A stereoselective and scalable synthesis of a conformationally constrained S1P1 agonist

Article abstract of DOI:10.1016/j.tetlet.2009.04.099

A scalable and enantioselective synthesis of a potent S1P₁ agonist containing two stereogenic centers on a cyclopentane ring is described. Control of the absolute chirality of an amino alcohol precursor, generated via a robust phase-transfer ca

Full text of DOI:10.1016/j.tetlet.2009.04.099

Tetrahedron Letters 50 (2009) 4081–4083
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Tetrahedron Letters
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A stereoselective and scalable synthesis of a conformationally constrained
S1P1 agonist
b
b
b
Shannon R. Fix-Stenzel a, Martin E. Hayes b, , Xiaolei Zhang , Grier A. Wallace , Pintipa Grongsaard ,
*
Lisa M. Schaffter b, Steven M. Hannick a, Thaddeus S. Franczyk a, Robert H. Stoffel b, Kevin P. Cusack b
a Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
b Abbott Bioresearch Center, 381 Plantation Dr, Worcester, MA 01605, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A scalable and enantioselective synthesis of a potent S1P1 agonist containing two stereogenic centers on a
cyclopentane ring is described. Control of the absolute chirality of an amino alcohol precursor, generated
via a robust phase-transfer catalyzed alkylation protocol, allows for substrate directed hydrogenation to
install the second stereogenic center providing access to gram-quantities of compound 2.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 March 2009
Revised 16 April 2009
Accepted 24 April 2009
Available online 3 May 2009
Agonism of sphingosine-1-phosphate (S1P) receptors, specifi-
cally the S1P1 receptor, has been linked to many diverse cellular
functions including sequestration of lymphocytes into secondary
lymph organs thereby preventing them from causing an autoim-
mune response.1 FTY720 represents a new class of immunomodu-
lating agents that act via agonism of the S1P1 receptor and has
been shown to be active in Phase II clinical trials for multiple scle-
rosis.2 Compound 1 (see Fig. 1) is a conformationally constrained
analog of FTY720 that has been shown to induce sequestration of
lymphocytes in mice.3 Two diastereomers, (1R,3S) (2) and (1R,3R)
(3, Fig. 1), have been prepared in milligram-quantities and con-
firmed to be the stereoisomers that are active in vivo. Herein, we
disclose a gram-scale, enantioselective route to one of the active
stereoisomers which provides intermediates suitable for analog
synthesis to establish structure–activity relationships.
A synthetic route was chosen that would set the conserved (1R)
stereogenic center of the two diastereomers that induce lympho-
penia while allowing for late-stage induction of the benzylic ste-
reocenter through either chirality transfer or reagent control (see
Scheme 1). In addition, an alkene such as compound 4, which could
be prepared via ring-closing metathesis (RCM), would likely be
amenable to stereoselective hydrogenation allowing access to
either the (3R) or (3S) stereoisomers.
NH2
OH
OH
FTY720
H2N
OH
O
H2N
O
OH
NH
1
O
O
mixture of 4
stereoisomers
Br
H2N
H2N
4
2
OH
OH
O
Cl
2
3
H2N
O
(1R,3S) isomer
(1R,3R) isomer
O
N
O
Figure 1. FTY720 and conformationally constrained analogs.
Br
6
5
* Corresponding author. Tel.: +1 5086888081.
E-mail address: martin.hayes@abbott.com (M.E. Hayes).
Scheme 1. Retrosynthesis of the (1R,3S) isomer.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.099

4082
S. R. Fix-Stenzel et al. / Tetrahedron Letters 50 (2009) 4081–4083
Table 1
imine intermediate was hydrolyzed with citric acid to provide
Evaluation of hydrogenation catalysts
the quaternary amino ester 5 in 97% ee on a multi-gram scale. Pro-
tection of the amine as the Boc carbamate facilitated a Ru-cata-
lyzed ring-closing metathesis using the Grubbs–Hoveyda second
generation catalyst.12
O
O
O
NH
NH
OH
O
OH
This provided rapid access to multi-gram quantities of 4
(Scheme 2), which could be used for analog synthesis via cross-
coupling reactions of the aryl bromide moiety. To enable the
synthesis of compound 2, an n-octyl chain was installed using
standard Suzuki coupling conditions followed by reduction of the
ester to the corresponding alcohol with LiBH4 resulting in cyclo-
pentene intermediate 7.
Compound 7 provided a reasonable scaffold with which to
investigate methods for installing the second stereogenic center.
A number of methods for asymmetric hydrogenation of olefins
have been reported including the Iridium–threoninephosphinite–
oxazoline (Ir[COD]ThrePHOX) catalysts developed by Pfaltz and
co-workers that have been shown to provide excellent enantiose-
lectivities for trisubstituted olefins without the need for substrate
complexation.13 However, evaluation of the Pfaltz catalyst14
system on the functionalized cyclopentene 7 resulted, surprisingly,
in no conversion of the starting material (Table 1, entries 1
and 2).15
C8H17
C8H17
7
8
Entry
Compound
H2 (psi)
Catalysta
% convb (% de)
1
2
3
4
5
6
7
8
9
7
7
50
970
50
Ir(COD)ThrePHOX
Ir(COD)ThrePHOX
Ir(COD)ThrePHOX
Ir(COD)ThrePHOX
Ir(COD)Py(PCy3)
Pd/BaSO4
1% Pt/C
5% Pd/CaCO3
PtO2
0c
0c
1-Methylstilbene
7, 1-Methylstilbene
100c,d
50
0, 100c,d
100 (33)c
100 (70)e
100 (20)e
100 (50)e
100 (33)e
100 (60)e
7
7
7
7
7
7
15
15
15
15
15
15
10
2% Pd/SrCO3
a
All reactions were conducted at rt using 5 mol % of catalyst.
Diastereomeric excess as measured by chiral HPLC.
Reaction run in CH2Cl2.
>95% ee was observed for the reduction of 1-methylstilbene.
Reaction run in MeOH.
b
c
d
e
Control experiments using 1-methylstilbene, both with and
without the cyclopentene 7, showed excellent conversion of the
acyclic trisubstituted olefin, and no catalyst inhibition by the cyclo-
pentene substrate 7 (Table 1, entries 3 and 4).
Synthesis of an amino alcohol precursor with control of abso-
Crabtree’s catalyst was also screened to evaluate a substrate di-
rected approach utilizing either the primary alcohol or it’s t-butyl
ester precursor moiety for catalyst complexation.16 However, only
modest de’s were observed, presumably due to the competing
directing potential of the Boc carbamate group (Table 1, entry 5).
A further screen of catalysts, which included heterogeneous hydro-
genation catalysts, identified Pd/BaSO4 as a promising reagent (Ta-
ble 1, entry 6). The Pd/BaSO4 hydrogenation system provided
compound 8 as an 85:15 mixture of diastereomers, favoring the
stereochemistry (1R,3S) found in compound 2. This mixture could
be further enriched to a 95:5 mixture by recrystalization from hep-
tane.17 To complete the synthesis of compound 2, the Boc group
was removed via hydrolysis at elevated temperature. The remain-
ing undesired stereoisomer was removed by semi-preparative chi-
ral HPLC to furnish compound 2 in >98% de.
lute stereochemistry could be achieved through a variety of meth-
ods including selective-Strecker reactions,4 the use of chiral
auxiliaries such as the Williams diphenyloxazinone,5 or through
recently developed techniques such as the DuBois nitrene insertion
protocol.6 In addition, phase-transfer catalysts, such as those
developed by Maruoka and co-workers, have been shown to be
effective in preparing quaternary amino acid precursors with high
enantioselectivity and chemical yield.7 Initial attempts at bis-alkyl-
ation of the known glycine imine 6 using a chiral phase-transfer
catalyst via the reported one-pot protocol8 led to incomplete alkyl-
ation. However, employing the standard two-step protocol using
n-BuLi to install the allyl group followed by CsOHÁH2O and
(S,S)-3,4,5-trifluorophenyl-NAS bromide9 to enable the second
alkylation with 1-bromo-4-(3-bromoprop-1-en-2-yl)benzene10
led to greater conversion and higher isolated yields.11 The chiral
1) n-BuLi, allyl bromide, THF, 0 °C
O
O
O
O
Cl
NH
2) (S,S)-ß-Naphthyl-NAS bromide,
1) Boc2O, Na2CO3,
THF, 87%
H2N
Ot-Bu
Ot-Bu
CsOH, 1-bromo-4-(3-bromoprop-1-
O
en-2-yl)benzene, CH2Cl2, -10°C
N
2) 2nd Gen Grubbs-
Hoveyda, CH2Cl2,
73%
Ot-Bu
Br
Br
3) 0.5M Citric Acid, THF, rt,
61% over 3 steps, >97% ee
4
5
6
1) Octylboronic
acid, Pd(PPh3)4,
Cs2CO3, THF,
54%
2) LiBH4, ether,
87%
O
O
H2N
O
NH
5 mol% Pd/BaSO4
50 psi H2, MeOH,
93%, 70% de
OH
NH
7M NaOH, dioxane,
OH
O
OH
reflux
semi-prep chiral
HPLC 54%
C8H17
C8H17
2
8
7
Scheme 2. Synthesis of the (1R,3S) isomer.

S. R. Fix-Stenzel et al. / Tetrahedron Letters 50 (2009) 4081–4083
4083
2005, 23, 127; (e) Chun, J.; Rosen, H. Curr. Pharm. Des. 2006, 12, 161; (f) Ryan, J.
J.; Spiegel, S. Drug News Perspectives 2008, 21, 89; (g) Huwiler, A.; Pfeilschifter, J.
Biochem. Pharmacol. 2008, 75, 1893.
In conclusion, we have developed a stereoselective route that
was used to successfully provide gram-quantities of the S1P1 ago-
nist 2. This route demonstrates excellent enantioselectivity in set-
ting the stereochemistry at the quaternary center which facilitates
moderate stereo-induction at the benzylic site. This route also en-
abled the preparation of multi-gram quantities of 4, an intermedi-
ate suitable for analog synthesis and SAR evaluation. Additional
details of analog synthesis efforts will be published in due course.
2. (a) Kappos, L.; Antel, J.; Comi, G.; Montalban, X.; O’Connor, P.; Polman, C. H.;
Haas, T.; Korn, A. A.; Karlsson, G.; Radue, E. W. New Engl. J. Med. 2006, 255,
1124; (b) Baumruker, T.; Billich, A.; Brinkmann, V. Expert Opin. Investig. Drugs
2007, 16, 283.
3. Zhu, R.; Snyder, A. H.; Khrarel, Y.; Schaffter, L.; Sun, Q.; Kennedy, P. C.; Lynch, K.
R.; Macdonald, T. L. J. Med. Chem. 2007, 50, 6428.
4. Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147.
5. Williams, R. M.; Im, M-N. J. Am. Chem. Soc. 1991, 113, 9276.
6. Espino, C.; When, P.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935.
7. Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
8. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122,
5228.
Acknowledgments
The authors would like to acknowledge Dr. Dominique Bona-
foux and Thomas Gordon for helpful discussions and Kimberly
Yach for assisting in the generation of spectral data.
9. The S,S-ammonium bromide catalyst, [287384-12-7], is commercially available
from several vendors including Sigma–Aldrich.
10. Prepared according to the method described in: Yamanaka, M.; Arisawa, M.;
Nishida, A.; Nakagawa, M. Tetrahedron Lett. 2002, 43, 2403.
11. Isolated yields of the free amine 5 using the one-pot procedure ranged from
29% to 38% while the two-pot protocol provided 61–72% yield of 5 on multi-
gram scale.
Supplementary data
12. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
13. (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew.Chem., Int. Ed. 1998, 37, 2897; (b)
Menges, F.; Pfaltz, A. Adv. Synth. Catal. 2002, 344, 40.
14. Both enantiomers of the diphenylphosphinite precatalyst are commercially
available from Strem: S,S-[405235-55-4] and R,R-[880262-16-8].
15. Macdonald and co-workers also reported a lack of reactivity using the Pfaltz
catalyst on a similar substituted cyclopentene, as described in Ref. 3.
16. (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977, 141, 205;
(b) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331.
Full experimental details for the preparation of compound 2, 1H
NMR spectra, and chiral HPLC traces are provided. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.04.099.
References and notes
1. (a) Pyne, S.; Pyne, J. N. Biochemistry 2000, 349, 385; (b) Rosen, H.; Sanna, G.;
Alfonso, C. Immunol. Rev. 2003, 195, 160; (c) Pettus, B. J.; Chalfant, C. E.;
Hannun, Y. A. Curr. Mol. Med. 2004, 4, 405; (d) Cyster, J. G. Annu. Rev. Immunol.
17. Modest mass recovery was observed upon recrystalization from heptane under
unoptimized conditions.