Chemoenzymatic total synthesis of stagonolide-E

Article abstract of DOI:10.1016/j.tetlet.2011.11.059

Asymmetric total synthesis of small ring macrolide stagonolide-E has been described in this communication. The main highlight of our synthetic strategy is the application of ME-DKR (metal enzyme combo dynamic kinetic resolution) reaction, asymmetric reduc

Full text of DOI:10.1016/j.tetlet.2011.11.059

Tetrahedron Letters 53 (2012) 256–258
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Tetrahedron Letters
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Chemoenzymatic total synthesis of stagonolide-E
⇑
Tapas Das, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of small ring macrolide stagonolide-E has been described in this communica-
tion. The main highlight of our synthetic strategy is the application of ME-DKR (metal enzyme combo
dynamic kinetic resolution) reaction, asymmetric reduction with Noyori’s BINAL-H reagent system, ster-
eoselective cross metathesis, and RCM (ring closing metathesis) reaction at a late stage enables us to
achieve the synthesis of the target molecule in an efficient way.
Received 18 October 2011
Revised 8 November 2011
Accepted 11 November 2011
Available online 18 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Small ring macrolide
MEDKR
Cross metathesis
Ring closing metathesis
Total synthesis
Naturally occurring 10-membered ring lactones from fungal
metabolites present a wide variety of bioactive substances.1 Mac-
rolides, particularly lactones with medium-sized rings (8–10 mem-
bered), have continued to attract the attention of both biologists
and chemists during current years, due to the interesting biological
properties and scarce availability of macrolides.2 Stagonospora cir-
sii, a fungal pathogen isolated from Cirsium arvense and proposed
as a potential mycoherbicide of this perennial noxious weed, pro-
duces phytotoxic metabolites in liquid and solid cultures.3 Re-
cently, the main metabolite, stagonolide, with interesting
phytotoxic properties, was isolated from a liquid culture and char-
acterized as a new nonenolide. Five new nonenolides, named stag-
onolides B–F, were isolated and characterized using spectroscopic
methods.3 A further four nonenolides were isolated and character-
ized by spectroscopy. Three were new compounds and named
stagonolides G–I, and the fourth was identified as modiolide A, pre-
OH
OH
OH
O
O
OH
OH
OH
O
O
O
O
O
O
HO
O
O
O
nPr
OH
OH
Modiolide-B
Stagonolide-C
Stagonolide-D
Stagonolide-B
Z; Modiolide-A
E; Stagonolide-I
O
O
OH
O
OH
OH
O
O
O
O
Stagonolide-H
HO
O
OH
O
Stagonolide-F
Stagonolide-E
Stagonolide G
Figure 1. Naturally occurring stagonolides.
⇑
Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.059

T. Das, S. Nanda / Tetrahedron Letters 53 (2012) 256–258
257
OH
OP
OP
OP
RCM
3
CM
6
1
O
O
P'O
P'O
2
O
O
4
3
2
Stagonolide-E; 1
P = ethoxymethyl (EOM)
P' = TBDPS; P'' = TBS
CM = cross metathesis
OH
MEDKR
P''O
HO
OTBS
6
5
Scheme 1. Retrosynthetic analysis of stagonolide-E.
OH
OH
OAc
a
OTBDPS
b
OH
c
OTBS
OTBS
OH
OTBS
h
6
(R)-7, ee = 97%
8
O
OTBDPS
OTBDPS
d
e
f
g
OH
CHO
k
TBDPSO
TBDPSO
9
10
11
12
OR'
OEOM
OEOM
OEOM
j
OHC
TBDPSO
l
m
TBDPSO
TBDPSO
HO
15
3
16
13; R' = H
14; R = EOM
i
Ph
Ph
NHiPr
DKR catalyst
Ph
Cl
OEOM
OH
OEOM
o
n
Ph
O
O
O
O
Ru
CO
CO
O
O
2
17
stagonolide-E; 1
N
Cl
N
MeS
MeS
Ru
O
O
O
AlH2-
Cl
Nayori's BINAL-H reagents from M-binol
Hoveyda-Grubbs catalyst (HG-II)
Scheme 2. Asymmetric synthesis of stagonolide-E. Reagents and conditions: (a) NaH, TBS-Cl, rt, 6 h, 92%; (b) CAL-B, isopropenylacetate, chlorodicarbonyl(1-
(isopropylamino)-2,3,4,5-tetraphenylcyclopentadienyl) ruthenium(II), K2CO3, KOtBu, 88%; (c) K2CO3, MeOH, 1 h; imidazole, TBDPS-Cl, 86%; (d) PPTS, MeOH, rt, 6 h, 85%;
(e) DMP, DCM, rt, 2 h, 91%; (f) CH2@CHMgBr, THF, À78 °C, 82%; (g) (COCl)2, DMSO, Et3N, À78 °C, 90%; (h) M-(+)-binapthol, LiAlH4, À100 °C, 3 h, then add 12, À78 °C, 6 h, 85%;
(i) EOM-Cl, DIPEA, rt, 12 h, 87%; (j) HG-II, acrolein, reflux, DCM, 6 h, 92%; (k) LHMDS, PH3P+MeI, 0 °C, 1 h, 80%; (l) TBAF, THF, rt, 3 h, 84%; (m) CH2@CHCOCl, DIPEA, 6 h, rt, 80%;
(n) G-II, DCM, reflux, 6 h, 62%; (o) 2.0 M HCl, THF, rt, 6 h, 88%.
viously isolated from Paraphaeosphaeria sp., a fungus separated
from the horse mussel (Fig. 1).4 In our continuous effort for the syn-
thetic studies toward the small ring macrolides, we have already
reported the total synthesis of stagonolide C,5 stagonolide D &
G,6 chloriolide,7 and achaetolide.8 The main highlight of our previ-
ous synthetic strategy is chemoenzymatic kinetic resolution cou-
pled with Mitsunobu inversion and chemoenzymatic dynamic
kinetic resolution to access some valuable chiral secondary alcohol
intermediates. These intermediates are then employed succes-
sively to gain access of more advanced intermediates, which has
close resemblance of the target molecule. In the final step of the
synthesis we often apply RCM reaction by Grubbs catalyst as well

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T. Das, S. Nanda / Tetrahedron Letters 53 (2012) 256–258
as Yamaguchhi macrolactonization protocol. The success of our
synthetic strategy depends on the optimization of Grubbs RCM
method and Yamaguchhi macrolactonization protocol.
In this letter we wish to report a short and efficient asymmetric
synthesis of stagonolide-E by chemoenzymatic approach. The first
stereoselective synthesis of the parent molecule has been reported
by Sabitha et al.,9 which involves Yamaguchi macrolactonization at
the penultimate stage.
The retrosynthetic scheme for the target molecule is depicted in
Scheme 1. We envisioned that the C2–C3 bond can be connected
through RCM reaction of a properly substituted olefinic species 2,
which can be accessed from a conjugated olefinic compound 3.
Cross metathesis could be serving as a good option for the synthe-
sis of conjugated olefinic species from precursor 4. Compound 4
can be easily accessed from racemic 6 by adopting ME-DKR reac-
tion and asymmetric reduction of carbonyl functionality by Noy-
ori’s BINAL-H reagent.
We have started our synthetic journey from the known pentane
1,4-diol. Monosilylation with TBS-Cl by McDougal’s protocol10 affor-
ded the monosilylated compound 6 in a 92% yield. Metal-enzyme
combined DKR11 of compound 6 with CAL-B (Candida antartica li-
pase) and Ru-based racemization catalyst (DKR catalyst) in the pres-
ence of isopropenyl acetate afforded acetate 7 in an 88% yield
(ee = 97%; determined by chiral HPLC of the corresponding benzoate
derivative; Chiralcel OJ-H). Deprotection of the acetate functionality
with K2CO3–MeOH afforded (R)-6, which was subsequently pro-
tected as its TBDPS ether by treatment with imidazole and TBDPS-
Cl to afford compound 8 in an 86% yield (in two steps). Selective
deprotection of TBS group in 8 was achieved by treatment with PPTS
in methanol yielded alcohol 9 (85% yield). Oxidation of compound 9
with DMP furnished the aldehyde 10 in a 91% yield. Vinylmagne-
sium bromide addition of aldehyde 10 at À78 °C afforded alcohol
11 as inseparable diastereomeric mixtures in an 82% yield. Oxida-
tion of the alcohol functionality under Swern condition12 afforded
the ketone 12 in a 90% yield. Asymmetric ketone reduction with
Noyori’s BINAL-H reagent13 (M-binapthol and LiAlH4, attack from
the Si face of the ketone occurs) afforded alcohol 13 in an 85% yield,
which on protection with EOM-Cl (ethoxy methyl chloride)14 and
DIPEA (diisopropyl ethyl amine) afforded compound 14 in an 87%
yield. Compound 14 on cross metathesis (CM) with acrolein in the
presence of Hoveyda–Grubbs metathesis catalyst15 (HG-II,
5 mol %) afforded the unsaturated aldehyde 15 in a 92% yield (exclu-
sively E isomer). Wittig olefination of 15 with methyltriphenylphos-
phonium iodide in the presence of LHMDS afforded conjugated
olefin 3 in an 80% yield. Deprotection of TBDPS group in compound
3 is achieved by TBAF to afford compound 16 in an 84% yield. Com-
pound 16 on treatment with acryloyl chloride in the presence of DI-
PEA afforded the RCM precursor acrylic ester 2 in an 80% yield. Ring
closing metathesis reaction of compound 2 with G-II catalyst16 in
refluxing DCM afforded compound 17 as a major product in a 62%
yield. Finally deprotection of EOM group is achieved with 2 M HCl
in THF to afford stagonolide-E (1, yield = 88%; overall yield = 9.9%
from 1,4-pentanediol; Scheme 2). The spectral data (1H and 13C
NMRvalue) of our synthesized stagonolide-E matchesperfectly with
the natural stagonolide-E.
In conclusion an efficient asymmetric synthesis of the target
molecule stagonolide-E has been accomplished in a linear way.
The main highlights of our synthetic strategy involves application
ME-DKR reaction, stereoselective reduction of carbonyl functional-
ity with Noyori’s BINAL-H reagent system, cross metathesis reac-
tion with Hoveyda–Grubbs catalyst and finally RCM reaction
with Grubbs second generation catalyst afforded the target mole-
cule (overall yield = 9.9%).
Acknowledgment
We are thankful to CSIR (New Delhi, India; Grant No: 01-2109/
07/EMR-II) for the financial support. One of the authors (T.D.) is
thankful to CSIR for senior research fellowship.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.11.059.
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