Synthesis of Penitrem D

Structure of Penitrem D

C37H45NO4

Principal investigatorAmos B. Smith, III
Publication year2003
Synthesis typeTotal
Number of steps 56 (3 parts)
References
Part 1 of 3
intermediate structure
Methyl acrylate
CH2Cl2
0 °C, 8.5 h
"The product depicted is the major component of an uncharacterized mixture of isomers."
intermediate structure
Amberlyst 15, HC(OMe)3
0 °C, 2.5 h
"The product depicted is the major component of an uncharacterized mixture of isomers."
intermediate structure
MeMgBr
Et2O, PhH
0 °C to RT, 90 min
"The product depicted is the major component of an uncharacterized mixture of isomers."
intermediate structure
Pyr.TsOH
Acetone
RT, 2.5 h, 49% (4 steps)
intermediate structure
i-Pr2NEt, MeOCH2Cl
CH2Cl2
0 °C to RT, 74 h
intermediate structure
NaH, HCO2Et
THF
0 °C to RT, 3 h
intermediate structure
Ethyl vinyl ketone
Et3N
0 °C to RT, 7 h
intermediate structure
KOH
H2O, MeOH
Reflux, , 71% (4 steps)
intermediate structure
NaOAc, NH2OH.HCl
MeOH
Reflux, 3 h, 83%
intermediate structure
Bz2O
110 °C, 4.5 h
intermediate structure
NaOH
EtOH, H2O
Reflux, ON, 67% (2 steps)
intermediate structure
H2, Pd(OH)2/C
EtOH, i-PrOH, MeOH
RT, 48 h, 96%
intermediate structure
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."
intermediate structure
HCl
H2O, MeOH
RT, 3 h, 89%
intermediate structure
DMAP, TIPSCl
Et3N
RT, 25 h, 95%
intermediate structure
DMAP, TMSCl
Et3N, THF
RT, 48 h, 48%
"The yield was 100% brsm."
intermediate structure
Part 2 of 3
intermediate structure
  1. CuI
  2. MeLi
  3. TMSCl
Et2O, Et3N
0 °C to RT, 3.5 h, 80%
intermediate structure
  1. O2
  2. Ph3P
  3. Rose Bengal
THF
-78 °C to RT, 24 h, 50%
intermediate structure
  1. CuI
  2. (CH2NMe2)2
  3. TMSCl
  4. VinylMgBr
Et3N, THF
90%
intermediate structure + intermediate structure
MeLi, MgBr2.OEt2
Et2O
-5 °C to RT, 70 min, 65%
See the Aldol Addition
intermediate structure
PhH
Reflux, 60 min, 79%
intermediate structure
KOt-Bu, MeI, Ph2SO
THF
0 °C to RT, 4 h, 59%
intermediate structure
Pyr.TsOH
Acetone, H2O
RT, 24 h, 98%
intermediate structure
Zn, NiCl2.6H2O
2-Methoxyethanol, Buffer (pH = 9)
RT, 27 h, 90%
intermediate structure
  1. Me2S
  2. O3
CH2Cl2, MeOH
-78 °C to RT, ON, 86%
"R = Bn, Bz (mixture)"
intermediate structure
KMnO4, NaH2PO4
H2O, t-BuOH
RT, 90 min
"R = Bn, Bz (mixture)"
intermediate structure
CH2N2
CH2Cl2, Et2O
RT, , 92% (2 steps)
"R = Bn, Bz (mixture)"
intermediate structure
H2, Pd(OH)2
EtOH, H2O
RT, 24 h, 92%
"R = Bn, Bz (mixture); R = H, Bz (mixture)"
intermediate structure
KOt-Bu
MeOH
Reflux, 3 h, 86%
"R = H, Bz (mixture)"
intermediate structure
KOt-Bu
THF
Reflux, 6 h, 75%
intermediate structure
Camphorsulfonic acid, Neopentyl glycol
PhH
Reflux, 6 h, 96%
intermediate structure
i-Bu2AlH
CH2Cl2
-78 °C, 20 min, 83%
intermediate structure
HCl
MeOH
0 °C to RT, 2 h, 96%
"Both C1-epimers were separated and the following steps were carried in separate vessels."
intermediate structure
AcOH, Me2NNH2, MgSO4
PhH
RT, 2 h, 94% / 91 %
"Mixture of E and Z hydrazones."
intermediate structure + intermediate structure
i-Pr2NLi
THF
-78 to 65 °C, 5.5 h
intermediate structure
BzCl, DMAP
CH2Cl2
RT, 18 h, 76% / 60 % (2 steps)
intermediate structure
AcOH, NaOAc
PhH
65 °C, 14 h, 53% / 56 %
intermediate structure
HClO4
H2O, MeCN
55 °C, 2 h, 90% / 74 %
intermediate structure
H2Cr2O7.2Pyr
CH2Cl2
RT, 5 h, 78%
intermediate structure
TfOH, Et3SiH
PhMe
-40 °C to RT, 90 min, 60%
intermediate structure
K2CO3
H2O, MeOH
55 °C, 15 h
intermediate structure
DMAP, EDC
CH2Cl2
RT, 60 min, 90% (2 steps)
intermediate structure
Dess-Martin Periodinane
CH2Cl2
RT, 3 h, 90%
intermediate structure
O2, SiO2
EtOAc
RT, 40 h, 72%
intermediate structure
Ph3P
PhH
RT, 60 min, 93%
intermediate structure
Li(s-Bu)3BH
THF
-78 °C, 20 min
intermediate structure
2,6-Lutidine, TESOTf
CH2Cl2
RT, 60 min, 72% (2 steps)
intermediate structure
Part 3 of 3
intermediate structure + intermediate structure
  1. n-BuLi
  2. TMSCl
  3. s-BuLi
Et2O, THF
-78 to 0 °C, 2 h, 62%
intermediate structure
Et3N, Pyr.SO3
DMSO
RT, 30 min, 85%
intermediate structure
HCl
H2O, THF
RT, 60 min, 89%
intermediate structure
Sc(OTf)3
PhH
RT, 60 min, 62%
intermediate structure
Ac2O, DMAP
CH2Cl2, Et3N
RT, 60 min, 80%
intermediate structure
n-Bu4N+ F-
THF
RT, 30 min, 84%
intermediate structure
n-Bu3P, o-NO2PhSeCN
THF
RT, 15 min, 81%
intermediate structure
mCPBA, NaHCO3
CH2Cl2
RT, 18 h, 84%
intermediate structure
K2CO3
MeOH
RT, 4 h, 82%
intermediate structure