Process for the synthesis of polyhalogenated alkaloids caulamidines and isocaulamidines

Abstract

The application discloses a synthesis method of a multi-halogenated alkaloid Caulamidines and Isocaulamidines, and the synthesis method comprises the following steps: taking a thujanol derivative as raw material, and performing a series of synthesis and separation operations, and then performing an asymmetric Meerwein- Eschenmoser-Claisen rearrangement to build C10 and C23 continuous key stereogenic centers, and finally realizing a 6-exo-dig / 6-exo-tet amine / cyan group tandem cyclization reaction, so that the multi-halogenated alkaloid Caulamidines and Isocaulamidines are obtained. The synthesis method can be amplified, and can be used to solve the 'drug source bottleneck' problem of natural samples and homologues thereof in future drug research.

Description

Technical Field

[0001] The present invention relates to an organic chemical total synthesis method, in particular to a synthesis method of polyhalogenated alkaloids Caulamidines and Isocaulamidines. Background Art

[0002] Gastropods (Coleoptera) are a very important group of marine invertebrates because they provide structurally interesting and biologically promising secondary metabolites. The incorporation of halogens is a unique strategy used by marine organisms to decorate their versatile metabolic compounds, often resulting in altered biological activities.

[0003]

[0004] As shown above, the polyhalogenated alkaloids Caulamidines B–D (compounds 1, 3, and 5) and Isocaulamidines B–D (compounds 2, 4, and 6) have been isolated by Gustafson and colleagues from the gastropod Polyandrocarp asp. near Palau. Compared to the previously reported Caulamidine A (compound 7) and trace amounts of Caulamidine B isolated from the bryozoan Caulibugula intermis, the gastropod-derived homologs exhibit a more extensive halogenation pattern and isomerization of the amine sequence on the DEF ring in Isocaulamidines B–D. Importantly, these natural compounds exhibit selective inhibition against chloroquine-resistant Plasmodium falciparum strains at low micromolar concentrations and exhibit moderate cytotoxicity in NCI-60 cell screening. Their unprecedented molecular structure and excellent biological activity have made (Iso)caulamidines promising candidates for antimalarial drugs, attracting widespread attention from the synthetic and pharmaceutical communities. However, the amount of polyhalogenated alkaloids isolated is extremely small and cannot meet the research needs. Therefore, how to obtain polyhalogenated alkaloids through chemical synthesis is the focus of the next study.

[0005] Caulamidines B–D possess an asymmetric, multi-ring skeleton, which renders the previous asymmetric strategy based on dimerization of two tryptamines followed by functional group reassembly unfeasible. Structurally, these caulamidines share a hydrogenated 2,6-naphthyridine core, an indole unit, and a quinoline fragment, forming a novel alkaloid with two six-carbon rings. They possess adjacent quaternary carbon stereocenters at C10 and C23. The multiple cyclic skeleton exacerbates their synthetic difficulty. Furthermore, the chiral chlorine at the neopentyl C11 carbon further complicates the synthetic challenge of caulamidin, as stereocontrol of electrophilic and / or radical chlorination is not a trivial task. Therefore, the synthesis of polyhalogenated alkaloids remains an urgent challenge. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a method for synthesizing polyhalogenated alkaloids Caulamidines and Isocaulamidines, so that Caulamidines and Isocaulamidines can be obtained simultaneously using the same method, which can solve the "drug source bottleneck problem" of natural samples and homologues in future drug research.

[0007] To achieve the above object, the technical solution of the present invention is as follows:

[0008] The synthesis method of polyhalogenated alkaloids Caulamidines and Isocaulamidines comprises the following steps:

[0009] In the first step, starting from compound 8, intermediate 10 was obtained by addition elimination, and then

[0010] Chiral intermediate 11 was synthesized under Meerwein-Eschenmoser-Claisen rearrangement conditions; then, the Boc protecting group was removed to obtain indole compound 12.

[0011] In the second step, the indole compound 12 was treated with Red-Al to construct a piperidine ring, and the only compound isolated was compound 13;

[0012] In the third step, compound 13 was subjected to ozonolysis, and the resulting aldehyde was directly condensed with hydroxylamine, and finally dehydrated under the action of perfluorobutanesulfonyl fluoride and DBU to obtain cyanide 14;

[0013] In the fourth step, 2-nitro-4-bromobenzyl bromide was used to selectively benzylate compound 14 at C23 to achieve the construction of the adjacent quaternary carbon to obtain compound 15 and its isomer epi-20;

[0014] In the fifth step, the TIPS protecting group of compound 15 is removed and the hydroxyl group is oxidized to obtain compound 16;

[0015] In the sixth step, compound 16 undergoes L-proline and NCS-mediated electrophilic chlorination to obtain compound 17 and its isomer epi-17;

[0016] In the seventh step, compound 17 was treated with iron as a reducing agent to convert -NO2 into a nucleophilic -NH2 group via the 6-exo-dig / 6-exo-tet pathway, yielding the hexacyclic compound 18 and the minor compound 19.

[0017] In the eighth step, the hexacyclic compound 18 is methylated to obtain compounds 5 and 6, which are polyhalogenated alkaloids (-)-Caulamidine D and (-)-Isocaulamidine D, respectively;

[0018] The specific reaction process is as follows:

[0019]

[0020] In the above scheme, the obtained (-)-Caulamidine D and (-)-Isocaulamidine D are brominated at the C6 position of the indole ring to obtain compounds 1 and 2, respectively, which are polyhalogenated alkaloids (-)-Caulamidine B and (-)-Isocaulamidine B;

[0021] The specific reaction process is as follows:

[0022]

[0023] A method for synthesizing polyhalogenated alkaloids Caulamidines and Isocaulamidines, characterized by comprising the following steps:

[0024] In the first step, starting from compound 8, intermediate 10 was obtained by addition elimination, and then

[0025] Chiral intermediate 11 was synthesized under Meerwein-Eschenmoser-Claisen rearrangement conditions; then, the Boc protecting group was removed to obtain indole compound 12.

[0026] In the second step, the indole compound 12 was treated with Red-Al to construct a piperidine ring, and the only compound isolated was compound 13;

[0027] In the third step, compound 13 was subjected to ozonolysis, and the resulting aldehyde was directly condensed with hydroxylamine, and finally dehydrated under the action of perfluorobutanesulfonyl fluoride and DBU to obtain cyanide 14;

[0028] In the fourth step, 2-nitrobenzyl bromide was used to selectively benzylate compound 14 at C23 to achieve the construction of the adjacent quaternary carbon to obtain compound 15' and its isomer epi-15';

[0029] The fifth step is to remove the TIPS protecting group of compound 15' and oxidize the hydroxyl group to obtain compound 16';

[0030] In the sixth step, compound 16' undergoes L-proline and NCS-mediated electrophilic chlorination to obtain compound 17' and its isomer epi-17';

[0031] In the seventh step, compound 17' was treated with iron as a reducing agent to convert -NO2 into a nucleophilic -NH2 group via the 6-exo-dig / 6-exo-tet pathway to obtain the hexacyclic compound 18';

[0032] In the eighth step, the hexacyclic compound 18' is methylated to obtain compound 20, and then C7 and C19 of compound 20 are dichlorinated to obtain compound 7, i.e., polyhalogenated alkaloid caulamidine A;

[0033] The specific reaction process is as follows:

[0034]

[0035] In the above scheme, in the first step, compound 8 and MS was dissolved in DCM and cooled to 0°C, and then DABCO was added, followed by recrystallized NCS, and the mixture was stirred at 0°C for 2 h. Compound 9, MsOH, and DCM were added, and the mixture was stirred at 0°C for 1 h to obtain inseparable compound 10. The reaction was continued at room temperature for 24 h. The reaction solution was filtered through a sand-core funnel containing diatomaceous earth, rinsed with DCM, and the filtrate was collected and concentrated in vacuo to obtain the crude product indole compound 11;

[0036] Indole compound 11 was added to DCM at -40°C, and 2,6-Lutdine and TMSOTf were added. The mixture was stirred at the same temperature for 3 h, and then H2O was added. The mixture was extracted with DCM and finally washed with brine, dried over MgSO4, and the filtrate was evaporated in vacuo. Compound 12 was obtained by column chromatography.

[0037] In the second step, toluene and compound 12 were added to a dry round-bottom flask, and the reaction was placed at 0°C. Red-Al was then added and the reaction was stirred at room temperature for 12 hours. MeOH and saturated aqueous potassium sodium tartrate were then added and extracted with ethyl acetate. The mixture was washed with brine, the organic layer was dried, and the filtrate was evaporated in vacuo. Compound 13 was obtained by column chromatography.

[0038] In the above scheme, in the third step, CSA is added to a DCM solution containing compound 13 at 0°C, the resulting reaction mixture is further cooled to -78°C, and ozone is introduced into the reaction system until a blue color persists; until TLC shows complete consumption of the starting material, MeOH is added, followed by dimethyl sulfide, the reaction mixture is warmed to 0°C, and stirred for 15 minutes, at which point saturated aqueous sodium bicarbonate is added, and the two-phase mixture is stirred for 4 hours. The aqueous layer is extracted with ethyl acetate at room temperature, the organic layer is collected and dried over anhydrous MgSO4, and the solvent is removed by rotary evaporation to obtain the crude product S1;

[0039] The crude product S1 was dissolved in MeOH (120 ml), and NH2OH·HCl and AcONa were added at 0°C. The reaction was stirred at room temperature overnight, and then a saturated aqueous NaHCO3 solution was added. The mixture was extracted with DCM and washed with brine. The organic layer was collected and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation to obtain the crude product S2.

[0040] The crude product S2 was dissolved in DCM, and the reaction was placed at 0°C. DBU and n-C4F9SO2F were then added, and the reaction was stirred at room temperature for 10 minutes. Saturated aqueous NaHCO3 was then added, extracted with DCM, and washed with brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Compound 14 was obtained by column chromatography.

[0041] In the above scheme, in the fourth step, compound 14 is added to THF at -78°C, followed by the addition of LDA, and the reaction flask is stirred at -78°C for 1 hour. 2-NO2-4-Br-BnBr is then added to the reaction system, and the reaction mixture is stirred at room temperature for 1-2 hours; saturated aqueous NH4Cl solution is then added, extracted with ethyl acetate, and washed with brine; the combined organic layer is dried over anhydrous MgSO4, and the filtrate is evaporated in vacuo; column chromatography yields compounds 15 and epi-15;

[0042] In the fifth step, compound 15 was added to THF, and TBAF was added at 0°C. The reaction flask was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl solution was then added, extracted with ethyl acetate, and washed with brine. The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S3.

[0043] A dry round bottom flask was prepared and protected with nitrogen, oxalyl chloride and DCM were added to the flask, the flask was cooled to -78°C, DMSO was slowly added to the system, after the reaction was stirred at -78°C for 20 min, DCM containing crude product S3 was added dropwise, stirring was continued at -78°C for 1 h, triethylamine was slowly added, then the reaction was heated to room temperature, quenched with H2O, extracted with ethyl acetate, the organic extract was collected and washed with brine, and dried over anhydrous MgSO4, the organic extract was concentrated under reduced pressure, and compound 16 was obtained by silica gel column chromatography.

[0044] In the above scheme, in the sixth step, l-proline and NCS were added to a solution of compound 16 stirred at 0°C in DCM and Et2O, the reaction bottle was stirred at 5°C for 2 hours, then MeOH and NaBH4 were added, the reaction bottle was stirred at room temperature for 2 hours, then saturated aqueous NH4Cl was added, extracted with DCM, washed with brine, the combined organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuum to obtain crude product S4;

[0045] The crude product S4 was dissolved in DCM, Et3N and MsCl were added at 0°C, stirred at room temperature for 30 min, then saturated aqueous NaHCO3 was added, extracted with DCM, washed with brine, the organic layer was collected, dried over anhydrous MgSO4, and the filtrate was evaporated in vacuum, and compound 17 and its isomer epi-17 were obtained by column chromatography; in the seventh step, compound 17 was added to iron powder in EtOH and saturated NH4Cl solution under stirring at room temperature, the mixture was stirred at 90°C for 3 hours; then saturated NaHCO3 was added, extracted with DCM, washed with brine; the organic phases were combined and dried over NaSO4, separated and purified by column chromatography with silica gel to obtain compound 18 and compound 19.

[0046] In the above scheme, in the eighth step, NaH was added to a DMF solution containing compound 18, the reaction was stirred at 0°C for 5 min, then MeI was slowly added dropwise, the reaction mixture was stirred at room temperature for 30 min; then saturated aqueous NH4Cl was added, extracted with ethyl acetate, washed with H2O and brine; the organic layer was collected, dried over anhydrous MgSO4, and the filtrate was evaporated in vacuum, and compound 5 and compound 6 were obtained by column chromatography;

[0047] In the ninth step, PPh3S and NBS were added to DCM solutions containing compounds 5 and 6 respectively, the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, washed with brine; the organic phases were combined and dried over NaSO4, separated and purified by column chromatography with silica gel to obtain compounds 1 and 2 respectively.

[0048] In the above scheme, in the fourth step, compound 14 is added to THF at -78°C, followed by the addition of LDA, and the reaction flask is stirred at -78°C for 1 hour. 2-NO2BnBr is then added to the reaction system, and the reaction mixture is stirred at room temperature for 1-2 hours. Saturated aqueous NH4Cl solution is then added, extracted with ethyl acetate, and washed with brine. The combined organic layer is dried over anhydrous MgSO4, and the filtrate is evaporated in vacuo. Column chromatography affords compounds 15' and epi-15'.

[0049] In the fifth step, compound 15' was added to THF, and then TBAF was added at 0°C. The reaction flask was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl solution was then added, and the mixture was extracted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S3'.

[0050] Prepare a dry round-bottom flask and protect it with nitrogen. Add oxalyl chloride and DCM to the flask, cool the flask to -78°C, slowly add DMSO dropwise to the system, stir the reaction at -78°C for 20 minutes, then add DCM containing the crude product S3' dropwise, continue stirring at -78°C for 1 hour, slowly add triethylamine, then warm the reaction to room temperature, quench with H2O, extract with ethyl acetate, collect the organic extracts and wash with brine, and dry over anhydrous MgSO4. The organic extracts are concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 16'.

[0051] In the above scheme, in the sixth step, l-proline and NCS were added to a solution of compound 16′ in DCM and Et2O, stirred at 0°C, and the reaction flask was stirred at 5°C for 2 hours, and then MeOH and NaBH4 were added. The reaction flask was stirred at room temperature for 2 hours, and then a saturated NH4Cl aqueous solution was added, extracted with DCM, washed with brine, and the combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain a crude product S4′;

[0052] The crude product S4' was dissolved in DCM, Et3N and MsCl were added at 0°C, stirred at room temperature for 30 minutes, then saturated aqueous NaHCO3 solution was added, extracted with DCM, washed with brine, the organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography gave compound 17 and its isomer epi-17;

[0053] In the seventh step, compound 17' was dissolved in EtOH and saturated NH4Cl solution, and iron powder was added under stirring at room temperature. The mixture was stirred at 90°C for 3 hours. Saturated NaHCO3 was then added, extracted with DCM, and washed with brine. The organic phase was combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compound 18'.

[0054] In the eighth step, NaH was added to a DMF solution containing compound 18', and the reaction was stirred at 0°C for 5 minutes. Then, MeI was slowly added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate and washed with H2O and brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo and purified by column chromatography to obtain compound 20.

[0055] PPh3S and NCS were added to the DCM solution containing compound 20, and the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compound 7.

[0056] Through the above technical solution, the present invention provides a method for synthesizing polyhalogenated alkaloids Caulamidines and Isocaulamidines, which has the following beneficial effects:

[0057] The method of the present invention completes the enantioselective total synthesis of (-)-Caulamidine D and its homolog Isocaulamidine D for the first time, simultaneously determining their absolute configurations. A key finding from comparing NMR data is that the natural sample of (Iso)caulamidine D is a TFA salt. Using a unified strategy, only 13 synthetic steps (including only 8 isolations) are required to obtain the natural compound (-)-Caulamidine D and its homolog Isocaulamidine D.

[0058] Single crystals of the synthesized natural compounds 5 and 6 were successfully grown, and their structures were clearly confirmed by X-ray crystallography. The optical rotation values ​​determined by polarimetry were [α] 20 D -60(c 0.05,DCM) and [α] 20 D -62 (c0.01, MeOH) compared to [α] 20 D -59(c 0.10,DCM) and [α] 20 D-60(c0.02, MeOH) vs. 5 and 6. These data correlated well, thus elucidating the absolute configuration of 5 and 6. Meanwhile, the construction of the key core skeleton of Caulamidine A, Caulamidine B, Isocaulamidine B and Caulamidine C, Isocaulamidine C were also accomplished by the above-mentioned method.

[0059] The key reactions include: 1) development and application of asymmetric Meerwein-Eschenmoser-Claisen rearrangement to construct the C10, C23 continuous key stereogenic center; 2) propose and realize the 6-exo-dig / 6-exo-tet amine / cyan group tandem cyclization strategy. The scalability of this synthetic route can solve the "supply problem" of these natural samples in future drug research. DETAILED DESCRIPTION

[0060] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner.

[0061] Embodiment 1

[0062] The present application provides a synthetic method of polyhalogenated alkaloids Caulamidines and Isocaulamidines, and the specific method is as follows:

[0063]

[0064] Firstly, a color alcohol derivative, compound 8 (19 g, 60 mmol) and MS (5 g) was dissolved in DCM (200 mL) and cooled to 0°C, then DABCO (4.04 g, 36 mmol) was added, followed by the addition of recrystallized NCS (8.8 g, 66 mmol). After stirring at 0°C for 2 h, compound 9 (6.9 g, 30 mmol), MsOH (0.78 mL, 12 mmol) (added every 8 h) and DCM (100 mL) were added. After stirring at 0°C for 1 h, compound 10 was obtained, which could not be separated, and the reaction was continued at room temperature for 24 h. The reaction solution was filtered through a sand core funnel containing diatomite, and washed with DCM (50 mL). The filtrate was concentrated in vacuum to obtain the crude product oxyindole 11.

[0065] Crude oxidized indole 11 was added to DCM (300 mL) at -40°C, followed by 2,6-Lutdine (15.7 mL, 135 mmol) and TMSOTf (22.7 mL, 120 mmol). The mixture was stirred at the same temperature for 3 h. H₂O was then added, and the mixture was extracted with DCM and washed with brine. The mixture was dried over MgSO₄ and the filtrate was evaporated in vacuo. Column chromatography (DCM / MeOH = 10 / 1) afforded compound 12 (6 g, 45% yield over two steps) as a yellow oil.

[0066] R f =0.3 (DCM / MeOH=20 / 1);

[0067] 1 H NMR (400MHz, Chloroform-d) δ7.21(td,J=7.6,1.3Hz,1H),7.09(dd,J=7.7,1.3Hz,1H),7.01(dtd,J=7.4,3.8,3.4,2.3Hz,2H),5.76( dd,J=15.2,6.5Hz,1H),5.38-5.27(m,1H),3.90(s,1H),3.36-3.23(m,2H),2.81-2.71(m,2H),2.60(s,3H),2.53-2.44(m,1H),2.17-

[0068] 2.07(m,2H),1.79(dd,J=6.5,1.6Hz,3H),1.65-1.56(m,1H),1.13(dd,J=12.1,6.2Hz,1H),0.90(s,21H).

[0069] 13 C NMR(100MHz,Chloroform-d)δ182.5,141.9,130.9,129.9,128.6,128.1,124 .5,122.1,110.4,59.6,54.3,49.1,48.4,39.1,34.6,27.2,18.3,18.0,12.0.

[0070] HRMS calcd.for C26H45N2O2Si + [M+H] + :445.3245.Found:445.3245.

[0071] [a] D 25 =-26(c 0.2,DCM)

[0072] In the second step, toluene (120 mL) and compound 12 (5.5 g, 12.4 mmol) were added to a dry round-bottom flask, and the reaction was placed at 0°C. Red-Al (14 mL, 49.5 mmol, 3.5 M) was then added. The reaction was stirred at room temperature for 12 hours. MeOH and saturated aqueous potassium sodium tartrate solution were then added, extracted with ethyl acetate (30 mL × 3), and washed with brine (20 mL). The organic layer was dried (MgSO4), and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave compound 13 (4.1 g, 78% yield) as a yellow oil.

[0073] R f =0.45(petroleum ether / EtOAc=2 / 1);

[0074] 1 H NMR(500MHz,Chloroform-d)δ7.34-7.29(m,1H),7.22(td,J=7.6,1.3Hz,1H),7.08(dd,J=7.3,1.3Hz,1H),6.96(td,J=7.4,1.1Hz,1H),5. 46(dtd,J=16.0,6.5,1.0Hz,1H),4.92-4.80(m,1H),3.51(ddd,J=12.0,7.1,2.8Hz,1H),3.43(ddd,J=10.2,9.2,4.9Hz,1H),3.33(ddd,J= 10.0,8.5,6.4Hz,1H),3.29-3.23(m,1H),3.23-3.17(m,1H),3.15(s,3H),2.69(dddd,J=14.1,10.4,7.1,5.3Hz,1H),2.23(dddd,J=13.3,9 .2,6.5Hz,1H),1.97(td,J=8.5,4.3Hz,1H),1.87-1.75(m,1H),1.46(dd,J=6.5,1.7Hz,3H),1.03(d,J=2.1Hz,21H),0.97(d,J=3.4Hz,2H).

[0075] 13 C NMR(125MHz,Chloroform-d)δ177.7,154.5,137.9,129.0,127.8,127.3,122.3, 121.2,116.6,59.6,54.8,48.7,41.5,41.4,38.2,26.4,18.1,18.0,17.9,12.0.

[0076] HRMS calcd.for C26H43N2OSi + [M+H] + :427.3139.Found:427.3143.

[0077] [α] 25 D 82 (c 0.13, DCM).

[0078] In the third step, CSA (5.4 g, 23.5 mmol) was added to a DCM (100 mL) solution containing compound 13 (3 g, 11.7 mmol) at 0°C. The resulting reaction mixture was further cooled to -78°C, and ozone was passed through the reaction system until the blue color persisted. MeOH (25 mL) was added until TLC showed complete consumption of the reaction starting materials, followed by dimethyl sulfide (2.6 mL). The reaction mixture was warmed to 0°C and stirred for 15 minutes, at which point saturated aqueous sodium bicarbonate solution (50 mL) was added. The two-phase mixture was stirred for 4 hours at room temperature. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The collected organic layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to obtain the crude product S1.

[0079] Crude product S1 was dissolved in MeOH (120 ml), and NH2OH·HCl (1.4 g, 17.6 mmol) and AcONa (1.1 g, 15.2 mmol) were added at 0°C. The reaction was stirred at room temperature overnight. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM (3 x 50 mL) and washed with brine (50 mL). The collected organic layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to obtain crude product S2.

[0080] The crude product S2 was dissolved in DCM (120 mL) and the reaction was placed at 0°C. DBU (85 mL, 58.5 mmol) and n-C4F9SO2F (4.2 mL, 23.4 mmol) were then added. The reaction was stirred at room temperature for 10 minutes. Saturated aqueous NaHCO3 was then added, extracted with DCM (3 x 30 mL), and washed with brine (40 mL). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave compound 14 (3.6 g, 76% over three steps) as a yellow oil.

[0081] R f =0.42(petroleum ether / EtOAc=2 / 1);

[0082] 1H NMR(400MHz,Chloroform-d)δ7.33(dd,J=7.9,1.2Hz,1H),7.28(dd,J=7.5,1.3Hz,1H),7.24(dd,J=7.3,1.3Hz,1H),7.01(td,J=7.4,1.2Hz,1H),4.06(dd,J=4.9,2.9Hz,1H),3.70(ddd,J=10.9,9.2,4.8Hz,1H),3.58(ddd,J=10.6,6.0,4.1Hz,1H),3.50(ddt,J=13.4,7.0,3.5Hz,1H),3.36(td,J=11.8,5.2Hz,1H),3.05(s,3H),2.78(dddd,J=14.6,11.5,6.4,4.9Hz,1H),2.31(ddd,J=14.2,9.2,6.0Hz,1H),2.15-2.07(m,1H),1.50(dt,J=14.2,4.4Hz,1H),1.03(d,J=4.2Hz,21H).

[0083] 13 C NMR(100MHz,Chloroform-d)δ176.4,155.1,136.5,129.3,122.0 121.9,118.3,118.1,60.2,53.1,49.0,39.7,38.4,30.8,23.7,18.1,11.9.

[0084] HRMS calcd.for C24H38N3OSi + [M+H] + :412.2779.Found:412.2773.

[0085] [α] 25 D 105(c 0.24,DCM).

[0086] In the fourth step, compound 14 (2.14 g, 5.2 mmol) was added to THF (50 ml) at -78°C. LDA (7.8 ml, 15.6 mmol, 2 M) was then added. The reaction flask was stirred at -78°C for 1 hour. Commercially available 2-NO2-4-Br-BnBr (2.3 g, 7.8 mmol) was then added to the reaction system. The reaction mixture was stirred at room temperature for 1-2 hours. Saturated aqueous NH4Cl solution was then added, extracted with ethyl acetate (3 x 10 mL), and washed with brine (20 mL). The combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 7 / 1) gave compound 15 (1.4 g, 44%) and epi-15 (324 mg, 10%) as yellow solids.

[0087] Compound 15:

[0088] R f =0.44(petroleum ether / EtOAc=2 / 1);

[0089] 1 H NMR(400MHz,Chloroform-d)δ8.17(d,J=2.1Hz,1H),7.74(dd,J=8.3,2.1Hz,1H),7.48(d,J=8.3Hz,1H),7.40 -7.31(m,3H),7.07(td,J=7.3,1.5Hz,1H),4.09(d,J=13.6Hz,1H),3.66(d,J=13.5Hz,1H),3.44(ddd,J=12.0 ,6.7,1.8Hz,1H),3.20(dd,J=9.9,4.1Hz,1H),3.12(dt,J=11.7,5.8Hz,1H),2.99(s,3H),2.79(td,J=9.8,5. 5Hz,1H),2.55(ddd,J=14.2,11.4,6.7Hz,1H),2.34-2.15(m,2H),1.75-1.60(m,3H),0.92(d,J=2.8Hz,23H).

[0090] 13 C NMR(100MHz,Chloroform-d)δ174.5,155.8,150.6,136.6,135.4,135.1,129.8,128.5,128 .2,122.8,122.7,118.4,58.9,56.0,49.4,46.2,38.3,35.8,33.7,27.5,17.99,12.0,11.9.

[0091] M.p.=51-54℃;[α] 25 D -45(c 0.1,DCM).

[0092] HRMS calcd.for C31H42BrN4O3Si + [M+H] + :625.2204.Found:625.2201.

[0093] 化合物epi-15:

[0094] R f =0.5(petroleum ether / EtOAc=2 / 1);

[0095] 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=2.1Hz,1H),7.58(dd,J=8.3,2.1Hz,1H),7.40(dt,J=7.4,1.0Hz,1H),7.33-7.27(m,2H),7.00(ddd,J=7.3,6.2,2.4Hz,1H),6.96(d,J=8.3Hz,1H),3.79-3.67(m,1H),3.33-3.22(m,1H),3.18(s,3H),3.16-3.09(m,1H),3.02(d,J=14.3Hz,1H),2.99-2.94(m,1H),2.57(d,J=14.0Hz,1H),2.50(td,J=9.3,8.8,4.9Hz,1H),2.43-2.34(m,1H),2.07(ddd,J=14.8,8.0,3.4Hz,1H)0.92(s,1H).

[0096] 13 C NMR(100MHz,Chloroform-d)δ172.5,156.1,150.3,136.2,135.5,133.8,129.8,128.9,128.3,122.44,122.35,122.2,120.6,117.4,58.9,56.1,46.4,43.5,38.1,37.9,33.1,26.6,18.0,11.9.

[0097] HRMS calcd.for C31H42BrN4O3Si + [M+H] + :625.2204.Found:625.2203.

[0098] Mp=49-52℃;[α] 25 D 99(c 0.26,DCM).

[0099] In the fifth step, compound 15 (1.2 g, 1.92 mmol) was added to THF (20 ml), followed by the addition of TBAF (3.8 ml, 3.84 mmol, 1 M) at 0°C. The reaction was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate (3 x 10 mL) and washed with brine (20 mL). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to afford crude product S3.

[0100] A dry 200 mL round-bottom flask was prepared under nitrogen atmosphere. Oxalyl chloride (0.32 mL, 3.8 mmol) and DCM (10 mL) were added to the flask. The flask was cooled to -78°C, and DMSO (0.4 mL, 5.7 mmol) was slowly added dropwise. The reaction was stirred at -78°C for 20 min, and then DCM (20 mL) containing the crude product S3 (~1.9 mmol) was added dropwise. Stirring was continued at -78°C for 1 h, and triethylamine (1.58 mL, 11.4 mmol) was slowly added. The reaction was then warmed to room temperature, quenched with H2O (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic extracts were collected, washed with brine, and dried over anhydrous MgSO4. The organic extracts were concentrated under reduced pressure and purified by silica gel column chromatography to yield 16 (590 mg, 67% over two steps) as a yellow solid.

[0101] Rf=0.4(petroleum ether / EtOAc=0 / 1);

[0102] 1H NMR(400MHz,Chloroform-d)δ8.70(t,J=2.6Hz,1H),8.13(d,J=2.1Hz,1H),7.58(dd,J=8.3,2.1Hz,1H),7.48(dt,J=7.6,1.0Hz,1H),7.43-7.34(m,2H),7.07(ddd,J=7.4,5.7,2.9Hz,1H),6.85(d,J=8.3Hz,1H),3.69(ddd,J=13.1,8.2,2.7Hz,1H),3.34(ddd,J=13.1,9.1,7.5Hz,1H),3.25(d,J=2.7Hz,1H),3.20(s,3H),3.09(d,J=14.2Hz,1H),2.92(dd,J=14.8,2.6Hz,1H),2.65(d,J=14.2Hz,1H),2.51(dt,J=16.3,8.6Hz,1H),2.17(ddd,J=15.0,7.5,2.7Hz,1H).

[0103] 13 C NMR(100MHz,Chloroform-d)δ197.9,171.9,155.4,150.1,136.3,135.3,132.8,130.8,128.6,128.5,123.2,123.0,122.7,119.9,118.4,54.7,47.5,46.8,43.1,38.1,32.6,26.9.

[0104] HRMS calcd.for C22H20BrN4O3 + [M+H] + :467.0713.Found:467.0708.

[0105] M.p.=65-69℃;[α] 25 D -50(c 0.1,DCM).

[0106] In the sixth step, l-proline (42 mg, 0.37 mmol) and NCS (172 mg) were added to a solution of compound 16 (570 mg, 1.22 mmol) in DCM (9 mL) and Et2O (3 mL) and stirred at 0°C. The reaction flask was stirred at 5°C for 2 hours. MeOH (10 mL) and NaBH4 (138 mg, 3.66 mmol) were then added. The reaction flask was stirred at room temperature for 2 hours. Saturated aqueous NH4Cl solution was then added, extracted with DCM (3×10 mL), and washed with brine (20 mL). The combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain crude product S4.

[0107] The crude product S4 (~1.22 mmol) was dissolved in DCM (15 ml), and Et3N (0.34 ml, 2.44 mmol) and MsCl (0.113 ml, 1.46 mmol) were added at 0°C. The mixture was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM (3 x 5 mL) and washed with brine (10 mL). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound 17 (262 mg, 37%) and epi-17 (212 mg, 30%) as yellow solids.

[0108] Compound 17:

[0109] R f =0.55(petroleum ether / EtOAc=1 / 2);

[0110] 1H NMR(400MHz,Chloroform-d)δ8.12(d,J=2.1Hz,1H),7.62(dd,J=8.3,2.1Hz,1H),7.42(ddd,J=9.5,7.5,1.7Hz,2H),7.36(dt,J=7.7,1.1Hz,1H),7.08(td,J=7.4,1.3Hz,1H),6.95(d,J=8.3Hz,1H),5.26(dd,J=11.8,2.3Hz,1H),4.80(dd,J=9.0,2.3Hz,1H),4.12(dd,J=11.8,9.0Hz,1H),3.82(ddd,J=12.9,8.9,3.8Hz,1H),3.39(ddd,J=13.2,8.6,6.8Hz,1H),3.26(s,3H),3.06(d,J=14.2Hz,1H),3.03(s,3H),2.73-2.66(m,1H),2.63(d,J=14.0Hz,1H),2.20-2.12(m,1H).

[0111] 13 C NMR(100MHz,Chloroform-d)δ170.1,157.4,136.4,135.4,131.4,129.1,128.5,127.8,123.4,122.9,122.4,120.9,118.3,71.0,60.7,59.2,46.3,41.7,38.1,37.9,34.8,26.0.

[0112] IR:ν max 3461,2930,2409,2364,1605,1356,1157,951cm -1 .

[0113] M.p.=85-89℃;

[0114] [α] 25 D -37(c 0.1,DCM).

[0115] HRMS calcd.for C23H23BrClN4O5S + [M+H] + :581.0256.Found:581.0254.

[0116] 化合物epi-17:

[0117] R f=0.5(petroleum ether / EtOAc=1 / 2);

[0118] 1 H NMR(400MHz,)δ8.10(d,J=2.1Hz,1H),7.78(ddd,J=7.5,1.3,0.6Hz,1H),7.61(dd,J=8.3,2.1Hz,1H),7.43(td,J=7.7,1.3Hz,1H),7.35(dt,J=7.9,0.8Hz,1H),7.11(td,J=7.5,1.1Hz,1H),6.95(d,J=8.4Hz,1H),4.71(dd,J=7.3,4.1Hz,1H),3.92-3.86(m,1H),3.80(ddd,J=13.2,9.3,2.6Hz,1H),3.57(dd,J=11.8,7.3Hz,1H),3.40(ddd,J=13.5,8.8,7.4Hz,1H),3.23(s,3H),3.18(d,J=14.1Hz,1H),2.94(s,3H),2.60-2.48(m,2H),2.17(ddd,J=15.1,8.8,2.6Hz,1H).

[0119] 13 C NMR(100MHz,Chloroform-d)δ169.8,156.7,150.5,136.2,135.9,131.3,128.7,128.4,127.6,125.3,122.8,122.7,118.0,70.4,59.1,45.9,41.9,37.8,37.8,33.5,25.2.

[0120] HRMS calcd.for C23H23BrClN4O5S + [M+H] + :581.0256.Found:581.0252.

[0121] M.p.=82-84℃;[α] 25 D 4.8(c 0.125,DCM).

[0122] In the seventh step, iron powder (24 mg, 0.431 mmol) was added to a room temperature stirred solution of compound 17 (50 mg, 0.086 mmol) in EtOH (0.6 mL) and saturated NH4Cl (aq.) (0.3 mL). The mixture was stirred at 90°C for 3 hours. Saturated NaHCO3 (aq.) (1 mL) was then added, and the mixture was extracted with DCM (3 mL x 3) and washed with brine (3 mL). The organic phase was combined and dried over NaSO4. The mixture was separated and purified by column chromatography containing silica gel to obtain compound 18 (23 mg, 60% yield) and compound 19 (9 mg, 24% yield) as white solids.

[0123] Compound 18:

[0124] R f =0.75(petroleum ether / EtOAc=1 / 5);

[0125] 1 H NMR(500MHz,Chloroform-d)δ7.40(d,J=7.7Hz,1H),7.37-7.32(m,1H),7.10-7.06(m,2H),7.06-6 .99(m,2H),6.78(d,J=8.0Hz,1H),5.27(s,1H),4.80(dd,J=10.9,6.0Hz,1H),4.11(dd,J=15.4,6.0 Hz,1H),3.88(dd,J=15.4,10.9Hz,1H),3.44-3.33(m,1H),3.19-3.10(m,1H),3.08(s,3H),2.67(d, J=16.3Hz,1H),2.34(td,J=13.2,6.5Hz,1H),2.25(d,J=16.4Hz,1H),1.92(dd,J=14.8,5.0Hz,1H).

[0126] 13 C NMR(125MHz,Chloroform-d)δ173.3,159.9,156.4,138.8,130.6,130.2,129.8,125.9,1 23.2,122.8,121.5,120.0,119.8,118.4,57.7,55.3,48.7,48.4,40.6,38.5,29.0,26.7.

[0127] Mp = 157-160 ° C;

[0128] [α] 25 D-78 °C (0.32, DCM).

[0129] HRMS calcd. for C22H21BrClN4 + [M+H] + : 455.0633. Found: 455.0630.

[0130] Compound 19:

[0131] R f = 0.15 (petroleum ether / EtOAc = 1 / 5);

[0132] 1 H NMR (400 MHz, Chloroform-d) δ 7.31 (dd, J = 7.9, 1.4 Hz, 1H), 7.28 (dd, J = 7.1, 1.2 Hz, 1H), 7.09 (dd, J = 7.4, 4.3 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.91 (td, J = 7.2, 1.4 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.45 (dt, J = 7.8, 5.2 Hz, 1H), 4.03 (ddd, J = 10.1, 7.9, 2.5 Hz, 1H), 3.74 - 3.61 (m, 1H), 3.51 (ddd, J = 9.9, 6.7, 5.3 Hz, 1H), 3.29 (s, 3H), 3.26 - 3.21 (m, 1H), 3.19 (d, J = 15.9 Hz, 1H), 2.74 (s, 3H), 2.10 (d, J = 15.6 Hz, 1H), 2.04 (dd, J = 14.4, 2.4 Hz, 1H), 1.45 - 1.36 (m, 1H).

[0133] 13 C NMR (100 MHz, Chloroform-d) δ 174.4, 166.6, 157.4, 139.8, 130.6, 129.6, 125.2, 124.9, 121.2, 120.8, 120.4, 119.9, 117.6, 70.6, 69.3, 63.0, 49.9, 48.5, 38.4, 37.1, 35.8, 34.5.

[0134] HRMS calcd. for C23H24BrN4O3S + [M+H] + : 515.0747. Found: 515.0745.

[0135] M.p. = 250-253 °C; [a] 25D 126 (c 0.18, DCM).

[0136] In the eighth step, NaH (3 mg, 0.076 mmol, 60%) was added to a DMF (0.6 ml) solution containing compound 18 (23 mg, 0.051 mmol) at 0°C. The reaction was stirred at 0°C for 5 minutes. Then MeI (3.8 μL, 0.061 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Saturated NH4Cl aqueous solution was then added, extracted with ethyl acetate (3x2 ml), and washed with H2O (3x 5 ml) and brine (5 ml). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave compounds 5 (10.2 mg, 43%) and 6 (9.9 mg, 42%) as white solids.

[0137] Compound 5: (-)-Caulamidine D:

[0138] R f =0.4(petroleum ether / EtOAc=2 / 1);

[0139] 1 H NMR(400MHz,Chloroform-d)δ7.39(dt,J=7.8,1.0Hz,1H),7.33(td,J=7.6,1.3Hz,1H),7.24(d,J=2.1Hz,1H),7 .01(td,J=7.4,1.2Hz,1H),6.96(dd,J=7.9,2.1Hz,1H),6.92-6.88(m,1H),6.70(dd,J=8.0,1.2Hz,1H),4.87(d d,J=9.6,7.8Hz,1H),3.82-3.75(m,2H),3.33(dd,J=7.0,1.5Hz,1H),3.30(s,3H),3.12(dd,J=12.1,5.5Hz,1H) ,3.07(s,3H),2.63-2.56(m,1H),2.26-2.18(m,1H),2.14(d,J=16.2Hz,1H),1.87(ddd,J=14.9,5.5,1.5Hz,1H).

[0140] 13C NMR(100MHz,Chloroform-d)δ173.9,159.9,156.6,146.3,131.0,130.0,128.7,126.5,125.3,123.6,122.4,122.2,121.1,118.3,58.9,54.8,53.5,48.7,40.4,38.4,36.8,30.0,25.7.

[0141] HRMS calcd.for C23H23BrClN4 + [M+H] + :469.0789.Found:469.0788.

[0142] M.p.=265-269℃;

[0143] [a] D 20 =-60(c 0.05,DCM).

[0144] 化合物6:(-)-Isocaulamidine D:

[0145] R f =0.41(petroleum ether / EtOAc=2 / 1);

[0146] 1 H NMR(400MHz,Chloroform-d)δ7.39(dt,J=7.8,1.0Hz,1H),7.36-7.30(m,1H),7.05(d,J=1.8Hz,1H),7.03-6.99(m,2H),6.96(dd,J=7.9,1.8Hz,1H),6.75(dd,J=7.9,1.1Hz,1H),4.75(dd,J=10.7,6.1Hz,1H),4.30(dd,J=17.6,6.1Hz,1H),3.94(dd,J=17.7,10.7Hz,1H),3.43(s,3H),3.29(ddd,J=12.0,6.9,1.6Hz,1H),3.07(s,3H),3.01(dt,J=12.1,6.0Hz,1H),2.63(dt,J=15.9,1.7Hz,1H),2.27-2.15(m,1H),2.11(d,J=15.8Hz,1H),1.74-1.70(m,1H).

[0147] 13C NMR(100MHz,Chloroform-d)δ174.4,156.7,156.3,142.1,131.5,129.7,129.4,123.8,123. 4,122.5,121.4,121.3,118.0,117.1,58.5,57.0,52.2,48.5,41.3,38.4,31.9,29.6,27.2.

[0148] IR:ν max 3349,2942,2723,2367,1685,1582,1375,1165,963,700cm -1 .

[0149] HRMS calcd.for C23H23BrClN4 + [M+H] + :469.0789.Found:469.0790.

[0150] Mp = 271-274°C;

[0151] [a] D 20 =-59 (c 0.05, DCM).

[0152] In the ninth step, PPh3S (1 mg) and NBS (4.1 mg, 0.023 mmol) were added to DCM (0.8 mL) solutions containing compounds 5 (10 mg, 0.021 mmol) and 6 (10 mg), respectively, and the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compound 1 (5.4 mg) and compound 2 (5.5 mg), respectively.

[0153] Compound 1: (-)-Caulamidine B:

[0154] R f =0.42(petroleum ether / EtOAc=2 / 1);

[0155] 1H NMR(400MHz,Methol-d)δ7.63(dt,J=7.8,1.2Hz,1H),7.50(d,J=2.2Hz,1H),7.46(d,J=7.6,1.5Hz,1H),7.41,7.34,7.17(dd,J=8.0,0.8,1H),5.34(dd,J=10.6,6.8Hz,1H),4.33(dd,J=14.6,6.6Hz,1H),3.90(dd,J=14.0,10.5Hz,1H),3.81(dd,J=14.1,8.5Hz,1H),3.69(s,3H),3.60(dd,J=14.1,8.6Hz,1H),3.39(s,3H),2.76(d,J=16.4Hz,1H),2.72(dd,J=16.4,2.0Hz,1H),2.46(d,J=16.4Hz,1H),1.97(ddd,J=14.9,1.5,1.0Hz,1H).

[0156] 13 C NMR(100MHz,Methol-d)δ169.9,161.2,147.5,135.9,131.9,130.5,129.0,127.4,126.0,124.5,122.8,122.2,121.8,118.1,57.8,55.0,52.9,41.5,40.2,40.1,30.2,25.1.

[0157] HRMS calcd.for C23H22Br2ClN4 + [M+H] + :546.9894.Found:546.9898.

[0158] 化合物2:(-)-Isocaulamidine B:

[0159] R f =0.43(petroleum ether / EtOAc=2 / 1);

[0160] 1H NMR(400MHz,Methol-d)δ7.64(d,J=1.6Hz,1H),7.52(d,J=1.4Hz,1H),7.49(dd,J=8.2,1.8Hz,1H),7.40,7.32(d,J =7.9Hz,1H),7.16(dd,J=7.9,1.1Hz,1H),5.39(dd,J=10.7,6.3Hz,1H),4.33(dd,J=17.6,6.1Hz,1H),4.01(dd,J=1 7.7,10.7Hz,1H),3.97(ddd,J=12.0,6.9,1.6Hz,1H),3.69(ddd,J=14.0,9.0,7.6Hz,1H),3.60(s,3H),3.43(s,3H) ,2.88(dt,J=12.1,6.0Hz,1H),2.81(dt,J=15.9,1.7Hz,1H),2.61(d,J=15.8Hz,1H),2.17(dt,J=15.3,7.0Hz,1H).

[0161] 13 C NMR(100MHz,Methol-d)δ170.0,161.7,148.9,140.0,131.6,130.1,128.7,127.2,125.8,12 5.5,123.5,123.2,121.5,118.4,58.4,53.8,48.8,47.8,42.3,39.8,39.7,35.9,29.8,25.3.

[0162] HRMS calcd.for C23H22Br2ClN4 + [M+H] + :546.9894.Found:546.9892.

[0163] Example 2

[0164] Simultaneously, a similar method was used to replace the 2-nitro-4-bromobenzyl bromide used in the benzylation reaction with compound 14 with 2-nitrobenzyl bromide. A similar reaction process was then carried out to obtain the key intermediate 18', which was then methylated and dichlorinated to synthesize caulamidine A. Steps 1 to 3 were the same as in Example 1 and are not described here.

[0165] Starting from the fourth step, the reaction route is as follows:

[0166]

[0167] In the fourth step, compound 14 (1 g, 2.37 mmol) was added to THF (25 ml) at -78°C. LDA (4.8 ml, 4.74 mmol, 2 M) was then added. The reaction flask was stirred at -78°C for 1 hour. Commercially available 2-NO2-BnBr (0.77 g, 3.56 mmol) was then added to the reaction system. The reaction mixture was stirred at room temperature for 1-2 hours. Saturated aqueous NH4Cl solution was then added, extracted with ethyl acetate (3 x 10 mL), and washed with brine (20 mL). The combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 7 / 1) afforded compound 15' (280 mg, 54%) and epi-15' (62 mg, 12%) as yellow solids.

[0168] Compound 15':

[0169] R f =0.41(petroleum ether / EtOAc=2 / 1);

[0170] 1 H NMR(400MHz,Chloroform-d)δ7.93(d,J=8.1Hz,1H),7.50(t,J=7.5Hz,1H),7.47-

[0171] 7.40(m,2H),7.29(q,J=5.3,4.4Hz,2H),7.20(d,J=7.7Hz,1H),7.01(td,J=6.8,6.3,2.5Hz,1H), 3.70(td,J=8.8,4.2Hz,1H),3.30(dt,J=13.0,7.8Hz,1H),3.19(s,3H),3.15(dt,J=9.7,5.0Hz,1 H),3.02(d,J=14.3Hz,1H),2.97(dt,J=9.8,4.8Hz,1H),2.67(d,J=14.2Hz,1H),2.51(qd,J=8.8, 5.0Hz, 2H), 2.38 (ddd, J=12.8, 9.4, 5.9Hz, 1H), 2.07 (ddd, J=14.8, 8.0, 3.3Hz, 1H), 0.91 (s, 22H).

[0172] 13C NMR (100 MHz, Chloroform-d) δ 172.5, 156.1, 150.1, 134.2, 133.9, 133.2, 129.8, 129.7, 129.0, 125.3, 122.4, 122.1, 120.8, 117.3, 58.9, 56.0, 46.4, 43.6, 38.1, 37.9, 33.0, 26.2, 18.0, 11.9.

[0173] Compound epi-15’:

[0174] 1 H NMR (400 MHz, Chloroform-d) δ 8.05-7.99 (m, 1H), 7.64-7.58 (m, 2H), 7.50 (ddd, J = 8.7, 5.8, 3.2 Hz, 1H), 7.40-7.32 (m, 3H), 7.07 (td, J = 7.3, 1.5 Hz, 1H), 4.15 (d, J = 13.5 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.42 (dd, J = 6.8, 1.8 Hz, 1H), 3.20 (td, J = 9.9, 6.0 Hz, 1H), 3.16-3.08 (m, 1H), 2.99 (s, 3H), 2.79 (td, J = 9.7, 5.7 Hz, 1H), 2.58 (ddd, J = 14.3, 11.4, 6.7 Hz, 1H), 2.25 (dt, J = 9.7, 5.9 Hz, 2H), 1.66 (ddd, J = 14.3, 5.7, 1.8 Hz, 2H), 0.92 (d, J = 2.4 Hz, 24H).

[0175] 13 C NMR (100 MHz, Chloroform-d) δ 174.7, 150.3, 135.2, 134.1, 133.6, 129.7, 129.2, 125.5, 122.7, 118.3, 58.9, 56.0, 49.5, 46.3, 38.3, 35.8, 34.0, 27.4, 18.0, 11.9.

[0176] IR: v max 3364, 2919, 2857, 1627, 1575, 1520, 1092, 746 cm -1 .

[0177] HRMS calcd for C31H43N4O3Si + [M+H] + : 547.3099. Found: 547.3096.

[0178] In the fifth step, compound 15' (1 g, 1.83 mmol) was added to THF (20 mL), followed by the addition of TBAF (3.7 mL, 3.66 mmol, 1 M) at 0°C. The reaction was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate (3 x 10 mL) and washed with brine (20 mL). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to yield crude product S3'.

[0179] A dry 200 mL round-bottom flask was prepared under nitrogen atmosphere. Oxalyl chloride (0.3 mL, 3.6 mmol) and DCM (10 mL) were added to the flask. The flask was cooled to -78°C, and DMSO (0.38 mL, 5.4 mmol) was slowly added dropwise. The reaction was stirred at -78°C for 20 min. DCM (20 mL) containing the crude product S3' (~1.8 mmol) was then added dropwise. Stirring was continued at -78°C for 1 h, and triethylamine (1.51 mL, 10.8 mmol) was slowly added. The reaction was then warmed to room temperature, quenched with H2O (20 mL), and extracted with ethyl acetate (3 x 20 mL). The organic extracts were collected, washed with brine, and dried over anhydrous MgSO4. The organic extracts were concentrated under reduced pressure and purified by silica gel column chromatography to yield 16' (525 mg, 74% over two steps) as a yellow solid.

[0180] In the sixth step, compound 16' (200 mg, 0.52 mmol) was added to DCM (6 mL) and Et2O (2 mL) in a round-bottom flask and placed at 0°C, followed by the addition of L-proline (18 mg, 0.16 mmol) and NCS (72 mg). The reaction flask was stirred at 5°C for 2 hours. MeOH (5 mL) and NaBH4 (59 mg, 1.56 mmol) were then added. The reaction flask was stirred at room temperature for 2 hours. Saturated aqueous NH4Cl solution was then added, extracted with DCM (3×10 mL), and washed with brine (20 mL). The combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S4'.

[0181] The crude product S4' (~0.5 mmol) was dissolved in DCM (5 ml), and Et3N (0.14 ml, 1 mmol) and MsCl (0.056 ml, 0.6 mmol) were added at 0°C. The mixture was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO3 was then added, and the mixture was extracted with DCM (3 x 5 mL) and washed with brine (10 mL). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 1 / 2) afforded compound 17' (98 mg, 38%) and epi-17' (83 mg, 32%) as yellow solids.

[0182] Compound 17':

[0183] R f =0.52(petroleum ether / EtOAc=1 / 2);

[0184] 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=8.2Hz,1H),7.54(t,J=7.5Hz,1H),7.47(dd,J=12.0,7.7Hz,2H),7.41(d,J= 7.6Hz,1H),7.37(d,J=7.9Hz,1H),7.19(d,J=7.7Hz,1H),7.09(t,J=7.4Hz,1H),5.35-5.23(m,1H),4.81(d,J=8.9Hz ,1H),4.13(dd,J=11.7,9.1Hz,1H),3.86-3.76(m,1H),3.41(dt,J=14.2,7.7Hz,1H),3.28(d,J=1.5Hz,3H),3.08(d, J=13.8Hz,1H),3.04(d,J=1.4Hz,3H),2.73(d,J=14.1Hz,1H),2.65(dt,J=15.4,7.6Hz,1H),2.17(t,J=11.4Hz,1H).

[0185] 13 C NMR(100MHz,Chloroform-d)δ170.1,157.4,150.1,134.2,133.4,131.2,129.5,129.1,128. 7,125.6,123.3,122.3,121.1,118.2,71.1,60.6,59.2,46.3,41.8,38.1,37.8,34.8,25.6.

[0186] Compound epi-17':

[0187] R f =0.47(petroleum ether / EtOAc=1 / 2);

[0188] 1 H NMR(400MHz,Chloroform-d)δ7.99-7.92(m,1H),7.81(d,J=7.5Hz,1H),7.57-7.49(m,1H),7.49-7.40(m,2H),7.34(d,J=7.8Hz,1H) ,7.17(d,J=7.7Hz,1H),7.15-7.09(m,1H),4.71(dd,J=7.5,4.1Hz,1H),3.90(dd,J=11.8,4.1Hz,1H),3.86-3.74(m,1H),3.57(dd,J=

[0189] 11.7,7.3Hz,1H),3.43(dt,J=13.4,8.4Hz,1H),3.24(s,3H),3.20(d,J=13.8Hz,1H),2.95 (d,J=1.5Hz,3H),2.61(d,J=14.2Hz,1H),2.51(dt,J=16.2,8.3Hz,1H),2.23-2.12(m,1H).

[0190] 13 C NMR(100MHz,Chloroform-d)δ169.8,156.6,150.2,134.7,133.2,131.2,129.4,128.7,128.5 ,125.4,125.3,122.6,119.5,117.8,70.5,59.09,59.06,46.0,42.0,37.8,37.8,33.4,24.9.

[0191] In the seventh step, iron powder (16 mg, 0.24 mmol) was added to a room temperature stirring solution of compound 17' (30 mg, 0.06 mmol) in EtOH (0.5 mL) and saturated NH4Cl (aq.) (0.25 mL). The mixture was stirred at 90°C for 3 hours. Saturated NaHCO3 (aq.) (1 mL) was then added, and the mixture was extracted with DCM (3 mL x 3) and washed with brine (3 mL). The organic phase was combined and dried over NaSO4. The mixture was separated and purified by column chromatography containing silica gel to yield compound 18' (16 mg) as a white solid.

[0192] Compound 18':

[0193] R f=0.4(petroleum ether / EtOAc=0 / 1);

[0194] 1 H NMR(500MHz,Chloroform-d)δ7.40(d,J=7.7Hz,1H),7.33(tt,J=7.6,1.3Hz,1H),7.17-7.12(m,1H),7.10(ddd,J=7.5,3.5,1.2Hz,1H),7.00(tdd,J=7.4,3.9,1.1Hz,1H),6.90(dt,J=7.5,1.4Hz,1H),6.83(td,J=7.4,1.1Hz,1H),6.76(dd,J=7.9,1.1Hz,1H),4.81(ddd,J=10.8,6.0,1.4Hz,1H),4.14(ddd,J=16.3,6.0,3.7Hz,1H),3.91(ddd,J=16.3,10.8,1.6Hz,1H),3.34(ddd,J=12.0,6.8,1.6Hz,1H),3.14(dt,J=12.1,5.9Hz,1H),3.09(s,3H),2.74(d,J=16.1Hz,1H),2.38-2.28(m,1H),2.24(d,J=16.1Hz,1H),1.94(ddd,J=14.7,5.2,1.6Hz,1H).

[0195] 13 C NMR(125MHz,Chloroform-d)δ174.2,158.4,158.3,156.5,138.3,131.4,129.8,128.6,128.1,123.5,122.5,121.7,120.5,120.5,118.1,115.5,58.1,56.7,50.6,48.7,40.8,38.5,29.8,29.8,27.1.

[0196] In the eighth step, NaH (3 mg, 0.076 mmol, 60%) was added to a DMF (0.6 ml) solution containing compound 18' (23 mg, 0.049 mmol) at 0°C. The reaction was stirred at 0°C for 5 minutes. Then MeI (3.8 μL, 0.06 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Saturated NH4Cl aqueous solution was then added, extracted with ethyl acetate (3x2 ml), and washed with H2O (3x 5 ml) and brine (5 ml). The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography (petroleum ether / ethyl acetate = 2 / 1) gave compound 20 as a white solid.

[0197] PPh3S (1 mg) and NBS (5.0 mg, 0.028 mmol) were added to a DCM (0.8 mL) solution containing compound 20 (10 mg, 0.026 mmol), and the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to give compound 7 (6.4 mg).

[0198] Compound 7: (-)-Caulamidine A:

[0199] R f =0.42(petroleum ether / EtOAc=2 / 1);

[0200] 1 H NMR (400MHz, CD3CN): δ7.29(dd,J=8.3,2.0Hz,1H),7.14(d,J=8.3Hz,1H),7.10(ddd,J=8.4,2.5,1.1Hz,1H),6.94(dd ,J=2.5,1.2Hz,1H),6.93(d,J=1.9Hz,1H),6.92(d,J=8.3Hz,1H),5.00(dd,J=11.0,6.3Hz,1H),3.85(dd,J=12.8,6.4 Hz,1H),3.69(dd,J=12.7,11.1Hz,1H),3.36(dd,J=12.3,7.3Hz,1H),3.22(s,3H),3.15(td,J=12.0,5.8Hz,1H),2.98 (s,3H),2.45(ddt,J=16.2,2.3,1.0Hz,1H),2.26(d,J=16.1Hz,1H),2.25-2.19(m,1H),1.72(dd,J=15.1,5.8Hz,1H).

[0201] 13 C NMR (100MHz, CD3CN): δ175.0,160.0,157.3,145.1,134.5,130.2,128.2,128.2,127.2,1 26.8,126.4,125.3,124.6,118.8,59.9,55.9,53.7,48.6,40.8,38.3,36.7,30.6,25.8.

[0202] HRMS calcd.for C23H22Cl3N4 + [M+H] + :459.0905.Found:459.0915.

[0203] Alternatively, we can also use the aforementioned general method to introduce a chlorine atom into compound 9, and then use existing general routes to synthesize other natural compounds such as Caulamidine C and Isocaulamidine C. The resulting compounds 18 and 18' are the core nucleus of the Caulamidine family of natural compounds. The remaining natural compounds can be converted to the final natural compounds through functional group transformation based on the core nucleus.

[0204] The specific synthetic route is as follows:

[0205]

[0206] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines, characterized in that: The steps include: In the first step, starting from compound 8, intermediate 10 is obtained by addition elimination, and then chiral intermediate 11 is synthesized under standard Meerwein-Eschenmoser-Claisen rearrangement conditions; then, after removing the Boc protecting group, indole compound 12 is obtained; In the second step, the indole compound 12 was treated with Red-Al to construct a piperidine ring, and the only compound isolated was compound 13; In the third step, compound 13 was subjected to ozonolysis, and the resulting aldehyde was directly condensed with hydroxylamine, and finally dehydrated under the action of perfluorobutanesulfonyl fluoride and DBU to obtain cyanide 14; In the fourth step, 2-nitro-4-bromobenzyl bromide was used to selectively benzylate compound 14 at C23 to achieve the construction of the adjacent quaternary carbon to obtain compound 15 and its isomer epi-15; In the fifth step, the TIPS protecting group of compound 15 is removed and the hydroxyl group is oxidized to obtain compound 16; In the sixth step, compound 16 undergoes L-proline and NCS-mediated electrophilic chlorination to obtain compound 17 and its isomer epi-17; In the seventh step, compound 17 was treated with iron as a reducing agent to convert -NO2 into a nucleophilic -NH2 group via the 6-exo-dig / 6-exo-tet pathway, yielding the hexacyclic compound 18 and the minor compound 19. In the eighth step, the hexacyclic compound 18 is methylated to obtain compounds 5 and 6, which are polyhalogenated alkaloids (-)-Caulamidine D and (-)-Isocaulamidine D, respectively; The specific reaction process is as follows:

2. The method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 1, wherein: The obtained (-)-Caulamidine D and (-)-Isocaulamidine D were brominated at the C6 position of the indole ring to give compounds 1 and 2, respectively, which are polyhalogenated alkaloids (-)-Caulamidine B and (-)-Isocaulamidine B; The specific reaction process is as follows:

3. A method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines, characterized in that: The steps include: In the first step, starting from compound 8, intermediate 10 is obtained by addition elimination, and then chiral intermediate 11 is synthesized under standard Meerwein-Eschenmoser-Claisen rearrangement conditions; then, after removing the Boc protecting group, indole compound 12 is obtained; In the second step, the indole compound 12 was treated with Red-Al to construct a piperidine ring, and the only compound isolated was compound 13; In the third step, compound 13 was subjected to ozonolysis, and the resulting aldehyde was directly condensed with hydroxylamine, and finally dehydrated under the action of perfluorobutanesulfonyl fluoride and DBU to obtain cyanide 14; In the fourth step, 2-nitrobenzyl bromide was used to selectively benzylate compound 14 at C23 to achieve the construction of the adjacent quaternary carbon to obtain compound 15' and its isomer epi-15'; The fifth step is to remove the TIPS protecting group of compound 15' and oxidize the hydroxyl group to obtain compound 16'; In the sixth step, compound 16' undergoes L-proline and NCS-mediated electrophilic chlorination to obtain compound 17' and its isomer epi-17'; In the seventh step, compound 17' was treated with iron as a reducing agent to convert -NO2 into a nucleophilic -NH2 group via the 6-exo-dig / 6-exo-tet pathway to obtain the hexacyclic compound 18'; In the eighth step, the hexacyclic compound 18' is methylated to obtain compound 20, and then C7 and C19 of compound 20 are dichlorinated to obtain compound 7, i.e., polyhalogenated alkaloid caulamidine A; The specific reaction process is as follows:

4. A method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 1 or 3, characterized in that: In the first step, compound 8 and After dissolving it in DCM and cooling to 0°C, DABCO was added, followed by recrystallized NCS, and the mixture was stirred at 0°C for 2 h. Compound 9, MsOH, and DCM were added, and the mixture was stirred at 0°C for 1 h to obtain inseparable compound 10. The reaction was continued at room temperature for 24 h. The reaction solution was filtered through a sand-core funnel containing diatomaceous earth, rinsed with DCM, and the filtrate was collected and concentrated in vacuo to obtain the crude product indole compound 11. Indole compound 11 was added to DCM at -40°C, and 2,6-Lutdine and TMSOTf were added. The mixture was stirred at the same temperature for 3 h, and then H2O was added. The mixture was extracted with DCM and finally washed with brine, dried over MgSO4, and the filtrate was evaporated in vacuo. Compound 12 was obtained by column chromatography. In the second step, toluene and compound 12 were added to a dry round-bottom flask, and the reaction was placed at 0°C. Red-Al was then added and the reaction was stirred at room temperature for 12 hours. MeOH and saturated aqueous potassium sodium tartrate were then added and extracted with ethyl acetate. The mixture was washed with brine, the organic layer was dried, and the filtrate was evaporated in vacuo. Compound 13 was obtained by column chromatography.

5. A method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 1 or 3, characterized in that: In the third step, CSA was added to a DCM solution containing compound 13 at 0°C. The resulting reaction mixture was further cooled to -78°C, and ozone was introduced into the reaction system until a blue color persisted. MeOH was added until TLC showed complete consumption of the starting material, followed by dimethyl sulfide. The reaction mixture was warmed to 0°C and stirred for 15 minutes, at which point saturated aqueous sodium bicarbonate was added. The two-phase mixture was stirred for 4 hours. The aqueous layer was extracted with ethyl acetate at room temperature, and the organic layer was collected and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation to obtain the crude product S1. The crude product S1 was dissolved in MeOH (120 ml), and NH2OH·HCl and AcONa were added at 0°C. The reaction was stirred at room temperature overnight, and then a saturated aqueous NaHCO3 solution was added. The mixture was extracted with DCM and washed with brine. The organic layer was collected and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation to obtain the crude product S2. The crude product S2 was dissolved in DCM, and the reaction was placed at 0°C. DBU and n-C4F9SO2F were then added, and the reaction was stirred at room temperature for 10 minutes. Saturated aqueous NaHCO3 was then added, extracted with DCM, and washed with brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Compound 14 was obtained by column chromatography.

6. The method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 1, characterized in that: In the fourth step, compound 14 was added to THF at -78°C, followed by the addition of LDA. The reaction flask was stirred at -78°C for 1 hour, and then 2-NO2-4-Br-BnBr was added to the reaction system. The reaction mixture was stirred at room temperature for 1-2 hours. Saturated aqueous NH4Cl solution was then added, extracted with ethyl acetate, and washed with brine. The combined organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography afforded compounds 15 and epi-15. In the fifth step, compound 15 was added to THF, and TBAF was added at 0°C. The reaction flask was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl solution was then added, extracted with ethyl acetate, and washed with brine. The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S3. Prepare a dry round-bottom flask and protect it with nitrogen. Add oxalyl chloride and DCM to the flask. Cool the flask to -78°C. Slowly add DMSO dropwise to the system. After the reaction is stirred at -78°C for 20 minutes, add DCM containing the crude product S3 dropwise. Continue stirring at -78°C for 1 hour. Slowly add triethylamine. Then, warm the reaction to room temperature, quench with H2O, extract with ethyl acetate, collect the organic extracts, wash with brine, and dry over anhydrous MgSO4. The organic extracts are concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 16.

7. The method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 1, characterized in that: In the sixth step, l-proline and NCS were added to DCM and Et2O, and the solution of compound 16 was stirred at 0°C. The reaction flask was stirred at 5°C for 2 hours, and then MeOH and NaBH4 were added. The reaction flask was stirred at room temperature for 2 hours, and then a saturated NH4Cl aqueous solution was added. The mixture was extracted with DCM and washed with brine. The combined organic layers were dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S4. The crude product S4 was dissolved in DCM, Et3N and MsCl were added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Then, a saturated aqueous NaHCO3 solution was added, extracted with DCM, and washed with brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography was performed to obtain compound 17 and its isomer epi-17; in the seventh step, compound 17 was dissolved in EtOH and saturated NH4Cl solution, and iron powder was added while stirring at room temperature. The mixture was stirred at 90°C for 3 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compounds 18 and 19.

8. The method for synthesizing polyhalogenated alkaloids Caulamidines and Isocaulamidines according to claim 1, characterized in that: In the eighth step, NaH was added to a DMF solution containing compound 18, and the reaction was stirred at 0°C for 5 minutes. Then, MeI was slowly added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate and washed with H2O and brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Compounds 5 and 6 were obtained by column chromatography. In the ninth step, PPh3S and NBS were added to the DCM solutions containing compounds 5 and 6, respectively, and the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compounds 1 and 2, respectively.

9. The method for synthesizing polyhalogenated alkaloids Caulamidins and Isocaulamidines according to claim 3, characterized in that: In the fourth step, compound 14 was added to THF at -78°C, followed by the addition of LDA. The reaction flask was stirred at -78°C for 1 hour, and then 2-NO2BnBr was added to the reaction system. The reaction mixture was stirred at room temperature for 1-2 hours. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate and washed with brine. The combined organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography afforded compounds 15' and epi-15'. In the fifth step, compound 15' was added to THF, and then TBAF was added at 0°C. The reaction flask was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl solution was then added, and the mixture was extracted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S3'. Prepare a dry round-bottom flask and protect it with nitrogen. Add oxalyl chloride and DCM to the flask, cool the flask to -78°C, slowly add DMSO dropwise to the system, stir the reaction at -78°C for 20 minutes, then add DCM containing the crude product S3' dropwise, continue stirring at -78°C for 1 hour, slowly add triethylamine, then warm the reaction to room temperature, quench with H2O, extract with ethyl acetate, collect the organic extracts and wash with brine, and dry over anhydrous MgSO4. The organic extracts are concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 16'.

10. The method for synthesizing polyhalogenated alkaloids Caulamidines and Isocaulamidines according to claim 3, characterized in that: In the sixth step, l-proline and NCS were added to DCM and Et2O, and the solution of compound 16' was stirred at 0°C. The reaction flask was stirred at 5°C for 2 hours, and then MeOH and NaBH4 were added. The reaction flask was stirred at room temperature for 2 hours, and then a saturated NH4Cl aqueous solution was added. The mixture was extracted with DCM and washed with brine. The combined organic layer was dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo to obtain the crude product S4'. The crude product S4' was dissolved in DCM, Et3N and MsCl were added at 0°C, stirred at room temperature for 30 minutes, then saturated aqueous NaHCO3 solution was added, extracted with DCM, washed with brine, the organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo. Column chromatography gave compound 17 and its isomer epi-17; In the seventh step, compound 17' was dissolved in EtOH and saturated NH4Cl solution, and iron powder was added under stirring at room temperature. The mixture was stirred at 90°C for 3 hours. Saturated NaHCO3 was then added, extracted with DCM, and washed with brine. The organic phase was combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compound 18'. In the eighth step, NaH was added to a DMF solution containing compound 18', and the reaction was stirred at 0°C for 5 minutes. Then, MeI was slowly added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous NH4Cl was then added, and the mixture was extracted with ethyl acetate and washed with H2O and brine. The organic layer was collected and dried over anhydrous MgSO4, and the filtrate was evaporated in vacuo and purified by column chromatography to obtain compound 20. PPh3S and NCS were added to the DCM solution containing compound 20, and the reaction was stirred at 0°C for 2 hours; then saturated NaHCO3 was added, extracted with DCM, and washed with brine; the organic layers were combined and dried over NaSO4, and separated and purified by column chromatography containing silica gel to obtain compound 7.

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