Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Article abstract of DOI:10.1021/jo0201070

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (±)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).

Full text of DOI:10.1021/jo0201070

J . Org. Chem. 2002, 67, 4337-4345
4337
Ster eoselective Tota l Syn th eses of th e Ra cem ic F or m a n d th e
Na tu r a l En a n tiom er of th e Ma r in e Alk a loid Lep a d ifor m in e via a
Novel N-Acylim in iu m Ion /Allylsila n e Sp ir ocycliza tion Str a tegy
Pu Sun, Cuixiang Sun, and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
smw@chem.psu.edu
Received February 14, 2002
Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine
alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization
of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of
the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology
for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-
catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15.
Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound
19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde
protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary
alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-
catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction
to an iminium salt, and removal of the O-benzyl protecting group to give (()-lepadiformine (6).
The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived
from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of
N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally
occurring lepadiformine to be 2(R),5(S),10(S),13(S).
In a series of papers published in the 1990s, Blackman
et al. reported the isolation of a small group of interest-
ing, structurally related tricyclic alkaloids from the
marine ascidian Clavelina cylindrica, collected at various
sites off the eastern coast of Tasmania.1 The most
abundant of these alkaloids are cylindricines A (1) and
B (3), whose structures and relative stereochemistry were
unambiguously established by X-ray crystallography.
These two compounds slowly form a 3:2 equilibrium mix-
ture upon standing in solution, presumably interconvert-
ing through an aziridinium intermediate.1a Subsequent
investigations led to the characterization of several other
minor congeneric compounds having the cylindricine A
pyrroloquinoline framework and relative stereochemistry
but differing in the functionality at C-14 such as cyclid-
ricine C (2) and/or having an n-butyl rather than a hexyl
group at C-2. One additional compound in the cylindri-
cine B pyridoquinoline series was also isolated.1c,2 If one
focuses on the A/B ring fusion in these alkaloids, all
members can be considered cis-1-azadecalin derivatives.
More recently, a related compound, fasicularin, was
isolated from the stalked green ascidian Neptheis fasicu-
laris collected in Pohnpei (Micronesia).3 The constitution
of this new alkaloid was established by a series of NMR
and NOE experiments that led to the assignment of the
structure and relative stereochemistry depicted by 4, thus
putting the compound in the cylindricine B pyridoquino-
line alkaloid series, but epimeric at the C-10 quaternary
center (i.e., a trans-1-azadecalin A/B ring system) and
lacking the C-4 oxygenation usually found in the cylin-
dricines. Fasicularin is also of considerable interest due
to its biological activity against a DNA repair-deficient
strain of yeast, as well as its cytotoxicity against Vero
cells.
In 1994, the Biard group reported the isolation of
another alkaloid of this general class, lepadiformine, from
the tunicate Clavelina lepadiformis (Muller) collected in
the Mediterranean near Tunisia and from Clavelina
moluccensis (Sluiter) obtained near the Djibouti coast.4
(2) For synthetic work on the cylindricines, see: Snider, B. B.; Liu,
T. J . Org. Chem. 1997, 62, 5630. Molander, G. A.; Ronn, M. J . Org.
Chem. 1999, 64, 5183. Liu, J . F.; Heathcock, C. H. J . Org. Chem. 1999,
64, 8263.
(3) Patil, A. D.; Freyer, A. J .; Reichwein, R.; Carte, B.; Killmer, L.
B.; Faucette, L.; J ohnson, R. K.; Faulkner, D. J . Tetrahedron Lett. 1997,
38, 363.
(4) Biard, J . F.; Guyot, S.; Roussakis, C.; Verbist, J . F.; Vercauteren,
J .; Weber, J . F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
(1) (a) Blackman, A. J .; Li, C.; Hockless, D. C. R.; Skelton, B. W.;
White, A. H. Tetrahedron 1993, 49, 8645. (b) Li, C.; Blackman, A. J .
Aust. J . Chem. 1994, 47, 1355. (c) Li, C.; Blackman, A. J . Aust. J . Chem.
1995, 48, 955.
10.1021/jo0201070 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/24/2002

4338 J . Org. Chem., Vol. 67, No. 12, 2002
Sun et al.
Sch em e 1
Lepadiformine was reported to have moderate in vitro
cytotoxic activity against several tumor cell lines,4 as well
as various cardiovascular effects in vivo and in vitro.5 On
the basis of primarily NMR spectroscopic data, lepadi-
formine was initially formulated as having the pyrrolo-
quinoline constitution 5 related to the cylindricine A cis-
azadecalin series of ascidian alkaloids. It was also
proposed on the basis of spectral analysis that the
compound existed in the very unusual zwitterionic
structure shown. Initially, lepadiformine was reported to
have a D-line rotation of zero; however these data have
recently been reacquired, and the alkaloid actually has
produce the requisite trans-1-azadecalin.7 The plan was
to effect a novel intramolecular spirocyclization of an
N-acyliminium ion with an allylsilane to generate the
spirocyclic A/C ring system and attendant stereochem-
istry of lepadiformine (6), followed by construction of the
B ring.11 In this paper, we provide the details of this work,
which has led to a total synthesis of racemic lepadiform-
ine and has now also been applied in an enantioselective
synthesis of the alkaloid that has allowed us to assign
its absolute configuration.12,13
The synthesis began with commercially available
2-methyl-1-pyrroline (7), which was metalated with
LDA14 and then exposed to the known, easily prepared
(Z)-allylsilane iodide 815 to give an alkylated imine
(Scheme 1). This material was then treated in situ with
o-nitrobenzoyl chloride/triethylamine to afford enamides
9 as a mixture of double-bond isomers. Without purifica-
tion, compound 9 was treated with 10 equiv of trifluoro-
acetic acid in methylene chloride at room temperature
to afford a single, crystalline spirocyclization product 11
in 57% overall yield based on imine 7.16 The structure
25
a small positive rotation ([R]D +4.6 (c 1.28, CHCl3)),
although the absolute configuration was indeterminate.6
In 1999, we demonstrated by total synthesis that the
putative structure 5 does not represent lepadiformine
(nor is 5 a zwitterion).7 Moreover, Pearson and co-workers
synthesized the other three diastereomers of structure
5 at C-2 and C-13, showing that none of these compounds
corresponds to the natural product, and suggested that
lepadiformine might in fact be in the fasicularin trans-
1-azadecalin stereochemical series.8
(5) J uge, M.; Grimaud, N.; Biard, J . F.; Sauviat, M. P.; Nabil, M.;
Verbist, J . F.; Petit, J . Y. Toxicon 2001, 39, 1231.
(6) Biard, J . F. Personal communication.
(7) Werner, K. M.; De los Santos, J . M.; Weinreb, S. M.; Shang, M.
J . Org. Chem. 1999, 64, 686. Werner, K. M.; De los Santos, J . M.;
Weinreb, S. M.; Shang, M. J . Org. Chem. 1999, 64, 4865.
(8) Pearson, W. H.; Barta, N. S.; Kampf, J . W. Tetrahedron Lett.
1997, 38, 3369. Pearson, W. H.; Ren, Y. J . Org. Chem. 1999, 64, 688.
(9) Abe, H.; Aoyagi, S.; Kibayashi, C. J . Am. Chem. Soc. 2000, 122,
4583.
(10) For another recent total synthesis of racemic fasicularin, see:
Maeng, J .-H.; Funk, R. L. Org. Lett. 2002, 4, 331.
(11) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(b) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1988; Vol. 32, p 271. (c) Hiemstra, H.;
Speckamp, W. N. In Comprehensive Organic Synthesis; Trost, B. M.,
As part of a project on the total synthesis of fasicularin
(4), Kibayashi and co-workers prepared some pyrrolo-
quinoline compounds related to lepadiformine and found
one that corresponded to the alkaloid. It was also
conclusively proven by X-ray crystal analysis that lep-
adiformine is indeed a trans-1-azadecalin with the rela-
tive configuration and conformation shown in structure
6.9,10 Interestingly, the natural product exists with the
B ring as a boat, thereby having the hexyl group in an
equatorial position. In addition, it was shown that the
natural material isolated by Biard is actually the hydro-
chloride salt of 6 rather than a zwitterion as originally
postulated.
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
p 1047. (d)
Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817.
(12) For a preliminary account of portions of this work, see: Sun,
P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507. Taken in part
from: Sun, P. Ph.D. Thesis, The Pennsylvania State University,
University Park, PA, 2001.
(13) For an elegant total synthesis of racemic lepadiformine, see:
Maeng, J .-H.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(14) For C-alkylations of metalated endocyclic imines, see: (a)
Gramain, J .-C.; Husson, H.-P.; Troin, Y. J . Org. Chem. 1985, 50, 5517.
(b) Evans, D. A. J . Am. Chem. Soc. 1970, 92, 7593. (c) Houk, K. N.;
Strozier, R. W.; Rondan, N. G.; Fraser, R. R.; Chauqui-Offermanns,
N. J . Am. Chem. Soc. 1980, 102, 1426.
(15) Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J .; Speckamp, W. N.
J . Org. Chem. 1985, 50, 4014.
With the structure of lepadiformine now secure, we
decided to turn to a completely new synthetic approach
to this interesting alkaloid since our nitrone-based
strategy leading to structure 5 could not be modified to
(16) For some related imine spirocyclizations, see: Tanner, D.;
Hagberg, L. Tetrahedron 1998, 54, 7907. Evans, D. A.; Thomas, E. W.;
Cherpeck, R. E. J . Am. Chem. Soc. 1982, 104, 3695. David, M.;
Dhimane, H.; Vanucci-Bacque, C.; Lhommet, G. Heterocycles 2001, 55,
941.

Marine Alkaloid Lepadiformine
J . Org. Chem., Vol. 67, No. 12, 2002 4339
Sch em e 2
Sch em e 3
nucleophilic attack of the organometallic reagent from
the least congested face of the N-acyliminium salt derived
from R-methoxybenzamide 15. Tamao oxidation20 of 17
then cleanly afforded the hydroxymethyl compound 19,
whose stereochemistry was confirmed by X-ray analysis.17
The initial strategy for construction of the B ring of
the alkaloid was based upon a Mannich-like cyclization.
Thus, we hoped to generate an (E)-iminium ion like 24,
which would be expected cyclize in a 6-endo process with
the alkene moiety via a chairlike transition state to afford
a tricycle 23 having the desired C-2 configuration (Scheme
3).22,23 Hydrolysis of benzamide 19 with aqueous lithium
hydroxide gave amino alcohol 20, which on treatment
with heptanal afforded oxazolidine 21 in high yield.
Unfortunately, all attempts to rearrange 21 to tricyclic
amine 23 under acidic conditions failed, with only start-
ing material or amino alcohol 20 being recovered. Alter-
natively, amino alcohol 20 was first protected as the
benzyl ether 22, which was exposed to heptanal under
the conditions developed by Overman for related olefin
Mannich cyclizations.23 However, once again, only start-
ing material was recovered, rather than the desired
cyclization product 23 (X ) I). It might be noted that the
Overman Mannich cyclizations of alkenes have only been
effected with formaldehyde-derived iminium salts.24 It is
possible that the iminium compounds generated from
higher aldehydes are not sufficiently electrophilic to
participate in this process.
and conformation of this product was determined by
X-ray crystallography to be as shown.17 This cyclization
undoubtedly occurs via a reactive N-acyliminium ion,11
which we believe cyclizes through the preferred confor-
mation 10 having both the allylsilane and N-acylimine
groups quasi-equatorial. The alternative conformation 12,
which would lead to diastereomer 13, is probably desta-
bilized relative to 10 by a steric interaction between the
bulky quasi-axial N-acyl group and the axial hydrogens
of the newly forming six-membered ring.
Having efficiently prepared the A/C-ring spirocycle 11,
we next turned to introduction of the hydroxymethyl
group at C-13 of the alkaloid. The intent was to make
use of our methodology for oxidative remote functional-
ization of o-aminobenzamides in effecting this transfor-
mation.18 Therefore, o-nitrobenzamide 11 was first re-
duced to the o-amino compound 14 with sodium boro-
hydride catalyzed by Cu(acac)219 (Scheme 2). Subsequent
exposure of amine 14 to sodium nitrite/HCl in methanol
containing a catalytic amount of cuprous chloride led to
the formation of the desired R-methoxybenzamide 15 in
good yield. Treatment of 15 with a hydroxymethyl
carbanion equivalent, the cuprate derived from Grignard
reagent 16,20,21 in the presence of boron trifluoride
etherate, provided a chromatographically separable 7:1
mixture of alkylation products 17 and 18 in high yield.
The desired major product 17 presumably arises via
In view of the failure of the Mannich annulation
approach, we turned to another methodology for elabora-
tion of the remaining B ring. Therefore, alkene 19 was
first hydroformylated25 and the resulting aldehyde was
immediately protected as the dimethyl acetal 25 (Scheme
4). Basic hydrolysis of the benzamide group of 25 then
afforded the amino alcohol 26 in excellent yield. Although
we had hoped to complete the total synthesis without
having to resort to protecting the primary alcohol group
of 26, this proved to be unworkable.26 Therefore, alcohol
26 was next converted to the benzyl ether 27. Upon
treatment with p-toluenesulfonic acid, amino acetal 27
cyclized to enamine 28, which proved to be rather
(17) We are grateful to Dr. Louis Todaro (Hunter College, CUNY)
for the X-ray analyses of compounds 11 and 19. Data has been
deposited with the Cambridge Crystallographic Data Centre (11:
CCDC 177 834; 19: CCDC 177 835).
(18) (a) Han, G.; McIntosh, M. C.; Weinreb, S. M. Tetrahedron Lett.
1994, 35, 5813. (b) Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb,
S. M.; Parvez, M. J . Org. Chem. 1996, 61, 9483. (c) Chao, W.; Weinreb,
S. M. Tetrahedron Lett. 2000, 41, 9199.
(22) Cf.: Rischke, H.; Wilcock, J . D.; Winterfeldt, E. Chem. Ber.
1973, 106, 3105. Bohlmann, F.; Winterfeldt, E. Chem. Ber. 1960, 93,
1956. Demailly, G.; Solladie, G. Tetrahedron Lett. 1977, 1885.
(23) McCann, S. F.; Overman, L. E. J . Am. Chem. Soc. 1987, 109,
6107.
(24) Some examples do exist of Overman Mannich cyclizations with
higher aldehydes involving alkynes. We thank Professor Overman for
providing this information.
(19) Hanaya, K.; Muramatsu, T.; Kudo, H.; Chow, Y. L. J . Chem.
Soc., Perkin Trans. 1 1979, 2409.
(20) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4249.
(21) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573.
(25) Ojima, I.; Tsai, C.-Y.; Tzamarioudaki, M.; Bonafoux, D. Org.
React. 2000, 56, 1.

4340 J . Org. Chem., Vol. 67, No. 12, 2002
Sun et al.
Sch em e 4
Sch em e 5
mational inversion to the more stable lepadiformine B
ring boat conformation 35. Attack on the iminium species
31 from the opposite (“equatorial”) face (path b) will
initially produce an unfavorable B ring boat 34, which
ring-flips to the more stable chair conformer 33 having
an equatorial C-2 hexyl group. In simpler ring systems,
path a is ordinarily highly preferred over path b.27,28
However, in the case of iminium compound 31, a devel-
oping severe 1,3-diaxial interaction between the incoming
nucleophile and the bridge carbon (C-11) is probably
responsible for the lower than normal stereoselectivity
in the alkylation step.
To complete the total synthesis, cleavage of the benzyl
ether group from compound 35 using sodium/liquid
ammonia afforded racemic lepadiformine (9) in high
yield. Both the synthetic alkaloid 6 and its HCl salt have
spectral data identical to those of authentic material.29
Similarly, the epimer 33 could be deprotected to afford
2-epi-lepadiformine (36).9
The next goal of this program was to attempt to extend
the basic strategy outlined here to achieve an enantiose-
lective total synthesis of lepadiformine. Toward this end,
known bromide 3730 derived from inexpensive (S)-pyro-
glutamic acid was chosen as the starting material
(Scheme 6). We decided that it would be prudent to use
as sterically bulky a group as possible to block one face
of the system in the key spirocyclization step (vide infra),
and therefore bromide 37 was first converted to the
phenyldimethylsilyl derivative 38. The lactam 38 was
then converted to the N-Cbz compound 39. Iodide (Z)-
allylsilane 40, prepared from the known corresponding
alcohol,31 was transformed to the lithium species with
tert-butyllithium and was added to Cbz lactam 39.
Without purification, adduct 41 was exposed to boron
trifluoride acetic acid complex in methylene chloride to
provide spirocycle 43 as a single stereoisomer in 52%
overall yield based upon 39. As we had anticipated, this
cyclization involves selective attack by the allylsilane
unstable and could not be purified by chromatography.
A few attempts were made to C-alkylate this enamine
directly (e.g., allyltrimethylsilane, TFA; TFA, and then
hexylmagnesium bromide, CuBr‚Me2S), but none of the
desired products could be detected. Alternatively, enam-
ine 28 could be converted to R-amino nitrile 29, which
showed somewhat better stability than the enamine. The
nitrile is formed initially as a kinetic product to which
we have tentatively assigned the stereostructure shown
in 29. Upon standing in solution, nitrile 29 slowly
isomerizes to the thermodynamically more stable stere-
oisomer, which we expect is epimer 30.
We next investigated the possibility of introducing the
C-2 hexyl chain by treating the crude kinetic amino
nitrile 29 with commercially available hexylmagnesium
bromide under various reaction conditions. The optimum
yield and stereoselectivity was eventually achieved using
the Grignard reagent in the presence of boron trifluoride
etherate in THF, which produced a 3:1 mixture of the
desired alkylation product 35 along with its C-2 epimer
33 (56% overall total yield from amino acetal 27) (Scheme
5).27 The results of this reaction can be rationalized on
the basis of the stereoelectronic principles outlined by
Stevens28 via antiperiplanar addition of the Grignard
reagent to intermediate iminium salt 31 from the pre-
ferred “axial” direction (path a ), which would lead to an
initial chair 32. This compound then undergoes confor-
(26) Amino alcohol 26 could in fact be converted to tricyclic alcohol
nitrile A as was done for benzyl-protected compound 27 (cf. Scheme
4), but all attempts to alkylate this compound with organometallic
reagents to directly produce lepadiformine (6) failed.
(29) We thank Professor J . F. Biard for copies of the proton and
carbon NMR spectra, as well as a sample of natural lepadiformine.
We are also grateful to Professor Raymond L. Funk for NMR spectra
of synthetic (()-lepadiformine free base and the corresponding hydro-
chloride salt.13
(30) Misun, M.; Pfaltz, A. Helv. Chim. Acta 1996, 79, 961.
(31) Tietze, L. F.; Ruther, M. Chem. Ber. 1990, 123, 1387.
(27) Polniaszek, R. P.; Belmont, S. E. J . Org. Chem. 1990, 55, 4688.
(28) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.

Marine Alkaloid Lepadiformine
J . Org. Chem., Vol. 67, No. 12, 2002 4341
Sch em e 6
Sch em e 7
derived from natural lepadiformine and our synthetic
enantiomerically pure alkaloid, sharp single resonances
1
were observed. Portions of the H NMR spectra of these
derivatives are shown in Figure 1. It can be clearly seen
from the figure that our synthetic material in fact
corresponds to the natural enantiomer. Therefore the
absolute configuration of naturally occurring lepadiform-
ine (6) has been established to be 2(R),5(S),10(S),13(S)
as indicated in the structure.
In summary, we have successfully completed a total
synthesis of racemic lepadiformine (6) that utilizes as key
steps a novel stereoselective spirocyclization of an N-
acyliminium ion with an allylsilane, followed by an
application of our radical-based remote amide oxidation
methodology for generation of N-acyliminium compounds,
which allows efficient introduction of the C-13 hydroxy-
methyl group. The spirocyclization strategy has also been
extended to an enantioselective total synthesis of the
alkaloid starting from an (S)-pyroglutamic acid deriva-
tive. This synthesis has now definitively proven the
absolute configuration of lepadiformine to be as shown
in structure 6.
onto the less encumbered face of N-acyliminium ion 42.
The stereochemistry of intermediate 43 was proven by
its eventual conversion into lepadiformine (vide infra).
To continue the synthesis, the silyl group of 43 was
converted to the primary alcohol 44 by a Tamao oxidation
(Scheme 7). Since the Cbz compounds 43 and 44a show
mixtures of carbamate rotamers in their NMR spectra,
the product 44a was cleaved to amino alcohol 44b for
characterization purposes (see Experimental Section).
The alkene moiety of 44a could then be cleanly hydro-
formylated,25 and the aldehyde that was produced was
transformed to the dimethyl acetal 45. Removal of the
Cbz group by a dissolving metal reduction yielded the
amino alcohol 46, which was identical in all respects
except for optical rotation to the racemic material 26 (cf.
Scheme 4). Using exactly the same methodology applied
in the racemic series (vide supra), we converted amino
alcohol 46 in five steps to enantiomerically pure lepadi-
formine (6).
Exp er im en ta l Section
(2-Nitr op h en yl)-(6-vin yl-1-a za sp ir o[4.5]d ec-1-yl)m eth -
a n on e (11). To a solution of diisopropylamine (813 µL, 5.80
mmol) in 12 mL of THF was added n-BuLi (2.2 M in hexanes,
2.64 mL) at -78 °C. The reaction mixture was warmed to 0
°C and stirred for 10 min. The mixture was then cooled to -78
°C, and neat 2-methyl-1-pyrroline (7, 95% purity, 401 mg, 4.83
mmol) was added dropwise. The resulting mixture was stirred
for 1 h at -78 °C, followed by the addition of iodide (Z)-
allylsilane 8 (1.50 g, 5.31 mmol). The mixture was gradually
warmed to room temperature over 1 h and kept at that
temperature for an additional 2 h. To the reaction mixture
was then added triethylamine (2.0 mL, 14.5 mmol) and
2-nitrobenzoyl chloride (90% purity, 2.13 mL, 14.5 mmol). The
resulting reaction mixture was stirred for an additional 15 min
at room temperature, diluted with brine (20 mL), and extracted
with Et2O. The organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The residue was filtered
through a short column of neutral alumina (containing 5%
H2O), eluting with EtOAc/hexanes (1:2).
The hydrochloride salt of synthetic 6 showed a small
20
positive D-line rotation ([R]D +2.5 (c 0.51, CHCl3))
similar to that of natural material (vide supra).6,29,32
However, since the magnitude of the rotation is so small,
a more reliable comparison with the natural product was
done by NMR analysis. Therefore, racemic lepadiformine,
the natural alkaloid, and the synthetic enantiomerically
pure material were all converted to their corresponding
Mosher esters using the (R)-Mosher acid. The proton and
19F NMR spectra of the Mosher ester of racemic lepadi-
formine showed most resonances to be doubled (see
Supporting Information). In the case of the Mosher esters
To a solution of crude enamides 9 in CH2Cl2 (125 mL) at
-78 °C were added flame-dried 4 Å molecular sieves (∼2 g)
and trifluoroacetic acid (3.73 mL, 48.3 mmol). The reaction
mixture was gradually warmed to room temperature over 1.5
h. The reaction mixture was stirred for an additional 1.5 h at
(32) The D-line rotation of natural lepadiformine free base has not
been reported.

4342 J . Org. Chem., Vol. 67, No. 12, 2002
Sun et al.
1
F igu r e 1. Portions of the H NMR spectra (400 MHz, CDCl3) of the (R)-Mosher esters of racemic and natural lepadiformine (6)
and its synthetic enantiomer.
room temperature, diluted with saturated aqueous NaHCO3
(100 mL), and extracted with CH2Cl2. The organic extracts
were combined, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (1:2 EtOAc/hexanes) to afford spirocyclic
amide 11 (860 mg, 57% from 2-methyl-1-pyrroline) as a white
solid. Recrystallization of the purified product from CH2Cl2
gave single crystals suitable for X-ray analysis: mp 83-84 °C;
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J ) 8.3 Hz, 1 H), 7.66
(td, J ) 7.5 Hz, 1.0 Hz, 1 H), 7.50 (td, J ) 8.4, 1.4 Hz, 1 H),
7.22 (dd, J ) 7.6, 1.2 Hz, 1 H), 5.95 (br s, 1 H), 5.20-5.15 (m,
2 H), 3.70 (ddd, J ) 11.3, 7.3, 3.4 Hz, 1 H), 3.18-3.05 (m, 2
H), 2.81 (td, J ) 12.4, 4.1 Hz, 1 H), 2.04-1.97 (m, 1 H), 1.93-
1.87 (m, 1 H), 1.77-1.71 (m, 6 H), 1.43-1.24 (m, 3 H); 13C NMR
(75 MHz, CDCl3) δ 165.3, 144.2, 139.6, 135.3, 134.5, 129.1,
127.7, 124.5, 115.6, 69.4, 51.0, 44.0, 32.3, 31.0, 28.9, 24.9, 23.7,
23.3; CIMS (APCI+) (relative intensity) 315.2 (MH+, 100),
was diluted with saturated aqueous NaHCO3 (30 mL) and
extracted with CH2Cl2. The organic extracts were dried over
K2CO3 and concentrated under reduced pressure. The residue
was purified by flash column chromatography (1:9 EtOAc/
MeOH) on neutral alumina (containing 8% H2O) to afford a
diastereomeric mixture (ratio ) 3:1) of R-methoxybenzamides
15 (372 mg, 81%) as a colorless liquid: IR (film) 2927, 1636,
1
1445, 1389, 1070 cm-1; H NMR (400 MHz, CDCl3) δ 7.43-
7.36 (m, 5 H), 6.12 (ddd, J ) 17.0, 10.7, 6.0 Hz, 0.25 H), 5.75
(ddd, J ) 18.6, 10.3, 8.5 Hz, 0.75 H), 5.15-5.04 (m, 2 H), 3.69
(m, 1 H), 2.91 (s, 2.25 H), 2.83 (s, 0.75 H), 2.23 (m, 1 H), 1.89-
1.38 (m, 12 H); HRMS (ESI+) calcd for C19H26NO2 (MH+)
300.1964, found 300.1975.
{2-[(Allyld im eth ylsila n yl)-m eth yl]-6-vin yl-1-a za sp ir o-
[4.5]d ec-1-yl}-p h en yl-m eth a n on e (17). To a solution of
CuBr‚Me2S (331 mg, 1.61 mmol) in Et2O (4 mL) was added
Grignard reagent 16 (2.1 M in Et2O, 767 µL) at -50 °C. After
30 min at that temperature, the reaction mixture was cooled
to -78 °C and neat BF3‚OEt2 (228 mg, 1.61 mmol) was added.
After being kept at -78 °C for 5 min, the reaction mixture
was transferred via a cannula into a solution of amide 15 (96
mg, 0.32 mmol) in THF (5 mL). The mixture was stirred at
-78 °C for 3 h and then allowed to warm to room temperature
over 1 h. The reaction mixture was diluted with saturated
aqueous NH4Cl (10 mL) and extracted with Et2O. The organic
extracts were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (1:9 EtOAc/hexanes) to afford a 7:1 ratio of
diastereomers allylsilane 17 (93 mg, 76%) and allylsilane 18
149.1 (21); HRMS (APCI+) calcd for
C
18H23N2O3 (MH+)
315.1709, found 315.1694.
(2-Am in oph en yl)-(6-vin yl-1-azaspir o[4.5]dec-1-yl)-m eth -
a n on e (14). To a solution of amide 11 (1.010 g, 3.21 mmol) in
anhydrous ethanol (20 mL) was added a catalytic amount of
Cu(acac)2 (168 mg, 0.642 mmol) and NaBH4 (365 mg, 9.64
mmol) under argon. The reaction mixture was stirred for 3 h
at room temperature and then diluted with water (10 mL).
The mixture was extracted with CH2Cl2. The organic extracts
were dried over K2CO3 and concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography (1:2 EtOAc/hexanes) to afford o-aminobenzamide 14
(863 mg, 95%) as a white solid: mp 105-106 °C; 1H NMR (300
MHz, CDCl3) δ 7.10-7.05 (m, 2 H), 6.70-6.66 (m, 2 H), 5.88
(ddd, J ) 17.5, 10.4, 7.7 Hz, 1 H), 5.18-5.10 (m, 2 H), 4.23 (br
s, 2 H), 3.73 (br t, J ) 8.2 Hz, 1 H), 3.36-3.31 (m, 2 H), 2.87
(td, J ) 12.7, 4.1 Hz, 1 H), 1.93-1.89 (m, 2 H), 1.76-1.66 (m,
5 H), 1.55-1.28 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 168.7,
144.0, 139.6, 129.7, 126.8, 124.4, 117.5, 116.4, 115.8, 69.2, 51.7,
43.8, 33.0, 30.6, 29.0, 25.0, 24.0, 23.3; CIMS (APCI+) (relative
intensity) 285.2 (MH+, 45), 149.1 (25), 120.1 (100); HRMS
(APCI+) calcd for C18H25N2O (MH+) 285.1967, found 285.1952.
(2-Meth oxy-6-vin yl-1-azaspir o[4.5]dec-1-yl)ph en ylm eth -
a n on e (15). To a solution of o-aminobenzamide 14 (436 mg,
1.54 mmol) and NaNO2 (159 mg, 2.31 mmol) in anhydrous
MeOH (30 mL) was added HCl/MeOH (1 N, 8.6 mL) dropwise
over 5 min at 0 °C. After the reaction was stirred at this
temperature for an additional 40 min, 4 Å molecular sieves
(∼600 mg) were added and the resulting mixture was stirred
for 5 min. CuCl (15 mg, 0.15 mmol) was then added, and the
mixture was stirred at 18 °C for 1.5 h. The reaction was
quenched with NaOMe (466 mg, 8.6 mmol), and the mixture
(13 mg, 11%). Allylsila n e 17: IR (film) 2925, 1627, 1397 cm-1
;
1H NMR (360 MHz, CDCl3) δ 7.36-7.29 (m, 5 H), 5.78 (ddd, J
) 17.9, 9.8, 8.6 Hz), 5.47 (dq, J ) 17.9, 8.3 Hz, 1 H), 5.15-
5.07 (m, 2 H), 4.75-4.67 (m, 2 H), 3.98 (dd, J ) 12.1 6.3 Hz,
1 H), 3.69 (br t, J ) 8.0 Hz, 1 H), 3.01 (td, J ) 13.1, 3.2 Hz, 1
H), 2.23-2.18 (m, 1 H), 1.93-1.57 (m, 6 H), 1.45-1.15 (m, 6
H), 0.91-0.83 (m, 1 H), 0.67-0.63 (m, 1 H), -0.31 (s, 3 H),
-0.42 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 169.7. 139.9, 139.8,
134.2, 128.5, 128.3, 126.1, 115.4, 113.1, 68.8, 58.6, 42.6, 37.9,
31.2, 30.4, 29.6, 24.9, 24.4, 23.9, 23.1, -3.4, -4.0; HRMS
(APCI+) calcd for C24H36NOSi (MH+) 382.2566, found 382.2577.
Allylsila n e 18: IR (film) 2924, 1625, 1398 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.31-7.20 (m, 5 H), 5.92 (ddd, J ) 17.2, 11.1,
6.9 Hz, 1 H), 5.45 (dddd, J ) 17.4, 8.4, 8.4, 8.4 Hz, 1 H), 5.12-
5.06 (m, 2 H), 4.73-4.64 (m, 2 H), 3.91 (dd, J ) 12.0, 5.6 Hz,
1 H), 3.80 (br t, J ) 8.4 Hz, 1 H), 2.66 (td, J ) 10.9, 3.4 Hz, 1
H), 1.86-1.70 (m, 6 H), 1.52-1.30 (m, 4 H), 1.19-1.10 (m, 3
H), 0.74 (dd, J ) 14.4, 12.6 Hz, 1 H), 0.47 (d, J ) 14.5 Hz, 1
H), -0.35 (s, 3 H), -0.48 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 169.8, 140.2, 140.0, 134.3, 128.2, 128.1, 125.7, 115.1, 112.9,

Marine Alkaloid Lepadiformine
J . Org. Chem., Vol. 67, No. 12, 2002 4343
2856, 1447, 1126, 1071 cm-1 1H NMR (300 MHz, CDCl3) δ
69.9, 57.5, 43.8, 31.3, 28.5, 28.2, 26.7, 25.0, 24.0, 23.3, 23.1,
-3.4, -4.0; HRMS (ESI+) calcd for
382.2566, found 382.2559.
;
C
24H36NOSi (MH+)
4.34 (t, J ) 5.4 Hz, 1 H), 3.49 (dd, J ) 9.7, 3.5 Hz, 1 H), 3.30
(s, 3 H), 3.28 (s, 3 H), 3.37-3.25 (m, 2 H), 2.50 (br s, 2 H),
1.74-1.00 (m, 17 H); 13C NMR (75 MHz, CDCl3) δ 104.6, 64.8,
64.3, 59.7, 53.0, 52.2, 46.5, 40.7, 30.9, 28.7, 27.9, 24.5, 24.3,
24.1; CIMS (APCI+) (relative intensity) 272.2 (MH+, 100),
240.2 (MH+ - OMe, 28), 208.2 (14); HRMS (APCI+) calcd for
(2-Hydr oxym eth yl-6-vin yl-1-azaspir o[4.5]dec-1-yl)-ph e-
n ylm eth a n on e (19). To a solution of allylsilane 17 (140 mg,
0.37 mmol) in CH2Cl2 (5 mL) was added BF3‚2AcOH (150 µL,
0.73 mmol) at room temperature. After 15 min, the mixture
was diluted with saturated aqueous NaHCO3 (5 mL) and
extracted with CH2Cl2. The organic extracts were dried over
MgSO4 and concentrated under reduced pressure to give the
fluorosilane: 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5
H), 5.78 (dt, J ) 17.9, 9.9 Hz, 1 H), 5.17-5.08 (m, 2 H), 4.07
(dd, J ) 11.8, 6.3 Hz, 1 H), 3.68 (t, J ) 8.6 Hz, 1 H), 3.01 (t,
J ) 12.4 Hz, 1 H), 2.32-2.21 (m, 1 H), 1.90-0.67 (m, 12 H),
-0.06 (d, J ) 7.5 Hz, 3 H), -0.29 (d, J ) 7.6 Hz, 3 H).
To a solution of the above fluorosilane in a mixture of MeOH
(5 mL) and THF (5 mL) was added NaHCO3 (16 mg, 0.20
mmol) at room temperature. After 15 min, H2O2 (35 wt %
solution in water, 500 µL) was added to the reaction mixture.
After being refluxed overnight, the mixture was diluted with
saturated aqueous NH4Cl (10 mL) and extracted with CH2-
Cl2. The organic extracts were dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography (1:1 EtOAc/hexanes) to afford
alcohol 19 (89 mg, 95%) as a white solid. Recrystallization from
EtOAc/CH2Cl2 provided X-ray quality crystals: mp 169-170
°C; 1H NMR (300 MHz, CDCl3) δ 7.33-7.27 (m, 5 H), 5.77 (dt,
J ) 17.4, 8.9 Hz, 1 H), 5.14-5.09 (m, 2 H), 3.86 (dd, J ) 13.0,
7.2 Hz, 1 H), 3.61 (br t, J ) 7.7 Hz, 1 H), 3.20-3.09 (m, 2 H),
2.89 (td, J ) 13.0, 3.5 Hz, 1 H), 2.29 (br s, 1 H), 2.18 (br t, J
) 7.2 Hz, 1 H), 1.84-1.67 (m, 6 H), 1.46-1.24 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 170.4, 139.7, 139.2, 128.7, 128.3,
126.1, 115.7, 69.6, 63.6, 62.3, 42.7, 37.4, 30.9, 29.8, 25.8, 24.9,
23.9; CIMS (APCI+) (relative intensity) 300.1 (MH+, 100);
HRMS (APCI+) calcd for C19H26NO2 (MH+) 300.1963, found
300.1958.
C
15H29NO3 (MH+) 272.2226, found 272.2244.
2-Ben zyloxym eth yl-6-(3,3-dim eth oxypr opyl)-1-azaspir o-
[4.5]d eca n e (27). To a suspension of NaH (60% w/w in
mineral oil, 50 mg, 1.24 mmol) in THF (12 mL) at -8 °C were
added the above amino alcohol 26 and BnBr (147 µL, 1.24
mmol). The reaction mixture was stirred at room temperature
for 3 days, diluted with water, and extracted with CH2Cl2. The
organic extracts were dried over Na2SO4 and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy on silica gel (100:3:1.5 CHCl3/MeOH/NH4OH) to afford
the benzyl ether 27 (169 mg, 75%) as a colorless oil: IR (film)
2927, 2856, 1654, 1451, 1125, 1075 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.25-7.16 (m, 5H), 4.44 (dd, J ) 12.2, 14.0 Hz, 2H),
4.30 (t, J ) 5.0 Hz, 1H), 3.37 (dddd, J ) 4.0, 4.0, 3.9, 3.4 Hz,
1H), 3.31-3.22 (m, 3H), 3.23 (s, 3H), 3.22 (s, 3H), 1.76-0.89
(m, 17 H); 13C NMR (75 MHz, CDCl3) δ 138.4, 128.1, 127.4,
127.3, 104.7, 74.2, 72.9, 64.7, 58.6, 52.7, 52.2, 47.4, 40.6, 30.9,
30.0, 29.0, 28.5, 24.7, 24.3; HRMS (APCI+) calcd for C22H36
-
NO3 (MH+) 362.2695, found 362.2691.
3-Ben zyloxym et h yl-5-h exyld eca h yd r op yr r olo[2,1-j]-
qu in olin e (35). To a solution of amino acetal 27 (34 mg,
0.0968 mmol) in a mixture of acetone (3 mL) and H2O (2 mL)
was added p-TsOH‚H2O (22 mg, 0.116 mmol) at room tem-
perature. The resulting reaction mixture was stirred at reflux
for 3.0 h, diluted with saturated aqueous NaHCO3 (5 mL), and
extracted with CH2Cl2. The organic extracts were dried over
Na2SO4 and concentrated under reduced pressure to afford the
unstable enamine 28 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.33-7.24 (m, 5H), 5.78 (d, J ) 7.9 Hz, 1H), 4.55
(ABq, J ) 12.2 Hz, 2H), 4.56 (dt, J ) 4.4, 7.3 Hz, 1H), 3.52
(dd, J ) 7.6, 9.2 Hz, 1H), 3.39 (dd, J ) 6.2, 9.2 Hz, 1H), 3.32-
3.22 (m, 1H), 2.07-1.12 (m, 15H); 13C NMR (75 MHz, CDCl3)
δ 140.1, 138.6, 128.2, 127.5, 127.4, 100.9, 76.4, 73.1, 65.3, 64.5,
41.5, 37.1, 26.1, 25.34, 25.30, 25.2, 23.6.
The above enamine 28 was dissolved in acetone (0.4 mL)
and water (4 mL) at room temperature. KCN (54 mg, 0.968
mmol) and 1 N HCl in MeOH (97 µL, 0.097 mmol) were added
to the reaction mixture. The solution was stirred at room
temperature for 2.5 h, diluted with saturated aqueous NaHCO3
(5 mL), and extracted with CH2Cl2. The organic extracts were
dried over Na2SO4 and concentrated under reduced pressure
to afford the amino nitrile 29 as a colorless oil: IR (film) 2929,
2858, 2244 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-7.22 (m,
5H), 4.54 (ABq, J ) 12.1 Hz, 2H), 4.16 (dd, J ) 3.8, 8.2 Hz,
1H), 3.70 (dd, J ) 5.4, 9.0 Hz, 1H), 3.44 (m, 1H), 3.34 (dd, J )
7.1, 9.0 Hz, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.87-1.08 (m,
15H); 13C NMR (100 MHz, CDCl3) δ 138.6, 128.3, 127.6, 127.5,
121.3, 76.1, 73.1, 67.7, 63.4, 50.1, 40.6, 39.4, 30.7, 27.4, 26.6,
26.1, 26.0, 23.8, 22.9; HRMS (APCI+) calcd for C21H29N2O
(MH+) 325.2280, found 325.2275.
[6-(3,3-Dim eth oxypr opyl)-2-h ydr oxym eth yl-1-azaspir o-
[4.5]d ec-1-yl]-p h en ylm eth a n on e (25). To a solution of olefin
19 (76 mg, 0.25 mmol) in THF (5 mL) were added Rh(CO)2-
(acac) (4 mg, 0.015 mmol) and P(OPh)3 (7 µL, 0.025 mmol)
under argon. The reaction mixture was transferred to a glass
reaction vessel with a flat bottom, long narrow neck, and open
top and subsequently placed in a stainless steel autoclave. The
reaction was carried out at 60 °C and 4 atm (initial pressure
at 20 °C) of CO and H2 (1:1) for 6 h with stirring. After the
autoclave was cooled to room temperature, the gases were
released and the reaction mixture was concentrated under
reduced pressure.
To a solution of the crude aldehyde in dry MeOH (3 mL)
were added trimethyl orthoformate (139 µL, 1.27 mmol) and
HCl/MeOH (1 N, 50 µL) at room temperature. After 10 min,
the mixture was diluted with saturated aqueous NaHCO3 (10
mL) and extracted with CH2Cl2. The organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatography (3:1
EtOAc/hexanes) to afford acetal 25 (77 mg, 81%) as a white
1
solid: mp 96-97 °C; H NMR (400 MHz, CDCl3) δ 4.36 (br s,
5 H), 4.36 (t, J ) 5.2 Hz, 1 H), 3.97 (br m, 1 H), 3.26 (s, 3 H),
3.25 (s, 3 H), 3.38-3.18 (m, 2 H), 2.86 (t, J ) 10.1 Hz, 2 H),
2.12 (t, J ) 10.3 Hz, 1 H), 1.88-1.02 (m, 15 H); 13C NMR (100
MHz, CDCl3) δ 170.2, 139.3, 128.9, 128.4, 126.1, 104.4, 70.6,
64.0, 62.5, 53.2, 52.1, 38.5, 37.6, 30.5, 30.1, 29.1, 25.8, 25.5,
24.7, 24.0; HRMS (ESI+) calcd for C22H34NO4 (MH+) 376.2488,
found 376.2466.
Am in o Nitr ile 30: 1H NMR (400 MHz, CDCl3) δ 7.37-7.27
(m, 5H), 4.56 (ABq, J ) 12.0, 32.8 Hz, 2H), 3.85 (dd, J ) 3.5,
5.8 Hz, 1H), 3.35-3.44 (m, 2H), 3.08 (m, 1H), 2.20-1.04 (m,
17H); HRMS (APCI+) calcd for C21H29N2O (MH+) 325.2280,
found 325.2285.
The above cyanide 29 was dissolved in dry THF (4 mL) and
cooled to -20 °C, and 2.0 M C6H13MgBr in Et2O (339 µL, 0.678
mmol) and BF3‚Et2O (25 µL, 0.19 mmol) were added dropwise.
The reaction mixture was allowed to warm to room temper-
ature slowly and stirred overnight (∼12 h). The reaction
mixture was diluted with 1 N NaOH and extracted with CH2-
Cl2. The organic extracts were dried with K2CO3 and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (100:20:1.5 hexanes/
EtOAc/conc NH4OH) to give a 3:1 mixture of diastereomers
35 and 33 (25 mg, 67% from 27). The two diastereomers were
separated by preparative TLC (20:100:5 Et2O/hexanes/TEA)
to give 35 (19 mg, 50%) and 33 (6 mg, 17%). Ma jor Dia ste-
[6-(3,3-Dim e t h oxyp r op yl)-1-a za sp ir o[4.5]d e c-2-yl]-
m eth a n ol (26). To a solution of amide 25 (250 mg, 0.666
mmol) in a mixture of H2O (22 mL) and EtOH (11 mL) was
added LiOH‚H2O (3.25 g, 77.5 mmol) at room temperature.
After being refluxed for 7 days, the reaction mixture was
diluted with saturated aqueous NaHCO3 (10 mL) and ex-
tracted with CH2Cl2. The combined organic extracts were dried
over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (5:100:1.5 MeOH/CHCl3/NH4OH) to afford amino alcohol
26 (179 mg, 99%) as a colorless liquid: IR (film) 3360, 2932,

4344 J . Org. Chem., Vol. 67, No. 12, 2002
Sun et al.
r eom er 35: pale yellow oil; IR (film) 2927, 2856, 1090 cm-1
;
was added to a suspension of CuCN (4.675 g, 52 mmol) in 500
mL of dry THF under argon at 0 °C and the mixture was
stirred for 30 min. A solution of bromide 3730 (2.891 g, 16.2
mmol) in 40 mL of dry THF was added to the mixture at -40
°C over 2 h, and then the mixture was stored in a freezer (-20
°C) overnight (about 19 h). To the solution was added 30 mL
of saturated of NH4Cl. The mixture was stirred for 1 h and
extracted with Et2O. The combined organic layers were dried
over MgSO4 and evaporated. The residue was purified by flash
chromatography on silica gel (gradient from 2:1 EtOAc/
hexanes to 5:1 EtOAc/MeOH) to provide 38 as a colorless oil
(3.503 g, 92%): [R]20.0D -22.3 (c 1, EtOH); IR (film) 3222, 3069,
2954, 1694 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.49-7.47 (m,
2H), 7.46-7.34 (m, 3H), 6.17 (br s, 1H), 3.72 (tt, J ) 7.0, 7.1
Hz, 1H), 2.26-2.20 (m, 2H), 1.58-1.51 (m, 1H), 1.20 (dd, J )
5.7, 14.4 Hz, 1H), 1.02 (dd, J ) 8.6, 14.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 177.6, 137.9, 133.4, 129.4, 128.0, 52.0, 30.8,
30.5, 24.9, -2.4, -2.5; HRMS (APCI+) calcd for C13H19NOSi
(MH+) 234.1314, found 234.1314.
1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.49 (s, 2H),
3.54 (dd, J ) 4.1, 8.6 Hz, 1H), 3.27-3.26 (m, 1H), 3.13-3.03
(m, 2H), 2.02-1.96 (m, 1H), 1.67-0.99 (m, 26 H), 0.86 (t, J )
6.5 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 138.8, 128.3, 127.6,
127.4, 77.9, 73.2, 70.6, 67.6, 57.6, 53.7, 41.4, 37.9, 34.4, 31.9,
31.0, 29.6, 29.3, 28.1, 27.7, 26.4, 24.5, 24.0, 22.6, 14.1; HRMS
(ESI+) calcd for C26H42NO (MH+) 384.3266, found 384.3236.
Min or Dia ster eom er 33: colorless oil; IR (film) 2926, 2856,
1
1099 cm-1; H NMR (360 MHz, CDCl3) δ 7.31-7.23 (m, 5H),
4.52 (ABq, J ) 12.1 Hz, 2H), 3.61 (dd, J ) 6.0, 9.0 Hz, 1H),
3.59 (t, J ) 8.8 Hz, 1H), 3.10-3.06 (m, 1H), 2.14-2.10 (m, 2H),
1.83-1.01 (m, 26 H), 0.85 (t, J ) 6.6 Hz, 3H); 13C NMR (90
MHz, CDCl3) δ 138.8, 128.3, 127.5, 127.4, 77.6, 73.1, 67.5, 65.3,
62.7, 43.6, 38.8, 37.4, 32.0, 31.4, 31.0, 29.7, 27.1, 26.5, 26.4,
26.0, 24.9, 23.7, 22.7, 14.1; HRMS (ESI+) calcd for C26H42NO
(MH+) 384.3266, found 384.3277.
(()-Lep a d ifor m in e (6). To a solution of the above alkyla-
tion product 35 (18 mg, 0.0470 mmol) in THF (2 mL) and NH3
(10 mL) at -78 °C was added sodium metal (∼5 mg). The color
of the reaction solution changed to dark blue. The reaction
mixture was stirred at -78 °C for 1 h and quenched with NH4-
Cl (solid). The mixture was slowly warmed to room tempera-
ture with occasional replacement of the evaporating NH3 with
THF. The resulting solution was made basic with 1 N aqueous
NaOH and extracted with CH2Cl2. The organic extracts were
dried with K2CO3 and concentrated under reduced pressure.
The residue was purified by flash column chromatography on
silica gel (100:5:1.5 CHCl3/MeOH/concd NH4OH) to give (()-
lepadiformine free base (6, 14 mg, 100%) as a colorless oil: IR
(2S)-2-[(Dim et h ylp h en ylsila n yl)-m et h yl]-5-oxop yr r o-
lid in e-1-ca r boxylic Acid Ben zyl Ester (39). Potassium
hydride in mineral oil (35%, 4.008 g, 34.98 mmol) was
prewashed with dry hexane and dried under high vacuum.
THF (20 mL) was added, followed by lactam 38 (3.407 g, 14.60
mmol) in 50 mL of THF by cannula at 0 °C. The mixture was
stirred at 0 °C for 5 min and room temperature for 50 min.
The solution was then recooled to 0 °C and benzyl chlorofor-
mate (3.287 mL, 21.90 mmol) was added. The reaction mixture
was stirred at room temperature for 4 h and diluted with CH2-
Cl2. The mixture was washed with saturated sodium bicarbon-
ate and water, dried over MgSO4, and concentrated. The
residue was purified by flash column chromatography on silica
gel (25-50% EtOAc/hexanes) to provide the N-Cbz lactam 39
(film) 3412, 2931, 2857 cm-1 1H NMR (360 MHz, CDCl3) δ
;
3.37-3.30 (m, 2H), 3.19 (d, J ) 8.1 Hz, 1H), 3.13-3.10 (m,
1H), 1.78-1.13 (m, 27H), 1.04-0.97 (m, 1H), 0.85 (t, J ) 6.6
Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 67.4, 62.4, 58.4, 53.3,
40.2, 38.3, 34.1, 31.8, 30.5, 29.6, 28.2, 27.7, 27.6, 26.3, 24.3,
23.3, 22.7, 22.6, 14.0; HRMS (ESI+) calcd for C19H36NO (MH+)
294.2797, found 294.2789.
(5.130 g, 96%) as a pale yellow oil: [R]20.0 -33.9 (c 1, EtOH);
D
IR (film) 2955, 1788, 1748, 1714 cm-1 1H NMR (360 MHz,
;
CDCl3) δ 7.48-7.36 (m, 10H), 5.31 (d, J ) 12.2 Hz, 1H), 5.22
(d, J ) 12.3 Hz, 1H), 4.30 (ddt, J ) 11.8, 8.2, 2.2 Hz, 1H), 2.55
(ddd, J ) 17.8, 10.5, 9.1 Hz, 1H), 2.37 (ddd, J ) 17.8, 9.3, 3.2
Hz, 1H), 2.05-1.94 (m, 1H), 1.54-1.50 (m, 2H), 1.09 (dd, J )
11.9, 14.1 Hz, 1H), 0.32 (s, 3H), 0.317 (s, 3H); 13C NMR (90
MHz, CDCl3) δ 173.8, 151.1, 137.7, 135.3, 129.3, 128.5, 128.4,
128.3, 128.0, 67.8, 56.1, 31.1, 24.8, 22.1, -2.5, -2.7; HRMS
(APCI+) calcd for C21H25NO3Si (MH+) 368.1682, found 368.1704.
The above oil was dissolved in 2 mL of MeOH containing
1% 1 N aqueous HCl, and the solution was evaporated in vacuo
to give the hydrochloride salt of (()-lepadiformine as a white
solid: 1H NMR (360 MHz, CDCl3) δ 10.14 (br s, 1H), 5.23 (br
s, 1H), 4.17 (d, J ) 13.5 Hz, 1H), 3.61-3.70 (m, 3H), 2.49 (m,
1H), 2.38 (m, 1H), 2.16 (m, 2H), 2.02-2.08 (m, 2H), 1.90-1.97
(m, 2H), 1.65-1.82 (m, 5H), 1.24-1.55 (m, 13H), 0.98-1.08
(m, 1H), 0.86 (t, J ) 6.6 Hz, 3H); 13C NMR (90 MHz, CDCl3)
δ 77.2, 63.5, 59.9, 58.7, 36.2, 33.7, 31.6, 30.8, 29.9, 29.0, 26.5,
26.4, 24.9, 24.3, 23.2, 22.6, 22.4, 19.2, 14.0; HRMS (ESI+) calcd
for C19H36NO (M - Cl+) 294.2797, found 294.2789.
(2Z)-(7-Iod oh ep t-2-en yl)-tr im eth ylsila n e (40). To a solu-
tion of triphenylphosphine (5.629 g, 21.46 mmol) in CH2Cl2
were added imidazole (2.922 g, 42.93 mmol) and iodine (5.462
g, 21.46 mmol) at 0 °C. After stirring the mixture for 30 min,
7-trimethylsilanylhept-5-en-1-ol 31(2.000 g) in CH2Cl2 (10 mL)
was added dropwise. The resulting mixture was warmed to
room temperature and stirred for 1.5 h. Brine was added, and
the mixture was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated. The residue
was purified by flash column chromatography (hexanes) to
provide iodide 40 (2.694 g, 85%) as a colorless oil: IR (film)
(5-Hexyld eca h yd r op yr r olo[2,1-j]qu in olin -3-yl)-m eth a -
n ol (36). To a solution of the alkylation product 33 (11 mg,
0.0287 mmol) in THF (2 mL) and NH3 (10 mL) at -78 °C was
added sodium metal (∼5 mg). The color of the reaction solution
changed to dark blue. The mixture was stirred at -78 °C for
1 h, and the reaction was quenched with NH4Cl (solid). The
mixture was slowly warmed to room temperature with oc-
casional replacement of the evaporating NH3 with THF. The
resulting solution was made basic with 1 N aqueous NaOH
and extracted with CH2Cl2. The organic extracts were dried
with K2CO3 and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel (100:5:1.5 CHCl3/MeOH/conc NH4OH) to give 36 (7 mg,
1
3005, 2953, 16545 cm-1; H NMR (300 MHz, CDCl3) δ 5.42-
5.35 (m, 1H), 5.26-5.20 (m, 1H), 3.17 (t, J ) 7.1 Hz, 2H), 1.99
(q, J ) 7.0 Hz, 2H), 1.83 (p, J ) Hz 2H), 1.48-1.38 (m, 4H),
-0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 126.6, 126.1, 33.2,
30.5, 25.9, 18.5, 7.1, -1.8; HRMS (ESI+) calcd for C10H21ISi
(MH+) 297.0536, found 297.0560.
83%) as a colorless oil: IR (film) 3402, 2926, 2857 cm-1 1H
;
(2S,5S)-2-[(Dim eth ylp h en ylsila n yl)-m eth yl]-6-vin yl-1-
a za sp ir o[4.5]d eca n e-1-ca r boxylic Acid Ben zyl Ester (43).
To a stirred solution of iodide 40 (2.10 g, 7.07 mmol) in 11 mL
of Et2O at -78 °C was added dropwise 1.7 M t-BuLi in pentane
(8.53 mL, 14.5 mmol). The reaction mixture was kept at -78
°C for 40 min and slowly warmed to room temperature over
30 min. The solution was kept at room temperature for 0.5 h,
cooled to -78 °C, and transferred by cannula to a solution of
Cbz lactam 39 (1.30 mg, 3.54 mmol) in 8 mL of THF at -78
°C. The mixture was slowly warmed to -20 °C over 4 h, and
the reaction was quenched by a solution of saturated NaHCO3.
The aqueous layer was extracted with Et2O; the combined
organic layers were dried over Na2SO4 and concentrated, and
the residue was dried in vacuo.
NMR (360 MHz, CDCl3) δ 3.50 (dd, J ) 5.8, 10.3 Hz, 1H),
3.32-3.28 (m, 1H), 3.11-3.08 (m, 1H), 2.20-2.19 (m, 1H),
1.93-1.88 (m, 2H), 1.71-1.10 (m, 26H), 0.85 (t, J ) 6.6 Hz,
3H); 13C NMR (90 MHz, CDCl3) δ 66.7, 66.3, 64.9, 60.4, 41.8,
39.4, 38.0, 31.9, 31.2, 29.5, 27.7, 27.0, 26.3, 25.9, 25.85, 24.4,
23.9, 22.6, 14.1; HRMS (ESI+) calcd for C19H36NO (MH+)
294.2797, found 294.2818.
(5S)-5-[(Dim eth ylp h en ylsila n yl)-m eth yl]-p yr r olid in -2-
on e (38). To a stirred mixture of lithium shot (4.345 g, 626
mmol) in THF (100 mL) under argon at 0 °C was added
dropwise a solution of dimethylphenylsilyl chloride (17.53 mL,
104 mmol) in 25 mL of dry THF, and the mixture was warmed
to room temperature. After stirring for 16 h, the red solution

Marine Alkaloid Lepadiformine
J . Org. Chem., Vol. 67, No. 12, 2002 4345
The residue was diluted with dry CH2Cl2 (65 mL) and then
cooled to -78 °C. Flame-dried 4 Å molecular sieves (∼6 g) were
added followed by BF3‚2AcOH (983 µL, 7.08 mmol). The
mixture was kept at -78 °C for 1 h and warmed to room
temperature overnight. The reaction mixture was diluted with
saturated sodium bicarbonate solution and extracted with CH2-
Cl2. The organic layer was dried over MgSO4 and concentrated.
The residue was purified by flash column chromatography on
silica gel (10-25% EtOAc/hexanes) to provide spirocycle 43
as a pale yellow oil (828 mg, 52%) (4:1 mixture of rotamers):
a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.85-5.76 (m,
1H), 5.10-5.05 (m, 2H), 3.46 (dd, J ) 4.0, 10.0 Hz, 1H), 3.34-
3.28 (m, 1H), 3.24 (dd, J ) 6.0, 10.0 Hz, 1H), 2.43 (br s, 2H),
2.02-1.98 (m, 1H), 1.75-1.54 (m, 8H), 1.31-1.27 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 139.6, 116.4, 64.5, 64.3, 59.0, 51.7,
41.3, 30.5, 30.1, 28.0, 24.8, 24.3.
6-(3,3-Dim eth oxyp r op yl)-2-h yd r oxym eth yl-1-a za sp ir o-
[4.5]d eca n e-1-ca r boxylic Acid Ben zyl Ester (45). To a
solution of olefin 44a (419 mg, 1.27 mmol) in THF (6 mL) were
added Rh(CO)2(acac) (20 mg, 0.076 mmol) and P(OPh)3 (100
µL, 0.38 mmol) under argon. The round-bottomed flask was
subsequently placed in a stainless steel autoclave. The reaction
was carried out at 60 °C and 4 atm (initial pressure at 20 °C)
of CO and H2 (1:1) for 6 h with stirring. After the autoclave
was cooled to room temperature, the gases were released and
the reaction mixture was concentrated under reduced pressure.
To a solution of the above crude aldehyde in dry MeOH (6
mL) was added trimethyl orthoformate (696 µL, 6.36 mmol)
and HCl/MeOH (1 N, 254 µL) at room temperature. After 50
min, the mixture was diluted with saturated aqueous NaHCO3
(10 mL) and extracted with CH2Cl2. The organic extracts were
dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(30-50% EtOAc/hexanes) to afford acetal 45 as a colorless oil
[R]20.0 -13.0 (c 1, EtOH); IR (film) 2930, 2857, 1746, 1694
D
1
cm-1; H NMR (360 MHz, CDCl3) δ 7.21-7.05 (m, 10H), 5.40
(ddd, J ) 17.3, 7.5, 7.2 Hz, 1H), 5.05-4.82 (m, 2H), 4.67-4.62
(m, 2H), 4.05 (m, 0.2H), 3.90 (dd, J ) 7.9, 10.9 Hz, 0.8H), 3.10
(m, 0.8H), 2.75 (m, 0.2H), 2.50 (dt, J ) 3.5, 13.2 Hz, 0.8H),
2.15 (m, 0.2H), 1.78 (m, 1H), 1.50-1.03 (m, 11H), 0.74 (dd, J
) 11.9, 14.1 Hz, 1H), 0.13 (s, 0.6H), 0.11 (s, 0.6H), 0.0 (s, 2.4H),
-0.02 (s, 2.4H); 13C NMR (75 MHz, d8-toluene) δ 152.8, 140.6,
140.2, 139.8, 139.1, 139.0, 138.1, 137.7, 137.4, 134.0, 133.8,
114.8, 114.7, 68.0, 67.3, 66.5, 66.0, 58.0, 56.7, 45.2, 43.3, 40.2,
39.0, 32.2, 31.2, 30.5, 30.2, 30.1, 29.4, 25.7, 25.5, 24.8, 24.5,
-2.4, -2.6. 1H NMR (70 °C, 300 MHz, d8-toluene) δ 7.17-
6.97 (m, 10H), 5.57 (ddd, J ) 17.5, 7.3, 7.1 Hz, 1H), 5.07-4.42
(m, 4H), 4.26 (br s, 1H), 3.65 (br s, 1H), 2.90 (br s, 1H), 1.65-
0.85 (m, 12H), 0.21 (br s, 6H); HRMS (APCI+) calcd for C28H37
-
(466 mg, 90%) (1:1 mixture of rotamers): [R]20.0 -45.1 (c 1,
D
NO2Si (MH+) 448.2672, found 448.2672.
EtOH); IR (film) 3418, 2930, 1682 cm-1; H NMR (300 MHz,
1
2-Hyd r oxym eth yl-6-vin yl-1-a za sp ir o[4.5]d eca n e-1-ca r -
boxylic Acid Ben zyl Ester (44a ). To a solution of the above
silane 43 (116 mg, 0.259 mmol) in CH2Cl2 (5 mL) was added
BF3‚2AcOH (108 µL, 0.777 mmol) at room temperature. After
15 min, the mixture was diluted with saturated aqueous
NaHCO3 (5 mL) and extracted with CH2Cl2. The organic
extracts were dried over MgSO4 and concentrated under
reduced pressure to give the fluorosilane.
CDCl3) δ 7.35-7.26 (m, 5H), 5.17 (ABq, J ) 12.3, 25.5 Hz,
1H), 5.09 (ABq, J ) 12.3, 25.5 Hz, 1H), 4.26 (t, J ) 5.6 Hz,
0.5H), 4.20 (m, 0.5H), 4.10 (m, 0.5H), 3.94 (m, 0.5H), 3.64 (m,
1.5H), 3.47 (m, 0.5H), 3.25 (s, 1.5H), 3.24 (s, 1.5H), 3.22 (s,
1.5H), 3.21(s, 1.5H), 2.51-2.49 (m, 1H), 2.24-2.17 (m, 1H),
2.04-0.84 (m, 16H); 13C NMR (75 MHz, CDCl3) δ 156.8, 153.1,
137.0, 136.3, 128.5, 128.0, 127.8, 127.78, 104.4, 104.36, 69.7,
69.2, 67.3, 67.2, 66.1, 64.5, 63.2, 60.9, 52.6, 52.4, 52.1, 41.7,
39.5, 38.4, 38.2, 31.0, 30.8, 30.4, 30.2, 29.2, 26.1, 25.7, 25.6,
25.0, 24.8, 24.1, 24.0; HRMS (ESI+) calcd for C23H36NO5 (MH+)
406.2593, found 406.25933.
To a solution of the above fluorosilane in a mixture of MeOH
(5 mL) and THF (5 mL) was added NaHCO3 (109 mg, 1.30
mmol) at room temperature. After 15 min, H2O2 (35 wt %
solution in water, 275 µL) was added to the reaction mixture.
After being refluxed overnight, the mixture was diluted with
saturated aqueous NH4Cl (10 mL) and extracted with CH2-
Cl2. The organic extracts were dried over MgSO4 and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography ( 4:1 EtOAc/hexanes) to afford
alcohol 44a as a colorless oil (76 mg, 89%) (1:1 mixture of
[6-(3,3-Dim e t h oxyp r op yl)-1-a za sp ir o[4.5]d e c-2-yl]-
m eth a n ol (46). To a solution of the above alcohol 45 (40 mg,
0.099 mmol) in THF (2 mL), t-BuOH (0.2 mL), and NH3 (∼8
mL) at -78 °C was added sodium metal (∼10 mg). The color
of the reaction solution slowly changed to dark blue. The
reaction mixture was stirred at -78 °C for 10 min, and the
reaction was quenched with saturated aqueous NH4Cl. The
mixture was slowly warmed to room temperature, made basic
with 1 N aqueous NaOH, and extracted with CH2Cl2. The
organic extracts were dried with Na2SO4 and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (100:5:1 CHCl3/MeOH/
concentrated NH4OH) to give the amino alcohol 46 (25 mg,
94%) as a colorless oil, having spectral data identical to those
rotamers): [R]20.0 -31.9 (c 1, EtOH); IR (film) 3401, 2928,
D
2858, 1682 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m,
5H), 5.71-5.58 (m, 1H), 5.19-5.02 (m, 2H), 4.96-4.77 (m, 2H),
4.14-4.00 (m, 1H), 3.67-3.54 (m, 1.5H), 3.47-3.41 (dd, J )
7.3, 10.4 Hz, 0.5H), 3.20 (m, 0.5H), 3.06-3.03 (m, 0.5H), 2.61-
2.52 (m, 0.5H), 2.33-2.25 (m, 0.5H), 2.12-2.00 (m, 1H), 1.91-
1.09 (m, 11H); 13C NMR (75 MHz, CDCl3) δ 156.6, 153.3, 139.5,
138.9, 136.9, 136.1, 128.4, 128.3, 128.0, 127.7, 127.6, 115.4,
115.0, 69.0, 68.8, 67.2, 66.8, 66.0, 64.3, 62.9, 60.8, 44.8, 43.0,
38.2, 37.8, 31.4, 31.1, 29.2, 29.0, 26.1, 25.1, 24.9, 23.9; HRMS
(APCI+) calcd for C20H27NO3 (MH+) 330.2069, found 330.2071.
(6-Vin yl-1-a za sp ir o[4.5]d ec-2-yl)-m eth a n ol (44b). To a
solution of the above alcohol 44a (3 mg, 0.009 mmol) in THF
(2 mL), t-BuOH (0.5 mL), and NH3 (∼8 mL) at -78 °C was
added sodium metal (∼5 mg). The color of the reaction solution
slowly changed to dark blue. The reaction mixture was stirred
at -78 °C for 10 min; the reaction was quenched with
saturated aqueous NH4Cl, and the mixture was slowly warmed
to room temperature. The mixture was basified with 1 N
aqueous NaOH and extracted with CH2Cl2. The organic
extracts were dried with Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (100:5:1 CH2Cl2/MeOH/concen-
trated NH4OH) to give the amino alcohol 44b (2 mg, 100%) as
of the racemic compound 26: [R]20.0 -42.2 (c 1, EtOH).
D
Enantiomers 27, 35, and 6 and the HCl salt of 6 were
prepared as described for the racemic compounds and had
spectral data identical to those of corresponding racemates.
27: [R]20.0 -30.7 (c 1, EtOH). 35: [R]20.0 -22.3 (c 0.61,
D
D
MeOH). 6 free base: [R]20.0 -14.0 (c 0.45, MeOH). 6 HCl
D
salt: [R]20.0 +2.5 (c 0.51, CHCl3).
D
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (CA-34303) for financial support of
this research.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0201070