Isomerization of E-α,β-epoxyamides to Z-α,β- epoxyamides and synthetic applications based on regio- and stereoselective oxirane ring openings

Article abstract of DOI:10.1016/j.tetlet.2004.10.034

The regioselective opening reaction of 2,3-epoxyamides with various nucleophiles offers a variety of β-hydroxyamides with diverse synthetic utility depending on the introduced nucleophile. Due to the exclusive stereoselectivity in the formation of trans epoxyamides in reactions of aldehydes with stabilized sulfur ylides, we studied the isomerization of trans epoxyamides into the cis isomers with the objective of obtaining the corresponding syn opening products, which together with the anti isomers represent a variety of enantiomerically pure building blocks.

Full text of DOI:10.1016/j.tetlet.2004.10.034

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9069–9072
Isomerization of E-a,b-epoxyamides to Z-a,b-epoxyamides
and synthetic applications based on regio- and stereoselective
oxirane ring openings
´
Laura Martın-Ortiz, Samy Chammaa, Marıa Soledad Pino-Gonzalez,
´ ´
Antonio Sanchez-Ruiz, Miguel Garcıa-Castro, Carmen Assiego and Francisco Sarabia
´
´
*
´ ´ ´
Departamento de Bioquımica, Biologıa Molecular y Quımica Organica, Facultad de Ciencias, Universidad de Malaga,
´
´
29071 Malaga, Spain
´
Received 19 July 2004; accepted 6 October 2004
´ ´
This paper is dedicated to the memories of Professor Lopez Herrera and J. M. Sanchez Porras, recently deceased,
for their important contributions on this research
Abstract—The regioselective opening reaction of 2,3-epoxyamides with various nucleophiles offers a variety of b-hydroxyamides
with diverse synthetic utility depending on the introduced nucleophile. Due to the exclusive stereoselectivity in the formation of trans
epoxyamides in reactions of aldehydes with stabilized sulfur ylides, we studied the isomerization of trans epoxyamides into the cis
isomers with the objective of obtaining the corresponding syn opening products, which together with the anti isomers represent a
variety of enantiomerically pure building blocks.
Ó 2004 Elsevier Ltd. All rights reserved.
The significant role of epoxides in organic chemistry is
clearly proven by the intense and continuous flurry of
synthetic activity in which the oxirane ring plays an
essential role in synthesis,1 constituting one of the most
valuable classes of functional groups in organic
synthesis.2
fides,8 selenides9 and organometallics.5a,10 In all cases,
the anti relative stereochemistry of the resulting ring
opened products is imposed by the trans-geometry of
the starting epoxyamide. With the purpose of broaden-
ing the synthetic utility of epoxyamides, we decided to
investigate a way of obtaining the corresponding cis-
epoxyamides (compound 3) from the trans isomer 1, in
order to access to the syn-ring opened products of type
4 (Scheme 1).
The stereoselective synthesis of epoxyamides by reaction
of chiral aldehydes with stabilized sulfur ylides has occu-
pied a central position in our research during the last
years,3 finding interesting synthetic applications in the
field of carbohydrates.4 In particular, the high stereofa-
cial selectivity showed by 2,3-O-isopropylidene-D-glyc-
Our first approach directed towards the execution of this
objective was based on the chemical properties of hyd-
roxyl selenides type 2i. Thus, oxidation of this selenide
to the corresponding selenoxide (intermediate A)
(Scheme 2), in the presence of a base,11 resulted in the
formation of the starting epoxyamide 1, through the
intermediate B, which evolves to 1 by the intramolecular
attack of the emerging oxyanion with the concomitant
formation of the epoxide. In a similar way, the phenyl-
selenide 4i should undergo, through the same synthetic
pathway, to the cis-epoxyamide 3. We initially tried
the epimerization of 2i, to obtain the syn hydroxyl
selenide 4i, through the silylether 5, by treatment with
base. However, after scanning a wide variety of basic
conditions, that included reactions with LDA, sodium
eraldehyde
7 in its reactions with sulfur ylides
represents an important synthetic feature with numerous
applications in the synthesis of natural products.5 Par-
ticularly, the regioselective opening with nucleophiles
at C-2 offers an extensive range of synthetic possibilities
via reactions with nitrogen nucleophiles,6 halides,7 sul-
Keywords: Sulfur ylides; Epoxy amides; Epoxide opening; trans–cis
Isomerization; Stereoselective synthesis.
*
Corresponding author. Tel.: +34 952134258; fax: +34 952131941;
e-mail: frsarabia@uma.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.034

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L. Martın-Ortiz et al. / Tetrahedron Letters 45 (2004) 9069–9072
9070
SePh
O
O
O
X
O
a
a
O
O
O
O
NMe2
NMe2
NMe2
NMe2
O
1
O
OH
O
O
O
OH
O
2i
1
2a, X = N3
2f, X = Br
2g, X = SPh
2h, X = SMe
2i, X = SePh
2j, X = Me
2b, X = NH2
2c, X = NHBn
2d, X = NMe2
2e, X = Cl
?
Ph
Se
Ph
O
O
O
O
b
H
H
Se
HO
O
O
O
NMe2
O
H
OH
H
X
O
O
O
CONMe2
CONMe2
O
NMe2
A
B
O
OH
4
O
3
SePh
O
SePh
O
c
Scheme 1. Reagents and conditions: (a) (i) 12.0equiv NaN3, 5.0equiv
AcOH, DMF, 100°C, 12h, 70% for 2a, (ii) 5.0equiv NH3, EtOH,
25°C, 4days, 97% for 2b, (iii) 5.0equiv H2NBn, H2O, reflux, 5h, 90%
for 2c, (iv) 5.0equiv HNMe2, H2O, 25°C, 2h, 96% for 2d, (v) 2.0equiv
LiCl, 2.0equiv AcOH, THF, reflux, 6h, 70% for 2e, (vi) 5.0equiv
NaBr, Amberlyst 15, acetone, ꢀ30°C, 24h, 87% for 2f, (vii)
3.0equiv NaSPh, 3.0equiv AcOH, DMF, 25°C, 24h, 82% for 2g,
(viii) 3.0equiv NaSMe, 3.0equiv AcOH, DMF, 25°C, 24h, 75% for 2h,
(ix) 2.0equiv Ph2Se2, 2.0equiv NaBH4, EtOH, 25°C, 2h, 75% for 2i,
(x) 2.0equiv Me2CuLi, Et2O, 0°C, 1h, 90% for 2j.
O
O
O
O
NMe2
NMe2
NMe2
NMe2
TBSO
TBSO
O
5
6
SePh
O
O
O
O
d or e
OH
2i
O
7
hydride, dicyclohexyliodoborane and sodium methoxide,
the results were quite disappointing with the recovery
of starting material. Alongside to this study, the reaction
of 2,3-O-isopropylidene-D-glyceraldehyde 7 with the
lithium enolate of N,N-dimethyl 2-phenylselenoacet-
amide12 provided us a 2:1 mixture of stereoisomers 2i–
4i. Contrastingly, when this reaction was carried out
with titanium tetrachloride and triethylamine as the eno-
lization system, the proportion of the syn adduct was
slightly increased, providing a 2:3 mixture of stereoiso-
mers 2i–4i in 80% yield. The inseparable mixture of
stereoisomers was then subjected to the action of m-
chloroperbenzoic acid, in the presence of potassium car-
bonate, to obtain the corresponding mixture of E–Z
epoxyamides 1–3 in a 2:3 ratio in a poor yield of 45%
(Scheme 2).
+
O
O
NMe2
SePh
O
O
f
O
3 +
OH
O
4i
1
Scheme 2. Reagents and conditions: (a) 1.5equiv mCPBA, 1.5equiv
K2CO3, MeOH, ꢀ15°C, 15min, 70%; (b) 1.5equiv TBSOTf, 2.0equiv
2,6-lutidine, CH2Cl2, 0°C, 1h, 90%; (c) see text for conditions; (d)
1.2equiv PhSeCH2CONMe2, 1.2equiv LDA, THF, ꢀ78°C ! 0°C,
40min; then 1.0equiv 7, THF, ꢀ78°C, 1h, 85% of a 2:1 mixture of 2i–
4i; (e) 1.2equiv PhSeCH2CONMe2, 1.2equiv TiCl4, 1.2equiv Et3N,
CH2Cl2, ꢀ78°C, 0.5h; then 1.0equiv 7, CH2Cl2, ꢀ78°C, 1h, 80% of a
2:3 mixture of 2i–4i; (f) 1.5equiv mCPBA, 1.5equiv K2CO3, MeOH,
ꢀ15°C, 15min, 45% of a 2:3 mixture of 1–3.
Our assessment of the interesting result obtained in the
aldolic reaction and subsequent transformation of the
hydroxyl selenides 2i and 4i to epoxides 1 and 3, respec-
tively, was that it was not satisfactory for synthetic pur-
poses. Consequently, we decided to explore a second
strategy based on a nucleophilic attack of the chloride
8, obtained by silylation of chlorohydrine 2e, that would
lead to the desired syn isomers.13 In fact, as it is depicted
in Scheme 3, the syn products azide 9a, phenylsulfide 9b
and methylsulfide 9c were obtained without difficulty by
treatment of 8 with the corresponding nucleophiles in
DMF at reflux. Similarly, the displacement of chloride
by a selenide was attempted and, unfortunately, in this
case, the reactions did not yield the desired product.
On the other hand, in a related strategy to the selenides,
the sulfides could be activated and transformed into
good leaving groups, amenable to an intramolecular dis-
placement by the oxy anion, via formation of the corre-
sponding sulfonium salt.14 Thus, after silyl ether
cleavage of 9 with TBAF to obtain alcohol 10, the reac-
tion of this compound with the MerweinÕs salt, yielded
quantitatively the sulfonium salt 11. Once again, the at-
tempted cyclization of 11 by treatment with base re-
sulted in a highly discouraging 30% yield of the
targeted epoxyamide 3. In contrast to the displacement
reactions described before, the nucleophilic substitution
of chloride by alkyl groups, by treatment with organo-
metallics, required harsh conditions (e.g., Me3Al, re-
flux). Under these conditions, in addition to the
nucleophilic substitution, the reductive cleavage of the
acetal occurred to afford tert-butylether 12 as the sole
product in a 70% yield.
Our continuous efforts in our laboratories devoted to
the epoxide opening reactions, led us to the fortuitous
observation that the reaction of epoxide 1 with lithium
bromide, under neutral conditions, afforded the forma-
tion of a 1:2 inseparable mixture of bromohydrines 2f–
4f, which were separated and identified as their acetates

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L. Martın-Ortiz et al. / Tetrahedron Letters 45 (2004) 9069–9072
9071
Cl
O
O
X
Cl
O
O
a
a
O
O
O
O
O
O
O
NMe2
NMe2
NMe2
NMe2
O
OH
2e
O
O
OR
O
TBSO
O
8
1
2f: X = Br, R = H
b
13: X = Br; R = Ac
2k: X = I, R = H
+
b
f
O
NMe2
X
O
O
OH Me
X
O
c
NMe2
O
O
NMe2
NMe2
for 2k:4k
O
OR
O
TBSO
O
OR
O
3
4f: X = Br, R = H
14: X = Br; R = Ac
4k: X = I, R = H
12
9a, X = N3, R = TBS
9b, X = SPh, R = TBS
9c, X = SMe, R = TBS
b
d
c
10, X = SMe, R = H
X
O
4a, X = N3
4e, X = Cl
d
NMe2
4g, X = SPh
4j, X = Me
OH
O
O
NMe2
BF4
S
O
O
e
Scheme 4. Reagents and conditions: (a) (i) 2.0equiv LiBr, 0.5equiv
AcOH, THF, reflux, 8h, 80% of a 1:2 mixture of 2e–4e, (ii) 2.0equiv
LiI, 0.5equiv AcOH, THF, reflux, 8h, 80% of a 1:9 mixture of 2e–4e;
(b) 5.0equiv Ac2O, pyridine, 25°C, 12h, 95%; (c) 0.2equiv NaOMe,
MeOH, 25°C, 0.5h, 98%; (d) (i) 12.0equiv NaN3, 5.0equiv AcOH,
DMF, 100°C, 16h, 61% for 4a, (ii) 2.0equiv LiCl, 2.0equiv
AcOH, THF, reflux, 96h, 65% for 4e, (iii) 3.0equiv NaSPh, 3.0equiv
AcOH, DMF, 25°C, 24h, 55% for 4g, (iv) 2.0equiv Me2CuLi,
Et2O, 0°C, 8h, 67% for 4j.
O
O
NMe2
O
OH
11
O
3
Scheme 3. Reagents and conditions: (a) 1.5equiv TBSOTf, 2.0equiv
2,6-lutidine, CH2Cl2, 0°C, 0.5h, 78%; (b) (i) 10.0equiv NaN3, DMF,
reflux, 1h, 95% for 9a, (ii) 10.0equiv NaSPh, DMF, reflux, 5h, 75% for
9b, (iii) 10.0equiv NaSMe, DMF, reflux, 1h, 73% for 9c; (c) 1.2equiv
TBAF, THF, 25°C, 1h, 70%; (d) 1.5equiv Me3OBF4, MeCN, 0°C, 1h,
quantitative; (e) 1.1equiv tBuOK, CH2Cl2, 0°C, 0.5h, less than 30%;
(f) 3.0equiv AlMe3, toluene, reflux, 8h, 70%.
by different nucleophiles, to obtain either anti or syn
opening products. These products represent useful
building blocks for the synthesis of diverse natural prod-
ucts. In this sense, we have described the synthesis of 2-
amine-3-hydroxy, 2-sulfides-3-hydroxy, 2-halohydrines
and 2-alkyl-3-hydroxy amides, which occur extensively
as structural motifs in natural products.
13 and 14, respectively. This unexpected and, in princi-
ple, promising result was ascribed to a thermodynamic
equilibrium initiated with bromohydrine 2f that suffered
a SN2 substitution by a new bromide anion with the con-
sequent inversion of the configuration at C-2 position,
with a resulting retention of configuration at this posi-
tion.15 In contrast to the chlorohydrine 2e, the higher
reactivity of the C–Br bond combined with the enhanced
nucleophilicity of the bromide anion explain this obser-
vation. By the same reasoning, the iodohydrine 2k
should present even a larger tendency to this epimeriza-
tion process with respect to the bromo derivative 2f.
Thus, treatment of epoxyamide 1 with lithium iodide,
under the same conditions as before, led to a 1:9 mixture
of iodohydrines 2k and 4k. Subsequent treatment of this
inseparable mixture with sodium methoxide provided
the epoxyamides 1 and 3, which were separated by flash
column chromatography, providing pure cis-epoxya-
mide 3 in a 70% overall yield from trans-epoxyamide
1. Finally, a series of oxirane ring opening reactions of
3 were carried out to afford the corresponding syn
opened products (4a, 4e, 4g, 4j) in good yields as indi-
cated in Scheme 4.
Acknowledgements
´
This work was financially supported by Fundacion Ra-
mon Areces and the Direccion General de Investigacion
y Cientıfica Tecnica (ref. BQU2001-1576). We thank
Dr. J. I. Trujillo from Pharmacia (St Louis, MI) for
assistance in the preparation of this manuscript. We
thank Unidad de Espectroscopıa de Masas de la
Universidad de Sevilla for exact mass spectroscopic
assistance.
´
´
´
´
´
´
References and notes
1. (a) Gorzynski-Smith, J. Synthesis 1984, 629–656; (b) Rao,
A. S.; Paknikar, S. K.; Kirtane, J. K. Tetrahedron 1983,
36, 2323–2367; (c) Behrens, C. H.; Sharpless, K. B.
Aldrichim. Acta 1983, 16, 67–80; (d) Sharpless, K. B.;
Verhoeven, T. R. Aldrichim. Acta 1979, 12, 63; (e)
Hanson, R. M. Chem. Rev. 1991, 91, 437; (f) Hodgson,
D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52,
14361.
In conclusion, the synthetic availability of either trans or
cis epoxyamides offers an extense battery of synthetic
opportunities via regioselective opening of the epoxide

´
L. Martın-Ortiz et al. / Tetrahedron Letters 45 (2004) 9069–9072
9072
2. (a) Mitsunobu, O. In Comprehensive Organic Synthesis;
F.; Bonini, C. Tetrahedron 2001, 57, 5649–5656; (c)
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org. Chem. 2001,
66, 4719–4722.
Trost, B. M., Fleming, I., Pattenden, G., Eds.; Pergamon:
Oxford, 1990; Vol. 6, pp 88–93; (b) Birkinshaw, T. N. In
Comprehensive Organic Functional Group Transformations;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Roberts, S.
M., Eds.; Pergamon: Oxford, 1990; Vol. 1, pp 204–220.
8. (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50,
1557–1560; (b) Behrens, C. H.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 5696–5704; (c) Chong, J. M.; Sharpless,
K. B. J. Org. Chem. 1985, 50, 1560–1563; (d) Deng, B.-L.;
Demillequand, M.; Laurent, M.; Touillaux, R.; Belmans,
´
´
3. (a) Lopez-Herrera, F. J.; Sarabia-Garcıa, F. R.; Pino-
Gonzalez, M. S. Recent Res. Dev. Org. Chem. 2000, 4,
´
´
465–490; (b) Valpuesta Fernandez, M.; Durante Lanes, P.;
Lopez-Herrera, F. J. Tetrahedron 1990, 46, 7911–7922; (c)
´ ´
M.; Kemps, L.; Ceresiat, M.; Marchand-Brynaert, J.
´
Tetrahedron 2000, 56, 3209–3217; (e) Sasaki, M.; Tanino,
K.; Miyashita, M. J. Org. Chem. 2001, 66, 5388–5394; (f)
Cossy, J.; Bellosta, V.; Hamoir, C.; Desmurs, J.-R.
Tetrahedron Lett. 2002, 43, 7083–7086; (g) Aggarwal, V.
K.; Hynd, G.; Picoul, W.; Vasse, J.-L. J. Am. Chem. Soc.
2002, 124, 9964–9965.
´
Valpuesta Fernandez, M.; Durante Lanes, P.; Lopez-
Herrera, F. J. Tetrahedron 1993, 49, 9547–9560; (d) Lopez
´
´
´
Herrera, F. J.; Pino Gonzalez, M. S.; Sarabia Garcıa, F.;
Heras Lopez, A.; Ortega Alcantara, J. J.; Pedraza
´
´
´
´
Cebrian, M. G. Tetrahedron: Asymmetry 1996, 7, 2065–
2071.
9. The oxirane opening of epoxyamide 1 was performed
under similar conditions than reported by Gruttadauria,
M.; Aprile, C.; DÕAnna, F.; Lo Meo, P.; Riela, S.; Noto,
R. Tetrahedron 2001, 57, 6815–6822.
´
4. (a) Lopez Herrera, F. J.; Heras Lopez, A.; Pino Gonzalez,
M. S.; Sarabia Garcıa, F. J. Org. Chem. 1996, 61, 8839–
´
´
´
´
8848; (b) Lopez Herrera, F. J.; Sarabia Garcıa, F.; Heras
Lopez, A.; Pino Gonzalez, M. S. J. Org. Chem. 1997, 62,
´
´
´
´ ´
10. (a) Sarabia Garcıa, F.; Pedraza Cebrian, G. M.; Heras
´
6056–6059; (c) Heras Lopez, A.; Pino Gonzalez, M. S.;
Sarabia Garcıa, F.; Lopez Herrera, F. J. J. Org. Chem.
´
´
Lopez, A.; Lopez Herrera, F. J. Tetrahedron 1998, 54,
6867–6896; (b) Schneider, C.; Brauner, J. Tetrahedron
´
´
´
´
1998, 63, 9630–9634; (d) Pino Gonzalez, M. S.; Assiego,
C.; Lopez Herrera, F. J. Tetrahedron Lett. 2003, 44, 8353–
´
Lett. 2000, 41, 3043–3046; (c) Concellon, J. M.; Bardales,
E. Org. Lett. 2003, 5, 4783–4785.
´
´
´
8356; (e) Assiego, C.; Pino Gonzalez, M. S.; Lopez
Herrera, F. J. Tetrahedron Lett. 2004, 45, 2611–2613.
11. Demarcus, M.; Ganadu, M. L.; Mura, G. M.; Porcheddu,
A.; Quaranta, L.; Reginato, G.; Taddei, M. J. Org. Chem.
2001, 66, 697–706.
12. Nakamura, S.; Hayakawa, T.; Nishi, T.; Watanabe, Y.;
Toru, T. Tetrahedron 2001, 57, 6703–6711.
13. (a) Righi, G.; Rumboldt, G.; Bonini, C. J. Org. Chem.
1996, 61, 3557–3560; (b) Righi, G.; DÕAchille, C.; Pesca-
tore, G.; Bonini, C. Tetrahedron Lett. 2003, 44, 6999–
7002.
´
´
5. (a) Lopez Herrera, F. J.; Sarabia Garcıa, F.; Pedraza
Cebrian, M. G.; Pino Gonzalez, M. S. Tetrahedron Lett.
´
´
´
1999, 40, 1379–1380; (b) Sarabia, F.; Martın-Ortiz, L.;
Lopez-Herrera, F. J. Org. Lett. 2003, 5, 3927–3930.
´
´
´
6. (a) Valpuesta-Fernandez, M.; Durante Lanes, P.; Lopez
Herrera, F. J. Tetrahedron Lett. 1995, 36, 4681–4684; (b)
Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahe-
dron 1995, 51, 13409–13422; (c) Izquierdo, I.; Plaza, M. T.;
Robles, R.; Mota, A. J. Tetrahedron: Asymmetry 2000, 11,
4509–4519.
14. Aggarwal, V.; Charmant, J.; Ciampi, C.; Hornby, J.;
OÕBrien, C.; Hynd, G.; Parsons, R. J. Chem. Soc., Perkin
Trans. 1 2001, 3159–3166.
7. (a) Righi, G.; Rumboldt, G.; Bonini, C. Tetrahedron 1995,
51, 13401–13408; (b) Righi, G.; Pescatore, G.; Bonadies,
15. Cardellach, J.; Font, J.; Ortun˜o, R. M. Tetrahedron Lett.
1985, 26, 2815–2816.