A Unified Strategy To Construct the Tetracyclic Ring of Calyciphylline

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A Unified Strategy To Construct the Tetracyclic Ring of Calyciphylline A Alkaloids: Total Synthesis of Himalensine A Jiaxin Zhong,† Kuanwei Chen,† Yuanyou Qiu,† Haibing He,‡ and Shuanhu Gao*,†,‡ †

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China ‡ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China

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S Supporting Information *

ABSTRACT: The synthetic approach to the core framework of the calyciphylline A-type Daphniphyllum alkaloids and total synthesis of himalensine A were described herein. Nitrone-induced 1,3-dipolar [3 + 2] cycloaddition was applied for the construction of A/C rings along with the all-carbon quaternary center. Pd-catalyzed enolate alkenylation and ring closing metathesis (RCM) were adopted to install the B/D rings to accomplish the [6,6,5,7] core framework. Nazarov reaction was utilized to install the F ring to complete the total synthesis of himalensine A.

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ore than 320 members of the structurally diverse family of natural alkaloids have been isolated and identified from the genus Daphniphyllum.1 These members have been classified into more than 20 subgroups based on structural features. Natural alkaloids exhibit a wide range of biological activities, including anticancer, vasorelaxation, and HIV inhibition, providing opportunities for medicinal studies and drug discoveries. Synthesis of the complex azapolycyclic architectures of Daphniphyllum alkaloids1 have attracted considerable attention,2 and various methods have been developed to improve synthetic efficiency and scalability. Elegant total syntheses of Daphniphyllum alkaloids have been described by the groups of Heathcock,3 Carreira,4 Smith,5 Fukuyama,6 Hanessian,7 Li,8 Zhai,9 Dixon,10 Qiu,11 and Xu12 which have enabled promising downstream syntheses13 and mechanistic studies of natural alkaloids. In 2003, Kobayashi and co-workers isolated calyciphylline A (1) from the leaves of D. calycinum.14 Calyciphylline A (1) possesses (a) a fascinating hexacyclic fused-ring system (A−BC−D−E−F rings); (b) seven stereogenic centers, including two all-carbon quaternary centers at C-5 and C-8; and (c) an N-oxide group. Subsequently, several biogenetically related members of this subfamily were isolated.1 In 2006, for example, daphniyunnines B−E (2−5)15a and daphnilongeranin A (6)15b were discovered by Yue and co-workers in D. yunnanense and D. longeracemosum (Figure 1). A decade later, the same research group isolated himalensine A (7) from D. himalense.16 Himalensine A (7) features a 13,14,22-trinorcalyciphylline A-type skeleton lacking the E ring and the all-carbon quaternary center C-8. The first enantioeselective total synthesis of himalensine A has been accomplished by Dixon’s group in 22 steps through a remarkable Diels−Alder reaction to build the core ring structure.10a Another synthetic breakthrough of this subgroup alkaloids has recently been © XXXX American Chemical Society

Figure 1. Structures of calyciphylline A-type Daphniphyllum alkaloids.

reported for daphenylline,6,8a,9,11 daphniyunnine C,8b daphnilongeranin B,9a daphnipaxianine A,8d hybridaphniphylline B,8c and himalenine D.8d Our research group is interested in the total synthesis of bioactive natural products and their medicinal studies,17 so we initiated a research program toward the chemical synthesis of daphniglaucins18 and calyciphylline Atype Daphniphyllum alkaloids. Here we report a unified strategy to build the basic tetracyclic skeleton of calyciphylline A alkaloids, which can support the total synthesis of himalensine A. Structural analysis suggested to us that the challenge in synthesizing calyciphylline A alkaloids lies in the stereocontrolled construction of the core tetracyclic ring (A−B−C− Received: April 4, 2019

A

DOI: 10.1021/acs.orglett.9b01184 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters D rings) and four contiguous stereogenic centers C-4,5,6 and C-8 (Figure 1). We speculated that the core tetracyclic ring (8) together with the tricyclic ring (11) can serve as an advanced intermediate for the divergent synthesis of daphniyunnines and himalensines, in which the B ring could be formed by a Pdcatalyzed enolate alkenylation from 12 (Scheme 1).13h Then

Scheme 2. Studies of the Key Nitrone 3 + 2 Reactions

Scheme 1. Retrosynthetic Analysis of Calyciphylline A Type Alkaloids

nitrone/olefin 1,3-dipolar cycloaddition19 followed by isooxazolidine ring cleavage and lactamization could be utilized to build a tricyclic skeleton containing a seven-membered D ring. The configuration of the substituted cycloheptene D ring and the geometry of the newly formed nitrone would determine the regio- and diastereoselectivity of the 1,3-dipolar cycloaddition.13r−v The cis configuration A−C rings could be obtained through an endo-1,3-dipolar cycloaddition between the Z-nitrone and C5−C6 olefin (via TSI) or an exocycloaddition between the E-nitrone and C5−C6 olefin (via TSII), which would lead to the same adduct independent of the nitrone configuration.20 N−O bond reductive cleavage of isooxazolidine 9 followed by lactamization would generate the C ring. As a back-up strategy, a linear intermediate such as nitrone 13 might be used to tune the endo- or exo-selectivity of 1,3-dipolar cycloaddition. Our synthetic journey began with investigation of the stereoselectivity of the intramolecular nitrone-alkene cycloaddition (Scheme 2). Based on the retrosynthetic analysis, model substrate 14, containing the necessary aldehyde group and cycloheptene D ring, was first designed to construct the core tricyclic A−C−D rings, which was prepared from substituted cyclohexanone through a 5-step sequence (see details in Supporting Information). Condensation of 14 with BnNHOH (benzyl hydroxylamine) generated a nitrone intermediate 15, which underwent thermodynamic 1,3-dipolar cycloaddition with the electron-deficient alkene to produce cycloadduct 16 as a single diastereomer in 52% yield over 3 steps. N−O bond reductive cleavage of isooxazolidine 16 followed by a spontaneous lactamization furnished tricyclic product 17 in 85% overall yield, with the A, C, and D rings all in the trans configuration. The relative stereochemistry of 17

was confirmed by X-ray crystallographic analysis, which also suggested that the transition state 15 en route to exocycloaddition between Z-nitrone and α,β-unsaturated ester or endocycloaddition between the E-configuration nitrone and α,β-unsaturated ester. To be able to tune the diastereoselectivity of this cycloaddition, we wanted to understand the selectivity for the linear intermediate, so we planned to remove the cycloheptene fragment and test the linear substrate 18 for formation of the cis A−C rings. Preparation of 18 was simplified by introduction of a 1,3dithiane group, which also facilitated subsequent cycloaddition through the Thorpe−Ingold effect. We were pleased to find that the reaction of 18 with different hydroxylamines gave rise to the desired endo-cycloadducts 20a−d, which were efficiently transformed into the cis-hydroindoles 21a−d (A−C rings) in good overall yield. The configurations of 21 were confirmed by X-ray crystallographic analysis of 21a′ and 21c′. The vinyl bromide group in 21d′ can function in the subsequent steps to form the B ring. As a common fragment of calyciphylline A alkaloids, the cishydroindoles 21 might be applied to build the core tetracyclic skeleton through the F to D ring-forming sequence. We decided to test this proposal with himalensine A (7) as the synthetic target. Protection of 21d′ as its TBS ether followed by the removal of the 1,3-dithiane group yielded ketone 22, the precursor for constructing the B ring (Scheme 3). Following the optimized protocol developed by Bonjoch,13h we treated a mixture of 22 with catalytic Pd(PPh3)4 in the presence of PhONa in THF to obtain the cyclized product 23 in 74% yield. B

DOI: 10.1021/acs.orglett.9b01184 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Total Synthesis of Himalensine Aa

a Procedures: (a) TBSCl, DMAP, imidazole, rt, 81%; (b) I2, NaHCO3, MeCN, 0 °C to rt, 90%; (c) Pd(PPh3)4, PhONa, THF, reflux, 74%; (d) Crabtree’s catalyst, H2 (balloon), CH2Cl2, then TfOH, (TMSOCH2)2, CH2Cl2, 0 °C to rt, 51% (21% for 24′); (e) DMSO, (COCl)2, then Et3N, CH2Cl2, −78 °C to rt; (f) NaHMDS, triethylphosphonoacetate, THF, rt, 68% (2 steps); (g) Pd/C, H2 (balloon), MeOH, rt, then LiAlH4, THF, −40 °C, 80%; (h) DMSO, (COCl)2, then Et3N, CH2Cl2, −78 °C to rt; (i) PPh3CH3Br, t-BuOK, THF, rt, 90% (2 steps); (j) HCl (10%), THF, rt; (k) KHMDS, TMSCl, THF, −78 °C; (l) Yb(OTf)3, HCHO(aq.), THF, 71% (3 steps); (m) TMSOTf, (TMSOCH2)2, CH2Cl2, −78 °C to rt, 65%; (n) DMP, NaHCO3, CH2Cl2, rt; (o) ethenylMgBr, THF, 0 °C, 63% (2 steps); (p) Grubbs (II) cat., CH2Cl2, reflux, 87%; (q) Pd/C, H2 (balloon), EtOAc; (r) DMP, NaHCO3, CH2Cl2, rt, 72% (2 steps); (s) KHMDS, PhN(Tf)2, THF, −78 °C, 71%; (t) Pd(PPh3)4, CO (balloon), tributylvinylstannane, LiCl, CuCl, DMF, 60 °C, 90%; (u) Cu(OTf)2, DCE, 60 °C, 74%; (v) [IrCl(CO)(PPh3)2], TMDS, then AcOH, NaBH(OAc)3, rt, 14%. TBSCl: tert-Butyldimethylsilyl chloride; DMAP: 4-Dimethylaminopyridine; DMP: Dess-Martin periodinane; KHMDS: Potassium bis(trimethylsilyl)amide; NaHMDS: Sodium bis(trimethylsilyl)amide; TMDS: 1,1,3,3-Tetramethyldisiloxane.

Selective hydrogenation of exocyclic olefin with Crabtree’s catalyst, followed by one-pot protection of the carbonyl group and deprotection of the TBS group, furnished azatricyclic compound 24 in 51% yield and unprotected compound 24′. We first attempted to use a radical reaction to introduce an allyl group on C-6. For this purpose, we prepared thioester 25 and subjected it to Keck’s condition.21 Reaction of 25 with allyltri-n-butylstannane at 90 °C in degassed toluene containing catalytic AIBN generated 26 as a single detectable diastereomer, in which the C-6 allyl group was oriented opposite to its position in the naturally occurring molecule (Scheme 4).

We reasoned that the bowl-shaped radical intermediate 27 completely blocked the Re-face, such that radical termination occurred from the same side of the C-5 methyl group. Ring strain blocked our attempts to isomerize via enolization under basic conditions. To continue with this compound nevertheless, we used oxidation and Horner−Wadsworth−Emmons (HWE) olefination to introduce an α,β-unsaturated ester on C-6, producing 28. Stereocontrolled hydrogenation, oxidationstate adjustment, and olefination formed 29 bearing the allyl group in the desired α-configuration in overall 90% yield. Acetal deprotection of 29 under acidic condition produced the related ketone, which was subjected to an aldol reaction to produce the allylic alcohol. After extensive screening of reaction conditions, we found that the silyl enol ether was more reactive than the active metal enolate. An Yb(OTf)3mediated Mukaiyama aldol reaction with formaldehyde formed 30 with a hydroxylmethane group, while acrylaldehyde did not react at all. The relative stereochemistry of 30 was confirmed by X-ray diffraction analysis. Oxidation of 30 with Dess-Martin periodinane followed by two-carbon homologation through ethenylmagnesium bromide addition and ring closing metathesis yielded 31 containing the seven-membered D ring in 87% overall yield. We planned to adopt a cascade reaction of Rupe rearrangement and Nazarov cyclization22 to install the cyclopentanone F ring. Therefore, 31 was efficiently converted to 32−34 through hydrogenation, oxidation of the allylic alcohol, and deprotection of the acetal group (Scheme 4). We then investigated 1,2-addition of (methoxypropynyl)-lithium or magnesium bromide to the carbonyl group in 32−34 and failed to obtain an adduct under these conditions (see details in Supporting Information). We speculated that it may be

Scheme 4. Structural Analysis and Chemoselectivities

C

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21772044), the “National Young Top-Notch Talent Support Program”, Program of Shanghai Academic/Technology Research Leader (18XD1401500), Program of Shanghai Science and Technology Committee (18JC1411303), and “the Fundamental Research Funds for the Central Universities” for generous financial support.

possible to achieve this transformation through stepwise bond formation and Nazarov reaction,23 based on the pioneering total synthesis of calyciphylline N by the Smith group.5 31 was hydrogenated by Pd/C and oxidized to the corresponding ketone which was transformed into vinyl triflate under basic condition. Carbonylative Stille coupling of the triflate with tributylvinylstannane generated dienone 35 in good yield, which underwent selective Nazarov cyclization with copper triflate to provide pentacyclic 36 in 74% yield, which is an advanced intermediate in the first enantioselective total synthesis of himalensine A reported by the Dixon group.10a The spectroscopic data (1H and 13C NMR spectra, as well as HRMS) of synthetic 36 were fully consistent with the corresponding reported data. The lactam carbonyl group in 36 was selectively reduced in the presence of Vaska’s catalyst [IrCl(CO)(PPh3)2], which was developed by Dixon and coworkers,10a allowing us to achieve the total synthesis of himalensine A (7). In summary, we have accomplished the total synthesis of himalensine A, a pentacyclic calyciphylline A alkaloid. To build the core tetracyclic skeleton (A−B−C−D rings) of this family of molecules, we developed a strategy of nitrone/olefin 1,3dipolar cycloaddition, isooxazolidine ring cleavage, and lactamization, which facilitated construction of cis-hydroindole (A−C rings). The Pd-catalyzed enolate alkenylation was adopted to install a B ring. The challenging seven-membered D ring was formed through ring closing metathesis from the bowl-shaped tricyclic A−C−F rings. The cyclopentanone F ring was installed using a Lewis acid promoted Nazarov reaction inspired by Smith’s work. Currently, we are using this synthetic approach to synthesize more challenging Daphniphyllum alkaloids, which will be reported in due course.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01184. General experimental procedures, characterization data, 1 H and 13C NMR spectra of new compounds, and X-ray data (PDF) Accession Codes

CCDC 1875788, 1875860, 1875863, 1875873, 1875884, 1875921, and 1875932 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Shuanhu Gao: 0000-0001-6919-4577 Notes

The authors declare no competing financial interest. D

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