Structure elucidation and enantioselective total synthesis of the HMG-CoA reductase inhibitors FR901512 and FR901516

Article abstract of DOI:10.1055/S-0029-1216980

The enantioselective total synthesis of the potent HMGCoA 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.

Full text of DOI:10.1055/S-0029-1216980

3694
FEATURE ARTICLE
Structure Elucidation and Enantioselective Total Synthesis of the
HMG-CoA Reductase Inhibitors FR901512 and FR901516
HMG-CoA
Reductase
a
Inhibitors
F
s
R901512
a
and
F
R901
h
516 iro Inoue, Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Fax +81(3)52863240; E-mail: mnakada@waseda.jp
Received 24 June 2009; revised 22 July 2009
ure 2).3 Furthermore, 1 and 2 contain 3,5-dihydroxyhept-
Abstract: The enantioselective total synthesis of the potent HMG-
6-enoic acid in the side chain, while mevastatin and
lovastatin contain 3,5-dihydroxyheptanoic acid in the side
chain.
CoA reductase inhibitors FR901512 (1) and FR901516 (2) is re-
viewed. 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 devel-
oped by us. These reactions enabled the concise, efficient, and pro-
tecting-group-free enantioselective total syntheses of these new
statins.
HO
H
O
HO
H
O
O
O
O
O
O
O
Key words: asymmetric catalysis, enantioselective synthesis,
Nozaki–Hiyama reaction, structure elucidation, total synthesis
H
H
mevastatin (compactin)
lovastatin (Mevacor®)
Introduction
Figure 2 Structures of mevastatin (compactin) and lovastatin
(Mevacor®)
A research group at the Fujisawa (now, Astellas) Pharma-
ceutical Company isolated FR901512 (1) and FR901516
(2) (Figure 1) from the fermentation broth of agono-
mycete strain no. 14919.1 Both these statins are new, spe-
cific, and strong inhibitors of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase (IC50 values of 0.95
and 14.0 nM, respectively). In addition, 1 inhibits choles-
terol synthesis from [14C]-acetate in Hep G2 cells with an
IC50 value of 1.0 nM. Single oral administration of 1
strongly inhibits sterol synthesis in rats, and daily oral ad-
ministration of 1 to beagle dogs reduces plasma cholester-
ol levels. Therefore, 1 is expected to have a hypolipidemic
effect in humans.
New statins 1 and 2 are attractive compounds from the
viewpoint of their potent bioactivity and unique structural
features. In 2007, we carried out the enantioselective total
synthesis of 1 and 2 and elucidated their absolute struc-
tures.4 This article presents a detailed review of the enan-
tioselective total synthesis of 1 and 2.
Results and Discussion
Although 1 had been chemically correlated to 2, the abso-
lute structure of 1 had not been elucidated.1a Hence, we
decided to elucidate the structure of 1 through enantiose-
lective total synthesis. A divergent synthetic approach is
required for this purpose, because all diastereomers and
enantiomers of the target compound must be prepared in
order to compare the spectroscopic data. A chiral starting
material with a known absolute configuration has often
been utilized for the total synthesis to elucidate the abso-
lute structure.
Unlike previously reported naturally occurring HMG-
CoA reductase inhibitors,2 1 and 2 possess a unique tetra-
lin core with two stereogenic centers, while mevastatin
and lovastatin possess a hexahydronaphthalene ring (Fig-
HO
HO
O
CO2H
OH
O
AcO
AcO
However, total synthesis using enantioselective reactions
is advantageous for introducing a stereogenic center into
the target molecule when asymmetric induction is diffi-
cult. Although it is necessary to confirm the absolute con-
figuration of the stereogenic center generated by the
enantioselective reaction, it would be a powerful tool for
enantiodivergent synthesis, because both enantiomers
and/or diastereomers of the target compound could be
produced when both enantiomers of the chiral reagent are
available.
FR901512 (1)
FR901516 (2)
Figure 1 Structures of FR901512 (1) and FR901516 (2)
SYNTHESIS 2009, No. 21, pp 3694–3707
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216980; Art ID: F12609SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3695
Ph
O
Ph
O
1) CrCl2 (10 mol%)
Mn, DIPEA, THF, r.t.
2) R1X, r.t.
R2
R1
OH
N
H
3) R2CHO, TMSCl, r.t.
4) TBAF or H+
N
N
R
R
3
(10 mol%)
allenylation
DMS
R2
propargylation
allylation, methallylation
R2
R2
R2
OH
OH
OH
OH
R2 = aryl, alkenyl, alkyl, steroidal
50_98%, 86_97% ee
R2 = aryl, alkyl
81_99%, 72_83% ee
R2 = aryl, alkenyl, alkyl
20_95%, 51_98% ee
Scheme 1 Ligand 3 and catalytic asymmetric Nozaki–Hiyama reactions with 3; DMS = dimethylsilyl
We have developed a new chiral ligand 35 (Scheme 1) and
R1
AcO
CHO
PO
used it for catalytic asymmetric Nozaki–Hiyama reac-
tions, allylations,5a,b methallylations,5a propargylations,5c
FR901512 (1)
and allenylations;5d these reactions are reliable and have
5
4
wide applicability.
tetralin moiety
OH R1
These enantioselective reactions yield both enantiomers
of the product with high enantioselectivity because the
chiral ligand 3 can be readily prepared in both enantio-
meric forms. Scheme 2 shows an outline of the retrosyn-
thetic analysis of structurally unknown 1.
R1
OHC
R2
6
7
We expected that the side chain moiety of 1 would be con-
nected at the benzylic position, and that both diastereo-
mers of the tetralin moiety 4 would be derived from 5 via
diastereoselective hydrogenation. In addition, we expect-
Scheme 2 Retrosynthetic analysis of FR901512 (1)
Biographical Sketches
Masahiro Inoue was born pervision of Prof. Masahisa 2007, he joined Daiichi San-
in 1979 in Mie, Japan. He Nakada. During his Ph.D. kyo Co., Ltd., where he is
received his B.S. (2002), course, he was appointed as currently a researcher. His
M.S. (2004), and Ph.D. assistant professor (2005– current research interests
(2007) degrees from Wase- 2007) and worked with are in the area of medicinal
da University under the su- Prof. Masahisa Nakada. In chemistry.
Masahisa Nakada was and joined Prof. Shibasaki’s He was awarded the Phar-
born in 1959 in Tokyo, Ja- group in 1991. He spent one maceutical Society Award
pan. He received his B.S. year and four months from for Young Scientist (1997)
(1982) and M.S. (1984) de- the beginning of 1992 as a and the SSOCJ Astellas
grees from the University of postdoctoral fellow with Award for Organic Chemis-
Tokyo, and was appointed Prof. K. C. Nicolaou at the try in Life Science 2008. His
as assistant professor at the Scripps Research Institute, research interests include
University of Tokyo during USA. He was promoted to the total synthesis of bioac-
his Ph.D. course in 1987. He associate professor at Wase- tive complex natural prod-
received his Ph.D. degree in da University in 1995. Since ucts, asymmetric catalysis,
1988 from the University of 2000, he has been a profes- new synthetic reactions, and
Tokyo (Prof. Masaji Ohno) sor at Waseda University. chemical biology.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3696
M. Inoue, M. Nakada
FEATURE ARTICLE
ed that alkene 5 would be obtained from 6 via ring-closing action. Although most oxidizing reagents afforded lactone
metathesis, and both enantiomers of 6 were anticipated to 10, pyridinium dichromate successfully afforded alde-
be produced by the catalytic asymmetric Nozaki–Hiyama hyde 11.
methallylation of 7. Consequently, we decided to first elu-
The enantioselective methallylation of 11 was carried out
cidate the absolute structure of the tetralin moiety 4, and,
with ligand 12 to afford a trimethylsilyl ether as the prod-
hence, we commenced the catalytic asymmetric prepara-
uct; which was treated with tetrabutylammonium fluoride
tion of 6.
to afford lactone 13 (Scheme 5). The yield and enantio-
Initially, the starting material 7 was prepared via the tran- meric excess of the product were unexpectedly low. This
sition-metal-mediated [2+2+2] cyclization of acetylene low ee could be attributed to steric hindrance, or the amide
and diyne 8 (Scheme 3), because this reaction was expect- group, which could act as a ligand for the catalyst and dis-
ed to efficiently introduce four successive substituents on turb the transition state. In fact, we had observed the same
the benzene ring of 7.
phenomenon in the enantioselective allylation of a similar
substrate.
R1
O
Ph
O
Ph
O
OHC
O
H
+
R2
N
H
H
R2
7
8
N
N
Scheme 3 Retrosynthetic analysis of aldehyde 7
O
N
O
O
12 (30 mol%)
methallyl chloride
O
The monoprotection of a hydroxy group of but-2-yn-1,4-
diol as a tert-butyldimethylsilyl ether (Scheme 4) and the
subsequent condensation of the resulting alcohol with but-
2-enoic acid yielded diyne 9. Diyne 9 was subjected to
transition-metal-mediated [2+2+2] cycloaddition with
acetylene. Although reactions mediated by cobalt,6 palla-
dium,7 and iridium8 did not yield the desired products, me-
diation by a nickel catalyst prepared in situ from nickel(II)
acetylacetonate and diisobutylaluminum hydride9 yielded
the desired lactone 10. The ligand suitable for this reaction
was found to be triphenylphosphine, and, interestingly,
the reaction with tricyclohexylphosphine selectively af-
forded another structurally unidentified product. The ring-
opening reaction of lactone 10 with morpholine proceed-
ed smoothly; however, the product readily released mor-
pholine to regenerate lactone 10. Therefore, one-pot
oxidation was carried out following the ring-opening re-
OHC
CrCl2 (30 mol%), Mn
DIPEA, TMSCl, THF
TBSO
HO
then TBAF
30%, 40% ee
11
13
Scheme 5 Enantioselective methallylation of aldehyde 11 with li-
gand 12. The ee of 13 was determined by HPLC [DAICEL CHIRAL-
PAK AS-H, 0.46 cm × 25 cm; hexane–i-PrOH, 3:1; flow rate, 0.5
mL/min; tR = 16.9 min (S), 23.7 min (R)].
Consequently, another aldehyde 15 that contained a vinyl
group instead of a (tert-butyldimethylsiloxy)methyl group
was prepared to examine the enantioselective reaction
(Scheme 6). The tert-butyldimethylsilyl ether 10 was
treated with tetrabutylammonium fluoride, and, subse-
quently, Parikh–Doering oxidation and the Wittig reac-
tion were carried out to afford lactone 14; lactone 14 was
O
O
O
O
O
O
OH
O
a_c
c
a, b
d
Ni
O
TBSO
OTBS
OH
but-2-yn-1,4-diol
OTBS
14
10
9
O
O
O
O
N
O
N
O
O
O
d
e
OHC
OHC
TBSO
TBSO
16
10
15
11
Scheme 6 Reagents and conditions: (a) TBAF, THF, 0 °C, 97%; (b)
SO3·py, Et3N, DMSO, CH2Cl2, 90%; (c) Ph3PMeBr, t-BuOK, THF, 0
°C, 91%; (d) morpholine, i-PrMgCl, CH2Cl2, 0 °C, then PDC, 0 °C,
60%; (e) 12 (30 mol%), methallyl chloride, CrCl2 (30 mol%), Mn,
DIPEA, TMSCl, THF, then TBAF, 8%.
Scheme 4 Reagents and conditions: (a) TBSCl, Et3N, CH2Cl2, 0 °C,
71%; (b) but-2-enoic acid, DCC, DMAP, CH2Cl2, –25 to –10 °C,
98%; (c) acetylene, Ni(acac)2 (20 mol%), DIBAL-H (40 mol%), Ph3P
(80 mol%), THF, hexane, 0 °C, 82%; (d) morpholine, i-PrMgCl,
CH2Cl2, 0 °C, then PDC, 0 °C, 75%.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3697
converted into aldehyde 15 according to the same proce-
dure as that shown in Scheme 4.
Table 1 Enantioselective Methallylation of Ynals or Ynal Equiva-
lentsa
CrCl2 (10 mol%)
ligand 12 (10 mol%)
Mn, TMSCl, DIPEA
The enantioselective methallylation of aldehyde 15 gave
a low yield because the pinacol coupling reaction of alde-
hyde 15 was the major pathway for the decreased yield.
This result could be attributed to the increased stability of
the radical anion derived from aldehyde 15, in which a vi-
nyl group was incorporated.
OH
Cl
+
RCHO
19a_f
R
THF, r.t., then H+
20a_f
Entry Aldehyde
Product Yield ee
(%)a (%)b
Next, we tried to synthesize compound 17 via the transi-
tion-metal-mediated [2+2+2] reaction of acetylene with
diyne 18, which would be prepared from aldehyde 19 by
enantioselective methallylation with ligand 12 (Scheme
7).
1
19a
20a
20b
66
52
46
50
TBSOCH2
CHO
2
19b
TMS
CHO
(OC)3Co Co(CO)3
TBSOCH2
3
4
19c
19d
20c
20d
0
0
–
–
CHO
O
Br
Br
OH R1
CHO
CHO
O
[2+2+2]
*
R2
17
*
+
5
6
19e
19f
20e
20f
0
–
R2
18
Br
H
H
CHO
31
90c
enantioselective
methallylation
TBSO
Cl
R2
OHC
19
a Reagents and conditions: methallyl chloride (2 equiv), CrCl2 (10
mol%), ligand 12 (10 mol%), Mn (2 equiv), TMSCl (2 equiv), DIPEA
(30 mol%).
Scheme 7 Retrosynthetic analysis of 17
b The ee was determined by 1H NMR analysis of the corresponding
(R)-a-methoxy-a-(trifluoromethyl)phenylacetic acid ester [(R)-
MTPA ester].
The enantioselective methallylation of aldehyde 19a af-
forded the desired product 20a; however, the yield and
enantioselectivity were low (Table 1, entry 1). The low
yield was attributed to the concomitant pinacol coupling
of aldehyde 19a. Moreover, the enantioselective reaction
of ynal 19b gave the same results as those shown in entry
1. The low yield and enantioselectivity of aldehydes 19a
and 19b (entries 1 and 2) could be attributed to their less
bulky structures. Therefore, we carried out the enantiose-
lective methallylation of a more bulky aldehyde, namely
hexacarbonylcobalt complex 19c (entry 3), which was
readily available from 19a. However, aldehyde 19c de-
composed during the reaction, and no desired product was
obtained.
c The ee was determined by HPLC [DAICEL CHIRALPAK OD-H,
0.46 cm × 25 cm; hexane–i-PrOH, 99:1; flow rate, 0.5 mL/min; tR =
43.3 min (S), 53.2 min (R)].
reaction of 24 and subsequent diisobutylaluminum hy-
dride reduction afforded diol 25 and the tetrahydrofuran
derivative 26 as a side product. The primary hydroxy
group of 25 was selectively protected as a tert-butyldi-
methylsilyl ether, and the subsequent ring-closing meta-
thesis with the Grubbs second-generation catalyst10
successfully afforded the dihydronaphthol derivative 27.
Although the optimization of the reaction conditions dur-
ing the preparation of compound 27 would improve the
overall yield, an alternative synthetic route to compound
27 was found to be more efficient. Consequently, the total
synthesis via the synthetic route shown in Scheme 8 was
not pursued.
Next, we carried out the reactions of enals 19d–f, which
are ynal equivalents. The reactions of 19d (Table 1, entry
4) and 19e (entry 5) yielded the same results as that of 19c
(entry 3), but the reaction of enal 19f yielded the desired
product 20f (entry 6). Although the yield was only 30%,
due to the concomitant pinacol coupling of the substrate,
the enantiomeric excess of 20f was 90%. Therefore, we
examined further synthetic studies using 20f, with the ob-
jective of achieving a total synthesis.
An extensive investigation of the enantioselective meth-
allylation of benzaldehyde derivatives with ligand 12 re-
vealed that the reactions of 2,6-disubstituted
benzaldehyde derivatives afforded the desired products,
but in low enantiomeric excess. Thus, we found that the
benzaldehyde derivative must have a hydrogen atom at
the ortho position to afford the product in high enantiose-
lectivity. We assumed that substituent R of compound 28
could be introduced by hydroxy-group-directed lithiation
of compound 29 (Scheme 9), which was to be obtained by
ring-closing metathesis of alcohol 30. Alcohol 30 would
Product 20f was treated with n-butyllithium to afford the
corresponding alkyne 20a, which was converted into but-
2-ynoate 21 (Scheme 8). The transition-metal-mediated
[2+2+2] cycloaddition of 21 with acetylene under Mori’s
conditions9 proceeded smoothly to afford the desired
product 23 in high yield, probably via intermediate 22.
Subsequent removal of the tert-butyldimethylsilyl group
and Dess–Martin oxidation afforded aldehyde 24. Wittig
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3698
M. Inoue, M. Nakada
FEATURE ARTICLE
Br
O
OHC
c, d
a, b
OH
O
H2N
OHC
a, b
c
32
33
31
Cl
OH
OTBS
Ni
RO
20f
21
OTBS
O
f
e
O
O
O
d, e
34
35 R = H
36 R = OTBS
g
TBSO
OTBS
Scheme 10 Reagents and conditions: (a) NBS, CHCl3, –50 °C,
94%; (b) NaNO2, HCl, –10 °C, H2C=NOH, NaOAc, CuSO4,
Na2SO3, HCl, reflux, 54%; (c) Ph3PMeBr, t-BuOK, THF, 0 °C, 92%;
(d) n-BuLi, THF, DMF, –78 °C, 96%; (e) methallyl chloride, CrCl2
(5 mol%), 12 (6 mol%), Mn, TMSCl, DIPEA, THF, 93%;
(f) [Ru(=CHPh)(IMes)(PCy3)Cl2] (3 mol%), toluene (0.03 M), 50 °C,
96%; (g) TBSCl, imidazole, CH2Cl2, 98%.
23
22
OH
O
OH
O
f, g
h, i
O
24
25
The enantioselective methallylation of aldehyde 31 with
ligand 12 successfully afforded alcohol 34 in excellent
yield and with excellent enantioselectivity (93%, 92% ee)
(Scheme 10).13 We used a Grubbs second-generation cat-
alyst under high dilution conditions for the ring-closing
metathesis of alcohol 34 to generate trisubstituted alkene
35 (96%). The protection of the hydroxy group of com-
pound 35 by reaction with tert-butyldimethylsilyl chlo-
ride afforded tert-butyldimethylsilyl ether 36.
OTBS
O
OH
27
26
Scheme 8 Reagents and conditions: (a) n-BuLi, THF, –78 °C, 53%;
(b) but-2-ynoic acid, DCC, DMAP, CH2Cl2, –25 to –10 °C, 100%; (c)
acetylene, Ni(acac)2 (20 mol%), DIBAL-H (40 mol%), Ph3P (80
mol%), THF, hexane, 0 °C; (d) TBAF, THF, 0 °C, 90% (2 steps); (e)
DMP, CH2Cl2, 0 °C, 88%; (f) Ph3PMeBr, t-BuOK, THF, 0 °C, 91%;
(g) DIBAL-H, CH2Cl2, hexane, –10 °C to r.t., 56%; (h) TBSCl, imi-
dazole, CH2Cl2, quant; (i) [Ru(=CHPh)(IMes)(PCy3)Cl2] (10 mol%),
toluene (0.02 M), 61%.
The stereoselective hydrogenation of compounds 35 and
36 was examined (Table 2). The hydrogenation of alkene
35 with Wilkinson’s catalyst merely provided naphtha-
lene derivative 39 (entry 1), whereas hydrogenation of 35
with Crabtree’s catalyst14 afforded trans-37 as a single
diastereomer. This stereoselectivity could be well ex-
plained by the directing effect of the hydroxy group. How-
ever, the reaction was accompanied by the formation of a
certain amount of 39 (33%) (entry 2). This aromatization
was believed to be due to the dehydration caused by Crab-
tree’s catalyst, which could act as a Lewis acid. Conse-
quently, the solvent effect on the hydrogenation was
examined. As Crabtree’s catalyst was almost insoluble in
diethyl ether, the reaction in diethyl ether afforded no
products (entry 3). The reaction in tetrahydrofuran im-
proved the yield of 37 and suppressed the formation of 39
(entry 4). Conducting the reaction in a more basic solvent
such as 1,2-dimethoxyethane successfully resulted in the
formation of trans-37 in high yield (94%), almost as a sin-
gle diastereomer (entry 5, >100:1 dr).
HO
*
R
HO
*
OH-directed
lithiation
ring-closing
metathesis
*
*
28
29
OH
asymmetric
methallylation
*
OHC
31
30
Scheme 9 Retrosynthetic analysis of compound 28
be prepared by an enantioselective reaction of aldehyde
31 with ligand 12.
The hydrogenation of 35 with rhodium/alumina afforded
cis-37, but the diastereoselectivity was low (Table 2, entry
6, 1.6:1 dr). The use of platinum black as the catalyst
slightly improved the cis/trans ratio (entry 7, 2.7:1 dr).
Therefore, we examined the hydrogenation of tert-bu-
tyldimethylsilyl ether 36, and found that the hydrogena-
tion with the Adams catalyst afforded cis-38 in a cis/trans
ratio of 10:1 (entry 8). Finally, the hydrogenation with
platinum black successfully afforded cis-38 in 92% yield
in a cis/trans ratio of 32:1 (entry 9).
Although aldehyde 33 was available commercially, it
could be prepared by a two-step process from p-toluidine
(32) (Scheme 10). Treatment of 32 with N-bromosuccin-
imide resulted in bromination at the ortho position, and
the subsequent reaction with sodium nitrite under acidic
conditions afforded a diazonium salt, which was subjected
to the reaction reported by Rajagopal,11 to afford aldehyde
33. The Wittig reaction of aldehyde 33 afforded an o-bro-
mostyrene,12 and subsequent lithiation and formylation
afforded aldehyde 31.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3699
Table 2 Stereoselective Hydrogenation of Compounds 35 and 36
RO
RO
RO
H2, cat.
solvent, r.t.
cis-37 R = H
cis-38 R = OTBS
trans-37 R = H
trans-38 R = OTBS
39
35 R = H
36 R = OTBS
Entry
Substrate
Catalyst
Solvent
CH2Cl2
CH2Cl2
Et2O
Yield (%)a
cis/transa
–
1
35
35
35
35
35
35
35
36
36
[RhCl(PPh3)3]
[Ir(cod)(PCy3)py]PF6
[Ir(cod)(PCy3)py]PF6
[Ir(cod)(PCy3)py]PF6
[Ir(cod)(PCy3)py]PF6
Rh/Al2O3
91 (39)
2
59 (37), 33 (39)
no reaction
73 (37), 16 (39)
94 (37), 3 (39)
93 (37)
1:>50
–
3
4
THF
1:>100
1:>100
1.6:1
2.7:1
10:1
5b
6c
7c
8c
9c
DME
EtOH
EtOH
EtOH
EtOH
Pt black
98 (37)
PtO2
45 (38)
Pt black
92 (38)d
32:1
a The ratio was determined by 1H NMR analysis.
b The reaction was carried out at 0 °C.
c The reaction was carried out at 60 °C
d The TBS group was removed with TBAF to afford cis-37 in 83% yield (2 steps from 36).
The tert-butyldimethylsilyl group of cis-38 was removed °C afforded acetate 43 in low yields, due to the formation
with tetrabutylammonium fluoride, thus affording cis-37 of an unidentified byproduct; however, performing the
(Table 2, entry 9). As the enantiomers of cis-37 and trans- acetylation at –78 °C improved the yield of 42 (94%, 74%
37 would be synthesized starting from ent-34, which conversion). Alcohol ent-cis-37 was also converted into
would be prepared by use of ent-ligand 12, the synthetic acetate 42 via aldehyde 40 by transformations identical to
route that afford all the isomers of compound 37 has been those in the method used to provide acetate 43.
established.
A comparison of the 1H NMR spectra of acetates 42, 43,
Alternatively, ent-cis-37 was prepared from trans-37 by and naturally occurring 1 clearly indicated that the tetralin
an oxidation–stereoselective reduction sequence (Scheme moiety of 1 had a trans relative configuration (Figure 3).
11). Thus, Dess–Martin oxidation of trans-37 and its sub- Furthermore, alcohol 41 was satisfactorily transformed
sequent reduction with sodium borohydride in the pres- into a crystalline derivative 45 via three steps (Scheme
ence of cerium(III) chloride heptahydrate provided ent- 13), and the X-ray crystallographic analysis of 45 (Figure
cis-37 in excellent yield and with excellent diastereoselec- 4)16 established its absolute structure, as shown in Scheme
tivity.
13.
R1
R1
CHO
R2
R2
OH
OH
a
a, b
40 R1 = OH, R2 = H
41 R1 = H, R2 = OH
ent-cis-37 R1 = OH, R2 = H
trans-37 R1 = H, R2 = OH
trans-37
ent-cis-37
Scheme 11 Reagents and conditions: (a) DMP, CH2Cl2, 0 °C; (b)
NaBH4, CeCl3·7H2O, MeOH, –78 °C, 100% (2 steps), >99% de.
R1
CHO
R2
b
The regioselective lithiation of trans-3715 and its subse-
quent formylation were crucial in that these reactions af-
forded aldehyde 41 in 43% yield under optimized
conditions (Scheme 12). A nonpolar solvent, N,N,N¢,N¢-
tetramethylethylenediamine (which acted as an additive),
and a large excess of the reagents were required to com-
plete the reaction. The acetylation of alcohol 41 above 0
42 R1 = OAc, R2 = H
43 R1 = H, R2 = OAc
Scheme 12 Reagents and conditions: (a) s-BuLi, TMEDA, hexane,
–10 °C, then DMF, THF, –40 to –10 °C 43% (41); (b) Ac2O, DMAP,
THF, –78 °C, 13% (14% conversion) (42), 94% (75% conversion)
(43).
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3700
M. Inoue, M. Nakada
FEATURE ARTICLE
formation of 1, and its subsequent reaction with 2,2-
dimethoxypropane under acidic conditions afforded ace-
tonide 46. The reduction of ester 46 with lithium borohy-
dride and selective tert-butyldimethylsilyl ether formation
afforded 47. The reaction of 47 with osmium tetroxide and
sodium periodate cleanly afforded the corresponding al-
dehydes; subsequent reduction with sodium borohydride
afforded 44 and 48. Diol 44 thus prepared was spectro-
scopically identical to the synthetic 44 (Scheme 13) in all
respects; the absolute structure of 48 was determined by
its comparison with known ent-4817 (Figure 5). As a re-
sult, we could elucidate the entire absolute structure of
FR901512 (1), as shown in Figure 1.
HO
CO2H
OH
δ = 6.53
δ = 6.47
δ = 5.98
dd, J = 10.2, 6.3 Hz dd, J = 3.7, 2.2 Hz dd, J = 3.4, 2.0 Hz
O
MeO2C
CHO
CHO
OAc
AcO
H
H
H
OAc
O
a, b
c, d
AcO
FR901512 (1)
42
43
FR901512 (1)
Figure 3 Comparison of 1H NMR spectra of 42, 43, and 1
46
OH
HO
CHO
HO
O
O
TBSO
a
O
OTBS
O
OH
44
CH2OC(O)C6H4-4-Br
41
OH
e, f
48
HO
HO
+
3,5-(O2N)2C6H3C(O)O
b, c
47
44
45
Scheme 14 Reagents and conditions: (a) MeI, K2CO3, acetone,
reflux; (b) 2,2-dimethoxypropane, CSA, CH2Cl2, 0 °C; (c) LiBH4,
MeOH, THF; (d) TBSCl, imidazole, CH2Cl2, 86% (4 steps); (e) OsO4,
NaIO4, Et2O/H2O, 50 °C; (f) NaBH4, MeOH, 0 °C, 85% (44, 2 steps),
72% (48, 2 steps).
Scheme 13 Reagents and conditions: (a) NaBH4, MeOH, 0 °C,
100%; (b) p-bromobenzoyl chloride, DIPEA, CH2Cl2, 10 °C; (c) 3,5-
dinitrobenzoyl chloride, Et3N, DMAP, CH2Cl2, 75% (2 steps).
OH
HO
O
O
OTBS
OH
48
44
synthetic:
authentic:
[α]D23 _12.1 (c 0.90, CHCl3)
Lit. (for ent-48)17
[α]D20 +10.2 (c 0.40, CHCl3)
[α]D29 _42.9 (c 0.68, CHCl3)
authentic:
:
[α]D29 _42.5 (c 0.68, CHCl3)
Figure 5 Specific rotation of 44 and 48
To achieve the total synthesis of 1, we attempted to as-
semble the side-chain moiety of 1, which could be pre-
pared via the enantioselective allylation of
cinnamaldehyde with ligand 12 (Scheme 15). Homoallyl-
ic alcohol 49, which was obtained by the enantioselective
allylation of cinnamaldehyde with ligand 12,4 was con-
verted into acrylate 50, which was subjected to ring-
closing metathesis with a Grubbs first-generation catalyst,
followed by stereoselective epoxidation and ozonolysis to
afford aldehyde 51. However, all the attempts to assemble
Figure 4 X-ray crystal structure of 45
At the same time, we succeeded in preparing 44 and 48
from naturally occurring 1 (Scheme 14). The methyl ester
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3701
Styr
CHO
a
b_d
AcO
CHO
Ph
O
AcO
a
OH
b
O
49 87%, 95% ee
50 Styr = styryl
43
52
OHC
O
O
FR901512 (1)
O
OH
O
O
51
AcO
c,d
e
AcO
Scheme 15 Reagents and conditions: (a) CH2CHCOCl, DIPEA,
CH2Cl2, 0 °C to r.t., 82%; (b) [Ru(=CHPh)(PCy3)2Cl2] (10 mol%),
CH2Cl2 (0.05 M), reflux, 54%; (c) H2O2, NaOH, i-PrOH, r.t., 58%; (d)
O3, CH2Cl2, –78 °C, then Me2S, 73%.
53
54
the side chain moiety using 51 and its derivative with the
tetralin moiety failed.
O
O
After several attempts, we found that the Horner–
Wadsworth–Emmons reaction of aldehyde 43 afforded
the desired product. Consequently, we carried out further
synthetic studies beginning from 43 via the stepwise con-
struction of the side-chain moiety (Scheme 16). The reac-
tion of aldehyde 43 with Nagata’s reagent18 provided
aldehyde 52 in excellent yield (88%). Although a reactive
benzylic acetate was incorporated in aldehyde 52, the
enantioselective allylation of 52 with ligand 12 afforded
53 in excellent yield and with excellent stereoselectivity
(99%, 90% de). As no stereoselectivity was observed in
the Nozaki–Hiyama allylation of aldehyde 52 in the ab-
sence of ligand 12, this stereoselective allylation must be
a chiral-reagent-controlled reaction.
O
f
g,h
AcO
FR901512 (1)
FR901516 (2)
55
Scheme 16 Reagents and conditions: (a) (EtO)2P(O)CH2CH=NCy,
KHMDS, THF, –78 to –30 °C, then aq oxalic acid, 88%; (b) allyl bro-
mide, CrCl2 (15 mol%), 12 (16 mol%), Mn, DIPEA, TMSCl, THF, 3
°C, 99%, 90% de; (c) acryloyl chloride, DIPEA, CH2Cl2, 10 °C, 94%;
(d) [Ru(=CHPh)(PCy3)2Cl2] (10 mol%), CH2Cl2 (0.005 M), reflux,
100%; (e) TBHP, Triton B, toluene, 0 °C, 70%; (f) (PhSe)2, NaBH4,
AcOH, THF–EtOH, 0 °C, 100%; (g) MeOH, toluene, r.t.; (h)
TMSOK, THF, 0 °C, 95% (2 steps).
The acrylate derived from 53 was subjected to ring-clos-
ing metathesis with a Grubbs second-generation catalyst;
however, a complex mixture was formed. Fortunately, the
reaction with a Grubbs first-generation catalyst19 afforded
54 in 100% yield (Scheme 16). The chemoselective and
diastereoselective epoxidation of 54 was well achieved
with tert-butyl hydroperoxide (TBHP) and Triton B in tol-
uene, affording 55 as the sole product.20 This stereoselec-
tivity could be explained by the axial attack of the tert-
butyl hydroperoxide ion. Epoxide 55 was reacted with
diphenyldiselenide, sodium borohydride, and acetic acid
in tetrahydrofuran–ethanol,21 affording 2 in 100% yield
with complete regioselectivity. The methanolysis of 2 and
the subsequent cleavage of the resultant methyl ester fur-
nished 1.
HO
HO
O
CO2H
OH
O
AcO
AcO
FR901512 (1)
FR901516 (2)
synthetic:
[α]D24 +19 (c 0.39, MeOH)
Lit.1a
[α]D23 +20 (c 0.38, MeOH)
synthetic:
[α]D24 _58 (c 0.45, CHCl3)
natural product:
[α]D23 _61 (c 0.50, CHCl3)
:
Figure 6 Comparison of the specific rotations of synthetic 1 and 2
with those of naturally occurring 1 and 2
The synthesized 1 and 2 were spectroscopically identical
to natural FR901512 and FR901516, respectively (Figure
6). Although the specific rotation of 2 measured in meth-
anol was unreproducible,22 the specific rotation of syn-
thetic 2 measured using chloroform as solvent {[a]D24 –58
(c 0.45, CHCl3)} was in good agreement with the specific
rotation of naturally occurring 2 {[a]D –61 (c 0.50,
CHCl3)}; this confirmed the absolute structure of synthet-
ic 2.
Conclusion
The structure elucidation and enantioselective total syn-
theses of FR901512 (1) and FR901516 (2) were carried
out. FR901512 (1) was prepared in 15 steps from com-
mercially available 2-bromo-4-methylbenzaldehyde in
16.3% overall yield (89% average yield). This study vali-
23
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3702
M. Inoue, M. Nakada
FEATURE ARTICLE
Colorless oil; yield: 0.723 g (96%).
IR (neat): 2926, 2856, 1691, 1610 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.3 (s, 1 H), 7.63 (br, 1 H), 7.49
(dd, J = 17.3, 11.0 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.38 (d,
J = 8.0 Hz, 1 H), 5.67 (d, J = 17.3 Hz, 1 H), 5.47 (d, J = 11.0 Hz, 1
H), 2.41 (s, 3 H).
dated the applicability and reliability of the catalytic
asymmetric Nozaki–Hiyama reactions that were devel-
oped by us. These reactions enabled the concise, efficient,
and protecting-group-free enantioselective total syntheses
of these new statins.
13C NMR (100 MHz, CDCl3): d = 192.5, 137.9, 137.8, 134.6, 133.0,
Chiral HPLC analysis was performed on JASCO PU-980 and UV-
970 instruments. Melting points were recorded on a Yanako micro
melting point apparatus and are uncorrected. Optical rotations were
measured using a 2-mL cell with 1 dm path length on a JASCO DIP-
1000 instrument. IR spectra were recorded on a JASCO FT/IR-8300
132.6, 131.4, 127.3, 118.6, 20.9.
HRMS (EI): m/z [M]+ calcd for C10H10O: 146.0732; found:
146.0733.
1
spectrometer. H and 13C NMR spectra were recorded on a JEOL
(S)-3-Methyl-1-(5-methyl-2-vinylphenyl)but-3-en-1-ol (34)
To a mixture of Mn (0.784 g, 14.3 mmol), ligand 12 (215 mg, 0.396
mmol), and CrCl2 (46.1 mg, 0.375 mmol) was added anhyd THF
(70 mL) to form a brown suspension. After the mixture had stirred
for 1 h, DIPEA (0.370 mL, 2.12 mmol) and methallyl chloride (1.40
mL, 14.2 mmol) were added and the mixture was stirred for 30 min.
A soln of 31 (1.04 g, 7.08 mmol) in THF (5 mL) and TMSCl (1.80
mL, 14.2 mmol) were added successively to the suspension. The re-
sulting mixture was stirred vigorously at r.t. for 24 h. The reaction
was quenched with sat. aq NaHCO3 (100 mL) and the mixture was
extracted with Et2O (5 × 70 mL). The combined organic layer was
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane–Et2O, 12:1 to 4:1); this
afforded 34.
AL-400 or a Bruker AVANCE-600 spectrometer. 1H and 13C chem-
ical shifts are reported relative to TMS, with the solvent resonances
as internal standards. Mass spectra and elemental analyses were car-
ried out at the Materials Characterization Central Laboratory,
Waseda University. All reactions were carried out under an argon
atmosphere with anhyd, freshly distilled solvents under anhyd con-
ditions, unless otherwise noted. All reactions were monitored by
TLC carried out on 0.25-mm E. Merck silica gel plates (60F-254)
using UV light for visualizing and phosphomolybdic acid and heat
for development. Merck silica gel (60, particle size 0.040–0.063
mm) was used for flash chromatography. Preparative TLC (PTLC)
separations were carried out on self-made 0.3-mm E. Merck silica
gel plates (60F-254). THF was distilled from Na/benzophenone
ketyl. Toluene was distilled from Na. CH2Cl2, benzene, and DMF
were distilled from CaH2. CrCl2 (99.99%) and Mn (powder,
99.99%) were purchased from Aldrich, and all other reagents were
purchased from Aldrich, TCI, or Kanto Chemical Co. Ltd.
Colorless oil; yield: 1.32 g (93%); 92% ee {determined by HPLC
[254 nm; DAICEL CHIRALCEL OD-H, 0.46 cm × 25 cm; hexane–
i-PrOH, 9:1; flow rate, 0.4 mL/min; tR = 15.1 min (S), 16.4 min
(R)]}; [a]D27 –46.1 (c 0.90, CHCl3).
IR (neat): 3410, 3074, 2918, 1649 cm–1.
2-Bromo-4-methyl-1-vinylbenzene
To a suspension of Ph3PMeBr (25.2 g, 70.5 mmol) in THF (100 mL)
was added a soln of t-BuOK (7.90 g, 70.4 mmol) in THF (100 mL)
at 0 °C. The mixture was stirred for 1 h at the same temperature, and
to the yellow suspension was added 2-bromo-4-methylbenzalde-
hyde (8.77 g, 44.1 mmol) in THF (50 mL). After the mixture had
stirred at 0 °C for an additional 15 min, sat. aq NH4Cl (100 mL) was
added and the resultant mixture was extracted with Et2O (3 × 100
mL). The combined organic layer was dried (Na2SO4) and concen-
trated in vacuo. The residue was purified by flash column chroma-
1H NMR (400 MHz, CDCl3): d = 7.37 (s, 1 H), 7.36 (d, J = 7.8 Hz,
1 H), 7.07 (d, J = 7.8 Hz, 1 H), 6.99 (dd, J = 17.3, 11.0 Hz, 1 H),
5.59 (dd, J = 17.3, 1.2 Hz, 1 H), 5.28 (dd, J = 11.0, 1.2 Hz, 1 H),
5.12 (ddd, J = 10.3, 2.7, 2.2 Hz, 1 H), 4.95 (s, 1 H), 4.90 (s, 1 H),
2.41 (dd, J = 14.2, 2.7 Hz, 1 H), 2.36 (s, 3 H), 2.32 (dd, J = 14.2,
10.3 Hz, 1 H), 2.09 (d, J = 2.2 Hz, 1 H), 1.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 142.6, 140.8, 137.7, 133.7, 132.4,
128.1, 126.0, 125.7, 115.6, 113.8, 67.7, 47.4, 22.2, 21.2.
HRMS–FAB: m/z [M + Na]+ calcd for C14H18ONa: 225.1255;
found: 225.1256.
tography
(hexane);
this
afforded
2-bromo-4-methyl-1-
vinylbenzene.
Colorless oil; yield: 8.00 g (92%).
IR (neat): 2922, 1605, 910 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.44 (d, J = 7.8 Hz, 1 H), 7.38 (br,
1 H), 7.08 (d, J = 7.8 Hz, 1 H), 7.02 (dd, J = 17.3, 11.0 Hz, 1 H),
5.65 (d, J = 17.3 Hz, 1 H), 5.30 (d, J = 11.0 Hz, 1 H), 2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.3, 135.5, 134.5, 133.2, 128.3,
126.4, 123.4, 115.7, 20.7.
HRMS (EI): m/z [M]+ calcd for C9H9Br: 195.9888; found:
195.9888.
(S)-3,7-Dimethyl-1,2-dihydronaphthalen-1-ol (35)
To a soln of 34 (1.58 g, 7.79 mmol) in toluene (250 mL, 0.03 M)
was added [Ru(=CHPh)(IMes)(PCy3)Cl2] (0.207 g, 0.244 mmol) in
toluene (10 mL) at 50 °C. The resulting mixture was stirred at the
same temperature for 30 min and the solvent was removed in vacuo.
The residue was purified by flash column chromatography (hex-
ane–EtOAc, 20:1 to 6:1); this afforded 35.
25
White solid; yield: 1.30 g (96%); mp 73 °C; [a]D –96.6 (c 0.75,
CHCl3).
IR (KBr): 3280, 3163, 2920, 1651, 1612 cm–1.
5-Methyl-2-vinylbenzaldehyde (31)
1H NMR (400 MHz, CDCl3): d = 7.17 (br, 1 H), 7.06 (d, J = 7.8 Hz,
1 H), 6.96 (d, J = 7.8 Hz, 1 H), 6.27 (s, 1 H), 4.74 (ddd, J = 7.1, 5.3,
4.8 Hz, 1 H), 2.53 (dd, J = 17.3, 5.3 Hz, 1 H), 2.47 (dd, J = 17.3, 4.8
Hz, 1 H), 2.34 (s, 3 H), 1.94 (s, 3 H), 1.65 (d, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 136.3, 134.8, 133.8, 130.9, 128.9,
127.5, 125.7, 121.7, 68.4, 38.0, 23.6, 21.2.
To a soln of 2-bromo-4-methyl-1-vinylbenzene (1.03 g, 5.20 mmol)
in THF (20 mL) was added 1.60 M n-BuLi in hexane (3.58 mL, 5.73
mmol) at –78 °C. The reaction mixture was stirred at the same tem-
perature for 1 h, and to the yellow suspension DMF (0.48 mL, 6.22
mmol) was added dropwise. After the mixture had stirred at –78 °C
for an additional 20 min, sat. aq NH4Cl (20 mL) was added and the
mixture was extracted with Et2O (3 × 15 mL). The combined organ-
ic layer was dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane–EtOAc,
50:1 to 20:1); this afforded 31.
HRMS–FAB: m/z [M + H] calcd for C12H15O: 175.1123; found:
175.1117.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3703
(S)-1-(tert-Butyldimethylsiloxy)-3,7-dimethyl-1,2-dihydro-
naphthalene (36)
13C NMR (100 MHz, CDCl3): d = 137.5, 135.7, 134.1, 130.0, 128.9,
128.8, 68.2, 39.9, 37.7, 23.8, 21.8, 20.9.
Imidazole (27.9 mg, 0.410 mmol) and TBSCl (60.8 mg, 0.403
mmol) were added successively to a soln of 35 (44.0 mg, 0.253
mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred for 24 h,
and then hexane (10 mL) was added. The solvent was removed to
10% of its volume and silica gel was charged with the resulting sus-
pension. Purification by flash column chromatography (hexane–
EtOAc, 100:1) gave 36.
Colorless oil; yield: 71.6 mg (98%); [a]D25 –17.2 (c 0.81, CHCl3).
IR (neat): 2954, 2927, 2856, 1255 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22 (br, 1 H), 6.99 (d, J = 7.8 Hz,
1 H), 6.89 (d, J = 7.8 Hz, 1 H), 6.19 (s, 1 H), 4.93 (dd, J = 11.5, 6.8
Hz, 1 H), 2.38 (dd, J = 16.2, 11.5 Hz, 1 H), 2.35 (s, 3 H), 2.28 (dd,
J = 16.2, 6.8 Hz, 1 H), 1.91 (s, 3 H), 0.98 (s, 9 H), 0.15 (s, 3 H), 0.13
(s, 3 H).
HRMS [M + Na]+ calcd for C12H16ONa: 199.1099; found:
199.1098.
(6R,8S)-8-Hydroxy-2,6-dimethyl-5,6,7,8-tetrahydronaphtha-
lene-1-carbaldehyde (41)
To a soln of trans-37 (1.20 g, 6.80 mmol) and TMEDA (3.05 mL,
20.2 mmol) in hexane (60 mL) was added a fresh 1.01 M soln of s-
BuLi in hexane and cyclohexane (54.0 mL, 54.5 mmol) at –10 °C.
The reaction mixture was stirred at the same temperature for 7 h,
and then a soln of DMF (5.27 mL, 68.1 mmol) in THF (10 mL) was
added dropwise to the orange suspension at –40 °C. After stirring of
the mixture at 0 °C for an additional 20 min, sat. aq NH4Cl (40 mL)
was added, and the mixture was extracted with EtOAc (3 × 50 mL).
The combined organic layer was dried (Na2SO4) and concentrated
in vacuo. The residue was purified by flash column chromatography
(hexane–EtOAc, 20:1 to 10:1); this afforded 41.
13C NMR (100 MHz, CDCl3): d = 136.9, 136.0, 134.5, 131.5, 127.6,
125.3, 125.0, 122.4, 69.7, 39.0, 25.9, 23.4, 21.5, 18.3, –4.5, –4.8.
HRMS–FAB: m/z [M – H]+ calcd for C18H27OSi: 287.1831; found:
287.1829.
Pale yellow solid; yield: 589 mg (43%); mp 48 °C; [a]D23 +31.8 (c
0.56, CHCl3).
IR (KBr): 3295, 2956, 2926, 1676, 1458 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.6 (s, 1 H), 7.25 (d, J = 7.8 Hz,
1 H), 7.12 (d, J = 7.8 Hz, 1 H), 4.89 (m, 1 H), 4.28 (d, J = 2.9 Hz, 1
H), 2.88 (dd, J = 16.1, 2.7 Hz, 1 H), 2.62 (s, 3 H), 2.33 (dd, J = 16.1,
12.0 Hz, 1 H), 2.24 (m, 1 H), 2.15 (ddd, J = 13.7, 4.2, 2.2 Hz, 1 H),
1.43 (ddd, J = 13.7, 12.9, 3.9 Hz, 1 H), 1.09 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 195.7, 140.2, 139.1, 136.4, 135.2,
133.2, 130.8, 64.2, 39.2, 38.7, 22.9, 21.8, 19.3.
(1S,3S)-3,7-Dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol
(cis-37)
Pt black (5.4 mg, 0.028 mmol) was added to a soln of 36 (53.8 mg,
0.186 mmol) in absolute EtOH (8 mL), and the mixture was stirred
under a H2 atmosphere at 60 °C. After 18 h, the catalyst was re-
moved by filtration, and the solvent was evaporated to afford crude
cis-38. The well-dried crude cis-38 was dissolved in THF (3 mL),
and to the soln was added 1.0 M TBAF in THF (0.240 mL, 0.24
mmol) at 0 °C. After 1 h, sat. aq NH4Cl (10 mL) was added and the
mixture was extracted with Et2O (3 × 10 mL). The combined ex-
tracts were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane–CH2Cl2–
EtOAc, 8:2:1); this afforded cis-37 with its diastereomer.
HRMS–FAB: m/z [M + Na]+ calcd for C13H16O2Na: 227.1048;
found: 227.1055.
(1S,3R)-8-Formyl-3,7-dimethyl-1,2,3,4-tetrahydronaphthalen-
1-yl Acetate (43)
To a soln of DMAP (98.9 mg, 0.810 mmol) in THF (4 mL) was add-
ed Ac2O (0.072 mL, 0.76 mmol) at –78 °C. The resulting white sus-
pension was stirred for 1 h and a soln of well-dried 41 (110 mg,
0.539 mmol) in THF (3 mL) was added dropwise. After the mixture
had stirred at the same temperature for 3 h, pH 7 buffer soln (10 mL)
was added at –78 °C and the mixture was extracted with Et2O (4 ×
10 mL). The combined organic layer was dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by flash column chro-
matography (hexane–EtOAc, 15:1 to 6:1); this afforded 43 and
recovered starting material 41 (28.8 mg, 26%).
Yield: 27.1 mg (83%); 32:1 dr.
IR (KBr): 3320, 2947, 2868, 1498, 1450 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (br, 1 H), 7.00 (d, J = 7.8 Hz,
1 H), 6.97 (d, J = 7.8 Hz, 1 H), 4.80 (m, 1 H), 2.75 (dd, J = 16.1, 3.9
Hz, 1 H), 2.41 (dd, J = 16.1, 11.7 Hz, 1 H), 2.33 (s, 3 H), 2.23 (dddd,
J = 12.2, 5.9, 2.7, 2.2 Hz, 1 H), 1.92 (m, 1 H), 1.65 (m, 1 H), 1.34
(ddd, J = 12.2, 12.0, 11.7 Hz, 1 H), 1.08 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.2, 135.7, 133.6, 128.4, 128.0,
127.0, 69.8, 42.5, 38.0, 28.4, 22.1, 21.1.
HRMS–FAB: m/z [M + Na]+ calcd for C12H16ONa: 199.1099;
found: 199.1098.
30
Yield (43): 92.1 mg (70%, 94% brsm); mp 89 °C; [a]D –51.6 (c
0.60, CHCl3).
IR (KBr): 2924, 1724, 1684, 1240 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.5 (s, 1 H), 7.23 (d, J = 7.8 Hz,
1 H), 7.18 (d, J = 7.8 Hz, 1 H), 6.47 (dd, J = 3.7, 2.2 Hz, 1 H), 2.91
(dd, J = 16.6, 4.4 Hz, 1 H), 2.57 (s, 3 H), 2.39 (dd, J = 16.6, 12.0 Hz,
1 H), 2.22 (ddd, J = 14.6, 4.4, 2.2 Hz, 1 H), 2.07 (m, 1 H), 2.03 (s,
3 H), 1.54 (ddd, J = 14.6, 12.7, 3.7 Hz, 1 H), 1.08 (d, J = 6.6 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 193.1, 169.9, 139.2, 137.0, 134.4,
134.0, 132.7, 132.2, 66.8, 38.2, 37.0, 23.5, 21.6, 21.2, 20.4.
HRMS–FAB: m/z [M + Na]+ calcd for C15H18O3Na: 269.1154;
(1S,3R)-3,7-Dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol
(trans-37)
A soln of 35 (1.30 g, 7.46 mmol) in DME (40 mL) was stirred with
[Ir(cod)(PCy3)py]PF6 (0.251 mg, 0.311 mmol) under a H2 atmo-
sphere at 0 °C for 12 h, and then the solvent was removed in vacuo.
The residue was purified by flash column chromatography (hex-
ane–EtOAc, 10:1); this afforded alcohol trans-37.
White solid; yield: 1.23 g (94%); >50:1 dr; mp 62 °C; [a]D24 –21.0
(c 0.75, CHCl3).
found: 269.1144.
IR (KBr): 3304, 2939, 1506, 1456 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.17 (br, 1 H), 7.03 (d, J = 8.0 Hz,
1 H), 7.00 (d, J = 8.0 Hz, 1 H), 4.79 (ddd, J = 5.4, 3.3, 2.4 Hz, 1 H),
2.82 (dd, J = 16.4, 4.2 Hz, 1 H), 2.32 (s, 3 H), 2.29 (dd, J = 16.4,
11.5 Hz, 1 H), 2.15 (m, 1 H), 2.03 (ddd, J = 13.9, 4.2, 2.4 Hz, 1 H),
1.63 (d, J = 5.4 Hz, 1 H), 1.55 (m, 1 H), 1.09 (d, J = 6.3 Hz, 3 H).
(1R,3R)-3,7-Dimethyl-1,2,3,4-tetrahydronaphthalen-1-ol
(ent-cis-37)
To a soln of trans-37 (14.2 mg, 0.0806 mmol) in CH2Cl2 (2 mL) was
added DMP (64.7 mg, 0.153 mmol) at 0 °C. After the mixture had
stirred at the same temperature for 1 h, the soln was diluted with
Et2O (10 mL), and sat. aq NaHCO3 (10 mL) and sat. aq Na2S2O3 (5
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3704
M. Inoue, M. Nakada
FEATURE ARTICLE
mL) were added. The mixture was extracted with Et2O (3 × 10 mL).
The combined organic layer was dried (Na2SO4) and concentrated
in vacuo. The crude ketone and CeCl3·7H2O (60.0 mg, 0.161 mmol)
were dissolved in MeOH (6 mL). The soln was cooled to –78 °C
and NaBH4 (10.1 mg, 0.267 mmol) was added. The resultant mix-
ture was stirred at the same temperature for 1 h. The reaction was
quenched with sat. aq NH4Cl (10 mL) and the mixture was extracted
with EtOAc (4 × 10 mL). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 6:1); this afforded
ent-cis-37.
HRMS–FAB: m/z calcd for C13H18O2Na [M + Na]+: 229.1204;
found: 229.1204.
(1S,3R)-8-(4-Bromobenzoyloxymethyl)-3,7-dimethyl-1,2,3,4-
tetrahydronaphthalen-1-yl 3,5-Dinitrobenzoate (45)
DIPEA (0.025 mL, 0.14 mmol) and p-bromobenzoyl chloride (27.7
mg, 0.126 mmol) were added successively to a soln of 44 (13.8 mg,
0.0669 mmol) in CH2Cl2 (1 mL) at 10 °C. After the mixture had
stirred at r.t. for 12 h, the reaction mixture was filtered through a
short pad of silica gel, eluted with CH2Cl2, and concentrated. Et3N
(0.015 mL, 0.11 mmol), DMAP (2.0 mg, 0.016 mmol), and 3,5-
dinitrobenzoyl chloride (22.4 mg, 0.0972 mmol) were added to a
soln of the residue in CH2Cl2 (2 mL), and the mixture was stirred for
8 h. The reaction was quenched with sat. aq NH4Cl (10 mL) and the
mixture was extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic layer was dried (Na2SO4) and concentrated in vacuo. The res-
idue was purified by flash column chromatography (CH2Cl2); this
afforded 45. (A single crystal for X-ray crystallography was pre-
pared by recrystallization from hexane–CH2Cl2.)
24
White solid; yield: 14.2 mg (100%); >50:1 dr; mp 100 °C; [a]D
–148 (c 0.21, CHCl3).
IR (KBr): 3320, 2947, 2868, 1498, 1450 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40 (br, 1 H), 7.00 (d, J = 7.8 Hz,
1 H), 6.97 (d, J = 7.8 Hz, 1 H), 4.80 (m, 1 H), 2.75 (dd, J = 16.1, 3.9
Hz, 1 H), 2.41 (dd, J = 16.1, 11.7 Hz, 1 H), 2.33 (s, 3 H), 2.23 (dddd,
J = 12.2, 5.9, 2.7, 2.2 Hz, 1 H), 1.92 (m, 1 H), 1.65 (m, 1 H), 1.34
(ddd, J = 12.2, 12.0, 11.7 Hz, 1 H), 1.08 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.2, 135.7, 133.6, 128.4, 128.0,
127.0, 69.8, 42.5, 38.0, 28.4, 22.1, 21.1.
White solid; yield: 29.3 mg (75%, 2 steps from 41); mp 188 °C;
[a]D24 –18.5 (c 0.72, CHCl3).
IR (KBr): 3113, 2960, 2920, 1720, 1539, 1344, 1277 cm–1.
HRMS–FAB: m/z [M + Na]+ calcd for C12H16ONa: 199.1099;
found: 199.1098.
1H NMR (400 MHz, CDCl3): d = 8.94 (t, J = 2.1 Hz, 1 H), 8.85 (d,
J = 2.1 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.28 (d, J = 7.8 Hz, 1 H),
7.26 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 7.8 Hz, 1 H), 6.69 (dd, J = 3.4,
2.4 Hz, 1 H), 5.35 (d, J = 12.4 Hz, 1 H), 5.22 (d, J = 12.4 Hz, 1 H),
3.04 (dd, J = 16.6, 3.9 Hz, 1 H), 2.48 (dd, J = 16.6, 12.0 Hz, 1 H),
2.41 (s, 3 H), 2.26 (ddd, J = 14.6, 3.9, 2.0 Hz, 1 H), 2.16 (m, 1 H),
1.72 (ddd, J = 14.6, 13.7, 3.4 Hz, 1 H), 1.10 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.3, 161.3, 148.2, 137.5, 137.1,
133.8, 132.7, 131.9, 131.6, 131.4, 130.6, 130.5, 129.2, 128.3, 128.2,
121.8, 70.5, 61.2, 38.4, 37.8, 23.9, 21.6, 19.4.
(1R,3R)-8-Formyl-3,7-dimethyl-1,2,3,4-tetrahydronaphthalen-
1-yl Acetate (42)
Acetate 42 was prepared from ent-cis-37 via 40 according to the
same procedure as that used for the synthesis of 43 from trans-37.
Yield: 13% (14% conversion); [a]D23 –166 (c 0.15, CHCl3).
IR (KBr): 2926, 1740, 1699, 1230 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.3 (s, 1 H), 7.16 (d, J = 8.0 Hz,
1 H), 7.12 (d, J = 8.0 Hz, 1 H), 6.40 (dd, J = 8.1, 7.5 Hz, 1 H), 2.77
(ddd, J = 16.0, 4.1, 1.7 Hz, 1 H), 2.57–2.47 (m, 2 H), 2.50 (s, 3 H),
2.02 (s, 3 H), 1.94 (m, 1 H), 1.40 (ddd, J = 12.7, 12.0, 8.8 Hz, 1 H),
1.09 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 193.6, 170.2, 137.4, 136.9, 135.6,
133.6, 132.8, 131.4, 69.5, 38.1, 37.4, 27.4, 21.5, 21.0, 20.0.
HRMS–FAB: m/z calcd for C27H23BrN2O8Na [M + Na]+: 605.0535;
found: 605.0557.
(E)-8-(2-{6-[2-(tert-Butyldimethylsiloxy)ethyl]-2,2-dimethyl-
1,3-dioxan-4-yl}vinyl)-3,7-dimethyl-1,2,3,4-tetrahydronaph-
thalen-1-ol (47)
A mixture of FR901512 (1) (authentic sample, 42.1 mg, 0.112
mmol), MeI (0.070 mL, 1.1 mmol), and K2CO3 (95.1 mg, 0.688
mmol) in acetone (7 mL) was refluxed for 3 h. The precipitate was
removed by filtration and sat. aq NH4Cl (10 mL) was added to the
filtrate. The mixture was extracted with EtOAc (4 × 10 mL). The
combined organic layer was dried (Na2SO4) and concentrated in
vacuo. To a soln of the residue in CH2Cl2 (5 mL) were added 2,2-
dimethoxypropane (0.060 mL, 0.49 mmol) and CSA (2.1 mg,
0.0090 mmol) at 0 °C. After the mixture had stirred for 15 min, Et3N
(0.005 mL, 0.036 mmol) was added, and the solvent was removed
in vacuo. To a soln of the residue in THF (4 mL) were added LiBH4
(20.7 mg, 0.950 mmol) and MeOH (0.100 mL, 2.47 mmol). After
stirring of the mixture for 24 h, sat. aq NH4Cl (5 mL) was added, and
the mixture was extracted with EtOAc (4 × 10 mL). The combined
organic layer was dried (Na2SO4) and concentrated in vacuo. Imida-
zole (20.3 mg, 0.298 mmol) and TBSCl (33.9 mg, 0.225 mmol)
were added successively to a soln of the crude diol in CH2Cl2 (5
mL). After the mixture had stirred for 2 h, sat. aq NH4Cl (10 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layer was dried (Na2SO4) and concentrated
in vacuo. The residue was purified by flash column chromatography
(hexane–EtOAc, 8:1); this afforded 47.
HRMS–FAB: m/z [M + Na]+ calcd for C15H18O3Na: 269.1154;
found: 269.1161.
(1S,3R)-8-(Hydroxymethyl)-3,7-dimethyl-1,2,3,4-tetrahydro-
naphthalen-1-ol (44)
To a soln of 41 (70.3 mg, 0.344 mmol) in MeOH (5 mL) was added
NaBH4 (16.3 mg, 0.431 mmol) at 0 °C. After the mixture had stirred
for 15 min, sat. aq NH4Cl (10 mL) was added and the mixture was
extracted with EtOAc (4 × 10 mL). The combined organic layer was
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (hexane–CH2Cl2–EtOAc, 2:2:1);
this afforded diol 44.
White solid; yield: 71.0 mg (100%).
Recrystallization from EtOAc afforded optically pure 44; mp
115.2 °C; [a]D29 –42.9 (c 0.68, CHCl3).
IR (KBr): 3310, 2906, 1439, 1321 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.09 (d, J = 7.8 Hz, 1 H), 7.00 (d,
J = 7.8 Hz, 1 H), 5.16 (dd, J = 3.6, 2.7 Hz, 1 H), 4.82 (s, 2 H), 2.85
(ddd, J = 16.3, 3.9, 1.5 Hz, 1 H), 2.41 (s, 3 H), 2.34 (dd, J = 16.3,
12.0 Hz, 1 H), 2.17–2.07 (m, 2 H), 1.56 (ddd, J = 13.9, 13.0, 3.6 Hz,
1 H), 1.09 (d, J = 6.3 Hz, 3 H).
Colorless oil; yield: 46.2 mg (86%, 4 steps from 1); [a]D26 +15.3 (c
2.0, CHCl3).
IR (neat): 3435, 2951, 2927, 2856, 1379, 1254, 1095, 962, 835 cm–1.
13C NMR (100 MHz, CDCl3): d = 137.7, 136.6, 135.5, 135.0, 130.3,
129.2, 65.5, 58.6, 40.4, 38.8, 23.1, 21.8, 19.5.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3705
1H NMR (400 MHz, CDCl3): d = 7.06 (d, J = 7.8 Hz, 1 H), 6.92 (d,
J = 7.8 Hz, 1 H), 6.79 (d, J = 16.3 Hz, 1 H), 5.80 (dd, J = 16.3, 6.1
Hz, 1 H), 4.96 (m, 1 H), 4.59 (m, 1 H), 4.14 (m, 1 H), 3.75 (ddd,
J = 10.2, 7.7, 5.5 Hz, 1 H), 3.68 (ddd, J = 10.2, 5.4, 5.1 Hz, 1 H),
2.83 (dd, J = 15.9, 3.7 Hz, 1 H), 2.30 (dd, J = 15.9, 11.7 Hz, 1 H),
2.28 (s, 3 H), 2.06 (m, 1 H), 2.03 (ddd, J = 13.7, 4.1, 2.0 Hz, 1 H),
1.82 (m, 1 H), 1.71–1.65 (m, 2 H), 1.52 (s, 3 H), 1.48–1.38 (m, 2 H),
1.44 (s, 3 H), 1.08 (d, J = 6.6 Hz, 3 H), 0.90 (s, 9 H), 0.06 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 137.2, 136.8, 135.4, 134.5, 133.7,
129.8, 127.8, 127.0, 98.7, 70.3, 65.4, 65.2, 58.8, 40.0, 39.4, 38.4,
37.6, 30.2, 25.9, 23.2, 22.0, 20.7, 19.9, 18.3, –5.4.
HRMS–FAB: m/z [M + Na]+ calcd for C28H46O4SiNa: 497.3063;
found: 497.3056.
(1S,3R)-8-[(S,E)-3-Hydroxyhexa-1,5-dienyl]-3,7-dimethyl-
1,2,3,4-tetrahydronaphthalen-1-yl Acetate (53)
To a mixture of Mn (71.0 mg, 1.29 mmol), ligand 12 (56.3 mg,
0.104 mmol), and CrCl2 (11.7 mg, 0.0952 mmol) was added anhyd
THF (4 mL) to form a brown suspension. After the mixture had
stirred for 1 h, DIPEA (0.055 mL, 0.316 mmol) and allyl bromide
(0.115 mL, 1.33 mmol) were added, and the mixture was stirred for
20 min. Compound 52 (175 mg, 0.643 mmol) in THF (3 mL) and
TMSCl (0.165 mL, 1.30 mmol) were added successively to the sus-
pension at 3 °C. The resulting mixture was stirred vigorously at the
same temperature for 12 h. The reaction was quenched with sat. aq
NaHCO3 (0.5 mL), filtered through Celite, and evaporated. The
crude product was dissolved in THF (5 mL) and the stirred mixture
was treated with 0.02 M HCl (0.05 mL). After the desilylation was
complete, sat. aq NaHCO3 (10 mL) was added and the mixture was
extracted with Et2O (4 × 15 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 10:1); this afforded
53 with its inseparable minor diastereomer.
(4S,6S)-{6-[2-(tert-Butyldimethylsiloxy)ethyl]-2,2-dimethyl-1,3-
dioxan-4-yl}methanol (48)
A 0.039 M soln of OsO4 in t-BuOH (0.20 mL, 0.0078 mmol) and
NaIO4 (49.1 mg, 0.230 mmol) were added to a soln of 47 (39.0 mg,
0.0821 mmol) in Et2O/H2O (6 mL/2 mL). The reaction mixture was
stirred at 50 °C for 2 h. Sat. aq Na2SO3 (5 mL) was added to the soln
and the mixture was extracted with Et2O (3 × 10 mL). The com-
bined organic layer was dried (Na2SO4) and concentrated in vacuo.
To a soln of the residue in MeOH (3 mL) was added NaBH4 (12.0
mg, 0.317 mmol) at 0 °C. After the mixture had stirred for 5 min,
sat. aq NH4Cl (10 mL) was added and the mixture was extracted
with EtOAc (5 × 10 mL). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 10:1 to 2:1); this af-
forded 44 and 48.
Yield: 200 mg (99%); 90% de.
IR (KBr): 3440, 2951, 1714, 1639, 1242 cm–1.
1H NMR (400 MHz, CDCl3): d (53) = 7.11 (d, J = 7.8 Hz, 1 H), 6.97
(d, J = 7.8 Hz, 1 H), 6.37 (d, J = 16.3 Hz, 1 H), 6.27 (dd, J = 3.4, 2.0
Hz, 1 H), 5.87 (dddd, J = 17.3, 10.2, 7.3, 7.1 Hz, 1 H), 5.67 (dd,
J = 16.3, 6.8 Hz, 1 H), 5.18–5.10 (m, 2 H), 4.24 (m, 1 H), 2.86 (ddd,
J = 16.3, 4.3, 1.1 Hz, 1 H), 2.59 (d, J = 2.7 Hz, 1 H), 2.47–2.31 (m,
3 H), 2.21 (s, 3 H), 2.09–1.96 (m, 2 H), 2.03 (s, 3 H), 1.52 (ddd,
J = 14.4, 12.7, 3.4 Hz, 1 H), 1.06 (d, J = 6.3 Hz, 3 H); d (epi-
53) = 6.47 (d, J = 16.3 Hz, 1 H), 6.13 (dd, J = 3.4, 2.0 Hz, 1 H), 5.63
(dd, J = 16.3, 6.8 Hz, 1 H), 4.31 (m, 1 H).
44: Yield: 14.3 mg (85%); [a]D29 –42.5 (c 0.68, CHCl3).
20
48: Yield: 18.0 mg (72%); [a]D23 –12.1 (c 0.90, CHCl3) [Lit.2 [a]D
+10.2 (c 0.40, CHCl3) for ent-48].
13C NMR (100 MHz, CDCl3): d = 171.0, 138.3, 137.6, 135.9, 134.3,
133.7, 131.1, 130.1, 127.8, 127.5, 117.7, 72.2, 68.1, 41.2, 38.3,
37.9, 24.0, 21.7, 21.5, 20.3.
(1S,3R)-3,7-Dimethyl-8-[(E)-3-oxoprop-1-enyl]-1,2,3,4-tetra-
hydronaphthalen-1-yl Acetate (52)
HRMS–FAB: m/z [M + Na]+ calcd for C20H26O3Na: 337.1780;
found: 337.1773.
A 0.5 M soln of KHMDS in toluene (1.7 mL, 0.85 mmol) was added
dropwise to a soln of (EtO)2P(O)CH2CH=NCy (313 mg, 1.20
mmol) in THF (10 mL) at 0 °C. The resulting yellow soln was
stirred at the same temperature for 15 min and then a soln of 43 (175
mg, 0.710 mmol) in THF (2 mL) was added at –78 °C. The reaction
mixture was warmed to –30 °C over 4 h, and then 1% aq oxalic acid
(0.5 mL) was added under vigorous stirring. The mixture was ex-
tracted with Et2O (3 × 15 mL), dried (Na2SO4), and concentrated to
10% of its volume. The soln was filtered through a short pad of sil-
ica gel and concentrated. The residue was purified by flash column
chromatography (hexane–EtOAc, 20:1 to 12:1); this afforded 52.
(S,E)-1-[(6R,8S)-8-Acetoxy-2,6-dimethyl-5,6,7,8-tetrahydro-
naphthalen-1-yl]hexa-1,5-dien-3-yl Acrylate
DIPEA (0.145 mL, 0.832 mmol) and acryloyl chloride (0.065 mL,
0.800 mmol) were added successively to a soln of 53 (161.8 mg,
0.515 mmol) in CH2Cl2 (7 mL) at 10 °C. After the mixture had
stirred at the same temperature for 4 h, sat. aq NH4Cl (10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layer was dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
(hexane–EtOAc, 15:1); this afforded the acrylate title compound.
White solid; yield: 178.3 mg (94%); mp 49 °C; [a]D23 –103 (c 0.28,
CHCl3).
IR (KBr): 2951, 1732, 1238, 1188 cm–1.
23
White solid; yield: 169 mg (88%); mp 93 °C; [a]D –233 (c 0.88,
CHCl3).
IR (KBr): 2950, 2923, 1732, 1686, 1228 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.66 (d, J = 7.8 Hz, 1 H), 7.57 (d,
J = 16.3 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1
H), 6.30 (dd, J = 16.3, 7.8 Hz, 1 H), 6.07 (dd, J = 3.4, 2.4 Hz, 1 H),
2.90 (dd, J = 16.6, 4.1 Hz, 1 H), 2.37 (m, 1 H), 2.32 (s, 3 H), 2.11–
2.03 (m, 2 H), 1.98 (s, 3 H), 1.53 (ddd, J = 14.6, 13.2, 3.4 Hz, 1 H),
1.08 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 193.6, 170.0, 151.0, 136.4, 135.7,
134.6, 133.7, 131.5, 131.1, 130.0, 67.8, 38.1, 37.5, 23.7, 21.6, 21.1,
20.8.
1H NMR (400 MHz, CDCl3): d = 7.11 (d, J = 7.8 Hz, 1 H), 6.97 (d,
J = 7.8 Hz, 1 H), 6.52 (d, J = 16.3 Hz, 1 H), 6.44 (dd, J = 17.3, 1.5
Hz, 1 H), 6.18 (dd, J = 17.3, 10.2 Hz, 1 H), 5.99 (dd, J = 3.5, 2.2 Hz,
1 H), 5.85 (dd, J = 10.2, 1.5 Hz, 1 H), 5.82 (dddd, J = 17.3, 10.2,
7.1, 6.9 Hz, 1 H), 5.68 (dd, J = 16.3, 6.3 Hz, 1 H), 5.55 (ddd,
J = 12.9, 6.3, 1.0 Hz, 1 H), 5.15 (m, 1 H), 5.10 (m, 1 H), 2.87 (ddd,
J = 16.6, 4.4, 1.5 Hz, 1 H), 2.53–2.49 (m, 2 H), 2.33 (dd, J = 16.6,
11.8 Hz, 1 H), 2.22 (s, 3 H), 2.12 (ddd, J = 14.4, 4.4, 2.2 Hz, 1 H),
2.02 (m, 1 H), 1.99 (s, 3 H), 1.46 (ddd, J = 14.4, 12.9, 3.5 Hz, 1 H),
1.05 (d, J = 6.6 Hz, 3 H).
HRMS–FAB: m/z [M + Na]+ calcd for C17H20O3Na: 295.1310;
found: 295.1300.
13C NMR (100 MHz, CDCl3): d = 169.9, 165.4, 137.6, 135.9, 133.9,
133.2, 132.8, 131.0, 130.6, 130.4, 128.9, 128.7, 128.0, 118.1, 73.2,
68.5, 38.8, 38.3, 37.3, 23.8, 21.8, 21.3, 20.6.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

3706
M. Inoue, M. Nakada
FEATURE ARTICLE
HRMS–FAB: m/z [M + Na]+ calcd for C23H28O4Na: 391.1885;
found: 391.1872.
soln (0.6 mL) was added to a soln of epoxide 55 (13.5 mg, 0.0379
mmol) in THF–EtOH (1 mL/0.5 mL) at 0 °C. The resulting mixture
was stirred at the same temperature for 1 h. Sat. aq NaCl (5 mL) was
added and the mixture was extracted with EtOAc (5 × 10 mL). The
combined organic layer was dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash column chromatography
(hexane–EtOAc, 1:1 to 1:2); this afforded FR901516 (2).
(1S,3R)-3,7-Dimethyl-8-{(E)-2-[(S)-6-oxo-3,6-dihydro-2H-pyr-
an-2-yl]vinyl}-1,2,3,4-tetrahydronaphthalen-1-yl Acetate (54)
A soln of [Ru(=CHPh)(PCy3)2Cl2] (36.0 mg, 0.0437 mmol) in
CH2Cl2 (5 mL) was added to a refluxing soln of (S,E)-1-[(6R,8S)-8-
acetoxy-2,6-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl]hexa-1,5-
dien-3-yl acrylate (161 mg, 0.438 mmol) in CH2Cl2 (90 mL, 0.005
M). The resulting mixture was stirred at the same temperature for 7
h and the solvent was removed in vacuo. The residue was purified
by flash column chromatography (hexane–EtOAc, 6:1 to 3:1); this
afforded 54.
White solid; yield: 149 mg (100%); mp 108 °C; [a]D22 –142 (c 0.27,
CHCl3).
IR (KBr): 2951, 1724, 1635, 1240 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.14 (d, J = 7.8 Hz, 1 H), 7.00 (d,
J = 7.8 Hz, 1 H), 6.93 (ddd, J = 9.8, 4.4, 3.9 Hz, 1 H), 6.64 (d,
J = 16.3 Hz, 1 H), 6.08 (ddd, J = 9.8, 2.0, 1.7 Hz, 1 H), 5.99 (dd,
J = 3.4, 2.2 Hz, 1 H), 5.76 (dd, J = 16.3, 5.6 Hz, 1 H), 5.08 (m, 1 H),
2.89 (ddd, J = 16.6, 4.6, 1.5 Hz, 1 H), 2.57–2.51 (m, 2 H), 2.34 (dd,
J = 16.6, 11.8 Hz, 1 H), 2.27 (s, 3 H), 2.12–2.03 (m, 2 H), 2.02 (s, 3
H), 1.48 (ddd, J = 14.6, 13.2, 3.4 Hz, 1 H), 1.06 (d, J = 6.3 Hz, 3 H).
White solid; yield: 13.7 mg (100%); mp 167 °C (Lit.1a 167–
168 °C); [a]D24 –58 (c 0.45, CHCl3).
IR (KBr): 3408, 2951, 1724, 1716, 1371, 1241, 953 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.13 (d, J = 7.8 Hz, 1 H), 6.99 (d,
J = 7.8 Hz, 1 H), 6.59 (d, J = 16.3 Hz, 1 H), 5.98 (dd, J = 3.4, 2.0
Hz, 1 H), 5.68 (dd, J = 16.3, 5.1 Hz, 1 H), 5.36 (m, 1 H), 4.45 (m, 1
H), 2.88 (dd, J = 16.1, 3.4 Hz, 1 H), 2.85 (dd, J = 17.8, 4.9 Hz, 1 H),
2.67 (ddd, J = 17.8, 3.9, 1.5 Hz, 1 H), 2.34 (dd, J = 16.1, 11.7 Hz, 1
H), 2.26 (s, 3 H), 2.15–1.95 (m, 4 H), 2.11 (m, 1 H), 2.01 (s, 3 H),
1.48 (ddd, J = 14.6, 13.2, 3.4 Hz, 1 H), 1.06 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.5, 169.8, 137.5, 135.9, 133.9,
132.8, 131.0, 130.4, 128.5, 128.1, 75.3, 68.6, 62.7, 38.7, 38.2, 37.5,
35.5, 23.8, 21.8, 21.4, 20.4.
HRMS–FAB: m/z [M + Na]+ calcd for C21H26O5Na: 381.1678;
found: 381.1675.
13C NMR (100 MHz, CDCl3): d = 170.2, 164.0, 144.9, 137.1, 136.0,
134.0, 131.9, 131.0, 130.5, 129.8, 128.3, 121.5, 77.6, 68.5, 38.1,
37.4, 29.2, 23.8, 21.8, 21.5, 20.5.
HRMS–FAB: m/z [M + Na]+ calcd for C21H24O4Na: 363.1572;
found: 363.1571.
FR901512 (1)
To a soln of FR901516 (2) (8.0 mg, 0.022 mmol) in toluene (1 mL)
was added MeOH (1 mL). The mixture was stirred at r.t. for 24 h
and the solvent was removed in vacuo. The residue was dissolved
in THF (2 mL), and a 90% soln of TMSOK (8.0 mg, 0.056 mmol)
in THF (1 mL) was added to the soln at 0 °C. After the mixture had
stirred for 15 min, sat. aq NH4Cl (5 mL) was added and the mixture
was extracted with EtOAc (5 × 10 mL). The combined organic layer
was dried (Na2SO4) and concentrated in vacuo. The residue was pu-
rified by flash column chromatography (CHCl3–MeOH–AcOH,
200:20:1); this afforded FR901512 (1).
(1S,3R)-3,7-Dimethyl-8-{(E)-2-[(1R,3S,6R)-5-oxo-4,7-dioxabi-
cyclo[4.1.0]heptan-3-yl]vinyl}-1,2,3,4-tetrahydronaphthalen-1-
yl Acetate (55)
To a soln of 54 (7.0 mg, 0.021 mmol) and a 4.13 M soln of TBHP
in toluene (0.010 mL, 0.041 mmol) in toluene (2 mL) was added a
40% soln of Triton B in MeOH (0.003 mL, 0.007 mmol) at 0 °C.
The pale yellow soln was stirred at the same temperature for 30 min.
Sat. aq NH4Cl (5 mL) was added and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 6:1); this afforded
55.
White solid; yield: 5.2 mg (70%); mp 112 °C; [a]D21 –20.0 (c 0.64,
CHCl3).
IR (KBr): 2924, 1747, 1714, 1250 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.13 (d, J = 7.8 Hz, 1 H), 6.99 (d,
J = 7.8 Hz, 1 H), 6.59 (d, J = 16.3 Hz, 1 H), 5.97 (dd, J = 3.2, 2.0
Hz, 1 H), 5.60 (dd, J = 16.3, 5.6 Hz, 1 H), 5.14 (m, 1 H), 3.74 (dd,
J = 4.1, 3.2 Hz, 1 H), 3.63 (d, J = 4.1 Hz, 1 H), 2.89 (dd, J = 16.4,
3.2 Hz, 1 H), 2.52 (ddd, J = 14.9, 3.2, 2.9 Hz, 1 H), 2.34 (dd,
J = 16.4, 11.8 Hz, 1 H), 2.23 (s, 3 H), 2.17 (dd, J = 14.9, 12.0 Hz, 1
H), 2.09–2.00 (m, 2 H), 2.02 (s, 3 H), 1.47 (ddd, J = 14.6, 13.2, 3.2
Hz, 1 H), 1.06 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.2, 167.2, 137.1, 136.0, 133.9,
131.1, 131.0, 130.4, 129.6, 128.3, 73.3, 68.4, 52.1, 49.2, 38.1, 37.4,
29.3, 23.8, 21.8, 21.5, 20.4.
HRMS–FAB: m/z [M + Na]+ calcd for C21H24O5Na: 379.1521;
found: 379.1535.
24
White solid; yield: 7.9 mg (95%, 2 steps from 2); mp 134 °C; [a]D
+19 (c 0.39, MeOH) (Lit.1a [a]D20 +20 (c 0.68, MeOH)).
IR (KBr): 3317, 2951, 1705, 1672, 1373, 1271, 1254, 1086, 974
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.11 (d, J = 7.8 Hz, 1 H), 6.98 (d,
J = 7.8 Hz, 1 H), 6.40 (d, J = 16.3 Hz, 1 H), 6.29 (dd, J = 3.6, 2.0
Hz, 1 H), 5.64 (dd, J = 16.3, 7.2 Hz, 1 H), 4.49 (m, 1 H), 4.37 (m, 1
H), 2.86 (dd, J = 16.1, 3.4 Hz, 1 H), 2.63 (dd, J = 16.2, 4.5 Hz, 1 H),
2.59 (dd, J = 16.2, 7.2 Hz, 1 H), 2.35 (dd, J = 16.1, 12.4 Hz, 1 H),
2.19 (s, 3 H), 2.04 (s, 3 H), 2.01 (m, 1 H), 1.96 (ddd, J = 14.4, 3.7,
2.0 Hz, 1 H), 1.85 (ddd, J = 14.4, 10.0, 9.5 Hz, 1 H), 1.75 (ddd,
J = 14.4, 3.0, 2.4 Hz, 1 H), 1.52 (ddd, J = 14.4, 12.9, 3.6 Hz, 1 H),
1.07 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.8, 171.5, 137.7, 136.6, 136.0,
133.6, 130.9, 130.1, 128.3, 128.1, 73.4, 68.2, 68.2, 41.6, 41.2, 38.2,
38.0, 24.0, 21.7, 21.6, 20.2.
HRMS–FAB: m/z [M + Na]+ calcd for C21H28O6Na: 399.1784;
found: 399.1787.
Acknowledgment
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)],
Scientific Research (B), and the Global COE program ‘Center for
Practical Chemical Wisdom’ from MEXT, Japan.
FR901516 (2)
To a soln of (PhSe)2 (156 mg, 0.500 mmol) in EtOH (5 mL) was
added NaBH4 (38.0 mg, 1.00 mmol) at 0 °C. After the mixture had
stirred for 15 min, AcOH (0.075 mL, 1.3 mmol) was added to the
reaction mixture at r.t. (this provided the PhSeH soln).3 The PhSeH
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York

FEATURE ARTICLE
References
HMG-CoA Reductase Inhibitors FR901512 and FR901516
3707
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23
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–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, d-lactone 2
was converted into the methyl ester of 1 by its reaction with
MeOH, which was used as the solvent.
Synthesis 2009, No. 21, 3694–3707 © Thieme Stuttgart · New York