Facile entry to substituted decahydroquinoline alkaloids. Total synthesis of lepadins A-E and H

Article abstract of DOI:10.1021/jo061070c

Condensation of a L-alanine derived δ-bromo-β-silyloxy- propylamine with 1,3-cyclohexadione followed by alkylative cyclization produces a bicyclic enone. Diastereoselective Pt/C-catalyzed hydrogenation of this enone in HOAc provides a 5-oxo-cis-fused decahydroquinoline. Wittig olefination of this decahydroquinoline and subsequent epimerization of the resulting 5-formyl intermediate gives rise to a 5-β-formyl decahydroquinoline exclusively. In a parallel procedure, Peterson reaction of this decahydroquinoline and subsequent hydrogenation of the generated 5-exo-olefin provides a decahydroquinoline with a 5-α-substituent predominantly. For these two diastereoselective processes, using the intermediates without N-protection as the substrates is essential because the corresponding N-Boc intermediates give poor diastereoselectivity. The intermediate with β-form side chain is further converted into lepadins A-C via carbon chain elongation, while the intermediate with α-form side chain is transformed into lepadins D, E, and H and corresponding 5′-epimers via connection with two sulfones generated from two Sharpless epoxidation products. By comparison of the rotations and NMR data, the stereochemistry of lepadins D, E, and H is assigned as 2S,3R,4aS,5S,8aR,5′R.

Full text of DOI:10.1021/jo061070c

Facile Entry to Substituted Decahydroquinoline Alkaloids. Total
Synthesis of Lepadins A-E and H
Xiaotao Pu 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@mail.sioc.ac.cn
ReceiVed May 25, 2006
Condensation of a L-alanine derived δ-bromo-â-silyloxy-propylamine with 1,3-cyclohexadione followed
by alkylative cyclization produces a bicyclic enone. Diastereoselective Pt/C-catalyzed hydrogenation of
this enone in HOAc provides a 5-oxo-cis-fused decahydroquinoline. Wittig olefination of this
decahydroquinoline and subsequent epimerization of the resulting 5-formyl intermediate gives rise to a
5-â-formyl decahydroquinoline exclusively. In a parallel procedure, Peterson reaction of this decahy-
droquinoline and subsequent hydrogenation of the generated 5-exo-olefin provides a decahydroquinoline
with a 5-R-substituent predominantly. For these two diastereoselective processes, using the intermediates
without N-protection as the substrates is essential because the corresponding N-Boc intermediates give
poor diastereoselectivity. The intermediate with â-form side chain is further converted into lepadins A-C
via carbon chain elongation, while the intermediate with R-form side chain is transformed into lepadins
D, E, and H and corresponding 5′-epimers via connection with two sulfones generated from two Sharpless
epoxidation products. By comparison of the rotations and NMR data, the stereochemistry of lepadins D,
E, and H is assigned as 2S,3R,4aS,5S,8aR,5′R.
Introduction
Sea.4 Four years later, from the same species and other sources,
lepadins B (1b) and C (1c) were isolated.5 These compounds
have been found to possess significant in vitro cytotoxicity
against several human cancer cell lines.5 Recently, two groups
independently discovered the other members of lepadin family.
Lepadins D-F were isolated by Wright and co-workers from a
new Didemnum species collected from the Great Barrier Reef,6
while lepadins F-H were found by Carroll and co-workers from
Aplidium tabascum Kott.7 The major structural difference of
these new members with lepadins A-C is the substituents and
their stereochemistry at the 5-position. These disparities could
influence their biological activities, as preliminary biological
studies revealed that lepadins D-F had low cytotoxicity but
significant and selective antiplasmodinium and antitrypanosomal
Lepadins belong to an increasing alkaloid family with over
60 members that contain a decahydroquinoline moiety with
either cis or trans configuration. The first member of this family
named pumiliotoxin C, was isolated from skin extracts of the
Panamanian poison-frog Dendrobates pumilio in 1969.1 Since
then about 50 2,5-disubstituted decahydroquinolines have been
isolated from similar species.2 Their interesting structures and
biological activities have attracted numerous synthetic efforts
during the past decades.3 In 1991, Steffan reported the discovery
of lepadin A (1a) (Figure 1), a 2,3,5-trisubstituted decahydro-
quinoline, from the tunicate ClaVelina lepadiformis in the North
(1) Daly, J. W.; Tokuyama, T.; Habermehl, G.; Karle, I. L.; Witkop, B.
Liebigs Ann. Chem. 1969, 729, 198.
(2) For a review, see Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat.
Prod. 2005, 68, 1556.
(3) For selected examples, see the following: (a) Sklenicka, H. M,;
Hsung, R. P.; McLaughlin, M. J.; Wei, L.; Gerasyuto, A. I.; Brennessel,
W. B. J. Am. Chem. Soc. 2002, 124, 10435. (b) Weymann, M.; Schultz-
Kukula, M.; Kunz, H. Tetrahedron Lett. 1998, 39, 7835. (c) Naruse, M.;
Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1994, 35, 9213.
(4) Steffan, B. Tetrahedron 1991, 47, 8729.
(5) Kubanek, J.; Williams, D. E.; de Silva, E. D.; Allen, T.; Anderson,
R. J. Tetrahedron Lett. 1995, 36, 6189.
(6) Wright, A. D.; Goclik, E.; Ko¨nig, G. M.; Kaminsky, R. J. Med. Chem.
2002, 45, 3067.
(7) Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65,
454.
10.1021/jo061070c CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/20/2006
6562
J. Org. Chem. 2006, 71, 6562-6572

Total Synthesis of Lepadins A-E and H
FIGURE 2. Retrosynthetic analysis of lepadins.
SCHEME 1
FIGURE 1. Structures of lepadins A-H.
activity.6 These findings suggested that these compounds might
serve as new lead structures for the development of novel
antimalarial drugs. In addition, a recent report revealed that
lepadin B could block neuronal nicotinic acetylcholine receptors
with IC50 values of 0.7-0.9 µM.8 However, further pharma-
cological research on these alkaloids is hampered by lack of
materials. Consequently a facile route to these alkaloids or their
analogues is highly required.
demonstrated their attempts13 to lepadins by aminocyclization
of 2-(3-aminoalkyl)cyclohexenones. Herein we wish to describe
that most of the lepadins could be assembled through intermedi-
ate 7 via stereoselective introduction of both R- and â-form side
chains into its C5 position. The preparation of the ketone 7 could
be accomplished by condensation of an amine liberated from
bromide 8 with 1,3-cyclohexadione and subsequent alkylative
cyclization. Together with the total syntheses of lepadins D, E
and H, their stereochemistry was fully established.
Prior to our synthetic studies,9 three groups had disclosed
their efforts toward the assembly of lepadins A-C. The first
total synthesis of lepadin B was achieved by Toyooka group,10
in which an intramolecular aldol type of cyclization of the
piperidine derivative 4 was used as the key step (Figure 2). On
the basis of stereocontrolled intramolecular acylnitroso-Diels-
Alder reaction of 6, Kibayashi and co-workers developed
another protocol to lepadin B and elaborated lepadins A and C
first.11 The common feature of these two routes is using
intramolecular aldol reaction (from 4 or 5) to build the left
cyclohexane ring, which required lengthy reaction sequences
and therefore greatly reduced the synthetic efficiency. In 2002,
Zard described a short formal route to racemic lepadin B,12 but
many more steps would obviously be necessary if applied to
enantioselective synthesis. Quite recently, Bonjoch and Mena
Results and Discussion
As outlined in Scheme 1, our synthesis started from ketone
9, a known intermediate prepared from L-alanine.14 Reduction
of 9 with NaBH4 in ethanol at -78 °C followed by protection
of the resultant alcohol with TBSCl afforded the bromide 8 in
80% yield. Removal of Boc-protecting group in 8 with formic
acid produced amine 10 as a formic acid salt. Initially,
condensation of this salt with 1,3-cyclohexadione was attempted.
However, this reaction only worked in refluxed toluene, giving
the desired product 11 in about 10% yield. After some
experimentation, we found that reaction of a free amine
generated from 10 with 1,3-cyclohexandione proceeded well
to afford 11 in 65-75% yields. Noteworthy is that attempts to
(8) Tsuneki, H.; You, Y.; Toyooka, N.; Sasaoka, T.; Nemoto, H.; Dani,
J. A.; Kimura, I. Biol. Pharm. Bull. 2005, 28, 611.
(9) Part of the result has been reported as a communication, see Pu, X.;
Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222.
(10) (a) Toyooka, N.; Okumura, M.; Takahatam, H. J. Org. Chem. 1999,
64, 2182. (b) Toyooka, N.; Okumura, M.; Takahatam, H.; Nemoto, H.
Tetrahedron 1999, 55, 10673.
(11) (a) Ozawa, T.; Aoyagi, S.; Kobayashi, C. Org. Lett. 2000, 2, 2955.
(b) Ozawa, T.; Aoyagi, S.; Kobayashi, C. J. Org. Chem. 2001, 66, 3338.
(12) Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002, 1430.
(13) Mena, M.; Bonjoch, J. Tetrahedron 2005, 61, 8264.
(14) Rotella, P. D. Tetrahedron Lett. 1995, 36, 5453.
J. Org. Chem, Vol. 71, No. 17, 2006 6563

Pu and Ma
SCHEME 2
SCHEME 3
18 exclusively. As we expected, after cleavage of the Boc group
in 17 with TFA selectively, and subsequent treatment with K2-
CO3 in methanol, aldehyde 18 was isolated as a single isomer.
obtain 11 via reacting 10 with vinyl chloride 12a or vinyl
mesylate 12b failed because of no reaction or isolation of
sulfonamide 13.15
Alkylative cyclization of 13 was accomplished at 110 °C in
DMF under the action of triethylamine and sodium iodide to
produce enone 14 in 98% yield (Scheme 2). Adding sodium
iodide to this reaction system was important for excellent yield,
as only 67% yield was observed in the absence of sodium iodide.
The next planned step was diastereoselective hydrogenation of
the C-C double bond of 14. On the basis of our previous
observation16 we envisaged that a stereoelectronic controlled
axial addition of hydrogen would occur from the Re face of the
more stable conformation A, thereby giving the desired C-4a
and C-8a stereochemistry for synthesizing lepadins A-E and
H. This step was challenging as evidenced from that no reaction
occurred using PtO2, Rh/C, and Rh/Al2O3 as the catalysts, and
only 23% conversion was obtained in the presence of Pt/Al2O3.
Fortunately, when this reaction was conducted under the
catalysis of Pt/C in dry acetic acid at 80 atm and 50 °C,
hydrogenated product 15 was isolated in 85% yield as a single
isomer. Next, protection of 15 with (Boc)2O and subsequent
Dess-Martin oxidation provided the designed intermediate 7.
After NOESY studies of 7, we were gratified to notice that it
has an expected (4aR,8aR)-configuration.
FIGURE 3. Conformation analysis of aldehydes 17 and 18.
The assembly of lepadins A and B was depicted in Scheme
4. Initially, extension of the C-1′ to C-8′ from the aldehyde 18
was attempted by employing the Kocienski-Julia coupling
reaction.19 Although there have appeared several reports that
(E,E)-dienes were exclusively obtained when allyl substituted
PT-sulfones were used,20 we found that reaction of PT-sulfone
19 with the aldehyde 18 gave only (E,Z)-diene 20 in 90% yield.
The reason for this stereoselectivity is unclear yet. At this stage
we moved our attention to the Emmons-Wadsworth-Honer
reaction.21 To our delight, coupling of 18 with an anion
generated from phosphonate 21 produced the desired E,E-diene
22 in greater than 95% selectivity. The remaining task now for
finishing the synthesis was inversion of the C-3 stereocenter.
We decided to perform it via an oxidation/reduction strategy.
As a result, protection of 22 with (Boc)2O, cleavage of the silyl
ether with TBAF, and subsequent Dess-Martin oxidation
yielded ketone 23. Reduction of 23 with NaBH4 gave the
corresponding alcohol as a single diastereomer, which was
treated with TFA to furnish lepadin B as its TFA salt. In a
parallel procedure, the alcohol that resulted from 23 was
esterified with TBS-protected 2-hydroxyacetic acid to furnish
lepadin A, after deprotection with boron trifluoride diethyl
etherate.
With the ketone 7 in hand, we next tried to install suitable
â-form side chains at its C-5, which were required for
assembling lepadins A-C (Scheme 3). Accordingly, olefination
of 7 via a Wittig reaction provided enol ether 16, which was
selectively hydrolyzed with trichloroacetic acid in methylene
1
chloride containing trace water to give aldehyde 17.17 By H
NMR determination it was found that there existed inseparable
diastereomers in a ratio of 1:1.3. Treatment of this mixture with
K2CO3 in methanol did not give an enhanced ratio (1:1.5), which
indicated that two isomers might have similar stability by taking
the conformations B and C respectively (Figure 3). At this stage
we considered to remove the N-Boc group in 17 to get aldehyde
18. On the basis of Booth’s studies,18 we realized that the
favored conformations would be D and E for 18 and its
5-epimer. The stronger 1,5-strain displayed in E would make
conformer D more stable, thereby affording â-form aldehyde
(19) For a review, see Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1
2002, 2563.
(20) (a) Williams, D. R.; Cortez, G. S.; Bogen, S. L.; Rojas, C. M. Angew.
Chem., Int. Ed. 2000, 39, 4612. (b) Shimizu, T.; Masuda, T.; Hiramoto,
K.; Nakata, T. Org. Lett. 2000, 2, 2153. (c) Takano, D.; Nagamitsu, T.; Ui,
H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.; Kuwajima, I.; Omura, S. Org.
Lett. 2001, 3, 2289.
(21) For recent examples, see (a) Trost, B. M.; Gunzner, J. L.; Dirat,
O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396. (b) Boeckman, R.
K., Jr.; Weinder, C. H.; Perni, R. B.; Napier, J. J. J. Am. Chem. Soc. 1989,
111, 8036.
(15) (a) Kowalski, C. J.; Fields, K. W. J. Org. Chem. 1981, 46, 197. (b)
Clark, R. D.; Heathcock, C. H. Synthesis 1974, 47.
(16) Pu, X.; Ma, D. J. Org. Chem. 2003, 68, 4400.
(17) Harrington, P. E.; Stergiades, I. A.; Erickson, J.; Makriyannis, A.;
Tius, M. A. J. Org. Chem. 2000, 65, 6576.
(18) (a) Booth, H.; Bostock, A. H. J. Chem. Soc., Perkin Trans. 2 1972,
615. (b) Booth, H.; Griffiths, D. V. J. Chem. Soc., Perkin Trans. 2 1975,
111.
6564 J. Org. Chem., Vol. 71, No. 17, 2006

Total Synthesis of Lepadins A-E and H
SCHEME 4
SCHEME 5
SCHEME 6
For synthesis of lepadin C, a phosphonate with a functional
group at its C-6′ position should be prepared. As shown in
Scheme 5, commercial available 6-methyl-5-hepten-2-one was
selected for this purpose. After protection of this ketone with
1,2-ethanediol to afford 24, ozonolysis of the C-C double bond
was conducted to give an aldehyde, which was subjected to
Wittig olefination to deliver ester 25. Reduction of 25 with
DIBAL-H and subsequent bromination with CBr4/PPh3 provided
an allyl bromide, which was reacted with triethyl phosphite to
give the desired phosphonate 26. Next, treatment of 26 with
KHMDS followed by trapping the resultant anion with the
aldehyde 18 produced diene 27 in 92% yield. Protection of 27
with (Boc)2O and then cleavage of the silyl ether provided
alcohol 28. Finally, inversion of the C-3 stereochemistry via
oxidation/reduction afforded alcohol 29 in 90% yield, which
was connected with TBS-protected 2-hydroxyacetic acid, and
then treated with boron trifluoride diethyl etherate, to furnish
lepadin C in 74% yield.
After success in elaboration of lepadins A-C, we next
explored synthesizing lepadins D, E, and H from the intermedi-
ate 7. The first task for us was to introduce the R-form side
chain into C-5 of the ketone 7. We planned to reach this goal
via a stereoselective hydrogenation of an exo-alkene derived
from 7. Obviously, Wittig olefination of 7 with 31, a phospho-
nium salt prepared from homoallyl alcohol 30 in four steps,
was quite attractive because it would give the desired molecules
in a very convergent manner. As a result, reaction of 31 with 7
mediated with n-BuLi was conducted. However, no olefination
products were isolated under various reaction conditions (Scheme
6). Considering that the enol ether 16 had been obtained via a
similar Wittig reaction, we thought that the ylide generated from
31 might be too hindered to attack the ketone 7, and therefore
other olefination methods were attempted. To our delight, when
the Peterson reaction22 was employed, the desired olefin 33 was
isolated as a mixture of E- and Z-isomers in 98% yield (Scheme
7). Direct Pt/C-catalyzed hydrogenation of 33 in dry acetic acid
gave a diastereomer mixture 34 in a ratio of 3:1. Switch of the
catalyst to Pd/C, Rh/C, and Raney-Ni or changing solvents could
not enhance the ratio greatly. However, we were pleased to
observe that hydrogenation of 35, a derivative of 33 without
the N-Boc group, produced 36 in a highly diastereoselective
manner (>95% de). By X-ray crystal studies of 37, a tosylation
product of 17, we confirmed that the side chain at C-5 was in
the R-form.
The above two stereochemical courses might be rationalized
as that different steric hindrances, met by hydride, attack in
two favored conformations F and G as depicted in Figure 4.
When X was Boc, the preferred conformer might be F because
there existed larger steric interaction between the Boc group
and two equatorial groups at the 2 and 8a positions in conformer
(22) Shimoji, K.; Taguchi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1974, 96, 1620.
J. Org. Chem, Vol. 71, No. 17, 2006 6565

Pu and Ma
SCHEME 8
FIGURE 4. Stereochemical course for hydrogenation of olefins 33
and 35.
SCHEME 7
SCHEME 9
G. The steric difference for both Re or Si faces of the olefin
moiety in conformer F might be limited and thereby give a
mixture of 34-R and 34-â. In contrast, the steric hindrance of
the Re face of the olefin moiety in conformer G was larger
than that of the Si face. Thus, exclusive formation of 36 was
observed.
To elongate the side chain of 36 to finish the synthesis of
lepadins D, E, and H, both (R)- and (S)-sulfones 40 were
prepared, which provided a chance to establish the C-5′
stereochemistry of these natural products. The reaction sequence
for this preparation was shown in Scheme 8. By tuning the chiral
ligands in Sharpless epoxidation, both (R)- and (S)-diols 38 were
obtained. Selective protection of the primary hydroxy group in
38 with TBDPSCl and subsequent treatment with MOMCl
afforded a silyl ether, which was deprotected with TBAF, and
then subjected to Mitsunobu reaction with BTSH to give
thioethers 39.23 Oxidation of 39 with mCPBA produced 40 in
85% yield.
SCHEME 10
The completion of lepadins D, E, and H was depicted in
Scheme 9. Protection of 36 with (Boc)2O followed by reduction
with DIBAL afforded alcohol 41, which was oxidized to
aldehyde, coupled with sulfones 40, and hydrogenated over Pd/C
to produce decahydroquinolines 42a and 42b. After deprotection
of the silyl ethers 42a and 42b with TBAF, alcohols 42c and
42d were isolated, which were further treated with HCl to afford
2a and its 5′-epimer 43, respectively. Moreover, acylation of
42c and 42d with 2-(E)-octenoic acid (Cl3C6H2COCl/i-PrNEt2)24
(23) (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.
6566 J. Org. Chem., Vol. 71, No. 17, 2006

Total Synthesis of Lepadins A-E and H
or (2E,4E)-octadienoic acid (EDC/DMAP),25 and followed by
deprotection with TFA furnished 2b, 44, 2c, and 45, respec-
tively. Noteworthy is that when esterification of 42c was
conducted with 2-(E)-octenoic acid in the presence of EDC and
DMAP, migration of C-C double bond occurred to give a
mixture of R,â-unsaturated ester 46 and â,γ-unsaturated ester
47. The formation of 47 might go through a vinylketene
intermediate derived from 2-(E)-octenoic acid. Similar unex-
pected isomerization was also noticed by Danishefsky and co-
workers during the synthesis of migrastatin.26 We solved this
problem by using the Yamaguchi procedure.24 However, the
sequence for adding reagents was essential as no migration took
place only when DMAP was introduced after alcohol.
a Dean-Stark dehydration trap. The mixture was heated to gently
reflux for about 4 h and then cooled to room temperature. After
saturated sodium bicarbonate solution was added, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and evapo-
rated in vacuo to give yellow-orange oil, which was purified via
chromatography, eluting with 1:1:0.02 ethyl acetate/petroleum ether/
MeOH to afford 2.4 g (65%) of 10. [R]17D +2.7 (c 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3, amide rotamer): δ -0.11 (s, 3H), -0.03
(s, 3H), 0.91 (s, 9H), 1.12 (d, J ) 6.3 Hz, 3H), 1.90 (m, 2H) 2.3
(m, J ) 6.3, 7.2 Hz, 4H), 3.10 and 3.31 (dd, J ) 4.8, 10.5 Hz, 2H
in 3:1 ratio), 3.75 and 3.89 (dt, J ) 2.5, 5.1 Hz, 1H in 3:1 ratio)
3.99 (dq, J ) 2.7, 6.2 Hz, 1H), 4.61 (bd, J ) 6.9 Hz, 1H), 5.15
and 5.18 (s, 1H in 3:1 ratio). 13C NMR (75 MHz, CDCl3, amide
rotamer): δ -4.0, -4.7, 12.4, 12.1, 18.0, 21.9, 25.8, 32.6, 36.4,
44.2, 48.9, 49.1, 71.6, 72.0, 97.2, 162.5, 197.4. IR (neat): 3269,
1604 cm-1. ESI-MS: m/z 376 (M + H)+. ESI-HRMS calcd for
C16H30NO2BrSi (M + H)+: requires, 376.1295; found, 376.1301.
Although both NMR spectra and optical rotation for 2a and
43, 2b and 44, or 2c and 45 were very close, marked difference
1
of 2c and 45 in H NMR at δ 1.2-1.5 clearly showed that 2c
but not 45 had all-identical data with those reported for lepadin
Alkylative Cyclization of 10. To a solution of compound 10
(1.22 g, 3.2 mmol) in anhydrous DMF (degassed) was added NaI
(2.44 g, 16 mmol). The resultant mixture was heated under argon
for about 0.5 h at 80 °C before Et3N (0.53 mL, 3.8 mmol) was
slowly added via syringe. The reaction temperature was slowly
raised to 110 °C, and the stirring was continued for about 10 h.
The cooled solution was evaporated under reduced pressure, and
the residue was partitioned between brine and ethyl ether. The
organic layer was separated, and the aqueous layer was extracted
with ethyl ether. The combined organic layers were dried over
MgSO4, and the solvent was removed in vacuo. The residue was
purified via chromatography, eluting with 1:1:0.02 ethyl acetate/
petroleum ether/MeOH to yield 920 mg (98%) of 14. [R]18D -196.8
H. Furthermore, the hydrochloride salt of 2a showed [R]20
)
D
-12 (c 1.0 MeOH), which was close to that reported for
hydrochloride salt of lepadin D ([R]20D ) -14 (c 0.2 MeOH)),
while hydrochloride salt of 43 had relatively big difference in
rotation ([R]20 ) -5.7 (c 0.9 MeOH)). Therefore, we
D
concluded that the absolute configuration for lepadins D, E, and
H was 2S,3R,4aS,5S,8aR,5′R.
In summary, we have developed an efficient and divergent
strategy for access of lepadins together with a concise synthesis
of lepadins A-C and the first total synthesis and establishment
of all stereochemistry of lepadins D, E, and H. The key elements
in this approach included a concise elaboration of the cis fused
decahydroquinoline via condensation of a L-alanine derived
γ-bromo-â-silyloxy-propylamine with 1,3-cyclohexadione and
introducing 5R and 5â side carbon chains via diastereoselective
hydrogenation of a 5-exo-olefine and epimerization of a 5-formyl
intermediate, respectively. The possible stereochemical courses
for the latter two processes were discussed, which should be
valuable for decahydroquinoline chemistry. Noteworthy, for
assembly of lepadins A-C, more than 5% yields were obtained
by using less than 21 linear steps from N-Boc-L-alanine, which
is more efficient when compared with the previous two
protocols.10,11 These results should prompt further studies on
the synthesis and biological testing of these compounds and
their analogues.
1
(c 0.24, CHCl3). H NMR (300 MHz, CDCl3): δ 0.05 (s, 3H),
0.09 (s, 3H), 0.91 (s, 9H), 1.21 (d, J ) 6.6 Hz, 3H), 1.90 (ddd, J
) 6.3, 7.2, 6.0 Hz, 2H), 2.11 (dd, J ) 9.3, 15.6 Hz, 1H), 2.31 (q
like, J ) 6.0, 7.0 Hz, 4H), 2.71 (dd, J ) 7.7, 15.1 Hz, 1H) 3.11
(dq, J ) 6.6, 6.8 Hz, 1H), 3.50 (ddd, J ) 6.4, 8.1, 9.0 Hz, 1H),
4.50 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ -4.8, -4.1, 18.0,
18.9, 21.6, 25.8, 28.8, 28.9, 36.5, 53.4, 70.5, 103.5, 158.2, 194.7.
IR (neat): 3271, 1665, 1571 cm-1. EI-MS: m/z 295 (M+), 280,
238, 222, 164, 146, 115. HRMS calcd for C16H29NO2Si (M+):
requires, 295.1948; found, 295.1929.
(2S,3R,4aS,5S,8aR)-2-Methyl-3-(tert-butyldimethylsilyloxy)-
5-hydroxy-decahydroquinoline 15. A solution of 14 (1.2 g, 4
mmol) in glacial acid (20 mL) was hydrogenated over platinum on
charcoal (5% Pt, 1.2 g) at 50 °C and 80 atm for 12 h. It was then
filtered through Celite, and the filtrate was concentrated and diluted
with saturated aqueous NaHCO3. The aqueous layer was extracted
several times with ethyl acetate, and the combined organic layers
were dried over MgSO4. The solution was concentrated, and the
residue was purified via chromatography, eluting with 10:1 ethyl
Experimental Section
(2S,3R)-3-(2-Cyclohexenon-3-yl)amino-2-(tert-butyldimethyl-
silyloxy)butyl Bromide 10. To an ice-cooled solution of bromide
8 (3.82 g, 10 mmol) in 50 mL of CH2Cl2 was added 50 mL of
formic acid dropwise. After the mixture was warmed to room
temperature and then stirred for about 4 h, the solution was
concentrated in vacuo. The residue was diluted with saturated
sodium bicarbonate solution and then stirred for 5 min. The aqueous
layer was extracted with ethyl acetate, and the combined organic
layers were washed with brine and dried over MgSO4. After removal
of solvent, the residue was dried under vacuum to give crude free
amine.
acetate/MeOH to give 1.0 g (86%) of 15 as a colorless oil. [R]18
D
1
-53.6 (c 1.5, CHCl3). H NMR (300 MHz, CDCl3): δ 0.07 (s,
3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.22 (d, J ) 6.2 Hz, 3H), 1.4 (m,
2H), 1.6 (m, 3H), 1.68 (m, 2H), 1.98 (m, 2H), 2.03 (dd, J ) 5.8,
15.1 Hz, 1H), 2.71 (dq, J ) 3.9, 6.0 Hz, 1H), 3.20 (m, 2H), 3.91
(m, 2H), 4.11 (ddd, J ) 4.2, 5.7, 13.5 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ -4.6, -3.8, 14.4, 18.0, 19.4, 25.9, 31.4, 33.8, 39.1,
39.9, 56.3, 59.5, 71.5, 72.1. IR (neat): 3366, 1712 cm-1. ESI-MS:
m/z 300 (M + H)+. ESI-HRMS calcd for C16H33NO2Si (M + H)+:
requires, 300.2367; found, 300.2353.
(2S,3R,4aS,8aR)-1-(tert-Butyloxycarbonyl)-2-methyl-3-(tert-
butyldimethylsilyloxy)-5-oxo-decahydroquinoline 7. To a solution
of the alcohol 15 (1.0 g, 3.3 mmol) in 20 mL of anhydrous CH3-
CN were sequentially added (Boc)2O (1.33 g, 6.1 mmol) and K2-
CO3 (45 mg, 0.3 mmol). The resultant mixture was heated to gently
reflux under argon for 72 h. After water was added to quench the
reaction, the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
A mixture of the above amine and cyclohexadione (1.6 g, 15
mmol) in 10 mL of benzene was placed in a flask equipped with
(24) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikota, M.; Sakurai, Y.; Horita,
K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
(25) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.; Charette,
A. B.; Lautens, M. Angew. Chem. Int. Ed. Engl. 1998, 37, 2354.
(26) Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc.
2003, 125, 6042.
J. Org. Chem, Vol. 71, No. 17, 2006 6567

Pu and Ma
over MgSO4 and evaporated in vacuo to give a crude carbamate,
which was pure enough to be used for next step.
1.98 (m, 1H), 2.07 (q, J ) 6.6 Hz, 2H), 2.41 (m, J ) 2.4, 11.8 Hz,
1H), 2.42 (br s, 1H), 2.56 (dq, J ) 2.7, 6.0 Hz, 1H), 3.01 (br d, J
) 1.1 Hz, 1H), 3.28 (ddd, J ) 4.5, 6.0, 6.7 Hz, 1H), 5.26 (dd, J )
9.1, 14.1 Hz, 1H), 5.54 (dt, J ) 6.6, 14.2 Hz, 1H), 5.96 (dd, J )
7.2, 15.0 Hz, 1H), 6.02 (dd, J ) 5.4, 14.7 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ -4.8, -4.2, 13.8, 17.9, 19.1, 20.2, 22.0, 25.8,
29.6, 31.7, 32.1, 33.6, 37.2, 39.3, 41.7, 54.7, 59.6, 70.5, 129.9,
130.6, 132.7, 135.9. IR (neat): 1716, 1413 cm-1. EI-MS: m/z 391
(M+), 376, 348, 334, 260, 214, 188. HRMS calcd for C24H46NOSi
(M+): requires, 391.3256; found, 391.3242.
(2S,4aS,5R,8aR)-1-(tert-Butyloxycarbonyl)-2-methyl-3-oxo-5-
((1′E,3′E)-octadien-1-yl)decahydroquinoline 23. To a solution of
22 (50 mg, 0.15 mmol) in anhydrous benzene were sequentially
added (Boc)2O (160 mg, 0.73 mmol) and K2CO3 (2 mg, 0.015
mmol). The resultant solution was heated to gently reflux under
argon for 72 h. After water was added to quench the reaction, the
organic layer was separated, and the aqueous layer was extracted
To a solution of the above carbamate in 25 mL of CH2Cl2 was
added Dess-Martin reagent (1.68 g, 4.1 mmol) dropwise at room
temperature. After the resultant mixture was stirred for about 5 h,
saturated sodium bicarbonate solution was added to quench the
reaction. The organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated in vacuo to give a colorless oil, which
was purified via chromatography, eluting with 10:1 ethyl acetate/
petroleum ether to afford 1.0 g (86%) of 7. [R]15 -35.2 (c 0.9,
D
CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.87 (s, 9H),
1.18 (d, J ) 7.2 Hz, 3H), 1.44 (s, 9H), 1.61 (m, 2H), 1.78 (ddd, J
) 3.2, 12.7, 12.9 Hz, 1H), 1.92 (m, 2H), 1.93 (ddd, J ) 2.1, 11.2,
11.3 Hz, 1H), 2.31 (ddd, J ) 6.0, 5.4, 15.0 Hz, 2H), 3.11 (dt, J )
4.9, 13.5 Hz, 1H), 3.81 (m, 1H), 4.11 (q, J ) 7.1 Hz, 1H), 4.30
(dt, J ) 4.9, 12.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ -5.2,
-4.9, 17.9, 19.4, 21.7, 25.6, 26.6, 27.5, 28.3, 38.1, 44.7, 51.4, 52.5,
67.9, 79.5, 155.0, 212.8. IR (neat): 2975, 1711, 1676 cm-1. ESI-
MS: m/z 420 (M + Na)+. ESI-HRMS calcd for C21H39NNaO4Si
(M + Na)+: requires 420.2541; found, 420.2541.
with CH2Cl2. The combined organic layers were dried over MgSO4
and evaporated in vacuo to give a colorless oil, which was purified
via chromatography, eluting with 1:100 ethyl acetate/petroleum
ether to give a crude carbamate. This crude product was dissolved
in anhydrous THF (2 mL), and then TBAF (2 M in THF, 0.76
mL) was added via syringe at room temperature. The reaction
mixture was stirred for 72 h, and then partitioned between ether
and saturated ammonium chloride. The organic layer was separated,
and the aqueous layer was extracted with ether. The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by chromatography, eluting
with 1:5 ethyl acetate/petroleum ether to give an alcohol (45 mg,
82%).
(2S,3R,4aS,5R,8aR)-2-Methyl-3-(tert-butyldimethylsilyloxy)-
5-formyl-decahydroquinoline 18. To a solution of the enol ether
16 (177 mg, 0.42 mmol) in 50 mL of CH2Cl2 at room temperature
were added wet trichloroacetic acid (653.6 mg, 4 mmol) and 1 drop
of water. After the starting material was consumed as monitored
by TLC, saturated sodium bicarbonate was added to quench this
reaction. The aqueous layer was extracted several times with ethyl
acetate, and the combined organic layers were washed with brine
and dried over MgSO4. After being concentrated and dried under
vacuum, the crude aldehyde was obtained.
To a solution of the above alcohol (31 mg, 0.082 mmol) in 1
mL of CH2Cl2 was added Dess-Martin reagent (52.4 mg, 0.123
mmol) dropwise at room temperature. The resultant solution was
stirred for about 5 h before saturated sodium bicarbonate was added
to quench the reaction. The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated in vacuo. The residue
was purified via chromatography, eluting with 1:15 ethyl acetate/
petroleum ether to afford 23 mg (76%) of 23. [R]15D -21 (c 0.42,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.89 (t, J ) 7.5 Hz, 3H),
1.21-1.60 (m, 9H), 1.35 (d, J ) 7.2, 3H), 1.47 (s, 9H), 1.76 (m,
J ) 3.9, 5.1 Hz, 1H), 2.11 (q like, J ) 6.6, 7.2 Hz, 2H), 2.25 (m,
2H), 2.73 (dd, J ) 4.8, 16.2 Hz, 1H), 4.35 (q like, J ) 6.9 Hz,
1H), 4.4 (m, 1H), 5.62 (dt, J ) 6.6, 14.1 Hz, 1H), 5.75 (dd, J )
6.9, 14.7 Hz, 1H), 6.02 (dd, J ) 7.2, 15.1 Hz, 1H), 6.02 (dd, J )
6.0, 15.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 13.9, 20.1, 20.9,
22.2, 24.8, 27.5, 28.4, 31.4, 32.2, 38.4, 38.7, 41.6, 48.7, 58.3, 80.2,
130.1, 130.9, 133.1, 133.9, 154.1, 209.5. IR (neat): 1719, 1692,
1400 cm-1. ESI-MS: m/z 376 (M + H)+. HRMS calcd for C23H38-
NO3 (M + H)+: requires, 376.2832; found, 376.2846.
Lepadin B (1b). To a solution of 23 (20 mg, 0.053 mmol) in
anhydrous methanol was added NaBH4 (2 mg) at -40 °C with
stirring. After being stirred at this temperature for 1 h, the mixture
was neutralized with 0.5 N HCl, and extracted with CHCl3. The
combined organic layers were dried over MgSO4 and evaporated
in vacuo to give a colorless oil, which was dissolved in 1 mL dry
CH2Cl2 before trifluoroacetic acid (0.06 mL) was added. The
mixture was stirred until the starting material disappeared monitored
by TLC, and then saturated methanolic K2CO3 was added to quench
the reaction. After the mixture was stirred for 5 h, it was
concentrated, and the residue was chromatographed eluting with
5:1:0.06 ethyl acetate/MeOH/NH4OH to afford 10 mg (73%) of
1b, which was treated with trifluoroacetic acid to give its salt for
analysis. [R]15D -82 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 0.89 (t, J ) 7.0 Hz, 3H), 1.06 (m, 1H), 1.29-1.37 (m, 4H), 1.39
(d, J ) 6.7 Hz, 1H), 1.56-1.66 (m, 5H), 1.74 (d like, J ) 13.4
Hz, 1H), 2.06 (q, J ) 6.9 Hz, 2H), 2.10 (d, J ) 9.5 Hz, 1H), 2.31
(d, J ) 13.9 Hz, 1H), 2.78 (q like, J ) 11.0 Hz, 1H), 3.35 (br s,
1H), 3.49 (br s, 1H) 3.89 (br s, 1H), 4.14 (br s, 1H), 5.30 (dd, J )
To a solution of the above crude product in 50 mL of dry CH2-
Cl2 was added trifluoroacetic acid (2.5 mL) dropwise at room
temperature. The reaction was carefully monitored by TLC and
quenched with a saturated methanolic K2CO3. After removal of
the solvent under reduced pressure, the residue was dissolved in
20 mL of methanol. To this solution was added K2CO3 (200 mg,
1.5 mmol). After the resultant mixture was stirred at room
temperature for about 10 h, it was evaporated, and the residue was
triturated with water and extracted with ethyl acetate. The organic
layers were washed with brine, dried over MgSO4, and concentrated.
The residue was allowed to pass a short column of silica gel to
afford 97 mg (76%) of aldehyde 18 as an unstable product, which
1
was used immediately. [R]17 -48.8 (c 0.36, CHCl3). H NMR
D
(300 MHz, CDCl3): δ 0.03 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H),
1.13 (dq, J ) 1.8, 10.1 Hz, 1H), 1.33 (d, J ) 6.2 Hz, 3H), 1.61 (m,
4H), 2.11 (m, 4H), 2.92 (dq, J ) 2.4, 6.1 Hz, 1H), 3.11 (t, J )
12.1 Hz, 1H), 3.41 (m, 1H), 3.71 (ddd, J ) 4.5, 6.1, 6.6 Hz, 1H),
9.61 (d, J ) 3.6 Hz, 1H). IR (neat): 1720, 1681 cm-1. EI-MS:
m/z 311 (M+) 296, 282, 254, 240, 180, 150, 124, 101. HRMS calcd
for C17H34NO2Si (M + H)+: requires, 312.2341; found, 312.2353.
(2S,3R,4aS,5R,8aR)-2-Methyl-3-(tert-butyldimethylsilyloxy)-
5-((1′E,3′E)-octadien-1-yl)decahydroquinoline 22. To a solution
of hept-2-enyl-phosphonic acid diethyl ester 21 (150 mg, 0.64
mmol) in 2 mL of DME was added KHMDS (1 M in THF, 0.65
mL) dropwise by a syringe at -78 °C over 20 min. The resultant
solution was stirred for 0.5 h before a solution of the aldehyde 18
(50 mg, 0.16 mmol) in 2 mL of DME was added dropwise via
syringe over 10 min. The reaction mixture was maintained at -78
°C for 6 h and then allowed to slowly warm to room temperature.
The resultant solution was diluted with ether before saturated
ammonium chloride was added. The organic layer was separated,
and the aqueous layer was extracted with ether. The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
The residue was purified by chromatography, eluting with 1:10 ethyl
acetate/petroleum ether to give 57 mg (92%) of 22. [R]20 -23.5
D
1
(c 1.95, CHCl3). H NMR (300 MHz, CDCl3): δ 0.03 (s, 3H),
0.05 (s, 3H), 0.86 (s, 9H), 0.89 (t, J ) 7.2 Hz, 3H), 1.06 (dd, J )
2.7, 12.3 Hz, 1H), 1.13 (d, J ) 6.1 Hz, 3H), 1.21-1.70 (m, 12H),
6568 J. Org. Chem., Vol. 71, No. 17, 2006

Total Synthesis of Lepadins A-E and H
8.6, 15.1 Hz, 1H), 5.64 (dt, J ) 6.9, 15.1 Hz, 1H), 5.99 (dd, J )
10.0, 15.1 Hz, 1H), 6.11 (dd, J ) 10.5, 15.2 Hz, 1H), 7.47 (br s,
1H), 9.70 (br s, 1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 14.9,
19.5, 22.3, 28.9, 31.4, 32.1, 32.3, 33.0, 36.9, 39.6, 56.8, 57.5, 66.5,
129.9, 132.3, 134.0, 134.3. IR (neat): 3389, 1450 cm-1. ESI-MS:
m/z 278 (M + H)+.
CO2H (26.6 mg, 0.14 mmol), DMAP (1 mg, 0.1 mmol), and EDC
(30 mg, 0.15 mmol). The mixture was warmed to room temperature
and then stirred for about 12 h. After water was added to quench
the reaction, the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and evaporated in vacuo to give crude ester, which
was dissolved in 1.5 mL of dry CH2Cl2. To this solution was added
F3B‚OEt2 (8.5 mg, 0.06 mmol) at 0 °C. The resultant solution was
stirred at room temperature until the starting material disappeared
monitored by TLC. Saturated methanolic NaHCO3 was added to
quench the reaction, and then stirring was continued for 1 h. After
removal of the solvents via rotavapor, the residue was purified by
chromatography (1:2:0.02 MeOH/EtOAc/NH4OH as eluent) to
afford 16.5 mg (74%) of 1c, which was transformed into its
Lepadin A 1a. Following the procedure for reduction of 23
mentioned above, the corresponding alcohol was obtained. This
alcohol (26 mg, 0.07 mmol) was dissolved in 1 mL of anhydrous
CH2Cl2 before TMSOCH2CO2H (26.6 mg, 0.14 mmol), DMAP (1
mg, 0.1 mmol), and EDC (30 mg, 0.15 mmol) were added
sequentially at 0 °C. The mixture was warmed to room temperature
and stirred for about 12 h. After water was added to quench the
reaction, the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and evaporated in vacuo to give a colorless oil, which
was purified via chromatography, eluting with 1:30 ethyl acetate/
petroleum ether to give an ester (36 mg, 90%), which was dissolved
in 1.5 mL of dry CH2Cl2. To this solution was added F3B‚OEt2
(7.2 mg, 0.05 mmol) at 0 °C. The resultant solution was stirred at
room temperature until the starting material disappeared monitored
by TLC. Saturated methanolic NaHCO3 was added to quench the
reaction, and then stirring was continued for 1 h. After removal of
the solvents via rotavapor, the residue was purified by chromatog-
raphy (1:2:0.02 MeOH/EtOAc/NH4OH as eluent) to afford 15.6
mg (76%) of 1a, which was transformed into its trifluoroacetic acid
salt for analysis. [R]30D -50.7 (c 0.2, MeOH). 1H NMR (300 MHz,
CDCl3): δ 0.89 (t, J ) 7.0 Hz, 3H), 1.06 (m, 1H), 1.29-1.42 (m,
4H), 1.33 (d, J ) 6.9 Hz, 3H), 1.56-1.75 (m, 5H), 2.0-2.10 (q
like, J ) 6.9, 9.1 Hz, 3H), 2.32 (d, J ) 13.6 Hz, 1H), 2.77 (br s,
1H), 2.80 (m, 1H), 3.39 (br s, 1H) 3.47 (br s, 1H), 4.33 (br m,
2H), 5.25 (dd, J ) 8.6, 15.1 Hz, 1H), 5.27 (br s, 1H), 5.62 (dt, J
) 7.0, 15.1 Hz, 1H), 5.95 (dd, J ) 10.0, 15.2 Hz, 1H), 6.11 (dd,
J ) 10.5, 15.2 Hz, 1H), 7.42 (br, 1H), 9.92 (br s, 1H). 13C NMR
(75 MHz, CDCl3): δ 13.8, 14.8, 19.4, 22.2, 28.9, 29.6, 31.3, 32.2,
32.8, 36.9, 39.5, 56.7, 57.4, 61.0, 68.5, 129.9, 132.7, 133.2, 134.6,
171.5. ESI-MS: m/z 336 (M + H)+.
trifluoroacetic acid salt for analysis. [R]30 -60.3 (c 0.3, MeOH).
D
1H NMR (300 MHz, CDCl3): δ 1.06 (m, 1H), 1.26 (d, J ) 6.7
Hz, 3H), 1.60-1.79 (m, 6H), 2.06 (m, 1H), 2.15 (s, 3H), 2.27 (m,
1H), 2.33 (q like, J ) 6.6 Hz, 2H), 2.52 (t, J ) 7.8 Hz, 2H), 2.80
(m, 1H), 3.39 (q, J ) 7.0 Hz, 1H), 3.48 (br s, 1H), 4.09 (br s, 1H),
4.30 (m, 2H), 5.24 (br s, 1H), 5.26 (dd, J ) 10.5, 14.7 Hz, 1H),
5.57 (dt, J ) 6.9, 15.1 Hz, 1H), 5.97 (dd, J ) 10.3, 15.1 Hz, 1H),
6.15 (dd, J ) 10.5, 15.5 Hz, 1H), 7.39 (br, 1H), 9.74 (br, 1H). 13
C
NMR (125 MHz, CDCl3): δ 15.0, 19.6, 26.7, 29.1, 29.8, 33.0, 33.4,
37.0, 39.9, 43.1, 57.0, 57.6, 61.5, 68.2, 130.9, 131.5, 132.4, 134.7,
171.5, 208.2. ESI-MS: m/z 350 (M + H)+.
(2S,3R,4aS,5S,8aR)-2-Methyl-3-(tert-butyldimethylsilyloxy)-
5-(ethoxy-carbonyl)methyldecahydroquinoline 36. A solution of
35 (370 mg, 1.01 mmol) in glacial acid (20 mL) was hydrogenated
over platinum on charcoal (5%, 200 mg) at room temperature and
1 atm for 6 h before it was filtered through Celite. The filtrate was
concentrated and then diluted with saturated NaHCO3. The aqueous
layer was extracted several times with ethyl acetate, and the
combined organic layers were washed with brine and dried over
MgSO4. The solution was concentrated and the residue was purified
via chromatography, eluting with 2:1:0.01 ethyl acetate/petroleum
ether/methanol to give 351 mg (95%) of 36 as a colorless oil. [R]15
D
1
+10.1 (c 0.25, CHCl3). H NMR (300 MHz, CDCl3): δ 0.03 (s,
(2S,3S,4aS,5R,8aR)-1-(tert-Butyloxycarbonyl)-2-methyl-3-hy-
droxy-5-((1′E,3′E)-7,7-ethylenedioxy-octadien-1-yl)decahydro-
quinoline 29. To a solution of 28 (41 mg, 0.094 mmol) in 1 mL of
CH2Cl2 were added NaHCO3 (118 mg, 1.4 mmol) and Dess-Martin
reagent (60.5 mg, 0.141 mmol) at room temperature. The resultant
mixture was stirred for about 0.5 h before saturated sodium
bicarbonate was added to quench the reaction. The organic layer
was separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and evapo-
rated in vacuo. The residue was purified via chromatography, eluting
with 1:15 ethyl acetate/petroleum ether to yield a crude ketone.
To a solution of the above ketone (31 mg, 0.072 mmol) in
anhydrous methanol was added NaBH4 (1.8 mg) at -40 °C. After
being stirred at this temperature for 0.6 h, the mixture was
neutralized with 0.1 N HCl and then extracted with CHCl3. The
combined organic layers were dried over MgSO4 and evaporated
in Vacuo. The residue was purified via chromatography, eluting
with 5:1 ethyl acetate/petroleum ether to afford 28 mg (91% for
two steps) of 29. [R]30D -2.8 (c 0.2, CHCl3). 1H NMR (300 MHz,
CDCl3, amide rotamer): δ 1.17 (d, J ) 6.6 Hz, 3H), 1.33 (s, 3H),
1.47 (s, 9H), 1.46-1.78 (m, 9H), 1.74 (dd like, J ) 7.9, 6.2 Hz,
2H), 1.84 (m, 1H), 1.92 (q, J ) 9.6, 12 Hz, 1H), 2.20 (dd like, J
) 6.9, 6.6 Hz, 2H), 3.86 (m, 1H), 3.96 (dd like, J ) 3.5, 4.0 Hz,
4H), 4.00-4.17(m, 1H), 4.32 (m, 1H), 5.60 (m, 1H), 5.82 (m, 1H),
6.01 (m, 1H), 6.06 (m, 1H). 13C NMR (75 MHz, CDCl3, amide
rotamer): δ 21.1, 21.2, 22.6, 23.9, 26.1, 27.2, 28.4, 29.6, 29.9,
38.6, 38.7, 40.2, 49.1, 53.9, 64.6, 70.1, 79.4, 109.8, 130.1, 130.4,
132.5, 135.0, 155.1. IR (neat): 3428, 1681 cm-1. ESI-MS: m/z
436 (M + H)+. HRMS calcd for C25H42NO5 (M + H)+: requires,
436.3063; found, 436.3068.
3H), 0.05 (s, 3H), 0.85 (s, 9H), 1.11 (d, J ) 6.9 Hz, 3H), 1.22 (t
with m, J ) 7.2 Hz, 3H), 1.41 (m, 2H), 1.55 (m, 1H), 1.66 (m,
2H), 1.78 (m, 2H), 1.85 (br s, 1H), 2.15 (m, 2H), 2.31 (dd, J )
5.4, 14.9 Hz, 1H), 2.45 (dd, J ) 10.1, 14.6 Hz, 1H), 2.65 (dq like,
J ) 3.9, 4.2 Hz, 1H), 2.91 (dq like, J ) 4.2, 4.3 Hz, 1H), 3.50 (q
like J ) 5.5 Hz, 1H), 4.12 (dq like, J ) 2.8, 7.1 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ -4.9, -4.4, 14.1, 17.8, 20.4, 21.0, 25.7,
28.2, 30.2, 31.4, 35.3, 35.6, 38.2, 54.6, 55.8, 59.9, 71.7, 173.4; IR
(neat): 3421, 1735, 1675 cm-1. ESI-MS: m/z 370 (M + H)+.
HRMS calcd for C20H40NO3Si (M + H)+: requires, 370.2775;
found, 370.2772.
(2S,3R,4aS,5S,8aR)-1-Tosyl-2-methyl-3-(tert-butyldimethylsi-
lyloxy)-5-(ethoxycarbonyl)methyldecahydroquinoline 37. To an
ice cooled solution of 36 (19 mg, 0.053 mmol) in 1 mL of
anhydrous CH2Cl2 were sequentially added NEt3 (0.023 mL, 0.16
mmol) and TsCl (30.1 mg, 0.158 mmol). The mixture was warmed
to room temperature and then stirred for about 4 h. After water
was added to quench the reaction, the organic layer was separated,
and the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and then evaporated in
vacuo. The residue was purified via chromatography, eluting with
1:30 ethyl acetate/petroleum ether to give 21 mg (75%) of 37. [R]15
D
-9.2 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.01 (s, 3H),
0.02 (s, 3H), 0.82 (s, 9H), 1.01 (dq like, J ) 3.0, 9.3 Hz, 1H), 1.22
(t, J ) 7.2 Hz, 3H), 1.21-1.40 (m, 3H), 1.72 (m, 3H), 1.90 (m,
2H), 2.18 (m, 2H), 2.41 (s, 3H), 3.50 (dt, J ) 3.4, 7.5 Hz 1H),
3.81 (m, J ) 1.0 1H), 4.05 (dq, J ) 3.9, 4.5, 1H), 4.10 (dq like, J
) 2.8, 7.0 Hz, 2H), 7.21 (d, J ) 7.4 Hz, 2H), 7.8 (d, J ) 7.5 Hz,
2H). 13C NMR (75 MHz, CDCl3): δ -5.53, -5.48, 13.7, 17.7, 20.9,
21.4, 22.1, 24.6, 25.3, 25.7, 28.8, 30.8, 36.5, 38.1, 55.2, 55.3, 59.8,
69.2, 126.6, 128.8, 138.2, 142.0, 172.1. IR (neat): 3421, 1735, 1675
Lepadin C 1c. To an ice cooled solution of 29 (28 mg, 0.064
mmol) in anhydrous CH2Cl2 were sequentially added TMSOCH2-
J. Org. Chem, Vol. 71, No. 17, 2006 6569

Pu and Ma
cm-1. ESI-MS: m/z 524 (M + H)+. HRMS calcd for C27H45NO5-
SSiNa (M + Na)+: requires, 546.2680; found, 546.2696.
(m and dt, J ) 5.1, 10.2 Hz, 2H in 2:1 ratio due to rotamer), 4.65
(s, 2H). IR (neat): 1689, 1465 cm-1. ESI-MS: m/z 556 (M + H)+.
HRMS (ESI) calcd for C31H61NO5SiNa (M + Na)+: requires,
578.4211; found, 578.4194.
(2S,3R,4aS,5R,8aR)-1-(tert-Butyloxycarbonyl)-2-methyl-3-
(tert-butyl-dimethylsilyloxy)-5-(2′-hydroxyethyl)decahydroquin-
oline 41. To a solution of 37 (500 mg, 1.36 mmol) in 15 mL of
anhydrous benzene were sequentially added (Boc)2O (1.8 g, 8
mmol) and K2CO3 (19 mg, 0.13 mmol). The resultant mixture was
heated at reflux under argon for 72 h. After water was added to
quench the reaction, the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated in vacuo to give a
colorless oil, which was purified via chromatography, eluting with
1:40 ethyl acetate/petroleum ether to afford a crude carbamate,
which was reduced with DIBAL (4.1 mmol) in THF at -40 °C.
After completion of this reaction, methanol and saturated seignette
salt solution were sequentially added at the same temperature, and
then the solution was allowed to warm to room-temperature
overnight. The organic layer was separated, and the aqueous layer
was extracted with diethyl ether. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The residue was
purified by chromatography, eluting with 1:10 ethyl acetate/
(2S,3R,4aS,5S,8aR,5′S)-1-(tert-Butyloxycarbonyl)-2-methyl-3-
(tert-butyl-dimethylsilyloxy)-5-(5′-methoxymethoxyoctan-1-yl)-
decahydroquinoline 42b. Following the same procedure from 41a
to 42a, 42b was obtained from 41b in 89% yield. [R]19D -12.9 (c
1
0.25, CHCl3). H NMR (300 MHz, CDCl3): δ 0.02 (s, 3H), 0.04
(s, 3H), 0.86 (s, 9H), 0.92 (t and m, J ) 6.9 Hz, 4H), 1.10 (d, J )
7.2 Hz, 3H), 1.21-1.50 (m, 10H), 1.44 (s, 9H), 1.63-1.71 (m,
3H), 2.42 (br d, J ) 13.8 Hz, 1H), 3.38 (s, 3H), 3.54 (pent, J )
5.2 Hz, 1H), 3.75 and 3.79 (m, 1H in 1: 2 ratio due to rotamer),
3.88 and 4.05 (m and dt, J ) 5.1, 10.2 Hz, 2H in 2:1 ratio due to
rotamer), 4.65 (s, 2H). IR (neat): 1689, 1465 cm-1. ESI-MS: m/z
556 (M + H)+. HRMS (ESI) calcd for C31H61NO5SiNa (M +
Na)+: requires, 578.4211; found, 578.4194.
(2S,3R,4aS,5S,8aR,5′R)-1-(tert-Butyloxycarbonyl)-2-methyl-
3-hydroxy-5-(5′-methoxymethoxyoctan-1-yl)decahydroquino-
line 42c. To a solution of 42a (166 mg, 0.3 mmol) in anhydrous
THF (3 mL) was added TBAF (1 M in THF, 0.9 mL, 0.9 mmol)
via syringe at room temperature. This reaction mixture was stirred
for 72 h and then diluted with ether before addition of water. The
organic layer was separated, and the aqueous layer was extracted
with ethyl ether. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The residue was purified by
chromatography, eluting with 1/5 ethyl acetate/petroleum ether to
give 136 mg of 42c (100%). [R]19D +2.5 (c 1.8, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 0.89 (t, J ) 7.2 Hz, 3H), 0.97 (q, J ) 11.4
Hz, 1H), 1.16 (d, J ) 7.2 Hz, 3H), 1.21-1.50 (m, 16H), 1.46 (s,
9H), 1.65 (q like, J ) 13.8 Hz, 3H), 2.25 (m, 3H), 3.38 (s, 3H),
3.53 (p, J ) 5.3 Hz, 1H), 3.81 and 3.86 (narrow m, 1H in 1: 2
ratio due to rotamer), 3.86 and 4.12 (m and dt, J ) 7.2, 12.3 Hz,
2H in 2:1 ratio due to rotamer), 4.60 (s, 2H). 13C NMR (75 MHz,
CDCl3, amide rotamers): δ 14.0, 14.2, 18.4, 19.8, 20.2, 20.5, 20.7,
20. 8, 25.3, 25.5, 26.8, 27.1, 27.2, 27.8, 28.4, 28.5, 28.8, 30.7, 30.8,
33.1, 33.3, 34.1, 36.6, 39.7, 52.9, 53.4, 53.6, 54.6, 55.4, 68.8, 69.1,
petroleum ether to give 512 mg (90% for two steps) of 41. [R]18
D
1
-8.9 (c 0.26, CHCl3). H NMR (300 MHz, CDCl3): δ -0.01 (s,
3H), 0.01 (s, 3H), 0.83 (s, 9H), 0.98 (dq like, J ) 2.7, 12.6 Hz,
1H), 1.21-1.50 (m, 8H), 1.07 (d, J ) 7.2 Hz, 3H), 1.41 (s, 3H),
1.65 (m, 3H), 2.35 (br d, J ) 10.1 Hz, 1H), 3.63 (d, J ) 6.9 Hz,
2H), 3.72 and 3.78 (m, 1H in 1: 2 ratio due to rotamer), 3.88 and
4.05 (m and dt, J ) 5.1, 10.2 Hz, 2H in 2:1 ratio due to rotamer).
13C NMR (75 MHz, CDCl3): δ -5.2, -4.9, 17.9, 20.0, 21.5, 25.3,
25.67, 27.12, 27.85, 28.36, 30.9, 36.2, 36.15, 53.0, 53.7, 60.7, 69.5,
78.9, 155.4. IR (neat): 3490, 1687 cm-1. ESI-MS: m/z 428 (M +
H)+. HRMS (ESI) calcd for C23H45NO4SiNa (M + Na)+: requires,
450.3010; found, 450.3027.
(2S,3R,4aS,5S,8aR,5′R)-1-(tert-Butyloxycarbonyl)-2-methyl-
3-(tert-butyl-dimethylsilyloxy)-5-(5′-methoxymethoxyoctan-1-yl)-
decahydroquinoline 42a. A precooled solution of DMSO (212.8
µL) in dry CH2Cl2 was added to a solution of oxalyl chloride (128.6
µL, 1.5 mmol) in dry CH2Cl2 at -78 °C. After stirring for 10 min,
the alcohol 41 (320 mg, 0.75 mmol) in CH2Cl2 was added dropwise
within 10 min, and the mixture was stirred at this temperature for
additional 1 h. Then NEt3 (0.83 mL, 6 mmol) was added, and the
cooling bath was removed. After the reaction mixture was warmed
to room temperature, brine was added to quench the reaction. The
organic layer was separated, and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over MgSO4
and evaporated in vacuo to give the crude aldehyde (320 mg, 100%).
To a solution of sulfone 40a (250 mg, 0.7 mmol) in 2 mL of
THF was added dropwise NaHMDS (2 M in THF, 0.35 mL, 0.7
mmol) at -78 °C. The mixture was stirred for 30 min, and then a
solution of the above aldehyde (140 mg, 0.35 mmol) in THF was
added. After stirring was continued for 3 h at -78 °C, the reaction
mixture was allowed to warm to room temperature. Then brine was
added to quench the reaction, the organic layer was separated, and
the aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated in vacuo to give a
colorless oil, which was purified via chromatography, eluting with
1:30 ethyl acetate/petroleum ether to give the crude coupling
product. After this product was dissolved in methanol (40 mL), 10
mg of 10% palladium on charcoal was added. The resultant mixture
was stirred under hydrogen atmosphere at room temperature and
ordinary pressure for 6 h. After Pd/C was filtered off, the filtrate
was concentrated, and the residue was purified via chromatography,
eluting with 1:30 ethyl acetate/petroleum ether to give 166 mg (90%
73.1, 79.3, 95.2, 155.5, 155.6. IR (neat): 3458, 1687, 1666 cm-1
.
ESI-MS: m/z 464 (M + Na)+. HRMS (ESI): calcd for C25H47-
NO5Na, 464.3346 (M + Na)+; found, 464.3352.
(2S,3R,4aS,5S,8aR,5′S)-1-(tert-Butyloxycarbonyl)-2-methyl-3-
hydroxy-5-(5′-methoxymethoxyoctan-1-yl)decahydroquinoline
42d. Following the same procedure as mentioned above, 42d was
obtained from 42b: [R]19D +1.9 (c 1.5, CHCl3). 1H NMR (300 MHz,
CDCl3): δ 0.87 (t, J ) 7.2 Hz, 3H), 0.95 (q, J ) 12 Hz, 1H), 1.11
(d, J ) 7.2 Hz, 3H), 1.21-1.51 (m, 16H), 1.41 (s, 9H), 1.65 (q
like, J ) 13.5, 12.6 Hz, 3H), 2.23 (m, 3H), 3.33 (s, 3H), 3.49 (pent,
J ) 5.8 Hz, 1H), 3.77 and 3.82 (narrow m, 1H in 1:2 ratio due to
rotamer), 3.86 and 4.12 (m and dt, J ) 7.2, 12.3 Hz, 2H in 2:1
ratio due to rotamer), 4.60 (s, 2H). 13C NMR (75 MHz, CDCl3,
amide rotamers): δ 14.2, 18.4, 19.8, 20.2, 20.5, 20.7, 20.8, 25.3,
25.4, 26.7, 26.9, 27.1, 27.3, 27.7, 28.3, 28.5, 30.6, 30.7, 33.1, 33.3,
34.1, 36.6, 39.5, 39.7, 52.8, 53.4, 53.5, 54.5, 55.4, 68.7, 69.0, 79.1,
79.2, 95.2, 155.4, 155.5. IR (neat): 3459, 1687 cm-1. ESI-MS:
m/z 464 (M + Na)+. HRMS (ESI): calcd for C25H47NO5Na,
464.3346 (M + Na)+; found, 464.3360.
Lepadin D 2a. To a solution of 42c (25 mg, 0.057 mmol) in 5
mL methanol (degassed) was added 5 drops of concentrated HCl.
The resultant solution was heated at reflux under argon for 5 h.
Then the mixture was quenched with a solution of K2CO3 in
methanol and stirred for additional 5 h. After removal of the solvent
in vacuo, the residue was chromatographed, eluting with 1:5:0.6
for three steps) of 42a as a colorless oil. [R]19 -7.4 (c 0.38,
D
CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.02 (s, 3H), 0.04 (s, 3H),
0.86 (s, 9H), 0.95 (t and m, J ) 7.3 Hz, 4H), 1.10 (d, J ) 7.2 Hz,
3H), 1.21-1.50 (m, 12H), 1.44 (s, 9H), 1.61-1.72 (m, 3H), 2.41
(br d, J ) 13.8 Hz, 1H), 3.38 (s, 3H), 3.74 (pent, J ) 5.2 Hz, 1H),
3.76 and 3.78 (m, 1H in 1: 2 ratio due to rotamer), 3.88 and 4.05
MeOH/ethyl acetate/NH4OH to afford the free amine 2a (15 mg,
1
85%). [R]19 +2.4 (c 0.62, MeOH). H NMR (300 MHz, CD3-
D
OD): δ 1.01 (t, J ) 7.0 Hz, 3H), 1.17 (q like, J ) 11.7, 12.0 Hz,
6570 J. Org. Chem., Vol. 71, No. 17, 2006

Total Synthesis of Lepadins A-E and H
1H), 1.28 (d, J ) 6.6 Hz, 3H), 1.35-1.62 (m, 17H), 1.65 (q like,
J ) 4.0, 12.0 Hz, 1H), 1.78 (m, 1H), 1.91 (ddd, J ) 13.8, 13.8, 5.4
Hz, 1H), 2.38 (dq like, J ) 4.2, 12.3 Hz, 1H), 2.90 (dq, J ) 6.0,
6.9 Hz, 1H), 2.99 (ddd, J ) 5.1, 6.0, 11.1 Hz, 1H), 3.60 (m, 1H),
3.70 (q like, J ) 4.2, 4.8, 5.1 Hz, 1H). 13C NMR (75 MHz, CD3-
OD): δ 14.5, 19.9, 20.3, 25.6, 25.8, 27.1, 28.4, 28.5, 31.3, 34.0,
34.5, 38.4, 40.4, 40.8, 53.6, 55.8, 72.1, 72.2. IR (neat): 3336, 1463
cm-1. ESI-MS: m/z 298 (M + H)+.
23.1, 25.7, 27.2, 27.4, 27.6, 31.3, 31.4, 32.1, 32.8, 34.0, 37.5, 38.9,
39.6, 50.6, 54.6, 71.5, 73.7, 121.3, 149.6, 166.3. IR (neat): 3411,
1718, 1655 cm-1. UV λmax (MeOH): 211 nm (ꢀ 13502). ESI-MS:
m/z 422 (M + H)+.
5′-Epimer of Lepadin E 44. Following the same procedure as
mentioned above, 44 was obtained from 42d. [R]19 -5.5 (c 0.5,
D
MeOH). 1H NMR (500 MHz, CDCl3): δ 0.90 (t, J ) 7.0 Hz, 3H),
0.93 (t, J ) 6.6 Hz, 3H), 1.10 (q like, J ) 11.3, 12.3, 12.4 Hz,
1H), 1.17 (d, J ) 6.9 Hz, 3H), 1.20 (m, 1H) 1.28-1.54 (m, 22H),
1.66 (m, 2H), 1.75 (br, 1H), 1.59 (ddd, J ) 4.2, 12.0, 11.3 Hz,
1H), 2.18 (m, 1H), 2.20 (q like, J ) 7.0, 7.3, 7.4 Hz, 2H), 2.92
(ddd, J ) 4.0, 4.4, 10.4 Hz, 1H), 3.04 (dq like, J ) 6.5, 6.3, 6.0
Hz, 1H) 3.59 (narrow m, J ) 4.3 Hz, 1H), 4.77 (ddd, J ) 4.6, 4.8,
4.6 Hz, 1H), 5.84 (d, J ) 15.6 Hz, 1H), 6.99 (dt, J ) 6.9, 15.6 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 14.1, 18.8, 21.0, 22.4,
23.2, 23.6, 25.8, 27.3, 27.5, 27.6, 31.3, 31.5, 32.2, 32.8, 34.1, 37.5,
38.9, 39.7, 50.8, 54.6, 71.5, 73.7, 121.4, 149.6, 166.3. IR (neat):
3317, 1717, 1655 cm-1. UV λmax (MeOH): 209 nm (ꢀ 13983).
ESI-MS: m/z 422 (M + H)+.
5′-Epimer of Lepadin D 43. Following the same procedure as
mentioned above, 43 was obtained from 42d. [R]19D +5.8 (c 0.32,
1
MeOH). H NMR (300 MHz, CD3OD): δ 1.02 (t, J ) 7.0 Hz,
3H), 1.16 (q like, J ) 11.7, 12.0 Hz, 1H), 1.28 (d, J ) 6.6 Hz,
3H), 1.35-1.58 (m, 17H), 1.65 (q like, J ) 4.0, 12.0 Hz, 1H),
1.78 (m, 1H), 1.89 (ddd, J ) 13.8, 13.8, 5.4 Hz, 1H), 2.37 (dq
like, J ) 4.2, 12.3 Hz, 1H), 2.91 (dq, J ) 6.0, 6.9 Hz, 1H), 2.99
(ddd, J ) 5.1, 6.0, 11.1 Hz, 1H), 3.62 (m, 1H), 3.70 (q like, J )
4.2, 4.8, 5.1 Hz, 1H). 13C NMR (75 MHz, CD3OD): δ 14.5, 20.0,
20.2, 25.6, 25.6, 27.1, 28.4, 28.5, 31.0, 33.9, 34.5, 38.4, 40.4, 40.8,
53.6, 55.9, 71.9, 72.1. IR (neat): 3336, 1463 cm-1. ESI-MS: m/z
298 (M + H)+.
Lepadin H 2c. To an ice-cooled solution of compound 42c (45
mg, 0.102 mmol) in anhydrous CH2Cl2 were sequentially added
DMAP (36.5 mg 0.3 mmol), (2E,4E)-octadienoic acid (39 mg, 0.3
mmol), and EDC (62 mg). The mixture was warmed to room
temperature and stirred for about 12 h. After water was added to
quench the reaction, the organic layer was separated, and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated in vacuo to give a
colorless oil which was purified via chromatography, eluting with
1/40 ethyl acetate/petroleum ether to give ester. This product was
dissolved in 1.5 mL of dry CH2Cl2, and then trifluoroacetic acid
(1.5 mL) was added dropwise at room temperature. After the starting
material disappeared monitored by TLC, the mixture was quenched
with saturated methanolic NaHCO3 and then stirred for an additional
5 h. After removal of the solvent, the residue was chromatographed,
Hydrochloride Salts of 2a and 43. The free bases obtained
above were dissolved in methanolic hydrochloride (about 1 M) and
stirred for 30 min. Then solvent was evaporated in vacuo to give
the hydrochloride salts of 2a and 43, respectively. Salt of 2a: [R]19
D
-12 (c 1.0, MeOH). 1H NMR (400 MHz, CD3OD): δ 0.92 (t, J )
7.1 Hz, 3H), 1.11 (q like, J ) 11.7, 12.3, 12.4 Hz, 1H), 1.28-1.52
(m, 17H), 1.43 (d, J ) 7.2 Hz, 3H), 1.59 (br d, J ) 14.3 Hz, 1H),
1.85-1.91 (m, J ) 14.2, 6.8, 11.6 Hz, 3H), 2.55 (d like, J ) 10.3
Hz, 1H), 3.37 (m, J ) 4.2, 6.6 Hz, 1H), 3.41 (dq like, J ) 2.2, 6.2
Hz, 1H) 3.51 (m, 1H), 3.91 (narrow m, 1H). 13C NMR (100 MHz,
CD3OD): δ 14.8, 17.7, 20.2, 21.8, 26.2, 27.2, 27.6, 27.9, 28.2,
31.3, 34.3, 38.6, 40.4, 41.0, 55.7, 57.4, 68.3, 72.4. ESI-MS: m/z
298 (M + H)+. Salt of 43: [R]19 -5.7 (c 0.9, MeOH). H NMR
1
D
(400 MHz, CD3OD): δ 0.91 (t, J ) 7.1 Hz, 3H), 1.12 (q like, J )
11.7, 12.3, 12.1 Hz, 1H), 1.30-1.52 (m, 17H), 1.43 (d, J ) 7.2
Hz, 3H), 1.59 (br d, J ) 14.3 Hz, 1H), 1.85-1.91 (m, 3H), 2.55 (d
like, J ) 11 Hz, 1H), 3.38 (m, J ) 5.2 Hz, 1H), 3.41 (q like, J )
6.2 Hz, 1H) 3.51 (m, 1H), 3.90 (narrow m, 1H). 13C NMR (100
MHz, CD3OD): δ 14.8, 17.7, 20.2, 21.8, 26.2, 27.2, 27.6, 27.9,
28.3, 31.3, 34.3, 38.6, 40.5, 41.0, 55.7, 57.4, 68.3, 72.4. ESI-MS:
m/z 298 (M + H)+.
eluting with 1:2:0.02 MeOH/ethyl acetate/NH4OH to afford 2c (29
1
mg, 68% in two steps). [R]19 +9.5 (c 1.25, CH2Cl2). H NMR
D
(500 MHz, C6D6): δ 0.76 (t, J ) 7.4 Hz, 3H), 0.93 (t, J ) 7.0 Hz,
3H), 1.07 (m, 2H), 1.12 (d, J ) 6.9 Hz, 3H), 1.18 (m, 1H), 1.20 (q
like, J ) 7.4, 7.3 Hz 2H), 1.24 (m, 2H), 1.32-1.42 (m, 11H), 1.49
(m, 1H), 1.56 (m, 1H), 1.60 (m, 1H), 1.68 (m, 1H), 1.75 (ddd, J )
4.0, 4.3, 10.5 Hz, 1H), 1.82 (ddd, J ) 7.1, 7.1, 7.2 Hz, 1H), 2.23
(ddd, J ) 4.5, 4.7, 9.8 Hz, 2H), 2.85 (br s, 2H), 2.96 (ddd, J )
4.8, 4.0 9.5 Hz, 1H), 3.12 (dq like, J ) 6.3, 6.0 Hz, 1H) 3.52 (m,
1H), 4.99 (ddd, J ) 4.9, 5.0, 5.0 Hz, 1H), 5.82 (dt, J ) 7.0, 15.2
Hz, 1H), 5.98 (dd, J ) 11.9, 15.4 Hz, 1H), 6.01 (d, J ) 15.4 Hz,
1H), 7.60 (dd, J ) 10.8, 15.4 Hz, 1H). 13C NMR (125 MHz,
C6D6): δ 13.7, 14.4, 19.3, 19.8, 22.1, 22.7, 22.9, 26.0, 27.6, 28.0,
30.8, 32.9, 34.1, 35.1, 38.1, 38.9, 40.3, 52.3, 55.1, 71.1, 73.3, 120.1,
129.0, 144.3, 145.6, 166.5. IR (neat): 3406, 1675 cm-1. UV λmax
(MeOH): 264 nm (ꢀ 24000). ESI-MS: m/z 420 (M + H)+.
Lepadin E 2b. To a stirred solution of 2-(E)-octenoic acid (41.8
mg, 0.3 mmol) in benzene (2 mL) were added i-Pr2NEt (77 µL,
0.45 mmol) and Cl3C6H2COCl (111 mg, 0.44 mmol). After alcohol
42c (65 mg, 0.147 mmol) was added in benzene, the mixture was
stirred for 30 min. Then a solution of DMAP (48.6 mg) in benzene
was added dropwise for 20 min, and the resulting solution was
stirred for 8 h before it was partitioned between ether and brine.
The organic layer was separated, and the aqueous layer was
extracted with diethyl ether. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The residue was purified
by chromatography, eluting with 1/40 ethyl acetate/petroleum ether
to give the ester, which was dissolved in 2 mL dry CH2Cl2 before
trifluoroacetic acid (2 mL) was added dropwise at room temperature.
After the starting material disappeared monitored by TLC, the
mixture was quenched with saturated methanolic NaHCO3 and then
stirred for an additional 5 h. After removal of the solvent, the residue
was chromatographed, eluting with 1:2:0.02 MeOH/ethyl acetate/
5′-Epimer of Lepadin H 45. Following the same procedure as
mentioned above, 45 was obtained from 42d. [R]19D +11.3 (c 1.3,
CH2Cl2). 1H NMR (500 MHz, C6D6): δ 0.76 (t, J ) 7.4 Hz, 3H),
0.93 (t, J ) 6.9 Hz, 3H), 1.06 (m, 2H), 1.20-1.29 (m, 6H), 1.32-
1.43 (m, 9H), 1.48 (m, J ) 8 Hz, 1H), 1.49 (m, 1H), 1.56 (m, 1H),
1.60 (m, 1H), 1.72 (m, 1H), 1.75 (ddd, J ) 4.0, 4.3, 10.5 Hz, 1H),
1.82 (ddd, J ) 7.1, 7.1, 7.2 Hz, 1H), 2.23 (ddd, J ) 5.0, 4.4, 9.4
Hz, 2H),, 2.99 (ddd, J ) 4.7, 4.5 9.5 Hz, 1H), 3.01 (br, 2H), 3.12
(dq like, J ) 6.1, 6.0 Hz, 1H), 3.51 (m, 1H), 4.99 (ddd, J ) 4.7,
4.7, 4.8 Hz, 1H), 5.84 (dt, J ) 7.0, 15.2 Hz, 1H), 5.98 (dd, J )
11.9, 15.4 Hz, 1H), 6.01 (d, J ) 15.4 Hz, 1H), 7.60 (dd, J ) 10.8,
15.4 Hz, 1H). 13C NMR (125 MHz, C6D6): δ 13.7, 14.4, 19.3,
19.6, 22.1, 22.7, 22.8, 26.2, 27.8, 28.1, 30.6, 32.9, 34.2, 35.1, 38.2,
38.9, 40.3, 52.3, 55.1, 71.2, 73.2, 120.1, 129.0, 144.3, 145.7, 166.5.
IR (neat): 3406, 1675 cm-1. UV λmax (MeOH): 264 nm (ꢀ 23168).
ESI-MS: m/z 420 (M + H)+.
NH4OH to afford 2b (34 mg, 56% in two steps). [R]19 -5.3 (c
D
1
1.2, MeOH). H NMR (500 MHz, CDCl3): δ 0.89 (t, J ) 7.0 Hz,
3H), 0.93 (t, J ) 6.6 Hz, 3H), 1.09 (q like, J ) 11.3, 12.3, 12.4
Hz, 1H),, 1.17 (d, J ) 6.9 Hz, 3H), 1.21 (m, 1H) 1.25-1.53 (m,
22H), 1.66 (m, 2H), 1.77 (br s, 1H), 1.59 (ddd, J ) 4.2, 12.0, 11.3
Hz, 1H), 2.17 (m, 1H), 2.20 (q like, J ) 7.0, 7.3, 7.4 Hz, 2H), 2.91
(ddd, J ) 4.0, 4.3, 10.5 Hz, 1H), 3.04 (dq like, J ) 6.5, 6.3, 6.0
Hz, 1H) 3.58 (narrow m, J ) 4.0 Hz, 1H), 4.78 (ddd, J ) 4.6, 4.8,
4.6 Hz, 1H), 5.84 (d, J ) 15.6 Hz, 1H), 6.99 (dt, J ) 6.9, 15.6 Hz,
1H). 13C NMR (125 MHz, CDCl3): δ 13.9, 14.1, 18.8, 21.0, 22.4,
J. Org. Chem, Vol. 71, No. 17, 2006 6571

Pu and Ma
Supporting Information Available: Experimental for preparing
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation of
China (Grant 20321202) and Science and Technology Com-
mission of Shanghai Municipality (Grants 02JC14032 and
03XD14001) for their financial support.
1
compounds 8, 16, 27, 28, 33, and 35, and copies of H NMR and
13C NMR spectrum for key intermediates and final products. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO061070C
6572 J. Org. Chem., Vol. 71, No. 17, 2006