11

Reduction of Carbonyl Compounds

Organocatalytic asymmetric carbonyl reductions have been achieved with boranes

in the presence of oxazaborolidine and phosphorus-based catalysts (Section 11.1),

with borohydride reagents in the presence of phase-transfer catalysts (Section

11.2), and with hydrosilanes in the presence of chiral nucleophilic activators (Sec-

tion 11.3).

11.1

Borane Reduction Catalyzed by Oxazaborolidines and Phosphorus-based Catalysts

Probably the most frequently applied catalytic metal-free and highly enantioselec-

tive reduction of carbonyl compounds is the oxazaborolidine-catalyzed borane re-

duction (the Corey–Bakshi–Shibata (CBS) method) [1–8]. In this approach, which

is based on initial work by Itsuno et al. [1, 6–8], oxazaborolidines serve as the cata-

lysts. These latter materials are derived from readily available amino alcohols; the

most frequently used is probably the proline-derived bicyclic compound 4. The

CBS method has been successfully applied to all types of ketones, for example dia-

ryl, dialkyl, and aryl alkyl ketones, haloalkyl ketones, transition metal p-complexes

of aryl alkyl ketones, cyclic and open-chain enones, etc. [1–8]. Scheme 11.1 shows

the explicit example of acetophenone (1) which can be reduced with boranes such

as BH3 �THF (2a), BH3 �Me2S, catechol borane, or the borane–diethylaniline com-

plex (2b) to give 1-phenylethanol 3 in very good yields and almost perfect enantio-

meric excess.

Scheme 11.1 also summarizes other impressive examples of the performance of

the CBS method [1–8]. Several excellent reviews on the CBS method have ap-

peared recently [1, 2], and no detailed discussion of the development of the process

or substrate scope shall be presented in this review. Please note, however, that the

oxazaborolidine-catalyzed borane reduction of ketones is a prime example of bi-

functional catalysis [2, 9] – as shown in Scheme 11.2, the current mechanistic

picture involves simultaneous binding of both the ketone and the borane to the

Lewis-acidic (boron) and Lewis-basic (nitrogen) sites of the catalyst A. In the result-

ing ternary complex B, the reaction partners are synergistically activated toward hy-

dride transfer.

Asymmetric Organocatalysis. Albrecht Berkessel and Harald GrogerCopyright 8 2005 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 3-527-30517-3

314

Related catalysts for asymmetric borane reduction of ketones are open chain and

cyclic phosphoric amides, in the oxidation state þ3 or þ5 (Scheme 11.3) [10, 11].

Early examples are the phosphonamides and phosphinamides 5a and 5b of Wills

et al. [12] and the oxazaphospholidine–borane complex 6a of Buono et al. [13]. In

the presence of 2–10 mol% catalysts 5a,b, o-chloroacetophenone was reduced by

BH3 �SMe2 with 35–46% ee [12]. For catalyst 6a a remarkable 92% ee was reported

for the catalytic reduction of methyl iso-butyl ketone and 75% ee for acetophenone

R

O

O

R

CH3

OCH3

HHO

NB

O

PhPhH

CH3

NEt2•BH3

O

N

CH3

O

POi-Pr

O O

Oi-Pr

OH3C

CH3

O

CH3

O

Fe H

O

THF•BH3

1. 1-5 mol-% catalyst 42. 0.6-1 eq. of borane

1

2b

4

2a

3borane 2a: 97 % eeborane 2b: 99 % ee

20-30 oC

L-proline-derivedcatalyst:

examples of boranes:

CBS-Reduction of acetophenone (1):

Some other substrates for the CBS-reduction:

> 99 % ee 99 % ee 91 % ee

93 % ee

97 % ee

> 99 % ee

R = n-, s-alkyl, Ph> 99 % ee

98 % ee

Scheme 11.1

11.1 Borane Reduction Catalyzed by Oxazaborolidines and Phosphorus-based Catalysts 315

(71% ee with 6b) [13]. Martens and Peper tested several cyclic phosphonamides

and identified the proline derivatives 7 as the most enantioselective catalysts. In

the presence of as little as 1 mol% 7a, o-chloroacetophenone was reduced by

BH3 �THF with 96% ee [14]. Under similar conditions the related catalyst 7b of

Buono et al. afforded 94% ee [15]. Mechanistically, it is believed that for oxygenated

phosphorus(V) compounds the borane molecule binds to the oxygen atom and ren-

ders the phosphorus atom sufficiently electrophilic to bind the ketone substrate.

Overall, a ternary complex analogous to B, Scheme 11.2, is formed [16c]. Wills et

al. introduced hydroxy phosphoric amides such as 8a and 8b (Scheme 11.3) [16]

and Brunel, Buono, et al. prepared (o-hydroxyaryl)oxazaphospholidine oxides such

as 9 which afforded 84% ee in the reduction of o-chloroacetophenone [17]. With

the hydroxylated catalysts it is believed that a boronic ester, formed initially from

the catalyst and the borane, acts as the electrophilic binding site for the substrate

ketone, whereas the second, ‘‘reducing’’ borane molecule is coordinated to the

oxygen atom of the PbO bond [16c].

The binaphthyl-derived phosphoramidites 10a and 10b have been used as cata-

O

NB

Ph

PhR

O

NB

Ph

PhR

H2BH

O

NB

Ph

Ph

R

H2BH

OCH3

CH3

O

O

NB

Ph

Ph

R

H2B

O CH3

H

CH3

H2BO H

CH3

HO H

CH3

H2BO H

A

B

"BH3"

hydrolysis

intra-complexhydride shift

Scheme 11.2

316 11 Reduction of Carbonyl Compounds

lysts in the asymmetric borane reduction of acetophenone by Tang et al. and Mul-

ler et al., respectively (Scheme 11.3). With THF�BH3 as reducing agent, 6 mol% of

the catalyst 10a afforded 1-phenylethanol in ca. 95% yield and withb98% ee [18].

Similarly, 5 mol% 10b gave almost quantitative yield and 96% ee [19].

NH

PPh

CH3H OPh

NH

PCH3H O

Et NP

O

R

BH3

H

NP

O

OPh

H RR N

H

P OR1

R1

R2

OHR2

ClO

CH3

O

CH3

O

MeO

CH3

O

NP

O

O

H

OH

Ph Ph

O

O

P NEt2

O

O

P NMe2

Phosphoric amide catalysts for the borane reduction of ketones:

25a 5b6a: R = Ph6b: R = NMe2

7a: R = Ph7b: R = H

8a: R1 = Ph, R2 = Me

8b: R1 = 4-MeO-Ph, R2 = Ph

Some ketone substrates, catalysts and ees achieved:

7a: 96 % ee (ref. 14)8a: 92 % ee (refs. 16a,c)8b: 94 % ee (ref. 16b)9: 84 % ee (ref. 17)

6a: 75 % ee (ref. 13a,b)6b: 71 % ee (ref. 13a)8a: 62 % ee (refs. 16a,c)8b: 88 % ee (ref. 16b)10a: 98 % ee (ref. 18)10b: 96 % ee (ref. 19)

8b: 90 % ee (ref. 16b) 8b: 90 % ee (ref. 16b)

9

10a 10b

Scheme 11.3

11.1 Borane Reduction Catalyzed by Oxazaborolidines and Phosphorus-based Catalysts 317

11.2

Borohydride and Hydrosilane Reduction in the Presence of Phase-transfer Catalysts

Compared with boranes, borohydrides are inexpensive and easy to handle. As early

as 1978 Colonna and Fornasier reported that aryl alkyl ketones such as aceto-

phenone can be reduced asymmetrically by sodium borohydride by use of an

aqueous–organic two-phase system and chiral phase transfer catalysts [20]. In this

study, the best enantiomeric excess (32%) was achieved when pivalophenone (11)

was reduced in the presence of 5 mol% benzylquininium chloride (12) (Scheme

11.4) [20]. Other chiral phase-transfer catalysts, for example ephedrinium salts,

proved less effective.

Almost twenty years later, Lawrence et al. reported that benzylquininium fluo-

ride 13a, prepared from commercially available 12 by ion exchange, is an active

and selective catalyst in the reduction of acetophenone (1) with triethoxysilane

(51% ee; Scheme 11.5) [21].

The enantioselectivity achieved was highly dependent on the substituent present

on the quaternary nitrogen atom of the quinine nucleus. For example, the 4-nitro-

benzylammonium salt 13b afforded a slightly increased ee (53%), whereas the 4-

CF3-substituted catalyst 13c gave an almost racemic product (Scheme 11.5) [21].

When the pseudo-enantiomeric quinidine salt 14 was used the enantiomeric phe-

nylethanol was obtained with slightly higher ee (62%). Further studies on the

range of substrates and catalysts revealed that the aryl substituent in the substrate

ketone is crucial for good enantioselection, and that increasing the steric bulk of

the alkyl substituent improves the ee (65% for both phenyl ethyl and phenyl iso-propyl ketone). Polymethylhydrosiloxane (PMHS), an inexpensive and readily avail-

able hydrosilane, is a very active reducing agent under the reaction conditions stud-

ied, but ee are low. On the other hand, tris(trimethlysiloxy)silane gave best enantio-

selectivity (78% ee in the reduction of acetophenone using 14 as the catalyst). The

authors also noted that N-benzylquininium hydroxide afforded almost the same

t-Bu

O

t-Bu

HHO

N

N

H3CO

H

OH Cl

5 mol-% catalyst 120.6 eq. NaBH4

11 95 %, 32 % ee

12

Scheme 11.4

318 11 Reduction of Carbonyl Compounds

enantioselectivity as the fluoride 13a. This result is interesting preparatively, but

throws some doubt on the assumption that a hypervalent fluoride–alkoxide hydro-

silicate anion is the active reducing agent [21].

11.3

Reduction with Hydrosilanes in the Presence of Chiral Nucleophilic Activators

In the phase-transfer processes discussed in Section 11.2 it is assumed that the

anionic hydride source, i.e. borohydride or a hypervalent hydrosilicate, forms an

ion-pair with the chiral cationic phase-transfer catalyst. As a consequence, hydride

transfer becomes enantioselective. An alternative is that the nucleophilic activator

needed to effect hydride transfer from a hydrosilane can act as the chiral inducer

itself (Scheme 11.6).

In 1988, Hosomi et al. established that hydride transfer from hydrosilanes can

be rendered enantioselective by using chiral anionic activators such as the di-

lithium salts of the diol 15 or of phenylalaninol 16 (Scheme 11.6) [22]. In the pres-

ence of stoichiometric amounts of the dilithium salt of 15, isobutyrophenone was

reduced by trialkoxysilanes with 69% ee, whereas 40 mol% of the corresponding

salt of 16 was sufficient to effect reduction of acetophenone with 49% ee [23].

Kagan and Schiffers carefully studied the effect of the lithium salts of BINOL

(17) and related axially chiral binaphthols on the reduction of a variety of ketones

with trialkoxysilanes [24]. They found that diethyl ether, with TMEDA as an ad-

ditive, was the best solvent for asymmetric reduction of ketones. In the pres-

ence of 5 mol% of the monolithium salt of BINOL (17), acetophenone (1) could

be reduced with trimethoxysilane in 80% yield and with 61% ee. Enantiomeric

excesses > 90% were achieved under the same conditions with 2 0,4 0,6 0-trimethyl-

acetophenone (18) or a-tetralone (19) as substrates. Aliphatic ketones such as

CH3

O

CH3

HHO

N

N

H3CO

H

OH

R

N

N

HOH

H3CO

FF

10 mol-% catalyst 13a1.5 eq. (EtO)3SiH

1 quant., 51 % ee

13a: R = H13b: R = NO213c: R = CF3

14

up to 78 % ee using (TMSO)3SiHas the hydride source (ref. 21)

Scheme 11.5

11.3 Reduction with Hydrosilanes in the Presence of Chiral Nucleophilic Activators 319

4-phenyl-2-butanone (20) gave lower ee (46%), and racemic mixtures were ob-

tained from benzophenones 21a,b (Scheme 11.6) [24].

It should finally be mentioned that asymmetric reduction of prochiral ketones in

chiral reverse micelles has also been attempted. Zhang et al. employed surfactants

derived from ephedrine and achieved enantiomeric excesses up to 27% [25].

OBnOBn

HO

HO H2NOH

CH2-PhH

ROSi

R*-OH

OR

OR

Ph CH3

O

RO

Si

R*-O

H OR

OROPh

H3C

RO

Si

R*-O

OR

ORO

Ph

H3C

H

Ph CH3

O-Si(OR)3H

CH3

O

CH3

HHO

OHOH

CH3

O

CH3

CH3

H3C

O

H3C

O

Ph

O

R

(RO)3SiH

15 16

chiral anionicactivator

R*-O substrateketone

R*-O+

silylated productalcohol

5 mol-% mono-Li-salt of 171 eq. (MeO)3SiH

1up to 96 %, up to 70 % ee

17

chiral activators:

ether/TMEDA 30:1, 0 oC

18; 57 %, 90 % ee

other substrates:

19; 39 %, 93 % ee 20; 74 %, 46 % ee21a: R = CH321b: R = CF3

Hosomi et al., refs. 22,23 Kagan et al., ref. 24

Scheme 11.6

320 11 Reduction of Carbonyl Compounds

Conclusions

At the current stage of development of transition metal-free catalytic reductions the

Corey–Bakshi–Shibata (CBS) method is the most widely applied procedure and

affords excellent results for a wide range of ketone substrates. Substrates that can

bind to metal ions and can thus inhibit transition metal catalysts are well tolerated

by the CBS method, a typical advantage of transition metal-free catalytic methods.

Borane reductions catalyzed by phosphoric amides also seem to have great poten-

tial. Recent years have seen remarkable improvement of the latter catalysts, and

enantiomeric excessesb 95% have been achieved. Both oxazaborolidine and phos-

phoric amide catalysts are of similar ready availability, but activity and selectivity

are still higher for the former. An attractive feature of organocatalytic carbonyl

reductions with silanes and, in particular, boranates is their even greater experi-

mental simplicity. Significant potential for improvement can thus be seen in the

further development of chiral activators or chiral phase-transfer catalysts for these

purposes.

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322 11 Reduction of Carbonyl Compounds