I.S. Young
Baran Group Meeting
5/10/2008
So Many Hof(f)man(n)s
Hof(f)man(n) #2 (Many contributions to chemistry)
Hof(f)man(n)s Discussed
-
- studied under Justus von Liebig (University of
Giessen)
K. A. Hofmann and J. Sand (Paper from 1900, no other info available)
- oxymercuration of alkenes
- taught in Bonn, London and Berlin
August Wilhelm von Hofmann (1818-1892)
- many named reaction and aniline dyes
- first to use molecular models (colors still conserved)
Felix Hoffmann (1868-1946)
- first useful synthesis of aspirin and heroin
- invented many named reactions
August Wilhelm
von Hofmann
Albert Hofmann (1906-2008)
- father of LSD and first synthesis of psilocybin
Roald Hoffmann (Cornell University)
- organic and inorganic chemist, 1981 Nobel Prize (orbital symmetry)
Robert V. Hoffman (Professor Emeritus, New Mexico State University)
- chemistry of N-sulfonyloxy compounds
Hofmann Rearrangement (Ber. 1881, 14, 2725.)
O
H. Martin R. Hoffmann (Professor at Hannover University, Germany)
- chiral allyl cations, chemistry of cinchona alkaloids, natural product
synthesis
Br2
NH2
R
Reinhard W. Hoffmann (Professor at University of Marburg, Germany)
- natural product synthesis and reactive organometallic compounds
- his student (Perkin) responsible for aniline dyes
R
NaOH
N
C
O
PMPO MOMO
OMe
PMPO MOMO
Br2
NaOMe
MeOH
O
O
Steps
O
MeO
N
O
N
Me
O
(+)-cepharamine
Hofmann Elimination (Annalen der Chemie und Pharmacie 1851, 78, 253)
Hg
MeO
OMe
Br2
Br
MeO
Berichte der deutschen chemischen Gesellschaft 1900, 33, 1340 - 1353
H
H
O
OAc O
CH3OH
OMe
HO
O
O
H2N
OMe
O
(K. A.) Hofmann-Sand Reaction (not the Hofmann with all the other reactions)
OMe + Hg(OAc)2
For base sensitive substrates
can use hypervalent iodine or
lead tetraacetate
Example from Recent Literature (J. Am. Chem. Soc. 1998, 120, 8259)
Hof(f)man(n) #1 (not much known on this one)
O
R-NH2
-CO2
HO
Oxymercuration of double bonds
H2O
OMe
R2
R1
R3
N
R4
MeI
R1
H
R2
I
R3 N R4
Me
Ag2O
H2O
Heat
R1
R2
OH
R3 N R4
Me
-H2O
R1
R2
alkene formed often does not follow Zaitsev's rule
1
I.S. Young
Which Hof(f)man(n) is Which?
Recent Example of Hofmann Elimination (Tetrahedron Lett. 1989, 30, 5989)
Hofmann-Martius Reaction (Ber. 1871, 4, 742)
OMe
1) CH3I
2) 20% NaOH
EtOAc
MeO
Baran Group Meeting
5/10/2008
MeO
O
R
O
NH2
NH2
NH
R
steps HO
+
- R-group must be able an efficient
cation stabilizer
H
85%
O
O
H
NMe2
O
O
(+)-picrasin
Recent Example of Hofmann-Martius Reaction (Org. Lett. 2006, 8, 3497)
Me
Ph
N
Cl2
N
H
R
Me
Hofmann-Löffler-Freytag Reaction (Ber. 1883, 16, 558)
N
NaOH(aq)
- Similar to Fries Rearrangement
O
NH
or CF3CO2H(cat)
PhH/25 oC
MeHN
Cl
ligroin
H
- Hofmann had his student
(Perkin) attempt to oxidize
aniline to quinine
HO
N
Recent Example of Hofmann-Loffler-Freytag (Chem. Pharm. Bull. 1985, 33, 3187)
N
NCS, DCM
0 oC
H
N
H3C CH3
H3C CH3
Cl
NH
Creation of the Textile Dyeing Industry
N
Cl
O
71 or 82%
H2SO4(aq)
N
Ph
Me
PhMe/80 oC
1) Hg-lamp
CF3CO2H
5h, r.t.
MeO
N
N
2) 5% KOH, EtOH
reflux, 2h, 39%
Me
core of kobusine
quinine
William Henry Perkin
Synthesis of first synthetic dye
NH2
- led to black tar that made
a bright purple solution in
ethanol
- purple solution was used to
dye silk, Perkin became rich
Me
N
H2N
N
NH2
K2Cr2O7
+
NH
Hofmann Isocyanide Synthesis (aka carbylamine test)
NH2
+ CHCl3
+ KOH
heat
qualitative test
N
C
"smell of isocyanides described by Hofmann and Guatier as " highly specific, almost
overpowering, horrible, and extremely distressing"
Me
(impurity)
mauveine A
prior to mauveine, purple dye came from the fresh mucus secretion from tthe
hypobranchial gland of a medium sized predatory sea snail (extremely expensive!!!)
2
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Hof(f)man(n) #3 - Bayer Pharmaceutical Chemist
Hof(f)man(n) #5 - of Woodward-Hoffmann Rule Fame
- synthesized aspirin (1897) and heroin (1897) in forms that
could be used medicinaly
AcO
- professor at Cornell University
- interests lie in the application of theoretical and computational
methods to inorganic and organic systems
OAc
CO2H
N
O
- Awards include: 1981 Nobel Prize
Priestly Medal
ACS Organic and Inorganic Award
Arthur C. Cope Award
National Medal of Science
H
aspirin
AcO
heroin
Felix Hoffmann
- also has an interest in and writes poetry
Roald Hoffmann
Hof(f)man(n) #4 - Father of LSD (and psilocybin)
- first to synthesize, ingest and study the psychodelic
effects of LSD (synthesis 1938, test 1943)
Hof(f)man(n) #6 - Professor Emeritus, New Mexico State
α-oxidation and installation of a leaving group
(Synthesis 1985, 760)
- was a chemist at Sandos (now Novartis)
- accidently absorbed some through fingertip, then rode
bike home (purposely ingested 0.25 mg the next day,
see results below)
R1
OAc
- recently passed away (april 29, 2008, age 102)
R2
R3
+
Albert Hofmann
O
O
HN
HO P
O
-O
psilocybin
N
H
N
Ar =
NMe
H
Robert V. Hoffman
LSD
N
H
First Accidental Experience With LSD - "In a dreamlike state, with eyes closed, I
perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with
intense, kaleidoscopic play of colors. After some two hours, this condition faded away."
Second (0.25 mg experience), excerpts - commenting on his neighbour " She was no
longer Mrs. R. but rather a malevolent, insidious witch with a colored mask."
"A demon had invaded me, had taken possesion of my body, mind and soul. I jumped
up and screamed, trying to free myself of him, but sank down again and lay helpless
on the sofa."
(Ar-SO2-O)2
Ethyl Acetate
Methanol
81-95%
R1
R2
O
R3
OSO2Ar
O2N
Also applied to enamines (J. Org. Chem. 1985, 50, 5148) and
β-ketoesters (J. Org. Chem, 1990, 55 ,1267)
C-to-N Rearrangement of N-(Arylsulfonoxy)amine
(J. Org. Chem. 1988, 53, 3317)
NH2
(Ar-SO2-O)2
filter through
SiO2 (-78 oC)
warm
to rt
N
82%
EtOAc
-78 oC
Yields typically not this high, generally 40-80%
3
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Synthesis of α-azidoketones (J. Org. Chem. 1994, 59, 2902)
O
Synthesis of 2-Oxazolone-4-carboxylates (J. Org. Chem. 2002, 67, 1102)
O
X
R1
N3-
R2
- installation of halogen can be difficult
N3
R1
R
- doesn't work well when β-hydrogens
R2
(X = Cl, Br)
O
X
Solution
O
O
ONs N 3
R1
R1
R2
+ MeO
NH2
Hof(f)man(n) #7 - Professor, University of Marburg, Germany
Main Research Focuses
O
O
N
CO2Et
R
The Products can be hydrolyzed (ester), acylated (nitrogen), reduced (ester)
General Reaction
EtO
N
O
Toluene
Reflux
(AgOTf for X = Br)
- yields range from 68-96%
R2
Generation and Trapping of α-Lactams by Weak Nucleophiles
(J. Org. Chem. 2000, 65, 2591)
O
p-TsOH
X = ONs
X = Br
- -ONs can be installed regiospecifically
- reaction conditions milder than halide (rt)
N3
O
O
O
OEt
O
Base
R
EtO2C
R
N
R
Nu:
1) Total Synthesis of Natural Products
N
EtO
Nu
2) Chiral Organometallic Reagents
O
OMs
3) Stereoselective allylboration reactions
Reinhard W. Hoffmann
If a primary amine and excess base is used.
O
O
O
EtO
NaH (1.2 eq)
N
C6H11
OMs
C6H11
BnNH2
THF, rt, 10h
N
Example of Research Focus 1 and 3 (J. Am. Chem. Soc. 1997, 119, 7499)
65%
NBn
Previous work by others (for references see original paper)
O
Br
Sonication no nucleophile added
O
O
O
EtO
N
CH3
NaH
O
O
N CH3
83%
sonication
OMs
EtO
P
OEt
N
OMs
NaH
+
N
H
O
M = TMS
M = trialkyltin
M = tributyltin
O
CH3
OAc
Lewis Acid HO
or Protic Acid
H
HO
H
+
H
O
H
O
M
EtO
Preparation of phosphonomethyl ureas
O
O
H
THF
EtO
O
CH3
P
N
OEt
(+)-Laurencin
N
BF3 Et2O
BF3 Et2O
triflic acid
Major
Major
Major
Yields are low and the example to form the cis has never
been exploited further
79%
O
4
I.S. Young
So Many Hof(f)man(n)s
Laurencin Continued - Use of Masking Strategy
O
iBu2Al
MeO
N
Interesting transformations along the way to the tetrahydropyran
OH
O
MeO
Me
2. s-BuLi
Me
-78 oC
B OiPr
3.
OMe
O
-78 oC
O
2. aq pH 7
rt
MeO
N
Me
O Li+
B
55 %
O
O
MeO
O
OMe
KH, THF, 0
Cl2CCHCl, -78 -> 20 oC
MeLi, -78 -> -40 oC
O
H
O B
OBn OH
Yb(OTf)3
MeCN
2% H2O
O
O
2) CH2ICl, n-BuLi
o
OBn OTBS -100 -> 20 C
OMe
What happens when the additional stereocenter is included?
1. DIBAL
O
2. s-BuLi
MeO
HO
HO
3.
O
H2
N
B OMe
Pd / C
O
Me
O
O
97%
4. aq pH 7
O
38%
TBSO
TBSO
single diastereomer
TBSO
This completed formal synthesis, nine steps remained to form (+)-Laurencin
79%
1) pinacolborane
Cp2ZrClH
O
O
B
H
HO
35%
O
O
OBn
oC
O
Li
HO
OTBS
MeO
O
N
1. DIBAL
O
O
Baran Group Meeting
5/10/2008
67%
MeO
OBn OTBS
OMe
Research Area #2 - Chiral Grignard Chemistry
So What is the Deal with the Chrial Grignard Reagents?
Debate about mechanism of Grignard Addition
- ionic could lead to enantioenriched products
- single electron transfer would likely lead to racemic products
- chiral Grignards reagents can act as mechanistic probes as well
as form new asymmetric centers is process is ionic
Preparation of Chiral Grignard (Angew. Chem. Int. Ed. 2000, 39, 3072)
(halogen metal exchange on enantiomerically pure halide not an option)
Example of Research Focuse 1 and 3 Org. Lett. 2006, 8, 3829
Retrosynthesis
organolithium
addition
HO
5
O
O
hydroformylatoin/Wittig H
H
H H
OH
HO
H
O
H
OH
Cl
O
O
OH
Cl
Jimenezin
Ph
8
OH
Julia-Kocienski
Cl
5 eq. EtMgCl
S
O
enantiomerically pure
O
OH
HO
O
OH
O
THF, -78 to - 30 oC
S
ClMg
MgCl
O
Ph
e.e. ca. 90%
racemizes with halflife of 5 h at -10 oC.
O
5
I.S. Young
Which Hof(f)man(n) is Which?
Reactions of Chiral Grignards (Angew. Chem. Int. Ed. 2000, 39, 3072)
(Org. Lett. 2001, 3, 1945)
ClMg
Ph
Preparation of Conjunctive Reagent
S
1) PhNCS
2) H2O
Ph
N
Ph
56% yield
93% ee
Ph
HO
MoOPH
84% yield
92% ee
Ph
THF
ClMg
Ph
1) PhS-CH2-N3
-60 oC
Ac
N
N
O
SPh
KOH
NH
Ph
Ph
2) Ac2O
B O
Cl
-78 oC, Et2O
Reagent allows for allylboration and subsequent cycloreversion of the
dioxene ring to install an additional enal unit.
82% yield
92% ee
Kumada Couplings (Chem. Commun. 2003, 732)
O
B O
OTBS
ClMg
Ph
ca. 90% e.e.
Ph +
Br
PdCl2dppf
5d, -78 oC
THF
O
3% yield
OTBS
N
H
OTBS
O
Ph
O
+ (EtO)2P
allylboration
OTBS
O
O
+
O
OH
O
O
Horner-Emmons
toluene, rt, 2d
then reflux 2h
I2
Ph
Ph
O
O
Phenalamide A2 (Org. Lett. 1999, 1, 1713)
Ph
+
Ph
Ph
57% yield
88% ee
OH
92%
O
O
Ac
N
O
O
B O
tBuLi
O
H
ClMg
Baran Group Meeting
5/10/2008
69% 9:1 alkene isomers (major is all E, after dehydration all manipulaitons had
to be performed in the dark)
OH
O
N
H
Hof(f)man(n) #8 - Professor, University of Hannover
- has impressive pedigree: PhD - Ingold
Postdoc - Cram and Woodward
OTBS
O
B O
Retro is standard for these molecules: allylboration, aldol, Wittig, etc. One interesting
step will be highlighted.
H. Martin R.
Hoffmann
Major Areas of Research:
1) Total Synthesis of Natural Products
2) Chemistry of the Cinchona Alkaloids
3) Allyl Cation Chemistry
4) Methodology Development
6
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Synlett 1996, 690. For mechanism see paper, it is crazy
Cinchona Alkaloid Chemistry (Research Area 2)
- approximately 700 t/year are isolated from the bark of the Cinchona tree
LiAlH4, iPrOH, THF;
then O2, r.t. -> 45 oC
OMe
- quinine is a traditional antimalarial drug, quinidine treats irregular heart beat
N
- cinchonidine and cinchonine and their salts crystallize well (resolutions)
- are used as chiral ligands (Sharpless Asymmetric Dihydroxylation)
N
- used for the resolution of naproxen
N
N
OH
H
HO
H
-
quinine
"psuedoenantiomers"
R = OMe quinine
R=H
cinchonidine
1) MsCl
2) Phosphide
or
R = OMe quinidine
R=H
cinchonine
N
- it has been suggested that the Cinchona bases "are unlikely to find application as
chiral building blocks" J. Crosby, Chirality in Industry, 1992, pp 19-20.
- it was HMR Hoffmann's goal to prove this statement incorrect
HO
HO
quinocorine
N
quincoridine
Hydrosilylation
Ox.
N
O
+
R: 54% ee
MeO
Ligand 2
MgCl
S: 1% ee
R: 65% ee
Br
Ligand 1
N
enantiomer
H
Kumada-Corriru
CO2-
Mechanism of the last step???
N
H
Ligand 1
KOtBu
Beznene
3O
2
O
Ligand 2
Ph2SiH2
O
N
Ligand 1
Ligand 2
O
N
OH
H
N
Ph2P
HO H
OMe
N
Ph2P
or
N
Applications of Ligands (For references see within Eur. J. Org. Chem. 2004, 4293,
not HMRH)
Known Reaction (W. E. Doering, J. Am. Chem. Soc. 1946, 68, 586.)
OMe
quinocorine
Preparation of bidentate ligands (Tetrahedron 2000, 56, 4453)
N
N
HO
N
mechanism involves radical, radical ion-SET and ionic chemistry with sequential
oxidation and also hydrogenation steps, all in a single flask. Has been caried out on
100 kg scale.
R
R
N
OMe
OH
H
enantiomer
S: 86% ee
7
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Further Applications (note: diamine Ligands this time)
(Org. Biomol. Chem. 2003, 1, 2522, not HMRH))
First Cinchona Rearrangement (Angew. Chem. Int. Ed. 1999, 38, 2540).
OH
Ligand 3
N
O
N
92% ee
H2N
[IrCl(COD)]2
Ligand 3
OH
Q
AgOBz
Q
H
Br
Q = quinoline
H
MeOH
N
N
Q
H
OMe
H
Ligand 4
N
H2N
94% ee
Stereospecific Capture of Rearrangement Product by Nucleophiles
Ligand 4
Me
KBr
H3PO4
H OH
53%
N
N
N
Me
OMe
N
OMe
H
OH
N
catalyst 5
H
O2N
+
CF3
O
10 mol %
catalyst 5
OH
O
CF3
O
o
CF3 -55 C, DMF
O2N
BF3 OEt2
H
N
BF3 OEt2
OSiMe3
DCM, MTBE (20:1), 70%
CO2Me
H
N
note: the quinoline portion is not on the substrate
Application to Asymmetric Baylis-Hillman Reaction
(J. Am. Chem. Soc. 1999, 121, 10219; Not HMRH)
O
OMe
H
N
H
1) Bu3Sn
2) KF, H2O
O
(E:Z = 1:1)
O
OMe
H
Preparation of Baylis-Hillman Catalyst (Tetrahedron 1998, 54, 3495)
CF3
There are many, many more reactions published by Hoffmann on the chemistry of
the cinchona alkaloids, for a recent review by Hoffmann see: Eur. J. Org. Chem.
2004, 4293.
58% yield, 91% ee
- First practical example of asymmetric Baylis-Hillman reaction
- it was previously noted that a suitably disposed hydroxyl group on the amine
catalyst increases yield and ee, the catalyst with -OMe instead of -OH on the
quinoline led to grealy decreased ee (10%)
8
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Chiral Allyl Cation Chemistry (Angew. Chem. Int. Ed. 1998, 37, 1266)
2,5-dimethylfuran
TMSOTf
OBn DCM, -78 oC
General Reaction
O
OMe
OMe
O
OTMS
furan
OTES
TMSOTf
OMe DCM, -78 oC
LDA, TESCl
THF, -78 oC
quantitative
OMe
OH
OBn
DIBAL
THF, -78 oC
O
O
OBn
94%
53%
MeO O
72%
1) NaH, CS2, CH3I
THF, 0 oC, 77%
2) Bu3SnH, AIBN
toluene, 95 oC
92%
racemic
Preparation of Mixed Chiral Acetal and Reaction
O
O
O
OMe
OMe
AcBr
OMe
89%
OMe
1-phenylethanol
n-BuLi, ether
O
92% BRSM
Br
both enantiomers of
1-phenylethanol available
O
OTES
LDA, TESCl
o
Ph THF, -78 C
O
OMe
OMe
furan
TMSOTf
Ph DCM, -95 oC
Ph
67% yield
76% de
BF3 OEt2
DCM, 0 oC
OH
O
O
Ph
- the smaller Methoxy group is the leaving group under Lewis acid conditions
- Switching the phenyl of the auxilary to a naphthyl increased de to 100% (no yield given)
72%
O
Methodology Applicable to Natural Products with
2,6-cis Tetrahydropyrans
Phorboxazole A and B
A: R1 = OH, R2 = H
B: R1 = H, R2 = OH
O
OMe
H
OH
O
OH
O
O
O
OH H
dictyoxetane
O
O
O
O
Br
HO
Northern Half of Bryostatin 1
R1
O
N
OMe
R2
N
Tetrahedron 1999, 55, 4315
H
O
O
2) H2, Pd / C, 85%
HO
Application of this Methodology to Natural Product Synthesis
(Tetrahedron Lett. 1998, 39, 8259 and Tetrahedron 2002, 58, 6199)
O
OBn
1) m-CPBA, 85%
Studies Towards Phorboxazole and Bryostatin 1 using Allyl Cations
O
O
O
O
Me
Improved Reaction Conditions (Chem. Eur. J. 2000, 6, 684)
O
OBn
O
H
HO
O
O
MeO2C
Org. Lett. 2001, 3, 929
H
OAc
O
O
OH
OH
Hoffmann's concern was with construction of the dioxatricyclic framework
9
I.S. Young
Baran Group Meeting
5/10/2008
Which Hof(f)man(n) is Which?
Reasearch Area 4 - Development of New Methodologies
Deprotection of SEM Group Using MgBr2 (Org. Lett. 2000, 2, 1447)
SmI2 Mediated Pinacolization of Diketones (Tetrahedron 1996, 52, 11783
and Tetrahedron 1996, 52, 11799)
Me
Me
SEM protecting group can be difficult to remove, especially in a selective manner
O
- Is quite resistant to TBAF, but TFA will remove (Harsh!!)
O
TMS
O
HO
ΔE = 33.9 kcal mol
76% yield
OH
Me
Me
Me
The large increase in strain energy, and the facility of the reaction suggests that this
process could be applied to the synthesis of cyclobutanes, which are usually prepared
by ionic or photochemical processes.
Examples of Utility
Me
1.5 eq TBAF
THF, 0 oC, 1.5 h
S
99%
S
OSEM O
OH
HO
-1
Me
- MgBr2 in ether/MeNO2 is a good mild selective alternative to TFA and other
harsh conditions
SmI2
O
OSEM O
O
O
OH
OH
Me
CH3
SmI2
S
H
OTBDPS
S
ΔE = 41.4 kcal mol-1
32% yield
O
Me
Me
HO
Me
ylangene
yield not great, but the ring system is quite complex for one-step generation
S
MgBr2 (14 eq)
Et2O/MeNO2
81%
OH
O
O
OTBDPS
CH3
CH3
S
94%
O
12 eq. TBAF, 4 A MS
DMPU, 45 oC, 0.5 h
CN
O
HO
HO
HO
OH
yield very high in many examples and a variety of tricyclic ring systems were generated
decomposition
More Almost Total Syntheses from the HMR Hoffmann Group
OSEM OBn OSEM OTBDPS
CHO
TESO
HO
20 eq MgBr2
Et2O/MeNO2, 8 h
Me
SmI2
CN
OH
OBn OH
O
- naturally occuring antimalarial compounds
OTBDPS
OHC
TESO
94%
alcohols, esters, benzyl groups, dithians, methoxy acetals, TBS, TIPS, TBDPS and
cyanohydrins are all tolerated under SEM deprotection conditions
J. Org. Chem. 1993, 58, 6163.
- originally assigned structure was incorrect
OH
- key steps are Knoevenagel condensation,
hetero-Diels-Alder and aromatization
Robustadial A, isopropyl = β
Robustadial B, isopropyl = α
10
I.S. Young
Which Hof(f)man(n) is Which?
Baran Group Meeting
5/10/2008
Precursor to Robustadial Continued
MeO2C
O
MeO2C
OHC
O
+
O
mechanism?
MeO2C
O
OMe
HOAc (1.8 M)
KOAc (0.1 eq)
MS 3 A, hydroquinone
100 oC, 20 h, 80%
O
BSA, DDQ
dioxane
110 oC
MeO2C
O
1) KF, HBr, DMF
2) Acetone, K2CO3
(MeO)2SO2
TMSO
85% (2 steps)
MeMgI
ether
reflux
98%
HO
selenation/oxidation, α-halogenation
α-oxidation, and DDQ alone failed or
gave low yields. BSA necessary
O
OMe
1) 85% H2O2, p-TsOH
MeO
2) pyr. (CF3CO)2O
3) CF3CO2H, H2O/CH2Cl2
4) Acetone, K2CO3,(MeO)2SO2
74%, 4 steps
O
OMe
mechanism???
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