Rh-Catalyzed diastereoselective desymmetrization of enone tethered-cyclohexadienones: Via tandem arylative cyclization

Article abstract of DOI:10.1039/c8ob02284d

The rhodium-catalyzed arylative cyclization of enone tethered-cyclohexadienones has been developed with high efficiency, thus providing cis-fused bicyclic enones in good yields and with excellent diastereoselectivities. Furthermore, this mild transformation has a broad range of substrate scope and excellent functional group tolerance. In addition, bicyclic products have an enone functionality, which can be a synthetically valuable handle for further transformations.

Full text of DOI:10.1039/c8ob02284d

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Rh-Catalyzed diastereoselective desymmetrization
of enone tethered-cyclohexadienones via tandem
arylative cyclization†‡
Cite this: DOI: 10.1039/c8ob02284d
Sandip B. Jadhav,§a,b Satish B. Thopate,§a,b Jagadeesh Babu Nanubolua,b and
a,b
Rambabu Chegondi
*
The rhodium-catalyzed arylative cyclization of enone tethered-cyclohexadienones has been developed
with high efficiency, thus providing cis-fused bicyclic enones in good yields and with excellent diastereo-
selectivities. Furthermore, this mild transformation has a broad range of substrate scope and excellent
functional group tolerance. In addition, bicyclic products have an enone functionality, which can be a
synthetically valuable handle for further transformations.
Received 15th September 2018,
Accepted 4th October 2018
DOI: 10.1039/c8ob02284d
rsc.li/obc
the nature of O-substituents at N-hydroxybenzamides.5d
Recently, Lautens and co-workers established the desymmetri-
Introduction
Multiple C–C bond formation through single transformation zation of cyclohexa-2,5-dienols using rhodium-catalyzed redox-
for the synthesis of bioactive complex molecules has high isomerization.5e Our research group very recently demon-
demand in modern organic chemistry.1 In particular, strated the use of asymmetric hydrogenation in the desymme-
diastereoselective tandem reactions have significant impor- trization of alkyne-tethered cyclohexadienones to afford cis-
tance in the natural products and small molecule syntheses in hydrobenzofurans and cis-hydroindoles in high yields with
terms of minimization of synthetic steps and increasing excellent enantioselectivity.7
overall yields. Hence, a number of enantio- and diastereo-
As part of our program aimed at the desymmetrization of
selective tandem processes have been developed. Recently, the C2-symmetric molecules8 and enthused by recent advances in
catalytic desymmetrization of cyclohexadienones, which are the area of rhodium catalyzed tandem Michael additions,9 we
readily available from oxidative dearomatization of corres- envisaged that the Rh-catalyzed arylative diastereoselective
ponding phenols, has been found as one of the most powerful desymmetrization of prochiral cyclohexadienone-containing
tools in complex natural product synthesis.2 In recent elegant bis-enones via tandem double conjugate addition would be a
reports, many research groups demonstrated the use of tran- novel approach to provide factionalized bicyclic products with
sition-metal catalysis in the desymmetrization of cyclohexadie- a high level of diastereoselectivity. To the best of our knowl-
nones to construct stereoselective complex frameworks.3–6 In edge, desymmetrization enone tethered-cyclohexadienones
2013, Tian/Lin research groups reported the rhodium-catalyzed have not been explored until now.
enantioselective desymmetrization of 1,6-dienynes via arylative
cyclization.5b Later, the same research group demonstrated the
Results and discussion
arylative cyclization of alkyne-tethered cyclohexadienones by
Rh(III)-catalyzed C–H activation with dual reactivity based on
We initiated our studies with the arylation of cyclohexadienone
1a with phenylboronic acid 2a in the presence of 2.5 mol% of
[Rh(COD)Cl]2 and 5 mol% of common phosphine ligands in
1,4-dioxane using various bases and results are summarized in
Table 1. To our delight, the reaction at 90 °C with various
aDepartment of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of
Chemical Technology (CSIR-IICT), Hyderabad 500007, India.
E-mail: rchegondi@iict.res.in, cramhcu@gmail.com
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
†CSIR-IICT Manuscript Communication Number: IICT/Pubs./2018/274
‡Electronic supplementary information (ESI) available: Copies of 1H, 13C NMR
spectra for all new compounds, 19F NMR spectra for all fluorinated compounds,
and X-ray crystallographic data (CIF file) of compound 3t. CCDC 1866550. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02284d
bases (1 equiv.) gave desired cyclization product 3a along with
an appreciable amount of uncycled product 4a, albeit with a
low diastereoselectivity (Table 1, entries 1–3). Additional
optimization revealed that the loading of the K2CO3 base from
1 equivalent to 2 equivalents at 90 °C (entries 4 & 5) led to
further increases in the yield of 3a (86%) and diastereo-
selectivity (14 : 1). Next, various mono- and bisphosphine
§These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
3a + 4a
Entry
[Rh]-Catalyst
Ligand (mol%)
Base (equiv.)
T °C
Yieldb [%]
dr (3a)c
1
2
3
4
5
6
7
8
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
DPPF, L2
DPPE, L3
DPPP, L4
SPhos, L5
RuPhos, L6
tBuOK (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
K2CO3 (1.5)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
tBuOK (2.0)
tBuOK (0.1)
tBuOK (0.3)
—
90
90
90
90
90
90
90
90
90
90
90
90
90
rt
60 + 29
72 + 21
36 + 32
84 + 5
2 : 1
5 : 2
2 : 1
9 : 1
14 : 1
17 : 1
7 : 1
18 : 1
11 : 1
9 : 1
12 : 1
12 : 1
6 : 1
—
86 + 5
40 + 38
30 + 40
65 + 12
68 + 10
72 + 5
65 + 12
80 + 7
32 + 42
12 + 55
91 + 3
12 + 73
23 + 65
0 + 89
9
10
11
12
13
14
15
16
17
18
XPhos, L7
PCy3, L8
HPCy3·BF4, L9
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
(rac)-BINAP, L1
rt
rt
rt
rt
21 : 1
—
—
—
a The reaction was carried out with 1a (0.1 mmol), 2a (0.2 mmol), [Rh(COD)Cl]2 (2.5 mol%), ligand (5 mol%), H2O (0.5 mmol) in dioxane (1 mL)
under a N2 atmosphere at room temperature. b Yield of the isolated products 3a and 4a. c Diastereomeric ratio (dr) was determined by 1H NMR
analysis of the crude reaction mixture.
ligands (L2–L9) were screened to further improve the yield and diastereoselectivities (Table 2, 3a–3i). However, strong activat-
diastereoselectivity. However, none of the tested ligands ing and deactivating substituents at the para-position gave
improved the reaction outcome (entries 6–13). Interestingly, slightly lower diastereoselectivity (3e, 3f & 3i). When the 3-halo
the reaction at room temperature in the presence of the L1 substituted boronic acids were examined, the corresponding
ligand and KOtBu base afforded required product 3a in excel- products (3j–3m) were all obtained in moderate yields. Other
lent yield (91%) and diastereoselectivity (dr 21 : 1). On the substituents in the meta-position gave desired products (3n–
other hand, the use of K2CO3 at room temperature furnished 3p) in good yields and with good distereoselectivities. The
the cyclization product 3a in lower yield along with major reaction with ortho-substituted boronic acid gave corres-
uncycled product 4a (entries 14–15). Finally, decreasing the ponding product 3q in moderate yield (59%) most likely due to
base loading to below 1 equivalent gave no better results and steric hindrance and with an excellent diastereomeric ratio
the reaction without a base at room temperature furnished (21 : 1). As for the 2-naphthylboronic acid and other heteroaro-
exclusively the uncycled product 4a in 89% yield (Table 1, matic boronic acid, the reaction progressed, thus providing the
entries 16–18). This clearly indicates that the Rh-enolate corresponding bicyclic products (3r–3t) with good yields and
trapping via Michael addition is slower than the protonation diastereoselectivities. Single-crystal X-ray analysis of compound
of enolate. From the above screening results, two equivalents 3t unambiguously established its relative stereochemistry of
of the KOtBu base in the presence of the BINAP ligand (L1) at the bicyclic framework (Fig. 1).10
room temperature were the best condition for the tandem
cyclization (Table 1, entry 15).
As shown in Table 3, a range of enone tethered-cyclohexa-
dienones underwent arylative cyclization smoothly under the
With the optimal reaction conditions in hand, the scope of standard conditions to afford bicyclic products with good to
bicyclic product formation was demonstrated with a variety of excellent diastereoselectivity. Substrates containing aryl
substituted boronic acids. As shown in Table 2, all para-substi- ketones substituted with electron-donating and electron-with-
tuted arylboronic acids, regardless of the electron-withdrawing drawing groups furnished good yields and good diastereo-
or electron-donating character of the substituent at the phenyl selectivities (3u–3aa). It is also noted that the reaction with
ring, furnished products with good to excellent yields and 4-phenyl substituted aryl ketone gave corresponding product
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Substrate scope for boronic acidsa,b,c,d
Table 3 Substrate scope for cyclohexadienonesa,b,c
a The reaction was carried out with 1 (0.1 mmol), 2a (0.2 mmol), [Rh
(COD)Cl]2 (2.5 mol%), ligand (5 mol%), and H2O (0.5 mmol) in
dioxane (1 mL) under a N2 atmosphere at room temperature. b Yield of
the isolated products 3. c Diastereomeric ratio (dr) was determined by
1H NMR analysis of the crude reaction mixture.
3x with excellent yield (92%; dr = 24 : 1). Although there were
i
various R substituents (Et, Pr and C2H4OTBS) at the quatern-
ary carbon center, the tandem reaction proceeded well with
good yields (Table 3; entries 3ab–3ad).
In addition, the tandem Michael addition of cyclohexadie-
none 5 bearing the ethylbromide group at the quaternary
carbon center under standard reaction conditions with phenyl-
boronic acid 2a afforded dehalogenated product 3ac in 74%
yield with excellent diastereoselectivity (dr = 35 : 1) (Scheme 1).
Interestingly, arylative cyclization of α,β-ester 6 did not partici-
pate to give corresponding cyclization product 7.
The bicyclic product 1 has an enone functionality, which
can be a synthetically valuable handle for further transform-
ations. This was demonstrated with the treatment of 3ab with
TBAF in dry THF which afforded the more complex tricyclic
product 8 in 80% yield as a single diastereomer (Scheme 2).
a The reaction was carried out with 1a (0.1 mmol), 2 (0.2 mmol), [Rh
(COD)Cl]2 (2.5 mol%), ligand (5 mol%), and H2O (0.5 mmol) in
dioxane (1 mL) under a N2 atmosphere at room temperature. b Yield of
the isolated products 3. c Diastereomeric ratio (dr) was determined by
1H NMR analysis of crude reaction mixture. d Minor isomers of 3e & 3f
(3e′ & 3f′, respectively) were isolated and data were included in the
Experimental section.
Fig. 1 ORTEP diagram of compound 3t at the 30% probability level.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
of water prevents the β-hydride elimination from the Rh-
enolate intermediate. Further investigations on the appli-
cations of enone tethered-cyclohexadienones are in progress in
our laboratory and will be reported in due course.
Experimental section
General information
Unless otherwise noted, all reagents were used as received
from commercial suppliers. All reactions were performed
under a nitrogen atmosphere and in a flame-dried or oven-
dried glassware with magnetic stirring. All solvents were dried
before use following the standard procedures. Reactions were
monitored using thin-layer chromatography (SiO2). TLC plates
were visualized with UV light (254 nm), iodine treatment or
using p-anisaldehyde stain and β-naphthol stain. Column
chromatography was carried out using silica gel
(100–200 mesh) packed in glass columns. NMR spectra were
recorded at 300, 400, and 500 MHz (H) and at 75, 100, and
125 MHz (C), respectively. Chemical shifts (δ) are reported in
ppm, using the residual solvent peak in CDCl3 (H: δ = 7.26 and
C: δ = 77.16 ppm) as the internal standard, and coupling con-
stants (J) are given in Hz. HRMS spectra were recorded using
ESI-TOF techniques.
Scheme 1 Other miscellaneous reactions.
Scheme 2 Synthetic utility.
From the above experimental outcome and on the basis of
previous Rh-catalyzed enone conjugate additions,9 we pro-
posed the reaction pathway for the Rh-catalyzed arylative cycli-
zation of cyclohexadienone-containing bis-enones in
Scheme 3. The transmetalation of arylboronic acid to a more
active hydroxorhodium(I) intermediate A furnished arylrho-
dium(I) intermediate B. The coordination of rhodium complex
B to enone 1a followed by insertion into the aryl-rhodium
bond gave intermediate C which is an equilibrium with
rhodium enolate D as an oxa-π-allylrhodium complex. The
hydrolysis of Rh-enolate D with H2O avoids the β-hydride elim-
ination of intermediate C, followed by the base mediated cycli-
zation to afford the required product and regenerates active
hydroxorhodium(I) complex A.
General procedure for the rhodium-catalyzed
diastereoselective arylative cyclization of enone-tethered
cyclohexadienones
To a stirred solution of boronic acid 2 (2 equiv.) in dioxane
(0.1 M) at room temperature were added [Rh(COD)Cl]2
(2.5 mol%) and (rac)-BINAP (5 mol%) under an inert atmo-
sphere. After 5 minutes, KOtBu (2 equiv.), H2O (5 equiv.) and
enone-tethered cyclohexadienone 1 (1 equiv.) were added to
the reaction mixture, successively. The reaction mixture was
allowed to stir at room temperature, until complete consump-
tion of the starting material (monitored by TLC), at which
point the reaction solvent was evaporated under reduced
pressure. The residue was purified by flash column chromato-
graphy on silica gel (EtOAc in hexane) to give the desired
product 3 along with its minor isomer 4.
In summary, we have developed
a rhodium-catalyzed
diastereoselective desymmetrization of prochiral cyclohexadie-
nones via a tandem conjugate addition reaction. The reaction
proceeds via arylation of enone and subsequent hydrolysis of
Rh-enolate followed by the base mediated cyclization. The use
4-Benzoyl-8a-methyl-3-phenyl-3,4,4a,8a-tetrahydro-2H-chromen-
6(5H)-one (3a). Prepared according to the general procedure as
described above in 91% yield (71 mg). It was purified by flash
chromatography (30% EtOAc/hexanes; Rf = 0.4) to afford a
1
brown semi solid; H NMR (400 MHz, CDCl3) δ 7.89–7.82 (m,
2H), 7.59–7.52 (m, 1H), 7.48–7.41 (m, 2H), 7.32–7.23 (m, 4H),
7.20–7.14 (m, 1H), 6.66 (d, J = 10.0 Hz, 1H), 6.00 (dd, J = 10.0,
0.8 Hz, 1H), 4.54 (dd, J = 11.7, 4.4 Hz, 1H), 3.95 (dd, J = 12.1,
5.7 Hz, 1H), 3.83 (t, J = 12.0 Hz, 1H), 3.66 (td, J = 11.8, 5.6 Hz,
1H), 2.89 (dd, J = 16.4, 13.7 Hz, 1H), 2.48 (dt, J = 13.6, 4.2 Hz,
1H), 1.98 (ddd, J = 16.4, 4.0, 0.8 Hz, 1H), 1.81 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 198.9, 198.1, 150.5, 139.5, 135.8, 133.7,
129.1, 128.8, 128.2, 128.0, 127.3, 69.9, 66.4, 46.3, 38.7, 37.6,
35.3, 22.4; HRMS (ESI) calcd for C23H23O3 [M + H]+: 347.1647;
found: 347.1649.
Scheme 3 Reaction pathway.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
4-Methyl-4-(4-oxo-2,4-diphenylbutoxy)cyclohexa-2,5-dienone 128.9, 128.3, 128.2, 70.0, 65.9, 46.4, 38.6, 37.9, 35.2, 26.7, 22.4;
(4a). It was purified by flash chromatography (30% EtOAc/ HRMS (ESI) calcd for C25H25O4 [M + H]+: 389.1753; found:
hexanes; Rf = 0.5) to afford a brown semi solid; 1H NMR 389.1753.
(400 MHz, CDCl3) δ 7.97–7.92 (m, 2H), 7.58–7.53 (m, 1H),
4-Benzoyl-8a-methyl-3-(4-(trifluoromethyl)phenyl)-3,4,4a,5-
7.48–7.42 (m, 2H), 7.33–7.26 (m, 2H), 7.26–7.18 (m, 3H), 6.62 tetrahydro-2H-chromen-6(8aH)-one (3e). Prepared according to
(ddd, J = 10.1, 2.4, 1.5 Hz, 1H), 6.55 (ddd, J = 10.4, 2.4, 1.5 Hz, the general procedure as described above in 63% yield
1H), 6.24–6.16 (m, 2H), 3.65–3.58 (m, 1H), 3.53–3.44 (m, 3H), (59 mg). It was purified by flash chromatography (20% EtOAc/
3.24 (dd, J = 16.6, 6.5 Hz, 1H), 1.31 (s, 3H); 13C NMR (126 MHz, hexanes; Rf = 0.5) to afford an orange solid; mp = 165–167 °C;
CDCl3) δ 198.7, 185.2, 151.8, 151.8, 141.9, 137.19, 133.1, 130.1, 1H NMR (400 MHz, CDCl3) δ 7.88–7.82 (m, 2H), 7.60–7.55 (m,
130.0, 128.6, 128.5, 128.1, 127.9, 126.9, 72.5, 69.4, 41.9, 41.4, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 17.4, 8.1 Hz, 4H),
26.2; HRMS (ESI) calcd for C23H22O3Na [M + Na]+: 369.1467; 6.66 (d, J = 10.0 Hz, 1H), 6.01 (dd, J = 10.0,0.7 Hz, 1H), 4.52
found: 369.1471.
(dd, J = 11.5, 4.4 Hz, 1H), 3.94 (dd, J = 11.8, 5.3 Hz, 1H), 3.82 (t,
4-Benzoyl-3-(4-chlorophenyl)-8a-methyl-3,4,4a,5-tetrahydro- J = 9.4 Hz, 1H), 3.73 (td, J = 11.6, 5.3 Hz, 1H), 2.86 (dd, J = 16.3,
2H-chromen-6(8aH)-one (3b). Prepared according to the 13.7 Hz, 1H), 2.52 (dt, J = 13.6, 4.2 Hz, 1H), 1.97 (ddd, J = 16.2,
general procedure as described above in 71% yield (40 mg). It 4.0, 0.7 Hz, 1H), 1.82 (s, 3H); 13C NMR (101 MHz, CDCl3)
was purified by flash chromatography (20% EtOAc/hexanes; Rf δ 198.6, 197.9, 150.3, 143.8, 135.5, 134.0, 132.2 (q, JCF
=
= 0.4) to afford a white solid; mp = 139–141 °C; 1H NMR 8.7 Hz), 129.3, 129.2 (q, JCF = 32.6 Hz), 128.4, 128.2, 126.9 (q,
(400 MHz, CDCl3) δ 7.85 (dt, J = 8.5, 1.6 Hz, 2H), 7.59–7.54 (m, JCF = 272.5 Hz), 125.8 (q, JCF = 3.4 Hz), 70.0, 66.0, 46.4, 38.7,
1H), 7.48–7.43 (m, 2H), 7.25–7.21 (m, 4H), 6.66 (d, J = 10.0 H z, 37.8, 35.2, 22.4; 19F NMR (CDCl3) δ −62.6 (s); HRMS (ESI) calcd
1H), 6.00 (dd, J = 10.0, 0.9 Hz, 1H), 4.46 (dd, J = 11.7, 4.4 Hz, for C24H22O3F3 [M + H]+: 415.1521; found: 415.1518.
1H), 3.91 (dd, J = 12.1, 5.6 Hz, 1H), 3.79 (t, J = 12.0 Hz, 1H),
Minor isomer of 3e (3e′). Prepared according to the general
3.64 (td, J = 11.8, 5.6 Hz, 1H), 2.86 (dd, J = 16.3, 13.7 Hz, 1H), procedure as described above in 8% yield (7.4 mg). It was puri-
2.49 (dt, J = 13.7, 4.2 Hz, 1H), 1.96 (ddd, J = 16.2, 4.02, 0.8 Hz, fied by flash chromatography (20% EtOAc/hexanes; Rf = 0.5) to
1H), 1.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.8, 197.9, afford a white solid; mp = 134–136 °C; 1H NMR (500 MHz,
150.4, 138.0, 135.6, 133.9, 133.0, 129.4, 129.2, 129.0, 128.2, CDCl3) δ 7.77 (dd, J = 8.3, 1.2 Hz, 2H), 7.63–7.59 (m, 1H), 7.48
69.9, 66.1, 46.5, 38.7, 37.2, 35.2, 22.4; HRMS (ESI) calcd for (dd, J = 10.7, 4.9 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.25 (dd, J =
C23H22O3Cl [M + H]+: 381.1257; found: 381.1256.
6.4, 2.3 Hz, 2H), 6.89 (dd, J = 10.4, 2.2 Hz, 1H), 6.19 (dd, J =
4-Benzoyl-8a-methyl-6-oxo-3,4,4a,5,6,8a-hexahydro-2H-chromen- 10.4, 1.2 Hz, 1H), 4.17 (dd, J = 12.0, 3.0 Hz, 1H), 4.06 (dd, J =
3-yl)benzoate (3c). Prepared according to the general procedure 12.0, 1.2 Hz, 1H), 4.02 (dd, J = 12.0, 5.4 Hz, 1H), 3.19–3.15 (m,
as described above in 89% yield (83 mg). It was purified by 1H), 3.07–3.01 (m, 1H), 2.75 (dd, J = 17.8, 5.2 Hz, 1H),
flash chromatography (30% EtOAc/hexanes; Rf = 0.3) to afford 2.33–2.28 (m, 1H), 1.72 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
1
an orange semi solid; H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 198.2, 197.3, 154.8, 143.6, 136.8, 133.8, 131.2, 129.7, 129.2,
8.3 Hz, 2H), 7.87–7.82 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, 128.3, 127.0(q, JCF = 286.9 Hz), 125.1 (q, JCF = 3.4 Hz), 74.2,
J = 7.7 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 10.0 Hz, 67.3, 47.2, 42.5, 39.9, 36.9, 29.8, 26.8; 19F NMR (CDCl3) δ −62.6
1H), 6.01 (dd, J = 10.0, 0.7 Hz, 1H), 4.54 (dd, J = 11.6, 4.4 Hz, (s); HRMS (ESI) calcd for C24H22O3F3 [M + H]+: 415.1521;
1H), 4.3 (q, J = 7.1 Hz, 2H), 3.94 (dd, J = 11.9, 5.5 Hz, 1H), 3.84 found: 415.1514.
(t, J = 11.8 Hz, 1H), 3.73 (td, J = 11.6, 5.5 Hz, 1H), 2.87 (dd, J =
4-Benzoyl-8a-methyl-3-(4-nitrophenyl)-3,4,4a,5-tetrahydro-2H-
16.3, 13.7 Hz, 1H), 2.51 (dt, J = 13.7, 4.2 Hz, 1H), 1.94 ((ddd, J = chromen-6(8aH)-one (3f). Prepared according to the general
16.3, 4.1, 0.7 Hz, 1H), 1.82 (s, 3H) 1.3 (t, J = 7.1 Hz, 3H); 13C procedure as described above in 69% yield (60 mg). It was puri-
NMR (101 MHz, CDCl3) δ 198.7, 197.9, 166.3, 150.3, 144.8, fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.3) to
135.6, 133.9, 130.1, 129.6, 129.2, 128.2, 128.1, 70.0, 66.0, 61.0, afford a yellow solid; mp = 203–205 °C; 1H NMR (400 MHz,
46.4, 38.6, 37.9, 35.2, 22.4, 14.4; HRMS (ESI) calcd for CDCl3) δ 8.15–8.10 (m, 2H), 7.84 (dt, J = 8.5, 1.6 Hz, 2H),
C26H27O5 [M + H]+: 419.1858; found: 419.1856.
7.61–7.55 (m, 1H), 7.51–7.43 (m, 4H), 6.66 (d, J = 10.0 Hz, 1H),
3-(4-Acetylphenyl)-4-benzoyl-8a-methyl-3,4,4a,5-tetrahydro-2H- 6.01 (dd, J = 10.0, 0.8 Hz, 1H), 4.52 (dd, J = 11.2, 4.4 Hz, 1H),
chromen-6(8aH)-one (3d). Prepared according to the general 3.95 (dd, J = 11.2, 4.8 Hz, 1H), 3.89–3.74 (m, 2H), 2.84 (dd, J =
procedure as described above in 83% yield (72 mg). It was puri- 16.3, 13.7 Hz, 1H), 2.55 (dt, J = 13.7, 4.2 Hz, 1H), 2.00–1.93
fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.4) to (ddd, J = 16.2, 4.08, 0.8 Hz, 1H), 1.83 (s, 3H); 13C NMR
afford a white solid; mp = 240–242 °C; 1H NMR (500 MHz, (101 MHz, CDCl3) δ 198.3, 197.7, 150.1, 147.4, 147.2, 135.3,
CDCl3) δ 7.88–7.83 (m, 4H), 7.59–7.54 (m, 1H), 7.45 (dd, J = 134.1, 129.3, 129.0, 128.2, 124.1, 70.1, 65.7, 46.7, 38.6, 38.0,
10.7, 4.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 10.0 Hz, 35.1, 22.4; HRMS (ESI) calcd for C23H22O5N [M + H]+:
1H), 6.01 (dd, J = 10.0, 0.6 Hz, 1H), 4.54 (dd, J = 11.6, 4.4 Hz, 392.1498; found: 392.1494.
1H), 3.94 (dd, J = 12.0, 5.5 Hz, 1H), 3.84 (t, J = 11.9 Hz, 1H),
Minor isomer of 3f (3f′). Prepared according to the general
3.73 (td, J = 11.7, 5.5 Hz, 1H), 2.87 (dd, J = 16.3, 13.7 Hz, 1H), procedure as described above in 9% yield (8 mg). It was puri-
2.53 (s, 3H), 2.50 (dt, J = 13.7, 7.9 Hz, 1H), 1.97 (ddd, J = 16.3, fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.3) to
1
4.0, 0.7 Hz, 1H), 1.82 (s, 3H); 13C NMR (126 MHz, CDCl3) δ afford a pale yellow semi solid; H NMR (400 MHz, CDCl3) δ
198.6, 197.9, 197.6, 150.3, 145.2, 136.2, 135.5, 133.9, 129.2, 8.07–8.02 (m, 2H), 7.80–7.76 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H),
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
7.50 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 35.2, 22.4, 16.0; HRMS (ESI) calcd for C24H25O3S [M + H]+:
10.4, 2.2 Hz, 1H), 6.20 (dd, J = 10.4, 1.0 Hz, 1H), 4.18 (dd, J = 393.1524; found: 393.1517.
12.2, 3.0 Hz, 1H), 4.07 (dd, J = 11.1, 0.9 Hz, 1H), 4.05 (dd, J =
(4-Benzoyl-3-(3-bromophenyl)-8a-methyl-3,4,4a,8a-tetrahydro-
12.1, 5.5 Hz, 1H), 3.25–3.19 (m, 1H), 3.02 (ddd, J = 9.9, 5.1, 2.5 2H-chromen-6(5H)-one (3j). Prepared according to the general
Hz, 1H), 2.76 (dd, J = 17.8, 5.2 Hz, 1H), 2.27 (dt, J = 17.8, 1.5 procedure as described above in 47% yield (30 mg). It was puri-
Hz, 1H), 1.73 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.04, fied by flash chromatography (20% EtOAc/hexanes; Rf = 0.5) to
197.05, 154.52, 147.25, 147.20, 136.59, 134.01, 131.25, 130.23, afford a pale yellow semi solid; 1H NMR (500 MHz, CDCl3)
129.33, 128.26, 123.36, 74.27, 66.87, 47.12, 42.49, 39.92, 36.95, δ 7.87–7.84 (m, 2H), 7.60–7.55 (m, 1H), 7.49–7.44 (m, 2H), 7.43
26.81; HRMS (ESI) calcd for C23H22NO5 [M + H]+: 392.1498; (t, J = 1.8 Hz, 1H), 7.33–7.30 (m, 1H), 7.26–7.22 (m, 1H), 7.14
found: 392.1497.
(t, J = 7.8 Hz, 1H), 6.66 (d, J = 10.0 Hz, 1H), 6.00 (dd, J = 10.0,
4-Benzoyl-3-(4-(tert-butyl)phenyl)-8a-methyl-3,4,4a,8a-tetra- 0.8 Hz, 1H), 4.46 (dd, J = 11.8, 4.5 Hz, 1H), 3.92 (dd, J = 12.1,
hydro-2H-chromen-6(5H)-one (3g). Prepared according to the 5.6 Hz, 1H), 3.80 (t, J = 12.0 Hz, 1H), 3.63 (td, J = 11.8, 5.5 Hz,
general procedure as described above in 85% yield (51 mg). It 1H), 2.84 (dd, J = 16.3, 13.7 Hz, 1H), 2.49 (dt, J = 13.7, 4.2 Hz,
was purified by flash chromatography (30% EtOAc/hexanes; 1H), 1.96 (ddd, J = 16.4, 4.1, 0.8 Hz, 1H), 1.81 (s, 3H); 13C NMR
Rf = 0.4) to afford a white solid mp = 215–217 °C; 1H NMR (126 MHz, CDCl3) δ 198.6, 197.7, 150.2, 141.9, 135.5, 133.8,
(400 MHz, CDCl3) δ 7.91–7.84 (m, 2H), 7.60–7.53 (m, 1H), 130.8, 130.4, 130.3, 129.1, 128.1, 126.9, 122.8, 69.8, 66.0, 46.3,
7.49–7.42 (m, 2H), 7.29–7.25 (m, 2H), 7.23–7.19 (m, 2H), 6.66 38.6, 37.4, 35.0, 22.3; HRMS (ESI) calcd for C23H22BrO3
(d, J = 10.0 Hz, 1H), 5.99 (dd, J = 10.0, 0.8 Hz, 1H), 4.52 (dd, J = [M + H]+: 425.0752; found: 425.0748.
11.7, 4.4 Hz, 1H), 3.94 (dd, J = 12.1, 5.6 Hz, 1H), 3.81 (t, J =
4-Benzoyl-3-(3-chlorophenyl)-8a-methyl-3,4,4a,8a-tetrahydro-
12.0 Hz, 1H), 3.64 (td, J = 11.8, 5.6 Hz, 1H), 2.89 (dd, J = 16.4, 2H-chromen-6(5H)-one (3k). Prepared according to the general
13.7 Hz, 1H), 2.47 (dt, J = 13.7, 4.2 Hz, 1H), 1.97 (ddd, J = 16.3, procedure as described above in 58% yield (49 mg). It was puri-
4.0, 0.8 Hz, 1H), 1.80 (s, 3H) 1.24 (s, 9H); 13C NMR (126 MHz, fied by flash chromatography (20% EtOAc/hexanes; Rf = 0.5) to
1
CDCl3) δ 198.9, 198.1, 150.5, 149.8, 136.1, 135.8, 133.5, 129.0, afford a colourless oil; H NMR (500 MHz, CDCl3) δ 7.88–7.84
128.1, 127.5, 125.6, 69.8, 66.4, 46.2, 38.6, 36.9, 35.2, 34.4, 31.3, (m, 2H), 7.60–7.55 (m, 1H), 7.46 (dd, J = 10.7, 4.8 Hz, 2H),
22.3; HRMS (ESI) calcd for C27H30NaO3 [M + Na]+: 425.2093; 7.28–7.26 (m, 1H), 7.22–7.12 (m, 3H), 6.66 (d, J = 10.0 Hz, 1H),
found: 425.2095.
6.00 (dd, J = 10.0, 0.8 Hz, 1H), 4.47 (dd, J = 11.7, 4.5 Hz, 1H),
3-([1,1′-Biphenyl]-4-yl)-4-benzoyl-8a-methyl-3,4,4a,5-tetrahydro- 3.93 (dd, J = 12.1, 5.6 Hz, 1H), 3.81 (t, J = 12.0 Hz, 1H), 3.64 (td,
2H-chromen-6(8aH)-one (3h). Prepared according to the general J = 11.8, 5.6 Hz, 1H), 2.85 (dd, J = 16.3, 13.7 Hz, 1H), 2.49 (dt,
procedure as described above in 79% yield (50 mg). It was puri- J = 13.6, 4.2 Hz, 1H), 1.96 (ddd, J = 16.4, 4.0, 0.8 Hz, 1H), 1.81
fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.5) to (s, 3H); 13C NMR (126 MHz, CDCl3) δ 198.6, 197.8, 150.2,
afford a white solid; mp = 216–218 °C; 1H NMR (400 MHz, 141.6, 135.5, 134.5, 133.8, 130.0, 129.1, 128.1, 127.9, 127.4,
CDCl3) δ 7.89 (d, J = 7.7 Hz, 2H), 7.59–7.54 (m, 1H), 7.53–7.43 126.4, 69.8, 66.0, 46.3, 38.6, 37.4, 35.1, 22.3; HRMS (ESI) calcd
(m, 6H), 7.39 (ddd, J = 8.2, 6.6, 3.1 Hz, 4H), 7.33–7.28 (m, 1H), for C23H22ClO3 [M + H]+: 381.1257; found: 381.1255.
6.68 (d, J = 10.0 Hz, 1H), 6.01 (d, J = 10.0 Hz, 1H), 4.57 (dd, J =
4-Benzoyl-3-(3-fluorophenyl)-8a-methyl-3,4,4a,8a-tetrahydro-
11.7, 4.4 Hz, 1H), 3.99 (dd, J = 12.0, 5.6 Hz, 1H), 3.87 (t, J = 2H-chromen-6(5H)-one (3l). Prepared according to the general
12.0 Hz, 1H), 3.72 (td, J = 11.8, 5.6 Hz, 1H), 2.92 (dd, J = 16.3, procedure as described above in 55% yield (44 mg). It was puri-
13.7 Hz, 1H), 2.51 (dt, J = 13.7, 4.2 Hz, 1H), 2.00 (dd, J = 16.3, fied by flash chromatography (20% EtOAc/hexanes; Rf = 0.5) to
4.0 Hz, 1H), 1.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.9, afford a white solid mp = 200–202 °C; 1H NMR (400 MHz,
198.2, 150.5, 140.8, 140.2, 138.5, 135.8, 133.7, 129.2, 128.8, CDCl3) δ 7.88–7.84 (m, 2H), 7.60–7.55 (m, 1H), 7.49–7.43 (m,
128.4, 128.2, 127.6, 127.4, 127.1, 70.0, 66.4, 46.4, 38.7, 37.3, 2H), 7.23 (dt, J = 14.0, 4.0 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H),
35.3, 22.4; HRMS (ESI) calcd for C29H27O3 [M + H]+: 423.1960; 7.02–6.97 (m, 1H), 6.87 (tdd, J = 8.5, 2.5, 0.9 Hz, 1H), 6.66 (d,
found: 423.1942.
J = 10.0 Hz, 1H), 6.00 (dd, J = 10.0, 0.8 Hz, 1H), 4.48 (dd, J =
4-Benzoyl-8a-methyl-3-(4-(methylthio)phenyl)-3,4,4a,5-tetra- 11.7, 4.4 Hz, 1H), 3.94 (dd, J = 12.0, 5.5 Hz, 1H), 3.81 (t, J =
hydro-2H-chromen-6(8aH)-one (3i). Prepared according to the 11.9 Hz, 1H), 3.67 (td, J = 11.7, 5.5 Hz, 1H), 2.86 (dd, J = 16.3,
general procedure as described above in 79% yield (45 mg). It 13.7 Hz, 1H), 2.49 (dt, J = 13.7, 4.2 Hz, 1H), 2.00–1.94 (ddd, J =
was purified by flash chromatography (20% EtOAc/hexanes; 16.3, 4.1, 0.8 Hz, 1H), 1.81 (s, 3H); 13C NMR (101 MHz, CDCl3)
Rf = 0.4) to afford a pale brown solid; mp = 214–216 °C; δ 198.6, 197.8, 162.9 (d, JCF = 246.4 Hz), 150.2, 142.0 (d, JCF
=
1H NMR (400 MHz, CDCl3) δ 7.87–7.83 (m, 2H), 7.59–7.54 (m, 6.4 Hz), 135.5, 133.7, 130.2 (d, JCF = 8.4 Hz), 129.1, 128.1, 123.8
1H), 7.48–7.42 (m, 2H), 7.24–7.20 (m, 2H), 7.17–7.13 (m, 2H), (d, JCF = 2.1 Hz), 114.7 (d, JCF = 21.5 Hz), 114.1 (d, JCF = 21.1
6.66 (d, J = 10.0 Hz, 1H), 6.00 (dd, J = 10.0, 0.8 Hz, 1H), 4.48 Hz), 69.9, 66.0, 46.3, 38.5, 37.4, 35.1, 22.29; 19F NMR (CDCl3)
(dd, J = 11.7, 4.4 Hz, 1H), 3.92 (dd, J = 12.1, 5.6 Hz, 1H), 3.80 (t, δ −112.6 (s); HRMS (ESI) calcd for C23H22FO3 [M + H]+:
J = 12.0 Hz, 1H), 3.62 (td, J = 11.8, 5.6 Hz, 1H), 2.87 (dd, J = 365.1553; found: 365.1552.
16.4, 13.7 Hz, 1H), 2.84 (dt, J = 13.6, 4.2 Hz, 1H), 2.41 (s, 3H),
4-Benzoyl-8a-methyl-6-oxo-3,4,4a,5,6,8a-hexahydro-2H-chromen-
1.96 (ddd, J = 16.4, 4.0, 0.8 Hz, 1H), 1.80 (s, 3H); 13C NMR 3-yl)-2-fluorobenzonitrile (3m). Prepared according to the
(101 MHz, CDCl3) δ 198.9, 198.0, 150.5, 137.2, 136.4, 135.8, general procedure as described above in 64% yield (56 mg). It
133.8, 129.2, 128.5, 128.2, 127.1, 69.9, 66.3, 46.5, 38.7, 37.2, was purified by flash chromatography (30% EtOAc/hexanes; Rf
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
= 0.4) to afford a white solid; mp = 175–177 °C; 1H NMR 5.6 Hz, 1H), 3.83–3.75 (m, 1H), 3.73 (s, 6H), 3.64–3.54 (m, 1H),
(400 MHz, CDCl3) δ 7.87–7.82 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 2.86 (dd, J = 16.3, 13.7 Hz, 1H), 2.46 (dt, J = 13.6, 4.1 Hz, 1H),
7.56–7.50 (m, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.23 (dd, J = 8.1, 1.5 1.97 (ddd, J = 16.3, 3.5, 0.7 Hz, 1H), 1.78 (s, 3H); 13C NMR
Hz, 1H), 7.17 (dd, J = 9.8, 1.4 Hz, 1H), 6.65 (d, J = 10.0 Hz, 1H), (126 MHz, CDCl3) δ 198.9, 198.1, 161.0, 150.5, 142.0, 135.8,
6.01 (d, J = 10.0 Hz, 1H), 4.43 (dd, J = 11.3, 4.4 Hz, 1H), 3.93 133.7, 129.2, 128.2, 106.5, 98.5, 70.0, 66.5, 55.4, 46.1, 38.6,
(dd, J = 11.6, 5.1 Hz, 1H), 3.80 (t, J = 11.6 Hz, 1H), 3.76–3.67 38.0, 35.3, 22.4; HRMS (ESI) calcd for C25H27O5 [M + H]+:
(m, 1H), 2.80 (dd, J = 16.2, 13.7 Hz, 1H), 2.54 (dt, J = 13.7, 4.2 407.1858; found: 407.1855.
Hz, 1H), 1.94 (dd, J = 16.2, 3.9 Hz, 1H), 1.81 (s, 3H); 13C NMR
4-Benzoyl-3-(2-methoxyphenyl)-8a-methyl-3,4,4a,5-tetrahydro-
(101 MHz, CDCl3) δ 198.2, 197.6, 163.3 (d, JCF = 259.6 Hz), 2H-chromen-6(8aH)-one (3q). Prepared according to the
150.0, 148.6 (d, JCF = 7.3 Hz), 135.1, 134.2, 133.8, 129.4, 129.3, general procedure as described above in 59% yield (50 mg). It
128.2 (d, JCF = 2.8 Hz), 124.8, 116.2 (d, JCF = 19.6 Hz), 113.8, was purified by flash chromatography (20% EtOAc/hexanes;
100.3 (d, JCF = 15.4 Hz), 70.1, 65.5, 46.6, 38.6, 38.2, 35.0, 22.41; Rf = 0.4) to afford a white solid; mp = 159–161 °C; 1H NMR
19F NMR (CDCl3)
C24H21O3NF [M + H]+: 390.1505; found: 390.1502.
δ
−105.7 (s); HRMS (ESI) calcd for (500 MHz, CDCl3) δ 7.86 (dd, J = 8.3, 1.1 Hz, 2H), 7.55 (ddd, J =
8.6, 2.4, 1.2 Hz, 1H), 7.44 (dd, J = 10.6, 4.8 Hz, 2H), 7.19 (dd,
3-(3-Acetylphenyl)-4-benzoyl-8a-methyl-3,4,4a,5-tetrahydro-2H- J = 7.7, 1.5 Hz, 1H), 7.17–7.12 (m, 1H), 6.86–6.82 (m, 2H), 6.66
chromen-6(8aH)-one (3n). Prepared according to the general (d, J = 10.0 Hz, 1H), 5.98 (dd, J = 10.0, 0.7 Hz, 1H), 4.95 (d, J =
procedure as described above in 81% yield (72 mg). It was puri- 6.0 Hz, 1H), 3.98–3.90 (m, 3H), 3.89 (s, 3H), 2.94 (dd, J = 16.4,
fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.4) to 13.7 Hz, 1H), 2.46 (dt, J = 13.6, 4.2 Hz, 1H), 1.97 (ddd, J = 16.4,
afford a white solid; mp = 229–231 °C; 1H NMR (400 MHz, 3.9, 0.7 Hz, 1H), 1.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
CDCl3) δ 7.91 (t, J = 1.7 Hz, 1H), 7.87–7.83 (m, 2H), 7.77–7.75 199.4, 198.7, 157.9, 150.8, 136.2, 133.5, 129.5, 129.1 (2C), 128.2
(m, 1H), 7.57–7.53 (m, 2H), 7.48–7.42 (m, 2H), 7.38 (dd, J = 9.6, (2C), 127.1, 121.1, 111.3, 70.0, 64.1, 55.6, 44.0, 39.0, 35.2, 34.1,
5.8 Hz, 1H), 6.67 (d, J = 10.0 Hz, 1H), 6.01 (dd, J = 10.0, 0.8 Hz, 22.4; HRMS (ESI) calcd for C24H25O4 [M + H]+: 377.1753;
1H), 4.55 (dd, J = 11.7, 4.4 Hz, 1H), 3.94 (dd, J = 12.0, 5.8 Hz, found: 377.1751.
1H), 3.86 (t, J = 11.9 Hz, 1H), 3.76–3.68 (m, 1H), 2.88 (dd, J =
4-Benzoyl-8a-methyl-3-(naphthalen-1-yl)-3,4,4a,5-tetrahydro-
16.3, 13.7 Hz, 1H), 2.56 (s, 3H), 2.51 (dt, J = 13.8, 4.4 Hz, 1H), 2H-chromen-6(8aH)-one (3r). Prepared according to the
1.97 (ddd, J = 16.3, 4.0, 0.8 Hz, 1H), 1.83 (s, 3H); 13C NMR general procedure as described above in 60% yield (35 mg). It
(101 MHz, CDCl3) δ 198.6, 198.1, 198.0, 150.3, 140.2, 137.4, was purified by flash chromatography (30% EtOAc/hexanes;
135.5, 133.7, 133.6, 129.1, 129.1, 129.0, 128.1, 127.6, 126.7, Rf = 0.5) to afford a white solid; mp = 230–232 °C; 1H NMR
69.9, 66.0, 46.5, 38.6, 37.6, 35.1, 26.7, 22.4; HRMS (ESI) calcd (500 MHz, CDCl3) δ 8.45 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 7.3 Hz,
for C25H24NaO4 [M + Na]+: 411.1572; found: 411.1574.
2H), 7.83 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 7.2, 2.0 Hz, 1H), 7.63
4-Benzoyl-3-(3-methoxyphenyl)-8a-methyl-3,4,4a,5-tetrahydro- (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.51 (td,
2H-chromen-6(8aH)-one (3o). Prepared according to the J = 7.2,0.7 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.34–7.29 (m, 2H),
general procedure as described above in 73% yield (62 mg). It 6.70 (d, J = 10.0, 1H), 6.04 (dd, J = 10.0, 0.7 Hz, 1H), 4.87 (dd,
was purified by flash chromatography (30% EtOAc/hexanes; J = 11.7, 4.4 Hz, 1H), 4.58 (td, J = 11.8, 5.2 Hz, 1H), 4.09 (dd, J =
1
Rf = 0.5) to afford a pale yellow semi solid; H NMR (500 MHz, 12.3, 5.2 Hz, 1H), 3.81 (t, J = 12.1 Hz, 1H), 3.09 (dd, J = 16.3,
CDCl3) δ 7.86 (dd, J = 8.3, 1.1 Hz, 2H), 7.59–7.53 (m, 1H), 13.7 Hz, 1H), 2.62 (dt, J = 13.7, 4.2 Hz, 1H), 2.07 (ddd, J = 16.3,
7.48–7.42 (m, 2H), 7.18 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.7 Hz, 4.0, 0.7 Hz, 1H), 1.86 (s, 3H); 13C NMR (101 MHz, CDCl3)
1H), 6.86–6.82 (m, 1H), 6.71 (ddd, J = 16.1, 6.4, 4.6 Hz, 1H), δ 198.9, 198.1, 150.5, 135.9, 135.8, 134.2, 133.8, 132.3, 129.2,
6.66 (d, J = 10.0 Hz, 1H), 5.99 (dd, J = 10.0, 0.7 Hz, 1H), 4.52 129.0, 128.3, 127.8, 126.7, 126.1, 125.2, 123.2, 122.5, 70.2, 66.4,
(dd, J = 11.8, 4.4 Hz, 1H), 3.94 (dd, J = 12.1, 5.6 Hz, 1H), 3.80 46.1, 39.2, 35.5, 32.1, 22.5; HRMS (ESI) calcd for C27H25O3
(ddd, J = 9.3, 7.1, 6.4 Hz, 1H), 3.76 (s, 3H), 3.64 (td, J = 11.8, 5.6 [M + H]+: 397.1804; found: 397.1800.
Hz, 1H), 2.88 (dd, J = 16.4, 13.7 Hz, 1H), 2.47 (dt, J = 13.6, 4.2
4-Benzoyl-8a-methyl-3-(thiophen-2-yl)-3,4,4a,5-tetrahydro-2H-
Hz, 1H), 1.98 (ddd, J = 16.4, 4.0, 0.7 Hz, 1H), 1.80 (s, 3H); 13C chromen-6(8aH)-one (3s). Prepared according to the general
NMR (101 MHz, CDCl3) δ 198.9, 198.1, 159.8, 150.5, 141.2, procedure as described above in 77% yield (61 mg). It was puri-
135.8, 133.7, 129.8, 129.2, 128.2, 120.3, 114.5, 112.0, 70.0, 66.5, fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.3) to
55.3, 46.3, 38.7, 37.7, 35.3, 22.4; HRMS (ESI) calcd for afford a white semi solid; 1H NMR (400 MHz, CDCl3) δ 7.88
C24H25O4 [M + H]+: 377.1753; found: 377.1746.
(dt, J = 8.5, 1.6 Hz, 2H), 7.59–7.54 (m, 1H), 7.49–7.43 (m, 2H),
4-Benzoyl-3-(3,5-dimethoxyphenyl)-8a-methyl-3,4,4a,8a-tetra- 7.10 (dd, J = 5.1, 1.2 Hz, 1H), 6.94 (dd, J = 3.5, 1.1 Hz, 1H),
hydro-2H-chromen-6(5H)-one (3p). Prepared according to the 6.90–6.87 (m, 1H), 6.65 (d, J = 10.0 Hz, 1H), 5.99 (dd, J = 10.0,
general procedure as described above in 74% yield (67 mg). It 0.9 Hz, 1H), 4.44–4.38 (m, 1H), 4.07–3.95 (m, 2H), 3.94–3.82
was purified by flash chromatography (30% EtOAc/hexanes; (m, 1H), 2.83 (dd, J = 16.4, 13.7 Hz, 1H), 2.43 (dt, J = 13.7,
Rf = 0.4) to afford a pale yellow solid; mp = 197–199 °C; 1H 4.2 Hz, 1H), 1.98 (ddd, J = 16.3, 4.0, 0.8 Hz, 1H), 1.78 (s, 3H);
NMR (400 MHz, CDCl3) δ 7.89–7.85 (m, 2H), 7.55 (dd, J = 10.5, 13C NMR (101 MHz, CDCl3) δ 198.7, 197.8, 150.4, 142.5, 135.8,
4.3 Hz, 1H), 7.49–7.42 (m, 2H), 6.65 (d, J = 10.0 Hz, 1H), 6.44 133.8, 129.2, 128.2, 127.1, 125.6, 123.7, 69.9, 66.6, 48.5, 38.6,
(d, J = 2.2 Hz, 2H), 6.27 (t, J = 2.2 Hz, 1H), 5.99 (dd, J = 10.0, 35.2, 33.1, 22.2; HRMS (ESI) calcd for C21H20O3NaS [M + Na]+:
0.6 Hz, 1H), 4.50 (dd, J = 11.8, 4.4 Hz, 1H), 3.94 (dd, J = 12.1, 375.1031; found: 375.1029.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
4-Benzoyl-3-(dibenzo[b,d]thiophen-4-yl)-8a-methyl-3,4,4a,5-tetra- 1H), 3.93 (dd, J = 12.2, 5.7 Hz, 1H), 3.82 (t, J = 12, 1H), 3.63
hydro-2H-chromen-6(8aH)-one (3t). Prepared according to the (ddd, J = 11.8, 8.7, 4.4 Hz, 1H), 2.88 (dd, J = 16.3, 13.7 Hz, 1H),
general procedure as described above in 65% yield (66 mg). It 2.42 (dt, J = 13.7, 4.2 Hz, 1H), 1.92 (ddd, J = 16.3, 4.0, 0.8 Hz,
was purified by flash chromatography (30% EtOAc/hexanes; 1H), 1.79 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.5, 197.4,
Rf = 0.3) to afford a pale yellow solid; mp = 286–288 °C; 150.4, 139.1, 138.5, 135.0 (q, JCF = 33.0 Hz), 129.2, 129.0, 128.5,
1H NMR (400 MHz, CDCl3) δ 8.11–8.07 (m, 1H), 7.99 (dd, J = 128.0, 127.5, 126.3 (q, JCF = 3.4 Hz), 123.5 (q, JCF = 273.0 Hz),
6.1, 2.9 Hz, 1H), 7.91–7.87 (m, 3H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 69.9, 66.3, 46.9, 38.5, 37.6, 35.2, 22.4; 19F NMR (CDCl3)
(dtd, J = 11.7, 7.3, 3.1 Hz, 4H), 7.39–7.33 (m, 2H), 6.70 (d, J = δ −63.26 (s); HRMS (ESI) calcd for C24H22O3F3 [M + H]+:
10.0 Hz, 1H), 6.04 (dd, J = 10.0, 0.7 Hz, 1H), 4.95 (s, 1H), 415.1521; found: 415.1523.
4.17–3.94 (m, 3H), 3.01 (dd, J = 16.3, 13.7 Hz, 1H), 2.59 (dt, J =
4-([1,1′-Biphenyl]-4-carbonyl)-8a-methyl-3-phenyl-3,4,4a,5-
13.7, 4.2 Hz, 1H), 2.08–2.01 (m, 1H), 1.90 (s, 3H); 13C NMR tetrahydro-2H-chromen-6(8aH)-one (3x). Prepared according
(101 MHz, CDCl3) δ 198.8, 197.9, 150.4, 139.0, 136.5, 135.9, to the general procedure as described above in 92% yield
135.6, 134.0, 133.7, 129.2, 129.2, 128.3, 127.1, 125.1, 124.6, (68 mg). It was purified by flash chromatography (20% EtOAc/
122.9, 121.7, 120.6, 70.1, 64.4, 45.4, 38.8, 37.6, 35.3, 22.6; hexanes; Rf = 0.4) to afford a pale yellow solid; mp =
HRMS (ESI) calcd for C29H25O3S [M + H]+: 453.1524; found: 227–229 °C; 1H NMR (400 MHz, CDCl3) δ 7.96–7.91 (m, 2H),
453.1522.
7.67–7.63 (m, 2H), 7.59–7.55 (m, 2H), 7.48–7.42 (m, 2H),
4-(4-Ethylbenzoyl)-8a-methyl-3-phenyl-3,4,4a,5-tetrahydro-2H- 7.42–7.36 (m, 1H), 7.34–7.29 (m, 2H), 7.29–7.23 (m, 2H),
chromen-6(8aH)-one (3u). Prepared according to the general 7.20–7.14 (m, 1H), 6.67 (d, J = 10.0, 1H), 6.00 (dd, J = 10.0,
procedure as described above in 60% yield (46 mg). It was puri- 0.6 Hz, 1H), 4.58 (dd, J = 11.7, 4.4 Hz, 1H), 3.95 (dd, J = 12.1,
fied by flash chromatography (20% EtOAc/hexanes; Rf = 0.4) to 5.7 Hz, 1H), 3.85 (t, J = 12.0 Hz, 1H), 3.68 (td, J = 11.8, 5.6 Hz,
afford a pale yellow semi solid; 1H NMR (400 MHz, CDCl3) 1H), 2.92 (dd, J = 16.4, 13.7 Hz, 1H), 2.53 (dt, J = 13.6, 4.1 Hz,
δ 7.81–7.77 (m, 2H), 7.32–7.26 (m, 4H), 7.26–7.23 (m, 2H), 1H), 2.06–1.99 (ddd, J = 16.4, 4.1, 0.8 Hz, 1H), 1.83 (s, 3H);
7.18–7.14 (m, 1H), 6.66 (d, J = 10.0 Hz, 1H), 5.99 (dd, J = 10.0, 13C NMR (101 MHz, CDCl3) δ 198.9, 197.6, 150.5, 146.4, 139.7,
0.9 Hz, 1H), 4.52 (dd, J = 11.7, 4.4 Hz, 1H), 3.94 (dd, J = 12.1, 139.5, 134.4, 129.1 (2C), 128.8 (2C), 128.5, 128.0, 127.8, 127.3,
5.6 Hz, 1H), 3.82 (t, J = 12.0 Hz, 1H), 3.72–3.61 (m, 1H), 2.88 127.2, 69.9, 66.4, 46.3, 38.7, 37.6, 35.3, 22.4; HRMS (ESI) calcd
(dd, J = 16.4, 13.7 Hz, 1H), 2.67 (q, J = 7.6 Hz, 2H), 2.48 (dt, J = for C29H27O3 [M + H]+: 423.1960; found: 423.1961.
13.6, 4.2 Hz, 1H), 1.98 (ddd, J = 16.3, 4.0, 0.8 Hz, 1H), 1.81 (s,
4-(3-Bromobenzoyl)-8a-methyl-3-phenyl-3,4,4a,5-tetrahydro-
3H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) 2H-chromen-6(8aH)-one (3y). Prepared according to the
δ 199.0, 197.5, 150.6, 150.4, 139.5, 133.4, 129.0, 128.7, 128.5, general procedure as described above in 65% yield (48 mg). It
128.3, 127.9, 127.1, 69.8, 66.4, 46.1, 38.7, 37.5, 35.2, 29.0, 22.3, was purified by flash chromatography (20% EtOAc/hexanes;
15.1; HRMS (ESI) calcd for C25H27O3 [M + H]+: 375.1960; Rf = 0.4) to afford a pale yellow semi solid; H NMR (500 MHz,
1
found: 375.1963.
CDCl3) δ 7.95 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J =
4-(4-(tert-Butyl)benzoyl)-8a-methyl-3-phenyl-3,4,4a,5-tetra- 7.8 Hz, 1H), 7.38–7.23 (m, 5H), 7.19 (d, J = 5.8 Hz, 1H), 6.67 (d,
hydro-2H-chromen-6(8aH)-one (3v). Prepared according to the J = 10.0 Hz, 1H), 6.01 (d, J = 10.0 Hz, 1H), 4.45 (dd, J = 11.7, 4.1
general procedure as described above in 61% yield (45 mg). It Hz, 1H), 3.94 (dd, J = 12.1, 5.5 Hz, 1H), 3.83 (t, J = 12.0 Hz,
was purified by flash chromatography (20% EtOAc/hexanes; 1H), 3.64 (td, J = 11.7, 5.6 Hz, 1H), 2.89 (dd, J = 15.7, 14.3 Hz,
Rf = 0.5) to afford a white semi solid; 1H NMR (400 MHz, 1H), 2.45 (dd, J = 9.8, 3.8 Hz, 1H), 1.94 (dd, J = 16.3, 3.5 Hz,
CDCl3) δ 7.83–7.78 (m, 2H), 7.48–7.43 (m, 2H), 7.31–7.26 (m, 1H), 1.81 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 198.7, 196.8,
3H), 7.25–7.23 (m, 1H), 7.19–7.14 (m, 1H), 6.66 (d, J = 10.0 Hz, 150.4, 139.2, 137.5, 136.6, 131.3, 130.7, 129.2, 128.9, 128.0,
1H), 5.99 (dd, J = 10.0, 0.8 Hz, 1H), 4.52 (dd, J = 11.7, 4.5 Hz, 127.4, 126.6, 123.6, 69.9, 66.3, 46.7, 38.6, 37.6, 35.3, 22.4;
1H), 3.94 (dd, J = 12.1, 5.7 Hz, 1H), 3.82 (t, J = 12.0 Hz, 1H), HRMS (ESI) calcd for C23H22O3Br [M + H]+: 425.0752; found:
3.69 (ddd, J = 16.4, 8.1, 3.7 Hz, 1H), 2.88 (dd, J = 16.4, 13.7 Hz, 425.0757.
1H), 2.50 (dt, J = 13.7, 4.2 Hz, 1H), 2.01–1.95 (ddd, J = 16.4, 4.1,
4-(3,4-Dichlorobenzoyl)-8a-methyl-3-phenyl-3,4,4a,5-tetrahydro-
0.8 Hz, 1H), 1.81 (s, 3H), 1.31 (s, 9H); 13C NMR (101 MHz, 2H-chromen-6(8aH)-one (3z). Prepared according to the general
CDCl3) δ 199.0, 197.4, 157.4, 150.4, 139.5, 133.1, 129.1, 128.7, procedure as described above in 68% yield (50 mg). It was puri-
128.1, 127.9, 127.1, 126.0, 69.8, 66.4, 46.1, 42.1, 38.7, 37.5, fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.6) to
35.2, 31.0, 22.3; HRMS (ESI) calcd for C27H31O3 [M + H]+: afford a pale pink semi solid; 1H NMR (500 MHz, CDCl3)
403.2273; found: 403.2277.
δ 7.89 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d,
8a-Methyl-3-phenyl-4-(4-(trifluoromethyl)benzoyl)-3,4,4a,5- J = 8.4 Hz, 1H), 7.27–7.25 (m, 4H), 7.21–7.16 (m, 1H), 6.66 (d,
tetrahydro-2H-chromen-6(8aH)-one (3w). Prepared according J = 10.0 Hz, 1H), 6.01 (dd, J = 10.0, 0.9 Hz, 1H), 4.41 (dd, J =
to the general procedure as described above in 67% yield 11.8, 4.4 Hz, 1H), 3.94 (dd, J = 12.2, 5.6 Hz, 1H), 3.82 (dd, J =
(49 mg). It was purified by flash chromatography (20% EtOAc/ 15.2, 8.9 Hz, 1H), 3.63 (td, J = 11.8, 5.6 Hz, 1H), 2.89 (dd, J =
hexanes; Rf = 0.4) to afford a colourless semi solid; 1H NMR 16.3, 13.7 Hz, 1H), 2.43 (dt, J = 13.7, 4.2 Hz, 1H), 1.92 (ddd, J =
(400 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.2 Hz, 16.3, 4.0, 0.8 Hz, 1H), 1.80 (s, 3H); 13C NMR (101 MHz, CDCl3)
2H), 7.27–7.22 (m, 4H), 7.19–7.14 (m, 1H), 6.65 (d, J = 10.0, Hz δ 198.5, 196.0, 150.4, 139.1, 138.5, 135.3, 134.0, 131.3, 130.2,
1H), 5.99 (dd, J = 10.0, 0.8 Hz, 1H), 4.50 (dd, J = 11.7, 4.4 Hz, 129.2, 129.0, 128.0, 127.5, 127.1, 69.9, 66.3, 46.7, 38.6, 37.7,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
35.3, 22.4; HRMS (ESI) calcd for C23H21O3Cl2 [M + H]+: (400 MHz, CDCl3) δ 7.89–7.84 (m, 2H), 7.59–7.51 (m, 1H), 7.44
415.0868; found: 415.0871. (t, J = 7.7 Hz, 2H), 7.32–7.27 (m, 3H), 7.26–7.23 (m, 1H),
4-(3,4-Dimethylbenzoyl)-8a-methyl-3-phenyl-3,4,4a,5-tetrahy- 7.19–7.14 (m, 1H), 6.86 (d, J = 10.2 Hz, 1H), 6.03 (dd, J = 10.0,
dro-2H-chromen-6(8aH)-one (3aa) (inseparable diastereomers). 0.7 Hz, 1H), 4.53 (dd, J = 11.6, 4.4 Hz, 1H), 3.96–3.84 (m, 3H),
Prepared according to the general procedure as described 3.80 (t, J = 11.9 Hz, 1H), 3.67 (td, J = 11.7, 5.5 Hz, 1H), 2.90 (dd,
above in 52% yield (39 mg). It was purified by flash chromato- J = 16.3, 13.6 Hz, 1H), 2.60 (dt, J = 13.7, 4.3 Hz, 1H), 2.48 (td,
graphy (20% EtOAc/hexanes; Rf = 0.3) to afford a brown semi J = 6.8, 3.6 Hz, 2H), 1.99 (dd, J = 16.0, 3.8 Hz, 1H), 0.91 (s, 9H),
solid; 1H NMR (400 MHz, CDCl3) δ 7.64–7.58 (m, 2H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 198.7,
7.31–7.26 (m, 3H), 7.25–7.23 (m, 1H), 7.20–7.13 (m, 2H), 6.66 198.2, 148.7, 139.4, 135.9, 133.5, 129.5, 129.0, 128.7, 128.1,
(d, J = 10.0, 1H), 5.99 (dd, J = 10.0, 0.8 Hz, 1H), 4.50 (dd, J = 127.9, 127.2, 71.3, 66.5, 58.6, 46.0, 37.3, 36.7, 36.6, 35.2, 26.0,
11.7, 4.4 Hz, 1H), 3.94 (dd, J = 12.0, 5.6 Hz, 1H), 3.82 (t, J = 18.4, −5.3; HRMS (ESI) calcd for C30H38NaSiO4 [M + Na]+:
12.0 Hz, 1H), 3.65 (ddd, J = 11.8, 8.7, 5.5 Hz, 1H), 2.87 (dd, J = 513.2437; found: 513.2451.
16.4, 13.7 Hz, 1H), 2.47 (dt, J = 13.7, 4.2 Hz, 1H), 2.29 (s, 3H),
4-Benzoyl-3-phenyloctahydrofuro[2,3-i]chromen-6(2H)-one (8).
2.28 (s, 3H), 1.98 (ddd, J = 16.3, 4.0, 0.8 Hz, 1H), 1.80 (s, 3H); To a stirred solution of silyl ether 3ab (20 mg, 0.04 mmol) in
13C NMR (101 MHz, CDCl3) δ 199.1, 197.9, 150.5, 143.4, 139.6, anhydrous THF (2 mL) was added TBAF (12 μL, 1.0 M in THF,
137.6, 133.8, 130.2, 129.5, 129.2, 128.8, 128.0, 127.2, 125.7, 0.04 mmol) at 0 °C and then stirred for 1 hour at room temp-
70.0, 66.5, 46.1, 38.9, 37.6, 35.3, 22.4, 20.2, 20.0; HRMS (ESI) erature. After completion of the reaction (monitored by TLC),
calcd for C25H27O3 [M + H]+: 375.1960; found: 375.1956.
the reaction solvent was evaporated in vacuo, and then the
4-Benzoyl-8a-ethyl-3-phenyl-3,4,4a,8a-tetrahydro-2H-chromen- residue was purified by flash column chromatography (40%
6(5H)-one (3ab). Prepared according to the general procedure EtOAc/hexane; Rf = 0.3) to give oxa-Michael product 8 (12 mg,
1
as described above in 61% yield (31 mg). It was purified by 80% yield) as a white semi solid; H NMR (500 MHz, CDCl3)
flash chromatography (30% EtOAc/hexanes; Rf = 0.4) to afford δ 7.89–7.82 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz,
a white solid; mp = 178–180 °C; 1H NMR (500 MHz, CDCl3) 2H), 7.26 (d, J = 0.6 Hz, 2H), 7.26–7.25 (m, 2H), 7.24–7.12 (m,
δ 7.89–7.81 (m, 2H), 7.59–7.52 (m, 1H), 7.46 (dt, J = 7.4, 6.5 Hz, 1H), 4.37 (dd, J = 11.1, 4.2 Hz, 1H), 4.06 (dtd, J = 11.6, 9.2,
2H), 7.31–7.26 (m, 3H), 7.26–7.24 (m,1H), 7.21–7.15 (m, 1H), 5.5 Hz, 4H), 3.74–3.62 (m, 2H), 2.78–2.69 (m, 2H), 2.57 (ddd,
6.72 (d, J = 10.2 Hz, 1H), 6.06 (dd, J = 10.2, 0.8 Hz, 1H), 4.50 J = 12.9, 7.8, 5.2 Hz, 1H), 2.51–2.41 (m, 2H), 2.37 (dt, J = 12.4,
(dd, J = 11.6, 4.4 Hz, 1H), 3.92 (dd, J = 12.0, 5.5 Hz, 1H), 3.77 (t, 7.5 Hz, 1H), 1.93 (ddd, J = 16.4, 4.1, 0.8 Hz, 1H); 13C NMR
J = 12.0 Hz, 1H), 3.67 (td, J = 11.8, 5.5 Hz, 1H), 2.92 (dd, J = (126 MHz, CDCl3) δ 208.5, 198.0, 139.3, 135.8, 133.8, 129.2,
16.3, 13.6 Hz, 1H), 2.55 (dt, J = 13.6, 4.2 Hz, 1H), 2.25(q J = 7.5 128.9, 128.2, 128.0, 127.4, 82.9, 81.4, 69.4, 66.1, 46.8, 42.3,
Hz, 2H), 1.99 (ddd, J = 16.3, 4.1, 0.8 Hz, 1H), 1.10 (t, J = 7.5 Hz, 37.9, 37.0, 34.2, 31.1; HRMS (ESI) calcd for C24H25O4 [M + H]+:
3H); 13C NMR (126 MHz, CDCl3) δ 198.9, 198.2, 148.6, 139.5, 377.1753; found: 377.1749.
135.8, 133.6, 130.2, 129.0, 128.7, 128.0, 127.9, 127.1, 72.2, 66.3,
45.9, 37.2, 35.8, 35.1, 26.2, 7.8; HRMS (ESI) calcd for
C24H24NaO3 [M + Na]+: 383.1623; found: 383.1628.
Conflicts of interest
4-Benzoyl-8a-isopropyl-3-phenyl-3,4,4a,8a-tetrahydro-2H-
chromen-6(5H)-one (3ac). Prepared according to the general
procedure as described above in 69% yield (35 mg). It was puri-
fied by flash chromatography (30% EtOAc/hexanes; Rf = 0.4) to
afford a white solid; mp = 189–191 °C; 1H NMR (400 MHz,
CDCl3) δ 7.86 (dd, J = 5.2, 3.3 Hz, 2H), 7.60–7.52 (m, 1H), 7.45
(dd, J = 10.5, 4.7 Hz, 2H), 7.33–7.26 (m, 3H), 7.26–7.23 (m, 1H),
7.20–7.14 (m, 1H), 6.76 (d, J = 10.3 Hz, 1H), 6.10 (d, J = 10.3
Hz, 1H), 4.52 (dd, J = 10.8, 4.5 Hz, 1H), 3.90 (dd, J = 9.8,
3.7 Hz, 1H), 3.71 (dd, J = 10.6, 4.5 Hz, 2H), 3.07 (dt, J = 13.7,
6.8 Hz, 1H), 2.99–2.90 (m, 1H), 2.75 (dt, J = 13.4, 4.1 Hz, 1H),
2.00 (ddd, J = 16.1, 4.0, 0.8 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H),
1.04 (d, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 198.0,
197.2, 144.5, 138.5, 134.7, 132.5, 130.3, 128.0, 127.7, 127.0,
126.9, 126.1, 73.3, 65.1, 44.5, 35.9, 34.3, 33.5, 26.5, 17.2, 14.1;
HRMS (ESI) calcd for C25H26O3Na [M + Na]+: 397.1780; found:
397.1775.
There are no conflicts to declare.
Acknowledgements
SBJ thanks the University Grants Commission, New Delhi and
SBT thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship. RB thanks SERB
and CSIR-IICT for financial support.
References
1 (a) B. M. Trost, F. D. Toste and A. B. Pinkerton, Chem. Rev.,
2001, 101, 2067–2096; (b) A. Alexakis, J. E. Bäckvall,
N. Krause, O. Pàmies and M. Diéguez, Chem. Rev., 2008,
108, 2796–2823; (c) J. T. Mohr, M. R. Krout and B. M. Stoltz,
Nature, 2008, 455, 323–332; (d) Q. Liu, R. Jackstell and
M. Beller, Angew. Chem., Int. Ed., 2013, 52, 13871–13873;
(e) T. Tsubogo, T. Ishiwata and S. Kobayashi, Angew. Chem.,
Int. Ed., 2013, 52, 6590–6604; (f) C. M. R. Volla,
I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114, 2390–
4-Benzoyl-8a-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-phenyl-
3,4,4a,8a-tetrahydro-2H-chromen-6(5H)-one (3ad). Prepared
according to the general procedure as described above in 70%
yield (16 mg). It was purified by flash chromatography (30%
EtOAc/hexanes; Rf = 0.3) to afford a yellow oil; 1H NMR
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
2431; (g) N. G. Schmidt, E. Eger and W. Kroutil, ACS Catal.,
2016, 6, 4286–4311.
Z.-T. He, N.-Y. Wu, P. Tian and G.-Q. Lin, J. Am. Chem. Soc.,
2014, 136, 15607–15614; (e) S. Kress, T. Johnson,
F. Weisshar and M. Lautens, ACS Catal., 2016, 6, 747–750.
6 For other transition metal catalyzed desymmetrization of
cyclohexadienones, see: (a) S.-Y. Cai, Z. Liu, W.-B. Zhang,
X.-Y. Zhao and D. Z. Wang, Angew. Chem., Int. Ed., 2011, 50,
11133–11137; (b) C. Clarke, C. A. Incerti-Pradillos and
H. W. Lam, J. Am. Chem. Soc., 2016, 138, 8068–8071;
(c) R. Kumar, Y. Hoshimoto, E. Tamai, M. Ohashi and
S. Ogoshi, Nat. Commun., 2017, 8, 32.
2 (a) W. Sun, G. Li, L. Hong and R. Wang, Org. Biomol.
Chem., 2016, 14, 2164–2176; (b) K. A. Kalstabakken and
A. M. Harned, Tetrahedron, 2014, 70, 9571–9585. For recent
review on enantioselective desymmetrization reactions, see:
(c) X.-P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou and J. Zhou,
Chem. Rev., 2016, 116, 7330–7396.
3 For Pd-catalyzed enantioselective desymmetrization of
cyclohexadienones to access cis-hydrobenzofuranones, see:
(a) K. Takenaka, S. C. Mohanta and H. Sasai, Angew. Chem.,
Int. Ed., 2014, 53, 4675–4679. For other Pd-catalyzed desym-
metrizations, see: (b) K. Kondo, M. Sodeoka, M. Mori and
M. Shibasaki, Tetrahedron Lett., 1993, 34, 4219–4222;
(c) R. Imbos, A. J. Minnaard and B. L. Feringa, J. Am. Chem.
Soc., 2002, 124, 184–185; (d) R. Tello-Aburto and
A. M. Harned, Org. Lett., 2009, 11, 3998–4000; (e) C. He,
C. Zhu, Z. Dai, C.-C. Tseng and H. Ding, Angew. Chem., Int.
Ed., 2013, 52, 13256–13260.
7 K. K. Gollapelli, S. Donikela, N. Manjula and R. Chegondi,
ACS Catal., 2018, 8, 1440–1447.
8 (a) A. S. Murthy, S. Donikela, C. S. Reddy and R. Chegondi,
J. Org. Chem., 2015, 80, 5566–5571; (b) S. Kallepu,
K. K. Gollapelli, J. B. Nanubolu and R. Chegondi, Chem.
Commun., 2015, 51, 16840–16843; (c) K. K. Gollapelli,
S. Kallepu, N. Govindappa, J. B. Nanubolu and
R. Chegondi, Chem. Sci., 2016, 7, 4748–4753;
(d) L. N. Chavan, K. K. Gollapelli, R. Chegondi and
A. B. Pawar, Org. Lett., 2017, 19, 2186–2189; (e) R. R. Anugu
and R. Chegondi, J. Org. Chem., 2017, 82, 6786–6794.
9 For selected examples of Rh-catalyzed enone conjugate
addition, see: (a) M. Sakai, H. Hayashi and N. Miyaura,
Organometallics, 1997, 16, 4229–4231; (b) Y. Takaya,
M. Ogasawara, T. Hayashi, M. Sakai and N. Miyaura, J. Am.
Chem. Soc., 1998, 120, 5579–5580; (c) Y. Takaya,
M. Ogasawara and T. Hayashi, Tetrahedron Lett., 1998, 39,
8479–8482; (d) S. Sakuma, M. Sakai, R. Itooka and
N. Miyaura, J. Org. Chem., 2000, 65, 5951–5955;
(e) S. Sakuma and N. Miyaura, J. Org. Chem., 2001, 66,
8944–8946; (f) T. Hayashi, M. Takahashi, Y. Takaya and
M. Ogasawara, J. Am. Chem. Soc., 2002, 124, 5052–5058;
(g) K. Yoshida, M. Ogasawara and T. Hayashi, J. Am. Chem.
Soc., 2002, 124, 10984–10985; (h) D. F. Cauble, J. D. Gipson
and M. J. Krische, J. Am. Chem. Soc., 2003, 125, 1110–1111;
(i) B. M. Bocknack, L.-C. Wang and M. J. Krische, Proc. Natl.
Acad. Sci. U. S. A., 2004, 101, 5421–5424.. For a review on
Rh-catalyzed enantioselective enone conjugate addition,
see: T. Hayashi, Synlett, 2001, 879–887.
4 For Cu-catalyzed enantioselective desymmetrization of
cyclohexadienones to access cis-hydrobenzofuranones, see:
(a) P. Liu, Y. Fukui, P. Tian, Z.-T. He, C.-Y. Sun, N.-Y. Wu
and G.-Q. Lin, J. Am. Chem. Soc., 2013, 135, 11700–11703;
(b) Z.-T. He, X.-Q. Tang, L.-B. Xie, M. Cheng, P. Tian and
G.-Q. Lin, Angew. Chem., Int. Ed., 2015, 54, 14815–14818.
For
other
Cu-catalyzed
desymmetrizations,
see:
(c) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and
A. H. M. de Vries, Angew. Chem., Int. Ed. Engl., 1997, 36,
2620–2623; (d) R. Imbos, M. H. G. Brilman, M. Pineschi
and B. L. Feringa, Org. Lett., 1999, 1, 623–626; (e) R. Imbos,
A. J. Minnaard and B. L. Feringa, Tetrahedron, 2001, 57,
2485–2489; (f) A. C. Meister, P. F. Sauter and S. Bräse,
Eur. J. Org. Chem., 2013, 7110–7116.
5 For Rh-catalyzed enantioselective desymmetrization of
cyclohexadienones to access cis-hydrobenzofuranones, see:
(a) J. Keilitz, S. G. Newman and M. Lautens, Org. Lett.,
2013, 15, 1148–1151; (b) Z.-T. He, B. Tian, Y. Fukui,
X. Tong, P. Tian and G.-Q. Lin, Angew. Chem., Int. Ed., 2013,
52, 5314–5318. For other Rh-catalyzed desymmetrizations,
see: (c) F. Guo, L. C. Konkol and R. J. Thomson, J. Am. 10 CCDC – 1866550‡ (compound 3t) contains the supplemen-
Chem. Soc., 2011, 133, 18–20; (d) Y. Fukui, P. Liu, Q. Liu,
tary crystallographic data for this paper.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018