First stereoselective total synthesis and reconfirmation of absolute structure of nonenolide (?)-stagonolide D

Article abstract of DOI:10.1016/j.tetlet.2016.12.042

The first stereoselective total synthesis of nonenolide (?)-stagonolide D has been accomplished. Midland Alpine borane reduction to install hydroxyl group at C4, Henbest epoxidation to introduce epoxide stereoselectively between C7 and C8, Yamaguchi ester

Full text of DOI:10.1016/j.tetlet.2016.12.042

Accepted Manuscript
First stereoselective total synthesis and reconfirmation of absolute structure of
nonenolide (-)-stagonolide D
A. Sravanth Kumar, K. Praneeth, P. Srihari, J.S. Yadav
PII:
S0040-4039(16)31687-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.042
TETL 48454
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
23 November 2016
17 December 2016
Please cite this article as: Sravanth Kumar, A., Praneeth, K., Srihari, P., Yadav, J.S., First stereoselective total
synthesis and reconfirmation of absolute structure of nonenolide (-)-stagonolide D, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.12.042
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Graphical Abstract
.
First stereoselective total synthesis and
reconfirmation of absolute structure of
nonenolide (-)-stagonolide D
Leave this area blank for abstract info.
A. Sravanth Kumar, K. Praneeth, P. Srihari, J. S. Yadav

1
Tetrahedron Letters
First stereoselective total synthesis and reconfirmation of absolute structure of
nonenolide (-)-stagonolide D
A. Sravanth Kumara,b†, K. Praneethb†, P. Sriharib, J. S. Yadava,b,
aAcademy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2-Rafi Marg, New Delhi 110001, India.
bDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first stereoselective total synthesis of nonenolide (-)-stagonolide D has been accomplished.
Midland Alpine borane reduction to install hydroxyl group at C4, Henbest epoxidation to
introduce epoxide stereoselectively between C7-C8, Yamaguchi esterification and Olefin
metathesis reaction are the key steps involved in the total synthesis.
Available online
Keywords:
macrolides
Yamaguchi esterification
epoxidation
stereoselective reduction
phytotoxic
———
†: Both authors contributed equally to this work.
 Corresponding author. . Tel.: +91 40 27191815; fax: +91 40 27160512; e-mail: srihari@iict.res.in.
 Corresponding author. . Tel.: +91 40 27191895; fax: +91 40 27160512; e-mail: yadavpub@gmail.com.

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1. Introduction
During the last decade, there has been significant interest for the
10-membered macrolides due to their impressive biological
properties.1 The scarcity of the natural products coupled with
complexity provided by them attracts a notable challenge for
synthetic chemists. In 2007, a new nonenolide stagonolide A was
isolated from fungus Stagonospora Cirsii,2 a pathogen of Cirsium
arvense that causes necrotic lesions on leaves and found to
display herbicidal activity. In 2008, Evidente et al reported the
isolation of five new nonenolides, which have been named as
stagonolide B-F respectively from fungus Stagonospora cirsii.3
These compounds were found to display strong inhibitory
activity on root growth in seedlings of C. Arvense and some other
Asteraceae species. Stagonolide F was found to display
antibacterial, antifungal and cytotoxic properties.4 Stagonolides
have an allylic system in the ring, a double bond with trans
geometry, and an alkyl group at C9 position. Our own interest in
this class of molecules in the synthetic perspective made us to
accomplish the total synthesis of stagonolide A, B and G in a
concise manner.5 In continuation to our work on the total
synthesis of macrolides,6 we have targeted stagonolide D,
structurally unique among others with an epoxy appendage at C7
and C8 for the total synthesis. Though couple of groups has
already taken initiatives in accomplishing the total synthesis of
natural stagonolide D, either the data of the final product was in
disagreement with the natural product data or the efforts ended
up in the structural revision of the product.7 This feature has also
prompted us to take up the initiative for the total synthesis of
natural product stagonolide D, and reconfirmation of the absolute
structure.
Scheme 1.Retrosynthetic analysis of stagonolide D (7)
The synthesis of acid fragment 9 commenced from the readily
available R-glycidol 11, which was converted to the
corresponding ,-unsaturated ester 14 through oxidation to
aldehyde with BAIB, TEMPO followed by 2C-Wittig reaction
with methyl-2-(triphenylphosphoranylidene)acetate in an overall
yield of 85% yield.8 Double bond reduction was smoothly
achieved with phenylsilane in the presence of [CuH(PPh3)]6 as
catalyst to afford 15 in 90% yield.9 Compound 15 was subjected
to an epoxide ring opening reaction with TMSI and n-BuLi under
Corey-Chaykovsky conditions to yield alcohol 16.10 The allylic
alcohol 16 was protected as the corresponding silyl ether 17 with
TBSCl and imidazole and subsequently the ester functionality
was hydrolyzed to acid 9 with of LiOH in 94% yield.11
Scheme 2 Reagents and conditions: (a) (i) BAIB/TEMPO,
CH2Cl2,
0
oC–rt,
1
h
and, (ii) methyl 2-
(triphenylphosphoranylidene)acetate, rt, 3 h, 85% over two
o
steps; (b) [CuHP(PPh3)]6, PhSiH3, THF, 0 C–rt , 2 h, 90%;
o
(c) TMSI, n-BuLi, THF, -20 C–rt, 3 h, 82%. (d) TBSCl,
o
imidazole, CH2Cl2, 0 C–rt, 3 h, 95%; (e) LiOH, THF:H2O
(3:1), 4 h, 94%.
The other key fragment alcohol 10 was synthesized from
commercially available propargyl alcohol 13 which was
protected as the corresponding benzyl ether. Treatment of
acetaldehyde with lithium acetylide (generated in situ by
treating O-benzylated propargyl alcohol with lithium
diisopropylamide, LDA) afforded alcohol 18 in 88% yield.12
PCC oxidation of 18 in CH2Cl2 resulted in ynone 19 in 91%
yield. The carbonyl functionality in 19 was subjected to chiral
reduction employing R-alpine borane to afford chiral alcohol
20 in 88% yield with >80% ee.13 Compound 20 upon
hydrogenation14 reaction under Lindlars conditions afforded
cis–alkene 12 which was subjected to diastereoselective
alcohol directed epoxidation (Henbest epoxidation) reaction
with mCPBA to afford mixture of easily separable
diastereomers in 9:1 ratio.15 The hydroxyl group in 21 (major
compound) was protected as the corresponding TBS ether 22
and treated with Pd/C (10 mol%) in EtOAc to obtain
Figure 1. Structures of stagonolides A-F.
Our retrosynthetic analysis of stagonolide D is based on the
convergent approach starting from acid 9 and alcohol 10, which
are coupled through an esterification reaction to yield the α, ω-
diene 8. The diolefin 8 can be subjected to RCM reaction to
provide the 10-membered skeleton that, on desilylation provides
the target molecule stagonolide D (Scheme 1). While the acid 9
can be synthesized from readily available R-glycidol 11, the
epoxy alcohol 10 can be accessible from allyl alcohol 12,
which in turn can be easily synthesized from commercially
available propargylic alcohol 13 in a five-step sequence.

3
debenzylated alcohol 23. The alcohol 23 upon oxidation
followed by one carbon Wittig olefination reaction with
PPh3CH3Br and KOtBu yielded 24 in 78% yield over two
steps. Treatment of 24 with HF.Py in THF afforded 10 in 95%
yield.
Scheme 4: Reagents and conditions: (a) 2,4,6-
o
Trichlorobenzoyl chloride, Et3N, DMAP, THF, toluene, 0 C,
8 h, 80%; (b) Grubbs' 2nd generation catalyst, CH2Cl2, reflux,
o
24 h, 60% (E/Z = 85:15) ; (c) HF-Py., THF, 0 C – rt, 4 h,
95%.
In conclusion, the first total synthesis of stagonolide D has
been achieved in 8 shortest steps with an overall yield of
21.2% from glycidol or in 13 longest linear steps with an
overall yield of 10.7% starting from propargylic alcohol. The
key reactions involved in the strategy were Midland alpine
borane reduction, Henbest epoxidation and Grubbs
cyclization. Application of this strategy for preparing other
analogues towards investigation for biological activity is
under progress.
Acknowledgements
Scheme 3. Reagents and conditions: (a) Benzyl bromide,
NaH, THF, 0 oC–rt, 6 h, 98%; (b) LDA, CH3CHO, THF, 0 oC,
6 h, 88%; (c) PCC, Celite, CH2Cl2, rt, 4 h, 91%; (d) Alpine
ASK and KP thank CSIR, New Delhi for fellowship. The
authors thank CSIR, New Delhi for funding in the form of XII
Five Year Plan project ORIGIN under budget head CSC-0108.
JSY thank CSIR, New Delhi for Bhatnagar fellowship.
o
borane® (0.5M, THF, 2 equiv.), THF, 0 C, 1 h, 88%; (e)
o
Pd/BaSO4/quinoline, EtOAc, 0 C, 20 h, 82%; (f) mCPBA,
CH2Cl2, 0 oC–rt, 12 h, 74%; (g) TBSCl, imidazole, CH2Cl2, 0
oC–rt, 3 h, 96%; (h) Pd/C, EtOAc, 4 h, 95% (i) (i) DMP,
o
CH2Cl2 , 0 C–rt, 3 h and (ii) PPh3CH3Br, KOtBu, THF, -10
References and Notes
o
oC, 2 h, 78% over two steps; (j) HF-Py., THF, 0 C–rt, 4 h,
95%.
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With the two key intermediates acid 9 and alcohol 10 in
hand, we proceeded further for coupling them together under
Yamaguchi conditions to provide ester 8, the precursor for
RCM reaction in 80% yield.16 The diolefin 8 was subjected to
meathesis reaction using Grubbs’ 2nd generation catalyst17 in
CH2Cl2 under reflux condition to afford the inseparable
mixture of diastereoisomers (E/Z = 85:15) in 60% yield.
Finally, exposure of 25 to HF.Py followed by coloumn
chromatography provided stagonolide D in 95% yield. E-
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1
geometry of the product was confirmed by the H NMR
analysis, where in the coupling constant for olefinic proton
was found to be JH5, H6 = 17 Hz. In the 1H NMR spectra of
the synthesized product, the signals corresponding to the
minor conformer were also observed, however, the chemical
shifts of 13C NMR spectra were indistinguishable.7b The
chemical shifts and coupling constants of major
conformational isomer was in good agreement with that of the
data of natural product.3a, 18 The specific rotation of synthetic
stagonolide [-79.7 (c 0.2, CHCl3)] was in good agreement
with that of the naturally occurring stagonolide D {Ref.3a
[−82.0 (c 0.2, CHCl3)]}, thus conforming the abosolute
structure as 7 for the natural stagonolide D.
6.
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4
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25
25
18. Analytical data of 7: [α]D -79.7 (c 0.2, CHCl3); {Lit.3a [α]D
=
=
−82 (c 0.51, CHCl3)}; IR max: 3435, 1730, 1643, 1090 cm-1; 1H
NMR (500MHz, CDCl3): δ 5.66 (dd, J = 17.0, 4.9 Hz, 1H), 5.54
(dd, J = 16.3, 8.4 Hz, 1H), 5.35 (dq, J = 6.7, 2.6 Hz, 1H), 4.15
(ddd, J = 8.4, 6.7, 4.3 Hz, 1H), 3.66 (dd, J = 5.0, 4.0 Hz, 1H), 3.06
(dd, J = 4.3, 2.8 Hz, 1H), 2.30 (ddd, J = 13.8,7.8, 2.7 Hz, 1H),
2.13 (dd, J = 13.1, 11.6 Hz, 1H), 2.06 (dd, J = 14.3, 1.6 Hz, 1H),
2.02 (ddd, J = 13.7, 11.0, 4.3 Hz, 1H), 1.39 (d, J = 6.7 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 173.5, 134.1, 128.2, 75.2, 65.7,
58.2, 55.4, 35.0, 31.2, 16.2.; HRMS (m/z) calcd for C10H14O4Na
[M+Na]+ 215.1043 found 215.1040.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at doi:.

5
Highlights
Justification for publication
This manuscript provides the first total synthesis of
stagonolide D, a unique compound in the family of
stagonolides with an epoxide moiety.
Earlier attempts for the total synthesis of this
molecule (stagonolide D) resulted in product whose
data was in disagreement with the data of the
natural product or ended up with the revision of the
structure.
The strategy followed by us is a convergent
approach utilizing coupling (an esterification
reaction) and ring closing metathesis reaction to get
the basic 10-membered scaffold.
Midland Alpine borane reduction and Henbest
epoxidation reactions have been employed as other
key reactions in the total synthesis to get the chiral
centers.
The total synthesis was achieved in 8 shortest steps
starting from known compound R-glycidol.
By maneuvering the reagents, the other isomers can
be easily synthesized and the synthesis is
practically amenable for large scale reactions.