Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Daphniphyllum Alkaloids Classical "Total Synthesis of Methyl Homodaphniphyllate COmE Methyl Homodaphniphyllate Me Me Methyl Homosecodaphniphylate Daphnilactone A 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 Jorg.chem.1992,57,2531-2594 u Zasshi 1909. 6. 208 Jorg.chem.1992,57,2531 Tet Lett. 1965. 965 JAm.chem.So.1975,97,6116 Angew. Chem. Int. Ed. Eng. 1992, 31, 665 32D-0112/11/0011:53AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 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 Daphnilactone A Bukittinggine Methyl Homosecodaphniphyllate Methyl Homodaphniphyllate Secodaphniphylline Daphniphylline N O O O Me Me AcO iPr O iPr CO2Me HN N Me iPr O CO2Me O O Me N HN Me iPr O O O Me Me iPr 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 CO2Me iPr iPr Me Me CO2Me 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 O O O O N Me N O O O O CO2H O O Me NH2 O Daphniphyllum Alkaloids 32D-01 12/11/00 11:53 AM
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Synthesis of Methyl Homodaphniphyllate Construction of the Methyl H0人 Homodaphniphyllate Skeleton LDA, THF 1 isomer 1. Me30BF 3. HOAC, HCI 1. LTMP. PhSecl Lawesson's 2. HO(CH2)OH OBn OBn 3. LDA, THF R=Pr 10-1 J Am 90,6177 Nouv. J. Chem. 1980. 4. 47 2D0212/8009:51AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 4:1 Construction of the Methyl Homodaphniphyllate Skeleton 1 isomer NaOMe MeOH 70% 2 steps H2SO4, Acetone 1. LTMP, PhSeCl 2. MCPBA 60% 1. Me3OBF4 2. NaBH4 3. HOAc, HCl 87% 1. Et3OBF4 2. Et3N 80% X H Et3N ClCO2Et 89% pTsOH, tol. ∆ 83% LDA, THF LDA, THF 8:1 74% Lawesson's Reagent 1. H3O+ 2. HO(CH2)2OH 3. LDA, THF R=iPr 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 + HO2C O H2N Me O O Me N O O 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 iPr Me O N N O S BnO S N O BnO O O O Me R R BnO Br iPr 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
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Synthesis of Methy! Homodaphniphyllate cont'd i Proposed Biosynthesis of the Daphniphyllum Alkaloid H30 0 alene dialdehyde 1. Me2C EtO)2 POCI O2P(OEt) OHC、 OHC EtoH,120°c Tet Lett1969,2145 Pure& App/. Chem. 1989, 61, 289 J.Am.chem.Soc.1986,108,8274 2D-0312/110011:27AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 LDA, THF MeCHO 100% H30+ 2. LDA, THF, HMPA (EtO)2POCl 73% Li/EtNH2 64% 120 atm H2 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)2PO2 iPr O2P(OEt)2 Me O N N OBn O O Me Me N O HO H OBn OBn N N OH H iPr H H H OH N iPr N OH H iPr H H H H H iPr H CO2Me H N H Me Me R N 1. Me2CuLi (EtO)2POCl 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 Ar NH NH R R N Me Me Me N Me R Me Me R HN Me Me 32D-03 12/11/00 11:27 AM
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Proposed biosynthesis contd Retrosynthesis of Methyl Homosecodaphniphyllate CHO OR O2H CO2H OR 2D-0412/110011:31AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Squalene 7 10 14 15 3 + Proposed Biosynthesis cont'd Daphnilactone A + + H+ + iPr HN Me CO2H Me HO CHO OP* CO2H N Me iPr N HO Me OP* H OP* Me HO N N iPr Me CO2H CO2H H N Me iPr N HO Me OP* iPr CO2Me N O O iPr N Me CO2H HN Me iPr Me Me Me Methyl Homodaphniphyllate + + + + + Retrosynthesis of Methyl Homosecodaphniphyllate iPr HN Me CO2Me HN Me OR OR N Me N H H N Me 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
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Synthesis of Methyl Homosecodaphnipyllate The vollhardt "ammonia"incident 3.HcH2o100% 1.LAH96% OBn PrT LMel 28Cm5器4 978.17.476. 32D0512/110011:36AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 J. Org Chem. 1989, 54, 1215. Tet. Lett. 1986, 27, 959. Top. Stereochem. 1990, 20, 87. + + 4% 87% 1. DIBAL 83% 2. KOH, H2O, 95°C 3. HCl,H2O 100% 8% 1. LAH 96% 2. Swern 1. NH3 2. AcOH, NH4OAc 70°C 82-95% 1. H2, Pd/C 2. Jones 3. MeOH, H+ Synthesis of Methyl Homosecodaphnipyllate Me I Me Me MeO2C OHC Me N OBn O Me Me OBn OHC iPr HN Me N Me Me Me OBn MeO2C O O N MeO2C OBn Me Me Me N Me Me Me OBn MeO2C O O Me Me Me O R CO2Me 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. MeNH2 2. HOAc, NH4OAc 75% + + + + OHC Me Me Me OBn OHC HN Me OBn Me Me OBn N N Me OBn Me Me Me CH3 CH3 H N OBn N Me Me OBn H 32D-05 12/11/00 11:36 AM
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Stepwise vs Concerted Cyclization One-Pot Pentacyclization Reaction: Formation of Protodaphniphylline 2. HyO% Concerted [BuO2C 1.MsCI, EIN 1. Swern 1. Swern Stepwise Other amines TIMel 79% isclated yield 32D0612/110011:43AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Stepwise vs Concerted Cyclization Concerted Stepwise AcOH 70°C 95% AcOH 25°C 90% NH3 44% 79% isolated yield Concerted Stepwise + + + + +N R Me R’ H N R Me R’ H N H N H R’ R Me R’ R Me 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 R Me 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. MeNH2 3. HOAc, 80°C 65% 1. Swern 2. NH3 3. AcOH, 80°C 15% 1. MsCl, Et3N 2. DBU 3. DIBAL 80% 1. LDA, Br(CH2)3CH(OMe)2 2. H3O+ 83% LDA, THF CH3CO2tBu Me 83% I Me Me Me Me Me OtBu O Me Me Me Me Me Me Me Me Me CO2tBu OH CO2tBu Me Me Me CHO tBuO2C 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
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Synthesis of ()-Secodaphniphylline Rationale for Stereoselectivity in Michael Additions COmE COX OBn 2. HgSOA COmE Lo. 3.(COCa CHCh 28 90%ee 器e 43% overall 32D0712/110011:47AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 + 99.6% ee NaCN, DMSO 150°C 43% overall 92% ee 90% ee 1. separate 2. KOH EtOH 3. (COCl)2, CH2Cl2 31% 1. RuCl3, NaIO4 2. CH2N2 1 : 5 HgSO4 H2SO4 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 iPr O O O Me Me O O HO2C 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 Me CH2OH HOCH2 Me O O O O Me MeO2C Me CO2Me Me Me O O O OMe Me COCl HN Me iPr HN Me iPr O O O Me Me MeO2C Me Me O O O iPr HN Me COX Me Me O O CO2Me iPr HN Me Me Li MeO OLi 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 CO2Me N Me Me Me OBn MeO2C O OMe N O OBn H H Me Me O Li N MeO O H BnO O Me Me Li O N MeO2C OBn Me Me Me N Me Me Me OBn MeO2C O Me Me Me Me H 32D-07 12/11/00 11:47 AM
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Retrosynthesis of Daphnilactone A Synthesis of Daphnilactone A LDA, homogeranyliodide 1. LAH 3.H3O+ Zn, THF, HMPA 100% Ang. Chem. Int J. Org. Chem. 1992, 57, 2585 32D-0812110011:51AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Retrosynthesis of Daphnilactone A J. Org. Chem. 1992, 57, 2585 Angew. Chem. Int. Ed. Engl. 1992, 31, 665 O O iPr N Me CO2H HN Me iPr HN iPr Me OH HN Me iPr O O N Me Me Me Me Me Me O O O O O Br Br O Me Me Me EtO EtO2C Me Me Me CO2Et OEt 3. H3O+ Synthesis of Daphnilactone A : 1 + DIBAL tol. ∆ 87% H2, Pt 100% 1. Swern 2. NH3 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 CO2Et OEt EtO EtO2C Me Me Me O O Br Br O Me Me Me Br COBr Br Me Me Me O O O O Br OZnBr O Me Me Me H HO O HO Me Me Me HN Me O HN Me iPr O HN iPr Me OH HO iPr HN Me 32D-08 12/11/00 11:51 AM
Andrew ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 Total Synthesis of Daphnilactone and Conversion to the Daphniphylline Skeleton 2. CH,O, pH7" 32D-0912110011:52AM
Andrew Ratz Daphniphyllum Alkaloids Evans Group Seminar, June 1993 + 1. CrO3, H2SO4 2. CH2O, pH7 50% 1. CrO3, H2SO4 2. MeOH, H+ 60% PhNCO HCO2H 50% Total Synthesis of Daphnilactone and Conversion to the Daphniphylline Skeleton HN iPr Me OH O O iPr N Me OH CO2H HN Me iPr N iPr Me O O- HN Me iPr HN iPr Me CO2Me N HN CO2Me Me i i Pr Pr CO2Me N Ph O 32D-09 12/11/00 11:52 AM
