Letter pubs.acs.org/OrgLett
Synthesis of the ABC Tricyclic System of Daphnicyclidin A Jian Long Li,† Hong Wei Shi,† Qi Wang, Yong Hai Chai, and Jun Yang* Innovative Research Center of Medicine, Key laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Chang’an Campus: No. 620, West Chang’an Avenue, Chang’an District, Xi’an 710119, China S Supporting Information *
ABSTRACT: A substrate-stereocontrolled synthesis of the ABC tricyclic system of daphnicyclidin A is developed. The key reactions include an efficient tandem N-allylation−SN2′ reaction to assemble 2,3,4-cis trisubstituent pyrrolidine ring C and two intramolecular Horner−Wadsworth−Emmons reactions to construct cycloheptanone ring A and piperidine ring B.
T
he daphniphyllum alkaloids,1 isolated from the genus Daphniphyllum, have attracted considerable attention from the synthetic community for decades due to their structural diversity and potential biological activities, which have led to innovation in synthetic strategies and elegant accomplishments in total synthesis.2 To date, more than 320 daphniphyllum alkaloids have been isolated and classified into 14 structural types according to their characteristic ring systems.1a Daphnicyclidins A−H were first isolated from the stems of Daphniphyllum humile and Daphniphyllum Teijsmanni by Kobayashi and co-workers in 2001.3 Preliminary biological assay showed them to possess moderate cytotoxic activity against murine lymphoma L1210 and human epidermoid carcinoma KB cells with IC50 values in the range of 0.8−10 μM. The structure of daphnicyclidins is characterized by an unprecedented 7/5/7/5 ring system, containing a 2,3,4-cis trisubstituent pyrrolidine (ring C) and a highly reactive fulvene moiety (ring E) embedded in two fused cycloheptanones (ring A and D). More daphnicyclidin-type alkaloids have been isolated in recent years;4 four examples are depicted in Figure 1. The highly fused hexacyclic system and
Our retrosynthetic analysis is described in Scheme 1. The plan explores the assembling of the reactive fulvene ring at the last Scheme 1. Retrosynthesis of Daphnicyclidin A
stage via an oxidative coupling of enolates8 followed by dehydrogenation. The six-membered δ-valerolactone ring F and seven-membered cycloheptanone ring D were expected to be formed in one step from 2 via a tandem radical Michael addition.9 Intermediate 2 can be obtained via a several-step conversion from ABC tricyclics intermediate 3. Cycloheptanone ring A and six-membered piperidine ring B of 3 could be constructed via two intramolecular Horner−Wadsworth− Emmons reactions from pyrrolidine 4. Finally, pyrrolidine 4 can be accessed from 2,3,4-cis trisubstituent pyrrolidine 5. In our previous studies, a tandem N-allylation−SN2′ reaction has been developed to access fast and stereoselective construction of the 2,3-trans-3,4-cis pyrrolidine from oxazolidinone substrate 6 and 1,4-dihalogen-2-butene. Based on this method, the BCD tricyclics skeleton of macrocyclic diamine
Figure 1. Representative daphnicyclidin-type alkaloids.
contiguous stereogenic centers make the synthesis of daphnicyclidins a challenging task. To date, three innovative approaches toward the fused-ring system of daphnicyclidins have been attempted, including ABCD tetracyclics by the Overman group,5 ent-BCD tricyclics by the Iwabuchi group,6 and ABC tricyclics by the Williams group.7 Herein, we disclose a novel synthesis of the ABC tricyclics skeleton of daphnicyclidin A. © XXXX American Chemical Society
Received: January 22, 2017
A
DOI: 10.1021/acs.orglett.7b00230 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters alkaloids densanins A-B10 and the formal total synthesis of kainic acid11 were achieved via 2,3-trans-3,4-cis pyrrolidine intermediates 7 and 8, respectively. It is believed that the 2,3-trans selectivity in this reaction should originate from the steric effect between N-1, the C-2 oxazolidinone ring and C-3 ester, and the half-chair transition-state of the five-membered pyrrolidine ring, resulting in 3,4-cis selectivity (Scheme 2A). Consequently, it is
Scheme 3. Synthesis of the ABC Rings of Daphnicyclidin A
Scheme 2. Synthesis of 2,3,4-Cis-Trisubstituted Pyrrolidine 5 via Tandem N-Allylation−SN2′ Reaction
configuration of 13 was determined as 2,3,4-cis by X-ray analysis. Reduction of the ester group of 13 with LiAlH4 in THF under −20 °C followed by protection of the alcohol with benzyl afforded 14 in 85% yield. Upon treatment of 14 with t-BuOK in aqueous t-BuOH under 100 °C overnight, the oxazolidinone underwent hydrolysis to afford an amine intermediate, which reacted with phosphate ester 15 to deliver amide 16 in 78% yield. Subsequent Dess−Martin oxidation of 16 produced the aldehyde as a substrate for intramolecular Horner−Wadsworth−Emmons reaction. Under Rathke’s conditions,12 ring B was formed smoothly to afford 17 in 77% yield. After hydrogenolysis of 17 with 10% Pd/C under 1 atm of hydrogen, the benzyl group was removed, and two double bonds were reduced. The resulting ester reacted with the lithium salt of dimethyl methylphosphonate at −78 °C in THF to afford the corresponding βketophosphonates 18 in 65% yield. Compound 18 is a single isomer, as the epimerization probably emerges in the latter Horner−Wadsworth−Emmons reaction. The configuration of C-7 was not determined. Alcohol 18 was subsequently converted to aldehyde by Dess−Martin oxidation, which was treated with K2CO3/18-crown-6 in toluene and stirring at 80 °C overnight, eventually affording ring A. The structure of 20 has been determined by X-ray analysis in which the configuration of all stereogenic centers is consistent with that of (+)-daphnicyclidin A. Having efficiently prepared the ABC tricyclic intermediate 20, we turned our attention to synthesis of the key intermediate 3. As described in Scheme 4, oxidative cleavage of the vinyl of 14 with OsO4 and NaIO4 in aqueous methanol followed by reaction with triethyl phosphonoacetate afforded α,β-unsaturated ester 21 in 79% overall yield. Hydrogenolysis of the double bond of 17 followed by reduction of the ester group with LiAlH4, alcohol 22 was delivered in 91% yield. After treatment of 22 with MOMCl
reasonable that if (S)-3-Cbz-amino-γ-butyrolactone is used as the substrate, the C-3 formate ester and C-2 methylol will be fixed at the same side of the newly formed pyrrolidine ring, and the 2,3-cis selectivity will occur. As shown in Scheme 2B, treatment of (S)-3-Cbz-amino-γbutyrolactone with NaH in DMF under −30 to −20 °C deliver pyrrolidine 5 and its diastereisomer 10 in 61% and 10% yield, respectively. Owing to the existence of rotamers in 5 and 10, it is arduous to identify their stereochemistry by NOEDS experiment. Finally, the major isomer 5 was determined as 2,3,4-cis by X-ray crystallography, and the minor isomer 10 was determined as 2,3-cis-3,4-trans by the conversion of 10 to 11 and then taken by NOEDS spectra. We believe the 3,4-cis configuration of 5 was derived from the more stable half-chair transition state, and the 3,4-trans configuration of 10 originated from the steric effect between the C-2, C-3 lactone and C-4 vinyl of 12. Further efforts aimed at improving the diastereoselectivity and yield by altering the base (LiHMDS/NaHMDS/KH), temperature (−78 to 0 °C), and solvent (THF/toluene/DMSO) have been unsuccessful. With 5 in hand, we next attempted to incorporate the C-3 quaternary carbon center. As shown in Scheme 3, after treatment of 5 with LiHMDS and iodomethane in THF at −78 to −58 °C, the product of C-3 methylation was delivered with no formation of undesired isomer evident. The crude product was then treated with 2 equiv of sodium hydroxide in aqueous methanol followed by changing the solvent to DMF and addition of iodomethane, and oxazolidinone 13 was obtained in 86% yield from 5. The B
DOI: 10.1021/acs.orglett.7b00230 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
Scheme 4. Synthesis of the ABC Tricyclic Intermediate 3
Yong Hai Chai: 0000-0003-3157-179X Jun Yang: 0000-0002-8093-828X Author Contributions †
J.L.L. and H.W.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (21372149, 21572125) and Shaanxi Normal University.
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and DIPEA in CH2Cl2, the hydroxyl group of 22 was blocked by the MOM group, affording 23 in 92% yield. Subsequently, following the procedure of preparing 19 from 14, compound 23 was converted to aldehyde 26 in 29% overall yield. Eventually, the tricyclic intermediate 3 was delivered in 56% yield by treatment of 26 with K2CO3 and 18-crown-6 in toluene at 80 °C for 8 h. By comparing the 1H NMR spectra of 3 with 20, the structure of 3 was further confirmed. In summary, we have developed a novel synthesis toward the ABC tricyclic skeleton of daphnicyclidin A. A substratestereocontrolled tandem N-allylation−SN2′ reaction was utilized to produce a highly efficient construction of the 2,3,4-cistrisubstituted pyrrolidine core, methylation of the α-position of ester to install the C-3 quaternary carbon center, and two intramolecular Horner−Wadsworth−Emmons reaction to construct the six-membered ring B and seven-membered ring A. The total synthesis of daphnicyclidin A is underway in our laboratory and will be disclosed in due course.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures for preparation of new compounds including spectra, and X-ray data for compound 5, 13, 20 in CIF format. The Supporting Information is available free of charge on the ACS Publications Web site The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00230. Experimental procedures for preparation of new compounds including spectra (PDF) X-ray data for compound 5 (CIF) X-ray data for compound 13 (CIF) X-ray data for compound 20 (CIF)
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DOI: 10.1021/acs.orglett.7b00230 Org. Lett. XXXX, XXX, XXX−XXX
