Formal cycloaddition of disubstituted ketenes with 2-oxoaldehydes catalyzed by chiral n-heterocyclic carbenes

Article abstract of DOI:10.1021/jo801494f

(Chemical Equation Presented) Chiral N-hetereocyclic carbenes were found to be efficient catalysts for the formal [2 + 2] cycloaddition reactions of alkyl(aryl)ketenes with 2-oxoaldehydes to afford β-lactones with α-quaternary-β-tertiary stereocenters in

Full text of DOI:10.1021/jo801494f

challenged substrates than unsubstituted ones for this formal
cycloaddition reaction.7 In this context, a strategy of combination
of cinchona alkaloid as Lewis base and lithium perchlorate or
lanthamide triflates as Lewis base was successfully employed.8
The intramolecular version of this reaction was also realized
by employing O-acetyl quinidine as catalyst.9
Formal Cycloaddition of Disubstituted Ketenes
with 2-Oxoaldehydes Catalyzed by Chiral
N-Heterocyclic Carbenes
Lin He, Hui Lv, Yan-Rong Zhang, and Song Ye*
Disubstituted ketenes are less reactive and become the most
challenging substrate for this process.10 Remarkably, Fu et al.
reported that planar-chiral 4-pyrrolidin-1-ylpyridine (1) was an
efficient catalyst for the formal cycloaddition of disubstituted
ketenes with aldehydes to furnish ꢀ-lactones in good yields with
excellent enantioselectivities (up to 91% ee) (eq 1).11 Although
this catalytic system worked very well for dialkylketenes, it
failed for alkyl(aryl)ketenes.
Beijing National Laboratory for Molecular Sciences,
Laboratory of Chemical Biology, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
songye@iccas.ac.cn
ReceiVed July 7, 2008
Chiral N-hetereocyclic carbenes were found to be efficient
catalysts for the formal [2 + 2] cycloaddition reactions of
alkyl(aryl)ketenes with 2-oxoaldehydes to afford ꢀ-lactones
with R-quaternary-ꢀ-tertiary stereocenters in high yields with
good diastereoselectivities and excellent enantioselectivities
(up to 99% ee). Both alkyl(aryl)ketenes and diarylketene
worked well in this reaction.
Recently, N-heterocyclic carbenes (NHCs) were found to be
efficient organocatalysts for the umpolung of aldehydes for
benzoin reaction and Stetter reaction,12 extended umpolung of
functional aldehydes,13 intramolecular ꢀ-alkylation of Michael
acceptors,14 aza-Mortia-Baylis-Hillman reaction15 and many
other reations.16
Smith et al. and our group have independently reported that
NHCs were efficient catalysts for the formal cycloaddition of
(7) (a) Nelson, S. G.; Zhu, C.; Shen, X. J. Am. Chem. Soc. 2004, 126, 14.
(b) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem.
Soc. 2006, 128, 7438. (c) Nelson, S. G.; Wan, Z. Org. Lett. 2000, 2, 1883.
(8) (a) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352.
(c) Calter, M. A.; Tretyak, O. A.; Flashchenriem, C. Org. Lett. 2005, 1809.
(9) (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001,
123, 7945. (b) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70,
2835. (c) Henry-Riyad, H.; Lee, c.; Purohit, V. C.; Romo, D. Org. Lett. 2006,
8, 4363.
(10) For asymmetric reactions of disubstituted ketenes, see: (a) Hodous, B. L.;
Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637. (b) Lee, E. C.;
Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
11586. (c) Li, C.-Y.; Sun, X.-L.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980.
(11) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 6358.
(12) (a) Ugai, T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63,
296. (b) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719. (c) Stetter, H. Angew.
Chem., Int. Ed. 1976, 15, 639. (d) Enders, D.; Kallfass, U. Angew. Chem., Int.
Ed. 2002, 41, 1743. (e) Li, G. Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007,
852.
(13) (a) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506. (b) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205. (c) Sohn, S. S.; Rosen, E. L.;
Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370. (d) Li, G.-Q.; Li, Y.; Dai,
L.-X.; You, S.-L. Org. Lett. 2007, 9, 3519. (e) Chan, A.; Scheidt, K. A. J. Am.
Chem. Soc. 2008, 130, 2740. (f) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008,
130, 418. (g) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796. (h)
Nari, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128,
8736.
The asymmetric [2 + 2] cycloaddition of ketenes with
aldehydes to construct optically active ꢀ-lactones has been
continuously pursued for decades.1 Chiral Lewis bases, Lewis
acids, and bifunctional catalysts have been employed for this
process. In 1982, Wynberg et al. published their pioneering work
of the highly enantioselective cinchona alkaloid-catalyzed formal
cycloaddition of unsubstituted ketene (CH2dCdO) with chlo-
ral.2 The asymmetric reaction of unsubstituted ketene with a
variety of aldehydes was then achieved by using an aluminum-
triamine complex catalyst,3 chiral oxazaborolidine catalyst,4 and
Lewis acid-Lewis base bifunctional catalyst.5 Bis(oxazoline)-
copper complexes were demonstrated to be efficient catalysts
for the reaction of silylketene (TMSCHdCdO) with chelating
carbonyl substrates.6 Alkylketenes were found to be more
(1) For synthesis and applications of ꢀ-lactones, see: (a) Schneider, C. Angew.
Chem., Int. Ed. 2002, 41, 744. (b) Yang, H. W.; Romo, D. Tetrahedron 1999,
55, 6403. (c) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64,
605.
(2) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166.
(3) (a) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,
9742. (b) Nelson, S. G.; Kim, B.-K.; Peelen, T. J. J. Am. Chem. Soc. 2000, 122,
9318.
(14) Fisher, C.; Smith, S. W.; Powell, D. A.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 1472.
(4) Gnandesikan, V.; Corey, E. J. Org. Lett. 2006, 8, 4943.
(5) Lin, Y.-M.; Boucau, J.; Li, Z.; Casarotto, V.; Lin, J.; Nguyen, A. N.;
Ehrmantrau, J. Org. Lett. 2007, 9, 567.
(15) (a) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466. (b) He, L.;
Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825.
(16) For a recent comprehensive review, see: (a) Enders, D.; Niemeier, O.;
Henseler, A. Chem. ReV. 2007, 107, 5606.
(6) Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125.
10.1021/jo801494f CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8101–8103 8101

TABLE 1. Chiral NHCs for the Formal Cycloaddtion of Ketene
2a with 2-Oxoaldehyde 3a
TABLE 2. Cycloaddition Reaction of Disubstituted Ketenes with
2-Oxoaldehydes Catalyzed by NHC 5b
entry
2: Ar1, R
3: Ar2
4
drb
4a >20:1e
yield (%)c ee (%)d
1
2
3
4
5
6
7
8
9j
2-ClC6H4, Et Ph
85
98
99
65
88
76
77
76
73
99
63
k
97
99g
99g
95
97
99g
94
99g
98
78
4
2-ClC6H4, Et 4-MeOC6H4 4bf >20:1e
2-ClC6H4, Et 4-BrC6H4
2-ClC6H4, Et 1-naphthyl
2-ClC6H4, Et 2-naphthyl
4c
h
4d 10:1
4e
h
i
4-ClC6H4, Pr Ph
4f 4:1i
4g 4:1i
4h 4:1i
4h 4:1i
4i
i
4-ClC6H4, Pr 4-MeC6H4
i
Ph, Pr
Ph
Ph
Ph
Ph
i
Ph, Pr
10 Ph, Ph
11 (CH2)6
12 2-ClC6H4, Pr benzyl
entry
NHCa
yield (%)b
drc
ee (%)d
4j
i
1
2
3
4
5
5a
5b
6
7
8
75
85
69
76
60
>20:1
>20:1
>20:1
>20:1
>20:1
89
97
a NHC 5b was generated from the precursor 5b′ (12 mol %) with
Cs2CO3 (10 mol %) in THF at room temperature in 1 h and used
immediately. b Determined by 1H NMR (300 MHz) of the reaction
mixture. c Isolated yields of pure trans-isomers. d Determined by HPLC
on Chiral Column. e Only trace cis-isomer detected. f The absolute
configuration of lactone 4b was determined by X-ray to be (3R,4S), and
the configuration of other lactones was determined by comparison of its
specific rotation and CD sepectrum with those of lactone 4b. g Only one
enantiomer detected by HPLC. h trans only. i Yields and ee’s of the
cis-isomers: 4f-cis (23%, 65% ee), 4g-cis (20%, 65% ee), 4h-cis of
entry 8 (22%, 13% ee), 4h-cis of entry 9 (23%, 13% ee). j The reaction
was carried out at 0 °C. k No reaction.
-24e
-58e
4
a NHCs 5-8 were generated from NHC precursors 5′-8′ (12 mol %)
with Cs2CO3 (10 mol %) in THF at room temperature in 1 h and used
immediately. b Isolated yields. c Determined by 1H NMR (300 MHz),
with only trace trans-isomers detected. d Determined by HPLC on
Daicel Chiralpak As-H column. e ent-4a was the major product.
disubstituted ketenes with imines (eq 2).17 Thus, it is quite
interesting for us to explore the NHC-catalyzed formal cycload-
dition of alkyl(aryl)ketenes with aldehydes to give ꢀ-lactones
bearing R-quaterary-ꢀ-tertiary stereocenters.18
then achieved by employing catalyst NHC 5b with a bulky tert-
butyldimethylsilyl substituent (entry 2). Several other NHCs
(6-8) were also tested, and low to moderate enantioselectivities
were resulted (entries 3-5).
The scope of the reaction is showed by the use of a variety
of ketenes and aldehydes in this cycloaddition reaction (Table
2). Both 2-oxo-2-arylacetaldehydes with an electron-donating
substituent (4-MeO) and with an electron-withdrawing substitu-
ent (4-Br) worked very well and afforded the corresponding
ꢀ-lactone in high yields with excellent diastereo- and enanti-
oselectivities (entries 2 and 3). Aldehydes with bulky aryl groups
(1- and 2-naphthyl) also worked well (entries 4 and 5). The
reactions of aryl(isopropyl)ketenes went smoothly. Though the
diastereoselectivities dropped to 4:1, the excellent enantiose-
lectivities were kept in these cases (entries 6-8). Lowering the
reaction temperature to 0 °C had no beneficial effect on the
yield and selectivity of the reaction (entry 9). The reaction of
diphenylketene went smoothly, but only 78% ee was achieved
(entry 10). The symmetric cyclic ketene, cycloheptyliden-
emethanone, which worked well in Fu’s ketene-aldehyde
cycloaddition, gave the product in only 63% yield with very
low enantioselectivity (entry 11). And the reaction of 2a and
benzil (PhCOCOPh) did not occur under the current reaction
conditions (entry 12).
Unfortunately, initial experiments showed that the formal
cycloaddition reaction of ethyl(2-chlorophenyl)ketene (2a) with
4-chlorobenzaldehyde did not occur in the presence of achiral
or chiral NHCs (10-20 mol %), and 1H NMR showed that most
ketene and aldehyde remained unchanged.
2-Oxoaldehydes, which are more active than normal alde-
hydes and represent an important substance class as versatile
building blocks in organic synthesis, were then explored. It was
found that NHC 5a,19 generated from the corresponding
precursor 5a′ with Cs2CO3, could catalyze the cycloaddition
reaction of ketene 2a with 2-oxo-2-phenylacetaldehyde at room
temperature to afford the corresponding ꢀ-lactones in 75% yield
with highly diastereo- and enantioselectivity (dr ) 20:1, 89%
ee) (Table 1, entry 1). An enantiomerical excess of 97% was
One possible catalytic cycle for this NHC-catalyzed reaction
is depicted in Figure 1. The N-heterocyclic carbene attacks the
R-carbon of the ketene to give a triazolium enolate 9. The
nucleophilic addition of enolate 9 to aldehyde furnishes tria-
zolium aldolate 10, which collapses to afford the desired
ꢀ-lactone 4 and regenerate NHC catalyst.
(17) (a) Zhang, Y. R.; He, L.; Wu, X.; Shao, P. L.; Ye, S. Org. Lett. 2008,
10, 277. (b) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org.
Biomol. Chem. 2008, 6, 1108.
(18) For asymmetric creation of quaternary carbon centers, see: (a) Quater-
nary Stereocenters: Challenges and Solution for Organic Synthesis; Christoffers,
J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005. (b) Juji, K. Chem. ReV. 1993,
93, 2037.
(19) Except our report (ref 17a), Enders et al. have also reported the synthesis
of NHC precursor 5a′ and 5b′ from L-pyroglutamic acid:Enders, D.; Han, J.
Tetrahedron: Asymmetry 2008, 19, 1367.
In conclusion, the N-heterocyclic carbene 5b was demon-
strated as an efficient catalyst for the formal cycloaddition of
8102 J. Org. Chem. Vol. 73, No. 20, 2008

and the reaction mixture was stirred overnight. The mixture was
then filtered through a pad of silica gel and washed with petroleum
ether/ethyl acetate (10:1). The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography on
silica gel (petroleum ether/ethyl acetate, 20:1) to give the desired
product as a white solid.
Lactone 4a (Table 2, entry 1). Yield: 266 mg (85%); Rf ) 0.61
(petroleum ether/ethyl acetate ) 10:1); white solid, mp 125-126
1
°C; [R]25 -20.6 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) δ
D
7.96 (d, J ) 8.5 Hz, 2H), 7.74-7.58(m, 2H), 7.55-7.45 (m, 2H),
7.45-7.38 (m, 1H), 7.38-7.29 (m, 2H), 5.93 (s, 1H), 2.49-2.27
(m, 1H), 2.26-2.06 (m, 1H), 0.84 (t, J ) 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 193.8, 170.1, 136.2, 134.1, 133.2, 132.4, 131.0,
129.7, 129.4, 128.8, 128.7, 127.0, 77.7, 69.6, 23.5, 9.1; IR (KBr)
V 1830, 1696, 1597, 1449, 1231, 1120, 914, 754, 697; EIMS m/z
314 (M+, 1.28), 270 (M+ - CO2, 10.36), 235 (M+ - CO2 - 35Cl,
65.85), 105 (PhCO+, 100); HRMS-EI (m/z) [M+] calcd for
C18H15ClO3, 314.0710; found 314.0713. HPLC analysis: 97% ee
[Daicel CHIRALPAK AS-H column; 20 °C; 1.0 mL/min; solvent
system ) 2-propanol/hexane, 10:90; retention times ) 11.5 min
(major), 15.4 min (minor)].
FIGURE 1. Proposed catalytic cycle.
alkyl(aryl)ketenes with 2-oxoaldehydes to give the correspond-
ing ꢀ-lactones with R-quaternary-ꢀ-tertiary stereocenters in good
yields with good diasteroselectivities and excellent enantiose-
lectivities. Further exploration of NHC-catalyzed reaction of
ketenes is underway in our laboratory.
Acknowledgment. We are grateful to the Chinese Academy
of Sciences and Natural Sciences Foundation of China (no.
20602036) for financial support.
Experiment Section
General Procedure for Asymmetric Synthesis of ꢀ-Lactones. To
an oven-dried 50 mL reaction tube containing a stir bar were added
triazolium salts 5b′ (70 mg, 0.12 mmol), anhydrous Cs2CO3 (32
mg, 0.1 mmol), and THF (4 mL). The reaction mixture was stirred
for 1 h at room temperature. Ketene (1.5 mmol) was then added
via a syringe followed by addition of 2-oxoaldehyde (1.0 mmol),
Supporting Information Available: Experimental proce-
dures, compound characteriations, and crystal structure data of
lactone 4b in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801494F
J. Org. Chem. Vol. 73, No. 20, 2008 8103