Enantioselective Total Synthesis of (+)-6-epi-Mevinolin and Its Analogs. Efficient Construction of the Hexahydronaphthalene Moiety by High Pressure-Promoted Intramolecular Diels - Alder Reaction of (R,2Z,8E,10E)-1-[(tert-Butyldimethylsilyl)oxy]6-methyl-2,8,10-dodecatrien-4-one

Article abstract of DOI:10.1021/jo970444m

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a) and (+)-6-epi-4a,5-dihydromevinolin (2b), were prepared by combining two nonracemic units, phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a and 7b by diastereoselective ring opening by means of (S)-benzyl mandelate as a common chiral auxiliary. The construction of decalin moiety 4 was accomplished by asymmetric intramolecular Diels - Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller. The IMDA diastereoselectivity of trienone 6 is discussed in terms of the configuration of (E)- and (Z)-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of (R)-(Z)-6 under high pressure is highly selective and gives cis-decalins exclusively with preferential formation of 4 over 16. The inhibitory activity of (+)-6-epi-mevinolin (2a) and several analogs against HMG-CoA reductase was compared with mevinolin (1b). (4-)-6-epi-Mevinolin (2a) was shown to be half as potent as mevinolin (1b) while (+)-6-epi-4a,5-dihydromevinolin (2b) was as potent as mevinolin.

Full text of DOI:10.1021/jo970444m

J . Org. Chem. 1997, 62, 5299-5309
5299
En a n tioselective Tota l Syn th esis of (+)-6-epi-Mevin olin a n d Its
An a logs. Efficien t Con str u ction of th e Hexa h yd r on a p h th a len e
Moiety by High P r essu r e-P r om oted In tr a m olecu la r Diels-Ald er
Rea ction of (R,2Z,8E,10E)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-
6-m eth yl-2,8,10-d od eca tr ien -4-on e
Yoshitaka Araki and Toshiro Konoike*
Shionogi Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553, J apan
Received March 11, 1997X
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, (+)-6-epi-mevinolin (2a )
and (+)-6-epi-4a,5-dihydromevinolin (2b), were prepared by combining two nonracemic units,
phosphonate 3 and decalin 4, which were prepared from enantiopure 3-substituted pentanedioic
acid monoesters 5a and 5b, respectively. Each acid was synthesized from cyclic anhydrides 7a
and 7b by diastereoselective ring opening by means of (S)-benzyl mandelate as a common chiral
auxiliary. The construction of decalin moiety 4 was accomplished by asymmetric intramolecular
Diels-Alder (IMDA) reaction of nonracemic trienone 6 bearing a methyl group as a chiral controller.
The IMDA diastereoselectivity of trienone 6 is discussed in terms of the configuration of (E)- and
(Z)-dienophiles which are activated by an endogenous carbonyl group. The IMDA reaction of (R)-
(Z)-6 under high pressure is highly selective and gives cis-decalins exclusively with preferential
formation of 4 over 16. The inhibitory activity of (+)-6-epi-mevinolin (2a ) and several analogs
against HMG-CoA reductase was compared with mevinolin (1b). (+)-6-epi-Mevinolin (2a ) was
shown to be half as potent as mevinolin (1b) while (+)-6-epi-4a,5-dihydromevinolin (2b) was as
potent as mevinolin.
Compactin (1a ),1 isolated from the culture broth of the
fungus Penicillium citrinum and Penicillinus brevicom-
pactum, was found to be a potent inhibitor against HMG-
CoA reductase (HMGR), a rate-limiting enzyme in the
biosynthesis of endogenous cholesterol.2 Structurally
related compounds, mevinolin (1b)3 and the 4a,5-dihydro
derivatives of 1a and 1b,4,5 were isolated thereafter, and
numerous structural modifications have been done to
improve their potency and pharmacological properties as
a potential therapeutic for treating hypercholesterolemia.
Consequently, a number of novel HMGR inhibitors have
been discovered6-8 and three inhibitors of natural ori-
gin,6,7 mevinolin (1b), pravastatin (1d ),9 and simvastatin
(1c),10 have been marketed.
The (3R)-hydroxy lactone moiety is essential for HMGR
inhibition; however, the structural requirement for the
remaining decalin moiety is not strict. There have been
some reports on the substituent effects at the 6-position
on the decalin moiety,7 and most involving R-alkyl
substituents.7a,b We were particularly interested in
introducing the 6â-methyl group into compactin because
simple replacement of the C-6 hydrogen with the R-
methyl group (mevinolin (1b )) or the â-hydroxy group
(pravastatin (1d )) had led to successful drugs. Here, we
report on the enantioselective total synthesis and HMGR
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) Isolation of (+)-compactin: (a) Brown, A. G.; Smale, T. C.; King,
T. J .; Hasenkamp, R.; Thompson, R. H. J . Chem. Soc., Perkin Trans.
1 1976, 1165. (b) Endo, A.; Kuroda, M.; Tsujita, Y. J . Antibiot. 1976,
29, 1346.
(6) (a) Review: Endo, A.; Hasumi, K. Nat. Prod. Rep. 1993, 10, 541.
(b) For a review on synthetic work, see: Chapleur, Y. The Chemistry
and Total Synthesis of Mevinic Acids in Recent Progress in the
Chemistry of Antibiotics; Lukacs, G., Ueno, S., Eds.; Springer: New
York, 1993; Vol. 2, pp 829-937. Recent synthetic work on natural
products: (c) Total synthesis of (+)-compactin: Hagiwara, H.; Nakano,
T.; Kon-no, M.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1995, 777. (d)
Total synthesis of (+)-mevinolin: Clive, D. L. J .; Murthy, K. S. K.;
Wee, A, G, H.; Prasad, J . S.; da Silva, G. J .; Majewski, M.; Anderson,
P. C.; Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J . R. J . Am.
Chem. Soc. 1990, 112, 3018. (e) Total synthesis of (+)-4a,5-di-
hydrocompactin: Hagiwara, H.; Kon-no, M.; Nakano, T.; Uda, H. J .
(2) Endo, A. J . Med. Chem. 1985, 28, 401.
(3) Isolation of (+)-mevinolin: (a) Alberts, A. W.; Chen, J .; Kuron,
G.; Hunt, V.; Huff, J .; Hoffman, C.; Rothrock, J .; Lopez, M.; J oshua,
H.; Harris, E.; Patchett, A.; Monaghan, R.; Currie, S.; Stapley, E.;
Albers-Scho¨nberg, G.; Hensens, O.; Hirshfield, J .; Hoogsteen, K.;
Liesch, J .; Springer, J . Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 3957.
(b) Endo, A. J . Antibiot. 1980, 33, 334.
(4) Isolation of (+)-4a,5-dihydrocompactin: Lam, Y. K. T.; Gullo, V.
P.; Goegelman, R. T.; J orn, D.; Huang, L.; DeRiso, C.; Monaghan, R.
L.; Putter, I. J . Antibiot. 1981, 34, 614.
(5) Isolation of (+)-4a,5-dihydromevinolin: Albers-Scho¨nberg, G.;
J oshua, H.; Lopez, M. B.; Hensens, O. D.; Springer, J . P.; Chen, J .;
Ostrove, S.; Hoffman, C. H.; Alberts, A. W.; Patchett, A. A. J . Antibiot.
1981, 34, 507.
Chem. Soc., Perkin Trans. 1 1994, 2417. (f) Total synthesis of
(+)-4a,5-dihydromevinolin: Hanessian, S.; Roy, P. J .; Petrini, M.;
Hotges, P. J .; Fabio, R.; Carganico, G. J . Org. Chem. 1990, 55, 5766
and earlier references cited therein.
S0022-3263(97)00444-1 CCC: $14.00 © 1997 American Chemical Society

5300 J . Org. Chem., Vol. 62, No. 16, 1997
Araki and Konoike
Sch em e 1. Retr osyn th etic An a lysis
The synthesis of enantioenriched diacid 5b was also
reported in our report13 starting from 3-methylpentane-
dioic anhydride 7b and (S)-benzyl mandelate, and 5b was
further transformed to (R)-3-methylvalerolactone 18
(Scheme 3). We assumed that the enantioenriched
dodecatrienone 6 could be derived from 5b, and subse-
quent IMDA reaction of 6 would lead to decalin unit 4.
In our scheme, all of the stereocenters were envisaged
to be derived from a single source, (S)-benzyl mandelate.
Syn th esis of Ra cem ic Tr ien on es a n d Th eir IMDA
Rea ction . We tried to construct the decalin framework
of mevinolins by IMDA cyclization of 6-methyl-2,8,10-
dodecatrien-4-one 6. We thought that the endogenous
carbonyl group at C-4 would facilitate the IMDA reaction
by activating the dienophile, and it could be reduced to
the hydroxy group in a later step. The C-6 methyl group
was expected to work as a chiral controller to regulate
the introduction of the remaining stereocenters.
The IMDA reaction has been explored as a useful
protocol for assembling several stereogenic centers in a
single step.14,15 There have been reports on the IMDA
reaction of 1,7,9-decatrien-3-ones,16,17 and the influence
of a substituent at the 5-position of decatrienones (cor-
responding to the 6-position of 2,8,10-dodecatrien-4-one)
has been demonstrated. However, the influence of the
configuration of the dienophile has not been investigated,
probably because of the configurational lability of both
dienophiles and the IMDA adducts.
For preliminary investigation of the IMDA reaction of
trienone 6, we prepared racemic 6 with both the (E)- and
(Z)-configurations (Scheme 2). (2E,4E)-1-Bromo-2,4-
hexadiene (8)18 was converted into aldehyde 9 (six steps,
23% yield). The isomeric purity of the (E,E)-diene part
of 9 was estimated to be about 80% by 13C NMR analysis.
Treatment of 9 with the (E)-vinyllithium reagent, pre-
pared from (E)-vinyltin 10,19 and subsequent Swern
oxidation gave (E)-6 (40% yield). Trienone (Z)-6 was
prepared in 37% yield from 9 in a similar way. Aldehyde
9 was treated with the (Z)-vinyllithium reagent, prepared
from (Z)-vinyl iodide 11,20 and oxidized to give (Z)-6. As
neat (E)-6 and (Z)-6 oligomerize at room temperature,
they were stored at -20 °C in a dichloromethane solution.
The IMDA reactions of (E)-6 were slow in solution at
room temperature, and we tried to increase the rate by
using higher pressure, by adding Lewis acids, and by
heating (Table 1). Only the (E,E)-diene isomer under-
went IMDA cyclization. The other isomers were recov-
ered. All four possible diastereomeric adducts were
obtained regardless of the reaction conditions, and cis-
inhibitory activity of (+)-6-epi-mevinolin (6â-methyl-
compactin) (2a ), (+)-6-epi-4a,5-dihydromevinolin (2b),
and their analogs.11
Resu lts a n d Discu ssion
We planned to prepare 2a by combining two enantio-
pure units, lactone precursor 3 and decalin moiety 4
(Scheme 1). Heathcock12a and Karanewsky12c had dem-
onstrated that enantiopure phosphonate 3 is a useful
synthon for HMGR inhibitors. We later found a more
practical synthesis of 3 which utilized desymmetrization
of 3-(silyloxy)pentanedioic anhydride 7a by means of (S)-
benzyl mandelate to give diastereomerically pure dicar-
boxylic acid 5a .13
(7) Recent synthetic work on decalin derivatives: (a) Blackwell, C.
M.; Davidson, A. H.; Launchbury, S. B.; Lewis, C. N.; Morrice, E. M.;
Reeve, M. M.; Roffey, J . A. R.; Tipping, A. S.; Todd, R. S. J . Org. Chem.
1992, 57, 5596. (b) Clive, D. L. J .; Zhang, C. J . Org. Chem. 1995, 60,
1413. (c) Stokker, G. E. J . Org. Chem. 1994, 59, 5983. (d) Turabi, N.;
DiPietro, R. A.; Mantha, S.; Ciosek, C.; Rich, L.; Tu, J .-I. Bioorg. Med.
Chem. 1995, 3, 1479.
(8) Recent work on novel synthetic HMG-CoA reductase inhibitors:
(a) Chan, C.; Bailey, E. J .; Hartley, C. D.; Hayman, D. F.; Hutson, J .
L.; Inglis, G. G. A.; J ones, P. S.; Keeling, S. E.; Kirk, B, E.; Lamont, R.
B.; Lester, M. G.; Pritchard, J . M.; Ross, B. C.; Scicinski, J . J .; Spooner,
S. J .; Smith, G.; Steeples, I. P.; Watson, N. S. J . Med. Chem. 1993, 36,
3646. (b) Connolly, P. J .; Westin, C. D.; Loughney, D. A.; Minor, L. K.
J . Med. Chem. 1993, 36, 3674. (c) Masamichi, W.; Haruo, K.; Teruyuki,
I.; Tetsuo, O.; Shujiro, S.; Kentaro, H. Bioorg. Med. Chem. 1997, 5,
437.
(13) Konoike, T.; Araki, Y. J . Org. Chem. 1994, 59, 7849.
(14) Reviews on the intramolecular Diels-Alder reaction, see: (a)
Ciganek, E. Org. React. 1984, 32, 1. (b) Fallis, A. G. Can. J . Chem.
1984, 62, 183. (c) Craig, D. Chem. Soc. Rev. 1987, 16, 187. (d)
Ahlbrecht, H. In Methods Org. Chem. (Houben-Weyl), Vol. E21c of
4th ed.; Helmchen, G., Ed.; Thieme: Stuttgart, 1995.
(15) The intramolecular Diels-Alder reaction approach for construc-
tion of the decalin framework of mevinic acids, see: (a) Schnaubelt,
J .; Reissig, H.-U. Synlett 1995, 452. (b) Witter, D. J .; Vederas, J . C. J .
Org. Chem. 1996, 61, 2613 and references cited therein.
(16) (a) Gras, J .-L.; Bertrand, M. Tetrahedron Lett. 1979, 20, 4549.
(b) Oppolzer, W.; Snowden, R. L.; Simmons, D. P. Helv. Chim. Acta
1981, 64, 2002.
(9) Serizawa, N.; Nakagawa, K.; Hamano, K.; Tsujita, Y.; Terahara,
A.; Kuwano, H. J . Antibiot. 1983, 36, 604.
(10) Simvastatin displays two or three times more activity than
mevinolin. Hoffman, W. F.; Alberts, A. W.; Anderson, P. S.; Chen, J .
S.; Smith, R. L.; Willard, A. K. J . Med. Chem. 1986, 29, 849.
(11) Konoike, T.; Araki, Y. J pn. Kokai Tokkyo Koho J P 06,157,393
[94,157,393], 1994. The preliminary results were reported: Araki, Y.;
Konoike, T. Abstracts of Papers, 37th Symposium on the Chemistry of
Natural Products, Tokushima, J apan, 1995, p 631.
(12) (a) Rosen T.; Heathcock, C. H. J . Am. Chem. Soc. 1985, 107,
3731. (b) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1988, 53,
2374. (c) Karanewsky, D. S.; Malley, M. F.; Gougoutas, J . Z. J . Org.
Chem. 1991, 56, 3744.
(17) (a) Zschiesche, R.; Grimm, E. L.; Reissig, H.-U. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 1086. (b) Frey, B.; Hunig, S.; Koch, M.; Reissig,
H.-U. Synlett 1991, 854. (c) Grieco, P. A.; Handy, S. T.; Beck, J . P.
Tetrahedron Lett. 1994, 35, 2663.
(18) J acobsen, M. J . Am. Chem. Soc. 1955, 77, 2461.
(19) (a) Labadie, J . W.; Stille, J . K. J . Am. Chem. Soc. 1983, 105,
6129. (b) Bansal, R.; Cooper, G. F.; Corey, E. J . J . Org. Chem. 1991,
56, 1329.
(20) (a) Moss, R. A.; Wilk, B.; Krogh-J espersen, K.; Westbrook, J .
D. J . Am. Chem. Soc. 1989, 111, 6729. (b) J ones, K.; Storey, M. D.
Tetrahedron 1993, 49, 4901.

Enantioselective Total Synthesis of (+)-6-epi-Mevinolin
J . Org. Chem., Vol. 62, No. 16, 1997 5301
Ta ble 2. Th e IMDA Cycliza tion of (Z)-6a (R )
Sch em e 2. P r ep a r a tion of Ra cem ic (E)- a n d
(Z)-Tr ien on es 6 (R ) CH2OTBDMS)
CH2OTBDMS)
Ta ble 1. Th e IMDA Cycliza tion of (E)-6a (R )
CH2OTBDMS)
Ta ble 3. Th er m a l IMDA Rea ction of
1,7,9-Deca tr ien -3-on e a n d An a logs16,17
ratio
cis-
decalins
trans-
decalins
R1
R2
R3
R4
R5
yield (%)
entry
entry
conditions
12
13
14
15
1
2
3
4
5
CO2Me
CO2Me
CO2Me
H
H
Me
H
Me
Me
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
100
61
45
62
57
1
39
55
38
43
1
2
3
10 kbar, rt
Et2AlCl, 0 °C
PhCl, reflux
7
13
17
2
47
27
29
22
11
22
trace
3
H
Me
a
(E,Z)- and (Z,E)-diene isomers were recovered.
yield and stereoselectivity (4 (53% yield) and 16 (8%
yield)). Under Lewis acid-catalyzed condition, (Z)-6
partially isomerized to (E)-6, and the IMDA adducts from
(E)-6 were present as contaminants of cis-decalins 4 and
16. In contrast, double bond isomerization of (Z)-6 to silyl
enol ether 17 was observed on heating, and cis-decalins
were obtained in low yield.
cis-Decalins 4 and 16 were epimerized by treatment
with NaOMe in MeOH into trans-decalins 12 and 13,
respectively, in high yields. These findings suggested
that the IMDA cyclization of nonracemic (Z)-6 and
subsequent epimerization of the major adduct would be
a promising protocol for the synthesis of trans-decalin
12 and of (+)-6-epi-mevinolin.
There are a few reports on the IMDA reactions of 1,7,9-
decatrien-3-one and analogs, and the predominance of
cis-decalins from the endo transition state was estab-
lished for the parent substrate.16 Table 3 shows some
examples of IMDA reactions of substituted decatrienones
under thermal conditions.17 The methoxycarbonyl group
at the 5-position did not affect the selectivity, and cis-
decalins were obtained exclusively (entry 1). The exist-
decalins (14 and 15) were obtained in preference to trans-
decalins (12 and 13) in all the reactions. These findings
are in accord with previous observations of the major
adducts being cis-decalins generated via the endo transi-
tion state.21 The configurations of the cycloadducts were
1
determined by analyses of the H-1H coupling constants
in the 1H NMR spectra and the chemical shifts in the
13C NMR spectra.22 trans-Decalins 12 and 13 have the
same configurations as those of (+)-6-epi-mevinolin and
mevinolin, respectively. However, we did not exploit 12
and 13 for the synthesis of (+)-6-epi-mevinolin or mevi-
nolin because these trans-decalins were minor products
in the IMDA reaction and could not be purified by simple
silica gel chromatography.
The IMDA reactions of (Z)-6, which were also slow at
room temperature, were conducted under conditions
similar to those of the IMDA reaction of (E)-6. These
reactions of (Z)-6 were more selective than those of (E)-6
and gave only cis-decalins with a preference for 4 over
16 (Table 2). The high pressure-promoted IMDA reac-
tion23 gave the most satisfactory result in terms of the
(23) Review on organic synthesis under high pressure, see: Isaacs,
N. S. Tetrahedron 1991, 47, 8463. High pressure-mediated IMDA
reactions, see: (a) Buback, M.; Abeln, J .; Hubsch, T.; Ott, C.; Tietze,
L. F. Liebigs Ann. 1995, 9. (b) Heiner, T.; Michalski, S.; Gerke, K.;
Kuchta, G.; Buback, M.; de Meijere, A. Synlett 1995, 355 and references
cited therein.
(21) Coe, J . W.; Roush, W. R. J . Org. Chem. 1989, 54, 915.
(22) (a) Beierbeck, H.; Saunders, J . K. Can. J . Chem. 1976, 54, 2985.
(b) Beierbeck, H.; Saunders, J . K.; ApSimon, J . W. Can. J . Chem. 1977,
55, 2813. (c) Irikawa, H.; Okumura, Y. Bull. Chem. Soc. J pn. 1978,
51, 2086.

5302 J . Org. Chem., Vol. 62, No. 16, 1997
Araki and Konoike
F igu r e 1. Endo-boat transition state for the IMDA reaction
of 1,1-disubstituted undeca-1,7,9-trien-3-one, leading to cis-
decalins.
F igu r e 2. Steric interactions in the transition states leading
to cis-decalins (R ) CH2OTBDMS).
ence of a methyl group at the 2-position of 5-(methoxy-
carbonyl)-1,7,9-decatrien-3-one (entry 2) diminished the
cis preference and resulted in mixtures of cis- and trans-
decalins (61:39). When two methyl groups were intro-
duced at the terminal 1-position (entry 3), trans-decalins
became the major products (45:55). A similar decrease
in the cis adduct was observed for 2-methyl substituents
when no methoxycarbonyl group was present at the
5-position (entries 4, 5).
Sch em e 3. P r ep a r a tion of (R)-(Z)-6
The stereoselectivity of the IMDA reaction has gener-
ally been explained by considering the steric and elec-
tronic interactions in the transition states. The results
obtained for methylated decatrienones can be discussed
in relation to steric repulsion between a diene and a
dienophile portion. Houk’s theoretical study of the
Diels-Alder transition state24 suggests a nonparallel
alignment of the two planes, one occupied by a dienophile
and the other by a diene (Figure 1). In this transition
state, the methyl group on the opposite side of the
carbonyl group (R2 and R4 in Table 3) experiences a steric
repulsion with the inside hydrogen of the diene, while
the methyl group on the same side of the carbonyl (R3)
does not. This steric repulsion explains the decreased
preference formation of cis-decalins for trienones meth-
ylated at positions R2 and R4 (Table 3, entries 2, 3, 5).
The ratios of the cis- and trans-decalins in our IMDA
reactions of (E)- and (Z)-trienone 6 are explained in the
context of the steric repulsion between the TBDMSOCH2
group and the inside hydrogen of the diene. Comparison
of the transition states of the IMDA reaction of (E)-6 and
(Z)-6 leads to the conclusion that the exclusive formation
of cis-decalins from (Z)-6 should be expected. In the endo
transition state of (E)-6 that conceivably leads to cis-
decalin, the C-1 TBDMSOCH2 group displays an un-
favorable nonbonded interaction with the C-10 inside
hydrogen. This steric repulsion is avoided in the exo
transition state leading to trans-decalin, and hence all
possible diastereomers were obtained for the IMDA
cyclization of (E)-6. In contrast to (E)-6, the endo
transition state in the IMDA reaction of (Z)-6 is free from
such repulsion, and cis-decalins 4 and 16 were obtained
exclusively.
2). The stabilities of these transition states have been
compared in terms of the energy difference of the
conformation of the tether connecting the diene and the
dienophile. In the energetics of conformations around
the sp3-sp2 bond of alkenes or carbonyl groups, it is
generally believed that a skew butene conformation is
more stable than a gauche butene, and likewise, an
eclipsed ethanone conformation is more stable than a
gauche ethanone.25 In this regard, transition state A
(Figure 2) has two stable sp3-sp2 conformations which
are an eclipsed ethanone conformation around the C-4-
C-5 unit and a skew butene conformation around the
C-7-C-8 unit. Chair transition state B (Figure 2) has a
gauche ethanone conformation and a gauche butene
conformation around the sp3-sp2 single bonds, which are
less stable than transition state A. The preference of 4
over 16 results from these steric factors in transition
states A and B.
Syn th esis of En a n tioen r ich ed Tr ien on e (R)-(Z)-
6. Scheme 3 shows the synthesis of trienone (R)-(Z)-6
which is a precursor of octalin (R)-4. The stereocenter
at the 6-position of (R)-(Z)-6 was derived from (R)-4-
methyltetrahydropyran-2-one (18).26 As reported in our
previous paper,13 18 was synthesized with high optical
purity (93% ee) from diacid 5b , prepared by desym-
metrization of 3-methylpentanedioic anhydride (7b )27
The product ratio of the two cis-decalins, 4 and 16, can
be explained by considering the energy difference be-
tween the two transition states, boat A and chair B,
which lead to cis-decalin 4 and 16, respectively (Figure
(25) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; J ohn Wiley & Sons: New York, 1994; Chapter
10.
(26) (a) Irwin, A. J .; J ones, J . B. J . Am. Chem. Soc. 1977, 99, 556.
(b) Lam. L. K. P.; Hui, R. A. H. F.; J ones, J . B. J . Org. Chem. 1986,
51, 2047. (c) Terunuma, D.; Motegi, M.; Tsuda, M.; Sawada, T.;
Nozawa, H.; Nohira, H. J . Org. Chem. 1987, 52, 1630.
(27) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1993, 58, 142.
(24) Transition state modeling study for IMDA reaction was reported
by using a combination of molecular mechanics and ab initio meth-
ods: (a) Raimondi, L.; Brown, F. K.; Gonzalez, J .; Houk, K. N. J . Am.
Chem. Soc. 1992, 114, 4796. (b) Brown, F. K.; Singh, U. C.; Kollman,
P. A.; Raimondi, L.; Houk, K. N.; Bock, C. W. J . Org. Chem. 1992, 57,
4862.

Enantioselective Total Synthesis of (+)-6-epi-Mevinolin
J . Org. Chem., Vol. 62, No. 16, 1997 5303
Sch em e 4. Syn th esis of
(+)-6-epi-4a ,5-Dih yd r om evin olin (2b)
with (S)-benzyl mandelate. The (R)-lactone 18 was first
converted to the Weinreb amide 19.28 As lactone 18 was
prone to polymerization, we surveyed the reaction condi-
tions for preparing 19. Weinreb’s original aluminum
reagent,29 prepared from Me3Al and MeHNOMe‚HCl,
gave amide 19 in moderate yield (70%), but this method
required a laborious filtration to remove the aluminum
salts, followed by silica gel chromatography. A thermal
reaction of 18 and MeHNOMe in CH3CN (110 °C) gave
only polymeric products. High pressure aminolysis30
proved to be most satisfactory, giving amide 19 (90%
yield) by pressurizing a mixture of lactone 18, MeH-
NOMe, and CH3CN under 9 kbar at room temperature.
Amide 19, obtained by simple evaporation of volatile
materials, was pure enough for practical use. This
procedure offered the advantage of eliminating an aque-
ous workup which would have been difficult for water-
soluble 19. These results showed that high pressure
aminolysis is beneficial for Weinreb amide formation in
several respects, including simple operation, mild neutral
reaction condition, easy workup, and high efficiency.
PDC oxidation of amide alcohol 19 afforded the alde-
hyde, which was converted to diene 20 by the J ulia olefin
synthesis.31 The aldehyde was treated with lithiated (E)-
1-benzenesulfonyl-2-butene,32 and the resulting lithium
alkoxide was benzoylated. Reductive elimination of the
benzoyloxy sulfone by sodium amalgam gave an isomeric
mixture of (E,E)-diene 20 and other dienes. The purity
of the (E,E)-diene part was 75% (13C NMR). Treatment
of 20 with the (Z)-vinyllithium reagent, prepared from
(Z)-vinyl iodide 11, gave trienone (R)-(Z)-6 (72% yield).
Syn th esis of (+)-6-epi-4a,5-Dih ydr om evin olin (2b).
High pressure-promoted IMDA cyclization of (R)-(Z)-6
gave a mixture of cis-decalins (R)-4 and (R)-16 at room
temperature under 10 kbar (Scheme 4). cis-Decalin (R)-4
was isolated by silica gel chromatography, and its 8a-
position was epimerized to give the trans-isomer (R)-12
(92% yield). L-Selectride reduction of (R)-12 gave the
(8S)-alcohol 21, which served as a common intermediate
for (+)-6-epi-mevinolin (2a ) and (+)-6-epi-4a,5-dihydro-
mevinolin (2b).
Sch em e 5. Syn th esis of (+)-6-epi-Mevin olin (2a )
(+)-6-epi-4a,5-Dihydromevinolin (2b) was prepared
from 21 by a sequence of reactions similar to Heathcock’s
method.12a Alcohol 21 was acylated with commercially
available (S)-2-methylbutyric anhydride, and the silyl
protecting group was removed. Swern oxidation, followed
by Horner-Wadsworth-Emmons olefination of the re-
sulting aldehyde with phosphonate 3 (Cs2CO3 in 2-pro-
panol),33 gave the (E)-enone 22. (Ph3P)3RhCl-catalyzed
hydrosilylation of 22 with Et3SiH gave a mixture of (E)-
and (Z)-silyl enol ethers. Subsequent desilylation af-
forded the saturated ketone, which was reduced to the
syn-diol (NaBH4 and Et2BOMe in THF-MeOH at -78
°C).34 The anti-diol was not observed by 13C NMR. Final
lactonization by HF/pyridine35 gave (+)-6-epi-4a,5-dihy-
dromevinolin (2b).
(28) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15.
(29) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989.
(30) Matsumoto, K.; Hashimoto, S.; Uchida, T.; Okamoto, T.; Otani,
S. Bull. Chem. Soc. J pn. 1989, 62, 3138.
(31) (a) J ulia, M.; Paris, J .-M.; Tetrahedron Lett. 1973, 14, 4833.
(b) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S. Tetrahedron
Lett. 1995, 36, 5607.
(32) Hirama, M.; Uei, M. J . Am. Chem. Soc. 1982, 104, 4251.
(33) Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.; Amemiya, M.;
Inazu, T. Chem. Lett. 1989, 335.
Syn th esis of (+)-6-epi-Mevin olin (2a ). The 4a,5-
double bond was introduced to 21 for the synthesis of (+)-
6-epi-mevinolin 2a (Scheme 5). The double bond in 21
was brominated with Br2 and NEt3, and subsequent
dehydrobromination by DBU gave diene 23 in 32% yield
along with two double-bond isomers (13% and 10%
yield).36 Conversion of 23 into (+)-6-epi-mevinolin 2a was
accomplished by the same procedure as that of 2b except
(34) Chen, K.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J . Tetrahedron Lett. 1987, 28, 155.
(35) J ohnson, W. S.; Kelson, A. B.; Elliot, J . D. Tetrahedron Lett.
1988, 29, 3757.
(36) Funk, R. L.; Zeller, W. E. J . Org. Chem. 1982, 47, 180.

5304 J . Org. Chem., Vol. 62, No. 16, 1997
Araki and Konoike
Ta ble 4. HMG-CoA Red u cta se In h ibitor y Activities
inactive (entry 6), the introduction of the double bond
led to recovery of the potency to one-third of that of (+)-
6-epi-4a,5-dihydromevinolin (entry 7).
Con clu sion
We have achieved an enantioselective total synthesis
of (+)-6-epi-mevinolins 2a and 2b, which is the first
synthesis of 6â-alkyl substituted compactins. All stereo-
centers of (+)-6-epi-mevinolins, except for the butyroxy
group at the 8-position, were generated from a single
chiral auxiliary, (S)-benzyl mandelate. We used the
IMDA reaction of the (6R)-trienone 6 to construct the
decalin unit. The diastereoselectivity of this addition is
dependent on the configurations of the dienophile moiety.
We evaluated the HMGR inhibitory potency of several
6-epi-mevinolin analogs and found (+)-6-epi-4a,5-dihy-
dromevinolin (2b) to have the highest potency, being as
potent as mevinolin. The high pressure procedure proved
quite effective for the IMDA reaction and Weinreb amide
formation.
Exp er im en ta l Section
Gen er a l. Reactions were carried out under a nitrogen
atmosphere in anhydrous solvents (dried over molecular sieves
type 4A). Organic extracts were dried over anhydrous MgSO4.
Solvent removal was accomplished under aspirator pressure
using a rotary evaporator. TLC was performed with Merck
precoated TLC plates silica gel 60 F254, and compound visu-
alization was effected with 10% H2SO4 containing 5% of
ammonium molybdate and 0.2% of ceric sulfate. Gravity
chromatography was done with Merck silica gel 60 (70-230
mesh). 1H NMR and 13C NMR spectra were determined as
CDCl3 solutions at 200 and 50.3 MHz, unless specified
otherwise. J values are given in hertz. The high pressure
apparatus was purchased from Hikari High Press Inc. High-
resolution mass spectra (HR-LSIMS) were recorded on a
Hitachi M-90 instrument.
(5E,7E)-3-Meth yl-5,7-n on a d ien a l (9). Diisopropylamine
(64.20 g, 634.4 mmol) was dissolved in THF (300 mL), and
BuLi (400 mL of 1.6 M hexane solution, 640 mmol) was added
dropwise over 20 min at -78 °C. After 30 min, tert-butyl
propionate (82.60 g, 634.4 mmol) was added dropwise over 30
min, and the mixture was stirred for 30 min. (2E,4E)-1-
Bromo-2,4-hexadiene (8)18 (102.16 g, 634.4 mmol) in THF (100
mL) was added over 20 min, and the whole mixture was stirred
for an additional 3 h at -78 °C. The reaction mixture was
quenched with water and extracted with ethyl acetate (EtOAc)
three times. The organic extracts were washed with saturated
NaHCO3, combined, dried, and concentrated. Residual oil was
distilled (bp 75-103 °C at 6 torr) to give tert-butyl (4E,6E)-
2-methyl-4,6-octadienoate (112.79 g, 85% yield). IR (film)
2972, 1726, 1365 cm-1; 1H NMR δ 1.09 (d, 3, J ) 6.8), 1.43 (s,
9), 1.73 (d, 3, J ) 6.0), 2.0-2.5 (m, 3), 5.3-5.8 (m, 2), 5.9-6.1
(m, 2); TLC (EtOAc/hexane ) 1/9) Rf 0.56.
for the desilylation of 24 which was achieved with TBAF
and AcOH to give 25 (98% yield). The desilylation of 24
by TBAF without AcOH gave a significant amount of the
acyl migration product. Alcohol 25 was converted into
(+)-6-epi-mevinolin 2a by a procedure similar to that
employed for the preparation of 2b.
HMGR In h ibition Activity. We prepared several
mevinolin analogs including 2a and 2b, and they were
converted into the corresponding sodium salts of the
carboxylic acids, a biologically active form of HMGR
inhibitors. Their in vitro inhibitory activities for rat liver
microsomal HMGR37 were compared with that of mevi-
nolin (Table 4).
The relative potency of (+)-6-epi-mevinolin (2a ) (entry
1) is about half that of mevinolin, which is in contrast to
the enhanced activity of pravastatin (1d )9 and several
6R-alkyl substituted compactins.7a,b (+)-6-epi-4a,5-Dihy-
dromevinolin (2b) (entry 2) is twice as potent as (+)-6-
epi-mevinolin (2a ) and as potent as mevinolin (1b). In
the natural series, mevinolin and its 4a,5-dihydro deriva-
tive were reported to have equal potency for HMGR
inhibitors.5
The ester (112.79 g, 536.3 mmol) in Et2O (200 mL) was
added to LiAlH4 (20.4 g, 536.3 mmol) in Et2O (400 mL)
dropwise over 1 h at 0 °C. The mixture was stirred at room
temperature for 67 h. After cooling down to 0 °C, saturated
Na2SO4 (20 mL) was added carefully with vigorous stirring
and MgSO4 was added. The mixture was diluted with Et2O,
and solids were filtered off through a pad of Hyflo Super-cel.
Solids were washed with Et2O and then with EtOAc. The
filtrates were combined and concentrated. Residual oil was
distilled (bp 89-92 °C at 4 torr) to give (4E,6E)-2-methyl-4,6-
octadien-1-ol (62.50 g, 83% yield). IR (film) 3334, 2912, 1451
cm-1; 1H NMR δ 0.92 (d, 3, J ) 6.8), 1.73 (d, 3, J ) 6.4), 1.8-
2.2 (m, 3), 3.46 (dd, 1, J ) 6.0, 10.6), 3.51 (dd, 1, J ) 6.0, 10.6),
5.4-5.7 (m, 2), 5.9-6.1 (m, 2); 13C NMR δ 16.5, 18.0, 36.1, 36.5,
67.7, 127.1, 129.7, 131.7, 132.0; TLC (EtOAc/hexane ) 1/6) Rf
0.21.
We modified the acyloxy side chain at the 8-position
of (+)-6-epi-4a,5-dihydromevinolin (2b). Replacement of
the (S)-2-methylbutyroxy group with the butyroxy group
(entry 3) lowered the activity by one-half. (+)-6-epi-4a,5-
Dihydrosimvastatin (entry 4), which has a 2,2-dimeth-
ylbutyroxy group, showed diminished activity although
simvastatin (1c) is twice as potent as mevinolin 1b.10
We introduced the double bond into the (+)-6-epi-4a,5-
dihydromevinolin (2b) between its lactone and decalin
unit (entry 5) because more recent and potent synthetic
HMGR inhibitors often have a double bond at this
position;8 however, the resulting compound was not
active. Although the analog whose decalin unit is enan-
tiomeric to that of (+)-6-epi-4a,5-dihydromevinolin was
MsCl (27.66 mL, 357 mmol) was added to a solution of
(4E,6E)-2-methyl-4,6-octadien-1-ol (38.54 g, 275 mmol) in
(37) Kuroda, M.; Endo, A. Biochim. Biophys. Acta 1977, 486, 70.

Enantioselective Total Synthesis of (+)-6-epi-Mevinolin
J . Org. Chem., Vol. 62, No. 16, 1997 5305
pyridine (200 mL) over 1 min. The reaction mixture was
stirred at room temperature for 40 min. Next, Et2O and H2O
were added to the mixture, and the organic phase was
separated. The aqueous phase was extracted twice with Et2O,
and the organic extracts were combined, dried, and concen-
bined, dried, and concentrated. Residual oil was purified by
silica gel chromatography (EtOAc/hexane )1/15, 1/6, 1/1) to
give the allylic alcohol (15.8 g, 99% yield). 1H NMR δ 0.07 (s,
6), 0.91 (s, 9), 0.92 (d, 3, J ) 6.6), 1.3-2.2 (m, 5), 1.73 (d, 3, J
) 6.8), 4.1-4.3 (m, 3), 5.4-5.8 (m, 4), 5.9-6.1 (m, 2); TLC
(EtOAc/hexane ) 1/9) Rf 0.20.
trated to give the crude mesylate. IR (film) 2956, 1456 cm-1
;
1H NMR δ 0.99 (d, 3, J ) 6.6), 1.74 (d, 3, J ) 6.4), 1.9-2.3 (m,
3), 3.00 (s, 3), 3.9-4.2 (m, 2), 5.4-5.7 (m, 2), 5.9-6.1 (m, 2);
TLC (EtOAc/toluene ) 1/10) Rf 0.42.
To a solution of oxalyl chloride (7.92 g, 62.4 mmol) in CH2Cl2
(100 mL) were added DMSO (9.75 g, 125 mmol) in CH2Cl2 (20
mL) and the alcohol (13.5 g, 41.6 mmol) in CH2Cl2 (40 mL) at
-78 °C. After stirring for 20 min at -78 °C, NEt3 (40.6 mL,
291 mmol) was added dropwise over 20 min, and stirring was
continued for 20 min at -78 °C. Next, the reaction mixture
was diluted with CH2Cl2 and acidified with 1 N HCl. The
organic phase was separated, and the aqueous phase was
extracted twice with CH2Cl2. Each organic extract was washed
with saturated NaHCO3 and brine, dried, and concentrated.
Purification by silica gel chromatography (EtOAc/hexane )
1/19 to 1/9) gave trienone (E)-6 (9.00 g, 67% yield). 1H NMR
δ 0.08 (s, 6), 0.91 (d, 3, J ) 6.3), 0.93 (s, 9), 1.73 (d, 3, J ) 6.3),
1.9-2.2 (m, 3), 2.52 (dd, 1, J ) 7.7, 15.5), 2.57 (dd, 1, J ) 5.4,
15.5), 4.36 (dd, 2, J ) 2.2, 3.5), 5.4-5.7 (m, 2), 5.9-6.1 (m, 2),
6.36 (dt, 1, J ) 2.2, 15.8), 6.84 (dt, 1, J ) 3.5, 15.8); TLC
(EtOAc/hexane ) 1/19) Rf 0.31; HR-LSIMS m/ z 322.2317 M+
(calcd for C19H34O2Si, 322.2325).
The crude mesylate was dissolved in DMF (250 mL) and
warmed to 70 °C. A mixture of KCN (23.25 g, 357 mmol) and
KI (22.74 g, 137 mmol) in H2O (80 mL) was gradually poured
in, and the resulting mixture was refluxed for 30 h. After
being cooled to room temperature, the mixture was poured into
ice-cold H2O and extracted twice with Et2O. Each organic
extract was washed successively with H2O, 1 N HCl, saturated
NaHCO3, and brine. The organic layers were combined and
then dried, concentrated, and distilled (bp 99-104 °C at 5 torr)
to obtain (5E,7E)-3-methyl-5,7-nonadienenitrile (33.66 g, 82%
yield). IR (film) 2958, 2242, 1454 cm-1; 1H NMR δ 1.08 (d, 3,
J ) 6.6), 1.74 (d, 3, J ) 6.6), 1.8-2.0 (m, 1), 2.0-2.4 (m, 4),
5.3-5.8 (m, 2), 5.9-6.1 (m, 2); TLC (EtOAc/hexane ) 1/9) Rf
0.42.
DIBALH (270 mL of 1.0 M toluene solution, 270 mmol) was
added dropwise to a solution of the nitrile (33.66 g, 226 mmol)
in CH2Cl2 (340 mL) over 30 min at 0 °C. The reaction mixture
was stirred at room temperature for 30 min. After cooling to
0 °C, MeOH (32 mL) was added cautiously until the gas
evolution ceased. The mixture was stirred at room tempera-
ture for 30 min and then poured into a mixture of ice and 1 N
HCl. The mixture was extracted twice with Et2O, and each
organic extract was washed successively with H2O, saturated
NaHCO3, and brine. The combined organic extract was dried,
concentrated, and distilled (bp 86-87 °C at 6 torr) to give
aldehyde 9. Further purification by silica gel chromatography
(EtOAc/hexane ) 1/9 to 1/6) and distillation (bp 84.5 °C at 5.5
torr) gave aldehyde 9 (21.01 g, 61% yield). IR (CHCl3) 3019,
1721 cm-1; 1H NMR δ 0.97 (d, 3, J ) 6.0), 1.74 (d, 3, J ) 6.1),
2.0-2.3 (m, 4), 2.3-2.5 (m, 1), 5.3-5.7 (m, 2), 5.9-6.1(m, 2),
9.75 (t, 1, J ) 2.1); 13C NMR δ 18.1, 20.0, 28.6, 40.0, 50.4, 127.4,
129.0, 131.8, 132.9, 201.8; TLC (EtOAc/hexane ) 1/9) Rf 0.40.
Anal. Calcd For C10H16O: C, 78.90; H, 10.59. Found: C,
78.75; H, 10.59. The ratio of the diene part was estimated to
be 10:1:1 for (E,E):(E,Z):(Z,E)-isomers by 13C NMR analysis.
ter t-Bu t yld im et h yl-[[(3E)-(t r ib u t ylst a n n a n yl)a llyl]-
oxy]sila n e (10).19 To a solution of propargyl alcohol (28.0 g,
0.5 mol) in CH2Cl2 (200 mL) was added tert-butylchlorodi-
methylsilane (75.4 g, 0.5 mol) followed by imidazole (68.1 g,
1.0 mol) at room temperature. The reaction mixture was
refluxed for 1 h and then quenched with ice and H2O. The
mixture was extracted three times with CH2Cl2, and the
organic extracts were combined, dried, and concentrated.
Residual oil was distilled (bp 48-50 °C at 11 torr) [lit.38 bp 45
°C at 10 torr] to give 3-[(tert-butyldimethylsilyl)oxy]propyne
(68.7 g, 81% yield). 1H NMR δ 0.13 (s, 6), 0.91 (s, 9), 2.39 (t,
1, J ) 2.4), 4.31 (d, 2, J ) 2.4); TLC (hexane) Rf 0.14.
The silyl ether (30.6 g, 180 mmol) was dissolved in benzene,
and tributyltin hydride (49.9 mL, 180 mmol) and AIBN (0.30
g, 1.8 mmol) were added at room temperature. The reaction
mixture was refluxed for 20 min and concentrated, and then
the residual oil was purified by silica gel chromatography
(EtOAc/hexane ) 1/100 to 1/10) to give 10 (70.2 g, 85% yield).
1H NMR δ 0.07 (s, 6), 0.91 (s, 9), 0.8-1.0 (m, 15), 1.2-1.6 (m,
12), 4.21 (dd, 2, J ) 1.0, 3.6), 6.0-6.3 (m, 2); TLC (hexane) Rf
0.35.
ter t-Bu tyl-[[(3Z)-Iod oa llyl]oxy]d im eth ylsila n e11.20b (Z)-
3-Hydroxy-1-iodopropene was prepared according to Moss’s
procedure.20a To a solution of (Z)-3-hydroxy-1-iodopropene
(56.4 g, 306 mmol) in CH2Cl2 (280 mL) were added tert-
butyldimethylchlorosilane (57.2 g, 368 mmol) and imidazole
(41.7 g, 613 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C for 1.5 h and poured into ice and H2O, and the organic
phase was separated. The aqueous phase was extracted with
CH2Cl2, and each organic extract was washed with brine,
dried, and concentrated. Residual oil was distilled (bp 79-88
°C at 5 torr) to give iodide 11 (87.6 g, 96% yield). IR (film)
1
2952, 1468, 1254 cm-1; H NMR δ 0.10 (s, 6), 0.91 (s, 9), 4.25
(dd, 2, J ) 1.8, 5.2), 6.23 (dt, 1, J ) 1.8, 7.8), 6.42 (dt, 1, J )
5.2, 7.8); TLC (hexane) Rf 0.19. Anal. Calcd For C9H19OISi:
C, 36.25; H, 6.42; I, 42.55. Found: C, 36.14; H, 6.32; I, 42.34.
(2Z,8E,10E)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-m eth yl-
2,8,10-d od eca tr ien -4-on e (Z)-6. To a solution of iodide 11
(11.93 g, 40 mmol) in Et2O (150 mL) was added BuLi (25 mL
of 1.6 M hexane solution, 40 mmol) over 15 min at -78 °C.
The mixture was stirred at -78 °C for 2 h and then cooled to
-95 °C. Aldehyde 9 (2.44 g, 16 mmol) in Et2O (25 mL) was
added over 15 min, and the mixture was stirred at -90 °C for
1 h. The reaction mixture was quenched with 1 N HCl and
extracted twice with Et2O. The organic extracts were washed
with H2O, combined, dried, and concentrated. Residual oil was
purified by silica gel chromatography (EtOAc/hexane ) 1/6)
to give the allylic alcohol (3.52 g, 68% yield). IR (CHCl3) 3420,
2926, 1460 cm-1; 1H NMR δ 0.09 (s, 6), 0.91 (s, 9), 0.9-1.0 (m,
3), 1.1-2.2 (m, 5), 1.73 (d, 3, J ) 6.8), 4.1-4.4 (m, 2), 4.50 (q,
1, J ) 7.0), 5.4-5.7 (m, 4), 5.9-6.1 (m, 2); TLC (EtOAc/hexane
) 1/6) Rf 0.27.
To a solution of oxalyl chloride (1.97 g, 15.48 mmol) in
CH2Cl2 (20 mL) was added DMSO (2.2 mL, 30.96 mmol)
followed by the alcohol (3.53 g, 10.88 mmol) in CH2Cl2 (20 mL)
at -78 °C. After stirring for 30 min at -78 °C, NEt3 (10.1
mL, 72.24 mmol) was added dropwise over 5 min, and stirring
was continued for 1.5 h at -78 °C. Next, the reaction mixture
was diluted with Et2O and acidified with 1 N HCl. The organic
phase was separated, and the aqueous phase was extracted
twice with Et2O. Each organic extract was washed with
saturated NaHCO3 and brine, dried, and concentrated. Pu-
rification by silica gel chromatography (EtOAc/hexane ) 1/30)
gave trienone (Z)-6 (2.51 g, 72% yield). IR (CHCl3) 2950, 1680,
(2E,8E,10E)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-m eth yl-
2,8,10-d od eca tr ien -4-on e (E)-6. To a solution of tin reagent
10 (34.0 g, 73.7 mmol) in THF (170 mL) was added BuLi (36.9
mL of 1.6 M hexane solution, 59.0 mmol) dropwise over 10
min at -78 °C. After stirring for 10 min, aldehyde 9 (7.48 g,
49.1 mmol) in THF (75 mL) was added dropwise over 15 min.
The mixture was stirred at -78 °C for 50 min and then
quenched with saturated NaHCO3 and extracted twice with
EtOAc. The organic extracts were washed with H2O, com-
1
1406 cm-1; H NMR δ 0.07 (s, 3), 0.08 (s, 3), 0.90 (s, 9), 0.90
(d, 2, J ) 5.8), 1.73 (d, 3, J ) 6.6), 1.9-2.6 (m, 5), 4.71 (dd, 2,
J ) 2.2, 4.2), 5.3-5.8 (m, 2), 5.9-6.4 (m, 2), 6.10 (dt, 1, J )
2.2, 11.6), 6.24 (dt, 1, J ) 4.2, 11.6); TLC (toluene) Rf 0.63.
IMDA Cycliza tion u n d er High P r essu r e. A stock solu-
tion of trienone (9.2 mL of 50 mg/mL CH2Cl2 solution, 1.43
mmol) was placed in a Teflon capsule, which was then put in
a high pressure apparatus. The reaction was carried out at
10 kbar for 8 h at room temperature. The pressure was
released, and the solvent was evaporated. Residual oil was
(38) Yerino, L. V.; Osborn, M. E.; Mariano, P. S. Tetrahedron 1982,
38, 1579.

5306 J . Org. Chem., Vol. 62, No. 16, 1997
Araki and Konoike
subjected to silica gel chromatography (EtOAc/hexane ) 1/30,
1/19, 1/9), and the reaction products were separated. For the
reaction of (E)-6: 12 (7% yield), 13 (2% yield), 14 (47% yield),
15 (22% yield). For the reaction of (Z)-6: 4 (53% yield), 16
(8% yield).
5.04 (dt, 1, J ) 7.6, 12.2), 5.4-5.7 (m, 2), 5.9-6.1 (m, 2), 6.28
(dt, 1, J ) 1.2, 12.2); 13C NMR δ -5.3, -5.3, 18.0, 18.2, 19.9,
25.6, 29.3, 39.9, 42.2, 48.2, 103.4, 127.2, 129.3, 131.5, 132.3,
143.3, 209.2; TLC (EtOAc/hexane ) 1/19) Rf 0.29.
(R)-5-Hyd r oxy-3-m eth ylp en ta n oic Acid , N-Meth oxy-N-
m eth yla m id e (19). In a Teflon capsule were placed lactone
18 (2.90 g, 25.4 mmol) and N,O-dimethylhydroxylamine (2.33
g, 38.1 mmol), and the tube was filled with CH3CN. The
capsule was then placed in a high pressure apparatus, and
the reaction was carried out at 9 kbar for 7 h at room
temperature. The pressure was released, and the solvent and
excess amine were evaporated. Residual oil was purified by
silica gel chromatography (EtOAc/acetone ) 3/1 to 1/1) to give
IMDA Cycliza t ion u n d er Lew is Acid Ca t a lyst . To a
solution of trienone in CH2Cl2 was added 1 equiv of Lewis acid
(Et2AlCl or EtAlCl2, each 1 M hexane solution) at 0 °C. After
1 h, the mixture was quenched with 1 N HCl and extracted
twice with CH2Cl2. The organic extracts were washed with
brine, dried, and concentrated. Residual oil was subjected to
silica gel chromatography (EtOAc/hexane ) 1/30, 1/19, 1/9),
and the reaction products were separated. For the reaction
of (E)-6: 12 (13% yield), 13 (trace), 14 (27% yield), 15 (11%
yield). For the reaction of (Z)-6: 4 (42% yield), 16 (16% yield).
IMDA Cycliza tion u n d er Th er m a l Con d ition s. A solu-
tion of trienone in chlorobenzene was refluxed for 15 h and
then concentrated. Residual oil was subjected to silica gel
chromatography (EtOAc/hexane ) 1/30, 1/19, 1/9), and the
reaction products were separated. For the reaction of (E)-6:
12 (17% yield), 13 (3% yield), 14 (29% yield), 15 (22% yield).
For the reaction of (Z)-6: 4 (20% yield), 16 (5% yield), 17 (22%
yield).
19 (3.98 g, 90% yield). IR (CHCl3) 3418, 3000, 1634, 1455 cm-1
;
1H NMR δ 1.01 (d, 3, J ) 6.6), 1.4-1.7 (m, 2), 2.1-2.5 (m, 3),
3.20 (s, 3), 3.64 (t, 2, J ) 5.9), 3.69 (s, 3); 13C NMR δ 21.0,
26.3, 32.4, 39.0, 40.2, 60.6, 61.5, 174.9; [R]24 +0.8 (c 1.01,
D
CHCl3); TLC (EtOAc) Rf 0.26; HR-LSIMS m/ z 176.1294 [M +
H]+ (calcd for C8H18NO3, 176.1285).
(3R,5E,7E)-3-Meth yl-5,7-n on a d ien oic Acid , N-Meth oxy-
N-m eth yla m id e (20). To a solution of 19 (13.41 g, 76.53
mmol) in CH2Cl2 was added PDC (58.76 g, 153 mmol) at room
temperature. Stirring was continued for 4.5 h, and the
mixture was diluted with Et2O (400 mL). The orange suspen-
sion was filtered through a pad of Hyflo Super-cel, and the
filtrate was concentrated. Residual oil was purified by silica
gel chromatography (EtOAc/hexane ) 2/1) to give the aldehyde
(1R*,2R*,4a S*,6S*,8a R*)-1-[[(ter t-Bu t yld im et h ylsilyl)-
oxy]m eth yl]-2,6-dim eth yl-1,2,4a,5,6,7-h exah ydr o-8H-n aph -
th a len -8-on e (12). IR (CHCl3) 2950, 1705, 1089, 834 cm-1
;
1H NMR δ 0.01 (s, 3), 0.04 (s, 3), 0.87 (s, 9), 0.95 (d, 3, J )
7.0), 1.05 (d, 3, J ) 6.0), 1.1-1.4 (m, 1), 1.8-2.6 (m, 8), 3.60
(dd, 1, J ) 8.6, 9.7), 4.07 (dd, 1, J ) 3.1, 9.7), 5.41 (ddd, 1, J
) 1.6, 1.6, 10.0), 5.67 (ddd, 1, J ) 2.2, 2.8, 10.0); 13C NMR δ
-5.7, -5.5, 16.4, 18.2, 22.4, 25.9, 31.4, 35.9, 37.9, 41.7, 44.1,
48.8, 51.5, 61.3, 128.4, 134.3, 212.7; TLC (EtOAc/hexane )
1/19) Rf 0.44.
(7.57 g, 57% yield). IR (CHCl3) 3002, 1717, 1646, 1457 cm-1
;
1H NMR δ 1.05 (d, 3, J ) 6.6), 2.2-2.8 (m, 5), 3.18 (s, 3), 3.68
(s, 3), 9.76 (t, 1, J ) 2.0); [R]23 -6.17 (c 1.49, CHCl3); TLC
D
(EtOAc) Rf 0.59; HR-LSIMS m/ z 173.1052 M+ (calcd for C8H15
-
NO3, 173.1051).
(E)-1-Benzenesulfonyl-2-butene32 (8.41 g, 42.8 mmol) was
dissolved in THF (130 mL), and BuLi (26.8 mL of 1.6 M hexane
solution, 42.9 mmol) was added dropwise over 15 min at -78
°C. After 30 min, the aldehyde (7.42 g, 42.8 mmol) was added,
and the mixture was stirred for 30 min. Next, benzoyl chloride
(9.95 mL, 85.7 mmol) was added, and the stirring was
continued at -78 °C for 40 min and at 0 °C for 1 h. The
reaction mixture was poured into ice-cold saturated NH4Cl
(200 mL) and extracted with EtOAc (2 × 200 mL). The organic
extracts were washed with brine (2 × 200 mL), combined,
dried, and concentrated. Residual oil was dissolved in MeOH
(180 mL) and EtOAc (90 mL), and 5% Na(Hg) (52.0 g, 113.1
mmol Na) was added at -20 °C. The mixture was stirred for
2 h at -20 °C and decanted. The precipitate was washed with
EtOAc (50 mL) by decantation. The organic layer was washed
with brine (200 mL), and the aqueous phase was extracted
with EtOAc (200 mL). The combined organic extract was dried
and concentrated. Residual oil was purified by silica gel
chromatography (EtOAc/hexane ) 1/3 to 1/2) to give diene 20
(1R*,2R*,4a S*,6R*,8a R*)-1-[[(ter t-Bu t yld im et h ylsilyl)-
oxy]m eth yl]-2,6-dim eth yl-1,2,4a,5,6,7-h exah ydr o-8H-n aph -
th a len -8-on e (13). 1H NMR δ 0.04 (s, 6), 0.88 (s, 9), 0.96 (d,
3, J ) 6.9), 0.99 (d, 3, J ) 6.7), 1.6-2.8 (m, 9), 3.63 (dd, 1, J
) 8.7, 9.8), 4.05 (dd, 1, J ) 3.2, 9.8), 5.37 (d, 1, J ) 9.8), 5.69
(ddd, 1, J ) 1.8, 4.5, 9.8); TLC (EtOAc/hexane ) 1/19) Rf 0.44.
(1R*,2S*,4a R*,6R*,8a R*)-1-[[(ter t-Bu t yld im et h ylsilyl)-
oxy]m eth yl]-2,6-dim eth yl-1,2,4a,5,6,7-h exah ydr o-8H-n aph -
th a len -8-on e (14). 1H NMR δ 0.09 (s, 6), 0.93 (s, 9), 1.01 (d,
3, J ) 6.4), 1.07 (d, 3, J ) 6.8), 1.1-1.4 (m, 1), 1.6-2.0 (m, 4),
2.1-2.5 (m, 4), 3.49 (dd, 1, J ) 7.0, 10.0), 3.66 (dd, 1, J ) 2.5,
10.0), 5.45 (d, 1, J ) 10.0), 5.67 (ddd, 1, J ) 2.2, 4.6, 10.0); 13
C
NMR δ -5.8, -5.7, 18.4, 20.4, 22.5, 26.0, 32.5, 34.3, 38.1, 39.1,
42.5, 48.1, 54.4, 64.5, 129.1, 132.9, 214.7; TLC (EtOAc/hexane
) 1/19) Rf 0.30.
(1R*,2S*,4a R*,6S*,8a R*)-1-[[(ter t-Bu t yld im et h ylsilyl)-
oxy]m eth yl]-2,6-dim eth yl-1,2,4a,5,6,7-h exah ydr o-8H-n aph -
th a len -8-on e (15). 1H NMR δ 0.02 (s, 3), 0.03 (s, 3), 0.89 (s,
9), 0.97 (d, 3, J ) 6.8), 1.07 (d, 3, J ) 7.2), 1.5-2.3 (m, 6), 2.48
(t, 1, J ) 7.0), 2.65 (dd, 2, J ) 5.0, 13.4), 3.42 (dd, 1, J ) 8.2,
10.0), 3.59 (dd, 1, J ) 4.2, 10.0), 5.51 (s, 2); 13C NMR δ -5.6,
18.4, 20.3, 21.0, 26.0, 30.1, 31.4, 33.6, 36.7, 41.1, 47.7, 51.8,
64.7, 129.0, 134.1, 213.5; TLC (EtOAc/hexane ) 1/19) Rf 0.36.
(1R*,2R*,4aS*,6S*,8aS*)-1-[[(ter t-Bu tyldim eth ylsilyl)oxy]-
m et h yl]-2,6-d im et h yl-1,2,4a ,5,6,7-h exa h yd r o-8H -n a p h -
th a len -8-on e (4). IR (CHCl3) 2950, 1686, 1458 cm-1; 1H NMR
δ 0.01 (s, 6), 0.86 (s, 9), 1.01 (d, 3, J ) 6.4), 1.01 (d, 3, J ) 7.6),
1.1-1.4 (m, 1), 1.7-2.0 (m, 2), 2.2-2.7 (m, 6), 3.70 (d, 2, J )
7.4), 5.39 (br d, 1, J ) 10.0), 5.59 (ddd, 1, J ) 2.6, 2.6, 10.0);
13C NMR δ -5.6, -5.5, 18.4, 18.5, 22.3, 26.0, 30.8, 33.7, 36.1,
37.8, 44.3, 48.9, 49.8, 60.9, 129.9, 130.9, 215.6; TLC (EtOAc/
hexane ) 1/19) Rf 0.35.
(4.86 g, 54% yield). IR (CHCl3) 3002, 1642, 1456 cm-1 1H
;
NMR δ 0.94 (d, 3, J ) 6.0), 1.73 (d, 3, J ) 6.2), 1.9-2.5 (m, 5),
3.17 (s, 3), 3.66 (s, 3), 5.3-5.8 (m, 2), 5.9-6.5 (m, 2); 13C NMR
δ 18.0, 19.9, 30.1, 32.2, 38.4, 40.0, 61.2, 127.1, 129.7, 131.6,
132.1, 174.0; [R]23D -4.84 (c 1.26, CHCl3); TLC (EtOAc/hexane
) 1/3) Rf 0.31; HR-LSIMS m/ z 211.1582 M+ (calcd for C12H21
-
NO2, 211.1571). The ratio of isomeric dienes was determined
to be 7:1:2 for (E,E):(E,Z):(Z,E) or (E,E):(Z,E):(E,Z)-isomers by
13C NMR analysis.
(R,2Z,8E,10E)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-m eth -
yl-2,8,10-d od eca tr ien -4-on e [(R)-(Z)-6]. A solution of 11
(10.34 g, 34.65 mmol) in Et2O (100 mL) was cooled to -78 °C,
and BuLi (21.6 mL of 1.6 M hexane solution, 34.7 mmol) was
added dropwise. The reaction mixture was stirred for 1 h and
then cooled to -100 °C. Amide 20 (2.44 g, 11.6 mmol) in Et2O
(25 mL) was added dropwise over 20 min so that the inner
temperature was kept below -90 °C. The reaction mixture
was stirred at -78 °C for 1 h and poured into ice-cold saturated
NH4Cl. The mixture was extracted twice with EtOAc, and the
organic extract was washed with saturated NaHCO3 and brine.
The combined organic extract was dried and concentrated.
Purification by silica gel chromatography (toluene) gave
(1R*,2R*,4a S*,6R*,8a S*)-1-{[(ter t-Bu t yld im et h ylsilyl)-
oxy]m eth yl]-2,6-dim eth yl-1,2,4a,5,6,7-h exah ydr o-8H-n aph -
th a len -8-on e (16). 1H NMR δ 0.03 (s, 6), 0.05 (s, 3), 0.88 (s,
9), 0.97 (d, 3, J ) 6.0), 0.99 (d, 3, J ) 7.5), 1.5-2.7 (m, 8), 2.82
(br s, 1), 4.02 (dd, 1, J ) 3.4, 7.5) 5.33 (dt, 1, J ) 1.8, 10.0),
5.66 (dt, 1, J ) 3.3, 10.0); 13C NMR δ -5.6, -5.5, 16.5, 18.3,
22.1, 26.0, 28.5, 30.5, 38.7, 39.3, 43.2, 46.3, 50.7, 63.9, 128.6,
136.0, 211.9; TLC (EtOAc/hexane ) 1/19) Rf 0.54.
(1E,8E,10E)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-m eth yl-
1,8,10-d od eca tr ien -4-on e (17). IR (CHCl3) 2950, 1708, 1660
trienone (R)-(Z)-6 (2.68 g, 72% yield) as a colorless oil. [R]24
D
cm-1
;
1H NMR δ 0.14 (s, 6), 0.89 (d, 3, J ) 6.4), 0.92 (s, 9),
-49.6 (c 1.38, CHCl3). IR, 1H NMR data, and TLC Rf value
1.73 (d, 3, J ) 6.6), 1.9-2.6 (m, 5), 2.92 (dd, 2, J ) 1.2, 7.6),
were identical to those of (Z)-6.

Enantioselective Total Synthesis of (+)-6-epi-Mevinolin
J . Org. Chem., Vol. 62, No. 16, 1997 5307
(1S,2S,4a R,6R,8a R)-1-[[(ter t-Bu t yld im et h ylsilyl)oxy]-
m et h yl]-2,6-d im et h yl-1,2,4a ,5,6,7-h exa h yd r o-8H -n a p h -
th a len -8-on e [(R)-4]. (R)-(Z)-6 (9.2 mL of 50 mg/mL CH2Cl2
solution, 1.43 mmol) was placed in a Teflon capsule, which
was then put in a high pressure apparatus. The reaction was
carried out at 10 kbar for 8 h at room temperature. The
pressure was released, and the solvent was evaporated.
Residual oil was purified by silica gel chromatography (EtOAc/
hexane ) 1/30, 1/19, 1/9) to obtain (R)-4 (212 mg, 46% yield).
was extracted with EtOAc. Each organic extract was washed
with brine, dried, and concentrated. The residue was purified
by silica gel chromatography (EtOAc/hexane ) 1/3) to give the
alcohol (85 mg, 96% yield). IR (CHCl3) 3486, 2956, 1715, 1457
cm-1; 1H NMR δ 0.6-0.9 (m, 1), 0.89 (d, 3, J ) 6.4), 0.92 (t, 3,
J ) 7.3), 0.93 (d, 3, J ) 7.0), 1.0-1.3 (m, 2), 1.16 (d, 3, J )
7.0), 1.4-1.9 (m, 6), 1.9-2.1 (m, 1), 2.2-2.6 (m, 2), 3.54 (dd, 1,
J ) 9.0, 10.5), 3.71 (dd, 1, J ) 5.4, 10.5), 5.06 (m, 1), 5.41 (br
d, 1, J ) 10.0), 5.61 (ddd, 1, J ) 2.6, 2.6, 10.0); [R]24 +115 (c
D
[R]24 +50.0 (c 1.59, CHCl3); HR-LSIMS m/ z 322.2309 M+
1.22, CHCl3); TLC (EtOAc/hexane ) 1/6) Rf 0.10.
D
(calcd for C19H34O2Si, 322.2326). IR, H NMR, 13C NMR data
1
To a solution of oxalyl chloride (168 mg, 1.33 mmol) in
CH2Cl2 (2 mL) were added DMSO (188 µL, 2.65 mmol) and
the alcohol (260 mg, 0.883 mmol) in CH2Cl2 (4 mL) at -78 °C.
After stirring for 30 min at -78 °C, NEt3 (862 µL, 6.18 mmol)
was added dropwise, and stirring was continued for 30 min
at -78 °C. The reaction mixture was then diluted with Et2O
and acidified with 1 N HCl. The organic phase was separated,
and the aqueous phase was extracted with Et2O. Each organic
extract was washed with saturated NaHCO3 and brine, dried,
and concentrated. Purification by silica gel chromatography
(EtOAc/hexane ) 1/6) gave the aldehyde (238 mg, 92% yield).
1H NMR δ 0.7-1.0 (m, 1), 0.89 (t, 3, J ) 7.5), 0.91 (d, 3, J )
7.2), 0.96 (d, 3, J ) 7.0), 1.13 (d, 3, J ) 7.0), 1.2-1.9 (m, 6),
1.9-2.1 (m, 1), 2.2-2.4 (m, 2), 2.6-2.8 (m, 2), 5.34 (m, 1), 5.46
(br d, 1, J ) 10.0), 5.58 (ddd, J ) 2.6, 2.7, 10.0), 9.75 (d, 1, J
) 2.5); TLC (EtOAc/hexane ) 1/6) Rf 0.36.
and TLC Rf value were identical to those reported for 4.
Another diastereomer (R)-16 was also obtained. 1H and 13C
NMR data and TLC Rf value were identical to those of 16.
(1S,2S,4a R,6R,8a S)-1-[[(ter t-Bu t yld im et h ylsilyl)oxy]-
m et h yl]-2,6-d im et h yl-1,2,4a ,5,6,7-h exa h yd r o-8H -n a p h -
th a len -8-on e [(R)-12]. To a solution of (R)-4 (2.35 g, 7.28
mmol) in MeOH (12 mL) was added NaOMe (7.0 mL of 28%
MeOH solution, 36.4 mmol) dropwise at room temperature.
After 1 h, the reaction mixture was poured into ice-cold 1 N
HCl (50 mL) and extracted with EtOAc (2 × 100 mL). The
organic extracts were washed with saturated NaHCO3 and
brine, dried, and concentrated. Residual material was purified
by silica gel chromatography (EtOAc/hexane ) 1/30) to give
(R)-12 (2.17 g, 92% yield). [R]24D +168.4 (c 1.24, CHCl3). Anal.
Calcd for C19H34O2Si: C, 70.75; H, 10.62. Found: C, 70.61;
H, 10.71; HR-LSIMS m/ z 321.2253 [M - H]+ (calcd for
The mixture of the aldehyde (238 mg, 0.814 mmol), Cs2CO3
(531 mg, 1.63 mmol), and phosphonate 3 (624 mg, 1.63 mmol)
in 2-propanol (1 mL) was stirred at room temperature for 4 h
and then diluted with EtOAc. After being cooled to 0 °C, 5%
citric acid solution was added, and the organic phase was
separated. The aqueous phase was extracted with EtOAc, and
each organic extract was washed with brine, dried, and
concentrated. The residue was purified by silica gel chroma-
tography (EtOAc/hexane ) 1/9) to give enone 22 (407 mg, 91%
yield). 1H NMR δ 0.04 (s, 3), 0.07 (s, 3), 0.7-1.0 (m, 1), 0.84
(s, 9), 0.89 (t, 3, J ) 7.4), 0.89 (d, 3, J ) 6.4), 0.96 (d, 3, J )
7.0), 1.13 (d, 3, J ) 7.0), 1.0-1.9 (m, 6), 1.9-2.1 (m, 1), 2.2-
2.6 (m, 4), 2.46 (dd, 1, J ) 6.6, 14.7), 2.55 (dd, 1, J ) 5.3, 14.7),
2.74 (dd, 1, J ) 6.3, 15.9), 2.80 (dd, 1, J ) 6.3, 15.9), 3.67 (s,
3), 4.62 (quintet, 1, J ) 6.5), 4.89 (br s, 1), 5.46 (br d, 1, J )
10.0), 5.59 (ddd, 1, J ) 2.2, 2.5, 10.0), 6.00 (d, 1, J ) 15.8),
6.79 (dd, 1, J ) 10.4, 15.8); TLC (EtOAc/hexane ) 1/9) Rf 0.17;
HR-LSIMS m/ z 548.3512 M+ (calcd for C31H52O6Si, 548.3529).
(1S,2S,4a R,6R,8S,8a S,4′R,6′R,2′′S)-6′-[2-{1,2,4a ,5,6,7,8,
8a -Octa h yd r o-2,6-d im eth yl-8-[(2′′-m eth ylbu tyr yl)oxy]-1-
n a p h th a len yl}eth yl]tetr a h yd r o-4′-h yd r oxy-2′H-p yr a n -2′-
on e (6-epi-4a ,5-d ih yd r om evin olin ) (2b). A solution of
(Ph3P)3RhCl (15 mg, 0.016 mmol), 22 (298 mg, 0.543 mmol),
and Et3SiH (2.60 mL, 16.3 mmol) in benzene (7.5 mL) was
heated to 70 °C with stirring for 1.5 h. The volatile materials
were removed by evaporation, and to the resulting oil was
added 6 mL of a solution of 46% aqueous HF and CH3CN (1:
19) at room temperature. After stirring for 1 h, Et2O and
saturated NaHCO3 were added, and the organic phase was
separated. The aqueous phase was extracted with EtOAc, and
each organic extract was washed with brine, dried, and
concentrated. The residue was purified by silica gel chroma-
tography (EtOAc/hexane ) 1/3 to 1/2) to give the saturated
ketone (150 mg, 64% yield). 1H NMR δ 0.6-1.0 (m, 1), 0.84
(t, 3, J ) 6.8), 0.88 (d, 3, J ) 7.2), 0.92 (d, 3, J ) 7.4), 1.15 (d,
3, J ) 7.0), 1.0-1.8 (m, 10), 1.9-2.1 (m, 1), 2.1-2.5 (m, 4),
2.51 (d, 1, J ) 6.2), 2.62 (d, 1, J ) 5.6), 3.71 (s, 3), 4.45 (quintet,
1, J ) 6.0), 5.18 (br s, 1), 5.41 (br d, 1, J ) 10.0), 5.59 (ddd, 1,
J ) 2.6, 2.6, 10.0); TLC (EtOAc/hexane ) 1/2) Rf 0.28.
1
C19H33O2Si, 321.2248). IR and H NMR data and TLC Rf value
were identical to those of 12.
(1S,2S,4aR,6R,8S,8aS)-1-[[(ter t-Bu tyldim eth ylsilyl)oxy]-
m eth yl]-2,6-d im eth yl-8-h yd r oxy-1,2,4a ,5,6,7,8,8a -octa h y-
d r on a p h th a len e (21). To a solution of (R)-12 (2.05 g, 6.35
mmol) in THF (40 mL) was added L-Selectride (12.7 mL of 1
M THF solution, 12.7 mmol) dropwise at -78 °C. After
stirring for 30 min at 0 °C, H2O (3.2 mL), EtOH (8.0 mL), 6 N
NaOH (8.0 mL), and 30% H2O2 (12.0 mL) were added succes-
sively, and the mixture was stirred for 15 min at 0 °C. The
reaction mixture was poured into a mixture of H2O (50 mL)
and EtOAc (80 mL) and partitioned. The aqueous phase was
extracted with EtOAc (80 mL), and the combined organic
extract was dried and concentrated. The residue was purified
by silica gel chromatography (EtOAc/hexane ) 1/19) to give
alcohol 21 (2.06 g, 100% yield). IR (CHCl3) 3470, 2950, 1454
cm-1; 1H NMR δ 0.10 (s, 6), 0.6-0.8 (m, 1), 0.79 (d, 3, J ) 7.0),
0.89 (d, 3, J ) 6.8), 0.91 (s, 3), 1.0-1.3 (m, 2), 1.6-1.8 (m, 1),
1.8-2.0 (m, 3), 2.2-2.5 (m, 2), 3.49 (q, 1, J ) 1.6), 3.59 (dd, 1,
J ) 2.7, 9.7), 3.69 (dd, 1, J ) 9.6, 9.7), 4.12 (m, 1), 5.40 (br d,
1, J ) 10.0), 5.49 (ddd, 1, J ) 2.0, 2.2, 10.0); [R]24 +42.9 (c
D
1.26, CHCl3); TLC (EtOAc/hexane ) 1/19) Rf 0.40. Anal. Calcd
for C19H36O2Si: C, 70.31; H, 11.18. Found: C, 70.10; H, 11.05;
HR-LSIMS m/ z 325.2555 [M + H]+ (calcd for C19H37O2Si,
325.2560).
Meth yl (1S,2S,4a R,6R,8S,8a S,3′R,2′′S)-7′-{2,6-Dim eth yl-
8-[(2′′-m eth ylbu tyr yl)oxy]-1,2,4a,5,6,7,8,8a-octah ydr on aph -
t h a len -1-yl}-3′-[(ter t-b u t yld im et h ylsilyl)oxy]-5′-oxo-6′-
h ep ten oa te (22). To a solution of 21 (98 mg, 0.30 mmol) in
pyridine (2 mL) was added (S)-(+)-2-methylbutyric anhydride
(90 µL, 0.45 mmol) and DMAP (7.3 mg, 0.06 mmol) at room
temperature. After being stirred at room temperature for 2
days, the reaction mixture was diluted with Et2O and poured
into ice-cold 1 N HCl. The organic phase was separated, and
the aqueous phase was extracted with Et2O. Each organic
extract was washed with saturated NaHCO3 and brine, dried,
and concentrated. Purification by silica gel chromatography
(EtOAc/hexane ) 1/30) gave the ester (123 mg, 100% yield).
IR (CHCl3) 2950, 1715, 1458 cm-1; 1H NMR δ 0.00 (s, 3), 0.03
(s, 3), 0.87 (s, 9), 0.88 (d, 3, J ) 6.0), 0.91 (d, 3, J ) 6.6), 0.92
(t, 3, J ) 7.4), 0.6-0.9 (m, 1), 1.0-1.3 (m, 2), 1.15 (d, 3, J )
7.0), 1.3-2.1 (m, 6), 2.2-2.6 (m, 3), 3.45 (dd, 1, J ) 10.0, 10.4),
3.62 (dd, 1, J ) 4.3, 10.4), 5.03 (br d, 1, J ) 2.2), 5.39 (br d, 1,
J ) 10.0), 5.61 (ddd, 1, J ) 2.5, 4.5, 10.0); [R]22D +87.8 (c 1.12,
CHCl3); TLC (EtOAc/hexane ) 1/30) Rf 0.46.
To a solution of the ketone (122 mg, 0.281 mmol) in THF (3
mL) was added Et2BOMe (0.31 mL of 1.0 M THF solution, 0.31
mmol) at -78 °C. After stirring for 35 min, NaBH4 (12 mg,
0.31 mmol) was added, and the reaction mixture was stirred
at -78 °C for 1 h. EtOAc and 1 N HCl were added to the
mixture, and the organic phase was separated. The aqueous
phase was extracted with EtOAc, and each organic extract was
washed with brine, dried, and concentrated. Residual material
was dissolved in MeOH and concentrated under reduced
pressure. This operation was repeated three times. Purifica-
tion by silica gel chromatography (EtOAc/hexane ) 2/3) gave
the syn-diol (91 mg, 74% yield). 1H NMR δ 0.6-1.0 (m, 1),
The silyl protecting group was removed by treatment with
a 1:19 mixture of 46% aqueous HF solution and CH3CN (1.5
mL) at room temperature for 1 h. The reaction mixture was
diluted with EtOAc and poured into ice-cold saturated NaH-
CO3. The organic phase was separated, and the aqueous phase

5308 J . Org. Chem., Vol. 62, No. 16, 1997
Araki and Konoike
0.85 (t, 3, J ) 7.0), 0.88 (d, 3, J ) 6.4), 0.92 (d, 3, J ) 7.4),
1.0-1.3 (m, 3), 1.13 (d, 3, J ) 7.2), 1.3-1.8 (m, 10), 1.9-2.1
(m, 1), 2.2-2.4 (m, 3), 2.49 (d, 2, J ) 6.2), 3.72 (s, 3), 3.80 (m,
1), 4.26 (m, 1), 5.20 (br s, 1), 5.40 (br d, 1, J ) 9.8), 5.60 (ddd,
1, J ) 2.4, 2.8, 9.8); TLC (EtOAc/hexane ) 1/1) Rf 0.41.
To a solution of the diol (20.2 mg, 0.046 mmol) in CH3CN
(0.2 mL) was added HF/pyridine (60 µL) dropwise at room
temperature. After being stirred for 2 h, the reaction mixture
was diluted with EtOAc and poured into ice-cold saturated
NaHCO3. The organic phase was separated, and the aqueous
phase was extracted with EtOAc. Each organic layer was
washed with brine, dried, and concentrated. The residue was
purified by silica gel chromatography (EtOAc/hexane ) 2/1)
to give 6-epi-4a,5-dihydromevinolin (2b) (9.1 mg, 49% yield).
2.5-2.7 (m, 1), 3.49 (dd, 1, J ) 9.6, 9.8), 3.68 (dd, 1, J ) 4.0,
9.8), 5.16 (br s, 1), 5.41 (br s, 1), 5.77 (dd, 1, J ) 5.8, 9.8), 5.96
(d, 1, J ) 9.8); [R]23 +168 (c 1.21, CHCl3); TLC (toluene) Rf
D
0.72.
(1S,2S,6R,8S,8a S,2′S)-1-(Hyd r oxym eth yl)-2,6-d im eth yl-
8-[(2′-m et h ylb u t yr yl)oxy]-1,2,6,7,8,8a -h exa h yd r on a p h -
th a len e (25). To a solution of ester 24 (170 mg, 0.418 mmol)
in THF (1.7 mL) were added AcOH (0.215 mL, 3.76 mmol) and
TBAF (2.1 mL of 1.0 M THF solution, 2.1 mmol) at room
temperature. After being heated under reflux for 1.5 h and
then cooled, the mixture was diluted with EtOAc and poured
into ice-cold NaHCO3. The organic phase was separated, and
the aqueous phase was extracted with EtOAc. Each organic
extract was washed with brine, dried, and concentrated.
Purification by silica gel chromatography (EtOAc/hexane )
1/3) gave alcohol 25 (120 mg, 98% yield). IR (CHCl3) 3474,
2954, 1711, 1453 cm-1; 1H NMR δ 0.90 (t, 3, J ) 7.4), 0.99 (d,
3, J ) 6.6), 1.02 (d, 3, J ) 6.6), 1.13 (d, 3, J ) 7.2), 1.1-1.8
(m, 3), 1.9-2.1 (m, 1), 2.1-2.5 (m, 4), 2.5-2.7 (m, 1), 3.58 (ddd,
1, J ) 5.2, 9.2, 10.2), 3.77 (ddd, 1, J ) 4.9, 4.9, 10.2), 5.19 (br
s, 1), 5.43 (br s, 1), 5.78 (dd, 1, J ) 5.8, 9.8), 5.99 (d, 1, J )
1
IR (CHCl3) 3454, 2952, 1715, 1456 cm-1; H NMR δ 0.6-1.0
(m, 1), 0.86 (d, 3, J ) 6.9), 0.89 (d, 3, J ) 7.2), 0.90 (t, 3, J )
7.5), 1.0-2.1 (m, 13), 1.14 (d, 3, J ) 7.0), 2.2-2.5 (m, 3), 2.61
(ddd, 1, J ) 1.5, 3.9, 17.7), 2.73 (dd, 1, J ) 4.8, 17.7), 4.37 (br
s, 1), 4.62 (m, 1), 5.19 (br s, 1), 5.41 (br d, 1, J ) 9.9), 5.60
(ddd, 1, J ) 2.7, 4.8, 9.9); 13C NMR δ 11.7, 14.9, 16.9, 22.1,
23.4, 26.8, 27.4, 31.6, 33.1, 36.1, 36.7, 37.6, 38.6, 39.3, 41.5,
41.5, 41.9, 62.7, 69.5, 76.2, 130.8, 132.2, 170.3, 176.3; [R]25
9.8); [R]25 +205 (c 1.07, CHCl3); TLC (EtOAc/hexane ) 1/4)
D
D
+102 (c 0.46, CHCl3); TLC (EtOAc/hexane ) 2/3) Rf 0.17; HR-
LSIMS m/ z 407.2790 [M + H]+ (calcd for C24H39O5, 407.2795).
(1S,2S,4aR,6R,8S,8aS)-1-[[(ter t-Bu tyldim eth ylsilyl)oxy]-
m e t h yl]-2,6-d im e t h yl-8-h yd r oxy-1,2,6,7,8,8a -h e xa h y-
d r on a p h th a len e (23). To a solution of 21 (487 mg, 1.5 mmol)
in CHCl3 (5 mL) were added NEt3 (0.836 mL, 6.0 mmol) and
bromine (3.0 mL of 2 M CHCl3 solution, 6.0 mmol) dropwise
at 0 °C. After being stirred for 1 h at 0 °C, the reaction mixture
was poured into ice-cold NaHSO3 and extracted twice with
CH2Cl2. The organic extract was dried and concentrated. The
residue was purified by silica gel chromatography (EtOAc/
hexane ) 1/19) to give the dibromide (722 mg, 99% yield). IR
(CHCl3) 3466, 2944, 1454 cm-1; 1H NMR δ 0.10 (s, 6), 0.92 (s,
9), 1.0-1.4 (m, 2), 1.23 (d, 3, J ) 7.0), 1.24 (d, 3, J ) 7.8),
1.4-1.7 (m, 2), 1.8-2.1 (m, 2), 2.3-2.6 (m, 3), 3.37 (m, 1), 3.48
(dd, 1, J ) 2.0, 10.0), 3.71 (dd, 1, J ) 8.0, 10.0), 4.14 (quintet,
1, J ) 2.9), 4.58 (br s, 1), 4.84 (br s, 1); 13C NMR δ -5.6, -5.5,
18.1, 18.3, 22.3, 25.0, 25.8, 34.9, 38.5, 38.6, 41.0, 59.0, 60.4,
Rf 0.18; HR-LSIMS m/ z 292.2044 M+ (calcd for C18H28O3,
292.2037).
Met h yl (1S,2S,6R,8S,8a S,3′R,2′′S)-7′-{2,6-Dim et h yl-8-
[(2′′-m eth ylbu tyr yl)oxy]-1,2,6,7,8,8a -h exa h yd r on a p h th a -
len -1-yl}-3′-[(ter t-b u t yld im et h ylsilyl)oxy]-5′-oxo-6′-h ep -
ten oa te 26. To a solution of oxalyl chloride (77 mg, 0.605
mmol) in CH2Cl2 (1 mL) were added DMSO (86 µL, 1.21 mmol)
and a solution of alcohol 25 (118 mg, 0.403 mmol) in CH2Cl2
(1 mL) at -78 °C. After stirring for 30 min at -78 °C, NEt3
(394 µL, 2.83 mmol) was added dropwise, and stirring was
continued for 30 min at -78 °C. The reaction mixture was
then diluted with Et2O and poured into ice-cold NH4Cl. The
organic phase was separated, and the aqueous phase was
extracted with Et2O. Each organic extract was washed with
saturated NaHCO3 and brine, dried, and concentrated. Pu-
rification by silica gel chromatography (EtOAc/hexane ) 1/9)
gave the aldehyde (103 mg, 88% yield). IR (CHCl3) 2956, 1717,
1453 cm-1; 1H NMR δ 0.86 (t, 3, J ) 7.4), 0.97 (d, 3, J ) 6.8),
1.04 (d, 3, J ) 6.8), 1.10 (d, 3, J ) 7.0), 1.2-1.5 (m, 2), 1.5-
1.8 (m, 1), 2.1-2.5 (m, 3), 2.6-3.0 (m, 3), 5.44 (br s, 1), 5.52
(br s, 1), 5.73 (dd, 1, J ) 5.4, 9.8), 6.01 (d, 1, J ) 9.8), 9.75 (d,
66.3, 66.8; [R]24 -5.4 (c 1.19, CHCl3); TLC (EtOAc/hexane )
D
1/19) Rf 0.24; HR-LSIMS m/ z 483.0917 [M + H]+ (calcd for
C19H37O2SiBr2, 483.0928).
1, J ) 1.8); [R]22 +222 (c 1.28, CHCl3); TLC (EtOAc/hexane
To a solution of the dibromide (666 mg, 1.37 mmol) in
benzene (7 mL) was added DBU (2.06 mL, 13.7 mmol)
dropwise at room temperature. The reaction mixture was
refluxed for 5 h, cooled to room temperature, and diluted with
EtOAc. The mixture was poured into ice-cold 1 N HCl, and
the organic phase was separated. The aqueous phase was
extracted with EtOAc, and each organic extract was washed
with saturated NaHCO3, dried, and concentrated. Purification
by silica gel chromatography (toluene) gave diene 23 (196 mg,
44% yield) along with isomers. IR (CHCl3) 3450, 2952, 1452
D
) 1/9) Rf 0.32; HR-LSIMS m/ z 290.1875 M+ (calcd for
C18H26O3, 290.1880).
A mixture of the aldehyde (91 mg, 0.313 mmol), Cs2CO3 (306
mg, 0.940 mmol), and phosphonate 3 (360 mg, 0.940 mmol) in
2-propanol (0.3 mL) was stirred at room temperature for 7.5
h. The mixture was diluted with EtOAc and poured into ice-
cold NH4Cl. The organic phase was separated, and the
aqueous phase was extracted with EtOAc. Each organic
extract was washed with brine, dried, and concentrated.
Purification by silica gel chromatography (EtOAc/hexane )
1/9) gave enone 26 (101 mg, 59% yield). IR (CHCl3) 2968, 1721,
cm-1 1H NMR δ 0.11 (s, 3), 0.12 (s, 3), 0.86 (d, 3, J ) 7.0),
;
0.92 (s, 9), 1.04 (d, 3, J ) 7.0), 1.2-1.4 (m, 1), 1.9-2.2 (m, 2),
2.2-2.3 (m, 1), 2.3-2.5 (m, 1), 2.5-2.7 (m, 1), 3.67 (dd, 1, J )
3.0, 10.2), 3.72 (br s, 1), 3.74 (dd, 1, J ) 8.2, 10.2), 4.22 (br s,
1), 5.47 (br s, 1), 5.65 (dd, 1, J ) 5.8, 9.4), 5.96 (d, 1, J ) 9.4);
13C NMR δ -5.6, -5.6, 14.8, 18.2, 21.5, 25.9, 26.0, 33.7, 37.6,
1456 cm-1 1H NMR δ 0.07 (s, 6), 0.84 (s, 9), 0.87 (t, 3, J )
;
7.2), 1.01 (d, 3, J ) 7.0), 1.02 (d, 3, J ) 6.8), 1.11 (d, 3, J )
7.0), 1.2-1.5 (m, 2), 1.5-1.8 (m, 1), 2.1-2.4 (m, 4), 2.4-2.7
(m, 4), 2.75 (dd, 1, J ) 6.3, 16.1), 2.80 (dd, 1, J ) 6.0, 16.1),
3.67 (s, 3), 4.62 (quintet, 1, J ) 5.9), 5.00 (br s, 1), 5.48 (br s,
1), 5.75 (dd, 1, J ) 5.6, 9.8), 6.02 (d, 1, J ) 9.8), 6.04 (d, 1, J
) 16.0), 6.82 (dd, 1, J ) 9.8, 16.0); [R]23D +85.6 (c 1.02, CHCl3);
TLC (EtOAc/hexane ) 1/6) Rf 0.33; HR-LSIMS m/ z 546.3379
M+ (calcd for C31H50O6Si, 546.3374).
39.1, 40.8, 65.5, 66.7, 128.9, 130.7, 132.4, 133.0; [R]23 +113.6
D
(c 1.09, CHCl3); TLC (toluene) Rf 0.30.
(1S,2S,6R,8S,8a S,2′S)-1-[[(ter t-Bu tyld im eth ylsilyl)oxy]-
m et h yl]-2,6-d im et h yl-8-[(2′-m et h ylb u t yr yl)oxy]-1,2,6,7,
8,8a -h exa h yd r on a p h th a len e (24). To a solution of 23 (183
mg, 0.567 mmol) in pyridine (2 mL) were added (S)-(+)-2-
methylbutyric anhydride (175 µL, 0.851 mmol) and DMAP (14
mg, 0.113 mmol) at room temperature. After stirring at 50
°C for 6 h, the reaction mixture was cooled to 0 °C, diluted
with Et2O, and poured into ice-cold 1 N HCl. The organic
phase was separated, and the aqueous phase was extracted
with Et2O. Each organic extract was washed with saturated
NaHCO3 and brine, dried, and concentrated. Purification by
silica gel chromatography (CH2Cl2/hexane ) 1/4) gave ester
(1S,2S,6R,8S,8a S,4′R,6′R,2′′S)-6′-[2-{1,2,6,7,8,8a -Hexa h y-
d r o -2 , 6 -d i m e t h y l -8 -[ ( 2 ′′-m e t h y l b u t y r y l ) o x y ] -1 -
n a p h th a len yl}eth yl]tetr a h yd r o-4′-h yd r oxy-2′H-p yr a n -2′-
on e (6-epi-m evin olin ) (2a ). The mixture of 26 (80 mg, 0.146
mmol), (Ph3P)3RhCl (2.7 mL of 5 mg/mL benzene solution,
0.0146 mmol), and Et3SiH (1.17 mL, 7.30 mmol) was stirred
at 65 °C for 2 h. The volatile materials were evaporated, and
the residue was treated with a 1:19 mixture of 46% aqueous
HF solution and CH3CN (1.5 mL) at room temperature. The
reaction mixture was stirred for 1.5 h, diluted with Et2O, and
poured into ice-cold saturated NaHCO3. The organic phase
was separated, and the aqueous phase was extracted with
EtOAc. Each organic extract was washed with brine, dried,
24 (188 mg, 82% yield). IR (CHCl3) 2954, 1713, 1456 cm-1
;
1H NMR δ 0.01 (s, 3), 0.04 (s, 3), 0.87 (s, 9), 0.90 (t, 3, J ) 7.6),
0.96 (d, 3, J ) 7.0), 1.01 (d, 3, J ) 7.0), 1.13 (d, 3, J ) 7.0),
1.2-1.6 (m, 3), 1.6-1.8 (m, 1), 1.8-2.1 (m, 1), 2.1-2.5 (m, 3),

Enantioselective Total Synthesis of (+)-6-epi-Mevinolin
J . Org. Chem., Vol. 62, No. 16, 1997 5309
and concentrated. The residue was purified by silica gel
chromatography (EtOAc/toluene ) 1/3) to give the saturated
ketone (46 mg, 72% yield). IR (CHCl3) 3508, 2960, 1715, 1437
0.9 (m, 9), 1.06 (d, 3, J ) 7.0), 1.1-2.4 (m, 19), 3.9-4.1 (m, 1),
4.1-4.2 (m, 1), 5.2-5.6 (m, 4); TLC (EtOAc/AcOH/H2O ) 30/
1/1) Rf 0.77.
1
cm-1; H NMR δ 0.87 (t, 3, J ) 7.4), 0.87 (d, 3, J ) 7.0), 1.01
En tr ies 6 a n d 7. This compound was prepared by a slight
modification of Heathcock’s procedure39 which utilized chiral
R-methoxyphenylacetic acid for the optical resolution of the
intermediary racemic diol for dihydromevinolin synthesis. We
applied his method for the optical resolution of the racemic
diol derived from racemic 21, and prepared compounds, which
have a decalin moiety enantiomeric to (+)-6-epi-4a,5-dihydro-
mevinolin, as described above. En tr y 6: 1H NMR (CD3OD) δ
0.7-1.0 (m, 9), 1.16 (d, 3, J ) 7.0), 1.0-2.5 (m, 19), 3.6-3.8
(m, 1), 4.0-4.2 (m, 1), 5.17 (br s, 1), 5.41 (br d, 1, J ) 9.8),
5.5-5.7 (m, 1); TLC (EtOAc/AcOH/H2O ) 30/1/1) Rf 0.71.
En tr y 7: 1H NMR (CD3OD) δ 0.8-1.0 (m, 9), 1.14 (d, 3, J )
7.0), 1.0-2.5 (m, 17), 3.9-4.1 (m, 1), 4.2-4.4 (m, 1), 4.6-5.1
(m, 2), 5.3-5.5 (m, 1), 5.5-5.7 (m, 1); TLC (EtOAc/AcOH/H2O
) 30/1/1) Rf 0.70.
HMG-CoA Red u cta se In h ibition Assa y. P r ep a r a tion
of Ra t Liver Micr osom es. Sprague-Dawley rats, which were
allowed free access to ordinary diets containing 2%
cholestyramine and water for 2 weeks, were used for the
preparation of rat liver microsomes. The microsomes obtained
were then purified as described by Kuroda.37 The microsomal
fraction obtained by centrifugation at 105000g was washed
once with a buffered solution containing 15 mM nicotinamide
and 2 mM magnesium chloride (in 100 mM potassium phos-
phate buffer, pH 7.4). It was homogenized with a buffer
containing nicotinamide and magnesium chloride at the same
weight as the liver employed. The homogenate obtained was
cooled and kept at -80 °C.
Mea su r em en t of HMG-CoA Red u cta se In h ibitor y Ac-
tivities. The rat liver microsome sample (8 mg/mL, 100 mL),
which was preserved at -80 °C, was fused at 0 °C and diluted
with 0.7 mL of a cold potassium phosphate buffer (100 mM,
pH 7.4). This was mixed with 0.8 mL of 100 mM EDTA
(buffered with the potassium phosphate buffer) and 0.4 mL of
100 mM dithiothreitol solution (buffered with the potassium
phosphate buffer), and the mixture was kept at 0 °C. The
microsome solution (1.675 mL) was mixed with 670 mL of 25
mM NADPH (buffered with the aforementioned potassium
phosphate buffer), and the solution was added to the solution
of 0.5 mM [3-14C]HMG-CoA (3 mCi/mmol). A solution (5 mL)
of sodium salt of a test compound dissolved in potassium
phosphate buffer was added to 45 mL of the above mixture.
The resulting mixture was incubated at 37 °C for 30 min and
cooled. After termination of the reaction by addition of 10 mL
of 2 N HCl, the mixture was applied to preparative TLC on
silica gel of 0.5 mm in thickness (Merck AG, Art 5744). The
chromatograms were developed in toluene/acetone (1/1) to
nearly the top and bands of Rf value between 0.45 to 0.60
obtained by scraping. The products obtained were put into a
vial containing 10 mL of scintillator to measure specific
radioactivity with a scintillation counter. The activities of the
test compounds are shown in Table 4, and compared with that
of mevinolin (sodium salt).
(d, 3, J ) 6.8), 1.12 (d, 3, J ) 7.0), 1.1-1.9 (m, 6), 2.1-2.5 (m,
7), 2.51 (d, 2, J ) 6.4), 2.62 (m, 2), 3.39 (br s, 1), 3.71 (s, 3),
4.43 (m, 1), 5.31 (br s, 1), 5.42 (br s, 1), 5.74 (dd, 1, J ) 6.0,
9.8), 5.98 (d, 1, J ) 9.8); [R]24 +154 (c 1.24, CHCl3); TLC
D
(EtOAc/toluene ) 1/9) Rf 0.19; HR-LSIMS m/ z 434.2678 M+
(calcd for C25H38O6, 434.2666).
To a solution of the ketone (39 mg, 0.09 mmol) in THF (0.8
mL) and MeOH (0.2 mL) was added Et2BOMe (0.10 mL of 1.0
M THF solution, 0.10 mmol) at -78 °C. The mixture was
stirred at -78 °C for 50 min, and then NaBH4 (3.8 mg, 0.10
mmol) was added. The reaction mixture was stirred at -78
°C for 2 h, diluted with EtOAc, and poured into ice-cold
saturated NaHCO3. The organic phase was separated, and
the aqueous phase was extracted with EtOAc. Each organic
extract was washed with brine, dried, and concentrated.
Residual oil was dissolved in MeOH and concentrated under
reduced pressure. This operation was repeated three times.
Purification by silica gel chromatography (EtOAc/hexane )
1/1) gave syn-diol (19 mg, 48% yield). IR (CHCl3) 3498, 2952,
1714, 1453 cm-1; 1H NMR δ 0.88 (t, 3, J ) 7.4), 0.89 (d, 3, J )
7.0), 1.02 (d, 3, J ) 7.0), 1.12 (d, 3, J ) 7.0), 1.1-1.8 (m, 9),
2.1-2.5 (m, 5), 2.49 (d, 2, J ) 6.2), 3.42 (m, 1), 3.72 (s, 3), 3.80
(m, 1), 4.26 (quintet, 1, J ) 6.4), 5.34 (br s, 1), 5.41 (br s, 1),
5.76 (dd, 1, J ) 5.8, 9.4), 5.97 (d, 1, J ) 9.4); [R]25 +108 (c
D
1.52, CHCl3); TLC (EtOAc/hexane ) 1/1) Rf 0.34; HR-LSIMS
m/ z 436.2813 M+ (calcd for C25H40O6, 436.2822).
To a solution of the diol (7.9 mg, 0.018 mmol) in CH3CN
(0.1 mL) was added HF/pyridine (24 µL) dropwise at room
temperature. After being stirred for 1 h, the reaction mixture
was diluted with EtOAc and poured into ice-cold saturated
NaHCO3. The organic phase was separated, and the aqueous
phase was extracted with EtOAc. Each organic extract was
washed with brine, dried, and concentrated. The residue was
purified by silica gel chromatography (EtOAc/hexane ) 2/1)
to give 6-epi-mevinolin 2a (3.5 mg, 48% yield). IR (CHCl3)
1
3416, 2952, 1717, 1258 cm-1; H NMR δ 0.88 (t, 3, J ) 7.0),
0.90 (d, 3, J ) 6.6), 1.02 (d, 3, J ) 7.0), 1.12 (d, 3, J ) 7.0),
1.2-2.1 (m, 9), 2.1-2.5 (m, 5), 2.62 (ddd, 1, J ) 1.1, 4.0, 17.6),
2.74 (dd, 1, J ) 5.0, 17.6), 4.38 (m, 1), 4.62 (m, 1), 5.33 (br s,
1), 5.41 (br s, 1), 5.76 (dd, 1, J ) 6.0, 9.6), 5.98 (d, 1, J ) 9.6);
13C NMR δ 11.8, 13.8, 16.9, 21.3, 24.1, 26.6, 26.7, 31.0, 33.0,
35.5, 36.3, 36.8, 37.6, 38.7, 41.7, 62.8, 68.4, 76.1, 128.2, 130.1,
132.8, 133.2, 170.0, 176.7; [R]25D +115.4 ( 4.4 (c 0.35, CHCl3);
TLC (EtOAc/hexane ) 2/1) Rf 0.36; HR-LSIMS m/ z 404.2563
M+ (calcd for C24H36O5, 404.2561).
Com p ou n d s Listed in Ta ble 4. En tr y 1. The compound
was prepared by hydrolysis of 2a . 1H NMR (CD3OD) δ 0.76
(t, 3, J ) 7.2), 0.77 (d, 3, J ) 6.8), 0.88 (d, 3, J ) 6.8), 0.98 (d,
3, J ) 7.0), 0.7-1.6 (m, 12), 2.0-2.3 (m, 4), 3.5-3.7 (m, 1),
3.8-4.0 (m, 1), 5.15 (br s, 1), 5.23 (br s, 1), 5.62 (dd, 1, J ) 5.8,
9.6), 5.81 (d, 1, J ) 9.6); TLC (EtOAc/AcOH/H2O ) 30/1/1) Rf
0.62.
En tr y 2. The compound was prepared by hydrolysis of 2b.
1H NMR (CD3OD) δ 0.8-1.0 (m, 9), 1.13 (d, 3, J ) 7.0), 1.0-
2.5 (m, 19), 3.6-3.7 (m, 1), 4.0-4.1 (m, 1), 5.15 (br s, 1), 5.38
(br d, 1, J ) 9.4), 5.5-5.7 (m, 1); TLC (EtOAc/AcOH/H2O )
30/1/1) Rf 0.72.
En tr y 3. This compound was prepared by acylation of 21
with butyric anhydride, followed by a sequence of transforma-
tions of the acylated compound in a similar manner to that
used to prepare 2b. 1H NMR (CD3OD) δ 0.6-2.0 (m, 19), 0.61
(d, 3, J ) 6.6), 0.84 (d, 3, J ) 6.6), 0.88 (t, 3, J ) 7.2), 2.24 (t,
3, J ) 7.2), 3.63 (br s, 1), 4.01 (br s, 1), 4.5-5.6 (m, 2); TLC
(EtOAc/AcOH/H2O ) 30/1/1) Rf 0.70.
En tr y 4. This compound was prepared by acylation of 21
with 2,2-dimethylbutyryl chloride, followed by a sequence of
transformations of the acylated compound in a similar manner
to that used to prepare 2b. 1H NMR (CD3OD) δ 0.8-2.4 (m,
35), 3.71 (br s, 1), 4.10 (br s, 1), 5.0-5.7 (m, 2); TLC (EtOAc/
AcOH/H2O ) 30/1/1) Rf 0.74.
Ack n ow led gm en t. The authors are grateful to Dr.
Shujiro Seo for measuring the HMG-CoA reductase
inhibition activities.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the synthesis of the compounds in Table 4 and H
NMR spectra of compounds not analyzed (40 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O970444M
En tr y 5. The compound was prepared by a procedure
similar to that for the preparation of 2b except that the
hydrosilylation step was eliminated. 1H NMR (CD3OD) δ 0.7-
(39) Hecker, S. J .; Heathcock, C. H. J . Am. Chem. Soc. 1986, 108,
4586.