Abstract
The enantioselective total synthesis of the potent HMG-CoA reductase
inhibitors FR901512 (1 ) and FR901516 (2 ) is reviewed. FR901512 was prepared in
15 steps from commercially available compound via 2 in
16.3% overall yield (89% average yield). This
study validated the applicability and reliability of the catalytic
asymmetric Nozaki-Hiyama reactions that were developed
by us. These reactions enabled the concise, efficient, and protecting-group-free
enantioselective total syntheses of these new statins.
Key words
asymmetric catalysis - enantioselective synthesis - Nozaki-Hiyama reaction - structure elucidation - total synthesis
References
1a Hatori H.
Sato B.
Sato I.
Shibata T.
Tsurumi Y.
Sakamoto K.
Takase S.
Ueda H.
Hino M.
Fujii T.
J. Antibiot.
2004,
57:
264
1b Hatori H.
Sato B.
Sato I.
Shibata T.
Ueda H.
Hino M.
Fujii T.
J. Antibiot.
2004,
57:
390
2a Endo A.
J. Lipid Res.
1992,
33:
1569
2b Tobert JA.
Nat. Rev. Drug Discovery
2003,
2:
517
2c Statins:
The HMG CoA Reductase Inhibitors in Perspective
2nd
ed.:
Gaw A.
Packard CJ.
Shepherd J.
Martin
Dunitz;
London:
2004.
1 and 2 are the
first naturally occurring statins found to possess a tetralin core.
Total syntheses of statins incorporating a hexalin core or an octalin core
have been reported. For an early review, see:
3a Rosen T.
Heathcock CH.
Tetrahedron
1986,
42:
4909
3b Sammakia T.
Johns DM.
Kim G.
Berliner MA.
J. Am. Chem. Soc.
2005,
127:
6504
4 Inoue M.
Nakada M.
J. Am. Chem. Soc.
2007,
129:
4164
5a Inoue M.
Suzuki T.
Nakada M.
J. Am. Chem. Soc.
2003,
125:
1140
5b Suzuki T.
Kinoshita A.
Kawada H.
Nakada M.
Synlett
2003,
570
5c Inoue M.
Nakada M.
Org. Lett.
2004,
6:
2977
5d Inoue M.
Nakada M.
Angew. Chem. Int. Ed.
2006,
45:
252
5e Inoue M.
Nakada M.
Heterocycles
2007,
72:
133
5f Inoue M.
Suzuki T.
Kinoshita A.
Nakada M.
Chem. Rec.
2008,
8:
169
6a Vollhardt KPC.
Angew.
Chem., Int. Ed. Engl.
1984,
23:
539
6b Lautens M.
Klute W.
Tam W.
Chem.
Rev.
1996,
96:
49
6c Saito S.
Yamamoto Y.
Chem. Rev.
2000,
100:
2901
7 Yamamoto Y.
Nagata A.
Itoh K.
Tetrahedron
Lett.
1999,
40:
5035
8 Takeuchi R.
Tanaka S.
Nakaya Y.
Tetrahedron
Lett.
2001,
42:
2991
9a Sato Y.
Ohashi K.
Mori M.
Tetrahedron Lett.
1999,
40:
5231
9b Sato Y.
Tamura T.
Mori M.
Angew.
Chem. Int. Ed.
2004,
43:
2436
10 Trnka TM.
Grubbs RH.
Acc. Chem. Res.
2001,
34:
18
11 Jolad SD.
Rajagopal S.
Org. Synth., Coll. Vol. V
1973,
139
12 Wu X.
Nilsson P.
Larhed M.
J. Org. Chem.
2005,
70:
346
13 The use of ent -12 afforded ent -34 accordingly.
14 Crabtree RH.
Morris GE.
J. Organomet. Chem.
1977,
135:
395
15a Katsuura K.
Snieckus V.
Can.
J. Chem.
1987,
65:
124
15b Loh TP.
Hu QY.
Org.
Lett.
2001,
3:
279
16 CCDC 647745 contains the supplementary
crystallographic data (excluding structure factors) for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
17 Nicolaou KC.
Daines RA.
Uenishi J.
Li WS.
Papahatjis DP.
Chakraborty TK.
J.
Am. Chem. Soc.
1988,
110:
4672
18a Nagata W.
Hayase Y.
J.
Chem. Soc. C
1969,
460
18b Friese A.
Hell-Momeni K.
Zündorf I.
Winckler T.
Dingermann T.
Dannhardt G.
J. Med. Chem.
2002,
45:
1535
19 Grubbs RH.
Chang S.
Tetrahedron
1998,
54:
4413
20 Ghosh AK.
Lei H.
J.
Org. Chem.
2000,
65:
4779
21 Miyashita M.
Suzuki T.
Hoshino M.
Yoshikoshi A.
Tetrahedron
1997,
53:
12469
22 The specific rotation of 2 {[α]D
²5 -8.4
(c 0.35, MeOH)} differed significantly
from the reported value {Lit.¹a [α]D
²³ -16
(c 0.40, MeOH)}. However, we
soon found out that this difference was due to the methanolysis
of 2 during the measurement of the specific
rotation. That is, δ-lactone 2 was
converted into the methyl ester of 1 by
its reaction with MeOH, which was used as the solvent.
