Efficient catalyst for tandem solvent free enantioselective Knoevenagel-formal [3+3] cycloaddition and Knoevenagel-hetero-Diels-Alder reactions

Article abstract of DOI:10.1039/c5ra09865c

In this study a highly efficient catalyst has been observed for tandem solvent free enantioselective Knoevenagel-formal [3+3] cycloaddition and Knoevenagel-hetero-Diels-Alder reactions. Thus, the synthesis of bicyclic tetrahydro-2H-chromen-5(6H)-one and tricyclic octahydro-2H-benzo[c]-chromen-1(6H)-one derivatives with enantioselectivity up to ee 99% has been achieved in the presence of a chiral Lewis acid assisted Bronsted acid (LBA), titanium-isopropoxy-(S)-BINOLate under solvent free conditions. The stereochemistry of the tricyclic product 10 has been further supported by single crystal X-ray analysis. This domino powerful strategy combines both the economic and environmental aspects of organic chemistry, which are necessary for academic and industrial applications.

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Graphical Abstract
Efficient catalyst for tandem solvent free enantioselective
Knoevenagel-formal [3+3] cycloaddition and Knoevenagel-Hetero-
Diels-Alder Reactions
a
b
a
Sylvia Fernandes, P. Rajakannu and Sujata V. Bhat*
Me
n
O
O
X
O
H
Chiral LBA
Chiral LBA
OR1
X
H
Me
Me
or O
R2
R3
Me
R
R2
R3
R2
R3
O
O
CBC analogues
ee% up to 98.6
X = CH
2
THC analogues
ee% up to 98.8
In this study highly efficient catalyst has been observed for one-pot solvent free enantioselective Knoevenagel-[3+3] cycloaddition
and Knoevenagel-Hetero-Diels-Alder reactions. Thus, the synthesis of bicyclic tetrahydro-2H-chromen-5(6H)-one and tricyclic
octahydro-2H-benzo[c]-chromen-1(6H)-one derivatives with enantioselectivity up to ee 98.8% has been achieved in the presence of
chiral LBA, titanium-isopropoxy-(S)-BINOLate under a solvent free condition. The stereochemistry of tricyclic product 10 has been
further supported by single crystal X-ray analysis.

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DOI: 10.1039/C5RA09865C
Journal Name
ARTICLE
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Efficient catalyst for tandem solvent free enantioselective
Knoevenagel-formal [3+3] cycloaddition and Knoevenagel-
Hetero-Diels-Alder Reactions
a
b
a
Sylvia Fernandes, P. Rajakannu and Sujata V. Bhat*
In this study highly efficient catalyst has been observed for tandem solvent free enantioselective Knoevenagel-formal
3+3] cycloaddition and Knoevenagel-Hetero-Diels-Alder reactions. Thus, the synthesis of bicyclic tetrahydro-2H-
chromen-5(6H)-one and tricyclic octahydro-2H-benzo[c]-chromen-1(6H)-one derivatives with enantioselectivity up to ee
9% has been achieved in the presence of chiral Lewis acid assisted Brønsted acid, (LBA), titanium-isopropoxy-(S)-
[
9
BINOLate under a solvent free condition. The stereochemistry of tricyclic product 10 has been further supported by
single crystal X-ray analysis.This domino powerful strategy combines both the economic and environmental aspects of
organic chemistry, which are necessary for academic and industrial applications.
Introduction
Several bioactive natural products contain tetrahydro-benzopyran
1
2
3a
moiety, some examples being forskolin, hongoquercin A,
3
b
3c
9
O
HO
+
Ref. (14b)
RO
O
zanthosimuline,
chromazonarol,
∆ -tetrahydrocannabinol
n
n
4
5a
(
THC), cannabichromene (CBC). etc. Asymmetric catalysis of
Ar
organic reactions to provide enantiomerically enriched products is
of central importance to modern synthetic and pharmaceutical
chemistry. Therefore, the need for truly efficient and practical
asymmetric synthesis has been one of the greatest challenges for
O
O
N
H
Ar
OTMS
R
up to 97% ee,
dr up to > 20:1
Ref. (14c)
6
R
synthetic chemists.
Pd-SPRIX
Ref. (14a)
HO
O
A common approach for the synthesis of bicyclic tetrahydro-
O
R
1
2
H-chromen-5(6H)-one and tricyclic octahydro-2H-benzo[c]-
2-Alkenyl-
enone
chromen-1(6H)-one rings utilizes Knoevenagel-[3+3] cycloaddition
and Knoevenagel-Hetero-Diels-Alder reactions. Several catalysts
have been reported for these reactions. In previous reports, the
R
R
O
up to 87-97% ee
O
1
7
-13
up to 84% ee,
reactions between 1,3-dicarbonyls (2 or 3) and olefinic aldehydes
7
Scheme 1 Reported asymmetric syntheses of chromanonesin the
presence of chiral catalysts
4
a or 4b were evaluated in the presence of catalysts such as InCl3,
8
9
9
9
9
EDDA, p-TSA,
BF OEt
TiCl4,
In(OTf) ,
phosphoric
etc. A recent
report utilizes a new hollow-structured ZIF-8-H nanosphere
3
2,
3
1
0
11
12
13a
acid, EDDA/ZnCl
2
,
water, NaOMe/MeOH
1
4b,c
substituted-2-hydroxy or 2-acyloxy-chromenones
97% (Scheme 1).
in ee up to
1
3b
as a catalyst for [3+3] cycloaddition reactions.
We report herein a highly efficient tandem solvent free
enantioselective Knoevenagel-formal[3+3] cycloaddition and
Knoevenagel-Hetero-Diels-Alder reactions in the presence of the
chiral LBA titanium-isopropoxy-(S)-BINOLate (1) (Figure 1).
In previous reports, enantioselective cyclization of 2-alkenyl-
,3-diones promoted by Pd-SPRIX catalyst was evaluated, where
1
isomeric 2,2-dialkyl-6,7-dihydro-2H-chromen-5(3H)-ones were
1
4a
formed in ee up to 88%. Similarly, the enantioselective addition
of conjugated aldehyde to 1,3-cyclohexadione and
cyclopentadione in the presence of organo-catalyst (trimethylsilyl-
,1-diaryl-prolinol) has been achieved, which yielded 4-
1
O
O
Ti
O
O
a.
b.
Laboratory for Advanced Research in Natural and Synthetic Chemistry, V. G Vaze
College, Mumbai University,Mithagar Road, Mulund East, Mumbai 400 081, India.
E mail: Sujata8b@gmail.com
Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400
o76, India
2
2 2 4
Figure 1 [(S)-(-)-BINOLate] Ti (O-i-Pr) 1 (LBA)
† Electronic Supplementary Informaꢀon (ESI) available: Experimental
procedures, characterisation data for new compounds, X-ray crystal structure
details, copies of NMR
DOI: 10.1039/x0xx00000x
, GCMS spectra and chiral GC analysis . See
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Thus, the synthesis of bicyclic tetrahydro-2H-chromen-5(6H)-
one and tricyclic octahydro-2H-benzo[c]-chromen-1(6H)-one
derivatives with enantioselectivity up to 98.8% has been achieved
in the presence of chiral LBA, under a solvent free condition
Table 1 Products of enantioselective reactions in the presence of
a,b,c
2 2 4
[(S)-(-)-BINOLate] Ti (O-i-Pr)
(
Scheme 2, Table 1).
Path B
Path A
O
(n)
O
O
O
X
Chiral LBA,
Melonal or
Citronellal
Chiral LBA,
Conjugated
aldehyde
H
X
Results and discussion
The chiral catalyst 1 was prepared according to the reported
procedure. Initially, the reaction of 1,3-cyclohexadienone (2) and
2 2 2
citral (4a) in CH Cl at 0 °C under N atmosphere was attempted,
which went to completion in ½ h, with 79% yield. A similar
reaction of 1,3-cyclohexadienone (2) and citral (4a) in the
presence of chiral catalyst 1 under solvent free condition gave
similar yield in the same duration of time. Hence we carried
further reactions under solvent free condition.
X
R2
R1
H
R2
R1
R4
R3
R2
R1
X
O
OH
15
4b,4c
4
a, 4d
R1,R2,= H or Me
n = 0 or 1
X = O, -CH2
R1,R2,= H, Me...
, 8, 11
2
: R1=R2=H, X= CH2;
3: R1=R2=Me, X = CH2
2 : R1=R2=Me. X = O
5
1
6,7,9,10,13
Entry
Aldehydes
Product
Yield %,
ee%)
(
The reaction between α,β-unsaturated aldehyde such as citral
(4a) (17.90 mmol) and 1,3-cyclohexadienone (2) or dimedone (3)
8
(99)
0
1
2
.
.
(
17.90 mmol) was achieved in the presence of 1 (3 mol %) at 0 °C
under solvent free condition. The reaction was monitored by GC
and TLC analyses and was completed within ½ h to give the bicyclic
tetrahydro-2H-chromen-5(6H)-one derivatives 5 (80% yield and
O
9
1
9% ee) and 8 (77% yield and 89% ee respectively (Table 1, entries
and 4).
7
6
(97)
Additional reactions of 1,3-dicarbonyl compounds 2 or 3 with
4
b
terpenic olefinic aldehydes such as (R)-citronellal (4b), (R)-melonal
4c) were also evaluated on the same reaction scale, which yielded
tricyclic octahydro-2H-benzo[c]-chromen-1(6H)-one derivatives 6,
(
O
3
.
77
7
, 9 and 10 respectively in ~77% yields and ee in the range of 88-
(88)
9
8% (Table 1, entries 2, 3, 5, 6). Similarly, the reaction of
cyclohexa-1,3-dione (2) with conjugated aldehyde (E)-7-formyl-3-
methyl-oct-6-enyl acetate (4d) yielded bicyclic chromenone adduct
4
c
1
1 (75% yield and 98% ee). The reaction of Meldrum’s acid (12)
with (R)-citronellal (4b) gave tricyclic [1,3]dioxino[4,5-
c]isochromen-1(6H)-one derivative 13 The reaction of
4
5
.
.
77
89)
4
a
.
(
cyclopenta-1,3-dione ) with (R)-citronellal (4b) did not yield
tricyclic product. Apparently Knoevenagel adduct intermediate in
case of cyclopenta-1,3-dione does not undergo hetero-Diels-Alder
reaction under present reaction condition.
76
4
b
(89)
The required aldehydes (R)-melonal (4c) and (R)-(E)-7-formyl-
3
-methyl-oct-6-enyl acetate (4d) were synthesised with minor
1
6
modifications of reported procedures.
The structures of compounds 5-11, 14 and 15 were identified
1
13
1
with IR, H NMR, C NMR, GC/MS and HRMS data. In H-NMR
6
.
.
77
99)
4
c
spectrum, the olefinic protons of 5 absorbed at δ 6.45 (d, J = 10.12
(
13
Hz, 1 H), 5.18 (d, J = 10.12 Hz, 1 H). C NMR spectrum of
compound 5 showed peaks at δ 194.9 and 172.1 due to C-5
carbonyl and C-8a enol carbon respectively. The olefinic carbons
absorbed at δ 131.9, 123.6, 121.6, 116.4, 110.3 and ethereal
7
8
75
98)
1
carbon at δ 82.4. H-NMR compound 6 showed absence of olefinic
(
1
3
protons. The C NMR spectrum of compound 6 showed peaks at δ
97.8 and 170.5 due to carbonyl and enol carbon respectively. The
1
1
13
H-NMR and C-NMR of remaining molecules were also in
agreement with their structures.
4b
72
O
H
(83)
O
H
O
O
13
a
Reaction conditions: catalyst 1 (3 mol%) at 0 °C, N
Isolated yield
Enantiomeric excess (ee%) was obtained in GC analysis using chiral
2
atmosphere
b
c
Beta Dex column
2
| J. Name., 2012, 00, 1-5
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O
The molecules 7, 10 and 11 are novel to the best of our
knowledge.
The probable mechanism for stereoselective formation of (2R)-
,6,7,8-tetrahydro-5-oxo-2H-chromene derivatives is shown in
R
2
5
HO
R
1
Figure 3. In Intermediate A the bulky substituent (R-) in aldehyde
prefers equatorial position, which is converted to condensation
product intermediate B. The elimination of water molecule leads
to intermediate C, subsequent attack by isopropanol releases (2R)-
5,6,7,8-tetrahydro-5-oxo-2H-chromene derivative and the catalyst
1 is regenerated. Similar mechanism for stereospecific formation
of tricyclic octahydro-6,6,9-trimethyl-2H-benzo[c]-chromen-1(6H)-
onederivatives is given in scheme 4. The Aldol condensation of
Intermediate A leads to Intermediate B, which undergoes
dehydration to give C, the hetero-Diels-Alder reaction, subsequent
attack by isopropanol and release of tricyclic octahydro-6,6,9-
trimethyl-2H-benzo[c]-chromen-1(6H)-one derivative regenerates
the catalyst 1.
2
3
, R
, R
1
1
=R
=R
2
2
=H,
=Me
Conjugated
aldehydes, 4a, 4d
(R)-Citronellal, 4b
(R)-Melonal, 4c
Chiral LBA 1
Chiral LBA 1
Path B
Path A
O
n
O
H
R
R
2
1
R
2
O
O
R
1
R
4
R
3
The present catalytic system provides an attractive protocol to
various optically active derivatives of bicyclic chromen-5(6H)-one
and tricyclic benzo[c]-chromen-1(6H)-onein terms of the following
features: (i) the catalyst is inexpensive and easily available; (ii) the
protocol has a broad scope of substrates; (iii) the reactions show
ee% 89- 99 %
O
ee% 88 - 99 %
n
O
H
R
2
R
4
H
R
R
2
1
O
R
1
R
3
O
5
, 8, 11
O
OH
OH
6
, 7, 9, 10
O
n = 0 or 1
Ti
O
O
OH
H
O
+
O
O
(
S)-BINOL
Scheme 2 Stereoselective reactions of cyclohexa-1,3-dienones
with Aldehydes in the presence of [(S)-(-)-BINOLate] Ti (O-i-Pr)
Chiral LBA, 1)
OH
O
R
2
2
4
R
(
A
O
O
O
O
H
H
Ti
Ti
O
O
O
R
O
O
O
1
B
O
R
O
R
2
H O
OH
O
Ti
O
O
O
C
Figure 3 The probable mechanism of formation of (2R)-5,6,7,8-
tetrahydro-5-oxo-2H-chromene derivatives
Figure 2 ORTEP diagram of compound 10
high enantioselectivity; (iv)short reaction time, reactions are
completed within ½ h; (v) the reaction is environmentally benign
because of solvent-free condition; and (vi) low catalyst loading (5
mol %) is sufficient to achieve high yield and optical purity of the
products. We hope our findings in this research will stimulate
further work on practical asymmetric synthesis of more molecules
of biological and pharmacological importance.
The enantiomeric excess (ee%) of compounds 5-11, 14, 15 was
obtained in GC analysis using chiral Beta-Dex column. High
stereoselectivity was observed, ee% ranging from 88.1-98.8%, for
both bicyclic (5, 8, 11) and tricyclic (6, 7, 9, 10) molecules (Table 1).
The structure and stereochemistry of tricyclic compound 10 was
1
7-19
further supported by single crystal X-ray analysis,
shown in Figure 1. It is noteworthy, that the stereochemistry at
ring junction positions 3a and 9b of analogue 10 is opposite to that Conclusions
which is
4
of natural (R,R)-THC. In view of strong analgesic activity of (S,S)-
In summary, highly efficient catalyst has been observed for
tandem solvent free enantioselective Knoevenagel-formal[3+3]
cycloaddition and Knoevenagel-Hetero-Diels-Alder Reactions.
5
b
daxanabinol the present report has more significance.
The 2-(R)-stereochemistry of 7,8-dihydro-2H-chromen-5(6H)-
one derivatives 5, 8 and 11 was assigned based on (-)-optical
20,21
rotation and CD spectra.
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General procedure for synthesis of compounds 5-11, 14 and 15
A mixture of cyclohexa-1,3-dione (2) or 5,5-dimethyl-cycohexa-
1
,3-dione (3) or Meldrum's acid (12), (17.90 mmol), terpenic
aldehyde (4a-4d, 17.90 mmol) and catalyst (1) (3 mol %) was
°
stirred at 0 C under solvent free condition for 30 min under N
atmosphere. After completion of the reaction (monitored by TLC/
GC analysis), the reaction mixture was diluted with hexane: CH Cl
1:1, 5 mL) and filtered. The filtrate was evaporated and the
2
2
2
(
residue was purified by silica gel column chromatography to afford
the pure products.
(
R)-2-methyl-2-(4-methylpent-3-enyl)-7,8-dihydro-2H-
chromen-5(6H)-one (5). Yellow oil; [α] = - 65.2° (c = 1 in MeOH),
Chiral GC analysis: 33.79 (major), 33.19 (minor) min, ee 99%; IR (
D
-1
CHCl
184, 1111, 1081, 967, 864, 787; H-NMR (CDCl3, 400 MHz, TMS):
δ (PPM) 6.45 (d, J = 10.12 Hz, 1 H), 5.18 (d, J = 10.12 Hz, 1 H), 5.09-
3
, cm ): 2939, 1647, 1603, 1428, 1381, 1333, 1285, 1257,
1
1
5
1
.07 (m, 1H), 2.42-2.39 (m, 4H), 2.01-1.94 ( m, 4H), 1.74-1.71 (m,
1
3
H), 1.68 (s, 3H), 1.59 (s, 3H),1.68-1.53 (m,1H), 1.36 (s, 3H);
C
NMR (150 MHz, TMS): δ (PPM) 194.9, 172.1, 131.9, 123.6, 121.6,
16.4, 110.3, 82.4, 41.7, 36.4, 28.6, 27.4, 25.7, 22.5, 20.6, 17.6;
GC-MS (m/z) : 246, 231, 213, 203, 190, 175, 163, 155, 147, 135,
1
+
1
2
22 2
22, 107, 99, 91, 77, 69, 55, 41; HRMS (EI ) calcd for C16H O
Figure 4 The probable mechanism of formation of octahydro-
,6,9-trimethyl-2H-benzo[c]-chromen-1(6H)-onederivatives
46.1620, found m/z 246.1622.
6
Synthesis of (±)-2-methyl-2-(4-methylpent-3-enyl)-7,8-dihydro-
2
H-chromen-5(6H)-one (5)using ethylenediamine diacetate as
Thus, the synthesis of bicyclic tetrahydro-2H-chromen-5(6H)-one
and tricyclic octahydro-2H-benzo[c]-chromen-1(6H)-one
catalyst. To a mixture of 1,3-cyclohexadione, 2 (2g, 17.9 mmol)
and citral 4a , (2.73g ,17.9 mmol) was added catalyst EDDA (5 mol
%
the reaction, the reaction mixture was purified by column
chromatography using n-hexane/ EtOAc (4:1) as eluent to provide
derivatives with enantioselectivity up to ee 99% has been achieved
in the presence of titanium-isopropoxy-(S)-BINOLate under a
solvent free condition. The stereochemistry of tricyclic product 10
has been further supported by single crystal X-ray analysis. The
methodology reported herein can be used for the synthesis of
various natural and non-natural molecules with chromenone
moiety. This one-pot powerful strategy combines both the
economic and environmental aspects of organic chemistry which
are necessary for academic and industrial applications.
) and stirred at room temperature for 1h. After completion of
5
D
(3.31 g, 75.4%) as a yellow oil. [α] = 0.
(
6aS,9R,10aS)-6,6,9-trimethyl-2,3,4,6,6a,7,8,9,10,10a-dehydro-
H-benzo[c]chromen-1-one (6). Colourless solid; [α] = -100.1° (c
1 in MeOH), Chiral GC analysis 36.61 min (major), 37.78 min
1
=
D
-1
(
3
minor), ee% 97); IR (CHCl , cm ): 2920, 2847, 1649, 1598, 1447,
1
1
4
2
379, 1273, 1252, 1192, 1128, 999, 850, 775, 693; H-NMR (CDCl3,
00 MHz, TMS): δ (PPM) 2.80-2.77 (ddt, J= 11.5,3,1.7 Hz,1H),
.43-2.18 (m,4 H), 2.13-2.06 (dt, J= 11.08, 2.2 Hz, 1H), 1.92-1.86
Experimental
General procedures
The monitoring of reaction and checking the purity of the products
were done using pre-coated silica gel plates (Merck) and
visualization using anisaldehyde/ H
(
m, 2H), 1.86-1.78 (m, 1H), 1.78-1.72 (m, 1H), 1.61-1.50 (m, 1H),
1
0
.33 (s, 3H), 1.29-1.23 (td, J = 11.3,2.6Hz, 1H), 1.05 (s, 3 H), 1.12-
.95 ( m,2H), 0.91-0.89 (d, J = 6.6 Hz, 3H), 0.49 (q, J =11.5 Hz, 1H);
2
SO
4
reagent. FT-IR spectra
13
C NMR ( 100 MHz, TMS): δ (PPM) 197.8, 170.5, 114.7, 80.3, 48.6,
8.8, 37.5, 35.5, 33.6, 32.3, 29.6, 27.5, 27.2, 22.5, 20.2, 19.4;
GCMS (m/z) : 248, 233, 219, 205, 192, 177, 163, 150, 137, 123,
1
were recorded on a Perkin-Elmer Spectrum One spectrometer. H
NMR spectra were recorded on a Varian spectrometer at 400 MHz
3
1
3
and
standard, J in Hz. Multiplicities is reported as follows: s = singlet, d
doublet, dd = doublets of doublet, t = triplet, q = quartet, m =
multiplet, brs = broad singlet.GC-MS was carried on an Agilent
instrument, where GC-6890 was coupled with mass
C-NMR at 100 MHz; δ in ppm rel. to Me
4
Si as internal
+
1
09, 95, 81, 68, 55, 41; HRMS (EI ) calcd for C16
24 2
H O 248.1776,
found m/z 248.1774.
=
(
1R,3aS,9bS)-1,4,4-trimethyl-1,2,3,3a,4,7,8,9b-octahydrocyclo-
penta[c]chromen-6(6H)-one (7). Colourless liquid. [α] = - 86.6° (c
1, MeOH); Chiral GC analysis 34.23 (major), 33.88 (minor) min,
a
D
spectrometer MS-5973 N with quadrapole mass detector, using a
HP-5 (5% phenyl methyl siloxane) column. Electrospray ionization
and a TOF mass analyser were used for HRMS measurements. The
compounds (5-11) showed the required m/z: (M ) values in HR-
MS. Enantiomeric excess (ee%) was obtained in GC analysis using
=
-1
(
ee% 88); IR (CHCl
3
, cm ): 2945, 2869, 1651, 1582, 1455, 1428,
1
379, 1334, 1278, 1226, 1192, 1113, 1064, 1004, 991, 848, 629;
+
1
H-NMR (CDCl3, 400 MHz, TMS): δ (PPM) 2.41-2.34 ( dt,
J=11.4,5Hz, 1H), 2.35-2.30 (m, 2H), 2.29-2.26 (m, 2H), 2.04-1.98
chiral Beta Dex 120 column (30 m x 0.25µm x 0.25 mm). Silica gel
(
m, 1H), 1.91-1.87 (m,1H), 1.86-1.81 (m, 4H), 1.72-1.55 (m,2H),
(
100-200 mesh), which was used for column chromatography (CC)
13
1
1
3
.41-1.39 (d, J= 6.16 Hz, 3H), 1.36 (s, 3H), 1.13 (s, 3H); C NMR (
00 MHz, TMS): δ (PPM) 197.5, 171.2, 115.4, 81.5, 53.5, 42.6,
7.6, 36.6, 34.4, 29.7, 28.4, 24.8, 23.4, 20.4, 20.1; GC purity :
°
was activated by heating at 120 for 4 h. All asymmetric reactions
were performed under inert atmosphere and at 0 C.
°
4
| J. Name., 2012, 00, 1-5
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Pleas
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Page 6 of 7
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DOI: 10.1039/C5RA09865C
Journal Name
0.0%; GCMS (m/z): 234, 219, 191, 177, 163, 151, 137, 125, 109,
ARTICLE
9
9
(6aS,9R,10aS)-6a,7,8,9,10,10a-hexahydro-3,3,6,6,9-
pentamethyl-[1,3]dioxino[4,5-c]isochromen-1(6H)-one
Yellow oil. [α] = -40.2 ° (c =1, MeOH), Chiral GC analysis 33.77 min
+
1, 79, 67, 55, 41; HRMS (EI ) calcd for C15
22
H O
2
234.1620, found
(13).
m/z 234.1622.
D
-
1
(
3
major), 32.76 min (minor), (ee% 83); IR (CHCl , cm ): 2925, 2855,
1
(
R)-2,7,7-trimethyl-2-(4-methylpent-3enyl)-7,8-dihydro-2H-
chromen-5(6H)-one (8). Yellow oil. [α] = - 66.2° (c =1, MeOH);
Chiral GC analysis) 33.86 (major), 32.39 (minor) min, (ee% 89); IR
1736, 1726, 1620, 1455, 1390, 1280, 1155, 994, 965, 891, 731; H-
D
NMR (CDCl3, 400 MHz, TMS): δ (PPM) 2.65 (dd, J= 5.6, 18.4 Hz,
1H), 2.08- 2.01 (m, 1H), 1.85-0.95 (m, 6H), 1.68 (s,3H), 1.60(s,3H),
-
1
13
C
(
1
CHCl
3
, cm ): 2961, 1680, 1606, 1449, 1382, 1331, 1287, 1217,
1.41 (s,3H), 1.26 (s,3H), 0.91 (d,J=6.5 Hz ,3H), 0.78-0.62 (m,1H)
1
198, 1165, 1112, 1077, 1034, 936, 889; H-NMR (CDCl 400 MHz,
NMR (100 MHz, TMS): δ (PPM) 171.4, 167.3, 124.4, 85.9, 47.4,
42.3, 37.2, 36.3, 32.0, 31.8, 28.7, 27.6, 25.9, 23.5, 22.3. GCMS
(m/z) : 280,; HRMS (EI ) calcd for C H O 280.1704 found m/z
3,
TMS): δ (PPM) 6.44 (d, J= 10Hz,1H), 5.17 (d, J= 10Hz, 1H), 5.11-
+
5
1
1
1
2
2
.07 (m,1H), 2.29-2.23 (m,4H), 2.08-2.01 (m,2H), 1.76-1.69 (m,1H),
.67 (s,3H), 1.57(s, 3H), 1.56-1.54 (s,1H), 1.37( s,3H), 1.08 (s, 3H),
1
6
24
4
280.1703.
13
.06 (s,3H); C NMR ( 100 MHz, TMS): δ (PPM) 194.4, 170.6,
31.8, 123.6, 121.4, 116.2, 109.0, 82.5, 50.3, 42.4, 41.7, 32.1, 28.6,
8.2, 27.5, 25.7, 22.5 , 17.6; GCMS (m/z): 274, 259, 241, 231, 218,
X-ray single crystal structure determination of molecule 10. A
suitable crystal of size 0.06 × 0.18 × 0.24 mm was mounted on a
diffractometer for unit cell determination and three dimensional
intensity data collection. 800 frames in total were collected at 150
K with the exposure time of 16 s per frame. Data integration,
indexing and absorption correction were followed by structure
solution using the programs in a WinGX module. The structure
was solved by direct methods (SIR-92) and the final refinement
of the structure was carried out using full least-squares methods
on F using SHELXL-97. Unit cell determination using both high
and low angle reflections reveals that compound 10 crystallizes in
3
05, 191, 175, 165, 157, 149, 141, 129, 121, 107, 91, 77, 69, 55, 41;
+
HRMS (EI ) calcd for C18
H
26
O
2
274.1933, found m/z 274.1930.
(
6aS,9R,10aS)-3,3,6,6,9-pentamethyl-2,3,4,6,6a,7,8,9,10,10a-
decahydro-1H-benzo[c]chromen-1-one(9). Yellow oil. [α] = -
01.5° (c =1, MeOH); Chiral GC analysis 34.33 (major), 33.78
1
7
D
1
8
1
(
1
6
1
-
1
3
minor) min, (ee% 89); IR (CHCl , cm ): 2957, 2868, 1644, 1606,
2
19
455, 1381, 1360, 1278, 1236, 1165, 1088, 1031, 1013, 941, 865,
1
65; H-NMR (CDCl3, 400 MHz, TMS): δ (PPM) 2.85 (ddt, J=
1.2,3,1.7 Hz,1H), 2.22-2.18 (m, 4H), 2.02-2.18 (m,1H), 1.84-1.78
a monoclinic P2 /c space group. Non-hydrogen atoms were
1
(
1
m,1H), 1.78-1.72 (m,1H), 1.61-1.50 (m,1H), 1.35 (s,3H), 1.26 (td,J=
1.2,2.2 Hz, 1H), 1.12-0.98 (m, 2H), 1.05 (s,3H), 1.04 (s, 3H), 1.03
refined anisotropically. C–H hydrogen atoms were placed in
geometrically calculated positions by using a riding model.
1
3
(
s,3H). 0.90 (d, J=6.5 Hz, 3H), 0.49 (q, J= 11.2 Hz,1H); C NMR ( 100
MHz, TMS): δ (PPM) 197.9, 175.3, 168.8, 113.2, 80.4, 51.4, 48.8,
Acknowledgements
4
2
1
C
5.4, 43.3, 43.2, 38.6, 35.6, 33.5, 32.3, 31.6, 29.3, 28.1, 27.6, 27.3,
We are grateful to Kelkar Education Trust, Mumbai, for
encouragement. We are also thankful to the Department of
Chemistry and Sophisticated Analytical Instrumentation Facility,
Indian Institute of Technology, Bombay, and Tata Institute of
Fundamental Research, Mumbai, for NMR spectral data. We also
thank Prof. R.Murugavel for the use of his Single Crystal X-ray
Diffraction Facility established through a DAE-SRC outstanding
investigator award.
7.2, 22.5, 19.5; GCMS (m/z) : 276, 261, 243, 220, 205, 192, 177,
+
65, 153, 134, 123, 109, 91, 81, 69, 55, 41; HRMS (EI ) calcd for
18 28 2
H O 276.2089, found m/z 276.2091.
(1R,3aS,9bS)-1,4,4,7,7-pentamethyl-1,2,3,3a,4,7,8,9b-
octahydrocyclo-penta[c]chromen-9(6H)-one (10). Yellow oil. [α]
=
min (minor), (ee% 99); IR (CHCl , cm ): 2950, 1728, 1651, 1586,
3
1
D
- 89.6° (c =1, MeOH), Chiral GC analysis 33.55 min (major), 34.23
-1
1
468, 1378, 1230, 1118, 1024, 938, 860, 757; H-NMR (CDCl3, 400
MHz, TMS): δ (PPM) 2.29-2.10 (m,4H), 2.08-1.99 (m, 1H), 1.99-
Notes and references
1
3
.91 (m, 1H), 1.89-1.81 (m,1H), 1.73-1.57 (m,2H), 1.44 (d, J=6 Hz,
‡
Crystallographic data -Unit cell determination using both
high and low angle reflections revealed that compound 10, C17
2; 262.38;crystallizes in a, monoclinic P2 /c space group; Unit
cell dimensions a = 5.9897(17), alpha = 90°, b = 12.612(4), beta
96.062°(5), c = 19.986(6) Å, gamma = 90°; Volume 1501.3(8)
A^3
See supporting information for more details. CCDCNumber-
H), 1.38 (s,3H), 1.22-1.13 ( m,2H), 1.16 (s, 3H), 1.07 (s,3H), 1.04
13
(
s,3H); C NMR (100 MHz, TMS): δ (PPM) 198.4, 197.6, 169.4,
H
26
O
1
1
3
2
67.5, 114.1, 81.6, 78.3, 53.7, 51.8, 43.5, 42.5, 42.8, 36.4,
4.6,31.7, 28.7, 28.5, 27.9, 25.0, 23.7, 20.4; GCMS (m/z) : 262,
=
47, 219, 205, 191, 179, 165, 151, 109, 91, 83, 67, 55, 41; HRMS
+
(
EI ) calcd for C17
H
26
O
2
262.1933, found m/z 262.1930.
1
060831
(
R)-3-methyl-5-((R)-3-methyl-5-oxo-5,6,7,8-tetrahydro-2H-
chromen-2-yl)pentyl acetate (11). Yellow oil. [α] = - 90.5° (c =1,
MeOH), Chiral GC analysis 33.88 min (major), 32.39 min (minor),
D
1
(a) I. Larrosa, P. Romea, F. Urpi, Tetrahedron 2008, 64, 2683;
(b) Y. Tang, J. Oppenheimer, Z. Song, L. You, X. Zhang,
Hsung , Tetrahedron 2006, 62, 10785.
(a) S. V. Bhat, B. S. Bajwa, H. Dornauer, N. J. de Souza, H.-W.
Fehlhaber, Tetrahedron Lett. 1977, 18, 1669; (b) S. V. Bhat,
B. S. Bajwa, H. Dornauer, N.J. D' Souza, J. Chem. Soc., Perkin
Trans. 1 1982, 767.
-1
(
3
ee% 98); IR (CHCl , cm ): 2920, 2847, 1729, 1649, 1598, 1447,
1
1
4
1
379, 1273, 1252, 1192, 1128, 999, 850, 775, 693; H-NMR (CDCl3,
00 MHz, TMS): δ (PPM) 6.21 (s, 1H), 4,75 (dd, J= 10.8 Hz,3.5 Hz,
H), 4.18-4.12 (m, 4H), 2.42-2.35 (m, 4H), 2.05 (s, 3H), 1.99-1.93
m, 2H), 1.72 (s, 3H), 1.68-1.62 (m, 1 H), 1.62-1.53 (m, 2H), 1.50-
2
3
(
1
1
3
.38 (m, 2H), 0.95-0.90 (dd,J =6.4 Hz,3H); C NMR (100 MHz,
(a) D. M. Roll, J. K. Manning, G. T. Carter J.Antibiot. 1998, 51
6
,
35; (b) X. Wang, Y. R. Lee,Synthesis 2007, 3044; (c) S.
TMS): δ (PPM) 195.1, 171.2, 169.9, 126.1, 112.5, 80.9, 62.7, 36.4,
5.4, 35.1, 31.3, 30.3, 29.7, 27.9, 26.3, 20.9, 19.5, 19.1; GCMS
m/z) : 306, 291, 263, 189, 163, 121, 107, 91, 77, 56, 43; HRMS
3
(
(
deRose, L. Minale, R. Riccio, G. Sodano, J. Chem. Soc. Perkin
Trans. I 1976, 1408.
+
26 4
EI ) calcd for C18H O 306.1831 found m/z 306.1833.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-5 | 5
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RSC Advances
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DOI: 10.1039/C5RA09865C
ARTICLE
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| J. Name., 2012, 00, 1-5
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