Development of copper-mediated allylation of γ-activated-α,β-unsaturated lactam toward peptide mimetic synthesis

Article abstract of DOI:10.1016/j.tetlet.2007.03.017

Reactions of γ-activated-α,β-unsaturated lactams with allylboronate in the presence of LiOi-Pr and CuX (stoichiometric or catalytic amount) proceed in an anti-S_N2′ manner to yield α-allylated compounds that serve as a potential synthetic interm

Full text of DOI:10.1016/j.tetlet.2007.03.017

Tetrahedron Letters 48 (2007) 3221–3224
Development of copper-mediated allylation of c-activated-
a,b-unsaturated lactam toward peptide mimetic synthesis
Yoshikazu Sasaki,a,b Keiko Yamaguchi,a Takashi Tsuji,a Akira Shigenaga,a
Nobutaka Fujiib and Akira Otakaa,*
aGraduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505, Japan
bGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 15 February 2007; revised 5 March 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—Reactions of c-activated-a,b-unsaturated lactams with allylboronate in the presence of LiOi-Pr and CuX (stoichiometric
or catalytic amount) proceed in an anti-SN20 manner to yield a-allylated compounds that serve as a potential synthetic intermediate
for cis-aminoacyl-Pro mimetics.
Ó 2007 Elsevier Ltd. All rights reserved.
L
The introduction of allyl units into an organic func-
R1
P
I
I
R1
I
OAc
Organocopper
tional group serves as a versatile transformation, which
allows a molecule to be subjected to further synthetic
manipulations.1 Numerous studies on allylations of
aldehydes,2 ketones3 or imines4 with allylic metal
reagents, including catalytic and asymmetric versions,5
have appeared in the literature. Although 1,4-6 or
SN20-sense reactions7 of allylic metals in the presence
of copper salts also constitute an indispensable part of
allylation, many controversial issues regarding the
regioselectivity of the reaction (1,2- vs 1,4-addition or
SN2 vs SN20) and nature of the reagent (r-allyl vs p-allyl)
remain.8
anti-SN2' reaction
N
N
P
O
O
1
2
This
study
3 steps
R1
P
R1
P
I
B(alkyl)2
N
N
N
Suzuki
coupling
O
O
O
4
3
R1
P
R1
Lactam
opening
CO2H
NH
Recently, we prepared configuration-fixed cis-amino-
acyl-Pro dipeptide mimetics 6,9 which is a useful bio-
probe for evaluating the structure–function relation-
ships of Pro-containing peptides/proteins,10 where (Z)-
alkenes are substituted for the cis-peptide bond that is
in equilibrium with the corresponding trans-peptide
bond11 (Scheme 1). A key transformation in our synthe-
sis is the construction of a five-membered ring, which
corresponds to the Pro moiety on unsaturated lactam
1. Such five-membered ring formation involves the
incorporation of a C3 unit at the a-position of 1, fol-
P
5
cis-aminoacyl-Pro mimetics 6
Scheme 1. Outline for the synthesis of cis-aminoacyl-Pro mimetics.
lowed by intramolecular Suzuki coupling, to give bi-
cyclic lactam 5 as a crucial precursor of the (Z)-Pro
mimetic. The ‘CH2CH2CH2OAc’ group as the C3 unit
is incorporated at the a-position in regio- and diastereo-
selective manners with the aid of zinc–copper reagents12
(e.g., (IZn)2Cu(CN)[(CH2)3OAc]2Æ2LiCl) and is subse-
quently converted to the corresponding C3-borane moi-
ety via an allyl group (Scheme 1, 1 to 4 via 2 and 3).
Directly incorporating the allyl group into 1 could de-
crease the synthetic steps; however, attempted reaction
using allyl Grignard reagents in the presence of a copper
Keywords: Allylation; Copper-mediated anti-SN20; Dipeptide mimetic;
Proline.
*
Corresponding author. Tel.: +81 88 633 7283; fax: +81 88 633
9505; e-mail: aotaka@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.017

3222
Y. Sasaki et al. / Tetrahedron Letters 48 (2007) 3221–3224
salt met with failure to give desired product in 9% yield
with concomitant formation of various compounds
including a reductive product. This situation prompted
us to reconsider the feasibility of copper-mediated
SN20-type allylation, which is applicable to the Pro-
mimetic synthesis in the light of recent progress in the
allylation reaction.
other allylmetal reagents as alternatives to the Grignard
reagent.
Recently, Shibasaki’s group has disclosed the synthetic
utility of allylsilanes or allylboronates in the presence
of copper salts and chiral ligands in the allylation of
carbonyl compounds.5 Inspired by their reports, we
explored the synthetic applicability of a combination
of allylsilanes (or allylboronates) and copper salts to
the SN20-conversions. Treatment of 7a with a reagent
that consisted of allyltrimethoxysilane, tetrabutylammo-
nium difluorotriphenylsilicate (TBAT), and CuCN in
THF gave a mixture, which contained anti-SN20 product
8a (44%) and SN2 product 9a (23%) (Table 1, entry 5).
In our previous study on the anti-SN20 reaction on
unsaturated lactams,11b the addition of lithium salts into
the reaction mixture suppressed the formation of SN2
products. However, the presence of lithium salts in the
allylsilane–TBAT system inhibited the reaction, which
was also the case for the allylboronate–TBAT system
as discussed later (Table 1, entries 6 and 8). Our exten-
sive search for suitable reaction conditions using allyl-
silanes was fruitless.
c-Phosphoryloxy-a,b-unsaturated lactams13 7a–c were
selected as substrates for the examined reactions.
Although non-b-halogenated substrate 7a does not have
potential as a precursor for mimetic synthesis, it is read-
ily available. Using these substrates, we explored suit-
able reaction conditions (Table 1). Treatment of 7a
and 7b with the allyl Grignard reagent in the presence
of CuCNÆ2LiCl following methods described in the liter-
ature7b–d gave desired products 8a and 8b, respectively,
in unacceptable yields accompanied by a non-negligible
amount of reduced compound 10a or 10b (Table 1,
entries 1 and 2). The addition of ZnCl2 to the above
reaction of 7a improved the reaction outcomes, whereas
the same tuning was unsatisfactory for the reaction of 7b
(Table 1, entries 3 and 4). Therefore, we next examined
Table 1. Examination of anti-SN20 allylation with various allylmetal reagents in the presence of copper salts
OP(O)(OPh)2
R
P
X
R
P
X
R
P
X
R
P
X
Allyl Reagent
N
N
N
N
Copper Salt, Additives
O
O
O
O
Substrates
anti-SN2' products
SN2 products
Reduction products
7a (X = H, R = Me, P = Bzl)
7b (X = I, R = Me, P = DMB)
7c (X = I, R = CH2OBzl, P = DMB)
8a
8b
8c
9a
9b
9c
10a
10b
Entry Sub. Allylmetal reagenta (equiv) Cu salt (equiv) Additive(s) (equiv) Conditions
Solvent(s)
ꢀ78 °C, 30 min THF
Products (isolated yield %)
1
2
7a
7b
7a
7b
7a
7a
7a
7a
7a
7a
7a
7b
7b
7c
7c
7c
7a
7b
7c
7a
7b
7c
7b
7c
Allyl Grignard (4)
Allyl Grignard (2)
Allyl Grignard (4)
Allyl Grignard (4)
Allylsilane (4)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCl (2)
LiCl (4)
LiCl (4)
8a (43), 10a (27)
8b (9), 10b (12)
ꢀ78 °C, 30 min THF
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
ZnCl2 (4), LiCl (4) 0 °C, 30 min
ZnCl2 (4), LiCl (4) 0 °C, 30 min
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DMF
DMF
DMF
DMF
THF
8a (81), 9a (6), 10a (4)
8b (22), 9b (5), 10b (24)
8a (44), 9a (23)
TBAT (4)
TBAT (4), LiCl (4) 0 °C, 1 h
TBAT (4) 0 °C, 1 h
TBAT (4), LiCl (4) 0 °C, 1 h
0 °C, 1 h
b
Allylsilane (4)
—
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
Allylboronate (4)
8a (72), 9a (16)
b
—
TBAT (4)
TBAT (4)
TBAT (4)
TBAT (4)
TBAT (4)
TBAT (4)
TBAT (4)
TBAT (4)
TBAF (4)
TBAF (4)
TBAF (4)
LiOi-Pr (4)
LiOi-Pr (4)
LiOi-Pr (4)
LiOi-Pr (4)
LiOi-Pr (4)
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
0 °C, 1 h
rt, 6 hd
8a (72), 9a (15)c
8a (68), 9a (19)c
8a (64), 9a (8)c
8b (15), 9b (39)
8b (28), 9b (42)
8c (67), 9c (20)
8c (56), 9c (28)
8c (40), 9c (25)
8a (72), 9a (4)
CuBr (2)
CuSCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCl (2)
CuBr (2)
CuSCN (2)
CuSCN (2)
CuSCN (2)
CuCN (2)
CuCN (2)
CuCN (2)
CuCN (0.1)
CuCN (0.1)
DMF–THF 8b (61), 9b (21)
DMF–THF 8c (73), 9c (11)
THF
THF
THF
THF
THF
8a (81), 9a (1)
8b (73), 9b (24), 7b (3)
8c (72), 9c (4), 7c (17)
8b (92), 9b (4)
rt, 6 hd
rt, 2 hd
rt, 2 hd
8c (84), 9c (4), 7c (10)
a Allyl magnesium chloride (allyl Grignard), allyltrimethoxysilane (allylsilane), or pinacol 2-propenylboronic ester (allylboronate) was used.
b Starting material was recovered.
c a-Phenylated material (ca. 5% (CuCl and CuBr) and 21% (CuSCN)) was detected.
d Because the starting materials were observed after 1 h, the reaction times were increased. However, the reactions are yet to be optimized.

Y. Sasaki et al. / Tetrahedron Letters 48 (2007) 3221–3224
3223
OBn
Next, we examined the synthetic applicability of pinacol
OBn
2-propenylboronic ester as an allylboronate to the anti-
SN20 reaction. Reactions of 7a with the allylboronate in
the presence of various copper salts (CuCN, CuCl,
CuBr, or CuSCN) and TBAT gave desired 8a in moder-
ate isolated yields (64–72%) with the accompanying SN2
product (8–19%) (Table 1, entries 7, 9–11). In these reac-
tions, an a-phenyl product was also formed. Especially,
the use of CuSCN gave the phenyl product in 21% iso-
lated yield, but a good regioselectivity was observed.14
Encouraged by the fact that the desired product was
obtained in moderate yield, we attempted reactions of
7b and 7c with CuX (X = Cl, Br or CN)–TBAT–allyl-
boronate mixtures to prepare proline mimetics. Reac-
tion of 7b (Ala-Pro type) gave the anti-SN20/SN2
mixture, but the SN2 product was preferentially formed
(Table 1, entries 12 and 13). Although treatment of 7c
(Ser-Pro type) afforded the anti-SN20 product as the main
compound, the conversion efficiency and anti-SN20/SN2
selectivity remained unsatisfactory (Table 1, entries
14–16).
X
OBn
DMB
O
N
N
iv, v
i, ii
O
I
BocHN
59%
88%
CO2Me
11: X = DMB
8c
13
cis-Ser-Pro type
Z)-alkene dipeptide mimetic
iii
12: X = H (82%)
(
Scheme 2. Conversion of 8c to cis-Ser-Pro mimetic 13. Reagents and
conditions: (i) 9-BBN–H (6 equiv) in THF at room temperature for
7 h; (ii) CsF (6 equiv) and PdCl2(dppf) (10 mol %) in DMF at 50 °C for
3.5 h; (iii) TFA at 0 °C for 2 h then at room temperature for 4 h; (iv)
Me3OÆBF4 (3 equiv) and 2,6-di-t-butylpyridine (1.1 equiv) in CH2Cl2 at
room temperature for 5 h; (v) 0.1 M HCl in CH2Cl2–THF–MeOH–
H2O at 0 °C to room temperature for 12 h then Boc2O (5.4 equiv) and
Et3N (5.0 equiv) for 5 h.
tion of 7b with allylboronate (4 equiv) and LiOi-Pr
(4 equiv) in the presence of 10 mol % CuCN yielded 8b
in 92% isolated yield with concomitant formation of
9b (4%) (Table 1, entry 23). Application of this catalytic
system to the conversion of 7c also gave satisfactory
results to give the desired 8c in 84% isolated yield
(SN20/SN2 = 21:1 in Table 1, entry 24).
Hence, we reconsidered the reaction conditions in con-
nection with the formation of the a-phenyl product.
We speculated that the reaction of allylboronate with
TBAT gave a mixture of the borate and silicate, and
the remaining silicate formed of the a-phenyl product
via a phenyl copper reagent (Fig. 1). Therefore, we ini-
tially examined the use of tetrabutylammonium fluoride
(TBAF) as a non-silicate type fluoride source with the
aid of CuSCN. Reactions of 7a–c with the allylboro-
nate–CuSCN–TBAF proceeded with moderate regio-
selectivities to afford the corresponding anti-SN20
product 8a–c,15 respectively, without the accompanying
a-phenylated product (Table 1, entries 17–19). Further-
more, to improve the regioselectivity, we employed an
alkoxide (LiOi-Pr), which has been reported to effec-
tively convert the borane to the corresponding borate.5c
Fortunately, the reaction of 7a with allylboronate–
CuCN in the presence of LiOi-Pr in THF proceeded
with almost perfect selectivity to furnish 8a in 81% iso-
lated yield (anti-SN20:SN2 = 81:1) (Table 1, entry 20).
Applying this system to the reaction of 7b and 7c
improved the products distribution, albeit some of the
starting material remained (Table 1, entries 21 and 22).16
At this stage, origin of the improvement of the anti-
SN20/SN2 ratio in the use of allylboronate–CuCN–
LiOi-Pr remains to be disclosed. Analysis of reagent
formed in the reaction mixture by spectroscopic mea-
surements would give some insight to clarify the factors
responsible for the reaction outcomes.
Finally, the conversion of 8c to the Ser-Pro type alkene
dipeptide mimetic was conducted according to our pre-
vious synthetic protocol9b for the cis-Ala-Pro mimetic
(Scheme 2).
In summary, we have developed a reliable anti-SN20 allyl-
ation of c-activated-a,b-unsaturated lactams using
allylboronate and LiOi-Pr in the presence of a stoichio-
metric or catalytic amount of copper salt. Although
the reason for the observed high regioselectivity has
yet to be elucidated, the developed reactions have short-
ened the route to cis-Pro mimetics. Finally, our protocol
may provide valuable insight into the development of
copper-mediated allylation protocols on a wide variety
of substrates.
In order to demonstrate the synthetic usefulness of this
system, we planned to use a catalytic amount of CuCN
(10 mol %). It should be noted that the attempted reac-
Acknowledgements
This research was supported in part by the 21st Century
COE Program ‘Knowledge Information Infrastructure
for Genome Science’, a Grand-in-Aid for Scientific Re-
search (KAKENHI). Y.S. is grateful for the Research
Fellowships from JSPS for Young Scientists.
(n-Bu)4N
O
O
B
B
O
O
F
+
+
Ph3SiF
CuX
Allylation
(n-Bu)4N Ph3SiF2
CuX
Supplementary data
Phenylation
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
03.017.
Figure 1. Plausible explanation for the formation of the a-phenylated
product.

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Y. Sasaki et al. / Tetrahedron Letters 48 (2007) 3221–3224
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15. Relative configuration of 8b was established by the
comparison with the authentic sample in Ref. 9b.
Reduction of the halogen in 8b afforded 8b0 (N-DMB).
On the basis of both NMR analyses of 8b and 8b0
and the empirical rule mentioned below, cis-configuration
was established. To our knowledge, copper-mediated
SN20-reaction to the allyl phosphate proceeds in anti-
manner with no exceptions.7b,11a,b,13a,b Therefore, rela-
tive configuration of 8c was also tentatively assigned as
cis.
16. The use of CuCN is critical in the allylboronate–LiOi-Pr
system: reaction of 7b with CuSCN resulted in the
decrease in regioselectivity (8b/9b = 2.4:1); reaction with
CuCl did not complete the reaction (7b (25%) was
recovered).
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