Intramolecular nucleophilic epoxidation of γ-amino-α,β- unsaturated esters with an N-hydroperoxymethyl group

Article abstract of DOI:10.1055/s-2005-871558

Intramolecular nucleophilic epoxidation reactions of γ-amino-α, β-unsaturated esters have been studied for the first time with a hydroperoxymethyl group attached to the nitrogen atom. The epoxidation was fast under mild basic conditions and highly anti se

Full text of DOI:10.1055/s-2005-871558

LETTER
1707
Intramolecular Nucleophilic Epoxidation of g-Amino-a,b-Unsaturated Esters
with an N-Hydroperoxymethyl Group
I
ntramolecular Epo
o
xidation of
g
-Amino-
a,
b
g
-Unsaturated
w
E
sters on Yoo, Hyeonjeong Kim, Young Gyu Kim*
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Fax +82(2)8856989; E-mail: ygkim@snu.ac.kr
Received 17 May 2005
Boc
R
Boc
R
NH
NH
Abstract: Intramolecular nucleophilic epoxidation reactions of g-
amino-a,b-unsaturated esters have been studied for the first time
with a hydroperoxymethyl group attached to the nitrogen atom. The
epoxidation was fast under mild basic conditions and highly anti
selective (>20:1) when the alkyl group is small.
vii
CO2Me
CO2Me
O
7a (80%), 7b (80%)
6a (65%), 6b (65%)
syn:anti = 9:1
vi
Key words: asymmetric synthesis, ring-opening, peroxides, nu-
cleophile, intramolecular epoxidation, amino epoxide
Boc
Boc
R
N
OAc
CO2Me
N
OH
i
R
CO2Me
2a (98%), 2b (98%)
1a: R = i-Bu, 1b: R = Bn
Stereoselective epoxidation of olefins is one of the impor-
tant subjects in organic synthesis because epoxides can
undergo regio- and stereoselective attack by various nu-
cleophiles.1 Substrate-directed control of stereoselectivity
has been well utilized for this purpose without using chiral
catalysts or ligands.2 We have been interested in stereo-
selective synthesis of g-amino-a,b-epoxy esters because
they can serve as useful chiral building blocks for bioac-
tive products with an amino alcohol moiety.3 In principle,
they can be efficiently prepared from an amino group-di-
rected epoxidation of g-amino-a,b-unsaturated esters that
are derived from a Wittig olefination of readily available
a-amino aldehydes.
ii
Boc
Boc
N
OH
O
N
OOH
CO2Me
iii
R
CO2Me
R
4a (72%), 4b (75%)
3
iv, v
Boc
R
R'
5a (65%), 5b (70%) R' = CHO
6a (70%), 6b (71%) R' = H
N
CO2Me
syn:anti = 1:>20
O
Scheme 1 Reagents and conditions: (i) Ac2O, DMAP, TEA,
CH2Cl2; (ii) 30% aq H2O2, p-TsOH, MgSO4, DME; (iii) K2CO3,
MeOH; (iv) PDC, CH2Cl2; (v) Cs2CO3, MeOH; (vi) p-TsOH, CH2Cl2,
reflux; (vii) MCPBA, CH2Cl2.
However, intermolecular epoxidation reactions of a,b-un-
saturated esters with peroxyacids such as MCPBA are
generally slow and base is often necessary to effect the
reactions.4 Sometimes stronger base is used to achieve a
successful epoxidation.5 The stereoselectivities in all of
these epoxidation reactions are syn to the allylic amino
group.5a,6 We have found out that a facile and stereoselec-
tive epoxidation reaction of g-amino-a,b-unsaturated
esters is possible with intramolecular addition of an N-hy-
droperoxymethyl group under mild basic conditions.7
High anti selectivity obtained in the present study is com-
plementary to the usual syn selectivity of the intermole-
cular epoxidation reactions. We believe it is the first
report of the stereoselective intramolecular epoxidation
reaction of electron-poor alkenes, whereas there have
been several scattered reports on the intramolecular regio-
or stereoselective epoxidation reactions of electron-rich
alkenes.8
were prepared as reported.9,10 Introduction of the N-hy-
droperoxymethyl group was facilitated after acetylation
of the N-hydroxymethyl group of 1, and 2 were treated
with aqueous H2O2 under acidic conditions for four hours
in the presence of MgSO4.11 After filtration of MgSO4
from the resulting mixture, the epoxidation reaction was
completed within 30 minutes at room temperature by se-
quential addition of MeOH and K2CO3 to the filtrate. It
should be noted that the epoxidation was very fast even
under mild basic conditions probably because of the
intramolecular nature of the reaction.
The diastereoselectivity of the intramolecular epoxidation
was determined at the stage of 6 because the diastereo-
meric mixtures of 4 and 5 were not separated on the H
1
We planned to introduce the N-hydroperoxymethyl group
by reacting the N-hydroxymethyl group of g-amino-a,b-
unsaturated esters 1 with H2O2 (Scheme 1). Compounds 1
NMR spectra. The ratio of 6-anti to 6-syn epoxides was
more than 20:1 by 1H NMR, indicating that the in situ in-
tramolecular epoxidation reaction gave the anti-epoxides
with high selectivity. The minor epoxides 6-syn were
obtained separately from 7 as major products by the inter-
molecular epoxidations with MCPBA as reported.3a The
minor products from the MCPBA epoxidation of 7 were
SYNLETT 2005, No. 11, pp 1707–1710
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871558; Art ID: U15805ST
© Georg Thieme Verlag Stuttgart · New York

1708
D. Yoo et al.
LETTER
Boc
the same as the major products 6-anti derived from the
intramolecular epoxidation. The assignment of the rela-
tive configuration was confirmed by transformation of 6a
into 8a, a diastereomeric derivative of statine, with regio-
Boc
N
N
OAc
CO2Me
NH
i, ii
iii, iv
i-Pr
i-Pr
CO2Me
O
6c
2c
syn:anti = 2:1
1
selective reduction (Scheme 2).12a The H NMR and 13C
Boc
NMR spectra of the major product matched those in the
Boc
NH
OAc
CO2Me
literature.12b
i, ii
CO2Me
iii, iv
O
2d
Boc
TBDMSO
Boc
TBDMSO 6d
NH
NH
i, ii
syn:anti = 1:>20
i-Bu
CO2Me
i-Bu
CO2H
O
Scheme 4 Reagents and conditions: (i) 30% aq H2O2, p-TsOH,
MgSO4, DME; (ii) K2CO3, MeOH; (iii) PDC, CH2Cl2; (iv) Cs2CO3,
MeOH.
6a
OH
8a
Scheme 2 Reagents and conditions: (i) SmI2, DMAE, HMPA, THF,
60%; (ii) NaOH, MeOH–H2O, 70%.
The stereoselectivity observed in the present study could
be rationalized based on the more favorable N-eclipsed
allylic conformation (Figure 1). In contrast to the N-hy-
droxymethyl group used for (–)-statine,9 an H-eclipsed al-
lylic conformation would be disfavored because of the
dipole-dipole repulsion between the peroxy group and the
double bond. The selectivity shown here is opposite to
that of the conjugate addition of the N-hydroxymethyl
group described in the synthesis of (–)-statine. When the
alkyl group R is bulky, however, the N-eclipsed confor-
mation should be disfavored due to the A1,3-strain. There-
fore, the valine derivative 2c having an isopropyl side
chain produced the syn epoxide as a major product with
low selectivity.
Further evidence for the anti configuration was obtained
from measurement of the vicinal coupling constant be-
tween the protons at C-3 and C-4 of oxazolidinones 9
(Scheme 3). When treated with silica gel, 4 underwent a
completely regio- and stereoselective ring closure to give
1
9.13 A H NMR analysis of 9a and 9b showed J3,4 of 4.6
Hz and 4.2 Hz, respectively, which are typical values for
the trans oxazolidinones of comparable structure.13,14b
The similar cis oxazolidinones were reported to have a
larger coupling constant of 7–10 Hz.14 The peroxide inter-
mediate 3a that was isolated by flash column chromato-
graphy in 70% yield reacted as expected to give epoxide
4a in 80% yield under similar conditions (Scheme 3).
In summary, we have demonstrated an efficient and
highly stereoselective synthesis of anti-g-amino-a,b-
epoxy esters via the first examples of an intramolecular
nucleophilic epoxidation of readily available g-amino-
a,b-unsaturated esters. The anti selectivity in the present
study is complementary to the usual syn selectivity of the
intermolecular epoxidation reactions with MCPBA. The
present results can be applied directly to prepare an amino
diol moiety that is present in biologically active com-
pounds. For example, (2S,3S,4S)-3,4-dihydroxy-L-
glutamic acid, a selective agonist of mGluR1,15 can be
prepared from 4d by a neighboring group-assisted regio-
and stereoselective epoxide opening as shown in
Scheme 3. Application of this strategy to the synthesis of
dihydroxyglutamic acid is currently underway in our
laboratory.
O
Boc
N
OH
O
HN
i
9a (90%)
9b (76%)
O
R
CO2Me
4
3
R
iii, 50%
CO2Me
4a: R = i-Bu, 4b: R = Bn
HO
N
ii
Boc
Boc
iii
O
N
OOH
CO2Me
10a
i-Bu
R
CO2Me
HO
3a, R = i-Bu
Scheme 3 Reagents and conditions: (i) SiO2, MeOH; (ii) K2CO3,
MeOH at 0.08 M, 80%; (iii) K2CO3, MeOH at 1.0 M, 65%.
Interestingly, 3a reacted at higher concentration to give
directly oxazolidine 10a that was produced presumably
by an in situ attack of the N-hydroxymethyl group of 4a
on the epoxide ring. The formation of 10a from 3a via 4a
was confirmed by an independent synthesis of 10a by
treating 4a in MeOH with K2CO3 although the yield was
lower (50%).
Boc
R
H
OH
N
OH
Boc
O
N
CO2Me
R
CO2Me
O
H
dipole–dipole
repulsion
4 syn (2:1)
R = i-Pr
The intramolecular epoxidation protocol was extended to
a couple of other g-amino-a,b-unsaturated esters, 2c and
2d, that were obtained from L-valine and D-serine, respec-
tively (Scheme 4). The high selectivity for the anti ep-
oxide 6d was observed with 2d, whereas the opposite syn
selectivity was shown with 2c. Their relative stereochem-
istry was determined similarly as described above.
Boc
H
OH
N
OH
Boc
O
N
H
R
CO2Me
R
O
A1,3-strain
4 anti (>20:1)
R = i-Bu, Bn, TBDMSOCH2
H
CO2Me
Figure 1 Favored conformations of the intramolecular epoxidation.
Synlett 2005, No. 11, 1707–1710 © Thieme Stuttgart · New York

LETTER
Intramolecular Epoxidation of g-Amino-a,b-Unsaturated Esters
1709
Preparation of Compound 2a
Preparation of Compound 6a
To a solution of 1a9 (106 mg, 0.35 mmol) in CH2Cl2 (10 mL) was
added Ac2O (72 mg, 0.70 mmol), TEA (71 mg, 0.70 mmol) and
DMAP (4 mg, 0.04 mmol). The mixture was stirred for 1 h at r.t.
The resulting mixture was partitioned between H2O (2 × 20 mL)
and Et2O (2 × 20 mL). The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was purified with SiO2 column chromatography (2:1 hexane–
EtOAc) to give 2a (118 mg, 98%) as colorless oil. Rf = 0.50 (2:1
To a solution of 5a (47 mg, 0.15 mmol) in MeOH (5 mL) was added
Cs2CO3 (49 mg, 0.15 mmol). The mixture was stirred for 0.5 h at r.t.
The resulting mixture was partitioned between H2O (2 × 20 mL)
and Et2O (2 × 20 mL). The combined organic layers were dried with
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was purified with SiO2 column chromatography (2:1 hexane–
EtOAc) to give 6a (30 mg, 70%) as white solid. Rf = 0.34 (2:1 hex-
ane–EtOAc). 1H NMR (300 MHz, DMSO, 70 °C): d = 0.82 (d, 3 H,
J = 6.6 Hz), 0.86 (d, 3 H, J = 6.6 Hz), 1.20–1.50 (m, 2 H), 1.36 (s,
9 H), 1.50–1.75 (m, 1 H), 3.01 (dd, 1 H, J = 5.7, 1.8 Hz), 3.40–3.55
(m, 1 H), 3.47 (d, 1 H, J = 1.8 Hz), 3.66 (s, 3 H), 6.82 (br d, 1 H,
J = 9.3 Hz). 13C NMR (75 MHz, DMSO): d = 21.5, 23.0, 24.0, 28.0,
48.4, 50.0, 51.1, 52.2, 59.4, 77.9, 155.6, 169.1. Anal. Calcd for
C14H25NO5: C, 58.52; H, 8.77; N, 4.87. Found: C, 58.49; H, 8.93; N,
4.74.
1
hexane–EtOAc). H NMR (300 MHz, CDCl3): d = 0.93 (d, 3 H,
J = 6.2 Hz), 0.95 (d, 3 H, J = 6.2 Hz), 1.35–1.55 (m, 2 H), 1.48 (s,
9 H), 1.55–1.70 (m, 1 H), 2.04 (s, 3 H), 3.74 (s, 3 H), 4.50–4.95 (m,
1 H), 5.20 (br s, 1 H), 5.40 (d, 1 H, J = 10.8 Hz), 5.86 (dd, 1 H,
J = 15.8, 1.5 Hz), 6.88 (dd, 1 H, J = 15.8, 5.5 Hz). 13C NMR (75
MHz, CDCl3): d = 21.0, 22.0, 22.9, 24.5, 28.2, 40.9, 51.7, 54.3,
69.9, 81.4, 121.3, 147.6, 155.5, 166.6, 171.8. Anal. Calcd for
C17H29NO6: C, 59.46; H, 8.51; N, 4.08. Found: C, 59.41; H, 8.69; N,
3.95.
Preparation of Compound 9a
To a solution of 4a (40 mg, 0.13 mmol) in MeOH (5 mL) was added
SiO2 (145 mg). The mixture was stirred for 2.5 d at r.t. The resulting
mixture was filtered, and concentrated under reduced pressure. The
residue was purified with SiO2 column chromatography (1:1 hex-
ane–EtOAc) to give 9a (36 mg, 90%) as colorless oil. Rf = 0.07 (2:1
Preparation of Compound 3a
To a solution of 2a (110 mg, 0.32 mmol) in DME (5 mL) was added
30% aq H2O2 (300 mg, 2.65 mmol), p-TsOH (6 mg, 0.03 mmol) and
MgSO4 (300 mg). The mixture was stirred for 7 h at r.t. The result-
ing mixture was concentrated under reduced pressure. The residue
was purified with SiO2 column chromatography (2:1 hexane–
1
hexane–EtOAc). H NMR (300 MHz, CDCl3): d = 0.918 (d, 3 H,
J = 6.4 Hz), 0.922 (d, 3 H, J = 6.4 Hz), 1.20–1.40 (m, 1 H), 1.45–
1.70 (m, 2 H), 3.83 (s, 3 H), 3.82–3.93 (m, 1 H), 4.43 (dd, 1 H,
J = 4.6, 3.6 Hz), 4.50 (d, 1 H, J = 3.6 Hz), 6.28 (br s, 1 H). 13C NMR
(75 MHz, CDCl3): d = 22.0, 22.9, 24.6, 45.3, 51.1, 52.9, 71.1, 82.3,
159.0, 171.2. MS (CI): m/z (%) = 232 (100) [M + 1]+, 142 (17), 90
(20). HRMS (CI): m/z calcd for C10H18NO5: 232.1185; found:
232.1184.
1
EtOAc) to give 3a (71 mg, 70%) as colorless oil. H NMR (300
MHz, CDCl3, 60 °C): d = 0.926 (d, 3 H, J = 6.3 Hz), 0.933 (d, 3 H,
J = 6.3 Hz), 1.40–1.65 (m, 2 H), 1.47 (s, 9 H), 1.65–1.80 (m, 1 H),
3.72 (s, 3 H), 4.45–4.65 (m, 1 H), 4.99 (d, 1 H, J = 11.9 Hz), 5.09
(d, 1 H, J = 11.9 Hz), 5.87 (dd, 1 H, J = 15.8, 1.5 Hz), 7.00 (dd, 1
H, J = 15.8, 6.2 Hz). 13C NMR (75 MHz, CDCl3): d = 22.2, 22.6,
24.5, 28.3, 41.1, 51.5, 55.5, 81.0, 81.6, 121.3, 148.0, 155.9, 166.9.
IR (KBr): 3364, 1705, 1684, 1157 cm–1.
Acknowledgment
Preparation of Compound 4a
We thank the BK 21 Program administered by the Ministry of
Education and Human Resources.
To a solution of 3a (52 mg, 0.16 mmol) in MeOH (2 mL) was added
K2CO3 (34 mg, 0.25 mmol). The reaction was complete within 30
min. The resulting mixture was partitioned between H2O (2 × 20
mL) and Et2O (2 × 20 mL). The combined organic layers were dried
with MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified with SiO2 column chromatography (4:1 hex-
ane–EtOAc) to give 4a (42 mg, 80%) as colorless oil. Rf = 0.28 (2:1
hexane–EtOAc). 1H NMR (300 MHz, CDCl3, 60 °C): d = 0.91 (d, 3
H, J = 6.7 Hz), 0.93 (d, 3 H, J = 6.7 Hz), 1.35–1.55 (m, 2 H), 1.49
(s, 9 H), 1.55–1.75 (m, 1 H), 3.30 (dd, 1 H, J = 5.9, 1.8 Hz), 3.41 (d,
1 H, J = 1.8 Hz), 3.70–3.90 (m, 1 H), 3.76 (s, 3 H), 4.62–4.74 (m, 1
H), 4.74–4.84 (m, 1 H). 13C NMR (75 MHz, CDCl3): d = 21.6, 23.2,
24.3, 28.3, 38.3, 51.9, 52.5, 55.0, 59.9, 69.2, 81.5, 155.6, 169.1. IR
(KBr): 3420, 1720, 1680 cm–1. This compound 4a was so reactive
that it began to cyclize to 9a during storage at r.t. Conformational
isomerism of 4a made some of the NMR peaks blurred.
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Synlett 2005, No. 11, 1707–1710 © Thieme Stuttgart · New York