Structure tuning of lithium amide for asymmetric 1,4-addition to cinnamate and subsequent demasking

Article abstract of DOI:10.1016/j.tetlet.2004.10.050

Systematic structure tuning of lithium amides derived from benzyl-N-TMS-, allyl-N-TBDMS-, and diisopropylamines lead to several candidates including anthracen-9-ylmethanamine which provided high performance in the enantioselective 1,4-addition (91% ee) an

Full text of DOI:10.1016/j.tetlet.2004.10.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9261–9263
Structure tuning of lithium amide for asymmetric 1,4-addition to
cinnamate and subsequent demasking
Takeo Sakai, Hirohisa Doi, Yoshito Kawamoto, Ken-ichi Yamada and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 13 September 2004; revised 6 October 2004; accepted 12 October 2004
Available online 2 November 2004
Abstract—Systematic structure tuning of lithium amides derived from benzyl-N-TMS-, allyl-N-TBDMS-, and diisopropylamines
lead to several candidates including anthracen-9-ylmethanamine which provided high performance in the enantioselective 1,4-addi-
tion (91% ee) and following hydrogenolysis with 10% Pd/C-H in methanol to afford b-amino ester.
2
Ó 2004 Elsevier Ltd. All rights reserved.
1
We have been engaged in the chiral diether 1 -controlled
asymmetric conjugate addition reaction of N-trialkylsil-
Ph
Ph
O
n-BuLi
Ph
Ot-Bu
2
,3
4
MeO
1
OMe
yl lithium amides derived from 2 and 3 with enoates,
5
5
amine
affording b-aminoalkanoates with high enantioselectiv-
ity (Fig. 1). The total scheme constitutes two processes;
toluene
toluene
–78 ˚C, 0.5 h –78 ˚C, 0.5 h
toluene
–78 ˚C, time
6
R1 R2
the first is asymmetric conjugate addition and the
second is the demasking of N-silyl and N-organic groups
from the adducts, for example, 6 to primary amines 7
(R = R = H) (Scheme 1). A trialkylsilyl group was
readily removed from 6 during purification by silica
N
O
NH2 O
hydrogenolysis
MeOH
Ph
Ot-Bu
Ph
Ot-Bu
1
2
1
2
6 R , R = organic, SiR , H
7
3
Scheme 1. Asymmetric addition to 5 and following demasking of 6
to 7.
gel column chromatography or by HF treatment. How-
ever, the benzyl-type group of 6 (R = CH Ph) some-
1
2
times suffered from the cleavage of undesired C–N
bond by hydrogenolysis to result in the formation of
other amines, thereby providing an alternative for benz-
yl- and allylamines.
3
(
-phenylpropanoate, although an allyl-type group
R = allyl) was removed by rhodium-catalyzed isomeri-
1
In order to extract amine candidates for asymmetric
conjugate addition and hydrogenolytic or isomerization
demasking, we set up the structure 8 that contains struc-
zation. As part of our continuing effort to broaden the
scope of the asymmetric conjugate addition of lithium
amide, we are interested in the possibility of developing
7
tural features of 2–4. New amine structures 9 and 10
contain the two and three aromatic units of A–C of 8,
which might increase bulkiness for asymmetric induc-
tion and hydrogenolysis activity for selective cleavage.
Dibenzylamine 11 corresponds to the open version of
Ph
Ph
2
SiMe2But
10, which was proven to be less satisfactory. The struc-
N
N
MeO
OMe
SiMe3
H
ture 12 is positioned between 2 and 3. The structures 13
and 14 contain both features, A and D, of 2 and 4, and
are expected to be much more easily cleaved by hydro-
H
N
1
H
2
3
4
Figure 1. Chiral ligand 1 and amides 2–4.
8
genolysis than the simple benzyl group. PMP-amine
15 is the aromatic version of 4 and it is possible to be
cleaved by oxidation. These N-TMS amines with reaso-
9
Keywords: Asymmetric conjugate addition; Lithium amide; Chiral
ligand; Hydrogenolysis; Amino acid.
nably high purity were prepared from the corresponding
1
0
*
Corresponding author. Tel.: +81 757534553; fax: +81 757534604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
amine by the standard silylation procedure in high
2
yields (see Fig. 2).
,4
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.050

9262
T. Sakai et al. / Tetrahedron Letters 45 (2004) 9261–9263
72% yield (run 8). Diphenylmethylamine 13b recovered
its reactivity by removing an electron-withdrawing and
B
A
C
B
A
B
A
C
R
A
C
1
bulky TMS group to afford 6 (R , R = Ph CH, H) with
2
2
D
SiR3
R
N
H
N
H
N
H
N
H
57% ee in 73% yield (run 9). Triphenylmethylamine 14b
did not give the conjugate adduct 6, recovering 5 in 65%
yield, together with the corresponding cinnamamide as
an isolable by-product in 34% yield (run 10). PMP-
8
9a R = TMS
b R = H
10a R = TMS
10b R = H
1
1
9
1
2
A
A
A
amine 15b was found to give 6 (R , R = PMP, H) with
4% ee in 36% yield, together with the corresponding
MeO
1
D
R
R
cinnamamide in 38% yield and its conjugate adduct in
17% yield (run 11). These results indicated that a bal-
ance of steric and electronic features is the key to high
reactivity and enantioselectivity.
N
H
R
R
N
H
N
H
N
H
D
D
1
1
2a R = TMS
2b R = H
13a R = TMS
13b R = H
14a R = TMS
14b R = H
15a R = TMS
15b R = H
Figure 2. Structures 9–15 extracted systematically from the structure 8.
Handling of 10a is easier than 2 because 10a is needles of
1
mp 69.5–70.5°C. The product amine 6 (R = 9-anthra-
2
CH , R = H) is also needles of mp 109–111°C, which
2
The asymmetric conjugate addition reaction of these
lithium amides with tert-butyl cinnamate 5 was con-
ducted using 3equiv of an amine and 3.6equiv of 1 in
is enantioenriched by recrystallization from methanol
to give the amine of mp 114–115°C with >99% ee in
70% recovery yield. These are practical merits of 10a
in the use of asymmetric amination.
1
1
toluene (Scheme 1). The reaction of 9a and 10a pro-
ceeded smoothly at À78°C within a reasonable time.
Purification by silica gel column chromatography gave
the corresponding desilylated adducts 6 with 87% ee
and 91% ee in reasonably high yields (Table 1, runs 1
and 2). The ee of 6 was determined by a chiral stationary
phase HPLC (Daicel Chiralcel OD-H, hexane/isopropa-
nol = 100/1, 1.0mL/min, 254nm). The absolute configu-
ration was determined by converting to the known
Since the reasonably high enantioselectivity in the reac-
tion with 1-naphthylmethyl- and anthracen-9-ylmethyl-
amines 9a and 10a was obtained, the demasking of the
products
(
6 was examined. Hydrogenolysis of 6
R = Bn, 1-naphCH , 9-anthraCH , Ph CH, R = H)
1
2
2 2 2
was conducted in methanol at room temperature to find
out efficiency and selectivity in C–N cleavage (Table 2).
1
2
1
2
primary amine 7. Isobutenylamine 12a gave 6 with
0% ee in 73% yield, being less satisfactory than the cor-
A benzyl group in 6 (R = Bn, R = H) was a good
masking one to be selectively cleaved giving 7 in high
yields under the conditions of Pd(OH) –7atm of hydro-
5
responding allylamine 3 (run 3). Contrary to our expec-
tation TMS-amines 13a, 14a and 15a did not give the
products 6 even under the enforced higher temperature
conditions, probably due to too much bulkiness and
poor nucleophilicity (runs 4–6).
2
2
gen as well as 10% Pd/C–ordinary hydrogen atmos-
phere (runs 1 and 2). 1-Naphthylmethyl group was
easily cleaved to give 7 in 92% yield (run 3). Anthr-
acen-9-ylmethyl group of 6 with 90% ee was also cleaved
readily to give 7 with 90% optical purity in reasonable
yields (runs 4 and 5). However, by-product 16 was
obtained in less than 5% yield (Scheme 2). It is noteworthy
Other than TMS-amines, amines themselves were also
examined with respect to their reactivities. Benzylamine
1
2
b underwent the reaction at À78°C to afford 6 (R ,
2
R = Bn, H) in 64% yield, although ee was as low as
6% (run 7). Unfortunately, lithium amide prepared
from 9b was insoluble in toluene. Interestingly, 10b gave
2
Table 2. Hydrogenolysis of 6 (R = H) in MeOH at rt giving 7
a
1
1
Run 6 R (R = H) Pd
2
H
2
Time Yield
1
2
ent-6 (R , R = anthracen-9-ylmethyl, H) with 27% ee in
(
atm) (h)
(%)
1
2
3
4
5
6
PhCH
PhCH
2
20% Pd(OH)
10% Pd/C
2
7
1
7
7
1
1
24
40
24
24
24
41
94
92
92
69
81
84
2
1-naphCH
2
20% Pd(OH)
2
Table 1. The chiral diether 1-controlled asymmetric conjugate addi-
a
tion of amines to cinnamate 5 giving 6
9-anthraCH2
20% Pd(OH)2
9-anthraCH
Ph CH
2
10% Pd/C
10% Pd/C
c
Run Amine Temp (°C)
Time (h) Yield (%) ee (%)
2
1
2
3
4
5
6
7
8
9
1
1
9a
À78
0.2
1.5
1.5
6
94
90
73
0
87
91
a
The 0.1–0.2equiv (20–30% w/w) of palladium catalyst was used.
10a
12a
13a
14a
15a
À78
À78
50
À78 to rt
À78 to rt
À78 to rt
À78
nd
nd
nd
16
5
0
3
0
b
2b
0.5
2
64
72
73
0
Pd-H2
NH2 O
10b
13b
14b
15b
À78
ent-27
57
+
À78
1
NH
O
MeOH Ph
Ot-Bu
NH
O
0
1
À78 to reflux
À78 to 20
3
nd
14
Ph
Ot-Bu
Ph
Ot-Bu
3
36
1
6
R = anthracen-9-ylmethyl
R = H
7
16
a
b
c
2
Amines (3equiv) and 1 (3.6equiv) were used.
Benzylamine was used instead of TMS-amine.
nd: Not determined.
Scheme 2. Hydrogenolysis of 6 giving 7 and 16.

T. Sakai et al. / Tetrahedron Letters 45 (2004) 9261–9263
9263
that the hydrogenolysis was possible with 10% Pd/C
under hydrogen balloon conditions for 24 h shorter than
the hydrogenation time, 40h, required for the benzyl
group-come off (runs 2 and 5). Expectedly, a diphenyl-
methyl group was cleaved easily to give 7 in a good yield
Kambara, T.; Hussein, M. A.; Fujieda, H.; Iida, A.;
Tomioka, K. Tetrahedron Lett. 1998, 39, 9055–9058; (c)
Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999,
5
5, 11219–11228; (d) Kambara, T.; Tomioka, K. J. Org.
Chem. 1999, 64, 9282–9285; (e) Tomioka, K.; Fujieda, H.;
Hayashi, S.; Hussein, M. A.; Kambara, T.; Nomura, Y.;
Kanai, M.; Koga, K. Chem. Commun. 1999, 715–716; (f)
Hata, S.; Iguchi, M.; Iwasawa, T.; Yamada, K.; Tomioka,
K. Org. Lett. 2004, 6, 1721–1724; (g) Hata, S.; Iwasawa,
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1471–1475.
(
1
run 6). These hydrogenolysis reactions indicated that
0% Pd/C–ordinary atmosphere of hydrogen in metha-
nol is the conditions of choice. It is also important to
note that no racemization was observed in these hydro-
genolysis reactions of 6, indicating potential utility of
these N-masking groups in the synthetic manipulation
of 6.
6. For the leading reference of asymmetric conjugate addi-
tion of chiral lithium amide, see: Davies, S. G.; Garner, A.
C.; Nicholson, R. L.; Osborne, J.; Savory, E. D.; Smith, A.
D. Chem. Commun. 2003, 2134–2135.
. Although the reaction of 2.2equiv of LDA derived from 4
was reported to give the adduct with 68% ee, 4equiv of
LDA was found to improve the enantioselectivity up to
In conclusion, systematic survey of lithium amide struc-
tures lead to anthracen-9-ylmethylamine potentially
applicable in asymmetric conjugate addition to cinna-
mate and following hydrogenolytic demasking to b-amino
ester. Since b-amino esters are constituents of organic
7
8
3% ee.
8
. Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; John Wiley & Sons: New York, 1999.
9. (a) Tomioka, K.; Inoue, I.; Shindo, M.; Koga, K.
Tetrahedron Lett. 1990, 31, 6681–6684; (b) Taniyama,
D.; Hasegawa, M.; Tomioka, K. Tetrahedron Lett. 2000,
1
3
compounds with promising function, the journey in
1
4,15
this line will be continued in our laboratories.
41, 5533–5536; (c) Hasegawa, M.; Taniyama, D.; Tomi-
oka, K. Tetrahedron 2000, 56, 10153–10158.
Acknowledgements
1
0. These amines are commercially available except 10b,
which was prepared according to the reported procedure.
This research was partially supported by the 21st Cen-
tury COE (Center of Excellence) Program ÔKnowledge
Information Infrastructure for Genome ScienceÕ and a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.
(
a) Rai, R.; Katzenellenbogen, J. A. J. Med. Chem. 1992,
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1. The use of 3equiv of lithium amide gives the comparable
level of selectivity with the reaction in the presence of
TMSCl.
1
1
2. Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A.
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