Construction of Iterative Tetrahydrofuran Ring Units and Total Synthesis of (+)-Goniocin

Abstract

Cytotoxic acetogenin (+)-goniocin has been synthesized in 17 steps from (R)-O-tritylglycidol. The core structure of the contiguous C22-C10 threo-trans-threo-trans-threo-trans-tris-tetrahydrofuran (THF) ring involving an iterative THF-ring unit was synthesized. An iterative THF ring unit was constructed from an alkenyl-substituted THF ring in four steps including a Pd(II)-catalyzed ring-closing reaction and cross-metathesis. This method is general and allows the preparation of both trans-threo-trans- and trans-threo-cis-THF ring units flexibly.

Towards the generalized iterative synthesis of small molecules

“…For example, Uenishi and co-workers developed an iterative protocol for the stereoselective synthesis of linked tetrahydrofuran (THF) rings (Figure 2k). 94 The iterative sequence commences with formation of a homoallylic alcohol through Grignard addition to an aldehyde or epoxide, followed by cross-metathesis with a stereodefined allylic alcohol. Pd(II) mediated ring closure forms the THF ring, and finally, ozonolysis of the resultant olefin forms an aldehyde to allow further iteration.…”

Additions of Organomagnesium Halides to α-Alkoxy Ketones: Revision of the Chelation-Control Model

“…Competition experiments also suggest why additions of organomagnesium halides to α-alkoxy aldehydes generally proceed with low stereoselectivity. , The addition of either MeMgCl or allylmagnesium chloride to a mixture of α-alkoxy aldehyde 17 and alkyl aldehyde 18 resulted in the formation of both addition products (eq ). The low selectivity observed in the reaction of MeMgCl with aldehydes 17 and 18 contrasts significantly with the high selectivities observed in competition experiments with ketones 13 and 14 (Table , entries 1 and 2).…”

Total Synthesis of (+)-Goniodenin

“…The intermediate 7 was prepared from 9 in 28% overall yield by the same seven-step sequence developed for the synthesis of ent-7. 7 Acid-catalyzed deprotection of the O-trityl group of 7 gave 10 in quantitative yield. Cross-metathesis of 10 with 8 in the presence of Grubbs's (II) catalyst gave 5 in 58% yield.…”

“…The total synthesis of 2 was reported by Sinha and Keinan et al in 1998 6 and recently by our group in 2016. 7 Several Annonaceous acetogenins possessing a trans-threotrans-bis-THF ring unit on the C 10 to C 17 carbon chain and an additional hydroxy group adjacent to the ring at C 18 are shown in Figure 2. They consist of two pairs of the enantiomeric isomers (I and ent-I and also II and ent-II).…”