Synthesis of (−)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition–Rearrangement and Cross-electrophile Coupling

Abstract

An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp-Csp cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product.

Reductive Decarboxylative Alkynylation of N‐Hydroxyphthalimide Esters with Bromoalkynes

“…In particular, the coupling of aryl [2] and vinyl halides [3] with alkyl halides has proven to be a useful alternative to other cross-coupling approaches. [6] In contrast, cross-electrophile coupling to form C(sp)-C(sp x ) bonds has not been demonstrated (Scheme 1), even though bromoalkynes are easily generated from terminal alkynes. [7] [8] …”

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

“…Although the reaction of alkylated tartrate 17 with NaHMDS/2-(phenylsulfonyl)-3-phenyloxaziridine [31] gave an unidentifiable mixture, the use of LDA and MoOPH [32–33] at −78 °C followed by warming to −50 °C for 3 h gave the hydroxy acetonide 19a (Scheme 6) in 92% yield as a mixture of 4 diastereomers. Similarly, the enolate of the simpler propylated tartrate 33a [12] reacted with MoOPH to give the analogous hydroxy acetonide 19b in 96% yield (3:1 dr); if the MoOPH was added to the enolate which had been warmed to −40 °C, a more typical hydroxylation temperature, then a reduced yield of 19b was observed (53%). Indirect hydroxylation of the propylated tartrate enolate was also attempted using CBr 4 (at −78 °C) as a more readily available/convenient electrophile, which also gave the hydroxy acetonide 19b presumably by way of hydrolysis on work-up of an intermediate bromo acetonide, albeit in significantly reduced yield (33%).…”

“…In contrast to the unsuccessful propylation with LiHMDS/LiCl mentioned above, following our modified Seebach‘s protocol, propylation could be achieved to give propylated tartrate 33a [12] (Scheme 9), in 66% yield and 97:3 er by chiral HPLC, with the trans -dipropylated product 34a also being separately isolated, in 7% yield. Other primary ‘non-activated’ alkyl iodides also led to alkylated tartrates 33b , c and the corresponding dialkylated side-products 34b , c (Scheme 9).…”

“…Our studies in this area have recently culminated in two communicated syntheses of 6,7-dideoxysqualestatin H5 (DDSQ ( 2 ), Fig. 1) [12–13]. The centrepiece of both of these strategies is a rhodium(II)-catalysed tandem carbon ylide formation from a diazoketone 3 (Scheme 1) and stereoselective [3 + 2] cycloaddition with a glyoxylate ( 3 → 4 → 5 ) [14–15], followed by an acid-catalysed rearrangement to generate the desired dideoxysqualestatin core 6 with the requisite tricarboxylate functionality installed.…”

Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey

“…Partly in parallel with the bromide approach above, an alternative strategy for the total synthesis of DDSQ (2) was pursued by Tanzeel Arif and subsequently Younes Fegheh-Hassanpour; this involved a different cross-coupling strategy for direct delivery of unsaturated side chain 101 to the halide-substituted postrearrangement core 102 (Schemes 24 and 36). 41 The approach aimed to avoid the unwanted reactivity of the alkene moiety in the side chain during the rearrangement step (103 → 102) and also to shorten the synthesis by attaching the side chain later in the synthesis. In another key step, the carbonyl ylide precursor diazoketone 104 was envisaged to be generated from unsaturated hydrazone 105 through sequential chemoselective alkene ozonolysis and hydrazone to diazo transformation.…”