Strategies in Synthetic Planning Modern Stylistic Points in Retrosynthetic Analysis

Jen Alleva MacMillan Group Meeting January 8th 2014

Thursday, January 9, 14 Strategies in Synthetic Planning Development and Conceptualization of Retrosynthetic Analysis

"By the end of this course I will be able to look at all of your retrosyntheses and know which one of you produced it. You will all develop your own unique and recognizable style over the next few months."

–Paul Reider, Graduate Synthesis

Common trend: Modern organic chemists have unique retrosynthetic strategies rendering their syntheses easily recognizable to the well-read practitioner of organic chemistry

Thursday, January 9, 14 Strategies in Synthetic Planning Development and Conceptualization of Retrosynthetic Analysis

"Retrosynthetic analysis is a problem-solving technique for transforming the structure of a synthetic target (TGT) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for chemical synthesis."

■ E. J. Corey, Harvard University

■ MIT 1945–1950, John Sheehan ■ Appointed as Instructor at UIUC at age 22 ■ Earned professorship at UIUC at age 27 ■ Moved to Harvard in 1959

■ Nobel Prize in Chemistry 1990

■ Detailed retrosynthetic analysis and techniques

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

Thursday, January 9, 14 Strategies in Synthetic Planning Development and Conceptualization of Retrosynthetic Analysis

Target Molecule

retron keying elements Int1 Int2 transform: Diels-Alder SM1

Int3 Int4

SM2

Int5 Int6

SM3 SM4

Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 3–5. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

Thursday, January 9, 14 Strategies in Synthetic Planning Development and Conceptualization of Retrosynthetic Analysis

OH Me Me Me Me

OH O O

retron alkene keying element

Me Me

Me O O O Cu

Br Me OR Me Me

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

1. The application of powerful transforms: forming key bonds in the molecular skeleton (i.e. C–C bonds) aldol, Diels-Alder, intramolecular alkylations, C–H activation, cross couplings forging stereocenters through substrate control (modernly reagent control) cascade reactions

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

Me O O O Me Me Me Me H Me O O H Me Me O O Me O O cyanthiwigin F

Enquist Jr., J. A.; Stoltz, B. M. Nature, 2008, 453, 1228.

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

2. Lateral movement through a non-simplifying transform skeletal rearrangements, transpositions, isomerization reactions, epimerizations

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

2. Lateral movement through a non-simplifying transform skeletal rearrangements, transpositions, isomerization reactions, epimerizations

O Me O Me O Me

H H H O H Me O H Me O H Me

Me N N N H O O Me H O O H O O H H H

(–)-tuberostemonine

Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc., 2002, 124, 14848.

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

2. Lateral movement through a non-simplifying transform skeletal rearrangements, transpositions, isomerization reactions, epimerizations

3. Disconnections that actually increase molecular complexity protecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds

Thursday, January 9, 14 Strategies in Synthetic Planning decreasing complexity

The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

2. Lateral movement through a non-simplifying transform skeletal rearrangements, transpositions, isomerization reactions, epimerizations

3. Disconnections that actually increase molecular complexity protecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds

PMP O PMP O O O OH H O O SePh O O AcO Me

Me Me Me Me Me Me Me Me Me Me Me guanacastepene E Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc., 2006, 128, 7025.

Thursday, January 9, 14 Strategies in Synthetic Planning Classes of Retrosynthetic Disconnections

Transform-Based Structure-Goal Topological Strategies

look-ahead to powerfully simplifying directed at the structure of a potential strategic analysis of correlated transform or tactic intermediate or SM bond disconnections

i.e. the "Key Step" i.e. the branch point i.e. rearrangements and network analysis

Stereochemical Strategies Functional Group-Based Strategies

retrosynthetic strategy which clears stereocenters reduction in molecular complexity based on the with either mechanism or substrate control interchange, installation and removal of functional groups

most common in modern synthesis "redox relay", directing groups, heterocycle formation

Thursday, January 9, 14 Strategies in Synthetic Planning Acyclic Systems

What to disconnect and what to preserve

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

Thursday, January 9, 14 Strategies in Synthetic Planning Acyclic Systems

What to disconnect and what to preserve

Disconnect Preserve

to make symmetrical fragments building block groups (alkyl, aryl)

C–X bonds (C–heteroatom, esters, amides, etc) remote stereocenters (more than 3C is remote)

either E or Z double bonds skeletal bonds proximal to remote stereocenters

1–3 bonds away from functional groups

bonds that attach rings to chains (produce the largest fragment)

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

Thursday, January 9, 14 Strategies in Synthetic Planning Acyclic Systems

What to disconnect and what to preserve

Disconnect Preserve

to make symmetrical fragments building block groups (alkyl, aryl)

C–X bonds (C–heteroatom, esters, amides, etc) remote stereocenters (more than 3C is remote)

either E or Z double bonds skeletal bonds proximal to remote stereocenters

1–3 bonds away from functional groups

bonds that attach rings to chains (produce the largest fragment)

Wittig

O HO TBSO (CH ) CO H 2 3 2 CHO O C H C5H11 5 11 O

OH OH

PGA2 SN2 cuprate addition

Corey, E. J.; Mann, J. J. Am. Chem. Soc. 1973, 95, 6832. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

Thursday, January 9, 14 Strategies in Synthetic Planning Ring-Bonds in Isolated Rings

What to disconnect and what to preserve

Disconnect

to make symmetrical fragments

C–X bonds (C–heteroatom, esters, amides, etc)

easily formed rings (lactone, lactam, hemiacetal)

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

Thursday, January 9, 14 Strategies in Synthetic Planning Ring-Bonds in Isolated Rings

What to disconnect and what to preserve

Disconnect

to make symmetrical fragments

C–X bonds (C–heteroatom, esters, amides, etc)

easily formed rings (lactone, lactam, hemiacetal)

HO O H O iodolactonization HO O CH2I H O acylation/desulfurization O PhO S O Me 2 H S S Me Me Me H

Me Me H H (+)-dihydromevinolin

Falck, J. R.; Yang, Y.-L. Tetrahedron Lett. 1984, 25, 3563. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

Thursday, January 9, 14 Strategies in Synthetic Planning Disconnection of Fused Rings

What to disconnect and what to preserve

Disconnect Preserve

[2+1] and [2+2] retrons building block rings (aryl)

cocyclic bonds (cycloaddition retrons) bonds that make >7 membered rings

heteratom containing rings (lactones, lactam, ketal) skeletal bonds proximal to remote stereocenters

fused rings with exendo bonds (cation-π-cyclizations) bonds that make stereocenters

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 39.

Thursday, January 9, 14 Strategies in Synthetic Planning Disconnection of Fused Rings

What to disconnect and what to preserve

Disconnect Preserve

[2+1] and [2+2] retrons building block rings (aryl)

cocyclic bonds (cycloaddition retrons) bonds that make >7 membered rings

heteratom containing rings (lactones, lactam, ketal) skeletal bonds proximal to remote stereocenters

fused rings with exendo bonds (cation-π-cyclizations) bonds that make stereocenters

oxidative Me Me dimerization Me Me Me H H O O O O O O O O O O O O O OH O oxidative dimerization carpanone

Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am. Chem. Soc. 1971, 93, 6696. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 41.

Thursday, January 9, 14 Strategies in Synthetic Planning Disconnection of Bridged Rings

What to disconnect and what to preserve

Disconnect Preserve

exendo bonds in 4–7 membered rings bridges that if disconnected yield >7 membered rings

C–heteratom bonds preferentially over C–C bonds bonds that would yield medium size rings

bonds that contain the most bridgehead atoms (network analysis) bonds that yield pendant chains

Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 42.

Thursday, January 9, 14 Strategies in Synthetic Planning Disconnection of Bridged Rings

What to disconnect and what to preserve

Disconnect Preserve

exendo bonds in 4–7 membered rings bridges that if disconnected yield >7 membered rings

C–heteratom bonds preferentially over C–C bonds bonds that would yield medium size rings

bonds that contain the most bridgehead atoms (network analysis) bonds that yield pendant chains

HO Me O Me

O Me O Me

en route to longifolene

McMurry, J. E.; Isser, S. J. J. Am. Chem. Soc., 1972, 94, 7132. Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 42.

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Utilizing Network Analysis: a topological strategy

■ potent anti-cancer, antibiotic, anti-inﬂammatory properties H O O CO2Me AcO ■ AcO highly oxygenated triterpenoid AcO Me Me ■ key challenge is synthesis of the carbocyclic core Me O O OH O Me

Xyloccensin O phragmalin-type limonoid octahydro-1H-2,4-methanoindene core

OTBS CO2Me 6 steps O

CO2Me OBn O MeO C 2 OBn

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Utilizing Network Analysis: a topological strategy

Guiding Principles of Network Analysis

■ in general: it is easier to synthesis fused rings that bridged systems

■ identify the bonds that are made to the most bridged system

■ retrosynthetic removal of these bonds will lead to the most simple keying element

longifolene

Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J. Am. Chem. Soc. 1964, 86, 487.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Utilizing Network Analysis: a topological strategy

Guiding Principles of Network Analysis

■ in general: it is easier to synthesis fused rings that bridged systems

■ identify the bonds that are made to the most bridged system

■ retrosynthetic removal of these bonds will lead to the most simple keying element

most bridged ring system

homodaphniphyllate framework

Heathcock, C. Angew. Chem. Int. Ed., 1992, 31, 665.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Retrosynthetic Analysis

O intermolecular alkylation

H O OBs CO2Me AcO O H AcO O O AcO Me Me OBn OBn Me MeO C O 2 MeO2C O OH O Me Xyloccensin O

Diels-Alder

OTBS OBs OBs O OBn H CO Me OBn 2 O MeO2C CO2Me O OBn more reactive conformer

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Diels-Alder Approach

OTBS OTBS OTBS H H PhMe, 100 °C Pd/C, H2

CO2Me (>10:1 endo:exo) EtOAc O O O OBn 89% OBn OBn CO Me 2 CO2Me

OH OBs H H 1M HCl BsCl, pyr. precursor to intramolecular MeOH cat. DMAP O O alkylation OBn CH2Cl2 OBn CO Me 2 CO2Me 82% over 3 steps

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Intramolecular Alkylation

OBs

H BnO2C conditions O H

(below) OBn H O OBn MeO2C MeO2C CO2Me 14 21

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Intramolecular Alkylation

OBs

H BnO2C conditions O H

(below) OBn H O OBn MeO2C MeO2C CO2Me 14 21

BnO C BnO 2 O O H OBn CO2Bn OBn OBn OBn H MeO2C MeO2C MeO2C MeO2C

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Thursday, January 9, 14 Synthesis of the Framework of Phragmalin-Type Limonoids Intramolecular Alkylation

CO2Me OH 1. DMP, NaHCO CO2Me H 3 H CH2Cl2 KOtBu, THF O

2. Ph3P=CHCO2Me –78 °C - 0 °C OBn O OBn O CH2Cl2 OBn MeO2C CO Me 2 CO2Me 49% over 2 steps 79%

Lebold, T. M.; Gallego, G. M.; Marth, C. J.; Sarpong, R. Org. Lett., 2012, 8, 2110.

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

Key Features of a Functional Group-based Approach

■ functional group in the target directly keys a disconnection

■ functional group in the target is poised to assist in the installation of a key stereocenter

■ often times installed and later removed in order to enable a key transform (overbred intermediate)

■ may extend to modern photoredox radical chemistry, traceless directing groups, C–H activation

nepatalactone enamine-α,β-enal cycloaddition

Clark, K. J.; Fray, G. I.; Jaeger, R. H.; Robinson, R. Tetrahedron, 1959, 6, 217.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

Key Features of a Functional Group-based Approach

■ functional group in the target directly keys a disconnection

■ functional group in the target is poised to assist in the installation of a key stereocenter

■ often times installed and later removed in order to enable a key transform (overbred intermediate)

■ may extend to modern photoredox radical chemistry, traceless directing groups, C–H activation

functional group installed to assist key step

accessing (+)-Gliocladin C

functional group removed by photochemical reduction

Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2011, 50, 9655.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

Key Features of a Functional Group-based Approach

■ functional group in the target directly keys a disconnection

■ functional group in the target is poised to assist in the installation of a key stereocenter

■ often times installed and later removed in order to enable a key transform (overbred intermediate)

■ may extend to modern photoredox radical chemistry, traceless directing groups, C–H activation

reserpine

LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem., 2012, 5, 126.

Thursday, January 9, 14 Total Synthesis of Ouabagenin retrosynthetic analysis

Pd-catalyzed coupling reduction

O epoxidation/ Me reductive opening O Me O O deprotection HO Me Me O O Me O H HO O HO HO H HO HO H H OH H H

H OH O O O B OH HO oxidation OH Et

chemo/regioselective Norrish type 2 C–C fragmentation O O HO Me Me O O Me O O Me H HO O H H O H H H H H H O O O andrenosterone

LeBold, T. P.; Wood, J. L.; Deitch, J.; Lodewyk, M. W.; Tantillo, D. J.; Sarpong, R. Nat. Chem., 2012, 5, 126.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O + HO Me Me O 1. H O OH O HO H Me H O H H H H 2. hυ O O Norrish Type 2 adrenosterone 55% over two steps

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O + HO Me Me O 1. H O OH O HO H Me H O H H H H 2. hυ O O Norrish Type 2 adrenosterone 55% over two steps

Me O Me O O HO

Me H H2C H

H H H H O O

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O + HO Me Me O 1. H O OH O HO H NIS, Li2CO3 Me H O H H H H 2. hυ O O Norrish Type 2 adrenosterone 55% over two steps

O O O Me Me Me O O O I O TiCl HO O 1. H O HO O H 4 H 2 2 H AgOAc O H H H H 2. SeO2 H H O O O O 85% 71%

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O O Me Me O O HO O H O HO O H 2 2 O H

H H H H O O O O

50% over 3 steps

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O O O Me Me Me O O O HO O H O HO O Al-Hg HO O H 2 2 O H HO H

H H H H H2O H H O O O O O OH

50% over 3 steps 56%

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O O O Me Me Me O O O HO O H O HO O Al-Hg HO O H 2 2 O H HO H

H H H H H2O H H O O O O O OH

50% over 3 steps 56%

Me Me O O Me Me HO O Me Me O O O O H O H 1. Li, NH3 1. PPTS, Me2CO H H H H 2. LiBEt H 3 1. PPTS, Me2CO O O O O B B Et Et

63% over 2 steps 69% over 2 steps

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

Me Me O Me O 1. TMSOTf, NEt3, Pd(OAc)2 Me HO HO Me Me O MeCN, then FeCl3 O O H O H

H H H 2. SiO2, DIPEA F O O O O B B F3C F Et Et

F F 55% over 2 steps F O

Me Me Me O Me 1. N2H4: I2, NEt3 HO HO Me Co(acac) (20 mol%) Me O O 2 O H CH2Cl2/EtOH O H

O PhSiH H OH 2, 3 H OH 2. CuTC (3 equiv) dioxane Pd(PPh ) (15 mol%) O O O 3 4 O O B B DMF Et O Et Bu Sn 86% 3 42% over 2 steps

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O O

O O Me Me Me 1. CoCl •6H O, NaBH Me HO 2 2 4 HO Me Me O EtOH, 0 °C to rt. O O H O H

H OH 2. PhH, 100 °C H OH

Me2N O O NtBu O O B B Me N 70% over two steps Et 2 Et

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Total Synthesis of Ouabagenin a functional group-based approach

O O

O O Me Me Me 1. CoCl •6H O, NaBH Me HO 2 2 4 HO Me Me O EtOH, 0 °C to rt. O O H O H

H OH 2. PhH, 100 °C H OH

Me2N O O NtBu O O B B Me N 70% over two steps Et 2 Et

HCl (conc.) Me HO HO ouabagenin MeOH, rt. HO H 20 steps from andrenosterone 90% H OH HO OH

Renata, H.; Zhou, Q.; Baran, P. S. Science 2013, 339, 59.

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin A Transform-Based Approach

Key Features of a Transform-Based Approach

■ in general: the late-stage key-step

■ look-ahead to apply a highly simplifying synthetic strategy

■ often cascades, rearrangements, transformations which assemble multiple C–C bonds

Estrone

Corey, E. J.; Ohno, M., Mitra, R. B.; Vatakancherry, P. A. J. Am. Chem. Soc. 1964, 86, 487.

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin A Transform-Based Approach

Key Features of a Transform-Based Approach

■ in general: the late-stage key-step

■ look-ahead to apply a highly simplifying synthetic strategy

■ often cascades, rearrangements, transformations which assemble multiple C–C bonds

Squalene

Werthermann, L.; Johnson, W. S.; Proc. Nat. Acad. Sci., 1970, 67, 1465.

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin Retrosynthetic Analysis

benzyne acyl- alkylation

OH O OBn O Me

HO BnO O

O O Me RCM

OR O Me O Me

O Me O

known acetate Aldol 2 steps from commercial

Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin preparation of the β-ketolactone

1. Mg, THF, I2 (trace) Me O O Me O 2. CuI Me 1.) LDA then acrolein Me O O Br 3. Ac-Cl, pyr. THF, –78 °C HO

85%, >99% ee 76% (1:1)

O Me O Me HMDS, THF 70 °C; 1. Pd/C, H2, EtOH O O Grubbs 3 (10 mol%) 2. DMP, CH2Cl2 PhH, reﬂux; HO O 1 N HCl, THF 92% over 2 steps 57%

Lin, W.; Zercher, C. K.; J. Org. Chem., 2007, 72, 4390. Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin Key Step

O Me OBn OBn O TMS CsF O MeCN, 40 °C O BnO OTf BnO

30% O O Me

Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.

Thursday, January 9, 14 Total Synthesis of (–)-Curvularin Key Step

O Me OBn OBn O TMS CsF O MeCN, 40 °C O BnO OTf BnO

30% O O Me

OH O Pd/C, H2

MeOH, THF HO 60% O O Me

(–)-Curvularin

Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett., 2010, 7, 1612.

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A A Structure-Goal Approach

Key Features of a Structure-Goal Approach

■ Implemented when a large number of target structures are desired (collective synthesis)

■ bulk of synthetic strategy relies on the synthesis of a highly simplifying intermediate

■ allows the implementation of multiple retrosynthetic techniques

common intermediate tetracycle

Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature, 2011, 475, 183.

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A A Structure-Goal Approach

Key Features of a Structure-Goal Approach

■ Implemented when a large number of target structures are desired (collective synthesis)

■ bulk of synthetic strategy relies on the synthesis of a highly simplifying intermediate

■ allows the implementation of multiple retrosynthetic techniques

Cortisol deoxycholic acid targeted starting material

Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645–659.

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A A Structure-Goal Approach

Key Features of a Structure-Goal Approach

■ Implemented when a large number of target structures are desired (collective synthesis)

■ bulk of synthetic strategy relies on the synthesis of a highly simplifying intermediate

■ allows the implementation of multiple retrosynthetic techniques

Buspirone

targeted starting materials

Fieser, L. F.; Fieser, M. Steroids Reinhold Publishing, New York, 1959. pp 645–659.

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A A Structure-Goal Approach

O ■ more than 250 Lycopodium alkaloids have been characterized O O

Me ■ contains a unique 6/6/6/7 tetracyclic skeleton N ■ unprecedented carbinolamine lactone motif

(–)-Lycojapodine A ■ biosynthesis suggests that many natural products can be accessable through a common intermediate fawcettimine-type alkaloid

O O O O OH OH H H H H Me H Me H Me Me OH N N O N N

(+)-fawcettimine (+)-fawcettidine (+)-lycoﬂexine (+)-alopecuridine

Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

Me carbon O O skeleton OH H H HO Me N N H rearrangement

lycolidine (+)-fawcettimine

biosynthetic common intermediate

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

Me carbon O O O skeleton OH H H HCHO H HO Me Me N N O H rearrangement condensation N

lycolidine (+)-fawcettimine

biosynthetic common intermediate

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

Me carbon O O O skeleton OH H H HCHO H HO Me Me N N O H rearrangement condensation N

lycolidine (+)-fawcettimine

biosynthetic common intermediate O H Me O N

(+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

Me carbon O O O skeleton OH H H HCHO H HO Me Me N N O H rearrangement condensation N

lycolidine (+)-fawcettimine

biosynthetic common –H2O intermediate O O H Me H H Me O N N

(+)-fawcettidine (+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

O OH Me H OH N

(+)-alopecuridine

[O] Me carbon O O O skeleton OH H H HCHO H HO Me Me N N O H rearrangement condensation N

lycolidine (+)-fawcettimine

biosynthetic common –H2O intermediate O O H Me H H Me O N N

(+)-fawcettidine (+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A simpliﬁed biogenesis

O O OH O O Me H OH [O] N Me N –H2O

(+)-alopecuridine (–)-lycojapodine A

[O] Me carbon O O O skeleton OH H H HCHO H HO Me Me N N O H rearrangement condensation N

lycolidine (+)-fawcettimine

biosynthetic common –H2O intermediate O O H Me H H Me O N N

(+)-fawcettidine (+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A retrosynthetic analysis

O OH Me H H N

(+)-fawcettimine

O H O O Me O N O Boc Me N proposed common intermediate (–)-Lycojapodine A

O H Me O N

(+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A retrosynthetic analysis

O OH Me H H tandem conjugate addition/ N Aldol intramolecular alkylation (+)-fawcettimine O OH Boc O H O O N OTBDPS Me

O O N Boc Me Me N proposed common intermediate (–)-Lycojapodine A

O O H H Me N OTBDPS O N O Boc Me

MgBr (+)-lycoﬂexine

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A preparing the common intermediate

MgBr O O OH Boc CuBr, Me S, LiCl, THF –78 °C NEt3•HF 2 N OTBDPS

MeCN, rt Me then: Me H N OTBDPS 75% O Boc

O OH Boc 1. collidine, MsCl O O Boc

N OH CH2Cl2, 4 °C N OMs

Me 2. DMP, CH2Cl2 Me

94% 80% over 2 steps

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A preparing the common intermediate

O O Boc O O Boc NaI N OMs N I acetone, rt.

Me Me

84%

O O Boc DBU N I O H Me O MeCN, rt. Me H N O Me Boc O RBocN 65%

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A synthesis of (+)-alopecuridine

CHO 1. NaBH , MeOH, rt. 4 OsO4, NaIO4 TMSO H O H TMSO H O O O Me Me 2. TMSOTf, 2,6-lutidine Me DABCO N N Boc CH2Cl2, –78 °C N dioxane/H O Boc Boc 2

87% 96%

OH O SmI2 (5 equiv) TMSO 1. TBAF, THF, rt O H Me H OH Me OH HMPA (20 equiv) N 2. TPAP, NMO•H O N Boc 2 Boc THF, –78 °C to rt. 4 Å MS, CH2Cl2, rt

80% 50%

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A synthesis of (+)-alopecuridine and (–)-lycojapodine A

HO O O H O TFA, CHCl Me OH H 3 Me OH N •TFA N then NaHCO3 Boc 94% (+)-alopecuridine•TFA 12 steps

Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.

Thursday, January 9, 14 Total Synthesis of (–)-Lycojapodine A synthesis of (+)-alopecuridine and (–)-lycojapodine A

HO O O H O TFA, CHCl Me OH H 3 Me OH N •TFA N then NaHCO3 Boc 94% (+)-alopecuridine•TFA 12 steps

O O HO DMP, TFA Me H OH O O N 4 Å MS, 30 °C, 4 h Me •TFA N 80%

(–)-Lycojapodine A 13 steps

Li, H.; Wang, X.; Hong, B.; Lei, X. J. Org. Chem., 2013, 78, 800.

Thursday, January 9, 14 Applied Strategies in Retrosynthetic Analysis

Topological Functional Group-Based

O CO2Me

O Me HO HO HO H OBn

MeO2C H OH HO OH

Phragmalin-type Limonoids Ouabagenin Sarpong Group, Berkeley Baran Group, Scripps

Transform-Based Structure-Goal

OH O O

O O Me HO N O O Me

(–)-Curvularin (–)-Lycojapodine A Stoltz Group, Caltech Lei Group, Tianjin University

Thursday, January 9, 14