Total Synthesis of (+)‐Exiguolide

Abstract

Exiguolide (1) is a unique 16-membered macrolide isolated from the marine sponge Geodia exigua Thiele (order Astrophorida, family Geodiidae).[1] It specifically inhibits fertilization of sea urchin (Hemicentrotus pulcherrimus) gametes but not embryogenesis of the fertilized egg. The macrolide structure incorporates two cis-2,6-disubstituted oxane rings, one of which carries an exocyclic enoate appendage reminiscent of bryostatins. The unique structural features and interesting biological activity of 1 has generated considerable interest in this compound, and herein we report our recent results for the total synthesis of 1.Scheme 1 shows the retrosynthetic analysis of 1. Thus, the target would be synthesized through a ring-closing olefin metathesis reaction of the carboxylate ester A followed by construction of the triene side chain. Fragments B and C are the constituents of the ester A. Fragment B may be obtained from Prins cyclization [2] of the b-alkoxyacrylate D, which should be accessible from the oxane derivative E. Fragment E may in turn be obtained by radical cyclization [3] of the b-alkoxyacrylate F.For synthesis of the B fragment, the secondary alcohol 3 was prepared from the known aldehyde 2[4] through Brown allylation, [5] hydroboration-oxidation, and protection of the primary hydroxy group with TBS (Scheme 2). The reaction of 3 with methyl propiolate in the presence of N-methylmorpholine produced the corresponding b-alkoxyacrylate derivative, which was converted into the iodide 4 by cleavage of the TBS group and iodide substitution. Radical cyclization [3] of 4 in the presence of 1-ethylpiperidinium hypophosphite and triethylborane in ethanol [6] proceeded efficiently and selectively to yield, almost quantitatively, the oxane 5. DIBAL reduction of 5 and a second Brown allylation led to a homoallylic secondary alcohol product, from which a second b-alkoxyacrylate derivative 6 was obtained by reaction with methyl propiolate. In the presence of trifluoroacetic acid, Prins cyclization [2] of 6 was successful and the products were hydrolyzed to a mixture ( % 3:1) of alcohols, which was then converted into the ketone derivative 7 by Dess-Martin oxidation. There were signs of partial ( % 7:1) racemization [7] in the Prins cyclization step. The keto ester 7 was converted into the keto acid 8 by dimethyl ketalization-hydrogenolysis, Dess-Martin oxidation, and rhodium-catalyzed methylenation [8] of the product aldehyde, followed by hydrolysisdeketalization and subsequent chromatographic separation.The known aldehyde 9 [9] served as the starting material in the synthesis of the C fragment (Scheme 3). Brown crotylation [10] of 9 produced the allylic alcohol 10, but a Sharpless kinetic resolution [11] step had to be included for improvement of the enantiomeric purity. For preparation of the final Scheme 1. Retrosynthetic analysis of exiguolide (1).

Hypervalent iodine reagents in the total synthesis of natural products

“…77,78 The oxidation of a complex substrate bearing a primary alcohol has been described by Hirama and co-workers (Scheme 5). ROMPM, 114,115,118,183 ROBn, 80,90,104,106,110,124,191,192 ROTr, 180 ROMe, 94,101,107,113,192 RONPhth, 88 RON=CMe 2 , 88 ArOAllyl, 193 ArOMe, 108,130,131,192,194,195 ArOBn, 127,131 ArOTBS, 174 R 2 NBoc, 174,[194][195][196][197] 208 This IBX analogue generates only water during the oxidation, while DMP releases acetic acid. When DMP was applied the required keto ester was obtained in only 60%, with 40% of the starting lactone recovered (Scheme 6).…”

Catalytic Asymmetric Total Synthesis of Exiguolide

“…The significant biological properties and structural challenges have made the exiguolides attractive targetsf or synthesis. The first synthesis of (+ +)-exiguolide, an enantiomer of 1,h as been achieved by Lee et al, [7] and itsa bsolute configuration was also elucidated.T he total synthesis of the naturally occurring (À)-exiguolide (1)w as accomplished by Fuwa and Sasaki, [8] followed by Roulland, [9] Scheidt, [5] and Song. [10] The formal synthesis of 1 was also reported by Reddy et al [11] Furthermore, Fuwa investigated the structure-activity relation-ships of 1,i ndicating that the terminus of the side chain tolerates structural modificationa nd the C15 methyl group is not important but the C18m ethyl group is indispensable for the potent antiproliferative activity.H erein we report an ovel total synthesis of (À)-exiguolide (1)a nd 15-epi-exiguolide by utilizing two catalytic asymmetric reactions in entirely stereocontrolled manner.…”

Alternative Non-Ionic Pathway for Uncatalyzed Prins Cyclization: DFT Approach

“…1,3-Dioxanes, for example, can be synthesized with an excess of suitable aldehyde in presence of an acid catalyst. 12 It has been well established that either strong Lewis (e.g., TiCl 4 , TiBr 4 , InCl 3 , SnCl 4 , BF 3 .OEt 2 ) [13][14][15][16][17][18] or Brønsted acids (e.g., H 2 SO 4 , trifluoroacetic acid, p-toluenesulfonic acid, triflic acid) [19][20][21][22] have to be employed to the effective synthesis of these heterocycles. Some studies have demonstrated that concomitant usage of both types of acid catalysts has positive synergistic effect.…”