N-allyl-N-tert-butyldimethylsilylamine for chiral ligand-controlled asymmetric conjugate addition to tert-butyl alkenoates

Article abstract of DOI:10.1039/b405347h

The chiral ligand controlled asymmetric conjugate addition reaction of lithium N-allyl-N-(tert-butyldimethylsilyl)amide to alkenoates proceeded smoothly to give, after protodesilylation, the corresponding 3-allylaminoalkanoates with high enantioselectivit

Full text of DOI:10.1039/b405347h

N-Allyl-N-tert-butyldimethylsilylamine for chiral ligand-controlled
asymmetric conjugate addition to tert-butyl alkenoates†
Hirohisa Doi, Takeo Sakai, Ken-ichi Yamada and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: tomioka@pharm.kyoto-u.ac.jp; Fax: +81-75-753-4604; Tel: +81-75-753-4553
Received (in Cambridge, UK) 8th April 2004, Accepted 26th May 2004
First published as an Advance Article on the web 30th June 2004
The chiral ligand controlled asymmetric conjugate addition
reaction of lithium N-allyl-N-(tert-butyldimethylsilyl)amide to
alkenoates proceeded smoothly to give, after protodesilylation,
the corresponding 3-allylaminoalkanoates with high enantiose-
lectivities in high yields. The allyl group on the nitrogen atom
was easily removable to afford 3-aminoalkanoates.
established absolute configuration as shown below. Dramatic
improvement of enantioselectivity was observed by changing a
TMS group to TES (triethylsilyl) (1c: R1 = TES) giving 4a with
83% ee in 91% yield (entry 3). A TES group was not removed on
silica gel column chromatography, but easily protodesilylated with
aqueous HF in acetonitrile at room temperature for 5 min to afford
7
1
8
4
a. TBS (tert-butyldimethylsilyl) amide 1d (R = TBS) was
Asymmetric conjugate addition of chiral lithium amides to
alkenoates has been one of the most powerful methods for the
synthesis of chiral 3-aminoalkanoates as has been extensively
much more effective to give 4a with 86% ee in 95% yield (entry 4).
The enantioselectivity was improved to 89% ee by conducting the
1
reaction at 295 °C (entry 5). TIPS (triisopropylsilyl) amide 1e (R
1
,2
studied by Davies and his group. A chiral ligand-controlled
= TIPS) was a poor nucleophile not to give a conjugate addition
3
asymmetric reaction of an achiral lithium amide has been recently
product probably because of a too much steric hindrance (entry
6).
4
reported as a new entry to this interesting field. However, this
9
method relies on the use of N-benzy-N-trimethylsilylamine as a
nitrogen source that requires hydrogenolysis for removal of the
benzyl group. We describe herein that allylamine is also a good
source of a nitrogen nucleophile in the asymmetric addition to
alkenoates, and the allyl group is easily removable by the
The allyl group of 4a was easily removed with rhodium chloride
1
0
in refluxing aqueous acetonitrile for 3 h to give (+)-(R)-5 in 87%
isolated yield without any racemisation (Scheme 2). The ster-
eochemistry of the newly created stereogenic center was thus
established to be (R).
5
,6
isomerisation reaction with a rhodium catalyst.
The asymmetric addition reactions of 1d with other acyclic and
cyclic alkenoates 2 were also controlled by 3 at 278 °C or 295 °C
in toluene to afford 4 with up to 94% ee (Scheme 3). Crotonate 2b
(R = Me) was converted to 4b in 90% yield (Table 2, entry 1). The
We began our studies with the reaction of allylamine (Scheme 1).
1
The lithium amide 1a (R = H) was in situ prepared from
allylamine with butyllithium in the presence of chiral ligand 3 in
toluene and was then treated with tert-butyl cinnamate 2a.
Although the reaction proceeded within a half hour at 278 °C to
give 4a in 64% isolated yield, the enantioselectivity was un-
fortunately almost marginal (Table 1, entry 1).
1
ee of 4b was determined to be 90% by H NMR using (S)-(2)-1,1A-
bi-2,2A-naphthol as a chiral shift reagent.11 The reaction of
The reaction of lithium N-allyl-N-trimethylsilylamide 1b (R1
=
TMS, 3 equiv) was effected by 3 (3.6 equiv) at 278 °C to give, after
purification by silica gel column chromatography, 4a with 69% ee
in 94% yield (entry 2). The absolute configuration and enantiose-
lectivity of 4a were determined by converting to 5 with the
Scheme 2 Removal of the allyl group of 4a to give 5 with the established
absolute configuration.
Scheme 1 Asymmetric reactions of lithium allylamides 1 with tert-butyl
cinnamate 2a by the mediation of 3.
Scheme 3 Asymmetric addition of 1d to 2 by the mediation of a chiral
ligand 3.
Table 1 Asymmetric addition of lithium allylamides 1 to cinnamate 2a in
toluene at 278 °C giving 4a
Table 2 Asymmetric addition of N-TBS-allylamide 1d to 2 in toluene at
Entry
1
R1
time (h)
Yield (%)
Ee (%)
295 °C giving 4‡
1
2
3
4
5
6
a
b
c
d
d
e
H
0.5
0.5
1
1
1.5
5
64
94
91
95
95
0
5
69
83
86
89
Yield
(%)
TMS
TES
TBS
TBS
TIPS
Entry
1
2
R
time (h)
4
Ee (%)
b
c
d
e
f
Me
i-Pr
1
5
b
c
d
e
90
84
88
89
82
90
76
75
94
82
a
a
2
3
a
(E)-MeCHNCH 18
1-Naph
a
Performed at 295 °C.
4
5
3
1.5
cis-f
trans-f
11
84
†
Electronic supplementary information (ESI) available: general procedure
for addition reaction, deallylation, silylation of allylamine and data for
compounds. See http://www.rsc.org/suppdata/cc/b4/b405347h/
a
Performed at 278 °C.
1
850
C h e m . C o m m u n . , 2 0 0 4 , 1 8 5 0 – 1 8 5 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

alkenoate 2c having an isopropyl terminal group (R = i-Pr) gave 4c
with 76% ee in 84% yield (entry 2). Sorbate 2d (R = (E)-
MeCHNCH) was regioselectively converted to 1,4-addition product
In summary, an external chiral ligand-controlled asymmetric
conjugate addition of allylamine to alkenoates was developed.
Since both of enantiomers 3 are available, either enantiomer of 4 is
accessible. Synthetic utility of the products is the next target.
This project was financially supported by the 21st Century
Centre of Excellence Program “Knowledge Information Infra-
structure for Genome Science” and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
4d with 75% ee in 88% yield (entry 3). The reaction of 2e (R =
1-naphthyl) gave 4e with 94% ee in 89% yield (entry 4).
Cyclopentenecarboxylate 2f was also applicable in the reaction to
give diastereoselectively cis-4f with 82% ee as a major product in
82% yield (entry 5). The minor trans-4f with 84% ee was also
produced in 11% yield. It is important to note that chiral ligand 3
was recovered in high yield and was re-used in the asymmetric
reaction without loss of selectivity.
Deallylation of 4b and cis-4f was achieved by treatment with
Wilkinson’s catalyst in refluxing aqueous acetonitrile to give
Notes and references
‡
Procedure (Table 2, entry 1): n-BuLi (3.0 mmol) was added to 1d (3.0
mmol) in toluene (8 mL) at 278 °C over 5 min. After 0.5 h, 3 (3.6 mmol)
in toluene (6 mL) was added. The mixture was stirred for 0.5 h at 278 °C,
then cooled to 295 °C. A toluene (2 mL) solution of 2b (1.0 mmol) was
added over 5 min. The mixture was stirred at 295 °C for 1.5 h and quenched
with satd. NH Cl (3 mL). After addition of satd. NaHCO (4.5 mL), the
(
2)-(S)-6 in 44% overall yield after conversion to a Cbz
12 13
derivative, and (2)-(1R,2S)-7 in 93% yield without any
racemisation. It is important to note that allylamine attacks to the
bottom face of linear and cyclic alkenoates shown as 2 giving 4.
The stereocontrolled formation of chiral 4 is predictable by using
a model (Scheme 5). Coordination of the carbonyl oxygen atom of
4
3
whole was extracted with AcOEt. The organic layer was washed with brine,
dried, and concentrated. The crude product in MeCN (30 mL) was treated
with 46% HF (3 mL) at rt for 5 min. After addition of satd. NaHCO , the
3
2
to a lithium atom in a chelate 8 may be the first event for the
mixture was extracted with AcOEt. The organic layer was washed with
brine and dried. Concentration and chromatography (AcOEt/hexane = 1/1)
reaction. Two etheral methyl groups are fixed in trans relationship
to the adjacent two phenyl groups. It is reasonable to speculate that
coordination of 2 takes place in the less hindered region avoiding
steric repulsion by the methyl groups of 3 as shown in 9.14 The
intra-complex attack of the nitrogen atom to the si-face (for
example R = Me) at the 3-position of s-cis-2 provides chiral 4 with
the observed absolute configuration.
1
gave 3 (quant. recovery) and 4b with 90% ee (determined by H NMR using
(S)-(2)-1,1A-bi-2,2A-naphthol as a chiral shift reagent).
1
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established absolute configurations.
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6
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1
1
1
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Scheme 5 Plausible stereoselection for the production of 4 from 9.
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C h e m . C o m m u n . , 2 0 0 4 , 1 8 5 0 – 1 8 5 1
1851