Stereoselective epoxidation of 4-deoxypentenosides: A polarized-π model

Article abstract of DOI:10.1021/ol0617401

The high facioselectivity in the epoxidation of 4-deoxypentenosides (4-DPs) by dimethyldioxirane (DMDO) correlates with a stereoelectronic bias in the 4-DPs' ground-state conformations, as elucidated by polarized-π frontier molecular orbital (PPFMO) analy

Full text of DOI:10.1021/ol0617401

ORGANIC
LETTERS
2
006
Vol. 8, No. 20
545-4548
Stereoselective Epoxidation of
-Deoxypentenosides: A Polarized-
Model
4
4
π
Gang Cheng, Fabien P. Boulineau, Siong-Tern Liew, Qicun Shi,
Paul G. Wenthold, and Alexander Wei*
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
alexwei@purdue.edu
Received July 15, 2006
ABSTRACT
The high facioselectivity in the epoxidation of 4-deoxypentenosides (4-DPs) by dimethyldioxirane (DMDO) correlates with a stereoelectronic
bias in the 4-DPs’ ground-state conformations, as elucidated by polarized- frontier molecular orbital (PPFMO) analysis.
π
4
-Deoxypentenosides (4-DPs) are unsaturated pyranoside
stereocenters (1-4) or transannular substituents with different
electronic character (5-8, 10) and cannot be simply ex-
plained by previously established stereodirecting effects.5
The epoxidations of R-methyl 4-DPs 1, 5, and 7 proceed
syn rather than anti with respect to the C3 stereocenter, which
precludes the allylic oxygen from being the dominant
derivatives with structural homology to glycals but bear
heteroatomic substituents at the anomeric position rather than
carbon. Studies from our laboratory have shown that 4-DPs
and glycals have similar reactivity profiles, with intriguing
-7
1
ramifications for carbohydrate and natural product synthesis.
8
For example, the 4-DP derived from R-methyl glucoside (R-
Glc-4-DP, 1) can be epoxidized stereoselectively at low
temperatures by dimethyldioxirane (DMDO), followed by
nucleophilic additions to produce pyranosides with rare or
unnatural configurations.2
director. The direct involvement of local steric effects is
also unlikely: for instance, in the ground-state conformation
of â-methyl 4-DP 2, both density functional theory (DFT)
9
calculations and NMR coupling constant analysis suggest
Additional DMDO oxidation studies involving 4-DPs
derived from the methyl glycosides of glucose, mannose,
and glucosamine (2-10) reveal a striking trend with respect
(4) The anticipated â-epoxide from 2-dibenzylamino-4-DP derivative 9
could not be isolated presumably due to its cross reactivity with the C2
dibenzylamino group, although the R-epoxide derived from 10 was stable
upon isolation.
(5) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994. (b) Franck, R. W. In
Conformational BehaVior of Six-Membered Rings; Juaristi, E., Ed.; VCH
Publishers: Weinheim, 1995; pp 159-200.
(6) (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J.
Science 1986, 231, 1108-1117. (b) Martinelli, M. J.; Peterson, B. C.; Khau,
V. V.; Hutchison, D. R.; Leanna, M. R.; Audia, J. E.; Droste, J. J.; Wu,
Y.-D.; Houk, K. N. J. Org. Chem. 1994, 59, 2204-2210.
(7) Washington, I.; Houk, K. N. Angew. Chem., Int. Ed. 2001, 40, 4485-
4488.
(8) In comparing these results with earlier reports on the DMDO
oxidation of glycals, we note that a gulal derivative (stereoanalogue of 1)
produced a 1:1 mixture of stereoisomers at 0 °C: Halcomb, R. L.;
Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6661-6666.
3
to stereochemical outcome (see Table 1). The facioselective
epoxidation proceeds anti to two of the three substituents
on the 4-DP reactant, producing epoxyacetals in essentially
4
quantitative yield in nearly all cases. This empirical “major-
ity rule” is independent of the relationship among contiguous
(
1) (a) Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. ReV. 1993, 62,
79-601. (b) Ferrier, R. J.; Hoberg, J. O. In AdV. Carbohydr. Chem.
Biochem.; Horton, D., Ed.; Academic Press: New York, 2003; Vol. 58, pp
5-119.
2) (a) Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281-2283. (b)
Boulineau, F. P.; Wei, A. J. Org. Chem. 2004, 69, 3391-3399.
3) The synthesis of compounds 5-10 will be reported elsewhere.
5
5
(
(
1
0.1021/ol0617401 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/30/2006

Table 1. Stereoselective DMDO Epoxidation of 4-DPs
Figure 1. Front and side views of the transition-state geometries
for dioxirane addition to â-Glc-4-DP triol, the parent structure of
2
, based on DFT-B3LYP calculations (R-TS favored over â-TS,
but differences in torsional strain or O‚‚‚H interactions appear to
be insignificant). Output files are available upon request.
through an early transition state with an asynchronous spiro
geometry and very little change from the 4-DP’s initial
ground-state conformation, in accord with earlier studies of
dioxirane addition to simple alkenes and enol ethers.10 The
difference in the activation energies of R- and â-epoxide
formation compares favorably with the experimental results
q
q
for 2 (∆G calcd(R) and ∆G calcd(â) ) 18.7 and 20.8 kcal/mol,
using the 6-31G* basis set).
The transition-state geometries do not reveal specific
enthalpic interactions which would explain the preference
for R epoxidation. No significant differences in torsional
6
strain could be determined, and the axial hydrogens do not
approach the incoming oxygen, ruling out the possibility of
7
CH‚‚‚O hydrogen bonding (see Figure 1). On the other hand,
the early transition states and low activation energies allow
for the possibility of an intrinsic polarization in π-orbital
reactivity. We thus considered theoretical models that could
describe stereoelectronic bias in the π-orbitals of the 4-DPs
based on their ground-state conformations.
a
Reaction conditions: (A) DMDO (2-3 equiv), -55 °C, 2 days; (B)
DMDO (2 equiv), 0 °C, 15 min; (C) DMDO (1.1 equiv), -55 °C, 1 day.
Stereochemistry determined by H NMR analysis after SN2 ring opening
with EtSLi. Reported previously in ref 2a. See ref 4.
b
1
c
d
We found the polarized-π frontier molecular orbital
(
PPFMO) approach developed by Dannenberg to be appeal-
1
1
ing in this regard, and its implementation into DFT
calculations proved to be straightforward. Briefly, the
that all substituents are preferentially pseudoequatorial and
project away from the site of epoxidation.
9
PPFMO approach is a perturbation method which desym-
Transition-state geometries for the addition of dioxirane
to the R or â face of the â-Glc-4-DP triol (the parent structure
of 2) were calculated at the B3LYP/6-31G* level of theory,
followed by computation of B3LYP/6-311+G(2df,2p) single-
point energies (see Figure 1). Addition to either face proceeds
metrizes 2p orbitals by introducing s-functions near each lobe
(10) (a) Houk, K. N.; Liu, J.; DeMello, N. C.; Condroski, K. R. J. Am.
Chem. Soc. 1997, 119, 10147-10152. (b) Jenson, C.; Liu, J.; Houk, K. N.;
Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 12982-12983.
(11) (a) Huang, X. L.; Dannenberg, J. J.; Duran, M.; Bertr a´ n, J. J. Am.
Chem. Soc. 1993, 115, 4024-4030. (b) Dannenberg, J. J. Chem. ReV. 1999,
99, 1225-1241.
(9) See Supporting Information for details.
4546
Org. Lett., Vol. 8, No. 20, 2006

Figure 2. PPFMO analysis of R- and â-Glc-4-DP trimethyl ether (analogues of 1 and 2). Two s-functions are superimposed onto the 2p
y
orbitals at C4 and C5 to produce an asymmetric function ø, whose coefficients can be used to derive p, the net electronic polarization per
orbital (in purple). 2p orbitals and added s-functions are spatially separated for clarity. ( values refer to the sign of the coefficients for each
lobe (open/filled).
(
see Figure 2).11 The linear combination of these orbitals
yields an asymmetric function whose coefficients (c and
) describe the polarization of each 2p orbital. PPFMO
polarizations at C4 and C5 agree with the epoxidation
outcomes. The influence of C4 outweighs that of C5 in cases
of opposing polarizations, which coincides with its dominant
role in the asynchronous transition state. Overall, these
calculations support a significant stereoelectronic bias in the
π-bond reactivity of the 4-DPs.
R
c
â
analysis is qualitative but not computationally demanding
and has been used to examine the facioselectivity of
electrophilic additions to cyclic enol ethers such as glycals.
12
However, the validity of the predicted outcomes depends
strongly on the similarities of the reactants’ ground-state and
transition-state structures, which appears to be the case in
the epoxidation of 4-DPs.
To determine if PPFMO analysis could be used in a
predictive manner, we further considered the epoxidation of
4
-DP derivatives with only two substituents. For example,
the epoxidation of 2,4-dideoxypent-4-enoside derivative 11
is subject to competing directing effects from the anomeric
and allylic substituents, and its outcome cannot be predicted
on the basis of a “majority rule”. However, PPFMO
calculations performed on the DFT-optimized structure
Table 2. PPFMO Analysis of 4-DP Permethyl Ethersa
compd
atom
cRb
câb
pc
suggest 2p
Figure 3, left). This was confirmed by the DMDO oxidation
of 11 followed by S 2 ring opening with MeOH, which
y
polarization in the R direction (see Table 2 and
R-Glc-4-DP (1)
C4
C5
C4
C5
C4
C5
C4
C5
C4
C5
-0.620 0.748 0.175 (â)
-0.180 0.098 0.023 (R)
-0.718 0.713 0.007 (R)
-0.194 0.152 0.015 (R)
-0.616 0.615 0.002 (R)
-0.116 0.095 0.004 (R)
-0.641 0.575 0.081 (R)
-0.185 0.235 0.021 (â)
-0.719 0.719 0.000
N
â-Glc-4-DP (2)
produced the corresponding C4 alcohol 12 with high stereo-
selectivity (R: â > 10:1).
R-Man-4-DP (3)
â-Man-4-DP (4)
R-Glc-2-deoxy-4-DP (11)
-0.201 0.180 0.008 (R)
a
All structures optimized by DFT-B3LYP calculations (6-31+G(d,p))
b
prior to insertion of s-functions. Each coefficient is calculated as the linear
combination of s-function and 2py; ( values refer to the sign of the
c
coefficients for each lobe. Polarization of each orbital in parentheses. See
Supporting Information for procedures.
Figure 3. Left: PPFMO analysis of 2-deoxy-4-DP dimethyl ether.
Right: stereoselective epoxidation of 2-deoxy-4-DP derivative 11.
Applying the PPFMO theory to the permethyl ethers of
1
-4 yields c
R â
and c for the occupied 2p orbitals and the
polarization in electron density for each orbital, calculated
as p ) |c
These studies indicate that the facioselectivity in 4-DP
epoxidation can be predetermined by the polarized-π model.
The absence of local interactions in the transition state makes
this reaction especially well-suited for PPFMO analysis,
enabling stereochemical outcome to be correlated with
ground-state electronic structure.
2
2
R
- c
â
| (see Table 2). In all cases, the combined
(12) (a) Franck, R. W.; Kaila, N.; Blumenstein, M.; Geer, A.; Huang,
X. L.; Dannenberg, J. J. J. Org. Chem. 1993, 58, 5335-5337. (b) Boschi,
A.; Chiappe, C.; De Rubertis, A.; Ruasse, M. F. J. Org. Chem. 2000, 65,
8
470-8477.
Org. Lett., Vol. 8, No. 20, 2006
4547

Acknowledgment. This work was supported by the
American Cancer Society (03-135-01-CDD) and the National
Institutes of Health (GM-06982-01). The authors thank Prof.
Joseph Dannenberg for helpful discussions regarding PPFMO
calculations and gratefully acknowledge the Rosen Center
for Advanced Computing at Purdue University for compu-
tational support.
Supporting Information Available: Experimental pro-
cedures and NMR spectra and characterization related to
4-DP epoxidation and S 2 ring opening (PDF); output log
N
files for DFT geometry optimizations and transition-state and
PPFMO calculations. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0617401
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Org. Lett., Vol. 8, No. 20, 2006