Asymmetric Total Synthesis of (−)-Awajanomycin

Abstract

The first asymmetric total synthesis of the unnatural enantiomer of cytotoxic awajanomycin (1) is reported. The synthetic approach features first a convergent strategy using the cross-olefin metathesis reaction to link the lipid side chain 2 and the piperidinone core structure 3. The second feature of the synthesis resides on the construction of segment 3 from the building block 5 via a three-component tandem reaction on the mixed imide 12. Through this work, the stereochemistry at C-11 and the absolute configuration of awajanomycin were established as 3R,5R,6S,8S,11S.

Asymmetric syntheses of (8R,8aS)- and (8R,8aR)-8-hydroxy-5-indolizidinones: Two promising oxygenated indolizidine building blocks

“…Following our previously established procedure for preparing (S)-1-allyl-3-benzyloxy-2,6-piperidinedione [40] but using D-glutamic acid as starting material, (R)-1-allyl-3-benzyloxy-2,6-piperidinedione (20) was obtained as a colorless oil in an overall yield of 35% (3 steps …”

“…In recent years, we have been engaged in the development of protected 3-hydroxyglutarimides 8-based synthetic methodologies [14][15][16]. The value of this chiral building block is being demonstrated by our group [17][18][19][20][21][22][23][24], and also by other research groups [25][26][27][28].…”

Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

“…Successive treatment of 20 with LDA (1.4 equiv) and PhSeBr (1.6 equiv) yielded the crude phenylselenylated product, which, which was directly used for oxidative elimination [22,26] to produce the ,-unsaturated indolizidinone 10 in 70% overall yield. On the other hand, The indolizidinone 20 was treated with a freshly prepared methanolic solution of HCl (AcCl, MeOH) to give the desilylated product 11 in 96% yield (Scheme 5).…”

“…In this approach, the N-Cbz-protected pyrrolidin-2-yl pyridin-2-yl sulfide 13 and functionalized aldehyde 14 were designed as the synthetic equivalents of E and F, respectively. According to the literature precedents, the -lactam moiety in 12 can be used for the diastereoselective ,-dihydroxylation 10 (8-epi-B) [13,21], which can be easily available via the selenium-based method [22], on the other hand of 12a, the pyrrolidinol moiety can either be incorporated into target molecules, or be used for the dihydroxylation of C after dehydration of 11 via the Chugaev reaction [14] or Martin sulfurane [12]. Thus, indolizidinones 10 and 11 can be conceived as two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids and related compounds.…”

Synthesis of the Precursors of Pumiliotoxin 251D and Awajanomycin and Related Studies

“…5 (+)-Pumiliotoxin 251D was isolated from the frogs (Dendrobates pumilio) in South America, 6 and some total syntheses 7,8 and many formal syntheses [9][10][11][12][13][14][15][16] have been reported. 18,19 Herein we report that compounds 3 can also be utilized to achieve a formal synthesis of (±)-pumiliotoxin 251D and (±)-awajanomycin ( Figure 1). AWA16-1), 17 also with some syntheses being reported.…”