Diastereocontrolled approach

A good diastereocontrol is obtained for the debromination of Reaction (4.14) and it is attributed to the bulky reducing agent, which approaches the radical intermediate from the less hindered face anti to the two vicinal substituents [35]. 

There have been two main approaches to the development of dipolarophile facial selectivity (1) the use of chiral substrates, templates, and auxiharies and (2) the use of chiral rhodium catalysts [35]. In one of the earhest examples of chiral substrate selectivity, Pirmng and Lee reported a selective hydroxy-directed cycloaddition with chiral hydroxy-substituted vinyl ethers [95]. This effort was followed by a number of chiral template approaches to diastereocontrol, including the use of (R)- or (S)-phenylglycinol to form a cycHc phenyloxazinone for the facially selective cycloaddition of isomtinchnones [96, 97]. Padwa and Prein demonstrated acycHc diastereofacial control in the cycloaddi-... 

Addition of a nucleophile diastereoselectively produces the a-enolate 4 due to approach of the nucleophile from the less-hindered side of the iron atom. Quenching of 4 by electrophiles is also controlled by the iron center, and diastereocontrolled alkylation of the a-carbon occurs from the less hindered face of elaborated enolate 4 (see also Section 1.1.1.3.4.1.3.) to produce complex 5. 

Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, /26,8664) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbenc or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol. 

An alternative multistep approach to the synthesis of a-amino acids, using the boronic acid as the precursor of the carboxylic acid group, was reported by Harwood et al. [56]. Thus, reaction of a chiral morpholinone derivative with furyl boronic acid and various aldehydes gave, in a diastereocontrolled manner, the corresponding adducts which were converted in several steps to the a-amino acids [56],... 

Another approach towards diastereo- and enantio-enriched homoalyllic ethers was used by Panek et al. during their synthesis of kabiramide C [18]. In this case, optically pure allylsilane 35 was allowed to react with acetal 36, forming the expected syn ether 37 with moderate diastereocontrol (Scheme 13.14). 

In an effort to explain these atypical reactivity patterns, a mechanistic postulate based on direct electrostatic activation (DEA) was proposed (Scheme 3.8). Indeed, the zwitterionic iminium ions derived from catalyst 10 and a,/i-un saturated aldehydes enable both iminium geometry control and direct electrostatic activation of the approaching sulfonium ylides. The combination of geometric and electronic control seems to be essential for enantio- and diastereocontrol in the formation of the desired cyclopropyl compound. 

The idea of matching individual diazoacetate enantiomers with a particular chiral dirhodium (II) has been very successfully exploited by Doyle s group to optimize diastereocontrol and regiocontrol in product formation. The behavior of the individual enantiomers of ds-2-methylcyclohexyl diazoacetate, Eq. (47) provides an illustrative example of the power of this approach in regioselective synthesis. Whereas the (lS,lR)-enantiomer of (41) forms the all ds-bicyclic lac-... 

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant a-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004, 6, 3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontrol. Keiji Maruoka of Kyoto University has developed J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastereocontrol. 

Eric N. Jacobsen of Harvard University has devised a family of catalysts for the enantioselective Pictet-Spengler reaction of tryptamine 21. He has now (Organic Lett. 2008, 10, 745) used this approach to prepare the triene 22 in 94% ee. The Diels-Alder cyclization of 22 proceeded with high diastereocontrol to give 23, the immediate precursor of (-)-yohimbine 24. 

One could envision reduction of the lactam carbonyl of 1 to an aldehyde equivalent, that would then, imder acidic conditions, condense to form the desired aminal 2. This approach was, however, not successful. As an alternative, conditions were developed to convert 1 to the amidine 16. Reduction then proceeded with the expected high diastereocontrol, to give the cis 1,3-fused aminal 2. This was not isolated, hut was directly acylated with acryloyl chloride, to 17. 

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