Observation of neighboring ortho-hydroxyl group participation in organocatalytic asymmetric sequential Michael-lactonization reactions: Synthesis of highly substituted chiral spirodihydrocoumarins

Article abstract of DOI:10.1039/c2ob07122c

A general approach to asymmetric synthesis of highly substituted spirodihydrocoumarins with a quaternary stereocenter was achieved through neighboring ortho-hydroxyl group induced sequential Michael-lactonization reactions on 2-(2-nitrovinyl)phenols with alkyl cyclopentanone-2-carboxylates in the presence of a catalytic amount of quinine-NH-thiourea followed by p-TSA.

Full text of DOI:10.1039/c2ob07122c

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COMMUNICATION
Observation of neighboring ortho-hydroxyl group participation in
organocatalytic asymmetric sequential Michael-lactonization reactions:
synthesis of highly substituted chiral spirodihydrocoumarins†‡
Dhevalapally B. Ramachary,* R. Madhavachary and M. Shiva Prasad
Received 18th December 2011, Accepted 10th February 2012
DOI: 10.1039/c2ob07122c
provided many efficient methods.4 Recently, our group, Enders
A general approach to asymmetric synthesis of highly substi-
et al., Gong et al., and Hong et al. have independently devel-
oped an organocatalytic Michael–acetalization–oxidation/
reduction reaction sequence for the efficient synthesis of chro-
manes and 3,4-dihydrocoumarins in a highly enantioselective
manner.5 However, there is no suitable asymmetric method to
prepare spirodihydrocoumarins in enantiomerically pure form
with more functional diversity. As a continuation of our research
in this area, we envisaged (E)-2-(2-nitrovinyl)phenols and alkyl
cyclopentanone-2-carboxylates as the potential substrates for a
newly designed Michael–lactonization (M–L) reaction
(Scheme 1).6
As our group is working on the development of asymmetric
sequential one-pot synthesis of drug-like compounds,7 herein we
propose that medicinally important spirocyclic dihydrocoumarins
6 and tetrahydrocyclopenta[b]chromenes 7 with a quaternary
stereocenter could be constructed through newly designed neigh-
boring ortho-hydroxyl group induced asymmetric sequential
Michael–lactonization (M–L) reactions between alkyl cyclopen-
tanone-2-carboxylates 1 and (E)-2-(2-nitrovinyl)phenols 2 with
suitable organocatalysts 3 followed by p-TSA or BF3·OEt2-cata-
lysis (Scheme 1).
tuted spirodihydrocoumarins with a quaternary stereocenter
was achieved through neighboring ortho-hydroxyl group
induced sequential Michael–lactonization reactions on 2-(2-
nitrovinyl)phenols with alkyl cyclopentanone-2-carboxylates
in the presence of a catalytic amount of quinine–NH–
thiourea followed by p-TSA.
Despite rapid progress in asymmetric organocatalytic sequential
one-pot reactions,1 mimicking cellular and highly efficient asym-
metric sequential one-pot approaches remain in high demand.
An ideal asymmetric sequential one-pot multi-catalysis reaction
would be atom-economical, rapid, have a high substrate scope,
and performed under the mild conditions to yield quantitative
and enantiomerically pure drug-like products with a vast library
of catalysts and substrates. Recently the organocatalytic aldol,
Michael, Mannich or Diels–Alder reactions have become trigger-
ing reactions for a combination of other reactions like Michael,
Henry, alkylation, amination, aldol, epimerization or acetaliza-
tion in a sequential one-pot manner for the synthesis of complex
chiral molecules.2 The development of new and highly efficient
cellular-type organocatalytic sequential one-pot approaches based
on the high-yielding asymmetric reactions to form drug-like mol-
ecules is significant. Herein, we describe an unusual efficient
neighboring ortho-hydroxyl group induced asymmetric organoca-
talytic sequential one-pot reaction for the synthesis of drug-like
chiral spirodihydrocoumarins from simple substrates and catalysts
by using sequential Michael–lactonization reactions.
As we were interested in investigating the role of neighboring
ortho-hydroxyl group participation in organocatalytic asym-
metric reactions, we decided to explore the 2-(2-nitrovinyl)
phenols 2 as Michael acceptors in an amine-catalyzed M–L reac-
tion with keto-esters 1.8 We expected that the reaction of 2-(2-
nitrovinyl)phenol 2a with in situ generated enolate from keto-
ester 1a under the standard reaction conditions would lead to
Chromanes and 3,4-dihydrocoumarins are important classes of
heterocyclic cores found in many natural products and are
widely used as drug intermediates and ingredients in pharmaceu-
ticals.3 Therefore, high-yielding asymmetric syntheses of these
heterocycles have been extensively studied in recent years and
School of Chemistry, University of Hyderabad, Hyderabad-500 046,
India. E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR and HRMS) for all
new compounds. CCDC 856223. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob07122c
Scheme 1 Design of a new sequential M–L reaction for the asym-
metric synthesis of spirodihydrocoumarins.
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Table 1 Optimization for the sequential M–L reaction
Catalyst 3
(10 mol%)
Solvent-1
(0.3 M)
Solvent-2
(0.075 M)
Yielda (%)
4aa/5aa
Yieldb (%)
6aa
eec (%)
6aa
dec (%)
6aa
Entry
Time (h)
1
2
3
4
5
6
7
8
3a
3d
3a
3d
3a
3b
3c
3e
3f
Toluene
Toluene
DCE
DCE
DCM
DCE
DCE
DCE
DCM
DCM
DCM
DCM
24
24
24
24
20
8
14
8
3
Toluene
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
90
90
95
95
98
95
95
95
98
90
98
99%
conv.
70
73
70
73
70
70
76
70
75
60
75
70
−31
38
−51
47
−49
−61
−85
91
>99.9
97
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
9
10
11
12d
3g
3h
3f
4
3
3
DCE
DCE
−98
91
a Yield refers to the quickly filtered product. b Yield refers to the column-purified product. c ee and de determined by CSP HPLC analysis. d Reaction
performed in a cascade one-pot manner.
Michael adduct 4aa with high ee. However, Michael adduct 4aa
was not detected alone and instead it has shown the existence of
fast dynamic equilibrium with lactol 5aa with high ee under the
modified conditions. This unexpected result represents a novel
methodology for the preparation of 4/5 and a new reactivity for
amine-catalysts. Herein, we report our findings regarding these
new sequential reactions.
yield via p-TSA-catalyzed lactonization in toluene or DCE at
80 °C for 3–4 h (see Table 1). In a further optimization, reaction
of 1a and 2a in DCE with 10 mol% of quinine 3a catalyst at
25 °C for 24 h followed by p-TSA-catalyzed lactonization in
DCE at 80 °C for 3–4 h furnished the product cis-6aa in 70%
yield with only 51% ee and >99% de (Table 1, entry 3). Interest-
ingly, reaction of 1a with 2a in DCE under 10 mol% of HO–Q–
OH 3b-catalysis at 25 °C for 8 h furnished the products 4aa/5aa
in 95% yield, which on further lactonization with p-TSA-cataly-
sis furnished the product cis-(+)-6aa in 70% yield with 61% ee
and >99% de (Table 1, entry 6). Same reaction under 10 mol%
of HO–Q–OBn 3c-catalysis in DCE for 14 h furnished the pro-
ducts 4aa/5aa in 95% yield, which on further lactonization with
p-TSA catalyst furnished the spirodihydrocoumarin cis-(+)-6aa
in 76% yield with 85% ee and >99% de (Table 1, entry 7). In a
further optimization, sequential M–L reaction of 1a with 2a in
DCE using 10 mol% of HO–QD–OH 3e catalyst at 25 °C for
8 h furnished the products 4aa/5aa in 95% yield, which on
further lactonization with p-TSA catalyst in DCE furnished the
product cis-(−)-6aa in 70% yield with 91% ee and >99% de
(Table 1, entry 8). Correlation of these results with simple (2-
nitrovinyl)benzene reveals that the outcome of product selectiv-
ity and reactivity is controlled by neighboring group (O–H) par-
ticipation in the transition state along with the catalyst.8i
For the optimization of designed M–L reaction, we screened a
number of organocatalysts for the reaction of 2-(2-nitrovinyl)
phenol 2a with 1.3 equiv. of keto-ester 1a and some important
results are shown in Table 1. Interestingly, reaction of 2a with
1.3 equiv. of 1a under 10 mol% of quinine 3a-catalysis in
toluene at 25 °C for 24 h furnished the 1 : 1 ratio of 4aa and 5aa
in 90% yield with only 31% ee and >99% de (Table 1, entry 1).
Structure and fast dynamic equilibrium between 4aa↔5aa was
1
confirmed by IR, H and 13C NMR analysis of pure 4aa↔5aa.
1
The H and 13C NMR spectra exhibited two set of signals for
4aa↔5aa including broad singlet at δ 6.61 due to the phenolic-
OH, a broad singlet at δ 4.56 due to the tert-OH group, a qua-
ternary carbon resonance at δ 214.4 due to the carbonyl carbon
(CvO) of the ketone, and a quaternary carbon at δ 106.3 due to
the ketal carbon (O–C–OH) confirmed the equilibrium structures
of the 4aa↔5aa. For a clear understanding of diastereoselectiv-
ity and also for clear HPLC separation, we transformed the
quickly filtered products 4aa/5aa into easily separable and also
very important spirodihydrocoumarin cis-6aa with 70–76%
To further improve the asymmetric sequential M–L reaction,
especially to decrease the reaction time to <5 h and increase the
5826 | Org. Biomol. Chem., 2012, 10, 5825–5829
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Table 2 Synthesis of chiral M–L products 6abc
ee/de to >99%, for the first time we tested the M–L reaction of
1a and 2a catalyzed by quinine–NH–thiourea catalysts 3f–h9 fol-
lowed by p-TSA-catalysis. Interestingly, sequential M–L reaction
of 1a with 2a in DCM using 10 mol% of quinine–NH–thiourea
3f catalyst at 25 °C for 3 h furnished the products 4aa/5aa in
98% yield, which on further lactonization with p-TSA catalyst
furnished the cis-(−)-6aa in 75% yield with >99.9% ee and
>99% de (Table 1, entry 9). After achieving the successful result
with 3f as the catalyst, we screened alkaloid based primary
amine thioureas like 3g and 3h as the catalysts for the M–L reac-
tion to monitor the outcome of reaction rate and selectivity
(Table 1, entries 10–11). Results from sequential M–L reaction
of 2a with 1.3 equiv. of 1a in DCM using 10 mol% of 3g or 3h
catalyst followed by lactonization are not superior as compared
to catalyst 3f (Table 1, entries 10–11). Finally, we envisioned the
optimized conditions to be 25 °C in DCM using 10 mol% of
quinine–NH–thiourea 3f catalyst followed by p-TSA induced
lactonization to furnish the spirodihydrocoumarin cis-(−)-6aa in
75% yield with >99.9% ee and >99% de (Table 1, entry 9). Sur-
prisingly, the same reaction when performed in cascade one-pot
manner furnished the product cis-(−)-6aa with reduced yield and
ee as shown in entry 12, Table 1. Structure and absolute stereo-
chemistry of M–L products 4aa/5aa and 6aa was confirmed by
NMR analysis and also finally confirmed by X-ray structure
analysis on (−)-6aa as shown in Fig. S1 (see ESI‡).10
With the optimized reaction conditions in hand, the scope of
the quinine–NH–thiourea/p-TSA-catalyzed asymmetric sequen-
tial M–L reactions was investigated.11 A series of substituted 2-
(2-nitrovinyl)phenols 2b–i were reacted with 1.3 equiv. of keto-
esters 1a–c and keto-aldehyde 1d catalyzed by 10 mol% of 3f or
3h at 25 °C in DCM for 3–12 h to furnish chiral products 4ab-
dd/5ab-dd with very good yields, ee’s and de’s, which on
further lactonization with p-TSA catalyst or oxidation with PCC
furnished the chiral products 6ab–6dd respectively (Table 2).12
Without showing much effect of electronic factors; neutral, elec-
tron-withdrawing and electron-donating substituted 2-(2-nitrovi-
nyl)phenols 2b–i generated the expected products 4ab–dd/5ab–
dd and 6ab–dd with excellent yields, ee’s and de’s (see
Table 2). Surprisingly, reaction of (E)-3-(2-nitrovinyl)benzene-
1,2-diol 2h with keto-ester 1a using catalyst 3h followed by lac-
tonization furnished the cis-(+)-6ah as the major product in 70%
yield with only 76% ee and >99% de (Table 2, entry 9). Obser-
vation of lower ee in this reaction may be due to the involvement
of a second OH group in the transition state of the Michael reac-
tion. Fascinatingly, 2-methoxy-6-(2-nitrovinyl)phenol 2i were
reacted with keto-esters 1a–b catalyzed by 10 mol% of 3f at
25 °C in DCM for 3–4 h to furnish chiral Michael products
(+)-4ai and (+)-4bi with very good yields, ee’s and de’s, which
on further lactonization with catalyst p-TSA in DCE for 5–6 h at
80 °C didn’t furnish the cyclized products 6ai–bi respectively
(Table 2). Reaction of (E)-2-(2-nitrovinyl)phenol 2a with keto-
ester 1c using 3f or 3h catalyst followed by lactonization furn-
ished the pure two enantiomers cis-(−)-6ca and cis-(+)-6ca in
each 60% yield with >99.9/97% ee and >99% de respectively
(Table 2). Interestingly, reaction of (E)-2-(2-nitrovinyl)phenol 2a
with methyl 2-oxocyclohexanecarboxylate using catalyst 3f or
3h didn’t furnish the expected Michael product, but the same
reaction with 2-oxocyclohexanecarbaldehyde 1d in DCM for 2 h
at 25 °C followed by PCC mediated oxidation furnished the
a Reactions were carried out in DCM (0.3 M) with 1.3 equiv. of 1a–d
relative to the 2b–i (0.3 mmol) in the presence of 10 mol% of catalyst 3f
or 3h at 25 °C for 3–12 h. After one quick filtration, resulting products
4/5 were treated with 10 mol% of p-TSA in DCE (0.075 M) for 3–4 h at
80 °C. bYield refers to the column-purified product. cEe and de
were determined by CSP HPLC analysis. dReaction performed with
e
10 mol% of 3h as catalyst. Time taken for Michael reaction was 8 h.
fTime taken for Michael reaction was 12 h. gPCC mediated oxidation
was utilized for the cyclization reaction
functionalized spiro[chroman-3,1′-cyclohexane]-2,2′-dione cis-
(−)-6da in 65% yield with 99% ee and >99% de (Table 2, entry
14). In a similar manner, another chiral spiro[chroman-3,1′-
cyclohexane]-2,2′-dione cis-(−)-6dd was also furnished in 70%
yield with 79% ee and >99% de from 1d and 2d (Table 2, entry
15). Structure and stereochemistry of M–L products 4ab–dd/
5ab–dd and 6ab–dd were confirmed by NMR analysis.
ð1Þ
With synthetic applications in mind, we decided to explore the
utilization of dynamic equilibrium products 4↔5 in the synthesis
of functionalized chiral chromanes and chromenes via Lewis
acid-catalysis as shown in eqn (1). Reaction of the pure chiral
products (+)-4aa/5aa (99% ee) with 1.1 equiv. of BF3·OEt2
in DCM at 0–25 °C for 1.5 h furnished the cyclized ethyl
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enol as shown in TS-1.13 The outcome of high selectivity and
reactivity for the keto-ester 1 addition to the 2-(2-nitrovinyl)
phenols 2 could be explained by neighboring group participation
of Ar–O–H through hydrogen-bonding with carbonyl of 1 as
shown in Fig. 1. The asymmetric Michael reaction between
simple (E)-(2-nitrovinyl)benzene 2j and (E)-3-(2-nitrovinyl)
phenol 2k with keto-ester 1a via 3f-catalysis in DCM, furnished
the expected Michael products (+)-4aj and (+)-4ak with moder-
ate yields, ee’s and de’s under longer reaction times as shown in
eqn (3). The observed moderate selectivity for the products
(+)-4aj and (+)-4ak could be explained due to the lack of neigh-
boring ortho-hydroxyl group participation and also the catalyst
quinine–NH–thiourea 3f is activating both the substrates in the
transition state, which is not enough to control the selectivity as
like in other substrates 2a–i.
Fig. 1 Proposed transition state for the asymmetric Michael reactions.
9-(nitromethyl)-1,2,9,9a-tetrahydrocyclopenta[b]chromene-9a-
carboxylate trans-(−)-7aa in 52% yield with only 60% ee and
unreacted products (+)-4aa/5aa in 37% yield with 86% ee as
shown in eqn (1). Formation of less ee product in this reaction
may be due to the decomposition or racemization of 4aa↔5aa
or 7aa through retro-Michael and Michael reaction under the
Lewis acid-catalysis.
ð3Þ
In summary, for the first time we have developed the quinine–
NH–thiourea 3f and p-TSA-catalyzed asymmetric sequential
M–L reaction of keto-esters 1 with 2-(2-nitrovinyl)phenols 2.
The sequential asymmetric M–L reaction proceeds with very
good yields and high selectivity through a favoured 21-mem-
bered supramolecular transition state using 3f followed by p-
TSA as the catalyst. Furthermore, we have demonstrated the
application of chiral products 4/5 in the synthesis of functiona-
lized chiral spirochromans. Further work is in progress to utilize
chiral products 4–9 as intermediates for bio-active molecules
synthesis.
ð2Þ
Treatment of dynamic equilibrium products (−)-4aa↔5aa
with AcCl using Et3N catalyst in DCM at 0 °C → 25 °C for 12 h
selectively furnished the protected open product (−)-8aa in 85%
yield with 98% ee and >99% de as shown in eqn (2). Hydrogen-
ation of (−)-8aa with 10% Pd/C in ethyl acetate at 25 °C for
24 h furnished the partially hydrogenated imine (+)-9aa in 90%
yield with 98% ee and >99% de (see eqn (2)). Compounds
(−)-6ab to (−)-6dd, (−)-7aa, (−)-8aa and (+)-9aa are drug-like
molecules; these types of molecules are used for the treatment of
potent anti-ischemic properties, anti-hypertensives, aldose
reductase, spasmolytics for blood vessels, potassium channel
blockers and also as HIV-1 reverse transcriptase, which empha-
sizes the value of this M–L approach to the pharmaceutical
industry.3 In addition, the presently discovered sequential M–L
reaction will be suitable to develop substituted 3,4-dihydro-
coumarins unit, which is found in many natural products and
designed drug molecules.3,4
With controlled experimental data in hand, herein we firmly
elucidate the mechanism of neighboring ortho-hydroxyl group
involvement in an asymmetric Michael reaction through 21-
membered supramolecular assembly by 3f-catalysis, the reaction
most likely proceeds via a TS-1 mechanism (Fig. 1).13 In the
case of the addition of keto-esters 1a–d to substituted 2-(2-nitro-
vinyl)phenols 2a–i via quinine–NH–thiourea 3f-catalysis, we
can rationalize the observed stereochemistries through a favoured
21-membered supramolecular transition state where the less hin-
dered si-face of 2a–i approaches the si-face of in situ generated
Acknowledgements
This work was made possible by a grant from the Department of
Science and Technology (DST), New Delhi [Grant No.: DST/
SR/S1/OC-65/2008]. RM and MSP thank Council of Scientific
and Industrial Research (CSIR), New Delhi for their senior
research fellowship. We thank Dr P. Raghavaiah for his help in
X-ray structural analysis.
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6 For recent papers on sequential Michael and lactonization reactions, see:
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7 For selected papers on asymmetric sequential one-pot reactions from our
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8 For recent papers on Michael addition of 1,3-diketones to simple nitros-
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Chem. Commun., 2011, 47, 9621–9623; (b) R. Manzano, J. M. Andres,
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9 For selected papers on amine-thiourea catalyzed asymmetric reactions,
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473–477; (b) B. Tan, G. Hernandez-Torres and C. F. Barbas III, J. Am.
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10 CCDC-856223 contains the supplementary crystallographic data for this
paper for (−)-6aa. See ESI‡ for crystal structure.
5 For selected examples of organocatalytic asymmetric syntheses of chro-
mans and 3,4-dihydrocoumarins, see: (a) P. Kotame, B.-C. Hong and J.-
H. Liao, Tetrahedron Lett., 2009, 50, 704–707; (b) L. Zu, S. Zhang,
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11 For organocatalytic synthesis of substituted 2-(2-nitrovinyl)phenols 2a–k,
see: D. B. Ramachary and R. Sakthidevi, Org. Biomol. Chem., 2010, 8,
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12 For organocatalytic high-yielding synthesis of racemic products 6 from 1
and 2 through [Q (3a) + QD (3d)]-catalysis followed by p-TSA-catalysis,
see Table S1 in ESI-I.‡.
13 For reviews on supramolecular assembly in catalysis, see: (a) L.
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