Total synthesis of clavepictines A and B and pictamine

Article abstract of DOI:10.1021/ol060960b

A short route for assembling clavepictines A and B and pictamine is described, which features elaboration of its trisubstituted piperidine moiety via condensation of a β-keto sulfone with an L-alanine-derived bromide and subsequent alkylative cyclization and construction of its quinolizidine skeleton via a diastereoselective intramolecular conjugate addition. The possible stereochemical course for this conjugate addition is discussed.

Full text of DOI:10.1021/ol060960b

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3179-3182
Total Synthesis of Clavepictines A and
B and Pictamine
Shanghai Yu, Xiaotao Pu, Tiejun Cheng, Renxiao Wang, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@pub.sioc.ac.cn
Received April 21, 2006
ABSTRACT
A short route for assembling clavepictines A and B and pictamine is described, which features elaboration of its trisubstituted piperidine
moiety via condensation of a -keto sulfone with an -alanine-derived bromide and subsequent alkylative cyclization and construction of its
â
L
quinolizidine skeleton via a diastereoselective intramolecular conjugate addition. The possible stereochemical course for this conjugate addition
is discussed.
Clavepictines A and B (1a and 1b) and pictamine (1c) are
three quinolizidine alkaloids that were isolated from the
tunicate ClaVelina picta in 1991 by the Cardellina and
Faulkner groups, respectively (Figure 1).1 Preliminary bio-
logical studies on clavepictines A and B indicated that these
two compounds possessed significant cytotoxicity against
murine leukemia and human solid tumor cell lines (P-388,
A-549, U-251, and SN12K1) at concentrations lower than 9
µg/mL.1a A recent study on the structure-activity relationship
(SAR) revealed that their cytotoxicity was primarily deter-
mined by the side chain connected with C10, as no activity
was observed when this unsaturated side chain was replaced
with some substituents.2 Although there have not been any
reports on cytotoxicity of pictamine, this alkaloid was
recently found to be a potent blocker for two neuronal
nicotinic acetylcholine receptors with IC50 values of 1.5 and
1.3 µM, respectively.3
After the structures of 1a-c were resolved, synthetic
studies toward these natural products were immediately
(1) (a) Raub, M. F.; Cardellina, J. H.; Choudhary, M. I.; Ni, C.-Z.; Clardy,
J.; Alley, M. C. J. Am. Chem. Soc. 1991, 113, 3178. (b) Kong, F.; Faulkner,
D. J. Tetrahedron Lett. 1991, 32, 3667.
(2) Agami, C.; Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org.
Chem. 2003, 2062.
Figure 1. Structures and retrosynthetic analysis of clavepictines
and pictamine.
10.1021/ol060960b CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/21/2006

conducted. In 1995, Hart and Leroy disclosed their unsuc-
cessful attempts.4 One year later, the first enantioselective
total synthesis of clavepictines was accomplished by the
Momose group, in which 32 linear steps were required.5 Soon
after, Ha and Cha demonstrated their alternative route (in
27 linear steps) to these two target molecules.6 Interestingly,
in their initial investigations, both the Momose and Cha
groups chose an intramolecular conjugate addition of an
amine liberated from R,â-unsaturated ester 3a or 3b to
elaborate the desired bicyclic intermediate 2a or 2b.5a,6b
Unfortunately, this process gave rise to undesired 10-epimer
4a or 4b as the major or exclusive product (Figure 2), which
3a or 3b may prefer the conformer A to deliver the undesired
isomer 4a or 4b, because in the conformer B the long carbon
side chain must be axial. To inhibit the formation of the
conformer A, Momose and co-workers employed sulfone 5
as a substrate, in which an additional ring was introduced to
fix the conformation of the piperidine ring into trans-decalin
type. As expected, compound 5 underwent a deprotection/
conjugate addition process to provide the desired quinolizi-
dine 6 exclusively, which was subsequently transformed into
the advanced intermediate 2d.5
During the studies on the synthesis of bicyclic alkaloids,7,8b,9a
we became interested in development of a more efficient
protocol for assembling clavepictines A and B and pictamine.
We envisaged that revising the balance from the conformer
A to the conformer B could also be achieved by replacing
the MOM protecting group and R,â-unsaturated ester moiety
with larger TBS and R,â-unsaturated sulfone, respectively.
These measurements would make the conformer A less stable
because of its axially disposed bulky silyloxy group and
severe repulsive interaction between the benzenesulfon-
methyl, methyl and silyloxy groups, thereby giving 2c
predominantly through cyclization of the conformer B. The
investigations thus undertaken are detailed here.
Scheme 1
Figure 2. Possible stereochemical courses for formation of
quinolizidines 2, 4, and 6.
forced them to give up this obviously short protocol, and
completed the total synthesis via another intramolecular
conjugate addition (from 5 to 6), or a silver(I)-promoted
cyclization of δ-amino allenes, as the key steps. Notable
drawbacks in these two known routes are that the former
one required long steps to manipulate the substituents at C2
and C35 while the latter one suffered from unsatisfactory
diastereoselectivity at the cyclization step.6
To rationalize the stereochemical outcome for the intramo-
lecular conjugate addition, two possible conformers A and
B were proposed (Figure 2).5,6 The amine generated from
As depicted in Scheme 1, the required piperidine ring was
constructed from Boc-protected γ-amino bromide 8, which
was prepared from N-Boc-L-alanine via Arndt-Eistert
(3) Tsuneki, H.; You, Y.; Toyooka, N.; Sasaoka, T.; Nemoto, H.; Dani,
J. A.; Kimura, I. Biol. Pharm. Bull. 2005, 28, 611.
(4) Hart, D. J.; Leroy, V. Tetrahedron 1995, 51, 5757.
(5) (a) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T. J. Org. Chem.
1996, 61, 4882. (b) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T.;
Nemoto, H. Tetrahedron 1999, 55, 15209.
(6) (a) Ha, J. D.; Lee, D.; Cha, J. K. J. Org. Chem. 1997, 62, 4550. (b)
Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.
(7) (a) Zhu, W.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 5545. (b) Zhu, W.;
Dong, D.; Pu, X.; Ma, D. Org. Lett. 2005, 7, 705. (c) Pu, X.; Ma, D. J.
Org. Chem. 2003, 68, 4400. (d) Zhu, W.; Ma, D. Org. Lett. 2003, 5, 5063.
(e) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927. (f) Ma, D.; Sun, H. Org.
Lett. 2000, 2, 2503. (g) Ma, D.; Zhang, J. Tetrahedron Lett. 1998, 39, 9067.
(8) (a) Rotella, P. D. Tetrahedron Lett. 1995, 36, 5453. (b) Pu, X.; Ma,
D. Angew. Chem., Int. Ed. 2004, 43, 4222.
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Org. Lett., Vol. 8, No. 15, 2006

synthesis and subsequent transformations, and has been
successfully utilized in the total synthesis of lepadins.8b After
cleavage of the Boc group in 8 with AlCl3, the liberated
amine was immediately condensed with â-keto sulfone 9
under solvent free conditions to provide an enamine sulfone,
which was then treated with triethylamine and sodium iodide
at 120 °C to produce the alkylative cyclization product 10
in 75% overall yield.8b,9
For further conversion, we had to protect the enamine in
10 with a Boc group, which was proven a challenging task
owing to its poor reactivity and sterically hindered environ-
ment. After some trials, we found that this goal was reached
by treatment of 10 with n-BuLi and subsequent trapping the
anion with di-tert-butyl dicarbonate. Next, Raney-Ni-
catalyzed hydrogenolysis of 11 was carried out at 60 °C to
afford alcohol 12, which was reduced with NaBH3CN in the
presence of TFA to yield 2,6-trans-substituted piperidine 13.10
After Swern oxidation of 13, olefination of the resultant
aldehyde via a Wittig reaction provided R,â-unsaturated
sulfone 3c. Then it was time to check our hypothesis about
the stereochemistry of cyclization step. To our delight,
removal of the Boc group in 3c with AlCl3 followed by
exposure of the liberated amine to aqueous NaHCO3
delivered 2c as a single isomer. Its stereochemistry was
determined by NOESY studies and was further confirmed
by X-ray diffraction analysis (Figure 3). Importantly, the
we are currently exploring each possible reaction pathway
in Figure 2 through high-level density function theory
calculations. Nevertheless, a comparison of the electronic
energies of the products given by cyclization of conformers
A-D may already provide some insights into the probability
of each reaction pathway. For this purpose, molecular models
of the four possible products were built by using the Gaussian
03 program.11 The geometry of each molecule was fully
optimized at the B3LYP 6-31++G(d,p) level, and the single-
point electronic energy of each molecule was computed at
the same level (Table 1). We noticed that Ha and Cha6
Table 1. Electronic Energies of the Direct Products by
Cyclization of Conformers A-D
electronic energya (kcal/mol)
product given by
cyclization of
R ) TBS, X ) SO2Ph R ) TIPS, X ) CO2Et
A
B
C
D
0.25
0
2.43
4.52
-0.78
0
2.44
3.95
a The product by cyclization of conformer B is chosen as the reference
in both reactions.
reported a similar reaction before showing different stereo-
chemistry. Their reactant was different from ours only by R
and X (R ) TIPS, X ) CO2Et). To make a comparison, we
studied their reaction with the same computational method
above. The results are also summarized in Table 1.
According to our computations, the products of C and D
in both reactions are considerably unfavorable as compared
to the ones of A and B. In these two products, the -CH2X
branch is in fact close to the methyl group in space, which
leads to steric repulsions. In contrast, cyclization of B or A
does not result in a molecule with such a problem. It is thus
reasonable to expect that these two reaction pathways should
govern the stereochemistry in the final product. Our com-
putation indicates that in our reaction the electronic energy
of the product of B is 0.25 kcal/mol lower than the
counterpart of A, while in Ha and Cha’s reaction, however,
the electronic energy of the product of A is lower by 0.78
kcal/mol (Table 1). Both results are in agreement with the
stereochemistry observed in experiment. Therefore, the
preference between these two reaction pathways seems to
stem from the relative magnitude of the 1,2-gauche interac-
tion between the methyl group and the -OR branch. As a
larger substituent group, TIPS is more sensitive than TBS
to the spatial hindrance from the nearby methyl group. Thus,
TIPS tends to stay away from the methyl group even on the
price of taking an axial orientation, as seen in the product
of conformer A (Figure 2). In fact, Ha and Cha found by 1H
NMR spectrum that conformer A of their reactant was indeed
favored over conformer B.6
Figure 3. X-ray structure of 2c.
X-ray structure clearly showed that 2c has an exact confor-
mation as indicated in Figure 2, in which the quinolizidine
has a cis ring junction, both silyloxy and methyl groups are
in equatorial orientations, and benzenesulfonmethyl group
is disposed at an axial position. This result serves as a strong
evidence for the mechanism proposed in Figure 2.
To obtain an in-depth understanding of the stereoselectivity
exhibited in our intramolecular conjugate addition reaction,
(9) This strategy has been used for assembling 3-acyl-substituted
piperidines; see: (a) Yu, S.; Zhu, W.; Ma, D. J. Org. Chem. 2005, 70,
7364. Beak and Nakajima have reported an alternative approach to
3-benzenesulfonylpiperidines; see: (b) Back, T. G.; Nakajima, K. Org. Lett.
1999, 1, 261. (c) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543.
(10) Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506.
With sulfone 2c in hand, we decided to employ Julia
coupling to complete our synthesis.12 As outlined in Scheme
2, deprotonation of 2c with n-BuLi followed by trapping the
resultant anion with 2(E)-nonenal or 2(E)-heptenal to provide
Org. Lett., Vol. 8, No. 15, 2006
3181

about 12% inseparable (E,Z)-isomers, analytical data of the
major isomers were all identical with those reported.1
In conclusion, we have described here a facile protocol to
clavepictines A and B and pictamine by using a diastereo-
selective intramolecular conjugate addition as the key step.
The overall yields were about 7.7% for less than 19 linear
steps. The stereochemical outcome in formation of quino-
lizidine 2c clearly indicated that subtle change in substituents
of the piperidine ring could alter the stereochemical course
greatly. This work shall be of value to quinolizidine
chemistry.
Scheme 2
Acknowledgment. The authors are grateful to Chinese
Academy of Sciences, National Natural Science Foundation
of China (Grant No. 20321202), for their financial support.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 1, 2c, 3c, and
10-16. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060960B
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Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
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esters 14, after esterification with benzoic chloride. Initially,
direct treatment of 14 with sodium amalgam was attempted.
This approach gave the desired dienes 15 with unsatisfactory
stereoselectivity (4:1 for (E,E)- and (E,Z)-isomers). Fortu-
nately, Danishefsky’s sequential elimination/reduction pro-
cedure (DBU then Na/Hg) could improve the selectivity to
8:1.13 The overall yields for four steps were 56-59%.
Removal of the silyl protectiong group in 15a with 20%
HF in acetonitrile furnished clavepictine B (1b), which was
acylated with acetic anhydride to afford clavepictines A (1a).
Similarly, deprotection of 15b followed by acylation provided
pictamine (1c). Although these three final products all contain
(12) (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833. For a recent
review, see: (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563.
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S. J. J. Org. Chem. 1991, 56, 5834.
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