4-Hydroxyphenylglycine-based oxazaborolidines for enantioselective reductions of ketones

Article abstract of DOI:10.1002/adsc.200600297

Amino alcohols 6 featuring the diphenyl-hydroxymethyl group are prepared from the commercial amino acid (R)-4-hydroxyphenylglycine 3. Oxazaborolidines generated in situ from the amino alcohols 6 and borane-dimethyl sulfide serve as catalysts in enantioselective reductions of acetophenone. The para-substituents of the phenyl ring at the stereogenic carbon atom have a substantial influence on the enantioselectivity. When mediated by the nonaflate 6d, the reduction of ketones 7, 9, 11, and 13 leads to the carbinols 8, 10, 12, and 14 in 90 to 96% ee.

Full text of DOI:10.1002/adsc.200600297

FULL PAPERS
DOI: 10.1002/adsc.200600297
4-Hydroxyphenylglycine-Based Oxazaborolidines for Enantio-
selective Reductions of Ketones
Manfred Braun,a,* Michael Sigloch,a and Jens Cremera
a
Institut für Organische Chemie und Makromolekulare Chemie, Universität Düsseldorf, 40225 Düsseldorf, Germany
Fax : (+49)-211-811-5079; e-mail: braunm@uni-duesseldorf.de
Received: June 21, 2006; Published online: January 8, 2007
Abstract: Amino alcohols 6 featuring the diphenyl- on the enantioselectivity. When mediated by the
hydroxymethyl group are prepared from the com- nonaflate 6d, the reduction of ketones 7, 9, 11, and
mercial amino acid (R)-4-hydroxyphenylglycine 3. 13 leads to the carbinols 8, 10, 12, and 14 in 90 to
Oxazaborolidines generated in situ from the amino 96% ee.
alcohols 6 and borane-dimethyl sulfide serve as cata-
lysts in enantioselective reductions of acetophenone.
The para-substituents of the phenyl ring at the ste- Keywords: amino alcohols; asymmetric catalysis;
reogenic carbon atom have a substantial influence boron; substituent effects; synthetic methods
Introduction
far as a-amino acids, the raw materials of most oxaza-
borolidines, are concerned, that postulate is in general
Oxazaborolidines that are derived from chiral 2- fulfilled by non-proteinogenic, synthetic rather than
amino alcohols have proven themselves to be highly natural amino acids.
efficient catalysts for the reduction of carbonyl com-
The (R)-enantiomer of 4-hydroxyphenylglycine (3)
pounds and other enantioselective transformations.[1] is produced on a scale of more than 1000 tons per
After early attempts using the diphenylvalinol back- annum and serves as a building block for amoxicilline
bone,[2] the proline-based oxazaborolidines developed and other antibiotics.[8] In addition, the (S)-enantio-
by Coreyꢀs group, the so-called CBS catalysts 1 mer is commercially available as well. In this article,
(Scheme 1) distinctly helped the enantioselective re- we describe the conversion of 4-hydroxyphenylglycine
duction by borane on the road to success.[3] In addi- into the novel amino alcohol 5, the phenolic moiety
tion, oxzaborolidines derived from other amino alco- of which permits us to synthesize a series of para-sub-
hols have been developed,[1] most of them featuring stituted derivatives. After their incorporation in oxa-
the diarylhydroxymethyl group.[4] Thus, boronate 2a zaborolidines, they shall be tested in the borane re-
generated from 2-amino-1,1,2-triphenylethanol has duction of ketones in order to find out the influence
been used for the enantioselective reduction of ke- of the substituents on the enantioselectivity.
tones,[5,6] whereas the reaction mediated by the corre-
sponding borane 2b was reported to occur with mod-
erate enantioselectivity only.[7] With respect to the ap- Results and Discussion
plication of enantioselective catalysts, the latter
should be readily available as both enantiomers. As A straightforward route (Scheme 2) was elaborated
that permitted us to convert (R)-hydroxyphenylgly-
cine 3 into the amino alcohol 5 in two steps. Thus, the
amino acid 3 was first esterified by treatment with hy-
drogen chloride in methanol.[9] The salt 4 thus ob-
tained was allowed to react with an excess of phenyl-
magnesium bromide to give aminoethanol 5 in 48%
overall yield.
The free phenolic group then served for the intro-
duction of different substituents in the phenyl group
at the stereogenic center (Scheme 3), in order to find
out how their electronic properties will influence the
Scheme 1. Oxazaborolidines derived from 2-(diphenylhydro-
methyl)pyrrolidine and 2-amino-1,1,2-triphenylethanol.
Adv. Synth. Catal. 2007, 349, 337 – 342
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
337

Manfred Braun et al.
FULL PAPERS
sulted as the single product from the Williamson reac-
tion. In a similar way, the sodium phenolate of 5 was
generated and treated subsequently with N-phenyl-
bis(trifluoromethane)sulfonimide or nonafluorobut-
anesulfonyl fluoride to give the triflate 6c and the
nonaflate 6d, respectively.[10] Selective deprotonation
of the amino alcohol 4 also occurred with butyllithium
so that the subsequent treatment with toluenesulfonyl
chloride led to the sulfonate 6b.
With respect to a study of the influence on the
enantioselecitvity, not only hetero but also carbon
substituents in the para position of the phenyl residue
at the stereogenic center might be relevant. There-
fore, the triflate 6c and the nonaflate 6d were consid-
ered as suitable substrates for aryl-aryl coupling reac-
tions. However, various attempts to react the triflate
6c with phenylboronic acid or phenylzinc chloride in
the presence of tetrakis(triphenylphosphino)palladi-
um failed completely. In contrast with these ap-
proaches, the Stille-type coupling was successful, in
particular, when the nonaflate 6d was used as the sub-
strate. Thus, coupling with tributylphenylstannane
mediated with tetrakis(triphenylphosphosphino)palla-
dium led to the formation of biphenyl-substituted
amino alcohol 6e (Scheme 4).
Scheme 2. Synthesis of amino alcohol 5 from 4-hydroxyphe-
nylglycine 3.
Acetophenone 7 was chosen as a prochiral ketone
in order to test the performance of amino alcohols 6
in the reduction with borane. In all cases, the corre-
sponding oxazaborolidine was generated in situ from
the corresponding aminoethanol 6 and borane-di-
methyl sulfide complex. Thereafter, the ketone was
added within 90 min, what turned out to provide
higher enantioselectivity than the addition in one por-
tion. Following this protocol, the non-catalyzed reduc-
tion by the borane could be widely suppressed. The
resulting phenylethanol 8 was found to be (S) config-
ured in all the reductions performed with (R)-amino-
ethanols 6. The absolute configuration was assigned
by comparison of the optical rotation with the data of
authentic samples.[11] After purification of the product
by column chromatography and subsequent distilla-
tion, the enantiomeric excess was determined based
on the optical rotation and GC on a chiral column.
The results of the reductions are outlined in Table 1.
Scheme 3. Conversion of phenolic amino alcohol 5 into de-
rivatives 6a–d.
enantioselectivity in the reduction of ketones. Thus,
the benzyl ether 6a was easily obtained by protection
of the phenolic hydroxy group, which, due to its acidi-
ty, was selectively deprotonated with sodium hydride.
Scheme 4. Conversion of nonaflate 6d into biphenyl-substi-
As a consequence, the phenolic benzyl ether 6a re- tuted amino alcohol 6e.
338
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 337 – 342

Enantioselective Reductions of Ketones
FULL PAPERS
Table 1. Enantioselective reduction of acetophenone 7 medi-
ated by oxazaborolidines-derived amino alcohols 6a–e.
dride transfer to the ketone. Concerning the triflate
6c and the nonaflate 6d, one can assume that the
strong electron-withdrawing effect of the trifluoro-
methyl and the nonafluorobutyl groups prevents the
oxygen atoms in these substituents from acting as
donors that could coordinate to the borane.
As, for practical reasons, the readily available nona-
flate 6d is the most suitable one for applications, the
protocol was applied to the reduction of the ketones
9, 11, and 13 to give the secondary alcohols 10, 12,
and 14, respectively, upon reduction with borane-di-
methyl sulfide complex (Scheme 5). Here again, re-
markable enantioselectivity was obtained. The optical
purity and the absolute configuration of the alcohols
10, 12 and 14 was determined by the comparison of
their optical rotations with those of authentic sam-
ples.[11] In addition, the enantiomeric excesses were
confirmed by NMR spectroscopy of the Mosherꢀs
esters[13] of the carbinols 12 and 14.
As the amino alcohol 6a bearing the electron-donat-
ing benzyloxy group gave an enantiomeric excess of Conclusions
85% for the product 8 (entry 1), it was an obvious
idea to try to improve the selectivity by introducing In summary, it has been show that 4-hydroxyphenyl-
electron-demanding substituents. However, the enan- glycine-derived amino alcohols 6 can be used for effi-
tioselectivity vanished almost completely with the tol- cient borane reductions of ketones provided that they
uenesulfonyl-substituted amino alcohol 6b (entry 2). are suitably substituted in para-position of the phenyl
Quite surprisingly, the oxazaborolidines originating residue at the stereogenic carbon atom. Thus nona-
from triflate 6c and nonaflate 6d, both catalysts with flate 6d, readily accessible from 4-hydroxyphenylgly-
electron-withdrawing substituents, gave high enantio- cine in three steps, efficiently catalyzes the reduction
selectivities of 95 and 96% ee, respectively (entries 3 of several ketones, so that the corresponding secon-
and 4). Again, it is remarkable that the phenyl sub- dary alcohols are obtained in up to 96% ee. In con-
stituent, exhibiting only a marginal electronic effect, trast to known protocols using phenylglycine-derived
leads to a high enantioselectivity (97% ee) as well boronates, the catalytically active oxazaborolidine is
(entry 5).
generated in situ so that its isolation and purification
The conclusion to be drawn from the results given can be avoided.
in Table 1 is clearly that the electronic character of
the para substituent is not the selectivity determining
parameter. Neither the good performance of oxaza-
borolidines with electronically very different substitu-
ents (entry 1 versus entries 3 and 4) nor the very dif-
ferent selectivity obtained with electronically similar
substituents (entry 2 versus entries 3 and 4) suggest
any linear effect of the substituents in compounds
6.[12] An explanation for the non-uniform enantiose-
lectivity is offered by the ability of the substituent to
act as a donor that might coordinate to the borane,
thus competing with the 2-amino alcohol moiety. This
seems to be the case for the benzyl ether 6a and the
sulfonate 6b. As the borane might be bound at this
site of the molecule, far away from the “chiral site”,
the transfer of the hydride to the ketone is expected
to be rather unselective. This could be the case to a
smaller extent for the benzyl ether 6a, but to a consid-
erable degree for the sulfonate 6b. Obviously, the bi-
phenyl derivative 6e does not offer an undesired bind-
ing site to the borane thus avoiding an unselective hy- 9, 11, and 13.
Scheme 5. Enantioselective reduction of aryl alkyl ketones
Adv. Synth. Catal. 2007, 349, 337 – 342
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
339

Manfred Braun et al.
FULL PAPERS
(125 MHz, THF-d8): d=51.5 (C-2), 63.8 (C-1), 116.2–134.3
(aromatic C), 142.7–144.4 (aromatic ipso C), 159.0 (phenolic
C); MS (FAB, NBA): m/z (%)=306 (33) [M+1]+, 305 (6)
[M]+, 212 (21), 195 (25), 167 (22), 120 (35), 107 (78), 89
(93), 77 (100); anal. calcd. for C20H19NO2: C 78.60, H 6.47,
N 4.54; found: C 78.66, H 6.27, N 4.59.
Experimental Section
General Remarks
Melting points (uncorrected) were determined with a Büchi
melting point apparatus 540. Specific rotations were deter-
mined with a Perkin–Elmer 341 polarimeter. IR spectra:
Bruker Vector 22. Mass spectra: Varian MAT 311 A. NMR
spectra: Vairan VXR 200, VXR 300, and DRX 500. The
spectra were recorded in CDCl3 with TMS as internal stan-
dard. TLC: Silica gel 60 F254 (Merck). Column chromatogra-
phy: Macherey–Nagel Kieselgel 60 and Merck Kieselgel 60,
mesh size 0.04–0.063. Reactions at temperatures below
À208C were monitored by a thermocouple connected to a
resistance thermometer (Ebro). General remarks concerning
the handling of moisture-sensitive compounds are given in
ref.[14]
(R)-2-Amino-2-(4-benzyloxyphenyl)-1,1-diphenyl-
ethanol (6a)
A 10-mL two-necked flask was equipped with a connection
to the combined nitrogen/vacuum line and a magnetic stirrer
and charged with 5 (2.0 g, 6.6 mmol). The flask was closed
with a septum, the air in the flask was replaced by nitrogen,
and 10 mL of anhydrous DMF were injected by syringe. A
95% suspension of sodium hydride in mineral oil (0.158 g,
6.6 mmol) was added under vigorous stirring in a counter-
current of nitrogen. The mixture was stirred at room tem-
perature until the sodium hydride had completely disap-
peared and a bright yellow solution had formed (about 1 h).
Benzyl bromide (0.78 mL, 6.6 mmol) was injected and the
mixture was stirred at room temperature for 5 h. After addi-
tion of water (100 mL), the mixture was extracted three
times with chloroform (50 mL portions). The combined or-
ganic layers were dried with magnesium sulfate, and the sol-
vent was removed in a rotary evaporator. The residual vis-
cous yellow liquid crystallized upon addition of water
(25 mL). The solid was recrystallized from ethanol and dried
in an oil pump vacuum to give 6a; yield: 2.3 g (87%); mp
158–1598C; [a]2D0: +205 (c 1, chloroform). IR (KBr): n=
(R)-4-Hydroxyphenylglycine methyl ester hydrochloride
(4) was prepared from 3 in quantitative yield as described in
ref.[9]
(R)-2-Amino-2-(4-hydroxyphenyl)-1,1-diphenyl-
ethanol (5)
A 500-mL three-necked flask was equipped with a pressure-
equalizing dropping funnel, a reflux condenser with a con-
nection to the combined nitrogen/vacuum line and a mag-
netic stirrer. The flask was charged with magnesium turnings
(14.6 g, 0.60 mol) and a few crystals of iodine and closed
with a septum. The air in the flask was replaced by nitrogen,
anhydrous THF (50 mL) was added in a countercurrent of
nitrogen, and the mixture was stirred until the color had dis-
appeared. Bromobenzene (2 mL) was added through the
dropping funnel and the magnesium turnings were heated
by a heat gun to start the reaction. A solution of bromoben-
zene (91.2 g, 61.2 mL, 0.58 mol) in anhydrous THF
(200 mL) was added through the dropping funnel at such a
rate that the solution kept boiling gently. Thereafter, the
mixture was refluxed for 1 h and cooled to 08C. Under a
countercurrent of nitrogen, 4 (10.0 g, 60.0 mmol) was added
in one portion. The suspension was stirred for 20 h at 08C
and allowed to warm up to room temperature. Then, the
mixture was poured into ice (400 g) and the precipitate was
dissolved by the addition of 18% hydrochloric acid (80 mL).
The organic solvent was removed in a rotary evaporator and
the hydrochloride of 5, precipitating thereby, was filtered
and washed with diethyl ether (100 mL). The precipitate
was suspended in 150 mL of a 2M solution of NaOH in
methanol. After filtration, water (200 mL) was added to the
filtrate. Under vigorous stirring, the solution was brought to
pH 7 by careful addition of 4M hydrochloric acid. Methanol
was removed in a rotary evaporator, the precipitate formed
thereby was filtered and recrystallized from a mixture of
ethanol, ethyl acetate, and water (3:2:1). The product was
dried in an oil-pump vacuum to give colorless 5; yield: 6.9 g
(48%); mp 195–1968C; [a]2D0: +214( c 1, THF); IR (KBr):
n=3510, 3060, 3054, 2582, 1614, 1517, 1449, 1249, 1177,
3380, 3059, 3031, 2887, 1612, 1514, 1254, 1178, 748, 700 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=1.58 (s, 2H, NH2), 4.65 (s,
1H, OH), 5.00 (s, 1H, 2-H), 5.01 (s, 2H, PhCHO), 6.75 (d,
J=7.9 Hz, 1H, aromatic H), 7.08–7.45 (m, 15H, aromatic
H), 7.76 (d, J=7.3 Hz, 2H, aromatic H); 13C NMR
(125 MHz, CDCl3): d=70.3 (C-1), 72.1 (PhCH2O), 103.7 (C-
2), 114.2–130.0 (aromatic C), 137.4, 148.1, 149.4 (aromatic
ipso C), 158.3 (aromatic ipso C); MS (FAB, NBA): m/z
(%)=397 (5) [M+1]+, 396 (11) [M]+, 379 (50), 303 (28),
212 (45), 195 (33), 167 (26), 105 (39), 91 (100), 77 (52); anal.
calcd. for C27H25NO2: C 82.00, H 6.37, N 3.54; found: C
81.89, H 6.27, N 3.60.
(R)-2-Amino-2-[4-(toluene-4-sulfonyloxy)phenyl]-1,1-
diphenylethanol (6b)
A 100-mL two-necked flask was connected to the combined
nitrogen/vacuum line, equipped with a magnetic stirrer,
charged with 5 (0.62 g, 2.0 mmol), and closed with a septum.
The air in the flask was replaced by nitrogen and anhydrous
THF (25 mL) was injected. After cooling to À708C, a 1.6M
solution of n-butyllithium in hexane (1.28 mL, 2.0 mmol)
was added. The solution, which turned dark blue, was
warmed to À258C. A solution of 4-toluenesulfonyl chloride
(0.40 g, 2.0 mmol) in anhydrous THF (10 mL) was added
slowly by syringe so that the temperature did not exceed
À188C. In the course of this, the solution turned to yellow.
Stirring was continued at À208C for 1 h and at 08C for 12 h.
After the addition of water (45 mL) the mixture was extract-
ed with three 30 mL portions of diethyl ether. The combined
organic layers were dried with magnesium sulfate and the
solvent was removed in a rotary evaporator. The residual
1
1033, 836, 748, 700 cmÀ1; H NMR (500 MHz, THF-d8): d=
2.65 (s, 2H, NH2), 4.95 (s, 1H, OH), 5.04 (s, 1H, 2-H), 6.42
(d, J=8.5 Hz, 2H, aromatic H), 6.90–7.98 (m, 5H, aromatic
H), 7.20–7.31 (m, 5H, aromatic H), 7.75 (d, J=7.3 Hz, 2H,
aromatic H), 7.92 (s, 1H, phenolic OH); 13C NMR
340
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 337 – 342

Enantioselective Reductions of Ketones
FULL PAPERS
colorless solid was purified by column chromatography to
give 6b; yield: 0.68 g (74%); mp 163–165 8C; Rf =0.35 (n-
hexane/ethyl acetate, 3:2); [a]2D0: +176 (c 1, chloroform);
1H NMR (500 MHz, DMSO-d6): d=2.44 (s, 3H, CH3), 4.96
(s, 1H, 2-H), 5.64(1H, s, OH), 6.64(d, J=8.5 Hz, 2H, aro-
matic H), 6.98–7.36 (m, 10H, aromatic H), 7.45 (d, J=
8.2 Hz, 2H, aromatic H), 7.58 (d, J=8.5 Hz, 2H, aromatic
H), 7.69 (d, J=7.25 Hz, 2H, aromatic H); 13C NMR
(125 MHz, DMSO-d6): d=21.6 (CH3), 60.9 (C-2), 80.3 (C-
1), 112.8–130,4 (aromatic C), 145.9 (aromatic C), 147.3–
147.6 (aromatic C); MS (FAB, NBA): m/z (%)=482 (7)
[M+ +Na], 460 (29) [M+1]+, 443 (30), 329 (13), 307 (39),
289 (27), 276 (100); anal. calcd. for C27H25NO4S: C 70.57, H
5.48, N 3.05; found: C 70.40, H 5.61, N 3.09.
08C for 3 h. Then, nonafluorobutanesulfonyl fluoride
(1.56 g, 0.94mL, 5.17 mmol) was added in a countercurrent
of nitrogen. The mixture was stirred at room temperature
overnight, poured into a saturated solution of sodium car-
bonate and extracted with three 50 mL portions of diethyl
ether. The combined organic layers were dried with magne-
sium sulfate and the solvent was removed in a rotary evapo-
rator. The residue was purified by column chromatography
to give colorless solid 6d; yield: 1.74g (74%); mp 113–
1158C, Rf =0.47 (n-hexane/ethyl acetate, 2:1); [a]2D0: +131 (c
1
1, chloroform); H NMR (500 MHz, DMSO-d6): d=1.97 (s,
2H, NH2), 5.07 (s, 1H, OH), 5.74(s, 1H, 2-H), 6.96–7.05 (m,
3H, aromatic H), 7.14–7.39 (m, 9H, aromatic H), 7.71 (d,
J=7.9 Hz, 2H, aromatic H); 13C NMR (125 MHz, DMSO-
d6): d=61.6 (C-2), 79.9 (C-1), 123.9, 127.0, 130.7 (CF2), 123
(CF3), 120.5 (aromatic C), 126.2–130.7 (aromatic C), 140.9,
143.7, 146,2, 149.3 (aromatic ipso C); 19F NMR (470 MHz,
CDCl3): d=À81.1 (CF3), À109.3, À121.3, À126.3 (CF2); MS
(FAB, NBA): m/z (%)=588 (18) [M+1]+, 404 (27), 183
(17), 154(100), 77 (58); anal. calcd. for C 24H18F9NO4: C
49.07, H 3.09, N 2.38; found: C 49.12, H 3.17; N 2.34.
(R)-2-Amino-2-[4-(trifluoromethanesulfonyloxy)phen-
yl]-1,1-diphenylethanol (6c)
A 50-mL two-necked flask was equipped with a magnetic
stirrer, connected to the combined nitrogen/vacuum line,
charged with an 80% suspension of sodium hydride in min-
eral oil (0.29 g, 9.5 mmol), and closed with a septum. The air
in the flask was replaced by nitrogen, and anhydrous DMF
(20 mL) was injected by syringe. The mixture was cooled in
an ice bath and a solution of 5 (1.53 g, 5.0 mmol) in anhy-
drous DMF (25 mL) was slowly added under stirring so that
the temperature did not exceed 58C. Stirring was continued
in an ice bath for 3 h. In a counter current of nitrogen, N-
phenylbis(trifluoromethanesulfonamide) (2.32 g, 6.5 mmol)
was added in one portion. The ice bath was removed, and
the mixture was stirred at room temperature overnight. The
mixture was poured into a saturated solution of sodium car-
bonate (8 mL) and extracted three times with ethyl ether
(50 mL portions). The combined organic layers were dried
with magnesium sulfate and the solvent was removed under
reduced pressure. The residue was purified by column chro-
matography to give colorless, solid 6c; yield: 1.09 g (50%);
mp 125–1278C; Rf =0.39 (n-hexane/ethyl acetate, 2:1); [a]2D0:
+188 (c 1, chloroform); 1H NMR (500 MHz, DMSO-d6):
d=1.97 (s, 2H, NH2), 5.07 (s, 1H, OH), 5.75 (s, 1H, 2-H),
6.97–7.06 (m, 3H, aromatic H), 7.15–7.38 (m, 9H, aromatic
H), 7.71 (d, J=7.9 Hz, 2H, aromatic H); 13C NMR
(125 MHz, CDCl3): d=61.2 (C-2), 79.5 (C-1), 120 (CF3),
120.1 (aromatic C), 125.8–130.3 (aromatic C), 140.6, 143.2,
145.8, 148.6 (aromatic ipso C); 19F NMR (470 MHz, CDCl3):
d=À73 (CF3); MS (FAB, NBA): m/z (%)=438 (68) [M+
1]+, 420 (90), 343 (10), 307 (38), 289 (26), 254 (100); anal.
calcd. for C21H18F3NO4S: C 57.67, H 4.51, N 3.20; found: C
57.59, H 4.15, N 3.26.
(R)-2-Amino-2-(biphenyl-4-yl)-1,1-diphenylethanol
(6e)
Under nitrogen, a mixture containing 6d (0.88 g, 1.5 mmol),
tributylphenylstannane (0.49 mL, 0.55 g, 1.5 mmol), lithium
chloride (0.19 g, 4.5 mmol), tetrakistriphenylphosphane
(0.045 g, 0.039 mmol), 10 mL of freshly distilled 1,4-dioxane,
and a few crystals of 2,6-di-tert-butyl-4-methylphenol was
heated under stirring at 98–1008C for 23 h. After cooling to
room temperature, a 10% solution of ammonium hydroxide
(20 mL) was added. The mixture was diluted with diethyl
ether and filtered through celite. The filtrate was washed
with water and with brine, dried with magnesium sulfate
and concentrated under vacuum. The residue was purified
by column chromatography to give colorless solid 6e; mp
193–1958C; Rf =0.4( n-hexane/ethyl acetate, 1:1); [a]2D0:
+242 (c 1, chloroform); 1H NMR (500 MHz, DMSO-d6):
d=1.89 (s, 2H, NH2), 5.08 (s, 1H, OH), 5.68 (s, 1H, 2-H),
6.92–7.08 (m, 3H, aromatic H), 7.21–7.43 (m, 12H, aromatic
H), 7.58 (d, J=7.25 Hz, 2H, aromatic H), 7.75 (d, J=
7.25 Hz, 2H, aromatic H); 13C NMR (125 MHz, DMSO-d6):
d=61.9 (C-2), 80.0 (C-1), 126.5–129.5 (aromatic C), 139.6–
141.2 (aromatic ipso C), 144.2 (aromatic ipso C); MS (FAB,
NBA): m/z (%)=366 (10) [M+1]+; anal. calcd. for
C26H23NO: C 85.44, H 6.34, N 3.83; found: C 85.50, H 6.58,
N 3.83.
General Procedure for the Enantioselective
Reduction of Ketones 7, 9, 11 or 13 with Borane-
Dimethyl Sulfide in the Presence of Amino Alcohol
6d
(R)-2-Amino-2-[4-(nonafluorobutanesulfonyloxy)phen-
yl]-1,1-diphenylethanol (6d)
A 50-mL two-necked flask was equipped with a magnetic
stirrer, connected to the combined nitrogen/vacuum line,
charged with an 80% suspension of sodium hydride in min-
eral oil (0.23 g, 7.6 mmol), and closed with a septum. The air
in the flask was replaced by nitrogen, and anhydrous DMF
(40 mL) was added by syringe. The mixture was cooled in
an ice-bath, and a solution of 5 (1.22 g, 4.0 mmol) in anhy-
drous DMF (40 mL) was injected at such a rate that the
temperature was kept below 58C. Stirring was continued at
A 25-mL two-necked flask was charged with amino alcohol
6d (0.059 g, 0.10 mmol), equipped with a magnetic stirrer
and a connection to the combined nitrogen/vacuum line and
closed with a septum. The air in the flask was replaced by
nitrogen. The amino alcohol 6 was dissolved in THF (6 mL)
under stirring and a 2M solution of the borane-dimethyl sul-
fide complex in THF (0.66 mL, 1.32 mmol) was added by sy-
ringe. After stirring at room temperature for 24h, the fresh-
Adv. Synth. Catal. 2007, 349, 337 – 342
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
341

Manfred Braun et al.
FULL PAPERS
ly distilled ketone (1.00 mmol) was added within 90 min by
means of a micro syringe. After stirring for 24h at room
temperature, methanol (2 mL) was added and the solvent
was removed in a rotary evaporator. The residue was puri-
fied by column chromatography (n-hexane/ethyl acetate, 2 :
1 or 1 : 1) and subsequently distilled in a microdistillation
apparatus, the receiving flask being cooled in a bath of
liquid nitrogen.
[2] S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda, K. Ito,
A. Hirao, S. Nakahama, J. Chem. Soc., Perkin Trans. 1
1985, 2039, and references cited therein.
[3] a) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem.
Soc. 1987, 109, 5551; b) E. J. Corey, R. K. Bakshi, S.
Shibata, C.-P. Chen, V. K. Singh, J. Am. Chem. Soc.
1987, 109, 7925; c) E. J. Corey, S. Shibata, R. K. Bakshi,
J. Org. Chem. 1988, 53, 2861; d) E. J. Corey, J. O. Link,
Tetrahedron Lett. 1989, 30, 6275.
[4] M. Braun, Angew. Chem. 1996, 108, 565; Angew.
Chem. Int. Ed. Engl. 1996, 35, 519.
[5] a) R. Berenguer, J. Garcia, J. Vilarrasa, Tetrahedron:
Asymmetry 1994, 5, 165; b) J. Bach, R. Berenguer, J.
Garcia, T. Loscertales, J. Vilarrasa, J. Org. Chem. 1996,
61, 9021.
[6] For reductions with related, phenyglycine-derived oxa-
zaborolidines, see: a) C. Dauelsberg, J. Martens, Syn.
Commun. 1993, 23, 2091; b) I. Reiners, J. Wilken, J.
Martens, Tetrahedron: Asymmetry 1995, 6, 3063.
[7] K. R. K. Prasad, N. N. Joshi, Tetrahedron: Asymmetry
1996, 7, 3147.
[8] a) J. Crosby, in: Chirality in Industry, (Eds.: A. N. Col-
lins, G. N. Sheldrake, J. Crosby), John Wiley and Sons,
New York, 1992, chapt. 1; b) J. Kamphuis, W. H. J.
Boesten, B. Kaptein, H. F. M. Hermes, T. Sonke, Q. B.
Broxterman, W. J. J. van den Tweel, H. E. Schoemaker,
in: Chirality in Industry, (Eds.: A. N. Collins, G. N.
Sheldrake, J. Crosby), John Wiley and Sons, New York,
1992, chapt. 8.
According to this protocol, the following alcohols were
obtained. Their spectroscopic data are in accordance with
those of authentic samples.
(S)-1-Phenylethanol (8): [a]2D0: À40.5 (c 1.25, methanol);
ee: 96% according to GC on a FS-Lipodex A column (Ma-
cherey–Nagel; 50 m, 0.25 mm; 908); (S)-8: tR: 108.8 min;
(R)-8: tR: 112.3 min.
(R)-2-Chloro-1-phenylethanol (10): [a]2D0: À4 6 c( 1, cyclo-
hexane); authentic sample: À48.
(S)-1-Indanol (12): [a]2D0: À28 (c 1, chloroform); authentic
sample: À31; MTPA ester: 1H NMR: major product: d=
6.38 (dd, J=6.7 Hz, J=3.3 Hz); minor product: d=6.35.
(S)-1,2,3,4-Tetrahydro-1-naphthol (14): [a]2D0: À30 (c 1,
chloroform); authentic sample: À33; MTPA ester:
1H NMR: major product: d=6.17 (t, J=4.1 Hz); minor
product: d=6.14.
Acknowledgements
[9] M. Penso, D. Albanese, D. Landini, V. Lupi, G. Tricari-
This workwas supported by the Deutsche Forschungsgemein-
schaft (Br 604–13/1–2).
co, Eur. J. Org. Chem. 2003, 4513.
[10] T. W. Greene, P. G. M. Wuts, Protective Groups in Or-
ganic Synthesis 3rd edn., John Wiley and Sons, New
York, 1999, chapt. 3.
[11] Authentic samples were purchased from Sigma–Al-
drich, Laborchemikalien und analytische Reagenzien.
[12] For electronic effects on enantioselectivity, see: E. N.
Jacobsen, W. Zhang, M. L. Güler, J. Am. Chem. Soc.
1991, 113, 6703; M. Braun, K. Opdenbusch, Liebigs
Ann./Recueil 1997, 141.
[13] Cf. R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kita-
mura, N. Oguni, M. Hayashi, T. Kaneko, Y. Matsuda, J.
Organomet. Chem. 1990, 382, 19.
[14] R. Devant, U. Mahler, M. Braun, Chem. Ber. 1988, 121,
397.
References
[1] For reviews, see: a) V. K. Singh, Synthesis 1992, 605;
b) S. Walbaum, J. Martens, Tetrahedron: Asymmetry
1992, 3, 1475; c) L. Deloux, M. Srebnik, Chem. Rev.
1993, 93, 763; d) D. J. Mathre, I. Shinkai, in: Encyclope-
dia of Reagents for Organic Synthesis, Vol. 4, (Ed.:
L. A. Paquette), John Wiley and Sons, New York, 1995,
pp 2247–2250; e) E. J. Corey, C. J. Helal, Angew.
Chem. 1998, 110, 2092; Angew. Chem. Int. Ed. 1998, 37,
1986.
342
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 337 – 342