Diastereoselective synthesis of fused lactone-pyrrolidinones; Application to a formal synthesis of (-)-salinosporamide a

Article abstract of DOI:10.1021/ol501662t

A mild, diastereoselective synthesis of fused lactone-pyrrolidinones using an oxidative radical cyclization is reported. The methodology is demonstrated in a formal synthesis of (-)-salinosporamide A.

Full text of DOI:10.1021/ol501662t

Letter
pubs.acs.org/OrgLett
Diastereoselective Synthesis of Fused Lactone-Pyrrolidinones;
Application to a Formal Synthesis of (−)-Salinosporamide A
†
†
†
†
‡
Angus W. J. Logan, Simon J. Sprague, Robert W. Foster, Leo
́
B. Marx, Vincenzo Garzya,
Michal S. Hallside,†,§ Amber L. Thompson, and Jonathan W. Burton*
†,§
,†
†Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
‡
GlaxoSmithKline, Harlow, Essex CM19 5AW, United Kingdom
*
S Supporting Information
ABSTRACT: A mild, diastereoselective synthesis of fused
lactone-pyrrolidinones using an oxidative radical cyclization is
reported. The methodology is demonstrated in a formal
synthesis of (−)-salinosporamide A.
7
8
he development of new methodology for the rapid
Scheme 1. Cyclization Precedent from Miller and Citterio
T
generation of molecular complexity from relatively simple
starting materials is a continuing goal of modern target-oriented
synthesis. Within this arena, oxidative radical reactions have
emerged as powerful processes for the mild formation of
carbon−carbon and carbon−heteroatom bonds with control
with Relation to Current Work
1
over multiple stereocenters. In these reactions, substrate
prefunctionalization is frequently not required, and the product
generally ends up at a higher oxidation level than the substrate
thus providing a handle for subsequent synthetic manipulation.
Manganese(III) acetate is a mild, economical, and relatively
nontoxic reagent for the formation of electron-deficient C-
centered radicals from malonates and related CH-acidic
compounds and has found wide use in organic synthesis in
both method development and in the total synthesis of complex
2
natural products. Recently we reported an efficient synthesis of a
number of [3.3.0]-bicyclic γ-lactones from variously substituted
3
4
-pentenyl malonates along with application of this method-
ology to a diastereoselective synthesis of a cyclopentane-
4
containing natural product. Herein, we report the extension of
this methodology to an efficient, diastereoselective synthesis of
fused lactone-pyrrolidinones from acyclic precursors. These
bicyclic products contain multiple adjacent stereocenters and
differentiated oxygen functionality and are formed in good yields
5
under mild conditions. Application of this methodology to the
formal synthesis of the potent proteasome inhibitor (−)-salino-
6
sporamide A is also reported.
Precedent for the proposed transformation comes from the
7
8
groups of Miller and Citterio. The Miller group synthesized
two tricyclic γ-lactones by the cyclization of α-amido malonates
in the presence of manganese(III) acetate, and Citterio reported
related reactions between α-amido malonates and alkenes for the
formation of two γ-lactones and numerous other products. We
aimed to extend these results to a mild and general
diastereocontrolled synthesis of [3.3.0]-bicyclic γ-lactones
bearing a variety of substituents (Scheme 1).
The mechanism of the proposed reaction most likely involves
single electron oxidation of the substrate 1 in the presence of
manganese(III) acetate to deliver the corresponding α-
Received: June 9, 2014
Published: July 28, 2014
©
2014 American Chemical Society
4078
dx.doi.org/10.1021/ol501662t | Org. Lett. 2014, 16, 4078−4081

Organic Letters
Letter
9
13
amidomalonyl radical 2. Cyclization of the α-amidomalonyl
radical 2 may occur stereoselectively, via pretransition state
Table 2. Cyclization of α-Substituted Substrates
1
0
assembly 3, to give the adduct radical 4, which after further
single electron oxidation and trapping by the adjacent oxygen
atom would give oxocarbenium ion 5. Hydrolysis of 5 would give
the desired fused lactone-pyrrolidinones 6. We were mindful that
the α-amidomalonyl radical 2 would likely exist as a mixture of s-
cis and s-trans rotamers and that cyclization would be
geometrically possible only from the s-trans conformer; hence,
efficient interconversion of the two rotameric forms would be a
a
b
c
entry
substrate 9
R
10, yield (%)
dr
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Me
Et
84
76
81
65
76
74
87
70
6.6:1
10.4:1
>25:1
8.4:1
18:1
11
i-Pr
n-Bu
prerequisite for efficient cyclization. We have previously used
copper(II) triflate as an additive in manganese(III) acetate3
CH
CCH
2
mediated cyclization reactions to promote γ-lactone formation
Allyl
Bn
19:1
and therefore elected to use the amide 7 as our test substrate with
12
g
h
11:1
copper(II) triflate as additive.
(CH ) OBn
25:1
2
2
Initial scoping reactions indicated that the lactone-pyrrolidi-
none 8 was formed in highest yield from the amidomalonate 7
using manganese(III) acetate and copper(II) triflate under
relatively dilute reaction conditions, contrary to what we had
a
Reaction conditions: manganese(III) acetate (2 equiv), copper(II)
triflate (1 equiv) in MeCN at 25 °C for 4 h; yields and diastereomeric
ratios for reactions conducted at 40 and 80 °C can be found in the
b
c
Supporting Information. Yield for mixture of diastereomers. The
diastereomeric ratio (dr) refers to the mixture of diastereomers formed
3a,4,13
observed in the all-carbon series (Table 1, entry 1).
The
1
5
at C-3.
Table 1. Optimization and Single Crystal X-ray Diffraction
14
Structure of 8
10
pretransition state assembly 3) with the α-amido substituent
occupying a pseudo-equatorial position.
1
6
The success of these cyclization reactions is likely in part due to
the adduct radical (4) being benzylic. Indeed, cyclization of the
terminal alkene substrate 1 (R, R′, R″ = H) was initially found to
be highly capricious with the corresponding lactone pyrrolidi-
none 6 (R, R′, R″ = H) being isolated in highly variable yield
a
b
c
entry
t (°C)
yield (%)
dr
(
∼20−70%). However, we found that the N-PMB-protected
1
2
80
40
25
82
73
72
6:1
8:1
substrates 11 gave the corresponding lactone-pyrrolidinones 12
that were isolated with synthetically useful yields and with high
diastereoselectivities (Table 3). The success of these cyclizations
may be related to the increased proportion of the s-trans radical
corresponding to s-trans 2 with tertiary amide substrates
compared with secondary amide substrates.
3
14:1
a
Reaction conditions: manganese(III) acetate (2 equiv), copper(II)
triflate (1 equiv) in MeCN and 0.05 M substrate concentration for 5 h;
control experiments can be found in the Supporting Information.
b
c
Yield for mixture of diastereomers. The diastereomeric ratio (dr)
refers to the mixture of diastereomers formed at C-4.
1
3
Table 3. Cyclization of Terminal Olefin Substrates
diastereocontrol was improved by conducting the reactions at
lower temperature, with the highest diastereocontrol being
observed at 25 °C, which gave the product in 72% yield as a 14:1
mixture of diastereomers at C-4 (Table 1, entry 3). The structure
of the major diastereomer of 8 was confirmed by single crystal X-
a
b
entry
substrate 11
R
R′
12, yield (%)
14
ray diffraction studies.
1
2
3
4
a
b
c
d
e
e
e
H
Me
74
48
75
Next we turned our attention to the cyclization of substituted
substrates 9, with a view to the substituent acting as a control
element for the formation of two further stereocenters in the
product lactone-pyrrolidinone 10 (Table 2). Gratifyingly, α-
substituted amides 9 gave the highly substituted lactone-
pyrrolidinones 10 with good yields and stereoselectivities
H
Et
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
c
Bn
52
d,
d,
d,
e
f
5
6
7
allyl
allyl
allyl
43
65
10
g
1
5
(
Table 2). The methyl-substituted substrate 9a was found to
a
cyclize in excellent yield to give the lactone-pyrrolidinone 10a as
Reaction conditions: manganese(III) acetate (2 equiv), copper(II)
triflate (1 equiv) in MeCN at 40 °C for 2 h; yields for reactions
conducted at 25 and 80 °C, along with control experiments, can be
found in the Supporting Information. The products were isolated
with >15:1 dr; it was not possible accurately to measure the
diastereomeric ratio from the crude reaction mixture. A [4.3.0]-
13
a 6.6:1 mixture of C-3 epimers (Table 2, entry 1). Three further
substrates 9b−d with saturated alkyl side chains were found to
b
13
cyclize similarly (Table 2, entries 2−4). A range of unsaturated
side chains were also found to direct the stereochemical outcome
of the cyclization with high levels of stereocontrol, affording
lactone pyrrolidinones functionalized with propargyl, allyl,
c
bicyclic lactam corresponding to (−)-16 was also isolated.
d
e
Enantiopure starting material was used. (−)-16 was also isolated
13
f
benzyl, and benzyloxyethyl groups (Table 2, entries 5−8). In
all cases, the major diastereomer formed is in accord with
cyclization via the chairlike Beckwith−Houk transition state (see
in 26% yield. 2 equiv of copper(II) triflate was used, and (−)-16 was
g
also isolated in 19% yield. 0.1 equiv of copper(II) triflate was used,
and (−)-16 was also isolated in 79% yield.
4
079
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Organic Letters
Letter
17
A range of dialkyl malonates were tolerated, and substrates
bearing unsaturated side chains gave the corresponding lactone-
pyrrolidinones with high levels of diastereocontrol (Table 3,
entries 3−5). Cyclization of the allyl-substituted amide (−)-11e
with 2 equiv of manganese(III) acetate and 1 equiv of copper(II)
triflate gave the desired lactone-pyrrolidinone (+)-12e in 43%
yield along with the trans-fused [4.3.0]-bicyclic alkene (−)-16 in
Scheme 3. Formal Synthesis of (−)-Salinosporamide A
2
6% yield, the structure of which was confirmed by single crystal
14
X-ray diffraction studies (Scheme 2). The lactone-pyrrolidi-
Scheme 2. Proposed Mechanism of Formation of (+)-12e and
(
−)-16 with the Structure of 16 from Single Crystal X-ray
14
Diffraction Studies
step. The methodology has been applied to the enantioselective
formal synthesis of (−)-salinosporamide A.
none (+)-12e could be isolated in 65% yield by increasing the
copper loading to 2 equiv, with the cyclohexene being formed in
1
9% yield (Table 3, entry 6). Conversely reducing the copper
loading to 0.1 equiv gave the cyclohexene in 79% yield along with
% of the lactone (+)-12e (Table 3, entry 7). The trans-fused
4.3.0]-bicyclic alkene (−)-16 is most likely formed from the
initial adduct radical 14, which may arise from pretransition state
ASSOCIATED CONTENT
Supporting Information
■
*
S
9
[
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
10
assembly 13 (Scheme 2). Further 6-endo-trig cyclization can
occur, followed by oxidation of the second adduct radical 15 by
copper(II) to give the trans-fused bicyclic cyclohexene (−)-16.
Alternatively, the initially formed adduct radical 14 can be
directly oxidized by copper(II) to give the lactone-pyrrolidinone
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: jonathan.burton@chem.ox.ac.uk.
Notes
(
+)-12e; this is the major pathway at higher concentrations of
The authors declare no competing financial interest.
Authors to whom correspondence regarding X-ray crystallog-
raphy should be addressed.
copper(II).
§
The synthetic utility of the developed methodology was
demonstrated by the enantioselective synthesis of the lactone-
pyrrolidinone 24, an intermediate in Danishefsky’s synthesis of
the proteasome inhibitor (−)-salinosporamide A (Scheme 3).
The known carboxylic acid 18 was readily prepared and
converted into the allyl-substituted oxazolidinone 21 using an
Evans asymmetric alkylation. Hydrolysis of the chiral auxiliary
in 21 required initial conversion into the corresponding benzyl
ester followed by in situ hydrolysis to the carboxylic acid so as to
avoid endo cleavage of the oxazolidinone. The carboxylic acid
was coupled with the amino malonate 22 under Schotten−
Baumann conditions to give the amide 23. Oxidative
elimination of the selenide in amide 23 gave the enantioenriched
cyclization substrate (−)-11e. Cyclization of malonate (−)-11e
gave the required bicyclic γ-lactone (+)-12e in 65% yield, which
was subjected to ozonolysis with a reductive workup to afford
6d
ACKNOWLEDGMENTS
We thank GlaxoSmithKline and AstraZeneca for CASE awards
and the EPSRC for funding. We are grateful to Prof. Danishefsky
Sloan Kettering Institute for Cancer Research and Columbia
University) for providing spectroscopic data. We thank the
Diamond Light Source for an award of beamtime on I19
■
18
19
(
19
(
MT7768), and the instrument scientists for their generous help
and support.
6
f
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■
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(
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21
4
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(
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8
7
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except that there was a small discrepancy in the C NMR resonance of
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13
6d
benzyl ether, which was an excellent match with the literature data.
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(
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(
1
(
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4
081
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