Elaboration of a Baylis-Hillman adduct to (-)-acaterin and its diastereomer through ring closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01069-9

A short and efficient synthesis of acaterin, a biologically important natural product has been achieved by elaboration of a Baylis-Hillman adduct. The key step for the synthesis is a ring closing metathesis reaction using Grubbs' catalyst.

Full text of DOI:10.1016/S0040-4039(02)01069-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5393–5395
Elaboration of a Baylis–Hillman adduct to (−)-acaterin and its
diastereomer through ring closing metathesis
R. Vijaya Anand, S. Baktharaman and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 1 May 2002; revised 29 May 2002; accepted 7 June 2002
Abstract—A short and efficient synthesis of acaterin, a biologically important natural product has been achieved by elaboration
of a Baylis–Hillman adduct. The key step for the synthesis is a ring closing metathesis reaction using Grubbs’ catalyst. © 2002
Elsevier Science Ltd. All rightrs reserved.
The Baylis–Hillman reaction1,2 has attracted the atten-
tion of many synthetic organic chemists because the
R
R
O
O
resulting adducts can be transformed into a variety of
natural and unnatural compounds.3 Several biologically
important natural products such as (+)-mikanecic acid,4
( )-sarkomycin ester,5 sitophilate,6 epopromycin B,7a
and (−)-mycestericin E7b have been synthesized using
this reaction as a key step. While working on the
asymmetric version of Baylis–Hillman reaction, we dis-
covered that some of its adducts can be used in the
synthesis of acaterin (−)-1 and its diastereomer 2. Aca-
terin, isolated from a culture broth of Pseudomonas sp.
A92 by Endo and co-workers,8 is an inhibitor of acyl-
CoA cholesterol acyltransferase (ACAT). These
inhibitors are expected to be effective for treatment of
atherosclerosis and hypercholesterolemia. The absolute
stereochemistry of natural acaterin (−)-1 was confirmed
after the synthesis of all the diastereomers of acaterin
by Kitahara and co-workers.9,10 The ACAT inhibition
activity of all four possible stereoisomers of acaterin
was tested using microsomes prepared from rat liver
and it was found that all the diastereomers including
the natural one showed a similar activity. We disclose
here a short and efficient synthesis of natural acaterin 1
and its diastereomer 2 from a Baylis–Hillman adduct
through ring closing metathesis (RCM).
R
S
O
O
OH
OH
2
1
ate in the presence of
a catalytic amount of
quinuclidine11 gave an adduct 3 in 72% isolated yield.12
We planned to protect the hydroxyl group of 3 and
then hydrolyze the ester. It was observed that the
hydrolysis of the TBDMS ether protected ester gave
poor yields (30%) of the acid even under mild condi-
tions (1N LiOH in THF:H2O). All attempts to improve
the yield of the acid using other reagents and conditions
failed. However, a very clean hydrolysis was obtained
when the hydroxyl group of 3 was protected as its
methoxyethoxymethyl (MEM) ether. Thus, when 4 was
treated with 1N LiOH solution in a mixture of THF
and water at rt, the desired acid 5 was obtained in a
quantitative yield. The acid 5 was coupled with R-(−)-
3-buten-2-ol in the presence of dicyclohexylcarbodi-
imide (DCC) and 4-(dimethylamino)pyridine (DMAP)
to provide
6
as an inseparable mixture of
diastereomers, a substrate for RCM. Although electron
deficient olefins in general and acrylates, in particular,
are known to be problematic substrates for RCM, some
successful reports are known using Grubbs catalyst.13 It
was heartening to discover that treatment of 6 with
Grubbs’ catalyst in DCM under dilute conditions14
gave a 1:1 diastereomeric mixture of cyclized products
715 and 8,16 which were separated by radial chromatog-
raphy and their absolute configurations were assigned
after conversion to natural acaterin 117 and its
diastereomer 218 using TiCl4.
Our strategy towards the synthesis of (−)-acaterin 1 and
its diastereomer 2 is presented in Scheme 1. The Baylis–
Hillman reaction of caprylic aldehyde with methyl acryl-
* Corresponding author. Fax: +91-512-597436; e-mail: vinodks@
iitk.ac.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01069-9

5394
R. V. Anand et al. / Tetrahedron Letters 43 (2002) 5393–5395
a
b
OMe
OMe
CHO
83 %
72 %
OH O
O
MEMO
3
4
OH
c
d
O
e
98 %
O
73 %
MEMO
O
54 %
MEMO
5
6
O
O
O
+
O
MEMO
MEMO
8
7
f
93 %
f
92 %
1
2
Scheme 1. (a) Methyl acrylate, quinuclidine, 48 h; (b) 2-methoxyethoxymethyl chloride, N-ethyl diisopropylamine, DCM, 6 h. (c)
1N aq. LiOH, THF/water (2:1), 24 h; (d) R-(−)-3-buten-2-ol, DCC, DMAP, DCM, 24 h; (e) Grubbs’ catalyst (30 mol%), DCM,
reflux, 48 h; (f) TiCl4, DCM, 8 h.
In conclusion, we have accomplished a short synthesis
of natural (−)-acaterin 1 and its diastereomer 2 in an
overall yield of 22%.
4. Basavaiah, D.; Pandiaraju, S.; Sarma, P. K. S. Tetra-
hedron Lett. 1994, 35, 4227.
5. Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron Lett.
1989, 30, 7381.
6. Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.;
Almeida, N.-P. Tetrahedron 2001, 57, 6901.
7. (a) Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama,
S. Tetrahedron Lett. 2001, 42, 7867; (b) Iwabuchi, Y.;
Furukawa, M.; Esumi, T.; Hatakeyama, S. Chem. Com-
mun. 2001, 2030.
Acknowledgements
We thank the CSIR (Government of India) for funding
our research and a senior research fellowship to R.V.A.
One of us (V.K.S.) thanks DST for a Swarnajayanti
fellowship.
8. Naganuma, S.; Sakai, K.; Hasumi, K.; Endo, A. J.
Antibiot. 1992, 45, 1216.
9. Ishigami, K.; Kitahara, T. Tetrahedron 1995, 51, 6431.
10. While writing this manuscript, another synthesis of aca-
terin was published, see: Franck, X.; Figadere, B. Tetra-
hedron Lett. 2002, 43, 1449.
References
11. Hine, J.; Chen, Y.-J. J. Org. Chem. 1987, 52, 2091.
12. Using DABCO as a catalyst, a 78% yield was obtained
but the reaction took 7 days for completion.
13. (a) Fu¨rstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463; (b)
Nicolaou, K. C.; Rodriguez, R. M.; Mitchel, H. J.; van
Delft, F. L. Angew. Chem., Int. Ed. 1998, 37, 1874; (c)
Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743; (d)
Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130.
14. 6 was cyclized as follows: A solution of Grubbs’ catalyst
(358 mg, 0.44 mmol) in dry DCM (100 mL) was added
dropwise to a stirred solution of the diene 6 (500 mg, 1.45
mmol) in dry DCM (100 mL) at 40°C over a period of
1.5 h. The resulting solution was allowed to stir at reflux
for 48 h. The solvent was distilled under reduced pressure
and the residue was passed through a short plug of silica
gel to give a 1:1 diastereomeric mixture of products (7
and 8) as a pale brown liquid (246 mg, 54%). These
diastereoisomers were easily separated by radial chro-
matography using 1–2 mm thick plates coated with silica
gel PF254 (E-Merck) to give 7 (116 mg) and 8 (110 mg).
1. Reviews: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001; (b) Ciganek, E. Org. React.
1997, 51, 201.
2. For an enantioselective version of the reaction, see:
Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219.
3. (a) Gruiec, A.; Foucaud, A.; Moinet, C. New J. Chem.
1991, 15, 943; (b) Buchholz, R.; Hoffmann, H. M. R.
Helv. Chim. Acta 1991, 74, 1213; (c) Hoffmann, H. M.
R.; Weichert, A.; Slawin, A. M. Z.; Williams, D. J.
Tetrahedron 1990, 46, 5591; (d) Bauchat, P.; Foucaud, A.
Tetrahedron Lett. 1989, 30, 6337; (e) Paquette, L. A.;
Andino, J. M. Tetrahedron Lett. 1999, 40, 4301; (f)
Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S.
Tetrahedron Lett. 2001, 42, 85; (g) Basavaiah, D.;
Kumaragurubaran, N.; Sharada, D. S.; Reddy, R. M.
Tetrahedron 2001, 57, 8167; (h) Weichert, A.; Hoffmann,
H. M. R. J. Chem. Soc., Perkin Trans. 1 1990, 2154; (i)
Kanemasa, S.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1993,
66, 2685.

R. V. Anand et al. / Tetrahedron Letters 43 (2002) 5393–5395
5395
15. 7 was characterized as: Rf 0.48 (50% ethyl acetate in
petroleum ether); [h]D25 +21.9 (c 0.60, CHCl3); IR (film)
for C17H30O5: C, 64.97; H, 9.95. Found: C, 64.94; H,
9.92.
1
1753 cm−1; H NMR (400 MHz, CDCl3) l 0.87 (t, J=6.4
17. The spectral data of the natural acaterin (−)-1 was identi-
cal with that reported.9 It was characterized as: Rf 0.40
(50% ethyl acetate in petroleum ether); [h]2D5 −18.9 (c 0.95,
CHCl3) {lit.8 [h]D19 −17 (CHCl3); lit.9 [h]2D0 −19.7 (c 0.61,
Hz, 3H), 1.26–1.29 (m, 10H), 1.43 (d, J=6.8 Hz, 3H),
1.71–1.78 (m, 2H), 3.38 (s, 3H), 3.54 (t, J=4.9 Hz, 2H),
3.64–3.69 (m, 1H), 3.73–3.78 (m, 1H), 4.48 (t, J=6.1 Hz,
1H), 4.73 (d, J=2.4 Hz, 2H), 5.04 (q, J=6.8 Hz, 1H),
7.26 (s, 1H); 13C NMR (100 MHz, CDCl3) l 14.07, 19.08,
22.61, 25.05, 29.18, 29.32, 31.77, 33.89, 59.06, 67.37,
71.54, 71.66, 77.58, 94.10, 134.88, 150.71, 171.84. Mass
(EI, m/z): 269 (base peak). Anal. Calcd for C17H30O5: C,
64.97; H, 9.95. Found: C, 64.84; H, 9.97.
1
CHCl3)}; IR (film) 3458, 1750, 1652 cm−1; H NMR (400
MHz, CDCl3) l 0.88 (t, J=7.1 Hz, 3H), 1.27–1.30 (m,
10H), 1.45 (d, J=6.8 Hz, 3H), 1.64–1.81 (m, 2H), 2.69
(bs, 1H), 4.47–4.50 (m, 1H), 5.07 (q, J=6.8 Hz, 1H), 7.19
(s, 1H); 13C NMR (100 MHz, CDCl3) l 14.05, 18.90,
22.59, 25.23, 29.15, 29.28, 31.73, 35.41, 66.99, 77.95,
136.15, 149.32, 172.67.
16. 8 was characterized as: Rf 0.5 (50% ethyl acetate in
petroleum ether); [h]D25 −82.4 (c 0.85, CHCl3); IR (film)
18. The pseudo acaterin 2 was characterized as: Rf 0.42 (50%
ethyl acetate in petroleum ether); [h]2D5 −54.7 (c 0.75 in
CHCl3) {lit.9 [h]D25 −63.7 (c 0.53, CHCl3)}; IR (film) 3458,
1
1755 cm−1; H NMR (400 MHz, CDCl3) l 0.87 (t, J=6.6
Hz, 3H), 1.26–1.29 (m, 10H), 1.43 (d, J=6.8 Hz, 3H),
1.72–1.80 (m, 2H), 3.39 (s, 3H), 3.54 (t, J=4.9 Hz, 2H),
3.64–3.69 (m, 1H), 3.74–3.79 (m, 1H), 4.48 (t, J=6.3 Hz,
1H), 4.73 (s, 2H), 5.05 (q, J=6.8 Hz, 1H), 7.22 (s, 1H);
13C NMR (100 MHz, CDCl3) l 14.06, 19.11, 22.60,
25.13, 29.18, 29.32, 31.78, 33.92, 59.05, 67.36, 71.55,
71.66, 77.58, 94.12, 134.85, 150.67, 171.86. Anal. Calcd
1
1750, 1652 cm−1; H NMR (400 MHz, CDCl3) l 0.88 (t,
J=7.1 Hz, 3H), 1.27–1.32 (m, 10H), 1.44 (d, J=6.8 Hz,
3H), 1.66–1.81 (m, 2H), 2.62 (bs, 1H), 4.49 (m, 1H), 5.07
(q, J=6.8 Hz, 1H), 7.19 (s, 1H); 13C NMR (100 MHz,
CDCl3) l 14.05, 18.93, 22.59, 25.28, 29.16, 29.28, 31.74,
35.43, 67.08, 77.95, 136.21, 149.28, 172.63.