ennoxazole A 1 6 11 17 24 Philip Williams Group eting December 12, 2007
Discovered Discovered by Paul cheuer at the University of awaii in 1991. Isolated 480mg ennoxazole A from 4.5kg from the sponge Polyfibrospongia species. Also obtained ennoxazoles B D, though smaller amounts. Initial bio activity assays displayed that ennoxazole A is activeagainst against herpes simplex virus type 1 (IC 50 0.6 μg/ml) and has peripheral analgesic activity similar to indomethacin when tested in mice. The absolute stereochemistry was not fully determined. cheuer, P. J., et. al, J. Am. Chem. oc., 1991 113, 3173
tructure and Design 1 6 11 17 24 (+) ennoxazole A Cl Cl Muscoride A Diazonamideid A xazole xazoline xazolidine 2-xazolidinone
etro? 1 6 11 (+) ennoxaxole A 17 24 4 Total yntheses: Wipf, Williams, hioiri, and mith.
etro 1996 Wipf 1 6 11 17 24 1 6 2 11 + 17 24 Br I Wipf was the first to synthesize ennoxazole A. Designed his endgame to couple the bis oxazole moiety last the big challenge. emember, he didn t know the stereochemistry at C8 and C22! Wipf, P., et. al, Chimia, 1996 50(4), 157.
etro 1999 Williams, D. 1 6 11 17 24 Piv C 3 + 24 X X = Ph Piv nbu 3 + TBDP Concern over the stability of the skipped triene caused Williams to build that in to the molecule last. Williams, D., et. al, J. Am. Chem. oc., 1999 121, 4924.
etro 2007 mith 1 6 11 17 24 1 6 11 Br 11 mith intended to apply some of the oxazole alkylation work his lab had been working on. mith, T.E., et. al., J. rg. Chem. 2007 AAP
Wipf s ynthesis Western alf Br 6M a BnEt 3 Cl Br BuLi, -78 to r.t. 1. MCPBA 2. Et 2, 1. harpless Epox. 2. ed-al, TF, Tol. 1. TBDM-Cl, Imid., C 2 Cl 2 2. Li, 3, t-amyl alcohol TBDM 1. 3 TBDM Ts, TF 2. 2,Pd() 2 TBDM ab 4,CeCl 3 TBDM 1. TIP-Cl 2. PPTs,, () 3 C 3. Li, dioxane/et/ 2 TIP 1. M, TPAP 2. (Et 2 ) 2 P()C 2 C 2 Et TIP 1. DIBAL-, TF 2. harpless Epox. TIP Absolute configuration of C8 stereocenter was chosen arbitrarily. Et Installing the desired anomer of the mixed acetal was challenging due to the potential elimination of the beta silyl ether. Wipf, P., et. al, Chimia, 1996 50(4), 157.
Wipf s ynthesis Western alf TIP TIP BnC, TEA, C 2 Cl 2 Bn a, TF TIP 6.7:1 Bn 1. a, I 2. Li, dioxane/et/ 2 3. Pd() 2,Et, 2 TIP 2 Urethane cyclization proceded in a 6.7:1 ratio of isomers. 22 steps, 5% yield. Wipf, P., et. al, Chimia, 1996 50(4), 157.
Wipf s ynthesis Eastern alf (Ph)(Bu 3 n)culi nbu 3 catecholborane Bu ()-oxazaborolidine 3 n 2,6-lutidine C Cl Bu 3 n TMB 2 CuLi Bu 3 n 2 TBDM 1. 2 4, g 4 2. TBDM-Cl, Imid. 3. C() 3, + 4. Li, 2, TF TBDM TBDM 1. er-, IBCF 2. Burgess eagent Et 3 CuBr 2,MTA DBU, C 2 Cl 2 1. TBAF 2. B, Ph 3 P Br EWG was critical for first oxazole formation. thyl stereocenter at C22 was also arbitrarilychosen Wipf, P., et. al, Chimia, 1996 50(4), 157.
Wipf s ynthesis coupling Pd 0 tille Coupling Bu 3 n Br I 2 1. t-buli I 2. ZnCl 2 3. Pd 2 (dba) 3 CCl 3 (5 mol%) Ph 3 As (20 mol%) 4. Li, 2 Br Bu 3 n tille coupling failed presumably due to the severe A 1 3 strain of the stannane.
Wipf s ynthesis Endgame TIP TIP P-Br PF 6 3 2 1. DMP 2. BrCl 2 C-CCl 2 Br, Ph 3 P 3. DBU, C 3 C 4. TBAF (+) ennoxazole A 28 steps (longest sequence). pectroscopic investigation determined the natural stereoisomer of the natural product. Matches up with van t off s principle p of optical superposition. p
mith s ynthesis Western alf 2 -Cl Et -Cl 1. TEA 2. CuBr 2,DBU MTA 3. a, 2 1. Cl 2,reflux 2. er--cl, TEA 1. Deoxo-Fluor 2. DBU, BrCCl 3 3. DIBAL- TM, TMTf n-buli, TBTf =TB F 3 Deoxo-Fluor mith, T.E., et. al., J. rg. Chem. 2007 AAP
mith s ynthesis Western alf TE 1. soft enolization 2. dimethyl acetal BF 3 -Et 2 TE 1. DIBAL- 2. ipr n(tf) 2, -Et-piperidine then aldehyde ipr magnesiumm acetoacetate imid., DMF then 2M Cl - 2 1. ab 4,CeCl 3 2. TB-Cl, imid, DMAP 3. C() 3,,PPT TB TB Many of the current directed acetate aldol auxiliaries were tested. mith, T.E., et. al., J. rg. Chem. 2007 AAP
mith s ynthesis Eastern alf K, Bu 3 nc 2 I then n-buli 1. DMP 2. a, (Et) 2 P()CC 2 Et 3. DIBAL- 4. MsCl, TEA - then LiBr Br mith s design of a [2,3] Wittig till rearrangement allowed him to access this fragment in 6 steps fewer than Williams synthesis. mith, T.E., et. al., J. rg. Chem. 2007 AAP
mith s ynthesis Endgame 1. LiEt 2,then TB TB Br 2. TBAF (-) ennoxazole A 14 steps from commercially available materials. (really 17 steps ) Employed a one pot acylation/decarboxylation/cyclodehydration and determined the alkylation selectivities for bis oxazoles. mith, T.E., et. al., J. rg. Chem. 2007 AAP
eferences cheuer, P. J., et. al, J. Am. Chem. oc., 1991 113, 3173. 3 Wipf, P., et. al, Chimia, 1996 50(4), 157. Wipf, P., Miller, C.P., J. rg. Chem., 1993 58, 3604. mith, T.E., et. al., J. rg. Chem. 2007 AAP. mith, T.E., et. al., rg. Lett., 2004 6(14), 2317. mith, TE T.E., Balskus, EP E.P., eterocycles, 2002 57(7), 1219. mith, T.E., et. al., rg. Lett., 2007 9(6), 1153. hioiri, T., et. al., rg. Lett., 2000 2(26), 4169. hioiri, T., et. al., ynlett, 1997 1, 109. hioiri, T., et. al., eterocycles, 1998 47(8), 73. Leahy, J. W., et. al., ynlett, 2007 4, 623. Williams, D.., et. al., Tett. Lett., 1997 38(3), 331. Williams, D., et. al, J. Am. Chem. oc., 1999 121, 4924.