A chiral base desymmetrisation - Ring-closing metathesis route to chiral azaspirocycles: Synthesis of core structures related to pinnaic acid and halichlorine

Article abstract of DOI:10.1055/s-2004-831335

A range of highly functionalised chiral azaspirocycles was synthesised, starting from a piperidine diester that is available in 90% ee from a chiral base desymmetrisation. The approach depends upon the use of Grignard addition reactions or a Claisen rearr

Full text of DOI:10.1055/s-2004-831335

LETTER
2295
A Chiral Base Desymmetrisation–Ring-Closing Metathesis Route to Chiral
Azaspirocycles: Synthesis of Core Structures Related to Pinnaic Acid and
Halichlorine
S
ynthesis of Co
i
re Stru
m
ctures Related to Pi
o
A
cid
a
n
t
d Hali
h
chlorine y Huxford, Nigel S. Simpkins*
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax +44(115)9513564; E-mail: nigel.simpkins@nottingham.ac.uk
Received 18 July 2004
Some time ago we described a new type of chiral lithium
Abstract: A range of highly functionalised chiral azaspirocycles
was synthesised, starting from a piperidine diester that is available
in 90% ee from a chiral base desymmetrisation. The approach de-
pends upon the use of Grignard addition reactions or a Claisen rear-
amide base reaction, which provided chiral polyfunctional
piperidines with high levels of stereocontrol.7 In the
present paper we describe how one such piperidine can be
rangement to provide intermediates capable of undergoing ring- usefully transformed into a range of azaspirocyclic sys-
closing metathesis. A number of intermediates related to the core
tems, with a focus on compounds closely related to the
pinnaic acid core structure.8
structure of pinnaic acid were synthesised by concise routes using
the approach.
The previously described desymmetrisation reaction in-
volves enolisation of the readily available piperidine di-
Key words: azaspirocycle, pinnaic acid, ring-closing metathesis
ester 4 with chiral base 5, and subsequent alkylation to
give products such as the allyl derivative 6, Scheme 1.9
Natural products incorporating azaspirocyclic structures,
such as the well known histrionicotoxin family [e. g. his-
(i)
Ph
Ph
trionicotoxin (1)], have long attracted the interest of syn-
thetic chemists.1 A more recently disclosed structure is
pinnaic acid (2), which has stimulated substantial activity
due to its potency as an inhibitor of cPLA2 (phospholipase
A2).2 The closely related alkaloid, halichlorine (3), found
to inhibit VCAM-1 (vascular cell adhesion molecule-1),
was isolated around the same time and has also sparked a
great deal of interest (Figure 1).3
5
Ph
N
Li
N
Li
Ph
CO2Me
N
MeO2C
N
CO2Me
MeO2C
THF, –78 °C
Br
Ph
6 77% (90% ee)
Ph
(ii)
4
(i) LiAlH4, THF, 0 °C (75%)
(ii) TBDPSCl, DMAP, Et3N,
CH2Cl2 (82%)
TBDPSO
t
N
CO2 Bu
(iii) DMSO, (COCl)2, Et3N,
CH2Cl2 (80%)
Ph
t
HN
HO
7
(iv) Me3SiCH2CO2 Bu, LDA,
THF, –78 °C (70%)
Scheme 1
H
N
H
HO
O
HN
O
Subsequent differentiation of the ester functions was then
carried out by reduction of 6 to the corresponding diol, se-
lective protection of the less hindered primary alcohol,
oxidation and Peterson olefination. This sequence provid-
ed quantities of a,b-unsaturated ester 7, and we initially
hoped to develop this compound to a spirocyclic system
by establishing a novel cyclisation protocol for linking the
terminus of the allyl group to the b-position of the enoate.
1
O
H
H
Cl
Cl
OH
HO
OH
2
3
Figure 1
The first plan was to effect regioselective hydrometalla-
tion of the allylic appendage to give a terminal organome-
tallic, which, on activation by transmetallation, would
then undergo intramolecular Michael addition. In the
event, a series of studies, focussed on the combination of
initial hydroboration or hydrozirconation, followed by
transmetallation chemistry using zinc or copper, failed to
provide an effective means of ring-closure.10,11
Since these compounds exhibit potentially useful biologi-
cal activity, synthetic approaches, which deliver highly
functionalised azaspirocycles, of various ring size combi-
nations, in a stereocontrolled fashion are of intense cur-
rent interest.4–6
SYNLETT 2004, No. 13, pp 2295–2298
0
3
.1
1
.2
0
0
4
Advanced online publication: 08.09.2004
DOI: 10.1055/s-2004-831335; Art ID: D19704ST
© Georg Thieme Verlag Stuttgart · New York
As a back-up tactic we expected that conversion of the al-
lyl group into a terminal halide, or similar, would allow

2296
T. Huxford, N. S. Simpkins
LETTER
conventional 5-exo-trig radical mediated ring-closure, or The success of the diene metathesis route opens up a num-
perhaps a metal–halogen exchange with concomitant ber of opportunities for progress towards natural products,
Michael addition. Again, we were unable to bring these including pinnaic acid. Firstly, we were able to carry out
ideas to fruition,12 and were prompted to explore an alter- a range of further transformations of spirocyclic allylic al-
native approach, which employs a key ring-closing meta- cohol 10, as shown in Scheme 4.
thesis step.
Aldehyde 8 (the product of Swern oxidation in Scheme 2)
MesN
NMes
was found to undergo smooth addition reactions with vi-
nyl magnesium bromide, providing access to secondary
alcohol product 9 as single diastereoisomer, Scheme 2.
Cl
Cl
Ru
(i) PCC (alumina)
toluene (80%)
O
Ph
PCy3
RO
10
9
N
(ii) CoCl2·6H2O
NaBH4, MeOH
(74%)
toluene, 80 °C
R = SitBuPh2
80%
H
OH
Ph
MgBr
16
RO
RO
Et2O, –78 °C
CHO
N
N
Ph
Ph
8
9 91%
HO
HO
PCy2
Ru
MgBr
RO
Cl
Cl
TBSO
N
N
CeCl3, THF
–78 °C
(41%)
H
OBn
Ph
OH
Ph
PCy3
R = SitBuPh2
RO
18
17
N
CH2Cl2, 20 °C
Ph
Scheme 4
10 62%
Scheme 2
We first established that the efficiency of ring-closing
metathesis of 9 to give cyclopentene 10 was improved on
changing to the ‘second generation’ Grubbs catalyst (sim-
ilarly, the use of this catalyst gave 15 in a substantially im-
proved yield of 85%). Applying a straightforward
oxidation–conjugate-reduction sequence to allylic alcohol
10 then provided ketone 16.14 This ketone bears a striking
resemblance to a racemic intermediate employed by Kiba-
yashi in their recently disclosed synthesis of pinnaic acid.4
In this synthesis Grignard addition reactions led to inter-
mediate 18. Our ketone underwent similar stereoselective
additions, for example to provide allylic alcohol 17, which
may well be capable of being further transformed towards
pinnaic acid via the Kibayashi approach.
The sense of induction at the new stereogenic centre in 9
was predicted from examination of molecular models, by
assuming a least hindered approach on aldehyde 8 (see
later), and was subsequently proved by X-ray analysis.13
Diene 9, on treatment with the first generation Grubbs cat-
alyst underwent the desired ring-closure process to give
allylic alcohol 10 in good yield. As shown in Scheme 3,
we were also able to access the corresponding products 14
and 15 with the azaspiro[5,5]undecane and aza-
spiro[5,6]dodecane structures, respectively.
H
OH
RMgBr
Bearing in mind the apparent utility of the RCM process
for spiro-annulation, we sought to devise flexible entries
to appropriate dienes that would all enable access to more
advanced intermediates towards pinnaic acid and hali-
chlorine. Two such synthetic sequences, which pay spe-
cial attention to addressing stereocontrol issues, are
illustrated in Scheme 5.
( )n
RO
8
N
Et2O, –78 °C
Ph
11 n = 1 72%
12 n = 2 45%
13 n = 3 50%
PCy2
Ru
OH
H
Cl
Cl
OH
H
Addition of Grignard reagents to aldehyde 8 had been
shown to occur with high selectivity from the rear (Si)
face as shown, the front face presumably being blocked by
the N-benzyl substituent. It seemed possible that analo-
gous selectivity might also be observed in addition to ho-
mologated systems, exemplified by unsaturated ester 7.
However, in the hope of anticipating either stereochemi-
cal outcome, we planned two stereocomplementary se-
Ph
RO
RO
PCy2
N
N
CH2Cl2, –78 °C
Ph
Ph
14 40%
from 11
15 50%
from 12
R = SitBuPh2
Scheme 3
These sequences are unoptimised, and we observed some quences designed to provide either epimer of the RCM
competing aldehyde reduction in the Grignard addition precursor diene.
step. Also, exposure of the extended diene 13 to the met-
athesis conditions did not result in formation of the de-
sired 8-membered ring product.
In the first sequence (route A) Michael addition of a vinyl-
ic unit to a,b-unsaturated ester 7 might provide 19, which
would undergo RCM to give the spirocyclic product 20
Synlett 2004, No. 13, 2295–2298 © Thieme Stuttgart · New York

LETTER
Synthesis of Core Structures Related to Pinnaic Acid and Halichlorine
2297
Si
The process provides the final spirocycle 24, which was
assigned as the undesired epimer for pinnaic acid synthe-
sis,17 as predicted by our simple model.
H
H
X
N
N
RO
O
RO
Bn
Re
Bn
This route to substituted azaspirocycle 24 requires only
seven steps from the initial chiral base product 6, and
opens up several potential avenues to the natural systems,
based on the stereochemical model that we have estab-
lished. Firstly, we expect that the cuprate addition process
(7 to 19) will provide the required RCM precursor, and we
intend preparing less hindered acceptors, and employing
cuprate reagents known to be effective with hindered sys-
tems. Secondly, effective inversion of the undesired
stereochemistry in 24 can be envisaged by a dehydrogena-
tion (or C=C migration)–hydrogenation sequence, provid-
ed the stereochemical model holds.
t
8
e.g. 7 X = CO2 Bu
t
CO2 Bu
H
t
H
CO2 Bu
*
RO
route
A
RO
N
*
N
7
Ph
Ph
19
20
route B
CO2Me
H
In conclusion, the present results show that a range of
functionalised and substituted azaspirocycles can be gen-
erated, starting from the non-racemic piperidine 6. Further
developments of the strategy are expected to provide con-
cise and versatile syntheses of pinnaic acid and close ana-
logues.
OMe
H
*
RO
O
N
N
RO
Bn
Ph
21
22
Scheme 5
Acknowledgment
with the desired stereochemistry for pinnaic acid and hal-
ichlorine.
We thank The Engineering and Physical Sciences Research Council
(EPSRC) and the University of Nottingham for support of TH. We
thank Nick Goldspink for preliminary work.
Alternatively, we could reduce 7 to the corresponding al-
lylic alcohol and then perform a Claisen rearrangement
(route B) to give 22, which should give complementary
stereochemistry at the crucial new stereocentre (C*) com-
pared to route A, provided that reaction followed the pat-
tern identified for 8.
References
(1) For leading references to histrionicotoxin, see: Stockman, R.
A.; Sinclair, A.; Arini, L. G.; Szeto, P.; Hughes, D. L. J. Org.
Chem. 2004, 69, 1598.
(2) (a) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.;
Yazawa, K.; Uemura, D. Tetrahedron Lett. 1996, 37, 3871.
(b) Carson, W.; Kim, G.; Hentemann, M. F.; Trauner, D.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4450.
(c) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner, D.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 2001, 40, 4453.
(3) (a) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.;
Hayashi, Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867.
(b) Trauner, D.; Schwartz, J. B.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 1999, 38, 3542. (c) Trauner, D.;
In the event we explored route B first, since preliminary
attempts to apply cuprate chemistry to enoate 7 were not
fruitful. Thus, reduction of ester 7 with DIBAL gave allyl-
ic alcohol 23, which was subsequently transformed into
product 24,15 having the azaspiro core with the desired
carboxymethyl side chain, by the Johnson ortho-ester
Claisen rearrangement,16 followed by ring closing meta-
thesis, Scheme 6.
Danishefsky, S. J. Tetrahedron Lett. 1999, 40, 6513.
(d) Trauner, D.; Churchill, D. G.; Danishefsky, S. J. Helv.
Chim. Acta 2000, 83, 2344.
MeC(OEt)3
DIBAL
OH
RO
7
N
EtCO2H (cat.)
140 °C
(4) For very recent formal syntheses of both ( )-halichlorine and
( )-pinnaic acid, and further references, see: Matsumura, Y.;
Aoyagi, S.; Kibayashi, C. Org. Lett. 2004, 6, 965.
CH2Cl2 –78 °C
Ph
23 50%
(5) For varied approaches, see for example: (a) Willand, N.;
Beghyn, T.; Nowogrocki, G.; Gesquire, J.-C.; Deprez, B.
Tetrahedron Lett. 2004, 45, 1051. (b) Canesi, S.; Belmont,
P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A. Tetrahedron
Lett. 2002, 43, 5193. (c) Ciblat, S.; Canet, J.-L.; Troin, Y.
Tetrahedron Lett. 2001, 42, 4815.
(6) For methods based on ring closing metathesis, see:
(a) Wright, D. L.; Schulte, J. P. II.; Page, M. A. Org. Lett.
2000, 2, 1847. (b) Suga, S.; Watanabe, M.; Yoshida, J. J.
Am. Chem. Soc. 2002, 124, 14824. (c) Nieczypor, P.; Mol,
J. C.; Bespalova, N. B.; Bubnov, Y. N. Eur. J. Org. Chem.
2004, 812. (d) Edwards, A. S.; Wybrow, R. A. J.; Johnstone,
C.; Adams, H.; Harrity, J. P. A. Chem. Commun. 2002,
1542. (e) Wybrow, R. A. J.; Stevenson, N. G.; Harrity, J. P.
MesN
NMes
CO2Et
Cl
Cl
Ru
Ph
H
*
PCy3
19/22
RO
N
toluene
80 °C
(ca. 1:4)
Ph
24 46% over
two steps
Scheme 6
Synlett 2004, No. 13, 2295–2298 © Thieme Stuttgart · New York

2298
T. Huxford, N. S. Simpkins
LETTER
A. Synlett 2004, 140.
(7) Goldspink, N. J.; Simpkins, N. S.; Beckmann, M. Synlett
1999, 1292.
(8) Clive has also recognised the possibility of applying our
chiral base reaction to this problem, see: Yu, M.; Clive, D. L.
J.; Yeh, V. S. C.; Kang, S.; Wang, J. Tetrahedron Lett. 2004,
45, 2879.
56.9 (CH2), 62.3 (CH), 67.6 (CH2), 71.6 (C), 126.3 (CH),
127.2 (CH), 127.5 (CH), 127.8 (CH), 129.5 (CH), 129.5
(CH), 133.7 (C), 133.9 (C), 135.5 (CH), 135.6 (CH), 142.0
(C), 220.0 (C=O). HRMS (APCI): m/z calcd for
C33H42NO2Si [M + H]: 512.2985; found: 512.2999.
(15) The Claisen rearrangement gave a mixture of intermediates,
assigned as 19/22 in a ca. 1:4 ratio. So far we have been able
to isolate only the metathesis product derived from the major
component. Data for ester 24: [a]D27 –4.2 (c 1.0 in CHCl3).
IR (CDCl3): nmax = 2957 (s), 2930 (s), 2858 (s), 1726 (s),
1588 (w), 1427 (m) cm–1. 1H NMR (500 MHz, CDCl3): d =
0.96 (9 H, s, t-BuSi), 1.17 (3 H, t, J = 7.3 Hz, Me), 1.45–1.69
(5 H, m), 1.97 (1 H, br d, J = 13.0 Hz), 2.13 (1 H, dd, J =
14.9, 10.7 Hz, CH2CO2), 2.25 (1 H, dd, J = 17.2, 2.3 Hz, 4-
H), 2.54 (1 H, d, J = 17.2 Hz, 4-H), 2.58–2.63 (2 H, m, 7-H
and CH2CO2), 3.05 (1 H, m, 1-H), 3.07 (1 H, dd, J = 9.9, 7.6
Hz, CH2OSi), 3.30 (1 H, d, J = 17.4 Hz, NCH2Ph), 3.55 (1
H, dd, J = 9.9, 3.8 Hz, CH2OSi), 3.85 (1 H, d, J = 17.4 Hz,
NCH2Ph), 4.05 (2 H, m, OCH2Me), 5.56 (1 H, br dd, J = 6.1,
1.9 Hz, 2-H), 5.71 (1 H, br dd, J = 6.1, 2.3 Hz, 3-H), 7.10 (1
H, m, Ar), 7.14–7.19 (4 H, m, Ar), 7.28–7.31 (4 H, m, Ar),
7.36–7.40 (2 H, m, Ar), 7.42–7.45 (4 H, m, Ar). 13C NMR
(125 MHz, CDCl3): d = 14.2 (CH3), 19.2 (C), 20.2 (CH2),
27.0 (CH3), 29.9 (CH2), 33.1 (CH2), 35.7 (CH2), 37.6 (CH2),
49.8 (CH), 53.9 (CH2), 60.3 (CH2), 63.6 (CH), 68.1 (CH2),
68.7 (C), 125.9 (CH), 126.8 (CH), 127.6 (CH), 127.9 (CH),
129.5 (CH), 132.8 (CH), 133.8 (C), 133.9 (C), 135.5 (CH),
135.6 (CH), 143.2 (C), 173.4 (C=O). HRMS (APCI): m/z
calcd for C37H48NO3Si [M + H]: 582.3403; found: 582.3398.
(16) Martin Castro, A. M. Chem. Rev. 2004, 104, 2939.
(17) This assignment is based on gradient NOE enhancements
seen between the methine at C-1 of the cyclopentene (C*)
and the methylene of the N-Bn group. By contrast no such
enhancement to the methylene of the CH2CO2Et substituent
was seen.
(9) In ref.8, Clive reports only a 69% ee was possible in the
preparation of 7, whereas we have observed 90–95% ee in
several runs. We are presently in communication with
Professor Clive in order to resolve this disparity.
(10) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.;
Knochel, P. J. Org. Chem. 1996, 61, 8229.
(11) For reviews, see: (a) Wipf, P.; Jahn, H. Tetrahedron 1996,
52, 12853. (b) Wipf, P.; Xu, W.; Smitrovich, J. H.;
Lehmann, R.; Venanzi, L. M. Tetrahedron 1994, 50, 1935.
(12) It appears that the basic tertiary amine interferes with the
organometallic chemistry; and in the radical reactions we
suspected 1,6-hydrogen atom abstraction from the N-CH2Ph
group.
(13) Analysis of allylic alcohol 10, in the form of its 4-nitroben-
zoate ester revealed the stereochemistry shown. We thank Dr
A. J. Blake of this school for this result, full details of which
will be published later.
(14) Data for ketone 16: [a]D28 –6.2 (c 1.0 in CHCl3). IR (CDCl3):
nmax = 2930 (s), 2858 (s), 1737 (s), 1588 (m), 1453 (m), 1362
(m), 1089 (s) cm–1. 1H NMR (400 MHz, CDCl3): d = 0.96 (9
H, s, t-Bu), 1.26–1.30 (1 H, m), 1.50–1.54 (3 H, m), 1.67–
1.78 (2 H, m), 1.97–2.06 (4 H, m), 2.14 (1 H, m, 2-H), 2.31
(1 H, m, 2-H), 2.61 (1 H, m, 7-H), 2.89 (1 H, dd, J = 9.9, 8.4
Hz, CH2OSi), 3.21 (1 H, d, J = 15.9 Hz, NCH2Ph), 3.33 (1
H, d, J = 15.9 Hz, NCH2Ph), 3.56 (1 H, dd, J = 9.9, 3.8 Hz,
CH2OSi), 7.07–7.14 (3 H, m, Ar), 7.23–7.27 (2 H, m, Ar),
7.27–7.35 (4 H, m, Ar), 7.36–7.45 (6 H, m, Ar). 13C NMR
(100 MHz, CDCl3): d = 17.7 (CH2), 19.2 (C), 19.8 (CH2),
25.9 (CH2), 26.9 (CH3), 29.3 (CH2), 31.3 (CH2), 37.2 (CH2),
Synlett 2004, No. 13, 2295–2298 © Thieme Stuttgart · New York