Transcript Statins
Statins Family: Cholesterol-Lowering Drugs 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.
MAUREEN ROUHI , ‘CHIRAL CHEMISTRY’,
C&EN News
, 2004, 82, Number 24, 47-62
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
Introduction
•
Cholesterol biosynthesis
•
The missing members of the family
•
Merck reduction of complexity of natural statins
•
Synthetic Statins
•
Exemple of industrail synthesis: Lescol
O
Statins Family: Cholesterol-Lowering Drugs
HO O HO O O O O O O H O H HO O H O O , Na + OH Lovastatin mevinolin, monacolin K, Mevacor ® ,
Merck First to be marketed in 1987
HO O O HO O O O O H OH H Synvinolin, Zocor HO H H Simvastatin O O ® O ,
Merck
O O HO H HO Pravastatin eptastatin, Pravachol ® ,
Bristol-Myers Squibb/Sankyo
O O HO OH O O H O O N H Mevastatin compactin, ML-236B, CS-500
METKINEN OY Balkanpharma-Razgrad AD
Monacolin J F O O OH OH ONa O O S N N N O OH F
Lescol® (fluvastatin sodium) NOVARTIS
Crestor® Rosuvastatin AstraZeneka FDA approval in Aug. 2003 Monacolin L F HN O N Lipitor® Atovarstatin Pfizer Monacolin X O O OH H 3 CO F N OH OH CO 2 Na Baycol® Cerivastatin sodium Bayer Monacolin M F N OH OH CO 2 Ca 2+ pitavastatin (NK 104) phase III clinical trials 2
HO O O H O O
Statins : Natural and Natural-like structures
HO O O H O O Lovastatin mevinolin, monacolin K, Mevacor ® ,
Merck First to be marketed in 1987
$389.5m
FERMENTATION Simvastatin Synvinolin, Zocor ® ,
Merck FDA approval in 1998
$2.3b
ESTER MODIFICATION FROM LOVASTATIN HO O O , Na + OH O O H HO Pravastatin eptastatin, Pravachol ® ,
Bristol-Myers Squibb/Sankyo FDA approval in 1996
$1.18b
OXIDATION FROM Mevastatin O O HO H O O HO OH H H Mevastatin Compactin ® , ML-236B, CS-500 SANKYO METKINEN OY Balkanpharma-Razgrad AD Monacolin J O O HO H H O O O HO O O H Monacolin L Monacolin X FERMENTATION O O OH O HO O H Monacolin M O O
Statins : Natural and Natural-like structures
HO O O common main polyketide portion R 1 H hexahydro naphthalene ring system R 1 = H, OH, O R 2 O , O O , O O O , OH O O
R
2
= H, CH
3
, 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 review 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):555-64.
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
Introduction
•
Cholesterol biosynthesis
•
The missing members of the family
•
Merck reduction of complexity of natural statins
•
Synthetic Statins
•
Exemple of industrail synthesis: Lescol
The Mevanolate Pathway: Cholesterol Biogenesis The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation)
HO CH 3 C H 2 C CH 2 C SCoA O C O O HMG-CoA 2NADPH 2NADP + + HSCoA HO H 2 C HMG-CoA Reductase C CH 3 CH 2 H 2 C OH C O O mevalonate O O HO OH 5-pyrophosphomevalonate squalene 2,3-oxidosqualene HMG-CoA Reductase like inhibior isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate 19 steps Binding site of the enzyme HO HO Lanosterol Cholesterol
Natural statins O HO O H O O O HO O H O O HO O O , Na + OH O O H mevinolin, monacolin K, Mevacor O O HO H Lovastatin O O HO OH H ® ,
Merck
O O H Simvastatin Synvinolin, Zocor HO H ® ,
Merck
O O O HO O O H HO Pravastatin eptastatin, Pravachol ® ,
Bristol-Myers Squibb/Sankyo
O O OH O HO O H O O H Mevastatin compactin, ML-236B, CS-500
METKINEN OY Balkanpharma-Razgrad AD
Monacolin J Monacolin L Monacolin X Monacolin M 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.
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
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
Total synthesis of natural and natural-like statins HO O O common main polyketide portion Hexahydro or Octahydro naphthalene ring system Hexaline or octaline R 1 = H, OH, R 1 H R 2 O
R
2
= H, CH
3
, OH
O O O , O , O O , OH O O
Synthetic statins, The missing members of the family…
Synthetic studies 1.
2.
3.
4.
5.
6.
Danishefsky, S .; Kerwin, J. F., Jr.; Kobayashi, S . J. Am. Chem. Soc. 1982, 204, 358.
Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982,47, 180. Deutsch, E. A.; Snider, B. B.
J. Org. Chem. 1982, 47, 2682.
Prugh, J. D.; Deana, A. A. Tetrhedron Lett. 1982,23, 281.
Yang, Y.-L.; Falck, J. R. Tetrahedron Lett. 1982, 23,4305.
Heathcock, C. H.; Taschner, M. J.; R a n , T.; Thomas, J. A.; Hadley, C. R.; Popjak, G. Tetrahedron Lett. 1982, 23,4747. Lee, T.-J.; Holtz, W. J.; Smith, R. L. J. Org. Chem. 1982,47,4750. MERCK 7.
8.
9.
Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373. 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. NOVARTIS 14. 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.
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51 .
Deutsh and Sinder approach to Hexaline system EtO O OEt O .
O O 0.5% BHT, benzene, sealed tube.150°C-2h .
O
Excusively
EtO O OH O OEt 1-Base-catalyzed isomerizationg KO t Bu, t BuOH, 12 h, 40 °C, 50% 2-[O] PGO Deutsch, E. A.; Snider, B. B., J. Org. Chem. 1982, 47, 2682. O Br HO O O H O O (+) Compactin O OEt
Heatcock approach to the Octaline system, Total synthesis of (+) Dihydromevinolin HO O O O O H O OH O O O O Alkylation O DA (+)Dihydro Mevinolin Cl Zeller intermediate O 3 Endo 2 Exo Re Face of the dienophile OH O O Alkylation O DA Cl Zeller intermediate O 6 Endo Hecker,S.; Heathcock, C. H.
J. Am. Chem. Soc.
1986, 108, 45861.
O O O 1 Exo
Heatcock approach to Octaline system, Total synthesis of (+) Dihydromevinolin O O 1-DA 2-MethylCuprate O O MeCuprate Axial attack O O
Heatcock approach to Octaline system O O 1-TsNHNH 2 2-BuLi Shapiro reaction OH 1-H 2 / Lindlar 2-Ac 4-BF 2 3 O 3-m-CPBA OH O O OMe Ph O H O OH 1-Acylation 2- separation H 1-Acylation 2- selective saponification 3- swern oxydation MeO 2 C O O (MeO) 3 P OH 1-TsNHNH 2 2-BuLi Shapiro reaction OSiR 3 O OAc H O OAc H O O O OH O OH O 3 LiAl( t BuO) 3 OAc O H O DBU OAc O H O 95:5 H 1-Wittig 2 3,4 hydrogenation with Et 3 SiH, (PPH 3 ) 3 RhCl 3 desillylation 4-cetone reduction 5-Lactonisation H (+) dihydro-mevanolin
Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51 .
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
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
F • Semi- synthetic statins, Modifications of Lovastatin
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
Cl HO O O Cl O O O O OH HO H
LOVASTATIN
Synthetic statins, Hoffman- Stokker Modifications I HO O O Cl Cl
Hoffman, Stokker et al, J. Med. Chem.
1986, 28, 347-358
Synthetic statins, Hoffman- Stokker Modifications II F HO O O Cl 100 (+) Cl
Hoffman, Stokker, J. Med. Chem.
1986,29, 170-181
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
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
Semi- synthetic statins F HO O O Cl
5
Cl
4
HO O O HO O O
2
HO O O
1
HO O O Cl
3
Cl N F OH OH ONa
Lescol® (fluvastatin sodium) NOVARTIS
O O O S N N N F O O F OH HN O N Crestor® Rosuvastatin AstraZeneka FDA approval in Aug. 2003 Lipitor® Atovarstatin Pfizer O O OH H 3 CO F N OH OH Baycol® Cerivastatin sodium Bayer CO 2 Na
Statins Family: Common side chain
HO R O O
Enzymatic and chemo enzymatic approach
R OH O O OH Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols OH OH O R OH 1,3
syn
diol Absolute configuration (3R, 5S) Chemo and stereoselective epoxyde reduction Iodolactonization R OH OH O O OH (...)
O O HO R O H + OH R= PhCH 2 CH 2 PhCH=CH PhCH 2 OCH 2 B Statins side chain, H. C. Brown approach [O] R OH Acylation R O O Grubbs cat., I st generation O O O R O OH (PhSe) 2 / NaBH 4 AcOH/ EtOH R O
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’
O H H 2 O 2 MeOH
R
/NaOH H O O O R 92-96% ee H H O (a) M. Venkat Ram Reddy, Herbert C. Brown*, P. Veeraraghavan Ramachandran
*, J. Organomet. Chem.
(b) 624 (2001) 239 P. Veeraraghavan Ramachandran*, Kamlesh J. Padiya, Vivek Rauniyar, M. Venkat Ram Reddy, Herbert C. Brown*, –243.
J. Fluorine Chem.
125 (2004) 615–620.
O
Regioselective 1,3 reduction of epoxyde
Na + ,Ph(BR 3 )Se R O O O Na + ,Ph(BR 3 )Se R O O SePh OB(R 3 ) , Na + 2 Na + ,[BR 3 (EtO)] R O OB(R 3 ) , Na + OB(R 3 ) , Na + 2 EtOH R O O OH M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikishi, Tetahedron, 53, 12469
Statins Family: Common side chain
HO R O O
Enzymatic and chemo enzymatic approach
R OH O O OH Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols OH OH O R OH 1,3
syn
diol Absolute configuration (3R, 5S) Chemo and stereoselective epoxyde reduction Iodolactonization R OH OH O O OH (...)
O Statins side chain, Narasaka(84), Prasad(87),
Ghosh(2002)
approach O HO O OH O O NO 2 OTIPS O + CHO NO 2 OH OTIPS 1-DBU, CH 3 CN, 83%; 2-CuCl, DCC, CH 3 CN, 87%; O O OH O OH O 1-
p
-TsOH, CH 2 Cl 2, 65% 2-H 2, Pd(OH) 2, , EtOAc, 85% O O OBn OH O NO 2 OTIPS O 1-Zn, HOAc, THF 2-NaHSO 3 , EtOH-H 2 O 90% O O OTIP S LiI, LAH, Et2O, -78°C yield 93% syn: anti > 99:1 1- NaH, BnBr, TBAI, THF 2-TBAF, THF, 76% 3-NaIO 4, RuCl 3 .3H
2 O, CCl 4 -CH 3 CN-H 2 O, O O OH OTIPS (a) (b) 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.
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 Li O O O OR Li R= Bn, CHPh 2 , Tr, TIPS syn:anti= 2.4:1; 7.5:1;11.5:1;99:1 O O Li O Li OR O Li O O OBn O O O Li O O O Li OBn H OTIPS syn:anti= 2.4:1 Arun K. Ghosh* and Hui Lei, , J. Org. Chem., 2002 ,
67
, 8783-8788.
Statins Family: Common side chain
HO R O O
Enzymatic and chemo enzymatic approach
R OH O O OH Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols OH OH O R OH 1,3
syn
diol Absolute configuration (3R, 5S) Chemo and stereoselective epoxyde reduction Iodolactonization R OH OH O O OH (...)
Statins side chain, Via Iodolactonization Substarte controlled NC O O O O OH NC O O
Cis-Racemate
OH O
(i) BuLi/THF (ii) CO 2 (iii) I 2
I 91% O O O
(iv) p-TsOH, acetone, rt;
90% I O O
(ix) CrO 3 –H 2 SO 4 acetone, 0°C
NC 70% O X
(xii) CrO 3, H 5 IO 6, acetone.
O 75-80%
(v) KCN/DMSO, 40°C; (vi) OsO 4 –NaIO 4 /dioxane–H 2 O; or (vii) O 3 ; then (viii) Me 2 S;
NC O 65%-70% O O 60%
(xi) H 5 IO 6 /Et 2 O, rt;
86%
(x) mCPBA/CH 2 Cl 2, rt;
O O O NC (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.
Reagent Controlled Iodolactonizations are rare…
NH 2 I R 1 CO 2 H (2 eq.) R 1 O O ICl (1 eq.)
R 1 = para-substituted aryl groups
-78 o C
approx. 5 - 25 % ee
CH 2 Cl 2 Haas, J.; Piguel, S.; Wirth*, T.
Org. Lett
.
2002
,
2
, 297 – 300.
X R 2 O H N R 3 (30 mol %) R 1 I I + O CH 2 Cl 2 , NaHCO 3 aq, I 2 , 0 o C R 1 O O R 1 O O
R 1
OH
= aryl groups
yield = 37 - 93 % (combined, though typically 5-exo products are heavily favoured)) approx. 6 - 28 % ee
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…
HO R 1
R 1 = alkyl groups t
-Bu N N O Co O
t
-Bu
t
-Bu 1. 30 mol % salen-Co, NCS. PhMe, rt, 30 min, 2. I 2, -78 o C, CH 2 Cl 2
t
-Bu R 1 I O
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
HO R O O
Enzymatic and chemo enzymatic approach
R OH O O OH Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols OH OH O R OH 1,3
syn
diol Absolute configuration (3R, 5S) Chemo and stereoselective epoxyde reduction Iodolactonization R OH OH O O OH (...)
HO OH OH Statins side chain, Other methods… Rh/C H 2 H 2 O OH TBDPSiCl (2 eq) DMF Imidazole HO OH Mixture of
cis- cis
and
cis- trans
TBDPSO OTBDPS OH PCC O OPG OPG O OEt 1-EtOH/TFA 2-PCC TBDPSO TBDPSO O O OH OH HO mCPBA TBDPSO OH OH OTBDPS O OH
internal plan of symmetry C
O. Repic. K. Prasad,
Org. Pro. R&D
, 2001, 5, 519 3
symmetry
Statins Family: Common side chain
HO R O O
Enzymatic and chemo enzymatic approach
R OH O O OH Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols OH OH O R OH 1,3
syn
diol Absolute configuration (3R, 5S) Chemo and stereoselective epoxyde reduction Iodolactonization R OH OH O O OH (...)
Stereoselective synthesis vs. traditional chemistry
‘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 syntheses chemistry, based on including chiral conventional substrates or stoichiometric chiral induction and separations, such as chromatographic resolutions’.
MAUREEN ROUHI MAUREEN ROUHI , ‘CHIRAL CHEMISTRY’,
C&EN News
, June 14, 2004, Volume 82, Number 24, p. 47-62
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 Michael Muller,
Angew. Chem. Int. Ed.,
2005, 44, 362 –365
Statins side chain, Chemo-Enzymatic approach Cl O OR O O
( α-Chymotrypsine-BioFac) Highly scalable process (400g in one batch)
R. Öhrlein*, G. Baisch,
Adv. Synth. Catal.
, 2003, 345, 713 -715 (CIBA)
Statins side chain, Chemo-Enzymatic approach Cl O O O OMe O OEt (CH 2 Cl) 2, 0°C, ethylene, AlCl 3 89% Cl Cl O OR O O O OMe O O O OEt PLE, pH7, 76% Cl
PLE: Pig liver esterase
O OH O OEt 1- BEt 3, NaBH 4, 91% 2-Dimetoxypropane, H + , 99% 3-NaN 3 , DMF, 94%, ee 98.1%, de 98.8% N 3 O O O OEt ‘This so called ‘aza’-W ittig reaction, which proceeds via an imine intermediate is promoted by a phosphine reagent and a weak, sterically hindered acid’.
R. Öhrlein R. Öhrlein*, G. Baisch,
Adv. Synth. Catal.
, 2003, 345, 713 -715 (CIBA)
Statins side chain, Chemo-Enzymatic approach Michael Muller,
Angew. Chem. Int. Ed.,
2005, 44, 362 –365
DERA
Statins side chain, Total- Enzymatic approach N 3 O O O O
~‘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
Statins side chain, Total -Enzymatic approach N 3 O O O O (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.
X Statins side chain, Direct Cross Aldol approach OH O H + 2 O H Asymmetic catalyst X O OH 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
X O Statins side chain, Direct Aldol approach OH O Asymetic catalyst O + 2 H H X OH 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
Houk/ List Model for Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions…
R N O H R H O O Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B.
J. Am. Chem. Soc
.
2003
,
125
, 2475 – 2479.
Statins side chain, Direct Aldol approach (…) Review: S. Saito*, H. Yamamoto*,
Acc. Chem. Res.
2004, 37, 570-579
Statins Family: Cholesterol-Lowering Drugs OUTLINE
•
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
The story of Lescol ® N F OH OH ONa O O. Repic. K. Prasad,
Org. Pro. R&D
, 2001, 5, 519