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

Article abstract of DOI:10.3762/bjoc.6.8

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.

Full text of DOI:10.3762/bjoc.6.8

Synthesis of (3R,5R)-harzialactone A
and its (3R,5S)-isomer
Gowravaram Sabitha*, Rangavajjula Srinivas, Sukant K. Das
and Jhillu S. Yadav
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 8.
Organic Division I, Indian Institute of Chemical Technology,
Hyderabad 500 007, India, Fax: +91-40-27160512
doi:10.3762/bjoc.6.8
Received: 31 August 2009
Accepted: 20 January 2010
Published: 29 January 2010
Email:
Gowravaram Sabitha* - gowravaramsr@yahoo.com
* Corresponding author
Associate Editor: J. N. Johnston
Keywords:
© 2010 Sabitha et al; licensee Beilstein-Institut.
License and terms: see end of document.
dithiane; harzialactone A; hydroxyl directed reduction; stereoisomer
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.
Introduction
Marine microorganisms such as bacteria, fungi, and microalgae
have proved to be a rich source of structurally novel and biolo-
gically 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
Figure 1: Natural harzialactone A (1), and its (3R,5S)-isomer (2).
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 consider- formations. 3 can be made by hydroxyl directed reduction of 4
able interest due to its potent biological activity and unique which in turn could be prepared by epoxide 6 opening with
structure. A few methods for its synthesis have been docu- dithiane 5.
mented in the literature [3-10] as well as a synthesis of nonnat-
ural (−)-harzialactone A [11]. However, the anti-tumor activity Results and Discussion
of Harzialactone A coupled with its unique structural architec- The synthesis of natural (3R,5R)-1 was initiated from the known
ture prompted us to attempt its synthesis.
epoxide 6, which is commercially available. Treatment of
2-phenylacetaldehyde 7 with 1,3-propanedithiol in the presence
The retrosynthesis is depicted in Scheme 1. Harzialactone 1 of BF3·Et2O in CH2Cl2 afforded thioacetal 5 in 90% yield
could be made from 3 by successive protecting group trans- (Scheme 2). The epoxide 6 was coupled with the acyl anion
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Beilstein Journal of Organic Chemistry 2010, 6, No. 8.
Scheme 1: Retrosynthesis of harzialactone A (1).
equivalent 5 (1.0 equiv), prepared by metallation at –78 °C with The synthesis of (3R,5S)-2 was also accomplished in an
1.0 equiv of n-butyllithium in the presence of BF3·Et2O to identical manner from 4 (Scheme 3). The substrate hydroxyl
obtain 8 in 64% yield. Removal of the dithioketal using HgCl2/ directed asymmetric reduction with Me4NBH(OAc)3 [15,16]
CaCO3 in CH3CN/H2O (4:1)[12] provided the corresponding was performed at 0 °C to afford the anti diol 11 as the major
hydroxyketone 4 in 82% yield. Treatment of 5 with NaBH4 and product, which was converted into stereoisomer (3R,5S)-2 via
MeOBEt2 [13,14] stereoselectively formed the syn diol 9 in acetonide 12, deprotection of benzyl group to give 13, and
good yield (80%). The diol 9 was subsequently transformed into further functional group transformations by use of the same
the isopropylidene derivative 3 by treatment with 2,2-dimeth- reagents and conditions as those described for the conversion of
oxypropane and a catalytic amount of PPTS in CH2Cl2.
10 into 1. The IR absorption at 1775 cm−1 confirms the pres-
ence of δ-lactone in (3R,5S)-2.
In the 13C NMR spectrum of 3, the acetonide methyl groups
resonated at 19.6 and 29.9 ppm indicating a 1,3-syn-relation- The anti relationship of two hydroxyl groups was studied in
ship that was further substantiated by the appearance of the compound 12. In the 13C NMR of 12, the acetonide methyl
quaternary carbon in the downfield region (98.7 ppm). Depro- groups resonated at 24.9 and 34.2 ppm indicating a 1,3-anti-
tection of the benzyl group using Li/liq. NH3 gave alcohol 10. relationship that was further substantiated by the appearance of
Oxidation of alcohol 10 under Swern conditions and further the quaternary carbon in the downfield region (100.5 ppm) [7].
oxidation of the resulting aldehyde using NaH2PO4, NaClO2 in
DMSO/H2O furnished the target hydroxylactone (3R,5R)-1 as In conclusion, a stereoselective synthesis of natural (+)-
reported earlier. The IR absorption at 1774 cm−1 indicates the (3R,5R)-harzialactone A and its nonnatural stereoisomer
presence of δ-lactone system.
(3R,5S) has been accomplished.
Scheme 2: Synthesis of natural harzialactone A (1).
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Beilstein Journal of Organic Chemistry 2010, 6, No. 8.
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License and Terms
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Scheme 3: Synthesis of (3R,5S)-harzialactone A (2).
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permits unrestricted use, distribution, and reproduction in
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Experimental section and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-8-S1.doc]
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The definitive version of this article is the electronic one
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Acknowledgements
R. S. thanks CSIR, S. K. D thanks UGC, New Delhi for the
doi:10.3762/bjoc.6.8
award of fellowships.
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