Asymmetric synthesis of (2S,3R)-(-)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters

Article abstract of DOI:10.1016/j.tetlet.2009.06.125

A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed in the synthesis of the amino piperidine (2S,3R)-(-)-epi-CP-99,994. Key steps in the synthesis included the chemoselective hydrolysis of the C-2 N,N-(dip

Full text of DOI:10.1016/j.tetlet.2009.06.125

Tetrahedron Letters 50 (2009) 5205–5207
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Asymmetric synthesis of (2S,3R)-(ꢀ)-epi-CP-99,994 using sulfinimine-derived
anti-2,3-diamino esters
*
Franklin A. Davis , Yanfeng Zhang
Department of Chemistry, Temple University, Philadelphia, PA 19122, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A differentially protected C-3 N-sulfinyl, C-2 N,N-(diphenylmethylene) 2,3-diamino ester was employed
in the synthesis of the amino piperidine (2S,3R)-(ꢀ)-epi-CP-99,994. Key steps in the synthesis included
the chemoselective hydrolysis of the C-2 N,N-(diphenylmethylene) group and its reprotection as a dib-
enzylamino group.
Received 18 May 2009
Revised 18 June 2009
Accepted 29 June 2009
Available online 3 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Optically active syn- and anti-2,3-diamino acids are an impor-
tant class of non-protein amino acids. They are key components
of natural products including peptide antibiotics, antifungal
agents, as well as other medicinally valuable compounds.1 They
are also useful precursors of chiral 1,2-diamines (vicinal diamines)
which are found in a broad variety of natural products, are useful
ligands for catalysis, and are building blocks for asymmetric syn-
theses.2 In 2004 we reported the enantioselective synthesis of
syn-2,3-diamino esters via the addition of the enolate of ethyl (dib-
enzylamino) acetate (1) to sulfinimines (N-sulfinyl imines).3,4 For
example, the lithium E-enolate of 1 was added to sulfinimine
(S)-(+)-2 to give syn-2,3-diamino ester (+)-3 in 68% yield of the ma-
jor diastereoisomer (Fig. 1).4 In 2007 we disclosed that the Z-lith-
ium enolate of N,N-(diphenylmethylene)glycine ethyl ester (4), in
the presence of water, adds to (S)-(+)-2 to give the anti-2,3-diamino
ester (ꢀ)-5 in high dr and in excellent yield.5 In the absence of
water, an excess of this enolate afforded the syn-2,3-diamine es-
ters.5 Our asymmetric synthesis of the novel tetracyclic marine
antitumor agent (ꢀ)-agelastatin A (5)6 and the potent neurokinin
substance P receptor antagonist (2S,3S)-(+)-CP-99,994 (6)7 relied
on the fact that the two amino groups in the syn-2,3-diamino es-
ters were differentially protected.8 A key step in these syntheses
was the selective removal of the N-sulfinyl group. We describe
here an efficient asymmetric synthesis of (2S,3R)-(ꢀ)-epi-CP-
99,994 (8) from anti-2,3-diamino ester (ꢀ)-5.9
accomplish this with TFA/MeOH or HCl/H2O under various reaction
conditions failed, always resulting in removal of both protecting
groups. Recently, Viso and co-workers reported that in the hydro-
lysis of N-sulfinylimidazolidines with H3PO4 the sulfinamide group
was left intact.10 They attributed the remarkable chemoselectivity
of this acid to the low nucleophilicity of the phosphate counterion.
Significantly, treatment of (ꢀ)-5 with 4 equiv of H3PO4 (85 wt %
in H2O) in THF at 0 °C for 4 h produced an 86% isolated yield of the
C-2 deprotected amine (SS,2S,3S)-(+)-9 (Scheme 1). While reaction
of (+)-9 with benzyl bromide gave (+)-10 in excellent yield,
O
1) LDA, -78oC, THF
O
S
p-Tolyl
NH
O
Bn2N
OEt
O
S
H
Ph
OEt
1
Bn2N
2)
p-Tolyl
N
Ph
syn-(+)-3
(S)-(+)-2 (68%)
O
S
p-Tolyl
NH
O
1) LDA-H2O, -78oC, THF
O
Ph
N
Ph
N
OEt
OEt
Ph
(S)-(+)-2 (86%)
2)
4
Ph
Ph
anti-(-)-5 (>33:1)
In considering the synthesis of (ꢀ)-8 from (ꢀ)-5 we envisioned
a route similar to that used in the preparation of (+)-7, namely the
construction of a diamino diene and using ring closing metathesis
(RCM) to form the piperidine ring.7 However this requires selective
hydrolysis of the N,N-(diphenylmethylene)amino group in (ꢀ)-5
without disturbing the N-sulfinylamino group. Initial attempts to
Me
HO
N
N
O
H
N
H
N
H
N
Br
NH
H
OMe
OMe
Ph
N
H
N
H
Ph
H
H
O
(2
S,3S)-(+)-CP-99,994 (7)
(2
S,3R)-(-)-CP-99,994 (8)
(-)-Agelastatin A (6)
* Corresponding author. Tel.: +1 215 204 0477; fax: +1 215 204 0478.
E-mail address: fdavis@temple.edu (F.A. Davis).
Figure 1. Applications of N-sulfinyl 2,3-diamino esters.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.125

5206
F. A. Davis, Y. Zhang / Tetrahedron Letters 50 (2009) 5205–5207
O
S
O
S
O
S
O
S
p-Tolyl
NH
O
O
p-Tolyl
NH
O
p-Tolyl
NH
O
p-Tolyl
NH
O
H3PO4-H20
PhC(O)Cl, rt
Ph
OEt
Ph
Ph
OEt
Ph
OEt
Ph
OEt
DCM, Et3N (70%)
THF, 4 h (86%)
N
NH
N
NH2
Bn
Bn
Ph
Ph
(SS,2S,3S)-(+)-10
(SS,2S,3S)-(-)-15
anti-(-)-5 (>33:1)
(SS,2S,3S)-(+)-9
O
1) DMP, 0 oC
O
S
S
LAH, -78 oC to rt
DCM
N
p-Tolyl
NH
1) TFA-MeOH
p-Tolyl
NH
O
N
Ph
OH
THF (84%)
Bn-Br/K2CO3
MeCN (93%)
SO2Me
2)
Bn2N
Ph
OEt
O
N
N
Pn
NH
2)
Bn
N
N
KHMDS, -20 o
(2 steps, 70%)
C
N
(SS,2S,3S)-(+)-16
N
(SS,2S,3S)-(+)-10
Et3N
O
S
(2 steps 83%)
O
1) KHMDS/THF-DMF
0 o
2) CH2=CHCH2Br
Boc
C
p-Tolyl
NH
NH
1) KHMDS
O
1) TFA-MeOH
2) CH2=CH-CH2Br
Ph
Ph
N
NBn
CO2Et
(4S,5S)-(-)-12
HN
Ph
NBn
CO2Et
2) (Boc)2O,Et3N
(2 steps 98%)
Bn2N
(74%)
Bn2N
THF (87%)
Ph
(SS,1S,2R)-(+)-17
(1S,2R)-(+)-18
(4S,5S)-(+)-11
O
1) DMP/0 o
2) Ph3PCH2Br/
n-BuLi/-78 o
C
Mes
N
N Mes
O
N
NBn
Cl
Cl
O
LAH-THF
Ru
C
N
NBn
CH2OH
(4S,5S)-(-)-13
Scheme 1. Synthesis of diamino diene (ꢀ)-14.
Boc
N
NBn2
Ph
Ph
(4R,5S)-(-)-14
-78 oC to rt
(87%)
(2 steps 48%)
Ph
Ph
N
20
94%
Bn2N
Boc
(1S,2R)-(+)-19
(5R,6S)-(+)-21
Scheme 2. Synthesis of amino tetrahydropyridine (+)-21.
attempts to add a second N-benzyl group resulted in complex mix-
tures of products. In an effort to prepare a diamine in which the C-3
amino group could be selectivity allylated, (+)-10 was hydrolyzed
(TFA–MeOH) and urea (+)-11 was prepared in 83% yield using ex-
cess 1,1-carbonyldiimidazole/Et3N. Allylation with 8 equiv of allyl
bromide/KHMDS afforded (ꢀ)-12 that on reduction with LAH gave
alcohol (ꢀ)-13 all in good yields (Scheme 1). Next, (ꢀ)-13 was oxi-
dized to the aldehyde with Dess–Martin periodinane (DMP). The
aldehyde was treated with Na2S2O3, dried (Na2SO4), and added to
a ꢀ78 °C THF solution of the Wittig reagent (Ph3PCH3Br/n-BuLi)
to give the diamino diene (ꢀ)-14 in 48% isolated yield. Unfortu-
nately, all attempts to hydrolyze the urea under acid (5 N HCl,
5 N H2SO4) or base (NaOH, Ba(OH)2) conditions failed, and starting
material was recovered under all conditions.
Pd(OH)2/H2
MeOH
NBn2
Ph
NBn2
Ph
Pt-C/H2-MeOH
(96%)
N
N
(95%)
Boc
Boc
(5R,6S)-(+)-21
(2S,3R)-(+)-22
NH2
H
N
o-anisaldehyde
OMe
N
Ph
NaB(OAc)3H
(98%)
N
Ph
Boc
Boc
(2S,3R)-(+)-23
(2S,3R)-(+)-24
For this reason we returned to (+)-10 in hopes of finding condi-
tions for the chemoselective modification of one of the amino
groups. Reasoning that the N-benzyl-protected amine was a harder
nucleophile than the N-sulfinyl amine, (+)-10 was treated with
benzoyl chloride, a hard Lewis acid. Remarkably, (ꢀ)-15 was selec-
tively formed in 70% yield (Scheme 2). Next, reduction of (ꢀ)-15
with 4 equiv of LAH at ꢀ78 °C to rt accomplished the reduction
of both the amide and ester groups to give the N,N-dibenzylamino
alcohol (+)-16 in 84% yield. Oxidation of the alcohol with DMP gave
the aldehyde, which quickly decomposed on isolation. For this rea-
son the crude aldehyde was treated with Na2S2O3, dried (Na2SO4),
and immediately used in the next step. The Kocienski-modified Ju-
lia olefination11 using phenyltetrazole methyl sulfone (1.5 equiv)
and KHMDS (3.6 equiv) at ꢀ20 °C gave (+)-17 in 70% yield for the
two steps (Scheme 3). The sulfinyl group was removed (TFA–
MeOH), replaced with a Boc group, and (+)-18 was allylated with
excess allyl bromide/KHMDS at 0 °C to give the diamino diene
(+)-19 in 74% yield. This highly aminated diene smoothly under-
went RCM with the Grubbs-Hoveyda catalyst 2012 to give the ami-
H
N
HCl-dioxane
(80%)
OMe
N
H
Ph
(2S,3R)-(-)-CP-99,994 (8)
Scheme 3. Conversion to (ꢀ)-CP-99.994 (8).
no tetrahydropyridine (+)-21 in 94% isolated yield. 1,2,4,6-
Tetrahydropyridines such as (+)-21 are useful chiral building
blocks for the synthesis of natural products because of the many
methods available for ring functionalization of the C–C double
bond.13
The conversion of (+)-21 into the target (2S,3R)-(ꢀ)-epi-CP-
99,994 (8) followed the procedure that we used to prepare (+)-
CP-99,994 (7).7 The double bond in the key tetrahydropyridine

F. A. Davis, Y. Zhang / Tetrahedron Letters 50 (2009) 5205–5207
5207
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.
intermediate (+)-21 was reduced (Pt–C, H2) to give (+)-22. Depro-
tection (Pd(OH)2–C, H2) of the dibenzyl amino group gave (+)-23
which was subjected to a one-pot reductive amination reaction
with o-anisaldehyde/NaB(OAc)3H affording (+)-24 in 98% isolated
yield (Scheme 3).14 Finally, removal of the N-Boc group (HCl–diox-
ane) gave (2S,3R)-(ꢀ)-epi-CP-99,994 (8) in 80% yield as the hydro-
chloride salt.15
In summary, a new synthesis of (2S,3R)-(ꢀ)-epi-CP-99,994 (8),
the anti-analog of the potent neurokinin substance P receptor
antagonist (2S,3S)-(+)-CP-99,994 (8) has been achieved. Highlights
of this synthesis include the chemoselective hydrolysis of the N,N-
(diphenylmethylene)-protected C-2 amino group in (ꢀ)-5 to give
N-sulfinyl diamino ester (ꢀ)-9 and the chemoselective N-benzoyl-
ation of the C-2 N-benzyl group in (+)-10 to give (ꢀ)-15.
4. Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789–2792.
5. Davis, F. A.; Zhang, Y.; Qiu, H. Org. Lett. 2007, 9, 833–836.
6. (a) Davis, F. A.; Deng, J. Org. Lett. 2005, 7, 621–623; (b) Davis, F. A.; Zhang, J.;
Zhang, Y.; Qiu, H. Synth. Commun. 2009, 39, 1914–1919.
7. Davis, F. A.; Zhang, Y.; Li, D. Tetrahedron Lett. 2007, 48, 7838–7840.
8. For other examples of the asymmetric synthesis of heterocycles using
sulfinimine-derived 2,3-diamino esters see: (a) Viso, A.; Fernandez de la
Pradilla, R.; Urena, M. Tetrahedron 2009, 65, 3757–3766; (b) Viso, A.; Fernandez
de la Pradilla, R.; Flores, A.; Garcia, A. Tetrahedron 2007, 63, 8017–8026. and
references cited therein; (c) Viso, A.; Fernandez de la Pradilla, R.; Flores, A.;
Garcia, A.; Tortosa, M.; Lopez-Rodrigez, M. L. J. Org. Chem. 2006, 71, 1442–1448.
9. For an asymmetric synthesis of the (+)-(2R,3S) isomer of CP-99,994 see: Ahari,
M.; Perez, A.; Menant, C.; Vasse, J-L.; Szymoniak, J. Org. Lett. 2008, 10, 2473–2479.
10. Viso, A.; Fernandez de la Pradilla, R.; Lopez-Rodrigez, M. L.; Garcia, A.; Flores,
A.; Alonso, M. J. Org. Chem. 2004, 69, 1542–1547.
11. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. J. Chem. Soc., Perkin
Trans. 1 1999, 955–968.
12. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168–8179.
Acknowledgments
13. For a review see: (a) Felpin, F.-X.; Lebreton, J. Curr. Org. Syn. 2004, 1, 83–109;
For leading references see: (b) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem. 2007,
72, 2046–2052.
14. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849–3862.
This work was supported by grants from the National Institutes
of General Medical Sciences (GM57878 and GM51982) and Boeh-
ringer Ingelheim Pharmaceuticals.
15. Selected data: (+)-9, oil, ½a D20
ꢁ
+92.5 (c 1.3, CHCl3); (+)-10, oil, ½a D20
ꢁ
+102.8 (c 1.3,
CHCl3); (+)-11, oil, ½a D20
ꢁ
+33.6 (c 2.4, CHCl3); (ꢀ)-12, oil, ½a D20
ꢀ77.8 (c 2.0, CHCl3);
ꢁ
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(ꢀ)-13, oil, ½a 2D0
ꢁ
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ꢁ
15, oil, ½a 2D0
ꢁ
ꢀ50.8 (c 0.6, CHCl3); (+)-16, oil, ½a D20
ꢁ
+27.1 (c 0.45, CHCl3); (+)-17, oil,
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a 2D0
ꢁ
+62.5 (c 0.4, CHCl3); (+)-18, oil, ½a D20
ꢁ
+59.0 (c 0.5, CHCl3); (+)-19, oil, ½a D20
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ꢁ
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ꢁ
+48.0 (c
0.2, CHCl3); (+)-23, oil, ½a D20
ꢁ
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ꢁ
+35.2 (c 0.5,
CHCl3); (ꢀ)-8, oil, ½a D20
ꢁ
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½ ꢁ ꢀ78 (c 1.0, MeOH)].
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