Transcript Brittany - University of Maryland

Total Synthesis of Bryostatin 1
Brittany Wheeler
Chemistry Department
University of Maryland
J. Am. Chem. Soc. Keck, G. E.; Poudel,Y. B.; Cummins, T. J.; Rudra, A.; Covel, J.A. 2011, 133, 744-747.
Gary E. Keck
 Professor at the University of Utah, Salt Lake City, Utah.
 Group interests focus on total synthesis of natural products
that have biological interest such as anti-tumor activity.
 Another interest is developing new synthetic methods to be
used in synthesis of natural products.
Bryostatin 1
HO
O
O
O
O
O
O
O
OH
O
OH
O
OH
O
O
O
O
History
 Bryostatins were first isolated in the 1960’s by George Pettit
from Bugula neritina, a species of bryozoa (filter-feeding
aquatic invertebrates).
 20 different kinds of bryostatins isolated
 Strong protein kinase C regulators
 Exhibit anti-cancer and anti-Alzheimer’s qualities
 One gram of bryostatin can be extracted from one ton of
Bugula neritina  synthesis is a research priority
Esterification
OTBS
OTBS
HO
OH
OPMB
+
OBOM
EDCl, DMAP,
DMAP-HCl
O
87%
O
O
12
OPMB
OBOM
13
14
Selective oxidation of terminal
alkene to an alcohol
OTBS
O
OTBS
OPMB
9-BBN, then
H2O2, NaOH
O
OPMB
74%
O
O
OBOM
14
OBOM
15
HO
Oxidation followed by Witting reaction
OTBS
OTBS
1)SO3-py, DMSO,
O
OPMB
O
OBOM
15
HO
i-Pr2NEt 93%
O
2) Ph3P=CH2
74%
OPMB
O
OBOM
16
Rainier Metathesis
OTBS
OTBS
TiCl4, Zn, PbCl2,
O
OPMB
O
OPMB
TMEDA 80%
O
OBOM
16
MeCHBr2,
17
OBOM
Oxidative functionalization
OTBS
O
OTBS
1)MMPP,
MeOH/CH2Cl2
OMe
O
OPMB
2) TPAP, NMO
66%
17
OBOM
O
18
OPMB
OBOM
Selective reduction, acylation
OTBS
OTBS
OMe
O
OPMB
O
OBOM
1)CeCl3-7H2O, NaBH4,
MeOH, -40 C
2) Ac2O, DMAP,
py, 84%
OMe
O
OPMB
AcO
OBOM
CO2Me
CO2Me
19
20
OTBS
OMe
O
OPMB
HO
OBOM
CO2Me
Deprotection and oxidation
OTBS
O
OMe
O
OPMB
AcO
OBOM
H
OMe
O
1) HF-py 93%
2) TPAP, NMO
91%
AcO
OBOM
CO2Me
CO2Me
20
OPMB
21
Formation of third ring
MeO
TMS
OH
O
MeO
OAc
O
22
H
COStBu
OBPS
OMe
O
O
O
TMSOTf, Et2O
-78C
OMe
O
61%
OAc
COStBu
OBPS
OPMB
OPMB
AcO
AcO
21
OBOM
OBOM
CO2Me
CO2Me
23
Oxidative coupling,
MeO
O
MeO
OAc
O
O
OMe
O
1) DDQ, CH2Cl2/ pH
8 buffer
AcO
OBOM
CO2Me
23
Et3N, THF then
DMAP, tol 71%
OAc
O
O
O
CO2H
OTES
OPMB 2) 2,4,6-Cl3PhCOCl,
OMe
O
OTES
O
AcO
OBOM
CO2Me
24
MeO
O
1) AD mix-
tbuOH/H2O
OAc
O
O
OMe
O
OTES
O
2) NaIO4,
THF/H2O 81%
AcO
OBOM
CO2Me
25
Asymmetric Horner-WadsworthEmmons Reaction
MeO
O
O
MeO
OAc
MeO 2C
O
O
OMe
O
O
O P
OTES
O
OBOM
CO2Me
Co2Me
28, NaHMDS,
THF then 27
O
OMe
O
OTES
O
-78C to 0C 85%
28
AcO
27
O
O
O
OAc
AcO
OBOM
CO2Me
29
Methanolysis and esterification
MeO
MeO 2C
HO
O
O
O
O
O
O
O
1) K2CO3/MeOH
O
OMe
O
O
OAc
OTES
O
O
2) (C8H11O)2O, py,
OH
O
DMAP, CH2Cl2
71%
OTES
O
OH
O
AcO
OBOM
CO2Me
29
O
O
O
30
Bryostatin 1 (yield 1.44%)
HO
O
O
O
O
O
O
O
OH
O
OH
O
OH
O
O
O
O