Palladium-catalyzed construction of amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions

Article abstract of DOI:10.1016/j.tetlet.2005.07.139

The palladium catalyzed regio- and diastereo-selective allylic alkylation of (R)-2-acetoxy-4-aryl-3-butene with N-(diphenylmethylidene)glycinate and N-(diphenylmethylidene)alaninate occurred. The stereochemistry was controlled by the use of o-(diphenylphosphino)carboxylic acid, and produced new amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions.

Full text of DOI:10.1016/j.tetlet.2005.07.139

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6663–6666
Palladium-catalyzed construction of amino acid
derivatives possessing vicinal chiral quaternary and tertiary
carbon centers at the a and b positions
Daiji Ikeda,a Motoi Kawatsuraa,b, and Junichi Uenishi
a
*
aKyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
bFaculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 7 July 2005; revised 28 July 2005; accepted 28 July 2005
Available online 15 August 2005
Abstract—The palladium catalyzed regio- and diastereo-selective allylic alkylation of (R)-2-acetoxy-4-aryl-3-butene with N-(diphen-
ylmethylidene)glycinate and N-(diphenylmethylidene)alaninate occurred. The stereochemistry was controlled by the use of
o-(diphenylphosphino)carboxylic acid, and produced new amino acid derivatives possessing vicinal chiral quaternary and tertiary
carbon centers at the a and b positions.
Ó 2005 Elsevier Ltd. All rights reserved.
The construction of a chiral quaternary carbon center1
catalyzed by a transition metal catalyst is one of the
most challenging topics in organic synthesis. The palla-
dium catalyzed asymmetric allylic alkylation2 is also one
of the most widely and frequently used carbon–carbon
bond forming reactions catalyzed by transition metal
complexes because of its high reactivity, high catalytic
activity, and easy manipulation. The carbon nucleo-
philes successfully used for the asymmetric alkylation
have been limited to stabilized carbanion generated
from active methylene and methine compounds such
as malonate esters, and there have been few investiga-
tions into the construction of chiral quaternary carbon
centers by this reaction.3 The use of a-substituted
unsymmetrical b-diketones, a-substituted b-ketoesters,
and a-substituted aminoester derivatives for the reac-
tion with unsymmetric allylic esters generally gives a
mixture of regio- and stereo-isomers with poor selectiv-
ity. However, if a chiral allylic acetate is employed,4 the
remaining problems for this reaction would be con-
densed to the control of the regio- and diastereo-selec-
tivities, because the allylic alkylation reaction
stereospecifically proceeds with a net retention of the
stereochemistry. Recently, we reported the regio- and
diastereo-selective construction of vicinal quaternary
and tertiary carbon centers catalyzed by palladium cat-
alyst with 2-(diphenylphosphino)benzoic acid as the
ligand.5 We now report the application of this catalyst
system for the reaction with aminoester derivatives,6
and we succeeded in controlling its regio- and diaste-
reo-selectivities, and constructed the amino acid deriva-
tives possessing vicinal chiral tertiary and quaternary,
or tertiary and tertiary carbon centers at the a and b
positions, respectively.
Several reaction conditions were examined for the
palladium catalyzed regio- and diastereo-selective allylic
alkylation of (R)-2-acetoxy-4-phenyl-3-butene (1a) with
N-(diphenylmethylidene)glycinate (2a–c) and N-(diphen-
ylmethylidene)alaninate (2d–f) using 2-(diphenylphos-
phino)benzoic acid (L1) as the ligand (Scheme 1).
These results are summarized in Table 1. The reaction
of 1a with the ethyl ester of N-(diphenylmethyli-
dene)glycinate (2b) in the presence of 5 mol %
Pd(OAc)2/L1 in dioxane gave 3ab with 88% diastereose-
lectivity in 65% yield. The diastereoselectivity and yield
were slightly low compared with the reaction of 1a with
2-methylacetoacetate5 (entry 2). The reaction conditions
were optimized for the reaction of 1a with 2b. As the
palladium precursor and base, the combination of
Pd2(dba)3 and NaHMDS was the best for the yield
Keywords: Pd-catalyzed allylic alkylation; Regio- and diastereo-
selectivity; Vicinal chiral carbon centers; Amino acids derivatives.
*
Corresponding author. Tel./fax: +81 857 31 5179; e-mail: kawatsur@
chem.tottori-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.139

6664
D. Ikeda et al. / Tetrahedron Letters 46 (2005) 6663–6666
Me
Ph
OAc
[Pd]/L
Ph2C
N
CO2R'
+
α
N
α
Ph2C
N
CPh2
+
Ph
Me
base
solvent
Ph
R
R
CO2R'
R'O2C R
(R)-1a
2a: R = H, R' = Me
2b: R = H, R' = Et
2c: R = H, R' = tBu
2d: R = Me, R' = Me
2e: R = Me, R' = Et
2f: R = Me, R' = tBu
(R)-3: α position = R
(S)-3: α position = S
(R)-4: α position = R
(S)-4: α position = S
PPh2
PPh2
CO2H
CO2H
L1 =
L2 =
Scheme 1.
Table 1. Regio- and diastereo-selective allylic alkylation of (R)-1a with diphenylimino glycinate and diphenylimino alaninate 2a–fa
Entry
2
[Pd]
L
Base
Solvent
Temperature (°C)
Yieldb (%)
3:4c
(R)-3:(S)-3c
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2b
2b
2b
2a
2c
2d
2e
2f
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
PPh3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
NaHMDS
NaHMDS
NaHMDS
NaH
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
Et2O
Et2O
Et2O
Et2O
0–rt
0–rt
0–rt
0–rt
0–rt
0–rt
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
99 (3ab+4ab)
65 (3ab+4ab)
86 (3ab+4ab)
94 (3ab+4ab)
88 (3ab+4ab)
99 (3ab+4ab)
99 (3ab+4ab)
93 (3ab+4ab)
92 (3aa+4aa)
95 (3ac+4ac)
60 (3ad+4ad)
65 (3ae+4ae)
99 (3af+4af)
60 (3af+4af)
98:2
98:2
98:2
96:4
98:2
95:5
98:2
97:3
98:2
>99:1
98:2
96:4
>99:1
>99:1
53:47
88:12
91:9
75:25
85:15
55:45
82:18
98:2
96:4
>99:1
5:95
5:95
47:53
9:91
LiHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
9
10
11
12
13
14
Et2O
Et2O
Et2O
2f
a Reaction conditions: (R)-1 (1 mmol), 2a–e (1.5 mmol), base (1.4 mmol), solvent (7.6 mL), Pd(OAc)2 (0.05 mmol), or Pd2(dba)3 (0.025 mmol), ligand
(0.1 mmol), 12 h.
b Isolated yield by silica gel column chromatography.
c The ratio was determined by 400 MHz 1H NMR spectrum of the crude materials.
and stereoselectivities (entries 3–6). Ether was the best
solvent for the diastereoselectivity of the reaction of
1a with 2b, and up to a 98% diastereoselectivity was
obtained at ꢀ10 °C (entry 8). Methyl ester of N-(diph-
enylmethylidene)glycinate (2a) were also gave high ste-
reoselectivities (entry 9). A highly stereo-controlled
coupling was attained by the reaction with the tert-butyl
ester of N-(diphenylmethylidene)glycinate (2c), while
(R)-3ac7 was obtained with >99% regioselectivity and
>99% diastereoselectivity (entry 10). This coupling reac-
tion gave optically active new amino acid derivatives,
possessing a tertiary chiral carbon center at the a posi-
tion which was adjacent to the tertiary carbon center.
The reaction with (S)-2-acetoxy-4-phenyl-3-butene ((S)-
1a) and 2a gave (2S,3S)-3aa with 96% diastereoselectiv-
ity and 98% regioselectivity in 92% yield (Scheme 2). The
coupling products were easily converted to 3-methyl-
aspartic acid ((2S,3R)-5aa)8 with reported procedure,9
and stereochemistry was confirmed the (2S,3S) for 3aa
1
by the comparison of the reported H NMR data and
specific rotation.10
Me
2.5 mol% Pd2(dba)3
OAc
2
N
Ph2C
10 mol% L1
Ph2C
N
CO2Me
3
Ph
+
NaHMDS
Et2O, –10 ºC
H CO2Me
Ph
H
2a
(S)-1a
(2S, 3S)-3aa
7 stepsref. 8)
Me
H2N
2
3
CO2H
H CO2H
(2S, 3R)-5aa
Scheme 2.

D. Ikeda et al. / Tetrahedron Letters 46 (2005) 6663–6666
6665
2.5 mol% Pd2(dba)3
The reaction with the methyl or ethyl ester of N-(diph-
OAc
enylmethylidene)alaninate (2d and 2e) indicated a
slightly decreasing yield, regioselectivity and diastereo-
selectivity (Table 1, entries 11 and 12). The reaction with
the tert-butyl ester of N-(diphenylmethylidene)alaninate
(2f) gave a low diastereoselectivity (53%) while the iso-
lated yield and regioselectivity were high (entry 13). This
low diastereoselectivity was improved by using 1-(diph-
enylphosphino)-2-naphthoic acid (L2),11 which gave a
91% diastereoselectivity with a 60% yield (entry 14).
The coupling product 3ad, possessing vicinal chiral qua-
ternary and tertiary carbon centers at the a and b posi-
tions, was also converted to 3-methylaspartic acid
((2S,3S)-5ad)12 (Scheme 3), and stereochemistry was
confirmed by the (2S,3R) for 3ad by the comparison
10 mol% L1
Ph2C N
CO2Et
+
NaHMDS
Et2O, –10 ºC
Ar
R
1b: Ar = 4-MeOC6H4
1c: Ar = 4-CF3C6H4
1d: Ar = 1-Naphthyl
1e: Ar = 2-Naphthyl
2b: R = H
2e: R = Me
PPh2
L1 =
CO2H
Me
Ar
α
α
N CPh2
Ph2C N
+
Ar
Me
R CO2Et
EtO2C R
(R)-3: α position = R
(S)-3: α position = S
(R)-4: α position = R
(S)-4: α position = S
Scheme 4.
1
of the reported H NMR data and specific rotation.9,13
Table 2 summarizes the reactions of several allylic ace-
tates (1b–e) with 2b or 2e (Scheme 4). Under the opti-
mized conditions, all reactions proceeded in a highly
regio- and diastereo-selective manner. In particular,
the reactions of (R)-2-acetoxy-4-(1-naphthyl)-3-butene
(1d) with 2b proceeded in a highly stereo-controlled
manner and gave almost a single stereoisomer (R)-3db
in 82% isolated yield (Table 2, entry 3).
Acknowledgements
This work was partially supported financially by the
Ministry of Education, Science, Sports, and Culture,
Grant-in Aid for the Encouragement of Young Scien-
tists (B), 15790021, and Mitsubishi Chemical Corpora-
tion Fund. We thank Professors Y. Ohfune and K.
Sakaguchi (Osaka City University) for helpful informa-
tion. M.K. also acknowledges the TORAY Award in
Synthetic Organic Chemistry, Japan.
In conclusion, we have succeeded in the regio- and dia-
stereo-selective palladium catalyzed allylic alkylation
of (R)- or (S)-2-acetoxy-4-aryl-3-butene with N-(di-
phenylmethylidene)alaninate or N-(diphenylmethylid-
ene)glycinate, and this reaction provides vicinal chiral
quaternary and tertiary, or tertiary and tertiary carbon
centers at the a and b positions, respectively. It is
noteworthy that the face selectivity of the enolates
was highly controlled by the use of o-(diphenylphos-
phino)carboxylic acid. A mechanistic study will be the
subject of a future work.
References and notes
1. (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591–4597; (b) Corey, E. J.; Perez, A. G. Angew.
Chem., Int. Ed. 1998, 37, 389–401; (c) Fuji, K. Chem. Rev.
1993, 93, 2037–2066.
2. (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33,
336–345; (b) Pfaltz, A.; Lautens, M. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. M., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, pp
833–884; (c) Hayashi, T. J. Organomet. Chem. 1999, 576,
195–202; (d) Johnson, M.; Jorgensen, K. A. Chem. Rev.
1998, 1689–1708; (e) Trost, B. M.; Van Vranken, D. L.
Chem. Rev. 1996, 96, 395–422.
Me
Me
7 stepsref. 8)
H2N
2
Ph2C
N
2
3
3
CO2H
Ph
3. (a) Kuwano, R.; Uchida, K.; Ito, Y. Org. Lett. 2003, 5,
2177–2179; (b) Kanayama, T.; Yoshida, K.; Miyabe, H.;
Kimachi, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6197–
6201; (c) Trost, B. M.; Schroeder, G. M.; Kristensen, J.
Angew. Chem., Int. Ed. 2002, 41, 3492–3495; (d) Kuwano,
R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236–3237; (e)
Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999,
121, 6759–6760; (f) Trost, B. M.; Ariza, X. Angew. Chem.,
Int. Ed. 1997, 36, 2635–2637; (g) Trost, B. M.; Radinov,
R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879–
7880; (h) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem.
Soc. 1996, 118, 3309–3310.
4. (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121,
4547–4554; (b) Hayashi, T.; Yamamoto, A.; Hagihara, T.
J. Org. Chem. 1986, 51, 3236–3237.
5. Uenishi, J.; Kawatsura, M.; Ikeda, D.; Muraoka, N. Eur.
J. Org. Chem. 2003, 3909–3912.
Me CO2H
Me CO2Me
(2S, 3S)-5ad
(2S, 3R)-3ad
Scheme 3.
Table 2. Regio- and diastereo-selective allylic alkylation of (R)-1b–e
with diphenylimino glycinate 2b and diphenylimino alaninate 2ea
Entry
1
2
Yield (%)b
3:4c
(R)-3:(S)-3c
1
2
3
4
5
1b
1c
1d
1e
1d
2b
2b
2b
2b
2e
85 (3bb+4bb)
81 (3cb+4cb)
82 (3db+4db)
80 (3eb+4eb)
79 (3de+4de)
98:2
97:3
97:3
>99:1
98:2
98:2
>99:1
>99:1
>99:1
14:86
a Reaction conditions: Pd2(dba)3 (0.025 mmol), L1 (0.1 mmol), 1
(1 mmol), (1.5 mmol), NaHMDS (1.4 mmol), ether (7.6 mL),
ꢀ10 °C, 12 h.
6. (a) Baldwin, I. C.; Williams, J. M. J.; Beckett, R. P.
Tetrahedron: Asymmetry 1995, 6, 679–682; (b) Kazmaier,
U.; Zampe, F. L. Angew. Chem., Int. Ed. 1999, 38,
1468–1470; (c) Kazmaier, U.; Lindner, T. Angew.
Chem., Int. Ed. 2005, 44, 3303–3306, and references cited
therein.
2
b Isolated yield by silica gel column chromatography.
c The ratio was determined by 400 MHz 1H NMR spectrum of the
crude materials.

6666
D. Ikeda et al. / Tetrahedron Letters 46 (2005) 6663–6666
7. General procedure (Table 1, entry 10): To a solution of
8. Reagents and conditions: (i) 1 N HCl, THF, 0 °C, 1 h; (ii)
Boc2O, Na2CO3, H2O/dioxane (1/2), rt, 1 h (97% in
2steps); (iii) O3, AcOEt, ꢀ78 °C, 10 min, then Me2S, rt,
1 h (65%); (iv) Jones oxidation, 0 °C, 2 h; (v) CH2N2,
ether, rt, 30 min; (vi) 1 M NaOH, THF, 0 °C–rt, 19 h; (vii)
TFA, CH2Cl2, 0 °C, 3.5 h (64% in four steps).
Pd2(dba)3 (22.9 mg, 0.025 mmol), 2-(diphenylphos-
phino)benzoic acid (30.6 mg, 0.10 mmol) and tert-butyl
ester of diphenylimino glycinate 2c (443 mg, 1.50 mmol)
in anhydrous Et2O (7.6 mL) was added (R)-2-acetoxy-4-
phenyl-3-butene (1a) (190 mg, 1.0 mmol). The solution
was cooled to ꢀ10 °C, then NaHMDS (1.4 mL of 1.0 M
in THF, 1.40 mmol) was added slowly. The mixture was
stirred at ꢀ10 °C for 12 h. The reaction mixture was
quenched with water, and extracted with ether. The
organic phase was washed with brine, dried over anhy-
drous MgSO4 and evaporated. The regio and diastereo
9. Sakaguchi, K.; Yamamoto, M.; Kawamoto, T.; Yamada,
T.; Shinada, T.; Shimamoto, K.; Ohfune, Y. Tetrahedron
Lett. 2004, 45, 5869–5872.
10. Compound (2S,3R)-5aa: 1H NMR (300 MHz, D2O): d
3.68 (d, J = 5.3 Hz, 1H), 2.88 (dq, J = 5.3, 7.5 Hz, 1H),
26
1.29 (d, J = 7.5 Hz, 3H). ½aꢁD 32.5 (c 2.00, 5N HCl) {lit.
26
1
ratios of 3 and 4 were determined by 400 MHz H NMR
½aꢁD 34.3 (c 2.05, 5 N HCl)}.
for this crude material. The residue was chromato-
graphed on silica gel (EtOAc/hexane = 1/9) to give
304 mg (95%) of 3ac. major isomer (2R,3R)-3ac: 1H
NMR (400 MHz, CDCl3): d 7.68–7.10 (m, 15H), 6.43 (d,
J = 15.9 Hz), 6.33 (dd, J = 15.9, 8.2 Hz, 1H), 3.91
(d, J = 5.4 Hz, 1H), 3.08–2.99 (m, 1H), 1.42 (s, 9H),
1.07 (d, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3): d
170.5, 139.7, 137.7, 136.8, 132.5, 130.3, 128.8, 128.4,
128.3, 127.9, 126.2, 80.9, 71.1, 41.5, 28.1, 17.6; HR-EI-
MS calcd for C29H31NO2 (M+) m/z 425.2355, found
11. Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L.
J. Am. Chem. Soc. 2000, 122, 5968–5976.
12. Reagents and conditions: (i) 1 N HCl, THF, 0 °C, 1 h; (ii)
Boc2O, Na2CO3, H2O/dioxane (1/2), rt, 72 h (71% in two
steps); (iii) O3, AcOEt, ꢀ78 °C, 10 min, then Me2S, rt, 1 h
(67%); (iv) Jones oxidation, 0 °C, 2 h; (v) CH2N2, ether, rt,
30 min; (vi) 1 M NaOH, THF, rt, 5 days; (vii) TFA,
CH2Cl2, 0 °C, 4 h (49% in four steps).
13. Compounds (2S,3S)-5ad: 1H NMR (300 MHz, D2O): d 2.75
(q, J = 7.4 Hz, 1H), 1.48 (s, 3H), 1.13 (d, J = 7.4 Hz, 3H).
26
26
26
425.2347. ½aꢁD 39.9 (c 1.00, CHCl3).
½aꢁD 13.1 (c 1.00, 5 N HCl) {lit. ½aꢁD 11.9 (c 0.91, 5 N HCl)}.