Baran Group Meeting The Chemistry of Lewis N. Mander Emily ... · Baran Group Meeting The Chemistry...
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Emily Cherney Baran Group Meeting The Chemistry of Lewis N. Mander Isolation Work Biography - Born Sept. 8,1939 in Auckland, NZ Education - University of Auckland, B.S., 1960, M.S. 1961 (R.C. Cambie) - University of Sydney; Ph.D., 1964 (C.W. Shoppee, E. Ritchie, and W.C. Taylor) - Univeristy of Michigan/Caltech; Postdoc., 1966 (R.E. Ireland) Academic Career 1966- Lecturer in organic chemistry at the University of Adelaide 1970- Promoted to senior lecturer in organic chemistry 1975- Moved to Australian National University as a senior fellow in the Research School of Chemistry 1980- Appointed to Professor at Australian National University 1981-1995- Dean of the Research School of Chemistry Currently: Adjunct Professor at Australian National University Honors and Awards 1972- Nuffield Fellow at Cambridge University with A.R. Battersby 1977- Fulbright Senior Scholar at Cal. Inst. of Tech. with D.A. Evans 1983- Elected to Australian Academy of Science 1986- Fulbright Senior Scholar at Harvard with D.A. Evans 1990- Elected to the Royal Australian Institute of Chemistry and Royal Society (London) 1991- Honoroary Fellow of the Royal Society of New Zealand 1993- Jeffery Medal 1994- Birch Medal 1995- Archibald Olle Prize 2002- David Craig Medal 2004- Australian Journal of Chemistry published an issue dedicated to Mander on the occasion of his 65th Birthday (Aust. J. Chem. 2004, 611) "On one occasion we stopped in the bush for drinks and Lew...started to sit down. He was already well into the downward tragectory when...he saw a poisonous snake...on the spot where he was about to land. I have yet to understand how he did it, but he immediately went into levitation mode and seemed to hang, sliding sideways so dropping onto a snake free zone. He explained to me that life in Australia was not like the UK. He then gave us clear instructions on what to do about snakes, spiders, or when caught in a bush fire; Lew is a man of many parts." -Alan Battersby Galbulimima Alkaloids N OMe H OBz H H H H Me CO 2 Me OH himandrine HN H O H H H H Me OH G.B. 13 H N O O Me H H HO H H G.B. 17 Aust. J. Chem. 1967, 1029 Aust. J. Chem. 2006, 629 Aust. J. Chem. 1967, 1473 Tet. Lett. 2009, 7089 R 1 OH OH Me H H Me Me O Me Me OH O O O O O COOH H H H H HO HO HO H OH H H OH H HO H OH OH H H HO H H H saponins R 2 J. Nat. Prod. 2002, 115 N HN OH HO bisdimethylaaptamine Tetrahed. 2004, 6101 CO 2 H Me O OC HO H antheridiogen Phytochem. 1989, 63 CO 2 H Me O OC H R R R R R gibberellins Phytochem. 1998, 331 Phytochem. 1998, 587 Phytochem. 2001, 749 Org. & Biomolec. Chem. 2006, 2532 Org. & Biomolec. Chem. 2008, 1416
Transcript of Baran Group Meeting The Chemistry of Lewis N. Mander Emily ... · Baran Group Meeting The Chemistry...
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Isolation WorkBiography- Born Sept. 8,1939 in Auckland, NZ
Education- University of Auckland, B.S., 1960, M.S. 1961(R.C. Cambie)- University of Sydney; Ph.D., 1964(C.W. Shoppee, E. Ritchie, and W.C. Taylor)- Univeristy of Michigan/Caltech; Postdoc., 1966(R.E. Ireland)
Academic Career1966- Lecturer in organic chemistry at the University of Adelaide1970- Promoted to senior lecturer in organic chemistry1975- Moved to Australian National University as a senior fellow in the Research School of Chemistry 1980- Appointed to Professor at Australian National University1981-1995- Dean of the Research School of ChemistryCurrently: Adjunct Professor at Australian National University
Honors and Awards1972- Nuffield Fellow at Cambridge University with A.R. Battersby1977- Fulbright Senior Scholar at Cal. Inst. of Tech. with D.A. Evans1983- Elected to Australian Academy of Science1986- Fulbright Senior Scholar at Harvard with D.A. Evans1990- Elected to the Royal Australian Institute of Chemistry and Royal Society (London)1991- Honoroary Fellow of the Royal Society of New Zealand1993- Jeffery Medal1994- Birch Medal1995- Archibald Olle Prize2002- David Craig Medal2004- Australian Journal of Chemistry published an issue dedicated to Mander on the occasion of his 65th Birthday (Aust. J. Chem. 2004, 611)
"On one occasion we stopped in the bush for drinks and Lew...started to sit down. He was already well into the downward tragectory when...he saw apoisonous snake...on the spot where he was about to land. I have yet tounderstand how he did it, but he immediately went into levitation mode andseemed to hang, sliding sideways so dropping onto a snake free zone. Heexplained to me that life in Australia was not like the UK. He then gave usclear instructions on what to do about snakes, spiders, or when caught in abush fire; Lew is a man of many parts." -Alan Battersby
Galbulimima Alkaloids
N
OMeH
OBz
H
H
H
H
MeCO2Me
OH
himandrine
HN
HO
H
H
H
H
Me
OH
G.B. 13
H
N
OO
Me
H
H
HO
H
H
G.B. 17Aust. J. Chem. 1967, 1029Aust. J. Chem. 2006, 629
Aust. J. Chem. 1967, 1473 Tet. Lett. 2009, 7089
R1
OH
OHMeH
HMeMe
O
Me Me
OHOO
O
OO
COOH
H
H
H
HHO
HOHO
HOH
H
HOHH
HOH
OHOH
HH
HO
HH
H
saponins
R2
J. Nat. Prod. 2002, 115
N
HN
OH
HO
bisdimethylaaptamineTetrahed. 2004, 6101
CO2HMe
O
OC
HOH
antheridiogenPhytochem. 1989, 63
CO2HMe
O
OC
HR
R
RR
R
gibberellinsPhytochem. 1998, 331Phytochem. 1998, 587Phytochem. 2001, 749
Org. & Biomolec. Chem. 2006, 2532
Org. & Biomolec. Chem. 2008, 1416
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Mander's Reagent: methyl cyanoformateTet. Lett. 1983, 5425
- Almost exclusive O-acylation observed with THF - Ether reverses selectivity for !-ketoester formation (emperical observation)- Similar results observed for decalin systems and R-(-)-carvone
A [Very] Brief Synopsis of Total Syntheses
MeLi MeO
O
CNO O
OMe
HMPA
- Lithium enolate necessary, no reaction with potassium or sodium derivatives- Note stability of methyl cyanoformate in the presence of liberated amine- First direct synthesis of non-enolizable !-ketoesters
OTMS OLi
72%
O LDAOLi
MeO
O
CN
HMPA
85%
OCO2Me
Synlett. 1990, 169, Org. Synth. 1992, 256
OMe
HLiO
OMe
HMeO2CO
OMe
HO
CO2Me
NCCO2Me
THF
EtO2
71%
[>98% d.s.]
OMe
O
Li, NH3, tBuOH
Hainanolidol and HarringtonilideJACS 1998, 1914
O
MeO
CO2MeHsteps
MeOCO2MeH
MeOO
N2
OMe
ODEIPS
Rh2(mandelate)4
MeOCO2MeH
MeOO OMe
ODEIPS
MeO
CO2MeH
MeOO
OMe
ODEIPS
DBUMeO
CO2MeH
MeOO
OMe
ODEIPS
1. ZnBr22. Al2O3
MeO
CO2Me
H
O HOH
ODEIPS
1. K2CO3, MeOH-H2O (33%)2. TBAF3. NaBH4
O
MeO
H
HO
O
HO
HCl-THF
O
O
HO
HOHainanolidol
84%
46%(2 steps)
>50%overall O
HO
HO
HO
base
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Hainanolidol and Harringtonolide cont'd.JACS 1998, 1914
O
O
HO
HOhainanolidol
Pb(OAc)4h!
O
O
HO
OH
H H
harringtonolide
transannularoxidation
G.B. 13JACS 2003, 2400
MeO
OMe
OMe
HO2C
steps MeO N
MOMO OTBS
Yb(thd)3
MeO
N
MOMO
H
H
stepsO H
MOMO
H
H
O
H
OMOM
H
pNO2ArSO2NHNH2Pyridine, EtOH, THF
H
MOMO
H
H
H
OMOM
H
O H2NOH, HCl, Pyridine
H
MOMO
H
H
H
OMOM
H
N
OH
NHO
G.B. 13 cont'dJACS 2003, 2400
H
MOMO
H
H
H
OMOM
H
N
OH
N
1. ZrCl4, NaBH42. Zn, HOAc3. TFAA, NEt3
H
MOMO
H
H
H
OMOM
H
N
OF3C
H
H
HO
HH
O
H
HN
H
G.B. 13
HO
steps
32%(4 steps)
76%
87% Himandrine Skeleton SynthesisOrg. Lett. 2004, 703
OMe
OMOM
O
H
H
H
MeO2COMe
OMOM
O
H
H
H
HO2C
HMPA, NaH,SH
OMe
OMOM
O
H
H
H
HNO
O
O
OMOM
H
H
H
HNO
O
H
97%
1. (COCl)2, DMF NaN32. toluene, "3. NaOMe, MeOH
77%
1. Li, NH3, MeOH2. AcOH, THF, H2O3. MOMCl, iPr2NEt, DMAP4. HCl, CHCl3
32%
MOMO
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
1. DIBAL-H, NaBH42. MOMCl; TsOH
OMOM
H
OMOM
O
90%(4 steps)
1. LiHDMS, MeOCOCN2. NaH, PhNTf2
OMOM
H
OMOM
CO2Me
69%3 steps
SordaricinOrg. Lett. 2003, 1321
O Osteps
MOMO
O
MOMO
!
steps
I
MOMO
CN
O
O
LDA, HMPA,then A
A
CN
O
O
OMOM
H
85%
55%
O
OMOM
H
H
H
HNO
O
OH
OMOM
H
H
H
HNO
O
OHOH
HH
1. 9-BBN, THF, MeOH, H2O22. OsO4, Py
Pb(OAc)4 MeOH
N
MOMO MOMO
MOMO
NH O
MOMO
OO
O
OMOM
NH O
MOMO
OO
OMOM
NH
MOMO
OO
OMOM
OMs
OMOM
NH
MOMO
OMOM
N
MOMO
OMOM NH
PhOCO
OH
MeO
MeO2C
himandrine
K2CO3, MeOH
P
N2
OOMeO
MeO
1. Li/NH3, MeOH2. CH2SO2Cl, Et3N
1. NaH, DMF2. NaH, HMPA
PdCl2, CuCl, O2nBuNH4Cl, K2CO3
Rh, Al2O3, H2(CF3)2CHOH
Dowex " 50W60%
95%
85%
88%
93%
91%
70%
75%
OMOM
H
OMOM
CO2Me
2-Th(CN)CuLi,
iPrMgCl
TfO
SH
N
HO
OH
N
PhOCO
OH
HO
MeO2C
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Intramolecular Alkylations and their evolution into Gibberellin SynthesisAust. J. Chem. 1971, 343
HO
BrTHPO
KOtBu, tBuOH
reflux
O
OTHP
50%
HO
N2
O
BF3•OEt2NO2CH3
30%
O
O
Aust. J. Chem. 1972, 137
MeO
N2
O
MeO
MeO
N2
O
MeO
Cu powdercyclohexane
Cu powdercyclohexane
- copper(I) oxide and copper(II) sulfate were inferior catalysts- basic alumina can also catalyze the retro-Michael reaction
70-80%
70-80%
MeOMeO
MeOMeO
O
O
HCl, H2O,acetone
HCl, H2O,acetone
O
O
O
O
(stereochemistry not specified)
"In preparation for projected syntheses of more complex diterpene alkaloids, we have investigated the preparation of isomeric dienones...which should afford more directaccess to compunds based on the atisine skeleton" -Mander
Aust. J. Chem. 1974, 1287
MeO MeO
steps
O
N2
MeO
O
MeO
O
H
TFA, 0 °C (neat)
Quant.
Aust. J. Chem. 1974, 1977
"In this paper we describe a particularly short and efficient apprach to the synthesesof tetracyclic ketones which could serve as valuable intermediates in the synthesis of gibberellins." -Mander
Intramolecular Alkylations and their evolution into Gibberellin Synthesis(continued)
MeOO
MeO
steps
OMOM
H
OMOM
CO2Me
1. MgBr2, butanethiol2. MnO2
92%(2 steps)
O
H
OH
CO2Me
180 °C
76% combined yield4:1
O
H
OH
CO2Me
CO2Me
HO
OCO2Me
HO
Ominor
CO2H
HO
O
sordaricin
SNa
CO2Me
HO
O
major
26 steps3% overall yield
79%
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Synthesis of Gibberellic Acid (GA3) ( JACS 1980, 6626)
Gibberellins: A Brief BiographyStructural deconvolution: -Originally isolated from fungus Gibberella fujikuroi in 1938-first unequivocal assignment in 1962 by x-ray cystallography by McCapra & coworkers (Proc. Chem. Soc. London 1962, 185)
In Plants: -responsible for stem growth (involved in biogenetic differences between tall and dwarf pea plants used by Mendel to study inheritance)- stimulates flowering- breaks winter dormancy
Isolation Horror Stories: In an effort to isolate meaningful quantitites of GA32, ten 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 of GA19 was obtained from 44 tons of bamboo shoots!
GA3 Production: produced in ton-quantities annually fromfermentation of Gibberella fujikuroi
HO
OHO
HCO2H
OC
OH
OH
GA32
H
Gibberellins: BiosynthesisArise from kaurenoic acid via C-7 hydroxylation followed by ring contraction:
C-20 methyl group can be oxidized to a formyl group which can then be lost to form C19-gibberellins upon cyclization to a !-lactone:
H
H
CO2H
[O]
H
H
CO2H
OH
Henzyme
CHO
H
HCO2H
CO2H
H
HCO2H
[O]
CO2H
H
HCO2H
O
CO2H
H
H
O
OC
12
3
4
5
6
7
2013
1211
89
10
14
15
16 17
18
19 7
"In an attempt to convince a University to employ him, and granting agencies to provide him with funding, the author also proposed to carry out a synthesis of this intriguing molecule." -Mander (Nat. Prod. Rep. 2003, 48)
N2
O
OCOCCl3
OMe
O
OCOCCl3
O
OH
O
O
O
OH
O
O
O
N2
OHO
O
CO2Me
OHO
O
CO2Me
HHO
OHO
O
CO2Me
HHO
OHO
O
CO2Me
HO
OHO
O
CO2Me
HHO
OHO
O
CO2Me
HEtOCO
OHO
O
CO2Me
HO
OC
H
OHO
O
CO2Me
HO
OC
HO
TFA 1. Na2CO3 (aq.)
2. (CH2OH)2,
(CH2Cl)
Dowex" 50W
4 Å sieves
3. K-select.
SO2
N3
nBu4NBr,
KOH
PhH, H2O
82%
82%
80%
1. h#, Na2CO3 (aq.)2. CH2N2
1:3 $:%
thexylborane,Na2HPO4, H2O2
1. PhSeSePh, KH2. H2O2
90%
MnO2
60%(3 steps)
Al 3
(d.s.> 95%)
(EtCO)2O,Et3N, DMAP
78%
THF, -78 °C, 5 min
KH, DMF;Quench Et3N+H•Ac-
2:1$:%
disiamylborane;Na2HPO4, H2O2;CrO3•2Py
89%
A moment in chemical history: The first total synthesis of was completed by Corey (reported in JACS 1978,8031) in which he wrote that GA3 posessed "... asingularly diabolical placement and density offunctionality..." (Mander completed his first totalsynthesis in 1980)
HO
OHO
H CO2H
OC
gibberellic acid(GA3)
H
-CH2O
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Synthesis of Gibberellic Acid (GA3) cont'dOH
O
O
CO2Me
H
O
OC
HO
OHO
O
CO2Me
H
O
OC
HHO
OTMS
CO2Me
H
O
OC
HTMSO
O
OH
CO2Me
H
O
OC
H
O
O
OH
CO2Me
H
O
OC
HPhOCO
O
gibberellic acid
Gibberellin Core Modification: The A ring
K2CO3
29%1. 3M HCl2. TMSCl, DIPEA
OH
CO2H
H
O
OC
HHO
1. PPh3+Me•Br-,
KOtBu
2.
(H+ workup)
80%
(4 steps)
gibberellin A1
OHO
O
CO2Me
H
O
OC
HHO
1. PhSO2Cl,
Pyridine
2. nBu4NBr
3. DBN
78%(3 steps)
1. OsO4, NMO2. PhCHO, TsOH 4 A sieves3. NBS, CCl4, then h!
OH
CO2Me
H
O
OC
H
O
O
PhOCO
Br
1. DBN2. 3N HCl
(H+ workup)
1. K2CO3/KHCO32.
OH
CO2H
H
O
OC
HHO
OH
CO2Me
H
O
OC
HPhOCO
1. TMSCl, DIPEA
2. PPh3+Me•Br-,
KOtBu
29%
84%(3 steps)
90%(2 steps)
(yield not specified)
OR2
CO2Me
H
O
OC
HR1O
Li, NH3, tBuOH
OMOM
CO2Me
H
HO2CH
93%
1 2(Tet. Lett. 1985, 363)
1. TsCl, Py2. NaBr, HMPA3. Zn, EtOH
OH
CO2Me
H
HO2C
H
m-CPBA
OH
CO2Me
HCO
HHO
O Me2BBr
7 8
OH
CO2Me
HO
OC
HHO
(JOC 1990, 4860) 1"iso-lactone"
OMOM
CO2Me
H
N2HCOCH
OMOM
CO2Me
H
H
O
OMOM
CO2Me
H
H
O
OMOM
CO2Me
H
H
O
CO2H
(Tet. Lett. 1985, 5725)
1. (COCl)2, DMF2. CH2N2
75% 49%
Cu-bronzeNH3, Li, tBuOH
KH, DMFO2
95%
C20 gibberellins
3 4 5
6
SLi SLi
192 10
when R1,R2=H
when R1= MsR2= MOM
89%
86%
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Gibberellin Core Modification: The C ring
OAc
CO2Me
H
O
OC
HAcO
12!-Hydroxy
1
1. SeO2, tBuOOH
2. PCC•SiO2
OAc
CO2Me
H
O
OC
HAcO
O70%
(Tet. Lett. 1991, 6203)
1. H2, RhAl2O32. pyrrolidone, HBr33. NaB(CN)H3
OAc
CO2Me
H
O
OC
HAcO
OH42% Br
Pb(OAc)4, I2, h"
OAc
CO2Me
H
O
OC
HAcO
Br
O
74%
Zn, HOAc
OAc
CO2Me
H
O
OC
HAcO
OH
80%
2 3 4 5
12#-Hydroxy
OAc
CO2Me
H
O
OC
HAcO
OH
Note: Inversion via Mitsunobu fails.
OAc
CO2Me
H
O
OC
HAcO
O
CO2Me
H
O
OC
HAcO
OH
CO2Me
H
O
OC
HAcO
OH
OH
5 6 7 8
(Tet. Lett. 1996, 719)
OAc
CO2Me
H
O
OC
HMOMO
(Tetrahedron 1998, 11637)
14!-Hydroxy
9
O3, Et3N
56%
OAc
CO2Me
H
O
OC
HMOMO
O
OH
CO2Me
H
O
OC
HMOMO
O
1. K2CO32. H2, Rh-Al2O3 NaH
OH
CO2Me
H
O
OC
HMOMO
O
1. (Ac)2O, DMAP2. TBSOTf, Et3N
OAc
CO2Me
H
O
OC
HMOMO
OTMS
OAc
CO2Me
H
O
OC
HMOMO
O
DMDO
OTMS
10 11 12 13
1415
TBAF
OAc
CO2Me
H
O
OC
HMOMO
O
OH
NaOMe
CO2Me
H
O
OC
HMOMO
OOH
OH
16
78%from 13
98% 80% 73%
CO2Me
H
O
OC
HMOMO
OOTMS
OTMSTMSCl
imidazole
CO2Me
H
O
OC
HMOMO
OH
OHPPh3
+Me•I-, KH
1718
(H+ workup)
H2CrO4 K2CO3, MeOH ZnCl2, NaBH4
95% 72%
O
57%
30%from 16
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Gibberellins: conversion to Antheridic Acid
CO2Me
H
O
OC
HMOMO
(JACS 1987, 6391)
CO2Me
HO2C
HMOMOCO2MeHMOMO
OO
CO
I
CO2MeHMOMO
O
O
CO
CO2MeHMOMO
O
OC
O
CO2MeHMOMO
O
OC
O
CH2O2MeHMOMO
O
OC
O
CO2MeHMOMO
OC
O
CO2MeHHO
OC
O
OH
CO2HHMOMO
OC
O
OH
H2NNH2•H2O, DMF
19%
1. KI3, KHCO32. O3, Pyridine, Me2S KH
1. LiOH2. KI3
1. (TFA)2O, Pyridine2. Zn, KI
DBU
1. H2, Rh-Al2O3 (80%)
2. PPh3CH2
3. LiCA, Et3NH+Ac-*
1. SeO2, tBuOOH
2. MeBBr2LiOH
66%
1 2 3 4 5
678910
80% 47%
I
HO
82%
93%* 74% BRSM, 3 cycles
67%83%
Antheridic Acid
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."
CO2Me
H
HO2C
H
(~ $21/gram)
O OMOM
CO2Me
H
H
OMOM
NaBH4 O
CO
Dowex! 50W
CO2Me
H
H
OH
O
CO
1. MeO2CCOCl,
iPr2NEt, DMAP
2. nBu3SnH, AIBN
CO2Me
H
H
H
O
CO
COCl
H
H
O
H
O
CO
1. O3; Et3N2. NaOH3. (COCl)2, Py
CH2OH
H
H
H
O
CO
NaBH4
H
H
H
O
COH
H
H
O
CO
OHO OH
1. DMP2. OsO4, NMO3. DMP
OH
O
BF3•Et2OO
H
H
H
O
OH
CO
O
CH2SeAr
H
H
H
O
CO
OHH2O2
11 12 13 14 15
1617181920
Kaurane Skeleton
88% 90% 88% 73%
82%
90%
O2N SeCN
nBu3P
78%60%Quant.
Emily CherneyBaran Group MeetingThe Chemistry of Lewis N. Mander
Gibberellins: conversion to Longirabdolactone(J. Aust. Chem. 2003, 805)
H
H
H
O
CO
OH
OH
KH
H
H
H
OHNaO2C
O
OH
H
H
H
OMeO2C
O
O
1. NaIO42. CH2N2
H
H
H
O
O
O
1. NaBH42. H2CrO4
O
H
H
H
O
O
O
O
1. SeO2, tBuOOH
2. DMP
O
H
H
H
O
CO
OH
O
DMSO, (COCl)2, Et3N NaOH, MeOH
1 2 3 5
678
Longirabdolactone
86% 86%
45%(3 steps)
92%23%
H
H
H
O
O
OH
O 4
H
H
H
OH
O
CO
O
Further reading:
- Mander, L.N. "Exploitation of aryl synthons in the synthesis of polycyclic natural products" Synlett, 1991, 135
- Hook, J.M., Mander, L.N., "Recent developments in the Birch reduction of aromatic compounds: applications to the synthesis of natural products" Natural Product Reports, 1986, 35
- Mander, L.N., Williams, C.M., "Oxidative degradation of benzene rings" Tetrahedron, 2003, 1105
- Mander, L.N., Williams, C.M., "Chromatography with silver nitrate" Tetrahedron, 2001, 425
- Mander, L.M., "Twenty years of gibberellin research" Natural Product Reports, 2003, 49
