Deconstructive Functionalization via
C(sp3)-C(sp3) Bond Cleavage

2021/09/30
Literature Seminar
Mina Yamane (M2)1

Table of Contents
1. Introduction
2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary2

Table of Contents
1. Introduction
2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary3

Introduction
33FG

FG

22FG

FG

3FG

2FG

3FG

2FG

OOOHOHPhO
OHOMe“Fast/efficient explorationof new chemical space fordrug discovery”

from mycophenolic acidT. Fujita, et al. Angew. Chem. Int. Ed. 2021, just accepted.

S. Morcillo, et al. Angew. Chem. Int. Ed. 2019, 58, 14044.
4

A Brief Introduction to C-C Bond Cleavage
C-C bond cleavage can be encountered in…
 Steam cracking process of crude oil at high temperature/pressure in thepetroleum oil industry
 Classical reactions (e.g. sigmatropic rearrangements, Beckmann
rearrangement, Baeyer-Villiger oxidation, retro-aldol/allylation, etc.)
 Strategic approaches for total syntheses

R. Woodward, et al. J. Am. Chem. Soc. 1944, 66, 849.
(scheme from: R. Sarpong, et al. Angew. Chem. Int. Ed. 2020, 59, 18898.)⇒ Remaining Challenge:Activation of unbiased C(sp3)-C(sp3) bonds in a general/efficient manner
B. Morandi, et al. Chem. Rev. 2021, 121, 300. 5

Concepts of C(sp3)-C(sp3) Fragmentation
Pioneering Approaches by Eschenmoser (1950s) ⇢ ⇢ Grob

Transition Metal Catalyzed Approaches (over the last 3 decades)

Another Recent Approach

J. Williams, Angew. Chem. Int. Ed. 2013, 52, 11222.
6S. Morcillo, et al. Angew. Chem. Int. Ed. 2019, 58, 14044.

C(sp3)-C(sp3) Bond Activation

Compared to other bonds:✘Less polarized✘Less favorable orbital directionality forinteractions w/ transition metals✘Substituents on both ends sterically
prevent metal approach

B. Morandi, et al. Chem. Rev. 2021, 121, 300. 7

Concepts of C(sp3)-C(sp3) Fragmentation
Pioneering Approaches by Eschenmoser (1950s) ⇢ ⇢ Grob

Transition Metal Catalyzed Approaches (over the last 3 decades)

Another Recent Approach

J. Williams, Angew. Chem. Int. Ed. 2013, 52, 11222.
8S. Morcillo, et al. Angew. Chem. Int. Ed. 2019, 58, 14044.

Point to Note

Most common tactic: uses strain-release as crucial driving force
This seminar: covers activation of unstrained compounds
J. Bower et al. Chem. Rev. 2017, 117, 9404.

9

Table of Contents
1. Introduction
2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary10

Deconstructive Functionalization of Cyclic Alcohols
Strategy: Prefunctionalization of alcohols⇒ BDE(O-H) ≈ 105 kcal/mol >> BDE(O-NO) ≈ 37 kcal/mol✔ Tandem β-fragmentation/iodolactonization of steroidal alcohols
E. Suarez, et al. J. Org. 1994, 59, 4393.

S. Morcillo, et al. Angew. Chem. Int. Ed. 2019, 58, 14044.11

Photocatalyzed Approaches
Photoredox catalyst×Bronsted Base×Thiol H-donor✔ 1st photocatalyzed activation of unstrained alcohols✔ Selective cleavage of distal C-C bonds via generation of “spatially removed”
alkoxy radicals
R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 12

Proposed Catalytic Cycle
Photoredox catalyst×Bronsted Base×Thiol H-donor

Photocat.

PMP (e- rich arene)

Key alkoxy radical
intermediate

Ring opening:
generation of aryl ketone and distal alkyl radical
R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 13

Screening of Reaction Conditions[Ir(dFCF3ppy)2-(5,5′-dCF3bpy)]PF6

R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 14

Substrate Scope
1.0 mmol scale
Arenes for initial site of oxidation

β-substR. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 15

Mechanistic Insights
Q. Does the charge transfer between arene radical cation and O-H bond proceedvia stepwise PT/ET or concerted PCET ?
ASSUMPTION: if d→∞, then pKa → ~40 (value for isolated tert-alkanol in MeCN)
dC-C cleavage was observed w/ up
to 4 carbon atoms separating thearene and alcohol.

Deprotonation by collidine (pKa =15.0 in MeCN) ⇒ ΔG ≈+34 kcal/mol
vsCharge recombination of Ar radical cation w/ reduced photocatalyst ⇒ ΔG ≈-53 kcal/mol

Strongly Suggestive of a concerted PCET mechanism
R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 16

Table of Contents
1. Introduction2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary17

Deconstructive Functionalization of Cyclic Amines
Bioactive Molecules Containing N-heterocycles

R. Sarpong, et al. Nature 2018, 564, 244. 18

Deconstructive Fluorination⇒ Cyclic amines assynthons for amino
alkyl radicals

Challenges:
1) Competing over-oxidation to amides (instead of hemiaminals)
2) Limited examples of ring-opening fluorination of unstrained cycloalkanols
R. Sarpong, et al. Science 2018, 361, 171. 19

Optimization of Reaction Conditions(optimized)→ 2nd best Ag source→ substoichiometric Ag,
modest yield✔ cheap / commercially available AgBF4✔ mild reaction conditions
R. Sarpong, et al. Science 2018, 361, 171. 20

Deconstructive Fluorination: Substrate Scope

1st report⇒ mild/direct αoxygenation of
cyclic amides

Various ringsizes

Deformylatedpros.

⇒ Dualfunctionalization

R. Sarpong, et al. Science 2018, 361, 171. 21

Decarboxylative Fluorination: Previous Studies
oxidation

fastSET※Detailed mechanism is still unclear…??

C. Li, et al. J. Am. Chem. Soc. 2012, 134, 4258. 22

Proposed Mechanism: This Study

SETSET※ An alternative pathway (reversed order of events) cannot be ruled out

NMR EXPERIMENTS:
1) Consumption of Selectfluor was observed only under the presence of cyclicamine (according to 19F NMR)
2) Broadening of 1H NMR spectrum ⇒ formation of paramagnetic Ag(II)3) Downfield shifts of cyclic amine 1a upon addition of AgBF4⇒ binding of Ag(I) to amide moiety
R. Sarpong, et al. Science 2018, 361, 171. 23

Possible Mechanisms for Fluorination?

R. Sarpong, et al. Science 2018, 361, 171. 24

Deconstructive Fluorination: Substrate Scope

1st report⇒ mild/direct αoxygenation ofcyclic amides

Various ringsizes

Deformylatedpros.

⇒ Dualfunctionalization

R. Sarpong, et al. Science 2018, 361, 171. 25

Possible Mechanisms for Fluorination (continued)
Red → in favor of path A
Blue → in favor of path B
Start from aldehyde:⇒ Pro. Accessible by path A only
Prolonged rxn time:⇒ Deformylated pros. were major
No equilibrium with hemiaminal:⇒ Fluorination proceeded fromaldehyde
Start from carboxylic acid:⇒ Decarboxylation proceeded

Neither path could be ruled out...R. Sarpong, et al. Science2018, 361, 171.

26

Deconstructive Halogenation of Cyclic Amines
Bioactive Molecules Containing N-heterocycles

R. Sarpong, et al. Nature 2018, 564, 244. 27

Proposed Mechanism forAg-mediated Deconstructive Halogenation
Optimization of Reaction Conditions※ Screening was conducted on Ag salts,
halogenating reagents, and solvent
combinations (see Science, 2018).

✔ Electrophile is independent of initial redox cycle✔ Can be performed w/out strict exclusion of air✔ Choice of halogenating reagent leads to divergence of products
R. Sarpong, et al. Nature 2018, 564, 244. 28

Deconstructive Halogenation: Substrate Scope
Various ring sizes
bulkyness:
Piv > Boc

Halogenated amino acid derivatives
242゜amides(major)⇒ int. for unnatural amino acids
29

R. Sarpong, et al. Nature 2018, 564, 244.

Application of Deconstructive Halogenation※ showcases C-N bond cleavage only…

Ring Contraction: piperidine → pyrrolidine*4

Choice of halogenating reagent led
to product divergence.

2*lower yield due to imide bp from halogenating reagent
R. Sarpong, et al. Nature 2018, 564, 244. 30

Late-Stage Diversification ofL-Proline-Containing TripeptideR. Sarpong, et al. Nature 2018, 564, 244. 31

Late-Stage Diversification of Other n-peptides※oxidizedChallenging Tripeptide

R. Sarpong, et al. Nature 2018, 564, 244. 32

Table of Contents
1. Introduction
2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary

33

Scaffold Hopping (omake)…“scaffold-hopping”, that is, identification of isofunctional molecular
structures with significantly different molecular backbones…
G. Schneider, et al. Angew. Chem. Int. Ed. 1999, 38, 19, 2894.

H. Sun, et al. Drug Discovery Today. 2012, 17, 310. 34

Table of Contents
1. Introduction
2. Deconstructive Functionalization of Cyclic Alcohols
3. Deconstructive Functionalization of Cyclic Amines
4. Scaffold Hopping
5. Summary35

Summary Deconstructive functionalization of C(sp3)-C(sp3)provides access to unprecedented structures And seems to be a good strategy for “scaffold hopping”
 Leading to efficient exploration of new chemical spacefor drug discovery…!

Thank you for your attention.

36

Appendix37

General Strategies for Inert C-C Bond Cleavages

B. Morandi, et al. Chem. Rev. 2021, 121, 300. 38

C-C vs C-H Bonds

β-hydride elimination > β-carbon elimination⇒ selective activation of a C-C bond within a substrate bearing β-hydrogenatoms (i.e., 1° and 2° alcohols) is still a challenge
BDE(C-H) ≈ 100-110 kcal/mol > BDE(C-C) ≈ 90-105 kcal/mol⇒ C-H bond is thermodynamically more stable than a C-C bond

B. Morandi, et al. Chem. Rev. 2021, 121, 300. 39

Heterolytic C-C Bond Cleavages

J. Williams, Angew. Chem. Int. Ed.
2013, 52, 11222.
40

Stern-Volmer Studies

1st order dependence on alcohol conc.
0 order dependence on collidine conc.
⇒ Direct Ar oxidation is suggested, rather than O-H PCET
R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794. 41

Mechanistic Insights II
Purpose: Examine the relationship between effective BDFEs and reaction outcomes.
oxidation
potential

basicity

Forecast the feasibilityof PCET process.

BDFE ≥ O-H BDFE ≈ 102 kcal/mol ⇒ rxn proceeded
BDFE < ~98 kcal/mol ⇒ rxn did NOT proceed
J. Mayer, et al. Chem. Rev. 2010, 110, 6961.
42R. Knowles, et al. J. Am. Chem. Soc. 2016, 138, 10794.

PCET and BDFEThe capacity of any given oxidant/base pair to function as a formal
H・ acceptor can be quantified as an effective bond strength (BDFE).

BDFEsol(X-H) = 1.37pKa + 23.06E°+ CG,sol

J. Mayer, et al. Chem. Rev. 2010, 110, 6961. 43

Ag Catalyzed Decarboxylative Chlorination

C. Li, et al. Chem. Rev. 2012, 134, 4258. 44

Oxazine Formation via Autocyclization
5,6-dihydro-4H-1,3-oxazine formation via autocylization

R. Sarpong, et al. Nature 2018, 564, 244.

E. Prabharakan, et al. J. Org. Chem 2011, 76, 680.
45

Oxidation with Peroxydisulfate Ion※1st step: unimolecular homolytic scission of peroxydisulfate ion

rapid hydration

J. Edwards, et al. J. Org. Chem. 1971, 36, 4089. 46