Total synthesis of (–)-cephalosporolide D

Article abstract of DOI:10.1080/14786419.2021.1896509

In this communication, a concise and efficient synthetic route for the synthesis of (–)-Cephalosporolide D in enantioselective way has been described. In this synthesis, Mitsunobu esterification and Ring Closing Metathesis (RCM) for macrocyclic ring formation have been applied as key steps.

Full text of DOI:10.1080/14786419.2021.1896509

Natural Product Research
Formerly Natural Product Letters
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Total synthesis of (–)-cephalosporolide D
Chiranjeevi Kalavakuntla, Vijaya Babu Kummari & Jhillu Singh Yadav
To cite this article: Chiranjeevi Kalavakuntla, Vijaya Babu Kummari & Jhillu Singh
Yadav (2021): Total synthesis of (–)-cephalosporolide D, Natural Product Research, DOI:
10.1080/14786419.2021.1896509
To link to this article: https://doi.org/10.1080/14786419.2021.1896509
View supplementary material
Published online: 15 Mar 2021.
Submit your article to this journal
Article views: 72
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=gnpl20

NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1896509
SHORT COMMUNICATION
Total synthesis of (–)-cephalosporolide D
Chiranjeevi Kalavakuntlaa, Vijaya Babu Kummaria and Jhillu Singh Yadava,b
aCentre for Semiochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India;
bSchool of Science, Indrashil University, Ahmedabad, India
ABSTRACT
ARTICLE HISTORY
Received 12 June 2020
Accepted 22 February 2021
In this communication, a concise and efficient synthetic route for
the synthesis of (–)-Cephalosporolide D in enantioselective way
has been described. In this synthesis, Mitsunobu esterification and
Ring Closing Metathesis (RCM) for macrocyclic ring formation
have been applied as key steps.
KEYWORDS
(–)-Cephalosporolide D;
Barbier allylation;
Mitsunobu esterification;
Ring Closing
Metathesis (RCM)
1. Introduction
The molecules containing medium-sized ring systems have attracted considerable
attention from synthetic, as well as bioorganic chemists, because of their interesting
structures and important biological activities (Celmer 1971; Keller-Schierlein 1973;
Boeckman et al. 1974; Omura and Nakagawa 1975).
Cephalosporolides (Ackland et al. 1985; Farooq et al. 1995; Li et al. 2007) have
become highly attractive target molecules for the synthesis due to their biological pro-
files and structural features. Among them (–)-cephalosporolide D (Figure 1) is an eight-
membered ring lactone isolated from fermentation fungus, Cephalosporium aphidicola
ACC 3490 (Ackland et al. 1985). The absolute configuration of 1 was determined as
(4 R,8S) by a combination of spectroscopic, chemical and X-ray analyses.
The first synthesis of (–)-cephalosporolide D (1) and the determination of its relative
and absolute stereochemistry was developed by Shiina et al. (2000). To date several
synthesis of 1 have been reported (Shiina et al. 1998; Buszek et al. 2001; Shiina 2004;
CONTACT Jhillu Singh Yadav
yadavpub@gmail.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2021.1896509.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
C. KALAVAKUNTLA ET AL.
Figure 1. Structure of (ꢁ) Cephalosporolide D.
Reddy et al. 2010; Sabitha et al. 2011; Harkala et al. 2014; Murthy et al. 2014;
Sreenivasa Murthy et al. 2014; Umanadh et al. 2015; Alluraiah et al. 2016; Halle and
Fernandes 2016). Due to its interesting structural pattern and impressive bio activity,
we have synthesized 1 with an alternative approach, which we would like to
report here.
1.1. Retrosynthesis
The retrosynthetic analysis of the target molecules (1) is depicted in Scheme 1, reveals
that target molecule 1 can be obtained from bis-olefin 2, which on RCM protocol
would give the macrolide ring structure. Bis-olefin 2, in turn, could be realized by
esterification of acid segment 3 with alcohol segment 4. Acid 3 and alcohol 4 could
be synthesized from PMB ether 5, wherein 5 could be envisaged from known alde-
hyde 6.
2. Results and discussion
The total synthesis of 1 was initiated with the known chiral aldehyde 6 as illustrated
in Scheme 2. Accordingly, 6 (Bradshaw et al. 1990) on zinc mediated Barbier allylation
with allyl bromide and magnesium in THF at 0 ꢀC for 6 h provided carbinols 7a and 7b
as a separable mixture of syn and anti in 1:9 ratio in 79% yield. Treatment of alcohol
7b with PMB-Br and sodium hydride in dry THF at room temperature for 6 h gave
PMB ether 5 in 88% yield. Treatment of PMB ether with periodic acid followed by
reduction of the resulting aldehyde with NaBH4 in MeOH at 0 ꢀC for 6 h gave the alco-
hol 8 in 84% yield over two steps. The alcohol 8 was tosylated using p-TsCl in the
presence of Et3N in CH2Cl2 to furnish Tosylate 8a, which on subsequent treatment
with LiAlH4 in THF at 0 ꢀC for 12 h under nitrogen atmosphere gave 9 in 77% yield
over two steps. Deprotection of PMB ether in 9 with DDQ in aq. CH2Cl2 gave alcohol
segment 4 in 85% yield.
On the other hand, PMB ether 5 was subjected to oxidation with RuCl3/NaIO4 in
CCl4/MeCN/H2O to furnish acid 10 in 82% yield. Next, the resulting acid 10 was con-
verted to methyl ester 11 using dimethyl sulfate in acetone at reflux temperature for
4 h in 87% yield. Deprotection of acetonide moiety in ester 11 with 60% Acetic acid at
room temperature for 6 h furnished the diol 12 in 79% yield. The resulting diol 12 on
treatment with Ph3P, imidazole and I2 at room temperature for four hours gave olefin
13 in 76% yield. Ester group in 9 on subsequent hydrolysis (LiOH in THF:MeOH:H2O-
3:1:1) afforded acid 3 in 88% yield.
Having both the acid 3 and alcohol 4 in the hand, we next focused on its coupling
towards the synthesis of (ꢁ)-cephalosporolide D. Accordingly, the esterification reac-
tion of 3 with acid 4 was carried out under Mitsunobu esterification (DEAD, Ph3P,

NATURAL PRODUCT RESEARCH
3
Scheme 1. Retro synthesis of (ꢁ) Cephalosporolide D.
Scheme 2. Synthesis of (ꢁ) Cephalosporolide D. Reagents and conditions: (a) Allyl bromide, Zn,
o
THF, 0 C, 6 h; (b) PMBBr, NaH, THF, 0 ꢀC to rt, 6 h; (c) i) H5IO6, Et2O, rt, 8 h; ii) NaBH4, MeOH, 0 ꢀC
ꢀ
to rt, 6 h; (d) ) i) TꢀsCl, Et3N, DMAP, CH2Cl2, 0 ꢀC to rt 2 h; ii) LiAlH4, dry THF, 0 C to rt, 12 h; (e)
DDQ, aq. CH2Cl2, 0 C to rt, 1 h. (f) RuCl3, NaIO4, CCl4/MeCN/H2O 2:2:3, 4 h; (g) DMS, Acetone, reflux,
4 h; (h) 60% aq. acetic acid, rt, 12 h; (i) Ph3P, imidazole, I2, CH2Cl2, 3 h; (j) LiOH, THF:MeOH:H2O
ꢀ
(3:1:1), rt, 4 h; (k) (i) 4, DEAD, Ph3P toluene, 0 C to r.t., 12 h; (l) Grubb’s second generation catalyst,
CH2Cl2, reflux, 6 h; (m) H2, Pd/C, MeOH, rt, 12 h.
toluene) (Mitsunobu 1981; Swamy et al. 2009) to furnish the diene 2 in 73% yield.
Then diene 2 was subjected to the RCM reaction using G-II (Scholl et al. 1999; Love
et al. 2003) (10 mol %) in anhydrous CH2Cl2 at reflux temperature yielded eight-mem-
bered ring 14 in 66% yield. Finally, reduction of double bond followed by deprotec-
tion of p-methoxy benzyl (PMB) group in compound 14 was achieved in single step
using Pd/C, H2 in EtOAc to afford target compound 1 in 81% yield. The analytical data
of our synthetic compound 1 was in good agreement with the reported data (Shiina

4
C. KALAVAKUNTLA ET AL.
et al. 2000). Thus, we accomplished the total synthesis of cephalosporolide in an enan-
tioselective way.
3. Conclusion
We have developed a concise and divergent and convergent approach as compound
5 is utilised in divergent fashion to make 3 and 4, later 3 and 4 are coupled to get 2
and finally target molecule 1. The overall yield is 3.37% and total no. of steps are 13.
The present strategy involves Barbier allylation, Mitsunobu esterification and ring-clos-
ing metathesis as the key steps.
Acknowledgements
The authors are thankful to CSIR-Indian Institute of Chemical Technology, Hyderabad and CSIR,
New Delhi for constant encouragement in providing laboratory facilities and analytical data.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
Ackland MJ, Hanson JR, Hitchcock PB, Ratcliffe AH. 1985. Structures of the cephalosporolides
B–F, a group of C10 lactones from Cephalosporium aphidicola. J Chem Soc Perkin Trans. 1:
843–847.
Alluraiah G, Sreenivasulu R, Sadanandam P, Anitha K, Raju RR. 2016. A concise stereoselective
total synthesis of (-)-cephalosporolide D. Monatsh Chem. 147(2):451–455.
Boeckman RK, Fayos J, Clardy J. 1974. Letter: A revised structure of vermiculine. A novel macro-
lide dilactone antibiotic from Penicillium vermiculatum. J Am Chem Soc. 96(18):5954–5956.
Bradshaw JS, Huszthy P, McDaniel CW, Zhu CY, Dalley N, K, Izatt RM. 1990. Enantiomeric recogni-
tion of organic ammonium salts by chiral dialkyl-, dialkenyl-, and tetramethyl-substituted pyri-
dino-18-crown-6 and tetramethyl-substituted bispyridino-18-crown-6 ligands: comparison of
temperature-dependent proton NMR and empirical force field techniques. J Org Chem. 55:
3129–3137.
Buszek KR, Jeong Y, Sato N, Still PC, Muino PL, Ghosh I. 2001. Facile synthesis of saturated eight
membered ring lactones. Synth Commun. 31(11):1781–1791.
Celmer WD. 1971. Stereochemical problems in macrolide antibiotics. Pure Appl Chem. 28(4):
413–453.
Farooq A, Gordon J, Hanson JR, Takahashi JA. 1995. Two C10 lactones from Cephalosporium aphi-
dicola. Phytochemistry. 38(2):557–558.
Halle MB, Fernandes RA. 2016. Total synthesis of marine natural products: cephalosporolides.
Asian J Org Chem. 5(7):839–854.
Harkala KJ, Eppakayala L, Maringanti TC. 2014. Stereoselective synthesis of (-) cephalosporolide
D. Eur J Chem. 5(1):127–132.
Keller-Schierlein W. 1973. Chemie der makrolide antibiotics. Fortschr Chem Org Naturst. 30:
313–460.
Li X, Yao Y, Zheng Y, Sattler I, Lin W. 2007. Cephalosporolides H and I, two novel lactones from
a marine-derived fungus, Penicillium sp. Arch Pharm Res. 30(7):812–881.
Love JA, Sanford MS, Day MW, Grubbs RH. 2003. Synthesis, structure, and activity of enhanced
initiators for olefin metathesis. J Am Chem Soc. 125(33):10103–10109.

NATURAL PRODUCT RESEARCH
5
Mitsunobu O. 1981. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis
and transformation of natural products. Synthesis. 1981(01):1–28.
Murthy IS, Sreenivasulu R, Alluraiah G, Raju RR. 2014. An alternative stereoselective total synthe-
sis of (þ)-cephalosporolide D. LOC. 11(5):327–332.
Omura S, Nakagawa A. 1975. Chemical and biological studies on 16-membered macrolide antibi-
otics. J Antibiot (Tokyo). 28(6):401–433.
Reddy GV, Kumar RSC, Sreedhar E, Babu KS, Rao JM. 2010. Stereoselective synthesis (þ)-cephalo-
sporolide D. Tetrahedron Lett. 51(13):1723–1726.
Sabitha G, Reddy TR, Ramesh M, Srinivas C, Yadav JS. 2011. Synthesis of (ꢁ)-cephalosporolide D
using an iterative acetylene–epoxide coupling strategy. BCSJ. 84(2):229–231.
Scholl M, Ding S, Lee CW, Grubbs RH. 1999. Synthesis and activity of a new generation of ruthe-
nium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-
ylidene ligands. Org Lett. 1(6):953–956.
Shiina I. 2004. An effective method for the synthesis of carboxylic esters and lactones using sub-
stituted benzoic anhydrides with Lewis acid catalysts. Tetrahedron. 60(7):1587–1599.
Shiina I, Fujisawa H, Ishii T, Fukuda H, Mukaiyama T. 1998. Determination of relative and abso-
lute stereochemistry of cephalosporolide D and its enantioselective total synthesis. Chem
Lett. 27(8):831–832.
Shiina I, Fujisawa H, Ishii T, Fukuda Y. 2000. Stereoselective total synthesis of cephalosporolide
D. Heterocycles. 52(3):1105–1123.
Sreenivasa Murthy I, Sreenivasulu R, Alluraiah G, Raju R. 2014. An alternative stereoselective total
synthesis of (þ)-cephalosporolide D. LOC. 11(5):327–332.
Swamy KC, Kumar NN, Balaraman E, Kumar KV. 2009. Mitsunobu and related reactions: advances
and applications. Chem Rev. 109(6):2551–2651.
Umanadh Y, Omprakash G, Srinivasareddy N. 2015. A concise stereoselective total synthesis of
(–)-cephalosporolide D. LOC. 12(6):424–428.