Kishi synthesis

Diastereoselective Cr-mediated allylation reactions have been documented in numerous applications. In a classic synthesis, Kishi demonstrated the synthetic utility of crotyl chromium couplings to access the C15-C29 fragment (136) of the antibiotic rifamycin S (Scheme 5.22) [97]. The allylation of aldehydes 132 and 134 proceed smoothly to afford the corresponding products 133 and 135, respectively, in dr >20 1. 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

The issue of stereochemistry, on the other hand, is more ambiguous. A priori, an aldol condensation between compounds 3 and 4 could proceed with little or no selectivity for a particular aldol dia-stereoisomer. For the desired C-7 epimer (compound 2) to be produced preferentially, the crucial aldol condensation between compounds 3 and 4 would have to exhibit Cram-Felkin-Anh selectivity22 23 (see 3 + 4 - 2, Scheme 9). In light of observations made during the course of Kishi s lasalocid A synthesis,12 there was good reason to believe that the preferred stereochemical course for the projected aldol reaction between intermediates 3 and 4 would be consistent with a Cram-Felkin-Anh model. Thus, on the basis of the lasalocid A precedent, it was anticipated that compound 2 would emerge as the major product from an aldol coupling of intermediates 3 and 4. 

An important stereochemical issue presents itself here. A priori, an aldol condensation between intermediates 2 and 3 could result in the formation of a mixture of diastereomeric aldol adducts, epi-meric at C-7, with little or no preference for a particular stereoisomer. Cram s rule2,4 predicts the formation of aldol adduct 43. This intermediate possesses the correct absolute configuration at C-7, and it should be noted that Kishi et al. had demonstrated during the course of their monensin synthesis that a similar aldol condensation produced the desired C-7 epimer as the major product.12... 

Using Kishi s modification of the Suzuki coupling procedure,45 Nicolaou et al. accomplished the convergent union of compounds 112 and 113 (see Scheme 28).38b 46 This coupling is the key step in a synthesis of (55,6/ )-dihydroxyeicosatetraenoic acid [(55,6/ )-diHETE] methyl ester (115). Importantly, the configurations of the two coupling partners are reflected in the Suzuki coupling product 114. 

Numerous applications of the Ni(n)/Cr(ii)-mediated coupling reaction in total synthesis have already been reported.11 Some of the more noteworthy examples derive from Kishi s laboratories and played a role in the syntheses of such complex molecules as (+)-ophiobolin C16 and halichondrin B17 (see Scheme 5). Another elegant application can be found in the enantioselective total syntheses of (+)-brefeldin C and 4-ep/-brefeldin C by Schreiber and Meyers (see Scheme 5).18... 

The extremely high sensitivity of bacteriochlorins to various reactions makes their chemistry very difficult. This might also be one reason why methods for the total synthesis of bacteriochlorins had not, until very recently, been developed.13 Total synthesis of a tolyporphin model was reported by Kishi et al.13 using an approach that is very closely related to Eschenmoser s syntheses of hexahydroporphyrins from reduced linear tetrapyrroles by cyclization (see Section 1.5.1). 

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]. 

Kishi s synthesis 290 ring closing metathesis 302 ring expansion 65, 98... 

Thus, oxyluciferin has a molecular formula of C21H27ON72HCI. The total synthesis of Cypridina luciferin has been accomplished (Kishi et al., 1966c Inoue et al., 1969 Karpetsky and White, 1971 Nakamura et al., 2000). 

Kishi, Y., et al. (1966c). Cypridina Bioluminescence. III. Total synthesis of Cypridina luciferin. Tetrahedron Lett., pp. 3445-3450. 

In the 1970s, Kishi published a series of landmark papers [36] describing the total syntheses of ( )-dehydrogliotoxin (1973) [36b], ( )-sporidesmin A (1973) [36c], ( )-gliotoxin (1976) [36d], and ( )-hyalodendrin (1976) [36e] in which he employed a new method for epidithiodiketopiperazine synthesis (Scheme 9.4). Cognizant of the harsh conditions required in all of the sulfur incorporation methods developed at the time, it was determined that thiolation would be performed in the early stages of the syntheses. A dithiol intermediate obtained in a similar fashion to Trown s epidithiodiketopiperazine was protected as a dithioacetal, and after elaboration of this core diketopiperazine structure, the dithioacetal was unraveled under mild conditions in the final steps to afford the target epidisulfides. 

Nozaki-Hiyama-Kishi (NHK) reactions215,216 are well known and often employed as a useful method for the synthesis of natural products by coupling of allyl, alkenyl, alkynyl, and aryl halides or triflates with aldehydes. The organochromium reagents are prepared from the corresponding halides or triflates and chromium(ll) chloride, and are employed in polar aprotic solvents (THF, DMF, DMSO, etc.). Subsequently, it was found that nickel salts exhibited a significant catalytic effect on the formation of the C-Cr bond217,218 (Equation (19)). 

The total synthesis of rifamycin S was one of Kishi s many achievements in organic synthesis.6 Kishi recognized that a certain type of (Z)-olefin such as 51 tends to take a conformation in which C-l, C-2, C-3, and H-3 are nearly co-... 

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