An Access to the Bicyclic Nucleus of the Sponge Alkaloid Halicyclamine A by Successive Condensation of Malondialdehyde Units, Aldehyde Derivatives, and Primary Amines

Article abstract of DOI:10.1021/jo034099e

First results of an evaluation of the synthetic sequence depicted in Scheme 4 are reported. This sequence is based upon biosynthetic considerations concerning the manzamine family of sponge alkaloids. Stable equivalents 21 and 31 of the tetraaldehyde 7 have thus been obtained by using the chemistry of malondialdehyde previously reported by Tietze. These compounds afforded pyridinium salts 23 and 33 when treated with a primary amine in acidic medium. Further reductive amination and cyclization yielded bicyclic derivatives 25 and 35, thus demonstrating the feasibility of this synthetic approach for the preparation of halicyclamine derivatives 13. Products resulting from cycloaddition reactions leading to 9 were not observed.

Full text of DOI:10.1021/jo034099e

An Access to th e Bicyclic Nu cleu s of th e Sp on ge Alk a loid
Ha licycla m in e A by Su ccessive Con d en sa tion of Ma lon d ia ld eh yd e
Un its, Ald eh yd e Der iva tives, a n d P r im a r y Am in es
Maria del Rayo Sanchez-Salvatori, and Christian Marazano*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
marazano@icsn.cnrs-gif.fr
Received J anuary 27, 2003
First results of an evaluation of the synthetic sequence depicted in Scheme 4 are reported. This
sequence is based upon biosynthetic considerations concerning the manzamine family of sponge
alkaloids. Stable equivalents 21 and 31 of the tetraaldehyde 7 have thus been obtained by using
the chemistry of malondialdehyde previously reported by Tietze. These compounds afforded
pyridinium salts 23 and 33 when treated with a primary amine in acidic medium. Further reductive
amination and cyclization yielded bicyclic derivatives 25 and 35, thus demonstrating the feasibility
of this synthetic approach for the preparation of halicyclamine derivatives 13. Products resulting
from cycloaddition reactions leading to 9 were not observed.
In tr od u ction
advantages since it can also explain the biosynthesis of
natural pyridinium salts according to Scheme 2.4 Experi-
mental results supported rather well this modified
hypothesis, in particular with respect to the synthesis of
the ABC ring of manzamine A.5
While these models thus gave encouraging synthetic
results, they all implicated intermediate dihydropyridium
salts, as initially postulated by Baldwin and Whitehead.
Accordingly, fundamental studies concerning the con-
densation of molecules such as 1 and 2 or their equiva-
lents remained to be performed. For these reasons we
recently embarked on model experiments addressing the
problem of the multicomponent condensation depicted in
Scheme 1 and summarized in Scheme 3.
Such condensations were expected to be of potential
synthetic value for the generation of a variety of natural
(or eventually nonnatural) molecular scaffolds. Thus, for
example (Scheme 4), this process can produce the tet-
raaldehyde intermediate 7. Reaction of this intermediate
with primary amines (adducts 8 and 11) can lead, via
formation of a new carbon-carbon bond (8 f 9), to the
manzamine A skeleton 10 or, via the formation of a
pyridinium salt 12, to the natural halicyclamine A6
skeleton 13.
Numerous new alkaloids have been recently isolated
from sponges of the order Haplosclerida.1 The most well-
known natural product in this series is probably man-
zamine A (Scheme 1) owing to its original structure and
biological activity.2
The intriguing problem of the biosynthetic origin of
manzamine A can be rather well rationalized starting
from a comparison with a natural analogue, manzamine
C (Scheme 1). Indeed, both products can be formed by
reductive condensation of tryptamine with strictly identi-
cal precursors: a three-carbon unit (for example, mal-
ondialdehyde 1), a dialdehyde 2 derived from fatty acids,
and ammonia. Considering this hypothesis, the only
difference in origin between these alkaloids would be that
manzamine C is formed from one molecule of each
precursor and tryptamine, while manzamine A is the
result of condensation of two molecules of the same
precursors 1 and 2 and tryptamine.
Such an hypothesis was initially formulated by Bald-
win and Whitehead and experimentally investigated.3 In
this proposal involving dihydropyridine and dihydropy-
ridinium salt intermediates, acrolein was proposed as the
three-carbon unit. We suggested later that involvement
of malondialdehyde 1 instead of acrolein would have some
In this paper we report a synthesis of stable equiva-
lents of tetraaldehyde 7 and their transformation into the
bicyclic skeleton of halicyclamine A according to a process
similar to the sequence 7 f 13.
(1) (a) Matzanke, N.; Gregg, R. J .; Weinreb, S. M. Org. Prep. Proc.
Int. 1998, 30, 3-51. (b) Tsuda, M.; Kobayashi, J . Heterocycles 1997,
46, 765-794. (c) Andersen, R. J .; Van Soest, R. W. M.; Kong, F.
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon Press/Elsevier Science: New York, 1996; Vol. 10, pp 301-
355. (d) Crews, P.; Cheng, X.-C.; Adamczeski, M.; Rodriguez, J .; J aspar,
M.; Schmitz, F. J .; Traeger, S. C.; Pordesimo, E. O. Tetrahedron 1994,
50, 13567-13574.
Resu lts a n d Discu ssion
There are many different ways of assembling alde-
hydes 1, 3, and 4 and amine precursors 5 and 6 shown
(2) Sakai, R.; Higa, T.; J efford, C. W.; Bernardinelli, G. J . Am. Chem.
Soc. 1986, 108, 6404-6405.
(4) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.; Das, B.
C. J . Am. Chem. Soc. 1998, 120, 8026-8034.
(5) (a) Herdemann, M.; Al-Mourabit, A.; Martin, M.-T.; Marazano,
C. J . Org. Chem. 2002, 67, 1890-1897. (b) J akubowicz, K.; Ben
Abdeljelil, K.; Herdemann, M.; Martin, M.-T.; Gateau-Olesker, A.;
Almourabit, A.; Marazano, C.; Das, B. C. J . Org. Chem. 1999, 64,
7381-7387.
(3) (a) Baldwin, J . E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33,
2059-2062. For the latest results in this field and previous references
see: (b) Gomez, J .-M.; Gil, L.; Ferroud, C.; Gateau-Olesker, A.; Martin,
M.-T.; Marazano, C. J . Org. Chem. 2001, 66, 4898-4903. (c) Baldwin,
J . E.; Claridge, T. D. W.; Culshaw, A. J .; Heupel, F. A.; Lee, V.; Spring,
D. R.; Whitehead, R. C. Chem. Eur. J . 1999, 5, 3154-3161.
10.1021/jo034099e CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003
J . Org. Chem. 2003, 68, 8883-8889
8883

Sanchez-Salvatori et al.
SCHEME 1
SCHEME 2
practically equal ratio (undefined geometry for the ex-
ternal double bond). This product can be considered as
an equivalent of the key tetraaldehyde 7 (cf. also Scheme
4).
The next sequence addressed the question of the
reactivity of aldehyde 21 toward primary amines (corre-
sponding to 5 and 6). The results are summarized in
Scheme 8. The imino derivative 22 was readily obtained
from n-butylamine. This derivative was not isolated but
was directly treated with methanesulfonic acid, according
to our reported procedure,5b to give pyridinium salt 23
in 66% isolated yield. Formation of a second imino
derivative 24 followed by reduction afforded amino
derivative 25 as a single isomer (undefined stereochem-
istry), accompanied by diastereoisomeric regioisomers
26a ,b (25/26a /26b ratio 82/13/5). Amine 25 was isolated
in 50% yield after chromatography on silica gel. Hydroly-
sis of the acetal and reductive amination finally led to
the bicyclic derivative 27, which was recovered in 70%
yield. This product was also isolated in comparable
overall yield when the same procedure was conducted
without isolation of intermediate amino derivative 25.
Acidic hydrolysis of acetal 25 in the presence of acetone
resulted in formation of 28 as two unseparable isomers
28a /28b in a 3/2 ratio (undefined stereochemistry).
Filtration over silica gel resulted in a new equilibrium11
in favor of isomer 28b (28a /28b ratio 1/4). Derivatives
28 possess some structural analogies with the skeleton
of sarain 1, another alkaloid extracted from sponges.12
A brief investigation of the reaction of aldehyde deriva-
tive 19b with a primary amine in acidic medium, followed
by NaBH4 reduction, is presented in Scheme 9. The only
product isolated was the olefinic piperidine 30, a mixture
of two diastereoisomers in 1/1 ratio, resulting presumably
from the reduction of an intermediate 1,4-dihydropyri-
dine 29.
SCHEME 3
in Scheme 3. A reasonable starting point would be a
sequence based on the well-known properties of malon-
dialdehyde 1.7 This highly reactive intermediate is indeed
known to very easily give Knoevenagel derivative 14
(Scheme 5). Unfortunately, the use of this adduct is
limited due to its high instability resulting from addition
of a third molecule of malondialdehyde to give cyclic
trimer 15.
In contrast, Tietze and co-workers have reported8 that
the monoprotected analogue 16 afforded Knoevenagel
adduct 17, again rather unstable, but which gave, after
reaction with enol ethers 18, cycloadducts such as 19
(Scheme 6).9
By using this approach, aldehydes 19a ,b were synthe-
sized following the reported procedures in 60% and 48%
yield, respectively. Considering Scheme 3, this sequence
corresponds to the condensation of two dialdehydes 1 and
aldehyde 3.
Reaction of aldehyde 19a with the anion of the silyl-
imino derivative 2010 gave, after hydrolysis, the new
aldehyde 21 as a mixture of two diastereoisomers in
Finally, we investigated the reaction sequence starting
from substituted aldehyde 19b (Scheme 10). Reaction
with imino derivative 29, under the conditions used for
preparation of aldehyde 21, led to aldehyde 31, isolated
in 82% yield as a mixture of diastereoisomers. This
(6) J aspars, M.; Pasupathy, V.; Crews, P. J . Org. Chem. 1994, 59,
3253-3255.
(7) Gomez-Sanchez, A.; Hermosin, I.; Lassaletta, J .-M.; Maya, I.
Tetrahedron 1993, 49, 1237-1250 and references therein.
(8) (a) Tietze, L. F.; Meier, H.; Nutt, H. Liebigs Ann. Chem. 1990,
253-260. (b) Tietze, L. F.; Meier, H.; Nutt, H. Chem. Ber. 1989, 122,
643-650. (c) Tietze, L. F.; Glu¨senkamp, K. H.; Holla, W. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 793-794.
(10) (a) Corey, E. J .; Enders, D.; Bock, M. G. Tetrahedron Lett. 1976,
7-10. (b) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P.
Tetrahedron Lett. 1985, 26, 2391-2394.
(9) Noteworthy is the fact that one such iridoid derivative, loganin,
is a precursor of the biosynthesis of thousands of natural alkaloids.
For a review, see: Szantay, C.; Honty, K. In Monoterpenoid Indole
Alkaloids; Saxton, J . E., Ed.; J ohn Wiley: Chichester, UK, 1994;
Chapter 4.
(11) Similar reversible equilibria have been observed for analogous
â-amino-ketones, see for example: Compe`re, D.; Marazano, C.; Das,
B. C. J . Org. Chem. 1999, 64, 4528-4532 and references therein.
(12) Cimino, G.; Spinella, A.; Trivellone, E. Tetrahedron Lett. 1989,
30, 133-136.
8884 J . Org. Chem., Vol. 68, No. 23, 2003

Preparation of Halicyclamine Derivatives
SCHEME 4
SCHEME 5
SCHEME 7 a
SCHEME 6
a
Reagents and conditions: (a) LDA, THF-HMPA, 0 °C, (b)
H2O; 70% overall yield.
four new bicyclic derivatives 35a -d in 16/27/47/9 ratio.
The structure of compound 35a was deduced from a
comparison with an authentic sample.5b The stereochem-
ical assignments for the other isomers were made after
a comparison of the 1H NMR signals of the benzylic
protons. These two protons appeared as singlets in
isomers 35a and 35b and as two distinct doublets in
isomers 35c and 35d . According to unambiguous data
from the literature,13 this clearly established a trans
relationship for substituents at the 3 and 4 positions of
the N-benzyl piperidine ring in 35a /35b and a cis
relationship for these substituents in 35c/35d . These
mixture was treated successively with n-butylamine to
give the corresponding imino derivatives 32 and then by
methanesulfonic acid affording finally two isomeric py-
ridinium salts 33 in 1/1 ratio and 66% yield.
Treatment of salts 33 under the conditions used for
the preparation of halicyclamine analogue 27 yielded the
J . Org. Chem, Vol. 68, No. 23, 2003 8885

Sanchez-Salvatori et al.
SCHEME 8 a
a
Reagents and conditions: (a) BuNH2, 3Å molecular sieves, MeOH, 60 °C; (b) MeSO3H, 60 °C, 66% overall yield for 23; (c) BnNH2, 3Å
molecular sieves, MeOH, 60 °C; (d) NaBH4, MeOH, 50% yield for 25; (e) 2 N HCl, dioxane then NaBH4;( f) TsOH, acetone, H2O.
SCHEME 9
data were, however, insufficient to distinguish these last
two isomers. Noteworthy is the fact that some natural
bis-piperidine analogues of halicyclamine A feature the
3,4 cis arrangement of the piperidine ring as in 35c/35d .14
sarain 1 (28). The synthetic route implicates nine reac-
tions which can be conducted in only four steps involving
consecutive reactions 16 f 19a f 21 f 23 f 27
(analogous sequences for 35a -d ). Bicyclic derivative 35
was produced as a diastereoisomeric mixture due to the
lack of selectivity observed for the reduction of open-chain
intermediate 33. For future synthetic purposes it will be
necessary to access, by a variation of the reported
procedure, intermediate 36 whose reduction has been
reported by us5b to be highly selective (leading to hali-
cyclamine A relative stereochemistry). The main present
limitation is the difficulty encountered in the cycloaddi-
tion reaction of the Knoevenagel derivative 17 with other
enol ethers 18, in particular those substituted by a long
lipophilic R1 alkyl chain.
Con clu sion
In conclusion, we have shown that it is possible to
make use of the condensation reactions of Scheme 3,
involving malondialdehyde, two aldehydes, and two
primary amines, for a practical access to analogues of
the natural sponge alkaloid halicyclamine A (27, 35). The
same procedure also allowed final introduction of a keto
derivative leading to adducts having some features of
(13) Lyle, R. E.; Pridgen, L. N. J . Org. Chem. 1973, 38, 1619-1620.
(14) (a) Mary J .; Brereton, I. M.; Willis, A. C.; Hooper, J . N. A.
Tetrahedron 1996, 52, 9111-9120. (b) Clark, R. J .; Field, K. L.; Charan,
R. D.; Garson, M. J .; Brereton, I. M.; Willis, A. C. Tetrahedron 1998,
54, 8811-8826. (c) Torres, Y. R.; Berlinck, R G. S.; Magalhaes, A;
Schefer, A B.; Ferreira, A. G.; Hajdu, E.; Muricy, G J . Nat. Prod. 2000,
63, 1098-1105.
Considering the synthetic route depicted in Scheme 4,
based upon a biogenetic proposal, it can be noted that
while analogues of tetraaldehydes 7 (21, 31) have been
obtained and shown to lead to bicyclic derivatives 13, the
formation of manzamine A-like adduct 10 was not
8886 J . Org. Chem., Vol. 68, No. 23, 2003

Preparation of Halicyclamine Derivatives
SCHEME 10 a
istic signals at δ 5.22 (dd, J ) 3, 4 Hz, 1H) and 5.23 (dd, J )
3, 3 Hz, 1H), 7.18 (s, 1H) and 7.19 (s, 1H), 9.22 (s, 1H) and
9.23 (s, 1H) (see Supporting Information for details); 13C NMR
(CD3OD, 75 MHz) δ 15.2 (2 × 1C), 22.0-22.5, 23.2-23.5, 30.2
(2 × 1C), 30.8-31.7, 38.2-38.9, 65.1-65.4, 77.3 (2 × 1C),
100.1-100.4, 101.4-101.6, 122.7-123.3, 162.7-163.3, 190.0-
190.6; SM (EI) m/z 284 (M+•), 255, 182; HRMS (CI, isobutane)
calcd for C15H25O5 (MH+) 285.1702, found 285.1706.
4-(5,5-Dim et h yl[1,3]d ioxa n -2-yl-m et h yl)-6-et h oxy-5-
m eth yl-5,6-d ih yd r o-4H-p yr a n -3-ca r ba ld eh yd e (19b). This
aldehyde was obtained from aldehyde 16 (7.9 g, 50 mmol),
malondialdehyde sodium salt (8.4 g, 65 mmol), and vinyl ether
18b (mixture of E and Z isomers, 19.3 mL, 175 mmol) by the
procedure used for the preparation of aldehyde 19a . Aldehyde
19b was recovered, after chromatography over silica gel
(AcOEt/heptane, 20/80), as a colorless oily mixture of four
diastereoisomers (ratio 47/35/14/4, 7.12 g, 48% yield): IR (film)
1674, 1119 cm-1; SM (EI) m/z 298 (M+•), 269, 196; HRMS (CI,
isobutane) calcd for C16H26O5 (MH+) 298.1780, found 298.1792.
A sample of the major isomer was isolated by chromatography
over silica gel for NMR analysis: 1H NMR (CDCl3, 250 MHz)
δ 0.71 (s, 3H), 0.85 (d, J ) 7 Hz, 3H), 1.17 (s, 3H), 1.25 (t, J )
7.2 Hz, 3H), 1.65 (dt, J ) 5, 8 Hz, 1H), 1.90 (dt, J ) 5, 8 Hz,
1H), 2.25 (m, 1H), 2.60 (m, 1H), 3.33-3.60 (m, 4H), 3.65, (q, J
) 7.5 Hz, 2H), 4.01 (dd, J ) 7.1, 7.1 Hz, 1H), 4.56 (t, J ) 5 Hz,
1H), 5.04 (d, J ) 2.5 Hz, 1H), 7.21 (s, 1H), 9.26 (s, 1H); 13C
NMR (CD3OD, 75 MHz) δ 11.5, 15.0, 21.8, 23.1, 30.1, 31.7,
34.0, 39.7, 65.7, 77.2, 101.2, 101.9, 121.2, 162.9, 190.6. HRMS
(CI, isobutane) calcd for C16H27O5 (MH+) 299.1859, found
285.1862.
3-[4-(5,5-Dim et h yl[1,3]d ioxa n -2-yl-m et h yl)-6-et h oxy-
5,6-d ih yd r o-4H-p yr a n -3-yl]-2-eth yl-p r op en a l (21). To a
solution of LDA, freshly prepared from n-butyllithium (1.6 M
in hexane, 11.2 mL) and diisopropylamine (2.57 mL, 18.3
mmol) in THF (4 mL), was added dropwise, at 0 °C and under
a nitrogen atmosphere, a solution of iminoderivative 20, in
THF (4 mL). The resulting mixture was stirred at 0 °C for 1
h. Hexamethylphosphotriamide (3.06 mL, 17.6 mmol) was then
added, followed after 0.2 h by dropwise addition of aldehyde
19a (2 g, 7.0 mmol) in THF (4 mL) over a period of 0.5 h. After
1 h at ambient temperature under stirring, the resulting
mixture was hydrolyzed with H2O (50 mL). Extraction with
Et2O (3 × 50 mL) and washing of the combined organic phase
with a saturated NaCl aqueous solution gave after the usual
workup and chromatography over silica gel (AcOEt/heptane,
10/90) aldehyde 21 as a mixture of two isomers in practically
1:1 ratio (colorless oil, 1.65 g, 70% yield). Mixture of the two
isomers: IR (film) 1677, 1139 cm-1; 1H NMR (CDCl3, 300 MHz)
characteristic signals at δ 4.49 (dd, J ) 4, 4 Hz, 2 × 1H), 5.07
(m, 2 × 1H), 6.52 (s, 2 × 1H), 6.75 (s, 1H), and 6.76 (s, 1H)
(see Supporting Information for details); 13C NMR (CD3OD,
75 MHz) δ 13.4 (2 × 1C), 15.2 (2 × 1C), 18.3 (2 × 1C), 21.9 (2
× 1C), 23.0 (2 × 1C), 27.3-27.9, 30.2 (2 × 1C), 31.1-32.0,
38.8-39.8, 64.5-64.8, 77.2 (2 × 2C), 97.4-98.2, 100.4 (2 ×
1C), 115.0-115.4, 140.6-140.8, 146.4-147.3, 149.1-149.6,
195.3 (2 × 1C); MS (CI) m/z 339 (MH+), 293, 163, 115; HRMS
(CI, isobutane) calcd for C19H31O5 (MH+) 339.2170, found
339.2150.
1-Bu t yl-3-[1-(5,5-d im et h yl[1,3]d ioxa n -2-yl-m et h yl)-3-
oxo-p r op yl]-5-eth yl-p yr id in iu m Meth a n esu lfon a te (23).
A solution of aldehyde 21 (1.43 g, 4.2 mmol) and n-butylamine
(1.25 mL, 12.6 mmol), in MeOH (70 mL) and in the presence
of 3 Å molecular sieves, was refluxed for 2 h. Methanesulfonic
acid (0.55 mL, 8.4 mmol) was added to the resulting mixture
and the solution was further refluxed overnight. Removal of
solvent and chromatography over silica gel (MeOH/CH2Cl2, 15/
85) afforded pyridinium salt 23 as a gum (1.24 g, 66% yield):
IR (film) 1717, 1395, 1197 cm-1; 1H NMR (CDCl3, 300 MHz) δ
0.65 (s, 3H), 0.93 (t, J ) 7.5 Hz, 3H), 1.01 (s, 3H), 1.32 (t, J )
7.2 Hz, 3H), 1.35 (m, J ) 5, 7 Hz, 2H), 1.96 (m, J ) 5, 5 Hz,
2H), 2.15 (m, 2H), 2.74 (s, 3H), 2.87 (q, J ) 7.2 Hz, 2H), 3.10
(dd, J ) 2 Hz, 7 Hz, 1H), 3.2-3.5 (m, 5H), 3.73 (m, 1H), 4.36
a
Reagents and conditions: (a) LDA, THF-HMPA, 82% yield;
(b) BnNH2, 3Å molecular sieves, MeOH, reflux; (c) MeSO3H,
MeOHn reflux, 66% yield from 31; (d) BnNH2, 3Å molecular sieve,
MeOH reflux, then NaBH4; (e) 2 N HCl, dioxane, then NaBH4,
55% yield (mixture of 35a /35b/35c/35d in 16/27/47/9 ratio).
observed. We believe that the difficulty encountered in
the formation of this product is likely to be due to the
reversibility of formation of adducts such as 9, while the
formation of pyridinium salts such as 12 is irreversible.
Research concerning the applications in natural prod-
uct synthesis of the multicomponent assembly depicted
in Scheme 3 is currently underway in our laboratory.
Exp er im en ta l Section
4-(5,5-Dim et h yl[1,3]d ioxa n -2-yl-m et h yl)-6-et h oxy-5,6-
d ih yd r o-4H-p yr a n -3-ca r ba ld eh yd e (19a ). A solution of
aldehyde 16 (2 g, 12.6 mmol) and malondialdehyde sodium salt
(2.12 g, 16.4 mmol), in H2O (20 mL), was stirred, under a
nitrogen atmosphere, during 48 h at 5 °C. The resulting
mixture was allowed to warm to 20 °C and ethyl vinyl ether
18a (4 0.24 mL, 44.3 mmol), in 1,2-dichloroethane, was added
dropwise followed by portionwise addition of NaH2PO4‚2H2O
(7.59 g). After stirring at rt for 2 h the solution was neutralized
with sodium bicarbonate (6.3 g) and diluted with H2O (30 mL).
Extraction with CH2Cl2 (3 × 30 mL) and the usual workup
gave a residue that was chromatographed over silica gel with
AcOEt/heptane (20/80) as eluent. Aldehyde 19a was isolated
as a mixture of two isomers in approximately 1:1 ratio (pale
yellow oil, 5.5 g, 60% yield). Mixture of the two isomers: IR
(film) 1673, 1145 cm-1; 1H NMR (CDCl3, 300 MHz) character-
J . Org. Chem, Vol. 68, No. 23, 2003 8887

Sanchez-Salvatori et al.
(t, J ) 4.5 Hz, 1H), 4.79 (m, 2H), 8.09 (s, 1H), 8.72 (s, 1H),
9.04 (s, 1H), 9.65 (s, 1H); 13C NMR (CD3OD, 75 MHz) δ 13.7,
14.6, 19.3, 21.7, 23.0, 25.9, 30.0, 32.6, 33.8, 39.3, 39.6, 49.4,
61.7, 77.4 (2C), 99.9, 141.4, 142.3, 144.1, 144.4, 146.0, 200.5;
MS (ESI) m/z 348 (M+).
28.3, 29.2, 30.6, 32.2, 33.9, 39.9, 40.3, 45.7, 53.5, 54.2, 56.1,
58.3, 58.9, 120.4, 126.9, 128.2, 129.6, 138.1, 139.4, 208.8;
HRMS (CI, isobutane) calcd for C26H41N2O (MH+) 397.3219,
found 397.3215.
1-Bu tyl-4-[5,5-d im eth yl[1,3]d ioxa n -2-yl-m eth yl]-3-m e-
th ylen e-p ip er id in e (30). A solution of aldehyde 19a (0.18 g,
0.6 mmol), n-butylamine (0.12 mL, 1.2 mmol), and 2 N HCl
(0.2 mL) in MeOH (5 mL) was refluxed overnight. After
removal of solvents under reduced pressure, the resulting
mixture was dissolved in MeOH and an excess of NaBH4 was
added. After overnight stirring at ambient temperature, the
usual workup left a gum that was chromatographed over
alumina (AcOEt/heptane: 10/90). Piperidine 30 was obtained
as a mixture of two isomers (0.50 g, 28% yield): IR (film) 1649,
Ben zyl[3-(1-bu tyl-5-eth yl-1,2,3,6-tetr a h yd r o-p yr id in -3-
yl)-4-(5,5-d im et h yl[1,3]d ioxa n -2-yl)-b u t yl]a m in e (25). A
solution of pyridinium salt 23 (0.9 g, 2 mmol) and benzylamine
(0.33 mL, 3 mmol), in MeOH (35 mL), was refluxed over 3 Å
molecular sieves for 2 h. The resulting imino derivative 24 was
not isolated, but was directly reduced at ambient temperature
by addition of an excess of sodium borohydride, followed by
stirring of the resulting mixture overnight. The usual workup
left a gum (mixture of amino derivative 25 and two isomeric
amines 26 in a 82/13/5 ratio as determined by GC). Chroma-
tography over silica gel (AcOEt/heptane, 50/50) allowed sepa-
ration of major amino derivative 25 as a colorless oil (442 mg,
1 mmol, 50% yield): IR (film) 1455, 1119, 1019 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.69 (s, 3H), 0.92 (t, J ) 7.2 Hz, 3H), 0.99
(t, J ) 7.5 Hz, 3H), 1.16 (s, 3H), 1.30 (q, J ) 7.5 Hz, 2H), 1.48-
1.67 (m), 1.98 (m, 3H), 2.42 (t, J ) 7.5 Hz, 2H), 2.55 (m, 1H),
2.65 (m, 3H), 2.78 (dt, J ) 5.5, 11 Hz, 1H), 3.02 (d, J ) 13 Hz,
1H), 3.35 (d, J ) 11 Hz, 2H), 3.55 (d, J ) 11 Hz, 2H), 3.78 (s,
2H), 4.45 (t, J ) 5 Hz, 1H), 5.26 (s, 1H), 7.28 (m, 5H); 13C NMR
(62.8 MHz, CDCl3) δ 12.1, 14.0, 20.7, 21.7, 23.0, 27.8, 29.0,
30.0, 31.5, 34.3, 36.6, 38.1, 47.6, 52.9, 53.7, 55.8, 58.2, 77.1,
101.3, 120.7, 126.9, 128.1, 128.3, 138.4, 139.8; HRMS (CI,
1
1468, 1393, 1135 cm-1; H NMR (CDCl3, 300 MHz) δ 0.69 (s,
3H), 0.86 (m, 6H), 1.17 (s, 3H), 1.20 (q, J ) 7.5 Hz, 2H), 1.47
(q, J ) 7.5 Hz, 2H), 1.6-1.8 (m, 2H), 1.95 (m, 1H), 2.36 (m,
4H), 2.59 (dd, J ) 3, 11 Hz, 1H), 2.76 (m, 1H), 2.96 (m, 1H),
3.38 (m, 2H), 3.50 (m, 2H), 4.41 (dd, J ) 3, 4 Hz, 1H), 4.50 (t,
J ) 6 Hz, 1H), 4.55 (t, J ) 6 Hz, 1H), 4.71 (d, J ) 14.5 Hz,
2H), 4.80 (d, J ) 6 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ
14.1 and 14.7, 18.6, 20.9, 21.9, 23.1, 29.3, 30.2 and 30.3, 31.9
and 33.8, 35.5 and 35.6, 40.9 and 43.4, 53.0 and 58.1, 58., and
58.8, 59.2 and 60.0, 77.4 (2C), 101.1 and 101.3, 110.0 and 110.2,
146.0; HRMS (CI, isobutane) calcd for C18H34NO2 (MH+)
296.2572, found 296.2589.
3-[4-(5,5-Dim eth yl[1,3]d ioxa n -2-yl-m eth yl)-6-eth oxy-5-
m eth yl-5,6-dih ydr o-4H-pyr an -3-yl]-2-m eth yl-pr open al (31).
To a solution of LDA, freshly prepared from n-butyllithium
(1.6 M in hexane, 13.4 mL) and diisopropylamine (3 mL, 21.8
mmol) in THF (5 mL), was added dropwise, at 0 °C and under
a nitrogen atmosphere, a solution of imino derivative 29 (3.88
g, 21 mmol), in THF (5 mL). The resulting mixture was stirred
at 0 °C for 1 h. Hexamethylphosphotriamide (3.64 mL, 21
mmol) was then added, followed after 0.2 h by dropwise
addition of aldehyde 19b (2.5 g, 8.4 mmol) in THF (5 mL) over
a period of 0.5 h. After 1 h at ambient temperature under
stirring, the resulting mixture was hydrolyzed with H2O (50
mL). Extraction with Et2O (3 × 50 mL) and washing of the
combined organic phase with a saturated NaCl aqueous
solution gave after the usual workup and chromatography over
silica gel (AcOEt/heptane 10/90) aldehyde 31 as a mixture of
isomers (colorless oil, 2.31 g, 82% yield). Mixture of isomers
isobutane) calcd for
443.3635.
C
28H47N2O5 (MH+) 443.3635, found
1-Ben zyl-1-bu tyl-5-eth yl-1,2,3,6,1,2,3,4,5,6-d eca h yd r o-
[3,4]bip yr id in yl (27). A solution of amino derivative 25 (440
mg, 1 mmol) and aqueous 2 N HCl (13 mL), in dioxane (13
mL), was heated at 50 °C overnight. The resulting mixture
was allowed to cool to room temperature and sodium borohy-
dride (0.33 g, 8.8 mmol) was then added portionwise. After 5
h under stirring, the solvent was evaporated under reduced
pressure, H2O was added, and the product was extracted with
CH2Cl2. The usual workup gave a residue that was chromato-
graphed over silica gel (heptane/AcOEt 50/50) to give pure
bicyclic derivative 27 (240 mg, 0.7 mmol, 70% yield) as a
colorless oil: IR (film) 1494, 1456, 1196 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.91 (t, J ) 7.5 Hz, 3H), 0.99 (t, J ) 7.8 Hz, 3H),
1.30 (q, J ) 7.8 Hz, 2H), 1.33 (m, 3H), 1.52 (q, J ) 7.8 Hz,
2H), 1.59 (dt, J ) 3, 13 Hz, 2H), 1.71 (dt, J ) 3, 13 Hz, 2H),
1.91 (dt, J ) 3, 15 Hz, 2H), 1.97 (q, J ) 7.5 Hz, 2H), 2.07 (m,
2H), 2.37 (t, J ) 7.8 Hz, 2H), 2.64 (m, 2H), 2.88 (m, 2H), 2.95
1
(see Supporting Information for H NMR): IR (film) 1674, 1162
cm-1; HRMS (CI, isobutane) calcd for C19H31O5 (MH+) 339.2172,
found 339.2175. A small quantity of one of the major isomer
was isolated by chromatography over silica gel: 1H NMR
(CDCl3, 300 MHz) δ 0.71 (s, 3H), 0.97 (d, J ) 7.5 Hz, 3H),
1.17 (s, 3H), 1.26 (t, J ) 7.5 Hz, 3H), 1.71 (m, 1H), 1.83 (m,
1H), 1.91 (s, 3H), 2.16 (m, 1H), 2.50 (m, 1H), 3.37 (d, J ) 11
Hz, 2H), 3.60 (d, J ) 11 Hz, 2H), 3.64 (q, J ) 7.5 Hz, 1H),
3.97 (q, J ) 7.5 Hz, 1H), 4.49 (t, J ) 5 Hz, 1H), 4.95 (d, J )
2.1 Hz, 1H), 6.61 (s, 1H), 6.82 (s, 1H), 9.36 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ 11.0, 12.0, 15.1, 21.8, 22.9, 30.1, 34.1,
36.9, 40.4, 65.3, 77.1, 77.2, 99.4, 100.1, 113.7, 133.9, 148.5,
150.5, 195.1; HRMS (CI, isobutane) calcd for C19H31O5 (MH+)
339.2172, found 339.2173.
(d, J ) 15 Hz, 1H), 3.47 (s, 2H), 5.40 (s, 1H), 7.25 (m, 5H); 13
C
NMR (75.5 MHz, CDCl3) δ 12.4, 14.2, 20.9, 28.0, 29.4, 29.6,
29.7, 39.5, 40.6, 53.8, 54.2, 56.3, 58.5, 63.6, 120.7, 126.9, 128.1,
129.2, 138.1, 138.6; SM (CI) m/z 341 (MH+), 249; HRMS (CI,
isobutane) calcd for C25H37O2 (MH+) 341.2956, found 341.2943.
1-(1-Ben zyl-1-bu tyl-5-eth yl-1,2,3,6,1,2,3,4,5,6-decah ydr o-
[3,4]bipyr idin yl-2-yl)-pr opan -2-on e (28). A solution of amino
derivative 25 (75 mg, 0.17 mmol), in a mixture of acetone/H2O
(1/4, 6 mL), was refluxed for 30 h in the presence of pyridinium
p-toluenesulfonate (40 mg, 0.16 mmol) and p-toluenesulfonic
acid (126 mg, 0.66 mmol). The resulting mixture was neutral-
ized with a saturated solution of aqueous sodium bicarbonate.
Extraction with CH2Cl2 followed by the usual workup gave
crude adduct 28, which was found to be a mixture of two
unseparable diastereoisomers 28a and 28b in an approximate
ratio of 3/2 respectively as determined by 1H NMR spectroscopy
(CH3CO signals). Filtration over silica gel (MeOH/CH2Cl2 1/99)
resulted in equilibration in favor of diastereoisomer 28b (28a /
1-Bu t yl-3-[1-(5,5-d im et h yl[1,3]d ioxa n -2-yl-m et h yl)-2-
m eth yl-3-oxo-p r op yl]-5-m eth yl-p yr id in iu m Meth a n esu l-
fon a te (33). A solution of aldehyde 31 (1.0 g, 2.96 mmol) and
n-butylamine (0.87 mL, 8.87 mmol), in MeOH (50 mL), was
refluxed over 3 Å molecular sievesfor 2 h. Methanesulfonic acid
(0.38 mL, 5.9 mmol) was added to the resulting mixture and
the solution further refluxed overnight. Removal of solvent
followed by chromatography over silica gel (MeOH/CH2Cl2, 15/
85) afforded pyridinium salt 33, which was isolated as a
mixture of two isomers in approximately 1:1 ratio (850 mg,
65% yield). Mixture of isomers 33: IR (film) 1718, 1633, 1196
28b 1/4, 30 mg, 45% yield): IR (film) 1710, 1494, 1353 cm-1
;
SM (ESI) m/z 397 (MH)+, 339; HRMS (CI, isobutane) calcd
for C26H41N2O (MH+) 397.3219, found 397.3232. NMR data for
the major isomer (28b): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t,
J ) 6.9 Hz, 3H), 1.02 (t, J ) 7.5 Hz, 3H), 1.36 (m, 4H), 1.50
(m, 5H), 1.96 (m, 4H), 2.09 (m, 5H), 2.40 (q, J ) 7.2 Hz, 2H),
2.61 (m, 4H), 2.90 (m, 1H), 3.4-3.6 (m, 4H), 5.38 (s, 1H), 7.28
(m, 5H); 13C NMR (75.5 MHz, CDCl3) δ 12.3, 14.0, 20.8, 27.9,
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.58 (2 × 3H), 0.90 and
0.94 (t, J ) 7.3 Hz, 3H), 0.99 and 1.15 (d, J ) 7.1 Hz, 3 H),
1.35 (m, 2 × 2H), 2.00 (m, 2 × 2H), 2.14 (m, 2 × 2H), 2.60 and
2.61 (s, 3H), 2.75 (s, 2 × 3H), 2.98 and 3.11 (q, J ) 6.6 Hz,
8888 J . Org. Chem., Vol. 68, No. 23, 2003

Preparation of Halicyclamine Derivatives
1H), 3.28 (m, 2 × 2H), 3.44 (m, 2 × 2H), 3.58 and 3.67 (m,
1H), 4.25 and 4.33 (t, J ) 6.6 Hz, 1H), 4.80 (t, J ) 7 Hz, 2 ×
2H), 8.01 and 8.07 (s, 1H), 8.88 and 8.94 (s, 1H), 9.07 and 9.17
(s, 1H), 9.60 and 9.66 (s, 1H), 36 (s, 1H); 13C NMR (75.5 MHz,
CDCl3), see Supporting Information; SM (ESI) m/z 348 (M+).
Ha licycla m in e A An a logu es (35a -d ). Amino derivatives
34 (four diastereoisomers, 62 mg, 62% yield, see Supporting
Information for the 1H NMR spectrum of the diastereoisomeric
mixture) were obtained from pyridinium salts 33 (100 mg, 0.22
mmol) according to the procedure used for the preparation of
amino derivative 25. These amino derivatives (100 mg, 0.22
mmol) were treated according to the procedure used for the
preparation of 27 to give halicyclamine A diastereoisomeric
analogues 35a , 35b, 35c (major), and 35d (minor) (42 mg, 55%
yield) as a mixture of four diastereoisomers in a 16/27/47/9
ratio as determined by integration of olefinic proton signals
in the 1H NMR spectrum of the crude mixture. Mixture of
isomers: IR (film) 1455, 1633, 1196 cm-1); MS (CI) m/z 341
(MH+), 249, 186, 91; HRMS (CI, isobutane) calcd for C23H37N2
(MH+) 341.2957, found 341.2958. Careful chromatography over
silica gel allowed separation of a small quantity of the four
isomers. Isomer 35a : 1H NMR (CDCl3, 300 MHz) and 13C NMR
(75.5 MHz, CDCl3) spectra superimposable to the correspond-
ing spectra of an authentic sample.5b Isomer 35b: 1H NMR
(CDCl3, 300 MHz) δ 0.85 (d, J ) 7 Hz, 3H), 0.84 (t, J ) 7.5
Hz, 3H), 1.15-1.60 (m, 7H), 1.56 (s, 3H), 1.79 (ddd, J ) 2.5,
11, 11 Hz, 1H), 1.97 (dd, J ) 9.6, 9.9 Hz, 1H), 2.28 (dt, J ) 2,
8 Hz, 2H), 2.53 (m, 3H), 2.74 (m, 2H), 2.89 (d, J ) 15.3 Hz,
1H), 2.92 (br d, J ) 15.3 Hz, 1H), 3.36 (s, 3H), 5.29 (br s, 1H),
7.17 (m, 5H). Isomer 35c: 1H NMR (CDCl3, 300 MHz) δ 0.84
(t, J ) 7 Hz, 3H), 0.95 (d, J ) 6.5 Hz, 3H), 1.15-1.33 (m, 4H),
1.35-1.52 (m, 4H), 1.58 (s, 3H), 1.68-2.08 (m, 6H), 2.19-2.41
(m, 2H), 2.48-2.67 (m, 3H), 2.75-2.88 (m, 2H), 3.26 (d, J )
13 Hz, 1H), 3.42 (d, J ) 13 Hz, 1H), 5.42 (br s, 1H), 7.10-7.36
(m, 5H). Isomer 35d : 1H NMR (CDCl3, 300 MHz) δ 0.87 (t, J
) 7 Hz, 3H), 0.96 (d, J ) 6.5 Hz, 3H), 1.59 (s, 3H), 2.80-2.91
(m, 1H), 3.00 (br d, J ) 17 Hz, 1H), 3.14 (br d, J ) 14.5 Hz,
1H), 3.27 (d, J ) 13 Hz, 1H), 3.43 (d, J ) 13 Hz, 1H), 5.56 (br
s, 1H), 7.12-7.37 (m, 5H).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of derivatives 19a ,b, 21, 23, 25, 27, 30, 31, and
33 with attribution of signals, and 1H NMR spectra of
derivatives 28, 34, and 35a -d . This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034099E
J . Org. Chem, Vol. 68, No. 23, 2003 8889