Total synthesis of patulolide A through ring closing metathesis

Article abstract of DOI:10.1080/00397911.2017.1384019

A simple and efficient total synthesis of patulolide A from readily available 7-octen-1-ol is reported by asymmetric synthetic approach. The key reactions involved are asymmetric dihydroxylation using AD-mix-β and Grubbs’ ring-closing metathesis reaction

Full text of DOI:10.1080/00397911.2017.1384019

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Total synthesis of Patulolide A via ring closing
metathesis
N. J. P. Subhashini, B. Bhadraiah, P. Janaki & Gattu Sridhar
To cite this article: N. J. P. Subhashini, B. Bhadraiah, P. Janaki & Gattu Sridhar (2017):
Total synthesis of Patulolide A via ring closing metathesis, Synthetic Communications, DOI:
10.1080/00397911.2017.1384019
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1384019
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Date: 17 November 2017, At: 21:36

Total synthesis of Patulolide A via ring closing metathesis
N. J. P. Subhashini
Department of Chemistry, University College of Technology, Osmania University, Hyderabad,
India
B. Bhadraiah
Department of Chemistry, University College of Technology, Osmania University, Hyderabad,
India
Chemistry services, GVK Biosciences Pvt.Ltd, IDA Nacharam, Hyderabad, India
P. Janaki
Department of Chemistry, University College of Technology, Osmania University, Hyderabad,
India
Gattu Sridhar
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
Address correspondence to N. J. P. Subhashini, Department of Chemistry, University College of
Technology, Osmania University, Hyderabad 500 007, India. E-mail: njps1org@yahoo.com
Full experimental details, spectral data of the products, 1H NMR and 13C NMR of all the new
compounds can be found via the Supplementary Content section of this article’s Web page.
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ABSTRACT
A simple and efficient total synthesis of Patulolide A from readily available 7-Octen-1-ol
is reported by asymmetric synthetic approach. The key reactions involved are asymmetric
dihydroxylation using AD-mix-β and Grubbs’ RCM reaction for the synthesis macrocyclic ring
system”.
GRAPHICAL ABSTRACT
KEYWORDS: 1,3 dithiane, AD-mix, Patulolide A, ring closing metathesis
Introduction
Patulolide A is naturally occurring antimicrobial twelve membered α,β- unsaturated γ-
keto macrolide isolated from culture broth of the Penicillium urticae mutant S11R59 by Yamada
and co-workers.[1] Interestingly, Patulolide A exhibited antibacterial, antifungal, and anti-
inflammatory activities.[2,3] Current reports postulates that the R-antipode of Patulolide A inhibits
IgE induced release of histamine for human leucocytes better than the degranulation inhibitor,
theophylin.[4]
The first total synthesis of Patulolide A was reported by Mori and Co-Workers in 1987
beginning from ethyl (R)-3-hydroxybutanoate.[5] To date several approaches for the synthesis of
Patulolide A have been described and attracted attention from synthetic chemists due to its
interesting biological activities.[6–10] Nevertheless, the reported synthetic routes to Patulolide A
mainly associated with the long reaction sequences, lower yields, inaccessible materials and
2

dependence on the chiral pool resources are some of the disadvantages in the earlier reported
methods. To overcome the problems associated with the earlier approaches, here in, we report a
concise and facile synthesis of Patulolide A using enantioselective dihydroxylation and RCM
approach as key steps from commercially available inexpensive starting materials.
Results and Discussion
Ring closing metathesis widely used practice of olefin metathesis in organic chemistry
for the synthesis of unsaturated rings using intra molecular metathesis of two terminal alkenes.
We envisioned that olefinic double bond in Patulolide A can plausibly accessed via ring closing
metathesis by using suitable bis-olefin.
As shown in Scheme 1, the retrosynthetic analysis of macrolide 1 revealed that bis-olefin
2 could be the late stage intermediate, which on RCM protocol would generate the macrolide
ring structure. We intended to obtain patulolide A by suitable bis-olefin assembling together.
Bis-olefin 2in turn, could be prepared from alcohol 3, while, the alcohol 3 could be readily
accessible and synthesized from commercially available 7-Octen-1-ol 4.
The synthesis of 1 commenced with readily available 7-Octen-1-ol 4, accordingly, which
on treatment with PMB-Br in presence of NaH in THF as solvent at RT for 8h afforded PMB
protected ether 5in 79% yield. Terminal olefin in PMB ether 5 was subjected to Asymmetric
dihydroxylation with AD-mix-β to afford Diol 6in 76% yield. (dr 9:1).[11] Diol 6 on further mono
tosylation in the presence of TsCl and Et3N in CH2Cl2 followed by the deoxygenation using
LiAlH4in dry THF furnished 7in 73% yield. Next Hydroxyl group in 7 was masked with TBSCl
in the presence of imidazole at 0C to afford silyl ether 8in 81% yield. As expected selective
cleavage of PMB group was achieved from 8in the presence of DDQ in aq. CH2Cl2 to give the
3

alcohol 3in 88% yield. Alcohol 3 was converted into bromide 3a by using with CBr4 in the
presence of Ph3P in CH2Cl2, which on alkylation with 2-vinyl-1,3-dithiane in dry THF gave
compound 9in 77% yield. Subsequent desilylation of 9 with TBAF in dry THF afforded alcohol
10in 88% yield, which on esterification with acryloyl chloride and DIPEA in CH2Cl2 furnished
bis-olefin 2in 71% yield. Bis-olefin 2 was then subjected to the RCM reaction using 10mol % of
Grubb’s-II[12] generation catalyst in dry CH2Cl2 at reflux temperature yielded macrolide 11in
69% yield. Finally, deprotection of 1, 3 dithaine group in compound 11 with CaCO3 and I2, in
THF: H2O (4:1) for 5h afforded the Patulolide A 1in 71% yield. The analytical data of our
synthetic compound are in full agreement with the reported data.[4] Thus we accomplished the
total synthesis of Patulolide A in an enantioselective way via RCM approach.
Experimental Section
(R, E)-11-Methyl-10-oxa-1, 5-dithiaspiro [5.11] heptadec-7-en-9-one (11):
To a solution of 2 (0.26g, 0.29 mmol) in CH2Cl2 (250mL ), 10mol % Grubbs catalyst II
(54mg, 0.06 mmol) was added and stirred for 12h at reflux under N2 atmosphere. Most of the
solvent was then distilled off and the concentrated solution left to stir at room temperature for 2h
under air bubbling in order to decompose the catalyst. The reaction mixture was evaporated to
dryness to give a brown residue, which was purified by column chromatography (60-120 Silica
gel, 10% EtOAc in pet. ether) to furnish 11 (0.16g, 69%) as a syrup; []25 = + 6.4 (c 0.74,
D
EtOH); IR (neat): 3080, 3052 2955, 2880, 1705, 1470, 1370, 1260, 910, 730, 698cm -1; 1H NMR
(CDCl3, 400MHz ): δ 6.98 (d, 1H, J = 16.1Hz, olefinic), 6.26 (d, 1H, J = 16.1Hz, olefinic), 5.09-
5.09 (m, 1H, -OCH), 2.94-2.62 (m, 4H, 2 x -SCH2), 2.07-1.99 (m, 2H, -CH2), 1.93-1.61 (m, 5H,
5 x -CH), 1.62-1.37 (m, 7H, 7 x -CH), 1.31 (d, 3H, J = 6.2Hz, –CH3); 13C NMR (100MHz,
4

CDCl3): δ 168.0, 152.1, 125.1, 89.8, 73.2, 42.4, 33.3, 28.2, 27.6, 27.3, 25.4, 22.4, 21.6, 19.7;
HRMS (ESI): m/z calculated for C15H24O2S2Na [M + Na] + 323.1218, found 323.1222.
Patulolide A (1)
To a solution of compound 11 (110mg, 0.36 mmol) and CaCO3 (360mg, 3.66 mmol) in
THF/H2O (v/v, 4:1, 10mL ) was added I2 (270mg, 1.02 mmol) at 0 oC. The resulting mixture was
stirred at 0oC for 20min . The reaction was quenched by adding saturated aqueous Na2S2O3,
filtered through a pad of celite, and then extracted with EtOAc (3 × 20mL ), water, brine, dried
over Na2SO4 and concentrated in vacuo . Purification by flash chromatography on silica gel (60-
o
120 Silica gel, 15% EtOAc in pet. ether) gave compound 1 (54mg, 71% yield; M.P. 82–84 C;
o
(lit.:1 83–85 C); []25 = + 33.4 (c 0.39, EtOH); (lit.:1 + 30.1 (c 0.95, EtOH); IR (neat): 3400,
D
3325, 3070, 3025, 2935, 2855, 1700, 1680, 1620, 1460, 1340, 1260, 1200, 980, 776, 698cm -1;
1H NMR (CDCl3, 400MHz ): δ 7.23 (d, 1H, J = 15.9Hz, olefinic), 6.81 (d, 1H, J = 15.9Hz,
olefinic), 4.91-4.86 (m, 1H, –OCH), 2.81-2.72 (m, 1H, –CH), 2.50-2.42 (m, 1H, –CH), 1.93-1.83
(m, 2H, –CH2), 1.79-1.64 (m, 4H, 2 x –CH2), 1.57-1.44 (m, 4H, 2 x –CH2), 1.37 (d, 3H, J =
7.1Hz, -CH3); 13C NMR (100MHz, CDCl3): δ 202.4, 166.5, 141.3, 130.1, 74.7, 38.6, 34.9, 25.6,
25.3, 24.5, 22.3, 20.3; HRMS (ESI): m/z calculated for C12H18O3Na [M + Na] + 233.1256, found
233.1259.
Conclusion
In conclusion, total synthesis of Patulolide A (1) has been accomplished in a divergent
way starting from commercially available inexpensive materials. In this approach asymmetric
dihydroxylation and ring-closing metathesis reactions (RCM) used as a key reactions. Efforts to
5

explore this methodology for the synthesis of other natural products will be published in due
course.
Acknowledgements
The autohrs are thankful to GVK Bio sciences and CSIR, New Delhi for constant
encouragement in providing laboratory facilities and analytical data.
References
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Figure 1. Structure of Patulolide A (1).
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Scheme 1. Retro-analysis of Patulolide A (1).
8

Scheme 2. Synthesis of Patulolide A (1).
9