Masamune reaction

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

A second route was devised using chiral /3-keto ester 14, which was identified as our precursor for 2 [7]. This idea was in analogy with the carbapenem chemistry [8], as depicted in Scheme 2.4, where Masamune reaction [9] for carbon elongation, diazo-transfer, and transition metal-mediated carbene insertion reaction [10] were employed as key steps sequentially. 

Decarboxylation, Masamune reaction, and diazotransfer Diazo 25 was prepared under optimized conditions, as summarized in Scheme 2.9. Decarboxylation of the malonate could be done under either acidic or basic conditions. Reaction of 17 under acidic conditions provided the desired mono-carboxylic acid 18 but lactone 35 was simultaneously formed (Figure 2.2). Under basic conditions,... 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

The examples addressed thus far adequately convey the utility of the SAE reaction as a tool for the reagent-control strategy. Nonetheless, the power of the SAE reaction and the capabilities of the new reagent-control strategy are demonstrated even more forcefully in the total synthesis of all eight L-hexoses (compounds 1-8) by the groups of Masamune and Sharpless.11 The remainder of this chapter is devoted to this elegant joint venture. 

Double asymmetric synthesis was pioneered by Horeau et al.,87 and the subject was reviewed by Masamune et al.88 in 1985. The idea involves the asymmetric reaction of an enantiomerically pure substrate and an enantiomerically pure reagent. There are also reagent-controlled reactions and substrate-controlled reactions in this category. Double asymmetric reaction is of practical significance in the synthesis of acyclic compounds. 

As mentioned in the previous section, chiral dienophile 17 is highly enantiose-lective and meets the criteria for double asymmetric induction. A set of asymmetric reactions have been performed by Masamune s group using 49 as an achiral diene and (S)/(R -methyl mendelates (S)/(R)-51 as chiral dienes.2a The Diels-Alder reaction between (,S)-17 and 49 exhibits the high diastereoselective potential of 17. As shown in Scheme 5-17, in the presence of a catalytic amount of BF3 Et20, the reaction of (.S )-17 and 49 gives compound 50 as the major product with a diastereoselectivity of over 100 1. The reaction of (S )-17 with... 

Of the catalysts that are based on boron, the Masamune oxazaborolidines (44) are typical, being able to promote aldol reactions of the type described in Scheme 42[124]. 

The groundwork for this study was laid in the bis(oxazoline)-copper-catalyzed cyclopropanation reaction reported by Evans, Masamune, Pfaltz, and their coworkers (32-34) (cf. Section II.A.6). Indeed, two of these early papers reported that the same catalysts were capable of effecting nitrenoid transfer to acceptor alkenes in moderate ee. 

Evans et al. (34) reported preliminary results showing that 55c CuOTf is moderately selective in mediating the aziridination of styrene, producing the heterocycle in 61% ee. Lowenthal and Masamune (44) mention in a footnote to their cyclopropanation paper that the copper complex of camphor-derived bis(oxa-zoline) (103) provides the aziridine of styrene in 91% yield and 88% ee. However, this reaction has been found to be irreproducible (76,77) and further reports of aziridination from the Masamune laboratories have not appeared. 

The data from Masamune s papers underscore the impressive range the results can cover when the substituents are varied. The last reaction utilises a very bulky ester group to make practically one diastereomer in 94% e.e. The catalyst is CuC104 or CuOTf. For styrene cyclopropanation Evans [7] found a similar relationship between the steric bulk of the ester group of the diazocompound and the selectivity for trans products. 

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

Now, if we allow one enantiomer of the chiral aldehyde 59 to react with the two enantiomers of the chiral enolate M, in one case the two chiral reagents will both promote the same absolute configuration at the two new chiral centres (65a ). However, no such effect will be observed in the other possible combination (c/. 65) (Scheme 9.21). In the first case, the effective "Cram s rule selectivity" shown by the aldehyde will be greater than in its reactions with achiral enolates. For the selectivities chosen the "Cram anti-Cram ratio" should be in our example of the order of 100 1 (see below 9.3.4., Masamune s "double asymmetric induction"). 

The next step was, therefore, to develop chiral enolates which show high diastereoselectivities (>100 1) in single asymmetric reactions. Of the many chiral (Z)-enolates which were prepared and studied by Masamune and his associates, those shown (74) in Scheme 9.24 -prepared from optically pure (S)- and R)-mandelic acid- meet the requirements set for a chiral reagent [22c]. Thus, the chiral... 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

Of the cyclopropanation reactions studied, the reaction between styrene and ethyl diazoacetate has become the benchmark for determining the utility of a bis(oxazoline) ligand in cyclopropanations. In 1990, Masamune and co-workers introduced several bis(oxazoline) ligands including 2 and 35-40 as catalysts for the cyclopropanation of styrene with ethyl diazoacetate. The reactive species in these reactions were determined to be the bis(oxazoline) dimers of type 2a and 38a-40a, as shown in Figure 9.10. 

Cyclopropanations using bis(oxazoline) catalysts are not limited to reactions of styrene many different types of olefins can be used in cyclopropanations. The work of Masamune and co-workers included an example using 2,3,3-trimethylbutene with his bu-box complex 2a and /-(—)-menthyl diazoacetate. The product was obtained in 60% yield, trans/cis ratio of 95 5, trans ee of 80% and cis ee of 91%. 

Structures 1 and 1, with identical relative configuration at C-2. C-3, are not covered by Masamune s very scant directions which do not include a guideline on the definition of the backbone. Thus, an allylmetal expert , having prepared 1 as one member of a series with the substituent of the ally] group varied, will probably describe 1 as syn, but investigators working on aldol reactions or conjugate additions will certainly prefer the term anti for 1. ... 

The Masamune team also proposed a simple relationship between AG values of reference reactions, AG and AGf, and double-induced reaction pairs ... 

It must be emphasized that the Masamune analysis exclusively refers to induced diastereoselectivity and to reactions between enantiomerically pure reactants32. 

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