Conversion of pravastatin into an advanced intermediate for the synthesis of the HMG-CoA reductase inhibitor BB-476

Article abstract of DOI:10.1016/j.tetlet.2009.10.080

Rearrangement of the decalin system of pravastatin under S_N2′ Mitsunobu conditions and subsequent selective hydrolysis and oxidation afforded a key dienone 23, which upon copper-catalyzed addition of a 1E-propenyl moiety established the carbon framework of BB-476 3 in high diastereomeric excess.

Full text of DOI:10.1016/j.tetlet.2009.10.080

Tetrahedron Letters 51 (2010) 57–59
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conversion of pravastatin into an advanced intermediate for the synthesis
of the HMG-CoA reductase inhibitor BB-476
*
J. J. Cronje Grove, Pieter S. van Heerden, Daneel Ferreira, Barend C. B. Bezuidenhoudt
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa
a r t i c l e i n f o
a b s t r a c t
Rearrangement of the decalin system of pravastatin under SN20 Mitsunobu conditions and subsequent
selective hydrolysis and oxidation afforded a key dienone 23, which upon copper-catalyzed addition of
a 1E-propenyl moiety established the carbon framework of BB-476 3 in high diastereomeric excess.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 21 July 2009
Revised 7 October 2009
Accepted 16 October 2009
Available online 22 October 2009
Inhibition of the enzyme HMG-CoA reductase, a rate-limiting
step in the human de novo cholesterol biosynthesis pathway, has
become an important therapeutic strategy in the management of
atherosclerosis in humans.1–3 Among the known inhibitors of
HMG-CoA reductase,4,5 one example with potential for clinical
development is the mevinic acid analogue, BB-476 3. Owing to
the many steps and low overall yield (ca. 2%) of the existing total
synthesis6 of BB-476 3, alternative routes for commercial access
to this compound were investigated. The ready availability of prav-
astatin 1 from a fermentation process, prompted us to investigate a
methodology involving the transformation of the pravastatin sys-
tem into that of BB-476. Herein, we report a new protocol for the
synthesis of a key intermediate 2 in the synthesis of BB-476.
The extremely acid-sensitive pravastatin 1 was isolated from a
commercial source as the methyl ester 4. Apart from converting
the 8-O-(2S)-methylbutyryl group and the 1-(3,5-dihydroxyhepta-
noyl) side chain into 2,2-dimethylbutyryl and d-lactone moieties,
respectively, modification of the decalin unit in 4 requires substitu-
Protection of the 1,3-diol function of the side chain of the trihy-
droxy methyl ester 4 as the isopropylidene derivative 5, a prerequi-
site for both substitution of the 6-OH group and reduction of the
C4a–C5 double bond, proved to be problematic due to the extreme
acid-sensitivity of pravastatin resulting in aromatization of its
A-ring. Isopropylidene formation was eventually effected with
2,2-dimethoxypropane through application of the mild acidic cata-
lyst pyridinium p-toluenesulfonate (PPTS)7 in THF to afford the pro-
tected derivative 5 in 82% yield (Scheme 1). Saponification of the
axial 8-(2-methylbutyryl) ester in 5 followed by acidification and
methylation of the carboxylic acid functionality afforded diol 6 in
90% yield. Subsequent selective mono-silylation of the 6-OH group
afforded the 8-hydroxy compound 7 as a substrate for selective
reduction of the diene system. However, despite the literature prec-
edent for the successful utilization of the Crabtree catalyst8 for the
reduction of mevinolin,9 selective hydrogenation of the C4a–C5 ole-
finic bond in 7 was hampered by two major difficulties, that is,
over-reduction to the fully saturated product 10 (ratio of
9:10 = 0:1) and/or inexplicable cessation of the reaction after a cer-
tain period of time.
tion of the equatorial 6b-OH by an a-E-propenyl group and regio-
and stereoselective reduction of the C4a–C5 double bond.
O
O
HO
HO
O
CO2Me
O
O
O
O
O
O
H
O
H
O
O
H
1
7
A
5
B
4
3
O
HO
H
2
BB-476 3
Pravastatin 1
Although electronic manipulation of the C4a–C5 double bond,
via selective acylation of 6-OH as the pivaloyl ester 8, increased
the selectivity towards reduction (ratio of 11:12 = 1:0), the reac-
tion was slow, and low conversion (15%) was observed after 24 h.
* Corresponding author. Tel.: +27 51 401 9021; fax: +27 51 444 6384.
E-mail address: bezuidbc.sci@ufs.ac.za (B.C.B. Bezuidenhoudt).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.080

58
J. J. Cronje Grove et al. / Tetrahedron Letters 51 (2010) 57–59
HO
HO
OMe
O
OMe
O
OMe
O
O
O
O
O
O
O
HO
i
ii,iii
90%
H
H
H
O
O
82%
HO
HO
HO
6
5
4
HO
HO
HO
H
H
H
H
H
iv or v
vi
+
RO
RO
RO
7
R=TBDMS 77%
8 R=Piv 98%
9
R=TBDMS 0%
11
10
12
R=TBDMS 84% (99% de)
R=Piv 0%
R=Piv 15% (99% de)
Scheme 1. Reagents and conditions: (i) 2,2-dimethoxypropane, PPTS, THF, rt; (ii) NaOH (aq), MeOH, reflux, then NaHSO4; (iii) CH2N2, ꢀ15 °C; (iv) tBuMe2SiCl, imidazole, THF,
i
rt; (v) pivalic anhydride, pyridine, CH2Cl2, rt; (vi) [Ir(COD)Py(PCy3)]PF6, H2, PrOH, CH2Cl2, rt.
Attention was thus focussed on substitution of the 6b-hydroxy
group with a carbon fragment prior to further attempts at hydroge-
nation of the diene system. Attempts at introducing the 6a-substi-
static attractions operating in the Mitsunobu reaction11 was subse-
quently investigated. Treatment of the hydroxy-ester 15 with
DEAD/PPh3 in dry benzene at 0 °C, however, again led to A-ring
aromatization.
In a final attempt at intramolecular nucleophilic attack at C-6 of
compound 16, it was anticipated that a palladium species would be
directed to the sterically less congested b-face of the allylic sys-
tem.12 Substitution of the O-acetyl moiety may then afford the tar-
get tricyclic lactone 17. Efforts at inducing the transformation
16?17 using Pd(PPh3)4/NaH, failed invariably.
tuent by treatment of the pivaloyloxy group in 8 with the butyl
Gillman cuprate reagent,10 however, resulted in substitution exclu-
sively via a 1,5-conjugative process leading to the 3a-alkylated
product 13 (62%, 99% de) (Scheme 2). The regiochemical course
of the reaction can be explained in terms of the relative inaccessi-
*
bility of the C6–O
r -antibonding orbital, as well as the steric
hindrance exercised by the axial C-8 hydroxy function.
In order to circumvent these problems, intramolecular displace-
In order to overcome both the problems of A-ring aromatization
and steric inaccessibility at C-6, we investigated methods for intro-
ducing the 6E-propenyl group via a double SN20 reaction approach.
Thus, application of Mitsunobu conditions11 to compound 5, affor-
ment by transferring the carbon fragment from the 8
an approach that possesses the dual advantages of stereocontrol at
C-6 and essentially no steric influence from the 8 -substituent,
a-OH to C-6,
a
was next investigated. Thus, acylation of the mono-silylated
methyl ester 7 with ethyl malonyl chloride followed by desilyla-
tion and acetylation afforded the di-acylated compound 16 in good
overall yield (84%) (Scheme 3). Deprotonation of the malonate side
chain of 16 with LDA (10% molar excess) at ꢀ78 °C, however, failed
to give the desired lactone 17 via the anticipated intramolecular
substitution. Such failure is attributable to conformational restric-
tions of the bulky C-8 ester group which was shown by molecular
modeling calculations, to be preferentially directed away from the
A-ring towards the side chain on the B-ring. In order to attain the
required conformation for substitution, the potential of the electro-
ded the 3a-benzoate ester 18 in 52% yield, and a mixture of epi-
mers 19 and 20 in 16% and 26% yields, respectively. Formation of
the benzoate ester 18 as the major product is promoted by the
preference for an SN20 pathway due to the hindered nature of the
allylic system.12 Selective saponification of the C-6 benzoate by-
products 19 and 20 afforded epimerized starting material which
was recycled. Selective hydrolysis of 18 afforded alcohol 21 and
diol 22 in 75% and 9% yield, respectively. Subsequent PDC oxida-
tion13 of 21 yielded dienone 23 (87% yield), the key intermediate
for introducing the propenyl group (Scheme 4). Copper-catalyzed
addition14 of 1-propenyl-magnesium bromide to the stereoelec-
tronically preferred
carbon framework 2 of BB-476 3 in 66% yield,16 but also circum-
vented the problems involving selective hydrogenation. The -ori-
a
-face at C-615 of 23 not only established the
a
HO
H
HO
H
entation of the C-6 propenyl substituent was confirmed by the
observed NOE between the vinylic methyl group and the methyl
groups of the 8-methylbutyryl side chain.
In conclusion, an efficient synthesis to establish the carbon
backbone 2 of BB-476 3 in five steps starting from readily available
pravastatin 1 has been developed. Apart from a transesterification
nBu2CuLi / Et2O
-78 to -30 ºC
PivO
Bun
13 62% (99% de)
8
Scheme 2.
O
O
HO
H
H
O
EtO
H
O
O
i
O
TBDMSO
94%
RO
OEt
7
17
14 R=TBDMS
15
ii 95%
iii 99%
R=H
16 R=Ac
Scheme 3. Reagents and conditions: (i) ethyl malonyl chloride, 2,6-lutidine, CH2Cl2, 0 °C; (ii) TBAF, THF, rt; (iii) Ac2O, Py, 40 °C

J. J. Cronje Grove et al. / Tetrahedron Letters 51 (2010) 57–59
59
O
O
RO
H
O
O
H
H
iii
i
ii
5
O
87%
OH
O
Ph
O
O
23
18 52% (99% de)
75%
21 R=
+
iv
22 R=H 9%
O
O
H
O
O
H
O
Ph
O
O
19 = 16%
20 = 26%
2 66% (99% de)
Scheme 4. Reagents and conditions: (i) DEAD, PPh3, PhCO2H, THF, ꢀ78 °C; (ii) NaOMe, MeOH, rt; (iii) PDC, CH2Cl2, rt; (iv) CuI, (10 mol %), TMEDA, CH3CHCHMgBr, THF,
ꢀ25 °C.
5. Arseniyadis, S.; Brondi-Alves, R.; Yashunsky, D. V.; Potier, P.; Toupet, L.
Tetrahedron 1997, 53, 1003.
6. Blackwell, C. M.; Davidson, A. H.; Launchburg, S. B.; Lewis, C. N.; Morrice, E. M.;
step to attach the desired ester functionality at C8 and removal of
the protecting group on the side chain, it only remains to introduce
the B-ring double bond which should be possible through a trivial
reductive elimination sequence. We have thus demonstrated the
synthetic potential of this intermediate towards the total synthesis
of BB-476.
Reeve, M. M.; Roffey, J. A. R.; Tipping, A. S.; Todd, R. S. J. Org. Chem. 1992, 57,
5596.
7. Fanton, G. J.; Horton, D. J. Chem. Soc., Chem. Commun. 1980, 21.
8. Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
9. DeCamp, A. E.; Verhoeven, T. R.; Shinkai, I. J. Org. Chem. 1989, 54, 3207.
10. Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7777.
11. Mitsunobu, O. Synthesis 1981, 1.
Acknowledgements
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14. Millar, J. G.; Underhill, E. W. J. Org. Chem. 1986, 51, 4726.
15. Senanayake, C. H.; Bill, T. J.; DiMichele, L. M.; Chen, Y. C.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1993, 34, 6021.
16. Characterization of 2: HRMS C29H43O7 requires m/z 503.3008. Found: m/z
503.3009 (M+ꢀCH3). 1H NMR (300 MHz, CDCl3) d 5.90 (1H, br s, H-4), 5.85 [1H,
Support by Bioclones (Pty) Ltd, Sandton, the Foundation of Re-
search Development, Pretoria, and the ‘Sentrale Navorsingsfonds’
of this University is acknowledged.
*
br s, H-4 (minor diastereomer)], 5.27–5.50 (3H, m, H-100, H-2000, H-8), 4.20–4.31
References and notes
(1H, m, H-30), 3.68–3.78 (1H, m, H-50), 3.67 (3H, s, OCH3), 2.60–2.70 (1H, m),
2.53 [1H, dd, J = 16.0, 7.0 Hz, H-20(a)], 2.35 [1H, dd, J = 16.0, 6.0 Hz, H-20(b)],
2.20–3.15 (4H, m), 1.90–2.00 (3H, m), 1.56 (3H, dd, J = 7.0, 2.0 Hz, 2000-CH3), 1.41
(3H, s, isopropylidene CH3), 1.33 (3H, s, isopropylidene CH3), 1.05 (3H, d,
J = 7.0 Hz, 200CH3), 0.99 (3H, d, J = 7.5 Hz, 2-CH3), 0.82 (3H, t, J = 7.5 Hz, 300CH3),
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.
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