An asymmetric catalytic Darzens reaction between diazoacetamides and aldehydes generates cis-glycidic amides with high enantiomeric purity

Full text of DOI:10.1002/anie.200903061

Angewandte
Chemie
DOI: 10.1002/anie.200903061
Asymmetric Catalysis
An Asymmetric Catalytic Darzens Reaction between Diazoacetamides
and Aldehydes Generates cis-Glycidic Amides with High Enantiomeric
Purity**
Wei-Jun Liu, Bing-Da Lv, and Liu-Zhu Gong*
Optically pure epoxides are one of the most important classes
of chiral molecules because they have broad application in
organic synthesis, and thus occupy a privileged position.[1] The
presence of ester and amide functionality in glycidic esters
and amides provides more flexibility in the modulation of
these molecules and thus allows better access to the synthesis
of structurally diverse targets in comparison with simple
expoxides. Indeed, by starting with enantiomerically pure
glycidic esters or amides, the bulky synthesis of some key
chiral intermediates for building up medicinally relevant
molecules has been realized, as exemplified by the prepara-
tion of the side chain of taxol.[2] Recently, the glycidic amide
was found to be a key structural motif present in natural
products such as SB-204900 and prebalamide.[3] The well-
established methods to access optically active glycidic esters
and amides include asymmetric catalytic epoxidation of a,b-
unsaturated carbonyl compounds using either chiral organo-
or metal-based catalysts.[2] Despite these elegant advances,
relatively few protocols are available for accessing both cis-
glycidic esters or amides. Although asymmetric epoxidation
affords optically active cis-glycidic esters, the diastereochem-
istry depends essentially on the geometry of the carbon–
carbon double bond and thus (Z)-acrylates are necessary.[4]
The Darzens reaction represents a robust alternative to
expoxidation for producing a,b-epoxy carbonyl and related
compounds.[5] An asymmetric Darzens reaction with chiral
phase transfer catalysts resulted in moderate enantioselectiv-
ity.[6,7] Recently, North and co-workers reported an asym-
metric Darzens reaction using a chiral cobalt complex as the
catalyst, giving epoxy esters with moderate diastereoselectiv-
ity and enantioselectivity.[8] The catalytic asymmetric syn-
thesis of trans-glycidic amides through chiral sulfur ylides,
which are generated in situ from diazoacetamides and chiral
binaphthylsulfide using a copper complex, provided a low
yield and moderate enantioselectivity.[9a] Camphor-derived
sulfonium amide could participate in a Darzens reaction with
aldehydes to yield trans-glycidic amides with high enantiose-
lectivity, although stoichiometric amounts of chiral sulfide
was required.[9b,c] To date, no reports describe a highly cis-
selective Darzens reaction with excellent enantioselectivity.
Herein, we report an asymmetric Darzens reaction between
diazoacetamides and aldehydes catalyzed by a readily acces-
sible binol/titanium(IV) complex to yield cis-glycidic amides
with excellent enantioselectivity [Eq. (1); LA = Lewis acid].
Diazo carbonyl compounds are an important type of
reactant used in many transformations.[10] Diazoacetates
generally participate in an aldol reaction in the presence of
Lewis acid catalysts.[11] Very recently, Maruoka and co-
workers found that diazoacetamides of type 3 (see Table 1)
underwent an aziridination reaction,[12] whereas diazoacetates
preferred Mannich reactions under similar reaction condi-
tions.[13] The aziridine product was preferentially formed,
probably because the lower acidity of the a proton of the
diazoacetamide group compared with that of the diazoacetate
group resists hydrogen abstraction. This outcome inspired us
to consider whether it is possible to initiate an asymmetric
Darzens reaction between diazoacetamides (3) and aldehydes
using an appropriate chiral Lewis acid [Eq. (1)].
To validate our hypothesis, we examined a reaction of
diazo-N,N-dimethylacetamide (3a) with benzaldehyde in
CH2Cl2 at 08C using a chiral titanium complex, formed
in situ from (R)-binol and Ti(OiPr)4,[14] as the catalyst.
Unfortunately, no reaction occurred (Table 1, entry 1). N-
benzyl-2-diazoacetamide (3b) also showed no reactivity and
decomposed under the reaction conditions (Table 1, entry 2).
Gratifyingly, N-(p-methoxylphenyl)-diazoacetamide (3c)
reacted smoothly with benzaldehyde and furnished cis-
glycidic amide 4c in a high yield with excellent enantiose-
lectivity (95% ee; Table 1, entry 3). Notably, N-phenyl-diaz-
oacetamide (3d) participated in a similar reaction and
generated cis-glycidic amide 4d with 99% ee (Table 1,
entry 4). Significantly, this reaction exhibited excellent dia-
stereoselectivity and no trans-diastereomer was detected by
1H NMR analysis of the crude product. Lowering the catalyst
loading resulted in a slow reaction with diminished enantio-
selectivity (Table 1, entry 5). An evaluation of titanium (IV)
[*] Dr. W.-J. Liu, B.-D. Lv, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax: (+86)551-3600-622
E-mail: gonglz@ustc.edu.cn
[**] We are grateful for financial support from CAS, the 973 program
(grant no. 2009CB825300), and the Ministry of Education (China).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903061.
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Table 1: Darzens reaction of benzaldehyde with diazoacetamide using
various binol/Ti complexes.[a]
could be tolerated and gave high stereoselectivity, as exem-
plified by picolinaldehyde and 2-quinolinyl carbaldehyde
(Table 2, entries 14 and 15). More importantly, unsaturated
aldehydes afforded vinyl epoxides in good yields and with
excellent enantiomeric purity (Table 2, entries 16 and 17).
Significantly, ynals were also good reactants for the Darzens
reaction, as exemplified by oct-2-ynal (Table 2, entry 18). The
relative and absolute configurations of the products were
determined by X-ray crystal structure analysis of 4h (see the
Supporting Information).
Further exploration of the scope of the current Darzens
reaction for aliphatic aldehydes is shown in Table 3. Either
linear or branched aliphatic aldehydes underwent a highly
stereoselective Darzens reaction, and gave epoxides with
ee values ranging from 97 to more than 99% (Table 3,
entries 1–6). The Darzens reactions of cyclohexanecarbalde-
hyde and ethyl 2-oxoacetate were conducted at room temper-
ature, and yielded cis-glycidic amides with comparably lower
enantiomeric excess (87% and 89% ee, respectively; Table 3,
entries 7 and 10). Linear aliphatic aldehydes bearing a remote
vinyl or an adjacent benzoxy group also afforded high yields
and excellent enantioselectivity (Table 3, entries 8 and 9).
These additional functionalities definitely increase the flex-
ibility for the transformation of glycidic amides into other
structurally diverse chiral building blocks.
Entry
4
R1, R2
1
Solvent t [h] Yield [%][b] ee [%][c]
1
4a Me, Me 1a CH2Cl2
4b Bn, H 1a CH2Cl2
4c PMP, H 1a CH2Cl2
1
1
n.r.
–
–
–
2[d]
3
1
1
7
18
30
18
1
1
1
87
88
81
77
67
69
84
84
92
92
65
95
99
88
89
20[f]
26[f]
97
99
98
92
97
4
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
4d Ph, H
1a CH2Cl2
1a CH2Cl2
1b CH2Cl2
5[e]
6
7
8
9
10
11
12
13
1c
CH2Cl2
1d CH2Cl2
1a CHCl3
1a DCE
1a (Et)2O
1a THF
1
On the basis of previous reports,[15] a reaction mechanism
consistent with the results observed is proposed (Scheme 1).
Activation of aldehydes by coordination with the titanium
complex of (R)-binol and subsequent re-face selective nucleo-
philic addition of diazoacetamides leads to the favorable
formation of intermediate II owing to steric considerations.
Bond rotation results in the formation of intermediate III,
which subsequently undergoes a backside displacement to
give cis-epoxides of type 4 and releases the Lewis acid
catalyst.
1a toluene 18
[a] The reaction was carried out on a 0.2 mmol scale in solvent (2 mL)
with M.S. (4 ꢀ, 120 mg) in an argon atmosphere, and the ratio of 2/3 was
1.2:1. [b] Yield of isolated product was based on 3. [c] Determined by
HPLC on a chiral stationary phase. [d] 3b decomposed under these
reaction condition. [e] 2.5 mol% of the catalyst was used. [f] The
opposite enantiomer was obtained. Bn=benzyl, M.S.=molecular
sieves, PMP=para-methoxyphenyl, THF=tetrahydrofuran.
The potential of the current Darzens reactions in the
synthesis of important chiral intermediates or building blocks
is demonstrated in Scheme 2. The treatment of glycidic
amides (2R,3R)-4d and (2S,3S)-4aa with (Boc)2O and
DMAP, and subsequent alcoholysis with sodium ethoxide
afforded glycidic esters 5 and 6, respectively, in good yields
and with the high level of stereoselectivity maintained. By
using readily available synthetic procedures, (2R,3R)-ethyl-3-
phenyloxiranyl carboxylate (5) could be converted into
enantiomerically pure (2R,3S)-3-benzamido-2-hydroxy-3-
phenylpropanoic acid (7),[16] which is the side chain of taxol.
Meanwhile, (2S,3S)-ethyl-3-benzyloxirane-2-carboxylate (6)
served as a key synthetic intermediate for (À)-bestatin (8),
which could be prepared according to an established proce-
dure.[17]
In conclusion, we have disclosed a highly diastereo- and
enantioselective Darzens reaction of aldehydes with diazo-
acetamides catalyzed by a chiral titanium complex formed
in situ from commercially available Ti(OiPr)4 and (R)-binol,
thus giving cis-glycidic amides with excellent enantiomeric
purity. The protocol tolerated a broad range of structurally
diverse aldehydes, including aromatic, unsaturated, and
aliphatic aldehydes. This new method has high potential in
the enantioselective synthesis of biologically active substan-
complexes of different binaphthol derivatives 1a–d revealed
that the 3,3’ substituents have considerable effect on the
enantioselectivity (compare Table 1, entry 4 with entries 6–8).
Among them, the (R)-binol/titanium complex turned out to
be the most efficient catalyst and offered the highest
stereoselectivity. An investigation of solvents found that
halogenated and ether solvents were suitable reaction media
(Table 1, entries 9–13). Among which, dichloromethane and
1,2-dichloroethane (DCE) were the solvents of choice in
terms of the stereoselective outcome (Table 1, entries 4 and
10). Nonpolar solvent provided a much slower reaction,
although the enantioselectivity remained high (Table 1,
entry 13).
Under the optimized reaction conditions, we first
explored the generality of the use of aromatic and unsatu-
rated aldehydes in the current Darzens reaction (Table 2).
Benzaldehyde derivatives bearing electron-withdrawing sub-
stituents at either para, ortho, or meta positions provided cis-
epoxides in high yields and with excellent enantioselectivity
(96–99% ee; Table 2, entries 1–9). Electron-rich and neutral
aromatic aldehydes also participated in clean Darzens
reactions with excellent enantioselectivity (Table 2,
entries 10–13). Interestingly, heteroaromatic aldehydes
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Table 2: Scope of the Darzens reaction with aromatic and unsaturated aldehydes.[a]
Entry
1
Product
Yield [%][b]
88
ee [%][c]
Entry
10
Product
Yield [%][b]
81
ee [%][c]
4d
99
4m
96
2
3
4
5
6
7
4e
4 f
4g
4h
4i
91
89
80
83
86
82
99
99
11
12
13
14
15
16
4n
4o
4p
4q
4r
87
93
83
81
88
52
97
97
98
97
98
95
99
99
>99
98
4j
4s
8
9
4k
4l
84
95
96
99
17
18
4t
62
66
98
88
4u
[a] The reaction was carried out on a 0.2 mmol scale in CH2Cl2 (2 mL) with M.S. (4 ꢀ, 120 mg) in an argon atmosphere at 08C, and the ratio of 2/3 was
1.2:1. [b] Yield of isolated product was based on 3. [c] Determined by HPLC methods using a chiral stationary phase.
Table 3: Scope of the Darzens reaction with aliphatic aldehydes.[a]
Entry
Product
Yield [%][b]
ee [%][c]
Entry
6
Product
Yield [%][b]
88
ee [%][c]
1
4v
75
98
4aa
92 (98)[d]
2
3
4
5
4w
4x
4y
4z
76
86
80
88
>99
>99
98
7[e]
8[f]
9
4ab
4ac
4ad
4ae
67
93
64
87
87
94
99
89
97
10[e]
[a] The reaction was carried out on a 0.2 mmol scale in CH2Cl2 (2 mL) with M.S. (4 ꢀ, 120 mg) in an argon atmosphere at 08C, and the ratio of 2/3 was
1.2:1. [b] Yield of isolated product was based on 3. [c] Determined by HPLC methods using a chiral stationary phase. [d] The result in parentheses was
obtained after single recrystallization. [e] The reaction temperature was 258C. [f] The ratio of 2/3 was 3:1.
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[5] For a review, see: T. Rosen in Comprehensive
Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I.
Fleming, C. H. Heathcock), Pergamon, Oxford,
1991, pp. 409 – 439.
[6] a) S. Arai, T. Shioiri, Tetrahedron Lett. 1998, 39,
2145 – 2148; b) S. Arai, Y. Shirai, T. Ishida, T.
Shioiri, Tetrahedron Lett. 1998, 39, 8299 – 8302;
c) S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Chem.
Commun. 1999, 49 – 50; d) S. Arai, Y. Shirai, T.
Ishida, T. Shioiri, Tetrahedron 1999, 55, 6375 –
6386; e) S. Arai, T. Shioiri, Tetrahedron 2002,
58, 1407 – 1413; f) S. Arai, K. Tokumaru, T.
Aoyama, Tetrahedron Lett. 2004, 45, 1845 – 1848.
[7] a) P. Bakꢁ, A. Szꢂllꢃsy, P. Bombicz, L. Tꢃke,
Synlett 1997, 291 – 292; b) P. Bakꢁ, K. Vizꢄrdi, Z.
Bajorm, L. Tꢃke, Chem. Commun. 1998, 1193 –
1195; c) P. Bakꢁ, K. Vizꢄrdi, S. Toppet, E.
Van der Eycken, G. J. Hoornaert, L. Tꢃke, Tetra-
hedron 1998, 54, 14975 – 14988; d) P. Bakꢁ, E.
Czinege, T. Bakꢁ, M. Czugler, L. Tꢃke, Tetrahe-
dron: Asymmetry 1999, 10, 4539 – 4551; e) P.
Bakꢁ, A. Makꢁ, G. Keglevich, M. Kubinyi, K.
Pꢄl, Tetrahedron: Asymmetry 2005, 16, 1861 –
1871.
Scheme 1. Proposed reaction mechanism.
[8] T. J. R. Achard, Y. N. Belokon, M. Ilyin, M.
Moskalenko, M. North, F. Pizzato, Tetrahedron
Lett. 2007, 48, 2965 – 2969.
[9] a) R. Imashiro, T. Yamanaka, M. Seki, Tetrahe-
dron: Asymmetry 1999, 10, 2845 – 2851; b) V. K.
Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am.
Chem. Soc. 2002, 124, 9964 – 9965; c) V. K.
Aggarwal, J. P. H. Charmant, D. Fuentes, J. N.
Harvey, G. Hynd, D. Ohara, W. Picoul, C. Smith,
J.-L. Vasse, C. L. Winn, J. Am. Chem. Soc. 2006,
128, 2105 – 2114.
Scheme 2. Synthetic application of cis-glycidic amides. (Boc)2O=di-tert-butyl dicarbon-
ate, DMAP=4-dimethylaminopyridine.
ces as demonstrated by the preparation of chiral building
block for the side chain of taxol and (À)-bestatin.
[10] For reviews, see: a) M. P. Doyle, M. A. Mckervey, T. Ye, Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds,
Wiley, New York, 1998; b) A. Padwa, M. D. Weingarten, Chem.
Rev. 1996, 96, 223 – 270; c) T. Ye, M. A. Mckervey, Chem. Rev.
1994, 94, 1091 – 1160.
Received: June 7, 2009
Published online: July 27, 2009
[11] a) W.-G. Yao, J.-B. Wang, Org. Lett. 2003, 5, 1527 – 1530; b) B. M.
Trost, S. Malhotra, B. A. Fried, J. Am. Chem. Soc. 2009, 131,
1674 – 1675.
[12] T. Hashimoto, N. Uchiyama, K. Maruoka, J. Am. Chem. Soc.
2008, 130, 14380 – 14381.
Keywords: asymmetric catalysis · binol · glycidic amides ·
Darzens reaction · epoxidation · titanium
.
[13] T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 10054 –
10055.
[1] For reviews, see: a) Q.-H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-
X. Su, Chem. Rev. 2005, 105, 1603 – 1662; b) E. M. McGarrigle,
E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches, V. K. Aggarwal,
Chem. Rev. 2007, 107, 5841 – 5883; c) O. A. Wong, Y. Shi, Chem.
Rev. 2008, 108, 3958 – 3987.
[2] For a review, see: a) D. Diez, M. G. Nunez, A. B. Anton, P.
Garcia, R. F. Moro, N. M. Garrido, I. S. Marcos, P. Basabe, J. G.
Urones, Curr. Org. Synth. 2008, 5, 186 – 216; b) J. P. Michael, S.
John, Chem. Commun. 2000, 1215 – 1225.
[3] a) P. H. Milner, N. J. Gilpin, S. R. Speat, D. S. Eggleston, J. Nat.
Prod. 1996, 59, 400 – 402; b) B. Riemer, O. Hofer, H. Greger,
Phytochemistry 1997, 45, 337 – 341.
[4] a) E. N. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker, L. Deng, J.
Am. Chem. Soc. 1991, 113, 7063 – 7064; b) L. Deng, E. N.
Jacobsen, J. Org. Chem. 1992, 57, 4320 – 4323; c) E. N. Jacobsen,
L. Deng, Y. Furukawa, L. E. Martꢀnez, Tetrahedron 1994, 50,
4323 – 4334; d) S. Watanabe, T. Arai, H. Sasai, M. Bougauchi, M.
Shibasaki, J. Org. Chem. 1998, 63, 8090 – 8091; e) K. M. S. Tony,
L. To, M. Lee, M. L. Chi, Tetrahedron 2006, 62, 6621 – 6629.
[14] For reviews, see: a) D. J. Ramon, M. Yus, Chem. Rev. 2006, 106,
2126 – 2208; b) K. Mikami, Y. Matsumoto, T. Shiono in Science
of Synthesis, Vol. 2 (Ed.: T. Imamoto), Thieme, Stuttgart, 2003,
pp. 457 – 679; c) E. Bermudez, J. B. Mangum, B. Asghariam,
B. A. Wong, E. E. Reverdy, D. B. Janszen, P. M. Hext, D. B.
Warheit, J. I. Everitt, Toxicol. Sci. 2002, 70, 86 – 97; d) K.
Mikami, M. Mashiro in Lewis Acids in Organic Synthesis,
Vol. 2 (Ed.: H. Yamamoto), Wiley-VCH, Weinheim, 2000,
pp. 799 – 847.
[15] a) Y. Zhang, A. Desai, Z. Lu, G. Hu, Z. Ding, W. D. Wuff, Chem.
Eur. J. 2008, 14, 3785 – 3803; b) L. Casarrubios, J. A. Perez, M.
Brookhart, J. L. Templeton, J. Org. Chem. 1996, 61, 8358 – 8359.
[16] L. Deng, E. N. Jacobsen, J. Org. Chem. 1992, 57, 4320 – 4323.
[17] B. D. Feske, J. D. Stewart, Tetrahedron: Asymmetry 2005, 16,
3124 – 3127.
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