Asymmetric Diels-Alder reactions of chiral 1-amino-3-siloxy-1,3- butadiene: Application to the enantioselective synthesis of (-)-α-elemene [5]

Full text of DOI:10.1021/ja971272d

J. Am. Chem. Soc. 1997, 119, 7165-7166
7165
Asymmetric Diels-Alder Reactions of Chiral
1-Amino-3-siloxy-1,3-butadiene: Application to the
Enantioselective Synthesis of (-)-r-Elemene
Sergey A. Kozmin and Viresh H. Rawal*
(2)
Department of Chemistry
The UniVersity of Chicago
Chicago, Illinois 60637
trans-diphenylpyrrolidine (5), available in >98% ee by Chong’s
protocol,7 with methoxybutenone afforded vinylogous amide 2
in 90% yield.8 Compound 2 was converted to the potassium
enolate and silylated using tert-butyldimethylsilyl chloride (TBS-
Cl) to afford the desired chiral amino siloxy diene 3 in
essentially quantitative yield after removal of the solvent and
volatile reagents.
We first examined the thermal Diels-Alder reaction of diene
3 with methacrolein, which proceeded from 0 °C to rt and gave
in 94% yield a single cycloadduct (4), assigned to be the endo
diastereomer. Reduction of the carbonyl group followed by
hydrolysis gave rise to the corresponding cyclohexenone 5 in
85% ee, as determined by GLC analysis of the corresponding
trimethylsilyl (TMS) ether using a chiral B-DM column (eq 3).
Diphenylpyrrolidine (1) was fully recovered, with its enantio-
meric purity unchanged.
ReceiVed April 22, 1997
The development of efficient methods for the preparation of
structurally complex molecules in enantiomerically pure form
is a fundamental challenge of modern organic synthesis. Among
various processes capable of controlling the absolute stereo-
chemistry of the final product, the asymmetric Diels-Alder
reaction is perhaps the most powerful. The vast majority of
investigations on this topic have taken advantage of chirally-
modified dienophiles1 to induce asymmetry in the cycloaddition
reaction, although the use of chiral Lewis acid catalysts has
also received considerable attention of late.2 By contrast, there
are very few examples of the use of chiral dienes for the Diels-
Alder reaction.3-5 We recently developed an efficient method
for the preparation of 1-amino-3-siloxybutadienes and demon-
strated their usefulness in various [4 + 2] cycloadditions (eq
1).6 In a significant advance in this methodology, we report
(1)
(3)
The absolute stereochemistry of the newly created quaternary
chiral center was established through a concise synthesis of
R-elemene, a naturally-derived terpene (Scheme 1).9 Thus,
Wittig methylenation of the Diels-Alder adduct 4 followed by
hydrolysis afforded vinylcyclohexenone 7 in high yield. The
that chirally-modified versions of the amino siloxy dienes
undergo Diels-Alder cycloadditions with high to excellent facial
selectivity and provide a simple, reliable route to substituted
cyclohexenones having high enantiomeric excesses (ee).
An important advantage of the amino siloxy diene, aside from
its high reactivity,6 is that the amino substituent opens up the
possibility of using a chiral amine. Resonance interactions were
expected to cause the substituents on the amine to be held in
the same plane as the alkene, such that the chiral portion would
block one quadrant around the diene. We elected to examine
a C2-symmetric amine, in the hope of circumventing a potential
rotomer issue, thereby reducing the number of possible diaster-
eomeric transition states and making the asymmetry-inducing
step more predictable.
10
reaction of the enone with i-PrLi in the presence of CeCl3
gave the 1,2-addition product, which was oxidized to enone 8
using pyridinium chlorochromate (PCC).11 A second CeCl3-
promoted addition of i-PrLi followed by acid-catalyzed dehy-
dration afforded R-elemene (9) that was spectroscopically
identical to the reported compound. The optical rotation of the
synthetic material ([R]20D ) -99.0°, CHCl3, c ) 1.1, 88% ee)
confirmed it to possess the opposite absolute stereochemistry
to that of the naturally-derived material (lit.9b [R]25D ) +112°).
The required chiral diene 3 was prepared by the two-step
sequence shown (eq 2). Condensation of the C2-symmetric (+)-
(7) Chong, J. M.; Clarke, I. S.; Koch, I.; Olbach, P. C.; Taylor, N. J.
Tetrahedron: Asymmetry 1995, 6, 409-418.
(8) Lienhard, U.; Fahrni, H.-P.; Neuenschwander, M. HelV. Chim. Acta
1978, 61, 1609-1621.
(1) For reviews, see: (a) Oppolzer, W. Angew. Chem., Int. Ed. Engl.
1984, 23, 876-889. (b) Taschner, M. J. Asymmetric Diels-Alder Reactions;
Taschner, M. J., Ed.; Jai Press, Inc.: Greenwich, 1989; Vol. 1, pp 1-101.
(2) For reviews, see: (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92,
1007-1019. (b) Narasaka, K. Synthesis 1991, 1-11.
(3) For reviews, see: (a) Enders, D.; Meyer, O. Liebigs Ann. 1996, 1023-
1035. (b) Krohn, K. Angew. Chem., Int. Ed., Engl. 1993, 32, 1582-1584.
(4) For examples of chiral alkoxy dienes, see: (a) Trost, B. M.;
O’Krongly, D.; Belletire, J. L. J. Am. Chem. Soc. 1980, 102, 7595-7596.
(b) Lubineau, A.; Queneau, Y. J. Org. Chem. 1987, 52, 1001-1007. (c)
Gupta, R. C.; Larsen, D. S.; Stoodley, R. J.; Slawin, A. M. Z.; Williams,
D. J. J. Chem. Soc., Perkin. Trans. 1 1989, 739-749 and references cited
therein. (d) Tripathy, R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem. Soc.
1991, 113, 7630-7640. (e) Boehler, M. A.; Konopelski, J. P. Tetrahedron
1991, 47, 4519-4538.
(9) (a) Paknikar, S. K.; Bhattacharyya, S. C. Tetrahedron 1962, 18,
1509-1517. (b) Mehta, G.; Acharyulu, P. V. R. J. Chem. Soc., Chem.
Commun. 1994, 2759-2760.
(10) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904-3912.
(11) Dauben, W., G.; Michno, D., M. J. Org. Chem. 1977, 42, 682-
685.
(12) Typical procedure for the Diels-Alder reaction, followed by
reduction and hydrolysis. (i) A solution of diene 3 (1 mmol) in toluene (2
mL) was treated with the dienophile (1.5-3 mmol) and stirred at 20 °C for
1-3 days. Concentration of the solution in vacuo, followed by flash
chromatography on silica gel (with 2-5% triethylamine in the eluent),
afforded the corresponding cycloadducts. (ii) The cycloadducts were reduced
with lithium aluminum hydride (3-6 mmol) in ether (2-6 mL, 78 °C to
rt). The excess hydride was quenched with a minimum amount of water
and anhydrous Na2SO4 to afford the expected alcohol, which was sufficiently
pure for the hydrolysis step. (iii) A solution of the crude alcohol in
acetonitrile (3 mL) was treated with 10% aqueous HF in acetonitrile (0.55
mL, 2.0 mmol). After stirring the mixture for 1 h at room temperature,
solid K2CO3 was added and stirring was continued for 30 min. The solids
were removed, and the residue was concentrated and purified directly by
flash chromatography to give the desired cyclohexenones shown (Table
1).
(5) For examples of chiral amino dienes, see: (a) Menezes, R. F.; Zezza,
C. A.; Sheu, J.; Smith, M. B. Tetrahedron Lett. 1989, 30, 3295-3298. (b)
Enders, D.; Meyer, O.; Raabe, G. Synthesis 1992, 1242-1244. (c)
Barluenga, J.; Aznar, F.; Valdes, C.; Martin, A.; Garcia-Granda, S.; Martin,
E. J. Am. Chem. Soc. 1993, 115, 4403-4404. (d) Schlessinger, R. H.; Pettus,
T. R. R. J. Org. Chem. 1994, 59, 3246-3247. (e) Murphy, J. P.;
Nieuwenhuyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J.
Tetrahedron Lett. 1995, 36, 9533-9536.
(6) Kozmin, S. A.; Rawal, V. H. J. Org. Chem., in press.
S0002-7863(97)01272-9 CCC: $14.00 © 1997 American Chemical Society

7166 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Communications to the Editor
Table 1. The Diels-Alder Reaction of Diene 7 with Various
Dienophiles
Scheme 1
The asymmetric induction observed for the cycloaddition with
methacrolein can be rationalized by considering the two endo
transition states (A and B). The major adduct arises via
transition state A, in which the larger group on the dienophile
is placed in the open pocket of the chiral pyrrolidine.
1
a See ref 12 for a general procedure. b ee determined by H NMR
analysis of the corresponding Mosher ester. c ee of the corresponding
acetate determined by capillary GLC analysis using a chiral B-DM
column (Advanced Separation Technologies, Inc.). d ee of the corre-
sponding TMS ether determined by HPLC analysis using chiral
Whelk-O 1 column (Regis Technologies, Inc.). e Initial cycloaddition
carried out at 85 °C.
We have examined the reaction of diene 3 with several
different dienophiles, and the results are summarized in Table
1. The reactions of 3 with R-unsubstituted dienophiles are
particularly interesting (entries 2-7). For example, the reaction
of diene 3 with methyl acrylate proceeded at room temperature
to yield a mixture of three diastereomers in ca. 20:2:1 ratio.
However, upon reduction of the ester group and acid hydrolysis
of the resulting product, the cyclohexenone species was obtained
as a 96.5:3.5 ratio of enantiomers by chiral GC (93% ee), much
higher than might have been anticipated from the mixture of
diastereomers of cycloaddition products. This result emphasizes
the advantage of using a C2-symmetric auxiliary: diastereofacial
selection by the diene induces the same absolute stereochemistry
at the carbon R to the withdrawing group, for both the endo
and exo cycloadducts. Also noteworthy is the absolute stere-
ochemistry of the electron-withdrawing group, which is opposite
to that found for meth- and ethacrolein, seemingly inconsistent
with the proposed model. In fact, the result is fully consistent
with a steric-effect model. Of the four possible transition states,
the two favored should be C and D, in which the larger group
on the dienophile is away from the phenyl group. A sterically
more demanding withdrawing group would be expected to result
in even better facial selectivity. Indeed, the cycloaddition using
tert-butyl acrylate afforded the cyclohexenone product with
greater than 98% ee. As can be seen from the table, other
R-unsubstituted acrylates undergo cycloaddition with excellent
facial selectivity and provide access to differently functionalized
cyclohexenones. Facial discrimination was high even for cyclo-
additions carried out at rather high temperatures (entry 4, 85
°C).
Our results show that chiral 1-amino-3-siloxy-1,3-butadiene
(3) represents an important advance to the available methods
for asymmetric synthesis. Diene 3 is prepared efficiently and
reacts readily with a variety of dienophiles. The cycloadditions
proceed with high to excellent facial selectivity, which is
particularly remarkable for reactions carried out at room
temperature or higher, and allow a simple preparation of
substituted cyclohexenones with high ee.
Acknowledgment. We thank the University of Chicago for financial
support of this work. Pfizer Inc. and Merck & Co. are also gratefully
acknowledged for additional financial support.
Supporting Information Available: Experimental procedures and
spectral data of all new compounds employed in this study (37 pages).
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JA971272D