Chiral chlorohydrine

In an effort to develop easy-to-use ketoreductase toolbox , we have surveyed the activity and enantioselectivity of a collection of ketoreductases (KRED) from various sources toward the reduction of a variety of ketones [90,91]. These studies served as a useful guideline for developing enzymatic processes for the production of optically pure chiral alcohols. For example, several chiral chlorohydrins of pharmaceutical importance were synthesized in both enantiomeric forms using the enzymes in this ketoreductase collection (Table 7.2) [92]. Further applications of this collection and other commercially available ketoreductases can be found in a recent review [9]. 

Table 7.2 Enzymatic preparation of both enantiomers of chiral chlorohydrins...

A microbial reduction with a Rhodococcus erythropolis strain was used by BMS scientists to prepare the chiral chlorohydrin from the chloroketone (Scheme 19.15). This intermediate is incorporated into the human immunodeficiency virus (HIV) protease inhibitor Atazanavir (26). This strain was identified through screening and provided >90% yield with a diastereomeric purity of >98% and an ee of >99%.62... 

Synthesis of Epoxides from Chiral Chlorohydrins. Asymmetric halogenation of CSA-derived esters allows for the formation of enantiomerically pure halohydrins and terminal epoxides (eq 23). ... 

With olefins other than ethene two isomeric chlorohydrins can be obtained, one of them being chiral. When pyridine was replaced by monodentate chiral amines in [PdCl3(pyridine)], the enantioselectivities were low (8-12%) (Scheme 8.3) [14]. The mononuclear [PdCl2(L2)] complexes (L2 = sulfonated p-tolyl-BINAP) performed better providing the chiral chlorohydrin in 46-76% e.e. Even better activities and... 

DBU (1) was used as a base in the dehydrochlorination/ring closure of chiral chlorohydrins with high retention of optical purity [60]. A -Acyl-p-hydroxy-4-phenyloxazolidinethiones are rapidly converted into the corresponding ethyl thioesters in high yields by treatment with ethanethiol (EtSH) in the presence of a catalytic DBU (1) [61] (Scheme 3.37). Thus, the chiral auxiliary could be removed cleanly and non-destmctively. 

The studies described in the last section provided the background for the development of a new asymmetric chlorohydrin synthesis. If the neutral ligand that encourages chlorohy-drin formation is made chiral, there is the possibility of forming chiral chlorohydrins. First, pyridine was replaced with chiral monodentate ligands such as (5)-(-)-Af, Af-dimethyl-l-phenethylamine.f f Scheme 23 shows the general reaction sequence. As might be expected the enantioselectivities were low 10-15% for propene. The Wacker oxidation product, acetone, was a side product in the reaction. 

The route toward the chiral epoxide 107 and 108 starts from the synthesis of the enantiopure a-chloro aldehydes 101, 102 with (L)-proUnamide 100 as the chiral catalyst. The addition of the dialkyne 103,104 to the aldehydes 101, 102 afforded the chiral chlorohydrins 105,106, which were readily converted into the chiral epoxides 107 and 108 under basic conditions (Scheme 42.29). 

Chiral alkenyl and cycloalkenyl oxiranes are valuable intermediates in organic synthesis [38]. Their asymmetric synthesis has been accomplished by several methods, including the epoxidation of allyl alcohols in combination with an oxidation and olefination [39a], the epoxidation of dienes [39b,c], the chloroallylation of aldehydes in combination with a 1,2-elimination [39f-h], and the reaction of S-ylides with aldehydes [39i]. Although these methods are efficient for the synthesis of alkenyl oxiranes, they are not well suited for cycloalkenyl oxiranes of the 56 type (Scheme 1.3.21). Therefore we had developed an interest in the asymmetric synthesis of the cycloalkenyl oxiranes 56 from the sulfonimidoyl-substituted homoallyl alcohols 7. It was speculated that the allylic sulfoximine group of 7 could be stereoselectively replaced by a Cl atom with formation of corresponding chlorohydrins 55 which upon base treatment should give the cycloalkenyl oxiranes 56. The feasibility of a Cl substitution of the sulfoximine group had been shown previously in the case of S-alkyl sulfoximines [40]. 

Chiral halohydrins epoxides.1 The esters (2) of the chiral alcohol 1 derived from camphor-10-sulfonic acid, are converted to a-chloro esters (3) by O-silylation and reaction with NCS with high diastereoselectivity. Reduction of 3 with Ca(BH4)2 results in the recovered auxiliary and the chlorohydrin 4 with clean retention. Cyclization of 4 to the terminal epoxide 5 proceeds with clean inversion. 

In metal-free catalysis enantioselective ring-opening of epoxides according to Scheme 13.27 path B has been achieved both with chiral pyridine N-oxides and with chiral phosphoric amides. These compounds act as nucleophilic activators for tetrachlorosilane. In the work by Fu et al. the meso epoxides 71 were converted into the silylated chlorohydrins 72 in the presence of 5 mol% of the planar chiral pyridine N-oxides 73 (Scheme 13.36) [74]. As shown in Scheme 13.36, good yields... 

Chiral epoxides.1 Alkylation of the anion (LDA) of 1 (97% ee) with 1-iodo-decane provides 2, which reacts with symmetrical ketones at —40° to give a single (S)-chlorohydrin (5) with complete 1,2-asymmetric induction. However, use of an aldehyde or unsymmetric ketones results in formation of two chlorohydrins, which can usually be separated by chromatography. Thus the reaction of 2 with 6-methyl-1-... 

Addition of several lithium ester enolates to chiral 1-aminoalkyl choromethyl ketones gave the corresponding chlorohydrins which, when the solvent was completely evaporated to dryness at room temperature, underwent an intramolecular heterocyclization affording 3-hydroxyazetidinium salts 5 <02OL1299>. Azetidinium salts 5 were isolated in enantiomerically pure form, and with total or high diastereoselectivity. The degree of stereoselectivity was only moderately affected by the size of R1 in the a-amino-ketone and the substituents in the ester enolate. 

Finally, mention may be made of those articles in which this method is utilized in the synthesis of optically active oxiranes for example, the simple synthesis of monosubstituted (S)-oxiranes and the asymmetric cyclization of some chlorohydrins catalyzed by optically active cobalt (salen)-type complexes, or in the enantiomeric selection of racemic oxiranes via halohydrins and /3-hydroxy sulfides. A useful three-step synthesis has been worked out from (S)-amino acids to (R)-alkyloxiranes as well as enantiomer resolution for chiral oxiranes by complexation gas chromatography. ... 

Chloroethanol is also formed from ethylene in the presence of pyridine and necessarily cupric chloride even with low chloride ion concentration [55], whereas in the absence of CUCI2 acetaldehyde is the sole product. With chiral amines and phosphines as ligands instead of pyridine, optically active chlorohydrins can be obtained from higher a-oleftns [56, 57]. 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

El-Qisairi, A. K., Qaseer, H. A., Henry, P. M. Oxidation of olefins by palladium(ll). 18. Effect of reaction conditions, substrate structure and chiral ligand on the bimetallic palladium(ll) catalyzed asymmetric chlorohydrin synthesis. J. Organomet. Chem. 2002, 656,168-176. 

The catalyzed hydrocyana a stable (salen)aluminum c BUjSnCN. It is important to An asymmetric synthesi A -(benzyloxyiminoacety 1 )-bi Mo(CO) and LiOH sequenti Addition of allylmetals t directly attached to the yyn-chlorohydrins and anti-via two oxygen atoms and th useful for the synthesis of < en-4-ols, respectively. (-)-Sx A chiral reagent derived f tartrate reacts with aromahe alcohols sometimes in excel been conducted in the presei. Allylsilanes modified by a tai... 

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