Asymmetric total synthesis coupling

The asymmetric total synthesis of (-)-steganone (67) was achieved through the asymmetric Mg-mediated coupling of bromide 64 and oxazoline 65, which provided a... 

A as-fused dithiadecalin ring system has been utilized as an important building block in the asymmetric total synthesis of erythromycin (81JA3210, 3213, 3215). Coupling of the... 

The first asymmetric total synthesis of acosamine and daunosamine starting from a nonsugar precursor was reported by Fuganti and co-workers [288,289,290,291]. They found that baker s yeast catalyzes the asymmetric pinacolic cross-coupling of cinnamaldehyde and ethenal giving a ft-diol 156. This diol is protected as an acetonide and submitted to ozonolysis giving L-157. Olefination of L-157 with PhsP = CHCOOMe, followed by treatment with ammonia, provides 158 that is then converted into W-trifluoroacetylacosamine 158 (O Scheme 61). 

C.H. Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

The asymmetric total synthesis of prostaglandin Ei utilizing a two-component coupling process was achieved in the laboratory of B.W. Spur. The hydroxylated side-chain of the target was prepared via the catalytic asymmetric reduction of a y-iodo vinyl ketone with catecholborane in the presence of Corey s CBS catalyst. The reduction proceeded in 95% yield and >96% ee. The best results were obtained at low temperature and with the use of the B-n-butyl catalyst. The 6-methyl catalyst afforded lower enantiomeric excess and at higher temperatures the ee dropped due to competing non-catalyzed reduction. 

In the laboratory of G.A. Molander, a general route for the synthesis of eunicellin diterpenes was developed and was applied for the asymmetric total synthesis of deacetoxyalcyonin acetate. One of the key steps was an inramolecular NHK coupling reaction between an enol triflate and an aldehyde. The cyclopentenol product was formed in high yield as a 2 1 mixture of diastereomers. The undesired diastereomer could be transformed to the desired one using a Mitsunobu reaction. 

In the laboratory of D.P. Curran, the asymmetric total synthesis of (20R)-homocamptothecin was achieved using the Stale coupling and the SAE as key steps." The SAE was used to install the key C20 stereocenter. The ( )-allylic alcohol was epoxidized rapidly in the presence of stoichiometric amounts of L-(+)-DET and TBHP at -20 °C to afford the corresponding epoxide in 93% ee. Interestingly, the (Z)-allylic alcohol reacted with D-(-)-DET sluggishly and gave the epoxide in very iow yieid and with only 31% ee. 

Strychnine was first isolated in 1818 from Strychnos ignatii by Pelletier and Caventou. Overman and colleagues did the first asymmetric total synthesis of strychnine [51]. A palladium-catalyzed carbonylative coupling of aryl iodide with an organostannanes reagent was used for the preparation of one of the intermediates (Scheme 10.6). The entire synthesis was accomplished in 20 steps and... 

A dichromium derivative has been prepared from pinacol (dichloromethyl)-boronate (163), anhydrous chromous chloride, and lithium iodide in THF at 25 °C [90]. With various aldehydes, RCHO, this reagent adds to the carbonyl carbon to form trans-l-alkenylboronic esters, RCH=CH-B(02C2Me4). For most examples yields were 84-91%, E Z ratios >95 5. This reaction was used recently to convert aldehyde 162 into alkenylboronic ester 164, an intermediate used for a Suzuki-Miyaura coupling in the asymmetric total synthesis of quinine and quinidine (Scheme 8.39) [91]. In the modified procedure, the chromium reagent was generated from 163 in the presence of the aldehyde substrate. 

The consistent observation of the arylated products with 92% ee confirms that the enantioselectivity of the asymmetric deprotonation was preserved during the transmetalation with ZnCl2 and retained during the Pd-catalyzed coupling. In fact, the Negishi coupling with 3-bromopyridine (entry 16) was performed at 60 °C, and still provided 26m in 92% ee, which constitutes a formal total synthesis of (R)-nicotine [27]. 

Mikami and co-workers16-19 have done extensive work for developing catalysts for the asymmetric carbonyl-ene reaction. Excellent enantioselectivites are accessible with the binol-titanium catalyst 17 (Equation (10)) for the condensation of 2-methyl butadiene (R1 = vinyl) and glyoxalates (binol = l,T-binaphthalene-2,2 -diol).16 The products were further manipulated toward the total synthesis of (i )-(-)-ipsdienol. The oxo-titanium species 18 also provides excellent enantioselectivity in the coupling of a-methyl styrene with methyl glyoxalate.17 Reasonable yields and good enantioselectivites are also obtained when the catalyst 19 is formed in situ from titanium isopropoxide and the binol and biphenol derivatives.18... 

The first enantioselective total synthesis of ( )-7,8-epoxycembrene C (33) was achieved via a general approach by employing an intramolecular McMurry coupling and Sharpless asymmetric epoxidation as key steps from readily available starting material. The syntheses presented here verified the absolute stereochemistry assignment of the epoxy configuration of 33 as assumed (1R,8R) (Scheme 6-20). °... 

The first enantioselective total synthesis of (- -)-l 1,12-epoxycembrene C (28) has been accomplished via a macro-olefination strategy by employing titanium-mediated McMurry coupling as a key step and the Sharpless asymmetric epoxidation for the introduction of chiral epoxide. Based on the enantioselective Sharpless asymmetric epoxidation, Li et al. assumed the configuration of natural 28 to be (115,125) (Scheme 6-21). ... 

Of the various possible asymmetric cross-coupling reactions, (1) asymmetric alkylation with secondary alkylmetals, (2) asymmetric biaryl synthesis, and (3) asymmetric allylation with allylic electrophiles have been most extensively studied with chiral Ni and Pd complexes [166]. The initial study in this area was reported as early as 1974 by Kumada and his co-workers, but only a meager range of 8-15% ee was reported [167]. By the end of the 1970s, however, the cross-coupling reaction had been sufficiently developed so that its application to the asymmetric synthesis was already practically attractive, as indicated by an asymmetric total sythesis of (R)-(—)-a-curcumene in five steps in 66% ee and 34% overall yield shown in Scheme 1-47 [168]. 

During the total synthesis of rhizoxin D by J.D. White et al., an asymmetric aldol reaction was utilized to achieve the coupling of two key fragments. " The aldol reaction of the aldehyde and the chiral enolate derived from (+)-chlorodiisopinocampheylborane afforded the product with a diastereomeric ratio of 17-20 1 at the CIS stereocenter. During their studies. White and co-workers also showed that the stereochemical induction of the chirai boron substituent and the stereocenters present in the enolate reinforce each other thus representing a matched aldol reaction. 

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