Platinum-Catalyzed Enantioselective Diboration of Terminal Alkenes and Vinyl Boronates

541 Pages·2015·18.41 MB·English

Platinum-Catalyzed Enantioselective
Diboration of Terminal Alkenes
and Vinyl Boronates: Construction
of Multiborylated Compounds for
Asymmetric Synthesis
Author: John Ryan Coombs
Persistent link: http://hdl.handle.net/2345/bc-ir:104624
This work is posted on eScholarship@BC,
Boston College University Libraries.
Boston College Electronic Thesis or Dissertation, 2015
Copyright is held by the author, with all rights reserved, unless otherwise noted.
Boston College
The Graduate School of Arts and Sciences
Department of Chemistry

PLATINUM-CATALYZED ENANTIOSELECTIVE DIBORATION OF TERMINAL
ALKENES AND VINYL BORONATES: CONSTRUCTION OF
MULTIBORYLATED COMPOUNDS FOR ASYMMETRIC SYNTHESIS

a dissertation

by
JOHN RYAN COOMBS

Submitted in partial fulfillment of the requirements
for the degree of
Doctor of Philosophy

May 2015
© copyright by JOHN RYAN COOMBS
2015
PLATINUM-CATALYZED ENANTIOSELECTIVE DIBORATION OF TERMINAL
ALKENES AND VINYL BORONATES: CONSTRUCTION OF
MULTIBORYLATED COMPOUNDS FOR ASYMMETRIC SYNTHESIS

by
JOHN RYAN COOMBS

Dissertation Advisor:
Professor James P. Morken

ABSTRACT: This dissertation will discuss in depth four main projects pertaining to the
synthesis and utility of organoboronates for the construction of enantioenriched small
molecules. First, reaction optimization and substrate scope expansion of the platinum-
catalyzed enantioselective diboration of alkenes are reported. Based on extensive
experimental and computational mechanistic analysis, a preliminary stereochemical
model is also proposed. A practical boron-Wittig reaction is presented in which
synthetically challenging di- and trisubstituted vinyl boronates can be accessed in a
highly stereoselective fashion from readily available starting materials. The
enantioselective diboration of cis- and trans-vinyl boronates furnished novel 1,1,2-
tris(boronate) esters in up to 95:5 er. The intermediate tris(boronate) esters were
employed successfully in deborylative alkylations to furnish enantioenriched internal
vicinal bis(boronates) in excellent diasteoselectivity. In the final chapter, an
enantioselective palladium-catalyzed intramolecular Suzuki-Miyaura coupling between
allyl boronates and aryl electrophiles is disclosed. The newly developed transformation
provides enantioenriched 5, 6, and 7-membered carbocycles in up to 93:7 er.
Dedicated to:
My parents, Lorie and John Coombs, for their unwavering love and support, and for their
priceless lessons throughout the years.

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ACKNOWLEDGEMENTS
I would like to thank my advisor, Professor James P. Morken, for shaping me into
the chemist who I am today. Jim’s enthusiasm and sharp outlook on chemistry during
our discussions provided me with the passion and desire to work to the best of my
abilities. He has been the most ideal advisor throughout my entire graduate career,
allowing me to think independently while also giving guidance when I need it most.
I will always be proud to say that I came from such a fine and intelligent group of
chemists. Throughout my time in the Morken group, everyone was thoroughly involved
in each other’s work and had a genuine interest in helping one another. Specifically, I
would like to thank Dr. Laura Kliman, Dr. Scott Mlynarski, and Dr. Christopher Schuster
for their training and for teaching me the important lessons that will follow me
throughout my career. I appreciate their time and patience, especially during my early
years in the lab. I have had the great pleasure of working with many collaborators and
co-workers on my projects, including Dr. Laura Kliman, Dr. Christopher Schuster (who’s
breadth of knowledge still continues to amaze me), and Liang Zhang. Liang and I have
become great friends and co-workers over the past couple of years, and I know he will
continue to accomplish great things. Despite the many obstacles and challenges we came
across, I’m proud of our persistence and ability to overcome them.
In addition, I would like to thank Dr. Mike Ardolino (despite his never-ending
jokes at my expense), Bo Potter (for the hours of brain-storming), Meredith Eno, Emma
Edelstein, Adam Szymaniak, Dr. Rob Ely, and Dr. Bob Kyne. I thank Bo Potter,
Meredith Eno, Liang Zhang, and Emma Edelstein for proof reading my thesis.
I am extremely grateful for my family, who provided me with their unconditional
love and support throughout my graduate career. Despite my absence from time to time,
they always understood my schedule while also giving me the advice and guidance that
no one else could. Lastly, I am incredibly appreciative of Maggie Sheehan, who has
provided me with an unbelievable amount of support and comfort over the last 5 years.
She has helped me through countless hard times in the past few years, and it is my strong
belief that I could not have been successful without her by my side.
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LIST OF ABBREVIATIONS
Å: angstrom cod: 1,5-cyclooctadiene
Ac: acetyl conv: conversion
Acac: acetylacetonyl Cy: cyclohexyl
Ad: adamantyl d: day(s)
Aliquat 336: trioctylmethylammonium DART: direct analysis in real time
chloride
dba: dibenzylideneacetone
atm: atmosphere(s)
DCC: diboration/cross-coupling
AQN: anthraquinone
DCE: dichloroethane
B (cat) : bis(catecholato)diboron
2 2
DCM: dichloromethane
B (pin) : bis(pinacolato)diboron
2 2
DFT: density functional theory
9-BBN: 9-borabicylco[3.3.1]nonane
DHQ: dihydroquinine
BHT: 2,6-di-t-butyl-4-methylphenol
DHQD: dihydroquinidine
BINAP: 2,2’-bis(diphenylphosphino)-
1,1’-binaphthyl
DI: deionized
Bn: benzyl
DME: dimethoxyethane
cat: catechol
DMF: N,N-dimethylformamide
CBz: carboxybenzyl
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dmpd: 2,4-dimethylpenane-2,4-diol GLC: gas-liquid chromatography
DMPU: 1,3-dimethyl-3,4,5,6-tetrahydro- h: hour(s)
2(1H)-pyrimidinone
HOMO: highest occupied molecular
DMSO: dimethyl sulfoxide
orbital
dppb: 1,1’-bis(diphenylphosphino) HPLC: high performance liquid
butane chromatography
dppf: 1,1’-bis(diphenylphosphino) HRMS: high resolution mass
ferrocene spectrometry
dppm: 1,1’-bis(diphenylphosphino) Hz: hertz
methane
IPA: isopropanol
dppp: 1,1’-bis(diphenylphosphino)
propane
IR: infrared spectroscopy
dr: diastereomeric ratio
KIE: kinetic isotope effect
ee: enantiomeric excess
LDA: lithium diisopropylamide
elim: elimination
LiTMP: lithium 2,2,6,6-
eq: equation(s)
tetramethylpiperidide
LUMO: lowest unoccupied molecular
equiv: equivalent(s)
orbital
er: enantiomeric ratio M: molar
ESI: electrospray ionization MALDI: matrix-assisted laser
desorption/ionization
EtOAc: ethyl acetate
MeCN: acetonitrile
GC: gas chromatography
min: minutes
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MOP: 2-(diphenylphosphino)-2’- RCM: ring-closing metathesis
methoxy-1,1’-binaphthyl
RPKA: reaction progress kinetic analysis
MS: molecular sieves
rr: regioisomeric ratio
MTBE: methyl tbutyl ether
RT: room temperature
nbd: norbornadiene
SAD: Sharpless asymmetric
NHC: N-heterocyclic carbine
dihydroxylation
NMO: N-methylmorpholine N-oxide salen: bis(salicylidine)ethylenediamine
NMR: nuclear magnetic resonance SES: 2-(trimethylsilyl)ethanesulfonyl
npg: neopentylglycol SFC: supercritical fluid chromatography
NR: no reaction TADDOL: 2,2-dimethyl-,,’,’-
tetraaryl-1,3-dioxolane-4,5-dimethanol
PHAL: phalazine
TBAF: tetrabutylammonium fluoride
pin: pinacol
tbc: 4-t-butylcatechol
PMA: phosphomolybdic acid
TBDPS: t-butyldiphenylsilyl
ppm: parts per million
TBS: t-butyldimethylsilyl
PYR: pyrimidine
Tces: trichloroethoxysulfonyl
Quinap: 1-(2-diphenylphosphino-1-
temp: temperature
naphthyl)isoquinoline
rac: racemic TEMPO: 2,2,6,6-tetramethyl-1-
piperidinyloxy free radical
v
TES: triethylsilyl

Tf: trifluoromethanesulfonyl

THF: tetrahydrofuran

TLC: thin layer chromatography

TMEDA: N,N,N’,N’-

tetramethylenediamine

TMS: trimethylsilyl

tol: toluene

Ts: p-toluenesulfonyl

UV: ultraviolet

xylyl: dimethylphenyl

y: yield

ZACA: zirconium-catalyzed asymmetric
carboalumination

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