yassir el-azizi literature meeting a. charette group 15 feb. 2005
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Yassir EL-AZIZI
Literature meeting A. Charette group
15 Feb. 2005
Statins Family: Cholesterol-Lowering Drugs
• Statin drugs constituted 6% of the total annual sale of the top 200 drugs in
1999, worth $125 billion in the USA.
Statins Family: Cholesterol-Lowering Drugs
MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, 2004, 82, Number 24, 47-62
•Introduction
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
OH
O
OHO
O
Lovastatinmevinolin, monacolin K, Mevacor®, Merck
First to be marketed in 1987
OH
O
OHO
O
O
HO
H
OH
HO
O
O O-, Na+
Pravastatineptastatin, Pravachol®,
Bristol-Myers Squibb/Sankyo
SimvastatinSynvinolin, Zocor®, Merck
OH
O
OHO
O
Mevastatincompactin, ML-236B, CS-500
METKINEN OYBalkanpharma-Razgrad AD
OHH
O
OHO
Monacolin J
H
O
OHO
Monacolin L
OH
O
OHO
OO
Monacolin X
OH
O
OHO
OOH
Monacolin M
H
H
Statins Family: Cholesterol-Lowering Drugs
O
ONa
N
F
OH OH
Lescol® (fluvastatin sodium)
NOVARTIS
O
OH
O
N
OHN
F
Lipitor®Atovarstatin
Pfizer
O
OH
O
N
N
F
NSO
O
CO2NaOHOH
N
H3CO
F
Baycol®Cerivastatin sodium
Bayer
Crestor®RosuvastatinAstraZeneka
FDA approval in Aug. 2003
CO2-
OHOH
N
F
2
Ca2+
pitavastatin (NK 104)
phase III clinical trials
OH
O
OHO
O
Lovastatinmevinolin, monacolin K, Mevacor®, Merck
First to be marketed in 1987$389.5m
FERMENTATION
OH
O
OHO
OO
HO
H
OH
HO
O
O O-, Na+
Pravastatineptastatin, Pravachol®,
Bristol-Myers Squibb/SankyoFDA approval in 1996
$1.18bOXIDATION FROM Mevastatin
SimvastatinSynvinolin, Zocor®, Merck
FDA approval in 1998$2.3b
ESTER MODIFICATION FROM LOVASTATIN
OH
O
OHO
O
MevastatinCompactin®, ML-236B, CS-500
SANKYOMETKINEN OY
Balkanpharma-Razgrad AD
OHH
O
OHO
Monacolin J
H
O
OHO
Monacolin L
OH
O
OHO
OO
Monacolin X
OH
O
OHO
OOH
Monacolin M
H
H
FERMENTATION
Statins : Natural and Natural-like structures
R1
R2
H
O
OHO
common main polyketide portion
hexahydro naphthalene ring system
R1= H, OH, O
O
O
O
O
OO
O
OOH
, , ,
R2= H, CH3, OH
‘…the mechanism involved in the control of endogenous cholesterol levels by statins makes these molecules suitable for therapeutic use…, Different
types of statins are currently available: the natural statins obtained directly by fermentation, and the semi-synthetic and synthetic statins . Cerivastatin,
a fully synthesized statin approved in the United States in 1997, has been employed until the recent withdrawal from the market. ’ *
Mini reviewManzoni* M, Rollini M., ‘Biosynthesis and biotechnological production of statins
by filamentous fungi and application of these cholesterol-lowering drugs’, Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-64.
Statins : Natural and Natural-like structures
•Introduction
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
+ HSCoA
H2CC
CH3HO
CH2C
O O
C SCoA
O
H2CC
CH3HO
CH2C
O O
H2C OH
2NADP+
2NADPHHMG-CoA
mevalonate
HMG-CoA Reductase
5-pyrophosphomevalonateisopentenyl pyrophosphate
geranyl pyrophosphatefarnesyl pyrophosphate
squalene 2,3-oxidosqualene
The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)
The Mevanolate Pathway: Cholesterol Biogenesis
HOHO
19 steps
Lanosterol Cholesterol
OH
HO
O O-
Binding site of the enzyme
HMG-CoA Reductase like inhibior
OH
O
OHO
O
Lovastatinmevinolin, monacolin K, Mevacor®, Merck
OH
O
OHO
O
O
HO
H
OH
HO
O
O O-, Na+
Pravastatineptastatin, Pravachol®,
Bristol-Myers Squibb/Sankyo
SimvastatinSynvinolin, Zocor®, Merck
OH
O
OHO
O
Mevastatincompactin, ML-236B, CS-500
METKINEN OYBalkanpharma-Razgrad AD
OHH
O
OHO
Monacolin J
H
O
OHO
Monacolin L
OH
O
OHO
OO
Monacolin X
OH
O
OHO
OOH
Monacolin M
H
H
Manzoni M, Rollini M., ‘Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs’, Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-564.
Natural statins
•Introduction and problematic
•Cholesterol biosynthesis
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
Total synthesis of natural and natural-like statins
R1
R2
H
O
OHOcommon main polyketide portion
Hexahydro or Octahydro naphthalene ring system Hexaline or octaline
R1= H, OH, O
O
O
O
O
OO
O
OOH
, , ,
R2= H, CH3, OH
Synthetic statins, The missing members of the family…
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.
Synthetic studies
1. Danishefsky, S.; Kerwin, J. F., Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 204, 358.2. Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982,47, 180. 3. Deutsch, E. A.; Snider, B. B. J. Org. Chem. 1982, 47, 2682.4. Prugh, J. D.; Deana, A. A. Tetrhedron Lett. 1982,23, 281.5. Yang, Y.-L.; Falck, J. R. Tetrahedron Lett. 1982, 23,4305.6. Heathcock, C. H.; Taschner, M. J.; R a n , T.; Thomas, J. A.; Hadley, C. R.; Popjak, G. Tetrahedron Lett.
1982, 23,4747. 7. Lee, T.-J.; Holtz, W. J.; Smith, R. L. J. Org. Chem. 1982,47,4750. MERCK8. Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373. 9. Kuo, C. H.; Patchett, A. A,; Wendler, N. L. J. Org. Chem. 1983, 48, 1991. 10. Deutsch, E. A,; Snider, B. B. Tetrahedron Lett. 1983, 24, 3701. 11. Funk, R. L.; Mossman, C. J.; Zeller, W. E. Tetrahedron Lett. 1984, 25, 1655. 12. Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett. 1984, 25, 2101. 13. Prasad, K.; Repic,O. Tetrahedron Lett. 1984,25, 2435. NOVARTIS14. R a n , T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1984, 49, 3994. 15. Rosen, T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 1190. 16. Burke, S. D.; Saunders, J. 0.; Oplinger, J. A.; Murtiashaw, C. W. Tetrahedron Lett. 1985, 26, 1131. 17. Guindon, Y.; Yoakim, C.; Bernstein, M. A,; Morton, H. E. Tetrahedron Lett. 1985, 26, 1185. 18. Kozikowski, A. P.; Li, C.3. J. Org. Chem. 1985, 50, 778.
Deutsh and Sinder approach to Hexaline system
O
O
.
O
O
OEtEtO
0.5% BHT, benzene, sealed tube.150°C-2h
Excusively
O
O
.
EtO
OH
O OEt
OO OEt
BrPGO
1-Base-catalyzed isomerizationgKOtBu,tBuOH, 12 h, 40 °C, 50%2-[O]
Deutsch, E. A.; Snider, B. B., J. Org. Chem. 1982, 47, 2682.
OH
O
OHO
O
(+) Compactin
Heatcock approach to the Octaline system, Total synthesis of (+) Dihydromevinolin
OH OOAlkylation DA
OO
OCl
Zeller intermediate
OO
3Endo
2Exo
OH
O
OHO
O
(+)Dihydro Mevinolin
OH OOAlkylation DA
OO
OCl
Zeller intermediate
OO
6Endo
1Exo
Re Face of the dienophile
Hecker,S.; Heathcock, C. H. J. Am. Chem. Soc. 1986, 108, 45861.
Heatcock approach to Octaline system, Total synthesis of (+) Dihydromevinolin
OO
OO
1-DA2-MethylCuprate
O O
MeCuprate Axial attack
OO 1-TsNHNH2
2-BuLi
Shapiro reaction
OH1-H2/ Lindlar
2-Ac2O3-m-CPBA4-BF3
OAc
HO
O3
OAc O
HO
OAc O
HO
DBU
OAcOH
HO
LiAl(tBuO)3OH
OH
H
1-TsNHNH22-BuLi
Shapiro reaction
OHO
H
OMe
PhO
1-Acylation
2- separation
O O
H
O
1-Acylation2- selective saponification3- swern oxydation
O
H
OO
O OH
(+) dihydro-mevanolin1-Wittig2- 3,4 hydrogenation with Et3SiH, (PPH3)3RhCl3- desillylation4-cetone reduction5-Lactonisation
MeO2CO
OSiR3
(MeO)3P
95:5
Heatcock approach to Octaline system
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
• New drug design approaches are geared towards making lovastatin analogs that will have longer interaction with the enzyme –increase duration of drug occupancy of active site.
• Structural modification: (Lee, et. al. 1982, Merck & Co)
• Structural modification and simplification: (Hoffman*, Stokker**, et. al. 1985, Merck & Co)
• suppression of the hexahydro-naphtaline system
• Progress toward the introduction of the (3 ,5-Disubstituted [ l, l’-biphenyl] system
Semi- synthetic statins, Modifications of Lovastatin
ClCl
F
O
HO O
HO
O
H
OO
O OH
LOVASTATIN
Synthetic statins, Hoffman- Stokker Modifications I
Cl
Cl
O
OHO
Hoffman, Stokker et al, J. Med. Chem. 1986, 28, 347-358
Synthetic statins, Hoffman- Stokker Modifications II
Hoffman, Stokker, J. Med. Chem. 1986,29, 170-181
ClCl
F
O
HO O
100 (+)
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrail synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
Semi- synthetic statins
O
ONa
N
F
OH OH
Lescol® (fluvastatin sodium)
NOVARTIS
O
OH
O
N
OHN
F
Lipitor®Atovarstatin
Pfizer
O
OH
O
N
N
F
NSO
O
CO2NaOHOH
N
H3CO
F
Baycol®Cerivastatin sodium
Bayer
Crestor®RosuvastatinAstraZeneka
FDA approval in Aug. 2003
F
Cl
Cl
O
OHO
O
OHO
O
OHO
Cl
Cl
O
OHO
O
OHO
2 145 3
Statins Family: Common side chain
R
O
OHO
OH
OOHOHR
1,3 syn diolAbsolute configuration
(3R, 5S)
Enzymatic and chemo-enzymatic approach
OH
OOOHR
Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols
Chemo and stereoselective epoxyde reduction
OH
OOHR
O
OHIodolactonization
(...)
R H
O+
BR
OH
R
O
O
R
O
O
R
O
O
OR
O
O
OH
(PhSe)2/ NaBH4
AcOH/ EtOH
H2O2/NaOH
MeOH
Grubbs cat.,Ist generation
Acylation
92-96% ee
[O]
R= PhCH2CH2- PhCH=CH- PhCH2OCH2-
O
H
R
H
HO
O
OH
Statins side chain, H. C. Brown approach
Yields:
•Allylboration with (-)-B-allyldiisopinacocamphenylborane 71-76%•Esterification 80% •RCM up to 84%•Epoxydation 86%•1,3-reduction of the epoxyde 87% (Miyashita conditions,ee up to 92%, 99% after recrystallization)
‘It is believed that this reduction proceeds via the formation of PhSeH’
(a) M. Venkat Ram Reddy, Herbert C. Brown*, P. Veeraraghavan Ramachandran*, J. Organomet. Chem. 624 (2001) 239–243.(b) P. Veeraraghavan Ramachandran*, Kamlesh J. Padiya, Vivek Rauniyar, M. Venkat Ram Reddy, Herbert C. Brown*, J. Fluorine Chem. 125 (2004) 615–620.
O
O
OHHO
Regioselective 1,3 reduction of epoxyde
R
O
O
O
Na+,Ph(BR3)Se-
R
O
O
OB(R3)-, Na+
SePh
Na+,Ph(BR3)Se-
R
O
OB(R3)-, Na+
OB(R3)-, Na+
2 EtOH
2 Na+,[BR3(EtO)]-
R
O
O
OH
M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikishi, Tetahedron, 53, 12469
Statins Family: Common side chain
R
O
OHO
OH
OOHOHR
1,3 syn diolAbsolute configuration
(3R, 5S)
Enzymatic and chemo-enzymatic approach
OH
OOOHR
Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols
Chemo and stereoselective epoxyde reduction
OH
OOHR
O
OHIodolactonization
(...)
Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach
O
O
OHHO
OO
CHO+
NO2
OTIPS
NO2
OH
OO OTIPS
OTIPSNO2O
O
1-DBU, CH3CN, 83%;2-CuCl, DCC, CH3CN, 87%;
OTIPS
OO
O
1-Zn, HOAc, THF 2-NaHSO3, EtOH-H2O 90%
OTIPSOHO
O
LiI, LAH, Et2O, -78°C
yield 93%syn: anti > 99:1
OHOBnO
O
OOO
OH
OH
1- NaH, BnBr, TBAI, THF2-TBAF, THF, 76%3-NaIO4, RuCl3.3H2O, CCl4-CH3CN-H2O,
1-p-TsOH, CH2Cl2, 65%
2-H2, Pd(OH)2,, EtOAc, 85%
(a) Arun K. Ghosh* and Hui Lei, ‘Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols and Synthesis of Compactin and Mevinolin Lactone’, J. Org. Chem., 2002, 67, 8783-8788.
(b) Narasaka*, K.; Pai, F., Tetrahedron 1984, 40, 2223.(c) Chen, K.-M.; Hardtmann, G. E.; Prasad*, K.; Repic*, O.; Shapiro, M., Tetrahedron Lett. 1987, 28, 155. (Novartis)
,
Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach
OTIPS
OO
O
Li H
OR
OO
O
Li
R= Bn, CHPh2, Tr, TIPS
OROO
O
Li Li
Li
syn:anti= 2.4:1; 7.5:1;11.5:1;99:1
OBnOO
O
Li
OBn
OO
O
Li
syn:anti= 2.4:1
Arun K. Ghosh* and Hui Lei, , J. Org. Chem., 2002, 67, 8783-8788.
,
Statins Family: Common side chain
R
O
OHO
OH
OOHOHR
1,3 syn diolAbsolute configuration
(3R, 5S)
Enzymatic and chemo-enzymatic approach
OH
OOOHR
Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols
Chemo and stereoselective epoxyde reduction
OH
OOHR
O
OHIodolactonization
(...)
Statins side chain, Via IodolactonizationSubstarte controlled
O
OOONC
(a) Stanislav Ràdl,* Jan Stach and Josef Hajicek, Tetrahedron Letters, 43 (2002) 2087–2090(b) Butler, D. E.; Deering, C. F.; Millar, A.; Nanninga, T. N.; Roth, B. D. (Warner-Lambert Co.) US Patent 5,245,047.
OH OI
O
O
OONC
O
OONC
O
(i) BuLi/THF(ii) CO2 (iii) I2
(iv) p-TsOH, acetone, rt;
(v) KCN/DMSO, 40°C;
(vi) OsO4–NaIO4/dioxane–H2O; or (vii) O3; then (viii) Me2S;(ix) CrO3–H2SO4
acetone, 0°C
90%
75-80%
70%
OOI
OONC
91%
65%-70%
OH
OONC
O
X (x) mCPBA/CH2Cl2, rt;(xi) H5IO6/Et2O, rt;
86%60%
(xii) CrO3, H5IO6, acetone.
Cis-Racemate
Reagent Controlled Iodolactonizations are rare…
R1 CO2H
R1 = para-substituted aryl groups
NH2
ICl (1 eq.)
(2 eq.)
-78 oCCH2Cl2
OOR1
I
approx. 5 - 25 % ee
O
R1
OH
R1 = aryl groups
N
R3
R2OH
X
(30 mol %)
CH2Cl2, NaHCO3 aq, I2, 0 oC OR1
I
O O O
I
R1+
yield = 37 - 93 % (combined, though typically 5-exo products are
heavily favoured))
approx. 6 - 28 % ee
Haas, J.; Piguel, S.; Wirth*, T. Org. Lett. 2002, 2, 297 – 300.
Wang, M.; Gao*, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874 – 2876.
Reagent Controlled Iodolactonizations are rare…
2. I2, -78 oC, CH2Cl2
1. 30 mol % salen-Co, NCS. PhMe, rt, 30 min,
N N
t-Bu
t-Bu t-Bu
t-BuO OCo
R1
HO
R1 = alkyl groups
OR1
I
yield = 83 - 94 %approx. 67 - 90 % ee
Kang, S. H.; Lee, S. B.; Park, C. H. J. Am. Chem. Soc. 2003, 125, 15748 – 15749.
Statins Family: Common side chain
R
O
OHO
OH
OOHOHR
1,3 syn diolAbsolute configuration
(3R, 5S)
Enzymatic and chemo-enzymatic approach
OH
OOOHR
Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols
Chemo and stereoselective epoxyde reduction
OH
OOHR
O
OHIodolactonization
(...)
OH
OH
C3 symmetryinternal plan of symmetry
HO OH
OHOH
OH
HO OH
OH
HO OH
Rh/CH2H2O
OTBDPS
TBDPSO OH
TBDPSiCl (2 eq)DMF Imidazole
PCC
OTBDPS
TBDPSO O
mCPBA
O
TBDPSO
TBDPSOO
1-EtOH/TFA2-PCC
OEt
OOPGOPG
O
Mixture of cis- cis and cis- trans
Statins side chain, Other methods…
O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519
Statins Family: Common side chain
R
O
OHO
OH
OOHOHR
1,3 syn diolAbsolute configuration
(3R, 5S)
Enzymatic and chemo-enzymatic approach
OH
OOOHR
Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols
Chemo and stereoselective epoxyde reduction
OH
OOHR
O
OHIodolactonization
(...)
MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, June 14, 2004, Volume 82, Number 24, p. 47-62
‘Despite the unrelenting pace of research in catalytic asymmetric chemistry, relatively few catalytic
enantioselective processes are currently operated on a commercial scale.
Until more bio- and chemocatalytic chiral routes are developed that are robust and cost-effective for
large-scale production, the bulk of optically pure compounds will have to be prepared through traditional chemistry, including conventional
syntheses based on chiral substrates or stoichiometric chiral induction and separations, such
as chromatographic resolutions’.
MAUREEN ROUHI
Stereoselective synthesis vs. traditional chemistry
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach
DERA
After 15 h, product isolated in 96% yield (98.5%ee), 619 g.L-1d-1.
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach
Statins side chain, Chemo-Enzymatic approach
R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)
(α-Chymotrypsine-BioFac)
Highly scalable process (400g in one batch)
Cl O
OORO
Statins side chain, Chemo-Enzymatic approach
R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)
PLE: Pig liver esterase
‘This so called ‘aza’-W ittig reaction, whichproceeds via an imine intermediate is promoted by a
phosphine reagent and a weak, sterically hindered acid’.R. Öhrlein
Cl O
OORO
Cl OEt
OO O(CH2Cl)2, 0°C, ethylene, AlCl3
89%OEt
OO O
Cl OEt
OO OH
Cl
PLE, pH7, 76%
OEt
OO O
N3
1- BEt3, NaBH4, 91%2-Dimetoxypropane, H+, 99%3-NaN3, DMF, 94%, ee 98.1%, de 98.8%
O OMe O OMe
Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach
DERA
Statins side chain, Total- Enzymatic approach
~‘Absolute’ stereo control>99.9% ee, >96.6% de
(a) Junjie Liu, Che-Chang Hsu and Chi-Huey Wong* , Tetrahedron Letters, 45 (2004) 2439–2441. Scripps RI, La Jolla. 10 dec 2003 (Early work since 1994)(b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.14 Nov. 2003
O
OOO
N3
Statins side chain, Total -Enzymatic approach
(b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.
O
OOO
N3
Statins side chain, Direct Cross Aldol approach
XH H
O O+ 2
Asymmetic catalyst O
OH
OHX
Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799
Statins side chain, Direct Cross Aldol approach
Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799
Statins side chain, Direct Aldol approach
XH H
O O+ 2
Asymetic catalyst O
OH
OHX
Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154
Statins side chain, Direct Aldol approach
Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154
Statins side chain, Direct Aldol approach (…)
Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579
Statins side chain, Direct Aldol approach (…)
Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579
N
RO
R H
O
OH
Houk/ List Model for Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions…
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475 – 2479.
Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579
Statins side chain, Direct Aldol approach (…)
•Introduction and problematic
•Cholesterol biosynthesis (what can we learn from a biochemical process?)
•The missing members of the family
•Merck reduction of complexity of natural statins
•Synthetic Statins
• Exemple of industrial synthesis: Lescol
Statins Family: Cholesterol-Lowering Drugs
OUTLINE
The story of Lescol®
O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519
O
ONa
N
F
OH OH
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