Total Synth GM Short.Pptx
Total Synthesis
New Methodology
MacMillan Group Meeting 3-31-10 an opinion by Anthony Casarez What Classifies as Innovative?
Innovation \i-nə-ˈvā-shən\ n:
1. The act of introducing something new.
2. A new idea, method, or device.
Would introducing a new method in a total synthesis make it innovative? Yes but…
Some innovations are considered to be more significant than others. How do we qualify these?
In my view an innovation must dramatically change the landscape of our field or provide a method that is widely applicable. How Our Field was Born: UREA
O
H2N NH2
Isolated in 1773 from human urine (hence the name) by Hilaire M. Rouelle
Intriguing to scientists who were eager to understand the mysteries of bodily functions . How Our Field was Born: UREA
Friedrich Wöhler: 1800-1882; student of Jöns Jakob Berzelius.
The synthesis of urea is known as the event that begot the field of synthetic organic chemistry.
“I cannot, so to say, hold my chemical water, and must tell you that I can make urea, without thereby needing to have kidneys, or anyhow, an animal, be it human or dog.”
Wöhlerʼs discovery shouldʼve refuted vitalism, the belief that organic molecules can only come from life which possesses a “vital force,” but the skeptics remained because he did not synthesize a C–C bond.
O NH4Cl AgNCO AgCl H2N NH2 How Our Field was Born: UREA
As if the birth of synthetic organic chemistry wasnʼt enough…
Wöhler thought he was using AgOCN (silver cyanate) instead of AgNCO (silver isocyanate), both possessing the same formula as AgCNO (silver fulminate), studied by Justus von Liebig, but having different chemical properties.
This gave rise to the notion of isomerism.
O NH4Cl AgNCO AgCl H2N NH2 Convincing the Skeptics
15 years later Hermann Kolbe silenced (most) skeptics by synthesizing acetic acid, literally from elements.
FeS2 C CS2 Fe
2Cl2 CS2 CCl4 2S
pyrolysis Cl Cl 2CCl4 2Cl2 Cl Cl
Cl Cl pyrolysis O 3HCl Cl Cl Cl3C OH
O O 3H2 3HCl Cl3C OH H3C OH Retrosynthetic Application: Tropinone
“By the imaginary hydrolysis at the points indicated by the dotted lines, the substance may be resolved into succinaldehyde, methylamine, and acetone, and this observation suggested a line of attack of the problem which has resulted in a direct synthesis.” –Sir Robert Robinson J. Chem. Soc. 1917, 762.
Sir Robert Robinson NMe CO
Sir Robertʼs analysis was one of the simplest yet most powerful suggestions of its time. The fact that it worked was a testament to his intuition. Tropinone Retrosynthetic Application: Tropinone
“In Searching for a method of synthesis of any substance it is always convenient to be able to recognize the formation of traces of the desired product…tropinone is obtained in small yield by the condensation of succinaldehyde with acetone and methylamine in aqueous solution.”
–Sir Robert Robinson J. Chem. Soc. 1917, 762-8.
The forward synthesis only required a slight modification of starting materials.
Me Me CO2H N N CHO CaCO3 CO2CaX HCl H2NMe O CHO H2O H2O O O CO2H XCaO2C Tropinone, 42% Tropinone: Mechanism
CO2H CO2CaX CHO CaCO3 H2NMe O N Me OH CHO H2O CO2H OH CO2CaX
Me N Me N CO2CaX CO2CaX
OH O CO2CaX OH CO2CaX
Me Me N N
CO2CaX HCl
XCaO2C O O 2CO2 “We have here a case where three rather simple molecules spontaneously unite into a complicated system, which earlier we could only build up step by step through a long series of reactions (13). We may suppose that here Sir Robert has found the key to natureʼs own way of working.” –A. Fredga: Robinsonʼs Nobel presentation speech (1947). Reserpine
N MeO N H H H O H OMe MeO2C O OMe OMe (-)-reserpine OMe
R. B. Woodward
Known as one of the hallmarks of synthetic manipulation by a master of the field.
One of the greatest achievements of Woodwardʼs career especially considering only IR and elemental analysis were used as guides.
The dramatic conclusion taught chemists an invaluable lesson of thermodynamic engineering.
Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J; Kierstead, R. W. J. Am. Chem. Soc., 1956, 78, 2023. Reserpine: Retrosynthetic Analysis
Reductive N O N amination MeO N MeO N H H H H H O Lactamization H H Bischler- OMe Napieralski MeO2C O MeO2C OAc OMe OMe OMe (+)-reserpine OMe
O H Diels–Alder OAc O O H MeO2C OMe H CO2Me H O CO2Me O CO2Me
NH2 p-benzoquinone MeO N H 6-methoxytryptamine Reserpine
O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br A Diels–AlderH sets the first three stereocentersH O O O O Meerwein–Pondorff–Verley reduction creates the next two causing a spontaneous lactonization with the nearby ester. H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo
O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H Br MeONa O H 2 BromoetherificationO sets the next two. Br MeOH Br H H O O O O
H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo
O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br H H O O O O
H H H Br H H H O O O H H NSubstitutionBS of methoxide occurs with OMe HO OMe retention of configuration.H H OMe H H2SO4 (aq) O O O O O O Reserpine: Molecular Judo
O OH H H PhH, ! Al(Oi-Pr)3 MeO2C O H i-PrOH H H O O CO2Me O O endo-TS H H H H MeONa Br2 O O H Br MeOH Br H H O O O O
H H H Br H H H O O H NBS O H OMe HO OMe H H OMe H H2SO4 (aq) O O O O O O Reserpine
H H Br Br H H H H Cr O Br H O H 2 2 7 O H Zn Zn O H HO OMe AcOH O OMe H H AcOH O OMe O O Zn H O O CO2H H
H H OAc OH OsO 1. CH N 4 H 2 2 H
NaClO3, O OMe 2. Ac2O O OMe H O H H 2 CO2Me CO2H
OH O H H O N HO OAc MeO N OAc H H 1. HClO4 1. PhH, 1 H H MeO2C OMe H O OMe 2. CH2N2 2. NaBH4, H H CO Me MeOH MeO2C CO2Me 2 OAc OMe Reserpine
O N N MeO N 1. POCl , ! MeO N H H 3 H H H
2. NaBH4, H MeOH H MeO2C OAc MeO2C OAc OMe OMe
(+)-methyl-O-acetylisoreserpate
H Reduction of theH iminium ion happens on the convex face providing the undesired epimer. N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN
OMe OAc MeO Reserpine
O N N MeO N 1. POCl , ! MeO N H H 3 H H H
2. NaBH4, H MeOH H MeO2C OAc MeO2C OAc OMe OMe
(+)-methyl-O-acetylisoreserpate
H H N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN
OMe OAc MeO
Thermodynamics favors the wrong conformation for an acid catalyzed epimerization. Reserpine
O N N MeO N 1. POCl , ! MeO N H H 3 H H H
2. NaBH4, H MeOH H MeO2C OAc MeO2C OAc OMe OMe
(+)-methyl-O-acetylisoreserpate
H H H H H N H H H H N N N N N N OMe N ONAc H H H H HCO Me H H MeO 2 CO2Me HN
OMe H OAc MeO N N N N H H H H Reserpine: Molecular Judo
Hydrolysis and lactone formation lock the molecule in the thermodynamically unfavorable conformation.
H H N H H H N N OMe OAc H H CO Me MeO 2 CO2Me HN
OMe OAc MeO
H H
N H N H H H OAc O CO Me 1. KOH, MeOH MeO 2 MeO O HN HN 2. DCC, pyr
MeO MeO Reserpine: Molecular Judo
H H N H N H O H t-BuCO H O O 2 MeO O HN MeO H HN xylenes, !
OMe MeO
NaOMe, Epimerization is now favored, correcting the stereochemistryMeO H, !
N MeO N H H H N Pyridine MeO N O H H H H O OMe OMe Cl MeO2C O H H OMe OMe MeO2C OH OMe OMe OMe OMe (+)-reserpine Reserpine
H H N H N H O H t-BuCO H O O 2 MeO O HN MeO H HN xylenes, !
OMe MeO
NaOMe, MeOH, !
N MeO N H H H N Pyridine MeO N O H H H H O OMe OMe Cl MeO2C O H OMe OMe MeO2C OH OMe OMe OMe OMe (+)-reserpine Reserpine
(+)-reserpine
1. (+)-CSA 2. NaOH
N MeO N H H H O H OMe MeO2C O OMe OMe (-)-reserpine OMe
Woodward: Organic Ninja
When defeated by both kinetics and thermodynamics, Woodward manipulated the system so that it worked in his favor.
“It is sometimes said that you have demonstrated that nothing is impossible in organic synthesis. This is perhaps a slight exaggeration. You have, however, in a spectacular way expanded and enlarged the domain of the possible.” –A. Fredga: Woodwardʼs Nobel presentation speech (1965). Progesterone
O Me Me H Me H
H H O
(+)-progesterone
W. S. Johnson
A synthesis inspired by the polyene cyclization of squalene oxide to dammaradienol in the biosynthesis of lanosterol.
Displayed a synthetically useful domino reaction and demostrated the utility of the Johnson– Claisen rearrangement.
Johnson, W. S.; Gravestock, M. B.; McCarry, B. E. J. Am. Chem. Soc., 1973, 95, 20, 6832. Progesterone: Retrosynthetic Analysis
O O O Me Me Me Me Me Me H H H O Me H Me H Me H Me H H H H H H O O Aldol/dehydration Me Ozonolysis
(+)-progesterone Cation-!- cyclization Me Me Me
Me Me Me O Me Me Me
Me O O Aldol/dehydration OH
Me
Me I O O Me O O PPh3 Me Me CHO
O O Me O O Wittig/Schloser modification Cyclization of Squalene Oxide
Me Stork and Eschenmoser independently yet Me Me concomitantly proposed that the trans olefins in the Me Me H O substrate controlled stereoselectivity. H Me H Eschenmoser states: “It seems that with polyenes of Me this complexity (below), acid-catalyzed cyclization ceases to be a useful reaction from the preparative enzyme catalyzed point of view.” Me
Me Me Me Me Me HO CO2Me Me Me Me Me dammaradienol Me further enzymatic steps 5-10%
Me H OH Me Me Me H CO2Me Me H H Me Me Me HO lanosterol Me Me Progesterone: Right Half
Me Me BrMg
CHO Me HO 138 °C, Me CH3C(OEt)3, C2H5CO2H, 55% 2-steps
Me Me Me 1. LiAlH4 CHO 2. CrO3, EtO O EtO O Me pyr, 77% Me Me
Johnson–Claisen rearrangement sets the γ,δ-usaturation Progesterone: Left Half
Me Me O O nBuLi, THF HO(CH2)2OH, Br O –30 °C O p-TsOH Me —20 to 23 °C, 75% hydroquinone, PhH, Br Br reflux, 71% O O Br
NaI, MgO O O I O O C2H5COCH3, PPh3 I Me PPh3, PhH Me 80 °C, 99% 80 °C, 94% O O O O
Furan starting material installs the 1,4-diketo relationship. Progesterone: Converging Two Halves
Me
Me I O O Me O O PPh3 PhLi, –70 to –30 °C Me Me CHO then MeOH, -30 °C
O O Me O O
Me Me Me 0.1 N HCl (aq), Me EtOH, reflux O MeOH (3:10), 2% NaOH (aq) Me 40 °C Me 40%
O O
Schlosser modification of the Wittig provides the requisite E-olefin.
Deprotection and cyclization installs the final unsaturation. Progesterone: Cation-π-Cylization
Me Me
Me Me MeLi, ether Me 99% Me O
Cl(CH2)2Cl, Me O O O OH TFA, 0°C
Me Me O Me O Me O O O Me Me H O H H
Me Me
O Me K2CO3, Me H2O/MeOH, H 71% Me H
H H
Me Progesterone
O O Me Me Me Me H O , MeOH/CH Cl H 3 2 2 O Me H –70 °C Me H Me H H then Zn, AcOH, H2O, H H –15 °C to rt, 88% O Me
O Me Me H KOH, H2O Me H 51%
H H O
(+)-progesterone
Cation-π-cylization forges all six stereocenters in a tandem operation from the crude tertiary alcohol.
Though biomimetic cation-π-cylizations had been previously demonstrated by Stork, Eschenmoser, and van Tamlen, this is the most elegant and highest yielding example applied to a total synthesis. Prostaglandin A2
O
CO2H Me H OH
PGA2
Elias James Corey
The first example of a total synthesis using the TBS protecting group, which also directs a SN2- selective organocuprate addition.
Addition of a chiral organocuprate facilitates convergence within the synthesis.
Introduction of the TBS protecting group has been one of the most enabling innovations of the 20th century. Corey, E. J.; Mann, J. J. Am. Chem. Soc., 1973, 95, 20, 6832. Prostaglandin A2: Retrosynthetic Analysis
Wittig HO O TBSO CHO (CH ) CO H O 2 3 2 H O C5H11 C5H11 H OH OH SN2 cuprate elimination Iodoetherification PGA2 addition
Baeyer–Villiger H O O O HO O !-NH3MePh Cl H Cl CO2 Cl H Ketene H 2 + 2 Prostaglandin A2
O Cl H H Cl O O Cl Zn, AcOH Cl NEt3, 0 °C, 75% H Cl H
O NaOH, H2O H2O2, H2O HO !-NH MePh O 3 0 °C, then H AcOH, 90%
CO2 !-NH2MePh H
1. I2, 85% TBSO TBSO 2. TBS-Cl, DMF O DBN, THF imidazole, 72% 70 °C, 94% O O O
I
Ketene 2 + 2 installs requisite lactone carbons. Prostaglandin A2
O Cl H H Cl O O Cl Zn, AcOH Cl NEt3, 0 °C, 75% H Cl H
O NaOH, H2O H2O2, H2O HO !-NH MePh O 3 0 °C, then H AcOH, 90%
CO2 !-NH2MePh H
1. I2, 85% TBSO TBSO 2. TBS-Cl, DMF O DBN, THF imidazole, 72% 70 °C, 94% O O O
I
Baeyer-Villiger oxidation followed by hydrolysis and resolution furnishes the enantioenriched hydroxy acid. Prostaglandin A2
O Cl H H Cl O O Cl Zn, AcOH Cl NEt3, 0 °C, 75% H Cl H
O NaOH, H2O H2O2, H2O HO !-NH MePh O 3 0 °C, then H AcOH, 90%
CO2 !-NH2MePh H
1. I2, 85% TBSO TBSO 2. TBS-Cl, DMF O DBN, THF imidazole, 72% 70 °C, 94% O O O
I
Iodolactonization, TBS protection, and elimination provide the necessary precursor for cuprate addition. Prostaglandin A2
TBSO TBSO O C5H11 ether/pentane CO2H LiCu O C H OTBS 2 –70 ! –20 °C 5 11 H OTBS
O O
O O HCl (aq), DCM, PPTS acetone, 80%
C5H11 C5H11 99% H O H OTHP OH
1. DIBAlH, – 78 °C, O toluene HO (CH2)3CO2H 2. Ph3P=CH(CH2)3CO2, (CH2)3CO2H DMSO 1. Collins [O] C5H11 C5H11 2. AcOH/H2O H H OH OTHP PGA2
Organicuprate addition happens in an SN2 fashion over SN2´ due to blocking from the –OTBS group. Prostaglandin A2
TBSO TBSO O C5H11 ether/pentane CO2H LiCu O C H OTBS 2 –70 ! –20 °C 5 11 H OTBS
O O
O O HCl (aq), DCM, PPTS acetone, 80%
C5H11 C5H11 99% H O H OTHP OH
1. DIBAlH, – 78 °C, O toluene HO (CH2)3CO2H 2. Ph3P=CH(CH2)3CO2, (CH2)3CO2H DMSO 1. Collins [O] C5H11 C5H11 2. AcOH/H2O H H OH OTHP PGA2 Olefination, deprotection, and oxidation complete
the synthesis of PGA2 Prostaglandin A2
O
CO2H Me H OH
PGA2
TBS protecting group is one of the most widely used protecting groups in synthesis (43,200 web hits, original paper cited 2,256 times).
“Corey's most important syntheses are concerned with prostaglandins and related compounds…No other chemist has developed such a comprehensive and varied assortment of methods, often showing the simplicity of genius, which have become commonplace in organic synthesis laboratories. –S. Gronowitz: Coreyʼs Nobel presentation speech (1990). Vernolepin/Vernomenin
OH O O O H O O O H H H O OH
O vernolepin vernomenin
Samuel Danishefsky
First synthesis employing the synergistic diene: Danishefskyʼs diene (32,400 web hits, original paper cited 431 times).
Brought this concept to the scientific community, inspiring additional contributions e.g. Rawal diene.
Danishefsky, S.; Schuda, P. F.; Kitahara, T.; Etheredge, S. J. J. Am. Chem. Soc., 1977, 99, 18, 6066. Vernolepin: Retrosynthetic Analysis
Wittig
OH OH OH O O O H O O O H H O H O O OH CO2Me vernolepin O Epoxide Lactonization opening
O O O O O Lactonization O OHC O
MeO2C O O H O Directed H O H O epoxidation
O Iodolactonization OMe O CO Me 2 CO2Me
O O TMSO H Elimination H
Diels–Alder Vernolepin/Vernomenin
OMe
CO Me CO2Me 2 MeO2C TMSO
mesitlene, O reflux, 60% H
O O NaHCO3, CO2H NaOH (aq), I2, KI, 88% THF, quant
O I O H H
O
PhH, O CO2H DBU, NaOH (aq), OH 87% THF, quant
O O H H
Sequential Diels–Alders, the second utilizing Danishefskyʼs Diene, forge the
quaternary decalone. Vernolepin/Vernomenin
OMe
CO Me CO2Me 2 MeO2C TMSO
mesitlene, O reflux, 60% H
O O NaHCO3, CO2H NaOH (aq), I2, KI, 88% THF, quant
O I O H H
O
PhH, O CO2H DBU, NaOH (aq), OH 87% THF, quant
O O H H
Soponification followed by iodolactonization afford the tricyclic lactone. Vernolepin/Vernomenin
OMe
CO Me CO2Me 2 MeO2C TMSO
mesitlene, O reflux, 60% H
O O NaHCO3, CO2H NaOH (aq), I2, KI, 88% THF, quant
O I O H H
O
PhH, O CO2H DBU, NaOH (aq), OH 87% THF, quant
O O H H
E2 Elimination and a second sponification provide the allylic alcohol necessary for epoxidation. Vernolepin/Vernomenin
O CO2H dioxane, PhH, CO2H O OH OH m-CPBA Ac2O, NaOAc
O O 76%, 2-steps O H H O H O
O O HO OsO4, THF, O Pb(OAc) , PhH O B(ClO ) , H O, 4 HO 3 2 2 OHC MeOH, 86% 47 °C, 84%
MeO2C O H O H O
1. LiAl(Ot-Bu)3H O OH O THF, –10 °C HO 2. Amberlite 105 O p-TsOH, PhH, O PhH, !", 93% O MgSO4, 66% O O O H O O H O
Directed epoxidation installs the correct stereochemistry of the latent
alcohol and esterification regenerates the lactone. Vernolepin/Vernomenin
O CO2H dioxane, PhH, CO2H O OH OH m-CPBA Ac2O, NaOAc
O O 76%, 2-steps O H H O H O
O O HO OsO4, THF, O Pb(OAc) , PhH O B(ClO ) , H O, 4 HO 3 2 2 OHC MeOH, 86% 47 °C, 84%
MeO2C O H O H O
1. LiAl(Ot-Bu)3H O OH O THF, –10 °C HO 2. Amberlite 105 O p-TsOH, PhH, O PhH, !", 93% O MgSO4, 66% O O O H O O H O
Dihydroxylation followed by oxidative diol cleavage prepares the molecule for
γ-lactone formation. Vernolepin/Vernomenin
O CO2H dioxane, PhH, CO2H O OH OH m-CPBA Ac2O, NaOAc
O O 76%, 2-steps O H H O H O
O O HO OsO4, THF, O Pb(OAc) , PhH O B(ClO ) , H O, 4 HO 3 2 2 OHC MeOH, 86% 47 °C, 84%
MeO2C O H O H O
1. LiAl(Ot-Bu)3H O OH O THF, –10 °C HO 2. Amberlite 105 O p-TsOH, PhH, O PhH, !", 93% O MgSO4, 66% O O O H O O H O
Reduction and cyclization forge the γ-lactone functionality and surprising protection of this moiety via the orthoester happens under acetal forming
conditions. Vernolepin/Vernomenin
O O 1. DIBAlH, – 76 °C, OH 1. LDA, AcOH, O toluene, DME, 94% O DME then Dowex O O 2. Ph3P=CH2, 2. EtOAc, acetone, O H O O H O DME, 87% CH2N2, 56%
OH O p-TsOH, OH O O PhH, !" O H O O O O H H H H OH O OH CO2Me 61% O 31%
LDA, THF Me2NCH2 I, OH O then MeI, O O NaHCO3 H O O O H H H O OH
vernolepin O vernomenin Ambigiune H
Me H Me
Me Me N Me
NH C
(+)-ambiguine H
Phil S. Baran
Reintroduced the notion of protecting group free (PGF) synthesis with the completion of (+)- hapalindole Q in 2004.
Synthesized (+)-ambiguine H in 13 steps in a PGF manner. Provoked the chemical community to rethink its approach toward synthesis. Do we rely on protecting groups as a crutch?
Have protecting groups ultimately held us back regarding step efficiency and more importantly development of new methodology? Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature, 2007, 446, 404. Ambigiune H
CO2Me Me Me Me OMe O 1. ClCOCCl3, Zn H ether, sonication H 1. DIBALH, DCM H
2. NaOMe, MeOH 2. MsCl, pyr, then OH 61% OH AcOH/H O, 73% OMs Me Me 2 Me
Br Me H Me 1. NaI, acetone Me O 2. DBU, THF, N H H !, 87% O Br LiHMDS, THF, NH Cu(II), –78 °C, 50% Me
Me Me Pd(II), H H Me Me NaOCHO, NaBH3CN, 65% NH4OAc Me O Me N HCO2H, CDMT, NH COCl2, 60% NH C Ambigiune H
Me Me Me H Me H H Me t-BuOCl Me prenyl-9-BBN Me N Me Me N N 60% N Cl C NH C NH Me Cl B Me
Me Me H H Me Me h!, TEA, Me PhH, 41% Me Me R N N
N H Cl N Cl Me B B
Me H Me Me H Me Me R N Me Me Me N Cl H N B NH C
(+)-ambiguine H Recap
Urea: Gave birth to our field
Tropinone: Demonstrated retrosynthetic analysis and was one of the first examples of a biomimetic synthesis.
Reserpine: Illustrated the power of diasteroselective transformations and taught us a lesson about thermodynamic engineering.
Progesterone: Exemplified how a bioinspired transformation can be applied in the lab efficiently and aslo the utility of the Johnson-Claisen.
PGA2: Gave us the TBS protecting group and demonstrated how it can be used to control reactivity.
Vernolepin: Demonstrated the concept of the synergistic diene in the Diels–Alder reaction. Danishefskyʼs Diene has inspired other useful variations.
Ambigiune H: Reminded us why we should strive to develop protecting group free syntheses. Presented an innovative example of said concept.