Adventures in Synthesis,
or, Formic Acid is my Friend
David E. Lewis
Department of Chemistry
University of Wisconsin - Eau Claire
Gustavus Adolphus College, April 8, 2005
Lewis Research Group Members
contributing to this talk
Graduates
2004
The Big Picture
What got us started?
Flowers that are beautiful
• Aconitum spp. — monkshoods
(wolfsbane)
– Ornamental species; late-flowering.
– Beautiful blue or purple flowers resembling
the hood of a monk’s habit (hence the name)
• Delphinium spp. — larkspurs
– Native to western USA
– Beautiful blue flowers with a long “spur”
resembling the foot of a lark (hence the
name)
– Many ornamental cultivars available
…but deadly
•Aconitum spp.
– A. napellus one of the most toxic
plants known
•Delphinium spp.
– Responsible for cattle losses worth
tens of millions of dollars annually in
western states of United States
•All parts of both species are toxic
– Occasionally responsible for
poisoning by ingestion of honey (even
the nectar and pollen contain the toxic
compounds!)
An evil reputation since
antiquity…
...., lurida terribiles miscent aconita novercae,
Ovid, Metamorphoses, Book I, 144-150.
huius in exitium miscet Medea, quod olim
attulerat secum Scythicis aconiton ab orbis.
.....quae quia nascuntur dura vivacia caute,
agrestes aconita vocant. .....
Ovid, Metamorphoses, Book VII, 406-420.
..., nec miseros fallunt aconita legentis,
Virgil, Georgics, Book II, 152.
....constat omnium venenorum
ocissimum esse aconitum ....
That from the Echydnaean monster's jaws
Deriv'd its origin, and this the cause.
Thro' a dark cave a craggy passage lies,
To ours, ascending from the nether skies;
Thro' which, by strength of hand, Alcides drew
Chain'd Cerberus, who lagg'd, and restive grew,
With his blear'd eyes our brighter day to view.
Thrice he repeated his enormous yell,
With which he scares the ghosts, and startles Hell;
At last outragious (tho' compell'd to yield)
He sheds his foam in fury on the field,Which, with its own, and rankness of the ground,
Produc'd a weed, by sorcerers renown'd,
The strongest constitution to confound;
Call'd Aconite, because it can unlock
All bars, and force its passage thro' a rock.
Pliny, Natural History, Book XXVII, II.
— John Dryden’s translation of Ovid, VII, 404-420
The aconitane skeleton
The carbon skeleton has six rings: A, B, C, D, E and F
C
B
A
N
N
R
N
R
R
D
F
N
aconitine: the
defining toxin
R
E N
N
R
R
The synthetic challenge:
Bridged rings
• The hexacyclic carbon skeleton of these molecules has:
– 2 bridged-ring carbocyclic systems based on 5- and 6-membered
rings
– 2 bridged-ring heterocyclic systems based on 5- and 6-membered
rings
N
N
R
N
R
N
R
R
The synthetic challenge:
Fused rings
• The hexacyclic carbon skeleton of these molecules
has:
– 3 fused-ring carbocyclic systems based on 5- and 6membered rings
– 1 fused-ring heterocyclic system ( a cis-perhydroquinoline)
– 1 spirocyclic ring system
N
N
R
N
R
N
R
N
R
R
The synthetic challenge
• These molecules are densely
functionalized
– In aconitine, only 8 of the 19
skeletal carbon atoms do not
carry a functional group; in
cardopetaline (the simplest
member of this class), 5 of 19
skeletal carbons still carry a
functional group
MeO
OH
OAc
MeO
N
N
Et
HO
OMe
OH
OMe
• These molecules are densely
populated with stereocenters
– In cardiopetaline, only 7 of 19
skeletal carbons are not chiral
centers (fortunately, all are not
independent; in fact 9 chiral
centers are fixed by the carbon
skeleton)
OCOPh
OH
OMe
OH
OMe
MeO
N
Et
Et
OMe
Our focus
the “southern hemisphere”
The spirocycic A/F ring system
The heterocyclic ring
N
N
R
R
Retrosynthetic analysis of
target
O
O
O
(–)
E'
N
E'
NHR
N
R
E
O
R
E'
NHR
E
E
OR
OH
OH
O
X
Ar
X
(–)
E
O
X
E'
NHR
(–)
E'
NHR
E
E'
NHR
E
The first key intermediate
OH
E'
NHR
E
OH
OH
E'
E
CHO
NHR
EtO2C
NHR
The aldehyde group must be present in protected
form capable of surviving a number of different
reactions, but capable of being revealed at a later
stage of the synthesis. An aryl group is the most
logical precursor in light of our preliminary results.
OH
EtO2C
Ph
CN
Preparing the starting compounds:
the Fossé reaction
CO2H
OH
CH2 (CO2H) 2/
X
X
X
• Reaction succeeds when X = OH, OMe, NR2
Fossé, R. Compt. rend. 1907, 145, 1290-1293; 1908, 146, 1039-1042, 1277-1280; Bull. Soc.
Chim. France 1909, 3, 1075; Ann. chim. phys. 1910, 18, 400-432, 503-530, 531-569.
X
But…
CO2H
OH
CH2 (CO2H) 2/
• Reaction fails when X = H
– benzhydrol returns only starting material
A Partial Solution:
Benzhydrylation of Active Methylene Compounds
O
OH
O
R1
O
R1
O
R2
R2
HCO2H/
R1 = R2 = Me
R1 = Me; R2 = OEt
R1 = R2 = OEt
R1, R2 = OCMe2O
73%
61%
trace
29%*
Gullickson, G.C.; Lewis, D.E. Aust. J. Chem. 2003, 56, 385-388. [Bowie Festschrift]
There are limitations…
H
Ph
Ph
OH
Ph
Ph
H
Ph
Ph
Ph
Ph
OH
Ph
Ph
Ph
Ph
O
O
HCO2H/
NC
CO2Et
HCO2H/
O
Ph
O
Ph
Ph
NC
CO2Et
Ph
Ph
Ph
triphenylmethanol always returns triphenylmethane
Aust. J. Chem. 2003, 56, 385-388.
…and unexpected results
O
OH
HN
(80%)
Ph
Ph
Ph
Ph
O
Ph
Ph
CO2Et
HCO2H/
NC
CO2Et
Ph
Ph
O
CO2H
HN
NC
CO2Et
HN
Ph
Ph
This Ritter reaction is highly reproducible, and highly chemoselective
Aust. J. Chem. 2003, 56, 385-388.
Ritter reactions by solvolysis
of benzhydrol in formic acid
Nitrile
CH2(CN)2
EtO2CH2CN
C6H5CN
p-MeC6H4CN
Yield
Nitrile
60%
CH3CH2CN
80%
CH2=CHCN
80% CH2=C(Me)CN
76%
Gullickson, G.C.; Lewis, D.E. Synthesis, 2003, 681-684.
Yield
86%
65%
73%
which may lead to a useful
application…
HCO2H/RCN/
+
(ZnO)
OH
OCHO
NHCOR
• only bornyl compounds are obtained: no isobornyl compounds
are isolated
– bornylamides are racemic
• bornyl formate is a liquid, b. ≈50°C near 1 mm Hg
• the bornylamides are solids, m. >100°C.
• the products are easily separated by vacuum distillation
Glen C. Gullickson, Joel D. Lischefski, Paul J. Erdman
Mechanism…
HCO2H
RCN/
(ZnO)
OH
+
OCHO
NHCOR
OCHO
By using a chiral nitrile, we may be able to obtain both amides
optically pure
An alternative approach to the
target
Use an aldol addition to build the
system…
Aldol additions using amide
dianions
anti isomer obtained
stereochemically pure from
crude reaction mixture by
direct crystallization.
Ph
H
N
R
O
Ph
Li
N
1) RCHO
OLi
2) H2 O
Ph
H
N
R
O
Typical recovery of unreacted
propionanilide: 10-30%.
Ph
OH
H
N
O
Gullickson, G.C.; Khan, M.A.; Baughman, R.G.; Walters, J.A. Lewis,
D.E. Synthesis, accepted for publication.
OH
Stereochemistry assigned by single
crystal X-ray structure analysis
OH
H
N
OH
O
O
O
OH
H
N
H
N
H
N
OH
O
O
Baughman, R.G.; Gullickson, G.C.; Khan, M.A.; Lewis, D.E. Acta Crystallogr. C,
submitted for publication; manuscript under revision.
anti Aldols from dilithiated
propionanilidea
Ph
H
N
O
1) 2 BuLi/THF/0‚C
2) RCHO/0°C
3) H2O
Ph
H
N
R
O
aIsolated
OH
R
Isolated Yield
4-MeOC6H4
31 (40)
2-ClC6H4
15 (16)
2-C4H3Ob
26 (33)
C6H5CH=CH
31 (37)
CHMe2
19 (26)
2-C10H7b
24 (29)
1-C10H7
52 (64)
Meb
25 (27)
yields of purified anti isomer. Values in parentheses are isolated yields of crystalline
material prior to recrystallization. bStructures of these compounds have been determined by
single crystal X-ray structure analysis.
What’s happening here?
• product ratio is largely insensitive to:
– temperature
– solvent
– length of reaction
• effects of other metal ions
– zinc
• 2 eq. ZnCl2 reverses stereochemical preference to
approximately 70:30 syn.
• 1 eq. ZnCl2 yields exclusively anti, but only in low yield.
– magnesium
• reaction fails when MgCl2 is added
Enolate stereochemistry
Ph
H
N
BuLi
Ph
O
Me 3SiCl
Li
N
Me
+ Ph
OLi
Ph
SiMe 3
N
+
Me
OSiMe3
21
Li
N
Me
OLi
Me3Si
N
Ph
Me
Me
+
Ph
OSiMe 3
:
1
:
N
SiMe3
OSiMe3
1.7
Rationalization of reaction
stereochemistry
– rapid equilibrium between aldols
– slower equilibrium involving acetal dianion
Z-azaenolate
Z-enolate
O-nucleophile
Cyclization of -hydroxyanilides
H
N
R
O
HCO2H/
H
N
O
OH
R
H
N
R
O
OH
HCO2H/
H
N
(ZnO)
R
O
R = C6H5
10%
*
R = p-MeOC6H5
33%
R = -C10H7
69%
*single run; not optimized
R = C6H5CH=CH
52%
R = p-MeOC6H4
79%
R = -C10H7
75 %
R = -C10H7
40%
E:Z ≈ 3:2
• permits early incorporation of heterocyclic ring
• reaction tolerates even sensitive functional groups
– cinnamyl group does not lead to polymerization
Glen C. Gullickson, Jessica A. Walters
The reaction has its limitations
NMe 2
NMe 2
H
N
NMe 2
H
N
O
OH
H
N
O
O
O
NMe 2
HN
H
N
O
NMe 2
Similarly…
NMe 2
H
N
NMe 2
HCO2H/
O
OH
H
N
O
Glen C. Gullickson, Jessica A. Walters
Attempts at an alternative
approach to closing the A-ring
Attempted spirocyclization by
reductive alkylation
OH
OH EtO C
2
OHC
CN
NH4OAc/AcOH
PhMe/
60-65%
O
Na/NH3
EtO2 C
CN
EtO2C
CN
Br
Br
OH
O
NC
O
NC
CO2Et
HN
- 30% (crude)
Joseph M. Schaefer, Paul J. Erdman
What’s happening? A putative
answer…
O
EtO2C
CN
Br
Br
NH3 (SN 2)
O
O
OH
NC
O
HN
O
NH3 (SN 2)
NC
EtO2C
S N2
NC
EtO2C
NC
NH2
Br
NH3 (SN 2)
CO2Et
How might we overcome the
problem? …the plan…
OH
NH2NH2

H 2NHN
EtOH/
EtO2C
OH
OH
CN
EtO2 C
CN
H
N
HN
CN
O
Br
Br
O
OH
Br
N
Br/base
N
N
N
O CN
CN
O
…the reality…
OH
NH 2NH 2
N
H2NHN
EtOH/
EtO2C
CN
OH
OH
EtO2C
N
HO
CN
OH
H
N
HN
CN
O
Erdman, P.J.; Gosse, J.L.; Jacobson, J.A.; Lewis, D.E. Synth. Commun. 2004,
34, 1141-1149.
Have we tried anything about
the “northern hemisphere”?
Retrosynthetic analysis of the
“northern hemisphere”
Synthesis of the nortricyclane
synthon: the norbornane pathway
Br
CO2H•H2O
O
MeOH
TsOH/
75-80%
Br
CO2Me
O
O
CO2Me
LDA/Et2O/0°C
- 50%
O
O
O
CO2 Me
O
MeO2 C
O
O
O
Joel D. Lischefski
Possible reaction pathways
with base
O
H
O
O
base?
O
O
O
H
H
OMe
OMe
OMe
O
O
O
Base-Promoted Fragmentation
O
O
O
Nu
OMe
O
O
OMe
Nu
OMe
O
Homoconjugate Addition
O
O
O
What actually happened?
O
O
NaNH2
CO2Me
Br
NaNH2
CO2Me
+
O
O
O
O
O
O
HN
O
NaOH
O
HO
CO2 Me
Me2SO
O
O
Joel D. Lischefski
O
Why the observed
regiochemistry of cyclopropane
cleavage?
Calculations at the AM1 level predict an overwhelming preference for
the endo bridged norbornane ring system.
O
O
O
O
H°f = – 63.3 kcal/mole
H°f = – 75.1 kcal/mole
Side benefit: a “green” synthesis
sequence experiment for the
organic laboratory
O
O
H2O/
CO2H
H2O
CO2H
CO2H
>95%
O
detergent
60-70%
+
CO2H
NaOCl/NaBr/H2 O
50-80%
Br

CO2H
O
O
- 100%
Br
CO2H•H2 O
O
NaHCO3/H2O/
50-60%
O
O
O
Lischefski, J.D.; Lewis, D.E. J. Chem. Educ. accepted for publication
O
O
Attempted Grignard synthesis
of allyl carbinols
Br
Mg/Et2O
MgBr
CHO
Mg/Et2O
HO
This problem is not new…
• formation of “biallyl” observed as a major
problem by 1920’s
• Gilman developed the method for preparing
allylmagnesium bromide in the 1940’s
– 3-fold excess of magnesium
– slow addition of allyl bromide to magnesium
– temperature control: temperature kept below 15°C
throughout addition.
Our solution…
• return to original method: the BarbierGrignard addition
– involves adding a solution containing both
halide and carbonyl compound to
magnesium in ether
– traditionally, equimolar amounts of halide
and carbonyl compound are used.
– our modification: use 1 eq. excess of
magnesium and allyl bromide
Barbier-Grignard addition of
allylmagnesium bromide
Br
Mg
R'
O
R'
HO
R
R
carbonyl
compound
product(s)
isolated
yield
-C10H7—CHO
-C10H7—CH(OH)—CH2CH=CH2
81
(CH3)2CH—CHO
(CH3)2CH—CH(OH)—CH2CH=CH2
70
cyclohexanone
H2C=CHCH2—CH(OH)(CH2)5
76
C6H5COCH3
C6H5C(CH3)(OH)CH2CH=CH2
82
CH3—CO2C2H5
CH3—C(OH)(CH2CH=CH2)2
77
C6H5—CO2CH3
C6H5—C(OH)(CH2CH=CH2)2
43
Sormunen, G.J.; Lewis, D.E. Synth. Commun. 2004, 34, 3473-3480.
Some observations
• a full equivalent excess of allyl bromide
and magnesium is not needed
– the aqueous quench after the addition
gives copious quantities of gas
• the minimum amount of allyl bromide
and magnesium is under active
investigation
And now for something
completely different…
An organic chemist’s adventures
with fluorescence
…with apologies to Monty Python
Fluorescent Tröger’s bases
O
N
OH
O
R
N
H2CO
HCl/EtOH
H2CO
HCl/EtOH/
O
O
N
R
O
NH2
O
N
R
N
O
N
R
O
O
R = n-Bu
57%
R = n-C8H18 66%
N
N
N
R
O
R = n-C6H13 74%
Deprez, N.R.; McNitt, K.A.; Petersen, M.E.; Brown, R.G.;
Lewis, D.E. Tetrahedron Lett. 2005, 46, 2149-2153.
Fluorescence Microscopy
• high selectivity for the target molecule or organelle.
• resistant enough to photochemical degradation under normal
illumination conditions to permit the target cell feature to be
visualized conveniently.
• preferably sufficiently non-toxic to allow live cells to be used for
the experiment.
• highly fluorescent (i.e. it should have a high quantum yield for
fluorescence), so that only small amounts of the dye are needed
to visualize the cell target of interest.
• large Stokes shift to minimize problems from light scattering by
the cell
• preferably easy to make from readily available, inexpensive
starting materials, and chemically stable to permit long-term
storage.
A new lysosomal stain
Cl
Cl
C6H13NH2 (1 eq)
PhMe/, 89%
O
O
O
O
N
O
H2N
, 71%
NH2
HN
O
N
O
InstantLyso LLT-1
NH2
A new stain for cholesterolrich microdomains
NH2
NH2
1) NaOMe/DMF
2) Br(CH2)7CH3
O
N
H
O
80%
O
O
N
C8H17
InstantLipo Sep-1
And for Golgi apparatus…
Me
O
O S
NH
NH2
HN
HN
TsCl (2 eq.)/CH2Cl2
16 h, 60%
O
N
O
O
N
O
InstantGolgi McN-1
A new mitochondrial probe
O
H 2N
NH
O
O
1) NaOMe/MeOH/DMF
H 2N
N (CH2) n Br
2) Br(CH2) nBr/DMF
O
n=4, 76%; n=6, 91%
Me2N
n = 6 InstantMito LMT-1
n = 4 InstantMito LMT-2
N/EtOH/
n=4, 56%
n=6, 30%
O
H 2N
N (CH2) n N
O
Br
NMe 2
Where to now?
• Synthesis of new fluorescent dyes using
formic acid cyclization as an important
reaction step
• Elucidating reason for responsiveness
of Tröger’s base fluorescence spectra to
medium
• Application of new fluorescent dyes to
fluorescence microscopy
Financial Support
• UW-Eau Claire Office of Research and
Sponsored Programs
• Research Corporation
• Cottrell College Science Award
• National Institutes of Health
• AREA Grant