Organocatalytic asymmetric anti-selective Michael reactions of aldehydes and the sequential reduction/lactonization/pauson-khand reaction for the enantioselective synthesis of highly functionalized hydropentalenes

Article abstract of DOI:10.1021/ol302527z

A new method has been developed for the enantioselective synthesis of highly functionalized hydropentalenes bearing up to four stereogenic centers with high stereoselectivity (up to 99% ee). This process combines an enantioselective organocatalytic anti-selective Michael addition with a highly efficient one-pot reduction/lactonization/Pauson-Khand reaction sequence. The structures and absolute configurations of the products were confirmed by X-ray analysis.

Full text of DOI:10.1021/ol302527z

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5346–5349
Organocatalytic Asymmetric
Anti-Selective Michael Reactions of
Aldehydes and the Sequential Reduction/
Lactonization/PausonÀKhand Reaction
for the Enantioselective Synthesis of
Highly Functionalized Hydropentalenes
Bor-Cherng Hong,*,† Nitin S. Dange,† Po-Jen Yen,† Gene-Hsiang Lee,‡ and
Ju-Hsiou Liao†
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 September 13, 2012
ABSTRACT
A new method has been developed for the enantioselective synthesis of highly functionalized hydropentalenes bearing up to four stereogenic
centers with high stereoselectivity (up to 99% ee). This process combines an enantioselective organocatalytic anti-selective Michael addition with
a highly efficient one-pot reduction/lactonization/PausonÀKhand reaction sequence. The structures and absolute configurations of the products
were confirmed by X-ray analysis.
With high stereoselectivity and wide applications, orga-
nocatalyzed conjugate additions are finding increasing
uses in synthetic chemistry.1 Despite many successful anti-
selective organocatalytic Michael reactions of ketones,
numerous organocatalytic conjugate additions of aldehydes
to nitroalkenes have been reported to be highly syn-selective
(Scheme 1, eq 1).2,3 Details of the reaction mechanism that
account for this high syn-stereoselectivity have been ad-
vanced by a recent discovery.4 Similarly, organocatalyzed
Michael reactions of aldehydes to alkylidene malonates
have been reported, as exemplified by the reactions
with the JørgensenÀHayashi catalyst,5 which preferentially
afforded the (2R,3R)-syn-adduct (Scheme 1, eq 2).6 Never-
theless, efforts to obtain anti-selective conjugate addi-
tions of aldehydes have been elusive until a recent tactic
† National Chung Cheng University.
‡ National Taiwan University.
(1) For recent reviews in organocatalyzed Michael reactions, see: (a)
ꢀ
(4) (a) Bures, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
2011, 133, 8822–8825. (b) Patora-Komisarska, K.; Benohoud, M.;
Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94,
719–745. (c) Bures, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem.
Soc. 2012, 134, 6741–6750.
(5) Jensen, K. L.; Ickmeiss, G.; Iang, H.; Albrecht, Ł.; Jørgensen,
K. A. Acc. Chem. Res. 2012, 45, 248–264.
(6) (a) Zhao, G.-L.; Vesely, J.; Sun, J.; Christensen, K. E.; Bonneau,
C.; Cørdova, A. Adv. Synth. Catal. 2008, 350, 657–661. (b) Sun, X.; Ma,
D. Chem.;Asian J. 2011, 6, 2158–2165. (c) Wen, L.; Shen, Q.; Lu, L.
Org. Lett. 2010, 12, 4655–4657.
ꢀ
Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123–3135. (b)
ꢀ
Vicario, J. L.; Badıa, D.; Carrillo, L. Synthesis 2007, 2065–2092.
(2) For a review: Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716.
(3) For recent examples: (a) Belot, S.; Vogt, K. A.; Besnard, C.;
Krause, N.; Alexakis, A. Angew. Chem., Int. Ed. 2009, 48, 8923–8926. (b)
Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett.
2008, 10, 4557–4560. (c) Hong, B.-C.; Nimje, R. Y.; Wu, M.-F.; Sadani,
A. A. Eur. J. Org. Chem. 2008, 1449–1457. (d) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215.
r
10.1021/ol302527z
Published on Web 10/04/2012
2012 American Chemical Society

introduced by Barbas et al. which exploited the anti-selective
Michael reaction of R-alkoxyaldehydes.7 Inspired by the
organocatalyzed anti-selective Michael reaction of ketones,8
Barbas’s strategy ingeniously employed an alkoxyacet-
aldehyde stabilized through intramolecular H-bonding
throughout the synclinal transition state to furnish the Z
enamine (Scheme 1, eq 3).
Table 1. Screening of Catalysts, Solvents, and Reaction
Conditions for the Stereoselective Michael Reactiona
Scheme 1. Preferential Stereoselectivity of the Organocatalytic
Michael Reaction of Aldehydes
cat.-
t
yieldb
(%)
drc
eed,e
entry
additive
solvent (h)
syn/anti
(%)
1
IÀHOAc
I
CHCl3
34
83
80
95
94
91
68
87
83
81
65:35
52:48
3:97
94f /26g
99f /95g
99f /96g
32f /99g
99f /97g
91f /98g
89f /86g
69f /99g
À73i/90g
na
2
CH3CN 20
CH3CN 46
3
IÀDBU
IÀDBU
IÀDBU
IÀDBU
IÀDBU
IÀDBU
IÀDBU
IIÀDBU
IIIÀDBU
IVÀDBU
VÀDBU
VIÀDBU
Scheme 2. Retrosynthetic Analysis
4
CHCl3
64
7:93h
12:88
19:81
34:66
19:81
13:87
na
5
CH2Cl2 66
6
EtOH
DMF
THF
20
23
39
7
8
9
toluene 89
10
11
12
13
14
15
16
17
18
CH3CN 109 ∼0
CH3CN 134 trace
nd
nd
CH3CN 62
CH3CN 52
CH3CN 73
80
17/83
48/52
nd
0/0
87
À13i /2
trace
trace
87
nd
Nevertheless, a practical and expedient methodology
forthe anti-selectiveMichael reaction ofregular aldehydes,
e.g. nonalkoxy aldehydes, has yet to be achieved and is an
attractiveand compelling subject of exploration. However,
recent advances in PausonÀKhand reactions (PKRs) have
provided a versatile protocol for the synthesis of polycyclic
complex molecules,9 and the synergistic efforts of organo-
catalysis and metal catalysts also have recently received
much attention with appealing outcomes. Considering
the above background in the context of organocatalytic
asymmetric annulations,10 we envisioned an approach to
VIIÀDBU CH3CN 60
IÀDBN CH3CN 85
IÀDABCO CH3CN 19
IÀTMG CH3CN 94
nd
nd
25:75
41:59
18:82
À77i /95
83
8j
86/15
À73i /86
a Unless otherwise noted, the reactions were performed on a
0.2-mmol scale of 2a and 1a (2 equiv), using 20 mol % of the catalyst
and additive at 0 °C in a vial containing the appropriate solvent.
b Isolated yields of 3a. c Determined by HPLC and 1H NMR of the
reaction mixture. d Determined by HPLC with chiral column Chiralpak
AD. e Ee of syn-3a and anti-3a, respectively. f Major isomer (3R,4R)-syn-
3a. g Major isomer (3S,4R)-anti-3a. h Direct concentration of the reac-
tion mixture led to the isomerization of 3a, syn/anti = 32/68; À99/85%
ee, respectively, showing that some of the (3S,4R)-anti-3a was isomer-
ized to (3S,4S)-syn-3a and some of the (3R,4R)-syn-3a was isomerized
to (3R,4S)-anti-3a. i The opposite enantiomer, i.e. (3S,4S)-syn-3a,
was obtained. j Slow conversion. nd = not determined. na = not
available.
(7) (a) Uehara, H.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2009, 48,
ꢀ
9848–9852. (b) Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Bar-
bas, C. F., III. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20672–20677. (c)
Imashiro, R.; Uehara, H.; Barbas, C. F., III. Org. Lett. 2010, 12, 5250–
5253.
(8) For recent examples, see: (a) Mandal, T.; Zhao, C.-G. Angew.
Chem., Int. Ed. 2008, 47, 7714–7717. (b) Huang, H.; Jacobsen, E. N.
J. Am. Chem. Soc. 2006, 128, 7170–7171.
(9) For recent reviews, see: (a) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org.
Chem. 2010, 789–811. (b) Takanori, S. Adv. Synth. Catal. 2006, 348,
2328–2336. (c) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005,
44, 3022–3037. (d) Bonaga, L. V. R.; Krafft, M. E. Tetrahedron 2004, 60,
9795–9833. (e) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed.
cyclopenta[g]isochromen-3-one that could be accom-
plished by a sequence of organocatalytic asym-
metric Michael reactions of aldehydes and reductionÀ
lactonizationÀPKR (Scheme 2). Herein, we report details
of the development of highly anti-selective asymmetric
Michael reactions of aldehydes and alkylidene malonates,
by a nucleophilic-catalysis strategy,11 which affords
~
ꢀ
2003, 42, 1800–1810. (f) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano,
ꢀ
L.; Domınguez, G.; Perez-Castells, J. Chem. Soc . Rev. 2004, 33, 32–42.
Org. Lett., Vol. 14, No. 20, 2012
5347

syn-selectivity was diminished, as compared with other
examples of alkylidene malonates (Scheme 1, eq 2),6 prob-
ably due to the lesser steric bulk of the alkyne substituent
(R2), i.e., sp vs sp3 and sp2 in other literature examples.
Additionally, the syn-3a was obtained with 94% ee, while
a 26% ee was observed for anti-3a (Table 1, entry 1).
Conducting the same reaction with the catalyst I in the
absence of the acetic acid additive in CH3CN did, however,
afford a 52/48 ratio of syn- and anti-3a, with 99% ee and
95% ee, respectively (Table 1, entry 2).
Table 2. Scope of Organocatalytic Sequential Michael Reduc-
tion Lactonization and PausonÀKhand Reactiona
Interestingly and notably, the reaction with catalyst I
(20 mol %) and DBU (20 mol %) under the same reaction
conditions in CH3CN provided a 3/97 ratio of syn- and
anti-3a, with 99% ee and 96% ee, respectively (Table 1,
entry 3). A similar result was observed for the same
reactioninCHCl3 and CH2Cl2 albeitwitha longerreaction
time (Table 1, entries 4 and 5).12 The highly anti-selective
Michael reaction of aldehyde observed herein is remark-
able and unusual, vide supra.7 Moreover, during the isola-
tion and purification process, direct concentration of the
Michael adducts in vacuo caused a degree of epimerization
and decreased the syn/anti ratio to ca. 32/68 with the
inversion of ee of syn-3a (Table 1, entry 4, footnote h). It
is noteworthy that the major enantiomeric syn-Michael
adduct obtained, i.e., (3S,4S)-syn-3a, from this epimeriza-
tion of the cat. IÀDBU catalyzed product was found to be
the enantiomer of the major syn-Michael adduct obtained,
i.e., (3R,4R)-syn-3a, from the reaction with cat. IÀHOAc.
Notably, this epimerization could be circumvented by
direct loading of the reaction mixture onto a silica gel
column, thereby avoiding the direct concentration of the
reaction mixture. Such prompt purification (EtOAcÀ
hexane, 1:19) afforded the anti-Michael adduct in a 96:4
diastereomeric ratio. These observations led us toconclude
that epimerization of acyclic syn- and anti-3a can occur
under the harsh reaction conditions (e.g., concentrated
under basic conditions) to produce the ∼2:1 or 1:1 diaste-
reomeric mixtures, depending on the time of exposure.
However, the highly diastereo- and enantioselective forma-
tion of anti-3a observed herein did not simply arise from the
R-epimerization of syn-3a since such an isomerization
would not be able to drive all of the syn-/anti-3a mixture
toward anti-3a and would lead to the opposite enantiomers
and thereby decrease the enantioselectivities.
yield
tb
drc
of 5
dre
Ee
entry
R
(h) of 4 (%)d of 5 (%)f
1
2
3
a R1 = Ph; R2 = Et
45 88:12 85
b R1 = 4-MeC6H4; R2 = Et 46 80:20 71
88:12 98
85:15 96
86:14 99
c R1 = 4-CO2Me-C6H4;
R2 = Et
d R1 = 4-FC6H4; R2 = Et
e R1 = 4-ClC6H4; R2 = Et
f R1 = 3-ClC6H4; R2 = Et
26 80:20 67
4
5
5
9
88:12 79
85:15 77
85:15 54
94:06 99
93:07 96
80:20 98
84:16 98
76:24 99
62:38 98
82:18 97
5
6
7
g R1 = 4-BrC6H4; R2 = Et 15 85:15 81
8
h R1 = 4-IC6H4; R2 = Et
i R1 = n-C5H11; R2 = Et
j R1 = Ph; R2 = Me
k R1 = Ph; R2 = i-Pr
l R1 = thiophen-2-yl;
R2 = Et
15 84:16 62
48 74:26 63
48 75:25 68
40 68:32 65g 85:15 97
40 75:25 62
81:19 97h
9
10
11
12
a Unless otherwise noted, the reactions were performed on a 0.2-
mmol scale of 1a and 2, in a ratio of 2:1, using 20 mol % of the catalyst I
and DBU at 0 °C in a vial containing the appropriate solvent. b Time
required for first Michael reaction. c Diastereomeric ratio of cis-/trans-4,
determined by 1H NMR of the crude reaction mixture after lactoniza-
tion. d Isolated yield of 5 and its isomer after four steps. e Diastereomeric
ratio determined by 1H NMR of crude reaction mixture after PausonÀ
Khand reaction. f Ee of the major isomer of 5, unless otherwise noted,
determined by HPLC with Chiralpak IA. g 12 h reactiontime was required
for the lactonization. h Determined by HPLC with Chiralcel OD-H.
cyclopenta[g]isochromen-3-ones in good yields and excel-
lent stereoselectivities up to 99% ee.
Initially, a solution of 1a and 2a in CHCl3 was treated
with JørgensenÀHayashi catalyst IÀHOAc (20 mol %),
and an 83% yield of syn-3a and anti-3a was obtained in a
ratio of 65/35 (Table 1, entry 1). To a certain extent, the
The reactions with catalyst IÀDBU in other solvents
produced lesser yields, dr’s, and/or ee’s (Table 1, entries
5À9). Inaddition, a seriesof organocatalystswerescreened
in the reactions (Table 1, entries 10À15). Among them,
most reactions did not proceed or gavea reduced dr and ee.
Moreover, the product obtained from the pyrrolidine
(IV)ÀDBU was used as a racemic standard for the HPLC
analysis (Table 1, entry 12). Some amine bases, e.g., DBN,
DABCO, and tetramethylguanidine, were tested with cat-
alyst I in the reactions, but the results were not as promis-
ing as the outcome of the reactions with DBU (Table 1,
(10) (a) Hong, B.-C.; Chen, P.-Y.; Kotame, P.; Lu, P.-Y.; Lee, G.-H.;
Liao, J.-H. Chem. Commun. 2012, 48, 7790–7792. (b) Hong, B.-C.;
Dange, N. S.; Ding, C.-F.; Liao, J.-H. Org. Lett. 2012, 14, 448. (c)
Hong, B.-C.; Hsu, C.-S.; Lee, G.-H. Chem. Commun. 2012, 48, 2357. (d)
Hong, B.-C.; Kotame, P.; Lee, G.-H. Org. Lett. 2011, 13, 5758. (e) Hong,
B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H.; Lee, G.-H. Org. Lett. 2011,
13, 1338. (f) Hong, B.-C.; Nimje, R. Y.; Lin, C.-W.; Liao, J.-H. Org. Lett.
2011, 13, 1278. (g) Hong, B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H.
Org. Lett. 2010, 12, 4812. (h) Hong, B.-C.; Kotame, P.; Tsai, C.-W.;
Liao, J.-H. Org. Lett. 2010, 12, 776 and references cited therein.
(11) An interesting and creative diastereodivergent asymmetric sulfa-
Michael addition of R-branched enones with the choice of acidic
additives and reaction media has been reported; however, its detailed
reaction mechanism remains unclear; see: Tian, X.; Cassani, C.; Liu, Y.;
Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P.
J. Am. Chem. Soc. 2011, 133, 17934–17941.
(12) For the reaction in CHCl3, Table 1 entry 4, a certain amount of
R-epimerization of (3S,4R)-anti-3a might have occurred and reduced the
ee of syn-3a.
5348
Org. Lett., Vol. 14, No. 20, 2012

entries 16À18). For the reaction in toluene, Table 1 entry 9,
a longer reaction time was required for completion of the
reaction, and a certain amount of R-epimerization of
(3S,4R)-anti-3a to (3S,4S)-syn-3a might have occurred.
As a result, reverse enantioselectivity was observed.
To shed light on the mechanism of isomerization, a
solution of 3a(syn/anti= 4:96) was stirred inCDCl3ÀD2O
in the presence of silica gel. Subsequent 1H NMR analysis
of the diastereomers of 3a showed a change of syn/anti
ratio (25:75 after 12 h; 34:66 after 66 h). In addition,
deuteration of the C2ÀH took place after a few minutes
of the reaction, while C4ÀH, the methine adjacent to
the aldehyde, was deuterated after prolonged exposure,
and the C3ÀH remained untouched. Alternatively, freshly
prepared 3a (anti/syn = 95:5) in the same reaction medium
(cat. IÀDBU) with a few drops of D2O was concentrated
in vacuo to yield 3a with a decreased anti/syn ratio, and the
same deuteration phenomenon was observed but in a more
facilitated process. These observations point to the fact
that the highly selective anti-adduct (3S,4R)-3a obtained in
the cat. IÀDBU reaction is not produced in a straightfor-
wardprocessthrough theDBU epimerization ofthe C3ÀH
on syn-adduct (3R,4R)-3a (β-epimerization, Pathway B, or
A, and C, Table 1).13
We then undertook a one-pot strategy in the reductionÀ
lactonization reaction sequence. Reduction of 3a
(NaBH3CN, HOAc, 25 °C, 3 h), followed by the addition
of p-TsOH, with stirring for an additional 3 h, gave the
cis- and trans-lactone 4a in a ratio of 88:12 (Schemes in
Table 2). These lactones were somewhat unstable during
the silica-gel chromatography purification process and so
were subjected to the PKR without purification. A solu-
tion of crude 4a and Co2(CO)8 in CH2Cl2 was stirred at
ambient temperature for 2 h until completion of the
reaction, as monitored by TLC. To this dark-red solution
was added N-methylmorpholine N-oxide (NMO), and the
dark-purple reaction mixture was then stirred for 12 h at rt.
After filtration through a pad of Celite, the solution was
concentrated in vacuo and purified by SiO2 flash column
chromatography to give 5a (85% yield), in a diastereo-
meric ratio of 88:12.14 It is worth noting that the three-step
reaction sequence from 1a and 2a to 4a proceeded in one
pot, with only regular extraction and concentrative work-
up, without purification of 4a. The PKR afforded lactone
5a in 85% overall yield, from the four-step reaction
sequence. With this protocol in hand, we applied the
method to a series of 1a and 2 derivatives. The reaction is
general with respect to the substrates tested, providing the
desired adducts with excellent enantioselectivities (95 to
>99% ee) (Table 2). In general, the Michael reaction of 1a
and 2 was completed in a short period of time when
electron-withdrawing substituents were present in the R1
phenyl group (Table 2, entries 3À8). In the case of (()-5a
and (À)-5l the structures were assigned by X-ray crystal-
lography (see Supporting Information).15 In addition,
extending the protocol to other substituted aldehydes
was also realized.16
In summary, we have elucidated an unusual organoca-
talytic anti-selective asymmetric Michael addition of
aldehydes to alkylidene malonates.17 The introductory
reaction along with the subsequent one-pot reductionÀ
lactonizationÀPKR provides an efficient protocol for
the enantioselective synthesis of highly functionalized
hydropentalenes containing four stereogenic centers. The
reaction not only adds to the limited repertoire of organo-
catalysis withmetal catalyzed cyclization reactionsbutalso
demonstrates for the first time the utilization of nucleo-
philic catalysts in the stereodivergent asymmetric Michael
reaction. The strategy focused on solving the intractable
problem of anti-selective Michael addition of aldehydes,
and with the appropriate selection of nucleophilic catalysts
and organocatalysts, this strategy could provide a venue
for wide applications in asymmetric synthesis. The benign
reaction conditions and the efficient construction of
complex products confirm the merit of this strategy. The
structures and the absolute configurations of the pro-
ducts were verified by X-ray analysis of the appropriate
adducts. Further work is underway to elaborate the de-
tailed mechanism, as well as the synthetic applications of
this strategy.
(13) For a proposed mechanism, see Supporting Information.
(14) trans-4a was unable to undergo a PausonÀKhand reaction and
was decomposed during recovery purification by silica-gel chromato-
graphy. A sample with a ca. 1:1 ratio of cis- and trans-4a was subjected to
the same reaction conditions affording only a 40% yield of 5a with the
same 88:12 diastereomeric ratio.
(15) X-ray crystal structure analysis of (()-5a: Formula C20H20O5,
Acknowledgment. We acknowledge financial support
for this study from the National Science Council, Taiwan,
ROC and are thankful to the instrument center of the
National Science Council for compound analyses.
weight 340.36 g molÀ1, colorless crystal. CCDC-893145; X-ray crysÀta1l
structure analysis of (À)-5l: Formula C18H18O5S, weight 346.38 g mol
,
colorless crystal. CCDC-893205, CCDC-893206, CCDC-893207, and
CCDC-893208 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
and X-ray crystallographic data for (()-5a and (À)-5l
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) For an example, see:
(17) For a recent example of an anti-selective Mannich reaction, see:
ꢀ
ꢀ
Gomez-Bengoa, E.; Jimenez, J.; Lapuerta, I.; Mielgo, A.; Oiarbide, M.;
The authors declare no competing financial interest.
Otazo, I.; Velilla, I.; Vera, S.; Palomo, C. Chem. Sci. 2012, 3, 2949–2957.
Org. Lett., Vol. 14, No. 20, 2012
5349