Intermolecular oxidative enolate heterocoupling

Article abstract of DOI:10.1002/anie.200603024

(Chemical Equation Presented) No priming necessary: The intermolecular oxidative heterocoupling of imides and oxindoles to esters, ketones, and lactones is shown for the first time to be synthetically viable. Strategic use of the initial oxidation state o

Full text of DOI:10.1002/anie.200603024

Angewandte
Chemie
ꢀ
Oxidative C C Coupling
Herein,this approach is explored in an intermolecular setting
with application to the enantioselective synthesis of medic-
inally relevant compounds[6] and the anticancer natural
product (ꢀ)-bursehernin (1).
DOI: 10.1002/anie.200603024
Intermolecular Oxidative Enolate
Heterocoupling**
The intermolecular heterocoupling of two enolates is a
particularly challenging chemical transformation given the
potential background reactions that can occur. These include,
but are not limited to, a-hydroxylation of each monomer,
dehydrogenation of either the monomers or the newly forged
Phil S. Baran* and Michael P. DeMartino
ꢀ
C C bond,intermolecular cross- and homo-Dieckmann/aldol
Oxidative dimerization of enolates has been known since
1935[1] and was studied further by Saegusa,Mislow,and others
in the 1970s (Scheme 1a).[2] Formally,this transformation
condensations,and oxidative homodimerization of either
coupling partner. In fact,if the intermolecular cross- and
homocoupling processes alone were governed by only sta-
tistics,the heterocoupling of an equimolar mixture of two
enolate species would take place with a maximum of 50%
conversion. Cross-coupling of two different ketones has been
reported,but required a large excess of one partner (3–
[2d,e]
3.5 equiv,along with additional base and oxidant).
In
principle,intermolecular heterocoupling of enolates could be
synthetically pragmatic if sufficient differences existed in
their respective oxidation potentials and/or relative rates of
homodimerization,such that equimolar ratios of the starting
materials can be used. As depicted in Table 1,the cross-
couplings of imides with ketones (entries 1–8),esters
(entries 9–11),and lactones (entry 12) are now possible.
Lactams such as oxindoles were also found to be amenable
to cross-coupling (entries 13–17). In nearly all cases,equimo-
lar ratios of the carbonyl species are employed and syntheti-
cally useful yields (greater than the 50% statistical limit) were
obtained,even when performed on a gram scale (entries 3 and
11,Table 1). In all cases,the remaining material was largely
recovered monomer,although minor amounts of imide/
oxindole homodimer were produced in entries 9–17. Notably,
in entries 9–12 (Table 1),products with stereochemistry
analogous to those of Evansꢀ model for the diastereoselective
alkylation of N-acyl oxazolidinones were produced,[7] whereas
in entries 1–8,the adducts obtained were epimeric at this
carbon center. This empirical observation is not fully under-
stood at this time,and the mechanistic basis for this finding is
under investigation. Although the diastereoselectivity is
modest in most cases,this method offers a clear strategic
ꢀ
Scheme 1. Oxidative C C bond formation via enolates.
accomplishes the direct union of two identical sp3-hybridized
carbon atoms with no substrate prefunctionalization by
exploiting their innate oxidation state. The analogous process
using two different types of coupling partners has remained
unexplored.[2d,e] In 2004,we presented a method for the direct
coupling of NH-containing heterocycles to various carbonyl
compounds through enolate heterocoupling (Scheme 1b).[3,4]
It was later shown that two different types of carbonyl species
can be coupled in an intramolecular sense (ester-amide).[5]
ꢀ
benefit when forging such C C bonds and thus provides
molecules that would be difficult to access directly through
use of current methods. Moreover,products may be amenable
to thermodynamic equilibration,as in the following applica-
tion to natural product synthesis.
[*] Prof. P. S. Baran, M. P. DeMartino
Department of Chemistry
The Scripps Research Institute
(ꢀ)-Bursehernin (1) is a member of a large class of
naturally occurring bioactive g-butyrolactone lignans.[8]
Inspection of 1 reveals that oxidative coupling of two
dihydrocinnamic acid derivatives would be an intuitive and
expedient route to construct these lignan lactones
(Scheme 2a). Indeed,symmetric dibenzyl lignan lactones
(R1 = R2) have been synthesized in this manner.[9] Prior to this
work,however,methodology necessary to accomplish inter-
molecular heterocoupling for the synthesis of unsymmetrical
dibenzyl lignans was unavailable. Using the simple method
described above,the oxidative union of oxazolidinone 2 and
dihydrocinnamic ester 3 was accomplished (d.r. = 1.6:1). The
crude mixture was submitted directly to chemoselective
10650 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] We thank Dr. D. H. Huang and Dr. L. Pasternak for NMR
spectroscopic assistance, and Dr. G. Suizdak and Dr. R. Chadha for
mass spectrometric and X-ray crystallographic assistance, respec-
tively. We are grateful to Professor M. G. Finn for the use of his cyclic
voltammetry apparatus and Tomµs Llamas for early contributions to
the project. Financial support for this work was provided by The
Scripps Research Institute, Amgen, Bristol-Myers Squibb, DuPont,
Eli Lilly, GlaxoSmithKline, Roche, the Searle Scholarship Fund, and
the NIH/NIGMS (GM071498).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Table 1: Intermolecular oxidative enolate couplings.[a]
reduction of the oxazolidinone
using lithium borohydride,fol-
lowed by treatment with DBU to
furnish
(ꢀ)-bursehernin
(Scheme 2b). The NMR spectral
data of synthetic 1 was identical to
that reported for the natural sub-
stance.[10] Notably,the low diaste-
reoselectivity (at C3) observed in
the coupling step was inconsequen-
tial as this center was easily epi-
merized and driven to the trans-
configured product. Strategic use
of oxidative coupling facilitated
the first,concise (three sequential
synthetic operations with one pu-
rification),and enantioselective
synthesis of 1,accomplished in
41% overall isolated yield. By
comparison,previous unsymmetri-
cal lignan syntheses required a
minimum of six steps proceeding
overall in much lower yields.[11]
While a-aryl imides,oxindoles,
Entry Carbonyl
compound 1
Carbonyl
compound 2
Oxidant Product
Yield [%][b]
(d.r.)[c]
52 (2.7:1)
(X-ray)
1
FeIII
2
3
59 (2.8:1)
FeIII
60 (2.6:1)[d]
FeIII
4
5
6
7
8
R1 =a-Bn
R1 =a-Bn
R1 =b-iP
R1 =b-iP
R1 =b-iP
R2 =H
R2 =OMe
2 =Br
R3 =a-H
R3 =a-H
57 (2.8:1)
67 (2.5:1)
55 (2.5:1)
66 (2.1:1)
65 (2.3:1)
r
r
r
R
R
R
R3 =b-H (X-ray)
and diketopiperizines[5] couple
most effectively using FeIII-based
2 =H
R3 =b-H
R3 =b-H
2 =OMe
[3a]
oxidants,simple imides,indoles,
and pyrroles[4] require CuII-based
oxidants. The precise role of the
oxidants in enolate coupling has
not been clearly determined and it
was assumed[2] that they function as
simple electron acceptors (possibly
through an outer-sphere electron-
transfer process).[12] To determine
if the oxidative heterocoupling of
enolates is amenable to reagent
control,the coupling of oxindole 4
and carvone was studied (Table 2).
In this case,homodimerization of
the components is preferred over
the desired heterocoupling using
the standard copper- and iron-
based oxidants,resulting in dimin-
ished yields. The absence of 3-
substitution on oxindole coupling
partner 4 is the apparent cause,as a
steric bias disfavoring homodime-
rization is not present (compare
CuII
9[e]
10[e]
11[e]
R=Me
R=tBu
R=tBu
51 (1.0:1)
51 (1.6:1)
53 (1.6:1)[f]
54 (2.4:1)
(X-ray)
12[e]
CuII
FeIII
13[g]
14
15
R=R1 =Me
91 (1.2:1)
60 (1.2:1)
54 (1.0:1)
R=R1 =Me
R=MOM, R1 =prenyl
FeIII
with entry 15,Table 1). Notably,
[10]
Fe(tBuCOCHCOCF3)3
fur-
16
17
R=R1 =Me
72 (2.6:1)
73 (2.0:1)
nished the heterocoupled product
5 in 83% isolated yield (entry 5,
Table 2). In control reactions using
either 4 or carvone alone,this
oxidant was still competent in pro-
moting homodimerization. Cyclic
voltammetry revealed a unique
oxidation potential for each oxi-
R=MOM, R1 =prenyl
[a] Stereochemistry of a-carbon (oxazolidinone) for entries 2–3 and 5–11 for the major diastereomers
has been assigned by analogy to those confirmed by X-ray crystallographic analysis (entries 1, 6, and 12).
[b] Isolated yields after chromatography. [c] Diastereomeric ratios refer to carbon b-carbon (oxazolidi-
none) for entries 1–12. [d] Gram scale (3.7 mmol). [e] 1.75 equiv ester/lactone used. [f] Gram scale
(4.3 mmol). [g] 2 equiv ketone used. FeIII =[Fe(acac)3] (acac=acetylacetonate), CuII =copper(II) 2-
ethylhexanoate, LDA=lithium diisopropylamide, Bn=benzyl, MOM=methoxymethyl.
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Angewandte
Chemie
anticipated that this conceptually unique method for merging
sp3-hybridized carbon atoms will continue to find useful
applications in synthesis.[13]
Experimental Section
General procedure for Fe-based couplings (see Supporting Informa-
tion). Oxazolidinone or oxindole (0.10 mmol,1.0 equiv) and carbonyl
compound (0.10 mmol,1.0 equiv) were dissolved in benzene
(1.0 mL),and the solvent was removed in vacuo. This process was
repeated a second time (azeotropic water removal). The starting
materials were then dissolved in THF (340 mL,0.3 m),and the solution
was cooled to ꢀ788C. A solution of LDA (0.50m in THF,428 mL,
2.1 equiv) was added dropwise by syringe over 30 s. The reaction was
allowed to stir for 30 min at ꢀ788C and then warmed to ambient
temperature. After 5 min of stirring at 238C,a solution of [Fe(acac) 3]
(0.50m,408 mL,2.0 equiv) was added all at once (less than 1 s addition
time). The reaction mixture was stirred at ambient temperature for
20 min and then quenched by the addition of 1n HCl (1 mL). The
aqueous layer was partitioned with EtOAc (2 mL),separated,and
then extracted twice with EtOAc (2 mL). The organic portions were
Scheme 2. Short, enantioselective synthesis of (ꢀ)-bursehernin (1). Reagents
and conditions: 2, LDA (THF, 1.15 equiv), LiCl (5.0 equiv), PhMe, ꢀ78!0!
ꢀ788C (10 min each), 3 (1.75 equiv), PhMe, LDA (THF, 1.85 equiv), ꢀ788C,
30 min, then CuII, ꢀ78!238C, 20 min; LiBH4 (10 equiv), MeOH (5.0 equiv),
THF, ꢀ78!ꢀ108C, 1.5 h; DBU (10 equiv), PhMe, 1108C, 24 h, 41% overall.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
combined,washed with brine (5 mL),dried over anhydrous MgSO
,
4
filtered,and concentrated in vacuo. Flash chromatography (silica gel)
of the crude reaction afforded pure coupled product.
General procedure for Cu-based couplings (see Supporting
Information). Oxazolidinone (0.33 mmol,1.0 equiv) and powdered
lithium chloride (1.64 mmol,5.0 equiv) were taken up in benzene
(1.0 mL),and the solvent was removed in vacuo. This process was
repeated a second time (azeotropic water removal). Toluene (546 mL,
0.6m) was added to this mixture,and the resulting solution was cooled
to ꢀ788C. A solution of LDA (0.50m in THF,759 mL,1.15 equiv) was
added by syringe down the sides of the reaction vessel over 10 s. After
stirring at ꢀ788C for 10 min,the solution was warmed to 0 8C for
10 min (color change from pale to bright yellow),and then cooled to
ꢀ788C for 5 min. In a separate reaction vessel,the carbonyl
compound (0.57 mmol,1.75 equiv) was dissolved in benzene
(1.0 mL) and the solvent was then removed in vacuo. This process
was repeated a second time. Toluene (546 mL,0.6 m) was added to the
carbonyl compound,and the solution was cooled to ꢀ788C. A
solution of LDA (0.50m in THF,1.2 mL,1.85 equiv) was added by
syringe down the sides of the reaction vessel over 10 s,and the
resulting solution was stirred at ꢀ788C for 25 min. At this time,the
carbonyl enolate solution was transferred by canula into the
oxazolidinone enolate solution. The reaction mixture was stirred at
ꢀ788C for an additional 5 min,at which time a solution of copper(II)-
2-ethylhexanoate (0.3m in toluene,3.0 mL,2.75 equiv) at ꢀ788C was
transferred into the reaction vessel by canula. Immediately following
addition,the vessel was quickly removed from the ꢀ788C bath and
placed into a room-temperature water bath,which led to a color
change from light blue to brown. The reaction mixture was stirred for
20 min and subsequently quenched by the addition of 5% aqueous
NH4OH (5 mL). The aqueous layer was partitioned with EtOAc
(5 mL),separated,and then extracted twice with EtOAc (2 mL). The
organic portions were combined,washed with brine (5 mL),dried
over anhydrous MgSO4,filtered,and concentrated in vacuo. Flash
chromatography (silica gel) of the crude reaction afforded pure
coupled product.
Table 2: Oxidative coupling is amenable to reagent control.[a]
Entry
Oxidant
Eox [eV][b]
Yield [%][c]
1
2
3
4
5
6
7
Cu(2-ethylhexanoate)2
PhI(OAc)2
[Fe(acac)3]
Fe(PhCOCHCOMe)3
Fe(tBuCOCHCOCF3)3
Fe(MeCOCHCOCF3)3
Fe(C10H7COCHCOCF3)3
ꢀ1.65
ꢀ1.53
ꢀ1.14
ꢀ1.07
ꢀ0.60
ꢀ0.51
ꢀ0.46
15
ꢁ10
45
30
83
40
40
[a] 2 equiv carvone used. [b] Oxidation potentials measured using cyclic
voltammetry, relative to ferrocene/ferrocenium standard. [c] Isolated
yields after chromatography.
dant employed,suggesting that rationally controlled hetero-
coupling of enolates is possible. This trend,as well as the
success of reagent-controlled coupling,underscores great
mechanistic complexity and is the subject of further study.[5c]
This work has demonstrated for the first time that
ꢀ
oxidative C C bond formation through the intermolecular
union of two different types of enolates can be accomplished
by exploiting the natural electronic or steric differences in
coupling partners. Furthermore,undesirable homocoupling
processes can sometimes be stifled by careful reagent control.
As demonstrated in the total synthesis of 1,conservation of
the oxidation state of the starting material prior to the
coupling event eliminates the need for prefunctionalization of
the substrate (e.g. enol-silane formation or halogenation). It is
Received: July 27,2006
Published online: September 29,2006
ꢀ
Keywords: C C coupling · enolates · lignans ·
synthetic methods · total synthesis
.
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Communications
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[10] See Supporting Information for details.
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[13] Detailed experimental procedures,copies of spectral data,and
full characterization of compounds are contained in the Sup-
porting Information. CCDC 617245–617247 (Table 1,entries 12,
1,and 6,respectively) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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