Total Synthesis of Meayamycin B

Abstract

Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey–Chaykovsky-type reaction, and a modified Horner–Wadsworth–Emmons Z-selective olefination. We also discuss a Z–E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.

Synthetic and biosynthetic methods for selective cyclisations of 4,5-epoxy alcohols to tetrahydropyrans

“…25,26 Examples include the preparation of mucocin, amphidinol 3 and the formation of the E ring in maitotoxin, as well as the botcinins, and more recently in the total synthesis of meayamycin B, illustrating the widespread value of the method (Scheme 3). [27][28][29][30][31][32] In 1997, Nakata and co-workers reported that introduction of a styryl group adjacent to the epoxide provided greater stabilisation in the 6-endo transition state compared with the alkenic epoxides. 33,34 Treatment of trans-epoxides containing a styryl group with either acid or base generated THP products in excellent yield, but improved stereocontrol was achieved using NaH (entries 1 and 2, Table 1).…”

Total Synthesis of Meayamycin and O-Acyl Analogues

“…After several iterations on the approach, each subunit used to assemble 1 herein is derived from chiral pool starting materials with all 8 chiral centers introduced or controlled by chirality found in inexpensive commercial starting materials (Figure ). The approach provided 1 in a longest linear sequence of 12 steps (22 steps overall), complementary to an improved approach recently disclosed by Koide (11 longest linear sequence, 24 steps overall) …”

“…Although inspired by Koide’s original synthesis, it is substantially shorter (5 vs 8 steps) and enlists further optimized protocols for overlapping steps. Analogous improvements were independently reported by Koide earlier this year for synthesis of intermediate lactone 12 . Additional subtle improvements are also highlighted herein for the original conversion of 12 to 15 .…”

“…The approach provided 1 in a longest linear sequence of 12 steps (22 steps overall), 18 complementary to an improved approach recently disclosed by Koide (11 longest linear sequence, 24 steps overall). 19 The most challenging subunit is the right-hand tetrahydropyran 7, bearing three of the stereocenters and the essential epoxide. Intermediate 7 was accessed in four steps from known aldehyde 2, 20 itself prepared from D-ribose in three steps (Scheme 1).…”

“…Analogous improvements were independently reported by Koide earlier this year for synthesis of intermediate lactone 12. 19 Additional subtle improvements are also highlighted herein for the original conversion 6 of 12 to 15. 18 Central to the synthesis of 15 was use of the known starting material 9, 22 the BocNH-L-Thr derived variant of Garner's aldehyde, available in three steps from BocNH-L-Thr (1 equiv of MeONHMe, 1.2 equiv of EDCI, 1.2 equiv of HOBt, 2 equiv of (iPr 2 )NEt, CH 2 Cl 2 , 23 °C, 22 h; 0.2 equiv of PPTS, 10 equiv of MeC(OMe) 2 Me, THF, reflux, 18 h, 85−88% for two steps), including the reported DIBAL-H reduction of the Weinreb amide (2 equiv DIBAL-H, CH 2 Cl 2 , −78 °C, 3 h).…”