Studies towards the total synthesis of Phostriecin

Article abstract of DOI:10.1016/j.tetlet.2017.12.068

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown's protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.

Full text of DOI:10.1016/j.tetlet.2017.12.068

Accepted Manuscript
Studies towards the total synthesis of Phostriecin
Gavireddy Chaithanya kumar, Katta Muralikrishna, Vavilapalli Satyanarayana,
Chintakrinda Suresh kumar, Jhillu Singh Yadav
PII:
S0040-4039(17)31599-X
https://doi.org/10.1016/j.tetlet.2017.12.068
TETL 49570
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
17 November 2017
19 December 2017
21 December 2017
Please cite this article as: kumar, G.C., Muralikrishna, K., Satyanarayana, V., kumar, C.S., Yadav, J.S., Studies
towards the total synthesis of Phostriecin, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.12.068
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Studies towards the total synthesis of
Phostriecin
Gavireddy Chaithanya kumar, Katta Muralikrishna, Vavilapalli Satyanarayana, Chintakrinda Suresh kumar,
Jhillu Singh Yadav*
Browns'
O
alkoxyallyboration
RCM
O
TBSO
OMOM
O
OTBS
OH
H
OTBS
HO
OH
OH
BnO
OMOM
Crimmins'Aldol

Tetrahedron Letters
1
Tetrahedron Letters
jour nal homepage: w ww.elsevier. com
Studies towards the total synthesis of Phostriecin
Gavireddy Chaithanya kumar, Katta Muralikrishna, Vavilapalli Satyanarayana, Chintakrinda Suresh kumar, Jhillu
Singh Yadav*
Centre for Semiochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Email: yadavpub@gmail.com; Fax: 91-40-27160512
ARTICLE INFO
ABSTRACT
Article history:
Received
A synthetic approach toward the phostriecin, an antitumor natural product is
described. The key features of the present synthesis are Wittig reaction, synthesis
of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM
for the creation of unsaturated lactone moiety of phostriecin.
Received in revised form
Accepted
Available online
Keywords:
Wittig reaction, alkoxyallylboration,
homoallylic alcohol, Ring-closing metathesis,
antitumor natural products.
2009 Elsevier Ltd. All rights reserved.
Phostriecin is a structurally unique phosphate ester produced
by Streptomyces roseiscleroticus No.L827-7 which was
isolated from a soil sample of Gujarat state in India.1 (Figure
1) Initially the natural product was represented as Sultriecin
and assigned as C-9 sulfate ester at the time of its isolation
and its structure was proposed without the precision of its
relative and absolute stereochemistry. Studies with original
compound confirmed that phostriecin, but not sultriecin is an
efficient and selective inhibitor of protein phosphatase 2A
(PP2A), which is responsible for its antitumor activity2.
Phostriecin also showed a broad spectrum of antifungal
activity in vitro and moderate in vivo cytotoxic activity
against human cell lines3a. Natural products structurally
3b
related
to phostriecin were Fostriecin, Cytostatin,
Leustroducsin and Phoslactomycin. From structural
perspective phostriecin contains an electrophilic unsaturated
lactone and the hydrophobic Z,Z,E-triene tail and contains a
4
central functionalized 1,3 diol. Recently, Boger et al
reported the first total synthesis of phostriecin (aka sultriecin)
and also established their relative, absolute configuration and
prepared a series of analogues5.
OH
OR OH
O
O
O
O
1.Phostriecin ,R = PO3HNa
OR OH
OH
OH
2.Fostriecin;R = PO3HNa
OR OH
O
O
3
.Cytostatin;R = PO3HNa
R
Et
OR OH
O
O
4.
Phospholine, R = H
5.Leustroducsin, H, R = OH
H2N
6.Phoslactomycins,R = OCOR
Figure 1: Structures of Phostriecin and related natural products

2
In continuation of our interest in the synthesis of antitumor
natural products, herein we report the synthesis of C1- C13
and C14 - C22 fragment of phostriecin. (For the synthesis of
the side chain C14 - C22 fragment see reference 16). Our
retro-synthetic strategy of 1 is illustrated in Scheme 1, in
which the key building block 7 would be transformed into 1
by reduction of alkyne triple bond and introduction of the
phosphate group. Compound 7 was in turn obtained from
compound 9 using ring-closing metathesis. Compound 9 can
be prepared from compound 11 by opting Brown’s
alkoxyallylboration strategy. Compound 13 could be accessed
from 1,3-propanediol using Criminns aldol reaction.
DMAP in CH2Cl2 at 0 oC for 2 h afforded the corresponding
ester 17 in good yield.9 Selective deprotection of primary TBS
ether group using a catalytic amount of CSA in CH2Cl2-
MeOH (9:1) mixture at -20 oC to gave the primary alcohol 18
in 76% yiled. (Scheme 3)
Oxidation of the resulting primary alcohol using DMP10 in
CH2Cl2 afforded aldehyde 19, which was purified and
subjected to next reaction directly. Addition of TMS protected
o
acetylene on aldehyde 19 in THF at -20 C provided 65:35
diastereomeric mixture of the secondary alcohols 9 and 9a
respectively in 90% yield and the resulting diastereomeric
mixture was separated by column chromatography.11 (Scheme
4)
Results and Discussion
1. DMP, CH2Cl2, NaHCO3 , rt, 2h, 80%,
Our synthesis began with the diol compound 13 by the
application of the Crimmin’s method to the known aldehyde
which in turn was prepared from 1,3-propane diol according
to a literature procedure.6 The diol was protected as its bis-
silyl ether using TBSOTf and 2,6-lutidine in CH2Cl2 at 0 oC to
get the bis silyl ether compound 14 in quantitative yield.
(Scheme 2)
2. (R)-CBS, THF, BH3.SMe2 ,rt, 2h, dr-95:5, 83%
O
O
TMS,
-78 oC
OTBS
OH
OTBS
OH
O
O
19
n-BuLi,
THF, -20 o
OMOM
TMS
OMOM
TMS
C
9a
9
90%
dr-6.5:3.5
1. CSA, DCM:MeOH
1. CSA, DCM:MeOH
2. 2,2-dimethoxypropane
PPTS, CH2Cl2, rt, 30 min
2. 2,2-dimethoxypropane
PPTS, CH2Cl2, rt, 30 min
OTBS
OH
TBSOTf,
2,6-lutidine
Li-Naphthalene
BnO
OTBS
BnO
OH
100.8, ppm
THF, rt to -20 oC
88%
99.5, ppm
CH2Cl2, 2 h
0 oC-rt, 92%
14
13
23.5ppm
O
27.6 ppm
29.8 ppm
19.1ppm
H3C CH3
O
H3C CH3
O
OTBS
OTBS
O
O
OTBS
O
O
O
O
1. IBX-DMSO
H
HO
OTBS
2. OHCCHPPh3
Benzene,
reflux, 76%
OMOM
TMS
OMOM
TMS
20a
20
11
15
Anti-1,3-diol acetonide
syn-1,3-diol acetonide
Scheme 4
Scheme 2
At this stage deprotection of benzyl ether was achieved using
o
Li and naphthalene in THF at -20 C to get the primary
Rychnovsky’s protocol was used for confirmation of the
stereochemistry at newly generated chiral center by 13C NMR
analysis.12 To achieve this separately little amount of both the
compounds 9 and 9a were subjected to TBS ether
deprotection using a catalytic amount of CSA in CH2Cl2 :
MeOH (9:1) mixture at -20 oC provided the secondary
alcohols in good yields. 1,3-diol protection as the acetonide in
alcohol 15 in 88% yiled. Oxidation of the resulting primary
alcohol using IBX: DMSO afforded aldehyde which was
subjected to two carbon Wittig reaction by treatment with
(triphenylphosphoranylidene)acetaldehyde in benzene under
reflux conditions to afford α,β-unsaturated aldehyde 11 in 76
% yield (Scheme 2).7
o
CH2Cl2 at 0 C using 2,2-dimethoxypropane and a catalytic
amount of CSA to get the corresponding isopropylidene
derivatives 20 and 20a in good yield. The geometry at the
newly created hydroxy center was established as anti for
compound 20 and syn for 20a based on the 13C NMR value
for the 1,3-diol acetonide carbons. In order to convert the
minor quantities of the undesired diastereomer to a required
diastereomer, we further proceeded with a two-step sequence.
Accordingly compound 9a was oxidized under DMP
conditions to provide the ketone, which was again reduced
with (R)-CBS catalyst to get the desired alcohol 9 in good
yield.13 (Scheme 4)
O
MOMCl,DIPEA
Hoveyda-Grubbs
TBSO
O
OMOM
CH2Cl2
12h, 0 oC-rt
85%
2 nd gen
9
Toluene, reflux
72 h, 66%
OMOM
TMS
O
21
Having prepared the key intermediate aldehyde compound 11
in hand we then investigated the synthesis of homoallylic
alcohol using Brown’s protocol8 (alkoxyallylboration).
Accordingly treatments of aldehyde using (+)-Ipc2BOMe as
the chiral-source produced chiral homoallylic alcohol 16 in
72% yield. Acrylolation of compound 16 using acryloyl
chloride in the presence of DIPEA and a catalytic amount of
O
TBAF,THF
O
TBSO
OMOM
O
TBSO
OMOM
-20 oC, 10 min
86%
OMOM
TMS
OMOM
22
7
Scheme 5

Tetrahedron Letters
3
8. (a) Yadav, J. S.; Palash Dutta,; Bogonda Ganganna,
Eedubilli Srinivas. Eur. J. Org. Chem. 2015, 6891–6899;
(b) Christopher M. Schneider,; Wei Li, Kriangsak
Khownium,; Gerald H,; Lushington,; Gunda I. Georg.
ChemMedChem. 2016, 11, 1600–1616.
9. J. Alberto Marco,; Jorge García-Pla,; Miguel Carda,; Juan
Murga,; Eva Falomir,; Chiara Trigili,; Sara Notararigo c,;
J. Fernando Díaz c,; Isabel Barasoain. European Journal of
Medicinal Chemistry. 2011, 46, 1630-1637.
10. D. B. Dess and J. C. Martin, J. Am. Chem. Soc. 1991, 113,
277–7287.
11. (a) Rui Fu, Jie Chen, Lu-Chuan Guo, Jian-Liang Ye, Yuan-
Ping Ruan, Pei-Qiang Huang, Org. Lett. 2009, 11,
5242-5245; (b) P. Sankara Rao,; P. Srihari. Org. Biomol.
Chem., 2016, 14, 9629–9638.
At this stage protection of the required secondary alcohol 9 as
its MOM ether was carried out using MOMCl, in the presence
o
of DIPEA in CH2Cl2 at 0 C to RT for 12 h, furnished the
MOM ether 21 in good yield. Having prepared the key
intermediate in hand we next turned our attention to RCM
reaction, accordingly the resulting MOM ether 21 was then
subjected to undergo ring-closing metathesis using Hoveyda-
Grubbs second generation catalyst in refluxing toluene lead to
the formation of the desired lactone 22 in 66% yield.14 Finally
deprotection of TMS group in lactone 22 using TBAF in THF
o
at -20 C for 10 min furnished the required alkyne 7 in 86%
yield.15 (Scheme 5)
12. (a) Rychnovsky, S. D.; Skalitxky, D. J. Tetrahedron
Letters. 1990, 31, 945-948; (b) D. A. Evans, D. L.
Rieger J. R. Gage, Tetrahedron Letters. 1990, 31,
7099–7100.
Conclusions
In conclusion we have achieved the pivotal C1 - C13 and C14
- C22 fragments of the antitumor natural product phostriecin.
The synthesis of an advanced intermediate 7 from compound
13 in 11 steps with 10% overall yield. The key steps involved
are Wittig reaction, Browns’ alkoxyallylboration, CBS
reduction and Rring-closing metathesis. Further research was
under progress for the completion of total synthesis of
phostriecin and will be reported in due course.
13. (a) K. A. Parker, M. W. Ledeboer, J. Org. Chem. 1996,
61, 3214-3217; (b) E. J. Corey, R. K. Bakshi, S. Shibata, J.
Am. Chem. Soc. 1987, 109, 5551-5553.
14. (a) S. Michaelis, S. Blechert, Org. Lett. 2005, 7, 5513-
5516; (b) Grubbs, R. H; Chang, S. Tetrahedron. 1998, 54,
4413–4450; (c) Schwab, P.; France, M. B.; Ziller, J. W.;
Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34,
2039–2041; (d) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J.
Am. Chem. Soc. 1996, 118, 100–110.
15. Cai, C.; Vasella, A.; Helv. Chem. Acta, 1995, 78, 732.
16. The side chain C14- C22 fragment 21 which in turn was
prepared from trans-2-Octenal in two steps according to a
literature procedure. (a) Chao Shu , Yong-Heng
Wang , Cang-Hai Shen , Peng-Peng Ruan , Xin Lu , Long-
Wu Ye. Organic Letters 2016 18 (13), 3254-3257. (b)
Corey, E. J.; Fuchs, P. L. Tetrahedron Letters 1972, 13,
3769–3772. (c) Rosenthal, M.; Li, L.;. Hernandez, J.J.;
Zhu, X.; Ivanov, D.A.; Mçller,M.; Chem. Eur. J. 2013, 19,
4300 – 4307
Acknowledgements
G.C.R., C.H.S.K. thanks Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for the award of
fellowship. VSN, KMK thanks UGC. JSY thanks CSIR and
DST, New Delhi for Bhatnagar and J. C. Bose Fellowships
respectively.
References and notes:
Br
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Hoshino, Y.; Sawada, Y.; Konishi, M.; Oki, T. J. Antibiot.
1992, 45, 1239-1249.
TPP,CBr4,
CH2Cl2, 0 oC-rt
NBS,Acetone
-20 oC, 82%
n-BuLi,-78 oC,
O
THF 78%
12
2. (a) Swingle, M.; Ni, L.; Honkanen, R. E. Methods Mol.
Biol. 2007, 365, 23. (b) Virshup, D. M.; Shenolikar, S.
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3. (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L.
Curr. Med.Chem. 2002, 9, 2005-2032. (b) For related
natural products see ref 4 and ref 5 and references cited
therin.
10
8
Supplementary Material: Experimental procedures, spectral
data, copies of 1H NMR and 13C NMR spectra available.
4. Burke, C. P.; Haq, N.; Boger, D. L. J. Am. Chem. Soc.
2010, 132, 2157-2159.
5. Burke,; C. P.; Swingle,; M.R.; Honkanen,; R.E.; Boger,;
D. L. J. Org. Chem. 2010, 75, 7505-7513.
6. The known diol compound 13 was readily prepared from
commercially available 1,3-propanediol as per the
literature procedure. (a) Chandrasekhar, S,; Sathish, K,;
Pavan Kumar Reddy, G; Prathama S. Mainkar.
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S; Eppa Gyanchander, Anand Kumar Mishra, Peddapuram
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5882.
OH
O
S
OH
BnO
N
BnO
OH
HO
OH
S
13
Ph
7. (a) Trost, B.M.; Weiss, A.H; Angew. Chem. Int. Ed. 2007,
46, 7664 –7666; (b) Birakishore, P.; Srinivas Reddy, D.;
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Highlights of The Phostriecin Synthesis
ꢀ
C1 - C13 fragment of the antitumor natural product phostriecin was
synthesized.
ꢀ
Synthesis of chiral homoallylic alcohol by using Brown’s protocol.
Creation of lactone moiety by using Hoveyda-Grubbs second generation
catalyst.
ꢀ
ꢀ
Key steps are Wittig reaction, Brown’s protocol, CBS reduction and RCM.
The advanced intermediate 7 was achieved in 11 steps with 10% overall
yield.
ꢀ