Total synthesis of lepadins B, D, E, and H; determination of the configuration of the latter three alkaloids

Article abstract of DOI:10.1002/anie.200460128

A common bicyclic intermediate was used in an efficient strategy towards lepadins B, D, E, and H shown. These alkaloids are members of a family of natural products with diverse biological activity. The described total syntheses of lepadins D, E, and H ena

Full text of DOI:10.1002/anie.200460128

Communications
Natural Products Synthesis
Total Synthesis of Lepadins B, D, E, and H;
Determination of the Configuration of the Latter
Three Alkaloids**
Xiaotao Pu and Dawei Ma*
Lepadins are a growing family of alkaloids with a cis-fused
decahydroquinoline ring. Its first member, lepadin A (1a,
Scheme 1), was isolated in 1991 by Steffan from the tunicate
[
1]
Clavelina lepadiformis in the North Sea. Two other mem-
bers, lepadins B (1b)and C, were isolated from the same
[*] X. Pu, Prof. Dr. D. 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)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
[
**] The authors are grateful to the Chinese Academy of Sciences, the
National Natural Science Foundation of China (grant 20321202),
and the Science and Technology Commission of Shanghai Munic-
ipality (grants 02JC14032 and 03XD14001) for their financial
support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460128
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Chemie
Scheme 2. a) TBSCl, imidazole, DMF; b) HCO H/CH Cl , then aque-
Scheme 1. Structures and retrosynthetic analysis of lepadins A (1a), B
1b), D (2a), E (2b), and H (2c). Boc=tert-butoxycarbonyl, TBS=tert-
butyldimethylsilyl.
2
2
2
ous NaHCO , 80% from 4; c) 1,3-cyclohexandione, benzene, reflux,
(
3
6
5
9
5%; d) NEt , NaI, DMF, 1108C, 98%; e) Pt/C, 80 atm H , dry AcOH,
3
2
08C, 85%; f) (Boc) O, benzene, 90%; g) Dess–Martin oxidation,
2
2%. DMF=N,N-dimethylformamide.
[
2]
species and other sources four years later. These compounds
have been found to possess significant in vitro cytotoxicity
conformation A, thus leading to the desired configuration at
C4a and C8a for the synthesis of lepadins A, B, D, E, and H.
As expected, this reaction worked well under the catalysis of
Pt/C in dry acetic acid at 80 atm and 508C to afford 8 as a
single isomer with the 4aR,8aR configuration, as established
by NOESY studies. Other catalysts, such as Raney-Ni, Pd/C,
[
2]
against several human cancer cell lines. Very recently,
Wright et al. reported the isolation of lepadins D–F from a
new Didemnum species collected from the Great Barrier
[
3]
Reef, whereas Carroll and co-workers described their
[
4]
discovery of lepadins F–H in Aplidium tabascum Kott.
Interestingly, lepadins D–F showed low cytotoxicity but
significant and selective antiplasmodinium and antitrypano-
somal activity and therefore may serve as lead structures for
and Pd(OH) /C, failed to promote the reaction. Finally, the
protection of 8 with a Boc group followed by a Dess–Martin
oxidation provided 3.
2
[
3]
the development of novel antimalarial drugs.
The stage was now set for the installation of the b-oriented
side chain at C5 of the ketone 3 to complete the synthesis of
lepadin B. Accordingly, 3 was successfully transformed into
the olefin 9 through a Wittig reaction (Scheme 3). Selective
hydrolysis of the enol ether moiety of 9 with trichloroacetic
acid in dichloromethane containing a trace of water gave the
During the past five years, considerable effort has been
directed towards the total synthesis of lepadins, and two
[
5,6]
successful protocols have resulted.
However, the require-
ment by both routes of lengthy reaction sequences to
construct the left cyclohexane ring greatly diminished their
synthetic efficiency. In 2002 Zard and co-workers described a
[
10]
1
aldehyde 10.
By H NMR spectroscopic analysis it was
[
7]
short formal synthesis of racemic lepadin B, but many more
steps would evidently be necessary if this strategy was applied
in an enantioselective synthesis. Herein we wish to describe a
very efficient and general entry into the lepadin family. The
key elements include a concise synthesis of the bicyclic ketone
found that an inseparable mixture of diastereomers were
present in a ratio of 1:1.3. After failure to enhance the ratio by
treatment of this mixture with K CO3 in methanol, we
2
realized that the two isomers might have similar stability
and occupy the favored conformations B and C, respectively.
Further conformational analysis based on the studies of
3
(Scheme 1)and subsequent stereoselective introduction of
[
11]
both a- and b-oriented side chains at C5 of this intermediate.
Furthermore, the configuration of lepadins D (2a) , E 2( b),
and H (2c)was established fully through this study; in
previous reports the absolute configuration of these three
compounds and their configuration at C5’ were undefined.
The assembly of the bicyclic ketone 3 from N-Boc-l-
alanine is outlined in Scheme 2. N-Boc-l-alanine was con-
verted in three steps by a literature procedure into the a-
amino alcohol 4 (63% overall yield), which was protected as
the silyl ether 5. After selective cleavage of the Boc group of 5
with formic acid, the resulting amine was condensed with 1,3-
cyclohexandione in benzene at reflux to give the enamine 6.
Booth and co-workers showed that if the N-Boc group was
removed, the favored conformations would be D and E for
the two possible aldehydes. The more pronounced 1,5-strain
in E would make conformer D more stable, and thus
compound 11 with the aldehyde substituent in the b
orientation would be afforded exclusively. Indeed, after
selective cleavage of the Boc group in 10 with trifluoroacetic
acid (TFA)and subsequent treatment with K CO in meth-
2
3
[
8]
anol, the aldehyde 11 was isolated as a single isomer.
The C1’–C8’ side chain was installed by a Horner–
[
12]
Wadsworth–Emmons reaction, and the desired E,E diene
12 was obtained with greater than 95% selectivity. (Several
methods for a modified Julia olefination gave a mixture in
Subsequent alkylative cyclization of 6 mediated by Et N at
3
[
13]
1
108C in DMF produced the enone 7. The next planned step
favor of the E,Z diene. )The remaining task for completion
of the synthesis was the inversion of the C3 stereocenter, for
which we employed an oxidation/reduction strategy. Thus,
after protection of the N atom with a Boc group, desilyation
with TBAF and a subsequent Dess–Martin oxidation pro-
was the diastereoselective hydrogenation of the CꢀC double
[
9]
bond in 7. Based on a previous observation, we envisaged
that a stereoelectronically controlled axial addition of hydro-
gen would occur at the Re face of the more stable
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Scheme 4. a) TMSCH CO Et, LDA, ꢀ788C!RT, 98%; b) CF CO H,
2
2
3
2
CH Cl , 100%; c) Pt/C, H (1 atm), dry AcOH, 508C, 95%; d) TsCl,
2
2
2
Et N, CH Cl , 80%. LDA=lithium diisopropylamide, TMS=trimethyl-
3
2
2
silyl, Ts=p-toluenesulfonyl.
Scheme 3. a) Ph P=CHOMe, ꢀ408C!RT, 75%; b) CCl CO H, CH Cl ,
3
3
2
2
2
H O (trace); c) K CO , MeOH, 79% for 10 and 76% for 11 from 9;
2
2
3
d) CF CO H, CH Cl ; e) diethyl (2E)-heptenylphosphonate, KHMDS,
3
2
2
2
THF, 95%; f) (Boc) O, benzene, reflux; g) TBAF, THF; h) Dess–Martin
2
oxidation, 60% for 3 steps; i) NaBH , MeOH, ꢀ788C, 90%;
4
j) CF CO H (5%), CH Cl , 80%. HMDS=hexamethyldisilazide,
3
2
2
2
TBAF=tetrabutylammonium fluoride.
vided the ketone 13. The reduction of 13 with NaBH gave a
4
single diastereomer, which was treated with TFA to furnish
lepadin B as its TFA salt, whose analytical data were identical
[
2]
to those reported. The overall yield was about 5.3% over 20
linear steps from N-Boc-l-alanine.
To introduce the a-oriented side chain at C5 of the ketone
[
14]
3
, a Peterson reaction was employed to provide the olefin
1
4 (Scheme 4). Direct Pt/C-catalyzed hydrogenation of 14 in
dry acetic acid gave 15 with a diastereomeric ratio of 3:1.
However, we were pleased to observe that the hydrogenation
of 16, a derivative of 14 without the N-Boc group, produced 17
in a highly diastereoselective manner (d.r. > 97:3). X-ray
crystal-structure analysis of 18, a tosylation product of 17,
confirmed that the side chain at C5 was in the a orientation.
These two stereochemical courses might be rationalized by
the difference in steric hindrance towards hydrogen attack in
the two favored conformations F and G, as depicted in
Scheme 4.
The completion of lepadins D, E, and H is depicted in
Scheme 5. a) (Boc)
dation; c) 20, NaHMDS, THF; d) Pd/C, H , 90%; e) TBAF, THF, room
2
O, DMAP, then DIBAL, ꢀ408C, 95%; b) Swern oxi-
Scheme 5. The protection of 17 by treatment with (Boc) O,
2
2
temperature, 100%; f) HCl, iPrOH/MeOH, 85%; g) (2E)-octenoic acid,
Cl C H COCl, iPr NEt, DMAP, 64%; h) CF CO H, CH Cl , 87%;
followed by reduction with DIBAL, afforded the alcohol 19,
which was oxidized to the aldehyde, coupled with the sulfone
0, and hydrogenated over Pd/C to produce 21. Since the
3
6
2
2
3
2
2
2
i) (2E,4E)-octadienoic acid, EDCI, DMAP, CH Cl , 73%; j) CF CO H,
2
2
3
2
2
CH Cl , 90%. DIBAL=diisobutylaluminum hydride, DMAP=4-dimeth-
2
2
sulfones 20 could be constructed by a Sharpless epoxidation/
reductive ring opening sequence and subsequent transforma-
ylaminopyridine, EDCI=1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide hydrochloride, MOM=methoxymethyl.
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Chemie
[
15]
tions, both (R)-20 and (S)-20 were readily accessible by
tuning the ligands in the Sharpless epoxidation, thus provid-
ing a chance to establish the configuration at C5’. The
complete deprotection of 21 led to both 2a and its C5’ epimer
[14] K. Shimoji, H. Taguchi, K. Oshima, H. Yamamoto, H. Nozaki, J.
Am. Chem. Soc. 1974, 96, 1620.
[
15] a)L. J. DꢀSouza, S. C. Sinha, S. Lu, E. Keinan, S. C. Sinha,
Tetrahedron 2001, 57, 5255; b)P. A. Blackemore, W. J. Cole, P. J.
Kocienski, A. Morley, Synlett 1998, 26.
2
2. The cleavage of just the silyl ether in 21 yielded two
alcohols, which were acylated with (2E)-octenoic acid
[
16] C. Gaul, J. T. Njardarson, S. J. Danishefsky, J. Am. Chem. Soc.
2003, 125, 6042.
[
16]
(
(
Cl C H COCl/iPrNEt )
or (2E,4E)-octadienoic acid
EDCI/DMAP), and then deprotected to furnish 2b and
3, and 2c and 24, respectively. Although both the NMR
spectra and the optical rotation for 2a and 22, 2b and 23, and
c and 24 were very similar, a marked difference in the
[17] D. A. Evans, P. H. Carter, E. M. Carreira, J. A. Prunet, A. B.
Charette, M. Lautens, Angew. Chem. 1998, 37, 2526; Angew.
Chem. Int. Ed. Engl. 1998, 37, 2354.
3
6
2
2
[
17]
2
2
1
H NMR spectra of 2c and 24 at d = 1.2–1.5 ppm clearly
showed that the data for 2c, but not for 24, were identical to
those reported for lepadin H. Furthermore, the value [a] =
2
0
D
ꢀ
12 (c = 1.0 MeOH)observed for the hydrochloride salt of 2a
is close to that reported for the hydrochloride salt of
2
D
0
[3]
lepadin D ([a] = ꢀ14 (c = 0.2 MeOH) ), whereas the
value for the optical rotation of the hydrochloride salt of 22
2
0
was significantly lower ([a] = ꢀ5.7 (c = 0.9 MeOH)). There-
D
fore, we concluded that lepadins D, E, and H have the
absolute configuration 2S,3R,4aS,5S,8aR,5’R.
In summary, we have developed an efficient and divergent
strategy towards the lepadins, including a concise synthesis of
lepadin B, as well as the first total synthesis of lepadins D, E,
and H, which enabled us to fully determine their configu-
ration. These results should prompt further studies on the
synthesis and biological activity of these compounds and their
analogues.
Received: March 26, 2004 [Z460128]
Keywords: alkaloids · configuration determination ·
.
hydrogenation · olefination · total synthesis
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