Synthesis of the stereogenic triad of the halicyclamine A core

Article abstract of DOI:10.1016/j.tetlet.2010.11.162

We describe herein our progress toward the synthesis of halicyclamine A, which possesses very interesting biological activities and has never been synthesized. For this purpose, we proposed a stereoselective Diels-Alder reaction as a key step for the establishment of the stereogenic triad of the bis(piperidinyl) core of this molecule. A series of NMR studies was then conducted to establish the correct stereochemical assignment subsequent to the Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2010.11.162

Tetrahedron Letters 52 (2011) 2199–2202
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of the stereogenic triad of the halicyclamine A core
⇑
Gary A. Molander , Frédéric Cadoret
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 5 December 2010
We describe herein our progress toward the synthesis of halicyclamine A, which possesses very interesting
biological activities and has never been synthesized. For this purpose, we proposed a stereoselective
Diels–Alder reaction as a key step for the establishment of the stereogenic triad of the bis(piperidinyl) core
of this molecule. A series of NMR studies was then conducted to establish the correct stereochemical
assignment subsequent to the Diels–Alder reaction.
Keywords:
Total synthesis
Marine alkaloid
Organotrifluoroborate
Stereoselective Diels–Alder reaction
Halicyclamine A
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Halicyclamine A is one member of a growing class of tetracyclic
diamine alkaloids isolated from the marine sponge Haliclona sp.
(Fig. 1). Crews and coworkers first isolated halicyclamine A and
determined its structure.1 Haliclona sp. inhibits inosine monophos-
phate dehydrogenase (IMPDH) at concentrations of
1 lg/mL.
IMPDH is a major therapeutic target, and drugs that are directed
at IMPDH have been approved or are currently being evaluated
for antiproliferative, antiviral, and anticancer chemotherapies as
well as immunosuppressive activity. Halicyclamine A is cytotoxic
Figure 1. Sponge Haliclona sp. and structure of halicyclamine A.
against P388 with an IC50 value of 0.45
ity, it was recently shown that this molecule has great potential
against tuberculosis with MIC values of 1.0–5.0 g/mL for
l
g/mL.2 Besides this activ-
l
Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuber-
culosis H37Ra growth inhibition in both active and dormant states.3
Although there is considerable evidence concerning its bioge-
netic origin, and efforts directed toward biomimetic syntheses
have been recorded,4,5 this molecule has yet to succumb to total
synthesis, and its absolute configuration has yet to be determined.
Noteworthy, however, is the recent synthesis of the related ( )-hal-
iclonacyclamine C by Sulikowski and Smith, who built the core of
that molecule by Stille cross-coupling of the two piperidinyl
moieties followed by a non-stereoselective hydrogenation of the
resulting diene, with subsequent separation of the formed diaste-
reomers.6 There are two fundamental challenges associated with
the synthesis of halicyclamine A. The first is the establishment of
the three contiguous stereocenters about the bis(piperidinyl) ring
system. The second challenge is the formation of two macrocyclic
ring systems in which the stereochemistry about the conjugated
⇑
Corresponding author. Tel.: +1 215 573 8604; fax: +1 215 573 7165.
E-mail address: gmolandr@sas.upenn.edu (G.A. Molander).
Scheme 1. Proposed retrosynthesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.162

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Scheme 2. Synthesis of the Diels–Alder substrate.
Scheme 3. Stereochemistry of the Diels–Alder reaction.
Scheme 4. Diels–Alder reaction and oxidative cleavage.

G. A. Molander, F. Cadoret / Tetrahedron Letters 52 (2011) 2199–2202
2201
hydroboration.8 The resulting boronic acid was quenched with
potassium hydrogen fluoride to access the corresponding potas-
sium alkenyltrifluoroborate 3 as a waxy solid. Attempts at recrys-
tallization failed because of the high solubility of 3 in most organic
solvents. The volatile byproducts stemming from the reaction were
removed by Kugelrohr distillation, and the resulting purified
compound 3 was used in the next step without further purification.
Suzuki–Miyaura cross-coupling9 of 3 with TBDPS-protected 2-bro-
mo-2-propen-1-ol 4 provided the cross-coupled product 5 in good
yield. Deprotection of the acetal using Amberlyst 15Ò led to the
free aldehyde 6, which was subjected to a Wittig reaction with
(triphenylphosphoranylidene)acetaldehyde in chloroform in
moderate yield. Of note, only one isomer of enal 7 was observed.
The latter was assigned as the E isomer based on the coupling
constant of the vinylic protons (J = 15.1 Hz, see also Supplementary
data), which is in agreement with the reported reactivity of
(triphenylphosphoranylidene)acetaldehyde.10 The removal of the
TBDPS group of compound 7 with a mixture of acetic acid and TBAF
in DMF provided the desired product 8 in moderate yield.11
With compound 8 in hand, the Diels–Alder reaction was at-
tempted. The reaction worked well using the conditions described
by Sherburn et al.,7 affording only one diastereoisomer of the bicy-
clic alcohol 9 (Scheme 3). A reductive amination with benzylamine
in the presence of sodium triacetoxyborohydride afforded the cor-
responding amine 10 (Scheme 4), the stereochemistry of which
was confirmed by NMR experiments (vide infra). The primary alco-
hol and the secondary amine were successively protected with a
TBS group (11) and a Cbz group (12), respectively. An ozonolysis
was then performed using zinc and acetic acid as a reducing
reagent, providing the keto-aldehyde 13 in moderate yield. The
selective reduction of the aldehyde with sodium borohydride at
Figure 2. The two possible stereoisomers for amine 10.
diene systems must be controlled. Herein, we report the assembly
of the stereogenic triad in the central nucleus of halicyclamine A.
2. Results and discussion
The central concept for the synthesis was to install the three
stereocenters at once using a diastereoselective intramolecular
Diels–Alder reaction, taking advantage of an internal hydrogen
bonding effect that was reported earlier on other substrates.7 We
envisioned that a Suzuki–Miyaura cross-coupling reaction be-
tween a potassium alkenyltrifluoroborate and a 2-bromoallylic
alcohol would lead to the diene, while a Wittig–Horner reaction
would be utilized to construct the dienophile. The Diels–Alder ad-
duct could be subjected to a reductive amination, with subsequent
oxidative cleavage of the cyclohexene leading to an a-hydroxy ke-
tone derivative. Appropriate manipulation of this intermediate and
cyclization would yield the core of halicyclamine A (Scheme 1).
Following the synthetic approach outlined in Scheme 2, the
synthesis began with the Boc-protection of propargylamine (1)
followed by N-alkylation using sodium hydride and 3-chloro-1,
1-diethoxypropane. Amine 2 was then subjected to a Snieckus
Figure 3. NOESY NMR 2D experiment for amine 10.

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G. A. Molander, F. Cadoret / Tetrahedron Letters 52 (2011) 2199–2202
obtained, corresponding to the stereochemical relationship re-
ported for halicyclamine A.
4. Conclusion
In summary, an advanced intermediate for the synthesis of the
core of halicyclamine A was prepared with the correct stereochem-
istry, in 17-steps and a global yield of 1.27%. The original approach
for this synthesis featured a diastereoselective intramolecular
Diels–Alder reaction. Initial attempts at ring closure to form the
second piperidinyl ring have failed but studies are still in progress
Figure 4. 3D Structure of the amine 10 deduced from NMR analyses.
for the completion of the synthesis by activating the a-hydroxy ke-
tone or protecting the ketone to avoid side-reactions.
low temperature gave the expected keto-alcohol 14. Owing to the
relative instability of the intermediate keto-aldehyde, the se-
quence was conducted without any purification, which resulted
in a significantly improved yield. The resulting alcohol was pro-
tected with TBDPS chloride to access the ketone 15. Selective
deprotection of the TBS ether yielded the corresponding alcohol
16. Hydrogenolysis of the Cbz group of the amine required the
use of palladium(II) hydroxide to give the secondary amine of com-
pound 17. A Mitsunobu cyclization12 was attempted to access the
core of Halicyclamine A 18 but initial attempts at this transforma-
tion have not been successful. The formation of an unidentified
product was observed, perhaps due to side-reactions involving
the carbonyl functional group or the low reactivity of the primary
alcohol and benzylamine system.
Acknowledgments
This work was supported by a grant from the French Ministère
des Affaires étrangères (BFE—Lavoisier) and the NIH (R01 GM-
081376). We thank Dr. Rakesh Kohli (University of Pennsylvania)
for the HRMS data. We are also grateful to Johnson-Matthey for
their donation of palladium(II) acetate.
Supplementary data
Supplementary data (experimental procedures and spectral
characterization for all compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.162.
3. Studies on the stereochemistry of the amine 10
References and notes
The stereochemistry of the three contiguous stereocenters
simultaneously formed by the Diels–Alder reaction was investi-
gated. The study was conducted on the amine 10 instead of the
aldehyde 9 because the NMR spectrum of the amine was more
suitable for this purpose. The chemical shifts of each of the protons
of the molecule were assigned by 2D NMR experiments (COSY,
HMQC; see also Supplementary data).
The relative stereochemistry between protons 4a and 5 in the
Diels–Alder adduct 9 or the amine 10 was assigned as trans owing
to their stereochemical relationship in the enal 7. Consequently, it
remained to assign the hydrogens at the ring junction (4a and 8a)
as being either in a cis or in a trans relationship (Fig. 2).
The NOESY NMR experiment clearly showed an NOE effect be-
tween the two signals at 1.59–1.77 and 1.80–1.96 ppm (Fig. 3),
which correspond to protons 6/8a and 40/5, respectively.
With the help of the NOESY spectrum and Chem3D model
(Fig. 4, see also Supplementary data for the discussion), we deter-
mined that this effect can be attributed to protons 5 and 8a, which
demonstrated that trans-10 is the stereoisomer which was
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