An organocatalytic route to the synthesis of lactone moiety of compactin and mevinolin

Article abstract of DOI:10.1016/j.tetlet.2010.08.093

An efficient synthesis of lactone moiety of compactin has been achieved. The stereogenic centers were generated by means of iterative proline-catalyzed sequential α-aminoxylation and Horner-Wadsworth-Emmons (HWE) olefination of aldehydes.

Full text of DOI:10.1016/j.tetlet.2010.08.093

Tetrahedron Letters 51 (2010) 5838–5839
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An organocatalytic route to the synthesis of lactone moiety of compactin
and mevinolin
Pradeep Kumar a, , Menaka Pandey a, Priti Gupta a, Dilip D. Dhavale b
⇑
a Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
b Department of Chemistry, University of Pune, Pune 411 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of lactone moiety of compactin has been achieved. The stereogenic centers were
Received 12 August 2010
Revised 30 August 2010
Accepted 31 August 2010
Available online 6 September 2010
generated by means of iterative proline-catalyzed sequential
worth–Emmons (HWE) olefination of aldehydes.
a-aminoxylation and Horner–Wads-
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lactone
Proline
Organocatalysis
Aminoxylation
Compactin
Compactin (1a) and mevinolin (1b) (Fig. 1) are potent compet-
itive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-
CoA) reductase, the enzyme involved in the rate-limiting step of
cholesterol biosynthesis in humans.1 Their ability to lower blood
cholesterol levels, especially plasma low-density lipoprotein
(LDL)2 cholesterol in human beings, is important for the mitigation
of arteriosclerosis. The unique structural features of this class of
compounds called ‘mevinic acids’, and their potential applications
as hypocholesterolemic agents have aroused a great interest
among synthetic organic chemists, resulting in an onslaught of
activity directed at the synthesis of these challenging target
molecules.
synthesis of syn/anti-1,3-polyols, which are based on proline-cata-
lyzed sequential
a-aminoxylation and Horner–Wadsworth–Em-
mons (HWE) olefination of aldehydes.7
As a part of our research programme aimed at developing
enantioselective synthesis of biologically active natural products,8
we became interested in devising a simple and concise route to
lactone moiety (2) of compactin/mevinolin via our recently devel-
oped methodology7 for enantiopure syn/anti-1,3-polyols using
organocatalysis. Herein we report our successful endeavors
toward the total synthesis of
2 employing proline-catalyzed
sequential -aminoxylation and Horner–Wadsworth–Emmons
a
(HWE) olefination of aldehyde as the key step. As shown in
Synthetic studies in mevinic acids can be grouped into three
primary sections: (1) total synthesis, (2) synthesis of the decalin
units, and (3) synthesis of b-hydroxy-d-lactone moiety. The key
structural feature of these molecule is chiral b-hydroxy-d-lactone
moiety which in its open acid form closely mimics mevalonic acid,
a crucial intermediate in the biosynthesis of cholesterol,3 hence
several research groups worldwide have focused much attention
on the stereocontrolled synthesis of the d-lactone moiety (2).4
In recent years, the area of organocatalysis has emerged as a
promising strategy and as an alternative to expensive protein
catalysis and toxic metal catalysis,5 thus becoming a fundamental
tool in the catalysis toolbox available for asymmetric synthesis.6
Recently, we developed an iterative approach to the enantiopure
Scheme 1, the synthesis of target compound 2 began with the
aldehyde 3, which was subjected to sequential
using
a
-aminoxylation
L
-proline as a catalyst followed by HWE-olefination reaction
HO
O
O
O
O
H
O
O
H
OH
2
R
1a
(+)-Compactin ( R = H)
1b
(+)-Mevinolin
(
R = Me)
⇑
Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
Figure 1. Structures of (+)-compactin (1a), (+)-mevinolin (1b) and b-hydroxy-d-
lactone moiety (2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.093

P. Kumar et al. / Tetrahedron Letters 51 (2010) 5838–5839
5839
OH
anti-1,3-diol with high degree of enantio- and diastereoselectivi-
ties. The desired stereocenters can simply be achieved by changing
the catalyst. Further application of this methodology to the synthe-
ses of biologically active compounds containing 1,3-polyols is cur-
rently underway in our laboratory.
a
c
CHO
COOEt
3
4, P = H
5, P = TBS
b
TBSO
OH
Acknowledgments
ONHPh
OH
TBSO
OH
e
d
7
6
M.P. and P.G. thank DST, New Delhi and CSIR, New Delhi for
financial assistance. Financial support from DST, New Delhi (Grant
No. SR/S1/OC-44/2009) is gratefully acknowledged.
TBSO
OP
TBSO
O
f
g
References and notes
9
, P = H
8
b
1. (a) Endo, A. J. Med. Chem. 1985, 28, 401–405; (b) Vega, L.; Crundy, S. J. Am. Med.
Assoc. 1987, 257, 33–38. and references cited therein.
10
, P = TBS
2. Goldstein, J. L.; Brown, M. S. Annu. Rev. Biochem. 1977, 46, 897–930.
3. (a) Stokker, G. E.; Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J., Jr.; Deana, A. A.;
Gilfilan, J. L.; Huff, J. W.; Novello, F. C.; Prugh, J. D.; Smith, R. L.; Willard, A. K. J.
Med. Chem. 1985, 28, 347–358; (b) Hoffman, W. F.; Alberts, A. W.; Cragoe, E. J.,
Jr.; Deana, A. A.; Evans, B. E.; Gilfilan, J. L.; Gould, N. P.; Huff, J. W.; Novello, F. C.;
Prugh, J. D.; Rittle, K. E.; Smith, R. L.; Stokker, G. E.; Willard, A. K. J. Med. Chem.
1986, 29, 170–181; (c) Yadav, V. K.; Kapoor, K. K. Ind. J. Chem. 1996, 35B, 1125–
1143.
4. For the synthesis of arylethyl or (E)-arylethenyl substituted b-hydroxy-d-
lactone, see: (a) Sabitha, G.; Sudhakar, K.; Srinivas, C.; Yadav, J. S. Synthesis
2007, 705–708; (b) Bouzbouz, S.; Cossy, J. Tetrahedron Lett. 2000, 41, 3363–
3366; (c) Kiyooka, S.-I.; Yamaguchi, T.; Maeda, H.; Kira, H.; Hena, M. A.; Horiike,
M. Tetrahedron Lett. 1997, 38, 3553–3556; (d) Honda, T.; Ono, S.; Mizutani, H.;
Hallinan, K. O. Tetrahedron: Asymmetry 1997, 8, 181–184; (e) Solladie, G.;
Bauder, C.; Rossi, L. J. Org. Chem. 1995, 60, 7774–7777; (f) Minami, T.;
Takahashi, K.; Hiyama, T. Tetrahedron Lett. 1993, 34, 513–516; (g) Bonini, C.;
Pucci, P.; Viggiani, L. J. Org. Chem. 1991, 56, 4050–4052; (h) Roth, B. D.; Roark,
W. H. Tetrahedron Lett. 1988, 29, 1255–1258; (i) Lynch, J. E.; Volante, R. P.;
Wattley, R. V.; Shinkai, I. Tetrahedron Lett. 1987, 28, 1385–1387; (j) Guindon, Y.;
Yoakim, C.; Bernstein, M. A.; Morton, H. E. Tetrahedron Lett. 1985, 26, 1185–
1188; (k) Prasad, K.; Repic, O. Tetrahedron Lett. 1984, 25, 2435–2438; (l)
Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett. 1984, 25, 2101–
2104.
O
TBSO
OP
O
O
h
OH
OH
11
2
Scheme 1. Reagents and conditions: (a) (i) nitrosobenzene,
(EtO)2P(O)CH2COOEt, DBU, LiCl, CH3CN; (ii) H2/Pd–C, EtOAc, 8 h, 65%; (b) TBSCl,
-proline,
L-proline, DMSO;
imidazole, DMF, overnight, 91%; (c) (i) DIBAL-H, DCM, ꢀ78 °C; (ii)
L
nitrosobenzene, DMSO; (iii) NaBH4, MeOH, 0.5 h, 70% (over three steps); (d) H2/Pd–
C, EtOAc, 8 h, 92%; (e) (i) TsCl, Bu2SnO, Et3N, 2 h; (ii) K2CO3, MeOH, rt, 1 h, 82% (over
two steps); (f) vinylmagnesium bromide, 1 h, 81%; (g) TBSCl, imidazole, DMF,
overnight, 88%; (h) RuCl3ꢁ3H2O, NaIO4, CCl4–H2O–CH3CN = 4:1:1, 5 h, 44%, (i) cat.
HCl, MeOH, overnight, 79%.
to furnish O-amino-substituted allylic alcohol which was directly
subjected to hydrogenation conditions using catalytic amounts of
Pd/C to furnish the
c
-hydroxy ester 49 in good yield and in >97%
ee.10
5. Dalko, P. I. Enantioselective Organocatalysis: Reactions and Experimental
Procedures; Wiley-VCH: Weinheim, 2007.
6. MacMillian, D. W. C. Nature 2008, 455, 304–308.
The free hydroxy group of c-hydroxy ester 4 was protected as
TBS ether to furnish compound 5 in 91% yield. The Dibal-H reduc-
7. Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611–2614.
tion of ester 5 at ꢀ78 °C furnished aldehyde which was subjected
8. (a) Kumar, P.; Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843–2846; (b)
Kumar, P.; Naidu, S. V. J. Org. Chem. 2005, 70, 4207–4210; (c) Gupta, P.; Naidu, S.
V.; Kumar, P. Tetrahedron Lett. 2005, 46, 6571–6573; (d) Kumar, P.; Gupta, P.;
Naidu, S. V. Chem. Eur. J. 2006, 12, 1397–1402; (e) Kumar, P.; Naidu, S. V. J. Org.
Chem. 2006, 71, 3935–3941; (f) Gupta, P.; Kumar, P. Eur. J. Org. Chem. 2008,
1195–1202; (g) Pandey, S. K.; Pandey, M.; Kumar, P. Tetrahedron Lett. 2008, 49,
3297–3299; (h) Chowdhury, P. S.; Gupta, P.; Kumar, P. Tetrahedron Lett. 2009,
50, 7018–7020.
to
a-aminoxylation catalyzed by L-proline, followed by in situ
reduction using NaBH4 to furnish the O-amino-substituted diol
6 in overall 70% yield and 92% de (determined from the 1H and
13C NMR spectral analysis). Compound 6 was subjected to reduc-
tive hydrogenation conditions to afford the diol 711 in 92% yield,
which on selective monotosylation and base treatment furnished
epoxide 8 in 82% yield. Epoxide 8 was opened with vinylmagne-
sium bromide to get the homoallylic alcohol 9 in 81% yield, which
on protection of free hydroxy as TBS ether afforded compound 10
in 88% yield. Olefinic oxidation of 10 using RuCl3ꢁ3H2O and NaIO4
furnished the acid 11, which was cyclized under acidic conditions
(catalytic amount of HCl in MeOH) to give the lactone 2 in good
9. Spectral data of 4: ½a D25
ꢀ12.25 (c 1, CHCl3). IR (neat, cmꢀ1): mmax 3486, 1730,
ꢂ
1602, 1491, 1023, 931. 1H NMR (200 MHz, CDCl3): d 1.32 (t, J = 7.2 Hz, 3H),
1.86–1.71 (m, 2H), 1.87–2.00 (m, 2H), 2. 52 (t, J = 7.1 Hz, 2H), 2.67–2.95 (m,
2H), 3.66–3.76 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 7.40–7.23 (m, 5H); 13C NMR
(50 MHz, CDCl3): 14.1, 27.9, 30.8, 32.2, 39.1, 60.5, 70.6, 125.8, 128.4, 128.5,
141.9, 174.2. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.20; H,
8.46.
10. The enantiomeric excess was determined by converting the alcohol 4 into the
Mosher ester and analyzing the 19F spectrum.
yield. Mp: 106ꢀ107 °C; lit.4e mp: 108 °C, ½a D25
ꢂ
+68.69 (c 2.0,
11. Spectral data of 7: ½a D25
ꢂ
ꢀ20.8 (c 0.14, CHCl3). IR (CHCl3, cmꢀ1): mmax 3412,
CHCl3); lit.4h
½
a 2D5
+68.88 (c 2.29, CHCl3). The physical and spec-
ꢂ
3018, 2938, 1612, 1513, 1248, 1215. 1H NMR (200 MHz, CDCl3): d 0.10 (s, 6H),
0.91 (s, 9H), 1.25–1.28 (m, 2H), 1.54–1.62 (m, 1H), 1.67–1.71 (m, 1H), 1.78–
1.89 (m, 2H), 2.58–2.68 (m, 2H), 3.47 (dd, J = 4.9, 11.1 Hz, 1H), 3.61 (dd, J = 7.5,
11.1 Hz, 1H), 3.85–4.08 (m, 2H), 7.09–7.31 (m, 5H); 13C NMR (50 MHz, CDCl3):
d ꢀ4.7, ꢀ4.1, 17.9, 25.8, 31.1, 38.9, 39.5, 67.0, 71.1, 72.0, 122.8, 125.9, 128.2,
128.4, 141.9. Anal. Calcd for C18H32O3Si: C, 66.62; H, 9.94. Found: C, 66.56; H,
9.88.
troscopic data of 2 were in full agreement with the literature
data.4h,e
In conclusion a short and efficient asymmetric synthesis of lac-
tone moiety of compactin has been achieved by using a practical
and efficient organocatalytic strategy amenable to both syn and