Formal synthesis of 14-membered unsymmetrical bis-macrolactone, (?)-colletodiol

Article abstract of DOI:10.1016/j.tetlet.2017.11.001

Formal synthesis of 14-membered unsymmetrical bis-macrolactone, (?)-colletodiol was accomplished from homopropargylic alcohol derivative. Building of the two different hydroxy acid fragments from the same intermediate of homoallylic alcohol was particular

Full text of DOI:10.1016/j.tetlet.2017.11.001

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formal synthesis of 14-membered unsymmetrical bis-macrolactone,
(ꢀ)-colletodiol
Navnath B. Khomane a,b, Rayala Naveen Kumar a, Prakash R. Mali a,b, Prashishkumar K. Shirsat a,b
,
H.M. Meshram a,
⇑
a Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b Academy of Scientific and Innovative Research, New Delhi 110 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Formal synthesis of 14-membered unsymmetrical bis-macrolactone, (ꢀ)-colletodiol was accomplished
from homopropargylic alcohol derivative. Building of the two different hydroxy acid fragments from
the same intermediate of homoallylic alcohol was particularly advantageous. A Sharpless asymmetric
dihydroxylation, homologation of carbon chain, a Pinnick oxidation, and a macrolactonization to assem-
ble the 14-membered macrodiolide were the additional salient features of this convergent synthesis.
Ó 2017 Elsevier Ltd. All rights reserved.
Received 1 October 2017
Revised 30 October 2017
Accepted 1 November 2017
Available online xxxx
Keywords:
Colletodiol
Macrolactonization
Sharpless dihydroxylation
Horner-Wadsworth-Emmons olefination
Pinnik oxidation
Introduction
and also significant activities against Bacillus subtilis, and the fungi
Trichophyton mentagrophytes.6 Colletodiol 4, itself known to inhibit
Naturally occurring 14 membered bis-lactones, which are iso-
lated from various fungi and marine sponges, are a family of sec-
ondary metabolites with prominent biological activity.1 The 14-
membered macrodiolide, colletodiol 4 is a heterodimer with two
different subunits. In 1966, initial colletodiol 4 was isolated from
a metabolic product of Colletotrichum capsici by J.F. Grove and his
co-workers.2 Seebach and Mitsunobu established the absolute,
and relative stereochemistry of colletodiol 4.3 In 1968 along with
colletodiol, MacMillan group isolated another three 14 membered
bis-lactone, colletol 2, colletoallol 1 and colletoketol 3 from plant
colletotricum capsici.4 While Ronald and Gurusiddhai isolated a
macrocyclic bis-lactone, Grahamimycine A1 (not shown) from
cytospora which exhibits potential antibiotic activity against many
pathogenic microorganism, blue green algae, and various species of
bacteria while colletodiol 4 possess mild antibiotic activity.5 Previ-
ous studies shown that the mechanism of action of this antibiotic
agent was differs from the known agents which indicated that this
was new class of antibiotic agent. 4-Keto-clonostachydiol 6 from
the same family of colletodiol, exhibits various biological proper-
the replication of influenza A virus WSN/H1N1 by reducing the
activity of viral RNA polymerase.7 These new class of macrodiolide
antibiotics in which bis-lactone ring is made up of two unsymmet-
rical subunits (Fig. 1). Due to their limited availability from biolog-
ical sources, these bis-macrolides have not been fully tested for
their biological activity. In many natural products, reversal of
stereochemistry at one centre or its enantiomer is more active than
8
natural isolated products.
Due to their promising biological activity and distinctive struc-
tural features, these metabolites became attractive synthetic tar-
gets for the synthetic chemists. However, synthetic approaches in
this area have not been entirely explored. There have been several
syntheses of colletol 2,9 grahamimycine A 3.10 But there are few
report for the synthesis of (+)-colletodiol 4.3,11 Synthesis of gra-
hamimycin A 3 was easily achieved from the selective oxidation
of hydroxyl group at C11 of colletodiol
4 in a single step
(Scheme 1).11f
As a part of our interest on the synthesis of antibiotic agent12 and
total synthesis of bioactive natural products.13 Herein we report the
stereoselective formal synthesis of unnatural (ꢀ)-colletodiol 5 by a
convergent synthetic strategy involving enantioselective prochiral
ketone reduction, Sharpless asymmetric dihydroxylation, and
intramolecular macrolactonization. Synthesis of other bioactive
ties, such as potent cytotoxicity against P388 cells (IC50 0.55 lM)
⇑
Corresponding author.
E-mail
addresses:
hmmeshram@yahoo.com,
meshram@iict.res.in
(H.M. Meshram).
https://doi.org/10.1016/j.tetlet.2017.11.001
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Khomane N.B., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.001

2
N.B. Khomane et al. / Tetrahedron Letters xxx (2017) xxx–xxx
O
O
O
O
O
O
OPMB
O
O
O
O
O
O
O
HO
HO
HO
HO
HO
O
O
O
O
O
O
O
2
Colletol ( )
3
O
O
colletoallol (1)
Grahamimycin A ( )/
7
Colletoketol
5
mirror image
O
O
O
O
O
O
6
11
12
HO
HO
HO
HO
O
HO
O
O
3
OPMB
2
O
O
O
O
O
O
O
1
OH
6
(+)-Collatodiol (4)
enantiomers
4-Keto-clonostachydiol ( )
5
(-)-Colletodiol ( )
OPMB
(revised structure)
8
Acid fragment ( )
TBSO
+
Fig. 1. The colletodiols and grahamimycins are the family of unsymmetrical
macrodiolide.
10
OH
TBSO
O
Alcohol ragment (9)
O
Scheme 2. Retrosynthesis of (ꢀ)-colletodiol 5.
O
O
ref. 11f
O
HO
HO
Tempo, p-TsOH
NaH, PMB-Br, THF,
OH
OPMB
0 °C-rt, 12h ,83%
TBSO
TBSO
HO
10
11
O
O
O
O
TBAF, 0 °C-rt,
2h, 94%,
Red-Al, THF, 0 °C-rt,
4h, 91%
OPMB
HO
3
Grahamimycin A ( )/
4
(+)-Collatodiol ( )
Colletoketol
12
Scheme 1. Previous reports for the selective oxidation of colletodiol
grahamimycin A 3.
4 to
DDQ, CH2Cl2:H2O,
rt, 3h, 62%,
OH
OPMB
TBSO
Alcohol fragment (9)
R
Common intermediate (14)
natural products from macrodiolide family are under investigation
and results will be reported in due course.
13
R = OH (
)
TBSCl, Imidazole,
CH2Cl2 ,0 °C, 2h, 93%
Retrosynthesis of (ꢀ)-colletodiol 5 as illustrated in Scheme 2,
we designed the synthesis of targeted molecule based on a conver-
gent approach wherein (ꢀ)-colletodiol 5 could be obtained from
intramolecular macrolactonization of acid which derived from
aldehyde 7. The aldehyde 7 could be achieved from esterification
of acid fragment 8 and alcohol fragment 9. The acid fragment 8
was envisioned to come from homopropargylic alcohol 10 by suc-
cessive implementation of Red-Al reduction, Sharpless dihydroxy-
lation, homologation, and oxidation protocols. Alcohol fragment 9
could be obtained easily through simple procedures from 10.
Homopropargylic alcohol 10 was envisaged as being accessible
from commercially available propylene oxide (Scheme 3).
14
R = OTBS (
)
Scheme 3. Synthesis of alcohol fragment 9.
removal of TBS group with TBAF to provide a primary alcohol 12
in 94% yield. Hydroxy group of alcohol 10 was made free from sillyl
protection as require for the transformation of alkyne to trans
alkene using Red-Al. Thus, the controlled reduction of homo-
propargylic alcohol 12 to its homoallylic alcohol 13 was carried
out using sodium bis-(2-methoxyethoxy)-aluminumhydride
(Red-Al).15 Then the corresponding homoallylic alcohol 13 was
protected as TBS by treating with tert-butyldimethylsilyl chloride
(TBSCl) and imidazole to obtain protected alcohol 14 in 93% yield.
This protected homoallylic alcohol 14 was served as common
intermediate for building two fragments for the final macrolac-
tonization to achieve the title macrodiolide, (ꢀ)-colletodiol 5. The
alcohol fragment 9 was accomplished in single step by the depro-
tection of p-methoxy benzyl (PMB) of alcohol 14 in 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) condition.16
Result and discussion
Our synthesis commenced with the preparation of enantiopure
homopropargylic alcohol 11. Initially, regioselective epoxide ring
opening of (ꢀ)-propylene oxide was carried out by anion of silyl
propynol in the presence of BF.3OEt2 at -78 °C to obtain alcohol
11 in quantitative yield.14 Subsequently, p-methoxy benzyl
(PMB) of secondary alcohol 11 resulted in the corresponding
PMB-protected alcohol 10 which was directly subjected to the
Now our efforts directed to construct the coupling partner, acid
fragment 8 from a common intermediate 14. The requisite stereo-
chemistry at C11 and C12 in final bis-macrolactone was achieved
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N.B. Khomane et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
through a Sharpless asymmetric dihydroxylation of olefin 14
aldehyde 18 in 79% yield (two steps). The aldehyde 18 on a Hor-
ner-Wadsworth-Emmons (HWE) homologation with triethyl phos-
(Scheme 4).17 Therefore, the asymmetric dihydroxylation was
achieved from olefin 14 by treating with AD-mix-
a
in t-BuOH
phonoacetate afforded a,b-unsaturated ethyl ester 19 favouring
and H2O afforded diol 15 in 89% yield with 84% dr as determined
by 1HNMR. The resulting diol 15 was protected as acetonide using
2,2-dimethoxy propane and camphorsulfonic acid (CSA) to obtain
protected diol 16 in 90% yield. TBS deprotection of protected diol
16 with TBAF at 0 °C in THF and the subsequent oxidation using
SO3. Py and DMSO in CH2Cl2 at 0 °C furnished the corresponding
the desired E-isomer in 82% yield.18 Finally the acid fragment 8
was achieved by ester hydrolysis of ethyl ester 19 using LiOH in
68% yield.
Finally to complete the formal synthesis of (ꢀ)-colletodiol 5, we
focused on the macrolactonization of the two fragments, acid 8 and
alcohol 9. Intermolecular esterification of acid 8 and alcohol 9 was
Ad-mix-α, t-BuOH:H2O,
methanesulfonamide,
OPMB
OH OPMB
2,2 dimethoxypropane,
CSA, acetone, 2h, 90%
0 °C, 24 h, 89%
TBSO
TBSO
OH
14
Common intermediate (
)
15
SO3.Py, DMSO, NEt3
CH2Cl2, 0 °C, 4h, 79%
triethyl phosphonoacetate
NaH, THF, 0 °C, 2h, 82%
O
OPMB
O
OPMB
O
O
O
R
18
R = OTBS 16
R = OH 17
TBAF, 0 °C-rt
O
O
OPMB
O
OPMB
O
LiOH, THF:H2O,
2h, 68%
O
O
O
OH
Acid fragment ( )
8
19
Scheme 4. Synthesis of acid fragment (8).
OPMB
O
O
OPMB
O
O
OH
DCC, DMAP,
CH2Cl2, rt, 8h, 69%
+
TBSO
O
OH
O
O
R
Alcohol fragment (9)
8
Acid fragment ( )
20
R = OTBS
TBAF,0 °C-rt, 2h
21
R = OH
R
OPMB
O
O
DMSO, (CO)Cl2, CH2Cl2,
Et3N, -78 °C, 2h,
NaClO2,NaH2PO4,
O
O
2-methyl-2-butene,
84% over two steps
t-BuOH:H2O, 12h, 58%
OH
O
O
O
O
O
O
7
22
R = OPMB
DDQ, CH2Cl2:H2O,
rt, 3h.
23
R = OH
O
O
O
O
dipyridyl disulfide, PPh3,
ref. 11f
HO
O
O
xylene, 18h, 54%
Dowex/MeOH
Corey-Nicolaou
lactonization
HO
O
O
O
O
5
(-)-Colletodiol
24
Scheme 5. Formal synthesis of (ꢀ)-colletodiol.
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4
N.B. Khomane et al. / Tetrahedron Letters xxx (2017) xxx–xxx
(c) Krohn K, Farooq U, Flörke U, et al. Eur J Org Chem. 2007;3206;
(d) Kastanias MA, Tokousbalides MC. Pest Manage. Sci.. 2000;56:227;
(e) Kastanias MA, Tokousbalides MC. J Agric Food Chem. 2005;53:5943.
2. Grove JF, Speake RN, Ward G. J Chem Soc C. 1966;230.
3. Schnurrenberger P, Hungerbiihler E, Seebach D. Liebigs Ann Chem. 1987;733.
4. MacMillan J, Pryce RJ. Tetrahedron Lett. 1968;5497.
5. Gurusiddaiah S, Ronald RC. Antimicrob Agents Chemother. 1981;153.
6. (a) Lang G, Mitova MI, Ellis G, et al. J Nat Prod. 2006;69:621;
(b) Han J, Su Y, Jiang T, et al. J Org Chem. 2009;74:3930.
7. Lai W, Wang S, Ye X. Wei Sheng Wu Xue Bao. 2013;53:1334.
8. (a) Kanduluru AK, Banerjee P, Beutler JA, Fuchs PL. J Org Chem. 2013;78:9085;
(b) Chhabra N, Aseri1 ML, Padmanabhan D. Int J App Basic Med Res. 2013;
(c) Hutf AJ, O’Grady J. J Antimicrob Chemother. 1996;37:7.
9. (a) Yadav JS, Reddy NM, reddy PAN. Synthesis. 2010;1473;
(b) Yadav JS, Reddy PMK, Gupta MK. Synthesis. 2007;3639;
(c) BouzBouz S, Cossy J. Tetrahedron Lett. 2006;47:901;
(d) Sharma GVM, Rao AVSR, Murthy VS. Tetrahedron Lett. 1995;36:4117;
(e) Shimizu I, Omura T. Chem Lett. 1993;1759;
carried out using N,N’-Dicyclohexylcarbodiimide (DCC) and cat-
alytic amount of 4-dimethylaminopyridine (DMAP) in CH2Cl2
afforded coupled product 20 in 69% yield.19 TBS deprotection of
coupled product 20 was executed using TBAF, and followed by
Swern oxidation furnished the aldehyde 7 in 84% yield (two steps).
This aldehyde 7 was converted into corresponding acid 22 using
sodium chlorite (NaClO2) under mild acidic conditions, a well-
known Pinnick oxidation protocol.20 After screening with several
reagents for the p-methoxy benzyl (PMB) deprotection,16 finally
we optimised the reaction conditions by treating with DDQ (1
equiv.) in CH2Cl2:H2O for 3 h at room temperature to afford the
macrocyclization precursor 23. Corey-Nicolaou intramolecular
macrolactonization21 was carried out on the precursor 23 using
2,20-dipyridyldisulfide (DPS) and triphenylphosphine to accom-
plish macrodiolide 24 in 54% yield (Scheme 5). 1H NMR and 13C
NMR spectral data for the protected bis-macrolactone 24 was in
complete agreement with the reported data by G. A. O’Doherty
group11f and keck.11a The deprotection of acetonide could be
achieved using previously reported protocol of Dowex in MeOH
condition.11f Here we have successfully accomplished the formal
synthesis of (ꢀ)-colletodiol 5 in 13 steps with overall 3.2% yield.
(f) Keck GE, Murry JA. J Org Chem. 1991;56:6606.
10. (a) Kobayashi Y, Matsuumi M. J Org Chem. 2000;65:7221;
(b) Seidel W, Seebach D. Tetrahedron Lett. 1982;23:159;
(c) Ghiringhelli D. Tetrahedron Lett. 1983;24:287;
(d) Hillis LR, Ronald RC. J Org Chem. 1985;50:470;
(e) Bestmann H-J, Schobert R. Tetrahedron Lett. 1987;28:6587;
(f) Ohta K, Miyagawa O, Tsutsui H, Mitsunobu O. Bull Chem Soc Jpn.
1993;66:523.
11. (a) Keck GE, Boden EP, Wiley MR. J Org Chem. 1989;54:896;
(b) Ohta K, Mitsunobu O. Tetrahedron Lett. 1991;32:517;
(c) Tsutsui H, Mitsunobu O. Tetrahedron Lett. 1984;25:2159;
(d) Tsutsui H, Mitsunobu O. Tetrahedron Lett. 1984;25:2163;
(e) Ferrié L, Capdevielle P, Cossy J. Synlett. 1933;2005:12;
(f) Hunter TJ, O’Doherty GA. Org Lett. 2002;4:4447.
Conclusion
In conclusion we have developed convergent synthetic strategy
for the formal synthesis of (ꢀ)-Colletodiol initiated from propylene
oxide in a highly concise way with overall 3.2% yield. A Sharpless
asymmetric dihydroxylation, a Pinnick oxidation, and a Corey-
Nicolaou intramolecular macrolactonization was found to be effec-
tive in synthesis. The present strategy improved the existing syn-
theses by achieving the projected target in a convergent and
efficient manner. This synthetic route may useful for synthesis of
other similar natural products.
12. (a) Kumar RN, Kumar NS, Meshram HM. Synlett. 2017;28:1046;
(b) Kumar RN, Meshram HM. Tetrahedron. 2015;71:5669;
(c) Kumar NS, Kumar RN, Rao LC, et al. Synthesis. 2017;49:3171.
13. (a) Kumar RN, Meshram HM. Tetrahedron Lett. 2011;52:1003;
(b) Kumar NS, Kumar RN, Rao LC, Meshram HM. ChemistrySelect. 2016;1:5034;
(c) Ramesh P, Meshram HM. Tetrahedron. 2012;68:9289;
(d) Kumar RN, Meshram HM. Tetrahedron. 2017;73:5547;
(e) Kumar RN, Lee S. Steroids. 2017;118:68;
(f) Kumar RN, Lee S. Steroids. 2017;126:74;
(g) Meshram HM, Reddy BC, Prasad BRV, Goud PR, Kumar GS, Kumar RN. Synth
Commun. 2012;42:1669.
14. Haug T. T.; Kirsch, S. F. Org Biomol Chem. 2010;8:991.
15. (a) Bates RW, Diez-Martin D, Kerr WJ, Knight JG, Ley SV, Sakellaridis A.
Tetrahedron. 1990;46:4063;
(b) Watanabe T, Imaizumi T, Chinen T, et al. Org Lett. 2010;12:1040.
16. (a) Sharma GVM, Kumar K. R. Tetrahedron Asymmetry. 2004;15:2323;
(b) Shiozaki M, Arai M, Kobayashi Y, Kasuya A, Miyamoto S. J Org Chem.
1994;59:4450.
17. (a) Jacobsen EN, Marko I, Mungall WS, Schroeder G, Sharpless KB. J Am Chem
Soc. 1968;1988:110;
(b) Kolb HC, Van Nieuwenhze MS, Sharpless KB. Chem Rev. 1994;94:2483;
(c) Krishna PR, Prabhakar S. Tetrahedron Lett. 2013;54:3788.
18. (a) Wadsworth Jr WS, Emmons WD. J Am Chem Soc. 1961;83:1733;
(b) Wadsworth Jr WS, Emmons WD. Organic Syntheses. Coll.. 1973;5:547;
Acknowledgment
NBK, RNK, PRM, and PKS thank CSIR-UGC for the award of fel-
lowships. The authors thank CSIR, New Delhi, for financial support
as part of XII five year plan program under the title ORIGIN (CSC-
0108).
A. Supplementary data
(c) Mukai C, Moharram SM, Azukizawa S, Hanaoka M.
1997;62:8095.
19. Neises B, Steglich W. Angew Chem Int Ed. 1978;17:522.
20. (a) Bal BS, Childers Jr WE, Pinnick HW. Tetrahedron. 1981;37:2091;
(b) Kraus GA, Roth B. J Org Chem. 1980;45:4825.
J Org Chem.
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.11.001.
References
21. (a) Corey EJ, Nicolaou KC. J Am Chem Soc. 1974;96:5614;
(b) Nicolaou KC. Tetrahedron. 1977;33:683.
1. (a) Kind R, Zeeck A, Grabley S, Thiericke R, Zerlin M. J Nat Prod. 1996;59:539;
(b) Christner C, Kullertz G, Fischer G, et al. J Antibiot. 1998;51:368;
Please cite this article in press as: Khomane N.B., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.001