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J. Org. Chem. 1997, 62, 6374-6378
Enantioselective Total Synthesis of the (-)-(6R,11R,14S)-Isomer of Colletallol Sonia J. Amigoni,† Loı¨c J. Toupet,‡ and Yves J. Le Floc’h*,† Synthe` ses et Activations de Biomole´ cules, CNRS ESA 6052, Ecole Nat. Sup. de Chimie de Rennes, av. du Ge´ ne´ ral Leclerc, 35700 Rennes, France, and Groupe Matie` re Condense´ e et Mate´ riaux, CNRS URA 804, Universite´ de Rennes, av. du Ge´ ne´ ral Leclerc, 35042 Rennes Cedex, France Received January 2, 1997X
The total synthesis of the (-)-(6R,11R,14S)-isomer of colletallol was achieved in 15 steps. The key steps of the sequence were the building of the macrocycle via two consecutive Wittig reactions, the first intermolecular and the second intramolecular, instead of the classical macrolactonization methods. The family of macrodiolide antibiotics consists of two classes of natural compounds displaying interesting biological properties.1 The first class consists of 16membered macrocycles with C2 symmetry, such as pyrenophorol, pyrenophorin, and vermiculin. The second class comprises those compounds possessing an unsymmetrical 14-membered macrocycle such as colletallol (1), colletol, colletoketol, and colletodiol.2 Quite recently, two novel metabolites possessing a 13-membered macrocyclic ring, bartanol and bartallol, have been also isolated.3 Many syntheses of macrodiolides have been reported already.2 However, in order to obtain detailed structureactivity relashionships in these series, it appears important to design a versatile synthetic scheme giving a unified access to the natural macrodiolides, their stereoisomers, and selected structural analogues. Towards this goal we proposed a strategy involving two key points: (a) the use of two consecutive Wittig reactions to build efficiently the macrodiolide with a complete control of the ring size4 and (b) the use of a versatile key intermediate (enone 2) for the control of the stereogenic centers.5 To fully demonstrate the potential of this approach, we selected the colletallol derivative 1 as a target molecule. Since the natural product (6R,11R,14R) has been already prepared and was found biologically inactive, its (6R,11R,14S) isomer was chosen in order to start some structure-activity data in this family. Our strategy was clearly formulated in previous papers.2,4-6 The retrosynthetic Scheme 1 shows the two fragments that join by the means of two successive Wittig reactions. The lower segment can be prepared from the polyfunctional enone 2, for which the synthesis and asymmetric reduction were described recently.5 The †
CNRS ESA 6052. CNRS URA 804. Abstract published in Advance ACS Abstracts, August 1, 1997. (1) Omura, S. Macrolide Antibiotics: Chemistry, Biology and Practice; Academic; New York: 1984; pp 538-541. (2) For full documentation about macrodiolides up to 1995, see: Amigoni, S. J. Ph.D. Thesis, Rennes I University, 1996, and Le Floc’h, Y.; Dumartin, H.; Gre´e R. Bull. Soc. Chim. Fr. 1995, 132, 114-118. (3) Hanson, K.; O’Neill, J. A.; Simpson, T. J.; Willis, C. L. J. Chem. Soc., Perkin Trans. 1 1994, 2493-2497. (4) Yvergnaux, F.; Le Floc’h, Y.; Gre´e, R. Tetrahedron Lett. 1989, 30, 7397-7398. Le Floc’h, Y.; Yvergnaux, F.; Gre´e, R. Bull. Soc. Chim. Fr. 1992, 129, 62-70. (5) Dumartin, H.; Le Floc’h, Y.; Gre´e, R. Tetrahedron Lett. 1994, 35, 6681-6684. Contrary to an earlier report from one of us, the reduction of enone 2 with the (S)-CBS reagent gave an allylic alcohol with (S)-configuration; the right columns of Tables 1 and 2 in the cited article thus concern the ratio 7/6 and not 6/7. (6) Dommerholt, L. J.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1991, 32, 1495-1498. ‡
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S0022-3263(97)00020-0 CCC: $14.00
Scheme 1
upper segment is easily accessible in two steps from commercial (R)-ethyl 3-hydroxybutanoate (3). Results and Discussion The purpose of this paper is to report the total synthesis of the colletallol isomer 1. One of the key points during the synthesis was the protection of the alcohol function at C11: the p-anisyl group proved to be the best choice since it is easily introduced by a Mitsunobu-type procedure and is efficiently removed under mild conditions during the last step. The synthesis started with the preparation of the protected enone 25 followed by a diastereoselective reduction with the oxazaborolidine derived from (S)-2-(hydroxydiphenylmethyl)pyrrolidine and bis(trifluoroethyl) n-butylboronate according to Corey and Link.7 This procedure was simpler and easier to reproduce than the initially described CBS method8 (Scheme 2). This reduction by BH3-Me2S as the reductant and with 1 equiv of oxazaborolidine at rt in THF afforded allylic alcohol 4 (86%) in 95% de. The (S)-configuration of the newly created asymmetric carbon was inferred later by an X-ray structural analysis of the target compound 1. On the basis of the mechanistic studies of Corey et al.,9 we have to consider the acetal group as the smaller one although this statement seems to be counterintuitive. This could be explained by the possible steric hindrance during the reaction between the phenyl groups of the catalyst and those of the protecting group (7) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 4141-4144. (8) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614. (9) Corey, E. J.; Azimioara, M.; Sarshar, S. Tetrahedron Lett. 1992, 33, 3429-3430.
© 1997 American Chemical Society
Enantioselective Synthesis of (-)-(6R,11R,14S)-Colletallol Scheme 2a
J. Org. Chem., Vol. 62, No. 18, 1997 6375 Scheme 3a
a (i) (S)-CBS-nBu, BH ‚Me S, THF, rt (86%); (ii) H , Pd/C 10%, 3 2 2 AcOEt, rt (68%); (iii) p-MeOC6H4OH, PPh3, DEAD, THF, 80 °C (85%); (iv) nBu4N+F-, THF, rt (81%).
on the γ-hydroxyl function of enone 2. This hypothesis did not find any confirmation in the literature. Allylic alcohol 4 was then hydrogenated under standard conditions (10% Pd/C) in good yield to give the saturated alcohol 5. It was necessary to protect the free secondary hydroxyl group. After many studies, the protection of this alcohol 5 as a p-anisyl ether was found to be the best solution. We also verified that the deprotection of this secondary alcohol could be achieved in acceptable yield while sparing the various functionalities present in the molecule. According to the literature,10 p-methoxyphenyl ethers can resist various drastic acidic, basic, and oxidative conditions. The formation of p-anisyl ethers from secondary alcohols has already been used by Corey and Link11 to invert an asymmetric carbon. We found that this protection was conveniently achieved via a Mitsunobu reaction (PPh3, DEAD) with p-methoxyphenol in THF at 80 °C for 3 h. Compound 6 was obtained in good yield (85%). In agreement with preceding results, this reaction proceeded with inversion of configuration as unambiguously established by 1H (400 MHz) and 13C (100 MHz) NMR analysis. The comparison of chemical shifts for the H1, C3, and C4 signals of 5 (2S,5S) and deprotected 6 (2R,5S) showed that they were diastereomers. The protected diol acetal 6 was submitted to the action of the tetrabutylammonium fluoride to afford 7 (81%). This monoprotected diol possesses two asymmetric centers, each of which can be independently set, and so this basic strategy could be used for the construction of several isomers of macrodiolides such as pyrenophorol and colletallol. The alcohol 7 (Scheme 3) was esterified using bromoacetyl bromide and pyridine in CH2Cl2 at -20 °C to give the bromo ester 8a (86%) which was converted almost quantitatively into the phosphonium salt 8b by addition of triphenylphosphine. Concurrently, the commercial (R)-ethyl 3-hydroxybutanoate (3) was transformed into the corresponding aldehyde 9b by almost quantitative silylation of the free hydroxyl function under classical conditions (ClSi+BuPh2, imidazole, DMF, rt)12 followed by reduction of the ester by DIBALH at -78 °C according to Baker’s method13 to give aldehyde 9b in 87% (10) The p-methoxyphenyl group has been used in order to protect some primary alcohols: Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985, 26, 6291-6292. Petitou, M.; Duchaussoy, P.; Choay, J. Tetrahedron Lett. 1988, 29, 1389-1390. To our knowledge, this is the first time that this group has been used for the protection of a secondary alcohol. (11) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 3431-3434. (12) Hopkins, M. H.; Overman, L. E.; Rishton, G. M. J. Am. Chem. Soc. 1991, 113, 5354-5365.
a (i) BrCOCH Br, pyridine, CH Cl , -20 °C (86%), (ii) PPh , 2 2 2 3 CH3CN, rt (94%); (iii) ClSitBuPh2, imidazole, THF, rt (96%), (iv) DIBALH, Et2O, -78 °C (87%); (v) TEA, CH3CN, 40 °C (74%); (vi) nBu4N+F-, THF, rt (73%); (vii) BrCOCH2Br, pyridine, CH2Cl2, -20 °C (90%); (viii) HCOOH, rt (93%); (ix) PPh3, CH3CN, rt (quant); (x) TEA, CH3CN, high dilution, 70 °C (65%); (xi) CAN, CH3CN/ H2O, 0 °C (70%).
yield. The phosphonium salt 8b was treated with 0.8 equiv of TEA to generate in situ the corresponding phosphorane which was condensed with 1.5 equiv of the aldehyde 9b in CH3CN to give enoate 10 in good yield (74%). The exclusively (E)-configuration of the double bond was established by the large (15.8 Hz) vicinal coupling observed between the olefinic protons. At this stage of the synthesis, the upper segment of the target molecule has been introduced with a new asymmetric center. The cleavage of the silyl ether 10 was next achieved with tetrabutylammonium fluoride in THF (Scheme 3). These conditions afforded alcohol 11a in good yield. Esterification with bromoacetyl bromide proceeded smoothly to afford 11b. Deprotection of the aldehyde function in neat formic acid for 12 h at rt then yielded 12 (93%) (Scheme 3). The addition of triphenylphosphine generated the phosphonium salt which was directly dissolved in a large volume of acetonitrile. This dilute solution (4 × 10-2 mol/ L) was added over 35 h to a solution of 6 equiv of TEA in CH3CN heated at 70 °C. These high-dilution conditions allowed the cyclic monomer 13 to be formed exclusively in relatively good yields (65%). This intramolecular (13) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983, 48, 5180-5182.
6376 J. Org. Chem., Vol. 62, No. 18, 1997
Wittig reaction afforded the (E)-alkene as established by the large (15.7 Hz) vicinal coupling between the olefinic protons. The (E)-configuration of the double bonds and the configurations of the three asymmetric carbons of the molecule were verified by X-ray crystallographic analysis. Cleavage of the p-anisyl ether with CAN in aqueous acetonitrile at 0 °C afforded the (-)-(6R,11R,14S)-isomer of colletallol 1 in 70% yield; the structure was again unambiguously established by X-ray crystallography.15 This total synthesis gave the desired colletallol stereoisomer 1 in 15 steps and 4% overall yield. It is important to note that the enantiomers of the starting building blocks are commercially available and that the two esterifications with bromoacetyl bromide could be achieved using bromoacetic acid under Mitsunobu conditions14 with inversion of configuration at the asymmetric centers. Similarly, the asymmetric reduction of enone 2 by Corey’s (R)-oxazaborolidine gives allylic alcohol 4′ (2R,5S) with the same de as previously reported for the (S)-enantiomer and in good yields. Thus this strategy is extremely flexible and should be useful for the preparation of any stereoisomer of colletallol. It could be similarly developed for the synthesis of the symmetrical 16-membered macrodiolides such as pyrenophorol2 for instance.
Experimental Section General Procedures. Melting points are uncorrected. Optical rotations were measured at 25 °C. IR spectra were recorded on a FT-IR spectrometer. 1H NMR spectra were recorded at 400 MHz and 13C NMR at 100 MHz in CDCl3. Mass spectra were obtained at 70 eV either in EI mode (HRMS) or using CI/NH3 (MS). Elemental analyses were performed by the Service de microanalyses (ICSN Gif sur Yvette). All separations were carried out under flash chromatographic conditions on Merck silica gel Geduran Si60 (230-240 mesh) using as eluent mixtures of ether (E) and low-boiling (
