Divergent synthesis of (6S,1′S,2′R)-hydroxypestalotin via tandem conjugate addition-lactonization sequence

Article abstract of DOI:10.1016/j.tetlet.2015.01.069

The stereoselective synthesis of (6S,1′S,2′R)-hydroxypestalotin from trans-hex-2-en-1-ol utilizing asymmetric dihydroxylation and Luche's reduction and tandem conjugative addition-lactonization as the key steps is reported.

Full text of DOI:10.1016/j.tetlet.2015.01.069

Accepted Manuscript
Divergent synthesis of (6S,1’ S,2’ R)-Hydroxypestalotin via tandem conjugate
addition-lactonization sequence
Venkata Satyanarayana Mallula, Batthula Srinivas, Palakodety Radha Krishna
PII:
S0040-4039(15)00084-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.069
TETL 45739
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 November 2014
8 January 2015
9 January 2015
Please cite this article as: Mallula, V.S., Srinivas, B., Krishna, P.R., Divergent synthesis of (6S,1’ S,2’ R)-
Hydroxypestalotin via tandem conjugate addition-lactonization sequence, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.01.069
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GRAPHICAL ABSTRACT
Leave this area blank for abstract info.
Divergent synthesis of (6S,1'S,2'R)-Hydroxypestalotin
via tandem conjugate addition-lactonization sequence
Venkata Satyanarayana Mallula, Batthula Srinivas and Palakodety Radha Krishna*
O
O
O
OH
OH
O
O
OH
O
O
OH
5
2
(6S,1'S,2'R)-Hydroxypestalotin
β)
(LL-P880
1
1

Divergent synthesis of (6S,1'S,2'R)-Hydroxypestalotin via tandem
conjugate addition-lactonization sequence
Venkata Satyanarayana Mallula, Batthula Srinivas and Palakodety Radha Krishna*
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Abstract: The stereoselective synthesis of (6S,1'S,2'R)-Hydroxypestalotin from trans-hex-2-
en-1-ol utilizing asymmetric dihydroxylation and Luche’s reduction and tandem conjugative
addition-lactonization as the key steps is reported.
Keywords: Hydroxypestalotin (LL-P880β), Jacobsen's hydrolytic kinetic resolution, Luche’s
reduction, conjugative addition-lactonization.
___________________________________________________________________________
α,β-Unsaturated δ-lactones exhibits various pharmacological properties, while some
exhibits antitumor activity, others posses interesting biological activities.1 Notable among
them was a C6-side chain containing hydroxypestalotin 1 (LL-P880β, Figure 1) showing a
potent gibberellin-synergistic activity was isolated as a minor metabolite from the culture
filtrate of unidentified Pencillium sp.2 Previous reports on the synthesis of 1 not only banked
on chiron approach for gathering the stereogenic carbon framework consisting of the β-keto
ester moiety but also relied on lactonization followed by methylation of the enol as the
common synthetic approach.3 In continuation with our interest in the synthesis of δ-lactone
containing bioactive natural products4 herein we report the stereoselective synthesis of 1 by a
strategically different route wherein tandem conjugate addition-lactonization reaction set
conceived on the chiral propargylic ester 2 (vide infra Scheme 1) formed the key step.
O
1
O
OH
2
3
′
1
4
O
6
′
2
5
OH
1
Figure 1. (6S,1'S,2'R)-Hydroxypestalotin
β)
(LL-P880
Accordingly the retrosynthetic strategy envisaged for (6S,1'S,2'R)-Hydroxypestalotin
1 is delineated in Scheme 1, involving Jacobsen's hydrolytic kinetic resolution,5 Luche's
reduction and asymmetric dihydroxylation, conjugative addition-lactonization as the key
steps is described herein.
_______________________
*Corresponding Author. Email: prkgenius@iict.res.in. Fax: +914027160387.
2

O
O
O
OH
OH
O
O
O
route I
OPMB
O
4
2
O
OH
1
route II
O
OTBS
OH
O
5
3
Scheme 1: Retrosynthetic analysis
OR
OBn
O
(c)
(a)
(d)
OPMB
OPMB
OBn
OH
8
4
6, R = H
7, R = Bn
(b)
OH
OBn
(h)
(f)
(g)
OH
12
OH
R
11
9, R =
10, R =
OH
O
(e)
O
O
O
OH
O
O
O
(i)
(k)
2a
O
14
O
O
13
Scheme 2. Reagents and conditions: (a) (i) CuI, EtMgBr, dry Et2O, -20 oC to 0 oC, 0.5 h, 85%; (b) NaH, Bn-Br, THF, 0 oC to
rt, 2 h, 90%; (c) (i) DDQ, CH2Cl2:H2O (19:1), 0 oC to rt, 0.5 h, 90%; (d) (i) (COCl)2, DMSO, Et3N, dry CH2Cl2, 1 h; (ii)
vinylmegesiumbromide, dry THF, 0 oC, 0.5 h, 80% (over two steps); (e) (i) DMP, CH2Cl2, 0 oC to rt, 1 h, 90%; (f) CeCl3.7H2O,
NaBH4, CH3OH, -100 oC, 2 h, 95%; (g)) Li, C10H8, dry THF, -20 oC, 1 h, 69%; (h) 2,2-DMP, PPTS, dry CH2Cl2, 0 oC to rt, 1
h, 92%; (i) mCPBA, CH3Cl, 0 oC, 3 h, 90%; (k) HCCCO2Et, n-BuLi, BF3.OEt2, dry THF, -78 0 oC, 1 h, 20%.
Accordingly, our initial approach Scheme 2 (route I) to build the homopropargylic
ester 2 followed a literature procedure.6 Thus, the known (R)-glycidol PMB ether 4 on
exposure to EtMgBr in presence of CuI furnished secondary alcohol 6 (85%). Protection of
secondary hydroxyl group as its benzyl ether (BnBr/NaH/THF) furnished the benzyl ether 7
o
(90%). Next, oxidative cleavage (DDQ/CH2Cl2/H2O/0 C/0.5 h) of PMB-ether afforded the
primary alcohol 8 (90%). Later alcohol 8 was oxidized under Swern conditions to afford the
corresponding chiral aldehyde which was subjected to Grignard reaction with vinyl
magnesium bromide to furnish the olefinic compound 9 (80%). Then, the olefinic compound
9 was oxidized under Swern conditions to afford the conjugated enone 10 (90%), was
reduced under Luche’s conditions to result in the chiral olefinic alcohol 11 (95%) as a major
diastereomer (dr = 98:2) was confirmed by LCMS analysis. The reductive deprotection of
benzyl ether using Li metal in presence of catalytic amount naphthlene7 afforded the desired
diol 12 and protection of diol as its acetonide 13 (2,2-DMP/PPTS/65% over two steps). The
3

1,2-syn stereochemistry of isomer 13 was confirmed by the 13C NMR which revealed the
carbon atoms in 13 due to the acetonide methyls resonating at δ 27.2 and at δ 26.9 ppm
characteristic of the acetonide of a syn-1,2-diol moiety.8 The olefin 13 on exposure to m-
CPBA gave diasteromeric epoxide 14 (90%). Later, 14 on ring-opening reaction with
lithiated anion of ethylpropiolate in dry THF under acidic conditions resulted in 2a albeit in
poor yields (20%). Efforts to improve the yields were unsuccessful.
OH
O
O
OH
(b)
(c)
(a)
OH
OBz
OH
5
16
OH
17
O
O
18
O
O
O
OH
O
OTBS
(d)
(e)
(f)
3
O
O
19
O
20
Scheme 3. Reagents and conditions: (a) (i) C6H5COCl, Et3N, dry CH2Cl2, 0 oC to rt, 2 h, 95%; (ii) AD-mix β, tBuOH:H2O, 0
oC to rt, 8 h, 86% (major isomer); (b) (i) 2,2-DMP, PPTS, dry CH2Cl2, 0 oC to rt, 1 h, 92%; (ii) K2CO3, MeOH, 0 oC to rt, 4 h,
81%; (c) (i) (COCl)2, DMSO, Et3N, dry CH2Cl2, 1 h; (ii) C3H3MgBr, dry THF, -30 oC to rt, 2 h, 80% (over two steps); (d)
DMP, CH2Cl2, 0 oC to rt, 1 h, 90%; (e) CeCl3.7H2O, NaBH4, CH3OH, -100 oC, 2 h, 90%; (f) imidazole, TBS-Cl, DMAP, dry
CH2Cl2, 1 h, 94%.
An alternative synthetic Scheme 3 (route II) was conceived to construct the chiral
propargylic alcohol 3 from trans-hex-2-en-1-ol 5. Accordingly, allylic alcohol 5 was
protected as its benzoate ester (Bz-Cl/Et3N/CH2Cl2/1 h) to give the allylic benzoate which on
Sharpless asymmetric dihydroxylation protocol (AD-mix-β/tBuOH/H2O/0 oC to rt/12 h) gave
the diol 16 (86%) as the separable major isomer. The resulting diol 16 was protected as its
acetonide (92%) followed by the benzoyl group deprotection to give the corresponding
alcohol 17 (81%). The 1,2-syn stereochemistry of major isomer 17 was determined by the
same analogy as done for 13 (δ 27.3, 26.9 ppm). Later, alcohol 17 was oxidized under Swern
conditions to afford the corresponding aldehyde which was subjected to Grignard reaction
with propargyl bromide in the presence of Zn dust and NH4Cl in THF gave to the alkyne
compound 18 (80%, over two steps), followed by oxidation (Dess-Martin
periodinane/CH2Cl2/0 oC to rt/1 h) furnished homopropargyl ketone 19 (90%). Ketone 19 on
reduction under Luche’s conditions9 gave the chiral homopropargyl alcohol 20 as a major
diastereomer in 90% yield with 97% de (For details please see SI). The diastereoisomer
purity of product 20 was determined by LCMS analysis. The protection of 20 as its silyl-ether
(TBS-Cl/imidazole/DMAP/CH2Cl2/0 oC to rt/1 h) provided the crucial intermediate 3 (94%).
4

O
O
O
OH
O
OTBS
O
OTBS
O
O
(b)
(a)
3
O
O
O
21
2
O
O
O
O
OH
OH
O
O
O
O
(d)
(c)
O
O
O
OH
1
O
A
22
O
Reagents and conditions: (a) ClCO2Et, n-BuLi, dry THF, -78 oC, 1 h, 90%; (b) HF-CH3CN, CH3CN, 0 oC, 4 h, 94%;
Scheme 4
(c) NaOMe, CH3OH, 0 oC to rt, 8 h, 75%; (d) TFA, CH2Cl2, 0 oC to rt, 4 h, 85%.
Further, the lithiated anion anion of homoproparglic alcohol 3, generated in situ, was
quenched (Scheme 4) with ethylchloroformate to give the homopropargylic ester 21 (90%).10
Next, the silyl group was deblocked (HF/CH3CN/rt/4 h)11 to afford the corresponding
secondary alcohol 2 (94%) which on treatment with NaOMe in MeOH led to a conjugate
addition first, thus generating the enol ether A in situ, facilitating the easy attack of the free
hydroxyl group onto the ester to furnish lactone 22 (75%) by an intramolecular fashion.6,12
Finally, acetonide deprotection (TFA/CH2Cl2/0 oC to rt) led to target compound 1 (85%). The
purity of compound 1 was determined by LCMS analysis and de was found to be 96.6%.13
The physical and spectroscopic data of 1 is in complete agreement with the reported
values.2,13
In summary, the stereoselective synthesis of (6S,1'S,2'R)-Hydroxypestalotin 1 was
reported via asymmetric dihydroxylation, Luche’s reduction and conjugative addition-
lactonization as the key steps. Comparing the overall yields of intermediate propargylic esters
2 and 2a, obtained by two different routes, are 31.3% and 5.38% respectively. Consequently,
employing route-II target compound 1 was obtained in 20% overall yield.
Acknowledgements. Two of the authors (M. V. S and B.S) thank the CSIR and UGC, New
Delhi for the financial support in the form of fellowships.
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1.
2.
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5

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13. For experimental data and spectral data see supporting information.
6