Total synthesis of the marine alkaloid (-)-lepadin B.

Article abstract of DOI:10.1021/ol000153r

An enantioselective total synthesis of (-)-lepadin B has been developed starting from (2S,4S)-2,4-O-benzylidene-2, 4-dihydroxybutanal. The key steps in the synthesis include the use of an aqueous intramolecular acylnitroso Diels-Alder reaction to afford t

Full text of DOI:10.1021/ol000153r

ORGANIC
LETTERS
2000
Vol. 2, No. 19
2955-2958
Total Synthesis of the Marine Alkaloid
(−)-Lepadin B
Tetsuji Ozawa, Sakae Aoyagi, and Chihiro Kibayashi*
School of Pharmacy, Tokyo UniVersity of Pharmacy & Life Scienc,
Horinouchi, Hachioji, Tokyo 192-0392, Japan
kibayasi@ps.toyaku.ac.jp
Received June 12, 2000
ABSTRACT
An enantioselective total synthesis of (−)-lepadin B has been developed starting from (2S,4S)-2,4-O-benzylidene-2,4-dihydroxybutanal. The key
steps in the synthesis include the use of an aqueous intramolecular acylnitroso Diels−Alder reaction to afford the trans-1,2-oxazinolactam and
Suzuki cross-coupling reaction to elaborate the (E,E)-octadienyl unit.
Lepadin A (1) was first isolated in 1991 from the tunicate
ClaVelina lepadiformis collected in the North Sea1 and
represents the first example of a decahydroquinoline alkaloid
from a marine natural source. Subsequently, the very closely
related compounds, lepadins B (2) and C (3), along with
(-)-lepadin B that features the use of an intramolecular
hetero-Diels-Alder reaction of an N-acylnitroso compound.4
We have recently demonstrated5 the utility of enantiopure
2,4-O-benzylidene-2,4-dihydroxybutanal (4) as a C4 chiral
synthon for the total synthesis of several natural products
based on the acylnitroso Diels-Alder approach. We thus
planned to employ (2S)-configured 4, conveniently available
on a large scale from L-malic acid,6 as the simple starting
material for the synthesis of the natural enantiomer of lepadin
B (2). Thus, the synthesis began with a Horner-Emmons
reaction of 4 to give a 20:1 E/Z mixture of the corresponding
unsaturated esters (86% combined yield), wherein no epimer-
ization at the C2 chiral center was detected (Scheme 1).7
The major E-isomer 5 was subjected to DIBALH reduction
lepadin A, have been found in the flatworm Prostheceraeus
Villatus and its tunicate prey C. lepadiformis.2 Both lepadins
A (1) and B (2) have been shown to exhibit significant in
vitro cytotoxicity against human cancer cell lines.2 Quite
recently, the first total synthesis of 2 has been reported, which
confirmed its absolute configuration as shown.3 Herein, we
report an enantioselective strategy for the total synthesis of
(3) (a) Toyooka, N.; Okumura, M.; Takahata, H. J. Org. Chem. 1999,
64, 2182-2183. (b) Toyooka, N.; Okumura, M.; Takahata, H.; Nemoto,
H, Tetrahedron 1999, 55, 10673-10684.
(4) For applications of intramolecular acylnitroso-Diels-Alder reaction
to natural products synthesis from our laboratory, see: Kibayashi, C.;
Aoyagi, S. Synlett 1995, 873-879.
(5) (a) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59,
1358-1364. (b) Naruse, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
1994, 35, 9213-9216. (c) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem.
Soc., Perkin Trans. 1 1996, 1113-1124.
(6) Corcoran, R. C. Tetrahedron Lett. 1990, 31, 2101-2104. (b) Thiam,
M.; Slassi, A.; Chastrette, F.; Amouroux, R. Synth. Commun. 1992, 22,
83-95.
(1) Steffan, B. Tetrahedron 1991, 47, 8729-8732.
(2) Kubanek, J.; Williams, D. E.; de Silva. E. D.; Allen, T.; Andersen,
R. J. Tetrahedron Lett. 1995, 36, 6189-6192.
10.1021/ol000153r CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

the treatment with Pr4NIO4 at 0 °C in water-DMF (50:1)
the hydroxamic acid 11 underwent cycloaddition via the in
situ generated acylnitroso compound 12, yielding the trans
(with respect to C4a and C5) cycloadduct 13 as a major
isomer with a significantly increased diastereoselectivity of
6.6:1 compared with the reaction conducted in a chloroform
solution which afforded a 1.7:1 trans/cis ratio.
Scheme 1a
Catalytic hydrogenation (Pd-C, THF) of the olefin moiety
of the trans-cycloadduct 13 gave 15 (Scheme 2). The Davis
Scheme 2a
a Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, NaH, THF,
-20 °C to rt; (b) (i) DIBALH, THF, rt; (ii) MnO2, CH2Cl2; (c)
Ph3P+(CH2)3OHI-, LiHMDS, THF, 0 °C to rt; (d) MOMCl,
i-Pr2NEt, CH2Cl2; (e) DIBALH, CH2Cl2; (f) TsCl, DMAP, Et3N,
CH2Cl2; (g) NaCN, DMSO, 50 °C; (h) NaOH, MeOH-H2O, reflux;
(i) CH2N2, Et2O; (j) NH2OH‚HCl, KOH, MeOH, 0 °C; (k) Pr4NIO4,
H2O-DMF (50:1), 0 °C.
followed by MnO2 oxidation of the resultant alcohol to afford
the aldehyde 6 in 82% overall yield. Subsequent Wittig
olefination of 6 with Ph3PdCH(CH2)2OLi8 yielded the de-
sired (3E,5E)-diene 7 in 69% yield along with a small amount
(9%) of the (3Z,5E)-isomer. Protection of 7 as its MOM ether
followed by reductive ring opening of the benzylidene acetal
with DIBALH produced the (E,E)-4,6-nonadienol 9. Conver-
sion of 9 to 10 was straightforward. Thus, tosylation,
displacement by cyanide, alkaline hydrolysis, and then
diazomethane esterification afforded 10 in 70% overall yield
(four steps). Compound 10 was then transformed to the
hydroxamic acid 11 (80%) by treatment with hydroxylamine
under alkaline conditions. In our earlier study, use of aqueous
media for intramolecular Diels-Alder reaction of the acyl-
nitroso compounds effected significant enhancement of the
trans selectivity compared with the reaction under non-
aqueous conditions.9 Consistent with these observations, on
a Reagents and conditions: (a) H2, Pd-C, THF; (b) LiHMDS,
(+)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine, THF, -78 °C;
(c) TBDPSCl, imidazole, DMF; (d) MeMgBr, THF, 0 °C, then
NaBH3CN, AcOH, THF, 0 °C; (e) Zn, 90% AcOH, 60 °C; (f)
PhCOCl, then 5% KOH; (g) CS2, NaH, imidazole, then MeI, THF;
(h) Bu3SnH, AIBN, benzene, reflux; (i) PPTS, t-BuOH, reflux; (j)
H2, Pd(OH)2, MeOH; (k) (COCl)2, DMSO, Et3N, -78 f 0 °C; (l)
piperidine (0.2 equiv), AcOH (0.2 equiv), benzene, reflux; (m) (i)
PDC, DMF; (ii) CH2N2, Et2O; (n) SOCl2, Et3N.
methodology10 was then exploited to introduce a hydroxyl
group into the C7 position of 15 to form 16. Oxidation of
the sodium enolate (NaHMDS, THF, -78 °C) of 15 with
(()-2-(phenylsulfonyl)-3-phenyloxaziridine11 followed by
protection of the resultant hydroxyl group as the tert-
butyldiphenylsilyl (TBDPS) ether afforded the oxygenated
product in 86% yield but with a very low diastereoselectivity
of 1.1:1 in favor of the requisite (7S)-isomer 17. With the
(7) The reason no epimerization occurs in the Wittig reaction of the (2R)-
enantiomer of 4 has been discussed in a previous publication (ref 5a).
(8) Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J. Am. Chem.
Soc. 1985, 107, 217-226.
2956
Org. Lett., Vol. 2, No. 19, 2000

oxidation of the lithium enolate (LiHMDS, THF, -78 °C)
of 15 using (+)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine,12
constituting a matched pair, subsequent silyl protection gave
rise to 17 (78%) with remarkable increase in the diastereo-
selectivity (17:1). The next step required a stereoselective
introduction of the methyl group into C8. This was smoothly
accomplished by the tandem Grignard reaction-reduction
procedure developed earlier in these laboratories.13 Thus,
when 17 was allowed to react with methylmagnesium
bromide followed by NaBH3CN in acidic medium (AcOH),
reduction of the intermediary iminium ion 18 proceeded with
steric and stereoelectronic controls to afford 19 as a single
diastereomer (82% overall yield from 17). Reductive cleav-
age of the N-O bond of 19 (Zn, AcOH) followed by
N-benzoylation of the resulting amino alcohol gave 20, which
was converted to the S-methyl dithiocarbonate 21 and
subjected to a four-step sequence of reactions, involving
deoxygenation with tributyltin hydride,14 acidic removal of
the methoxymethyl group, hydrogenolysis of the benzyl
group, and Swern oxidation, to provide the keto aldehyde
22 (66% overall yield from 21). Intramolecular aldol reaction
conditions (KOH, MeOH, 0 °C) led to the desired product
23 but in very low yield (10%) accompanied by complex
side reactions. However, the use of a catalytic amount of
piperidine and acetic acid in refluxing benzene resulted in a
clear reaction to form 23 in much improved yield (87%) as
a single diastereomer. After several failed attempts at
dehydration of the aldehyde 23, 23 was converted to the ester
24 (PDC, then CH2N2), which smoothly underwent dehydra-
tion with SOCl2 and Et3N to form the octahydroquinoline
25 (84%).
27 to 26 can be interpreted in terms of more thermodynami-
cally stable 26A, in which the methoxycarbonyl group orients
axial to avoid an allylic strain.
With compound 26 in hand, it was converted to the amino
alcohol 28 (87%) through silylation followed by LiAlH4
reduction of the methoxycarbonyl and N-benzoyl groups
(Scheme 4). Catalytic hydrogenation of 28 (5 atm H2, Pd-
Scheme 4a
Exposure of 25 to Bu4NF at room temperature caused
cleavage of the TBDPS ether and epimerization at the labile
C5 stereocenter under the reaction conditions to give a 2:1
chromatographically separable mixture of the 5â- and the
5R-esters 26 and 27 in favor of 26 in 87% total yield (Scheme
3). The 5R-isomer 27 with undesired C5 chirality could be
a Reagents and conditions: (a) TBDMSCl, imidazole, DMF; (b)
LiAlH4, THF, reflux; (c) (i) H2 (5 atm), Pd-C, THF; (ii) (Boc)2O,
CH2Cl2; (d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 f 0 °C; (e) CHI3,
CrCl2, THF; (f) (E)-1-hexenyldihydroxyborane, Pd(PPh3)4 (5 mol
%), 2 M aqueous KOH, THF, 50 °C; (g) Bu4NF, THF, then
CF3CO2H, CH2Cl2.
Scheme 3
C, THF) resulted in exclusive formation of the decahydro-
quinoline 29 with the cis ring juncture in 85% yield after
N-Boc protection. The stereochemical outcome in this case
implies hydroxyl-directed hydrogenation15 wherein the sub-
strate is bound to the catalyst surface on the same side as
(9) Naruse, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994, 35,
595-598. See also refs 5b and 5c.
(10) Reviews: (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45,
5703-5742. (b) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919-
934.
(11) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774-1775.
(12) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R. T.; Chen,
B.-C. J. Org. Chem. 1992, 57, 7274-7285.
(13) (a) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Am. Chem. Soc. 1985,
107, 5534-5535. (b) Watanabe, Y.; Iida, H. Kibayashi, C. J. Org. Chem.
1989, 54, 4088-4097. (c) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992,
57, 2876-2883. See also ref 5c.
converted to a 2:1 equilibrium mixture of 26 and 27 by
treatment under the same conditions (Bu4NF, THF, rt, 5 d);
in this manner, the conversion of 25 into required 26 could
be increased to 75% yield. The observed epimerization of
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585.
(15) For a comprehensive review on heteroatom-directed organic reaction,
see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-
1370.
Org. Lett., Vol. 2, No. 19, 2000
2957

the hydroxyl group, resulting in the addition of hydrogen
syn to the coordinating moiety. After Swern oxidation, the
resultant aldehyde 30 was subjected to Takai olefination16
with CHI3 and CrCl2 in THF as a single geometric isomer
to form the (E)-alkenyl iodide 31 (79% yield from 29).
Subsequent elaboration of the octadienyl side chain was
achieved by palladium-catalyzed Suzuki cross-coupling17
with (E)-hexenyldihydroxyborane (Pd(PPh3)4, aqueous KOH,
THF, 50 °C), affording 32 in 77% yield. The final depro-
tection of the silyl and N-Boc groups provided (-)-lepadin
B (2), whose trifluoroacetate salt was obtained in a crystalline
NMR) in full agreement with those of the trifluoroacetate
of natural 2.
In summary, the enantioselective synthesis of (-)-lepadin
B has been achieved through the exploitation of an intra-
molecular acylnitroso Diels-Alder reaction. Application of
this methodology to the synthesis of other members of this
family of natural alkaloids is underway and will be reported
in due course.
Acknowledgment. We are grateful to Professor R. J.
Andersen for providing authentic spectra of 1H and 13C NMR
of the trifluoroacetate salt of natural lepadin B.
form,18 mp 212-214 °C (CHCl3-hexane); [R]28 -67.4 (c
D
0.25, MeOH). This showed spectral properties (1H and 13C
OL000153R
(16) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
(17) For a recent review, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457-2483.
(18) The trifluoroacetate salt of 2 has been reported2 as an oil having
[R]D -96 (MeOH).
2958
Org. Lett., Vol. 2, No. 19, 2000