Au-catalyzed cyclization of allenylsilanes. Regioselective conversion to 2-amino-4-silylmethylene γ-butyrolactone

Article abstract of DOI:10.1016/j.tetlet.2011.07.144

The Au(I)-catalyzed cyclization of an allenylglycine, which possessed a silyl group attached to the opposite side of the allenic terminus, occurred at the allenic center to produce the 2-amino-4-silylmethylenesubstituted γ-butyrolactone 2a in a highly reg

Full text of DOI:10.1016/j.tetlet.2011.07.144

Tetrahedron Letters 52 (2011) 5740–5743
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Tetrahedron Letters
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Au-catalyzed cyclization of allenylsilanes. Regioselective conversion
to 2-amino-4-silylmethylene c-butyrolactone
⇑
⇑
Takuya Okada, Kazuhiko Sakaguchi , Tetsuro Shinada, Yasufumi Ohfune
Graduate School of Science, Osaka City University, Sugimoto, Osaka 558-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 6 August 2011
The Au(I)-catalyzed cyclization of an allenylglycine, which possessed a silyl group attached to the oppo-
site side of the allenic terminus, occurred at the allenic center to produce the 2-amino-4-silylmethylene-
substituted
c
-butyrolactone 2a in a highly regio- and stereoselective manner. The presence of a silyl
Keywords:
Au-catalyzed cyclization
Allenylsilane
group at the allenic terminus is crucial for the present 5-endo-dig
c-butyrolactonization.
Ó 2011 Elsevier Ltd. All rights reserved.
c
-Butyrolactone
H
The
c-butyrolactone skeleton represents an important core
X
type A
A
type B
structure in many biologically active natural products. The devel-
opment of new methods for the synthesis of functionalized lac-
tones has received considerable attention.1 The Au-catalyzed
intramolecular cyclization of an allene is one of the useful methods
for the synthesis of not only substituted lactones but also hetero-
cyclic compounds.2 The mode of the allene cyclization can be clas-
sified into three types (Eq. 1). In most cases, the Au catalyst
promoted the cyclization reaction in an endo- or exo-mode at the
allenic terminus (type A or B) to provide various substituted oxy-
gen-, nitrogen- and sulfur-containing heterocycles. The Ag or Pd-
catalyzed lactonization of 2-allenylacetic acid also occurred at
the allenic terminus to give a d-valerolactone (X–Y = CO2, n = 1,
type A).3 The cyclization reactions of types A and B are advanta-
geous for the efficient chirality transfer from the axis chirality of
an allene to the product, whose stereochemistry can be predicted
by the steric bias of the allenyl substituent. On the other hand, only
limited examples have been reported for the type C cyclization at
the allenic center which included the pyrrole, pyrrolidine, and
isoxazole formations.4
Y
X
Y
Y
C
(n = 0,1)
(n = 2,3)
( )n
X
B
( )n
( )n
R
•
endo
exo
R
R
[Au]
ð1Þ
type C
5-endo
or exo
(n = 1)
R = alkyl or aryl
X = O, NP (P = Boc, Cbz, etc), S
Y = CO or CHR' (R' = H, alkyl, or aryl)
Y
X
R
O
O
OH
R1
HO
O
[Au]
O
TBS
TBS
•
R1
*
ð2Þ
*
R1
*
TBS
Au R2
β-silyl vinyl cation
*
5-endo
R2
R2
1
2
R
1 = H, NHBoc, OH, alkyl, aryl
R2 = alkyl, aryl
Our studies focusing on the type C cyclization commenced with
the Au-catalyzed reaction of the amino acid-containing allenylsilane
1a (racemic, >95% dr), prepared by the enolate Claisen rearrange-
ment of the
a-acyloxy-a-alkynylsilane possessing Boc-Gly as the
acyloxy group6 (Table 1). Initial attempts using AuCl or AuCl3 were
unsuccessful resulting in the recovery of the starting material (en-
tries 1 and 2). On the other hand, we found that the addition of
During the course of our recent studies regarding the Au-cata-
lyzed rearrangement of
a-acyloxy-a-alkynylsilanes, we observed
the regioselective generation of a putative b-silylvinyl cation spe-
cies at the allenic center in which the silyl group played a crucial
role as the directing group.5 Based on this experiment, we hypoth-
esized that the Au-catalyzed reaction of an allenylsilane possessing
a glycyl moiety at the opposite allenic terminus would generate
the b-silylvinyl cation, which would facilitate the internal addition
of the carboxylic acid to give the type C cyclization product (Eq. 2).
Herein, we report a novel Au-catalyzed regio- and stereoselective
K2CO3 induced the AuCl-catalyzed cyclization to give the c-butyro-
lactone 2a having a (4Z)-silylmethylidene group as a single diaste-
reomer7 (entry 3). Encouraged by this finding, further screening of
the catalyst revealed that [(Ph3PAu)3O]BF4 in CH2Cl2 underwent
smooth cyclization without K2CO3 to afford 2a in 81% yield
(dr = >20:1, entry 4). The more electrophilic Ph3PAuOTf produced
2a in poor yield (entry 5). Although AgOTf and Hg(OAc)2 showed
moderate catalytic activities, PtCl2 and PdCl2(PPh3)2 were ineffec-
tive (entries 6–9). A Brönsted acid, such as TFA, did not catalyze
the lactonization, but removed the Boc group with significant epi-
merization at C2 to give a mixture of diastereomers (dr = 4:1, entry
conversion of the allenylsilane 1 to the c-butyrolactone 2.
⇑
Corresponding authors.
E-mail address: sakaguch@sci.osaka-cu.ac.jp (K. Sakaguchi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.144

T. Okada et al. / Tetrahedron Letters 52 (2011) 5740–5743
5741
Table 1
Optimization of the reaction conditionsa
O
O
5
CO2H
NHBoc
catalyst
4
O
2
O
TBS
•
NHBoc
NHBoc
+
3
TBS
solvent, rt
TBS
3
1a
dr = >20 : 1
cis-2a
trans-2a
Entry
Catalyst
Solvent
Time (h)
trans:cis
Yield (%)
1
2
AuCl (10 mol %)
AuCl3 (5 mol %)
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Toluene
Dioxane
THF
1.5
1.5
1.5
1
2
1
16
3
40
—
—
0
0
68
3
AuCl (10 mol %)/K2CO3 (10 mol %)
[(Ph3PAu)3O]BF4 (3 mol %)
Ph3PAuCl (3 mol %)/AgOTf (3 mol %)
AgOTf (10 mol %)/i-Pr2NEt (50 mol %)
Hg(OAc)2 (5 mol %)
PtCl2 (5 mol %)
PdCl2(PPh3)2 (10 mol %)
TFA
[(Ph3PAu)3O]BF4 (3 mol %)
[(Ph3PAu)3O]BF4 (3 mol %)
[(Ph3PAu)3O]BF4 (3 mol %)
[(Ph3PAu)3O]BF4 (3 mol %)
>20:1
>20:1
15:1
>20:1
10:1
—
—
—
10:1
2:1
1.5:1
1.5:1
4b
5
81 (>95% ee)c
33
52
64
0
0
—
83
62
73
90
6
7
8
9
10
11
12
13
14
d
1.5
1.5
1
4
a
b
c
Racemic silylallenes were used for the reactions.
The optically pure 1a was used for the reaction.
The optical purity was determined by the modified Mosher’s method.
d
The product was a diastereomeric mixture (4:1) of the Boc group-removed free amine of 1a (80%).8
10).8 Upon optimization of the reaction conditions, CH2Cl2 was
found to be the most suitable solvent for the [(Ph3PAu)3O]BF4-cata-
lyzed cyclization (entries 4 and 11–14). The 1H NMR data and NOE
cyclization at C5 from the NH group (type A mode) to give the pyr-
rolidine 5 in quantitative yield (dr = >20:1, Eq. 3).10
CO2H
n-Bu
[(Ph3PAu)3O]BF4
(3 mol%)
5
CO2H
NHBoc
Boc
experiments of the
c-lactone 2a indicated that the product pos-
N
•
sessed the Z-geometry of the olefin and two contiguous stereocen-
ters at C2 and C3 with a trans relationship.9 The reaction of the
optically active (S,aS)-1a (>95% ee) under the optimized conditions
(entry 4) gave the enantio- and diastereomerically pure (2S,3S)-2a
(>95% ee),9 clearly indicating that the present transformation pro-
ceeded in a highly diastereoselective manner.
To examine the substrate scope, various allenylsilanes 1b–i
were subjected to the cyclization reaction under the optimized
conditions. All reactions occurred at the allenic center to give the
ð3Þ
CH2Cl2, rt, 1 h
quant.
n-Bu
4 (dr = >20 : 1)
5 (dr = >20 : 1)
To gain some mechanistic insights into the present lactoniza-
tion, we examined the deuterium labeling experiment using
1a,b,d (Eq. 4). These experiments indicated that a D atom was
incorporated only into the allylic C3 position. These experiments
together with the exclusive formation of the (4Z)-silylmethylid-
ene-2,3-trans-disubstituted
c-butyrolactone 2a suggested that
corresponding c-butyrolactones 2b–i in high yields in which none
the Au-catalyst activated the C3,C4 double bond from the oppo-
site face of the sterically bulky TBS group (D)11 (Scheme 1). The
subsequent anti-addition of the carboxy group to the cationic
allenic center, which is stabilized by the silyl group, would pro-
ceed in the 5-endo-dig cyclization mode to produce 2a in a dia-
stereomerically pure form via the Au species (E). It is
noteworthy that the diastereomeric mixture of the 2-hydroxy
allenylsilane 1d (dr = 1.5:1) exclusively produced the 2,3-trans-
isomer 2d (dr = >20:1). Since the D atom was not incorporated
into the C2, but into the C3 position of 2d (Eq. 4), certain epi-
merization occurred in the Au species at C3. The neighboring po-
lar functional group, such as the NHBoc or OH group syn to the
Lewis acidic Au species at C3 (E), would attribute to the exclu-
sive formation of the 2,3-trans isomers 2a,d.12
of the regio-isomers were observed (Table 2). On the other hand,
the diastereoselectivities of the products depended on their substi-
tuent patterns. The reaction of N-Boc amino acids 1b,c (dr = >20:1),
which possessed a quaternary carbon center, gave the correspond-
ing
tries 1 and 2). The reaction of 1d (dr = 1.5:1), which possessed an
OH group at the -position, exclusively gave the trans- -lactone
c-lactone 2b,c as a mixture of diastereomers, respectively, (en-
a
c
2d (dr = >20:1, entry 3). The reaction of 1f with a methyl group
at C2 afforded 2f as a mixture of diastereomers (dr = 1:1, entry
5). The Ph group at either the C2 1g or the C3-position 1h resulted
in a moderate selectivity (entries 6 and 7). However, the reaction of
1i with a sterically bulky cyclohexyl (Cy) group underwent stereo-
selective lactonization to give 2i (trans/cis = >20:1, entry 8). The
relative stereochemistries of 2a–i were determined by the 1H
NMR data and NOE experiments, and their cis to trans isomeriza-
tion experiments.9 A control experiment using the methyl ester
1j resulted in the complete recovery of the starting material with-
out loss of its dr, indicating that no epimerization occurred at both
the C2 and C4 chiral centers of 1 even under the prolonged reaction
conditions (entry 9).
O
1) CD3OD, rt
R2
1a,b (dr = > 20:1)
O
R1
1d (dr = 1.5:1)
4
2) [(Ph3PAu)3O]BF4
(3 mol%)
CH2Cl2, rt, 1 h
2
ð4Þ
TBS
3
D
2a: 55%, 2b: 81%: 2d: 69%
The regioselectivity of the Au-catalyzed cyclization to provide
-butyrolactones was apparently directed by the silyl group. In
fact, the treatment of 4, possessing a t-Bu group instead of the
TBS group, under the same reaction conditions proceeded the
On the other hand, the C2-disubstituted 2b,c and the C2
methyl analog 2f were obtained as a 1–2:1 mixture of diastereo-
mers despite the use of diastereomerically pure starting materi-
als (Table 2, entries 1,2 and 5). The 1,2-steric repulsion of the
c

5742
T. Okada et al. / Tetrahedron Letters 52 (2011) 5740–5743
Table 2
Au-catalyzed synthesis of c-butyrolactones
a
Racemic compounds were used for the reactions.
The reaction was conducted at rt for 6 h.
b
O
O
3
OH
R2
TBS
Au
3
X
1a,d
2
O
TBS
O
H
cat.Au
X
O
1
•
TBS
4
3
R1
E
D
Au
R3
2a,d, dr = >20 : 1
stabilized by the heteroatom
(X = NHBoc or OH)
5-endo-dig
1f-h
1b,c
O
R
Au
NHBoc
Me
Au
3
R3
O
O
2
TBS
O
O
O
O
O
TBS
NHBoc
3
Me
2
R
TBS
R
TBS
R
R3
Au
Au
(R = Me or Bn)
H
G
F
(R,R3 = Me, Ph or Cy)
H
2f,h,i
2b,c
Scheme 1.
nonpolar functional groups between C2 and C3 would facilitate
equilibration (F or G) by the epimerization at C3. Increased steric
bulkiness at C2 or C3 (2h and 2i, entries 7 and 8) would affect
its trans selectivity except for 2g (entry 6) whose stereochemical
outcome cannot be explained at this stage.
Further studies toward the synthesis of other heterocycles using
allenylsilanes are now in progress. Their application to the total
synthesis of
c-butyrolactone-containing natural products is
described in the following Letter.
In summary, the synthetic method for the 2,3-disubstituted c-
Acknowledgment
butyrolactones using a novel Au-catalyzed cyclization of silylalle-
nyl carboxylic acid was developed. The regioselectivity upon regio-
selective addition to the allenic center was completely directed by
This study was financially supported by
(16201045 and 19201045) for Scientific Research from the Japan
Society of the Promotion of Science (JSPS).
a Grant-in-Aid
the silyl group to give highly functionalized
c-butyrolactones.

T. Okada et al. / Tetrahedron Letters 52 (2011) 5740–5743
5743
5. Sakaguchi, K.; Okada, T.; Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2008, 49, 25–
Supplementary data
28.
6. Okada, T.; Oda, N.; Suzuki, H.; Sakaguchi, K.; Ohfune, Y. Tetrahedron Lett. 2010,
51, 3765–3768.
7. The NOEs were observed between the methyl proton and the vinyl proton in
both trans- and cis-2a.
Supplementary data (full experimental details and characteriza-
tion data of all synthetic compounds are available) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.144.
O
O
O
O
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TBS
TBS
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