highlights in the total synthesis of enediyne containing...
TRANSCRIPT
Highlights in the Total Synthesis of Enediyne Containing Natural Products
Evans Group Evening Seminar
Travis Dunn
Friday, November 10, 2000
H
H
H-DNA DNA
Reviews:
Nicolaou, K. C.; Dai, W.-M. Angew. Chem. Int. Ed. Engl.1991, 30, 1387.
Percy Carter. Evans Group Evening Seminar, May 1993.
Lhermitte, H.; Grierson, D. S. Contemporary Organic Synthesis 1996,3, 41.
Lhermitte, H.; Grierson, D. S. Contemporary Organic Synthesis 1996,3, 93.
Grissom, J. W. et al.Tetrahedron 1996,52, 6453.
Caddick, S. et al. Synthesis of enediynes and dienediynes. In The Chemical Synthesis of Natural Products,Hale, K. J., Ed.; CRC Press: Boca Raton, 2000; 229.
Enediyne Natural Products
O
OO
NCl
OO
O
OMe
NMe2
OH
HN
O
OH
OMe
MeO
i-PrO
OOH
Me
MeHO
HN
Me
OH
H
O
OMe
COOHOH
OH
O
O
O
OO
O
O
O
O
OH
OMe
Me
OMe
HO
HO
MeHN
OO
O
N
O OS O
O
NOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
O
H
H
Et
HO
NHCOOMe
O
OKedarcidin Chromophore
Dynemicin A
Neocarzinostatin Chromophore
Calicheamicin γI1
Tetrahedron Lett. 1985, 26, 331.
Antibiot. 1989, 42, 1449.J. Am. Chem. Soc. 1990,112, 3715.
J. Am. Chem. Soc. 1992, 114, 7946.
J. Am. Chem. Soc. 1993, 115, 8432.
J. Am. Chem. Soc. 1987, 109, 3464.
J. Am. Chem. Soc. 1987, 109, 3466.
SS
SMe
Handout01-02 11/9/00 10:00 PM
D
D
D
D
H
H
D
D
Bergman Cyclization
200 °C
∆H=14 kcal/mol
∆H‡=32 kcal/mol
Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
H
H
RH CCl4
Gas Phase
Cl
Cl
Heat Heat
n ring size r (Å, calc.) stability at 25 °C
1 10 3.25 half life=18 hrs2 11 3.61 stable3 12 3.90 stable
r
Nicolaou, K. C. et al. Acc. Chem. Res. 1992, 25, 497.
O
TBSO
Enediyne stability a function of internuclear distance
O
TBSO
n
Cyclic Enediyne Stability
O
Cpd r (Å) ∆G‡(124 °C)
1 3.39 26.9 kcal/mol2 3.37 32.0 kcal/mol
O
TBSO
O
TBSO
O
heat
heat
1
2
StrainModel
15.1 kcal/mol19.6 kcal/mol
r
r
Magnus, P. et al. J. Am. Chem. Soc. 1992, 114, 2544.
Enediyne stability a function of strain energy
Model 1
Model 2
Handout03-04 11/9/00 10:01 PM
Nicolaou, K. C. et al. Angew. Chem. Int. Ed. Engl.1991, 30, 1387.
Base
O
O
O
P
P
OO
O
OOO
HBase
O
O
O
P
P
OO
O
OOO
Base
O
O
O
P
P
OO
O
OOO
O
OH
Base
O
O
O
P
P
OO
O
OOO
OHBase
O
O
O
P
P
OO
O
OOO
O
Mechanism of DNA Damage
H
O2; H•
Reduction
Calicheamicin Mechanism of Action
HO
NHCOOMe
O
S
O
S
S
Me
Sugar
HO
NHCOOMe
O
S
O
Sugar
HO
NHCOOMe
O
O
SugarS
RS
HO
NHCOOMe
O
O
SugarS
Trisulfide cleavage
Conjugate addition
Bergman cyclization
Handout05-06 11/9/00 10:04 PM
HO
(±)-Calicheamicin Retrosynthesis: Danishefsky
O
OMe
Br
H
O
H
HO
NHCOOMe
HO
O
SS
MeS
HO
NHCOOMe
O
OO
O
OMe
Br
CHOO
O
HO
Br
OH
OO
O
OMe
COOMeMeO
HO
OMe
COOMeMeO
(±)-Calicheamicin: Core Construction
OMe
Br
COOMeHO
CHO
OMe
Br
CHOO
O
1) LiNMePh, THF
2)
Li
H
OMe
Br
CHO
O
HO
H
O
OMe
Br
TMSO
O
OMe
Br
H
1) TMSOCOCF3, Et3N
60%
2) KOCEt3, toluene
60%
HO O
H
dr > 20:1
1) NBS2) Cl2CHOMe,
TiCl43) BCl3
56%
1) DIBAL
2) NaIO4
3) Dess-Martin
40%
dr > 20:1
-78 °C
Handout07-08 11/9/00 10:05 PM
TMSO
O
OMe
Br
OH
HO
OH
Br
OH
OO
AcO
1) HOOH
CSA
2) KOAc, HOAc,
DMSO
78%
HO
Br
OH
OO
O
1) NH3, MeOH
2) NaIO4
80%
HO
N3
OH
OO
O
NaN3,
82%
HO
N3
O
OO
O
EtOP
Cl
OO
EtO
1)
pyridine
2) LiBr, Et3N
59%
O
NHCOOMe
O
OO
O
1) H2S, MeOH,piperidine
2) triphosgene,pyridine;MeOH70%
(±)-Calicheamicin: Carbamate Installation
MeOH
MeO
O
MeOOCO
NHCOOMe
O
OO
O
HO
NHCOOMe
HO
OO
HO
1) DIBAL
2) NaBH4
65%
HO
NHCOOMe
HO
OO
HS
1) DIAD, Ar3P,
2) DIBAL
N
O
O
SS
Me1)
(Harpp reagent)
2) CSA, THF, H2O
HO
NHCOOMe
HO
O
60%
65%
(±)-Calicheamicinone Danishefsky, S. J. et al. J. Am. Chem. Soc. 1990, 112, 3253.
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1991, 113, 3850.
(±)-Calicheamicin: Aglycone Completion
46%
SS
MeS
AcSH
Handout09-10 11/9/00 10:06 PM
Calicheamicin: Enzymatic Resolution of an Intermediate
HO
OH
Br
OH
OO
HO
Danishefsky, S. J. et al. Tetrahedron Lett. 1991, 32, 6671.
1) Pseudomonas cepacia
vinyl acetate, DME, 6 days
HO
OH
Br
OH
OO
HO
OH
OH
Br
OH
OO
OH
+
Racematethree cycles,
42% yield
2) MeOH, NH3
three cycles,45% yield
98% ee 98% ee
lipase PS-30
OO
O
N
O OS O
O
NOMe
OH
Me
OTESMe
OMe
OMeI
Me
OTESMeO
MeTESO
Calicheamicin: Glycosylation
O
Teoc
Fmoc
Et
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5750.
HO
NHCOOMe
HO
O
HO
NHCOOMe
O
O
OO
O
N
O OS O
O
NOMe
OH
Me
OTESMe
OMe
OMeI
Me
OTESMeO
MeTESO
O
Teoc
Fmoc
Et
O
OO
O
N
O OS O
O
NOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
O
H
H
Et
HO
NHCOOMe
O
O
AgOTf, 4 Å MS
1) CSA, H2O
2) TBAF
32%
(-)-Calicheamicin γI1
Danishefsky, S. J. et al. Angew. Chem. Int. Ed. Engl. 1994, 33, 858.
+S
S
SMe
SS
SMe
SS
SMe
Cl3C
NH
one anomer
34%
α:β 3:1
Handout11-12 11/9/00 10:06 PM
TBSO
Li
LiO
Calicheamicin Approach: Magnus
O
OTBS
THPO
OTBS
OTHP
TBSO
OLi
OTHP
TBSO
OAlloc
OTHP
AllocOTHPO
+
AllocCl
90%
TBSO
OTHPO
cat. Pd(OAc)2
76%
Magnus, P. et al. J. Am. Chem. Soc. 1997, 119, 6739.
TBSO
HOO
TBSO
OTHPO
TBSO
OCo(CO)3
Co(CO)3HO
1) Amberlyst resin, MeOH
2) Co2(CO)8
96%
regioselection 6:1
TBSO
OCo(CO)3
Co(CO)3O
H
L3Co Co(CO)3
SPh
TBSO
HOO
Me2AlSPh,
Ti(Oi-Pr)4
45-71%
1) m-CPBA
2) CAN49%
Magnus, P. et al. J. Am. Chem. Soc. 1997, 119, 6739.
-78 °C;
Oxidation
Calicheamicin Approach: Magnus
Handout13-14 11/9/00 10:50 PM
Dynemicin Mechanism of Action
HN
Me
OH
H
O
OMe
COOHOH
OH
O
O
HN
Me
OH
H
O
OMe
COOHOH
OH
OH
OH
N
Me
OH
H
HO
OMe
COOHOH
OH
OH
OH
H
HN
Me
OH
H
HO
OMe
COOHOH
OH
OH
OH
Nu
HN
Me
OH
H
HO
OMe
COOHOH
OH
OH
OH
Nu
Reduction Epoxide opening
SolvolysisBergman
cyclization
(±)-Dynemicin Retrosynthesis: Schreiber
N
Me
OMe
H
H
N
OMe
BrN
OMe
MeOOCHOOC
Me
OHMeOOC
O
OH
H
H
N
Me
OMe
H
H
H COOMe
OMe
O
O
OMe
OMe
ON
Me
OMe
H
H
'"ROOC COOMe
OH
N
Me
OMe
H
H
ROOC
O
O
H
H
Handout15-16 11/9/00 10:08 PM
(±)-Dynemicin: Core Construction
N
Me
OMe
H
H
N
OMe
BrN
OMe
N
OMe
MeOOC
N
OMe
MeOOC
H
HOOC
OTBS OH
Me Me
Me
OHMeOOC
O
OH
H
H
N
Me
OMe
HMeOOC
O
OH
H
Bu3Sn OTBS
Me
cat. Pd(PPh3)4
85%
SiMe2Thexyl MgBrClCOOMe
2) TBAF
60%
1)
Br OMe
O
Pd(PPh3)4, CuI
1)
2) LiOH, H2O, THF
65%
PyBroP
Et3N
51%
N P
3
Br
PF6
PyBroP =
N
Me
OMe
H
H
MeOOC
O
OH
H
H
N
Me
OMe
H
H
ROOC
O
OH
H
H
1) DBU, 92%
MeAlCl2;
2) KOH, H2O;
Cl O OBz
O
82%
~ 97%
Me
MeMe
O2S
NH
NH2
N
Me
OMe
H
H
ROOC
O
O
H
H
N
Me
OMe
H
H
ROOC
O
OOH
H
H
CAN, H2O
~ 92%O
MeH
H OOH
O
MeH
H ONHHN
SO2
Ar
O
MeH
H ON
N
H
O
MeH
H O
H
Allylic Diazene Rearrangement
- ArSO2H
- H2O
ArSO2NHNH2
- N2
R=(CH2)3OBz
(±)-Dynemicin: Allylic Transposition
Handout17-18 11/9/00 10:08 PM
N
Me
OMe
H
H
ROOC
O
O
H
H
R=(CH2)3OBz
N
Me
OMe
H
H
ROOC
CH2OH
CH2OHH
OH
1) KHMDS;
~72%
2) NaBH4
~74%
N
Me
OMe
H
H
R'OOC CH2OHH
R=(CH2)3OBz
OO
O
R'=(CH2)3OH
1) NaOMe,
2) Triphosgene
MeOH
~88%
N
Me
OMe
H
H
"ROOC COOHH
OO
R"=(CH2)2COOH
1) Dess-Martin
2) NaClO2
1) LiOH; HCl
R"'=(CH2)2COOMeR"'=(CH2)2COOMe
2) CH2N2
five steps
N
Me
OMe
H
H
'"ROOC COOMe
OH
O
N
Me
OMe
H
H
'"ROOC COOMeH
OHOH
NaIO4
MoOPh
(±)-Dynemicin: A Ring Functionalization
~20%
R"'=(CH2)2COOMe
N
Me
OMe
H
H
'"ROOC COOMe
OH
R"'=(CH2)2COOMe
N
Me
OMe
H
H
'"ROOC COOMe
OMe
O
O
Br
OMe
OMe
AgOTf, 4Å MS
1)
2) Me2SO4, K2CO357%, 1:1 dr
OO
OMeMeO
R"'=(CH2)2COOMe
N
Me
OMe
H
H
'"ROOC COOMe
OMe
OHO
OMeMeOR"'=(CH2)2COOMe
N
Me
OMe
H
H
'"ROOC COOMe
OMe
O
OH
OMe
OMe
MeAlCl2,
82%
1) SOCl22) TMSOTf
3) DDQ
51%
Et3SiH
(±)-Dynemicin: DE Ring Appendage
Handout19-20 11/9/00 10:09 PM
R"'=(CH2)2COOMe
N
Me
OMe
H
H
'"ROOC COOMe
OMe
O
OH
OMe
OMe
N
Me
OMe
H
H
'"ROOC COOMe
OMe
O
OH
OMe
OMe
m-CPBA, pH 7 buffer
73%
O
N
Me
OMe
H
H
H COOMe
OMe
OH
OH
OMe
OMe
O
Tautomerization
does not occur
R"'=(CH2)2COOMe
N
Me
OMe
H
H
H COOMe
OMe
O
OH
OMe
OMe
O
DBU,
MeOH
(±)-Dynemicin: Epoxidation
N
Me
OMe
H
H
H COOMe
OMe
O
OH
OMe
OMe
ON
Me
O
H
H
COOMe
OMe
O
OH
OMe
OMe
O
N
Me
OH
H
H
H COOMe
OMe
O
O
OMe
OMe
ON
Me
OMe
H
H
H COOMe
OMe
O
O
OMe
OMe
O
CAN, H2O
Tautomerization
Cs2CO3, MeI
50%, three steps
(±)-Tri-O-methyl dynemicin A methyl ester
Schreiber, S. L.; et al. J. Am. Chem. Soc. 1993, 115, 10378.
MeCN
(±)-Dynemicin: Endgame
Schreiber, S. L. et al. J. Am. Chem. Soc. 1992, 114, 5898.
Schreiber, S. L. et al. J. Am. Chem. Soc. 1990, 112, 7410.
Handout21-22 11/9/00 10:10 PM
(+)-Dynemicin Retrosynthesis: Myers
Me
TfO OMe
*ROOC
Me
OMe
HN
O
OMe
HN
Me
OH
H
O
OMe
H
COOHOH
OH O
O N
Me
O
H
O
OMe
H
COOTIPS N
Me
OTBS
H
OH
Alloc
O
OMe
OMe
Me
N
OTBS
OHOMe
OMe
TBS
Alloc
(+)-Dynemicin: Quinoline Construction
O Me
O
Me
i-PrO
KOt-Bu
36%
Me OEt
O
Me
O O
*ROOC
Me
O OMe
*ROOCCSA, MeOH
4:1 regioisomeric mixture
89%
Me
TfO OMe
*ROOC
Me
OMe
*ROOC
NHBoc
MeO
B(OH)2
NHBoc
MeO
+
Me
OMe
HN
O
OMe
4-Chlorophenol
180 °C
Me
OMe
N
OTf
OMe
Me
N
OTf
OMe
OHOMe
OMe
Me
N
H
OMe
OHOMe
OMe
NaH; Tf2O
95%
cat. Pd(PPh3)4,
90%Tf2O,
4-Chloropyridine
85%
m-CPBA
dr 4.5:183%
Et3N, HCOOH
97%
99% heat, Na2CO3
cat. Pd(PPh3)4,heat
Handout23-24 11/9/00 10:14 PM
N
Me
OTBS
H
OH
Alloc
Me
N
OMe
OHOMe
OMe
1) EtMgBr; NaSEt,DMF, reflux
3) TBSCl, imidazole
70%
Me
N
OTBS
OHOMe
OMe
Me
N
OTBS
OHOMe
OMe
TBS MgBr
TBS
1) EtMgBr
2) AllocCl
dr >20:189%
Alloc
Me
N
OTBS
OHOMe
OMe
H
Alloc
O
1) m-CPBA
2) TBAF
3) TBSCl,
84%
Me
N
OTBS
OMe
OMe
H
Alloc
OO
OMe
OMe
O
Swern Oxidation
92%
KHMDS, CeCl3
94%
(+)-Dynemicin: Core Construction
imidazole
(+)-Dynemicin: Alternate Coupling Strategies
Me
N
OMe
OMsOMe
OMe
H
MeOOC
Me
N
OMe
OMsOMe
OMe
H
Alloc
O
Me
N
OMe
OMe
OMe
H
MeOOCBase
BaseNo Reaction
Me
N
OMe
H
Alloc
O
O
BaseNo Reaction
or
Decomposition
Cyclization attempts result in 1,4 elimination
Installation of the epoxide could solve this problem...
...but a suitable electrophilic coupling partner could not be accessed.The corresponding triflate could not be prepared.
Handout25-26 11/9/00 10:15 PM
(+)-Dynemicin: A Ring Functionalization
N
Me
OTBS
H
OH
Alloc
O
OMe
OMe
1) TsOH, acetone83%
2) Thiocarbonyl-diimidazole,
DMAP
85%
N
Me
OTBS
HAlloc
O
OO
S
n-Bu3SnH, AIBN,
toluene, 70 °C
97%
N
Me
OTBS
HAlloc
O
O
H
"This seemingly simple sequence proved to be the single most difficult transformation in the entire synthetic route."
1) MgBr2, Et3N,CO2, MeCN
2) KOt-Bu; MeOTf
54%
N
Me
OTBS
HAlloc
O
OMe
H
COOHN
Me
O
HAlloc
O
OMe
H
COOTIPSMeON
Me
O
H
O
OMe
H
COOTIPSn-Bu3SnH,
78%
1) TIPSOTf,imidazole
2) PhIO,MeOH
61%
Pd(PPh3)2Cl2
cat.
(+)-Dynemicin: DE Ring Installation
N
Me
O
H
O
OMe
H
COOTIPS
O
OTMS
OTMS
OTMS
+
N
Me
O
H
O
OMe
H
COOTIPSOTMS
OTMS OTMS
THF, -20 °C to 55 °C
75% yield
THF
H
H
HN
Me
OH
H
O
OMe
H
COOHOH
OH O
O
O
N
O
OH
OH OH
H
H
O
N
O
O
O O
H
H
OH
53%
(+)-Dynemicin A
Myers, A. G. et al. J. Am. Chem. Soc. 1994, 116, 11556.
Myers, A. G. et al. J. Am. Chem. Soc. 1997, 119, 6072.Myers, A. G. et al. Chem. Biol. 1995, 2, 33.
MnO2,
Et3N•3HF,
Handout27-28 11/9/00 10:15 PM
(±)-Dynemicin Retrosynthesis: Danishefsky
OH
OMe
CHO
O
H
HCHO
Me
OMe
N
OTBS
Me
OTBS
N
OTBS
Me
Teoc
H
H
OH
OH
N
Me
OTBS
HTeoc
O
OH
OH
N
Me
O
H
O
OMe
COOMOMHN
Me
OH
H
O
OMe
COOHOH
OH
O
O
(±)-Dynemicin: Intramolecular Diels-Alder
OH
OMe
CHO
O
OMe
Me
COOEt
O
OMe
Me
CHO
O
H
HCHO
Me
OMe
O
H
O
Me
O
HO
N
OTBS
Me
OTBS
1)Br Me
2)
EtOP COOEt
OEtO
NaH91%
1) DIBAL
2) Swern
91%
ZnCl2, CH2Cl2
60%
dr 20:1
CAN, MeCN,
90%
1) NH4OAc, AcOH,
100 °C
2) TBSCl, imidazole
87%
K2CO3
H2O
Handout29-30 11/9/00 10:16 PM
N
OTBS
Me
OTBS
N
OTBS
Me
OTBS
O
O
Ph
Ph1) OsO4, NMO
2) Ph2C(OMe)2, H2SO4
3) TBSCl, imidazole
75%
N
OTBS
Me
OTBS
O
O
Ph
PhBrMg TIPS
AllocCl
89%
dr 9:1
Alloc
TIPS
N
OTBS
Me
O
O
Ph
PhAlloc
TIPS
H
1) HCl, THF
2) Swern Oxidation
3) PPh3, CBr4
4) BuLi
53%
N
OTBS
Me
Alloc
H
H
1) TBAF
2) Conc. HCl, MeOH
63%
3) TBSCl, NaH
N
OTBS
Me
Teoc
H
H
cat. Pd(PPh3)4
2) morpholine,
3) TeocCl, NaH,
1) Ac2O, Et3N,
DMAP
DMAP
4) NH3, MeOH
86%
OH
OH
OH
OH
(±)-Dynemicin: Diyne Construction
N
OTBS
Me
Teoc
H
H
OH
OH
1) m-CPBA, 87%
2) AgNO3, NIS
91%
N
OTBS
Me
Teoc
I
I
OH
OH
ON
Me
OTBS
HTeoc
O
OH
OH
Me3Sn SnMe3
cat. Pd(PPh3)4,
DMF, 75 °C
81%
N
Me
OTBS
HTeoc
O
OTf
O
N
Me
OTBS
HTeoc
O
O
1) Tf2O, pyridine
2) Dess-Martin
90%
CrCl2
75%N
Me
OTBS
HTeoc
O
OMe
COOMOM
Hünig's base
1) MgBr2, Et3N,CO2, MeCN
2) MOMCl,
3) CH2N2, MeOH
43%
(±)-Dynemicin: Core Construction
Handout31-32 11/9/00 10:17 PM
N
OTBS
Me
O
O
Me
Me
H
N
OTBS
Me
O
O
Me
Me
H
MeOOCN
OTBS
Me
H
OH
LiHMDS i-PrMgBr,
ClCOOMe
N
OTBS
Me
H
OAc
OAc
O N
OR
Me
OAc
OAc
O
TMS
Once again (c.f. Myers) kinetic acidity of the propargylic proton proved to be problematic.
H
N
OMe
Me
H
OAc
OAc
O
X
AllocOMe
OMe O
O
X
Y
R'
R'
Epoxidation of the olefin was again investigated as a solution, but elaboration to the enediyne cyclization precursor was not possible from these intermediates.
(±)-Dynemicin: Alternate Coupling Strategies
N
Me
OTBS
HTeoc
O
OMe
COOMOMN
Me
O
H
O
OMe
COOMOM
TBAF PhI(OAc)2
60%
N
Me
O
H
O
OMe
COOMOMMOMO
MOMO
O
O
OLi
O
MOMO
MOMO
HN
Me
OH
H
O
OMe
COOMOMMOMO
MOMO OH
H
O O
Li
N
Me
OH
HH
O
OMe
COOMOM
(±)-Dynemicin: DE Ring Installation
Handout33-34 11/10/00 8:59 PM
HN
Me
OH
H
O
OMe
COOMOMMOMO
MOMO O
N
Me
O
H
O
OMe
COOMOMMOMO
MOMO OH
PhI(OCOCF3)2
HN
Me
OH
H
O
OMe
COOMOMMOMO
MOMO
O
O
air, light,
THF, rt,
20 hrs
HN
Me
OH
H
O
OMe
COOHOH
OH
O
O
MgBr2, Et2O
15% over four steps
(±)-Dynemicin A
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1996, 118, 9509.
Danishefsky, S. J. et al. Angew. Chem. Int. Ed. Engl. 1995, 34, 1721.
(±)-Dynemicin: Endgame
Danishefsky, S. J. et al. J. Org. Chem. 1996, 61, 16.
Neocarzinostatin/Kedarcidin Mechanism of Action
OH
OO
O
ArCO2
SugO
SR
SugO
RS
ArCO2
OO
O
OHSN2''' opening Myers
O
SugOO
NCl
OO
OSug
HN
OAr
O
SugO
NCl
OO
OSug
HN
OAr
HO
SR
SRO
SugO
NCl
OO
OSug
HN
OAr
HO
SR
O
OO
O
ArCO2
SugO
RS
SN2' opening Bergman
cyclization
cyclization
Neocarzinostatin Chromophore
Kedarcidin ChromophoreHandout35-36 11/9/00 10:57 PM
(+)-Neocarzinostatin Chromophore Retrosynthesis
H OO
MeMe
O
OO
MeMe
H
TBS
O
OH
Me
OMe
O
OOO
O
O
O
OMe
HO
HOMeHN
O
OOArCOO
O
OTES
O
OO
MeMe
H
O
TBSO OTMS
CHOO
O
TBSO
CH(OMe)2
+
(+)-Neocarzinostatin: Epoxy Diyne
H OO
MeMe
O
OO
MeMe
O
TMS1) Li TMS
81%
2) PDC
79 %
3:1 E/Z
OO
MeMe
TMS
TBS
Ph3P
H
TBS
H
TBS
1) K2CO3,
2) HCl64 %
H
TBS
O
OO
MeMe
H
TBS
O
2) Sharpless
1) TDSCl, Et3N,DMAP
Epoxidation94%
OH OH
OTDS OH1) Et3N•3HF
Me
OMe2)
TsOH75%
Myers, A. G. et al. J. Am. Chem. Soc. 1996, 118, 10006.
MeOH
Handout37-38 11/9/00 10:20 PM
OO
MeMe
H
TBS
OO
OMe
Me
TBS
O
TBSO
OH
CH(OMe)2
O
O
Me
Me
H
O
TBSO
TMSO
CHO
O
O
Me
Me
H
O
TBSO
TMSO
CHO
O
1) TBAF
2) TBSCl, Et3N,DMAP
1) TsOH,
92%
79%
2) TMSOTf,
1) DIBAL
2) SharplessEpoxidation
3) Dess-Martin
81%
O
TBSO
CH(OMe)2LiHMDS
75%
+
O
O
Me
Me
H
O
TBSO
HO
CH(OMe)2
dr > 20:1
Myers, A. G. et al. J. Am. Chem. Soc. 1996, 118, 10006.
acetone
2,6-Lut.
(+)-Neocarzinostatin: Cyclization Precursor
O
O
Me
Me
H
O
TBSO
TMSO
CHO
O
O
O
O
TBSO
Me
Me
TMSO
OOH
O
O
O
ArCOO
Me
Me
HO
OOH
(PhMe2Si)2NLi 1) (ClCH2CO)2O
2) Et3N•3HF, 72%
OH
Me
MeO
3) DCC, ArCOOH;
Ar =
n-PrNH2
71%
O
O
O
ArCOO
HO
OOH
OO
O
O
ArCOO
OOTES
OO
O
O
ArCOO
O
OH
1) TsOH, MeOH67%
2) Carbonyl-diimidazole
3) CSA, H2O
67%
1) TESOTf, 2,6-Lut.79%
2) Martin sulfurane
1) Et3N•3HF
79%
2) Ph3P, I2
65-72%
Neocarzinostatin Aglycone
Myers, A. G. et al. J. Am. Chem. Soc. 1996, 118, 10006.
LiCl
dr > 20:1
79%
imidazole
(+)-Neocarzinostatin Chromophore Aglycone
Handout39-40 11/10/00 8:58 PM
LA
OH
Me
OMe
O
OOO
O
HO
O
O
O
MeTESO
TESOMeHN
CCl3
NH
OH
Me
OMe
O
OOO
O
O
O
OMe
TESO
TESOMeHN
OH
Me
OMe
O
OOO
O
O
O
OMe
HO
HOMeHN
BF3•OEt2, 3Å MS,
one anomer
O
O
MeTESO
TESO MeN
HN
CCl3
H
OMe
TESO
TESO MeN LA
51%
HF•pyridine
49%
(+)-Neocarzinostatin Chromophore
Myers, A. G. et al. J. Am. Chem. Soc. 1998, 120, 5319.
(+)-Neocarzinostatin Chromophore: Glycosylation
LA
O
O
MeTESO
TESO MeN
H R
O
O
MeTESO
TESO MeN
H R
Kedarcidin Core Retrosynthesis: Myers
Br
BrO
HO
N
Cl
TBS
OO
MeMe
H
TBS
OTBS
OOO
TBSO
N
Cl
MeMe
O
OOO
TBSO
N
Cl
MeMe
Br
H
OH
O
O
O
O
Me
Me
Br
O
TBSO
N
Cl
H
H
O
O
MeMe
OH
H OO
MeMe
O
+
Myers, A. G. Goldberg, S. D. Angew. Chem. Int. Ed. Engl. 2000, 39, 2732.
Handout41-42 11/9/00 10:22 PM
Kedarcidin: Vinyl Dibromide
O
O
O
O
Me
Me
Br
BrO
HO
N
Cl
TBS
Br
Br
TBS
O
S
O
O
O Br
Br
TBS
O
O
Me
Me
OH
TBS
O
O
Me
Me
OH
H
O
O
Me
Me1) DIBAL, 96%
2) LDA, TMSCHN2
81%
1) LiHMDS; TBSOTf
3) Et3N•3HF
82%
1) Swern Oxidation
2) PPh3, CBr4
86%
1) TsOH, EtOH95%
2) SO2Cl2, Et3N,
DMAP50-70%
OH
N
Cl
NaH
82%
2) LiHMDS; TBSOTf
H OO
MeMe
O
OO
MeMe
O
TMS1) Li TMS
81%
2) PDC
OO
MeMe
TMS
H
OH
OO
MeMe
TMS
H
OTBS
OO
MeMe
TMS
TBS
OTBS
OO
MeMe
H
TBS
OTBS
H
MgBr
H
H
dr 3:188%
TBSOTf,
2,6-lutidine
96%
LiHMDS;
TBSOTf
93%
MeOH, K2CO3
91%
Goldberg, S. D. Synthesis of the Kedarcidin Core Structure by a Transannular Cyclization Pathway. Ph. D. thesis, Harvard University, Cambridge, MA, May 2000.
Kedarcidin: Diyne Construction
Handout43-44 11/9/00 10:23 PM
Br
Br
O
OH
N
Cl
TBS
TBS
O
O
Me
Me
OTBS
H Br
O
OH
N
Cl
TBS
TBS
O
OMe
Me
OTBS
Br
O
OTBS
N
Cl
H
H
O
OMe
Me
OHO
O
O
OTBS
N
Cl
Me
Me
BrH
OH
O
O
O
OTBS
N
Cl
Me
Me
OH
cat. Pd(PPh3)4,
Et3N, CuI
61%
+
1) TBAF,2-nitrophenol
2) TBSOTf,2,6-lutidine
83%
CuI, THF,
74-86%
Cu(OAc)2,
pyridine
LiHMDS, THF, -96 °C;
t-BuLi (1.05 equiv.),
-96 °C; HOAc
44-60%
Kedarcidin: Transannular Cyclization
Myers, A. G. Goldberg, S. D. Angew. Chem. Int. Ed. Engl. 2000, 39, 2732.
OOO
TBSO
N
Cl
MeMe
OH
OOO
TBSO
N
Cl
MeMe
OH
O
OOO
TBSO
N
Cl
MeMe
O
OOO
TBSO
N
Cl
MeMe
O
1) Et3N•3HF
2) VO(acac)2, TBHP
3) TBSOTf, 2,6-lutidine
53%
MsCl, Et3N,
CH2Cl2, 0 °C;
DBU, 0 °C
78%
Kedarcidin core structure
1,4-cyclohexadiene,
room temp,18 hrs
Myers, A. G. Goldberg, S. D. Angew. Chem. Int. Ed. Engl. 2000, 39, 2732.
Kedarcidin Core: Endgame
Handout45-46 11/9/00 10:23 PM
Kedarcidin Core Retrosynthesis: Hirama
OOTBSO
PMBO
MeMe
O
OOTBSO
PMBO
MeMe
HO
TESO
OTES
TBSO
OH OH
H
OO
MeMe
OTES
HO
H
TES
OO
MeMe
OTESO
TBSO
OO
H
OH
Ar
O
I
TBSO
H OO
MeMe
O
+
Kedarcidin: Cyclopentanone Construction
O
I
TBSO
OH
COOMe
TBSO
OAc
TBSO
OAc
1) NaBH4, CeCl3dr 15:1
2) cat. Pd(PPh3)2Cl2,
CO, Et3N, MeOH,
60 °C
91%
1) DIBAL
2) Ac2O, pyridine
96%
1) ArCHO, CSA
2) MeOH, K2CO3
dr 2:1
87%
98%
MeO
MeO
Ar =
OH
TBSO
OO
H
OH
Ar
OAc
TBSO
HOOAc
dr > 20:1
OsO4, NMO
HO
O
TBSO
OO
H
OH
Ar
n-Bu2SnO; NBS
83%
Hirama, M. et al. Synlett 1997, 250.
Hirama, M. et al. J. Am. Chem. Soc. 1995, 117, 8875.
Handout47-48 11/9/00 10:24 PM
O
TBSO
OO
H
OH
Ar
H
TES
OO
MeMe
OTES
TBSO
OO
H
OTES
ArTES
OO
MeMe
OTES
OH1) n-BuLi, CeCl3
dr 1.8:1, 84%
2) TESCl, pyridine
1) MsCl, Et3N,
DMAP
2) DBU, xylene,reflux
81%
TBSO
OO
H
OTES
ArTES
OO
MeMe
OTES1) DDQ, H2O
2) AgNO3, 2,6-lutidine,EtOH
3) MeOH, K2CO3
68%
TBSO
OH OH
H
OO
MeMe
OTES
HO
+
Hirama, M. et al. Synlett 1997, 250.
Hirama, M. et al. J. Am. Chem. Soc. 1995, 117, 8875.
Kedarcidin:Fragment Coupling
100%
TBSO
OH OH
H
OO
MeMe
OTES
HO
1) Pivaloyl chloride,pyridine
2) PMB-OC(=NH)CCl3,
CSA3) TESCl, imidazole
TBSO
OTES OH
H
OO
MeMe
OTES
PMBO
4) DIBAL
38%
OOTBSO
PMBO
MeMe
HO
TESO
OTES
1) Dess-Martin, 96%
2) LiHMDS, CeCl3
OOHO
PMBO
MeMe
OH
O
1) MsCl, Et3N, DMAP
2) TBAF
46%
dr > 20:1
65%
Hirama, M. et al. Synlett 1997, 250.
Hirama, M. et al. J. Am. Chem. Soc. 1995, 117, 8875.
Kedarcidin: Cyclization
Handout49-50 11/9/00 10:25 PM
OOHO
PMBO
MeMe
OH
O
OOTBSO
PMBO
MeMe
OMs
O2) MsCl, Et3N
1) TBSOTf, 2,6-lutidine76%
OOTBSO
PMBO
MeMe
O
OOTBSO
PMBO
MeMe
O
DBU, CD2Cl2,
1,4-cyclohexadieneroom temperature
This molecule has a half life of approximately 30 minutes in dichloromethane at room temperature.
Isolated in 32% yield from the alcoholKedarcidin core structure
Hirama, M. et al. Synlett 1997, 250.
Hirama, M. et al. J. Am. Chem. Soc. 1995, 117, 8875.
Kedarcidin Core: Endgame
O
TBSO
OO
NHBoc
OO
Me Me
I
NCl
N
HO
Cl COOMe
NHBoc
O
EEOOAc
I
N
O
Cl COOMe
NHBoc
EEOOAc
I
TBSO
N
O
Cl COOH
NHBoc
I
TBSOO
O
Me Me
TES
H
OH
OH
OPMBM
I
O
MOMO
MOMO
Ten steps
12%
1)
CsF, DMF, 60 °C
2) TBSCl, imidazole
72%
1) MeOH, K2CO3
2) MeOH, PPTS
3) 2-methoxypropene,PPTS
4) KOH73%
TES
H
OTES
OPMBM
EDC•HCl ,DMAP
74%
1)
2) TESCl, imidazole
Hirama, M. et al. Tetrahedron Lett. 1999, 40, 8281.
Kedarcidin Core: Macrocycle Precursor
Handout51-52 11/9/00 10:26 PM
O
TBSO
NCl
OO
OPMBM
NHBoc
OO
Me Me TES
OTES
O
TBSO
OO
NHBoc
OO
Me Me
I
NCl
TES
H
OTES
OPMBMPd2(dba)3, CuI,
Hünig's base, DMF
45%
O
TBSO
NCl
OO
OPMBM
NHBoc
PMBOOTBS
TES
OTES
O
TBSO
OO
NHBoc
PMBOOTBS
I
NCl
TES
H
OTES
OPMBMPd2(dba)3, CuI,
Hünig's base, DMF
single atropisomer
Hirama, M. et al. Tetrahedron Lett. 1999, 40, 8281.
Kedarcidin Core: Atropselective Macrocyclization
Handout53-54 11/20/00 12:15 PM
Calicheamicin: Danishefsky
O Me
PMBOOTMS
PMBOHO
O Me
PMBOOH
PMBOO
O
IMeO
N
I+ClO4- (sym-collidine)2
1) Ph3SnH, AIBN,
benzene, reflux
92%
O Me
PMBOOTf
PMBOO
O
MeO
N
OO
O
NH
O OS O
O
O
NHEtOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
O
O
OMe
OMsOMe
O
OMe
OMe
AcHNO
OMe
OMe
N
FMOC
Et
O
OMe
N
Fmoc
EtO
OMe
N
Fmoc
Et
Fmoc
Et
Et
Fmoc
1) Oxone
2) toluene, 90 °C
82%
1) NaN3
2) H2, Pd/C,
86%
1) LiAlH4
2) FmocCl,
86%PhSH,
BF3•OEt2,
95%1)
2) AcOH, H2O
90%
2) Tf2O, pyridine
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
α:β 1:1,
SPh
Ac2O K2CO3
Calicheamicin: Danishefsky
O CH2OAc
OAcAcO
1) PhSH, SnCl4
2) NaOMe, MeOH O Me
OH
SPh
3) TsCl; LiAlH4
78%
1) MsCl, Et3N
2) KSAc, DMF
O Me
SPh
SAr4)
3) LiAlH4
F
NO2O2N
O MeSAr
OTES
1) m-CPBA
3) TESOTf, DMAP,
pyridine84%
OO
O
NH
O OS O
O
O
NHEtOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
O
α:β 5.4:1, 96%
79%
2) Et2NH
β:α 7:1, 40%
1) Ph3P•HBr,
Teoc-NHOH,O MeSH
OTESO
HNTeoc
2) EtSH, K2CO3
89%
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
HandoutAdd01-02 11/10/00 9:00 PM
Calicheamicin: Danishefsky
OO
O
NH
O OS O
O
O
NHEtOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
O
O
O
Me OMe
OMe
O
Me OMe
OMe
CNTMSO CN
OH
Me OMe
OMe
CN
OH
Me OMe
OMeI
TMSCN, KCN,
18-crown-6
SmI2
82%
I Cl
93%
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
OO
O
NH
O OS O
O
O
NHEtOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
Calicheamicin: Danishefsky
O
AcO
AcOMe O
TBSOMe
OBn
OTBSO
Me
OBn
MeOOH
OTBSO
Me
OH
MeOOAc
OTBSO
Me
O
MeOOAc
CCl3
NH
O
1) BF3•OEt2, BnOH,
2) NaOMe, MeOH
3) TBSCl, imidazole
2) n-Bu2SnO; MeI
67%
1) OsO4, NMO
regioselectivity 4:1
96%1) Ac2O, DMAP,
pyridine
2) H2, Pd(OH)2/C,
91%
15:1 α:β
NaH, Cl3CCN,
95%9:1 α:β
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
HandoutAdd03-04 11/10/00 10:48 AM
OO
O
NH
O OS O
O
O
NHEtOMe
OH
Me
OHMe
OMe
OMeI
Me
OHMeO
MeHO
Calicheamicin: Danishefsky
OTBSO
Me
O
MeOOAc
CCl3
NH
O
CN
OH
Me OMe
OMeI
CN
Me OMe
OMeI
OTBSO
Me
O
MeOOAc
CN
Me OMe
OMeI
OTESO
Me
O
MeOOTES
BF3•OEt2
α:β 21:1, 95%
1) TBAF
2) NaOMe, MeOH
3) TESOTf, DMAP,
pyridine
93%
Me OMe
OMeI
OTESO
Me
O
MeOOTES
1) DIBAL, toluene2) NaClO2
3) Oxalyl chloride
77%
Cl O
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
OO
O
N
O OS O
O
HO
NOMe
OH
Me
OTESMe
OMe
OMeI
Me
OTESMeO
MeTESO
Calicheamicin: Danishefsky
O
Me OMe
OMeI
OTESO
Me
O
MeOOTES
Cl O
O MeSH
OTESO
HNTeoc
O MeS
OTESO
HNTeoc
Me OMe
OMeI
OTESO
Me
O
MeOOTES
O
Et3N, DMAP
62%
O Me
PMBOOTf
PMBOO
O
MeON
Et
Fmoc
Teoc
Fmoc
Et
OO
O
N
O OS O
O
PMBO
NOMe
OPMB
Me
OTESMe
OMe
OMeI
Me
OTESMeO
MeTESO
O
Teoc
Fmoc
Et
68%
80%
Danishefsky, S. J. et al. J. Am. Chem. Soc. 1995, 117, 5720.
NaH, DMF
DDQ
HandoutAdd05-06 11/10/00 9:03 PM