Kinetic Resolution of Racemic Allylic Alcohols

The preparations of d- and L-chalcose were achieved in a similar way to the racemic mixtures of threo-dipropcnylglycol ( )-502, obtained by reductive dimerization of crotonal-dehyde [221]. 

Application of the Katsuki-Sharpless enantioselective epoxidation to racemic mono-O-benzylated divinylglycol allowed the preparation of enantiomerically pure L-lyxo and D-lyxo-pentoses and analogs [224,225]. 

---

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

Enantioselective isomerization can be advantageously used for the kinetic resolution of racemic allyl alcohols. For example treatment of 4-hydroxy-2-cyclopente-none (rac-28) in the presence of Rh[(R)-BINAP](MeOH)2 + gives rise to the enan-tiomerically enriched allyl alcohol (R)-29 (Scheme9) [13]. This unsaturated hydroxy ketone is an important building block for the synthesis of prostaglandins... 

Application of the Sharpless procedure for the kinetic resolution of racemic allyl alcohols [Ti(0/Pr)4 BuOOH and L- or D-DET] to such a process provided an optically active dihy-drop)Tan together with enantiomerically pure unreacted furylcarhinol [6]. The Casiraghi approach leads to 2,3-unsaturated furanoses (or amino furanoses) hy an acid-catalyzed reaction of 2-(trimethylsilyloxy)furan with sugar aldehydes or aminoaldehydes. 

Synthesis of Chiral Oxirans. The recently introduced Katsuki-Sharpless reagent (titanium alkoxide with tartrate) has proved highly effective for the maiden introduction of chirality into prochiral allylic alcohols. An interesting development of this procedure has afforded the possibility of kinetic resolution of racemic allylic alcohols. The basis of the method involves the... 

Representative examples are shown in Scheme 9. The Sharpless AE of geraniol (57) with (+)-diethyl tartrate (DET) gave a-epoxide 58 with 95% ee. In a double asymmetric induction, epoxidation of allylic alcohol 59 with (—)- and (+)-DET provided a- and P-epoxides, 60 and 61, in ratios of 40 1 and 1 14, respectively [23]. It is noteworthy that high asymmetric selectivity was induced even in the mismatched case. The Sharpless AE is also effective for the kinetic resolution of racemic allylic alcohols. In the reaction of 62 with 0.6 equiv. of t-BuOOH and... 

Martin VS, oodard SS, Katsuki T et al (1981) Kinetic resolution of racemic allylic alcohols by enantioselective epoxidation - a route to substances of absolute enantiomeric purity. J Am Chem Soc 103 6237-6240... 

The crystal structures of two catalyst precursors have been determined, A-(/ )-[(8)Ru(02CR)2] and A-(5)-[(8)Ru(02CR)2]/ These complexes also achieve the kinetic resolution of racemic allylic alcohols by asymmetric hydrogenation of one isomer only see equation (14). The asymmetric reduction of functionalized... 

Using the same concept, Hoveyda and co-workers recently employed molybdenum derived chiral complexes to develop a net catalytic enantioselective, cross metathesis process based on either the kinetic resolution of racemic allylic alcohols or the asym-... 

Akai, S. (2014). Dynamic kinetic resolution of racemic allylic alcohols via hydrolase-metal combo catalysis An effective method for the synthesis of optically active compounds. Chem. Lett., 43,746-754. 

The ophcally active Pd complex with a chiral allenyl ligand undergoes epimer-izahon in the presence of a catalytic amount of Pd(0) complex. This reaction does not involve the isomerization to the propargyl complex, but takes place via a dinuclear intermediate as depicted in Scheme 5.39. The -allenyl ligand in the dinuclear palladium intermediate may racemize via a vinyl-vinyidene intermediate. This type of reaction is prohahly involved in a kinetic resolution of racemic propargyl alcohols promoted hy chiral transihon metal complex [203]. The intermolecular allyl ligand transfer from Pd to Ee complexes occurs under... 

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using fert-butylhydroperoxide in the presence of a chiral titanium-tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of a-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used . Thus treatment of racemic A-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [( )-74] with fert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-/)4], calcium hydride (CaHa), silica gel and L-(+)-diisopropyl tartrate [l-(+)-DIPT] gave (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [(S)-74] in high chemical yield and enantiomeric excess . Similarly prepared were the (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)-n-propylamine and other homologues of (S)-74 using l-(+)-D1PT. When D-(—)-DIPT was used, the enantiomers were formed . ... 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

The growing interest in enantioselective isomerization of meso oxiranes to allylic alcohols arises from the ready availabihty of starting materials and the synthetic value of the homochiral products. First apphed to simple meso cycloalkene oxides, this methodology has been successfully exteuded to fuuctioualized meso oxiranes, and even to the kinetic resolution of racemic oxiranes, demonstrating its potential in accessing highly advanced synthons. 

Table 14. Kinetic Resolution of Racemic Primary Allylic Alcohols via Sharplcss Epoxidation...

The isomerization of cyclic allyl alcohols to produce ketones proceeds more cleanly [17]. Effective kinetic resolution of racemic cyclic allylic alcohols has been reported [18]. The isomerization of racemic 4-hydroxy-2-cyclopentanone (29) in the presence of 0.5 mol % of [Rh[(/ )-BlNAP](MeOH)2 + in THF proceeded with 5 1 enantiomeric discrimination at 0°C to give 1,3-cyclopentadione (31) via enol ketone 30, leaving the /(-starting allylic alcohol (91% ee and 27% recovery yield) at 72% conversion after 14 days (eq 3.12). (R)-4-Hydroxy-2-cy-clopentenone is a key building block for prostaglandin synthesis [19]. 

The kinetic resolution of racemic tertiary hydroperoxides via catalytic Sharpless epoxidation with various allylic alcohols was investigated (Eq. 6AA.3).9 The reaction of 1-cyclohexyl-1-phenylethyl hydroperoxide gave partially resolved hydroperoxide with up to 29% at about 50% conversion. 

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

As summarized in Schemes 12.9 and 12.10, kinetic resolution of propargylic [21] and allylic [22] alcohols work equally well. The DMAP-ferrocene hybrid 21c was also used for kinetic resolution of racemic diols and for the desymmetrization of meso diols [20]. These two applications are discussed in Section 13.3. 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

A review of the metal-catalysed ring opening of achiral epoxides by achiral carbon-, sulfur-, nitrogen- and halogen-containing nucleophiles and kinetic resolution of racemic epoxides has been published.24 The review also discusses the reactions of chiral bases with epoxides that give allylic alcohols. 

Scheme 9. Kinetic resolution of racemic cyclic allyl alcohols (a) Rh[(R)-BINAP](MeOH)2 +, THF, 0°C, 14days.

Fig. 3.39. Sharpless epoxida-tions of chiral racemic secondary allylic alcohols if they are stopped at (a good) 50% conversion they become kinetic resolutions. The unreacted allylic alcohol is obtained as enantiomerically pure(st) material.

The combination of the chemistry shown in Scheme 22,100 with the Sharpless kinetic resolution (SKR) of secondary allylic alcohols 46101 provides a method for the conversion of racemic allylic alcohols 46 into a single enantiomer with 100% theoretical yield.102 The reaction of sodium telluride with the mesylate 48 derived from 47 affords 46a. In this way, a single enantiomer of the allylic alcohol 46 is obtained in high yield (Scheme 23).102... 

---