Exploration of the enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters

Article abstract of DOI:10.1021/jo0621423

(Chemical Equation Presented) Quaternary stereocenters on a 2-cyclohexen-1-one ring are synthesized with good to excellent levels of enantioselectivity. The quaternary stereocenter is created through a new synthetic sequence involving three reactions: the

Full text of DOI:10.1021/jo0621423

Exploration of the Enantioselective Birch-Cope Sequence for the
Synthesis of Carbocyclic Quaternary Stereocenters
Tapas Paul, William P. Malachowski,* and Jisun Lee
Department of Chemistry, Bryn Mawr College, Bryn Mawr, PennsylVania 19010-2899
wmalacho@brynmawr.edu
ReceiVed October 16, 2006
Quaternary stereocenters on a 2-cyclohexen-1-one ring are synthesized with good to excellent levels of
enantioselectivity. The quaternary stereocenter is created through a new synthetic sequence involving
three reactions: the enantioselective Birch reduction-allylation, enol ether hydrolysis, and the Cope
rearrangement. To illustrate the ability of the sequence to enantioselectively generate complex structures,
a variety of substrates are described. Notably, the sequence works for the enantioselective generation of
vicinal quaternary-tertiary stereocenters, the generation of congested arylic quaternary stereocenters, and
hydroxyalkyl substituted quaternary stereocenters.
SCHEME 1. Birch-Cope Sequence
Introduction
The enantioselective construction of quaternary stereocenters
is a significant challenge in contemporary synthetic organic
chemistry.1 New synthetic tools capable of generating quaternary
carbons with stereocontrol are necessary due in part to the
abundance of bioactive natural products containing quaternary
stereocenters. In a preliminary report,2 we related a new method,
the Birch-Cope sequence, which can enantioselectively gener-
ate quaternary stereocenters on a carbocyclic ring. The Birch-
Cope sequence combines three reactions: an enantioselective
Birch reduction-allylation,3 an enol ether hydrolysis reaction,
(1) (a) McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
7738-7739. (b) Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71,
1581-1587. (c) Lee, K-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H.
J. Am. Chem. Soc. 2006, 128, 7182-7184. (d) Fillion, E.; Wilsily, A.
J. Am. Chem. Soc. 2006, 128, 2774-2775. For reviews see: (e) Douglas,
C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363-
5367. (f) Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, Federal Republic of Germany, 2005. (g) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363-5367. (h)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105-10146. (i)
Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591-4597.
(j) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-
401. (k) Fuji, K. Chem. ReV. 1993, 93, 2037-2066.
and a Cope rearrangement4 (Scheme 1). The product of the
sequence is a 4,4-disubstituted-2-carboxamide-2-cyclohexen-
1-one, which is a versatile intermediate in natural product
synthesis5 as previously illustrated in a succinct synthesis of
(+)-mesembrine.2 Our earlier report contained only two sub-
strate examples. For the Birch-Cope sequence to have broad
applicability in the synthesis of carbocyclic quaternary stereo-
(4) For reviews of the Cope rearrangement see: (a) Nubbemeyer, U.
Synthesis 2003, 961-1008. (b) Hill, R. K. Cope, Oxy-Cope and Anionic
Oxy-Cope Rearrangements. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 5,
Chapter 7.1, pp 785-826. For recent examples of the Cope rearrangement
see: (c) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006,
128, 2485-2490. (b) Sauer, E. L. O.; Barriault, L. J. Am. Chem. Soc. 2004,
124, 8569-8575.
(2) Paul, T.; Malachowski, W. P.; Lee, J. Org. Lett. 2006, 8, 4007-
4010.
(3) (a) Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.;
Welch, M. J. Am. Chem. Soc. 1988, 110, 7828-7841. For reviews of the
asymmetric Birch reduction-alkylation, see: (b) Schultz, A. G. Chem.
Commun. 1999, 1263-1271. (c) Schultz, A. G. Acc. Chem. Res. 1990, 23,
207-213.
10.1021/jo0621423 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/10/2007
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J. Org. Chem. 2007, 72, 930-937

EnantioselectiVe Birch-Cope Sequence
SCHEME 2. Allyl Derivatives in Birch-Cope Sequence
SCHEME 3. Cope Rearrangement Results for 3c
quaternary center in 2a and of all subsequent Birch products is
based on the preferences reported by Schultz et al.3 and was
confirmed in the previous report2 with the enantioselective
synthesis of (+)-mesembrine. The enantioselectivities seen in
the reactions reported herein are similar to those previously
reported for related C-5 substituted L-prolinol benzamide
substrates.7
Hydrolysis of the enol ether provided 3-cyclohexen-1-one 3a.
Heating 3a at reflux for 10 h in 1,2-dichlorobenzene (1,2-DCB)
resulted in complete conversion to the more thermodynamically
stable 2-cyclohexen-1-one 4a.9 Microwave reactor heating of
3a provided a comparable yield (96%) of 4a but in a much
shorter time (1 h). This represents the first example of
acceleration of a standard Cope rearrangement through micro-
wave heating.10 The three-step Birch-Cope sequence with the
5-methyl derivative 1 was performed on gram scale in 61%
overall yield.
SCHEME 4. Suzuki Reactions with C-5-Halo-o-anisic Acid
Derivatives
Under identical conditions, substitution of trans-crotyl bro-
mide for allyl bromide in the Birch reduction-alkylation provided
a 62% yield of 2b (entry 2, Scheme 2) and much lower
enantioselectivity (dr ) 8:1). Performing the Birch reduction
with lithium instead of potassium afforded the less reactive
lithium enolate (entry 3), which upon reaction with trans-crotyl
bromide improved the enantioselectivity slightly (dr ) 11:1).
Use of a less reactive alkylating agent, trans-crotyl chloride
(entry 4), restored the excellent stereoselectivity to the process
with either lithium or potassium. Presumably, the more reactive
enolates or alkylating agents contributed to a less selective
outcome.
centers, the sequence will have to permit variations of the
o-anisic acid structure and the allylation agent. In this report, a
more thorough exploration of the Birch-Cope sequence is
undertaken, with particular attention to variability in the allyl
group6 and the R group7 (Scheme 1).
Results and Discussion
Reaction of the lithium enolate generated in the Birch
reduction of 1 with dimethylallyl bromide afforded an 88% yield
Allyl Derivatives in the Birch-Cope Sequence. As previ-
ously communicated,2 Birch reduction-allylation of the 5-meth-
yl-o-anisic acid derivative, 1, afforded exceptionally high levels
of enantioselectivity (dr ) 110:1) in the new quaternary center
of 2a (entry 1, Scheme 2).8 The absolute sense of the new
(7) For previous examples of Birch reduction-alkylation with C-5
substituted L-prolinol benzamides see: (a) Guo, Z.; Schultz, A. G.
Tetrahedron Lett. 2004, 45, 919-921. (b) Khim, S.-K.; Dai, M.; Zhang,
X.; Chen, L.; Pettus, L.; Thakkar, K.; Schultz, A. G. J. Org. Chem. 2004,
69, 7728-7733. (c) Schultz, A. G.; Malachowski, W. P.; Pan, Y. J. Org.
Chem. 1997, 62, 1223-1229. (d) Reference 3a.
(8) Diastereomeric ratios for all compounds were determined on purified
material by comparison with an independently synthesized diastereomeric
mixture. The most convenient manner to generate the mixture was to remove
ammonia after the Birch reduction and prior to alkylation.
(5) For previous examples of asymmetric syntheses of 4,4-dialkyl-
cyclohexenones, see: (a) Trost, B. M.; Bream, R. N. Xu, J. Angew. Chem.,
Int. Ed. 2006, 45, 3109-3112. (b) Mohr, P. J.; Halcomb, R. L. J. Am. Chem.
Soc. 2003, 125, 1712-1713. (c) Kozmin, S. A.; Rawal, V. H. J. Am. Chem.
Soc. 1999, 121, 9562-9573. (d) Meyers, A. I.; Berney, D. Org. Synth. 1990,
69, 55-65. For previous examples of asymmetric syntheses of 4-alkyl-4-
aryl-cyclohexenones, see: (e) Taber, D. F.; He, Y. J. Org. Chem. 2005,
70, 7711-7714. (f) Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron:
Asymmetry 1993, 4, 21-24. (g) Meyers, A. I.; Lefker, B. A.; Wanner,
K. T.; Aitken, R. A. J. Org. Chem. 1986, 51, 1936-1938. (h) Otani, G.;
Yamada, S. Chem. Pharm. Bull. 1973, 21, 2125-2129.
(6) For previous examples of Birch reduction-allylation with L-prolinol
benzamides see: (a) Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991,
113, 4931-4936. (b) Schultz, A. G.; Macielag, M.; Podhorez, D. E.;
Suhadolnik, J. C.; Kullnig, R. K. J. Org. Chem. 1988, 53, 2456-2464. (c)
Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109,
6493-6502. (d) Schultz, A. G.; Sundararaman, P. Tetrahedron Lett. 1984,
25, 4591-4594.
(9) Attempted Cope rearrangement of 2a leads to a mixture of products
resulting from competing rearrangements between the two different 1,5-
diene systems.
(10) For examples of oxy-Cope rearrangements accelerated by microwave
see: (a) Gauvreau, D.; Barriault, L. J. Org. Chem. 2005, 70, 1382-1388.
(b) Farand, J. A.; Denissova, I.; Barriault, L. Heterocycles 2004, 62, 735-
748. For examples of silyloxy-Cope rearrangements accelerated by micro-
wave see: (c) Schneider, C.; Khaliel, S. Synlett 2006, 1413-1415. (d)
Davies, H. M. L.; Beckwith, R. E. J. J. Org. Chem. 2004, 69, 9241-9247.
For examples of aza-Cope rearrangements accelerated by microwave see:
(e) Kvaerno, L;, Norrby, P-O; Tanner, D. Org. Biomol. Chem. 2003, 1,
1041-1048. (f) Yadav, J. S.; Subba Reddy, B. V.; Abdul Rasheed, M.;
Sampath Kumar, H. M. Synlett 2000, 487-488.
J. Org. Chem, Vol. 72, No. 3, 2007 931

Paul et al.
SCHEME 5. C-5 Aryl Derivatives in Birch-Cope Sequence
SCHEME 6. Spontaneous Cope Rearrangement of 7a
Under Cope rearrangement conditions, 3c afforded a very
small amount (∼2%) of the expected product, 4c (Scheme 3).
The more common transformation of 3c involved 1,3-migration
of the dimethylallyl group to form 4d (∼8% yield), along with
a considerable amount of decomposition. The creation of two
adjacent quaternary centers is not favored under the equilibrium
conditions of the Cope rearrangement of 3c.
SCHEME 7. Synthesis of C-5 Hydroxyalkyl o-Anisic Acid
C-5 Aryl o-Anisic Acid Derivatives. A variety of biaryl
o-anisic acid derivatives were prepared that would lead to
arylated quaternary carbocyclic stereocenters. Their synthesis
was easily accomplished using a divergent strategy involving
Suzuki coupling reactions of the 5-bromo (5a) or the 5-iodo
o-anisic acid derivative (5b).2 Besides the previously reported
3,4-dimethoxyphenylboronic acid which lead to the synthesis
of (+)-mesembrine,2 phenyl-, 4-methoxyphenyl-, and 2,3-
dimethoxyphenylboronic acid, all provided excellent yields of
the biaryl products (Scheme 4).
Derivatives
Birch reduction-allylation of 6a-d afforded good yields and
high enantioselectivities for all cases (Scheme 5). In our
experience, lithium worked better than potassium for the
reduction of the biaryl compounds.12 The isolated phenyl
derivative 7a was unstable and spontaneously underwent a Cope
rearrangement to form 7e (Scheme 6) while being stored at room
temperature. All other aryl derivatives were stable and did not
show any propensity to undergo rearrangements or degrade.
Hydrolysis of the enol ether occurred uneventfully in high
yield for 7b-d to form 8b-d (Scheme 5). The lower hydrolysis
yield for 7a was partially due to its inherent instability. Cope
rearrangement of 8a-d occurred in high yield for most cases,
but a less favorable equilibrium than for 3a was seen because
of the loss of styrene conjugation in 8a-d and due to the
formation of more congested quaternary centers (9d). Neverthe-
less, the starting material is recovered and can be resubjected
to the Cope equilibrium making for an efficient transformation.
Surprisingly, the styrene conjugation in 8a-d is not a prohibitive
barrier to formation of the 2-cyclohexen-1-one systems of 9a-
d. This represents the first case of a Cope equilibrium that
balances the stabilization of phenyl group conjugation versus
conjugation with a ketone. Amide conjugation is expected to
be weak because the steric bulk of the amide forces it orthogonal
to the enone system (vide infra).2
of 2c (entry 5, Scheme 2) with modest enantioselectivity (dr )
11:1). In all probability, the factors that compromised the
enantioselectivity in the alkylation with crotyl bromide were
also present with dimethylallyl bromide. Nevertheless, with our
focus on the amenability of 3c to generate adjacent quaternary
centers in the Cope rearrangement (vide infra), we did not
attempt to further optimize the enantioselectivity of the Birch
reduction-alkylation to 2c. In all the Birch reduction-allylation
reactions described, the most common side product results from
gamma-allylation of the enolate at the C-3 carbon (o-anisic acid
numbering).
Hydrolysis of both 2b and 2c occurred efficiently to afford
3b and 3c in 99 and 86% yield, respectively. As anticipated,
the equilibrium in the Cope rearrangement of 3b to 4b was less
favorable than for 3a/4a due to the concomitant creation of a
tertiary carbon center adjacent to the quaternary center. Nev-
ertheless, a 70% yield of the rearranged product 4b was isolated,
along with the recovery of 24% of the starting material, 3b.
Despite the high temperatures of the Cope rearrangement, little
decomposition occurs. Consequently, the recovered starting
material can be recycled making the process efficient.
Besides forming the highly congested contiguous tertiary-
quaternary carbon centers, the Cope rearrangement of 3b to 4b
occurred with complete stereocontrol. Chromatography of 4b
showed only one diastereomer, and NOESY studies identified
the product to be the result of a boat transition state (see
Supporting Information).11 In addition to the transfer of chiral
information generated in the Birch reduction-allylation to the
C-4 quaternary center, the alkene stereochemistry is translated
into the new tertiary chiral center through the stereospecific
Cope rearrangement.
C-5 Hydroxyalkyl o-Anisic Acid Derivatives. Functional-
ized alkyl groups were appended at the C-5 position of the
(11) For examples of Cope rearrangements occurring by a boat transition
state in sterically constrained 1,5-dienes see: (a) Kato, N.; Kataoka, H.;
Ohbuchi, S.; Tanaka, S.; Takeshita, H. J. Chem. Soc., Chem. Commun. 1988,
354-356. (b) Ziegler, F. E.; Piwinski, J. J. J. Am. Chem. Soc. 1980, 102,
6576-6577.
(12) For other examples of chemoselective biaryl Birch reduction-
alkylations, see: (a) Lebeuf, R.; Frederic, R.; Landais, Y. Org. Lett. 2005,
7, 4557-4560. (b) Guo, Z.; Schultz, A. G.; Antoulinakis, E. Org. Lett.
2001, 3, 1177-1180. (c) See also refs 6a, 7a, and 7b.
932 J. Org. Chem., Vol. 72, No. 3, 2007

EnantioselectiVe Birch-Cope Sequence
SCHEME 8. C-5 Hydroxyalkyl Derivatives in Birch-Cope Sequence
proton.15 The amenability of these complex substrates to Birch
reduction-alkylation further illustrates the versatility of this
underutilized synthetic tool.
SCHEME 9. Deprotection of Allyl Ether in 13a
The hydrolysis reaction of 11a/b and the Cope rearrangement
of 12a/b occurred in high yield (Scheme 8). The larger
hydroxypropyl substituent of 12b made the Cope equilibrium
slightly less favorable than 12a, with approximately 27% of
the starting material recovered. The allyl ether of 13a has been
selectively cleaved without isomerization of the other terminal
alkene (Scheme 9).16 In this manner, two uniquely functionalized
alkyl groups can be created in the C-4 position of the
2-cyclohexen-1-one.
SCHEME 10. Cope Equilibrium with Methyl Ester
Derivative
Controlling Elements in the Cope Equilibrium. As previ-
ously described,2 the Cope rearrangement equilibrium is con-
trolled primarily by the formation of the stable conjugated enone
system. Computational studies2 and previous reports17 with
related systems show the amide is orthogonal to the enone
system, therefore, offering no stabilization through conjugation.
Nevertheless, besides inducing stereocontrol in the enolate
alkylation step, the amide also plays an essential role in
controlling the Cope equilibrium. Studies with the analogous
methyl esters 14a/b (Scheme 10) showed the equilibrium of
the Cope rearrangement was much less favorable under identical
thermal conditions. Furthermore, computational studies18 that
determined the lowest energy conformation of 15a showed the
methyl ester substituent to be coplanar with the enone (see
Supporting Information). Despite the more extensive conjugation
o-anisic acid derivatives through Grignard reactions. Although
conventional Grignard formation did not work, the transmet-
allation conditions of Knochel et al.13 were successful when
applied to 5b. Quenching the Grignard reagent with formalde-
hyde provided 10a, while adding CuBr and reacting with (R)-
propylene oxide provided 10b (Scheme 7).
Both 10a and 10b were successfully subjected to Birch
reduction-allylation (Scheme 8). tert-Butyl alcohol was not
needed in the Birch reduction due to the presence of an alcohol
in 10a/b, which provides a proton source to quench the radical
anion intermediate. Allylation of the alkoxide could not be
avoided during the alkylation step. To avoid inseparable
mixtures, we used an excess of allyl bromide to alkylate both
(15) For previous examples of asymmetric Birch reduction-alkylations
with kinetically acidic N-H groups see: (a) Casimiro-Garcia, A.; Schultz,
A. G. Tetrahedron Lett. 2006, 47, 2739-2742. (b) Schultz, A. G.;
McClosky, P. J.; Sundararaman, P. Tetrahedron Lett. 1985, 26, 1619-1622.
(c) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987,
109, 6493-6502.
(16) Chandrasekhar, S.; Reddy, C. R.; Rao, R. J. Tetrahedron 2001, 57,
3435-3438.
(17) Schultz, A. G.; Harrington, R. E. J. Am. Chem. Soc. 1991, 113,
4926-4931.
(18) Energy minimization calculations were accomplished with semiem-
pirical calculations (AM1) using Gaussian 03 suite of programs. Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.05; Gaussian, Inc.: Wallingford, CT, 2004.
the enolate and the alkoxide.
The diastereoselectivity in Birch reduction-allylation of 10a
and 10b was somewhat compromised by the presence of the
alkoxide, a strong chelating group. Through the formation of
aggregates, the alkoxide might disrupt the enolate structure that
results in the higher levels of enantioselectivity normally seen.14
The detrimental effect of chelation on the reaction stereoselec-
tivity was more pronounced with 10a. Nevertheless, this
represents a rare example of an asymmetric Birch reduction-
alkylation with a substrate containing a kinetically acidic
(13) (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu,
V. A.; Knochel, P. Synthesis 2002, (4), 565-569. (b) Knochel, P.; Dohle,
W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.;
Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302-4320.
(14) With the o-anisic acid derivatives, enantioselectivity in the Birch
reduction-alkylation arises from the rigid structure created from the
coordination of the metal between the enolate oxygen and the 2-methoxy
group. The alkoxide ion generated in the Birch reduction of 10a/b might
compete intermolecularly with the 2-methoxy group for metal coordination,
thereby compromising the structure of the normal enolate intermediate.
J. Org. Chem, Vol. 72, No. 3, 2007 933

Paul et al.
9.4 Hz), 3.42, 3.06 (two s, 3H), 3.32-3.23, 3.10-3.06 (two m,
1H), 2.10-1.70 (m, 4H). 13C NMR (CDCl3, a mixture of rotational
isomers) δu 128.3, 128.0, 126.0, 114.2, 111.6, 59.1, 58.8, 57.3, 56.3,
55.8, 55.7, 55.3; δd 167.9, 158.9, 154.3, 133.7, 133.6, 132.8, 127.7,
127.5, 73.5, 72.4, 48.5, 45.8, 29.7, 28.5, 27.8, 24.2, 22.2. IR (CDCl3)
with the methyl ester analogue 15a, the Cope equilibrium is
more favorable for the formation of 4a. The absence of
coplanarity for the amide in 4a is due to its steric bulk; however,
the steric bulk of the amide creates considerable congestion at
the quaternary center of 3a, which is relieved in the Cope
rearrangement to form 4a. Therefore, the Cope equilibria in the
Birch-Cope sequence benefit from both the conjugation of the
enone system in the products and the reduction of steric strain
in the starting materials.
1610 cm-1. GC tR ) 22.73 min. EI-MS m/z (%): 356 (2, M+
+
1), 355 (M+, 1), 310 (8), 242 (17), 241 (100).
(S)-(2-(Methoxymethyl)pyrrolidin-1-yl)(2′,3′,4-trimethoxybi-
phenyl-3-yl)methanone (6d). Use of the general procedure with
5d and 2,3-dimethoxyphenylboronic acid afforded a 96% yield.
Column eluted with 1:1 EtOAc/hexanes. TLC Rf ) 0.40 (EtOAc).
1H NMR (CDCl3, mixture of rotational isomers) δ 7.57 (dd, 1H, J
) 8.6, 2.2 Hz), 7.45 (d, 1H, J ) 2.2 Hz), 7.09 (t, 1H, J ) 8.0 Hz),
6.99-6.88 (m, 3H), 4.50-4.40, 3.87-3.78 (two m, 1H), 3.90 (s,
3H), 3.87 (s, 3H), 3.75 (dd, 1H, J ) 9.4, 3.3 Hz), 3.67-3.50 (m,
1H), 3.57 (s, 3H), 3.41, 3.09 (two s, 3H), 3.35-3.25 (m, 1H), 3.15-
3.08 (m, 1H), 2.08-1.72 (m, 4H). 13C NMR (CDCl3, mixture of
rotational isomers) δu 132.0, 130.9, 128.5, 124.0, 122.2, 111.2,
110.8, 60.3, 59.0, 58.6, 57.2, 56.1, 55.8, 55.6, 55.5; δd 167.7, 154.4,
153.0, 146.3, 134.7, 130.5, 127.1, 126.6, 73.3, 72.2, 48.6, 45.7,
28.3, 27.7, 24.1, 22.1. IR (CDCl3) 1623 cm-1. GC tR ) 21.9 min.
EI-MS m/z (%): 385 (M+, 3), 353 (11), 340 (16), 272 (28), 271
(100).
Conclusion
The Birch-Cope sequence has demonstrated the ability to
efficiently and enantioselectively generate quaternary stereo-
centers on a carbocyclic ring. Importantly, a variety of substit-
uents have been incorporated at the quaternary center of the
2-cyclohexen-1-one product in good yield and with good to
excellent levels of enantioselectivity. Use of a defined allylic
alkylating agent allows the generation of two adjacent chiral
centers. Quaternary stereocenters with ortho-substituted aryl
substituents and hydroxyalkyl substituents were both efficiently
generated with stereocontrol. In the process of this study, an
understanding of the unique features of the Cope equilibria in
the Birch-Cope sequence has been developed. As previously
illustrated,2 the prolinol chiral auxiliary can be easily removed
with hydroxylamine reagents, and subsequent transformations
of the 2-cyclohexen-1-one structures into complex natural
product targets have been accomplished. Future applications of
the Birch-Cope sequence to challenges in natural product
synthesis are underway and will be reported in due course.
(S)-(5-(Hydroxymethyl)-2-methoxyphenyl)(2-(methoxymeth-
yl)pyrrolidin-1-yl)methanone (10a). Isopropyl magnesium chloride
(0.73 mL, 2.0 M soln in THF) was added dropwise to 5b (500 mg,
1.33 mmol) in THF (7 mL) at 0 °C. The reaction was warmed to
rt, was stirred for
1
h, and then was recooled to
0 °C. Formaldehyde gas (generated by heating paraformaldehyde)
was passed through the reaction solution for several minutes, after
which the reaction was stirred at 0 °C for 1 h. The reaction was
quenched with cold water, was warmed to rt, was treated with
saturated NH4Cl, and the product was extracted with EtOAc. The
combined organic layers were washed with brine, were dried with
Na2SO4, and were concentrated. Column chromatography (4:1,
EtOAc/hexanes) of the crude product provided pure 10a, 150 mg
Experimental Section
1
General Procedure for the Suzuki Reaction. The 5-halo-o-
anisic acid derivative (1.0 equiv) was dissolved in 1-propanol (5.5
mL/mmol halo derivative) with the arylboronic acid derivative (1.1
equiv) and was treated with Pd(OAc)2 (0.05 equiv), Ph3P (0.15
equiv), and the 10% K2CO3 solution (1.25 equiv K2CO3). The dark
green reaction was heated at reflux overnight turning progressively
darker with time. The crude reaction was partially concentrated
and filtered through a plug of cotton. The product was extracted
with EtOAc and the organic layer was washed with 5% NaHCO3
and brine, was dried with MgSO4, and was concentrated. Purifica-
tion by column chromatography afforded pure product.
(40% yield). TLC Rf ) 0.20 (EtOAc). H NMR (CDCl3, mixture
of rotational isomers) δ 7.34 (dd, 1H, J ) 8.5, 1.9 Hz), 7.26 (s,
1H), 6.90 (d, 1H, J ) 8.5 Hz), 4.62 (s, 2H), 4.43-4.38, 3.80-3.76
(two m, 1H), 3.84 (s, 3H), 3.73 (dd, 1H, J ) 9.4, 3.3 Hz), 3.57
(dd, 1H, J ) 9.4, 6.7 Hz), 3.42, 3.09 (two s, 3H), 3.30-3.15 (m,
2H), 3.08-3.03 (m, 1H), 2.10-1.70 (m, 4H). 13C NMR (CDCl3, a
mixture of rotational isomers) δu 129.0, 126.5, 111.1, 59.0, 58.7,
57.3, 56.3, 55.7; δd 168.1, 154.4, 133.8, 127.3, 126.8, 73.3, 72.2,
64.0, 48.4, 45.7, 28.3, 27.7, 24.1, 22.1. IR (CDCl3) 1611 cm-1
.
GC tR ) 15.76 min. EI-MS m/z (%): 279 (M+, 1), 247 (10), 234
(18), 164 (11), 165 (100).
(S)-(4-Methoxybiphenyl-3-yl)(2-(methoxymethyl)pyrrolidin-
1-yl)methanone (6a). Use of the general procedure with 5a and
phenylboronic acid afforded a 100% yield of a white crystalline
product. Column eluted with 7:3 EtOAc/hexanes. TLC Rf ) 0.40
(7:3 EtOAc/hexanes), mp ) 80-81 °C. 1H NMR (CDCl3, mixture
of rotational isomers) δ 7.60-7.45 (m, 4H), 7.44-7.36 (m, 2H),
7.31-7.26 (m, 1H), 6.98-6.94 (m, 1H), 4.50-4.38 (m, 1H), 3.85
(s, 3H), 3.75 (dd, 1H, J ) 9.4, 3.3 Hz), 3.57 (dd, 1H, J ) 9.4, 6.8
Hz), 3.41, 3.05 (two s, 3H), 3.30-3.20 (m, 2H), 3.10-3.05 (m,
1H), 2.10-1.86 (m, 3H), 1.78-1.70 (m, 1H). 13C NMR (CDCl3,
mixture of rotational isomers) δu 128.8, 128.7, 127.0, 126.7, 126.4,
111.6, 59.1, 58.8, 57.4, 56.4, 55.8; δd 167.9, 167.8, 154.8, 140.1,
134.0, 133.9, 128.0, 127.6, 73.6, 72.4, 48.5, 45.8, 28.5, 27.8, 24.2,
22.2. IR (CDCl3) 1617 cm-1. GC tR ) 27.54 min. EI-MS m/z (%):
325 (M+, 1), 293 (9), 280 (32), 211 (100).
(S)-(4,4′-Dimethoxybiphenyl-3-yl)(2-(methoxymethyl)pyrro-
lidin-1-yl)methanone (6b). Use of the general procedure with 5b
and 4-methoxyphenylboronic acid afforded a 96% yield. Column
eluted with 1:1 EtOAc/hexanes. TLC Rf ) 0.50 (EtOAc). 1H NMR
(CDCl3, mixture of rotational isomers) δ 7.52-7.43 (m, 4H), 6.96-
6.92 (m, 3H), 4.45-4.40, 3.92-3.80 (two m, 1H), 3.85 (s, 3H),
3.83 (s, 3H), 3.76 (dd, 1H, J ) 9.5, 3.5 Hz), 3.56 (dd, 1H, J ) 6.9,
(5-((R)-2-Hydroxypropyl)-2-methoxyphenyl)((S)-2-(methoxy-
methyl)pyrrolidin-1-yl)methanone (10b). Isopropyl magnesium
chloride (1.50 mL, 2.0 M soln. in THF) was added dropwise to 5b
(1.00 g, 2.67 mmol) in THF (14 mL) at 0 °C. The reaction was
warmed to rt, was stirred for 1 h, and then was recooled to -15
°C. CuBr (211 mg, 1.47 mmol) was added and the reaction was
stirred for several minutes at -15 °C. A solution of (R)-propylene
oxide (0.41 mL, 5.85 mmol) in THF (0.5 mL) was added dropwise
and the reaction was stirred overnight at 0 °C. The reaction was
quenched with cold water, was warmed to rt, was treated with
saturated NH4Cl, and the product was extracted with EtOAc. The
combined organic layers were washed with brine, were dried with
Na2SO4, and were concentrated. The crude product was purified
with column chromatography (4:1, EtOAc/hexanes) to afford pure
10b (370 mg, 45% yield). TLC Rf ) 0.20 (EtOAc). 1H NMR
(CDCl3, mixture of rotational isomers) δ 7.17 (dd, 1H, J ) 8.4,
2.2 Hz), 7.09 (d, 1H, J ) 2.2 Hz), 6.85 (d, 1H, J ) 8.4 Hz), 4.42-
4.37, 3.85-3.75 (two m, 1H), 4.00-3.90 (m, 1H), 3.81 (s, 3H),
3.73 (dd, 1H, J ) 9.4, 3.4 Hz), 3.55 (dd, 1H, J ) 9.4, 6.8 Hz),
3.41, 3.09 (two s, 1H), 3.27-3.12 (m, 1H), 3.27-3.12, 3.10-3.03
(two m, 1H), 2.75-2.59 (m, 2H), 2.06-1.70 (m, 4H), 1.21 (d, 3H,
J ) 6.2 Hz). 13C NMR (CDCl3, a mixture of rotational isomers) δu
934 J. Org. Chem., Vol. 72, No. 3, 2007

EnantioselectiVe Birch-Cope Sequence
131.0, 128.4, 111.2, 68.6, 59.0, 58.6, 57.3, 56.2, 55.6, 22.5; δd 167.9,
153.8, 130.9, 127.4, 126.9, 73.4, 72.2, 48.3, 45.6, 44.6, 28.4, 27.7,
24.1, 22.1. IR (CDCl3) 3413, 1617 cm-1. GC tR ) 21.57 min. EI-
MS m/z (%): 307 (M+, 1), 275 (11), 262 (18), 193 (100).
General Procedure for the Birch Reduction-Allylation. To a
solution of benzamide (1.0 equiv) and tert-butyl alcohol (1.0 equiv)
in THF (10 mL/mmol amide) and NH3 (130 mL/mmol amide) at
-78 °C was added alkali metal in small pieces until a blue
coloration was maintained for 20 min. Piperylene was added
dropwise to consume the excess metal, and then allyl bromide (2.5
equiv) was added. The solution was stirred at -78 °C and was
allowed to slowly warm to rt to allow the NH3 to evaporate. Water
was added and the mixture was extracted with CH2Cl2. The organic
layer was washed with brine, was dried (Na2SO4), and was
concentrated in vacuo to give 2,5-cyclohexadiene product. Pure
product was obtained by column chromatography (3:7 or 1:3
EtOAc/hexanes). Diastereomeric ratios were determined by GC or
LC on purified material in comparison with independently synthe-
sized diastereomeric mixtures.
((R)-1-((E)-but-2-enyl)-2-methoxy-5-methylcyclohexa-2,5-di-
enyl)((S)-2-(methoxymethyl)-pyrrolidin-1-yl)methanone (2b). Use
of the general procedure with 1 and potassium followed by the
addition of crotyl chloride instead of allyl bromide afforded a 73%
yield. TLC Rf ) 0.80 (EtOAc). 1H NMR (CDCl3, mixture of
rotational isomers) δ 5.40-5.28 (m, 1H), 5.27-5.14 (m, 1H), 5.04
(s, 1H), 4.69 (t, 1H, J ) 3.6 Hz), 4.40-4.28 (m, 1H), 3.58 (dd,
1H, J ) 9.4, 3.4 Hz), 3.48 (s, 3H), 3.44-3.21, 3.15-2.98 (two m,
3H), 3.35 (s, 3H), 2.79-2.55 (m, 3H), 2.34 (dd, 1H, J ) 14.0, 6.6
Hz), 2.00-1.55 (m, 4H), 1.74 (s, 3H), 1.59 (d, 3H, J ) 6.1 Hz).
13C NMR (CDCl3) δu 127.0, 121.9, 92.6, 58.8, 57.7, 54.2, 22.3,
18.1; δd 171.2, 152.8, 133.0, 72.0, 52.9, 46.1, 40.0, 31.5, 26.5, 24.7.
IR (CDCl3) 1618 cm-1. GC tR ) 16.88 (major), 16.92 (minor) min.
dr ) >99:<1. EI-MS m/z (%): 319 (M+, 7), 304 (3), 288 (3),
264 (15), 176 (39), 149 (100).
(s, 3H), 3.75 (s, 3H), 3.66-3.62 (m, 1H), 3.54 (s, 3H), 3.43-3.30
(m, 2H), 3.35 (s, 3H), 3.17 (dq, 2H, J ) 22, 2.8 Hz), 2.87 (dd, 1H,
J ) 14.2, 7.7 Hz), 2.63 (dd, 1H, J ) 14.2, 7.0 Hz), 2.00-1.68 (m,
4H). 13C NMR (CDCl3) δ 170.0, 152.8, 152.3, 146.4, 136.4, 136.3,
135.0, 125.5, 124.0, 121.3, 116.9, 111.5, 93.2, 72.0, 60.9, 58.8,
58.1, 55.7, 54.2, 52.8, 46.1, 41.3, 30.5, 26.4, 25.0. IR (CDCl3) 1616
cm-1. HPLC tR ) 8.752 (minor), 9.121 (major) min. dr ) >99:
<1.
((R)-1-Allyl-5-(allyloxymethyl)-2-methoxycyclohexa-2,5-dienyl)-
((S)-2-(methoxymethyl)-pyrrolidin-1-yl)methanone (11a). Use of
the general procedure with 10a and potassium afforded a 68% yield.
1
TLC Rf ) 0.67 (7:3 EtOAc/hexanes). H NMR (CDCl3) δ 5.94-
5.85 (m, 1H), 5.66-5.57 (m, 1H), 5.38-5.16 (m, 3H), 5.00-4.93
(m, 2H), 4.78 (t, 1H, J ) 3.6 Hz), 4.35-4.25 (m, 1H), 3.94-3.91
(m, 4H), 3.62 (dd, 1H, J ) 9.5, 3.2 Hz), 3.55-3.48 (m, 1H), 3.51
(s, 3H), 3.36-3.25 (m, 2H), 3.34 (s, 3H), 2.90-2.68 (m, 3H), 2.55
(dd, 1H, J ) 14.1, 7.0 Hz), 1.95-1.69 (m, 4H). 13C NMR (CDCl3)
δu 134.8, 124.4, 123.7, 92.5, 58.8, 58.1, 54.2; δd 169.8, 152.8, 134.3,
116.9, 116.8, 72.9, 71.9, 70.5, 52.5, 46.0, 41.1, 27.4, 26.3, 24.8.
IR (CDCl3) 1623 cm-1. GC tR ) 20.73 (minor), 21.06 (major) min.
dr ) 16:1. EI-MS m/z (%): 361 (M+, 1), 346 (1), 320 (2), 290 (5),
258 (7), 218 (8), 205 (10), 200 (10), 176 (9), 161 (37), 142 (100).
HPLC tR ) 11.07 (major), 11.91 (minor) min. dr ) 14:1.
((R)-1-Allyl-5-((R)-2-(allyloxy)propyl)-2-methoxycyclohexa-
2,5-dienyl)((S)-2-(methoxymethyl)-pyrrolidin-1-yl)methanone
(11b). Use of the general procedure with 10b and potassium
1
afforded a 57% yield. TLC Rf ) 0.70 (3:1 EtOAc/hexanes). H
NMR (CDCl3, mixture of rotational isomers) δ 5.95-5.82 (m, 1H),
5.71-5.57 (m, 1H), 5.28, 5.23 (two d, 1H, J ) 1.6 Hz), 5.16, 5.13
(two s, 2H), 4.99, 4.94, 4.91 (three s, 2H), 4.72 (t, 1H, J ) 3.5
Hz), 4.35-4.25 (m, 1H), 4.04 (dd, 1H, J ) 12.6, 5.5 Hz), 3.89
(dd, 1H, J ) 12.5, 5.5 Hz), 3.65-3.54 (m, 3H), 3.49 (s, 3H), 3.35
(s, 3H), 3.32-3.21 (m, 2H), 2.90-2.66 (m, 3H), 2.53 (dd, 1H,
J ) 14.1, 6.5 Hz), 2.31 (dd, 1H, J ) 14.2, 6.8 Hz), 2.12 (dd, 1H,
J ) 14.2, 5.8 Hz), 1.90-1.65 (m, 4H), 1.14 (d, 3H, J ) 6.1 Hz).
13C NMR (CDCl3) δu 135.1, 122.9, 92.7, 73.7, 58.9, 58.0, 57.8,
54.2, 19.5; δd 170.3, 152.8, 134.7, 116.5, 116.4, 72.0, 69.3, 52.7,
((R)-1-Allyl-2-methoxy-5-phenylcyclohexa-2,5-dienyl)((S)-2-
(methoxymethyl)pyrrolidin-1-yl)methanone (7a). Use of the
general procedure with 6a and lithium afforded a 62% yield. TLC
46.0, 43.2, 41.2, 30.7, 26.3, 24.9, 24.7. IR (CDCl3) 1617 cm-1
.
1
Rf ) 0.50 (1:1 EtOAc/hexanes). H NMR (CDCl3) δ 7.44-7.28
GC tR ) 23.09 min. EI-MS m/z (%): 389 (M+, 1), 348 (20), 233
(26), 189 (100). HPLC tR ) 4.72 (minor), 4.951 (major) min. dr )
47:1.
(m, 5 H), 5.82 (t, 2 H, J ) 1.5 Hz), 5.80-5.65 (m, 1H), 5.05-
4.87 (m, 3 H), 4.40-4.32 (m, 1 H), 3.64 (dd, 1 H, J ) 9.5, 3.2
Hz), 3.58-3.52 (m, 1 H), 3.56 (s, 3H), 3.38-3.32 (m, 2 H), 3.36
(s, 3H), 3.30-3.15 (m, 2 H), 2.91-2.84 (m, 1 H), 2.68 (dd, 1 H,
J ) 14.1, 6.7 Hz), 1.92-1.65 (m, 4 H). 13C NMR (CDCl3) δ 169.9,
152.8, 139.9, 135.7, 134.8, 128.5, 127.6, 125.2, 123.5, 117.1, 92.7,
72.0, 58.9, 58.2, 54.4, 53.1, 46.1, 41.4, 28.8, 26.4, 24.9. IR (film)
1620 cm-1. GC tR ) 26.99 (minor), 27.68 (major) min. dr ) 35:1.
EI-MS m/z (%): 367 (M+, 5), 326 (9), 225 (72), 224 (100), 211
(95), 184 (87), 142 (98).
General Procedure for the Hydrolysis Reaction. Enol ether
(1.0 equiv) was dissolved in MeOH (6 mL/mmol enol ether) and
was treated with 6 N HCl (2.5 mL/mmol enol ether). After stirring
at rt for 15 h, the reaction solution was diluted with H2O and was
extracted with CH2Cl2. The organic layers were combined and
washed with saturated NaHCO3 and brine and then were dried with
MgSO4. Concentration afforded an oil which was purified by
column chromatography (1:3 or 3:7 EtOAc/hexanes).
(R)-2-((E)-But-2-enyl)-2-((S)-2-(methoxymethyl)pyrrolidine-
1-carbonyl)-4-methylcyclohex-3-enone (3b). Use of the general
procedure with 2b afforded a 99% yield. TLC Rf ) 0.60 (EtOAc).
1H NMR (CDCl3, mixture of rotational isomers) δ 5.47-5.40 (m,
2H), 5.33 (s, 1H), 4.38-4.27 (m, 1H), 3.53 (dd, 1H, J ) 9.3, 3.1
Hz), 3.40-3.29 (m, 1H), 3.33 (s, 3H), 3.28-3.18 (m, 1H), 3.13-
3.01 (m, 1H), 2.67-2.38 (m, 6H), 1.96-1.70 (m, 4H), 1.64, 1.59
(two d, 3H, J ) 3.6 Hz). 13C NMR (CDCl3) δu 128.6, 126.5, 123.6,
58.9, 57.7, 23.1, 17.9; δd 208.7, 169.4, 135.4, 72.0, 61.3, 46.6, 40.5,
36.9, 30.5, 26.7, 24.5. IR (CDCl3) 1709, 1628 cm-1. GC tR ) 17.58
min. EI-MS m/z (%): 306 (M+ + 1, 3), 305 (M+, 17), 260 (39),
249 (46), 206 (25), 163 (43), 142 (100).
(R)-2-Allyl-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-
4-phenylcyclo hex-3-enone (8a). Use of the general procedure with
7a provided a 64% yield. TLC Rf ) 0.30 (7:3 EtOAc/hexanes). 1H
NMR (CDCl3) δ 7.43-7.29 (m, 5H), 5.99 (s, 1H), 5.95-5.80 (m,
1H), 5.11 (s, 1H), 5.07 (d, 1H, J ) 3.9 Hz), 4.35-4.20 (m, 1H),
3.68-3.60 (m, 1H), 3.43-3.28 (m, 2H), 3.36 (s, 3H), 3.20-3.08
(m, 1H), 3.05-2.84 (m, 2H), 2.80-2.57 (m, 4H), 1.98-1.65 (m,
4H).13C NMR (CDCl3) δu 134.3, 128.5, 127.9, 125.2, 125.0, 58.8,
((R)-1-Allyl-2-methoxy-5-(4-methoxyphenyl)cyclohexa-2,5-di-
enyl)((S)-2-(methoxymethyl)-pyrrolidin-1-yl)methanone (7b). Use
of the general procedure with 6b and lithium afforded a 58% yield.
1
TLC Rf ) 0.60 (EtOAc). H NMR (CDCl3, mixture of rotational
isomers) δ 7.37 (d, 2H, J ) 8.9 Hz), 6.89 (d, 2H, J ) 8.9 Hz),
5.73 (s, 1H), 5.72-5.62 (m, 1H), 5.03-4.86 (m, 3H), 4.38-4.28
(m, 1H), 3.81 (s, 3H), 3.64 (dd, 1H, J ) 9.5, 3.2 Hz), 3.57-3.50
(m, 1H), 3.55 (s, 3H), 3.40-3.28 (m, 2H), 3.36 (s, 3H), 3.22-
3.10 (m, 2H), 2.90-2.83 (m, 1H), 2.66 (dd, 1H, J ) 14.0, 6.7 Hz),
1.90-1.67 (m, 4H). 13C NMR (CDCl3) δu 134.7, 126.1, 121.6,
113.7, 92.6, 58.8, 58.0, 55.2, 54.2; δd 170.0, 159.1, 152.6, 134.9,
132.2, 116.9, 71.8, 52.8, 46.0, 41.3, 28.7, 26.2, 24.8. IR (CDCl3)
1617 cm-1. HPLC tR ) 15.32 (major), 16.24 (minor) min. dr )
50:1.
((R)-1-Allyl-5-(2,3-dimethoxyphenyl)-2-methoxycyclohexa-
2,5-dienyl)((S)-2-(methoxymethyl)-pyrrolidin-1-yl)methanone (7d).
Use of the general procedure with 6d and lithium afforded a 70%
1
yield. TLC Rf ) 0.70 (EtOAc). H NMR (CDCl3) δ 7.00 (t, 1H,
J ) 7.9 Hz), 6.85 (dd, 1H, J ) 8.2, 1.3 Hz), 6.71 (dd, 1H, J ) 7.6,
1.2 Hz), 5.85-5.65 (m, 1H), 5.43 (s, 1H), 5.06-4.98 (m, 2H), 4.83
(t, 1H, J ) 3.6 Hz), 4.38-4.28 (m, 1H), 3.90-3.76 (m, 1H), 3.86
J. Org. Chem, Vol. 72, No. 3, 2007 935

Paul et al.
57.9; δd 207.0, 168.0, 139.8, 138.4, 118.3, 71.7, 61.3, 46.7, 41.3,
36.7, 27.7, 26.5, 24.5. IR 1710, 1635 cm-1. GC tR ) 28.52 min.
EI-MS m/z (%): 353 (M+, 6), 308 (11), 297 (19), 211 (24), 142-
(100).
GC analysis showed the reaction was 96% product 4a and 4%
starting material 3a. The product obtained was identical to that
previously reported2 for conventional heating over a 10-h period.
(R)-4-((S)-but-3-en-2-yl)-2-((S)-2-(methoxymethyl)pyrrolidine-
1-carbonyl)-4-methylcyclohex-2-enone (4b). Use of the general
procedure with 3b afforded a 70% yield of 4b, along with 24% of
(R)-2-Allyl-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-
4-(4-methoxyphenyl)cyclohex-3-enone (8b). Use of the general
procedure with 7b provided an 89% yield. TLC Rf ) 0.50 (EtOAc).
1H NMR (CDCl3, mixture of rotational isomers) δ 7.35 (d, 2H,
J ) 8.7 Hz), 6.89 (d, 2H, J ) 8.9 Hz), 5.90 (s, 1H), 5.95-5.80 (m,
1H), 5.10 (s, 1H), 5.05 (d, 1H, J ) 4.1 Hz), 4.35-4.25 (m, 1H),
3.82 (s, 3H), 3.64 (dd, 1H, J ) 9.3, 2.9 Hz), 3.40-3.30 (m, 2H),
3.36 (s, 3H), 3.15-3.07 (m, 1H), 3.02-2.83 (m, 2H), 2.80-2.55
(m, 4H), 1.98-1.65 (m, 4H). 13C NMR (CDCl3) δu 134.2, 126.4,
123.2, 113.9, 58.9, 57.9, 55.3; δd 207.4, 168.3, 159.5, 137.7, 132.2,
118.3, 71.7, 61.3, 46.5, 41.6, 36.9, 27.7 26.6, 24.5. IR (CDCl3)
1712, 1610 cm-1. HPLC tR ) 20.32 min.
1
recovered starting material. TLC Rf ) 0.40 (EtOAc). H NMR
(CDCl3, mixture of rotational isomers) δ 6.84 (t, 1H, J ) 6.0 Hz),
5.88-5.65 (m, 1H), 5.15-5.02 (m, 2H), 4.35-4.25, 3.81-3.72 (two
m, 1H), 3.67 (dd, 1H, J ) 9.5, 3.4 Hz), 3.43 (dd, 1H, J ) 9.4, 7.2
Hz), 3.38, 3.26 (two s, 3H), 3.30-3.10 (m, 2H), 2.58-2.48 (m,
2H), 2.40-2.20 (m, 1H), 2.10-1.68 (m, 6H), 1.18, 1.17 (two s,
3H), 1.06 (d, 3H, J ) 6.9 Hz). 13C NMR (CDCl3, mixture of
rotational isomers) δu 156.7, 156.5, 139.4, 139.0, 59.1, 58.9, 57.6,
56.3, 47.0, 46.1, 21.4, 21.2, 15.4, 14.4, 14.3; δd 195.6, 195.2, 165.9,
137.2, 116.7, 116.2, 116.1, 74.0, 72.1, 48.4, 48.3, 45.5, 38.2, 38.1,
33.9, 30.9, 30.6, 30.0, 28.3, 27.6, 24.1, 21.8. IR (CDCl3) 1684,
1617 cm-1. GC tR ) 15.83 min. EI-MS m/z (%): 306 (M+ + 1,
1), 305 (M+, 3), 260 (89), 250 (39), 206 (100), 191 (31), 163 (33),
137 (56).
(R)-2-Allyl-4-(2,3-dimethoxyphenyl)-2-((S)-2-(methoxymeth-
yl)pyrrolidine-1-carbonyl)cyclohex-3-enone (8d). Use of the
general procedure with 7d provided a 96% yield. TLC Rf ) 0.50
1
(EtOAc). H NMR (CDCl3) δ 7.03 (t, 1H, J ) 7.9 Hz), 6.89 (dd,
1H, J ) 8.2, 1.4 Hz), 6.76 (dd, 1H, J ) 7.6, 1.4 Hz), 5.96-5.82
(m, 1H), 5.73 (s, 1H), 5.11 (d, 1H, J ) 1.4 Hz), 5.06 (d, 1H, J )
2.4 Hz), 4.35-4.25 (m, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.72-3.60
(m, 1H), 3.58-3.48 (m, 1H), 3.45-3.30 (m, 1H), 3.36 (s, 3H),
3.27-3.17 (m, 1H), 2.95-2.83 (m, 2H), 2.77 (d, 2H, J ) 7.4),
2.72-2.52 (m, 2H), 2.03-1.70 (m, 4H). 13C NMR (CDCl3) δ 207.4,
168.2, 152.8, 146.3, 139.1, 136.0, 134.2, 127.1, 124.1, 120.9, 118.3,
112.0, 71.8, 61.5, 60.8, 59.0, 57.9, 55.8, 46.5, 41.2, 37.1, 29.3, 26.7,
24.6. IR (CDCl3) 1710, 1628 cm-1. HPLC tR ) 15.04 min.
(R)-2-Allyl-4-(allyloxymethyl)-2-((S)-2-(methoxymethyl)pyr-
rolidine-1-carbonyl)cyclohex-3-enone (12a). Use of the general
procedure with 11a provided a 90% yield. TLC Rf ) 0.60 (EtOAc).
1H NMR (CDCl3) δ 5.96-5.72 (m, 2H), 5.65 (s, 1H), 5.30-5.17
(m, 2H), 5.06 (s, 1H), 5.01 (d, 1H, J ) 6.6 Hz), 4.35-4.15 (br s,
1H), 3.97 (s, 4H), 3.61 (dd, 1H, J ) 9.3, 2.7 Hz), 3.40-3.25 (m,
2H), 3.34 (s, 3H), 3.10-3.03 (m, 1H), 2.69-2.42 (m, 6H), 2.00-
1.70 (m, 4H). 13C NMR (CDCl3) δu134.4, 134.0, 125.0, 58.9, 57.9;
δd 207.6, 168.1, 136.7, 118.2, 117.1, 72.7, 71.8, 71.1, 70.0, 46.5,
41.2, 36.6, 26.6, 26.1, 24.5. IR (CDCl3) 1712, 1629 cm-1. GC tR
) 16.25 min. EI-MS m/z (%): 347 (M+, 8), 302 (45), 291 (19),
244 (14), 205 (21), 142 (100).
(R)-2-Allyl-4-((R)-2-(allyloxy)propyl)-2-((S)-2-(methoxymeth-
yl)pyrrolidine-1-carbonyl)cyclohex-3-enone (12b). Use of the
general procedure with 11b provided a 94% yield. TLC Rf ) 0.60
(EtOAc). 1H NMR (CDCl3, mixture of rotational isomers) δ 5.93-
5.76 (m, 2H), 5.42 (s, 1H), 5.28, 5.23 (two d, 1H, J ) 1.5 Hz),
5.17, 5.14 (two s, 1H), 5.06 (s, 1H), 5.02 (d, 1H, J ) 5.8 Hz),
4.35-4.25 (m, 1H), 4.06 (dd, 1H, J ) 12.6, 5.4 Hz), 3.88 (dd, 1H,
J ) 12.6, 5.6 Hz), 3.63 (dd, 2H, J ) 9.2, 3.1 Hz), 3.36 (s, 3H),
3.35-3.25 (m, 2H), 3.12-3.05 (m, 1H), 2.67 (d, 2H, J ) 7.3 Hz),
2.60-2.44 (m, 4H), 2.36 (dd, 1H, J ) 14.2, 7.1 Hz), 2.23 (dd, 1H,
J ) 14.2, 5.2 Hz), 1.97-1.67 (m, 4H), 1.18 (d, 3H, J ) 6.1 Hz).
13C NMR (CDCl3) δu 134.9, 134.3, 124.7, 73.5, 58.9, 57.8, 19.5;
δd 207.9, 168.5, 137.4, 118.0, 116.7, 71.8, 61.2, 46.4, 44.1, 41.4,
36.9, 29.2, 26.6, 24.6. IR (CDCl3) 1709, 1627 cm-1. GC tR ) 17.34
min. EI-MS m/z (%): 375 (M+, 4), 330 (37), 319 (35), 246 (22),
142 (100).
(S)-4-Allyl-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-
4-phenylcyclo hex-2-enone (9a). Use of the general procedure with
8a afforded an 80% yield of 9a along with 18% recovered starting
1
material. TLC Rf ) 0.42 (EtOAc). H NMR (CDCl3, mixture of
rotational isomers) δ 7.38-7.23 (m, 5H), 7.19, 7.15 (two s, 1H),
5.61-5.47 (m, 1H), 5.13-5.06 (m, 2H), 4.39-4.29, 3.87-3.80 (two
m, 1H), 3.68 (dd, 1H, J ) 9.5, 3.4 Hz), 3.49 (dd, 1H, J ) 9.5, 6.9
Hz), 3.38, 3.21 (two s, 3H), 3.33-3.18 (m, 2H), 2.77-2.68 (m,
1H), 2.65-2.52 (m, 1H), 2.45-2.26 (m, 4H), 2.05-1.78 (m, 4H).
13C NMR (CDCl3, mixture of rotational isomers) δ 195.8, 195.3,
166.0, 165.9, 153.4, 152.6, 142.6, 139.2, 138.6, 133.0, 132.9, 128.8,
128.7, 127.0, 126.7, 119.4, 119.3, 74.0, 72.2, 59.1, 58.9, 58.0, 56.5,
48.5, 46.2, 46.0, 45.4, 43.8, 43.7, 35.2, 35.1, 34.6, 34.5, 28.4, 27.7,
24.3, 22.0. IR (CDCl3) 1684, 1617 cm-1. GC tR ) 10.983 min.
EI-MS m/z (%): 353(M+, 6), 312 (30), 308 (93), 239 (100), 198
(71), 141 (52).
(S)-4-Allyl-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-
4-(4-methoxyphenyl)cyclohex-2-enone (9b). Use of the general
procedure with 8b afforded an 80% yield of 9b along with 15%
1
recovered starting material. TLC Rf ) 0.30 (EtOAc). H NMR
(CDCl3, mixture of rotational isomers) δ 7.23 (d, 2H, J ) 8.8 Hz),
7.17, 7.12 (two s, 1H), 6.89 (d, 2H, J ) 8.8 Hz), 5.62-5.48 (m, 1
H), 5.12-5.06 (m, 2H), 4.38-4.30, 3.88-3.75 (two m, 1H), 3.80
(s, 3H), 3.69 (dd, 1H, J ) 9.5, 3.3 Hz), 3.49 (dd, 1H, J ) 9.4, 7.1
Hz), 3.39, 3.24 (two s, 3H), 3.30-3.18 (m, 2H), 2.75-2.65 (m,
1H), 2.60-2.49 (m, 1H), 2.45-2.20 (m, 4H), 2.08-1.79 (m, 4H).
13C NMR (CDCl3, mixture of rotational isomers) δu 153.6, 152.7,
133.0, 127.8, 114.1, 59.1, 58.9, 58.0, 56.5, 55.2; δd 195.9, 195.4,
165.9, 158.4, 139.0, 138.3, 134.3, 119.3, 74.0, 72.2, 48.5, 46.2,
46.0, 45.4, 43.0, 35.3, 34.5, 28.3, 27.7 24.3, 21.9. IR (CDCl3) 1685,
1617 cm-1. GC tR ) 22.67 min. EI-MS m/z (%): 384 (M+ + 1,
2), 383 (M+, 9), 342 (23), 338 (53), 269 (100), 241 (22), 228 (50).
(S)-4-Allyl-4-(2,3-dimethoxyphenyl)-2-((S)-2-(methoxymeth-
yl)pyrrolidine-1-carbonyl)cyclohex-2-enone (9d). Use of the
general procedure with 8d afforded a 50% yield of 9d along with
40% recovered starting material. TLC Rf ) 0.40 (EtOAc). 1H NMR
(CDCl3, mixture of rotational isomers) δ 7.40 (d, 1H, J ) 1.6 Hz),
7.34 (d, 1H, J ) 1.5 Hz), 6.99 (q, 1H, J ) 8.0 Hz), 6.89 (d, 1H,
J ) 8.2 Hz), 6.79, 6.78 (two dd, 1H, J ) 7.8, 1.5 Hz), 5.63-5.47
(m, 1H), 5.12-5.04 (m, 1H), 4.39-4.30, 3.97-3.78 (two m, 1H),
3.88 (s, 6H), 3.68 (dd, 1H, J ) 9.5, 3.3 Hz), 3.49 (dd, 1H, J ) 9.4,
7.0 Hz), 3.39, 3.22 (two s, 3H), 3.29 (t, 1H, J ) 6.6 Hz), 3.20-
3.15 (m, 1H), 2.85 (dd, 1H, J ) 6.2 Hz), 2.70-2.58 (m, 2H), 2.50-
2.30 (m, 2H), 2.23-2.08 (m, 1H), 2.08-1.75 (m, 4H). 13C NMR
(CDCl3, mixture of rotational isomers) δu 155.6, 153.9, 133.5, 133.3,
123.3, 123.1, 120.5, 120.3, 111.8, 60.3, 58.9, 58.6, 57.8, 56.2, 55.5;
δd 196.0, 195.6, 166.0, 153.3, 147.8, 136.7, 136.4, 134.6, 134.4,
118.6, 118.5, 73.7, 72.0, 48.2, 45.3, 44.3, 44.2, 43.6, 43.5, 34.8,
General Procedure for the Cope Rearrangement. The 1,5-
diene was dissolved in 1,2-dichlorobenzene (2 mL/mmol diene)
and was heated at reflux temperature for 10 h. The solvent was
removed in vacuo and the crude product was purified by chroma-
tography (1:1 or 3:7 EtOAc/hexanes).
Microwave Procedure for the Cope Rearrangement of 3a.
The 1,5-diene 3a (70 mg, 0.24 mmol) was transferred as a neat oil
to a reactor tube, was capped, and was placed in the microwave
reactor. The reaction was conducted neat with the following
parameters: temperature, 250 °C; max pressure, 250 psi; max
power, 300 W; ramp time, 2 min; reaction time, 30 min. The heating
period was repeated a second time. After a total of 1-h heating,
33.1, 32.8, 28.2, 27.5, 24.1, 21.8. IR (CDCl3) 1680, 1622 cm-1
.
936 J. Org. Chem., Vol. 72, No. 3, 2007

EnantioselectiVe Birch-Cope Sequence
GC tR ) 23.78 min. EI-MS m/z (%): 414 (M+ + 1, 2), 413 (M+,
9), 372 (15), 368 (56), 350 (15), 300 (20), 299 (100), 271 (28),
258 (51).
156.6, 156.1, 134.9, 134.8, 133.2, 133.1, 71.8, 59.1, 58.9, 57.7,
56.3, 20.3; δd 195.8, 195.3, 166.1, 136.9, 136.5, 119.1, 116.9, 116.8,
73.7, 72.1, 69.2, 48.2, 45.5, 45.3, 45.2, 42.3, 41.5, 38.2, 38.1, 34.0,
32.1, 32.0, 28.3, 27.6, 24.1, 21.9. IR (CDCl3) 1679, 1616 cm-1
.
(S)-4-Allyl-4-(allyloxymethyl)-2-((S)-2-(methoxymethyl)pyr-
rolidine-1-carbonyl)cyclohex-2-enone (13a). Use of the general
procedure with 12a afforded a 100% yield of 13a. TLC Rf ) 0.55
(EtOAc). 1H NMR (CDCl3, mixture of rotational isomers) δ 6.85,
6.83 (two s, 2H), 5.92-5.70 (m, 2H), 5.28-5.10 (m, 4H), 4.32-
4.26, 3.83-3.70 (two m, 1H), 3.97-3.95 (m, 2H), 3.66 (dd, 1H,
J ) 9.5, 3.4 Hz), 3.48-3.30 (m, 3H), 3.37, 3.25 (two s, 3H), 3.23-
3.16 (m, 2H), 2.63-2.45 (m, 2H), 2.38-2.25 (m, 2H), 2.05-1.70
(m, 6H). 13C NMR (CDCl3, mixture of rotational isomers) δu 152.6,
152.4, 134.3, 132.8, 59.1, 58.9, 57.6, 56.3; δd 195.7, 195.3, 166.1,
165.9, 138.9, 119.2, 117.2, 117.1, 74.4, 74.1, 72.3, 72.2, 48.4, 45.6,
40.1, 39.8, 39.6, 34.0, 33.9, 28.5, 28.4, 27.6, 24.1, 22.0. IR (CDCl3)
1681, 1619 cm-1. GC tR ) 17.33 min. EI-MS m/z (%): 347 (M+,
2), 332 (1), 315 (2), 306 (9), 303 (20), 302 (100), 246 (52).
(R)-4-Allyl-4-((R)-2-(allyloxy)propyl)-2-((S)-2-(methoxymeth-
yl)pyrrolidine-1-carbonyl)cyclohex-2-enone (13b). Use of the
general procedure with 12b afforded a 72% yield of 13b along
with 27% recovered starting material. TLC Rf ) 0.43 (EtOAc). 1H
NMR (CDCl3, mixture of rotational isomers) δ 7.00, 6.96 (two s,
1H), 5.98-5.70 (m, 2H), 5.32-5.08 (m, 4H), 4.35-4.25, 3.70-
3.60 (two m, 1H), 4.15-4.05 (m, 1H), 3.90-3.78 (m, 1H), 3.78-
3.65 (m, 2H), 3.53-3.40 (m, 1H), 3.38, 3.27 (two s, 3H), 3.32-
3.08 (m, 2H), 2.51 (t, 2H, J ) 7 Hz), 2.36 (t, 2H, J ) 7 Hz),
2.05-1.70 (m, 7H), 1.55 (dd, 1H, J ) 14.7, 2.1 Hz), 1.17 (d, 3H,
J ) 6.0 Hz). 13C NMR (CDCl3, mixture of rotational isomers) δu
GC tR ) 18.18 min. EI-MS m/z (%): 375 (M+, 1), 360 (1), 343
(2), 334 (24), 331 (24), 330 (100), 274 (27), 203 (45).
Acknowledgment. We thank the Petroleum Research Fund
(PRF #43238-AC1) administered by the American Chemical
Society, the Pennsylvania Department of Health, and Bryn Mawr
College for their generous financial support of this work. We
thank CEM for use of their microwave reactor system and
Sanjeev Kumar for performing the microwave experiments. Iva
Yonova is gratefully acknowledged for her synthesis and
analysis of 5-bromo-2-methoxy-benzoic acid. We also thank
Prof. Douglass F. Taber of the University of Delaware for his
advice in the preparation of the manuscript.
Supporting Information Available: General experimental
details; experimental procedures for the synthesis of 2c, 3c, 5a,
1
and 14; copies of H and 13C NMR spectra and chromatographs
for compounds described in the Experimental Section and in the
Supporting Information; NOESY for 4b; COSY for 13b; and
minimized structures of 4a and 15a. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO0621423
J. Org. Chem, Vol. 72, No. 3, 2007 937