Chemo- and Diastereoselective Michael-Michael-Acetalization Cascade for the Synthesis of 1,3-Indandione-Fused Spiro[4.5]decan Scaffolds

Article abstract of DOI:10.1021/acs.joc.7b01415

A novel, organobase-catalyzed and highly chemoselective Michael-Michael-acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons. Following this very simple protocol, a broad range of products was obtained in good yield

Full text of DOI:10.1021/acs.joc.7b01415

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Note
Chemo- and Diastereoselective Michael-Michael-Acetalization Cascade
for the Synthesis of 1,3-Indandione-fused Spiro[4.5]decan Scaffolds
Shu-Mei Yang, Yi-Ling Tsai, Ganapuram Madhusudhan Reddy, Lennart Möhlmann, and Wenwei Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01415 • Publication Date (Web): 31 Jul 2017
Downloaded from http://pubs.acs.org on August 4, 2017
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Chemo- and Diastereoselective Michael-Michael-Acetalization
Cascade for the Synthesis of 1,3-Indandione-fused Spiro[4.5]decan
Scaffolds
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Shu-Mei Yang,† Yi-Ling Tsai,† Ganapuram Madhusudhan Reddy, Lennart Möhlmann, and
Wenwei Lin*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan,
R.O.C.
*Tel.: +886-2-77346131. E-mail: wenweilin@ntnu.edu.tw
ABSTRACT: A novel, organobase-catalyzed and highly chemoselective Michael-Michael-
acetalization cascade is presented for the efficient synthesis of spiro-indandione skeletons.
Following this very simple protocol, a broad range of products could be obtained in good yields
with excellent diastereocontrol. The role of steric factors in acetalization step has been evaluated.
Due to their wide-spread occurrence in natural products, dyes and biologically active compounds,
spirocyclic-1,3-indandione derivatives are treated as structural motifs of significant synthetic
importance.1-5 Despite extensive efforts made towards synthesizing spirocyclic derivatives,6-8 the
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efficient construction of all-carbon spiro connections involving indandione scaffolds still persists
as a topic of interest for synthetic chemists.7,8
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One very elegant method for synthesis of such derivatives is the application of organocatalytic
tandem processes starting from readily available 2-arylidene-1,3-indandiones. These reaction
sequences generally utilize the ability of 2-arylidene-1,3-indandiones to act as potent Michael
acceptors which will, in case of a 1,4-addition, be transformed into 1,3 diketone nucleophiles that
can participate in additional transformations.8 The development of such tandem processes using
multifunctional substrates which feature both nucleophilic as well as electrophilic properties in
the same molecule has nowadays become a subject of interest in synthetic chemistry because it
allows an efficient and rapid synthesis of elaborated chemical structures without isolation of
intermediates.9,10 However, tuning the chemoselectivity is considered as a key factor in such
cascade reactions.11-13 The course of the reaction not only depends on relative reactivity of
multiple active sites, but also on reaction conditions which could alter the reactivity of particular
sites, and the stability of intermediates/products being formed. The reaction parameters and
inherent functional groups have to be tailored precisely in order to prevent unwanted side
reactions.
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Scheme 1. Envisaged chemoselective cascade for the
synthesis of spiro[4.5]decan indandione scaffolds.
Motivated by this challenge, we decided to investigate the possible chemoselective synthesis of
complex spiro[4.5]decan scaffolds via a base promoted Michael-Michael-acetalization cascade
using o-hydroxy-bearing 2-arylidene-1,3-indandione 1 and diketone 2 as two bifunctional
substrates (Scheme 1). We thereby envisaged the subsequent formation of three new bonds (two
C-C and one C-O bond) in a single reaction step with the generation of one quaternary and three
tertiary stereogenic centers. However, the fact that both substrates bear a Michael acceptor unit
as well as a nucleophilic site made the outcome of this proposed transformation uncertain.
Previously, few related methods have been designed for the synthesis of indandione-fused
spirocyclohexanones either via the L-proline-catalyzed Knoevenagel/Diels-Alder/epimerization
sequence of aldehydes, 1,3-indandione and methyl vinyl ketones7f,7g or the double Michael
addition of 2-arylidene indandiones and curcumins.8j However, presence of an additional o-
hydroxyl functionality on arylidene indandione makes the present work more challenging as it
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could assist in further acetalization of the initially formed cyclohexanone adducts resulting in
complex spiro[4.5]decan scaffolds.
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We started our investigations using 1a and 2a14 as model substrates in presence of 1 equiv of
cyclopentylamine with toluene as solvent to mimic the conditions that we used in our earlier
report (Table 1, entry 1).8a However, the reaction did not proceed and 2a could be completely
recovered, while 1a decomposed in the reaction. When DABCO was used, the reaction
proceeded smoothly and spiro adduct 3aa could be isolated in 80% yield (entry 2) remarkably as
a single diastereomer. After this promising result, further screening was performed in order to
find optimal reaction conditions for better results. At first, other bases were tested (entries 3-7).
Using the tertiary amines such as Et3N or N-methylmorpholine instead of DABCO led to reduced
yields of the product (entry 3 and 4). Surprisingly, use of DBU as a base resulted in complete
decomposition of substrate 1a without the formation of product (entry 5). When a secondary
amine such as piperidine was used, reaction did not proceed and starting materials could be
recovered after 48h (entry 6). Interestingly, an inorganic base such as Na2CO3 could also
promote the reaction (entry 7) albeit resulting in lower yield and longer reaction time as
compared to DABCO. Therefore, DABCO was the best choice to be used as a base for further
optimization.
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Table 1. Optimization of reaction conditionsa
entry
base
solvent
time (h)b yield (%)c
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1
CpNH2
Toluene
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14d
15e
DABCO
Et3N
NMM
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
Xylenes
THF
EtOAc
MeOH
EtOH
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3
6
7
2
2
80
55
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--
DBU
Piperidine
Na2CO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
--
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MeOH
MeOH
aUnless otherwise specified, all the reactions were carried
out using 1a (0.1 mmol), 2a (1.1 equiv) and base (1.0 equiv)
in the indicated solvent (0.5 mL) at 30 °C. Reaction time
indicates the time after which no further increase in the
b
c
yield of 3aa was observed. Yield of 3aa as determined by
1H NMR analysis of the crude reaction mixture using
d
Ph3CH as internal standard. 40 mol % DABCO was used.
e10 mol % DABCO was used. CpNH2=cyclopentylamine.
Next, different solvents were tested for their effect on the outcome of cascade reaction (entries 8-
13). Use of solvents such as DCM, xylenes, THF and ethyl acetate gave slightly lower yields
when compared to toluene. A slight improvement in the yield of 3aa could be observed when
MeOH or EtOH was used as solvent (entries 12 and 13). It is worthy to mention that the rate of
reaction was enhanced in polar solvents to some extent. This could be a result of keto-enol
tautomerism in 2a being influenced by the solvent used. It was promising to see that the reaction
underwent smoothly even under catalytic conditions without any drop in yield of 3aa, although
the reaction rate was significantly affected: use of 40 mol % DABCO required 12 h (entry 14),
while 10 mol % of it took 24 h to achieve full consumption of starting material 1a (entry 15).
The structure and relative configuration of 3aa was established by single-crystal X-ray analysis
(see supporting information).15
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With the optimized reaction conditions in hand, we were then interested in exploring the
substrate scope of this novel cascade reaction. Therefore, we first synthesized various new 2-
arylidene-1,3-indandione substrates 1 bearing additional substituents at meta or para positions
relative to the hydroxyl group and employed them for the cascade reaction. To our delight, all
these substrates were capable of undergoing the required transformation, albeit with varied
reactivities (Table 2, entries 2 to 4). Presence of an additional hydroxyl group reduced the
reactivity of substrate 1b and hence required the use of stoichiometric amount of DABCO to
achieve optimal yield of the product (entry 2). In contrast, a methoxy substituent in same
position (entry 3) did not have a major influence on its reactivity and the reaction rate was
slightly lowered as compared to that of unsubstituted substrate 1a. However, presence of the
methoxy group at meta position relative to existing hydroxyl group revealed a distinct steric
effect resulting in reduced reactivity and required the use of stoichiometric amount of DABCO to
achieve optimal conversion (entry 4).
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Table 2. Substrate scope for the cascade reactiona
entry R1/R2/R3
R4/R5
time (h) yield (%)b
1
H/H/H (1a)
H/H/OH (1b)
Ph/Ph (2a)
Ph/Ph (2a)
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82 (3aa)
82 (3ba)
77 (3ca)
83 (3da)
82 (3ea)
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67 (3ad)
2c
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H/H/OMe (1c) Ph/Ph (2a)
H/OMe/H (1d) Ph/Ph (2a)
H/H/Br (1e)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
4c
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Ph/Ph (2a)
p-OMePh/Ph (2b) 75.5
p-BrPh/Ph (2c)
p-ClPh/Ph (2d)
96
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H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
H/H/H (1a)
m-ClPh/Ph (2e)
o-ClPh/Ph (2f)
Ph/p-BrPh (2g)
Ph/o-BrPh (2h)
Ph/p-ClPh (2i)
Ph/m-ClPh (2j)
Ph/o-ClPh (2k)
Ph/p-OMePh (2l) 48
Ph/thienyl (2m)
Ph/i-Pr (2n)
24
24
72 (3ae)
72 (3af)
78 (3ag)
76 (4ah)d
82 (3ai)
73 (3aj)
77 (4ak)d
84 (3al)
71 (3am)
58 (4an)d
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aUnless otherwise specified, all the reactions were carried out
using 1 (0.1 mmol), 2 (1.1 equiv), and DABCO (10 mol %) in
MeOH (0.5 mL) at 30 °C. Isolated yields. 1.0 equiv of DABCO
was used. Double Michael addition product 4 was obtained (dr
b
c
d
>20:1).
We next tested the scope of various bifunctional substrates 2 featuring different R4 and R5
groups. Presence of an electron-donating (Table 2, entry 6) or electron-withdrawing group on the
para, meta or ortho position of the aryl group of R4 substitution (entries 7-10) resulted in
corresponding products in varied reaction times. Next, the effect of varying R5 substitutions on
the reaction outcome was investigated. In addition to aromatic substituents (entries 11-16), even
the heteroaromatic thienyl group (entry 17) was tolerated well and resulted in the product in
good yield. However, presence of an ortho substitution on aryl group of R5 (2h and 2k) resulted
in double Michael addition products 4ah and 4ak15 respectively without further acetalization
(entries 12 and 15). Likewise, even the presence of an aliphatic i-propyl substitution on R5
resulted in double Michael addition product 4an15 (entry 18) which indicated that steric factors
played an important role in the acetalization step. In these three cases, double Michael addition
adduct 4 existed in enolic form so as to reduce the steric repulsions between the arylidene group
on indandione and the acyl group, thereby leaving no possibility for further acetalization.
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To test the significance of o-hydroxy group in initial Michael addition steps, we carried out a
reaction using alkylidene indandione with hydroxy group masked (1f). The expected double
Michael addition product 4fa was obtained as a single diastereomer in good yield (Scheme 2).
This indicated that the free hydroxyl group in 1 would not play any role in controlling the
stereochemical outcome of initial double Michael addition.
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Scheme 2. Double Michael addition of 1f and 2a.
Scheme 3. Plausible mechanism for the formation of 3aa.
A plausible mechanism for the diastereoselective formation of 3aa is presented in scheme 3. An
initial deprotonation of 2a by base would result in the enolate which would undergo Michael
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addition on to 1a furnishing the intermediate I. This would subsequently result in a second
Michael addition generating the intermediate II. In case of 4ah, 4ak and 4an, intermediate II
was found to be stable in the enolic form15 to minimize the steric repulsions between the adjacent
aryl and acyl groups and the reaction terminated at this stage. However, in other cases,
intermediate II would transform into the more stable conformation III, which upon proton
transfer, acetalization and protonation would result in the cascade product 3.
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CONCLUSIONS:
In conclusion, we have developed a new Michael-Michael-acetalization cascade for the
diastereoselective synthesis of highly functionalized spiro[4.5]decan scaffolds by the
simultaneous formation of two C-C and one C-O bond and generation of four stereocenters. The
reaction is found to be highly chemo- and diastereoselective and formation of any unexpected
side products was not observed in spite of the presence of multiple reactive sites. The cascade
products are obtained in good yields with a broad range of substrates by using inexpensive
organic base (DABCO) as a catalyst. Spiro[4.5]decan scaffolds are found to have useful
biological properties and their functionalized derivatives could prove to be useful in drug
discovery.16 Studies towards developing an enantioselective format of this reaction and
evaluation of bioactivity of synthesized compounds are being carried out in our laboratory and
the results would be published in due course.
EXPERIMENTAL SECTION:
General experimental methods:
Analytical thin layer chromatography (TLC) was performed on pre-coated, alumina-backed
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silica gel plates (Merck 60 F254, 0.2 mm thickness) which were developed using UV irradiation
at 254 nm. Flash column chromatography was performed using silica gel (SiliCycle SiliaFlash
P60, 230-400 mesh). Melting points were measured on a Fargo melting point apparatus and are
uncorrected. IR spectra were recorded on a Perkin Elmer 500 spectrometer and only selected
peaks are mentioned. 1H NMR spectra were recorded on either a Bruker AV-400 spectrometer or
a Bruker AV-III HD-400 spectrometer. Chemical shifts are reported in δ ppm referenced to an
internal TMS standard (δ = 0.0 ppm) for 1H NMR, chloroform-d (δ = 77.00 ppm) for 13C NMR.
The following abbreviations (or combinations thereof) were used to explain the multiplicities: s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, td = triplet
of doublet, tt = triplet of triplet, qd = quartet of doublet, b = broad, p = pseudo. High resolution
mass spectra were recorded on JEOL MStation JMS-700 (2) using EI (Magnetic sector analyzer)
or on Waters Xevo G2-S Tof using ESI (TOF analyzer). The X-ray diffraction measurements
were carried out at 200 K on a Bruker KAPPA APEX II CCD area detector system equipped
with a graphite monochromator and a Mo-Kα fine-focus sealed tube (k = 0.71073 Å ).
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a) General procedure A for the synthesis of starting material 1:
A suspension of 1.1 mmol of aldehyde (finely powdered in case of solid aldehyde) in 18 mL of
water was rapidly stirred at 30 °C for 15 min. Then 1.0 mmol of finely powdered indan-1,3-
dione was added in one portion. The mixture was stirred at this temperature for 16 h and then
heated in an oil bath maintained at 80 °C for 4 h. The reaction mixture was then cooled and
filtered. The filter cake was washed with EtOH until it was clear of any residual starting
materials (determined by 1H NMR analysis) and dried under vacuum to give the pure product 1.
2-(2-hydroxybenzylidene)-1H-indene-1,3(2H)-dione (1a):17 Following the general procedure
A, 1a was obtained from 2-hydroxybenzaldehyde in 83% yield (207.7 mg) as an orange solid.
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mp.: 198.6-199.3 °C; H NMR (400 MHz, CDCl3) δ/ppm: 9.63 (brs, 1H), 8.11-8.01 (m, 3H),
5
6
7.93-7.81 (m, 3H), 7.49 (td, J = 7.7, 1.2 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 7.6 Hz,
7
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1H).
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2-(2,5-dihydroxybenzylidene)-1H-indene-1,3(2H)-dione (1b): Following the general
procedure A, 1b was obtained from 2,5-dihydroxybenzaldehyde in 42% yield (118.8 mg) as an
orange solid. Rf 0.08 (ethyl acetate/hexanes: 1/3); mp.: 242.8-243.2 °C; 1H NMR (400 MHz, d6-
DMSO) δ/ppm: 10.22 (s, 1H), 9.13 (s, 1H), 8.40 (d, J = 3.0 Hz, 1H), 8.29 (s, 1H), 8.00-7.88 (m,
13
4H), 6.97 (dd, J = 8.8, 3.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H); C NMR (100 MHz, d6-DMSO)
δ/ppm: 190.0, 188.9, 153.7, 149.3, 141.8, 140.2, 139.3, 135.7, 135.5, 126.6, 124.7, 122.8, 120.2,
117.6, 116.6; IR (KBr) ṽ (cm−1): 3432 (s), 1637 (m); HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C16H9O4 265.0501; Found: 265.0500.
2-(2-hydroxy-5-methoxybenzylidene)-1H-indene-1,3(2H)-dione (1c): Following the general
procedure A, 1c was obtained from 2-hydroxy-5-methoxybenzaldehyde in 96% yield (269.1 mg)
as an orange solid. Rf 0.23 (ethyl acetate/hexanes: 1/3); mp.: 219.7-220.5 °C; 1H NMR (400
MHz, d-acetone, 25 oC) δ/ppm: 9.27 (s, 1H), 8.86 (d, J = 3.1 Hz, 1H), 8.51 (s, 1H), 8.08-7.92 (m,
4H), 7.10 (dd, J = 8.9, 3.1 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H); 13C NMR (100 MHz,
o
d-acetone, 25 C) δ/ppm: 190.7, 190.2, 155.2, 153.5, 143.4, 141.1, 140.9, 136.3, 136.2, 128.4,
124.9, 123.8, 123.7, 121.6, 117.8, 116.6, 56.1; IR (KBr) ṽ (cm−1): 3299 (m), 3125 (w), 2959 (w),
1719 (m), 1671 (s), 1581 (s), 1498 (m), 1168 (w), 816 (w), 739 (m); HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C17H11O4 279.0657; Found: 279.0658.
2-(2-hydroxy-4-methoxybenzylidene)-1H-indene-1,3(2H)-dione (1d): Following the general
procedure A, 1d was obtained from 2-hydroxy-4-methoxybenzaldehyde in 95% yield (266.3 mg)
1
as a yellow solid. Rf 0.13 (ethyl acetate/hexanes: 1/3); mp.: 245.6-246.3 °C; H NMR (400 MHz,
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d6-DMSO) δ/ppm: 11.1 (s, 1H), 9.10 (d, J = 9.0 Hz, 1H), 8.26 (s, 1H), 7.92-7.77 (m, 4H), 6.55 (d,
J = 9.0 Hz, 1H), 6.50 (s, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ/ppm: 190.3, 189.1,
166.3, 162.9, 141.5, 139.8, 139.1, 135.4, 135.3, 135.1, 123.7, 122.53, 122.47, 114.1, 107.0, 100.2,
55.6; IR (KBr) ṽ (cm−1): 3434 (s), 1637 (m); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C17H11O4
279.0657; Found: 279.0657.
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2-(5-bromo-2-hydroxybenzylidene)-1H-indene-1,3(2H)-dione (1e): Following the general
procedure A, 1e was obtained from 2-hydroxy-5-bromobenzaldehyde in 77% yield (253.4 mg) as
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a yellow solid. Rf 0.75 (ethyl acetate/hexanes: 1/2); mp.: 227.5-227.9 °C; H NMR (400 MHz,
d6-DMSO) δ/ppm: 11.2 (s, 1H), 9.10 (d, J = 2.5 Hz, 1H), 8.16 (s, 1H), 8.01-7.89 (m, 4H), 7.58
(dd, J = 8.8, 2.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ/ppm:
189.5, 188.9, 159.0, 141.9, 139.4, 137.8, 137.8, 135.9, 135.8, 134.7, 128.2, 123.1, 123.0, 121.6,
118.2, 110.0; IR (KBr) ṽ (cm−1): 3167 (m), 1681 (s), 1585 (m), 1392 (m), 1352 (m), 1221 (m),
812 (w), 733 (m); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C16H8O3Br 326.9657; Found:
326.9655.
b) General procedure B for the synthesis of 1f:6a
A mixture of 1,3-indanedione (292 mg, 2.0 mmol, 1.0 equiv), aldehyde (100 mg, 2.2 mmol, 1.1
equiv) and L-proline (70 mg, 30 mol %) in MeOH (4.0 mL) was stirred at room temperature for
12 h. The precipitate was then filtered-off, sequentially washed with MeOH (10.0 mL), and dried
in vacuo to afford the condensation product 1f.
2-(2-methoxybenzylidene)-1H-indene-1,3(2H)-dione (1f):
Following the general procedure B, 1f was obtained from 2-methoxybenzaldehyde in 89% yield
(470.4 mg) as a yellow solid; Rf 0.5 (ethyl acetate/hexanes: 1/5); mp.: 168.2-169.9 °C; 1H NMR
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(400 MHz, CDCl3) δ/ppm: 8.91 (dd, J = 7.9, 1.5 Hz, 1H), 8.52 (s, 1H), 8.04-7.97 (m, 2H), 7.84-
7.78 (m, 2H), 7.54 (td, J = 7.6, 1.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H),
3.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ/ppm: 190.5, 189.2, 160.5, 142.3, 141.3, 140.0,
135.3, 135.1, 134.9, 133.9, 128.2, 123.12, 123.10, 122.0, 120.3, 110.6, 55.7; IR (KBr) ṽ (cm−1):
3431 (s), 1620 (m), 1239 (w), 735 (w); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H13O3
265.0865; Found: 265.0867.
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c) General procedure C for the synthesis of starting material 2:18
o
To a stirred solution of LDA (12.5 mL, 2.0 M in THF) in anhydrous THF at -78 C under N2
atmosphere was added a solution of corresponding ketone (10.0 mmol) dissolved in THF (10.0
mL). The mixture was stirred at -78 oC for 30 min. Then the acid chloride (1.1 equiv) was added
drop-wise to the reaction mixture and stirred for another 30 min. Then the solution was poured
into aqueous hydrochloric acid (1N). The aqueous phase was extracted with ethyl acetate (3 x 10
mL) and the combined organic layers were washed successively with brine and water. Following
drying over anhydrous MgSO4, the volatile components were removed under reduced pressure.
The residue was purified by column chromatography to give the desired product 2.
(1Z,4E)-1-hydroxy-1,5-diphenylpenta-1,4-dien-3-one (2a): Following the general procedure C,
2a was obtained from benzylacetone and benzoyl chloride in 62% yield (1.550 g) as a yellow
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solid. Rf 0.61 (ethyl acetate/hexanes: 1/10); mp.: 110.9-111.1 °C; H NMR (400 MHz, CDCl3)
δ/ppm: 16.20 (brs, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.67 (d, J = 15.8 Hz, 1H), 7.58-7.47 (m, 3H),
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7.45 (t, J = 7.7 Hz, 2H), 7.39-7.29 (m, 3H), 6.61 (d, J = 15.8 Hz, 1H), 6.32 (s, 1H); C NMR
(100 MHz, CDCl3) δ/ppm: 189.2, 179.4, 139.9, 136.1, 134.9, 132.5, 129.9, 128.8, 128.5, 127.9,
127.3, 123.3, 97.6; MS (70eV, EI) m/z (%): 250 [M]+ (50), 145 (60), 115 (35), 105 (90), 103 (40),
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77 (100); IR (KBr) ṽ (cm−1): 3436 (s), 1630 (m), 1277 (w), 977 (w), 764 (m), 692 (m), 686 (m);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15O2 251.1072; Found: 251.1073.
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(1Z,4E)-1-hydroxy-5-(4-methoxyphenyl)-1-phenylpenta-1,4-dien-3-one (2b): Following the
general procedure C, 2b was obtained from (E)-4-(4-methoxyphenyl)but-3-en-2-one and benzoyl
chloride in 45% yield (1.260 g) as a yellow solid. Rf 0.46 (ethyl acetate/hexanes: 1/10); mp.:
122.5-123.4 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 16.30 (brs, 1H), 7.94 (dd, J = 8.5, 1.1 Hz,
2H), 7.65 (d, J = 15.8 Hz, 1H), 7.58-7.41 (m, 5H), 6.92 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 15.8 Hz,
1H), 6.31 (s, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ/ppm: 188.4, 180.5, 161.2, 139.9,
136.2, 132.3, 129.7, 128.6, 127.7, 127.2, 121.0, 114.4, 97.2, 55.3; MS (70eV, EI) m/z (%): 280
[M]+ (30), 203 (3), 185 (10), 175 (100), 161 (30), 105 (50), 77 (52), 69 (25); IR (KBr) ṽ (cm−1):
3448 (m), 3055 (w), 2930 (w), 1623 (s), 1601 (s), 1524 (s), 1262 (s), 822 (s); HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H17O3 281.1178; Found: 281.1178.
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(1Z,4E)-5-(4-bromophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3-one (2c): Following the
general procedure C, 2c was obtained from (E)-4-(4-bromophenyl)but-3-en-2-one and benzoyl
chloride in 30% yield (0.982 g) as a yellow solid. Rf 0.73 (ethyl acetate/hexanes: 1/10); mp.:
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162.0-163.0 °C; H NMR (400 MHz, CDCl3) δ/ppm: 16.09 (brs, 1H), 7.95 (d, J = 7.8 Hz, 2H),
7.61 (d, J = 15.8 Hz, 1H), 7.58-7.45 (m, 5H), 7.41 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 15.8 Hz, 1H),
6.34 (s 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 189.7, 178.7, 138.5, 136.2, 134.0, 132.7,
132.1, 129.3, 128.7, 127.4, 124.1, 124.0, 97.9; MS (70eV, EI) m/z (%): 328 [M]+ (30), 330
[M+2]+ (30), 173 (20), 144 (70), 105 (100), 77 (45); IR (KBr) ṽ (cm−1): 3448 (w), 3048 (w),
1631 (s), 1546 (s), 1402 (m), 1278 (m), 1072 (m), 822 (s); HRMS (EI-MS) m/z: [M]+ Calcd for
C17H13O2Br 328.0099; Found: 328.0099.
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(1Z,4E)-5-(4-chlorophenyl)-1-hydroxy-1-phenylpenta-1,4-dien-3-one (2d): Following the
general procedure C, 2d was obtained from (E)-4-(4-chlorophenyl)but-3-en-2-one and benzoyl
chloride in 41% yield (1.171 g) as a yellow solid. Rf 0.73 (ethyl acetate/hexanes: 1/10); mp.:
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157.8-158.5 °C; H NMR (400 MHz, CDCl3) δ/ppm: 16.09 (brs, 1H), 7.95 (d, J = 7.7 Hz, 2H),
7.63 (d, J = 15.8 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.53-7.46 (m, 4H), 7.37 (d, J = 8.4 Hz, 2H),
6.62 (d, J = 15.8 Hz, 1H), 6.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 189.6, 178.8, 138.5,
136.2, 135.8, 133.6, 132.7, 129.2, 129.1, 128.7, 127.4, 123.9, 97.9; MS (70eV, EI) m/z (%): 284
[M]+ (50), 286 [M]+ (25),179 (50), 165 (52), 144 (40), 105 (100), 77 (50), 69 (46); IR (KBr) ṽ
(cm−1): 3449 (s), 3048 (w), 1635 (s), 1587 (s), 1274 (m), 1083 (m), 758 (m); HRMS (ESI-TOF)
m/z: [M-H]+ Calcd for C17H12O2Cl 283.0526; Found: 283.0520.
(1Z,4E)-5-(3-chlorophenyl)-1-Hydroxy-1-phenylpenta-1,4-dien-3-one (2e): Following the
general procedure C, 2e was obtained from (E)-4-(3-chlorophenyl)but-3-en-2-one and
benzoylchloride in 55% yield (1.813 g) as a yellow solid. Rf 0.65 (ethyl acetate/hexanes: 1/10);
mp.: 125.6-126.3 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 16.05 (brs, 1H), 7.96 (d, J = 7.5 Hz,
2H), 7.60 (d, J = 15.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.45-7.39 (m, 1H),
7.36-7.31 (m, 2H), 6.64 (d, J = 15.8 Hz, 1H), 6.35 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm:
190.0, 178.3, 138.1, 137.0, 136.2, 134.9, 132.7, 130.1, 129.7, 128.6, 127.5, 127.4, 126.2, 124.6,
98.0; IR (KBr) ṽ (cm−1): 3442 (s), 1638 (m), 691 (w); HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C17H1235ClO2 283.0526; Found: 283.0527 and m/z: [M-H]- Calcd for C17H1237ClO2 285.0496;
Found: 285.0504.
(1Z,4E)-5-(2-chlorophenyl)-1-Hydroxy-1-phenylpenta-1,4-dien-3-one (2f): Following the
general procedure C, 2f was obtained from (E)-4-(2-chlorophenyl)but-3-en-2-one and benzoyl
chloride in 11% yield (0.360 g) as a yellow solid. Rf 0.59 (ethyl acetate/hexanes: 1/10); mp.:
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99.8-100.1 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 16.03 (brs, 1H), 8.09 (d, J = 15.8 Hz, 1H),
7.96 (d, J = 7.4 Hz, 2H), 7.70-7.64 (m, 1H), 7.56 (t, J = 7.2 Hz,1H), 7.49 (t, J = 7.7 Hz, 2H),
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MHz, CDCl3) δ/ppm: 190.0, 178.4, 136.2, 135.6, 135.0, 133.3, 132.7, 130.6, 130.2, 128.6, 127.4,
127.0, 125.8, 97.9; IR (KBr) ṽ (cm−1): 3460 (s), 1634 (s), 764 (m); HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C17H1235ClO2 283.0526; Found: 283.0525 and m/z: [M-H]- Calcd for C17H1237ClO2
285.0496; Found: 285.0497.
(1Z,4E)-1-(4-bromophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3-one (2g): Following the
general procedure C, 2g was obtained from benzylacetone and 4-bromobenzoyl chloride in 41%
yield (1.354 g) as a brown colored solid. Rf 0.63 (ethyl acetate/hexanes: 1/10); mp.: 153.5-154.1
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°C; H NMR (400 MHz, CDCl3) δ/ppm: 16.08 (brs, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.72 (d, J =
15.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 7.5, 1.5 Hz, 2H), 7.47-7.37 (m, 3H), 6.67 (d,
J = 15.8 Hz, 1H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 188.0, 179.8, 140.5, 135.2,
135.0, 131.9, 130.1, 128.9, 128.8, 128.1, 127.4, 123.2, 128.29, 97.4; MS (70eV, EI) m/z (%): 328
[M]+ (30), 330 [M+2]+ (30), 251 (20), 185 (60), 145 (100), 115 (70), 77 (90); IR (KBr) ṽ (cm−1):
3448 (m), 3055 (w), 1588 (s), 1447 (s), 1280 (m), 781 (s); HRMS (ESI-TOF) m/z: [M-H]- Calcd
for C17H12O2Br 327.0021; Found: 327.0017.
(1Z,4E)-1-(2-bromophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3-one (2h): Following the
general procedure C, 2h was obtained from benzylacetone and 2-bromobenzoyl chloride in 16%
yield (526.7 mg) as a yellow solid. Rf 0.61 (ethyl acetate/hexanes: 1/10); mp.: 80.6-81.2 °C; 1H
NMR (400 MHz, CDCl3) δ/ppm: 15.41 (brs, 1H), 7.70 (d, J = 15.8 Hz, 1H), 7.65 (dd, J = 7.9,
0.9 Hz, 1H), 7.58-7.52 (m, 3H), 7.44-7.35 (m, 4H), 7.30 (td, J = 7.7, 1.7 Hz, 1H), 6.59 (d, J =
15.8 Hz, 1H), 6.12 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 192.4, 177.9, 140.6, 139.3,
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134.9, 133.8, 131.6, 130.1, 129.7, 129.0, 128.1, 127.4, 122.7, 119.8, 102.2; IR (KBr) ṽ (cm−1):
3698 (w), 1635 (s), 1582 (s), 660 (w); HRMS (EI-MS) m/z: [M]+ Calcd for C17H1379BrO2
328.0099; Found: 328.0098 and m/z: [M]+ Calcd for C17H1381BrO2 330.0078; Found: 330.0079.
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(1Z,4E)-1-(4-chlorophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3-one (2i): Following the
general procedure C, 2i was obtained from benzylacetone and 4-chlorobenzoyl chloride in 40%
yield (1.141 g) as a yellow solid. Rf 0.69 (ethyl acetate/hexanes: 1/10); mp.: 139.0-139.8 °C; 1H
NMR (400 MHz, CDCl3) δ/ppm: 16.08 (brs, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 15.8 Hz,
1H), 7.56-7.50 (m, 2H), 7.42 (d, J =8.5 Hz, 2H), 7.40-7.31 (m, 3H), 6.61 (d, J = 15.8 Hz, 1H),
6.27 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 188.0, 180.6, 140.4, 138.8, 135.0, 134.7,
130.1, 128.9, 128.7, 128.0, 123.1, 97.4; MS (70eV, EI) m/z (%): 284 [M]+ (60), 145 (100), 131
(60), 77 (90), 69 (55); IR (KBr) ṽ (cm−1): 3430 (w), 3048 (w), 1638 (s), 1584 (s), 1447 (s), 1278
(m), 1076 (m), 780 (s); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C17H12O2Cl 283.0526; Found:
283.0521.
(1Z,4E)-1-(3-chlorophenyl)-1-hydroxy-5-phenylpenta-1,4-dien-3-one (2j): Following the
general procedure C, 2j was obtained from benzylacetone and 3-chlorobenzoyl chloride in 41%
yield (1.172 g) as a yellow solid. Rf 0.66 (ethyl acetate/hexanes: 1/10); mp.: 120.1-121.3 °C; 1H
NMR (400 MHz, CDCl3) δ/ppm: 16.01 (brs, 1H), 7.93 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.71 (d,
J = 15.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.46-7.36 (m, 4H), 6.65 (d, J =
15.8 Hz, 1H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 187.6, 179.8, 140.6, 138.0,
134.8, 132.3, 130.1, 129.8, 128.9, 128.0, 127.4, 125.3, 123.0, 97.6; IR (KBr) ṽ (cm−1): 3609 (w),
1634 (s), 1582 (s), 766 (m); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C17H1235ClO2 283.0526;
Found: 283.0526 and m/z: [M-H]- Calcd for C17H1237ClO2 285.0496; Found: 285.0500.
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(1Z,4E)-1-(2-chlorophenyl)-1-Hydroxy-5-phenylpenta-1,4-dien-3-one (2k): Following the
general procedure C, 2k was obtained from benzylacetone and 2-chlorobenzoyl chloride in 40%
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yield (1.142 g) as a yellow solid. Rf 0.63 (ethyl acetate/hexanes: 1/10); mp.: 74.5-75.3 °C; H
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NMR (400 MHz, CDCl3) δ/ppm: 15.55 (s, 1H), 7.70 (d, J = 15.8 Hz, 1H), 7.62 (dd, J = 7.3, 1.9
Hz, 1H), 7.56 (dd, J = 7.8, 2.3 Hz, 2H), 7.48-7.32 (m, 6H), 6.6 (d, J = 15.8 Hz, 1H), 6.19 (s, 1H);
13C NMR (100 MHz, CDCl3) δ/ppm: 191.0, 178.4, 140.6, 137.1, 135.0, 131.7, 131.6, 130.7,
130.1, 130.0, 129.0, 128.1, 127.0, 122.9, 102.4; IR (KBr) ṽ (cm−1): 3696 (w), 1634 (s), 1580 (s),
766 (m); HRMS (EI-MS) m/z: [M]+ Calcd for C17H1335ClO2 284.0604; Found: 284.0605 and
m/z: [M]+ Calcd for C17H1337ClO2 286.0575; Found: 286.0586.
(1Z,4E)-1-hydroxy-1-(4-methoxyphenyl)-5-phenylpenta-1,4-dien-3-one (2l): Following the
general procedure C, 2l was obtained from benzylacetone and 4-methoxybenzoyl chloride in
43% yield (1.211 g) as a yellow solid. Rf 0.39 (ethyl acetate/hexanes: 1/10); mp.: 120.0-120.9 °C;
1H NMR (400 MHz, CDCl3) δ/ppm: 16.23 (brs, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 15.8
Hz, 1H), 7.58 (d, J = 6.7 Hz, 2H), 7.48-7.35 (m, 3H) 6.99 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 15.8
13
Hz, 1H), 6.31 (s, 1H), 3.90 (s, 3H); C NMR (100 MHz, CDCl3) δ/ppm: 189.2, 178.0, 163.4,
139.3, 135.3, 129.8, 129.5, 129.1, 128.9, 127.9, 123.5, 114.0, 97.2, 55.5; MS (70eV, EI) m/z (%):
280 [M]+ (10), 135 (100), 121 (40), 103 (45), 77 (75), 69 (30); IR (KBr) ṽ (cm−1): 3412 (s), 2959
(w), 1627 (s), 1602 (s), 1447 (m), 1260 (s), 792 (s); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C18H17O3 281.1178; Found: 281.1180.
(1Z,4E)-1-hydroxy-5-phenyl-1-(thiophen-2-yl)penta-1,4-dien-3-one (2m): Following the
general procedure C, 2m was obtained from benzylacetone and 2-thiophenecarbonyl chloride in
39% yield (0.991 g) as a yellow solid. Rf 0.48 (ethyl acetate/hexanes: 1/10); mp.: 110.2-112.1
°C; 1H NMR (400 MHz, CDCl3) δ/ppm: 15.34 (brs, 1H), 7.74 (d, J = 3.6 Hz, 1H), 7.66-7.59 (m,
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2H), 7.54 (d, J = 6.6 Hz, 2H), 7.44-7.32 (m, 3H), 7.14 (t, J = 4.2 Hz, 1H), 6.58 (d, J = 15.8 Hz,
1H), 6.17 (s, 1H); 13C NMR (100 MHz, CDCl3) δ/ppm: 184.9, 175.5, 143.1, 139.4, 135.1, 132.9,
130.4, 129.9, 128.9, 128.3, 127.9, 122.4, 97.9; MS (70eV, EI) m/z (%): 256 [M]+ (60), 153 (8),
145 (40), 131 (35), 111 (100), 84 (45), 77 (70), 69 (50), 51 (20); IR (KBr) ṽ (cm−1): 3436 (m),
3077 (m), 1630 (s), 1580 (s), 1438 (s), 1281 (s), 694 (s); HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C15H13O2S 257.0636; Found: 257.0630.
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(1E,4Z)-5-hydroxy-6-methyl-1-phenylhepta-1,4-dien-3-one (2n): Following the general
procedure C, 2n was obtained from benzylacetone and isobutyryl chloride in 20% yield (432.5
mg) as an orange colored sticky semi-solid. Rf 0.72 (ethyl acetate/hexanes: 1/10); 1H NMR (400
MHz, CDCl3) δ/ppm: 15.46 (brs, 1H), 7.58 (d, J = 15.8 Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 2H),
7.40-7.30 (m, 3H), 6.49 (d, J = 15.8 Hz, 1H), 5.66 (s, 1H), 2.57 (sept, J = 6.9 Hz, 1H), 1.17 (d, J
13
= 6.9 Hz, 6H); C NMR (100 MHz, CDCl3) δ/ppm: 205.0, 177.2, 139.3, 135.0, 129.7, 128.8,
127.8, 122.9, 98.8, 38.3, 19.1; MS (70eV, EI) m/z (%): 216 [M]+ (40), 173 (100), 155 (10), 131
(30), 91 (6), 77 (17), 69 (5); IR (KBr) ṽ (cm−1): 3702 (w), 2969 (s), 1585 (s), 1440 (s), 1128 (s),
693 (m); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H17O2 217.1229; Found: 217.1225.
d) General procedure D for the synthesis of Michael-Michael cascade products 4 and
Michael-Michael-acetalization cascade products 3:
To a solution of DABCO (1.1 mg, 0.01 mmol) and 2-arylideneindane-1,3-dione 1 (0.1 mmol) in
0.5 mL of methanol was added α,β-unsaturated-1,3-diketone 2 (0.11 mmol) at 30 °C and the
resulting mixture was stirred at this temperature until the completion of reaction (monitored by
1H NMR). Then the solvent was removed under reduced pressure and the residue was purified by
column chromatography to give the desired product 3.
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11-benzoyl-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-methanobenzo[b]oxocine-5,2'-
indene]-1',3'-dione (3aa): Following the general procedure D, 3aa was obtained from 1a and 2a
in 82% yield (41.0 mg) as a yellow solid. Rf 0.18 (ethyl acetate/hexanes: 1/5); mp.: 210.6-211.7
°C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.96 (d, J = 7.5 Hz, 1H), 7.78-7.67 (m, 3H), 7.56 (dd, J
= 8.3, 1.2 Hz, 2H), 7.47 (tt, J = 7.4, 1.2 Hz, 1H), 7.37-7.27 (m, 3H), 7.07-6.93 (m, 6H), 6.74 (td,
J = 7.4, 1.0 Hz, 1H), 6.31 (dd, J = 7.6, 1.5 Hz, 1H), 5.31 (1, 1H), 5.25 (d, J = 2.5 Hz, 1H), 3.59
(dd, J = 13.7, 4.6 Hz, 1H), 3.34 (d, J = 2.5 Hz, 1H), 3.22 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7,
4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 200.7, 198.0, 156.3, 141.4, 140.5,
137.6, 136.1, 135.8, 135.7, 133.2, 130.6, 130.1, 128.9, 128.8, 128.2, 127.9, 127.3, 123.3, 123.1,
119.6, 116.2, 115.9, 98.9, 60.6, 45.1, 44.6, 41.6, 41.2; MS (70 eV, EI) m/z (%): 500 [M]+ (15),
248 (45), 105 (100), 77 (55); IR (KBr) ṽ (cm−1): 3474 (s), 3055 (w), 1700 (s), 1228 (s), 753 (m);
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H24O5Na 523.1521; Found: 523.1517.
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11-benzoyl-2,8-dihydroxy-4-phenyl-2,3,4,6-tetrahydrospiro
[2,6-methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ba): Following the general procedure
D, 3ba was obtained from 1b and 2a in 82% yield (42.4 mg) as a brown solid; Rf 0.58 (ethyl
acetate/hexanes: 1/3); mp.: 211.4-212.2 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.96 (d, J = 7.4
Hz, 1H), 7.79-7.67 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.6 Hz,
1H), 7.04-6.94 (m, 5H), 6.92 (d, J = 8.7 Hz, 1H), 6.78 (dd, J = 8.8, 2.8 Hz, 1H), 5.82 (d, J = 2.6
Hz, 1H), 5.26 (brs, 1H), 5.88 (d, J = 1.8 Hz, 1H), 4.48 (s, 1H), 3.60 (dd, J = 13.7, 4.5 Hz, 1H),
3.26 (s, 1H), 3.19 (t, J = 13.7 Hz, 1H), 2.41 (dd, J = 13.5, 4.5 Hz, 1H); 13C NMR (125 MHz, d-
acetone) δ/ppm: 204.4, 199.4, 199.0, 151.0, 150.6, 142.5, 141.5, 139.4, 137.3, 136.9, 133.9,
129.8, 129.6, 129.0, 128.8, 128.1, 124.0, 123.8, 118.5, 118.1, 117.4, 116.2, 99.0, 61.5, 45.4, 45.0,
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43.9, 42.2; IR (KBr) ṽ (cm−1): 3398 (s), 2930 (w), 1699 (s), 1219 (s), 1051 (w), 707 (m), 492 (w);
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H24O6Na 539.1471; Found: 539.1476.
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methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ca): Following the general procedure D,
3ca was obtained from 1c and 2a in 77% yield (40.8 mg) as a yellow solid. Rf 0.13 (ethyl
acetate/hexanes: 1/3); mp.: 195.7-196.8 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.96 (d, J = 7.5
Hz, 1H), 7.77-7.68 (m, 3H), 7.57 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.7 Hz,
2H), 7.02-6.96 (m, 6H), 6.87 (dd, J = 8.8, 2.9 Hz, 1H), 5.85 (d, J = 2.9 Hz, 1H), 5.37-5.16 (m,
2H), 3.65-3.58 (m, 4H), 3.29 (d, J = 2.2 Hz, 1H), 3.20 (t, J = 13.7 Hz, 1H), 2.42 (dd, J = 13.6,
4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 200.6, 197.9, 152.4, 150.5, 141.4,
140.4, 137.7, 136.1, 135.8, 135.7, 133.2, 128.9, 128.8, 128.2, 127.9, 127.3, 123.3, 123.1, 116.8,
116.2, 115.9, 115.6, 98.7, 60.5, 55.7, 45.1, 44.7, 41.6, 41.3; IR (KBr) ṽ (cm−1): 3458 (s), 2932
(w), 1686 (m), 1222 (m), 1052 (w), 699 (w), 494 (w); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C34H26O6Na 553.1627; Found: 553.1626.
11-benzoyl-2-hydroxy-9-methoxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-Indene]-1',3'-dione (3da): Following the general procedure D,
3da was obtained from 1d and 2a in 83% yield (44.0 mg) as a brown solid; Rf 0.2 (ethyl
acetate/hexanes: 1/3); mp.: 203.3-204.3 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.96 (d, J = 7.4
Hz, 1H), 7.79-7.67 (m, 3H), 7.56 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.7 Hz,
2H), 7.05-6.94 (m, 5H), 6.60 (d, J = 2.4 Hz, 1H), 6.33 (dd, J = 8.4, 2.4 Hz, 1H), 6.20 (d, J = 8.4
Hz, 1H), 5.34 (brs, 1H), 5.19 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.29 (t, J = 2.2 Hz, 1H), 2.42 (d, J
= 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 200.6, 197.9, 152.4, 150.5,
141.4, 140.4, 137.7, 136.1, 135.8, 135.7, 133.2, 128.9, 128.8, 128.2, 127.9, 127.3, 123.2, 123.1,
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116.8, 116.2, 115.9, 115.6, 98.7, 60.5, 55.7, 45.0, 44.7, 41.6; IR (KBr) ṽ (cm−1): 3465 (s), 2930
(w), 1696 (s), 1619 (s), 1197 (m), 1108 (m), 1036 (m), 700 (m), 576 (m), 500 (w); HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C34H26O6Na 553.1627; Found: 553.1622.
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11-benzoyl-8-bromo-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ea): Following the general procedure D,
3ea was obtained from 1e and 2a in 82% yield (47.5 mg) as a white solid; Rf 0.75 (ethyl
acetate/hexanes: 1/2); mp.: 230.6-231.3 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.95 (d, J = 7.9
Hz, 1H), 7.78-7.66 (m, 3H), 7.59 (d, J = 7.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.36 (t, J = 7.4 Hz,
3H), 7.03-6.90 (m, 6H), 6.47 (s, 1H), 5.30 (s, 1H), 5.25 (s, 1H), 3.54 (dd, J = 13.6, 3.9 Hz, 1H),
13
3.31 (s, 1H), 3.20 (t, J = 13.8 Hz, 1H), 2.43 (dd, J = 13.8, 4.5 Hz, 1H); C NMR (125 MHz,
CDCl3) δ/ppm:203.2, 200.3, 197.8, 155.4, 141.3, 140.4, 137.2, 136.3, 135.9, 135.3, 133.5,
132.91, 132.87, 128.9, 128.8, 128.3, 128.0, 127.5, 123.4, 123.1, 118.4, 117.7, 111.5, 99.1, 60.1,
44.6, 43.9, 41.4, 41.3; IR (KBr) ṽ (cm−1): 3482 (m), 1698 (s), 1668 (m), 1265 (m), 1237 (m), 704
(m), 593 (m); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H23O5BrNa 601.0627; Found:
601.0621.
11-benzoyl-2-hydroxy-4-(4-methoxyphenyl)-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ab): Following the general procedure D,
3ab was obtained from 1a and 2b in 72% yield (38.2 mg) as a yellow solid. Rf 0.33 (ethyl
acetate/hexanes: 1/3); mp.: 210.7-211.3 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.97 (d, J = 7.5
Hz, 1H), 7.80-7.68 (m, 3H), 7.55 (d, J =7.4 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.37-7.26 (m, 3H),
7.04 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 8.7 Hz,2H), 6.74 (t, J = 7.4 Hz, 1H), 6.54 (d, J = 8.7 Hz,
2H), 6.31 (dd, J = 7.6, 1.0 Hz, 1H), 5.30 (s, 1H), 5.22 (d, J = 2.4 Hz, 1H), 3.61 (s, 3H), 3.54 (dd,
J = 13.7, 4.6 Hz, 1H), 3.31 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.41 (dd, J = 13.7, 4.6
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Hz, 1H); C NMR (125 MHz, CDCl3) δ/ppm: 203.5, 200.7, 198.2, 158.5, 156.3, 141.4, 140.5,
136.1, 135.8, 135.7, 133.2, 130.6, 130.0, 129.9, 129.7, 128.8, 127.9, 123.3, 123.1, 119.5, 116.2,
115.9, 113.6, 98.9, 60.8, 55.0, 45.0, 44.5, 41.9, 40.2; IR (KBr) ṽ (cm−1): 3505 (s), 2932 (m),
1698 (s), 1595 (m), 1273 (s), 1253 (s), 1051 (s), 1036 (m), 752 (s), 576 (m); HRMS (EI-MS)
m/z: [M]+ Calcd for C34H26O6 530.1729; Found: 530.1727.
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11-benzoyl-4-(4-bromophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ac): Following the general procedure D,
3ac was obtained from 1a and 2c in 72% yield (41.7 mg) as a yellow solid. Rf 0.2 (ethyl
acetate/hexanes: 1/5); mp.: 196.9-198.1 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 8.00 (d, J = 7.5
Hz, 1H), 7.84-7.73 (m, 3H), 7.54 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.37-7.26 (m, 3H),
7.15 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.75 (t, J = 7.5 Hz,
1H), 6.29 (d, J = 7.5 Hz, 1H), 5.28 (brs, 1H), 5.16 (d, J = 2.3 Hz, 1H), 3.54 (dd, J = 13.7, 4.5 Hz,
13
1H), 3.32 (d, J = 2.0 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.40 (dd, J = 13.7, 4.5 Hz, 1H); C
NMR (125 MHz, CDCl3) δ/ppm: 203.1, 200.4, 197.7, 156.2, 141.2, 140.2, 136.8, 136.4, 136.1,
135.5, 133.3, 131.4, 130.7, 130.6, 130.2, 128.8, 127.8, 123.5, 123.3, 121.4, 119.7, 115.9, 98.6,
60.6, 44.9, 44.7, 41.5, 40.2; IR (KBr) ṽ (cm−1): 3462 (s), 2927 (w), 1699 (s), 1597 (m), 1231 (s),
1053 (m), 754 (m), 576 (w); HRMS (EI-MS) m/z: [M]+ Calcd for C33H23BrO5 578.0729; Found:
578.0735.
11-benzoyl-4-(4-chlorophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ad): Following the general procedure D,
3ad was obtained from 1a and 2d in 67% yield (35.8 mg) as a yellow solid. Rf 0.25 (ethyl
acetate/hexanes: 1/3); mp.: 206.0-207.1 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.99 (d, J = 7.4
Hz, 1H), 7.83-7.73 (m, 3H), 7.54 (d, J = 8.1 Hz, 2H), 7.47 (t, J =7.5 Hz, 1H), 7.36-7.26 (m, 3H),
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7.06-6.94 (m, 5H), 6.74 (t, J = 7.4 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.30 (s, 1H), 5.17 (d, J =
1.8 Hz, 1H), 3.56 (dd, J = 13.8, 4.5 Hz, 1H), 3.32 (s, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.41 (dd, J =
13.5, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.1, 200.5, 197.7, 156.2, 141.26,
141.29, 136.4, 136.3, 136.1, 135.6, 133.3, 133.2, 130.6, 130.4, 130.2, 128.8, 128.4, 127.9, 123.4,
123.3, 119.7, 116.0, 115.9, 98.7, 60.7, 45.0, 44.7, 41.6, 40.2; IR (KBr) ṽ (cm−1): 3504 (s), 2928
(w), 1699 (s), 1270 (m), 1231 (s), 1053 (m), 746 (m), 576 (m); HRMS (EI-MS) m/z: [M]+ Calcd
for C33H23ClO5 534.1234; Found: 534.1235.
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methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ae): Following the general procedure D,
3ae was obtained from 1a and 2e in 72% yield (38.5 mg) as a white solid. Rf 0.13 (ethyl
acetate/hexanes: 1/5); mp.: 184.2-185.1 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 8.01 (d, J = 7.4
Hz, 1H), 7.74-7.65 (m, 3H), 7.55 (d, J = 7.4 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.28-7.18 (m, 3H),
7.04 (d, J = 8.6 Hz, 2H), 6.97-6.84 (m, 3H), 6.75 (t, J = 7.4 Hz, 1H), 6.31 (d, J = 7.4 Hz, 1H),
5.29 (s, 1H), 5.19 (d, J = 2.2 Hz, 1H), 3.55 (dd, J = 13.7, 4.6 Hz, 1H), 3.34 (s, 1H), 3.17 (t, J =
13
13.7 Hz, 1H), 2.42 (dd, J = 13.7, 4.6 Hz d, 1H); C NMR (125 MHz, CDCl3) δ/ppm: 202.9,
200.5, 197.6, 156.2, 141.2, 140.3, 139.8, 136.4, 136.0, 135.6, 134.0, 133.3, 130.6, 130.2, 129.5,
129.2, 128.8, 127.9, 127.6, 127.1, 123.4, 123.3, 119.7, 115.9, 98.6, 60.5, 44.9, 44.6, 41.5, 40.6;
IR (KBr) ṽ (cm−1): 3448 (s), 2926 (w), 1677 (m), 1232 (m), 756 (w); HRMS (EI-MS) m/z: [M]+
Calcd for C33H23ClO5 534.1234; Found: 534.1230.
11-benzoyl-4-(2-chlorophenyl)-2-hydroxy-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3af): Following the general procedure D,
3af was obtained from 1a and 2f in 72% yield (38.5 mg) as a white solid. Rf 0.28 (ethyl
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acetate/hexanes: 1/3); mp.: 219.3-220.2 °C; H NMR (400 MHz, CDCl3) δ/ppm: 8.11 (dd, J =
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7.7, 0.7 Hz, 1H), 7.86-7.60 (m, 1H), 7.78-7.72 (m, 2H), 7.56 (dd, J = 8.1, 1.0 Hz, 2H), 7.48 (tt, J
= 7.4, 1.2 Hz, 1H), 7.37-7.26 (m, 3H), 7.21-7.13 (m, 2H), 7.07 (dd, J = 8.3, 0.7 Hz, 1H), 6.96-
6.89 (m, 2H), 6.74 (dt, J = 7.4, 1.0 Hz, 1H), 6.29 (dd, J = 7.6, 1.5 Hz, 1H), 5.28-5.25 (m, 2H),
4.38 (dd, J = 13.6, 4.5 Hz, 1H), 3.35 (d, J = 2.3 Hz, 1H), 2.98 (t, J = 13.6 Hz, 1H), 2.40 (dd, J =
13.6, 4.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 204.3, 200.7, 196.4, 156.4, 141.2, 140.6,
136.4, 136.1, 135.9, 135.6, 134.4, 133.2, 130.5, 130.3, 130.2, 128.8, 128.6, 128.3, 127.9, 126.7,
123.5, 123.3, 119.7, 115.74, 115.69, 98.5, 59.8, 45.2, 44.9, 42.6, 36.6; IR (KBr) ṽ (cm−1): 3449
(s), 2932 (w), 1684 (s), 1228 (s), 1107 (m), 1054 (m), 754 (m), 583 (w); HRMS (EI-MS) m/z:
[M]+ Calcd for C33H23ClO5 534.1234; Found: 534.1230.
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11-(4-bromobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ag): Following the general procedure D,
3ag was obtained from 1a and 2g in 78% yield (45.2 mg) as a yellow solid. Rf 0.2 (ethyl
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acetate/hexanes: 1/12); mp.: 185.8-186.7 °C; H NMR (400 MHz, CDCl3) δ/ppm: 7.94 (d, J =
7.5 Hz, 1H), 7.77-7.69 (m, 3H), 7.49-7.41 (m, 4H), 7.32-7.26 (m, 1H), 7.05-6.94 (m, 6H), 6.75
(td, J = 7.4, 1.0 Hz, 1H), 6.33 (dd, J = 7.5, 1.8 Hz, 1H), 5.36-5.01 (m, 2H), 3.61-3.54 (m, 1H),
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3.27 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.43 (dd, J = 13.6, 4.6 Hz, 1H); C NMR
(125 MHz, CDCl3) δ/ppm: 203.6, 199.6, 197.9, 156.2, 141.4, 140.4, 137.5, 136.2, 135.8, 134.4,
132.2, 130.6, 130.2, 129.4, 128.9, 128.5, 128.3, 127.4, 123.3, 123.1, 119.7, 116.0. 115.9, 98.7,
60.4, 45.1, 44.5, 41.6, 41.2; MS (70 eV, EI) m/z (%): 580 [M+1]+ (50), 578 [M-1]+ (50), 499 (2),
395 (10), 328 (98), 248 (55), 183 (100), 77 (18); IR (KBr) ṽ (cm−1): 3464 (s), 2926 (s), 1696 (s),
1228 (m), 1050 (m), 581 (m); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C33H23BrO5Na
601.0627; Found: 601.0624.
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6'-(2-bromobenzoyl)-5'-hydroxy-1'-(2-hydroxyphenyl)-3'-phenylspiro[cyclohex[5']ene-2',2'-
indene]-1',3'-dione (4ah): Following the general procedure D, 4ah was obtained from 1a and
2h in 76% yield (44.0 mg) as a white solid. Rf 0.55 (ethyl acetate/hexanes: 1/1); mp.: 177.6-
179.3 °C; 1H NMR (400 MHz, d-acetone) δ/ppm: 16.07 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.85 (t,
J = 7.4 Hz, 1H), 7.74 (td, J = 7.4 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.1
Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.11-6.96 (m, 7H), 6.90 (t, J = 7.4 Hz, 2H), 6.41 (d, J = 7.9 Hz,
1H), 4.27 (s, 1H), 3.84 (dd, J = 12.2, 7.0 Hz, 1H), 3.51 (dd, J = 19.4, 12.2 Hz , 1H), 3.10 (dd, J =
19.4, 7.0 Hz, 1H); 13C NMR (125 MHz, d-acetone) δ/ppm:202.0, 197.7, 196.8, 185.9, 155.9,
143.6, 141.7, 140.6, 139.6, 136.4, 136.0, 132.8, 131.6, 131.0, 129.8, 129.1, 128.9, 128.2, 127.9,
127.5, 123.7, 123.4, 119.9, 114.9, 109.5; IR (KBr) ṽ (cm−1): 3448 (s), 3033 (w), 2366 (w), 1701
(s), 1598 (s), 1253 (s), 761 (m), 573 (w); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C33H23BrO5Na 601.0627; Found: 601.0620.
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11-(4-chlorobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3ai): Following the general procedure D,
3ai was obtained from 1a and 2i in 82% yield (43.9 mg) as a white solid. Rf 0.3 (ethyl
acetate/hexanes: 1/5); mp.: 212.2-213.5 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.95 (d, J = 7.3
Hz, 1H), 7.80-7.68 (m, 3H), 7.51 (d, J = 8.6 Hz, 2H), 7.35-7.26 (m, 3H), 7.07-6.94 (m, 6H), 6.76
(t, J = 7.4 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H),5.23 (d, J = 2.2 Hz, 1H), 5.17 (brs, 1H), 3.58 (dd, J =
13.8, 4.6 Hz, 1H), 3.28 (d, J = 1.9 Hz, 1H), 3.19 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7, 4.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.6, 199.4, 197.9, 156.2, 141.3, 140.4, 139.8, 137.5,
136.2, 135.9, 133.9, 130.6, 130.1, 129.3, 129.2, 128.9, 128.2, 127.4, 123.3, 123.1, 119.7, 116.0,
115.9, 98.7, 60.4, 45.0, 44.5, 41.6, 41.2; IR (KBr) ṽ (cm−1): 3468 (s), 2934 (w), 1693 (s), 1592
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(m), 1401 (m), 1226 (s), 1049 (m), 753 (m); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
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C33H23ClO5Na 557.1132; Found: 557.1127.
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11-(3-chlorobenzoyl)-2-hydroxy-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
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methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3aj): Following the general procedure D,
3aj was obtained from 1a and 2j in 73% yield (42.3 mg) as a white solid. Rf 0.38 (ethyl
acetate/hexanes: 1/3); mp.: 215.4-216.5 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.98 (d, J = 7.4
Hz, 1H), 7.80-7.68 (m, 3H), 7.54 (s, 1H), 7.50-7.42 (m, 2H), 7.34-7.27 (m, 2H), 7.07-6.94 (m,
6H), 6.78 (td, J = 7.5 Hz, 1H), 6.35 (d, J = 7.4 Hz, 1H), 5.23 (d, J = 1.8 Hz, 1H), 5.07 (brs, 1H),
3.58 (dd, J = 13.7, 4.6 Hz, 1H), 3.30 (s, 1H), 3.21 (t, J = 13.7 Hz, 1H), 2.44 (dd, J = 13.7, 4.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 199.0, 197.8, 156.2, 141.3, 140.4, 137.6, 137.1,
136.2, 135.9, 135.2, 133.3, 130.6, 130.20, 130.15, 128.9, 128.3, 128.2, 127.4, 125.9, 123.3, 123.2,
119.8, 115.92, 115.88, 98.6, 60.6, 45.2, 44.6, 41.7, 41.0; IR (KBr) ṽ (cm−1): 3456 (s), 3068 (w),
1702 (s), 1599 (m), 1245 (m), 1159 (m), 754 (m); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C33H23ClO5Na 557.1132; Found: 557.1138.
6'-(2-chlorobenzoyl)-5'-hydroxy-1'-(2-hydroxyphenyl)-3'-phenylspiro[cyclohex[5']ene-2',2'-
indene]-1',3'-dione (4ak): Following the general procedure D, 4ak was obtained from 1a and
2k in 77% yield (41.2 mg) as a white solid. Rf 0.55 (ethyl acetate/hexanes: 1/1); mp.: 184.7-
186.0 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 15.9 (brs, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.70 (t, J
= 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.5Hz, 1H), 7.13-
6.95 (m, 9H), 6.79 (s, 1H), 6.30 (d, J = 7.7 Hz, 1H), 6.17 (s, 1H), 4.20 (s, 1H), 4.02 (s, 1H), 3.72
(dd, J = 12.1, 6.0 Hz, 1H), 3.61 (dd, J = 19.5, 13.0 Hz, 1H), 3.01 (dd, J = 19.2, 6.1 Hz, 1H); 13C
NMR (125 MHz, d-acetone) δ/ppm: 206.32, 206.26, 205.9, 202.2, 197.8, 196.0, 185.8, 155.8,
143.6, 141.6, 140.5, 137.5, 136.4, 135.9, 131.4, 130.9, 129.8, 129.7, 129.0, 128.8, 128.1, 127.9,
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127.0, 123.6, 123.3, 119.8, 114.9, 109.8, 59.9, 39.9, 39.2, 36.6; MS (70 eV, EI) m/z (%): 534
[M]+ (23), 395 (20), 247 (100), 139 (40); IR (KBr) ṽ (cm−1): 3448 (s), 3063 (m), 1702 (s), 1598
(s), 1458 (m), 1255 (s), 1092 (m), 756 (s), 703 (s); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C33H23ClO5Na 557.1132; Found: 557.1127.
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2-hydroxy-11-(4-methoxybenzoyl)-4-phenyl-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3al): Following the general procedure D,
3al was obtained from 1a and 2l in 84% yield (44.6 mg) as a yellow solid. Rf 0.15 (ethyl
acetate/hexanes: 1/2); mp.: 219.4-220.5 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.97 (d, J = 7.4
Hz, 1H), 7.78-7.67 (m, 3H), 7.59 (d, J = 8.8 Hz, 2H), 7.31-7.26 (m, 1H), 7.05-6.94(m, 6H),
6.81(d, J = 8.8 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 5.27 (s, 1H), 5.21 (d, J
= 2.2 Hz, 1H), 3.79 (s, 3H), 3.59 (dd, J = 13.6, 4.6 Hz, 1H), 3.36 (d, J = 1.8 Hz, 1H), 3.20 (t, J =
13.7 Hz, 1H), 2.43 (dd, J = 13.6, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 198.6,
198.0, 163.7, 156.3, 141.4, 140.5, 137.7, 136.1, 135.7, 130.6, 130.4, 130.0, 128.9, 128.3, 128.2,
127.3, 123.3, 123.1, 119.5, 116.3, 115.8, 114.0, 98.8, 60.8, 55.4, 45.0, 44.6, 41.6, 41.1; MS (70
eV, EI) m/z (%): 530 [M]+ (35), 395 (17), 135 (100); IR (KBr) ṽ (cm−1): 3448 (s), 2926 (w),
1702 (s), 1601 (s), 1266 (s), 1180 (s), 1081 (m), 762 (m), 606(w); HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C34H26O6Na 553.1627; Found: 553.1630.
2-hydroxy-4-phenyl-11-(thiophene-2-carbonyl)-2,3,4,6-tetrahydrospiro[2,6-
methanobenzo[b]oxocine-5,2'-indene]-1',3'-dione (3am): Following the general procedure D,
3am was obtained from 1a and 2m in 71% yield (36.0 mg) as a white solid. Rf 0.1 (ethyl
acetate/hexanes: 1/5); mp.: 232.6-233.5 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 7.97 (d, J = 8.2
Hz, 1H), 7.81-7.68 (m, 3H), 7.62-7.54 (m, 2H), 7.30 (td, J =8.5, 1.6 Hz, 1H), 7.09-6.93 (m, 7H),
6.80 (td, J = 7.3, 1.0 Hz, 1H), 6.47 (dd, J = 7.5, 1.3 Hz, 1H), 5.22 (d, J = 2.4 Hz, 1H), 3.60 (dd, J
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= 13.7, 4.6 Hz, 1H), 3.53 (d, J = 2.2 Hz, 1H), 3.18 (t, J = 13.7 Hz, 1H), 2.42 (dd, J = 13.6, 4.6 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ/ppm: 203.4, 197.9, 191.5, 156.1, 142.2, 141.3, 140.4, 137.6,
136.2, 135.8, 134.6, 132.6, 130.7, 130.1, 129.0, 128.3, 127.4, 123.3, 123.2, 119.7, 116.2, 115.8,
98.3, 60.8, 46.0, 45.6, 41.7, 41.1; MS (70 eV, EI) m/z (%): 506 [M]+ (35), 111 (100); IR (KBr) ṽ
(cm−1): 3490 (s), 2950 (w), 1699 (s), 1652 (m), 1487 (w), 1238 (s), 1050 (m), 747 (s), 579 (m);
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C31H22O5SNa 529.1086; Found: 529.1083.
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5'-hydroxy-1'-(2-hydroxyphenyl)-6'-isobutyryl-3'-phenylspiro[cyclohex[5']ene-2',2'-
indene]-1',3'-dione (4an): Following the general procedure D, 4an was obtained from 1a and
2n in 58% yield as (27.1 mg) a white solid. Rf 0.08 (ethyl acetate/hexanes: 1/5); mp.: 225.7-
227.4 °C; 1H NMR (400 MHz, CDCl3) δ/ppm: 16.8 (brs, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.72 (t, J
= 6.10 Hz, 1H), 7.64-7.56 (m, 2H), 7.24-7.16 (m, 2H), 7.06-6.95 (m, 6H), 6.66 (d, J = 7.8 Hz,
1H), 4.90 (brs, 1H), 4.53 (s, 1H), 3.67-3.63 (m, 1H), 3.47 (dd, J = 19.3, 12.4 Hz, 1H), 2.90 (dd, J
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= 19.3, 6.6 Hz, 1H), 2.45-2.32 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.53 (d, J = 6.6 Hz, 3H); C
NMR (125 MHz, CDCl3) δ/ppm: 206.0, 201.8, 199.1, 183.5, 152.9, 142.3, 140.8, 138.6, 135.4,
135.1, 130.8, 129.0, 128.8, 128.2, 127.2, 123.2, 122.8, 120.8, 115.0, 106.2, 59.2, 38.8, 38.5, 35.6,
32.9, 19.8, 18.1; IR (KBr) ṽ (cm−1): 3403 (s), 2966 (m), 1702 (s), 1583 (s), 1459 (s), 1342 (s),
1253 (s), 1086 (m), 752 (m); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C30H26O5Na 489.1678;
Found: 489.1686.
(1'S,3'R)-6'-benzoyl-5'-hydroxy-1'-(2-methoxyphenyl)-3'-phenylspiro[cyclohex[5']ene-2',2'-
indene]-1',3'-dione (4fa): Following the general procedure D, 4fa was obtained from 1f and 2a
in 76% yield (39.1 mg) as a white solid. Rf 0.25 (ethyl acetate/hexanes: 1/5); mp.:191.3-192.1 °C;
1H NMR (400 MHz, CDCl3) δ/ppm: 7.94 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.63 (t, J
= 7.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.30-7.21 (m, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.08-6.95 (m,
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