Concise stereoselective total synthesis of (4 R, 6 R)-lactone moiety analog of mevinoline and compactin

Article abstract of DOI:10.1080/00397911.2012.754470

A simple and highly efficient synthetic route has been developed for analogue of HMGCo A reductase inhibitor (1). The strategy utilizes S-Corey-Bakshi-Shibata (CBS) reduction, FeCl₃-catalyzed C-H insertion of ethyl diazoacetate.

Full text of DOI:10.1080/00397911.2012.754470

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Concise Stereoselective Total Synthesis
of (4R, 6R)-Lactone Moiety Analog of
Mevinoline and Compactin
D. Chandra Rao a , D. Kumar Reddy a , B. Chinnababu a , V. Shekhar a
& Y. Venkateswarlu a
a Natural Products Chemistry Division, Natural Products Laboratory ,
Indian Institute of Chemical Technology , Hyderabad , India
Accepted author version posted online: 18 Jun 2013.Published
online: 08 Aug 2013.
To cite this article: D. Chandra Rao , D. Kumar Reddy , B. Chinnababu , V. Shekhar & Y. Venkateswarlu
(2013) Concise Stereoselective Total Synthesis of (4R, 6R)-Lactone Moiety Analog of Mevinoline
and Compactin, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:22, 2980-2984, DOI: 10.1080/00397911.2012.754470
To link to this article: http://dx.doi.org/10.1080/00397911.2012.754470
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Synthetic Communications1, 43: 2980–2984, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.754470
CONCISE STEREOSELECTIVE TOTAL SYNTHESIS
OF (4R, 6R)-LACTONE MOIETY ANALOG
OF MEVINOLINE AND COMPACTIN
D. Chandra Rao, D. Kumar Reddy, B. Chinnababu,
V. Shekhar, and Y. Venkateswarlu
Natural Products Chemistry Division, Natural Products Laboratory,
Indian Institute of Chemical Technology, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A simple and highly efficient synthetic route has been developed for analogue of
HMGCo A reductase inhibitor (1). The strategy utilizes S-Corey–Bakshi–Shibata
(CBS) reduction, FeCl3-catalyzed C-H insertion of ethyl diazoacetate.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 for the following free supplemental resource: Full
experimental and spectral details.]
Keywords FeCl3; HMGCo A reductase inhibitor; S-CBS reduction
INTRODUCTION
Development of new synthetic strategies for the synthesis of biologically active
natural products and their analogs is always essential. Statins (or HMG-CoA
reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting
the enzyme HMG-CoA reductase, which plays a central role in the production of
cholesterol in the liver. Mevinoline (2), compactin (3), and simvastatin (4) were
isolated from Aspergillus terreus sp. (Fig. 1).[1–4] The simplified structural analog
of these inhibitors is b-hydroxy-d-lactone, which is essential for biological activity.[5]
b-hydroxy-d-lactone (1) is the common structural feature of all mevinic acids.[6] The
lactone moiety having (4R, 6R) configuration, closely resembles the HMG portion of
Received July 18, 2012.
Address correspondence to Y. Venkateswarlu, Natural Products Chemistry Division, Natural
Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India. E-mail:
luchem@iict.res.in
2980

SYNTHESIS OF (4R, 6R)-LACTONE
2981
Figure 1. b-Hydroxy-d-lactones.
the enzyme, acts as inhibitor by blocking the enzyme,[7,8] and reduces cholesterol
levels in blood by involvement in the rate-limiting step of cholesterol biosynthesis
in humans. Recently, we reported the synthesis of mevinic acid analog from
D-manitol.[9] Subsequently, Kumar et al. reported the synthesis of lactone moiety
from 4-phenylbutanal.[10] The biological activity of the lactone prompted us to estab-
lish an efficient route for synthesis of the lactone analog employing Corey–Bakshi–
Shibata (CBS) reduction to generate the (R) C-6-hydroxy methine configuration
present in compound 1. Further, the required two-carbon chain elaboration is car-
ried out by FeCl3-catalyzed C-H insertion of ethyl diazoacetate. The FeCl3 is a com-
mercially inexpensive and environmentally benign catalyst[11] as compared with
earlier reported reagents such as zeolites, MoO2Cl2, NbCl5, SnCl2, HBF4 ꢀ OEt2,
and yttria–zirconia employed for carbonyl insertion reactions.[12]
RESULTS AND DISCUSSION
Compound 1 was synthesized from the known a, b-unsaturated ketone[13]5,
which was reacted with (S)-(þ)-2-methyl-CBS-oxazaborolidine and BH3 ꢀ DMS at
ꢁ40 ꢂC to furnish allyl alcohol 6 with an (R)-configuration in 90% yield.[9] Allylic
alcohol 6 was protected as its tert-butyl(diphenyl)silane (TBDPS) ether using
tert-butyldiphenylsilyl chloride (TBDPSCl) to obtain compound 7, which on selec-
tive hydroboration with BH3 ꢀ DMS in tetrahydrofuran (THF) followed by treat-
ment with sodium hydroxide and H2O2, gave alcohol 8.[14] The primary alcohol in
8 was oxidized using 2-iodo-
xybenzoic acid (IBX) in dimethylsulfoxide (DMSO) to afford the corresponding
aldehyde in 90% yield, which was converted into b-keto ester 9 (80% yield) by the
reaction with ethyl diazoacetate in the presence of a catalytic amount of ferric chlor-
ide. Earlier we developed one methodology for preparation of long-chain esters
using FeCl3 via retro Claisen condensation. Now, we are reporting for the first time
the C-H insertion of aldehyde generated from compound 8, with ethyl diazoacetate
using FeCl3 at room temperature for 2 h to give compound 9.[11] The TBDPS ether in
compound 9 was removed using tetrabutylammonium fluoride (TBAF) to afford
d-hydroxy-b-keto ester 10 in 80% yield. The b-keto ester 10 was stereoselectively
reduced using catecholborane (2.2 equiv) to give syn-1,3-diol 11 in 95% yield with
high diastereoselectivity. The stereochemistry of the syn diol 11 was confirmed by
analyzing the 13C NMR spectral data of the corresponding acetonide 12, which
showed characteristic signals at d ¼ 19.8, 30.1, and 99.0 for two quaternary
methyls and methylene dioxy carbon respectively.[15] Finally, by the reaction 11 with

2982
D. C. RAO ET AL.
Scheme 1. Reagents and conditions: (a) S-CBS catalyst, THF, ꢁ40 ꢂC, BH3 ꢀ DMS, 2 h, 90%; (b)
TBDPSCl, imidazole, CH2Cl2, 0 ꢂC to rt, 4 h, 95%; (c) BH3 ꢀ DMS, THF, 0 ꢂC to rt, 4 h, NaOH, H2O2,
89%; (d) (i) IBX, THF, DMSO, rt, 3 h, 80%; (ii) FeCl3, N2CHCO2Et, DCM, rt, 2 h, 68%; (e) TBAF,
THF, 2 h, 85%; (f) catecholborane, THF, ꢁ10 ꢂC, 5 h, 95%; (g) PTSA, CH2Cl2, 3 h, 85%; and (h) PPTS,
acetone, 2,20-dimethoxy propane, 12 h, 90%.
p-toluenesulfonic acid (PTSA) in dichloromethane, furnished the target lactone 1 in
84% yield (Scheme 1). The spectral data (1H and 13C NMR) and optical rotation
25
f½aꢃD þ 47:2 (c 0.3, CHCl3)g of lactone 1 are in good agreement with the previously
reported compound.[9,16]
CONCLUSION
In conclusion, a new and efficient strategy has been developed to synthesize the
analog of HMGCo A reductase inhibitor (1) employing Corey–Bakshi–Shibata
(CBS) reduction, FeCl3-catalyzed C-H insertion of ethyl diazoacetate. FeCl3 is used
for the first time in C-H insertion of ethyl diazoacetate to build up the b-keto ester.
In addition, we have achieved synthesis of compound 1 in seven steps in 28.4% yield.
EXPERIMENTAL
All solvents and reagents were purified by standard techniques. Crude products
were purified by column chromatography on silica gel (Acheme Chemical 60–120
mesh). Melting points were obtained using a Buchi 535 melting-point apparatus
¨
and are uncorrected. Optical rotations were recorded on a Horiba polarimeter using
a 10 mm cell. Fourier transform–infrared (FT-IR) spectra were obtained using a
1
Thermo Nicolet Nexus 670 spectrometer. H and 13C NMR spectra were recorded
on Bruker Avance 300 and Varian Gemini 200 spectrometers using CDCl3 as the
solvent. Chemical shifts are reported in ppm (d) with respect to tetramethylsilane
(TMS) as the internal standard. Coupling constants (J) are quoted in hertz (Hz).
Mass spectra were obtained using a Micromass Quattro microTM API (Waters)
spectrometer or a high-resolution QSTARXL hybrid tandem mass spectrometry
(MS=MS) system (Applied Biosystems, US) spectrometer.

SYNTHESIS OF (4R, 6R)-LACTONE
2983
Ethyl 2-[(4R,6R)-2,2-Dimethyl-6-phenethyl-1,3-dioxan-4-yl]acetate
(12)[16]
Pyridinium p-toluenesulfonate (PPTS) (0.003 g, 0.0112 mol) was added to a sol-
ution of diol 11 (0.03 g, 0.112 mmol) and 2,2-dimethoxy propane (2.2 mL,
0.0156 mol) in dry acetone (5 mL) and stirred at rt for 12 h. After completion of
the reaction, NaHCO3 solution (5 mL) was added and extracted into ethyl acetate
(2 ꢄ 5 mL). The combined organic layer was concentrated under reduced pressure
to give the crude residue, which was purified by silica gel column (60–120 mesh)
(n-hexane–EtOAc, 9:1) to afford the acetonide 12 (30 mg, 90%) as a colorless liquid;
25
½aꢃD ¼ ꢁ9:5 (c 1, CHCl3). IR (neat, cmꢁ1): 2989, 2936, 1737, 1636, 1454, 1379, 1263,
1
1165, 1026, 950. H NMR (300 MHz, CDCl3): d ¼ 1.26 (t, J ¼ 7.1 Hz, 3 H,), 1.36 (s,
3 H), 1.41 (s, 3 H), 1.48–1.86 (m, 4 H), 2.25–2.53 (m, 2 H), 2.55–2.79 (m, 2 H)
3.69–3.82 (m, 1 H), 4.12 (q, J ¼ 7.1 Hz, 2 H), 4.14–4.26 (m, 1 H), 7.1–7.24 (m, 5 H).
13C NMR (75 MHz, CDCl3): d ¼ 14.2, 19.8, 30.1, 31.0, 37.0, 38.0, 41.5, 60.5, 66.0,
67.7, 99.0, 126.0, 128.4, 128.5, 142.0, 171.0. ESI-MS: m=z ¼ 329 [M þ Na]þ.
(4R,6R)-4-Hydroxy-6-phenethyltetrahydro-2H-2-pyranone (1)[16]
A catalytic amount of p-toluenesulfonic acid was added under an N2 atmos-
phere to a stirred solution of 11 (0.01 g, 0.037 mmol) in dry dichloromethane
(5 mL) and stirred at rt for 3 h. After completion of the reaction, the reaction was
quenched by the addition of solid NaHCO3 (0.005 g). The mixture was filtered,
and the solvent was removed under reduced pressure. The crude residue was purified
over a silica-gel column (n-hexane–EtOAc, 4:6) to afford 1 (7 mg, 85%) as colorless
25
solid, mp 108 ꢂC; ½aꢃD ¼ þ47:2 (c 0.3, CHCl3). IR (KBr, cmꢁ1): 3417, 2922, 2853,
1711, 1255. 1H NMR (300 MHz, CDCl3): d ¼ 1.0–1.5 (br s, 1 H), 1.71–2.09 (m,
4 H), 2.59–2.96 (m, 4 H), 4.32–4.39 (m, 1 H), 4.60–4.71 (m, 1 H), 7.11–7.30 (m,
5 H). 13C NMR (75 MHz, CDCl3): d ¼ 32.0, 36.0, 37.5, 38.6, 75.0, 77.0, 126.0,
128.3, 128.5, 141.1, 170.5. ESI-MS: m=z ¼ 243 [M þ Na]þ.
SUPPORTING INFORMATION
Detailed experimental procedures and compound characterization data for all
products are available online.
ACKNOWLEDGMENT
The authors are thankful to the Council of Scientific and Industrial Reserch,
New Delhi, India, for financial support.
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