Highly cis- and trans-selective alkyl radical addition to α-methylene-γ-phenyl-γ-butyrolactams

Article abstract of DOI:10.1016/j.tetlet.2009.01.007

The 1,3-asymmetric induction in alkyl radical additions to α-methylene-γ-phenyl-γ-butyrolactams was investigated. The reactions of N-unsubstituted lactam using (Me₃Si)₃SiH under UV irradiation give cis-α,γ-disubstituted lactams, wher

Full text of DOI:10.1016/j.tetlet.2009.01.007

Tetrahedron Letters 50 (2009) 1301–1302
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Tetrahedron Letters
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Highly cis- and trans-selective alkyl radical addition to a-methylene-c-
phenyl-
c-butyrolactams
*
*
Tomoko Yajima , Masako Hamano, Hajime Nagano
Department of Chemistry, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-asymmetric induction in alkyl radical additions to a-methylene-c-phenyl-c-butyrolactams was
Received 5 December 2008
Revised 26 December 2008
Accepted 8 January 2009
Available online 10 January 2009
investigated. The reactions of N-unsubstituted lactam using (Me3Si)3SiH under UV irradiation give cis-
-disubstituted lactams, whereas reactions of N-pivaloyllactams using Et3B and Bu3SnH in the presence
of Yb(OTf)3 give trans- -disubstituted lactams, both with high diastereoselectivities.
Ó 2009 Published by Elsevier Ltd.
a,c
a,c
Stereocontrol in radical-mediated carbon–carbon bond-forming
reactions has been investigated with great interest, and significant
levels of diastereoselectivity have been well documented in reac-
tions involving a stereogenic center adjacent to the radical center
(1,2-asymmetric induction).1 However, there are a limited number
of reports on radical-mediated 1,3-asymmetric induction.2–4 More-
over, most of them are concerned with the preparation of one diaste-
reomer, and only a few reports are known to provide either
diastereomer efficiently.5 Herein, we report that 1,3-asymmetrically
(entry 7). On the other hand, the reaction in the presence of MgBr2-
OEt2 gave adduct 6 with high trans-selectivity (entry 8). Further-
more, the use of Yb(OTf)3 improved both the yield and the stere-
oselectivity (entry 9).
Since the combinations of N-substituent and reaction condi-
tions suitable for the diastereoselective additions were revealed,
they were applied to the reactions with various alkyl iodides. The
results are summarized in Table 2. Under the reaction conditions
of entry 3 in Table 1 (conditions A), the cis-selectivities were over
92:8 for all alkyl iodides (entries 1–4). In contrast, the reactions
using the conditions of entry 9 in Table 1 (conditions B) gave
24:76 to 14:86 trans-selectivities (entries 5–8).
induced alkyl radical additions to a-methylene-c-phenyl-c-butyro-
lactams provided both cis- and trans-products successfully, simply
by changing the combination of the N-protecting groups of the start-
ing lactams and the radical reaction conditions (Scheme 1).
Stereochemical outcome is determined at the stage of hydrogen
radical transfer from n-Bu3SnH or TTMSS to the intermediate rad-
icals (Scheme 2). Under the conditions A, the hydrogen-atom trans-
fer takes place predominantly from the less-hindered face of the
Our investigation began with the radical reaction of
a-methy-
lene- -phenyl-
c
c
-butyrolactam (1)6 with i-PrI in CH2Cl2 (Table 1).
The radical addition to lactam 1 using Et3B and n-Bu3SnH afforded
adduct 4 with cis-stereoselectivity (entry 1). Entry 2 shows that
the addition of MgBr2-OEt2 improved the yield of 4, although the
diastereoselectivity remained unchanged. For improving cis-selec-
tivity, n-Bu3SnH was replaced by (Me3Si)3SiH (TTMSS) as a H rad-
ical donor.7 The reaction of 1 under UV irradiation in the presence
of TTMSS and 2,20-azobis(isobutyronitrile) (AIBN) gave adduct 4
with higher cis-selectivity (entry 3). The radical reaction of N-(t-
butoxycarbonyl)lactam 2 using Et3B and n-Bu3SnH in the absence
of Lewis acid also proceeded to give 5 with cis-stereoselectivity
(entry 4). However, the radical addition of N-(t-butoxycar-
bonyl)lactam 2 in the presence of MgBr2–OEt2 gave the Boc-elim-
inated product 4 with trans-selectivity (entry 5). The use of BF3–
OEt2 also gave 4, but with cis-selectivity (entry 6). To prevent the
elimination of the N-substituent, N-pivaloyllactam 3 was used as
a substrate. When lactam 3 was treated under the same conditions
of entry 4, adduct 6 was obtained in 69% yield with cis-selectivity
radical center opposite to the face shielded by the c
-phenyl group.7
The more sterically demanding character of TTMSS than n-Bu3SnH
could account for the higher selectivity. BF3-OEt2 coordinates the
lactam monodentately, and does not affect the cis-selectivity.
In the case of the trans-selective reaction (conditions B), the
coordination of the carbonyl oxygens to the metal reagent during
P
N
Ph
Ph
O
P
N
Cis and trans selective
radical addition
R
cis
or
Ph
O
RI
P
N
O
trans
R
* Corresponding authors.
E-mail addresses: yajima.tomoko@ocha.ac.jp (T. Yajima), nagano.hajime@
ocha.ac.jp (H. Nagano).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.007

1302
T. Yajima et al. / Tetrahedron Letters 50 (2009) 1301–1302
Table 1
Addition of i-PrI to
a
-methylene-
c
-phenyl-
c-butyrolactams
P
P
N
P
N
i-PrI (3 equiv)
N
Ph
O
Ph
O
Ph
O
+
CH2Cl2
conditions
i-Pr
trans
i-Pr
cis
1: P = H
4: P = H
2: P = Boc
3: P = Piv
5: P = Boc
6: P = Piv
Entry
Substrate
Conditions
n-Bu3SnH (2 equiv), Et3B (1 equiv), 0 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), MgBr2–OEt2 (3 equiv), 0 °C
Product
Yield (%)
cis:transa
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
4
4
4
5
4
4
6
6
6
64
92
55
84
70
85
69
64
71
79:21
77:23
93:7
82:18
18:82
76:24
68:32
11:89
9:91
(Me3Si)3SiH (2 equiv), AIBN (0.2 equiv), h
m, rt
n-Bu3SnH (2 equiv), Et3B (1 equiv), 0 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), MgBr2–OEt2 (3 equiv), 0 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), BF3–OEt2 (3 equiv), 0 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), 0 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), MgBr2–OEt2 (3 equiv), ꢀ78 °C
n-Bu3SnH (2 equiv), Et3B (1 equiv), Yb(OTf)3 (3 equiv), ꢀ78 °C
a
Diastereomer ratios were determined by 1H NMR. The relative configuration of 4 was assigned by NOE analysis. The relative configurations of 5 and 6 were determined by
comparing the chemical shift values in 1H and 13C NMR with those of 4.
Table 2
Addition of RI to
TTMSS
a
-methylene-
c
-phenyl-
c-butyrolactams
H
N
P
N
P
R
P
N
Ph
H
RI (3 equiv)
P = H
Ph
Ph
O
N
Ph
O
Ph
O
Ph
O
O
N
H
+
CH2Cl2
R
conditions A or B
R
cis
R
trans
cis
P
N
TTMSS
Ph
O
1: P = H
7-10: P = H
11-14: P = Piv
3: P = Piv
n-Bu3SnH
a
Entry
Substrate
Conditions
R
Product Yield (%)
cis:transb
Piv
N
R
1
2
3
4
5
6
7
8
1
1
1
1
3
3
3
3
A
A
A
A
B
B
B
B
Et
7
8
9
10
11
12
13
14
75
55
62
63
75
94
66
80
98:2
93:7
94:6
92:8
14:86
20:80
20:80
24:76
O
Ph
n-Bu
t-Bu
Cyclo-hex
Et
n-Bu
t-Bu
O
N
H
P = Piv
L.A.
R
R'
O
L.A.
trans
n-Bu3SnH
Scheme 2. Diastereoselectivities in the addition of RI to a-methylene-c-phenyl-c-
Cyclo-hex
butyrolactams.
a
Conditions A; TTMSS (2 equiv), AIBN (0.2 equiv), hm, rt. Conditions B; Bu3SnH
(2 equiv), Et3B (1 equiv), Yb(OTf)3 (3 equiv), ꢀ78 °C.
b
Diastereomer ratios were determined by 1H NMR. The relative configuration of
11 was assigned by NOE analysis. The relative configurations of 7–10 and 12–14
were determined by comparing the chemical shift values in 1H and 13C NMR with
those of 4 and 11, respectively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.007.
References and notes
the hydrogen transfer may participate in the face selectivity. The
carbonyl oxygen of lactam and that of the N-protecting group
(Boc or Piv) coordinate with the Lewis acid (MgBr2–OEt2 or
Yb(OTf)3) to form a six-membered chelate. The Lewis acid coordi-
nates from the less-hindered convex face (opposite to the phenyl
group), and forces the incoming hydrogen donor to attack the rad-
ical face where the phenyl is located.
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lactam 3 using Et3B and n-Bu3SnH in the presence of Yb(OTf)3 give
trans-disubstituted lactams. Because synthetic methods for such
a,c-disubstituted lactams are scarce, this methodology provides
an efficient stereoselective synthetic route to new lactam com-
pounds. Further applications and improvements of the reaction
are now in progress, and the mechanistic details are being
resolved.
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