CBS reduction

The hydroxydiene A could be obtained by enantioselective CBS reduction of dienone B in 90% ee, which led to an enantioselective synthesis of the natural occurring form of forskolin. 

Borane reduction catalyzed by chiral oxazaborolidines (CBS reduction, CBS = Corey, Bakshi, and Shibata) exhibits excellent enantio- and chemoselectiv-ity for a wide variety of ketonic substrates (Figure 1.27). This reaction was originally developed as a stoichiometric system consisting of diphenylvalinol and borane, ° but was later extended to a useful catalytic method. Because of the high efficiency of this reaction, many chiral oxazaborolidines have been synthesized from p-amino alcohols.Among them the prolinol-derived oxazaboro-lidine is one of the most widely used catalysts. ... 

The CBS-reduction [137] of prochiral ketones is a well-known process which employs a chiral oxazaboroHdine as catalyst and BHs-THF or catecholborane as stoichiometric reductants. It is believed that the active catalytic species is a LLA, resulting from coordination of the oxazaborolidine nitrogen with the boron reagent to render the oxazaborolidine boron atom highly Lewis acidic [87]. Similarly, Corey... 

To achieve synthesis of (-)-arisugacin A [1], (7 J-89 was obtained readily from 2-methyl-l,3-cyclohexanedione 88 in 4 steps with an overall yield of 46%, featuring vinylogous ester formation, Stork-Danheiser double alpha methylation,52,68,69 vinyl Grignard addition followed by acidic work-up,68 and an asymmetric CBS reduction [Scheme 21].70,71... 

A related enantiotopos-differentiating desymmetrization, the CBS-reduction of cyclic meso imides, was reported in 1997 by Hiemstra et al. [18]. 

The pioneering studies by Itsuno [1] and Corey [2] on the development of the asymmetric hydroboration of ketones using oxazaborolidines have made it possible to easily obtain chiral secondary alcohols with excellent optical purity [3]. Scheme 1 shows examples of Corey s (Corey-Bakshi-Shibata) CBS reduction. When oxazaborolidines 1 were used as catalysts (usually 0.01-0.1 equiv), a wide variety of ketones were reduced by borane reagents with consistently high enan-tioselectivity [2]. The sense of enantioselection was predictable. Many important biologically active compounds and functional materials have been synthesized using this versatile reaction [2-4]. 

Corey originally used borane-THF as a stoichiometric reducing agent [2, 5]. The use of more robust borane sources, borane-N,N-diethylaniline [6, 7] and borane-N-ethyl-N-isopropylaniline [8, 9], rendered the CBS reduction easier to handle without sacrificing enantioselectivity. Borane-THF prepared in situ from NaBH4 and (CHalaSiCl in THF [10] was also shown to be useful for this type of reduction [11]. 

Extensive studies by Corey have clearly revealed the wide range of applications of the CBS reduction [2]. However, recent observations of high enantioselectivity in the reduction of several a-hetero substituted aliphatic ketones catalyzed by 1 are worthy of mention (Scheme 2). A series of aliphatic a-hydroxyketones protected with tetrahydropyranyl [7], trialkylsilyl [12], and sulfonyl groups [8] as well as p-ketosulfones [9] were reduced to give the corresponding alcohols in up to >99% ee. 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

Numerous theoretical treatments have been carried out to understand the mode of asymmetric induction of the Corey-Bakshi-Shibata (CBS) reduction, more thoroughly.12 Liotta et al. carried out computational studies to identify the transition states for CBS reductions of various ketones13 (Scheme 4.3k).In the asymmetric reduction of acetophenone with the catalyst (R)-28a, four transition states were found. Of the lowest energy is chairlike transition state A, which would lead to formation of the major enantiomer. In transition state A, the phenyl group of acetophenone occupies an equatorial position that is free from any steric interaction, as it is 5.5 A away from one of the two phenyl groups of the diphenylprolinol ring. On the other hand, transition state B, leading to the... 

The CBS reduction has also proven to be an efficient method for asymmetric reduction of a,ft-unsaturated enones14 and ynones15 (Scheme 4.31). The asymmetric reduction of alkynyl ketones affords propargylic alcohols 30 with high levels of enantioselectivity and in moderate to good yields. Optimized reaction conditions for the reduction are the use of THF at — 30° C, 2 equivalents of chiral oxazaborolidine 28b, and 5 equivalents of borane methyl sulfide complex. 

The CBS reduction has been employed in numerous synthetic applications.16 The cetirizine hydrochloride 32 (Zyrtec) is an effective treatment as a second-generation histamine HI antagonist for a range of allergic diseases. Zyrtec is one of the leading antihistamine drugs, with sales of 1.3 billion in 2004 in the United States alone. Corey and Helal prepared a chiral benzylic alcohol intermediate 34 en route to their enantioselective synthesis of Zyrtec17 (Scheme 4.3m). The asymmetric reduction of the ketone 33 in toluene with catecholborane in... 

Overman et al. exercised the CBS reduction strategy during synthesis of the natural opium alkaloid (—)-morphine (50)21 (Scheme 4.3q). Enantioselective reduction of 2-allylcyclohex-2-en-l-one (51) with catecholborane in the presence of the (R)-oxazaborolidinc catalyst (l )-28a provided the corresponding (S)-cyclohexenol 52 in greater than 96% ee. Condensation of this intermediate with phenyl isocyanate, regioselective catalytic dihydroxylation of the terminal double bond, and protection of the resulting diol afforded 53 in 68% overall yield from 51. The ally lie silane 54 for the upcoming iminium ion-ally lsilane cycliza-tion step was obtained in 81% yield by a stereoselective Sn2 displacement of allylic carbamate. 

CBS reductions are best when the ketone s two substituents are well-differentiated sterically— just as Ph and Me are in the example above. Only when the ketone is complexed with the other boron atom (in the ring) is it electrophilic enough to be reduced by the weak hydride source. The hydride is delivered via a six-membered cyclic transition slate, with the enantioselectivity arising from the preference of the larger of the ketone s two substituents (RL) for the pseudoequatorial position on this ring. 

This makes it relatively expensive, but the expense is offset by the economy of catalyst required in such reactions. Whereas about 10 mol% catalyst is needed for CBS reductions, many hydrogenations of this type give high enantiomeric excesses with only 0.0002 mol% BINAP-ruthenium(II)... 

For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. [35] also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic a,//-enones and -ynones only on the carbonyl group. In the re-... 

Several novel catalysts in which borohydride is complexed with a difiinctional chiral ligand have been developed and used for the enantioselective reduction of prochiral ketones to chiral alcohols. Corey-Bakshi-Shibatareduction (CBS reduction) is an organic reaction which reduces ketones enantioselectively into alcohols by using chiral oxazaborolidines and BHs-THF or catecholborane as stoichiometric reductants (CBS reagent, 1.64) (also see Chapter 6, section 6.4.2). 

Alcohols 3-8, obtained by the reduction of the corresponding ketones with equimolar amounts of BMS and are obtained with high ees (ee values given are obtained using 0.1 equiv of (R)-1). Enantioselectivity is excellent (often similar or only slightly lower than those reported in the CBS reduction) for aromatic and hindered methyl ketones, (e.g. 3-5) and is also good for linear and a-monobranched enones (e.g. 7 and 8), but lower for linear methyl ketones like 2-octanone (6). In should be noted that in the reduction of unsaturated ketones, the time of addition is critical (the optimum being around 15-20 min) in order to avoid concomitant olefin hydroboration. In sharp contrast to the CBS process, the use of catecholborane (instead of BMS) or alternative solvents proved to be detrimental. 

Preparation. [(i )-a-(2-Naphthyl)aminomethyl]ferrocene was prepared in three steps from ferrocenyl 2-naphthyl ketone featuring an asymmetric CBS reduction with >99% ee (eq 1). After protection of the secondary hydroxyl group with an acetyl group, a nucleophilic displacement of the acetoxy group with an amino group proceeded with retention of stereochemistry. A range of different variations of [(i )-a-(2-naphthyl)aminomethyl]ferro-cene could be prepared using this sequence with similar efficiency. 

Modern reactions While there is no shortage of new chemical reactions to present in an organic chemistry test, I have chosen to concentrate on new methods that introduce a particular three-dimensional arrangement in a molecule, so-called asymmetric or enanti-oselective reactions. Examples include Sharpless epoxidation (Chapter 12), CBS reduction (Chapter 20), and enantioselective synthesis of amino acids (Chapter 28). 

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