Total synthesis of (+)-cassaine via transannular diels-alder reaction

Article abstract of DOI:10.1021/ja805097s

A full account of the total synthesis of (+)-cassaine (1) using the transannular Diels-Alder (TADA) reaction as the pivotal construction is described. The strategy began from Evans' oxazolidine 8, the only chiral source used for the total stereochemical outcome of the target molecule. The key intermediate 3 was obtained from 8 in 10 steps in 40% overall yield. Following extensive optimization, the coupling of 3 on both ends with another densely functional partner 2 followed by TADA reaction on macrocycle 4 cleanly furnished the tricycle 5. The stereochemical outcome in 5 was expected via a least-energetic transition state T4. A stereoselective reduction, hydroboration, and methyl cuprate 1,4-addition along with a few other functional interconversions transformed 5 into the key intermediate 37. Final tethering of dimethylaminoethyloxycarbonyl along with epimerization at C8 and alcohol deprotection at C3 yielded the natural product 1.

Full text of DOI:10.1021/ja805097s

Published on Web 09/26/2008
Total Synthesis of (+)-Cassaine via Transannular Diels-Alder
Reaction
Serge Phoenix, Maddi Sridhar Reddy, and Pierre Deslongchamps*
Laboratoire de Synthe`se Organique, De´partement de Chimie, Institut de Pharmacologie,
UniVersite´ de Sherbrooke, 3001, 12e aVe nord, Sherbrooke, Que´bec J1H 5N4, Canada
Received July 2, 2008; E-mail: pierre.deslongchamps@usherbrooke.ca
Abstract: A full account of the total synthesis of (+)-cassaine (1) using the transannular Diels-Alder (TADA)
reaction as the pivotal construction is described. The strategy began from Evans’ oxazolidine 8, the only
chiral source used for the total stereochemical outcome of the target molecule. The key intermediate 3
was obtained from 8 in 10 steps in 40% overall yield. Following extensive optimization, the coupling of 3
on both ends with another densely functional partner 2 followed by TADA reaction on macrocycle 4 cleanly
furnished the tricycle 5. The stereochemical outcome in 5 was expected via a least-energetic transition
state T4. A stereoselective reduction, hydroboration, and methyl cuprate 1,4-addition along with a few
other functional interconversions transformed 5 into the key intermediate 37. Final tethering of dimethy-
laminoethyloxycarbonyl along with epimerization at C8 and alcohol deprotection at C3 yielded the natural
product 1.
Introduction
isolated (+)-cassaine from the bark of Erythrophleum guinneese.
The structural elucidation was achieved by the Turner group6
Our laboratory has for many years investigated the synthetic
potential of the transannular Diels-Alder (TADA) reaction for
the construction of polycyclic natural and non-natural products.1
We2 and others3 have successfully used this reaction as a key
step in the total synthesis of natural products. We now report
the successful construction of (+)-cassaine (1) using this
strategy.
in 1959. In 1967, the same group realized the only total synthesis
of (+)-cassaine, although they had some difficulty with the
functionalization of rings B and C, and at the same time they
established its absolute configuration.7 (+)-Cassaine has been
the subject of work in the biological area because of its efficient
cardiotonic property, equal to that of digitalis glycoside.
Structurally, 1 features a trans-anti-trans (TAT) tricyclic
system possessing six stereocenters and an exo-R,ꢀ-unsaturated
ester containing a dimethylamino group (Figure 1). Our strategy
for the synthesis of 1 was based on the expected stereocontrolled
construction of trans-anti-cis (TAC) tricycle 5 through the
use of the TADA reaction on trans-trans-trans (TTT) mac-
rocyclic triene 4 (Figure 1).1e Macrocycle 4 was available from
2 and 3, as shown in our previous studies.8 Steric bias in 5 was
predicted to be useful for reducing the keto group at C3
stereoselectively and introducing an R-hydroxyl group at C7.
Also, elimination of the C14 alkoxy group in ring C would
produce a TAC tricycle whose structural feature would allow
the introduction of the axially oriented C14 methyl group having
the desired R configuration. Moreover, when this 1,4-addition
reaction was carried out on a tricycle containing a conjugated
aldehyde, such as 6, the enolate formed during the reaction
pathway could be trapped to give the exo-triflate 7, which should
serve as a basis for tethering of the remaining amino ester tail.
(+)-Cassaine is a nonsteroidal inhibitor of Na+,K+-ATPase
that is known to possess a pharmacological action similar to
that of the digitalis glycosides, such as digitoxin, even though
their structures are quite different.4 In 1935, the Dalma group5
(1) (a) Baettig, K.; Dallaire, C.; Pitteloud, R.; Deslongchamps, P.
Tetrahedron Lett. 1987, 28, 5249. (b) Baettig, K.; Marinier, A.;
Pitteloud, R.; Deslongchamps, P. Tetrahedron Lett. 1987, 28, 5253.
(c) Be´rube´, G.; Deslongchamps, P. Tetrahedron Lett. 1987, 28, 5255.
(d) Lamothe, S.; Ndibami, A.; Deslongchamps, P. Tetrahedron Lett.
1988, 29, 1639. (e) Lamothe, S.; Ndibwami, A.; Deslongchamps, P.
Tetrahedron Lett. 1988, 29, 1641. Also see the following reviews: (f)
Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831. (g) Marsault,
E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron Rep. 2001,
57, 4243.
(2) (a) Caussanel, F.; Wang, K.; Ramachandran, S.; Deslongchamps, P.
J. Org. Chem. 2006, 71, 7370. (b) Soucy, P.; L’Heureux, A.; Toro´,
A.; Deslongchamps, P. J. Org. Chem. 2003, 68, 9983. (c) Toro´, A.;
Deslongchamps, P. J. Org. Chem. 2003, 68, 6847. (d) Germain, J.;
Deslongchamps, P. J. Org. Chem. 2002, 67, 5269. (e) Toro´, A.; Nowak,
P.; Deslongchamps, P. J. Am. Chem. Soc. 2000, 122, 4526.
(3) (a) Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043. (b) Suzuki,
T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada, M. Org. Lett. 2004,
6, 553. (c) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorensen,
E. J. J. Am. Chem. Soc. 2003, 125, 5393. (d) Munakata, R.; Katakai,
H.; Ueki, T.; Kurosaka, J.; Takao, K.-i.; Tadano, K.-i. J. Am. Chem.
Soc. 2003, 125, 14722. (e) Evans, D. A.; Starr, J. T. Angew. Chem.,
Int. Ed. 2002, 41, 1787. (f) Bodwell, G. J.; Li, J. Angew. Chem., Int.
Ed. 2002, 41, 3261. (g) Layton, M. E.; Morales, C. A.; Shair, M. D.
J. Am. Chem. Soc. 2002, 124, 773. (h) Shing, T. K. M.; Yang, J. J.
Org. Chem. 1995, 60, 5785.
(5) Dalma, G. Ann. Chim. Appl. 1935, 25, 569.
(6) (a) Turner, R. B.; Herzog, E. G.; Morin, R. B.; Riebel, A. Tetrahedron
Lett. 1959, 1 (2), 7. (b) Gensler, W. J.; Sherman, G. M. J. Am. Chem.
Soc. 1959, 81, 5217.
(7) The synthesis was realized by first producing a racemic advanced
tricyclic intermediate that was found to be identical with the same
compound obtained by degradation of (+)-cassaine. The degraded
material was used as a relay compound to complete the synthesis.
See: Turner, R. B.; Buchardt, O.; Herzoy, E.; Morin, R. B.; Riebel,
A.; Sanders, J. M. J. Am. Chem. Soc. 1966, 88, 1766.
(4) De Munari, S.; Barassi, P.; Cerri, A.; Fedrizzi, G.; Gobbini, M.;
Mabilia, M.; Melloni, P. J. Med. Chem. 1998, 41, 3033.
(8) Phoenix, S.; Bourque, E.; Deslongchamps, P. Org. Lett. 2000, 2, 4149.
9
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A R T I C L E S
Phoenix et al.
Figure 1. Synthetic analysis of 1.
Scheme 1. Synthesis of Intermediate 3
Finally, carbonylation followed by oxidation at C7 would allow
the required epimerization at C8 to furnish the TAT framework,
yielding 1.
aldehyde 13 using triphenylphosphoranylidene propionalde-
hyde13 to give the R,ꢀ-unsaturated aldehyde having only the E
geometry, and after a reduction with sodium borohydride, allylic
alcohol 14 was obtained in 80% yield. Transformation of that
alcohol to the chloride 3 was carried out using the Magid
procedure14 in 89% yield. In summary, the eastern part of the
macrocycle was synthesized in 10 steps in 40% overall yield,
which was much better than the 12% yield obtained in our
previous synthesis.
Results and Discussion
In order to increase the yield efficiency for the synthesis of
the previously reported macrocycle 4, a novel route was
elaborated for the eastern part 3 (Scheme 1). The synthesis began
with an Evans aldol condensation9 between known imide 8 and
aldehyde 9 in excellent yield. Transformation of 10 to Weinreb
amide10 11 followed by protection of the alcohol as the TBS
ether, regioselective oxidation of the terminal olefin to a primary
alcohol using 9-BBN/H2O2,11 and exchange of stannane with
iodide realized vinyl iodide 12 in 72% yield from 8. The primary
alcohol was oxidized using the Swern protocol12 to give
aldehyde 13 in 89% yield. A Wittig reaction was performed on
Coupling of chloride 3 with the known stannane 22e was
achieved in the presence of cesium carbonate, cesium iodide,
and crown ether 18-crown-6 in acetone in an excellent yield of
95% (Scheme 2). When the reaction was performed in the
absence of the crown ether, the yield dropped to 60%. This
result suggests that the crown ether can complex the cesium,
facilitating the coupling reaction. Once the desired precursor
15 had been formed, the macrocyclization was achieved using
conditions developed in our laboratory to give a diastereomeric
mixture of macrocycles 4 in 71% yield.15 This result is excellent
in view of the fact that 14-membered TTT macrocycles are in
general strained and usually difficult to obtain in high yields.1e
To avoid the diastereomeric mixture of macrocycles, a
macrocyclization/decarboxylation reaction was planned. Allyl
(9) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Evans, D. A.;
McGee, R. L. Tetrahedron Lett. 1980, 21, 3975. (c) Evans, D. A.;
Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099. (d) Evans, D. A.; Clark, J. S.; Metternich, R.; Novak, V. J.;
Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866.
(10) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Lipton, M. F.; Basha, A.; Weinreb, S. M. Organic Syntheses; John
Wiley & Sons: New York, 1988; Collect. Vol. VI, p 492. (c) Levin,
J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989. (d)
Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110,
2506.
(13) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Liu, P. Tetrahedron
Lett. 1985, 26, 2391.
(11) Soderquist, J. A.; Negron, A. Org. Synth. 1992, 70, 169.
(12) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1979, 43,
2480. (b) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(14) Magid, R. M.; Fruchey, O.; Johnson, W. L.; Allen, T. G. J. Org. Chem.
1979, 44, 359.
(15) Marsault, E.; Deslongchamps, P. Org. Lett. 2000, 2, 3317.
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Total Synthesis of (+)-Cassaine
A R T I C L E S
Scheme 2. Synthesis of Macrocycle 4
Scheme 3. Synthesis of Intermediates 18 and 5
methyl group would have the right stereochemistry after the
TADA reaction, provided that this process is still stereoselective
(Figure 2).
The synthesis of the new macrocycle began with a crotyl
boration using the Roush reagent 20 on the aldehyde 21 to give
alcohol 22 in 47% yield (74% based on recovered starting
material) (Scheme 5).18 The secondary alcohol was then
protected as a TBPDS ether in 95% yield, and the double bond
was ozonolyzed to obtain the desired aldehyde 24 in 80% yield.
A Takai reaction19 was performed on 24 using chromium
chloride and iodoform to give the (E)-iodoalkene, and depro-
tection of the TBS ether was achieved to give the primary
alcohol 25 in 73% yield for the two steps. This alcohol was
oxidized with Dess-Martin periodinane to yield aldehyde 26
in 90% yield. The same sequence of a Wittig reaction followed
by sodium borohydride reduction was used as before to form
the alcohol 27 in 71% yield. This alcohol was then transformed
into the corresponding allylic chloride 28 via the Magid
procedure in 90% yield.
Coupling of chloride 28 and the known stannane 2 using the
same conditions as described earlier afforded triene 29 in a good
yield of 75% (Scheme 6). The macrocyclization to give 30 was
then realized in 74% yield using Stille coupling conditions.
The TADA reaction of macrocycle 30 was carried out in
toluene in a sealed tube at 115 °C, but unfortunately, the reaction
was not stereoselective and yielded many products that were
not separable by chromatography. GC-MS and NMR analyses
of that mixture clearly indicated the presence of four decar-
boxylated products with the same mass (equal to that of the
target tricycle), thereby revealing that the TADA reaction with
macrocycle 30 was not stereoselective.
The two macrocycles 4 and 30, which differ only in the two
substituents at C13 and C14, gave totally different results for
their TADA reactions. It was known from our previous model
studies1e that a TTT macrocycle can lead to two tricyclic
structures, TAC and CAT. However, the TADA reaction can
favor one diastereoisomer over the other if the steric and/or
stereoelectronic factors are well set in favor of a given
macrocycle. This was the case for 4, reaction of which led only
ester can be easily decarboxylated in the presence of palladium.
Thus, stannane 2 was transformed into the corresponding
stannane allyl ester 16 in 81% yield using Taber’s protocol16
(Scheme 3). This ꢀ-keto ester was coupled to chloride 3 in the
same manner as previously described8 to give 17 in 84% yield.
The macrocyclization/decarboxylation17 was effected in the
presence of tris(dibenzylideneacetone)palladium, triphenylarsine,
and morpholine at 90 °C to give a mixture of macrocycle 18
and tricycle 5 in 56% yield and a 10:1 ratio.
Once macrocycles 4 and 18 were in hand, the TADA reaction
was carried out at a higher temperature of 123 °C, since it is
known that some tricycle can be observed at 90 °C during
macrocyclization of 17. As indicated in Scheme 4, 4 gave a
mixture of the TAC tricycle 19 along with its decarboxylated
TAC derivative 5. Heating of 19 at 150 °C produced TAC
tricycle 5 in high yield. On the other hand, heating the
decarboxylated macrocycle 18 at 123 °C produced only the TAC
tricycle 5, as expected.
In order to verify whether the synthesis could be shortened,
a new macrocycle in which the C14 alkoxy group was replaced
by methyl group was designed. Indeed, with the alkoxy group
replaced by a methyl group, the new macrocyle could give a
much more straightforward synthesis of 1 because the C14
Figure 2. New synthetic analysis of 1.
Scheme 4
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A R T I C L E S
Phoenix et al.
Scheme 5
Scheme 6. Synthesis and TADA Reaction of Macrocycle 30
to tricycle 5. The specific formation of that tricycle can be
explained by examining the four possible transition states having
a boat-boat-chair conformation (Figure 3); because of the gem-
dimethyl unit at C4, the usually preferred chair-boat-chair
conformation is eliminated due to severe steric repulsion. The
transition state T1, which leads to CAT tricycle X1, suffers from
severe steric interactions of the diene with the alkoxy group on
one side and one of the methyl groups of the gem-dimethyl
unit on the other side. In case of transition state T2, which leads
to CAT tricycle X2, a steric repulsion exists between the diene
and the gem-dimethyl unit. In addition, there is a stereoelectronic
effect caused by the alkoxy group at C14, which is antiperiplanar
to the new C-C bond formed during the Diels-Alder reaction.20
The resulting inductive effect of the C-OR bond, which
withdraws electrons from the C-C bond being formed, increases
the energy of this transition state as previously observed and is
thus also disfavored.
On the other hand, advancement along the transition states
T3 and T4 can both lead to TAC tricycles (X3 and X4,
respectively). While T4 experiences no noticeable steric repul-
(16) Taber, D. F.; Amedio, J. C.; Patel, Y. K. J. Org. Chem. 1985, 50,
3618.
(17) (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett.
1967, 8, 215. (b) Krapcho, A. P. Synthesis 1982, 805, 893.
(18) (a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186. (b) Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc.
1986, 108, 294. (c) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.;
Park, J. C. J. Org. Chem. 1990, 55, 4109. (d) Roush, W. R.; Audo,
K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem.
Soc. 1990, 112, 6339.
(19) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (b) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.;
Moriwake, T.; Utimoto, K. Synlett 1995, 963.
Figure 3. Possible transition states for the cyclization reaction.
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Total Synthesis of (+)-Cassaine
A R T I C L E S
Scheme 7. Synthesis of Intermediate 33
Figure 4. Feasibility of nucleophilic attack.
C10 methyl groups, the ketone at C3 was stereoselectively
reduced with sodium borohydride and the resulting ꢀ alcohol
(88% yield) protected as a MOM ether in 98% yield (Scheme
7). Having thus constructed the basic skeleton of the molecule
in the form of 31, we turned our attention to the introduction
of a hydroxyl group at C7 by hydroboration of the double bond
formed during the TADA reaction. We expected that the
regioselectivity of the reaction would be controlled by the steric
bias generated by the gem-dimethyl group and the C10 methyl
group and hence that the borane addition would favor the R
side at C7.
The reaction was first attempted with a borane-THF com-
plex, but this approach yielded a mixture of three alcohols. We
were even not rewarded when the reaction was carried out with
larger borane sources, such as 9-BBN and disiamylborane,
where only the starting material was recovered. Elevated
temperatures also proved unfruitful. The reaction was then tried
with thexylborane, which is intermediate in size, and to our
delight, we obtained only the desired R alcohol 32 in 77% yield.
The newly formed alcohol was then protected with p-methoxy-
benzyloxymethyl chloride to get 33 in 82% yield.
As we had by this point set the rings A and B conveniently
for the final operations, we turned our attention to a crucial
manipulation, namely, introduction of an R-methyl group in the
place of the existing hydroxyl group in ring C. Compound 33
was deprotected with TBAF to give 34 in 86% yield (Scheme
8). DIBAL-H reduction of the Weinreb amide was surprisingly
unsuccessful and led to decomposition. Inversion of the sequence
was then attempted. DIBAL-H-mediated reduction of 33 worked
well to give the corresponding aldehyde in 80% yield, but the
deprotection step led to the undesired elimination product 35.
However, reduction of the Weinreb amide was successfully
achieved with LiAlH4 at -78 °C to give aldehyde 36 in 79%
yield.21 Several sets of elimination conditions for forming the
enal were then tested, and Martin’s sulfurane22 was found to
be a suitable reagent for transforming 36 to desired enal 6 in
69% yield. Here again, the inversion of the sequence was
sion, there is an important steric interaction that prevails between
the pseudoaxial R group and the diene in T3. In addition, T4 is
also favored because of a destabilizing stereoelectronic effect
in T3 similar to that in the case of T2. As a consequence, the
only favored product during the TADA reaction is the TAC
tricycle X4 that evolves from the most favored transition state
T4. Thus, it is interesting to point out that the alkoxy group at
C14 plays a major role in this TADA reaction. Since the
macrocyclic precursor contains two stereocenters and is chiral,
the transannular strategy allows complete stereochemical control,
yielding a single chiral tricycle containing four new stereocenters
in a TAC arrangement (i.e., 5) in a single step under mild
conditions. In addition, it is interesting to point out that the
transannular strategy allows the use of a nonactivated dienophile.
In the case of macrocycle 30, where the alkoxy group is
replaced by a methyl group, the destabilizing stereoelectronic
effect that eliminates T2 and T3 does not exist. On the other
hand, when the various steric effects are examined, it appears
that transition state T4 cannot be considered to have an energy
low enough to completely eliminate T2 and T3. Thus a mixture
of stereoisomers is formed.
The synthesis was therefore continued with tricycle 5.
Because of the steric hindrance caused by the C4 ꢀ-methyl and
Scheme 8. Synthesis of Intermediate 6
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A R T I C L E S
Phoenix et al.
Scheme 9. Completion of the Synthesis of 1
investigated, and we were delighted to see better results.
Accordingly, elimination of alcohol 34 with Martin’s sulfurane
at 0 °C in dichloromethane worked well (88% yield) to give
the unsaturated amide, which on reduction with DIBAL-H
furnished the desired enal 6 in 86% yield.
Examination of the TAC shape of enal 6 (Figure 4) indicated
that essentially only the R-face was sterically available for the
1,4-addition of a methyl group, leading to the desired R
stereochemistry at C14. After severe experimentation on models,
the addition was realized using copper cyanide, methyllithium,
and TMSCl at -30 °C and led to the desired (although unstable)
enol ether (Scheme 9).23 To avoid decomposition, this enol ether
was immediately transformed into the corresponding stable triflic
enol ether 7 using methyllithium and N-phenyltrifluoromethane
sulfonimide24 in THF in 54% yield for the last two steps.
The successful introduction of the methyl group at C14 and
the simultaneous formation of the triflic enol ether made
completion of the synthesis possible at last. Deprotection of
p-methoxybenzyloxymethyl-protected hydroxyl group was
achieved using DDQ to give the corresponding alcohol 37 in
93% yield, and subsequent oxidation was accomplished with
Dess-Martin periodinane to form ketone 38 in 79% yield. An
X-ray diffraction crystal structure analysis provided absolute
proof of the structure of 38 (Figure 5).
giving 39 with the desired epimerization to give the TAT
stereochemistry in 90% yield. Finally, deprotection of the MOM
ether was carried out with lithium tetrafluoroborate in a mixture
of acetonitrile and water to yield (+)-cassaine 1 in 76% yield.
Since very little supporting data for (+)-cassaine 1 was available
in the literature for comparison, we sought a thorough analysis
to prove the epimerization under the coupling conditions. With
the help of COSY, we could clearly position H12, H3, H14,
H6ax, H6eq, H8, and H5 along with a few other protons,26 all of
which were in good accordance with previous analyses of
analogous compounds.27 H14 couples with H8 with a small
coupling constant (J ) 3.57 Hz), whereas H8 couples with H9
with large coupling constant (J ) 12.62 Hz),27 which is possible
only after epimerization of proton H8 to the axial position. In
addition, NOESY (Figure 6) revealed that H8 is spatially closer
to H14, H6ax, and the CH3 group on C10, whereas H14 is closer
to the olefinic hydrogen, providing further support for the
inversion.27b
The next crucial task was the tethering of the dimethylami-
noethyl ester group along with epimerization. We assumed that
the preceding coupling conditions would also facilitate the
epimerization at C8. Pleasingly, the coupling was realized using
dichlorobis(triphenylphosphine)palladium, potassium carbonate,
and N,N-dimethylaminoethanol in N-methylpyrrolidinone,25
(20) Dory, Y. L.; Ouellet, C.; Berthiaume, S.; Favre, A.; Deslongchamps,
P. Bull. Soc. Chim. Fr. 1994, 131, 121.
(21) (a) Mootoo, D. R.; Fraser-Reid, B. Tetrahedron 1990, 46, 185. (b)
Kobayashi, M.; Wang, W.; Tsutsui, Y.; Sugimoto, M.; Murakami, N.
Tetrahedron Lett. 1998, 39, 8291.
(22) (a) Arhat, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003. (b)
Evans, D. A.; Black, C. W. J. Am. Chem. Soc. 1993, 115, 4497.
(23) Piers, E.; Fleming, F. F. J. Chem. Soc., Chem. Commun. 1989, 1665.
(24) (a) Nozawa, D.; Takikawa, H.; Mori, K. J. Chem. Soc., Perkin Trans.
1 2000, 2043. (b) Torneiro, M.; Fall, Y.; Castedo, L.; Mourini, A.
Tetrahedron 1997, 53, 1085.
Figure 5. X-ray structure of compound 38 (ORTEP view).
(25) (a) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumara, T. Angew.
Chem., Int. Ed. 2002, 41, 1023. (b) Coperet, C.; Ma, S.; Sugira, T.;
Negishi, E. Tetrahedron 1996, 52, 11529. (c) Shishido, K.; Goto, K.;
Miyoshi, S.; Takaishi, Y.; Shibuija, M. J. Org. Chem. 1994, 59, 406.
(d) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. (e) Malleron, J.-L.; Fiaud, J.-C.; Legris, J.-Y. Handbook of
Palladium Catalysed Organic Reactions; Academic Press: London,
1997; p 304.
Figure 6. NOE interactions in compound 1.
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Total Synthesis of (+)-Cassaine
A R T I C L E S
Conclusion
methyl group at C14 and the regioselective formation of an enol
triflate; and (4) a successful carbonylation with a concomitant
epimerization at C8 to produce 1.
In summary, macrocycle 4, which was obtained in two steps
from building blocks 2 and 3, was converted into (+)-cassaine
1 in 13 steps using the following key transformations: (1) a
completely selective transannular Diels-Alder reaction with a
nonactivated dienophile, leading to a chiral TAC tricycle having
four new stereogenic centers; (2) a regioselective hydroboration
to introduce an alcohol at C7; (3) a stereocontrolled 1,4-addition
on the TAC tricyclic framework. leading to the R-oriented
Acknowledgment. The research chair in organic chemistry
granted to P.D. by BioChem Pharma and financial support from
NSERC (Canada) and FCAR (Quebec) are greatly appreciated. We
also thank Dr. Andreas Decken for X-ray analysis.
Supporting Information Available: Full experimental details,
1H and 13C NMR spectra, full characterization of all of the new
compounds described herein, and a CIF file for compound 38.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(26) See the Supporting Information.
(27) (a) Hauth, H.; Stauffacher, D.; Niklaus, P.; Melera, A. HelV. Chim.
Acta 1965, 48, 1087. (b) Qu, J.; Hu, Y.-C.; Yu, S.-S.; Chen, X.-G.;
Li, Y. Planta Med 2006, 72, 442. (c) Abad, A.; Agullo, C.; Arno, M.;
Domingo, L. R.; Zaragoza, R. J. Tetrahedron Lett. 1986, 27, 3289.
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