Stereochemistry control in the lewis acid mediated lactonization reaction of γ,δ-epoxy-β-silyloxy esters

Article abstract of DOI:10.1002/1099-0690(200111)2001:22<4247::AID-EJOC4247>3.0.CO;2-W

ZnCI₂-triggered lactonization reactions of γ,δ-epoxy-β-silyloxy esters with remote alkoxy groups (CH₂)_nOR (n = 2, 3), producing five- and/or six-membered ring lactones, have been investigated. Under such conditions, the re

Full text of DOI:10.1002/1099-0690(200111)2001:22<4247::AID-EJOC4247>3.0.CO;2-W

FULL PAPER
Stereochemistry Control in the Lewis Acid Mediated Lactonization Reaction of
γ,δ-Epoxy-β-silyloxy Esters
Kassoum Nacro,*[a] Liliane Gorrichon,[b] Jean-Marc Escudier,[b] and Michel Baltas*[b]
Keywords: Cyclizations / Epoxy esters / Lactones / Lewis acids
ZnCl2-triggered lactonization reactions of γ,δ-epoxy-β-silyl-
X-ray crystallographic structure of a γ-lactone (compound
oxy esters with remote alkoxy groups (CH2)nOR (n = 2, 3), 24Ј) and a 13C NMR correlation for the C(4) carbon chemical
producing five- and/or six-membered ring lactones, have
been investigated. Under such conditions, the regiochemistry
of the reaction is governed by the cis or trans nature of the
starting epoxy ester and also by its C(3) stereochemistry. An
shifts of all γ-lactones were obtained and used to determine
the regioselectivity of the epoxide ring-opening. A mechan-
istic hypothesis, involving an oxocarbenium ion as a common
intermediate, is presented in interpretation of the results.
Introduction
accounts of these lactone syntheses and present a mechan-
istic interpretation of the results.
The high interest attracted by lactones, evident in numer-
ous publications and reviews,[1Ϫ5] is related (or attributed)
to their involvement either in biological activity and
response[6Ϫ7] or as key intermediates in the syntheses of nat-
ural products,[1Ϫ5,8Ϫ12] antibiotics,[8Ϫ12] carbohydrates and
nucleosides.[13Ϫ15]
Results and Discussion
Optically active lactones were synthesized by a ZnCl2-
triggered intramolecular cyclization of compounds 5؊9 and
12؊14 (Scheme 1). The starting materials were obtained in
good to excellent yields by silylation of the secondary hy-
droxyl groups of the corresponding β-hydroxy-γ,δ-epoxy es-
ters.[18]
The five-membered ring lactones produced in the lacton-
ization were classified as exo or endo[23Ϫ25] lactones on the
basis of the regioselectivity of the epoxide ring-opening at
positions 4 or 5 respectively.
In connection with a program directed towards the total
synthesis of ulosonic esters and deoxynucleosides,[13Ϫ15]
chiral lactones obtained from chiral β-hydroxy-γ,δ-epoxy
esters[16Ϫ18] were used as pivotal intermediates. These com-
pounds have proved useful for syntheses of modified sugars
and nucleosides.[13Ϫ15] We have previously described lacton-
izations of epoxy esters possessing CH2OR[19] or
methyl[20,21] groups at C(5). For these two types of epoxy
esters, the outcome of the reaction was unambiguous, and
ultimately gave one γ-lactone. In this paper, however, we
present the findings of our ongoing investigations into the
lactonization reaction, starting from epoxy esters with re-
mote alkoxy groups at the C(5) positions [(CH2)nOR (n ϭ
2, 3)], which often produce mixtures of γ-lactones and δ-
lactones. These compounds can also act as intermediates
for syntheses of modified sugars, particularly fucose deriv-
atives, and they may be helpful for understanding of the
biochemical and biological roles of the -fucose present in
many oligosaccharidic structures and a potential biological
indicator of abnormal processes.[22] Here we describe full
Cyclization Reactions Conducted on trans Epoxy Esters
The results of the Lewis acid mediated cyclizations of
trans epoxy esters are presented in Table 1. When the reac-
tion was performed using trans epoxy ester 6a, three lac-
tones (18, 19, and 20; Scheme 2) were isolated in almost
quantitative overall yield. δ-Lactone 19 was quantitatively
converted into γ-lactone 18 on basic treatment with diisop-
ropylamine, according to a previously published proced-
ure.[20] This conversion confirms that compounds 18 and 19
were both generated by the same endo cyclization process.
The minor lactone 20 was generated through an exo-5 ring-
closure process.
Lactonization of epoxy esters 5a, 5Јa, and 6a (n ϭ 2 and
R1 ϭ tBuPh2Si) gave lactones from C(5) epoxide ring-open-
ing as major products. The six-membered ring lactones 16,
16Ј, and 19 (endo-6) and γ-lactones 17, 17Ј, and 18 (endo-
5), respectively, were isolated. The five-membered ring lac-
tones 15, 15Ј, and 20, generated by an exo-5 cyclization pro-
cess, were obtained as minor products in each reaction
(Table 1, entries 1Ϫ3). For n ϭ 3 (compounds 8a, 8aЈ, and
9a/9s), we still observed epoxide ring-opening at C(5) as the
[a]
Georgetown University Medical Center, Lombardi Cancer
Center, NRB, Room W224A,
3970 Reservoir Rd., NW, Washington, DC 2000, USA
Fax: (internat.) ϩ 1-202/687-7505
E-mail: kn7@gunet.georgetown.edu
[b]
`
´
´ ˆ
Synthese et Physicochimie de Molecules d’Interet Biologique,
´
UMR CNRS 5068, Universite Paul Sabatier,
118 route de Narbonne, 31062 Toulouse cedex 04, France
Fax: (internat.) ϩ 33-5/61556011
E-mail: baltas@chimie.ups-tlse.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the corresponding
author (M. B.).
Eur. J. Org. Chem. 2001, 4247Ϫ4258
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
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4247

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
Scheme 1
Table 1. Yields and ratios obtained on performing the ZnCl2 lactonization reaction on trans epoxy esters (A ϭ tBuPh2Si, B ϭ
tBuMe2Si, C ϭ pBrBn. a ϭ anti, s ϭ syn, 8Јa ϭ enantiomer of 8a)
Epoxy ester
No.
yield
(%)
exo-5
(%)
endo-6
(%)
endo-5
(%)
Entry
n
C(5) C(4) C(3)
R1
R
No.
No.
No.
1
2
3
4
5
6
7
8
2
2
2
3
3
2
3
2
5a
S R S
R S R
S R S
S R S
A
A
A
A
A
C
C
A
A
A
B
A
A
A
A
B
93
82
99
78
73
72
80
Ͼ99
12
8
20
0
15
22
4
55
0
0
0
16
16Ј
19
Ϫ
Ϫ
؊
66
88
25
100
100
nd
nd
14
17
5Јa
15Ј
17Ј
6a
8a
8Јa
7Јa/7Јs
9a/9s
6Јs
20
Ϫ
Ϫ
24/23
26Ј/25Ј
21[b]/18
18
22
22Ј
23Ј/24Ј
25/26
20
R S R
0
R S R/R S S
S R S/S R R
R S S
nd[a]
nd
86
0
0
؊
؊
[a]
[b]
nd: not determined for the mixtures. Ϫ exo-5 lactone bearing OtBu at C(5) position.
Scheme 3
Scheme 2
ondary hydroxyl function) and an endo-5 lactone 20, in an
major reaction, but no six-membered ring lactone was de- overall ratio of 87:13.
tected. Interestingly, the two compounds 20 and 18 were gener-
Compound 6Јs, on treatment with zinc chloride, gave dif- ated from the diastereoisomeric mixture of epoxy esters 6a
ferent results (Scheme 3). The regioselectivity in the epoxide and 6Јs. These diastereoisomers [at C(4) and C(5)] preferen-
ring-opening switched from C(5) to C(4), mostly resulting tially gave the five-membered ring lactone 18. Epoxy ester
in two exo-5 lactones 18 and 21 (tert-butylated on the sec- 6Јs afforded 18 as an exo-5 lactone, while 6a gave the same
4248
Eur. J. Org. Chem. 2001, 4247Ϫ4258

Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters
FULL PAPER
Scheme 4
γ-lactone through a two-step process: an endo-6 ring-clos- Lactonization Reaction on cis Epoxy Esters
ure gave a six-membered ring lactone to 19, which was fur-
cis Epoxy esters 12a, 13a, 13s, and 14a, under the same
ther converted into 18. This example highlights the fact that
two diastereoisomers can give identical products, depending
on the regiochemical opening of the epoxide ring. A further
observation also supports that point; the enantiomeric ex-
cesses (ees) measured for the same lactone (or product) were
different, depending on whether the reaction had been con-
ducted with a mixture of syn and anti epoxy esters or from
one of the isolated compounds (Scheme 4). In the former
case, the ee was smaller. Compounds 7Јa and 7Јs, for ex-
ample, are the silylated major and minor products, respect-
ively, from the aldol condensation between tert-butyllithio
ester and a single α,β-epoxyaldehyde (diastereoisomeric ra-
tio anti/syn 72:18).[18] As they were not separable by liquid
chromatography, the lactonization reaction was conducted
on the diastereoisomeric mixture (Table 1, entry 6 and
Scheme 4).
cyclization conditions as applied to trans epoxy esters, gen-
erally afforded four lactones (Scheme 5, Table 2) in excellent
overall yields.
Scheme 5
With epoxy esters 12a and 13a as starting materials, for
example, three types of exo lactones were isolated from a
Combinations of 7Јa and 7Јs mostly yielded γ-lactones C(4)-opening of the epoxide ring. Two of these (29 and 30
23Ј and 24Ј, products of C(5)-opening of the epoxide ring for 12a; 35 and 34 for 13a) were γ-lactones of the same
of the two epoxy esters. Nevertheless, during the cyclization absolute configuration, one of them tert-butylated on the
process on the minor syn adduct 7Јs, a competitive C(4)- secondary hydroxyl group. The third (28 and 33, respect-
opening of the epoxide also took place, affording γ-lactone ively), were valerolactones (exo-6), which were transformed
23, the enantiomer of 23Ј. The existence of 23 was con- into the corresponding γ-lactones (29, 34, respectively). Fi-
firmed by measuring the enantiomeric excesses (ees) of lac- nally, γ-lactones resulting from a C(5)-opening of the epox-
tones 23/23Ј on an HPLC system equipped with a chiral ide ring (27 and 31 from 12a and 13a, respectively) were
column. The ee dropped from 78% for the starting epoxy identified. The observed regioselectivity ratio of 73:27 ob-
ester to 26%, implying that the reaction 7Јs Ǟ exo-5 lactone served was in favour of the exo cyclization.
23 was the reaction competing with 7Јa Ǟ 23Ј, obtained
With the epoxy ester 14a (n ϭ 3) as starting material, no
through an endo ring-closure. The same trends were ob- valerolactone was observed and the regioselectivity of the
served when the lactonization reaction was conducted on intramolecular cyclization, as evidenced by a 4:1 ratio, was
the diastereoisomeric mixture 9a/9s (Table 2, entry 8) to again in favour of the exo process. Finally, the same regiose-
generate lactones 25, 25Ј, and 26.
lectivity was observed for the minor aldol adduct 13s
Table 2. Yields and ratio obtained on performing the ZnCl2 lactonization reaction on cis epoxy esters (A ϭ tBuPh2Si, B ϭ tBuMe2Si)
Epoxy ester
Yield total
%
exo-5b
No.
exo-5a
No.
exo-6
No.
endo-5
No.
Entry
n
No.
C(5) C(4) C(3)
R1
R
%
%
%
%
1
2
3
4
2
2
3
2
12a
13a
14a
13s
R R S
R R S
R R S
R R R
A
A
A
A
A
B
B
B
99
90
90
90
29
34
37
32
27
27
18
14
30
35
38
31Ј
42
51
67
86
28
33
Ϫ
15
11
Ϫ
27
31
36
Ϫ
16
11
15
Ϫ
Ϫ
Ϫ
Eur. J. Org. Chem. 2001, 4247Ϫ4258
4249

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
Scheme 6
(Scheme 6), with only two γ-lactones (32 and 31Ј) being ob-
tained. So, regardless of the diastereoisomer (syn or anti)
of the cis epoxysilyloxy esters and the secondary alcohol
protecting group, exo cyclization is the major event.
In summary of these detailed results, the regioselectivity
of the lactonization reaction in terms of exo to endo ratio,
independently of the lactone size, is presented in Table 3. It
appears that endo cyclization processes are predominant for
trans epoxy esters, with the exception of compound 6Јs,
while exo ring-closure prevails for cis isomers.
Table 3. exo versus endo epoxide ring-opening regioselectivity for
lactonization reactions performed on trans and cis epoxy esters.
The ratio are calculated on the basis of purified products
Scheme 7
ation reaction may ultimately give rise to two diastereo-
isomeric γ-lactones originating from C(4)- and/or C(5)-
opening of the epoxide ring, with (3S,4S,5S) and
(3S,4R,5R) absolute configurations, corresponding to er-
ythro, and threo C(3)/C(4) relative configurations, respect-
ively.
Starting, on the other hand, from the epimeric at C(3)
syn aldol adduct (3S,4R,5S), C(4) and/or C(5)-opening of
the epoxide will produce γ-lactones with (3R,4S,5S) and
(3R,4R,5R) absolute configurations, corresponding to
threo/erythro C(3)/C(4) relative configurations, respectively.
Thus, the threo and erythro lactones produced from epoxy
No.
exo %
endo %
trans
cis
5a
12
8
20
Ϫ
86
84
89
85
Ͼ99
88
92
80
Ͼ99
14
16
11
15
Ϫ
5Јa
6a
8a
6Јs
12a
13a
14a
13s
Identification of Lactones
The cyclization reaction in this study involves an intram- esters epimeric at C(3) (anti and syn) are enantiomers. The
olecular opening of the epoxide ring to give the lactones. same observation is also valid for the cis aldol series.
The determination of the absolute configurations of all γ-
This is observed experimentally when the lactonization
lactones obtained, and hence the regioselectivity of the ep- reaction is conducted on cis epoxy ester 13s (syn) to yield
oxide ring-opening, was based on the following points: lactones 31Ј and 32 and on cis epoxy ester 13a (anti) to
i) the capability to obtain enantiomeric lactones; the enanti- provide 31 (enantiomer of 31Ј). The decrease in the enanti-
omers arising from the diastereoisomeric epoxy esters syn omeric excess observed when the lactonization reaction is
or anti [epimers at C(3)], and ii) the X-ray crystallographic conducted on a mixture of epoxy esters (anti and syn) is
structure of γ-lactone 24Ј, together with the correlation of additional evidence, Scheme 8.
the 13C NMR C(4) chemical shifts of all the γ-lactones
studied and also observations from some of our previous re- b) X-ray Structures and 13C NMR Correlation
sults.
γ-Lactone 24Ј was crystallized and its X-ray structure es-
tablished (Figure 1). It displayed an erythro relative config-
a) Lactonization and Enantiomerization
uration about the C(3)/C(4) carbon atoms. 13C NMR spec-
In the knowledge of the absolute configurations of the tra revealed that the C(4) chemical shift was δ ϭ 85.19. On
asymmetric centres of the reactant epoxy ester, we present examination of the C(4) chemical shifts (13C NMR) of all
in Scheme 7 a Newman projection of all the possible five- the γ-lactones synthesized, we observed (Table 4) that all
membered ring lactones that can hypothetically be ob- compounds have their C(4) chemical shift values either at
tained. Starting, for example, from an anti aldol adduct δ ϭ approximately 85 or at δ ϭ approximately 90. A
with the (3S,4R,5S) absolute configuration, the lactoniz- correlation[26Ϫ28] could therefore be made between the C(4)
4250
Eur. J. Org. Chem. 2001, 4247Ϫ4258

Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters
FULL PAPER
Scheme 8
Figure 1. ORTEP drawing of the X-ray structure of compound 24Ј, δ(C4) ϭ 85.19
Table 4. C(4) Chemical shifts of all γ-lactones (13C NMR spectra in CDCl3)
Nature epoxy
ester
γ-Lactones n N° Absolute
configuration
δ C(4) [ppm] Nature epoxy
γ-Lactones n N° Absolute
δ C(4) [ppm]
ester
configuration
2 17
2 18
2 21
2 20
2 19Ј
2 24Ј
2 23Ј
3 22
3 25
3 26
S R R
90.7
90.4
89.9
85.6
90.5
85.2
90.3
91.1
90.8
85.3
2 35
3 38
3 37
3 36
2 31
2 34
2 29
2 27
2 30
2 32
S S R
S S R
S S R
S R S
S R S
S S R
S S R
S R S
S S R
R S R
85.1
85.5
85.7
90.4
90.5
86.2
86.2
90.6
84.3
89.5
S R R
S R R
S S S
R S S
S S S
R S S
S R R
S R R
R R R
T
R
A
N
S
C
I
S
chemical shifts and the γ-lactone C(3)/C(4) relative config- ginating from a cis epoxy ester (anti), reported in our first
urations (erythro or threo), and hence with the regioselectiv- communication,[29] possessed an erythro configuration
ity of the lactonization reaction. To be precise, for a γ-lac- [C(4)-opening of the epoxide ring] and δC(4) ϭ 86.2. A se-
tone with erythro or threo C(3)/C(4) relative configuration, cond X-ray crystal structure of a functionalized γ-lactone
the C(4) chemical shift will be observed at δ ഠ 85 or at ഠ originating from an epoxy ester (anti) generated from nerol
90, respectively. Thus, as the epoxy ester isomer used as the had a threo configuration (C(5)-opening of the epoxide
starting material is known, the C(4) chemical shift of its ring) and δC(4) ϭ 92.1.[20]
five-membered ring lactone derivative in this system will
permit a determination to be made as to which carbon of
Lactonization Regioselectivity
the epoxide ring was involved in the initial ring-closure and
thus the C(4) and C(5) absolute configurations to be as- or at C(5) of the epoxide ring[30Ϫ32] need not in either case
signed. exclusively generate a five-membered ring lactone; a six-
Considering the results obtained, opening either at C(4)
These results are in agreement with our previous observa- membered ring lactone is also possible. While it can readily
tions. In fact, an X-ray crystal structure of a γ-lactone ori- be imagined that a direct attack at C(5) may afford a six-
Eur. J. Org. Chem. 2001, 4247Ϫ4258
4251

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
membered ring lactone, a C(4)-opening to afford a δ-lac- bital might be developed either on the C(4) or on the C(5)
tone was rather unanticipated. This fact prompted us to carbon atom of the corresponding epoxy ester, depending
infer the existence of an intermediate that could be gener- on possible stabilisation through adjacent substituents.[36]
ated either by C(5)-opening or by C(4)-opening of the This is the case with epoxy esters originating from nerol
epoxy ester epoxide function, and which could then collapse and/or geraniol, in which the opening of the epoxide ring
to afford a five and/or a six-membered ring lactone. The occurs exclusively at the C(5) carbon atom (quaternary car-
cyclization process at the C(4) and C(5) carbon atoms of bon atom) to afford δ-lactones.[20Ϫ21] The two alkyl sub-
the epoxy ester may be triggered by intramolecular attack stituents in this (C(5)) position efficiently stabilise the devel-
of the carbonyl oxygen atom on the epoxide function. Such oping positive charge, resulting in a completely regioselec-
a cyclization process would result in the formation of an tive reaction. We may also mention the results of the lacton-
oxocarbenium ion (Scheme 9), which may react in situ with ization reaction concerning γ,δ-epoxy-β-hydroxy esters (cis
the just formed alkoxide in two different ways. One way or trans) possessing only one methylenic group at the C(5)
would be by formation of an orthoester intermediate, Lewis position (ROCH2Ϫ; n ϭ 1). These compounds are almost
acid catalysed elimination of the tert-butyl group of which symmetrically substituted around the epoxy function, and
would result in a γ-and/or a δ-lactone. The alternative so there is no preferential position for the development of
would be alkoxide attack on the activated tertiary carbon positive charge. The regioselectivity of this reaction, as ex-
of the tert-butyl group, producing a γ-lactone bearing a pected, always results in the smaller ring [γ-lactones, C(4)
tert-butoxy group at the C(5) position. Both the exo and attack] because of the better antiparallel alignment of the
endo cyclization process could follow the oxocarbenium and incipient and rupturing bonds.[19]
the corresponding orthoester formation pathways, and so
In the case of epoxy esters possessing remote alkoxy
the orthoester fragmentation according to route 2 would groups at their C(5) positions (n ϭ 2, 3), as analysed in this
afford δ-lactones (exo-6, endo-6).
study, we can predict a small preference for the C(5) posi-
tion for the development of positive charge during the acid-
catalysed cyclisation reaction, due to the better positive in-
ductive effect from the two (or three) methylenic groups.
Stereoelectronic and conformational effects may act com-
petitively or synergistically. For cis epoxy esters, conforma-
tional and steric effects should predominate, resulting in all
cases in C(4)-opening of the epoxide ring as the major
event. For anti aldol adducts of trans epoxy esters, steric
effects are not preponderant, so the acid-catalysed cyclis-
ation reaction produces δ-lactones through predominant
C(5)-opening of the epoxide ring. A synergistic effect is ob-
served for the cyclisation of compound 8a (n ϭ 3), in which
an exclusively endo attack is observed. Finally, for the mi-
nor aldol adduct 6Јs, the regioselectivity of the reaction is
reversed, due to conformational effects that become pre-
dominant in this case.
To explain the conformational or steric effects on the re-
gioselectivity of the lactonization reaction, we still have two
possible conformations, E and F, for the lactonization reac-
tion of the anti aldol adducts, together with conformation
G for the minor syn aldol adducts. Here we present the
Newman projections (Figure 2) in which the carbonyl group
Scheme 9
The proposed mechanism involving oxocarbenium ion
intermediates in this reaction type is in agreement with re-
sults previously reported by Chamberlin et al.,[33Ϫ35] study-
ing Lewis acid mediated cyclization of a number of γ,δ-
epoxy ketones and esters.
In an attempt to account for of the regioselectivity of the
lactonization reaction, we can consider stereoelectronic and
conformational effects that may steer the reaction into the
Figure 2. Selected conformers of epoxy esters undergoing intramo-
endo or the exo mode of attack. An electron-deficient or- lecular cyclization
4252
Eur. J. Org. Chem. 2001, 4247Ϫ4258

Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters
FULL PAPER
anhydrous grade if required, unless otherwise noted. Tetrahydrofu-
ran (THF) was freshly distilled from sodium wire; diethyl ether
(Et2O) was distilled from sodium and kept over sodium wire.
Dichloromethane (CH2Cl2) was distilled from calcium hydride and
is in a suitable position for antiperiplanar opening of the
epoxide ring either at C(4) or at C(5). Zinc may participate
through intermolecular chelation of the oxygen atom of the
epoxide ring, and possibly of the C(3) silyloxy group.
For the syn epoxy ester, conformer G would be the more
representative conformation, since steric interactions would
be minimised and intermolecular chelation with zinc would
be favoured. The cis or trans isomeric nature of the epoxy
ester would have little influence on its stability. This con-
˚
kept in the dark over 4 A molecular sieves. Ϫ Reactions were mon-
itored by thin layer chromatography carried out on RiedelϪde
Hae¨n 60 f254 special (0.2 mm) thin layer plates, using UV light as
visualizing agent and a phosphomolybdic acid solution in ethanol
and heating as developing agents. Ϫ NMR spectra were recorded
on Bruker AC 200 or AC 250 instruments and calibrated using
former offers a good explanation of why the C(4)-opening deuterated solvent as internal reference. Ϫ IR spectra were re-
corded on a PerkinϪElmer model 883 Series FTIR spectrometer.
Ϫ Optical rotations were recorded on a PerkinϪElmer model 141
polarimeter. Ϫ Mass spectra were recorded on a Nermag R10-10
mass spectrometer under electronic impact or chemical ionization
conditions. Ϫ Liquid chromatography purifications were per-
formed under the following conditions, classified according to in-
creasing difficulty in purification:
of the epoxide ring is the major event taking place for all
minor syn aldol adducts.
Lactonization of the major anti aldol adducts produced
from a cis epoxyaldehyde [R1 ϭ H, R2 ϭ RO(CH2)n] may
occur through a favoured conformer F. This conformation
might be preferred over the more stable one found in the
absence of Lewis acid,[18] due to favourable complexation
on both oxygen atoms. The major event is therefore the
C(4)-opening of the epoxide ring, as observed experiment-
ally. For anti aldol adducts originating from trans epoxyal-
dehydes, and for the same reasons as before (Lewis acid and
complexation), conformer E is favoured. It becomes very
competitive in comparison with conformer F because there
is a very weak interaction between R2 ϭ H and the ester
group while conformer F has not noticeably changed in
stability. In this case we therefore observe experimentally an
inversion of regioselectivity in the epoxide opening, which
takes place at the C(5) carbon atom of the epoxy ester.
Ϫ A Gravity chromatography using silica particle size of 70Ϫ200
µm, supplied by Amicon.
Ϫ B Flash chromatography using silica particle size of 35Ϫ70 µm,
supplied by Amicon.
Ϫ C Medium pressure chromatography with a Jobin-Yvon axial
compression apparatus, using silica particle size of 6Ϫ35 µm (Am-
icon) or 15 µm (Merck).
Enantiomeric excesses were measured by high performance liquid
chromatography on the following set-up: Kratos Spectroflow 400
pump, abI 759A UV detector and Chiracel OD l ϭ 25 cm, Ø ϭ
0.46 cm chiral column. Ϫ The same apparatus with a Waters Nova-
Pak normal phase silica column (l ϭ 15 cm, Ø ϭ 0.39 cm) was used
for diastereoisomeric ratio measurements, performed on the crude
products of aldolisation reactions, and also for product purity
monitoring.
Conclusion
Although lactonization reactions of trans or cis silylated
epoxy esters can potentially give five types of lactones (exo-
5b, exo-5a, exo-6, endo-5, and endo-6), the results demon-
strated good (to excellent in some cases) regioselectivity in
the opening of the epoxide function. This is governed by:
Ϫ the cis or trans structure of the starting epoxy ester
Ϫ the C(3) stereochemistry in the epoxy ester;
Melting points were measured with a Kofler apparatus and are
uncorrected. Ϫ Molecular sieves (4 A) were heated to dryness at
150 °C for four hours under 0.1 Torr vacuum. Zinc chloride was
dried under the same conditions.
˚
Note: Reagents quantities in mL/mmol or % are expressed relative
to the starting material.
Ϫ stereoelectronic and conformational effects.
The syntheses of compounds 1a, 1Јa, 1Јs, 2Јa, 2Јs, 3a, 3Јa, 4a, 4s,
10a, 10s, and 11a have already been reported.[18]
In all cases, an oxocarbenium ion is the most probable
common intermediate. The C(4) chemical shifts of the γ-
lactones synthesized, along with their X-ray crystallo-
graphic structures, were essential for determination of the
Lactonization Reactions
Synthesis of Compounds 15, 16, and 17: A solution of epoxy esters
regioselectivity of the epoxide ring-opening. For cis epoxy 5a (0.31 g, 0.43 mmol) in anhydrous CH2Cl2 (8 mL, 18 mL/mmol)
at room temp. was treated with dry zinc chloride (0.13 g,
0.96 mmol, 2.2 equiv.) (3 h at 150 °C, under a vacuum of 0.1 Torr).
After this had been stirred for 4 h at room temp., a saturated aque-
ous solution of sodium bicarbonate (3 mL) was added, and the
aqueous layer was extracted with Et2O (3 ϫ 10 mL). The organic
phases were combined, dried with MgSO4, filtered, and concen-
trated to afford a residue, which was purified according to method
C (100 g of silica 6Ϫ35 µm), eluent PE/EA, 8:2 (TLC, Rf17 ϭ 0.34,
Rf15 ϭ 0.25, Rf16 ϭ 0.17). We isolated 0.172 g (0.26 mmol, 66%) of
γ-lactone 17, 0.057 g (0.087 mmol, 22%) of valerolactone 16, and
0.042 g of a mixture containing 76% of γ-lactone 15 (0.032 g,
0.05 mmol, 12%). The overall reaction yield was 93%.
ester anti or syn adducts, opening is at C(4). In contrast,
for trans epoxy esters, when the starting material is an anti
adduct, C(5)-opening is the major event. The situation is
reversed for the syn adduct, resulting in C(4)-opening of
the epoxide.
Experimental Section
General: Reactions were performed in oven-dried glassware, which
was sealed with a rubber septum, and stirred with a magnetic stir-
ring bar, under argon or nitrogen if required. Materials were ob-
tained from commercial suppliers and were used without purifica-
(3S,4S,1ЈS)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
Ϫ1
˜
tion, unless otherwise stated. The solvents used were from Aldrich, silyloxy)-1Ј-hydroxypropyl]-γ-lactone (15): IR (CHCl3): ν cm
:
Eur. J. Org. Chem. 2001, 4247Ϫ4258
4253

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
3497 (OϪH). 3075Ϫ2935: (CϪH), 1782 (CϭO), 1110 (CϪO). Ϫ and stirred for 1 h at room temp. until complete conversion of the
1H NMR (250 MHz, CDCl3): δ ϭ 7.71 and 7.66 (m, 20 H), 4.76 starting material. A saturated aqueous solution of NaHCO3
(m, 1 H), 4.56 (m, 1 H), 4.10 (dd, J ϭ 2.5; 7.5 Hz, 1 H), 3.98 (m,
2 H), 3.86 (d, J ϭ 2.75 Hz, 1 H), 2.28 (m, 2 H), 2.10 and 1.90 (m, with Et2O. The combined organic phases were dried with MgSO4,
2 H), 1.12 and 1.08 (2s, 18 H). Ϫ 13C NMR (CDCl3, 63 MHz): δ ϭ
filtered, and concentrated. The residue was purified according to
(10 mL) was added and the aqueous layer was extracted three times
175.2, 136.0, 135.7, 135.6, 133.4, 132.9, 130.5, 130.0, 129.8, 128.2, method C (180 g of silica 6Ϫ35 µm), eluting with PE/EA, 8:2 (TLC,
127.9, 85.6, 70.0, 68.3, 63.4, 39.1, 35.1, 26.9, 19.4, 19.0. Ϫ Rf18 ϭ 0.32, Rf20 ϭ 0.22, Rf19 ϭ 0.15). We obtained 0.324 g
C39H48O5Si2: calcd. C 71.74, H 7.41; found C 73.03, H 7.60.
(0.61 mmol) of 18, 0.248 g (0.47 mmol) of 20 and 0.708 g
(1.34 mmol) of 19 as white crystals. The yield was quantitative.
(3S,4R,1ЈR)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (17): [α]D ϭ ϩ0.78 (c ϭ 2.30,
(3S,4R,1ЈR)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (18): [α]D ϭ ϩ2.7° (c ϭ 0.7,
CHCl3) ee ϭ 95%. Ϫ IR (film): ν˜ ϭ 3435 (OϪH); 3073Ϫ2934
CHCl3). Ϫ IR (CHCl3): ν cmϪ1: 3625Ϫ3493 (OϪH), 3005Ϫ2936:
˜
(CϪH), 1776 (CϭO), 1110 (CϪO). Ϫ 1H NMR (250 MHz,
CDCl3): δ ϭ 7.64 and 7.43 (m, 20 H), 4.58 (m, 1 H), 4.28 (d, J ϭ
4.1 Hz, 1 H), 3.85 (m, 1 H), 3.67 (m, 2 H), 3.14 (d, J ϭ 3.0 Hz, 1
H), 2.72 (A part of ABX, J ϭ 18.0, J ϭ 6.2, 1 H), 2.42 (B part of
ABX, J ϭ 18.0; 1.5 Hz, 1 H), 1.20 (m, 2 H), 1.06 and 1.02 (2s, 18
H). Ϫ 13C NMR (CDCl3, 63 MHz): δ ϭ 176.2, 135.9, 135.8, 135.5,
132.9, 132.8, 132.6, 130.1 130.0, 128.0 127.9, 90.7, 70.8, 69.6, 62.6,
38.8, 33.3, 26.8, 19.1, 19.0. Ϫ C39H48O5Si2 (653.0): calcd. C 71.74,
H 7.41; found C 71.49, H 7.12.
1
(CϪH); 1784 (CϭO); 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz,
CDCl3): δ ϭ 7.61 and 7.40 (m, 10 H), 4.64 (X part of ABX, J ϭ
6.7; 2.4; 1.8 Hz, 1 H), 4.22 (dd, J ϭ 5.3; 1.8 Hz, 1 H), 3.92 (m, 3
H), 2.85 (A part of ABX, J ϭ 18.0; 6.7 Hz, 1 H), 2.39 (B part of
ABX, J ϭ 18.0; 2.4 Hz, 1 H), 1.77 (m, 2 H), 1.05 (s, 9 H), 0.89 (s,
1
9 H), 0.09 (s, 6 H). Ϫ H NMR (250 MHz, C6D6): δ ϭ 7.70 and
7.23 (m, 10 H), 4.47 (ddd, X part of ABX, J ϭ 6.7; 5.5; 2.44 Hz,
1 H), 4.10 (dd, J ϭ 5.5; 1.8 Hz, 1 H), 3.74 and 3.54 (m, 2 H), 3.28
(m, 1 H), 2.52 (A part of ABX, J ϭ 17.7; 6.7 Hz, 1 H), 2.20 (B
part of ABX, J ϭ 17.7; 2.4 Hz, 1 H), 1.55 (m, 2 H), 1.10 (s, 9 H),
0.94 (d, J ϭ 3.8 Hz, 1 H), 0.87 (s, 9 H), Ϫ0.024 and Ϫ0.088 (2s, 6
H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 175.8, 135.5, 132.7, 132.6,
130.1, 127.9, 90.4, 70.6, 68.3, 62.6, 38.6, 34.0, 26.8, 25.8, 19.0, 17.9,
4.6, 4.8. Ϫ C29H44O5Si2 (528.8): calcd. C 65.87, H 8.39; found C
65.60, H 8.40
(3S,4R,5R)-3-(tert-Butyldiphenylsilyloxy)-5-[2Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-ethyl]-4-hydroxy-δ-lactone (16): NMR, IR, identical to
those of compound 16Ј. Ϫ C39H48O5Si2 (653.0): calcd. C 71.74, H
7.41; found C 71.34, H 7.53.
Synthesis of Compounds 15Ј, 16Ј, and 17Ј: A solution of epoxy ester
5Јa (1.27 g, 1.79 mmol) in anhydrous CH2Cl2 (27 mL, 15 mL/
mmol) was treated with dry ZnCl2 (0.486 g, 3.59 mmol, 2 equiv.)
and stirred for 4 h 30 min. A saturated aqueous solution of
NaHCO3 (8 mL) was added. The aqueous layer was extracted with
Et2O (3 ϫ 20 mL). The combined organic phases were dried with
MgSO4, filtered, and concentrated. The residue was purified ac-
cording to method C (150 g of silica 15 µm), eluent PE/AE, 8:2
(TLC, Rf17Ј ϭ 0.31, Rf15Ј ϭ 0.25, Rf16Ј ϭ 0.17). We obtained 0.862 g
(1.32 mmol, 90%) of γ-lactone 95Ј, 0.036 g (0.050 mmol, 4%) of
valerolactone 16Ј as a white solid and 0.081 g of a mixture con-
taining 75% of 15Ј (0.061 g, 0.09 mmol, 6%). The overall reaction
yield was 82%.
(3S,4R,5R)-3-(tert-Butyldimethylsilyloxy)-5-[2Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-ethyl]-4-hydroxy-δ-lactone (19): M.p. 88.0 °C. [α]D
ϭ
˜
ϩ46.4 (c ϭ 0.8, CHCl3). Ϫ IR (film): ν ϭ 3571 (OϪH), 3075Ϫ2959
1
(CϪH), 1734 (CϭO), 1111 (CϪO) cmϪ1. Ϫ H NMR (250 MHz,
CDCl3): δ ϭ 7.67 and 7.41 (m, 10 H), 4.67 (t d, J ϭ 8.0; 4.2 Hz, 1
H), 4.19 (t d, J ϭ 4.5; 3.0 Hz, 1 H), 3.86 (m, J ϭ 10.0; 5.0; 4.0 Hz,
2 H), 3.67 (dd, J ϭ 8.0; 3.0 Hz, 1 H), 2.70 (d, J ϭ 4.5 Hz, 2 H),
2.13 (m, 1 H), 1.83 (m, 1 H), 1.50 and 0.91 (2s, 18 H), 0.14 (s, 6
H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 168.9, 135.6, 133.3, 133.2,
129.8, 127.8, 76.4, 69.8, 66.9, 59.7, 37.8, 35.8, 26.8, 25.7, 19.2, 18.0,
4.6, 4.8. Ϫ C29H44O5Si2 (528.8): calcd. C 65.87, H 8.39; found C
(3R,4R,1ЈR)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl- 65.75, H 8.45.
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (15Ј): NMR, IR: identical to
(3S,4S,1ЈS)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldi-
phenylsilyloxy)-1Ј-hydroxypropyl]-γ-lactone (20): [α]D ϭ Ϫ9.5 (c ϭ
those of compound 15.
(3R,4S,5S)-3-(tert-Butyldiphenylsilyloxy)-5-[2Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-ethyl]-4-hydroxy-δ-lactone (16Ј): M.p. 125.5 °C. [α]D
˜
0.8, CHCl3) ee ϭ 95%. Ϫ IR (neat): ν ϭ 3503 (OϪH), 3019Ϫ2933
1
(CϪH), 1787 (CϭO), 1111 (CϪO) cmϪ1. Ϫ H NMR (250 MHz,
ϭ
Ϫ32.5 (c ϭ 1.1, CHCl3). Ϫ IR (CHCl3): ν˜ ϭ 3572 (OϪH),
CDCl3): δ ϭ 7.69 and 7.40 (m, 10 H), 4.60 (ddd, J ϭ 4.9; 3.4;
1.0 Hz, 1 H), 4.30 (dd, J ϭ 8.8; 2.9 Hz, 1 H), 4.12 (dd, J ϭ 8.8;
3.4 Hz, 1 H), 3.93 (m, 2 H), 3.76 (d, J ϭ 2.9 Hz, 1 H), 2.71 (dd,
J ϭ 17.2; 4.9 Hz, 1 H), 2.47 (dd, J ϭ 17.2; 1 Hz, 1 H), 2.04 (m, 1
H), 1.81 (m, 1 H), 1.06 (s, 9 H), 0.94 (s, 9 H), 0.14 and 0.10 (2s, 6
H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 175.4, 135.5, 132.61,
130.0, 127.9, 85.6, 68.8, 68.4, 63.6, 39.9, 35.0, 26.78, 25.7, 19.0,
18.1, Ϫ4.8, Ϫ5.2. Ϫ C29H44O5Si2 (528.8): calcd. C 65.87, H 8.39;
found C 65.81, H 8.39
1
3007Ϫ2935 (CϪH), 1735 (CϭO), 1111 (CϪO) cmϪ1. Ϫ H NMR
(250 MHz, CDCl3): δ ϭ 7.67 and 7.41 (m, 20 H), 4.80 (ddd, J ϭ
7.0; 6.8; 4.5 Hz, 1 H), 4.17 (X part of ABX, J ϭ 5.4; 4.7; 2.7 Hz,
1 H), 3.80 (m, 2 H), 3.61 (ddd, J ϭ 6.8; 6.0; 2.7 Hz, 1 H), 2.73 (d,
J ϭ 6.0 Hz, 1 H), 2.64 (A part of ABX, J ϭ 17.7; 5.4 Hz, 1 H),
2.46 (B part of ABX, J ϭ 17.7; 4.7 Hz, 1 H), 1.86 (m, 2 H), 1.11
and 1.04 (2s, 18 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 168.8,
135.8, 135.7, 135.4, 133.2, 132.7, 132.4, 130.4, 130.3, 129.8, 128.1,
127.8, 133.3, 76.7, 70.0, 67.5, 59.6, 36.9, 36.0, 27.0, 26.8, 19.3, 19.2.
Synthesis of Compounds 18, 20, and 21 from the Minor syn Adduct
of Type 6: A solution of epoxy ester 6Јs (1.10 g, 1.88 mmol) in
anhydrous CH2Cl2 (34 mL) at room temp. was treated with dry
ZnCl2 (0.638 g, 4.70 mmol, 2.5 equiv.) and stirred for 10 h at room
temp. Saturated aqueous NaHCO3 (8 mL) was then added and the
aqueous layer was extracted with Et2O (3 ϫ 16 mL). The combined
organic phases were dried with MgSO4, filtered, and concentrated.
(3R,4S,1ЈS)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (17Ј): NMR, IR: identical to
those of compound 17.
[α]D ϭ Ϫ1.40 (c ϭ 1.42, CHCl3) 94% ee.
Synthesis of 18, 19, and 20: A solution of epoxy ester 6a (1.30 g,
2.23 mmol) in anhydrous CH2Cl2 (34 mL, 15 mL/mmol) at room The residue was purified according to method C (120 g of silica
temp. was treated with dry ZnCl2 (0.753 g, 5.56 mmol, 2.5 equiv.) 15Ϫ40 µm), eluting with PE/EA, 8:2 (TLC, Rf21 ϭ 0.54, Rf18
ϭ
4254
Eur. J. Org. Chem. 2001, 4247Ϫ4258

Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters
FULL PAPER
0.33, Rf20 ϭ 0.18). We isolated 0.134 g (0.23 mmol, 12%) of 22,
0.730 g (1.38 mmol, 74%) of 18 and 0.130 g (0.25 mmol, 13%) of butyldiphenylsilyloxy)-γ-lactone (23Ј): [α]D
(3R,4S,1ЈS)-4-[3Ј-(p-Bromobenzyloxy)-1Ј-hydroxypropyl]-3-(tert-
ϩ2.6 (c ϭ 1.1,
ϭ
˜
20. The overall yield was 99%.
CHCl3). Ϫ IR (film): ν ϭ 3449 (OϪH), 3073Ϫ2936 (CϪH), 1786
1
(CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
(3S,4R,1ЈR)-4-[1Ј-(tert-Butoxy)-3-(tert-butyldimethylsilyloxy)-3Ј-
7.64, 7.44 and 7.13 (m, 14 H), 4.58 (X part of ABX, J ϭ 6.1; 1.4;
1.0 Hz, 1 H), 4.37 (s, 2 H), 4.28 (bd, J ϭ 4.6; 1.0 Hz, 1 H), 3.75
(m, J ϭ 3.1 Hz, 1 H), 3.50 (m, 2 H), 2.94 (d, J ϭ 3.1 Hz, 1 H),
2.69 (A part of ABX, J ϭ 18.0; 6.1 Hz, 1 H); 2.41 (B part of ABX,
J ϭ 18.0; 1.4 Hz, 1 H), 1.33 (m, 2 H), 1.06 (s, tBu, 9 H). Ϫ 13C
NMR (63 MHz, CDCl3): δ ϭ 176.12, 144.0, 135.9, 135.8, 134.8,
132.9, 131.7, 130.2, 129.3, 127.9, 121.9, 90.5, 72.6, 70.6, 69.6, 68.6,
38.7, 31.5, 28.8, 19.1. Ϫ C30H35BrO5Si (583.6): calcd. C 61.74, H
6.04; found C 61.76, H 6.11.
˜
(tert-butyldiphenylsilyloxy)propyl]-γ-lactone (21): IR (film): ν ϭ
1
3052Ϫ2934 (CϪH), 1786 (CϭO), 1097 (CϪO) cmϪ1. Ϫ H NMR
(250 MHz, CDCl3): δ ϭ 7.67 and 7.40 (m, 10 H), 4.50 (X part of
ABX, J ϭ 7.5; 1.8; 1.5 Hz, 1 H), 4.35 (m, J ϭ 1.8 Hz, 1 H), 4.02
(ddd, J ϭ 9.0; 3.5; 2.2 Hz, 1 H), 3.73 (m, 2 H), 2.83 (dd, A part of
ABX, J ϭ 17.5; 7.5 Hz, 1 H), 2.28 (B part of ABX, J ϭ 17.5;
1.5 Hz, 1 H), 1.77 and 1.61 (m, 2 H), 1.14, 1.07 and 0.84 (3s, 27
H), 0.05 and 0.02 (2s, 6 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ
176.8, 135.6, 133.4, 133.2, 129.8, 127.8, 89.9, 74.9, 66.7, 66.2, 60.6,
39.9, 36.1, 28.5, 26.7, 25.6, 19.2, 17.8, Ϫ4.5, Ϫ4.8. Ϫ C33H52O5Si2
(584.9): calcd. C 67.79, H 11.23; found C 67.43, H 10.95.
(3S,4S,1ЈS)-4-[3Ј-(p-Bromobenzyloxy)-1Ј-hydroxypropyl]-3-(tert-
butyldiphenylsilyloxy)-γ-lactone (24Ј): [α]D
ϭ ϩ0.5 (c ϭ 0.9,
˜
CHCl3). Ϫ IR (neat): ν ϭ 3503 (OH), 2934Ϫ2861 (CϪH), 1789
(3S,4R,1ЈR)-3-(tert-Butyldiphenylsilyloxy)-4-[4Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxybutyl]-γ-lactone (22): A solution of epoxy ester
8a (2.0 g, 2.77 mmol) in anhydrous CH2Cl2 (42 mL) at room temp.
was treated with dry ZnCl2 (0.75 g, 5.54 mmol, 2 equiv.) and stirred
for 4 h 50 min at room temp. A saturated aqueous solution of
NaHCO3 (10 mL) was then added and the aqueous layer was ex-
tracted with Et2O (3 ϫ 30 mL). The combined organic phases were
dried with MgSO4, filtered, and concentrated. The residue was
purified according to method C (150 g of silica 15 µm), eluting with
PE/EA, 8:2 (TLC, Rf ϭ 0.27). We isolated 1.47 g (2.22 mmol) of
1
(CϭO), 1111 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.74, 7.46, and 7.19 (m, 14 H), 4.71 (dd, J ϭ 3.5; 3.3 Hz, 1 H), 4.50
(s, 2 H), 4.38 (tt, J ϭ 8.5; 2.1; 3.7 Hz, 1 H), 4.07 (dd, J ϭ 8.5;
3.5 Hz, 1 H), 3.77 (m, 2 H), 2.30 (d, 2 H), 2.15 (m, 1 H), 1.92 (m,
1 H), 1.09 (s, 9 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 174.97,
136.9, 135.9, 135.8, 133.1, 132.1, 131.9, 130.3, 129.3, 128.0, 121.7,
85.2, 72.6, 70.1, 68.8, 67.8, 38.9, 33.2, 28.9, 19.3. Ϫ C30H35BrO5Si
(583.6): calcd. C 61.74, H 6.04; found C 61.59, H 6.13.
Synthesis of Compounds 25 and 26: A solution of epoxy esters 9a
and 9s (mixture, 1.44 g, 2.21 mmol) in anhydrous CH2Cl2 (33 mL)
at room temp. was treated with dry ZnCl2 (0.597 g, 4.41 mmol, 2
equiv.). A saturated aqueous solution of NaHCO3 (4 mL) was ad-
ded and the aqueous layer was extracted with Et2O (2 ϫ 10 mL).
The combined organic phases were dried with MgSO4, filtered, and
concentrated. The residue was purified according to method C
(80 g of silica 15 µm), eluting with PE/EA/CH2Cl2, 4:2/4 (CCM,
Rf26 ϭ 0.37, Rf25 ϭ 0.29). We isolated 0.931 g (1.56 mmol) of lac-
tone 25 and 0.12 g (0.20 mmol) of 25. The overall yield was 80%.
lactone 22. Yield 80%. [α]D ϭ ϩ1.44 (c ϭ 1.9, CHCl3). [α]D
ϭ
˜
ϩ1.22 (c ϭ 0.91, CHCl3), ee ϭ 88%. Ϫ IR (CHCl3): ν ϭ
3626Ϫ3390 (OϪH), 3075Ϫ2863 (CϪH), 1775 (CϭO), 1110 (CϪO)
1
cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.65 and 7.41 (m, 20
H), 4.56 (X part of ABX, J ϭ 6.3; 4.1; 1.5 Hz, 1 H), 4.29 (m, J ϭ
4.1; 3.8 Hz, 1 H), 3.50 (m, 3 H), 2.95 (d, J ϭ 4.5 Hz, 1 H), 2.71 (A
part of ABX, J ϭ 18.0; 6.3 Hz, 1 H), 2.41 (B part of ABX, J ϭ
18.0; 1.5 Hz, 1 H), 1.63 (m, 2 H), 1.22 (m, 2 H), 1.10 and 1.04 (2s,
18 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 176.4, 135.9, 135.8,
135.5, 133.2, 132.9, 132.8, 130.1, 129.8, 128.0, 127.9, 127.8, 91.1,
71.1, 69.6, 64.0, 39.0, 29.4, 28.7, 26.8, 19.1. Ϫ C40H52O5Si2 (669.0):
calcd. C 72.03, H 7.56; found C 71.90, H 7.62.
(3S,4R,1ЈR)-4-[4Ј-(p-Bromobenzyloxy)-1Ј-hydroxybutyl]-3-(tert-
butyldiphenylsilyloxy)-γ-lactone (25): [α]D ϭ Ϫ1.1 (c ϭ 1.9, CHCl3).
Ϫ IR (film): ν˜ ϭ 3438 (OϪH), 3073Ϫ2861 (CϪH), 1781 (CϭO),
1110 (CϪO) cmϪ1. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 7.64, 7.43,
and 7.14 (m, 14 H), 4.55 (X part of ABX, J ϭ 6.3; 1.7; 1.5 Hz, 1
H), 4.41 (s, 2 H), 4.28 (dd, J ϭ 3.2; 1.5 Hz, 1 H), 3.56 (m, 1 H),
3.37 (m, 2 H), 3.10 (d, J ϭ 4.8 Hz, 1 H), 2.67 (A part of ABX, J ϭ
18.0; 6.3 Hz, 1 H), 2.40 (B part of ABX, J ϭ 18.0; 1.7 Hz, 1 H),
1.60 (m, 2 H), 1.25 (m, 2 H), 1.06 (s, 9 H). Ϫ 13C NMR (63 MHz,
CDCl3): δ ϭ 176.2, 136.7, 135.9, 135.8, 132.9, 131.6, 130.1, 129.4,
128.0, 127.9, 121.7, 90.8, 72.4, 71.1, 70.2, 69.6, 38.9, 29.9, 26.8,
26.2, 19.1. Ϫ C31H34BrO5Si (594.6): calcd. C 62.30, H 6.24; found
C 62.44, H 6.41.
(3R,4S,1ЈS)-3-(tert-Butyldiphenylsilyloxy)-4-[4Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxybutyl]-γ-lactone (22Ј): A solution of epoxy ester
8Јa (2.82 g. 3.91 mmol) in anhydrous CH2Cl2 (59 mL) at room
temp. was treated with dry ZnCl2 (2.12 g, 15.66 mmol, 4 equiv.)
and stirred for 14 h at room temp. A saturated aqueous solution of
NaHCO3 (20 mL) was then added and the aqueous layer was ex-
tracted with Et2O (3 ϫ 40 mL). The combined organic phases were
dried with MgSO4, filtered, and concentrated. The residue was
purified according to method C (100 g of silica 6Ϫ35 µm), eluting
with PE/EA, 8:2 (TLC, Rf ϭ 0.24). We isolated 1.90 g (2.86 mmol)
of lactone 22Ј and 0.33 g of the starting material. The yield was
85%, based on recovered starting material. [α]D ϭ Ϫ1.96 (c ϭ 1.12,
CHCl3). IR and NMR: identical to those of the above compound
(22).
(3R,4R,1ЈR)-4-[4Ј-(p-Bromobenzyloxy)-1Ј-hydroxybutyl]-3-(tert-
butyldiphenylsilyloxy)-γ-lactone (26): [α]D ϭ Ϫ5.4 (c ϭ 1.3, CHCl3).
Ϫ IR (neat): ν˜ ϭ 3438 (OϪH), 3072Ϫ2861 (CϪH), 1782 (CϭO),
1111 (CϪO) cmϪ1. Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 7.67, 7.43,
and 7.19 (m, 14 H), 4.69 (d, J ϭ 3.7 Hz, 1 H), 4.47 (s, 2 H), 4.11
(td, J ϭ 8.6; 8.5; 2.5 Hz, 1 H), 4.06 (td, J ϭ 8.5; 8.5; 3.7 Hz, 1 H),
3.55 (td, J ϭ 6.5; 1.5 Hz, 2 H), 2.32 (m, 2 H), 2.04 (m, 1 H), 1.84
(quint, J ϭ 6.6; 6.5 Hz, 2 H), 1.58 (m, 1 H), 1.05 (s, 9 H). Ϫ 13C
NMR (63 MHz, CDCl3): δ ϭ 174.9, 137.0, 135.8, 132.9, 132.0,
131.6, 130.4, 129.4, 128.1, 121.2, 85.3, 72.4, 70.8, 70.3, 68.2, 38.7,
31.6, 27.0, 26.8, 19.3. Ϫ C31H34BrO5Si (594.6): calcd. C 62.30, H
6.24; found C 62.12, H 6.17.
Synthesis of Compounds 23Ј and 24Ј: A solution of epoxy ester 7Јa
(5.33 g, 8.56 mmol) and 7Јs (mixture) in anhydrous CH2Cl2
(132 mL) at room temp. was treated with dry ZnCl2 (4.8 g, 4
equiv.). A saturated aqueous solution of NaHCO3 (25 mL) was ad-
ded, and the aqueous layer was extracted three times with Et2O.
The combined organic phases were dried with MgSO4, filtered, and
concentrated. The residue was purified according to method C
(200 g of silica 6Ϫ35 µm), eluting with pentane/THF/CH2Cl2:
3.5:0.5:6, (TLC, Rf23Ј ϭ 0.21, Rf24Ј ϭ 0.28). We isolated 2.46 g
(4.22 mmol) of lactone 23Ј, 0.75 g (1.29 mmol) of 24Ј and 0.36 g
(0.62 mmol) of 23Ј and 24Ј mixture. The overall yield was 72%.
Synthesis of Compounds 27, 28, 29, and 30: A solution of epoxy
ester 12a (1.0 g, 1.41 mmol) in CH2Cl2 (21 mL) at room temp. was
Eur. J. Org. Chem. 2001, 4247Ϫ4258
4255

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
treated with ZnCl2 (0.765 g, 4 equiv.) and stirred for 17 h. After
dilution with Et2O (60 mL), a saturated aqueous solution of
A saturated aqueous solution of NaHCO3 (10 mL) was then added.
The aqueous layer was extracted with Et2O (3 ϫ 20 mL). The com-
NaHCO3 (8 mL) was then added. The aqueous phase was extracted bined organic phases were dried over MgSO4, filtered and concen-
with Et2O (2 ϫ 20 mL). The combined organic layers were dried trated under vacuum. The residue was purified according to
with MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified according to purification method C (180 g
method C (80 g of silica 15Ϫ40 µm), eluent PE/EA, 8:2 (TLC,
f34 ϭ 0.32, Rf31 ϭ 0.19, Rf35 ϭ 0.10, Rf33 ϭ 0.07) to afford 0.242 g
R
of silica 6Ϫ35 µm), eluting with PE/EA, 8:2 (TLC, Rf29 ϭ 0.42, (0.41 mmol) of 34, 0.07 g (0.13 mmol) of 31, 0.414 g (0.78 mmol)
Rf27 ϭ 0.26, Rf30 ϭ 0.21, Rf28 ϭ 0.10) to afford 0.281 g (0.40 mmol)
of 35 and 0.105 g (0.20 mmol) of 33. The overall yield was 90%.
of 29, 0.154 g (0.24 mmol) of 27, 0.398 g (0.61 mmol) of 30 and
0.142 g (0.22 mmol) of 28. The overall yield was quantitative.
(3S,4R,1ЈS)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (31): [α]D ϭ ϩ28.3 (c ϭ 2.6,
(3S,4R,1ЈS)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (27): [α]D ϭ ϩ24.4 (c ϭ 0.1,
˜
CHCl3). Ϫ IR (film): ν ϭ 3450 (OϪH), 3073Ϫ2934 (CϪH), 1782
1
(CϭO), 1109 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
˜
CHCl3). Ϫ IR (film): ν ϭ 3464 (OϪH), 3074Ϫ2935 (CϪH), 1780
7.68 and 7.42 (m, 10 H), 4.59 (X part of ABX, J ϭ 6.8; 3.0; 3.0 Hz,
1 H), 4.19 (m, 1 H), 4.10 (m, J ϭ 8.0; 2.9; 2.0 Hz, 1 H), 3.99 (m,
2 H), 3.35 (d, J ϭ 2.92 Hz, 1 H), 2.95 (A part of ABX, J ϭ 17.5;
6.8 Hz, 1 H), 2.39 (dd, B part of ABX, J ϭ 17.5; 3.0 Hz, 1 H), 2.00
(m,1 H), 1.69 (m, 1 H), 1.04 (s, 9 H), 0.90 (s,9 H), 0.10 (s, 6 H). Ϫ
1H NMR (250 MHz, C6D6): δ ϭ 7.73 and 7.24 (m, 10 H), 4.46 (X
part of ABX, J ϭ 7.0; 4.0; 3.0 Hz, 1 H), 4.04 (dd, J ϭ 3.0; 2.0 Hz,
1 H), 3.94 (ddd, J ϭ 9.0; 2.5; 2.0 Hz, 1 H), 3.72 (m, 1 H), 3.58 (m,
1 H), 2.73 (A part of ABX, J ϭ 17.5; 7.0 Hz, 1 H), 2.21 (B part of
ABX, J ϭ 17.5; 4.0 Hz, 1 H), 1.81 (m, 1 H), 1.43 (m, 1 H), 1.11 (s,
9 H), 0.86 (s, 9 H), Ϫ0.04 and Ϫ0.10 (2s, 6 H). Ϫ 13C NMR
(63 MHz, CDCl3): δ ϭ 176.2, 135.6, 135.5, 132.8, 132.6, 130.1,
130.0, 128.0, 127.9, 90.5, 71.1, 70.1, 63.0, 39.0, 34.8, 26.8, 25.7,
19.0, 17.9, Ϫ4.7, Ϫ4.8. Ϫ MS (DCI/NH3): m/z: 546 [M ϩ 18]
(100%).
1
(CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.64 and 7.40 (m, 20 H), 4.58 (X part of ABX, J ϭ 6.5; 1.7; 1.7 Hz,
1 H), 4.14 (br. s, 1 H), 3.77 and 3.67 (m, 2 H), 3.42 (m, J ϭ 1.7;
9.5 Hz, 1 H), 3.22 (d, J ϭ 1.95 Hz, 1 H), 2.82 (A part of ABX, J ϭ
18.0; 6.5 Hz, 1 H), 2.44 (B part of ABX, J ϭ 18.0; 1.7 Hz, 1 H),
1.85 and 1.38 (m, 2 H), 1.08 and 1.01 (2s, tBu, 18 H). Ϫ 13C NMR
(63 MHz, CDCl3): δ ϭ 176.6, 135.8, 135.7, 135.5, 135.5, 133.4,
132.2, 130.2, 130.0, 129.9, 128.0, 127.9, 127.9, 90.6, 71.5, 63.2, 38.7,
34.4, 26.9, 26.8, 19.0, 18.9.
(3S,4S,5R)-3-(tert-Butyldiphenylsilyloxy)-5-[2Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-ethyl]-4-hydroxy-δ-lactone (28): [α]D ϭ ϩ1.3 (c ϭ 2.0,
˜
CHCl3). Ϫ IR (neat): ν ϭ 3419 (OϪH), 3074Ϫ2935 (CϪH), 1712
1
(CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.64 and 7.44 (m, 20 H), 5.00 (m, 1 H), 4.28 (X part of ABX, J ϭ
4.3; 3.84; 1.9 Hz, 1 H), 3.95 (d, J ϭ 2.5 Hz, OH, 1 H), 3.91 and
3.69 (m, 2 H), 3.80 (d, J ϭ 3.8 Hz, 1 H), 2.79 (A part of ABX, J ϭ
17.5; 4.3 Hz, 1 H), 2.46 (B part of ABX, J ϭ 17.5; 1.9 Hz, 1 H),
2.08 (m, 2 H), 1.09 and 1.03 (2s, 18 H). Ϫ 13C NMR (63 MHz,
CDCl3): δ ϭ 170.0, 135.7, 135.6, 135.6, 135.4, 133.0, 132.8, 132.4,
132.2, 130.2, 130.2, 130.1, 128.0, 76.4, 68.4, 67.9, 59.3, 34.7, 33.9,
26.9, 26.7, 19.1, 19.0. Ϫ MS (DCI/NH3): m/z: 670 [M ϩ 18] (100%),
653 [M ϩ 1] (1.17%).
(3S,4S,5R)-3-(tert-Butyldimethylsilyloxy)-5-[2Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-ethyl]-4-hydroxy-δ-lactone (33): [α]D ϭ ϩ9.6 (c ϭ 3.2,
˜
CHCl3). Ϫ IR (film): ν ϭ 3519 (OϪH), 3072Ϫ2933 (CϪH), 1709
1
(CϭO), 1099 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.66 and 7.45 (m, 10 H), 4.85 (ddd, J ϭ 7.0; 5.0; 1.5 Hz, 1 H), 4.25
(X part of ABX, J ϭ 4.0; 4.0; 2.3 Hz, 1 H), 4.18 (d, J ϭ 3.0 Hz, 1
H), 3.93 (ddd, J ϭ 11.0; 6.5; 2.6 Hz, 1 H), 3.82 (m, 1 H), 3.69 (ddd,
J ϭ 11.0; 8.0; 6.5 Hz, 1 H), 2.97 (A part of ABX, J ϭ 18.0; 4.0 Hz,
1 H), 2.48 (B part of ABX, J ϭ 18.0; 2.3 Hz, 1 H), 2.03 (m, 2 H),
1.06 (s, 9 H), 0.89 (s, 9 H), 0.12 and 0.11 (2s, 6 H). Ϫ 13C NMR
(63 MHz, CDCl3): δ ϭ 170.1, 135.5, 132.4, 132.2, 130.1, 128.0,
76.2, 68.5, 67.7, 59.3, 35.1, 33.8, 26.7, 25.7, 19.0, 17.9, Ϫ4.8, Ϫ4.9.
Ϫ MS (DCI/NH3): m/z: 546 [M ϩ 18], 529 [M ϩ 1] (0.35).
(3S,4S,1ЈR)-4-[1Ј-tert-Butoxy-3Ј-(tert-butyldiphenylsilyloxy)propyl]-
3-(tert-butyldiphenylsilyloxy)-γ-lactone (29): IR (film): ν˜
ϭ
3074Ϫ2965 (CϪH), 1783 (CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR
(250 MHz, CDCl3): δ ϭ 7.65 and 7.42 (m, 20 H), 4.53 (m, 2 H),
4.37 (m, 1 H), 4.00 (m, 1 H), 3.64 (m, 1 H), 2.43 (A part of ABX,
J ϭ 17.0; ഠ1 Hz, 1 H), 2.21 (B part of ABX, J ϭ 17.0; 4.7 Hz, 1
H), 1.79 (m, 2 H), 1.24, 1.09 and 0.93 (3s, 27 H). Ϫ 13C NMR
(63 MHz, CDCl3): δ ϭ 175.4, 135.8, 135.8, 135.5, 133.5, 133.4,
133.3, 130.3, 130.2, 129.7, 129.7, 128.2, 127.9, 127.7, 86.2, 74.4,
71.2, 67.5, 59.3, 39.6, 34.6, 28.8, 28.6, 26.9, 19.3, 19.0. Ϫ MS (DCI/
NH3): m/z: 726 [M ϩ 18] (100%).
1
(3S,4S,1ЈR)-4-[1Ј-tert-Butoxy-3Ј-(tert-butyldiphenylsilyloxy)propyl]-
3-(tert-butyldimethylsilyloxy)-γ-lactone (34): [α]D ϭ Ϫ29.4 (c ϭ 1.5,
CHCl3). Ϫ IR (film): ν˜ ϭ 3073Ϫ2959 (CϪH), 1785 (CϭO), 1090
1
(CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.69 and 7.44
(m, 10 H), 4.33 (dd, J ϭ 8.3; 3.3 Hz, 1 H), 4.24 (m, 1 H), 4.13 (X
part of ABX, J ϭ 4.8, J ϭ 1.3, 1 H), 4.11 (m, 1 H), 3.87 (m, 1 H),
2.28 (A part of ABX, J ϭ 16.9; 1.3 Hz, 1 H), 2.09 (B part of ABX,
J ϭ 16.9;4.9 Hz, 1 H), 1.84 (m, 2 H), 1.17, 1.13 and 0.87 (3s, 27
H), Ϫ0.03 et Ϫ0.11 (2s, 6 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ
175.4, 135.6, 135.6, 133.5, 133.4, 129.7, 127.7, 86.2, 74.4, 69.5, 67.4,
65.9, 59.5, 40.1, 34.4, 28.7, 26.9, 25.7, 19.1, 17.9, Ϫ3.9, Ϫ5.0.
(3S,4S,1ЈR)-3-(tert-Butyldiphenylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (30): [α]D ϭ Ϫ5.1 (c ϭ 1.0,
˜
CHCl3). Ϫ IR (film): ν ϭ 3510 (OϪH), 3074Ϫ2935 (CϪH), 1787
1
(CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.66 and 7.46 (m, 20 H), 4.68 (X part of ABX, J ϭ 7.5; 6.5; 6.3 Hz,
1 H), 4.56 (m, 1 H), 4.21 (dd, J ϭ 6.5; 2.5 Hz, 1 H), 3.87 (m, 2 H),
3.12 (m, 1 H), 2.64 (dd, A part of ABX, J ϭ 17.3; 6.0 Hz, 1 H),
2.30 (B part of ABX, J ϭ 17.3; 7.5 Hz, 1 H), 1.93 and 1.77 (m, 2
H), 1.15 and 1.06 (2s, 18 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ
174.5, 135.7, 135.6, 133.4, 133.2, 132.5, 132.0, 128.2, 128.9, 127.8,
84.3, 70.4, 68.1, 61.2, 37.8, 34.9, 26.9, 19.2, 19.1. Ϫ MS (DCI/
NH3): m/z: 670 [M ϩ 18] (100%), 653 [M ϩ 1] (14%).
(3S,4S,1ЈR)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (35): [α]D ϭ Ϫ3.9 (c ϭ 1.2,
CHCl3). Ϫ IR (film): ν˜ ϭ 3517 (OϪH), 3073Ϫ2934 (CϪH), 1785
1
(CϭO), 1108 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.68 and 7.42 (m, 10 H), 4.68 (X part of ABX, J ϭ 6.5; 4.3; 4.3 Hz,
1 H), 4.36 (m, 2 H), 3.88 (m, 2 H), 3.00 (d, J ϭ 1.92 Hz, 1 H), 2.72
(A part of ABX, J ϭ 17.5; 6.5 Hz, 1 H), 2.61 (B part of ABX, J ϭ
17.0; 4.5 Hz, 1 H), 1.86 (m, 2 H), 1.05 (s, 9 H), 0.91 (s, 9 H), 0.13
Synthesis of Compounds 31, 33, 34, and 35: A solution of epoxy
ester 13a (1.0 g, 1.68 mmol) in CH2Cl2 (25 mL) at room temp. was (s, 6 H). Ϫ 13C NMR (63 MHz, CDCl3): δ ϭ 174.5, 135.5, 133.5,
treated with dry ZnCl2 (1.4 g, 5 equiv.) and stirred for 11 h 30 min.
4256
133.3, 129.8, 127.8, 85.1, 69.7, 67.7, 60.7, 38.9, 34.7, 26.9, 25.7,
Eur. J. Org. Chem. 2001, 4247Ϫ4258

Lewis Acid Mediated Lactonization Reaction of γ,δ-Epoxy-β-silyloxy Esters
19.2, 17.9, Ϫ4.5, Ϫ5.1. Ϫ C29H44O5Si2 (528.8): calcd. C 70.55, H 175.2, 135.6, 133.9, 133.8, 129.6, 127.6, 85.7, 74.5, 69.3, 68.2, 64.4,
FULL PAPER
10.66; found C 70.25, H 11.06.
40.1, 28.9, 28.5, 27.2, 26.9, 25.6, 19.2, 17.9, Ϫ4.0, Ϫ5.1.
(3S,4S,1ЈR)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxybutyl]-γ-lactone (38): [α]D ϭ ϩ0.3 (c ϭ 1.0,
CHCl3). Ϫ IR (film): ν˜ ϭ 3463 (OϪH), 3073Ϫ2934 (CϪH), 1785
Synthesis of Compounds 31Ј and 32: A solution of epoxy ester 13s
(1.13 g, 1.93 mmol) in anhydrous CH2Cl2 (35 mL) was treated with
dry ZnCl2 (1.3 g, 9.60 mmol, 5 equiv.) and stirred for 5 h at room
temp. A saturated aqueous solution of NaHCO3 (10 mL) was then
added and the aqueous phase was extracted with Et2O (3 ϫ
10 mL). The combined organic phases were dried with MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
purified according to purification method C (100 g of silica 15Ϫ40
µm), eluting with PE/EA, 8:2 (TLC Rf32 ϭ 0.47, Rf31Ј ϭ 0.26) to
afford 0.148 g (0.25 mmol, 14%) of 32 and 0.779 g (1.48 mmol,
86%) of 31Ј. The overall yield was 90%.
1
(CϭO), 1109 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
7.66 and 7.40 (m, 10 H), 4.61 (X part of ABX, J ϭ 6.5; 5.0; 3.5 Hz,
1 H), 4.20 (dd, J ϭ 5.1;5.0 Hz, 1 H), 4.00 (m, 1 H), 3.70 (m, J ϭ
5.5; 5.0 Hz, 2 H), 2.74 (A part of ABX, J ϭ 17.5; 6.5 Hz, 1 H),
2.57 (B part of ABX, J ϭ 17.5; 3.5 Hz, 1 H), 1.80 and 1.66 (m, 4
H), 1.05 (s, 9 H), 0.90 (s, 9 H), 0.10 and 0.09 (2s, 6 H). Ϫ 13C
NMR: (63 MHz, CDCl3): δ ϭ 174.5, 135.6, 133.7, 129.6, 127.7,
85.5, 69.8, 69.6, 63.9, 39.2, 29.0, 28.6, 26.9, 25.6, 19.2, 17.8, Ϫ4.5,
Ϫ5.10.
(3R,4R,1ЈS)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxypropyl]-γ-lactone (31Ј): [α]D ϭ Ϫ29.6 (c ϭ 1.1,
CHCl3). NMR, IR spectra are identical to those of compound 31.
Crystal Data for 24Ј: Crystal data C30H35BrO6Si, M ϭ 583.59,
white crystal centric monoclinic, space group C2/c, lattice type mc,
3
˚
˚
a ϭ 19.924, b ϭ 13.0854, c ϭ 23.736 A, V ϭ 5705.9 A , Z ϭ 9,
F(000) ϭ 2432.0. Data collected on a CAD4 EnrafϪNonius dif-
fractometer at room temperature, using graphite monochromated
Mo-Kα radiation. 3439 unique reflections were collected in the
range of 0 Յ θ Յ 24.36. The data were corrected for Lorentz polar-
ization but absorption effects were ignored. The structure was
solved by direct methods and refined (difference Fourier synthesis;
full-matrix, least-squares), using 3439 reflections with I Ͼ 3σ(I).
The final residuals were R ϭ 0.085 and Rw ϭ 0.093.
(3R,4S,1ЈR)-4-[1Ј-tert-Butoxy-3Ј-(tert-butyldiphenylsilyloxy)propyl]-
3-(tert-butyldimethylsilyloxy)-γ-lactone (32): [α]D ϭ Ϫ10.3 (c ϭ
0.74, CHCl3). Ϫ IR (film): ν˜ ϭ 2934Ϫ2860 (CϪH), 1788 (CϭO),
1
1083 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ 7.66 and
7.41 (m, 10 H), 4.53 (dd, J ϭ 2.8, J ϭ 1.5, 1 H), 4.43 (X part of
ABX, J ϭ 6.5; 1.5; 1.5 Hz, 1 H), 4.03 (ddd, J ϭ 8.0; 5.0; 2.8 Hz, 1
H), 3.74 (dd, J ϭ 7.0; 5.0 Hz, 2 H), 2.83 (dd, A part of ABX, J ϭ
17.7; 6.5 Hz, 1 H), 2.33 (B part of ABX, J ϭ 17.7; 1.5 Hz, 1 H),
1.77 (m, 2 H), 1.20, 1.05 and 0.88 (3s, 27 H), 0.09 (s, 6 H). Ϫ 13C
NMR (63 MHz, CDCl3): δ ϭ 176.2, 135.5, 133.6, 133.4, 129.8,
129.7, 127.8, 127.7, 89.5, 74.3, 70.3, 68.2, 60.5, 39.3, 34.8, 28.8,
26.9, 25.7, 19.2, 17.9, Ϫ4.6, Ϫ4.7.
Supporting Information Available (see also footnote on page 1): Syn-
thesis and characterization details for compounds 5a, 6a, 5Јa, 6Јs,
7Јa, 7Јs, 8a, 8Јa, 9a, 9s, 12a, 13a, 13s, 14a (5 pages). Spectroscopic
data for selected compounds 16Ј, 22Ј, and 25؊38. Crystal data and
ORTEP drawing for 24Ј and compound ‘‘3a’’ of reference 6[29] have
been deposited at the Cambridge Crystallographic Data Centre.
Synthesis of Compounds 36, 37, and 38: A solution of epoxy ester
14a (1.0 g, 1.64 mmol) in CH2Cl2 (25 mL) at room temp. was
treated with ZnCl2 (1.12 g, 4.5 equiv.) and stirred for 11 h. After
dilution with Et2O (60 mL), a saturated aqueous solution of
NaHCO3 (10 mL) was added. The aqueous phase was extracted
with Et2O (2 ϫ 40 mL). The combined organic phases were dried
with MgSO4, filtered, and concentrated under reduced pressure.
Purification: Method C, 100 g of silica 6Ϫ35 µm, eluent EP/AE:
8:2 (CCM, Rf37 ϭ 0.21, Rf36 ϭ 0.13, Rf38 ϭ 0.06). We isolated
0.162 g (0.27 mmol), of 37, 0.119 g (0.22 mmol) of 36, and 0.534 g
(0.99 mmol) of 38. The yield was 90%.
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS France) and K. Nacro’s Fellowship was sup-
`
´
ported by the Ministere de lЈEnseignement Superieur et de la Re-
cherche Scientifique of Burkina Faso. We also thank Joe¨l Jaud
(CNRS) for the X-ray structure. We are grateful to Prof. Dr. And-
rea Vasella (ETH Zurich) for fruitful discussions.
[1]
(3S,4R,1ЈS)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
silyloxy)-1Ј-hydroxybutyl]-γ-lactone (36): [α]D ϭ ϩ18.9 (c ϭ 0.9,
CHCl3). Ϫ IR (film): ν˜ ϭ 3444 (OϪH), 3073Ϫ2934 (CϪH), 1783
I. Colins, J. Chem. Soc., Perkin Trans. 1 1998, 1869Ϫ1888.
[2]
N. Petragnani, M. C. Helena, G. Ferraz, V. J. Silva, Synthesis
1986, 157Ϫ183.
H. M. R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. Engl.
[3]
1
(CϭO), 1110 (CϪO) cmϪ1. Ϫ H NMR (250 MHz, CDCl3): δ ϭ
1985, 24, 94Ϫ110.
7.65 and 7.39 (m, 10 H), 4.54 (X part of ABX, J ϭ 6.8; 3.0; 3.0 Hz,
1 H), 4.20 (dd, J ϭ 3.0; 2.0 Hz, 1 H), 3.80 (m, 1 H), 3.70 (m, 2 H),
3.10 (m, 1 H), 2.92 (A part of ABX, J ϭ 17.5; 6.8 Hz, 1 H), 2.59
(B part of ABX, J ϭ 17.5; 3.0 Hz, 1 H), 1.76 (m, 4 H), 1.05 (s, 9
H), 0.89 (s, 9 H), 0.09 (s, 6 H). Ϫ 13C NMR (63 MHz, CDCl3):
δ ϭ 176.0, 135.6, 133.2, 133.0, 129.9, 127.8, 90.4, 71.1, 70.2, 64.2,
38.9, 31.1, 28.7, 26.8, 25.7, 19.1, 17.9, Ϫ4.7, Ϫ4.8.
[4]
S. S. C. Koch, R. A. Chamberlin, J. Org. Chem. 1993, 58,
2725Ϫ2737 and references cited therein.
[5]
W. R. Li, S. Y. Han, M. M. Joullie, Tetrahedron 1993, 49,
785Ϫ802.
V. E. Marquez, K. Nacro, S. Benzaria, J. Lee, R. Sharma, K.
Teng, G. W. A. Milne, B. Bienfait, S. Wang, N. E. Lewin, P.
[6]
Blumberg, Pharmacol. Ther. 1999, 82, 2Ϫ3, 251Ϫ261.
[7]
M. De Rosa, S. Giordano, A. Scettri, G. Sodano, A. Soriente,
´
P. G. Pastor, M. J. Alcaraz, M. Paya, J. Med. Chem. 1998, 41,
(3S,4S,1ЈR)-3-(tert-Butyldimethylsilyloxy)-4-[3Ј-(tert-butyldiphenyl-
3232Ϫ3238.
silyloxy)-1Ј-hydroxybutyl]-γ-lactone (37): [α]D ϭ Ϫ10.3 (c ϭ 1.1,
[8]
J. R. Wheatley, C. J. F. Bichard, S. J. Mantell, J. C. Son, D. J.
Hughes, G. W. J. Fleet, D. Brown, J. Chem. Soc., Chem. Com-
mun. 1993, 1065Ϫ1067.
Ϫ1
˜
CHCl3). Ϫ IR (film): ν ϭ 3073Ϫ2961 (CϪH), 1792 (CϭO) cm
.
Ϫ 1H NMR (250 MHz, CDCl3): δ ϭ 7.67 and 7.42 (m, 10 H), 4.36
(X part of ABX, J ϭ 4.5; 3.3; 1.5 Hz, 1 H), 4.16 (dd, J ϭ 8.3;
3.3 Hz, 1 H), 4.10 (m, 1 H), 3.68 (m, 2 H), 2.64 (A part of ABX,
J ϭ 17.0; 4.5 Hz, 1 H), 2.49 (B part of ABX, J ϭ 17.0; 1.5 Hz, 1
H), 1.72 and 1.58 (m, 4 H), 1.20 (s, 9 H), 1.05 (s, 9 H), 0.88 (s, 9
H), 0.09 and 0.04 (2s, 6 H). Ϫ 13C NMR: (63 MHz, CDCl3): δ ϭ
[9]
´
S. Y. Han, M. M. Joullie, V. V. Fokin, N. A. Petasis, Tetrahed-
ron: Asymmetry 1994, 5, 2535Ϫ2562.
[10]
E. J. Corey, X. M. Cheng, in: The logic of chemical synthesis;
John Wiley & Sons, Inc., New York, USA, 1989, p. 359. For
examples of macrocyclic antibiotic syntheses.
Eur. J. Org. Chem. 2001, 4247Ϫ4258
4257

K. Nacro, L. Gorrichon, J.-M. Escudier, M. Baltas
FULL PAPER
[11]
A. R. Chamberlin, M. Dezube, S. H. Reich, D. J. Sall, J. Am.
6 process). endo-5: opening of the epoxide ring at C(5) to give
a five-membered ring lactone (endo-5 process). endo-6: direct
opening of the epoxide ring at C(5) to give a six-membered
ring lactone (endo-6 process).
J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734Ϫ738.
J. Y. Lallemand, M. Onanga, Tetrahedron Lett. 1975, 8,
585Ϫ588.
Chem. Soc. 1989, 111, 6247Ϫ6256.
S. Hanessian, P. J. Murray, S. P. Sahoo, Tetrahedron Letters
[12]
1985, 26, 5623Ϫ5626; S. Hanessian, P. J. Murray, S. P. Sahoo,
Tetrahedron Letters 1985, 26, 5627Ϫ5630; S. Hanessian, P. J.
Murray, S. P. Sahoo, Tetrahedron Letters 1985, 26, 5631Ϫ5634.
[24]
[25]
[13]
K. Nacro, M. Baltas, J.-M. Escudier, L. Gorrichon, Tetrahed-
[26]
ron Letters 1995, 36, 7867Ϫ7870.
G. Devianne, J.-M. Escudier, M. Baltas, L. Gorrichon, J. Org.
Empirical correlations between the physical properties (Cotton
effect, [α]D values) and the absolute configuration or conforma-
[14]
Chem. 1995, 60, 7343Ϫ7347.
C. Dehoux, E. Fontaine, J.-M. Escudier, M. Baltas, L. Gor-
tion of 4,5-disubstituted γ-lactones are reported in refs.[26,27]
F.-H. Kang, C.-L. Yin, Tetrahedron 1998, 54, 13155Ϫ13166.
.
[15]
[27]
[28]
richon, J. Org. Chem. 1998, 63, 2601Ϫ2608.
C. Forzato, P. Nitti, G. Pitacco, Tetrahedron: Asymmetry 1997,
8, 4101Ϫ4110. Concerning our compounds, we will discuss this
point in a future paper.
[16]
J.-M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron 1993,
49, 5253Ϫ5266.
K. Nacro, M. Baltas, J.-M. Escudier, L. Gorrichon, Tetrahed-
Ref.[19]; X-ray structure of compound 3a of this reference (de-
posited at the Cambridge Crystallographic Data Centre).
For studies on regioselective opening of the epoxide by a re-
[17]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
ron 1996, 52, 9047Ϫ9056.
[18]
K. Nacro, M. Baltas, L. Gorrichon, Tetrahedron 1999, 55,
14013Ϫ14030.
mote hydroxy group see refs.[31,32]
.
[19]
J.-M. Escudier, M. Baltas, L. Gorrichon, Tetrahedron Letters
K. D. Janda, C. G. Shevlin, R. A. Lerner, J. Am. Chem. Soc.
1995, 117, 2659Ϫ2660
1992, 33, 1439Ϫ1442.
K. Nacro, M. Baltas, J.-M. Escudier, L. Gorrichon, Tetrahed-
[20]
K. C. Nicolaou, M. E. Duggan, C. K. Huang, J. Am. Chem.
Soc. 1989, 111, 6676 Ϫ6682 and references therein.
A. R. Chamberlin, M. Dezube, P. Dussault, M. C. McMills, J.
Am. Chem. Soc. 1983, 105, 5819Ϫ5825.
C. H. Fotsch, A. R. Chamberlin, J. Org. Chem. 1991, 56,
4141Ϫ4147.
R. L. Jr Mulholland, A. R. Chamberlin, J. Org. Chem. 1988,
53, 1082Ϫ1085.
K. C. Nicolaou, C. V. C. Prasad, P. K. Somers, C.-K. Huang,
J. Am. Chem. Soc. 1989, 111, 5330Ϫ5334.
Received March 30, 2001
ron 1997, 53, 659Ϫ672.
K. Nacro, M. Baltas, C. Zedde, L. Gorrichon, J. Jaud, Tetra-
[21]
hedron 1999, 55, 5129Ϫ5138.
C. Vogel, C. Bergemann, A. J. Ott, T. K. Lindhorst, J. Thien, W.
[22]
V. Dahlhoff, C. Hällguen, M. M. Palcic, O. Hindgaul, Liebigs
Ann./Recueil 1997, 601Ϫ612 and references cited therein.
exo-5a: opening of the epoxide ring at C(4) to give a five-mem-
[23]
bered ring lactone (exo-5a process). exo-5b: opening of the ep-
oxide ring at C(4) to give a five-membered ring lactone with a
tert-butyl group at C(5) (exo-5b process). exo-6: opening of the
epoxide ring at C(4) to give a six-membered ring lactone (exo-
[O01155]
4258
Eur. J. Org. Chem. 2001, 4247Ϫ4258