An efficient and stereoselective synthesis of obolactone via modified Evans' Aldol protocol

Article abstract of DOI:10.1016/j.tet.2017.08.001

Stereocontrolled total synthesis of obolactone was achieved from trans-cinnamaldehyde. The key steps in this synthetic sequence are a asymmetric Mukaiyama Aldol, a Crimmins' modified Evans' Aldol reaction to introduce C2′ stereocentre, a nucleophilic addi

Full text of DOI:10.1016/j.tet.2017.08.001

Accepted Manuscript
An efficient and stereoselective synthesis of obolactone via modified Evans' Aldol
protocol
Rayala Naveen Kumar, H.M. Meshram
PII:
S0040-4020(17)30814-1
10.1016/j.tet.2017.08.001
TET 28895
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 June 2017
Revised Date: 2 August 2017
Accepted Date: 3 August 2017
Please cite this article as: Kumar RN, Meshram HM, An efficient and stereoselective synthesis of
obolactone via modified Evans' Aldol protocol, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.001.
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An efficient and stereoselective synthesis of
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Rayala Naveen Kumar*, H. M. Meshram
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India.

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Tetrahedron
journal homepage: www.elsevier.com
An efficient and stereoselective synthesis of obolactone via modified Evans' Aldol
protocol
*
Rayala Naveen Kumar , H. M. Meshram
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Stereocontrolled total synthesis of obolactone was achieved from trans-cinnamaldehyde. The
key steps in this synthetic sequence are a asymmetric Mukaiyama Aldol, a Crimmins' modified
Evans' Aldol reaction to introduce C2’ stereocentre, a nucleophilic addition of potassium salt of
mono methyl malonate, a Z-olefination using Andos' modified Horner-Wadsworth-Emmons
reagent to introduce Z-olefin at C3,C4 in the final lactone skeleton, and a tandem deprotection
and lactonization.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Thiazolidinethione auxiliary
Crimmins' modified Evans Aldol
Andos' diaryl phosphonate
1
,3-Syn reduction
Tandem lactonization
1
. Introduction
Two dihydro pyrone rings are fused to styryl skeletal,
obolactone 1 was isolated from the fruits and the trunk bark of
Cryptocarya obovate in the Hanoi,Vietnam by Guéritte and co-
6
-Substituted-5,6-dihydro-2H-pyran-2-ones are significan1t
structural subunits in many biologically potent natural products.
The 5,6-dihydro-α-pyrone units are widely spread in all parts of
plants like Lamiaceae, Piperaceae, Lauraceae, and Annonaceae
families including leaves, stems, flowers, and fruits. Natural
products containing these subunits are recognized for a wide
variety of biological activities, such as insect growth
5
workers. Obolactone 1 shows a significant activity in vitro
cytotoxic assays against the human nasopharyngeal KB cell line
5
with an IC50 values of 3 µM. The 2'R, 6R configuration of
1
obolactone 1 was assigned by X-ray crystallographic analysis and
5
Cotton effect in CD curve. Due to its promising biological
activity and skeletal structure, draws the attention of chemists to
synthesize. Up until now, there were four syntheses appeared in
2a,b
2c
2d
inhibition,
antimicrobial, antifungal, and potent in vitro
3
activity against a broad range of cancer cell. The styryl α-pyron
skeleton of obolactone 1 is closely related to those of
cryptofolione, cryptocaryalactone and fostriecin (Figure 1). Most
of these styryl α-pyrone containing natural products showed
6-9
the literature. In continuation of our research for the synthesis
10
of new bioactive molecules, herein we wish to report
enantioselective synthesis of obolactone 1. The Structure-activity
relationship of obolactone 1 is under exploration and the results
will be reported elsewhere in due course.
4
cytotoxicity against human tumour cells.
In 2006, She and co-workers reported the first asymmetric
total synthesis of obolactone 1, ring-closing metathesis and
6
asymmetric allylation as the key steps of their approach . In
Sabitha et al., Prins cyclization and ring-closing metathesis as
7
strategic approach, and the following synthesis from Krishna et
al. in 2010, Brønsted acid mediated cyclization and Keck
8
allylation as their central approach. Recently, desymmetrization
9
via Wacker oxidation was the significant approach by Bruckner.
Here the salient features of our synthetic strategy include:
Mukaiyama Aldol using 1,3-bis(trimethylsiloxy)diene 4 (Chan’s
diene), chiral thiazolidinethione mediated modified Evans' Aldol
reaction which is finest technique to introduce stereogenic 1, 3
dihydroxy centers in the chain elongation route, usage of our
Figure 1: Obolactone 1 and some natural products containing 5,6-
dihydro-
α
-pyrone.
—
——
*
Corresponding author. Tel.: +15129981537; fax: +91-40-27193275; e-mail: navirayala@gmail.com.

2
Tetrahedron
MAdi
modified chopping method of the chiral a
A
ux
C
ilia
C
ry
E
a
P
d
T
du
E
ct
D
3
N
ffe
previous ones. Diastereoselective asymmetric acetate Aldol
reaction of chlorotitanium enolate of 4-(S)-N-acetyl-4-
U
ren
S
t
C
c
R
om
I
plimentary diastereoselectivity compared to the
P
T
11
using magnesium iodide, 1,3-syn reduction of δ-hydroxy-β-keto
ester 11 with Zn(BH ) and introducing Z-olefin in α-pyrone by
Andos' diaryl phosphonate. Introduction of double Aldol reaction
makes the synthetic strategy highly stereoselective and reduces
the number of steps.
a
4
2
17c
benzylthiazolidine-2-thione 9 with aldehyde 8 to introduce the
desired stereogenic center at C2’, yielding 3 as the major
diastereomer (dr-9:1) (Scheme 2). The subsequent treatment of
Aldol adduct 3 with the methyl potassium malonate 10 and MgI
2
1
1, 17b
in the presence of imidazole resulted in β-keto-ester 11.
Diastereoselective reduction of δ-hydroxy-β-keto ester 11 with
1
8, 12
o
Zn(BH4)2
8
at -30 C afforded the desired syn-1,3-diol 12 in
19
4% yield (syn:anti 10:1). We be obliged to select the
protecting group such a way that it would reduce the number of
steps in the synthesis and should be intact during the acetonide
deprotection at C6’C4’. Here our choice of protecting group was
MOM protection. Thus, the resultant two secondary hydroxyl
groups in syn-1,3-diol 12 were protected with methoxymethyl
chloride (MOMCl) to obtain MOM ether 13 in 89% yield under
an extended reaction condition.
Scheme 1. Retrosynthetic strategy of obolactone 1.
The retrosynthetic pathway of obolactone 1 is depicted in
Scheme 1, we envisioned that obolactone
accomplished via sequential operation of selective deprotection
of acetonide, oxidation of two 1,3-anti alcohols to 1, 3 diketones
and direct lactonization of the Z-olefin 2. Z-olefin 2 could be
readily obtained from Evans' Aldol adduct 3. Aldol adduct 3 was
envisaged as being accessible from Chan’s diene 4 by
Mukaiyama asymmetric Aldol onto the commercially available
trans-cinnamaldehyde 5.
O
O
O
O
i) DIBAL-H, THF, 0°C, 1h;
ii) IBX, EtOAc,
reflux, 2 h
O
O
O
O
O
O
O
O
O
O
1
could be
O
79%
1
3
14
O
O
OEt
O
O
(
Cresol)2P(O)CH2COOEt (15),
NaH, THF, -78°C, 30 min
CSA (5 mol%),
MeOH, 30 min, 0 °C
O
O
O
Z:E = 11:1, 81%
86%
Ando's Z-olefination
2
O
O
OEt
O
O
OEt
O
O
O
O
2
. Results and Discussion
OH OH
O
O
O
O
IBX , EtOAc,
5 °C, 6 h
8
8
2%
1
6
17
O
O
O
PTSA (10mol%), MeOH,
0 °C, 4 h
O
5
7
4%
Obolactone 1
Scheme 3. Completion of synthesis of obolactone 1.
The ester 13 was reduced to alcohol by DIBAL-H in THF at 0
C, the subsequent oxidation of which using ortho-iodoxybenzoic
acid (IBX) in EtOAc reflux provided the corresponding aldehyde
4 in 79% yield. Precursor, (Cresol) P(O)CH COOEt 15 was
°
1
2
2
obtained through standard method of preparation produced by
Ando which allowed access to the (Z)-olefins with high
20
stereoselectivity.
Andos' modified Horner–Wadsworth–
Emmons (HWE) olefination of aldehyde 14 using diaryl
phosphonate, (Cresol) P(O)CH COOEt 15 provided a α,β-
2
2
unsaturated ester 2 favoring the desired Z-isomer in 81% yield
Z:E ratio-11:1) (Scheme 3). The E:Z ratio of the HWE
Scheme 2. Synthesis of intermediate ester 13.
Synthesis of obolactone 1 commenced with the transformation
(
olefination was confirmed based on coupling constant 11.6 Hz
of Chan’s diene 4 into aldehyde 8 according to our earlier
1
and integration values in H NMR. Controlled deprotection of
12
published protocol. To introduce 2’R, 6R stereocentre in
obolactone 1, herein we executed Crimmins' modified Evans'
Aldol reaction with aldehyde 8. Chiral auxiliaries facilitated
asymmetric Aldol reaction is considered to be one of the
significant methods for asymmetric C-C bond formation and
acetonide in the Z-olefin adduct 2 using camphorsulfonic acid
(
1
CSA) in MeOH at 0 °C was proceeded efficiently to afford diol
6 in quantitative yield. Obtained 1,3 diol 16 was oxidised to the
corresponding 1, 3 diketone 17 using IBX in EtOAc at 85 °C for
h. Finally, the treatment of 1,3 diketone 17 with PTSA in
6
13
chain elongation. Most applied type of auxiliaries are the class
8
MeOH afforded obolactone 1 in 74% yield. In this asymmetric
acetate Aldol synthetic strategy, obolactone 1 was successfully
accomplished in 10 steps from aldehyde 8. H and C NMR data
1
4
of chiral oxazolidinones, initially developed in the Evans group,
and further modified by other groups.
oxazolidinones has been most effective in the stereoselective
construction of numerous chiral building blocks, as well as
antibiotics, natural products, and bioactive compounds.
15
These chiral
1
13
5, 6
of obolactone 1 was completely agreed with the literature data.
16
3. Conclusion
Modified Evans' chiral auxiliaries like chiral thiazolidinethiones
are become prevalent tools for the modern organic synthesis
attributed to their efficient stereoselective transformations. This
Crimmins modified imides have been developed to exhibit
In conclusion, we have completed the stereoselective
synthesis of obolactone 1 in a concise approach and the overall
17
yield of this synthetic strategy is about 9.9% from
a

3
commercially available
trans-cinnamalde
A
hy
C
deCE
5
P
.
TE
T
D
he MA12
N
8.
U
48
S
,
C
12
R
7.6
I
6, 126.43, 100.69, 67.45, 61.98, 49.14, 37.59,
P
T
+
significance of our synthetic sequence lies in employing a
Mukaiyama Aldol addition using Chan’s diene, building of the
desired stereocentre C2’ by a modified form of Evans'
thiazolidinethione auxiliary, diastereoselective 1,3-syn reduction
of δ-hydroxy-β-keto ester with Zn(BH ) , a Z-olefination using
25.29, 24.74. EI-MS: m/z 261[M +H].
4
2
1
.2. (S)-1-((S)-4-benzyl-2-thioxothiazolidin-3-yl)-4-((4S,6R)-
,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-yl)-3-hydroxybutan-
-one (3)
4
2
Andos' modified HWE reagent, and a tandem sequence of MOM
deprotection and lactonization. An upgraded method of chopping
the Evans' Aldol auxiliary was found to be extremely
advantageous, and a selective deprotection of acetonide over
MOM with CSA reduced the number of steps in this synthesis.
In a dry round bottom flask under argon atmosphere, (S)-1-(4-
benzyl-2-thioxothiazolidin-3-yl)ethanone 9 (1.26 g, 5 mmol) was
dissolved in CH Cl (10 mL), then cooled to 0 °C. A solution of
2
2
TiCl (0.66 mL, 6 mmol) in CH Cl (5 mL) was added dropwise
4
2
2
to the reaction mixture, and the thick suspension was stirred for
0 minutes, upon which diisopropylethylamine (1.07 mL, 6
2
4
. Experimental Section
mmol) was added dropwise at 0 °C. The solution after stir for 20
min at same temperature, then cooled to -78 °C and to the
reaction mixture was added freshly prepared aldehyde 8 (1.3 g, 5
mmol) in CH Cl (10 mL). The reaction was further stirred for 1
All reactions were performed under inert atmosphere. All
glassware apparatus used for reactions are perfectly oven/flame
dried. Anhydrous solvents were distilled prior to use: THF from
Na and benzophenone; CH Cl , DMSO from CaH ; MeOH from
2
2
h, then quenched with saturated NH Cl, and warmed to rt. The
4
2
2
2
layers were separated and the aqueous layer was extracted
CH Cl (3x100 mL). The combined organic layers were dried
Mg cake. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel (60–
2
2
over anhydrous Na SO , filtered and concentrated under reduced
1
20 mesh) unless otherwise mentioned. Analytical thin layer
2
4
pressure. The crude product was purified by flash column
chromatography on silica gel (petroleum ether–EtOAc, 7:3) to
chromatography (TLC) was run on silica gel 60 F254 pre-coated
plates (250 ꢀm thickness). Mass spectral data were obtained
using MS (EI) ESI, HRMS mass spectrometers. High resolution
mass spectra (HRMS) [ESI+] were obtained using either a TOF
provide the product 3 (1.98 g, 78%) as a yellow liquid. R = 0.4
f
(
2
1
petroleum ether–EtOAc, 7:3). IR (KBr) νmax = 3424, 3027, 2992,
1
940, 1754, 1650, 1492, 1448, 1381, 1260, 1199, 1164, 1136,
or a double focusing spectrometer. H NMR spectra were
-1 1
13
078, 966, 876, 748, 694, 523 cm . H NMR (300 MHz, CDCl )
recorded at 300 MHz, and C NMR spectra 75 MHz in CDCl3
solution unless otherwise mentioned, chemical shifts are in ppm
downfield from tetramethylsilane and coupling constants (J) are
reported in hertz (Hz). The following abbreviations are used to
designate signal multiplicity: s = singlet, d = doublet, t = triplet, q
3
δ 7.43-7.16 (m, 10H), 6.62 (d, J = 16.0 Hz, 1H), 6.19 (ddd, J =
1
4
1
6.0, 6.2, 1.0 Hz, 1H), 5.29-5.21 (m, 1H), 4.62-4.51 (m, 1H),
.35-4.16 (m, 1H), 3.94-3.88 (m, 1H), 3.68 (d, J = 11.1, 2.8 Hz,
H), 3.43-3.32 (m, 2H), 3.23 (dd, J = 12.3, 4.1 Hz, 1H), 3.03 (dt,
J = 10.4, 2.0 Hz, 1H), 2.84 (d, J = 11.4 Hz, 1H), 2.67-2.49 (br,
=
quartet, quin = quintet, sex = sextet, m = multiplet, br = broad.
13
1
H), 1.89-1.61 (m, 4H), 1.55 (s, 3H), 1.47 (s, 3H). C NMR (75
4
.1. 2-((4R,6R)-2,2-dimethyl-6-((E)-styryl)-1,3-dioxan-4-
MHz, CDCl ) δ 201.75, 172.18, 136.45, 136.37. 130.70, 130.58,
3
yl)acetaldehyde (8)
1
6
(
29.50, 129.25, 128.35, 127.59, 126.35, 100.79, 69.76, 68.78,
4.15, 63.40, 46.38, 43.31, 37.72, 36.55, 32.14, 25.52, 24.21. MS
To a stirred solution of the ethyl 2-((4R,6R)-2,2-dimethyl-6-
+
ESI): m/z = 534 [M + Na] . HRMS: calcd. for C H NO S Na
28
33
4 2
((E)-styryl)-1,3-dioxan-4-yl)acetate (2.6 g, 10 mmol) in 40 mL
+
[
M + Na] : 534.17487: found: 534.17478.
dry THF at 0 °C was slowly added DIBAL-H (25 mL, 25 mmol;
1
0
M in hexanes) over 20 min. The reaction mixture was stirred at
°C for 1 h, then methanol (10 mL) was added dropwise slowly.
4.3. Methyl (S)-6-((4S,6R)-2,2-dimethyl-6-((E)-styryl)-1,3-
dioxan-4-yl)-5-hydroxy-3-oxohexanoate (11)
The resulting solution was poured into aq. potassium sodium
tartrate solution (100 mL) and EtOAc (100 mL) and stirred
vigorously for l h. The organic layer was separated, and the
aqueous layer extracted with further EtOAc (3x100 mL). The
To a solution of thiazolidinethione Aldol adduct 3 (5 mmol,
.0 equiv) in THF (20 mL) was added methyl potassium
1
malonate 10 (10 mmol, 2.0 equiv) followed by MgI (5 mmol,
2
1
.0 equiv) under Argon. The suspension was stirred at rt for 30
combined organic layers were dried (MgSO ), filtered and
4
min, then imidazole (5 mmol, 1.0 equiv) was added in one
portion, and the reaction mixture was stirred at rt for 5 h. After
completion, the reaction was diluted with EtOAc (100 mL),
washed with 0.5 M HCl (50 mL), and the aqueous layer was
extracted with EtOAc (3 x 50 mL). The combined organic layers
concentrated in vacuo. Purification by flash chromatography on
silica gel gave the corresponding alcohol as a colorless oil.
Add 2-Iodoxybenzoic acid (IBX) (3.78 g, 13.5 mmol) to the
stirred solution of above alcohol (2.36 g, 9 mmol) in EtOAc (18
mL) at rt, then heat the reaction mixture to 85 °C, then reflux for
were then washed with 0.5 M NaHCO (50 mL). Finally, the
3
2
h. After completion of reaction, quench with saturated aq.
combined organic layers were dried over Na SO , filtered, and
2
4
NaHCO (50 mL), and the mixture stirred for 20 min at rt. The
3
concentrated in vacuo to give a light yellow oily liquid. The
resulting crude mixture was purification by flash chromatography
(petroleum ether–EtOAc, 3:2) to afford the pure δ-hydroxy-β-
organic layer was extracted with ethyl acetate (3x100 mL), dried
over MgSO , rotary evaporated, and flash chromatography to
4
give the corresponding aldehyde 8 (1.85 g, 79%) as a colourless
ketoester 11 (1.73 g, 92%). R = 0.3 (petroleum ether–EtOAc,
f
oil. R = 0.6 (petroleum ether–EtOAc, 3:2). IR (KBr) ν = 3440,
f
max
7:3). IR (KBr) νmax = 3478, 2992, 2923, 2854, 1745, 1715, 1652,
3
1
026, 2993, 2921, 2854, 2730, 1725, 1654, 1495, 1381, 1262,
200, 1165, 1137, 1097, 968, 874, 750, 695, 523 cm . H NMR
1
438, 1381, 1324, 1262, 1200, 1163, 1093, 968, 937, 748, 695
-1 1
-
1 1
cm . H NMR (300 MHz, CDCl ) δ 7.45-7.12 (m, 5H), 6.59 (d, J
3
(
300 MHz, CDCl ) δ 9.77 (t, J = 1.9 Hz, 1H), 7.40-7.19 (m, 5H),
3
= 15.9 Hz, 1H), 6.15 (ddd, J = 16.0, 6.2, 4.7 Hz, 1H), 4.55 (ddd,
J = 9.8, 6.6, 2.7 Hz, 1H), 4.42-4.15 (m, 2H), 3.73 (s, 3H), 3.51 (d,
J = 7.0 Hz, 2H), 3.08 (br, 1H), 2.83-2.58 (m, 2H), 1.77-155 (m,
6
4
3
1
.56 (dd, J = 16.0, 1.3 Hz, 1H), 6.21 (dd, J = 16.0, 6.1 Hz, 1H),
.54 (dtd, J = 9.4, 6.3, 1.5 Hz, 1H), 4.44 (dtd, J = 10.7, 5.9, 5.2,
.0 Hz, 1H), 2.67 (ddd, J = 16.7, 8.1, 2.3 Hz, 1H), 2.52 (ddd, J =
6.6, 4.8, 1.6 Hz, 1H), 1.98 (ddd, J = 12.9, 9.0, 5.9 Hz, 1H), 1.81
13
4
H), 1.54 (d, J = 5.3 Hz, 3H), 1.45 (s, 3H). C NMR (75 MHz,
CDCl ) δ 202.23, 167.35, 136.45, 130.70, 129.50, 128.35,
3
13
(ddd, J = 12.9, 9.4, 6.2 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H).
C
1
27.59, 126.35, 100.29, 69.91, 65.89, 64.15, 52.25, 49.80, 49.49,
+
NMR (75 MHz, CDCl ) δ 199.79, 136.54, 130.48, 129.35,
3
42.15, 36.88, 25.22, 24.63. MS (ESI): m/z = 399 [M + Na] .

4
Tetrahedron
+
HRMS: calcd. for C H O Na [M + Na] : 3
A
99
C
.1
C
77
E
81
P
:
T
fo
E
un
D
d: MAco
NU
nc
en
S
tra
CRI
inPTvacuo. The crude extract was purified by flash
te
d
21
28
6
3
99.17671.
column chromatography (petroleum ether–EtOAc, 1:1) to give
corresponding alcohol as a thick liquid. R = 0.3 (petroleum
f
4
1
.4. Methyl (3S,5R)-6-((4S,6R)-2,2-dimethyl-6-((E)-styryl)-
,3-dioxan-4-yl)-3,5-dihydroxyhexanoate (12)
ether–EtOAc, 1:1). Add IBX (767 mg, 1.74 mmol) to the stirred
solution of above alcohol (180 mg, 0.40 mmol) in EtOAc (10
mL) at rt, then heat the reaction mixture at 85 °C reflux for 2 h
and check TLC for the completion of reaction. After completion
A freshly prepared solution of Zn(BH ) in ether (~1M, 5 mL)
4
2
was added to a solution of δ-hydroxy-β-ketoester 11 (1.5 g, 4
mmol) in ether (20 mL) at -30 °C and the reaction mixture was
stirred for 1 h at this temperature. The reduction was almost
completed within 10 min. The reaction was quenched by the
successive addition of water (10 mL) and aqueous 0.1N HCl (20
mL), and the mixture was extracted with ether (3x100 mL). The
combined ether layers was washed with saturated aqueous
NaHCO (50 mL) solution and brine, then dried over MgSO and
concentrated. The crude product was purified by chromatography
on silica gel (petroleum ether–EtOAc, 1:1) to obtain syn-1,3-diol
1
3
1
of reaction, quench with saturated aqueous NaHCO (20 mL) and
3
the mixture stirred for another 30 min. The organic layer was
extracted with ethyl acetate (3x75 mL), dried over MgSO and
4
rotary evaporated to give aldehyde 14 (689 mg, 79%) as a
colourless oil. R = 0.5 (petroleum ether–EtOAc, 3:2). This
f
aldehyde used for further reaction without purification.
3
4
To a stirred suspension of NaH (60% dispersion in oil) (48
mg, 1.2 mmol) in dry THF (5 mL) was added a solution of
(
Cresol) P(O)CH COOEt phosphonate 15 (417 mg, 1.2 mmol) in
2 2
2 (1.27 g, 84%) with dr-10:1. R = 0.3 (petroleum ether–EtOAc,
f
dry THF (2.5 mL) at -78 °C under argon, and the reaction
mixture was stirred for 30 min at the same temperature. Then a
solution of the aldehyde 14 (436 mg, 1.0 mmol) in THF (2.5 mL)
was added dropwise, and the reaction mixture was stirred at −78
:2). IR (KBr) νmax = 3449, 2925, 2859, 1732, 1641, 1436, 1381,
-
1 1
263, 1201, 1164, 1090, 927, 935, 877, 750, 694, 522 cm . H
NMR (300 MHz, CDCl ) δ 7.42-7.17 (m, 5H), 6.57 (d, J = 16.0
Hz, 1H), 6.23 (dt, J = 16.0, 5.7 Hz, 1H), 4.63-4.46 (m, 1H), 4.42-
4
2
3
°
C for about 30 min. After completion of reaction, brought the
.16 (m, 2H), 3.88-4.04 (m, 1H), 3.71 (s, 3H), 3.35-3.14 (br, 1H),
.74-2.47 (m, 2H), 1.73-1.50 (m, 7H), 1.50-1.31 (m, 5H).
reaction mixture to −35 °C and quenched with aq. ammonium
chloride. The reaction mixture was extracted with CH Cl (3x50
13
C
2
2
NMR (75 MHz, CDCl ) δ 172.61, 136.47, 130.89, 129.32,
3
mL), and the organic layer was washed with brine, dried over
1
5
4
4
28.46, 127.70, 126.47, 100.74, 71.40, 69.94, 68.73, 66.44,
MgSO , filtered, and concentrated. The crude residue was
4
1.68, 43.13, 42.75, 41.59, 37.12, 25.49, 24.83. MS (ESI): m/z =
purified by column chromatography (petroleum ether–EtOAc,
+
+
01 [M + Na] . HRMS: calcd. for C H O Na [M + Na] :
21
30
6
7
:3) to give (Z)-α,β-unsaturated ester 2 (409 g, 81%) as a thick
01.1935: found: 401.1925.
liquid. R = 0.3 (petroleum ether–EtOAc, 4:1). IR (KBr) ν
=
max
f
2
926, 2856, 1727, 1647, 1456, 1377, 1278, 1170, 1106, 1036,
4
1
.5. Methyl (3S,5R)-6-((4S,6R)-2,2-dimethyl-6-((E)-styryl)-
,3-dioxan-4-yl)-3,5-bis(methoxymethoxy)hexanoate (13)
-1 1
953, 758, 700, 514 cm . H NMR (300 MHz, CDCl
) δ 7.41-7.21
3
(m, 5H), 6.59 (dt, J = 16.6, 1.3 Hz, 1H), 6.34 (dtt, J = 10.3, 6.8,
To a solution of 12 (1.13 g, 3 mmol) in dry CH Cl (6 mL)
2
2
3.3 Hz, 1H), 6.17 (ddd, J = 16.0, 6.3, 1.6 Hz, 1H), 5.88 (dt, J =
10.3, 1.8 Hz, 1H), 4.73-4.63 (m, 4H), 4.57-4.50 (m, 1H), 4.32-
4
2
3.5 Hz, 3H), 1.46-1.42 (m, 3H), 1.30-1.22 (m, 3H). C NMR (75
MHz, CDCl ) δ 166.12, 145.47, 136.56, 131.38, 129.76, 128.37,
126.39, 125.26, 121.41, 100.33, 95.85, 95.34, 73.84, 71.91,
7
were added i-Pr NEt (3.16 mL, 18 mmol) and methoxymethyl
chloride (MOMCl, 0.905 mL, 12 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 16 h. Then the
reaction was quenched with sat. aqueous NH Cl and the whole
was extracted with EtOAc (3x75 mL). The organic layer was
washed with brine, dried over MgSO , filtered, and concentrated.
The residue was purified by column chromatography (petroleum
ether–EtOAc, 7:3) to give 13 (1.25 g, 89%) as a thick liquid. R =
0
2
7
5
4
3
2
2
.06 (m, 4H), 3.94-3.79 (m, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 3.07-
.83 (m, 2H), 1.96-1.84 (m, 2H), 1.73-1.55 (m, 4H), 1.51 (d, J =
13
4
3
4
0.08, 65.44, 61.88, 55.62, 55.58, 42.19, 39.31, 37.20, 33.66,
+
f
25.38, 24.77, 14.17. MS (ESI): m/z = 529 [M + Na] . HRMS:
calcd. for C H O Na [M + Na] : 529.27719: found: 529.27542.
+
.3 (petroleum ether–EtOAc, 7:3). IR (KBr) νmax = 2991, 2946,
853, 1739, 1600, 1440, 1379, 1200, 1151, 1100, 1035, 969, 918,
28
42
8
-
1
1
4.7. Ethyl (2Z,5R,7S,9R,11R,12E)-9,11-dihydroxy-5,7-
bis(methoxymethoxy)-13-phenyltrideca-2,12-dienoate (16)
48, 695, 522 cm . H NMR (300 MHz, CDCl ) δ 7.44-7.16 (m,
3
H), 6.60 (d, J = 16.0 Hz, 1H), 6.16 (dd, J = 16.0, 6.1 Hz, 1H),
.72-4.60 (m, 4H), 4.59-4.46 (m, 1H), 4.23-4.04 (m, 2H), 3.95-
.81 (m, 1H), 3.69 (d, J = 1.2 Hz, 3H), 3.41 (s, 3H), 3.36 (s, 3H),
.72-2.45 (m, 2H), 2.03-1.82 (m, 2H), 1.79-1.56 (m, 4H), 1.51 (d,
CSA (4 mg, 5 mol%) was added to a solution of (Z)-α,β-
unsaturated ester 2 (151 mg, 0.30 mmol) in MeOH (3 mL) and
the mixture was stirred at 0 °C for 30 min. After completion of
reaction, extracted with ether (2x50 mL). The ether extract was
13
J = 3.4 Hz, 3H), 1.44 (s, 3H). C NMR (75 MHz, CDCl ) δ
3
1
9
4
71.69, 136.58, 130.64, 129.76, 128.41, 127.58, 126.44, 100.36,
6.35, 95.87, 72.27, 71.70, 70.10, 67.67, 55.77, 55.61, 51.52,
0.85, 40.11, 39.46, 38.22, 25.86, 24.94. MS (ESI): m/z = 489
washed with saturated aq. NaHCO solution, and NaCl solution,
3
then dried over MgSO4 and concentrated. The residue was
purified by flash chromatography on silica gel (petroleum ether–
EtOAc, 1:1) to afford diol 16 (120 mg, 86%) as a thick liquid. Rf
+
+
[
M + Na] . HRMS: calcd. for C H O Na [M + Na] : 489.2458:
25 38 8
found: 489.2444.
=
0.3 (petroleum ether–EtOAc, 1:1). IR (KBr) νmax = 3446, 2925,
-1 1
2
856, 1723, 1634, 1454, 1278, 1035, 762, 502 cm . H NMR
(300 MHz, CDCl ) δ 7.41-7.18 (m, 5H), 6.61 (d, J = 15.9 Hz,
H), 6.31 (dtd, J = 11.5, 7.3, 2.0 Hz, 1H), 6.21 (dd, J = 15.9, 6.3
Hz, 1H), 5.88 (dq, J = 11.5, 1.9 Hz, 1H), 4.67 (ddt, J = 13.8,
2.4, 5.6 Hz, 4H), 4.56 (q, J = 4.6, 3.9 Hz, 1H), 4.16 (q, J = 7.1
4
1
.6. Ethyl (5R,7R,Z)-8-((4S,6R)-2,2-dimethyl-6-((E)-styryl)-
,3-dioxan-4-yl)-5,7-bis(methoxymethoxy)oct-2-enoate (2)
3
1
To a stirred solution of the ester 13 (932 mg, 2 mmol) in dry
THF (10 mL) at 0 °C was slowly added DIBAL-H (5 mL, 5
mmol; 1 M in hexanes) over 20 min. The reaction mixture was
stirred at 0 °C for 1 h, then MeOH (10 mL) was added dropwise
slowly. The resulting solution was poured into aqueous sodium
potassium tartrate solution (15 mL) and EtOAc (50 mL) and
stirred vigorously for l h. The organic layer was separated and the
aqueous layer extracted with further EtOAc (3x75 mL). The
1
Hz, 2H), 4.10-3.88 (m, 2H), 3.86-3.73 (m, 1H), 3.38 (d, J = 1.1
Hz, 3H), 3.36 (s, 3H), 3.03-2.81 (m, 2H), 1.97-1.84 (m, 1H),
1
CDCl ) δ 166.28, 145.20, 136.75, 131.93, 129.49, 128.41,
1
5
13
.82-1.54 (m, 4H), 1.32-1.23 (m, 4H). C NMR (75 MHz,
3
27.40, 126.34, 121.66, 95.30, 95.15, 73.66, 72.71, 70.89, 68.47,
9.95, 55.79, 55.68, 43.70, 42.34, 39.54, 33.52, 14.14. MS (ESI):
combined organic layers were dried (MgSO ), filtered and
4

5
+
+
1
976, 15, 566. (c) Sehlapelo, B. M.; Drewes, S. E.; Scottshaw,
m/z = 489 [M + Na] . HRMS: calcd. for C H
4
A
O Na
8
C
C
E
[M
P
+
TED
N
a
] : MANUSCRIPT
25
38
R. Phytochemistry 1994, 37, 847.
(a) Tawata, S.; Fukuta, M.; Xuan, T. D.; Deba, F. J. Pestic. Sci.,
2
89.2458 : found: 489.2445.
2
3
.
.
008, 33, 40. (b) Neal, J. J.; Wu, D. Pesticide Biochemistry and
4
.8. Ethyl (2Z,5R,7R,12E)-5,7-bis(methoxymethoxy)-9,11-
dioxo-13-phenyltrideca-2,12-dienoate (17)
Physiology 1994, 50, 43. (c) Cowan, M. M. Clinical Microbiology
Reviews 1999, 12, 564. (d) Juliawaty, L. D.; Kitajima, M.;
Takayama, H.; Achmad, S. A.; Aimi, N. Phytochemistry 2000, 54,
Add IBX (560 mg, 2 mmol, 5 equiv.) to the stirred solution of
diol 16 (187 mg, 0.40 mmol, 1 equiv.) in ethyl acetate (5 mL) at
rt, then heat the reaction mixture at 85 °C reflux for 6 h and
check TLC for the completion of reaction. After completion of
9
89.
(a) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
007, 63, 2929. (b) Kalesse, M.; Christmann, M. Synthesis 2002,
2
981. (c) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot.
1983, 36, 1595. (d) Stamplwala, S. S.; Bunge, R. H.; Hurley, T.
R.; Willmer, N. E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka,
T. A.; French, J. C. J. Antibiot. 1983, 36, 1601. (e) Leopold, W.
R.; Shillis, J. L.; Mertus, A. E.; Nelson, J. M.; Roberts, B. J.;
Jackson, R. C. Cancer Res. 1997, 44, 1928. (f) Spencer, G. F.;
England, R. E.; Wolf, R. B. Phytochemistry 1984, 23, 2499.
reaction, quench with saturated aqueous NaHCO (20 mL), and
3
the mixture stirred for 20 min. The organic layer was extracted
with EtOAc (3x75 mL), dried over MgSO4 and rotary
evaporated. The residue was purified by flash chromatography on
silica gel (petroleum ether–EtOAc, 3:2) to give the corresponding
diketone 17 (152 mg, 82%) as a colourless thick liquid. R =0.3
4. (a) Fang X.; Anderson, J. E.; Chang, C.; Fanwick; McLaughlin. J.
Chem. Soc., Perkin Trans. I. 1990, 1655. (b) Fu, X.; Seavenet, T.;
Hadi, A.; Remy, F.; Paoes, M. Phytochemistry 1993, 33, 1272.
f
20
(
petroleum ether–EtOAc, 7:3). [α]D = -42 (c = 0.5, CHCl ). IR
3
(
1
KBr) νmax = 2923, 2852, 1716, 1638, 1586, 1445, 1379, 1217,
149, 1098, 1031, 917, 771, 696 cm . H NMR (300 MHz,
5
.
Dumonter, V.; Hung, N. V.; Adeline, M.-T.; Riche, C.; Chiaroni,
A.; Sevenet, T.; Gueritte, F. J. Nat. Prod. 2004, 67, 858.
Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem.
2006, 71, 2918.
-
1
1
CDCl ) δ 7.66-7.47 (m, 3H), 7.45-7.31 (m, 3H), 6.48 (d, J = 15.9
6.
3
Hz, 1H), 6.33 (dt, J = 11.5, 7.3 Hz, 1H), 5.89 (dt, J = 11.5, 1.9
Hz, 1H), 5.70 (d, J = 3.5 Hz, 1H), 4.68 (d, J = 9.4 Hz, 4H), 4.19
7
.
Sabitha, G.; Prasad, M. N.; Shankaraiah, K.; Yadav, J. S. Synthesis
2
010, 7, 1171.
(p, J = 7.0 Hz, 2H), 3.88 (dt, J = 12.2, 6.0 Hz, 1H), 3.39 (s, 3H),
8
9
.
.
Krishna, P. R.; Srinivas, P. Tetrahedron Letters 2010, 51, 2295.
Walleser, P.; Bruckner, R. Organic Letters 2013, 15, 1294.
3
1
1
1
1
4
.34 (s, 3H), 3.09-2.85 (m, 2H), 2.66 (dd, J = 6.3, 1.8 Hz, 2H),
.95 (dt, J = 13.8, 6.7 Hz, 1H), 1.71 (dt, J = 14.4, 6.1 Hz, 2H),
10. (a) Kumar, R. N.; Meshram, H. M. Tetrahedron 2015, 71, 5669.
(b) Kumar, R. N.; Lee, S. Steroids 2017, 118, 68. (c) Kumar, R.
N.; Kumar, N. S.; Meshram, H. M. Synlett 2017, 28, 1046. (d)
Kumar, N. S.; Kumar, R. N.; Rao, L. C.; Muthineni, N.; Ramesh,
T.; Babu, N. J.; Meshram, H. M. Synthesis 2017, 49, 3171. (e)
Kumar, N. S.; Kumar, R. N.; Rao, L. C.; Meshram, H. M.
ChemistrySelect 2016, 1, 5034. (f) Ramesh, P.; Meshram, H. M.
Tetrahedron 2012, 68, 9289.
13
.32-1.24 (m, 4H). C NMR (75 MHz, CDCl ) δ 197.81, 177.22,
3
66.21, 145.26, 139.94, 135.02, 129.91, 128.88, 127.91, 122.75,
21.71, 101.75, 95.87, 95.36, 73.62, 72.19, 59.92, 55.81, 55.68,
5.76, 39.76, 33.52, 29.69, 14.25. MS (ESI): m/z = 485 [M +
+
+
Na] . HRMS: calcd. for C H O Na [M + Na] : 485.2146:
25
34
8
found: 485.2148.
.9. Obolactone (1)
To a stirred solution of diketone 17 (46 mg, 0.1 mmol) in
1
1. Rao, N. N.; Meshram, H. M. Tetrahedron Letters 2013, 54, 4544.
12. Kumar, R. N.; Meshram, H. M. Tetrahedron Letters, 2011, 52,
003.
4
1
13. (a) Ager, D. J. Chem Rev. 1996, 96, 835. (b) Evans, D. A. J. Am.
Chem. Soc. 1981, 103, 2127.
MeOH was added PTSA (2 mg, 0.01 mmol) under an N2
o
1
4. (a) Evans, D. A.; Aldrichimica Acta, 1982, 15, 23. (b) Evans, D.
A.; Tedrow, J. S;, Shaw, J. T.; Downey C. W.; J. Am. Chem. Soc.,
atmosphere. Heat the reaction mixture to 50 C and stir at this
temperature for 4 h. After completion of the reaction, quenched
2
002, 124, 392.
with solid NaHCO and filtered off, the solvent was removed
3
15. (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E.;
Chem. Commun., 1985, 1418. (b) Crimmins, M. T.; King, B. W.;
Tabet, E. A.; J. Am. Chem. Soc., 1997, 119, 7883.
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (petroleum ether-EtOAc,
20
1
1
6. (a) Arya, P.; Qin, H. Tetrahedron, 2000, 56, 917. (b) Velàzquez,
F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303. (c) Hodge, M. B.;
Olivo, H. F. Tetrahedron, 2004, 69, 9397. (d) Crimmins, M. T. J.
Org. Chem., 2001, 66, 894. (e) Paquette, L. A.; Braun, A.
Tetrahedron Lett., 1997, 38, 5119. (f) Crimmins, M. T.; DeBaillie,
A. C. J. Am. Chem. Soc. 2006, 128, 4936.
7. (a) Crimmins, M. T.; Chaudhary, K. Organic Letters 2000, 2, 775.
(b) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.;
Carroll, K. A.; Alphen, S. Organic Letters 2004, 6, 2317. (c)
Yadav, J. S.; Ganganna, B.; Bhunia, D. C. Synthesis 2012, 44,
1365.
1
:1) to afford obolactone 1 as a yellow solid (22 mg, 74%). [α]D
=
+247 (c = 0.1, CHCl ). IR (KBr) ν = 2927, 2853, 1726, 1650,
3 max
1
447, 1377, 1279, 1211, 1149, 1098, 1035, 974, 917, 750, 697
-1 1
cm . H NMR (300 MHz, CDCl ) δ 7.59–7.49 (m, 2 H), 7.45–
3
7
6
2
.26 (m, 4 H), 6.95–6.82 (m, 1 H), 6.53 (d, J = 16.0 Hz, 1 H),
.09 (dt, J = 9.7, 1.6 Hz, 1 H), 5.62 (s, 1 H), 4.85–4.64 (m, 2 H)
.63–2.45 (m, 5 H), 2.21–1.98 (m, 1 H). C NMR (75 MHz,
13
CDCl ) δ 192.02, 167.97, 163.66, 144.64, 137.40, 134.75,
3
1
4
29.66, 128.64, 127.43, 121.54, 121.02, 106.27, 75.67, 74.49,
+
1.32, 39.18, 29.27. MS (ESI): m/z = 311 [M + H] . HRMS:
18. (a) Gensler, W. J.; Johnson, F.; Sloan, A. D. B. J. Am. Chem. Soc.
960, 82, 6074. (b) Crabbe, P.; Garcia, G. A.; Rius, C. J. Chem.
Soc., Perkin Trans. I 1973, 810.
+
1
calcd. for C H O [M + H] : 311.1278: found: 311.1275.
19
19
4
1
1
2
9. syn and anti-1,3-diol ratio was determined based on H NMR.
0. Ando, K. J. Org. Chem. 1998, 63, 8411.
Acknowledgment
RNK thanks to CSIR, New Delhi for the award of fellowship
and to Dr. S. Chandrasekhar, Director of IICT, for the support
and encouragement.
Supplementary data
1
13
H and C NMR spectra of compounds are available.
References and Notes
1
.
(a) Andrianaivoravelona, J. O.; Sahpaz, S.; Terreaux, C.;
Phytochemistry 1999, 52, 265. (b) Siegel, S. M. Phytochemistry