Spirodiepoxide reaction with cuprates

Article abstract of DOI:10.1021/ja068813w

The first example of transition-metal-mediated transformations of spirodiepoxides and the first general method for carbon-carbon bond formation using the spirodiepoxide functional group are reported. Organocopper-mediated addition to spirodiepoxides gives

Full text of DOI:10.1021/ja068813w

Published on Web 02/09/2007
Spirodiepoxide Reaction with Cuprates
Partha Ghosh, Stephen D. Lotesta, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received December 9, 2006; E-mail: ljw@rutchem.rutgers.edu
Scheme 1
Here we report a new approach to synthesize densely function-
alized R-hydroxy ketones by way of copper-mediated spirodi-
epoxide (SDE) opening. Since SDEs (2) are unstable to Brønsted
acid,1 the prospects of transition-metal-mediated reactions and other
potential applications would seem limited. Yet provided such issues
are navigable, the transformation (1 f 2 f 3, Scheme 1) would
set two stereocenters, install two oxygen atoms and one C-C bond,
and thus result in the formation of a vicinal triad composed of
hydroxyl, ketone, and syn-substituted carbon substituent. Moreover,
the anti product (5) would be available as well by using R2 as the
nucleophile and R1 as the allene substituent. This motif, and the
closely related motif wherein the carbonyl is replaced with hydroxyl,
is widely distributed in substances of biomedical relevance including
erythromycin,2a cytochalasinD,2b andthegalbonolides,2c oligomycins,2d
and streptovaricins2e among others.
Our study focused on organocuprates, owing to the advantages
of these mild reagents.3 Dioxirane oxidation of allenes [e.g., 4 )
dimethyl dioxirane (DMDO)] gave isolable SDEs, and as sum-
marized in Table 1, a survey of methylcuprate reactions revealed
that this class of reagent effects two types of SDE transforma-
tions: regioselective nucleophilic opening to give the R-hydroxy,
R′-substituted ketone (7) and regioselective reductive opening to
give the R-hydroxy ketone (8). The stoichiometry of cuprate reagent,
solvent, and source of organic ligand significantly influence the
course of the reaction. Higher order cuprates, known to be the
reagents of choice for halide displacement, tosylate displacement,
and epoxide opening,4 gave lower product selectivity in ether. As
with simple epoxide opening, ether is superior to THF, in that the
reactions appear cleaner and faster.5 Still, most reaction conditions
favor the reduction pathway (f8) over addition (f7), except for
lower order cyanocuprates. For this type of cuprate, typically used
to displace activated halides and related leaving groups,3,4,6 the more
Lewis acidic Grignard-derived reagents gave the reduced product
(entries 6 and 7), whereas organolithium-derived reagents gave the
addition product (entries 9 and 10).
Table 1. Methyl Cuprate Reactionsa
cuprate
temp
C)
yield (%)
entry
allene
conditions
solvent
(
°
7:8
1
2
3
4
5
6
7
8
9
6b
6b
6b
6b
6b
6a
6b
6b
6a
6b
Me2CuLi, LiI
THF
THF
THF
ether
THF
ether
ether
THF
ether
ether
-78 to 0
-78 to 0
-78 to 0
-78 to 0
-78 to 0
-10 to rt
-10 to rt
-10 to rt
-10 to rt
-10 to rt
23:53
21:52
33:42
17:52
44:15
<3:72
<3:78
51:20
74:<3
81:<3
Me2CuLi, LiBr
Me2CuLi, Me2S, LiBr
Me2Cu(CN)Li2
(MeCuBr)MgBr, LiBr
MeCu(CN)MgBr
MeCu(CN)MgBr
MeCu(CN)Li
MeCu(CN)Li
MeCu(CN)Li
10
a Reactions employed 3.0 equiv of DMDO in CHCl3, -40 °C to rt, 2 h.
substituted double bond, is excellent (r1 ) >20:1). The selectivity
of the second oxidation is modest to good (r2 ) 2-8:1). In all
cases, the ratio of SDEs obtained from allene oxidation matched
the ratio of products obtained from cuprate addition. Crystal-
lographic analysis of a derivative of the major product of entry 3
confirmed the syn stereochemistry of the addition product.11 Thus,
copper-mediated nucleophilic addition takes place with inversion.
Allene oxidation/organocuprate addition gives substituted hy-
droxy ketones with high efficiency. Delivery of methyl generally
takes place rapidly at 0 °C (entries 1-3). Consistent with known
trends in cuprate addition, other alkyl ligands transfer from copper
more rapidly than methyl and could be carried out at -78 °C
(entries 5-15) or -40 °C (data not shown) with no variation in
yield. A slight monotonic decrease in yield is notable with increased
â-branching of the nucleophile (methyl f butyl f TMSCH2). For
trisubstituted SDEs (entries 13-15), the yield with phenyl cyano-
cuprate was low (10-20%). We were pleased to find that the more
reactive Gilman reagent efficiently delivered phenyl. Although
lower order cyanocuprates are preferred, the more reactive Gilman
reagents prove useful when fast transferring ligands are of inter-
est.3,4,12 In each instance, the nucleophile was delivered regiose-
lectively to the most accessible site of the SDE. No special
precautions were required beyond those normally used for cuprate
additions. The yields from allene to hydroxy ketone are excellent
(77-92% average for oxidation and addition).
Reduction of alkyl halides7 and epoxides8 by Cu(I), instead of
substitution, is known. When the reaction of entry 7 was quenched
with D2O, the R-hydroxy R′-deutero ketone was obtained, indicating
SDE reduction to the R-hydroxy R′-ketone enolate or closely related
species. One explanation consistent with these data is that the
Cu(I) reagent adds to the SDE to form an R-keto-Cu(III) species.
Such an intermediate could either reductively eliminate to give 7
or convert to the corresponding enolate and ultimately give 8.
According to this model, reductive elimination (f7) could be faster
than rearrangement in the presence of the lithium counterion,
whereas the more acidic magnesium counterion could induce
isomerization (f8).9
We focus the remainder of the discussion on the method of
carbon nucleophile delivery to SDEs. Allenes 6a-d were oxidized
with DMDO in chloroform10 and then exposed to organocuprates
(Table 2). The selectivity of the first oxidation, at the more
We prepared the stereotetrad of erythromycin (10) by using this
method (Scheme 2). Known glycolic acid derivative 1313 was
9
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J. AM. CHEM. SOC. 2007, 129, 2438-2439
10.1021/ja068813w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
tion,16 directed by the primary alcohol, gave 16 (see box in Scheme
2). Proof of stereochemical assignment was established by preparing
17. Selective conversion of 16 to the p-methoxy benzylidine
followed by formation of the benzyl ether gave the known protected
tetrol.17 Thus, this oxygenated polypropionate stereotetrad was
prepared in a short, efficient, and selective route.
Table 2. Conversion of Allenes to Substituted Hydroxy Ketones
(Condition A: DMDO/CHCl3, -40 °C to rt, 2 h)
In summary, we have disclosed the first example of a transition-
metal-mediated transformation of SDEs and the first general method
for addition of carbon nucleophiles to spirodiepoxide, an emergent
functional group with considerable potential in synthetic applica-
tions. The method constitutes a concise approach to densely
functionalized branched oxygenated motifs.
Selectivity
temp
C)
time
(h)
yield
(%)
entry
allene
R4
(
°
r1
r2
1a
6a
6b
6c
6d
6a
6b
6c
6d
6a
6b
6c
6a
6b
6c
6d
CH3
CH3
CH3
CH3
0
0
0
0.5
0.5
0.5
5.5
2
2
2
7
2
2
2
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
2:1
na
6:1
8:1
na
74
81
84
80
67
72
76
66
66
65
68
59
71
65
62
2a
3a
4b,e
5a
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
-78 to rt
Acknowledgment. Financial support from Merck & Co.,
Johnson & Johnson (Discovery Award), and Rutgers, The State
University of New Jersey, is gratefully acknowledged. We thank
Dr. Tom Emge for crystallographic analysis, and Dr. Sreenivas
Katukojvala for preliminary studies toward 16.
n-Bu
n-Bu
n-Bu
n-Bu
TMS-CH2
TMS-CH2
TMS-CH2
Ph
6a
na
7a
6:1
8:1
2:1
na
6:1
2:1
na
8b,e
9a
10a
11a
12a
13c
14c
15d,e
Supporting Information Available: Synthetic methods and char-
acterization data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
2
2
2
5
Ph
Ph
Ph
6:1
8:1
References
a 2.5 equiv of CuCN, 2.5 equiv of RLi, ether. b 5 equiv of CuCN, 5
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of CuI, 12 equiv of PhLi, ether. e See Scheme 1 for the structure of 6d.
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