Pd-catalyzed asymmetric allylic alkylation of glycine imino ester using a chiral phase-transfer catalyst

Article abstract of DOI:10.1021/jo0260645

Pd-catalyzed asymmetric allylic alkylation of the glycine imino ester 1a has been developed using a chiral quaternary ammonium salt 3d without chiral phosphine ligands. The proper choice of the achiral Pd ligand, P(OPh)₃, is important to achieve high enantioselectivity. By this method with the dual catalysts, numerous enantiomerically enriched α-allylic amino acids 4a-h could be prepared with comparable to higher enantioselectivity than that of the conventional asymmetric alkylation of 1a. In addition, the Pd-catalyzed reaction of 1a with 1-phenyl-2-propenyl acetate 2i afforded the branch product 6 with high enantio- and diastereoselectivity (>95% de, 85% ee).

Full text of DOI:10.1021/jo0260645

P d -Ca ta lyzed Asym m etr ic Allylic Alk yla tion of Glycin e Im in o
Ester Usin g a Ch ir a l P h a se-Tr a n sfer Ca ta lyst
Masayoshi Nakoji, Takatoshi Kanayama, Tomotaka Okino, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, J apan
takemoto@pharm.kyoto-u.ac.jp
Received J une 17, 2002
Pd-catalyzed asymmetric allylic alkylation of the glycine imino ester 1a has been developed using
a chiral quaternary ammonium salt 3d without chiral phosphine ligands. The proper choice of the
achiral Pd ligand, P(OPh)3, is important to achieve high enantioselectivity. By this method with
the dual catalysts, numerous enantiomerically enriched R-allylic amino acids 4a -h could be
prepared with comparable to higher enantioselectivity than that of the conventional asymmetric
alkylation of 1a . In addition, the Pd-catalyzed reaction of 1a with 1-phenyl-2-propenyl acetate 2i
afforded the branch product 6 with high enantio- and diastereoselectivity (>95% de, 85% ee).
In tr od u ction
chiral centers in R-alkylated amino acids. On the other
hand, the asymmetric allylation of the glycine imino ester
through a chiral π-allyl palladium(II) complex can con-
struct two stereogenic centers on both the allylic sub-
strate and the prochiral nucleophile, albeit the stereo-
selectivity of the latter chiral center might be low.4 In
general, the enantioselective nucleophilic attack of a
prochiral nucleophile to give a π-allyl complex is not
easily controlled by a chiral ligand on the palladium atom
located at the opposite side of the π-allyl carbon structure
from the approching nucleophile.7 To overcome the
problems incurred in this reaction, several ingenious
ligands for constructing an effective chiral environment
around the π-allyl-palladium(II) complex have been
developed.8 With the aim of establishing a different
methodology, we examined the palladium-catalyzed nu-
cleophilic substitution in the presence of a chiral PTC as
Chiral R-alkyl and R,R-dialkyl-R-amino acids are an
important class of nonproteogenic amino acids and have
attracted considerable attention in biological and phar-
macological studies, because introduction of these amino
acids to peptides induces conformational constraints and
enhances metabolic stability.1 As a result, thus far, a
number of diastereoselective synthetic methods of R-alky-
lated amino acids using various chiral auxiliaries have
been reported.2 Recently, catalytic asymmetric synthesis
has been intensively studied, and some efficient methods
have been developed other than the asymmetric hydro-
genation of dehydroamino acids.3-6 The asymmetric
alkylation of glycine imino esters by a chiral phase-
transfer catalyst (PTC) would be a versatile method in
terms of operational simplicity and high enantioselec-
tivity.3 However, the PTC-mediated reaction suffers from
the limitation of the allylic halide sources, and it is
difficult to extend this procedure to construct contiguous
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You, S.-L.; Hou, X.-L.; Dai, L.-X.; Cao, B.-X.; Sun, J . Chem. Commun.
2000, 1933-1934; Trost, B. M.; Ariza, X. J . Am. Chem. Soc. 1999, 121,
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S.; Mallart, S.; Montes, J . R.; Levif, G. Tetrahedron 1988, 44, 5263-
5275. Very recently a similar reaction has been reported by the Chinese
groups: Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; J iang, Y.; Choi,
M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567-
1571.
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10.1021/jo0260645 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/21/2002
7418
J . Org. Chem. 2002, 67, 7418-7423

Pd-Catalyzed Asymmetric Allylic Alkylation
TABLE 1. Asym m etr ic Allyla tion of 1a u n d er P TC
Con d ition sa
cocatalyst, which might construct an effective chiral
environment around a prochiral nucleophile (eq 1).
entry PTC ligand (mol %)
base
KOH
KOH
KOH
KOH
KOH
KOH
KOH
yield, %b ee, %c
1
2
3a
3b
3c
3d
3d
3d
3d
3d
3d
3d
DPPE (8)
DPPE (8)
83
71
91
74
69
32
25
19
82
83
3
12
9
24
4
59
50
82
94
93
3
DPPE (8)
4
DPPE (8)
5
6
n-Bu3P (16)
Ph3P (16)
7
8
(EtO)3P (16)
(PhO)3P (16)
(PhO)3P (16)
DPPE(O) (10)
KOH
50% KOH
50% KOH
9d
10d
In this paper, we present a full account of our investiga-
tion into the enantioselective allylic alkylation (up to 96%
ee) of tert-butyl N-(diphenylmethylene)glycinate 1a with
several allylic acetates 2a -j, catalyzed by the achiral
metal complex [Pd(π-allyl)Cl]2/(PhO)3P in the presence
of the chiral O-methyl cinchonidinium salt 3d .9 The
results of the double asymmetric induction by the com-
bination of a chiral PTC and chiral Pd ligand are also
described.
a
All reactions were carried out in toluene at room temperature.
The ratio of 1a :2a :base:[Pd(π-allyl)Cl]2:PTC was 100:200:150:3.5:
10, unless otherwise noted. b Isolated yield. c Determined by HPLC
d
analysis with a Daicel Chiral Pack OD-H column. The reaction
was carried out with 50% aqueous KOH (3 equiv) at 0 °C.
TABLE 2. Allylic Alk yla tion of 1a w ith Va r iou s Allylic
Aceta te 2b-ga
entry
acetate (X)
time, h
yield, %b
ee, %c
1
2
3
4
5
6
2b (X ) H)
2c (X ) Cl)
2d (X ) F)
2e (X ) NO2)
2f (X ) Me)
2g (X ) OMe)
3
7
6
5
9
89
85
83
96
93
93
91
91
96
Resu lts a n d Discu ssion
Asym m etr ic Allylic Alk yla tion of 1a w ith Allyl
Aceta te in th e P r esen ce of Ch ir a l P TCs 3a -d . The
first attempt for asymmetric Pd-mediated allylation of
1a with allyl acetate 2a was carried out in toluene in
the presence of the cinchonidinium salts 3a -d (0.1 equiv)
and various achiral phosphine or phosphite ligands
(Table 1). These representative results are shown in
Table 1 (eq 2).
47
67d
39d
23
a
All reactions were carried out in toluene at 0 °C. The ratio of
1a :2b-g:50% aq KOH:[Pd(π-allyl)Cl]2:(PhO)3P:PTC was 100:200:
300:9:0-36:10. Isolated yield. c Determined by HPLC analysis
b
d
with a Daicel Chiral Pack OD-H column. The starting material
1a was not consumed completely.
that of Ph3P, (EtO)3P, and (PhO)3P gave the desired
product 4a in 50-82% ee at the expense of the chemical
yield, respectively (entries 5-8). Furthermore, it was
revealed that the best result (82% yield, 94%ee) was
obtained when the reaction was performed at 0 °C with
3 equiv of a 50% aqueous KOH solution in the pres-
ence of 3d and (PhO)3P (entry 9). In addition, it is
revealed that 1,2-bis(diphenylphosphino)ethane mono-
oxide [DPPE(O)]11 could be employed for the preparation
of 4a with the same enantioselectivity as (PhO)3P (entry
10). From the result that (S)-4a was always obtained as
the major product in the reaction with the cinchonidine-
derived ammonium salt 3d , the Pd-catalyzed allylic
alkylation of 1a with 2a would proceed in a similar chiral
environment constructed by 3d as the PTC-catalyzed
alkylation of 1a with allyl bromide.3
Asym m etr ic Allylic Alk yla tion of 1a w ith Va r iou s
Allylic Acet a t es 2b -h Usin g t h e Ch ir a l P TC 3d .
Having established higher levels of enantioselectivity, the
allylic alkylation of 1a with some allylic substrates 2b-h
was examined using a combination of [(allyl)PdCl]2/
(PhO)3P and 3d , and the representative results are
summarized in Table 2 (eq 3).
The Pd-catalyzed reaction of 1a in the presence of 3a ,
1,2-bis(diphenylphosphino)ethane (DPPE), and solid KOH
(1.5 equiv) was completed in 6 h to give the corresponding
allylated product 4a 10a in good yield but with low enan-
tioselectivity (3% ee, entry 1). Similar reactions with
O-alkylated PTCs 3b-d afforded the same product 4a
with slightly improved enantioselectivity (entries 2-4).
We next examined the effect of Pd ligands other than
DPPE on the enantioselectivity. Whereas the addition of
n-Bu3P in place of DPPE decreased the enantioselectivity,
(8) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z. Org. Lett. 2001, 3,
149-151; Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed.
2000, 39, 3494-3497; Trost, B. M.; Surivet, J .-P. J . Am. Chem. Soc.
2000, 122, 6291-6292; Kuwano, R.; Ito, Y. J . Am. Chem. Soc. 1999,
121, 3236-3237; Trost, B. M.; Schroeder, G. M. J . Am. Chem. Soc.
1999, 121, 6759-6760; Trost, B. M.; Radinov, R.; Grenzer, E. M. J .
Am. Chem. Soc. 1997, 119, 7879-7880; Sawamura, M.; Sudoh, M.; Ito,
Y. J . Am. Chem. Soc. 1996, 118, 3309-3310; Sawamura, M.; Nagata,
H.; Sakamoto, H.; Ito, Y. J . Am. Chem. Soc. 1992, 114, 2586-2592.
(9) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett.
2001, 3, 3329-3331.
(10) (a) Corey, E. J .; Xu, E.; Noe, M. C. J . Am. Chem. Soc. 1997,
119, 12414-12415. (b) Ooi, T.; Kameda, M.; Maruoka, K. J . Am. Chem.
Soc. 1999, 121, 6519-6520. (c) Qiu, W.; Soloshonok, V. A.; Cai, C.;
Tang, X.; Hurby, V. J . Tetrahedron 2000, 56, 2577-2582. (d) O’Donnell,
M. J .; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591-594.
(11) Vladimir, V. G. Organometallics 2001, 20, 3950-3961.
J . Org. Chem, Vol. 67, No. 21, 2002 7419

Nakoji et al.
SCHEME 1
Various enantiomerically enriched allylation products
4b-h were obtained with 91-96% ee in moderate to good
yields. The allylation of 1a with γ-substituted allylic
substrate 2b-g provided selectively the corresponding
products 4b-g without accompanying regio- and (Z)-
geometrical isomers. Noteworthy is that the enantiose-
lectivity of 4b-g was not affected by the para-substituent
of the aromatic ring of 2b-g, while the reaction rate
decreased with increasing the electron-donating ability
of the substituent. In addition, similar treatment of 1a
with 1,4-diacetoxypropene 2h gave rise to the monosub-
stituted product 4h in 69% yield with 94% ee (eq 4).
the Pd/PTC dual-catalyzed allylic alkylation of 1a with
the racemic acetate 2i (eq 6).
The Pd-catalyzed reaction of 1a with 2i under the optimal
conditions described above afforded the same product,
(S)-4b, as that obtained with 2b with nearly identical
enantioselectivity (29% yield, 89% ee). The moderate
chemical yield is attributed to the production of the
regioisomer 6 (11%).12 Interestingly, the regioisomer 6
was obtained with high enantio- and diastereoselectivity
(>95% de, 85% ee). Then, expecting to synthesize 6 as a
major product, we performed the same reaction of 2i in
the presence of 3c and the chiral Pd ligand [(R)-MeO-
MOP]. Hayashi reported that the MeO-MOP ligand
promotes an inner attack of nucleophiles to the π-al-
lylpalladium(II) complex generated from 2i, producing
the terminal alkene such as 6 predominantly.12b In
contrast to their results, the (R)-MeO-MOP ligand only
promoted the generation of the linear product 4b (71%
yield, 90% ee), giving rise to 6 as a minor diastereomer
(13% yield, 90% de, 85% ee). The absolute configuration
of the C1 center of 6 is assumed to be S, the same as
that observed for other allylic acetates 4a -g. The relative
stereochemistry of 6 was determined by the chemical
transformation of 6 into the cyclic compounds 8a ,b
(Scheme 1). Namely, the sequential subjection of 6 to
hydrolysis and benzoylation gave the amido ester 7,
which was converted to the 5,6-dihydro-4H-[1,3]oxazines
8a and 8b by the reaction with NBS. The NOE experi-
ment of 8a ,b revealed that both 8a and 8b possess
(4S,5R)-configuration (Figure 1). Although the regio- and
enantioselectivity should be improved in the future, the
result suggests that the chiral Pd/PTC-mediated asym-
metric allylic alkylation would be a useful alternative to
the chiral Pd-ligand-mediated reaction for constructing
contiguous stereogenic centers.
In this case, the bis-substituted product could not be
obtained, even with excess of the imino ester 1a . To
extend the applicability of this method, we next inves-
tigated the asymmetric synthesis of the R,R-disubstituted
amino acid derivatives (eq 5).
The Pd-mediated reaction of the tert-butyl N-(4-chlo-
robenzylidene)alaninate 1b with allyl acetate 2a pro-
ceeded smoothly to afford the desired product 5 after
subjecting the crude product to subsequent hydrolysis
and benzoylation. Although the chemical yield was
moderate, due to the volatile intermediate, the enantio-
selectivity of 5 was good. The enantiomeric excess and
absolute configuration of the known products 4b, 4d , 4f,
and 5 were determined by HPLC analysis on comparison
with the authentic samples obtained from the chiral PTC-
catalyzed alkylation.10b-d The absolute configuration of
4c, 4e, 4g, and 4h was assumed to be the same as that
observed for 4b-g. In addition, it is interesting to note
that the PTC-mediated allylic alkylation of 1a was
dramatically influenced by the ratio of (PhO)3P/Pd. When
the reaction of 1a with 2b was carried out in the presence
of 1 or 2 equiv of (PhO)3P to palladium, the desired
product 4b was obtained in good yield (56-89%) with
high enantioselectivity (>95% ee). However, no desired
product 4b could be obtained without the ligand or with
more than 3 equiv of (PhO)3P to palladium.
Asym m etr ic Allylic Alk yla tion of 1a w ith Ra ce-
m ic 1-P h en yl-2-p r op en yl Aceta te. The regio- and
stereocontrol of 2b and its regioisomer 2i in the transi-
tion-metal-catalyzed allylic alkylation is an important
research topic in organometallic chemistry. To clarify the
different reactivity between 2b and 2i, we next examined
(12) (a) Fuji, K.; Ohnishi, H.; Moriyama, S.; Tanaka, K.; Kawabata,
T.; Tsubaki, K. Synlett 2000, 351-352. (b) Hayashi, T.; Kawatsura,
M.; Uozumi, Y. J . Am. Chem. Soc. 1998, 120, 1681-1687. (c) Pre´tot,
R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323-325. (d) Hayashi,
T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997, 561-562. (e)
Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1996, 118, 235-236.
7420 J . Org. Chem., Vol. 67, No. 21, 2002

Pd-Catalyzed Asymmetric Allylic Alkylation
TABLE 3. Allylic Alk yla tion of 1a w ith 2j u n d er P TC
Con d ition sa
entry
ligand
(PhO)3P
yield, %b de, %c ee 9, %d ee 10, %d
1
0
2
3
4
DPPE
DPPE(O)
(R)-BINAP(O)
(S)-BINAP(O)
(R)-BINAP(O)
97
76
61
33
33
46
70
32
33
33
0
0
51 (S,R) 42 (S,S)
57 (R,S) 77 (S,R)
72 (S,R) 70 (R,S)
43 (R,S) 55 (S,R)
5
6e
a
b
All reactions were carried out in toluene at 0 °C. Isolated
yield. c Calculated from the isolated yields. Determined by HPLC
d
F IGURE 1. NOE experiment of 8a and 8b.
analysis with a Daicel Chiral Pack AD column.
SCHEME 2. P la u sible Rea ction Mech a n ism s for
th e Asym m etr ic Allylic Alk yla tion of 1a w ith 2a -i
Med ia ted by th e Ch ir a l P TC 3d
proceeds slowly due to the severe steric hindrance and
then the isomerization from C and D into A via exchange
of the coordination site of L and X would occur more
rapidly. Consequently, the linear product 4b was ob-
tained predominantly in a highly stereoselective manner.
Du a l Asym m etr ic In d u ction in th e P r esen ce of
th e Ch ir a l P TC 3d a n d Ch ir a l P d Liga n d . Since we
have succeeded in the enantioselective synthesis of the
branch product 6, we next investigated the Pd-catalyzed
allylic alkylation of 1,3-diphenyl-2-propenyl acetate 2j
under the PTC conditions (eq 7).
Th e Rea ction Mech a n ism of th e Allylic Alk yla -
tion u n d er th e P TC Con d ition s. From the fact that
the reaction did not proceed without the palladium
catalyst and the same product (S)-4a was obtained
similarly to the asymmetric alkylation of 1a with 3a -d ,
the chiral ion-pair of the enolate of 1a and 3d , which
seems to be the most reactive nucleophile,3 would react
with the π-allylpalladium complex A, giving the chiral
product 4a with high enantioselectivity (Scheme 2). It is
known that the cationic complex B is more reactive than
the neutral complex A for the following nucleophilic
substitution.13 Therefore, if the more σ-donating ligands
such as DPPE and n-Bu3P are used, the active cationic
complex B might be formed predominantly, and any
achiral enolates as well as the chiral ion pair of the
enolate of 1a and 3d can react with B, resulting in poor
enantioselectivity. In contrast, when the more π-accept-
ing ligand such as (PhO)3P is used, the less reactive
complex A might be formed exclusively, and complete
suppression of the racemic reactions with achiral enolates
leads to the highly enantiomeric pure product.14 On the
other hand, the reaction of 2i with Pd(0) initially gener-
ates another type of π-allylpalladium complexes C and
D (L ) (PhO)3P, MOP).12b It is reasonably considered that
nucleophilic attack takes place selectively on the carbon
trans to the phosphite (or phosphine) ligand because of
its stronger trans influence than that of X (chloride or
acetate). Furthermore, the chiral ion pair of the enolate
of 1a and 3d effectively discriminates between the
racemic π-allyl complexes C and D, giving the branch
product 6 with high diastereo- and enantioselectivity.
However, the nucleophilic attack of the enolate of 1a at
the secondary carbon center of the complex D probably
In this case, there is no need to take the regioselectivity
of the reaction into consideration. Unfortunately, the
same reaction of 1a with 2j using (PhO)3P and MOP as
a Pd ligand did not proceed, resulting in recovery of the
starting material (Table 3, entry 1). Then, more effective
bidentate ligands bearing bis-phosphine and phosphine-
phosphineoxide were employed to enhance the reactivity
of the π-allylpalladium complexes. Among the ligands
examined, DPPE(O)11 ligand gave the best results (en-
tries 2 and 3), but stereoselectivities (70% de and 51%
ee) were still moderate. To overcome the problem, we
undertook the dual asymmetric inductive method using
dual chiral catalysts: chiral PTC 3d and chiral Pd ligand
[BINAP(O)]11 (entries 4-6). In fact, the enantioselectivity
of the diastereomers 9 and 1015 was enhanced by the dual
addition of the chiral PTC 3d and (R)- or (S)-BINAPO,
but the results were very complicated and could not be
explained. We should look for a more suitable combina-
tion of the chiral anion host and the chiral Pd ligand for
the dual asymmetric induction.
Con clu sion
We have succeeded in the first highly enantioselective
allylic alkylation of the prochiral nucleophile 1a by using
(13) Frost, C. G.; Howarth, J .; Williams, J . M. J . Tetrahedron:
Asymmetry 1992, 3, 1089-1122.
(14) Kuhn, O.; Mayr, H. Angew. Chem., Int. Ed. 1999, 38, 343-346.
(15) Weiss, T. D.; Helmchen, G.; Kazmaier, U. Chem. Commun.
2002, 1270-1271; Baldwin, I. C.; Williams, J . M. J .; Beckett, R. P.
Tetrahedron: Asymmetry 1995, 6, 1515-1518.
J . Org. Chem, Vol. 67, No. 21, 2002 7421

Nakoji et al.
78.81; H, 7.15; N, 3.17. A colorless oil; [R]23 ) -28° (c 1.0,
the chiral PTC 3d but not a chiral Pd ligand. The
combination of the chiral PTC 3d and achiral Pd/(PhO)3P
complex is the choice of the dual catalysts to achieve high
enantioselectivity. By the asymmetric reaction using the
dual catalysts, numerous enantiomerically enriched R-al-
lylic amino acids 4a -h could be prepared with compa-
rable to higher enantioselectivity than that of the asym-
metric alkylation of 1 with 3a or 3b at 0 °C to room
temperature. In addition, the Pd-catalyzed reaction of
1a with 1-phenyl-2-propenyl acetate 2i afforded the
branch product 6 with high enantio- and diastereoselec-
tivity (>95% de, 85% ee). This means that the Pd-
catalyzed asymmetric allylic alkylation with a chiral PTC
would be a useful alternative to the chiral Pd-ligand-
mediated reaction for constructing contiguous stereogenic
centers.
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 2.68-2.83
(m, 2H), 3.78 (s, 3H), 4.06 (dd, 1H, J ) 5.2 Hz, 7.4 Hz), 5.93
(ddd, 1H, J ) 7.4 Hz, 7.4 Hz, 15.6 Hz), 6.34 (d, 1H, J ) 15.6
Hz), 6.81 (d, 2H, J ) 8.9 Hz), 7.09-7.44 (m, 10H), 7.64 (d, 2H,
J ) 7.3 Hz); 13C NMR (126 MHz, CDCl3) δ 28.1, 37.3, 55.2,
66.3, 81.0, 113.9, 124.2, 127.1, 127.9, 128.0, 128.4, 128.5, 128.8,
130.2, 130.4, 131.8, 136.7, 139.7, 158.8, 170.2, 170.9; IR
(CHCl3) ν 1725, 1614, 1454, 1156, 969 cm-1; MS (FAB) m/z
442 (MH+, 92), 386 (60), 238 (100), 149 (77), 57 (43).
ter t-Bu tyl (2S)-6-Acetoxy-2-[(d ip h en ylm eth ylen e)a m -
in o]-4-p en ten a te (4h ). The enantioselectivity was determined
by chiral HPLC [Chiralcel OD-H column, 1% 2-propanol/
hexane, 0.55 mL/min, λ ) 254 nm, retention times: S (major)
11.5 min, R (minor) 13.5 min]. A colorless oil; [R]31 ) -70° (c
D
1
0.9, CHCl3); H NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 1.95
(s, 3H), 2.55-2.67 (m, 2H), 3.98 (dd, J ) 5.2, 7.3 Hz, 1H), 4.45
(d, J ) 5.5 Hz, 2H), 5.56-5.69 (m, 2H), 7.12-7.63 (m, 10H);
13C NMR (126 MHz, CDCl3) δ 20.8, 28.0, 36.5, 64.8, 65.6, 81.1,
126.7, 127.9, 127.9, 128.4, 128.5, 128.8, 130.2, 132.0, 136.6,
139.6, 170.3, 170.6, 170.7; IR (CHCl3) n 3029, 1729, 1445, 1154,
970 cm-1; MS (FAB) m/z 408 (MH+, 100), 352 (41), 306 (41),
238 (95), 292 (26), 238 (39), 165 (22); HRMS (FAB) calcd for
Exp er im en ta l Section
Gen er a l P r oced u r e for Asym m etr ic Allylic Alk yla tion .
ter t-Bu tyl (2S)-2-[(Dip h en ylm eth ylen e)a m in o]-5-(4-ch lo-
r op h en yl)-4-p en ten a te (4c) (En tr y 2). To a suspension of
1a (50.0 mg, 0.169 mmol), 3d (10.6 mg, 0.0169 mmol), [PdCl-
(p-C3H5)]2 (5.4 mg, 0.015 mmol), and triphenyl phosphite (21.0
mg, 0.677 mmol) in toluene (0.28 mL) were successively added
a solution of p-chlorocinnamyl acetate (35.7 mg, 0.169 mmol)
in toluene (0.56 mL) and an aqueous 50% KOH solution (66.4
mg, 0.591 mmol) at 0 °C under an argon atmosphere. After
being stirred vigorously at 0 °C for 7 h, the mixture was diluted
with ether (15 mL). The organic phase was washed with
aqueous saturated NaHCO3 (3 × 5 mL) and brine (5 mL). The
extract was dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by column chromatog-
raphy [basic silica gel, hexane/AcOEt (300/1)] to give 66.1 mg
(85%) of 4c as colorless crystals. The enantioselectivity was
determined by chiral HPLC [Chiralcel OD-H column, 0.5%
2-propanol/hexane, 1.0 mL/min, λ ) 254 nm, retention times:
C
25H30NO4 (MH+) 408.2175, found 408.2163.
ter t-Bu t yl (2S,3R)-2-[(Dip h en ylm et h ylen e)a m in o]-3-
p h en yl-4-p en ten a te 6. To a suspension of 1-phenylpropenyl
acetate (30.0 mg, 0.170 mmol), 1a (75.5 mg, 0.256 mmol), 3d
(10.7 mg, 0.0170 mmol), [Pd2(dba)3CHCl3] (16.0 mg, 0.0153
mmol), and triphenyl phosphite (9.5 mg, 0.0307 mmol) in
toluene (0.57 mL) was added an aqueous 50% KOH solution
(57.3 mg, 0.511 mmol) at 0 °C under an argon atmosphere,
and the resulting mixture was stirred vigorously at 0 °C for 3
h. After the usual workup, the crude was purified by column
chromatography [basic silica gel, hexane/AcOEt (300/1)] to give
19.8 mg (29%) of 4b and 7.6 mg (11%) of 6 as a colorless oil. 6:
The enantioselectivity was determined by chiral HPLC [Chiral-
cel OD-H column, 0.4% 2-propanol/hexane, 0.75 mL/min, λ )
254 nm, retention times: (S,R) (major) 11.7 min, (R,S) (minor)
12.4 min]. A colorless oil; [R]23 ) -165° (c 0.8, CHCl3); 1H
D
NMR (500 MHz, CDCl3) δ 1.29 (s, 9H), 4.05-4.11 (m, 1H), 4.22
(d, 1H, J ) 6.1 Hz), 5.12-5.18 (m, 2H), 6.23-6.33 (m, 1H),
6.82-7.64 (m, 15H); 13C NMR (126 MHz, CDCl3) δ 27.9, 53.7,
70.9, 81.0, 117.0, 126.4, 127.8, 127.9, 128.1, 128.2, 128.3, 128.6,
128.9, 130.1, 136.5, 137.8, 139.6, 141.3, 169.9, 170.6; IR
(CHCl3) ν 3008, 1726, 1623 cm-1; MS (FAB) m/z 412 (MH+,
S (major) 10.8 min, R (minor) 17.3 min]. Anal. Calcd for C28H28
-
ClNO2: C, 75.41; H, 6.33; Cl, 7.95; N, 3.14. Found: C, 75.12;
H, 6.45; N, 3.05. Mp 109-110 °C (hexane); [R]28 ) -32° (c
D
0.9, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 2.69-
2.84 (m, 2H), 4.08 (dd, 1H, J ) 4.9 Hz, 7.6 Hz), 6.07 (ddd, 1H,
J ) 7.6 Hz, 7.6 Hz, 15.9 Hz), 6.35 (d, 1H, J ) 15.9 Hz), 7.09-
7.66 (m, 14H); 13C NMR (126 MHz, CDCl3) δ 28.1, 37.3, 66.0,
81.2, 127.2, 127.3, 127.9, 128.0, 128.4, 128.55, 128.60, 128.8,
130.3, 131.2, 132.6, 136.0, 136.6, 139.6, 170.3, 170.8; IR
(CHCl3) ν 1726, 1622, 1486, 1450, 1155, 970 cm-1; MS (FAB)
m/z 446 (MH+, 100), 390 (92), 238 (98), 193 (35), 149 (35), 57
(36).
100), 356 (43), 310 (22), 238 (69); HRMS (FAB) calcd for C28H30
-
NO2 (MH+) 412.2277, found 412.2285.
(4S,5R,6RS)-6-Br om om eth yl-2,5-d ip h en yl-5,6-d ih yd r o-
4H-[1,3]oxa zin e-4-ca r boxylic Acid ter t-Bu tyl Ester (8a
a n d 8b) To a solution of 6 (13.4 mg, 0.033 mmol) in THF (0.5
mL) was added a 15% citric acid solution (0.10 mL) at room
temperature and the mixture was stirred for 12 h. After being
washed with ether, the mixture was neutralized with solid
K2CO3 and extracted with AcOEt. The combined extracts were
dried over Na2SO4 and concentrated in vacuo. To a solution of
the residue in THF (0.3 mL) were successively added Et3N (4.9
mg, 0.050 mmol) and benzoyl chloride (5.0 mg, 0.036 mmol)
at 0 °C. After being stirred for 5 h, the mixture was quenched
with a saturated NH4Cl solution and extracted with AcOEt.
The combined extracts were washed with a saturated NaHCO3
and brine, dried over MgSO4, and then concentrated in vacuo.
The residue was purified by column chromatography [silica
gel, hexane/AcOEt (7/1)] to give 7 (8.4 mg, 76%). To a solution
of 7 (8.4 mg, 0.024 mmol) in CH2Cl2 (0.3 mL) was added NBS
(9.7 mg, 0.055 mmol) at 0 °C and the mixture was stirred for
7 h at 50 °C. After evaporation of the solvent, the obtained
residue was purified by column chromatography [silica gel,
hexane/AcOEt (10/1)] to give 8b (5.7 mg, 53%) and 8a (3.8 mg,
ter t-Bu tyl (2S)-2-[(Dip h en ylm eth ylen e)a m in o]-5-(4-n i-
tr op h en yl)-4-p en ten a te (4e) (En tr y 4). The enantioselec-
tivity was determined by chiral HPLC [Chiralcel OD-H
column, 0.6% 2-propanol/hexane, 0.75 mL/min, λ ) 254 nm,
retention times: S (major) 16.9 min, R (minor) 21.5 min]. Anal.
Calcd for
C28H28N2O4‚5H2O: C, 73.23; H, 6.21; N, 6.10.
Found: C, 73.16; H, 6.29; N, 6.07. Brown crystals; mp 161-
162 °C (hexane/Et2O); [R]23 ) -8° (c 1.20, CHCl3); H NMR
1
D
(500 MHz, CDCl3) δ 1.44 (s, 9H), 2.77-2.87 (m, 2H), 4.12 (dd,
1H, J ) 5.2, 7.4 Hz), 6.34 (td, 1H, J ) 7.3, 15.8 Hz), 6.48 (d,
1H, J ) 15.8 Hz), 7.11-8,15 (m, 14H); 13C NMR (126 MHz,
CDCl3) δ 28.1, 37.4, 65.6, 81.4, 124.0, 126.4, 127.8, 128.0, 128.5,
128.7, 128.8, 130.4, 130.6, 132.0, 136.5, 139.4, 143.9, 146.6,
170.5; IR (CHCl3) ν 2981, 1727, 1596, 1518, 1344 cm-1; MS
(FAB) m/z 457 (MH+, 90), 401 (100), 355 (35), 238 (60).
ter t-Bu t yl (2S)-2-[(Dip h en ylm et h ylen e)a m in o]-5-(4-
m eth oxyp h en yl)-4-p en ten a te (4g) (En tr y 6). The enanti-
oselectivity was determined by chiral HPLC [Chiralcel OD-H
column, 0.5% 2-propanol/hexane, 1.0 mL/min, λ ) 254 nm,
retention times: S (major) 20.5 min, R (minor) 26.7 min]. Anal.
Calcd for C29H31NO3: C, 78.88; H, 7.08; N, 3.17. Found: C,
1
36%). 8b: a colorless oil; H NMR (500 MHz, CDCl3) d 1.50
(s, 9H), 3.21 (dd, J ) 6.7, 10.4 Hz, 1H), 3.35 (dd, J ) 7.0, 10.4
Hz, 1H), 3.61 (dd, J ) 2.4, 3.6 Hz, 1H), 4.53 (d, J ) 2.4 Hz,
1H), 4.76 (ddd, J ) 3.6, 6.7, 7.0 Hz, 1H), 7.21-7.50 (m, 8H),
7422 J . Org. Chem., Vol. 67, No. 21, 2002

Pd-Catalyzed Asymmetric Allylic Alkylation
8.05 (d, J ) 7.0 Hz, 2H); IR (CHCl3) ν 2982, 2360, 1728, 1653,
1495, 1152 cm-1; MS (FAB) m/z 432 (MH+, 84), 430 (86), 376
(60), 105 (100); HRMS (FAB) calcd for C22H2579BrNO3 430.1018,
found 430.1005. 8a : a colorless oil; 1H NMR (500 MHz, CDCl3)
δ 1.21 (s, 9H), 3.21 (dd, J ) 10.7, 11.0 Hz, 1H), 3.30 (dd, J )
5.5, 11.3 Hz, 1H), 3.56 (dd, J ) 2.5, 11.3 Hz, 1H), 4.42 (d, J )
11.0 Hz, 1H), 4.56 (ddd, J ) 2.5, 5.5 Hz, 10.7, 1H), 7.24-7.48
(m, 8H), 8.05 (d, J ) 7.3 Hz, 2H); IR (CHCl3) ν 2982, 2360,
Ack n ow led gm en t. This work was supported in part
by Grant-in-Aid for Scientific Research (C) from the
Ministry of Education, Science, Sports, and Culture,
J apan.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization for 3d , 4a , 4b, 4d , 4f, 5, 9, and
10; 1H NMR spectra for all new compounds 4c, 4e, 4g, 4h , 6,
and 8a ,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
1732, 1655, 1495, 1153 cm-1; MS (FAB) m/z 432 (MH+, 73),
79
430 (74), 376 (67), 105 (100); HRMS (FAB) calcd for C22H25
BrNO3 (MH+) 430.1018, found 430.1027.
-
J O0260645
J . Org. Chem, Vol. 67, No. 21, 2002 7423