Total Synthesis of Marine Macrolide Natural Products by the Macrocyclization/Transannular Pyran Cyclization Strategy

Abstract

In this Account, we summarize the development of a new strategy for streamlined synthesis of tetrahydropyran-embedded macrolactones and its successful implementation to a 13-step synthesis of (–)-exiguolide and an 11-step synthesis of (+)-neopeltolide.

1 Introduction

2 Development of Macrocyclization/Transannular Pyran Cyclization Strategy

3 Total Synthesis of (–)-Exiguolide

4 Total Synthesis of (+)-Neopeltolide

5 Conclusions

Key words

synthetic methods - tandem reactions - total synthesis - macrolides - step-economy

Publication History

Received: 02 September 2023

Accepted after revision: 26 September 2023

Accepted Manuscript online:
26 September 2023

Article published online:
02 November 2023

• References


For recent reviews, see:
• 1a Karpiński TM. Mar. Drugs 2019; 17: 241
• 1b Wang M, Zhang J, He S, Yan X. Mar. Drugs 2017; 15: 126
• 1c Kanakkanthara A, Northcote PT, Miller JH. Nat. Prod. Rep. 2016; 33: 549
• 1d Chen Q.-H, Kingston DG. I. Nat. Prod. Rep. 2014; 31: 1202
• 1e Qi Y, Ma S. ChemMedChem 2011; 6: 399
• 1f Miller JH, Singh AJ, Northcote PT. Mar. Drugs 2010; 8: 1059
• 1g Yamada K, Ojika M, Kigoshi H, Suenaga K. Nat. Prod. Rep. 2009; 26: 27
• 1h Kobayashi J. J. Antibiot. 2008; 61: 271 ; and references cited therein

For recent reviews, see:
• 2a Fuwa H. Org. Chem. Front. 2021; 8: 3990
• 2b Stockdale TP, Lam NY. S, Anketell MJ, Paterson I. Bull. Chem. Soc. Jpn. 2021; 86: 713
• 2c Fuwa H. Mar. Drugs 2016; 14: 65
• 2d Lee K, Lanier ML, Kwak J.-H, Kim H, Hong J. Nat. Prod. Rep. 2016; 33: 1393
• 2e Bai Y, Dai M. Curr. Org. Chem. 2015; 19: 871
• 2f Lorente A, Lamariano-Merketegi J, Albericio F, Álvarez M. Chem. Rev. 2013; 113: 4567
• 2g Hale KJ, Manaviazar S. Chem. Asian J. 2010; 5: 704 ; and references cited therein
• 3a Fuwa H, Naito S, Goto T, Sasaki M. Angew. Chem. Int. Ed. 2008; 47: 4737
• 3b Fuwa H, Saito A, Naito S, Konoki K, Yotsu-Yamashita M, Sasaki M. Chem. Eur. J. 2009; 15: 12807
• 4a Fuwa H, Saito A, Sasaki M. Angew. Chem. Int. Ed. 2010; 49: 3041
• 4b Fuwa H, Kawakami M, Noto K, Muto T, Suga Y, Konoki K, Yotsu-Yamashita M, Sasaki M. Chem. Eur. J. 2013; 19: 8100
• 5a Fuwa H, Yamaguchi H, Sasaki M. Org. Lett. 2010; 12: 1848
• 5b Fuwa H, Yamaguchi H, Sasaki M. Tetrahedron 2010; 66: 7492
• 6a Fuwa H, Sasaki M. Org. Lett. 2010; 12: 584
• 6b Fuwa H, Suzuki T, Kubo H, Yamori T, Sasaki M. Chem. Eur. J. 2011; 17: 2678
• 7a Fuwa H, Okuaki Y, Yamagata N, Sasaki M. Angew. Chem. Int. Ed. 2015; 54: 868
• 7b Fuwa H, Yamagata N, Okuaki Y, Ogata Y, Saito A, Sasaki M. Chem. Eur. J. 2016; 22: 6815
• 8a Sakamoto K, Hakamata A, Tsuda M, Fuwa H. Angew. Chem. Int. Ed. 2018; 57: 3801
• 8b Sakamoto K, Hakatama A, Iwasaki A, Suenaga K, Tsuda M, Fuwa H. Chem. Eur. J. 2019; 25: 8528
• 9a Sakurai K, Sasaki M, Fuwa H. Angew. Chem. Int. Ed. 2018; 57: 5143
• 9b Sakurai K, Sakamoto K, Sasaki M, Fuwa H. Chem. Asian J. 2020; 15: 3494
• 10a Fuwa H, Noto K, Sasaki M. Org. Lett. 2010; 12: 1636
• 10b Fuwa H, Noto K, Sasaki M. Org. Lett. 2011; 13: 1820
• 10c Fuwa H, Ichinokawa N, Noto K, Sasaki M. J. Org. Chem. 2012; 77: 2588
• 10d Fuwa H, Noguchi T, Noto K, Sasaki M. Org. Biomol. Chem. 2012; 10: 8108
• 10e Murata K, Sakamoto K, Fuwa H. Org. Lett. 2019; 21: 3730
• 10f Murata K, Takeshita H, Sakamoto K, Fuwa H. Chem. Asian J. 2020; 15: 807

For selected reviews on tandem (or domino/cascade) reactions, see:
• 11a Nicolaou KC, Chen JS. Chem. Soc. Rev. 2009; 38: 2993
• 11b Pellissier H. Chem. Rev. 2013; 113: 442
• 11c Volla CM. R, Atodiresei I, Rueping M. Chem. Rev. 2014; 114: 2390
• 11d Lohr TL, Marks TJ. Nat. Chem. 2015; 7: 477
• 11e Camp JE. Eur. J. Org. Chem. 2017; 425
• 11f Shivam Shivam, Tiwari G, Kumar M, Chauhan AN. S, Erande RD. Org. Biomol. Chem. 2022; 20: 3653
• 12 For a review, see: Connon SJ, Blechert S. Angew. Chem. Int. Ed. 2003; 42: 1900

For reviews on oxa-Michael addition, see:
• 13a Ahmad T, Ullah N. Org. Chem. Front. 2021; 8: 1329
• 13b Hu J, Bian M, Ding H. Tetrahedron Lett. 2016; 57: 5519
• 13c Nising CF, Bräse S. Chem. Soc. Rev. 2012; 41: 988
• 13d Fuwa H. Heterocycles 2012; 85: 1255
• 14 Engel J, Smit W, Foscato M, Occhipinti G, Törnroos KW, Jensen VR. J. Am. Chem. Soc. 2017; 139: 16609
• 15 Hong SH, Sanders DP, Lee CW, Grubbs RH. J. Am. Chem. Soc. 2005; 127: 17160

For reviews, see:
• 16a Justaud F, Hachem A, Grée R. Eur. J. Org. Chem. 2021; 514
• 16b Cadierno V, Crochet P, García-Garrido SE, Gimeno J. Dalton Trans. 2010; 4015
• 16c Engel DA, Dudley GB. Org. Biomol. Chem. 2009; 7: 4149
• 17 Egi M, Yamaguchi Y, Fujiwara N, Akai S. Org. Lett. 2008; 10: 1867
• 18 Mizukami D, Iio K, Oda M, Onodera Y, Fuwa H. Angew. Chem. Int. Ed. 2022; 61: e202202549

For successful examples, see:
• 19a Hilli F, White JM, Rizzacasa MA. Org. Lett. 2004; 6: 1289
• 19b Kanematsu M, Yoshida M, Shishido K. Angew. Chem. Int. Ed. 2011; 50: 2618
• 19c Ehrlich G, Stark CB. W. Org. Lett. 2016; 18: 4802
• 19d Gaddam J, Reddy AV. V, Sarma AV. S, Yadav JS, Mohapatra DK. J. Org. Chem. 2020; 85: 12418

For reviews on transannular reactions, see:
• 20a Reyes E, Prieto L, Carrillo L, Uria U, Vicario JL. Synthesis 2022; 54: 4167
• 20b Reyes E, Uria U, Carrillo L, Vicario JL. Tetrahedron 2014; 70: 9461
• 20c Clarke PA, Reeder AT, Winn J. Synthesis 2009; 691

For selected reviews, see:
• 21a Lecourt C, Dhambri S, Allievi L, Sanogo Y, Zeghbib N, Othman RB, Lannou M.-I, Sorin G, Ardisson J. Nat. Prod. Rep. 2018; 35: 105
• 21b Cheng-Sánchez I, Sarabia F. Synthesis 2018; 3749
• 21c Fürstner A. Science 2013; 341: 1229713
• 21d Fürstner A. Chem. Commun. 2011; 47: 6505 ; and references cited therein
• 22 Unpublished result.
• 23 Csókás D, Ho AX. Y, Ramabhadran RO, Bates RW. Org. Biomol. Chem. 2019; 17: 6293
• 24 We have confirmed that the stereochemical consequence of the transannular oxa-Michael addition to give macrolactone 12a is kinetically controlled by resubmission of its 2,6-trans-isomer to the reaction conditions.
• 25 Ohta S, Uy MM, Yanai M, Ohta E, Hirata T, Ikegami S. Tetrahedron Lett. 2006; 47: 1957
• 26a Kwon MS, Woo SK, Na SW, Lee E. Angew. Chem. Int. Ed. 2008; 47: 1733
• 26b Cook C, Guinchard X, Liron F, Roulland E. Org. Lett. 2010; 12: 744
• 26c Crane EA, Zabawa TP, Farmer RL, Scheidt KA. Angew. Chem. Int. Ed. 2011; 50: 9112
• 26d Cook C, Liron F, Guinchard X, Roulland E. J. Org. Chem. 2012; 77: 6728
• 26e Reddy CR, Rao NN. RSC Adv. 2012; 2: 7724
• 26f Li H, Xie H, Zhang Z, Xu Y, Lu J, Gao L, Song Z. Chem. Commun. 2015; 51: 8484
• 26g Zhang Z, Xie H, Li H, Gao L, Song Z. Org. Lett. 2015; 17: 4706
• 26h Oka K, Fuchi S, Komine K, Fukuda H, Hatakeyama S, Ishihara J. Chem. Eur. J. 2020; 26: 12862
• 26i For a review, see: Fuwa H. Heterocycles 2022; 104: 1709
• 27 Riefert A, Maier ME. Synthesis 2018; 50: 3131
• 28 For structure–activity relationship studies, see ref. 6b and 26c. See also: Fuwa H, Mizunuma K, Sasaki M, Suzuki T, Kubo H. Org. Biomol. Chem. 2013; 11: 3442
• 29 Tanaka K, Ohta Y, Fuji K, Taga T. Tetrahedron Lett. 1993; 34: 4071

For reviews, see:
• 30a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 30b Suzuki A. Angew. Chem. Int. Ed. 2011; 50: 6722
• 31 Lewis MD, Cha JK, Kishi Y. J. Am. Chem. Soc. 1982; 104: 4976
• 32 Zhan Z.-YJ. US 2007/0043180 A1, 2007 ; Chem. Abstr. 2007, 146, 142834
• 33 Hsu IT, Tomanik M, Herzon SB. Acc. Chem. Res. 2021; 54: 903
• 34 Wright AE, Botelho JC, Guzmán E, Harmody D, Linley P, McCarthy PJ, Pitts TP, Pomponi SA, Reed JK. J. Nat. Prod. 2007; 70: 412
• 35 Youngsaye W, Lowe JT, Pohlki F, Ralifo P, Panek JS. Angew. Chem. Int. Ed. 2007; 46: 9211
• 36a Custar DW, Zabawa TP, Scheidt KA. J. Am. Chem. Soc. 2008; 130: 804
• 36b Custar DW, Zabawa TP, Hines J, Crews CM, Scheidt KA. J. Am. Chem. Soc. 2009; 131: 12406
• 37 Ulanovskaya OA, Janjic J, Suzuki M, Sabharwal SS, Schumacker PT, Kron SJ, Kozmin SA. Nat. Chem. Biol. 2008; 4: 418
• 38a Fuwa H, Sato M. Mar. Drugs 2017; 15: 320
• 38b Fuwa H, Sato M, Sasaki M. Mar. Drugs 2014; 12: 5576
• 39a Awale S, Lu J, Kalauni SK, Kurashima Y, Tezuka Y, Kadota S, Esumi H. Cancer Res. 2006; 66: 1751
• 39b Awale S, Baba H, Phan ND, Kim MJ, Maneenet J, Sawaki K, Kanda M, Okumura T, Fujii T, Okada T, Maruyama T, Okada T, Toyooka N. J. Med. Chem. 2023; 66: 8054 ; and references cited therein
• 40 Yanagi S, Sugai T, Noguchi T, Kawakami M, Sasaki M, Niwa S, Sugimoto A, Fuwa H. Org. Biomol. Chem. 2019; 17: 6771
• 41 For a review, see: Peña-Corona SI, Hernández-Parra H, Bernal-Chávez SA, Mendoza-Muñoz N, Romero-Montero A, Del Prado-Audelo ML, Cortés H, Ateşşahin DA, Habtemariam S, Almarhoon ZM, Razis AF. A, Modu B, Sharifi-Rad J, Leyva-Gómez G. Front. Pharmacol. 2023; 1206334
• 42a Woo SK, Kwon MS, Lee E. Angew. Chem. Int. Ed. 2008; 47: 3242
• 42b Vintonyak VV, Maier ME. Org. Lett. 2008; 10: 1239
• 42c Paterson I, Miller NA. Chem. Commun. 2008; 39: 4708
• 42d Kartika R, Gruffi TR, Taylor RE. Org. Lett. 2008; 10: 5047
• 42e Vintonyak VV, Kunze B, Sasse F, Maier ME. Chem. Eur. J. 2008; 14: 11132
• 42f Tu W, Floreancig PE. Angew. Chem. Int. Ed. 2009; 48: 4567
• 42g Kim H, Park Y, Hong J. Angew. Chem. Int. Ed. 2009; 48: 7577
• 42h Guinchard X, Roulland E. Org. Lett. 2009; 11: 4700
• 42i Yadav JS, Kumar GG. K. S. N. Tetrahedron 2010; 66: 480
• 42j Martinez-Solorio D, Jennings MP. J. Org. Chem. 2010; 75: 4095
• 42k Yang Z, Zhang B, Zhao G, Yang J, Xie X, She X. Org. Lett. 2011; 13: 5916
• 42l Sharma GV. M, Reddy SV, Ramakrishna KV. S. Org. Biomol. Chem. 2012; 10: 3689
• 42m Raghavan S, Samanta PK. Org. Lett. 2012; 14: 2346
• 42n Athe S, Chandrasekhar B, Roy S, Pradhan TK, Ghosh S. J. Org. Chem. 2012; 77: 9840
• 42o Ghosh AK, Shurrush KA, Dawson ZL. Org. Biomol. Chem. 2013; 11: 7768
• 42p Yu M, Schrock RR, Hoveyda AH. Angew. Chem. Int. Ed. 2015; 54: 215
• 42q Meissner A, Tanaka N, Takamura H, Kadota I. Tetrahedron Lett. 2019; 60: 432
• 42r Masiuk US, Faletrov YV, Kananovich DG, Mineyeva IV. J. Org. Chem. 2023; 88: 355

See also refs. 3 and 4. For reviews, see refs. 2c, 2d, and
• 42s Gallon J, Reymond S, Cossy J. C. R. Chim. 2008; 11: 1463
• 42t Jiangfan Y, Ruokun F, Zhen Y. Chin. J. Org. Chem. 2017; 37: 2526

For synthetic studies, see:
• 43a Hartmann E, Oestreich M. Angew. Chem. Int. Ed. 2010; 49: 6195
• 43b Florence GJ, Cadou RF. Tetrahedron Lett. 2010; 51: 5761
• 43c Mineeva IV. Russ. J. Org. Chem. 2015; 51: 1061
• 43d Hari TP. A, Wilke BI, Davey JA, Boddy CN. J. Org. Chem. 2016; 81: 415
• 43e Li J, Preinfalk A, Maulide N. Angew. Chem. Int. Ed. 2019; 58: 5887
• 43f Masiuk US, Mineyeva IV, Kananovich DG. Symmetry 2021; 13: 470
• 43g Reddi RN, Sudalai A, Jo C. Bull. Korean Chem. Soc. 2022; 43: 1169

For analogue synthesis and structure–activity relationship studies, see:
• 44a Cui Y, Tu W, Floreancig PE. Tetrahedron 2010; 66: 4867
• 44b Cui Y, Balachandran R, Day BW, Floreancig PE. J. Org. Chem. 2012; 77: 2225
• 44c Fuwa H, Noto K, Kawakami M, Sasaki M. Chem. Lett. 2013; 42: 1020
• 44d Fuwa H, Noguchi T, Kawakami M, Sasaki M. Bioorg. Med. Chem. Lett. 2014; 24: 2415
• 44e Larsen EM, Chang C.-F, Sakata-Kato T, Arico JW, Lombardo VM, Wirth DF, Taylor RE. Org. Biomol. Chem. 2018; 16: 5403
• 44f Zhu X.-L, Zhang R, Wu Q.-Y, Song Y.-J, Wang Y.-X, Yang J.-F, Yang G.-F. J. Agric. Food Chem. 2019; 67: 2774
• 44g Xiong M.-Q, Chen T, Wang Y.-X, Zhu X.-L, Yang G.-F. Bioorg. Med. Chem. Lett. 2020; 30: 127324
• 45a Takai K, Hotta Y, Oshima K, Nozaki H. Bull. Chem. Soc. Jpn. 1980; 53: 1698
• 45b Okazoe T, Hibino J, Takai K, Nozaki H. Tetrahedron Lett. 1985; 26: 5581

For reviews, see:
• 46a Mitsunobu O. Synthesis 1981; 1
• 46b Swamy KC. K, Kumar NN. B, Balaraman E, Kumar KV. P. Chem. Rev. 2009; 109: 2551
• 47 Iwasaki K, Wan KK, Oppedisano A, Crossley SW. M, Shenvi RA. J. Am. Chem. Soc. 2014; 136: 1300
• 48a Nakazato K, Oda M, Fuwa H. Org. Lett. 2022; 24: 4003
• 48b Nakazato K, Oda M, Fuwa H. Bull. Chem. Soc. Jpn. 2023; 96: 257
• 49 We define a reaction step as one in which a substrate is transformed into a product without intermediate workup or purification. We consider that a one ‘step’ transformation may consist of a sequence of mechanistically distinct reactions, for example, acylation of alcohols/amines with mixed anhydrides or hydroboration/oxidation. For a recent discussion on step counts, see: Johnson JS. Nat. Synth. 2023; 2: 6