Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

Article abstract of DOI:10.1016/j.tetlet.2007.07.020

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.

Full text of DOI:10.1016/j.tetlet.2007.07.020

Tetrahedron Letters 48 (2007) 6304–6307
Pd-catalyzed enantioselective synthesis of quaternary a-amino
acid derivatives using a phenylalanine-derived P-chirogenic
diaminophosphine oxide
Tetsuhiro Nemoto, Teisuke Harada, Takayoshi Matsumoto and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 16 May 2007; revised 2 July 2007; accepted 5 July 2007
Available online 30 July 2007
Abstract—A Pd-catalyzed enantioselective synthesis of quaternary a-amino acid derivatives using a phenylalanine-derived P-chiro-
genic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic b-keto esters with a nitrogen functional
group at the a-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diamino-
phosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary a-amino acid derivatives in excellent
yield and in up to 92% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
The incorporation of quaternary a-amino acids in pep-
tide chains is one of the most commonly utilized methods
for developing peptidomimetics.1 Such modifications
provide higher stability against metabolic degradation,
and influence the conformational rigidity and lipophilic-
ity of peptidic compounds, which often allow for higher
selectivity toward receptors. In addition to these biolog-
ical aspects, unnatural quaternary a-amino acids serve as
valuable chiral building blocks in organic synthesis.2
Therefore, asymmetric synthesis of quaternary a-amino
acid derivatives has attracted considerable attention,
and various catalytic asymmetric synthetic methods have
been reported to date.3,4
for this type of reaction, affording N-acetyl quaternary
a-amino acid derivatives with up to 95% ee.6a We
recently reported that aspartic acid-derived P-chirogenic
diaminophosphine oxides function as effective chiral
ligands in transition metal catalysis in the presence of
N,O-bis(trimethylsilyl)acetamide (BSA).8,9 These chiral
diaminophosphine oxides were successfully applied to
enantioselective construction of quaternary carbons
through Pd-catalyzed asymmetric allylic substitution
using b-keto esters as prochiral nucleophiles.8a–c Prod-
ucts possessing an all-carbon quaternary stereocenter
were obtained with up to 95% ee using cyclic b-keto
esters as the prochiral nucleophiles. In contrast, enantio-
selectivity was moderate when acyclic b-keto esters with
an acetamido group at the a-carbon were used as the
prochiral nucleophiles (e.g., Table 1, entry 1). We hoped
to overcome this drawback by tuning the reaction con-
ditions. Herein, we report a Pd-catalyzed enantioselec-
tive synthesis of quaternary a-amino acid derivatives
using a phenylalanine-derived P-chirogenic diamino-
phosphine oxide.
Pd-catalyzed asymmetric allylic substitution using b-
keto esters with a nitrogen functional group at the a-
carbon as the prochiral nucleophiles is one of the most
straightforward approaches for synthesizing chiral qua-
ternary a-amino acid derivatives. Although several types
of Pd-catalyzed asymmetric allylic substitutions using
prochiral nucleophiles have been investigated since
1980s,5 there are only a few reports of asymmetric syn-
thesis of such tetrasubstituted carbons using this strat-
egy.6,7 The catalyst system using a chiral BINAP-Pd
complex, developed by Ito et al., is the state of the art
We first examined the effect of the structure of chiral dia-
minophosphine oxide using asymmetric allylic substitu-
tion of cinnamyl acetate 2 with 3a (Fig. 1 and Table 1).
When 5 mol % of Pd catalyst and 10 mol % of (S,RP)-
1a were used as the catalyst, the reaction proceeded at
4 °C to provide the corresponding product (R)-4a in
90% yield with 78% ee (entry 1). Although the same reac-
tion was performed using other structurally modified
Keywords: Asymmetric allylic alkylation; Diaminophosphine oxides;
Palladium; Quaternary a-amino acids.
*
Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@
p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.020

T. Nemoto et al. / Tetrahedron Letters 48 (2007) 6304–6307
Table 1. Effect of the structure of chiral diaminophosphine oxidea
6305
(Table 2, right column).11,12 The reaction adducts were
highly crystalline compounds and the optical purity
was efficiently enriched by a single recrystallization (en-
try 1). The present reaction conditions were also effective
in asymmetric allylic substitution using carbamate-type
substrates 3k and 3l. The corresponding products 4k
and 4l were obtained in excellent yield with high enanti-
oselectivity (entries 11–12).
AcO
Ph
2
O
O
Pd cat.
S,R )-1
(
+
P
H C
3
OCH
3
O
O
BSA, toluene
AcHN
3a
(1.5 eq)
Ph
H C
3
OCH
(R)-4a
3
NHAc
Entry
(S,RP)-1
Time (h)
Yieldb (%)
eec (% ee)
In striking contrast to alkyl ketone-type substrates, no
reaction occurred when phenyl ketone-type substrate 3h
was used as the prochiral nucleophile (Table 2, entry 8).
This unsatisfactory result led us to focus on the asym-
metric allylic substitution of 2 using 3h as the nucleophile
(Table 3). The effect of the addition of other potassium
salts using 3h was examined, revealing that the counter
anion of the potassium salt dramatically affected the cat-
alytic activity. When 10 mol % of KCl was used as the
additive, the corresponding product 4h was obtained in
99% yield with 82% ee (entry 4). There was a remarkable
increase in the reactivity when both KCl (10 mol %) and
KOAc (10 mol %) were used as the additive, affording
the corresponding products without significant loss of
the enantiomeric excess (entry 7). When the reaction
was performed using 20 mol % of KCl, there was a de-
crease in both the yield and enantioselectivity (entry 8).
This result indicates that KCl and KOAc would function
independently in this reaction system. Asymmetric allylic
substitution of c-alkyl-substituted allylic alcohol deriva-
tives was also examined (Scheme 1). Although asymmet-
ric allylic substitution of acetate derivative 5a with 3a
was performed using 5 mol % of the catalyst, the reaction
did not proceed to completion in the presence of KOAc
(72 h, 49% yield, 70% ee), or in the presence of both KCl
and KOAc (72 h, 60% yield, 81% ee). There was a signif-
icant increase in the reactivity when methyl carbonate
derivative 5b was used as the electrophile, affording 6
in 99% yield and in 82% ee.
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
48
60
48
48
48
20
48
48
60
24
90
23
94
90
49
99
36
95
60
98
78
51
78
79
77
69
79
88
78
92
1g
1h
1i
10
1j
a Reaction conditions: 2 (0.2 mmol scale), (g3-C3H5PdCl)2 (2.5 mol %),
1 (10 mol %), 3a (1.5 equiv), BSA (4 equiv), toluene (0.15 M), 4 °C.
b Isolated yield.
c Determined by HPLC analysis.
preligands (S,RP)-1a–g, there was no increase in the
enantioselectivity (entries 2–7). Further studies revealed
that enantioselectivity was improved when the reaction
was performed using P-chirogenic diaminophosphine
oxides prepared from other amino acids. Finally,
(S,RP)-1j, prepared from (S)-phenylalanine, was best
for asymmetric induction, affording (R)-4a in 98% yield
with 92% ee (entry 10).
We next examined the scope and limitations of other
nucleophiles. When the developed conditions were
employed for methyl ketone-type substrates 3a,b, ethyl
ketone-type substrate 3d, and benzamido-type substrate
3i, the corresponding quaternary a-amino acid deriva-
tives were obtained in excellent yield with high enantio-
selectivity. There was, however, a remarkable decrease
in the reactivity when other substrates were used (Table
2, left column). To improve the reactivity, we investi-
gated the effect of the addition of acetate salt to the
reaction. Detailed screening revealed that 10 mol % of
KOAc dramatically increased the reactivity.10
Asymmetric allylic substitutions using N-acyl-protected
alkyl ketone-type substrates 3a–g, 3i, and 3j proceeded
smoothly in the presence of KOAc, affording the corre-
sponding quaternary a-amino acid derivatives in excel-
lent yield with high enantioselectivity (86–92% ee)
Transformation of the reaction adduct into the corre-
sponding quaternary a-amino acid was also examined
using 4k as the substrate (Scheme 2). syn-Selective
reduction of the ketone using L-SelectrideÒ gave syn-b-
hydroxy a-amino ester 7 in 93% yield as a single diaste-
reomer.6a This compound was transformed into the
corresponding quaternary a-amino acid 8 by treatment
with LiOH in THF–H2O (95% yield).
In conclusion, we succeeded in the Pd-catalyzed
enantioselective synthesis of quaternary a-amino acid
X
X
Y
1a: X = H, Y = H, Ar = phenyl
1b: X = H, Y = H, Ar = 1-naphthyl
Y
1h: R =
NHPh
1c: X = H, Y = H, Ar = 2-naphthyl
1d: X = OMe, Y = H, Ar = phenyl
1e: X = OMe, Y = OMe, Ar = phenyl
1f: X = t-Bu, Y = H, Ar = phenyl
N
H
O
R
HN
N
H
O
P
1i: R =
1j: R =
P
N
Ph
H
N
H
1g: X = CF , Y = H, Ar = phenyl
3
Ph
Ar
Figure 1. Chiral diaminophosphine oxides (S,RP)-1a–j.

6306
T. Nemoto et al. / Tetrahedron Letters 48 (2007) 6304–6307
Table 2. Scope and limitationsa
Pd cat.
S,R )-1j
O
O
O
O
(
P
+
1
3
1
2
3
AcO
Ph
R
OR
2
R
OR
BSA, toluene
Additive
R HN
2
NHR
Ph
4a-l
3a-l
1
2
3
1
2
3
3a, 4a: R = CH , R = Ac, R = CH
3g, 4g: R = cHex, R = Ac, R = CH
3
3
3
1
2
3
1
2
3
3b, 4b: R = CH , R = Ac, R = CH CH
3h, 4h: R = Ph, R = Ac, R = CH
3
3
2
3
1
2
3
1
2
3
3c, 4c: R = CH , R = Ac, R = CH Ph
3i, 4i: R = CH , R = benzoyl, R = CH
3
2
3
3
1
2
3
1
2
3
3d, 4d: R = CH CH , R = Ac, R = CH
3j, 4j: R = CH , R = crotonoyl, R = CH
3 3
2
3
3
1
2
3
1
2
3
3e, 4e: R = CH CH Ph, R = Ac, R = CH
3k, 4k: R = CH , R = COOMe, R = CH
3 3
2
2
3
1
2
3
1
2
3
3f, 4f: R = i-Pr, R = Ac, R = CH
3l, 4l: R = CH , R = COOBn, R = CH
3 3
3
Entry
Nucleophile
Additive free
Yieldb (%)
Additive: KOAc (10 mol %)
Time (h)
eec (% ee)
Time (h)
Yieldb (%)
eec (% ee)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
24
24
48
48
24
72
72
24
30
24
48
48
98
99
52
96
92 (R)
92
91
86
—
89
83
—
92
12
16
48
24
24
48
48
24
20
24
60 (24)f
60
99 (70)d
99
99
98
99
99
99
90 (99)e (R)
92
89
87
89
90
86
—
92
90
89 (90)f
89
No reaction
38
32
No reaction
99
No reaction
No reaction
No reaction
3g
3h
3i
No reaction
99
10
11
12
3j
—
—
—
99
3k
3l
73 (99)f
99
a Reaction conditions: 2, (g3-C3H5PdCl)2 (2.5 mol %), (S,RP)-1j (10 mol %), 3a–l (1.5 equiv), BSA (4 equiv), toluene (0.15 M), KOAc (0 mol % or
10 mol %), 4 °C.
b Isolated yield.
c Determined by HPLC analysis.
d Yield of recrystallization from EtOH.
e Enantiomeric excess after single recrystallization from EtOH.
f 10 mol % of KOAc and 10 mol % of KCl were used as the additive.
Table 3. Asymmetric allylic substitution of 2 with 3ha
OH
O
OH
O
Entry Additive
Time (h) Yieldb (%)
eec (% ee)
H C
O
OCH
3
a
3
b
H C
3
OH
1
2
3
4
5
6
7
—
72
No reaction
No reaction
Trace
99
99
—
—
—
82
76
73
80
4k
NH
H N
2
KOAc (10 mol %) 72
KF (10 mol %)
KCl (10 mol %)
KBF4 (10 mol %) 72
KPF6 (10 mol %) 96
KOAc (10 mol %) 46
KCl (10 mol %)
Ph
Ph
OCH
72
96
7
8
3
Scheme 2. Conversion of 4k into quaternary a-amino acid 8. Reagents
and conditions. (a) L-SelectrideÒ, THF, À78 °C, 93%, syn/
anti = >99:1. (b) LiOH, THF/H2O, rt, 95%.
81
99
8
KCl (20 mol %)
46
89
73
derivatives using a phenylalanine-derived P-chirogenic
diaminophosphine oxide. Asymmetric allylic substitu-
tion using various types of b-keto esters with a nitrogen
functional group at the a-position proceeded in the
presence of the appropriate additives, providing the
corresponding quaternary a-amino acid derivatives in
up to 92% ee. Application to asymmetric synthesis of
a Reaction conditions: 2, (g3-C3H5PdCl)2 (2.5 mol %), (S,RP)-1j
(10 mol %), 3h (1.5 equiv), BSA (4 equiv), toluene (0.15 M), additive,
4 °C.
b Isolated yield.
c Determined by HPLC analysis.
Pd cat. (5 mol %)
From 5a
O
O
72 h, 49%, 70% ee (KOAc)
(
S,R )-1j (10 mol %)
P
72 h, 60%, 81% ee (KOAc, KCl)
X
Ph
3a (1.5 eq)
H C
OCH
3
3
From 5b
additive (10 mol %)
BSA, toluene, 4 ˚C
AcHN
5a: X = OAc
5b: X = OCOOMe
96 h, 99%, 82% ee (KOAc)
47 h, 99%, 82% ee (KOAc, KCl)
6
Ph
Scheme 1. Asymmetric allylic substitution of 5.

T. Nemoto et al. / Tetrahedron Letters 48 (2007) 6304–6307
6307
5. For representative examples of enantioselective construc-
tion of a quaternary carbon through Pd-catalyzed asym-
metric allylic substitution, see: (a) Hayashi, T.; Kanehira,
K.; Tsuchiya, H.; Kumada, M. J. Chem. Soc., Chem.
Commun. 1982, 116; (b) Sawamura, M.; Nagata, H.;
Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586;
(c) Sawamura, M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc.
1996, 118, 3309; (d) Trost, B. M.; Radinov, R.; Grenzer,
E. M. J. Am. Chem. Soc. 1997, 119, 7879; (e) Trost, B. M.;
Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759; (f)
You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett.
2001, 3, 149; (g) Nakoji, M.; Kaneyama, T.; Okino, T.;
Takemoto, Y. J. Org. Chem. 2002, 67, 7418; (h) Kuwano,
R.; Uchida, K.; Ito, Y. Org. Lett. 2003, 5, 2177; (i)
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004,
126, 15044; (j) Trost, B. M.; Frederiksen, M. U. Angew.
Chem., Int. Ed. 2005, 44, 308; (k) Trost, B. M.; Xu, J. J.
Am. Chem. Soc. 2005, 127, 2846; (l) Mohr, J. T.; Behenna,
D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int.
Ed. 2005, 44, 6924; (m) Trost, B. M.; Bream, R. N.; Xu, J.
Angew. Chem., Int. Ed. 2006, 45, 3109; For a review, see:
(n) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
biologically active compounds, as well as mechanistic
investigation into the role of additives, is currently in
progress.
Acknowledgment
This work was supported in part by Grant-in Aid
for Encouragement of Young Scientists (A) from the
Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.07.020.
References and notes
6. (a) Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121,
3236; (b) Ogasawara, M.; Ngo, H. L.; Sakamoto, T.;
Takahashi, T.; Lin, W. Org. Lett. 2005, 7, 2881; (c) a-
Acetamido b-keto phosphonates as the nucleophiles, see:
Kuwano, R.; Nishio, R.; Ito, Y. Org. Lett. 1999, 1,
837.
1. For reviews on peptidomimetic chemistry, see: (a) Giannis,
A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244;
(b) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699;
(c) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
2. For reviews on asymmetric synthesis of quaternary a-
7. Azlactones are also useful nucleophiles for providing
access to chiral quaternary a-amino acid derivatives, see:
(a) Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. 1997,
36, 2635; (b) Trost, B. M.; Ariza, X. J. Am. Chem. Soc.
1999, 121, 10727; (c) Trost, B. M.; Dogra, K. J. Am.
Chem. Soc. 2002, 124, 7256.
´
amino acid derivatives, see: (a) Cativiela, C.; Dıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517; (b)
´
Cativiela, C.; Dıaz-de-Villegas, M. D. Tetrahedron: Asym-
metry 2000, 11, 645; (c) Park, K.-H.; Kurth, M. J.
Tetrahedron 2002, 58, 8629; (d) Gro¨ger, H. Chem. Rev.
2003, 103, 2795.
8. (a) Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitomi, T.;
Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126,
3690; (b) Nemoto, T.; Masuda, T.; Matsumoto, T.;
Hamada, Y. J. Org. Chem. 2005, 70, 7172; (c) Nemoto,
T.; Fukuda, T.; Matsumoto, T.; Hitomi, T.; Hamada, Y.
Adv. Synth. Catal. 2005, 347, 1504; (d) Nemoto, T.;
Masuda, T.; Akimoto, Y.; Fukuyama, T.; Hamada, Y.
Org. Lett. 2005, 7, 4447; (e) Nemoto, T.; Jin, L.;
Nakamura, H.; Hamada, Y. Tetrahedron Lett. 2006, 47,
6577; (f) Nemoto, T.; Sakamoto, T.; Matsumoto, T.;
Hamada, Y. Tetrahedron Lett. 2006, 47, 8737; (g) Nemoto,
T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda,
T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett.
2007, 9, 927; (h) Nemoto, T.; Sakamoto, T.; Fukuyama,
T.; Hamada, Y. Tetrahedron Lett. 2007, 48, 4977.
3. For recent leading references of catalytic asymmetric
synthesis of quaternary a-amino acid derivatives, see: (a)
Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2001, 123, 10784; (b) Vachal, P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012; (c)
Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634; (d)
Sabby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc.
2004, 126, 8120; (e) Zhuang, W.; Saaby, S.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2004, 43, 4476; (f) Belokon, Y.
N.; Bhave, D.; D’Addario, D.; Groaz, E.; North, M.;
Tagliazucca, V. Tetrahedron 2004, 60, 1849; (g) Kitamura,
M.; Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed.
2005, 44, 1549; (h) Liu, X.; Li, H.; Deng, L. Org. Lett.
2005, 7, 167; (i) Ooi, T.; Miki, T.; Maruoka, K. Org. Lett.
2005, 7, 191; (j) Suri, J. T.; Steiner, D. D.; Barbas, C. F.,
III Org. Lett. 2005, 7, 3885; (k) Balskus, E. P.; Jacobsen,
E. N. J. Am. Chem. Soc. 2006, 128, 6810; (l) Fustero, S.;
9. For reviews on phosphine oxide preligands in transition
metal catalysis, see: (a) Dubrovina, N. V.; Bo¨rner, A.
Angew. Chem., Int. Ed. 2004, 43, 5883; (b) Ackermann, L.
Synthesis 2006, 1557; (c) Ackermann, L. Synlett 2007, 507;
(d) Nemoto, T.; Hamada, Y. Chem. Rec. 2007, 7, 150.
10. See Supplementary data for details.
´
´
Sanchez-Rosello, M.; Rodrigo, V.; del Pozo, C.; Sanz-
´
Cervera, J. F.; Simon, A. Org. Lett. 2006, 8, 4129.
4. For asymmetric synthesis of quaternary a-amino acid
derivatives via memory of chirality, see: (a) Kawabata, T.;
Kawakami, S.; Majumdar, S. J. Am. Chem. Soc. 2003,
125, 13012; (b) Kawabata, T.; Matsuda, S.; Kawakami, S.;
Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006,
128, 15394.
11. For the general procedure, see Supplementary data.
12. Although the role of additives in the present catalytic
asymmetric reaction is unknown, NMR experiments
indicated that KOAc might be related to the generation
of active nucleophiles. For experimental data, see Supple-
mentary data.