Determination of the Absolute Configuration of Gliomasolide D through Total Syntheses of the C-17 Epimers

Article abstract of DOI:10.1021/acs.jnatprod.6b00926

The absolute configuration at C-17, the carbon bearing the distal hydroxy group of the 14-membered natural product gliomasolide D, was assigned as R by comparison of ¹³C NMR shifts and specific rotation values of the epimers at C-17. The first

Full text of DOI:10.1021/acs.jnatprod.6b00926

Note
pubs.acs.org/jnp
Determination of the Absolute Configuration of Gliomasolide D
through Total Syntheses of the C‑17 Epimers
B. Seetharamsingh,† Routholla Ganesh, and D. Srinivasa Reddy*
,‡
†
,†,‡
†
CSIR−National Chemical Laboratory, Division of Organic Chemistry, Dr. Homi Bhabha Road, Pune, 411008, India
Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India
‡
*
S Supporting Information
ABSTRACT: The absolute configuration at C-17, the carbon bearing the distal hydroxy group of the 14-membered natural
13
product gliomasolide D, was assigned as R by comparison of C NMR shifts and specific rotation values of the epimers at C-17.
The first total synthesis of gliomasolide D along with its C-17 epimer, regioselective macrocyclization (18 membered vs 14
membered), and regioselective Wacker oxidation are highlights of the present work.
1
3
liomasolides A−E (1−5) (Figure 1) are 14-membered
macrolides isolated from the sponge-derived fungus
the help of C NMR and specific rotation comparison of both
3
G
possible configurations at C-9. The structures of these natural
products are close to the structure of previously isolated and
well-known natural product Sch-725674 (6). From a biological
4
activity point of view, Sch-725674 has shown good antifungal
activity, but the biological activities of gliomasolides A−E were
not fully evaluated. However, gliomasolide A (1) showed
moderate cytotoxic activity against HeLa (human epithelial
1
carcinoma cell line) cells. Because of the interesting structure
and biological activity, the natural product Sch-725674 has
been a popular target for synthesis and has attracted the
5
2
attention of many researchers including our group.
Considering structural similarities between compound 6 and
the new gliomasolide family, we became interested in this class
of compounds. Determination of the correct absolute
configuration of gliomasolide D (4) would be more challenging
due to the placement of the hydroxy group at C-17 in the side
chain, which is quite distant from the other stereocenters.
Having synthesized one member of this family (gliomasolide C,
Figure 1. Structures of gliomasolides A−E and Sch-725674.
2
3
) and the challenge associated with the assignment of the
configuration at a remote stereocenter in gliomasolide D (4)
prompted us to focus on the synthesis of two possible
stereoisomers of 4, epimeric at the C-17 position. This exercise
will help in determining the actual structure of gliomasolide D
and also will provide sufficient quantities of materials for
biological evaluation. With this background, we initiated our
efforts, and the details are presented in this Note.
Gliomastix sp. ZSDS1-F7-2, collected from the South China
Sea by the research groups of Liu and Xu. The structure and
1
stereochemical configuration of gliomasolide A (1) and
gliomasolide B (2) were determined by extensive 2D NMR
analysis followed by single-crystal X-ray analysis. The structure
of gliomasolide C (3) was determined by 2D NMR analysis and
2
was later confirmed by its total synthesis by our group.
The key disconnections and sources of chirality for the
planned synthesis are shown in Figure 2. As per the plan, our
However, the configurations at C-17 in gliomasolide D (4) and
at C-9 in gliomasolide E (5) were not established by the Liu
and Xu groups because of the limited quantities of the isolated
1
natural products. Very recently the absolute configuration of
Received: October 10, 2016
gliomasolide E (5) was established by Mohapatra’s group with
©
XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.6b00926
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
deprotection of the acetonide resulted in the desired macro-
cycle 15 (S-configuration at C-17 of gliomasolide D) (Scheme
1
).
Scheme 1. Synthesis of Gliomasolide D (15, with S-
Configuration at C-17)
Figure 2. Sources of chirality and key disconnections to access both C-
1
7 stereoisomers of gliomasolide D.
synthesis started with commercially available (S)-propylene
oxide 7, which on treatment with 3-butenylmagnesium bromide
followed by protection of the resulting alcohol with tert6-
butyldimethylsilyl chloride (TBSCl) afforded TBS ether 8.
Compound 8 was converted to the diasteromeric mixture of
epoxide 9 using oxone, which was then subjected to hydrolytic
7
kinetic resolution with (R,R)-salen Co(III)-OAc (prepared
7
from commercially available precatalyst using AcOH) to afford
pure epoxide 10. The epoxide was regioselectively opened with
8
5-hexenylmagnesium bromide followed by a cross metathesis
between the resulting olefin and intermediate 11 (a known
9
compound prepared from D-ribose) in the presence of Grubbs’
second-generation catalyst, affording the key intermediate 12,
in which most of the desired functional groups are in place.
The ester group present in 12 was hydrolyzed with LiOH to
give the corresponding carboxylic acid, which upon Wacker-
1
0
type oxidation (PdCl in DMA/H O, 200 psi of O , 70 °C)
2
2
2
produced the desired carbonyl compound 13 in a highly
regioselective manner. To our delight, the TBS group was also
removed under these reaction conditions. This result also
prompted us to test selective macrocyclization between two
possibilities (14-membered vs 18-membered macrocycles)
because of two free hydroxy groups present in 13. The seco
acid was subjected to Yamaguchi conditions, yielding
macrocycle 14 in 47% isolated yield. Considering the two
possible modes of cyclization, we wanted to confirm the
structure of the macrocycle. For that purpose, we have recorded
the HMBC spectrum of 14 and confirmed the structure (Figure
The 1H NMR spectra of both natural product 4 and
synthetic compound 15 were compared and were found to be
very similar. However, careful comparison of the C NMR
1
3
spectra revealed minor discrepancies at two positions (C-18: δC
2
3.53 vs 23.46 ppm and C-15: δ 22.86 vs 22.74). We also
C
1
1
measured the optical rotation of 15 and found a significant
difference with respect to that of natural gliomasolide D
1
3
including the sign of rotation (Table 1). Although the
C
NMR shift differences are minor, the difference in the specific
rotations clearly suggests that C-17 of the natural gliomasolide
D has the R-configuration and not the S-configuration as
present in compound 15. To prove this aspect, we have
synthesized compound 23 (Scheme S1) through the
intermediacy of 17 to 22 starting from commercially available
3
). In the HMBC spectrum, we found that H-13 (δ 4.82) has
H
a correlation to the ester carbonyl carbon C-1 (δC 165.7),
which clearly confirms the 14-membered ring. Compound 14,
5d,2
on substrate-controlled reduction using NaBH4,
followed by
(
R)-propylene oxide 16 using a similar reaction sequence to
that described in Scheme 1. (Compounds 16−22 are either the
enantiomers or epimers of compounds 7−14.) After the
successful synthesis of macrocycle 23 with the C-17 R-
13
configuration, the C NMR spectra were compared. To our
delight, the 13C NMR spectra of 23 and natural gliomasolide
were a better match than the NMR data of 15 (Table 1). Also,
compound 23 has the same sign of the specific rotation as the
natural product. However, the magnitude of specific rotation of
2
3 ([α]25 −5.7, c 0.15, MeOH) is significantly lower than the
D
specific rotation reported for gliomasolide D (−13.1) (Table
1
2
1
). We believe, based on this evidence, the absolute
configuration at C-17 of natural gliomasolide D can be assigned
as the R-configuration.
Thus, we have assigned the absolute configuration at C-17 of
gliomasolide D as the R-configuration by synthesizing both the
C-17 epimers and comparing 13C NMR shifts and specific
Figure 3. HMBC correlation of H-13 to ester carbonyl C-1 of
compound 14.
B
DOI: 10.1021/acs.jnatprod.6b00926
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
Table 1. 13C NMR and Specific Rotation Comparisons of
Natural Gliomasolide D (75 MHz), Compounds 15 (100
a reference standard. Column chromatography was performed on silica
gel (100−200 or 230−400 mesh size). HRMS (ESI) spectra were
recorded on a Thermo Scientific Q Exactive ORBITRAP mass
analyzer. Chemical nomenclature was generated using Chem Bio Draw
,
1 a
MHz), and 23 (100 MHz) in CD OD
3
Ultra 14.0.
5
(S)-tert-Butyl(hept-6-en-2-yloxy)dimethylsilane (8). 3-Bute-
nylmagnesium bromide (freshly prepared from 3-butenyl bromide,
2.5 mL, 123.9 mmol, Mg 2.97 g, 123.9 mmol in 250 mL of anhydrous
1
tetrahydrofuran (THF)) was added dropwise to a suspension of (S)-
propylene oxide (5.4 mL, 77.4 mmol) and CuI (1.5 g, 7.44 mmol) in
anhydrous THF (80 mL) at −15 °C and stirred at the same
temperature for 2 h. The reaction mixture was quenched with
saturated aqueous NH Cl (50 mL) and extracted with Et O (3 × 50
4
2
mL), and the combined organic layers were washed with brine (50
mL). The Et O solution was dried over anhydrous Na SO and then
2
2
4
evaporated under reduced pressure.
Imidazole (11.7 g, 172 mmol), TBSCl (14.2 g, 94.7 mmol), and
N,N-dimethylaminopyridine (DMAP) (1.05 g, 8.6 mmol) were added
to the crude compound obtained above in CH Cl (200 mL) at 0 °C.
2
2
The resulting mixture was stirred at room temperature (rt) for 5 h,
quenched with saturated aqueous NaHCO (50 mL), and extracted
3
with CH Cl (3 × 50 mL). The combined organic layers were dried
2
2
over anhydrous Na SO and evaporated under reduced pressure. The
2
4
crude product was purified by flash chromatography over 200−400
mesh silica gel (0−5% CH Cl /petroleum ether) to afford compound
2
2
2
5
8
(12.5 g, 71%) as a light yellow liquid: [α] +11.2 (c 3.7, CHCl );
IR νmax (film) 3015, 1371, 1257, 850 cm ; H NMR (CDCl , 200
D
3
−
1 1
3
MHz) δ 5.82 (m, 1H), 4.95 (m, 2H), 3.78 (m, 1H), 2.04 (q, J = 6.5
H
Hz, 2H), 1.43 (m, 4H), 1.12 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
6
H); 13C NMR (CDCl , 50 MHz) δ 139.0, 114.3, 68.5, 39.2, 33.8,
3 C
2
5.9 (3C), 25.1, 23.8, 18.1, −4.4, −4.7.
tert-Butyldimethyl(((2S)-5-(oxiran-2-yl)pentan-2-yl)oxy)-
silane (9). Oxone (37 g, 246 mmol) was added portionwise to a
solution of compound 8 (7.0 g, 30.7 mmol) and NaHCO (26 g, 300
3
mmol) in CH Cl (200 mL) and H O (150 mL) at 0 °C, followed by
2
2
2
acetone (44 mL, 614 mmol), and the mixture was stirred at rt for 24 h.
The layers were separated, and the aqueous layer was extracted with
CH Cl (3 × 50 mL). The combined organic layers were dried over
a
2
2
The NMR shifts for natural gliomasolide D were extracted from the
C NMR spectrum in the Supporting Information of ref 1 (reported
anhydrous Na SO and evaporated under reduced pressure. The crude
1
3
2
4
product was purified by column chromatography over 200−400 mesh
silica gel (0−5% EtOAc/petroleum ether) to afford compound 9 (4.0
g, 53%, 72% based on recovery of starting material) as a light yellow
as 0.01 ppm).
−1 1
rotation values. The small chemical shift differences between
the diastereomers, coupled with a comparison of the specific
rotations, helped us to determine the C-17 absolute
configuration of the natural product. The first total synthesis
of gliomasolide D and regioselective macrocyclization (18-
membered vs 14-membered) are highlights of the present
synthesis.
liquid: IR νmax (film) 2955, 1463, 1255, 1216, 896 cm ; H NMR
(CDCl , 400 MHz) δ 3.76 (m, 1H), 2.87 (m, 1H), 2.71 (t, J = 4.3
Hz, 1H), 2.42 (m, 1H), 1.44 (m, 6H), 1.10 (d, J = 6.1 Hz, 3H), 0.86
3
H
(
s, 9H), 0.04 (s, 6H); 13C NMR (CDCl , 100 MHz) δ 68.3, 68.3,
3 C
5
−
2.2, 52.2, 46.9, 39.4, 39.3, 32.5, 32.4, 25.8 (3C), 23.7, 22.2, 22.1, 18.1,
4.4, −4.8; HRESIMS m/z 245.1934 [M + H] (calcd for
+
C H O Si, 245.1931).
13
29
2
tert-Butyldimethyl(((S)-5-((R)-oxiran-2-yl)pentan-2-yl)oxy)-
silane (10). (R,R)-Salen Co(III)-OAc (25 mg, 0.041 mmol) catalyst
was added to neat epoxide 9 (2.0 g, 8.2 mmol) at 0 °C, and H O (88
EXPERIMENTAL SECTION
■
2
General Experimental Procedures. All reagents, starting
materials, and solvents (including dry solvents) were obtained from
commercial suppliers and used as such without further purification.
Reactions were carried out in oven-dried glassware under a positive
pressure of argon unless otherwise mentioned. Air-sensitive reagents
and solutions were transferred via syringe or cannula and were
introduced to the apparatus via rubber septa. Reactions were
monitored by thin-layer chromatography with 0.25 mm precoated
silica gel plates (60 F254). Visualization was accomplished with either
UV light, iodine adsorbed on silica gel, or immersion in an ethanolic
solution of phosphomolybdic acid, p-anisaldehyde, or KMnO4
followed by heating with a heat gun for ∼15 s. Optical rotations
were recorded on a JASCO P-2000 polarimeter at 589 nm. Infrared
spectra were recorded on a Bruker Alpha FT-IR spectrometer as thin
μL, 4.92 mmol) was added dropwise over 10 min, followed by THF
(3.0 mL). The resulting reaction mixture was allowed to warm to rt
and stirred for 18 h. The solvent was evaporated, and the mixture was
purified by column chromatography over 200−400 mesh silica gel (0−
5% EtOAc/petroleum ether) to afford compound 10 (900 mg, 45%)
as a light yellow liquid: [α]25 +14.6 (c 0.98, CHCl ); IR ν (film)
D
3
max
−1
1
3019, 2955, 1464, 1255, 1216, 896 cm ; H NMR (CDCl , 400
3
MHz) δ 3.77 (m, 1H), 2.89 (m, 1H), 2.73 (t, J = 4.6 Hz, 1H), 2.45
H
(dd, J = 4.9, 2.4 Hz, 1H), 1.58−1.36 (m, 6H), 1.11 (d, J = 5.9 Hz, 3H),
0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl , 100 MHz) δ 68.4,
3
C
52.3, 47.0, 39.4, 32.5, 25.9 (3C), 23.8, 22.2, 18.1, −4.4, −4.8;
+
HRESIMS m/z 245.1935 [M + H] (calcd for C H O Si, 245.1931).
13
29
2
E t h y l ( E ) - 3 - ( ( 4 R , 5 S ) - 5 - ( ( 8 S , 1 2 S , E ) - 1 2 - ( ( t e r t -
Butyldimethylsilyl)oxy)-8-hydroxytridec-1-en-1-yl)-2,2-di-
methyl-1,3-dioxolan-4-yl)acrylate (12). 5-Hexenylmagnesium bro-
mide (0.5 M, 18.04 mL, 9.02 mmol) was added dropwise to a
suspension of epoxide 10 (1.1 g, 4.5 mmol) and CuI (88 mg, 0.45
mmol) in THF (50 mL) at −15 °C. The suspension was stirred at the
1
13
films in chloroform using NaCl plates. All H NMR and C NMR
spectra were obtained using a 200, 400, or 500 MHz Bruker
spectrometer. Coupling constants were measured in hertz. All
chemical shifts are quoted in ppm using the residual solvent peak as
C
DOI: 10.1021/acs.jnatprod.6b00926
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
same temperature for 2 h, then quenched with saturated aqueous
41.5, 39.0, 34.4, 31.8, 28.6, 27.8, 25.3, 24.4, 24.0, 23.5, 21.7; HRESIMS
+
NH Cl (20 mL) and extracted with EtOAc (3 × 20 mL). The
m/z 405.2252 [M + Na] (calcd for C H O Na, 405.2248).
4
21 34
6
combined organic layers were washed with brine (30 mL) and dried
over anhydrous Na SO , and the solvent was evaporated. The product
(5R,6S,8R,14S,E)-5,6,8-Trihydroxy-14-((S)-4-hydroxypentyl)-
oxacyclotetradec-3-en-2-one (15). To a solution of compound 14
(25 mg, 0.07 mmol) in MeOH (3.0 mL) was added NaBH (5.4 mg,
4
0.14 mmol) at −78 °C, and the mixture was allowed to warm to rt for
3 h. The reaction mixture was diluted with EtOAc (10 mL) and
2
4
was purified by short-column chromatography over 100−200 mesh
silica gel (5−10% EtOAc/petroleum ether) to afford an olefinic
intermediate (1.1 g, 73%), which was used in the next step without
further purification.
washed with saturated NaHCO (5.0 mL). The organic layer was
3
separated, dried over anhydrous Na SO , and evaporated under
Grubbs’ second-generation catalyst (G-II) (62 mg, 0.073 mmol)
was added to a solution of the above obtained olefin (3.65 mmol) and
ester 11 (550 mg, 2.43 mmol) in dry degassed CH Cl (10 mL), and
2
4
reduced pressure. The product obtained was dissolved in 4:1 AcOH/
H O (3.0 mL) and stirred at 60 °C for 4 h. After evaporation of
2
2
2
solvent the crude product was purified by flash chromatography over
the resulting solution was stirred under reflux for 4 h. The mixture was
concentrated in vacuo, and the crude product was purified by flash
chromatography over 200−400 mesh silica gel (20−25% EtOAc/
2
00−400 mesh silica gel (0−5% MeOH/CH Cl ) to afford compound
2
2
27
1
5 (16 mg, 72%) as a white, amorphous solid: [α]
+7.0 (c 0.8,
D
−1 1
MeOH); IR νmax (film) 3330, 3020, 2400, 1715, 1210 cm ; H NMR
petroleum ether) to afford hydroxy ester 12 (810 mg, 63%) as a light
yellow oil: [α]25 +37.7 (c 1.8, CHCl ); IR ν (film) 3350, 3020,
(CD OD, 400 MHz) δ 6.87 (dd, J = 15.9, 6.1 Hz, 1H), 6.06 (s, 1H),
3
H
D
3
max
−1
1
4.96 (m, 1H), 4.48 (m, 1H), 3.97 (m, 1H), 3.84 (m, 1H), 3.69 (m,
H), 1.83 (m, 1H), 1.68 (m, 3H), 1.56 (m, 3H), 1.33 (m, 11H), 1.14
2
400, 1720, 1215 cm ; H NMR (CDCl , 400 MHz) δ 6.79 (dd, J =
3 H
1
1
=
1
(
5.6, 5.4 Hz, 1H), 6.05 (d, J = 15.6 Hz, 1H), 5.77 (m, 1H), 5.31 (dd, J
7.8, 15.2 Hz, 1H), 4.69 (m, 2H), 4.19 (q, J = 7.3 Hz, 2H), 3.77 (m,
H), 3.57 (m, 1H), 2.05 (m, 2H), 1.53 (s, 3H), 1.36 (m, 14H), 1.39
s, 3H), 1.28 (t, J = 6.8 Hz, 3H), 1.11 (d, J = 5.9 Hz, 3H), 0.88 (s,
13
(
d, J = 6.1 Hz, 3H); C NMR data, Table 1; HRESIMS m/z 367.2094
M + Na] (calcd for C H O Na, 367.2091).
+
[
18 32 6
(
5R,6S,8R,14S,E)-5,6,8-Trihydroxy-14-((R)-4-hydroxypentyl)-
oxacyclotetradec-3-en-2-one (23). To a solution of compound 22
12 mg, 0.03 mmol) in MeOH (3.0 mL) was added NaBH (2.2 mg,
13
9
1
3
H), 0.04 (s, 6H); C NMR (CDCl , 100 MHz) δ 166.0, 144.2,
3 C
(
4
36.9, 125.0, 122.4, 109.2, 79.7, 77.6, 71.8, 68.6, 60.5, 39.7, 37.5, 37.3,
0
.06 mmol) at −78 °C, and the mixture was allowed to warm to rt for
2.1, 29.0, 28.7, 27.8, 25.9 (3C), 25.3, 25.3, 23.8, 21.9, 18.1, 14.2, −4.4,
+
3 h. The reaction mixture was diluted with EtOAc (10 mL) and
−
5
4.7; HRESIMS m/z 549.3587 [M + Na] (calcd for C H O SiNa,
29
54
6
washed with saturated NaHCO (5.0 mL). The organic layer was
3
49.3582).
3aR,8S,15aS,E)-8-((S)-4-Hydroxypentyl)-2,2-dimethyl-
,9,10,11,12,13,15,15a-octahydro-6H-[1,3]dioxolo[4,5-e][1]-
separated, dried over anhydrous Na SO , and evaporated under
2
4
(
reduced pressure. The product obtained was dissolved in 4:1 AcOH/
8
H O (3.0 mL) and stirred at 60 °C for 4 h. After evaporation of
oxacyclotetradecine-6,14(3aH)-dione (14). To a solution of 12
2
solvent the crude product was purified by flash chromatography over
(
500 mg, 0.95 mmol) in 10 mL of MeOH/THF/H O (1:1:1) at 0 °C
2
2
00−400 mesh silica gel (0−5% MeOH/CH Cl ) to afford compound
was added LiOH·H O (120 mg, 2.85 mmol). The mixture was allowed
2
2
2
25
2
3 (7.8 mg, 75%) as a white, amorphous solid: [α] −5.7 (c 0.15,
to warm to rt and was stirred for 3 h. The organic solvent was
evaporated, and the aqueous solution was neutralized with 10%
aqueous citric acid (5 mL) at 0 °C, then extracted with EtOAc (3 × 10
D
−1 1
MeOH); IR νmax (film) 3450, 2935, 1717, 1650, 1217 cm ; H NMR
(
1
1
(
CD OD, 400 MHz) δ 6.87 (dd, J = 15.9, 6.1 Hz, 1H), 6.08 (d, J =
3 H
5.9 Hz, 1H), 4.97 (m, 1H), 4.48 (m, 1H), 3.99 (m, 1H), 3.85 (m,
H), 3.69 (m, 1H), 1.82 (m, 1H), 1.65 (m, 6H), 1.40 (m, 9H), 1.20
mL). The combined organic layers were dried over anhydrous Na SO4
2
and evaporated, and the crude product was used in the next step
without further purification.
PdCl2 (52 mg, 0.3 mmol) was added to a solution of
13
m, 2H), 1.14 (d, J = 6.1 Hz, 3H); C NMR data, Table 1; HRESIMS
+
m/z 367.2093 [M + Na] (calcd for C H O Na, 367.2091).
18 32
6
dimethylacetamide (DMA, 20 mL) and H O (2.0 mL) in a 100 mL
2
Parr steel reactor, then stirred under 200 psi O pressure for 1 h at rt.
ASSOCIATED CONTENT
■
* Supporting Information
2
The above obtained compound (0.95 mmol) in DMA (3.0 mL) was
S
added and heated at 70 °C under 200 psi O pressure for 14 h. The
2
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00926.
mixture was cooled to rt, and the solvents were evaporated under
reduced pressure. The residue was dissolved in EtOAc (20 mL) and
washed with H O (3 × 5 mL), and the combined organic extracts were
2
Copies of H NMR, 13C NMR, and 2D NMR spectra
1
dried over anhydrous Na SO , filtered, and concentrated in vacuo. The
2
4
crude product was purified by flash chromatography over 200−400
(PDF)
mesh silica gel (5−10% MeOH/EtOAc) to afford seco acid 13 (160
+
mg, 40%) as a light yellow oil: HRESIMS m/z 423.2342 [M + Na]
AUTHOR INFORMATION
(
calcd for C H O Na, 423.2353).
21 36 7
■
Corresponding Author
2,4,6-Trichlorobenzoyl chloride (83 μL, 0.54 mmol) was added to a
solution of the seco-acid 13 (200 mg, 0.5 mmol) and Et N (140 μL,
3
*E-mail: ds.reddy@ncl.res.in.
1
.0 mmol) in THF (2.0 mL) at 0 °C and was stirred at rt for 6 h. After
ORCID
dilution with dry toluene (20 mL) the mixture was added dropwise to
a refluxing solution of DMAP (610 mg, 5.0 mmol) in toluene (150
mL) over a period of 18 h. The resulting reaction mixture was further
stirred under reflux for 24 h. After cooling, the solvents were
evaporated, and the crude product was dissolved in EtOAc (10 mL),
D. Srinivasa Reddy: 0000-0003-3270-315X
Notes
The authors declare no competing financial interest.
washed with aqueous saturated NaHCO (10 mL) and brine (10 mL),
3
ACKNOWLEDGMENTS
dried over anhydrous Na SO , filtered, and concentrated in vacuo. The
■
2
4
crude product was purified by flash chromatography over 200−400
We acknowledge the CSIR, New Delhi, for the support through
XII Five Year Plan projects (CSC0108: ORIGIN and
CSC0130: NaPAHA). We thank Mr. K. Handore, CSIR-
NCL, for his help in manuscript revision. B.S. thanks CSIR for
the award of a fellowship.
mesh silica gel (45−50% EtOAc/petroleum ether) to afford
compound 14 (85 mg, 47%) as a light yellow oil: [α]25 −16.5 (c
D
−1 1
2
.7, CHCl ); IR ν (film) 3440, 2935, 1717, 1650, 1217 cm ; H
3 max
NMR (CDCl , 400 MHz) δ 6.61 (dd, J = 15.6, 6.8 Hz, 1H), 6.07 (d, J
3
H
=
15.6 Hz, 1H), 4.97 (m, 1H), 4.82 (m, 1H), 4.74 (m, 1H), 3.75 (m,
1
2
8
H), 2.87 (dd, J = 18.6, 10.7 Hz, 1H), 2.70 (dd, J = 18.6, 2.5 Hz, 1H),
REFERENCES
.45 (m, 1H), 2.15 (m, 1H), 1.63 (m, 6H), 1.50 (m, 3H), 1.37 (m,
■
H), 1.38 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl , 100
(1) Zhang, J.; Lin, X.-P.; Li, L.-C.; Zhong, B.-L.; Liao, X.-J.; Liu, Y.-
H.; Xu, S.-H. RSC Adv. 2015, 5, 54645−54648.
3
MHz) δ 208.7, 165.7, 140.6, 124.8, 108.7, 76.5, 75.5, 74.1, 67.9, 45.8,
C
D
DOI: 10.1021/acs.jnatprod.6b00926
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
(
2) Seetharamsingh, B.; Khairnar, P. V.; Reddy, D. S. J. Org. Chem.
016, 81, 290−296.
3) Reddy, R. G.; Venkateshwarlu, R.; Ramakrishna, K. V. S.; Yadav,
J. S.; Mohapatra, D. K. J. Org. Chem. 2017, 82, 1053−1063.
4) Yang, S. W.; Chan, T. M.; Terracciano, J.; Loebenberg, D.; Patel,
M.; Chu, M. J. Antibiot. 2005, 58, 535−538.
5) (a) Moretti, J. D.; Wang, X.; Curran, D. P. J. Am. Chem. Soc.
2
(
(
(
2
012, 134, 7963−7970. (b) Sunnam, S. K.; Prasad, K. R. Tetrahedron
2
014, 70, 2096−2101. (c) Bali, A. K.; Sunnam, S. K.; Prasad, K. R. Org.
Lett. 2014, 16, 4001−4003. (d) Ramakrishna, K.; Kaliappan, K. P. Org.
Biomol. Chem. 2015, 13, 234−240. (e) Bodugam, M.; Javed, S.;
Ganguly, A.; Torres, J.; Hanson, P. R. Org. Lett. 2016, 18, 516−519.
(
f) Sharma, B. M.; Gontala, A.; Kumar, P. Eur. J. Org. Chem. 2016,
2
016, 1215−1226. (g) Reddy, Y.; Sabitha, G. ChemistrySelect 2016, 1,
2
156−2158.
(
6) Dermenci, A.; Selig, P. S.; Domaoal, R. A.; Spasov, K. A.;
Anderson, K. S.; Miller, S. J. Chem. Sci. 2011, 2, 1568−1572.
(
7) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307−1315. (b) Tokunaga, M.; Larrow, J. F.;
Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936−938.
(
8) Selected references for cross metathesis: (a) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953−956. (b) Calder, E.
D. D.; Zaed, A. M.; Sutherland, A. J. Org. Chem. 2013, 78, 7223−7233.
(
c) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360−11370. (d) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900−1923. (e) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18−29.
(
9) (a) Choi, W. J.; Moon, H. R.; Kim, H. L.; Yoo, B. N.; Lee, J. A.;
Shink, D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634−2636.
(
(
b) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622−2624.
c) Blanchette, M. A.; Chey, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
183−2186. (d) Si, D.; Sekar, N. M.; Kaliappan, K. P. Org. Biomol.
Chem. 2011, 9, 6988−6997.
10) Narute, S. B.; Kiran, N. C.; Ramana, C. V. Org. Biomol. Chem.
011, 9, 5469−5475. (b) Mitsudome, T.; Mizumoto, K.; Mizugaki, T.;
Jitsukawa, K.; Kaneda, K. Angew. Chem., Int. Ed. 2010, 49, 1238−1240.
11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989−1993.
12) Attempts were made to obtain an authentic sample for
comparison, but a sample was not available.
2
(
2
(
(
E
DOI: 10.1021/acs.jnatprod.6b00926
J. Nat. Prod. XXXX, XXX, XXX−XXX