Sulfinimine-derived 2,3-diamino esters in the asymmetric synthesis of piperidine (2S,3S)-(+)-CP-99,994

Article abstract of DOI:10.1016/j.tetlet.2007.08.132

Sulfinimine-derived, differentially protected, 2,3-diamino esters are useful building blocks for the asymmetric synthesis of heterocycles and is illustrated by an efficient synthesis of amino piperidine (+)-CP-99,994.

Full text of DOI:10.1016/j.tetlet.2007.08.132

Tetrahedron Letters 48 (2007) 7838–7840
Sulfinimine-derived 2,3-diamino esters in the asymmetric
synthesis of piperidine (2S,3S)-(+)-CP-99,994
Franklin A. Davis,* Yanfeng Zhang and Danyang Li
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
Received 16 August 2007; revised 30 August 2007; accepted 31 August 2007
Available online 5 September 2007
Abstract—Sulfinimine-derived, differentially protected, 2,3-diamino esters are useful building blocks for the asymmetric synthesis of
heterocycles and is illustrated by an efficient synthesis of amino piperidine (+)-CP-99,994.
Ó 2007 Elsevier Ltd. All rights reserved.
2,3-Diamino acids are non-protein amino acids, which
H
are key components of natural and synthetic biologi-
cally active compounds.1 For example (2S,3S)-(+)-CP-
99,994 (1), a synthetic 2,3-disubstituted piperidine, is a
potent neurokinin substance P receptor antagonist,
which exhibits antiemetic activity.2 Several asymmetric
syntheses of this compound or its epimer have been
reported, however, with few exceptions,3 most of these
syntheses are multi-step procedures that provide (+)-1
in low overall yield (Fig. 1).4,5 An additional problem
is that most of these methods begin with an optically
active monoamine.5 This means that the second amino
group needs to be introduced stereospecifically later in
the synthesis resulting in the undesirable separation of
diastereomers and resulting in lower efficiencies.
N
OMe
N
H
Ph
(2
S,3S)-(+)-CP-99,994 1
Figure 1. Substance P receptor antagonist.
O
S
p-Tolyl
NH O
O
Ph
OEt
(PhCH2)2N
Bn2N
OEt
OEt
(S
S,2
R,3S
)-(+)-5 (68%)
1) LDA, -78 oC, THF
2
3
We have been exploring the addition of prochiral eno-
late species to sulfinimines (N-sulfinyl)6 where two new
stereogenic centers are created in a single operation,
and with the possible formation of four diastereoiso-
mers.7 In this context we reported the addition of the
E-lithium enolate of ethyl (dibenzylamino)acetate (2)7a
or a large excess of the Z-lithium enolate of N-(diphenyl-
methylene)glycine ethyl ester (3)7d to (S)-(+)-N-(benzyl-
idene)-p-toluenesulfinamide (4) gives differentially
N-protected (SS,2R,3S)-(+)-syn-2,3-diamino-3-phenyl-
propanoate (+)-5 and (+)-6, respectively in good to
excellent yields (Scheme 1). Employing (SS,2R,3S)-(+)-
5 we describe here a highly efficient 12-step (nine opera-
tions) asymmetric synthesis of (+)-1 in 38% overall yield
from (+)-5. Furthermore, because of the diversity of
or
O
O
S
H
O
S
2)
p
-Tolyl
N
Ph
Ph
N
p
-Tolyl
NH
O
(
S
)-(+)-4
Ph
4-XPh
OEt
(68%)
N
Ph
S,2
Ph
(
S
R
,3S
)-(+)-6 (86%)
Scheme 1.
available sulfinimines, our synthesis is particularly sui-
ted for analogue synthesis.6
The N-sulfinyl group in (+)-5 was removed with TFA–
MeOH to give the mono amine, which was not isolated,
but was treated, after concentration, with (Boc)2O–
Et3N–THF to give the N-Boc protected diamine
*
Corresponding author. Tel.: +1 215 204 0477; fax: +1 215 204
0478; e-mail: fdavis@temple.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.132

F. A. Davis et al. / Tetrahedron Letters 48 (2007) 7838–7840
7839
metathesis (RCM) of amino dienes.9a However, to the
best of our knowledge there are no reports of diamino
dienes and RCM being used to prepare amino piperi-
dines. Furthermore, RCM’s functional group tolerance
problems with amines have been reported.10 Signifi-
cantly, highly-aminated diene (+)-12 smoothly under-
goes RCM with the Grubbs–Hoveyda catalyst11 13 to
give amino tetrahydropyridine (ꢀ)-14 in 94% yield
(Scheme 2).
O
S
Boc
Ph
1) TFA-MeOH
p
-Tolyl
NH
O
NH
O
2) (Boc)2O/Et3N
Ph
OEt
OEt
90% ( 2 steps)
Bn2N
Bn2N
(
SS,2
R,3S
)-(+)-5
(2R,3
S
)-(+)-7
Boc
Br
Boc
N
LiAlH4/THF
94%
N
O
KHMDS
Ph
OH
Ph
OEt
75%
Bn2N
The double bond in the key tetrahydropyridine interme-
diate (ꢀ)-14 was selectively reduced with Pt–C, H2 to give
(2S,3S)-(+)-15 in 97% yield (Scheme 3). The N-benzyl
groups were removed using Pd(OH)2, H2 affording
amino piperidine (2S,3S)-(+)-16 in 97% yield. It was
not necessary to isolate (+)-15 and the reaction sequence,
reduction and deprotection was carried out in one-pot to
give (+)-16 in 95% yield for the two steps. Attempts to
reduce the double bond and remove N-benzyl groups
using Pd(OH)2, H2 resulted in decomposition. Impor-
tantly, one-pot reductive amination of o-anisaldehyde
with (+)-16 using NaB(OAc)3H gave (2S,3S)-(+)-17 in
97% yield.12 Earlier reports using NaBH3CN or NaBH4
as the reducing agents reportedly give this material in
lower yield (ca. 80%).5a,b Removal of the Boc group
(HCl–dioxane) gave the title compound, (2S,3S)-(+)-
CP-99,994 (1) in 80% yield.13
Bn2N
(2R,3
S
)-(+)-8
(2R,3S)-(+)-9
N
N
N
1)
SO2Me
N
11
Ph
Boc
Ph
N
O
DMP
KHMDS, THF, -20 o
C
2)
H
Bn2N
88% (2 steps)
10
Mes
N
N Mes
Cl
Cl
Ru
O
Boc
N
NBn2
Ph
N
Boc
Ph
13
94%
Bn2N
(1
S,2S)-(+)-12
(5S,6
S)-(-)-14
In summary, a concise 12-step, nine operations, asym-
metric synthesis of the neurokinin substance P receptor
antagonist amino piperidine (+)-CP-99,994 (1) was
developed. The overall yield from the sulfinimine-
derived differentially N-protected diamino ester (+)-5
was 38%. Highlights of the synthesis include an efficient
Kocienski-modified Julia olefination and ring-closing
metathesis of a diamino diene using the Grubbs–Hov-
eyda catalyst 13 to give tetrahydropyridine (ꢀ)-14. The
flexibility of the synthesis using sulfinimines makes this
methodology well suited for enantiomer and analogue
preparation.
Scheme 2.
(2R,3S)-(+)-7 in 90% yield for the two steps (Scheme 2).
Initial attempts to allylate the N-Boc amino group with
allyl bromide and NaH or K2CO3 were unsuccessful.
However, reaction of (+)-7 with 1.5 equiv of KHMDS
followed with 6 equiv of allyl bromide at 0 °C gave
(2R,3S)-(+)-8 in 75% yield. Alcohol (1S,2R)-(+)-9 was
obtained in 94% yield by reduction of the ester group
in (+)-8 with 5 equiv of LiAlH4 in THF at rt. With
(+)-9 in hand the idea was to oxidize the alcohol to alde-
hyde 10 and use a Wittig-type olefination reaction to
generate the diene. Reaction of (+)-9 with 1.5 equiv of
the Dess–Martin periodinane (DMP) reagent did indeed
give the aldehyde as evidenced by the appearance of an
aldehyde proton at d 9.7 ppm, but all attempts to isolate
it proved unsuccessful because it quickly decomposed at
room temperature. For this reason the crude aldehyde,
isolated by treating with Na2S2O3 and drying, was used
directly in the next step. However, attempts to effect the
NBn2
Ph
Pt-C/H2/MeOH
(97%)
NBn2
Ph
Pd(OH)2/H2/MeOH
(97%)
N
Boc
N
Boc
(2S,3S
)-(+)-15
(5S,6S
)-(-)-14
H
N
o
-anisaldehyde
NH2
Ph
OMe
Ph
Wittig reaction using Ph3PCHþBrꢀ=t-BuOꢀKþ resulted
3
N
Boc
NaB(OAc)3H
(97%)
N
Boc
in decomposition. More successful was the Kocienski-
modified Julia olefination.8 Gratifyingly a THF solution
of crude 10 and phenyltetrazole methyl sulfone 11
(1.4 equiv) on treatment with 3.6 equiv of KHMDS at
ꢀ20 °C afforded diamino diene (1S,2S)-(+)-12 in 93%
yield (Scheme 2).
(2S,3S
)-(+)-17
(2S,3S
)-(+)-16
1) HCl-dioxane
2) sat. NaHCO3
H
N
OMe
(80%)
N
H
Ph
1,2,5,6-Tetrahydropyridines such as (ꢀ)-14 are useful
chiral building blocks for the asymmetric synthesis of
natural products because of the many methods available
for ring functionalization of the C–C double bond.9 One
method for their preparation employs ring-closing
(2S,3S)-(+)-CP-99,994 1
Scheme 3.

7840
F. A. Davis et al. / Tetrahedron Letters 48 (2007) 7838–7840
6. For recent reviews on the chemistry of sulfinimines see: (a)
Acknowledgments
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.
This work was supported by grants from the National
Institute of General Medical Sciences (GM57878 and
GM51982). We thank Jianghe Deng for helpful
discussions.
7. For recent examples see: (a) Davis, F. A.; Deng, J. Org.
Lett. 2004, 6, 2789–2792; (b) Davis, F. A.; Yang, B. J. Am.
Chem. Soc. 2005, 127, 8398–8407; (c) Davis, F. A.; Deng,
J. Org. Lett. 2005, 7, 621–623; (d) Wang, Y.; He, Q.-F.;
Wang, H.-W.; Zhou, X.; Huang, Z.-Y.; Qin, Y. J. Org.
Chem. 2006, 71, 1588–1591; (e) Davis, F. A.; Zhang, Y.;
Qiu, H. Org. Lett. 2007, 9, 833–836; (f) Davis, F. A.; Song,
M. Org. Lett. 2007, 9, 2413–2416.
8. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K.
J. Chem. Soc., Perkin Trans. 1 1999, 955–968.
9. For a review see: (a) Felpin, F.-X.; Lebreton, J. Curr. Org.
Synth. 2004, 1, 83–109; For leading references see: (b)
Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem. 2007, 72,
2046–2052.
References and notes
1. For an excellent review on the syntheses and significance
of 2,3-diamino esters see: Viso, A.; Pradilla, R. F. d. l.;
Garcia, A.; Flores, A. Chem. Rev. 2005, 105, 3167–3198.
2. (a) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo,
K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911–4913;
For a review see: (b) Data, P.; Srivastava, S.; Coutinho,
E.; Govil, G. Curr. Top. Med. Chem. 2004, 4, 75–103.
3. Lemire, A.; Grenon, M.; Pourashraf, M.; Charettee, A. B.
Org. Lett. 2004, 6, 3517–3520.
4. (a) Tsuritani, N.; Yamada, K.-i.; Yoshikawa, N.; Shiba-
saki, M. Chem. Lett. 2002, 276–277; (b) Xu, X.; Furu-
kawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.
Eur. J. 2006, 12, 466–476; (c) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M.
Angew. Chem., Int. Ed. 2005, 44, 4564–4567.
5. (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett.
1999, 40, 5071–5072; (b) Huang, P.-Q.; Liu, L.-X.; Wei,
B.- G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927–1929; (c)
Atobe, M.; Yamazaki, N.; Kibayashi, C. J. Org. Chem.
2004, 69, 5595–5607; (d) Takahashi, K.; Nakano, H.;
Fujita, R. Tetrahedron Lett. 2005, 46, 8927–8930; (e)
Oshitari, T.; Mandai, T. Synlett 2006, 3395–3398.
10. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856–9857.
11. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. Am. Chem. Soc. 2000, 122, 8168–8179.
12. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849–3862.
20
13. Selected data: (+)-8, ½aꢁD +121.2 (c 1.05, CHCl3); (+)-12,
20
20
½aꢁD +29.4 (c 0.87, CHCl3); (ꢀ)-14, ½aꢁD ꢀ6.9 (c 1.1,
20
20
CHCl3); (+)-15, ½aꢁD +69.1 (c 0.6, CHCl3); (+)-16, ½aꢁD
20
+27.0 (c 0.8, CHCl3); (+)-17, ½aꢁD +27.5 (c 0.3, CHCl3);
20
(+)-1, ½aꢁD +74.2 (c 0.5, CHCl3).