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Total Synthesis of Platensimycin
Zhensheng Ding October 19 2007
Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90 Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5 Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4 Nicolaou, K. C. Chem. Commun., 2007, 1922-3 Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8 Heretsch, P.; Giannis, A. Synthesis 2007, 2614-6 Ghosh, A. Org. Lett., 2007, 9, 4013-6 Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9 Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 9534 –5 Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5 Corey, E. J. Org. Lett., 2007, xxxx
O O
O
NH
HO
OH
COOH
Introduction
Super Drug: Platensimycin and Its Structure Features
http://www.chemistry.msu.edu/courses/cem958/FS06_SS07/irosha.pdf
O∗
∗
∗
∗
∗
O
O
NH
HO
OH
COOH
*
Tetracyclic motif Cage-like 6 chiral centers 3 tertiary carbons Ether linkage
Tetra-substituted resorcine Amino acid
Introduction
Outline
O
O
O
O
ketyl radical cyclization/ etherification
O O
OFnFn
O
H
FnFn
Fn= functional groups
O O
O
NH
HO
OH
COOH
amide bond formation
O O
O
H2N
HO
OH
COOH
OH +
O O
O
Fn Fn
Fn
Nicolaou
Introduction
NicolaouCorey
Nicolaou, K. C.; Angew. Chem., Int. Ed. 2002, 41, 996-1000.
Summary: Enone Synthesis from Ketone
Introduction
Summary: Enone Synthesis from Ketone
R
O
Base
TMSClR
OTMSPd(OAc)2 R
OPdOAc +TMSOAc
R R R
R
O
R
R
O
R
PhSeBr
BaseR
OSePh
R
OxidationR
OSePh
H
O
R
R
O
R
R
OOH
H
NaOHH2O
R
O
RR
Yamamoto
Nicolaou
Nicolaou
R
OOH
H
R
O
RRSnider
R
OOTf
HR
Tf2OBase
Base
Nicolaou’s
Nicolaou’ s Racemic Synthesis: Retrosynthesis
Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90
O
O
Me
4
O
O
6
Synthesis
Nicolaou’s
92%, 1:1 diastereomeric ratio
89%, two steps 84%, two steps
68%, two steps85%
Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90
Synthesis
Nicolaou’s
O
O
2.2 eq SmI2
1.5 eq (CF3)2CHOHTHF/ HMPA (10:1)-78 °C, 1min
O
14
OH
646%, ca. 2:1 d.r.
OSmI2
OSm (III) OSm (III) O
E+
H
E
R
RRh+
R
RRh+
R
[Rh]
R
Large-scale Synthesis of Monomer 5 of VAPOL
87%
88%
79%
85% 6:1 E/ Z
95% 95%
Nicolaou’s
Nicolaou, K. C. Angew. Chem. Int. Ed., 2006, 45, 7086-90
Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5
Nicolaou’s
Nicolaou’ s Asymmetric Synthesis: Retrosynthesis
Xumu Zhang’s chemistry
A. G. Myers’s chemistry
Nicolaou’ s Asymmetric Synthesis
Nicolaou’s
91% 90%
49%, 3 steps 90%
Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 3942-5
Summary
Pathway a) was able to scale up; expensive and toxic reagents; multiple step.
Cr(CO)6: $266/ 50g, toxic and carcinogen; BuLi: $107/ 800mL (2.5M), corrosive, highly sensitive to air
Pathway b) Moderate yield, one step synthesis; hard to purify, not suitable for old VAPOL synthesis.
Purpose: To find an efficient way to prepare both ligands with inexpensive starting materials.
How to optimize pathway b) ?
1) Solvent---must be high bp, inert, easily removable;
2) Lower the reaction temperature (base);
3) None-toxic reagents;
4) More efficient
Nicolaou’s
Nicolaou’ s Asymmetric Synthesis: Another Pathway
Redic, R.; Schuster, G. Journal of Photochemistry and Photobiology, A: Chemistry, 2006, 179, 66-74.
Nicolaou’s
100%
87%
91%
92%
94%
100%
90%
Nicolaou’s Analogues Synthesis: Adamantaplatensimycin
Nicolaou’s
Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4
Nicolaou’s Analogues Synthesis: Adamantaplatensimycin
Nicolaou’s
Nicolaou, K. C. Angew. Chem. Int. Ed., 2007, 46, 4712-4
51%, 4 steps
65%
88%
86%
Outline
Outline
O O
OFnFn
O
H
FnFn
Fn= functional groups
O O
O
NH
HO
OH
COOH
amide bond formation
O O
O
H2N
HO
OH
COOH
OH +
Yamamoto: Asymmetric DA-Robinson Annulation Sequence
Yamamoto’s
OCHO
O
8
Michael addition
OCHO
O OCHO
O
O Oaldol
9O
O
Me9H2O
Yamamoto: Asymmetric DA-Robinson Annulation Sequence
Yamamoto’s
O
O
O
O
O
O
O
Baeyerrearrangement O
H
O
3 4
Yamamoto: Asymmetric DA-Robinson Annulation Sequence
Yamamoto’s
O O Michael addition
O O O O
O Oaldol
9O
O
Me9
NH
B:
O O
N N N
Ghosh: Intramolecular Diels-Alder Reaction Retrosynthesis
Ghosh’s (Purdue U.)
O
OMe
Me
EtO2C
Diels-AlderO
OMe
Me
EtO2CO CO2Et
OMe
3
O
(+)-6Hg(OAc)2, THF, H2ONaBH4, MeOH
HOO
6aO
OH6b
OOH
O
mCPBA
OOH
HOHOHO
OO
6c 6d 6e
mCPBA
KOH
Oxidation
O
H
OO 5
a) Srikrishna, A.; Hemamalini, P. J. Org. Chem. 1990, 55, 4883. (b) Weinges, K.; Reichert, H. Synlett 1991, 785. (c) Weinges, K.; et al Liebigs Ann. Chem. 1993, 403. (d) Weinges, K. et al Chem. Ber. 1994, 127, 549.
Ghosh: Intramolecular Diels-Alder Reaction
Ghosh’s (Purdue U.)
Ghosh, A. Org. Lett., 2007, 9, 4013-6
Introduction
Outline
Fn= functional groups
O O
O
NH
HO
OH
COOH
amide bond formation
O O
O
H2N
HO
OH
COOH
OH +
O O
O
Fn Fn
Fn
Starting from decaline derivatives
Retrosynthetic Analysis: Summary
etherification
O
X
HO
ring closure
Mulzer's synthesis
CO2H
OMe
N2CH2TMS
O
O
Me
O O
etherification
O
E+
HO
O
O
O
HO
X
H
C-C bond formation
Kaliappan's synthesisNicolaou's synthesisSnider's synthesis
O
O
MeSN2 elimination
O
OH
E
O
OH
Eetherification
OH
HO
E+
Corey's synthesis
Caron-ring construction first
O
O
Me
O O
etherification
O
E+
HO
O
O
O
HO
X
H
C-C bond formation
Kaliappan's synthesisNicolaou's synthesisSnider's synthesis
Nicolaou, K. C. Chem. Commun., 2007, 1922-3 Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8 Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9
Nicolaou, K. C. Chem. Commun., 2007, 1922-3
Nicolaou’s Synthesis
Caron-ring construction first
64%
1) Protection 2) Oxidation (IBX)
86%
91%
85%
Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9
Kaliappan’s Retrosynthesis
Caron-ring construction first
O
O
MeetherificationC-C bond formation
Kaliappan, K. P. and Ravikumar, V. Org. Lett., 2007, 9, 2417-9
Kaliappan’s Synthesis
Caron-ring construction first
Snider’s Retrosynthesis
Caron-ring construction first
Zou, Y.; Snider, B. Org. Lett., 2007, 9, 1825-8
C-C bond formation
C-C bond formation etherification
Mulzer’s Synthesis
Caron-ring construction first
1) Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5 2) D. J. Beames, T. R. Klose, L. N. Mander, Aust. J. Chem. 1974, 27, 1269. 3) P. Anantha Reddy, G. S. Krishna Rao, Indian J. Chem. Sect. B 1981, 20, 100.
O
O
MeetherificationO
X
HO
ring closure
CO2H
OMe
N2CH2TMS
O O
Conclusions
1) Nicolaou’s racemic: 10 steps, 11%;
2) Nicolaou’s asymmetric: 16 steps, 5.6% using chrial catalysis; 11 steps, chiral auxiliary;
3) Snider’s: 7 steps + equilibration + one step for conversion of a diasteromer, 32%;
4) Mulzer’s: protecting-group-free; 5 steps from 7 (overall yield 20%);
5) Corey’s: 14 steps, 25.6%; (calculated by meeeee!)
6) Kaliappan’s: 13 steps, 5.6%; (calculated by meeeee!)
7) Yamamoto’s: 8 steps + one step for conversion of a diasteromer, 18% (calculated by me! not sure!!!)
Total synthesis of platensimycin
O O
O
NH
HO
OH
COOH
Mulzer, J. Angew. Chem. Int. Ed. 2007, 46, 8074-5