A new strategy for the synthesis of himbacine

Article abstract of DOI:10.1055/s-0030-1259918

A new strategy for the assembly of himbacine and analogues, which display potent biological activity, is described. A four-step route to a key intermediate has been developed, in which the key step is a highly diastereoselective Michael-Dieckmann domino reaction. Use of an enantioenriched Michael acceptor, readily obtained by an asymmetric dihydroxylation reaction, allowed kinetic resolution of the Michael donor, which was itself prepared by a domino reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259918

LETTER
801
A New Strategy for the Synthesis of Himbacine
A
N
ew Strategy for the
i
Synth
k
esis of
H
imb
e
acine Casey,* Robert McCarthy
School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
Fax +353(1)7181178; E-mail: mike.casey@ucd.ie
Received 7 February 2011
that it would be possible to use it to make novel analogues
that would not be readily accessible by the Diel–Alder
routes. We now report preliminary results that demon-
strate the viability of this strategy.
Abstract: A new strategy for the assembly of himbacine and ana-
logues, which display potent biological activity, is described. A
four-step route to a key intermediate has been developed, in which
the key step is a highly diastereoselective Michael–Dieckmann
domino reaction. Use of an enantioenriched Michael acceptor,
readily obtained by an asymmetric dihydroxylation reaction, al-
lowed kinetic resolution of the Michael donor, which was itself pre-
pared by a domino reaction.
O
O
H
H
H
H
NHCO2Et
A
B
C
N
O
O
Key words: alkaloids, domino reactions, kinetic resolution, Michael
additions, stereoselective synthesis
H
H
H
H
R
Me
N
Himbacine 1 (R = Me), a natural product isolated from a
species of magnolia trees,1 is a potent, subtype-selective
muscarinic receptor (M2) antagonist, and is regarded as a
promising lead in the development of treatments for neu-
rodegenerative disorders such as Alzheimer’s disease.2 A
number of himbacine analogues show related activity and
it is notable that normethyl himbacine 1 (R = H) is a more
potent M2 receptor antagonist than himbacine itself.3
Moreover, a major effort by Chackalamannil et al. result-
ed in the discovery that several series of analogues of the
enantiomer of himbacine, in which the piperidine ring is
replaced by an aromatic ring and the C-ring is modified,
are nanomolar inhibitors of thrombin receptor, potentially
useful for the treatment of disorders such as arterial
thrombosis, atherosclerosis and restenosis.4 The most
promising lead in the series, SCH 530348 (Vorapaxar) 2
is an orally active thrombin receptor antagonist with po-
tent antiplatelet activity.4d
1
F
2
X
RO
O
O
H
H
H
H
+
O
H
X
H
R
R
O
Ot-Bu
3
4
5
Scheme 1 Retrosynthetic analysis
Our first objective was to test the feasibility of the key
MIRC reaction, and, in particular, to determine the diaste-
reoselectivity of the Michael reaction. The racemic cyclo-
hexane diester 7 was prepared using the method of
Yamaguchi et al.,6 again using a MIRC reaction
(Scheme 2). Reaction of an excess of the lithium enolate
formed from tert-butyl acetate, with the readily accessible
w-iodo enoate 6,7 and addition of potassium tert-butoxide
to induce cyclisation, gave the trans disubstituted cyclo-
hexane 7 in 70% yield with complete trans diastereoselec-
tivity.
Beginning with the work of Hart, Kozikowski and co-
workers in 1995, a number of syntheses of himbacine, and
of analogues, have been reported.5 Remarkably, all of
these syntheses utilise a Diels–Alder reaction for con-
struction of the stereochemically complex decalin seg-
ment. While the Diels–Alder strategy has proven to be
extremely effective and versatile, we decided to explore a
different approach. Our retrosynthetic analysis
(Scheme 1) envisaged the coupling of a tricyclic interme-
diate of type 3 with a piperidine fragment, as in earlier
syntheses. Analysis of intermediate 3 suggested that it
could be obtained by a Michael-Initiated Ring Closure
(MIRC) reaction involving a trans disubstituted cyclo-
hexane 5 and a butenolide 4. We hoped that this approach
would provide a short route to the key intermediate 3 and
The crucial MIRC reaction was then attempted using the
unsubstituted furanone, suitable for the synthesis of norm-
ethyl himbacine 1 (R = H). Regioselective deprotonation
of diester 7 using LTMP, addition of furanone and warm-
ing in the presence of potassium tert-butoxide to induce
an in situ intramolecular Claisen condensation gave the
desired tricyclic lactones 8 and 9 and a small amount un-
cyclised triester 10 along with some unreacted starting
material.
SYNLETT 2011, No. 6, pp 0801–0804
x
x.
x
x.
2
0
1
1
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259918; Art ID: D39911ST
© Georg Thieme Verlag Stuttgart · New York

802
M. Casey, R. McCarthy
LETTER
OLi
a-substituted lithium enolates to butenolides does not ap-
pear to have been reported previously, so we were grati-
fied to find excellent stereoselectivity for the desired
relative configuration at C-3a. Formation of the cis con-
figuration at carbons 3a and 9a, in the Dieckmann step, is
inevitable in this case because the methylene of the lac-
tone is axial on a trans-decalin system.
H
I
a)
MeO2C
t-BuO
MeO2C
THF, –78 °C
b) KOt-Bu
70%
H
O
t-BuO
6
7
O
H
O
H
H
Having demonstrated the feasibility of the method for tri-
cycle formation, we turned to an asymmetric synthesis of
a MIRC precursor of type 5. A chiral auxiliary approach
was adopted in this first study. Although a number of
chiral auxiliaries have given good results in asymmetric
Michael reactions,8a,9,10 we were only able to locate one
example involving a-unsubstituted acetate derivatives.11
Following the precedent for phenylacetate analogues,10
we investigated the use of pseudoephedrine as a chiral
auxiliary (Scheme 3). Conjugate addition of amide 11 was
successful only when an excess of lithium chloride was
added,12 and even then it gave adduct 12 in moderate
yield, accompanied by cyclisation product 13 (Scheme 3).
The presence of amide rotamers made analysis of the dia-
stereomer ratio by NMR more difficult, but we were un-
able to detect any other stereoisomers so it is clear that the
chiral auxiliary was very effective. Attempts to induce
complete ring closure of the enolate from the Michael re-
action in situ were unsuccessful, but treatment of the
Michael reaction product with KHMDS provided the
trans disubstituted cyclohexane 13 as a single stereoiso-
mer, in 46% overall yield.
H
LTMP
THF, –78 °C;
2-furanone;
MeO2C
O
9a
3a
O
+
4
O
KOt-Bu
–78 to –30 °C
H
H
O
H
O
t-BuO
t-BuO
CO2t-Bu 53%
CO2t-Bu
8
9
10
Scheme 2 Double MIRC sequence
The reaction produced two diastereoisomers of the prod-
uct, 8 and 9, and careful analysis of the 1H NMR spectra,
supported by molecular mechanics calculations, clearly
showed that both had the desired relative configuration at
the fused lactone ring and that they were epimeric at C-4,
a to the tert-butyl ester. Chromatography yielded the ma-
jor isomer 8 (53% yield, 63% based on unrecovered start-
er), the tricycle with the incorrect configuration at C-4,
which is potentially epimerisable. The minor diastereo-
mer 9 and the triester 10 together constituted less than
25% of the mixture, but were not obtained in pure form.
The good stereoselectivity in the formation of three chiral-
ity centres in the Michael–Dieckmann domino reaction is
notable. The stereochemical outcome at C-4, relative to
the existing centres on the cyclohexane, is in accord with
results in related systems.8 Good diastereoselectivity a
and b to the carbonyl of the nucleophilic component is of-
ten observed in Michael reactions of ester enolates,6,8 and
may be ascribed to the involvement of a well-ordered
cyclic transition state. However, the addition of simple
Selective reduction of the ester group (73%) and treatment
of the resulting hydroxy amide with acid resulted in cleav-
age of the auxiliary to yield lactone 14 (61%). The abso-
lute stereochemistry of the bicyclic lactone 14 was
assigned by analogy with that of the lactone 19 obtained
from methyl crotonate in the same way (Scheme 4). The
specific rotation of lactone 19 {[a]D –22.0 (c = 0.5,
CHCl3)} was in good agreement with the value reported
for (S)-19 {[a]D –26.2 (c = 0.83, CHCl3)}.13 This stereo-
I
H
MeO2C
H
MeO2C
3. LiAlH4
THF, –30 °C, 73%
1. LDA
THF, 0 °C;
Me
O
2. KHMDS
N
O
HO
4. HBF4⋅OEt2
CH2Cl2, r.t., 61%
LiCl, 6
THF, –78 °C
THF, –78 °C
46% (from 11)
O
H
N
H
N
Me
Me
H
O
O
Ph
HO
HO
14
5. HBr, AcOH
75 °C; MeOH
75%
Ph
Ph
13
11
12
I
Br
Br
O
O
O
O
H
H
H
H
H
H
H
H
H
6. LTMP
THF, –78 °C;
7. NaI
8. LiNR2
<20%
O
O
acetone
60 °C, 88%
2-furanone
37%
H
O
H
H
OMe
O
OMe
O
OMe
O
OMe
18
17
16
15
Scheme 3
Synlett 2011, No. 6, 801–804 © Thieme Stuttgart · New York

LETTER
A New Strategy for the Synthesis of Himbacine
803
chemical outcome is the same as that found in reactions of acceptor. Addition of two equivalents of racemic diester 7
phenylacetamides derived from the pseudoephedrine aux- to enantioenriched butenolide 21, followed by in situ
iliary.10 Ring opening of the lactone 14 with HBr, and in Dieckmann reaction, gave tricyclic product 22 (46%),16
situ methyl ester formation,14 then gave the desired MIRC along with two minor diastereoisomers 23 (10%) and 24
precursor 15 in 75% yield.
(18%). The three diastereomeric products were separated
by flash chromatography and the structure of the major
product 22 was confirmed by X-ray crystallography.17 Its
relative stereochemistry is that expected for addition trans
to the methyl substituent on the furanone, with the same
stereochemical preference relative to the chirality centres
on the cyclohexane as observed previously. Although
there was only a threefold difference in the reactivity of
the enantiomers of diester 7, the ease of preparation of the
enantioenriched lactone 21 and the brevity of the route
(the longest linear sequence is four steps), make this a
very practical synthetic strategy.
1. LDA, THF, 0 °C;
LiCl, methyl crotonate
THF, –78 °C, 81%
Me
O
N
O
HO
2. LiAlH4, THF, -30 °C, 76%
O
3. HBF4⋅OEt2, CH2Cl2, r.t., 53%
19
Ph
11
Scheme 4
Michael reaction with furanone yielded the conjugate ad-
duct 16 in just 37% yield, but with high diastereoselectiv-
ity as before. Conversion of the bromo lactone into the
iodo analogue 17 was efficient (88%; Scheme 3), but at-
tempts to effect cyclisation yielded the desired tricyclic
product 18 in low yields, together with unreacted starting
material and a rearranged product (see below). It would
appear that the intramolecular enolate alkylation reaction
was very much slower than the Dieckmann reaction used
in our initial studies.
H
O
MeO2C
LTMP, THF, –78 °C;
O
21; KOt-Bu, –78 to –30 °C
H
t-BuO
O
O
( )-7
21
O
O
O
H
H
H
H
H
During the work described above, it was apparent that
compounds 16 and 17 were contaminated with small
amounts of closely related materials. The structures of the
contaminants were revealed in the course of the attempts
to cyclise iodo lactone 17. Use of potassium bases, in an
effort to increase the reactivity of the enolate, produced a
clean reaction, but the product was the rearranged lactone
20 (Scheme 5). The structures of both lactones were un-
ambiguously determined by NMR spectroscopy using
HMBC experiments. A possible pathway for this rear-
rangement is fragmentation of the initially formed enolate
to give an alkoxy ketene, followed by cyclisation to give
the alternative lactone, with release of methoxide, which
then intercepts the ketene. Presumably, these reactions are
reversible and formation of the rearranged product 20 is
thermodynamically favoured.
8
5
1
9
4
9a
8a
4a
7
2 O
3
O
+
3a
6
H
H
H
O
t-BuO
O
t-BuO
24 18%
CO2t-Bu 46%
CO2t-Bu 10%
22
23
Scheme 6
The necessity to invert the configuration at C-4 in inter-
mediate 22 is not expected to cause problems. In order to
effect this epimerisation the ketone will be removed and
the lactone protected as an acetal.5b,d,e Formation of the
enolate anion of the tert-butyl ester, followed by kinetical-
ly controlled protonation of the ‘bottom’ face of the eno-
late, trans to the fused five-membered ring, will then
result in the correct configuration at C-4. Work on the hy-
droboration of 4-methylene derivatives by Takadoi and
Tereshima5d supports the belief that protonation will oc-
cur from the bottom face, as required.
O
I
O
I
H
H
MeO
KHMDS, THF
O
H
–78 to –30 °C
99%
H
H
H
H
O
In conclusion, the combination of two MIRC-type domino
reactions leads to a short enantioselective route to tricyclic
lactones 22 and 23, which have the correct stereochemis-
try and functionality to be useful intermediates for the
synthesis of himbacine. The high diastereoselectivity of
the Michael reactions with butenolides, and the demon-
stration that pseudoephedrine is an excellent chiral auxil-
iary for Michael reactions of acetate, are other noteworthy
aspects of this work, that may have wider implications.
Efforts to complete the synthesis of himbacine, and of
novel analogues, are underway.
O
OMe
O
17
20
Scheme 5
We then returned to the Michael–Dieckmann domino re-
action, but using an enantioenriched substituted furanone
21 (70% ee), which was prepared in two steps, using
asymmetric dihydroxylation (Scheme 6).15 We used race-
mic diester 7 in the hope that kinetic resolution might be
achieved in the reaction with the enantioenriched Michael
Synlett 2011, No. 6, 801–804 © Thieme Stuttgart · New York

804
M. Casey, R. McCarthy
LETTER
(7) For the precursor alcohol see: Breuning, M.; Steiner, M.
Acknowledgment
Synthesis 2006, 1386.
We thank Dr Helge Müller-Bunz for the X-ray crystal structure de-
termination and Dr Dilip Rai for the HRMS measurements. We
thank the Irish Research Council for Science Engineering and Tech-
nology, funded by the National Development Plan, for financial
support.
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T.-M.; Hesk, D.; Chintala, M. J. Med. Chem. 2007, 50,
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23
(16) Data for compound 22: white solid; mp 144–146 °C; [a]D
–6.0 (c = 0.85, CHCl3). IR (KBr): 2980, 2924, 2831, 1780,
1719, 1702, 1408, 1334, 1280, 1210, 1160, 1012 cm–1. 1H
NMR (500 MHz, CDCl3): d = 4.27 (1 H, dq, J = 10.3, 5.9
Hz, C3H), 3.80 (1 H, d, J = 8.6 Hz, C9aH), 2.66–2.77 (2 H,
m, C8aH, C3aH), 2.54 (1 H, app d, J = 4.6 Hz, C4H), 2.03
(1 H, m, C8HH), 1.77–1.87 (4 H, m, C4aH, C5HH, C6HH,
C7HH), 1.54 [9 H, s, C(CH3)3], 1.45 (3 H, d, J = 5.9 Hz,
C3HCH3), 1.34–1.40 (1 H, m, C5HH), 1.26–1.34 (1 H, m,
C8HH), 1.15–1.26 (2 H, m, C6HH, C7HH). 13C NMR (125
MHz, CDCl3): d = 203.7 (C9=O), 171.9 (OC=O), 170.9
(OC=O), 82.4 [C(CH3)3], 77.5 (C3H), 54.4 (C9aH), 48.3
(C3aH), 48.0 (C8aH), 44.1 (C4H), 41.0 (C4aH), 31.3 (C5H2),
28.2 [C(CH3)3], 25.6 (C7H2), 25.4 (C8H2), 25.0 (C6H2), 19.0
[C3H(CH3)]. HRMS (ESI): m/z [M+ + H] calcd for C18H27O5:
323.1858; found: 323.1847.
(17) CCDC 711490 contains the crystallographic data for
compound 22. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallograpic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; or
deposit@ccdc.cam.ac.uk].
(6) Yamaguchi, M.; Tsukamoto, M.; Hirao, I. Tetrahedron Lett.
1985, 26, 1723.
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