Asymmetric secondary alcohols

Typical compounds that have been found to show Preferential Enrichment are summarized in Figure 5, together with the compounds failing to show this phenomenon. These are analogous linear asymmetric secondary alcohols containing a glycerol moiety, an amide group, and a sulfonium sulfonate... 

The reaction with thionyl chloride affords a chlorosulfite, the decomposition of which may generate an alkyl chloride by the S i (substitution, nucleophilic, internal) mechanism (Scheme 2.16). This reaction, w hich may proceed by an ion pair, can lead to the retention of configuration of an asymmetric secondary alcohol in the conversion to the alkyl chloride. This is in contrast to the inversion of configuration found with the reaction with phosphorus pentachloride and with the nucleophilic displacement of a leaving group. 

The reaction of boronic esters with (dihalomethyl)lithium is particularly well suited to the building of asymmetric structures in which there are no functional substituents. At the end of the synthesis, the boronic ester group can be replaced by reaction with hydrogen peroxide to form the corresponding asymmetric secondary alcohol [11,12, 29]. 

Asymmetric secondary alcohol oxidation can also be performed with other metal complexes, in particular Toste showed that traditional Schiff based V catalysts prepared in situ from the corresponding ligand and VO(0-/Pr)3 allowed the kinetic resolution of a-hydroxy esters in acetone under mild experimental conditions and with 1 atm of O2 (Scheme 23.36). The reaction works well for both henzyUc and... 

Primary and secondary hydroxyl groups can be fluorinated by reaction with di-ethylaminosulfiir trifluoride (DAST) [103]. The reaction of asymmetric secondary alcohols produces inversion of the configuration. Thus, the reaction of the protected diacetone allose with DAST, followed by removal of the protective groups, gives 3-deoxy-3-fluoro-D-glucose [104] (reaction 4.100). 

SCHEME 3436. Structure of (—(-loheline (136( via (—(-sedamine 138 and details of the oxidative desymmetiization and asymmetric secondary alcohol oxidation kinetic resolution steps. 

SCHEME 34.37. Structure of (-l-)-amurensinine 141 and details of the asymmetric secondary alcohol oxidative kinetic resolution step. 

SCHEME 3439. Structure of fluoxetine 47, tomoxetine 46, and nisoxetine 150 and details of the asymmetric secondary alcohol oxidation kinetic resolution step that provides a common chiral intermediate. 

SCHEME 34.41. Asymmetric secondary alcohol oxidation kinetic resolution step in the synthesis of human neurokinin receptor antagonist h-NKl 156. 

Asymmetric hydrogenolysis of epoxides has received relatively little attention despite the utility such processes might hold for the preparation of chiral secondary alcohol products. Chan et al. showed that epoxysuccinate disodium salt was reduced by use of a rhodium norbornadiene catalyst in methanol/water at room temperature to give the corresponding secondary alcohol in 62% ee (Scheme 7.31) [58]. Reduction with D2 afforded a labeled product consistent with direct epoxide C-O bond cleavage and no isomerization to the ketone or enol before reduction. 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

The diastereomeric aldehyde adducts are not readily separated by chromatography. Upon direct reduction to the secondary alcohols, the optical purities (25-46%) reflect the poor degree of asymmetric induction in the addition step. 

Resting cell of G. candidum, as well as dried cell, has been shown to be an effective catalyst for the asymmetric reduction. Both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe [23]. Reduction of aromatic ketones with G. candidum IFO 5 767 afforded the corresponding (S)-alcohols in an excellent enantioselectivity when amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system, and the reduction with the same microbe afforded (R)-alcohols, also in an excellent enantioselectivity, when the reaction was conducted under aerobic conditions (Figure 8.31). 

The complex Pd-(-)-sparteine was also used as catalyst in an important reaction. Two groups have simultaneously and independently reported a closely related aerobic oxidative kinetic resolution of secondary alcohols. The oxidation of secondary alcohols is one of the most common and well-studied reactions in chemistry. Although excellent catalytic enantioselective methods exist for a variety of oxidation processes, such as epoxidation, dihydroxy-lation, and aziridination, there are relatively few catalytic enantioselective examples of alcohol oxidation. The two research teams were interested in the metal-catalyzed aerobic oxidation of alcohols to aldehydes and ketones and became involved in extending the scopes of these oxidations to asymmetric catalysis. 

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

C-chiral hydroxy phosphorus derivatives, which have been described so far in the literature, are secondary alcohols. Thus, the syntheses of non-racemic compounds of this type comprise two main approaches (cf. C-chiral hydroxyalkyl sulfones. Section 2.2) asymmetric reduction of the corresponding keto derivatives and resolution of racemic hydroxyalkanephosphorus substrates. 

The facile arylation of aldehydes with arylboronic acid has prompted the exploration of asymmetric versions of this reaction. However, this field has been scarcely explored and only few examples have been reported in the literature, with moderate results. The first diastereoselective example was described by Ftirstner and coworkers. By reacting the Gamer aldehyde 15 with phenylboronic acid under their set of experimental conditions (i.e. RhClj-SH O, IPr HCl) (Scheme 7.4) [21], the secondary alcohol was obtained in higher selectivity than that observed in the addition of phenylmagnesium bromide reported by Joullie (de = 94% versus 66%), with the anti isomer as the major compound [29]. 

Musa, M.M., Ziegelmann-Fjeld, K.I., Vieille, C. et al. (2007) Asymmetric reduction and oxidation of aromatic ketones and alcohols using W110A secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus. The Journal of Organic Chemistry, 72 (1), 30-34. 

Perhaps the most investigated reaction of organozinc compounds is their addition to the carbonyl group of aldehydes. A broad range of simple and functionalized diorganozincs and a great variety of aldehydes have been studied in this transformation. The reaction furnishes chiral secondary alcohols, which are essential building blocks in the synthesis of natural products and other important compounds. Recent studies of this transformation have been devoted to its asymmetric catalytic versions (Scheme 103). 

It is always advisable to examine the complete molecular topology in the neighborhood of the chiral carbon atom and to confirm the results by employing another analytical method before the final assignment. In conclusion, Prelog s rule does predict the steric course of an asymmetric synthesis carried out with a chiral a-keto ester, and the predictions have been found to be correct in most cases. Indeed, this method has been widely used for determining the absolute configuration of secondary alcohols. 

This asymmetric catalytic reaction has found wide application in converting functionalized ketones to the corresponding secondary alcohols with high ee. A general illustration is given in Scheme 6-32. Five- to seven-membered chelate complexes, formed by the interaction of the Ru atom with carbonyl oxygen and a heteroatom X, Y, or Z may be the key intermediates that cause the high enantioselectivity in the reaction.67... 

Oxazaborolidine catalysts behave like an enzyme in the sense of binding with both ketone and borane, bringing them close enough to undergo reaction and releasing the product after the reaction. Thus these compounds are referred to as chemzymes by Corey.78 The oxazaborolidines listed in Figure 6-6 are representative catalysts for the asymmetric reduction of ketones to secondary alcohols. 

Increasing effort has been applied to develope asymmetric transfer hydrogenations for reducing ketones to alcohols because the reaction is simple to perform and does not require the use of reactive metal hydrides or hydrogen. Ruthenium-catalyzed hydrogen transfer from 2-propanol to ketones is an efficient method for the preparation of secondary alcohols. 

Other amino alcohols have also been used as chiral ligands in asymmetric catalytic hydrogen transfer. Scheme 6-54 depicts another example. Ruthenium complex bearing 2-azanorbornyl methanol was used as the chiral ligand, and the corresponding secondary alcohols were obtained in excellent ee.116... 

Sharpless epoxidation reactions are thoroughly discussed in Chapter 4. This section shows how this reaction is used in the asymmetric synthesis of PG side chains. Kinetic resolution of the allylic secondary alcohol ( )-82 allows the preparation of (R)-82 at about 50% yield with over 99% ee (Scheme 7-23).19... 

Catalytic asymmetric hydrosilylation of prochiral olefins has become an interesting area in synthetic organic chemistry since the first successful conversion of alkyl-substituted terminal olefins to optically active secondary alcohols (>94% ee) by palladium-catalyzed asymmetric hydrosilylation in the presence of chiral monodentate phosphine ligand (MOP, 20). The introduced silyl group can be converted to alcohol via oxidative cleavage of the carbon-silicon bond (Scheme 8-8).27... 

---