An alternative stereoselective total synthesis of (-)-pyrenophorol

Article abstract of DOI:10.1080/14786419.2018.1499636

The total synthesis of 16-membered C₂–Symmetric dilactone (-)-Pyrenophorol was accomplished starting from commercially available (S)-epoxide prepared by hydrolytic kinetic resolution of (±)–epoxide with key steps of Grignard reaction, Swern oxidation, Wittig reaction and cyclization was achieved by intermolecular Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol accomplished from cheaply available starting material, easily work-up procedures and reduction of cost in industrial process were major advantages of this route.

Full text of DOI:10.1080/14786419.2018.1499636

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
An alternative stereoselective total synthesis of (-)-
pyrenophorol
Gurrala Alluraiah, Reddymasu Sreenivasulu, Choragudi Chandrasekhar &
Rudraraju Ramesh Raju
To cite this article: Gurrala Alluraiah, Reddymasu Sreenivasulu, Choragudi Chandrasekhar &
Rudraraju Ramesh Raju (2018): An alternative stereoselective total synthesis of (-)-pyrenophorol,
Natural Product Research, DOI: 10.1080/14786419.2018.1499636
To link to this article: https://doi.org/10.1080/14786419.2018.1499636
View supplementary material
Published online: 17 Sep 2018.
Submit your article to this journal
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gnpl20

NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2018.1499636
An alternative stereoselective total synthesis
of (-)-pyrenophorol
a
b
b
Gurrala Alluraiah , Reddymasu Sreenivasulu , Choragudi Chandrasekhar and
a
Rudraraju Ramesh Raju
a
b
Department of Chemistry, Acharya Nagarjuna University, Nagarjuna Nagar, A.P, India; Department
of Chemistry, University College of Engineering (Autonomous), Jawaharlal Nehru Technological
University, Kakinada, Andhra Pradesh, India
ABSTRACT
ARTICLE HISTORY
Received 13 May 2018
Accepted 9 July 2018
2
The total synthesis of 16-membered C –Symmetric dilactone
(
-)-Pyrenophorol was accomplished starting from commercially
available (S)-epoxide prepared by hydrolytic kinetic resolution of
±) – epoxide with key steps of Grignard reaction, Swern oxida-
KEYWORDS
(
(
S)-epoxide; swern
tion, Wittig reaction and cyclization was achieved by intermolecu-
lar Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol
accomplished from cheaply available starting material, easily
work-up procedures and reduction of cost in industrial process
were major advantages of this route.
oxidation; wittig reaction;
mitsunobu cyclization;
(
-)-pyrenophorol
1. Introduction
Macrodiolides belong to a relatively small but interesting class of natural products,
which can be isolated from various fungi and marine sponges, exhibiting many differ-
ent bioactivities. Macrocyclic dilactones (macrodiolides) are well represented in nature
as both homodimers such as pyrenophorol (Kis et al. 1969; Grove, 1971; Kind et al.
1
2
996; Kastanias and Chrysayi-Tokousbalides, 2000; Krohn et al. 2007; Ghisalberti et al.
002), pyrenophorin (Nozoe et al. 1965; Grove et al. 1966), tetrahydropyrenophorol
(
(
Krohn et al. 2007), vermiculin (Findlay et al. 2003), heterodimers including colletodiol
Grove et al. 1966; MacMillan and Pryce, 1968; Powell and Whalley, 1969; MacMillan
and Simpson, 1973), and grahamimycin A1 (Ronald and Gurusiddaiah 1980). The struc-
tures of (-)-pyrenophorin, (-)-tetrahydropyrenophorol, vermiculin, colletodiol and graha-
mimycin A1 were shown in Figure 1.
Researchers around the world concentrate the synthesis of these types of both
homo and hetero dimmers (macrocyclic dilactones) (Alluraiah et al. 2014; Edukondalu
CONTACT Rudraraju Ramesh Raju
rrraju1@gmail.com
ß 2018 Informa UK Limited, trading as Taylor & Francis Group

2
G. ALLURAIAH ET AL.
Figure 1. Structures of (-)-pyrenophorin, (-)-Tetrahydropyrenophorol, Vermiculin, Colletodiol and
Grahamimycin A1.
et al. 2015; Madala et al. 2016; Ramakrishna et al. 2016; Pratapareddy et al. 2017;
Ramanujan et al. 2017; Ashok et al. 2018) and macrocyclic monolactones (Murthy et al.
2
014; Pratapareddy et al. 2015; Alluraiah et al. 2016) due to their strong biological
activities such as antifungal (Kis et al. 1969; Krohn et al. 2007), anthelmintic (Kind et al.
996; Ghisalberti et al. 2010), and phytotoxic activities (Kastanias and Chrysayi-
1
Tokousbalides, 2000).
A 16-membered diolide, (-)-(5S,8R,13S,16R)-pyrenophorol 1 (Figure 2) was previously
isolated from the fungus Byssochlamys nivea (Kis et al. 1969) and subsequently found
in Stemphylium radicinum (Grove, 1971), Alternaria alternata (Kind et al. 1996),
Drechslera avenae (Kastanias and Chrysayi-Tokousbalides, 2000), and Phoma sp. (Krohn
et al. 2007). (-)-(5S,8R,13S,16R)-pyrenophorol (1) exhibits pronounced anthelmintic
properties (Kind et al. 1996; Christner et al. 1998) and is moderately active against the
fungus Microbotryum violaceum and it has been synthesized by five groups
(Dommerholt et al. 1991; Kibayashi and Machinaga, 1993; Yadav et al. 2009; Oh and
Kang, 2011; Edukondalu et al. 2015) due to its interesting structural features combined
with biological activities.
The reported synthesis routes to (-)-(5S,8R,13S,16R)- pyrenophorol are mainly associ-
ated with long reaction sequences, low yields, and dependence on the chiral pool
resources which are some of the disadvantages in the earlier reported methods.
Previously, Ashok et al. reported the synthesis of (-)-Pyrenophorol through an oxida-
tion–reduction protocol and cyclodimerisation under the Mitsunobu reaction condi-
tions as key steps. To overcome the problems associated with the earlier approaches,

NATURAL PRODUCT RESEARCH
3
Figure 2. Structure of (-)-Pyrenophorol.
Scheme 1. Retro synthetic analysis of (-)-Pyrenophorol.
herein we reported an alternative route. In the present study, we have undertaken the
synthesis of pyrenophorol (1) utilizing the Jacobsen’s hydrolytic kinetic resolution and
intermolecular Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol accomplished
from cheaply available starting material, easily work-up procedures and reduction of
cost in industrial process were major advantages of this route, when compared to the
previous reported methodologies.
2. Results and discussion
The retrosynthetic analysis of macrolide 1, reveals that it could be obtained from the
hydroxy-acid derivative 2 via cyclodimerisation under the Mitsunobu conditions fol-
lowed by deprotection of the benzyl ether. Hydroxy-acids 2 could be achieved from
racemic allylic alcohol 3. The racemic alcohol 3 could be prepared from (S)-propylene
epoxide 4 by Jacobson hydrolytic resolution of (±)-propylene epoxide (Scheme 1).
The stereoselective total synthesis of (-)-pyrenophorol was shown in Scheme 2. The
total synthesis of (-)-pyrenophorol was initiated from (S)-epoxide 4. Accordingly, hydro-
lytic kinetic resolution of epoxide using Jacobson (S,S)-catalyst in the presence of
ꢀ
AcOH and H O at 15 C for 14 h afforded the known (S)-epoxide 4 in 43% yield and
2
(
R)-diol 5 in 39% yield. Opening of the epoxide 4 with allylmagnesium chloride in
ꢀ
ether at ꢁ78 C for 2 h gave 6, which upon silylation with TBSCl and imidazole in
CH Cl at room temperature for 4 h afforded 7 in 72% yield as a colourless liquid.
2
2
ꢀ
Ozonolysis of 7 in CH Cl at ꢁ78 C for 30 min gave aldehyde 8, which on immediate
2
2
ꢀ
treatment with vinylmagnesium bromide in dry THF at ꢁ40 C for 4 h resulted in a dia-
stereomeric mixture of allylic alcohols 3 as an in separable mixture in syn and anti
1
(1:1; by H NMR) ratio in 78% yield. Oxidation of 3 under Swern reaction conditions
gave corresponding ketone 9, which on reduction with (S)-CBS catalyst to give alcohol
1
0 in 75% yield. The secondary allyl alcohol 10 in dry THF was treated with NaH and
ꢀ
BnBr at 0 C gave the Bn ether 11 in 77% yield. The olefin 11 was subjected to ozo-
nolysis in CH Cl at ꢁ78 C for 15 min gave the corresponding aldehyde which on
ꢀ
2
2

4
G. ALLURAIAH ET AL.
Scheme 2. Stereoselective total synthesis of (-)-Pyrenophorol.
immediate treatment with (ethoxycarbonyl methylene) triphenyl phosphorane in ben-
zene at reflux condition for 2 h furnished trans-Wittig product 12 in 79% yield.
Hydrolysis of ester 12 using LiOH in THF:MeOH:H O (3:1:1) at room temperature for
2
4
h afforded acid 13 in 84% yield. Further, desilylation in 13 with TBAF in dry THF
afforded the hydroxy-acid 2 in 81% yield. Hydroxy-acid 2 was subjected to cyclodimer-
isation under the Mitsunobu conditions according to Gerlach’s procedure. Thus, a rea-
sonably dilute solution of hydroxyl-acid 2 in toluene-THF (10:1) was treated with Ph P
3
ꢀ
and DEAD at ꢁ25 C for 10 h. The cyclodimerisation took place with complete inver-
sion of chirality at C-4 furnished 14 in 57% yield. Finally, oxidative deprotection of Bn

NATURAL PRODUCT RESEARCH
5
groups in 14 using DDQ in CH Cl and H O (19:1) gave (-)-pyrenophorol (1) in 69%
2
2
2
ꢀ
13
ꢀ
yield as a white solid, m.p. 137–139 C (lit. m.p. 135 C); [a] ꢁ3.7 (c 0.56, acetone) [lit.
D
1
[
a] ꢁ3.0 (c 1.0, acetone)]. The H, C NMR and IR data of the synthetic (-)-pyreno-
D
phorol (1) were in good accordance with that of reported for the natural product (Kis
et al. 1969).
3. Conclusion
In conclusion, the total synthesis of (-)-(5S,8R,13S,16R)-pyrenophorol with high enantio-
selectivity was achieved by Jacobsen’s hydrolytic kinetic resolution followed by
Grignard reaction, Swern oxidation, wittig reaction and cyclization was achieved by
intermolecular Mitsunobu cyclization. This synthetic protocol overcome the problems
associated with the earlier approaches.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
Alluraiah G, Sreenivasulu R, Murthy IS, Raju RR. 2014. Stereoselective total synthesis of
Verbalactone. Monatsh Chem. 145(12):2019–2024.
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.
Ashok D, Pervaram S, Chittireddy VRR, Reddymasu S, Vuppula NK. 2018. Stereoselective total
synthesis of (-)-Pyrenophorol. Chem Pap. 72(4):971–977.
Christner C, Kullertz G, Fischer G, Zerlin M, Grabley S, Thiericke R, Taddei A, Zeeck A. 1998.
Albocycline- and carbomycin-type macrolides, inhibitors of human prolyl endopeptidases.
J Antibiot. 51(3):368–371.
Edukondalu P, Sreenivasulu R, Chiranjeevi B, Kumar VN, Raju RR. 2015. Stereoselective total
synthesis of (-)-(5S, 8R, 13S, 16R)-Pyrenophorol. Monatsh Chem. 146(8):1309–1314.
Findlay JA, Li G, Miller JD, Womiloju TO. 2003. Insect toxins from spruce endophytes. Can
J Chem. 81(4):284–292.
Ghisalberti EL, Hargreaves JR, Skelton BW, White AH. 2002. Structural study of the Anthelmintic
macrodiolide pyrenophorol. Aust J Chem. 55:233–236.
Grove JF, Speake RN, Ward GJ. 1966. Metabolic products of Colletotrichum capsici: isolation and
characterization of acetylcolletotrichin and colletodiol. J Chem Soc C.:230–234.
Grove JF. 1971. Metabolic products of Stemphylium radicinum. Part IV. Minor products. J Chem
Soc C.:2261–2263.
Kastanias MA, Chrysayi-Tokousbalides M. 2000. Herbicidal potential of pyrenophorol isolated
from a Drechslera avenae pathotype. Pest Manag Sci. 56(3):227–232.
Kibayashi C, Machinaga N. 1993. Preparation of macrodiolides via a common chiral building
block. Total synthesis of (-)-Pyrenophorin and (-)-Pyrenophorol. Tetrahedron Lett.
34(5):841–844.
Kind R, Zeeck A, Grabley S, Thiericke R, Zerlin M. 1996. Secondary metabolites by chemical
screening. 30. Helmidol, a new macrodiolide from Alternaria alternata. J Nat Prod. 59(5):
539–540.
Kis Z, Furger P, Sigg H. 1969. Isolation of pyrenophorol. Experientia. 25(2):123–124.
Krohn K, Farooq U, Fl o€ rke U, Schulz B, Draeger S, Pescitelli G, Salvadori P, Antus S, Kurt ꢀa n T.
2007. Secondary metabolites isolated from an endophytic Phoma sp. absolte configuration of

6
G. ALLURAIAH ET AL.
tetrahydropyrenophorol using the solid-state TDDFT CD methodology. Eur J Org Chem.
2007(19):3206–3211.
MacMillan J, Pryce RJ. 1968. The structure of colletodiol, a macrocylic dilactone from
Colletotrichum capsici. Tetrahedron Lett. 9(53):5497–5500.
MacMillan J, Simpson TJ. 1973. Fungal products. Part V. The absolute stereochemistry of colleto-
diol and the structures of related metabolites of Colletotrichum capsici. J Chem Soc Perkin
Trans. 4(41):no–1493.
Madala M, Raman B, Sastry KV, Musulla S. 2016. A concise stereoselective total synthesis of
verbalactone. Monatsh Chem. 147(11):1985–1990.
Murthy IS, Sreenivasulu R, Alluraiah G, Raju RR. 2014. An alternative stereoselective total synthe-
sis of (þ)-Cephalosporolide D. LOC. 11(5):327–332.
Nozoe S, Hirai K, Tsuda K, Ishibashi K, Shirasaka M, Frederick Grove J. 1965. The structure of
Pyrenophorin. Tetrahedron Lett. 6(51):4675–4677.
Oh H-S, Kang H-Y. 2011. Synthesis of (-)-pyrenophorol. Bull Korean Chem Soc. 32(spc8):
2869–2870.
Powell JW, Whalley WB. 1969. The chemistry of fungi. 58. Structures of colletodiol, a metabolite
of Chaetomium funicola. J Chem Soc Perkin Trans I. 6:911–912.
Pratapareddy B, Sreenivasulu R, Hatti I, Rao MVB, Raju RR. 2015. A concise stereoselective total
synthesis of Diplodialide C. Monatsh Chem. 146(11):1921–1926.
Pratapareddy B, Sreenivasulu R, Thota P, Hatti I, Rao MVB, Kumar VN, Raju RR. 2017.
Stereoselective synthesis of (-)-tetrahydropyrenophorol. Monatsh Chem. 148(4):751–756.
Ramakrishna K, Sreenivasulu R, Vidavalur S, Reddy BJM. 2016. Stereoselective total synthesis of
(-)-Pyrenophorin. LOC. 13(9):693–697.
Ramanujan VB, Sreenivasulu R, Chavali M, Kumar CNSSP. 2017. Stereoselective total synthesis of
Decarestrictine. Monatsh Chem. 148(10):1865–1869.
Ronald RC, Gurusiddaiah S. 1980. Grahamimycin A : a novel dilactone antibiotic from cytospora.
1
Tetrahedron Lett. 21(8):681–684.
Yadav JS, Reddy UVS, Reddy BVS. 2009. Stereoselective total synthesis of (-)-pyrenophorol.
Tetrahedron Lett. 50(44):5984–5986.
Dommerholt FJ, Thijs L, Zwanenburg B. 1991. The total synthesis of the macrodiolide pyreno-
phorol. Tetrahedron Lett. 32(11):1499–1502.