Total Synthesis of the Marine Diterpenoid Blumiolide C

Abstract

First bloom: The total synthesis of the cytotoxic marine natural product blumiolide C (1) features a ring‐closing metathesis (RCM) for the closure of a nine‐membered ring to give the trans‐bicyclo[7.4.0]oxatridecene core (see scheme; PMB=para‐methoxybenzyl, TBS=tert‐butyldimethylsilyl). Attachment of the side chain at C4 of the bicyclic core was achieved in a highly stereoselective manner and excellent yield through an aldol reaction/elimination sequence.

Direct Catalytic Asymmetric Aldol Reaction of Thioamide with an α‐Vinyl Appendage

“…The first total synthesis of blumiolide C was achieved by Altmann et al. with the strategic use of the Evans‐aldol method to afford enantioenriched syn ‐β‐hydroxy α‐vinyl carboxylic acid derivative 5 , leading to a key intermediate 6 b . With the highly syn ‐selective and enantioselective direct aldol reaction of α‐vinyl thioacetamide in hand, we devised a catalytic alternative to access 6 using the aldol adduct 3 lb obtained from the present catalysis using corresponding aldehyde 1 l and 2 b .…”

“…After protection of the secondary hydroxyl group as a TBS ether, S ‐methylation by MeOTf followed by hydrolysis with phosphate buffer gave thioester 7 , which was subjected to reduction with LiBH 4 to furnish primary alcohol 6 a . According to the original synthesis of blumiolide C, the 6 a was converted to the corresponding acrylate that engaged in ring‐closing metathesis using Grubbs 2nd‐Gen catalyst to give unsaturated lactone 7 a . Conjugate addition of the requisite C5 unit followed by removal of the PMB group furnished reported intermediate 8 , whose spectroscopic data were in full accordance to those reported.…”

Enantio- and Diastereoselective Synthesis of syn-β-Hydroxy-α-vinyl Carboxylic Esters via Reductive Aldol Reactions of Ethyl Allenecarboxylate with 10-TMS-9-Borabicyclo[3.3.2]decane and DFT Analysis of the Hydroboration Pathway

“…1,2 Racemic 3 can be obtained with varying degrees of diastereoselectivity by allylation of aldehydes with γ-(alkoxycarbonyl)-substituted allyl metal reagents (e.g., indium, 3 tin, 4 zinc 5 and boron 6 reagents). Another approach to racemic 3 involves aldol 7,8 or Reformatsky 9 reactions of aldehydes with ester derived dienolates.…”

“…Given the widespread use of this structural unit in organic synthesis, 1,2 it is surprising that direct enantioselective methods for the synthesis of the syn or anti diastereoisomers of β-hydroxy-α-vinyl carboxylic esters 3 have not been reported. Both enantiomers of syn -β-hydroxy-α-vinyl imides 5 can be obtained by using enantioselective aldol reactions of chiral crotonate imides (Figure 1).…”

“…Both enantiomers of syn -β-hydroxy-α-vinyl imides 5 can be obtained by using enantioselective aldol reactions of chiral crotonate imides (Figure 1). Evans’ chiral N-acyl oxazolidinones 10 are widely applied for this purpose, 1 but other methods include use of Oppolzer’s chiral sultam 11 and Crimmins’ chiral oxazolidinethione reagents. 12 Here we report the development of an enantio- and diastereoselective synthesis of syn -β-hydroxy-α-vinyl carboxylate esters 3 via aldol reactions of aldehydes with (Z)-dienolborinate Z -(O)-8a that is generated in situ from the hydroboration of allenyl ester 2 with 10-trimethylsilyl-9-borabycyclo[3.3.2]decane ( 1R , also known as 10-TMS-9-BBD-H, and as the Soderquist borane).…”