Carbenes and Nitrenes: Application to the Total Synthesis of (–)-Tetrodotoxin Effiette Sauer March...
49
Carbenes and Nitrenes: Carbenes and Nitrenes: Application to the Total Application to the Total Synthesis of Synthesis of (–)-Tetrodotoxin (–)-Tetrodotoxin Effiette Sauer March 18 th 2004 Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. O O O OH OH OH HO HN NH H 2 N HO
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Transcript of Carbenes and Nitrenes: Application to the Total Synthesis of (–)-Tetrodotoxin Effiette Sauer March...
Carbenes and Nitrenes: Application Carbenes and Nitrenes: Application to the Total Synthesis of to the Total Synthesis of
(–)-Tetrodotoxin(–)-Tetrodotoxin
Effiette Sauer
March 18th 2004
Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.
O O
O
OH
OH
OH
HO
HN NH
H2N
HO
What are Carbenes? Nitrenes?What are Carbenes? Nitrenes?
• Neutral, divalent carbon species containing six valence electrons
• Neutral, monovalent nitrogen species containing six valence electrons
Highly Highly reactivereactive
Electron Electron deficientdeficient
CX
Y
N X
2
Carbene FormationCarbene Formation
• Diazoalkanes
• Halides
R2C N N R2C N Nhv or heat
R2C + N2
• Sulfonylhydrazones
R2C N NH R2C N NR2C N NSO2ArSO2Ar
Base
3
Cl
C
ClCl
BaseCl
CH
ClCl
alpha-elimination
+ ClCl2C
Reactions of CarbenesReactions of Carbenes
• Addition reactions
CH2
CH2CH2+
CH2+RnX Y RnX CH2 Y
• Ylide formation
• Insertion reactions
4
CH2RnX RnX CH2+
Singlet and Triplet StatesSinglet and Triplet States
X C Y X NX NX CY
• sp2 hybridized carbon
• non-bonding electrons have opposite spin - occupy an sp2 orbital
• XCY angle 100-110°
• sp2 hybridized carbon (or sp?)
• non-bonding electrons have same spin – occupy an sp2 and p orbital
• XCY angle 130-150°
TripletSinglet TripletSinglet
5
Singlet and Triplet StatesSinglet and Triplet States
X C Y X NX N
TripletSinglet TripletSinglet
X CY
1s
sp2
p
p
sp2
1s
sp2
p
p
sp2
6
Relative Stability of Singlet and Triplet StatesRelative Stability of Singlet and Triplet States
• Unless, added stabilization possible (X=O, N, S, halogen etc.)
• Triplet more stable than singlet (R=H, alkyl)
R C R
R C R
~ 8 kcal
7
Triplet
Singlet
X C R X C R X C R
Mode of Preparation – Singlet vs. TripletMode of Preparation – Singlet vs. Triplet
Ionic Mechanism:
Singlet
Photolysis:
Singlet Triplet
Cl
CH
ClCl
B:
Cl
C
ClCl
CClCl
8
C N NH
HC
H
HC
H
H
hv
Singlet Carbenes React Stereospecifically Singlet Carbenes React Stereospecifically
FMO interactions for cyclopropanation with singlet carbene:
C
HH
R
R H
H R
R H
H
C
HH
C
R
R H
H
H HC
HH
R
R H
H
R
R H
H
H
H
Mechanism:
ConcertedConcerted StereospecificStereospecific 9
Triplet Carbenes React StereoselectivelyTriplet Carbenes React Stereoselectively
Cyclopropanation with triplet carbenes - radical mechanism:
Two pathwaysTwo pathways Stereoselective Stereoselective
H
R
H
R
CHH
RRC
H H
RRC
H H H H
H H H H HH
RR
RHC
H H
R H
RHC
H H H H
R H HR
RH
slow
spin flip
slow
spin flip
free rotation mixture of isomers
10
Nitrene FormationNitrene Formation
• Azides
• Iminoiodanes
N N Nhv or heat
+ N2R R N
hv or heat+RO2S NAr I
N SO2R
ArI
• Sulfonamides
base+RSO2NH2 PhI(OAc)2 PhI NSO2R
11
Reactions of NitrenesReactions of Nitrenes
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.
• Ylide formation2
• Insertion reactions1
• Addition reactions1
N3+O
CO2EtN CO2Et
hv
hv
N3+O
CO2EtNHCO2Et
12
NN
N3 NN
Nhv
Free Carbenes/Nitrenes - Too ReactiveFree Carbenes/Nitrenes - Too Reactive
1 Zurawski, B.; Kutzelnigg, W. J. Am. Chem. Soc. 1978, 100, 2654.2 Richardson, D. B..; Simmons, M. C.; Dvoretzky. I. J. Am. Chem. Soc. 1961, 83, 1934.
• Free carbenes/nitrenes are highly reactive species → low activation energy for product formation1:
CH2
CH2CH2+
• Generally too reactive to afford useful selectivity2:
~ 0 kcal A.E.
H3CCH2
H2C
CH2
H2C
CH2
CH3 CH2N2 H3CCH2
H2C
CH2
H2C
CH2
CH3
25% 13%
38% 24%
13
Moderation of ReactivityModeration of Reactivity
• Intramolecular, rigid systems
• Rearrangement reactions (e.g. Wolff, Curtius)
N
Nhv
48%
Majerski, Z.; Hamersak, Z.; Sarac-Arneri, R. J. Org. Chem. 1988, 53, 5053.
Concerted or stepwise depending on conditions
14
hv or heat
R
O
C C OR
H
R1OHO
OR1
RNN
Moderation of ReactivityModeration of Reactivity
• Binding of carbene/nitrene with a metal
CX
YLnM
CarbenoidCarbenoid Nitrenoid Nitrenoid
NX
LnM
• Tune reactivity by changing L, M, X, Y
• Different species for 1) addition 2) ylide
formation3) insertion reactions 4) and more (e.g. RCM)
15
Generation of the MetalloidGeneration of the Metalloid
• Treat carbene/nitrene precursor with transition metal ion
• General mechanism
LnM → electrophilic → vacant coordination site
N2 C XY
LnM
LnM CX
YS
SCXY
N2
R2C N N N N NR IPhRO2SN
16
Tuning the Catalyst for CH InsertionTuning the Catalyst for CH Insertion
CX
YLnM
X, Y = acceptor (EWG) donor (EDG) or H
σ acceptor?π donor?
• Must tune electrophilicity of carbon atom to react selectively with inert CH bonds
CX
YLnMC
X
YLnM
lone pair into empty d orbital
d orbital into empty p orbital
σ bond π back bond
17
Tuning the Catalyst for CH InsertionTuning the Catalyst for CH Insertion
CX
YLnM
X, Y = acceptor (EWG) donor (EDG) or H
σ acceptor?π donor?
• Must tune electrophilicity of carbon atom to react selectively with inert CH bonds
18
σ acceptor π donor Properties
+ + strong M=C bond; nucleophilic
- + moderate M=C bond; nucleophilic
+ - moderate M=C bond; electrophilic
- - weak M=C bond (~ free carbene); electrophilic
The Early DaysThe Early Days
• Early investigations focus on copper catalysts (e.g. CuSO4, CuOTf2) → synthetic use confined to rigid systems1,2
1 Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361. 2 Burns, W.; McKervey, M. A.; Mitchell, T. R. B.; Rooney, J. J. J. Am. Chem. Soc. 1978, 100, 906.
O
N2HC
O
CHN2 OOtoluene, ruflux
CuSO4
19
The Early DaysThe 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
3 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.
Me
AcO
Me
H
HAcO
Me
AcO
Me
H
HAcO
Me
H
O70% with Rh2(OAc)4
trace with CuSO4
Me
O
CHN2
20
Dirhodium (II) CatalystsDirhodium (II) Catalysts
Rh Rh
O O
O O
O O
O O
Vacant site for carbene binding/
diazo decomposition Unique dirhodium bridge one Rh binds carbene, other assists insertion1,2
Electron withdrawing ligands increase
electrophilicity
1 Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.2 Pirrung, M. C.; Liu, H.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2002, 124, 1014. 21
Insertion MechanismInsertion Mechanism
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
IIIIRh Rh
O O
Me
A
CH
CB
C
A
CH
CB
YX
CC
A
HY
B
XC
Rh Rh
O O
Me
Rh Rh
O O
Me
Rh Rh
O O
Me
C
C N2
N2
C
X Y
N2
XY
X
Y
IIII
IIII
IIII
Insertion MechanismInsertion Mechanism
Rh Rh
O O
Me
C
A
CH
CB
YX
Rh Rh
O O
Me
C
A
CH
CB
YX
• 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
Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
• Role of dirhodium bridge is two-fold→ Enhances electrophilicity of carbon→ Assists in Rh-C cleavage
23
Insertion MechanismInsertion Mechanism
Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181. 24
Rh Rh
O O
Me
A
CH
CB
C
A
CH
CB
YX
CC
A
HY
B
XC
Rh Rh
O O
Me
Rh Rh
O O
Me
Rh Rh
O O
Me
C
C N2
N2
C
X Y
N2
XY
X
Y
IIII
I III
I III
Trends in SelectivityTrends in Selectivity
Rh Rh
O O
Me
C
A
CH
CB
YX
Build-up of positive charge in transition state → implications for selectivity
• 3° > 2° > 1°
• adjacent heteroatoms favour insertion
• EWGs hinder insertion
25
Trends in SelectivityTrends in Selectivity
23 1
1 Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686. 2 Adams, J; Spero, D. M. Tetrahedron 1991, 47, 1765. 3 Wang, P.; Adams, J. J Am. Chem. Soc. 1994, 116, 3296.
E
O
N2
O
E E
O
Rh2(OAc)4
84%
+
O
O O
O
O
O
Rh2(OAc)4
40%CHN2 +
Rh2(OAc)4
99%+
OMeO
AcO
O CHN2
OMeO
AcOO
MeO
AcO
O O
26
Trends in SelectivityTrends in Selectivity
1 Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686. 2 Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995, 321.
O
O
N2
OTIPS
O
O
OTIPS
Rh2OAc4
82%
Five membered ring not observed
Rh Rh
O O
Me
C
H C
XB
A
Y
→ steric, electronic and conformational influences may override this preference2
• Five membered rings form preferentially
Chair-like t.s. gives five
membered ring product1
27
Trends in SelectivityTrends 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
lower energy intermediate later TS more charge build-up greater selectivity
L4Rh2 CR2
Product
C
ACHC
B
YX
L4Rh2
28
Trends in SelectivityTrends in Selectivity
Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E. J. Am. Chem. Soc. 1993, 115, 958.
OH
O
N2
O O
"Rh"
56-96%+
Rh2(pfb)4 32 68
Rh2(OAc)4 53 47
Rh2(acam)4 >99 <1
A
B
A B
reactivityreactivity
selectivityselectivity Rh2(pfb)4 Rh2(OAc)4 Rh2(acam)4
29
Rh Rh
O O
C3F7
Rh Rh
O O
CH3
Rh Rh
O N
CH3
Trends in Selectivity – in SummaryTrends in Selectivity – in Summary
Rh Rh
O O
Me
C
A
CH
CB
YX
• Preference for most electron rich CH bond
• Five-membered ring formation preferred
• Enhanced selectivity by decreasing reactivity of carbenoid
30
What about those Nitrenoids?What about those Nitrenoids?
• Certain Fe, Mn, and Ru porphyrin complexes catalyze CH insertion1
1 Yu, X.; Huang, J.; Zhou, X.; Che, C. Org. Lett. 2000, 2, 2233. 2 Au, S.; Huang, J.; Yu, W.; Fung, W.; Che, C. J. Am. Chem. Soc. 1999, 121, 9120.
NHTs
PhI NTs+
78%
NMnN
NN
CO C6F5
C6F5
C6F5
C6F5
• Mechanistic studies on Ru(Por)(NTs)2 suggest a radical intermediate2
NRuN
NN
N
NTs
Ts HCR3
31
Good Ol’ RhodiumGood Ol’ Rhodium
• Rhodium was initially ignored – gave undesired insertion products (!)
• In 2001, Du Bois capitalizes on Rhodium’s preference for insertion1
1 Du Bois, J.; Espino, C. G. Angew. Chem. Int. Ed. 2001, 40, 598.
O
O
NH2(S)
HNO
O
no loss of eeas above
72%
O
HN O
O
O
NH2
Rh2(OAc)4, PhI(OAc)2, MgO
DCM, 40 C, 12 hr°
86%
• Reaction is stereospecific
32
(–)-Tetrodotoxin(–)-Tetrodotoxin
• 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
O O
O
OH
OH
OH
HO
HN NH
H2N
HO
1 Tahara, Y. J. Pharm. Soc. Jpn. 1909, 29, 587. 33
(–)-Tetrodotoxin(–)-Tetrodotoxin
• 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.
O O
O
OH
OH
OH
HN NH
H2N
OO O
O
OH
OH
OH
HO
HN NH
H2N
HO
34
RetrosynthesisRetrosynthesis
6 membered ring desired
O O
O
OH
OH
OH
HO
HN NH
H2N
HO
OH OH
O
OH
OH
OH
HO
H2N NH
H2N
OOHHO
OH
OHHO
O
HHO
O2C
HN
NH2
NH
self-
assembly
CH amination
ORRO
OR
ORRO
HCO2R
O
ONH2
(RO)2HC
RO N2
OR OR O
O
ORRO
RO
H
55
66
CH insertion
O
H6
65
5
35
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
NMe2
O
OH
O
O
H
O
OTBS
O
O
BnOOBn
O
O OH
O
O
O
OHO
O
BnOOTBS
2) 2,2-DMP, PTSA THF, 60 °C, 84%
1) TBSCl, pyridine 100 °C, 86%
2)DIBAL, nBuLi THF, HMPA
O
O
O
O
O
O
BnOOTBS
OBnNaOAc, THF
12:1 syn:anti
90% 2 steps
O
O
OH
OHHO
OH
aq. H2O2
Na2CO3
70%
O
O
HO
HO
1) Me2NH MeOH, 0°C
36
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
O
O
O
OHO
O
BnOOTBS
O
O
O
OPivO
O
OHOTBS
O
O
O
OPivO
O
OTBSN2
1) tBuCOCl, pyr
THF, 60 °C 95%
2) H2, Pd/C
THF, 88%
1) (COCl)2
2) CH2N2, DCM
70% 2 steps
cat. DMF, THF
O
O
O
OPivO
O
OTBSN2
O
O
O
OPivO
O
OTBS??
Double bond to favour six
membered ring
Change PG if need be
37
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
Catalyst Solvent % A % B
Rh2(oct)4 CH2Cl2 < 10 30
Rh2(oct)4 CCl4 45 45
Rh2(cap)4 CCl4 45 15
Rh2(tpacam)4 CCl4 > 95 ---
A B
O
O
O
OPivO
O
OTBSN2
O
O
O
OPivO
O
OTBScatalyst
solvent, rt
O
O
OPivO
O
TBS O
O
+
B via:
O
O
OPivO
O
RL4Rh2
TBS
38
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
Catalyst Solvent % A % B
Rh2(oct)4 CH2Cl2 < 10 30
Rh2(oct)4 CCl4 45 45
Rh2(cap)4 CCl4 45 15
Rh2(tpacam)4 CCl4 > 95 ---
A B
O
O
O
OPivO
O
OTBSN2
O
O
O
OPivO
O
OTBScatalyst
solvent, rt
O
O
OPivO
O
TBS O
O
+
B via:
O
O
OPivO
O
RL4Rh2
TBS
38
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
Catalyst Solvent % A % B
Rh2(oct)4 CH2Cl2 < 10 30
Rh2(oct)4 CCl4 45 45
Rh2(cap)4 CCl4 45 15
Rh2(tpacam)4 CCl4 > 95 ---
A B
O
O
O
OPivO
O
OTBSN2
O
O
O
OPivO
O
OTBScatalyst
solvent, rt
O
O
OPivO
O
TBS O
O
+
Rh Rh
O N
38
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
A B
O
O
O
OPivO
O
OTBSN2
O
O
O
OPivO
O
OTBScatalyst
solvent, rt
O
O
OPivO
O
TBS O
O
+
Rh Rh
O NH
CPh3
Catalyst Solvent % A % B
Rh2(oct)4 CH2Cl2 < 10 30
Rh2(oct)4 CCl4 45 45
Rh2(cap)4 CCl4 45 15
Rh2(tpacam)4 CCl4 > 95 ---
38
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
O
O
O
OPivO
O
OTBSO
O
O
OPivO
HO
OTBS
OH
OH
OH
OH
O
O OPiv
HO
O OPiv
H
O
O
O
O
O
TBSO
O
O
O
PivOH
OH
O
TBSO
O
HO
OH
CO2Me
OPivH
BH3·NH3
DCM, MeOH
75% 2 steps
H2, 1200psi
Rh-C
TFA, MeOH
2,2-DMP, PTSA
THF
77% 2 steps
39
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
O
O OPiv
H
O
O
O
O
H
O
O
O
O
O
OPiv
H
O
O
O
O
OPiv
H
O
O
O
O
OPiv
O
H
O
O
O
O
OPiv
O
O O
OOO
OPivCONMe2
HOAc
1) Me2NH, THF
2) TPAP, NMO
4Å MS, DCM
Zn, TiCl4, CH2I2
cat. PbCl2, THF
72%
94%
Ph2Se2, PhIO2, pyr
C6H6, reflux, 70%
MgBr
THF, CuI
83%
Me2NOC Me2NOC
Me2NOCMe2NOC
40
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
H
O
O
O
O
OPiv
O
Me2NOC
H
O
O
O
O
OPiv
HO
Me2NOC
O
O
O
OtBuNH2·BH3
DCE
77% 2 steps
O
HOPiv
O
tBuCO2H
200 °C
C6H5Cl
NaOMe
THF/MeOH
78% 2 steps
O
Cl3C NC
O
DCM
Zn
MeOH
93% 2 steps
O
O
O
O
O
HOH
O
O
O
O
O
O
HO
OHN CCl3
O O
O
O
O
O
O
HO
O
NH2
O 41
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
Only product
Rh Rh
O O
CPh3
Rh2(tpa)4
OO
OO O
O
O
O
NH2
H
OO
OO O
OO
O
NRh2(tpa)4, PhI(OAc)2
MgO, DCE, 40 °C
10%
O
O
O
O
O
HO
O
O
NH2
OO
OO O
O
NH
O
O
OO
OO O
O
O
O
NH2
H
H2, Pd/C
EtOAc, 96%
Rh2(tpa)4, PhI(OAc)2
MgO, DCE, 40 °C
20%
42
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
O
O
O
O
O
HOCONH2
O
O
O
O
O
O
HOCONH2
O
O
O
O
O
O
HOCONH2
O
C6H6, 65 °C, 77%
O3, then NaBH4
DCM/MeOH83%
MsCl, pyr
DCE, 87%
O
O
O
O
O
O NH
O
O
Rh2(tfacam)4
PhI(OAc)2, MgO
O
O
O
O
O
O NH
O
O
O
O
O
O
O
O NHBOC
OH
1) NaSePh THF/DMF 77%
2) mCPBA, pyr DCE, 55 °C 98%
Cl
HO Cl
1) BOC2O, TEA DMAP, THF
2) K2CO3 THF/MeOH 84% 2 steps
Rh Rh
O N
CF3
43
O O
O
OH
OHOH
HO
HN NH
H2N
HOSynthesis of (–)-TetrodotoxinSynthesis of (–)-Tetrodotoxin
O
O
O
O
O
O NHBOC
OH
O
O
O
O
O
O NH2
OH
O
O
O
O
O
O NOH
BOCHN NHBOC
OH
OH
OH
OH
O
O
O
NH
OHH2N NH2
H2O, 100 °C
95%
BOCN C NBOC
MeCN/DCM
80%
1) O3 then DMS2) aq. TFA
65 % 2 steps
O O
O
HN NH
H2N
HO
OH
OHOH
HOO OH
O
H2N NH
H2N
O
OH
OHOH
HO
44
O O
O
OH
OHOH
HO
HN NH
H2N
HOConclusionsConclusions
• 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
AcknowledgmentsAcknowledgments
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
