Catalytic δ-hydroxyalkynone rearrangement in the stereoselective total synthesis of centrolobine, engelheptanoxides A and C and analogues

Article abstract of DOI:10.1016/j.tet.2021.132375

A catalytic stereoselective total synthesis of centrolobine and engelheptanoxides A and C has been completed via a metal-free catalytic δ-hydroxyalkynone rearrangement to 2,3-dihydro-4H-pyran-4-one and diastereoselective hydrogenation to the all syn-2,4,6-trisubstituted pyran strategy. The onliest required chirality was introduced by Jacobsen kinetic resolution, which further directed the diastereoselective hydrogenation. A first stereoselective synthesis of engelheptanoxide A is also accomplished. The analogues and derivatives of centrolobine and engelheptanoxides prepared were evaluated for antitubercular activity against M. tuberculosis H₃₇Rv ATCC 27294.

Full text of DOI:10.1016/j.tet.2021.132375

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic
d
-hydroxyalkynone rearrangement in the stereoselective
total synthesis of centrolobine, engelheptanoxides A and C and
analogues
,
,
, c
Praveen Kumar a, Rodney A. Fernandes a *, Mohammad N. Ahmad b c, Sidharth Chopra b
a Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, Maharashtra, India
b Division of Microbiology, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow, 226031, Uttar Pradesh, India
c Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic stereoselective total synthesis of centrolobine and engelheptanoxides A and C has been
completed via a metal-free catalytic -hydroxyalkynone rearrangement to 2,3-dihydro-4H-pyran-4-one
Received 16 June 2021
Accepted 30 July 2021
Available online xxx
d
and diastereoselective hydrogenation to the all syn-2,4,6-trisubstituted pyran strategy. The onliest
required chirality was introduced by Jacobsen kinetic resolution, which further directed the diaster-
eoselective hydrogenation. A first stereoselective synthesis of engelheptanoxide A is also accomplished.
The analogues and derivatives of centrolobine and engelheptanoxides prepared were evaluated for
antitubercular activity against M. tuberculosis H37Rv ATCC 27294.
Keywords:
Centrolobine
Engelheptanoxides
Diastereoselective hydrogenation
Jacobsen kinetic resolution
Total synthesis
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
such as anti-inflammatory, antibacterial as well as antileishmanial
-.[3c,8] Its structure was elucidated in 1964 [3a] and the absolute
The tetrahydropyran (THP) moiety is ubiquitous in a wide range
of natural products and bioactive synthetic compounds that are
valuable in medicinal and pharmaceutical industry [1]. Over the
years, natural products containing 2,6-syn- and 2,6-anti-disubsti-
tuted-THP scaffolds have been synthesized by various approaches
depending on the substitutions on the THP ring [2]. Some of the
2,6-syn substituted THP natural products such as centrolobine (1
and ent-1) [3], engelheptanoxides (2 and 3) [4], diosniponols (4a
and 4b) [5], diospongin A (5) [6], etc display interesting bio-
activities including antitumor, anti-inflammatory, antioxidant,
anticancer and antifungal properties, [7] (see Fig. 1). Centrolobine,
engelheptanoxides A and C belong to the family of tetrahydropyr-
anyl diarylheptanoids consisting of an arylated 2,6-syn-disubsti-
tuted THP moiety attached with the two aromatic rings across the
termini of a seven-carbon chain. (ꢀ)-Centrolobine (ent-1) was first
isolated from the heartwood of Centrolobium robustum and then
from the stem of Brosinum potabile in the amazon forest [3a-d,f].
The antipodal (þ)-centrolobine (1) was isolated from Centrolobium
tomentosum[.3a,c-e] Centrolobine possess interesting bioactivities
configuration was confirmed on the basis of conformational and
configurational facts in Newman formulation in 1970 [3c]. This
absolute configuration was later revised by Colobert via the first
enantioselective total synthesis of (ꢀ)-centrolobine [9a]. While, the
latter [9] is extensively synthesized, there are few reports on
(þ)-centrolobine [10] synthesis.
Engelheptanoxides A (2) and C (3) were isolated from the roots
of Engelhardia roxburghiana found in India, China and Taiwan re-
gion by Chen and co-workers in 2012 [4]. Engelheptanoxide A is an
arylated 2,6-syn-disubstituted THP where as engelheptanoxide C is
an arylated 2,4,6-syn-trisubstituted THP natural product. These
show antitubercular activities against M. tuberculosis H37Rv having
168.6 and ꢁ 581.4 (in
mM) MICs values, respectively [4]. There is
only one reported synthesis on engelheptanoxide C [11] and no
report on engelheptanoxide A synthesis. While Prins cyclization
[12] is quite a popular approach towards 2,4,6-trisubstituted pyrans
synthesis, the same has resulted in lower yields (30e45 %) and
enantioselectivities toward engelheptanoxide C synthesis (72e88 %
ee) [11]. Considering the latter to have a 2,4,6-syn-trisubstituted
* Corresponding author.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
https://doi.org/10.1016/j.tet.2021.132375
0040-4020/© 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Kumar, R.A. Fernandes, M.N. Ahmad et al., Catalytic
d-hydroxyalkynone rearrangement in the stereoselective total
synthesis of centrolobine, engelheptanoxides A and C and analogues, Tetrahedron, https://doi.org/10.1016/j.tet.2021.132375

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
engelheptanoxide C (3) synthesis following similar strategy and a
further C-4 deoxygenation would result in engelheptanoxide A (2).
The synthesis of (þ)-centrolobine (1) began with the benzyl
protection of commercial 4-hydroxy benzaldehyde (10) to 11a fol-
lowed by chain elongation in two steps to alcohol 12a [14] (Scheme
2). The latter on one carbon Wittig olefination via the aldehyde and
subsequent epoxidation gave 8a′ in good yields. Next, the epoxide
was subjected to Jacobsen hydrolytic-kinetic resolution [15] with
the (R,R)-Co-salen complex (A) to render the enantiopure epoxide
8a in 42 % yield (>99 % ee) [16] and the antipode diol 9a in 45 %
yield. The diol was converted to the enantiomeric epoxide ent-8a
(>98 % ee) [16] in 2 steps via the tosylate in overall 75 % yield,
although it can also be prepared by using the (S,S)-Jacobsen cata-
lyst. Further, the epoxide opening using trimethylsilyl-acetylene in
presence of Lewis acid, BF3,OEt2 followed by subsequent desilyla-
tion using K2CO3 delivered the alkynols 13a and ent-13a in excel-
lent yields. The addition of Li-acetylide from 13a to p-anisaldehyde
and next chemoselective benzylic alcohol oxidation furnished the
Fig. 1. Natural products containing 2,6-syn-disubstituted-THP moiety.
d-hydroxyalkynone 7a in 69 % yield (over 2 steps).
The -hydroxyalkynone 7a was next subjected to catalytic
rearrangement to the (R)-2,3-dihydro-4H-pyran-4-one 6a using
acid catalysts as shown in Table 1. We chose the Lewis acid,
d
THP moiety, we visualized the 2,3-dihydro-4H-pyran-4-one syn-
thesis by our metal-free catalytic
d-hydroxyalkynone rearrange-
ment [13] followed by highly diastereoselective all-syn
a
hydrogenation strategy. Then, a simple C-4 deoxygenation would
enable engelheptanoxide A and centrolobine synthesis.
2. Results and discussion
In retrosynthetic considerations (Scheme 1), (þ)-centrolobine
(1) can be accessed by the diastereoselective hydrogenation of
enone 6 followed by C-4 deoxygenation. The latter enone is avail-
able through the metal-free p-TsOH-catalyzed rearrangement from
d-hydroxyalkynone 7 [13]. The synthesis of 7 can be achieved by
opening of epoxide 8 with acetylene followed by nucleophilic
addition of this alkyne to p-anisaldehyde and chemoselective
benzylic oxidation of secondary alcohol. The enantiopure epoxide 8
is accessible through the Jacobsen kinetic resolution. The diol 9
obtained during the resolution can be transformed into the antip-
ode epoxide ent-8. The latter has the requisite stereochemistry for
Scheme 1. Retrosynthetic analysis for (þ)-centrolobine and engelheptanoxides.
Scheme 2. Catalytic asymmetric synthesis of enone 7a.
2

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Acid-catalyzed d-hydroxyalkynone 7a rearrangement to 2,3-dihydro-4H-pyran-4-
one 6a.a
Entry
Acid [mol%]
Solvent
Temp.
Time [h]
Yield [%]b
1
2
3
4
5
BF3$OEt2 (20)
p-TsOH$H2O (10)
PhsOH (10)
MsOH (10)
p-TsOH$H2O (5)
CH2Cl2
MeOH
MeOH
MeOH
MeOH
reflux
24
12
20
24
20
35
93
75
78
82
rt
rt
rt
rt
a
Reaction conditions: 7a (0.5 mmol), acid (0.025e0.1 mmol), solvent (0.4 mL), rt
to reflux, 12e24 h.
b
Isolated yields.
BF3$OEt2 in 20 mol% in the rearrangement of 7a to result in 6a in
35 % yield (Table 1, entry 1). When the reaction was attempted with
the Brønsted acid, p-TsOH$H2O (10 mol%) in MeOH solvent, it
cleanly delivered 6a in good yield of 93 % (entry 2). Change of acid
catalyst to related benzene sulfonic acid gave 6a in 75 % yield (entry
3). A similar reaction with methane sulfonic acid gave comparable
yield (entry 4). Lowering the catalyst loading of p-TsOH$H2O to
5 mol% resulted in lower yield of 6a (82 %, entry 5). The reaction
occurs through MeOH addition across the alkynone catalyzed by
TsOH$H2O followed by dehydrative dihydro-pyran formation and
final enol-ether hydrolysis. Impressively, this rearrangement is
metal-free, atom-economic and occurs with cheaper hydrated p-
TsOH$H2O-catalysis in 10 mol% under open-flask conditions and
room temperature.
To complete the synthesis of (þ)-centrolobine (1) we relied on
the fact that the syn-2,4,6-trisubstituted-THP would result from the
hydrogenation of the enol from opposite face of the C-2 substituent.
This would also result in having all the substituents in the equa-
torial orientation. Thus, the diastereoselective catalytic hydroge-
nation of enone 6a exclusively delivered the single diastereomer
14a in 86 % yield (Scheme 3). Here the desired debenzylation also
occurred in the same reaction. Next, the C-4 deoxygenation was
effected by conversion of the hydroxyl group to bromide using CBr4
and PPh3 followed by reductive radical debromination using trib-
utyltin hydride to furnish the natural product (þ)-centrolobine (1)
Scheme 4. Catalytic asymmetric synthesis of centrolobine analogues 16a-c, 17a and
17b.
in 62 % yield over 2 steps. The optical rotation of (þ)-centrolobine,
25
[
a
]
þ93.8 (c ¼ 0.5, MeOH) and the spectral data was in good
D
25
agreement with that reported for the natural isolate, [
(c ¼ 0.1, MeOH) [3c].
a]
þ97.0
D
We considered the synthesis of a few analogues of (þ)-cen-
trolobine to generalize the strategy and for bioactivity studies. The
enantiopure alkynol 13b was prepared from p-anisaldehyde (11b)
by following a similar synthetic sequence as described for 13a (via
8b, 95 % ee, see Experimental Section for details). Addition of Li-
acetylide from 13a to aldehyde 15a and subsequent benzylic
alcohol oxidation furnished the
d-hydroxyalkynone 7b (65 %, 2
steps, Scheme 4). Similarly, the -hydroxyalkynones 7c and 7d were
d
prepared from 13b and using the aldehydes 15a and 15b, respec-
tively. Next, the p-TsOH$H2O-catalyzed rearrangement efficiently
gave the (R)-2,3-dihydro-4H-pyran-4-ones 6b-d in excellent yields
(89e93 %). Further, the diastereoselective catalytic hydrogenation
of enones delivered the all syn-2,4,6-trisubstituted-THP com-
pounds 14b-d, respectively in good yields (75e82 %). These
Scheme 3. Catalytic diastereoselective hydrogenation and completion of (þ)-cen-
trolobine synthesis.
3

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
Table 2
represent the methyl analogues of ent-engelheptanoxide C. Finally,
the C-4 deoxygenation via the bromide provided the centrolobine
analogues 16a-c, respectively. Centrolobine (1) and methoxy cen-
trolobine 16a were further derivatized to their acetates 17a and 17b,
respectively, in good yields (85e91 %).
Engelheptanoxides A (2) and C (3) have opposite configuration
to that of centrolobine. Thus, the diol 9a obtained in kinetic reso-
lution of 8a′ was transformed into alkynol ent-13a (via ent-8a,
Scheme 2) for the synthesis of 2 and 3. Addition of Li-acetylide from
ent-13a to benzyl protected vanillin 15c and subsequent benzylic
Antitubercular activities of 1e3 and their analogues and acetate derivatives against
M. tuberculosis H37Rv ATCC 27294.
Compounds
MICs reported4
MICs (mg/mL)
1
2
3
14a
14b
14c
14d
16a
16b
17a
17b
20a
20b
Ethambutola
e
>64
32
168.6
m
M or 55.4
m
g/mL
ꢁ581.4
m
M or ꢁ200.2
m
g/mL
>64
>64
>64
>64
>64
64
32
32
16
64
e
e
e
e
e
e
e
e
e
e
e
alcohol oxidation furnished the
d-hydroxyalkynone 18 (74 %, 2
steps, Scheme 5). Then, the p-TsOH$H2O-catalyzed rearrangement
cleanly provided the (S)-2,3-dihydro-4H-pyran-4-one 19 in 92 %
yield. Further, the diastereoselective catalytic hydrogenation of
enone and the desired concomitant debenzylation (phenolic hy-
droxy deprotection) furnished the all syn-2,4,6-trisubstituted-THP
molecule, engelheptanoxide C (3) in good yield of 92 %. The benzyl
protection was advantageous for a convergent deprotection and
requires no additional conversion step. The optical rotation of
64
1
a
Positive control.
synthetic engelheptanoxide C, [
spectral data was in good agreement with that reported for the
a
]
25 ꢀ 21.4 (c ¼ 0.14, MeOH) and the
were further derivatized to their acetates 20a and 20b, respectively
in good yields.
The synthesized natural products 1e3, their analogues and ac-
etate derivatives (14a-d, 16a, 16b, 17a, 17b, 20a and 20b) were
evaluated for antitubercular activity against M. tuberculosis H37Rv
ATCC 27294 in vitro with Ethambutol as a positive control (MIC:
D
25
natural isolate, [
a
]
D
ꢀ 7.44 (c ¼ 0.14, MeOH) [4] and the synthe-
sized compound earlier, [
the C-4 deoxygenation of 3 via the bromide provided engelhep-
tanoxide A (2) in 64 % yield over 2 steps. The optical rotation of
a
]
D
22 ꢀ 35.6 (c ¼ 0.54, MeOH) [11]. Finally,
engelheptanoxide A, [a]
25 ꢀ 70.0 (c ¼ 0.12, CHCl3) and the spectral
1
m
g/mL). The antitubercular activity data is presented in Table 2.
The MIC obtained in our hand (32 g/mL) for synthetic engelhep-
tanoxide A (2) is comparable to that reported for natural isolate
(55.4 g/mL, reported as 168.6 M) [4]. The acetate compound 17b
with MIC 16 g/mL exhibited potent antitubercular activity and
need further structure optimization. Other compounds 2, 16b and
D
m
data was in good agreement with that reported for the natural
isolate, [a]
25 ꢀ 66.9 (c ¼ 0.12, CHCl3) [4]. Both the natural products
D
m
m
m
17a showed comparable MIC values of 32
14a-d, 16a, 20a and 20b were higher.
mg/mL, while that of 1, 3,
3. Summary and conclusion
In summary, a concise and efficient catalytic total synthesis of
(þ)-centrolobine (1), engelheptanoxides A (2) and C (3) has been
achieved by catalytic
d-hydroxyalkynone rearrangement to 2,3-
dihydro-4H-pyran-4-one and a highly efficient diastereoselective
catalytic hydrogenation to the all syn-2,4,6-trisubstituted-THP
moiety. The desired first chiral center was introduced by the
Jacobsen kinetic resolution. This directed the diastereoselective
introduction of remaining stereogenic centers through catalytic
hydrogenation. The first stereoselective synthesis of engelheptan-
oxide A (2) has been achieved in this paper. Centrolobine, engel-
heptanoxides, few analogues and derivatives prepared were
evaluated for antitubercular activity. The acetate derivative 17b
showed potent antitubercular activity with MIC 16
undergoing further optimization.
mg/mL and is
4. Experimental section
4.1. General information
Solvents were dried by using standard procedures. Thin-layer
chromatography was performed on EM 250 Kieselgel 60 F254 sil-
ica gel plates. The spots were visualized by staining with KMnO4 or
by using a UV lamp. 1H NMR and 13C NMR were recorded with a
spectrometer operating at 400 or 500 and 100 or 125 MHz for
proton and carbon nuclei, respectively. The chemical shifts are
based on the CDCl3 peak at
CDCl3 peak at
peak at 29.83 (s) in carbon NMR. IR spectra were obtained on an
FT-IR spectrometer by evaporating compounds dissolved in CHCl3
d
¼ 7.26 ppm for proton NMR and the
d
¼ 77.00 ppm (t) for carbon NMR and acetone-d6
Scheme 5. Completion of the total synthesis of engelheptanoxides A and C.
4

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
on CsCl pellet or by preparing KBr pellets for solids. HRMS (ESI-TOF)
spectra were recorded using positive electrospray ionization by the
TOF method.
(3 ꢂ 30 mL). The combined organic layers were washed with water,
brine, dried (Na2SO4) and concentrated. The crude aldehyde (2.2 g)
was used without purification for next step.
To a white suspension of methyltriphenylphosphonium bro-
mide (6.5 g, 18.17 mmol, 2 equiv) in dry THF (20 mL) at 0 ꢃC was
added n-BuLi (7.3 mL, 18.17 mmol, 2.5 M in hexane, 2 equiv). The
resulting solution was stirred at 0 ꢃC for 30 min and then the so-
lution of above aldehyde (2.2 g) in THF (5 mL) was added dropwise
and stirred at 0 ꢃC to room temperature for 6 h. It was then
quenched with sat. aq. NH4Cl (10 mL) and the solution extracted
with EtOAc (3 ꢂ 20 mL). The combined organic layers were washed
with water, brine, dried (Na2SO4) and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1) as eluent to give 1-(benzyloxy)-4-(but-3-en-1-yl)
benzene (1.88 g, 87 %) as pale yellow oil. IR (CHCl3): nmax ¼ 3064,
3032, 2925, 2857,1639,1611,1583,1511,1454,1381,1297,1239,1176,
4.2. Synthetic procedures
4.2.1. 4-(Benzyloxy)benzaldehyde (11a). [17]
To a solution of 4-hydroxybenzaldehyde 10 (2.0 g, 16.38 mmol)
in acetone (60 mL) was added benzylbromide (2.14 mL,18.02 mmol,
1.1 equiv), followed by anhydrous K2CO3 (3.4 g, 24.58 mmol, 1.5
equiv). The mixture was stirred at room temperature for 10 h. This
was then concentrated and the residue dissolved in EtOAc and
water. The organic layer was separated and the aqueous layer
extracted with EtOAc (3 ꢂ 40 mL). The combined organic layers
were washed with water (2 ꢂ 40 mL), brine (50 mL), dried (Na2SO4)
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1) as eluent to
give 11a (3.34 g, 96 %) as a white solid. M.p. 76e78 ꢃC; IR (CHCl3):
nmax ¼ 2830, 2744, 1686, 1603, 1578, 1510, 1393, 1301, 1261, 1164,
1118, 1025, 912, 826, 756, 696, 605, 542 cmꢀ1
CDCl3):
;
1H NMR (400 MHz,
d
¼ 7.47 (d, J ¼ 7.6 Hz, 2H), 7.42 (d, J ¼ 7.6 Hz, 2H), 7.38e7.32
(m, 1H), 7.14 (d, J ¼ 8.3 Hz, 2H), 6.94 (d, J ¼ 8.3 Hz, 2H), 5.96e5.82
(m, 1H), 5.10e5.04 (m, 1H), 5.07 (s, 2H), 5.03e4.98 (m, 1H), 2.69 (t,
J ¼ 7.6 Hz, 2H), 2.38 (q, J ¼ 8.2 Hz, 2H) ppm; 13C{1H} NMR (100 MHz,
1019, 865, 831, 736, 696, 515 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼ 9.89 (s,1H), 7.84 (d, J ¼ 8.8 Hz, 2H), 7.46e7.38 (m, 4H), 7.38e7.32
(m, 1H), 7.08 (d, J ¼ 8.8 Hz, 2H) 5.15 (s, 2H) ppm; 13C{1H} NMR
CDCl3):
d
¼ 157.0, 138.1, 137.2, 134.2, 129.3, 128.5, 127.8, 127.4, 114.8,
(100 MHz, CDCl3):
d
¼ 190.8, 163.7, 135.9, 132.0, 130.1, 128.7, 128.3,
114.6, 70.0, 35.7, 34.4 ppm; HRMS (ESIꢀTOF) m/z: [M þ K]þ Calcd
127.4, 115.1, 70.2 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
for C17H18OK 277.0989; Found 277.0978.
C
14H12O2Na 235.0730; Found 235.0730.
4.2.4. 2-(4-Benzyloxyphenethyl)oxirane (8a0).[13b]
4.2.2. 3-(4-Benzyloxyphenyl)propan-1-ol (12a) [17]
To a stirred solution of above olefin 1-(benzyloxy)-4-(but-3-en-
1-yl)benzene (3.0 g, 12.6 mmol) in dry CH2Cl2 (50 mL) under N2 at
0 ꢃC was added m-CPBA (3.26 g, 18.9 mmol, 1.5 equiv) dissolved in
dry CH2Cl2 (60 mL). The mixture was stirred for 12 h at room
temperature. The reaction was quenched with sat. aq. NaHCO3
(40 mL) and the mixture stirred further for 1 h and then extracted
with CH2Cl2 (2 ꢂ 50 mL). The combined organic layers were dried
and concentrated in vacuo. The residue was purified by silica gel
column chromatography using petroleum ether/EtOAc (9:1) as
eluent to give 8a′ (2.95 g, 92 %) as colourless oil. The spectral data is
same as 8a below.
To a stirred solution of malonic acid (2.1 g, 20.21 mmol, 1.3
equiv) in pyridine (4 mL) was added piperidine (136 mg, 1.6 mmol,
0.1 equiv) and then aldehyde 11a (3.3 g, 15.55 mmol) dropwise
under N2 atmosphere. The resulting mixture was stirred at reflux
for 6 h when TLC indicated the disappearance of starting material.
The mixture was cooled to room temperature and neutralized with
10 % aq. HCl (5 mL) to give a white solid that was filtered and
washed with cold water. Recrystallization from aqueous EtOH (1:1)
afforded the acrylic acid (3.9 g), which was used directly for the
next reaction.
To a suspension of LiAlH4 (1.77 g, 46.65 mmol, 3.0 equiv) in THF
(100 mL) under N2 atmosphere at 0 ꢃC was added the solution of
above acrylic acid in THF (40 mL) dropwise. The resulting mixture
was stirred at reflux for 2 h. The mixture was then cooled to room
temperature and quenched with saturated aq. Na2SO4 solution
(40 mL) at 0 ꢃC. Then EtOAc (100 mL) was added and the mixture
stirred for 1 h. It was then filtered through a sintered glass funnel
and the filtrate was concentrated. The residue was purified by silica
gel column chromatography using petroleum ether/EtOAc (3:1) as
eluent to give the alcohol 12a (2.83 g, 75 %) as white solid. M.p.
68e70 ꢃC, IR (CHCl3): nmax ¼ 3339, 2939, 2865, 1610, 1581, 1512,
1453, 1381, 1298, 1246, 1176, 1112, 1041, 1014, 912, 810, 739, 696,
4.2.5. (R)-2-(4-Benzyloxyphenethyl)oxirane (8a) and (S)-4-(4-
benzyloxyphenyl)butane-1,2-diol (9a). [19]
Glacial acetic acid (0.24 mL, 4.25 mmol) was added dropwise to
a
solution of [(R,R)-N,N0-bis(3,5-di-tertbutylsalicylidene)-1,2-
cyclohexanediamino] cobalt-(II) (A) (0.121 g, 0.2 mmol, 2 mol%)
in toluene (6 mL) and the mixture was stirred at room temperature
for 2 h, when color change from red to brown was observed. The
solvent and remaining acid were removed in vacuo and 2-(4-
benzyloxyphenethyl)oxirane 8a′ (2.54 g, 10 mmol) was added.
The reaction mixture was cooled to 0 ꢃC and H2O (0.1 mL, 5.5 mmol)
was added and the mixture was warmed to room temperature and
stirred for 16 h. The mixture was concentrated and the crude
product was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1) as eluent to give the title compound
8a (1.07 g, 42 %) as colorless oil. Further elution with petroleum
ether/EtOAc (3:2) as eluent gave the diol 9a (1.22 g, 45 %) as white
667, 615, 551, 517 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.44 (d,
J ¼ 7.2 Hz, 2H), 7.41e7.37 (m, 2H), 7.36e7.31 (m, 1H), 7.13 (d,
J ¼ 8.1 Hz, 2H), 6.92 (d, J ¼ 8.2 Hz, 2H), 5.05 (s, 2H), 3.67 (t,
J ¼ 6.5 Hz, 2H), 2.66 (t, J ¼ 7.7 Hz, 2H), 1.92e1.82 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3):
d
¼ 157.0, 137.1, 134.1, 129.3, 128.5, 127.9,
127.4, 114.8, 70.0, 62.2, 34.3, 31.1 ppm; HRMS (ESIꢀTOF) m/z: [M þ
Na]þ Calcd for C16H18O2Na 265.1199; Found 265.1198.
solid.
25
Data for 8a: [
a]
þ9.5 (c ¼ 1, CHCl3); IR (CHCl3): nmax ¼ 3355,
D
4.2.3. 1-(Benzyloxy)-4-(but-3-en-1-yl)benzene. [18]
2922, 2851, 1613, 1515, 1452, 1367, 1304, 1248, 1177, 1066, 105, 909,
To a solution of DMSO (2.14 g, 27.24 mmol, 3.0 equiv) in CH2Cl2
(50 mL) at ꢀ78 ꢃC was added oxalyl chloride (1.2 mL, 13.62 mmol,
1.5 equiv). The resulting solution was stirred for 15 min, and then
the solution of alcohol 12a (2.2 g, 9.08 mmol, 1.0 equiv) in CH2Cl2
(10 mL) was added and stirring continued for 45 min. It was then
quenched with Et3N (4.38 mL, 43.33 mmol, 4.5 equiv) and sat. aq.
NaHCO3 (50 mL) and the solution extracted with CH2Cl2
829, 759, 612 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼ 7.45 (d,
J ¼ 7.2 Hz, 2H), 7.42e7.37 (m, 2H), 7.36e7.31 (m, 1H), 7.15 (d,
J ¼ 8.3 Hz, 2H), 6.92 (d, J ¼ 8.3 Hz, 2H), 5.05 (s, 2H), 2.99e2.92 (m,
1H), 2.83e2.68 (m, 3H), 2.51e2.45 (m, 1H), 1.89e1.78 (m, 2H) ppm;
13C{1H} NMR (100 MHz, CDCl3):
d
¼ 157.1, 137.1, 133.6, 129.3, 128.5,
127.9, 127.4, 114.8, 70.0, 51.8, 47.2, 34.4, 31.3 ppm; HRMS (ESIꢀTOF)
m/z: [M þ Na]þ Calcd for C17H18O2Na 277.1199; Found 277.1198. The
5

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
25
enantiomeric excess was determined by chiral HPLC: CHIRALPAK
OD-H column, hexane/i-PrOH ¼ 98.5:1.5, flow rate ¼ 1.0 mL/min,
13a (514 mg, 93 %) as pale yellow oil. [
a
]
ꢀ 11.5 (c 1.0, CHCl3).
D
Other spectral data is same as its enantiomer 13a.
tR ¼ 11.38 min, >99 % ee.
25
Data for 9a: M.p. 104e106 ꢃC; [
a]
ꢀ 10.6 (c ¼ 1, CHCl3); IR
4.2.9. (R)-7-(4-Benzyloxyphenyl)-5-hydroxy-1-(4-methoxyphenyl)
hept-2-yn-1-one (7a)
D
(CHCl3): nmax ¼ 3371, 3267, 3018, 2924, 2908, 2867, 1613,1512,1454,
1380, 1303, 1254, 1102, 1016, 917, 871, 811, 696, 668, 519 cmꢀ1 1H
NMR (400 MHz, CDCl3):
;
Alkyne 13a (0.2 g, 0.713 mmol) was dissolved in THF (10 mL) and
the solution cooled to ꢀ78 ꢃC and n-BuLi (1.6 M solution in hexane,
1.0 mL, 1.57 mmol, 2.2 equiv) was added dropwise. After the
addition, the reaction was left to stir for 0.5 h at ꢀ78 ꢃC and then p-
anisaldehyde (106 mg, 0.784 mmol, 1.1 equiv) in THF (5 mL) was
added in one portion. The reaction was allowed to warm to 0 ꢃC for
6 h and then quenched by addition of sat. aq. NH4Cl solution
(10 mL). The two layers were separated, and the aqueous phase was
extracted with EtOAc (3 ꢂ 40 mL). The combined organic layers
were washed with distilled water (20 mL), brine, dried (Na2SO4)
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (7:3 to 1:1) as eluent
to afford the diol (220 mg).
d
¼ 7.58 (d, J ¼ 8.1 Hz, 2H), 7.49e7.38 (m,
2H), 7.29e7.21 (m, 1H), 7.11 (d, J ¼ 7.9 Hz, 2H), 6.91 (d, J ¼ 8.1 Hz,
2H), 5.05 (s, 2H), 3.66e3.56 (m, 2H), 3.42e3.38 (m, 1H), 2.71e2.59
(m, 2H), 1.79e1.69 (m, 4H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
d
¼ 157.1, 137.1, 134.0, 129.3, 128.5, 127.9, 127.4, 114.8, 71.5, 70.1, 66.8,
34.8, 30.9 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
C
17H20O3Na 295.1305; Found 295.1306.
4.2.6. (S)-2-(4-Benzyloxyphenethyl)oxirane (ent-8a). [18]
To the diol 9a (0.5 g, 1.84 mmol) in pyridine (5 mL) was added
tosyl chloride (0.387 g, 2.03 mmol, 1.1 equiv) at 0 ꢃC and then the
reaction mixture was stirred at room temperature for 14 h. After
completion, the mixture was diluted with water and the solution
extracted with CH2Cl2 (2 ꢂ 40 mL). The combined organic layers
were concentrated. The crude residue was dissolved in MeOH and
K2CO3 (0.51 g, 3.7 mmol, 2.0 equiv) was added and stirred for 1 h at
room temperature. The reaction mixture was concentrated under
reduced pressure and the residue purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1) as eluent to
The above diol was dissolved in CH2Cl2 (30 mL) and MnO2
(0.62 g, 7.1 mmol, 10.0 equiv) was added to the solution. The
mixture was stirred at room temperature for 12 h and then MnO2
was filtered and the solvent evaporated. Purification of the residue
by silica gel column chromatography with petroleum ether/EtOAc
(7:3) as eluent gave 7a (204 mg, 69 %) as yellow semisolid.
25
[
a
]
þ9.5 (c ¼ 1.0, CHCl3); IR (CHCl3): nmax ¼ 2925, 2857, 2238,
D
give ent-8a (0.35 g, 75 %) as colorless oil. [
a
]
25 ꢀ11.3 (c ¼ 1.5, CHCl3).
2202, 1633, 1596, 1573, 1510, 1455, 1422, 1380, 1319, 1259, 1168,
D
The enantiomeric excess was determined by chiral HPLC: CHIR-
ALPAK OD-H column, hexane/i-PrOH ¼ 98.5:1.5, flow rate ¼ 1.0 mL/
min, tR ¼ 10.66 min (minor), tR ¼ 11.65 min (major), >98 % ee. Other
spectral data is same as that of 8a.
1112,1054, 1027, 916, 845, 758, 696, 600 cmꢀ1; 1H NMR (400 MHz,
CDCl3):
d
¼ 8.09 (d, J ¼ 8.6 Hz, 2H), 7.43 (d, J ¼ 7.2 Hz, 2H), 7.41e7.36
(m, 2H), 7.35e7.30 (m, 1H), 7.14 (d, J ¼ 8.2 Hz, 2H), 6.95e6.85 (m,
4H), 5.04 (s, 2H), 3.98e3.89 (m, 1H), 3.87 (s, 3H), 2.84e2.74 (m, 1H),
2.74e2.64 (m, 3H), 1.96e1.88 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
4.2.7. (R)-1-(4-Benzyloxyphenyl)hex-5-yn-3-ol (13a)
CDCl3):
d
¼ 176.8, 164.3, 156.9, 136.9, 133.7, 131.9, 129.7, 129.2, 128.4,
Trimethylsilyl acetylene (0.45 mL, 3.18 mmol, 1.5 equiv) in THF
(20 mL) was precooled at ꢀ78 ꢃC and n-BuLi (1.7 mL, 1.6 M in
hexane, 2.76 mmol, 1.3 equiv) was added to the solution dropwise.
The mixture was stirred for 30 min and then BF3$OEt2 (1.0 mL,
3.18 mmol, 1.5 equiv) was added to the solution dropwise. The
resulting solution was stirred for another 30 min and 8a (540 mg,
2.12 mmol) in THF (6 mL) was added dropwise and the reaction
mixture was stirred at 0 ꢃC for 4 h. After the reaction was
completed, the mixture was quenched with sat. aq. NH4Cl (5 mL)
and the solution was extracted with ether (2 ꢂ 40 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residual oil was diluted with MeOH (10 mL)
and K2CO3 (439 mg, 3.18 mmol, 1.5 equiv) was added to the solu-
tion. After stirring at room temperature for 6 h the reaction mixture
was concentrated under reduced pressure. The residual oil was
purified by flash column chromatography on silica gel using pe-
127.7, 127.3, 114.6, 113.6, 92.8, 81.0, 69.8, 68.6, 55.3, 38.2, 30.7,
28.1 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C27H26O4Na
437.1723; Found 437.1718.
4.2.10. (R)-2-(4-Benzyloxyphenethyl)-6-(4-methoxyphenyl)-2,3-
dihydro-4H-pyran-4-one (6a)
To a solution of d-hydroxyalkynone 7a (207 mg, 0.5 mmol) in
MeOH (0.4 mL) was added p-TsOH$H2O (9.5 mg, 0.05 mmol, 10 mol
%) at room temperature. The reaction mixture was stirred at room
temperature until the TLC showed total consumption of starting
material (12 h). MeOH was then evaporated under reduced pres-
sure and the residue purified by silica gel column chromatography
using petroleum ether/EtOAc (2:1) as eluent to give 2,3-dihydro-
4H-pyran-4-one 6a (193 mg, 93 % yield) as pale yellow solid. M.p.
25
192e194 ꢃC; [
a]
þ14.8 (c ¼ 1.0, CHCl3); IR (CHCl3): nmax ¼ 3040,
D
2925, 2857, 2237, 2202, 1652, 1594, 1573, 1510, 1454, 1423, 1385,
1339, 1299, 1259, 1238, 1175, 1115, 1056, 1027, 915, 837, 736,
troleum ether/EtOAc (7:3) as eluent to give 13a (541 mg, 91 % yield)
as a pale yellow oil. [
a
]
þ9.8 (c ¼ 1.0, CHCl3); IR (CHCl3):
697 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.70 (d, J ¼ 8.6 Hz, 2H),
25
D
nmax ¼ 3549, 3293, 3033, 2927, 2864, 1610, 1511, 1454, 1382, 1240,
1176, 1061, 1025, 917, 859, 829, 740, 697, 641 cmꢀ1 1H NMR
(500 MHz, CDCl3):
¼ 7.45 (d, J ¼ 7.3 Hz, 2H), 7.42e7.38 (m, 1H),
7.43 (d, J ¼ 7.2 Hz, 2H), 7.41e7.36 (m, 2H), 7.35e7.30 (m, 1H), 7.15 (d,
J ¼ 8.1 Hz, 2H), 6.98e6.90 (m, 4H), 5.96 (s, 1H), 5.04 (s, 2H),
4.59e4.46 (m, 1H), 3.86 (s, 3H), 2.84e2.74 (m, 2H), 2.64e2.44 (m,
2H), 2.33e2.21 (m, 1H), 1.96e1.88 (m, 1H) ppm; 13C{1H} NMR
;
d
7.37e7.31 (m, 1H), 7.14 (d, J ¼ 8.3 Hz, 2H), 6.93 (d, J ¼ 8.4 Hz, 2H),
5.06 (s, 2H), 3.82e3.75 (m, 1H), 2.81e2.73 (m, 1H), 2.70e2.62 (m,
1H), 2.45 (ddd, J ¼ 16.5, 4.8, 2.7 Hz 1H), 2.36 (ddd, J ¼ 16.5, 4.8,
2.7 Hz, 1H), 2.08 (t, J ¼ 2.6 Hz, 1H), 1.99 (s, 1H), 1.89e1.81 (m, 2H)
(100 MHz, CDCl3):
d
¼ 193.1, 170.2, 162.5, 157.3, 137.1, 133.1, 129.3,
128.5, 128.4, 127.9, 127.4, 125.0, 115.0, 114.1, 100.7, 78.3, 70.1, 55.4,
41.3, 36.4, 30.5 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 157.0, 137.1, 133.9, 129.3,
C27H26O4Na 437.1723; Found 437.1721.
128.5, 127.8, 127.4, 114.8, 80.7, 70.9, 70.0, 69.0, 37.9, 30.9, 27.4 ppm;
HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C19H20O2Na 303.1356;
Found 303.1348.
4.2.11. (2R,4S,6R)-2-(4-Hydroxyphenethyl)-6-(4-methoxyphenyl)
tetrahydro-2H-pyran-4-ol (14a)
To a solution of compound 6a (180 mg, 0.43 mmol) in EtOAc
(3.0 mL) was added 10 % Pd/C (23 mg, 0.021 mmol, 5 mol%) and the
mixture hydrogenated for 10 h in autoclave (pressure 30 psi) at
room temperature. Then, the reaction mixture was filtered through
4.2.8. (S)-1-(4-Benzyloxyphenyl)hex-5-yn-3-ol (ent-13a)
The titled compound was prepared from ent-8a (500 mg,
1.97 mmol) by a similar procedure as described for 13a, to give ent-
6

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
celite pad and the filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (1:1) as eluent to give 14a (121 mg, 86 %) as a pale
4.2.15. 2-(4-Methoxyphenethyl)oxirane (8b0)
The titled compound was prepared from above olefin 1-(but-3-
en-1-yl)-4-methoxybenzene (1.5 g, 9.24 mmol) by following a
similar procedure as described for 8a′ to give 8b′ (1.56 g, 95 %) as
colorless oil. The spectral data is same as 8b below.
25
yellow solid. M.p. 146e148 ꢃC; [
a
]
D
þ38.3 (c ¼ 1.0, CHCl3); IR
(CHCl3): nmax ¼ 3355, 2922, 2851, 1613, 1515, 1452, 1367, 1304, 1248,
1177, 1066, 1035, 909, 829, 759, 612 cmꢀ1 1H NMR (500 MHz,
CDCl3):
;
d
¼ 7.33 (d, J ¼ 8.5 Hz, 2H), 7.06 (d, J ¼ 7.2 Hz, 2H), 6.92 (d,
4.2.16. (R)-2-(4-Methoxyphenethyl)oxirane (8b) and (S)-4-(4-
methoxyphenyl)butane-1,2-diol (9b)
The titled compounds were prepared from 8b′ (1.5 g,
8.42 mmol) by following a similar procedure as described for 8a
and 9a, to give 8b (0.645 g, 43 %) as colorless oil and 9b (0.776 g,
47 %) as white solid.
J ¼ 8.2 Hz, 2H), 6.78 (d, J ¼ 8.1 Hz, 2H), 4.32 (d, J ¼ 10.1 Hz, 1H),
3.98e3.89 (m, 1H), 3.84 (s, 3H), 3.50e3.41 (m, 1H), 2.78e2.63 (m,
2H), 2.24e2.17 (m, 1H), 2.04e1.92 (m, 2H), 1.82e1.73 (m, 1H),
1.56e1.47 (m, 1H), 1.38e1.26 (m, 2H) ppm; 13C{1H} NMR (125 MHz,
CDCl3):
d
¼ 159.0, 153.7, 134.3, 134.1, 129.5, 127.2, 115.2, 113.8, 76.9,
74.7, 68.6, 55.3, 42.6, 40.9, 37.7, 30.7 ppm; HRMS (ESIꢀTOF) m/z:
Data for 8b: [
a
]
25 þ22.0 (c ¼ 2, CHCl3); IR (CHCl3): nmax ¼ 3049,
D
[M þ Na]þ Calcd for C20H24O4Na 351.1567; Found 351.1561.
2997, 2927, 2836, 1884, 1612, 1512, 1454, 1410, 1300, 1245, 1179,
1113, 1035, 960, 912, 828, 755, 702, 561, 523 cmꢀ1
(500 MHz, CDCl3):
;
1H NMR
4.2.12. (2S,6R)-2-(4-Hydroxyphenethyl)-6-(4-methoxyphenyl)
tetrahydro-2H-pyran, (þ)-centrolobine (1)
d
¼ 7.12 (d, J ¼ 8.5 Hz, 2H), 6.84 (d, J ¼ 8.6 Hz,
2H), 3.78 (s, 3H), 2.95e2.92 (m, 1H), 2.79e2.67 (m, 3H), 2.47e2.45
To a solution of compound 14a (100 mg, 0.304 mmol) in CH2Cl2
was added CBr4 (111 mg, 0.335 mmol, 1.1 equiv) and PPh3 (88 mg,
0.335 mmol, 1.1 equiv) at 0 ꢃC. The reaction mixture was stirred at
0 ꢃC to room temperature until the complete consumption (6 h) of
starting material. The reaction mixture was concentrated and the
crude product (119 mg) was dissolved in the dry toluene. Then,
AIBN (5.6 mg, 0.034 mmol, 0.1 equiv) and tributyltin hydride
(0.33 mL, 1.22 mmol, 4 equiv) were added under the nitrogen at-
mosphere. The reaction mixture was refluxed for 24 h. The volatiles
were evaporated under reduced pressure and the residue was pu-
rified by silica gel column chromatography using petroleum ether/
(m, 1H), 1.86e1.78 (m, 2H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 157.8, 133.2, 129.2, 113.8, 55.1, 51.7, 47.1, 34.4, 31.2 ppm. The
enantiomeric excess was determined by chiral HPLC: CHIRALPAK
OD-H column, hexane/i-PrOH ¼ 99:1, flow rate ¼ 1.0 mL/min,
tR ¼ 8.81 min (major), tR ¼ 9.20 min (minor), 95 % ee.
25
Data for 9b: M.p. 96e98 ꢃC; [
a
]
ꢀ 13.6 (c ¼ 1, CHCl3); IR
D
(CHCl3): nmax ¼ 3371, 3257, 3018, 2924, 2905, 2864, 1608, 1581,
1512, 1454, 1376, 1317, 1303, 1254, 1215, 1176, 1102, 1016, 917, 871,
811, 758, 696, 668, 519 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼ 7.09 (d,
J ¼ 8.2 Hz, 2H), 6.80 (d, J ¼ 8.1 Hz, 2H), 3.83 (m, 2H), 3.75 (s, 3H),
3.68e3.59 (m, 2H), 3.50e3.36 (m, 1H), 2.75e2.55 (m, 2H),
EtOAc (2:1) as eluent to give (þ)-centrolobine (1) (59 mg, 62 %) as a
1.78e1.59 (m, 2H) ppm; 13C{1H} NMR (100 MHz, CHCl3):
d 157.7,
25
colourless solid. M.p. 80e82 ꢃC; [
a]
þ93.8 (c ¼ 0.5, MeOH), lit.3c
133.7, 129.2, 113.7, 71.5, 66.6, 55.1, 34.8, 30.8 ppm; HRMS (ESIꢀTOF)
D
25
[
a
]
þ97.0 (c ¼ 0.1, MeOH); IR (CHCl3): nmax ¼ 3393, 3007, 2934,
m/z: [M þ Na]þ Calcd for C11H16O3Na 219.0992; Found 219.0988.
D
2856, 1613, 1514, 1453, 1304, 1247, 1175, 1077, 1035, 951, 901, 829,
765, 575, 545 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼ 7.33 (d,
4.2.17. (R)-1-(4-Methoxyphenyl)hex-5-yn-3-ol (13b)
The titled compound was prepared from 8b (0.500 g,
2.81 mmol) by following a similar procedure as described for 13a,
J ¼ 8.3 Hz, 2H), 7.04 (d, J ¼ 7.4 Hz, 2H), 6.89 (d, J ¼ 8.1 Hz, 2H), 6.71
(d, J ¼ 8.2 Hz, 2H), 5.19 (brs, 1H), 4.32 (d, J ¼ 10.5 Hz, 1H), 3.81 (s,
3H), 3.53e3.40 (m, 1H), 2.78e2.60 (m, 2H), 2.04e1.92 (m, 2H),
1.82e1.61 (m, 2H), 1.56e1.47 (m, 2H), 1.38e1.26 (m, 2H) ppm; 13C
25
to give 13b (0.521 g, 91 %) as colorless oil. [
a
]
þ21.1 (c ¼ 1.5,
D
CHCl3); IR (CHCl3): nmax ¼ 3543, 3292, 3008, 2938, 2836, 2117, 1879,
{1H} NMR (100 MHz, CDCl3):
d
¼ 158.7, 153.5, 135.7, 134.4, 129.5,
1612, 1583, 1512, 1464, 1300, 1246, 1178, 1061, 1033, 946, 858, 826,
127.1, 115.1, 113.6, 79.1, 77.2, 55.3, 38.2, 33.1, 31.2, 30.7, 24.0 ppm;
HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C20H24O3Na 335.1618;
Found 335.1624.
758, 641, 522 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.12 (d,
J ¼ 8.4 Hz, 2H), 6.83 (d, J ¼ 8.6 Hz, 2H), 3.78 (s, 3H), 3.77e3.74 (m,
1H), 2.78e2.60 (m, 2H), 2.47e2.31 (m, 2H), 2.12 (br s, 1H), 2.06 (t,
J ¼ 2.7 Hz 1H), 1.86e1.80 (m, 2H) ppm; 13C{1H} NMR (100 MHz,
4.2.13. 3-(4-Methoxyphenyl)propan-1-ol (12b). [20]
CDCl3):
d
¼ 157.7, 133.6, 129.2, 113.8, 80.7, 70.9, 69.0, 55.2, 37.9, 30.9,
The titled compound was prepared from 11b (2.0 g, 14.69 mmol)
by following a similar procedure as described for 12a, to give 12b
(1.90 g, 78 %) as colorless oil. IR (CHCl3): nmax ¼ 3381, 2937, 1612,
1583,1512,1461,1300,1245,1178, 1111,1037, 912, 839, 811, 766, 700,
27.4 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C13H16O2Na
227.1042; Found 227.1043.
4.2.18. 3,4-Bis(benzyloxy)benzaldehyde (15b)
564, 522 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.12 (d, J ¼ 8.1 Hz,
The titled compound was prepared from commercially available
3,4-dihydroxybenzaldehyde (0.50 g, 3.62 mmol) by following a
similar procedure as described for 11a, to give 15b (1.08 g, 94 %) as
white solid. M.p. 92e94 ꢃC; IR (KBr pallete): nmax ¼ 2830, 2744,
1690, 1603, 1578, 1512, 1393, 1261, 1168, 1019, 831, 736, 697,
2H), 6.84 (d, J ¼ 8.5 Hz, 2H), 3.78 (s, 3H), 3.65 (t, J ¼ 6.6 Hz, 2H), 2.65
(t, J ¼ 7.7 Hz, 2H), 1.90e1.81 (m, 2H); 13C{1H} NMR (125 MHz,
CDCl3):
31.0 ppm.
d
¼ 157.6, 133.8, 129.2, 113.6, 61.9, 61.86, 55.1, 34.2,
514 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
¼ 9.81 (s,1H), 7.50e7.44 (m,
4.2.14. 1-(But-3-en-1-yl)-4-methoxybenzene. [21]
5H), 7.42e7.37 (m, 5H), 7.35e7.31 (m, 2H), 7.02 (d, J ¼ 8.3 Hz, 1H),
The titled compound was prepared from 12b (1.90 g,
11.43 mmol) by following a similar procedure as described for 1-
(benzyloxy)-4-(but-3-en-1-yl)benzene to give the olefin 1-(but-3-
en-1-yl)-4-methoxybenzene (1.54 g, 83 %) as colorless oil. IR
(CHCl3): nmax ¼ 3075, 2997, 2930, 2834,1639,1612,1583,1513,1465,
1300, 1246, 1177, 1115, 1038, 996, 912, 823, 752, 702, 625, 552,
5.25 (s, 2H), 5.21 (s, 2H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 190.8, 154.2, 149.1, 136.5, 136.1, 130.2, 128.6, 128.5, 128.0, 127.9,
127.2, 127.0, 126.6, 113.0, 112.2, 70.9, 70.7 ppm; HRMS (ESIꢀTOF) m/
z: [M þ Na]þ Calcd for C21H18O3Na 341.1148; Found 341.1137.
4.2.19. (R)-7-(4-Benzyloxyphenyl)-1-(3,4-dimethoxyphenyl)-5-
hydroxyhept-2-yn-1-one (7b)
518 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.14 (d, J ¼ 8.6 Hz, 2H),
6.87 (d, J ¼ 8.6 Hz, 2H), 5.95e5.84 (m, 1H), 5.10e5.00 (m, 2H), 3.82
The titled compound was prepared from 13a (200 mg,
0.713 mmol) by following a similar procedure as described for 7a, to
(s, 3H), 2.70 (t, J ¼ 7.4 Hz, 2H), 2.39 (q, J ¼ 6.8 Hz, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3):
55.1, 35.7, 34.4 ppm.
d
¼ 157.7, 138.1, 133.9, 129.3, 114.8, 113.6,
give 7b (206 mg, 65 %) as yellow oil. [
(CHCl3): nmax ¼ 3433, 2932, 2223,1632,1581,1512,1463,1420,1340,
a
]
25 þ6.2 (c ¼ 1.0, CHCl3); IR
D
7

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
1272, 1223, 1177, 1142, 1110, 1022, 820, 750, 697 cmꢀ1
;
1H NMR
0.54 mmol) by following a similar procedure as described for 6a, to
give 6c (178 mg, 89 %) as yellow solid. M.p. 192e194 ꢃC;
(500 MHz, CDCl3):
d
¼ 7.81 (dd, J ¼ 8.1, 2.0 Hz, 1H), 7.59 (d,
J ¼ 1.7 Hz, 1H), 7.42 (d, J ¼ 7.0 Hz, 2H), 7.40e7.35 (m, 2H), 7.34e7.29
(m, 1H), 7.13 (d, J ¼ 8.7 Hz, 2H), 6.90 (d, J ¼ 8.7 Hz, 2H), 6.87 (d,
J ¼ 8.7 Hz, 1H), 5.02 (s, 2H), 3.96e3.93 (m, 1H), 3.93 (s, 3H), 3.90 (s,
3H), 2.83e2.76 (m, 1H), 2.73e2.65 (m, 3H), 1.96e1.88 (m, 2H) ppm;
[
a
]
D
25 þ125.8 (c ¼ 2.0, CHCl3); IR (CHCl3): nmax ¼ 3006, 2934, 2836,
1654, 1598, 1573, 1513, 1464, 1422, 1386, 1321, 1271, 1247, 1173, 1143,
1061, 1024, 965, 890, 811, 753, 700, 545 cmꢀ1
CDCl3):
;
1H NMR (500 MHz,
¼ 7.38 (d, J ¼ 8.6 Hz, 1H), 7.24 (d, J ¼ 1.5 Hz, 1H), 7.14 (d,
d
13C{1H} NMR (125 MHz, CDCl3):
d
¼ 176.8, 157.0, 154.2, 148.8, 137.0,
J ¼ 8.4 Hz, 2H), 6.91 (d, J ¼ 8.6 Hz, 1H), 6.84 (d, J ¼ 8.5 Hz, 2H), 5.94
(s, 1H), 4.53e4.49 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 3.78 (s, 3H),
2.92e2.79 (m, 2H), 2.61e2.46 (m, 2H), 2.31e2.23 (m,1H), 2.05e1.99
133.6,130.0,129.3,128.5,127.8,127.4,125.7,114.8,110.1,109.97, 92.4,
81.1, 69.9, 68.8, 56.0, 55.9, 38.2, 30.8, 28.2 ppm; HRMS (ESIꢀTOF) m/
z: [M þ Na]þ Calcd for C28H28O5Na 467.1829; Found 467.1828.
(m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 193.1, 170.0,
158.0, 152.1, 148.8, 132.6, 129.2, 125.2, 120.3, 114.0, 113.8, 110.8,
109.0, 100.9, 78.3, 56.0, 55.9, 55.2, 41.3, 36.4, 30.5 ppm; HRMS
(ESIꢀTOF) m/z: [M þ Na]þ Calcd for C22H24O5Na 391.1516; Found
391.1521.
4.2.20. (R)-1-(3,4-Dimethoxyphenyl)-5-hydroxy-7-(4-
methoxyphenyl)hept-2-yn-1-one (7c)
The titled compound was prepared from 13b (200 mg,
0.98 mmol) by following a similar procedure as described for 7a, to
give 7c (249 mg, 69 %) as colorless oil. [
a
]
25 þ8.2 (c ¼ 1.0, CHCl3); IR
4.2.24. (R)-2-(3,4-Bis(benzyloxy)phenyl)-6-(4-
D
(CHCl3): nmax ¼ 3443, 3008, 2936, 2839, 2223, 1634, 1580, 1513,
methoxyphenylethyl)-2,3-dihydro-4H-pyran-4-one (6d)
The titled compound was prepared from 7d (200 mg,
0.384 mmol) by following a similar procedure as described for 6a,
1464, 1419, 1345, 1274, 1219, 1177, 1143, 1108, 1021, 835, 750,
616 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.78 (d, J ¼ 8.3 Hz, 1H),
7.56 (s, 1H), 7.11 (d, J ¼ 8.1 Hz, 2H), 6.85 (d, J ¼ 8.3 Hz, 1H), 6.80 (d,
J ¼ 8.1 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H), 2.80e2.75 (m,
1H), 2.72e2.62 (m, 4H), 1.96e1.86 (m, 2H) ppm; 13C{1H} NMR
to give 6d (186 mg, 93 %) as yellow solid. M.p. 178e180 ꢃC;
25
[
a
]
D
þ90.1 (c ¼ 1.0, CHCl3); IR (CHCl3): nmax ¼ 3030, 2930, 2867,
1654,1597,1571,1512,1454,1433,1382,1320,1271,1246,1206,1178,
1140, 1061, 1024, 892, 848, 811, 750, 697, 545 cmꢀ1 1H NMR
(500 MHz, CDCl3):
(125 MHz, CDCl3):
d
¼ 176.8, 157.8, 154.2, 148.8, 133.3, 130.0, 129.2,
;
125.7, 113.8, 110.2, 110.0, 92.4, 81.1, 68.8, 56.1, 55.9, 55.2, 38.3, 30.8,
28.2 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C22H24O5Na
391.1516; Found 391.1514.
d
¼ 7.46e7.44 (m, 4H), 7.40e7.37 (m, 3H),
7.35e7.31 (m, 5H), 7.13 (d, J ¼ 8.4 Hz, 2H), 6.96 (d, J ¼ 8.2 Hz, 1H),
6.85 (d, J ¼ 8.5 Hz, 2H), 5.89 (s, 1H), 5.24 (s, 2H), 5.21 (s, 2H),
4.50e4.44 (m, 1H), 3.79 (s, 3H), 2.88e2.82 (m, 1H), 2.79e2.79 (m,
1H), 2.58e2.44 (m, 2H), 2.27e2.19 (m, 1H), 2.01e1.96 (m, 1H) ppm;
4.2.21. (R)-1-(3,4-Bis(benzyloxy)phenyl)-5-hydroxy-7-(4-
methoxyphenyl)hept-2-yn-1-one (7d)
13C{1H} NMR (125 MHz, CDCl3):
d
¼ 193.1, 169.9, 158.0, 152.0, 148.5,
The titled compound was prepared from 13b (200 mg,
136.7, 136.4, 132.7, 129.3, 128.6, 128.0, 127.95, 127.1, 127.08, 125.5,
120.8, 114.0, 113.96, 113.7, 112.8, 100.9, 78.2, 71.3, 70.8, 55.2, 41.2,
36.4, 30.4 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
0.98 mmol) by following a similar procedure as described for 7a, to
25
give 7d (321 mg, 63 %) as yellow semisolid. [
a
]
þ17.2 (c ¼ 1.0,
D
CHCl3); IR (CHCl3): nmax ¼ 3433, 3030, 2928, 2864, 2221, 1591, 1511,
C34H32O5Na 543.2142; Found 543.2140.
1463, 1418, 1275, 1178, 1143, 1021, 917, 834, 749, 697, 617 cmꢀ1; 1H
NMR (500 MHz, CDCl3):
d
¼ 7.78 (d, J ¼ 7.1 Hz, 1H), 7.72 (s, 1H),
4.2.25. (2R,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-hydroxy
phenethyl)tetrahydro-2H-pyran-4-ol (14b)
7.48e7.44 (m, 4H), 7.40e7.35 (m, 4H), 7.33e7.31 (m, 2H), 7.16e7.14
(m, 2H), 6.92 (d, J ¼ 8.4 Hz, 1H), 6.84 (d, J ¼ 8.3 Hz, 2H), 5.20 (s, 2H),
5.18 (s, 2H), 3.97e3.90 (m, 1H), 3.77 (s, 3H), 3.07 (br, 1H), 2.82e2.78
(m, 1H), 2.71e2.65 (m, 3H), 1.98e1.86 (m, 2H) ppm; 13C{1H} NMR
The titled compound was prepared from 6b (150 mg,
0.34 mmol) by following a similar procedure as described for 14a,
25
to give 14b (96 mg, 79 %) as pale yellow oil. [
a
]
þ39.1 (c ¼ 1.0,
D
(125 MHz, CDCl3):
d
¼ 176.7, 157.7, 154.0, 148.3, 136.5, 136.1, 133.4,
CHCl3); IR (CHCl3): nmax ¼ 3395, 2921, 2850, 1662, 1610, 1512, 1447,
130.1, 129.2, 128.5, 128.3, 127.9, 127.8, 127.2, 126.9, 125.7, 113.7, 113.5,
112.5, 92.7, 81.0, 70.8, 70.5, 68.7, 55.1, 38.2, 30.8, 28.1 ppm; HRMS
(ESIꢀTOF) m/z: [M þ Na]þ Calcd for C34H32O5Na 543.2142; Found
543.2141.
1368, 1288,1245, 1178, 1119,1025, 998, 920, 823, 760 cmꢀ1; 1H NMR
(500 MHz, CDCl3):
d
¼ 6.99 (d, J ¼ 8.4 Hz, 2H), 6.93 (s, 1H),
6.91e6.87 (m, 1H), 6.83 (d, J ¼ 8.4 Hz, 1H), 6.71 (d, J ¼ 8.4 Hz, 2H),
4.26 (d, J ¼ 11.9 Hz, 1H), 3.94e3.87 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
3.46e3.38 (m, 1H), 2.71e2.59 (m, 2H), 2.22e2.14 (m, 1H), 2.01e1.88
(m, 2H), 1.78e1.69 (m, 1H), 1.56e1.45 (m, 1H), 1.35e1.26 (m, 1H)
4.2.22. (R)-2-(4-Benzyloxyphenethyl)-6-(3,4-dimethoxyphenyl)-
2,3-dihydro-4H-pyran-4-one (6b)
ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 153.9, 148.7, 148.3, 134.6,
The titled compound was prepared from 7b (200 mg,
0.45 mmol) by following a similar procedure as described for 6a, to
133.6, 129.4, 118.3, 115.2, 110.9, 109.5, 77.0, 74.8, 68.5, 55.8, 55.76,
42.3, 40.6, 37.6, 30.6 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd
for C21H26O5Na 381.1672; Found 381.1677.
give 6b (184 mg, 92 %) as yellow solid. M.p. 164e166 ꢃC; [
a
]
25 þ70.8
D
(c ¼ 2.0, CHCl3); IR (CHCl3): nmax ¼ 3016, 2928, 1656, 1599, 1508,
1456, 1424, 1381, 1321, 1273, 1176, 1142, 1023, 853, 810, 756,
4.2.26. (2R,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-
methoxyphenethyl)tetrahydro-2H-pyran-4-ol (14c)
The titled compound was prepared from 6c (150 mg, 0.41 mmol)
695 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.45e7.35 (m, 5H),
7.35e7.30 (m, 1H), 7.27e7.24 (m, 1H), 7.15 (d, J ¼ 8.2 Hz, 2H),
6.96e6.90 (m, 3H), 5.97 (s, 1H), 5.05 (s, 2H), 4.59e4.46 (m, 1H), 3.94
(s, 3H), 3.92 (s, 3H), 2.96e2.78 (m, 2H), 2.65e2.46 (m, 2H),
2.34e2.24 (m, 1H), 2.07e1.98 (m, 1H) ppm; 13C{1H} NMR (100 MHz,
by following a similar procedure as described for 14a, to give 14c
25
(113 mg, 75 %) as colorless oil. [
a
]
D
þ41.9 (c ¼ 1.0, CHCl3); IR
(CHCl3): nmax ¼ 3418, 3008, 2939, 2836, 1611, 1595, 1513, 1464, 1418,
CDCl3):
d
¼ 193.1, 170.0, 157.3, 152.1, 148.9, 137.0, 132.9, 129.3, 128.5,
1364, 1299, 1246, 1179, 1162, 1138, 1070, 1029, 946, 885, 846, 810,
127.9, 127.4, 125.2, 120.3, 115.0, 110.8, 109.0, 100.9, 78.3, 70.0, 56.0,
55.9, 41.2, 36.3, 30.5 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd
for C28H28O5Na 467.1829; Found 467.1832.
757, 666, 643, 609, 560 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.10
(d, J ¼ 8.7 Hz, 2H), 6.95e6.90 (m, 2H), 6.86e6.81 (m, 3H), 4.29 (d,
J ¼ 10.1 Hz, 1H), 3.96e3.92 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s,
3H), 3.47e3.42 (m, 1H), 2.78e2.64 (m, 2H), 2.22e2.18 (m, 1H),
2.03e1.92 (m, 2H), 1.82e1.73 (m, 2H), 1.50 (q, J ¼ 11.4 Hz, 1H),
4.2.23. (R)-6-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenethyl)-2,3-
dihydro-4H-pyran-4-one (6c)
1.35e1.27 (m, 1H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
d
¼ 157.6,
The titled compound was prepared from 7c (200 mg,
148.8, 148.3, 134.7, 134.0, 129.3, 118.1, 113.7, 110.9, 109.3, 77.2, 74.7,
8

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
68.5, 55.9, 55.8, 55.2, 42.6, 40.8, 37.7, 30.7 ppm; HRMS (ESIꢀTOF) m/
z: [M þ Na]þ Calcd for C22H28O5Na 395.1829; Found 395.1832.
1.67e1.54 (m, 3H), 1.40e1.33 (m, 1H) ppm; 13C{1H} NMR (125 MHz,
CDCl3):
d
¼ 157.5, 143.5, 143.3, 135.2, 134.3, 129.3, 118.9, 115.1, 113.8,
79.7, 77.9, 55.3, 38.1, 32.5, 31.1, 30.7, 23.9 ppm; HRMS (ESIꢀTOF) m/
4.2.27. (2R,4S,6R)-2-(3,4-Dihydroxyphenyl)-6-(4-
methoxyphenethyl)tetrahydro-2H-pyran-4-ol (14d)
z: [M þ Na]þ Calcd for C20H24O4Na 351.1567; Found 351.1567.
The titled compound was prepared from 6d (150 mg,
0.29 mmol) by following a similar procedure as described for 14a,
4.2.31. (2S,6R)-4-[2-(6-(4-Methoxyphenyl)tetrahydro-2H-pyran-2-
yl)ethyl]phenyl acetate (17a)
to give 14d (81 mg, 82 %) as yellow semisolid. [
a
]
25 þ22.7 (c ¼ 1.0,
To a solution of 1 (40 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added
Et3N (0.04 mL, 0.26 mmol, 2 equiv) and acetic anhydride (0.02 mL,
0.2 mmol, 1.5 equiv) followed by addition of catalytic amount of
DMAP (1.6 mg, 0.013 mmol, 0.1 equiv). The mixture was stirred at
room temperature for 2 h. It was then quenched with sat. aq. NH4Cl
(1 mL) and the solution extracted with EtOAc (2 ꢂ 3 mL). The
combined organic layers were washed with water, brine, dried
(Na2SO4) and concentrated. The residue was purified by silica gel
column chromatography using petroleum ether/EtOAc (7:3) as
D
CHCl3); IR (CHCl3): nmax ¼ 3394, 2919, 2850, 2256, 1660, 1610, 1512,
1446, 1368, 1288, 1246, 1178, 1120, 1049, 1025, 998, 919, 823,
761 cmꢀ1; 1H NMR (500 MHz, acetone-d6):
d
¼ 7.90 (br s, 2H), 7.10
(d, J ¼ 8.2 Hz, 2H), 6.91 (d, J ¼ 1.8 Hz, 1H), 6.81 (d, J ¼ 8.5 Hz, 2H),
6.77 (d, J ¼ 8.5 Hz, 1H), 6.72e6.68 (m, 1H), 4.20 (d, J ¼ 10.6 Hz, 1H),
4.04 (br s, 1H), 3.87e3.80 (m, 1H), 3.73 (s, 3H), 3.43e3.37 (m, 1H),
2.77e2.60 (m, 2H), 2.10e2.05 (m, 1H), 1.96e1.91 (m, 1H), 1.87e1.78
(m, 1H), 1.76e1.68 (m, 1H), 1.39e1.31 (m, 1H), 1.23e1.16 (m, 1H)
ppm; 13C{1H} NMR (125 MHz, acetone-d6):
d
¼ 158.7, 145.6, 145.0,
eluent to give 17a (39 mg, 85 %) as colorless oil. [
a
]
25 þ45.8 (c ¼ 1.0,
D
135.9, 135.0, 130.1, 118.1, 115.6, 114.5, 114.1, 77.9, 75.4, 68.4, 55.4,
44.3, 42.0, 39.0, 31.4 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd
for C20H24O5Na 367.1516; Found 367.1518.
CHCl3); IR (CHCl3): nmax ¼ 2933, 2856, 1763, 1613, 1514, 1455, 1369,
1303,1247,1195, 1080, 1038, 911, 833, 766 cmꢀ1; 1H NMR (500 MHz,
CDCl3):
d
¼ 7.33 (d, J ¼ 8.4 Hz, 2H), 7.20 (d, J ¼ 8.4 Hz, 2H), 6.99 (d,
J ¼ 8.4 Hz, 2H), 6.89 (d, J ¼ 8.4 Hz, 2H), 4.31 (d, J ¼ 10.5 Hz, 1H), 3.81
(s, 3H), 3.50e3.42 (m, 1H), 2.85e2.68 (m, 2H), 2.29 (s, 3H),
1.97e1.87 (m, 2H), 1.87e1.81 (m, 1H), 1.80e1.72 (m, 1H), 1.66e1.59
(m, 2H), 1.56e1.46 (m, 1H), 1.39e1.31 (m, 1H) ppm; 13C{1H} NMR
4.2.28. (2S,6R)-6-(3,4-Dimethoxyphenyl)-2-(4-hydroxyphenethyl)
tetrahydro-2H-pyran (16a)
The titled compound was prepared from 14b (80 mg,
0.223 mmol) by following a similar procedure as described for 1, to
(125 MHz, CDCl3):
d
¼ 169.7, 158.7, 148.6, 140.0, 135.8, 129.4, 127.0,
give 16a (43 mg, 56 %) as colorless oil. [
a
]
25 þ8.0 (c ¼ 1.0, CHCl3); IR
121.2, 113.5, 79.0, 76.95, 55.2, 37.9, 33.3, 31.2, 31.0, 24.0, 21.1 ppm;
HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C22H26O4Na 377.1723;
Found 377.1727.
D
(CHCl3): nmax ¼ 3393, 3027, 2934, 2850, 1612,1514,1454,1303, 1247,
1176, 1075, 1035, 829, 765, 541 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
¼ 7.03 (d, J ¼ 8.3 Hz, 2H), 6.97 (s, 1H), 6.95e6.90 (m, 1H), 6.84 (d,
J ¼ 8.2 Hz, 1H), 6.71 (d, J ¼ 8.2 Hz, 2H), 4.31 (d, J ¼ 10.6 Hz, 1H), 3.89
(s, 3H), 3.86 (s, 3H), 3.50e3.43 (m, 1H), 2.76e2.61 (m, 2H),
1.97e1.88 (m, 2H), 1.87e1.82 (m, 1H), 1.78e1.71 (m, 1H), 1.69e1.60
(m, 2H), 1.58e1.50 (m, 1H), 1.39e1.29 (m, 1H) ppm; 13C{1H} NMR
4.2.32. (2S,6R)-4-[2-(6-(3,4-Dimethoxyphenyl)tetrahydro-2H-
pyran-2-yl)ethyl]phenyl acetate (17b)
The titled compound was prepared from 16a (40 mg, 0.12 mmol)
by following a similar procedure as described for 17a, to give 17b
(125 MHz, CDCl3):
d
¼ 153.6, 148.7, 148.1, 136.2, 134.3, 129.4, 118.1,
(42 mg, 91 %) as colorless oil. [
a
]
25 þ6.2 (c ¼ 1.0, CHCl3); IR (CHCl3):
D
115.1, 110.9, 109.4, 79.3, 77.3, 55.9, 55.8, 38.2, 33.2, 31.1, 30.7,
24.0 ppm; HRMS (ESIꢀTOF) m/z: [M þ K]þ Calcd for C21H26O4K
381.1463; Found 381.1465.
nmax ¼ 3000, 2936, 2838, 1762, 1605, 1592, 1517, 1464, 1416, 1369,
1313, 1265, 1195, 1163, 1137, 1085, 1030, 911, 852, 808, 636, 593,
566 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.20 (d, J ¼ 8.3 Hz, 2H),
6.99e6.96 (m, 3H), 6.92 (d, J ¼ 8.4 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz, 1H),
4.31 (d, J ¼ 11.1 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.50e3.43 (m, 1H),
2.84e2.69 (m, 2H), 2.28 (s, 3H), 1.98e1.88 (m, 2H), 1.88e1.82 (m,
1H), 1.82e1.74 (m, 1H), 1.67e1.61 (m, 2H), 1.57e1.47 (m, 1H),
4.2.29. (2R,6S)-2-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenethyl)
tetrahydro-2H-pyran (16b)
The titled compound was prepared from 14c (80 mg,
0.215 mmol) by following a similar procedure as described for 1, to
1.39e1.31 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 169.6,
give 16b (57 mg, 75 %) as pale yellow semi solid. [
a
]
25 þ94.1 (c ¼ 1.0,
148.7, 148.6, 148.0, 140.0, 136.3, 129.3, 121.2, 117.9, 110.9, 109.3, 79.2,
77.0, 55.9, 55.8, 37.9, 33.3, 31.2, 31.0, 23.9, 21.1 ppm; HRMS
(ESIꢀTOF) m/z: [M þ Na]þ Calcd for C23H28O5Na 407.1829; Found
407.1815.
D
CHCl3); IR (CHCl3): nmax ¼ 3018, 2936, 2838, 1611, 1513, 1465, 1388,
1300, 1261, 1246, 1216, 1179, 1137, 1076, 1030, 900, 808, 755,
667 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.12 (d, J ¼ 8.6 Hz, 2H),
6.98 (d, J ¼ 1.7 Hz, 1H), 6.93 (d, J ¼ 8.3 Hz, 1H), 6.86e6.82 (m, 3H),
4.31 (d, J ¼ 11.1 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H),
3.48e3.44 (m, 1H), 2.78e2.66 (m, 2H), 1.96e1.90 (m, 2H), 1.86e1.84
(m, 1H), 1.78e1.73 (m, 1H), 1.67e1.61 (m, 2H), 1.56e1.48 (m, 1H),
4.2.33. 4-(Benzyloxy)-3-methoxybenzaldehyde (15c). [22]
The titled compound was prepared from commercially available
vanillin (0.50 g, 3.29 mmol) by following a similar procedure as
described for 11a, to give 15c (0.764 g, 96 %) as colorless solid. M.p.
70e72 ꢃC; IR (KBr pallet): nmax ¼ 2830, 2744, 1686, 1603, 1579, 1513,
1393, 1320, 1302, 1261, 1164, 1019, 865, 831, 736, 693, 517 cmꢀ1; 1H
1.38e1.33 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 157.6,
148.7, 148.0, 136.3, 134.4, 129.3, 117.9, 113.6, 110.8, 109.3, 79.1, 77.1,
55.9, 55.7, 55.2, 38.2, 33.3, 31.2, 30.7, 24.0 ppm; HRMS (ESIꢀTOF) m/
z: [M þ Na]þ Calcd for C22H28O4Na 379.1880; Found 379.1873.
NMR (400 MHz, CDCl3):
7.39e7.35 (m, 3H), 7.34e7.29 (m,1H), 6.97 (d, J ¼ 8.3 Hz,1H), 5.22 (s,
2H), 3.92 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3):
d
¼ 9.81 (s, 1H), 7.45e7.40 (m, 3H),
4.2.30. (2R,6S)-2-(3,4-Dihydroxyphenyl)-6-(4-methoxyphenethyl)
tetrahydro-2H-pyran (16c)
The titled compound was prepared from 14d (80 mg,
0.232 mmol) by following a similar procedure as described for 1, to
d
¼ 190.8,
153.5, 149.9, 135.9, 130.1, 128.6, 128.1, 127.1, 126.5, 112.2, 109.2, 70.7,
55.9 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C15H14O3Na
265.0835; Found 265.0828.
give 16c (40 mg, 52 %) as colorless oil. [
a]
25 þ92.6 (c ¼ 1.0, CHCl3); IR
D
(CHCl3): nmax ¼ 3393, 3023, 2934, 2854,1615,1514,1452,1442,1247,
4.2.34. (S)-1-(4-Benzyloxy-3-methoxyphenyl)-7-(4-
benzyloxyphenyl)-5-hydroxyhept-2-yn-1-one (18)
The titled compound was prepared from ent-13a (200 mg,
0.713 mmol) by following a similar procedure as described for 7a, to
give 18 (275 mg, 74 %) as colorless oil. [
1175, 1076, 1035, 902, 829, 766, 544 cmꢀ1
CDCl3):
;
1H NMR (500 MHz,
d
¼ 7.10 (d, J ¼ 8.6 Hz, 2H), 6.83e6.81 (m, 3H), 6.75e6.69 (m,
2H), 5.98 (br s, 2H), 4.24 (d, J ¼ 11.1 Hz, 1H), 3.78 (s, 3H), 3.53e3.49
(m, 1H), 2.77e2.65 (m, 2H), 1.97e1.90 (m, 2H), 1.80e1.73 (m, 2H),
a]
25 ꢀ 8.3 (c ¼ 0.5, CHCl3); IR
D
9

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
(CHCl3): nmax ¼ 3433, 3064, 3031, 2928, 2864, 2222, 1632, 1581,
55.8, 38.2, 33.2, 31.1, 30.7, 24.0 ppm; HRMS (ESIꢀTOF) m/z: [M þ
1511, 1454, 1419, 1381, 1344, 1274, 1178, 1143, 1108, 1023, 919, 834,
Na]þ Calcd for C20H24O4Na 351.1567; Found 351.1554.
749, 697, 617 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
¼ 7.76 (d,
J ¼ 8.3 Hz, 1H), 7.62 (d, J ¼ 1.3 Hz, 1H), 7.46e7.41 (m, 4H), 7.41e7.36
(m, 4H), 7.35e7.30 (m, 2H), 7.14 (d, J ¼ 8.6 Hz, 2H), 6.95e6.86 (m,
3H), 5.21 (s, 2H), 5.04 (s, 2H), 3.97e3.93 (m, 1H), 3.91 (s, 3H),
4.2.38. (2S,4R,6S)-2-(4-Acetoxy-3-methoxyphenyl)-6-(4-
acetoxyphenethyl)tetrahydro-2H-pyran-4-yl acetate (20a)
The titled compound was prepared from 3 (30 mg, 0.09 mmol)
2.84e2.76 (m, 1H), 2.75e2.59 (m, 4H), 1.98e1.87 (m, 2H) ppm; 13
C
by following a similar procedure as described for 17a, to give 20a
25
{1H} NMR (100 MHz, CDCl3):
d
¼ 176.8, 157.0, 153.4, 149.3, 137.0,
(31 mg, 75 %) as colorless oil. [
a
]
ꢀ 20.4 (c ¼ 0.5, CHCl3); IR
D
135.9, 133.6, 130.2, 129.3, 128.6, 128.5, 128.1, 127.8, 127.4, 127.1,
125.5, 114.8, 112.0, 110.6, 92.3, 81.2, 70.7, 69.9, 68.8, 55.9, 38.2, 30.8,
28.2 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C34H32O5Na
543.2142; Found 543.2140.
(CHCl3): nmax ¼ 2930, 2854, 1764, 1742, 1605, 1508, 1468, 1369, 1324,
1246, 1217, 1196, 1165, 1122, 1070, 1034, 910, 837, 757, 668 cmꢀ1; 1H
NMR (500 MHz, CDCl3):
d
¼ 7.18 (d, J ¼ 8.5 Hz, 2H), 7.02e6.96 (m,
4H), 6.93 (d, J ¼ 8.2 Hz, 1H), 5.07e4.98 (m, 1H), 4.40 (d, J ¼ 10.5 Hz,
1H), 3.84 (s, 3H), 3.57e3.49 (m, 1H), 2.86e2.77 (m, 1H), 2.77e2.67
(m, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.27e2.22 (m, 1H), 2.04 (s, 3H),
2.04e2.00 (m, 1H), 2.00e1.93 (m, 1H), 1.86e1.78 (m, 1H), 1.56e1.50
(m, 1H), 1.47e1.39 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
4.2.35. (S)-6-(4-Benzyloxy-3-methoxyphenyl)-2-(4-
benzyloxyphenethyl)-2,3-dihydro-4H-pyran-4-one (19)
The titled compound was prepared from 18 (200 mg,
0.384 mmol) by following a similar procedure as described for 6a,
to give 19 (184 g, 92 %) as yellow solid. M.p. 168e170 ꢃC;
d
¼ 170.5, 169.7, 169.1, 150.9, 148.8, 140.8, 139.4, 138.9, 129.3, 122.5,
121.4, 117.9, 110.0, 76.7, 74.6, 70.5, 55.9, 39.1, 37.5, 37.0, 31.0, 21.3,
[
a
]
25 ꢀ 148.5 (c ¼ 1.0, CHCl3); IR (CHCl3): nmax ¼ 3012, 2934, 2871,
21.1, 20.7 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
D
1653, 1597, 1574, 1510, 1454, 1422, 1381, 1321, 1272, 1175, 1142, 1024,
C26H30O8Na 493.1833; Found 493.1828.
890, 853, 809, 697, 667 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.46e7.42 (m, 4H), 7.41e7.37 (m, 4H), 7.36e7.32 (m, 3H), 7.29 (d,
4.2.39. (2R,6S)-4-[2-(6-(4-Acetoxy-3-methoxyphenyl)tetrahydro-
2H-pyran-2-yl)ethyl]phenyl acetate (20b)
The titled compound was prepared from 2 (30 mg, 0.091 mmol)
by following a similar procedure as described for 17a, to give 20b
J ¼ 1.9 Hz, 1H), 7.16 (d, J ¼ 8.6 Hz, 2H), 6.96e6.91 (m, 3H), 5.97 (s,
1H), 5.22 (s, 2H), 5.05 (s, 2H), 4.57e4.48 (m, 1H), 3.93 (s, 3H),
2.95e2.78 (m, 2H), 2.63e2.47 (m, 2H), 2.32e2.22 (m, 1H),
25
2.07e1.97 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 193.1,
(34 mg, 89 %) as colorless oil. [
a
]
ꢀ 65.4 (c ¼ 1.0, CHCl3); IR
D
169.9, 157.2, 151.2, 149.3, 137.0, 136.2, 132.9, 129.3, 128.6, 128.5,
128.0, 127.9, 127.4, 127.1, 125.4, 120.1, 114.9, 113.0, 109.5, 100.9, 78.2,
70.7, 69.9, 55.9, 41.2, 36.3, 30.4 ppm; HRMS (ESIꢀTOF) m/z: [M þ
Na]þ Calcd for C34H32O5Na 543.2142; Found 543.2141.
(CHCl3): nmax ¼ 2932, 2854, 1764, 1606, 1508, 1465, 1416, 1369, 1274,
1196, 1155, 1121, 1084, 1038, 1017, 911, 893, 753 cmꢀ1 1H NMR
(500 MHz, CDCl3):
;
d
¼ 7.19 (d, J ¼ 8.1 Hz, 2H), 7.05 (s, 1H), 7.01e6.96
(m, 3H), 6.93 (d, J ¼ 8.1 Hz, 1H), 4.33 (d, J ¼ 11.3 Hz, 1H), 3.85 (s, 3H),
3.50e3.42 (m, 1H), 2.84e2.69 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H),
1.98e1.89 (m, 2H), 1.89e1.83 (m, 1H), 1.82e1.74 (m, 1H), 1.68e1.64
(m, 1H), 1.53e1.44 (m, 1H) 1.39e1.24 (m, 2H) ppm; 13C{1H} NMR
4.2.36. (2S,4R,6S)-2-(4-Hydroxy-3-methoxyphenyl)-6-(4-
hydroxyphenethyl)tetrahydro-2H-pyran-4-ol, engelheptanoxide C
(3)
(125 MHz, CDCl3):
d
¼ 169.7, 169.2, 150.8, 148.6, 142.6, 139.9, 138.6,
The titled compound was prepared from 19 (150 mg,
129.4, 122.3, 121.2, 117.9, 110.0, 79.0, 76.9, 55.8, 37.9, 33.6, 31.2, 31.0,
0.29 mmol) by following a similar procedure as described for 14a,
to give 3 (91 mg, 92 %) as white semisolid. [
MeOH), lit. [
23.9, 21.1, 20.7 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for
25
a
a
]
ꢀ 21.4 (c ¼ 0.14,
C24H28O6Na 435.1778; Found 435.1777.
D
a
]
25 ꢀ 7.44 (c ¼ 0.14, MeOH) [4], [
]
D
22 ꢀ 35.6 (c ¼ 0.54,
D
MeOH) [11]; IR (CHCl3): nmax 3395, 2920, 2850, 2256, 2128, 1664,
4.3. Antibacterial susceptibility testing
1610, 1512, 1446, 1368, 1287, 1246, 1178, 1120, 1025, 998, 919, 823,
761 cmꢀ1; 1H NMR (400 MHz, acetone-d6):
d
¼ 8.06 (s, 1H), 7.44 (s,
Antibacterial susceptibility testing was carried out utilizing
broth microdilution assay according to CLSI guidelines [23]. 10 mg/
mL Stock solutions of test and control compounds were prepared in
DMSO and stored at ꢀ20 ꢃC. Bacterial cultures were inoculated in
media and OD600 of cultures was measured, followed by dilution to
achieve ~106 CFU/mL. The compounds were tested from 64 to
1H), 7.04e6.98 (m, 3H), 6.86e6.82 (m, 1H), 6.78 (d, J ¼ 8.1 Hz, 1H),
6.73 (d, J ¼ 8.4 Hz, 2H), 4.27 (d, J ¼ 11.6 Hz, 1H), 3.89e3.85 (m, 1H),
3.84 (s, 3H), 3.48e3.38 (m, 1H), 2.94 (br s, 1H), 2.73e2.60 (m, 2H),
2.12e2.07 (m, 1H), 1.99e1.92 (m, 1H), 1.89e1.78 (m, 1H), 1.78e1.68
(m, 1H), 1.43e1.33 (m, 1H), 1.29e1.22 (m, 1H) ppm; 13C{1H} NMR
(100 MHz, acetone-d6):
d
¼ 156.2, 148.0, 146.5, 135.7, 133.8, 130.1,
0.5 mg/L in two-fold serial diluted fashion with 2.5
concentration added per well of a 96-well round bottom microtiter
plate. Later, 97.5 L of bacterial suspension was added to each well
containing the test compound along with appropriate controls and
incubated at 37 ꢃC for 7 days. The MIC is defined as the lowest
compound concentration where there is no visible growth. For each
compound, MIC determinations were carried independently 3
times in duplicate.
mL of each
119.4, 115.9, 115.3, 110.5, 78.0, 75.5, 68.4, 56.2, 44.4, 42.1, 39.1,
31.5 ppm; HRMS (ESIꢀTOF) m/z: [M þ Na]þ Calcd for C20H24O5Na
367.1516; Found 367.1516.
m
4.2.37. (2S,6R)-6-(4-Hydroxyphenethyl)-2-(4-hydroxy-3-
methoxyphenyl)tetrahydro-2H-pyran, engelheptanoxide A (2)
The titled compound was prepared from 3 (50 mg, 0.15 mmol)
by following a similar procedure as described for 1, to give 2 (31 mg,
25
64 %) as white semisolid. [
a]
ꢀ 70.0 (c ¼ 0.12, CHCl3), lit. [4],
Declaration of competing interest
D
[
a
]
25 ꢀ 66.9 (c ¼ 0.12, CHCl3); IR (CHCl3): nmax ¼ 3393, 2934, 2854,
D
1612, 1514, 1454, 1305, 1247, 1175, 1081, 1035, 902, 829, 765,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
548 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼ 7.03 (d, J ¼ 8.4 Hz, 2H),
6.96 (d, J ¼ 1.3 Hz, 1H), 6.90e6.85 (m, 2H), 6.70 (d, J ¼ 8.4 Hz, 2H),
5.67 (s, 1H), 5.50 (br s, 1H), 4.29 (d, J ¼ 11.3 Hz, 1H), 3.87 (s, 3H),
3.50e3.43 (m, 1H), 2.75e2.62 (m, 2H), 1.98e1.88 (m, 2H), 1.86e1.80
(m, 1H), 1.77e1.70 (m, 1H), 1.68e1.62 (m, 2H), 1.59e1.52 (m, 1H),
Acknowledgments
1.39e1.31 (m, 1H) ppm; 13C{1H} NMR (125 MHz, CDCl3):
d
¼ 153.6,
We thank SERB New Delhi, Grant No. EMR/2017/000499 for
financial support. P.K. and M.N.A. thank University Grants
146.3, 144.6, 135.5, 134.3, 129.4, 118.9, 115.1, 114.0, 108.8, 79.6, 77.4,
10

P. Kumar, R.A. Fernandes, M.N. Ahmad et al.
Tetrahedron xxx (xxxx) xxx
ꢀ
~
[9] (a) F. Colobert, R. Des Mazery, G. Solladie, M.C. Carreno, Org. Lett. 4 (2002)
1723e1725;
Commission (UGC) of India and CSIR New Delhi, India, respectively
for research fellowships.
(b) S. Marumoto, J.J. Jaber, J.P. Vitale, S.D. Rychnovsky, Org. Lett. 4 (2002)
3919e3922;
(c) P.A. Evans, J. Cui, S.J. Gharpure, Org. Lett. 5 (2003) 3883e3885;
(d) E. Lee, H.J. Kim, W.S. Jang, Bull. Kor. Chem. Soc. 25 (2004) 1609e1610;
(e) L. Boulard, S. BouzBouz, J. Cossy, X. Franck, B. Figadere, Tetrahedron Lett. 45
Appendix A. Supplementary data
ꢁ
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132375.
(2004) 6603e6605;
(f) K.-P. Chan, T.-P. Loh, Org. Lett. 7 (2005) 4491e4494;
(g) M.P. Jennings, R.T. Clemens, Tetrahedron Lett. 46 (2005) 2021e2024;
(h) S. Chandrasekhar, S.J. Prakash, T. Shyamsunder, Tetrahedron Lett. 46
(2005) 6651e6653;
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[16] The enantiomeric excess of epoxide 8a and ent-8a was determined by chiral
HPLC (see Experimental Section for details and chromatograms in Supporting
Information).
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