Total synthesis of (+)-lepadin F

Article abstract of DOI:10.1021/ol802068q

(Chemical Equation Presented) An enantioseleclive total synthesis of (+)-lepadin F is described. The synthetic sequence features an intermolecular aza-[3 + 3] annulation, homologation of a vinylogous amide via Eschenmoser's episulfide contraction, and a highly stereoselective hydrogenation essential for achieving the 1,3-anti relative stereochemistry at C2 and C8a.

Full text of DOI:10.1021/ol802068q

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4991-4994
Total Synthesis of (+)-Lepadin F
Gang Li, Richard P. Hsung,* Brian W. Slafer, and Irina K. Sagamanova
DiVision of Pharmaceutical Sciences and Department of Chemistry, 777 Highland
AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received September 3, 2008
ABSTRACT
An enantioselective total synthesis of (+)-lepadin F is described. The synthetic sequence features an intermolecular aza-[3 + 3] annulation,
homologation of a vinylogous amide via Eschenmoser’s episulfide contraction, and a highly stereoselective hydrogenation essential for achieving
the 1,3-anti relative stereochemistry at C2 and C8a.
The lepadin family (Figure 1), comprising eight cis-decahyd-
roquinoline members, was identified from 1991 to 2002 from
different sources such as tunicate ClaVelina lepadinformis,1
flatworm Prostheceraeus Villatus,2 tropical marine tunicate
Didemnum sp.,3 and Australian great barrier reef ascidian
Aplidium tabascum.4 They possess biological activities ranging
from cytotoxicity, inhibitions of tyrosine kinase, antiplasmodial
and antitrypanosomal properties, as well as antimalarial proper-
ties1-4 and have attracted attention from several synthetic
groups.5-11
While all contain a cis-1-azadecalinic motif, members of
the lepadin family display a diversified array of relative
stereochemical relationships at C2, C3, C4a, C5, and C8a
(Scheme 1). For the 1,2-stereochemical relationship, the C2,3
relative configuration consists of two types: cis in A-C, F,
and G and trans in D, E, and H for which the absolute
configuration was recently confirmed by Ma.9 The C4a,5
relative configuration also consists of two types: trans in
A-C and cis in D-H. For the 1,3-stereochemical relation-
ship, the C2,8a relative configuration consists of syn in A-E
and H with a more challenging anti relative configuration in
F and G. Consequently, the lepadin family can be divided
into three major subfamilies based on their relative stereo-
chemical relationships at C2, C3, C4a, C5, and C8a (Scheme
1).
(1) For isolation of (-)-lepadin A, see: Steffan, B. Tetrahedron 1991,
47, 8729.
(2) For isolation of (-)-B and (-)-C, see: Kubanek, J.; Williams, D. E.;
de Silva, E. D.; Allen, T.; ersen, R. J. Tetrahedron Lett. 1995, 36, 6189.
(3) For isolation of (+)-D, (-)-E, and (-)-F, see: Wright, A. D.; Goclik,
E.; Ko¨nig, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067.
(4) For isolation of (+)-F, (+)-G, and (+)-H, see: Davis, R. A.; Carroll,
A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65, 454.
(5) For the first total synthesis of a lepadin family member, (-)-lepadin
B, see: (a) Toyooka, N.; Okumura, M.; Takahata, H.; Nemoto, H.
Tetrahedron 1999, 55, 10673. (b) Toyooka, N.; Okumura, M.; Takahata,
H. J. Org. Chem. 1999, 64, 2182. Also see: (c) Toyooka, N.; Nemoto, H.
Trends Heterocycl. Chem. 2002, 8, 145. (d) Toyooka, N. Yakugaku Zasshi
(9) For total synthesis of lepadins A-E and H, see: (a) Pu, X.; Ma, D.
J. Org. Chem. 2006, 71, 6562. (b) Pu, X.; Ma, D. Angew. Chem., Int. Ed.
2004, 43, 4222.
(10) For total syntheses of (+)-lepadin F and (-)-lepadin G, see: Niethe,
A.; Fischer, D.; Blechert, S. J. Org. Chem. 2008, 73, 3088.
(11) For other studies, see: (a) Mena, M.; Valls, N.; Borreg, M.; Bonjoch,
J. Tetrahedron 2006, 62, 9166. (b) Mena, M.; Bonjoch, J.; Pardo, D. G.;
Cossy, J. J. Org. Chem. 2006, 71, 5930. (c) Mena, M.; Bonjoch, J.
Tetrahedron 2005, 61, 8264. (d) Barbe, G.; Charette, A. B. Abstracts of
Papers, 232nd National Meeting of the American Chemical Society, San
Francisco, CA, Fall 2006; American Chemical Society: Washington, DC,
2006; ORGN-747.
2001, 121, 467
(6) For total synthesis of (-)-lepadin B, see: Ozawa, T.; Aoyagi, S.;
Kibayashi, C. Org. Lett. 2000, 2, 2955
(7) For total syntheses of (-)-lepadin A and (-)-lepadin C, see: Ozawa,
T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338
(8) For a formal synthesiss of (()-lepadin B, see: Kalaï, C.; Tate, E.;
Zard, S. Z. Chem. Commun. 2002, 1430
.
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10.1021/ol802068q CCC: $40.75
Published on Web 09/27/2008
2008 American Chemical Society

Our total synthesis efforts commenced with the known
diol 518 (Scheme 2), which was prepared from 3 in two steps
Scheme 2. Reductive Removal of the C4-OH Group
Figure 1
.
Lepadin family.
Scheme 1. General Approach to Lepadins
consisting of aza-[3 + 3] annulation and OsO4 dihydroxy-
lation19,20 of C3,4 olefin of the initial annulation product 2.21
We focused on identifying a useful reductive protocol to
(14) For recent studies in this area, see: (a) Hayashi, Y.; Gotoh, H.;
Masui, R.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012. (b) Trost,
B. M.; Dong, G. Org. Lett. 2007, 9, 2357. (c) Schmidt, A.; Gu¨tlein, J.-P.;
Mkrrchyan, S.; Go¨rls, H.; Langer, P. Synlett 2007, 1305. (d) Pattenden,
L. C.; Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P. A. Org. Lett. 2006, 8,
3089. (e) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 6330. (f)
Halliday, J. I.; Chebib, M.; Turner, P.; McLeod, M. D. Org. Lett. 2006, 8,
3399. (g) Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata,
K. Heterocycles 2006, 68, 2087. (h) Bose, D. S.; Kumar, R. K. Heterocycles
2006, 68, 549. (i) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org.
Lett. 2005, 7, 2993. (j) Goodenough, K. M.; Moran, W. J.; Raubo, P.;
Harrity, J. P. A. J. Org. Chem. 2005, 70, 207. (k) Agami, C.; Dechoux, L.;
Hebbe, S.; Me´nard, C. Tetrahedron 2004, 60, 5433. (l) Ji, S.-J.; Jiang, Z.-
Q.; Lu, J.; Loh, T.-P. Synlett 2004, 831. (m) Hedley, S. J.; Moran, W. J.;
Price, D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286.
(15) For our work on developing the aza-[3 + 3] annulation method,
see: (a) Ghosh, S. K.; Buchanan, G. S.; Long, Q. A.; Wei, Y.; Al-Rashid,
Z. F.; Sklenicka, H. M.; Hsung, R. P. Tetrahedron 2008, 63, 883. (b)
Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611. (c)
Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org. Chem.
2005, 70, 4248. (d) Sydorenko, N.; Hsung, R. P.; Darwish, O. S.; Hahn,
J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732. (e) Sklenicka, H. M.; Hsung,
R. P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S. J.; Mulder,
J. A. Org. Lett. 2000, 2, 1161. (f) Hsung, R. P.; Wei, L.-L.; Sklenicka,
H. M.; Douglas, C. J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org.
Lett. 1999, 1, 509.
We12 had envisioned that all three subfamilies could be
accessed from the orthogonal protected common intermediate
1, which could be prepared from a stereoselective intermo-
lecular aza-[3 + 3] annulation13-15 using chiral vinylogous
amide 3. Given our recent success in the alkaloid synthesis
employing this annulation,16 we elected to first pursue the
most challenging member of the family, lepadin F,17
containing the 1,3-anti relative configuration for C2,8a.
Despite numerous efforts in the synthesis of lepadins, an
elegant total synthesis of lepadin F was only accomplished
very recently by Blechert.10 We report here our total
synthesis of (+)-lepadin F.
(16) (a) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P.
Angew. Chem., Int. Ed. 2001, 40, 1516. (b) Sklenicka, H. M.; Hsung, R. P.;
McLaughlin, M. J.; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. W. J. Am.
Chem. Soc. 2002, 124, 10435. (c) McLaughlin, M. J.; Hsung, R. P.; Cole,
K. C.; Hahn, J. M.; Wang, J. Org. Lett. 2002, 4, 2017. (d) Luo, S.; Zificsak,
C. Z.; Hsung, R. P. Org. Lett. 2003, 5, 4709. (e) Sydorenko, N.; Zificsak,
C. A.; Gerasyuto, A. I.; Hsung, R. P. Org. Biomol. Chem. 2005, 3, 2140.
(f) Swidorski, J. J.; Wang, J.; Hsung, R. P. Org. Lett. 2006, 8, 777. (g)
Wang, J.; Swidorski, J. J.; Sydorenko, N.; Hsung, R. P.; Coverdale, H. A.;
Kuyava, J. M.; Liu, J. Heterocycles 2006, 70, 423. (h) Gerasyuto, A. I.;
Hsung, R. P. Org. Lett. 2006, 8, 4899. (i) Gerasyuto, A. I.; Hsung, R. P. J.
Org. Chem. 2007, 72, 2476.
(12) Slafer, B.; Hsung, R. P.; Sklenicka, H. M. Abstracts of Papers,
227th National Meeting of the American Chemical Society, Anaheim, CA,
Spring 2004; American Chemical Society: Washington, DC, 2006; ORGN-
396.
(17) Both antipodes of lepadin F have been reported independently with
Wright et al. [reference 3] documenting (-)-F while Carroll et al. [reference
4] reporting (+)-F. Although no commitment was made regarding its
absolute configuration, in Wright’s paper, (-)-leapdin F was drawn as the
enantiomer of the one shown in Figure 1, and we elected to show Carroll’s
drawing of (+)-F.
(13) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23. (c) Coverdale, H. A.; Hsung, R. P. ChemTracts
2003, 16, 238
.
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Org. Lett., Vol. 10, No. 21, 2008

remove the C4-OH group. While the use of “Super Hydride”
[LiBEt3H] and Red-Al was not successful, an excess amount
of Et3SiH in the presence of 10-12 equiv of TFA19 led to
alcohol 6 in 95% yield. Removal of the chiral auxiliary in 6
was not eventful and could be achieved either directly by
using 1.1 equiv of TFA and 10-15 psi of H2 in the presence
of Pearlman’s catalyst Pd(OH)2/C or sequentially by first
removing the TBS group. It is noteworthy that lowering the
amount of TFA led to incomplete hydrogenation and a low
yield of vinylogous amide 7. When using >25 psi of H2,
over-reduction of 6 at C5 as well as C4a,8a was observed.
Stereochemical assignment of alcohol 6 was achieved
unambiguously using its single-crystal X-ray structure (Fig-
ure 2).
Scheme 3. Difficulties in Hydrogenating the C4a,8a-Olefin
Figure 2. X-ray structure of alcohol 6.
With vinylogous amide 7 in hand, we encountered
difficulties in distinguishing nucleophilicities of the C3-OH
group and the vinylogous amide. Silylation proved to be the
only way to selectively protect the C3-OH group, and a
subsequent trifluoroacetylation afforded the orthogonally
protected vinylogous amide 9 (Scheme 3). However, hydro-
genations of C4a,8a olefin in 9 employing standard conditions
such as Pt/C and Pd/C were not successful with the reduction
of C5 carbonyl being the major identifiable pathway when
using Adam’s catalyst PtO2.
This failure detours our original plan for setting up the
C2,8a-anti relative stereochemistry based on our earlier
work.16b We had anticipated that by analogy to that of 13
(Figure 3), the pseudoaxially oriented N-trifluoroacetyl group
would dictate the stereochemical outcome during the hy-
drogenation of the C4a,8a olefin in 9. On one hand, the
addition of C3-OTBS group in 9 should augment the desired
stereochemical outcome by further shielding the top face of
C4a,8a olefin. However, a close examination of its model
reveals that to be mutually axial while minimizing the gauche
Figure 3. Additional steric impact of the C3-OTBS group.
interaction, the C3-OTBS group also pushes C2-Me group
closer to C8a, thereby shielding the bottom face of the olefin.
Collective observations of over-reduction of the C5-
carbonyl group22 provoked us to explore an alternative route.
As shown in Scheme 4, a high-yielding standard protection
of alcohol 6 with Ac2O gave acetate ester 15. After failing
with Wittig-type olefination,23 a three-step sequence that
features Eschenmoser’s episulfide contraction24,25 led to R,ꢀ-
unsaturated ester 16 exclusively as an E-isomer (assigned
via NOE experiments)21 in 64% overall yield from 15. A
double hydrogenation of C4a,8a and C5,1′ olefins in 16 was
achieved with surprising ease, leading to ester 17 in 91%
(22) Another C5-over-reduction was observed using acetal i in an attempt
to protect the C5 ketone.
(18) Zehnder, L. R.; Wei, L.-L.; Hsung, R. P.; Cole, K. P.; McLaughlin,
M. J.; Shen, H. C.; Sklenicka, H. M.; Wang, J.; Zificsak, C. A. Org. Lett.
2001, 3, 2141.
(19) For related reductions, see: (a) Cole, K. P.; Hsung, R. P.; Yang,
X.-F. Tetrahedron Lett. 2002, 43, 3341. (b) Cole, K. P.; Hsung, R. P.
Tetrahedron Lett. 2002, 43, 8791. (c) Hsung, R. P.; Cole, K. P.; Zehnder,
L. R.; Wang, J.; Wei, L.-L.; Yang, X.-F.; Coverdale, H. A. Tetrahedron
2003, 59, 311.
(23) The use of Ph3PdCHCHO in toluene afforded no desired product.
(24) (a) Shiosaki, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 865. (b) Roth,
M.; Dubs, P.; Go¨tchi, E.; Eschenmoser, A. HelV. Chim. Acta 1971, 54,
(20) This dihydroxylation required a stoichiometric amount of OsO4.
The best conditions are: 1.0 equiv of OsO4, 5.0 equiv of pyridine, CH2Cl2,
rt and then workup with mannitol/10% aq KOH at rt for 48 h.
(21) See the Supporting Information.
710
.
(25) Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett. 1995,
36, 3715
.
Org. Lett., Vol. 10, No. 21, 2008
4993

Scheme 4
.
Homologation of a Vinylogous Amide Motif
Scheme 5. Total Synthesis of (+)-Lepadin F
yield as a separable 5:1 mixture of diastereomers with respect
to the C5 stereochemistry.
The anti relative stereochemistry at C2,8a as well as the
all-cis relationship at C8a,4a,5 in 17 was confirmed using
NOE experiments,21 and these stereochemical outcomes are
very reasonable judging from the model of 16 (inside the
box in Scheme 4), which was drawn based on the conforma-
tion shown for the X-ray structure of alcohol 6.
Success in executing this alternative plan allowed us to
complete a total synthesis of (+)-lepadin F from ester 17 as
summarized in Scheme 5. Key features are: (1) the reductive
removal of the chiral auxiliary in 17 concomitant with Boc-
protection; (2) inversion of C3-OH group in 18 through a
sequence of Dess-Martin periodinane oxidation and NaBH4-
reduction; (3) capping of the inverted C3-OH in 19 with
TBDPSCl under more forcing conditions to give silyl ether
20; (4) C5-side chain elongation in aldehyde 21 with sulfone
2226 via adopting Julia-Kocienski olefination conditions to
afford alkene 23; and (5) esterification of alcohol 24
employing Yamaguchi conditions. This culminates a total
synthesis of (+)-lepadin F in 20 steps with a 15.2% overall
yield from chiral vinylogous amide 3,
We have described here an enantioselective total synthesis
of (+)-lepadin F that confirms its absolute configuration. The
synthetic sequence features an intermolecular aza-[3 + 3]
annulation, homologation of a vinylogous amide through
Eschenmoser’s episulfide contraction, and a highly stereo-
selective hydrogenation essential for achieving the 1,3-anti
relative stereochemistry at C2 and C8a. Efforts are underway
to construct other lepadin family members.
Acknowledgment. We thank the NIH (NS38049) for
financial support.
It is noteworthy that Ma’s work with lepadin D, E, and
H9 as well as Blechert’s recent synthesis of F10 prompted us
to choose sulfone 22 with (S)-configuration at C5′. Spectro-
scopically, our synthetic sample matched those reported by
Carroll4 using C6D6 as the NMR solvent.27,28
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra, characterizations, and X-ray
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(26) For the synthesis of 22, see: (a) D’Souza, L. J.; Sinha, S. C.; Lu,
S.; Keinan, E.; Sinha, S. C. Tetrahedron 2001, 57, 5255. (b) Blackemore,
P. A.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26. (c) Also
see ref 9a.
OL802068Q
(27) When we used K2CO3-pretreated CDCl3 to avoid protonation of
the decahydroquinoline motif, our 13C NMR matched Wright’s data (ref 3)
and the 1H NMR comparison contains some minor variations. See the
Supporting Information.
(28) Our optical rotations matched more closely with Blechert’s numbers
than with those reported by Carroll and Wright. See the Supporting
Information.
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Org. Lett., Vol. 10, No. 21, 2008