Total synthesis of (± )-Haliclonacyclamine C

Article abstract of DOI:10.1002/anie.200905732

"Chemical Equation Presented" (±)-Haliolonacyolamine C First In Its class: The synthesis of the tetracyclic alkylpiperidine marine alkaloid (±)-haliclonacyclamine C has been completed, with a longest linear sequence of 24 steps. The key transformations are the stereoselective hydrogenation of an unsaturated macrocyclic bis (piperidine) and a ring-closing alkyne metathesis reaction.

Full text of DOI:10.1002/anie.200905732

Angewandte
Chemie
DOI: 10.1002/anie.200905732
Natural Product Synthesis
Total Synthesis of (ꢀ )-Haliclonacyclamine C**
Brian J. Smith and Gary A. Sulikowski*
The alkylpiperidine alkaloids are a group of natural products
that are hypothetically derived from nicotinic acid and
isolated from various marine organisms.[1,2] The simplest
family members are 3-alkylpyridines with molecular com-
plexity increasing with the incorporation of tricyclic, tetracy-
clic and pentacyclic structural motifs (Scheme 1). A number
iclonacyclamines have been reported to display cytotoxic,
antibiotic and antifungal properties.[8a]
Haliclonacyclamines A–F differ structurally in the
number and location of cis olefins in the alkyl side chain
Scheme 2. Variation in the bis(piperidine) stereochemistry of haliclona-
cyclamines.
Scheme 1. Alkylpiperidine alkaloids. Haliclonacyclamine C contains a
=
C C double bond between C25 and C26.
and in the relative stereochemistry within the bis(piperidine)
core (Scheme 2). As an entry point to developing a synthetic
route to members of the tetracyclic alkylpiperidine alkaloid
family, we chose haliclonacyclamine C (3) and dihydrohali-
clonacyclamine C (4) as targets for total synthesis. Dihydro-
haliclonacyclamine C (4) is the hydrogenation product of
haliclonacyclamines A–C; the structural assignments of hal-
iclonacyclamines A–B have been firmly supported by single-
crystal X-ray analyses.[8]
A major challenge associated with developing a synthetic
strategy toward tetracyclic alkylpiperidines is the introduc-
tion of the four stereocenters incorporated within the
bis(piperidine) core (Scheme 2). The selection of dihydroha-
liclonacyclamine C (4) as our initial synthetic target was
partially because the anticipated stereoselective hydrogena-
tion of diene 6 to bis(piperidine) 7, which leads to the relative
stereochemistry pattern for haliclonacyclamines A–D
(Scheme 3). Our stereochemical analysis of the hydrogena-
tion of 6 was based on the incorporation of the central 1,3-
diene of tricycle 6 into a 17-membered macrocycle that would
of alkylpiperidine alkaloids have been the subject of intense
synthetic investigation owing to their novel structures and
biological activity. To date, the majority of this synthetic effort
has been focused on a pentacyclic subgroup that includes
manzamines,[3] sarains[4] and madangamines.[5] Little progress
has been reported toward the synthesis of the intermediate
tetracyclic class of alkylpiperidines that feature a central 3,4-
linked bis(piperidine) core that is appended to two aliphatic
macrocycles.[6] Members of this subgroup include the halicycl-
amines,[7] haliclonacyclamines[8] and arenosclerins.[9] Over
sixteen tetracyclic alkaloids have been isolated from a variety
of marine sponges, with haliclonacyclamines A–F constituting
the largest subgroup of those isolated (Scheme 2).[8,9a] Hal-
[*] B. J. Smith, Prof. G. A. Sulikowski
Departments of Chemistry and Biochemistry, Vanderbilt University,
Vanderbilt Institute of Chemical Biology
Nashville, TN 37235 (USA)
ꢁ
favor the peripheral hydrogenation of the C9 C10 alkene to
afford a product with the desired cis relationship between the
C7 and C9 stereocenters.[10] Less certain was the diastereo-
Fax: (+1)615-343-4155
ꢁ
facial selectivity of the hydrogenation of the C2 C3 double
E-mail: gary.a.sulikowski@vanderbilt.edu
bond (6), as this carbon–carbon double bond is situated in a
piperidine ring that possesses a stereochemically dynamic
nitrogen atom (see 6a and 6b). Assuming that the latter
hydrogenation proceeds with modest facial selectivity, we
predicted the delivery of two diastereomers: the desired cis-
syn-cis isomer (7b) and the corresponding cis-anti-cis isomer
(7a) (Scheme 3). Assembly of the key intermediate (6)
required a combination of cross-coupling and ring-closing
metathesis reactions as described below. A ring-closing
metathesis (RCM) reaction, alkene hydrogenation and
[**] We thank the National Institutes of Health (GM067726) and the
Vanderbilt Institute of Chemical Biology for their support of this
research. We also thank Joseph Reibenspies (Center for Chemical
Characterization and Analysis, Texas A&M University) for the X-ray
crystallographic analysis of 25. We gratefully acknowledge Prof.
Mary Garson (University of Queensland) for providing a sample of
dihydrohaliclonacyclamine C and spectral data. We also acknowl-
edge Matthew Mulder and Chris Denicola (Lindsley Group,
Vanderbilt University) for providing valuable analytical support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905732.
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addition of 6-iodo-1-hexene completed the assembly of
iodoenamide 12.
Stannane 16 (Scheme 5) was derived from b-keto ester
13,[14] starting with the formation of an intermediate enol
triflate that afforded allyl alcohol 14 upon reduction with
diisobutylaluminum hydride. Silylation of 14 (TBSCl, imida-
zole, DMAP) preceded Stille coupling with hexamethyldis-
tannane to afford stannane 16.[15] The optimal conditions for
the cross-coupling reaction between 12 and 16 employed
copper(I) chloride as an accelerant and furnished bis(piper-
idine) 17 in 75% yield.[16] Exchange of TBS ether 17 for allylic
acetate 18 set the stage for a second Stille coupling between
18 and (E)-6-(tributylstannyl)hex-5-en-1-ol to provide 19 in
80% yield.[17] With all carbons now in place, we turned our
attention to the first of two ring-closing metathesis reactions.
To this end, hydrochloride salt 19·HCl was treated with
Fꢀrstnerꢁs ruthenium indenylidene catalyst in refluxing
dichloromethane to provide tricyclic amine 20 (> 90%
trans).[18–20] Exhaustive hydrogenation of 20·TFA at 500 psi
in ethanol over Pearlmanꢁs catalyst at 708C for 8 days led to
an inseparable 1.3:1 mixture of two isomers that were
tentatively assigned to 21a and 21b, respectively. The mixture
of diols (21) was oxidized with Dess–Martin periodinane to
give the moderately stable bis(aldehyde) 22. Without purifi-
cation, 22 was treated with 10 equivalents of methylenetri-
phenylphosphorane to provide bis(alkene) 23. The tetracyclic
ring system was completed upon treatment of the TFA salt,
derived from 23, with Grubbꢁs first generation catalyst to
provide the resolved isomers, 24a and 24b, in a combined
yield of 80%. Amines 24a and 24b were separated by flash
chromatography and each were determined to contain a trans
double bond [6:1 (24a) and > 95:5 (24b)]. Hydrogenation of
24a (100 psi, Pd(OH)2, EtOH) provided lactam 25, the single-
crystal X-ray analysis of which confirmed the cis-syn-cis
stereochemistry of the bis(piperidine) core (Figure 1).[21,23]
Scheme 3. Synthetic strategy toward haliclonacyclamine C (3) and
dihydrohaliclonacyclamine C (4). Haliclonacyclamine C contains a C C
double bond between C25 and C26.
=
lactam reduction would advance diene 7b (Y= H, CH2) to
dihydrohaliclonacyclamine C (4), whilst the total synthesis of
haliclonacyclamine C (3) would require a ring-closing alkyne
metathesis (RCAM) starting from the corresponding diyne
(7b, Y= CCH3), followed by semihydrogenation to introduce
[11]
ꢁ
the C25 C26 cis alkene.
Our synthesis started with a six-step preparation of 3-
iodoenamide 12 from glutarimide (8; Scheme 4). Iodoena-
mide 12 served as one of two piperidine units for a cross-
Scheme 4. Synthesis of fragment 12: a) 5-Benzyloxypentanol, PPh3,
DIAD, THF, 238C, 91%; b) NaBH4, HCl/EtOH, ꢁ208C; c) TFAA, THF,
238C, 79% from 9; d) ICl, MeOH, ꢁ788C; e) TFA, Toluene, 1458C,
66% from 10; f) LHMDS, 6-iodo-1-hexene, THF, ꢁ788C, 84%. DIA-
D=diisopropylazodicarboxylate, TFAA=trifluoroacetic anhydride,
TFA=trifluoroacetic acid, LHMDS=lithium hexamethyldisilazide.
Figure 1. X-ray crystal structure of lactam 25.[23]
ꢁ
coupling reaction that led to the formation of the central C3
C9 bond of 6 (Scheme 3). The reaction sequence started with
a Mitsunobu condensation of 8 with 5-benzyloxypentanol to
provide glutarimide 9. Sodium borohydride reduction of 9
followed by a trifluoroacetic anhydride-mediated dehydra-
tion afforded enamide 10 in 79% overall yield.[12] Reaction of
10 with iodine monochloride in methanol resulted in a
regioselective iodomethoxylation to afford an intermediate
d-methoxylactam that was briefly subjected to catalytic
trifluoroacetic acid in refluxing toluene (15 min) to provide
iodoenamide 11 from 10 in 66% yield.[13] Deprotonation of
amide 11 with LHMDS in THF at ꢁ788C followed by the
The X-ray analysis was significant since the reduction of 25
ꢁ
with Red Al led to the formation of dihydrohaliclonacycla-
mine C (4) whose 1H and 13C NMR spectra did not match the
NMR data of the dihydrohaliclonacyclamine C that had been
derived from the hydrogenation of haliclonacyclamine A.[22]
After passing both samples of synthetic and semi-synthetic
dihydrohaliclonacyclamine C through
a
strong cation
exchange (SCX) column, the spectral properties of both
samples were identical.
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ꢁ
Scheme 5. Final stages of the synthesis of 4: a) KHMDS, N,N-bis(trifluoromethylsulfonyl)-5-chloro-2-pyridylamine, THF, ꢁ788C, 94%; b) DIBAL
H, CH2Cl2, ꢁ508C!08C, 92%; c) TBSCl, imidazole, DMAP, THF, 0!238C, 88%; d) Me6Sn2, LiCl, [Pd(PPh3)4], THF, 808C, 75%; e) 12, CuCl, LiCl,
[Pd(PPh3)4], DMSO, 608C, 67%; f) TBAF, THF, 08C; g) Ac2O, NEt3, DMAP, CH2Cl2, 238C, 96% from 17. h) (E)-6-(tributylstannyl)hex-5-en-1-ol,
LiCl, [Pd(dba)2], DMF, 658C, 80%. i) HCl/Et2O, then bis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylidene ruthenium(II) dichloride (10 mol%),
CH2Cl2, 408C, 64%; j) TFA, H2 (500 psi), Pd(OH)2, EtOH, 708C, 79% (1.3:1, 21a/21b); k) Dess–Martin periodinane, CH2Cl2, 0!238C;
l) KHMDS, Methyltriphenylphosphonium bromide, THF, 08C, 51% from 21; m) TFA then bis(tricyclohexylphosphine) benzylidine ruthenium(IV)
ꢁ
chloride (10 mol%), CH2Cl2, 408C, 80%; n) TFA then H2 (100 psi), Pd/C, MeOH, 608C, 62%; o) Red Al, PhMe, reflux, 90%. KHMDS=potassium
hexamethyldisilazide, DIBAL=diisobutylaluminum, TBSCl=tert-butyldimethylsilylchloride, DMAP=N,N-dimethyl-4-aminopyridine, DMSO=di-
ꢁ
methyl sulfoxide, TBAF=tetra-n-butylammonium fluoride, dba=1,5-diphenyl 1,4-pentadiene-3-one, DMF=N,N-dimethylformamide, Red Al=so-
dium bis(2-methoxyethoxy)aluminumhydride.
ꢁ
Scheme 6. Synthesis of 3: a) (MeO)2P(O)C(N2)C(O)Me, K2CO3, MeOH, 54% from 21; b) Red Al, toluene, reflux, 51% (26a) and 39% (26b);
c) nBuLi (8 equiv), THF, ꢁ788C to 238C then MeI (excess), ꢁ78!238C; d) NaSPh (10 equiv), DMF, 1308C, 41% from 26a; e) Ph3SiOH
(3 equiv), [(Me3SiO)2{(Me3Si)2N}MoN], toluene, 808C then 28, 23 to 1308C, 63%; (f) H2, Lindlar catalyst, EtOAc, 238C, 88%.
The total synthesis of haliclonacyclamine C (3), which was
completed using the RCAM followed by semihydrogenation
strategy introduced by Fꢀrstner, required prior-conversion of
bis(aldehyde) 22 into diyne 28 (Scheme 6). To this end, 22 was
reacted with an excess of the Bestman–Ohira reagent[24] to
give the corresponding diyne. Reduction of the lactam
carbonyl group with Red-Al afforded a separable mixture
of amines 26a (51%) and 26b (39%). Bis(methylation) of
terminal alkyne 26a was invariably accompanied by N-
methylation to give quaternary salt 27. Amine 28 was
generated directly from ammonium salt 27 upon treatment
with an excess of sodium thiophenoxide in dimethylforma-
mide. The RCAM cyclization of 28 was examined using a
variety of catalysts and reaction conditions. Only the catalyst
system derived from the in situ combination of [(Me3SiO)2-
{(Me3Si)2N}MoN] and Ph3SiOH (3 equiv), as recently de-
scribed by Fꢀrstner and co-workers, led to the desired RCAM
reaction.[25] Under these conditions free amine 28 underwent
the RCAM reaction in 63% yield. Semihydrogenation of the
resulting cycloalkyne with the Lindlar catalyst afforded
haliclonacyclamine C, which was identical in all respects to
the natural product apart from optical rotation.[8b]
In summary, we have completed the synthesis haliclona-
cyclamine C (3) and dihydrohaliclonacyclamine C (4). The
synthetic strategy should be easily modifiable to provide
access to other haliclonacyclamines and their related tetracy-
clic alkylpiperidine alkaloids. Evaluation of the biological
activity of the structurally unique haliclonacyclamine C is
under investigation and will be reported in due course.
Received: October 12, 2009
Revised: December 14, 2009
Published online: February 2, 2010
Keywords: alkaloids · macrocycles · natural products ·
.
ring-closing metathesis · total synthesis
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Communications
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[23] CCDC 744717 (25) contains the supplementary crystallographic
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