Baran GM
Sigma - Aldrich
This meeting will provide a history of SIAL and will cover some chemistry of
reagents discussed herein.
NASDAQ: SIAL
Sigma - Aldrich: Formed after Sigma (a supplier of research
biochemicals)and Aldrich (a chemical supplier) merged in
August of 1975.
Key Numbers:
Revenue: $2.7 Billion (2013)
9,000+ employees
operates in 40+ countries
over 100,000 products
1 million+ customers worldwide
Aldrich (name decided on coin toss - Bettie Mae Aldrich
- Eisendrath's fiancee:
Founded: August 17, 1951 by Alfred Bader and
Jack Nathan Eisendrath (a lawyer)
Home of the Aldrichimica Acta : an open access review
journal established by the company to provide access
to current organic research free of cost.
Circulation: 130,000+ worldwide - available online also
Ranked #1 in impact factor (12.231 in 2012 and 16.333 in 2013)
for Organic Chemistry specific journals.
Editor: Dr. Sharbil Firsan
Gianatassio 1
03/28/2015
Alfred Bader
"The Chemist Collector"
- a chemist, businessman,
and art collector
Born: April 28, 1924 in Austria
Fled from Austria to England
to escape Nazi persecution.
Transferred to Canada via
the Kindertransport
Education:
Queen's University
BS Engineering Chemistry (1945) Dr. Bader shown with his
BA History (1946)
wife Isabel at Queen's
University in 2009.
MSc Chemistry (1947)
Harvard University:
MA Chemistry (1949)
PhD Chemistry (1950) Advisor: Louis Fieser
Alfred's ABC's of life: "Art, Bible, Chemistry"
The famous Aldrich Handbook - "Big Red"
The cover of the famous Aldrich
catalog is adorned with famous art
pieces- some of them from his
personal collection. The idea of placing
a painting on the cover came from an
Aldrich employee contrary to popular
belief.
Still used as a reference material
for many chemists and is collected
by art enthusiasts
contains 40,000+ chemicals, 10,000+
structures, extensive chemical and physical
data
Aldrich
Baran GM
Gianatassio
03/28/2015
2
Total Synthesis of Fawcettimine (Heathcock) JOC 1989, 54, 1548.
H
Me
H
Me
CH 2N 2
PhCO 2Ag,
TEA, MeOH
O
via Diazald
COCl
O
O
CN
Me
N2
CN
H
steps
H
Me
O
Me
N
N
H
NO
NHNO 2
MNNG
a diazomethane precursor
- was used as a convenient small scale precursor to diazomethane
-No longer offered by Aldrich
CN
Diazald® was later developed
as a more stable alternative.
Preparation and generation of MNNG and diazomethane:
NH
Me
N
H
N
H
NHNO 2
NH
NaNO 2/HNO3
Me
N
H 2O, 0°C
NO
N
H
NHNO 2
O
S O
Me
N N
N2
OCH 2CH 3
OH
Diazald®
shelf life: 1-2 years
N
CO2Me
N
Me
H
O
NH
Base (aq.)
O 2N
NO 2
O 2N
NO 2
H
H
H
strong oxidizer
used in rocket
propellants
O
via:
O
O
N
H
CH 2N 2
H
Me
O
Br-
TNM
O
Me
HO
Other Products from the early 50's
O
O
O
Aldrich as the "Middle Man"
originally sourced from 2 companies
and sold out of Eisendrath's office.
NaHCO 3
then, HBr (aq.)
Aldrich's First Reagent: 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)
NH
name?
H
N
H
H
*epimerization of C-4 occurs during neutralization or upon standing
in CHCl 3 for several days. (see Luzung GM for full synthesis)
*Diazomethane is extremely unstable and
toxic and requires flame polished glassware.
"The Hamburger Incident"
A 28 year old chemist dies of suspected
diazomethane poisoning after eating
a hamburger while tending to his experiment
which involved the generation of diazomethane
on large scale. It was suspected that the grease
in the hamburger contributed to the incident
due to the high fat solubility of CH2N 2.
American Journal of Medical Sciences 1949, 218, 556. Diazomethane set-up
Aldrich
Baran GM
LiBH 4: reducing agent for esters lactones, acyl chlorides, epoxides,
aldehydes (at rt) and ketones (at rt). Also, is a catalyst for other borohydrides
and serves as a catalyst for hydroborations. Esters and
lactones require long reaction times and high temp.
Rapid growth continued into the mid-50's and reagents such as LiBH 4,
sodium tetraphenyl boron (NaBPh 4), diketene (C 4H 4O2), and triallylamine.
O
O
O
O
N N
HO
N
Reactivity Spectrum
OH
Note: LiBH 4 can be generated in-situ by
addition of LiI or LiBr to NaBH 4
LiAlH 4 < LiBH 4< NaBH 4
O
diketene
Gianatassio 3
03/28/2015
O
1995 - Aldrich delivers first
p-phenylazomaleinanil bulk order of Suberic Acid
used for characterizing
to DuPont
conjugated dienes
(±) Valeranone (Takeshita) Bull. Chem. Soc. Jpn., 1993, 66, 2694.
Reagent carboxylic acid salt
LiAlH 4
alcohol
LiBH 4
not usually
NaBH 4
NR
tertiary amides
amine
not usually
NR
nitriles
amine
not usually
not usually
halogens
alkane
not usually
not usually
ketone
alcohol
alcohol
alcohol
esters
alcohol
alcohol (↑ T)
not usually
O
Me
Me
p-TsOH
Me
Me
O
Me
O
O
H
O
Another Top Selling Reagent from 1955 - 1959
1. hυ
O
2. separate
N
NMbs
O
OH
Me Me
DIBAL-H
O
O
Me
-60 °C
Me
O
H 2N
OHC
O
Me Me
Me
Me
O
NH
O
O
3. MeMgBr
4. H 2 / Pd/ C
1. MsCl
2. H 2 / Pd/ C
OH
O
3. separate
H 2N
O
Et 3SiH
Bu 4NF
EtOAc/CH 3CN/H2O
NH
O
HO
NH 2
O
B(O 2CCF 3)3
NH
57%
TFA
82%
NMbs
N
H
O
H
HO
N
O
N
H 2N
O
NH
valeranone
OH
NMbs
H 2N
Du Bois SXT intermediate
Confirmation of Stereochemistry Experiment
O
OsCl3, Oxone
Na 2CO 3
NH
O
O
NMbs
NH 2
Me
N
H
1. p-TsOH
2. separate
*low melting point - gentle warming
of container can ease use of this
reagent. *skin irritant for some people
N
dicyclohexylcarbodiimide
(61%)
Me
C
O
NH
NH 2
HO
DCC
NH
pyridinium trifluoroacetate
DMSO
NH 2
70%
name?
JACS 2006, 128, 3926.
EROS, 1999, Volume 5, 3046-3049.
N
O
HO
N
NH
NH 2
(+) - Saxitoxin
NH 2
The 60's: A Decade of Change
- Aldrich goes public
- The company grows via acquisitions and
mergers
- Launch of the famous Aldrichimica Acta
-The Aldrich catalog gets a new persona and
becomes a "handbook"
1962: annual sales of ~ $1million
- catalog grows to 303 pages and 10,000 products
- J.T. Baker's offer to buy Aldrich for $1.5 million is
rejected
1965: sales grow to ~ $1.8 million
- number of employees grows to over 100 (15
chemists (7 PhDs))
Compounds from Aldrich's Custom Synthesis
Business
O
NSi(CH 3)3
O
Gianatassio
03/28/2015
Aldrich
Baran GM
N3
Me
O
powerful silylating reagent;
broad functional group
reactivity; extreme moisture
sensitivity
NSi(CH 3)3
Preparation: by the reaction
of acetamide with a large
Me
OSi(CH3)3
excess of
chlorotrimethylsilane
BSA
N,O - Bis(trimethylsilyl)acetamide in the presence of TEA
The First Protection of a hindered Alcohol : Galbraith, M.N.; Horn, D. H. S.; Middleton, E. J.;
Hackney, R. J.; J. Chem. Soc. Chem. Commun., 1968, 466.
"This synthesis
O
O
Me
Me incorporates a
Me
Me
potentially useful
BSA
application of
Me
Me
a trimethylsilyl ether
O
O
as a protecting
78 °C, DMF
OH
OSiMe3
group for hindered
hydroxyl-groups."
O
O
H
Bn
H
O
O
Bn
O-
HN
OSi(CH3)3
explosive
BSA
discontinued
15
page
EROS entry
Boc 2O came later
S
Me
N
Cl
O
OH
HO
HN
S
N
OMe
Me
Me
OH
O
Me
O
Me
Me
OAc
OH
H 2N
1O
2
H 2O2
quant.
Ph
0 °C, 1 h
OOH
OOH
Ph
H
H
O
BSA
cat. TBAF,/DCM
Me Me O
Me
1. DDQ, BSTFA
cat. triflic acid
2. 110 °C
+
(OH) 2
Me
H
N
H H
Me CO2Me
BSA (ca. 30%)
Important Flavoring Raw Materials
Me Me O
Me
O
CO2H
SnCl 4, -10 °C
OH
H
H
O
CO2H
H
Cl
O
O
Me CO2Me
Me
HBr, BSA
Me
CO2H
(CH 3)3
O
O
Products Offered in Bulk (Late 50's)
Me
4
H
N
H H
OTMS
H 2N
BSA
56%
OOSiMe3
OOSiMe3
Ph
TMS protection facilitates
column chromatography
on silica gel
EROS,2007, retrieved 3/28/2015, DOI: 10.1002/047084289X.rb208.pub2 .
Aldrich
Baran GM
Gianatassio 5
03/28/2015
Woodward's syntheis of cephalosporin C : The Boc protection story
HO 2C
HO 2C
BocN 3
acetone
SH
HN
L-(+)cysteine
Me
H 2N
HO 2C
S
BocN
Δ
Me
Boc 2O
not available
side product
S
Me
Me
HO 2C
"I wondered if the published intermolecular reaction of 1 with benzyloxycarbonyl
chloride (BnOCOCl) to give the corresponding N-carbobenzoxy thiazolidine 4
via the assumed mixed anhydride could be modified by replacing benzyloxycarbonyl
chloride with the thermolabile Boc chloride. Boc chloride had been previously prepared
by the reaction of sodium tert-butoxide with phosgene at ca. +10 °C. As the preparation
of 5 with sodium tert-butoxide seemed to be rather impractical, we generated 5 from
absolute tert-butyl alcohol with phosgene in dichloromethane-pyridine at -74 °C."
- Helmut Vorbruggen
(excerpt from Synthesis 2008, 23, 3379.)
Me
O
Me
BocN 3
O
Δ
steric clash! HN
N
H
FYI: Phosgene was a chemical war agent in World War I. Causes suffocation by
damaging proteins (crosslinking) in the pulmonary alveoli - gas exchange site.
S
Me
Me
Side Product
HO 2C
O
BnOCOCl
O
BnO
HO 2C
O
H N
S
Me
BnOCON
S
Me
Me
HN
S
Me
Me
Boc-Cl
mechanism?
Me
S
O
Me
N
N
O Me
S
Me
ca. 15%
4
3
Me
HO 2C
HN
Me
S
1
Me
tBuOH + COCl2
py, DCM
The procedure was run on deca-gram
scale and published in the 2008 Synthesis paper.
Benzene was used for both extraction an
column chromatography. Thus,
O
O
O
Boc-Cl
Py, -74 °C
BocO
-Py•HCl
Boc-Cl
5
O
O
O
H N
Me
6
S
Me
- t-BuOH
O
BocN
S
Me
Me
7
- CO2
HO 2C
BocN
Me
8
73%
S
Me
- Synthesis 2008, 23, 3379.
Aldrich
Baran GM
(+) - cephalosporin C : Woodaward (1966)
"Often in the course of synthetic work one or two key ideas set the style, development and outcome of
the investigation, while providing the flexibility essential for any long journey through unknown
territory, beset with perils which at best can be only dimly forseen." - R.B. Woodward Nobel Lecture
CO2H
O
NH 2
O
N
OAc
"We must in some way introduce a nitrogen atom at that point." Our initial
decision (of choosing cysteine as a starting material) placed us in the
exhilerating position of having to make a discovery, and of being prepared
to deal with substances of an especially precarious constitution."
- R.B. Woodward Nobel Lecture
HO 2C
HO
N
H
O
H
Gianatassio 6
03/28/2015
S
H 2N
A
- isolated from the sewers of a small Italian town
by the mayor who was an amateur microbiologist
SH
L-(+)cysteine
The Highlights:
O
MeO 2C
MeO
BocN
H
N
S
Me
MeO 2C
BocN
CO2Me
Me
Me
N N
CO2Me
MeO 2C
HN
CO2Me
S N
CO2Me
Me
BocN
S N
CO2Me
Me
CO2Me
N N CO2Me
H Pb(OAc)
Me
BocN
Me
S
4
PhH, reflux
Me
MeO 2C
"I shall not detail here the many weapons which were brought into play against that still expectedly recalcitrant methylene grouping. Suffice it to say
that the protected ester reacted with excess dimethyl azodicarboxylate at 105 °C during 45 hours to give the hydrazo diester in almost quantitative yield."
OAc
O
MeO 2C
H
MeO 2C AcO H
MeO 2C HO H
BocN
SH
BocN
Me
Me
Me
NaOAc
S
MeOH
BocN
Me
Me
S
H OAc
MeO 2C
+
Me
BocN
Me
MeO 2C AcO N N CO2Me
-OAc
S
BocN
Me
Me
via
MeO 2C
Mechanism?
S
BocN
Me
Me
major
CO2Me
N N CO2Me
S
Me
4 steps
CO2CH2CCl 3
CHO
O
NH
H
BocN
Me
H
S
Me
CHO
octane
Me
Boc H
N
Me
S
CO2CH2Cl 3
O
N
H H
O
CO2CH2Cl 3
CHO
N
H
BocN
O
H
Me
O
H
S
Me
O H
CO2CH2Cl 3
O
1. TFA
2.
O
NHTroc
δ+ HO C
2
DCC, THF
R
CO2H
CHO
N
N
H
H
steps
S
adapted from R.B. Woodward
Nobel Lecture (12/11/1965)
A
Sigma - Aldrich
Baran GM
BF 3•OEt2 and The Story of (-)-colombiasin A: Note: Structures are generalized
1970's: The Borane Era
- Aldrich forms Aldrich-Boranes with help from Professor H. C. Brown (Purdue)
Some of the First Compounds Manufactured
BH 3
Me
OH
(CH 3)2S:BH 3
NaBH 3CN
H
O
Me
Me
Δ
H
KCN Me
(2001)
Jacobsen (2005)
Me
H
(-)-elisapterosin B
O
H 2O
Me
H
Me O
Me
tBuO
Me
Me
OH
THF, 110 °C
µw
O
H
Me
Me
Me
BF 3 catalyzed cycloadditions of p-Benzoquinone
Me
OH
O
BF 3
Me
O
OH
Me
O
OH
Me
H
Me
OH
R
Harrowven (2005)
OtBu
air, 25 °C
taut.
O
Me oxidation
H
Me
R
OH
Me
+
O
O
Me
Me
OtBu
Me
O
H
Me
Me
*Doesn't always work but not much in depth follow-up work done
OH
Me
O
O
H
BF 2
ACIEE 2006, 45, 7134 - 7186.
*Mechanistic Studies Org. Biomol. Chem. 2013, 11, 8357.
Me
Me
R
Me
O
O
Me
Jacobsen, 2005
6π electrocycloreversion
•
H
O
A
O
Me
Me
THF, 110 °C
µw
OtBu
4π electrocycloreversion
Me
OH
H
O
BF 2
[5+2]
Me
H
Me
H
Me
Me
R=Me Me
R=tBu (B)
OH
-Aldrich purchases a manufacturing site in Sheboygan, WI.
Home of SAFC (Sigma - Aldrich Fine Chemicals).
-Aldrich starts selling lab equipment and nonchemical items. The first
nonchemical item was The Aldrich Library of Infrared Spectra
-Sigma and Aldrich merge - Logo gets a facelift
-"Craftsmen in Chemistry" slogan gets phased out for "chemists helping
chemists" - Aldrich does not succumb to pressure to drop "chemists" from
slogan when the word had become a PR liability.
Me
O
[5+2]
H
then, deprotect
O
(-)-colombiasin A
BF 3•OEt2,
retro-[4+2]
DCM, rt
Me
BF 3•OEt2,
DCM,-78 °C
PhMe
Me
9-BBN
borane - THF
Rychnovsky and Kim (2003); Harrowven (2005); Davies (2006)
Me O
Me OH
O
OR
O
H
B
O
Gianatassio 7
03/28/2015
BF 3
polymeric material
O
Me
ACIEE, 2006, 45, 7134-7186
Me
Me
Me
Me
Me
Me
Me
JOC, 1982, 52, 759 - 763.
B
Baran GM
Sigma - Aldrich
80's - 2000
-Double digit growth became normal
-10+ companies become part of Aldrich
-Corporate sales in 2000 exceeds $ 1billion.
-Aldrich hires product managers for specific product lines.
2000 - 2015
-Internet sales becomes a major part of the company.
-Realizing importance of scientists to growth of the company,
Aldrich establishes the Professor Product Portal and
formalizes collaborations with academic institutions.
- Merk KGaA buys Sigma-Aldrich for $17 billion ($140/share)
(Sept. 22, 2014)
Gianatassio 8
03/28/2015
How New Reagents Enable Chemistry: A Recent Multi-Kg Scale Buchwald - Hartwig Reaction
Me
N
H 2N
N
H 2N
NH 2
N
I
N
N
N
54%
NH
Pd(PPh 3)4/THF H 2N
Cl KHCO 3/nBuOH
then, NIS/MeTHF
71%
F
Me
BrZn
39 Kg
Me
N
20.1Kg
i. 0.33 eq. Bu 3MgLi/THF/-10 °C
ii. 1 equiv. ZnBr2
A selection of professors with hot products in the Aldrich Portfolio
F
NH
N
84%
F
tBuOK
NMP
N
N
N
NBoc
N
HN
N
N
Cl
Prof. Stephen Buchwald (MIT)
Prof. John Hartwig (U.C. Berkeley)
Buchwald ligands and pre-cataylsts catalysts and TrifluoromethylatorTM
N
Boc
HN
N
O
N
N
Me
14.3 Kg
2 steps
N
N
Prof. Neil Garg (UCLA) Prof. Tobias Ritter (Harvard) Prof. Paul Knochel (LMU)
"Turbo" Reagents
Aryne preceursors
Phenofluor TM
H 2N
Pd(OAc) 2 1 mol%
BrettPhos 1.2 mol %
Me NaOtBu 1.2 equiv./IPA
(15 volumes)
3 h 60 °C
N
N
N
N
N
N
HCl
Me
OH AMG 925 HCL
*less than 10% conversion was observed
without a catalyst.
OPRD 2015, 19, 476-485.
Sigma - Aldrich
Baran GM
A personal favorite
The evolution of reagents : Turbo Grignard Reagents
i-PrMgCl LiCl
Me
"Turbo Grignard"
A
Explanation for enhanced reactivity:
Me
Me
Gianatassio 9
03/28/2015
Cl
Mg
N
Me
MgCl LiCl
2LiCl
Mg
Mg
Cl
2 ArBr
Li
Cl
1
B
*Useful alternatives to "traditional" metal reagents and frequently display
enhanced reactivity.
Cl
Ar Mg
Cl
Li
Cl
-2 iPrBr
2
3
Stoichiometric addition of LiCl breaks up aggregates of 1
*Reactivity of carbon-M bond increases with the ionic character of the
bond.
OR
The magnesiate character of [iPrMgCl 2-Li +] is responsible for enhanced
reactivity.
*C-Mg bond is more covalent in character which allows for more
functional group tolerance at higher temperatures (i.e. rt).
Regioselective metalation of heteroarenes and arenes with B
The Compatibility Spectrum
K, Na, Ca, Li Al, Mg
ionic C-Metal polarized
bond
C-metal bond
La, Co, Fe, Mn
transition metals
and lanthanides
I
Zn, Cd, Cu, In
Hg, B, Sn, Si
Br
Br
Br
N
covalent C-M
covalent C-M
bond with low
bond w/o empty
lying empty orbitals low lying orbitals
N
Cl
N
N
Cl
N
Cl
CO2Et
low
CO2Et
high
functional group compatibility
N
ACIEE 2011, 50, 9794 - 9824.
Turbo vs. Traditional Grignard
N
Br
N
N
Br
Br
iPrMgCl LiCl
rt
iPr 2Mg or
iPrMgCl LiCl
rt
PhCHO
F
N
F
MgY
Br
N
Br
Cl
CO2tBu
N
N
N
OBoc
CO2Et
N
N
N
OH
N
Me
EtO 2C
Br
CO2Et
PhCHO
Br
N
MgY
Br
N
OH
with iPrMgCl
iPrMgCl LiCl
ACIEE 2004, 43, 3333-3336.
N
I
iPr 2Mg or
F
Br
CO2Et
N
TMPLi vs. B
Li
OMe
(2 eq.)
42%
(1.05 eq.) 89%
N
N
OMe
TMPLi
OMe
OMe
B
N
N
N
OMe
N
OMe
Sigma - Aldrich
Baran GM
Discontinuation of reagents can happen for a number of reasons
-toxicty
-new hazard rules/guidelines
-someone buys all of it
-shortages
The Sparteine Story:
H
Gianatassio 10
03/28/2015
Very special thanks to Dr. Sharbil J. Firsan (Editor of Aldrichimica Acta)
for providing vital information that made this seminar possible. Much of
the information presented was from Aldrichimica Acta 2001 34, 2, 35-46.
N
N
N
N
H
(-)-sparteine
NH 2
I
Ph
Me
N
EtO 2C
TEA,EtOH
Δ, 16 h
EtO 2C
Me
Ph
Ph
2
Me
EtO
2. EtOCH 2Cl
-78 °C to rt
16 h
KO tBu, THF
-78 °C
8.5 h
Me
H
O
N
H
OEt
O
OEt
5
4
EtO
H
3
Ph
N
Dr. Sharbil J. Firsan
Thanks to Dr. Chris Thomas for teaching me the "Reagent Business"
2
1. LHMDS
THF, -78 °C
N
EtO 2C
H
1
Me
+
O
H
LDA
H
CO2Et THF, -78 °C
CO2Et
then, 5 (1 eq.)
N
R 2N
Me
EtO 2C H
ent - 2
2. crystallize from
H 2O
Global Product Manager
NR1
Ph
1. Pd(OH) 2/C,
NH 4+HCO 2-,
EtOH, Δ, 14 h
+ ent - 2
inseparable
O
H
N
N
H
O
LiAlH 4
THF, Δ,
H
N
N
H
16 h
Chem. Commin. 2004, 1830 -1831.