Approaches to the Total Synthesis of the Avermectins

Transcription

1 Approaches to the Total Synthesis of the Avermectins December 8, 000 Brian Raymer Avermectin B1a Structure Determination: Albers-Schonberg; JACS 1981, 103, 416 Absolute Configuration: Albers-Schonberg; JACS 1981, 103, 41 Lead Reviews: Davies, Green; NPR 1986,, Chem Soc. Rev. 1991, 0, Chem Soc. Rev. 1991, 0, xahydrindene Subunit Synthesis: Peak, Smith; Studies in Nat. Prod. Chem. 1993, 1, 3-31 Biosynthesis: mura, Ikeda; Chem. Rev. 1997, 97, Lead Reviews 1/7/00 11:4 PM

2 Avermectin B1a Avermectin B1a Discovered in soil sample from Japanese Golf Course (Kawana, Ito City; 197) First therapeutic target: gastrointestinal worms in horses (Dr. W. Cambell, rck) Broad spectrum anthelminic (worms), microfilaricide (heartworms), and miticide (mites) used for horses, cattle, pigs, household pets Commercial Avermectin Derivatives: Ivermectin (rck), Dormectin (Pfizer) Ivermectin used in humans, especially for river blindness (onchocerciasis) uman dose: 9.1 mg/100 lbs., one injection topic: mectizan 0 - Biology 1/8/00 1:0 AM

3 Avermectin Structure Avermectin B1a 8 7 macrocycle oxahydrindene with stereogenic centers at,, 6, 7 E, E diene from 8 to 11 anti 1 and stereocenters diglycoside (dioleandrose) trisubstituted alkene at 14 and 1 thermodynamic spiroketal with stereogenic centers at 17, 19, (3), 4, alkyl substituent at

4 Contents 1. Biosynthesis and Nomenclature. Degradation (anessian) 3. Total Syntheses anessian (B1a) JACS 1986, 108, 776 (communication) Pure & Appl. Chem. 1987, 9, 99 (full paper) Danishefsky (A1a) JACS 1987, 109, 8117 (communication) JACS 1989, 111, 967 (full paper) Ley (B1a) Synlett 1990, 33, 36, 39 (communication) J. Chem. Soc., Perkin Trans , 667 (full paper) White (B1a) JACS 1990, 11, 166 (communication) JACS 199, 117, 1908 (full paper) 4. Brief comparison of major synthetic steps 04 - Contents 1/8/00 :37 AM

5 Major Synthetic Steps glycosidation fragment coupling 11 oxahydrindene fragment formation spiroketal fragment formation macrolactonization C stereochemistry Avermectin B1a rder of Presentation 1. spiroketal fragment formation. oxahydrindene fragment formation 3. aglycone formation and glycosidation R rder of Presentation 1/8/00 1:08 PM 3 R 8 9 fragment coupling C stereochemistry macrolactonization glycosidation glycoside construction (appendix; Ley, Danishefsky)

6 Biosynthesis: Cyclohexenone and Spiroketal Formation 7 acetates, propionates L-isoleucine(a) or L-valine(b) AVERMECTIN PKS Enz S aldol spiroketalization Enz S Enz S R R 7 :B R 7 + B 7 S Enz macrocyclization 06 - Biosynthesis Aglycon 1 1/8/00 1:1 PM Chem Rev. (1997)

7 Biosynthesis: xahydrindene Formation C 7 C 7 C 7 Fe IV Fe IV Fe III Fe IV C 7 C 7 C 7 Fe III Fe IV Fe IV oxygen derived from molecular oxygen amino acid sequence of protein resembles cytochrome P Biosynthesis Aglycon 1/8/00 1:06 AM Chem Rev. (1997)

8 Biosynthesis: C reduction and C Glycosidation C ketoreductase C--methyltransferase thyl ether is also glycosylated dtdp-oleandrose C -glycosyltransferase 4' C4' -glycosyltransferase 4' Avermectin Ba dtdp-oleandrose 08 - Biosynthesis Glycosidation 1/8/00 1:10 AM Chem Rev. (1997)

9 Avermectin Nomenclature R 1 3 Y X R Avermectin B1a A: R 1 = ; B: R 1 = 1: X-Y = C=C ; : X-Y = C C() a: R = s-bu ; b: R = i-pr Avermectin R1 R X Y (1) A1a s-bu C=C () A1b i-pr C=C (3) Aa s-bu C C() (4) Ab i-pr C C() () B1a s-bu C=C (6) B1b i-pr C=C (7) Ba (8) Bb s-bu i-pr anessian, Ley, White: B1a Danishefsky: A1a C C() C C() 09 - Avermectin Nomenclature 1/8/00 1:1 PM

10 Avermectin is similar to Milbemycin and Nemadectin 3 3 Milbemycin α1 3 Avermectin B1a Nemadectin 10 - Milbemycin Nemadectin 1/8/00 1:11 AM

11 anessian: Avermectin Degradation TBS Avermectin B1a (minor component B1b) provided by rck 1. aq. K, DME. C N 3. TBSCl 71%, 3 steps TBS C TBS TBS 19 TBS + C TBS 3; NaB 4 (Sudan 7B) 9% yield mixture of 1a and 1b 79% yield used in fragment coupling 11 - anessian Avermectin Deg 1 1/8/00 1: PM anessian, TL 1986, 7, 699

12 anessian: Avermectin Degredation TBS TBS 1 TBS PCC, 90% 1 TBS KMDS, TF, -30 C, 8% TBS S N PyrSSPyr, PPh 3 no yield or experimental provided TBS + TBS mixture of 1a and 1b products 1 - anessian Avermectin Deg 1/8/00 1:14 PM anessian, TL 1986, 7, 699

13 anessian Disconnections glycosidation fragment coupling oxahydrindene fragment formation 10 9 spiroketal fragment formation 1 macrolactonization C stereochemistry Avermectin B1a - anessian Fragments 1/8/00 1:1 PM

14 anessian: Lactone Synthesis R B 3 DMS. acetone, Ts 9%, steps PCC 77% 1. BrMg. BnBr, Na 76%, Steps Bn S - malic acid 1:1 selectivity , DMS 3. BF 3 Et, 60%, 3 steps TBDPS Bn 1. aq. Ac. TBDPSCl, pyr. 3. PCC 73%, 3 steps Bn 1. PCC, 81%. Ph 3 P=C, 71% 3. 9-BBN, 97% Bn "It should be noted that the unwanted diastereomer would be an ideal precursor to the lactone portion of the compactins and mevinolins" See JC (1990) anessian Lactone Fragment 1/8/00 1:48 AM Pure & Appl. Chem. 1987, 9, 99 (full paper)

15 anessian: Spiroketal Formation 1. Ph 3 P=CC, 89%. DIBAL, 9% 1. Sharpless AE, 74%. Cu(CN)Li, 96% 0% from L-isoleucine 1. TBDPSCl, imidazole, 9%. MMCl, ünig's base DMAP, 94% TMS 3 1. Ph 3 P, CBr 4. n-buli, 77%, two steps 3. TMSBr 4. TMSCl, NEt 3, DMAP, MM 1. TBAF, 98%. PCC, sieves, 78% TBDPS MM 8%, two steps n-buli, 1, TBDPS then PPTS, 8% Bn TBDPS 1. Lindlar, pyr.,. BF 3 Et, 80%, steps Bn 3. TBAF, 87% Bn no dr reported 1 - anessian Spiroketal 1/8/00 :0 AM Pure & Appl. Chem. 1987, 9, 99 (full paper)

16 anessian: Skeleton Fragment 1 C C 1. Et, + 1. K C Et. LDA, I. cyclohexanone, BF 3 80%, steps C Et S-Malic acid no dr reported C 1. B 3 DMS. BF 3 Et 48%, 4 steps Bn 1 TBDPS TBDPSCl, imid 87%, 3 steps Bn 1. BnBr, Ag. Li 9 steps, 34% yield 16 - anessian Skeleton 1/8/00 :0 AM

17 anessian: Aglycone Elaboration 1. PhSSPh, Ph 3 P, 8%. m-cpba, -10 C, 90% Ph S Bn Bn n-buli, TF, -78 C, then 40% (9% based on rec sm) Bn TBDPS Na/g,, K P 4, 40%. TBAF, 9% 3. Li/N 3, 7% Bn S Ph TBDPS Bn no E:Z reported 17 - anessianaglycone1 1/8/00 :07 AM

18 anessian: xahydrindene Partial Synthesis C (-)-Quinic Acid 1. acetone, 3 +. Na, 3. PCC 60%, 3 steps C 1. PCl 3, pyr.. NaB 4 3. acetone, 3 + 8%, 3 steps C C 1. TlEt, DMF; Br C 1. PCC. MgBr C Br Ac Br. Ac, pyr. 0%, steps, 3 + 9%, 3 steps Ph 3 Sn, AIBN no dr reported 66% C Ac 1. Ac, pyr.. 3 ; DMS 91%, steps C Ac Ac Pb(Ac) 4, Ac, 7 C 7% 8 C R Ac Ac no dr reported R=Ac 11 % overall yield, 16 steps not used in coupling step 18- anessian xahydrinene1 1/8/00 1:16 PM

19 anessian: Aglycone Elaboration 1. 3 CCl, Et 3 N, 78%. TBSCl, imidazole, DMAP, 91% 3. Na,, 80% TBS 11 TBS 1. Ph S, PBu 3, 83%. m-cpba, 96% 3. n-buli, TF, -78 C, then 3, 77% 10 C R 3 TBS R=TMS from degradation C 1. SCl, pyr., then Na/g,. TBAF, 8%, steps TBS S Ph TBS C R no E:Z ratio indicated TBS R=TMS 19 - anessianaglycone 1/8/00 :11 AM

20 anessian: Macrocyclization and Glycosylation C 1. aq. K, then Dowex 0, 7 %. DCC, DMAP, 30% TBS 4 SPyr from degradation 1. TBSCl, imidazole, 91%. 4, C Cl, AgTf, 7% TBS 1. TMSCl, Et 3 N, DMAP, 96%. LDA, TMSCl, then Ac, 31% (7% based on rec. sm) 3. TBAF, 90% Avermectin B1a 3 4 Deconjugation to epi-c, then epimerization For a detailed discussion of the C epimerization: Fraser-Reid JACS 1987, 109, 933, anessian JACS 1987, 109, TBS 0 - anessiancyclglyc 1/8/00 :19 AM

21 anessian: Route Summary TBDPS [14 steps, 7%] Bn TMS 1 steps 6 steps (acetylene) 6% 34% Ph S Bn 18 linear steps, 11% yield linear steps, 0.% yield (71 total steps) 10 C R [degradation] R=TMS steps (Julia) 14% Macrolactonization: DCC, DMAP Bn 9 steps (Julia) 16% [9 steps, 34%] TBDPS TBS 11 S Ph TBS 7 linear steps, 1.4% yield TBDMS steps (AgTf) 40% Avermectin B1a 37 linear steps, 0.08% yield [degradation] SPyr Synthetic Strategy 1. spiroketal and oxahydrindene. fragment coupling (Julia, 10-11) C 10 Aldehyde / C 11 Sulfone (6%) 3. macrolactonization (DCC, DMAP) 4. glycosidation (AgCl 4 ). C isomerization 1 - anessian Route Summary 1/8/00 11:38 AM

22 Danishefsky Disconnections glycosidation fragment coupling 1 11 oxahydrindene fragment formation spiroketal fragment formation macrolactonization C stereochemistry Avermectin A1a - Danishefsky Fragments 1/8/00 :33 AM

23 Danishefsky: Spiroketal Assembly R 17 3 Piv Piv Piv steps from tri--acetyl-d-glucal Ph 3 Si BF 3 Et 90% Piv Piv dr: 4.:1 "...specific for axial attack." (74% yield of desired diastereomer), Pd/C 90% Piv Piv CuI, Li 73% dr: 4:1 TMS MgBr Et then TFA 77% 1. Li, 8%. Tf, pyr., then NaCN, 8% 3. DIBAL, 90% Piv Piv Piv SiPh 3 Mg TMS 3 - Danishefsky Spiroketal1 1/8/00 1:18 PM JACS 1989, 111, 967 (full paper)

24 Danishefsky: Spiroketal Assembly 4:1 anti:syn 1. NaB 4, CeCl 3, 63%. TBSTf, lutidine, 87% TBS no dr reported aq. NBS, then Ph 3 Sn, cat. AIBN 93% TBS α:β not determined 1. LiB 4, 93%. PivCl, DMAP, 89% 3. F, 87% I I I hυ [ I + ] g, I, hυ, 3% Piv Piv Suarez JC 1996, Piv 1. LiBEt 3, 78%. Swern, 91% Piv Piv 4 - Danishefsky Spiroketal 1/8/00 :44 AM JACS 1989, 111, 967 (full paper)

25 Danishefsky: Sidechain Elaboration PPh % Piv no E:Z given Piv C C B 99% PPh 3 9% TBS 11 Piv 1. TBSTf,,6-lut, 94%. s 4, pyr. 3. Pb(Ac) 4 66%, steps 1 Piv dr: 4:1 TBS C 9 Piv 1. DIBAL. Swern, TEA 9%, steps TBS 9 Piv C no E:Z given B C R L - Danishefsky Sidechain 1/8/00 :47 AM

26 Danishefsky: xahydrindene Precursor R 9 8 BF 3 Et, 79% SnBu 3 * dr: 10:1 1. Na, I, 86%. 1N Cl, then BF 3 Et, Et 3 Si, 79% 8 Br Ac Amberlite IRA-400, 9% C 1. LiBEt 3, 96%. 3 ; Zn, Ac 3. 84% Br Br one isomer PPh 3 1. DIBAL, 97%. TBSCl, TEA, DMAP, 97% TBS PCC, NaAc, 89% TBS SnBu Danishefsky xahydrindene 1/8/00 1:19 PM

27 Danishefsky: xahydrindene Synthesis TBS 10 Piv + 9 TBS LiMDS, then MsCl 67% TBS 9 10 Piv TBS 1. F, 90%. PCC, NaAc, 88% TBS Piv C 8 Al 3, LiSPh; m-cpba, DMS, 76% R C SPh 8 3 TBS Piv Danishefsky xahydrindene 1/8/00 3:08 AM

28 Danishefsky: Macrolactonization TBS Piv C 1. NaCl, Na P 4. C N, 79%, steps 3. Li, 9% TBS C N + Cl I - TEA 6% 1. TBAF, 87%. LDA, 71% 3. imidazole, 3% TBS 3 4 3,4 imidazole epimerization produced 1%,3 and 33% epi- 3,4 which could be reused., Danishefsky Aglycone 1/8/00 3:1 AM

29 Danishefsky: Glycosylation Ac NIS, 64% Ac I Bu 3 Sn, AIBN, 78% Ac LiEt 3 B, 97% Avermectin A1a 9 - Danishefsky Glycosidation 1/8/00 1:0 PM

30 Danishefsky: Route Summary Piv Piv Piv 16 steps, (crotylsilane, cycloaddition) 8 steps, (crotylboronate, wittig) 3% Piv % TBS 9 8 [10 steps, 33%] 8 11 steps (aldol) 3.7% Macrolactonization: Mukaiyama TBS 9 Piv 4 linear steps, 1.6% yield 3 linear steps, 0.06% yield (44 total steps) 3 steps (NIS) 48% Avermectin A1a 38 linear steps, 0.03% Ac [9 steps, 18%] Synthetic Strategy 1. spiroketal. fragment coupling (aldol, 8-9) C 8 enol / C 9 aldehyde (67%) 3. oxahydrindene (Nozaki) 4. macrolactonization (Mukaiyama). C isomerization 6. glycosidation (NIS) 30 - Danishefsky Route Summary 1/8/00 11:39 AM

31 Ley Disconnections glycosidation fragment coupling oxahydrindene fragment formation spiroketal fragment formation macrolactonization 8 C stereochemistry Avermectin B1a 31 - Ley Disconnections 1/8/00 1:1 PM

32 Ley: Spiroketal Precursor R 17 3 from l-isoleucine JACS (194) 37 Et C PPh 3 8% > 0:1 E Et C DIBAL, 91% 19 Sharpless AE, 81% (C) 3 Fe + Fe(C) 3 Fe (C) 9, 99% 1. Swern, 80%. Ph 3 P=C, 8% 1 no ee reported 40 atm C, 0 C 7 hours 40 atm C, 140 C 4 hours + + A 1., Pt, 100%. DIBAL, 93% 3. PhS, CSA, 71% Ph S 3 A B C From 1 40% 3% 7% From 6% 4% 10% desired hexenone % overall 3 - Ley Spiroketal Precursor 1/8/00 3:9 AM 9% axial J. Chem. Soc., Perkin Trans , 667 (full paper)

33 Ley: Spiroketal Precursor R ribonic acid-γ-lactone JCSPT1 (1984) 1 TBDPS Ts 1. TBAF. TsCl, pyr. IR-400, 60% 6%, steps Ts Br 1. TPAP, NM, mol. sieves, 94%. ((+)-IPC) B BF 3 Et, 7% Br TBDPSCl, imidazole, DMAP, 9% TBDPS Br R L M S L S B M L 1 "excellent selectivity" TBDPS 1 17 TBS 19 TBSCl, TEA, DMAP, 94% TBDPS t-buli, 3 Al, then 3, 8% 33 - Ley Spiroketal Precursor 1/8/00 1:6 PM J. Chem. Soc., Perkin Trans , 667 (full paper)

34 Ley: Spiroketal TBDPS TBS + Ph S t-buli, then BF 3 Et, 4% TBDPS 17 3 TBS PhSeCl, TEA, then CSA, 66% TBDPS 17 3 Davis oxaziridine, TEA, 76% TBDPS PhSe TBAF, 98%. TBSCl, imidazole, 9% TBS 11 TBS 1. s 4, NM, 77%. NaI 4, K P 4, 86% TBS 11 TBS 34 - Ley Spiroketal 1/8/00 3:0 AM

35 Ley: xahydrindene Precursor R 9 8 TBDPS Li, N 3, 9% Al 3, (C) n, 64% 1. TBDPSCl, DMAP, TEA, 98%. ethylene glycol, PPTS, 88% 1S-(-)-camphanic acid chloride Cl 4 1. s 4, NM, 71% 4% diastereomer. TEA, DMAP, 4, 43% 3. K C 3,, 88% TBDPS TBDPS TBDPS 1. B 3 DMS, then aq. Na,, 88%. PdCl (CN), 98% Ac,, 94% () 3 C, PPTS, 100% TBDPS 1. MsCl, TEA, 100%. dioxirane, 7% TBDPS SPh Li SPh TBDPS xone, 88% S Ph 9 8 TBDPS 9% dr: > 9: 4% undesired diastereomer 3 - Ley xahydrindene 1 1/8/00 3:38 AM J. Chem. Soc., Perkin Trans , 667 (full paper)

36 Ley: xahydrindene S Ph TBDPS S 4, 80% S Ph 1. TBDPSCl, imidazole, 91%. TBSTf, TEA, 86% S Ph TBDPS TBS Swern, 73% S Ph TBDPS B 3 DMS, then, Na, 66% S Ph TBDPS NaB 4, 79% S Ph TBDPS TBS no dr reported TBS dr: 6:1 TBS TsCl, pyr., 78% S Ph TBDPS S Ph TBDPS 1. t-buli, then PhSeCl, 6%. m-cpba, 100% DBU, 77% S Ph TBS TBS TBS TBDPS 17 steps from resolved material % yield 36 - Ley xahydrindene 1/8/00 3: AM

37 Ley: Macrolactonization TBS 11 TBS 1. t-buli,, 74%. Na/g, Na P 4, 34% 10 S Ph TBDPS TBS TBS TBDPS TBS TBS 1. TBAF, 93%. (Ph 3 P) 3 RuCl 3. NaCl, 3%, steps 19 N + TEA 47% Cl I - 19 C 37 - Ley Macrolactonization 1/8/00 3: AM

38 Ley: C - C 4 Transformation 1. TPAP, NM, mol. sieves, 61%. TMSTf, TEA, 88% R R 7 R=TMS 4 1. TEA, TMSTf; PhSeCl; 91%, dr: 1:1. F, pyr., 87% 1. Davis oxaziridine. NaB 4, CeCl 3 R 3 endo 4 9%, dr: 1:1, steps R=TMS 3 4 SePh R = R = Ac AcCl, pyr., DMAP, 97% 38 - Ley Aglycone 1/8/00 1:30 PM

39 Ley: Glycoside Construction Ac 1" S N N + 1. CaC 3, AgCl 4, 64%. LiBEt 3, 90% 1" Ac Avermectin B1a 7 linear steps, 0.01% yield 39 - Ley Glycosidation 1/8/00 4:08 AM

40 Ley: Route Summary TPDBS Br [3 steps, 6%] [3 steps, 39%] steps (vinyl metal) 77% TPDBS TBS linear steps, 0% yield ( total steps) 7 steps (epoxide opening) 14% 10 steps 14% Ph S Ac linear steps, 0.0% yield (48 total steps) steps (AgCl4) 0% Avermectin B1a 7 linear steps, 0.01% yield Ac 1" S Ph 10 TBDPS [17 steps, %] TBS steps (Julia) 0.3% Macrolactonization: Mukaiyama [1 steps, %] S Imid TBS 11 TBS 1 linear steps, 7% yield Synthetic Strategy 1. spiroketal and oxahydrindene. C pre-formed 3. fragment coupling (Julia, 10-11) C 10 Sulfone / C 11 Aldehyde (%) 4. macrolactionization (Mukaiyama). glycosidation (AgCl 4 ) 40 - Ley Route Summary 1/8/00 1:3 PM

41 White Disconnections glycosidation fragment coupling 1 11 oxahydrindene fragment formation spiroketal fragment formation macrolactonization C stereochemistry Avermectin B1a 41 - White Disconnections 1/8/00 4:3 AM

42 White: Spiroketal Precursor R Ac Ac Ac Ac Ac glucose pentaacetate thods Carb. Chem (1963) II, 374 LiBEt 3, 70% R R laevoglucosan R = TsCl, pyr, 90% R = Ts p-ts, 78% PMB K, PMBCl, 76% + PMB :1 LA, 94% CSA, 60% Swern, 9% PMB PMB PMB 7 steps, 19% yield 4 - White Lactol 1/8/00 4:6 AM JACS 199, 117, 1908 (full paper)

43 White: Spiroketalization 1. Br CrCl 3, LA, 3%. TBSTf, 86% CrCl Et 3; DMS, 9% TBS TBS 1. CBr 4, Zn, Ph 3 P, 83%. n-buli, 86% 1 PMB 1. CSA,, 88%. TBAF, 86% 17 PMB 1 TBS 1. EtMgBr, then 1, 83%. Swern, 9% 17 1 TBS 1. Lindlar, quinoline. CSA, 83%, steps 19 PMB 1 PMB Swern, 100% PMB 43 - White Spiroketalization 1/8/00 4:9 AM

44 White: Sidechain Construction C Et 1. Ts, 68%. DIBAL, 90% Sharpless AE, 90% 1. CuLi, 71%. PivCl, DMAP, pyr., 90% Piv 1. PPTS, 86%. SEMCl, ünig's base, 93% SEM Piv Ac, DMAP, pyr, then DBU, 87%. MgCl, 93% PMB SEM 17 Piv PMB 3: mixture of diastereomers LDA, then 80% 17 PMB SEM Piv SEMCl = Cl TMS Ph S SEM 14 PhSCl, TEA, 87% 16 oxone, 80% 11 Piv PMB SEM Piv S Ph 16 PMB 44 - White Sidechain 1 1/8/00 1:34 PM

45 White: Sidechain Construction SEM S Ph S 1. CAN, 9% Ph. TBSTf,,6-lutidine, 7% SEM LA, 77% Piv PMB TBS Na/g, Na P 4, 3% SEM 11 C 9 TBS 1. Swern, 90%. C, 98% PPh 3 no E:Z given SEM TBS Low yield due to 1,4 elimination of -SEM to form diene 1. DIBAL, 94%. NCS, DMS, 93% convergent with degradation material SEM SEM PhS Na, 84% TBS 9 9 TBS Cl S Ph 4 - White Sidechain 1/8/00 4:36 AM

46 White: xahydrindene Synthesis TMS, 60% TMS racemic TBAF 97% racemic N 1. Na, then (CCl). C N 66%, steps α-methyl benzylamine resolution 1% pure by optical rotation 10% S 4 + N - N C C N 64%, steps C White xahydrindene 1 1/8/00 1:3 PM

47 White: xahydrindene Synthesis C NBS,, 6% C Br DBU, 91% C Na, 79% SEM 1. TFA, %. SEMCl, ünig's base, 89% TES TESTf, lutidine, 78% K C 3,, 73% C SEM TESTf, lutidine, 84% TES C SEM 1. m-cpba, 7%. TESTf, lutidine, 89% 8 C R R = TES SEM 18 steps from resolved material % yield 47 - White xahydrindene 1/8/00 4:41 AM

48 White: Fragment Coupling SEM 9 S Ph TBS n-buli, then 3, 1% C R 8 R = TES SEM 3 SEM 9 S Ph TBS C R 8 3 R = TES SEM Na, Na P 4, 4% SEM 9 8 SEM 1. Na/g, Na P 4,, 71%. TBAF, 100% 9 S Ph TBS C R SEM R = TES SEM 48 - White Fragment Coupling 1/8/00 1:3 PM

49 White: Macrocyclization and Glycosylation SEM C SEM N + Cl I - 48% SEM SEM 1. imidazole, benzene, 33% starting material 46 % desired epimer 1%,3 conjugated. F, CN, 79% inseparable Avermectin B1a 36 linear steps, 0.003% yield 1. TBSCl, imidazole, 70%. AgTf, 4, mol. sieves, 3% 3. F pyr, 64% TBS 4 SPyr from anessian degradation TL (1986) 699 alcohols are seperable 49 - White Glycosidation 1/8/00 4:48 AM

50 White: Route Summary steps 30% TBS PMB [7 steps, 19%] 7 steps (acetylene) 48% PMB 1 linear steps, 14% yield 34 linear steps, 0.0% yield (6 steps total) C R [18 steps, 0.0%] R = TES SEM 8 steps (Julia).6% Macrolactonization: Mukaiyama 14 steps (aldol) Piv % SEM [7 steps, 8%] SEM TBS S Ph 6 linear steps, 0.8% yield TBDMS steps (AgTf) 1% Avermectin B1a 36 linear steps, 0.003% yield 0 - White Route Summary 1/8/00 11:4 AM [degradation] SPyr Synthetic Strategy 1. spiroketal and oxahydrindene. fragment coupling (Julia, 8-9) C 9 Sulfone / C 8 Ketone (1%) 3. macrolactonization (Mukaiyama) 4. C epimerization. glycosidation (AgCl 4 )

51 Synthetic Strategies spiroketal fragment formation Ph S R + 11 glycosidation fragment coupling macrolactonization R Ph S R oxahydrindene fragment formation 8 C stereochemistry Avermectin B1a R anessian Synthetic Strategy 1. spiroketal and oxahydrindene. fragment coupling (Julia, 10-11) C 10 Aldehyde / C 11 Sulfone (6%) 3. macrolactonization (DCC, DMAP) 4. glycosidation (AgCl 4 ). C isomerization Ley Synthetic Strategy 1. spiroketal and oxahydrindene. C pre-formed 3. fragment coupling (Julia, 10-11) C 10 Sulfone / C 11 Aldehyde (%) 4. macrolactionization (Mukaiyama). glycosidation (AgCl 4 ) 37 linear steps, 0.08% yield 7 linear steps, 0.01% yield 1 - Synthetic Strategies 1 1/8/00 1:0 PM

52 Synthetic Strategies spiroketal fragment formation R R M R glycosidation fragment coupling oxahydrindene fragment formation macrolactonization C stereochemistry Avermectin B1a Ph S R R R Danishefsky Synthetic Strategy 1. spiroketal. fragment coupling (aldol, 8-9) C 8 enol / C 9 aldehyde (67%) 3. oxahydrindene (Nozaki) 4. macrolactonization (Mukaiyama). C isomerization 6. glycosidation (NIS) 38 linear steps, 0.03% yield Danishefsky: Avermectin A1a White Synthetic Strategy 1. spiroketal and oxahydrindene. fragment coupling (Julia, 8-9) C 8 Ketone / C 9 Sulfone (1%) 3. macrolactonization (Mukaiyama) 4. C epimerization. glycosidation (AgCl 4 ) 36 linear steps, 0.003% yield

53 Julia: Ivermectin Aglycone 0. eq. PdCl (ACN) 19 TSE 9 I TES C TSE SnBu 3 E/Z = 8:1 TBS TBS 38% desired E/E 1. TBAF, p-ts. TEA, DMAP, trichlorobenzoylchloride, 30%, steps p-ts, 8% 19 TBS 3 - Julia Aglycone 1/8/00 :3 AM Ivermectin Aglycone Synlett 1991, 614 (communication) Bull. Soc. Chim. Fr. 1994, 1, 86 (full paper) Bull. Soc. Chim. Fr. 199,, 48 (full paper)

54 Parting Notes Avermectin B1a Yield of Glycosylated Avermectin from Fragment Coupling Step fragment coupling C stereochemistry macrolactonization glycosidation anessian:.6% Danishefsky: 1.8% White: 0.39% Ley: 0.1% 4 - Davies and Green 1/8/00 1:01 PM

55 Parting Notes Avermectin B1a " The present syntheses detailed in this review are outstanding examples of the synthetic art but there may will be shorter, more efficient, methods to the natural avermectins and milbemycins which can be devised in the future." Davies, Green; Chem. Soc. Rev. (1991) p linear steps, 0.08% yield 7 linear steps, 0.01% yield 38 linear steps, 0.03% yield 36 linear steps, 0.003% yield - Davies and Green 1/8/00 1:49 PM

56 6 - Fin 1/8/00 1:03 PM FIN

57 Danishefsky: Glycoside Formation Ac Ac NaB 4, CeCl 3, 9% Ag, I, 91% Ac JACS (1986) 7060 no dr given, K C 3, 96% Ac Ac I NIS, 6% single stereoisomer 3 SiSPh, ZnI, TBAI α:β 1.:1 (8% desired α) 1. NBS,. Bu 3 Sn, AIBN 9%, steps Ac Ac I Ac I m-cpba, 7%, steps Bu 3 Sn, AIBN, 81% α:β :1 SPh 9 steps, 18% yield Append - Danishefsky Glycoside 1/8/00 3: AM

58 Ley: Glycoside Construction TBS MgBr 74% TBS 1. Ts, 91%. SCl, 100% S Fe (C) 9 sonication 17 hours, 6% (C) 3 Fe Fe(C) 3 C (30 atm), 70 C, acrolein, 18 h, 9% + dimethyldioxirane, then TEA, pyr., 7% 49% 6% 10 DEAD, PPh 3, PhC, 9% DIBAL DBU,, 60% Bz DIBAL DBU, + 11 α:β = :1 α:β = :1 from 10 40% 1% from 11 47% 19% Append - Ley Glycoside 1/8/00 4:03 AM

59 Ley: Glycoside Construction AgCl 4, 64% Ac α:β = :1 CDI, Ac Ac Ac α:β = 1: 3% + Ac α:β = 1: 40% LiBEt 3, 9% Ac CDI 1" Ac 6% desired α-1" epimer 11% undesired β-1" epimer 1. LiBEt 3, 98%. CDI, 7% Ac 1" S N N