a concise, stereocontrolled total synthesis of rippertenol
DESCRIPTION
A Concise, Stereocontrolled Total Synthesis of Rippertenol. Scott A. Snyder Department of Chemistry, Columbia University. J. Am. Chem. Soc. 2011, 133, 8850–8853. 1)Compact polycyclic framework 2)seven stereogeniccenters (two of which are quaternary) - PowerPoint PPT PresentationTRANSCRIPT
A Concise, Stereocontrolled Total Synthesis of Rippertenol
Scott A. Snyder
Department of Chemistry, Columbia University
J. Am. Chem. Soc. 2011, 133, 8850–8853
Me
Me
H
H
Me
OH
Me
rippertenol(1)
1)Compact polycyclic framework
2)seven stereogeniccenters (two of which are quaternary)
3)Stereochemically rich but devoid of functionality to guide the formation of such complexity
this molecule has not succumbed to laboratory synthesis in the more than 30years since its original isolation
Me
Me
H
H
Me
OH
Me
rippertenol
Ring expansion
Me
H
H
Me
OPg
O OROR
Inverse demand
Diels-Alder
Me
Me
OPg
O
15
MeRO
OR
16
Double aldol
O
Me
Me
OPg
O
O
Me O
OPg
Me
Retrosynthetic analysis
Me
OMeLi/NH3
OMe
Me
(HOOC)2
O
Me83%
mCPBA
O
MeO
i-PrNEt2
Ac2O,DMAP
O
Me
OAc
Pig liver esterase
42%,84%ee
O
Me
OAc
Na2CO3
O
Me
OH
OO
MgBr
21
SiCl
TBDPSCl
TBDPSCl
imidazole,74%
O
Me
OTBDPS20
a)LDA,MeI
b)21,CuBr
(88%)
86%
O
MeOTBDPS
OO
22
c)23,P-TsOHO
Me
Me
OTBDPS
O
Me
24
singlediastereoisomer
d)KOt-Bu
68%
Me
Me
OTBDPS
OH
O
25[X-ray of p-BrBz derivative]
Me
Me
OTBDPS
O
e)MsCl,Et3N
72%
f)27,BF3-Et2O68%
26
Me
Me
O
OTBDPS
MeOO
H
28[X-ray]2.6/1 mixture of diastereoisomers
g)Zn,TiCl4,CH2Br2;HCl,46%
h)(PPh3)3RhClH2,98%,>19:1 dr
Me
Me
OTBDPS
Me
H
Me O
29[X-Ray]
i)BF3-Et2O,TMSCH2N2
21% (71% brsm)
Me
Me
OTBDPS
Me
H
Me
O
30
Me Cl
O
O
O
Me
23 27
Takai/Ohshima-Lombardo olefination
Me
Me
OTBDPS
Me
H
Me
O
30
j)NaBH4,93%k)1,1-thiocarbonyldiimidazole
DMAP,66%
l)AIBN,n-Bu3SnH69%
m)TBAF,93%
Me
Me
H
H
Me
OH
Me
rippertenol
TCDIN N
S
N N
Additional Approaches To Form Rippertenol’s 7-Membered Ring
Me
Me
OTBDPS
Me
H
Me
Me
Me
OTBDPS
Me
H
Me
O
30
OOH
22
Me
Me
OTBDPS
Me
H
MeN3
OH
34
the first total synthesis of rippertenol (1) has been achieved,selected privious effort(one methyl group could not be incorporated onto the final scaffold):
Me
H
H
H
Me
OH
Me
4
Enantioselective Synthesis of 4-Desmethyl-3a-hydroxy-15-Rippertene.
Peter Metz, Angew. Chem. Int. Ed. 2009, 48, 1157 –1159
Me
Me
H
H
Me
OH
Me
rippertenol(1)
(-)-isopulegol
HOH
TMSCl,imidazoleDMAP,99%
TMSOH
1)Et2BH,Et2O2)Et2O3)CuCN-2LiBr4)methallyl bromide
4)1 N HCl79%,>98%de
HOH
PCC,DCM
99%
OH
5
TMSCHN2, Me3Al, CH2Cl2 H HO
O
6(40%) 7(45%)
7
K2OsO2(OH)4, NaIO4,pyridine, THF, H2O
93%H
O
O
8
HO
6
1)LiHMDS, THF2)PhCHO,95%3)MsCl,Et3N
4)DBU, CH2Cl2,75%5)LiAlH4,99%
HHO
Ph
BuLi, THF,ClCO2Et,
96%HEtOOCO
Ph
9 10
Pd2dba3, Ph3P, HCO2H, Et3N, THF
89%H
Ph
11
OsO4, NaIO4,pyridine, THF, H2O
95% HO
O
8
tBuOK, tBuOH, THF
81%
LiHMDS, THF,allyl iodide
84%HO
12
1)PdCl2, p-benzoquinone,85%
2)tBuOK, tBuOH,THF, microwaves (150 W)
64%
p-benzoquinone
O O
H
4
H
OH
H
13
H
O 1)LiAlH4, Et2O,quan
2)propargyl bromide,TBAI50% aq. KOH,91%
H
14
H
O tBuOK, tBuOH, THF, microwave (300 W)83%
H
15
H
OH
1)TsOH, THF, H2O,80%
2)TPAP, NMO, MS 4A, CH2Cl2,quan
O
1)LiHMDS, THF; MoOPH, 85%
2)50% aq.KOH, THF3)LiAlH4, THF,89%4)NaIO4, THF, H2O, RT,98%
H
16
H
HOH
ON+
RuO
OO
O-
TPAP
N+OO-
NMO
MoO5-pyridine-HMPA
MoOPH
Transition-Metal Peroxide Reactions. Synthesis of a-Hydroxycarbonyl Compounds from Enolates:
J. Org. Chem. 1978, 43,188 – 196.
H
16
H
HOH
O
Me4NBH(OAc)3, HOAc,MeCN, THF,68%
H
H
R2OH
R1O
17:R1=R2=H
18:R1=MOM,R2=H
19:R1=R2=MOM
a)
b)
a)MOMCl, iPr2NEt, TBAI,CH2Cl2,57% 18, 27% 19
b)6N HCl, THF,81%
1). BuLi, THF2). CS23). MeI,84%
1)Bu3SnH, AIBN, toluene,80%
2)6N HCl, THF,91%H
H
H
HO
4
Installation of the methyl group at C4, which is still missing for thenatural product , is the subject of ongoing work.
