Stereoselective synthesis of the C21-C29 fragment of (+)-Sorangicin A employing iodocyclization reactions

Article abstract of DOI:10.1016/j.tetlet.2015.09.037

A stereoselective synthesis of the C21-C29 fragment of (+)-Sorangicin A has been described following our recently developed iodine-catalyzed tandem isomerization followed by C-O and C-C bond formation for the construction of trans-2,6-disubstituted dihydr

Full text of DOI:10.1016/j.tetlet.2015.09.037

Tetrahedron Letters 56 (2015) 5930–5932
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the C21–C29 fragment of (+)-Sorangicin A
employing iodocyclization reactions
⇑
Debendra K. Mohapatra , Shivalal Banoth, Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Academy of Scientific and Innovative Research, New Delhi 110001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C21–C29 fragment of (+)-Sorangicin A has been described following our
recently developed iodine-catalyzed tandem isomerization followed by C–O and C–C bond formation for
the construction of trans-2,6-disubstituted dihydropyran as the key step. In this Letter, the problem of
installing the C25 asymmetric center has been sorted out by utilizing an iodolactonization strategy.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 26 August 2015
Revised 11 September 2015
Accepted 13 September 2015
Available online 14 September 2015
Keywords:
Natural products
Iodocyclization
trans-2,6-Disubstituted dihydropyran
Isomerization
Asymmetric a-aminoxylation of aldehyde
Introduction
groups, with only total synthesis from Smith and co-workers9
and a formal synthesis from Crimmins and co-workers.10 As part
Antibiotics have been used to fight against infectious disease
caused by bacteria and other microbes. Antibacterial chemother-
apy has been a leading cause for the dramatic rise of average life
expectancy. However, in a world of ever-increasing antibiotic
resistance, the discovery and development of new, potent antibi-
otics are of utmost importance. The secondary metabolite (+)-Sor-
angicin A (1) was isolated by Höfle and co-worker1 in 1985 from
the gliding myxobacteria Sporangium cellulosum. This shows
extraordinary antibiotic activity against a broad panel of both
Gram-positive (MIC value of average 10 ng/mL) and Gram-negative
of our ongoing research on total synthesis of complex natural prod-
ucts11 following our own developed protocol of tandem isomeriza-
tion followed by C–O and C–C bond formation reaction leading to
trans-2,6-disubstituted dihydropyran, we have recently reported
the synthesis of C28–C37 fragment of Sorangicin A.12
In continuation of our effort toward the total synthesis of
Sorangicin A, herein, we describe our successful attempt on the
synthesis of the C21–C29 fragment and installation of the C25
hydroxyl by employing iodocyclization and base-induced isomer-
ization strategy.
bacteria (MIC value of average 10 l
g/mL).2 The mechanism of
action was subsequently determined to entail inhibition of RNA
polymerase in both Escherichia coli and Staphylococcus aureus with-
out affecting the eukaryotic cells.2 In addition, Sorangicin A is
active in vitro against several cancer cell lines.3 The structure of
Sorangicin A contains 31-membered macrocyclic lactone with
C1–C8 carboxylic acid side Chain and 15 stereogenic centers, and
was secured by X-ray crystallographic techniques. Owing to its
potent antibiotic activity and architectural complexity, the stereos-
elective total synthesis of Sorangicin A (1) has attracted consider-
able interest from a number of groups including pioneering
studies from Morken,4 Scinzer,5 Lee,6 Yadav,7 and Hong8 research
Results and discussion
The retrosynthetic route to C21–C29 fragment 2 of (+)-Sorangi-
cin A is presented in Scheme 1. For the stereoselective introduction
of the C22 hydroxyl group, we planned to perform an organocat-
alytic
a
-carbonyl oxidation using MacMillan’s protocol13 to the
aldehyde which would be obtained from compound 5 by following
Jin’s oxidative strategy.14 The functionalized pyran 5 could be
formed by 6-exo trig iodolactonization reaction of the correspond-
ing acid 6. The required precursor 7 in turn would be synthesized
from d-hydroxy
a,b-unsaturated aldehyde 8, which in turn could
be accessed from commercially available 1,3-propanediol (9).
Synthesis of trans-2,6-disubstituted-3,4-dihydropyran 7 began
with 1,3-propane diol 9 as detailed in (Scheme 2). Accordingly by
⇑
Corresponding author. Tel.: +91 40 2719 3128; fax: +91 40 2716 0512.
E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).
http://dx.doi.org/10.1016/j.tetlet.2015.09.037
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

D. K. Mohapatra et al. / Tetrahedron Letters 56 (2015) 5930–5932
5931
OPMB
DDQ, CH2Cl2, H2O
0 oC, 2 h, 85%
3
6
O
O
3
8
4
2
7
Me
O
OH
O
O
4
3
O
13
7
2
9
O
O
I2, KI, NaHCO3
O
1) DMP, 0 oC to rt, 2 h
6
5
H
H
O
OH
1
5
O
OH
HO
H2O, rt, 12 h
82%
2
1
2) NaClO2, NaH2PO4
2-methyl-2-butene
HO
HO
1
6
0
oC-rt, 82%
Sorangicin A
1
OTBS
OH
O
O
O
O
n-Bu3SnH, AIBN
O
I
Me
O
O
toluene, reflux,
30 min, 87%
HO
O
OEt
BnO
O
H
H
O
O
OH
OTBDPS
2
3
4
14
15
COOH
OH
Scheme 3. Synthesis of compound 15.
O
O
O
OH
O
OEt
With good quantities of acid 6 in hand, we performed the key
iodolactonization reaction using our previous reported reaction
conditions11e for the installation of the hydroxyl functionality at
C25 of 1. Iodolactonization of 6 with molecular iodine in the
presence of KI in aqueous NaHCO3 solution proceeded via a 6-exo
trig manner to furnish the desired iodo-lactone 14 as a single
diastereomeric product in 82% yield. Deiodination was achieved
smoothly by treatment of 14 with tri-n-butyltinhydride and in
the presence of catalytic amount of AIBN in toluene under reflux
condition to obtain 15 in 87% yield.22
The direct transformation of the lactone 15 under basic condi-
tion (sodium ethoxide in ethanol) yielded a complex mixture con-
taining a traceable amount of the hydroxy ester 5. Similarly, the
basic hydrolysis condition (LiOH in THF) was unfruitful to produce
the corresponding hydroxy acid. Therefore, the lactone 15 was first
converted into hydroxy aldehyde. The controlled reduction of 15
with DIBAL-H at ꢀ78 °C afforded the required aldehyde, which
on oxidation (Pinnick condition) and esterification (EtOH in
BF3ꢁOEt2) smoothly afforded the hydroxy ethyl ester 5 (46% over
3 steps). The stereochemistry of the ester 5 was assumed to be
the trans geometry at C23 and C27 positions by 2D-NMR analysis,
wherein the NOESY experiment for 5 displayed NOE interactions
for the C25 proton and C27 proton and did not show any interac-
tions for the C23 and C27 protons (d 3.99 and 3.76 ppm).23 The
resulting secondary alcohol 5 was protected as its TBS–ether using
TBSOTf and 2,6-lutidine in anhydrous CH2Cl2 to obtain 16 in 86%
yield (Scheme 4).
5
6
O
OH
HO
OH
H
OPMB
O
7
OPMB
1,3 propane diol (9)
8
Scheme 1. Retrosynthetic analysis of Sorangicin A.
following an earlier reported sequence,15 epoxy alcohol 10 was
25
synthesized in 92% ee [
a
]
ꢀ24.7 (c 1.7, CHCl3). The resulting
D
epoxy alcohol 10 was oxidized to the corresponding aldehyde by
Swern oxidation16 followed by a two carbon Wittig homologation
with PPh3 = CHCO2Et giving an
c,d-epoxy acrylate 11 as a single
isomer in 91% yield (over 2 steps). Following Miyashita’s protocol
of stereospecific methylation reaction, the epoxy ester 11 was
converted to homoallylic alcohol 12 in the presence of trimethyl
aluminum (TMA).17 The
to the d-hydroxy
a
,b-unsaturated ester 12 was converted
,b-unsaturated aldehyde 8 in 95% yield by
a
DIBAL-H reduction of the ester functionality followed by a subse-
quent selective oxidation of the primary hydroxyl group with
TEMPO/BAIB.18 A novel allylation strategy was performed with 8
by using our previous reaction condition (1.5 equiv of
allyltrimethylsilane and 0.25 equiv of iodine).12 Wherein the
allylation occurred stereoselectively, giving rise to the trans-3-
methyl-3,6-dihydropyran 7 as the sole product in 96% yield.
The oxidative removal of p-methoxybenzyl group of 7 with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) afforded primary alco-
hol 13 in 85% yield.19 Oxidation of primary alcohol 13 with
Dess–Martin periodinane20 gave the corresponding aldehyde,
which on further successive oxidation under Pinnick conditions21
furnished acid 6 in 82% yield over two steps (Scheme 3).
With the required skeleton present in 16, we sought to perform
epimerization of the stereochemistry at C27 via a retro-oxy-
Michael/oxy-Michael
process.
Thus,
the
base
induced
1) DIBAL-H, CH2Cl2
-78 oC, 30 min
OH
O
O
25
O
2) NaClO2, NaH2PO4
2-methyl-2-butene
0 oC-rt, 64%
3) Ethanol, BF3.OEt2
46% (over 3 steps)
23
27
1) DMSO, (COCl)2
22
78 oC, Et3N, CH2Cl2
O
O
OEt
ref. 15
HO
OPMB
EtOOC
HO
OH
O
15
5
2) Ph3P = CHCOOEt
Toluene,55 oC
9
10
91% over 2 steps.
OTBS
t-BuOK, THF, 0 o
C
OH
TBSOTf, 2,6-lutidine
CH2Cl2, 0 o
25
O
(CH3)3Al, H2O
OPMB
EtOOC
23
27
OPMB
22
15 min, 83%
C
- 40 oC, 3 h
92%
O
11
O
OEt
30 min, 86%
12
16
1) NaIO4, 2,6-lutidine
OsO4, dioxane:H2O
(3:1), rt, 3 h,
OTBS
OTBS
1) DIBAL-H, CH2Cl2
0 oC, 45 min, 90%
O
OH OPMB
OPMB
SiMe3
I2, 45 min, 96%
25
O
O
23
27
H
O
22
2) PhNO, L-proline
NaBH4, CuSO4.5H2O
MeOH, 12 h, 61%
2) TEMPO, BAIB
CH2Cl2, rt, 3 h
95%
O
OEt
HO
O
OEt
8
7
OH
2
17
Scheme 2. Synthesis of trans-3-methyl-3,6-dihydropyran 7.
Scheme 4. Synthesis of C21–C29 fragment of Sorangicin A.

5932
D. K. Mohapatra et al. / Tetrahedron Letters 56 (2015) 5930–5932
epimerization using t-BuOK was carried out at 0 °C. Gratifyingly,
the first attempt for the epimerization proceeded smoothly in a
stereoselective manner, favoring the desired C27 b-epimer 17 in
83% yield.24 The stereochemical configuration of 17 was confirmed
by NOESY measurement, which revealed strong NOE cross-peaks
between C23 and C27 protons (d 4.36 and 3.86–3.77).23 Suggesting
that the H-23 and H-27 are diaxially oriented with respect to each
other. One-step conversion of terminal olefin to aldehyde was
achieved by following Jin’s modified oxidative protocol in 83%
yield.14 For the installation of C22 b-hydroxyl functionality, we
References and notes
1. Jansen, R.; Wray, V.; Irschik, H.; Reichenbach, H.; Höfle, G. Tetrahedron Lett.
1985, 26, 6031.
2. Irschik, H.; Jansen, R.; Gerth, K.; Hӧfle, G.; Reichenbach, H. J. Antibiot. 1987, 40,
7.
3. Stavbers, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487.
4. Danek, S. C. The total synthesis of natural products and evaluating new assay
techniques for identification of novel catalysts using combinatorial chemistry
(Ph.D. Thesis); Morken Group, University of North Carolina at Chapel Hill, 2003.
5. Schinzer, D.; Schulz, C.; Krug, O. Synlett 2004, 2689.
6. Park, S. H.; Lee, H. W. Korean Bull. Chem. Soc. 2008, 29, 1661.
7. Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Tetrahedron 2009, 65, 6304.
8. Lee, K.; Kim, H.; Hong, J. Eur. J. Org. Chem. 2012, 1025.
adopted the direct catalytic asymmetric
a-aminoxylation of the
9. (a) Smith, A. B., III; Fox, R. J. Org. Lett. 2004, 6, 1477; (b) Smith, A. B., III; Fox, R. J.;
Vanecko, J. A. Org. Lett. 2005, 7, 3099; (c) Smith, A. B., III; Dong, S. Org. Lett.
2009, 1099, 11; (d) Smith, A. B., III; Dong, S.; Brenneman, J. B.; Fox, R. J. J. Am.
Chem. Soc. 2009, 131, 12109.
10. (a) Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223; (b) Crimmins, M. T.;
Haley, M. W.; O’Bryan, E. A. Org. Lett. 2011, 13, 4712.
resulting aldehyde by using enantiopure proline as the catalyst
and nitrosobenzene as the oxygen source and in situ reduction
gave the 1,2-diol 2 via one pot three steps procedure in 61% yield
(dr = 95:5, separated by column chromatography).13 The integrity
of the product was confirmed by its spectral and analytical data.
11. (a) Reddy, D. S.; Padhi, B. K.; Mohapatra, D. K. J. Org. Chem. 2015, 80, 1365–
1374; (b) Mohapatra, D. K.; Krishnarao, P. S.; Bhimireddy, E.; Yadav, J. S.
Synthesis 2014, 46, 1639; (c) Pradhan, T. R.; Das, P. P.; Mohapatra, D. K. Synthesis
2014, 46, 1177; (d) Mohapatra, D. K.; Maity, S.; Rao, T. S.; Yadav, J. S.; Sridhar, B.
Eur. J. Org. Chem. 2013, 2859; (e) Mohapatra, D. K.; Bhimireddy, E.; Krishnarao,
P. S.; Das, P. P.; Yadav, J. S. Org. Lett. 2011, 13, 744; (f) Yadav, J. S.; Pattanayak,
M. R.; Das, P. P.; Mohapatra, D. K. Org. Lett. 2011, 13, 1710.
12. Mohapatra, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S. Chem. Eur. J. 2010, 16,
2072.
13. (a) Northrup, Alan B.; MacMillan, David W. C. J. Am. Chem. Soc. 2002, 124, 6798–
6799; (b) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett.
2003, 44, 8293; (c) Zhong, G. A. Angew. Chem., Int. Ed. 2003, 42, 4247.
14. Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217.
15. Oka, T.; Murai, A. Tetrahedron 1998, 54, 1; (b) Gao, Y.; Hanson, R. M.; Ktunder, J.
M.; Ko, S. Y.; Masamune, H.; Sharpless, B. J. Am. Chem. Soc. 1987, 109, 5765; (c)
Zhou, B.; Li, Y. Tetrahedron Lett. 2012, 53, 502.
Conclusions
In conclusion, synthesis of the C21–C29 fragment of (+)-Soran-
gicin A was achieved following our recently developed protocol for
the highly stereoselective synthesis of trans-2,6-disubstituted
dihydropyran through tandem isomerization followed by C–O
and C–C bond formation as the key steps. The other important
reactions include iodolactonization, base-induced isomerization,
and a proline-catalyzed asymmetric a-aminoxylation of aldehyde.
In addition, the problem of fixing the C25 asymmetric center by
following iodolactonization strategy has been sorted out.
16. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651; (b) Mancuso, A. J.; Huang,
S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480.
17. Pfaltz, A.; Mattenberger, A. Angew. Chem., Int. Ed. Engl. 1982, 21, 71.
18. Mico, A. D.; Maragrita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974.
Acknowledgments
The authors thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial support as Part of
XII Five Year Plan Programme under title ORIGIN (CSC-0108). D.
K.M. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, India, for a research grant (INSA Young Scientist Award
Scheme). S.B. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, for financial assistance in the
form of research fellowship.
19. Horita, K.; Yoshioka, T.; Tanaka, T.; Yoikawa, Y.; Yonemitsu, O. Tetrahedron
1986, 42, 3021.
20. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277; (b) Dess, D. B.;
Martin, J. C. J. Org. Chem. 1983, 48, 4155.
21. (a) Ballakrishna, S. B.; Childers, W. E.; Pinnick, H. W., Jr. Tetrahedron 1981, 37,
2091; (b) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
22. Schultz, A. G.; Kirincich, S. J. J. Org. Chem. 1996, 61, 5626.
23. See ESIy for NOESY analysis.
24. Yakambram, P.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47, 3781.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
037.