Enantioselective synthesis of imperanene via enzymatic asymmetrization of an intermediary 1,3-diol

Article abstract of DOI:10.1021/ol048802c

(Chemical Equation Presented) Using a chemoenzymatic synthetic strategy, (S)-imperanene and its (R)-enantiomer has been synthesized from vanillin in nine steps. The key step in the synthesis involves the use of Pseudomonas cepacia lipase (PS-30) to induce

Full text of DOI:10.1021/ol048802c

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3297-3300
Enantioselective Synthesis of
Imperanene via Enzymatic
Asymmetrization of an Intermediary
1,3-Diol
Jason A. Carr and Kirpal S. Bisht*
Department of Chemistry, UniVersity of South Florida, Tampa, Florida 33620
kbisht@cas.usf.edu
Received June 23, 2004
ABSTRACT
Using a chemoenzymatic synthetic strategy, (S)-imperanene and its (R)-enantiomer has been synthesized from vanillin in nine steps. The key
step in the synthesis involves the use of Pseudomonas cepacia lipase (PS-30) to induce asymmetrization of the intermediary prochiral 1,3-diol
in >97% ee.
Imperanene (1), a phenolic compound of the rare C6-C4-
C6 class of natural products, has been isolated from Imperata
cylindrical1 and possesses platelet aggregation inhibitory
activity, making it a suitable candidate in the search for
platelet aggregation inhibitors for the treatment of diseases
such as stroke. Although imperanene was isolated as a single
(+)-isomer, its absolute stereochemistry was not reported.
Shattuck et al. have since established, through comparison
of optical rotation data, the natural product to be the (S)-
enantiomer.2
(-)-enantiomer starting from hydroxymatairesinol, a natural
lignan from the Norway spruce. Doyle et al.4 reported the
synthesis of (S)-(+)-imperanene using an asymmetric chiral
dirhodium(II) catalyst, and Davies et al.5 established the
efficient C-H activation of primary benzylic positions by
means of rhodium carbenoid induced C-H insertion toward
the synthesis of (+)-imperanene and (-)-conidendrin. In-
terestingly, all synthetic methods described above required
the use of a chiral auxiliary or an organometallic catalyst.
The semisynthetic method is very efficient but is not
amenable to synthesis of the natural enantiomer or its
structural analogues.
To date, four different synthetic approaches to imperanene
have been reported. Shattuck et al.2 employed the RAMP/
SAMP chiral auxiliary method for asymmetric synthesis of
both enantiomers of imperanene (1), whereas Eklund et al.3
used a semisynthetic method for the synthesis of the (R)-
* To whom correspondence should be addressed. Fax: 813 974 3203.
Tel: 813 974 0350.
(1) Matsunaga, K.; Shibuya, M.; Ohizumi Y. J. Nat. Prod. 1995, 58,
138.
(2) Shattuck, J. C.; Shreve, C. M.; Solomon, S. E. Org. Lett. 2001, 3,
3021.
(4) Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org. Chem. 2002, 67,
2954.
(3) Eklund, P. C.; Riska, A. I.; Sjo¨holm, R. E. J. Org. Chem. 2002, 67,
7544.
(5) Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941.
10.1021/ol048802c CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004

We envisaged a diVergent-conVergent synthetic strategy
to imperanene starting from vanillin, which can be converted
to a 1,3-diol (8) and the Wittig reagent (6) (Scheme 1).
Scheme 2a
Scheme 1a
a P ) protecting group.
a Conditions: (i) tosyl chloride, K2CO3, acetone, reflux, 24 h,
95%; (ii) NaBH4, MeOH, 0 °C, 8 h, 99%; (iii) PBr3, ether, rt, 3 h,
98%; (iv) triphenylphosphine, toluene, reflux, 24 h, 97%; (v)
diethylmalonate, NaH, 0 °C, 8 h, 88%.
The 1,3-diol is a key intermediate as it is prochiral and
can be converted to an enantiomerically pure intermediate
(B) in high yield. Thus diverging from a commercially
inexpensive starting material (vanillin), the two pieces of the
carbon skeleton of imperanene would be obtained. (S)-(+)-
Imperanene would be readily derived through a Wittig
coupling reaction of the aldehyde obtained from the (S)-
enantiomer of B with the ylide generated from A. Similarly,
the (R)-(-)-enantiomer would be derived from the (R)-
enantiomer of B. The highlight of this strategy is the
enantiocontrol exhibited by the biocatalyst during enzymatic
acetylation of the prochiral 1,3-diol. Asymmetrization of
prochiral diol intermediates is a very useful synthetic strategy
because the maximum feasible yield upon lipase-catalyzed
transformation is not limited to 50%, as happens when
resolving racemates.6
Our choice of lipases as biocatalyst for the asymmetriza-
tion of the prochiral 1,3-diol was based upon their ability to
assume a variety of conformations to accommodate substrates
of varying sizes and complexities, providing one of the most
useful and versatile biocatalytic methods in asymmetric
synthesis and resolution of organic substrates with high
efficiency and selectivity.7 Furthermore, the lipase used
herein was recyclable and was reused without significant loss
in activity.
Subsequent reduction with sodium borohydride yielded the
alcohol (4) in 99% yield, which was readily brominated using
phosphorus tribromide to afford the bromide (5) quantita-
tively.9 It is important to note that the first four steps were
readily amendable to large scales; high yields were achieved
and no purifications by wet column chromatography were
required. Purifications were easily accomplished by recrys-
tallization.
The bromide (5) served as the intermediate for the
divergent synthesis of the triphenylphosphonium bromide salt
(6) (yield ) 97%), which was synthesized by refluxing 5
with triphenylphosphine in toluene for 24 h and for the
symmetrical alkylation of diethylmalonate affording the
monoalkylated diethylmalonate (7) (yield ) 88%), which
was easily separated from the dialkylated product (5-10%
yield) by column chromatography.
Reduction of the alkylated diethylmalonate (7) to the
prochiral 1,3-diol (8) was accomplished using NaBH4/LiCl
(1:1.5) in methanol/ether (1:3) (Scheme 3).10 The resulting
diol was then selectively acylated using vinyl acetate as the
acylating agent in the presence of lipase form Pseudomonas
cepacia (Amano lipase PS-30). A systematic screening of a
number of different lipases available in our laboratories led
us to the most efficient route through use of the lipase PS-
30.
The reaction gave the (R)-(+)-monoacetate (9) in good
yield with high enantioselectivity.11 The enantiopurity of the
product acetate (9) was calculated from its 1H NMR spectra
acquired in the presence of (+)-Eu(tfc)3, a chiral shift reagent
Our strategy for synthesis of imperanene began with the
tosylation of vanillin (2) with tosyl chloride, affording the
tosylated aldehyde (3) in 95% yield (Scheme 2). The choice
of the protecting group turned out to be quite important.8
(6) (a) Carr, J. A.; Al-Azemi, T. F.; Long, T. E.; Shim, J. Y.; Coates, C.
M.; Turos, E.; Bisht, K. S. Tetrahedron 2003, 59, 9147. (b) Al-Azemi, T.
F.; Kondaveti, L; Bisht, K. S. Macromolecules 2002, 35, 3380. (c)
Kondaveti, L; Al-Azemi, T. F.; Bisht, K. S. Tetrahedron: Asymmetry 2002,
13, 129.
(7) (a) Carr, J. A.; Bisht, K. S. Tetrahedron 2003, 59, 7713. (b) Xu, C;
Yuan, C. Tetrahedron 2004, 60, 3883. (c) Sundby, E.; Perk, L.; Anthonsen,
T; Aasen, A. J.; Hansen, T. V. Tetrahedron 2004, 60, 521.
(8) Other protecting groups such as TBDMS, Bn, and PMB were initially
utilized, but they proved to be liabilities during the course of the subsequent
reactions, often resulting in low-yielding or failed reactions.
(9) Oeveren, A. V.; Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem.
1994, 59, 5999.
(10) Yang, C.; Pittman, C. U. Synth. Commun. 1998, 28 (11), 2027.
(11) Maximum yield upon enzymatic acetylation was 62%. The unreacted
diol was recovered, and acetylation was repeated with recovered enzyme
to give a total yield of 90% of combined enantiopure monoacetate (9), [R]25
) +7.9°.
D
3298
Org. Lett., Vol. 6, No. 19, 2004

(+)-Eu(tfc)3.12 The product monoacetate (9) obtained by
lipase desymmetrization reveals a singlet for both the
methoxy and acetoxy protons in the presence of (+)-Eu-
(tfc)3.12
Scheme 3a
The enantiomerically enriched monoacetate was oxidized
to the aldehyde (10), which was particularly sensitive to the
choice of oxidizing agent used. Oxidation with pyridinium
chlorochromate (PCC) or with Parikh-Doering reagent (SO3‚
pyridine) failed to furnish the desired aldehyde 10. Instead,
an appropriately substituted 2-benzylacrolein was isolated,
which we believe results upon â-elimination of the acetoxy
group in 10 with loss of acetic acid. However, Dess-Martin
periodinane in dry dichloromethane at 0 °C gave the desired
product 10 in 75% yield with minimal side reaction. It is
important to note that when the reaction was allowed to
proceed for longer than 6 h, the yield of the undesired
â-elimination side product leading to the loss of acetic acid
increased substantially. Because of its instability, the alde-
hyde 10 was taken directly to the next step without further
purification.
a Conditions: (i) NaBH4, LiCl in MeOH/ether (1:3), 0 °C, 24 h,
89%; (ii) vinyl acetate, PS-30, 40 °C, 48 h, 90%; (iii) Dess-Martin
periodinane, CH2Cl2, rt, 6 h, 75%.
(Figure 1). The resonance signal of the methoxy and acetoxy
protons in the racemic mixture, singlets in absence of the
chiral shift reagent, was split into a set of two signals of
equal intensity for the two enantiomers in the presence of
The final assembly of (R)-(-)-imperanene began with the
coupling of aldehyde 10 with Wittig reagent 6 that was
synthesized in Scheme 1. The trans-pertosylated imperanene
(11) was the favored diastereomer of the product alkene
(88%, a 9:1 diastereomeric ratio) (Scheme 4).13 The isomers
Scheme 4a
a Conditions: (i) 6, n-butyllithium, 0 °C, 24 h, 88%; (ii) KOH,
ethanol, reflux, 3 h, 60%.
were separated by wet column chromatography over silica
gel. Global deprotection of the p-tosyl and acetyl protecting
groups was achieved by refluxing isomer 11 in ethanolic
KOH for 3 h followed by chromatographic purification to
yield (R)-(-)-imperanene in 60% yield. The specific rotation
value of the product matched with that of the (R)-(-)-
imperanene reported in the literature ([R]25 ) -98.2° (c
D
0.011 g/mL, CHCl3)).14
To synthesize the (S)-(+)-imperanene, inversion of stereo-
chemistry in the monoacetate was accomplished after the
1
Figure 1. (a) H NMR of racemic monoacetate (9) with (+)-Eu-
(12) The enantiomeric excess was determined from the 1H NMR spectrum
recorded in the presence of the (+)-Eu(tfc)3 using the following equation:
ee ) [(R) - (S)]/[(R) + (S)] × 100%.
(tfc)3. (b) 1H NMR of enantiorich monoacetate by PS-30 with (+)-
Eu(tfc)3. 9c) 1H NMR of racemic and enantiorich monoacetate with
(+)-Eu(tfc)3. All spectra were taken in CDCl3 at 25 °C at 500 MHz.
(13) The diastereomeric ratio was determined via 1H NMR by comparing
the ratio of the alkenyl protons of the crude reaction mixture.
Org. Lett., Vol. 6, No. 19, 2004
3299

enantiopure monoacetate (9) was tosylated with tosyl chloride
in dichloromethane using triethylamine/DMAP to furnish 12
(yield ) 93%) (Scheme 5). Deacetylation of 12 using K2-
CO3 in methanol gave the mono-ol (13) in 86% yield, which
was oxidized under conditions previously stated to give the
desired aldehyde 14. The aldehyde (14) proved to be more
stable than its acetylated counterpart (10). This stability is
probably due to a steric encumbrance of the â-tosyl group,
suppressing elimination of the R-proton. Similarly, the final
assembly of (S)-(+)-imperanene began with the coupling of
aldehyde 14 with the Wittig reagent 6 to give 15 (yield )
72%), in a diastereomeric ratio 7:1 in favor of the trans-
stereoisomer. Separation of diastereomers was accomplished
via wet column chromatography, and removal of the p-tosyl
protecting groups in refluxing ethanolic KOH gave (S)-(+)-
Scheme 5a
imperanene in 56% yield ([R]25 ) + 104° (c 0.01 g/mL,
D
CHCl3)).14
In conclusion, an enantioselective synthesis of both (S)-
(+)- and (R)-(-)-imperanene has been demonstrated starting
from vanillin, with overall yields of 19% and 24%, respec-
tively. In the core reaction, PS-30 served as the biocatalyst
for asymmetrization of the prochiral diol (8), providing the
monoacetate (9) in enantiomeric excesses of >97%. The
specific rotation values are in agreement with reported
literature values.
Acknowledgment. Financial support for this work from
the American Cancer Society, the Herman Frasch Founda-
tion, and the American Lung Association is greatly appreci-
ated.
Supporting Information Available: Complete experi-
mental procedure and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048802C
a Conditions: (i) tosyl chloride, triethylamine, DMAP, dry
CH2Cl2, 0 °C, 93%; (ii) K2CO3, MeOH, 0 °C, 87%; (iii) Dess-
Martin periodane, CH2Cl2, rt, 6h, 83%; (iv) 6, n-butyllithium, THF,
0 °C, 80%; (v) KOH, ethanol, reflux, 3 h, 56%.
(14) Although the natural imperanene was reported to have [R]25
)
D
+700 by Matsunaga et al.1, Doyle et al.2 reported [R]25D ) +103 for 93%
enantioenriched sample and have explained the discrepancy in reported
[R]25 for natural product and observed value for the synthetic sample.
D
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Org. Lett., Vol. 6, No. 19, 2004