Versatile Enantiocontrolled Synthesis of (+)-Fostriecin. -Title compound (XIII) is enantioselectively synthesized in its naturally occurring form via a versatile route which allows to secure all possible stereoisomers of the C1-C13 fragment. Key steps of the approach are the asymmetric allylation of aldehyde (I), a ring closing metathesis affording (VI) and a Sharpless dihydroxylation to give diol (VII). -(ESUMI, T.; OKAMOTO, N.; HATAKEYAMA*, S.; Chem.

Fostriecin, a potent protein phosphatase inhibitor and antitumor agent, has been enantioselectively synthesized in naturally occurring form via a versatile route, which also allows one to secure all possible stereoisomeres of the C1-C13 fragment including the C11 stereocenter and the geometry of the delta 12-double bond.

Unresectable oral melanoma is often treated with radiation therapy (RT) and may show a temporary response to therapy. The clinical stage is one of the well-known prognostic factors for canine oral melanoma. However, the factors that directly affect the response to RT have remained unclear. This study aimed to validate the risk factors for recurrence after RT. Sixty-eight dogs with oral melanomas were included in this study. All dogs were treated with palliative RT using a linear accelerator without adjuvant therapies. After RT, the time to local recurrence (TTR) and overall survival (OS) were evaluated using the log-rank test. As a result, clinical stage and response to therapy were the significant independent prognostic factors in the multivariate analysis. The presence of local bone lysis and non-combination with cytoreductive surgery were associated with a worse response to RT. Immunohistochemical analysis for hypoxia-inducible factor-1α indicated that tumor cells invading the bone are under hypoxic conditions, which may explain a poorer efficiency of RT in dogs with bone lysis. In conclusion, clinical stage and combination with debulking surgery were needed to improve the efficiency of RT.

+)-Fostriecin and (+)-phoslactomycin B, which are potent and selective inhibitors of protein phosphatase, were synthesized by a highly enantio-and stereoselective approach that enabled us to prepare all possible isomers at both the C11 secondary alcohol position and the D 12 -double bond.The soil bacteria species Streptomyces produce a series of structurally novel antifungal and antitumor antibiotics that include fostriecin, 1 PD113,271, 1 the phoslactomycins A-F and I, 2 the phosphazomycins C 1 and C 2 , 3 and the leustroducsins A-C and H. 2e,4 These compounds are highly potent and selective inhibitors of protein serine/threonine phosphatase 2A, which may account for their antitumor activity. 5,6 Because of their intriguing molecular architectures and their potential as a lead compounds for anticancer drugs, as well as their importance as biological tools, this class of compounds has attracted much attention in the chemical and biological communities. 7 As a result, there have been a number of formal and total syntheses of fostriecin, 5a,8,9 PD113,271, 10 leustroducsin B, 11,12 and phoslactomycin A and B, 13 including ours. Here, we describe details of our total syntheses of (+)-fostriecin (1) 9f and (+)-phoslactomycin B (2); 13c the methods used also enabled us to prepare various analogues of these compounds.The close structural similarity between (+)-fostriecin (1) and (+)-phoslactomycin B (2) allowed us to devise a common synthetic plan, which is illustrated in Scheme 1. We envisaged ynone 7 as a precursor to make our approach flexible. We expected that the advanced intermediate 3, as well as its stereoisomers 4, 5, and 6, would each be available from 7 by a combination of stereoselective formation of the (E)-or (Z)-iodoenone 14 and C9-OH directed anti-or syn-selective reduction. 15 To access 7, we envisaged an approach from alcohol 8 involving ring-closing metathesis 16 and Sharpless asymmetric dihydroxylation, 17 both of which were thought to be challenging in terms of selectivity because of the possibility of reaction occurring at several sites. In addition, the key issues to be addressed for the synthesis of 2 were stereoselective construction of the C4 asymmetric center and the installation of the C8 asymmetric quaternary center along with its aminoethyl substituent. Scheme 1 Retrosynthetic analysis of fostriecin and phoslactomycin BThe synthesis of fostriecin (1) began with the stereoselective preparation of trienol 12 (Scheme 2). 2,3-Dihydrofuran was first converted into the (3E)-4-(tributylstannyl)pent-3-en-1-ol with complete E-selectivity by means of Aldisson's procedure. 18 (3E)-4-(Tributylstannyl)pent-3-en-1-ol was subjected to p-methoxybenzylation to give the ether 9, which was iodinated to give alkenyl iodide 10. Heck reaction 19 of the iodide 10 with acrolein, gave the aldehyde 11. Brown's asymmetric allylation 20 of 11 gave alcohol 12 in good yield. The optical purity of 12 was not determined at this stage because of its instability both under the conditions for HPLC analysis on a chiral column...