Carbenes and Nitrenes: Application
to the Total Synthesis of
(–)-Tetrodotoxin
O
HO
HO
HN
O
O
OH
OH
NH OH
H2N
Effiette Sauer
March 18th 2004
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
What are Carbenes? Nitrenes?
X
C
Y
N
X
• Neutral, divalent carbon species containing
six valence electrons
• Neutral, monovalent nitrogen species
containing six valence electrons
Electron
deficient
Highly
reactive
2
Carbene Formation
• Diazoalkanes
R2C
N
R2C
N
N
N
R2C
N
hv or heat
R2C
+
N2
R2C
N
• Sulfonylhydrazones
R2C
N
NH
SO2Ar
Base
N
N
SO2Ar
• Halides
Cl
H
C
Cl
Cl
Cl
Base
alpha-elimination
C
Cl2C
+
Cl
Cl
Cl
3
Reactions of Carbenes
• Addition reactions
CH2
+
CH2
+
CH2
RnX
+
CH2
RnX CH2 Y
CH2
• Ylide formation
RnX
CH2
• Insertion reactions
RnX Y
4
Singlet and Triplet States
Y
X
C
Singlet
X
N
Singlet
X
C
Triplet
Y
X
N
Triplet
• sp2 hybridized carbon
• sp2 hybridized carbon (or sp?)
• non-bonding electrons have
opposite spin - occupy an sp2
orbital
• non-bonding electrons have
same spin – occupy an sp2 and p
orbital
• XCY angle 100-110°
• XCY angle 130-150°
5
Singlet and Triplet States
Y
X
X
C
N
X
Singlet
Singlet
X
Triplet
p
sp2
p
sp2
sp2
1s

N

p
sp2
Y
Triplet

p
C
1s

6
Relative Stability of Singlet and Triplet States
• Triplet more stable than singlet (R=H, alkyl)
Singlet
R
C R
~ 8 kcal
R
C R
Triplet
• Unless, added stabilization possible (X=O, N, S, halogen etc.)
X
C R
X
C R
X
C R
7
Mode of Preparation – Singlet vs. Triplet
Ionic Mechanism:
Cl
B:
Cl
C
H
C
C
Cl
Cl
Cl
Cl
Cl
Cl
Singlet
Photolysis:
H
H
C
N
N
H
H
hv
C
Singlet
H
H
C
Triplet
8
Singlet Carbenes React Stereospecifically
FMO interactions for cyclopropanation with singlet carbene:
R H
R H
H H
H H
C
C
R H
R H
Mechanism:
R H
H
H
R H
C
H
H
R
H
H
C
H
R H
R H
Concerted
R
H
Stereospecific
9
Triplet Carbenes React Stereoselectively
Cyclopropanation with triplet carbenes - radical mechanism:
H
R
H
H
H
R
R
R
C H
H
C
slow
spin
flip
H
H
R
R
H H
C
H
H
R
H H
R
HH
free rotation
mixture of isomers
R
H
slow
R
H
H
R
spin
flip
H
R
C
H H
Two pathways
C
R
H
H
H H
R
HH
Stereoselective
10
Nitrene Formation
• Azides
R
N
N
N
hv or heat
R
N
+ N2
• Iminoiodanes
Ar
hv or heat
I
N
RO2S
N
+
ArI
SO2R
• Sulfonamides
RSO2NH2
+
PhI(OAc)2
base
PhI
NSO2R
11
Reactions of Nitrenes
• Addition reactions1
O
+ N3
hv
N CO2Et
CO2Et
• Ylide formation2
hv
N
N
N
N3
N
N
• Insertion reactions1
O
+ N3
hv
NHCO2Et
CO2Et
1 Lwowski,
W. Angew. Chem. Int. Ed. Engl. 1967, 6, 897. 2 Albini, A.; Bettinetti, G.; Minoli, G. J. Am. Chem. Soc., 1997, 119, 7308.
12
Free Carbenes/Nitrenes - Too Reactive
• Free carbenes/nitrenes are highly reactive species → low activation
energy for product formation1:
CH2
+
CH2
CH2
~ 0 kcal A.E.
• Generally too reactive to afford useful selectivity2:
25% 13%
H3C
C
H2
H2
C
C
H2
H2
C
C
H2
CH3
CH2N2
H3C
C
H2
H2
C
C
H2
H2
C
C
H2
CH3
38% 24%
1 Zurawski,
2
B.; Kutzelnigg, W. J. Am. Chem. Soc. 1978, 100, 2654.
Richardson, D. B..; Simmons, M. C.; Dvoretzky. I. J. Am. Chem. Soc. 1961, 83, 1934.
13
Moderation of Reactivity
• Intramolecular, rigid systems
hv
N
48%
N
• Rearrangement reactions (e.g. Wolff, Curtius)
O
N
R
N
hv or heat
R
H
R1OH
C C O
O
R
OR1
Concerted or stepwise depending on conditions
Majerski, Z.; Hamersak, Z.; Sarac-Arneri, R. J. Org. Chem. 1988, 53, 5053.
14
Moderation of Reactivity
• Binding of carbene/nitrene with a metal
X
X
LnM
LnM
C
N
Y
Carbenoid
Nitrenoid
• Tune reactivity by changing L, M, X, Y
• Different species for
1) addition
2) ylide formation
3) insertion reactions
4) and more (e.g. RCM)
15
Generation of the Metalloid
• Treat carbene/nitrene precursor with transition metal ion
R2C
N
N
R
N
N
N
RO2SN
IPh
• General mechanism
SCXY
Y
N2 C X
LnM
Y
S
LnM C
X
N2
LnM → electrophilic
→ vacant coordination site
16
Tuning the Catalyst for CH Insertion
• Must tune electrophilicity of carbon atom to react selectively with inert
CH bonds
σ acceptor?
π donor?
X
LnM
C
Y
π back bond
σ bond
LnM
C
X, Y = acceptor (EWG)
donor (EDG)
or H
X
Y
lone pair into
empty d orbital
LnM
C
X
Y
d orbital into
empty p orbital
17
Tuning the Catalyst for CH Insertion
• Must tune electrophilicity of carbon atom to react selectively with inert
CH bonds
σ acceptor?
π donor?
σ acceptor
+
+
-
π
d
o
n
+
+
-
o
r
X
LnM
X, Y = acceptor (EWG)
donor (EDG)
or H
C
Y
P
r
o
p
e
r
t
i e
s
strong M=C bond; nucleophilic
moderate M=C bond; nucleophilic
moderate M=C bond; electrophilic
weak M=C bond (~ free carbene); electrophilic
18
The Early Days
• Early investigations focus on copper catalysts (e.g. CuSO4, CuOTf2)
→ synthetic use confined to rigid systems1,2
N2HC
CHN2
O
O
1 Burke,
2 Burns,
CuSO4
toluene, ruflux
O
S. D.; Grieco, P. A. Org. React. 1979, 26, 361.
W.; McKervey, M. A.; Mitchell, T. R. B.; Rooney, J. J. J. Am. Chem. Soc. 1978, 100, 906.
O
19
The Early Days
• Early investigations focus on copper catalysts (e.g. CuSO4, CuOTf2)
→ synthetic use confined to rigid systems1,2
• Teyssie and coworkers introduce dirhodium (II) tetraacetate3
→ Scope and utility of carbenoid insertion reactions explode4
O
Me
Me
CHN2
Me
Me
O
70% with Rh2(OAc)4
H
AcO
AcO
3
H
Me
H
trace with CuSO4
AcO
AcO
H
H
Me
Paulissenen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1973, 2233. 4 Wenkert, E.; Davis, L. L.;
Mylari, B. L.; Solomon, M. F.; Warnet, R. J.; Pellicciari, R. J. Org. Chem. 1982, 47, 3242.
20
Dirhodium (II) Catalysts
Electron withdrawing
ligands  increase
electrophilicity
Vacant site for
carbene binding/
diazo decomposition
1
2
O
O
O O
Rh Rh
O O
O O
Unique dirhodium bridge
 one Rh binds carbene,
other assists insertion1,2
Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
Pirrung, M. C.; Liu, H.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2002, 124, 1014.
21
Insertion Mechanism
A
Me
C B
Y C
H C
X
N2
C
O
O
II
X Y
II
Rh
Rh
Me
Me

O
O
H
II
II
Rh
Rh C

A
C
C
O
B
II
Rh
O
II
N2
Rh C
XY
X
Y
Me
A
H
C
C
O
II
B
Rh
O
II
Rh C
Y
N2
X
Doyle, M. P.; Westrum, L. J.; Wolthuis,W. N. E.; See, M. M.; Boone, W. P; Bagheri, V.; Pearson, M. M.
J. Am. Chem. Soc. 1993, 115, 958.
22
Insertion Mechanism
• Nakamura suggests Rh-Rh cleavage occurs during diazo decomposition
giving rise to two simultaneous events at the transition state
→ Hydride Transfer
→ Regeneration of the Rh-Rh bond
Me
Me
A
O
O
Rh
H
Rh C
XY
C
C
B
A
O
Rh
O
H
Rh C
C
C
B
XY
• Role of dirhodium bridge is two-fold
→ Enhances electrophilicity of carbon
→ Assists in Rh-C cleavage
Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
23
Insertion Mechanism
A
Me
C B
Y C
H C
X
N2
C
O
O
Rh
Rh
II
X Y
II
Me
Me


O
Rh

O
H

Rh C
A
C
C
B
O
O
Rh
Rh C
I
XY
N2
III
X
Y
Me
A
H
C
C
B
O
O
Rh
Rh C
I
III
Y
N2
X
Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
24
Trends in Selectivity
Build-up of positive charge in transition state → implications for selectivity
Me

H
O
O
Rh
Rh C

A
C
C
B
XY
• 3° > 2° > 1°
• adjacent heteroatoms favour insertion
• EWGs hinder insertion
25
Trends in Selectivity
O
O
E
N2
O
Rh2(OAc)4
E
+
E
84%
23
O
O
CHN2
O
+
O
CHN2
O
Rh2(OAc)4
MeO
O
AcO
1
O
Rh2(OAc)4
40%
O
O
1
99%
O
+
MeO
O
AcO
MeO
O
AcO
Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686. 2 Adams, J; Spero, D. M. Tetrahedron 1991, 47, 1765.
P.; Adams, J. J Am. Chem. Soc. 1994, 116, 3296.
3 Wang,
26
Trends in Selectivity
• Five membered rings form preferentially
Me

O
O
Rh
Rh C
A
H 
C
XY
B
Chair-like t.s.
gives five
membered ring
product1
→ steric, electronic and conformational influences may override
this preference2
O
O
N2
Rh2OAc4
O
82%
O
OTIPS
Five membered
ring not observed
OTIPS
1
Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686.
E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995, 321.
2 Lee,
27
Trends in Selectivity
The Hammond postulate: Two species of similar energy occurring
consecutively along a reaction coordinate will be similar in structure
• High energy intermediates → TS resembles intermediate
• Low energy intermediates → TS resembles the product
L4Rh2
  A
H C
B
C
C
XY
 lower energy intermediate
 later TS
 more charge build-up
 greater selectivity
L4Rh2 CR2
Product
28
Trends in Selectivity
B
O
O
O
"Rh"
+
H
O
56-96%
N2
A
Rh2(pfb)4
Rh2(OAc)4
Rh2(acam)4
A
B
32
53
>99
68
47
<1
reactivity
C3F7
selectivity
CH3
CH3
O
O
O
O
O
N
Rh
Rh
Rh
Rh
Rh
Rh
Rh2(pfb)4
Rh2(OAc)4
Rh2(acam)4
Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E. J. Am. Chem. Soc. 1993, 115, 958.
29
Trends in Selectivity – in Summary
Me

H
O
O
Rh
Rh C

A
C
C
B
XY
• Preference for most electron rich CH bond
• Five-membered ring formation preferred
• Enhanced selectivity by decreasing reactivity of carbenoid
30
What about those Nitrenoids?
• Certain Fe, Mn, and Ru porphyrin complexes catalyze CH insertion1
O C F
6 5
C
N
C 6F 5
+
PhI
N
Mn
N
N
C 6F 5
NHTs
C 6F 5
NTs
78%
• Mechanistic studies on Ru(Por)(NTs)2 suggest a radical intermediate2
Ts
H
CR3
N
N
N
Ru
N
N
NTs
1 Yu,
2 Au,
X.; Huang, J.; Zhou, X.; Che, C. Org. Lett. 2000, 2, 2233.
S.; Huang, J.; Yu, W.; Fung, W.; Che, C. J. Am. Chem. Soc. 1999, 121, 9120.
31
Good Ol’ Rhodium
• Rhodium was initially ignored – gave undesired insertion products (!)
• In 2001, Du Bois capitalizes on Rhodium’s preference for insertion1
O
O
Rh2(OAc)4, PhI(OAc)2, MgO
NH2
O
HN
O
DCM, 40 °C, 12 hr
86%
• Reaction is stereospecific
O
O
NH2
(S)
O
1 Du
as above
HN
O
no loss of ee
72%
Bois, J.; Espino, C. G. Angew. Chem. Int. Ed. 2001, 40, 598.
32
(–)-Tetrodotoxin
O
HO
HO
HN
O
O
OH
OH
NH OH
H2N
• Isolated from the Japanese puffer
fish (Sphaeroides rubripes) in 19091
• Named after the puffer fish
family Tetraodontidae
• LD50 = 10 ng/Kg mouse
• Current interest in TTX as a
potent analgesic
1 Tahara,
Y. J. Pharm. Soc. Jpn. 1909, 29, 587.
33
(–)-Tetrodotoxin
O
HO
HO
HN
H2N
O
O
O
O
O
OH
OH
NH OH
HN
O
OH
OH
NH OH
H2N
• Relative stereochemistry assigned in 1964 by Hiratu-Goto1,
Tsuda2, and Woodward3
• Absolute stereochemistry established by X-ray in 19704
• First racemic synthesis by Kishi in 19725
• Enantioselective syntheses by Isobe6 (Jan. 2003) and Du Bois7
(June 2003)
1Tetrahedron
1965, 21, 2059. 2Chem. Pharm. Bull. 1964, 12, 1357. 3Pure. Appl. Chem. 1964, 9, 49. 4Bull. Chem. Soc. Jpn. 1970,
43, 3332. 5aJ. Am. Chem. Soc. 1972, 94, 9217. 5bJ. Am. Chem. Soc. 1972, 94, 9219. 6J. Am. Chem. Soc. 2003, 125, 8798. 7J. Am.
Chem. Soc. 2003, 125, 11510.
34
Retrosynthesis
O
HO
HO
HN
O
HO
O
O
OH
HO
H
6
5
selfOH
OH
O
H2N
assembly
NH OH
H2N
O
OH
OH
OH
NH OH
OH
HO
5
O
H
OH
NH
HN
HO
H2N
OH
6
O2C
NH2
CH amination
RO
H
6 membered
ring desired
RO
OR
OR
OR
O
N2
6
5
OR
RO
RO
RO
CH insertion
5
6
(RO)2HC
OR
H
CO2R
O
O
O
OR
NH2
35
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
OH
O
aq. H2O2
HO
1) Me2NH
MeOH, 0°C
O
Na2CO3
OH
HO
70%
O
2) 2,2-DMP, PTSA
THF, 60 °C, 84%
HO
O
O
NMe2
OH
OH
1) TBSCl, pyridine
100 °C, 86%
2)DIBAL, nBuLi
THF, HMPA
O
O
O
O
O
OTBS
BnO
O
O
HO
O
OTBS
BnO
BnO
OBn
O
O
O
OBn
OH
O
O
O
H
NaOAc, THF
OTBS
O
O
12:1 syn:anti
90% 2 steps
36
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
1) tBuCOCl, pyr
O
OTBS
BnO
O
HO
1) (COCl)2
O
OTBS
THF, 60 °C 95%
2) H2, Pd/C
O
O
OH
2) CH2N2, DCM
O
THF, 88%
O
PivO
O
70% 2 steps
OTBS
O
O
PivO
O
O
O
O
O
Double bond to
favour six
membered ring
OTBS
N2
PivO
O
O
N2
O
cat. DMF, THF
O
O
??
OTBS
O
O
PivO
Change PG
if need be
O
37
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
OTBS
N2
OTBS
catalyst
O
O
O
O
O
B
PivO
O
O
O
A
PivO
TBS
+
solvent, rt
O
O
O
PivO
O
Catalyst
Solvent
%A
%B
Rh2(oct)4
Rh2(oct)4
Rh2(cap)4
Rh2(tpacam)4
CH2Cl2
CCl4
CCl4
CCl4
< 10
30
45
45
45
15
O
B via:
TBS
L4Rh2
O
O
PivO
> 95
---
R
O
O
38
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
OTBS
N2
OTBS
catalyst
O
O
O
O
O
B
PivO
O
O
O
A
PivO
TBS
+
solvent, rt
O
O
O
PivO
O
Catalyst
Solvent
%A
%B
Rh2(oct)4
Rh2(oct)4
Rh2(cap)4
Rh2(tpacam)4
CH2Cl2
CCl4
CCl4
CCl4
< 10
30
45
45
45
15
O
B via:
TBS
L4Rh2
O
O
PivO
> 95
---
R
O
O
38
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
OTBS
N2
OTBS
catalyst
O
O
O
O
O
B
PivO
O
O
O
A
PivO
TBS
+
solvent, rt
O
O
O
PivO
O
O
Catalyst
Solvent
%A
%B
Rh2(oct)4
Rh2(oct)4
Rh2(cap)4
Rh2(tpacam)4
CH2Cl2
CCl4
CCl4
CCl4
< 10
30
45
45
O
N
45
15
Rh
Rh
> 95
---
38
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
OTBS
N2
OTBS
catalyst
O
O
O
O
O
B
PivO
O
O
O
A
PivO
TBS
+
solvent, rt
O
O
O
PivO
O
Catalyst
Solvent
%A
%B
Rh2(oct)4
Rh2(oct)4
Rh2(cap)4
Rh2(tpacam)4
CH2Cl2
CCl4
CCl4
CCl4
< 10
30
45
45
45
15
> 95
---
O
CPh3
O
Rh
NH
Rh
38
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
O
OTBS
BH3·NH3
OTBS
DCM, MeOH
O
O
PivO
75% 2 steps
O
O
TFA, MeOH
O
H
OPiv
2,2-DMP, PTSA
O
THF
77% 2 steps
O
TBSO
OH
O
OH
H
H
OPiv
HO
CO2Me
OH
O
O
O
O
OH
O
H
OH
O
OH
O
O
H2, 1200psi
Rh-C
HO
PivO
O
PivO
TBSO
O
O
OPiv
39
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
1) Me2NH, THF
O
2) TPAP, NMO
O
4Å MS, DCM
H
94%
OPiv
O
O
83%
O
O
O
O
O
Zn, TiCl4, CH2I2
O
O
cat. PbCl2, THF
O
72%
H
Me2NOC
H
OPiv
Me2NOC
OPiv
Ph2Se2, PhIO2, pyr
C6H6, reflux, 70%
O
O
O
O
O
O
O
O
H
Me2NOC
OPiv
O
MgBr
OPiv
CONMe2
O
O
O
O
O
THF, CuI
O
HOAc
H
Me2NOC
OPiv
40
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
O
O
O
H
Me2NOC
O
O
tBuNH2·BH3
HO
O
DCE
O
77% 2 steps
OPiv
H
Me2NOC
O
tBuCO2H
O
O
C6H5Cl
O
200 °C
O
H
OPiv
OPiv
NaOMe
THF/MeOH
78% 2 steps
O
O
O
O
O
O
O
Zn
O
Cl3C
N
C
O
O
O
O
O
O
O
H
O
NH2
MeOH
93% 2 steps
DCM
O
O
O
O
O
H H
N
CCl3
O
H
OH
O
O
O
41
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
O
O
O
O
H
O
O
H
O
NH2
O
O
O
O
O
O
Rh2(tpa)4, PhI(OAc)2
O
O
O
O
N
MgO, DCE, 40 °C
10%
O
O
O
Only
product
NH2
O
H2, Pd/C
EtOAc, 96%
CPh3
O
O
Rh
O
O
O
Rh
O
O
H
Rh2(tpa)4
O
O
O
O
NH2
O
O
Rh2(tpa)4, PhI(OAc)2
O
O
O
NH
MgO, DCE, 40 °C
20%
O
O
42
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O3, then
NaBH4
O
DCM/MeOH
83%
O
O
O
O
O
O
O
HO
O
MsCl, pyr
O
DCE, 87%
O
O
O
H
OCONH2
O
Cl
O
O
H
OCONH2
H
OCONH2
CF3
Rh2(tfacam)4
O
O
Rh
Rh
PhI(OAc)2, MgO
C6H6, 65 °C, 77%
O
O
1) BOC2O, TEA
DMAP, THF
O
O
O
O
NHBOC
OH
N
O
O
O
O
2) K2CO3
THF/MeOH
84% 2 steps
O
O
NH
O
1) NaSePh
THF/DMF
77%
2) mCPBA, pyr
DCE, 55 °C
98%
O
O
Cl
O
O
O
NH
O
O
O
43
O
Synthesis of (–)-Tetrodotoxin
HOO
HO
HN
O
OH
OH
NHOH
H 2N
O
O
O
O
O
O
H2O, 100 °C
O
95%
O
O
O
BOCN C NBOC
O
MeCN/DCM
O
O
O
O
NHBOC
80%
NH2
OH
O
O
O
N
OH
BOCHN
OH
NHBOC
1) O3 then DMS
2) aq. TFA
O
HO
O
O
OH
OH
HO
HN
OH
O
NH OH
H2N
65 % 2 steps
HO
O
H2N
H2N
O
OH
OH
OH
OH
OH
OO
OH
NH OH
O
NH
OH
H2N
NH2
44
O
Conclusions
HOO
HO
HN
O
OH
OH
NHOH
H 2N
• Completed the synthesis of (–)-TTX in 32 steps, overall yield of 0.8%,
average yield of 81%
• Used CH insertion to stereospecifically assemble quaternary carbon
centre at C6 and six-membered core ring of TTX in >95% yield
• Demonstrated the viability of their recently developed CH amination
reaction, forming the tertiary amine in 77% yield
• Reinforced the utility of carbenes and nitrenes as valuable
intermediates in organic synthesis
45
Acknowledgments
Dr. Louis Barriault
Patrick Ang
Steve Arns
Rachel Beingesser
Roxanne Clément
Irina Denissova
Julie Farand
Nathalie Goulet
Christiane Grisé
Roch Lavigne
Louis Morency
Maxime Riou
Jeff Warrington
Professor Justin Du Bois, Andrew Hinman