Synthesis of Penitrem D

C37H45NO4
Principal investigator | Amos B. Smith, III |
---|---|
Publication year | 2003 |
Synthesis type | Total |
Number of steps | 56 (3 parts) |
References |
Part 1 of 3

Methyl acrylate
hν
CH2Cl2
0 °C, 8.5 h
"The product depicted is the major component of an uncharacterized mixture of isomers."

Amberlyst 15,
HC(OMe)3
0 °C, 2.5 h
"The product depicted is the major component of an uncharacterized mixture of isomers."

MeMgBr
Et2O, PhH
0 °C to RT, 90 min
See the Grignard Reaction
"The product depicted is the major component of an uncharacterized mixture of isomers."

Pyr.TsOH
Acetone
RT, 2.5 h, 49% (4 steps)

i-Pr2NEt,
MeOCH2Cl
CH2Cl2
0 °C to RT, 74 h



KOH
H2O, MeOH
Reflux, 71% (4 steps)

NH2OH.HCl,
NaOAc
MeOH
Reflux, 3 h, 83%


NaOH
EtOH, H2O
Reflux, ON, 67% (2 steps)

H2,
Pd(OH)2/C
1 atm
EtOH, i-PrOH, MeOH
RT, 48 h, 96%

DMAP,
i-Pr2NEt,
TBSCl
CH2Cl2
0 °C to RT, 3 h, 88%
"The following protection / deprotection sequence was due to a late deviation from the initial plan."

HCl
H2O, MeOH
RT, 3 h, 89%

DMAP,
TIPSCl
Et3N
RT, 25 h, 95%

DMAP,
TMSCl
Et3N, THF
RT, 48 h, 48%
"The yield was 100% brsm."

Part 2 of 3
+
+


- O2 , Rose Bengal
- Ph3P
hν
THF
-78 °C to RT, 24 h, 50%





KOt-Bu,
MeI,
Ph2SO
THF
0 °C to RT, 4 h, 59%

Pyr.TsOH
Acetone, H2O
RT, 24 h, 98%

Zn,
NiCl2.6H2O
Ultrasound
2-Methoxyethanol, Buffer (pH = 9)
RT, 27 h, 90%

- O3
- Me2S
CH2Cl2, MeOH
-78 °C to RT, ON, 86%
"R = Bn, Bz (mixture)"

NaH2PO4,
KMnO4
H2O, t-BuOH
RT, 90 min
"R = Bn, Bz (mixture)"

CH2N2
CH2Cl2, Et2O
RT, 92% (2 steps)
"R = Bn, Bz (mixture)"

H2,
Pd(OH)2
1 atm
EtOH, H2O
RT, 24 h, 92%
"R = Bn, Bz (mixture); R = H, Bz (mixture)"

KOt-Bu
MeOH
Reflux, 3 h, 86%
"R = H, Bz (mixture)"


Neopentyl glycol,
Camphorsulfonic acid
Dean-Stark
PhH
Reflux, 6 h, 96%

i-Bu2AlH
CH2Cl2
-78 °C, 20 min, 83%

HCl
MeOH
0 °C to RT, 2 h, 96%
"Both C1-epimers were separated and the following steps were carried in separate vessels."

MgSO4,
Me2NNH2,
AcOH
PhH
RT, 2 h, 94% / 91 %
"Mixture of E and Z hydrazones."



i-Pr2NLi
THF
-78 to 65 °C, 5.5 h

DMAP,
BzCl
CH2Cl2
RT, 18 h, 76% / 60 % (2 steps)

AcOH,
NaOAc
PhH
65 °C, 14 h, 53% / 56 %

HClO4
H2O, MeCN
55 °C, 2 h, 90% / 74 %

H2Cr2O7.2Pyr
CH2Cl2
RT, 5 h, 78%

Et3SiH,
TfOH
PhMe
-40 °C to RT, 90 min, 60%

K2CO3
H2O, MeOH
55 °C, 15 h

EDC,
DMAP
CH2Cl2
RT, 60 min, 90% (2 steps)


SiO2,
O2
1 atm
EtOAc
RT, 40 h, 72%

Ph3P
PhH
RT, 60 min, 93%

Li(s-Bu)3BH
THF
-78 °C, 20 min

TESOTf,
2,6-Lutidine
CH2Cl2
RT, 60 min, 72% (2 steps)

Part 3 of 3
+




HCl
H2O, THF
RT, 60 min, 89%

Sc(OTf)3
PhH
RT, 60 min, 62%

DMAP,
Ac2O
CH2Cl2, Et3N
RT, 60 min, 80%

n-Bu4N+ F-
THF
RT, 30 min, 84%

o-NO2PhSeCN,
n-Bu3P
THF
RT, 15 min, 81%


K2CO3
MeOH
RT, 4 h, 82%
