Copper-catalysed addition of organometallic reagents to vinyl diepoxides - A novel route to oxa-bridged systems and to substituted allylic alcohols

Article abstract of DOI:10.1002/ejoc.200390181

The copper-catalysed addition of organometallic reagents (Grignard and dialkylzinc) to new vinyl diepoxides was examined. Cyclic vinyl diepoxides undergo clean S_N2′ reactions to afford oxa-bridged systems of various sizes after a domino intramolecular O-alkylation reaction. Acyclic vinyl diepoxides are alkylated in good yields and with good regioselectivities, and a new catalytic enantioselective desymmetrization reaction to afford an enantioenriched allylic epoxy alcohol by the use of catalytic amounts of a copper phosphorarnidite complex was demonstrated. Remarkable differences in terms of reactivity and selectivity are found when different organocopper reagents, generated in situ, are employed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390181

FULL PAPER
Copper-Catalysed Addition of Organometallic Reagents to Vinyl Diepoxides ؊
A Novel Route to Oxa-Bridged Systems and to Substituted Allylic Alcohols
Fabio Bertozzi,[a] Paolo Crotti,[a] Federica Del Moro,[a] Valeria Di Bussolo,[a]
Franco Macchia,[a] and Mauro Pineschi*[a]
Dedicated to the memory of Professor Serena Catalano
Keywords: Catalysis / Copper / Oxabicycles / Oxygen heterocycles
The copper-catalysed addition of organometallic reagents
alcohol by the use of catalytic amounts of a copper phos-
(Grignard and dialkylzinc) to new vinyl diepoxides was ex- phoramidite complex was demonstrated. Remarkable differ-
amined. Cyclic vinyl diepoxides undergo clean SN2Ј reac- ences in terms of reactivity and selectivity are found when
tions to afford oxa-bridged systems of various sizes after a
domino intramolecular O-alkylation reaction. Acyclic vinyl
diepoxides are alkylated in good yields and with good regio-
different organocopper reagents, generated in situ, are em-
ployed.
selectivities, and a new catalytic enantioselective desymme- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
trization reaction to afford an enantioenriched allylic epoxy
Germany, 2003)
Introduction
oxiranes.[9] Chiral copper complexes of phosphoramidites
were also found to be highly effective catalysts for alkylative
desymmetrization, with the aid of dialkylzinc reagents, of
methylidenecycloalkene oxides of type 1, containing en-
antiotopic double bonds in the allylic position with respect
to the epoxide ring (Figure 1).[10]
The reaction of organometallic reagents under copper ca-
talysis conditions is a very popular method for the con-
struction of carbonϪcarbon bonds.[1,2] Among their many
applications are substitution reactions on a wide variety of
allylic substrates by use of Grignard reagents. Regioselectiv-
ity and stereoselectivity are of prime importance in such
reactions, and many outstanding investigations to elucidate
the factors influencing these outcomes have been carried
out.[3] The SN2Ј cleavage of vinyloxiranes, which can be re-
garded as a subclass of allylic substrates, by copper-me-
diated organometallic addition is a well-established and
useful method by which to obtain allylic alcohols.[4] Among
the various ways of introducing chirality in a copper-cata-
lysed organometallic addition reaction, chiral copper com-
plexes of phosphoramidites, developed by Feringa et al.,[5,6]
have been found to be one of the most effective agents, al-
lowing the asymmetric addition of dialkylzinc reagents to
several substrates containing activated double bonds.[7] In
this field, we have recently reported a practical, catalytic
and enantioselective synthesis of 4-methyl-2-cyclohex-
enol,[8] together with a new, regiodivergent and highly en-
antioselective kinetic resolution of racemic semirigid vinyl-
Figure 1. New methylidene diepoxides 2Ϫ4
This result prompted us to investigate the copper-cata-
lysed addition of organometallic reagents (Grignard and di-
alkylzinc) to methylidene diepoxides 2؊4, containing en-
antiotopic (cis compounds 2b, 3b, and 4b) or homotopic
(trans compounds 2a, 3a, and 4a) oxirane rings in the allylic
position with respect to the exocyclic double bond (Fig-
ure 1).
Results and Discussion
[a]
Synthesis of Vinyl Diepoxides 2؊4
Dipartimento di Chimica Bioorganica
e
Biofarmacia,
`
Universita di Pisa,
The synthesis of cyclic diepoxides 2؊3a/b was ac-
complished by starting from the readily available cyclohep-
tanone (n ϭ 2) and cyclooctanone (n ϭ 3) and making use
of a known procedure to prepare cycloalkadienones 5 and
Via Bonanno 33, 56126 Pisa, Italy
Fax: (internat.) ϩ 39-050/43321
E-mail: pineschi@farm.unipi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1264
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1264 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1264Ϫ1270

Copper-Catalysed Addition of Organometallic Reagents to Vinyl Diepoxides
FULL PAPER
6 (Scheme 1).[11] Alkaline epoxidation of 5 and 6 with H2O2 EtMgCl proceeded in a similar way, affording a 72:28 mix-
in acetone/H2O in the presence of Na2CO3 afforded the cor- ture of SN2Ј-alkylated products 13 and 14 (1H NMR in
responding trans-diepoxy ketones 7 and 8 (67 and 56% iso- C6D6).[14]
lated yields, respectively). It is known from the literature
that cis/trans isomerization of related diepoxy ketones may
take place in a basic medium,[12] and also in our case it was
only possible to isolate the trans isomers 7 and 8. Wittig
olefination of 7 and 8 with methyltriphenylphosphonium
bromide in the presence of LDA in THF afforded the new
trans-vinyl diepoxides 2a and 3a (32 and 56% isolated
yields, respectively).[13]
Scheme 3
The above observations clearly indicated that the or-
ganometallic reagent produced in situ reacted with com-
plete SN2Ј regioselectivity to give the allylic epoxy alcohols
11 and 13 as the primary reaction products. Moreover, the
oxabicyclic compounds 12 and 14 are simply derived from
Scheme 1
The synthesis of aliphatic diepoxides 4a and 4b was simi-
larly accomplished by starting from readily available 4-hep-
tanone, which was smoothly converted into (E,E)-hepta-
2,5-dien-4-one (9) by a known procedure (Scheme 2).[11]
The alkaline epoxidation (H2O2/Na2CO3) of dienone 9 in
this case afforded an almost equimolar mixture of the diep-
oxy ketones 10a and 10b, which were separated by flash
chromatography and subjected to olefination with methyl-
triphenylphosphonium bromide in the presence of LDA in
THF to afford the new vinyl diepoxides 4a and 4b (44 and
62% isolated yields, respectively).
the corresponding allylic epoxy alcohols 11 and 13, respec-
tively, by intramolecular nucleophilic opening of the epox-
ide ring by the oxygenated functionality. The intramolecular
O-alkylation clearly demonstrates the trans relationship of
the two interacting groups (OH and the remaining oxirane
functionality) and as a consequence the trans relationship
of the two oxirane functionalities in the starting diepoxide
3a. The intramolecular O-alkylation occurs with complete
regioselectivity at the allylic position of the remaining vinyl-
oxirane, affording the bicyclo[4.2.1]nonane skeleton. The
quantitative formation of the oxa-bridged systems 12 and
14 can be achieved simply by treating the initially obtained
crude reaction mixtures with Amberlyst 15 in CH2Cl2 for
5 min at room temperature.
We subsequently applied the same copper-catalysed ad-
dition of Grignard reagents to the seven-membered vinyl
diepoxide 2a (Scheme 4). While the reactivity displayed by
this substrate seemed to be similar to that of the homologue
3a (complete conversion in 2 h at 0 °C), examination of the
composition of the crude reaction mixture clearly indicated
that the behaviour of 2a was very different: in this case reac-
tions performed with a threefold excess of the Grignard re-
agent (see Table 1) afforded the diols 17aϪd, deriving from
a double alkylation process, as the main reaction product.
The diol adducts of type 17 are always obtained as an ap-
proximately equimolar and inseparable mixture of dia-
stereoisomers and are accompanied by variable amounts of
alcohols 18Ϫ20a/20b, depending on the type of RMgX and
Scheme 2
Copper-Catalysed Additions of Grignard Reagents to Vinyl
Diepoxides 2؊4
On the basis of the well-documented role of CuI salts in reaction conditions used (Table 1).
promoting conjugate additions of Grignard reagents to α,β-
The allylic epoxy alcohols 19a and 19b, common inter-
unsaturated carbonyl compounds and to allylic halides and mediates deriving from the first SN2Ј process for the forma-
acetates,[3] we speculated that copper()-catalysed addition tion of compounds 17aϪd, 18a, 18b, 20a, and 20b, were in
of commercially available Grignard reagents to vinyl di- this case obtained only when RMgCl in Et2O was used (see
epoxides 2؊4 should be feasible. The CuCN-catalysed ad- Entries 2 and 4, Table 1). The use of RMgBr, on the other
dition of MeMgCl (3.0 equiv.) to the trans-vinyl diepoxide hand, did not offer any possibility to isolate the intermedi-
3a occurred smoothly in Et2O (2 h, from Ϫ40 °C up to 0 ate epoxide 19 under any of the reaction conditions exam-
°C) to afford a 62:38 mixture of the allylic epoxy alcohol ined (Entries 1, 3, 5Ϫ9). Use of THF as the solvent drasti-
1
11 and the oxabicyclic compound 12, as determined by H cally reduced the complexity of the reaction mixture, which
NMR in C6D6 (Scheme 3).[14] CuCN-catalysed addition of then turned out to be constituted essentially only of com-
Eur. J. Org. Chem. 2003, 1264Ϫ1270
1265

F. Bertozzi, P. Crotti, F. Del Moro, V. Di Bussolo, F. Macchia, M. Pineschi
Table 1. Copper()-catalysed addition of Grignard reagents to vinyl diepoxide 2a
FULL PAPER
Entry[a]
RMgX
Solvent
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
THF
THF
Copper salt
CuCN
Conversion
Ͼ 98%
Ͼ 95%
76%[c]
Product distribution[b]
1
2
3
4
5
6
7
8
9
MeMgBr
MeMgCl
17a,b (75%), 18a (17%)
19a (Ͻ 1%), 20a (7%)
17a,b (49%), 18a (21%)
19a (25%), 20a (5%)
17a,b (59%), 18a (35%)
19a (4%), 20a (6%)
17a,b (20%), 18a (20%)
19a (50%), 20a (10%)
17a,b (86%), 18a (10%)
19a (1%), 20a (4%)
17a,b (81%), 18a (14%)
19a (Ͻ 1%), 20a (4%)
17a,b (80%), 18a (16%)
19a (Ͻ 1%), 20a (3%)
17c,d (88%), 18b (8%)
19b (Ͻ 1%), 20b (3%)
17c,d (76%), 18b (17%)
19b (Ͻ 1%), 20b (6%)
CuCN
MeMgBr
(1.2 equiv.)
MeMgCl
(1.2 equiv.)
MeMgCl
CuCN
CuCN
82%
CuCN
Ͼ 98%
Ͼ 98%
Ͼ 95%
Ͼ 98%[d]
Ͼ 95%
MeMgBr
MeMgCl
EtMgBr
EtMgBr
CuCN
CuBr·Me2S
CuCN
CuBr·Me2S
[a]
[b]
All reactions were performed in accordance with the typical procedure [CuI salt (20 mol %), RMgX (3.0 equiv.)] see the Exp. Sect.
Determined by 1H NMR and GC analysis of the crude reaction mixtures.
unidentified by-products was obtained. 3-Propyl-2,4-cycloheptadien-1-ol (a deoxygenated product) was also obtained in this reaction
(see the Supporting Information for further details).
A relatively complex reaction mixture containing some
[c]
[d]
Scheme 4
Figure 2. Possible reaction pathways for the double alkylation
process
pounds of type 17 (main product) and 18, together with
some minor amounts of oxa-bridged systems of type 20
(Entries 5Ϫ9). The use of a catalytic amount of CuBr·Me2S and 17b had been formed at the exclusive expense of vinyl-
in place of CuCN gave similar results (Entries 7 and 9). We oxirane 19a, clearly indicating that alkylative ring-opening
were intrigued by the presence of the diol adducts of type of 19a was responsible for the formation of 17a and 17b.
17 as the main reaction products in all reactions examined The predominant active catalytic species in Et2O is prob-
(except for Entry 4). Theoretically, the diastereoisomeric di- ably RCu(CN)MgX, whereas in THF ‘‘higher order’’ mag-
ols 17a and 17b, deriving from a double alkylation process nesium cyanocuprates such as R2Cu(CN)(MgX)2 could
in which the alkyl moiety of the Grignard reagent is trans- also be involved.[16] It is known that dialkylcopper reagents
ferred twice, could form in two ways: (i) by alkylative anti- exhibit different reactivity and an increased preference for
stereoselective SN2 and SN2Ј ring-openings of the inter- SN2 substitution with respect to ‘‘lower order’’ cyanocup-
mediate vinyl oxirane 19, or (ii) by an alkylative, nonstereo- rates.[1,17]
selective ring-opening of the oxa bridged compound 20, de-
The different product distributions observed in the alky-
riving in turn from 19 through an intramolecular O-alky- lation reactions between the seven- and eight-membered vi-
lation in the allylic position (Figure 2).[15] In order to obtain nyloxiranes 2a and 2b could reasonably be explained by
evidence of the process associated with the formation of the comparison of the reactive conformations in the two sys-
diols 17a and 17b, an almost equimolar mixture of 19a and tems. In general, the prerequisite for allylic substitution to
20a was subjected to the standard procedure (MeMgBr/ occur is the ability of the system to adopt a conformation
THF/CuCN 20 mol %) and after 2 h at 0 °C the diols 17a in which the π-orbitals of the double bond and the σ-bond
1266
Eur. J. Org. Chem. 2003, 1264Ϫ1270

Copper-Catalysed Addition of Organometallic Reagents to Vinyl Diepoxides
FULL PAPER
connecting the leaving group to the allylic carbon atom
are aligned.[18] In the case of a vinyloxirane (such as 11
and 19a), the coplanarity necessary to attain the overlap
between the nucleophilic d-orbitals of the copper and the
π*-orbital of the double bond and of the σ*-orbital of the
oxirane moiety (as shown in A, Figure 3),[4] is seriously hin-
dered in the eight-membered vinyl diepoxide 11 by the steric
repulsion between the hydrogen atoms present in positions
2 and 5 (conformation B, Figure 3). The seven-membered
analogue, on the other hand, does not suffer from any nega-
tive steric repulsion (see, for example, conformation C, Fig-
ure 3) thus allowing the copper-catalysed addition of Grig-
nard reagents to the intermediate vinyl epoxide of type 19
to occur, as found experimentally.
Figure 4. Possible reaction pathways for the intramolecular O-alky-
lation of compounds 19a and 19b
main reaction products (Scheme 5, Entries 1 and 2,
Table 2). The use of EtMgBr in THF, on the other hand, in
this case also gave a mixture of the diastereoisomeric diols
22a and 22b (from 4a) and 24a and 24b (from 4b) deriving
from a double alkylation process in which the allylic epoxy
alcohols of types 21 and 23 are the corresponding most
likely intermediates (Entries 3 and 4).
Figure 3. Orbital overlaps and reactive conformation for the SN2Ј-
cuprate alkylation of viniloxiranes 11 (see B) and 19a (see C)
The regioselectivity of the intramolecular O-alkylation of
19a and 19b was somewhat surprising, considering that it
delivered regioisomeric bicyclo[3.2.1] compounds of type 18
in which the attack had occurred at the less activated homo- Scheme 5
allylic position of the oxirane moiety (path b, Figure 4). The
With meso substrate 4b, and in sharp contrast with sub-
oxa-bridged system of type 20, deriving from intramolecu-
lar oxygen alkylation of the intermediate epoxy alcohol 19
in the more activated allylic position was observed only in
very small amounts (path a, Figure 4). Recently, the regiose-
lective intramolecular alkylation observed in cyclohep-
tadienyl epoxyvinyl sulfones was explained in terms of a
bidentate coordination of the acid catalyst with both the
epoxide and the sulfonyl oxygen atoms.[19] Our results indi-
cate that there is an intrinsic preference, albeit modest, for
a bicyclic 6/5 ring system over the other (path b vs. path a,
Figure 4), without the intervention of any chelated activat-
ing functionality.
strate 4a, the commonly observed anti-SN2 and anti-SN2Ј
ring-opening of the intermediate epoxy allylic alcohol 23a
give the same product. The addition on 23a can reasonably
occur both in an anti- and in a syn-SN2Ј fashion to give a
ca. 80:20 mixture of the two diastereoisomers 24a and 24b,
as observed experimentally. The oxygen functionality prob-
ably directs the syn-SN2Ј addition mode.[20]
Copper Phosphoramidite Catalysed Addition of R2Zn to
Vinyl Diepoxides 2a, 3a, and 4b
The addition of Et2Zn (1.5 equiv.) to racemic vinyl di-
Similar control over reactivity, depending on the reagents epoxide 3a, catalysed by a copper complex obtained by mix-
and solvent used for the reaction, was also observed in the ing Cu(OTf)2 (1.5 mol %) with phosphoramidite (S,S,S)-15
aliphatic series of vinyldiepoxides of type 4: when 4a and (3.0 mol %) in toluene (3 h, Ϫ78 °C up to Ϫ10 °C, 45%
4b were treated with EtMgCl (3.0 equiv.) in Et2O in the conversion), afforded a ca. 8:2 mixture (1H NMR in
presence of catalytic amounts of CuCN (20 mol %), the ep- C6D6)[14] of SN2Ј adducts 13 and 14 with complete regiose-
oxy allylic alcohols (E)-21a and 23a were obtained as the lectivity (for formulas see Schemes 3 and 6). Chiral GC
Table 2. Copper()-catalysed addition of EtMgX to vinyldiepoxides 4a and 4b
Entry[a]
Substrate
EtMgX
Solvent
Conversion
Product distribution[b]
1
2
3
4
4a
4b
4a
4b
EtMgCl
EtMgCl
EtMgBr
EtMgBr
Et2O
Et2O
THF
THF
92%
21a (58%), 22a,b (42%)
Ͼ 95%
Ͼ 95%
Ͼ 95%
23a (57%), 24a,b (43%)
21a (Ͻ 3%), 22a,b (Ͼ 97%)
23a (ca. 5%), 24a,b (ca. 95%)
[a]
All reactions were performed in accordance with the typical procedure [CuI salt (20 mol %), RMgX (3.0 equiv.)] see the Exp. Sect.
[b] Determined by H NMR and GC analysis of the crude reaction mixtures.
1
Eur. J. Org. Chem. 2003, 1264Ϫ1270
1267

F. Bertozzi, P. Crotti, F. Del Moro, V. Di Bussolo, F. Macchia, M. Pineschi
FULL PAPER
analysis showed that the vinyl diepoxide 3a was essentially CuCN substantially delivered only the isomeric (E)-epoxy
racemic, indicating that a kinetic resolution of 3a was not allylic alcohol 23a (Scheme 5 and Table 2). It is likely that
effective with this chiral catalyst.
the different reaction conditions may also give rise to a
change in the active catalytic species in this case. In copper-
catalysed organometallic addition to allylic substrates, the
(E) isomer is usually formed preferentially.[21] In the copper
phosphoramidite catalysed addition of Et2Zn, an almost
equimolar (E)/(Z) mixture of the epoxy allylic alcohols 23a
and 23b (with essentially the same ee values) was formed
and this could be an indication that the ratio of s-trans/
s-cis conformers of vinyl diepoxide 4b does not affect the
enantiomeric excesses of epoxy allylic alcohols 23a and
23b.[22]
Conclusion
Scheme 6
In summary, we have examined the copper-catalysed ad-
The copper phosphoramidite-catalysed addition of dition of Grignard and dialkylzinc reagents to some new
Me2Zn to the seven-membered vinyl diepoxide 2a afforded methylidene diepoxides. Cyclic trans-vinyl diepoxides 2a
a complex reaction mixture in which the double alkylated and 3a undergo SN2Ј addition reactions with organocopper
diols 17a and 17b were not present (GC) even in trace reagents produced in situ with a high degree of regioselec-
amounts (Scheme 4).
tivity, thus allowing a new alkylative approach to oxa-
As the aliphatic series included the symmetrical substrate bridged systems of different sizes. Acyclic vinyl epoxides 4a
like 4b, possessing enantiotopic oxirane moieties, a study and 4b are alkylated with good yields and regioselectivities.
was made of a catalytic alkylative desymmetrization reac- A new catalytic enantioselective desymmetrization reaction
tion, previously explored with methylidenecycloalkene ox- of a meso-symmetrical system to give an enantioenriched
ides of type 1 (Figure 1).[10] At full conversion (5 h, from epoxy allylic alcohol has been accomplished by the use of
Ϫ78 °C up to 0 °C) the desymmetrization reaction of meso- Et2Zn and catalytic amounts of a chiral copper complex
vinyl diepoxide 4b with Et2Zn in the presence of a catalytic of phosphoramidite 15. The nature of the organometallic
chiral copper complex of phosphoramidite (S,S,S)-15, gave reagent plays an important role in determining the outcome
a mixture of different ring-opening products: the allylic al- of the reaction. While the copper phosphoramidite addition
cohols 23b and 23a (SN2Ј addition pathway, 90%), diol 25 of dialkylzinc reagents was not able to alkylate the inter-
(double anti-SN2 addition, 7%) and epoxy alcohol 26 (single mediate epoxyallylic alcohols of type 19, 21, and 23, the
anti-SN2 addition, ca. 3%) (Scheme 6). The homoallylic diol addition of Grignard reagents resulted in a new double al-
25 and the epoxyallylic alcohol 26 were easily separated by kylation process. The remarkable solvent effect on the prod-
flash chromatography from the crude reaction mixture con- uct distribution of the CuCN-catalysed cross-coupling reac-
taining the allylic alcohols 23a and 23b. Pure samples of tions of methylidene diepoxides 2a and 4a and 4b with
stereoisomers 23a and 23b could only be obtained by sub- Grignard reagents can be reasonably explained by assuming
sequent semipreparative TLC. These compounds showed the involvement of different active catalytic species. Fur-
(GC analysis on chiral stationary phase) moderate enanti- thermore, the different (E)/(Z) product ratios exhibited by
omeric excesses (23b: 48% ee; 23a: 52% ee), thus indicating 4b when different organocopper reagents are generated in
that enantioselective desymmetrization of meso-vinyl di- situ seems difficult to explain in terms of simply steric inter-
epoxide 4a had occurred to some extent. In this case, con- actions in reactant-like transition state conformers.
sistently with the results of the ring-openings observed pre-
viously, the epoxy allylic alcohols 23a and 23b do not un-
dergo a subsequent conjugate alkylation to give the corre-
sponding diastereoisomeric diols 24a and 24b (Scheme 6).
However, it was possible to isolate minor quantities of the
diol 25 and of the alcohol 26, originating from direct alky-
lation in the allylic position, in which the exomethylidene
unit had been maintained.
Another interesting feature of this addition reaction is
the formation of a 40:60 mixture of both (Z)-23b and (E)-
23a isomeric epoxy allylic alcohols (SN2Ј addition products)
when the reaction is performed with Et2Zn in the presence
of the chiral copper phosphoramidite catalyst. In contrast,
Experimental Section
General Remarks: All reactions were carried out in flame-dried
glassware with magnetic stirring under argon. Toluene, diethyl
ether, and THF were distilled from sodium/benzophenone ketyl
and stored under argon. Diisopropylamine was freshly distilled
from CaH2. Analytical TLC was performed on Alugram SIL G/
UV 254 silica gel sheets (MachereyϪNagel) with detection by 0.5%
phosphomolybdic acid solution in 95% EtOH. Silica gel 60
(MachereyϪNagel, 230Ϫ400 mesh) was used for flash chromatog-
raphy. Solvents for extraction and chromatography were of HPLC
grade. 1H NMR spectra were recorded with a Bruker AC 200 spec-
the use of EtMgX in the presence of a catalytic amount of trometer on CDCl3 or C6D6 solutions. Chemical shifts are reported
1268 Eur. J. Org. Chem. 2003, 1264Ϫ1270

Copper-Catalysed Addition of Organometallic Reagents to Vinyl Diepoxides
in ppm downfield from tetramethylsilane with the solvent reson-
FULL PAPER
Bäckvall, G. van Koten, Chem. Eur. J. 1995, 351Ϫ359 and ref-
erences therein.
ance as the internal standard (CDCl3: δ ϭ 7.26 ppm). 13C NMR
[4]
For a review, see: J. A. Marshall, Chem. Rev. 1989, 89,
spectra were recorded with a Bruker AC 200 (50 MHz) spec-
trometer with complete proton decoupling. Chemical shifts are re-
ported in ppm downfield from tetramethylsilane with the solvent
resonance as the internal standard (CDCl3: δ ϭ 77.7 ppm). Infrared
1503Ϫ1511.
[5]
A. H. M. de Vries, A. Meetsma, B. L. Feringa, Angew. Chem.
Int. Ed. Engl. 1996, 35, 2374Ϫ2376; Angew. Chem. 1996, 108,
2526Ϫ2528.
B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M.
de Vries, Angew. Chem. Int. Ed. Engl. 1997, 36, 2620Ϫ2623;
Angew. Chem. 1997, 109, 2733Ϫ2736.
For an overview of phosphoramidites in catalytic asymmetric
conjugate additions, see: B. L. Feringa, Acc. Chem. Res. 2000,
33, 346Ϫ353. For the use of phosphoramidites in asymmetric
conjugate addition reactions, see also: A. Alexakis, C.
Benhaim, S. Rosset, M. Human, J. Am. Chem. Soc. 2002, 124,
5262Ϫ5263 and pertinent references therein.
F. Bertozzi, P. Crotti, B. L. Feringa, F. Macchia, M. Pineschi,
Synthesis 2001, 483Ϫ486.
F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, B. L. Feringa,
Angew. Chem. Int. Ed. 2001, 40, 930Ϫ932.
F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold, B.
L. Feringa, Org. Lett. 2000, 2, 933Ϫ936.
H. O. Krabbenhoft, J. Org. Chem. 1979, 44, 4285Ϫ4294.
H. Prinzbach, W. Seppelt, H. Frintz, Angew. Chem. Int. Ed.
Engl. 1976, 16, 198Ϫ199; Angew. Chem. 1977, 89, 174Ϫ175.
The relative trans configuration of the oxirane functionalities
present in 2a and 3a was later confirmed on the basis of their
chemical behaviour. Therefore, in the cyclic case under examin-
ation (Scheme 1), it was not possible to obtain significant
amounts of the corresponding cis-diepoxides 2b and 3b, which
could be more challenging to study in a possible desymmetriz-
ation reaction with organometallic reagents in the presence of
a chiral catalyst.
[6]
spectra (IR) were obtained with a Mattson 3000 FTIR spec-
trometer. Enantioselectivities were determined with
a
PerkinϪElmer 8420 apparatus (FI detector) with a Chromopak
fused silica 25 m ϫ 0.25 mm column, coated with CP-Cyclodextrin-
B-236-M-19. In all cases the injector and detector temperatures
were 250 °C and a ca. 0.9 mL/min helium flow was employed. Con-
versions and regioselectivities were determined with an HP-5890
instrument fitted with an HP-5 capillary column (30 m ϫ
0.25 mm). The following compounds were commercially available
and were used without purification: Et2Zn (1.1  solution in tolu-
ene, Aldrich), EtMgCl (2.0  solution in THF, Aldrich), EtMgBr
(3.0  solution in Et2O, Aldrich), MeMgCl (3.0  in THF),
MeMgBr (3.0  in Et2O), and Cu(OTf)2 (Ͼ 98%, Aldrich), CuCN
and CuBr·Me2S (Fluka), butyllithium (1.6  solution in hexanes,
Aldrich) and methyltriphenylphosphonium bromide (98%) (Ald-
rich).
[7]
[8]
[9]
[10]
[11]
[12]
[13]
Typical Procedure for the Copper-Catalyzed Addition of Grignard
Reagents to Vinyl Diepoxides 2a, 3a, 4a and 4b (Table 1 and Table
2): To a stirred suspension of CuCN (9.0 mg, 0.1 mmol) in anhy-
drous Et2O or THF (1.0 mL), at Ϫ40 °C, was added dropwise a
solution of RMgX (1.5 mmol), and the heterogeneous mixture was
stirred at the same temperature for 30 min. A solution of the vinyl
diepoxide (0.5 mmol) in Et2O or THF (1.0 mL) was slowly added,
and the resulting mixture was allowed to warm to 0 °C. The reac-
tion was monitored by TLC and quenched at 0 °C with saturated
aqueous NH4Cl. Extraction with Et2O and concentration of the
dried (MgSO4) organic phase gave a crude reaction product which
was subjected to chromatography (SiO2). See Supporting Infor-
mation for further details.
[14]
[15]
[16]
The 11/12 and 13/14 ratio (determined by 1H NMR) depended
on the solvent in which the spectra were recorded: C6D6 gave
the highest proportions of compound 11, while the same com-
pound was almost negligible when the spectra were recorded
in CDCl3.
It is known that oxabicyclic compounds can react with or-
ganometallic reagents in both syn and anti fashion. For an
extensive review concerning the ring-opening of oxabicyclic
compounds, see: P. Chiu, M. Lautens, Top. Curr. Chem. 1997,
190, 1Ϫ85.
We are not concerned about the exact constitution of the spec-
ies involved in this reaction, but with the reactive species as a
reagent system. For a review regarding the structure and reac-
tivity of cyanocuprates, see: N. Krause, Angew. Chem. Int. Ed.
1999, 38, 79Ϫ81; Angew. Chem. 1998, 110, 83. For a recent
discussion about the decisive influence of the composition of
the reagents and the solvent used in a metal-catalysed addition
of Grignard reagents to allylic acetates, see: M. Ito, M. Matsu-
umi, M. G. Murugesh, Y. Kobayashi, J. Org. Chem. 2001, 66,
5881Ϫ5889 and references therein.
Typical Procedure for the Copper-Catalyzed Addition of Et2Zn to
Vinyl Diepoxides 3a, 4b: In a 25-mL Schlenk flask, under argon, a
solution of Cu(OTf)2 (5.5 mg, 0.015 mmol) and chiral ligand
(S,S,S)-15 (16 mg, 0.03 mmol) in anhydrous toluene (2 mL) was
stirred at room temp. 40 min. The colorless solution was cooled
to Ϫ78 °C, treated with a solution of vinyloxirane (1.0 mmol) in
anhydrous toluene (0.5 ml) and then with a 1.1  solution of Et2
Zn in toluene (1.35 mL, 1.5 mmol). The reaction was monitored
by TLC and quenched at 0 °C with saturared aqueous NH4Cl.
Extraction with Et2O and concentration of the dried (MgSO4) or-
ganic phase gave a crude reaction product which was subjected to
chromatography (SiO2).
[17]
[18]
[19]
[20]
´
For example, see: J.-E. Bäckvall, M. Sellen, B. Grant, J. Am.
Chem. Soc. 1990, 112, 6615Ϫ6621.
For example, see: C. N. Farthing, P. Kocovsky, J. Am. Chem.
Soc. 1998, 120, 6661Ϫ6672 and pertinent references therein.
W. Jiang, D. A. Lantrip, P. L. Fuchs, Org. Lett. 2000, 2,
2181Ϫ2184.
For a recent example of a O-directed conjugate addition of
Grignard reagents, see: K. A. Swiss, D. C. Liotta, J. Am. Chem.
Soc. 1990, 112, 9393Ϫ9394. For a review on substrate-di-
rectable chemical reactions, see: A. H. Hoveyda, D. A. Evans,
G. C. Fu, Chem. Rev. 1993, 93, 1307Ϫ1370.
For a recent example of an (E)-selective [(E)/(Z) ratios Ͼ 4]
copper-catalysed ring-opening of vinyloxiranes with organoz-
inc reagents, see: B. H. Lipshutz, K. Woo, T. Gross, D. J. Buz-
ard, R. Tirado, Synlett 1997, 477Ϫ478.
Needless to say, the ground state and the reactive conformer
are not necessarily the same. Although it is not possible to use
direct methods firmly to establish the formation of a π-allyl
Acknowledgments
We gratefully acknowledge funding by the M. I. U. R. (Rome), by
the University of Pisa and by Merck (2002 ADP Chemistry Award
to P. C.).
[21]
[22]
[1]
Modern Organocopper Chemistry (Ed.: N. Krause), Wiley-
VCH, Weinheim, 2002.
B. H. Lipshutz, in: Organometallics in Synthesis (Ed.: M.
[2]
Schlosser), John Wiley & Sons Ltd., Chichester, 1994, pp.
283Ϫ382.
[3]
E. S. M. Persson, M. van Klaveren, D. M. Grove, J.-E.
Eur. J. Org. Chem. 2003, 1264Ϫ1270
1269

F. Bertozzi, P. Crotti, F. Del Moro, V. Di Bussolo, F. Macchia, M. Pineschi
FULL PAPER
complex, it seems reasonable that its formation and subsequent
isomerization may give a different product distribution when
different organometallic reagents are employed. For an in-
terpretation of the different behaviour of a copper-catalysed
alkylation of dialkylzinc reagents with vinyloxiranes through
the involvement of regioisomeric σ-allylic CuIII species, see
ref.[9] and references therein. In general, a metal-bound allyl
ligand can undergo geometric interconversion by changing its
hapticity. However, the well-known π-σ-π isomerization, which
could explain the double bond isomerization, is often found in
Pd-catalysed allylic alkylations, but has never been invoked in
a Cu-catalysed allylic alkylation.
Received November 12, 2002
[O02628]
1270
Eur. J. Org. Chem. 2003, 1264Ϫ1270