Kishi epoxide

The spongistatins are a family of architecturally complex bisspiroketal macrolides, which display extraordinary cytotoxicity. During the second generation synthesis of the ABCD subunit of spongistatin 1, A.B. Smith and coworkers utilized the Keck allylation to construct the Kishi epoxide. The allylation was carried out under standard conditions, using tributyl-(2-ethylallyl)-stannane as the allylstannane reactant. The desired product was formed in high yield and a diastereomeric ratio greater than 10 1. 

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

The synthesis of tetrahydrofurans through cyclization via epoxide ring opening has been well investigated and has been applied to the preparation of a-bisabolol oxides (69IJC1060) and linalool oxides (77H(6)1365) and by Kishi et al. in the synthesis of lasalocid A (195), where the epoxide pathway resulted in a stereospecific construction of six out of the ten chiral centers (Scheme 93) (78JA2933). 

Finan, J. M. Kishi, Y. Reductive ring openings of allyl-alcohol epoxides. Tetrahedron Lett. 

A more complex example is seen in Kishi s tetrodotoxin synthesis.Enol ether (76) provided the precursor to a-acetoxy ketone (77), which was obtained as a single stereoisomer by acetic acid opening of the initial ethoxy epoxide. 

Kishi et al. have observed that the epoxidation of the allylic alctdiol (93) which has a suitably located ether oxygen is stereoselective (equation 32). In the transition state (SM), which delivers oxygen from the -face, MCPBA is complexed by two hydrogen bonds involving participation of ether oxygen as well as hydroxy. In the transition state (94) there is steric interference between allylic hydrogen at C-4 and methyl at C-2. In contrast, in the transition state which can deliver oxygen from the a-face, there is... 

Stereocontrolled epoxidation of acyclic systems. Stereoselectivity in the epoxi-dation of homoallylic alcohols is usually low. Nonetheless Kishi etal. have observed... 

We selected the natural product thyrsiferol as an ideal target to test our ideas. Its total synthesis was envisioned to proceed as illustrated in the Scheme 28. The successful coupling between aldehyde 84 and vinyl iodide 82 via a Nozaki-Hiyama-Kishi (NHK) reaction [66] had been demonstrated previously [29]. We therefore sought to model our final steps after precedence presented by Forsyth for the union of these two fragments. The focus of our synthetic strategy centered around the stereoselective synthesis of the ABC framework (84) of thyrsiferol (1) as a scaffold to validate the scope of the Cp2TiCl reaction with epoxides toward the assembly of Q-C-glycosides and cyclic ethers. 

A more typical early example is Kishi s polyether antibiotic syntheses using a sequence of epoxides made by controlled oxidation. The sequence starts with a somewhat similar reduction LiAlH4 with the diamine 229 reduces ketone 227 highly stereoselectively in a Felkin sense 230 to give almost exclusively anti-228 which was resolved as a urethane (chapter 22) to give the enantiomer shown.43... 

In synthetic studies directed toward the natural product gymnodimine, Kishi and co-workers epoxidized compound 21 using m-CPBA to yield 22.17... 

Several different authors have applied Shi s epoxidation in the synthesis of natural products. In this section, we will discuss some representative examples. In 2004, Kishi and co-workers published the triple epoxidation of triene 63 followed by epoxide opening with LiAlH4. From intermediate 64, (-l-)-glisoprenin A was obtained in five steps (Scheme 12.13) [104]. Another spectacular synthesis was developed by McDonald and co-workers [105] in 2005 (Scheme 12.14). Polyene 66 was epoxidized with Shi s reagent to give polyoxide 67, which was then opened via ewJo-regioselective tandem oxacyclyzation to obtain compound 68 (Scheme 12.13). 

Kishi and coworkers reported that triene 110 was stereoselectively epoxidized with ketone 42 to give compound 112 in 52% overall yield after epoxide opening with LiAlH4. (+ )-Glisoprenin A (113) was obtained from 112 in five steps (Scheme 3.36) [72]. 

Sharpless has extended his (+) or (-)dlalkyltartrate mediated asymmetric epoxidation procedure to synthesize alditols. Thus epoxide (8), obtained in high enantiomeric excess from the -enltol (9) was subjected to a specific epoxide opening reaction to provide threitol (10) (Scheme 2). Erythrltol was similarly synthesized from the E-isomer of (9), while all the possible D-pentitols and -hexltols were obtained from the E- and Z-lsomers of (11) and (12) respectively. Kishi et. al., synthesized D-pentltols, 2-deoxy-... 

Lasolocid A.—Kishi and his co-workers have reported the first total synthesis of the complex polyether antibiotic lasolocid A (8), in a paper that will repay close study. The route incorporated an early resolution by classical methods at the stage of the alcohol (9). Compound (9) was epoxidized and cyclized to the tetrahydro-furan (10) as the major product. A stereoselective aldol condensation was eventually used to form the C-11—C-12 bond [see dotted line in structure (8)] of the target in a convergent synthesis in which the left hand side of the molecule had been made from an optically active starting material. 

Coxon illustrated (Scheme 4.4) the inherent preference for the 5-cxo-pathway over the 6-cmfo-pathway under acidic conditions [21] through the conversion of hydroxy epoxide 18 to a greater than 5 1 mixture of tetrahydrofuran 19 and tetrahydropyran 20. Kishi showed that the 5-cxo-pathway is exclusively observed when the proximal carbon of the... 

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