Practical modifications and applications of the sharpless asymmetric aminohydroxylation in the one-pot preparation of chiral oxazolidin-2-ones

Article abstract of DOI:10.1021/ol006255z

Chiral oxazolidin-2-ones are synthetically valuable as chiral auxiliaries, and many have pharmaceutically interesting biological activity. This communication focuses on a convenient, practical one-pot preparation of chiral 4,5-disubstituted oxazolidan-2-o

Full text of DOI:10.1021/ol006255z

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2821-2824
Practical Modifications and Applications
of the Sharpless Asymmetric
Aminohydroxylation in the One-Pot
Preparation of Chiral Oxazolidin-2-ones
,†
Nancy S. Barta,* Daniel R. Sidler, Kara B. Somerville, Steven A. Weissman,
Robert D. Larsen, and Paul J. Reider
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
nancy.barta@pfizer.com
Received June 26, 2000
ABSTRACT
Chiral oxazolidin-2-ones are synthetically valuable as chiral auxiliaries, and many have pharmaceutically interesting biological activity. This
communication focuses on a convenient, practical one-pot preparation of chiral 4,5-disubstituted oxazolidan-2-ones in good yield with high
enantioselectivities, using a modified Sharpless asymmetric aminohydroxylation of â-substituted styrene derivatives followed by base-mediated
ring closure. This procedure has been demonstrated on both small and large scale, utilizing 1,3-dichloro-5,5-dimethyl hydantoin as an easily
handled, commercially available substitute for tert-butyl hypochlorite.
Since its introduction as a chiral auxiliary in 1981, the
oxazolidin-2-one moiety has emerged as a useful tool in
asymmetric synthesis.1 The oxazolidinone is also a common
heterocyclic motif in a variety of biologically active and
pharmaceutically interesting molecules.2 A survey of the
literature reveals a variety of both natural3 and unnatural4
starting points for the preparation of oxazolidinones including
the reaction of diols with isocyanates, epoxide openings,
amino acids, aziridines, oxetanes, 2-oxazolones, hydroxy
acids or esters, and perhaps the most common, amino
alcohols.5 The chiral oxazolidin-2-ones employed in the
chemistry of Evans are typically prepared from the amino
alcohol reduction products of naturally occurring R-amino
acids.6 Recently, Takacs has reported the preparation of
4-substituted oxazolidin-2-ones.7 In this procedure, a chiral
N-acyloxazolidinone titanium enolate is condensed with
formaldehyde or acetone followed by hydrolysis to the
â-hydroxy acid. Curtius rearrangement then allows access
to a variety of chiral oxazolidin-2-ones not available from
natural R-amino acids.
During the development of a novel drug candidate
containing the oxazolidin-2-one moiety, we required access
to asymmetric 4-aryl-5-alkyl oxazolidin-2-ones. After ex-
(3) (a) Zhao, H.; Thurkauf, A. Synlett 1999, 1280. (b) Feroci, M.; Inesi,
A.; Mucciante, V.; Rossi, L. Tetrahedron Lett. 1999, 40, 6059. (c) Kno¨lker,
H.-J.; Braxmeier, T. Tetrahedron Lett. 1998, 39, 9407. (d) Sudharshan, M.;
Hultin, P. G. Synlett 1997, 2, 171. (e) Imada, Y.; Mitsue, Y.; Ike, K.;
Washizuka, K. I.; Murahashi, S. I. Bull. Chem. Soc. Jpn. 1996, 69, 2079.
(f) Iwama, S.; Katsumura, S. Bull. Chem. Soc. Jpn. 1994, 67, 3363. (g)
Nicolas, E.; Russel, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766. (h)
Kubota, Y.; Kodaka, M.; Tomohiro, T.; Okuno, H. J. Chem. Soc., Perkin
Trans. 1 1993, 5. (i) Yan, T. H.; Chu, V. V.; Lin, T. C.; Wu, C. H.; Liu,
L. H. Tetrahedron Lett. 1991, 32, 4959. (j) Cage, J. R.; Evans, D. A. Org.
Synth. 1990, 68, 77. (k) Sakaitani, M.; Ohfune, Y. J. Am. Chem. Soc. 1990,
112, 1150. (l) Wuts, P. G. M.; Pruitt, L. E. Synthesis 1989, 622.
† Current address: Department of Chemistry, Pfizer Global Research
and Development Ann Arbor Laboratories, 2800 Plymouth Road, Ann
Arbor, MI 48105.
(1) (a) Evans, D. A. Aldrichimia Acta 1982, 15, 23-32. (b) Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichimia Acta 1997, 30, 3-12.
(2) (a) Brickner, S. J. Curr. Pharmaceut. Des. 1996, 2, 175-94. (b)
Genin, M. J.; Hutchinson, D. K.; Allwine, D. A.; Hester, J. B.; Emmert, D.
E.; Garmon, S. A.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R.
D.; Stapert, D.; Yagi, B. H.; Friis, J. M.; Shobe, E. M.; Adams, W. J. J.
Med. Chem. 1998, 41, 5144-7.
10.1021/ol006255z CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/12/2000

amination of the known asymmetric oxazolidinone prepara-
tion methods, we envisioned an additional approach using
the Sharpless asymmetric aminohydroxylation8 of a styrene
derivative followed by base-mediated selective ring closure
of the carbamate to afford oxazolidinones in a single step
(Scheme 1). During the development of this procedure, Li
potassium carbonate mediated ring closure.9 Herein, we wish
to report preliminary examples of a practical, one-pot
conversion of disubstituted styrene derivatives to chiral
oxazolidin-2-ones using a modified Sharpless carbamate-
based asymmetric aminohydroxylation that has been dem-
onstrated on both small (mg) and large (kg) scale.10
Of the many aminohydroxylation procedures reported by
Sharpless, only those utilizing a carbamate as the nitrogen
source were suitable for use in the direct conversion to
oxazolidinones (Scheme 2).8e,f,h,k According to Sharpless, the
Scheme 1
Scheme 2
reported a two-step process for the conversion of unsubsti-
tuted styrene derivatives to chiral oxazolidin-2-ones using a
(4) (a) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64, 2852.
(b) Ten Holte, P.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1998, 39,
7407. (c) Le Gendre, P.; Thominot, P.; Bruneau, C.; Dixneuf, P. H. J. Org.
Chem. 1998, 63, 1806. (d) Bach, T.; Schro¨der, J. Tetrahedron Lett. 1997,
38, 3707-10. (e) Lu¨tzen, A.; Ko¨ll, P. Tetrahedron: Asymmetry 1997, 8,
1193-206. (f) Clayden, J.; Nelson, A.; Warren, S. Tetrahedron Lett. 1997,
38, 3471-4. (g) Delft, F. L. v.; Timmers, C. M.; Marel, G. A. V. D.; Boom,
J. H. v. Synthesis 1997, 450-4. (h) Larksarp, C.; Alper, H. J. Am. Chem.
Soc. 1997, 119, 3709-15. (I) Rao, B. V.; Krishna, U. M.; Gurjar, M. K.
Synth. Commun. 1997, 27, 1335. (j) Matsunaga, H.; Ishizuka, T.; Kunieda,
T. Tetrahedron 1997, 53, 1275-94. (k) Ru¨ck-Braun, K.; Stamm, A.; Engel,
S.; Ku¨nz, H. J. Org. Chem. 1997, 62, 967-75. (l) Bergmeier, S. C.; Stanchia,
D. M. J. Org. Chem. 1997, 62, 4449-56. (m) Ghosh, A. K.; Cho, H.; Onishi,
M. Tetrahedron: Asymmetry 1997, 8, 821. (n) Banks, M. R.; Blake, A. J.;
Cadogan, J. I. G.; Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Thorburn,
P. Tetrahedron 1996, 52, 4079-94. (o) Ambroise, L.; Jackson, R. F. W.
Tetrahedron Lett. 1996, 37, 2311. (p) Cardillo, G.; Gentilucci, L.; Tomasini,
C.; Tomasoni, L. Tetrahedron: Asymmetry 1995, 6, 1947-55. (q) Jung,
M. E.; Jung, Y. H. Synlett 1995, 563. (r) Blas, J. D.; Carretero, J. C.;
Dominguz, E. Tetrahedron Lett. 1994, 35, 4603. (s) Xu, D.; Sharpless, K.
B. Tetrahedron Lett. 1993, 34, 951. (t) Banks, M. R.; Blake, A. J.; Cadogan,
J. I. G.; Dawson, I. M.; Gaur, S.; Gosney, I.; Gould, R. O.; Grant, K. J.;
Hodgson, P. K. G. J. Chem. Soc., Chem. Commun. 1993, 1146. (u) Trost,
B. M.; Van Vraiken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327.
(v) Ghosh, A. K.; Duong, T. T.; McKee, S. P. Chem. Commun. 1992, 1673-
4. (w) Katsumura, S.; Kondo, A.; Han, Q. Chem. Lett. 1991, 1245. (x)
Sato, T.; Mizutani, T.; Okumura, Y.; Fujisawa, F. Tetrahedron Lett. 1989,
30, 3701.
chemo-, regio-, and enantioselectivity of the aminohydroxyl-
ation reaction can be readily controlled by small variations
in the reaction parameters. In addition, these previous reports
support a suprafacial addition of nitrogen and oxygen to the
olefin, wherein asymmetric aminohydroxylation of trans-
olefins would afford trans-oxazolidinones.8e The most favor-
able conditions for carbamate-based aminohydroxylation of
styrenes resulting in benzylic amination are given as urethane
with PHAL ligands in n-PrOH/water solvent systems using
tert-butyl hypochlorite as the co-oxidant, so this was our
starting point.
The requirement for 3 equiv of freshly prepared tert-butyl
hypochlorite was untenable for large scale development of
an aminohydroxylation-based process. Therefore, alternative
co-oxidants/chlorine sources were examined for utility in the
asymmetric aminohydroxylation reaction. Despite the fact
that NCS, cyanuric chloride, and trichloroisocyanuric acid
were unsuccessful substitutes for tert-butyl hypochlorite,
either 1,3-dichloro-5,5-dimethyl hydantoin or dichloroiso-
(5) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
75.
(6) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(7) Takacs, J. M.; Jaber, M. R.; Vellekoop, A. S. J. Org. Chem. 1998,
63, 2742-8.
(9) (a) Li, G.; Lenington, R.; Willis, S.; Kim, S. H. J. Chem. Soc., Perkin
Trans. 1 1998, (11), 1753-4. (b) The work described herein was initiated
in mid-1997.
(10) (a) Typical Experimental Procedure. 4(S)-(3,4-Difluorophenyl)-
5(S)-methyloxazolidin-2-one. Sodium hydroxide (1.57 g, 39.3 mmol) was
dissolved in 50 mL of H2O. A 1-mL aliquot of the NaOH solution was
used to dissolve K2OsO2(OH)4 (0.048 g, 0.13 mmol) in a separate vial.
1-Propanol (25 mL) and ethyl carbamate (3.56 g, 40.0 mmol) were added
to the reaction flask at 20 °C, followed by 1,3-dichloro-5,5-dimethylhy-
dantoin (3.89 g, 19.7 mmol); the solids dissolved in approximately 5 min.
A solution of (DHQ)2PHAL (0.125 g) and trans-1-(3,4-difluorophenyl)-1-
propene (2.0 g, 12.97 mmol) in 25 mL of 1-propanol was added, followed
by addition of the potassium osmate solution. The reaction was monitored
for the disappearance of olefin using HPLC. A mixture of the hydroxy
carbamates was obtained in a 4:1 ratio, as determined by NMR or by HPLC.
Sodium hydroxide (2 g) was added to the flask at 20 °C. After 30 min, the
reaction mixture was diluted with H2O (50 mL) and extracted with 2 × 50
mL of EtOAc. The organic layers were combined and concentrated, and
the oxazolidinone products were purified by column chromatography. The
product was isolated as a pale yellow oil and was determined to have 90%
ee by SFC: 1H NMR (CDCl3) δ 7.19 (m, 2H), 7.08 (m, 1H), 5.58 (s, 1H),
4.41 (m, 2H), 1.51 (d, J ) 5.9 Hz, 3H). (b) Satisfactory analytical data
(IR, H NMR, C NMR, and elemental analysis) was obtained for all new
products.
(8) (a) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1,
783-6. (b) Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5151-
4. (c) Goossen, L. J.; Liu, H.; Dress, R.; Sharpless, K. B. Angew. Chem.
Int. Ed. 1999, 38, 1080-3. (d) Dress, K. R.; Goossen, L. J.; Liu, H.; Jerina,
D. M.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 7669-72. (e) Kolb,
H. C.; Sharpless, K. B. In Transition Metals for Organic Synthesis; Beller,
M., Bolm, C., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 1998;
Vol. 2, pp 243-60. (f) Reddy, K. L.; Dress, K. R.; Sharpless, K. B.
Tetrahedron Lett. 1998, 39, 3667-70. (g) Tao, B.; Schlingloff, G.; Sharpless,
K. B. Tetrahedron Lett. 1998, 39, 2507-10. (h) Reddy, K. L.; Sharpless,
K. B. J. Am. Chem. Soc. 1998, 120, 1207-17. (i) Rubin, A. E.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2637-40. (j) Bruncko, M.;
Schlingloff, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36,
1483-6. (k) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2813-7. (l) Rudolph, J.; Sennhenn, P. C.; Vlaar, C. P.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2810-3. (m) Li,
G.; Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649-51. (n) Li, G.;
Chang, H.-T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
451-4. (o) O’Brien, P.; Osborne, S. A.; Parker, D. D. Tetrahedron Lett.
1998, 39, 4099-102.
2822
Org. Lett., Vol. 2, No. 18, 2000

cyanuric acid sodium salt proved to be convenient, inex-
pensive, readily available alternatives that could be employed
without decreasing regio- or enantioselectivity or reaction
yield. This discovery is of particular utility because both of
these reagents are stable, commercially available solids,
obviating the need for large volumes of freshly prepared tert-
butyl hypochlorite. Interestingly, both chlorines on either 1,3-
dichloro-5,5-dimethyl hydantoin or dichloroisocyanuric acid
sodium salt are available for reaction, maximizing efficiency.
Using our optimized aminohydroxylation conditions [NaOH
(3.05 equiv), urethane (3.08 equiv), 1,3-dichloro-5,5-dimethyl
hydantoin (1.53 equiv), (DHQD)2- or (DHQ)2PHAL ligand
(0.025 equiv), and potassium osmate (0.02 equiv) in n-PrOH/
water (1:1)] several â-substituted styrene derivatives (1.0
equiv) were subjected to aminohydroxylation. Upon comple-
tion of the aminohydroxylation reaction, the acyclic car-
bamate could be isolated by standard techniques. These
products could be converted to the corresponding amino
alcohol if desired. Alternatively, a second charge of base
(NaOH, NaOMe, K2CO3, Cs2CO3, or Na2CO3 all afforded
comparable results) added directly to the reaction mixture
converted the acyclic carbamates to the oxazolidin-2-ones
in most cases. While this afforded a rapid, highly selective
route to substituted oxazolidinones, chromatographic separa-
tion of the regioisomers was required.
carbamate and (DHQ)2PHAL, which range from 1:1 to 10:
1. Isolated yields of the oxazolidinones ranged from poor
(28%, trans stilbene) to good (81%, p-methoxy â-methyl
styrene). Using the DHQ ligand series, the enantiomeric
excess of the resultant oxazolidinones was very good for the
benzylamine regioisomer (8) and low to moderate for the
benzyl alcohol isomer (9) without recrystallization. Interest-
ingly, aminohydroxylation of ethyl p-nitrocinnamate using
these modified conditions gave good yields and high regio-
and enantioselectivity, but the acyclic intermediates could
not be forced to cyclize even with excess base and prolonged
heating. Identical to the results with 1,3-dichloro-5,5-
dimethyl hydantoin (Table 1), the use of dichloroisocyanuric
acid sodium salt in the aminohydroxylation of trans-â-methyl
styrene afforded a 3:1 ratio of 8:9 in 65% yield. The
Sharpless AQN ligand series also works with the 1,3-
dichloro-5,5-dimethyl hydantoin or dichloroisocyanuric acid
oxidants, but the regio- and enantioselectivities are low to
moderate for 9 as the major product.
During the course of these studies, the separations of
regioisomers 8 and 9 were accomplished via column chro-
matography. During optimization of the reaction conditions,
closer examination of the acyclic carbamate reaction mixtures
immediately following aminohydroxylation showed that in
the presence of base the desired benzylic amine derivative
cyclized much more rapidly than the benzylic alcohol
derivative. This difference in cyclization rate for the regio-
isomers allowed for differentiation through careful base
selection, charge, and timing of an acidic reaction quench
(Scheme 3).
As expected, the regioselectivity of the aminohydroxyl-
ation reaction varied with the reaction conditions (Table 1).
The regioselectivities obtained using the modified conditions
are consistent with the results reported by Sharpless for the
aminohydroxylation of styrene derivatives using benzyl
Table 1. Aminohydroxylation with
Scheme 3
1,3-Dichloro-5,5-dimethylhydantoin as the Co-oxidant
Ar
R
liganda
yieldb
8:9
% ee 8, 9c
Ph
Me
Me
Me
Ph
Ph
CO2Et
CO2Et
B
A
B
A
B
A
B
65
81
42
28
72
76
73
2:1
5:1
4:1
88.1e, 73.4f
98.0g, 70.5h
98.0i, 99.4
87.4j
4-OMe-Ph
4-OMe-Ph
Ph
Ph
4-NO2-Ph
4-NO2-Ph
80.7k
4:1d
8:1d
90.0, 30.7d
90.6, 19.7d
The addition of sulfuric acid transformed the uncyclized
benzylic alcohol isomer 12 to the corresponding amino
alcohol, leaving the desired oxazolidinone 13 untouched. A
simple extraction sequence could then be used to separate
13 from the amino alcohol. Typically, the aminohydroxyl-
ation reactions were monitored for consumption of styrene,
a Ligand A ) (DHQ)2PHAL, major isomer is 4(S),5(S)-8, B )
(DHQD)2PHAL, major isomer is 4(R),5(R)-8. b Combined yield of 8 + 9.
c Enantioselectivity of the crude product as determined by SFC. d Open chain
products only (6 and 7). e [R]25D ) 25.3°. f [R]25D ) -7.4°. g [R]25D ) 1.1°.
h [R]25 ) -20.7°. i [R]25 ) -1.0°. j [R]25 ) -90.6°. k [R]25 ) 93.7°.
D
D
D
D
Org. Lett., Vol. 2, No. 18, 2000
2823

then 1 equiv of additional base was added, and the reaction
was monitored for cyclization of the benzylic carbamate. This
procedure was used to convert â-methyl styrene 10 to
oxazolidinone 13 in 71% yield and 90-93% ee. The present
method for the one-step preparation of chiral oxazolidin-2-
ones from â-substituted styrenes demonstrates that the
Sharpless asymmetric aminohydroxylation can be success-
fully employed in a practical and economical procedure using
1,3-dichloro-5,5-dimethyl hydantoin or dichloroisocyanuric
acid sodium salt in good yield and high regio- and enantio-
selectivity.
Acknowledgment. The authors thank Mr. Jason Kowal
for preparation of styrene 10 and Mr. Robert A. Reamer and
Ms. Lisa M. DiMichele for assistance with structure deter-
mination. The authors also thank Professors K. Barry
Sharpless and Eric Jacobsen for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL006255Z
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Org. Lett., Vol. 2, No. 18, 2000