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Synthesis of (3R,5R)-harzialactone A and its (3R,5S)-isomer

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Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India, Fax: +91-40-27160512
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Associate Editor: J. N. Johnston
Beilstein J. Org. Chem. 2010, 6, No. 8. https://doi.org/10.3762/bjoc.6.8
Received 31 Aug 2009, Accepted 20 Jan 2010, Published 29 Jan 2010
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Abstract

The total synthesis of (3R,5R)-harzialactone A (1) and its (3R,5S)-isomer (2) is described. Epoxide opening with thioacetal and diastereoselective reductions are used as key reactions.

Keywords: dithiane; harzialactone A; hydroxyl directed reduction; stereoisomer

Introduction

Marine microorganisms such as bacteria, fungi, and microalgae have proved to be a rich source of structurally novel and biologically active secondary metabolites [1]. (+)-Harzialactone A (1), a marine metabolite isolated from the culture broth of a strain of Trichoderma harzianum OUPS-N115 by Numata and co-workers, exhibited antitumor and cytotoxic activities against cultured P388 cells [2]. The absolute configuration of (+)-1 was established based on 1H NMR studies and by its synthesis [3,4]. Harzialactone A (1) (Figure 1) is a synthetic target of considerable interest due to its potent biological activity and unique structure. A few methods for its synthesis have been documented in the literature [3-10] as well as a synthesis of nonnatural (−)-harzialactone A [11]. However, the anti-tumor activity of Harzialactone A coupled with its unique structural architecture prompted us to attempt its synthesis.

[1860-5397-6-8-1]

Figure 1: Natural harzialactone A (1), and its (3R,5S)-isomer (2).

The retrosynthesis is depicted in Scheme 1. Harzialactone 1 could be made from 3 by successive protecting group transformations. 3 can be made by hydroxyl directed reduction of 4 which in turn could be prepared by epoxide 6 opening with dithiane 5.

[1860-5397-6-8-i1]

Scheme 1: Retrosynthesis of harzialactone A (1).

Results and Discussion

The synthesis of natural (3R,5R)-1 was initiated from the known epoxide 6, which is commercially available. Treatment of 2-phenylacetaldehyde 7 with 1,3-propanedithiol in the presence of BF3·Et2O in CH2Cl2 afforded thioacetal 5 in 90% yield (Scheme 2). The epoxide 6 was coupled with the acyl anion equivalent 5 (1.0 equiv), prepared by metallation at –78 °C with 1.0 equiv of n-butyllithium in the presence of BF3·Et2O to obtain 8 in 64% yield. Removal of the dithioketal using HgCl2/CaCO3 in CH3CN/H2O (4:1)[12] provided the corresponding hydroxyketone 4 in 82% yield. Treatment of 5 with NaBH4 and MeOBEt2 [13,14] stereoselectively formed the syn diol 9 in good yield (80%). The diol 9 was subsequently transformed into the isopropylidene derivative 3 by treatment with 2,2-dimethoxypropane and a catalytic amount of PPTS in CH2Cl2.

[1860-5397-6-8-i2]

Scheme 2: Synthesis of natural harzialactone A (1).

In the 13C NMR spectrum of 3, the acetonide methyl groups resonated at 19.6 and 29.9 ppm indicating a 1,3-syn-relationship that was further substantiated by the appearance of the quaternary carbon in the downfield region (98.7 ppm). Deprotection of the benzyl group using Li/liq. NH3 gave alcohol 10. Oxidation of alcohol 10 under Swern conditions and further oxidation of the resulting aldehyde using NaH2PO4, NaClO2 in DMSO/H2O furnished the target hydroxylactone (3R,5R)-1 as reported earlier. The IR absorption at 1774 cm−1 indicates the presence of δ-lactone system.

The synthesis of (3R,5S)-2 was also accomplished in an identical manner from 4 (Scheme 3). The substrate hydroxyl directed asymmetric reduction with Me4NBH(OAc)3 [15,16] was performed at 0 °C to afford the anti diol 11 as the major product, which was converted into stereoisomer (3R,5S)-2 via acetonide 12, deprotection of benzyl group to give 13, and further functional group transformations by use of the same reagents and conditions as those described for the conversion of 10 into 1. The IR absorption at 1775 cm−1 confirms the presence of δ-lactone in (3R,5S)-2.

[1860-5397-6-8-i3]

Scheme 3: Synthesis of (3R,5S)-harzialactone A (2).

The anti relationship of two hydroxyl groups was studied in compound 12. In the 13C NMR of 12, the acetonide methyl groups resonated at 24.9 and 34.2 ppm indicating a 1,3-anti-relationship that was further substantiated by the appearance of the quaternary carbon in the downfield region (100.5 ppm) [7].

In conclusion, a stereoselective synthesis of natural (+)-(3R,5R)-harzialactone A and its nonnatural stereoisomer (3R,5S) has been accomplished.

Supporting Information

Supporting Information File 1: Experimental section and analytical data.
Format: DOC Size: 4.4 MB Download

Acknowledgements

R. S. thanks CSIR, S. K. D thanks UGC, New Delhi for the award of fellowships.

References

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