NHC-catalyzed/titanium(iv)-mediated highly diastereo-and enantioselective dimerization of enals

Article abstract of DOI:10.1021/ol103112v

An NHC-catalyzed, diastereo-and enantioselective dimerization of enals has been developed. The use of Ti(Oi-Pr)₄ is a key element for the reactivity and selectivity of this process. The cyclopentenes are obtained with high levels of diastereo-a

Full text of DOI:10.1021/ol103112v

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1068–1071
NHC-Catalyzed/Titanium(IV)-Mediated
Highly Diastereo- and Enantioselective
Dimerization of Enals
Daniel T. Cohen, Benoit Cardinal-David, John M. Roberts, Amy A. Sarjeant, and
Karl A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Northwestern University, Silverman Hall,
2145 Sheridan Road, Evanston, Illinois 60208, United States
scheidt@northwestern.edu
Received December 22, 2010
ABSTRACT
An NHC-catalyzed, diastereo- and enantioselective dimerization of enals has been developed. The use of Ti(Oi-Pr)4 is a key element for the
reactivity and selectivity of this process. The cyclopentenes are obtained with high levels of diastereo- and enantioselectivity and their synthetic
utility is demonstrated by functionalization of the product alkene.
The field of N-heterocyclic carbene (NHC) catalysis has
undergone explosive growth over the past decade.1 In
addition to a pyruvate decarboxylase-type of acyl anion
reactivity,2,3 these unique Lewis base catalysts can induce
unusual homoenolate reactions that (a) create nucleophilic
character at the β-position of an enal and (b) involve a
terminal acylation event to release the azolium catalyst.4,5
We have been focused on developing new carbene cata-
lyzed reactions and specifically with regard to homoeno-
lates, engaging these nucleophlies with reactive partners to
generate new formal [M þ N] cycloaddition processes. In
our continuing investigations of different XdY systems
(suchasazo compoundsand azomethine imines, Scheme 1,
(1) For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534–541. (b) Nair, V.; Bindu, V.; Sreekumar, V. Angew. Chem.,
Int. Ed. 2004, 39, 5130–5135. (c) Zeitler, K. Angew. Chem., Int. Ed. 2005,
44, 7506–7510. (d) Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988–3000. (e) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606–5655. (f) Zeitler, K. In
Organocatalysis; Reetz, M. T., List, B., Jaroch, S., Weinmann, H., Eds.;
Springer-Verlag: Heidelberg, Germany, 2008; pp 183-206. (g) Glorius, F.;
Hirano, K. InOrganocatalysis; Reetz, M. T., List, B., Jaroch, S., Weinmann, H.,
Eds.; Springer-Verlag: Heidelberg, Germany, 2008; pp 183-206. (h) Phillips,
E. M.; Chan, A.; Scheidt, K. A. Aldrichim. Acta 2009, 42, 55–66.
(2) (a) Mizuhara, S.; Tamura, R. Proc. Jpn. Acad. 1951, 87, 302.
(b) Kluger, R. Chem. Rev. 1987, 87, 863–876. (b) Jordan, F. Nat. Prod.
Rep. 2003, 20, 184–201. (d) Jordan, F.; Nemeria, N. S.; Zhang, S.; Yan,
Y.; Arjunan, P.; Furey, W. J. Am. Chem. Soc. 2003, 125, 12732–12738.
(e) Frank, R. A. W.; Titman, C. M.; Pratap, J. V.; Luisi, B. F.; Perham,
R. N. Science 2004, 306, 872–876.
(3) (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. (b) Yatco-
Manzo, E.; Roddy, F.; Yount, R. G.; Metzler, D. E. J. Biol. Chem. 1959,
234, 733–737. (c) Sheehan, J. C.; Hunneman, D. H. J. Am. Chem. Soc.
1966, 88, 3666–3667. (d) Sheehan, J. C.; Hara, T. J. Org. Chem. 1974, 39,
€
1196–1199. (e) Stetter, H.; Ramsch, R. Y.; Kuhlmann, H. Synthesis
1976, 733–735. (f) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407–
496. (g) Hassner, A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 541-604.
(h) Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217–
1221. (i) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241–
8242. (j) Knight, R. L.; Leeper, F. J. Tetrahedron Lett. 1997, 38, 3611–
3614. (k) Dvorak, C. A.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 2925–
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(n) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
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r
10.1021/ol103112v
Published on Web 01/27/2011
2011 American Chemical Society

reactive oxo-butenoate (Bode)10 to produce cyclopentenes
after an unusual room temperature decarboxylation.11
Even with the numerous reports of NHC-homoenolate
reactions, the factors governing the partitioning between
these competing 1,2- vs 1,4-addition pathways are cur-
rently not well understood. Additionally, efficient conju-
gate addition reactions of NHC-derived homoenolates to
enals have remained difficult to accomplishefficiently. Our
recent success employing Lewis acids with NHC catalysis
promoted us to investigate this reaction using a NHC/
Lewis acid approach to control the regio- and enantios-
electivity outcome.12 To the best of our knowledge, these
are the first examples of a highly diastereo- and enantio-
selective dimerization of these reactive unsaturated carbo-
nyl systems using cooperative catalysis NHC/Lewis acid
conditions.
Scheme 1. Competing NHC Homoenolate Pathways
Our studies to explore this carbene/Lewis acid possibi-
lity began by combining cinnamaldehyde (1a) in THF with
a stoichiometric amount of Lewis acid (1 equiv) in the
presence of azolium salt A (20 mol %) and DBU at 60 °C.
Several metal alkoxides were initially tested in this reac-
tion, but most of them provided the γ-butyrolactones (1,2
addition) or led to the decomposition of the starting
material.13 After extensive investigation, we discovered
that the use of Ti(Oi-Pr)4 afforded compound 2 as a sole
diastereoisomer as detected by NMR spectroscopy (Table 1,
entry 1). The evaluation of several of the available chiral
azolium salts revealed that phenylalanine-derived azolium
C and tryptophan-derived azolium E14 provided the high-
est levels of enantioselectivity (entries 3 and 5). Impor-
tantly, performing the reaction in the absence of Ti(Oi-Pr)4
did not afford any of 2, which confirmed the essential role of
the Lewis acid in this process (entry 6). At this stage, the
efficiency and selectivity of the transformation (58% yield,
66% ee) was encouraging, but not synthetically viable.
Lowering the temperature to improve the enantioselectiv-
ity resulted in a mixture of desired 2 and an intermediate
β-hydroxyester (16, Scheme 2), which was observed by 1H
NMR spectroscopy. We anticipated that the full elimina-
tion of water to yield compound 215 could be promoted
eq 1) that could be successful reaction partners in these
carbene-catalyzed processes, we have encountered what
can be viewed as a “vinylogous benzoin” limitation.6
Similarly, for NHC-generated homoenolate reactions,
many times the most reactive electrophile present is the
homoenolate precursor, or enal 1. Consequently, the
major product can be the γ-lactone product when the
XdY reactant does not possess the optimal reactivity
(Scheme 1, eq 2, major product).
While successful new homoenolate reactions have been
realized by judicious choice of electrophile to circumvent
the vinylogous benzoin pathway, we have also been in-
vestigating alternative strategies to engage NHC-homo-
enolates in more general reactions.7 An interesting minor
product that we have observed in these homoenolate type
reactions is the β-lactone product, resulting from the 1,4-
addition of the homoenolate (Scheme 1, eq 2, minor
product).8 This alternate dimerization pathway competes
with the more standard 1,2-addition which leads to
γ-lactones. Prior to the disclosure of our 1,4-addition
observation, both Nair and Bode reported variations of
this manifold combining enals and chalcones (Nair)9 or a
(10) (a) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem.
Soc. 2007, 129, 3520–3521. (b) Chiang, P.-C.; Kaeobamrung, J.; Bode,
J. W. J. Am. Chem. Soc. 2007, 131, 8714–8715. (c) Kaeobamrung, J.;
Bode, J. W. Org. Lett. 2009, 11, 677–680.
(4) For a review of Lewis base catalysis, see: Denmark, S. E.; Beutner,
G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638. For a review of NHC-
generated homoenolate methodology, see: Nair, V.; Vellalath, S.; Babu,
B. P. Chem. Soc. Rev. 2008, 37, 2691–2698.
(5) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205–6208. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370–14371.
(11) (a) Faulkner, D. J. Synthesis 1971, 175–189. (b) Marshall, J. A.;
Karas, L. J. J. Am. Chem. Soc. 1978, 100, 3615–3616. (c) Mulzer, J.;
€
Zippel, M.; Bruntrup, G. Angew. Chem., Int. Ed. 1980, 19, 465–466.
(d) Danheiser, R. L.; Nowick, J. S. J. Org. Chem. 1991, 56, 1176–1185
and references cited therein.
(6) For the benzoin reaction, the acyl anion generated in situ adds to
the starting material benzaldehyde, thereby typically producing dimeric
products.
(7) (a) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908. (b) Chan,
A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558–4559. (c) Phillips,
E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed.
2007, 46, 3107–3110. (d) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 5334–5335. (e) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 2740–2741. (f) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2008, 130, 2416–2417.
(12) (a) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A.
Nature Chem. 2010, 2, 766–771. (b) Cardinal-David, B.; Raup, D. E. A.;
Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345–5347. (c) Cohen, D. T.;
Cardinal-David, B.; Scheidt, K. A. Angew. Chem., Int. Ed. 2011
Early view. For other examples of NHC-metal cooperative catalysis, see:
(d) Nemoto, T.; Fukuda, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 4365–
4368. (e) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243–
4246. (f) He, J.; Tang, S.; Liu, J.; Sun, Y.; Pan, X.; She, X. Tetrahedron
Lett. 2009, 50, 430–433. (g) Chen, Z.; Yu, X.; Wu, J. Chem. Commun.
2010, 46, 6356–6358 .
(13) Numerous metal alkoxides were examined including Mg(Ot-
Bu)2, Ba(Oi-Pr)2, and Sr(Oi-Pr)2.
(8) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 10098–10099.
(14) Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306–1315.
(15) The absolute and relative stereochemistry of compounds 2 was
determined by X-ray crystallography of a related derivative (see Sup-
porting Information) and additional assignments made by analogy.
(9) (a) Nair, V.; Vellalath, S.; Poonoth, S.; Suresh, E. J. J. Am. Chem.
Soc. 2006, 128, 8736–8737. (b) Nair, V.; Babu, B. P.; Vellalath, S.;
Varghese, V.; Raveendran, A. E.; Suresh, E. Org. Lett. 2009, 11, 2507–
2510.
Org. Lett., Vol. 13, No. 5, 2011
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Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope
entry
R
yield (%)a
ee (%)b
1
Ph
61(2)
61(3)
59(4)
58(5)
61(6)
60(7)
61(8)
62(9)
59(10)
63(11)
72(12)
90
90
90
84
90
90
90
85
85
86
84
2
p-Br-C6H4
3
P-Cl-C6H4
4
m-Cl-C6H4
p-OMe-C6H4
m-OMe-C6H4
p-Me-C6H4
m-Me-C6H4
1-Naphthyl
2-Naphthyl
p-CO2Me-C6H4
5
6
7
8
9
10
11c
a Isolated yield. b Enantiomeric excess determined by HPLC with a
chiral stationary phase. Diastereomeric ratio determined by H NMR
1
spectroscopy (500 MHz) of unpurified reaction mixture. c Lewis acid
(2.5 equiv); transesterification to p-(CO2i-Pr)-C6H4 was observed.
a All reactions performed on 0.38 mmol scale. b Isolated yield.
c Enantiomeric excess determined by HPLC with a chiral stationary
phase. Diastereomeric ratio determined by 1H NMR spectroscopy (500
MHz) of unpurified reaction mixture. d Reaction performed without
Ti(Oi-Pr)4. e 1.0 equiv of TBD added after 12 h. f 10 mol % azolium salt
and 20 mol % TBD.
When the para-methyl ester substrate was employed, an
increase in yield was observed, but the enantioselectivity
decreased slightly (entry 11). Meta-substituted aryl groups
at the β-position and naphthyl-derived enals were also
tolerated, but the enantiomeric excess was sometimes low-
er in these cases. Finally, more sterically demanding sub-
strates such as ortho-substituted aryl enals, β-alkyl or
R-substituted enals suffered from low yields or no conversion
(results not shown).
Scheme 2. 1H NMR Detection of β-Hydroxyl Intermediate
Our proposed reaction pathway for this dimerization is
shown in Scheme 3. The initial coordination of the R,β-
unsaturated aldehyde to the titanium(IV) Lewis acid in-
duces the formation of the extended Breslow intermediate
I. The coordination of a second enal to the aldehyde-
titanium(IV) complex increases its reactivity toward con-
jugate addition and organizes the reactants in space as
shown in II to promote 1,4-addition over 1,2-addition.18
Both the homoenolate and the enal are thus poised to react
through an s-cis conformation, ensuring high cis diaster-
eofacial selectivity in the products. Following the C-C
bond formation to give intermediate III, the bis-enolate
undergoes protonation, tautomerization and intramolecular
aldol to afford IV. The NHC catalyst is then regenerated
from acylation of the acyl azolium to give intermediate V
and the cyclopentene 2 is formed after base-promoted
elimination.
after consumption of the enal starting material by the
addition of excess base. After a short survey of bases and
temperature profiles (not shown) a significant improve-
ment in enantioselectivity and yield was obtained when the
reaction was conductedin toluene with1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD) as the base and 10 mol % of
triazolium salt E (entry 7). One key to the high yield of 2
was the addition of an equivalent of TBD after consump-
tion of the enal.16 Finally, decreasing the amount of Lewis
acid to substoichiometric levels (e.g., 20 mol %, not
shown) resulted in lower yields and enantioselectivities.
We next evaluated the substrate scope of differentially
substituted aryl enals using the chiral triazolium salt E
(Table 2).17 Both electron-donating and -withdrawing
substituents were tolerated at the para position, yield-
ing the cyclopentene in 59-61% yield and up to 90% ee.
This new carbene/Lewis acid reaction provides R,β-
unsaturated esters that can be processed in highly stereo-
selective synthetic transformations (Scheme 4). For example,
the reduction of the endocyclic double bond under hydro-
gen atmosphere followed by saponification proceeded in
(16) Increasing the loading of the base at the beginning of the reaction
(e.g., 120 mol %) resulted in <100% conversion with an effective
stalling of the process.
(17) The two side products observed in these reactions are; mainly
(E)-isopropyl 3-aryl-acrylate (see ref 14), and the γ-lactone (1,2-addition).
(18) For computational studies supporting an NHC homoenolate
ꢀ
Arno, M. Org. Biomol. Chem. 2010, 8, 4884–4891. For discussion of an
alternative benzoin/oxy-Cope pathway, see ref 10.
conjugate addition pathway, see: Domingo, L. R.; Zaragoza, R. J.;
ꢀ
1070
Org. Lett., Vol. 13, No. 5, 2011

Treatment of the cyclopentene with lithium dibenzylamide
afforded the protected amine 14 in 76% yield as a 6:1
mixture of diastereoisomers.20 These substituted β-amino
esters possess unusual substitution patterns that may be
useful in conformationally restricted peptides incorporat-
ing β-amino acids.21 The ozonolysis of the double
bond followed by reductive amination with benzylamine
produced the substituted pipecolic ester 15 as a single dia-
stereoisomer.22 Pipecolic acid derivatives are important
consituents of biologically active molecules,23 including
immunosuppressants,24 N-methyl-D-aspartic acid (NMDA)
antagonists,25 and antibiotics.26
Scheme 3. Proposed Reaction Pathway
In summary, an NHC-catalyzed, Lewis acid mediated
enantioselective dimerization of enals has been developed.
The use of Ti(Oi-Pr)4 promotes a selective 1,4 conjugate
addition versus the typical 1,2-addition. The synthetic
utility of these cyclopentene compounds produced from
carbene catalysis is predominantly a function of the un-
saturated ester produced in the reaction. The merging of
Lewis acid activation with N-heterocyclic carbene Lewis
bases is a powerful new strategy that opens new opportu-
nities for catalytic methodology development.
Scheme 4. Synthetic Transformation
Acknowledgment. Financial support has been gener-
ously provided by the NIH (RO1-NIGMS), Amgen,
AstraZeneca, GlaxoSmithKline. D.T.C is a recipent of
GAANN fellowship. B.C.-D. gratefully acknowledges
ꢀ ꢀ
FQRNT (Fonds Quebecois de la Recherche sur la Nature
et les Technologies) for a postdoctoral fellowship. Use of
the APS was supported by the U.S. Department of Energy
(Contract No. DE-AC02-06CH11357). Use of the LS-
CAT Sector 21 was supported by the Michigan Economic
Development Corp. (Grant 085P1000817).
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
94% yield over two steps to give the 1,2,3-trisubstituted
cyclopentane product 13 as the sole diastereoisomer.19 We
next explored the possibility of introducing nucleophiles
by conjugate addition on the R,β-unsaturated ester.
(22) The relative stereochemistry of compound 15 was determined by
1H NMR NOESY experiments (see Supporting Information for details
and reference to a related transformation).
(23) For reviews, see: (a) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989. (b) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701–1729. (c) Laschat, S.; Dickner, T.
Synthesis 2000, 1781–1813. For a related example, see: (d) Hutchison,
A. J.; Williams, M.; Angst, C.; De Jesus, R.; Blanchard, L.; Jackson,
R. H.; Wilusz, E. J.; Murphy, D. E.; Bernard, P. S. J. Med. Chem. 1989,
32, 2171–2178.
(19) The relative stereochemistry of compound 13 was determined by
X-ray crystallography (Advanced Photon Source) of a related derivative
(see Supporting Information).
(20) The absolute and relative stereochemistry of compound 14 was
determined by X-ray crystallography of a related derivative (see Sup-
porting Information).
(24) Dragovich, P. S.; Parker, J. E.; French, J.; Incuacuan, M.;
Kalish, V. J.; Kissinger, C. R.; Knighton, D. R.; Lewis, C. T.; Moomaw,
E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins, T. J.; Showalter, R. E.;
Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E. J. Med. Chem. 1996, 39,
1872–1884.
(25) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Leander, J. D.;
Lodge, D.; Paschal, J. W.; Elzey, T. J. Med. Chem. 1991, 34, 90–97.
(26) Vanderhaeghe, H.; Janssen, G.; Compernolle, F. Tetrahedron
Lett. 1971, 12, 2687–2688.
(21) For reviews, see: (a) Cheng, R. P.; Gellman, S. H.; DeGrado,
W. F. Chem. Rev. 2001, 101, 3219–3232. (b) Seebach, D.; Hook, D. F.;
Glattli, A. Biopolymers 2006, 84, 23–37. (c) Horne, W. S.; Gellman, S. H.
Acc. Chem. Res. 2008, 41, 1399–1408. Selected examples: (d) Appella,
D. H.; Christianson, L. A.; Klein, D. A.; Powell, D. R.; Huang, X.;
Barchi, J. J.; Gellman, S. H. Nature 1997, 387, 381. (e) Martinek, T. A.;
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