A diastereoselective approach for an asymmetric synthesis in pinnaic acid series

Article abstract of DOI:10.1016/j.tetlet.2005.04.019

An enantiopure spiran-bearing advanced intermediate in pinnaic acid series was obtained in 11 steps starting with CN(R,S) building block.

Full text of DOI:10.1016/j.tetlet.2005.04.019

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4065–4068
A diastereoselective approach for an asymmetric synthesis in
pinnaic acid series
a
Emmanuel Roulland, Angele Chiaroni and Henri-Philippe Husson
a
b,
*
`
aInstitut de Chimie des Substances Naturelles, CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette, France
b
´
´
`
´
´
Laboratoire de Chimie Therapeutique, UMR 8638 associee au CNRS et a l’Universite Rene Descartes (Paris 5),
Faculte des Sciences Pharmaceutiques et Biologiques. 4, Avenue de l’Observatoire, 75270 Paris cedex 06, France
´
Received 22 February 2005; revised 2 April 2005; accepted 5 April 2005
Available online 22 April 2005
Abstract—An enantiopure spiran-bearing advanced intermediate in pinnaic acid series was obtained in 11 steps starting with
CN(R,S) building block.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric synthesis of azaspiro[3,5]decane system
which is an integral feature of its remarkable structure.
In 1996, Uemura and co-workers1 reported the isolation
of pinnaic acid 1 from the bivalve Pinna muricata, an
indigenous shell of the sea surrounding the Okinawa
island. This alkaloid bears a unique spiranic skeleton
and displays anti-inflammatory and immuno-suppres-
sive properties mediated by the inhibition of phospholi-
pase A2. The potential medicinal importance of pinnaic
acid provides an impetus for the research of an efficient
The use of the CN(R,S) method2 was envisaged as it
provides access to enantiopure piperidines bearing a
large array of possible substituents. Although only one
total synthesis of pinnaic acid has been reported in the
past decade,3 other approaches4 have provided useful
insights (Scheme 1).
2. Results and discussion
22 Me
13 H
α-chain
The first step of our approach was the diastereoselective
alkylation of the lithio anion of amino-nitrile 2 with a
halogenated electrophile. The CN(R,S) strategy allowed
us to control with confidence2 the S absolute configur-
ation of the C9 quaternary centre of pinnaic acid 1. In-
deed, a unique diastereomer 35 was obtained by this
means (Scheme 2). We then built the B-ring via the
intramolecular attack on the nitrile function by an
organo-lithium nucleophile 4 which was generated by
a halogen/lithium exchange using lithium-naphthalenide
at À78 °C.
H
N
A
14
17
HO
1
9
21
B
CO2H
5
Cl
OH
β-chain
Pinnaic acid 1
Ph
O
NC
N
CN(R,S) building block 2
This led to the quite unstable spiranic enamine deriva-
tive 66 which arises from the opening of the postulated
bicyclic imine intermediate 5. We exploited the property
of enamine 6 to be protonated as iminium salt 7 in order
to introduce the b-chain, through nucleophilic attack of
a silylenolether (Scheme 3). The reaction was performed
using ytterbium triflate as a Lewis acid (10 mol%) in a
Scheme 1.
Keywords: Amino-nitrile; CN(R,S) strategy; Total synthesis; Pinnaic
acid.
*
Corresponding author. Tel.: +33 1 53 73 97 54; fax: +33 1 43 29 14
03; e-mail: henri-philippe.husson@univ-paris5.fr
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.019

4066
E. Roulland et al. / Tetrahedron Letters 46 (2005) 4065–4068
Ph
NC
8, BF3:OEt2,
Et2O/MeCN,
-50 °C.
NC
NC
Ph
1.Yb(OTf)3,
THF/H2O.
OH
Ph
Cl
Li, naphthalene,
THF, -78 °C.
O
N
LDA, THF, -78 °C,
I(CH2)3Cl (91%).
Ph
O
N
9
N
2
(73%)
2. BuLi, THF,
10
3
4
O
P
EtO
reflux.
CO2Et
12
nOe
CN
Ph
EtO
11
Li
O
N
H2N
NC
O
N
N
(23% three steps from 3)
N
LiO
Scheme 4. Introduction of a- and b-chains.
Ph
4
6
5
Scheme 2. Spiroannulation process by lithium/halogen exchange.
the lithium anion of diethyl(cyanomethyl)-phosphonate
in refluxing THF9 gave the expected compound 11
(23% yield in three steps from amino-nitrile 3) with
exclusive E-configuration and partial racemisation at
C5.
Ph
Ph
O
O
O
H2N
O
N
N
N
X
The b-chain was built at that point by reaction of silyl-
enolether 8 with the iminium ion generated from the
oxazolidine function10 of 11, leading to ester 12.
9
6
Yb(OTf)3 (10 mol%)
THF, H2O, reflux.
H
+
OTBS
Ph
Ph
O
8
H2N
HO
The expected axial attack occurred and led exclusively
to the unnatural stereochemistry at C5as demonstrated
by an NMR NOESY experiment on compound 12
(Scheme 4). Since an equatorial position for the b-chain
is more thermodynamically favoured, we are planning to
restore the correct stereochemistry at C5in the course of
a retro-Michael/Michael reaction sequence. This strat-
egy is supported by the fact that Danishefsky et al.3 built
the piperidine A-ring of pinnaic acid 1 using a Michael
reaction and obtained the correct stereochemistry at C5.
OEt
N
CO2Me
10 (18%)
X
7
Scheme 3. Attack of silylenolether on iminium 7 and Yb(OTf)3
catalysed hydrolysis of 6.
9/1 THF/water mixture and tert-butyldimethylsilylenol-
ether 87 as a nucleophile. The expected ester 10 was
obtained in poor yield only but as a unique diastereomer.
However, we found that the main reaction product
formed under these conditions was ketone 9.8 A more
classical acidic hydrolysis of 6 (hydrochloric acid 1
N/THF, 1/1) only led to decomposition products. We
decided to pursue this mild ytterbium triflate-mediated
hydrolysis to obtain ketone 9 in an optimised yield;
however, due to its acidic sensitivity, it could not be
purified by column chromatography.
In the next step of our studies we hoped to reduce the
C13–C14 double bond of the acrylonitrile function of
12 with control of the C13 stereochemistry. Unfortu-
nately, none of the reducing reagents tried (Mg/
MeOH,11 hydrogenation H2, Pd/C or RhCl(PPh3)3, dis-
solved metals (Li or Na)12 or copper hydride13) led to
the expected product; in most cases complex mixtures
of over-reduced products were obtained. As a result,
our strategy was modified and we decided to introduce
the C22 methyl by alkylation of the acrylonitrile func-
tion. To achieve this we first needed to protect alcohol
12 as silyl ether 13 (Scheme 5). The ester function of
Thus, crude ketone 9 was used directly in a Horner–Em-
mons olefination step to introduce the a-chain (Scheme
4). Since the ketone function of 9 is very hindered, only
NC
NC
Ph
R
Ph
Ph
OTBS
OTBS
OTBS
OTBS
Me
N
Me
N
OR1
R2
TBDMSCl, imidazole,
CH2Cl2.
LDA, HMPA, THF,
MeI, -78 °C.
DIBALH, PhMe,
-78 °C
N
12
(90%, 97% de)
(97%)
16
13 : R1 = TBS, R2 = CO2Et.
14 : R1 = TBS, R2 = CH2OH.
15 : R1 = TBS, R2 = CH2OTBS.
17 : R = CHO.
18 : R = CH2OH.
DIBALH, THF.
TBSCl, imidazole,DMF.
(84% two steps)
LiAlH4, THF.
(60% two steps)
5
OTBS
Me
13
Ph
H
9
13
H2, 5 bars, Pd/C,
EtOH/PhH (5/1).
HO
N
OTBS
12
MM2 calculation
for compound 18
9
5
H H
(81%)
19
Palladium surface
Scheme 5. Synthesis of advanced intermediate 19. Conformation of minimum energy for compound 18 and most plausible explanation for its
observed hydrogenation facial selectivity.

E. Roulland et al. / Tetrahedron Letters 46 (2005) 4065–4068
4067
reprotonation of the enolate of nitrile 16 is planned
for the inversion of the C14 stereochemistry.
Acknowledgments
Dr. Yves Janin and Professor David Aitken are
acknowledged for fruitful discussions.
References and notes
1. (a) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.;
Yazawa, K.; Uemura, D. Tetrahedron Lett. 1996, 37,
3871–3874; (b) Kuramoto, M.; Tong, C.; Yamada, K.;
Chiba, T.; Hayashi, D.; Uemura, D. Tetrahedron Lett.
1996, 37, 3867–3870.
Figure 1. ORTEP drawing of 16.
13 was selectively reduced into alcohol 14 and finally
protected as a silyl ether 15.
2. Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383–
394.
3. (a) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner,
D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4450–4452; (b) Carson, M. W.; Kim, G.; Danishefsky, S.
J. Angew. Chem., Int. Ed. 2001, 40, 4453–4456.
4. (a) Matsumura, Y.; Aoyagi, S.; Kibayashi, C. Org. Lett.
2004, 6, 965–968; (b) Matsumura, Y.; Aoyagi, S.; Kiba-
yashi, C. Org. Lett. 2003, 5, 3249–3252; (c) Takasu, K.;
Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017–3020; (d)
Hayakawa, I.; Arimoto, H.; Uemura, D. Heterocycles
2003, 59, 441–444; (e) Yokota, W.; Shindo, M.; Shishido,
K. Heterocycles 2001, 54, 871–885; (f) White, J. D.;
Blakemore, P. R.; Paul, R.; Korf, E. A.; Yokochi, A. F. T.
Org. Lett. 2001, 3, 413–415; (g) Wright, D. L.; Schulte, J.
P., II; Page, M. A. Org. Lett. 2000, 2, 1847–1850; (h)
Koviach, J. L.; Forsyth, G. J. Tetrahedron Lett. 1999, 40,
8529–8532; (i) Clive, D. J. L.; Yeh, V. S. C. Tetrahedron
Lett. 1999, 40, 8503–8507; (j) Lee, S.; Zhao, Z. Tetrahe-
dron Lett. 1999, 40, 7921–7924; (k) Lee, S.; Zhao, Z.
Org. Lett. 1999, 1, 681–683; (l) Arimoto, H.; Asano, S.;
Uemura, D. Tetrahedron Lett. 1999, 40, 3583–3586.
5. Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1993,
58, 6451–6456.
6. Ribeiro, C. M. R.; de Melo, S. J.; Bonin, M.; Quirion,
J.-C.; Husson, H.-P. Tetrahedron Lett. 1994, 35, 7227–
7230.
7. Rathke, M. W.; Sullivan, D. F. Synth. Commun. 1973,
3(1), 67–72.
8. The structures of all new products are supported by
1H, 13C NMR spectra and HRMS data.
9. (a) Erickson, K. L.; Markstein, J.; Kim, K. J. Org. Chem.
1971, 36, 1024–1030; (b) Garratt, P.; Doecke, C. W.;
Weber, J. C.; Paquette, L. A. J. Org. Chem. 1986, 51, 449–
452.
The alkylation of 15 in THF at À78 °C in the presence
of 1.5equiv of HMPA and LDA as a base gave com-
pound 1614 with high control of the C14 stereochemistry
(97% de). As expected, the alkylation of this a,b-unsat-
urated nitrile occurs a along with a double bond shift.15
Unfortunately, we obtained the unnatural stereochemis-
try at C14 as demonstrated by X-ray analysis performed
on compound 1616 (Fig. 1).
The nitrile function of 16 was reduced to alcohol 18 via
aldehyde 17. It was then possible to perform the planned
hydrogenation of the cyclopentene ring of 18 without
the over-reduction we encountered with the a,b-unsatu-
rated nitrile 12. Thus, a palladium-catalysed hydrogen-
ation of the C12–C13 double bond, performed under
pressure (5bar), led to compound 1917 as the sole diaste-
reomer. Despite NOESY 1H NMR experiments, the
C13 stereochemistry of compound 19 could not be
determined. Nevertheless, the course of a heterogeneous
phase hydrogenation reaction is predictable in the case
of a space-congested molecule. Thus, the fact that no
hydrogenation of the benzylic C–N bond took place
and that the methylation of 15 at C14 specifically pro-
ceeds on one side, suggests a strong steric hindrance in
this area of the molecule. This is plausible, as compound
18 bears two bulky TBS protective groups. This hin-
drance is probably at the origin of this face-selective
hydrogenation of the cyclopentene B-cycle that leads
to the correct stereochemistry at C13. Moreover, the
MM2 calculation of the lowest energy conformation of
compound 18 (Scheme 5) confirms that one face in
ring-B is far less congested than the other.
10. Berrien, J.-F.; Billion, M.-A.; Husson, H.-P.; Royer, J.
J. Org. Chem. 1995, 60, 2922–2924.
11. (a) Profitt, J. A.; Watt, D. S. J. Org. Chem. 1975, 40, 127–
128; (b) Osborn, M. E.; Kuroda, S.; Muthard, J. L.;
Kramer, J. D.; Engel, P.; Paquette, L. A. J. Org. Chem.
1981, 46, 3379–3388.
3. Conclusion
ˆ
12. Angibeaud, P.; Larcheveque, M.; Normant, H.; Tchoubar,
B. Bull. Chem. Soc. Chim. Fr. 1968, 595–600.
This work demonstrates that the enantiopure spiranic
core of pinnaic acid alkaloid 1 can be successfully built
using the CN(R,S) strategy. Further progress in pinnaic
acid total synthesis will focus on the stereochemical
inversion of the C5and C14 centres. At a final stage,
the internal 1-6 retro-Michael/Michael equilibration3
is envisaged to control C5stereochemistry. A kinetic
13. (a) Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K.
J. Org. Chem. 1985, 54, 5308–5313; (b) Osborn; Pegues,
J.F.; Paquette, L. A. J. Org. Chem. 1980, 45, 167–168.
14. Spectroscopic data for compound 16: colourless crystal
recryst from hexane, mp: 139 °C, 1H (400 MHz, CDCl3) d
0.04 (two s, 6H), 0.09 (two s, 6H), 0.93 (s, 18 H), 1.10–1.45
(m, 5H), 1.46 (d, 3H, J = 7.2 Hz), 1.59–1.88 (m, 5H), 2.20

4068
E. Roulland et al. / Tetrahedron Letters 46 (2005) 4065–4068
(m, J = 7.0 Hz), 2.40 (m, 1H, J = 9.9 Hz), 3.40–3.58 (m,
in the successive difference Fourier maps but displayed
very large displacement parameters explaining the very
poor diffraction quality of these crystals. Therefore,
refinement of the structure (excluding the 12 carbon
atoms of TBS groups) was stopped at a poor convergence
level (R = 0.24).
4H, J = 4.9, 4.6 and 5.9 Hz), 3.75 (t, 1H, J = 6.1 Hz), 4.03
(m, 2H, J = 7.3, 4.5, 10.4 Hz), 4.24 (t, 1H, J = 10.3 Hz),
6.11 (s, 1H), 7.21 (m, 5H). 13C (100 MHz, CDCl3) d À5.50,
À5.41, À5.32, 17.00, 18.42, 23.16, 26.04, 26.11, 28.47,
29.54, 33.17, 34.02, 37.43, 46.62, 61.69, 62.33, 63.47, 74.28,
123.99, 127.14, 127.77, 129.55, 130.64, 141.48, 148.50.
HRMS (CI+, CH4) calcd for C34H59N2O2Si2 (MH)+:
583.4115. Found: 583.4106.
17. Spectroscopic data for compound 19: colourless oil. 1H
NMR (400 MHz, CDCl3) d 0.02 (s, 12H), 0.86 (s, 18H),
0.93 (d, 3H, J = 7.0 Hz), 1.27 (m, 3H), 1.42 (m, 1H), 1.55
(m, 1H, J = 6.8 Hz), 1.70 (m, 4H, J = 7.6 Hz), 1.92 (m, 1H),
1.99 (m, 1H, J = 6.8 Hz), 2.22 (m, 4H), 2.46 (m, 1H), 2.70
(m, 1H, J = 6.8 Hz), 3.40 (m, 2H, J = 10.1, 6.1 Hz), 3.56
(m, 1H, J = 10.4 Hz), 3.61 (m, 2H), 3.86 (m, 1H, J =
4.1 Hz), 7.29 (m, 5H). 13C NMR, (100 MHz, CDCl3) d
À5.40, À5.30, À5.19, 15.42, 18.35, 21.85, 24.54, 25.99,
26.05, 28.43, 29.80, 30.95, 35.23, 35.38, 36.03, 36.93, 51.91,
60.47, 62.41, 66.08, 68.49, 127.26, 128.07, 128.21, 135.81,
139.48, 142.06. HRMS (CI+, CH4) calcd for C34H64NO2Si2
(MH)+: 590.4425. Found: 590.4417.
15. Anies, C.; Pancrazi, A.; Lallemand, J.-Y. Bull. Soc. Chim.
Fr. 1997, 134, 183–202.
16. Despite many recrystallisation attempts on compound 16
to improve the crystal diffracting quality, the resolution of
the best recorded full dataset did not exceed 2h = 43 deg
˚
(for k Cu Ka = 1.5418 A). Only 28 non-H atoms out of 40,
corresponding to the central core of compound 16, could
be solved by direct methods and refined isotropically by
full-matrix least squares on F2. Some carbon atoms of
both TBS protective groups could be partially recognized