Enantiopure cycloalkane fused tetrahydropyrans through domino Michael-ketalizations with organocatalysis

Article abstract of DOI:10.1039/b904662c

Enantiopure cyclohexane fused tetrahydropyrans have been synthesized using domino Michael-ketalization under organocatalysis.

Full text of DOI:10.1039/b904662c

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Enantiopure cycloalkane fused tetrahydropyrans through domino
Michael–ketalizations with organocatalysisw
Srivari Chandrasekhar,*a Kundarapu Mallikarjun,a Gangireddy Pavankumarreddy,a
Kakita Veeramohana Raob and Bharatam Jagadeeshb
Received (in Cambridge, UK) 6th March 2009, Accepted 16th June 2009
First published as an Advance Article on the web 9th July 2009
DOI: 10.1039/b904662c
Enantiopure cyclohexane fused tetrahydropyrans have been
synthesized using domino Michael–ketalization under organo-
catalysis.
Towards this endeavour, in the first instance the adduct 6a
(prepared by an atom economical, organocatalyzed
Baylis–Hillman reaction between nitro olefin and formaldehyde25)
was subjected to a domino Michael–ketalization reaction with
cyclohexanone in the presence of 20 mol% of L-proline to
successfully realize the fused cyclohexyl pyran derivative 8a in
75% yield (entry 1, Table 1). The enantiopurity was
disappointing though. Not discouraged, we screened other
pyrrolidine-based catalysts including one we have prepared
in our lab (2 to 5) and the data pertaining to this study are
tabulated (Table 1). We were pleased to note that the
pyrrolidine-triazole 5 gave a satisfactory yield of the product
and high enantiopurity (97% ee, 62% yield, entry 5, Table 1).
Giving a halt at this stage for further improvements in yields,
we rather focused on ‘diversity’ of substrates so that useful
scaffolds are accessed (Table 2 and Scheme 1). Based on this
optimized protocol,z a series of nitro alkenols were prepared
using a standard Baylis–Hillman reaction (entries 1–8, 6a to
The conjugate addition of nucleophiles in an enantioselective
fashion is a challenging process.1 This decade has seen an
unprecedented focus on the development and exploitation of
organocatalysts for achieving this transformation.2 The semi-
nal works of List et al.,3 Macmillan et al.,4 and Jorgensen
et al.5 have inspired researchers to develop newer organo-
catalysts not only for Michael type reactions but also for aldol
reactions and domino processes6 to synthesize optically pure
scaffolds which were hitherto very difficult to access. The cyclic
five membered chiral secondary amine structure (pyrrolidine
scaffold) has attained the status of being ‘privileged’ owing to
its outstanding performance in organocatalysis.7 Even though
other classes of chiral organocatalysts have proven to be
successful, more modifications were attempted while keeping
the pyrrolidine ring intact viz. biaryl pyrrolidinol (more popularly
called a CBS catalyst),8 trifluoroamido-pyrrolidine,9 imidazole
linked (ionic liquid kind) pyrrolidine,10 tetrazole linked
pyrrolidine,11 bifunctional pyrrolidine amides,12 protonated
proline-hydrazides,13 proline diamine,14 peptide–pyrrolidine,15
polystyrene-supported pyrrolidine16 and others.17 More recently
we18 and Luo et al.19 have efficiently incorporated ‘Click’
chemistry to synthesize pyrrolidine-triazole organocatalysts
to perform aldol and Michael reactions. Our own interest in
enantiopure synthesis of substituted tetrahydropyrans has
prompted us to adapt a recently explored intramolecular
‘oxa-Michael’ reaction developed by Evans and Prunet.20,21
We envisioned a more powerful procedure to synthesize
diverse skeletons on this backbone encompassing the synthe-
tically recognized components of atom economy,22 Click
chemistry23 and ‘domino reactions’24 from two achiral
reactants to an enantiopure fused tetrahydropyran with four
chiral centres. Our strategy has been to depend on the
achievement of complete stereocontrol during the Michael
reaction of a 2,3-disubstituted nitro olefin which triggers the
second domino ketalization to achieve tetrahydropyranol 8a–h
in an intramolecular fashion.
Table 1 Catalyst and solvent screening for the stereo- and enantio-
selective domino reaction
Entry Catalyst Solventc,d Additive t/d
Yield [%]a ee [%]b
1
2
3
4
5
6
7
8
1
2
3
4
5
5
5
5
5
5
5
DMSO
Neat
Neat
Neat
Neat
MeOH
iPrOH
Toluene
CH3CN
DMF
DMSO
—
1
15
15
3
75
0
0
25
—
—
40
97
95
92
93
89
96
95
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
50
62
37
39
42
43
44
43
7
10
10
14
14
8
9
10
11
8
a
b
Isolated yield of product after column chromatography. Determined
a Organic Chemistry Division-I, Indian Institute of Chemical
Technology (IICT), Hyderabad, India. E-mail: srivaric@iict.res.in;
Fax: +91-40-27160512; Tel: +91-40-27193210
c
by HPLC analysis on a chiral stationary phase. Conditions for neat
reactions: 0.27 mmol 6a, 10 equiv. cyclohexanone 7, 20 mol% catalyst 1
d
at rt. Conditions for solvent reactions: 0.27 mmol 6a, 6 equiv.
b NMR Group, Indian Institute of Chemical Technology (IICT),
Hyderabad, India
cyclohexanone 7, 20 mol% catalyst 2, 3, 4 and 5, 10 mol% TFA at rt
in 0.5 ml solvent.
w Electronic supplementary information (ESI) available: Experimental
section and spectral data. See DOI: 10.1039/b904662c
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Table 2 Catalytic asymmetric Michael–ketalization reaction of
cyclohexanone with various hydroxymethyl nitro olefins
Entry
6
Product
t/d
Yield [%]a
ee [%]b,c
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
R = Ph, 8a
7
12
10
12
8
8
8
10
62
53
60
41
45
57
59
45
97
99
91
94
88
89
92
98
R = p-MeO-Ph, 8b
R = p-Br-Ph, 8c
R = p-Me-Ph, 8d
R = p-CN-Ph, 8e
R = m-F-Ph, 8f
R = m-NO2-Ph, 8g
R = 2-Furyl, 8h
6g
6h
a
b
Isolated yield of product after column chromatography. Determined
c
by HPLC analysis on a chiral stationary phase. The stereochemistry
depicted is relative.
Scheme 2 Proposed catalytic cycle of the domino Michael–ketalization
reaction.
is drawn, which explains the stereocontrol and specificity of
the reaction (Scheme 2).
The highly enantioselective domino Michael–ketalization
reaction reported here constitutes a method to build tetra-
hydropyrans with four contiguous chiral centers fused onto a
cycloalkane. The reaction, being catalyzed by a trace amount
of TFA, and well-assisted by the pyrrolidine-triazole frame-
work has provided scaffolds hitherto not accessible in optically
pure form by other means.26
KM and KVR thank the CSIR and GP thanks UGC,
New Delhi for financial assistance.
Notes and references
z Typical procedure (entry 1, Table 2): hydroxymethyl nitrostyrene 6a
(50 mg, 0.27 mmol) and catalyst 5 (12 mg, 0.054 mmol) were mixed
with cyclohexanone 7 (0.55 ml, 5.5 mmol) in the presence of TFA
(0.027 mmol) at room temperature. The homogeneous reaction
mixture was stirred at room temperature for 7 days. The reaction
mixture was directly loaded onto silica gel column to afford the
Michael adduct 8a (47 mg, 62%) as a white solid. [a]2D7 +20.0
(c 0.25 M in CHCl3), 97% ee [by HPLC on a chiral phase Eurocel
column l = 225 nm, iPrOH–hexane (10 : 90), 1 ml minꢂ1; tR = 5.8 min
(minor), tR = 6.8 min (major)].
Scheme 1 Transformations of domino product.
6h, Table 2) and the domino Michael–ketalization was
attempted on unsubstituted cyclohexanone 7.
In the presence of 20 mol% of catalyst 5, 10 mol% of TFA
and solvent free conditions, excellent results were obtained in
terms of diastereocontrol and enantioselectivity. The products,
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namely, tetrasubstituted tetrahydropyranol
8 with four
contiguous stereocenters were thoroughly characterized using
NMR and mass spectroscopy for chemical identity. The
relative stereochemistry in the case of 8a was determined by
NOE experiments.
Further 8a was subjected to high yielding chemical
transformations to obtain diverse new chemical entities. For
instance, treatment of 8a with BF3ꢁOEt2 and allyl trimethyl-
silane at ꢂ78 1C furnished 11 having a quaternary allyl group
at the ring junction, whereas reduction with triethylsilane
provided 9. Alkylations of the angular ketal to 10 and 12 were
also uneventful (Scheme 1).
Even though, no thorough mechanistic insight studies were
attempted, a plausible pathway based on literature precedence
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