Chiral N-heterocyclic carbene-catalyzed formal [4+2] cycloaddition of ketenes with enones: Highly enantioselective synthesis of trans- And cis-δ-lactones

Article abstract of DOI:10.1002/chem.200801165

The chiral N-hetrocyclic carbenes (NHC)-catalyzed formal [4+2] cycloaddition of ketones with enones to give δ-lactones was reported. The results show that reaction at 0°C leads to better enantioselectivity and yield, while at -10°C result in slightly better enantioselectivity with lesser yield. It is also noted that the diasterometric ratios and enantiometric excess is improved by a single recrystallization from hexane/2-propanol 9:1. The cis-isomer of δ-lactones could be obtained with high diasteroselectivity and enantioselectivity by the in situ deprotonation-protonation after the NHC-catalyzed cycloaddition. The NHC-catalyzed [4+2] cycloaddition of ketones are possibly initiated by the nucleophilic addition of NHC to ketenes to give triazolium enolates.

Full text of DOI:10.1002/chem.200801165

COMMUNICATION
DOI: 10.1002/chem.200801165
Chiral N-Heterocyclic Carbene-Catalyzed Formal [4+2] Cycloaddition of
Ketenes with Enones: Highly Enantioselective Synthesis of trans- and
cis-d-Lactones
Yan-Rong Zhang, Hui Lv, Di Zhou, and Song Ye*[a]
Introduced by Staudinger a century ago, ketenes are re-
markable for the diverse range of useful products from their
reactions.[1] In 1982, Wynberg et al. reported the cinchona
alkaloid-catalyzed ketene–chloral cycloadditions to give the
corresponding b-lactones with up to 98% ee.[2] After that,
catalytic asymmetric ketene dimerizations,[3] ketene–alde-
hyde cycloadditons,[4] and ketene–imine cycloadditions[5]
have been developed. In comparison with these [2+2]
ketene cycloadditions, the enantioselective [4+2] ketene cy-
cloadditions are far less established. Evans et al. reported
the high enantioselective [4+2] cycloaddition of a silylke-
tene with an enone catalyzed by a bis(oxazoline)–copper
complex, but only one example was shown.[4c] Very recently,
the cinchona alkaloid-catalyzed reaction of ketenes with o-
benzoquinones, o-benzoquinone imides, o-benzoquinone di-
imides,[6] and N-thioacyl imines[7] to give the corresponding
[4+2] cycloaddition products with high enantioselectivities
were developed by Lectka et al. and Nelson et al., respec-
tively. And the [4+2] cycloaddition of vinylketenes with al-
dehydes to give d-lactones was achieved by Peters et al.[8]
Recently, N-heterocyclic carbenes were found to be effi-
cient catalysts for the umpolung of aldehydes, a3 to d3 umpo-
lung of enals, aza-Morita–Baylis–Hillman reaction, transes-
terification, acylation, ring-opening polymerization, activa-
tion of silylated nucleophiles and other reactions.[9] In our
previous publication, we proposed an activation mode of ke-
tenes by NHCs to give zwitterionic enolates, and demon-
strated that NHCs were efficient catalysts for the cycloaddi-
tion of ketenes with imines.[10] In this communication, we
wish to report the chiral NHCs-catalyzed formal [4+2] cy-
cloaddition of ketenes with enones to give d-lactones, which
are the key motifs for a wide range of bioactive compounds
and versatile intermediates in organic synthesis.[11] Very re-
cently, Bode et al. developed an elegant chiral NHCs-cata-
lzyed [4+2] cycloaddition of a-chloroaldehydes with enones
to give d-lactones.[12] Our [4+2] cycloaddition of disubstitut-
ed ketenes[13] with enones led to the highly functionalized d-
lactones with a-quaternary-b-tertiary stereocenters[14,15]
Chiral NHC precursor 1, easily prepared from l-pyroglu-
tamic acid,[10] was employed for the reaction of ethylphenyl-
ketene (2a) with enone 3a. It was found that 10 mol% pre-
catalyst 1, in the presence of Cs2CO3 (10 mol%), could cata-
lyze the reaction to give the corresponding d-lactone 4a in
55% yield with 10:1 diastereoselectivity and 84% ee for the
trans-isomer and 80% ee for the cis-isomer (Table 1,
entry 1). When the reaction was carried out at À208C, the
enantioselectivity was increased to 89% ee, while the yield
and diastereoselectivity dropped sharply (entry 2). Careful
experiments revealed that cis-isomer of lactone 4a could be
epimerized to trans-isomer in the conditions of cycloaddi-
tion.[16] Thus, an excess of the base of Cs2CO3 (20 mol%)
was employed, and the trans-isomer of d-lactone 4a was ob-
tained with high diastereomeric purity (entry 3).
Further experiments showed that the yields were in-
creased when the reactions were carried out by slow addi-
tion of ketenes (entries 4–5). Reaction at 08C led to better
enantioselectivity and yield, while reaction at À108C result-
ed in slightly better enantioselectivity with compromised
yield (entry 6). It is noteworthy that lactone 4a with trans/
cis 24:1 and 91% ee could be easily recrystallized from
hexane/2-propanol 9:1 to give pure trans-isomer in 70%
yield with 98% ee.
Substrate investigations revealed a variety of ketenes and
enones worked well in the NHC-catalyzed cycloadditions
(Table 2). Both arylenones with electron-withdrawing group
(4-Cl, 4-BrC6H4 and 4-NO2C6H4) and those with electron-
donating group (4-Me) are suitable substrates, furnishing d-
lactones in good yields with high enantioselectivities (en-
tries 2–5). Heteroarylenone (R3 =2-furyl) and bulky aryl-
enone (R3 =b-naphthyl) reacted with no notable difference
[a] Y.-R. Zhang, H. Lv, D. Zhou, Prof. S. Ye
Beijing National Laboratory for Molecular Sciences
Research Center of Chemical Biology, Institute of Chemistry
Chinese Academy of Sciences, Beijing 100190 (China)
Fax : (+86)10-62554449
E-mail: songye@iccas.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801165.
Chem. Eur. J. 2008, 14, 8473 – 8476
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8473

Table 1. Optimization of conditions.[a]
Table 2. Synthesis of trans-d-lactones by NHC-catalyzed ketene–enone
cycloaddition.[a]
Entry R1, R2
R3
Ph
6H4
4-BrC6H4
4-NO2C6H4 4d 61 (50)
4-MeC6H4
2-furyl
4
Yield
trans/
ee
[%][b,c]
cis[d,e]
[%][f–h]
Entry Cs2CO3
[mol%]
Conditions
Yield
[%][b]
trans/
ee (trans, cis)
cis[c]
[%][d]
1
Ph, Et
4a 79 (70)
4b 70 (59)
4c 68 (52)
24:1
18:1
22:1
20:1
25:1
39:1
25:1
15:1
17:1
16:1
91 (98)
90 (99)
87 (98)
91 (97)
90 (97)
92(95)
90 (95)
89 (99)
91 (90)
91 (99)
1
10
RT, 2h
55
10
51
73
79
28
10:1
3:1
22:1
20:1
24:1
32:1
84, 80
89, 69
84, 84
86, 88
91, 88,
91, 93
2Ph, Et
4-ClC
210
3
À208C, 12h
3
4
5
6
Ph, Et
Ph, Et
Ph, Et
Ph, Et
Ph, Et
20
20
2
RT, 2 h
4[e]
5[e]
6[e]
RT, 2 h
4e 69 (54)
4 f 78 (15)
0 8C to RT[f0]
20
À108C to RT[f]
7
b-naphthyl 4g 82(76)
8
9
10
4-ClC6H4, Et 4-ClC6H4
4-ClC6H4, Et Ph
4-MeOC6H4, Ph
Et
4h 74 (61)
4i 93 (63)
4j 57 (64)
[a] Ketene 2a (1.5 mmol), enone 3a (1.0 mmol) was employed. [b] Isolat-
ed yields. [c] Determined by 1H NMR (300 MHz) and/or HPLC. [d] De-
termined by HPLC on chiral columns. [e] The solution of ketene 2a in
THF (2.5 mL) was added over 1 hour. [f] After the addition of ketene 2a
over 1 hour, the reaction mixture was stirred for 30 min at 08C or
À108C, then was allowed to warm to RT and stirred for 24 h.
11
Ph, Me
4-ClC6H4
4k 82(63)
>99:1
84 (99)
[a] Ketene 2 (1.5 mmol), enone 3 (1.0 mmol) was employed. [b] Isolated
yields. [c] The yields of recrystallization were shown in parentheses.
[d] Determined by HPLC. [e] Only E isomers or E/Z> 99:1 was ob-
served after recrystallization. [f] Determined by HPLC on chiral columns.
[g] The ees after recrystallization are shown in parentheses. [h] The abso-
lute configuration of lactone 4h was determined by X-ray, and that of
other lactones was assigned by comparison of their specific rotation with
the specific rotation of 4h.
in yields and selectivities (entries 6 and 7). Arylalkylketenes
with electron-withdrawing groups worked well with enones
furnishing d-lactones in good yields and high enantioselecti-
vites (entries 8 and 9), while the one with electron-donating
group, 4-methoxylphenylethylketene, resulted in fair
yields[17] but high enantioselectivity (entry 10). The reaction
of phenylmethylketene afforded exclusively trans-isomer
with 84% ee (entry 11). It should be noted that the reaction
of monosubstituted ketenes under current reaction condition
failed to give the d-lactones but a complex mixture. It is
noteworthy that the diastereomeric ratios and enantiomeric
excess could be further improved by a single recrystalliza-
tion from hexane/2-propanol 9:1.
Scheme 1. Synthesis of cis-d-lactones from trans-d-lactones.
Since the trans-isomer of d-lactones were obtained as
major product through the in situ epimerization of cis-
isomer in the thermodynamically-controlled conditions, it
will be quite useful if the cis-isomer could be obtained pre-
dominately by kinetically controlled conditions. Indeed, the
cis-isomer was successfully obtained by deprotonation of
trans-isomer of the d-lactones, followed by kinetically con-
trolled protonation of the resulting carbanion at À788C
(Scheme 1).
Scheme 2. Synthesis of cis-d-lactones from ketene–enone cycloaddition.
The cis-isomer of d-lactones could also be obtained in
good yield with high diastereoselectivity and enantioselectiv-
ity by in situ deprotonation-protonation after the NHC-cata-
lyzed cycloaddition (Scheme 2). Both electron-donating and
electron-withdrawing substituents at the para-position of the
aryl group (4h-c, 4l-c) are tolerated; and the meta-substitu-
ent (2-Cl) has no notable effect for the reaction (4m-c).
Ketenes generated in situ from the corresponding acyl
chloride in the presence of excess NEt3 also worked well for
this NHC-catalyzed ketene–enone cycloaddition reaction,
but longer reaction times are required for full conversion of
enones. For example, ketene 2a, generated from acyl chlo-
ride 5, reacted with enone 3a to give d-lactone in 77% yield
with 88% ee (Scheme 3).
Scheme 3. In situ generation of ketene from acyl choride.
The b-carbonyl group in lactone 4 offer many possibilities
for further transformation. For example, lactone 4h could
easily be alkylated at the b-position to give d-lactone 6 with
two contiguous quaternary stereocenters. Similarly to the ki-
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Chem. Eur. J. 2008, 14, 8473 – 8476

Highly Enantioselective Synthesis of trans- and cis-d-Lactones
COMMUNICATION
was purified by flash column chromatography to give trans-isomer of d-
lactones 4 as the major product, which was recrystallized from hexane/2-
propanol 9:1 to give nearly pure trans-isomer. Lactone 4h: White solid;
Yield: 74%; Rf =0.35 (petroleum ether/EtOAc 9:1); m.p. 151–1528C;
netically controlled protonation, the stereochemistry in b-
carbon was reversed, and the cis-isomer was obtained exclu-
sively without erosion of enantiopurity (Scheme 4).
1
[a]2D5 = À196.4 (c=1.2, CHCl3); H NMR (300 MHz, CDCl3): d=7.41 (d,
J=8.7 Hz, 2H), 7.30–7.15 (m, 6H), 5.78 (d, J=7.1 Hz, 1H), 4.23 (q, J=
7.1 Hz, 2H), 3.93 (d, J=7.1 Hz, 1H), 2.30–2.20 (m, 1H), 2.00–1.85 (m,
1H), 1.29 (t, J=7.1 Hz, 3H), 0.70 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=170.14, 169.61, 151.06, 135.39, 134.84, 133.72,
129.81, 128.86, 128.57, 127.99, 125.95, 97.42, 61.88, 50.46, 45.19, 29.18,
13.92, 7.86 ppm; IR (KBr film): n = 2975, 1752, 1723, 1493, 1331, 1200,
1145, 1009, 826 cmÀ1
; HRMS (EI): m/z: calcd for: 418.0739, found
418.0737 [M]+; elemental analysis calcd (%) for C22H20O4Cl2: C 63.02, H
4.81, N 0.00; found: C 63.21, H 4.73, N <0.30; HPLC analysis: 89% ee
(99% ee after recrystallization), [Daicel CHIRALPAK AD-H column;
Scheme 4. b-Alkyation of d-kactone.
208C; 1.0 mLminÀ1; solvent system: isopropanol/hexanes 10:90; tR
=
This NHC-catalyzed [4+2] cycloadditions of ketenes are
possibly initiated by the nucleophilic addition of NHC to ke-
tenes to give triazolium enolates 7, which react with enones
by an inverse electron demand Diels–Alder reaction to give
the [4+2] cycloaddition adducts 8, followed by elimination
of NHC to furnish the corresponding d-lactones 4 and re-
generate the NHC catalyst (Scheme 5).[18]
9.5 min (minor), 11.5 min (major)].
Synthesis of cis-d-lactones 4-c (Scheme 2): The cycloaddition of ketenes
(1.5 mol) and enones (1.0 mol) was carried out as the procedure of syn-
thesis of trans-d-lactones with Cs2CO3 (33 mg, 0.1 mmol). After the full
conversion of enone, the reaction mixture was cooled to À788C, and
LDA (2.0m in THF, 1.0 mL) was added dropwise. After stirring for 8 h,
the reaction mixture was acidified by HCl (1.0m, aq) to pH 2.0 at À788C.
The solution was extracted with CH2Cl2, and the combined organic layer
was dried over Na2SO4, followed by concentration under reduced pres-
sure. The residue was purified by flash column chromatography to give
cis-d-lactones as the major product. Lactone 4h-c: white solid; Yield:
71%; Rf =0.35 (petroleum ether/EtOAc 9:1); m.p. 48–508C; [a]D25
=
+255.1 (c=1.04, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.53 (d, J=
8.7 Hz, 2H), 7.46 (d, J=8.9 Hz, 2H), 7.30–7.15 (m, 4H), 5.79 (d, J=
6.4 Hz, 1H), 3.90–3.80 (m, 4H), 2H), 3.56 (d, J=6.4 Hz, 1H), 2.20–2.00
(m, 2H), 0.95 (t, J=7.1 Hz, 3H), 0.72ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=170.00, 167.44, 150.50, 135.83, 135.64, 133.39,
130.01, 129.40, 128.83, 128.30, 126.13, 96.96, 61.60, 50.44, 45.19, 29.77,
13.73, 8.64 ppm; IR (KBr film): n = 1771, 1731, 1492, 1187, 1093, cmÀ1
;
HRMS (EI): m/z: calcd for C22H20O4Cl2: 418.0739, found 418.0742[ M]+;
HPLC analysis: 90% ee, [Daicel CHIRALPAK AD-H column; 208C;
1.0 mLminÀ1; solvent system: isopropanol/hexanes 10:90; tR = 23.6 min
(minor), 29.7 min (major)].
Scheme 5. Proposed mechanism.
In conclusion, the chiral NHC 1 was demonstrated as an
efficient catalyst for the formal [4+2] cycloaddition of dis-
ubstituted ketenes with enones to give d-lactones with a-
quaternary-b-tertiary stereocenters. Both the trans-isomers
and the cis-isomers of the d-lactones could be obtained in
good yields with high diastereo- and enantioselectivities by
in situ thermodynamically controlled epimerization and ki-
netically controlled protonation, respectively. Ketene gener-
ated in situ from acyl chloride also worked well for the reac-
tion. Further exploration of the NHC-catalyzed ketene cycli-
zation reactions is underway in our laboratory.
Acknowledgements
We are grateful to the Chinese Academy of Sciences and Natural Scien-
ces Foundation of China (No 20602036) for the financial support.
Keywords: asymmetric catalysis · carbenes · cycloaddition ·
ketenes · lactones
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[16] See Supporting Information for details.
[17] The low yields of several cases may be caused by the decomposition
of the ketene and/or the enone in the reaction condition.
[18] Another possible mechanism is the Michael addition of triazolium
enolate to enones, followed by intramolecular cyclization to give d-
lactones.
Received: June 13, 2008
Published online: August 7, 2008
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