Cascade polycyclization: Exploration of a convergent route to access various tricyclic and tetracyclic products related to sterols

Article abstract of DOI:10.1021/jo034280n

The expedient synthesis of tricyclic and tetracyclic compounds via a cascade polycyclization methodology is described. Nazarov substrates (II) containing two Michael acceptors and a cyclohexenone ester (I) underwent cycloaddition followed by intramolecula

Full text of DOI:10.1021/jo034280n

Ca sca d e P olycycliza tion : Exp lor a tion of a Con ver gen t Rou te to
Access Va r iou s Tr icyclic a n d Tetr a cyclic P r od u cts Rela ted to
Ster ols
Benoit Guay and Pierre Deslongchamps*
Laboratoire de Synthe`se Organique, De´partement de Chimie, Institut de Pharmacologie de Sherbrooke,
Universite´ de Sherbrooke, 3001, 12e Avenue nord, Sherbrooke, Que´bec J 1H 5N4, Canada
pierre.deslongchamps@courrier.usherb.ca
Received March 3, 2003
The expedient synthesis of tricyclic and tetracyclic compounds via a cascade polycyclization
methodology is described. Nazarov substrates (II) containing two Michael acceptors and a
cyclohexenone ester (I) underwent cycloaddition followed by intramolecular 1,4-addition to furnish,
in a highly stereoselective manner, tricyclic and tetracyclic products (III). Such compounds are
interesting intermediates for the synthesis of polycyclic natural and unnatural products.
In tr od u ction
recently pointed out9 that the intramolecular aldol reac-
tion seems to be very sensitive to the nature of the
functionality on the Nazarov substrate, particularly at
C-17. Even though specific methods were developed10 to
effect the aldol reaction, none were found to be of general
utility because of the reversibility of this reaction. This
prompted us to investigate the closure of the C ring using
a Michael reaction.11,12 This alternative method should
give access to many tricyclic and tetracyclic intermedi-
ates. We have, therefore, prepared the Nazarov key
intermediates 15, 27, 41, 53, 58, 81, and 82 and studied
their condensation with enone esters 1 and 60. We wish
to report herein on the results of this exploratory
investigation.13
Tricyclic and tetracyclic compounds are among the
more ubiquitous structural frameworks found in natural
products. Many such compounds, particularly steroids,
diterpenes, and triterpenes, elicit important pharmaco-
logical activities, for which they still find widespread use.
Despite this, few general methods have thus far been
developed to allow access to such structures.1 We report
herein a general and convergent method for the synthesis
of tricyclic and tetracyclic intermediates.
Several years ago, we reported a stereocontrolled
synthesis of cis-decalins.2,3 Subsequently, we also dis-
closed our synthetic approach to access the tetracyclic
product 3 by using the reaction between 2-carbomethoxy-
2-cyclohexenone4 (1) (Scheme 1) and the Nazarov sub-
strate5 2. Under basic conditions, 3 was obtained as the
sole product via a cascade of double-Michael-aldol con-
densation or the so-called anionic polycyclization reac-
tion.6 Similarly, the reaction between the chiral Nazarov
substrate 5 and the optically active cyclohexenone 4
yielded the tricyclic intermediate 6, which could be
converted to 14-â-hydroxysteroids 7 bearing a â-OBz
group at C-17 (steroid numbering) by an intramolecular
aldol condensation under basic conditions.7,8 We have
Resu lts a n d Discu ssion
The synthesis of the Michael acceptor Nazarov sub-
strate 15 (Scheme 2) was initiated by the TMSCl/HMPA-
catalyzed conjugate addition14 of the cuprate reagent
derived from 4-bromobutene on the cyclopentenone 8 to
afford the cyclopentanone 9. The olefin was oxidized with
ozone to yield the aldehyde, which was protected in situ
as a dimethylacetal 10. The cyclopentanone was success-
fully dehydrogenated by a palladium-catalyzed reaction15
to yield the cyclopentenone 11 in 50% yield along with
(1) (a) ApSimon, J . The Total Synthesis of Natural Products; J ohn
Wiley and Sons: New York, 1984, Vol. 6, pp 1-139. (b) Blickenstaff,
R. T.; Ghosh, A. C.; Wolf, G. C. Total Synthesis of Steroids, Organic
Chemistry, A Series of Monographs, vol. 30; Academic Press: New
York, 1974. (c) Akhrem, A. A.; Titov, Y. A. Total Steroid Synthesis;
Plenum Press: New York, 1970.
(9) Yang, Z.; Shannon, D.; Truong, V. L.; Deslongchamps, P. Org.
Lett. 2002, 4, 4693.
(10) Chapdelaine, D.; Belzile, J .; Deslongchamps, P. J . Org. Chem.
2002, 67, 5669.
(2) Lavalle´e, J .-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29,
5117.
(3) (a) Lavalle´e, J .-F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslong-
champs, P. Can. J . Chem. 1992, 70, 1406. (b) Ruel, R.; Hogan, K. T.;
Deslongchamps, P. Synlett 1990, 516.
(11) For a review on Michael reaction, see: Bergmann, E. D.,
Ginsburg, D.; Pappo, R. Org. React. 1967, 10, 179.
(12) For a review on the intramolecular version, see: Little, R. D.;
Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J . I. Org. React. 1995,
47, 315.
(4) Liotta, D.; Bomum, R.; Puleo, G.; Bayer, C.; Kezar, H. S. J . Org.
Chem. 1981, 46, 2920.
(5) Nazarov, I. N.; Zauyalou, S. I. Obshch. Khim. 1953, 23, 1703.
(6) Lavalle´e, J .-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29,
6033.
(7) Ruel, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3961.
(8) Ruel, R.; Deslongchamps, P. Can. J . Chem. 1992, 70, 1939.
(13) For other investigations in this area, see: (a) Lepage, O.;
Deslongchamps, P. J . Org. Chem. 2003, 68, 2183. (b) Lepage, O.; Stone,
C., Deslongchamps, P. Org. Lett. 2002, 4, 1091.
(14) (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025. (b) Nakamura, E.; Matsuzawa, S.;
Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4029.
(15) Shvo, Y.; Arisha, A. H. I. J . Org, Chem. 1998, 63, 5640.
10.1021/jo034280n CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/16/2003
6140
J . Org. Chem. 2003, 68, 6140-6148

Cascade Polycyclization
SCHEME 1 a
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) p-TsOH, C6H6, reflux, 47% (2 steps); (c) p-TsOH, C6H6, reflux, 60% (2 steps); (d)
Cs2CO3, CH3CN, reflux, 32%.
SCHEME 2 a
a
Reagents and conditions: (a) (i) Mg, 4-bromobutene, CuBr DMS, TMSCl, HMPA, THF -78 °C to rt, (ii) AcOH, 97%; (b) (i) O3, CH2Cl2-
MeOH, -78 °C, (ii) DMS, -78 °C to rt, (iii) p-TsOH, 72%, (90% corr); (c) Pd(OAc)2, (EtO)2P(O)-allyl, Na2CO3, THF, reflux, 50%, (100%
corr); (d) AcOH-H2O, 50 °C, 92%; (e) P(Ph)3C(Me)CHO, C6H6, reflux, 65%; (f) Zn, BrCH2CO2t-Bu, THF, 0 °C, 46% (85% corr); (g) Dess-
Martin, CH2Cl2, 0 °C to rt, 84%.
SCHEME 3 a
50% recovered starting material. The reaction curiously
stopped at 50% conversion, and all attempts to drive it
to completion were unsuccessful. Alternative approaches16
to obtain the enone by other common methods were either
unsuccessful or merely led to complex mixtures. The
acetal was hydrolyzed under acidic condition to give the
unstable aldehyde 12, which was immediately submitted
to Wittig olefination conditions with the stabilized phos-
phorane reagent to afford the R,â-unsaturated aldehyde
13. Addition of the Reformatsky reagent derived from
tert-butyl bromoacetate furnished the alcohol 14. Further
oxidation with Dess-Martin periodinane17 yielded the
γ,δ-unsaturated â-ketoester 15.
The cyclization of the Nazarov substrate 15 (Scheme
3) was achieved with the activated cyclohexenone 1 under
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) p-TsOH,
(16) Reaction such as R-bromination-dehydrobromination, R-sel-
enation-oxidation-selenoxide elimination. Standard Pd2+ enol ether
oxidation, DDQ silyl enol ether oxidation, cupric bromide dehydroge-
nation, R-ketosulfoxide elimination.
C6H6, reflux, 40% of 17 and 40% of 18.
basic condition to yield the tricyclic compound 16 as a
mixture of diastereoisomers. This result implies that the
(17) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.
J . Org. Chem, Vol. 68, No. 16, 2003 6141

Guay and Deslongchamps
SCHEME 4
SCHEME 5 a
a
Reagents and conditions: (a) P(Ph)3CHCO2Me, C6H6, reflux,
72%; (b) DIBAL-H, CH2Cl2-hexane, -78 °C, 94%; (c) Dess-
Martin, CH2Cl2, 63%; (d) Zn, BrCH2CO2t-Bu, THF, 0 °C, 63%; (e)
Dess-Martin, CH2Cl2, 0 °C to rt, 68%.
ring D enone is not sufficiently electrophilic to trap the
7,8
∆
enolate that is produced in situ after the first
cycloaddition step. To achieve this step would probably
require a more activated electrophile. Attempts at deal-
koxycarbonylation of the tert-butyl ester under acidic
conditions furnished directly, to our surprise, the corre-
sponding tetracyclic intramolecular Michael adducts 17
and 18. Each isomer was isolated in 40% overall yield,
and their three-dimensional structures were ascertained
by single-crystal X-ray diffraction crystallography. The
formation of these two racemic diastereoisomers in a 1:1
ratio is, of course, due to the complete lack of facial
selectivity in the course of the condensation of 15 with
the enonester 1. It is noteworthy that the 8R-methyl
group found in 17 and 18 have the reversed relative
stereochemistry compared to that found in natural di-
and triterpenes. Inspection of molecular models of the
possible transition states 19-22 (Scheme 4) reveals that
the forming carbon-carbon bond must be the result of a
pseudoaxial attack of the enol in both cases in order to
provide the maximum orbital overlap. The preferred
conformations 20 and 22 must therefore lead to the
attack of the enol from its â-face giving the R-configura-
tion for the 8-methyl group in the cyclized products.
Conformations 19 and 21 would have led to the 8â-methyl
products. The observed cis C/D ring junction can be
explained as a result of a sterically more suitable orbital
alignment between the enol and the enone.
SCHEME 6 a
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) p-TsOH,
C6H6, reflux, 50% of 29 and 20% of 30 (2 steps); (c) p-TsOH,
We then decided to look at the effect of the methyl
group on the reactivity of the ∆7,8 enol, since its presence
could be essential for the reaction to proceed. To this end,
the Nazarov substrate 27 lacking such a methyl group
was synthesized (Scheme 5).18 The synthesis was carried
out starting from the aldehyde 12, which was reacted
with the stabilized phosphorane to afford the R,â-
unsaturated ester 23. The ester was reduced to the diol
24 and subsequently oxidized to the R,â-unsaturated
aldehyde 25. The γ,δ-unsaturated â-ketoester 27 was
obtained by the same alkylation-oxidation sequence
already described.
When subjected to the cyclization conditions with
cyclohexanone 1 (Scheme 6), the Nazarov substrate 27
yielded the tricyclic product 28 as a mixture of racemic
diastereoisomers. On the other hand, when submitted to
the acid-catalyzed dealkoxycarbonylation-cyclization re-
action, only the tetracycle 29 was isolated as an insepa-
rable epimeric mixture19 at C-8 (50% overall yield) along
with the dealkoxycarbonylated 13R-methyl tricycle 30 in
toluene, reflux, 100%.
20% overall yield. The latter was cyclized when treated
with catalytic amount of p-TsOH at the higher temper-
ature of refluxing toluene to afford the 13R-methyl
tetracycle 31 in quantitative yield. The three-dimensional
structure of this new tetracyclic isomer 31 was ascer-
tained by single-crystal X-ray diffraction crystallography.
The X-ray crystallographic data demonstrates that the
tetracycle 31 has the 13R-methyl and 8â-H stereochem-
istry. If the previous results are taken into account
(Schemes 3 and 4), it is likely that the first tetracycle
formed from 30 must be the 8R-H isomer, which subse-
quently epimerizes in situ to the more stable cis-anti-
trans-anti-cis tetracycle 31 resulting in the 8â-H stere-
ochemistry. The cyclization results indicate that the
(18) We wish to thank Suzanne Girard for the synthesis of Nazarov
substrate 27.
(19) The mixture was characterized by 1H NMR only.
6142 J . Org. Chem., Vol. 68, No. 16, 2003

Cascade Polycyclization
SCHEME 7 a
SCHEME 8 a
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) p-TsOH,
C6H6, reflux, 13% of 43 and 13% of 44 (2 steps).
the butenyl cyclopentenone 35. The cyclopentenone was
R-methylated to yield 36. The terminal olefin was selec-
tively oxidized24 with ozone and the resulting aldehyde
37 was reacted with the stabilized phosphorane to yield
the R,â-unsaturated aldehyde 38. Methylphenyl sulfoxide
lithium salt25 was added to the latter to yield the hy-
droxysulfoxide 39. The carbonyl of the enone was reduced
to the alcohol followed by acid hydrolysis to afford directly
the cyclopentenone 40. The alcohol was finally oxidized
by Dess-Martin periodinane to yield the γ,δ-unsaturated
â-ketosulfoxide 41.
a
Reagents and conditions: (a) LDA, methylcyanoformate, THF,
-78 °C, 60%; (b) KH, bromobutene, DMF, 77%; (c) KOH, EtOH,
reflux, 74%; (d) LDA, MeI, THF, -78 °C, 81%; (e) (i) O3, Sudan 3,
CH2Cl2, -78 °C, (ii) PPh3, -78 °C to rt, 90%; (f) P(Ph)3C(Me)CHO,
C6H6, reflux, 76%; (g) CH3-S(O)-Ph, LDA, THF, -78 °C; 55%; (h)
DIBAL-H, CH2Cl2, -78 °C, 63%; (i) Dess-Martin, CH2Cl2, 0 °C
to rt, 89%.
The Nazarov substrate 41 (Scheme 8) and the cyclo-
hexenone 1 underwent the double-Michael cycloaddition,
and the sulfoxide was eliminated on silica gel during
flash chromatography to afford the tricycle 42 as a
mixture of racemic diastereoisomers. The latter, when
subjected to a catalytic amount of p-TsOH in refluxing
benzene, was converted to the racemic tetracyclic prod-
ucts 43 and 44 in 26% yield. The three-dimensional
structures were determined by single crystal X-ray
diffraction crystallography. These results confirmed that
the new carbon-carbon bond is formed on the same side
of the chain at C-9 resulting in a cis B/C ring junction.
Thus it is possible by this approach to obtain the
8â-methyl configuration, which is the one found in most
naturally occurring sterols.
presence of an additional methyl group at C-8 facilitates
the last Michael step from 16, since a higher temperature
is necessary to convert 30 into 31. This result can be
explained either by the fact that a tetrasubstituted enol
would be more nucleophilic (thus more reactive) than a
trisubstituted one20 or that it would have a longer half-
life once produced in situ. Moreover, the formation of 31
requires a temperature higher than that for 29. This can
be attributed to additional steric interaction generated
by approaching the B and D rings in the Michael addition
transition state leading to 31 (cf. 22) by comparison with
that of 29 (cf. 20).
Since the products of the intramolecular Michael
addition of γ,δ-unsaturated â-ketoester always possess
the 8R-methyl stereochemistry, we sought to contrive
means of inverting the stereochemical outcome of this
reaction. It was found some years ago in our laborato-
ries21 that when the â-ketoester moiety of the Nazarov
substrate is replaced by a â-ketosulfoxide, the double-
Michael cycloaddition with an activated cyclohexenone
yielded stereospecifically decalins with the substituent
at C-9 in the opposite configuration. On the basis of this
result we speculated that the â-ketosulfoxide Nazarov
substrate 41 (Scheme 7) should give the inverted stere-
ochemistry at C-9 (â configuration of the hydrogen) and
that should invert the stereochemistry at C-8 to yield the
8â-methyl tetracycles, assuming that the B/C ring junc-
tion will still be formed in a cis fashion.
We then sought to explore the possibility of making a
tricycle in a one-pot sequence using the same methodol-
ogy. This goal could be achieved with an acyclic Nazarov
substrate such as 53 and the cyclohexanone 1. This
sequence would give us the opportunity to employ an R,â-
unsaturated aldehyde Michael acceptor, a more activated
electrophile that should efficiently trap the in situ formed
7,8
∆
enolate resulting from the double-Michael cycload-
dition.
The synthesis started from the known R,â-unsaturated
ester26 45 (Scheme 9), which was reduced with DIBAL-H
to the allylic alcohol 46 and then protected as a silyl ether
47. The TBDMS was selectively removed in acidic EtOH
Accordingly, the â-ketosulfoxide 41 (Scheme 7) was
prepared starting from the acylation of the known
enolether protected 1,3-cyclopentandione 3222 using meth-
yl cyanoformate23 to afford the â-ketoester 33. The
potassium anion of 33 was alkylated with 4-bromobutene
to yield the butenyl-â-ketoester 34. The ester was hy-
drolyzed and the acid salt was decarboxylated to yield
(20) Quesnel, Y.; Bidois-Sery, L.; Poirier, J .-M.; Duhamel, L. Synlett
1998, 413.
(21) Spino, C.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3969.
(22) (a) Conia, J .; M.; Moinet, G. Bull. Soc. Chim. Fr. 1990, 500. (b)
Kikani, B. B.; McKee, J . R.; Zanger, M. Synthesis 1991, 176.
(23) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(24) Veysoglu, T.; Mitscher, L. A.; Swayze, J . K. Synthesis 1980, 807.
(25) Goldman, S. Synthesis 1980, 640.
J . Org. Chem, Vol. 68, No. 16, 2003 6143

Guay and Deslongchamps
SCHEME 9 a
SCHEME 11 a
a
Reagents and conditions: (a) LDA, PhS(O)Me, THF, -78 °C,
77%; (b) TBAF, THF, 88%; (c) Dess-Martin, CH2Cl2, 0 °C to rt,
45%.
SCHEME 12 a
a
Reagents and conditions: (a) DIBAL-H, CH2Cl2-hexane, 80%;
(b) TBDPSCl, imidazole, DMF, 96%; (c) PPTS, EtOH, 85%; (d)
Dess-Martin, CH2Cl2, 0 °C to rt, 91%; (e) P(Ph)3C(Me)CHO, C6H6,
reflux, 74%; (f) allyl acetate, LDA, THF, -78 °C, 87%; (g) TBAF,
THF, 53%; (h) Dess-Martin, CH2Cl2, 72%.
SCHEME 10 a
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 15%.
We then decided to examine the effect of a â-ketosul-
foxide Nazarov substrate for the tricycle synthesis. Thus,
the Nazarov substrate 58 (Scheme 11) was synthesized
starting from aldehyde 50 that was alkylated with
methylphenyl sulfoxide anion to yield the alcohol 56.
After desilylation, the diol 57 was further oxidized to the
Nazarov substrate 58. The cyclization with the activated
cyclohexenone 1 (Scheme 12) poorly yielded (15%) the
tricycle 59 according to spectroscopic analysis.27
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 80%; (b)
To finally access the stereochemistry of most natural
tricycles, we searched for other factors that could suitably
stabilize the transition state leading to the cyclized
product. Steric hindrance was regarded at first as one
such factor. Thus we surmised that it might be possible
to use a 4,4-disubtituted cyclohexenone in order to create
enough steric hindrance to force the cyclization to proceed
from the R-face of the enolate to yield the 8â-methyl
product. To verify this hypothesis, we looked at the
cyclization of our previously described Nazarov sub-
strates with the 4,4-dioxolane activated cyclohexenone
60.28 The first Nazarov substrate tried was the â-keto-
sulfoxide 58. When allowed to cyclize with cyclohexenone
60 (Scheme 13), a surprisingly efficient and specific
reaction took place to yield only the tricycle 61 in 48%
yield, for which the three-dimensional structure was
determined by single-crystal X-ray crystallography.
Cyclohexenone 60 is known28 to be more stable and
more reactive than the nonsubstituted one, yielding clean
cycloaddition reactions and higher reaction yields. Ex-
amination of the possible transition states (Scheme 14)
offers a rationale for the observed stereoselectivity. The
additional steric hindrance generated between the diox-
olane moiety and the B ring in 64 and 65 makes the
Pd(PPh3)4, morpholine, THF, 63%.
to yield the alcohol 48. Further oxidation to the aldehyde
49 using Dess-Martin periodinane and homologation
with the stabilized Wittig reagent afforded the R,â-
unsaturated aldehyde 50. Aldol reaction with the enolate
of allyl acetate at low temperature furnished the alcohol
51. The silyl ether was removed with TBAF to yield the
diol 52. Oxidation of the diol with Dess-Martin afforded
the Nazarov substrate 53.
When the Nazarov substrate 53 (Scheme 10) was
subjected under basic conditions to the activated cyclo-
hexenone 1, the double-Michael cycloaddition proceeded
and the resulting ∆7,8 enolate was efficiently trapped by
the R,â-unsaturated aldehyde to directly provide the
tricyclic intermediate 54 in 80% yield. This intermediate
was treated with Pd(PPh3)4 and morpholine, and the
dealkoxycarbonylation of the allyl ester proceeded
smoothly. The tricycle 55 was isolated in 63% yield, and
its three-dimensional structure was ascertained by single-
crystal X-ray diffraction analysis. Not too surprisingly,
the 8R-methyl and the 14â-hydrogen observed earlier
resulted from an attack of the â-face of the ∆7,8 enolate
on the R-face of the Michael acceptor.
(27) Compound 59 was fully characterized except by single-crystal
X-ray diffraction analysis.
(28) Lavalle´e, J . F.; Spino, C.; Ruel, R.; Hogan, K.; Deslongchamps,
P. Can. J . Chem. 1992, 70, 1406.
(26) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladros, E. A.; Abe, Y.; Carroll, P. J .; Snyder, J . P. J . Am. Chem.
Soc. 1990, 112, 3040.
6144 J . Org. Chem., Vol. 68, No. 16, 2003

Cascade Polycyclization
SCHEME 13 a
SCHEME 16
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 48%.
SCHEME 14
SCHEME 17 a
SCHEME 15 a
a
Reagents and conditions: (a) TBDMSCl, imidazole, THF, 98%;
(b) n-BuLi, DMF, THF, -40 °C to rt, 97%; (c) 1,3-propanediol,
PPTS, C6H6; (d) TBAF, THF, 0 °C to rt, 80% (2 steps); (e) Dess-
Martin, CH2Cl2, 0 °C to rt; 70%; (f) P(Ph)3C(Me)CHO, C6H6, reflux,
67%; (g) allyl acetate, LDA, THF, -78 °C, 52% (60% corr); (h)
p-TsOH, H2O, acetone, reflux, 87%; (i) Dess-Martin, CH2Cl2, 68%;
(j) Dess-Martin, CH2Cl2, 65%.
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 93% of 2.3:1
ratio; (b) Pd(PPh3)4, morpholine, THF, 67% of 68 and 52% of 69.
be increased using a more sterically hindered Nazarov
substrate.
Michael addition sterically impossible from the R-face of
the enolate. On the other hand, it allows a conformational
change to 62 and then to the more stable conformation
63, and the attendant cyclization to occur exclusively on
the â-face to give tricycle 61 with an 8R-methyl and a
9â-H.
At this stage of our exploration studies, it was ap-
propriate to try with the â-ketoester Nazarov substrate
53 (Scheme 15). This time, the cyclization with the
cyclohexenone 60 followed by dealkoxycarbonylation gave
a 2.3:1 mixture of inseparable tricycles 68 and 69. These
were obtained pure by separation of the mixture 66
and 67. Then palladium-catalyzed dealkoxycarbonyla-
tion of 66 afforded tricycle 68 in 67% yield, and the
same reaction on 67 furnished tricycle 69 in 52% yield.
Single-crystal X-ray diffraction analysis was used to
corroborate the three-dimensional structures of 68 and
69. A highly selective reaction was not obtained, but the
major product 68 is the one having the stereochemistry
at C-8 normally found in sterols. The ratio could probably
Looking at the transition states (Scheme 16) indicates
that the two sterically hindered conformations 70 and
71 yielded the minor product, 8R-methyl tricycle 68.
Molecular model examination suggests that conformation
72, despite less orbital overlapping and while generating
ring B in a boat conformation, can lead to the major prod-
uct 69. It is clear that in this case, the steric interactions
play an important role in the partial reversal of the
stereochemistry.
Finally, we looked for a method to make a tricycle with
a ∆14,15 olefin that could give access to trans C/D ring
junction after further reduction or hydrogenation. We
imagined a Nazarov substrate with a triple bond conju-
gated with an aldehyde as the Michael acceptor. The
synthesis began by the protection of 5-hexynol 73 with
TBDMSCl to yield the protected alcohol 74 in 98% yield
(Scheme 17). Lithium anion of the alkyne was acylated
with DMF29 to provide the aldehyde 75 in 97% yield.
Protection of the aldehyde and subsequent desilylation
yielded the corresponding dioxane-alcohol 76 in 80%
J . Org. Chem, Vol. 68, No. 16, 2003 6145

Guay and Deslongchamps
SCHEME 18 a
Exp er im en ta l Section
Gen er a l Met h od s. All reactions requiring anhydrous
conditions were conducted under a positive atmosphere of
nitrogen in flame-dried glassware, using standard syringe
techniques. Tetrahydrofuran (THF) and ether were distilled
from sodium/benzophenone under N2 atmosphere immediately
prior to use. Methanol was distilled from magnesium/iodine
under N2 atmosphere immediately prior to use. Dichlo-
romethane, diisopropylamine, pyridine, toluene, benzene, and
HMPA were freshly distilled from CaH2 under N2 atmosphere.
DIBAL-H (1 M solution in dichloromethane) was used. n-BuLi
(1.6 M solution in hexane) was titrated according to litera-
ture.30 Sodium and potassium hydrides were washed under
nitrogen with hexane prior to use. Methyl cyanoformate and
methylphenyl sulfoxide were distilled prior to use. Activated
zinc was prepared by washing granular zinc successively with
1 M hydrochloric acid, water, methanol, and then ether,
immediately before use in Reformatsky reactions. Drying of
organic extracts were performed with anhydrous magnesium
sulfate. Flash chromatography was performed on Merck silica
gel 60 (or Silicycle equivalent recycled product) using air
pressure according to literature’s procedure.31 Analytical thin-
layer chromatography (TLC) was carried out on precoated (0.25
mm) Merck silica gel 60f-254 plates. Detection of spots was
done by visualization under UV lamp and further treatment
with an aqueous revealing solution (sulfuric acid-molybdic
acid, cerium ammonium nitrate, or potassium permanganate-
potassium carbonate) and heating. Melting points were de-
termined on a Bu¨chi M-50 melting point apparatus and were
uncorrected. X-ray diffraction crystallographic analyses were
performed on a monocrystal of pure recrystallized compound.
Tetr a cycle 17 a n d Tetr a cycle 18. To a stirred suspension
of cesium carbonate (24 mg, 0.08 mmol) and â-ketoester 15
(15 mg, 0.05 mmol) in CH2Cl2 (1 mL) was rapidly added a
solution of cyclohexenone 1 (15 mg, 0.10 mmol) in CH2Cl2 (1
mL). The suspension was stirred for 5 h, filtered on a silica
gel pad, and washed with EtOAc-hexane (50:50). The filtrate
was concentrated under vacuum, and the residue was purified
by flash chromatography using EtOAc-hexane (40:60) to yield
the tricycle 16 (mixture of diastereoisomers) as a clear oil. The
tricycle was used without additionnal purification in the next
step. To a stirred solution of the tricyclic tert-butyl-â-ketoester
16 (23 mg, 0.05 mmol) in benzene (1.5 mL) was added p-TsOH
(1 mg, 0.005 mmol). The reaction mixture was refluxed for 2
h 30 min and then cooled to room temperature. The mixture
was filtered on a silica gel pad washed with EtOAc-hexane
(40:60), after which the filtrate was concentrated under
vacuum. The residue was purified by flash chromatography
using EtOAc-hexane (40:60) to yield tetracycles 17 (7 mg,
40%) and 18 (7 mg, 40%) as white crystalline solids. Spectral
data for 17. Molecular formula: C21H28O5. Melting point: 173-
174 °C. IR (film, ν cm-1): 1739, 1716. 1H NMR(300 MHz,
CDCl3, δ ppm): 3.72 (s, 3H), 3.28-3.38 (m, 1H); 3.06-3.10 (m,
1H); 2.92 (dd, 1H, J ) 9.5 Hz, J ) 11.5 Hz); 2.73 (dd, 1H, J )
4.2 Hz, J ) 16.7 Hz); 2.58 (dddd, 1H, J ) 3.5 Hz, J ) 5.5 Hz,
J ) 8.5 Hz, J ) 15.5 Hz); 2.17-2.44 (m, 6H); 2.07 (d, 1H, J )
17.2 Hz); 1.88-1.98 (m, 2H); 1.51-1.61 (m, 1H); 1.20-1.41 (m,
4H); 1.05 (s, 3H); 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3, δ
ppm): 216.9, 212.1, 204.9, 170.2, 64.2, 56.0, 53.3, 50.6, 45.1,
40.8, 40.1, 39.8, 38.6, 38.0, 35.3, 32.9, 29.5, 27.2, 25.6, 23.8,
19.8. MS (m/e): 360 (M+). HRMS: (M+) calcd 360.1937, found
360.1939 ( 0.0011. Spectral data for 18. Molecular formula:
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) Pd(PPh3)4,
morpholine, THF, 30% (2 steps); (c) p-TsOH, H2O, acetone, reflux,
45%.
yield. Further oxidation of the alcohol with Dess-Martin
periodinane furnished the aldehyde 77 in 70%, and
homologation with the stabilized Wittig reagent provided
the R,â-unsaturated aldehyde 78. The aldol reaction with
allyl acetate gave the alcohol 79. The acetal was hydro-
lyzed with p-TsOH in acetone to yield the propargylic
aldehyde 80 in 87% yield. Finally, the oxidation of the
alcohol furnished the Nazarov substrate 81 in 68% yield.
The cycloaddition of that Nazarov substrate 81 with
cyclohexenone 1 led, surprisingly, to a complex mixture
of intractable products. To circumvent this shortcoming,
we made the reaction stepwise. Oxidation of the alcohol
79 yielded the Nazarov substrate 82 (Scheme 17) in 65%
yield, followed by the cyclization with cyclohexenone 1
(Scheme 18) to obtain the bicyclic adduct 83, which was
dealkoxycarbonylated with Pd(PPh3)4 to afford 84. The
acetal was hydrolyzed with p-TsOH in wet acetone to
yield the aldehyde 85 in 45% yield. Curiously enough all
attempts to cyclize this bicyclic product under mild acidic
or basic conditions proved to be unsuccessful, much to
our dismay.
Con clu sion
In summary, seven new Nazarov substrates were
synthesized, and their cyclization with two different
activated cyclohexenones yielded tricycles or tetracycles
in seven times out of eight, giving a stereoselective access
to six different ring junctions.
This exploratory study shows that cascade polycycliza-
tion using Michael reaction can become a general method
to access tricyclic and tetracyclic intermediates with
either natural or unnatural stereochemistry. This meth-
odology permits rapid construction of the polycyclic ring
unit and gives access to a wide array of ring junctions.
The high degree of convergence makes this methodology
a rather powerful one, a fact that was demonstrated
herein by making use of cascade polycyclization strategy
to obtain a large variety of tricycles and tetracycles.
Applications of this attractive method for the total
synthesis of naturally occurring steroids and terpenoids
are currently underway in our laboratories.
C
21H28O5. Melting point: 171-172 °C. IR (film, ν cm-1): 1739,
1
1712. H NMR(300 MHz, CDCl3, δ ppm): 3.73 (s, 3H), 3.21-
3.30 (m, 1H); 3.01 (dd, 1H, J ) 2.4 Hz, J ) 12.1 Hz); 2.76 (t,
1H, J ) 14.3 Hz); 2.63 (dddd, 1H, J ) 2.4 Hz, J ) 5.5 Hz, J )
8.5 Hz, J ) 15.9 Hz); 2.42 (d, 2H, J ) 20.3 Hz); 2.20-2.37 (m,
2H); 2.01 (dd, 1H, J ) 5.9 Hz, J ) 14.4 Hz); 1.89-1.97 (m,
3H); 1.69 (d, 1H, J ) 17.5 Hz); 1.51-1.58 (m, 1H); 1.46 (td,
(29) J ournet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahe-
dron Lett. 1998, 39, 6427.
(30) Bergbreiter, D. E.; Pendergrass, E. J . Org. Chem. 1981, 46, 219.
(31) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem., 1978, 43, 2923.
6146 J . Org. Chem., Vol. 68, No. 16, 2003

Cascade Polycyclization
2H, J ) 4.1 Hz, J ) 13.9 Hz); 1.18 (s, 3H); 1.06 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ ppm): 218.0, 213.7, 205.2, 170.0, 64.8,
53.4, 53.2, 52.2, 48.3, 47.5, 41.5, 41.0, 38.3, 37.8, 35.7, 32.4,
29.7, 28.8, 27.4, 23.0, 19.7. MS (m/e): 360 (M+). HRMS: (M+)
calcd 360.1937, found 360.1939 ( 0.0011.
Hz); 2.31 (d, 2H, J ) 10.1 Hz); 2.03-2.26 (m, 2H); 1.64-1.93
(m, 1H); 1.20-1.54 (m, 5H); 0.95 (s, 3H); 0.89 (s, 3H). 13C NMR
(75 MHz, CDCl3, δ ppm): 216.6, 203.3, 199.7, 168.8, 155.7,
126.0, 67.0, 55.7, 53.7, 47.2, 46.3, 43.3, 40.6, 38.9, 38.2, 33.2,
32.5, 25.7, 24.6, 22.5, 20.2. MS (m/e): 358 (M+). HRMS: (M+)
calcd 358.1780, found 358.1783 ( 0.0011. Spectral data for 44.
Molecular formula: C21H26O5. Melting point: 181-182 °C. IR
(film, ν cm-1): 1747, 1732, 1714, 1674. 1H NMR (300 MHz,
CDCl3, δ ppm): 5.86 (d, 1H, J ) 1.8 Hz); 3.77 (s, 3H); 3.05-
3.17 (m, 1H); 2.91-2.99 (m, 2H); 2.63 (dt, 1H, J ) 4.4 Hz, J )
15.3 Hz); 2.54 (t, 2H, J ) 5.0 Hz); 2.44-2.51 (m, 1H); 2.19 (d,
1H, J ) 17.6 Hz); 2.03-2.14 (m, 1H); 1.82 (d, 1H, J ) 9.6 Hz);
1.46-1.78 (m, 5H); 1.14-1.24 (m, 1H); 1.06 (s, 6H). 13C NMR
(75 MHz, CDCl3, δ ppm): 217.9, 203.4, 202.1, 169.1, 153.9,
127.4, 68.4, 53.7, 53.0, 49.3, 48.9, 48.2, 40.9, 40.4, 39.0, 35.3,
32.7, 31.6, 23.6, 23.0, 20.4. MS (m/e): 358 (M+). HRMS: (M+)
calcd 358.1780, found 358.1783 ( 0.0011.
Tr icycle 55. To a stirred suspension of Cs2CO3 (44 mg, 0.13
mmol) and allylic â-ketoester 53 (35 mg, 0.13 mmol) in
CH2Cl2 (1 mL) was added a solution of cyclohexenone 1 (82
mg, 0.53 mmol) in CH2Cl2 (2 mL) at a rhythm of 1 equiv (0.5
mL, 0.13 mmol) first and the remaining material dropwise over
3 h using a syringe pump. After addition completed, the
mixture was stirred for 3 h and filtered on a silica gel pad,
washed with EtOAc-hexane (50:50). The filtrate was concen-
trated under vacuum, and the crude material was purified by
flash chromatography using EtOAc-hexane (50:50) to yield
the tricyclic â-ketoester 54 (44 mg, 80%) as a yellow oil. The
product was used for next step without further purification.
To a stirred solution of tricyclic â-ketoester 54 (44 mg, 0.11
mmol) in THF (1 mL) were added morpholine (42 µL, 0.50
mmol) and palladium tetrakis(triphenylphosphine) (3 mg,
0.002 mmol). The mixture was stirred for 2 h 30 min and
filtered on a silica gel pad, washed with EtOAc-hexane (50:
50). The filtrate was concentrated under vacuum, and the
crude material was purified by flash chromatography using
EtOAc-hexane (50:50) to yield tricycle 55 (10 mg, 63%) as a
white crystalline solid. Molecular formula: C19H26O5. Melting
point: 116-118 °C. IR (film, ν cm-1): 1714. 1H NMR (300 MHz,
CDCl3, δ ppm): 9.70 (dd, 1H, J ) 1.0 Hz, J ) 2.6 Hz); 3.73 (s,
3H); 3.36-3.50 (m, 1H); 3.00 (dd, 1H, J ) 5.5 Hz, J ) 9.4 Hz);
2.73-2.82 (m, 1H); 2.51-2.62 (m, 3H); 2.16-2.39 (m, 4H);
1.89-1.96 (m, 2H); 1.40-1.71 (m, 4H); 1.18-1.38 (m, 3H); 1.03
(s, 3H). 13C NMR (75 MHz, CDCl3, δ ppm): 212.9, 205.4, 201.9,
170.4, 64.1, 53.1, 50.8, 44.1, 40.9, 40.7, 39.2, 35.7, 32.7, 27.2,
26.8, 24.9, 20.4, 20.3. MS (m/e): 334 (M+). HRMS: (M+) calcd
334.1780, found 334.1775 ( 0.0010.
Tetr a cycle 29. The cyclization was done according to the
procedure already described for tetracycles 17 and 18. The
crude material was purified by flash chromatography using
EtOAc-hexane (40:60) to yield the tricycle 28 (mixture of
diastereoisomers) as a yellow oil. The product was used for
next step without further purification. To a stirred solution of
tricyclic tert-butyl-â-ketoester 28 (45 mg, 0.1 mmol) in benzene
(3 mL) was added p-TsOH (2 mg, 0.01 mmol). The reaction
mixture was refluxed for 10 h and then cooled to room
temperature. The mixture was filtered on a silica gel pad
washed with EtOAc-hexane (50:50) after which the filtrate
was concentrated under vacuum. The residue was purified by
flash chromatography using EtOAc-hexane (50:50) to yield
tetracycle 29 (18 mg, 50% (2 steps)) (mixture of epimers) as a
colorless oil and the dealkoxycarbonylated tricycle 30 (6 mg,
20% (2 steps)) as a colorless oil. Spectral data for 29 (mixture
of epimers). Molecular formula: C20H26O5. 1H NMR (300 MHz,
CDCl3, δ ppm): 3.81 (s, 3H), (diast. 3.79); 3.18 (dd, 2H, J )
6.2 Hz, J ) 13.1 Hz); 2.53-3.10 (m, 4H); 2.08-2.50 (m, 7H);
1.33-2.02 (m, 5H); 1.18-1.30 (m, 2H); 1.22 (s, 3H), (diast.
1
1.05). Spectral data for 30. Molecular formula: C20H26O5. H
NMR (300 MHz, CDCl3, δ ppm): 7.34 (d, 1H, J ) 5.6 Hz); 6.02
(d, 1H, J ) 5.6 Hz); 3.73 (s, 3H), 3.04-3.13 (m, 1H); 2.00-
2.78 (m, 10H); 2.12 (d, 2H, J ) 6.5 Hz); 1.20-1.96 (m, 5H);
1.18 (s, 3H).
Tetr a cycle 31. To a stirred solution of tricycle 30 (6 mg,
0.02 mmol) in toluene (2 mL) was added p-TsOH (0.5 mg, 0.002
mmol). The reaction mixture was refluxed for 2 h and then
cooled to room temperature. The mixture was filtered on a
silica gel pad washed with EtOAc-hexane (50:50) after which
the filtrate was concentrated under vacuum. The residue was
purified by flash chromatography using EtOAc-hexane (50:
50) to yield tetracycle 31 (6 mg, 100%) as a white crystalline
solid. Molecular formula: C20H26O5. Melting point: 167-168
1
°C. IR (film, ν cm-1): 1737, 1706. H NMR (300 MHz, CDCl3,
δ ppm): 3.79 (s, 3H), 3.06-3.14 (m, 1H); 2.77 (dd, 1H, J ) 7.5
Hz, J ) 19.6 Hz); 2.66 (d, 1H, J ) 11.3 Hz); 1.96-2.51 (m,
8H); 1.56-1.92 (m, 7H); 1.23-1.33 (m, 2H); 1.08 (s, 3H). 13C
NMR (75 MHz, CDCl3, δ ppm): 219.2, 208.7, 207.3, 171.3, 65.7,
52.4, 51.5, 46.5, 45.3, 45.0, 42.8, 41.6, 41.1, 38.3, 38.0, 34.8,
29.5, 26.3, 24.4, 21.6. MS (m/e): 346 (M+). HRMS: (M+) calcd
346.1780, found 346.1776 ( 0.0010.
Tr icycle 59. To a stirred suspension of Cs2CO3 (64 mg, 0.20
mmol) and â-ketosulfoxide 58 (60 mg, 0.20 mmol) in CH2Cl2
(2 mL) was added a solution of cyclohexenone 1 (120 mg, 0.77
mmol) in CH2Cl2 (2 mL) at a rhythm of 1 equiv (0.5 mL, 0.20
mmol) first and the remaining material dropwise over 3 h
using a syringe pump. After addition completed, the mixture
was stirred for 3 h and filtered on a silica gel pad, washed
with EtOAc. The filtrate was concentrated under vacuum, and
the crude material was purified by flash chromatography using
EtOAc-hexane (50:50) to yield the tricycle 59 (5 mg, 15%) as
a yellow oil. Molecular formula: C19H24O5. IR (film, ν cm-1):
Tetr a cycle 43 a n d Tetr a cycle 44. To a stirred suspension
of Cs2CO3 (45 mg, 0.14 mmol) and â-ketosulfoxide 41 (45 mg,
0.14 mmol) in CH2Cl2 (2 mL) was added a solution of cyclo-
hexenone 1 (85 mg, 0.54 mmol) in CH2Cl2 (3 mL) at a rhythm
of 1 equiv (1 mL, 0.18 mmol) first and the remaining material
dropwise over 3 h using a syringe pump. After addition
completed, the mixture was stirred for 3 h then filtered on a
silica gel pad, washed with EtOAc. The filtrate was concen-
trated under vacuum, and the residual â-ketosulfoxide 41 was
removed by flash chromatography using EtOAc to yield the
crude tricycle 42 (55 mg) as a yellow oil. The product was used
for next step without further purification. To a stirred solution
of tricycle 42 (55 mg, 0.15 mmol) in benzene (5 mL) was added
p-TsOH (6.0 mg, 0.03 mmol). The reaction mixture was
refluxed for 2 h and then cooled to room temperature. The
mixture was filtered on a silica gel pad washed with EtOAc-
hexane (50:50) after which the filtrate was concentrated under
vacuum. The residue was purified by flash chromatography
using EtOAc-hexane (50:50) to yield tetracycles 43 (3 mg, 13%
(2 steps)) and 44 (3 mg, 13% (2 steps)) as white crystalline
1
1738, 1720, 1670. H NMR (300 MHz, CDCl3, δ ppm): 9.78 (d,
1H, J ) 2.5 Hz); 5.69 (d, 1H, J ) 1.6 Hz); 3.80 (s, 3H); 3.36
(dd, 1H, J ) 16.7 Hz, J ) 2.3 Hz); 2.26-2.71 (m, 6H); 1.99-
2.10 (m, 2H); 1.51-1.78 (m, 4H); 1.11-1.31 (m, 3H); 0.97 (s,
3H). 13C NMR (75 MHz, CDCl3, δ ppm): 203.8, 202.8, 202.4,
171.4, 154.0, 125.9, 67.0, 53.4, 49.0, 48.3, 46.2, 41.0, 36.1, 33.1,
30.2, 26.5, 23.9, 23.1, 15.0. MS (m/e): 332 (M+). HRMS: (M+)
calcd 332.1624, found 332.1631 ( 0.0010.
Tr icycle 61. To a stirred suspension of Cs2CO3 (73 mg, 0.22
mmol) and â-ketosulfoxide 58 (68 mg, 0.22 mmol) in CH2Cl2
(2 mL) was added a solution of cyclohexenone 60 (57 mg, 0.27
mmol) in CH2Cl2 (2 mL). The mixture was stirred for 3 h and
then filtered on a silica gel pad, washed with EtOAc-hexane
(50:50). The filtrate was concentrated under vacuum, and the
solids. Spectral data for 43. Molecular formula:
C21H26O5.
Melting point: 161-163 °C. IR (film, ν cm-1): 1740, 1715, 1667,
1
1629. H NMR (300 MHz, CDCl3, δ ppm): 6.09 (d, 1H, J ) 1.6
Hz); 3.74 (s, 3H); 3.03-3.16 (m, 2H); 2.97 (d, 1H, J ) 8.3 Hz);
2.72 (dt, 1H, J ) 4.4 Hz, J ) 15.5 Hz); 2.55 (t, 1H, J ) 5.0
J . Org. Chem, Vol. 68, No. 16, 2003 6147

Guay and Deslongchamps
crude material was purified by flash chromatography using
mg, 1.0 mmol) in CH2Cl2 (3 mL) at a rhythm of 1 equiv (1 mL,
0.33 mmol) first and the remaining material dropwise over 3
h using a syringe pump. After addition completed, the mixture
was stirred for 3 h and then filtered on a silica gel pad, washed
with EtOAc-hexane (50:50). The filtrate was concentrated
under vacuum, and the crude material was purified by flash
chromatography using EtOAc-hexane (50:50) to yield the
decalinic â-ketoester 83 (155 mg) as a yellow oil. The product
was used for next step without further purification. To a
stirred solution of bicyclic â-ketoester 83 (155 mg, 0.32 mmol)
in THF (2 mL) were added morpholine (83 µL, 0.95 mmol) and
palladium tetrakis(triphenylphosphine) (37 mg, 0.03 mmol).
The mixture was concentrated under vacuum, and the crude
material was purified by flash chromatography using EtOAc-
hexane (30:70) to yield the decaline 84 (37 mg, 30% (2 steps))
as a clear oil. Molecular formula: C22H30O6. IR (film, ν cm-1):
2249, 1740, 1714, 1654. 1H NMR (300 MHz, CDCl3, δ ppm):
5.29 (d, 2H, J ) 0.7 Hz); 4.13 (dt, 2H, J ) 4.5 Hz, J ) 11.9
Hz); 3.73-3.83 (m, 2H); 3.71 (s, 3H); 3.08-3.18 (m, 1H); 2.98
(quint, 1H, J ) 6.5 Hz); 1.10-2.64 (m, 17H); 0.99 (d, 3H, J )
6.5 Hz). 13C NMR (75 MHz, CDCl3, δ ppm): 211.4, 206.1, 170.1,
90.7, 85.8, 75.8, 65.3, 64.5, 52.8, 44.9, 44.8, 42.7, 41.0, 39.9,
29.4, 26.9, 25.6, 24.7, 21.9, 18.6, 11.7. MS (m/e): 390 (M+).
HRMS: (M+) calcd 390.2042, found 390.2029 ( 0.0011.
EtOAc-hexane (50:50) to yield the tricycle 61 (40 mg, 48%)
as a white crystalline solid. Molecular formula:
C21H26O7.
Melting point: 150-151 °C. IR (film, ν cm-1): 1738, 1731, 1682.
1H NMR (300 MHz, CDCl3, δ ppm): 9.75 (t, 1H, J ) 1.4 Hz);
6.19 (d 1H, J ) 1.2 Hz); 3.95-4.10 (m, 3H); 3.73 (s, 3H); 3.66-
3.78 (m, 1H); 3.21 (dd, 1H, J ) 0.8 Hz, J ) 15.2 Hz); 3.19 (ddd,
1H, J ) 0.8 Hz, J ) 7.1 Hz, J ) 14.3); 2.47-2.62 (m, 2H);
1.89-2.12 (m, 3H); 1.68-1.72 (m, 1H); 1.53-1.57 (m, 1H);
1.38-1.44 (m, 1H); 1.08-1.25 (m, 2H); 0.90 (d, 3H, J ) 0.8
Hz). 13C NMR (75 MHz, CDCl3, δ ppm): 204.0, 202.2, 202.1,
171.1, 150.4, 125.0, 106.2, 65.5, 64.5, 64.2, 53.1, 49.6, 48.1, 46.4,
38.6, 35.9, 33.8, 30.0, 26.5, 23.8, 14.6. MS (m/e): 390 (M+).
HRMS: (M+) calcd 390.1678, found 390.1686 ( 0.0011.
Tr icycles 66 a n d 67. To a stirred suspension of Cs2CO3
(96 mg, 0.30 mmol) and allylic â-ketoester 53 (78 mg, 0.30
mmol) in CH2Cl2 (3 mL) was added a solution of cyclohexenone
60 (81 mg, 0.38 mmol) in CH2Cl2 (3 mL). The mixture was
stirred for 3 h and then filtered on a silica gel pad, washed
with EtOAc-hexane (50:50). The filtrate was concentrated
under vacuum, and the crude material was purified by flash
chromatography using EtOAc-hexane (50:50) to yield the
tricyclic â-ketoesters 66 and 67 (130 mg, 93%) (ratio 2.3:1
favoring 66). The products were separated by flash chroma-
tography with 50% EtOAc-hexane to yield 66 and 67 as keto
enol mixtures. These were used for next step without charac-
terization.
Tr icycle 85. To a stirred solution of acetal 84 (28 mg, 0.07
mmol) in acetone (5 mL) were added water (250 µL) and
p-TsOH (3 mg, 0.01 mmol). The mixture was refluxed for 36 h
and then cooled to room temperature. The mixture was diluted
with EtOAc and water and concentrated under vacuum. The
residue was diluted with EtOAc, the mixture was decanted,
and the aqueous phase was extracted with EtOAc. The
combined organic phases were washed with brine, dried, and
concentrated under vacuum. The crude material was purified
by flash chromatography using EtOAc-hexane (50:50) to yield
the propargylic aldehyde 85 (10 mg, 45%) as a clear oil.
Molecular formula: C19H24O5. IR (film, ν cm-1): 2200, 1739,
Tr icycle 68. To a stirred solution of tricyclic â-ketoester
66 (4 mg, 0.01 mmol) in THF (1 mL) were added morpholine
(7 µL, 0.10 mmol) and tetrakis(triphenylphosphine) palladium
(1 mg, 0.001 mmol). The mixture was stirred for 2 h and then
filtered on a silica gel pad, washed with EtOAc-hexane (50:
50). The filtrate was concentrated under vacuum, and the
crude material was purified by flash chromatography using
EtOAc-hexane (50:50) to yield the tricycle 68 (2.2 mg, 67%)
as a white crystalline solid. Melting point: 137-138 °C. IR
(film, ν cm-1): 1715, 1449. 1H NMR (300 MHz, CDCl3, δ ppm):
9.75 (d, 1H, J ) 2.2 Hz); 3.93-4.04 (m, 4H); 3.79 (s, 3H); 3.36
(dd, 1H, J ) 3.0 Hz, J ) 17.1 Hz); 3.25 (dd, 1H, J ) 5.1 Hz, J
) 7.1 Hz); 2.94 (dd, 1H, J ) 2.2 Hz, J ) 12.0 Hz); 2.55-2.74
(m, 3H); 2.22-2.35 (m, 2H); 1.86-2.11 (m, 3H); 1.58-1.77 (m,
2H), 1.16-1.43 (m, 4H); 1.07 (s, 3H). 13C NMR (75 MHz, CDCl3,
δ ppm): 213.6, 206.9, 202.2, 171.7, 107.8, 65.3, 64.6, 63.2, 52.2,
49.5, 47.9, 46.5, 45.4, 37.2, 36.4, 33.4, 30.1, 29.7, 26.4, 24.7,
13.5. MS (m/e): 392 (M+). HRMS: (M+) calcd 392.1844, found
392.1844 ( 0.0011.
1
1714, 1667, 1652. H NMR (300 MHz, CDCl3, δ ppm): 9.17 (t,
1H, J ) 0.7 Hz); 3.75 (s, 3H); 3.13-3.19 (m, 1H); 3.04 (quint,
1H, J ) 5.5 Hz); 2.67 (q, 1H, J ) 4,6 Hz); 2.13 (m, 6H); 1.89-
1.99 (m, 2H); 1.12-1.80 (m, 6H); 1.03 (d, 3H, J ) 6.6 Hz). 13C
NMR (75 MHz, CDCl3, δ ppm): 211.3, 206.0, 177.1, 170.1, 97.8,
81.9, 64.4, 52.8, 45.0, 44.8, 42.7, 41.0, 40.0, 28.6, 26.9, 24.7,
21.9, 19.2, 11.7. MS (m/e): 332 (M+), 317 (M+ - CH3), 303 (M+
- CHO), 301 (M+ - OCH3). HRMS: (M+) calcd 332.1624, found
332.1635 ( 0.0010; (M+ - CH3) calcd 317.1389, found 317.1396
( 0.0009.
Tr icycle 69. To a stirred solution of tricyclic â-ketoester
67 (7 mg, 0.01 mmol) in THF (1 mL) were added morpholine
(13 µL, 0.10 mmol) and tetrakis(triphenylphosphine) palladium
(2 mg, 0.002 mmol). The mixture was stirred for 2 h and then
filtered on a silica gel pad, washed with EtOAc-hexane (50:
50). The filtrate was concentrated under vacuum, and the
crude material was purified by flash chromatography using
EtOAc-hexane (50:50) to yield the tricycle 69 (3 mg, 52%) as
a white crystalline solid. Molecular formula: C21H28O7. Melting
point: 150-151 °C. IR (film, ν cm-1): 1741, 1714, 1644. 1H NMR
(300 MHz, CDCl3, δ ppm): 9.66 (d, 1H, J ) 1.1 Hz); 3.95-4.14
(m, 4H); 3.78 (s, 3H); 3.62 (ddd, 1H, J ) 1.9 Hz, J ) 4.9 Hz, J
) 11.6 Hz); 2.80-2.94 (m, 4H); 2.50-2.62 (m, 3H); 2.05-2.24
(m, 3H); 1.87-1.96 (m, 1H); 1.60-1.72 (m, 1H), 1.22-1.54 (m,
4H); 1.06 (s, 3H). 13C NMR (75 MHz, CDCl3, δ ppm): 213.6,
205.7, 201.8, 171.6, 107.5, 64.9, 64.0, 61.7, 52.9, 49.6, 45.7, 41.8,
40.8, 37.1, 36.9, 31.4, 30.9, 27.0, 23.0, 20.4, 19.8. MS (m/e):
392 (M+). HRMS: (M+) calcd 392.1835, found 392.1832 (
0.0011.
Ack n ow led gm en t. We would like to thank Mr.
Marc Drouin for providing us with the single-crystal
X-ray diffraction crystallographic results. Financial
support provided by BioChem Pharma Inc. (Research
Chair to P.D.), Fonds FCAR and NSERC (for scholar-
ships to B.G.) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and characterization data for all new compounds, H
NMR spectra for all compounds, and X-ray crystal structure
data for compounds 17, 18, 31, 43, 44, 55, 61, 68 and 69 in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org. The following crystal structures
have been deposited at the Cambridge Crystallographic Data
Centre: 17 (CCDC 197359), 18 (CCDC 197360), 31 (CCDC
197361), 43 (CCDC 197362), 44 (CCDC 197363), 55 (CCDC
197364), 61 (CCDC 197365), 68 (CCDC 197366), and 69
(CCDC 197367).
Tr icycle 84. To a stirred suspension of Cs2CO3 (105 mg,
0.33 mmol) and allylic â-ketoester 82 (105 mg, 0.33 mmol) in
CH2Cl2 (2 mL) was added a solution of cyclohexenone 1 (150
J O034280N
6148 J . Org. Chem., Vol. 68, No. 16, 2003