Synthesis of (+)-xestodecalactone A

Article abstract of DOI:10.1080/14786419.2021.1941948

The total synthesis of Benzannulated macrolide, (+)-Xestodecalactone A was accomplished starting from commercially available enantiomerically pure propylene oxide and 3,5-dihydroxyphenylacetic acid using Grignard reaction, alkylation of 1,3-dithiane and Y

Full text of DOI:10.1080/14786419.2021.1941948

Natural Product Research
Formerly Natural Product Letters
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Synthesis of (+)-xestodecalactone A
G. Nagendra Reddy, Gudisela Mura Reddy, Gattu Sridhar & K. R. S Prasad
To cite this article: G. Nagendra Reddy, Gudisela Mura Reddy, Gattu Sridhar & K. R.
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10.1080/14786419.2021.1941948
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1941948
Synthesis of (þ)-xestodecalactone A
G. Nagendra Reddy , Gudisela Mura Reddy , Gattu Sridhar and K. R. S Prasad
a
b
c
a
a
Department of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra
b
Pradesh, India; Tagoor laboratories Pvt. Ltd. IDA, Jeedimetla, Hyderabad, Telangana, India;
c
Department of Chemistry, Kakatiya Institute of Technology and Science, Warangal, Telangana, India
ABSTRACT
ARTICLE HISTORY
The
total
synthesis
of
Benzannulated
macrolide,
Received 17 March 2021
Accepted 6 June 2021
(
þ)-Xestodecalactone A was accomplished starting from commer-
cially available enantiomerically pure propylene oxide and 3,5-
dihydroxyphenylacetic acid using Grignard reaction, alkylation of
KEYWORDS
Benzannulated macrolac-
tones; Xestodecalactones;
Grignard reaction;
Yamaguchi
1,3-dithiane and Yamaguchi macrolactonisation as key steps.
macrolactonisation
1. Introduction
Macrolide molecules containing a large lactone ring in its structure and considered to
be derived from the corresponding hydroxyl acid by internal esterification (Collins
1
999). Macrodiolides and macrocyclic monolactones are two types of macrolides.
Researchers across the world concentrate on the synthesis of both homo and hetero
dimers (macrodilactones) (Alluraiah et al. 2014; Edukondalu et al. 2015; Ramakrishna et
al. 2016; Pratapareddy et al. 2017; Ramanujan et al. 2017; Ashok et al. 2018; Alluraiah
et al. 2019; Edukondalu et al. 2020; Ramakrishna et al. 2021) and macrocyclic monolac-
tones (Murthy et al. 2014; Pratapareddy et al. 2015; Alluraiah et al. 2016; Pratapareddy
et al. 2020).
Benzannulated macrolactones are one of the most important classes of compounds
due to their potent biological activities such as antibacterial, antifungal and anticancer
CONTACT K. R. S. Prasad
krsp1chem@gmail.com
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14786419.2021.1941948.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
G. N. REDDY ET AL.
Figure 1. Structure of Xestodecalactones A–C.
behaviour (Musgrave 1956; Robeson et al. 1985; Lai et al. 1989, 1991; Ghisalberti and
Rowland 1993; Sponga et al. 1999; Edrada et al. 2002; He et al. 2004; Zhan et al. 2004;
Huang et al. 2008). Selected examples of these macrolides are radicicol (Nozawa and
Nakajima 1979), Zearalenone (Stob et al. 1962; Urry et al. 1966), Lasiodiplodins
(
(
Aldridge et al. 1971; Li et al. 2005), sonnerlactones (Li et al. 2010), xestodecalactones
Petrier and Luche 1985; Luche and Einhorn 1987; Sharma and Kumar 2004) and cur-
vularin (Musgrave 1956; Gerlach 1977) which received significant attention due to their
interesting biological properties.
Among of these macrolactones, Xestodecalactones A-C (1a-c) are the novel
Benzannulated decalactones, isolated from the fungus Penicillium cf. montanense
obtained from the marine sponge Xestospongia exigua (Edrada et al. 2002). As shown
in Figure 1, Xestodecalactones constitute 10-membered macrolides with a fused 1,3-
dihydroxybenzene ring. Xestodecalactones A–C have been shown to exhibit antibac-
terial and antifungal activities (Bringmann et al. 2003). They are also found to be spe-
cific inhibitors of the epidermal growth factor (EGF) receptor, tyrosine kinase in vitro.
The potential biological importance as well as the unique structural feature of these
molecules prompted us to undertake the syntheses of these molecules. To date, sev-
eral approaches for syntheses of Xestodecalactones A–C have been reported
(Bringmann et al. 2004; Yoshino et al. 2006; Liang et al. 2007; Yadav et al. 2008; Rajesh
et al. 2009; Yadav et al. 2009; Pal et al. 2012; De Joarder and Jennings 2013, 2015; Rao
et al. 2019).
In this communication, we herein, report an alternative synthetic strategy to
achieve the total synthesis of Xestodecalactones A (1a) utilising the alkylation of 1,3-
dithiane and Yamaguchi macrolactonisation as the key steps.
2. Results and discussion
Our retro synthetic approach for the synthesis of xestodecalactone-A was outlined in
Scheme 1. The target molecule 1a could be made from hydroxy acid 2 by intra
molecular Yamaguchi macrolactonisation, whereas 2 could be synthesised from the
coupling reaction of two key fragments dithiane 3 and bromide 4. Dithiane intermedi-
ate 3 could be obtained from commercially available 3,5-dihydroxyphenylacetic acid 5
and bromide 4 was achieved from known chiral epoxide 6.
As discussed in the retrosynthetic analysis, the synthesis of the xestodecalactone-A
started with the preparation key intermediates 3 from commercially available 3,5-dihy-
droxyphenylacetic acid 5, which is outlined in Scheme 2. Accordingly, the 3,5-dihy-
droxyphenylacetic acid 5 was subjected to O-methylation and esterification with

NATURAL PRODUCT RESEARCH
3
Scheme 1. Retrosynthetic analysis of xestodecalactone-A.
Scheme 2. Reagents and conditions: (a) DMS, K CO , acetone, reflux, 4h; (b) DMF, POCl3, rt to
2
3
ꢀ
ꢀ
5
5 C, 12h; (c) 1,3-propanedithiol, BF OEt , CH Cl , 0 C to rt, 8h, 79%.
3ꢂ
2
2 2
dimethyl sulfate in acetone at reflex for 4 h to afford 7 in 86% yield. The resulting
16
ester 7 was transformed into aldehyde 8 via Vilsmeier-Haack formylation (von Delius
et al. 2017) using POCl in DMF at room temperature for 20 h. Later, aldehyde 8 on
3
ꢀ
treatment with 1,3-propanedithiol in the presence of BF .OEt in CH Cl at 0 C to rt
3
2
2
2
for 8 h afforded the key intermediate 1,3-dithiane 3 in 79% yield.
Synthesis of the other coupling partner 4 was commenced from known chiral epox-
ide 6 (Schaus et al. 2002). Accordingly, epoxide 6 on Regioselective ring-opening by
allyl magnesium bromide in the presence of CuI yielded the alcohol 6a in 78% yield.
Subsequent silylation of the resulting alcohol 6a with TBSCl and imidazole in CH Cl2
2
gave 9 in 76% yield. Later, the terminal olefin moiety of 9 was subjected to
ꢀ
Ozonolysis by using Ozone gas in CH Cl at ꢁ78 C for 15 min to furnish correspond-
2
2
ꢀ
ing aldehyde, which on immediate reduction with NaBH in MeOH at 0 C for 6 h gave
4

4
G. N. REDDY ET AL.
ꢀ
Scheme 3. Reagents and conditions: (a) i) allyl bromide, Mg, CuI, dry ether, ꢁ78 C, 2 h; ii) TBSCl,
ꢀ
ꢀ
Imidazole, CH Cl , rt, 4 h; (b) i) O , CH Cl , -78 C, 30 min; ii) NaBH , MeOH, 0 C to rt, 6 h; (c) CBr ,
2
2
3
2
2
4
4
ꢀ
Ph P, CH Cl , 0 C to rt, 3 h
3
2 2
ꢀ
Scheme 4. Reagents and conditions: (a) n-BuLi, dry THF, -20 C, 3 h; (b) LiOH, THF:MeOH:H O (3:1:1),
2
ꢀ
ꢀ
rt, 4 h, 83%; (c) TBAF, THF, 0 C to 25 C, 3 h, 89%; (d) i) 2,4,6-trichlorobenzoyl chloride, Et N, dry
THF, 25 C, 2 h; ii) DMAP, toluene, 90 C, 10 h, 67%; (e) CaCO , MeI, CH CN:H O (9:1), 45 C, 3 h,
3
ꢀ
ꢀ
ꢀ
3
3
2
ꢀ
6%; (f) BBr3, CH Cl , -78 C to r.t.
2 2
6
the alcohol 10 in 84% yield. Finally, treatment of alcohol 10 with CBr in the presence
4
of Ph P in CH Cl afforded bromide 4 in 81% yield.
3
2
2
With two subunits in hand, we proceeded to couple both intermediates 3 and 4 as
ꢀ
described in Scheme 3. Accordingly, dithiane 4 was lithiated by n-BuLi at ꢁ20 C and
then alkylated with bromide 3 to provide the desired product 11 in 86% yield
(Scheme 4). Later, the resulting compound 11 was subjected to base (LiOH) hydrolysis
in THF:MeOH:H O (3:1:1) to afford the corresponding acid 12, which on desilylation
2
ꢀ
ꢀ
with TBAF in THF at 0 C to 25 C for 3 h afforded hydroxy acid 2 in 91% yield. After
successful synthesis of hydroxy acid fragment 2, which was subjected to macrolactoni-
sation under Yamaguchi high dilution conditions (Inanaga et al. 1979) to provide the
lactone 13 in 69% yield.
Next, removal of 1, 3 dithiane group in compound 13 with CaCO and MeI, in
3
CH CN:H O for 3 h afforded the lactone 14 in 73% yield. Finally, the deprotection of
3
2
both methyl ether groups in lactone 14 using BBr in dichloromethane gave the xesto-
3
decalactone-A (1a) in 82% yield (Scheme 4). All the spectroscopic data of synthetic 1a
1
13
are ( H and C NMR, MS) and specific rotation fully consistent with the reported data
of the natural product (Edrada et al. 2002).

NATURAL PRODUCT RESEARCH
5
3. Conclusions
Thus, in summary, we have demonstrated an efficient synthetic route for the total syn-
thesis of xestodecalactone-A in a stereoselective manner with overall yield of 9.77%.
The key steps involved in this synthesis are Grignard reaction, alkylation of 1,3-dithiane
and Yamaguchi macrolactonisation.
Acknowledgements
The authors are thankful to Koneru Lakshmaiah Education Foundation, CSIR-Indian Institute of
Chemical Technology, Hyderabad and GVK Biosciences Private Limited for constant encourage-
ment in providing laboratory facilities and analytical data.
Disclosure statement
No potential conflict of interest was reported by the authors.
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