Stereoselective synthesis of styrene oxides via a Mitsunobu cyclodehydration.

Article abstract of DOI:10.1021/ol016167u

[reaction: see text] The Mitsunobu cyclodehydration of chiral phenethane-1,2-diols (4), readily accessed from the styrene derivative (5), has been demonstrated to provide the corresponding styrene oxides (2) with high levels of stereoretention (up to 99%). Optimized reaction conditions are described, from which the combination of tricyclohexylphosphine (Chx(3)P) and diisopropylazodicarboxylate (DIAD) in THF and R = EWG provides the best results.

Full text of DOI:10.1021/ol016167u

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2513-2515
Stereoselective Synthesis of Styrene
Oxides via a Mitsunobu
Cyclodehydration
Steven A. Weissman,* Kai Rossen, and Paul J. Reider
Department of Process Research, Merck & Co., Inc, Rahway, New Jersey 07065
steVen•weissman@merck.com
Received May 24, 2001
ABSTRACT
The Mitsunobu cyclodehydration of chiral phenethane-1,2-diols (4), readily accessed from the styrene derivative (5), has been demonstrated
to provide the corresponding styrene oxides (2) with high levels of stereoretention (up to 99%). Optimized reaction conditions are described,
from which the combination of tricyclohexylphosphine (Chx3P) and diisopropylazodicarboxylate (DIAD) in THF and R ) EWG provides the
best results.
The utility of enantiomerically enriched styrene oxide
derivatives as chiral buildings blocks for the synthesis of
natural products and biologically active compounds is well-
documented.1 Accordingly, tremendous efforts have been
aimed at developing catalytic, stereoselective epoxidation
methodologies.2 However, terminal olefins, such as styrene,
still remain a challenge for this powerful methodology. The
hydrolytic kinetic resolution of styrene oxides with (salen)-
cocatalyst3 and epoxide hydrolases4 have also been developed
for this purpose. Indirect routes to these epoxides are based
mainly on asymmetric dihydroxylation (AD) chemistry,5
which provides ready access to a range of chiral arenethane-
1,2-diols, which upon stereospecific cyclodehydration give
the chiral epoxides. Examples include dehydration via the
Sharpless acetoxonium ion,6 base-induced dehydration of the
corresponding cyclic sulfate,7 and selective hydroxyl activa-
tion followed by base-mediated ring closure.8
The Mitsunobu reaction,9 traditionally a proven regio-
selective cyclodehydration methodology, had yet to be
successfully applied to the synthesis of optically active
styrene oxides. Evans demonstrated that the triphenyl-
phosphine/diethylazodicarboxylate (DEAD) combination upon
reaction with (S)-phenethane-1,2-diol gave essentially race-
mic styrene oxide.10 It was postulated that the two regio-
isomeric oxyphosphonium betaine intermediates (A and B)
(1) For recent examples, see: (a) Hattori, K.; Nagano, M.; Kato, T.;
Nakanishi, I.; Imai, K.; Kinoshita, T.; Sakane, K. Bioorg. Med. Chem. Lett.
1995, 5, 2821. (b) Di Fabio, R.; Pietra, C.; Thomas, R. J.; Ziviani, L. Bioorg.
Med. Chem. 1995, 551. (c) Sher, P. M.; Mathur, A.; Fisher, L. G.; Wu, G.;
Skwish, S.; Michel, I. M.; Seiler, S. M.; Dickinson, K. E. J. Bioorg. Med.
Chem. 1997, 7, 1583.
(2) (a) Collman, J. P.; Wang, Z.; Straumanis, A.; Quelquejeu, M.; Rose,
E. J. Am. Chem. Soc. 1999, 121, 460. (b) Palucki, M.; Popisil, P. J.; Zhang,
W.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 9333. (c) For a review,
see: Jacobsen, E. N.; Wu, M. H. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
1999; Vol. II, Chapter 18.2. (d) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett.
2001, 3, 1929.
(3) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936. (b) Brandes, B. D.; Jacobsen, E. N. Tetrahedron:
Asymmetry 1997, 8, 3927.
(5) For a review, see: Kolb, H. C.; Sharpless, K. B. Transition Met.
Org. Synth. 1998, 2, 219.
(6) Kolb, H.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(7) Jang, D. O.; Joo, Y. H.; Cho, D. H. Synth. Commun. 2000, 4489.
(8) For review, see: Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K.
B. Chem. ReV. 1994, 94, 2483. (b) Adiyaman, M.; Khanapure, S. P.; Hwang,
S. W.; Rokack, J. Tetrahedron Lett. 1995, 7367. (c) O’Donnell, C. J.; Burke,
S. D. J. Org. Chem. 1998, 63, 8614.
(9) For a review, see: Hughes, D. L. Org. React. 1992, 42, 335.
(10) Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.; Evans, S.
A., Jr. J. Org. Chem. 1983, 48, 5396.
(4) For example, see: Pedragosa-Moreau, S.; Morriseau, C.; Zylber, J.;
Archelas, A.; Baratti, J.; Furstoss, R. J. Org. Chem. 1996, 61, 7402.
10.1021/ol016167u CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/13/2001

collapse at the same rate to give retention and inversion of
configuration, respectively, thus yielding racemic oxide
(Figure 1).
Thus, a modified Sharpless asymmetric dihydroxylation13
of 3,5-bis(trifluoromethyl)styrene 5a with (DHQ)2-PHAL
ligand provided (S)-diol 4a14 in 80% yield (92% ee). The
material was upgraded to 97-99% ee via a single recrys-
tallization from EtOAc/hexanes. Gratifyingly, the Mitsunobu
cyclodehydration of 4a with TBP/DIAD in THF provided
epoxide 2a of 96% ee (92% yield) with retention of
configuration (Scheme 2).15 This result prompted a systematic
Scheme 2a
a Reagents and conditions: (a) K2OsO2(OH)4 (1 mol %),
(DHQ)2-PHAL (1 mol %), NMO, aq t-BuOH, 6 h/20 °C (ref 14);
(b) Chx3P, DIAD, THF, 3 h/0-25 °C.
Figure 1.
During the course of our work on the synthesis of
Substance P Inhibitor/NK1 antagonist 1,11 we required (R)-
3,5-bis(trifluoromethyl)styrene oxide 2a en route to amino-
diol derivative 3 (Scheme 1) and sought to employ the
study of the dehydration reaction parameters using com-
mercially available (S)-(+)-1-phenyl-1,2-ethane-diol as the
substrate under standardized conditions.16
Initially, a series of solvents were screened in the standard
reaction, from which THF emerged as the solvent of choice
(Table 1).17
Scheme 1
Table 1. Effect of Solvent on Formation of (S)-Styrene Oxidea
solvent
% eeb
solvent
% eeb
THF
ethyl ether
MTBE
82c, 75d
81c
toluene
MeCN
CHCl3
68d
65d
58c
78c
DMF
70d
a Reactions were run according to ref 16. b Determined by GC (Chiraldex
γ-cyclodextrin trifluoroacetyl column); absolute configuration based on
comparison with authentic sample (Aldrich). c Chx3P employed; d TBP
employed.
cyclodehydration of the corresponding diol 4a via the
Mitsunobu reaction. The stereocenter in 2a subsequently
controls the remaining stereocenters in 1, and thus it was
crucial to induce a high level of asymmetry.
Although the utility of tributylphosphine (TBP) in the
Mitsunobu reaction is well documented,12 this more basic
reagent (relative to the more commonly employed tri-
phenylphosphine) had not been studied in connection with
the dehydration of phenethane-1,2-diols. Herein, we describe
the successful use of the Mitsunobu reaction for the stereo-
selective synthesis of styrene oxide derivatives.
Next, a series of commercially available phosphines were
screened using THF as the solvent. A dramatic effect was
observed, with tricyclopentyl (Cp) and tricyclohexyl (Chx)
phosphine emerging as the preferred phosphines (Table 2).
(13) Ahrgren, L.; Sutin, L. Org. Process Res. DeV. 1997, 1, 425.
(14) Owen, S. N.; Seward, E. M.; Swain, C. J.; Williams, B. J. WO
0056727, 2000.
(15) This stereospecific outcome is consistent with the Mitsunobu
cyclodehydration of propane-1,2-diol, which also gave 82-85% retention
of configuration. See ref 10. Retention should also be favored here on the
basis of steric considerations as the least hindered alcohol of vicinal diols
is typically activated.
(11) (a) Pye, P. J.; Rossen, K.; Weissman, S. A.; Maliakal, A.; Reamer,
R. A.; Ball, R.; Tsou, N.; Volante, R. P.; Reider, P. J. Chem. Eur. J.,
accepted for publication. (b) Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke,
P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.;
Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M.
J.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. J. Med.
Chem. 1998, 41, 4607.
(12) Diver, S. T. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley & Sons: Chichester, U.K., 1995; Vol. 7, p
5014.
(16) Standard Conditions. The phosphine (1.5 equiv) was combined
with the solvent (1.3 M) at 5 °C, followed by dropwise addition of the
DIAD (1.45 equiv) and warming to 15 °C. After aging for 15 min, the
solution was cooled to 5-10 °C and the diol was added (1 M in the solvent),
followed by warming to room temperature. Reactions were typically
complete within 2 h at 25-40 °C.
(17) Ethyl acetate showed low conversion in the standard reaction.
2514
Org. Lett., Vol. 3, No. 16, 2001

only satisfactory for mildly electron-donating groups (entry
f), and poor for electron-donating groups (entry h).
A Hammett plot of log((100 + ee)/(100 - ee))19 versus
Σσ of the substituents reveals a clear trend (Figure 2). The
Table 2. Effect of Phosphine on Steroretention of Styrene
Oxidea
phosphine
% eeb
phosphine
% eeb
Cp3P
84
82
80
75
60
47
(Chx)Ph2P
Ph3P
t-Bu3P
(Bn)3P
o-tolyl3P
25
-10c
nrd
nr
Chx3P
i-Bu3P
n-Bu3P
i-Pr3P
n-Pr3P
nr
a Reactions run according to ref 16. b Determined by GC (Chiraldex
γ-cyclodextrin TFA column). c Gave inversion of configuration. d nr ) no
reaction.
In general, the branched trialkylphosphines performed better
than the straight chain analogues, and the aryl-based phos-
phines gave only marginal results. The result giving 84% ee
styrene oxide compares favorably to those obtained using
the catalytic asymmetric epoxidation routes (83-86% ee).2
A brief screening of azodicarboxylates showed that the
diisopropyl derivative (DIAD) gave better results than the
tert-butyl analogue. The piperidinyl derivative gave no
reaction under the standard conditions.
Thus, the optimized combination of Chx3P/DIAD in THF
was selected for the subsequent studies to expand the scope
of this methodology to a series of substituted terminal styrene
derivatives (Table 3). The reactions were performed under
Figure 2. Hammett plot of optical yield vs Σσ of phenyl
substituents.
positive slope could be attributed to the expected stabilizing
effect of electron-withdrawing groups on the incipient oxygen
anion at the benzylic position in the betaine intermediate (A
from Figure 1), which gives rise to the epoxide with retention
of configuration.
In conclusion, the Mitsunobu cyclodehydration of chiral
phenethane-1,2-diols has been demonstrated to provide the
corresponding epoxide with high levels of stereoretention
in substrates lacking electron-donating groups on the arene
ring. The facile access to both enantiomers of a wide range
of arenethane-1,2-diols via the Sharpless AD reaction makes
this an attractive route to this important class of molecules.
Table 3. Synthesis of Styrene Oxides (2) from Styrenes (5) via
Phenethane Diols (4)
% ee
diol 4a,b
%
% ee
epoxide 2b
optical
yieldd
entry
R
yield 2c
a
b
c
d
e
f
3,5-CF3
H
3-Cl
4-Cl
4-F
4-Me
4-CF3
4-MeO
97 (S)
99 (S)
97.5 (S)
93 (S)
95 (S)
92 (S)
98.4 (S)
97.5 (R)
92
80
65
75
90
92
87
74
96.4 (S)
81 (S)
94 (S)
87.4 (S)
84 (S)
55 (S)
96 (S)
6 (R)
99.7
91
98
97
94.4
81
g
h
98.8
54
Acknowledgment. The authors wish to thank Drs. Chris
Welch and Dave Mathre for assistance in developing chiral
assays and Dr. Phil Pye for providing selected characteriza-
tion data for diol 4a and epoxide 2a.
a Diols 4a and c-g were prepared using either AD-mix-R or the (DHQ)2-
PHAL/K2OsO2(OH)4/NMO combination; diol 4h was prepared using AD-
mix-â. Diol 4b was purchased from Aldrich. b Percent ee measured by either
GC (Chiraldex γ-cyclodextrin trifluoroacetyl column, entries 2a-d, 4a; 4e,
4g assayed as the acetonides), HP chiral (20% permethylated â-cyclodextrin,
entries 2e-g), or SFC (Chiralpak AD column, entry 2h; OD column, entries
4d, 4f, 4h; AD column, entry 4c). Absolute configurations were determined
by comparison to an authentic sample (entries 2a-b) or by measurement
of optical rotation in chloroform and comparison to literature values (entries
2c-f, h) or were inferred on the basis of analogous behavior with other
entries (entry 2g). c HPLC assay yield measured versus authentic material.
d Defined as % major enantiomer in 2/% same enantiomer in 4.
Supporting Information Available: Representative ex-
perimental descriptions for diol 4a and epoxide 2a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016167U
(18) Pure epoxides were obtained by column chromatography of the
reaction mixture after removal of the volatiles in vacuo. See Supporting
Information.
the standard conditions16 and were complete within 3 h at
25-40 °C.18 The yields ranged from 65% to 92%. The level
of stereospecificity for the reaction is highest for the
arenediols containing electron-withdrawing groups (EWG),
(19) The term log((100 + ee)/(100 - ee)) equals -∆∆G‡/RT where
-∆∆G‡ is the free energy difference between two diastereomeric transition
states leading to enantiomeric products.
Org. Lett., Vol. 3, No. 16, 2001
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