Regioselective ring opening of enantiomerically enriched epoxides via catalysis with chiral (salen)Cr(III) complexes

Article abstract of DOI:10.1055/s-2001-14649

Chiral (salen)chromium(III)N₃ complexes are demonstrated to be catalysts for the regioselective ring opening a variety of enantiomerically enriched epoxides. Selective nucleophilic attack at either epoxide carbon atom can be achieved by selection of the appropriate enantiomer of catalyst. A highly selective synthesis of norpseudoephedrine is described using this strategy.

Full text of DOI:10.1055/s-2001-14649

LETTER
1013
Regioselective Ring Opening of Enantiomerically Enriched Epoxides via
Catalysis with Chiral (Salen)Cr(III) Complexes
Bridget D. Brandes, Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA
Fax (617) 496-1880
Received 2 February 2001
Dedicated with respect and admiration to Professor Ryoji Noyori.
meso epoxide:
Abstract: Chiral (salen)chromium(III)N3 complexes are demon-
Nu
R
OH
R
O
HO
R
Nu
R
strated to be catalysts for the regioselective ring opening a variety
of enantiomerically enriched epoxides. Selective nucleophilic at-
tack at either epoxide carbon atom can be achieved by selection of
the appropriate enantiomer of catalyst. A highly selective synthesis
of norpseudoephedrine is described using this strategy.
R
R
pro-R-
selective
catalyst
pro-S-
selective
catalyst
Nu:
Key words: regioselectivity, ring opening, (salen)Cr(III) complex-
es, epoxides
enantioenriched, chiral epoxide:
Nu
OH
O
HO
Nu
R2
R1
R2
R1
R2
R1
While the principal application of asymmetric catalysis is
clearly toward enantioselective or diastereoselective reac-
tions, the possibility also exists for a chiral catalyst to ex-
ert regiochemical control on a chiral substrate. This effect
has been observed in a few cases in the context of parallel
kinetic resolution reactions, wherein the two enantiomers
of a racemate may be transformed to regioisomeric prod-
ucts.1 A different manifestation of the same concept can
be envisaged wherein the two enantiomeric partners of a
chiral catalyst effect complementary regioselectivity on
an enantioenriched substrate.2 This principle is easily
grasped if one considers the nucleophilic ring-opening of
epoxides with a chiral catalyst (Scheme 1). Several exam-
ples have been uncovered of enantioselective nucleophilic
ring-opening of meso epoxides,3 wherein catalyst enanti-
oselectivity is manifested through selective nucleophilic
attack at one of the enantiotopic C-O bonds. Naturally, the
mirror-image catalyst reacts with the same selectivity at
the other C-O bond, leading to the enantiomeric product
in identical ee. In the case of an enantioenriched chiral ep-
oxide wherein the heterotopic C-O bonds might be con-
sidered pseudo-enantiotopic, the same selectivity
principles could result in enantiomeric catalysts affording
regiocomplementary products. Such a process would con-
stitute a peculiar example of “double asymmetric synthe-
sis,”4 and on a practical level could define a novel strategy
for effecting regioselective reactions of sterically and
electronically unbiased substrates. We have explored this
idea in the context of the (salen)Cr-catalyzed addition of
TMSN3 to epoxides,5 and describe our results herein.
pro-R-
selective
catalyst
pro-S-
selective
catalyst
Nu:
Scheme 1
enantioenriched epoxides were accessed by asymmetric
epoxidation of the corresponding alkenes catalyzed by the
enzyme chloroperoxidase using hydrogen peroxide.6 The
achiral (salen)CrN3 catalyst (1) effected ring-opening of
(2R,3S)- 3 and (2R,3S)-4 with no measurable regioselec-
tivity, affording the ring-opened products in a 1:1 ratio
(Table). Ring-opening with catalyst (R,R)-2 provided a
modest 2:1 regioselectivity, while use of the enantiomeric
(S,S)-2 led to a reversal in selectivity in both cases to af-
ford a 1:4 and 1:3 ratio of regioisomers. Thus, while chiral
(salen)CrN3 catalyst 2 exerted only marginal control over
the regioselectivity of epoxide ring opening, these exam-
ples provided a clear proof-of-principle of the desired ef-
fect.
More significant levels of catalyst control were revealed
in the ring opening of styrene oxide derivatives. Three
enantioenriched epoxides, (R)-styrene oxide (5), cis-β-
methylstyrene oxide (6), and trans-β-methylstyrene oxide
(7) were examined.8 Epoxides 5 and 7 were obtained in
highly enantiomerically enriched form (>99% ee) from
commercial sources.9 Epoxide 6 was synthesized by
asymmetric epoxidation using the previously reported
low temperature conditions with (salen)MnCl catalysts.10
Enantiomerically enriched cis dialkyl substituted ep-
oxides, such as cis-2-heptene oxide and cis-2-octene ox-
ide (3 and 4) bearing what may be viewed as
“pseudoenantiotopic” C-O bonds, were evaluated first for
regioselective epoxide ring opening in the (salen)CrN3-
catalyzed asymmetric ring opening (ARO) reaction. The
Treatment of (R)-styrene oxide (5) with 5 mol% achiral
catalyst 1 and Me3SiN3 at 20 °C, afforded a 4:1 ratio of re-
gioisomeric products with preferential azide attack at the
less hindered β-terminal position. Use of the chiral cata-
lyst (S,S)-2 enhanced the substrate bias to provide an 18:1
ratio of products favoring β-substitution. The enantiomer-
Synlett 2001, SI, 1013–1015 ISSN 0936-5214 © Thieme Stuttgart · New York

1014
B. D. Brandes, E. N. Jacobsen
LETTER
species.12 Sequential asymmetric epoxidation of cis-β-
methylstyrene, selective ring opening as described above,
and chromatographic purification afforded regioisomeri-
cally pure product in 51% overall yield. Azide reduction
with LiAlH4 provided 8 cleanly and in >99% ee.
Table Asymmetric Ring Opening (ARO) of Enantiomerically En-
riched Epoxides.7
TMSO
Ph
Me
N3
LiAlH4
23 °C
HO
Ph
Me
O
(R,R)-2
TMSN3, 0 °C
NH2
Ph
CH3
(1S,2R)-6
18:1 cis/trans
98% ee
72% yield
8, 82% yield
(cis isomer)
Scheme 2 Synthesis of norpseudoephedrine (8).
Acknowledgement
This work was supported by the National Institutes of Health (GM-
43214) and by an Eli Lilly & Company-sponsored ACS Organic Di-
vision Graduate Fellowship to B. D. B.
a
References and Notes
Catalyst concentrations were 0.12-0.13 M for substrates 5-7, and
0.06-0.08 M for 3 and 4. b Selectivities are expressed as the ratio of
products resulting from azide attack at positions a and b (a:b). Ratios
were determined by GC analysis for styrene oxide and its derivati-
ves, and by H NMR for the aliphatic substrates. Isolated yield of
the regioisomeric mixture.
(1) For reviews, see: (a) Kagan, H. B. Croat. Chem. Acta 1996,
69, 669-680. (b) Eames, J. Angew. Chem. Int. Ed. 2000, 39,
885-888.
1
c
(2) von Matt, P.; Lloyd-Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.;
Macko, L.; Neuburger, M.; Zehnder, M.; Rüegger, H.;
Pregosin, P. S. Helv. Chim. Acta 1995, 78, 265-284.
(3) For reviews, see: (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P.
Tetrahedron 1996, 52, 14361-14384. (b) Jacobsen, E. N.; Wu,
M. H. in Comprehensive Asymmetric Catalysis, Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York;
1999, Chapter 35.
ic catalyst, (R,R)-2, overrode the substrate bias to afford a
1:7 ratio of products, the major isomer resulting from
azide attack at the α-benzylic carbon atom. The enan-
tiopurity of the two product regioisomers in the epoxide
ring opening of 5 was conserved as determined by chiral
gas chromatographic analysis.
(4) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem. Int. Ed. Engl. 1985, 24, 1-30.
(5) (a) Martínez, L. E.; Leighton, J. L.; Carsten, D.; Jacobsen, E.
J. J. Am. Chem. Soc. 1995, 117, 5897-5898. (b) Schaus, S. E.;
Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1997, 62, 4197-
4199. (c) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.
(6) Allain, E. J.; Hager, L. P.; Deng, L.; Jacobsen, E. N. J. Am.
Chem. Soc. 1993, 115, 4415-4416.
The ring opening of cis- and trans-β-methylstyrene oxide
(6 and 7) revealed similar profound matched and mis-
matched effects with 2 (Table, entries 4-5). In the case of
6, the 3:1 substrate bias for β-substitution could be over-
come to afford the α-benzylic substituted product, albeit
with moderate 1:4 selectivity. The regioselectivity with
trans-disubstituted 7 was 1:9 for α-benzylic substitution
using achiral catalyst 1, and the mismatched catalyst
(R,R)-2 effectively nullified this inherent bias to afford a
1:1 ratio of products. The tendency for cis- and trans-sty-
rene oxide derivatives to display opposite regioselectivity
in nucleophilic attack is well-documented, and may be ex-
plained by considering the difference in the stereoelec-
tronic properties of the two disubstituted epoxides.11 In
cis-epoxide 6, the phenyl group is rotated to avoid steric
interactions with the methyl group, with the effect of
blocking nucleophilic attack at the benzylic center. In
contrast, the phenyl group of trans epoxide 7 is not subject
to such a steric interaction and thus attack at the more
electrophilic benzylic carbon atom is favored.
(7) CAUTION!: These experiments have proceeded without
incident, but extreme caution should be exercised in the
handling of organic and metal azides. Experimental
procedure: A 10-mL, oven-dried, round-bottomed flask
equipped with a magnetic stirbar and air-free adapter was
charged with catalyst (5 mol%, 0.13 M), tert-butyl methyl
ether (TBME), and epoxide under nitrogen and then cooled to
the appropriate temperature (thermostatted isopropanol bath).
Azidotrimethylsilane (1.1 equiv) was added via syringe until
the mixture became homogenous. The reaction mixture was
then stirred under nitrogen until completion, then TBME and
excess Me3SiN3 were removed. The residue was purified by
flash column chromatography eluting with 2.5-10% EtOAc in
pentane or 5-25% CH2Cl2 in pentane to yield the mixture of
azidotrimethylsilyl ethers.
(8) The regioselective addition of azide to racemic styrene oxide
derivatives has been reported, but these reactions do not
proceed stereospecifically when applied to enantiomerically
enriched substrates. (a) Sutowardoyo, K. I.; Emziane, M.;
Lhoste, P.; Sinou, D. Tetrahedron 1991, 47, 1435-1446.
(b) Morrison, J. D.; Atkins, R. L.; Tomaszewski, J. E.
Tetrahedron Lett. 1970, 4635-4638.
The new methodology was applied in a straightforward
manner to the synthesis of (1S,2S)-norpseudoephedrine
(8), a naturally occurring anorexiant found in several plant
Synlett 2001, SI, 1013–1015 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regioselective Ring Opening of Enantiomerically Enriched Epoxides
1015
(9) Terminal epoxides such as styrene oxide are also readily
accessible in enantiopure form through the hydrolytic kinetic
resolution reaction. See: Tokunaga, M.; Larrow, J. F.;
Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938.
(10) Palucki, M. P.; McCormick, G. J.; Jacobsen, E. N.
Tetrahedron Lett. 1995, 36, 5457-5460.
(12) The Merck Index; Budavari, S., Ed.; Merck & Co.: Rahway,
1996; no 6811.
Article Identifier:
1437-2096,E;2001,0,SI,1013,1015,ftx,en;Y04401ST.pdf
(11) For conformational analysis of cis- and trans-β-methylstyrene
oxide, see: Brown, H. C.; Narasimhan, S.; Somayaji, V. J.
Org. Chem. 1983, 48, 3091-3096.
Synlett 2001, SI, 1013–1015 ISSN 0936-5214 © Thieme Stuttgart · New York