Structure elucidation and enantioselective total synthesis of the potent HMG-CoA reductase inhibitor FR901512 via catalytic asymmetric Nozaki-Hiyama reactions

Article abstract of DOI:10.1021/ja070812w

The structure elucidation and enantioselective total synthesis of the potent HMG-CoA reductase inhibitor FR901512 were accomplished. FR901512 was prepared in 15 steps from the commercially available 2-bromo-4-methylbenzaldehyde via FR901516 in 16.3% overa

Full text of DOI:10.1021/ja070812w

Published on Web 03/17/2007
Structure Elucidation and Enantioselective Total Synthesis of the Potent
HMG-CoA Reductase Inhibitor FR901512 via Catalytic Asymmetric
Nozaki-Hiyama Reactions
Masahiro Inoue and Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda UniVersity, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Received February 5, 2007; E-mail: mnakada@waseda.jp
FR901512 (1) and FR901516 (2) (Figure 1), isolated from the
fermentation broth of agonomycete strain No. 14919,1 are new
specific and strong inhibitors of 3-hydroxy-3-methylglutaryl co-
enzyme A (HMG-CoA) reductase (IC50 values of 0.95 and 14.0
nM, respectively), and 1 inhibits cholesterol synthesis from [14C]-
acetate in Hep G2 cells with an IC50 of 1.0 nM. Single oral
administration of 1 strongly inhibits sterol synthesis in rats, and
daily oral administration of 1 to beagle dogs decreases plasma
cholesterol levels; hence, 1 is expected to have a hypolipidemic
effect in humans. Compared to the previously reported naturally
Figure 1. Structure of FR901512 (1) and FR901516 (2).
Scheme 1. Retrosynthetic Analysis of FR901512 (1) via 3
occurring HMG-CoA reductase inhibitors,2 1 and 2 possess a unique
tetralin core with two stereogenic centers instead of the hexahy-
dronaphthalene ring found in mevastatin and lovastatin.3 Further-
more, the side chain, 3,5-dihydroxy-6-heptenoic acid in both
compounds, differs from 3,5-dihydroxyheptanoic acid found in
mevastatin and lovastatin.
The potent bioactivity and unique structural features of 1 make
this compound an attractive target, and we report herein the
enantioselective total synthesis of 1 as well as elucidation of the
Scheme 2. Enantioselective Synthesis of 12 and 15a
absolute structures of both compounds.
Although 1 was chemically correlated to 2, the absolute structure
of 1 has not been elucidated1a and only a limited amount of 1 was
available. Hence, we decided to elucidate the structure of 1 through
asymmetric total synthesis. We have previously developed the
catalytic asymmetric Nozaki-Hiyama reactions,4 which were
widely applicable and reliable, providing both enantiomers of the
product with high enantiomeric excess because both enantiomers
of the chiral ligand are readily available. Therefore, we outlined
our retrosynthetic analysis of 1 as shown in Scheme 1.
We envisioned that the side chain moiety of 1 would be
connected at the benzylic position, and that both diastereomers of
the tetralin moiety 3 would be derived from 4 via a diastereose-
lective hydrogenation. We expected to obtain alkene 4 from 5 via
the ring-closing metathesis, and both enantiomers of 5 were thought
to be prepared by the catalytic asymmetric Nozaki-Hiyama
a Reagents and conditions: (a) n-BuLi, THF, -78 °C; DMF, 96%; (b)
methallylation of 6. Consequently, we decided to first elucidate
methallyl chloride, CrCl2 (5 mol %), 8 (6 mol %), Mn, DIPEA, TMSCl,
THF, rt, 93%, 92% ee; (c) Cl2(Cy3P)(IMes)RudCHPh (3 mol %), PhMe
the absolute structure of the tetralin moiety 3 and commenced with
the catalytic asymmetric preparation of 5.
(0.03 M), 50 °C, 96%; (d) H2, [Ir(cod)PCy3Py]PF6 (4 mol %), DME, 0 °C,
94%, dr ) >50/1; (e) s-BuLi, TMEDA, hexane, -10 °C; DMF, THF, -40
to 0 °C, 43%; (f) Ac2O, DMAP, THF, -78 °C, 70% (94% brsm); (g) Dess-
Martin periodinane, CH2Cl2, 0 °C; (h) NaBH4, CeCl3‚7H2O, MeOH,
-78 °C, 100% (2 steps), dr ) >50/1; (i) s-BuLi, TMEDA, hexane, -10 °C;
DMF, THF, -40 to 0 °C; (j) Ac2O, DMAP, THF, -78 °C, 13% (14%
conv, 2 steps).
Aldehyde 6 was prepared from readily available 75 via lithiation
and formylation (Scheme 2). The catalytic asymmetric Nozaki-
Hiyama methallylation of 6 successfully provided 5 with excellent
yield and enantioselectivity (93%, 92% ee).6 We employed Grubbs
second generation catalyst7 for the ring-closing metathesis of 5 to
generate the trisubstituted alkene 9 (96%). The hydroxyl group
directed hydrogenation of 9 with Crabtree’s catalyst8 in CH2Cl2 to
produce 10 with >50/1 dr; however, the yield was 59% because
the competing dehydration reaction occurred, generating the
naphthalene derivative in 33% yield.9 Conducting the reaction in
DME improved the yield (94%).10 The regioselective lithiation of
10 and subsequent formylation were crucial, providing 11 in 43%
yield under the optimized conditions. Acetylation of 11 above 0 °C
was low-yielding due to the formation of an unidentified byproduct,
but performing the acetylation at -78 °C improved the yield (94%,
74% conversion).11
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10.1021/ja070812w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Structure Elucidation of FR901512 (1)a
TBHP and Triton B in toluene, affording 22 as the sole product.17
The epoxide of 22 was reacted with diphenyldiselenide, NaBH4,
and acetic acid18 in THF/EtOH, providing 2 in 100% yield with
complete regioselectivity. Methanolysis of 2 and subsequent
cleavage of the resultant methyl ester furnished 1. The synthesized
1 and 2 were spectroscopically identical to natural FR901512 and
FR901516, respectively.
In summary, the structure elucidation and enantioselective total
syntheses of FR901512 and FR901516 were accomplished. FR901512
was prepared in 15 steps from the commercially available 2-bromo-
4-methylbenzaldehyde in 16.3% overall yield (89% average yield).
The catalytic asymmetric Nozaki-Hiyama reactions developed by
us proved their applicability and reliability through this work,
enabling the concise, efficient, and protecting-group-free enantio-
selective total syntheses of these new statins.
a Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 100%; (b)
p-bromobenzoyl chloride, DIPEA, CH2Cl2, 10 °C; (c) 3,5-dinitrobenzoyl
chloride, NEt3, DMAP, CH2Cl2, 75% (2 steps); (d) see Supporting
Information.
Scheme 4. Enantioselective Total Synthesis of FR901512 (1) and
FR901516 (2)a
Acknowledgment. This work is dedicated to Professor Masakat-
su Shibasaki on the occasion of his 60th birthday. We thank Drs.
Shigehiro Takase, Hidetaka Hatori, and Yuriyo Yamamoto (Astellas
Pharmaceutical Co. Ltd.) for kindly donating FR901512 and
FR901516. This work was financially supported in part by a Waseda
University Grant for Special Research Projects and a Grant-in-Aid
for Scientific Research on Priority Areas (Creation of Biologically
Functional Molecules (No. 17035082)) from MEXT, Japan. We
are also indebted to 21COE “Practical Nano-Chemistry.”
Supporting Information Available: Experimental and character-
ization details (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) (EtO)2P(O)CH2CHdN-cHex, KHMDS,
THF, -78 to -30 °C; aq. oxalic acid, 88%; (b) allyl bromide, CrCl2 (15
mol %), 8 (16 mol %), Mn, DIPEA, TMSCl, THF, 3 °C, 99%, 90% de; (c)
acryloyl chloride, DIPEA, CH2Cl2, 10 °C, 94%; (d) Cl2(Cy3P)2RudCHPh
(10 mol %), CH2Cl2 (0.005 M), reflux, 100%; (e) TBHP, Triton B, PhMe,
0 °C, 70%; (f) PhSeSePh, NaBH4, AcOH, THF/EtOH, 0 °C, 100%; (g)
MeOH, PhMe, rt; (h) TMSOK, THF, 0 °C, 95% (2 steps).
References
(1) (a) Hatori, H.; Sato, B.; Sato, I.; Shibata, T.; Tsurumi, Y.; Sakamoto, Y.;
K.; Takase, S.; Ueda, H.; Hino, M.; Fujii, T. J. Antibiot. 2004, 57, 264-
270. (b) Hatori, H.; Sato, B.; Sato, I.; Shibata, T.; Ueda, H.; Hino, M.;
Fujii, T. J. Antibiot. 2004, 57, 390-393.
(2) (a) Endo, A. J. Lipid Res. 1992, 33, 1569-1582. (b) Tobert, J. A. Nat.
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Shepherd, J., Eds. Statins: The HMG CoA Reductase Inhibitors in
PerspectiVe, 2nd ed.; Martin Dunitz: London, 2004.
(3) To the best of our knowledge, 1 and 2 are the first naturally occurring
statins possessing a tetralin core. Total syntheses of statins incorporating
a hexalin core or a octalin core have been reported. For an early review,
see: Rosen, T.; Heathcock, C. H. Tetrahedron 1986, 42, 4909-4951.
For a recent total synthesis of (+)-dihydrocompactin, see: Sammakia,
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The diastereomeric acetate 15 was successfully prepared from
10 via 13. Dess-Martin oxidation of 10 and subsequent highly
diastereoselective reduction with NaBH4 and CeCl3 (100%, >50/1
dr, two steps) provided 13, which was converted to 15 by the
transformations identical to those of the method for 12 from 10.
1
Comparison of the H NMR spectra of 12, 15, and 1 clearly
(4) (a) Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140-
1141. (b) Suzuki, T.; Kinoshita, A.; Kawada, H.; Nakada, M. Synlett 2003,
570-572. (c) Inoue, M.; Nakada, M. Org. Lett. 2004, 6, 2977-2980. (d)
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(6) Use of ent-8 afforded ent-5 accordingly.
indicated that the relative configuration of the tetralin moiety of 1
would be trans. Furthermore, alcohol 11 was gratifyingly trans-
formed to crystalline 16 via three steps (Scheme 3), and its X-ray
crystallographic analysis established the absolute structure of 16
as shown in Scheme 3. At the same time, we succeeded in preparing
17 and 18 from 1,12 and the alcohol prepared by reduction of 11
with NaBH4 was spectroscopically identical to 17 in all respects,
while the absolute structure of 18 was determined by comparison
with known ent-18.13 Consequently, we elucidated the entire
structure of FR901512 (1) as shown in Figure 1.
(7) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(8) Crabtree, R. H.; Morris, G. E. J. Organomet. Chem. 1977, 135, 395-
403.
(9) Hydrogenation of 9 with Wilkinson’s catalyst caused dehydration only.
(10) The naphthalene derivative formed only in 3% yield. The reaction in THF
provided 10 in 73% yield with 19% of the naphthalene derivative. The
basic solvents would reduce the acidity of Crabtree’s catalyst.
(11) The acetylation at 0 °C gave 12 in 58% yield (86% brsm).
Further synthetic studies were continued from 12 (Scheme 4),
but all the attempts to assemble the side chain moiety of 1 with 12
failed. However, reaction of 12 with Nagata’s reagent14 provided
aldehyde 19 in excellent yield (88%). Although a rather reactive
benzylic acetate was incorporated in aldehyde 19, the catalytic
asymmetric Nozaki-Hiyama allylation of 19 fortunately provided
20 with excellent yield and stereoselectivity (99%, 90% de).15
The acrylate of 20 was subjected to the ring-closing metathesis
with Grubbs second generation catalyst, but unexpectedly, a
complex mixture formed. Fortunately, the reaction with Grubbs first
generation catalyst16 afforded 21 in 100% yield. The chemoselective
and diastereoselective epoxidation of 21 was well achieved with
(12) See Supporting Information.
(13) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis, D. P.;
Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4672-4685.
(14) (a) Nagata, W.; Hayase, Y. J. Chem. Soc. C 1969, 460-466. (b) Friese,
A.; Hell-Momeni, K.; Zu¨ndorf, I.; Winckler, T.; Dingermann, T.;
Dannhardt, G. J. Med. Chem. 2002, 45, 1535-1542.
(15) The chiral ligand would induce this stereoselectivity because the reaction
of 19 with the racemic ligand 8 showed no selectivity.
(16) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(17) For the precedent synthesis of the â-hydroxy-δ-lactone moiety, see: Ghosh,
A. K.; Lei, H. J. Org. Chem. 2000, 65, 4779-4781.
(18) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron 1997,
53, 12469-12486.
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