Conservation of the planar chiral information in the tandem oxy-Cope/ene reaction

Article abstract of DOI:10.1021/jo047916z

(Chemical Equation Presented) We report the stereoselective synthesis of a Decalin unit using a tandem oxy-Cope/ene reaction. [3,3]-Shift of 1,2-divinylcyclohexenol 18 generates (1E, 3Z, 7E) cyclodecatrien-2-ol 23 which tautomerizes to ketone 21 (Figure 3

Full text of DOI:10.1021/jo047916z

Conservation of the Planar Chiral Information in the Tandem
Oxy-Cope/Ene Reaction
Danny Gauvreau1 and Louis Barriault*
Department of Chemistry, 10 Marie Curie, University of Ottawa, Ottawa, Canada K1N 6N5
lbarriau@science.uottawa.ca
Received November 23, 2004
We report the stereoselective synthesis of a Decalin unit using a tandem oxy-Cope/ene reaction.
[3,3]-Shift of 1,2-divinylcyclohexenol 18 generates (1E, 3Z, 7E) cyclodecatrien-2-ol 23 which
tautomerizes to ketone 21 (Figure 3). The chiral information embedded in 23 is transferred into
the newly formed stereogenic carbon C6 in 21. The efficiency of the chirality transfer is a reflection
of the difference in the rates of ring inversion versus tautomerization of 23. Ketone 21 undergoes
a carbonyl-ene reaction to give Decalin 20. Assuming a rapid equilibrium between macrocyclic
diastereomers, the diastereomeric ratio of the transannular ene reaction is governed by the Curtin-
Hammett principle. Analysis of the conservation of the planar chiral information in the tandem
oxy-Cope/ene reaction is presented.
Introduction
The limited freedom incurred by the presence of an E
olefin on a cyclic structure may introduce atropisomerism
to a ring.2 When the transannular portion of the meth-
ylene chain on a trans-cycloalkene is short enough, the
structures may exist as enantiomers even though the
molecule is devoid of stereogenic centers on the backbone
of the macrocycle. In 1962, Cope and co-workers reported
the first examples of atropisomerism in cycloalkenes with
the isolation of (+)-cis-trans-1,5-cyclooctadiene 2 from the
Hofmann elimination of (-)-methiodide 1 (eq 1) and the
resolution of (()-trans-cyclooctene 3 with platinum dichlo-
ride and (+)-1-phenyl-2-amino propane (eq 2) (Scheme
1).3,4 The chirality observed in these compounds was
explained by the high rigidity of these structures in
FIGURE 1. Structure of optically active cycloalkenes.
addition to the interaction of transannular hydrogens
which prevent the rotation of the E olefin.
Applying the resolution presented above to larger
cycloalkenes such as (()-trans-cyclononene 4 and (()-
trans-cycodecene 5 did not produce the corresponding
enantiopure macrocycles owing to their flexibility allow-
ing a rapid interchange between enantiomers (ring
inversion), thus preventing their isolation at room tem-
perature (Figure 1).5,6 In (()-4, however, it was possible
to observe optical activities at 0 °C after a rapid resolu-
tion of the racemic mixture followed by immediate cooling
to -80 °C.
(1) Current address: Merck-Frosst Canada, Pointe-Claire, Canada.
(2) For discussion on planar chirality in macrocycles, see (a) Eliel,
E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-
Interscience: New York, 1994. (b) Schlo¨gl, K. Top. Curr. Chem. 1984,
125, 27.
(3) (a) Cope, A. C.; Howell, C. F.; Knowles, A. J. Am. Chem. Soc.
1962, 84, 3190. (b) Cope, A. C.; Ganelin, C. R.; Johnson, H. W. J. Am.
Chem. Soc. 1962, 84, 3191. (c) Manor, P. C.; Shoemaker, D. P.; Parkes,
A. S. J. Am. Chem. Soc. 1970, 92, 5260.
(4) For the preparation of optically active (E)-cycloheptene and (E)-
cyclooctene from the corresponding (Z)-cycloalkenes in the presence
of a chiral sensitizer, see (a) Hoffmann, R.; Inoue, Y. J. Am. Chem.
Soc. 1999, 121, 10702. (b) Inoue, Y.; Matsushima, E.; Wada, T. J. Am.
Chem. Soc. 1998, 120, 10687. (c) Inoue, Y.; Yamasaki, N.; Yokoyama,
T.; Tai, A. J. Org. Chem. 1993, 58, 1011. (d) Inoue, Y.; Yamasaki, N.;
Yokoyama, T.; Tai, A. J. Org. Chem. 1992, 57, 1332.
(5) Cope, A. C.; Banholzer, K.; Keller, H.; Pawson, B. A.; Whang, J.
J.; Winkler, H. J. S. J. Am. Chem. Soc. 1965, 87, 3644.
(6) For transfer of planar chiral information in nine-membered
lactam rings, see (a) Nubbmeyer, U. Sudau, A.; Mu¨nich, W. Chem. Eur.
J. 2001, 7, 611. (b) Nubbmeyer, U. Sudau, A. Angew. Chem., Int. Ed.
1998, 37, 1140. (c) Nubbmeyer, U. Sudau, A.; Mu¨nich, W.; Bats, J. W.
J. Org. Chem. 2000, 65, 1710.
10.1021/jo047916z CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/22/2005
1382
J. Org. Chem. 2005, 70, 1382-1388

Tandem Oxy-Cope/Ene Reaction
SCHEME 1
SCHEME 2
From this, the energy barriers for rotation and the half-
lives of the optical activity at room temperature for 3,7
4,3 and 58 were measured and reported as 35.6 kcal/mol
(t1/2 ∼ 105 years), 20.0 kcal/mol (t1/2 ∼ 10 s), and 10.7 kcal/
mol (t1/2 ∼ 10-4 s), respectively. The superior flexibility
of 5 which accounts for its inability to be resolved was of
particular interest. In 1980, Marshall and co-workers
successfully isolated optically stable trans-1,2-dimethyl-
cyclodecene 6 and trans-1,2-dimethylcycloundecene 7.9
They demonstrated that the presence of the methyl
substituents on the double bond raised the activation
energy for racemization by increasing steric interactions
during double-bond rotation. Marshall reported that 7
showed no loss of optical activity after heating for 3 days
at 100 °C and two distillations at 190-205 °C. Wharton
and Johnson measured the rate constant for the conver-
sion of trans-1,2-divinylcyclohexane 8 to ent-8 on the
basis of its racemization (Scheme 2).10 Cope reaction of
8 followed by ring inversion of 9 and the reverse [3,3]
resulted in the loss of chirality of 8. Despite their high
rigidity, the trans-trans-1,5-cyclodecadiene 9 or ent-9
proved to be enantiomerically unstable.
centers. In this case, the molecular chirality of 12 is due
to all of the sp2 carbons embedded in the macrocyclic
backbone. We suggested that the chirality transfer
observed during the oxy-Cope rearrangement can be
explained on the basis of an energy barrier for inversion
of 12 to ent-12 and preferential stereofacial protonation
(Figure 2). The macrocycle 12 possesses a conjugated
In 2001, Barriault and Deon accomplished the first
total synthesis of (+)-arteannium M (10)11 using the
tandem oxy-Cope/ene reaction12 as the key step to create
the Decalin core 15.
The tandem process is triggered by an oxy-Cope
reaction of 11 (ee > 98%) to furnish enol 12 which
tautomerizes to enone 13. The latter is poised to undergo
a transannular ene reaction giving the desired Decalin
15. A close inspection of macrocyclic enol 12 reveals that
the backbone of the ring is devoid of sp3 stereogenic
FIGURE 2. Preferential stereofacial protonation of macro-
cyclic enols 12 and ent-12.
dienol (E, Z) and a second E double bond (ene donor)
which creates a strained and rigid macrocyclic ring. As
a result, the conversion of 12 into ent-12 requires that
the enol moiety rotates inside the macrocycle, which is
an energetically demanding process.7 At the same time,
protonation of enol 12 occurs from the â-face to yield
ketone 13. Complete transfer of chirality, however, was
not observed and a 20% loss of enantiopurity occurred
which suggests that a partial protonation from the R face
of 12 gave ent-13 directly. This represents a rare case of
the use of planar chirality in macrocycles in the total
synthesis of natural products. To explain the enantiose-
lectivity of the tandem process in greater detail, a series
of 1,2-divinylcyclohexenols was prepared and irradiated
with microwaves under various conditions.13
(7) Cope, A. C.; Pawson, B. A. J. Am. Chem. Soc. 1965, 87, 3649.
(8) Binsh, G.; Roberts, J. D. J. Am. Chem. Soc. 1965, 87, 5157.
(9) Marshall, J. A.; Konicek, T. R.; Flynn, K. E. J. Am. Chem. Soc.
1980, 102, 3287.
(10) Wharton, P. S.; Johnson, D. W. J. Org. Chem. 1973, 38, 4117.
(11) Barriault, L.; Deon, D. H. Org. Lett. 2001, 3, 1925.
(12) (a) Barriault, L.; Warrington, J. M.; Yap, G. P. A. Org. Lett.
2000, 2, 663. For other examples see (b) Paquette, L. A.; Nakatani, S.;
Zydowsky, T. M.; Edmondson, S. D.; Sun, Q.-L.; Skerlj, R. J. Org. Chem.
1999, 64, 3244. (c) Rajagopalan, K.; Srinivasan, R. Tetrahedron Lett.
1998, 39, 4133. (d) Shanmugan, P.; Devan, B.; Srinivasan, R.; Raja-
gopalan, K. Tetrahedron 1997, 53, 12637. (e) Rajagopalan, K.; Shan-
mugam, P. Tetrahedron 1996, 52, 7737. (f) Rajagopalan, K.; Janardha-
nam, S.; Devan, B. Tetrahedron Lett. 1993, 34, 6761. (g) Rajagopalan,
K.; Janardhanam, S.; Balakumar, A. J. Org. Chem. 1993, 58, 5482.
(h) Chorlton, A. P.; Morris, G. A.; Sutherland, J. K. J. Chem. Soc,
Perkin Trans. 1 1991, 1205.
Results and Discussion
1,2-Divinylcycohexenols 18a-f (ee > 98%) were readily
obtained by a halogen-metal exchange of the corre-
sponding haloalkene using tert-butyllithium, followed by
the addition of S-isopiperitenone 17 (Scheme 4).14 Sub-
J. Org. Chem, Vol. 70, No. 4, 2005 1383

Gauvreau and Barriault
SCHEME 3
SCHEME 4
TABLE 1. Tandem Oxy-Cope/Ene Reaction of 18a and 18b with Various Bases
yielda, (ee),c
19a R ) Me
yieldb, (ee),c
19b R ) Ph
entry
base
1
2
3
4
5
6
7
8
DBU
TMEDA
Et3N
60%, (93%)
48%, (>98%)
36%, (96%)
39%, (>98%)
decomp.
28%, (97%)
57%, (>98%)
46%, (96%)
93%, (35%)
86%, (>98%)
76%, (>98%)
36%, (>98%)
65%, (>98%)
75%, (>98%)
91%, (>98%)
98%, (>98%)
pyridine
2,6-di-tert-butylpyridine
DMAP
sparteine
2-t-Bu-1,1,3,3-tetramethylguanidine
a Ratio (19a/20a) ) 15:1. b Ratio (19b/20b) > 25:1. c Enantiomeric excesses were determined using HPLC with a ChiralPak AS column,
eluent: hexanes/i-PrOH.
strates 18a and 18b were irradiated at 600 W for 1 h
(T ) 220 °C)15 in toluene ([ ] ) 3.2 × 10-3 M) in the
presence of various bases (10 equiv) (Table 1).
Chemical yields obtained for the transformation of 18a
and 18b to 19a and 19b ranged from 28% to 98% with
diastereomeric ratios of 15:1 and greater that 25:1,
respectively. We noticed small differences in the transfer
of chirality in 18a (entries 3, 6, and 8). However, a
significant drop in the enantiopurity was observed when
DBU was used as a base (entry 1). This was most evident
in the transformation of 18b to 19b (R ) Ph, ee ) 35%).
Good chemical yields and enantiomeric excesses were
obtained when TMEDA and sparteine were used (entries
2 and 7).
(13) For review on Microwaves in Organic Synthesis, see (a) Loupy,
A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D.
Synthesis 1998, 1213. (b) Majetich, G.; Hichs, R. J. J. Microwave Power
Electromagnetic Energy 1995, 30, 27. (c) Loupy, A.; Perreux, L.
Tetrahedron 2001, 57, 9199. (d) Lidstro¨m, P.; Tierny, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225.
(14) Dauben, W. G.; Lorber, M.; Fullerton, D. S. J. Org. Chem. 1969,
34, 3587.
(15) We found that 220 °C is the minimal temperature to trigger
the tandem process.
1384 J. Org. Chem., Vol. 70, No. 4, 2005

Tandem Oxy-Cope/Ene Reaction
SCHEME 5
TABLE 2. Tandem Oxy-Cope/Ene Reaction of 18a and
18b with Various Amount of DBU
TABLE 3. Tandem Oxy-Cope/Ene Reactions of 1,
2-Divinylcyclohexenols 18c-f
equiv of
DBU
yielda, (ee)c 19a,
R ) Me
yieldb, (ee)c 19b,
R ) Ph
entry
1
2
3
4
5
0
0.5
1
49%, (97%)
47%, (>98%)
72%, (>98%)
65%, (95%)
60%, (93%)
74%, (>98%)
87%, (83%)
99%, (77%)
86%, (51%)
93%, (35%)
yield Ee
ratio
5
entry
substrate
18c, R ) CF3
base
DBU
TMEDA
no base
DBU
(%)a (%)b (19/20)
10
1
2
17
72
76
26
15
11
66
37
76
59
70
83
>98
74c
82c
91c
8.5:1
8.5:1
8.5:1
1:2.3
1:2.3
1:2.3
a Ratio 19a/20a ) 15:1. b Ratio 19b/20b > 25:1. c Enantiomeric
excesses were determined using HPLC with a ChiralPak AS
column, eluent: hexanes/i-PrOH.
18c, R ) CF3
18c, R ) CF3
18d, R ) OEt
18d, R ) OEt
18d, R ) OEt
3
4
5
TMEDA
no base
6
Owing to the noticeable decrease of enantiomeric
excess when DBU was used, the tandem reaction was
performed with various equivalents of DBU ([ ] ) 3.2 ×
10-3 M in toluene) (Table 2). When the reaction was
performed without base, almost no loss of chirality was
observed in either case (entry 1). In the conversion of 18a
to 19a, the increase in DBU equivalents did not affect
drastically the enantiomeric excess (entries 2-4). Despite
the beneficial effect of DBU on the chemical yield, a
significant erosion of enantioselectivity was noted when
18b was irradiated in the presence of various amounts
of DBU (entries 1-5).
To explore the electronic influence of the vinylic
substituents on the enantioselectivity erosion, various
1,2-divinylcyclohexanols were irradiated in toluene with
either DBU, TMEDA, or without base (Table 3). Irradia-
tion of 1,2-divinylcyclohexenols 18c and 18d in the
absence of base (entries 3 and 6) gave the corresponding
Decalins 19c and 19d in 76% and 11% yields, respec-
tively, with minimal loss of optical activity.16 However,
the enantiomeric excesses of these reactions were sig-
nifically diminished in the presence of base (entries 1, 2,
4, and 5). This effect became more pronounced when the
tandem reaction was performed with DBU (entries 1 and
7
18e, R ) (CH2)2ODPS DBU
82 >25:1
8
18e, R ) (CH2)2ODPS TMEDA
>98 >25:1
84 >25:1
9
18f, R ) naphthyl
18f, R ) naphthyl
DBU
TMEDA
10
>98 >25:1
a In all cases, the starting material was completely consumed.
b Enantiomeric excesses were determined using HPLC with a
ChiralPak AS column, eluent: hexanes/i-PrOH. c The enantio-
meric excess was measured on Decalin 20d.
4). Heating of 1,2-divinylcyclohexenols 18e and 18f in the
presence of TMEDA furnished Decalins 19e and 19f in
37% and 59% yield, respectively, without loss of chirality
(entries 8 and 10). The results reported in Tables 1-3
strongly suggest that the pKa of the proton at C6 in 21,
combined with the strength of the base used, are directly
responsible for the loss of chirality transfer.
In light of these results, one might propose that the
enol ring inversion competes with the tautomerization
process when strong bases are used. To verify this
hypothesis, 1,2-divinylcyclohexenols 18a and 18b were
treated with KHMDS (5 equiv) in DME at 110 °C
(Scheme 5). After 1 h, the reaction mixture was cooled
to -78 °C and a solution of acetic acid (1 M) in THF was
added to give macrocycles 21a (R ) Me) and 21b (R )
Ph) in 75% and 78% yield, respectively. Both macrocycles
were isolated in their racemic form.
(16) Tandem reaction precursor 18d is highly unstable and low
yields were consequently observed.
J. Org. Chem, Vol. 70, No. 4, 2005 1385

Gauvreau and Barriault
FIGURE 3. Proposed mechanism to explain the stereospecificity of the tandem oxy-Cope/ene reaction.
This observation can be rationalized as follows. As-
suming that the inversion is a fast process,17 this allows
a rapid conversion between 22 and ent-22 which after
protonation gives macrocycles 21 and ent-21 as an equal
mixture (ee ) 0%). Therefore, the previously suggested
hypothesis11 of an elevated inversion barrier can be ruled
out since its existence would predict a complete conserva-
tion of the stereochemical information during the anionic
oxy-Cope reaction.
the ring inversion process thereby producing a mixture
of 21 and ent-21.
Macrocycle 21 is poised to undergo an irreversible
transannular ene reaction.18 Assuming a rapid equilib-
rium takes place between ketone 21 and its diastereomer
24, the diastereomeric ratio of the transannular carbonyl-
ene reaction (19/20) should correspond to the energy
difference between TS A and TS B.19 A close examination
of TS A reveals destabilizing steric interactions between
On the basis of the results obtained above, the high
enantio- and diastereoselectivity of the tandem oxy-Cope/
ene can be explained as follows. After the sigmatropic
rearrangement of 18, macrocyclic enol 23 can invert to
give its mirror image ent-23 or tautomerize to afford
ketone 21 (Figure 3) assuming complete enantioselectiv-
ity in the protonation. If one assumes that the ring
inversion is a relatively slow process compared to tau-
tomerization, macrocycle 21 should be produced as a
single enantiomer when no base or weak bases are used.
On the other hand, when DBU is utilized as a base, a
partial deprotonation of 18 gives 18-H which rearranges
to enolate 22. The latter can be also obtained from a
deprotonation of 23. As a result, the protonation of
enolate 22 with the conjugate acid of DBU competes with
(18) (OH)D-19a was heated in toluene at 220 °C for 2 h in the
presence of 10 equiv of DBU. No incorporation of deuterium in the
exocyclic double bond, i.e., formation of (C11)D-19a, was not observed.
Only (OH)D-19a was isolated thereby proving that the ene reaction
is an irreversible process.
(17) This is in concordance with similar ring systems. The barriers
for swiveling the trans double bond through the unsaturated 10-
membered ring in E,E-1,6-cyclodecadiene and Z,E-1,6-cyclodecadiene
were calculated to be 14.8 and 24.5 kcal/mol, respectively, see Yavari,
I.; Hosseini-Tabatabaei, M. R.; Nori-Shargh, D.; Jabbari, A. J. Mol.
Struct. (THEOCHEM) 2001, 574, 9.
(19) (a) Curtin, D. Y. Rec. Chem. Prog. 1954, 15, 111. (b) Winstein,
S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77, 5562. (c) Eliel, E. L.
Stereochemistry of Carbon Compounds; McGraw-Hill: New York, 1962.
(d) Hammett, L. P. Physical Organic Chemistry; McGraw-Hill: New
York, 1970; Chapter 5. (e) Seeman, J. I Chem. Rev. 1983, 83, 83. (f)
Seeman, J. I. J. Chem. Educ. 1986, 63, 42.
1386 J. Org. Chem., Vol. 70, No. 4, 2005

Tandem Oxy-Cope/Ene Reaction
SCHEME 6
TABLE 4
the axial R group and the ring thereby favoring TS B
over TS A to provide 19. This readily explains the high
enantio- and diastereoselectivity obtained when various
1,2-divinylcyclohexenol 18 were irradiated with or with-
out the presence of weak bases.
However, lower diastereomeric ratios were observed
when R ) CF3 and OEt (Table 3, entries 1-6). It seems
unlikely, in these cases, that the ene reaction is governed
by the Curtin-Hammett principle. Alternatively, one
might propose that after the oxy-Cope/tautomerization
process, the ring inversion (21f24) competes with the
ene reaction since the latter reaction is accelerated by
electron-withdrawing groups such as R ) CF3 and OEt
adjacent to the carbonyl in 21.20 This effect is most
dramatic when R ) OEt, as the diastereoselectivity was
inverted and Decalin 20d, having an axial R group, was
isolated as the major isomer.21 Alternatively, one might
consider that the observed diastereoselectivity results
from the minimization of the carbonyl and ethoxy dipoles
at the transition state of the ene reaction. We previously
demonstrated that the dipoles have only a minor role, if
any, in governing the outcome of this tandem reaction.22
As discussed above, the presence of the trisubstituted
Z olefin C3-C4 in enol 23 introduces rigidity in the
macrocycle. Its importance in conserving the chiral
information during the cascade process was investigated.
The reduction of this olefin without creating a chiral
center was achieved by a 1,4-addition of lithium dimeth-
ylcuprate on 17 to afford ketone 25 (Scheme 6). The latter
was treated with 2-lithiopropene and R-lithiostyrene
vinyllithium to produce 5,5-dimethyl-1,2-divinylcyclohex-
enols 26a and 26b in 95% and 87% yield, respectively.
Irradiation of 26a and 26b at 220 °C for 1 h with and
without base gave the desired Decalins 27 in yields
ranging from 40% to 99% (Table 4). The conservation of
the enantiopurity was noticed in all cases even in the
presence of DBU. It is believed that the replacement of
the olefin by a gem-dimethyl group may lower the
ground-state energy of the enol A or ketone intermediate
thus preventing its racemization by increasing the re-
quired energy of activation for ring inversion. The basic-
entry
substrate
base
DBU
TMEDA
DBU
TMEDA
no base
yield (%)a
Ee (%)b
1
2
3
4
5
26a
26a
26b
26b
26b
93
99
92
58
40
95
98
96c
91c
98c
a All products were obtained with dr > 25:1 (27/28). b Enantio-
meric excesses were determined using HPLC with a ChiralPak
AS column, eluent: hexanes/i-PrOH. c Ee was measured after
treatment with TBAF.
ity of the gem-dimethyl enol intermediate A constitutes
another possibility to rationalize the high transfer of
chirality. Assuming a greater basicity of the nonconju-
gated enol A, the tautomerization process is likely to
occur faster with this substrate independent of the base
used. This demonstrates that this olefin is not crucial to
maintaining the chirality during the tandem process.
Conclusion
An analysis of the reaction mechanism reveals that the
chiral information embedded in the 1,2-divinylcyclohex-
enols 18 was conserved through the cascade process
owing to the rate of tautomerization which is much larger
than the rate of inversion of macrocycle 23. The enan-
tiomeric excess is dependent on the base used in the
cascade process and the electronic nature of the vinylic
substituent on 18. On the other hand, the diastereose-
lectivity of the process is controlled by the conformational
preferences of macrocycles at the transition state for the
ene reactions. In summary, the planar chiral information
generated in the tandem oxy-Cope/ene reaction was
transferred into new stereogenic centers in a highly
efficient manner at high temperature (220 °C). This
proves to be a powerful and simple method to produce
Decalin frameworks in high enantiomeric excesses.
(20) (a) Snider, B. B. In Comprehensive Organic Synthesis, Com-
bining C-C π bond; Paquette, L. A., Ed.; Pergamon Press: Oxford,
1991; Vol. 5, Chapter 1.1. (b) Snider, B. B. In Comprehensive Organic
Synthesis, addition to C-X π bond; Heathcock, C. H., Ed.; Pergamon
Press: Oxford, 1991; Vol. 2, Chapter 2.1.
(21) The relative stereochemistry of 20d was established without
ambiguity by 1-D NOE experiments.
(22) Tandem oxy-Cope/Claisen/ene reaction of 29 gave 30 (dr > 1)
in toluene. Repeating the experiment in a more polar solvent, such as
DMF, gave no change in the product ratio (25 > 1). Barriault, L.; Sauer,
E. L. O. J. Am. Chem. Soc. 2004, 126, 8569.
Acknowledgment. We thank the Natural Science
and Engineering Research Council of Canada (NSERC),
Merck-Frosst Canada, Boehringer Ingelheim, Bristol
Myers Squibb, AstraZeneca, Canada Foundation for
J. Org. Chem, Vol. 70, No. 4, 2005 1387

Gauvreau and Barriault
compounds 18a-f, 19a-f, 21a, 21b, 25, 26a, 26b, 27a, and
27b. This material is available free of charge via the Internet
at http://pubs.acs.org.
Innovation, Ontario Innovation Trust, and the Univer-
sity of Ottawa for generous funding. D. G. thanks
NSERC for a post-graduate scholarship (PGS-A).
Supporting Information Available: Experimental pro-
cedures, spectroscopic data and copies of 1H and 13C NMR for
JO047916Z
1388 J. Org. Chem., Vol. 70, No. 4, 2005