Pd-catalyzed stereospecific azide substitution of α,β- unsaturated γ,δ-epoxy esters with double inversion of configuration

Article abstract of DOI:10.1002/anie.200500838

(Chemical Equation Presented) Acyclic, cyclic, and optically active unsaturated γ,δ-epoxy esters are employed in a highly stereoselective synthesis of functionalized amino alcohols, amino acids, and α,α-disubstituted amino acids. The key step of the react

Full text of DOI:10.1002/anie.200500838

Communications
Synthetic Methods
stereoselective synthesis of a variety of amino alcohols, amino
acids, and quaternary amino acids, including acyclic and cyclic
congeners. This methodology involves the palladium-cata-
lyzed stereospecific azide substitution reaction of a,b-unsa-
turated g,d-epoxy esters with a double inversion of config-
uration as the key step.
DOI: 10.1002/anie.200500838
Pd-Catalyzed Stereospecific Azide Substitution of
a,b-Unsaturated g,d-Epoxy Esters with Double
Inversion of Configuration**
In connection with our recent studies on the palladium-
catalyzed stereospecific hydroxy substitution reactions of
[
5]
unsaturated g,d-epoxy esters with phenylboronic acid and
Masaaki Miyashita,* Taiku Mizutani, Genta Tadano,
Yasuhiro Iwata, Masahiro Miyazawa, and Keiji Tanino
[
6]
boric acid with a double inversion of configuration, we
anticipated that the palladium-catalyzed azide substitution
reaction of a,b-unsaturated g,d-epoxy esters with an appro-
priate azide reagent might occur by a similar p-allyl palladium
species to afford an azide substitution product with double
inversion of configuration, as shown in Scheme 1. Namely,
Over recent years, much interest has been focused on the
development of not only a stereoselective but also a practical
[
1]
methodology for the synthesis of chiral b-amino alcohols, a-
[
2]
[2–4]
amino acids, and a,a-disubstituted amino acids
(includ-
this new method involves two consecutive S 2 processes to
N
ing natural and unnatural congeners) in the context of
medicinal chemistry. Although many synthetic approaches
to these biologically important compounds have been
afford a substitution product with double inversion of
configuration in contrast with the normal S 2 epoxide-
N
[
7]
opening reactions.
Initially, we chose ethyl trans-4,5-epoxy-(2E)-octenoate
(1) as a model substrate and examined its palladium-
[
1–4]
reported,
there is still a need for a new type of method-
[
5]
ology that allows the stereospecific synthesis of functionalized
amino alcohols and amino acids that bear contiguous chiral
centers. We report herein an approach that permits the highly
catalyzed reaction with TMSN to confirm whether such a
3
reaction indeed takes place. Thus, first TMSN (2 equiv) then
3
0
Scheme 1. Pd -catalyzed stereospecific azide substitution reaction of unsaturated g,d-epoxy esters with double inversion of configuration.
TMS=trimethylsilyl,Bo c=tert-butoxycarbonyl,L =ligand.
[
*] Prof. Dr. M. Miyashita,T. Mizutani,G. Tadano,Dr. Y. Iwata,
Dr. M. Miyazawa, Dr. K. Tanino
a palladium catalyst ([Pd(PPh ) ] (10 mol%)) was added to a
3
4
+
solution of 1 in THF and the mixture was stirred at room
temperature for 20 minutes. The reaction was then quenched
with a solution of citric acid in MeOH. The azide substitution
reaction of 1 with double inversion of configuration did occur
at the g-position to afford a single syn azido alcohol 2 in 90%
yield of the isolated product after purification by chromatog-
raphy on silica gel (Scheme 2). The configuration of the
product was unambiguously determined by NOE interaction
studies of its d-lactone derivative 3, which was readily derived
Division of Chemistry
Graduate School of Science,Hokkaido University
060-0810 Sapporo (Japan)
Fax: (+81)11-706-4920
E-mail: miyasita@sci.hokudai.ac.jp
+
[
] Present Address:
Department of Chemistry
Faculty of Science,Toyama University
930-8555 Toyama (Japan)
[
**] Financial support from the Ministry of Education,Culture,Sports,
from 2 by catalytic hydrogenation in the presence of di-tert-
Science,and Technology,Japan (a Grant-in-Aid for Scientific
Research (A) (No. 12304042),a Grant-in-Aid for Scientific Research
[8]
butyl dicarbonate (Boc O) followed by lactonization with
2
PPTS in dichloroethane (Scheme 2). It should be noted that
the present palladium-catalyzed azide substitution reaction
took place not only in high yield but also with complete
stereoselectivity, thus giving rise to the single product with a
double inversion of configuration.
(
B) (No. 16350049),and a Grant-in-Aid for Scientific Research on
Priority Areas (A) “Exploitation of Multielement Cyclic Molecules”
No. 13029003)) is gratefully acknowledged.
(
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5
094
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Chemie
[
10]
epoxy-1-cylochexenecarboxylate (12).
Contrary to our
expectations, however, the reaction of 12 under the same
conditions as those for acyclic substrates was fruitless.
Namely, the reaction of 12 with TMSN (2 equiv), Pd(OAc)
3
2
(
10 mol%), and PPh (30 mol%) in THF afforded ketone 14
3
as the unexpected major product (61% yield), along with a
smaller amount of the desired product 13 (37% yield; Table 2,
entry 1). Therefore, we examined in detail the effect of a
phosphine ligand on the reaction, and it was found that the
azide substitution reaction of 12 was critically dependent on
0
Scheme 2. Pd -catalyzed azide substitution reaction of ethyl trans-4,5-
epoxy-(2E)-octenoate (1): a) TMSN (2 equiv),[Pd(PPh ) ] (10 mol%),
THF,RT,20 min (90%); b) H ,PtO ,Boc O,EtOAc,RT,5 h (84%);
3
3 4
2
2
2
c) PPTS,ClCH CH Cl,90 8C,3 h (96%). Ac =acetate,PPTS =pyridi-
2
2
nium para-toluenesulfonate,Boc =tert-butoxycarbonyl.
the nature of the phosphine ligand: The use of PnBu was
3
totally ineffective, and a large amount of the starting material
was recovered (Table 2, entry 2). Similarly, the reaction with a
bulky phosphine, such as P(C H ) , P(tolyl) , or PtBu ,
These excellent preliminary results led us to examine the
scope of the new synthetic methodology with various
substrates (Table 1). Thus, the reaction of ethyl 6-benzyloxy-
trans-4,5-epoxy-(2E)-hexenoate (4) proceeded cleanly to
furnish the syn azido alcohol 5 as a single product in 97%
6
11
3
3
3
merely resulted in the recovery of the starting material.
However, the use of P(OiPr) gave a similar result to that of
3
PPh3 (Table 2, entry 3). In contrast to these ligands, P(2-
furyl) was found to improve this
3
0
particular reaction dramatically.
Thus, the reaction of 12 with
Table 1: Pd -catalyzed azide substitution reactions of acyclic a,b-unsaturated g,d-epoxy esters with
[
a]
TMSN in THF.
3
TMSN3
(10 mol%),
(2 equiv),
and
Pd(OAc)2
P(2-furyl)3
Entry
Substrate
t
Product
[
b]
Yield [%]
syn/anti
>99:1
(30 mol%) in THF produced the
desired product 13 in 87% yield
along with 13% yield of 14
1
2
3
4
4
20 min
1h
5
7
9
97
(Table 2, entry 4). It is noteworthy
that the reaction with P(2-furyl)3
6
95
93
>1:99
>1:99
>99:1
was very fast and was completed in
5
minutes at 08C, thus producing 13
in high yield. The configuration of
3 was determined unambiguously
8
2 h
1
by X-ray crystallographic analysis
of its para-bromobenzoate deriva-
tive. In turn, we examined the
stoichiometry in which P(2-furyl)3
was added and the effect of the
solvent on the reaction, and it was
10
8 h
11 93
[a] The reaction was carried out with TMSN (2 equiv) and [Pd(PPh ) ] (10 mol%) in THF at room
3
3
4
temperature. [b] Yield of isolated product. Bn=benzyl.
yield (Table 1, entry 1). On the other hand, the reaction of a
unsaturated cis epoxy ester 6 afforded an anti azido alcohol 7
in 95% yield (Table 1, entry 2), and a benzyloxy-substituted
substrate 8 similarly produced the anti isomer 9 in 93% yield
with complete stereoselectivity (Table 1, entry 3). Further-
more, a trisubstituted unsaturated epoxy ester 10 containing a
methyl group at the g-position reacted smoothly to produce a
syn tert-azido alcohol 11 in 93% yield. It is critical to add
found eventually that the use of 25 mol% of P(2-furyl) in
3
THF gave the best result. Under these conditions, the desired
product 13 was obtained in 96% yield of isolated product and
the formation of 14 was suppressed to less than 4% (Table 2,
[
11]
entry 5).
0
Table 2: Pd -catalyzed azide substitution reactions of cyclic unsaturated
[a]
g,d-epoxy ester 12 with TMSN in THF.
3
TMSN first to the substrate in solution then the palladium
3
catalyst for a successful reaction. Thus, the palladium-
catalyzed azide substitution reaction of acyclic unsaturated
g,d-epoxy esters was shown to occur stereospecifically at the
g-position with complete stereoselectivity, namely, with
double inversion of configuration, regardless of the config-
uration and substitution pattern of the epoxide substrates.
Next, we focused on the azide substitution reaction of
cyclic unsaturated epoxy esters, since Tsuda, Saegusa, and co-
Entry
Phosphine
T [8C]
t
Yield [%]
13
14
1
2
3
4
PPh3
PnBu3
P(OiPr)3
P(2-furyl)3
RT
5 min
4 h
5 min
5 min
5 min
37
<2
39
87
96
61
10
57
13
4
0!50
0
0
0
0
workers reported that the Pd -catalyzed reaction of an a,b-
unsaturated g,d-epoxy ester containing a cyclohexane ring
[
b]
5
P(2-furyl)
3
with nitrogen nucleophiles did not produce the corresponding
substitution products at all. To probe the behavior of cyclic
substrates, we initially examined the reaction of methyl 3,4-
[
a] The reaction was carried out by adding a premixed solution of
[
9]
Pd(OAc) (5 mol%) and P(2-furyl) (30 mol%) in THF. [b] The reaction
was carried out with 25 mol% of P(2-furyl)3.
2
3
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Communications
We then applied these optimized conditions to various
To demonstrate the synthetic potential of the current
method, we performed a stereospecific synthesis of both (R)-
and (S)-N-tert-butoxycarbonyl-a-methylglutamic acid g-ethyl
ester (24 and 26, respectively; Scheme 3). Thus, treatment of
the diene ester 21, which is readily derived from ethyl (S)-
lactate, with meta-chloroperoxybenzoic acid
[
12]
cyclic substrates (Table 3). Both the Z-unsaturated ester 17
[
12]
and the cyclic E-unsaturated g,d-epoxy ester 15 (as seen
previously) were found to react smoothly under these
conditions (Table 3, entries 2 and 1, respectively), thus
0
[a]
(mCPBA) in CH Cl led to unsaturated b-
2 2
Table 3: Pd -catalyzed azide substitution reactions of cyclic unsaturated epoxy esters with TMSN .
3
epoxy ester 22 being obtained as a single
product in quantitative yield. When the
unsaturated epoxy ester 22 was subjected to
the palladium-catalyzed azide substitution
reaction under the conditions employed for
acyclic substrates, azido alcohol 23 was
produced exclusively in 93% yield with
double inversion of configuration. In con-
trast, the reaction of 22 with NaN3 and
Entry
Substrate
Ligand
Solvent t [h]
Product
Yield [%]
[
b]
1
15 P(2-furyl)3 THF
17 P(2-furyl)3 THF
19 P(2-furyl)3 THF
1
1
16 98
2
18 quant.
[
Ti(OEt) ] in DMF under modified Sharp-
4
[
15]
3
4
4
6
20 trace
20 92
less conditions
proceeded through an
SN2 process to afford the single azido alco-
hol 25 in 97% yield. These products were
efficiently transformed into 24 and 26 by the
two-step reaction sequence of 1) concom-
itant hydrogenation of the double bond and
the azido group over the Adams catalyst in
[
c]
19 PPh3
DMF
[
(
a] The reaction was carried out by adding a mixture of Pd(OAc)2 (5 mol%) and the phosphine
25 mol%) in THF to a solution of each substrate and TMSN (2 equiv) in THF at room temperature.
3
[
b] After the reaction mixture had been stirred for 50 min at room temperature,Pd(OAc) 2 (5 mol%) and
the phosphine (25 mol%) were added and then the mixture was stirred for an additional 10 min at room
temperature. [c] The reaction was carried out in DMF at 508C using TMSN (2 equiv) and [Pd(PPh ) ]
[
8]
3
3
4
EtOAc in the presence of Boc O and 2)
2
(
10 mol%); [Pd(PPh ) ] (10 mol%) was added after 2.5 and 4.5 h,respectively. TBS =tert-butyldime-
3 4
oxidative cleavage of the diol moiety with
thylsilyl,quant. =quantitative yield.
[16]
RuCl and NaIO in CCl /H O/CH CN.
3
4
4
2
3
The two enantiomers 24 and 26 were
efficiently and highly stereoselectively prepared starting
from the same compound 21 by applying two contrasting
azide substitution reactions.
In summary, we have developed a palladium-catalyzed
azide substitution reaction of a,b-unsaturated g,d-epoxy
furnishing the corresponding azide substitution products 18
and 16, respectively. It should be noted that products 16 and
1
8 were obtained in remarkably high yields, whereas they had
[
9]
been inaccessible using the previously reported method.
Contrary to our expectations, a trisubstituted unsaturated
[
13]
epoxy ester 19 did not react at all under similar conditions
esters with TMSN that occurs stereospecifically at the g-
3
and the starting material was recovered (Table 3, entry 3).
position to produce azido alcohols in excellent yields with
double inversion of configuration. This new method is widely
applicable to various acyclic and cyclic substrates and
provides a powerful tool in the synthesis of functionalized
b-amino alcohols and a-amino acids, including a,a-disubsti-
tuted amino acids. Further investigations into the synthetic
applications of this methodology are ongoing.
Fortunately, we found that the reaction of 19 with TMSN and
3
[
Pd(PPh ) ] in N,N-dimethylformamide (DMF) proceeded
3 4
smoothly at 508C and gave rise to the desired product 20 in
[
14]
9
2% yield (Table 3, entry 4).
These results demonstrate
unambiguously that the palladium-catalyzed azide substitu-
tion reaction of unsaturated g,d-epoxy esters with acyclic and
cyclic substrates occurs stereospecifically at the g-position
with double inversion of configuration, thus producing azido
alcohols in high yields regardless of the stereochemistry of the
epoxide and unsaturated ester moieties.
Received: March 7, 2005
Published online: July 15, 2005
Scheme 3. Stereospecific synthesis of both enantiomers of N-tert-butoxycarbonyl-a-methylglutamic acid g-ethyl ester: a) mCPBA (1.5 equiv),
CH Cl , 08C,1 h (99%); b) TMSN (2 equiv),[Pd(PPh ) ] (5 mol%),THF,RT,1 h (93%); c) H ,PtO ,Boc O (4 equiv),AcOEt,RT,4 h; d) RuCl
2
2
3
3
4
2
2
2
3
(
cat.),NaIO 4 (6 equiv),CCl ,aq. CH CN,RT,2 h; e) NaN (4 equiv),[Ti(OEt) ] (2 equiv),DMF,RT,1 h.
4
3
3
4
5
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Keywords: amino acids · asymmetric synthesis · azides ·
epoxides · palladium
[11] The use of P(2-furyl) in the reaction of acyclic substrates also
3
.
gave excellent results with even better yields of isolated product
than with the use of [Pd(PPh ) ].
3
4
[
[
[
12] B. Norbert, H. Juergen, M. Helga, W. Peter, Chem. Ber. 1979,
12, 2256.
13] The substrate 19 was prepared from 2-hydroxymethyl-2-cyclo-
hexenone in five steps.
14] The configuration of 20 was confirmed unambiguously by NOE
interaction studies of its acetonide derivative, which was
1
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Angew. Chem. Int. Ed. 2005, 44, 5094 –5097
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