H-Bonding Mediated Asymmetric Intramolecular Diels–Alder Reaction

Letter Cite This: Org. Lett. 2018, 20, 7312−7316

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H‑Bonding Mediated Asymmetric Intramolecular Diels−Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone‑1 Joon-Ho Lee and Cheon-Gyu Cho* Center for New Directions in Organic Synthesis, Department of Chemistry, Hanyang University, 222 Wangshimni-ro, Seongdong-gu, Seoul 04763, Korea

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S Supporting Information *

ABSTRACT: An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the π-facial selectivity of intramolecular Diels− Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an α-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky’s synthesis of aplykurodinone-1.

A

Scheme 1. Danishefsky’s Synthesis of Aplykurodinone-1

plykurodinone-1 is a degraded steroidal tricyclic lactone isolated from the sea hare Syphonato geographica belonging to the family Aplysiidae of phylum Mollusca.1 This substance, like its previously identified congeners (Figure 1), has an unusual cis-fused hydrindane skeleton, containing six

mediated conjugate addition and a Julia olefination. Similar convergent pathways, utilizing a variety of novel strategies and methods, have been reported by five other research groups.4 Recently, Qiu and co-workers described a de novo synthesis in which the C11 side chain was constructed by using an Ireland−Claisen rearrangement of a ketene silyl acetal formed from naturally occurring (R)-seudenol and (R)-citronellic acid, thus avoiding a cumbersome conjugate-addition-based process.5 As a part of an ongoing research program aimed at developing the use of 3,5-dibromo-2-pyrone in target oriented synthesis,6 we designed a route for the formal total synthesis of (+)-aplykurodinone-1 based on the proposal that the appropriately functionalized cis-fused hydrindane core present in Danishefsky’s intermediate (+)-3 could be generated from the tricyclolactone 4 (Scheme 2). Furthermore, we envisaged that this tricyclolactone could be produced by an endoselective intramolecular Diels−Alder cycloaddition of the enone-tethered 2-pyrone (S)-5, which, in turn, would be formed by a short route beginning with a C3-selective Sonogashira coupling reaction of 3,5-dibromo-2-pyrone (6) with alkyne (S)-7.

Figure 1. Aplykurodinone-1 and related natural products.

contiguous stereogenic centers, including an all C−C bonded quaternary carbon center at C7 and a methyl substituted side chain at C11 (Figure 1).2 While no studies aimed at assessing the biological activities of aplykurodinone-1 have been reported, several analogous aplykurodins have been shown to possess intriguing cytotoxic activities against various human cancer cell lines.2a In the context of the long-standing interest in “C20 problem” in steroid synthesis, Danishefsky and his co-workers carried out earlier studies focusing on the synthesis of aplykurodins, which contain a similar methyl substitution pattern at C13. The contrast between the unique cis-fused hydrindane framework of the aplykurodins and the usual transfused C/D hydrindane system found in steroids further stimulated efforts leading to Danishefsky’s first total synthesis of (±)-aplykurodinone-1.3 The key step in the route (Scheme 1) developed by this group involved anionic Diels−Alder reaction between dienolate 1 and cyclopentenone 2 that generated tricyclic enone 3 (referred to as the Danishefsky’s intermediate). Installation of C11 side chain in this route was accomplished using a five-step sequence including a BF3© 2018 American Chemical Society

Received: October 12, 2018 Published: November 7, 2018 7312

DOI: 10.1021/acs.orglett.8b03250 Org. Lett. 2018, 20, 7312−7316

Letter

Organic Letters

96% ee (determined by HPLC on chiral stationary phase; see Supporting Information (SI)). Alcohol (R)-7 was also prepared for the purpose of comparison (vide infra) through reduction using (R)-CBS as the catalyst and desilylation (83% yield and 96% ee). Sonogashira coupling reaction of (S)-7 with 3,5-dibromo-2pyrone (6) occurred with anticipated C3 chemoselectivity to form alkyne (S)-13 in 72% yield (Scheme 5).6b,9 Hydration of

Scheme 2. Retrosynthesis of Danishefsky’s Intermediate (+)-3

Scheme 5. Preparation of IMDA Substrates

A key feature of our strategy is the expectation that the secondary hydroxyl group (or a protected form) in the enone containing tether in (S)-5 would provide a bias for π-facial discrimination in an intramolecular Diels−Alder (IMDA) reaction.7 Specifically, we believed that endo-selective IMDA reaction of (S)-5 would take place preferentially via transition state TS-A, in which the OPG group is pseudo-equatorially positioned, rather than TS-B having the OPG group pseudoaxially disposed (Scheme 3). If this reasoning is valid, the Scheme 3. Hypothesis for the Control of π-Facial Selectivity

process would give rise to cycloadduct 4 possessing the desired absolute configurations at the newly created stereogenic centers. Below, we report the results of an effort testing the strategy described above, which led to preparation of Danishefsky’s intermediate (+)-3 thereby completing an asymmetric formal synthesis of (+)-aplykurodinone-1. The study commenced with the preparation of alcohol (S)-7 (Scheme 4). For this, α,β-unsaturated Weinreb amide 11 was produced by olefination of aldehyde 9 with phosphonate ester 10 and then treated with TBS-acetylide to form alkynyl ketone 12 in 80% yield. Corey−Itsuno reduction8 of the resulting ketone 12 with borane and (S)-CBS as the catalyst followed by removal of the TBS group generated (S)-7 in 77% yield and

the internal alkyne moiety in (S)-13 was investigated by using various catalyst systems and conditions. Despite initial concerns about a regioselectivity issue, we found that oxymercuration of (S)-13 took place upon treatment with HgO/H2SO4 in methanol to produce the desired ketone (S)14 exclusively in 83% yield.6b,10 Attempts to stereoselectively reduce the ketone moiety in (S)-14 using well-documented chelation-control reduction11 by Zn(BH4)2 and Red-Al resulted in the formation of a 1:1 mixture of syn- and antidiols (see SI for details). Fortunately, Luche reduction, performed after protecting the α-hydroxyl group as a TBS ether, took place highly selectively to form the syn alcoholether 16, which can be rationalized by the Felkin−Ahn polar model shown in the gray circle.12 The stereochemistry of 16 was unequivocally confirmed by the NMR spectroscopic analysis of its acetonide derivative (see SI for details).13 Desilylation of 16 followed by TEMPO oxidation of the resulting allylic alcohol afforded the IMDA substrate (S)-5a in 88% overall yield.14 Subsequent reactions of (S)-5a with TBS-

Scheme 4. Preparation of (S)-7 and (R)-7

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DOI: 10.1021/acs.orglett.8b03250 Org. Lett. 2018, 20, 7312−7316

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Organic Letters

The exceptional selectivity of the IMDA reaction of (S)-5a in contrast to its analogues containing a sterically larger OPG group demonstrates that steric factors are not responsible for the control of π-facial selectivity. Based on the current observations and those made in earlier studies,15 it is likely that IMDA reaction of (S)-5a proceeds through the endotransition state TS-A′ (Scheme 7, top), in which the

OTf, Ac2O, and Trt-Cl produced the respective IMDA substrates (S)-5b, (S)-5c, and (S)-5d in good yield. In refluxing toluene, (S)-5b, (S)-5c, and (S)-5d underwent highly endo-selective IMDA reactions to form the corresponding endo-cycloadducts. However, the levels of π-facial selectivity of these processes were not satisfactory. Specifically, reaction of (S)-5b generated a 1:1 mixture of 4b and 8b (69% total yield) (Table 1, entry 1). Also, the acetyl protected

Scheme 7. Internal H-Bond Mediated π-Face Selectivity

Table 1. IMDA Reactions of Precursors (S)-5a−(S)-5d

a

Cycloreversion product 17 was also isolated in 33% yield.

substrate (S)-5c formed 4c and 8c in a 1.4:1 ratio and a low 36% yield caused by cycloreversions of the cycloadducts (see SI for details). Lastly, (S)-5d bearing the sterically larger trityl group underwent IMDA reaction to produce a mixture of 4d and 8d in a 1.3:1 ratio and 75% yield. These findings suggest that the steric bulk of the −OPG group in the substrates has little to no effect on the π-facial selectivity of their IMDA reactions. In marked contrast to those of the hydroxyl-protected substrates, the free OH group containing substrate (S)-5a underwent refluxing toluene promoted IMDA reaction to form (−)-4a in 78% yield (96% ee). The absolute stereochemistry of the IMDA adduct (−)-4a was determined by its conversion to Danishefsky’s intermediate (+)-3 in enantiomerically pure form (vide infra). Moreover, the enantiomeric substrate (R)-5a reacted under the same conditions to produce cycloadduct (+)-4a (94% ee), and the racemate (±)-5a produced a 1:1 mixture of (−)-4a and (+)-4a. The high levels of π-facial selectivity of these IMDA reactions were demonstrated by using chiral stationary phase HPLC analysis (Scheme 6; see SI for details).

pseudoequatorially oriented hydroxyl group is intramolecularly hydrogen bonded to oxygen in the enone carbonyl group.16 In the alternative endo-transition state TS-B′, approach of the dienophile from behind the 2-pyrone places the hydroxyl group in a pseudo-axial orientation that prevents this hydrogen bonding interaction. The results of DFT calculations using a truncated model system supports this reasoning. Specifically, the calculations show that energy of transition TS_A′ (Scheme 7, bottom) is 4.13 kcal/mol lower than that of TS_B′.17 To complete a formal total synthesis of (+)-aplykurodinone1, the IMDA product (−)-4a was converted to the Danishefsky’s intermediate (+)-3 by using the reaction sequence displayed in Scheme 8. MOM-ether protection of the alcohol moiety in (−)-4a gave (−)-18 which was subjected to reductive lactone opening to form triol 19. Tosylation of the primary alcohol in 19 generated hydrindane (+)-20. Two reducing reactions using Adams’ catalyst18 and palladium/ charcoal successively transformed (+)-20 to the PMBprotected primary alcohol intermediate (+)-21 and the corresponding triol (+)-22 in 92% overall yield. Iodobenzene diacetate and TEMPO oxidation of (+)-22 then produced lactone (+)-23 in 74% yield.19 In this transformation, lactone formation, following oxidative formation of an aldehyde, protects the C4 secondary alcohol (aplykurodinone-1 numbering), whereas the C9 secondary alcohol is oxidized to form a ketone. Finally, treatment of (+)-23 with TsOH in refluxing toluene generated the Danishefsky intermediate (+)-3 in 70% yield (8.2% overall for 14 steps from 3,5-dibromo-2-pyrone), thus completing an asymmetric formal total synthesis of

Scheme 6. IMDA Reactions of (R)-6a and (±)-6a

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DOI: 10.1021/acs.orglett.8b03250 Org. Lett. 2018, 20, 7312−7316

Letter

Organic Letters Notes

Scheme 8. Synthesis of Danishefsky’s Intermediate (+)-3

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Research Foundation of Korea (2014R1A5A1011165) for funding. We also thank Prof. Hyunwoo Kim at KAIST, Daejeon, Korea for the DFT calculations.

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aplykurodinone-1. The optical rotation of (+)-3 synthesized using this route matches the value reported in the literature.4c,20 In summary, in the effort described above we completed a formal synthesis of (+)-aplykurodinone-1 through a pathway involving a novel IMDA cycloaddition reaction of a dienophile tethered 2-pyrone. Importantly, the excellent π-facial selectivity of the IMDA process is a consequence of hydrogen bonding between the secondary hydroxyl group on the α-carbon and the carbonyl oxygen of the enone dienophile. The stereochemically pure product of the IMDA reaction was converted to the Danishefsky intermediate, thereby completing a formal synthesis of (+)-aplykurodinone-1, in 14 steps from 3,5dibromo-2-pyrone 6 and 8.2% overall yield. The unprecedented, hydrogen bonding mediated π-facial control of IMDA reactions is being exploited in strategies for the synthesis of other natural products containing the cis-fused bicyclic ring system.

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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.8b03250. Experimental procedures; characterization data; 1H, 13C NMR spectra; DFT calculations (PDF)

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REFERENCES

(1) Gavagnin, M.; Carbone, M.; Nappo, M.; Mollo, E.; Roussis, V.; Cimino, G. Tetrahedron 2005, 61, 617. (2) (a) Ortega, M. J.; Zubía, E.; Salvá, J. J. Nat. Prod. 1997, 60, 488. (b) Spinella, A.; Gavagnin, M.; Crispino, A.; Cimino, G.; Martinez, E. J. Nat. Prod. 1992, 55, 989. (c) Miyamoto, T.; Higuchi, R.; Komori, T.; Fujioka, T.; Mihashi, K. Tetrahedron Lett. 1986, 27, 1153. (3) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567. (4) (a) Tao, C.; Zhang, J.; Chen, X.; Wang, H.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2017, 19, 1056. (b) Singh, N.; Pulukuri, K. K.; Chakraborty, T. K. Tetrahedron 2015, 71, 4608. (c) Tang, Y.; Liu, J.t.; Chen, P.; Lv, M.-c.; Wang, Z.-z.; Huang, Y.-k. J. Org. Chem. 2014, 79, 11729. (d) Liu, G.; Mei, G.; Chen, R.; Yuan, H.; Yang, Z.; Li, C.-c. Org. Lett. 2014, 16, 4380. (e) Peixoto, P. A.; Jean, A.; Maddaluno, J.; De Paolis, M. Angew. Chem., Int. Ed. 2013, 52, 6971. (5) Xu, B.; Xun, W.; Wang, T.; Qiu, F. G. Org. Lett. 2017, 19, 4861. (6) (a) Kim, J.-Y.; Kim, D.-H.; Jeon, T.-H.; Kim, W.-H.; Cho, C.-G. Org. Lett. 2017, 19, 4688. (b) Lee, J. H.; Cho, C.-G. Org. Lett. 2016, 18, 5126. (c) Shin, H.-S.; Jung, Y.-G.; Cho, H.-K.; Park, Y.-G.; Cho, C.-G. Org. Lett. 2014, 16, 5718. (d) Cho, H.-K.; Lim, H.-Y.; Cho, C.G. Org. Lett. 2013, 15, 5806. (e) Jung, Y.-G.; Lee, S.-C.; Cho, H.-K.; Darvatkar, N. B.; Song, J.-Y.; Cho, C.-G. Org. Lett. 2013, 15, 132. (f) Jung, Y.-K.; Kang, H.-U.; Cho, H.-K.; Cho, C.-G. Org. Lett. 2011, 13, 5890. (g) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett. 2010, 12, 2016. (h) Tam, N. T.; Jung, E.-J.; Cho, C.-G. Org. Lett. 2010, 12, 2012. (i) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601. (j) Tam, N. T.; Chang, J.; Jung, E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73, 6258. (k) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303. (l) Tam, N. T.; Cho, C.-G. Org. Lett. 2007, 9, 3391. (m) Kim, H.-Y.; Cho, C.-G. Prog. Heterocycl. Chem. 2007, 18, 1. (n) Ryu, K.; Cho, Y.-S.; Cho, C.-G. Org. Lett. 2006, 8, 3343. (o) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125, 14288. (7) (a) Shin, J.-T.; Hong, S.-C.; Shin, S.; Cho, C.-G. Org. Lett. 2006, 8, 3339. (b) Shin, J.-T.; Shin, S.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 5857. (8) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (9) Lee, J.-H.; Park, J.-S.; Cho, C.-G. Org. Lett. 2002, 4, 1171. (10) Wang, W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640. (11) Rosenstein, I. J.; Tynan, T. A. Tetrahedron Lett. 1998, 39, 8429. (12) Evidently, the Ce+3 mediated Cram chelation model does not operate in this case (which would give anti-diol, if it does), presumably due to the steric repulsion between two large chains on chelation). For a recent account on the diastereoselective addition to a polar substituted ketone, see: Rosenberg, R. E.; Kelly, W. J. J. Phys. Org. Chem. 2015, 28, 47. (13) Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 1999, 55, 4583. (14) (a) Nicolaou, K. C.; Cai, Q.; Qin, B.; Petersen, M. T.; Mikkelsen, R. J. T.; Heretsch, P. Angew. Chem., Int. Ed. 2015, 54, 3074. (b) Banwell, M. G.; Bridges, V. S.; Dupuche, J. R.; Richards, S. L.; Walter, J. M. J. Org. Chem. 1994, 59, 6338. (15) For a hydrogen bonding mediated π-facial selective intermolecular Diels−Alder reaction of α-hydroxy substituted enone dienophiles, see: (a) Bakalova, S. M.; Kaneti, J. J. Phys. Chem. A 2008, 112, 13006. (b) Cayzer, T. N.; Paddon-Row, M. N.; Sherburn, M. S. Eur. J. Org. Chem. 2003, 2003, 4059. (c) Choy, W.; Reed, L. A.; Masamune, S. J. Org. Chem. 1983, 48, 1137. (d) Masamune, S.; Reed, L. A.; Davis, J. T.; Choy, W. J. Org. Chem. 1983, 48, 4441.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Cheon-Gyu Cho: 0000-0003-4851-5671 7315

DOI: 10.1021/acs.orglett.8b03250 Org. Lett. 2018, 20, 7312−7316

Letter

Organic Letters (16) To our knowledge, internal hydrogen bonding controlled πfacial diastereoselectivity in intramolecular Diels−Alder reactions has not been previously observed. (17) Gaussian 09 was used for all calculations. B3LYP/6-31G(d,p) basis sets were used for all atoms. A model in which the side chain with PMB group was replaced by a methyl group was used to reduce the calculation time. (18) To our surprise, the hydrogenation of the vinyl bromide using Adam’s catalyst under the conditions was accompanied with unexpected and unprecedented reductive cleavage of the OTs group. This unusual reactivity will be studied and reported in due course. (19) (a) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974. (b) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293. (20) The optical rotation of +122.5 reported in the ref 4b is incorrect.

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DOI: 10.1021/acs.orglett.8b03250 Org. Lett. 2018, 20, 7312−7316