Stereoselective Mukaiyama-Michael/Michael/aldol domino cyclization as the key step in the synthesis of pentasubstituted arenes: An efficient access to highly active inhibitors of cholesteryl ester transfer protein (CETP)

Article abstract of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3373::AID-ANIE3373>3.0.CO;2-F

Seemingly heartbreaking for a stereochemist, the one-step selective construction of a stereopentad and its prompt destruction by aromatization has been proven to be an efficient strategy for the synthesis of fivefold substituted, pharmacologically highly active arenes (see scheme).

Full text of DOI:10.1002/(SICI)1521-3773(19991115)38:22<3373::AID-ANIE3373>3.0.CO;2-F

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[5] B. M. Trost, Tetrahedron 1977, 33, 2615; B. M. Trost, Acc. Chem. Res.
1980, 13, 385. The allyl esters are used as protecting groups for
carboxylates and can readily be removed by Pd0 in the prescence of a
nucleophile: P. D. Jeffrey, S. W. McCombie, J. Org. Chem. 1982, 47, 587;
S. F. Bochnitschek, H. Waldmann, H. Kunz, J. Org. Chem. 1989, 54, 751.
further testing demanded an efficient synthesis in order to
pave the way for applying this innovative principle. We have
tried a number of different strategies and with the example of
1b we present here a multigram synthesis which features a
new domino reaction as the key step.
Â
For a recent example, see A. Cotte, B. Bader, J. Kuhlmann, H.
Waldmann, Chem. Eur. J. 1999, 5, 922.
[6] These X-ray crystal structure analyses will be published elsewhere.
[7] K. Moseley, P. M. Maitlis, Chem. Commun. 1971, 1604.
Stereoselective Mukaiyama ± Michael/Michael/
Aldol Domino Cyclization as the Key Step in
the Synthesis of Pentasubstituted Arenes: An
Efficient Access to Highly Active Inhibitors of
Cholesteryl Ester Transfer Protein (CETP)**
Three structural elements are the main contributors to the
complexity of 1b: the spirocyclobutyl system, two stereo-
centers in sterically demanding positions, and a central,
pentasubstituted benzene ring. The first retrosynthetic trans-
formation consisted of interconversion of the stereocenters to
a diketone system. Diketone 2b thus becomes a key
intermediate (Scheme 1). Disconnection of the central ben-
zene ring into approximately equally large fragments gives the
greatest possible simplification of 2b. The Mukaiyama ± Mi-
chael addition is recognized as one of the most reliable
Holger Paulsen,* Stefan Antons, Arndt Brandes,
Michael Lögers, Stephan Nicholas Müller, Paul Naab,
Carsten Schmeck, Stephan Schneider, and
Jürgen Stoltefuû
Dedicated to Dr. Pol Bamelis
on the occasion of his 60th birthday
In spite of a number of successes, the treatment of
arteriosclerosis is still a challenge for medicine. In addition
to a high LDL-C (low density lipoprotein cholesterol) level, a
low HDL-C (high density lipoprotein cholesterol) level is a
further, main independent risk factor for coronary heart
disease. Whereas the regulation of the LDL-C level by
blockade of cholesterol biosynthesis with HMG-CoA reduc-
tase (3-hydroxy-methylglutaryl coenzyme A) inhibitors[1] is
established medical practice, the increase in HDL-C levels
offers a new and promising therapeutic principle. HDL
absorbs cholesterol from the periphery, including the coro-
nary arteries, and carries it to the liver for metabolic
degradation. The action of cholesteryl ester transfer protein
(CETP) leads to a transfer of cholesteryl ester molecules from
HDL to LDL in a triglyceride exchange. The disadvantageous
net effect is a reduction in HDL-C level and an increase in
LDL-C level.[2]
Scheme 1. Retrosynthesis of 1b.
methods for the synthesis of 1,5-diketones.[4a] In addition to
the obvious 1,5-diketo structure, 2b contains a strategic
Â
carbonyl group concealed behind a ªKekule double bondº
of the central arene. The translation of the resulting synthones
into starting materials with alternating acceptor± donor polar-
ization leads to the reagents 3, 4, and 5 (Scheme 1).
Compounds of structure 1 have been identified as highly
1
active CETP inhibitors (IC50 ꢀ 3 nmolL ).[3] The complexity
The enolate formed by the Mukaiyama ± Michael addition
has already been trapped with aldehydes, acetals, and
orthoformates, or by a second, intramolecular Michael
acceptor.[4b,c, 5] An intermolecular Mukaiyama ± Michael/Mi-
chael/aldol cascade has to our knowledge not been previously
published. The underlying domino concept has already been
realized,[6] but the example illustrated here is unique in the
degree of substitution and the steric hindrance of the acceptor
components, especially 4.
The following concept (Scheme 2) was devised for 2b: silyl
enol ether 6 and 4 yield the enolate 7 under Mukaiyama
conditions. Its selective intermolecular 1,4-addition to the
chalcone 5 leads to the enolate 8, which gives 9 in an
intramolecular aldol condensation. The cyclization ends a
of this class of structures and the substance requirements for
[*] Dr. H. Paulsen, Dr. A. Brandes, Dr. M. Lögers, Dr. S. N. Müller,
Dr. P. Naab, Dr. C. Schmeck, Dr. S. Schneider, Dipl.-Ing. J. Stoltefuû
Bayer AG, Pharmaforschung
PH-R-CF Chemisch-wissenschaftliches Laboratorium
D-42096 Wuppertal (Germany)
Fax: (‡49)202-364061
E-mail: holger.paulsen.hp@bayer-ag.de
Dr. S. Antons
Bayer AG, PH-OP-CE Verfahrensentwicklung
[**] We thank Dr. J. Benet-Buchholz for the X-ray structure analysis and
colleagues of PH-R-Strukturchemie for providing the analytical data.
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the author.
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Scheme 2. Concept for the synthesis of the key compound 2b.
reaction sequence in which the complete carbon framework
of 2b is constructed. The silyl enol ether 6 was formed from
ketone 3 in the usual manner.[7] The (E)-chalcone 5 was
obtained in 95% yield by the acid-catalyzed aldol condensa-
tion of 4-(trifluoromethyl)acetophenone and 4-fluorobenzal-
dehyde. Following preliminary investigations with cyclohex-
enone the sterically demanding spiro compound 4 was
synthesized (Scheme 3). To this effect, the cyclobutanone 10
was first transformed into the enone 11 in a Wittig reaction.
ˆ
Scheme 3. Synthesis of 4. a) Ph3P CHCOCH3, silicon oil, 1008C, cat.
PhCO2H, 87%; b) CH2(CO2Me)2, NaOMe, MeOH, 658C; c) aq. KOH,
reflux, 20% hydrochloric acid, pH 3 ± 5, 99%; d) isobutanol, toluene, cat.
p-TsOH, azeotropic distillation; e) RedAl (65% in toluene), 40 ± 508C,
77% relative to 12. Ts ˆ 4-methylphenylsulfonyl, RedAl ˆ sodium bis-
(2-methoxyethoxy)aluminum hydride.
Scheme 4. Synthesis of 1b: a) TiCl4/Ti(OiPr)4 (3/1; i.e., 4 equiv of
TiCl3(OiPr)), dichloromethane, 58C, 42%; b) pyridine, SOCl2, 08C,
83%; c) NCS, cat. (PhCO2)2, dichloromethane, RT, 85%; d) DBU, dioxane,
5, 968C, 64%; e) (1R,2S)-1-aminoindan-2-ol (0.3 equiv), BH3 NEt2Ph
(3 equiv), THF, RT, 78%; 94% ee for the crude product; f) TBDMSCl,
NEt3, DMAP, DMF, 708C, 80%; g) LAH, THF, 08C !RT, 55% 17,
>99% ds; h) MnO2, dichloromethane, RT, 77% 16; i) DAST (Et2NSF3),
toluene, 708C ! 608C, 75%; j) TBAF, THF, RT, 87%, >99% ee,
>99% ds. NCS ˆ N-chlorosuccinimide, DBU ˆ 1,8-diazabicyclo[5.4.0]un-
dec-7-ene, TBDMS ˆ tert-butyldimethylsilyl, DMAP ˆ 4-(dimethylami-
no)pyridine, LAH ˆ lithium aluminum hydride, TBAF ˆ tetra-n-butylam-
monium fluoride.
The addition of dimethyl malonate and cyclization by Claisen
condensation followed by hydrolysis and decarboxylation
gave the dimedone analogue 12. Enol ether synthesis and an
ensuing reduction with RedAl gave the desired starting
material 4. In the key reaction, 6 and 4 in dichloromethane at
about
58C were transformed into rac-13 by successive
addition of four equivalents of TiCl3(OiPr) in dichlorome-
thane and 5 (Scheme 4).[8] After aqueous workup, the product
is readily isolated diastereomerically pure in 42% yield by
simple crystallization from petroleum ether. The all-equato-
rial arrangement of the substituents and the axial position of
the hydroxyl functionality were confirmed by X-ray structure
analysis.[9] Until now the formation of only one additional
diastereoisomer was detected to an extent of 10% or less.[10]
The aldol condensation to 9 illustrated in Scheme 2 was not
observed in spite of the antiperiplanar arrangement of the
hydroxyl group and the H atom a to the carbonyl group.[9] The
correct establishment of the required connectivities was all
that was needed to be achieved. Therefore, the excess of
molecular complexity which was produced with the stereo-
selectively generated stereopentad was dismantled by subse-
quent aromatization with removal of all stereocenters. The
sterically highly loaded cyclohexanol derivative 13 was thus
subjected to a double halogenation ± elimination sequence
with subsequent oxidation at the cyclohexadiene stage (see
Scheme 4).
The system resisted shorter aromatization strategies, for
example the catalytic dehydrogenation at the cyclohexene
stage, because of the all-trans arrangement of the hydrogen
atoms and the large increase in steric interactions. Only
reaction in a sulfur melt also afforded the arene 2b success-
fully.
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[4] a) K. Narasaka, K. Soai, Y. Aikawa, T. Mukaiyama, Bull. Chem. Soc.
Jpn. 1976, 49, 779 ± 783; b) T. Mukaiyama, S. Kobayashi, Heterocycles
1987, 25, 205 ± 211; c) N. Giuseppone, Y. Courtaux, J. Collin,
Tetrahedron Lett. 1998, 39, 7845 ± 7848.
[5] a) H. Hagiwara, A. Okano, H. Uda, J. Chem. Soc. Chem. Commun.
1985, 1047; b) P. G. Klimko, D. A. Singleton, J. Org. Chem. 1992, 57,
1733 ± 1740; c) H. Hagiwara, Y. Yamada, H. Sakai, T. Suzuki, M.
Ando, Tetrahedron 1998, 54, 10999 ± 11010.
[6] a) C. Wakselman, M. Mondon, Tetrahedron Lett. 1973, 4285 ± 4288;
b) G. H. Posner, S.-B. Lu, E. Asirvatham, Tetrahedron Lett. 1986, 27,
659 ± 662; c) G. H. Posner, E. Asirvatham, Tetrahedron Lett. 1986, 27,
663 ± 666; d) G. H. Posner, S.-B. Lu, E. Asirvatham, E. F. Silversmith,
E. M. Shulman, J. Am. Chem. Soc. 1986, 108, 511 ± 512; e) S. Marczak,
A mixture of the elimination products 14 and 9 was
obtained rapidly and in high yield by treatment of rac-13 with
thionyl chloride in pyridine. Allylic halogenation gave a
regioisomeric mixture which provided 2b after elimination in
the presence of an oxidizing agent. To introduce the stereo-
centers 2b was next regio- and enantioselectively reduced to
the oxoalcohol 15. A variant of the Corey ± Bakshi ± Shibata
(CBS) reduction makes use of cis-1-aminoindane-2-ol as the
source of chirality.[11] With this procedure, the tetralone
system in the highly sterically hindered 2b was reduced with
high enantioselectivity (94% ee in the crude product) and
yield (78% of 15 after crystallization) with complete differ-
entiation of the two oxo groups. After protection of the
hydroxyl functionality as the TBDMS ether (16) the internal
1,5-induction of the stereocenter mediated by the biphenyl
system permitted a diastereoselective reduction of the second
oxo function with LAH in favor of the desired isomer 17
(17:epi-17 ˆ 2.3:1). This was isolated from the mixture by
crystallization. The alcohols remaining in the mother liquor,
17 and epi-17, could be reconverted into 16 by oxidation of the
double benzylic position with manganese dioxide. By reaction
of the unprotected hydroxyl functionality with DAST
(Et2NSF3) 17 is converted with inversion into the fluoro
compound 18. The final deprotection with TBAF yields the
target compound 1b in diastereomeric and enantiomeric pure
form (>99% ds, >99% ee after crystallization).
Â
K. Michalak, Z. Urbanczyk-Lipkowska, J. Wicha, J. Org. Chem. 1998,
63, 2218 ± 2223; reviews: f) G. H. Posner, Chem. Rev. 1986, 86, 831 ±
844; g) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137 ± 170;
Angew. Chem. Int. Ed. Engl. 1993, 32, 131 ± 163; h) M. Ihara, K.
Fukumoto, Angew. Chem. 1993, 105, 1059 ± 1071; Angew. Chem. Int.
Ed. Engl. 1993, 32, 1010 ± 1022; i) L. F. Tietze, Chem. Rev. 1996, 96,
115 ± 136.
[7] a) H. O. House, L. J. Czuba, M. Gall, H. D. Olmstead, J. Org. Chem.
1969, 34, 2324 ± 2336; b) T. Bach, K. Jödicke, Chem. Ber. 1993, 126,
2457 ± 2466.
[8] Because of the oxygen-containing functional groups 2 ± 4 equivalents
of titanium reagent are necessary. According to reference [4a],
cyclohexenone and
6 are labile towards titanium tetrachloride.
TiCl2(OiPr)2 on the other hand proved to be too weak an inducing
agent for the desired reaction. TiCl3(OiPr) can be freshly prepared by
the (exothermic) mixing of TiCl4 and Ti(OiPr)4 in a ratio of 3:1 or by
parallel addition of both components. A modification of this reaction
has meanwhile been carried out on a kilogram scale.
ˆ
[9] The C OH und C O bonds are almost parallel. In addition, the IR
and 1H NMR spectra suggest a hydrogen bond between the two
groups (low-field shift and W-coupling of the OH hydrogen atom with
an H atom of the neighboring AB system). By complexation with
titanium this conformation should be maintained in the reaction
mixture. Thus, the p orbitals of the carbonyl group and the s C H
bond in the a position are almost orthogonal to each other. Therefore,
acidification of the a H atom lacks conjugative stabilization. In
addition, elimination leads to greater steric hindrance of the
neighboring substituents.
The present synthesis of 1b, in its longest linear sequence 14
steps, can be carried out without any chromatographic
purification and can be converted in a kilogram-scale process.
The way is thus open for the in-depth evaluation of CETP
inhibition as a therapeutic principle.
Experimental Section
1
[10] The H NMR spectrum of this diastereomer indicates the absence of
the intramolecular hydrogen bridge.
rac-13: To a solution of 6 (72 mmol) and 4 (60 mmol) in dichloromethane
(40 mL) are added simultaneously TiCl4 (183 mmol) and Ti(OiPr)4 within
30 min under argon at 7 to 18C. After 5 min solid 5 (60 mmol) is added,
during which time the temperature increases to 38C. The reaction mixture
is stirred for 5 min with cooling, then for 2 h at room temperature. After
workup with 1n hydrochloric acid, washing with water, drying over sodium
sulfate, and removal of the solvent the residue is crystallized from
petroleum ether. The product rac-13 is obtained in 42% yield.
[11] a) B. Di Simone, D. Savoia, E. Tagliavini, A. Umani-Ronchi,
Tetrahedron: Asymmetry 1995, 6, 301 ± 306; b) review: A. K. Ghosh,
S. Fidanze, C. H. Senanayake, Synthesis 1998, 937 ± 961.
Received: June 16, 1999 [Z13574IE]
German version: Angew. Chem. 1999, 111, 3574 ± 3576
Keywords: asymmetric synthesis ´ cyclizations ´ domino
reactions ´ drug research ´ Mukaiyama ± Michael additions
[1] ªStatinsº such as cerivastatin; reviews: a) R. S. Rosenson, Arch.
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Lipidol. 1995, 6, 360 ± 364.
[2] a) M. Sugano, N. Makino, S. Sawada, S. Otsuka, M. Watanabe, H.
Okamoto, M. Kamada, A. Mizushima, J. Biol. Chem. 1998, 273, 5033 ±
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J. L. Breslow, A. R. Tall, Arterioscler. Thromb. Vasc. Biol. 1999, 19,
1105 ± 1110; c) review: C. G. Stevenson, Crit. Rev. Clin. Lab. Sci. 1998,
35, 517 ± 546.
[3] Significant HDL-C increase in hamsters and hCETP mice at doses of
<1 mgkg 1 p.o. (p.o. ˆ per os, oral administration).
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