α-Amino 1,3-dithioketal mediated asymmetric synthesis of piperidines (L-733,060) and tetrahydrofuran glycines

Article abstract of DOI:10.1016/j.tetlet.2007.11.170

Sulfinimine-derived α-amino 1,3-dithianes and α-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of (+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.

Full text of DOI:10.1016/j.tetlet.2007.11.170

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Tetrahedron Letters 49 (2008) 870–872
a-Amino 1,3-dithioketal mediated asymmetric synthesis
of piperidines (L-733,060) and tetrahydrofuran glycines
Franklin A. Davis *, Tokala Ramachandar
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA
Received 2 November 2007; revised 16 November 2007; accepted 27 November 2007
Available online 4 December 2007
Abstract
Sulfinimine-derived a-amino 1,3-dithianes and a-amino carbonyl chiral building blocks, are utilized in asymmetric syntheses of
(+)-(tetrahydrofuran-2-yl)glycine and the 2,3-disubstituted piperidine (+)-L-733,060.
Ó 2007 Elsevier Ltd. All rights reserved.
Enantiomerically pure a-amino aldehydes and ketones,
generally prepared from a-amino acids, are widely used
chiral building blocks for asymmetric synthesis.1 However,
a-amino carbonyl compounds are notoriously unstable and
rapidly epimerize and self-condense even when suitably N-
protected. Many of these problems can be avoided by using
N-sulfinyl a-amino 1,3-dithianes 1, new sulfinimine-derived
chiral building blocks for a-amino aldehyde, and ketone
synthesis (Scheme 1).2,3 These building blocks are readily
prepared in high diastereomeric purity by addition of
2-lithio-1,3-dithianes to sulfinimines.4 Acid hydrolysis
affords the enantiomerically pure free amine, leaving the
carbonyl group protected, resulting in unique opportunities
for functional group manipulation. We employed these a-
amino 1,3-dithianes in highly diastereoselective asymmetric
syntheses of functionalized prolines including (ꢀ)-3-
hydroxy-3-methyl proline (2)2 and (ꢀ)-2,3-trans-3,4-cis-
dihydroxyproline (3).3 As an extension of this methodo-
logy, we describe the concise asymmetric synthesis of the
2,3-disubstituted piperidine (2S,3S)-(+)-L-733,060 (4) and
the unnatural constrained a-amino acid (+)-(2R,20S)-(+)-
2-(tetrahydrofuran-2-yl)glycine (THFG 5) from a common
intermediate.
O
S
OH
OH
HO
HO2C
p-Tolyl
NH
S
Me
R'
R
N
H
HO2C
N
H
S
The key strategy employed in our synthesis of hydroxy
prolines (ꢀ)-2 and (ꢀ)-3 was the cyclization of a 2-
hydroxyethyl moiety (R0) in 1 to form the pyrrolidine ring.
Cyclization of a 3-hydroxypropyl group (R0) in 1 would
produce a piperidine ring. Addition of 2-lithium-1,3-dithi-
ane 75 to (S)-(+)-N-(benzylidene)-p-toluenesulfinamide
(6)6 gave N-sulfinyl a-amino 1,3-dithiane (SS,S)-(+)-8 in
94% de and 81% yield of the major diastereoisomer
(Scheme 2). Hydrolysis of (+)-8 with 1,3-dibromo-5,5-
dimethylhydantoin (9) in aqueous acetone not only hydro-
lyzes the thioketal group, but also oxidizes the N-sulfinyl
group to the N-tosyl protecting group affording (S)-(ꢀ)-
10 in 73% yield for the one pot sequence. Reduction
of the amino ketone with NaBH4 gives the expected syn
(-)-2
(-)-3
1
CF3
Ts
NH
O
MeO2C
CF3
O
N
H
Ph
(2R,2'S)-(+)-5
(2S,3S)-(+)-L-733,060 4
Scheme 1.
*
Corresponding author. Tel.: +1 215 204 0477; fax: +1 215 204 0478.
E-mail address: fdavis@temple.edu (F. A. Davis).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.170

F. A. Davis, T. Ramachandar / Tetrahedron Letters 49 (2008) 870–872
871
isolated as the methyl ester with TMSCHN2 affording
(2R,20S)-(+)-5 in 54% for the two steps.7 Conformationally
constrained unnatural amino acids such as (+)-5 are in
demand for the synthesis of constrained peptide surrogates,
which have increased potency, stability, bioavailability,
and selectivity.
TBSO
O
S
Li
S
S
p-Tolyl
NH
S
OTBS
O
S
H
7
Ph
p-Tolyl
N
Ph
-78 oC
94% de, (81%)
S
To prepare a piperidine from (+)-11 required protection
of the 2-hydroxy group as the OTBS ether. Treatment of
(+)-16 with p-TSA at 0 °C for less than 30 min made it pos-
sible to selectively deprotect the primary OTBS, affording
(+)-17 in 82% yield (Scheme 4). With TsCl/Et3N, (+)-17
gave piperidine (+)-18 in 88% yield and the hydroxy
piperidine (+)-19 was obtained in 90% yield using TBAF.
Etherification of the hydroxy group with NaH and 3,5-
bis(trifluoromethyl)benzyl bromide gave (2S,3S)-(+)-20.
Finally, N-tosyl deprotection with Na/liq. NH3 at ꢀ78 °C
afforded (2S,3S)-(+)-L-733,060 (4) in 78% yield (Scheme
4).8,9 (+)-L-733,060 (4) is a potent neurokinin substance
P receptor antagonist, which exhibits strong antiemetic
activity.10
(SS,S)-(+)-8
(S)-(+)-6
Br
N
O
O
N
Br
Ts
9
NH
OTBS
NaBH4, -78 oC
dr: 10:1 (87%)
Ph
acetone-H2O
(73%)
O
(S)-(-)-10
Ts
Ts
NH
NH
OTBS
OH
TBAF, 0 oC
(97%)
Ph
Ph
OH
(1S,2S)-(+)-11
OH
(1S,2S)-(+)-12
In summary, the utility of a-amino 1,3-dithianes as chi-
ral building blocks for the asymmetric synthesis of hetero-
cycles has been demonstrated by the preparation of amino
furan (+)-THFG-5 and 2,3-disubstituted piperidine (+)-L-
733,060 (4) from common amino diol intermediate (+)-
11.12 In particular, our synthesis of (+)-4 in 11 steps under
nine operations (18% overall yield) from sulfinimine (+)-6
is one of the most concise to date. 2,3-Disubstituted piper-
idines are structural units found in natural products and
Ts
Ph
NH
OTs
Ts-Cl/pyridine
0 oC, (87%)
OH
(1S,2S)-(+)-13
Scheme 2.
alcohol (1S,2S)-(+)-11 (dr = 10:1) in 87% yield of the
major diastereoisomer. Selective tosylation of the primary
alcohol in (+)-12 was readily accomplished with TsCl/pyr-
idine affording (1S,2S)-(+)-13 in 87% yield.
Next, treatment of amino alcohol (+)-13 with Et3N gave
the expected, kinetically favored, furan (+)-14 in 83% yield
(Scheme 3). Oxidation of the phenyl group in (+)-14 with
RuCl3/NaIO4 gave the carboxylic acid 15, which was
Ts
Ph
Ts
TBSOTf
NH
NH
OTBS
OTBS
Ph
2,6-lutidine
(85%)
OH
OTBS
(1S,2S)-(+)-11
(1S,2S)-(+)-16
Ts
OTBS
Ph
NH
OH
p-TSA
TsCl, Et3N
Ts
Ts
Ph
Et3N, 0 oC
N
NH
NH
(82%)
OTs
(82%)
Ts
OTBS
Ph
Ph
DCM (83%)
(1S,2S)-(+)-17
(2S,3S)-(+)-18
O
OH
(1S,2S)-(+)-13
(2R,2'S)-(+)-14
NaH (81%)
OH
TBAF/THF
(90%)
F3C
N
Ph
Ts
Br
NH
O
Ts
TMSCHN2
RuCl3/NaIO4
HO2C
(2S,3S)-(+)-19
CF3
(2 steps 54%)
CF3
15
Na/liq. NH3
Ts
(+)-L-733,060 4
O
NH
CF3
-78 oC (78%)
MeO2C
N
Ph
(2S,3S)-(+)-20
Ts
O
(2R,2'S)-(+)-5
Scheme 3.
Scheme 4.

872
F. A. Davis, T. Ramachandar / Tetrahedron Letters 49 (2008) 870–872
several drug candidates,11 and the structural diversity of
available sulfinimine-derived a-amino 1,3-dithianes make
this protocol well suited for enantiomer and analog
synthesis.10
7. For earlier asymmetric synthesis of THFG see: (a) Williams, R. M.;
Sinclair, P. J.; Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988, 110, 1547–
1557; (b) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron
Lett. 1999, 40, 3843–3846; (c) Kazamaier, U.; Pahler, S.; Endermann,
R.; Habich, D.; Kroll, H.-P.; Riedl, B. Bioorg. Med. Chem. 2002, 10,
3905–3913; (d) Jirgensons, A.; Marinozzi, M.; Pellicciari, R. Tetra-
hedron 2005, 61, 373–377.
Acknowledgment
8. For earlier asymmetric syntheses of (+)-4 see: (a) Bhaskar, G.; Rao,
B. V. Tetrahedron Lett. 2003, 44, 915–917; (b) Huang, P.-Q.; Liu,
L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927–1929; (c)
Kandula, S. R. V.; Kumar, P. Tetrahedron: Asymmetry 2005, 16,
3579–3583; (d) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim, Y.-H.; Oh,
C.-Y.; Ham, W.-H. Tetrahedron Lett. 2005, 46, 739–741; (e) Oshitari,
T.; Mandai, T. Synlett 2006, 3395–3398; (f) Cherian, S. K.; Kumar, P.
Tetrahedron: Asymmetry 2007, 18, 982–987.
This work was supported by grants from the National
Institute of General Medicinal Sciences (GM57878 and
GM51982).
References and notes
9. For related 2,3-disubstituted piperidines see: (a) Liu, L.-X.; Ruan,
Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001–6009;
(b) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org.
Lett. 2004, 6, 3517–3520; (c) Takahashi, K.; Nakano, H.; Fujita, R.
Tetrahedron Lett. 2005, 46, 8927–8930.
10. (a) Baker, R.; Harrison, T.; Swain, C. J.; William, B. J. EP 0
528,495A1, 1993; (b) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball,
R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2545–2550.
1. For reviews on the synthesis of chiral a-amino aldehydes and ketones
see: (a) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–164; (b)
Fisher, L. E.; Muchowski, J. M. Org. Prep. Proced. Int. 1990, 22, 399–
484; (c) Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162; (d) Gryko, D.;
Chalko, J.; Jurczak, J. Chirality 2003, 15, 514–541.
2. Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393–
3395.
3. Davis, F. A.; Ramachandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett.
2006, 47, 2743–2746.
4. For recent reviews on the chemistry of sulfinimines see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003–8030; (b)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichim. Acta 2005, 38, 93–104; (c) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869–8905; (d) Davis, F. A. J. Org. Chem. 2006,
71, 8993–9003.
5. Wei, W.-G.; Yao, Z.-J. Tetrahedron 2003, 59, 6621–6625.
6. Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403–1406.
11. For leading references see: Davis, F. A.; Zhang, Y.; Li, D.
Tetrahedron Lett. 2007, 48, 7838–7840.
20
12. Selected data: (+)-8, mp 109–110 °C; ½aꢁD 30.8 (c 0.4, CHCl3); (ꢀ)-
20
20
10, mp 93–95 °C; ½aꢁD ꢀ161.4 (c 0.42, CHCl3); (+)-11, ½aꢁD +26.5 (c
20
20
0.7, CHCl3); (+)-12, ½aꢁD 44.7 (c 1.3, CHCl3); (+)-13, ½aꢁD 16.8
20
20
(c 0.81, CHCl3); (+)-14, ½aꢁD +11.5 (c 0.68, CHCl3); (+)-5, ½aꢁD
20
+34.4 (c 1.1, CHCl3); (+)-16, ½aꢁD +27.1 (c 0.72, CHCl3); (+)-17,
20
20
mp 152–153 °C; ½aꢁD +35.1 (c 0.4, CHCl3); (+)-18, ½aꢁD +59.2
20
20
(c 0.32, CHCl3); (+)-19, ½aꢁD +76.31 (c 0.38, CHCl3); (+)-20, ½aꢁD
25
+58.6 (c 0.53, CHCl3); (+)-4, ½aꢁD +36.12 (c, 0.64, CHCl3).