Synthesis of (+)-Bullatacin via the Highly Diastereoselective [3+2] Annulation Reaction of a Racemic Aldehyde and a Nonracemic Allylsilane

Abstract

A total synthesis of (+)-bullatacin has been accomplished via a diastereoselective [3+2] annulation reaction of the highly enantiomerically enriched allylsilane 3 and racemic aldehyde 4, which provides the key bis-tetrahydrofuran fragment 15 with ≥ 20 : 1 ds.(+)-Bullatacin (1) is one of more than 350 Annonaceous acetogenins isolated from the tropical plant family Annonaceae (Figure 1). Many members of this structurally diverse family of natural products exhibit impressive antitumor activity in human tumor cell lines. 1 The acetogenins contain a long aliphatic backbone bearing a terminal butenolide unit and one or more tetrahydrofuran rings and hydroxyl groups at internal positions of the aliphatic chain. These compounds are intriguing synthetic targets owing to the variation of stereochemistry around the tetrahydrofuran rings and at the sites bearing additional hydroxyl groups. 2, 3The [3+2]-annulation reaction of aldehydes and chiral allylsilanes is an important method for the stereocontrolled synthesis of substituted tetrahydrofurans. 4, 5 β-Silyloxy-substituted allylsilanes undergo [3+2] annulation reactions with aldehydes and certain electrophilic ketones to give either 2, 5-trans or 2, 5-cis substituted tetrahydrofurans with excellent selectivity, depending on the use of chelating or non-chelating Lewis acids, respectively. 6 We have recently utilized this methodology in a highly stereoselective total synthesis of asimicin (2). 7As part of ongoing studies focusing on the development of a stereochemically general synthesis of members of the acetogenin family, we have developed and report herein a highly stereoselective synthesis of bullatacin (1), 8 which differs from asimicin (2) at a single stereocenter (C-24). We envisaged that the bis-tetrahydrofuran core unit of bullatacin could be synthesized from sequential chelate-controlled [3+2] annulation reactions of allylsilanes 3 and 6 (Figure 2). The proposed [3+2] annulation of 3 and 4 is expected to be a stereochemically matched double asymmetric reaction under chelate-controlled conditions, by analogy with the corresponding reaction in our asimicin synthesis that proceeded with ≥20 : 1 ds. 7The erythro stereochemistry of C(23)-C(24) of aldehyde 4 requires that a syn-β-silyloxy allylsilane 6 be used in a chelate-controlled [3+2] annulation reaction with α-benzyloxy acetaldehyde (5). Initial attempts to develop an enantioselective synthesis of syn-β-silyloxy allylsilanes related to 6 focused on asymmetric allylboration reactions using (Z)-γ-dimethylphenylsilyallylboronate 7 (Scheme 1). Thus, silylcupration 9 of acetylene, addition of ‡ Address correspondence to this author at Scripps Florida, Department of Medicinal Chemistry, 5353 Parkside Drive, RF-2, Jupiter, FL 33485; e-mail: roush@scripps.edu. A more convenient route to (racemic) syn-β-hydroxyallylsilanes 8 involves the γ-silylallylstannation of aldehydes using γ-(dimethylphenylsilyl)allylstannane 9. 12 Treatment of cyclohexanecarboxaldehyde with 9 at −78 °C in CH 2 Cl 2 in the presence of BF 3 ·...

Stereoselective Synthesis of γ-Substituted (Z)-Allylic Boranes via Kinetically Controlled Hydroboration of Allenes with 10-TMS-9-borabicyclo[3.3.2]decane

“…(entries 3, 4). We have previously documented the challenges associated with synthesis of ( Z )-γ-silylallylboranes, and the present route constitutes a significant improvement 24. Tributylstannylallene ( 14c ) also proved to be an excellent substrate for hydroboration with in situ generated 7 (entries 5,6).…”

“…These reagents, which undergo allylborations of aldehydes with typically 89-96% e.e., are representative of ( Z )-allylic boranes that are inaccessible, or accessible only with great difficulty,24 by alternative methods. This work also defines the opportunities for selective, kinetic hydroboration of monosubstituted allenes.…”

Transition metals in organic synthesis: Highlights for the year 2005

“…A palladium-catalyzed hydrocarbonylation was used in a synthesis of (+)-bullatacin (Eq. (195)) [980]. A ruthenium-catalyzed hydrocarbonylation of an allene was used in a synthesis of bipinnatin J (Eq.…”

Copper‐Catalyzed Borylcupration of Allenylsilanes

“…In addition, Rmay also be Et or nPr (entries 6and 7). ForR= aryl, the amount of base and B 2 (pin) 2 had to be increased and the reaction time prolonged to 15-17 hours to ensure full conversion (entries [8][9][10][11]. Gratifyingly,t he reaction could be run on ao ne-gram scale to give excellent yield and the same selectivity (entry 2).…”