Synthesis, stereoselective asymmetric induction

Of perhaps greater use for organic synthesis was the observation that photo-driven reactions of alkoxycarbenes with unsubstituted optically active ene carbamates [65] produced aminocyclobutanones in fair yield with high dia-stereoselectivity (Table 12) [66]. In contrast, with a gem-disubstituted ene carbamate, the syn-anti selectivity was low but high asymmetric induction a to nitrogen was observed (Eq. 16). Trans-monosubstituted ene carbamates failed to react, as did a,/J-unsaturated chromium carbene complexes. 

Chiral phosphoryl and sulfinyl groups are known as efficient auxiliaries in asymmetric synthesis. As reported below, their asymmetric induction in the a-posi-tion has been used to prepare chiral non-racemic organophosphorus compounds a-substituted by a sulfur function. Such compounds can also be obtained from their a-hydroxy analogues by OH-4 SR stereoselective transformation. 

Ethyl ethylthiomethyl sulphoxide anion 325 has been found to give better yield of 1,4-adducts compared with its methyl analogue . This anion has been used by Schlessinger and coworkers as a key reagent in the synthesis of 1,4-dicarbonyl precursors of naturally occurring cyclopentenones, e.g. dihydrojasmone 379 (equation 219). Michael addition of the anion of optically active (-l-)-(S)-p-tolyl p-tolylthiomethyl sulphoxide 380 to the properly substituted cyclopentenone constitutes an important step in the asymmetric synthesis of optically active cyclopentenone 381, which is a precursor of 11-deoxy-ent-prostanoids (equation 220). The reaction proceeds with a high and y-asymmetric induction (92%), but with a poor a-stereoselection (52 48). 

This procedure has been recently applied to the synthesis of L-lyxitol and the polyhydroxylated chain of amphotericin Interesting results have also been obtained in the reduction of ) -oxo derivatives of dithioacetal monoxides. In the reaction sequence of equation 322 two successive asymmetric inductions are involved. After the first reaction, involving acylation of the carbanion, a diastereoisomeric mixture in a 65 35 ratio is produced. When this mixture is reduced with NaBH4 in MeOH-conc. aqueous solution of ammonia, among four possible diastereoisomeric alcohols, the stereoisomer 523 is obtained with a stereoselectivity of 98% . Guanti and coworkers have found that the LiAlH4 reduction of the same substrates at — 78° in THF/ether leads to 523 with a stereoselectivity 99 i6i3.6i4... 

The lactone concept is not restricted to the simple model biaryl synthesis presented here. It has been successfully expanded to a broad series of structurally diverse biaryl substrates (e.g., lactones with additional stereocenters and functional groups, configurationally stable lactones, seven-membered lactones, and again configurationally unstable biaryl hydroxy aldehydes ), to different activation modes in the ring-opening step (e.g., use of metallated nucleophiles, carbonyl activation by Lewis acids, (Ti -complexation, etc.), and for various strategies of stereoselection (e.g., external vs. internal asymmetric induction). ... 

The stereoselective or stereospecific formation of these compounds and their interaction with butyllithium was studied with the help of NMR. Paquette and Freeman first applied asymmetric induction to the synthesis of four-membered rings, especially with the sulfene-enamine 2 -F 2 cycloaddition. The in situ generation of sulfene 68 by dehydrochlorination with butyllithium of the sulfonyl chloride allowed the formation of cycloadduct 69 in 88 % yield. In a variation, the sulfene may be generated by base-induced... 

It should be noted, however, that the 1,3-dipolar cycloaddition chemistry of diazo compounds has been used much less frequently for the synthesis of natural products than that of other 1,3-dipoles. On the other hand, several recent syntheses of complex molecules using diazo substrates have utilized asymmetric induction in the cycloaddition step coupled with some known diazo transformation, such as the photochemical ring contraction of A -pyrazolines into cyclopropanes. This latter process often occurs with high retention of stereochemistry. Another useful transformation involves the conversion of A -pyrazolines into 1,3-diamines by reductive ring-opening. These and other results show that the 1,3-dipolar cycloaddition chemistry of diazo compounds can be extremely useful for stereoselective target-oriented syntheses and presumably we will see more applications of this type in the near future. 

Cyclization of 8-allenylamines is successful also. Synthesis of 2-alkenylpiperidines can be effected with mercury(II) or silver salts, with silver salts giving higher yields (equation 141 and Table 35).268a The significant asymmetric induction found in the cyclization of a chiral allene (78% ee, entry 2) suggests that the low stereoselectivity observed in the synthesis of the 2,6-disubstituted system (entry 3)269 may be a result of starting with a diastereomeric mixture. Aminopalladation/methoxycarbonylation has been effected in moderate yield also (entry 4). 

An enantioselective Strecker reaction involving Brpnsted acid catalysis uses a BINOL-phosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at -40 °C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-l-amino-2-hydroxycyclohexane-l -carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl (g)... 

A general overview about advances in the catalytic, asymmetric synthesis of -lactams can be found in an article written by Thomas Lectka, whereas a publication by Claudio Palomo discusses reactions of acyl chlorides with imines, including diastereoselectivites and mechanistic insights of the ring closure leading to cis or trans substituted P-lactams and asymmetric induction from the ketene component. The influence of solvents and additives and the pathways of ketene generations and addition modes on the stereoselectivity. 

In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

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