Evans Group Seminar, June 1993 Andrew Ratz Daphniphyllum Alkaloids J. Org. Chem. 1992, 57, 2531-2594 Kyoto Igaku Zasshi 1909, 6, 208 Tet. Lett. 1965, 965 ? Isolated from bark and leaves of Yuzuriha tree ? Used to cure asthma and vermicide in the early 20th century ? Compounds have been known since 1909. First structure solved in 1965. ? 38 members in this alkaloid family Bukittinggine Daphnilactone A Methyl Homosecodaphniphyllate Methyl Homodaphniphyllate Secodaphniphylline Daphniphylline N O O O Me Me AcO i Pr O i Pr CO 2 Me HN N Me i Pr O CO 2 Me O O Me N HN Me i Pr O O O Me Me i Pr N Me "Classical" Total Synthesis of Methyl Homodaphniphyllate * * * * H + J. Org. Chem. 1992, 57, 2531 J. Am. Chem. Soc. 1975, 97, 6116 Angew. Chem. Int. Ed. Eng. 1992, 31, 665 N CO 2 Me i Pr i Pr MeMe CO 2 Me H R Me N N N Me R H Me Me O O N O BnO O O R O Me N O BnO O OO O O N NMe OO O O CO 2 H OO Me NH 2 O Daphniphyllum Alkaloids 32D-01 12/11/00 11:53 AM Evans Group Seminar, June 1993 Andrew Ratz Daphniphyllum Alkaloids 4:1 Construction of the Methyl Homodaphniphyllate Skeleton 1 isomer NaOMe MeOH 70% 2 steps H 2 SO 4 , Acetone 1. LTMP, PhSeCl 2. MCPBA 60% 1. Me 3 OBF 4 2. NaBH 4 3. HOAc, HCl 87% 1. Et 3 OBF 4 2. Et 3 N 80% X H Et 3 N ClCO 2 Et 89% pTsOH, tol. ? 83% LDA, THF LDA, THF 8:1 74% Lawesson's Reagent 1. H 3 O + 2. HO(CH 2 ) 2 OH 3. LDA, THF R= i Pr 10:1 R=Me 83:17 73% 46% 14% Synthesis of Methyl Homodaphniphyllate J. Am. Chem. Soc. 1986, 108, 5650 J. Org. Chem. 1992, 57, 2531 J. Am. Chem. Soc. 1968, 90, 6177 Nouv. J. Chem. 1980, 4, 47 + HO 2 C O H 2 NMe OO Me N OO O O O O O N N O O BnO O Me O O O BnO S N S BnO O O O N O i Pr Me O N N O S BnO S N O BnO O O O Me R R BnO Br i Pr Me O O Me R O O S N Me O Me OBn OBn Me N O O O O O O N Me OBn H H OBn Me N O O O N HO O Me H H OBn N OBn O O 32D-02 12/8/00 9:51 AM Evans Group Seminar, June 1993 Andrew Ratz Daphniphyllum Alkaloids LDA, THF MeCHO 100% H 3 0 + 2. LDA, THF, HMPA (EtO) 2 POCl 73% Li/EtNH 2 64% 120 atm H 2 Pd(OH) 2 EtOH, 120°C 81% ?? 1. Jones 2. MeOH, H + + + 68% 13% 1:1 ratio Synthesis of Methyl Homodaphniphyllate cont'd Tet. Lett. 1969, 2145. H OBn Me N O O O N O Me O O HO Me R H H R Me O EtO) 2 PO 2 i Pr O 2 P(OEt) 2 Me O N N OBn O O Me N Me O HO H OBn OBn N N OH H i Pr H H H OH N i Pr N OH H i Pr H H H H H i Pr H CO 2 Me H N H Me Me R N 1. Me 2 CuLi (EtO) 2 POCl 83% Pure & Appl. Chem. 1989, 61, 289 J. Am. Chem. Soc. 1986, 108, 8274 Proposed Biosynthesis of the Daphniphyllum Alkaloids Squalene Dialdehyde pyridoxamine Me CHO OHC Me Me Me Me Me OHC R R N N OP* HO Me N Ar OHC R R R R OHC N Ar NH O R NHAr NH R R N Me Me Me N Me R Me Me R HN Me Me 32D-03 12/11/00 11:27 AM Evans Group Seminar, June 1993 Andrew Ratz Daphniphyllum Alkaloids Squalene 7 10 14 15 3 + Proposed Biosynthesis cont'd Daphnilactone A + + H + + i Pr HN Me CO 2 H Me HO CHO OP* CO 2 H N Me i Pr N HO Me OP* H OP* Me HO N N i Pr Me CO 2 H CO 2 H H N Me i Pr N HO Me OP* i Pr CO 2 Me N O O i Pr N Me CO 2 H HN Me i Pr Me Me Me Methyl Homodaphniphyllate + + + ++ Retrosynthesis of Methyl Homosecodaphniphyllate i Pr HN Me CO 2 Me HN Me OR OR N Me N H H Me N OR OR Me Me Me H OHC Me Me Me OR OHC Me I Me Me R” O R’ OR O 32D-04 12/11/00 11:31 AM Evans Group Seminar, June 1993Andrew Ratz Daphniphyllum Alkaloids J. Org Chem. 1989, 54, 1215. Tet. Lett. 1986, 27, 959. Top. Stereochem. 1990, 20, 87. ++ 4% 87% 1. DIBAL 83% 2. KOH, H 2 O, 95°C 3. HCl,H 2 O 100% 8% 1. LAH 96% 2. Swern 1. NH 3 2. AcOH, NH 4 OAc 70°C 82-95% 1. H 2 , Pd/C 2. Jones 3. MeOH, H + Synthesis of Methyl Homosecodaphnipyllate Me I Me Me MeO 2 C OHC Me N OBn O Me Me OBn OHC i Pr HN Me N Me Me Me OBn MeO 2 C O O N MeO 2 C OBn Me Me Me N Me Me Me OBn MeO 2 C O O Me Me Me O R CO 2 Me HN Me OR LDA, THF -78°C to 25°C Angew. Chem. Int. Ed. Engl. 1978, 17, 476. J. Org. Chem. 1990, 57, 2544. The Vollhardt "Ammonia" Incident 1. MeNH 2 2. HOAc, NH 4 OAc 75% + + + + OHC Me Me Me OBn OHC HN Me OBn Me Me OBn N N Me OBn Me Me Me CH 3 CH 3 N H OBn N Me Me OBn H 32D-05 12/11/00 11:36 AM Evans Group Seminar, June 1993Andrew Ratz Daphniphyllum Alkaloids Stepwise vs Concerted Cyclization Concerted Stepwise AcOH 70°C 95% AcOH 25°C 90% NH 3 44% 79% isolated yield Concerted Stepwise + + + + + N R Me R’ H N Me R R’ H N H N H R’ MeR R’ Me R BnO R’ R’ Me R N N HN Me OR Me Me Me N OHC Me OHC Me R’ R’ N Me Me Me N Me R R’ H Me HN Me R’ Me Me R’ OHC Me OHC Me Me H Other amines: 38%y 32%y 1-2%ee 13%y 20-25%ee no reaction Glycine (S)-(+)-Alanine (S)-(+)-Valine (+)-α-Phenylethyl amine 70% One-Pot Pentacyclization Reaction: Formation of Protodaphniphylline 1. Swern 2. MeNH 2 3. HOAc, 80°C 65% 1. Swern 2. NH 3 3. AcOH, 80°C 15% 1. MsCl, Et 3 N 2. DBU 3. DIBAL 80% 1. LDA, Br(CH 2 ) 3 CH(OMe) 2 2. H 3 O + 83% LDA, THF CH 3 CO 2 tBu 83% Me I Me Me MeMe Me OtBu O Me Me Me Me Me Me MeMe Me CO 2 tBu OH CO 2 tBu Me Me Me CHO tBuO 2 C Me Me Me Me HN Me Me Me Me Me OH OH HN Me Me Me Me Me 32D-06 12/11/00 11:43 AM Evans Group Seminar, June 1993Andrew Ratz Daphniphyllum Alkaloids + 99.6% ee NaCN, DMSO 150°C 43% overall 92% ee 90% ee 1. separate 2. KOH EtOH 3. (COCl) 2 , CH 2 Cl 2 31% 1. RuCl 3 , NaIO 4 2. CH 2 N 2 5 :1 HgSO 4 H 2 SO 4 95% KAPA 1,3-diaminoprop. 87% 92% ee LAH Darvon Alc. 93% 1. Weinreb 2. Synthesis of (-)-Secodaphniphylline + + J. Org. Chem. 1980, 45, 582 Tet. Lett. 1981, 22, 4171 J. Org. Chem. 1981, 46, 3936 Tet Lett. 1967, 8, 215 HN Me i Pr O O O Me Me O O HO 2 C Me Me Me Me Me Me O O O Me Me OH O O Me Me Me Me Me Me O O OH O O Me Me CH 2 OHMe HOCH 2 Me O O O O Me MeO 2 C Me CO 2 Me Me Me O O O O Me Me COCl HN Me i Pr HN Me i Pr O O O Me Me MeO 2 C Me Me O O O i Pr HN Me COX Me Me O O CO 2 Me i Pr HN Me Me Li OLi MeO 1. LDA, THF 2. 3. Interference with Li cluster ?? Tet Lett 1986, 27, 959 J. Org. Chem. 1990, 55, 132 Topics in Stereochemistry 1989, 227 Rationale for Stereoselectivity in Michael Additions N OMe H O O Li BnO N OBn O LiO OMe H Me I Me Me N OBn O CO 2 Me N Me Me Me OBn MeO 2 C O OMe N O OBn H H Me Me O Li N MeO O H BnO O MeMe Li O N MeO 2 C OBn Me Me Me N Me Me Me OBn MeO 2 C O Me Me Me Me H 32D-07 12/11/00 11:47 AM Evans Group Seminar, June 1993Andrew Ratz Daphniphyllum Alkaloids Retrosynthesis of Daphnilactone A J. Org. Chem. 1992, 57, 2585 Angew. Chem. Int. Ed. Engl. 1992, 31, 665 O O i Pr N Me CO 2 H HN Me i Pr HN i Pr Me OH HN Me i Pr O O N Me Me Me MeMe Me O O O O O Br Br O Me Me Me EtO EtO 2 C MeMe Me CO 2 Et OEt 3. H 3 O+ Synthesis of Daphnilactone A 1: + DIBAL tol. ? 87% H 2 , Pt 100% 1. Swern 2. NH 3 3. HOAc, ? 87% LAH 90% Zn, THF, HMPA 89% 95% 1. LAH 2. LDA, homogeranyliodide 85% 4.5 Org. React. 1975, 22, 423 Ang. Chem. Int. Ed. Eng. 1967, 6, 1 Ang. Chem. Int. Ed. Eng. 1969, 8, 535 CO 2 Et OEt EtO EtO 2 C MeMe Me O O Br Br O Me Me Me Br COBr Br MeMe Me O O OO Br OZnBr O Me Me Me H HO O HO Me Me Me HN Me O HN Me i Pr O HN i Pr Me OH HO i Pr HN Me 32D-08 12/11/00 11:51 AM Evans Group Seminar, June 1993Andrew Ratz Daphniphyllum Alkaloids + 1. CrO 3 , H 2 SO 4 2. CH 2 O, pH7 50% 1. CrO 3 , H 2 SO 4 2. MeOH, H+ 60% PhNCO HCO 2 H 50% Total Synthesis of Daphnilactone and Conversion to the Daphniphylline Skeleton HN i Pr Me OH O O i Pr N Me OH CO 2 H HN Me i Pr N i Pr Me O O - HN Me i Pr HN i Pr Me CO 2 Me N HN CO 2 Me Me i Pri Pr CO 2 Me N Ph O 32D-09 12/11/00 11:52 AM