An alternative total synthesis of diplodialide-B

Article abstract of DOI:10.1080/00397911.2019.1663541

In this paper, an enantioselective synthesis of diplodialide-B has been described. To accomplish this target, a combination of regioselective ring opening of the chiral epoxide, Jacobsen hydrolytic kinetic resolution and Yamaguchi macrolactonization were used as the key steps.

Full text of DOI:10.1080/00397911.2019.1663541

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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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An alternative total synthesis of diplodialide-B
Chiranjeevi Kalavakuntla, Vijaya Babu Kummari & Jhillu Singh Yadav
To cite this article: Chiranjeevi Kalavakuntla, Vijaya Babu Kummari & Jhillu Singh Yadav
(2019): An alternative total synthesis of diplodialide-B, Synthetic Communications, DOI:
10.1080/00397911.2019.1663541
To link to this article: https://doi.org/10.1080/00397911.2019.1663541
Published online: 14 Sep 2019.
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https://doi.org/10.1080/00397911.2019.1663541
An alternative total synthesis of diplodialide-B
Chiranjeevi Kalavakuntlaa, Vijaya Babu Kummaria, and Jhillu Singh Yadava,b
aCentre for Semiochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India;
bSchool of Science, Indrashil University, Ahmedabad, India
ABSTRACT
ARTICLE HISTORY
Received 29 June 2019
In this paper, an enantioselective synthesis of diplodialide-B has
been described. To accomplish this target, a combination of regiose-
lective ring opening of the chiral epoxide, Jacobsen hydrolytic kinetic
resolution and Yamaguchi macrolactonization were used as the key
steps.
KEYWORDS
Diplodialide-B; Jacobsen
hydrolytic kinetic resolution;
(R)-propylene oxide;
stereoselective synthesis;
Yamaguchi
GRAPHICAL ABSTRACT
OTBS
OH
OMPM
COOH
O
O
5 steps
5 steps
macrolactonization
2 steps
O
O
HO
Diplodialide-B
Introduction
Naturally occurring 10-membered ring lactones, commonly known as decanolides, have
attracted considerable attention from synthetic organic chemists as well as bioorganic
chemists, because of their interesting structural features and various biological activities
such as plant growth inhibition and anti-feedant, anti-fungal and anti-bacter-
ial activities.
Diplodialides A (1a), B (1b), C (1c), and D (1d) (Figure 1) are the naturally occur-
ring ten-membered monocyclic ring lactones, which were isolated from the plant patho-
genic fungus Diplodiapinea (IFO 6472) by Wada and Ishida[1,2]. The absolute
stereochemistry of diplodialides (9 R)-1a, (3S,9R)-1b, and (3 R,9R)-1c was determined
by Wada and Ishida[3].
Due to the promising biological activity and the impressive structural features, diplo-
dialides appeared to be attractive targets for total synthesis. To date, several approaches
to the synthesis of diplodialides have been reported[4]. As a part of our interest in the
CONTACT Jhillu Singh Yadav
yadavpub@gmail.com
Centre for Semiochemicals Division, CSIR-Indian Institute of
Chemical Technology, Hyderabad 500007, India; School of Science, Indrashil University, Kadi, Mehsana, Ahmedabad,
Gujarat, India.
ß 2019 Taylor & Francis Group, LLC

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2
C. KALAVAKUNTLA ET AL.
O
O
O
O
O
O
O
O
O
O
Diplodialide A (
HO
HO
Diplodialide B (
HO
Diplodialide C (1c)
Diplodialide D (1d)
1a
1b
)
)
Figure 1. Structure of diplodialides.
OTBS
OH
OMPM
COOH
O
O
1b
3
4
2
Scheme 1. Retrosynthetic analysis of diplodialide-B (1b).
total synthesis of macrolides, herein, we report an efficient and alternate route to the
total synthesis of diplodialide-B starting from (R)-Propylene oxide. In our approach,
Jacobsen hydrolytic kinetic resolution and Yamaguchi macrolactonisation have been uti-
lized as the key steps.
Results and discussion
Retrosynthetic analysis of the target molecule has been depicted in Scheme 1. Target mol-
ecule could be obtained from hydroxy-acid 2 using Yamaguchi macrolactonisation condi-
tions followed by deprotection of 4-methoxybenzyl ether. While compound 2 could be
accessed from chiral epoxide 3. Compound 3 could be synthesized from known chiral epox-
ide 4 (Scheme 1).
Synthesis of diplodialide-B (2) began with known epoxide 4 (Scheme 2)[5].
Regioselective ring opening of chiral epoxide 4 with Grignard reagent in dry ether at
ꢀ78 ꢁC gave secondary alcohol 5 in 78% yield, which on subsequent masking of the
hydroxyl group in 5 with TBSCl in CH2Cl2 in the presence of imidazole afforded silyl
ether 6 in 76% yield. Next the double bond in silyl ether 6 was subjected to Ozonolysis
to give corresponding aldehyde, which upon subsequent Wittig olefination with
(methoxycarbonylmethylene)triphenyl phosphorane in benzene under reflux yielded
desired (E) a,b-unsaturated ester 7 in 79% yield. The E-geometry of the double bond
was confirmed by coupling constant between the respective olefin protons (J ¼ 15.6 Hz).
Further, selective reduction of the ester 7 with DIBAL-H in CH2Cl2 gave allylic alcohol
8 in 81% yield. Swern Oxidation of the alcohol 8 gave the corresponding aldehyde,
which on subsequent treatment with trimethylsulfonium iodide,[6] NaH and DMSO in
THF afforded the corresponding epoxide 9 as a diastereomeric mixture in 66% yield.
Later, hydrolytic kinetic resolution[7] of the epoxide 9 using Jacobsen reagent (R,R)-
(þ)-N,N0-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane diaminocobalt (II) afforded
chiral epoxide 3 and diol 3a, which was easily separated by column chromatography.
Diol 3a was recycled to 3 by a three-step sequence. Thus, 3a was mono-benzoylated
(BzCl/Et3N/CH2Cl2/0 ꢁC-rt) followed by tosylation of the secondary hydroxyl (TsCl/
Et3N/CH2Cl2/0 ꢁC-rt) to give the diprotected compound. which, on further reaction
with K2CO3 in methanol furnished the desired epoxide 3 with 69% yield (for 3 steps).

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3
OTBS
O
OR
O
d
a
c
OMe
4
79%
(
7
)
78%
(
)
)
5 R = OH
b
76%
6 R = OTBS (
OTBS
O
OTBS
OTBS
O
f
e
43%
)
3
+
(
g (69%)
OH
81%
8
(
)
66%
(
)
9
OTBS
OH
OH
41%
3a (
)
OTBS
OMPMS
OTBS
OH
S
j
i
h
S
S
84%
(
)
11
77%
( )
10
O
OH
OMPM
COOH
OTBS
OMPM
COOH
O
k
l
MPMO
89%
( )
78%
(
12
)
2
63%
(
)
13
O
O
m
HO
79%
(
)
1b
Scheme 2. Synthesis of diplodialide-B (1b). Reagents and conditions: (a) homoallyl bromide, Mg,
dry ether, ꢀ78 ꢁC, 2 h; (b) TBSCl, Imidazole, CH2Cl2, rt, 4 h; (c) (i) O3, CH2Cl2, ꢀ78 ꢁC, 30 min; (ii)
Ph3P ¼ CHCOOMe, Benzene, reflux, 2 h; (d) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 2 h; (e) (i) (COCl)2, DMSO,
ꢀ78 ꢁC, Et3N, CH2Cl2, (ii) Trimethylsulfonium iodide, DMSO, NaH, THF, 75 ꢁC to ꢀ5 ꢁC, 4 h.; (f)
(R,R)-salen-Co-(OAc) (0.5 mol %), distd H2O (0.55 equiv.), 0 ꢁC, 13 h; (g) (i) BzCl, Et3N, CH2Cl2, 0 ꢁC-
rt, 3 h (ii) p-TsCl, Et3N, CH2Cl2, 0 ꢁC-rt, 2 h; (iii) K2CO3, MeOH, 0 ꢁC-rt, 1 h; (h) 1,3-dithiane, n-BuLi,
dry THF, 4 ꢁC, 3 h; (i) PMBBr, NaH, THF, 25 ꢁC, 8 h; (j) CaCO3, MeI, CH3CN:H2O (9:1), rt, 19 h; (ii)
NaH2PO4, NaClO2, MeCN, H2O, 2-methyl-2-butene, rt, 3 h; (k) TBAF, THF, 0 ꢁC to rt, 3 h; (l) (i)
2,4,6-trichlorobenzoyl chloride, Et3N, dry THF, rt, 2 h; (ii) DMAP, toluene, 90 ꢁC, 10 h; (m) DDQ,
CH2Cl2:H2O (19:1), rt, 3 h.
Next, Regioselective ring opening of chiral epoxide 3 in the presence of an anion
derived from 1,3-dithane yielded compound 10 in 77% yield, which on subsequent pro-
tection with PMB-Br, NaH in dry THF gave 11 in 84% yield. Hydrolysis of the dithane
group in 11 afforded aldehyde, which was converted into acid 12 by using NaH2PO4,
NaClO2, 2-methyl-2-butene in CH3CN:H2O (1:1) (Pinnick’s oxidation) at room tem-
perature with 78% yield[4f]. Desilylation of the acid 12 with TBAF in dry THF afforded
the hydroxy-acid 2 in 89% yield.
Next, hydroxy-acid 2 was subjected to macrolactonisation under Yamaguchi high
dilution conditions[8] using 2,4,6-trichlorobenzoyl chloride and Et3N in dry THF to
afford the lactone 13 in 63% yield. Finally, PMB ether was deprotected using DDQ in
CH2Cl2:H2O (19:1) for 3 h to afford the diplodialide-B (1b) in 79% yield. The spectral
and analytical data of synthetic diplodialide B (1b) were in good agreement with the
reported values in the literature.[3] Thus, we accomplished the total synthesis of diplo-
dialide-B in an enantioselective way.