Enantioselective benzylation

Enantioselective Benzylic Microbial Hyciroxylation of Indan and Tetralin 369... 

Enantioselective Benzylic Microbial Hydroxylation of Indan and Tetralin... 

The enantioselective benzylic hydroxylation of indan and tetralin can be achieved with M. isabellina, affording 78 % conversion to 1-indanol (64 % yield, 86 % (11 )- ee) in a 2-day incubation and 52 % conversion to 1-tetralol (38 % yield, 92 % (11 )- ee) in a 4-day incubation. The good yields and ee allow their use in future scahng-up processes however, to avoid the lack of efficiency, careful control of the temperature, pH and medium is necessary, since the reactions are strongly dependent on the incubation and reaction conditions. Tables 12.2 and 12.3 give details of some of the different incubation condi-tions/results and time-course analysis found in the benzyhc hydroxylation of indan and tetrahn mediated by M. isabellina CCT3498. 

An important application of these precursors is the asymmetric synthesis of aminoacids, the key step being an enantioselective benzylation using a chiral auxiliary (route A, Scheme 25) [155] or a chiral phase transfer catalyst (PTC) [156] (route B, Scheme 25). This latter approach avoiding the use of dry reagents is particularly adapted to automated synthesis and enables the production of more than 7.4 GBq (200 mCi) of [6- F]fluoro-L-DOPA from 55.5 GBq (1.5 Ci) of starting [ F] fluoride [157]. 

Alternative routes for the multi-step preparation of 6-p F]fluoro-L-DOPA (given here as an example and also applicable to other amino acids) include the use of enantioselective benzylations using either a chiral auxiliary [Scheme 45, Pathway B (i) (ii) (iv) (viii)] [207-209] or a chiral phase transfer catalyst [Scheme 45, Pathway C (i) (ii) (v) (viii)] [210-212], The latter approach, avoiding the use of dry reagents, is well suited to automation and enables the production of more than 200 mCi (7.4 GBq) of 6-p F]fluoro-L-DOPA from 1.5 Ci (55.5 GBq) of starting [ F]fluoride [213]. 

Table 4.5 Phase-transfer-catalyzed enantioselective benzylation of aldimine Schiff bases derived from a-alkyl-a-amino acids.3) (For experimental details see Chapter 14.15.1).

SCHEME 99. Enantioselective benzylation of 1 -tetralone lithium enolate in the presence of a stoi-chiometric amount of chiral cyclic urea485... 

SCHEME 100. Enantioselective benzylation of lithium enolates of lactams and lactones in the presence of a stoichiometric amount of chiral tetramine489... 

SCHEME 101. Enantioselective benzylation of tetralones lithium enolates in the presence of catalytic amounts of chiral tetramines494... 

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50]. The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 % yield and 92 % ee. The amount... 

Enantioselective benzylation of ketone 19 gives further insight into the LiX effect (Sch. 13). In the absence of LiBr, the amount of ee is time-dependent, increasing as reaction time is increased. This phenomenon can he rationalized in terms of the effect of LiX which is gradually formed as the reaction proceeds, and which is assumed to involve conversion of a poorly selective aggregate into a much more selective mixed aggregate. 

Katsuki and coworkers have examined the enantioselective benzylic hydrox-ylation of 1,1-dimethylindan with the Mn-salen complex 4, which is a good catalyst for asymmetric epoxidation, but the reaction in acetonitrile showed only a... 

Table 1.11 Cu-catalyzed enantioselective benzylic amination reactions reported by Nicholas.

Table 6.12 Results of Pt-catalysed enantioselective benzylation of secondary phosphines.

Yu and Luo et al. reported a catalytic enantioselective benzylic C(sp )-H functionalization of 207 via a [l,5]-hydride transfer/cyclization sequence with the chiral complex of copper(II) and side-armed bisoxazoline 209 as catalyst, which provided tetrahydronaphthalene derivatives 208 in moderate to high yield with up to 69 % ee (Scheme 79). 

Z. (2009) Enantioselective benzylic hydroxylation of indan and tetralin with Pseudomonas monteilii TA-5. Tetrahedron Asymmetry, 20 (10), 1206-1211. 

The enantioselective benzylation of sulfoxides using a chiral organocatalyst has been achieved (Scheme 5.18) [19]. The chemistry required cryogenic conditions however, the product yields and enantioselectivity were outstanding. A range of benzyl halides bearing... 

Scheme 5.3 Catalytic use of chiral lithium amide 2b in enantioselective benzylation of a-tetralone.

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