Progress towards the decalin portion of (+)-compactin

Article abstract of DOI:10.1016/S0957-4166(02)00570-0

A new approach to a chiral tetrahydronaphthalene precursor for the decalin portion of (+)-compactin is disclosed. The strategy utilises two key steps: a boron-catalysed diastereoselective annulation reaction to a key dioxaborin ester which was then transf

Full text of DOI:10.1016/S0957-4166(02)00570-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1965–1967
Progress towards the decalin portion of (+)-compactin
Claude Dufresne,a,* David Cretney, Cheuk K. Lau, Vincent Mascitti and Nancy Tsoub
aMerck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire/Dorval, Quebec, Canada H9R 4P8
bMerck and Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 2 August 2002; accepted 6 September 2002
Abstract—A new approach to a chiral tetrahydronaphthalene precursor for the decalin portion of (+)-compactin is disclosed. The
strategy utilises two key steps: a boron-catalysed diastereoselective annulation reaction to a key dioxaborin ester which was then
transformed to a dioxaphosphinin-2-oxide for use in a diastereoselective SN2 reaction affording the two substituents at C-1 and
C-2 with the cis stereochemistry required in a (+)-compactin skeleton. © 2002 Published by Elsevier Science Ltd.
1. Introduction
2. Results and discussion
First discovered in 1976, compactin and the related
mevinic acids were found to be potent inhibitors of
HMGCoA reductase, the rate limiting enzyme in the
biosynthesis of cholesterol in humans.1 Clinical trials
have shown that compactin effectively reduces choles-
terol levels. As compounds with such biological activity
have great potential as pharmaceutical agents and their
study is of great interest. Indeed, Merck & Co., Inc.,
currently manufactures two hypocholesterolemic drugs,
Mevacor® and Zocor®, both of which are mevinic acid
analogs.
Herein, we describe a new approach to the chiral
tetrahydronaphthalene ring system 14 an alternative
precursor to the decalin portion of the mevinic acid
skeleton. Using the retrosynthetic sequence (Scheme 1),
compound 14, was prepared via a novel diastereoselec-
tive SN2 displacement of a cyclic leaving group in the
form of a chiral dioxaphosphinin-2-oxide 12 with a
vinyl cuprate reagent. The phosphonate ester 12 was
prepared from 10 via 9, which is derived from a novel
boron-catalysed diastereoselective annulation reaction.
We envisaged that Birch reduction3 of the tetra-
hydronaphthalene ring system would provide an
advanced intermediate that could be elaborated readily
to (+)-compactin (Scheme 1). These subsequent steps
will be disclosed in an upcoming paper.
The mevinic acids have therefore been the subject of
considerable synthetic interest. In most published syn-
theses of the mevinic acid skeleton, the key step in the
construction of the hexahydronapthalene unit involves
a Diels–Alders cyclization.2
Intermolecular ortho-specific hydroxyalkylations of
Scheme 1.
* Corresponding author. Tel.: 1-514-428-3037; fax: 1-514-428-4900; e-mail: claude l dufresne@merck.com
– –
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00570-0

1966
C. Dufresne et al. / Tetrahedron: Asymmetry 13 (2002) 1965–1967
phenols have previously been performed using titanium,
magnesium and aluminum catalysts and give, in con-
trast to the boron-catalysed reactions, good diastereose-
lectivities with a-substituted aldehydes.4,5 On the other
hand, we have found that intramolecular boron-
catalysed o-hydroxyalkylations of phenols via cyclic
boronate esters provide high diastereoselectivities with
a-substituted aldehydes.
We now report the application of this methodology for
the introduction of the two stereocenters of the decalin
ring of (+)-compactin. Starting from 3-hydroxybenz-
aldehyde 1, the TBDMS ether 2 is prepared in 84%
yield, and reacted with phosphonium salt 4 (prepared
from
(R)-3-bromo-2-methylpropan-1-ol
3
and
triphenylphosphine) to furnish alkene alcohol 5 in 76%
isolated yield. Hydrogenation of 5 in the presence of
10% Pd/C gave the saturated compound 6, which was
then subjected to Swern oxidation to give a 75% yield
of aldehyde 7. Desilylation of 7 using TBAF leads to
the key intermediate (2S)-4-(3-hydroxyphenyl)-2-
methylbutanal 8 in 82% yield. Reaction of the enan-
tiomerically pure aldehyde 8 (ee=99%, by HPLC,
Chiralcel AD column) with phenylboronic acid in the
presence of catalytic amount of propionic acid in
refluxing toluene with azeotropic removal of water for 2
h gave in 75% yield the trans isomer (3aR,4S)-4-methyl-
2 - phenyl - 3a,4,5,6 - tetrahydronaphtho[1,8 - de][1,3,2]-
dioxaborinine 9 (Scheme 2).6,7 Oxidative cleavage of the
boronic ester using H2O2 buffered at pH 7 gave diol 10
in 70% yield ([h]D=−102 (acetone)). Acetylation of 10
then gave the diacetate 11, which was fully character-
ized, including an X-ray crystallographic study (Fig. 1).
Figure 1. X-Ray structure of 11.
1
In the H NMR spectrum of 11 The methine proton at
Figure 2. Proposed transition state in formation of 9.
C-1 exhibited a coupling constant of 8 Hz, which
corresponds to the reported coupling constant of a
similar compound with trans stereochemistry.8
pseudo decalin ring system prefers to adopt a chair–
chair conformation with the C-2 methyl group posi-
tioned in the more favourable equatorial position which
leads to the anti diastereoselectivity observed in the
ortho-specific annulation reaction.
The preferred trans geometry of 9 can be rationalized
by the proposed transition state as shown in Fig. 2. The
Scheme 2.

C. Dufresne et al. / Tetrahedron: Asymmetry 13 (2002) 1965–1967
1967
Scheme 3.
Attempts to prepare the mesylate and tosylate of the
benzylic alcohol 10 as leaving group for subsequent SN2
displacement failed. Dimerization and/or elimination of
the benzylic alcohol resulted, even when the phenol was
protected as the methyl ether. The cyclic phosphonate
12 was considered as a more stable intermediate that
also serves as a novel leaving group. Thus, treatment of
10 with phenylphosphonic dichloride and 1-H-
tetrazole9 in refluxing toluene gave 12. Reaction of
6. Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365–
368.
7. Dufresne, C.; Lau, C. K.; Bernstein, M.; Bissada, S.
Tetrahedron Lett. 1994, 35, 3691–3694.
8. Schoofs, A.; Guette, J. P.; Horeau, A. Bull. Soc. Chim.
Fr. 1976, 1215–1221.
9. Zhao, K.; Landry, D. W. Tetrahedron 1993, 49, 363–368.
10. Nugent, W.; Hobbs, F. J. Org. Chem. 1986, 51, 3376–
3378.
11. All new compounds reported had spectral data in accord
with the assigned structure and gave satisfactory elemen-
tal analyses and/or high resolution mass spectral data.
dioxaphosphinin-2-oxide 12 with
a vinyl cuprate
reagent10 gave the cis-substituted intermediate (1S,2S)-
13, (J1,2=3.3 Hz) with 90% inversion at the C-1 center
(de=90%). The resulting phenol 13 was then protected
as the methyl ether 1411–13 with methyl iodide, with an
overall yield of 55% (Scheme 3).
12. Preparation
of
(1S,2S)-8-methoxy-2-methyl-1-vinyl-
1,2,3,4-tetrahydronaphthalene 14: Methyl lithium (1.4 M,
2.85 ml, 4 mmol) was added to a solution of tetravinyl tin
(0.240 g, 1 mmol) in tetrahydrofuran (5 ml) at 0°C and
stirred for 20 min. The temperature was then cooled to
−78°C and copper cyanide (0.190 g, 2 mmol) was added.
After 20 min, compound 12 (0.211 g, 0.7 mmol) was
added and the reaction mixture was warmed to −30°C.
After 10 min the reaction mixture as warmed to 0°C and
stirred for 25 min. The reaction mixture was quenched in
1 M HCl. The suspension was extracted with ethyl ace-
tate, dried with magnesium sulfate filtered and concen-
trated. The residue was purified by flash chromatography
to yield 0.153 g (55% for the two steps). Compound 13
(0.153 g, 0.8 mmol) was dissolved in DMF (1 mL), cooled
to 0°C, and sodium hydride (0.019 g, 0.8 mmol) was
added. The solution was stirred for 10 min, after which
time an excess of methyl iodide was added. The mixture
was then brought to room temperature. Quenched with
water and the product extracted with ether. The residue
was purified by flash chromatography to yield 14 (0.149
g, 91%) (de=90% by HPLC Chiralcel AD column using
10% hexane/isopropanol).
3. Conclusion
In summary, we have discovered a new methodology to
introduce two of the stereocenters for the decalin ring
system of (+)-compactin. The required 1S,2S stereocen-
ters have been incorporated stereoselectively into the
tetrahydronaphthalene intermediate 14. Elaboration of
this versatile intermediate 14 to the natural product is
currently in progress.
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13. 1H NMR (500 MHz, acetone-d6): major isomer l 7.06
(1H, t, J=7.86 Hz), 6.70 (2H, dd, J=8.22, 12.02 Hz),
5.88 (1H, m), 4.90 (1H, dtt, J=10.26, 2.20 Hz), 4.65 (1H,
dtt, J=17.54, 3.5, 3.5 Hz), 3.73 (3H, s), 3.45 (1H, m),
2.75 (2H, m), 1.95 (2H, m), 1.45 (1H, m), 0.94 (3H, d,
6.98 Hz); 13C NMR (125.75 MHz, acetone-d6): l 159.16,
143.58, 138.21, 127.25, 125.96, 121.91, 113.60, 108.42,
55.45, 43.79, 32.56, 25.79, 25.06, 18.85. Anal. calcd for
C14H18O (202.29): C, 83.12; H, 8.97. Found: C, 82.99; H,
8.88%. [h]D (acetone)=−9.9; HRMS found m/z: 203.1357
(M++1); calcd for C14H18O: 203.1357 ( M++1).