Enantiomerically pure epoxychromans via asymmetric catalysis

Article abstract of DOI:10.1016/S0040-4039(00)93426-9

A practical and highly effective process for the asymmetric epoxidation of several 2,2-dimethylchromene derivatives is reported. Catalysis by Mn(salen) complex 4 in all cases affords epoxychromans with >90% ee, and this method has been applied to the synthesis of two recently developed antihypertensive agents in enantiomerically pure form.

Full text of DOI:10.1016/S0040-4039(00)93426-9

Tetrahedron Letters, Vo1.32, No.38, pp 5055-5058, 1991
Printed in Great Britain
0040-4039/91 $3.00 + .00
Pergamon Press plc
Enantiomerically Pure Epoxychromans
via Asymmetric Catalysis
Nam Ho Lee, Alexander R. Muci, and Eric N. Jacobsen*
Contribution from the RogerAdams Laboratory,
Department ofChemistry,
University of lllinois, Urbana, IL 61801
Summary: A practical and highly effective process for the asymmetric epoxidation of several 2,2-
dimethylchromene derivatives is reported. Catalysis by Mn(salen) complex 4 in all cases affords
epoxychromans with >90% ee, and this method has been applied to the synthesis of two recently
developed antihypertensive agents in enantiomerically pure form.
Dimethylchromene derivatives (1) arise biosynthetically from the condensation of a phenol with an
isoprene unit, and, not surprisingly, this bicyclic structure recurs in a variety of natural products. Indeed,
several hundred natural and synthetic 2,2-dimethylchromene derivatives are known, and their biological
activity in both plants and animals has been the subject of considerable interest.1 We report here the first
successful strategy for the asymmetric elaboration of chromenes in the application of recently developed
Mn(III)salen epoxidation catalyst 42 to the oxidation of a variety of dimethylchromene derivatives with
remarkable enantioselectivity. Nucleophilic ring opening of 3,4-epoxy-2,2-dimethylchromans is generally
regioselective as both steric and electronic factors favor attack at the 4-position. Thus, asymmetric
epoxidation provides practical access to optically pure 3,4-disubstituted chroman derivatives. The
applicability of this technology is illustrated in the syntheses of (-)-2 (cromakalim) and (-)-3, the active
enantiomers of recently developed potassium channel activators with promising antihypertensive
activity.3,4
/)--°'1"°--(
X
NC
O ~ v . ~
2
N"N " ~ 0
MeI
"--~t-Bu CI
t.Bu/'-'-"
1
3
4
The substrates in Table 1 were prepared by literature methods.5 Epoxidations were carried out at
room temperature or at 0 °C with commercial bleach as the stoichiometric oxygen-atom source and 2-4
tool% of either enantiomer of 4 as catalyst.6 Lower temperature generally led to slight (1-3%) increases in
selectivity,2b although this proved unnecessary in certain cases. Reactions were generally very clean, with
epoxide as the only detectable product and complete reaction within 1 to 9 hours. Direct epoxidation of
chromene derivatives by traditional methods (e.g. mCPBA) is usually problematic,7 and indeed we found
that preparation of racemic epoxychromans for analytical purposes was more easily accomplished with
5055

5056
NaOC1 using racemic mixtures of the Mn(salen) catalysts. Geminal disubstitution at the 2-position of the
chromene nucleus proved important, as the unsubstituted derivative 19 underwent allylic oxidation to
coumarin.
The data in Table 1 illustrate the catalyst system's tolerance to both steric and electronic variation in
the dimethylchromene structure. In particular, trisubstituted alkenes 13 and 15 afforded excellent results,
demonstrating that high selectivity with the Mn(III) salen systems can be extended beyond cis-olefins.
Highly functionalized substrates such as 11 were also epoxidized cleanly. Epoxychromans 6, 8, and 16
were crystalline and could be purified further to enantiomeric homogeneity by a single recrystallization
(e.g. Figure 1). In the oxidation of 17, a diastereomeric mixture of diols was isolated in moderate yield
instead of epoxide. Enantiomeric excess of both diastereomers of 18 was high, an indication that the diols
were formed via hydrolytic ring-opening of the corresponding epoxide with retention of stereochemistry at
the 3-position.8
tt)
tD
O
(xl
t o
O
¢o
t o
O~
t~
t~
to
~
~to
B
C
A
y,
c~
oo
Figure 1. Gas chromatographic analyses of epoxide 6 acquired with a commercial J & W Scientific
Cyclodex-B capillary column, 30 m x 0.25 mm I.D., 0.25 I.tm film. A) Racemate. B) Crude product
(97.2% ee) obtained from the epoxidation of 5 by catalyst (R,R)-4. C) Epoxide obtained by a single
recrystallization of enriched material from 50% ethanol (=100% ee).
The successful application of the epoxidation process to the cyano-substituted substrate 5 is of
particular interest because epoxide 6 has previously been employed as an intermediate in the synthesis of
highly effective antihypertensive agents 2 and 3, and only the (3S,4R) enantiomers of these 3,4-
disubstituted chromanol derivatives displayed good activity.5a,9,10 Indeed, we were able to prepare each
of these important compounds in optically pure form and in a single step from (S,S)-6 (Scheme 1).
Scheme
1
H
Me
I
0 - - ~ OH
(3R 4S)-2
(S,S)-6
(3~ 4S)-3
560/0
N a i l , D M S O
p y r i d i n e
85../0

5057
Table 1. Asymmetric Epoxidation of Chromene Derivatives Catalyzed by (R,R)-4.a
Absolute
Olefin
Major Product(s)
. ee (%)b
Isolated Yield (%)c
Configura#on
97
g6
(3R, 4R)-(+)d
(3R, 4R)-(+)e
NC
o,,-
5
g4
76
NO
,,,.
7
9
8
98
87
75
sl
(3/:/, 4R)-(+)e
(3R, 4R)-(+)e
(3R, 4F~-(+)"
10
98f
0
OMe
11
O
OMe
12
>98
a2
(3R, 4R)-(+)~
NC
.... -
16
15
trans: 94f
l
38h
not determined
cis
: g5f
J
18: trans/cis = 2:1
17
O
49
19
a
EpoxidalJons carded out with (S,S)-4 afforded products of opposite configuration, b Ee's were determined by GC
(see caption to Figure 1) unless otherwise noted, c Isolated yields correspond to reactions carried out on lmrnol scale
with 4 mol% 4 and product isolation by flash chromatography, d Correlated with (3R,4S)-(+)-2 (ref. 9'0). e Absolute
configuration assigned by analogy to 6. f Es determined by 1H NMR using Eu(hfc)3 as chiral shift reagent, g Personal
communication from Drs. R. Gericke and J. Sombroek (E. Merck). h Isolated yield of the 2:1 mixture.

5058
This constitutes the first application of the Mn(salen) asymmetric epoxidation process to a practical
synthesis. The new availability of both enantiomers of a variety of epoxychroman chiral building blocks
in high enantiomeric purity should assist in the further development of chroman derivatives as a
biologically important class of compounds.
Acknowledgements. This work was supported by the National Institutes of Health (GM-43214-
01A1), a National Science Foundation PYI Award (CHE-9057740) to ENJ, and by generous
contributions from the Monsanto Corporation, ICI Pharmaceuticals, Merck and Co., and Rohm and Haas.
We thank Drs. R. Gericke and J. Sombroek (E. Merck) for extremely helpful correspondence and for gifts
of 5 and 15.
Notes and References
Chromenes, Chromanones, and Chromones; Ellis, G.P., Ed.; The Chemistry of Heterocyclic
Compounds; Wiley: New York, 1977; Chapter 2.
l.
a) Zhang, W.; Loebach, J.L.; Wilson, S.R.; Jacobsen, E.N.J. Am. Chem. Soc. 1990, 112, 2801.
b) Zhang, W.; Jacobsen, E.N.J. Org. Chem. 1991, 56, 2296. c) Jacobsen, E.N.; Zhang, W.;
Muci, A.R.; Ecker, J.R.; Deng, L. submitted for publication, d) See also: Irie, R.; Noda, K.; Ito,
Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055.
2.
Pharmacology ofAntihypertensive Therapeutics; Ganten, D. and Mulrow, P.J., Eds.; Handbook of
Experimental Pharmacology, Vol. 93; Springer-Verlag: New York, 1990; pp. 656-666.
3.
Evans, J.M.; Stemp, G. Chem. Brit. 1991, 439.
4.
5.
a) 5 and 7: Evans, J.M.; Fake, C.S.; Hamilton, T.C.; Poyser, R.H.; Watts, E.A.J. Med. Chem.
1983, 26, 1582. b) 9: Strunz, G.M.; Brillon, D.; Gigurre, P. Can. J. Chem. 1983, 61, 1963. c)
Compound 11 was prepared by methylation (K2CO3/MeI) of the corresponding phenol derivative:
Narkhede, D.D.; Iyer, P.R.; Iyer, C.S.R. Tetrahedron 1990, 46, 2031. The free phenol derivative
is not reactive toward the standard epoxidation conditions, d) 13 and 17: Talley, J. Synthesis
1983, 845. e) 19: Schweitzer, E.E.; Liehr, J.; Monaco, D.J.J. Org. Chem. 1968, 33, 2416.
The pH of a solution of commercial household bleach (Clorox®) was buffered to pH = 11.3 with
0.05 M Na2HPO4 and 1 N NaOH and then cooled to 0 °C. To 500 mL of this solution
(approximately 0.55 M in NaOC1) was added a solution of 5 (25.0 g, 0.135 mol) and catalyst 4 (3.1
g, 5.0 mmol, 3.7 mol%) in 135 mL ofCH2C12. The two-phase system was mechanically stirred at
0 °C and the reaction progress was monitored by HPLC. After 9 hours, the heterogeneous brown
mixture was filtered through a pad of Celite and the organic phase was separated, washed once with
500 mL saturated NaCI solution, and then dried (Na2SO4). The ee of the crude product obtained
after solvent removal was determined to be 97.2% by GC analysis (see Figure 1). The brown oily
residue was then dissolved in 200 mL of boiling absolute ethanol and then water (200 mL) was
added slowly to the hot solution. A hot gravity filtration afforded a pale yellow solution from which
crystallized 22.1 g of enantiomerically pure 6 as pristine white needles (81% isolated yield).
6.
Direct epoxidation of dimethylchromene derivatives by solutions of dimethyldioxirane in acetone has
7.
8.
9
been reported recently. Bujons, J.; Camps, F.; Messeguer, A. Tetrahedron Lett. 1990 31, 5235.
The instability of the racemic epoxide derived from 17 has been noted previously: Abbott, J.B.;
France, C.J.; Livingstone, R.; Morrey, D.P.J. Chem. Soc.(C) 1967, 1472.
a) Ashwood, V.A.; Buckingham, R.E.; Cassidy, F.; Evans, J.M.; Faruk, E.A.; Hamilton, T.C.;
Nash, D.J.; Stemp, G.; Willcocks, K. J. Med. Chem. 1986, 29, 2194.
Bergmann, R.; Eiermann, V.; Gericke, R. J. Med. Chem. 1990, 33, 2759.
10.
(Received in USA 22 June 1991)