Conjugate addition/Ireland-Claisen rearrangements of allyl fumarates: Simple access to terminally differentiated succinates

Article abstract of DOI:10.1021/jo701778k

(Chemical Equation Presented) The conjugate addition of dialkylzinc reagents to allyl fumarates with subsequent Ireland-Claisen rearrangement has been accomplished yielding substituted unsymmetrical succinic acid derivatives. This one-pot reaction creates two new carbon-carbon bonds at contiguous stereogenic centers. The reaction proceeds for several alkylzinc reagents and substituted allyl fumarates. The products contain distinguishable functional handles for further manipulation.

Full text of DOI:10.1021/jo701778k

SCHEME 1. General Three-Component Coupling with
Enoates
Conjugate Addition/Ireland-Claisen
Rearrangements of Allyl Fumarates: Simple
Access to Terminally Differentiated Succinates
Cory C. Bausch and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
SCHEME 2. Proposed Conjugate Addition/
[3,3]-Rearrangement
jsj@unc.edu
ReceiVed October 19, 2007
classic complexity-building reactions that exploit that latent
nucleophilic character of the R-carbon in Michael acceptors
(Scheme 1).3 Conjugate addition/[3,3]-rearrangement reactions
represent an important subcategory of these tandem processes.4
We envisioned that by using an allyl fumarate as the conjugate
acceptor with an organometallic nucleophile, the metal enolate
or derived silyl ketene acetal generated in situ would undergo
a subsequent ester enolate Claisen rearrangement (Scheme 2).5
In accord with precedent, the use of a chlorotrialkylsilane was
projected to both accelerate the conjugate addition and generate
the requisite silyl ketene acetal.6,7
Organometallic nucleophiles for conjugate addition to dial-
lylfumarates8 were evaluated. For the purpose of the initial
screen, we examined only the 1,4-addition. The two catalysts
utilized were the commercially available CuBr‚SMe2 and easily
synthesized bis(N-tert-butylsalicylideneaminato)copper(II),9 here-
after referred to as Cu(NtBu‚sal)2.
The conjugate addition of dialkylzinc reagents to allyl
fumarates with subsequent Ireland-Claisen rearrangement
has been accomplished yielding substituted unsymmetrical
succinic acid derivatives. This one-pot reaction creates two
new carbon-carbon bonds at contiguous stereogenic centers.
The reaction proceeds for several alkylzinc reagents and
substituted allyl fumarates. The products contain distinguish-
able functional handles for further manipulation.
The conjugate addition of nonstabilized organometallic nu-
cleophiles to R,â-unsaturated carbonyls is a staple of organic
synthesis, but the fumarate and maleate electrophile subclass
in this reaction family has received scant attention relative to
simple enones and enoates. The comparative lack of research
activity is surprising since maleic and fumaric acid derivatives
represent cheap progenitors to functionalized succinic acids.
Notable advances in this area have been reported. Ibuka and
co-workers disclosed organocopper(I)-Lewis acid additions to
fumarate esters that afforded good yields of the addition
products; however, olefin reduction was a competing reaction
pathway.1 Hayashi and co-workers have reported enantioselec-
tive rhodium-catalyzed 1,4-additions of arylboronic acids to
fumarates and maleates.2 While these examples provide useful
conjugate adducts, a nonobvious feature of the reported additions
is that the carbonyls in the products are still functionally
equivalent and therefore challenging to distinguish. In this paper,
we describe the conjugate addition of dialkylzinc reagents to
diallyl fumarates with subsequent Ireland-Claisen rearrange-
ment to give unsymmetrical succinate products. A defining
characteristic of the title reaction is chemodifferentiation of the
two carbonyls that can be exploited in further selective
manipulations.
The Cu(NtBu‚sal)2-catalyzed addition of ethylmagnesium
bromide led to the desired 1,4-addition product along with
products derived from 1,2-addition and SN2′ displacement (Table
1, entry 1). The conjugate addition of ethylmagnesium bromide
also proceeds in the absence of copper (entry 2). An alternative
organometallic reagent, diethylzinc, is considerably less reactive
in THF (entry 3), but simply switching solvents to diethyl ether
provides clean conjugate addition in 90 min (entries 4 and 5).
(3) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994; pp 298-322. (b) Guo, H.-C. and Ma, J.-A. Angew. Chem.,
Int. Ed. 2006, 45, 354-366.
(4) (a) Aoki, Y.; Kuwajima, I. Tetrahedron Lett. 1990, 31, 7457-7460.
(b) Chai, Y.; Hong, S. P.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C.
Tetrahedron 2002, 58, 2905-2928. (c) Eriksson, M.; Hjelmencrantz, M.
N.; Nilsson, M.; Olsson, T. Tetrahedron 1995, 51, 12631-12644. For an
alternative approach, see: (d) Lambert, T. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 13646-13647.
(5) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc.
1976, 98, 2868-2877.
(6) (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I.
Tetrahedron Lett. 1986, 27, 4025-4028. (b) Matsuzawa, S.; Horiguchi,
Y.; Nakamura, E.; Kuwajima, I. Tetrahedron 1989, 45, 349-362.
(7) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. (b) Sakata, H.; Kuwajima, I. Tetrahedron
Lett. 1987, 28, 5719-5722. (c) Sakata, H.; Aoki, Y.; Kuwajima, I.
Tetrahedron Lett. 1990, 31, 1161-1164. (d) Magot-Cuvru, A.; Blanco, L.;
Drouin, J. Tetrahedron 1991, 47, 8331-83388.
Multicomponent couplings initiated by conjugate addition and
terminated by electrophilic trapping of the resulting enolate are
(1) Ibuka, T.; Aoyagi, T.; Kitada, K.; Yoneda, F.; Yamamoto, Y. J.
Organomet. Chem. 1985, 287, C18-C22.
(2) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett. 2004,
6, 3425-3427.
(8) See the Supporting Information for the synthesis procedure.
(9) Sacconi, L.; Ciampolini, M. J. Chem. Soc. 1964, 276-80.
10.1021/jo701778k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/23/2008
J. Org. Chem. 2008, 73, 1575-1577
1575

TABLE 1. Initial Results of Conjugate Addition to Diallyl
Fumarate
entry
EtM
solvent
catalyst
resultsa
1
2
3
4
EtMgBr
EtMgBr
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
THF
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Cu(NtBu‚sal)2
None
mix of productsb
85% conv
12% conv
100% conv
100% conv
74% conv
Cu(NtBu‚sal)2
Cu(NtBu‚sal)2
CuBr‚DMS
Cu(NtBu‚sal)2
none
5
6c
7
80% conv
60% conv
8c
none
FIGURE 1. X-ray structure of amide 3.
a Conversion determined by 1H NMR spectroscopy. b Undetermined
mixture of 1,4-addition, 1,2-addition, and SN2′. c Reaction conducted without
TMSCl.
nate product in good yield and diastereocontrol. Diprenyl
fumarate is also an effective reaction partner (entry 3), with
SN2′ displacement as a competitive process that slightly
decreases the yield. The diastereoselectivity is eroded when a
bulkier nucleophile, diisopropylzinc (1.0 M in toluene), is used
(entry 4).
TABLE 2. Scope of Tandem Michael Addition/Ireland-Claisen
Rearrangement
Other diorganozinc reagents were prepared Via transmetala-
tion. By using n-butyllithium and ZnCl2 to generate Bu2Zn‚
(LiCl)2 in situ, the desired addition and subsequent rearrange-
ment was accomplished. The addition of Bu2Zn‚(LiCl)2 to both
diallyl and diprenyl fumarates proceeded in good yield, although
with decreased diastereoselectivity (entries 5 and 6). The reagent
Bu2Zn‚(MgX2)2 gave rise to the desired 1,4-addition, but with
little or no rearrangement observed. It is conceivable that the
magnesium salts inhibit the enolate silylation that is apparently
required for the [3,3]-rearrangement.
The addition of Et2Zn to either a cis- (entry 8) or trans-
substituted (entry 7) allyl fumarate proceeds in good yield but
gives an intractable mixture of diastereomers.
entry
R2Zn
substrate
product yield (%) (dr) a
1
2
3
4
5
6
7
8
Et2Zn
Et2Zn
Et2Zn
iPr2Zn
(E)-1a (R1, R2 ) H)
(Z)-1a (R1, R2 ) H)
(E)-1b (R1, R2 ) Me)
(E)-1a (R1, R2 ) H)
2a
2a
2b
2c
2d
2e
2f
83 (9:1)
74 (6.5:1)
68 (7.5:1)
70 (4.9:1)
88 (4.5:1)
63 (2:1)
The monocarboxylic acid derived from addition of diethylzinc
to diallyl fumarate (1a) was transformed in two steps to the
crystalline secondary amide 3. Its relative stereostructure was
ascertained via X-ray crystallography.10 The structure found in
Figure 1 reveals the anti disposition of the ethyl and allyl
moieties on the succinate backbone. A stereochemical model
consistent with this observation supposes that addition to the
favored s-trans conformation of the enoate occurs to give an
(E)-enolate intermediate.11 In a relevant study, Blanco and co-
workers reported that conjugate addition to the s-trans confor-
mation of an R,â-unsaturated enoate led to the E-silylketene
Bu2Znb (E)-1a (R1, R2 ) H)
Bu2Znb (E)-1a (R1, R2 ) Me)
Et2Zn
Et2Zn
(E)-1c (R1 ) Me, R2 ) H)
(E)-1d (R1 ) H, R2 ) Pr)
75 (mix)
78 (mix)
2g
a Yield of isolated products purified by column chromatography. b 1.5
equiv of Bu2Zn (generated from 3.0 equiv of BuLi and 1.5 equiv of ZnCl2
in Et2O), 4.0 equiv of TMSCl.
The desired addition proceeds in the absence of TMSCl and
copper additives (entries 6-8), although with decreased ef-
ficiency. The observation of uncatalyzed addition using Et2Zn,
even at low temperature, dramatically highlights the difference
in reactivity between fumarates and simple enoates. The identity
of the copper source was inconsequential to the progress of the
reaction. Upon heating of the reaction mixture, the presumed
silylketene acetal intermediate underwent Ireland-Claisen rear-
rangement. The carboxylic acid product was esterified with
dimethyl sulfate and potassium carbonate in acetone for ease
of characterization. With the optimized conditions identified,
the scope of the reaction was explored (Table 2).
acetal geometry upon trapping with chlorotrimethylsilane.7d
A
transition structure for the sigmatropic rearrangement that
minimizes allylic strain and involves approach of the allyl
moiety syn to the ester group has been previously invoked by
Martin and co-workers in their study of Ireland-Claisen
rearrangements of substituted succinates (Scheme 3).12
The desymmetrized succinate products are useful due to the
presence of several distinguishable functional handles that allow
(10) CCDC 635154 contains the supplementary crystallographic 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.
(11) Shida, N., Kabuto, C., Niwa, T., Ebata, T., Yamamoto, Y. J. Org.
Chem. 1994, 59, 4068-4075 and references therein.
The addition of diethylzinc (1.0 M in diethyl ether) to diallyl
fumarate (entry 1) or diallyl maleate (entry 2) and subsequent
rearrangement provides the disubstituted unsymmetrical succi-
1576 J. Org. Chem., Vol. 73, No. 4, 2008

SCHEME 3. Proposed Transition State for Ireland-Claisen
Rearrangement
SCHEME 5. Curtius Rearrangement to a â-Amino Ester
SCHEME 6. DCC Coupling of Carboxylic Acid and Amine
SCHEME 4. Site-Selective Bromolactonization
a 1:1 mixture of diastereomers (Scheme 6). The diastereotopic
methyl groups are clearly distinguishable by H NMR spec-
1
troscopy (δ 0.87 vs 0.78, CDCl3), which allows this simple
derivative to be used for assaying enantioselective variants.
Efforts to this end employing methods developed by Feringa17
and others have provided no enantiomeric enrichment to date.
The significant uncatalyzed background rate is almost certainly
a complication in these efforts. To achieve an enantioselective
variant, a substantially less reactive nucleophile will need to
be incorporated into this tandem sequence to suppress the
background addition of the achiral nucleophile.
In summary, we have developed a tandem conjugate addition/
Ireland-Claisen rearrangment of dialkylzinc reagents and allyl
fumarates in good to excellent yields giving substituted succinate
products. The reaction renders the two carboxyl groups non-
equivalent; consequently, the products can be selectively
manipulated in subsequent synthetic operations.
for further synthetic manipulation. Subjecting the carboxylic acid
intermediate to N-bromosuccinimide13 in the presence of
NaHCO3 gave efficient bromolactonization yielding the γ-lac-
tone (Scheme 4) in 80% yield and 9:1 diastereoselection. The
diastereomers result from the initial addition/sigmatropic rear-
rangement, indicating that the cyclization proceeds with com-
plete diastereoselectivity.14
Alternatively, the carboxylic acid can be employed in a
Curtius rearrangement to furnish a â-amino ester with diphe-
nylphosphoryl azide, benzyl alcohol, and triethylamine (Scheme
5).15 No purification of the intermediate acid was performed
for either the bromolactonization or Curtius rearrangement.
The amide formed with the racemic rearranged product and
(S)-phenylethylamine using DCC16 gives a secondary amide as
Acknowledgment. Funding for this work was provided by
the National Institutes of Health (National Institute of General
Medical Sciences, GM068443). Research support from Eli Lilly,
Amgen, and GSK is gratefully acknowledged. J.S.J. is an Alfred
P. Sloan Fellow and a Camille Dreyfus Teacher-Scholar.
Supporting Information Available: Spectroscopic and analyti-
cal data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO701778K
(12) Pratt, L. M.; Bowles, S. A.; Courtney, S. F.; Hidden, C.; Lewis, C.
N.; Martin, F. M.; Todd, R. S. Synlett 1998, 531-533.
(13) Fueloep, F.; Palko, M.; Forro, E.; Dervarics, M.; Martinek, T. A.;
Sillanpaeae, R. Eur. J. Org. Chem. 2005, 3214-3220.
(16) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067-
1068.
(14) The relative stereochemistry was determined by 2D COSY and
NOESY spectra. The correlations are shown in the Supporting Information.
(15) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94,
6203-6205.
(17) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Arnold,
L. A.; Imbos, R.; Mandoli, A.; De Vries, A. H. M.; Naasz, R.; Feringa, B.
L. Tetrahedron 2000, 56, 2865-2878. For a list of conditions that were
examined for the enantioselective addition, see the Supporting Information.
J. Org. Chem, Vol. 73, No. 4, 2008 1577