Chiral borate esters in asymmetric synthesis: Part 2 - Asymmetric borane reduction of prochiral ketones in the presence of a chiral spiroborate ester

Article abstract of DOI:10.1002/hlca.200490206

Asymmetric catalytic activity of the chiral spiroborate esters 1-9 with a O₃BN framework (see Fig. 1) toward borane reduction of prochiral ketones was examined. In the presence of 0.1 equiv. of a chiral spiroborate ester, prochiral ketones were reduced by 0.6 equiv. of borane in THF to give (R)-secondary alcohols in up to 92% ee and 98% isolated yields (Scheme 1). The stereoselectivity of the reductions depends on the constituents of the chiral spiroborate ester (Table 2) and the structure of the prochiral ketones (Table 1). The configuration of the products is independent of the chirality of the diol-derived parts of the catalysts. A mechanism for the catalytic behavior of the chiral spiroborate esters (R,S)-2 and (S,S)-2 during the reduction is also suggested.

Full text of DOI:10.1002/hlca.200490206

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Helvetica Chimica Acta Vol. 87 (2004)
Chiral Borate Esters in Asymmetric Synthesis
Part 2
Asymmetric Borane Reduction of Prochiral Ketones in the Presence of a Chiral
Spiroborate Ester
by Dejun Liu, ZixingShan* , Yan Zhou, Xiaojun Wu, and Jingui Qin
Department of Chemistry, Wuhan University, Wuhan 430072, China
(fax: ‡86-27-87647617; e-mail: kenshan@public.wh.hb.cn)
Asymmetric catalytic activity of the chiral spiroborate esters 1 9 with a O3BN framework (see Fig. 1)
toward borane reduction of prochiral ketones was examined. In the presence of 0.1 equiv. of a chiral spiroborate
ester, prochiral ketones were reduced by 0.6 equiv. of borane in THF to give (R)-secondary alcohols in up to
92% ee and 98% isolated yields (Scheme 1). The stereoselectivity of the reductions depends on the constituents
of the chiral spiroborate ester (Table 2) and the structure of the prochiral ketones (Table 1). The configuration
of the products is independent of the chirality of the diol-derived parts of the catalysts. A mechanism for the
catalytic behavior of the chiral spiroborate esters (R,S)-2 and (S,S)-2 during the reduction is also suggested.
1. Introduction. Although numerous asymmetric reactions mediated by tricoordi-
nated chiral boron compounds have been reported, asymmetric syntheses catalyzed by
tetracoordinated boron compounds have seldom been investigated. Yamamoto and co-
workers reported asymmetric syntheses catalyzed by a Br˘nsted acid derived from
enantiomerically pure [1,1'-binaphthalene]-2,2'-diol and boron compounds [1]. In 2002,
Kanth and Brown reported asymmetric borane reduction in the presence of chiral b-
amino alcohol derivatives of 9-borabicyclo[3.3.1]nonane (9-BBN) with a OC2BN
framework [2]. In 2002, we observed that chiral spiroborate esters with three BÀO
bonds and a N ! B coordination bond (i.e., with a O3BN framework) showed
asymmetric catalytic activity in borane reductions of prochiral ketones, imines, oximes,
and alkylation of aldehydes [3]. Recently, we disclosed the borane reduction of
acetophenone catalyzed by the chiral spiroborate esters (ˆspiroanhydrides) 1 formed
from boric acid (R)- or (S)-[1,1'-binaphthalene]-2,2'-diyl ester and l-proline [4]. In the
present paper, we report asymmetric borane reductions of various prochiral ketones in
the presence of the chiral spiroborate esters 1 9 (Fig. 1).
2. Results and Discussion. 2.1. Preamble. In our preceding paper [4], we have
shown that acetophenone was reduced by borane to give (1R)-1-phenylethanol in up to
76% ee in the presence of chiral spiroborate esters (R,S)- or (S,S)-1 as catalysts. To
examine extensively the asymmetric catalytic activity of chiral spiroborate esters with a
O3BN framework and reveal the law governing the asymmetric catalysis by this class of
boron compound, a series of chiral spiroborate esters with a O3BN framework have
been synthesized [5], of which eleven representatives (Fig. 1) were used to examine
catalysis during borane reduction of prochiral ketones. We found that the stereo-
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 87 (2004)
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Fig. 1. Examined chiral spiroborate esters with a O3BN framework
selectivity of the reduction was highly dependent on the constituents of the spiroborate
esters and the type of prochiral ketones; under appropriate conditions, (R)-secondary
alcohols in up to 92% ee and 98% yield were obtained (Scheme 1).
2.2. Influence of the Type of Prochiral Ketones on the Stereoselectivity of the
Reduction. Borane reductions of seven prochiral ketones, i.e. of pentan-2-one, 4-
methylpentan-2-one, 3-methylbutan-2-one, 3,3-dimethylbutan-2-one, acetophenone
(ˆ1-phenylethanone), propiophenone (ˆ1-phenylpropan-1-one) and 1-(pyridin-4-
yl)ethanone, were examined in the presence of (R,S)-1, (S,S)-1, (R,S)-2, or (S,S)-2.
Because the previous investigation indicated better conditions for borane reductions of
acetophenone [4], all reductions were performed under the same conditions as for
acetophenone. When a prochiral ketone was added to a solution formed from the
reaction of 0.1 equiv. of a spiroborate ester and 0.6 equiv. of borane in THF and then

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 1. Asymmetric Borane Reduction of Prochiral Ketones Catalyzed by Chiral Spiroborate Esters with a
O3BN Framework
stirred at 0 58 for 2 h (exception: 20 h for 1-(pyridin-4-yl)ethanone, a secondary
alcohol with (R)-configuration was obtained in all cases (Table 1). This indicated that
the configuration of the products is independent of the chirality of the constituents of
the catalysts.
Table 1. Enantiomer Excess (% ee) of (R)-SecondaryAlcohols Obtained from Asymmetric Borane Reduction
of Prochiral Ketones Catalyzed by (R,S)-1, (S,S )-1, (R,S)-2, and (S,S )-2a)
(R,S)-2
(S,S)-2
(R,S)-1
(S,S)-1
47
6
53
23
50
14
....
42
66
32
64
64
6892
....
....
1
8
6831
76
59
3
53
49
3
11
....
60
a) All reductions were performed in a ketone/borane/catalyst molar ratio of 1 : 0.6 : 0.1 in THF at 0 58 for 2 h;
exception: 20 h for 1-(pyridin-4-yl)ethanone and gave (R)-secondary alcohols in high yield. The ee of (R)-
secondary alcohols were obtained by comparison with the maximum of specific rotations (see [6 12], resp.) and
analysis of the 1H-NMR spectra of diastereoisomeric phosphite esters formed with the phosphorochloridite of
(4R,5R)-trans-2,2-dimethyl-a,a,a',a'-tetraphenyl-1,3-dioxolane-4,5-dimethanol as a chiral derivatizing agent
[3][13].
In the case of borane reduction of aliphatic ketones, the stereoselectivity increased
with increasing size of the alkyl group; in contrast, in the case of borane reduction of
phenyl-substituted ketones, the stereoselectivity descreased with increasing size of the
alkyl group (Table 1). The borane reduction of 1-(pyridin-4-yl)ethanone mostly
showed very low asymmetric induction, which can be explained by a B-coordination
competition between the O-atom of the ethanone moiety and the N-atom of the
pyridine ring, the latter being more efficient. Thus, the carbonyl group of 1-(pyridin-4-
yl)ethanone was reduced by borane in a relatively free state, i.e., usually there was no
dependence on the chirality of the catalyst, and 1-(pyridin-4-yl)ethanol was obtained in
low ee.
2.3. Influence of the Constituents of the Chiral Spiroborate Esters on the Stereo-
selectivityof the Reduction . Acetophenone and propiophenone were selected as

Helvetica Chimica Acta Vol. 87 (2004)
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substrates to study the influence of the constituents of the chiral spiroborate esters on
the stereoselectivity of the borane reduction. The results obtained in the presence of
different chiral spiroborate esters (Table 2) established that all the chiral spiroborate
esters containing a chiral chelating agent showed asymmetric catalytic activity toward
borane reduction of prochiral ketones whether the diol-derived constituents of the
spiroborate esters were chiral or achiral; but lower ee of the (R)-secondary alcohols
were obtained when these diol-derived parts were achiral. For the spiro[6.4] type of
chiral spiroborate esters in which the diol-derived part and chelating agent were both
chiral, the enantiomerically pure [1,1'-binaphthalene]-2,2'-diol derivatives 1 and 2
yielded higher ee than the (2R,3R)-a,a,a',a'-tetraphenyl-1,4-dioxaspiro[4.5]decane-
2,3-dimethanol (R,R,S)-3, whereas, for the chiral spiroborate esters containing the
[1,1'-biphenyl]-2,2'-diyl and pyrrolidine moieties, the asymmetric catalytic activity of
(l)-proline derivative (S)-5 was higher than that of (2S)-a,a-diphenylpyrrolidine-2-
methanol derivative (S)-6. For the chiral spiroborate esters containing the [1,1'-
binaphthalene]-2,2'-diyl and pyrrolidine moieties, asymmetric catalytic activity of (2S)-
a,a-diphenylpyrrolidine-2-methanol derivatives 2 was higher than that of l-proline
derivatives 1 and the derivatives (R,S)-1 and (R,S)-2 of (1R)-[1,1'-binaphthalene]-2,2'-
diol showed stronger chiral induction than those of (1S)-[1,1'-binaphthalene]-2,2'-diol.
It was also observed that the chiral spiroborate esters 7 9, formed from a chiral diol
and a chelating agent containing a quinoline (pyridine) ring, hardly showed catalytic
activity toward the borane reductions. It is obvious that this is due to p-electron transfer
of the heterocycle to the B-atom in those molecules. Thus, it appears that asymmetric
catalytic activity of the chiral spiroborate esters is mainly determined by the chirality of
the chelating-ring moiety, and an appropriate chiral diol-derived constituent enhances
the asymmetric catalytic ability of the chiral spiroborate esters.
Table 2. Enantiomer Excess (% ee) of (R)-SecondaryAlcohols Obtained from Asymmetric Borane Reduction
of Acetophenone and Propiophenone in the Presence of Different Chiral Spiroborate Ester Catalystsa)
(R,S)-1 (S,S)-1 (R,S)-2 (S,S)-2 (R,R,S)-3 (S)-4 (S)-5 (S)-6 (R)-7 (S)-8 (S)-9
76
60
92
6856
33
49
26
0.3
0.5
0.3
53
49
81
31
....
....
52
31
0
0
0
a) For the exper. conditions and ee determination, see Footnote a in Table 1. The (R)-secondary alcohols were
obtained in high yield, except for the reactions mediated by chiral spiroborate esters containing a quinoline ring.
2.4. Mechanism of Borane Reduction Catalyzed by Chiral Spiroborate Esters (R,S)-
2 and (S,S)-2. The spiroborate esters in the presence of borane in THF formed a
homogeneous solution, and 1 equiv. of H2 gas evolved when a BH3 ¥ THF solution was
added to (R,S)-2 or (S,S)-2. Obviously, H2 is generated from the reaction of borane and
the H-atom at the N-atom of the pyrrolidine ring (see Scheme 2), implying that the
NÀH bond of (R,S)-2 or (S,S)-2 is activated due to formation of an inner N ! B
coordination bond. The 11B-NMR spectra (CDCl3) of (S,S)- and (R,S)-2 (Fig. 2)
showed a single peak at d(B) ‡ 8.62 and 8.37, respectively, which is characteristic of
boron compounds with a O3BN framework (see A in Scheme 2). On addition of a THF

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Helvetica Chimica Acta Vol. 87 (2004)
solution of BH3 ¥ THF to the above CDCl3 solutions, 2-s at d(B) 17.62 and 8.86 for (S,S)-
2 and at d(B) 17.72 and 8.60 for (R,S)-2 appeared, respectively. The signal at d(B)
17.67 Æ 0.05 could be attributed to a common borate ester B with a O3B framework,
indicating that the B N bond of (S,S)-2 or (R,S)-2 has been broken (Scheme 2).
However, the signal at d(B) ca. 8.73 Æ 0.13 indicates that the borate ester with a O3B
framework was in a new tetracoordinated environment, and in this boron complex,
electron donation of the new ligand is lower than that of the pyrrolidine ring; this
suggests that the signal is due to the complex C of the borate ester (with a O3B
Scheme 2. Possible Mechanism of Asymmetric Borane Reduction of Prochiral Ketones Catalyzed by (R,S)-2
and (S,S)-2

Helvetica Chimica Acta Vol. 87 (2004)
2315
framework) with THF. It seems that there is an equilibrium between the tricoordinated
borate ester B and the tetracoordinated boron complex C. Moreover, a m was observed
in the region of d 0 to À2.65, which is attributed to an aminoborane dimer with a
(NBH2)2 framework (see C); but no signal for an amine ¥ borane (with a N ! BH3
framework) was observed (at ca. À20 ppm), indicating that the presence of excess
borane cannot decompose the aminoborane dimer. When a prochiral ketone is added
to the system, the concomitant action of the ketone and borane decomposes the dimer
( ! D), and a six-membered cyclic transition state E is formed. In the sequential step,
elimination of resulting chiral (alkyloxy)borane occurs, and the catalytic cycle is
completed. It appears that, in the mechanism of the asymmetric catalytic borane
reduction of prochiral ketones, the chiral spiroborate esters (S,S)-2 and (R,S)-2 with a
O3BN framework not only behave quite differently from those with a C2OBN
framework, but there is also a remarkable difference between (S,S)-1 and (R,S)-1,
which have the same framework.
Fig. 2. 11B-NMR Spectra (CDCl3, 300 MHz) of (S,S)-2 and (R,S)-2 and of their mixture with a THF solution of
borane

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Helvetica Chimica Acta Vol. 87 (2004)
3. Conclusions. A new class of chiral catalyst for borane reduction of prochiral
ketones was found. In the presence of 0.1 equiv. of a chiral spiroborate ester with a
O3BN framework, prochiral ketones were reduced by 0.6 equiv. of borane in THF to
give chiral secondary alcohols in up to 92% ee and 98% isolated yields. The asymmetric
catalytic activity of the chiral spiroborate esters depended heavily on their constituents.
All the reductions gave products with the (R) configuration, regardless of the chirality
of the diol-derived parts in the catalysts. The structures of the prochiral ketones
influenced considerably the stereoselectivity of the reduction.
Chiral spiroborate esters, with a O3BN framework are very stable to hydrolysis and
oxidation, in contrast to tricoordinated oxazaborolidine derivatives and ordinary
borate esters, which generally are susceptible to moisture in air. Therefore, it is quite
convenient to use chiral spiroborate esters with a O3BN framework as a catalyst for
asymmetric borane reductions of prochiral ketones.
Financial support of the National Natural Science Foundation of China (Projects 29972033 and 20372053) is
greatly appreciated.
Experimental Part
General. The chiral spiroborate esters were prepared according to [5]. The (2S)-a,a-diphenylpyrrolidine-2-
methanol [14], (2R,3R)-a,a,a',a'-tetraphenyl-1,4-dioxaspiro[4.5]decane-2,3-dimethanol [15], and the THF soln.
of BH3 ¥ THF [16] were prepared according to the literature. All the selected prochiral ketones were
commercially available, except for 3,3-dimethylbutan-2-one, which was prepared according to [17]; they were
purified by distillation over CaH2 and then dried over 4 ä molecular sieve. Other reagents were purchased.
M.P.: VEB-Wagetechnik-Rapio-PHMK05 instrument; not corrected. Optical rotatioins: PE-341 polarimeter;
for the determination of ee, see Table 1. IR Spectra: Testscan Shimadzu FTIR 8000; in KBr; nÄ in cmÀ1. 1H- and
11B-NMR Spectra: Varian MercuryVX 300 ; d values in ppm rel. to Me4Si and BF3 ¥ OEt2, resp., J in Hz.
Asymmetric Borane Reduction of Prochiral Ketones: Representative Procedure. Under Ar, 0.81m BH3 ¥ THF
in THF (4.5 ml, 3.6 mmol) was added by syringe to (R,S)-2 (0.328g, 0.6 mmol) at r.t., and the mixture was
stirred for 20 min. Then the mixture was cooled to 0 58, acetophenone (6 mmol, 0.7 ml) was added via syringe
with stirring, and the mixture was kept for 2 h at 0 58. After evaporation of THF, 2m HCl (20 ml) and Et2O
(20 ml) were added to the residue. The mixture was stirred and the solid filtered off: recovered (2S)-a,a-
diphenylpyrrolidine-2-methanol hydrochloride. The aq. phase of the mother liquor was extracted with Et2O
(15 ml  3) and the combined org. phase washed with 2m NaOH to remove (1R)-[1,1'-binaphthalene]-2,2'-diol.
The Et2O soln. was then washed successively with sat. NH4Cl soln., sat. NaCl soln., and H2O, dried (Na2SO4),
and evaporated and the oil distilled under reduced pressure: (1R)-1-phenylethanol (0.68g, 93%). [ a]2D0 ˆ ‡48.2
(c ˆ 2.65, in CH2Cl2); 92% ee ([10]: [a]D23 ˆ À52.5 (c ˆ 2.52, CH2Cl2). IR: 3363s (v.br., OH). 1H-NMR
(300 MHz, CDCl3, 258): 1.65 (d, J ˆ 9.0, Me); 4.22 (s, OH); 4.98( q, J ˆ 9.0, HÀC(1)); 7.54 (s, 5 arom. H).
Under similar conditions, reductions of other prochiral ketones catalyzed by chiral spiroborate esters (R,S)-
1, (S,S)-1, (S,S)-2, (R,R,S)-3, (S)-4, (S)-5, or (S)-6 gave (R)-secondary alcohols in high yield. For ee, see
Tables 1 and 2.
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Received February18, 2004