Copper-catalysed meso-bislactone ring opening using Grignard and mixed triorganozinc reagents

Article abstract of DOI:10.1016/j.tetlet.2006.07.146

An efficient copper-mediated S_N2′ ring-opening reaction of a meso-bislactone has been developed using Grignard reagents and, for the first time, mixed triorganozinc reagents.

Full text of DOI:10.1016/j.tetlet.2006.07.146

Tetrahedron Letters 47 (2006) 7205–7208
Copper-catalysed meso-bislactone ring opening using Grignard
and mixed triorganozinc reagents
Scott Borthwick, Wolfgang Dohle, Paul R. Hirst and Kevin I. Booker-Milburn*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK
Received 13 June 2006; revised 28 July 2006; accepted 28 July 2006
Available online 17 August 2006
Abstract—An efficient copper-mediated SN20 ring-opening reaction of a meso-bislactone has been developed using Grignard
reagents and, for the first time, mixed triorganozinc reagents.
Ó 2006 Elsevier Ltd. All rights reserved.
The formation of new carbon–carbon bonds by allylic
OMs
OMs
CN
CN
CO2H
CO2H
a
b
O
O
O
substitution has been shown to be especially convenient
for transferring the chirality of a C–X bond to a C–C
bond. To date, a large range of copper-mediated and
copper-catalysed stereoselective allylic substitutions
have been reported to achieve this.1
94%
85%
5
6
7
c
66%
O
O
OH
CO2H
CO2H
Recently, we described a rapid stereocontrolled entry to
the tetracyclic core of neotuberostemonine,2 where an
anti-selective SN20 ring-opening reaction of a racemic
C2-symmetric bislactone 1 was developed (Scheme 1).
O
O
3
Scheme 2. Synthesis of meso-bislactone 3. Reagents and conditions:
(a) KCN (3 equiv), DMSO 100 °C, 4 h; (b) KOH (8 equiv), H2O,
100 °C, 3 h; (c) 4 M HCl, 100 °C, 4 h.
In exploring the scope of this process, we identified the
corresponding meso-bislactone 3 (Scheme 2) as an alter-
native desymmetrisation substrate.3 Compound 3 differs
from the C2-symmetric bislactone 1 in two distinct ways:
(a) the cis-relationship between the two lactone groups
could potentially lead to a stereoselective addition (anti
vs syn); (b) a catalytically mediated asymmetric desym-
metrisation of 3 could provide access to enantioenriched
products containing four contiguous stereogenic carbon
centres.
O
O
O
O
O
O
The preparation of meso compound 3 was achieved, in
gram quantities, by modifying the previously described
synthetic route for the C2-symmetric compound 1.2
Thus, treatment of the readily available bismesylate 54
with KCN in DMSO allowed access to dinitrile 6.
Hydrolysis under basic conditions led to diacid 7, which
upon heating in 4 M HCl underwent double lactonisa-
tion to 3 in 66% yield (Scheme 2). Compared to the
C2-symmetric isomer the success of the ring opening/lac-
tonisation sequence of 7 was surprising, that is, the fur-
an is likely to first undergo protonation and cleavage to
a cation thus rendering it susceptible to side reactions
such as arene formation.
+
CO2H
CO2H
O
O
Et
Et
1
anti-2
syn-2
Scheme 1. SN20 ring-opening reaction of C2-symmetric bislactone 1
using organocopper reagents. Reagents and conditions: EtMgCl
(10 equiv), CuBrÆMe2S (10 equiv), THF/Me2S 2:1, ꢀ20 °C, 89%,
anti/syn = 8.5:1.
Keywords: Organocopper; Desymmetrisation; Grignard; Organozinc;
meso-Bislactone.
*
Corresponding author. E-mail: k.booker-milburn@bristol.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.146

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S. Borthwick et al. / Tetrahedron Letters 47 (2006) 7205–7208
Applying the original desymmetrisation conditions (see
Scheme 1) to 3 provided the desired product 4a in a rea-
sonable isolated yield. After a short optimisation pro-
gram, it was found that just 2 equiv of ethylcuprate in
THF (c 0.1 M w.r.t. Cu) at ꢀ20 °C provided 4a in
excellent yield (88%, Table 1). It was important to note
that the reaction was completely regioselective for SN20
addition, as well as stereoselective for the anti-product
4a.
and CuBrÆMe2S (10 mol %) in THF with EtMgCl
(1.8 equiv) resulted in a clean reaction to a mixture of
two compounds in a 2:1 ratio. The major component
was identified as the addition product 4a. After further
study, the minor product was identified as the double
ring-opened diene-diacid 8, which initially appeared to
be an unusual reduction product.
On further analysis, it can be suggested that under cata-
lytic Cu conditions diethylcuprate is formed which ini-
tially reacts as expected via anti-selective SN20 addition
resulting in the Cu(III) intermediate 9.5 Instead of trans-
ferring an ethyl group to form 4a, this then undergoes
reductive elimination by homocoupling to give Cu(I)
intermediate 10 and butane. Nucleophilic attack by
EtMgCl on the Cu(I) centre of 10 then induces b-metallo-
lactone fragmentation leading to 8, whilst returning
EtCu(I) to the catalytic cycle (Scheme 3).
With the intention of developing an asymmetric desym-
metrisation, it was appropriate to examine the use of
catalytic copper in this reaction. Thus, treatment of 3
Table 1. Copper-catalysed desymmetrisation of 3 using Grignard and
mixed triorganozinc reagents
Method A
O
O
RMgX (2 equiv.)
CuBr/Me2S (2 equiv.)
THF, -20 oC
O
O
O
O
O
O
HO2C
CO2H
O
+
Method B
CO2H
O
R
CO2H
O
RZnMe2MgX (3 equiv.)
CuCN/2LiCl (20 mol%)
THF, -10 oC
3
rac-4
O
Et
8: 31%
4a: 61%
3
i
ii
iv
Et2CuMgCl
Entry Product R(X)
Method Time Yield
EtCu
EtCu
(h)
(%)
O
O
O
O
1
2
3
4a
4b
4c
Et (Cl)
A
<1
<1
1
1
2
1
1
<1
1
88
84
78
78
83
75
73
62d
72
iii
B
Aa
B
CO2
10
CO2
n-Bu (Cl)
Me (Cl)
BuH
Et2CuIII
CuI
Ab
Bb
Ab
9
EtMgCl
4
5
4d
4e
TMSCH2 (Cl)
H2C@CH(CH2)2 (Br) Ac
Scheme 3. Formation of diacid 8. Reagents and conditions:
CuBrÆMe2S (10 mol %), EtMgCl (1.8 equiv) THF, ꢀ15 °C, 3 h. Path-
way: (i) SN20 ring opening; (ii) ‘normal’ alkyl transfer; (iii) reductive
elimination to 10; (iv) fragmentation.
B
O
6
4f
Aa
B
<1
1
58e
61e
O
(Br)
As we were unable to halt the formation of diene 8 when
using catalytic quantities of copper, attention was
focussed on an examination of the range of Grignard
nucleophiles, which could be employed in the desymmet-
risation (Table 1). In all cases, the organocopper
reagents (2 or 3 equiv overall) were pre-formed by
stirring a 1:1 mixture of the Grignard reagent and
CuBrÆMe2S for 30 min at ꢀ20 °C before the addition
of 3.
7
4g
i-Pr (Cl)
Aa
B
1
2
<1
1
8
5
4
4
1
4
88
64
8
9
4h
4i
Bn (Cl)
Allyl (Br)
A
58f
41
Aa,g
Bh
Aa
B
0i
10
11
12
4j
Ph (Cl)
80j
60j
66k
0l
4k
4l
4-MeO–C6H4 (Br)
4-EtO2C–C6H4 (Cl)
A
B
B
63m
As already mentioned, ethyl addition allowed the forma-
tion of 4a in excellent yield (entry 1, method A). Other
alkyl groups were introduced without difficulty, includ-
ing acetal and alkene functionalised examples (entries
2–6, method A). The introduction of a secondary alkyl
group was remarkably successful, furnishing 4g in 88%
yield (entry 7, method A), suggesting that steric factors
are of lesser importance in this reaction. Although an
extremely fast reaction was observed between the benzyl
cuprate reagent and 3, a mixture of both desired SN20
ring-opening product 4h and diacid 8 was formed in this
particular case. Careful chromatographic separation
allowed 4h to be isolated in 58% yield, with 42% of 8
(entry 8).
a 3 equiv of cuprate required.
b Carried out at rt.
c 2.5 equiv of cuprate used.
d Calculated from 1H NMR as inseparable from diacid 8.
1
e Calculated from H NMR as the product contains small amounts of
homocoupled Grignard reagent.
f Diacid 8 isolated in 42% yield.
g Me2S required as a co-solvent.
h Warmed to rt after 2 h.
i Compound 4c was isolated in 52% yield.
j Isolated in a 2:1 ratio of SN20:SN2 addition.
k Isolated in a 4:1 ratio of SN20:SN2 addition.
l Compound 4c was isolated in 81% yield.
m Isolated in a 1:4.5 ratio of SN20:SN2 addition.

S. Borthwick et al. / Tetrahedron Letters 47 (2006) 7205–7208
7207
Reaction of 3 with allylcuprate failed under the standard
O
O
HO2C
conditions, but was found to proceed to product 4i in a
moderate 41% yield with the use of dimethylsulfide as a
co-solvent (entry 9). Although stereoselective anti-addi-
tion was observed in all cases, aromatic cuprates showed
a reduction in regioselectivity. Phenyl cuprate, for exam-
ple, gave an inseparable mixture of the SN20 product 4j
and SN2 product 13a. A 2:1 ratio of 4j:13a was calcu-
lated from 1H NMR, although an excellent overall yield
of 80% was obtained (entry 10, method A). The 4-meth-
oxy substituted analogue provided a 4:1 ratio of
SN20:SN2 products 4k:13b in 66% total yield (entry 11,
method A). A possible explanation for this behaviour
is that reductive elimination from Cu(III) intermediate
11 is simply slower than the shift of the equilibrium to
Cu(III) species 12 (Scheme 4).
a) 86% (T = -78 oC)
O
O
CO2H
O
O
3
8
O
O
HO2C
a) 62% (T = -50 oC)
CO2H
1
14
Scheme 5. Selective synthesis of meso and C2-symmetric diacids 8 and
14. (a) MeMgCl (8 equiv), CuBrÆMe2S (4 equiv), THF.
use of substoichiometric amounts of copper to be used
without problematic formation of the diene-diacid 8.
O
O
O
O
ii
Finally, studies showed that it was possible to optimise
the synthesis of diacid 8 using a ratio of 2:1 of Grignard
reagent to Cu(I) and lowering the reaction temperature
to ꢀ78 °C. For example, using MeMgCl 8 could be iso-
lated as the only product in 86% yield (Scheme 5).
Applying these conditions to the C2-symmetric lactone
1, with a slight increase in temperature to aid dissolu-
tion, provided 14 in 62% yield.
CO2
CO2H
Ar(X)CuIII
Ar
4j-l
11
Ar = Ph,
13a:4j = 1:2
O
O
ArCuX
Ar = 4-MeO-C6H4-, 13b:4k = 1:4
Ar = 4-EtO2C-C6H4-, 13c:4l = 4.5:1
i
O
O
O
O
O
3
O
iii
CO2
CuIIIAr(X)
CO2H
In summary, a Cu(I)-mediated SN20 ring-opening
desymmetrisation reaction of meso-bislactones has been
developed using various Grignard reagents. Signifi-
cantly, mixed triorganozincates have been shown for
the first time to be excellent reagents for Cu(I)-catalysed
allylic substitution, particularly in this case where the
use of Grignard reagents with catalytic copper led to
pronounced side reactions. The desired anti-products
of type 4 were generally isolated in good to excellent
yields. A novel reaction pathway leading to meso-diacid
8 was also identified and optimisation of this process
was achieved by the variation of the Cu(I) stoichiometry
and temperature. The current work is focussed on the
use of these methodologies in an asymmetric9 manner
with polycyclic meso derivatives of 3.
Ar
12
13a-c
Scheme 4. Suggested mechanism for the formation of SN2 products
13a–c. Pathway: (i) equilibrium via p-allyl-Cu complex; (ii) reductive
elimination to give 4j–l (see Table 1); (iii) reductive elimination to give
13a–c.
To continue attempts at creating a catalytic desymmet-
risation, we turned our attention to the use of well doc-
umented organozinc reagents in place of Grignards.
Surprisingly, our initial studies showed that diethylzinc
in the presence of catalytic Cu(I) failed to react with 3
even at elevated temperatures. We therefore examined
the use of triorganozinc species, a class of reagents
known for nearly 150 years6 but rarely used as a
synthetic tool.7 After optimisation a mixed organozinc
species,7,8 prepared from Et2Zn (2 equiv) and
TMSCH2MgCl (2 equiv), was found to react with 3
(1 equiv) in the presence of catalytic CuCNÆ2LiCl
(20 mol %). It was extremely encouraging to note that
compound 4a was isolated in 84% yield with no transfer
of the less reactive TMSCH2 group and with no forma-
tion of diacid 8 observed (cf. entry 4, Table 1). It is
important to highlight that without any Cu(I) source
no reaction took place. In a more general approach
Grignard nucleophiles were first reacted with dimethyl-
zinc to form the mixed triorganozinc species before
addition of the catalyst. As methyl groups were found
to be less transferable, this method allows selective for-
mation of the organocuprate corresponding to the Grig-
nard species. In general, use of the mixed triorganozinc
reagents with catalytic copper (Method B) gave very
similar results to Method A (Table 1), yet allowed the
Acknowledgement
We thank the EPSRC for funding (GR/R02382/01 and
EP/C51890X/1).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.146.
References and notes
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