Dynamic kinetic resolution of β-azido alcohols. An efficient route to chiral aziridines and β-amino alcohols

Article abstract of DOI:10.1021/jo015579d

Enzymatic resolution of β-azido alcohols in combination with ruthenium-catalyzed alcohol isomerization led to a successful dynamic kinetic resolution. A variety of racemic β-azido alcohols were efficiently transformed to the corresponding enantiomerically pure acetates (ee up to 99% and conversion up to 98%). The synthetic utility of this procedure has been illustrated by the practical synthesis of (S)-propanolol I and (R)-β-azido-α-(4-methoxyphenyl)ethanol ((R)-1c), a direct precursor of denopamine II.

Full text of DOI:10.1021/jo015579d

4022
J . Org. Chem. 2001, 66, 4022-4025
Dyn a m ic Kin etic Resolu tion of â-Azid o Alcoh ols. An Efficien t
Rou te to Ch ir a l Azir id in es a n d â-Am in o Alcoh ols
Oscar Pa`mies and J an-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-10691 Stockholm, Sweden
jeb@organ.su.se
Received February 18, 2001
Enzymatic resolution of â-azido alcohols in combination with ruthenium-catalyzed alcohol isomer-
ization led to a successful dynamic kinetic resolution. A variety of racemic â-azido alcohols were
efficiently transformed to the corresponding enantiomerically pure acetates (ee up to 99% and
conversion up to 98%). The synthetic utility of this procedure has been illustrated by the practical
synthesis of (S)-propanolol I and (R)-â-azido-R-(4-methoxyphenyl)ethanol ((R)-1c), a direct precursor
of denopamine II.
Sch em e 1
In tr od u ction
The value of enantiopure azido alcohols lies in their
utility as direct precursors of aziridines1 and vicinal
amino alcohols2 (Scheme 1).
been reported.12 These studies have shown that azido
alcohols are esterified at good reaction rates and good
selectivity. However, a major drawback with KR is that
the yield is limited to a maximum of 50%. By applying
dynamic kinetic resolution (DKR) this limitation can be
overcome. To the best of our knowledge the only example
of DKR for obtaining vicinal azido alcohols is the expoxide
ring opening with trimethylsilyl azide (TMSN3), reported
by J acobsen,13 in which an epihalohydrin is employed as
starting material.
As a part of our ongoing project on chemoenzymatic
DKR of different substrates contaning a sec-alcohol
moiety,14 we now report on the efficient synthesis of
enantiopure vicinal azido acetates from vicinal azido
alcohols 1 via DKR. This procedure is applied to the
enantioselective synthesis of different phenyl and ary-
loxymethyl substituted azido alcohol derivatives, which
are important precursors of biologically active com-
pounds.15 The viability of this strategy is illustrated by
the practical syntheses of (S)-propanolol I (Figure 1), a
During recent years, there has been a growing interest
in chiral aziridines due to the increasing importance of
functionalized aziridines in organic synthesis3 and their
presence in bioactive molecules (e.g., radiation sensitizers
and enzyme inhibitors).4 Moreover, chiral â-amino alco-
hols are important structural elements in chiral ligands
for asymmetric catalysis5 as well as in biologically active
compounds (e.g., â-adrenergic receptor blockers and
immune stimulants).6 In contrast to chiral 2-amino-1-ols,
which are readily available by reduction of R-amino
acids,5a the corresponding regioisomeric chiral 1-amino-
2-ols are not as easy to access. The known approaches to
these synthetically valuable compounds include the ni-
troaldol reaction,7 hydrocyanation of aldehydes,8 asym-
metric amino- and dihydroxylation,9 asymmetric hydro-
genation,10 and ring opening of epoxides with amines or
amine equivalents.11
Several studies dealing with the kinetic resolution (KR)
of azido alcohols by lipase-catalyzed esterification have
(1) Leffler, J . E.; Temple, R. D. J . Am. Chem. Soc. 1967, 89, 5235.
(2) (a) Besse, P.; Veschambre, H.; Cheˆnevert, R.; Dickman, M.
Tetrahedron: Asymmetry 1994, 5, 1727. (b) Bosch, I.; Costa, A. M.;
Mart´ın, M.; Urp´ı, F.; Vilarrasa, J . Org. Lett. 2000, 2, 397.
(3) Deyrup, J . A. In The Chemistry of Heterocyclic Compounds;
Hassner, A., Ed.; J ohn Wiley & Sons: New York, 1993.
(4) (a) Tomasz, M.; J ung, M.; Verdine, G.; Nakanishi, K. J . Am.
Chem. Soc. 1984, 106, 7367. (b) Danishefsky, S.; Ciufolini, M. J . Am.
Chem. Soc. 1984, 106, 6424.
(5) (a) Blasser, H.-U. Chem. Rev. 1992, 92, 935. (b) Kolb, H. C.; Van
Nieeuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (c)
Pfaltz, A. In Advances in Catalytic Processes; Doyle, M. P., Ed.; J AI
Press: Greenwich, CT, 1995.
(10) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J . Am. Chem. Soc.
2000, 122, 6510.
(11) (a) Handson, R. M. Chem. Rev. 1991, 91, 437. (b) Larrow, J . F.;
Schaus, S. E.; J acobsen, E. N. J . Am. Chem. Soc. 1996, 118, 7420.
(12) See, for example: (a) Foelsche, E.; Hickel, A.; Ho¨nig, H.; Seufer-
Wasserthal P. J . Org. Chem. 1990, 55, 1749. (b) Faber, K.; Ho¨nig, H.;
Seufer-Wasserthal, P. Tetrahedron Lett. 1988, 29, 1903. (c) Pchelka,
B. K.; Loupy, A.; Plenkiewicz, J .; Blanco, L. Tetrahedron: Asymmetry
2000, 11, 2719.
(13) (a) J acobsen, E. N.; Schaus, S. E. Tetrahedron Lett. 1996, 37,
7937. (b) Furrow, M. E.; Schaus, S. E.; J acobsen, E. N. J . Org. Chem.
1998, 63, 6776.
(6) Powell, J . R.; Waimer, I. W.; Drayer, D. E. In Drug Stereochem-
istry Analytical Methods and Pharmacology; Marcel Dekker: New
York, 1998.
(14) (a) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J . E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.; Larsson, A.
L. E.; LeRay, M.; Ba¨ckvall, J . E. J . Am. Chem. Soc. 1999, 121, 1645.
(c) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J . E. J . Org. Chem. 1999,
64, 5237. (d) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J . E. Org. Lett.
2000, 2, 1037.
(15) See, for example: (a) Ostermayer, F.; Zimmermann, M.
US4460580, 1984. (b) Haynes, G. R. US4278687, 1981. (c) Nathanson,
J . A. US5366975, 1994. (d) Wang, Z. M.; Zhang, X. L.; Sharpless, K.
B. Tetrahedron Lett. 1993, 34, 2267. (e) Bristow, M. R.; Hersberger,
R. E.; Port, J . D.; Minobe, W.; Rasmussen, R. Mol. Pharmacol. 1989,
35, 295.
(7) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura,
K.; Shibasaki, M. J . Am. Chem. Soc. 1993, 115, 10372.
(8) Effenmerger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555.
(9) For dihydroxylation examples, see: Chang, M. T.; Sharpless, K.
B. Tetrahedron Lett. 1996, 37, 3219. For aminohydroxylation examples,
see: (a) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1997, 36, 2637. (b) Allen, A: T.; Sharpless, K. B. J . Org. Chem. 1999,
64, 8379. (c) Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett.
2000, 2, 2221.
10.1021/jo015579d CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

Dynamic Kinetic Resolution of â-Azido Alcohols
J . Org. Chem., Vol. 66, No. 11, 2001 4023
Ta ble 2. Dyn a m ic Kin etic Resolu tion of 1a a
% 2a b
% 5a b
% eec
F igu r e 1.
entry
solvent
T/°C
t/h
1
toluene
DIPE
60
60
60
60
60
60
70
80
80
48
48
48
48
48
48
36
24
24
76
70
68
78
62
89
94
94
94
7
6
6
6
3
7
6
6
6
>99
>99
>99
>99
92
>99
>99
>99
>99
widely used anti-hypertensive drug (â-blocker),11b,15d and
(R)-â-azido-R-(4-methoxyphenyl)ethanol, a precursor of
(R)-denopamine II (Figure 1) which is a potent orally
active â1 receptor agonist for the treatment of heart
failure.15d
2
3
TBME
toluene
toluene
toluene
toluene
toluene
toluene
4d
5e
6f
7f
8f
9g
Resu lts a n d Discu ssion
a
Reactions were performed on a 0.2 mmol scale with 20 mg of
N-435, 4 mol % of 4, and 3 equiv of acyl donor in 2 mL of solvent.
A primary requirement for a successful DKR is that
the KR conditions are compatible with the racemization
process.14 Therefore, we screened different commercially
available lipases in the kinetic resolution of 2-azido-1-
phenylethanol 1a under different reaction conditions,
using p-chlorophenyl acetate 3 as acyl donor. The latter
is known to be compatible with Ru-catalyzed racemiza-
tion of alcohols.14 The results are summarized in Table
1. Although the enzyme Pseudomonas cepacia lipase
(PS-C type II) showed the highest activity (entry 1), the
best enantioselectivity (>99%) was obtained using Can-
dida antarctica lipase B (Novozyme 435, N-435) (entry
2).
d
b Determined by 1H NMR. c % ee of 2a determined by HPLC. 0.02
g
mmol of NEt3. e 2 equiv of NEt3. f 30 mg of enzyme used. Using
the recovered enzyme from entry 8.
Ta ble 3. Dyn a m ic Kin etic Resolu tion of 1a -ga
entry substrate
R
t/h % 2b % 5b % eec
1
1a
1b
1c
1d
1e
1f
Ph
24 94 (86)
24 98 (87)
24 92 (84)
24 95 (85)
48 87 (80)
72 76 (70)
6
2
8
5
7
4
5
>99 (+)
>99 (+)
>99 (+)
>99 (+)
96 (-)
2
p-Br-C6H4
p-MeO-C6H4
2-naphthyl
benzyl
3
4
5d
6e
7e
Ta ble 1. Kin etic Resolu tion of 1a a
PhOCH2
1-naphthyl-OCH2 72 75 (71)
85 (+)
1g
86 (+)
a
Reactions were performed on a 0.6 mmol scale with 90 mg of
N-435, 4 mol % of 4, and 3 equiv of acyl donor in 6 mL of solvent
b
at 80 °C. Determined by NMR. Isolated yields in parentheses.
c % ee of 2 determined by HPLC. Absolute configuration in
d
parentheses. N-435 (15 mg), 6 mol % of 4. e T ) 60 °C, N-435
entry
enzyme
solvent
t/h
% 2a b
% eec
(1.5 mg), 6 mol % of 4.
1
2
3
4
5
PS-C
N-435
PF
N-435
N-435
toluene
toluene
toluene
DIPEe
5
5
48
5
38
28
8
31
32
93
>99
nmd
>99
>99
amounts of ketone 5a , formed during the hydrogen
transfer process,14 were observed.
Under “standard” conditions (i.e., 60 °C and 4 mol %
of 4), excellent enantioselectivity (>99%) was achieved.
However, the efficiency of the process was slightly
affected by the solvent (Table 2, entries 1-3). Thus,
reaction in toluene gave better conversion than in diiso-
propyl ether (DIPE) and tert-butyl methyl ether (TBME).
This can be attributed to the limited solubility of 4 in
the latter solvents.
Several attempts to increase the efficiency have been
carried out. Although the use of catalytic amounts of
triethylamine gave similar results (entry 4, Table 2), the
addition of larger amounts had a negative effect on both
activity and enantioselectivity (entry 5). The addition of
more enzyme increased the activity without loss of
enantioselectivity (entry 6). Moreover, increasing the
temperature led to significantly higher efficiency of the
process (entries 7 and 8). This is mainly due to an
increase of the racemization rate. Interestingly, at 80 °C
neither deactivation of the enzyme nor loss of ee has been
observed. The dynamic kinetic resolution of compound
1a with the recovered enzyme gave identical results to
that of the fresh enzyme, and azido acetate 2a was
obtained in high yield in >99% ee after 24 h (entry 9).
This new procedure was applied to different substrates
1a -g (Table 3). The DKR of various â-azido-R-phenethyl
alcohols 1a -c gave high yields in more than 99% ee
(Table 3, entries 1-3). These results further indicate that
TBMEf
5
a
Reactions were performed on a 0.2 mmol scale with 20 mg of
b
enzyme and 3 equiv of 3 in 2 mL of solvent at 60 °C. Determined
by NMR. c % ee of 2a determined by HPLC. Not measured.
d
e Diisopropyl ether. f tert-Butyl methyl ether.
Surprisingly, Pseudomonas fluorescens lipase (PF),
which has been successfully used in the KR of different
azido alcohols,12a showed very low activity under our
conditions. Moreover, these experiments showed that the
rate of the kinetic resolution of 1a is hardly affected by
the nature of the nonpolar solvents (entries 2, 4, and 5).
On the basis of our preliminary results on KR, we
combined the KR of azido alcohol 1a using N-435 and
the acyl donor 3 with a ruthenium-catalyzed racemization
process via hydrogen transfer with catalyst 4.16 The
results are summarized in Table 2. In all cases, small
(16) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885.

4024 J . Org. Chem., Vol. 66, No. 11, 2001
Sch em e 2. Syn th esis of (S)-P r op a n olol Ia
Pa`mies and Ba¨ckvall
B) was a generous gift from Novo Nordisk A/S, Denmark.
Lipase PS-C type II was a generous gift from Amano Phar-
maceutical Co. Ltd, J apan.
1H and 13C NMR spectra were recorded in CDCl3 at 400 and
100 MHz, respectively. Solvents for extraction and chroma-
tography were technical grade and distilled before use. Column
chromatography was performed with Merck 60 silica gel. The
enantiomeric excess of azido acetates 2a -g was determined
by analytical HPLC employing a Daicel, Chiracel OD-H
column using racemic compounds as references. The flow
parameters and retention times were as follows: 2a , 17.1 (R),
19.2 (S) (n-hexane/2-propanol ) 60:40, 0.5 mL/min, 254 nm);
2b, 53.9 (R), 58.3 (S) (n-hexane/2-propanol ) 99.6:0.4, 0.5 mL/
min, 254 nm); 2c, 18.3 (R), 19.8 (S) (n-hexane/2-propanol )
60:40, 0.5 mL/min, 254 nm); 2d , 57.7 (R), 67.6 (S) (n-hexane/
2-propanol ) 99.5:0.5, 0.5 mL/min, 254 nm); 2e, 20.5 (S), 27.8
(R) (n-hexane/2-propanol ) 99.5:0.5, 0.5 mL/min, 254 nm). 2f,
36.7 (S), 38.5 (R) (n-hexane/2-propanol ) 95:5, 0.5 mL/min,
254 nm); 2g, 43.9 (S), 46.8 (R) (n-hexane/2-propanol ) 90:10,
0.5 mL/min, 254 nm).
a
Key: (i) LiOH, MeOH, 2 h, rt; (ii) PtO2, acetone, H2 (1 atm),
4 h, rt, 98%.
the presence of different substituents in the para position
in the aromatic ring does not significantly influence the
efficiency of the process. The DKR of â-azido-R-(naphth-
2-yl)ethyl alcohol 1d under these conditions also gave
enantiopure azido acetate 2d in high yield (entry 4). For
the benzyl (1e) and aryloxymethyl derivatives (1f and
1g), the DKR under the conditions used for 1a -d (i.e.,
120 mg N-435/mmol product, 80 °C, 4 mol % 4) gave the
acetates in moderate to low enantioselectivity (around
70% ee for 1e and around 30% ee for 1f and 1g). This is
due to the lower enantiopreference of the enzyme for
these substrates.12c To obtain better enantioselectivity we
took full advantage of the DKR. Thus, by reducing the
enzyme/ruthenium catalyst ratio the enzymatic acylation
became the rate-determining step and the enantioselec-
tivity was therefore substantially improved (entries 5-7).
A wide range of synthetic applications of this dynamic
kinetic resolution procedure can be envisaged. For in-
stance, the in situ hydrolysis of acetate 2c with LiOH in
methanol gave quantitatively (R)-â-azido-R-(4-methoxy-
phenyl)ethanol (R)-1c, a precursor of (R)-denopamine II,
in essentially enantiomerically pure form (ee >99%).
This method was extended to the practical synthesis
of the anti-hypertensive drug propanolol I (Scheme 2).
Dynamic kinetic resolution of the racemic azido alcohol
1g afforded the corresponding azido acetate 2g in 71%
isolated yield and 86% ee (entry 7, Table 3). The
transformation to (S)-propanolol was performed in a one-
pot two-step procedure, hydrolysis with LiOH in metha-
nol followed by azide reduction and in situ reductive
alkylation using Adam’s catalyst in the presence of
acetone.11b Recrystallization from cyclohexane gave I in
almost enantiomerically pure form.
Gen er a l P r oced u r e for th e DKR of Azid o Alcoh ols. (R)-
1-Azid o-2-a cetoxy-2-p h en yleth a n e ((R)-2a ). In a typical
experiment, ruthenium catalyst 4 (32.5 mg, 4 mol %) and
Novozym-435 (90 mg) were placed in a Schlenk flask under
argon. A solution of 1a (97.9 mg, 0.6 mmol) and 3 (336 mg,
1.8 mmol) in dry toluene (6 mL) under argon (5 min of argon
bubbling) was transferred to the ruthenium catalyst and the
enzyme. The resulting reaction mixture was stirred at 80 °C
for 24 h. The enzyme was then filtered off and washed with
toluene (3 × 5 mL), the solvent was evaporated, and the
product was purified by flash chromatography (pentane/ethyl
acetate 15/1) to yield 105.8 mg (86%) of (R)-2a in >99% ee. 1H
2
NMR δ: 2.14 (s, 3H, CH3), 3.45 (dd, 1H, CH2, J H-H ) 12.9
Hz, 3J H-H ) 3.9 Hz), 3.64 (dd, 1H, CH2, 2J H-H ) 12.9 Hz, 3J H-H
3
3
) 8.4 Hz), 5.92 (dd, 1H, CH, J H-H ) 8.4 Hz, J H-H ) 3.9 Hz),
7.36 (m, 5H, CHd). 13C NMR δ: 21.6 (CH3), 55.8 (CH2), 75.2
(CH), 126.3 (CHd), 128.7 (CHd), 137.8 (C), 170.2 (CO).
(R)-1-Azid o-2-a cetoxy-2-(p-br om op h en yl)eth a n e ((R)-
2b). 1H NMR δ: 2.14 (s, 3H, CH3), 3.43 (dd, 1H, CH2, 2J H-H
)
3
2
12.8 Hz, J H-H ) 4.4 Hz), 3.60 (dd, 1H, CH2, J H-H ) 12.8 Hz,
3
3
3J H-H ) 7.6 Hz), 5.85 (dd, 1H, CH, J H-H ) 7.6 Hz, J H-H
)
4.4 Hz), 7.23 (d, 2H, CHd, 3J H-H ) 8.8 Hz), 7.51 (d, 2H, CHd,
3J H-H ) 8.8 Hz). 13C NMR δ: 21.2 (CH3), 55.0 (CH2), 74.2 (CH),
123.0 (C), 128.4 (CHd), 132.2 (CHd), 136.4 (C), 169.9 (CO).
(R)-1-Azido-2-acetoxy-2-(p-m eth oxyph en yl)eth an e ((R)-
1
2
2c). H NMR δ: 2.08 (s, 3H, CH3), 3.39 (dd, 1H, CH2, J H-H
)
3
2
12.8 Hz, J H-H ) 4.0 Hz), 3.63 (dd, 1H, CH2, J H-H ) 12.8 Hz,
3J H-H) 8.0 Hz), 3.80 (s, 3H, CH3O), 5.86 (dd, 1H, CH, 3J H-H
)
3
3
8.0 Hz, J H-H ) 4.0 Hz), 6.90 (d, 2H, CHd, J H-H ) 6.8 Hz),
7.25 (d, 2H, CH), J H-H ) 6.8 Hz). 13C NMR δ: 21.3 (CH3),
3
Con clu sion
55.2 (CH2), 55.5 (CH3O), 74.5 (CH), 114.3 (CHd), 128.1 (CHd
), 129.4 (C), 160.1 (C), 170.2 (CO).
We have developed a chemoenzymatic DKR to obtain
vicinal azido acetates in good to high yields and with high
enantioselectivity. The efficiency of the process together
with the easy transformation of these azido acetates to
â-amino alcohols and aziridines should make the present
method an attractive alternative to existing methods for
obtaining the latter two classes of compounds in enan-
tiomerically pure form.
(R)-1-Azid o-2-a cetoxy-2-(n a p h th -2-yl)eth a n e ((R)-2d ).
1H NMR δ: 2.18 (s, 3H, CH3), 3.52 (dd, 1H, CH2, 2J H-H ) 13.2
Hz, 3J H-H ) 4.0 Hz), 3.72 (dd, 1H, CH2, 2J H-H ) 13.2 Hz, 3J H-H
3
3
) 8.8 Hz), 6.08 (dd, 1H, CH, J H-H ) 8.8 Hz, J H-H ) 4.0 Hz),
7.50 (m, 3H, CHd), 7.85 (m, 4H, CHd). 13C NMR δ: 21.3 (CH3),
55.3 (CH2), 74.9 (CH), 124.0 (C), 126.2 (CHd), 126.8 (CHd),
127.9 (CHd), 128.3 (CHd), 128.9 (CHd), 133.3 (C), 133.5 (C),
134.7 (C), 170.1 (CO).
(R)-1-Azido-2-acetoxy-3-ph en ylpr opan e ((R)-2e). 1H NMR
δ: 2.07 (s, 3H, CH3), 2.88 (dd, 1H, CH2, 2J H-H ) 13.5 Hz, 3J H-H
Exp er im en ta l Section P r oced u r es
2
3
) 7.2 Hz), 2.98 (dd, 1H, CH2, J H-H ) 13.5 Hz, J H-H ) 6.3
Gen er a l Exp er im en ta l P r oced u r es. All reactions were
carried out under dry argon atmosphere in oven-dried glass-
ware. Solvents were purified by standard procedures. Solvents
for HPLC use were spectrometric grade. All other reagents
are commercially available and were used without further
purification. Compounds 5a -d were prepared according to
literature procedures.17 Racemic azido alcohols 1a -d were
prepared from the corresponding azido ketones 5 by reduction
with sodium borohydride under standard conditions. Azido
alcohols 1e-g were prepared by ring opening of the corre-
sponding epoxide by sodium azide in the presence of am-
monium chloride.18 Novozym-435 (Candida antarctica Lipase
Hz), 3.26 (dd, 1H, CH2, 2J H-H ) 13.2 Hz, 3J H-H ) 5.7 Hz), 3.40
2
3
(dd, 1H, CH2, J H-H ) 13.2 Hz, J H-H ) 3.6 Hz), 5.17 (m, 1H,
CH), 7.25 (m, 5H, CHd). 13C NMR δ: 21.2 (CH3), 37.8 (CH2-
Ph), 52.6 (CH2), 73.6 (CH), 127.1 (CHd), 128.9 (CHd), 129.6
(CHd), 136.4 (C), 170.5 (CO).
(S)-1-Azid o-2-a cetoxy-3-p h en oxyp r op a n e ((S)-2f). 1H
NMR δ: 2.12 (s, 3H, CH3), 3.62 (m, 2H, CH2), 4.12 (m, 2H,
CH2), 5.28 (m, 1H, CH), 6.90 (m, 3H, CHd), 7.30 (m, 2H, CHd
). 13C NMR δ: 21.2 (CH3), 51.0 (CH2), 66.2 (CH2O), 70.9 (CH),
114.8 (CHd), 121.7 (CHd), 129.8 (CHd), 158.3 (C), 170.5 (CO).
(S)-1-Azid o-2-a cet oxy-3-(1-n a p h t h oxy)p r op a n e ((S)-
2g). 1H NMR δ: 2.16 (s, 3H, CH3), 3.72 (m, 2H, CH2), 4.30 (m,

Dynamic Kinetic Resolution of â-Azido Alcohols
J . Org. Chem., Vol. 66, No. 11, 2001 4025
3
2H, CH2), 5.47 (m, 1H, CH), 6.81 (d, 1H, 3J H-H ) 7.2 Hz, CHd
), 7.37 (m, 1H, CHd), 7.49 (m, 2H, CHd), 7.81 (m, 1H, CHd),
8.18 (m, 1H, CHd). 13C NMR δ: 21.2 (CH3), 51.3 (CH2), 66.6
(CH2-O), 71.0 (CH), 105.1 (CHd), 121.3 (CHd), 121.9 (CHd
), 125.7 (CHd), 125.9 (CHd), 126.8 (CHd), 127.7 (CHd), 134.7
(C), 153.9 (C), 170.5 (CO).
(m, 2H, CHN, CH2N), 2.97 (dd, 1H, CH2-N, J H-H ) 3.6 Hz,
3J H-H ) 12.0 Hz), 4.10 (m, 1H, CH2O), 4.18 (m, 2H, CHO,
3
CH2O), 6.81 (d, 1H, CHd, J H-H ) 7.6 Hz), 7.36 (t, 1H, CHd,
3J H-H ) 8.0 Hz), 7.47 (m, 3H, CHd), 7.80 (dd, 1H, CHd, 3J H-H
) 5.6 Hz, 3J H-H ) 2.4 Hz), 8.24 (dd, 1H, CHd, 3J H-H ) 7.2 Hz,
3J H-H ) 3.2 Hz). 13C NMR δ: 23.2 (CH3), 23.3 (CH3), 49.2
(CHN), 49.9 (CH2N), 68.7 (CHO), 71.8 (CH2O), 105.2 (CHd),
120.8 (CHd), 122.1 (CHd), 125.5 (CHd), 125.8 (C), 126.1 (CHd
), 126.7 (CHd), 127.8 (CHd), 134.8 (C), 154.6 (C).
Syn th esis of (S)-P r op a n olol (I). To a solution of azido
acetate (S)-2g (285.3 mg, 1 mmol) in methanol (10 mL) was
added LiOH (24 mg, 1 mmol). The solution was allowed to stir
at room temperature for 2 h. Then PtO2 (12 mg, 0.05 mmol),
3 Å molecular sieves (0.45 g), and acetone (110 µL, 1.1 mmol)
were added. The flask was then flushed with hydrogen at 1
bar, and the reaction was allowed to stir for 4 h at room
temperature. The mixture was filtered through Celite and
concentrated to dryness affording the compound as a white
solid (253 mg, 98%). The resulting solid was recrystallized from
cyclohexane. The hydrochloride salt was formed by precipita-
tion from ether using gaseous hydrochloric acid. [R]21D ) -24.3
(c 1.15 (HCl salt), EtOH) [lit.19 [R]21D ) -25.5 (c 1.18 (HCl salt),
Ackn owledgm en t. Financial support from the Swed-
ish Foundation for Strategic Research is gratefully
acknowledged. We thank Dr. Hans Adolfsson for useful
comments and suggestions.
J O015579D
(17) Boyer, J . H.; Straw, D. J . Am. Chem. Soc. 1952, 74, 4506.
(18) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557.
(19) Klunder, J . M.; Ko, S. Y.; Sharpless, K. B. J . Org. Chem. 1986,
56, 3710.
3
EtOH). 1H NMR δ: 1.10 (d, 1H, CH3, J H-H ) 6.4 Hz), 2.84