total synthesis of stephacidin a, avrainvillamide and stephacidin b · pdf filetotal synthesis...
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Total Synthesis of Stephacidin A,Avrainvillamide and Stephacidin B
Jack LiuJul. 26, 2005
Isoprenylated Indole Alkaloids
NH
HN
N
O
O Me
MeMe
MeO
stephacidin A
N
HN
N
O
O Me
MeMe
MeOO
avrainvillamide(CJ-17,6665) N
N
NO Me
MeMe
MeO
N
NH
N
O
O Me
MeMe
MeO
OH
O
O H H
stephacidin B
N
HN
N
O
O Me
MeMe
MeO
HO
O
aspergamide A
NH
HN
NMe
Me O
Me
VM55599
HN
N
O
OH
NH
OMe
Me
brevianamide B
N
N
O
MeMe
NHO
O
O
Me Memarcfortine A
Me
Williams, R. M. et al. Top. Curr. Chem. 2000, 209, 97.
Isolation, Characterization and Biological ActivityStephacidins•Source: Aspergillus ochraceusWC76466 (Qian-Cutrone, BMS, 2002)• Off-white amorphous solids• Characterization: UV, IR, HR-FAB, 1H,13C NMR, NOE, 2D NMR techniques• X-ray structure of stephacidin Bobtained, thus established relativestereochemistry• Stephacidin A reisolated in 2005 byBaran (Scripps). Optical rotation and CDmeasured• Absolute stereochemistry establishedby comparison with synthetic samples• Anti-tumor. Stephacidin B much morepetent (IC50 against testosterone-sensitive prostate cancer: 0.06 mM)
Avrainvillamide (CJ-17,6665)• Source: a marine strain of Aspergillus sp.obtrained from algae of Avrainvillea sp.(Fenical, Scripps, 2000) and Aspergillusochraceus CL41582 (Sugie, Pfizer, 2001.)• Characterization: UV, IR, HR-FAB, 1H,13C NMR, NOE, COSY, DEPT, INEPT• Isolators only determined connectivity• Structure confirmed by synthesis• Anti-bacterial, against multi-drugresistant bacteria
Qian-Cutrone, J. et al. US Patent 6,291,461, 2001.Qian-Cutrone, J. et al. J. Am. Chem. Soc. 2002, 124,14556.
Sugie, Y. et al. J. Antibiot. 2001, 54, 911.Fenical, W. et al. US Patent 6,066,635, 2000.
Structural Features
NH
HN
N
O
O Me
MeMe
MeO
stephacidin A
N
N
NO Me
MeMe
MeO
N
NH
N
O
O Me
MeMe
MeO
OH
O
O H H
stephacidin B
• Complex ring systems• Dimeric structure of stephacidin B• Unique bicyclo[2.2.2]diazaoctanestructure• Rare oxidation state of the indolenitrogen: N-hydroxyindole and indolenitrone• “The unprecedented structuralarchitecture of stephacidin B providesa new level of complexity withinprenylated indole alkaloids from fungi.”
Nussbaum, F. v. Angew. Chem. Int. Ed. 2003, 42, 3068.
N
HN
N
O
O Me
MeMe
MeOO
avrainvillamide(CJ-17,6665)
Proposed Biosynthetic Pathways
[4+2]
NH
HN
N
O
X
YMe
MeO
stephacidin
NH
N
O
O
HN
c yclo- (L)-Tr p- (L)-P roanalogue
M e
M e
OPP
reverse pr enyltr ansferase
NH
N
O
O
HN
M e
Me X
YY
X
[O]
N
N
O H
O
HN
Me
M e X
Y
deoxy brev ianam ide Eanalogue
Williams, R. M. et al. Top. Curr. Chem. 2000, 209, 97.Williams, R. M. et al. Tetrahedron Lett. 2004, 45,4489.
CO2H
H2N
HN
Y
X
oxidativedeamination
CO2H
O
HN
Y
X
Me
Me
OPP
reverse prenyltransferase
CO2H
HN
MeMe X
Y
O
NH
CONH2
(L)-tryptophananalogue
Proposed Mechanisms of Dimerization
N
HN
N
O
O Me
MeM e
M eOO
N
N
N
O M e
MeM e
M eO
N
NH
N
O
O Me
MeM e
M eO
OH
O
O H H
N
NH
N
O
O M e
M eMe
M eOO
H+
N
HN
N
O
O M e
M eMe
MeOOH
N
NH
N
O
O Me
MeM e
M eOO
N
HN
N
O
O Me
MeM e
M eOO
N
NH
N
O
O M e
M eMe
MeOO
H+
N
N
N
O
O M e
M eMe
MeOO
N
NH
N
O
O Me
MeM e
M eOO H
H+
stephacid in B
Qian-Cutrone, J. et al. J. Am. Chem. Soc. 2002, 124, 14556.Nussbaum, F. v. Angew. Chem. Int. Ed. 2003, 42, 3068.
Support of the Conjugate Addition Pathway
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
M eM e
MeMe
NO Me
M e
M eM e
NOH
OM e
MeOHat equil ibrium , adduc t:s .m. = 2:1 at rtwi thout c ata ly st, equil ibrium ª 10 hwi th 10 m ol % of NaOMe, equil ibrium < 10 min.wi th 10 m ol % of Cl3 CCOOH, equil ibrium < 10 min.
M eM e
MeMe
NO Me
M e
M eM e
NOH
S Ph
P hS H at equi libr ium, adduct:s.m . = 9:1 at rtwith 20 mol % of E t3 N, equi librium < 10 m in.
MeMe
MeMe
NO MeMe
MeMe
NOH
NaBH4
89%
MeOH
Synthetic Studies and Total Syntheses
n Studies of Cyclization (Williams)
n SN2’/Electrophilic Cyclization Sequence
n Biomimetic Intramolecular Diels-Alder
n Bioinspired Synthesis (Baran)
n Non-Bioinspired Synthesis (Myers)
SN2’ Cyclization to Form Bicyclo[2.2.2]diazaoctane
N
N
N
O
M eO
HPM B
N H
N
N
O
O
PM BM e
Boc B oc
anti syn
+NaH (10 equiv) , benz ene, r elux, 30 h: 82%, anti :s yn = 3:97NaH (10 equiv) , 18-crown-6 ( 5 equiv), THF, r eflux , 5 h: 64%, anti:sy n = 4.9:1
conc. HCl,dioxane,
3 to 16 °C, 48 h
N
N
O
O
72%
HMeMe
NBoc Boc HN
N
O
OH
NH
OMe
Me
brevianamide BWilliams, R. M. et al. Acc. Chem. Res. 2003, 36, 127.Williams, R. M. et al. J. Am. Chem. Soc. 1990, 112, 808.
N
N
N
O
O
P MB
B ocN
N
N
O
O
P MB
B oc
"endo "more steric al ly demanding
Me
O OO
OO
ONa+ M e
ClNa
"exo "less sterica lly dem anding
NN
O
O
P MB
MeCl
NB oc
Cl
NaH
Biomimetic Diels-Alder Formation of Bicyclo[2.2.2]diazaoctane
HNNH
N
O
OH
A cCl,
rt, 14 d NNH
N
O
OAcH
MeMe
MeM e
H+
NNH
N
O
OAcM eM e
Me Me Me
Cl-
NH
HN
N
O
MeM e O
M e
35%
+ HN
N
O
O
Me
15%
H
HMe
M e
HN HN
N
O
O
M e
10%
HM e
Me
NH+
NH
HN
NMe
Me O
MeH
DIBAL,toluene,rt, 24 h
68%
VM55599
Williams, R. M. et al. Acc. Chem. Res. 2003, 36, 127.Williams, R. M. et al. J. Am. Chem. Soc. 2002, 124, 2556.
A Bioinspired Disconnection
N
N
N
O Me
MeMe
MeO
N
NH
N
O
O Me
MeMe
MeO
OH
O
O HH
stephacidin B
N
HN
N
O
O Me
MeMe
MeOO
avrainvillamide
NH
HN
N
O
O Me
MeMe
MeO
stephacidin A
NH
HN
N
O
O Me
MeMeO
O O
NH
CO2MeR +
ONH
CbzHN
MeO2C
MeMe
OTsNH
CbzHN
MeO2C
Synthesis of Substituted Tryptophan
N
CO2 M e
O
Cbz
1. L iE t3 BH (1.1 equiv),THF, -78 °C, 10 min.
2. P d( OAc )2 ( 5 m ol %),DA BCO (3 equiv ),
TBA I ( 3 equiv),
(1 .1 equiv ),DMF, 105°C, 4 h
I
NH2Ts O
TsO
I
NH
NHCbzMeO2 C
TsO NH
NHCbz
CO2 Me
75%
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.Chen, C.-Y.; Reider, P. J. et al. J. Org. Chem. 1997, 62, 2676.
I
NH2TsO
Ts O
I
NH
NHCbzM eO2C
TsO
PdL2I
NH
NHCbzM eO 2C
TsO NH
NHCbz
CO2 Me
Ts O NH
NHCbz
CO2 M ePdL2 I
NN
Pd(0)Ln
NN•HI+
CHO
NHCbzM eO2C
+
Formation of Chromene-Type Structure
TsO NH
NHCbz
CO2 Me
Ts O N
NHCbz
CO2 Me
Boc
B oc2 O (1.1 equiv),DM AP ( 10 mol %) ,
CH2Cl2/M eCN (1/1) , rt, 30 m in
M g ( 10 equiv ),
MeOH, 0 °C to rt,2 .5 h HO N
NHCbz
CO2 Me
Boc
95%
O NH
NHCbz
CO2 Me
MeM e
O N
NHCbz
CO2 M e
MeMe
(3 equiv) ,CuCl2 (0 .1 mol %),
DBU (3 equiv) ,
M eCN, 0 °C, 24 h
OCO2 Me
M eMe
75% ( 2 steps)
AcO H,
120 °C,80 min.
Boc2 O (1.1 equiv),DM AP ( 10 mol %) ,
CH2Cl2/M eCN (1/1), rt, 30 m in
77%79%
Boc
O N
NHCbz
CO2Me
MeMe
Boc
LiOH (15 equiv),
THF/H2O (1/1),0 °C, 3 h
O N
NHCbz
CO2H
MeMe
Boc
100 %
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.
Coupling with Proline Derivative
NH
CO2MeOTBS
O N
NHCbz
CO2H
MeMe
Boc
(1.5 equiv),BOPCl (1.1 equiv),
i-Pr2EtN (1.1 equiv),
CH2Cl2, 0 °C to rt, 10 h N
CO2Me
NOMe
Me O
62%
OTBS
NHCbz
Boc
1. Pd2(dba)3 (20 mol %),Et3SiH (40 equiv), Et3N (2 equiv), CH2Cl2, rt, 4 h
2. MeOH, reflux, 30 min.3. toluene, relux, 2 h
N
HN
N
O
OMe
MeOTBS
O
H
53%
NaH (1.2 equiv),MOMCl (1.1 equiv),
DMF, 0 °C, 1 hBoc
N
HN
N
O
OMe
MeO TBS
O
H1. TBA F (3 equiv) , T HF, rt, 1 h
2. Des s-M ar tin period inane(1.5 equiv), CH2 Cl2 , rt, 2 h
3. 2-m ethyl -2-betene (20 equiv ),NaH2 PO 4 ( 3 equiv), NaClO2
(2.8 equiv) , THF, H2 O, 20 min.4. CH2 N2 , E t2O , M eOH, 5 min.
69%
N
N
N
O
OMe
MeO Me
O
H
O
M OM
BocBoc
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.
A Question for You
How to make?
NH
CO2MeOTBS
Self-Reproduction of Chirality
NH
CO2 H
H
O
Me
MeMe
(5 equiv) ,
TFA, penatane,re lux, 48 h
NO
H
(L)- pr ol ineM e
M eMe
1. LDA (1.05 equiv ),THF , hexane, -78 °C, 30 min.
2. a l lyl br om ide (1.1 equiv),-78 to - 30 °C, 2 h
NO
M eM eMe
92% 87%
6 M HCl ,
H2O , r t, 2 d
99%
O O
NH
CO2 H
•HCl
1. CH2 N2, M eO H/benz ene(1/1) , 0 °C, 30 m in.
2. benzyl c h loroform ate(2 equiv ), 0 to 50 °C, 4 h
N
CO2 M e 3. 9- BBN (2 equiv ), THF, r t, 9 h4. NaOH, H2O 2
5. TBSCl (1 .1 equiv ), im idazole(1.2 equiv) , CH2 Cl2 , r t, 30 min.6. H2 , 10 % Pd/C (0.2 w %) , M eOH
Cbz
74%
NH
CO2 M e
79%
OTB S
N O
OLiH
MeMeMe
E+
E+Seebach, D. et al. J. Am. Chem. Soc. 1983, 105, 5390.Hinds, M. G. et al. J. Med. Chem. 1991, 34, 1771.Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.
An Even Faster Way
NH
CO2Me
CO2Me
O N
NHCbz
CO2H
MeMe
Boc
(1.0 equiv),HATU (1.1 equiv),i-Pr2EtN (3 equiv),
DMF, rt, 12h N
CO2Me
NOMe
Me O
81%
OMe
NHCbz
Boc
O
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
1. Pd2(dba)3•CHCl3 (20 mol %), Et3SiH
(40 equiv), Et3N (2 equiv), CH2Cl2, rt, 3.5 h
2. DMF/MeOH (3/1), reflux, 4 h
N
HN
N
O
OMe
MeOMe
O
H
80%
NaHMDS (1.1 equiv),MOMCl (1.4 equiv),
THF, -78 °C to rt, 1.5 hBoc
95%
O
N
N
N
O
OMe
MeOMe
O
H
O
MOM
Boc
Key Ring Closure EventModel study:
N
N
N
O
OMeO
HO
MOM
N
N
N
O
OMeOO
MOM1. LDA (2.5 equiv),
THF, -78 °C, 30 min.
2. Fe(acac)3 (2.5 equiv),THF, -78 to 25°C, 1 h
52%
Boc Boc
N
N
N
O
OMe
MeOMe
O
HO
MOM
N
N
N
O
OMe
MeOMeOO
OMe
H
NOE
1. LDA (2.2 equiv),THF, -78 °C, 5 min.
2. Fe(acac)3 (2.2 equiv),THF, -78 to 25°C, 1 h
61%8% of s.m. recovered
Boc Boc
OB
OB r
( 2 equiv),
CH2 Cl2 , 0 °C, 1 .5 h
N
HN
N
O
OMe
MeOM eOO
N
HN
N
O
OM e
M eMeO
78%
1. MeM gB r (5 equiv ), to luene, rt, 1 h
2.
( 2 equiv), benz ene, 50 °C, 30 m in.
NCO 2M eS
H3 N
OO
88%
Boc B oc
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
Cascade of Pericyclic Reactions
N
HN
N
O
OMe
MeM eO
OO
H
M eM e
sulfo lane,
240 °C, 1 h
CO2 +Me Me
N
HN
N
O
OM e
M eMeO
H
retr o- ene
ene
45%
N
HN
N
O
OMe
MeMe
Me O NH
HN
N
O
OMe
MeMe
Me O
[1,2]-shift
ent-(-)-stephacidin A
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 606.Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
An Oxidative Dead-End
NH
HN
N
O
O Me
MeMe
MeO
1. sunlamp,methylene blue, 3O2,
MeOH, -28 °C, 30 min.
2. DMS (100 equiv), -28 °C to rt, 10 min.
80%
N
HN
N
O
O Me
MeMe
MeO
HO
(+)-stephacidin A
N
HN
N
O
O Me
MeMe
MeO
HO
O
aspergamide A
N
HN
N
O
O Me
MeMe
MeOO
avrainvillamide
spontaneousdehydration
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
Back to the Drawing Board
NH
N
N
O
M eM e O
PM B
NaB H3CN (10 equiv),
A cOH, rt, 12 h NH
N
N
O
M eM e O
PM B
HH
Na2 WO4 •2H2O (0.2 equiv ),35% H2O 2 ( 50 equiv ),
M eOH, H2 O, rt, 6 h
53% ª30%
N
N
N
O
MeMe O
PMBH
ON
N
N
O
MeMe O
PMB
O
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
Final Oxidation and Dimerization
Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 3892.
NaBH3CN (50 equiv),
AcOH, rt, 12 h
93%
NH
HN
N
O
O Me
MeMe
MeO
(+)-stephacidin A
NH
HN
N
O
O Me
MeMe
MeO
HH
SeO2 (0.25 equiv ),35% H2 O2 (50 equiv),
d iox ane, r t. 40 h
27%50% of s.m. recovered
N
HN
N
O
O M e
M eMe
MeOO
N
HN
N
O
O Me
MeM e
M eOO
H
avra invi llam ide[a]D +11° (c = 0.1, CHCl3 )
natura l: [a]D +10.6° (c = 0.17, CHCl3)LCMS , Rf data agree with li terature
N
N
N
O Me
MeMe
MeO
N
NH
N
O
O Me
MeMe
MeO
OH
O
O H H
stephacidin B[a]D = -33° (c = 0.1, CHCl3)
natural: [a]D = -21.1° (c = 0.19, CHCl3)LCMS, Rf, 1H NMR data agree with literature
prep. TLC, EtOAcor
concentration from DMSO
Myers’ Non-Bioinspired Approach
N
N
NOMe
MeMe
Me O
N
NH
N
O
OMe
MeMe
Me O
HO
O
OHH
ent-stephacidin B
N
HN
N
O
OMe
MeMe
Me OO
ent-avrainvillamide
O2N
HN
N
O
O
Me MeMeO
O
HN
N
O
MeMeO
O
I+
O
Me
Me X
NO2
Me
HN
N
TBDPSO MeMe
O
HPhS
Boc
N
TBDPSO MeMe
Boc
O
TBDPSO MeMe
O
Cross-Coupling/Reductive Condensation Model Study
OM e
Me
Me Me
I2 (3 equiv),DM AP (0.2 equiv),
CCl4 /pyridine, 49 °C
OM e
Me
Me Me
I
96%
O2 N
( HO )2 B
(1 equiv), Pd2 (dba)3 (5 mol %) ,P (2-b iph) (t-Bu)2 (20 mol%),
Ba(OH)2 •8H2 O ( 3 equiv),THF/H2 O, 38°C
or
O2 N
I
( 2 equiv), P d2 (dba) 3 (2 .5 mol %),Cu (5 equiv ), DM SO, 70°C
OMe
M e
Me M e
O2 N
Z n (2.7 equiv) ,1 M NH4 Cl (2 .2 equiv) ,
EtOH, 48°C
73% (S uzuki)70% (Ul lm ann)
M e
Me
Me Me
NO
48%
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
Construction of Ring Systems
TB DP SO M eMe
OO
1 N H2 SO4
ac etone/H2 O/THF,0 to 23 °C, 3 .5 h
99%
T BDPS O MeM e
O
OS
i-P r
O ON
Boc
K HMDS ( 1.1 equiv ), THF, -35 °C, 30 h
(1 equiv )
TBDP SO M eMe
ON
B oc
70%
TBDPSO MeMe
ONBoc
NCTMSCN
(3 equiv),
HFIPA,0 °C, 4 d
d.r = 4:165% (major)16% (minor)
1. KHMDS(2.6 equiv),
THF, -78 to 23 °C,17 min.
2. PivOH, THF,-78 °C to 23 °C,
15 min.TBDPSO Me
Me
ONBoc
NC
85%Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
O MeMe
OO 1. LHMDS (1.1 equiv),
TMSCl (1.32 equiv),-78 to 23 °C, 45 min.
2. Pd(OAc)2 (1.2 equiv),MeCN, 23 °C, 2 d O Me
Me
OO
98%for large scale: IBX (3.5 equiv),MPO•H2O (3.5 equiv), DMSO,60 °C, 2.5 d, 70%
N BO
Me
HPh Ph
(10 mol %),BH3•DMS
THF, 0 °C, 26 hHO Me
Me
OO
96%, e.r > 97.5:2.5
TBDPSOTf(1.15 equiv),2,6-lutidine(1.5 equiv),
CH2Cl2, 23 °C, 17 h
99%
Formation of Bicyclo[2.2.2]diazaoctane Moiety
TM SOTf(5 equiv) ,
2 ,6-lu tid ine(10 equiv) ,
CH2Cl2,-78 to 0 °C,
40 m in.
HN
NH
TB DP SO MeMe
O
HPhS
Cl
OM e
(4.5 equiv) ,i-P r2 EtN
(6 equiv ),
CH2Cl2, 23 °C, 24 h
HN
N
TB DP SO M eM e
O
HPhS
OM e
t-AmO
O Ph
O
(1 equiv ),
t-BuPh, 119 °C,75 m in.
98% 92% 62%
HN
N
O
MeMeO
TBDPSO
HF,
MeCN,35 °C, 33 h
93%
HN
N
O
MeMeO
HO
Dess-Martinperiodinane(2.14 equiv),
CH2Cl2, 23 °C,40 min.
85%
HN
N
O
MeMeO
O
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
TBDPSO MeMe
O
NBoc
NC
OP
PtPO
H
MeMeMe
Me
(20 mol %)
EtOH/H2O70 °C, 1 h
PhSH (5 equiv),Et3N (10 equiv),
THF, 70 °C, 3.5 hTBDPSO Me
Me
O
NBoc
NH2
O
85% 95%
P HHOMe Me
HN
N
TBDPSO MeMe
O
HPhS
Boc
HO
Key Coupling/Reductive-Condensation Steps
HN
N
O
MeMeO
O
I2 (3 equiv),DMAP (3 equiv),
CCl4/pyridine, 60 °C,10 h
91%
HN
N
O
MeMeO
O
I
NO2
B
(1 equiv), Pd2(dba)3 (40 mol %),P(t-Bu)2(2-biph) (0.93 equiv),
Ba(OH)2•8H2O (3 equiv),THF/H2O, 40°C
or
NO2
I
(2.5 equiv), Pd2(dba)3 (10 mol %),Cu (5 equiv), DMSO, 70°C
56% (Suzuki),72% (Ullmann)
OMe
Me
OMe
Me
O
O
MeMe
Me
Me
O2N
HN
N
O
O
Me MeMeO
O
Me
Zn (2.2 equiv),1M NH4Cl (2.2 equiv),
EtOH, 40 °C
49%
N
HN
N
O
OMe
MeMe
Me OO
ent-avrainvillamideMyers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
Very Facile Dimerization
N
N
NOMe
MeMe
Me O
N
NH
N
O
OMe
MeMe
Me O
HO
O
OHH
ent-stephacidin Balso charaterized by:
Rf, 1H NMR, HRMS (FAB), [a]D
N
HN
N
O
OMe
MeMe
Me OO
ent-avrainvillamide[a]D = -35.1° (c = 0.1, CHCl3)
natural: [a]D = +10.6° (c = 0.17, CHCl3)also characterized by:
Rf, 1H, 13C NMR, HRMS (CI), [a]D
Et3N,
MeCN, 23 °C, 3.5 h
>95%
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
Comparison of Two Syntheses
N
HN
N
O
O Me
MeMe
MeOO
oxidaiton
self-reproductionof chirality
amidation
amidation
pericyclic reactions
radical oxidativecyclization
substrate control
N
HN
N
O
OMe
MeMe
Me OO
radical cyclization
Strecker-typeaddtion
relayed from adestroyed stereocenter
reductive cyclization alkylation
relayed from adestroyed stereocenter
Suzuki/Ullmanncopling
substrate control
Summaryn General methods to construct bicyclo[2.2.2]diazaoctane
n SN2’ cyclizationn Biomimetic Intramolecular Diels-Aldern Drawback: moderate selectivity
n Bioinspired total synthesisn Molecule built around tryptophann Chiral-pool material used (natural and unnatural proline)n Absolute configuration established unambiguouslyn Highlights:
n Fe-promoted oxidative enolate couplingn Cascade pericyclic reactions
n Non-bioinspired total synthesisn Molecule built around dimethylcyclohexene ringn Stereochemistry set by enantioselective CBS reduction and relayed to the
rest of the moleculen Highlights:
n Aminoacyl radical cyclizationn Suzuki/Ullman couplingn Zn-promoted reductive cyclization
Propargylic Claison Rearrangement
O NH
NHCbz
CO2Me
MeMe
O NH
NHCbz
CO2Me
Me
Me
[3,3]
O NH
NHCbz
CO2 Me
Me
M e
Ac OH,
120 °C,80 m in.
O NH
NHCbz
CO2 Me
•M e
Me
O NH
NHCbz
CO2 Me
•M e
M e
H
[3,3] [1,5]-sh i ft
Metal Promoted Oxidative Coupling of Enolates
O
O
+HN
1. LHMDS(3 equiv),
THF, -78°C
2. copper(II)2-ethylhexanoate
(1.5 equiv)
(2 equiv)
O
ONH
54%
O
+
HN
1. LHMDS(4 equiv),
THF, -78 to 0 °C
2. copper(II)2-ethylhexanoate(1.5 equiv), 3 h
(3 equiv) 53%, d.r. > 20:1
Me
Me OMe
Me
NH
R1
R2
OLi
+
N
Cu(II)
R1
R2
OCu
N
Cu(III)
Cu(II)Cu(I) Cu(I)
R1
R2
O N
R1
R2
O HN
Cu-promoted intermolecular reactions
Fe-promoted intramolecular reactions
NPh
Ot-Bu
LiO
Fe+
, TEMPO,
THF, HMPA, -78 to -60°C
PF6-
NPh
Ot-Bu
O
N
t-BuO2C
Ph
OTMP
85%, cis:trans = 1.3:1
Baren, P. S. et al. J. Am. Chem. Soc. 2004, 126, 7450.Baren, P. S. et al. Angew. Chem. Int. Ed. 2005, 44, 609.
Jahn, U. et al. J. Am. Chem. Soc. 2000, 122, 5212.
Oxidation of 2° Amines to Nitrones
Na2WO4-catalyzed SeO2-catalyzed
NH
Me
Na2WO4•4H2O(4 mol %), H2O2
(3 equiv),
0 °C, 3 h, H2O N MeO88%
N Me
w-OH + H2O
w-OH
w-OOH
w = WO3-, WO4
-, WO6-
OH
NH
SeO2(5 mol %), H2O2
(5 equiv),
0 °C, 3 h, acetone NO88%
N
HOSe(O)OOH
SeO2 + H2O2
H2SeO3
OHN
O OH
HOSe(O)OOH
H2O
SeO2 + H2OH2SeO3
Murahashi, S.-I. et al. J. Chem. Soc., Chem. Commun. 1984, 874. Murahashi, S.-I. et al. Tetrahedron Lett. 1987, 28, 2383.
R1
O
R2
H
OI
O
OHO
R1
O
R2
IOH
HO
O
R1
O
R2
IOH
HO
O
SE T
R1
O
R2
IOH
HO
O
H
H2 O
R1
O
R2
OI
O
HO
+
Oxidation of Ketones to EnonesPd(II)-promoted
IBX•N-oxide-promoted
R1
OSiMe3Pd(II)X2
R1
H
O PdX
2
b-hydrideelimination
R1
O
HX + Pd(0)
R2R2 R2
Saegusa, T. et al. J. Org. Chem. 1978, 43, 1011. Nicolaou, K. C. et al. Angew. Chem. Int. Ed. 2002, 41, 993.
can be turned into a catalytic process by employing benzoquinone as a co-oxidant
CBS Asymmetric Reduction of Ketones
Corey, E. J. et al. J. Am. Chem. Soc. 1987, 109, 874. Corey, E. J. et al. Angew. Chem. Int. Ed. 1998, 37, 1986.
P h
P h
NH
O H
P hPhH
M eB(OH)2( 1.1 equiv ),to luene, D
N
H
BO
P hPh
Me
N
H
BO
PhP h
M eH3 B
B H3•DM S
O
OO
MeM e
NB
O Me
H2 B H
P h
Ph
O
OO
M eM e
NB
O Me
BH2
hydride del iv er ed to the S i face
O O
OB H2
Me
M eHCl,
M eO HO O
OH
Me
M e
O O
O
M e
Me
H
Synthesis of the Alkylating Agent
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
N
B oc 1. n -BuLi (1 .1 equiv) , -20 °C, 3 h2. DMF ( 1.5 equiv ), -78 °C, 30 m in.
3. NaB H4 (1.1 equiv) , M eOH, 0 °C, 35 m in.
N
B oc
OH
i -P rSO2 Cl (1 .1 equiv) ,Et3 N (1.1 equiv),
CH2 Cl2 , 0 °C, 35 min.
NBoc
OS
i -Pr
OO
59% 97%
Pt-Catalyzed Hydrolysis of Nitriles
PtP
P P
H
O
OH OH
Me Me
MeMe
Me Me
PtP
P P
OH
O
OH OH
Me Me
MeMe
Me Me
PtP
P P
S
O
OH OH
Me Me
MeMe
Me Me
S = H2O, EtOH
OH-
PtP
P P
N
O
OH OH
Me Me
MeMe
Me Me
OH-
CR
PtP
PO
OH
Me Me
MeMe
OH-
N
OP
R
Me Me
PtP
PO
OH
Me Me
MeMe
OH-
NH2
OPMe Me
ROH
H
RCN
H2O
H2N R
O
H2O H2
Parkins, A. W. et al. Tetrahedron Lett. 1995, 36, 8657.Parkins, A. W. et al. J. Mol. Cat. A 2000, 160, 240.
X-Ray Structure of an Intermediate Analogue
Myers, A. G. et al. J. Am. Chem. Soc. 2003, 125, 12080.
Generation of Aminoacyl Radical
MeO
NPh
Rt-Am•
H H
MeO
NPh
R N PhR
O
Me
Walton, J. C. et al. Chem. Commun. 2000, 2327.Walton, J. C. et al. Org. Biomol. Chem. 2004, 2, 421.
A Biomimetic Model Study
MeMe Me
O (EtO2C)2, NaOH,
EtOH, reflux, 3 hMe Me
OOH
EtO2C
65%
LiOH,
THF, EtOH,H2O Me Me
OOH
HO2C
87%
HN
N
O
Me MeO
N
N
OH
O
O
NH
CO2 NH2
DCC,
CH2 Cl2 , re flux, 12 h
N
NH
O
O
O
M e
H
Me
+
N
OH
O
O
M e Me
CONH2
61%
O
M eM e4 M HCl ,
d ioxane
45%
N
N
OBoc
O
OBoc
M e Me
Boc2 O,DMA P,CH2 Cl228%
AlCl3 ,EtOA c,re lux,5 d
81%
H
relative stereochemistryverified by NOE experiments
Williams, R. M. et al. Tetrahedron Lett. 2004, 45, 4489.