TotalSynthesisof(±)Neofinaconitine David Y. Gin, JACS...
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Total Synthesis of (±) Neofinaconitine David Y. Gin, JACS, 2006 , 128, 8734–8735 1 1) TBSOTf, NEt 3 2) KOH, EtOH 3) B 4) H 2 , Pd/C 5) MeNHOMe HCl, AlCl 3 6) TBAF 7) HBr/AcOH 8) Vinylmagnesiumbromide 9) KHMDS, TBSOTf A 2-9 C O MeO OTIPS + What is a key orbital feature of the cyclopropene that facilitates this transformation? Draw a transition state to explain the selectivity of the reaction on steric grounds! TBSO OTIPS MeO TBSO MeO OTIPS OMe O P EtO O EtO B MeO Br TBSO H dr: 1:1.6 Significant HOMO portion on the cyclopropene sp 3 - carbon! secondary orbital interaction possible, endo- selective! This orientation of all possible con- formations is least sterically demanding, leading to regioselectivity! minor diasteromer, separated after step 5 (39% over 5 steps) TBSO MeO OTIPS 2) Hydrolysis of silyl enol ether to ketone 3) HWE-olefination (not diastereoselective) 4) Hydrogenation of the alkene 5) Conversion of methyl ester to Weinreb amide 6) TIPS deprotection 7) exo-methylene generation 8) Weinreb ketone synthesis 9) TBS-enol ether formation MeO OH 2 Br O N MeO Me Step 7:
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Transcript of TotalSynthesisof(±)Neofinaconitine David Y. Gin, JACS...
Total Synthesis of (±) NeofinaconitineDavid Y. Gin, JACS, 2006, 128, 8734–8735
11) TBSOTf, NEt3
2) KOH, EtOH3) B4) H2, Pd/C5) MeNHOMe HCl, AlCl36) TBAF7) HBr/AcOH8) Vinylmagnesiumbromide9) KHMDS, TBSOTf
A
2-9
C
O
MeOOTIPS
+
What is a key orbital feature of the cyclopropenethat facilitates this transformation?Draw a transition state to explain the selectivity ofthe reaction on steric grounds!
TBSO
OTIPS
MeO
TBSO
MeO OTIPS
OMe
O
PEtO
O
EtOB
MeO
Br
TBSO
H
dr: 1:1.6
Significant HOMOportion on thecyclopropene sp3-carbon! secondaryorbital interactionpossible, endo-selective!
This orientationof all possible con-formations is leaststerically demanding,leading to regioselectivity!minor diasteromer,
separated after step 5(39% over 5 steps)
TBSO
MeO OTIPS
2) Hydrolysis of silyl enol ether to ketone3) HWE-olefination (not diastereoselective)4) Hydrogenation of the alkene5) Conversion of methyl ester to Weinreb amide6) TIPS deprotection7) exo-methylene generation8) Weinreb ketone synthesis9) TBS-enol ether formation
MeO OH2
Br
O
NMeO
MeStep 7:
10 10) SnCl4, MS 4Å
D
11-14
E
11) OsO4, NMO then Pb(OAc)412) DBU13) Tf2NH (pKa ca 0.3 in MeCN)14) CAN, H2O, then MsCl, NEt3
What important substituent of bicycle C is crucialto the diastereoselectivity of this reaction?
C +EtN
O
OMe
O
Br
MeO
Br
N
H
CO2MeO
Et
Br
H
O
OMeO
NEtO
MeO2CO
Br
OMeO
O
N
Br
O
CO2Me
H
Et
MeO
Br
TBSO
H
EtN O
OMe
OBr
Bromine shields otherside of bicylce, leadingto formation of D in87% yield!
11) Dihydroxylation + diol cleavage to ketone12) Bromide elimination to enone13) Transannular Mannich-cascade14) Oxidation to allyic cation, water quench,mesylation and subseqent elimination;
Mechanisms of steps 13+14 see below!
15-1815) AIBN, Bu3SnH16) TMSOTf, NEt317) PhSeCl18) NaIO4, H2O
19-23
19) H2, Pd/C20) excess NaBH421) t-BuOK, MeI22) LiBH423) CrO3, 0.5N H2SO4
E
OMeO
NEtO
MeO2CO
HO
H
MeO
NEtHOO
HO
G
OMe
OMe
H
15) Radical generation at the bromine position,1,4-addition onto enone16) TMS enol ether formation17) -Selenylation of silyl enol ether18) Selenoxide elemination with concomittant1,4-addition of water to putative strained bridge-head enone
MeO
NEtO
MeO2CO
H
SeOPh
O
syn-Elimination
OMeO
NEtO
MeO2CO
HStep 18:
O
19) Enone hydrogenation to ketone20) Stereoselective reduction of both ketones21) Methylation of both secondary alcohols22) Ester reduction23) Decarboxylative hydroxylation to accesstertiary alcohol (Can. J. Chem 2006, 84, 1167)
OMeO
NEtO
MeO2CO
Step 15:
24-2624) LAH25) H, DMAP, NEt326) Zn, HCl
G
H
NO2 O
Cl
MeO
NEtO
HO
OMe
OMe
H
ONH2
(±) Neofinaconitine
24) Reduction of amide to amine25) Acylation of tertiary alcohol26) Reduction to aniline
OMeO
O
N
Br
O
CO2Me
H
EtN
H
CO2MeO
Et
Br
H
O
OMeO H
B
N
H
CO2MeO
Et
Br
O
OMeOH
H
H
HB
Iminium/ tetra-hydro pyrane
formationD
Tf2NHTransannular
Mannich reaction
CAN
Mechanisms for steps 13 and 14
OMeO
O
N
Br
O
CO2Me
H
Et
Allylic cation getsquenched by water,
alcohol gets mesylated
H2O, MsCl
O
N
Br
O CO2Me
H
EtOMs
OHOMe
Elimination
OMeO
O
N
Br
O
CO2Me
H
Et
E
OMeO
NEtO
MeO2CO
Br
rotate aroundthis bond for
alternative drawing
