Stereoselective synthesis of (3R,6S)-6-hydroxylasiodiplodin

Article abstract of DOI:10.1016/j.tetlet.2016.02.096

The first stereoselective synthesis of polyketide natural product (3R,6S)-6-hydroxylasiodiplodin (1) has been described starting from commonly available starting materials d-mannitol and 2,4,6-trihydroxybenzoic acid. The key reactions involved are Keck asymmetric allylation, Stille coupling, De Brabander's esterification, and ring-closing metathesis (RCM) reaction. The total synthesis was achieved in 19.3% overall yield making the route significant.

Full text of DOI:10.1016/j.tetlet.2016.02.096

Accepted Manuscript
Stereoselective synthesis of (3R,6S)-6-hydroxylasiodiplodin
Sheshurao Bujaranipalli, Saibal Das
PII:
S0040-4039(16)30205-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.096
TETL 47371
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 January 2016
22 February 2016
25 February 2016
Please cite this article as: Bujaranipalli, S., Das, S., Stereoselective synthesis of (3R,6S)-6-hydroxylasiodiplodin,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.096
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Stereoselective synthesis of (3R,6S)-6-hydroxylasiodiplodin
Sheshurao Bujaranipalli and Saibal Das*
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first stereoselective synthesis of polyketide natural product (3R,6S)-6-
hydroxylasiodiplodin (1) has been described starting from commonly available starting
materials D-mannitol and 2,4,6-trihydroxybenzoic acid. The key reactions involved are
Keck asymmetric allylation, Stille coupling, De Brabander’s esterification and Ring -
closing metathesis (RCM) reaction. The total synthesis was achieved in 19.3% overall
yield making the route significant.
Available online
Keywords:
Lasiodiplodin
Natural Products
Keck asymmetric allylation
Stille coupling
De Brabander’s esterification
Ring Closing Metathesis.
2
016 Elsevier Ltd. All rights reserved.
Introduction
1
Resorcylic acid lactones (RALs) are an important class of natural products with a wide range of biological activities and majority
of these lactones are 14-membered. However, 12-membered RALs (RAL12) have also been known since the first isolation of
2
3
lasiodiplodin and de-O-methyl-lasiodiplodin in 1971, followed by resorcylide in1978. Since then, nearly about thirty RAL12 have
been isolated from various sources. Lasiodiplodins show broad spectrum of biological activities such as proliferation function of
4
5
6
7
primary osteoblasts (OBs) in vitro, inhibition of prostaglandin biosynthesis, potent anti-leukemic activity, cytotoxic, potent
8
9
10
nonsteroidal antagonist of the mineralocorticoid receptor (MR), anti-microbial activity, potato micro-tuber inducing activities,
plant-gowth inhibitor and also act as a Hill reaction inhibitor. Recently, this family of compounds have been reported to exhibit α-
glucosidase inhibitory activity. Compound (3R,6S)-6-hydroxylasiodiplodin 1 (Figure 1) was isolated by Takahashi and co-workers
from Lasiodiplodia theobromae which is a common pathogenic fungus found in tropic and subtropical region. The structure of 1
was determined by means of spectroscopic analyses, modified Mosher’s method and chemical conversion. The compound 1
showed in particular potato micro tuber inducing activity at a concentration of 10 M.
2
11
1
2
1
3
13
-
4
O
O
O
HO
HO
O
O
O
O
O
O
HO
BnO
HO
BnO
1
2
OH
O
O
O
OH
OH
OH
O
+
HO
4
OBn
BnO
3
5
D-mannitol
Figure 1: Structure of (3R,6S)-6-hydroxylasiodiplodin (1)

3
*
Corresponding author. Phone : +91-40-2719-1887; Fax: +91-40-2716-0512. E-mail: saibal@iict.res.in
1
4
Our continued interest in the synthesis of bioactive natural products coupled with interesting biological activities of these classes
of compounds prompted us to synthesize 1. Herein, we report the first stereoselective total synthesis of (3R,6S)-6-
hydoxylasiodiplodin (1) using Keck asymmetric allylation, Stille coupling, De Brabander’s esterification and RCM reaction from
D-mannitol and 2,4,6-trihydroxybenzoic acid.
Results and Discussion:
Our retrosynthetic analysis is depicted in Scheme 1. Accordingly, 1 could be achieved under RCM reaction condition with
compound 2 which in turn could be visualized to be obtained by the coupling of lactone 3 and the secondary alcohol 4. Lactone 3
and alcohol 4 could be obtained from 2,4,6- trihydroxybenzoic acid (5) and D-mannitol respectively using general reaction
protocols.
Scheme 1: Retrosynthetic analysis of compound 1
'
(
The total synthesis began with first synthesizing the aliphatic subunit 4 from cheap and commercially available D-mannitol.'
15
Scheme 2). The known α,β-unsaturated ester 6 was prepared from D-mannitol using well known literature procedure. The double
16
4
bond as well as the ester were reduced with NaBH /LiCl to give saturated alcohol 7 in 82% yield. The primary alcohol 7 was
efficiently oxidized with IBX (2-Iodoxybenzoic acid) in DMSO/THF at ambient temperature to provide the expected aldehyde,
which upon treatment under Keck asymmetric allylation conditions {allyl tributyltin, (S)-BINOL, [(S)-(-)-1,1'-Bi (2-naphthol)]
i
o
o
17
4 2 2
Ti(O Pr ), 4Å MS, dry CH Cl , -78 C to -20 C} furnished the desired homo allylic alcohol 8 in 79% over two steps. The absolute
stereochemistry of the newly generated stereogenic center in compound 8 bearing the hydroxyl group was determined by preparing
the (S) and (R)-MTPA esters [prepared by using MTPA (Methoxytrifluoromethylphenylaceticacid) with DCC as the coupling
1
8
1
reagent] by modified Mosher’s method and was found to have R configuration by studying their H NMR spectra (Figure 2) .The
negative chemical shift difference to the left side of the MTPA plane and the positive chemical shift to the right side of the MTPA
plane indicated that the hydroxyl stereochemistry has R configuration.
O
OH OH
a
b
O
O
OEt
OH
O
OH
HO
c
6
O
7
OH OH
D-Mannitol
O
O
O
d
O
e
8
OH
9
OBn
HO
HO
HO
f
10
OBn
4
OBn
o
Scheme 2: Reagents and conditions: a) ref. 15 b) NaBH
4
:LiCl (1:1), THF:EtOH (1:1), 0 C to rt, 48 h, 82%; c) (1) IBX, DMSO/THF, 20
o
i
o
o
C, 4 h; (2) (S)-BINOL, Ti(O Pr
4
), , 4 Å molecular sieves, allyl tributyltin, CH
2
Cl
2
, -78 C then -20 C , 79% over two steps; d) NaH, BnBr,
THF, 0 C to rt, 6 h, 89%; e) 60% AcOH in water, rt, overnight, 87%; f) (1) p-TsCl, Et
o
o
3
N, n-Bu
2
SnO, CH
2
Cl
2
, 0 C to rt, 30 min; (2)
o
4
LiAlH , THF, 0 C to rt, 30 min, 74% over two steps.
+
70
O
+
20
+90
OMTPA
H
+
20
-90
O
+
10
-100
+20
-140
3
Figure 2: Determination of absolute configuration and ∆δ values for the (S) and (R) –MTPA ester derivatives of 8 (∆δ=δ
S
- δ
R
) x 10 .
The homoallylic alcohol 8 was then protected as its benzyl ether using benzyl bromide in the presence of NaH in THF to afford the
1
9
corresponding benzyl ether 9 in 89% yield (≥98 dr based on HPLC). The isopropylidine protection was removed using 60%
AcOH in water to afford the desired 1,2-diol 10 in 87% yield. A regioselective tosylation of the primary hydroxyl group in 10 was
20
achieved through dibutylstanylene acetal and subsequent reduction with LiAlH
4
gave alcohol 4 in 74% yield over two steps.
The aromatic coupling partner (3) was prepared starting from readily available 2,4,6-trihyroxybenzoic acid monohydrate (5) , which
2
1
was converted into its corresponding acetonide protected compound 11 using Danishefsky’s modified protocol (trifluoroacetic
acid (TFA), trifluoroacetic anhydride (TFAA) and acetone) in 60% yield (Scheme 3). Regioselective protection of 4-hydroxy group

4
as its benzyl ether was achieved under Mitsunobu conditions [PPh
3
and DIAD (Diisopropyl azodicarboxylate)] to obtain compound 12 in
22
8
8% yield. Compound 12 was converted into its corresponding triflate 13 using trifluoromethanesulfonic anhydride in the
23
presence of pyridine in 92% yield which was then subjected to Pd-catalysed Stille coupling with allylstannane in the presence of
24
LiCl gave the compound 3 in 72% yield.

5
OH
O
O
O
O
O
OH
OH
b
a
O
O
HO
HO
O
OH
BnO
O
OH
5
11
12
O
O
O
c
d
O
BnO
OTf
BnO
13
3
o
o
Scheme 3: Reagents and conditions: a) TFA, TFAA, acetone, 0 C to rt, 48 h, 60%; b) PPh
Tf
3
, DIAD, BnOH, THF, 0 C to rt, 3 h, 88%; c)
o
o
O, pyridine, CH Cl , 0 C to rt, 4 h, 92%; d) allyltributyltin, LiCl, Pd(PPh ) , DMF, 60 C, 8 h, 72%.
2 2 2 3 4
After successfully synthesizing the two fragments 3 and 4, we next focused to couple them to form an entire frame work.
2
5
o
Accordingly, compounds 3 and 4 were subjected to De Brabander’s esterification conditions (NaH, THF, 0 C - r.t.) for to the
formation of the desired ester 14 in 84% yield (Scheme 4). Free ortho-phenolic group present in 14 was methylated using dimethyl
26
2 3
sulphate and K CO in acetone to obtain compound 2 in 92% yield. Then, diene 2 was treated with 5 mol% of Grubbs second
generation catalyst under dilute conditions to give the required lactone 15 as a mixture of an E/Z in 83% yield. The newly formed
double bond after RCM, would be of no importance as it would be saturated in the later stage of the synthesis. Finally, deprotection
of the two benzyl groups as well as the saturation of the double bond in coumpound 15 was achieved using Pd/C to provide the
1
13
target compound 1 in 81% yield. The spectral data ( H, C and MS) and optical rotation of the thus synthesized target compound
were in good agreement with the reported values of the natural product 1. The optical rotation of 1 showed +10.0 (c = 0.1, MeOH)
1
3, 27
compared to reported value +12 (c = 0.1, MeOH).
o
Scheme 4: Reagents and conditions: a) NaH, THF, 0 C to rt, 6 h, 84%; b) K
catalyst (5 mol%), CH Cl , reflux, 4 h, 83%; d) 10% Pd/C, EtOAc, 6 h, 81%.
2 3 3 2 4
CO , (CH ) SO , Dry acetone, reflux, 6 h, 92%; c) Grubbs II
2
2
In conclusion, we have successfully accomplished the first stereoselective synthesis of (3R,6S)-6-hydroxylasiodiplodin (1) by
employing Keck asymmetric allylation, Stille coupling, De Brabander’s esterification and RCM reaction in 9 longest linear steps
with an overall yield of 19.3% starting from 6. The facile reaction protocol opens up the scope of the current synthesis in larger
quantities
for
screening
purposes
and
biological
studies.
Acknowledgments:
S.B thanks UGC, New Delhi, India for fellowship. Authors thank CSIR New Delhi for financial supports through Project ORIGIN
CSC-0108) under 12th Five Year Plan.
(
Supporting Information:
Supplementary data associated with this article can be found, in the online version.

6
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(
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2
7
(3R,6S)-6-hydoxylasiodiplodin (1): Mp = 230-234; [α]
D
= +10.0 (c = 0.1, MeOH); IR (KBr): 3371, 3132, 2951, 1677, 1604, 1467, 1435, 1348,
): δ 1.15-1.06 (m, 2H), 1.22 (d, J = 6.1 Hz, 3H), 1.28-1.24 (m, 1H), 1.66-1.42 (m, 6H),
.98-1.91 (m, 1H), 2.41-2.32 (m, 1H), 2.49-2.45 (m, 1H), 3.62-3.55 (m, 1H), 3.69 (s, 3H), 4.34 (d, J = 4.5 Hz, 1H), 5.16-5.06 (m, 1H), 6.22 (br s, 1H),
−1 1
1
1
6
1
271, 1167, 1081, 845 cm ; H NMR (300 MHz, DMSO-d
6
1
3
.26 (br s, 1H), 9.69 (s, 1H); C NMR (125 MHz, DMSO-d ): δ 18.8, 22.6, 28.4, 29.3, 29.4, 29.8, 32.3, 55.7, 68.7, 71.3, 97.0, 107.8, 116.1, 141.8,
57.4, 159.2, 167.9; MS (ESI): m/z = 309 (M+H) ; HRMS (ESI): calcd. for C17H O (M+H) 309.1696, found 309.1689.
25 5
6
+
+

7
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Stereoselective synthesis of
(3R,6S)-6-hydroxylasiodiplodin
Sheshurao Bujaranipalli and Saibal Das*

*Highlights
HIGHTLIGHTS

First stereoselective synthesis of natural product (3R,6S)-6-hydroxylasiodiplodin has been
achieved.


The total synthesis was achieved in 19.3% overall yield
Commonly available starting materials D-mannitol and 2,4,6-trihydroxybenzoic acid have been
utilized.