Dynamic kinetic asymmetric synthesis of five contiguous stereogenic centers by sequential organocatalytic stetter and Michael-Aldol reaction: Enantioselective synthesis of fully substituted cyclopentanols bearing a quaternary stereocenter

Article abstract of DOI:10.1021/ol200006e

A synthesis of fully substituted cyclopentanes bearing a quaternary carbon center and five contiguous stereogenic centers has been achieved by sequential organocatalyzed Stetter and Michael-Aldol reactions of heteroaromatic aldehydes, nitroalkenes, and α,

Full text of DOI:10.1021/ol200006e

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1338–1341
Dynamic Kinetic Asymmetric Synthesis of
Five Contiguous Stereogenic Centers by
Sequential Organocatalytic Stetter and
Michael-Aldol Reaction: Enantioselective
Synthesis of Fully Substituted
Cyclopentanols Bearing a Quaternary
Stereocenter
Bor-Cherng Hong,*,† Nitin S. Dange,† Che-Sheng Hsu,† Ju-Hsiou Liao,† and
Gene-Hsiang Lee‡
Department of Chemistry and Biochemistry, National Chung Cheng University,
Chia-Yi, 621, Taiwan, R.O.C. and Instrumentation Center, National Taiwan University,
Taipei, 106, Taiwan, R.O.C.
chebch@ccu.edu.tw
Received January 3, 2011
ABSTRACT
A synthesis of fully substituted cyclopentanes bearing a quaternary carbon center and five contiguous stereogenic centers has been achieved by
sequential organocatalyzed Stetter and Michael-Aldol reactions of heteroaromatic aldehydes, nitroalkenes, and R,β-unsaturated aldehydes via
the [1 þ 2 þ 2] annulation strategy with dynamic kinetic asymmetric transformation and excellent enantioselectivities (up to >99% ee).
The Stetter reaction is a long-standing, unique meth-
odology in the synthesis of 1,4-dicarbonyl compounds and
related derivatives.1 With the recent advancements in the
development of N-heterocyclic carbenes (NHCs),2 the
Stetter reaction has expanded its realm and provided a
convenient routeforthepreparation ofcycliccompounds.3
The asymmetric intramolecular Stetter reaction was first
introduced by Enders,4 later studied by Rovis and the
others.5 Nevertheless, only a few examples of the organo-
catalytic enantioselective intermolecular Stetter reactions
were reported.6 Recently, we have disclosed a sequential
organocatalytic Stetter and Michael-Aldol condensation
(4) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta
1996, 79, 1899.
(5) (a) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298. (b) de Alaniz, J. R.; Kerr, M. S.; Moore, J. L.; Rovis, T. J.
Org. Chem. 2008, 73, 2033. (c) de Alaniz, J. R.; Rovis, T. J. Am. Chem.
Soc. 2005, 127, 6284. (d) Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.;
Imbriglio, J. E.; Miller, S. J. Chem. Commun. 2005, 195. (e) Cullen, S. C.;
Rovis, T. Org. Lett. 2008, 10, 3141.
(6) (a) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989.
(b) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066.
(c) Liu, Q.; Rovis, T. Org. Lett. 2009, 11, 2856. (d) DiRocco, D. A.;
Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am. Chem. Soc. 2009, 131,
10872.
† National Chung Cheng University.
‡ National Taiwan University.
(1) (a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (b)
Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639.
(2) For reviews: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem.
Rev. 2007, 107, 5606. (b) Marion, N.; Diez-Gonzalez, S.; Nolan, I. P.
Angew. Chem., Int. Ed. 2007, 46, 2988. (c) Nair, V.; Bindu, S.; Sreekumar, V.
Angew. Chem., Int. Ed. 2004, 43, 5130.
ꢀ
(3) For reviews, see: (a) Christmann, M. Angew. Chem., Int. Ed. 2005,
44, 2632. (b) Alaniz, J. R.; Rovis, T. Synlett 2009, 1189.
r
10.1021/ol200006e
Published on Web 02/24/2011
2011 American Chemical Society

H-bonding strategy, with the subtle difference of the hetero-
aromatic substituent, not only furnished varied stereoselec-
tivity of the products, but also provided a vehicle for
organocatalytic dynamic kinetic asymmetric transformation
(DYKAT).11 Herein, we report the new stereoselective con-
secutive reaction starting with heteroaromatics (e.g., picolin-
aldehyde), nitroalkenes, and R,β-unsaturated aldehydes,
affording highly functionalized cyclopentanecarbaldehyde
with five new stereogenic centers in high yield and in high
stereoselectivities (up to >99% ee).
Table 1. Screening of Catalysts and Optimization Conditions
for the Stetter Reaction of 1 and 2a
In exploring the possibility of sequential organocatalytic
DYKAT Stetter and Michael-Aldol reactions,12 initially
we examined the Stetter reaction of picolinaldehyde
(1)13 and (E)-1-nitrooct-1-ene with the precatalyst I and
Cs2CO3 in DMF. The reaction was completed in 30 min
and afforded the Stetter adduct in 78% yield (Table 1,
entry 1). The same reaction in other solvents (e.g., EtOH,
CH3CN, CH2Cl2, THF) gave lower yields (14-48%).
Similarly, the same reaction with other base additives,
e.g., K2CO3, Et3N, and Na2CO3, also gave lower yields of
3a (Table 1, entries 2-4). Unlike its 1-(4-bromophenyl)-
counterpart,12 the 2-alkyl-3-nitro-1-(pyridin-2-yl)nitroal-
kanone was surprisingly stable under basic and acidic condi-
tions, and no elimination or decomposition was observed in
the above environment. Probably, the nature of the intra-
molecular H-bonding led to the enolization of the R-H of
ketone 3a and hampered the elimination of HNO2 to give 4
(Table 1). Alternatively, the same reaction using the pre-
catalyst II provided a lower yield, and attempts with pre-
catalyst III afforded no product 3 (Table 1, entries 5 and 6).
Accordingly, several β-nitroketones (3b-f) were prepared via
the I-Cs2CO3 conditions (Table 1, entries 7-11).
With the β-nitroketone 3a in hand, several catalysts and
reaction conditions were screened to explore the feasibility
and optimization of the domino Michael-Aldol reaction
(Table 2). Initially, the reaction was conducted in 0.2 M 5a
with a 2.4/1 ratio of 3a/5a in toluene. To our surprise,
reaction of 3a and 5a with 30 mol % of Jørgensen-
Hayashi catalyst (IV) and HOAc (30 mol %) in toluene
gave the disappointing outcome of products in low yield
after 5 days (Table 2, entry 1). Many attempts with various
reaction conditions were applied in order to improve the
reaction. Finally, the reaction proceeded smoothly with
the same amount of catalyst IV (30 mol %), but with an
time yield
entry
product
cat. additive (h) (%)b
1
2
3
4
5
6
7
8
9
3a: R1 = pyridin-2-yl; R2 = n-C6H13
3a: R1 = pyridin-2-yl; R2 = n-C6H13
3a: R1 = pyridin-2-yl; R2 = n-C6H13
3a: R1 = pyridin-2-yl; R2 = n-C6H13
3a: R1 = pyridin-2-yl; R2 = n-C6H13 II Cs2CO3
3a: R1 = pyridin-2-yl; R2 = n-C6H13 III Cs2CO3
3b: R1 = pyridin-2-yl; R2 = Ph(CH2)2
3c: R1 = pyridin-2-yl; R2 = n-C3H7
3d: R1 = pyridin-2-yl; R2 = c-C6H11
I
I
I
I
Cs2CO3 0.5
78
16
11
∼0
39
∼0
72
62
60
61
80
K2CO3
Na2CO3
Et3N
2
2
2
3
3
I
I
I
I
I
Cs2CO3 0.5
Cs2CO3 0.4
Cs2CO3 0.7
Cs2CO3 0.7
Cs2CO3 0.5
10 3e: R1 = furan-2-yl; R2 = c-C6H11
11 3f: R1 = quinolin-2-yl; R2 = n-C6H13
a Unless otherwise noted, the reactions were performed in 0.46 M
1 with a 1/1.1 ratio of 1/2 in DMF at 25 °C. b Isolated yields of the
adducts 3.
for the asymmetric synthesis of fully substituted cyclopen-
tenes, a methodology that demonstrated the first organo-
catalytic [1 þ 2 þ 2] annulation strategy.7 Despite the
success of our procedure, the cyclopentenes prepared from
that method bore only three stereogenic centers, and an
analogous annulation method toward the fully substituted
cyclopentane derivatives with the maximum (five con-
secutive) stereogenic centers8 is an attractive and compel-
ling area of investigation.9 Considering our earlier work in
the context of asymmetric organocatalysis,10 we envi-
sioned an intramolecular H-bonding strategy involving
the introduction of heteroaromatic components into the
organocatalytic [1 þ 2 þ 2] annulation that could improve
the reaction yields of the annulation as well as extend the
study to the successful synthesis of the fully substituted
cyclopentanes bearing a quaternary carbon center
(tertiary alcohol). More interestingly, the intramolecular
(11) For reviews, see: (a) Steinreiber, J.; Faber, K.; Herfried Grieng,
H. Chem.;Eur. J. 2008, 14, 8060. (b) Pellissier, H. Tetrahedron 2008, 64,
1563.
(12) For the previous results in the aldol condensation version of the
reaction with 1-(4-bromophenyl)-2-(nitromethyl)pentan-1-one (30a).
(7) Hong, B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H. Org. Lett. 2010,
12, 4812.
(8) For recent examples of the construction of five contiguous
stereocenters via organocatalysis, see: (a) Imashiro, R.; Uehara, H.;
Barbas, C. F., III Org. Lett. 2010, 12, 5250. (b) Urushima, T.; Sakamoto,
D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588.
(9) For a recent review of fully substituted cyclopentanes, see:
Heasley, B. Eur. J. Org. Chem. 2009, 1477.
(10) For our recent efforts in exploring new organocatalytic annula-
tions, see: (a) Hong, B.-C.; Kotame, P.; Liao, J.-H. Org. Biomol. Chem.
2011, 382. (b) Hong, B.-C.; Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org.
Lett. 2010, 12, 776. (c) Hong, B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje,
R. Y.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2009, 11, 5246. (d) Hong, B.-C.;
Nimje, R. Y.; Liao, J.-H. Org. Biomol. Chem. 2009, 7, 3095. (e) Kotame,
P.; Hong, B.-C.; Liao, J.-H. Tetrahedron Lett. 2009, 50, 704 and
references cited therein.
(13) (a) For a study of proton activating factors and keto-
enol-zwitterion tautomerism of acetylpyridines, see: McCann, G. M.;
O’Ferral, R. A. M.; Walsh, S. M. J. Chem. Soc., Perkin Trans. 2 1997,
2761. (b) For study in the effect of OH---N hydrogen bonding on the
oxidation potentials of enols, with the pyridin-2-yl ring on the R-ketone,
see: Lal, M.; Langels, A.; Deiseroth, H.-J.; Schlirf, J.; Schmittel, M.
J. Phys. Org. Chem. 2003, 16, 373.
Org. Lett., Vol. 13, No. 6, 2011
1339

additives (e.g., PhCO2H, PNBA, TFA, DABCO, i-
PrNEt, DBU, K2CO3) in DMF afforded lower yields
or only trace amounts of the products (e.g., DABCO,
Table 2, entry 11). Interestingly, the reaction was fea-
sible with less HOAc or even in the absence of any
additive in EtOH, a polar protic solvent (Table 2, entry
12). It is worth noting that the ratio of 6a/7a was changed
to 1/2.5 in the absence of HOAc, where IV acted as both
a catalyst and a base, vide infra. Owing to a kinetic asym-
metric transformation (KAT) and easy decomposition of
1-(4-bromophenyl)-2-(nitromethyl)alkanones observed in
the previous study in the Michael-Aldol condensation
with R,β-unsaturated aldehydes, vide supra,12 a 2.4/1 ratio
of 3a/5a was initially applied in the reactions in Table 2.
However, since 3a was quite stable and possessed a possi-
ble intramolecular H-bonding for racemization, a dynamic
kinetic asymmetric transformation (DYKAT) of 3a may
have taken place. In fact, the occurrence of DYKAT was
further supported by the fact that a racemic mixture of 3a
was recovered after the reaction of (()-3a with 0.7 equiv of
cinnamaldehyde (5a), and the reaction of a 1.2/1 ratio of 3a/5a
gave the same yields and ee values of the reactions in Table 2.
Having established the optimal reaction conditions
for 6a and 7a, we investigated the use of the β-nitroke-
tone 3 and R,β-unsaturated aldehydes 5, in a ratio of
1.2/1 of (()-3 to 5, for synthesizing a variety of fully
substituted cyclopentane derivatives. The two isomers
(6 and 7) were, in all cases, the only two observable
diastereoisomers with high enantioselectivities (up to
>99% ee, entries 1-12, Table 3).14 This transformation
contributes to the few examples of the organocatalytic
aldol reaction of aromatic ketones with aldehydes, and
has become a valuable addition to the limited repertoire
of the asymmetric organocatalytic synthesis of stable β-
hydroxy aldehydes bearing a tertiary alcohol.15 Some
variations in the diastereoselectivities of 6/7 were ob-
served in the study. For most cases, 6 predominated as
the major product with the ratio of 6/7 up to 85:15
(Table 3, entries, 1, 2, 3, 4, 6, 7, and 12). The 6/7 ratio
was decreased when a highly electronegative group was
attached at R3 (e.g., NO2 group, Table 3, entries 5 and
11). The same decreasing trend in the 6/7 ratio was
observed in the examples with bulky substituents at R2
(e.g., c-C6H11 and Ph(CH2)2 group, Table 3, entries
8-11). The structure and the absolute configuration of
the reaction adduct was revealed by single-crystal
X-ray analysis of (þ)-7d, (-)-6a, (-)-6g, and (-)-6j
(Figure 1). The evidence of the intramolecular H-bond-
ing of pyridine to alcohol in the X-ray diffraction may
account for the stabilization of these β-hydroxy
Table 2. Catalysts Screening and Optimization for Domino
Michael-Aldol Reactiona
ratio
cat.
additive
(mol %)
time
(h)
6a/
yieldb
(%)
entry (mol %)
solvent
7a
1
2
IV (30)
IV (30)
IV (30)
IV (30)
V (30)
HOAc (30)
HOAc (300)
HOAc (300)
HOAc (300)
HOAc (300)
HOAc (300)
toluene 120
1/1
28
54c
72d
73e
48
60f
20g
64
toluene
DMF
EtOH
DMF
DMF
DMF
DMF
EtOH
EtOH
80
2
1.4/1
3/1
3
4
3
2.2/1
3.5/1
3.3/1
3.8/1
4/1
5
65
65
65
3
6
VI (30)
7
VII (30) HOAc (300)
VIII (30) HOAc (300)
8
9
IV (5)
IV (1)
IV (5)
IV (30)
HOAc (300)
HOAc (300)
20
70
67
9
3/1
70
10
11
12
2.3/1
1/6.2
1/2.5
38
DABCO (300) DMF
EtOH
20
51
a Unless otherwise noted, the reactions were performed in 0.2 M 5a
with a 1.2/1 ratio of 3a/5a at 28 °C. b Isolated yields of the adducts 6a and 7a.
c 94% ee of 6a. d 95% ee of 6a. e 99% ee of 6a. f 35% ee of 6a. g 3% ee of 6a.
excess of acetic acid (300 mol %) to give 6a and 7a in a
ratio of 1.4 to 1 and 54% overall yield (Table 2, entry 2).
The same reaction in CH3CN, CH2Cl2, MeOH, and
dioxane also provided 6a and 7a in various ratios but
with lower yields and/or at slower rates for completion,
except for the reactions in DMF and EtOH that respec-
tively provided 72% and 73% yields of the adducts in
reaction times of 2 and 3 h (Table 2, entries 3 and 4). The
reactions in DMF and EtOH were completed in much
shorter times, as compared with the 1-(4-bromophenyl)-
counterpart12 (2 h vs hundreds of hours), and with
higher yields. In addition, the reaction not only pro-
duced the aldol adducts, 6a and 7a, bearing a tertiary
alcohol without undergoing the elimination to the more
stable enal, but also afforded products of different
stereoselectivities.12 In addition, the reaction condition
of IV-HOAc (excess) in EtOH provided 6a with the
highest enantioselectivity (99% ee) (Table 2, entry 4). On
the other hand, the reactions with other catalysts, e.g.,
V-VIII, gave lesser yields of the products (Table 2,
entries 5-8). Moreover, the reaction with less catalyst
loading was feasible and even proceeded with only 1 mol
% of IV and 300 mol % of HOAc, although longer time
was required for completion (Table 2, 9 and 10). Con-
ducting the reaction at higher concentrations (e.g., 0.2
and 0.4 M) did not enhance the reaction rate or increase
the yields. Replacement of acetic acid with other
(14) Reactions of the aliphatic R,β-unsaturated aldehydes gave com-
plicate self-dimerization products. For examples, see: (a) Bertelsen, S.;
ꢀ
Diner, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007,
129, 1536. (b) Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007,
63, 2840.
(15) For examples, see: (a) Hara, N.; Nakamura, S.; Shibata, N.;
Toru, T. Adv. Synth. Catal. 2010, 352, 1621–1624. (b) Rueping, M.;
Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699–
3702. (c) Xue, F.; Zhang, S.; Duan, W.; Wang, W. Chem. J. Asian 2009,
4, 1664–1667.
1340
Org. Lett., Vol. 13, No. 6, 2011

Table 3. Scope of Domino Michael-Aldol Reactiona
entry
product
time (h)
dr (%)b 6/7
yield (%)c
ee (%)d 6/7
1
2
6a, 7a: R1 = pyridin-2-yl; R2 = n-C6H13; R3 = 4-MeOC6H4
6b, 7b: R1 = pyridin-2-yl; R2 = n-C6H13; R3 = Ph
20
32
16
24
17
21
13
14
82
87
68
36
91
73:27
85:15
66:34
63:37
44:56
81:19
80:20
53:47
53:47
43:57
29:71
70:30
16:5:12:3:1
73
63
71
60
62
73
63
66
80
66
74
82
72g
99/99e
99/nd
97/99e
96/90e
99/98e
99/nd
97/nd
98/99e
98/97e
96/99e,f
96/90
99/nd
nd
3
6c, 7c: R1 = pyridin-2-yl; R2 = n-C6H13; R3 = 4-BrC6H4
6d, 7d: R1 = pyridin-2-yl; R2 = n-C6H13; R3 = 4-ClC6H4
6e, 7e: R1 = pyridin-2-yl; R2 = n-C6H13; R3 = 4-NO2C6H4
6f, 7f: R1 = pyridin-2-yl; R2 = n-Pr; R3 = 4-MeOC6H4
6g, 7g: R1 = pyridin-2-yl; R2 = n-Pr; R3 = 4-BrC6H4
6h, 7h: R1 = pyridin-2-yl; R2 = Ph(CH2)2; R3 = 4-BrC6H4
6i, 7i: R1 = pyridin-2-yl; R2 = c-C6H11; R3 = 4-MeOC6H4
6j, 7j: R1 = pyridin-2-yl; R2 = c-C6H11; R3 = 4-BrC6H4
6k, 7k: R1 =pyridin-2-yl; R2 = c-C6H11; R3 = 4-NO2C6H4
6l, 7l: R1 = quinolin-2-yl; R2 = n-C6H13; R3 = 4-MeOC6H4
6m, 7m: R1 = furan-2-yl; R2 = c-C6H11; R3 = 4-MeOC6H4
4
5
6
7
8
9
10
11
12
13
1
a Unless otherwise noted, the reactions were performed in 0.2 M of 5 with a 1.2/1 ratio of 3/5 at 25 °C. b Determined by H NMR of the crude
products. c Isolated yields of the adducts 6 and 7. d Unless otherwise noted, determined by HPLC with a chiral column (Chiralpak IC). e Determined as
their corresponding esters by subjecting 6 to Wittig reagent (Ph3PCH2CO2Et). f Determined by HPLC with a chiral column (Chiralpak IA). g Mixtures of
the alcohol and enal products was obtained, and the stereochemistry of the adducts was not determined.
aldehydes. Furthermore, the hypothesis can be further sup-
ported by the fact that the example of an aromatic group (R1)
with less H-bonding ability, e.g., a furan-2-yl group, afforded
complicated mixtures of stereoisomers of 6, 7, and 8 and the
elimination of enals (Table 3, entry 13)
To explain the stereochemistry of this transformation,
we proposed a plausible mechanism (Scheme 1).16 The
selective formation of adducts 6 and 7 in these reactions is
noteworthy. Different stereoselectivity was obtained in the
counterpart reaction where R1 was the 4-bromophenyl group
and adduct 8was the predominant product, as opposed to the
reactions affording 6 and 7 in which the R1 was the pyridin-
2-yl group.12 The different stereoselectivity may arise from
the fact that 4-bromophenyl ketone 3 favors the (E)-like
conformer while the pyridin-2-yl ketone 3 favors the (Z)-like
Figure 1. Stereo plots of the X-ray crystal structures of (-)-6a,
(-)-6g, (-)-6j, and (þ)-7d. Color code: C, gray; N, blue; O, red;
Cl, green; Br, purple. The hydrogen bonding distance is noted in teal.
conformer during the nitro-Michael addition. Thus, the
reaction underwent the subsequent intramolecular
aldol transformation (Scheme 1).16 In addition, under
these reaction conditions, 6 could isomerize to 7, which
became an important factor when the bulky R2 group
(e.g., c-C6H11) and/or a strong electron-withdrawing
group (e.g., NO2) were present on R3 in 6.17
In conclusion, we have discovered an unprecedented sequen-
tial organocatalytic Stetter and Michael-Aldol reaction with
the evidence of a dynamic kinetic asymmetric transformation.
The introduction of an intramolecular H-bonding strategy in
this system for increasing the yields, enabling DYKAT, and
obtaining a stable β-hydroxyaldehyde is especially noteworthy.
Acknowledgment. We acknowledge the financial support
for this study from the National Science Council, Taiwan,
ROC. Thanks are also given to the National Center for High-
Performance Computing (NCHC) for their assistance in
literature searching.
(16) See Supporting Information for Scheme 1.
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
and X-ray crystallographic data for compounds (þ)-7d,
(-)-6a, (-)-6g, and (-)-6j (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) The isomerization of 6 to 7 was further supported by the
following experiments: (a) treatment of 6k with DABCO in EtOH for
36 h gave a mixture of 6k and 7k with a ratio of 1:6. (b) Reaction with
IV-DABCO afforded a 1:6.2 ratio of 6a/7a (Table 2, entry 11). (c)
Reaction with only catalyst IV, a base, without any additive provided a
1:2.5 ratio of 6a/7a (Table 2, entry 12).
Org. Lett., Vol. 13, No. 6, 2011
1341