Total synthesis of diplodialides C and D

Article abstract of DOI:10.24820/ark.5550190.p010.703

A highly convergent, stereoselective total synthesis of diplodialides C and D is described. The protocol involves the use of regioselective ring opening of a chiral epoxide, sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide,

Full text of DOI:10.24820/ark.5550190.p010.703

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Total synthesis of diplodialides C and D
Vyasabhattar Ramanujan and Chebolu Naga Sesha Sai Pavan Kumar*
Division of Chemistry, Department of Sciences and Humanities, Vignan’s Foundation for Science,
Technology & Research (VFSTR) University, Vadlamudi, Guntur 522 213, Andhra Pradesh, India
Email: pavaniict@gmail.com
Received 07-30-2018
Abstract
Accepted 10-30-2018
Published on line 11-17-2018
A highly convergent, stereoselective total synthesis of diplodialides C and D is described. The protocol involves
the use of regioselective ring opening of a chiral epoxide, sequential double alkylation of 1,3-dithiane with a
bromide and a chiral epoxide, hydroboration and Yamaguchi macrolactonisation as key steps.
OH
OPMB
COOH
S S
O
O
Common Intermediate
O
O
O
HO
diplodialide C
HO
diplodialide D
Keywords: Pentaketides, chiral epoxides, Yamaguchi macrolactonisation, macrolides, oxecanones
DOI: https://doi.org/10.24820/ark.5550190.p010.703
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Introduction
Medium-sized-ring systems, those containing 8 to 11 atoms in the ring, are a subject of continuing interest to
organic chemists, as they form the core of many bioactive natural products.1-3 Diplodialides (C(1), and D(1a))
are the first 10-membered lactone pentaketides (Figure 1), which were isolated from the plant pathogenic
fungus Diplodia pinea (IFO 6472) by Wada and Ishida.4,5 Diplodialides possess unique biological activity, i.e.,
inhibitory activity against progesterone 11α-hydroxylase in vegetable cell cultures of Rhizopus stolonifer at 125
ppm. The absolute stereochemistry of diplodialides C and D is (3R, 9R), as determined by Wada and Ishida.6
O
O
O
O
O
HO
HO
diplodialide C (1)
diplodialide D (1a)
Figure 1
Though devoid of various biological activities, these natural products attracted many synthetic chemists
interested in its challenging architecture.7-12 The first total synthesis of (±)-diplodialide C was reported by
Wakamatsu et al.7 in 1977, using their own methodology, from enediol-bis(trimethylsilyl) ether which is
prepared by acyloin condensation of diethyl adipate in the presence of trimethyl chlorosilane and methyl
lithium. Later, Sharma et al.11 reported the stereoselective synthesis of diplodialides-B,C using a combination
of Jacobsen’s hydrolytic kinetic resolution and Sharpless epoxidation, further ring-closing metathesis strategy
was used for the construction of the lactone ring. Recently, Pratapareddy et al.12 reported the asymmetric
total synthesis of diplodialide C using Grubb’s cross-metathesis reaction as a crucial step. In this context, most
of the research groups only focused on the total synthesis of diplodialide A, B and C and to the best of our
knowledge, no reports were found in the literature regarding the total synthesis of diplodialide D. Intriguing by
this, in this communication, we report our successful total synthesis of diplodialides C 1 and D 1a using
sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide and Yamaguchi
macrolactonisation as the key steps in a simple and highly convergent approach.
Results and Discussion
Our retrosynthetic approach to the synthesis of 1 and 1a is outlined in Scheme 1. The target molecules 1 and
1a could be made from a common intermediate, hydroxyacid 2, by intramolecular Yamaguchi macrolacton-
ization, whereas 2 could be synthesized from the coupling reaction of two key fragments: the bromo
compound 4 and the chiral epoxide 5, with 1,3 dithiane, while both bromo compound 4 and chiral epoxide 5
could be obtained from the known chiral epoxide 6.
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Scheme 1. Retrosynthesis of diplodialides C and D.
As shown in the retrosynthesis (Scheme 1), our approach to the total synthesis of the title molecule was
initiated by regioselective opening of the known chiral epoxide13 6 with vinylmagnesium bromide in the
presence of CuI in THF, at −10 °C to room temperature, furnishing the tosylate 7 in 84% yield, which on
nucleophilic cyclization in the presence of K2CO3 in MeOH afforded epoxide 5 in 86% yield. On the other hand,
o
tosylate 7 on treatment with LiAlH4 in THF at 0 C for 12 h under a nitrogen atmosphere gave 8 in 92% yield,
which on subsequent silyl ether formation of the alcohol using TBSCl in the presence of imidazole in CH2Cl2 at
0 oC to rt for 6 h, provided the silyl ether 9 in 87% yield. Next, silyl ether 9 was subjected to hydroboration with
BH3-DMS followed by treatment with sodium hydroxide and H2O2 to give alcohol 10 in 77% yield. Treatment of
o
alcohol 10 with CBr4 and PPh3 in CH2Cl2 at 0 C to rt for 4 h gave the bromide 4 in 81% yield. The detailed
synthetic scheme is depicted in Scheme 2.
OH
O
O
b
a
TsO
TsO
5
7
6
c
OTBS
OR
OTBS
Br
OH
e
f
10
4
8 R = H
9 R = TBS
d
Reagents and conditions: (a) vinylmagnesium bromide, copper(I) iodide, dry THF, -10 °C, 2 h, 84%; (b)
K2CO3, MeOH, rt, 1 h, 86%; (c) LiAlH4, dry THF, 0 oC to rt, 12 h, 92% (d) TBSCl, imidazole, CH2Cl2, rt, 4 h, 87%
(e) i) BH3.SMe2, THF, 0 °C to rt, 4 h, ii) H2O2, NaOH, rt, 3 h, 77%; (f) CBr4, PPh3, CH2Cl2, rt, 3 h, 81%.
Scheme 2. Synthesis of intermediate 4.
Having both the bromo compound 4 and the epoxide 5 in hand, construction of the macrocyclic frame-
work was achieved as shown in Scheme 3.
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Sequential double alkylation of 1,3-dithiane14 with the bromide 4 and chiral epoxide 5 led to the alcohol
o
11 in 74% yield, which on subsequent treatment with PMBBr and NaH in tetrahydrofuran solvent at 0 C to rt
for 8 h afforded 12 in 87% yield. Next, ozonolysis of 12 followed by oxidation of resulting aldehyde with
NaClO2 and NaH2PO4, 2-methyl-2-butene in aqueous t-butanol afforded the acid 13 in 77% yield. In the next
step, the silyl protecting group (TBS) was removed from acid 13 using TBAF to afford the desired hydroxy-acid
segment 2 in 91% yield.
After successful synthesis of the intermediate 2, the next aim was macrolactonization and further
transformation to complete the synthesis of diplodialides C (1) and D (1a). Accordingly, the hydroxy-acid 2 was
subjected to macrolactonisation under Yamaguchi high-dilution conditions15 using 2,4,6-trichlorobenzoyl
chloride and Et3N in dry THF to afford the lactone 14 in 71% yield. Removal of the PMB group from lactone 14
was achieved using DDQ in aq. CH2Cl2 to give the compound 15 in 91% yield.
Finally, removal of the dithiane moiety from 15 under reductive conditions16 furnished diplodialide C (1) in
65% yield. On the other hand, deprotection of the 1,3-dithiane group in compound 15 with CaCO3 and I2 in
THF:H2O17 for 5 h afforded the diplodialide D (1a) in 68% yield. The analytical data of our synthetic compounds
are in good agreement with the reported data.4,5
Thus, we have accomplished the total synthesis of diplodialides C (1) and D (1a) in an enantioselective
way.
OTBS
OH
S S
OTBS
OTBS
OPMB
S S
a
b
c
Br
4
11
12
O
O
OTBS
OPMB
OH
OPMB
S S
S S
d
e
COOH
COOH
PMBO
f
S
S
13
2
14
O
O
O
O
O
O
g
h
O
HO
HO
HO
diplodialide C (1)
S
S
15
diplodialide D (1a)
o
o
o
Reagents and conditions:(a) 1,3-dithiane, n-BuLi, dry THF, –78 C to –20 C, 3 h, ii) n-BuLi, dry THF, –78 C
o
o
o
to –20 C, 5, 3 h, 74%; (b) PMBBr, NaH, THF, 0 C to rt, 8 h, 87%; (c) i) O3, CH2Cl2, Me2S, -78 C, 45 min; ii)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH:water (2:1), 0 oC to rt, 3 h, 77%; (d) TBAF, dry THF, 0 oC to rt, 3
h, 91%; (e) i) 2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h; ii) DMAP, toluene, 90 °C, 10 h, 71%; (f)
DDQ, CH2Cl2, rt, 3 h, 91%; (g) Raney Ni, EtOH, 40 oC, 65%; (h) CaCO3, I2, THF:H2O (9:1), 45 oC, 3 h, 68%.
Scheme 3. Synthesis of diplodialides C (1) and D (1a).
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Conclusions
In summary: we have developed a concise and highly convergent approach to the total synthesis of
diplodialides C (1) and D (1a). The present strategy involves regioselective ring opening of a chiral epoxide,
sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide and Yamaguchi macro-
lactonisation as the key steps. The syntheses of other related compounds are underway in our laboratory.
Experimental Section
General. All chemicals and reagents were obtained from Aldrich (Sigma-Aldrich, St. Louis, MO, USA), Lancaster
(Alfa Aesar, Johnson Matthey Company, Ward Hill, MA, USA) and were used without further purification.
Reactions were monitored by TLC, performed on silica gel glass plates containing 60 F-254, and visualization
1
13
on TLC was achieved by UV light or iodine indicator. H and C NMR spectra were recorded on 300 and 75
MHz instruments. Chemical shifts (δ) are reported in ppm downfield from internal TMS standard. ESI spectra
were recorded on Micromass, Quattro LC using ESI+ software with capillary voltage 3.98 kV and ESI mode
positive ion trap detector. Melting points were determined with an electrothermal melting point apparatus.
FT-IR spectra were taken on IR spectrophotometer by using NaCl optics. Optical rotation values are recorded
on digital polarimeter at 25 oC.
(S)-2-Allyloxirane (5). Copper iodide (0.75 g, 2.61 mmol) was gently heated under vacuum and slowly cooled
o
under nitrogen atmosphere, then THF (10 mL) was added, the resulting suspension was cooled to −10 C and
vinylmagnesium bromide (43.4 mL, 43.41 mmol, 1.0 M in THF, 1.1 eq) was added at the same temperature
while stirring. A solution of epoxide 6 (9.0 g, 39.47 mmol) in dry THF (20 mL) was added to the above reagent
and the mixture was stirred at -10 oC for 2 h. After completion of the reaction, the reaction was quenched with
saturated aqueous NH4Cl, extracted into EtOAc (3 × 30 mL), the combined organic layers was washed with
brine, dried over Na2SO4 and concentrated to give the tosylate 7 (8.47 g, 84%) which was used for the next
step without purification.
To a stirred solution of tosylate 7 (4.5 g, 17.57 mmol) in MeOH (20 mL) at 0 oC was added K2CO3 (4.85 g, 35.15
mmol) and the resultant mixture was allowed to stir for 1 h at rt. After completion of reaction as indicated by
TLC, the reaction was quenched by the addition of pieces of ice and the MeOH was evaporated. The
concentrated reaction mixture was then extracted with EtOAc (3 x 30 mL), the combined organic layers was
washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by column
1
chromatography (60-120 silica gel, 5% EtOAc in pet. ether) to afford 5 (1.26 g, 86%) as a colorless liquid. H
NMR (CDCl3, 300 MHz): δ 5.89–5.71 (m, 1H), 5.19–5.02 (m, 2H), 3.04-2.92 (m, 1H), 2.71 (dd, 1H, J 5.2, 3.9 Hz),
2.44 (dd, 1H, J 5.2, 2.7 Hz), 2.41–2.27 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 132.8, 117.3, 51.7, 46.1, 39.6.
(R)-tert-Butyldimethyl(pent-4-en-2-yloxy)silane (9). To a stirred suspension of LAH (0.78 g, 20.51 mmol) in dry
THF (10 mL), a solution of 7 (3.5 g, 13.67 mmol) in dry THF (15 mL) was added dropwise at 0 °C under a
nitrogen atmosphere, and the mixture was stirred at rt for 12 h. The reaction mixture was cooled to 0 °C,
treated with saturated aq. Na2SO4, filtered, and the filtrate was dried (Na2SO4) and the residue was
concentrated was purified by flash chromatography (60-120 silica gel, 5% EtOAc in pet. ether) to give
intermediate 8 (1.1 g, 92%) as a colorless syrup which was used immediately for the next step.
A mixture of the alcohol 8 (1.1 g, 12.79 mmol) and imidazole (1.73 g, 25.58 mmol) in dry CH2Cl2 (30 mL) was
treated with TBSCl (3.83 g, 15.34 mmol) at 0 °C under a nitrogen atmosphere and stirred at rt for 4 h. The
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reaction mixture was quenched with aq. NH4Cl solution (10 mL) and extracted with CH2Cl2 (2 × 50 mL). The
combined extracts were washed with water (30 mL), brine (30 mL), dried (Na2SO4) and concentrated. The
residue was purified by column chromatography (60-120 silica gel, 2% EtOAc in pet. ether) to furnish the silane
[]25
9 (2.22 g, 87%) as a colorless liquid.
+63 (c 0.8, CHCl3); 1HNMR (300 MHz, CDCl3): δ 5.84 (m,1H), 5.06-4.89
D
(m, 2H), 3.83-3.76 (m,1H), 2.27-2.13 (m, 2H), 1.12 (d, 3H, J 6.1 Hz), 0.89 (s, 9H), 0.11 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ 135.7, 116.7, 68.6, 44.4, 25.9, 23.8, 18.1, -4.3, -4.5; ESIMS (m/z): 201 (M + H)+, 223 (M + Na)+.
(R)-4-(tert-Butyldimethylsilyloxy)pentan-1-ol (10). To a stirred solution of 9 (2.1 g, 10.5 mmol) in dry THF (30
mL) at 0 C, a solution of borane-dimethylsulfide (2.0 N solution in THF) (6.3 mL, 12.63 mmol) was added
dropwise and allowed to stir for 4 h at rt. After that, the reaction mixture was cooled to 0 C and treated with
o
o
2N NaOH solution (15.7 mL) and H2O2 (2.8 mL) dropwise and stirred for 3 h at rt. After the completion of the
reaction, it was washed with water and extracted with EtOAc (2 × 50 mL). The organic layers were combined,
dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column
chromatography (60-120 silica gel, 25% EtOAc in pet. ether) to afford the silyloxy-pentanol 10 (1.76 g, 77%) as
[]25
1
a colorless liquid.
-12.3 (c 1.6, CHCl3); H NMR (CDCl3, 300 MHz): δ 3.91-3.84 (m, 1H), 3.66-3.53 (m, 2H),
D
13
2.37 (brs, 1H), 1.66-1.47 (m, 4H), 1.16 (d, 3H, J 6.1 Hz), 0.89 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); C NMR (CDCl3,
75 MHz): δ 68.5, 62.9, 35.8, 28.7, 26.0, 23.5, 18.1, -4.3, -4.6; ESIMS: 219 (M+ H)+.
(R)-(5-Bromopentan-2-yloxy)(tert-butyl)dimethylsilane (4). To a stirred solution of 10 (1.55 g, 7.11 mmol) in
CH2Cl2 (30 mL), CBr4 (2.82 g, 8.53 mmol) and Ph3P (2.79 g, 10.66 mmol) were added at 0 °C and stirred at rt for
3 h. The reaction mixture was evaporated and the residue purified by column chromatography (60-120 silica
1
gel, 5% EtOAc in pet. ether) to afford 4 (1.61 g, 81%) as a colourless syrup. H NMR (CDCl3, 300 MHz): δ 3.89-
3.81 (m, 1H), 3.44 (t, 2H, J 6.6 Hz), 1.81-1.69 (m, 2H), 1.55-1.39 (m, 2H), 1.13 (d, 3H, J 6.0 Hz), 0.88 (s, 9H), 0.14
13
(s, 3H), 0.08 (s, 3H); C NMR (CDCl3, 75 MHz): δ 67.9, 37.9, 34.3, 29.0, 25.9, 23.6, 18.0, -4.3, -4.7; ESIMS: 281
(M+ H)+.
(S)-1-(2-((R)-4-(tert-Butyldimethylsilyloxy)pentyl)-1,3-dithian-2-yl)pent-4-en-2-ol (11). To a stirred solution of
o
1,3-dithiane (0.7 g, 5.88 mmol) in dry THF at –78 C, n-BuLi (3.9 mL, 6.42 mmol, 1.6 M in hexane) was added
and the reaction mixture was allowed to warm to –20 oC while stirring for 1 h. The mixture was re-cooled to –
o
78 C and a solution of the bromide 4 (1.5 g, 5.35 mmol) in dry THF (5 mL) was added dropwise. The mixture
o
o
was warmed to –20 C stirred for 1 h, then the reaction mixture was again re-cooled to –78 C, and treated
with n-BuLi (3.9 mL, 6.42 mmol, 1.6 M in hexane) and stirred for 1 h at –20 oC. The mixture was re-cooled to –
o
78 C and a solution of the epoxide 5 (0.45 g, 5.35 mmol) in dry THF (2 mL) was added dropwise. The mixture
was warmed to –20 oC stirred for 1 h. After that the reaction was warmed to 0 C for 1 h and then to ambient
o
temperature for an additional 1 h, quenched with saturated aq. NH4Cl (40 mL) and extracted with EtOAc (2 ×
50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography (60-120 silica gel, 10% EtOAc in pet. ether) to
[]25
afford 11 (1.59 g, 74%) as a colorless syrup.
–58.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 5.91 (m, 1H),
D
5.04-4.91 (m, 2H), 3.83 (m, 1H), 3.64 (m, 1H), 2.89-2.71 (m, 4H), 2.47-2.36 (m, 1H), 2.31- 2.2 (m, 1H), 1.96 -
1.67 (m, 8H), 1.49-1.37 (m, 1H), 1.33-1.21 (m, 1H), 1.15 (d, 3H, J 6.1 Hz), 0.88 (s, 9H), 0.21 (s, 3H), 0.11 (s, 3H);
13C NMR (CDCl3, 75 MHz): δ 135.6, 117.2, 72.3, 68.2, 61.3, 52.1, 40.8, 40.4, 39.2, 26.9, 25.8, 24.4, 24.0, 22.4,
18.1, -4.4, -4.6; ESIMS: 427 (M+ H)+. Anal. Calcd. for C20H40O2S2Si : C, 59.35; H, 9.96; S, 15.84. Found: C, 59.32;
H, 9.88; S, 15.76.
tert-Butyl ((R)-5-{2-[(S)-2-(4-methoxybenzyloxy)pent-4-enyl]-1,3-dithian-2-yl}pentan-2-yloxy) dimethyl-
o
silane (12). To a cooled (0 C) solution of 11 (1.4 g, 3.46 mmol) in dry THF (10 mL), NaH (0.25 g, 10.38 mmol)
was added, the mixture stirred for 30 min and treated with a solution of PMBBr (0.82 g, 4.15 mmol) in dry THF
(5 mL). After 7.5 h stirring at rt, the reaction mixture was quenched with sat. NH4Cl solution (10 mL) and
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extracted with EtOAc (2 × 50 mL). The organic layers were washed with water (2 × 10 mL), brine (20 mL) and
dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue purified by column
[]25
chromatography (60-120 silica gel, 5% EtOAc in pet. ether) to furnish 12 (1.57 g, 87%) as a yellow liquid;
D
-26.3 (c 0.8, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.24 (d, 2H, J 8.7 Hz), 6.86 (d, 2H, J 8.7 Hz), 5.87 (m, 1H), 5.03-
4.91 (m, 2H), 4.49 (d, 1H, J 11.1 Hz), 4.41 (d, 1H, J 11.1 Hz), 3.73 (s, 3H), 3.69-3.61 (m, 1H), 3.53-3.44 (m, 1H),
2.91-2.69 (m, 4H), 2.37-2.21 (m, 2H), 1.93-1.59 (m, 9H), 1.29-1.21 (m, 1H), 1.17 (d, 3H, J 6.3 Hz), 0.91 (s, 9H),
0.23 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 160.1, 135.8, 128.9, 128.1, 116.3, 113.8, 79.9, 72.1, 68.0,
59.8, 56.3, 47.1, 40.7, 39.8, 39.1, 26.9, 25.9, 24.3, 24.0, 22.2, 18.2, -4.3, -4.7; ESIMS: 547 (M+ Na)+. Anal. Calcd.
for C28H48O3S2Si : C, 64.07; H, 9.22; S, 12.22. Found: C, 64.03; H, 9.25; S, 12.12.
(S)-4-{2-[(R)-4-(tert-Butyldimethylsilyloxy)pentyl]-1,3-dithian-2-yl}-3-(4-methoxybenzyloxy)butanoic acid (13).
Ozone was bubbled through a cooled (-78 °C) solution of 12 (1.35 g, 2.57 mmol) in CH2Cl2 (20 mL) until a pale
blue colour persisted. Excess of ozone was removed with Me2S (1 mL) and the mixture stirred for 30 min at 0
°C. The reaction mixture was concentrated under reduced pressure to give corresponding aldehyde, which
was immediately used for further reaction.
o
To a cooled (0 C) solution of the above aldehyde in t-butanol (6 mL), 2-methyl-2-butene (2 mL) was added,
followed by a solution of NaClO2 (0.27 g, 3.09 mmol) and NaH2PO4 (0.37 g, 3.09 mmol) in water (3 mL) and
stirred at rt for 3 h. t-Butanol was evaporated and the residue extracted with EtOAc (2 × 20 mL). The organic
layers were washed with water (2 ×20 mL), brine (30 mL), dried (Na2SO4), evaporated and purified the residue
by column chromatography (60-120 silica gel, 30% EtOAc in pet. ether) to furnish 13 (1.08 g, 77%); []D +22.8
1
(c 0.7, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.19 (d, 2H, J 8.8 Hz), 6.81 (d, 2H, J 8.8 Hz), 4.51 (d, 1H, J 11.1 Hz),
4.44 (d, 1H, J 11.1 Hz), 3.81 (m, 1H), 3.72 (s, 3H), 3.63 (m, 1H), 2.91-2.71 (m, 6H), 2.11-1.84 (m, 6H), 1.57-1.38
13
(m, 4H), 1.14 (d, 3H, J 6.0 Hz), 0.89 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); C NMR (75 MHz, CDCl3) δ 176.3, 160.1,
129.6, 128.8, 114.1, 75.3, 73.1, 66.3, 61.2, 56.3, 47.1, 43.2, 41.6, 39.3, 27.3, 25.9, 24.6, 24.2, 22.7, 18.8, -4.2, -
4.4; ESIMS: 543 (M+ H)+. Anal. Calcd. for C27H46O5S2Si : C, 59.74; H, 8.54; S, 11.81. Found: C, 59.69; H, 8.58; S,
11.77.
o
(S)-4-[2-((R)-4-Hydroxypentyl)-1,3-dithian-2-yl]-3-(4-methoxybenzyloxy)butanoic acid (2). To a cooled (0 C)
solution of 13 (1.0 g, 1.84 mmol) in dry THF (10 mL) under nitrogen atmosphere, TBAF (3.1 mL, 2.76 mmol)
was added and stirred for 3 h. After completion of reaction, reaction mixture was diluted with water (5 mL)
and extracted with EtOAc (2 × 20 mL). Organic layers were washed with water (2 × 10 mL), brine (10 mL), dried
(Na2SO4), evaporated and purified the residue by column chromatography (60-120 silica gel, 55% EtOAc in pet.
1
ether) to give 2 (0.71 g, 91%) as a liquid. H NMR (CDCl3, 300 MHz): δ 7.23 (d, 2H, J 8.8 Hz), 6.81 (d, 2H, J 8.8
Hz), 4.49 (d, 1H, J 11.3 Hz), 4.44 (d, 1H, J 11.3 Hz), 3.91 (m, 1H), 3.70 (s, 3H), 3.64 (m, 1H), 2.86-2.70 (m, 5H),
13
2.47 (dd, 1H, J 5.8, 7.4 Hz), 2.07-1.84 (m, 6H), 1.57-1.39 (m, 3H), 1.31-1.20 (m, 1H), 1.14 (d, 3H, J 6.1 Hz); C
NMR (75 MHz, CDCl3) δ 173.7, 160.3, 129.3, 128.8, 114.7, 80.2, 72.1, 67.6, 61.3, 56.1, 47.4, 42.7, 41.3, 39.8,
26.2, 24.5, 23.4, 21.0; ESIMS: 429 (M+ H)+. Anal. Calcd. for C21H32O5S2: C, 58.85; H, 7.53; S, 14.96. Found: C,
58.81; H, 7.58; S, 14.86.
(8S,12R)-8-(4-Methoxybenzyloxy)-12-methyl-11-oxa-1,5-dithiaspiro[5.9]pentadecan-10-one (14). To a stirred
solution of the hydroxy-acid 2 (0.4 g, 0.93 mmol) and Et3N (0.38 mL, 2.80 mmol) in dry THF (5 mL), a solution
of 2,4,6-trichlorobenzoyl chloride (0.34 mL, 1.39 mmol) in dry THF (1 mL) was added. The resulting mixture
was stirred for 2 h at rt under a nitrogen atmosphere and evaporated to afford the mixed anhydride. It was
diluted with toluene (10 mL) and filtered quickly through Celite. The filtrate was added dropwise to a stirred
solution of DMAP (0.11 g, 0.93 mmol) in toluene (400 mL) at 90 °C over a period of 10 h. It was cooled, washed
with 7% aq NaHCO3 (20 mL), 2M aqueous HCl (20 mL), brine (20 mL) and dried (Na2SO4). The organic layer was
evaporated and the obtained residue purified by column chromatography (60-120 silica gel, 12% EtOAc in pet.
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ether) to give 14 (0.27 g, 71%) as a syrup. []D +18.3 (c 1.2, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.23 (d, 2H, J
8.6 Hz), 6.82 (d, 2H, J 8.6 Hz), 4.86 (m, 1H), 4.51 (d, 1H, J 11.2 Hz), 4.44 (d, 1H, J 11.2 Hz), 4.13-4.04 (m, 1H),
3.73 (s, 3H), 2.93-2.76 (m, 4H), 2.44-2.28 (m, 2H), 2.04-1.89 (m, 2H), 1.89-1.69 (m, 6H), 1.47-1.30 (m, 2H), 1.17
(d, 3H, J 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 172.7, 160.3, 128.4, 128.1, 114.4, 79.1, 72.3, 61.3, 55.5, 46.8, 42.3,
39.8, 37.6, 26.5, 24.4, 22.1, 20.3; ESIMS: 411 (M+ H)+. Anal. Calcd. for C21H30O4S2: C, 61.43; H, 7.36; S, 15.62.
Found: C, 61.39; H, 7.32; S, 15.57.
(8S,12R)-8-Hydroxy-12-methyl-11-oxa-1,5-dithiaspiro[5.9]pentadecan-10-one (15). To a solution of the spiro-
dithiane 14 (0.24 g, 0.58 mmol) in aq. CH2Cl2 (2 mL, 19:1), DDQ (0.19 g, 0.87 mmol) was added and the mixture
stirred at rt for 3 h then quenched with sat. NaHCO3 solution (1 mL), filtered and washed with CH2Cl2 (10 mL).
The filtrate was washed with water (3 mL), brine (3 mL), dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by column chromatography (60-120 silica gel, 15% EtOAc in pet. ether) to
furnish 15 (0.15 g, 91%) as colourless syrup. []D +26.8 (c 0.8, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 4.91-4.83
(m, 1H), 4.17-3.94 (m, 1H), 2.88-2.74 (m, 4H), 2.71 (dd, 1H, J 4.0, 15.1 Hz), 2.44 (dd, 1H, J 8.9, 15.1 Hz), 2.03-
13
1.89 (m, 2H), 1.88-1.66 (m, 7H), 1.47-1.38 (m, 1H), 1.18 (d, 3H, J 6.8 Hz); C NMR (75 MHz, CDCl3) δ 172.8,
159.9, 128.7, 128.4, 114.3, 79.3, 72.1, 61.3, 55.8, 47.1, 42.2, 39.8, 37.7, 26.9, 24.5, 21.9, 20.2; ESIMS: 291 (M+
H)+. Anal. Calcd. for C13H22O3S2: C, 53.76; H, 7.63; S, 22.08. Found: C, 53.71; H, 7.58; S, 22.02.
Diplodialide C (1). To a stirred solution of lactone 15 (95 mg, 0.32 mmol) in EtOH (2.0 mL) was added freshly
prepared Raney 2400 Ni (~1.5 g) in EtOH (2.0 mL) at 25 oC. After stirring at 40 oC for 12 h, the reaction mixture
was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by column
chromatography (60-120 silica gel, 15% EtOAc in pet. ether) to furnish compound 1 (41 mg, 65% yield). []D –
41.3 (c 0.6, CHCl3); Lit:4 []D –41.0 (CHCl3); νmax (neat)/cm-1 3645, 3425, 1736, 1244, 1030; 1H NMR (CDCl3, 400
MHz): δ 5.05-4.94 (m, 1H), 4.15–4.03 (m, 1H), 2.67 (dd, 1H, J 4.2, 15.5 Hz), 2.47 (dd, 1H, J 9.3, 15.5 Hz), 1.91–
13
1.41 (m, 10H), 1.26 (d, 3H, J 6.6 Hz), C NMR (75 MHz, CDCl3) δ 171.3, 72.3, 70.1, 44.1, 35.5, 31.2, 29.6, 26.7,
21.7, 20.2; ESIMS: 209 (M+ Na)+.
Diplodialide D (1a). To a solution of compound 15 (0.11 g, 0.37 mmol) and CaCO3 (0.37 g, 3.79 mmol) in
o
THF/H2O (9:1, 2 mL) was added I2 (0.28 g, 1.11 mmol) at rt. The resulting mixture was stirred at 45 C for 3 h.
The reaction mixture was quenched by adding saturated aq. Na2S2O3, filtered through a pad of Celite, and then
extracted with EtOAc (3×20 mL), water, brine, dried over Na2SO4 and concentrated. The residue was purified
by column chromatography (60-120 silica gel, 15% EtOAc in pet. ether) to furnish compound 1a (51 mg, 68%
1
yield). []D +1.3 (c 0.9, CHCl3); Lit:5 []D +0.8 (CHCl3); νmax (neat)/cm-1 3425, 1735, 1700; H NMR (CDCl3, 400
MHz): δ 4.56 (m,1H), 4.37 (m, 1H), 3.23 (brs, 1H), 2.90 (dd, 1H, J 14, 3.2 Hz), 2.60 (dd, 1H, J 14.1, 4.2 Hz), 2.57
(d, 2H, J 5.6 Hz), 2.44 (m, 2H), 1.88-1.76 (m, 4H), 1.20 (d, 3H, J 6 Hz); 13C NMR (75 MHz, CDCl3) δ 207.6, 173.2,
72.6, 65.3, 51.5, 42.6, 41.2, 38.4, 21.6, 20.1; ESIMS: 223 (M+ Na)+.
Acknowledgements
VB and CHNSSP are thankful to Vice Chancellor, Dean R & D, VFSTRU for constant support and
encouragement.
Supplementary Material
1
13
Compounds characterization and H and C NMR spectra for all the intermediates and final compounds are
available in the supplementary material.
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