A concise and flexible synthesis of the core structure of pinnaic acid

Article abstract of DOI:10.1055/s-2007-977446

An efficient and flexible approach to the core structure of pinnaic acid has been developed that centres on the microwave-induced 1,3-dipolar cycloaddition of a novel spirocyclic nitrone 5 with alkene 7. The application of this nitrone to the synthesis of a diverse set of C5-substituted analogues of pinnaic acid is also demonstrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977446

LETTER
1219
A Concise and Flexible Synthesis of the Core Structure of Pinnaic Acid
A
Synthetic
A
u
pproach to th
n
e
Core Struc
g
ture of Pinna
-
ic
A
cidHyun Yang, Vittorio Caprio*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Fax +64(9)3737422; E-mail: v.caprio@auckland.ac.nz
Received 25 January 2007
Nitrones exhibit a diverse reactivity profile6,7 and we en-
visioned that 5 could be used to provide access to both the
core structure of halichlorine and a diverse set of C5-sub-
stituted analogues of compounds 1–3. It was planned to
Abstract: An efficient and flexible approach to the core structure of
pinnaic acid has been developed that centres on the microwave-in-
duced 1,3-dipolar cycloaddition of a novel spirocyclic nitrone 5
with alkene 7. The application of this nitrone to the synthesis of a
diverse set of C5-substituted analogues of pinnaic acid is also de- access core structure 4 by reductive cleavage of cyclo-
monstrated.
adduct 6 formed by 1,3-dipolar cycloaddition of alkene 7
with nitrone 5. We envisioned that 5 could be accessed by
Key words: pinnaic acid, nitrones, cycloadditions, isoxazolidine,
oxidative ring opening
oxidative cleavage of known isoxazolidine 8 (Scheme 1).8
O
10
5
Pinnaic acid 1 is a spirobicyclic alkaloid extracted, along
with tauropinnaic acid (2), from the Okinawan bivalve
Pinna muricata by Uemura and co-workers in 1996.1 The
unusual 6-azaspiro[4.5]undecane core of this alkaloid is
also present in the spiroquinolizidine alkaloid halichlorine
(3), isolated by the same research group from the black
marine sponge Halichondria okadai (Figure 1).2 Pinnaic
acid is an inhibitor of cytosolic phospholipase A2 (cPLA2;
IC50 0.2 mM), an enzyme that plays a key role in the bio-
synthesis of inflammatory mediators and as such is an
interesting lead in the search for novel anti-inflammatory
treatments.3
R1O
N
H
H
N
H
13
O
Me
14
Me
4
6
OR2
OH
CO2Bn
Me
CO2Bn
+
N
O
5
H
N
H
O
8
7
OH
Scheme 1
O
10
H
Multigram quantities of isoxazolidine 8 were synthesised
in five steps from 1,5-dibromopentane utilizing the syn-
thetic route developed by Gossinger et al.8 After some ex-
perimentation it was discovered that oxidative cleavage of
8 to give nitrone 5 could be effected in high yield by drop-
wise addition of a solution of MCPBA in dichloromethane
at 0 °C over a period of seven hours (Equation 1).9,10
While nitrone 5 decomposes over a period of two days at
room temperature it may be stored for up to five months
in a freezer.
5
N
1
R
N
H
13
Me
OH
Me
Cl
H
HO
Me
14
O
O
OH
Cl
halichlorine (3)
pinnaic acid (1) R = OH
tauropinnaic acid (2) R = NHCH2CH2SO3H
Figure 1
The intriguing core structure and therapeutic potential of
pinnaic acid has stimulated the development of a number
of total syntheses of this target and synthetic routes to the
azaspirodecane core structure.4,5 In an effort to develop a
synthetic strategy that could be applied to the synthesis of
all members of the 6-azaspiro[4.5]decane family of
alkaloids and analogues, in racemic fashion, we have
investigated an approach to core structure 4 that centres
on the use of spirocyclic nitrone 5 as a key intermediate.
a
N
N
H
H
O
O
5
8
OH
Equation 1 Reagents and conditions: (a) MCPBA, dropwise,
CH2Cl2, 0 °C to r.t., 20 h, 89%.
The reactivity and synthetic utility of nitrone 5 was
probed by investigating the 1,3-dipolar cycloaddition of
this molecule with a small number of diverse dipolaro-
philes and attempted reductive ring opening of the result-
ing cycloadducts. The results of this study are summarised
SYNLETT 2007, No. 8, pp 1219–1222
1
6.
0
5.
2
0
0
7
Advanced online publication: 18.04.2007
DOI: 10.1055/s-2007-977446; Art ID: D02607ST
© Georg Thieme Verlag Stuttgart · New York

1220
S.-H. Yang, V. Caprio
LETTER
Table 1 1,3-Dipolar Cycloadditions of Nitrone 5 with Dipolarophiles 9a–d and Reductive Cleavage of the Resulting Cycloadducts 10a–d
R
OH
Zn, 50% AcOH(aq)
9a–d
5
N
O
5
H
R
N
H
N
O
H
reflux
3 h
H
R
11a–d
OH
OH
OH
10a–d
Entry
Alkene 9a
R
Solvent
Temp (°C)
Time (h)
10c
Yield (%)d
11c
Yield (%)d
1
2
3
4
9a
9b
9c
Ph
CO2Et
PhMe
110
25
13
48
14
55
10a
10b
10c
10d
62
90
60
80
11a
11b
11c
11d
76
70
81
0
CH2Cl2
CH2CH2OBz PhMe
OEt EtOH
110
40
9db
a Unless otherwise stated, cycloadditions were carried out using 3 equiv of dipolarophile.
b Cycloaddition was carried out using 17 equiv of dipolarophile.
c Relative stereochemistry determined by 2D-NOESY studies performed on azaspirodecanes 11a–d.
d Isolated and chromatographically pure products.
in Table 1. The reaction conditions specified for the from the a-face of nitrone 5 to ultimately yield aza-
cycloadditions are those resulting in optimum yields of spiro[4.5]decanes 11a–c and 12 with unnatural stereo-
products. Nitrone 5 undergoes regio- and stereoselective chemistry at C5 (Figure 2). This stereoselectivity is
1,3-dipolar cycloaddition with a range of dipolarophiles similar to that obtained during the nucleophilic addition of
and compounds 10a–d were the sole products isolated as silyl enol ethers5a and allylsilanes12 to spirocyclic iminium
single diastereomers in good to high yield. Nitrone 5 is re- species comparable in structure to 5. While the relative
active towards both electron-poor and electron-rich alk- stereochemistry of the azaspiro[4.5]decanes obtained is
enes and undergoes cycloaddition with ethyl acrylate (9b) not that desired this short study reveals that nitrone 5 has
and ethyl vinyl ether (9d) at relatively low temperature.
the potential to act as the synthetic gateway to a diverse set
of C5-substituted, azaspirodecane-based analogues of
pinnaic acid and halichlorine.
Reductive cleavage of the cycloadducts 10a–c proceeded
under standard conditions, utilizing zinc powder in acetic
acid under reflux, to give the C5-substituted aza-
spiro[4.5]decanes 11a–c. Isoxazolidine 10d decomposed
under these reaction conditions and the expected alde-
hyde, arising from hydrolysis of hemiacetal 11d, was not
isolated. Reductive cleavage of isoxazolidine 10d could
only be effected by hydrogenation in the presence of
Pd(OH)2 in methanol11 and, under these conditions,
overreduction occurred to give the diol 12 in moderate
yield (Equation 2).
HO
14
NOE
H
11a; R = Ph
H
OH
H
11b; R = CO2Et
11c; R = CH2CH2OBz
12; R = H
H
13
5
R
HN
Figure 2 Selected NOE observed in azaspiro[4.5]decanes 11a–c
and 12.
The reduction of imines/iminium ions13 and spiro-2,3,4,5-
tetrahydropyridine N-oxides,14 similar to 5 proceeds via
hydride delivery from the a-face and we reasoned that
oxidative cleavage of cycloadducts 10a–d followed by re-
duction of the resulting nitrones would yield 5-substituted
azaspirodecanes with the desired relative stereochemistry.
The strategy was initially attempted on isoxazolidine 10a.
Oxidation of 10a with MCPBA gave nitrone 13 which un-
derwent stereoselective reduction with NaBH414,15 to give
hydroxylamine 14 as a single diastereomer. Further reduc-
tion, with aqueous TiCl3 in MeOH16 gave the C5-epimer
of 11a; azaspiro[4.5]decane 15 (Scheme 2).
OH
a
N
O
H
N
H
H
EtO
OH
OH
10d
12
Equation 2 Reagents and conditions: (a) H2, 20 mol% Pd(OH)2,
MeOH, r.t., 48 h, 44%.
The stereochemistry of cycloaddition was most conve-
niently determined by NOE studies performed on the re-
duction products 11a–c and 12 owing to overlapping of
Epimerisation was confirmed by analysis of the 2D-
NOESY spectrum of 14. While NOE cross-peaks between
the C5-proton and those at C13/C14 were absent, strong
NOE were observed between the axial proton at C5, the
C10-protons and the axial C7-proton (Figure 3).
1
crucial signals in the H NMR spectra of isoxazolidines
10a–d. Unfortunately, these studies did not allow us to
assign exo/endo-stereochemistry to the cycloadducts.
Strong NOE’s observed between the C5-proton and those
at C13 and C14 indicated that cycloaddition occurred
Synlett 2007, No. 8, 1219–1222 © Thieme Stuttgart · New York

LETTER
A Synthetic Approach to the Core Structure of Pinnaic Acid
1221
OH
a
a
CO2Bn
N
O
H
N
O
H
Ph
N
O
H
+
N
H
Me
O
5
Ph
13
BnO2C
10a
OH
OH
OH
7
17
OH
Me
b
Equation 4 Reagents and conditions: (a) MW, toluene, 165 °C, 1 h,
80%.
OH
OH
c
resulting nitrone gave azaspirodecane 18. Selective pro-
tection of the primary hydroxy group in 18 and treatment
of the resulting silyl ether 19 with two equivalents of
MsCl in triethylamine led to the formation of a readily
seperable 17:3 mixture of the desired E-a,b-unsaturated
ester 20a and the Z-isomer 20b.
Ph
N
H
Ph
N
H
H
OH
14
15
OH
OH
Scheme 2 Reagents and conditions: (a) MCPBA, CH2Cl2, 0 °C, 1 h,
90%; (b) NaBH4, MeOH, 0 °C, 20 min, 90%; (c) 20% TiCl3(aq), H2O,
MeOH, r.t., 2 h, 95%.
OH
a
17
BnO2C
OH
7
N
H
H
14
H
5
Me
Ph
18
OH
N
13
H
10
OH
H
OH
b
H
H
14
NOE
OH
Figure 3 Selected NOE observed in azaspiro[4.5]decane 14.
BnO2C
N
H
With multigram quantities of nitrone 5 in hand and proven
methodology for the synthesis of 5-substituted azaspiro-
decanes in place we next embarked on a synthesis of core
structure 4 utilising key dipolarophile 7.17 Alkene 7 was
synthesised by quenching of the Grignard reagent derived
from crotyl chloride (16) with carbon dioxide18 followed
by esterification of the resulting acid (Equation 3).
Me
H
19
OTBDPS
c
BnO2C
+
Me
N
H
N
H
Me
H
CO2Bn
H
20b
20a
a
OTBDPS
CO2Bn
OTBDPS
Cl
(E:Z = 17:3)
Me
7
16
Scheme 3 Reagents and conditions: (a) (i) MCPBA, CH2Cl2, 0 °C
to r.t., 1 h, 83%; (ii) NaBH4, MeOH, 0 °C, 20 min, 68%; (iii) 20%
TiCl3(aq), MeOH, r.t., 2 h, 94%; (b) TBDPSCl, DMAP, Et3N, CH2Cl2,
r.t., 3 h, quant.; (c) 2 equiv MsCl, Et3N, CH2Cl2, r.t., 2 h, 60%.
Equation 3 Reagents and conditions: (a) (i) Mg, THF, r.t. to reflux,
3 h; (ii) CO2, THF, 51%; (iii) BnOH, DCC, DMAP, r.t., 12 h, 98%.
1,3-Dipolar cycloaddition of alkene 7 with nitrone 5 pro-
ceeded poorly under conventional thermal conditions
using a variety of solvents and temperatures. It has been
shown that the rate and yield of nitrone cycloadditions can
be much enhanced under microwave irradiation19 and
irradiation of a mixture of a three-fold excess of 7 and 5 in
a microwave reactor for one hour resulted in clean cyclo-
addition to give isoxazolidine 17 as a separable mixture of
two diastereomers in 80% yield (Equation 4).20 In this
case NOE data obtained for these diastereomers con-
firmed that cycloaddition occurred from the a-face of
nitrone 5 and proceeded with complete exo-selectivity.
In conclusion, a concise stereoselective synthesis of the
core structure of pinnaic acid has been developed utilising
a novel, spirocyclic nitrone 5. Furthermore, we have de-
monstrated the use of this nitrone to access a small but
diverse array of C5-substituted analogues of pinnaic acid/
halichlorine with both natural and unnatural stereochem-
istry at this position. Current efforts are directed towards
the further elaboration of 20a and the application of our
synthetic strategy to the synthesis of the more challenging
spiroquinolizidine core of halichlorine.
Acknowledgment
The diastereomeric mixture 17 was then further elaborat-
ed to the pinnaic acid core structure (Scheme 3). Oxida-
tive ring opening of 17 followed by reduction of the
The authors wish to thank The University of Auckland Doctoral
Scholarship Fund (S.H.Y) and The University of Auckland
Research Committee for financial support of this project.
Synlett 2007, No. 8, 1219–1222 © Thieme Stuttgart · New York

1222
S.-H. Yang, V. Caprio
LETTER
(11) DeShong, P.; Leginus, J. M. J. Am. Chem. Soc. 1983, 105,
1686.
(12) Koviach, J. L.; Forsyth, C. J. Tetrahedron Lett. 1999, 40,
8529.
(13) (a) Arimoto, H.; Asano, S.; Uemura, D. Tetrahedron Lett.
1999, 40, 3583. (b) Matsumura, Y.; Aoyagi, S.; Kibayashi,
C. Org. Lett. 2003, 5, 3249. (c) Hayakawa, I.; Arimoto, H.;
Uemura, D. Heterocycles 2003, 59, 441. (d) Hayakawa, I.;
Arimoto, H.; Uemura, D. Chem. Commun. 2004, 1222.
(e) Matsumara, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett.
2004, 6, 965.
(14) Zhang, H.-L.; Zhao, G.; Ding, Y.; Wu, B. J. Org. Chem.
2005, 70, 4954.
(15) Ali, S. A. Tetrahedron Lett. 1993, 34, 5325.
(16) Yamada, K.; Kishikawa, K.; Yamamoto, M. J. Org. Chem.
1987, 52, 2327.
(17) Taniguchi, M.; Koga, K.; Yamada, S. Chem. Pharm. Bull.
1972, 20, 1438.
(18) Andreana, P. R.; McLellan, P. S.; Chen, Y.; Wang, R. G.
Org. Lett. 2002, 4, 3875.
References and Notes
(1) Chou, T.; Otani, Y.; Shikano, M.; Yazawa, K.; Uemura, D.
Tetrahedron Lett. 1996, 37, 3871.
(2) (a) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.;
Hayashi, Y.; Uemura, D. Tetrahedron Lett. 1996, 37, 3867.
(b) Arimoto, A.; Hayakawa, I.; Uemura, D. Tetrahedron
Lett. 1998, 39, 861.
(3) (a) Nevalainen, T. J.; Haapamäki, M. M.; Grönroos, J. M.
Biochim. Biophys. Acta 2000, 1488, 83. (b) Reid, R. C.
Curr. Med. Chem. 2005, 12, 3011. (c) Gomez-Paloma, L.;
Monti, M. C.; Terracciano, S.; Casapullo, A.; Riccio, R.
Curr. Org. Chem. 2005, 9, 1419.
(4) For a review of synthetic approaches to pinnaic acid and
halichlorine developed up to 2005, see: Clive, D. L. J.; Yu,
M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem. Rev. 2005, 105,
4483.
(5) Synthetic approaches not covered in ref. 4: (a)Roulland,E.;
Chiaroni, A.; Husson, H.-P. Tetrahedron Lett. 2005, 46,
4065. (b) Andrade, R. B.; Martin, S. F. Org. Lett. 2005, 7,
5733. (c) Sinclair, A.; Arini, L. G.; Rejzek, M.; Szeto, P.;
Stockman, R. A. Synlett 2006, 2321.
(6) For reviews covering cycloadditions of nitrones, see:
(a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396.
(b) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
(c) Fredrickson, M. Tetrahedron 1997, 53, 403. (d) De
March, P.; Figueredo, M.; Font, J. Heterocycles 1999, 50,
1213. (e) Koumbis, A. E.; Gallos, J. E. Curr. Org. Chem.
2003, 7, 585.
(7) For reviews covering nucleophilic additions to nitrones,
see: (a) Lombardo, M.; Trombini, C. Synthesis 2000, 759.
(b) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett
2000, 442. (c) Lombardo, M.; Trombini, C. Curr. Org.
Chem. 2002, 6, 695.
(19) (a) Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Moreno,
A.; Gómez-Escalonilla, M. J.; Loupy, A. Heterocycles 1996,
43, 1021. (b) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T.
J. Chem. Soc., Perkin Trans. 1 2001, 452. (c) Enderlin, G.;
Taillefumier, C.; Dideirjean, C.; Chapleur, Y. Tetrahedron:
Asymmetry 2005, 16, 2459.
(20) A 10 mL microwave reaction vessel was charged with ester
7 (0.62 g, 3.27 mmol), nitrone 5 (0.30 g, 1.63 mmol) and
toluene (5 mL). The vial was sealed with a cap containing a
silicon septum, loaded into the cavity of a focussed micro-
wave oven (Discover® CEM, 250 W) and heated for 1 h at
165 °C. The reaction mixture was cooled to r.t., concentrated
and purified by column chromatography on silica gel using
EtOAc–hexane (3:7) as eluent to give isoxazolidine 17 as
two diastereomers as colourless oils (0.48 g, 80%; dr = 1:1;
diastereomers unassigned).
(8) Gössinger, E.; Imhof, R.; Wehrli, H. Helv. Chim. Acta 1975,
58, 96.
(9) LeBel, N. A.; Post, M. E.; Hwang, D. J. Org. Chem. 1979,
44, 1819.
Diastereomer A: IR (neat): 3443, 2958, 1728 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.25 (d, 3 H, J = 7.1 Hz),
1.30–1.63 (m, 8 H), 1.64–1.93 (m, 3 H), 1.94–2.08 (m, 2 H),
2.09–2.12 (m, 2 H), 2.66 (dq, 1 H, J = 7.9, 7.1 Hz), 3.45 (d,
1 H, J = 5.8 Hz), 3.56–3.65 (m, 2 H), 4.12 (td, 1 H, J = 7.9,
(10) A solution of MCPBA (70%, 5.70 g, 33.0 mmol) in CH2Cl2
(130 mL) was added to a solution of isoxazolidine 8 (3.80 g,
22.7 mmol) in CH2Cl2 at 0 °C over 7 h. After the addition
was complete the mixture was warmed to r.t. and stirred for
a further 20 h. Then, sat. aq Na2S2O3 (60 mL) and sat.
NaHCO3 (60 mL) were added and the mixture extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were
dried over anhyd MgSO4, concentrated and purified by
column chromatography on silica gel using CH2Cl2–MeOH
(9.5:0.5) as eluent to give nitrone 5 as a yellow solid (3.72 g,
89%); mp 70–73 °C. IR (neat): 3410, 2961, 1642 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.30–2.10 (m, 10 H), 2.45–
2.52 (m, 2 H), 2.70–2.85 (m, 1 H), 3.65–3.80 (m, 2 H), 7.34
(t, 1 H, J = 4.0 Hz). 13C NMR (75 MHz, CDCl3): d = 15.4,
24.0, 26.3, 28.3, 37.0, 38.5, 52.7, 61.1, 76.5, 142.0. HRMS
(EI): m/z calcd for [C10H17NO2]+: 183.1253; found:
183.1259.
5.7 Hz), 5.11 (d, 2 H, J = 7.4 Hz), 7.30–7.38 (m, 5 H). 13
C
NMR (75 MHz, CDCl3): d = 14.5, 19.2, 21.2, 26.4, 27.8,
30.2, 38.2, 40.0, 45.3, 45.4, 57.8, 65.4, 66.1, 69.2, 76.0,
128.0, 128.1, 128.5, 135.9, 174.3. HRMS (EI): m/z = calcd
for [C22H31NO4]+: 373.2253; found: 373.2253.
Diastereomer B: IR (neat): 3448, 2958, 2931, 1727 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.11 (d, 3 H, J = 7.0 Hz),
1.23–1.68 (m, 10 H), 1.69–1.96 (m, 2 H), 1.97–2.08 (m, 2
H), 2.09–2.15 (m, 2 H), 2.70 (dq, 1 H, J = 8.5, 7.1 Hz), 3.45
(d, 1 H, J = 6.3 Hz), 3.54–3.64 (m, 2 H), 4.20 (td, 1 H,
J = 8.5, 6.0 Hz), 5.14 (d, 2 H, J = 4.9 Hz), 7.29–7.36 (m, 5
H). 13C NMR (75 MHz, CDCl3): d = 12.7, 19.2, 21.1, 26.4,
27.7, 29.6, 38.0, 39.1, 45.2, 45.4, 57.9, 65.4, 66.0, 69.1, 76.3,
127.9, 128.0, 128.4, 136.1, 174.5. HRMS (EI): m/z calcd for
[C22H31NO4]+: 373.2253; found: 373.2256.
Synlett 2007, No. 8, 1219–1222 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.