Chase Bruggeman CEM 852 Synthesis Proposal Final...CEM 852 Synthesis Proposal. Final. 1....
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Chase Bruggeman CEM 852 Synthesis Proposal Final 1
Transcript of Chase Bruggeman CEM 852 Synthesis Proposal Final...CEM 852 Synthesis Proposal. Final. 1....
Chase Bruggeman
CEM 852 Synthesis Proposal
Final 1
Characellide A
Org Lett 2019, 21, 246-251 Thomas et al.2
Characellide A
• Characella pachastrelloides• Deep sea sponge (below 500m)• Found near Ireland
• Characellides A-D• Metabolites in sponge• A & B show anti-inflammatory
behavior• Related metabolites show
antibacterial potential
3Org Lett 2019, 21, 246-251 Thomas et al.
Retrosynthesis: Threonine combines three building blocks
O OH2N
O
HOOH
NH2
O
NH2OO O NH
H2N
O
HOOH
NH2
O NH2
O
NH
O
NH
OH
O
O
HO O
O
NH
OH
O
HO
O
HN
O
O
O-
NH3+HO
O
1
2
3D-Threonine
Org Lett 2019, 21, 246-251 Thomas et al.4
Block 1
NH
OH
O
HO
O
HN
O
O
NH
OH
OH
HO
NH2
O
Org Lett 2019, 21, 246-251 Thomas et al.5
Boc-Asparagine added to Tyrosine, then amide group converted to alcohol
+H3NO
OH
O
L-Tyrosine methyl ester HCl
LiAlH4 (3 eq)
CH2Cl2, rtCl
-
H2NOH
OH
H2N
O
O-
+H2NBoc
O
Boc D-Asparagine (1 eq)CH2Cl2, 4 Å MS, rt N
H
OH
OH
H2N
O
HNBoc
O
DMF dimethyl acetal (3 eq)MeOH, rt, 1 h
N O
O
NH
OH
OH
O
O
HNBoc
OLiAlH4
(3 eq)
CH2Cl2, rtNH
OH
OH
HNBoc
OHO
Tet Lett 1997, 38, 2367-2368, Brocchetta et al.
HCl (5 mol %)CH2Cl2, rt N
H
OH
OH
NH2
OHO
Org Lett 2019, 21, 246-251 Thomas et al.6
Block 2O
HN
O
OCHPh2
CF3
O
NH2O
Org Lett 2019, 21, 246-251 Thomas et al.7
Propargyl alcohol transformed to terminal iodide to prepare for coupling
HOKH (2.5 eq)
APA, rt
NH2NH2
HO
O
DHP (1.5 eq)
Pyridine · TsOH (0.1 eq)CH2Cl2, rt
OO
(i-Bu)2AlH (1 eq)CH2Cl2, rt
I2 (1 eq)
THF, -50 °C
OO
I
Pyridine · TsOH (0.4 eq)EtOH, 45 °C
HO
I
Org Lett 2019, 21, 246-251 Thomas et al.8
Nerol converted to chiral Block 2 precursor with Sharpless epoxidation
Nerol
(citrus)
OH
D (-) diethyl tartrate (6 mol %)Ti(Oi-Pr)4
(5 mol %)
t-BuOOH (2 eq)CH2Cl2, 4 Å MS, -20 °C OH
O
Et3N (1 eq)TsCl (1 eq)
CH2Cl2, -20 °C OTsO
O
OO
O
OH
OH
Org Lett 2019, 21, 246-251 Thomas et al.9
LiAlH4 (2 eq)
CH2Cl2, -20 °C OH
HG-II (5 mol %)C2H4
(10 eq)
Et2O, -20 °C OH
H
RuPhPCy3
NN
Cl
Cl
OH
=
Palladium catalyzes ring forming/coupling, then terminal alcohol transformed to imine
OH
Pd2(dba)3
NaOt-BuDPE Phos OH
O
HO
I
NO
OK N O
OK
Potassium azodicarboxylate (5 eq)HOAc (10 eq)CH2Cl2, -40 °C
THF, 65 °C
NO
TEMPO (0.1 eq)NaOCl (1 eq)
NaHCO3 (1 eq)
CH2Cl2, rt
OH
O
O
O
NH2
benzhydrylamine (1.5 eq)pyrrolidine (0.1 eq)4 Å MS, CH2Cl2, rt
N
O
CHPh2
Org Lett 2019, 21, 246-251 Thomas et al.10
Chiral aziridination afforded by boron catalyst
Syn Lett 2009, 17, 2715-2739 Wulff et al.
N
O
Ph2HC
O
O
N2
OO
ON
CHPh21.1 eq
(R)-VANOL-B(OPh)3 (5 mol %)
toluene, 25 °C, 24 h
PhPh OH
OH
(R)-VANOL
Org Lett 2019, 21, 246-251 Thomas et al.11
Aziridine opened, then ester re-formed
Org Biomol Chem 2010, 8, 4266-4273 De Kimpe et al.
OO
ON
CHPh2 LiAlH4 (2.2 eq)
microwaveTHF, 130 °C, 2 h
O
HN
HO
CHPh2
O2 (0.2 bar)
Pt/C (5%)
pH 9H2O, 60 °C
F3CCH2I (1 eq)THF, rt O
HN
O
OCHPh2
CF3
Org Lett 2019, 21, 246-251 Thomas et al.12
Block 3
O OH2N
O
HOOH
NH2
O OH2N
O
OO
NHBoc
OMe
MeO
Na
Org Lett 2019, 21, 246-251 Thomas et al.13
Glucosamine aldehyde group protected with dithiane
O OHOH
HOOH
NHBoc
OH
OHHO
OHBocHN
HO HS SH
dithiane (1.2 eq)
Y(OTf)3 (5 mol %)
MeCN, rt
OH
OHHO
OHBocHN
HS
S
Tet Lett 2004, 45, 2339-2341 Surya Kanta De
Org Lett 2019, 21, 246-251 Thomas et al.14
Oxidation of primary alcohol allows amide to be formed
Tetrahedron: Asymmetry 1994, 5, 2475-2484 Johnson et al.
OH
OHHO
OHBocHN
HS
S
O2 (0.2 bar)
Pt/C (5%)
pH 9H2O, 60 °C
O
OHHO
OHBocHN
HS
S
HO
1) MeI (1 eq)NaHCO3
(2 eq)
MeCN, 0 °C
O
OHHO
OHBocHN
HS
S
H2N
2) NH3 (1 eq)
MeCN, 0 °C
Org Lett 2019, 21, 246-251 Thomas et al.15
Dithiane removal allows ring to close
HgO (1 eq)H2O/THF, rt
O
OHHO
OHBocHN
H
H2N
O
O OHH2N
O
HOOH
NHBoc
O
OHHO
OHBocHN
HS
S
H2N
Separatediastereomers +
recycle by re-equilibratingto racemic mixture
O OHH2N
O
HOOH
NHBoc
O OHH2N
O
HOOH
NHBoc
Org Lett 2019, 21, 246-251 Thomas et al.16
Amino sugar protected to expose pyranylalcohol group
O OHH2N
O
HOOH
NHBoc
camphorsulfonic acid (5 mol%)2,2,3,3-tetramethoxy butane (1.2 eq)
trimethyl orthoformate (4 eq)MeOH, reflux, 12 h
OHO3S O OHH2N
O
OO
NH2
OMe
MeO
82%
Boc2O (1.5 eq)DMAP (1 eq)
MeCN, rt
O OHH2N
O
OO
NHBoc
OMe
MeO
O
O trimethyl orthoformate (2.4 eq)H2SO4
(cat.)
MeOH, reflux, 20 h
OO
OOO
O O
2,2,3,3-tetramethoxy butane53%JOC 1996, 61, 3897-3899 Frost et al.
diacetyl
(butter)
Org Lett 2019, 21, 246-251 Thomas et al.17
Threonine joins Block 2 with Block 1, followed by methylation and oxidation
O-
NH3+
OH O
D-Threonine (1 eq)CH2Cl2, -25 °C to rtO
HN
O
OCHPh2
CF3O
+H2N
NH
OCHPh2O
-
HO
ONH
OH
OH
NH2
OHO
(1 eq)CH2Cl2, rt
O
HN
NH
OCHPh2NH
HO
ONH
OH
OH
OHO
O2 (0.2 bar)
Pt/C (5%)
pH 9H2O, 60 °C
O
HN
NH
O CHPh2NH
HO
ONH
OH
O
O
O
HO ONN
DBU (1 eq)MeI (1 eq)CH2Cl2, rt O
HN
NH
O CHPh2NH
HO
ONH
OH
O
OHO
Org Lett 2019, 21, 246-251 Thomas et al.18
Alcohol transformed to leaving group for amino sugar addition
O
HN
NH
O CHPh2NH
HO
ONH
OH
O
O
O
HO O NN
DBU (3 eq)MsCl (1 eq)CH2Cl2, rt O
HN
NH
O CHPh2NH
MsO
ONH
OH
O
O
O
HO O
O OHH2N
O
OO
NHBoc
OMeMeO
NaOt-Bu (1 eq)t-BuOH/CH2Cl2, rt
O OH2N
O
OO
NHBoc
OMeMeO
Na
DBU (2 eq) CH
2Cl2, -25 °C to rt
O
HN
NH
O CHPh2NH
O
ONH
OH
O
O
O
HO O
OH2N
O
OO
NHBoc
OMe
MeO
Org Lett 2019, 21, 246-251 Thomas et al.19
Final Steps: Protecting groups cleaved & phenol group re-methylated
O
HN
NH
O CHPh2NH
O
ONH
OH
O
O
O
HO O
OH2N
O
OO
NHBoc
OMe
MeO
O O NH
H2N
O
HOOH
NH2
O NH2
O
NH
O
NH
OH
OH
HO
O
CF3COOH (1 eq)H2O/CH2Cl2, rt
O
O
NN
DBU (3 eq)MeI (1 eq)CH2Cl2, rt
O O NH
H2N
O
HOOH
NH2
O NH2
O
NH
O
NH
OH
O
O
HO O
O
Org Lett 2019, 21, 246-251 Thomas et al.20
Thank you!
O O NH
H2N
O
HOOH
NH2
O NH2
O
NH
O
NH
OH
O
O
HO O
O
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