Non-enzymatic kinetic resolution of 1,2-azidoalcohols using a planar-chiral DMAP derivative catalyst

Article abstract of DOI:10.1016/j.tet.2012.10.077

Optically pure 1,2-azidoalcohols are widely used as precursors for other high value organic products. A non-enzymatic kinetic resolution procedure for the stereoselective synthesis of chiral 1,2-azidoalcohols from the readily available racemic counterpart

Full text of DOI:10.1016/j.tet.2012.10.077

Tetrahedron 69 (2013) 753e757
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Non-enzymatic kinetic resolution of 1,2-azidoalcohols using
a planar-chiral DMAP derivative catalyst
ꢀ
*
ꢀ
ꢀ
Laura Mesas-Sanchez, Alba E. Díaz-Alvarez, Peter Diner
Department of ChemistrydBMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 August 2012
Received in revised form 5 October 2012
Accepted 29 October 2012
Available online 6 November 2012
Optically pure 1,2-azidoalcohols are widely used as precursors for other high value organic products. A
non-enzymatic kinetic resolution procedure for the stereoselective synthesis of chiral 1,2-azidoalcohols
from the readily available racemic counterparts has been developed, employing a planar-chiral DMAP
derivative catalyst. Following this procedure, a range of aromatic 1,2-azidoalcohols was obtained in good
selectivities (up to S¼45) and high enantiomeric excess (up to 99% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Non-enzymatic kinetic resolution
1,2-Azidoalcohols
Planar-chiral DMAP derivative catalyst
Ferrocenyl catalyst
€
ꢁ
1. Introduction
Moreover, Backvall and Pamies combined the enzymatic reso-
lution of 1,2-azidoalcohols in combination with the ruthenium-
catalysed alcohol racemization in a dynamic kinetic resolution,
yielding acetylated 1,2-azidoalcohols in excellent yields and high
enantiomeric excess.9
The synthesis of enantiomerically pure compounds has emerged
into one of the most important fields of organic synthesis.1 In this
context, synthetic approaches to optically pure aziridines and ami-
noalcohols have received special attention since they constitute
important building blocks in the design of high-value products in
both organic and pharmaceutical industry.2 Particularly, 1,2-
aminoalcohols are often used as chiral ligands for asymmetric ca-
An alternative to enzymatic kinetic resolutions is to use a small
molecule catalyst, such as chiral DMAP10 and chiral amidines.11 In
1996, Vedejs and Chen introduced a chiral DMAP derivative catalyst
in the kinetic resolutions of 1-arylethanols.12 The use of this catalyst
in stoichiometric amounts in the presence of 2 equiv of a Lewis acid,
led to enantiomerically enriched products with high enantiomeric
excess.12,13 Independently, Fu and co-workers developed the syn-
thesis of planar-chiral ferrocenyl pyrrole/DMAP analogues.14 The
DMAP derivative (ꢀ)-1 catalysed the kinetic resolution of secondary
aryl and allylic alcohols (Scheme 2).15 This catalytic system also
proved to be very efficient in the kinetic resolution of a racemic
trans-diol,16 the desymmetrization of meso-diols,16 propargylic al-
cohols,17 and the secondary 1-arylamines18 and indolines.19 Since
those early developments, kinetic resolution of secondary alcohols
was achieved using different chiral DMAP-based catalysts.20
In this study, we wish to present the non-enzymatic kinetic
resolution of a variety of 2-azido-1-arylethanols with good selec-
tivities using the planar-chiral ferrocenyl DMAP catalyst (ꢀ)-1.
talysis3 and are also present in biologicallyactive compounds, e.g.,
b-
adrenergic receptor blockers and immune stimulants.4 A convenient
approach to chiral aziridines and 1,2-aminoalcohols is to use 1,2-
azidoalcohols as precursors (Scheme 1).5
Scheme 1. Retrosynthetic approaches to chiral aziridines and 1,2-aminoalcohols.
Several routes to enantiopure azidoalcohols are available, in-
cluding the ring-opening of epoxides,6 asymmetric reduction of the
corresponding azidoketones7 and also the enzymatic kinetic reso-
lution of racemic azidoalcohols.8 Using this approach, the enzy-
matic kinetic resolution of racemic 1,2-azidoalcohols was reported
to yield products in high enantiomeric excess.8
2. Results and discussion
A search for the optimal conditions for the resolution of the 2-
azido-1-phenylethanols was performed (Table 1). Initial studies
showed that triethylamine catalysed the acetylation of the 2-azido-
ꢀ
* Corresponding author. E-mail address: peter.diner@kemi.uu.se (P. Diner).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.077

ꢀ
L. Mesas-Sanchez et al. / Tetrahedron 69 (2013) 753e757
754
triethylamine (0.75 equiv) was added. Fortunately, at this temper-
ature, the rate of the reaction increased (6 h, 52% conv.) without any
loss of the selectivity (S¼17, Entry 5).21
In order to investigate the scope of the kinetic resolution, several
1,2-azidoalcohols with different substituents in the aromatic ring
were reacted under the optimized conditions (Table 2). The kinetic
resolutions of aromatic 1,2-azidoalcohols by catalyst (ꢀ)-1
(2 mol %) at 0 ꢁC in tert-amyl alcohol yielded the desired products
with good selectivity (S¼17e45) and excellent enantiomeric excess
(up to 99%). The larger 2-naphthyl derivative led to better results in
terms of selectivity and reactivity compared to the parent com-
Scheme 2. Non-enzymatic kinetic resolution of secondary alcohols catalysed by
planar-chiral DMAP derivative (ꢀ)-1.
Table 1
Screening of reaction conditions for the kinetic resolution of 2-azido-1-phenylethanol by (ꢀ)-1a
Entry
Base
Concn/M
Temp/ꢁC
Time/h
Conv. (%)b
Sb
1
2
3
4
5
None
None
None
None
0.5
0.5
0.5
0.25
0.25
rt
0
0
0
0
4
4
24
24
6
61
37
51
39
52
10
14
15
17
17
c
NEt3
a
Reaction conditions: 2 (0.25 mmol), Ac2O (0.75 equiv), (ꢀ)-1 (0.005 mmol, 2 mol %) in tert-amyl alcohol (0.5 mL or 1 mL).
b
c
Determined by chiral HPLC.
NEt3 (0.75 equiv).
Table 2
Kinetic resolution of aromatic 1,2-azidoalcohols by (ꢀ)-1a
Entry
R
Time/h
Conv. (%)b
eeROH (%)b
Sb
1
2
3
4
5
6
7
8
9
Ph (2a)
24
3
3
10
5
13
20
13
9
73
60
58
62
70
65
58
60
61
63
99.6
99.9
99.2
99.9
80.6
98.6
92.7
99.0
98.6
96.6
17
45
33
35
4
14
16
24
20
13
2-Napthyl (2b)
40-NO2ePh (2c)
40-CNePh (2d)
40-MeePh (2e)
40-OMeePh (2f)
40-BenzoylePh (2g)
20,50-DiOMeePh (2h)
30-BrePh (2i)
10
40-BrePh (2j)
4
a
Reaction conditions: 2 (0.25 mmol), Ac2O (0.75 equiv), triethylamine (0.75 equiv), (ꢀ)-1 (0.005 mmol, 2 mol %) in tert-amyl alcohol (1.0 mL) at 0 ꢁC.
b
Determined by chiral HPLC.
1-phenylethanol 2a at room temperature, and therefore, it was
pound 2a (3 h, 60% conv., S¼45). The presence of an electron-
withdrawing group in the 4-position, such as a nitro or cyano
group also increases the selectivity factor (S¼33 and 35, re-
spectively). The electron-donating methyl, methoxy and benzoate
group in the 4-position of the phenyl ring decreases the selectivity
compared to the parent compound 2a (Table 2, Entries 5e7), while
compound 2h having two methoxy substituents in the 20- and 50-
position of the phenyl ring shows a slight improvement of the
selectivity (Table 2, Entry 8). The aromatic 1,2-azidoalcohols 2iej
having bromo substituents in the aromatic ring (Entries 9 and 10)
also yielded the products with reasonable selectivity (S¼13e20).
excluded in the first part of the screening. The reaction was run
using 2a (0.25 mmol), (ꢀ)-1 (2 mol %), Ac2O (0.75 equiv) at room
temperature in tert-amyl alcohol (0.5 mL) leading to 61% conver-
sion in 4 h with a selectivity factor (S) of 10 (Table 1, Entry 1).
Performing the reaction at 0 ꢁC led to an improvement of the se-
lectivity (S¼14e15), but the reaction slowed down reaching only
51% conversion in 24 h (Entries 2 and 3). The dilution of the reaction
mixture (to 0.25 M) resulted in an increase of the selectivity (S¼17)
and a subsequent decrease of the rate of the reaction (24 h, 39%
conv., Entry 4). In order to accelerate the reaction at 0 ꢁC,

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L. Mesas-Sanchez et al. / Tetrahedron 69 (2013) 753e757
755
Finally, since 1,2-azidoalcohols are precursors to several phar-
maceutically active -blockers, such (R)-pronethalol and
borohydride.22,23 The corresponding racemic acetates rac-3aej
b
a
were prepared by acetylation under basic conditions.24,25
(R)-nifenalol, the synthetic utility of the present method was fur-
ther demonstrated in the preparation of the optically pure (R)-
pronethalol (Fig. 1). The kinetic resolution of the azidoalcohol 2b
(using 1 mmol scale) was performed using the general procedure,
obtaining compound (R)-2b in 43% yield with high enantiomeric
purity (S¼42, >99% ee). Compound (R)-2b was converted to (R)-
pronethalol in 83% yield via the reduction of the azide and sub-
sequent in situ reductive alkylation with acetone using hydrogen/
platinum(IV) oxide in ethanol at room temperature.
4.2. General procedure for the kinetic resolution
Catalyst (ꢀ)-1 (3.3 mg, 0.005 mmol), azidoalcohol rac-2aej
(0.25 mmol) and tert-amyl alcohol (1.0 mL) were sequentially
added to a vial. The vial was capped and stirred at room tempera-
ture to help dissolve the catalyst. The reaction mixture was cooled
to 0 ꢁC, and then triethylamine (26
hydride (18
m
L, 0.19 mmol) and acetic an-
m
L, 0.19 mmol) were added. After an appropriate
Fig. 1. Synthesis of (R)-pronethalol. (i) Compound rac-2b (1.0 mmol), Ac2O (0.75 equiv), triethylamine (0.75 equiv), (ꢀ)-1 (2 mol %) in tert-amyl alcohol (4.0 mL) at 0 ꢁC. (ii)
Compound (R)-2b (0.43 mmol), PtO2 (0.5 equiv), acetone (1.5 equiv), H2 (5 atm) in EtOH (5 mL), 4 h, room temperature.
3. Conclusion
amount of time, the reaction mixture was quenched by the addition
of a large excess of methanol. The resulting solution was concen-
trated, and the unreactive alcohol, the acetate, and the catalyst
were separated by flash chromatography using increasing polarity
mixtures of pentane/ethyl acetate as eluent. Characterization data
for these compounds are as follows (copies of the HPLC chro-
matograms, 1H and 13C{1H} spectra are included in Supplementary
data).
In summary, we have demonstrated that the chiral DMAP de-
rivative catalyst (ꢀ)-1 catalysed the resolution for a range of aro-
matic 1,2-azidoalcohols with good selectivities (selectivity factor up
to 45) and high enantiomeric excess (up to 99% ee) of the remaining
alcohol. To the best of our knowledge, these results represent the
first example of the kinetic resolution of aromatic 1,2-azidoalcohols
using a chiral DMAP derivative catalyst.
4.2.1. (R)-2-Azido-1-phenylethanol ((R)-2a).26 Yellow oil (11.0 mg,
27% yield); ee 99.9%, Kromasil 5-CellCoat, n-hexane/i-PrOH¼90:10,
0.5 mL/min, 220 nm, tR[(R)/(S)]¼17.0/18.8 min; 1H NMR (500 MHz,
4. Experimental section
4.1. General
CDCl3)
d
7.39e7.32 (m, 5H, AreH), 4.88 (dd, J¼8.1, 3.9 Hz, 1H, CH),
3.51e3.42 (m, 2H, CH2), 2.47 (br, 1H, OH). 13C{1H} NMR (126 MHz,
CDCl3) 140.6, 128.8, 128.5, 126.0, 73.6, 58.2.
Commercially available reagents were purchased from Sigma-
eAldrich Co. and used without further purification. Thin Layer
Chromatography (TLC) was performed on ALUGRAMÒ SIL G/UV254
plates (0.2 mm), using UV-light (254 nm) for visualization. Flash
column chromatography was performed using Merck silica gel
(0.04e0.06 mm). 1H and 13C{1H} NMR spectra were recorded on
a Varian Mercury 300 MHz, Varian Unity 400 MHz or Varian Unity
d
4.2.2. (R)-2-Azido-1-(naphthalen-2-yl)ethanol
((R)-2b).27 White
solid (21.3 mg, 40% yield); mp 82e83 ꢁC (Lit.27 80e81 ꢁC); ee 99.9%,
Kromasil 5-CellCoat, n-hexane/i-PrOH¼90:10, 0.75 mL/min,
220 nm, tR[(R)/(S)]¼21.8/26.3 min; 1H NMR (400 MHz, CDCl3)
d
7.87e7.46 (m, 7H, AreH), 5.05 (dd, J¼7.8, 4.2 Hz,1H, CH), 3.61e3.51
500 MHz spectrometer. The chemical shift values (
d
) are given in
(m, 2H, CH2), 2.46 (s,1H, OH).13C{1H} NMR (101 MHz, CDCl3)
133.4, 133.3, 128.6, 128.1, 127.8, 126.5, 126.4, 125.1, 123.7, 73.7, 58.1.
d 138.0,
parts per million (ppm) and are referred to the residual peak of the
deuterated solvent used (CDCl3). IR spectra were recorded on
a PerkineElmer Spectrum One (ATR Technique). High-resolution
mass spectra were provided by Stenhagen Analys AB.
The enantiomeric separations of 2a,b,d,e,hej and 3aej were
performed by high performance liquid chromatography (HPLC)
with a Young Lin 9100 instrument using the appropriate chiral
column (250ꢂ4.6 mm) at 25 ꢁC with n-hexane and isopropanol as
eluents. The enantiomeric separation of 2c,f,g was achieved con-
verting the alcohol to the corresponding acetate using DMAP and
triethylamine in DCM. The selectivity (S) values were calculated
with the equation: S¼ln[(1ꢀc)(1ꢀeeROH)]/ln[(1ꢀc)(1þeeROH)].
Racemic 1,2-azidoalcohols rac-2aej were prepared ‘one pot’
4.2.3. (R)-2-Azido-1-(40-nitrophenyl)ethanol
((R)-2c).26 Orange
solid (21.3 mg, 41% yield); mp 51e53 ꢁC; ee 99.2%, Kromasil 5-
CellCoat, n-hexane/i-PrOH¼90:10, 0.5 mL/min, 254 nm, tR[(R)/
(S)]¼23.8/25.6 min; 1H NMR (300 MHz, CDCl3)
d
8.17 (d, J¼8.6 Hz,
2H, AreH), 7.57 (d, J¼8.6 Hz, 2H, AreH), 5.04e5.01 (m, 1H, CH),
3.52e3.49 (m, 2H, CH2). 13C{1H} NMR (75 MHz, CDCl3)
d 148.4,147.7,
127.1, 124.0, 72.6, 57.8.
4.2.4. (R)-2-Azido-1-(40-cyanophenyl)ethanol
((R)-2d).26 Yellow
solid (17.9 mg, 38% yield); mp 52e53 ꢁC; ee 99.9%, Kromasil 5-
CellCoat, n-hexane/i-PrOH¼95:5, 0.75 mL/min, 220 nm, tR[(R)/
from the corresponding
sodium azide followed by reduction of the ketone using sodium
a
-bromoacetophenone by the addition of
(S)]¼37.0/42.5 min; 1H NMR (400 MHz, CDCl3)
d
7.66 (d, J¼8.3 Hz,
2H, AreH), 7.50 (d, J¼8.3 Hz, 2H, AreH), 4.95e4.92 (m, 1H, CH),

ꢀ
L. Mesas-Sanchez et al. / Tetrahedron 69 (2013) 753e757
756
3.51e3.42 (m, 2H, CH2), 2.69 (br, 1H, OH). 13C{1H} NMR (101 MHz,
CDCl3) 146.0, 132.7, 126.9, 118.7, 112.3, 72.8, 58.0.
d
8.13e7.69 (m, 4H, AreH), 7.71e7.32 (m, 3H, AreH), 4.87 (dd, J¼8.7,
d
3.7 Hz, 1H, CHOH), 3.05 (dd, J¼12.1, 3.7 Hz, 1H, CH2), 2.96e2.84 (m,
1H, CH(CH3)2), 2.78 (dd, J¼12.1, 8.7 Hz, 1H, CH2), 2.68 (br, 1H, OH),
1.13 (d, J¼2.5 Hz, 3H, CH3), 1.11 (d, J¼2.5 Hz, 3H, CH3). 13C{1H} NMR
4.2.5. (R)-2-Azido-1-(40-methylphenyl)ethanol ((R)-2e).28 Yellow oil
(13.3 mg, 30% yield); ee 80.6%, Kromasil 5-CellCoat, n-hexane/i-
PrOH¼95:5, 0.75 mL/min, 220 nm, tR[(R)/(S)]¼15.4/19.6 min; 1H
(101 MHz, CDCl3)
d 140.6, 133.4, 133.1, 128.2, 127.8, 126.1, 125.8,
124.6, 124.2, 124.1, 72.1, 54.7, 48.84, 23.1, 23.0.
NMR (500 MHz, CDCl3)
d
7.20 (d, J¼8.2 Hz, 2H, AreH), 7.15 (d,
J¼8.2 Hz, 2H, AreH), 4.74 (dd, J¼8.2, 3.9 Hz, 1H, CH), 3.39 (dd,
Acknowledgements
J¼12.7, 8.2 Hz, 1H, CH2), 3.32 (dd, J¼12.7, 3.9 Hz, 1H, CH2), 2.80 (br,
1H, OH), 2.33 (s, 3H, CH3). 13C{1H} NMR (126 MHz, CDCl3)
137.7, 129.3, 125.9, 73.2, 57.9, 21.1.
d
138.1,
ꢂ
P.D. is grateful for financial support from Vetenskapsradet (621-
2009-4018) and The Carl Trygger Foundation (CTS10:71) and P.G. at
AkzoNobel, Eka for support with CellucoatÒ HPLC column and J.S.M.
Samec for HPLC separations.
4.2.6. (R)-2-Azido-1-(40-methoxyphenyl)ethanol ((R)-2f).28 Slightly
yellow oil (16.9 mg, 35% yield); ee 98.6%, Kromasil 5-CellCoat, n-
hexane/i-PrOH¼90:10, 0.5 mL/min, 254 nm, tR[(R)/(S)]¼13.4/
Supplementary data
15.5 min; 1H NMR (400 MHz, CDCl3)
d
7.30 (d, J¼8.7 Hz, 2H, AreH),
6.92 (d, J¼8.7 Hz, 2H, AreH), 4.82 (dd, J¼8.1, 4.0 Hz, 1H, CH), 3.82 (s,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.10.077.
3H, CH3), 3.50e3.38 (m, 2H, CH2), 2.49 (br, 1H, OH). 13C{1H} NMR
(101 MHz, CDCl3)
d 159.7, 132.9, 127.3, 114.2, 73.1, 58.14, 55.4.
References and notes
4.2.7. (R)-4-(2-Azido-1-hydroxyethyl)phenyl benzoate ((R)-2g).
White solid (28.3 mg, 40% yield); mp 92e93 ꢁC; ee 92.7%, Kromasil
5-CellCoat, n-hexane/i-PrOH¼99:1, 0.5 mL/min, 220 nm, tR[(R)/(S)]¼
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22.0/27.3 min; 1H NMR (400 MHz, CDCl3)
d 8.21e7.22 (m, 9H, AreH),
5.42 (m, 1H, CH), 3.53e3.44 (m, 2H, CH2), 2.42 (br, 1H, OH). 13C{1H}
NMR (101 MHz, CDCl3) d 165.3, 150.9, 138.4, 133.8, 130.3, 129.5, 128.7,
127.2, 122.173.1, 58.2. IR(neat):
n
(cmꢀ1)¼3432 (br, OH), 2093 (s, N3),
1721 (s, C]O). HRMS (ESI) calcd for C15H13N3NaOþ3 [MþNaþ]:
ꢀ
ꢀ
4. Lopez-Sendo, J.; Swedberg,K.; McMurray, J.; Tamargo, J.; Maggioni,A. P.;Dargie, H.;
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4.2.8. (R)-2-Azido-1-(20,50-dimethoxyphenyl)ethanol
((R)-2h).28
€
Oto, A.;Smiseth, O. A.;AlonsoGarcía, M. A.;Ardissino, D.; Avendano, C.; Blomstrom
ꢀ
Lundqvist, C.; Clement, D.; Drexler, H.; Ferrari, R.; Fox, K. A.; Julian, D.; Kearney, P.;
White solid (22.3 mg, 40% yield); mp 54e55 ꢁC; ee 99.0%, Kromasil
5-CellCoat, n-hexane/i-PrOH¼95:5, 0.5 mL/min, 220 nm, tR[(R)/
€
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(S)]¼27.2/31.0 min; 1H NMR (400 MHz, CDCl3)
d 7.04e6.73 (m, 3H,
AreH), 5.07 (dd, J¼7.8, 3.8 Hz, 1H, CH), 3.79 (s, 3H, CH3), 3.76 (s, 3H,
CH3), 3.47 (dd, J¼12.5, 3.8 Hz, 1H, CH2), 3.41 (dd, J¼12.5, 7.8 Hz, 1H,
CH2), 2.98 (br, 1H, OH). 13C{1H} NMR (101 MHz, CDCl3)
150.4, 129.7, 113.6, 113.1, 111.5, 69.8, 56.5, 55.8.
d 153.9,
4.2.9. (R)-2-Azido-1-(30-bromophenyl)ethanol ((R)-2i).29 Brown oil
(21.2 mg, 35% yield); ee 98.6%, Kromasil 5-CellCoat, n-hexane/i-
PrOH¼90:10, 0.5 mL/min, 220 nm, tR[(R)/(S)]¼16.5/21.2 min; 1H
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Asymmetry 2004,15, 2615e2620; (g) Kamal, A.; Shaik, A. A.; Sandbhor, M.; Malik,
M. S. Tetrahedron: Asymmetry 2004, 15, 3939e3944; (h) Kamal, A.; Shaik, A. A.;
Sandbhor, M.; Malik, M. S. Tetrahedron: Asymmetry 2004, 15, 935e939; (i) Iaca-
zio, G.; Reglier, M. Tetrahedron: Asymmetry 2005,16, 3633e3639; (j) Molinaro, C.;
Guilbault, A.-A.; Kosjek, B. Org. Lett. 2010, 12, 3772e3775.
NMR (400 MHz, CDCl3)
d 7.53e7.21 (m, 4H, AreH), 4.89e4.68 (m,
1H, CH), 3.50e3.27 (m, 2H, CH2), 2.63 (m, 1H, OH). 13C{1H} NMR
(101 MHz, CDCl3) 143.0, 131.6, 130.5, 129.3, 124.8, 123.1, 72.9, 58.2.
d
4.2.10. (R)-2-Azido-1-(40-bromophenyl)ethanol
((R)-2j).27 Yellow
solid (21.2 mg, 35% yield); mp 60e61 ꢁC (Lit.27 66e67 ꢁC); ee 96.6%,
Kromasil 5-CellCoat, n-hexane/i-PrOH¼90:10, 0.5 mL/min, 220 nm,
tR[(R)/(S)]¼16.1/18.4 min; 1H NMR (400 MHz, CDCl3)
d
7.49 (d,
9. Pamies, O.; Backvall, J.-E. J. Org. Chem. 2001, 66, 4022e4025.
ꢁ
€
10. (a) Wurz, R. P. Chem. Rev. 2007, 107, 5570e5595; (b) Pellissier, H. Adv. Synth.
J¼7.7 Hz, 2H, AreH), 7.23 (d, J¼7.7 Hz, 2H, AreH), 4.81 (m, 1H, CH),
€
Catal. 2011, 353, 1613e1666; (c) Muller, C. E.; Schreiner, P. R. Angew. Chem., Int.
Ed. 2011, 50, 6012e6042.
3.50e3.31 (m, 2H, CH2), 2.72 (br, 1H, OH). 13C NMR (101 MHz,
CDCl3)
d 139.7, 132.0, 127.9, 122.5, 73.0, 58.1.
11. (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc.
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11532e11533; (d) Wurz, R. P.; Lee, E. C.; Ruble, J. C.; Fu, G. C. Adv. Synth. Catal.
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4.3. Synthesis of (R)-pronethalol6a
2-Azido-1-(naphthalen-2-yl)ethanol (213 mg, 1 mmol) was re-
solved following the general procedure described above (Section
4.2). The obtained optically pure alcohol (91.7 mg, 0.43 mmol, >99%
ee, S¼42) was dissolved in EtOH (5.0 mL). Then, platinum dioxide
(49 mg, 0.22 mmol), acetone (50 mL, 0.65 mmol) and molecular
ꢂ
sieves (4 A) were added. The reaction mixture was stirred at room
temperature under H2 atmosphere (5 atm) during 4 h. The desired
(R)-pronethalol was obtained as a white solid (82 mg, 83% yield)
15. (a) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492e1493; (b)
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16. Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794e2795.
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after filtration over Celite. [
a]
20 ꢀ19.4 (c 3.5, EtOH). [Lit.30
[
a]
D ꢀ22
D
(c 1, EtOH)]; mp 58e59 ꢁC (Lit.31 53 ꢁC); 1H NMR (400 MHz, CDCl3)

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L. Mesas-Sanchez et al. / Tetrahedron 69 (2013) 753e757
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21. Background reaction using 2a (0.25 mmol), Ac2O (0.75 equiv) and triethylamine
(0.75 equiv) in tert-amyl alcohol (1 mL) at 0 ꢁC was performed and after 6 h no
conversion was observed.
20. (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119,
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{1H} spectra for these available in Supplementary data.
C
25. The corresponding 1,2-azidoalcohols (0.25 mmol) were routinely acetylated in
dichloromethane at rt in the presence of catalytic amounts of DMAP and
triethylamine, delivered the desired compounds.
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