Discovery of 2-aminobuta-1,3-enynes in asymmetric organocascade catalysis: Construction of drug-like spirocyclic cyclohexanes having five to six contiguous stereocenters

Article abstract of DOI:10.1039/c2cc17219d

We present herein for the first time the asymmetric synthesis of drug-like spiranes through reflexive-Michael reaction by using 2-aminobuta-1,3-enyne catalysis under mild conditions.

Full text of DOI:10.1039/c2cc17219d

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COMMUNICATION
Discovery of 2-aminobuta-1,3-enynes in asymmetric organocascade
catalysis: construction of drug-like spirocyclic cyclohexanes having
five to six contiguous stereocenterswz
Dhevalapally B. Ramachary,* Chintalapudi Venkaiah and Patoju Murali Krishna
Received 20th November 2011, Accepted 22nd December 2011
DOI: 10.1039/c2cc17219d
We present herein for the first time the asymmetric synthesis of
drug-like spiranes through reflexive-Michael reaction by using
2-aminobuta-1,3-enyne catalysis under mild conditions.
physical activities (eqn S1, see ESIz).9 Recently, biphenyl-based
spirocyclic ketones have shown well-defined activity upon
apoptosis and differentiation, making them potential leads
for the development of new anticancer agents.9b However,
there is no suitable asymmetric method to prepare these
kinds of compounds in enantiomerically pure form with more
functional diversity.
Despite rapid progress in asymmetric organocascade catalysis,1
practical and efficient asymmetric cascade approaches remain in
high demand. An ideal asymmetric organocascade catalysis
reaction would be atom-economical, of high substrate scope,
rapid, and performed under mild conditions to yield quantitative
and enantiomerically pure products with simple catalysts and
substrates.2 Since the reflexive-Michael (r-M) or Diels–Alder
(D–A) reaction is arguably the most powerful organic trans-
formation available for the synthesis of complex cyclohexanes,3
development of new and highly efficient organocatalytic cascade
approaches to this reaction is significant. Organocatalytic
asymmetric D–A reactions have been approached using MacMillan
iminium catalysis,4 Barbas dienamine catalysis,5 Serebryakov
dienamine catalysis,6 Tan–Deng acid–base catalysis,7 and
Schreiner–Rawal hydrogen-bonding catalysis.8 For the first time,
here we describe an unusually efficient organocascade asymmetric
r-M reaction through in situ formation of 2-aminobuta-1,3-enynes
and 2-arylidene-indan-1,3-diones from simple substrates and
catalysts by using sequential iminium–enamine–iminium
activation.
As our group is working on the development of asymmetric
cascade synthesis of drug-like compounds,10 herein we propose
that medicinally important spirocyclic skeletons 6–10 with
multiple stereocenters could be constructed through newly designed
asymmetric r-M reactions between ynones 1, aldehydes 2
and indane-1,3-dione 3 with suitable organocatalysts 4 and
co-catalysts 5 followed by a few high-yielding reduction,
oxidation and Simmons–Smith transformations (eqn (1)).
We were surprised to find that the designed cascade reaction
of ynone 1a, benzaldehyde 2a and indane-1,3-dione 3 with a
catalytic amount of L-proline 4a in EtOH at 25 1C for 72 h
furnished the homocyclic r-M product 6aa in only o5% yield
(Table 1, entry 1). Same reaction under the catalysis of
L-diamine/benzoic acid 4b/5a in toluene at 25 1C for 26 h
furnished the r-M product 6aa in 18% yield with 28% ee,
which was accompanied by heterocyclic r-M product 7aa in
65% yield with 44% ee (entry 2). Same cascade reaction under
the 4b/5a catalysis in toluene at reduced temperature (ꢀ5 1C)
for 48 h furnished the 7aa in 60% yield with 64% ee, which
was accompanied by the minor product 6aa in 10% yield with
18% ee (entry 3). One quick crystallization of the (+)-7aa in
i-PrOH/Hex (2 : 1) at 25 1C, enriched the ee up to 91%
(entry 3). In the r-M reaction of 1a, 2a and 3 catalyzed by
4/5, we found that the solvent, temperature and nature of the
amine/acid catalyst had a significant effect on the outcome of
chemoselectivity, yields and ee’s (Table 1).
ð1Þ
Based on the various applications of spirocyclic ketones 6,
we showed interest in improving the competition towards the
homocyclization over the heterocyclization of the designed
cascade reaction. We tested the less basic D-DPPOTMS 4c and
topologically interesting primary amines 4d and 4e as catalysts
to improve the formation of r-M product 6aa. Reaction of 1a,
2a and 3 upon the catalysis of 4c/5a in toluene at 25 1C for 48 h
furnished the 6aa in 60% yield with 37% ee, and 7aa in only
5% yield (Table 1, entry 4). Among the various conditions
screened, surprisingly 4d/5b in toluene at 25 1C for 24 h proved
Spirocyclic cyclohexane scaffolds are present in many natural
and unnatural compounds that exhibit important biological and
School of Chemistry, University of Hyderabad, Hyderabad-500 046,
India. E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all new compounds. CCDC 848633
((+)-6ee) and 848634 ((+)-6be). For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc17219d
c
2252 Chem. Commun., 2012, 48, 2252–2254
This journal is The Royal Society of Chemistry 2012

Table 1 Reaction optimizationa
We further explored the scope of the primary amine/
acid-catalyzed r-M reaction by developing diversity-oriented
synthesis of optically pure spirocyclic cyclohexenones 6ab–ao
and 6bb–ee through cascade reaction of ynones 1a–e, aldehydes
2a–o and indan-1,3-dione 3 (Table 2).11 The chiral spiranes 6
were obtained in good to excellent yields and excellent ee/de’s
with a variety of aldehydes containing neutral, electron-donating,
electron-withdrawing, halogenated, hetero-atom substituted and
aliphatic Ar(R)-CHO 2a–2o and ynones containing neutral,
electron-donating, electron-withdrawing, and halogenated 1a–1e
from the asymmetric r-M reaction (Table 2). Surprisingly,
formation of the r-M products 7 from above reactions was
observed only in 0–5%. Herein, a variety of ynones 1a–e are
used as source for the in situ generation of 2-aminobuta-1,3-enynes
in a cascade r-M reaction to furnish the spirotriones 6ab–6ao
and 6bb–6ee with 85 to 499% ee and 499% de in good to
excellent yields (Table 2).12 The cascade reaction of ynone 1a,
chiral aldehyde 2o and 3 under the catalysis of 4b/5a furnished
only the heterocyclic r-M product 7ao in 40% yield with
499% ee/de (Table 2, entry 22). The structure and absolute
stereochemistry of the cascade r-M products 6 were confirmed
by NMR analysis and also finally confirmed by X-ray structure
analysis of (+)-6be and (+)-6ee as shown in Fig. S1 and S2
(see ESIz).
Product
yieldsb (%)
Catalyst 4/5 Solvent
Entry (20/30 mol%) (0.25 M) Time/h 6aa 7aa 6aa
eec (%) eec (%)
7aa
1
4a
4b/5a
4b/5a
EtOH 72
C6H5CH3 26
C6H5CH3 48
o5
18
10
—
65
60
—
28
18
—
2
ꢀ44
ꢀ64
(91)e
—
57
16
31
43
55
3d
4
5
6
7
8
9
4c/5a
4d/5a
4d/5a
4d/5a
4d/5b
4e/5b
C6H5CH3 48
60
75
50
70
70
70
5
10
5
5
7
10
37
80
89
89
92
95
Brine
Et2O
36
36
C6H5CH3 36
C6H5CH3 24
C6H5CH3 24
Table 2 Scope of the new reactiona,b,c
(499)e
94
97
10
11d
4e/5c
4e/5b
C6H5CH3 24
C6H5CH3 72
60
25
6
—
46
—
a
Reactions were carried out in solvent (0.25 M) with 2 equiv. of 1a
relative to 2a (0.2 mmol) and 3 (0.2 mmol) in the presence of
b
20/30 mol% of catalyst 4/5. Yield refers to the column-purified product.
c
d
ee determined by CSP HPLC analysis. Reaction performed at ꢀ5 1C.
e
ee values in parentheses obtained from one quick crystallization of 6/7 in
iPrOH/hex at 25 1C.
to be the good conditions for homocyclization with respect to
yield and ee, providing 6aa in 70% yield with 92% ee and 7aa
in only 7% yield with 43% ee (entry 8). Further optimization
of this reaction under the 4e/5b catalysis furnished the 6aa in
70% yield with 95% ee, and 7aa in only 10% yield with 55%
ee (entry 9). There is not much improvement in the yield and ee
of the reaction beyond these conditions as found in 4e/5c, and
at the low temperature 4e/5b-catalyzed r-M reactions (entries 10
and 11). One quick crystallization of (+)-6aa (95% ee) in
i-PrOH/Hex (2 : 1) at 25 1C enriched the ee up to 499% with
80% crystallization yield (entry 9). In the final optimization,
cascade r-M reaction of 1a, 2a and 3 through 4e/5b catalysis
furnished the chiral spirotrione (+)-6aa in 70% yield with
499% ee (Table 1, entry 9). Pure r-M products 6aa and 7aa
were treated under both optimized reaction conditions to test
the interconversion, because of their reactive enone group.
Interestingly, 7aa was able to transform into 6aa in 60–80%
conv. with 20–60% yields under 4b/5a or 4e/ 5b catalysis at
25 1C for 24/8 h, respectively. But this conversion rate is very
slow when ynone 1a is around, because catalyst amine will be
more reactive towards ynone 1a instead of 7aa. Surprisingly,
there is no reaction of 6aa with 4b/5a or 4e/5b catalysis at 25 1C
for 24 h (Scheme S1, see ESIz).
a
Reactions were carried out in toluene (0.25 M) with 2 equiv. of
1 relative to 2 (0.2 mmol) and 3 (0.2 mmol) in the presence of
b
20/30 mol% of catalyst 4e/5b. Yield refers to the column-purified
c
product. ee and de determined by CSP HPLC analysis. ee values in
d
parentheses obtained from quick crystallization of 6 in iPrOH/hex at
e
25 1C. Reaction performed under the catalysis of 4b/5a (20/30 mol%).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2252–2254 2253

contiguous stereogenic centers via simple reduction, epoxidation,
Simmons–Smith cyclopropanation and Suzuki coupling trans-
formations (Scheme 1). Discussions on reaction details, yields
and selectivities are summarized in ESIz-1, and some of the
compounds (+)-11aea and (+)-11aeb obtained from r-M and
Suzuki coupling sequence are drug-like molecules for the treatment
of cancer cells, which emphasizes the value of this r-M and
Suzuki coupling approach to the pharmaceutical industry.9
In summary, for the first time we have developed the chiral
primary amine/acid 4e/5b-catalyzed asymmetric r-M reaction of
ynones with aldehydes and indane-1,3-dione to furnish the spiranes
under ambient conditions via 2-aminobuta-1,3-enyne-catalysis.
We thank DST (New Delhi) for financial support. ChV and
PMK thank CSIR (New Delhi) for their research fellowship.
Scheme 1 Synthesis of drug-like spiranes for anticancer studies.
Reaction conditions: (a) NaBH4 (1.5 equiv.), dry CH3OH (0.25 M),
0–25 1C, 0.5 h; (b) Ar-B(OH)2 (2.0 equiv.), Pd(PPh3)4 (0.055 equiv.),
C6H5CH3 (2 mL), sodium succinate (4.2 equiv.), C6H5CH3 : H2O
(1.14 : 1; 1.5 mL), EtOH (1.4 mL), 90 1C, 8 h; (c) mCPBA (1.2 equiv.),
CH2Cl2 (0.2 M), 0–25 1C, 2 h; (d) CH2I2 (5.0 equiv.), Et2Zn
(5.0 equiv.), CH2Cl2 (0.065 M), ꢀ10 1C to 25 1C, 4 h.
Notes and references
1 For recent reviews on organocascade catalysis, see: (a) W. Notz,
F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004, 37, 580;
(b) J. Seayad and B. List, Org. Biomol. Chem., 2005, 3, 719;
(c) G. Lelais and D. W. C. McMillan, Aldrichim. Acta, 2006, 39, 79;
(d) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167;
(e) D. B. Ramachary and S. Jain, Org. Biomol. Chem., 2011, 9, 1277.
2 For selected papers on asymmetric organocascade reactions, see:
(a) D. Enders, M. R. M. Huettl, C. Grondal and G. Raabe, Nature,
2006, 441, 861; (b) M. Rueping, A. P. Antonchick and
T. Theissmann, Angew. Chem., Int. Ed., 2006, 45, 3683; (c) B. Tan,
N. R. Candeias and C. F. Barbas III, Nat. Chem., 2011, 3, 473.
3 (a) D. L. Boger, Tetrahedron, 1983, 39, 2869; (b) K. A. Jørgensen,
Angew. Chem., Int. Ed., 2000, 39, 3558; (c) K. C. Nicolaou,
S. A. Snyder, T. Montagnon and G. Vassilikogiannakis, Angew.
Chem., Int. Ed., 2002, 41, 1668.
ð2Þ
4 (a) K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243; (b) S. B. Jones, B. Simmons and
D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 13606;
(c) T. Kano, Y. Tanaka, K. Osawa, T. Yurino and K. Maruoka,
Chem. Commun., 2009, 1956.
Although further studies are needed to firmly elucidate
the mechanism of r-M reactions through 4e/5b catalysis, the
reaction proceeds in a stepwise manner between in situ generated
2-aminobuta-1,3-enynes A and 2-arylidene-indan-1,3-diones B
(eqn (2)). Based on the crystal structure studies, we can rationalize
the observed high stereoselectivity through an allowed transition
state where the si-face of B approaches the re-face of enyne A due
to the strong hydrogen-bonding/electrostatic/CH–p interactions
and less steric hindrance as shown in TS-1. Formation of the
minor enantiomer may be explained by model TS-2, in which
there is strong steric hindrance between the alkyl portion of the
catalyst and the aryl group of B (eqn (2)). In situ formation of the
proposed reactive species 2-aminobuta-1,3-enyne A and imine A0
from 1a and 4d in CDCl3 at 25 1C was established through the
controlled NMR experiment (eqn (3)). In this NMR experiment,
we have observed only the formation of 1,2-addition products
A/A0 and we didn’t see the 1,4-addition intermediate D.
5 (a) D. B. Ramachary, N. S. Chowdari and C. F. Barbas III, Angew.
Chem., Int. Ed., 2003, 42, 4233; (b) L.-Y. Wu, G. Bencivenni,
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10 For selected papers on asymmetric cascade reactions from our group,
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ð3Þ
11 For high-yielding synthesis of racemic products 6aa–an, 6bb–ee
and 7aa from 1a–e, 2a–n and 3 through pyrrolidine catalysis, see
Table S1 in ESIz-1.
With the medicinal applications in mind, we explored the
utilization of spiranes 6 bearing aryl bromide in the high-yielding
synthesis of functionalized chiral spiranes 8–11 having five to six
12 Recently Gouverneur et al. utilized unmodified ynones as starting
materials in organocatalytic asymmetric aldol reactions with aldehydes,
see: F. Silva, M. Sawicki and V. Gouverneur, Org. Lett., 2006, 8, 5417.
c
2254 Chem. Commun., 2012, 48, 2252–2254
This journal is The Royal Society of Chemistry 2012