The protecting-group directed diastereoselective Nozaki-Hiyama-Kishi (NHK) reaction: Total synthesis and biological evaluation of zeaenol, 7-epi-zeaenol and its analogues

Article abstract of DOI:10.1039/c4ob01811g

The stereoselective total synthesis of zeaenol and 7-epi-zeaenol is achieved in a convergent manner using Julia-Kocienski olefination, protecting group-directed intermolecular diastereoselective Nozaki-Hiyama-Kishi (NHK) reaction, De Brabander's lactoniza

Full text of DOI:10.1039/c4ob01811g

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2014, DOI: 10.1039/C4OB01811G.
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ARTICLE TYPE
Protecting-Group Directed Diastereoselective Nozaki-Hiyama-Kishi
(NHK) Reaction: Total Synthesis and Biological Evaluation of Zeaenol,
7-epi-Zeaenol and its Analogues
Debendra K. Mohapatra,*a,b D. Sai Reddy,a,b N. Arjunreddy Mallampudi,a Janardhan Gaddam,a,b
Sowjanya Polepalli,c Nishant Jain,c J. S. Yadava,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The stereoselective total synthesis of zeaenol and 7-epi-zeaenol was achieved in a convergent manner by
using Julia-Kocienski olefination, protecting group-directed intermolecular diastereoselective Nozaki–
10 Hiyama–Kishi (NHK) reaction, De Brabander’s lactonization reaction and CBS reduction as the key
steps. In this article, we have observed the most suitable protecting groups with respect to selectivity
during the protecting group directed intermolecular asymmetric Nozaki-Hiyama-Kishi reaction. The
Zeaenol, 7-epi-Zeaenol and its derivatives were analyzed for their biological activity and screened in four
cancer cell lines.
40 al.5 using RCM strategy. Recently, Yuguo Du and co-workers6
15 Introduction
reported the total synthesis of zeaenol along with cochliomycin B
using late stage RCM strategy. Their curious skeletal
connectivities and potent biological properties attracted our
attention to develop a flexible and general synthetic approach for
45 the total synthesis of zeaenol, 7-epi-zeaenol whose synthesis was
not reported so far and its derivatives for biological activity. As
part of our ongoing research on the total synthesis of macrolides
and RALs by protecting group-directed Nozaki-Hiyama-Kishi
reaction as the key step.7 In this report, we have applied the
50 protecting group-directed diastereoselective intermolecular
Nozaki-Hiyama-Kishi reaction for a convergent and concise
synthesis of zeaenol and 7-epi-zeaenol.
Zeaenol was first isolated and reported by Sugawara et al.1
from ethyl acetate extracts of the culture fluid Drechslera
portulacae. The relative and absolute configuration of zeaenol
was confirmed by its single X-ray crystallographic and
20 spectroscopic analysis. Later, Nicholas and co-workers reported
the isolation of 15-O-desmethyl-(5Z)-7-oxozeaenol and 7-epi-
zeaenol, along with known other resorcyclic acid lactones
(RALs) (Figure 1), from filamentous fungus MSX 63935
available from leaf litter in Nigeria.2 All these compounds exhibit
25 potent antibacterial activity as well as mitochondrial
transmembrane potential activity. The zeaenol (1) and 7-epi-
zeaeneol (2) show similar cytotoxic activity against human tumor
cell lines3,4 and inhibition activity towards NF-κB (IC50 values
>50 μM).
Our retrosynthetic strategy of zeaenol and 7-epi-zeaenol is
depicted in Scheme 1. The target molecule was anticipated to be
55 derived from the macrolactonization of
7 by using De
30
Brabander’s conditions, which could be obtained by protecting
group-directed intermolecular Diastereoselective Nozaki-
Hiyama-Kishi reaction of 8 and 9. The advanced fragment 8
could be prepared from 10 and 11 which in turn could be
60 synthesized from dioxinone (13) and D-mannitol (14). The vinyl
iodide fragment 9 could be derived from a known epoxide 12.
Results and Discussion
35
With the retrosynthetic blueprint in mind, our initial focus was
on the synthesis of the iodo fragment 9, which commenced with
65 the known chiral epoxide 12.8 The epoxide 12 was prepared by
using Jacobsen’s hydrolytic kinetic resolution protocol.8a
Reductive opening of epoxide 12 with LiAlH4 in THF afforded
alcohol 15 in 92% yield. The resulting secondary alcohol was
protected as its TBS-ether9 using TBSCl and imidazole in CH2Cl2
Figure 1. Structures of resorcylic acid lactones (RALs) (1-6).
The first total synthesis of zeaenol and its isopropylidine
protected compound cochliomycin A were reported by Nanda et
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5
10
25
30
15
20
Scheme 1. Retrosynthetic approach for 7-epi-zeaenol (1) and zeaenol (2)
to yielded TBS protected compound, which on treatment with
protected as its benzyl ether by using benzyl bromide and NaH to
DDQ10 in CH2Cl2/H2O (19:1) furnished primary hydroxyl 70 give 22 in 93% yield. The deprotection of cyclohexylidene group
35 compound 16 in 88% yield over two steps. The Dess-Martin
periodinane oxidation11 of primary alcohol 16 followed by Takai
olefination12 afforded the required trans-vinyl iodide compound 9
(E/Z = 95:5, by NMR) in 81% yield over two steps.
was easily achieved by camphorsulfonic acid (CSA) in MeOH to
O
O
O
O
a
O
Ref. 13
O
O
75
80
85
HO
O
13
a
40
b, c
17
HO
OPMB
OPMB
15
12
O
O
O
O
b
O
c
Br
MeO
d, e
MeO
I
45
TBSO
OH
TBSO
19
18
16
9
Scheme 2. Reagents and conditions: (a) LAH, THF 0 oC-rt 1 h 92%; (b)
TBSCl, imidazole, CH2Cl2, 0 oC-rt, 10 h (c) DDQ, CH2Cl2/H2O (19:1), 0
O
O
S
O
O
S
50 oC-rt, 2 h, 88% over two steps; (d) DMP, CH2Cl2, 0 C-rt, 3 h; (e) CrCl2,
o
O
d
O
O
CHI3, THF, rt, 16 h, 81% over two steps.
MeO
Ph
MeO
Ph
N
N
N
N
N
N
For the synthesis of another key fragment 10, we started from 17
which was prepared from commercially available 2,2,6-trimethyl-
4H-1,3-dioxin-4-one (13) by following a known protocol.13
55 Subsequently protection of the phenolic hydroxyl functionality
present in 17 was converted to methyl ether under Mitsunobu14
conditions to obtain 18 in 87% yield. Bromination of benzylic
position of 18 was achieved by NBS and benzoyl peroxide in
CCl4 under reflux conditions to afford benzyl bromide derivative
60 19 in 79% yield. Treatment of benzyl bromide derivative 19 with
1-phenyl-1H- tetrazole-5-thiol and Et3N in THF gave thio-ether
20, which was on further treatment with m-CPBA in CH2Cl2
furnished the corresponding sulfone fragment15 10 in 88% yield
over two steps.
O
20
N
10
N
90 Scheme 3. Reagents and conditions: (a) MeOH, TPP, DIAD, THF, 0 oC -
rt, 4 h, 87%; (b) NBS, benzoyl peroxide, CCl4, reflux, 6 h, 79%; (c) 1-
phenyl-1H- tetrazole-5-thiol, Et3N, THF, reflux, 6 h; (d) m-CPBA,
CH2Cl2, 0 oC-rt , 24 h, 88% over two steps.
afford diol in which the primary alcohol was selectively protected
95 as its TBS-ether by treatment with TBS-Cl and imidazole in
CH2Cl2 to give silyl ether compound 23 in 86% yield over two
steps. The resultant secondary hydroxyl group of 23 was
protected as its benzyl ether with benzyl bromide in presence of
NaH to afford 24 in 91% yield. The oxidative cleavage of
100 compound 24 under Jin’s one-pot conditions using OsO4-NaIO4
and 2,6-lutidine in dioxane-water (3:1) furnished aldehyde
fragment 1117 in 85% yield.
65 Synthesis of the fragment 11 was initiated from compound 21,
which was synthesized from commercially available D-mannitol
following a known protocol.16 The free hydroxyl group was
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OH
h, 92%; (d) 9, CrCl2, NiCl2, DMF, rt, 24 h, 81%; (e) MOM-Cl,
DIPEA, CH2Cl2, 0 oC-rt, 10 h, 96%; (f) TBAF, THF, 0 oC-rt, 10
h, 91%; (g) NaH, THF, 0 oC-rt, 4 h, 78%; (h) TiCl4, CH2Cl2, 0 oC
OH OH
a
OH
Ref. 15
HO
O
O
OH OH
o
21
0.5 h, 88%; (i) NaH, BnBr, THF, 0 C-rt, 5 h, 89%; (j) 2N HCl,
14
5
55 THF, 15 h, 91%, (k) H2, Pd/C, THF, rt, 24 h, 87%.
OBn
OBn
d
b, c
Resulting primary alcohol 26 was treated with Dess-Martin
periodinane reagent to afford the corresponding aldehyde 8 in
92% yield. The aldehyde was coupled vinyl iodo fragment 9
under mild conditions using Cr(II)/Ni(II)-mediated protecting
60 group-directed asymmetric intermolecular Nozaki-Hiyama-Kishi
(NHK)7 reaction to furnish the allyl alcohol 27 (9:1; separated by
column chromatography) as a major isomer in 81% combined
yield. The stereochemistry of the major isomer was ascertained
by using modified Mosher’s ester method at the later stage as at
O
OTBS
O
OH
23
22
10
OBn
OBn
e
OTBS
OTBS
O
OBn
24
OBn
11
15 Scheme 4. Reagents and conditions: (a) BnBr, NaH, TBAI, THF 65 this stage esterification was leading to an intractable mixture of
o
o
0 C-rt, 4 h, 93%; (b) CSA, MeOH, 0-rt C, 12 h, 90%; (c)
products.19 The major isomer was taken forward towards the total
synthesis of the target molecule. The secondary alcohol obtained
in NHK-reaction was protected as its MOM-ether by using
MOM-Cl and DIPEA to give 28 in 96% yield. The TBS group
o
TBSCl, Imidazole, CH2Cl2, 0 C, 0.5 h, 96%; (d) BnBr, NaH,
TBAI, THF, 0 C-rt, 6 h 91%; (e) OsO4, NaIO4, 2,6-lutidine,
dioxane/water (3:1), rt, 10 h, 85%.
o
20 Having both fragments 10 and 11 in hand, we procceded for 70 was deprotected with TBAF in THF to obtain compound 7 in
Julia-Kocienski olefination18 using KHMDS and 18-crown-6
ether in DME at ‒78 oC to afford desired olefin 25 exclusively in
84% yield. The TBS-ether protection in 25 was smoothly
removed with CSA in MeOH to obtain 26 in 94% yield.
91% yield.20 The intramolecular macrolactonization of 7 under
De Brabander’s conditions21 with NaH in THF furnished the
macrolactone core 29 in 78% yield. At this stage, the phenolic
OH group was protected as its benzyl ether and MOM group was
75 selectively deprotected to afford 36. According to the modified
Mosher’s ester method, the free hydroxyl group present in 36 was
converted to its (R)- and (S)-2-methoxy-2-(trifluoromethyl)-2-
phenylacetic acid (MTPA) ester with corresponding 2-methoxy-
2-(trifluoromethyl)-2-phenylacetic acid which showed negative
80 chemical shift differences (Δδ = δS − δR) for protons on C8
through C12 while protons on C3 through C6 showed positive
differences, which is consistent with C7 bearing an (S)-
configuration which was in accord to the stereochemistry of 7-
epi-zeaenol (2). Finally, global deprotection of benzyl and MOM
85 groups was achieved by TiCl4 to afford 7-epi-zeaenol (2) in 88%
yield representing the first total synthesis of 7-epi-zeaenol. The
spectral (1H and 13C NMR) and analytical data of 7-epi-zeaenol
was in good agreement with the reported values.2 To take the
advantage of SAR studies, the 7-epi-azeaenol (2) was treated with
90 Pd/C under hydrogen atmosphere to furnish tetrahydro-7-epi-
zeaenol 30 in 87% yield.
25
O
O
OBn
b
a
O
OTBS
O
OBn
11
MeO
OBn
OTBS
25
OBn
O
O
O
O
30
O
c
d
O
MeO
OBn
MeO
OBn
OH
+
26
O
8
OBn
OBn
O
O
OTBS
O
O
OTBS
35
O
O
e
f
MeO
OBn
MeO
OBn
OH
OMOM
27
OBn
OH
28
OBn
O
O
OR
O
g
O
4
h
O
1
3
12
MeO
OBn
6
MeO
OBn
8
9
11
OMOM
OR1
40
OBn
OBn
R = H; R1 = MOM
36. R = Bn; R1 = H
95
7
29.
i, j
OH
O
OH
O
O
O
k
MeO
OH
45
MeO
OH
OH
OH
OH
l (2)
OH
30
7--epi-Zeaeno
Scheme 5. Reagents and conditions: (a) 10, KHMDS, 18-crown-
o
o
6, DME, −78 C, 12 h, 84%; (b) CSA, MeOH, 0 C-rt, 0.5 h,
o
50 94%; (c) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0 C- rt, 3
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Page 4 of 12
presence of borane-dimethylsulfide complex], provided
compound 33 with required C7 stereocenter (97:3 dr, by HPLC,
separated by column chromatography) in 82% yield.
15 Deprotection of the benzyl group was achieved by treating
compound 33 with excess TiCl4 in CH2Cl2 at 0 oC to obtain
zeaenol (1) in 86% yield. Similarly, treatment of zeaenol (1) with
Pd/C under hydrogen atmosphere afforded tetrahydro-zeaenol
(34) in 89% yield. The spectral (1H and 13C NMR) and analytical
20 data of zeaenol was in accord with the reported values.2,5,6
The natural products zeaenol (1), 7-epi-zeaenol (2) and analogues
30 and 34 were tested for their cytotoxic activity and the results
are summarised in Table 1.
Scheme 6. Reagents and conditions: (a) 2N HCl, THF, 12 h,
88%, (b) Dess-Martin periodinane, CH2Cl2, 0 oC-rt, 3 h, 90%; (c)
(S)-CBS catalyst, BH3.Me2S, THF, −40 oC, 12 h, 82%; (d)
TiCl4, CH2Cl2, 0 oC 0.5 h, 86%; (e) H2, Pd/C, THF, rt, 24 h, 89%.
5
For the synthesis of zeaenol, compound 29 was treated with 2N
HCl to give secondary alcohol 31 in 88% yield. The resulting
secondary hydroxy group was oxidized under Dess-Martin
periodinane conditions to obtain α,β-unsaturated ketone 32 in
10 90% yield, which on asymmetric reduction using Corey-Bakshi-
Shibata22 (CBS) reagent [(S)-2-methyloxazaborolidine in the
25 Table 1: Cell lines were treated with different concentration of compounds for 48 h as mentioned in “materials and methods section. Cell
viability was measured employing SRB assay. GI50, TGI and IC50 (in µM) values are indicated as mean ± SD (standard deviation) of
three independent experiments
50
A549
TGI
HeLa
TGI
DU 145
TGI
MDA MB 231
TGI
code
GI50
178
IC50
GI50
IC50
GI50
33.4
IC50
GI50
IC50
368 ±
± 2.8 1.7
1207 ± 0.44± 84.1
4.6 0.03
564 ±
291 ±
± 0.8 1.6
738 ±
2.8
129 ± 262 ±
1.2 2.9
434 ±
1.78
1
2
± 0.3 3.1
254
567 ±
± 1.2 2.0
1145 ± 1.0 ± 231 ± 1098
0.18± 152 ±
531 ±
1.4
3.3 ± 80.2 ± 397 ±
1.5
0.08
0.95
± 4.3
0.05
2.1
0.09
0.5
3.1
8.9 ± 154±
263 ±
2.3
5.1 ± 192 ± 212 ±
23.3± 148 ±
0.7 0.9
253 ±
3.5
115 ± 195 ±
1.4 1.8
294 ±
2.14
30
34
0.1
1.52
0.05
3.1
1.8
1.0 ± 162 ±
0.06 2.15
241±3. 1.2 ± 58.4
12 0.06
184 ±
± 0.1 0.84
4.2 ± 162 ±
0.1 1.48
243 ±
2.61
4.0 ± 132±2 319 ±
0.07
.1
4.1
Nocod <0.0
azole
0.16 ± 6.6 ±
0.02 0.1
<0.01 0.11± 5.8 ±
0.02 0.4
<0.01 0.68 ± 10.5 ± <0.01 0.9 ±
0.05 0.3 0.01
1.3 ±
0.2
1
Biological studies:
30 In vitro cytotoxic activity:
GI50 values of 2 were at 1 µM and 1 at 0.44 µM in HeLa cells.
Based on these observations, the congeners contain potent
pharmacophores that elicit significant growth inhibitory response
55 in cancer cells. Thus further delineating these pharmacophores
from the molecules will possibly improve the potency of the
pounds.
The lead compounds inhibit the NF-kB albeit at 50µM,
nevertheless we investigated their ability to inhibit growth of
cancer cells. To evaluate this possibility, HeLa, A549, DU145
and MDA-MB-231 cancer cell lines were challenged with these
35 compounds. We followed the protocol set by NCI-60 cell screen
and performed the dose-response at five concentrations (0.01,
0.1,1,10 and 100 µM) of compounds. The cells were incubated.
Nocodazole was employed as standard agent. Based on linear
interpolation, we arrived at the values of GI50, with compounds
40 for 48 h. Nocodazole was employed as standard agent. Based on
linear interpolation, we arrived at the values of GI50, TGI and
IC50, TGI and IC50. Interestingly, our anti-proliferative assays
reveal that the congeners 30 and 34 demonstrate significant
growth inhibition effect. In particular, 34 manifested GI50 of 1
45 µM in A549 and HeLa cells. Moreover in MDA-MB-231 and
DU145 growth was inhibited at 4 µM concentrations of 34. In
contrast, 30 exhibited GI50 of 5 µM in HeLa cells. Similarly the
Conclusions
In conclusion, we have developed an efficient and concise route
60 for the total synthesis of both zeaenol and 7-epi-zeaenol in
convergent manner. The key steps involved in this synthesis are
Takai olefination, Julia-Kocienski olefination, protecting group-
directed asymmetric intermolecular Nozaki–Hiyama–Kishi
(NHK) reaction, and De Brabander’s lactonization. The obvious
65 and remarkable advantages of our protocol lie in high overall
yield. In addition, we identified that tetrahydro-zeaenol
demonstrated significant growth inhibitory activity and these
compounds are amenable for further structural modifications to
improve their efficacy for anticancer therapy.
4
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organic layer was extracted with CH2Cl2 (2 x 50 mL) and the
60 combined organic layer was washed with brine (60 mL), dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the crude mass was purified by silica gel column
chromatography (ethyl acetate /hexane = 1:19) to give 16 (1.0 g,
Experimental section
General Remarks: All reactions were performed under inert
atmosphere, if argon mentioned. All glassware apparatus used for
reactions are perfectly oven/flame dried. Anhydrous solvents
were distilled prior to use: THF from Na and benzophenone;
CH2Cl2, DMF from CaH2; MeOH from Mg cake. Commercial
reagents were used without purification. Column chromatography
was carried out by using silica gel (60–120 mesh) unless
5
25
93%) as a colorless liquid. [α]D + 21.2 (c 1.14, CHCl3); IR
65 (neat): 3376, 2957, 2932, 2859, 1739, 1615, 1467, 1375, 1254
cm‒1; 1H NMR (300 MHz, CDCl3): δ 4.09 (m, 1H), 3.79 (m, 1H),
3.68 (m, 1H), 2.3 (br s, 1H), 1.74 (m, 1H), 1.60 (m, 1H), 1.20 (d,
J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm; 13
C
10 otherwise mentioned. Analytical thin layer chromatography
(TLC) was run on silica gel 60 F254 pre-coated plates (250 μm
thickness). Optical rotations [α]D were measured on a polarimeter
and given in 10-1 degcm2g−1. Infrared spectra were recorded in
CHCl3/KBr (as mentioned) and reported in wave number (cm−1).
15 Mass spectral data were obtained using MS (EI) ESI, HRMS
NMR (75 MHz, CDCl3): δ 68.3, 60.4, 40.4, 25.7, 23.4, 17.9, ‒4.4,
70 ‒5.0 ppm; HRMS (ESI): calcd. for C10H22O2NaSi [M + Na]+
225.1281, found: 225.1261.
(S,E)-tert-Butyl(5-iodopent-4-en-2-yloxy)dimethylsilane (9):
To a stirred solution of primary alcohol 16 (0.9 g, 4.41 mmol)
and solid anhydrous NaHCO3 (1.0 g) in CH2Cl2 (25 mL) was
75 added Dess–Martin periodinane (4.0 g, 6.65 mmol) at 0 °C. The
resulting reaction mixture was stirred at 0 °C for 3 h. After
completion of the reaction (monitored by TLC), the mixture was
filtered through a bed of Celite. The filtrate was washed with
saturated NaHCO3 (2 x 25 mL). The aqueous layer was extracted
80 with CH2Cl2 (2 x 40 mL). The combined organic layer was dried
over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. Purification of the crude mass over silica gel
column chromatography (ethyl acetate/hexane = 1:25) to afford
corresponding aldehyde (0.82 g, 93%) as a pale-yellow liquid
85 which was immediately used for next step. To a stirred
suspension of CrCl2 (2.89 g, 23.76 mmol) in THF (25 mL) was
added the above aldehyde (0.8 g, 3.96 mmol) and CHI3 (4.67 g,
11.88 mmol) dissolved in THF (25 mL) at ambient temperature.
The reaction mixture was protected from light and stirred at
90 ambient temperature for 16 h. After completion of the reaction
(monitored by TLC), the green reaction mass was quenched with
water (30 mL). The reaction mixture was extracted with ethyl
acetate (3 x 40 mL). The combined organic extract was washed
with saturated aqueous Na2S2O3 (2 x 50 mL) followed by brine
95 (50 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (hexane) afforded 9 (1.12 g, 87%) as a
1
mass spectrometers. H NMR spectra were recorded at 300, 400,
500 and 13C NMR spectra 75, 125 MHz in CDCl3 solution unless
otherwise mentioned, chemical shifts are in ppm downfield from
tetramethylsilane and coupling constants (J) are reported in hertz
20 (Hz). The following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad.
(S)-4-(4-Methoxybenzyloxy)-butan-2-ol (15): To
a stirred
solution of epoxy compound 12 (2.0 g, 9.62 mmol) in THF (20
25 mL), was added LiAlH4 (731 mg, 19.24 mmol) at 0 °C. The
solution was warmed to room temperature and stirred for
additional 30 min. After completion of the reaction (monitored by
TLC), the reaction mixture was cooled to 0 °C and quenched with
saturated solution of Na2SO4 (20 mL). The residue was filtered
30 through Celite pad and the filtrate was concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (ethyl acetate/ hexane = 1:9) to furnish
25
the desired alcohol 15 (1.84 g, 92%) as a colorless liquid. [α]D
−4.5 (c 1.1, CHCl3); IR (neat): 3416, 2964, 2832, 2933, 1613,
35 1586, 1514, 1248 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.21 (d, J
= 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 4.43 (s, 2H), 3.94 (s, 3H),
3.68-3.51 (m, 2H) 2.77 (br s, 1H), 1.75-1.60 (m, 2H), 1.16 (d, J =
6.2 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3); δ 159.1, 129.9,
129.1, 113.6, 72.7, 68.5, 67.2, 55.1, 37.9, 23.2 ppm; HRMS
40 (ESI): calcd. for C12H18O3Na [M + 23]+ 233.1148, found:
233.1142.
25
pale-yellow oil. [α]D +9.7 (c 1.5, CHCl3); IR (neat): 2955,
1
2928, 2856, 1607, 1464, 1375, 1253 cm‒1; H NMR (300 MHz,
100 CDCl3): δ 6.48 (m, 1H), 6.02 (dd, J = 14.4, 1.5 Hz, 1H), 3.83 (m,
1H), 2.17-2.11 (m, 2H), 1.13 (d, J = 6.0 Hz, 3H), 0.88 (s, 9H),
0.04 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ 143.6, 76.5,
67.5, 45.9, 25.8, 23.5, 18.1, ‒4.6,‒4.7 ppm.
(S)-3-(tert-Butyldimethylsilyloxy)butan-1-ol (16): To a stirred
solution of alcohol 15 (1.5 g, 7.14 mmol) in CH2Cl2 (30 mL), was
added imidazole (1.2 g, 17.85 mmol) and TBSCl (2.14 g, 14.28
45 mmol) at 0 oC and the reaction mixture was stirred for 30 min at
the same temperature. After completion of the reaction
(monitored by TLC), it was quenched with water (30 mL) and
extracted with CH2Cl2 (3 x 30 mL). The combined organic layer
was dried over anhydrous Na2SO4 and the solvent removed under
50 reduced pressure. The crude mass was purified by silica gel
column chromatography (ethyl acetate/hexane = 2:5) to afford
TBS protected compound (2.2 g, 95%) as a colorless liquid and
immediately used for the next step. To a solution of above PMB
ether compound (1.7 g, 5.25 mmol) in CH2Cl2 (38 mL) and water
55 (2 mL) at room temperature was added DDQ (1.78 g, 7.87 mmol)
and the reaction mixture was stirred for 2 h at the same
temperature. After completion of the reaction (monitored by
TLC), it was quenched with saturated NaHCO3 (40 mL). The
7-Methoxy-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (18):
105 Compound 17 (3.5 g, 16.83 mmol) was taken in THF (40 mL)
and MeOH (1.0 mL, 25.25 mmol) was added followed by Ph3P
(6.6 g, 25.25 mmol) at 0 ºC. After being stirred for 5 minutes at
the same temperature, diisopropyl azodicarboxylate (4.9 mL,
25.25 mmol) was added drop wise to the reaction mixture and
110 stirred for an additional 4 h at room temperature. The reaction
mixture was concentrated under reduced pressure and purified by
silica gel column chromatography (ethyl acetate/hexane = 1:20)
to obtain 18 (3.2 g, 87%) as a white solid. Mp = 147−149 oC; IR
(neat): 2927, 2852, 1730, 1614, 1559, 1454, 1205, 1160 cm‒1; 1H
115 NMR (300 MHz, CDCl3): δ 6.41 (d, J = 2.3 Hz, 1H), 6.23 (d, J =
2.3 Hz, 1H), 3.82 (s, 3H), 2.63 (s, 3H), 1.69 (s, 6H) ppm; 13C
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Organic & Biomolecular Chemistry
Page 6 of 12
NMR (75 MHz, CDCl3): δ 164.7, 160.4, 158.8, 145.3, 112.7,
130.1, 129.3, 125.6, 116.1, 106.0, 105.7, 102.7, 59.2, 55.8, 25.4
104.9, 99.2, 98.1, 55.4, 25.6, 22.2 ppm; HRMS (ESI): calcd. for 60 ppm; HRMS (ESI): calcd. for C19H18O6N4SNa [M + Na]+
C12H14O4Na [M + Na]+ 245.0784, found: 245.0803.
453.0839, found: 453.0839.
5-(Bromomethyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]
dioxin-4-one (19): To a solution of 18 (3.0 g, 13.51 mmol) in
CCl4 (40 mL) was added NBS (1.3 g, 7.43 mmol) followed by
(R)-2-((S)-1-(Benzyloxy)but-3-enyl)-1,4-dioxaspiro[4.5]decane
(22): To a suspension of NaH (60% in mineral oil, 2.83 g, 70.75
mmol) in dry THF (60 mL), was added alcohol 21 (7.5 g, 35.37
5
benzoyl peroxide (40 mg) and the reaction mixture heated under 65 mmol) in THF (30 mL) at 0 °C. The suspension was stirred for 1
reflux. After 3 h, another portion of NBS (1.3 g, 7.43 mmol) and
benzoyl peroxide (40 mg) was added to the above reaction
h at room temperature. The benzyl bromide (4.2 mL, 35.37
mmol) was added slowly to the above reaction mixture at 0 C.
o
10 mixture and heated under reflux condition for an additional 3 h.
The reaction was cooled to room temperature, the solid
The reaction mixture was stirred at room temperature for
additional 4 h and quenched with water at 0 °C. The reaction
succinimide filtered off and the solvent removed under reduced 70 mixture was extracted with ethyl acetate (2 x 100 mL). The
pressure. The resulting orange oil was purified by silica gel
column chromatography (ethyl acetate/hexane = 1:19) to afford
15 compound 19 (3.18 g, 79%) as a white solid. Mp = 89−92 ºC; IR
combined organic layer was washed with brine solution (100
mL), dried over anhydrous Na2SO4 and the solvent removed
under reduced pressure. The residue was purified by silica gel
(neat): 2992, 2920, 2850, 1728, 1612, 1580, 1435, 1205, 1163
column chromatography (ethyl acetate/hexane = 1:19) to give 22
1
25
cm‒1; H NMR (500 MHz, CDCl3): δ 6.69 (s, 1H), 6.37 (s, 1H), 75 (9.93g, 93%) as a light-yellow liquid. [α]D +16.7 (c 1.15,
4.96 (s, 2H), 3.83 (s, 3H), 1.68 (s, 6H) ppm; 13C NMR (75 MHz,
CDCl3): δ 164.9, 159.6, 159.2, 143.3, 113.5, 105.5, 101.4, 98.2,
20 55.8, 31.1, 25.5 ppm; HRMS (ESI): calcd. for C12H14O4Br [M +
H]+ 301.0070 found, 301.0065.
CHCl3); IR (neat): 3343, 3069, 3033, 2936, 2861, 1723, 1450,
1160, 698 cm‒1; 1H NMR (500 MHz, CDCl3): δ 7.31-7.21 (m,
5H), 5.86 (m, 1H), 5.15-5.03 (m, 2H), 4.59 (q, J = 11.3 Hz, 2H),
4.04-3.94 (m, 2H), 3.82 (m, 1H), 3.51 (m, 1H), 2.47-2.26 (m,
80 2H), 1.63-1.52 (m, 8H), 1.43-1.35 (m, 2H) ppm; 13C NMR (75
MHz, CDCl3): δ 138.3, 134.2, 128.3, 127.7, 127.5, 117.4, 109.5,
78.9, 76.7, 72.4, 66.0, 36.3, 35.6, 34.8, 25.1, 23.9, 23.8 ppm;
HRMS (ESI): calcd. for C19H27O3 [M + H]+ 303.1954 found:
303.1954.
7-Methoxy-2,2-dimethyl-5-((1-phenyl-1H-tetrazol-5-ylthio)
methyl)-4H-benzo[d][1,3]dioxin-4-one (20): To
a
stirred
solution of 1-phenyl-1H-tetrazole-5-thiol (2.2 g,12.9 mmol) in
25 dry THF (30 mL), was added Et3N (1.74 mL, 12.9 mmol) and the
mixture was stirred at room temperature. After 40 min,
compound 19 (2.6 g, 8.67 mmol) was added and the reaction 85 (2R,3S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)hex-5-en-
mixture was refluxed for 6 h. The reaction mixture was diluted
with water (30 mL) and extracted with ethyl acetate (3 x 20 mL).
30 The combined organic layers were dried over anhydrous Na2SO4
and evaporated under reduced pressure to give the crude thioether
2-ol (23): To a stirred solution of 22 (9.0 g, 29.8 mmol) in MeOH
(20 mL) was added CSA (0.28 g, 2.98 mmol) at 0 C and the
reaction mixture was stirred for 12 h at rt. After completion of the
reaction (monitored by TLC), it was quenched with saturated
o
which was purified by flash chromatography (ethyl 90 solution of NaHCO3 (100 mL) and MeOH was removed under
acetate/hexane = 1:7) to afford compound 20 (3.3 g, 96%) as a
white solid. Mp. = 144−146 ºC; IR (neat): 3068, 3000, 2924,
reduced pressure. The residue was extracted with ethyl acetate (3
x 150 mL) and the combined organic layer was washed with
brine (150 mL), dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and purification of the crude
1
35 2853, 1717, 1611, 1579, 1499, 1386, 1289 cm‒1; H NMR (500
MHz, CDCl3): δ 7.59−7.45 (m, 5H), 7.13 (d, J = 2.5 Hz, 1H),
6.33 (d, J = 2.5 Hz, 1H), 4.96 (s, 2H), 3.87 (s, 3H), 1.68 (s, 6H) 95 product by silica gel column chromatography (ethyl
ppm; 13C NMR (75 MHz, CDCl3): δ 165.1, 160.6, 159.0, 154.8,
142.7, 133.5, 129.9,129.7, 123.7, 113.5, 105.6, 103.6, 101.6,
40 55.8, 35.8, 25.5 ppm; HRMS (ESI): calcd. for C19H19O4N4S [M +
H]+ 399.1121, found: 399.1124.
acetate/hexane = 1:1) furnished the desired diol (5.95 g, 90%) as
a viscous colorless liquid that was immediately used for next
step. To a stirred solution of above diol (5.5 g, 24.77 mol) in
CH2Cl2 (60 mL), was added imidazole (1.85 g, 27.25 mmol) and
(7-Methoxy-2,2-dimethyl-5-((1-phenyl-1H-tetrazol-5-ylsulfon- 100 TBSCl (3.71 g, 24.77 mmol) at 0 oC and the reaction was stirred
yl)methyl)-4H-benzo[d][1,3]dioxin -4-one (10): m-CPBA (70%
w/w) (4.1 g, 23.73 mmol) was added in small portions to a
45 solution of the thioether 20 (2.7 g, 6.78 mmol) in CH2Cl2 (30
mL) at 0 oC and the reaction mixture was stirred at room
for 30 min at the same temperature. After completion of the
reaction (monitored by TLC), it was quenched with water (50
mL) and extracted with CH2Cl2 (3 x 50 mL). The combined
organic layer was dried over anhydrous Na2SO4 and the solvent
temperature for 24 h. Then it was quenched with saturated 105 removed under reduced pressure. The crude mass was purified by
Na2SO3 solution (30 mL) and extracted with CH2Cl2 (3 x 50 mL).
The combined organic layer was washed with saturated NaHCO3
50 solution (75 mL), dried over anhydrous Na2SO4 and the solvent
removed under reduced pressure. The residue was purified by
silica gel column chromatography (ethyl acetate/hexane = 2:5) to
afford 23 (7.75 g, 96%) as a colorless liquid. [α]D25 +15.9 (c 1.0,
CHCl3); IR (neat): 3343, 3069, 2936, 2861, 1723, 1450, 1278
cm‒1; 1H NMR (500 MHz, CDCl3): δ 7.36-7.31 (m, 5H), 5.94 (m,
silica gel column chromatography (ethyl acetate/hexane = 1:6) to 110 1H), 5.21-5.06 (m, 2H), 4.65 (d, J = 11.0 Hz, 1H), 4.52 (d, J =
afford compound 10 (2.7 g, 92%) as a light yellow solid. Mp. =
102–104 oC; IR (neat): 3074, 2999, 2926, 2854, 1720, 1613,
55 1582, 1355, 1291cm−1; 1H NMR (500 MHz, CDCl3): δ =
7.68−7.49 (m, 5H), 6.80 (d, J = 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz,
11.0 Hz, 1H), 3.77 (q, J = 6.6 Hz, 1H), 3.72-3.66 (m, 2H), 3.53
(q, J = 6.6 Hz, 1H), 2.54-2.39 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H)
ppm; 13C NMR (75 MHz, CDCl3): δ 138.4, 134.7, 128.3, 127.8,
127.6, 117.2, 78.7, 72.4, 72.1, 63.6, 34.7, 25.8, 18.2, ‒5.4 ppm;
1H), 5.63 (s, 2H), 3.86 (s, 3H), 1.68 (s, 6H) ppm; 13C NMR (75 115 HRMS (ESI): calcd. for C19H32O3NaSi [M + Na]+ 359.2012,
MHz, CDCl3): δ = 164.8, 160.6, 159.2, 153.2, 132.9, 131.2,
found: 359.2010.
6
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Organic & Biomolecular Chemistry
2R,3S)-2,3-Bis(benzyloxy)hex-5-enyloxy)(tert-butyl)dimethyl
silane (24): To a suspension of NaH (60% in mineral oil, 1.6 g, 60 164.6, 160.1, 158.6, 143.9, 138.6, 131.6, 130.1, 129.9, 128.2,
0.90 (s, 9H), 0.06 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ
40.07 mmol) in dry THF (40 mL), was added alcohol 23 (6.85 g,
20.38 mmol) in THF (30 mL) at 0 °C. The suspension was stirred
for 1 h at room temperature. The benzyl bromide (3.6 mL, 30.57
127.9, 127.8, 127.5, 127.4, 108.2, 104.8, 100.1, 80.8, 78.5, 72.7,
72.1, 62.8, 55.5, 34.1, 25.9, 25.6, 25.6, 18.2, ‒5.4 ppm; HRMS
(ESI): calcd. for C37H48O7NaSi [M + Na]+ 655.3061, found:
655.3065.
5
o
mmol) was added slowly to the above reaction mixture at 0 C.
The reaction mixture was stirred at room temperature for 4 h and 65 5-((4S,5R,E)-4,5-Bis(benzyloxy)-6-hydroxyhex-1-enyl)-7-met-
quenched with water at 0 °C. The reaction mixture was extracted
with ethyl acetate (2 x 100 mL). The combined organic layer was
10 washed with brine solution (75 mL), dried over anhydrous
Na2SO4 and the solvent removed under reduced pressure. The
hoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (26): To a
stirred solution of compound 25 (1.45 g, 2.29 mmol) in MeOH
(20 mL) was added camphorsulfonic acid (53 mg, 0.229 mmol) at
0 °C and the resulting solution was stirred for 0.5 h at ambient
residue was purified by silica gel column chromatography (ethyl 70 temperature. After completion of the reaction (monitored by
acetate/hexane = 1:19) to give 24 (7.9 g, 91%) as a light-yellow
TLC), mixture was quenched with aqueous NaHCO3 (20 mL) and
MeOH was removed under reduced pressure. The residue was
extracted with ethyl acetate (3 x 50 mL) and the combined
organic layer was washed with brine (75 mL) and dried over
25
liquid. [α]D –2.1 (c 1.3, CHCl3); IR (neat): 3066, 3032, 2953,
15 2858, 1732, 1641, 1458, 1254 cm‒1; 1H NMR (300 MHz, CDCl3):
δ 7.42-7.23 (m, 5H), 5.88 (m, 1H), 5.15-5.01 (m, 2H), 4.78-4.55
(m, 4H), 3.87-3.74 (m, 2H), 3.66 (m, 1H), 3.59 (m, 1H), 2.43 (t, J 75 anhydrous Na2SO4. The solvent was removed under reduced
= 6.0 Hz, 2H), 0.96 (s, 9H), 0.05 (s, 6H) ppm; 13C NMR (75
MHz, CDCl3): δ 138.7, 138.5, 135.2, 128.1, 127.7, 127.6, 127.4,
20 127.3, 116.8, 80.7, 78.4, 72.6, 72.1, 62.7, 34.9, 25.9, 18.2, ‒5.4
ppm; HRMS (ESI): calcd. for C26H38O3NaSi [M + Na]+ 449.2482
found: 449.2469.
pressure and purification of the crude product by silica gel
column chromatography (ethyl acetate/hexane = 1:4) furnished
alcohol 26 (1.12 g, 94%) as a colorless liquid. [α]D −4.5 (c 0.7,
25
CHCl3); IR (neat) 3443, 2989, 2929, 1723, 1606, 1575, 1453,
1
80 1361, 1281 cm‒1; H NMR (300 MHz, CDCl3): δ 7.52 (d, J =
5-((4S,5R,E)-4,5-Bis(benzyloxy)-6-(tert-butyldimethylsilyloxy)
hex-1-enyl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-
25 4-one (25): To a stirred solution of the compound 24 (2.2 g, 5.16
mmol) in 1,4-dioxane (25 mL) was added 2,6‒lutidine (2.4 mL,
15.9 Hz, 1H), 7.38-7.25 (m, 10H), 6.68 (d, J = 2.3 Hz, 1H), 6.35
(d, J = 2.3 Hz, 1H), 6.17 (m, 1H), 4.73-4.60 (m, 4H), 3.86-3.76
(m, 6H), 3.63-3.57 (m, 1H), 2.71-2.64 (m, 2H), 1.70 (s, 6H) ppm;
13C NMR (75MHz, CDCl3): δ 164.7, 160.1, 158.6, 143.7, 138.0,
20.64 mmol) and NaIO4 (4.78 g, 20.64 mmol) in water (10 mL) 85 130.9, 130.3, 128.4, 127.9, 127.7, 127.6, 108.4, 104.9,103.6,
followed by OsO4 (0.51 mL, 0.51 mmol, 1 M solution in toluene)
at room temperature. The reaction mixture was stirred under dark
30 at room temperature for 6 h. After completion of the reaction
(monitored by TLC), it was quenched with saturated aq. Na2SO3
100.1, 79.9, 78.7, 72.1, 61.2, 55.8, 34.3, 25.6, 25.5 ppm; HRMS
(ESI): calcd. for C31H35O7 [M + H]+ 519.2377, found: 519.2364.
5-((1E,4S,5R,6R,7E,10S)-4,5-Bis(benzyloxy)-10-(tert-butyldi-
methylsilyloxy)-6-hydroxyundeca-1,7-dienyl)-7-methoxy-2,2-
(30 mL) solution. Organic solvent was removed under reduced 90 dimethyl-4H-benzo[d][1,3]dioxin-4-one (27): A solution of
pressure and the residual aqueous layer was extracted with ethyl
acetate (3 x 75 mL). The combine organic layers was washed
35 with brine (2 x 30 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give a colorless oil which
primary alcohol 26 (1.05 g, 2.03 mmol) and solid anhydrous
NaHCO3 (0.26 g, 3.12 mmol) in CH2Cl2 (30 mL) at 0 °C, was
added Dess–Martin periodinane (1.2 g, 3.04 mmol). The
resulting reaction mixture was stirred at the same temperature for
was purified by silica gel column chromatography (ethyl 95 3 h. After completion of the reaction (monitored by TLC), the
acetate/hexane = 1:19) to obtain aldehyde 11 (1.88 g, 85%) as a
colorless liquid which was immediately used for next step
40 without further purification and characterization. To a stirred
solution of 10 (2.36 g, 5.5 mmol) and 18-crown-6 (2.1 g, 8.2
mixture was filtered through Celite bed and the filtrate was
washed with saturated NaHCO3 (2 x 20 mL). The organic layer
was separated and extracted with CH2Cl2 (2 x 50 mL). The
combined organic layer was dried over anhydrous Na2SO4, and
mmol) in DME (25 mL) was added KHMDS (0.5 M in toluene, 100 the organic layer was removed under reduced pressure.
11.0 mL, 5.5 mmol) at –78 °C. After 20 min, a solution of 11
(1.57 g, 3.67 mmol) in DME (6 mL) was added and the mixture
45 was stirred at –78 °C for 1 h. The reaction mixture was gradually
warmed to –10 °C. After being stirred overnight at –10 °C, the
Purification of the crude reaction mass by flash chromatography
(ethyl acetate/hexane 1:10) afforded the corresponding
aldehyde 8 (0.96 g, 92%) as a pale-yellow liquid that was
=
immediately used for next step. Mixture of anhydrous CrCl2 (2.9
mixture was quenched with saturated NH4Cl (30 mL) and 105 g, 18.5 mmol) and NiCl2 (238 mg, 1.85 mmol) was added to a
extracted with ethyl acetate (3 x 50 mL). The extract was washed
with brine (75 mL), dried over anhydrous Na2SO4 and
50 concentrated under reduced pressure. The residue was purified by
mixture of aldehyde 8 (0.95 g, 1.85 mmol) and vinyl iodide 9 (1.2
g, 3.7 mmol) in degassed DMF (10 mL + 5 mL rinse twice) at
ambient temperature. The resultant mixture was stirred at ambient
temperature for 24 h. The reaction was quenched with saturated
silica gel column chromatography (ethyl acetate/hexane = 1:20)
25
to give 25 (1.94 g, 84%) as a colorless oil. [α]D −12.5 (c 1.65, 110 NH4Cl (50 mL) at 0 °C. The resultant solution was stirred at
CHCl3); IR (neat); 2928, 2854, 1728, 1607, 1572, 1278, 1159,
1097, 778 cm‒1; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J = 15.9
55 Hz, 1H), 7.37-7.22 (m, 10H), 6.68 (d, J = 3.0 Hz, 1H), 6.33 (d, J
= 2.3 Hz, 1H), 6.23 (m, 1H), 4.82-4.45 (m, 4H), 3.87 (dd, J =
room temperature for 15 min and mixture was extracted with
diethyl ether (3 x 50 mL). The organic layer was washed with
brine (100 mL), dried over anhydrous Na2SO4 and concentrated
under reduced pressure. Purification of the residue by silica gel
10.6, 3.8 Hz, 1H), 3.81 (s, 3H), 3.76 (m, 1H), 3.69-3.49 (m, 2H), 115 column chromatography (ethyl acetate/hexane = 1:7) furnished
2.65 (t, J = 6.0 Hz, 1H), 2.58 (t, J = 6.0 Hz, 1H), 1.69 (s, 6H),
27 (0.9 g, 81%), as colorless liquid. [α]D25 +2.1 (c 1.2, CHCl3); IR
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Organic & Biomolecular Chemistry
Page 8 of 12
(neat): 3448, 2925, 2854, 1725, 1606, 1575, 1458, 1378, 1283
5.63-5.60 (m, 2H), 4.84 (d, J = 11.1 Hz, 1H), 4.77-4.49 (m, 5H),
cm‒1; 1H NMR (300 MHz, CDCl3): δ 7.53 (d, J = 15.9 Hz, 1H), 60 4.33 (m, 1H), 3.82 (s, 3H), 3.76 (m, 1H), 3.71-3.65 (m, 2H), 3.35
7.39-7.29 (m, 10H), 6.70 (d, J = 3.0 Hz, 1H), 6.34 (d, J = 3.0 Hz,
1H), 6.26 (m, 1H), 5.81-5.61 (m, 2H), 4.75-4.59 (m, 4H), 4.35
(m, 1H), 3.86-3.72 (m, 5H), 3.59 (m, 1H), 2.82-2.65 (m, 2H),
2.35 (t, J = 7.6 Hz, 2H), 1.70 (s, 6H), 1.10 (d, J = 6.0 Hz, 3H),
(s, 3H), 2.77-2.66 (m, 2H), 2.27-2.11 (m, 2H), 1.69 (s, 6H), 1.17
(d, J = 6.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 164.7,
160.1, 158.6, 143.9, 138.3, 131.8, 131.3, 130.3, 130.2, 128.3,
128.2, 128.0, 127.5, 127.5, 127.3, 108.3, 104.9, 100.1, 93.7, 81.4,
5
0.88 (s, 9H), 0.04 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3): 65 78.5, 78.2, 73.9, 71.5, 66.9, 55.5, 42.0, 33.4, 25.6, 25.5, 22.8
164.8, 160.2, 158.7, 143.9, 138.3, 137.9, 131.1, 130.9, 130.7,
130.0, 128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 108.4, 104.9,
ppm; HRMS (ESI): calcd. for C38H46O9 Na [M + Na]+ 669.3034,
found: 669.3034.
10 103.6, 100.1, 82.1, 79.8, 74.0, 73.8, 71.7, 68.5, 55.6, 42.8, 33.7,
29.7, 25.8, 25.6, 23.4, 18.1, ‒4.6, ‒4.7 ppm; HRMS (ESI): calcd.
for C42H56O8NaSi [M + Na]+ 739.3636, found: 739.3639.
(3S,5E,7R,8S,9S,11E)-8,9-Bis(benzyloxy)-16-hydroxy-14-
methoxy-7-(methoxymethoxy)-3-methyl-3,4,7,8,9,10-hexahy-
70 dro-1H-benzo[c][1]oxacyclotetradecin-1-one (29): To
a
5-((1E,4S,5S,6R,7E,10S)-4,5-Bis(benzyloxy)-10-(tert-butyl
dimethylsilyloxy)-6-(methoxy methoxy)undeca-1,7-dienyl)-7-
15 methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (28): To
a stirred solution of compound 27 (0.855 g, 1.19 mmol)) in
suspension of NaH (0.256 g, 6.4 mmol, NaH was washed with
hexane twice to remove mineral oil and dried) in dry THF (10
mL), was added alcohol 7 (0.515 g, 0.8 mmol) in THF (5 mL) at
0 oC under argon atmosphere and the suspension was stirred for 4
CH2Cl2 (20 mL), was added diisopropyl ethylamine (0.63 mL, 75 h at room temperature. After completion of the reaction
3.5 mmol) and stirred for 30 min at 0 oC under argon atmosphere.
Methoxymethyl chloride (0.23 mL, 2.98 mmol) was added to the
20 above reaction mixture in CH2Cl2 (10 mL) at same temperature.
The resultant mixture was stirred at room temperature for
(monitored by TLC), it was quenched with ice pieces at 0 oC. The
organic layer was separated and the aqueous layer extracted with
ethyl acetate (3 x 5 mL). The combined organic layer was dried
over anhydrous Na2SO4 and solvent removed under reduced
additional 10 h. After completion of the reaction (monitored by 80 pressure. The crude mass was purified by silica gel column
TLC), it was quenched with water (20 mL) and extracted with
CH2Cl2 (3 x 30 mL). The combined organic layer was dried over
25 anhydrous Na2SO4 and solvent removed under reduced pressure.
The crude mass was purified by silica gel column
chromatography (ethyl acetate/hexane = 1:9) to afford 29 (366
mg, 78%) as a colorless liquid. [α]D −49.2 (c 1.7, CHCl3); IR
25
(neat): 2923, 2853, 1729, 1647, 1608, 1572, 1458, 1378, 1256
cm‒1; 1H NMR (500 MHz, CDCl3): δ 11.71 (s, 1H), 7.31-7.20
chromatography (ethyl acetate/hexane = 1:20) to afford MOM 85 (m, 10H), 7.09 (d, J = 15.8 Hz, 1H), 6.38 (br s, 1H), 6.35 (d, J =
25
ether 28 (0.87 g, 96%) as a colorless oil. [α]D −25.1 (c 1.2,
CHCl3); IR (neat): 2925, 2854, 1729, 1604, 1575, 1457, 1277,
30 1156, 1032, 833, 774 cm‒1; 1H NMR (300 MHz, CDCl3): δ 7.55
(d, J = 15.9 Hz, 1H), 7.39-7.22 (m, 10H), 6.70 (d, J = 2.3 Hz,
2.9 Hz, 1H), 5.89 (m, 1H), 5.79 (m, 1H), 5.61 (m, 1H), 5.12 (m,
1H), 4.80 (s, 2H), 4.63 (d, J = 6.9 Hz, 1H), 4.52-4.43 (m, 3H),
4.02 (m, 1H), 2.92 (m, 1H), 3.81 (s, 3H), 3.30 (s, 3H), 2.75-2.56
(m, 3H), 2.37 (m, 1H), 1.42 (d, J = 6.9 Hz, 3H) ppm; 13C NMR
1H), 6.33 (d, J = 2.3 Hz, 1H), 6.28 (m, 1H), 5.66 (m, 1H), 5.51 90 (75 MHz, CDCl3): δ 171.6, 164.9, 163.9, 143.5, 138.9, 138.3,
(dd, J = 15.9, 8.31 Hz, 1H), 4.86 (d, J = 11.3 Hz, 1H), 4.77-4.48
(m, 5H), 4.33 (dd, J = 8.3, 3.8 Hz, 1H), 3.87-3.80 (m, 4H), 3.78-
35 3.65 (m, 2H), 3.36 (s, 3H), 2.79-2.69 (m, 2H), 2.36-2.11 (m, 2H),
1.69 (s, 6H), 1.10 (d, J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 6H)
133.2, 132.2, 128.3, 128.1, 127.7, 127.5, 127.2, 107.3, 104.1,
99.7, 92.7, 83.6, 81.3, 78.4, 73.4, 73.1, 71.8, 55.4, 55.3, 38.6,
34.9, 20.5 ppm; HRMS (ESI): calcd. for C35H40O8Na [M + Na]+
611.2615, found: 611.2611.
ppm; 13C NMR (75 MHz, CDCl3): δ 164.7, 160.1, 158.6, 144.0, 95 7-epi-Zeaenol (2): To a stirred solution of 29 (50 mg, 0.09
138.7, 138.4, 132.9, 131.6, 130.1, 128.5, 128.3, 128.2, 128.0,
127.9, 127.7, 127.5, 127.4, 108.2, 104.9, 103.6, 100.1, 93.3, 81.5,
40 78.6, 77.5, 73.9, 71.5, 68.3, 55.6, 55.5, 42.9, 33.5, 25.8, 25.7,
25.5, 23.2, 18.1, ‒4.6, ‒4.8 ppm; HRMS (ESI): calcd. for
C44H60O9NaSi [M + Na]+ 783.3898, found: 783.3890.
5-((1E,4S,5S,6R,7E,10S)-4,5-Bis(benzyloxy)-10-hydroxy-6-
(methoxymethoxy)undeca-1,7-dienyl)-7-methoxy-2,2-dimethyl
45 -4H-benzo[d][1,3]dioxin-4-one (7): To a stirred solution of 28
(0.805 g, 1.08 mmol)) in dry THF (20 mL) was added TBAF (1
mmol) in CH2Cl2 (5 mL) was added TiCl4 (1.8 mL, 1.8 mmol, 1
M in CH2Cl2) at 0 °C, and the mixture was stirred for 30 min at 0
oC. After completion of the reaction (monitored by TLC), it was
quenched with a saturated solution of NaHCO3 (5 mL), extracted
100 with CH2Cl2 (2 x 10 mL) and washed with brine (15 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
to afford a yellowish liquid, which was purified by silica gel
column chromatography (acetone/hexane 1:1) to obtain
25
compound 2 (28 mg, 88%) as a white powder. [α]D −87 (c 1.2,
M in THF, 1.62 mL, 1.62 mmol) at 0 °C. The resulting mixture 105 MeOH); IR (neat): 3424, 2926, 2854, 2738, 2489, 1607, 1637,
was stirred for an additional 10 h at room temperature. The
reaction mixture was quenched with water (10 mL) and extracted
50 with ethyl acetate (3 x 30 mL) and washed with brine (50
mL).The organic layer was dried over anhydrous Na2SO4 and
1385, 1254 cm‒1; 1H NMR (500 MHz, DMSO-d6): δ 10.56 (s,
1H), 6.64 (d, J = 15.8 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.31 (d, J
= 2.2 Hz, 1H), 6.09 (m, 1H), 5.67-5.52 (m, 2H), 5.10 (m, 1H),
4.84 (s, 1H), 4.79 (s, 1H), 4.48 (d, J = 3.9 Hz, 1H), 4.05 (m, 1H),
concentrated to afford a yellowish liquid. Purification of the 110 3.74 (s, 3H), 3.58 (m, 1H), 3.45 (m, 1H), 2.48-2.31 (m, 3H), 2.17
above crude mass by silica gel column chromatography (ethyl
acetate/hexane = 2:3) furnished 7 (654 mg, 91%) as a colorless
55 viscous liquid. [α]D25 −19.1 (c 1.5, CHCl3); IR (neat); 3435, 2956,
(m, 1H), 1.31 (d, J = 5.9 Hz, 3H) ppm; 13C NMR (125 MHz,
DMSO-d6): δ 168.9, 161.6, 158.8, 139.5, 132.9, 132.4, 128.5,
126.9, 110.2, 102.6, 99.8, 77.4, 74.6, 72.8, 71.7, 55.2, 38.5, 36.7,
20.0 ppm; HRMS (ESI): calcd. for C19H24O7Na [M + Na]+
1
2926, 2855, 1727, 1608, 1578, 1453, 1283 cm‒1; H NMR (300
MHz, CDCl3): δ 7.53 (d, J = 16.1 Hz, 1H), 7.38-7.22 (m, 10H), 115 387.1417, found: 387.1405.
6.69 (d, J = 3.0 Hz, 1H), 6.33 (d, J = 2.7 Hz, 1H), 6.24 (m, 1H), 1,2,7,8-Tetrahydro-7-epi-zeaenol (30): The compound 2 (15
8
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DOI: 10.1039/C4OB01811G
Page 9 of 12
Organic & Biomolecular Chemistry
mg, 0.04 mmol) was in MeOH (5 mL) and commercial Pd/C (10
acetate/hexane = 1:19) afforded the corresponding keto 32 (83
mg, 10% w/w) was added in one portion. The resulting 60 mg, 90%) as a pale-yellow liquid. [α]D25 −58.6 (c 0.5, CHCl3); IR
suspension was stirred under an atmosphere of H2 for 24 h until
complete disappearance of starting material occurred (indicated
by TLC). The suspension was filtered through Celite pad and
washed with ethyl acetate (10 mL). The combined filtrates were
(neat): 3448, 2924, 2855, 1725, 1645, 1459, 1255 cm‒1; 1H NMR
(500 MHz, CDCl3): δ 11.83 (s, 1H), 7.35-7.18 (m, 10H), 7.00 (m,
1H), 6.94 (d, J = 14.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H), 6.41 (s,
1H), 6.40 (s, 1H), 5.82 (m, 1H), 5.35 (m, 1H), 4.72-4.66 (m, 2H),
5
washed with brine (10 mL), dried over anhydrous Na2SO4 and 65 4.60-4.46 (m, 3H), 3.86-3.78 (s, 4H), 2.75-2.66 (m, 2H), 2.58-
concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography (acetone/hexane =
2.48 (m, 2H), 1.36 (d, J = 5.9 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3): δ 199.0, 170.9, 165.4, 164.0, 143.6, 142.9, 141.8, 138.1,
137.4, 133.3, 132.9, 130.8, 129.8, 128.3, 128.2, 127.8, 127.7,
127.7, 127.6, 108.6, 103.7, 100.1, 83.4, 80.3, 72.5, 71.7, 71.2,
10 1:1) to afford 2,7,8-tetrahydro-7-epi-Zeaenol (12 mg, 87%) as
25
white power .[α]D −15.6 (c 1.2 CHCl3); IR (neat): 3375, 2924,
2853, 1743, 1628, 1591, 1258 cm‒1; 1H NMR (500 MHz, DMSO- 70 55.4, 37.7, 35.3, 19.5 ppm; HRMS (ESI): calcd. for C33H34O7Na
d6): δ 10.16 (s, 1H), 6.32 (s, 1H), 6.26 (s, 1H), 5.03 (m, 1H), 4.42
(d, J = 4.5 Hz, 1H), 4.31 (d, J = 4.5 Hz, 1H), 4.21 (s, 1H), 4.01 (s,
15 1H), 3.71 (s, 3H), 3.58 (m, 1H), 3.40 (m, 2H), 3.07 (m, 1H), 2.61
(m, 2H), 1.71-1.27 (m, 8H), 1.25 (d, J = 5.6 Hz, 3H) ppm; 13C
[M + Na]+ 565.2202, found: 565.2190.
(3S,5E,7S,8R,9S,11E)-8,9-Bis(benzyloxy)-7,16-dihydroxy-14-
methoxy-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxa
cyclotetradecin-1-one (33): To a 10 mL round bottom flask
NMR (125 MHz, DMSO-d6): δ 168.5, 161.0, 157.8, 143.3, 113.0, 75 charged with a magnetic stir bar was added (S)-CBS catalyst (66
105.9, 98.7, 77.6, 71.4, 71.1, 70.5, 54.9, 45.6, 35.0, 32.3, 32.1,
32.0, 27.5, 21.1, 20.4 ppm; HRMS (ESI): calcd. for C19H28O7Na
20 [M + Na]+ 391.1732, found: 391.1721.
3S,5E,7R,8R,9S,11E)-8,9-Bis(benzyloxy)-7,16-dihydroxy-14-
methoxy-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxa
cyclotetradecin-1-one (31): A solution of compound 29 (200
mg, 0.34 mmol) in THF (5 mL) was treated with 2N HCl (5 mL)
25 and allowed to stirred for 15 h at room temperature. After
completion of the reaction (monitored by TLC) ethyl acetate (5
mg, 0.24 mmol) THF (2 mL) under argon atmosphere. The
reaction mixture was cooled to –40 °C and BH3•Me2S (0.12 mL,
0.24 mmol, 2M in THF) was added. To this reaction mixture, a
solution of ketone 32 ( 65 mg, 0.12 mmol) dissolved in THF (2
80 mL) was added drop wise and stirred for 8 h at –40 °C. After
completion of the reaction (monitored by TLC), the reaction was
quenched with MeOH (1mL). The reaction mixture was diluted
with saturated aqueous NH4Cl (5mL) and extracted with ethyl
acetate (3 x 5mL). The combined organic extracts were washed
mL) and H2O (5 mL) were added. The layers were separated and 85 with brine (2 x 5mL), dried over anhydrous Na2SO4, and
the aqueous phase extracted with ethyl acetate (2 x 10 mL). The
combined organic portion was washed with saturated sodium
30 bicarbonate solution (2 x 15 mL) followed by brine solution (15
mL), dried over anhydrous Na2SO4 and concentrated under
concentrated under reduced pressure. The crude oil was purified
by silica gel chromatography (ethyl acetate/hexane = 1:7) to
furnish the desired alcohol 33 (49 mg, 82%) as a colorless liquid.
25
[α]D −61.3 (c 0.5, CHCl3); IR (neat): 3449, 3060, 3028, 2925,
reduced pressure. The residue was purified by silica gel column 90 2854, 1727, 1646, 1602, 1492, 1383, 1258 cm‒1; 1H NMR (500
chromatography (ethyl acetate/hexane = 1:6) to give 32 (162 mg,
88%) as a colorless liquid. [α]D25 −69.0 (c 1.2, CHCl3); IR (neat):
35 3449, 3060, 3028, 2925, 2854, 1727, 1646, 1602, 1492, 1383,
MHz, Acetone-d6): δ 11.91 (s, 1H), 7.49-7.12 (m, 11H), 6.46 (s,
1H), 6.38 (s, 1H), 6.08 (m, 1H), 5.95 (m, 1H), 5.80 (m, 1H), 5.29
(m, 1H), 4.97-4.43 (m, 4H), 4.35 (m, 1H), 3.95 (m, 1H), 3.85 (s,
3H), 3.65 (m, 1H), 2.65-2.46 (m, 4H), 1.46 (d, J = 6.2 Hz, 3H)
1
1258 cm‒1; H NMR (500 MHz, Acetone-d6): δ 11.79 (s, 1H),
7.48-7.16 (m, 11H), 6.46 (s, 1H), 6.39 (s, 1H), 5.99 (m, 1H), 5.89 95 ppm; 13C NMR (125 MHz, Acetone-d6): δ 173.5, 167.2, 166.0,
(m, 1H), 5.72 (m, 1H), 5.21 (m, 1H), 4.87-4.61 (m, 4H), 4.57 (m,
1H), 4.27 (m, 1H), 3.91-3.82 (m, 4H), 2.79 (m, 1H), 2.64-2.57
40 (m, 3H), 1.43 (d, J = 5.9 Hz, 3H) ppm; 13C NMR (125 MHz,
Acetone-d6): δ 173.5, 166.9, 166.0, 145.4, 141.2, 140.7, 134.0,
145.6, 141.5, 140.9, 134.0, 133.8, 133.4, 129.9, 129.6, 129.4,
129.0, 128.5, 108.6, 105.6, 101.5, 84.8, 83.9, 75.1, 74.3, 72.9,
56.9, 39.1, 35.9, 20.6 ppm; HRMS (ESI): calcd. for C33H38O7Na
[M + Na]+ 567.2358, found: 567.2340.
133.9, 130.0, 129.9, 129.6, 129.4, 129.2, 129.0, 108.6, 105.8, 100 Zeaenol (1): To a stirred solution of 33 (45 mg, 0.08 mmol) in
101.5, 85.2, 80.2, 76.0, 75.0, 73.4, 56.8, 40.1, 36.5, 21.3 ppm;
HRMS (ESI): calcd. for C33H36O7Na [M + Na]+ 567.2358,
45 found: 567.2340.
(3S,5E,8S,9S,11E)-8,9-Bis(benzyloxy)-16-hydroxy-14-meth-
oxy-3-methyl-3,4,9,10-tetrahydro-1H-benzo[c][1]oxacyclo
tetradecine-1,7(8H)-dione (32): A solution of alcohol 31 (90
mg, 0.17 mmol) in CH2Cl2 (10 mL) at 0 °C, was added Dess–
50 Martin periodinane (110 mg, 0.26 mmol). The resulting reaction
mixture was stirred at the same temperature for 3 h. After
CH2Cl2 (5 mL) was added TiCl4 (1.6 mL, 1.6 mmol, 1M in
CH2Cl2) at 0 °C and the mixture was stirred for 30 min at 0 C.
o
After completion of the reaction (monitored by TLC), it was
quenched with a saturated solution of NaHCO3 (5 mL), extracted
105 with CH2Cl2 (2 x 10 mL) and washed with brine (15 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
to afford a yellowish liquid which was purified by silica gel
column chromatography (acetone/hexane 1:1) to obtain
25
compound 1 (25 mg, 86%) as a white powder. [α]D ‒89 (c 0.6,
completion of the reaction (monitored by TLC), it was filtered 110 MeOH); IR (neat): 3424, 2926, 2854, 2738, 2489, 1607, 1637,
through Celite bed and the filtrate was washed with saturated
NaHCO3 (2 x 5 mL). The organic layer was separated and
55 extracted with CH2Cl2 (3 x 10 mL). The combined organic layer
was dried over anhydrous Na2SO4, and the organic layer was
1385, 1254 cm‒1; 1H NMR (500 MHz, CDCl3): δ 11.83 (s, 1H),
7.12 (d, J = 14.9 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 6.39 (d, J =
2.9 Hz, 1H), 5.83 (ddd, J = 11.0, 4.0 Hz, 1H), 5.70 (dd, J =14.9,
7.9 Hz, 1H), 5.32 (m, 1H), 4.26 (t, J = 6.9 Hz, 1H), 3.98 (t, J =
removed under reduced pressure. Purification of the crude 115 6.9 Hz, 1H), 3.81 (s, 3H), 3.59 (d, J = 7.9 Hz, 1H), 2.60 (br s, 3
reaction mass by silica gel column chromatography (ethyl
H), 2.55–2.25 (m, 4H), 1.46 (d, J = 6.9Hz, 3H) ppm; 13C NMR
This journal is © The Royal Society of Chemistry [year]
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Organic & Biomolecular Chemistry
DOI: 10.1039/C4OPB0a1g81e1G10 of 12
(125 MHz, CDCl3): δ 171.2, 165.2, 164.0, 142.9, 133.6, 131.5,
completion of the reaction (monitored by TLC), ethyl acetate (5
129.2, 128.5, 107.6, 103.8, 100.0, 73.1, 71.9, 71.4, 55.4, 37.8, 60 mL) and H2O (5 mL) were added. The layers were separated and
35.9, 19.6 ppm; HRMS (ESI): calcd. for C19H24O7Na [M + Na]+
387.1417, found: 387.1426.
1,2,7,8-Tetrahydro-zeaenol (34): The compound 1 (13 mg,
0.035 mmol) was in MeOH (5 mL) and commercial Pd/C (10 mg,
the aqueous phase extracted with ethyl acetate (2 x 5mL). The
combined organic portion was washed with saturated sodium
bicarbonate solution (2 x 15 mL) followed by brine solution (15
mL), dried over anhydrous Na2SO4 and concentrated under
5
10% w/w) was added in one portion. The resulting suspension 65 reduced pressure. The residue was purified by silica gel column
was stirred under an atmosphere of H2 for 24 h until complete
disappearance of starting material occurred (monitored by TLC).
chromatography (ethyl acetate/ hexane = 1:8) to give 36 (38mg,
91%),) `as a colorless liquid. [α]D −56.5 (c 0.7, CHCl3); IR
25
10 The suspension was filtered through Celite pad and washed with
ethyl acetate (10 mL). The combined filtrates were washed with
(neat): 3452, 2926, 2855, 1728, 1642, 1573, 1456, 1383, 1257
cm‒1; 1H NMR (500 MHz, CDCl3): δ7.43-7.21 (m, 16H), 6.46 (s,
brine (10 mL), dried over anhydrous Na2SO4 and concentrated 70 1H), 6.41 (s, 1H), 6.08 (m, 1H), 5.63 (m, 1H), 5.42 (m, 1H), 5.24
under reduced pressure. The crude product was purified by silica
gel column chromatography (acetone/hexane = 1:1) to afford
15 2,7,8-tetrahydro-7-epi-Zeaenol (10 mg, 89%) as white power .as
(m, 1H), 5.12-5.04 (m, 2H), 4.76-4.60 (m, 4H), 4.24 (m, 1H),
3.78 (s, 3H), 3.73-3.65 (m, 2H), 2.65 (m,1H), 2.49 (m, 1H), 2.40-
2.27 (m, 2H), 1.24 (d, J = 6.59, 3H) ppm; 13C NMR (100 MHz,
CDCl3):167.4, 161.2, 156.8, 138.5, 137.8, 136.6, 128.6, 128.5,
25
white power. [α]D ‒ 25 (c 0.4, CHCl3); IR (neat): 3375, 2924,
2853, 1743, 1628, 1591, 1258 cm‒1; 1H NMR (500 MHz, 75 128.4, 128.3, 127.8, 127.7, 127.5, 127.1, 116.6, 98.9, 76.4, 75.1,
CDCl3): δ 12.28 (s, 1H), 6.35 (d; J = 2.9 Hz, 1H), 6.26 (d, J = 1.9
Hz, 1H), 5.18 (m, 1H), 4.12 (d, J = 10.9 Hz, 1H), 3.93 (dd, J =
20 9.9, 3.9Hz, 1H), 3.80 (s, 3H), 3.63 (brs, 1H), 3.28 (td, J = 11.9
Hz, J = 3.9 Hz, 1H), 2.39 (m, 1H), 1.94-1.79 (m, 4H), 1.70-1.37
71.4, 70.4, 55.4, 39.4, 21.1 ppm; HRMS (ESI): calcd. for
C40H42O7Na [M + Na]+ 657.2822, found: 657.2825
(3S,5E,7S,8S,9S,11E)-8,9,16-tris(benzyloxy)-14-methoxy-3-
methyl-7-((R)-2,2,2-trifluoro-1-methoxy-1-phenylethoxy)-
(m,6H), 1.37 (d, J =5.9 Hz, 1H) ppm; 13C NMR (125 MHz, 80 3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxacyclotetradecin-1-
CDCl3): δ171.7, 166.6, 164.1, 147.1, 110.7, 104.4, 99.3, 75.7,
73.5, 69.9, 69.5, 55.3, 37.7, 34.7, 34.4, 31.9, 31.6, 28.7, 21.9,
25 21.5 ppm; HRMS(ESI): calcd. for C19H28O7Na [M + Na]+
391.1732, found: 391.1724.
one (36a): To a stirred solution of 36 (15 mg, 0.023 mmol),
MTPA (8 mg, 0.035 mmol) and DMAP (9 mg, 0.071 mmol) in
CH2Cl2 (3 mL) was treated with DCC (24 mg, 0.118 mmol) and
the reaction mixture was stirred for 12 h. After completion of the
85 reaction (monitored by TLC), the reaction mixture was quenched
with saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried over anhydrous Na2SO4, concentrated under
reduced pressure and the residue was purified by silica gel
(3S,5E,7S,8S,9S,11E)-8,9,16-Tris(benzyloxy)-14-methoxy-7-
(methoxymethoxy)-3-methyl-3,4,7,8,9,10-hexahydro-1H-
30 benzo[c][1]oxacyclotetradecin-1-one (35): To a suspension of
NaH (60% in mineral oil , 9.2 mg, 0.23 mmol) in dry THF (2
mL), was added alcohol 29 (50 mg, 0.09 mmol) in THF (2 mL) at 90 column chromatography (ethyl acetate/hexane = 1:19) to furnish
0 °C. The suspension was stirred for 1 h at room temperature. The
benzyl bromide (0.016mL, 0.14 mmol) was added slowly to the
35 above reaction mixture at 0 C. The reaction mixture was stirred
the desired esters 36a (16.3 mg, 82%) as a colorless oils. 1H
NMR (500M Hz, CDCl3): δ7.55-7.09 (m, 21H), 6.45 (d, J = 2.23,
1H), 6.38 (s, 1H), 6.13 (m, 1H), 5.53-5.32 (m, 2H), 5.09-4.96 (m,
4H), 4.68-4.58 (m, 2H), 4.43-4.33 (m, 2H), 3.77 (s, 3H), 3.68-
o
at room temperature for additional 4 h and quenched with water
at 0 °C. The reaction mixture was extracted with ethyl acetate (2 95 3.61 (m, 2H), 3.52 (s, 3H), 2.53-2.43 (m, 2H), 2.22-2.15 (m, 2H),
x 5 mL). The combined organic layer was washed with brine
solution (10 mL), dried over anhydrous Na2SO4 and the solvent
40 removed under reduced pressure. The residue was purified by
1.17 (d, J = 6.86Hz, 3H) ppm.
(3S,5E,7S,8S,9S,11E)-8,9,16-Tris(benzyloxy)-14-methoxy-3-
methyl-7-((S)-2,2,2-trifluoro-1-methoxy-1-phenylethoxy)-
3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxacyclotetradecin-1-
silica gel column chromatography (ethyl acetate/hexane = 1:25)
25
to give 35 (54 mg, 89%) as a light-yellow liquid [α]D −49.8 (c 100 one (36b): To a stirred solution of 36 (15 mg, 0.023 mmol),
0.8, CHCl3); IR (neat): 2933, 2953, 1604, 1460, 1257, 772 cm‒1;
1H NMR (500 MHz, CDCl3): δ 7.47-7.14 (m, 16H), 6.56 (d, J =
45 1.8 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 6.25 (m, 1H), 5.44 (m, 1H),
5.10 (m, 3H), 4.94-4.84 (m, 2H), 4.69-4.49 (m, 4H), 4.37 (m,
MTPA (8 mg, 0.035 mmol) and DMAP (9 mg, 0.071 mmol) in
CH2Cl2 (3 mL) was treated with DCC (24 mg, 0.118 mmol) and
the reaction mixture was stirred for 12 h. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
1H), 4.01 (m, 2H), 3.77 (s, 3H), 3.67-3.55 (m, 2H), 3.35 (s, 3H), 105 with saturated aqueous NaHCO3. The aqueous layer was
2.53-2.41 (m, 2H), 2.37-2.12 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H)
ppm; 13C NMR (125 MHz, CDCl3): δ 168.0, 161.0, 156.4, 139.1,
50 137.8, 137.5, 136.5, 132.5, 131.8, 128.9, 128.6, 128.4, 127.9,
127.8, 127.4, 126.9, 126.8, 116.9, 101.0, 98.4, 93.3, 83.9, 78.8,
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried over anhydrous Na2SO4, concentrated under
reduced pressure and the residue was purified by silica gel
column chromatography (ethyl acetate/hexane = 1:19) to furnish
77.6, 73.6, 71.3, 70.8, 70.4, 55.4, 55.1, 39.6, 31.6, 21.6 ppm; MS 110 the desired esters 36b (17.5 mg, 88%)as a colorless oils. 1H NMR
[ESI]: m/z [M + Na]+ 701:
(3S,5E,7S,8R,9S,11E)-8,9,16-Tris(benzyloxy)-7-hydroxy-14-
55 methoxy-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxa
cyclotetradecin-1-one (36): To a solution of compound 35 (45
(500M Hz, CDCl3): 7.55-6.99 (m, 21H), 6.46 (d, J = 2.28Hz,
1H), 6.38 (s, 1H), 6.14 (m, 1H), 5.55-5.43 (m, 2H), 5.08-4.93 (m,
4H), 4.66 (m, 1H), 4.48 (m, 1H), 4.35 (m, 1H), 4.22 (m, 1H),
3.77 (s, 3H), 3.58 (s, 1H), 3.54-3.45 (m, 4H), 2.46 (m, 1H), 2.33
mg, 0.07 mmol) in THF (5 mL) was treated with 2N HCl (5 mL) 115 (m, 1H), 2.27-2.11 (m, 2H), 1.16 (d, J = 5.72, 3H) ppm.
and allowed to stirred for 15 h at room temperature. After
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Organic & Biomolecular Chemistry
Delhi, India, for financial assistance in the form of research
fellowship. SP and NJ acknowledge the Council of Scientific and
60 Industrial Research (CSIR), India, for financial support under
the12th Five-Year Plan project and Small Molecule in Lead
Exploration (SMiLE-CSC-0111).
Biological evaluation Materials and methods Cell
Cultures, Maintenance and Antiproliferative Evaluation: The
cell lines, A549, HeLa, DU 145 and MDA MB 231 (lung,
cervical, prostate and breast cancer) which were used in this
study were procured from American Type Culture Collection
(ATCC), United States. The synthesized test compounds were
evaluated for their invitro antiproliferative activity in these six
different human cancer cell lines. A protocol of 48 h continuous
drug exposure was used, and a SRB cell proliferation assay was
5
Notes and references
aNatural Products Chemistry Division, CSIR-Indian Institute of Chemical
65 Technology, Hyderabad 500 007, India; E-mail: mohapatra@iict.res.in.
bAcademy of Scientific and Innovative Research, New Delhi, 110001,
Hyderabad-500007, India, Tel: -91-40-27193128; Fax: 91-40-
27160512;.
10 used to estimate cell viability or growth. All the cell lines were
grown in Dulbecco's modified Eagle's medium (containing 10%
FBS in a humidified atmosphere of 5% CO2 at 37 °C). Cells were
trypsinized when sub-confluent from T25 flasks/60 mm dishes
and seeded in 96-well plates in 100 μL aliquots at plating
15 densities depending on the doubling time of individual cell lines.
The microtiter plates were incubated at 37 °C, 5% CO2, 95% air,
and 100% relative humidity for 24 h prior to addition of
experimental drugs and were incubated for 48 hrs with different
doses (0.01, 0.1, 1, 10, 100 µM) of prepared derivatives. After 48
20 hours incubation at 37 °C, cell monolayers were fixed by the
addition of 10% (wt/vol) cold trichloroacetic acid and incubated
at 4 °C for 1h and were then stained with 0.057% SRB dissolved
in 1% acetic acid for 30 min at room temperature. Unbound SRB
was washed with 1% acetic acid. The protein –bound dye was
25 dissolved in 10 mM Tris base solution for OD determination at
510 nm using a microplate reader (Enspire, Perkin Elmer, USA).
Using the seven absorbance measurements [time zero, (Tz),
control growth, (C), and test growth in the presence of drug at the
five concentration levels (Ti)], the percentage growth was
30 calculated at each of the drug concentrations levels. Percentage
growth inhibition was calculated as:
cChemical Biology, CSIR-Indian Institute of Chemical Technology,
70 Hyderabad-500007, India, Tel: -91-40-27193128; Fax: 91-40-27160512
†Electronic Supplementary Information (ESI) available: [Scanned copies
of 1H, 13C NMR and HPLC data]. See DOI: 10.1039/b000000x/
‡ Footnotes should appear here. These might include comments relevant
75 to but not central to the matter under discussion, limited experimental and
spectral data.
1
F. Sugawara, K. W. Kim, K. Kobayashi, J. S. Yoshida, N. Murfushi,
N. Takahashi, G. A. Strobel, Phytochemistry 1992, 31, 1987–1990.
S. Ayers, T. N. Graf, A. F. Adcock, D. J. Kroll, S. Matthew, E.
J.Carcache deBlanco, Qi Shen, S. M. Swanson, M. C. Wani, Cedric J.
Pearce, N. H. Oberlies. J. Nat. Prod. 2011, 74, 1126–1131.
F. Q. Alali, T. El-Elimat, C. Li, A. Qandil, A. Alkofahi, K. Tawaha,
J. P. Burgess, Y. Nakanishi, D. J. Kroll, H. A. Navarro, J. O.
Falkinham, M. C. Wani, N. H. Oberlies, J. Nat. Prod. 2005, 68, 173–
178.
C. Li, D. Lee, T. N. Graf, S. S. Phifer, Y. Nakanishi, S. Riswan, F.
M. Setyowati, A. M. Saribi, D. D. Soejarto, N. R. Farnsworth, J. O.
Falkinham, D. J. Kroll, A. D. Kinghorn, M. C. Wani, N. H.
Oberlies, J. Nat. Prod. 2009, 72, 1949–1953.
2
80
85
3
4
90 5 N. Jana, S. Nanda, Eur. J. Org. Chem. 2012, 4313–4320.
6
Y. Gao, J. Liu, L. Wang, M. Xiao, Y. Du, Eur. J. Org. Chem. 2014,
2092–2098..
[(Ti-Tz)/(C-Tz)] x 100 for concentrations for which Ti>/=Tz
[(Ti-Tz)/Tz] x 100 for concentrations for which Ti<Tz.
7
(a) D. K. Mohapatra, D. S. Reddy, N. A. Mallampudi, J. S. Yadav,
Eur. J. Org. Chem. 2014, 5023-5032; (b) D. K. Mohapatra, P. P. Das,
M. R. Pattanayak, G. Gayatri, G. N. Sastry, J. S. Yadav, Eur. J. Org.
Chem. 2010, 4775–4784; (c) B. Tang, C. D. Bray, G. Pattenden, Org.
Biomol. Chem. 2009, 7, 4448–4457; (d) P. A. Roethle, D. Trauner,
Org. Lett. 2006, 8, 345–347; (e) W. Zhu, M. Jimenez, W.-H. Jung, D.
P. Camarco, R. Balachandran, A. Vogt, B. W. Day, D. P. Curran, J.
Am. Chem. Soc. 2010, 132, 9175–9187; (f) K. Namba, J. Wang, S.
Cui, Y. Kishi, Org. Lett. 2005, 7, 5421-5424; (g) K. B. Sharpless, W.
Amberg, L. B. Youssef, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-
L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L. Zhang, J. Org.
Chem. 1992, 57, 2768‒2771; (h) H. C. Kolb, M. S. VanNieuwenhze,
K. B. Sharpless, Chem. Rev. 1994, 94, 2483–2547; (i) A. Furstner,
Chem. Rev. 1999, 99, 991-1045; (j) K. Takai, K. Kimura, T. Kuroda,
T. Hiyama, H. Nozaki, Tetrahedron Lett. 1983, 24, 5281–5284; (k)
H. Jin, J. Uenishi, W. J Christ, Y. Kishi, J. Am. Chem. Soc. 1986,
108, 5644–5646.
Three dose response parameters were calculated for each
35 experimental agent. Growth inhibition of 50 % (GI50) was
calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which is the drug
concentration resulting in a 50% reduction in the net protein
increase (as measured by SRB staining) in control cells during the
drug incubation. The drug concentration resulting in total growth
40 inhibition (TGI) was calculated from Ti = Tz. The IC50
(concentration of drug resulting in a 50% reduction in the
measured protein at the end of the drug treatment as compared to
that at the beginning) indicating a net loss of cells following
treatment was calculated from [(Ti-Tz)/Tz] x 100 = ‒50. Values
45 were calculated for each of these three parameters if the level of
activity is reached; however, if the effect is not reached or is
exceeded, the value for that parameter was expressed as greater or
less than the maximum or minimum concentration tested.23
95
100
105
110 8 (a) M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science
1997, 277, 936-938; (b) M. E. Furrow, S. E. Schaus, E. N. Jacobsen,
J. Org. Chem. 1998, 63, 6776-6777; (c) D. K. Mohapatra, P. P. Das,
D. S. Reddy, J. S. Yadav, Tetrahedron Lett. 2009, 50, 5941–5944.
9. G. Deng, Z. Huang, X. Zhao, Z. Li, Y. Li, B. Jiang, Chin. J. Chem.
50
115
2013, 31, 15-17.
Acknowledgements
10 (a) K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa and O. Yonemitsu,
Tetrahedron 1986, 42, 3021–3028; (b) C. C. Sanchez and G. E.
Keck, Org. Lett. 2005, 7, 3053–3056.
11 (a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156; b)
D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7187.
12 K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108, 7408–
7410.
The authors thank CSIR, New Delhi, for financial support as part
of XII Five Year Plan Programme under title ORIGIN (CSC-
0108). DKM thanks the Council of Scientific and Industrial
55 Research (CSIR), New Delhi, India, for a research grant (INSA
Young Scientist Award Scheme). D.S.R., N.A.M. and J.G. thank
the Council of Scientific and Industrial Research (CSIR), New
120
13 J.-F. Basset, C. Leslie, D. Hamprecht, A. J. P. White, A. G. M.
Barrett, Tetrahedron Lett. 2010, 51, 783-785.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 11

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C4OPB0a1g81e1G12 of 12
14 (a) M. S. Kamisuki, S. Takahashi, Y. Mizushina, S. Hanashima, K.
Kuramochi, S. Kobayashi, K Sakaguchi, T. Nakata, F. Sugawara,
Tetrahedron 2004, 60, 5695–5700; (b) O. Mitsunobu, Synthesis,
1981, 1–28.
5 15 (a) F. Compostella, L. Franchini, L. Panza, D. Prosperi, F. Ronchetti,
Tetrahedron 2002, 58, 4425–4428; (b) B. Zhou, Z. Miao, G. Deng, J.
Ding, Y. Yang, H. Feng, Y. Li, Bioorg. Med. Chem. Lett. 2010, 20,
6217-6221.
16 A. Chattopadhyay, J. Org. Chem. 1996, 61, 6104-6107.
10 17 W. Yu, Y. Mei, Y. Kang, Z. Hua, Z. Jin, Org. Let. 2004, 6, 3217-
3219.
18 (a) P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett
1998, 26–29; (b) P.R. Blakemore, J. Chem. Soc., Perkin Trans. 2002,
1, 2563–2585.
15 19 (a) I. Ohtani, J. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem.
Soc. 1991, 113, 4092-4096; (b) W. Y. Yoshida, P. J. Bryan, B. J.
Baker, J. B. McClintock, J. Org. Chem. 1995, 60, 780-782.
20 G. Deng, Z. Li, S. Peng, L. Fang, Y. Li, Tetrahedron 2007, 63, 4630-
4635.
20 21 A. Bhattacharjee, O. R. Sequil, J. K. De Brabander, Tetrahedron Lett.
2000, 41, 8069.
22 (a) E. J. Corey, R. K. Bakshi, S. Shibata, C. P. Chen, V. K. Singh, J.
Am. Chem. Soc. 1987, 109, 7925; (b) E. J. Corey, R. K. Bakshi,
Tetrahedron Lett. 1990, 31, 61; (c) E. J. Corey, C. J. Helal, Angew.
25
Chem., Int. Ed. 1998, 37, 1986.
23 M. A. Reddy, N. Jain, D. Yada, C. Kishore, J. R. Vangala, P. R.
Surendra, A. Addlagatta, S. V. Kalivendi, B. Sreedhar, J. Med. Chem.
2011, 54, 6751-6760.
12
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