Progress toward the total synthesis of Cassaine via the transannular Diels-Alder strategy

Article abstract of DOI:10.1021/ol006670r

(equation presented) The transannular Diels-Alder reaction of trans-trans-trans macrocyclic triene A, bearing two eis substiuents in C₁₂ and C₁₃ as well as a gem-dimethyl in C₄, was studied. Under thermal conditions, only

Full text of DOI:10.1021/ol006670r

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4149-4152
Progress toward the Total Synthesis of
Cassaine via the Transannular
Diels−Alder Strategy
Serge Phoenix, Elyse Bourque, 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, Canada J1H 5N4
pierre.deslongchamps@courrier.usherb.ca
Received September 29, 2000
ABSTRACT
The transannular Diels−Alder reaction of trans-trans-trans macrocyclic triene A, bearing two cis substiuents in C and C as well as a
12
13
gem-dimethyl in C , was studied. Under thermal conditions, only the desired trans-anti-cis tricycle B was obtained. This tricycle represents an
4
advanced intermediate toward the total synthesis of cassaine C.
In the past years, studies on the transannular Diels-Alder
(TADA) reaction have proven this strategy to be a powerful
tool for the stereocontrolled synthesis of polycyclic com-
pounds.1,2 The trans-trans-trans (TTT) trienes turned out to
be the most difficult ones to macrocyclize;3 on the other hand,
their TADA reactions proved to be the easiest ones to
perform. Hence the TTT series has an interesting synthetic
potential.
four possible products was obtained (two TAC and two
CAT), having the desired stereochemistry of a number of
natural products. However, from a synthetic point of view,
the malonate connector was an obstacle to further elaboration
of ring A.
The TTT system can in principle lead to two adducts,
namely, the trans-anti-cis (TAC) and the cis-anti-trans
(CAT) tricycles.1,3 We have previously demonstrated that 14-
membered TTT macrocyclic triene 1 with cis substituents
led to the specific formation of TAC tricycle 2 due to steric
hindrance from the malonate and the alkoxy group (Figure
1).4 This result was very interesting since only one of the
(1) Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831.
(2) For applications in total synthesis, see: (a) Toro´, A.; Nowak, P.;
Deslongchamps, P. J. Am. Chem. Soc. 2000, 122, 4526. (b) Be´langer, G.;
Deslongchamps, P. Org. Lett. 2000, 2, 285. (c) Germain, J.; Deslongchamps,
P. Tetrahedron Lett. 1999, 40, 4051.
(3) Lamothe, S.; Ndibwami, A.; Deslongchamps, P. Tetrahedron Lett.
1988, 29, 1639, 1641.
(4) Dory, Y. L.; Soucy, P.; Deslongchamps, P. Bull. Soc. Chim. Fr. 1994,
131, 142.
Figure 1.
10.1021/ol006670r CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/28/2000

We wish now to report the synthesis of 14-membered TTT
macrocycle 3 with cis substituents in pro-ring C, where the
malonate connector was replaced by a â-ketoester with a
gem-dimethyl functionality at position 4. The cis substituents
in C12 and C13 were introduced, as before,4 by an intermo-
lecular aldol reaction between the dienophile and the diene
(Figure 1). For our model study, a racemic macrocycle was
used.
Having dienophile and diene in hand, both were connected
by an aldol condensation to give a mixture of syn and anti
adducts 9 and 10 in a 1:2 ratio which were separated by
flash chromatography. The alcohol was protected as a MOM
ether on both adducts and the THP removed to afford the
corresponding primary alcohol. The â-ketoester connector
was then elaborated by a sequence of oxidation, aldol
condensation with methyl acetate, and subsequent oxidation
to give â-ketoesters 11 and 12. The TBDPS group was then
removed, and the alcohols thus obtained were respectively
transformed into the corresponding chlorides 13 and 14 in
81% yield with hexachloroacetone and triphenylphosphine
in THF at -30 °C.6
Construction of macrocycle 3 began with the synthesis of
dienophile 5 from ester-aldehyde 7 available in one step
from commercial cyclopentene (Scheme 1).5 Wittig olefi-
The macrocyclization was then conducted by slow addition
of the chloride to a refluxing acetonitrile solution of Cs2-
CO3 and CsI under high dilution, to yield the desired
macrocycles 3 and 15 in 66 and 64% yields, respectively.
Now that the isomeric macrocycles 3 and 15 were
synthesized, their behavior toward the TADA reaction was
studied. As indicated in Table 1, only the TAC tricycle was
Scheme 1. Synthesis of the Macrocyclea
Table 1. Diels-Alder Studies of TTT Macrocycles 3 and 15
a (a) PPh3dC(CH3)CHO, C6H6, reflux, 75%; (b) NaBH4, EtOH,
0 °C, 77%; (c) TBDPSCl, imidazole, 82%; (d) DHP, PTSA, THF/
CH2Cl2 2:1, 82%; (e) DMSO, (ClCO)2, CH2Cl2, -78 °C, then Et3N,
rt, 94%; (f) (EtO)2PO-CH2CHdCHCO2Et, nBuLi, Et2O, 98%; (g)
LAH, Et2O, 0 °C, 84%; (h) TPAP, NMO, MS 4 Å, CH2Cl2, 89%;
(i) 5, LDA, THF, -78 °C, then 6, 85%; (j) MOMCl, DIPEA,
CH2Cl2, 79%; (k) PPTS, MeOH, reflux, 77%; (l) TPAP, NMO,
MS 4 Å, CH2Cl2, 73%; (m) AcOMe, LDA, THF, -78 °C, 81%;
(n) Dess-Martin periodinane, 86%; (o) TBAF, THF, rt; (p) HCA,
PPh3, THF, -30 °C; (q) Cs2CO3, CsI, CH3CN, reflux, slow addition
15 h, [2 × 10-3 M].
a All reactions were carried out in toluene. b 3 equiv of Et3N was added.
obtained with the cis substituents in ring C.7 The best result
was obtained at 125 °C, yielding a mixture of TAC tricycle
16 along with the corresponding decarboxylated tricycle 17
in a 3:1 ratio.8 With the anti substituents in ring C, no control
was observed and a mixture of CAT and TAC tricycles was
obtained, in keeping with results obtained in previous
studies.4
nation of the aldehyde provided the corresponding trans R,â-
unsaturated aldehyde in 75% yield. Reduction of the aldehyde
with NaBH4 and silyl protection afforded the desired
dienophile 5.
The synthesis of diene 6 started with the monoprotection
of 2,2-dimethylpropanediol with a THP group in 82% yield.
Swern oxidation of the primary alcohol followed by Horner-
Emmons reaction gave the trans-trans diene. Reduction of
the ester with LAH and subsequent oxidation to the aldehyde
afforded diene 6 in good yields.
On the basis of these results, an enantioselective synthesis
of cassaine was envisaged. Cassaine 18 is a cardioactive
alkaloid, isolated from Erythrophleum guineense bark, that
(6) Magid, R. M.; Fruchey, O.; Johnson, W. L.; Allen, T. G. J. Org.
Chem. 1979, 44, 359.
(7) For the X-ray crystal structure of compound 16, see the Supporting
Information.
(5) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867.
(8) Triethylamine was added to be sure that the conditions of the TADA
reaction were not acidic, even if it is not necessary.
4150
Org. Lett., Vol. 2, No. 26, 2000

has been known as inhibitor of Na+, K+-ATPase and to
possess a pharmacological action similar to the digitalis
glycosides.9
Scheme 2a
Our retrosynthetic analysis suggests that the TAT tricycle
of cassaine, as shown in Figure 2, could come from TAC
Figure 2. Retrosynthetic analysis of cassaine.
a (a) Ph3PdC(CH3)CHO, C6H6, reflux, 75%; (b) NaBH4, MeOH,
0 °C, 77%; (c) (MeO)2CH2, LiBr, PTSA, 85%; (d) KOH, MeOH,
97%; (e) Et3N, (CH3)3CCOCl, THF, -78 °C, then 31, nBuLi, THF,
-78 °C, 88%; (f) TiCl4, TMEDA, NMP, CH2Cl2, -78 °C, 55%;
(g) NaBH4, THF/H2O, 78%; (h) I2, CH2Cl2, 97%; (i) HCl (concd),
iPrOH, 55 °C, 16 h, 75%; (j) (MeO)2C(Me)2, PTSA, THF, 95%;
(k) 23, Pd(CH3CN)2Cl2, DMF, 85%; (l) HCA, PPh3, THF, -30
°C, 85%; (m) Cs2CO3, NaI, CH3CN, reflux, slow addition 12 h, [2
× 10-3 M], 71%, 29/30 ratio 9/1.
tricycle 19 after oxidation at C7 and epimerization at C8, with
19 being the TADA adduct obtained from triene 20. An
enantioselective synthesis of macrocycle 20 could be made,
in a more convergent manner than in the model study, first
by an asymmetric aldol reaction between dienophile 21 and
aldehyde 22 and then by further elaboration of the diene by
Stille coupling10 with â-ketoester stannane 23.2a
As shown in Scheme 2, the first two steps of the sequence
were similar to those of the model study, with the alcohol
protected as a MOM ether. Hydrolysis of ester 24 gave the
corresponding carboxylic acid and then the Evans chiral
auxiliary was introduced in a one-pot procedure to afford
imide 25 in 86% yield.11 The enantioselective aldol conden-
sation was then performed in the presence of TiCl4, TMEDA,
and NMP with aldehyde 2612 to afford the corresponding
aldol adduct in 55% yield.13 Reduction of the imide with
NaBH4 without racemization14 and then stannane/iodide
exchange provided the diol in good yields. Deprotection of
the MOM ether and protection of the two alcohols as an
acetonide furnished iodide 27. Stille coupling between iodide
27 and stannane â-ketoester 23 was then accomplished in
DMF in 80% yield.2a,10 The chlorination and macrocycliza-
tion were performed as previously described (vide supra)
and with similar yields.
However, this time, TAC tricycle 30 was obtained in small
quantities during the macrocyclization (29/30 ratio 9:1),
showing that the TADA reaction was even easier than in
the model study.
The TADA reaction was tried at 125 °C (Table 2) with
chiral macrocycle 29, but surprisingly, it gave a mixture of
Scheme 3a
(9) (a) De Munari, S.; Barassi, P.; Cerri, A.; Fedrizzi, G.; Gobbini, M.;
Mabalia, M.; Melloni, P. J. Med. Chem. 1998, 41, 3033. (b) Turner, R. B.;
Burchardt, O.; Herzog, E.; Morin, R. B.; Riebel, A.; Sanders, J. M. J. Am.
Chem. Soc. 1966, 88, 1766.
(10) (a) Stille, J. K.; Tanaka, M. J. Am. Chem. Soc. 1987, 109, 3785.
For a comprehensive review, see: Farina, V.; Krishnamurty, V.; Scott, W.
J. In Organic Reactions; Paquette, L. A., Ed.; John Wiley and Sons: New
York, 1997; Vol. 50, pp 1-652.
(11) Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.;
Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613.
(12) Lipshutz, B. H.; Lindsley, C. J. Am. Chem. Soc. 1997, 119, 4555.
(13) Hawkins, J. M.; Sieser, J. E.; Ende, D. J.; Clifford, P. J.; Castaldi,
M. J.; Bourassa, D. E. Asymmetric Aldol Chemistry: New Conditions,
Spectroscopic Studies, and Pilot Plant Applications. Abstract of Papers,
ChiraTech ’97, Philadelphia, PA, November 11-13, 1997.
(14) Prashad, M.; Har, D.; Kim, H. Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067.
a (a) HCl 1N, THF, 0 °C, 1 h, 95%; (b) PvCl, 2,6-lutidine,
CH2Cl2, 75%; (c) MOMCl, (i-Pr)2Net, CH2Cl2, 85%; (d) toluene,
sealed tube, 125 °C, 100%, 34/35 ratio 2.6/1.
Org. Lett., Vol. 2, No. 26, 2000
4151

Pursuing the total synthesis of cassaine, elaboration of ring
A was completed first by dealkoxycarbonylation15 of tricycle
30 in quantitative yield (Scheme 4). Reduction of the ketone
Table 2. TADA Studies on Macrocycle 29
Scheme 4a
a (a) NaOH 7%, MeOH/H2O 3:2, 100%; (b) NaBH4, MeOH, 0
°C, 95%.
yield (%)
at position 3 was accomplished with NaBH4 in MeOH at 0
°C to give â epimer 36 (ratio â/R 95:5).16,17
temp (°C)
time (h)
30
31
32
total yield (%)a
90
95
110
115
125
72
72
16
16
16
83
75
60
57
33
83
80
85
91
92
In conclusion, we have synthesized interesting TAC
tricycles by the TADA strategy, which can be used as key
intermediate for the synthesis of cassaine. Further elaboration
of the tricycles en route to the total synthesis of cassaine is
in progress and will be reported in due course.
5
10
17
20
15
17
39
a All reactions were carried out in toluene.
Acknowledgment. Basic Research Chair in organic
chemistry granted to Pr. Pierre Deslongchamps by BioChem
Pharma and financial support from NSERC (Canada) and
FCAR (Quebec) are highly appreciated. We also thank Dr.
Eric Marsault for assistance and Mr. Marc Drouin for X-ray
analysis.
two TAC (one decarboxylated) and one CAT tricycle (TAC/
CAT ratio 2.7:1). However, a brief temperature study showed
that at 90 °C only the desired TAC tricycle 30 was formed.
This result further indicates that the presence of the acetonide
function allows the TADA reaction to occur at lower
temperatures.
Knowing that without the acetonide only the TAC tricycle
was observed and in order to better understand its role, the
acetonide was cleaved (Scheme 3) and the primary alcohol
protected with a pivalate while the secondary alcohol was
protected as a MOM ether to give macrocycle 33.
The TADA reaction of this macrocycle gave only the TAC
ring junction at 125 °C, in agreement with the results
previously obtained in the model study. This confirmed that
the acetonide indeed lowers the transition state energy for
both tricycles.
Supporting Information Available: Experimental pro-
1
cedure and listing of spectral data (IR, H and 13C NMR,
MS) for all synthetic compounds and X-ray crystal structure
of compounds 16 and 36. This material is available free of
charge via the Internet at http//pubs.acs.org.
OL006670R
(15) Abraham, N. A. Tetrahedron Lett. 1973, 14, 451.
(16) Jabin, I.; Revial, G.; Melloul, K.; Pfau, M. Tetrahedron: Asymmetry
1997, 8, 1101.
(17) For the X-ray crystal structure of tricycle 37, see the Supporting
Information.
4152
Org. Lett., Vol. 2, No. 26, 2000