Asymmetric synthesis of highly substituted β-nitro alcohols and enantiomerically enriched 4,4,5-trisubstituted oxazolidinones

Article abstract of DOI:10.1021/jo026707g

It is demonstrated that α,α-disubstituted-α-nitroketones are reduced to the corresponding trisubstituted nitro alcohols in good to excellent yield and enantiomeric excess by borane-dimethyl sulfide in the presence of a chiral oxazaborolidine catalyst. Red

Full text of DOI:10.1021/jo026707g

In connection with an ongoing project we required a
method for the enantioselective synthesis of 1,1,2-trisub-
stituted-1-nitro-2-alkanols. In principle these might be
obtained directly by stereocontrolled Henry reactions;
however, we noted that all examples to date of the Lewis
acid-catalyzed asymmetric nitroaldol reaction make use
of primary nitroalkanes. Faced with the need to screen
for catalysts capable of promoting the more sterically
hindered, highly reversible condensation of secondary
nitroalkanes with aldehydes, we opted instead to explore
the stereocontrolled reduction of R,R-dialkyl-R-nitro-
ketones. We elected to follow this route as we considered
that tertiary nitroalkyl groups would perform as ideal
large groups in the stereocontrolled oxazaborolidine-
catalyzed reduction16 of ketones. The recent report17 of
the anti-selective reduction of R-nitroketones by borane-
dimethyl sulfide in the presence of TiCl4 provided a
measure of confidence that the tertiary nitro groups
themselves would be inert to the reaction conditions and
would not interfere actively in the reduction.
A series of substrates were readily prepared by clas-
sical condensation of secondary nitroalkanes with alde-
hydes,18 providing the racemic nitroaldols, followed by
Swern oxidation to the nitroketones. These were then
subjected to reduction with the (S)-oxazaborolidine cata-
lyst 2 in the presence of borane-dimethyl sulfide, using
the optimized conditions of Prasad and J oshi,19 resulting
in the formation of highly enantioenriched nitroaldols as
set out in Table 1. With the exception of alcohol 10,
wherein GC analysis over a cyclodextrin column was
employed, the enantiomeric excesses of the products were
determined by formation of the Mosher ester (18-23).
The absolute configurations displayed in Table 1 are
consistent with the use of the (S)-enantiomer of the
catalyst and the operation of the standard Corey model,
assuming no interference by the nitro group and the
tertiary nitro group as the large substituent. That this
is the case is borne out by the first example with the
absolute configuration of the product being confirmed by
comparison of the specific rotation with the literature
value.20 The absolute configuration of a further example
Asym m etr ic Syn th esis of High ly
Su bstitu ted â-Nitr o Alcoh ols a n d
En a n tiom er ica lly En r ich ed
4,4,5-Tr isu bstitu ted Oxa zolid in on es
David Crich,* Krishnakumar Ranganathan,
Sochanchingwung Rumthao, and Michio Shirai
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
Received November 13, 2002
Abstr a ct: It is demonstrated that R,R-disubstituted-R-
nitroketones are reduced to the corresponding trisubstituted
nitro alcohols in good to excellent yield and enantiomeric
excess by borane-dimethyl sulfide in the presence of a chiral
oxazaborolidine catalyst. Reduction of the nitro alcohols to
the corresponding amino alcohols and their subsequent
conversion to enantiomerically enriched 4,4,5-trisubstituted
oxazoldinones is also reported.
The asymmetric synthesis of oxazolidinones is of wide
interest to a broad spectrum of chemists, ranging from
those interested in the development of improved chiral
auxiliaries1-3 to those pursuing the exploitation of the
new oxazolidinone class of antibiotics active against
multi-drug-resistant gram-positive bacteria exemplified
by Linezolid (1).4-6
One entry into such compounds involves the reduction
of diastereomerically enriched vicinal nitro alcohols to
the corresponding amino alcohols followed by cyclization
with phosgene or a surrogate. Accordingly, in the past
few years there has been considerable interest and
progress in asymmetric variants of the Henry reaction.7-15
We report here on an alternative approach to the asym-
metric synthesis of 1,1,2-trisubstituted-1-nitro-2-alkanols
and their conversion, via the amino alcohols, to enantio-
merically enriched 4,4,5-trisubstituted oxazolidinones.
(8) Christensen, C.; J uhl, K.; J orgensen, K. A. Chem. Commun.
2001, 2222. Christensen, C.; J uhl, K.; Hazell, R, G.; J orgensen, K, A.
J . Org. Chem 2002, 67, 4875.
(9) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861.
(10) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002,
4, 2621.
(11) Corey, E. J .; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931.
(12) Misumi, Y.; Matsumoto, K. Angew. Chem., Int. Ed. 2002, 41,
1031.
(13) Sasai, H.; Watanabe, S.; Shibasaki, M. Enantiomer 1997, 2, 267.
(14) Sasai, H.; Tohunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.;
Shibasaki, M. J . Org. Chem. 1995, 60, 7388.
(15) Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetrahedron:
Asymmetry 1994, 5, 1393.
(16) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. Engl. 1998,
37, 1987.
(17) Ballini, R.; Bosica, G.; Marcantoni, E.; Vita, P. J . Org. Chem.
2000, 65, 5854.
(1) Bull, S. D.; Davies, S. G.; Key, M.-S.; Nicholson, R. L.; Savory,
E. D. Chem. Commun. 2000, 1721.
(2) Guz, N. R.; Phillips, A. J . Org. Lett. 2002, 4, 2253.
(3) Sibi, M. P.; J i, J .; Sausker, J . B.; J asperse, C. P. J . Am. Chem.
Soc. 1999, 121, 7517.
(4) Brickner, S. J .; Hutchinson, D. K.; Barbachyn, M. R.; Manninen,
P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.; Hendges, S. K.;
Toops, D. S.; Ford, C. W.; Zurenko, G. E. J . Med. Chem. 1996, 39, 673.
(5) Zurenko, G. E.; Gibson, J . K.; Shinabarger, D. L.; Aristoff, P. A.;
Ford, C. W.; Tarpley, W. G. Curr. Opin. Pharamcol. 2001, 1, 470.
(6) Very recently an N-acryloyl-4-benzyloxazolidinone has also been
described as a nonantibacterial oxazolidinone that, however, possesses
the very interesting property of inhibiting epithelial cell growth.
McHenry, K. T.; Ankala, S. V.; Ghosh, A. K.; Fenteany, G. ChemBio-
Chem 2002, 3, 101.
(18) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001.
(19) Prasad, K. R. K.; J oshi, N. N. Tetrahedron: Asymmetry 1996,
7, 3147.
(7) For a review see: Shibasaki, M.; Groger, H. In Comprehensive
Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, Germany, 1999; Vol. 3; p 1075.
(20) Moriarty, R. M.; Zhuang, H.; Penmasta, R.; Liu, K.; Awasthi,
A. K.; Tuladhar, S. M.; Rao, M. S. C.; Singh, V. K. Tetrahedron Lett.
1993, 34, 8029.
10.1021/jo026707g CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/11/2003
2034
J . Org. Chem. 2003, 68, 2034-2037

TABLE 1. Oxa za bor olid in e Red u ction of Nitr ok eton es
cyclohexane-substituted systems. The final example of
Table 1 reveals that the system is not limited to R-ni-
troketones derived from 2-nitropropane. In this feasibility
study we have only explored the use of the first genera-
tion oxazaborolidine catalyst (2). It is likely, however,
that higher enantioselectivities may be possible with
some of the later additions to the class which incorporate
substituents other than hydrogen on the ring boron.16
Finally, in view of the importance of oxazolidinones in
both asymmetric synthesis and medicinal chemistry we
briefly investigated reduction of the nitro alcohols to the
corresponding amino alcohols followed by phosgenation
to give the heterocycle. Nitro alcohols have been reduced
to amino alcohols under a variety of conditions although
the yields are often very modest.22-28 In our hands
similarly disappointing yields were obtained by most
methods. Eventually, it was found that hydrogenation
with Raney nickel afforded amino alcohols in modest
yield accompanied by considerable retro-Henry product
which, it was reasoned, arose from the basic nature of
the Raney nickel. Accordingly, this problem was circum-
vented by the use of acetic acid as cosolvent with ethanol
for Raney nickel reductions when significantly improved
yields were obtained as reported in Table 2.
a
A: GC analysis over a cyclodextrin column. B: 19F NMR
analysis of Mosher esters.
SCHEME 1. Con fir m a tion of th e Absolu te
Con figu r a tion of Nitr o Alcoh ol 12
In summary, the oxazaborolidine-catalyzed reduction
of R-nitroketones by borane-dimethyl sulfide provides
the corresponding nitro alcohols in good yield and good
to excellent enantiomeric excess. Reduction of the nitro
alcohols by Raney nickel in the presence of acetic acid,
followed by phosgenation affords enantiomerically en-
riched 4,4,5-trisubstituted oxazolidinones, a class of
compound previously restricted to the racemic modifica-
tion.
SCHEME 2. Tr a n sition Sta te Mod el for th e
Red u ction of Nitr ok eton es by Oxa za bor olid in e 2
Exp er im en ta l Section
Gen er a l P r oced u r es. All solvents were dried and distilled
by standard methods. All reactions were carried out under an
argon atmosphere unless otherwise stated. All NMR spectra
were recorded in CDCl3 as solvent unless otherwise stated. Mass
was confirmed by conversion to a substance of established
absolute configuration21 (Scheme 1) and comparison of
specific rotations. These two positive correlations provide
strong support for conformity with the standard Corey
model (Scheme 2).
Inspection of Table 1 reveals that high enantioselec-
tivities are obtained provided that the smaller substitu-
ent on the ketone is a primary alkyl group, i.e., when
the size difference between the two substituents is
maximized. A moderate enantioselectivity was observed
in the case of the 2-furanyl ketone whereas a significant
decrease was observed in the case of the thiophene- and
(22) Zn/HOAc: La Forge, R. G.; Whitehead, C. R.; Keller, B. R.;
Hummel, C. E. J . Org. Chem. 1952, 17, 457.
(23) Pt/H2: J ones, G. D. J . Org. Chem. 1944, 9, 491.
(24) Raney Ni/H2: Hass, H. B.; Hudgin, D. E. J . Am. Chem. Soc.
1954, 76, 2692. Skiles, J . W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger,
K. G.; Mauldin, S. C.; Vitous, J .; Mui, P. W.; J acober, S.; Chow, G.;
Matteo, M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J .; Letts,
G.; Rosenthal, A. S. J . Med. Chem. 1992, 35, 641. Al-Hassan, S. S.;
Cameron, R. J .; Curran, A. W. C.; Lyall, W. J . S.; Nicholson, S. H.;
Robinson, D. R.; Stewart, A. S. C.; Stirling, I.; Wood, H. C. S. J . Chem.
Soc., Perkin Trans. 1 1985, 1645.
(25) PtO2/H2/HOAc: Lichtenthaler, F. W.; Leinert, H.; Scheidegger,
U. Chem. Ber. 1968, 101, 1819.
(26) Zn/HCl: Bobowski, G.; Gottlieb, J . M. J . Heterocycl. Chem.
1982, 19, 21.
(27) Pd/C/H2: Benson, O.; Gaudiano, G.; Haltiwagner, C. R.; Koch,
T. H. J . Org. Chem. 1988, 53, 3036.
(21) Soai, K.; Hayase, T.; Takai, K.; Sugiyama, T. J . Org. Chem.
1994, 59, 7908.
(28) LiAlH4: Colvin, E. W.; Beck, A. K.; Seebach, D. Helv. Chim.
Acta 1981, 64, 2264.
J . Org. Chem, Vol. 68, No. 5, 2003 2035

TABLE 2. F or m a tion of Oxa zolid in on e fr om Nitr o
Alcoh ols
2.44 (q, J ) 7.2 Hz, 2H), 1.64 (s, 6H), 0.98 (t, J ) 7.2 Hz, 3H);
13C NMR δ 202.8, 94.1, 29.6, 23.1, 7.8.
4-Meth yl-4-n itr o-1-p h en yl-3-p en ta n on e (5). Following the
general procedure, (()-12 (1.90 g, 8.5 mmol) afforded 530 (1.56
g, 83%) as a colorless oil. IR (film, cm-1) ν 1728, 1543; 1H NMR
δ 7.28-7.14 (m, 5H), 2.93 (t, J ) 7.2 Hz, 2H), 2.80 (t, J ) 6.5
Hz, 2H), 1.66 (s, 6H); 13C NMR δ 201.2, 128.7, 128.7, 128.4, 128.4,
128.3, 126.5, 38.5, 29.9, 23.1.
1-Cycloh exyl-2-m eth yl-2-n itr o-1-p r op a n on e (6). Follow-
ing the general procedure, (()-13 (1.20 g, 5.97 mmol) afforded 6
1
(0.97 g, 82%) as a colorless oil. IR (film, cm-1) ν 1726, 1546; H
NMR δ 2.58-2.50 (m, 1H), 1.80-1.65 (m, 10H), 1.50-1.43 (m,
3H), 1.25-1.21 (m, 3H); 13C NMR δ 205.3, 94.4, 46.2, 30.6, 29.0,
25.5, 25.5, 25.4, 23.2. ESIHRMS: calcd for C10H17NO3 [M + Na]
222.1114, found 222.1106.
1-(2-F u r a n yl)-2-m eth yl-2-n itr o-1-p r op a n on e (7). Follow-
ing the general procedure, (()-14 (2.50 g, 13.5 mmol) afforded 7
(2.08 g, 84%) as a pale yellow oil. IR (film, cm-1) ν 1681, 1548;
1H NMR δ 7.51 (dd, J ) 0.6, 0.6 Hz, 1H), 7.28 (dd, J ) 0.6, 0.6
Hz, 1H), 6.51 (dd, J ) 3.6, 3.6 Hz, 1H), 1.82 (s, 6H); 13C NMR δ
180.6, 147.2, 120.1, 112.9, 91.7, 24.0. ESIHRMS: calcd for C8H9-
NO4 [M + Na] 206.0433, found 206.0429.
2-Meth yl-2-n itr o-1-(2-th ien yl)-1-p r op a n on e (8) Following
the general procedure, (()-15 (0.124 g, 0.616 mmol) afforded 8
(0.112 g, 91%) in the form of white crystals. Mp 43-44 °C; IR
1
(film, cm-1) ν 1675, 1558; H NMR δ 7.69 (dd, J ) 4.5, 0.9 Hz,
1H), 7.49 (dd, J ) 3.9, 0.9 Hz, 1H), 7.09 (dd, J ) 4.5, 3.9 Hz,
1H), 1.92 (s, 6H); 13C NMR δ 184.9, 139.2, 135.5, 132.1, 128.8,
92.7, 25.3. Anal. Calcd for C8H9NO3S: C, 48.23; H, 4.55.
Found: C, 48.56; H, 4.56.
1-(1-Nitr ocyclop en tyl)-3-p h en yl-1-p r op a n on e (9). Follow-
ing the general procedure, (()-16 (1.75 g, 6.99 mmol) afforded 9
(1.1 g, 64%) as a colorless oil. IR (film, cm-1) ν 2962, 1726, 1540,
1452; 1H NMR δ 7.31-7.14 (m, 5H), 2.94 (t, J ) 7.0 Hz, 2H),
2.81 (t, J ) 7.5 Hz, 2H), 2.54-2.46 (m, 2H), 2.24-2.15 (m, 2H),
1.80-1.69 (m, 4H); 13C NMR δ 200.1, 140.3, 128.7, 128.5, 126.6,
105.1, 39.2, 35.4, 30.0, 25.0. ESIHRMS: calcd for C14H17NO3Na
[M + Na] 270.1106, found 270.1095.
Gen er a l P r oced u r e for th e Oxa za bor olid in e-Ca ta lyzed
Red u ction of Nitr ok eton es. To a solution of (S)-(-)-R,R-
diphenyl-2-pyrrolidinemethanol (5-10 mol %) in THF/toluene
(1/1, 0.3 M in substrate) was added borane-dimethyl sulfide (1.0
M in CH2Cl2, 1.2 equiv). The mixture was warmed to 45 °C with
stirring for 17 h after which a solution of substrate in THF (0.5
M in substrate) was added over a period of 2 h with the use of
a motor-driven syringe pump. The reaction mixture was main-
tained at 45 °C until the starting material was consumed, then
cooled to room temperature and quenched by addition of
methanol (1.5 mL) dropwise until the vigor of the reaction
subsided. The reaction mixture was then diluted with ethyl
acetate and the organic layer washed with 1 M HCl, water,
saturated sodium bicarbonate solution, and brine, dried (Na2-
SO4), and concentrated under reduced pressure to afford the
crude product. Purification by silica gel chromatography (elu-
ent: ethyl acetate/hexanes, 1:5) afforded the corresponding
enantiomerically enriched nitro alcohols.
a
Reduction conducted in the presence of acetic acid.
spectra were recorded by the Research Resources Center at the
University of Illinois at Chicago. Melting points were recorded
on a hotstage microscope and are uncorrected. Microanalyses
were carried out by Midwest Microlabs, Indianapolis, IN.
Gen er a l P r oced u r e for th e Sw er n Oxid a tion of Nitr o-
a ld ols. A 0.4 M solution of oxalyl chloride in CH2Cl2 (2 equiv
wrt substrate) was treated at -78 °C with a 0.6 M solution of
DMSO in CH2Cl2 (4.0 equiv wrt substrate). After the mixture
was stirred for 15 min a 0.2 M solution of nitroaldol in CH2Cl2
was added dropwise, followed by stirring at -78 °C for 1 h.
Triethylamine (5.0 equiv) was then added over 5 min, during
which time the reaction mixture became a colorless solution.
After being stirred for 20 min, the reaction mixture was allowed
to warm to room temperature over 1.5 h. Water was then added,
the resulting mixture washed with 10% sodium acetate and
brine and dried (Na2SO4), and the solvent removed under
reduced pressure. Purification by silica gel chromatography
(eluent: ethyl acetate/hexanes, 7:1) afforded the respective
nitroketones.
(R)-3-Meth yl-3-n itr o-2-bu ta n ol (10). Following the general
procedure with 10 mol % catalyst, 3 (0.30 g, 2.30 mmol) afforded
1020 (0.217 g, 71%, ee 92.1% based on chiral GC analysis over a
2-Meth yl-2-n itr o-3-bu ta n on e (3). Following the general
procedure, except for purification which was achieved by careful
distillation of the solvent under atmospheric pressure followed
by the bulb-to-bulb distillation of the residue, (()-10 (2.52 g,
18.92 mmol) afforded 329 (1.57 g, 63%) as a colorless oil. IR (film,
26
R-cyclodextrin column) as a colorless oil, [R]D -25.3 (c 1.0,
23
CHCl3) [lit.20 [R]D -25.6 (c 0.5-1.0, CHCl3)], whose spectral
characteristics matched those of the racemate (()-10.
(R)-4-Meth yl-4-n itr o-3-p en ta n ol (11). Following the general
procedure with 10 mol % catalyst, 4 (0.4 g, 2.76 mmol) afforded
cm-1) ν 1730, 1548, 1350; H NMR δ 2.18 (s, 3H), 1.70 (s, 6H);
1
13C NMR δ 199.6, 94.2, 24.0, 23.1.
26
2-Meth yl-2-n itr o-3-p en ta n on e (4). Following the general
procedure, except for purification which was achieved by careful
distillation of the solvent under atmospheric pressure followed
by the bulb-to-bulb distillation of the residue under reduced
pressure, (()-11 (4.51 g, 30.6 mmol) afforded 429 (3.2 g, 72%) as
a colorless oil. IR (film, cm-1) ν 1731, 1553, 1346; 1H NMR δ
11 (0.30 g, 74%, 86% ee) as a colorless oil, [R]D +5.24 (c 2.1,
CHCl3), whose spectral characteristics matched those of the
racemate (()-11.
(R)-4-Meth yl-4-n itr o-1-p h en yl-3-p en ta n ol (12). Following
the general procedure with 5 mol % catalyst, 5 (0.10 g, 0.45
25
mmol) afforded 12 (0.083 g, 83%, 94% ee) as a colorless oil, [R]D
+32 (c 1.67 CH2Cl2), whose spectral characteristics matched
those of the racemate (()-12.
(29) Al-Hassan, S. S.; Cameron, R. J .; Curran, A. W. C.; Lyall, W.
J . S.; Nicholson, S. H.; Robinson, D. R.; Stewart, A. S. C.; Stirling, I.;
Wood, H. C. S. J . Chem. Soc., Perkin Trans. 1 1985, 1645.
(30) Ballini, R.; Petrini, M.; Rosini, G. J . Org. Chem. 1990, 55, 5159.
2036 J . Org. Chem., Vol. 68, No. 5, 2003

(R)-4-Meth yl-1-p h en yl-3-p en ta n ol (17). A mixture of 12
(0.091 g, 0.40 mmol), AIBN (33 mg, 0.20 mmol), and Bu3SnH
(0.174 g, 0.60 mmol) in degassed benzene (5 mL) was heated to
reflux at 90 °C for 10 h under an inert atmosphere. The reaction
mixture was then cooled to room temperature and concentrated
under reduced pressure to afford the crude reaction mixture.
Purification by silica gel chromatography (eluent: ethyl acetate/
washed with water and brine and dried (Na2SO4) and the solvent
removed under reduced pressure to afford crude oxazolidinone.
Purification of by silica gel chromatography (eluent: ethyl
acetate/hexanes, 1:3) afforded the pure oxazolidinones.
(R)-5-Eth yl-4,4-d im eth yloxa zolid in -2-on e (24). Following
the general procedure for reduction in the presence of acetic acid,
(R)-11 (0.42 g, 2.82 mmol) afforded (R)-24 (0.2 g, 50%) as a pale
25
26
yellow oil. [R]D +36.4 (c 1.0, CHCl3); IR (film, cm-1) ν 3296,
hexane 1:10) afforded 17 (0.049 g, 69%) as a colorless oil. [R]D
26
+36 (c 3.08, EtOH) [lit.21 [R]D +39 (c 3.08, EtOH)]; IR (film,
2975, 1745; 1H NMR δ 6.04 (br s, 1H), 4.04 (dd, J ) 9.9 Hz, 3.6
Hz, 1H), 1.73-1.63 (m, 1H), 1.62-1.46 (m, 1H), 1.29 (s, 3H),
1.17 (s, 3H), 1.05 (t, J ) 7.3 Hz, 3H); 13C NMR δ 159.4, 87.9,
57.9, 27.5, 22.8, 22.5, 10.9. ESIHRMS: calcd for C7H13NO2Na
[M + Na] 166.0844, found 166.0841.
cm-1) ν 3417; 1H NMR δ 7.25-7.12 (m, 5H), 3.35-3.32 (m, 1H),
2.78-2.73 (m, 1H), 2.61-2.58 (m, 1H), 1.74-1.58 (m, 4H), 0.86
(s, 3H), 0.84 (s, 3H); 13C NMR δ 142.5, 128.6, 128.5, 125.9, 76.2,
36.1, 33.8, 32.6, 18.9, 17.3.
(R)-Cycloh exyl-2-m eth yl-2-n itr o-1-p r op a n ol (13). Follow-
ing the general procedure with 5 mol % catalyst, 6 (1.1 g, 5.5
(R)-4,4-Dim eth yl-5-(2-p h en yleth yl)oxa zolid in -2-on e (25).
Following the general procedure for reduction in the presence
of acetic acid, (R)-12 (77 mg, 0.347 mmol) provided (R)-25 (33
25
mmol) afforded 13 (0.998 g, 92%, 60% ee) as a colorless oil, [R]D
25
+30 (c 0.15, CH2Cl2), whose spectral characteristics matched
those of the racemate (()-13.
mg, 53%) as white solid. [R]D +67 (c 0.15, CH2Cl2); mp 113-
1
116 °C; IR (film, cm-1) ν 3287, 1751; H NMR δ 7.32-7.18 (m,
(S)-(2-F u r a n yl)-2-m eth yl-2-n itr o-1-p r op a n ol (14). Follow-
ing the general procedure, with 5 mol % catalyst, 7 (0.50 g, 2.73
5H), 6.17 (br s, 1H), 4.14 (dd, J ) 2.27, 2.70 Hz, 1H), 2.95-2.89
(m, 1H), 2.73-2.63 (m, 1H), 2.00-1.91 (m, 1H), 1.81-1.73 (m,
1H), 1.28 (s, 3H), 1.19 (s, 3H); 13C NMR δ 159.0, 141.0, 128.7,
128.6, 126.3, 85.2, 57.9, 32.4, 31.4, 27.3, 23.0. Anal. Calcd for
25
mmol) afforded 14 (0.409 g, 81%, 68% ee) as a colorless oil, [R]D
-26 (c 3.85, CH2Cl2), whose spectral characteristics matched
those of the racemate (()-14.
C
13H16NO2: C, 71.21; H, 7.81. Found: C, 71.17; H, 7.83.
(S)-2-Meth yl-2-n itr o-1-(2-th ioen yl)-1-p r op a n ol (15). Fol-
lowing the general procedure with 10 mol % catalyst in THF as
the only solvent 8 (0.092 g, 0.46 mmol) afforded (()-15 (47 mg,
51%, 49% ee) as a white solid, [R]D26 +3.68 (c 2.2, CHCl3), whose
spectral characteristics matched those of the racemate (()-15.
(R)-(1-Nitr ocyclop en tyl)-3-p h en yl-1-p r op a n ol (16). Fol-
lowing the general procedure with 10 mol % catalyst, 9 (0.44 g,
1.78 mmol) afforded 16 (0.34 g, 76%, 94% ee) as a colorless oil,
(R)-5-Cycloh exyl-4,4-d im eth yloxa zolid in -2-on e (26). Fol-
lowing the general procedure for reduction in the absence of
acetic acid, (R)-13 (0.112 g, 0.56 mmol) provided (R)-26 (0.072
25
g, 67%) as a white solid. [R]D +10.33 (c 0.9, CH2Cl2); mp 149-
150 °C; IR (film, cm-1) ν 3233, 1721; 1H NMR δ 6.71 (br s, 1H),
3.84 (d, J ) 9.6 Hz, 1H), 2.10-1.06 (m, 1H), 1.78-1.62 (m, 5H),
1.35 (s, 3H), 1.27 (s, 3H), 1.30-1.01 (m, 5H); 13C NMR δ 159.2,
89.9, 58.1, 37.8, 29.7, 29.2, 28.0, 26.1, 25.4, 25.4, 22.4. Anal. Calcd
for C11H19NO2: C, 66.97; H, 9.71. Found: C, 66.81; H 9.62.
(S)-5-(2-F u r a n yl)-4,4-d im eth yloxa zolid in -2-on e (27). Fol-
lowing the general procedure for reduction in the presence of
acetic acid, (S)-14 (0.89 g, 4.80 mmol) provided (S)-27 (0.180 g,
23
[R]D +34.3 (c 3.1, CHCl3), whose spectral characteristics
matched those of the racemate (()-16.
Gen er a l P r oced u r e for th e Red u ction of Nitr o Alcoh ols
w ith Ra n ey Nick el in Acetic Acid /Eth a n ol w ith Su bse-
qu en t Oxa zolid in on e F or m a tion . To a solution of nitro
alcohol in a 1/1 mixture of ethanol and acetic acid (0.1 M in
substrate) was added Raney nickel (50% slurry in water, 1 g).
The reaction mixture was then shaken in a Parr hydrogenator
under a positive pressure of hydrogen (40-45 psi) overnight.
The reaction mixture was then filtered, the filter cake rinsed
with water, and the filtrate removed under reduced pressure.
The residue was redissolved in water and adjusted to pH 14 with
a saturated solution of NaOH. The aqueous solution was then
extracted with CHCl3 (thrice), the combined organic layers
washed with water and brine and dried (Na2SO4), and the
solvent removed under reduced pressure to afford the crude
amino alcohol, which was used as such for the subsequent
reaction. The crude amino alcohol was dissolved in toluene (0.1
M in substrate) and cooled to 0 °C, and triethylamine (2.2 equiv)
was added followed by phosgene (20% solution in toluene, 1.1
equiv) over a period of 10 min. The reaction mixture was then
stirred for 1.5 h at the same temperature. The contents were
then diluted with ethyl acetate, the organic layer washed
thoroughly with a saturated solution of sodium bicarbonate,
water, and brine and dried (Na2SO4), and the solvent removed
under reduced pressure. Purification by silica gel column (elu-
ent: ethyl acetate/hexanes, 1:3) afforded the corresponding
oxazolidinones.
25
45%) as a white solid. [R]D -24, (c 1.25, CH2Cl2); mp 89-91
1
°C; IR (film, cm-1) ν 3294, 1760; H NMR δ 7.42-7.42 (m, 1H),
6.43-6.37 (m, 2H), 6.21 (br s, 1H), 5.19 (s, 1H), 1.46 (s, 3H),
1.05 (s, 3H); 13C NMR δ 158.3, 148.7, 143.2, 110.5, 109.3, 81.5,
59.21, 28.1, 24.0. ESIHRMS: calcd for C9H11NO3 [M + Na]
204.0635, found 204.0637.
(S)-4,4-Dim eth yl-5-(2-th ioen yl)oxa zolid in -2-on e (28). Fol-
lowing the general procedure for reduction in the presence of
acetic acid, (S)-15 (0.11 g, 0.56 mmol) afforded (S)-28 (0.07 g,
64%) as a white solid. [R]D26 -23.3 (c 0.8, CHCl3); mp 91-94 °C;
IR (film cm-1) ν 3281, 1754; 1H NMR δ 7.33 (dd, J ) 5.1 Hz, 1.2
Hz 1H), 7.07-7.02 (m, 2H), 5.75 (br s, 1H), 5.47 (s, 1H), 1.47 (s,
3H), 1.01 (s, 3H); 13C NMR δ 158.3, 137.3, 127.3, 126.1, 84.6,
59.9, 27.6, 24.4. Anal. Calcd for C9H11NO2S; C, 54.80; H, 5.62.
Found: C, 54.90; H, 5.56.
(R )-1-Aza -3-oxa -4-(2-p h e n yle t h yl)sp ir o[4.4]n on a n -2-
on e (29). Following the general procedure for reduction in the
presence of acetic acid, (R)-16 (0.157 g, 0.62 mmol) afforded (R)-
26
29 (0.135 g, 87%) as white solid. [R]D +71.6 (c 2.7, CHCl3); mp
142-145 °C; IR (film, cm-1) ν 3240, 2960, 1747; 1H NMR δ 7.32-
7.2 (m, 5H), 4.34 (dd, J ) 10.8 Hz, 1.8 Hz, 1H), 3.0-2.92 (m,
1H), 2.74-2.64 (m, 1H), 2.08-1.60 (m, 11H); 13C NMR δ 159.6,
141.1, 128.7, 128.6, 126.3, 83.1, 68.8, 38.7, 33.4, 32.7, 32.3, 23.4,
22.3. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81. Found: C,
73.23; H, 7.82.
Gen er a l P r oced u r e for th e Red u ction of Nitr o Alcoh ols
w ith Ra n ey Nick el in Eth a n ol w ith Su bsequ en t Oxa zoli-
d in on e F or m a tion . To a solution of nitro alcohol in absolute
ethanol was added Raney nickel (50% slurry in water, 1 g)
followed by shaking in a Parr hydrogenator under a positive
pressure of hydrogen (40-45 psi) overnight. The reaction
mixture was filtered, the filter cake rinsed with ethanol, and
the filtrate removed under reduced pressure. The crude amino
alcohol was then dissolved in water (0.1 M) and K2CO3 (1.2
equiv) was added. After the mixture was cooled to 0 °C, phosgene
(20% solution in toluene, 1.1 equiv) was added over a period of
10 min. The reaction mixture was stirred for an additional 2-h
period at the same temperature, then diluted with CH2Cl2. The
organic layer was separated and the aqueous layer extracted
with CH2Cl2 (twice). The combined organic layers were then
Ack n ow led gm en t . We thank the NSF, CHE
9986200, for support of this work.
Su p p or tin g In for m a tion Ava ila ble: General protocols
for the Henry reaction and for the formation of Mosher esters;
characterization data for (()-10-(()-16, and 18-23; and
1
copies of the H and 13C NMR spectra of compounds 7, 9, 13,
24, and 27 and of the 1H, 13C, and 19F NMR spectra of
compounds 18, 19, 20, 21, 22, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026707G
J . Org. Chem, Vol. 68, No. 5, 2003 2037