Asymmetric remote stereocenter

In the Cope rearrangements of terminal substituted substrates, new stereogenic centers are created at positions 1 or 6. The configuration of these stereocenters is often regulated by a stereocenter which is immediately attached to the new one or by a remote stereocenter. This section discusses stereochemical aspects which concern relative asymmetric induction in Cope rearrangements. For the definition of the term relative asymmetric induction see also Section 1.6.3.1.1.5. p 3481. 

The stereoselectivity of the aldol additions shown in Schemes 5.25 and 5.26 are obviously the result of a complex series of factors, among which are the Felkin-Anh preference dictated by the a-substituent on the aldehyde, the proximal stereocenters on the enolate, etc. Additionally, the more remote stereocenters, such as at the p-position of the aldehyde, may influence the selectivity of these types of reactions. Evans has begun an investigation into some of the more subtle effects on crossed aldol selectivity, such as protecting groups at a remote site on the enolate [131], and of P-substituents on the aldehyde component [132], and also of matched and mismatched stereocenters at the a and P positions of an aldehyde (double asymmetric induction) [133]. Further, the effect of chiral enolates adding to a,P-disubstituted aldehydes has been evaluated [134]. The latter turns out to be a case of triple asymmetric induction, with three possible outcomes fully matched, partially matched, and one fully mismatched trio. 

Novo Nordisk showed in the synthesis of (-)-Ormeloxifene (48), a drug candidate for the treatment and prevention of osteoporosis, that the enzymatic asymmetric hydrolysis of potential intermediates can be carried out using Candida rugosa lipase (CRT) immobilized on Accurel (Scheme 15) [74]. Racemic czs-hexanoate mc-46 was subjected to enzymatic hydrolysis in aqueous acetonitrile and gave the phenol ds-(3R,4S)-47 in 95% ee. This transformation is a nice example to demonstrate that the enzyme can recognize and use remote stereocenters. The reaction was run on a 10 g scale, and it was even possible to recycle hexanoate (3S,4R)-46. Simple recovery of the immobilized enzyme by... 

The 1,4-addition of m anometallic reagents to a,3-unsaturated aldimines (11) 9 and aromatic aldimines (12) resembles additions to oxazolines (13) and (14), and provides a valuable method for generating a remote stereocenter (1,5-asyininetric induction). Other strategies have been employed for controlling azomethine diastereofacial selectivity. For example, organometallic treatment of chiral chromium complexes (15) of iV-arylaldimines leads to high stereoselectivi (presumably a result of steric control). Further investigations are required to assess the value of the chromium tricarbonyl complexes in asymmetric amine synthesis. 

A similar reaction was used for preparation of the remote stereocenter in 85, an intermediate in Paterson s synthesis of aurisides A and B. The asymmetric catalysis of the aldol reaction with fluoral has also been investigated by Mikami for highly enantioselective syntheses of fluorine-containing aldols. The reaction of the ketene trimethylsilyl acetal 86 with fluoral (87) in the presence of the BfNOL-catalyst 67 yielded the aldol adduct 88 in moderate yield (56%) and high enantioselectivity (90% ee). 

Asymmetric Induction by Remote Stereocenters (Beyond 1,3-Induction)... 

In studies of the asymmetric epoxidation of olefins, chiral peroxycarboxylic acid induced epoxidation seldom gives enantiomeric excess over 20%.1 Presumably, this is due to the fact that the controlling stereocenters in peroxycarboxylic acids are too remote from the reaction site. An enantiomeric excess of over 90% has been reported for the poly-(Y)-alanine-catalyzcd epoxidation of chalcone.2 The most successful nonmetallic reagents for asymmetric epoxidation have been the chiral TV-sulfonyloxaziridincs3 until asymmetric epoxidation reactions mediated by chiral ketones were reported. Today, the... 

Two aspects of this work are noteworthy Firstly, the excellent induced diastereoselectivity results from a very remote inducing stereocenter (1,6-asymme-tric induction) and secondly, the asymmetric induction can be reversed by changing the Lewis acid. Thus, the sequence also allows the entrance into the unnatural L-series by performing the cycloaddition with the same substrates but in the presence of TMSOTf. 

The Krapcho decarboxylation was also utilized as a beneficial side reaction in the key step in the Deslongchamps synthesis of (+)-maritimol.18 In this asymmetric synthesis, the Lewis acid mediated intramolecular Diels-Alder reaction of 11 to produce 12 was followed by thermal decarboxylation to yield 13. The thermal Diels-Alder reaction of 11 was then tested and found to proceed in slightly higher yield and resulted in decarboxylation occurring in the same pot. Remarkably, the complete diastereo- and enantiocontrol in this reaction is directed by the remote nitrile stereocenter. Additional... 

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