Total Synthesis of (+)-Fastigiatine Liau, B. B.; Shair, M.* D. J. Am. … · 2014-02-05 · Total...
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Total Synthesis of (+)-Fastigiatine Liau, B. B.; Shair, M.* D. J. Am. Chem. Soc. 2010, ASAP. Harvard University Hypervalent λ 3 -Bromane Strategy for Baeyer-Villiger Oxidation: Selective Transformation of Primary Aliphatic and Aromatic Aldehydes to Formates, Which is Missing in the Classical Baeyer- Villiger Oxidation Ochiai, M.*; Yoshimura, A.; Miyamoto, K.; Hayashi, S.; Nakanishi, W.* J. Am. Chem. Soc. 2010, ASAP. University of Tokushima Wakayama University Short Literature Presentation 7/5/2010 Erika A. Crane
Transcript of Total Synthesis of (+)-Fastigiatine Liau, B. B.; Shair, M.* D. J. Am. … · 2014-02-05 · Total...
Total Synthesis of (+)-Fastigiatine!Liau, B. B.; Shair, M.* D. J. Am. Chem. Soc. 2010, ASAP.!
Harvard University!
Hypervalent λ3-Bromane Strategy for Baeyer-Villiger Oxidation: Selective Transformation of Primary Aliphatic and Aromatic
Aldehydes to Formates, Which is Missing in the Classical Baeyer-Villiger Oxidation
Ochiai, M.*; Yoshimura, A.; Miyamoto, K.; Hayashi, S.; Nakanishi, W.*! J. Am. Chem. Soc. 2010, ASAP.!
University of Tokushima!Wakayama University!
Short Literature Presentation! 7/5/2010!
Erika A. Crane!
Total Synthesis of (+)-Fastigiatine!
lycopodium!Clubmoss!
• The lycopodium alkaloids are a family of 201 quinolizine, pyridine or α-pyridone-type alkaloids isolated from over 54 different species of the clubmoss, lycopodium.!
• There are four classes of compounds: !
HN
Me
N
lycodinelycopodine
Me
N
O
fawcettimine
N
OH
Me
O
miscellaneous
HN
NH
Me(i.e. phlegmarine)
N
Me
N
O Me
Me
(+)-fastigiatine
Isolated in 1986 from lycopodium
fastigiatum in New Zealand !
Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752-772.!
Gerard, R. V.; MacLean, D. B.; Fagianni, R.; Jock, C. J. Can. J. Chem. 1986, 64, 943-949.!
N
Me
N
O Me
Me
Total Synthesis of (+)-Fastigiatine!
adds more strain to the molecule!!
HN
Me
N
N
Me
N
O Me
Me
lycodine (+)-fastigiatine
410
contains a highly substituted pyrrolidine ring!
N
Me
N
O Me
Me
Total Synthesis of (+)-Fastigiatine!
Contains 5 contiguous stereocenters!!
HN
Me
N
N
Me
N
O Me
Me
lycodine (+)-fastigiatine
HN
Me
N
N
Me
N
O Me
Me
lycodine (+)-fastigiatine
N
Me
N
O Me
Me
Total Synthesis of (+)-Fastigiatine!
N
Me
N
O Me
Me
(+)-fastigiatine
413
N
Me
HN
R 4
!
R'
Transannular Mannich Reaction
HN
N
R'H
MeH
R
1376 " 4
!13
7
6"
1,4-addition Bis-condensation
R'H
Me
H 4
!
13
7
6
"NH2
O
ONHR11
Me
13
7
MO O
NR
O
!11
OPO
NP
X
"
LiR'6
Retrosynthesis:!
N
Me
N
O Me
Me
NH
OO
EtO1.15 mol % KH, TMSEOH, THF
2. Boc2O, DMAP, NEt3, CH2Cl2 83% (2 steps)
NBoc
OO
TMSEO
O
Cl
(S)-epichlorohydrin
NBoc
OO
TMSEO
O O
MeMe
ILi•LiCu
O
OtBu
THF, – 78°C to 0°C93%
Total Synthesis of (+)-Fastigiatine!
4 steps! electrophillic !cyclopropane ring opening!
cuprate made in 7 steps from (R)-pulegone!
N
Me
N
O Me
Me
NH
OO
EtO1.15 mol % KH, TMSEOH, THF
2. Boc2O, DMAP, NEt3, CH2Cl2 83% (2 steps)
NBoc
OO
TMSEO
O
Cl
(S)-epichlorohydrin
NBoc
OO
TMSEO
O O
MeMe
ILi•LiCu
O
OtBu
THF, – 78°C to 0°C93%
NBoc
O
O O
Me
N3
1. Cs2CO3, I(CH2)3Cl, DMF2. NaN3, NaI, DMF, 65 °C3. TBAF, DBU, THF, 50 °C 89% (3 steps)
1. 20 mol % Mg(ClO4)2, MeCN, 60 °C
2. LiHMDS, THF, NsCl, 0 °C to rt, 89% (2 steps)
N
O
O O
Me
N3
NsNHNs
O O
MetBu-O
OLi1.
THF, – 78 °C
2. PPh3, PhH, 50 °C 88% (2 steps)
NtBu-O
O H
Total Synthesis of (+)-Fastigiatine!
4 steps!
cleaves the ethyl ester and decarboxylates!
epimerization facilitated easier characterization!
aza-Wittig Reaction!
cuprate made in 7 steps from (R)-pulegone!
N
Me
N
O Me
Me
Total Synthesis of (+)-Fastigiatine!
The aza-Wittig mechanism:!
phosphazene formation!
N
O
O O
Me
N3
Ns
NHNs
O O
Me
NtBu-O
O H
tBu-O
OLiO
O O
Me
N3
NHNs
O
O-tBu+ H+
PPh3
– N2
O
O O
Me
N
NHNs
O
O-tBu
PPh3
O O
Me
NHNs
N
OPPh3
CO2tBu
[2+2]
retro [2+2]
O O
Me
NHNs
N
CO2tBu
– O=PPh3
taut.
N
Me
N
O Me
Me
NHNs
O O
Me
NtBu-O
O HMe
HN
4
!
CO2tBu
136 "
NHNsO
H+
10
Me
H2N
!
CO2tBu
13 5"
HNO
Ns removal
Total Synthesis of (+)-Fastigiatine!
Initial End-Game Attempts:!
Same product obtained with the N-Boc group too!!
N
Me
N
O Me
Me
NHNs
O O
Me
NtBu-O
O HMe
HN
4
CO2tBu
136
NHNsOTHF/H2O
92%
HCl [7-endo-trig]7
Me
NCO2tBu6
NHNsHO
7
Me
HN
4
CO2tBu
13
NHNsO
[taut.]
Me
HN
4
CO2tBu
13
NHNsHO
16
[transannular aldol reaction]
1. K2CO3, MeI, DMF, 0 °C to rt; then PhSH, 0 °C to rt, 87%
2. CF3CH2OH, 80 °C, 85%
N
Me
HN
Me
CO2tBu
N
Me
N
O Me
Me
(+)-fastigiatine
1. p-TsOH•H2O, PhH, 80 °C, 95%
2. Ac2O, Et3N, CH2Cl2, 85%
N
Me
HN
Me
CO2tBu
Total Synthesis of (+)-Fastigiatine!
Selectivity of axial attack
stereoelectronically controlled by C16
methyl group!
N
Me
N
O Me
Me
[3+3]!
pentacyclic core assembled!!
retro-aldol reaction!transannular Mannich reaction!
15 steps!~30% overall yield!
Hypervalent λ3-Bromane Oxidation!
The Baeyer-Villiger Oxidation, 1899:!
180° dihedral angle!!
HOMO of σ(C–R3) donates into σ*(O–O)!
when R3 > R2!
classical Criegee intermediate!
the group that best stabilizes a positive charge will migrate!!
R1
O
OO
H R2 R3
O
R1
O
OO
R2 R3
OH
OO R1
OR3
R2 OH
R3
R2 OO
O
R1
O
H
– R1CO2HR2
O
OR3
peracid ketone
ester
R1
O
OO
H R2 H
O
R1
O
OO
R2 H
OH
OO R1
OH
R2 OH
H
R2 OO
O
R1
O
H
– R1CO2HR2
O
OH
peracid aldehyde
carboxylic acid
Hypervalent λ3-Bromane Oxidation!
The Baeyer-Villiger Oxidation, 1899:!
180° dihedral angle!!
HOMO of σ(C–H) donates into σ*(O–O)!
classical Criegee intermediate!
the group that best stabilizes a positive charge will migrate!!
R1
O
OO
H R2 H
O
R1
O
OO
R2 H
OH
OO R1
OR2
H OH
R2
H OO
O
R1
O
H
– R1CO2HH
O
OR2
peracid aldehyde
formate ester
Hypervalent λ3-Bromane Oxidation!
The Baeyer-Villiger Oxidation, 1899:!classical Criegee
intermediate!
When R2 is very electron rich or α-branched, can get formation of formate ester!
Hypervalent λ3-Bromane Oxidation!
Dakin Oxidation, 1909:!
O
R2R1 R1
O R2
OR1
OHperoxide
or peracidbasic
hydrolysis
R1 = OH, NH2, alkyl, NHR; R2 = H, alkyl
Hypervalent λ3-Bromane Oxidation!
Classical nucleophillic addition pathway to Criegee intermediate:!
Ligand exchange pathway to Criegee intermediate:!
R1
O
OO
H R2 R3
OO
O R1
OR3
R2 OH
– R1CO2H R2
O
OR3
R2 R3
OO
OBr
FR3
R2 OH
– ArBr R2
O
OR3
H2O
R2 R3
HO OH
BrF F
CF3
Ar
α-hydroxyalkoxy-λ3-bromane!
Hypervalent λ3-Bromane Oxidation!
p-trifluoromethylphenyl(difluoro)-λ3-bromane!
Ochiai, M. Topics in Curr. Chem. Wirth, T., Ed.; Springer: Berlin, 2003; Vol. 224, p 5.!
BrF3C
F
F
• Tri- and pentavalent halide species are used in ligand exchange reactions.!
• They are used to generate highly reactive intermediates which can then be displaced to form carbenes, nitrenes, cations or arynes under mild conditions.!
• They also can oxidize alcohols, amines, sulfides, alkenes, alkynes and carbonyl compounds.!
• When these activated ligands leave, they do so through a reductive elimination.!
• Aryl-λ3-bromanes are 106 better nucleofuges than aryl-λ3-iodides.!
Hypervalent λ3-Bromane Oxidation!
Can oxidize straight-chain aliphatic and aromatic aldehydes to the corresponding formates!!
R H
O
H
O
OR
BrF F
CF3
1.5 equiv.2 equiv. H2O
CH2Cl2, 0 °C R
O
OH
BuCHO 89% 5%
BuCHO 0% 100%With mCPBA:
n-C9H19CHO 80% 6%
c-C6H11CHO 85% 0%
PhCHO 91% 0%
p-ClC6H4CHO 62% 0%
p-ClC6H4CHO 0% 85%With mCPBA:
p-MeC6H4CHO 65% 0%
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