The Chemistry of Lewis N. Mander Emily Cherney

Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Biography Isolation Work - Born Sept. 8,1939 in Auckland, NZ Galbulimima Alkaloids Education - University of Auckland, B.S., 1960, M.S. 1961 OH OH H H H (R.C. Cambie) HO - University of Sydney; Ph.D., 1964 H H H H H H H (C.W. Shoppee, E. Ritchie, and W.C. Taylor) N HN - Univeristy of Michigan/Caltech; Postdoc., 1966 H (R.E. Ireland) Me H Me H N CO Me H 2 H OMe OBz O O Me O Academic Career himandrine G.B. 13 G.B. 17 1966- Lecturer in organic chemistry at the University of Adelaide Aust. J. Chem. 1967, 1029 Aust. J. Chem. 1967, 1473 Tet. Lett. 2009, 7089 1970- Promoted to senior lecturer in organic chemistry Aust. J. Chem. 2006, 629 1975- Moved to Australian National University as a senior fellow in the R2 Research School of Chemistry 1980- Appointed to Professor at Australian National University OH R1 1981-1995- Dean of the Research School of Chemistry OH H Me Me Currently: Adjunct Professor at Australian National University H H COOH O O OH OH H OHO O H Me HO OH Honors and Awards H H OH H 1972- Nuffield Fellow at Cambridge University with A.R. Battersby H H H OH H H HO O O Me Me 1977- Fulbright Senior Scholar at Cal. Inst. of Tech. with D.A. Evans HO 1983- Elected to Australian Academy of Science HOH 1986- Fulbright Senior Scholar at Harvard with D.A. Evans H H saponins 1990- Elected to the Royal Australian Institute of Chemistry and Royal J. Nat. Prod. 2002, 115 R R Society (London) OH 1991- Honoroary Fellow of the Royal Society of New Zealand O R 1993- Jeffery Medal HO 1994- Birch Medal OC R 1995- Archibald Olle Prize HN 2002- David Craig Medal R H O Me CO2H 2004- Australian Journal of Chemistry published an issue dedicated to N Mander on the occasion of his 65th Birthday (Aust. J. Chem. 2004, 611) gibberellins bisdimethylaaptamine OC "On one occasion we stopped in the bush for drinks and Lew...started to sit Tetrahed. 2004, 6101 Phytochem. 1998, 331 HO Phytochem. 1998, 587 down. He was already well into the downward tragectory when...he saw a H poisonous snake...on the spot where he was about to land. I have yet to Me CO2H Phytochem. 2001, 749 understand how he did it, but he immediately went into levitation mode and antheridiogen Org. & Biomolec. Chem. seemed to hang, sliding sideways so dropping onto a snake free zone. He Phytochem. 1989, 63 2006, 2532 explained to me that life in Australia was not like the UK. He then gave us Org. & Biomolec. Chem. clear instructions on what to do about snakes, spiders, or when caught in a 2008, 1416 bush fire; Lew is a man of many parts." -Alan Battersby Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Mander's Reagent: methyl cyanoformate A [Very] Brief Synopsis of Total Syntheses Tet. Lett. 1983, 5425 Hainanolidol and Harringtonilide O JACS 1998, 1914 OTMS OLi O O MeO MeO MeLi MeO CN OMe CO Me H CO2Me H 2 HMPA steps 72% N2 O ODEIPS O O MeO OMe LDA MeO CN O OLi O Rh2(mandelate)4 CO2Me HMPA MeO 85% MeO - Lithium enolate necessary, no reaction with potassium or sodium derivatives H CO2Me H CO2Me - Note stability of methyl cyanoformate in the presence of liberated amine - First direct synthesis of non-enolizable !-ketoesters ODEIPS ODEIPS Synlett. 1990, 169, Org. Synth. 1992, 256 O MeO OMe O MeO OMe

84% DBU OMe MeO MeO O 1. ZnBr2 H CO2Me H THF 2. Al2O3 ODEIPS Li, NH3, OMe tBuOH 46% CO2Me (2 steps) OH MeO CO ODEIPS 2 H O O H MeO OMe 1. K2CO3, NCCO2Me OMe MeOH-H2O (33%) LiO 2. TBAF H 3. NaBH4 O HO MeO EtO2 OMe 71% O H base H HCl-THF H H O O O CO2Me >50% overall O [>98% d.s.] O O - Almost exclusive O-acylation observed with THF HO - Ether reverses selectivity for !-ketoester formation (emperical observation) HO HO HO - Similar results observed for decalin systems and R-(-)-carvone Hainanolidol Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Hainanolidol and Harringtonolide cont'd. G.B. 13 cont'd JACS 1998, 1914 JACS 2003, 2400 O O F C O OH 1. ZrCl , NaBH 3 4 4 H Pb(OAc)4 2. Zn, HOAc H H N H N H h! 3. TFAA, NEt O O H H 3 H H O transannular O H 32% H oxidation H H N MOMO H (4 steps) MOMO H H O HO HO OMOM OMOM hainanolidol harringtonolide steps G.B. 13 JACS 2003, 2400 H H N H HO C OMe 2 H H MeO steps MeO N H HO OTBS G.B. 13 O OMe MOMO 87% Yb(thd)3 Himandrine Skeleton Synthesis Org. Lett. 2004, 703 N O O O H OMOM H OMOM O MeO HMPA, NaH, H steps H H H H H SH H H H OMe 97% OMe MOMO H MOMO H MeO2C HO2C OMOM 1. (COCl) , DMF 76% pNO2ArSO2NHNH2 2 Pyridine, EtOH, THF 77% NaN3 2. toluene, " OH 1. Li, NH3, MeOH 3. NaOMe, MeOH O H H2NOH, HCl, N H MOMO 2. AcOH, THF, H2O O Pyridine H H H H H OMOM 3. MOMCl, iPr2NEt, H OMOM DMAP H H H H 4. HCl, CHCl3 MOMO H N MOMO H H H H HO 32% OMOM OMOM OMe HN O HN O O O O Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

MOMO MOMO Sordaricin H OMOM 1. 9-BBN, THF, H OMOM Org. Lett. 2003, 1321 O H MeOH, H2O2 H 2. OsO4, Py steps ! H H H H O O 75% O OH 85% HN HN OH O OH O MOMO MOMO O O Pb(OAc) O O 70% 4 steps MeO P MeOH OMOM MeO OMOM N2 MOMO MOMO MOMO K2CO3, MeOH NH O 91% NH O O O O I O O A 1. Li/NH , MeOH 1. DIBAL-H, 93% 3 OMOM OMOM 2. CH SO Cl, Et N NaBH4 2 2 3 LDA, HMPA, 2. MOMCl; CN 1. NaH, DMF then A TsOH OMOM 2. NaH, HMPA OMOM O SH 55% 90% MOMO OMs MOMO O H (4 steps) H 88% N CN NH H OMOM O O O PdCl2, CuCl, O2 85% MeO2C OH O O nBuNH4Cl, K2CO3 PhOCO 1. LiHDMS, MeO OMOM MeOCOCN OMOM N 2. NaH, PhNTf Rh, Al2O3, H2 H 2 MOMO (CF3)2CHOH MOMO N 95% N OMOM OMOM

60% Dowex " 50W 2-Th(CN)CuLi, MeO2C OH H OH iPrMgCl H PhOCO 69% HO HO OMOM OMOM N 3 steps N CO2Me TfO CO2Me himandrine Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

O OMOM Intramolecular Alkylations and their evolution into Gibberellin Synthesis

1. MgBr2, (continued) butanethiol Aust. J. Chem. 1972, 137 H 2. MnO2 H O O 92% N2 O 180 °C OH (2 steps) OMOM Cu powder HCl, H2O, cyclohexane acetone CO2Me CO2Me MeO 70-80% MeO MeO MeO O O (stereochemistry O O not specified) CO2Me CO2Me O N2 H Cu powder HCl, H O, HO 2 HO cyclohexane acetone O OH minor O MeO 70-80% MeO O CO2Me MeO MeO - copper(I) oxide and copper(II) sulfate were inferior catalysts CO H CO Me 2 O 2 O - basic alumina can also catalyze the retro-Michael reaction 26 steps SNa HO 3% overall yield HO Aust. J. Chem. 1974, 1287 79% major sordaricin O 76% combined yield 4:1 steps Intramolecular Alkylations and their evolution into Gibberellin Synthesis N2 Aust. J. Chem. 1971, 343 MeO MeO THPO Br TFA, 0 °C (neat) t t OTHP KO Bu, BuOH H reflux O O 50% HO O Quant. O MeO MeO N2 O "In this paper we describe a particularly short and efficient apprach to the syntheses BF3•OEt2 of tetracyclic ketones which could serve as valuable intermediates in the synthesis of NO2CH3 gibberellins." -Mander 30% Aust. J. Chem. 1974, 1977 HO O "In preparation for projected syntheses of more complex diterpene alkaloids, we have steps investigated the preparation of isomeric dienones...which should afford more direct O access to compunds based on the atisine skeleton" -Mander MeO MeO Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

A moment in chemical history: The first total synthesis Synthesis of Gibberellic Acid (GA3) ( JACS 1980, 6626) O of was completed by Corey (reported in JACS 1978, OH "In an attempt to convince a University to employ him, and granting agencies 8031) in which he wrote that GA3 posessed "... a to provide him with funding, the author also proposed to carry out a synthesis OC H singularly diabolical placement and density of of this intriguing molecule." -Mander (Nat. Prod. Rep. 2003, 48) HO functionality..." (Mander completed his first total H synthesis in 1980) OCOCCl3 OCOCCl3 OH CO2H O gibberellic acid O TFA O 1. Na2CO3 (aq.) (GA ) O 3 82% N2 2. (CH OH) , OMe O 2 2 O Gibberellins: A Brief Biography (CH2Cl) Structural deconvolution: -Originally isolated from fungus Gibberella fujikuroi in 1938 Dowex" 50W n -first unequivocal assignment in 1962 by x-ray cystallography by McCapra & coworkers 4 Å sieves Bu4NBr, (Proc. Chem. Soc. London 1962, 185) 3. K-select. KOH PhH, H O 2 SO2 In Plants: -responsible for stem growth (involved in biogenetic differences between tall 82% and dwarf pea plants used by Mendel to study inheritance) thexylborane, 1. h#, N3 - stimulates flowering OH Na2HPO4, OH Na2CO3 (aq.) OH O - breaks winter dormancy H O H2O2 2. CH2N2 O HO O 90% O Isolation Horror Stories: In an effort to isolate meaningful quantitites of GA32, ten 80% O students separated 1 ton of unripe peach pits from their flesh. It took them one month and only 38 mg of material was isolated. Additionally, 14 mg OH CO2Me 1:3 CO2Me O $:% of GA19 was obtained from 44 tons of bamboo shoots! GA32 N2 O 1. PhSeSePh, KH OH GA3 Production: produced in ton-quantities annually from 2. H2O2 fermentation of Gibberella fujikuroi OC H OH OH O HO H H O H OH MnO Al 3 Gibberellins: Biosynthesis HO 2 O CO2H O O Arise from kaurenoic acid via C-7 hydroxylation followed by ring contraction: 60% THF, -78 °C, 12 (3 steps) 5 min 11 13 CO2Me CO2Me 20 16 1 9 14 17 2 8 [O] OH OH 18 10 O (EtCO) O, O 5 H 15 H H 2 H 3 7 H KH, DMF; EtOCO HO Et3N, DMAP 4 6 OH Quench O O H H H CHO + - CO H CO HH Et3N H•Ac 19 2 2 enzyme CO2H 7 78% CO2Me CO2Me C-20 methyl group can be oxidized to a formyl group which can then be lost (d.s.> 95%) to form C -gibberellins upon cyclization to a !-lactone: 19 OH disiamylborane; OH O O Na HPO , H O ; O H 2 4 2 2 H O O CrO3•2Py O O [O] H -CH2O OC H O H OC 89% OC CO Me H H H 2:1 H 2 CO2Me CO2H CO2H CO2H O H CO2H CO2H $:% Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Synthesis of Gibberellic Acid (GA ) cont'd 1. PhSO Cl, 1. OsO4, NMO 3 2 2. PhCHO, TsOH OH OH Pyridine OH OH 4 A sieves OH O O O n 2. Bu4NBr O 3. NBS, CCl , O O K CO O O O 4 O 2 3 3. DBN then h! O O H O O Br O OC H OC OC H 78% OC H 84% OC H (3 steps) (3 steps) CO Me CO Me CO Me CO Me CO Me O H 2 HO H 2 HO H 2 H 2 PhOCO H 2 1. 3M HCl 29% 29% 2. TMSCl, 90% 1. DBN DIPEA (2 steps) 2. 3N HCl

+ - OTMS 1. PPh3 Me•Br , OH OH OH 1. TMSCl, DIPEA OH t + - KO Bu 1. K2CO3/KHCO3 2. PPh Me•Br , O SLi O O 3 O 2. O 2. SLi KOtBu O O + H H + OC H (H workup) OC OC H (yield not OC (H workup) OC H 80% CO H specified) CO Me H CO2Me H 2 H CO2H H 2 H CO2Me TMSO (4 steps) HO HO PhOCO PhOCO

gibberellin A1 gibberellic acid

Gibberellin Core Modification: The A ring

OMOM OMOM OR2 OMOM OMOM 1. (COCl) , DMF NH , Li, O t 2 3 Li, NH3, BuOH 2. CH2N2 Cu-bronze tBuOH H H H H H OC 93% 86% 75% 49% when R = Ms CO Me CO Me CO Me H CO2Me 1 H CO2Me H 2 H 2 H 2 R1O R2= MOM HO C N2HCOC 5 1 2 2 3 O 4 O (Tet. Lett. 1985, 363) (Tet. Lett. 1985, 5725) 1. TsCl, Py 95% KH, DMF 2. NaBr, HMPA when R1,R2=H O 3. Zn, EtOH 2

OH OH OH O OMOM C20 gibberellins H O O m-CPBA Me2BBr 2 10 H CO H OC H 19 89% CO Me CO Me CO Me CO Me H 2 HO H 2 HO H 2 H 2 HO2C CO2H 7 8 (JOC 1990, 4860) 1 6 "iso-lactone" Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Gibberellin Core Modification: The C ring (Tet. Lett. 1991, 6203) 12!-Hydroxy O OH 1. H , RhAl O OAc OAc 1. SeO , tBuOOH OAc 2 2 3 OAc OAc 2 2. pyrrolidone, HBr3 Pb(OAc)4, O O O O Br O 2. PCC•SiO2 3. NaB(CN)H3 I2, h" Zn, HOAc O Br OH 80% OC H 70% OC H 42% OC H 74% OC H OC H CO2Me H CO2Me H CO2Me H CO2Me H CO2Me AcO H AcO AcO AcO AcO 1 2 3 4 5 (Tet. Lett. 1996, 719) 12#-Hydroxy OH O O OH OAc OAc OH OH O H2CrO4 O K2CO3, MeOH O ZnCl2, NaBH4 O 95% 72% 57% OC H OC H OC H OC H H CO2Me H CO2Me H CO2Me CO2Me AcO AcO AcO AcO H 5 6 7 8 Note: Inversion via Mitsunobu fails. (Tetrahedron 1998, 11637) 14!-Hydroxy OAc OAc OH OH OAc 1. K2CO3 1. (Ac)2O, DMAP O O , Et N 3 3 O O 2. H2, Rh-Al2O3 O O NaH O O 2. TBSOTf, Et3N O OTMS OC H 56% OC H 98% OC H 80% OC H 73% OC H H CO2Me CO2Me CO2Me CO2Me CO2Me MOMO MOMO H MOMO H MOMO H MOMO H 9 10 11 12 13

DMDO

OH OTMS OH OAc OAc PPh +Me•I-, O 3 O TMSCl KH O imidazole O O NaOMe O O TBAF O O OH + OTMS OH OC H (H workup) OC H OC H 78% H H OC OH OC OTMS CO Me CO Me from 13 H 2 H 2 H CO2Me H CO2Me CO2Me MOMO MOMO MOMO MOMO MOMO H 18 30% 17 16 15 14 from 16 Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Gibberellins: conversion to Antheridic Acid (JACS 1987, 6391) O O

1. KI3, KHCO3 2. O , Pyridine, I O H2NNH2•H2O, 3 I 1. LiOH O O O O DMF Me2S KH 2. KI3 HO H OC OC 19% 66% CO 80% CO 47% H CO2Me CO2Me CO2Me CO2Me H CO2Me MOMO MOMO H MOMO H MOMO H MOMO 1 HO2C 2 3 4 5

1. (TFA)2O, 82% Pyridine 2. Zn, KI

1. H2, Rh-Al2O3 (80%) O O Antheridic Acid t 1. SeO2, BuOOH 2. PPh3CH2 + - LiOH 2. MeBBr2 3. LiCA, Et NH Ac * DBU O O O 3 O O OH 83% OH 67% * 74% BRSM, 93% OC OC OC 3 cycles OC OC H CO2H H CO2Me H CO2Me H CH2O2Me CO2Me MOMO HO MOMO MOMO MOMO H 10 9 8 7 6 Gibberellins: conversion to Kaurenoids Heterocycles, 1999, 365: "Considerable effort has been invested in transforming karuene derivatives into gibberellins...Most kaureniods, however, are not as easily obtained as the more common GAs, especially gibberellic acid, which is available in abundance in modest cost." (~ $21/gram)

OMOM OMOM OH 1. MeO2CCOCl, H 1. O3; Et3N H O i Pr2NEt, DMAP 2. NaOH NaBH Dowex! 50W n O 4 O O 2. Bu3SnH, AIBN O 3. (COCl)2, Py O H CO H CO H CO H CO H 88% 90% 88% 73% H CO2Me H CO2Me H CO2Me H CO2Me H COCl 15 HO2C 11 12 13 14

82% NaBH4

SeCN H H 1. DMP H H O2N H 2. OsO4, NMO O BF •Et O H2O2 n O 3 2 O O 3. DMP O OH O OH Bu3P O OH CO CO H Quant. CO H 60% CO H 78% CO H 90% H OH OH H H H CH2SeAr H CH2OH O H O 20 19 18 17 16 Kaurane Skeleton Baran Group Meeting The Chemistry of Lewis N. Mander Emily Cherney

Gibberellins: conversion to Longirabdolactone (J. Aust. Chem. 2003, 805)

H H H H H DMSO, O H H NaOH, MeOH H O (COCl)2, Et3N O KH CO H 86% CO H 86% CO O O OH OH O OH OH H H H H H OH O OH O NaO C OH 2 2 1 3 O 4 5

45% 1. NaIO4 (3 steps) 2. CH2N2

Longirabdolactone H H H t H 1. SeO2, BuOOH H 1. NaBH4 H 2. DMP 2. H2CrO4 O O O O 92% 23% O O H O H H O O MeO2C O O 8 O 7 6