Synthesis of α,α-disubstituted amino acids based on tandem reaction of dehydroamino acid derivatives

Article abstract of DOI:10.1016/j.tet.2004.10.104

The formation of all-substituted sp³-hybridized carbon-center was investigated via tandem reaction of dehydroamino acid derivatives. The diethylzinc-promoted reaction of dehydroamino acid derivatives with acid anhydride or π-allyl palladium complex proceeded smoothly to afford α,α-disubstituted amino acids via a radical and anionic carbon-carbon bond-forming processes. The tandem reductive reaction of N-phthaloyl dehydroalanine also proceeded effectively by using Bu₃SnH and Pd(PPh₃)₄.

Full text of DOI:10.1016/j.tet.2004.10.104

Tetrahedron 61 (2005) 385–393
Synthesis of a,a-disubstituted amino acids based on tandem
reaction of dehydroamino acid derivatives
*
Hideto Miyabe, Ryuta Asada and Yoshiji Takemoto
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 24 September 2004; accepted 28 October 2004
3
Abstract—The formation of all-substituted sp -hybridized carbon-center was investigated via tandem reaction of dehydroamino acid
derivatives. The diethylzinc-promoted reaction of dehydroamino acid derivatives with acid anhydride or p-allyl palladium complex
proceeded smoothly to afford a,a-disubstituted amino acids via a radical and anionic carbon–carbon bond-forming processes. The tandem
reductive reaction of N-phthaloyl dehydroalanine also proceeded effectively by using Bu
q 2004 Elsevier Ltd. All rights reserved.
3 3 4
SnH and Pd(PPh ) .
3
1
. Introduction
acidic property of a-hydrogen atom of 2. As an alternative
approach to a-substituted enolate anion A, we have studied
the tandem reaction of dehydroamino acid derivative 3,
providing a new and efficient method for the synthesis of
Non-proteinogenic a,a-disubstituted amino acids, which
restrict the conformational flexibility of the peptide, have
been attracting considerable attention in view of their
4
a,a-disubstituted amino acids.
1
biological and medicinal properties. Therefore, the
development of efficient methods for preparing all-
Multiple carbon–carbon bond formation based on tandem
radical reaction is of great significance from economical and
ecological points of view. In recent years, numerous radical
3
substituted sp -hybridized carbon-center has become a
1
great importance. Diphenylimino glycinate 1 is an useful
5
,6
methodologies have been reported.
However, tandem
anionic synthon for the synthesis of a-monosubstituted
amino acids, and extensive synthetic studies on the
radical and anionic reactions are not well explored.
Oshima’s group has demonstrated that tandem radical
addition-aldol condensations of enones or enals could be
2
a-alkylation of 1 have been conducted (Fig. 1). In contrast,
the difficulty of achieving the a-alkylation of a-substituted
diphenylimino esters 2 has remained unsolved due to poor
7
performed by Et B as a radical initiator. Recently, some
3
8
tandem radical and anionic reactions have been achieved.
Dehydroamino acid derivatives are well known to be
9
excellent radical acceptors. We report here in detail the
synthesis of a,a-disubstituted amino acids based on the
tandem radical and anionic reactions of dehydroamino acid
4
derivative 3. We also report the reductive reaction of
N-phthaloyl dehydroalanine using Bu SnH and Pd(PPh ) .
3 3 4
2. Results and discussion
2.1. Free radical-mediated tandem reaction of
dehydroamino acid derivative 3
Figure 1. Anionic synthon for the synthesis of amino acids.
At first, we investigated the formation of a-substituted
enolate anion A from dehydroamino acid derivative 3 by
using acid anhydrides as electrophiles (Scheme 1). The
Keywords: Radical; Palladium; Tandem; Dehydroamino acids; Amino
acids.
radical initiators of choice were Et Zn and Et B because of
2
*
Corresponding author. Tel.: C81 075 753 4610; fax: C81 075 753 4569;
e-mail: takemoto@pharm.kyoto-u.ac.jp
2
5
the exceptional tolerance of other functional groups. To a
,6
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.104

386
H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
not proceed when Et B was employed as an ethyl radical
3
source (entry 2). The failure of reaction with Et B may be
3
attributed due to the low reactivity of Et B toward the
3
1
2
radical a to an ester group. Therefore, the reaction of 3
having an a,b-unsaturated ester moiety did not proceed
when Et B was employed as an ethyl radical source. The
3
tandem reaction with acid anhydrides 5 and 6 gave the
products 9 and 10 by using Et Zn (entries 3 and 4). In
2
addition, acetyl chloride 7 also worked well under the
similar reaction conditions (entry 5).
As a major reaction pathway, the a-substituted zinc-enolate
anion C would be generated via the oxgen-initiated radical
1
3
mechanism as shown in Scheme 2. Initially, an ethyl
radical was generated from Et Zn and O , and then, the
ethyl radical added to dehydroamino acid 3 to give the
2
2
intermediate radical B. In this reaction, Et Zn acted as an
2
effective reagent for trapping the intermediate radical B to
give the zinc-enolate anion C and an ethyl radical. Recently,
the formation of zinc enolates from a,b-unsaturated esters in
diethylzinc-mediated radical reactions was reported by
8
b
Scheme 1.
Bertrand’s group.
a
Table 1. Tandem reaction of dehydroamino acid derivative 3
b
Entry
Et
n
M
Reagent
Product
Yield (%)
1
2
3
4
5
Et
2
Et
3
Et
2
Et
2
Et
2
Zn
B
Zn
Zn
Zn
4
4
5
6
7
8
63
No detection
43
41
56
9
10
8
a
2 2 2
Reactions were carried out with 3 (1 equiv), 4–7 (1.2 equiv) and Et Zn (1.5 equiv) in CH Cl .
Isolated yields after hydrolysis of diphenylimino group.
b
solution of dehydroamino acid derivative 3 and acetic
anhydride 4 (1.2 equiv) in CH Cl was added a 1.0 M
solution of Et Zn in hexane (1.5 equiv) at 0 8C (Table 1,
2.2. Combination of radical reaction and transition
metal-catalyzed reaction
2
2
2
entry 1). As expected, dehydroamino acid derivative 3
exhibited a good reactivity toward Et Zn to give the desired
On the basis of tandem acylation reaction, we next
investigated the tandem allylation reaction of 3 by using
different types of electrophiles 11a–15a (Scheme 3). In the
absence of palladium catalyst, the diethylzinc-promoted
reaction of 3 with cinnamyl bromide 11a did not give the
allylated product 16a (Table 2, entry 1). The electrophilic
2
a,a-disubstituted amino acid 8 in 63% yield, after
hydrolysis of diphenylimino moiety. A trace amount of O
2
1
0,11
was an essential source for successful reaction. Thus,
the reaction was carried out by using undegassed dry solvent
under Ar. In marked contrast, the tandem reaction of 3 did
Scheme 2.
Scheme 3.

H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
387
a
Table 2. Tandem palladium-catalyzed reaction of 3 with 11a–15a
b
Entry
Et
n
M
Catalyst
None
Reagent
Time (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
3
Et
3
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Et
2
Zn
Zn
Zn
Zn
Zn
Zn
B
11a
11a
12a
13a
14a
15a
13a
14a
13b
13c
13d
13e
13f
60
60
20
20
20
20
60
60
20
20
20
20
20
20
20
20
20
16a
16a
16a
16a
16a
16a
No detection
29
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
4
4
4
4
4
54
61
59
45
No detection
No detection
B
4
4
4
4
4
4
4
4
4
4
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
16b
16c
16d
16e
16f
16g
16d
16e
16f
40
51
61
56
47
46
68
46
41
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
13g
14d
14e
14f
a
2 3 4
Reactions were carried out with 3 (1 equiv), 11a–15a (1.5 equiv), and Et Zn (1.5 equiv) in the presence of Pd(PPh ) (0.15 equiv).
Isolated yields after hydrolysis of diphenylimino group.
b
p-allyl palladium complex has shown excellent reactivity
toward soft carbanions. Thus, we next studied the
diethylzinc-promoted reaction of 3 with p-allyl palladium
reaction proceeded smoothly even in the absence of toxic tin
hydride or heavy metals via the iodine atom-transfer radical
process as shown in Scheme 5.
1
4
complex. To a solution of dehydroamino acid derivative 3,
cinnamyl bromide 11a, and Pd(PPh3)4 (0.15 equiv) in
CH Cl was added Et Zn at 0 8C, and then the reaction
2
2
2
mixture was stirred for 60 min (entry 2). As expected, the
formation of the allylated product 16a was observed in the
presence of Pd(PPh ) , after hydrolysis of diphenylimino
3
4
moiety. To see the effect of allylic reagents, we investigated
the reactions with precursors 12a–15a. Among them,
phosphate 13a and branched acetate 14a were found to be
effective for tandem allylation reaction of 3 (entries 3–6).
The reaction of 3 with phosphate 13a proceeded smoothly in
the presence of Pd(PPh ) to give the allylated product 16a
3
4
in 61% yield, after being stirred at 0 8C for only 20 min
entry 4). The reaction with the branched acetate 14a also
gave the product 16a in 59% yield, after hydrolysis of
(
diphenylimino moiety (entry 5). The tandem allylation
reaction of 3 did not proceed when Et B was employed as an
Scheme 4.
3
ethyl radical source (entries 7 and 8). The tandem reaction
of 3 was performed with other p-allyl palladium complexes
a
Table 3. Tandem palladium-catalyzed reaction of 3 with 14a and RI
b
(
entries 9–17). The reactions of 3 with aromatic allylic
phosphates 13b–g and branched acetates 14d–f were carried
Entry
RI
Product
Yield (%)
1
2
3
4
i-PrI
17a
17b
17c
17d
56
56
58
30
out in the presence of Pd(PPh ) (0.15 equiv). As expected,
3
c-Hexyl I
c-Pentyl I
t-Bu I
4
the tandem allylation reaction proceeded smoothly to give
the a,a-disubstituted amino acids 16b–g, allowing facile
incorporation of structural variety. The present reaction is
the first example of a combination of radical reaction and
transition metal-catalyzed allylation in tandem carbon–
carbon bond-forming process.
a
Reactions were carried out with 3 (1 equiv), 14a (2.0 equiv), RI
(30 equiv), and Et Zn (3.0 equiv) in the presence of Pd(PPh
0.3 equiv).
2
3 4
)
(
b
Isolated yields after hydrolysis of diphenylimino group.
With the optimal allylic reagent 14a, three-component
reaction using several radical precursors (RI) was
examined (Scheme 4). The isopropylated amino acid
derivative 17a was obtained in 56% yield by using i-PrI
The following points should be noted for the success of the
present tandem allylation: (I) a high reactivity of Et Zn as a
radical initiator, (II) an excellent intermolecular reactivity
of dehydroamino acid derivative 3 as a radical acceptor, and
2
(
Table 3, entry 1). Other secondary alkyl radical
(III) a high reactivity of Et Zn as a trapping reagent toward
the alkoxycarbonyl-stabilized a-radical B (Scheme 2). The
precursors such as c-pentyl-I and c-hexyl-I worked
well to give the desired products 17b–c (Table 3, entries
2
reactivity of dehydroamino acid derivative 3 toward Et Zn
2
2
and 3). The reaction with a bulky tert-butyl radical also
is also important, because the reaction of electrophilic
p-allyl palladium complex E with Et Zn could give the allyl
zinc reagent as a by-product (Scheme 5).
gave the allylated amino acid 17d in 30% yield (entry 4).
These results supported the radical mechanism. A favorable
experimental feature of this radical method is that the
2
1
5

388
H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
expected that the direct comparison of 3 with 18 would lead
to informative and instructive suggestions regarding the
combination of radical reaction and transition metal-
catalyzed allylation.
The diethylzinc-promoted reaction of N-phthaloyl dehydro-
alanine 18 was investigated by using acetic anhydride as an
electrophile. In marked contrast to the excellent reactivity of
dehydroamino acid derivative 3, the tandem acylation
reaction of 18 proceeded slowly to give the desired product
1
9 in 50% yield, accompanied with a 19% yield of the
protonated product 20, after being stirred at 20 8C for 15 h.
The tandem allylation reaction of 18 with 12a was
investigated in the presence of Pd(PPh3)4 (0.15 equiv).
Although the desired allylated product 21 was obtained in
40% yield, the tandem allylation of 18 also proceeded with a
low chemical efficiency.
We also investigated the tandem allylation of 18 by using
radical precursors such as i-PrI or tert-BuI. However, the
palladium-catalyzed allylation of less reactive N-phthaloyl
dehydroalanine 18 did not proceed effectively in the
presence of alkyl iodides. The formation of the desired
products was not observed, probably due to deactivation of
Pd(PPh3)4 by alkyl iodides. As an important effect of
palladium catalyst, D. P. Curran reported the palladium (0)-
promoted radical cyclization of unsaturated a-iodocarbonyl
Scheme 5.
2.3. Reaction of N-phthaloyl dehydroalanine and its
application to tandem reductive reaction
1
6
compounds. These results indicated that Pd(PPh ) serves
3 4
as a radical initiator, and thus, the deactivation of Pd(PPh3)4
would proceed via the single-electron transfer (SET)
process from palladium (0) to alkyl iodides. In order to
In the case of dehydroamino acid derivative 3, it was
assumed that a stable 5-membered zinc-enolate anion D is
formed as a result of the coordination with nitrogen atom of
diphenylimino group. We next investigated the reaction of
N-phthaloyl dehydroalanine 18, which would not give
the stable coordinating zinc-enolate anion (Scheme 6). We
test the viability of Pd(PPh ) as a radical initiator, the
3 4
simple isopropyl radical addition to 18 was investigated
(Scheme 7). As expected, Pd(PPh ) served as a single-
9
b,d
3
4
electron transfer radical initiator to afford the isopropylated
product 22 in 35% yield. These results indicate that the
success of tandem allylation of 3 using radical precursors
reflects the excellent reactivity of 3.
Scheme 7.
The reductive aldol reactions are attractive reaction, since a
reductive method does not require preformation of
1
metal enolates or silyl enol ethers. Therefore, construction
7
Scheme 6.

H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
389
3
of all-substituted sp -hybridized carbon-center via a
reductive process is a challenging problem. As an
alternative approach to a-substituted enolate anion, we
finally investigated the reductive aldol reaction of 18
(
Scheme 8). In the presence of Pd(PPh ) , the reductive
3 4
aldol reaction of 18 with benzaldehydride was studied
Table 4). Among several reducing reagents evaluated,
Bu SnH was found to be the most effective for the reductive
(
3
aldol reaction of 18 to afford the desired product 23 in 65%
yield, accompanied with 16% yield of the protonated
product 24 (entry 1). The reaction would proceed via enolate
anion H or I generated from Pd(PPh ) and Bu SnH.
3
4
3
Scheme 9.
enolate anions from dehydroamino acid derivative 3 or
N-phthaloyl dehydroalanine 18. The diethylzinc-promoted
tandem reaction of 3 gave the a,a-disubstituted amino acids
by using acid anhydrides or p-allyl palladium complexes as
electrophiles. A remarkable feature of this reaction is the
3
construction of all-substituted sp -hybridized carbon-center
via a tandem process, which involves the sequential two
steps of carbon–carbon bond forming reactions. The
reductive reaction of 18 proceeded smoothly in the presence
of Bu SnH and Pd(PPh ) to give a,a-disubstituted amino
3
3 4
acid derivatives.
4. Experimental
4.1. General
1
13
H and C NMR spectra were recorded in CDCl3 at
5
00 MHz and at 125 MHz, respectively; chemical shifts are
measured in ppm. IR spectra were recorded using FTIR
apparatus. Mass spectra were obtained by EI, CI, or FAB
methods. Preparative TLC separations were carried out on
precoated silica gel plates (E. Merck 60F254).
Scheme 8.
Table 4. Reductive tandem reaction of 18 with benzaldehyde
a
b
4
.2. Typical experimental procedure for tandem
Entry
Reagent
Time
h)
Product (% yield)
(
reaction of dehydroamino acid derivative 3 with acid
anhydride 4–6 or acetyl chloride 7
1
2
3
4
Bu
Et
Cl(i-Pr)
(TMS) SiH
3
SnH
2
23 (65%), 24 (16%)
No reaction
No reaction
3
SiH
24
24
24
2
SiH
To a solution of 3 (1.00 g, 3.26 mmol) and acid anhydride
–6 or acetyl chloride 7 (3.91 mmol) in CH Cl (50 mL)
2 2
3
24 (72%)
4
was added Et Zn (1.0 M in hexane, 4.89 mL, 4.89 mmol) at
a
Reactions were carried out with 18 (1 equiv), reagent (1.2 equiv), and
)
2
benzaldehyde in the presence of Pd(PPh
Isolated yields.
3
4
(0.1 equiv).
0 8C. After being stirred at the same temperature for 10 min,
the reaction mixture was concentrated under reduced
pressure. The residue was diluted with THF (30 mL), and
then 1 M HCl (20 mL) was added to the reaction mixture at
b
To survey the scope of the present method, the reductive
allylation reaction of 18 was studied by using the branched
acetate 14a (Scheme 9). The allylation proceeded smoothly
to give the desired product 25 in 48% yield. In addition to
the diethylzinc-promoted tandem reactions, the reductive
reactions disclosed a broader aspect of the utility of
dehydroamino acids for the synthesis of a,a-disubstituted
amino acids.
2
0 8C. After being stirred at the same temperature for 5 min,
the reaction mixture was diluted with saturated aqueous
NaHCO and then extracted with CH Cl . The organic
phase was dried over MgSO4 and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (hexane–AcOEtZ5:1) afforded 8–10.
3
2
2
4.2.1. tert-Butyl 2-acetyl-2-aminopentanoate (8). A color-
less oil. IR (CHCl ) 3399, 1713 cm . H NMR (CDCl ) d
K1
1
3
3
2.23 (3H, s), 1.96 (1H, m), 1.86 (2H, br s), 1.77 (1H, m),
3. Conclusion
1.47 (9H, s), 1.27 (2H, br sex, JZ7.6 Hz), 0.95 (3H, t,
1
3
JZ7.6 Hz). C NMR (CDCl ) d 205.6, 171.0, 82.6, 71.3,
3
We have demonstrated the formation of a-substituted
37.8, 27.7, 25.1, 16.8, 14.3.

390
H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
4.2.2. tert-Butyl 2-amino-3-oxo-2-propylpentanoate (9).
A colorless oil. IR (CHCl ) 3400, 1713 cm . H NMR
4.3.3. (E)-tert-Butyl 2-amino-5-(4-fluorophenyl)-2-
propylpent-4-enoate (16c). A colorless oil. IR (CHCl )
K1
1
3
3
K1
3395, 1718 cm . H NMR (CDCl ) d 7.33–7.22 (2H, m),
1
(
CDCl ) d 2.64 (1H, m), 2.51 (1H, m), 1.93 (1H, m), 1.88
3
3
(
(
(
2H, br s), 1.78 (1H, m), 1.46 (9H, s), 1.25 (2H, m), 1.08
3H, t, JZ7.7 Hz), 0.95 (3H, t, JZ7.3 Hz). C NMR
6.99 (2H, br t, JZ8.6 Hz), 6.44 (1H, d, JZ15.9 Hz), 6.02
(1H, m), 2.64 (1H, dt, JZ13.4, 6.7 Hz), 2.35 (1H, dt, JZ
13.4, 8.2 Hz), 1.77 (1H, m), 1.73 (2H, br s), 1.52 (1H, m),
1
3
CDCl ) d 208.2, 171.0, 82.2, 70.9, 37.5, 30.3, 27.5, 16.6,
3
C C
4.0, 7.9. MS (CI ) m/z: 230 (MCH , 1.1), 116 (100).
1
HRMS calcd for C H NO (MCH ) 230.1756, found
1.47 (9H, s), 1.42 (1H, m), 1.23 (1H, m), 0.93 (3H, t, JZ
C
13
7.2 Hz). C NMR (CDCl ) d 176.3, 162.5 (d, JZ246 Hz),
1
2
24
3
3
2
30.1761.
133.6, 133.1, 127.9 (d, JZ7.2 Hz), 124.6, 115.7 (d, JZ
C
2 Hz), 81.3, 61.4, 43.9, 42.7, 28.3, 17.4, 14.7. MS (CI )
2
m/z: 308 (MCH , 0.6), 116 (100). HRMS calcd for
C
4.2.3. tert-Butyl 2-amino-4-methyl-3-oxo-2-propyl-
pentanoate (10). A colorless oil. IR (CHCl ) 3432, 1724,
1668 cm . H NMR (CDCl ) d 5.96 (1H, br m), 4.49 (1H,
3
br m), 2.40 (1H, m), 1.79 (1H, m), 1.61 (1H, m), 1.47 (9H,
s), 1.34 (2H, m), 1.17 (3H, d, JZ6.7 Hz), 1.16 (3H, t, JZ
6
H , 0.6), 72 (100). HRMS calcd for C H NO (MCH )
C
C H FNO (MCH ) 308.2026, found 308.2030.
18 27
2
3
K1 1
4.3.4. (E)-tert-Butyl 2-amino-5-(4-chlorophenyl)-2-
propylpent-4-enoate (16d). A colorless oil. IR (CHCl )
3
K1
413, 1717 cm . H NMR (CDCl ) d 7.31–7.20 (4H, m),
1
C
3
6
1
1
1
1
4
0
3
.7 Hz), 0.93 (3H, t, JZ7.3 Hz). MS (CI ) m/z: 244 (MC
3
C
C
.43 (1H, d, JZ15.9 Hz), 6.10 (1H, m), 2.65 (1H, dd, JZ
3.7, 6.7 Hz), 2.36 (1H, dd, JZ13.7, 8.2 Hz), 1.75 (1H, m),
.70 (2H, br s), 1.52 (1H, m), 1.47 (9H, s), 1.41 (1H, m),
1
3
25
3
2
44.1913, found 244.1908.
1
3
.23 (1H, m), 0.93 (3H, t, JZ7.2 Hz). C NMR (CDCl ) d
3
4
.3. Typical experimental procedure for tandem
75.9, 135.7, 132.9, 132.8, 128.7, 127.4, 125.4, 81.0, 61.2,
3.7, 42.4, 28.0, 17.1, 14.4. MS (CI ) m/z: 324 (MCH ,
reaction of dehydroamino acid derivative 3 with allyic
reagent 11–15
C
C
C
.5), 116 (100). HRMS calcd for C H ClNO (MCH )
24.1730, found 324.1729.
1
8
27
2
To a solution of 3 (100 mg, 0.32 mmol), allylic reagent
1
CH Cl (4 mL) was added Et Zn (1.0 M in hexane,
1–15 (0.48 mmol), and Pd(PPh ) (56 mg, 0.048 mmol) in
3 4
4.3.5. (E)-tert-Butyl 2-amino-5-(3-chlorophenyl)-2-
propylpent-4-enoate (16e). A colorless oil. IR (CHCl )
2
2
2
3
0
.48 mL, 0.48 mmol) at 0 8C. After being stirred at the
K1 1
394, 1718 cm . H NMR (CDCl ) d 7.31 (1H, s), 7.25–
3
7
3
same temperature for 20–60 min, the reaction mixture was
concentrated under reduced pressure. The residue
was diluted with THF (4 mL), and then 1 M HCl (2 mL)
was added to the reaction mixture at 20 8C. After being
stirred at the same temperature for 5 min, the reaction
.14 (3H, m), 6.41 (1H, d, JZ15.9 Hz), 6.15 (1H, m), 2.65
(1H, dd, JZ13.7, 6.7 Hz), 2.37 (1H, dd, JZ13.7, 8.4 Hz),
1
1
.76 (1H, m), 1.73 (2H, br s), 1.51 (1H, m), 1.47 (9H, s),
C
13
.42 (1H, m), 1.22 (1H, m), 0.93 (3H, t, JZ7.2 Hz).
NMR (CDCl ) d 176.1, 139.3, 134.7, 132.9, 130.0, 127.5,
126.6, 126.4, 124.6, 81.3, 61.4, 43.9, 42.6, 28.3, 17.4, 14.6.
MS (CI ) m/z: 324 (MCH , 0.6), 116 (100). HRMS calcd
3
mixture was diluted with saturated aqueous NaHCO and
3
then extracted with CH Cl . The organic phase was dried
2
C
C
2
over MgSO4 and concentrated under reduced pressure.
Purification of the residue by preparative TLC (CHCl3)
afforded 16a–g.
C
for C H ClNO (MCH ) 324.1730, found 324.1729.
1
8
27
2
4.3.6. (E)-tert-Butyl 2-amino-2-propyl-5-p-tolylpent-4-
enoate (16f). A colorless oil. IR (CHCl ) 3427,
3
K1
1
4.3.1. (E)-tert-Butyl 2-amino-5-phenyl-2-propylpent-4-
enoate (16a). A colorless oil. IR (CHCl ) 3366,
1
717 cm . H NMR (CDCl ) d 7.21 (2H, d, JZ7.6 Hz),
3
3
7.09 (2H, d, JZ7.6 Hz), 6.45 (1H, d, JZ15.6 Hz), 6.05 (1H,
m), 2.66 (1H, dd, JZ13.6, 6.6 Hz), 2.34 (1H, dd, JZ13.6,
K1
1
1
717 cm . H NMR (CDCl ) d 7.33–7.21 (5H, m), 6.48
3
(
6
(
0
1
2
1H, d, JZ15.6 Hz), 6.11 (1H, m), 2.67 (1H, dd, JZ13.4,
.4 Hz), 2.36 (1H, dd, JZ13.4, 8.5 Hz), 1.74 (1H, m), 1.68
2H, br s), 1.52 (1H, m), 1.48 (9H, s), 1.45–1.25 (2H, m),
8
(
.4 Hz), 2.32 (3H, s), 1.74 (1H, m), 1.69 (2H, br s), 1.51
1H, m), 1.47 (9H, s), 1.42 (1H, m), 1.22 (1H, m), 0.93 (3H,
1
3
t, JZ7.3 Hz). C NMR (CDCl ) d 175.9, 136.9, 134.2,
3
1
3
.93 (3H, t, JZ7.6 Hz). C NMR (CDCl ) d 176.1, 137.2,
3
133.7, 129.0, 125.8, 123.2, 80.7, 60.9, 43.5, 42.2, 27.8, 20.8,
C C
6.9, 14.2. MS (CI ) m/z: 304 (MCH , 0.6), 116 (100).
34.1, 128.5, 127.3, 126.2, 124.6, 81.0, 61.2, 43.7, 42.5,
8.0, 17.2, 14.4. MS (FAB ) m/z: 290 (MCH , 43), 234
1
HRMS calcd for C H lNO (MCH ) 304.2276, found
304.2281.
C
C
C
1
9
30
2
C
(
found 290.2123.
100). HRMS calcd for C H NO (MCH ) 290.2120,
18 28 2
4.3.7. (E)-tert-Butyl 2-amino-5-(naphthalen-2-yl)-2-
propylpent-4-enoate (16g). A colorless oil. IR (CHCl )
4.3.2. (E)-tert-Butyl 2-amino-5-(4-(trifluoromethyl)-
phenyl)-2-propylpent-4-enoate (16b). A colorless oil. IR
3
K1
1
3410, 1717 cm . H NMR (CDCl ) d 7.82–7.73 (3H, m),
3
K1 1
CHCl ) 3395, 1717 cm . H NMR (CDCl ) d 7.54 (2H, d,
(
7.67 (1H, s), 7.56 (1H, d, JZ8.6 Hz), 7.43 (2H, m), 6.65
(1H, d, JZ15.6 Hz), 6.25 (1H, m), 2.73 (1H, dd, JZ13.7,
7.0 Hz), 2.44 (1H, dd, JZ13.7, 8.9 Hz), 1.78 (1H, m), 1.71
(2H, br s), 1.57 (1H, m), 1.49 (9H, s), 1.42 (1H, m), 1.25
3
3
JZ8.2 Hz), 7.41 (2H, d, JZ8.2 Hz), 6.51 (1H, d, JZ
5.9 Hz), 6.25 (1H, m), 2.68 (1H, dd, JZ13.7, 6.7 Hz), 2.40
1H, dd, JZ13.7, 8.4 Hz), 1.75 (1H, m), 1.70 (2H, br s),
.54 (1H, m), 1.47 (9H, s), 1.42 (1H, m), 1.24 (1H, m), 0.94
1
(
1
3
1
(1H, m), 0.95 (3H, t, JZ7.2 Hz). C NMR (CDCl ) d
3
1
3
(
3H, t, JZ7.3 Hz). C NMR (CDCl ) d 175.9, 140.6, 132.6,
175.8, 134.4, 133.9, 133.4, 132.6, 127.9, 127.7, 127.5,
126.0, 125.7, 125.5, 124.8, 123.2, 80.8, 61.0, 43.6, 42.2,
3
1
2
29.2 (q, JZ32 Hz), 127.7, 126.3, 125.5, 124.2 (q, JZ
71 Hz), 81.1, 61.2, 43.7, 42.4, 28.0, 17.1, 14.4. MS (CI )
C
C C
27.8, 16.9, 14.2. MS (CI ) m/z: 340 (MCH , 1.5), 116
C
C
(100). HRMS calcd for C H lNO (MCH ) 340.2276,
found 340.2281.
m/z: 358 (MCH , 0.8), 116 (100). HRMS calcd for
C H F NO (MCH ) 358.1994, found 358.1989.
2
2
30
2
C
1
9
27
3
2

H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
391
C C
31.5, 31.2, 28.0. MS (FAB ) m/z: 318 (MCH , 45), 262
4
.4. Typical experimental procedure for tandem
C
(100). HRMS calcd for C H NO (MCH ) 318.2433,
found 318.2428.
reaction of dehydroamino acid derivative 3 with allyic
reagent 14a and radical precursor
2
0
32
2
To a solution of 3 (60 mg, 0.20 mmol), allylic reagent 14a
(
4.4.5. Ethyl 2-acetyl-2-(1,3-dioxoisoindolin-2-yl)pen-
tanoate (19). To a solution of 18 (50 mg, 0.2 mmol) and
acetic anhydride (0.07 mL, 0.71 mmol) in CH Cl (1 mL)
69 mg, 0.39 mmol), RI (5.9 mmol), and Pd(PPh ) (68 mg,
3 4
0
.059 mmol) in CH Cl (2 mL) was added Et Zn (1.0 M in
2 2 2
2
2
hexane, 0.59 mL, 0.59 mmol) at 0 8C. After being stirred at
the same temperature for 15 min, the reaction mixture was
concentrated under reduced pressure. The residue
was diluted with THF (4 mL), and then 1 M HCl (1 mL)
was added to the reaction mixture at 20 8C. After being
stirred at the same temperature for 5 min, the reaction
was added Et Zn (1.0 M in hexane, 0.41 mL, 0.41 mmol) at
2
20 8C. After being stirred at the same temperature for 15 h,
the reaction mixture was diluted with saturated aqueous
NaHCO and then extracted with AcOEt. The organic phase
3
was dried over MgSO and concentrated under reduced
4
pressure. Purification of the residue by preparative TLC
(hexane–AcOEtZ5:1) afforded 19 (32 mg, 50%) and 20
mixture was diluted with saturated aqueous NaHCO and
3
then extracted with CH Cl . The organic phase was dried
2
(10 mg, 19%). A colorless oil. IR (CHCl ) 1782,
3
2
K1
1719 cm . H NMR (CDCl ) d 7.87 (2H, m), 7.74 (2H,
1
over MgSO4 and concentrated under reduced pressure.
Purification of the residue by preparative TLC (CHCl3)
afforded 17a–d and 18.
3
m), 4.00 (2H, q, JZ7.0 Hz), 2.48 (2H, t, JZ7.6 Hz), 2.01
(3H, s), 1.42–1.28 (2H, m), 1.36 (3H, t, JZ7.0 Hz), 0.93
C
C
(
3H, t, JZ7.0 Hz). MS (EI ) m/z: 317 (M , 0.8), 229
C
4
enoate (17a). A colorless oil. IR (CHCl ) 3391, 1716 cm
.4.1. (E)-tert-Butyl 2-amino-2-isobutyl-5-phenylpent-4-
.
(100). HRMS calcd for C H NO (M ) 317.1263, found
17 19 5
K1
317.1258.
3
1
H NMR (CDCl ) d 7.35–7.18 (5H, m), 6.48 (1H, d, JZ
3
1
5.6 Hz), 6.09 (1H, m), 2.66 (1H, dd, JZ13.0, 6.3 Hz), 2.33
4.4.6. Ethyl 2-(1,3-dioxoisoindolin-2-yl)pentanoate (20).
A colorless oil. IR (CHCl ) 1739, 1715 cm . H NMR
K1
1
(
1H, dd, JZ13.0, 8.7 Hz), 1.76 (2H, m), 1.66 (2H, br s),
3
1
.53 (1H, m), 1.48 (9H, s), 0.97 (3H, d, JZ5.2 Hz), 0.90
(CDCl ) d 7.87 (2H, m), 7.74 (2H, m), 4.86 (1H, dd, JZ
3
1
3
(
3H, d, JZ5.2 Hz). C NMR (CDCl ) d 176.6, 137.2,
11.0, 4.6 Hz), 4.21 (2H, m), 2.27 (1H, m), 2.18 (1H, m), 1.34
(2H, m), 1.23 (3H, t, JZ7.0 Hz), 0.94 (3H, t, JZ7.3 Hz).
3
1
2
2
3
34.3, 128.6, 127.4, 126.2, 124.3, 81.1, 60.9, 48.3, 45.3,
8.0, 24.6, 24.4, 23.3. MS (FAB ) m/z: 304 (MCH , 38),
C
C
13
C NMR (CDCl ) d 169.5, 167.8, 134.1, 131.9, 123.5, 61.7,
3
C
48 (100). HRMS calcd for C H NO (MCH )
04.2276, found 304.2276.
C C
52.0, 30.5, 19.5, 14.0, 13.3. MS (EI ) m/z: 275 (M , 2.2),
1
9
30
2
C
202 (100). HRMS calcd for C H NO (M ) 275.1157,
found 275.1155.
1
5
17
4
4
.4.2. (E)-tert-Butyl 2-amino-2-(cyclohexylmethyl)-5-
phenylpent-4-enoate (17b). A colorless oil. IR (CHCl )
3
4.5.7. (E)-Ethyl 2-(1,3-dioxoisoindolin-2-yl)-5-phenyl-2-
propylpent-4-enoate (21). To a solution of 18 (50 mg,
0.20 mmol), allylic reagent 12a (83 mg, 0.31 mmol), and
Pd(PPh ) (36 mg, 0.03 mmol) in CH Cl (1 mL) was added
K1
390, 1715 cm . H NMR (CDCl ) d 7.35–7.17 (5H, m),
1
3
6
1
1
3
.47 (1H, d, JZ15.9 Hz), 6.08 (1H, m), 2.65 (1H, dd, JZ
3.4, 6.7 Hz), 2.33 (1H, dd, JZ13.4, 8.6 Hz), 1.76 (1H, m),
.65 (2H, br s), 1.50 (1H, m), 1.48 (9H, s), 1.45–0.88 (11H,
3
4
2
2
Et Zn (1.0 M in hexane, 0.41 mL, 0.41 mmol) at 20 8C.
2
1
3
m). C NMR (CDCl ) d 176.3, 136.9, 134.0, 128.3, 127.1,
3
After being stirred at the same temperature for 15 h, the
reaction mixture was diluted with saturated aqueous
NaHCO3 and then extracted with AcOEt. The organic
phase was dried over MgSO4 and concentrated under
reduced pressure. Purification of the residue by preparative
1
2
25.9, 124.1, 80.8, 60.6, 46.7, 44.9, 34.9, 33.8, 33.7, 27.7,
6.0 (2C), 25.9. MS (FAB ) m/z: 344 (MCH , 28), 288
C
C
C
(100). HRMS calcd for C H NO (MCH ) 344.2589,
22 34 2
found 344.2582.
TLC (CHCl ) afforded 21 (31 mg, 40%) and 20 (16 mg,
3
K1
24%). A colorless oil. IR (CHCl ) 1720, 1713 cm . H
NMR (CDCl ) d 7.78 (2H, m), 7.69 (2H, m), 7.26–7.12 (5H,
3
1
4.4.3. (E)-tert-Butyl 2-amino-2-(cyclopentylmethyl)-5-
phenylpent-4-enoate (17c). A colorless oil. IR (CHCl )
3
3
K1
410, 1716 cm . H NMR (CDCl ) d 7.36–7.20 (5H, m),
1
3
6
1
m), 6.36 (1H, d, JZ15.6 Hz), 6.14 (1H, m), 4.24 (2H, q, JZ
7.0 Hz), 3.31 (1H, dd, JZ13.7, 6.4 Hz), 3.07 (1H, dd, JZ
13.7, 7.3 Hz), 2.45 (1H, m), 2.30 (1H, m), 1.35 (2H, m), 1.24
3
.48 (1H, d, JZ15.6 Hz), 6.10 (1H, m), 2.68 (1H, dd, JZ
3.5, 6.4 Hz), 2.34 (1H, dd, JZ13.5, 8.5 Hz), 1.94–1.72
1
3
(
5H, m), 1.69 (2H, br s), 1.67–1.51 (4H, m), 1.48 (9H, s),
(3H, t, JZ7.0 Hz), 0.96 (3H, t, JZ7.3 Hz). C NMR
1
3
.17 (1H, m), 1.09 (1H, m). C NMR (CDCl ) d 176.8,
1
1
4
3
(CDCl ) d 171.0, 168.8, 137.2, 134.1, 131.5, 128.4, 127.3,
126.2, 124.4, 123.5, 123.2, 123.1, 67.1, 61.4, 38.0, 36.1,
30.5, 17.6, 14.2. MS (EI ) m/z: 391 (M , 1.0), 244 (100).
3
3
37.4, 134.5, 128.8, 127.6, 126.4, 124.7, 81.3, 61.6, 46.1,
5.0, 36.6, 34.4, 33.9, 28.3, 25.1, 25.0. MS (FAB ) m/z:
C
C
C
C
30 (MCH , 57), 274 (100). HRMS calcd for C H NO
C
HRMS calcd for C H NO (M ) 291.1783, found
291.1779.
2
1
32
2
24 25
4
C
(
MCH ) 330.2433, found 330.2437.
4
4
1
.4.4. (E)-tert-Butyl 2-amino-2-neopentyl-5-phenylpent-
-enoate (17d). A colorless oil. IR (CHCl ) 2956,
4.5.8. Ethyl 4-methyl-2-(1,3-dioxoisoindolin-2-yl)pen-
tanoate (22). To a solution of 18 (100 mg, 0.41 mmol)
and Pd(PPh ) (471 mg, 0.41 mmol) in CH Cl (2 mL) was
3
K1
715 cm . H NMR (CDCl ) d 7.34–7.20 (5H, m), 6.48
1
3
3 4
2
2
(
6
1
(
1H, d, JZ15.6 Hz), 6.05 (1H, m), 2.65 (1H, dd, JZ13.4,
added isopropyl iodide (0.40 mL, 4.1 mmol) at 20 8C. After
being stirred at the same temperature for 15 h, the reaction
mixture was diluted with saturated aqueous NaHCO and
3
then extracted with AcOEt. The organic phase was dried
over MgSO4 and concentrated under reduced pressure.
.4 Hz), 2.32 (1H, dd, JZ13.4, 8.9 Hz), 2.00 (1H, d, JZ
4.3 Hz), 1.74 (2H, br s), 1.56 (1H, d, JZ14.3 Hz), 1.49
1
3
9H, s), 1.01 (9H, s). C NMR (CDCl ) d 176.7, 137.2,
3
1
34.6, 128.6, 127.4, 126.2, 123.9, 81.3, 61.5, 52.0, 47.4,

392
H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
C
HRMS calcd for C H NO (MCH ) 364.1549, found
22 22 4
364.1544.
Purification of the residue by preparative TLC (hexane–
AcOEtZ5:1) afforded 22 (42 mg, 35%). A colorless oil. IR
K1 1
(
(
(
CHCl ) 1715 cm . H NMR (CDCl ) d 7.87 (2H, m), 7.74
2H, m), 4.94 (1H, dd, JZ11.6, 4.6 Hz), 4.20 (2H, m), 2.33
1H, m), 1.97 (1H, m), 1.50 (1H, m), 1.23 (3H, t, JZ
3
3
Acknowledgements
7
.0 Hz), 0.96 (3H, d, JZ6.4 Hz), 0.93 (3H, d, JZ6.7 Hz).
1
3
C NMR (CDCl ) d 169.8, 167.9, 134.2, 131.9, 123.5, 61.8,
3
This work was supported in part by The Japan Health
Sciences Foundation and Grant-in-Aid for Scientific
Research (B) (Y.T.) and for Young Scientists (B) (H.M.)
from the Ministry of Education, Culture, Sports, Science
and Technology of Japan, and for Reseach Grants, 21st
Century COE Program ‘Knowledge Information Infra-
structure for Genome Science’. We thank Mitsubishi
Chemical Corporation Fund (H.M.).
C
0.8, 37.2, 25.1, 23.1, 21.0, 14.0. MS (FAB ) m/z: 290
5
C
(
(
MCH , 48), 216 (100). HRMS calcd for C H NO
16 19 4
C
MCH ) 290.1393, found 290.1395.
4
2
0
.5.9. Ethyl 3-hydroxy-2-methyl-2-(1,3-dioxoisoindolin-
-yl)-3-phenylpropanoate (23). To a solution of 18 (50 mg,
.20 mmol), benzaldehyde (0.04 mL, 0.41 mmol) and
Pd(PPh3)4 (24 mg, 0.02 mmol) in CH Cl (1 mL) was
2
2
added Bu SnH (0.07 mL, 0.25 mmol) at 20 8C. After
3
being stirred at the same temperature for 2 h, the reaction
mixture was diluted with saturated aqueous NaHCO and
3
References and notes
then extracted with AcOEt. The organic phase was dried
over MgSO and concentrated under reduced pressure. After
4
1
. For recent review: (a) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517. And also see: (b)
Chinchilla, R.; Galindo, N.; N a´ jera, C. Synthesis 1999, 704.
. For some reviews: (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
being roughly removed the tin residue by flash chromato-
graphy (hexane–AcOEtZ5:1), purification of the residue by
preparative TLC (hexane–AcOEtZ5:1) afforded diastereo-
2
3
4
5
mixture of 23 (46 mg, 65%) in 9:1 ratio and 24 (8 mg, 16%).
Major isomer: a colorless oil. IR (CHCl ) 3526, 1718 cm
K1
.
H NMR (CDCl ) d 7.83–7.71 (4H, m), 7.32–7.15 (5H, m),
1
03, 3018. (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
3
1
´
. Lopez, A.; Moreno-Manas, M.; Pleixats, R.; Roglans, A.;
Ezquerra, J.; Pedregai, C. Tetrahedron 1996, 52, 8365.
. Miyabe, H.; Asada, R.; Yoshida, K.; Takemoto, Y. Synlett
3
5
.60 (1H, br s), 4.36 (1H, br s), 4.26 (2H, q, JZ7.0 Hz), 1.94
13
(
3H, s), 1.23 (3H, t, JZ7.0 Hz). C NMR (CDCl ) d 174.4,
3
2
004, 540.
1
6
3
3
68.3, 137.8, 134.5, 131.6, 128.5, 128.1, 127.7, 123.5, 73.8,
C C
5.9, 62.3, 15.7, 14.1. MS (FAB ) m/z: 354 (MCH , 21),
. For a recent review, see: (a) Renaud, P., Sibi, M. P., Eds.;
Radicals in Organic Synthesis; Wiley-VCH: Weinheim, 2001;
Vols. 1 and 2. For some examples, see: (b) Angoh, A. G.;
Clive, D. L. J. J. Chem. Soc., Chem. Commun. 1985, 941. (c)
Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang,
C.-T. J. Am. Chem. Soc. 1989, 111, 8872. (d) Marco-Contelles,
J. Chem. Commun. 1996, 2629. (e) Miyabe, H.; Fujii, K.;
Tanaka, H.; Naito, T. Chem. Commun. 2001, 831. (f) Tsuritani,
T.; Shinokubo, H.; Oshima, K. Org. Lett. 2001, 3, 2709. (g)
Sibi, M. P.; Miyabe, H. Org. Lett. 2002, 4, 3435. (h) Kitagawa,
O.; Yamada, Y.; Sugawara, A.; Taguchi, T. Org. Lett. 2002, 4,
C
36 (100). HRMS calcd for C H NO (MCH )
54.1341, found 354.1347.
2
0
20
5
4
.5.10. Ethyl 2-(1,3-dioxoisoindolin-2-yl)propanoate
K1
1
(24). A colorless oil. IR (CHCl ) 1720, 1716 cm . H
3
NMR (CDCl ) d 7.87 (2H, m), 7.75 (2H, m), 4.97 (1H, q,
3
JZ7.3 Hz), 4.21 (2H, m), 1.70 (3H, d, JZ7.3 Hz), 1.24
1
3
(
1
(
(
3H, t, JZ7.0 Hz). C NMR (CDCl ) d 169.7, 167.5, 134.1,
3
C
31.9, 123.5, 61.8, 47.5, 15.2, 14.0. MS (FAB ) m/z: 348
C
MCH , 72), 174 (100). HRMS calcd for C H NO
13 14 4
1
011. (i) Takasu, K.; Ohsato, H.; Kuroyanagi, J.; Ihara, M. J.
C
MCH ) 248.0923, found 248.0918.
Org. Chem. 2002, 67, 6001. (j) Demircan, A.; Parsons, P. J.
Eur. J. Org. Chem. 2003, 1729.
4
5
0
.5.11. (E)-Ethyl 2-methyl-2-(1,3-dioxoisoindolin-2-yl)-
-phenylpent-4-enoate (25). To a solution of 18 (32 mg,
.13 mmol), allylic reagent 14a (27 mg, 0.16 mmol), and
6. For our studies, see: (a) Ueda, M.; Miyabe, H.; Nishimura, A.;
Miyata, O.; Takemoto, Y.; Naito, T. Org. Lett. 2003, 5, 3835.
(b) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T.
J. Org. Chem. 2003, 68, 5618. (c) Miyabe, H.; Fujii, K.;
Tanaka, H.; Naito, T. Chem. Commun. 2001, 831. (d) Miyabe,
H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071.
7. (a) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett.
1988, 29, 1041. (b) Nozaki, K.; Oshima, K.; Utimoto, K. Bull.
Chem. Soc. Jpn 1991, 64, 403. (c) Chandrasekhar, S.;
Narsihmulu, C.; Reddy, N. R.; Reddy, M. S. Tetrahedron
Lett. 2003, 44, 2583.
Pd(PPh3)4 (15 mg, 0.014 mmol) in CH Cl (1 mL) was
2
added Bu SnH (0.04 mL, 0.16 mmol) at 20 8C. After being
3
stirred at the same temperature for 2 h, the reaction mixture
was diluted with saturated aqueous NaHCO3 and then
extracted with AcOEt. The organic phase was dried over
2
MgSO and concentrated under reduced pressure. After
4
being roughly removed the tin residue by flash chromato-
graphy (hexane–AcOEtZ5:1), purification of the residue by
preparative TLC (hexane–AcOEtZ5:1) afforded 25 (15 mg,
4
1
8. (a) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew.
Chem., Int. Ed. 1998, 37, 152. (b) Bazin, S.; Feray, L.; Siri, D.;
Naubron, J.-V.; Bertrand, M. P. Chem. Commun. 2002, 2506.
9. The simple radical addition to dehydroamino acid derivatives,
see: (a) Sibi, M. P.; Asano, Y.; Sausker, J. B. Angew. Chem.,
Int. Ed. 2001, 40, 1293. (b) Yim, A.-M.; Vidal, Y.; Viallefont,
P.; Martinez, J. Tetrahedron: Asymmetry 2002, 13, 503. (c)
Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J.
Tetrahedron Lett. 1999, 40, 4535. (d) Renaud, P.; Stojanovic,
8%) and 24 (9 mg, 19%). A colorless oil. IR (CHCl ) 1723,
3
K1 1
715 cm . H NMR (CDCl ) d 7.78 (2H, m), 7.70 (2H, m),
3
7
4
.26–7.15 (5H, m), 6.40 (1H, d, JZ15.6 Hz), 6.18 (1H, m),
.24 (2H, m), 3.28 (1H, dd, JZ14.0, 7.3 Hz), 3.00 (1H, dd,
1
3
JZ14.0, 7.3 Hz), 1.92 (3H, s), 1.25 (3H, t, JZ7.3 Hz). C
NMR (CDCl ) d 172.1, 168.6, 137.2, 134.3, 134.1, 131.7,
1
2
3
28.5, 127.3, 126.2, 124.2, 123.5, 123.2, 63.4, 61.6, 40.0,
2.3, 14.0. MS (FAB ) m/z: 364 (MCH , 51), 216 (100).
C
C

H. Miyabe et al. / Tetrahedron 61 (2005) 385–393
393
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Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org.
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1
1
1
1
0. Ryu and Komatsu reported that Et
initiator in the absence of O . See: Ryu, I.; Araki, F.; Minakata,
S.; Komatsu, M. Tetrahedron Lett. 1998, 39, 6335.
1. O -Effect on 1,4-addition of Et Zn to enone, see: Van der
Deen, H.; Kellogg, R. M.; Feringa, B. L. Org. Lett. 2000, 2,
593.
2. (a) Ollivier, C.; Renaud, P. Angew. Chem., Int. Ed. 2000, 39,
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2
Zn can serve as a radical
2
15. Marshall, J. A. Chem. Rev. 2000, 100, 3163.
2
2
16. Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1990, 31, 933.
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1
9
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2
Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org.
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