Stereoselective total synthesis of C2-symmetric natural products pyrenophorol and its derivatives

Article abstract of DOI:10.1080/14786419.2019.1577843

A stereoselective total synthesis of 16-membered C₂-symmetric macrodiolide Pyrenophorol, Tetrahydropyrenophorol and 4,4-diacetylpyrenophorol have been accomplished. The synthesis started from commercially available L-Aspartic acid and the key reactions involved are regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu dilactonization.

Full text of DOI:10.1080/14786419.2019.1577843

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Stereoselective total synthesis of C2-symmetric
natural products pyrenophorol and its derivatives
Siva Ganesh Narala, G. Nagalatha & A. Venkat Narsaiah
To cite this article: Siva Ganesh Narala, G. Nagalatha & A. Venkat Narsaiah (2019):
Stereoselective total synthesis of C2-symmetric natural products pyrenophorol and its derivatives,
Natural Product Research, DOI: 10.1080/14786419.2019.1577843
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1577843
Stereoselective total synthesis of C2-symmetric natural
products pyrenophorol and its derivatives
Siva Ganesh Narala, G. Nagalatha and A. Venkat Narsaiah
Organic Synthesis Laboratory, Fluoro-Agrochemicals Department, CSIR-Indian Institute of Chemical
Technology, Hyderabad, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 25 November 2018
Accepted 29 January 2019
A stereoselective total synthesis of 16-membered C2-symmetric
macrodiolide Pyrenophorol, Tetrahydropyrenophorol and 4,4-diac-
etylpyrenophorol have been accomplished. The synthesis started
from commercially available L-Aspartic acid and the key reactions
involved are regioselective epoxide opening, CBS reduction,
Pinnick oxidation and Mitsunobu dilactonization.
KEYWORDS
Macrodiolide; antimicrobiol
agent; CBS reduction;
Pinnick oxidation;
dilactonization
1. Introduction
Naturally occurring macrodiolides are showing interesting biological activities.
Structurally, these are broadly classified as homodimeric (Pyrenophorols,Vermiculine)
and heterodimeric (Elaiophylin) macrolides (Kis et al. 1969; Kastanias and
Tokousbalides 2005). Pyrenophorol and its derivatives are 16-membered macrocyclic
dilactones and arranged naturally head-to-tail connection of the two C8 hydroxy acid
subunits (Krohn et al. 2007; Zhang et al. 2008). Pyrenophorols are isolated from
Byssochlamys nivea, Pyrenophora avenae and Stemphylium radicinum cultures (Kastanias
and Tokousbalides 2000).
The broad spectrum of bioactivity and the unique structure has attracted the
synthetic chemists and led to its synthesis in different routes (Dommerholl et al. 1991;
CONTACT A. Venkat Narsaiah
vnakkirala2001@yahoo.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1577843.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

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S. G. NARALA ET AL.
Scheme 1. Retrosynthetic analysis
Machinaga and Kibayashi 1993; Amigoni and Le Floc’h 1997; Yadav et al. 2009; Oh
and Kang 2011; Chatterjee et al. 2014; Edukondalu et al. 2015; Risi et al. 2015;
Alluraiah et al. 2018; Ashok et al. 2018). As part of our regular research program in
synthesis of biologically active molecules (Narsaiah et al. 2015a, 2015b, 2016, 2018),
we have carry out the stereoselective total synthesis of Pyrenophorol and its deriva-
tives. The reported methods followed expensive protocols like Grubbs and AD-mix
and the resolution protocol involved the loss of one isomer. Our strategy was started
from commercially available starting materials and completed with good yield.
2. Results and discussion
As shown in the retrosynthetic analysis (Scheme 1), the target molecule has been
achieved from the monomer of compound 18, which obtained from stereoselective
reduction of keto compound 12, and which accomplished from compound 4.
The synthesis started from commercially available of (L)-Aspartic acid (2).
Brominative diazotisation of (L)-Aspartic acid using NaNO2 and KBr followed by reduc-
tion of dicarboxylic acid to diol (3) by using BH3DMS gave quantitative yield (Shibata
et al. 1986; Rabinson and Brimble 2007). Elimination of bromine, one pot intramolecu-
lar, base induced epoxide formation insitu, remaining primary alcohol protected as
benzyl ether using benzyl bromide NaH to furnish, (R)-epoxide (4) (Frick et al. 1992;
Naysmith and Brimble 2013). Regioselective epoxide opening with LiAlH4 gave second-
ary alcohol (5) exclusively (Kumar and Reddy 2012), which was protected as TBDPS
ether using TBDPS-Cl and TBAI afforded compound (6) 90% in yield. Reductive cleav-
age of benzyl ether selectively by lithium naphthalene at ꢀ40 ꢁC led to its primary
alcohol (7) in quantitative yield. Free alcohol group converted to tosyl group followed
by SN2 substitution with NaCN in presence of catalytic amount NaI in DMSO at 80 ꢁC
to furnish cyano compound (9) in 88% yield (Motozaki et al. 2005; Kadam and
Sudhakar 2015). Partial reduction of (9) with DIBAL-H at ꢀ78 ꢁC gave aldehyde
(Ishigami et al. 2006), which was subjected to nucleophilic addition with THP pro-
tected propargyl alcohol using n-BuLi at ꢀ78 ꢁC to afford compound (11) in 78% yield
(Dagmer and Philip 2010). The obtained secondary hydroxyl group was oxidized with
IBX in DMSO and DCM mixture (1:3) gave alkynone in (12) very good yields (Sabitha
et al. 2013) (Scheme 2).
Compound 12 was subjected to enantioselective reduction of keto group with bor-
ane dimethyl sulfide and a chiral ligand, Corey-Bakshi-Shibata ligand [(R)-methyl-oxaza-
borolidine], at ꢀ40 ꢁC in dry THF for 2 hr to afford compound (13) in very good yields
(Corey et al. 1987; Parker and Ledeboer 1996) with diastereoselecivity ratio of 92:8,
confirmed by 1H NMR and with optical rotation [a]D -16.79 (c ¼ 1, CHCl3). Thus
25
obtained chiral secondary alcohol was protected as benzyl ether in presence of NaH
and BnBr at 0 ꢁC to rt in dry THF to furnished compound (14) in 78% yield (Bulow

NATURAL PRODUCT RESEARCH
3
o
Scheme 2. Reagents and conditions: (a) (i) NaNO2, KBr, H2SO4, ꢀ10 C, 5 hr, 82%; (ii) BH3.DMS, dry
THF, ꢀ10 ꢁC to rt, 93%; (b) NaH, BnBr, TBAI, 0 ꢁC, 5 hr, 70%; (c) LAH, dry THF, rt, 1 hr, 90%; (d)
TBDPS-Cl, imidazole, DMAP, dry CH2Cl2, rt, 2 hr, 90%; (e) Li, Naphthalene, dry THF, ꢀ40 ꢁC, 1 hr,
83%; (f) Ts-Cl, Et3N, DMAP, dry CH2Cl2, 6 hr, 69%; (g) NaCN, NaI, dry DMSO, 80 ꢁC, 1.5 hr, 88%; (h)
DIBAL-H, ꢀ78 ꢁC, dry CH2Cl2, 1 hr; (i) C8H12O2, n-BuLi, ꢀ78 ꢁC, dry THF, 3 hr (73%, over two steps);
(j) IBX, DMSO, CH2Cl2 (1:3), rt, 1.5 hr, 86%; (k) (R)-CBS-catalyst, BH3.DMS, dry THF, ꢀ40 ꢁC, 1 hr,
81%; (l) NaH, BnBr, dry THF, rt, 4 hr, 78%; (m) PPTS, MeOH, rt, 2 hr, 89%; (n) Red-Al, dry THF, 0 ꢁC
to rt, 1 hr, 91%; (o) MnO2, hexane, rt, 20 hr; (p) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O
(5:1) 30 min (over two steps 92%); (q) HF.Pyridine, dry THF, 20 hr, 85%.
et al. 2011). The tetrahedropyranyl ring was selectively deprotected with pyridinium p-
toluene sulphanate (PPTS) in methanol to give compound 15, in 89% yield (Suffert
1990; Shekar et al. 2011). The propargyl alcohol to desired trans olefinic allylic alchol
was achieved by using Red-Al in dry THF at 0 ꢁC for 1 hr in quantitative yields, exclu-
sively trans allylic alcohol (16) (Oskari and Koskinen 2011). The allylic alcohol was oxi-
dized by using MnO2 in hexane for 20 hr to afford aldehyde. Thus obtained aldehyde,
further oxidized under Pinnick conditions in presence of sodium chlorate, sodium
dihydrogen phosphate, t-BuOH, 2-methyl-2-butene to obtained, a,b-unsaturated acid
(17) (Dubost et al. 2006) (over two steps 92% yield). Deprotection of TBDPS group was
achieved by using HF.Pyridine in dry THF for 20 hr to afford sec-acid (18) in 85% yield
(Scheme 3).
The monomer was subjected to Mitsunobu cyclization under Gerlach’s procedure,
using TPP, DEAD in THF:H2O solvent (10:1) mixture at ꢀ30 ꢁC for 18 hr, complete inver-
sion at C-4 configuration centre takes place to afford macrodilactone (20) in 55% yield
(Gerlach et al. 1977). Finally debenzylation of macrodilactone achieved by using TiCl4
in dry CH2Cl2 to afford, the Pyrenophorol (1) (Sharma et al. 2009) as white solid in
80% yield. Mp 130–132 ꢁC, Ref.(Krohn et al. 2007) (130–134 ꢁC), with optical rotation
[a]D -10.5 (c ¼ 1, CHCl3), Ref.(Krohn et al. 2007) [a]D -10.2, (c ¼ 1.04, CHCl3). The spec-
tral data and analytical data good agreement with the literature. Compound 1 sub-
jected to hydrogenation in presence of Pd/C (10%) under hydrogen atmosphere for
25
20

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S. G. NARALA ET AL.
Scheme 3. Reagents and conditions: (a) TPP, DEAD, THF:H2O (10:1), ꢀ30 ꢁC, 18 h, 55%; (b) TiCl4,
dry CH2Cl2, 2h, rt, 80%; (c) Pd/C, H2, EtOAc, 8h, 78%; (d) Ac2O, pyridine, rt, 18h 64%.
8 hr to afford Tetrahydropyrenophorol (1b) in 78% yield. Pyrenophorol (1) was treated
with acetic anhydride in presence of pyridine for 18 hr to achieve, 4,4-diacetyl pyreno-
phorol (1a) in 64% yield. All the compounds were compared with literature reports.
3. Experimental section
See the supplementary material
4. Conclusion
In conclusion, we have demonstrated a stereoselective total synthesis of Pyrenophorol,
Tetrahydropyrenophorol and diacetylpyrenophorols. The starting material used for syn-
thesis is commercially available (L)-Aspartic acid. The important reactions involved are
regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu mac-
rolactanization. All the reactions were very clean and good yields and the final prod-
ucts were good agreement with naturally isolated products.
Acknowledgements
Authors SGN and GNL are thankful to UGC-New Delhi and CSIR-New Delhi respectively for pro-
viding fellowships and Ministry of Science and Technology for providing financial support under
DST-SERB-GAP-0563 and Director CSIR-IICT for providing facilities.
Disclosure statement
No conflict of interest.
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