Synthesis of spiroketal fragment of ossamycin via Prins cyclization

Article abstract of DOI:10.1016/j.tetlet.2014.11.097

An asymmetric synthesis of spiroketal fragment of an antitumour antibiotic, ossamycin is described. Coupling of aldehyde and alkyne fragments followed by spiroketalization has afforded the spiroketal sub unit of ossamycin. Both the sub targets were constr

Full text of DOI:10.1016/j.tetlet.2014.11.097

Tetrahedron Letters 56 (2015) 365–367
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Synthesis of spiroketal fragment of ossamycin via Prins cyclization
⇑
J. S. Yadav , Md. Ataur Rahman, N. Mallikarjuna Reddy, A. R. Prasad
Academy of Scientific and Innovative Research (AcSIR), Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2014
Revised 14 November 2014
Accepted 21 November 2014
Available online 27 November 2014
An asymmetric synthesis of spiroketal fragment of an antitumour antibiotic, ossamycin is described.
Coupling of aldehyde and alkyne fragments followed by spiroketalization has afforded the spiroketal
sub unit of ossamycin. Both the sub targets were constructed via Prins cyclization.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Antitumour antibiotic
Prins cyclization
Reductive opening
Spiroketals
The 24-membered macrolide ossamycin is isolated from the
culture broth of Streptomyces sp.,1 in 1965. It is a member of such
macrolide antibiotics, as cytovaricin,2 oligomycins,3 A82548A4 and
rutamycins.5 Ossamycin has been proved to inhibit oxidative
phosphorylation by targeting the mitochondrial FOFl ATP synthase
and this is a typical mode of action. It has been considered a prom-
ising candidate for an effective antitumour agent from the survey
of recent biological screening of the natural products.6 Nishiyama
and co-workers have reported the studies on the synthesis of
ossamycin.7 In view of its biological significance the synthesis of
spiroketal moiety via Prins cyclization8 is investigated. As part
of our ongoing successful efforts in exploring Prins cyclization9
towards the total synthesis of biologically active natural products,
herein we report our accomplishment of stereoselective synthesis
of the spiroketal moiety via Prins cyclization and reductive
ring-opening sequence.
OH
OH
OH
O
HO
O
O
O
O
OH
OH
O
O
OH
Me2N
Figure 1. Structure of ossamycin.
stereogenic centres from pyranyl methanol 5 and 7, respectively
in a single operation by using Prins cyclization with high stereose-
lectivity (Scheme 1).
In our retrosynthetic analysis (Fig. 1), we envisaged that the
spiroketal moiety 2 could be derived from coupling of aldehyde 3
and alkyne 4 followed by spiroketalization. The fragments 3 and
4 were in turn to be obtained from pyranyl methanol 5 and 7,
respectively. Pyranyl methanol 5 and 7 could be easily constructed
via Prins cyclization, in analogy to our previous approaches9 from
known chiral homoallylic alcohols 6 and 8 whereas compounds 6
and 8 could be easily achieved by opening the chiral benzyl ether
protected glycidol. Jacobson catalyst could be used for the resolu-
tion of protected glycidol. The single stereogenic centre of homoal-
lylic alcohols 6 and 8 could be utilized to create four and three
The first requirement was the preparation of the aldehyde
fragment 3, which was conceived from homo allylic alcohol 6. Prins
cyclization between known homoallylic alcohol 6 and aldehyde 9
in the presence of TFA8,9 resulted in the trifluoroacetate of 5, which
on treatment with K2CO3 in MeOH gave tetrahydropyran diol 5 as
the only isolable diastereomer in 65% yield. The stereochemical
aspects of such Prins cyclization and structurally similar com-
pounds of 5 were discussed in detail previously.9 The primary
hydroxyl group of the diol 5 was tosylated by using 1.1 equiv of
tosyl chloride in the presence of TEA in CH2Cl2 produced the corre-
sponding primary tosylated compound 10, which on exposure to
NaI in refluxing acetone gave the corresponding iodide 11. The
reductive elimination of iodide 11 through Boord reaction condi-
tion with Zn in refluxing ethanol gave the key intermediate 12 with
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@gmail.com (J.S. Yadav).
http://dx.doi.org/10.1016/j.tetlet.2014.11.097
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

366
J. S. Yadav et al. / Tetrahedron Letters 56 (2015) 365–367
OH
O
OH
b
O
a
+
BnO
BnO
OH
8
O
7
HO
O
OBn
17
2
OTBS
OTBS
OTBS
O
O
d
OTBSOBn
c
TBDPSO
HO
Cl
BnO
e
O
O
O
O
3
4
18
19
20
OTBSOBn
OTBSOH
f
OH
O
OH
O
4
21
BnO
HO
HO
OBn
Scheme 3. Reagents and conditions: (a) TFA, CH2Cl2 then K2CO3, MeOH, r , 3 h, 65%;
(b) TBSOTf, 2,6 lutidine, CH2Cl2, 0 °C, 3 h, 96%; (c) Li/naphthalene, THF, À10 °C, 1 h,
92%; (d) CCl4, NaHCO3, reflux, 2 h, 86%; (e) n-BuLi, THF, À78 °C, 78%; (f) NaH, BnBr,
THF, 0 °C–rt, 88%.
7
5
BnO
OH
OH
8
6
gave compound 18 followed by removal of the benzyl group using
Li/naphthalene produced primary alcohol 19. Primary hydroxyl
pyranyl compound 19 was converted to chloro pyranyl compound
20 on treatment with triphenylphosphine (TPP) in CCl4, NaHCO3
reflux conditions in 86% yield.12 The corresponding alkyne 21
was obtained by the treatment of 20 with n-BuLi at À78 °C in
78% yield. The newly created secondary alcohol of 20 was
protected as its benzyl ether in the presence of NaH and BnBr in
THF to produce the alkyne fragment 4.
The union of the two sub targets 3 and 4 was established
through the acetylenic anion of 4 and the aldehyde functionality
of 3 using n-BuLi to generate the targeted carbon framework 22
as a diastereomeric mixture (Scheme 4). The newly created hydro-
xyl group was oxidized using Dess–Martin periodinane (DMP) in
CH2Cl2 to the compound 23. The saturation of the acetylenic
functionality of compound 23 was created using hydrogen with
Pd/BaSO4 in ethanol to produce saturated keto compound 24 in
96% yield. Compound 24 underwent deprotection of silyl groups
followed by spiroketalization using p-TSA in methanol to give the
corresponding spiroketal fragment 2 of antitumour metabolite,
Ossamycin in 72% yield.
Scheme 1. Retrosynthesis of spiroketal fragment of ossamycin.
required 1,3-anti diol system.10 Acetonide protection of 1,3-diol
using 2,2 DMP in CH2Cl2 produced compound 13 which on expo-
sure to ozonolysis followed by reduction with NaBH4 in MeOH
afforded primary alcohol 14 in 85% yield. Protection of primary
alcohol as its TBDPS ether using TBDPSCl and imidazole in CH2Cl2
followed by removal of the benzyl group using Li/naphthalene11
produced primary alcohol 16. Compound 16 when subjected to
oxidation using Dess–Martin periodinane afforded the aldehyde 3
(Scheme 2).
The synthesis of alkyne moiety 4 is described in Scheme 3. The
homoallylic alcohol 8 and propanal 17 to Prins cyclization in the
presence of TFA in CH2Cl2 followed by hydrolysis of the resulting
crude trifluoroacetate with K2CO3 in MeOH yielded tetrahydropy-
ran 7 in 65% yield. Protection of secondary hydroxyl functionality
of compound 7 as its TBS ether using TBSOTf 2,6 lutidine in CH2Cl2
OH
In summary, a stereoconvergent approach allowed us to com-
plete the spiroketal portion of the rather complex natural product,
a
O
OBn
OBn
HO
OH
HO
O
5
OBn
OH
6
9
OH
O
O
OTBS OBn
a
c
b
d
TBDPSO
TsO
I
O
O
10
O
11
OBn
3
4
O
O
O
OH
O
O
OH OH
OTBSOBn
b
c
TBDPSO
TBDPSO
e
f
OBn
OBn
22
13
12
O
O
OTBSOBn
OTBSOBn
O
O
O
O
h
g
TBDPSO
OBn
HO
OBn
23
14
15
O
O
O
d
O
O
O
O
TBDPSO
i
TBDPSO
OH
24
TBDPSO
O
OH
16
3
Scheme 2. Reagents and conditions: (a) TFA, CH2Cl2 then K2CO3, MeOH, rt, 3 h, 65%;
(b) TEA, p-TsCl, CH2Cl2, 0 °C–rt, 3 h, 95%; (c) NaI, acetone, reflux, 24 h, 94%; (d) Zn,
EtOH, NaHCO3, reflux, 2 h, 92%; (e) 2,2 DMP, p-TSA, CH2Cl2, 0 °C–rt, 3 h, 85%; (f) O3,
PPh3, CH2Cl2, then NaBH4, MeOH, 74%; (g) TBDPSCl, imidazole, CH2Cl2, 0 °C, 6 h,
86%; (h) Li/naphthalene, THF, À10 °C, 92%; (i) Dess–Martin periodinane (DMP),
CH2Cl2, 0 °C–rt, 3 h, 95%.
HO
O
OBn
O
2
Scheme 4. Reagents and conditions: (a) n-BuLi, THF, À78 °C, 2 h, 86%; (b) DMP,
CH2Cl2, 3 h, 84%; (c) Pd/BaSO4, H2, EtOAc, 96%; (d) p-TSA, MeOH, rt, 72%.

J. S. Yadav et al. / Tetrahedron Letters 56 (2015) 365–367
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N.M.R. thanks CSIR, New Delhi for the award of fellowship, J.S.Y.
thanks CSIR and DST, New Delhi for Bhatnagar and J.C. Bose Fellow-
ships, respectively.
Supplementary data
Supplementary data associated with this article can be found, in
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