).1H NMR (400 MHz, CDCI3) 6H3.64 (2H, s, H6), 3.45 (1H, d, J= 11.9 Hz, H2 / 3), 3.30 (1H, d, J= 11.8 Hz, H2 / 3), 3.23 (1H, d, J= 11.9 Hz, H2 / 3), 3.12 (1H, d, J= 11.9 Hz, H2 / 3), 1.38 (1H, d, J= 7.1 Hz, H5), 1.30 (1H, d, J= 7.2 Hz, H5).13C NMR (101 MHz, CDCI3) 6c 56.1, 50.3, 41.3, 35.7, 33.7, 22.9.8-(( 1 -Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)quinoline (18)To a solution of 1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 17 (812 mg, 16% w / w, 0.500 mmol, 1.0 eq.) and Na2COs (79.5 mg, 0.750 mmol, 1.5 eq.) in THF (0.8 mL) and water (0.8 mL) was added quinoline-8-sulfonyl chloride (171 mg, 0.750 mmol, 1.5 eq.) and the mixture was stirred at rt for 1 h. The THF was removed under reduced pressure and the mixture was diltued with water (10 mL) and extracted withEt2O (3 x 10 mL). The combined organicc extracts were dried over anhydrous MgSC, filtered and concentrated under reduced pressure. Recrystallisation from Et2O at -20 °C gave the product 18 (102 mg, 0.229 mmol, 46%) as a colourless crystalline solid.Rf 0.17 (8:2 pentane I Et20).1H NMR (400 MHz, CDCh) 6H9.08 (1H, dd, J= 4.2, 1.8 Hz, Ar H), 8.44 (1H, dd, J = 7.4, 1.5 Hz, Ar H), 8.24 (1H, dd, J= 8.3, 1.8 Hz, Ar H), 8.03 (1H, dd, J= 8.2, 1.5 Hz, Ar H), 7.60 (1H, t, J= 7.8 Hz, Ar H), 7.53 (1H, dd, J = 8.3, 4.2 Hz, Ar H), 4.34 (1H, d, J = 9.9 Hz, H2 / 3), 4.00 (1H, d, J = 9.9 Hz, H2 / 3), 3.81 (1H, d, J = 9.9 Hz, H2 / 3), 3.76 (1H, d, J= 10.0 Hz, H2 / 3), 3.55 (1H, d, J= 11.0 Hz, H6), 3.51 (1H, d, J= 11.1 Hz, H6), 1.27 (1H, d, J= 6.7 Hz, H5), 1.12 (1H, d, J= 6.9 Hz, H5).13C NMR (101 MHz, CDCh) 6c 151.5, 144.1, 137.1, 136.7, 133.9, 133.1, 129.2, 125.7, 122.4, 56.9, 52.0, 38.7, 35.3, 32.8, 24.5.IR (thin film, Vmax / cnr1; selected peaks): 2877, 1494, 1338, 1164, 1145.HRMS (ES+) calc, for C15H15N2O2S [M+H]+444.9216, found 444.9211.m.p. 130 °C1-Bromo-5-(bromomethyl)-3-(thiophen-2-ylsulfonyl)-3-azabicyclo[3.1.0]hexane (19)To a solution of 1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 17 (810 mg, 16% w / w, 0.500 mmol, 1.0 eq.) and Na2CO3 (79.5 mg, 0.750 mmol, 1.5 eq.) in THF (0.8 mL) and water (0.8 mL) was added thiophene-2-sulfonyl chloride (137 mg, 0.750 mmol, 1.5 eq.) and the mixture was stirred at rt for 1 h. The THF was removed under reduced pressure and the mixture was diltued with water (10 mL) and extracted with Et20 (3 x 10 mL). The combined organicc extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Recrystallisation from Et20 at -20 °C gave the product 19 (111 mg, 0.277 mmol, 55%) as a white crystalline solid.Rf 0.21 (7:3 pentane I Et2O).1H NMR (400 MHz, CDCh) 6H7.66 (1H, d, J= 5.1 Hz, Ar H), 7.60 (1H, dd, J = 3.8, l.3 Hz, Ar H), 7.18 (1H, dd, J = 5.0, 3.7 Hz, Ar H), 3.99 (2H, d, J = 9.5 Hz, H2 / 3), 3.67 (2H, d, J = 9.7 Hz, H2 / 3), 3.56 (2H, d, J = 11.1 Hz, H6), 3.49 (2H, d, J = 11.1 Hz, H6), 3.38 (2H, d, J= 9.6 Hz, H2 / 3), 3.36 (2H, d, J= 9.6 Hz, H2 / 3), 1.49 (2H, d, J = 6.8 Hz, H5), 1.23 (2H, d, J = 6.8 Hz, H5).13C NMR (101 MHz, CDCh) 6c 136.2, 132.9, 132.7, 128.0, 56.8, 52.0, 37.8, 34.7, 32.9, 24.7.IR (thin film, vmax / cm-1; selected peaks): 2861, 1722, 1358, 1228, 1165, 1045, 1018.HRMS (ES+) calc, for C10H12NO2S2 [M+H]+399.8671, found 399.8670.m.p. 98 °C3-(Quinolin-8-ylsulfonyl)-3-azatricyclo[3.1.1.01,5]heptane (20)To a stirred solution of 8-((1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)quinoline 18 (95.5 mg, 0.214 mmol, 1.0 eq.), in dry THF (2.1 mL) at -78 °C was added MeLi (0.165 mL, 1.3 M, 0.214 mmol, 1.0 eq.). The mixture was stirred at -78 °C for 10 min, then at rt for 1 h. MgSO4(200 mg) was added to the reaction mixture and this was stirred for 10 min. Then the mixture was passed through a celite filter, eluted with THF (1.0 mL). The mixture was partially concentrated under reduced pressure (120 mbar) to remove MeBr and Et20, giving the product 20 (49.5 mg, 0.173 mmol, 81%) as a colourless solution in THF (0.10 M, 1.8 mL), which was stored under nitrogen at -20 °C. The yield was determined by integrating the singlet at 3.79 ppm relative to the THF peak.1H NMR (500 MHz, C6D6) 6H8.67 (1H, dd, J = 4.2, 1.8 Hz, Ar H), 8.48 (1H, dd, J = 7.3, 1.5 Hz, Ar H), 7.62 (1H, dd, J= 8.3, 1.8 Hz, Ar H), 7.45 (1H, dd, J= 8.2, 1.5 Hz, Ar H), 7.10 (1H, dd, J= 8.2, 7.3 Hz, Ar H), 6.90 (1H, dd, J= 8.3, 4.2 Hz, Ar H), 3.79 (4H, s, H2), 2.10 (2H, t, J= 1.6 Hz, H3), 1.35 (2H, t, J= 1.5 Hz, H3).13C NMR (126 MHz, C6D6) 6c 150.9, 144.6, 139.3, 136.4, 133.1, 133.0, 129.2, 125.7, 122.0, 53.7, 52.1, 23.2.HRMS (ES+) calc, for C15H15N2O2S [M+ H]+287.0849, found 287.0853.3-(Thiophen-2-ylsulfonyl)-3-azatricyclo[3.1.1.01,5]heptane (21)To a stirred solution of 1-bromo-5-(bromomethyl)-3-(thiophen-2-ylsulfonyl)-3-azabicyclo[3.1.0]hexane 19 (85.5 mg, 0.213 mmol, 1.0 eq.), in dry THF (2.1 mL) at -78 °C was added MeLi (0.158 mL, 1.35 M in Et20, 0.213 mmol, 1.0 eq.). The mixture was stirred at -78 °C for 10 min, then at rt for 1 h. MgSO4(200 mg) was added to the reaction mixture and this was stirred for 10 min. Then the mixture was passed through a celite filter and eluted with THF (1.0 mL). The mixture was partially concentrated under reduced pressure (120 mbar) to remove MeBr and Et20, giving the product 21 (36.2 mg, 0.150 mmol, 70%) as a pale yellow solution in THF (0.13 M, 1.14 mL), which was stored under nitrogen at -20 °C. The yield was determined by integrating the triplet at 1.94 ppm relative to the THF peak.1H NMR (400 MHz, C6D6) 6H7.33 (1H, dd, J = 3.7, 1.3 Hz, Ar H), 7.01 (1H, dd, J = 5.0, 1.3 Hz, Ar H), 6.62 (1 H, dd, J = 5.0, 3.7 Hz, Ar H), 3.23 (4H, s, H2), 1.94 (2H, t, J = 1.7 Hz, H3), 1.29 (2H, t, J = 1.6 Hz, H3).13C NMR (101 MHz, C6D6) 6C138.2, 132.2, 131.7, 126.2, 53.8, 52.2, 22.7.HRMS (ES+) calc, for C10H12NO2S2 [M+H]+242.0304, found 242.0301.Further method of propellane formation:A 1.4:1.0 mixture of 16r:16r’ (21.0 mg total, including 16r (10.2 mg, 20.3 pmol, 1.0 eq.) and 16r’ (10.8 mg, 14.4 pmol, 0.70 eq.)) was dissolved in THF (0.17 mL) andcooled to -78 °C. MeLi (32.1 pL, 1.3 M solution in Et2O, 41.7 pmol, 2.1 eq.) was added and the mixture was stirred at -78 °C for 10 min. The mixture was then stirred at rt for 1 h. The yield was determined directly from the reaction mixture by1H NMR spectroscopy using a CH2CI2 internal standard (2.5 pL). The mixture contained 40.6 pmol product, 83% yield, and the NMR matched that reported above for compound 15.Alternative further method of propellane formation:A 1.0:0.15 mixture of 16aa:16aa’ (10.9 mg total, including 16aa (9.14 mg, 26.1 pmol, 1.0 eq.) and 16aa’ (1.75 mg, 3.92 pmol, 0.15 eq.)) was dissolved in Et20 (0.40 mL) and cooled to -78 °C. MeLi (26.0 pL, 1.35 M solution in Et20, 35.1 pmol, 1.3 eq.) was added and the mixture was stirred at -78 °C for 10 min. The mixture was then stirred at rt for 1 h. The yield was determined directly from the reaction mixture by1H NMR spectroscopy using a CH2CI2 internal standard (5.0 pL). The mixture contained 34.1 pmol product, 100% yield, and the NMR matched that reported above for compound 6.General procedure 4: Propellane formationTo a solution of propellane precursor (1.0 eq.) in THF (0.1 M) at -78 °C was added the organolithium reagent (1.0 eq.) and the mixture was stirred at -78 °C for 5 min. The mixture was then warmed to room temperature and stirred until completion. NaHCO3(1.0 eq.) was added and the mixture was stirred for another 5 min, then filtered through a celite pad and eluted with THF. The mixture was partially concentrated under reduced pressure to give the product as a solution in THF, which was stored in a glass bottle with an AcroSeal under N2 at -20 °C.Caution: During the partial concentration process, bromomethane will be released.General procedure 5: Photocatalysed ATRA ring-openingTo a solution of fac-lr(ppy)3(2.5 mol%) and an alkyl or aryl halide (1.0 eq.) in t-BuCN (0.10 M) was added the hetero[3.1.1]propellane (1.2 eq.) and the mixture wasdegassed with N2 for 5 min. The vial was placed in the photobox, and the stirred reaction mixture was irradiated with blue LEDs (Kessil PR160, 456 nm) with fan cooling for the specified time. The reaction mixture was concentrated under reduced pressure and the product was purified by column chromatography.Tert-butyl 1 -bromo-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (22)BocTo a solution of methyl 5-bromo-2-oxo-3-azabicyclo[3.1.0]hexane-1 -carboxylate (4.00 g, 17.1 mmol, 1.0 eq.) in THF (120 mL) at 0 °C was added Red-AI (16.7 mL, 60% wt., 51.3 mmol, 3.0 eq.) dropwise, then the mixture was stirred at rt for 17 h. Rochelle salt solution sat. (60 mL) was added and the mixture was stirred until it became clear. The layers were separated, then the aqueous layer was extracted with a 3:1 mixture of CHC / PrOH (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The product was directly re-dissolved in a 1:1 mixture of THF: H2< D ( 30 mL). BOC2O (4.48 g, 20.5 mmol, 1.2 eq.) was added and the mixture was stirred for 4 h at rt. Water (50 mL) and EtOAc (50 mL) were added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, pentane / EtOAc 6:4) gave the product (2.80 g, 9.58 mmol, 56%) as a white solid.Rf 0.35 (6:4 pentane I EtOAc).1H NMR (400 MHz, CDCI3) 6H 4.12 - 3.89 (2H, m, H2 / 3 / 6), 3.75 (1H, dd, J= 12.4, 4.9 Hz, H2 / 3 / 6), 3.68 - 3.52 (3H, m, H2 / 3 / 6), 1.78-1.72 (1H, m, H7), 1.44 (9H, s, Boc), 1.23 (1H, d, J= 6.5 Hz, H5), 1.15-1.12 (1H, m, H5).13C NMR (101 MHz, CDCI3) 154.5, 80.3, 64.4, 64.2, 56.1, 55.7, 49.0, 48.5, 36.1, 35.7, 34.1, 33.5, 28.5, 22.9.Note: the1H and13C spectra show additional peaks due to the presence of rotamers. IR (thin film, Vmax / cnr1; selected peaks): 3435, 2977, 1703, 1415, 1177.HRMS (ES+) calc, for CnHi8BrNO3Na [M+Na]+314.0362, found 314.0358.m.p. 70 °CTert-butyl 1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (23)BocTo a solution of Terf-butyl-1-bromo-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 22 (5.38 g, 18.4 mmol, 1.0 eq.) and NBS (3.93 g, 22.1 mmol, 1.2 eq.) in CH2CI2 (120 mL) at 0 °C was added a solution of PPhs (5.80 g, 22.1 mmol, 1.2 eq.) in CH2CI2 (10 mL) dropwise. The mixture was stirred at rt for 1 h then concentrated under reduced pressure. Purification by column chromatography (SiO2, pentante / EtOAc 9:1) gave the product (5.60 g, 15.8 mmol, 86%) as a white solid.Rf 0.33 (9:1 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H 4.10-3.99 (1H, m, H2 / 3 / 6), 3.79-3.45 (5H, m, H2 / 3 / 6), 1.43 (9H, s, Boc), 1.33 (1H, d, J = 6.6 Hz, H5), 1.29 (1H, d, J = 6.7 Hz, H5)13C NMR (101 MHz, CDCh) 154.2, 80.5, 55.8, 55.6, 50.5, 50.0, 38.9, 38.7, 35.7, 35.5, 33.2, 32.5, 28.5, 25.8.Note: the1H and13C spectra show additional peaks due to the presence of rotamers. IR (thin film, vmax / cm-1; selected peaks): 2977, 1704, 1404, 1175, 1120.HRMS (ES+) calc, for CiiHi7Br2NO2Na [M+Na]+375.9518, found 375.9508.m.p. 44 °C1-Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane (24)To a solution of tert-butyl 1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate 23 (6.18 g, 17.4 mmol, 1.0 eq.) in CH2CI2 (30 mL) was added TFA (6.66 mL, 87.0 mmol, 5.0 eq.) and the mixture was stirred at rt for 8 h. NaHCO3sat. (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The mixture was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product (4.10 g, 16.1 mmol, 92%) as a white solid.Rf 0.22 (2:8 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H3.66 (1 H, d, J = 10.8 Hz, H7), 3.62 (1 H, d, J = 10.8 Hz, H7), 3.35 (1H, d, J= 11.7 Hz, H2 / 4), 3.18 (1H, d, J = 11.7 Hz, H2 / 4), 3.09 (1H, d, J = 11.8 Hz, H2 / 4), 3.02 (1H, d, J= 11.8 Hz, H2 / 4), 1.79 (1H, s, H3), 1.35 (1H, d, J = 6.7 Hz, H6), 1.21 (1H, d, = 6.8 Hz, H6).13C NMR (101 MHz, CDCh) 6c 57.2, 51.1, 43.1, 36.7, 33.9, 22.8.IR (thin film, Vmax / cnr1; selected peaks): 2871, 1434, 1223, 908.HRMS (ES+) calc, for C6HioBr2N [M+H]+253.9174, found 253.9178.m.p. 68 °C3-Benzyl-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane (25)To a solution of 1-Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 24 (500 mg, 1.96 mmol, 1.0 eq.) and NEt3(0.410 mL, 2.94 mmol, 1.5 eq.) in THF (8.0 mL) was added benzyl bromide (0.350 mL, 2.94 mmol, 1.5 eq.) and the mixture was stirred at 50 °C for 22 h. The mixture was concentrated under reduced pressure, then water (10 mL) was added and the mixture was extractd with Et20 (3 x 10 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, pentane / EtOAc 98:2) gave the product (553 mg, 1.60 mmol, 82%) as a colourless oil.Rf 0.19 (98:2 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H7.39 - 7.24 (5H, m, Bn), 3.67 (2H, s, Bn), 3.65 (1 H, d, J = 10.9 Hz, H6), 3.62 (1H, d, J= 10.9 Hz, H6), 3.35 (1H, d, J= 8.6 Hz, H2 / 3), 3.05 (1H, d, J = 8.8 Hz, H2 / 3), 2.76 (1H, d, J= 8.7 Hz, H2 / 3), 2.61 (1H, d, J= 8.9 Hz, H2 / 3), 1.96 (1H, d, J = 5.6 Hz, H5), 1.09 (1H, d, J= 5.6 Hz, H5).13C NMR (101 MHz, CDCh) 6c 138.4, 128.6, 128.4, 127.3, 62.2, 58.6, 56.4, 41.1, 37.3, 32.6, 24.4.IR (thin film, Vmax / cnr1; selected peaks): 2800, 2360, 1226, 1151.HRMS (ES+) calc, for Ci3Hi6Br2N [M+H]+343.9644, found 343.9644.3-Allyl-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane (26)To a solution of 1-Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 24 (500 mg, 1.96 mmol, 1.0 eq.) and NEt3(0.410 mL, 2.94 mmol, 1.5 eq.) in THF (8.0 mL) was added allyl bromide (0.255 mL, 2.94 mmol, 1.5 eq.) and the mixture was stirred at 50 °C for 22 h. The mixture was concentrated under reduced pressure, then water (10 mL) was added and the mixture was extractd with Et20 (3 x 10 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiCh, pentane / EtOAc 19:1) gave the product (474 mg, 1.61 mmol, 82%) as a colourless oil.Rf 0.25 (19:1 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H5.79 (1H, ddt, J= 16.7, 10.1, 6.4 Hz, H8), 5.18 (1H, dq, J = 17.1, 1.6 Hz, H9), 5.10 (1H, ddt, J= 10.2, 2.1, 1.2 Hz, H9), 3.60 (2H, s, H6), 3.34 (1H, d, J= 8.8 Hz, H2 / 3), 3.10 (2H, dq, J= 6.5, 1.7 Hz, H7), 3.05 (1H, d, J= 8.9 Hz, H2 / 3), 2.67 (1H, d, J= 8.7 Hz, H2 / 3), 2.53 (1H, d, J= 8.9 Hz, H2 / 3), 1.85 (1H, d, J= 5.7 Hz, H5), 1.05 (1H, d, J= 5.7 Hz, H5).13C NMR (101 MHz, CDCh) 6c 135.2, 117.5, 62.3, 57.5, 56.5, 41.1, 37.3, 32.7, 24.5.IR (thin film, Vmax / crn’1; selected peaks): 3077, 2905, 2804, 1225, 923.HRMS (ES+) calc, for C9Hi4Br2N [M+ H]+293.9488, found 293.9488.1-(1-Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2,2-dimethylpropan-1-one (27)To a solution of 1-Bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 24 (500 mg, 1.96 mmol, 1.0 eq.) and NEts (0.410 mL, 2.94 mmol, 1.5 eq.) in THF (8.0 mL) was added pivaloyl chloride (0.362 mL, 2.94 mmol, 1.5 eq.) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure, then water (10 mL) was added and the mixture was extractd with Et2O (3 x 10 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, pentane / EtOAc 8:2) gave the product (491 mg, 1.45 mmol, 74%) as a white solid.Rf 0.34 (8:2 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H4.38 (1H, d, J = 11.1 Hz, H2 / 3 / 6), 4.03 (1H, d, J = 11.2 Hz, H2 / 3 / 6), 3.73-3.70 (2H, m, H2 / 3 / 6), 3.65 (1H, d, J= 10.9 Hz, H2 / 3 / 6), 3.60 (1H, d, J= 11.0 Hz, H2 / 3 / 6), 1.28 (2H, s, H5), 1.23 (9H, s, H9).13C NMR (101 MHz, CDCh) 6C177.0, 56.9, 51.6, 39.1, 35.3, 30.4, 27.6, 25.7, 24.9.IR (thin film, Vmax / cnr1; selected peaks): 2974, 1635, 1478, 1408, 1195.HRMS (ES+) calc, for CnHi8Br2NO [M+H]+337.9750, found 337.9749.m.p. 35 °C(5-Bromo-3-azabicyclo[3.1.0]hexan-1 -yl)methanol (28)To a solution of methyl 5-bromo-2-oxo-3-azabicyclo[3.1.0]hexane-1 -carboxylate (783 mg, 3.35 mmol, 1.0 eq.) in THF (24 mL) at 0 °C was added Red-AI (3.26 mL, 60% wt., 10.0 mmol, 3.0 eq.) dropwise, then the mixture was stirred at rt for 6 h. Rochelle salt solution sat. (20 mL) was added and the mixture was stirred until it became clear. The layers were separated, then the aqueous layer was extracted with a 3:1 mixture of CHCl3:iPrOH (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the product as a pale yellow solid (432 mg, 3.35 mmol, 67%), which was used in the next step without further purification.Rf0.07 (9:1 EtOAc / MeOH).1H NMR (400 MHz, CDCh) 6H3.93 (1H, d, J = 12.2 Hz, H2 / 4), 3.82 (1H, d, J = 12.2 Hz, H2 / 4), 3.34 (1H, d, J = 11.5 Hz, H2 / 4), 3.26 - 3.15 (2H, m, H7), 2.93 (1H, d, J = 11.7 Hz, H2 / 4), 2.15 (2H, s, H3 / 8), 1.18 (1H, d, J = 6.7 Hz, H6), 1.15 (1H, d, = 6.9 Hz, H6).13C NMR (101 MHz, CDCh) 6c 64.7, 57.2, 49.3, 40.0, 34.7, 19.9.IR (thin film, Vmax / crn’1; selected peaks): 3306, 2874, 1686, 1442, 1083.HRMS (ES+) calc, for C6H11BrNO [M+H]+192.0019, found 192.0011.m.p. 104 °C(5-Bromo-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol (29)To a solution of (5-Bromo-3-azabicyclo[3.1.0]hexan-1-yl)methanol 28 (411 mg, 2.14 mmol, 1.0 eq.), Pd(OAc)2 (24.0 mg, 0.107 mmol, 0.05 eq.), (±)-2,2'-Bis(diphenylphosphino)-1, T-binaphthalene (133 mg, 0.214 mmol, 0.1 eq.) and Cs2CO3(1.39 g, 4.28 mmol, 2.0 eq.) in DMF (10.7 mL) was added 2-bromopyridine (0.204 mL, 2.14 mmol, 1.0 eq.) and the mixture was stirred at 80 °C for 6 h. Water (50 mL) and Et20 (50 mL) were added and the mixture was washed with water (3 x 50 mL), with each water wash back-extracted with Et20 (3 x 50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiCh, pentane I EtOAc 6:4) gave the product (295 mg, 1.10 mmol, 51 %) as a pale yellow solid.Rf 0.14 (6:4 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H8.14 (1H, ddd, J= 5.0, 1.9, 0.9 Hz, Ar H), 7.45 (1H, ddd, J = 8.5, 7.2, 1.9 Hz, Ar H), 6.60 (1H, ddd, J = 7.2, 5.0, 0.9 Hz, Ar H), 6.36 (1H, dt, J = 8.5, 0.9 Hz, Ar H), 4.23 (1 H, d, J = 10.0 Hz, H2 / 3), 4.05 (1 H, d, J = 12.3 Hz, H6), 3.84 (1 H, d, J = 12.3 Hz, H6), 3.79 - 3.67 (3H, m, H2 / 3), 2.02 (1H, br s, H7), 1.31 (1H, d, J = 6.6 Hz, H5), 1.29 (1H, d, = 6.2 Hz, H5).13C NMR (101 MHz, CDCh) 6c 157.4, 148.3, 137.5, 113.0, 106.8, 64.6, 57.3, 49.9, 36.8, 34.3, 24.1.IR (thin film, Vmax / crn’1; selected peaks): 3365, 2856, 1601, 1493, 1442.HRMS (ES+) calc, for C11H14BrN2O [M+H]+269.0284, found 269.0277.m.p. 89 °CNote: the Buchwald-Hartwig reaction was incompatible with the bromomethyl group in intermediate 3, so it was performed on an earlier intermediate.1-Bromo-5-(bromomethyl)-3-(pyridin-2-yl)-3-azabicyclo[3.1.0]hexane (30)To a solution of 29 (296 mg, 1.10 mmol, 1.0 eq.) and CBr4(438 mg, 1.32 mmol, 1.2 eq.) in CH2CI2 (5.0 mL) was added PPhs (346 mg, 1.32 mmol, 1.2 eq.). The mixture was stirred at rt for 30 min, then concentrated under reduced pressure. Purification by column chromatography (SiO2, pentante / EtOAc 9:1) gave the product (317 mg, 0.955 mmol, 87%) as a white solid.Rf 0.31 (9:1 pentane / EtOAc).1H NMR (400 MHz, CDCh) 6H8.15 (1H, dd, J = 5.0, 1.9 Hz, Ar H), 7.47 (1H, ddd, J= 8.8, 7.0, 1.9 Hz, Ar H), 6.63 (1H, dd, J= 7.2, 5.1 Hz, Ar H), 6.38 (1H, d, J= 8.4 Hz, Ar H), 4.24 (1H, d, J = 9.9 Hz, H2 / 3 / 6), 3.87 (1H, d, J = 9.9 Hz, H2 / 3 / 6), 3.74 - 3.65 (3H, m, H2 / 3 / 6), 3.60 (1H, d, J= 9.9 Hz, H2 / 3 / 6), 1.50 (1H, d, = 6.3 Hz, H5), 1.36 (1H, d, J= 6.3 Hz, H5).13C NMR (101 MHz, CDCh) 6C157.2, 148.3, 137.5, 113.3, 106.8, 57.1, 51.6, 39.8, 36.1, 33.4, 26.9.IR (thin film, vmax / cm-1; selected peaks): 2854, 1599, 1490, 1475, 1444.HRMS (ES+) calc, for C11H13Br2N2[M+H]+330.9440, found 330.9445.m.p. 54 °C3-( / V-Benzyl)aza[3.1.1 ]propellane (31 )Prepared according to General Procedure 4, using 3-benzyl-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 25 (399 mg, 1.16 mmol, 1.0 eq.) and nBuLi (1.10 mL, 1.05 Msolution in hexanes, 1.16 mmol, 1.0 eq.). The mixture was stirred for 5 min. The product (7.6 mL, 0.15 M, 1.12 mmol, 97%) was obtained as a pale yellow solution. The concentration was determined using CH2CI2 as an internal standard.1H NMR (400 MHz, C6D6) bH7.25-7.12 (3H, m, Bn), 7.06 (2H, tt, J = 6.9, 1.7 Hz, Bn), 3.37 (2H, s, Bn), 2.52 (2H, t, J= 1.4 Hz, H3), 2.46 (4H, s, H2). The other signal for the H3 protons is obscured by the THF signal.13C NMR (101 MHz, C6D6) be 139.9, 128.6, 128.5, 127.1, 58.1, 57.8, 52.3, 21.1.3-( / V-Allyl)aza[3.1.1]propellane (32)Prepared according to General Procedure 4, using 3-allyl-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 26 (224 mg, 0.759 mmol, 1.0 eq.) and nBuLi (0.643 mL, 1.18 M solution in hexanes, 0.759 mmol, 1.0 eq.). The mixture was stirred for 5 min. The product (5.0 mL, 0.16 M, 0.780 mmol, 100%) was obtained as a colourless solution. The concentration was determined using CH2CI2 as an internal standard.1H NMR (400 MHz, C6D6) bH5.74 (1H, ddt, J = 17.2, 10.1, 6.3 Hz, H5), 5.02 (1H, dq, J = 17.1, 1.7 Hz, H6), 4.90 (1H, ddt, J = 10.1, 2.2, 1.3 Hz, H6), 2.85 (2H, dt, J = 6.3, 1.4 Hz, H4), 2.54 (2H, t, J = 1.3 Hz, H3), 2.48 (4H, s, H2). The other signal for the H3 protons is obscured by the THF signal.13C NMR (101 MHz, C6D6) bc136.6, 115.8, 58.1, 56.6, 52.4, 33.4.3-( / V-Boc)aza[3.1.1]propellane (33)BocPrepared according to General Procedure 4, using 3-Boc-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 23 (443 mg, 1.25 mmol, 1.0 eq.) and nBuLi (1.19 mL, 1.05 M solution in hexanes, 1.25 mmol, 1.0 eq.). The mixture was stirred for 5 min. The product (6.6 mL, 0.14 M, 0.945 mmol, 76%) was obtained as a yellow solution. The concentration was determined using CH2CI2 as an internal standard.1H NMR (500 MHz, C6D6) bH3.49 (2H, s, H2), 3.29 (2H, s, H2), 2.07 (2H, t, J = 1.6 Hz, H3), 1.41 (9H, s, Boc). The other signal for the H3 protons is obscured by the THF signal.13C NMR (126 MHz, C6D6) be 153.5, 52.2, 51.4, 28.5, 22.7.3-( / V-Piv)aza[3.1.1 ]propellane (34)Prepared according to General Procedure 4, using 3-Piv-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 27 (300 mg, 0.885 mmol, 1.0 eq.) and MeLi (0.719 mL, 1.23 M solution in Et20, 0.885 mmol, 1.0 eq.). The mixture was stirred for 1 h. The product (5.5 mL, 0.12 M, 0.672 mmol, 76%) was obtained as a colourless solution. The concentration was determined by integrating the1H peaks in the product relative to the THF peaks.1H NMR (400 MHz, C6D6) 6H2.24 (2H, t, J= 1.6 Hz, H3), 1.47 (2H, t, J= 1.5 Hz, H3), 1.06 (9H, s, H6). The signal for H2 is obscured by the THF signal.13C NMR (101 MHz, C6D6) 6C175.8, 52.4, 51.6, 38.4, 28.3, 27.0.3-(A / -Pyridin-2-yl)aza[3.1.1]propellane (35)Prepared according to General Procedure 4, using 3-pyridin-2-yl-1-bromo-5-(bromomethyl)-3-azabicyclo[3.1.0]hexane 30 (237 mg, 0.715 mmol, 1.0 eq.) and MeLi (0.581 mL, 1.23 M solution in Et2O, 0.715 mmol, 1.0 eq.). The mixture was stirred for 1 h. The product (7.5 mL, 0.097 M, 0.727 mmol, 100%) was obtained as a pale yellow solution. The concentration was determined by integrating the1H peaks in the product relative to the THF peaks.1H NMR (400 MHz, C6D6) 6H8.15-8.11 (1H, m, Ar H), 7.13 (1H, m, Ar H), 6.35 (1H, ddd, J = 7.1, 5.0, 1.1 Hz, Ar H), 6.00-5.94 (1H, m, Ar H), 3.44 (4H, s, H2), 2.23 (2H, m, H3). The other signal from H3 is obscured by the THF signal.13C NMR (101 MHz, C6D6) 6C 157.5, 148.3, 136.2, 111.6, 106.3, 52.3, 51.5, 21.6.Ethyl 2-(3-benzyl-5-iodo-3-azabicyclo[3.1.1]heptan-1-yl)acetate (36)Prepared according to General Procedure 5, using 3-( / V-Benzyl)aza[3.1.1]propellane 31 (1.00 mL, 0.15 M, 0.150 mmol, 1.2 eq.), ethyl 2-iodoacetate (14.8 pL, 0.125 mmol, 1.0 eq.) and fac-lr(ppy)3(2.1 mg, 3.1 pmol, 2.5 mol%). The mixture was stirred and irradiated for 4 h. Purification by column chromatography (SiO2, pentane I EtOAc 19:1) gave the product (15.1 mg, 37.6 pmol, 30%) as a yellow oil.Rf 0.22 (19:1 pentane I EtOAc).1H NMR (500 MHz, CDCh) 6H7.35 - 7.29 (5H, m, Bn), 4.09 (2H, q, J = 7.1 Hz, H8), 3.65 (2H, s, Bn), 3.26 (2H, s, H2 / 3), 2.69 (2H, s, H2 / 3), 2.57-2.52 (2H, m, H5), 2.51 -2.45 (2H, m, H5), 2.37 (2H, s, H6), 1.22 (3H, t, J= 7.1 Hz, H9).13C NMR (126 MHz, CDCh) 6c 170.7, 138.3, 128.8, 128.5, 127.2, 66.5, 60.6, 60.0, 58.1, 50.8, 42.9, 42.8, 27.7, 14.4.IR (thin film, vmax / cm-1; selected peaks): 3027, 1738, 1494, 1336.HRMS (ES+) calc, for C17H23INO2[M+H]+400.0768, found 400.0756.Ethyl 2-(3-allyl-5-iodo-3-azabicyclo[3.1.1]heptan-1-yl)acetate (37)Prepared according to General Procedure 5, using 3-( / V-Allyl)aza[3.1.1]propellane 32 (0.750 mL, 0.16 M, 0.120 mmol, 1.2 eq.), ethyl 2-iodoacetate (11.8 pL, 0.100 mmol, 1.0 eq.) and fac-lr(ppy)3(1.6 mg, 2.5 pmol, 2.5 mol%). The mixture was stirred and irradiated for 4 h. Purification by column chromatography (SiO2, pentane I EtOAc 9:1) gave the product (20.4 mg, 58.4 pmol, 58%) as a colourless oil.Rf 0.28 (9:1 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H5.83 (1H, ddt, J= 16.7, 10.2, 6.5 Hz, H11), 5.19 (1H, dq, J = 17.2, 1.7 Hz, H12), 5.12 (1H, d, J= 10.2 Hz, H12), 4.11 (2H, q, J = 7.1 Hz, H8), 3.25 (2H, s, H2 / 3), 3.12 (2H, d, J = 6.5 Hz, H10), 2.68 (2H, s, H2 / 3), 2.48 (4H, s, H5), 2.39 (2H, s, H6), 1.24 (3H, t, J= 7.1 Hz, H9).13C NMR (101 MHz, CDCh) 6C170.7, 134.9, 117.8, 66.3, 60.6, 58.8, 58.0, 50.7, 43.0, 42.7, 27.6, 14.4.IR (thin film, vmax / cm-1; selected peaks): 2788, 1733, 1369, 1236, 1191.HRMS (ES+) calc, for C13H20INO2Na [M+Na]+372.0431, found 372.0431.tert-Butyl 1-(2-ethoxy-2-oxoethyl)-5-iodo-3-azabicyclo[3.1.1]heptane-3-carboxylate (38)BocPrepared according to General Procedure 5, using 3-( / V-Boc)aza[3.1.1]propellane 33 (0.900 mL, 0.14 M, 0.126 mmol, 1.2 eq.), ethyl 2-iodoacetate (12.4 pL, 0.105 mmol, 1.0 eq.) and fac-lr(ppy)3(1.7 mg, 2.6 pmol, 2.5 mol%). The mixture was stirred and irradiated for 4 h. Purification by column chromatography (SiO2, pentane I EtOAc 9:1) gave the product (18.3 mg, 44.8 pmol, 43%) as a colourless oil.Rf 0.23 (9:1 pentane I EtOAc).1H NMR (500 MHz, CDCh) 6H4.18 - 4.07 (2H, m, H8), 3.94 (s) and 3.91 (s) (2H, H2 / 3), 3.39 (s) and 3.38 (s) (2H, H2 / 3), 2.65 - 2.54 (2H, m, H5), 2.46 (s) and 2.45 (s) (2H, H6), 2.36 - 2.28 (2H, m, H5), 1.48 (s) and 1.46 (s) (9H, Boc), 1.30-1.23 (3H, m, H9)13C NMR (126 MHz, CDCh) 6C170.3, 170.2, 154.9, 154.9, 60.8, 59.2, 58.9, 51.8, 51.6, 49.0, 48.9, 42.2, 42.1, 41.2, 41.2, 28.6, 28.6, 24.6, 23.8, 14.4.Note: the1H and13C spectra show additional peaks due to the presence of rotamers. IR (thin film, Vmax / crn’1; selected peaks): 2978, 1734, 1694, 1385, 1167.HRMS (ES+) calc, for C15H24INO4Na [M+Na]+432.0642, found 432.0638.Ethyl 2-(5-iodo-3-pivaloyl-3-azabicyclo[3.1.1]heptan-1-yl)acetate (39)Prepared according to General Procedure 5, using 3-( / V-Piv)aza[3.1.1]propellane 34 (1.00 mL, 0.12 M, 0.120 mmol, 1.2 eq.), ethyl 2-iodoacetate (11.8 pL, 0.100 mmol, 1.0 eq.) and fac-lr(ppy)3(1.6 mg, 2.5 pmol, 2.5 mol%). The mixture was stirred and irradiated for 4 h. Purification by column chromatography (SiO2, pentane I EtOAc 8:2) gave the product (21.3 mg, 54.2 pmol, 54%) as a yellow oil.Rf 0.26 (8:2 pentane I EtOAc).1H NMR (600 MHz, CDCh) 6H4.18 (2H, s, H2 / 3), 4.13 (2H, q, J= 7.1 Hz, H8), 3.66 (2H, s, H2 / 3), 2.62-2.55 (2H, m, H5), 2.47 (2H, s, H6), 2.35-2.29 (2H, m, H5), 1.29 (9H, s, H12), 1.25 (3H, t, J= 7.1 Hz, H9).13C NMR (151 MHz, CDCh) 6c 177.4, 170.2, 60.9, 60.5, 53.1, 49.0, 42.8, 42.2, 41.6, 39.6, 28.2, 14.4.IR (thin film, vmax / cm-1; selected peaks): 2977, 1731, 1627, 1358, 1188.HRMS (ES+) calc, for C15H25INO3[M+H]+394.0874, found 394.0868.Ethyl 2-(5-iodo-3-(pyridin-2-yl)-3-azabicyclo[3.1.1]heptan-1-yl)acetate (40)Prepared according to General Procedure 5, using 3-( / V-pyridin-2-yl)aza[3.1.1]propellane 35 (1.01 mL, 0.097 M, 98.4 pmol, 1.2 eq.), ethyl 2-iodoacetate (9.71 pL, 82.0 pmol, 1.0 eq.) and fac-lr(ppy)3(1.3 mg, 2.1 pmol, 2.5 mol%). The mixture was stirred and irradiated for 4 h. Purification by column chromatography (SiO2, pentane I EtOAc 8:2) gave the product (16.9 mg, 43.8 pmol, 53%) as a yellow oil.Rf 0.37 (8:2 pentane I EtOAc).1H NMR (400 MHz, CDCh) 6H8.21 (1H, dd, J= 4.9, 1.9 Hz, Ar H), 6.64 (1H, dd, J= 7.1, 4.9 Hz, Ar H), 6.48 (1H, d, J= 8.6 Hz, Ar H), 4.15 (2H, q, J= 7.2 Hz, Ar H), 4.07 (2H, s, H2 / 3), 3.54 (2H, s, H2 / 3), 2.73-2.68 (2H, m, H5), 2.57 (2H, s, H6), 2.49 - 2.38 (2H, m, H5), 1.27 (3H, t, J= 7.1 Hz, H9).13C NMR (101 MHz, CDCh) 6c 170.4, 157.1, 148.0, 137.4, 112.7, 105.2, 60.8, 60.3, 52.8, 49.5, 42.3, 41.6, 25.1, 14.4.IR (thin film, vmax / cm-1; selected peaks): 2980, 1731, 1598, 1474, 1372.HRMS (ES+) calc, for C15H20IN2O2 [M+H]+387.0564, found 387.0572.References1. Dasgupta, A. et a / ., Triarylborane-Catalyzed Carbene Transfer Reaction of a- Diazoesters: Benzylic Alkenylation of Aryl-Alkynyl Esters. Angew. Chem. Int. Ed., 59, 15492 (2020).2. Nugent, J. et al., a-Amino Bicycloalkylation through Organophotoredox Catalysis.Chem. Sc / ., 15, 10918 (2024).3. Pickford, H. et al., Twofold Radical-Based Synthesis of A / , C-Difunctionalized Bicyclo[1.1.1]pentanes, J. Am. Chem. Soc. 143, 9729 (2021).4. Pickford, H. et al., Rapid and Scalable Halosulfonylation of Strain-Release Reagents. Angew. Chem. Int. Ed., 62, e202213508 (2023).

[0099] Numbered embodiments1. A process for the preparation of a compound of formula 1:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi wherein R5, R6and R7are all H.2. The process according to embodiment 1 wherein X1is O or NR1, further comprising the step of:(ii) reactingoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine or CBr4and triphenylphosphine, more preferably in the presence of N-bromo succinimide and triphenylphosphine where X1is O orCBr4and triphenylphosphine where X1is NR1.3. The process according to embodiment 2 wherein X1is O, further comprising the step of:presence of a hydroxide source, preferably in the presence of potassium hydroxide.4. The process according to embodiment 3 wherein X1is O, further comprising the step of:(iv)optionally wherein the reaction occurs in the presence of a reducing agent, for example LiAlH4, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride.5. The process according to embodiment 4 wherein X1is NR1, further comprising the step of:(V) reactingpreferably wherein the reaction occurs in the presence of sulfonyl chloride and an amine base, more preferably in the presence of tosyl chloride and an amine base, yet more preferably in the presence of tosyl chloride and triethylamine.6. The process according to embodiment 5 wherein X1is NR1, further comprising the step of:preferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of sodium bis(2-methoxyethoxy)aluminium hydride.7. The process according to embodiment 6 wherein X1is NR1, further comprising the step of:(vii) reactingpreferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of a phosphine, even more preferably in the presence of PBu38. The process according to embodiment 7 wherein X1is NR1, further comprising the step of:preferably wherein the reaction occurs in the presence of a metal azide, more preferably in the presence of sodium azide.9. The process according to embodiment 1 wherein X1is NR1, further comprising the step of:optionally wherein the reaction occurs in the presence of a nitrogen deprotecting reagent, preferably in the presence of trifluoroacetic acid.10. The process according to embodiment 9 wherein X1is NR1, further comprising the step of:(x) reactingoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.11. The process according to embodiment 10 wherein X1is NR1, further comprising the step of:(xi)optionally wherein the reaction occurs in the presence of a reducing agent, preferably in the presence of diisobutylaluminium hydride.12. The process according to embodiment 1 wherein X1is S, further comprising the step of:optionally wherein the reaction occurs in the presence of a hydroxide source, preferably in the presence of potassium hydroxide.13. The process according to embodiment 12 wherein X1is S, further comprising the step of:(xiii)optionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.14. The process according to embodiment 13 wherein X1is S, further comprising the step of:optionally wherein the reaction occurs in the presence of an amine base, preferably in the presence of triethylamine, more preferably in the presence of potassium thioacetate, most preferably in the presence of potassium thioacetate and triethylamine.15. The process according to embodiment 14 wherein X1is S, further comprising the step of:(xv)optionally wherein the reaction occurs in the presence of a reducing agent, for example LiAlH4, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride.16. The process of any one of embodiments 1-15, further comprising the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III).17. The process according to any one of embodiments 1-16 wherein compound of formula 1 is obtained in step (i) in a purity of 85 mol% or higher, 90 mol% or higher, 95 mol% or higher, or 98 mol% or higher.18. The process according to any one of embodiments 1-17 wherein the yield of formula 1 in step (i) is 50 % or higher, 60 % or higher, or 70 % or higher.19. A process for the preparation of a compound of the structure:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III).20. The process of embodiment 19, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.21. The process of embodiment 19, wherein X1= NR1and R1is Bn.22. The process of embodiment 19, wherein X1is O.23. The process of embodiment 19, wherein X1is S.24. A compound having a structure selected from:wherein X1= O, NR1, S, SO, or SO2;each R1is each, independently, SO2R2, Bn, COCF3, COC(CH3)3, CO(1,3,5-trimethylphenyl), CO2OBn, C(C6Hs)3, CO2OtBu, 2-pyridine or allyl;R2is Me, Ph, 4-methoxyphenyl, 2-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 2-nitrophenyl, or 2-trimethylsilylethanyl, C6-C10 aryl, 5 to 10 membered heteroaryl, C1-C10 alkyl;R3is an acyl group, a C1-C10 acyl group, a benzoyl group or acetyl;R4is a C1-C10 alkyl group, C6-C10aryl group, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl or cyclohexyl;R5, R6and R7are all H;X2is each, independently, Cl, Br, or I;X3is each, independently, absent or =0;R8is optionally substituted benzyl, benzyl, substituted amine, alkyl, aryl, heteroalkyl,R9is Br, I, H, 4-tetrahydropyranyl, boronic ester, BO2C2(CH3)4, BF3K, S(2-pyridyl).25. The compound of embodiment 24, wherein R4is Me.26. The compound of embodiment 24 or 25, wherein X2is Br.27. The compound of any one of embodiments 24-26, wherein X1= NR1and R1is each, independently, (4-methylphenyl)sulfonyl, Bn, or CO2OtBu.28. The compound of any one of embodiments 24-26, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.29. The compound of any one of embodiments 24-26, wherein X1= NR1and R1is Bn.30. The compound of any one of embodiments 24-26, wherein X1is O.31. The compound of any one of embodiments 24-26, wherein X1is S.32. The compound according to any one of embodiments 24-31 having a structure0133. The compound according to any one of embodiments 24-32 having a structure selected from:34. The compound according to any one of embodiments 24-33 having a structure selected from:The compound according to any one of embodiments 24-34 having a structure selected from:49. Use of a process according to any one of embodiments 1-23 or a compound according to any one of embodiments 24-34 in the preparation of a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted aryl bioisostere, more preferably wherein the use is as a metasubstituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

Claims

CLAIMS1. A compound having a structure selected from:wherein X1= O, NR1, S, SO, or SO2;each R1is each, independently, SO2R2, Bn, COCF3, COC(CH3)3, CO(1,3,5-trimethylphenyl), CO2OBn, C(C6H5)3, CO2OtBu, 2-pyridine or allyl;R2is Me, Ph, 4-methoxyphenyl, 2-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-nitrophenyl, 2-nitrophenyl, or 2-trimethylsilylethanyl, C6-C10aryl, 5 to 10 membered heteroaryl, C1-C10 alkyl, optionally substituted aryls, optionally substituted phenyl;R3is an acyl group, a C1-C10 acyl group, a benzoyl group or acetyl;R4is a C1-C10 alkyl group, C6-C10aryl group, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl or cyclohexyl;R5is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R5groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R6is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, Ce-Cw aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3,CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe, or two R6groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;R7is each, independently, H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 fluoroalkyl, C2-C10 fluoroalkenyl, C2-C10 fluoroalkynyl, C3-C10 cycloalkyl, C3-C10 cyclofluoroalkyl, C1-C10 heteroalkyl, C2-C10 heteroalkenyl, C2-C10 heteroalkynyl, C3-C10 heterocyclyl, C3-C10 heterocyclenyl, C6-C10 aryl, 5 to 10 membered heteroaryl, benzyl, phenyl, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CFS)2, CHCH3CF3, CFWMe, or two R7groups on an adjacent carbon atom, together with the adjacent carbon atom, form a heterocyclic ring or a carbocyclic ring, for example a C3-C10 cycloalkyl ring, a C3-C10 cyclofluoroalkyl ring, C3-C10 heterocyclyl ring, cyclopentyl or cyclohexyl ring;X2is each, independently, Cl, Br, or I;X3is each, independently, absent or =0.

2. The compound according to claim 1 wherein:(a) R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(b) R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(c) R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(d) R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(e) R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(f) R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe; or(g) R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

3. The compound of claim 1 or 2 wherein:(a) R5is H;(b) R6is H;(c) R7is H;(d) R5and R6are H;(e) R5and R7are H;(f) R6and R7are H; or(g) preferably R5, R6and R7are H.

4. The compound of any one of claims 1-3, wherein R4is Me.

5. The compound of any one of claims 1-4, wherein X2is Br.

6. The compound of any one of claims 1-5, wherein X1= NR1and R1is each, independently, (4-methylphenyl)sulfonyl, Bn, or CO2OtBu.

7. The compound of any one of claims 1-6, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.

8. The compound of any one of claims 1-6, wherein X1= NR1and R1is Bn.

9. The compound of any one of claims 1-5, wherein X1is O.

10. The compound of any one of claims 1-5, wherein X1is S.

11. The compound according to any one of claims 1-10 having a structure selected from:

12. The compound according to any one of claims 1-11 having a structure selected from:

13. The compound according to any one of claims 1-12 having a structure selected from:

14. The compound according to any one of claims 1-13 having a structure selected from:

15. A process for the preparation of a compound of formula 1:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi.

16. The process according to claim 15 wherein X1is O or NR1, further comprising the step of:optionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine or CBr4 and triphenylphosphine, more preferably in the presence of N-bromo succinimide and triphenylphosphine where X1is O or CBr4and triphenylphosphine where X1is NR1.

17. The process according to claim 16 wherein X1is O, further comprising the step of:presence of a hydroxide source, preferably in the presence of potassium hydroxide.

18. The process according to claim 17 wherein X1is O, further comprising the step of:(iv)optionally wherein the reaction occurs in the presence of a reducing agent, for example LiAlH4, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride.

19. The process according to claim 16 wherein X1is NR1, further comprising the step of:preferably wherein the reaction occurs in the presence of sulfonyl chloride and an amine base, more preferably in the presence of tosyl chloride and an amine base, yet more preferably in the presence of tosyl chloride and triethylamine, or tosyl chloride and sodium carbonate.

20. The process according to claim 19 wherein X1is NR1, further comprising the step of:preferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of sodium bis(2-methoxyethoxy)aluminium hydride.

21. The process according to claim 20 wherein X1is NR1, further comprising the step of:(vii) reactingpreferably wherein the reaction occurs in the presence of a reducing agent, more preferably in the presence of a phosphine, even more preferably in the presence of PBu3.

22. The process according to claim 21 wherein X1is NR1, further comprising the step of:preferably wherein the reaction occurs in the presence of a metal azide, more preferably in the presence of sodium azide.

23. The process according to claim 15 wherein X1is NR1, further comprising the step of:optionally wherein the reaction occurs in the presence of a nitrogen deprotecting reagent, preferably in the presence of trifluoroacetic acid.

24. The process according to claim 23 wherein X1is NR1, further comprising the step of:(x) reactingoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.

25. The process according to claim 24 wherein X1is NR1, further comprising the step of:optionally wherein the reaction occurs in the presence of a reducing agent, preferably in the presence of diisobutylaluminium hydride.

26. The process according to claim 15 wherein X1is S, further comprising the step of:optionally wherein the reaction occurs in the presence of a hydroxide source, preferably in the presence of potassium hydroxide.

27. The process according to claim 26 wherein X1is S, further comprising the step of:(xiii) reactingoptionally wherein the reaction occurs in the presence of a phosphine and a bromine source, preferably in the presence of N-bromo succinimide and triphenylphosphine.

28. The process according to claim 27 wherein X1is S, further comprising the step of:optionally wherein the reaction occurs in the presence of an amine base, preferably in the presence of triethylamine, more preferably in the presence of potassium thioacetate, most preferably in the presence of potassium thioacetate and triethylamine.

29. The process according to claim 28 wherein X1is S, further comprising the step of:(xv) reactingoptionally wherein the reaction occurs in the presence of a reducing agent, for example LiAlH4, LiBH4, NaBH4, or diisobutylaluminium hydride, preferably in the presence of diisobutylaluminium hydride.

30. The process of any one of claims 15-29, wherein:(a) R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(b) R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(c) R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(d) R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(e) R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(f) R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe; or(g) R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

31. The process of any one of claims 15-30, wherein:(a) R5is H;(b) R6is H;(c) R7is H;(d) R5and R6are H;(e) R5and R7are H;(f) R6and R7are H; or(g) preferably R5, R6and R7are H.

32. The process of any one of claims 15-31, wherein R4is Me.

33. The process of any one of claims 15-32, wherein X2is Br.

34. The process of any one of claims 15-33, wherein X1= NR1and R1is each, independently, (4-methylphenyl)sulfonyl, Bn, or CO2OtBu.

35. The process of any one of claims 15-34, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.

36. The process of any one of claims 15-34, wherein X1= NR1and R1is Bn.

37. The process of any one of claims 15-33, wherein X1is O.

38. The process of any one of claims 15-33, wherein X1is S.

39. The process of any one of claims 15-38, further comprising the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III), or 4CzIPN.

40. The process according to any one of claims 15-39 wherein compound of formula 1 is obtained in step (i) in a purity of 85 mol% or higher, 90 mol% or higher, 95 mol% or higher, or 98 mol% or higher.

41. The process according to any one of claims 15-40 wherein the yield of formula 1 in step (i) is 50 % or higher, 60 % or higher, or 70 % or higher.

42. A process for the preparation of a compound of the structure:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of a radical initiator, preferably in the presence of Et3B or fac-tris(2-phenylpyridine)iridium(III).

43. The process of claim 42 wherein:(a) R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(b) R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(c) R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(d) R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(e) R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(f) R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe; or(g) R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

44. The process of claim 42 or 43 wherein:(a) R5is H;(b) R6is H;(c) R7is H;(d) R5and R6are H;(e) R5and R7are H;(f) R6and R7are H; or(g) preferably R5, R6and R7are H.

45. The process of any one of claims 42-44, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.

46. The process of any one of claims 42-44, wherein X1= NR1and R1is Bn.

47. The process of any one of claims 42-44, wherein X1is O.

48. The process of any one of claims 42-44, wherein X1is S.

49. A process for the preparation of a compound of formula 1:wherein the process comprises the step of:optionally wherein the reaction occurs in the presence of an organolithium reagent, preferably in the presence of nBuLi or MeLi, more preferably in the presence of MeLi; preferably wherein X2are each I or each Br, more preferably wherein X2is each I.

50. The process of claim 49 wherein:(a) R5is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(b) R6is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(c) R7is each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(d) R5and R6are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(e) R5and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe;(f) R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe; or(g) R5, R6and R7are each, independently, H, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl, hexyl, F, CH2F, CHF2, CF3, CH2CF3, CF2CF3, CH(CF3)2, CHCH3CF3, CH2OMe.

51. The process of claim 49 or 50 wherein:(a) R5is H;(b) R6is H;(c) R7is H;(d) R5and R6are H;(e) R5and R7are H;(f) R6and R7are H; or(g) preferably R5, R6and R7are H.

52. The process of any one of claims 49-51, wherein X1= NR1and R1is (4-methylphenyl)sulfonyl.

53. The process of any one of claims 49-51, wherein X1= NR1and R1is Bn.

54. The process of any one of claims 49-51, wherein X1is O.

55. The process of any one of claims 49-51, wherein X1is S.

56. Use of a compound according to any one of claims 1 to 14 or a process according to any one of claims 15 to 55 in the preparation of a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a metasubstituted aryl bioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

57. Use of a 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety, or 3-thiabicyclo[3.1.1]heptane moiety in a pharmacologically active compound, optionally wherein the use is as a bioisostere, preferably wherein the use is as a meta-substituted arylbioisostere, more preferably wherein the use is as a meta-substituted phenyl bioisostere or 3,5-disubstituted pyridine bioisostere.

58. The use of claim 57 wherein the 3-oxabicyclo[3.1.1]heptane moiety, 3-azabicyclo[3.1.1]heptane moiety, or 3-thiabicyclo[3.1.1]heptane moiety is covalently bonded to the rest of the pharmacologically active compound at one or both of the bridgehead atoms of the heterobicyclo[3.1.1]heptane moiety.

59. The use of claim 57 or 58 wherein the use comprises reacting 3-oxatricyclo[3.1.1.01’5]heptane, 3-azatricyclo[3.1.1.01’5]heptane, an N-substituted analogue of 3-azatricyclo[3.1.1.01’5]heptane, or 3-thiatricyclo[3.1.1.01’5]heptane to form the 3-oxabicyclo[3.1.1]heptane moiety, 3-oxabicyclo[3.1.1]heptane moiety, or 3-oxabicyclo[3.1.1]heptane moiety.

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