Enantiospecific oxidation

A series of new examples has recently emerged in the literature. Aquaticol (10), an unusual cuparane-type bis-sesquiterpene isolated from the medicinal plant Veronica anagailis-aquatica, can be derived from a Diels-Alder cyclodimerization of the ortfco-quinol 11, itself derived from an enantiospecific oxidative hydroxylation of (—)-d-cuparenol (12) (Figure 5) [37, 38]. Sorbicillinoid members of the vertinoid polyketide class of natural products also present the same chemical filiation inasmuch as they appear to originate biosynthetically from the sorbicillinol (13)-derived ortho-quinol 14 (Figure 6) (Section 15.3.3) [39, 40]. 

S)-reticuline to ( )-reticuline in Papver somniferum is achieved by enantiospecific oxidation of the (5 )-enantiomer (273), and it is followed by an NADPH-dependent enzymatic reduction of the dehydroreticulinium ion, which also is highly substrate specific since no reduction of 1,2-dehydronorreticuline was observed (275). 

Figure 16.2-39. Enantiospecific oxidation of racemic carveol to (-)-carvone and (—)-c/s carveol using whole cells of Rhodococcus erythropolis.

Stereoinversion catalyzed by two different alcohol dehydrogenases via enantiospecific oxidation followed by an asymmetric reduction. 

An example of this technique is shown in Scheme 5.57, where a chemoenzymatic enantiomerization occurs by the involvement of enantiomer-selective oxidation and non-selective hydride reduction [147]. It has been shown that one enantiomer of a racemic sec-amine can be enantiospecifically oxidized by an enzyme, giving an achiral intermediary imine. This is simultaneously reduced to the racemic starting amine in a non-selective manner. Repetition of the sequence leads to an overall chiral inversion of the faster-reacting enantiomer to the slower reacting enantiomer to give the final product in 100% theoretical chemical and optical yields. 

Huh, J. W., Yokoigawa, K., Esaki, N., and Soda, K., "S5mthesis of L-proline from the race-mate by coupling of enzymatic enantiospecific oxidation and chemical non-enantiospedfic reduction." /. Biosci. Bioeng., 74,189-190 (1992). 

Levitt MS, RE Newton, SM Roberts, AJ Willetts (1990) Preparation of optically active 6 -fluorocarbocyclic nucleosides utilising an enantiospecific enzyme-catalysed Baeyer-Villiger type oxidation. J Chem Soc Chem Comm 619-620. 

Another enantiospecific synthesis of longifolene shown in Scheme 13.32 used an intramolecular Diels-Alder reaction as a key step. An alcohol intermediate was resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the dihydropyrone ring was introduced by 7-addition of the ester enolate of methyl 3-methylbutenoate, followed by cyclization. 

Unless the last-mentioned product is removed by the inclusion of catalase, the oxoacid is liable to react further, undergoing oxidative decarboxylation to the carboxylic acid. An attractive feature of this group of enzymes in the present context is that there exist readily available representatives of both enantiospecificities. The well-studied and commercially available AAOs from vertebrate sources, such as l-AAO from snake venom and D-AAO from pig kidney, are expensive, however, and are increasingly being replaced by enzymes from microbial sources. 

Scheme 10.8 outlines the application of rhodium-catalyzed allyhc amination to the preparation of (il)-homophenylalanine (J )-38, a component of numerous biologically active agents [36]. The enantiospecific rhodium-catalyzed allylic amination of (l )-35 with the lithium anion of N-benzyl-2-nitrobenzenesulfonamide furmshed aUylamine (R)-36 in 87% yield (2° 1° = 55 1 >99% cee) [37]. The N-2-nitrobenzenesulfonamide was employed to facilitate its removal under mild reaction conditions. Hence, oxidative cleavage of the alkene (R)-36 followed by deprotection furnished the amino ester R)-37 [37, 38]. Hydrogenation of the hydrochloride salt of (l )-37 followed by acid-catalyzed hydrolysis of the ester afforded (i )-homophenylalanine (R)-3S in 97% overall yield. 

The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2PhSi)2Zn and Cul has been shown to occur by an oxidative addition - reduction elimination mechanism rather than an SN2 mechanism.16... 

Kinetic resolution relies on enantiospecific conversion of one enantiomer present in a racemic mixture while the other remains unchanged (except for parallel kinetic resolution in which both enantiomers are transformed but to different products). For secondary alcohols enantiospecific conversion might consist in oxidation of one enantiomer to a ketone while the other remains unchanged (Scheme 12.20). 

Oxidation of the chroman 1203 bearing a fused tetrahydrofuran moiety leads to the isochroman-4-one 1205 via oxidation of the quinoid-like intermediate 1204. This diketone is observed as an unwanted side-product during enantiospecific syntheses of monocerin analogues (Scheme 295) <1996T8535>. 

An oxidative spiroannulation reaction was carried out for simple phenols and as a result good yields of spiro-compounds containing tetrahydrofuran rings were obtained <02TL3597>. In the stereospecific and enantiospecific total synthesis of the sarpagine indole alkaloid dehydro-16-epinormacusine B, an oxidative cyclization of the alcohol shown below was the key and final step <02OL4681>. 

Recently, the first asymmetric cell-free application of styrene monooxygenase (StyAB) from Pseudomonas sp. VLB 120 was reported [294]. StyAB catalyses the enantiospecific epoxidation of styrene-type substrates and requires the presence of flavin and NADH as cofactor. This two-component system enzyme consists of the actual oxygenase subunit (StyA) and a reductase (StyB). In this case, the reaction could be made catalytic with respect to NADH when formate together with oxygen were used as the actual oxidant and sacrificial reductant respectively. The whole sequence is shown in Fig. 4.106. The total turnover number on StyA enzyme was around 2000, whereas the turnover number relative to NADH ranged from 66 to 87. Results for individual substrates are also given in Fig. 4.106. Excellent enantioselectivities are obtained for a- and -styrene derivatives. 

In many cases enantiospecific or enantioselective oxidation of acyclic hydrocarbons or their derivatives is possible using microorganisms, although in few cases has the extent of optical induction been accurately quantified. This is clearly an area where more work is required. In those cases studied so far hydroxylation has been found to occur with retention of configuration at the reacting carbon. 

Nonactivated tertiary hydrocarbon sites of enantiopure compounds 210 are oxyfunctionalized enantiospecifically by perfluoro-a.r-2- -butyl-3- -propyloxaziridine 80 under remarkably mild reaction conditions (Equation 8) <19990L281>. The reaction occurs with retention of the configuration at the oxidized stereogenic center and the enantiospecificity is highly independent of both the carbon framework of the substrate as well as functional groups (Table 16). 

In the enantiospecific total synthesis of the indole alkaloid trinervine, J.M. Cook and co-workers used the hydroboration/oxidation sequence to functionalize the C19-C20 exo double bond with excellent regioselectivity." ... 

Preparation of the hydroxypentanoic acid fragment was initiated by addition of the protected propargyl alcohol anion 109 to ethylene oxide. After silylation of the resulting alcohol, the ethoxy ethyl group was removed and the alkyne partially reduced to afford the (2)-alcohol 110 in 52% overall yield. Enantiospecific epoxidation of 110 under Sharpless s conditions and subsequent oxidation provided a 69% yield of diastereomerically pure epoxy acid 111. Treatment with trimethylaluminum gave almost exclusively the p-methyl acid, which was acylated to afford 112 (78%). 

The second route (272) is an enantiospecific one that starts from (+)-S-l-benzyloxycarbonyl-3-piperidein-5-ol (426), obtained from the corresponding racemate by preferential lipase-catalyzed esterification of its enantiomer by means of vinyl acetate, as in the preparation of 419. Reaction of 426 with triethyl orthoacetate, followed by Johnson-Claisen rearrangement, gave the tetrahydropyridine ester 427, which was converted by unexceptional means into the ketoamide 428. Reductive removal of the functional groups then provided another synthesis of (-I- )-R-demethoxy-carbonyl-15,16,17,20-tetrahydrosecodine (2), and Dess-Martin oxidation... 

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