Organocatalyzed Michael-Henry reactions: Enantioselective synthesis of cyclopentanecarbaldehydes via the dienamine organocatalysis of a succinaldehyde surrogate

Article abstract of DOI:10.1039/c2cc33309k

Asymmetric formal [3+2] cycloadditions of 4-hydroxybut-2-enal, a succinaldehyde surrogate, and nitroalkenes with an organocatalyst provided cyclopentanecarbaldehydes containing four consecutive stereogenic centers with excellent enantioselectivities.

Full text of DOI:10.1039/c2cc33309k

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Chemical Communications
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Volume 48 | Number 63 | 14 August 2012 | Pages 7761–7884
ISSN 1359-7345
COMMUNICATION
Bor-Cherng Hong et al.
Organocatalyzed Michael–Henry reactions: enantioselective synthesis
of cyclopentanecarbaldehydes via the dienamine organocatalysis of a
succinaldehyde surrogate
1359-7345(2012)48:63;1-#

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Organocatalyzed Michael–Henry reactions: enantioselective synthesis of
cyclopentanecarbaldehydes via the dienamine organocatalysis of a
succinaldehyde surrogatew
Bor-Cherng Hong,*a Po-Yuan Chen,a Prakash Kotame,a Pei-Ying Lu,a Gene-Hsiang Leeb
and Ju-Hsiou Liaoa
Received 8th May 2012, Accepted 24th May 2012
DOI: 10.1039/c2cc33309k
Asymmetric formal [3+2] cycloadditions of 4-hydroxybut-2-enal, a
succinaldehyde surrogate, and nitroalkenes with an organocatalyst
provided cyclopentanecarbaldehydes containing four consecutive
stereogenic centers with excellent enantioselectivities.
Scheme 1 Retrosynthetic analysis.
Traditionally, [3+2] annulations are the most efficient protocols
for the synthesis of five-membered-ring derivatives.1 Since the
Our initial attempt to realize this transformation was met
with a surprising dimerization pathway. Initially, reaction of
monumental advances introduced by MacMillan and coworkers
in 2000,2 intensive efforts have been devoted to the development of
4-hydroxybut-2-enal (1) and nitrostyrene 2a in CH3CN with
L-proline afforded trace amounts of the product 3a/4a; however,
organocatalyzed [3+2] cycloadditions. Essentially, many of those
to our surprise, instead of affording the expected [3+2]
approaches involved Lu’s reaction, e.g., phosphine-catalyzed
annulation adduct, an intriguing bicyclic product 5, as a
[3+2] cycloadditions of allenoates with electron-deficient olefins
and imines,3 Morita–Baylis–Hillman reactions, azomethine ylides,
racemate, was obtained in 10% yield (Table 1, entry 1). Very
likely, 5 was obtained through an unprecedented and unique
Michael–aldol reactions, double Michael reactions, N-heterocyclic
organocatalyzed dimerization of 4-hydroxybut-2-enal via the
carbenes organocatalysis, 1,3-dipolar cycloadditions, and electro-
dienamine catalysis,9 and the formation of this novel feature of
cyclization. Among the reported organocatalyzed formal [3+2]
cycloadditions,4 examples of asymmetric intermolecular catalyzed
bicyclic system 5 via organocatalysis is noteworthy. Later,
treatment of a solution of 1 in CH3CN with L-proline, in the
carbo-[3+2] annulations are relatively rare and their protocols
absence of nitrostyrene (2a), at ambient temperature afforded
stand out for their versatility and expedience in preparing highly
functionalized cyclopentanes and cyclopentenes.5 Consequently,
5 in 35% yield as the major isolable product. The structure of
5 was unambiguously elucidated via X-ray analysis (Fig. 1).
exploration of new methodologies for the organocatalyzed
Nevertheless, aldehyde 5 was only accessible in the reaction
intermolecular [3+2] annulation, therefore, remains attractive
with the proline catalyst and was not observed in the reactions
and essential.
with other organocatalysts subsequently screened (vide infra).
Considering the above background in the context of organoca-
talytic asymmetric annulations,6 we envisioned an approach to
The formation of aldehyde 5 in the reaction may arise from
a sequence of dienamine catalysis followed by a domino
organocatalyzed Michael–Henry reaction7 of succinaldehyde and
Michael–aldol reaction or Rauhut–Currier reaction–aldol reac-
cyclopentanecarbaldehydes that could be accomplished by an
tion, as illustrated by the two pathways proposed in Scheme 2.
olefinic nitroalkanes 2a (Scheme 1). Herein, we describe the details
Initial activation of 1 with L-proline afforded a dienamine
of such an approach, and the methodology with a succinaldehyde
surrogate 18 and a type of dienamine organocatalysis, which
intermediate, followed by a Michael–aldol condensation
sequence to yield 5 (pathway A, Scheme 2). Alternatively,
permits efficient production of cyclopentanecarbaldehydes in
the process may start from the Rauhut–Currier reaction of the
excellent yields and stereoselectivities with up to 98% ee.
dienamine intermediate toward the activated iminium inter-
mediate, which invokes the subsequent aldol condensation to
a Department of Chemistry and Biochemistry, National Chung Cheng
University, Chia-Yi 621, Taiwan, R.O.C. E-mail: chebch@ccu.edu.tw;
Fax: +886 5 272104; Tel: +886 5 2428174
b Instrumentation Center, National Taiwan University, Taipei 106,
Taiwan, R.O.C
w Electronic supplementary information (ESI) available: Experimental
details, spectroscopic characterization and HPLC analysis. CCDC
866017 and 866038. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc33309k
afford 5 (pathway B, Scheme 2).
We were delighted to observe that reaction of 1 and 2a with
20 mol% of pyrrolidine–HOAc yielded 10% of product 3a and
4a in a ratio of 1 : 1 (Table 1, entry 2). A series of organocatalysts
were then screened in the reactions (Table 1, entries 3–9).
Among them, the reaction with the Jørgensen–Hayashi
catalyst V gave the best result with 29% yield of 3a and 4a in a
c
7790 Chem. Commun., 2012, 48, 7790–7792
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Table 1 Screening of the catalysts, solvents and reaction conditions
for the domino reactiona
Ratioc
Entry Catalyst Additive Solvent Time (h) Yieldb (%) (3a/4a)
Scheme 2 Plausible reaction mechanisms for the formation of 5.
1
2
3
4
5
6
7
8
I
II
—
CH3CN 120
CH3CN 120
CH3CN 144
CH3CN 144
CH3CN 144
CH3CN 96
CH3CN 96
CH3CN 120
CH3CN 168
Traced
10
na
1 : 1
na
na
1 : 1
na
na
na
na
na
na
na
1 : 2
1 : 1
3f : 2g
3 : 2
1 : 1
1 : 1
conditions essentially gave no reaction after 24 h. The structure and
the absolute configuration of the product 3a was assigned based on
the X-ray analysis of (+)-10a, Fig. 1, which was obtained from the
hydrazone formation reaction of 3a (2,4-DNP, cat. p-TsOH,
CH2Cl2) and the subsequent protection reaction (TBSOTf, Et3N,
cat. DMAP, CH2Cl2). In addition, attempts to form the mesylate
of the alcohols 3a and 4a afforded the elimination product 6a.10
Reduction (NaBH4, MeOH) of the aldehyde 4a (or 3a) followed by
acetylation (Ac2O, cat. DMAP, Et3N, THF) led to the formation
of elimination acetate 7a.10
AcOH
AcOH
AcOH
AcOH
—
III
IV
V
VI
VII
VIII
IX
V
V
V
V
V
B0e
B0e
29
nr
nr
nr
—
—
9
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
B0e
B0e
B0e
B0e
21
10
11
12
13
14
15
16h
17
18
EtOH
Dioxane 96
THF 96
96
Toluene 168
CH2Cl2 120
Having established the optimal reaction conditions (Table 1,
entry 15), we next examined the scope and limitations of the above
system with variants of nitroalkenes. As shown in Table 2, the
reaction appears to be generally applicable with respect to the
substrates tested, providing the expected adducts with excellent
enantioselectivities in good yields. Usually, the reactions were
completed in B2 days, although much longer reaction times were
required in the cases with less reactive nitroalkenes. Presumably,
the slow reaction arose either from the inductive effect, as with
4-OMe substituents (2g), or by steric hindrance (2d and 2h)
45
65
55
56
V
V
V
V
CHCl3
CHCl3 148
36
PhCOOH CHCl3
PNBA CHCl3
40
40
53
a
Unless otherwise noted, the reactions were performed in 0.13 M of 2a
b
with a ratio of 2/1 of 1/2a at ambient temperature (B25 1C). Isolated
yields of 3a and 4a. Determined by crude 1H NMR. Trace amounts
c
d
e
f
of 3a and 4a, along with 10% yield of 5. Decomposition of 1. 91% ee
of 3a, determined by HPLC with Chiralpack IC on the corresponding
g
2,4-DNP derivatives. 93% ee of 4a, determined by HPLC with
h
Chiralpack IB on the corresponding 2,4-DNP derivatives. Reaction
performed at 0.06 M of 1. na: not available. nr: no reaction.
Table 2 Scope of the domino Michael–Henry reactiona
Ratioc eed,e (%)
Entry 2
Time (h) Yieldb (%) (3/4)
(3f/4g)
Fig. 1 Stereo plots of the X-ray crystal structures of (Æ)-5 and
(+)-10a: C, gray; N, blue; O, red; Si, purple.
1
2
3
4
5
6
7
8
9
10
2a R = Ph
36
36
50
120
72
78
65
56
53
51
60
59
55
57
65
62
3 : 2
3 : 2
3 : 2
3 : 1
3 : 2
1 : 1
3 : 2
1 : 1
2 : 1
3 : 2
91/93
90/91
91/94
94/81
95/92
94/90
91/90
90/95h
97/98f
98/94h
2b R = 4-FC6H4
2c R = 4-ClC6H4
2d R = 2-ClC6H4
2e R = 4-BrC6H4
2f R = 4-MeC6H4
ratio of 1 : 1 (Table 1, entry 5). Other reactions resulted in the
decomposition of 1 (Table 1, entries 3, 4 and 9) or gave no
reaction and recovery of starting materials (Table 1, entries 6–8).
To optimize the yields, the reaction was conducted in various
solvents (Table 1, entries 10–15), and the best result was obtained
with CHCl3 to give 65% yield of 3a and 4a in a ratio of 3 to 2,
with 91% ee and 93% ee, respectively (Table 1, entry 15).
The same reaction in CHCl3 with diluted concentration of 1
(0.06 M) afforded less yield, 55% vs. 65%, (Table 1, entries 15
and 16). Replacement of acetic acid with other acids, e.g., benzoic
acid and p-nitrobenzoic acid, did not increase the yields (Table 1,
entries 17 and 18). The reaction with cat. V–DABCO under basic
2g R = 4-MeOC6H4 160
2h R = c-C6H10
2i R = n-C3H7
2j R = CH2CH2Ph
200
15
17
a
Unless otherwise noted, the reactions were performed in 0.13 M of 2
b
with a ratio of 2/1 of 1/2 at rt (B25 1C). Isolated yields of 3 and 4.
c
d
Determined by crude 1H NMR. Determined by HPLC with a chiral
e
column on the corresponding 2,4-DNP derivatives of 3 (or 4). ee value
f
of 3 (or 4) obtained from the reaction with catalyst (S)-V. Determined
g
by HPLC with Chiralpak IC. Unless otherwise noted, determined by
h
HPLC with Chiralpak IB. Determined by HPLC with Chiralpak IA.
c
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Notes and references
1 For reviews: (a) H. Pellissier, Tetrahedron, 2007, 63, 3235; (b) G. Pandey,
P. Banerjee and S. R. Gadre, Chem. Rev., 2006, 106, 4484.
2 W. S. Jen, J. J. Wiener and D. W. C. MacMillan, J. Am. Chem.
Soc., 2000, 122, 9874.
3 For recent reviews on phosphine-catalyzed [3+2] cycloadditions, see:
(a) L.-W. Ye, J. Zhou and Y. Tang, Chem. Soc. Rev., 2008, 37, 1140;
(b) B. J. Cowen and S. J. Miller, Chem. Soc. Rev., 2009, 38, 3102.
4 For a recent review on organocatalyzed cycloadditions, see:
B.-C. Hong, in Enantioselective Organocatalyzed Reactions II, ed.
R. Mahrwald, Springer, 2011, ch. 3.
5 For recent examples, see: (a) W. Raimondi, G. Lettieri,
J.-P. Dulcere, D. Bonne and J. Rodriguez, Chem. Commun., 2010,
46, 7247; (b) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc., 2009,
131, 13628; (c) A. Ma and D. Ma, Org. Lett., 2010, 12, 3634;
(d) F. Nanteuil and J. Waser, Angew. Chem., Int. Ed., 2011,
50, 12075; (e) M. Rueping, A. Kuenkel, F. Tato and J. W. Bats,
Angew. Chem., Int. Ed., 2009, 48, 3699; (f) D. Enders, C. Wang and
J. W. Bats, Angew. Chem., Int. Ed., 2008, 47, 7539; (g) B. Tan,
Z. Shi, P. J. Chua and G. Zhong, Org. Lett., 2008, 10, 3425;
(h) G.-L. Zhao, F. Ullah, L. Deiana, S. Lin, Q. Zhang, J. Sun,
I. Ibrahem, P. Dziedzic and A. Cordova, Chem.–Eur. J., 2010,
16, 1585; (i) K. L. Jensen, P. T. Franke, C. Arroniz,
S. Kobbelgaard and K. A. Jørgensen, Chem.–Eur. J., 2010, 16, 1750.
6 For our recent efforts in exploring new organocatalytic annula-
tions, see: (a) B.-C. Hong, N. S. Dange, C.-F. Ding and J.-H. Liao,
Org. Lett., 2012, 14, 448; (b) B.-C. Hong, C.-S. Hsu and G.-H. Lee,
Chem. Commun., 2012, 48, 2357; (c) B.-C. Hong, P. Kotame and
G.-H. Lee, Org. Lett., 2011, 13, 5758; (d) B.-C. Hong, N. S. Dange,
C.-S. Hsu, J.-H. Liao and G.-H. Lee, Org. Lett., 2011, 13, 1338;
(e) B.-C. Hong, R. Y. Nimje, C.-W. Lin and J.-H. Liao, Org. Lett.,
2011, 13, 1278; (f) P. Kotame, B.-C. Hong and J.-H. Liao,
Tetrahedron Lett., 2009, 50, 704, and references cited therein.
7 For recent examples of organocatalyzed Michael–Henry reaction,
see: (a) S. Varga, G. Jakab, L. Drahos, T. Holczbauer, M. Czugler
and T. Soos, Org. Lett., 2011, 13, 5416; (b) H. Uehara,
R. Imashiro, G. Hernandez-Torres and C. F. Barbas, Proc. Natl.
Acad. Sci. U. S. A., 2010, 107, 20672; (c) B. Zhang, L. Cai,
H. Song, Z. Wang and Z. He, Adv. Synth. Catal., 2010, 352, 97;
(d) M. Rueping, A. Kuenkel and R. Frohlich, Chem.–Eur. J., 2010,
16, 4173; (e) Y. Hayashi, T. Okano, S. Aratake and D. Hazelard,
Angew. Chem., Int. Ed., 2007, 46, 4922.
Scheme 3 Plausible reaction mechanisms for the formation of 3/4.
Scheme 4 An efficient [1+2+2] manner.
(Table 2, entries 4, 7 and 8). It is noteworthy that for the reaction
with aliphatic nitroalkenes, e.g., 2i and 2j, higher enantioselectivities
were obtained, as compared to the reactions with the aromatic
nitroalkenes (Table 2, entries 9 and 10). To explain the cascade
Michael–Henry reaction, we proposed a plausible mechanism
(Scheme 3). Iminium activation of 1 with catalyst V would afford
iminium intermediate A, followed by isomerization to give the
dienamine intermediate B which would then undergo nucleophilic
attack to nitroalkene 2a.9 Subsequently, tautomerization of C and
Henry reaction would give the diastereomeric products 3a and 4a.
Finally, we explored the possibility of extending the protocol
in an efficient [1+2+2] manner (Scheme 4). 1,4-Dioxane-2,5-diol
(8), the 2-hydroxyacetaldehyde dimer, was reacted with 9 in
refluxing THF, followed by the addition of Merrifield resin11
and NaI at ambient temperature. The mixture was stirred over-
night. The solution was filtered through a pad of Celite–silica,
eluent with 30% EtOAc–hexane, and concentrated in vacuo to
afford 1, in 80% yield. A solution of 1 in CHCl3, nitroalkene (2a)
and the catalyst V were reacted via the typical procedure to
afford 3a and 4a.
8 In our study, reactions of succinaldehyde and nitroalkenes with
various organocatalysts gave complicated mixtures of products.
Indeed, polymerization of succinaldehyde was reported and the
polymer was the dominant product when exposed to catalysts and
therefore a suitable surrogate was needed. For the succinaldehyde
polymerization references, see: (a) P. M. Hardy, A. C. Nicholls and
H. N. Rydon, J. Chem. Soc., Perkin Trans. 2, 1972, 2270; (b) C. Aso,
A. Furuta and Y. Aito, Makromol. Chem., 1965, 84, 126.
In summary, we have achieved formal [3+2] cycloadditions
of 4-hydroxybut-2-enal and nitroalkenes for enantioselective
synthesis of cyclopentanecarbaldehydes containing four consecutive
stereogenic centers via an organocatalyzed Michael–Henry reaction.
The reaction not only adds to the limited repertories of dienamine
organocatalysis but also demonstrates for the first time the utiliza-
tion of a succinaldehyde surrogate in the synthesis. The benign
reaction conditions conducted at ambient temperature further
manifest the merit of this strategy. The formation of the novel
self-dimerization adduct of 4-hydroxybut-2-enal during the explora-
tion is notable and this observation may open a venue for future
synthetic applications. The structures as well as the absolute
configurations of the products were confirmed by X-ray analysis
of the appropriate adducts. Further work is underway to elaborate
the synthetic applications of these reactions.
9 For other recent examples of the dienamine organocatalysis, see:
(a) D. Enders, X. Yang, C. Wang, G. Raabe and J. Runsik,
Chem.–Asian J., 2011, 6, 2255; (b) Z.-J. Jia, H. Jiang, K.-L. Li,
B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen and
K. A. Jørgensen, J. Am. Chem. Soc., 2011, 133, 5053; (c) J. Stiller,
E. Marques-Lopez, R. P. Herrera, R. Frohlich, C. Strohmann and
M. Christmann, Org. Lett., 2011, 13, 70; (d) G. Bencivennia,
P. Galzeranoa, A. Mazzantia, G. Bartolia and P. Melchiorre, Proc.
Natl. Acad. Sci. U. S. A., 2010, 107, 20642; (e) J.-L. Li, T.-R. Kang,
S.-L. Zhou, R. Li, L. Wu and Y.-C. Chen, Angew. Chem., Int. Ed.,
2010, 49, 6418; (f) Ł. Albrecht, G. Dickmeiss, F. C. Acosta,
C. Rodrıguez-Escrich, R. L. Davis and K. A. Jørgensen, J. Am.
Chem. Soc., 2012, 134, 2543.
10
We acknowledge the financial support for this study from
the National Science Council (NSC), Taiwan, ROC. Thanks
to instrument center of NSC for compounds analysis.
11 The scavenger of triphenylphosphoxide which was generated in
the 1st-step Wittig reaction. B. H. Lipshutz and P. A. Blomgren,
Org. Lett., 2001, 3, 1869.
c
7792 Chem. Commun., 2012, 48, 7790–7792
This journal is The Royal Society of Chemistry 2012