Phosphine-dependent stereoselectivity in the mitsunobu cyclodehydration of 1,2-diols: Stereodivergent approach to triaryl-substituted epoxides

Article abstract of DOI:10.1021/ol0629420

Triaryl-1,2-ethanediols, readily available from natural mandelic acid, can be stereospecifically converted into their corresponding chiral nonracemic epoxides by means of a Mitsunobu cyclodehydration reaction. Upon selection of the phosphine component in

Full text of DOI:10.1021/ol0629420

ORGANIC
LETTERS
2007
Vol. 9, No. 4
635-638
Phosphine-Dependent Stereoselectivity
in the Mitsunobu Cyclodehydration of
1,2-Diols: Stereodivergent Approach to
Triaryl-Substituted Epoxides
Noem´ı Garc´ıa-Delgado, Antoni Riera, and Xavier Verdaguer*
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Institute for Research in
Biomedicine (IRB) and Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona,
c/Josep Samitier, 1-5, E-08028 Barcelona, Spain
xVerdaguer@pcb.ub.es
Received December 5, 2006
ABSTRACT
Triaryl-1,2-ethanediols, readily available from natural mandelic acid, can be stereospecifically converted into their corresponding chiral nonracemic
epoxides by means of a Mitsunobu cyclodehydration reaction. Upon selection of the phosphine component in the reaction, the two enantiomers
of the final epoxides are accessible in high enantiomeric excess. In view of this surprising phosphine-dependent stereoselectivity, here we
examine the influence of the steric and electronic nature of both the phosphine and the substrate.
Chiral epoxides are highly valuable synthetic building blocks
in asymmetric organic synthesis. In the last three decades,
metal-catalyzed and organocatalytic enantioselective epoxi-
dation technologies have advanced greatly, enabling the
direct preparation of optically enriched oxiranes from the
corresponding olefins.1-5 Complementary methodologies for
the preparation of chiral epoxides comprise the addition of
sulfur ylides to aldehydes or ketones6 and the cyclization of
1,2-diols. Chiral 1,2-diols, readily available through Sharpless
asymmetric dihydroxylation,7,8 represent a powerful alterna-
tive technology for the preparation of nonracemic epoxides.
The transformation of 1,2-diol to epoxide can be achieved
through several methodologies: selective hydroxyl activation
followed by base-promoted cyclization,8 dehydration via
acetoxonium ion,9 or cyclic sulfate dehydration.10
Mitsunobu reaction conditions (phosphine/ diazocarboxyl-
ate reagent) have also been applied to the dehydration of
chiral 1,2-diols.11 The mechanism for this transformation is
proposed to occur via a five-membered ring phosphorane
which evolves through an oxyphosphonium betaine (Scheme
1).12,13 Intramolecular cyclization of this betaine provides the
final epoxide product. For nonsymmetric 1,2-diols, two poss-
ible betaines may form. Depending on which of these two
betaines is formed the reaction will take place with either reten-
tion or inversion of configuration. For terminal 1,2-alkane-
diols, the reaction occurs stereospecifically with retention via
path A (Scheme 1).14,15 This behavior has been explained
(1) Katsuki, T.; Jacobsen, E. N.; Wu, M. H. In Epoxidation; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; ComprehensiVe Asymmetric Catalysis;
Springer: Berlin, 1999; Vol. II, pp 621-649.
(2) Arends, I. W. C. E. Angew. Chem., Int. Ed. 2006, 45, 6250-6252.
(3) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496.
(4) Yang, D. Acc. Chem. Res. 2004, 37, 497-505.
(9) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530.
(10) Jang, D. O.; Joo, Y. H.; Cho, D. H. Synth. Commun. 2000, 4489-
4494.
(5) Xia, Q. H.; Ge, H. Q.; Ye, C. P.; Liu, Z. M.; Su, K. X. Chem. ReV.
2005, 105, 1603-1662.
(6) Aggarwal, V. K. Epoxide formation of enones and aldehydes. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, 1999; Vol. II, p 679.
(7) Marko´, I. E.; Svendsen, J. S. Dihydroxylation of carbon-carbon
double bonds. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. II, p 713.
(8) Kolb, H. C.; VanNieuwenheze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(11) Schenk, S.; Weston, J.; Anders, E. J. Am. Chem. Soc. 2005, 127,
12566-12576.
(12) Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.; Evans, S.
A., Jr. J. Org. Chem. 1983, 48, 5396-5398.
(13) Robinson, P. L.; Barry, C. N.; Kelley, J. W.; Evans, S. A., Jr. J.
Am. Chem. Soc. 1985, 107, 5210-5219.
(14) Castejo´n, P.; Pasto´, M.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1995, 36, 3019-3022.
10.1021/ol0629420 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/25/2007

Scheme 1. Mitsunobu Cyclodehydration of 1,2-Diols:
Scheme 2. Phosphine-Dependent Stereodivergent Synthesis of
Commonly Accepted Mechanism
Triphenyloxirane
isolated the product with opposite absolute configuration and
exceptionally high ee (99%). In this case, an opposite
stereochemical pathway yielded inversion of the initial 1,2-
diol configuration. This example is an interesting case of
phosphine-dependent stereoselectivity in the Mitsunobu
cyclodehydration. To shed light on this subject, we undertook
a study to establish how the electronic factors in the starting
material affect the stereochemical outcome of the reaction.
Starting from optically pure (S)-mandelic acid and the
corresponding bromo benzene derivatives several 1,1-diaryl-
2-phenylethane-1,2-diols (Figure 1) were synthesized using
traditionally as the reaction pathway going through the less
sterically demanding betaine, the one bearing the oxyphos-
phonium ion in terminal position (path A). This trend, how-
ever, does not apply to the cyclodehydration of styrene 1,2-
diols. Evans and co-workers showed that the Mitsunobu dehy-
dration of (S)-1-phenyl-1,2-ehtanediol (PPh3/DEAD) provides
essentially racemic epoxide.12 It was postulated that the origin
of racemization was that the corresponding betaines, paths
A and B (Scheme 1), formed and collapsed at the same rate.
Recently, Weissman and co-workers reported that the stereo-
specificity of the Mitsunobu dehydration of 1-aryl-1,2-
ethanediols largely depends on the nature of the phosphine
used and the aryl groups in the substrate.16 Thus, electron-
rich phosphines (e.g., PCy3) and electron-withdrawing groups
in the aryl 1,2-diol moiety provide the corresponding epoxide
with retention of configuration (path A, Scheme 1).
Figure 1. Chiral 1,1-diaryl-2-phenylethane-1,2-diols used in this
study.
As part of a project devoted to the preparation of sterically
demanding chiral 1,2-amino alcohols and their use as a
catalysts in the enantioselective dialkylzinc addition to
carbonyl compounds,17-19 we explored the preparation of
optically active triphenylethylene oxide from the correspond-
ing 1,1,2-triphenylethanediol by means of the Mitsunobu
cyclodehydration reaction. With this purpose, we reacted
optically pure (S)-1,1,2-triphenylethandiol (1a) with triphenyl-
phosphine and diisopropylazodicarboxylate (DIAD) at room
temperature in CH2Cl2 (Scheme 2). We isolated the corre-
sponding oxirane 2a with retention of configuration and a
high optical purity (88% ee). Surprisingly, when the same
reaction was performed with n-Bu3P instead of PPh3 we
standard reaction procedures.20 The aryl groups introduced
were chosen to provide a diverse electronic environment at
the 1,2-diol quaternary center. Product diols were purified
by recrystallization until optically pure (99% ee) as deter-
mined by chiral HPLC.21 With these compounds in hand,
we examined the Mitsunobu cyclodehydration with DIAD
and three different phosphines, Ph3P, n-Bu3P and Oct3P,
which are widely used in synthesis (Table 1).
As with the parent compound 1a, cyclodehydration of diols
1b, 1d, 1e, and 1f also provided the corresponding epoxides
from excellent to moderate yields. Only oxirane derived from
1c could not be isolated or identified in the final reaction mix-
ture. This was probably due to the intrinsic instability of the
final product.22 The electron-releasing nature of the p-methoxy-
(15) Pautard-Cooper, A.; Evans, S. A., Jr. J. Org. Chem. 1989, 54, 2485-
2488.
(16) Weissman, S. A.; Rossen, K.; Reider, P. J. Org. Lett. 2001, 3, 2513-
2515.
(17) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M.
A.; Riera, A.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 1998, 63,
7078-7082.
(18) Fontes, M.; Verdaguer, X.; Sola, L.; Pericas, M. A.; Riera, A. J.
Org. Chem. 2004, 69, 2532-2543.
(20) Millar, A.; Mulder, L. W.; Mennen, K. E.; Palmer, C. W. Org. Prep.
Proced. Int. 1991, 23, 173-180.
(21) Diol 1e could not be purified by crystallization, and it was used as
obtained in 93% enantiomeric excess.
(19) (a) Garc´ıa-Delgado, N.; Reddy, K. S.; Sola, L.; Riera, A.; Pericas,
M. A.; Verdaguer, X. J. Org. Chem. 2005, 70, 7426-7428. (b) Garc´ıa-
Delgado, N.; Fontes, M.; Perica`s, M. A.; Riera, A.; Verdaguer, X.
Tetrahedron: Asymmetry 2004, 15, 2085-2090.
(22) As suggested by a reviewer, the inability to find the expected epoxide
could also be explained by the migration of the electron-rich aryl group
and concomitant loss of triphenylphosphine oxide in the initial betaine to
yield a rearranged ketone.
636
Org. Lett., Vol. 9, No. 4, 2007

Scheme 3. Formation of a Stable Phosphorane
Table 1. Mitsunobu Cyclodehydration of Several
(S)-1,1-Diaryl-2-phenylethane-1,2-diols
entry R3P
X
yield (%) eea (%) er (S/R) [R]D oxirane
1
2
3
4
5
6
7
8
9
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
n-Bu3P t-Bu
n-Bu3P Me
n-Bu3P H
n-Bu3P F
t-Bu
Me
H
F
CF3
57
43
45
94
77
40
57
70
81
63
77
99
99
61
83
79
90
88
65 (72b)
98
40
60
99
93 (99b)
>99
7
45
84
93 (99b)
99
8.3:1
20.0:1
15.6:1
(+)
(+)
(+)
2d
2b
2a
2e
2f
2d
2b
2a
2e
2f
2d
2b
2a
2e
2f
acteristic 31P resonance at -45.5 ppm could be observed for
3a. Although phosphorane 3a was fully characterized by
spectroscopic techniques, it decomposed slowly to provide
the corresponding epoxide. Decomposition of 3a for over a
month at room temperature in CH2Cl2 yielded the (S)-2a with
79% ee with retention of configuration. These two examples
are not useful from a synthetic point of view; nevertheless,
they confirm that electron-rich phosphines provide the
inversion product in high stereospecificity, while electron-
poor phosphines ensure retention of configuration.
1:6.1c (-)
1:110 (-)
1:2.3 (-)
1:4.0 (-)
1:198 (-)
1:199c (-)
1:999 (-)
10 n-Bu3P CF3
11 Oct3P t-Bu
12 Oct3P Me
13 Oct3P
14 Oct3P
1.1:1
(+)
1:2.6 (-)
1:11.4 (-)
1:199c (-)
1:255 (-)
H
F
From the results disclosed in Table 1, we may conclude
that two reaction pathways lead to opposite configurations
(R or S) in the final oxirane ring. Most intriguingly,
depending on the phosphine used, either one of these two
pathways will be favored. Linear fitting of the log S/R ratio,
which is related to the -∆∆Gq/2.3RT for the corresponding
transition states vs the Hammett σp values when using
triphenylphosphine, provided a negative slope (Figure 2).25
15 Oct3P CF3
a Product enantiomeric excess determined by chiral HPLC. b Corrected
ee based upon enantiomeric excess of starting material 1e (93% ee).
c Corrected er based on the enantiomeric ratio (S/R) of starting material 1e
(27:1, 93% ee).
benzene groups attached to the quaternary center facilitates the
formation of carbocationic species, hence preventing the forma-
tion of the epoxide. When using triphenylphosphine, the 1,2-
diols bearing electron-releasing groups (ERG) in the aryl moi-
ety (Table 1, entries 1 and 2) provided the corresponding epox-
ide with retention of configuration, thus confirming the behav-
ior observed for 1,1,2-triphenylethanediol (Table 1, entry 3).
In contrast, when electron-withdrawing groups (EWG) were
present the reaction occurred with inversion, which provided
the (R) enantiomer as the major isomer (Table 1, entries 4
and 5). When using trialkylphosphines (Bu3P and Oct3P),
the reaction took place mostly with inversion of configura-
tion, to provide the (R) enantiomer (Table 1, entries 6-15).
In this case, however, there was a clear trend by which EWG
provided higher stereospecific reactions while electron-
releasing substituents showed poor stereospecificity.
Figure 2. Hammett plot of log S/R ratio of enantiomers vs σ for
the Mitsunobu cyclodehydration when using Ph3P.
Furthermore, when using tricyclohexylphosphine (Cy3P) in
the cyclodehydration of (S)-1,1,2-triphenylethanediol (1a), a
poor yield (2%) of the corresponding (R)-epoxide was obtained
in high enantiomeric excess (96% ee). In contrast, when the
electron-deficient tris[3,5-bis(trifluoromethyl)phenyl] phos-
phine was used, the corresponding intermediate phosphorane
3a was isolated in (71%) yield (Scheme 3). Intermediate
phosphorane species have traditionally been observed only
in solution by NMR techniques.13,23 In some instances, rigid
1,2-diols have provided stable phosphoranes that not undergo
the corresponding cyclodehydration.24 In our case, a char-
This graphical representation is indicative that ERG in the
aromatic rings of the quaternary center favor the formation
of the S-enantiomer (retention). From a mechanistic perspec-
tive, this behavior is indicative that a positive charge close
to the aryl groups is involved in the reaction pathway leading
to the S-enantiomer.26 Alternatively, a Hammett plot of log
R/S ratio of enantiomers vs σp when using Oct3P provided a
(24) Chow, T. J.; Li, L.; Lee, V. Y. R.; Lin, K.; Chen, C. J. Chem. Soc.,
Perkin Trans. 2 1996, 2681-2685.
(25) Gawley, R. E. J. Org. Chem. 2006, 71, 2411-2416.
(26) Carey, F. A.; Sundberg, R. J. In AdVanced Organic Chemistry;
Kluwer Academic: New York, 2000.
(23) Guthrie, R. D.; Jenkins, I. D. Aust. J. Chem. 1982, 35, 767-774.
Org. Lett., Vol. 9, No. 4, 2007
637

positive slope, indicating that, a negative charge close to aryl
moieties is now involved in the mechanism that produces
the inverted configuration (Figure 3).16
In this scenario, formation of betaine (III) in which the
oxyphosphonium is placed at the less hindered oxygen atom
and the subsequent ring closure with inversion of configu-
ration explains the formation of the (R)-epoxide. Betaine III
is formed rapidly either directly from I and the corresponding
diol or through II. This reaction pathway should be favored
by electron-rich phosphines (n-Bu3P or Oct3P), which
stabilize the positive charge on phosphorus, and by EWG
on the aryl groups, which stabilize the nearby negative charge
on the alkoxide moiety of betaine III.
Alternatively, the use of triphenylphosphine ensures
formation of cyclic phosphorane II, as determined by NMR
experiments. From II, formation of regioisomeric betaine III′
or a carbocationic intermediate IV may explain the retention
product (Scheme 4). Observed electronic effects can be more
satisfactorily explained if the oxygen-quaternary carbon bond
is broken to yield a carbocationic intermediate like IV rather
than III′.12,27 In this case, the aryl substituents with ERG
stabilize the tertiary carbocation, while the negative charge
in the phosphorane moiety will be more effectively stabilized
by electron-poor phosphines (e.g., Ph3P). This mechanism
is also consistent with the Hammett plot, which indicates
the formation of a positive charge close to the aryl groups.28
Steric effects should also favor reaction through IV rather
than the sterically encumbered betaine III′. Evolution of
intermediate IV through either a concerted or a stepwise
elimination of triphenylphosphine oxide should eventually
lead to the retention product.
Figure 3. Hammett plot of log R/S ratio of enantiomers vs σ for
the Mitsunobu dehydration of triarylethanediols when using Oct3P.
When triphenylphosphine was used, cyclic phosphoranes
(II) were detected as intermediates by 31P NMR reaction
progress analysis (Scheme 4). Thus, for example, when
Scheme 4. Proposed Reaction Pathways for the
Phosphine-Dependent Mitsunobu Cyclodehydration
In summary, an unexpected phosphine-dependent stereo-
selectivity has been disclosed for the Mitsunobu cyclode-
hydration of chiral triaryl-1,2-ethanediols. Electron-rich
phosphines favor the inversion product while triphenylphos-
phine provides stereospecifically the retention epoxide. We
also have studied here the electronic effects of the benzene
groups attached to the quaternary center of the diol. Our
results show that EWG favor the inversion process and vice
versa. From the synthetic point of view, this stereochemical
behavior allows the formation of the two enantiomers of the
triphenylethylene oxide from a single diol precursor.
Acknowledgment. This work was supported by MEC
(CTQ2005-623). X.V. thanks the DURSI for a “Distincio´ per
a la Promocio´ de la Recerca Universita`ria”. N.G.-D. thanks
the DURSI and Universitat de Barcelona for a fellowship.
DIAD was added to a mixture of 1a and Ph3P, a major
resonance at -39.5 ppm, attributed to phosphorane II,
appeared along with a minor signal (45.7 ppm), attributed
to I. These resonances over time (2 h) disappeared to yield
triphenylphosphine oxide (29.3 ppm) and the corresponding
epoxide. Alternatively, intermediate cyclic phosphoranes
were not detected by 31P NMR when n-Bu3P was used
instead of Ph3P. Similar observations were made by Guthrie
and Jenkins for the cyclodehydration of trans-1,2-cyclohex-
anediol. These authors proposed that oxophosphonium salts,
like III, form rapidly when tributylphosphine is used.23 These
results indicate that when using electron-deficient phosphines
(i.e., Ph3P), cyclic phosphoranes are reaction intermediates
with a prolonged half-life. This would also explain the
extraordinary stability of phosphorane 3a.
Supporting Information Available: General methods,
experimental procedures, and spectroscopic data for all new
1
diols and epoxides. Copies of H and 13C NMR spectra for
diols 1a-f, epoxides 2a-f, and phosphorane 3a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0629420
(27) Carbocationic intermediates have been invoked in the thermolysis of
dioxaphosphoranes derived from (S)-1,1-diphenyl-1,2-propanediol and in
the cyclodehydration of 1-phenyl-1,2-ethanediol to styrene oxide. See: Murray,
W. T.; Evans, S. A., Jr. J. Org. Chem. 1989, 54, 2440-2446 and ref 12.
(28) For Ph3P, a better fitting was obtained with σ rather than with σ+.
For a positive charge that enters in conjugation with the aryl moieties a
better fitting with σ+ should be expected (see ref 25). In the present case,
the steric hindrance around the doubly benzylic carbocation hampers the
coplanarity with the aryl moieties, thus interfering in the conjugation.
638
Org. Lett., Vol. 9, No. 4, 2007