Total synthesis of (+)-oridamycins A and B

Abstract

We have accomplished a unified strategy to achieve the structurally intriguing indolosesquiterpene alkaloids with diverse biological activity, xiamycin A (1a), xiamycin A methyl ester (1b) and oridamycins A (2a), and B (2b), which possesses a complex 6/6/6/5/6-fused pentacyclic skeleton bearing a carbazole moiety fused with a highly functionalized trans-decalin motif. Lewis acid-mediated epoxy-ene cyclization establishes the required pentacyclic scaffold with the installation of the four contiguous stereogenic centers. Further oxidative cleavage of the vinyl functionality, followed by successive functional group interconversions, completed the total synthesis of the indolosesquiterpene alkaloids.

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Xiamycins (1a–d) and oridamycins (2a–b) are an enlarging series of secondary metabolites familiar for their notable biological activities, including antimicrobial, antiviral, antitumor, immunomodulatory, and enzyme inhibitory effects. Hertweck¹ and co-workers, in 2010, pioneered the isolation of xiamycin A (1a) and its methyl ester (1b) from the Streptomyces species GT2002/1503 and HKI0595, which are endophytes within the mangrove plants Bruguiera gymnorrhiza and Kandelia candel, respectively. Later, Zhang² and his team also succeeded in isolating xiamycin A (1a). In 2016, Kim³ and co-workers revealed structurally similar compounds, xiamycin C (1c) and D (1d), extracted from a different Streptomyces species. This discovery marks the first isolation of indolosesquiterpene alkaloids coming from bacterial origin. Researchers are now exploring the potential of these newly discovered indolosesquiterpene alkaloids as starting materials for creating pharmaceutical and agricultural products, due to their engaging biological activity. For example, xiamycin A (1a) and its methyl ester (1b) display antibiotic (MIC value of 64.0 μg mL⁻¹ for 1a) and anti-HIV activity,^1,2 whereas its C-16 epimer, oridamycin A (2a), which exhibits modest activity against the water mold Saprolegnia parasitica (MIC value of 3.0 μg mL⁻¹), was isolated from Streptomyces sp. KS84 by Takada⁴et al. Most recent studies revealed that antiviral compounds xiamycin A (1a), xiamycin A methyl ester (1b) and xiamycin C (1c) are the most promising inhibitors against nsp10 of SARS-CoV-2⁵ pathogenicity.

Structurally, these pentacyclic molecules possess a carbazole scaffold fused to a highly functionalized trans-decalin ring system containing four contiguous stereocenters, including two all-carbon quaternary centers. The major difference between the family members manifests at the C-16 quaternary center, and oridamycin A (2a) and oridamycin B (2b) each bear an axial carboxylic acid and an equatorial methyl/hydroxymethyl, while xiamycin A (1a) and xiamycin A methyl ester (1b) contain an axially disposed methyl and an equatorial carboxylic acid/methyl ester group. Indosespene (3) is found to be a biosynthetic precursor for the xiamycins (1a–d) (Fig. 1).¹ Because of their important bioprofiles, a few groups have reported elegant approaches to the xiamycin A (1a) and oridamycin A (2a) family of alkaloids. Towards this, Baran⁶et al. (2014) reported the total synthesis of xiamycin A (1a) and dixiamycin B. Li⁷et al. (2014) reported the total syntheses of xiamycin A (1a), dixiamycin C and oridamycins A [(±)-2a], and B [(±)-2b]. Later, Trotta⁸et al. reported the total syntheses of oridamycins A [(±)-2a], and B [(±)-2b]. In 2016, Krische⁹et al. reported the total synthesis of oridamycin A (2a). Later, Sarpong¹⁰et al. (2019) reported the total syntheses of xiamycin A (1a) and oridamycin A (2a) from carvone. Recently, Dethe¹¹et al. and our group¹² made significant efforts from a Wieland–Miescher ketone derivative and abietic acid, respectively. However, unified catalytic asymmetric approaches to these diastereometric indolosesquiterpene alkaloids (such as 1a–b and 2a–b; Fig. 1) are still elusive. Herein, we report the divergent asymmetric total syntheses of the xiamycins (1a–b) and oridamycins (2a–b) from a common intermediate. In our approach, the common diol-aldehyde 9 could be converted to xiamycins (1a–b) and oridamycin A (2a) following synthetic manipulations.

Fig. 1 Bioactive indolosesquiterpene alkaloids (1–2).

Retrosynthetically, the diol-aldehyde intermediate (9) could be obtained from the chiral acyclic epoxide 11via a diastereoselective epoxy-ene cyclization and oxidative cleavage of the vinyl moiety. The epoxy-ene (11) can be derived via reduction of 1,3-butadiene ester 12 followed by the Sharpless asymmetric epoxidation. Furthermore, 1,3-butadiene ester 12 was imagined to synthesize from allylic alcohol 14via ester 13a/13b (Schemes 1 and 2).

Scheme 1 Our unified strategy.

Scheme 2 Synthesis of the epoxy-ene cyclization precursor.

Next, tosylation¹² of 2-bromo-9H-carbazole, and Sonogashira coupling¹³ with propargyl alcohol followed by a three-step synthetic protocol provided allylic alcohol 14 (see, ESI‡ for details). Next, a series of optimizations for Johnson–Claisen orthoester rearrangement¹⁴ of in situ generated allyl–vinyl ether were carried out under heating conditions as well as microwave irradiation, where we found the microwave irradiation condition to be superior in terms of time and yield (see ESI‡ for details). Then, DIBAL-H controlled reduction of the γ,δ-unsaturated ester (13a/13b) and a reaction with Wittig reagent 16¹⁵ provided 15 with 86% yield over 2 steps. Next, the Suzuki–Miyaura coupling¹⁶ of 15 with potassium trifluoro vinyl borate exclusively gives the single isomer of the triene ester 12. DIBAL-H reduction of 12 and catalytic asymmetric Sharpless epoxidation¹⁷ of the resulting allylic alcohol afforded the enantioenriched epoxide 11 (93% ee) with 92% yield (see ESI‡ for details).

Next, several literature-known procedures were tried for cyclization.¹⁸ In many cases, the cyclization remained futile. Later we thoroughly screened optimization using several Lewis acids i.e., BF₃·OEt₂, SnCl₄, Cu(OTf)₂etc. In every case, we ended up with the desired pentacyclic core (10) along with an incomplete cyclization (17) as a minor product. By reducing the temperature, the yield got improved with significant reduction in the formation of the half-cycle product. The optimum conditions that we found were with TiCl₄ at −78 °C, forming the pentacyclic core with high diastereoselectivity and excellent yield. The possible T.S. for cascade cyclization is depicted in Scheme 3. Therefore, we have succeeded in installing four contiguous stereocenters, of which two are all carbon quaternary centers as per our synthetic requirements, and accordingly, the biggest challenge for the construction of the trans-decalin motif fused with a carbazole scaffold was resolved. This epoxy-ene cyclization^6,12b,18 was very facile due to the extra stabilization of the T.S. coming from the vinyl moiety while the hydroxy group plays a crucial role by coordinating with the Lewis acid rather than hampering the cyclization, which was thought initially. The incomplete cyclization product (17) can be attributed to the stabilization of the tertiary carbocation formed through the initial cyclization step, ultimately leading to the formation of a tetra-substituted olefin. Despite numerous attempts to convert 17 into a pentacyclic cyclized product (10) using various Lewis acids (BF₃·OEt₂, SnCl₄, and TiCl₄), all efforts remain unsuccessful.

Scheme 3 Lewis-acid mediated epoxy-ene cyclization.

Oxidative cleavage of the vinyl moiety in 10 afforded diol-aldehyde (9)¹⁹ in 78% yield. Wolff–Kishner reduction of 9²⁰ followed by a chemoselective oxidation of primary alcohol with TEMPO/PIDA²¹ provided the β-hydroxy aldehyde (20) with 64% yield over 2 steps. Next, Pinnick oxidation of 20²² furnished the corresponding carboxylic acid, which upon detosylation with Na/naphthalene²³ forms xiamycin A (1a) as a white foam with a 90% yield over 2 steps. Xiamycin A (1a) was further charged with K₂CO₃/Me₂SO₄ under reflux conditions to complete the total synthesis of another indolosesquiterpene alkaloid xiamycin A methyl ester (1b) with 94% yield (Scheme 4).

Scheme 4 Total syntheses of xiamycin A (1a) and methyl ester (1b).

We next turned our attention to indolosesquiterpene alkaloids oridamycins (2a–b). Pinnick oxidation of aldehyde (9) afforded the corresponding carboxylic acid, 21 (Scheme 5). As we were one step away from the target molecule oridamycin B (2b), the carboxylic acid (21) was directly charged for detosylation using Mg/MeOH²⁴ and Na/naphthalene conditions, but the reaction remained futile.

Scheme 5 Total synthesis of oridamycin B methyl ester (23).

Therefore, in our modified strategy, carboxylic acid 21 was converted to N-tosyl oridamycin B methyl ester (22) with 86% yield over 2 steps (Scheme 5). Next, the detosylation using Na/naphthalene completed the total synthesis of oridamycin B methyl ester (23) with 92% yield (Scheme 5). The diol ester, 22, was further taken towards the synthesis of oridamycin A (2a). Therefore, the primary alcohol was selectively converted to its corresponding unstable monoxanthate derivative, which was immediately charged for the Barton–McCombie deoxygenation reaction,²⁵ without characterization affording the N-tosyl oridamycin A methyl ester (24) with 74% yield. Next, its detosylation was performed using Na/naphthalene to afford the oridamycin A methyl ester (2c) with a yield of 92%. The structure and configuration of all the stereogenic centers of 2c were confirmed via X-ray crystallographic studies, thereby also conclusively confirming the stereo-centers formed during the epoxy-ene cyclization step. Finally, saponification of 2c under LiOH–KOH mediated refluxed conditions accomplished the total synthesis of oridamycin A (2a) with 86% yield (Scheme 6).

Scheme 6 Total synthesis of oridamycin A (2a).

However, the saponification of oridamycin B methyl ester 23 (Scheme 7) under similar conditions (see ESI‡ for details) leads to the formation of a mixture of oridamycin B (2b) and dehydroxymethyl oridamycin B (2d) [forming via the retro-Aldol reaction from 2b]. The saponification needs a longer time due to the structural orientation of the quaternary and less reactive methyl ester. Hence, very harsh conditions are required to achieve the tetrahedral T.S. during ester hydrolysis. Several literature reports support the bio-enzymatic retro-Aldol reaction.²⁶ A notable example of such is the threonine aldolase catalyzed equilibrium between L-threonine and glycine in biological systems where acetaldehyde is the retro-aldol by-product. This evidence indicates that the incorporation of a hydroxymethyl group adjacent to a carbonyl center could feasibly be achieved via a bio-enzymatic aldol reaction.

Scheme 7 Total synthesis of oridamycin B (2b).

However, when the crude mixture of dehydroxymethyl oridamycin B (2d) and oridamycin B (2b) was tried for purification by silica gel column chromatography, the mixture converted to dehydroxymethyl oridamycin B (2d) via a possible retro-Aldol reaction facilitated by silica gel. As a result after column chromatography, we could only collect the pure dehydroxymethyl oridamycin B (2d) as a single product. Even purification with neutral or acidic alumina remains unsuccessful. Using the reverse phase HPLC column (Varian Microsorb 300-5 C18 column), as suggested by Trotta⁸ and Ang Li et al.⁷ turns out to be futile. However, the crude NMR data and HRMS data were fully supported by the literature report (see ESI‡), indicating that the synthesis of oridamycin B (2b) was productive.

In conclusion, we have accomplished the asymmetric total syntheses of the indolosesquiterpene alkaloids, xiamycin A (1a), xiamycin A methyl ester (1b), and oridamycins A (2a) and B (2b) via a unified divergent synthetic strategy. The key transformations involve a Lewis-acid mediated epoxy-ene cyclization reaction. Hence, we have successfully synthesized xiamycin A (1a) and its methyl ester (1b) through the shortest reaction sequence of only 17 and 18 steps, respectively, whereas, the asymmetric total synthesis of both oridamycins A (2a) and B (2b) was completed in 18 steps. All the syntheses are in close alignment with both the isolation reports and the previous synthetic studies. The crystal structure of the oridamycin A methyl ester (2c) unambiguously confirms the stereogenic centres present in the natural product.

Financial support from the SERB [CRG/2023/000782], [SCP/2022/000486] and [STR/2020/000061], STARS-MoE [STARS/2023/0753], and CSIR [02(0403)/21/EMR-II] are gratefully acknowledged.

Data availability

Data availability Experimental details and spectral analysis are available free of charge from the ESI‡ available with this article.

Conflicts of interest

The authors declare no conflict of interest.

Notes and references

1. (a) L. Ding, J. Münch, H. Goerls, A. Maier, H.-H. Fiebig, W.-H. Lin and C. Hertweck, Bioorg. Med. Chem. Lett., 2010, 20, 6685–6687; (b) L. Ding, A. Maier, H.-H. Fiebig, W.-H. Lin and C. Hertweck, Org. Biomol. Chem., 2011, 9, 4029–4031; (c) Z. Xu, M. Baunach, L. Ding and C. Hertweck, Angew. Chem., Int. Ed., 2012, 51, 10293–10297.
2. (a) H. Li, Q. Zhang, S. Li, Y. Zhu, G. Zhang, H. Zhang, X. Tian, S. Zhang, J. Ju and C. Zhang, J. Am. Chem. Soc., 2012, 134(21), 8996–9005; (b) Q. Zhang, H. Li, S. Li, Y. Zhu, G. Zhang, H. Zhang, W. Zhang, R. Shi and C. Zhang, Org. Lett., 2012, 14, 6142–6145; (c) Q. Zhang, H. Li, L. Yu, Y. Sun, Y. Zhu, H. Zhu, L. Zhang, S. Li, Y. Shen, C. Tian, A. Li, H. Liu and C. Zhang, Chem. Sci., 2017, 8, 5067–5077.
3. S. H. Kim, T. K. Q. Ha, W. K. Oh, J. Shin and D. C. Oh, J. Nat. Prod., 2016, 79, 51–58.
4. K. Takada, H. Kajiwara and N. Imamura, J. Nat. Prod., 2010, 73, 698–701.
5. S. Muhammad, M. Qaisar, J. Iqbal, R. A. Khera, A. G. Al-Sehemi, S. S. Alarfaji and M. Adnan, Chem. Zvesti., 2022, 76, 3051–3064.
6. B. Rosen, E. Werner, A. O’Brian and P. Baran, J. Am. Chem. Soc., 2014, 136, 5571–5574.
7. Z. Meng, H. Yu, L. Li, W. Tao, H. Chen, M. Wan, P. Yang, D. Edmonds, J. Zhong and A. Li, Nat. Commun., 2015, 6, 6096–7003.
8. (a) A. Trotta, Org. Lett., 2015, 17, 3358–3361; (b) A. Trotta, J. Org. Chem., 2017, 82, 13500–13516.
9. J. Feng, F. Noack and M. Krische, J. Am. Chem. Soc., 2016, 138, 12364–12367.
10. M. Pfaffenbach, I. Bakanas, N. R. O'Connor, J. L. Herrick and R. Sarpong, Angew. Chem., Int. Ed., 2019, 58, 15304–15308.
11. D. H. Dethe and M. Shukla, Chem. Commun., 2021, 57, 10644–10646.
12. (a) M. Munda, R. Nandi, V. R. Gavit, S. Kundu, S. Niyogi and A. Bisai, Chem. Sci., 2022, 13, 11666–11671; (b) R. Nandi, S. Niyogi, S. Kundu, V. R. Gavit, M. Munda, R. Murmu and A. Bisai, Chem. Sci., 2023, 14, 8047–8053.
13. (a) M. Ates and N. Uludag, J. Solid State Electrochem., 2016, 20, 2599–2612; (b) K. Sonogashira, J. Organomet. Chem., 2002, 653, 46–49.
14. (a) L. Claisen, Chem. Ber., 1912, 45, 3157–3166; (b) W. S. Johnson, L. Werthemann, R. W. Bartlett, J. T. Brocksom, T.-T. Li, D. J. Faulkner and M. R. Petersen, J. Am. Chem. Soc., 1970, 92, 741–743.
15. D. B. Denny and S. T. Ross, J. Org. Chem., 1962, 27, 998–1000.
16. (a) N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun., 1981, 11, 513–519; (b) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483.
17. T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974–5976.
18. (a) N. R. Mente, J. D. Neighbors and D. F. Wiemer, J. Org. Chem., 2008, 73, 7963–7970; (b) J. K. Sutherland, Chem. Soc. Rev., 1980, 9, 265–280; (c) G. Rajendar and E. J. Corey, J. Am. Chem. Soc., 2015, 137(17), 5837–5844; (d) T.-K. Ma, T. Mies and A. G. M. Barrett, Synthesis, 2019, 67–82.
19. (a) V. Ley, C. Ramarao, A.-L. Lee, N. Ostergaard, S. C. Smith and I. M. Shirley, Org. Lett., 2003, 5, 185–187; (b) A. Abiko, J. C. Roberts, T. Takemasa and S. Masamune, Tetrahedron Lett., 1986, 27, 4537–4540.
20. (a) N. Kishner, J. Russ. Phys. Chem. Soc., 1911, 43, 582–595; (b) L. Wolff, Justus Liebigs Ann. Chem., 1912, 394, 86–108.
21. H. Tohma and Y. Kita, Adv. Synth. Catal., 2004, 346, 111–124.
22. B. S. Bal, W. E. Childers and H. W. Pinnick, Tetrahedron, 1981, 37, 2091–2096.
23. K. M. Harmon, A. B. Harmon and B. C. Thompson, J. Am. Chem. Soc., 1967, 89, 5311–5312.
24. G. H. Lee, I. K. Youn, E. B. Choi, H. K. Lee, G. H. Yon, H. C. Yang and C. S. Pak, Curr. Org. Chem., 2004, 8, 1263–1287.
25. (a) D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 1574–1585; (b) D. Crich and L. Quintero, Chem. Rev., 1989, 89, 1413–1432.
26. (a) A. More, T. Elder and Z. Jiang, Int. J. Biol. Macromol., 2021, 183, 1505–1513; (b) Y. Tsunematsu, N. Maeda, M. Yokoyama, P. Chankhamjon, K. Watanabe, K. Scherlach and C. Hertweck, Angew. Chem., Int. Ed., 2018, 57, 14051–14054; (c) K. Fesko, Front. Bioeng. Biotechnol., 2019, 7, 119–130.

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Footnotes

† This work is dedicated respectfully to Professor Ganesh P. Pandey, National Science Chair, SERB, India and Distinguished Professor, BHU, Varanasi, on the occasion of his 70th Birthday.

‡ Electronic supplementary information (ESI) available. CCDC 2338551. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4cc03070b

§ These authors contributed equally.

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