Scribd Logo
Importer

Bienvenue sur Scribd !

  • Thomas Hudlicky Et Al - A Model Study Directed Towards A Practical Enantioselective Total Synthesis of (-) - Morphine

    Transféré par

    PoloGreen
    78 vues5 pages

    Titre original

    Thomas Hudlicky et al- A Model Study Directed Towards a Practical Enantioselective Total Synthesis of (-)-Morphine

    Copyright

    © Attribution Non-Commercial (BY-NC)

    Formats disponibles

    PDF ou lisez en ligne sur Scribd

    Avez-vous trouvé ce document utile ?

    Ce contenu est-il inapproprié ?

    Signaler ce document

    Droits d'auteur :

    Attribution Non-Commercial (BY-NC)
    Téléchargez comme PDF ou lisez en ligne sur Scribd
    Signaler comme contenu inapproprié
    78 vues5 pages

    Thomas Hudlicky Et Al - A Model Study Directed Towards A Practical Enantioselective Total Synthesis of (-) - Morphine

    Transféré par

    PoloGreen

    Droits d'auteur :

    Attribution Non-Commercial (BY-NC)
    Téléchargez comme PDF ou lisez en ligne sur Scribd
    Signaler comme contenu inapproprié
    sur 5
    174 Papers SYNTHESIS, A Model Study Directed Towards a Practical Enantioselective Total Synthesis of (—)-Morphine ‘Tomas Hudlicky,* Christie H. Boros, Eric E. Boros Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA Received 13 September 1991; revised 9 October 1991 A tricyclic rng system 10 containing the stercogenic centers of the ‘nonaromatic portion of morphine (1) has been prepared in eight sleps from toluene by the combination of microbial oxidation and intramolecular Diels-Alder cycloaddition followed by 2 Cope rearrangement, Experimental and spectral data are provided forall key compounds and potential for a short synthesis of morphine is indicated Introduction ‘The elements of control over synthetic transformations have been refined over the years so that methodologies are now available to provide outstanding degrees of selecti- vity in the regio-, stereo-, and enantiomeric domains of synthesis. Increasingly, the issues of brevity, efficiency, and therefore overall practicality have also surfaced and will soon dominate those synthetic endeavors that are destined to furnish real solutions to current problems defined by pharmaceutical and medicinal communities Examples of recent union of artful design with the utmost in chemical efficiency can be seen in the synthesis of cedrene in four steps by Wender and Howbert,’ the preparation of lycopodine® and daphnilactone A by Heathcock et.al. in eight steps and eleven steps, respecti- vely, the formation of the taxane skeleton in five steps by Holton,* and the preparation of both enantiomers of pinitol in six steps in our laboratories.* From simple consideration of yields of chemical reactions, especially when such considerations are realistic,® it becomes ob- vious that an arbitrary limit of about ten operations can be placed on any total synthesis in order for it to be practical. With these criteria in mind we approached a significant challenge; namely, a practical synthesis of morphine. In this manuscript we report on the first two ‘model studies designed to provide information about the topology of the intermediates and the disposition of their stereogenic centers. The strategic disconnection from morphine to two optically pure subunits that form the intermediate 3s shown in Scheme 1. These subunits may ultimately be derived from styrenes by biocatalytic means.” Ho, Scheme 1 a Results and Discussion Morphine (1) remains a formidable target for total synthesis. None of the published syntheses" are suitab- Ie for commercial application.*® We envisioned an ap- proach to 1 by an intramolecular union of two fragments in 3 using a 4+2 cycloaddition (Scheme 1). The two halves would be accessible via microbial oxidation of the corresponding arenes by Pseudomonas putida. To test the steric integrity and the overall viability of this plan, we chose to perform a simple model study which would yield appropriate information with regard to the five stereoge- nic centers in the nonaromatic region of 1, We assumed that the formation of the ethylamino bridge would be one of the last operations, and therefore the target of this study would contain the asymmetric centers present in 2 For this model study (Scheme 2), we chose to use the cis-diol 4 which is obtained in enantiomerically pure form in multigram quantities from the microbial oxidation of toluene by Pseudomonas putida strain 39D.2"!° The diol 4 was selectively protected at the less-hindered hydroxy group by treatment with imidazole and dimethylthexylsi- Iyl chloride (THSCI) to yield 5 (93%) as the only protection product (Scheme 2). Treatment of § with sodium hydride in THF followed by addition of sorbyl bromide"! provided ether 6. oo ae BReTHs 1S = simethlteny ey = dane} 2-trimty rena (@) THSCVimidazole/DMF, 0°C, 18h. (6) Natl/sorbyl bromide THE, 0°G, then ft, 30h. (¢) CCl, 77°C, Th. (4) BuNF-3H,0) THE, rt, 24h, (@) PCCICH,Chy, #-t, 21h. (0) ylenes, 280°C (sealed tube). 22h. (g) NaBH, /CeCl, *7H,0/MeOH, r.t. 15 min, Scheme 2 January/February 1992 Two possibilities for intramolecular Diels-Alder reac- tions exist in 6: (1) combination of the diene a,6 with enophile , or (2) reaction of the more proximal side-chain olefin a with the diene ¢,d of the ring. A Diels-Alder reaction similar in regiochemistry to the latter was applied in the total synthesis of zeylena.” When a ca 0.02 M solution of 6 was refluxed in CCl, (77°C) for several hours, the adduct 7 was obtained and none of adduct 9 (Path A, Scheme 2) was detected. It remains to investigate whether transition-metal-catalyzed [4 + 2] cy- cloadditions'?" will alter this regiochemistry, Despite the observed regiochemistry in the intramolecu- lar cycloaddition of 6, we noted that adduct 7 could undergo a Cope rearrangement restricted to a boat-like transition state geometry to yield the desired framework in 9 (Path B, Scheme 2). Unfortunately, even the most vigorous attempts at this conversion were unsuccessful, and it became evident that some driving force would be necessary in order for the reaction to proceed. The simplest method seemed to be the oxidation of the hydroxy group in the deprotected adduct 8, allowing the formation of an a,f-unsaturated ketone 12 as a result of the Cope rearrangement. To this end, 7 was treated with tetrabutylammonium fluoride in THF to yield the alcohol 8 (82%) which was oxidized in 94% yield to ketone 11 with pyridinium chlorochromate in dichloromethane. As anticipated, 11 underwent the Cope rearrangement to provide the enone 12 (88%, Path C, Scheme 2) Iti interesting to note that, the overall topology observed in the synthesis of 12 (a regiochemistry not favored in the intramolecular cycload- dition of 6) is ultimately derived by a sigmatropic rearrangement via the observed regioisomer 7. The absolute stereochemistry of the five chiral centers in 12 ‘was determined by NOE experiments, extrapolating from the known stereochemistry of the chiral centers in the starting cis-diol 4, Reduction of the enone 12 with sodium borohydride in the presence of CeCl, *7H,0"* procee- ded with great facility providing a single diastereomeric alcohol 10 (98%). The stereochemistry illustrated for 10 is based on the reasonable assumption that hydride ion is delivered on the less hindered convex face of 12 which was also supported by NOE experiments. Assimplified model study which eliminates regiochemistry problems has been accomplished as shown in Scheme 3 In a preliminary experiment, triene 15, prepared from 4 via diimide reduction,'® hydroxy group protection, and subsequent alkylation, underwent intramolecular cyclo- addition at 210°C to the adduct 16 (68%). Optimum ‘conditions for this transformation, including nickel-'? and rhodium-mediated'? cyclizations, are being pursued. The feasibility of paths A and B (Scheme 2) remains to be investigated in detail in order to shorten the synthesis of 10. A third model study (17 -+18; Scheme 4) is planned to establish the intramolecular alkylation protocol and hence the formation of the ethylamino bridge prior to the effort toward the synthesis of 3 and application to the total synthesis of morphine (I). SYNTHESIS 175 tom) RO e HS Ro” Te Re THs (a) KO,CN=NCO,K/HOAc(MeOH, 0°C to .t. (b) THSCY/imid- azole|DMF, 0°C, 18h. (c) Nali/sorbyl bromide/THE, 0°C, then 1, 48h. (@) toluene, 210°C (sealed tube), 24h, Scheme 3 TH80” 7 Scheme 4 Conclusion In summary, an interesting tandem Diels~Alder/Cope strategy proved to be a viable stereo- and regioselective route to the desired ring system in 9, 10, and 12 which contain the necessary stereogenic centers, thus serving as models for the synthesis of 1. Assuming an intemal Sy2-like displacement for the formation of the ethylami- no bridge in 18, the completion of these studies will allow a focused pursuit of the synthesis of 1 as outlined in Scheme 1 SHINMR spectra were recorded in CDCI (ref. 8 = 7.24) at 200,270 and 400 Milzon Briker WP-200, Briker WP-270, and Varian Unity 400 instruments, respectively. !9C NMR spectra were recorded in CDCI, (re. 6 = 770) at $0 and 100 MHz on Briker WP-200 and Varian Unity 400 instraments respectively, and multiplicities were deermined by DEPT experiments. THF and F1,0 were disiled from sodium/benzophenone. CH,Cl, and hexanes were distilled ftom Cal, EWOAC and CCl, were HPLC grade. Flash column chromatography was performed on Merck silica gel (grade 60, 230-400 mesh). Air- and moistue-sasitive reactions were carried out in lame-dried reaction vessels under argon using oven-ri syringes. Elemental analyses were performed by Atlantic Microlabs, Norcross, GA (2R,3S)-cis-1-Methyleyclobexa-4,6-diene-2-4iol (: ‘Pseudomonas putida strain 39-D (Pp 39D) were grown in a B. Braun Biostat E 15 L fermenter in 8 L of mineral salts broth modified from that of Gibson:* Solution A (320mL), Solution B (160 mL), Solution C (120 mL), and L-arginine (40g) were combined and diluted to 6200 mL with distilled water and sterilized. p-Fructose (160 g) was diluted to 2000 mL with distilled water and sterilized before being combined with the mineral salts broth. The pH was ‘maintained at nominally 7.2 during the course of the oxidation by the automated addition of 5 M aq NH. The sticing rate was 250, pm, and toluene (125 mL) was bubbled through the fermenter over 2 period of 41.5 h when massive cell death occurred. About 2L of broth were lost during the course of the reaction to foaming. (Later fermentations utilized the addition of oxygen gas during. the {fermentation to maintain the oxygen level at about $0% ofthe initial 176 Papers dissolved oxygen content. This decreased foaming significantly and ‘increased the rate of eell growth.) The remaining 6 L (pH = 7.8) were processed by continuous centrifugation to remove cells, basification with 10 M aq NaOH topH = 8.8, saturation with NaCl, andextraction with base-washed EtOAc (12 x 300 mL). The organic layer was dried (Na,SO,), filtered, and concentrated in vacuo to yield 23.1 g of crude 4 which was reerystalized from EtOAc and hexanes. (2R,35)cs-3-Dimethy\11,2-trimethylpropyDsiloxy-I-methyleyco- hee edien al) The diol 4 (1.36, 10.79 mmo) was dissolved in DMF (20 mL Imidezole (054g, 126 mmol) was added fllowed by chloro- dimthy(,1,2-cimethyipropy)slane (dimethylthexylsi chloride, 2.24, 1256 mmol), and the resulting solution allowed to stand at 0°C for 18h. The mixture was dls with E10 (60 mL) and ‘washed with brine (325 mL). The brine was backestracted with Et,0 (3 15mL), and the combined organic layers were washed with sat. CuSO, Gxx30mL), HO (1x30mL), and brine (1x 30mL). The Organic layer was dried (Na,S0,) tered, and concentrated in vacuo to give Sas a yellow ol (4 g) which was chromatographed on silica gel (10% deactivated with H,O) eluting With $% base-washed ElOAcjhexanes to provide pure as colores oil; yield 2.69 g (3%): ap + 86.11 € = 1.26, CHC) HRMS: mz, CysH,404Si caled: 268.1859; found: 268.1860 IR (ueaty ¥ = 3557, 2988, 2867, 1465, 1396, 1252, 1091, 832, men! AH_NMR (CDCL): 5 = 0.13 (s, 6), 0.84 (5 6H), 0.87 (4, 6H, J = 68 He), 1.62 (Septet, 1H, J'= 68 Hz), 1.90 (4d, 3H, J = cx 0.62), 258 4,11, J = 48 He), 385(4 1H, J = 5312) 440 (m, 119), 588 (dd, 1H, Y= 9.6, 27 Tia, 8.70 (m, 11), 5.83 (ddd, 1H, = 956,53, 17H). (5S,6R)cis-S-Dimethy\1,1,2-rimethylpropy?silony-6-(2,4-hexadi- ‘eayloxy)-L-methyleyclobexa-1,3-ene (6: ‘Asoluion ofthe THS-protected diol 5 (294g, 10.95 mmol in THF (2SmL) was added dropwise to a stirring slurry of NaH (460 mg, 19.16mmol) in THE (5 mL) cooked to ~5°C. The resulting mixture ‘was sired for 10 min at this temperature followed by the rapid addition of sorbyl bromide 2.31 g, 14.4 mmol) in THF (20 mL), ‘The mixture was allowed to warm to r-t. and was stirred an additional 30 h during which timea thick orange precipitate formed, ‘The reaction was quenched with H,O (25 mL) and extracted with B1,0 3x40 mL). The combined E1,0 extracts were washed with 1,0 (50 mL) and brine (50 mL) and dried (Na,S0,). Filtration and concentration in vacuo provided 4.7 g of clear orange oil which was carried immediately on to the next step. Partially purified 6 was obtained by repeated flash chromatography on silica gel (deact- vated with 10% water) using hexanes/E1OAC. SHNMR (CDC): 6 = 0.13 (5, 6H), 0.86 (5, 6H), 089 4, 6H, 9 Hz), 1.66 m, 14), 1.72 (, 1H, J = 68 He), 1.87 (6, 3H), (4,11, J = 6.0 2), 403 (6d, 1H, J = 125, 7.2), 424 (4d, 25, 6.0 Hz), 4.47 (rm, 1 HD, 5.56 (dd, 1H, J = ca. 6.7 Hz), (i, 1H, J = 65, 6.1 Ha), 5775.69 (, 21), 5.80 (ddd, 1H, 7,52, 3.1 Ha), 398 (dg, 1H, J = 1033, 14 H2), 613 (dd, tH, 29, 10.3 Ha). 88 NMR (CDCI): 6 = —26 (2xCH,), 179 (CH), 187 (2xCH,), 204 @x CHy), 20.8 (CH), 251 (©), 343 (CH), 709 (CH, 71 (CH), 728 (CH), 121.2 (CH), 1233 (CH), 1280 (CH), 129 (CH), 1300 (CH), 131.2 (CH), 132.6 (CH), 136.0 ©. (1R25,3R6R,75,10R)2-Dimethy\(1,1,2-rimethylpropyDsiloxy.7- rmethy-10--propenl)-4-oxatricclo63.1.0° 'Wec-B-

    Vous aimerez peut-être aussi