Enantioselective synthesis of imperanene, a platelet aggregation inhibitor

Article abstract of DOI:10.1021/ol0164482

matrix presented Both enantiomers of imperanene, a platelet aggregation inhibitor, have been synthesized in 82-90% ee. The key step of establishing the chiral center was achieved through stereoselective alkylation with benzyl chloromethyl ether using Enders' RAMP/SAMP chiral auxiliary method. The natural product was determined to be the (S)-enantiomer through comparison of optical rotation data.

Full text of DOI:10.1021/ol0164482

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3021-3023
Enantioselective Synthesis of
Imperanene, a Platelet Aggregation
Inhibitor
James C. Shattuck,* Cheney M. Shreve, and Sandra E. Solomon
Department of Chemistry, UniVersity of Hartford,
West Hartford, Connecticut 06117-1599
shattuck@mail.hartford.edu
Received July 17, 2001
ABSTRACT
Both enantiomers of imperanene, a platelet aggregation inhibitor, have been synthesized in 82−90% ee. The key step of establishing the chiral
center was achieved through stereoselective alkylation with benzyl chloromethyl ether using Enders’ RAMP/SAMP chiral auxiliary method.
The natural product was determined to be the (S)-enantiomer through comparison of optical rotation data.
Imperanene (1) is a phenolic compound isolated from the
rhizomes of the plant Imperata cylindrica.1 This plant is used
in Chinese traditional medicine as an antiinflammatory and
diuretic agent. Imperanene was found to completely inhibit
rabbit platelet aggregation induced by thrombin at a con-
centration of 6 × 10-4M.
stroke is a very active research area. While imperanene was
isolated as a single enantiomer, the configuration of the
stereogenic carbon was not determined. The mode of action
of imperanene remains unexplored. The synthesis of both
enantiomers of imperanene is an important first step in further
studies on this class of compounds. We have synthesized
both enantiomers of imperanene in an eight-step synthesis
with 82-90% ee.
The key step of asymmetric induction utilizes Enders’
method with the chiral auxiliary (S)-1-amino-2-methoxy-
methylpyrrolidine (SAMP) or the (R)-enantiomer (RAMP).4
The chiral auxiliary reacts with an aldehyde to form a hydra-
zone that can then be alkylated. The enantiofacial selectivity
of alkylation is dependent on whether RAMP or SAMP is
used. This versatile route allows for formation of both enan-
tiomers of imperanene through a parallel reaction sequence.
Other members of this rare C6-C4-C6 class of natural
products have also shown biological activity,2 including
antiplatelet aggregation.3 The search for new platelet ag-
gregation inhibitors to treat diseases such as heart attack and
(3) (a) Gulavita, N. K.; Pomponi, S. A.; Wright, A. E.; Garay, M.; Sills,
M. A. J. Nat. Prod. 1995, 58, 954. (b) Chen, C. C.; Wu, L. G.; Ko, F. N.;
Teng, C. M. J. Nat. Prod. 1994, 57, 1271.
(4) (a) Enders, D.; Kipphardt, H.; Fey, P. In Organic Syntheses; Wiley:
New York, 1993; Collect. Vol. VIII, p 403. (b) Enders, D. In Asymmetric
Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984; Vol. 3, Chapter
4. (c) Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer, K. A.
M. Tetrahedron 1984, 40, 1345. (d) Enders, D.; Reinhold, U. Synlett 1994,
792.
(1) Matsunaga, K.; Shibuya, M.; Ohizumi Y. J. Nat. Prod. 1995, 58,
138.
(2) (a) Ishida, M.; Hamasaki, T.; Hatsuda, Y. Agric. Biol. Chem. 1975,
11, 2181. (b) Green, D.; Kashman, Y.; Miroz, A. J. Nat. Prod. 1993, 56,
1201.
10.1021/ol0164482 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/30/2001

Our synthesis of imperanene begins with the formation
of the appropriate aldehyde for the Enders’ sequence
(Scheme 1). Protection of eugenol (2) gave silyl ether 3 in
chiral hydrazone 5 in 84% yield. In a separate reaction, 4
was converted to the RAMP-based hydrazone 6 in 82% yield.
Benzyl chloromethyl ether6 was used as the alkylating agent
in the Enders’ reaction sequence to introduce a one-carbon
benzyl-protected alcohol group in a single step. Deprotona-
tion of 5 with LDA and alkylation with benzyl chloromethyl
ether at -120 °C gave a 77% yield of the (R)-enantiomer 7.
The corresponding (S)-enantiomer 8 was formed in 75% yield
from 6. Determining the diastereomeric excess for the
Scheme 1a
1
alkylated hydrazones was problematic. Analysis of H and
13C NMR spectra and the use of NMR chiral shift reagents
were unsuccessful. The stereoselectivity of the alkylation
reaction was determined after removal of the RAMP/SAMP
chiral auxiliary as shown in Scheme 3.
a (a) tert-Butyldimethylsilyl chloride, imidazole, DMF, rt, 19 h,
78%; (b) (i) disiamylborane, 0 °C, 3 h; (ii) PCC, CH2Cl2, reflux, 2
h, 75%.
Scheme 3a
78% yield. Following a procedure of Brown and co-workers,5
treatment of 3 with disiamylborane and subsequent oxidation
with pyridinium chlorochromate afforded aldehyde 4 in 75%
yield.
The asymmetric alkylation steps (Scheme 2) involve the
reaction of 4 with the SAMP chiral auxiliary to generate
Scheme 2a
a (a) Ozone, CH2Cl2, -78 °C, 30 min, (79% for 9, 75%for 10);
(b) TMSOTf (cat.), CH2Cl2, -78 °C for 3 h, then 0 °C for 1 h,
(76% for 12, 72% for 13).
Ozonolysis of the alkylated hydrazones 7 and 8 at -78
°C removed the chiral auxiliary to form aldehydes 9 and
10, respectively. For determining the enantioselectivity of
the alkylation step, aldehydes 9 and 10 were combined with
the (R,R)-diol derivative 11 to give acetals 12 and 13,
respectively.7 The 13C NMR spectra of these acetals were
analyzed to determine the ee values. The chiral shift reagent
Eu(fod)3 enhanced the separation of the carbon signals to
improve the resolution. The alkylation reaction was highly
selective with an enantiomeric excess of 82-90% for 12,
the acetal of aldehyde 9 formed from the SAMP reaction
sequence. The ee of 13, the acetal of aldehyde 10 formed
from the RAMP reaction sequence, ranged from 82 to 89%.
The final assembly of imperanene involved the coupling
of aldehyde 9 or 10 with the Wittig reagent synthesized as
shown in Scheme 4. Protection of 2-methoxy-4-methylphenol
14 gave 15 in 86% yield, which upon benzylic bromination,
(5) Brown, H. C.; Kulkarni, S. U.; Rao, C. G. Synthesis 1980, 151.
(6) Connor, S. J.; Klein, G. W.; Taylor, G. N.; Boeckman, R. K.; Medwid,
J. B. In Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p
101.
(7) (a) Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2183.
(b) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(c) Parker, D. Chem. ReV. 1991, 91, 1441.
a (a) SAMP, 0 °C f rt, 20 h, 84%; (b) RAMP, 0 °C f rt, 20 h,
82%; (c) (i) LDA, 0 °C, 5.5 h; (ii) benzyl chloromethyl ether, -120
°C for 20 min, then rt for 20 h, (77% for 7, 75% for 8).
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Org. Lett., Vol. 3, No. 19, 2001

potassium tert-butoxide as bases led to elimination of the
benzyl group from 9. Using the cosolvent HMPA gave
similar results. n-Butyllithium showed no such elimination
and gave complete conversion to the desired alkene 18.
Addition of the aldehyde to the Wittig reagent at 0 °C with
subsequent warming to room temperature gave the optimal
trans/cis ratio. This same reaction with the enantiomeric
aldehyde 10 produced alkene 19 in 63% yield.
Scheme 4a
Removal of the benzyl protecting group proved to be
problematic. Hydrogenation, treatment with acetic or hydro-
chloric acid,9 oxidation with DDQ,10 and reaction with
trimethylsilyl iodide11 were all either low-yielding or unsuc-
cessful. Our initial effort at debenzylation through the use
of phenylthiotrimethylsilane, zinc iodide, and tetrabutyl-
ammonium iodide at reflux for 2 h, following the literature
conditions,12 led to decomposition. However, we found that
in 2.5 h at room temperature, the benzyl group of 18 was
converted to the trimethylsilyl group to give 20 in 65% yield.
Benzyl ether 19 was converted to 21 (59% yield) in 1 h.
Final removal of the silyl protecting groups by treatment with
TBAF gave both enantiomers of imperanene 1a (82%) and
1b (75%). The synthetic imperanene showed spectroscopic
properties identical to those of the natural product, and
enantiomer 1b showed a comparable optical rotation.1
Therefore, (S)-imperanene is the natural and biologically
active enantiomer.
a (a) TBDMSCl, imidazole, DMF, rt, 3 h, 86%; (b) NBS, benzoyl
peroxide (cat.), CCl4, reflux, 3 h; (c) PPh3, toluene, reflux, 19 h,
50% from 15.
afforded the alkyl bromide 16, following the literature
procedure.8 This compound was unstable and therefore was
used in the next step directly without purification. Treatment
of 16 with triphenylphosphine gave the desired Wittig reagent
17 in 50% yield from 15.
Aldehyde 9 was coupled to 17 to produce alkene 18 in a
5:1 ratio of the desired trans alkene to the cis isomer.
(Scheme 5) Purification by silica gel flash chromatography
Scheme 5a
In conclusion, both enantiomers of imperanene were
synthesized in eight steps using the RAMP/SAMP chiral
auxiliary method for asymmetric induction. Enantiomeric
excess values of 82-90% have been obtained. Comparison
of the optical rotation values of 1a and 1b to the literature
value of the isolated imperanene reveals that the natural
product is the (S)-enantiomer. This synthetic route will enable
further investigation into the physiological properties of
related compounds.
Acknowledgment. This research was supported by a
Cottrell College Science Award from Research Corporation
and funding from the University of Hartford. Funding for
the Bruker 200 mHz NMR spectrometer from the National
Science Foundation (DUE-9750449) and the Alden Trust
Corporation is gratefully acknowledged.
Supporting Information Available: Complete experi-
mental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
a (a) n-BuLi (2 equiv), 17 (2 equiv), THF, 0 °C (30 min) f rt
(19 h), 18 ) 72%, 19 ) 63%; (b) PhSSiMe3(10 equiv), n-Bu4NI
(1.5 equiv), ZnI2 (5 equiv), ClCH2CH2Cl, rt, 20 ) 65%, 21 ) 59%;
(c) TBAF (3.3 equiv), THF, rt, 30 min, 1a ) 82%, 1b ) 75%.
OL0164482
(8) Hatanka, M.; Himeda, Y.; Imashiro, R.; Tanaka, Y.; Ueda, I. J. Org.
Chem. 1994, 59, 111.
(9) Cabedo, N.; Protais, P.; Cassels, B. K.; Cortes, D. J. Nat. Prod. 1998,
61, 709.
(10) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029.
(11) Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.
(12) (a) Hanessian, S.; Guindon, Y. Tetrahedron Lett. 1980, 21, 2305.
(b) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chem. Soc. 1982,
104, 2027.
successfully removed the minor cis-isomer. In optimizing
the Wittig reaction, the choice of base and the reaction
temperature were manipulated to improve both the yield and
the trans-selectivity. The use of NaHMDS, KHMDS, and
Org. Lett., Vol. 3, No. 19, 2001
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