Formal synthesis of nanaomycin D via a HausereKraus annulation using a chiral enone-lactone Najmah P.S. Hassan a, b , Briar J. Naysmith a, b , Jonathan Sperry a, b , Margaret A. Brimble a, b, * a School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand b Maurice Wilkins Centre for Molecular Biodiscovery, c/o School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand article info Article history: Received 4 May 2014 Received in revised form 27 June 2014 Accepted 5 September 2014 Available online xxx Keywords: Pyranonaphthoquinones HausereKraus annulation Nanaomycin g-Lactone abstract A formal total synthesis of nanaomycin D has been achieved. The strategy employed made use of a one- pot cyclisationestereoselective reduction of a hydroxyketone to install the pyranonaphthalene moiety after execution of a HausereKraus annulation using a chiral enone-lactone as the Michael acceptor to append the g-lactone ring. The chirality in the chiral enone-lactone was established using a Sharpless asymmetric dihydroxylation. The enone-lactone used herein represents an attractive chiral synthon for the construction of other g-lactone containing pyranonaphthoquinones such as griseusin A and crisa- micin A. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The pyranonaphthoquinones are a large family of natural products that all share a common naphtho[2,3-c]pyran-5,10-dione ring system. 1 These natural products remain attractive synthetic targets in our research group. 2 The nanaomycins are a subgroup of the pyranonaphthoquinones that bear a naphthol at C9 and a methyl group with the (S)-configuration at C1 of the dihy- dropyran ring. 1a Nanaomycins A 1 and B 2, were the first members of the family to be isolated from the cultured broth of a Strepto- myces sample during screening for anti-mycoplasmal agents (Fig. 1). 3 These compounds both contain a carboxylic acid sub- stituent at C3, while nanaomycin B 2 has also undergone hydration across the C4aeC10a double bond. Since then, eight further nanaomycins have been isolated, including nanaomycin D 3, in which the carboxylic acid side-chain is ring-closed to form a fused g-lactone. 4 Nanaomycin D 3 is the enantiomer of previously iso- lated kalafungin. 4 Nanaomycin C 4 contains an amide side-chain 5 while nanaomycin E 5 bears an epoxide at C4aeC10a. 6 Other nat- ural nanaomycins comprise methyl ester or reduced derivatives of the C3 side-chain (Fig. 1 , 6e10). 1a The nanaomycins display an im- pressive range of biological activity against mycoplasma, fungi and both Gram positive and Gram negative bacteria. 1a,7 They have also been found to exhibit inhibitory activity against platelet aggrega- tion, 8 topoisomerase II 2g and DNA methyl transferase B, 9 with possible applications for the treatment of bleeding disorders and cancer. A number of total and formal syntheses of nanaomycin D 3 have been reported. 10 One such synthesis involved construction of the pyranonaphthalene ring system using a HausereKraus (HK) Fig. 1. Nanaomycin natural products. * Corresponding author. E-mail address: m.brimble@auckland.ac.nz (M.A. Brimble). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.09.014 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved. Tetrahedron xxx (2014) 1e7 Please cite this article inpress as: Hassan, N. P.S.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.09.014