Construction of the [6,5,7,5] Tetracyclic Core of Calyciphylline A Type

Aug 24, 2017 - A novel and efficient approach toward the assembly of the synthetically challenging tetracyclic [6,5,7,5] core structure of calyciphyll...
0 downloads 11 Views 993KB Size
Download PDF
Letter pubs.acs.org/OrgLett

Construction of the [6,5,7,5] Tetracyclic Core of Calyciphylline A Type Alkaloids via a Tandem Semipinacol Rearrangement/Nicholas Reaction Hui Shao,† Wen Bao,‡ Ze-Ran Jing,‡ Yun-Peng Wang,‡ Fu-Min Zhang,‡ Shao-Hua Wang,*,‡ and Yong-Qiang Tu*,†,‡ †

School of Chemistry & Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China State Key Laboratory of Applied Organic Chemistry & School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China

‡

S Supporting Information *

ABSTRACT: A novel and efficient approach toward the assembly of the synthetically challenging tetracyclic [6,5,7,5] core structure of calyciphylline A-type alkaloids is developed. The synthetic route features a tandem semipinacol rearrangement/ Nicholas reaction that has been devised strategically to construct the spirocyclic A/B ring and the sterically congested vicinal allcarbon quaternary carbon centers in high diastereoselectivity. Late-stage installation of the hydropyrrole ring and the strained 7membered ring via a double-reductive amination and ring-closing metathesis, respectively, has also been realized.

C

functionalized tetracyclic intermediate is realized (Scheme 1), no total synthesis of them has been achieved to date.4 In connection with the structural features of calyciphylline A type alkaloids and our longstanding investigation on semipinacol rearrangement,5 we envisioned that the use of a tandem semipinacol rearrangement/Nicholas reaction6 might be viable for the construction of the two key structural units of these alkaloids, i.e., the A/B spiro ring system and the two contiguous

alyciphylline A ype alkaloids are a group of natural products consisting of more than 30 bioactive molecules isolated from the genus Daphniphyllum.1 Recent studies on these alkaloids have shown that some of them exhibit anti-HIV2 and inhibitory activity against some kinase enzymes,1e,f which has attracted increasing attention from organic chemists. From a structural perspective (Figure 1), calyciphylline A type

Scheme 1. Retrosynthetic Analysis of Daphniyunnine B

Figure 1. Representative calyciphylline A type alkaloids containing a [6,5,7,5] tetracyclic skeleton.

alkaloids all share a unique and architecturally sophisticated [6,5,7,5] tetracyclic ring system representing the most complex and synthetically challenging part of these molecules, of which the central cyclohexanone (ring A) forms a spirocyclic ring system with ring B, and has three contiguous stereocenters with two of them being vicinal quaternary carbon centers, whose construction is a generally accepted challenge in organic synthesis.3 Ring A is also fused with a synthetically difficult medium-sized ring C and a polysubstituted tetrahydropyrrole ring D. The above structural complexity has made these alkaloids formidable synthetic targets. Accordingly, although it is clear that the collective synthesis of some of these molecules should be feasible once the construction of a properly © 2017 American Chemical Society

Received: July 24, 2017 Published: August 24, 2017 4648

DOI: 10.1021/acs.orglett.7b02274 Org. Lett. 2017, 19, 4648−4651

Letter

Organic Letters

product was observed (Table 1, entries 1−5), except for the reactions using EtAlCl2 or AlCl3, in which alkyne 5 was obtained in only 7% and 15% yield, respectively, after demetalation with Fe(NO3)3·9H2O (Table 1, entries 6 and 7). A combination of different Lewis acids was next investigated (Table 1, entries 8−10). To our delight, a mixture of AlCl3 and EtAlCl2 (1:1 mol ratio) could promote this reaction more efficiently, increasing the yield of the two-step sequence to 50% (Table 1, entry 10). Structural assignments of products 5a, 5b, and 5c were unambiguously confirmed by X-ray crystallographic analysis (Figure 2).10 Pleasingly, the relative configuration between C5 and C8 of both isomers 5a and 5b was in agreement with that of daphniyunnine B.

all-carbon quaternary stereocenters. This single transformation would be highly efficient in simplifying the molecular complexity of this type of alkaloid if it could proceed in a diastereoselective manner and also represent the first carbon electrophile involved semipinacol rearrangement of allylic alcohol derivative for the construction of vicinal quaternary carbon centers. According to this assumption, daphniyunnine B was selected as our synthetic target. As illustrated in Scheme 1, daphniyunnine B could be synthesized from the tetracyclic compound 1 through functional group manipulations. The 7membered D ring in compound 1 was supposed to be constructed by an intramolecular ring-closing metathesis (RCM)7 from diene 2 after the tetrahydropyrrole ring in 3 was installed via a double-reductive amination of compound 4. The aldehyde 4 could then be obtained from alkyne 5 through the introduction of a formyl group at the C6 position. Alkyne 5 could be generated by our devised tandem reaction of enone 6 with Nicholas reagent 7. As shown in Scheme 2, the preparation of enone 6 commenced from known allyl alcohol 8.8 Protection of the Scheme 2. Synthesis of the Rearrangement Precursor 6

Figure 2. X-ray crystallographic analysis of 5a−c.

Next, we selected the major isomer 5a for further elaboration. Direct introduction of a functional group at C6 position next to the quaternary carbon atom proved difficult presumably because of the large steric hindrance surrounding the quaternary carbon center, and efforts to introduce a side chain at C6 using different electrophiles all met with failure.12 In an attempt to circumvent this problem, we finally resorted to Johnson−Claisen rearrangement13 of an allylic alcohol 16 to functionalize the C6 position. Accordingly, the allylic alcohol 16 was prepared from alkyne 5a using a five-step procedure (Scheme 3). Partial reduction of the alkynyl group of 5a with Lindlar Pd and H2 gave alkene 12 in quantitative yield, which was then isomerized to internal olefin 13 using Pd(MeCN)2Cl2.14 Ozonolysis of 13 followed by HWE reaction with aldehyde 14 produced α,β-unsaturated ester 15 (72% overall yield). Final reduction of the distal ester group of 15 using L-Selectride was also accompanied by the reduction of

secondary hydroxy group of 8 as its MOM ether afforded 9 in 90% yield. After Li−halogen exchange of 9 with t-BuLi, cyclobutanone was added to give the addition product 10 in 70% yield. Silylation of 10 with TMSCl was followed by allylic oxidation under Doyle’s conditions9 to generate the rearrangement precursor 6. With enone 6 in hand, we then explored the crucial tandem semipinacol rearrangement/Nicholas reaction for the assembly of B ring and the two vicinal all-carbon quaternary stereocenters (Table 1). For most Lewis acids screened, no desired Table 1. Optimization of Reaction Conditions11

Scheme 3. Synthesis of C6-Functionalized Products 17 and 18

entry

Lewis acid

time (h)

yield of 5a (%)

1b 2b 3b 4c 5c 6d 7d 8b,e 9b,e 10e,f

TiCl4 SnCl4 BF3·Et2O Et3Al Et2AlCl EtAlCl2 AlCl3 Et2AlCl/EtAlCl2 Et2AlCl/AlCl3 AlCl3/ EtAlCl2

1−2 1−2 6−7 1−2 6−7 6−7 6−7 6−7 6−7 6−7

none none none none none 7 15 none none 50

a

Isolated yield. bDecomposition. cDesilylation. ddr not determined. Lewis acids (1:1 mol ratio). fdr = 7:2:1.

e

4649

DOI: 10.1021/acs.orglett.7b02274 Org. Lett. 2017, 19, 4648−4651

Letter

Organic Letters the C4 carbonyl group, furnishing allylic alcohol 16 in 84% yield. To our delight, treatment of 16 with trimethyl orthoacetate and a catalytic amount of propionic acid at 130 °C successfully afforded the C6-vinylated product 17 and 18, albeit in low combined yield (25%). A major side product in this reaction was acetyl-protected allylic alcohol 19, which could be recycled after hydrolysis. Although we succeeded in introducing a vinyl group at the C6 position, the relative configuration was not yet determined. However, as both the vinyl and the methyl 2-carboxylate ethyl group contain a two-carbon unit for further functionalization, and the synthetic route could be adjusted if an advanced intermediate in late-stage synthesis was identified to have the false C6 configuration. Therefore, we decided to first use the vinyl part to construct the hydropyrrole ring (Scheme 4).

Scheme 5. Synthesis of Tetracyclic Compound 1

Scheme 4. Synthesis of Tricyclic Compound 3 substitution of 25 with thiophenol would generate sulfide 26 in quantitative yield, which could be oxidized to sulfoxide 27. Compound 27 would undergo thermodynamic elimination in the presence of DIPEA to furnish terminal olefin 28.17 Grignard addition of allylmagnesium bromide to the C9 ketone functionality of olefin 28 finally gave diene 2. To our delight, the intramolecular ring-closing metathesis (RCM) proceeded smoothly when Grubbs II catalyst was used, affording compound 1 with the [6,5,7,5] tetracyclic framework of calyciphylline A being established. In conclusion, we have developed an efficient synthetic route to access the [6,5,7,5] tetracyclic framework of calyciphylline A type alkaloids that features a tandem semipinacol rearrangement/Nicholas reaction to construct the spiro-cyclic A and B ring, a double-reductive amination to form the hydropyrrole ring, and an intramolecular ring-closing metathesis (RCM) to install the medium-sized C ring. Notably, the one-step construction of the challenging two vicinal quaternary carbon centers has further demonstrated the exceptional efficiency of 1,2-rearrangement reaction in the assembly of structurally congested carbon unit. Continued efforts toward the total synthesis of this type alkaloids are currently underway in our laboratory.

Reduction of methyl ester 17 or lactone 18 with L-Selectride afforded the same diol 20 in 85% or 80% yield, respectively. Selective protection of the primary hydroxyl group in 20 to its TBS silyl ether 21 followed by oxidation of the secondary hydroxyl group with Dess−Martin periodinane smoothly furnished diketone 22, which was converted to aldehyde 4 after ozonolysis in 52% overall yield. Next, we attempted the stereoselective construction of the hydropyrrole ring via a key double-reductive amination.15 The reaction could smoothly take place when aldehyde 4 was treated with benzylamine in the presence of NaBH3CN and HOAc, generating tricyclic compound 23. The N-benzyl protection of compound 23 was removed via hydrogenation under high pressure and replaced with a tosyl group to give sulfonamide 3 in 81% yield over three steps (with only one column chromatography needed in the final step). Fortunately, the relative configuration of C6 in 3 was consistent with daphniyunnine B after singal-crystal X-ray crystallographic analysis,16 suggesting a cis-configuration of the C6 vinyl and C5 methyl groups in lactone 18 (as drawn correctly in Scheme 3). Having accomplished the synthesis of tricyclic compound 3, the stage was set for the construction of the C ring via an intramolecular ring-closing metathesis (Scheme 5). Removal of the TBS protection in 3 and sulfonylation of the resulting primary hydroxy group gave sulfonate 25. The nucleophilic

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02274. Full experimental details (PDF) X-ray data for compound 5a (CIF) X-ray data for compound 5b (CIF) X-ray data for compound 5c (CIF) X-ray data for compound 3 (CIF)

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected], [email protected]. *E-mail: [email protected]. ORCID

Fu-Min Zhang: 0000-0001-5578-1148 Shao-Hua Wang: 0000-0002-4347-8245 Yong-Qiang Tu: 0000-0002-9784-4052 4650

DOI: 10.1021/acs.orglett.7b02274 Org. Lett. 2017, 19, 4648−4651

Letter

Organic Letters Notes

(10) X-ray structures of 5a, 5b, and 5c with thermal ellipsoids drawn at 30% probability level, CCDC 1559291 (5a), CCDC 1559292 (5b), and CCDC 1559293 (5c). (11) Reaction conditions: the mixture of enone 6 and cobalt complex 7 in DCM was cooled to −78 °C, and Lewis acid (1.3 equiv) was added. Then the reaction was stirred at rt for a given period of time as indicated in the Table. (12) See the Supporting Information. (13) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38, 3133−3148. (14) Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652−4658. (15) Jacquemot, G.; Maertens, G.; Canesi, S. Chem. - Eur. J. 2015, 21, 7713−7715. (16) X-ray structures of 3 with thermal ellipsoids drawn at 30% probability level, CCDC 1559528. (17) Nagaoka, H.; Shibuya, K.; Yamada, Y. Tetrahedron 1994, 50, 661−688.

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We gratefully acknowledge financial support from the NSFC (Nos. 21290180, 21372104, 21472077, and 21772071). REFERENCES

(1) (a) Wu, H.; Zhang, X.; Ding, L.; Chen, S.; Yang, J.; Xu, X. Planta Med. 2013, 79, 1589−1598. (b) Kobayashi, J. i.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936−962. (c) Dong, M.; Zhang, M. L.; Shi, Q. W.; Gu, Y. C.; Kiyota, H. Curr. Org. Chem. 2009, 13, 646−682. (d) Li, Z.-Y.; Guo, Y.-W. Chin. J. Org. Chem. 2007, 27, 565. For selected examples on the isolation toward calyciphylline A type alkaloids, see: (e) Zhang, H.; Zhang, D.-D.; Li, J.-Y.; Shyaula, S. L.; Li, J.; Yue, J.-M. RSC Adv. 2016, 6, 44402−44409. (f) Zhang, H.; Shyaula, S. L.; Li, J.-Y.; Li, J.; Yue, J.-M. J. Nat. Prod. 2015, 78, 2761−2767. (2) Xu, J.-B.; Zhang, H.; Gan, L.-S.; Han, Y.-S.; Wainberg, M. A.; Yue, J.-M. J. Am. Chem. Soc. 2014, 136, 7631−7633. (3) (a) Büschleb, M.; Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.; Overman, L. E. Angew. Chem., Int. Ed. 2016, 55, 4156−4186. (b) Long, R.; Huang, J.; Gong, J.; Yang, Z. Nat. Prod. Rep. 2015, 32, 1584−1601. (4) For reviews of synthetic studies toward calyciphylline A type alkaloids, see: (a) Chattopadhyay, A. K.; Hanessian, S. Chem. Rev. 2017, 117, 4104−4146. (b) Kang, B.; Jakubec, P.; Dixon, D. J. Nat. Prod. Rep. 2014, 31, 550−562. For selected examples on synthetic studies toward calyciphylline A type alkaloids, see: (c) Coussanes, G.; Bonjoch, J. Org. Lett. 2017, 19, 878−881. (d) Guo, J.-J.; Li, Y.; Cheng, B.; Xu, T.; Tao, C.; Yang, X.; Zhang, D.; Yan, G.; Zhai, H. Chem. Asian J. 2015, 10, 865−868. (e) Stockdill, J. L.; Lopez, A. M.; Ibrahim, A. A. Tetrahedron Lett. 2015, 56, 3503−3506. (f) Ma, D.; Cheng, H.; Huang, C.; Xu, L. Tetrahedron Lett. 2015, 56, 2492−2495. (g) Diaba, F.; Martínez-Laporta, A.; Coussanes, G.; Fernández, I.; Bonjoch, J. Tetrahedron 2015, 71, 3642−3651. (h) Xiong, X.; Li, Y.; Lu, Z.; Wan, M.; Deng, J.; Wu, S.; Shao, H.; Li, A. Chem. Commun. 2014, 50, 5294− 5297. (i) Ibrahim, A. A.; Golonka, A. N.; Lopez, A. M.; Stockdill, J. L. Org. Lett. 2014, 16, 1072−1075. (j) Wang, L.; Xu, C.; Chen, L.; Hao, X.; Wang, D. Z. Org. Lett. 2014, 16, 1076−1079. (k) Darses, B.; Michaelides, I. N.; Sladojevich, F.; Ward, J. W.; Rzepa, P. R.; Dixon, D. J. Org. Lett. 2012, 14, 1684−1687. (l) Yao, Y.; Liang, G. Org. Lett. 2012, 14, 5499−5501. (m) Yang, M.; Wang, L.; He, Z.-H.; Wang, S.H.; Zhang, S.-Y.; Tu, Y.-Q.; Zhang, F.-M. Org. Lett. 2012, 14, 5114− 5117. (n) Xu, C.; Wang, L.; Hao, X.; Wang, D. Z. J. Org. Chem. 2012, 77, 6307−6313. (o) Xu, C.; Liu, Z.; Wang, H.; Zhang, B.; Xiang, Z.; Hao, X.; Wang, D. Z. Org. Lett. 2011, 13, 1812−1815. (p) Sladojevich, F.; Michaelides, I. N.; Darses, B.; Ward, J. W.; Dixon, D. J. Org. Lett. 2011, 13, 5132−5135. (q) Solé, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461−5464. (5) (a) Wang, S.-H.; Li, B.-S.; Tu, Y.-Q. Chem. Commun. 2014, 50, 2393−2408. (b) Wang, B.; Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207− 1222. (c) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523−7556. (6) For reviews of the Nicholas reaction, see: (a) Green, J. Synlett 2012, 23, 1271−1282. (b) Kann, N. Curr. Org. Chem. 2012, 16, 322− 334. (c) Green, J. R. Eur. J. Org. Chem. 2008, 2008, 6053−6062. (d) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207−214. (e) Teobald, B. J. Tetrahedron 2002, 58, 4133−4170. (f) Muller, T. J. J. Eur. J. Org. Chem. 2001, 2001, 2021−2033. (g) Welker, M. E. Curr. Org. Chem. 2001, 5, 785−807. (h) Green, J. R. Curr. Org. Chem. 2001, 5, 809− 826. For our previous study, see: Shao, H.; Zhang, X. M.; Wang, S. H.; Zhang, F. M.; Tu, Y. Q.; Yang, C. Chem. Commun. 2014, 50, 5691− 5695. (7) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490−4527. (8) Wu, K.-M.; Okamura, W. H. J. Org. Chem. 1990, 55, 4025−4033. (9) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622−13623. 4651

DOI: 10.1021/acs.orglett.7b02274 Org. Lett. 2017, 19, 4648−4651