Organocatalytic asymmetric total synthesis of (R)-rolipram and formal synthesis of (3S,4R)-paroxetine

Article abstract of DOI:10.1021/ol800108u

(Chemical Equation Presented) An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.

Full text of DOI:10.1021/ol800108u

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1389-1391
Organocatalytic Asymmetric Total
Synthesis of (R)-Rolipram and Formal
Synthesis of (3S,4R)-Paroxetine
Peter S. Hynes,† Paul A. Stupple,‡ and Darren J. Dixon*,†
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester,
M13 9PL, United Kingdom, and Pfizer Global Research & DeVelopment,
Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Darren.Dixon@man.ac.uk
Received January 16, 2008
ABSTRACT
An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been
achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.
The highly enantioselective Michael addition of malonate
nucleophiles to nitro olefins catalyzed by a bifunctional
Lewis base, Brønsted acid organocatalyst derived from
9-amino(9-deoxy) epicinchonine has recently been re-
ported.1,2 This reaction provides direct access to â-substituted
γ-nitro carboxylic acid derivatives, compounds rich in
synthetic potential. In this paper we wish to demonstrate the
synthetic power of this Michael addition reaction by employ-
ing it as the key step in both the total asymmetric synthesis
of antidepressant (R)-rolipram3 1 and the formal asymmetric
synthesis of (3S,4R)-paroxetine 2, a selective serotonin reup-
take inhibitor (SSRI) used in the treatment of depression.4
to (3S,4R)-paroxetine, which requires a one carbon homolo-
gation, is not at first obvious.4,6 However, we believed an
(2) For recent applications of 9-amino(9-deoxy) epicinchona alkaloid
derivatives as organocatalysts, see: (a) Li, B.; Jiang, L.; Liu, M.; Chen,
Y.; Ding, L.; Wu, Y. Synlett 2005, 603. (b) Vakulya, B.; Varga, S.; Csa´mpai,
A.; Soo´s, T. Org. Lett. 2005, 7, 1967. (c) Tillman, A. L.; Ye, J.; Dixon, D.
J. Chem. Commun. 2006, 1191. (d) Bernardi, L.; Fini, F.; Herrera, R. P.;
Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375. (e) Song, J.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (f) Wang, Y. Q.; Song, J.;
Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128, 8156. (g) Wang,
J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem.
Soc. 2006, 128, 12652. (h) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron
2006, 62, 11499. (i) Liu, T.; Cui, H.; Long, J.; Li, B.; Wu, Y.; Ding, L.;
Chen, Y. J. Am. Chem. Soc. 2007, 129, 1878. (j) Song, J.; Shih, H.; Deng,
L. Org. Lett. 2007, 9, 603. (k) McCooey, S. H.; Connon, S. J. Org. Lett.
2007, 9, 599. (l) Wang, B.; Wu, F.; Wang, F.; Liu, X.; Deng, L. J. Am.
Chem. Soc. 2007, 129, 768. (m) Chen, W.; Du, W.; Yue, L.; Li, R.; Wu,
Y.; Ding, L.; Chen, Y. Org. Biomol. Chem. 2007, 5, 816. (n) Xie, J.; Chen,
W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.; Wu, Y.; Zhu, J.; Deng,
J. Angew. Chem., Int. Ed. 2007, 46, 389. (o) Xie, J.; Yue, L.; Chen, W.;
Du, W.; Zhu, J.; Deng, J.; Chen, Y. Org. Lett. 2007, 9, 413. (p) Mattson,
A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2006, 128, 3830. (q) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem.
Soc. 2007, 129, 4932. For mechanistic studies utilizing the cinchona
alkaloids, see: (r) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y.
Chem. Commun. 1991, 485. (s) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu,
X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105. (t) Hamza, A.; Schubert, G.; Soo´s, T.; Pa´pai, I. J. Am. Chem. Soc.
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Although the transformation of an appropriate Michael
adduct 5 to (R)-rolipram is tactically straightforward owing
to its γ-amino acid backbone,5 the analogous transformation
† The University of Manchester.
‡ Pfizer Global Research & Development.
(1) (a) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
See also: (b) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (c) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (d) McCooey, S. H.; Connon, S. J. Angew. Chem., Int.
Ed. 2005, 44, 6367.
10.1021/ol800108u CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/07/2008

effective route could exploit the natural reactivity of nitro
alkanes toward imines (the nitro-Mannich reaction) followed
by an intramolecular cyclization to the δ-lactam 4.7 This
would provide the core; the remainder of the synthesis would
require reductive manipulation of nitro, amide, and ester
functionalites (Scheme 1).
This material was recrystallized to enantiomeric purity
from hexane/TBME, (4:1) giving an overall reaction yield
of 87% to enantiopure 10. A nickel boride reduction of the
nitro group yielded the transesterified γ-lactam 11, which
was decarboxylated in a two stage hydrolysis/thermolysis
procedure to afford (R)-rolipram 1 as a single enantiomer in
63% overall yield over six steps (Scheme 2).
Scheme 1. Synthetic Plan to (R)-Rolipram 1 and
(3S,4R)-Paroxetine 2 from a Michael Adduct of Malonate and
Nitro Olefin
Scheme 2. Total Synthesis of (R)-Rolipram 1, Using
Bifunctional Organocatalyst 9
Key to the synthesis of (R)-rolipram 1 is the ready con-
struction of nitro olefin 8. This was prepared in 2 steps on
multigram scale from the commercially available hydroxy
aldehyde 6. An initial alkylation using cyclopentylbromide
and potassium carbonate in DMF provided ether 7 which
was then subjected to standard Henry condensation condi-
tions to give nitro olefin 8 in 80% yield over 2 steps. The
enantioselective Michael addition of dimethyl malonate to
8 catalyzed by 9 occurred smoothly at -20 °C in dichlo-
romethane; product 10 was formed in 96% yield and in
94% ee.
Our route to (3S,4R)-paroxetine 2 began in a similar
manner. The key nitro olefin 13 was prepared in a single
step from the commercially available aldehyde 12 in 92%
yield. The enantioselective malonate Michael addition to 13
(3) Schmiechen, R.; Horowski, R.; Palenschat, D.; Paschelke, G.;
Wachtel, H.; Kehr, W. U.S. Patent 4012495, 1975.
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Tschaen, D. M. Org. Lett. 2007, 9, 2669. For an early example of the nitro-
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(4) Barnes; R, D.; Wood-Kaczmar, M. W.; Curzons, A. D.; Lynch, I.
R.; Richardson; J. E.; Buxton; P. C. U.S. Patent 24721723, 1986.
(5) For previous stereoselective syntheses see: (a) Baures, P. W.;
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Org. Lett., Vol. 10, No. 7, 2008

reaction. Pleasingly, treatment of 14 with benzylamine and
formaldehyde in boiling methanol for 16 h lead smoothly to
the δ-lactam product 14 as a single diastereoisomer in 68%
yield.
Scheme 3. Formal Synthesis of (3S,4R)-Paroxetine 2, Using
Bifunctional Organocatalyst 9
For the nitro-Mannich lactamization step to be of any
synthetic value in the synthesis of target paroxetine, the
efficient reductive removal of the nitro group was necessary.
Although Nef-type chemistry was initially considered, the
reported reductive removal of nitro groups from alkanes
using tributyltin hydride and AIBN was attractive and
therefore investigated.8 Pleasingly, when a modification of
the Ono conditions were employed on 15 simultaneous
removal of the nitro group and dealkyl decarboxylation
occurred to give 16 in 78% yield. The synthesis of known
compound 16 constitutes a formal total synthesis of (3S,4R)-
paroxetine 2, the route to 16 being five steps and the overall
yield 38% (Scheme 3).6d
In summary, an efficient enantioselective total synthesis
of (R)-rolipram 1 and an efficient enantioselective formal
synthesis of (3S,4R)-paroxetine 2 has been achieved using
the highly enantioselective Michael addition of malonate
nucleophiles as key steps in both cases. In both routes, ready
improvement to the enantiomeric excess of the Michael
adduct was possible through the process of recrystallization,
and therefore the effective power of bifunctional catalyst 9
in the construction of target molecules as single enantiomers
has been demonstrated.
Acknowledgment. We gratefully acknowledge the EPSRC
and Pfizer Global Research and Development for a student-
ship (to P.S.H.).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for products 1, 7, 8, 10, 11,
13-16. This material is available free of charge via the
Internet at http://pubs.acs.org
catalyzed by 9 occurred smoothly to give the Michael adduct
14 in 92% yield and in 92% ee. Recrystallization from Et2O/
petroleum ether, (1:1) facilitated an efficient enantiomeric
upgrade to greater than 99% ee in a single operation; the
overall reaction yield to enantiopure 14 was 78%. With
Michael adduct 14 in hand, we were then poised to inves-
tigate the one carbon homologation via the nitro-Mannich
OL800108U
(8) Ono, N.; Miyake, H.; Tamura, R.; Kaji, A. Tetrahedron Lett. 1981,
22, 1750.
Org. Lett., Vol. 10, No. 7, 2008
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