Asymmetric synthesis of (R)-2-[3-(methoxymethoxy)propyl]- 3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one

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Azasilanes have excellent bioactivities; however, asymmetric synthesis of azasilinan-6-one with a substitution at the second potion has been investigated very little. In this paper, (R)-2-[3-(methoxymethoxy)propyl] -3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one was successfully synthesized.

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Nội dung Text: Asymmetric synthesis of (R)-2-[3-(methoxymethoxy)propyl]- 3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one

JOURNAL OF SCIENCE OF HNUE Chemical and Biological Sci., 2014, Vol. 59, No. 9, pp. 3-10 This paper is available online at http://stdb.hnue.edu.vn ASYMMETRIC SYNTHESIS OF (R)-2-[3-(METHOXYMETHOXY)PROPYL]- 3,3-DIPHENYL-1-TOSYL-1,3-AZASILINAN-6-ONE Duong Quoc Hoan1 and Scott McN. Sieburth2 1 Faculty of Chemistry, Hanoi National University of Education 2 Department of Chemistry, Temple University, the United States of America Abstract. Azasilanes have excellent bioactivities; however, asymmetric synthesis of azasilinan-6-one with a substitution at the second potion has been investigated very little. In this paper, (R)-2-[3-(methoxymethoxy)propyl] -3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one was successfully synthesized. The chiral center of silylsulfinamide was prepared by the addition of silyl lithium to (R)-Davis’ chiral sulfinimine. Cyclization of δ-amino carboxylic acid gave 1,3-azasilinan-6-one that can be an important product to synthesize 2-substituted 1,3-azasilinan rings. Structures of all new compounds were confirmed by IR, 1 H and 13 C-NMR, along with the exact mass. Keywords: Synthesis, (R)-2-[3-(methoxymethoxy)propyl]-3,3-diphenyl-1-tosyl-1,3- -azasilinan-6-one, IR, 1 H and 13 C-NMR. 1. Introduction Nitrogen-containing heterocycles constitute structural frameworks in a plethora of pharmaceuticals and alkaloids and are essential components of the pharmacophore [2, 3, 6]. In recent years, there has been an interest in the preparation of heterocycles in which one of the ring carbons has been replaced by silicon atoms. A few bioactive silicon-nitrogen heterocycles have thus far been synthesized and screened for bioactivity. For example, the dopamine receptor antagonist silahaloperidol 1 (Figure 1) displays improved selectivity compared to haloperidol. Furthermore, its metabolic fate in human liver microsomas does not produce a silicon analogue of the neurotoxic metabolite HPP+ (Hereditary pyropoikilocytosis), which is responsible for the severe side effects of haloperidol [4]. Other heterocyclic sila analogues have been prepared, including a class of spirocyclic acceptor ligands, such as 2 [5] the neurotropic tetrahydroisoquino-line sila Received January 2, 2014. Accepted August 15, 2014. Contact Duong Quoc Hoan, e-mail address: hoanqduong@gmail.com 3
Duong Quoc Hoan and Scott McN. Sieburth analogue 3 [5] and the silicon analogue 4 [9] of the anti-depressive agent dimetracrine (Figure 1). Another important compound in the biorganosilicon area is a sila analogue of proline prepared enantioselectively by Vivet et al. [8]. Figure 1. Examples of bioactive silicon-nitrogen heterocycles Annaliese K. Franz et al. have a detail review of advantages gained when carbons are replaced by silicon for bio-activities and medicinal properties of silicon containing compounds. Because it is larger than carbon, the silicon plays an important role in increasing lipophilicity, and flexibilities of organosilicon molecules often enhances cell and tissue penetration and alter the potency and selectivity of the silicon structure relative to the carbon structure [1]. Scheme 1. Retrosynthesis of 1,3-azasilinan-6-one (5) Different approaches have been developed to prepare such heterocyclic systems containing silicon and nitrogen [1, 8]. However, few syntheses have targeted 2-substituted 1,3-azasilaheterocycles. These include the reaction of a bishaloalkylsilane with a primary amine and a nonregioselective aminomercuration which yielded a 2-substituted azasilinane as a by-product [1]. In this paper, a flexible and efficient approach to the stereo controlled synthesis of a 2-substituted-1,3-azasilinan-2-one is reported. The synthetic route is outlined in Scheme 1, whereby the azasilaheterocycle 5 can be formed by an intra 4
Asymmetric synthesis of (R)-2-[3-(methoxymethoxy)propyl]- 3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one molecular cyclization, respectively. The substrates 6 would be prepared from sulfinimine 7 and silyl lithium would be made from lithiation of 8, a strategy recently and successfully developed by Sieburth’s group. 2. Content 2.1. Experiment All IR spectra were recorded on a Mattson 4020 GALAXY series FT-IR (Germany). NMR spectra were studied on 400 Bruker and Avance III 500 spectrometers (Germany). The Perkin Elmer Model 341 Polarimeter was used to obtain optical rotations. * 3-(Diphenylsilyl)propan-1-ol (8) To a solution of diphenylsilane (9) (10.0 g, 54.3 mmol) in heptane (150 mL) was added allylic alcohol (5.5 mL, 65.2 mmol), tert-dodecylmercaptan (1.2 mL, 5.4 mmol) and AIBN (0.44 g, 0.26 mmol). The resulting mixture was heated to 75 ◦ C for 19 h, and then concentrated in vacuo. Flash column chromatography using a gradient eluent (100:1 to 95:5 hexane and ethyl acetate) gave alcohol 8 (11.2 g, 80%) as a colorless oil. Rf = 0.6 (hexane/ethyl acetate 6:1). Rf = 0.30 (4: 1 hexane/ethyl acetate). IR (neat) 3337 (broad), 2931, 2119, 1428 cm−1 ; 1 H-NMR (400 MHz, CDCl3 ) 7.54 - 7.59 (m, 4H), 7.34 - 7.43 (m, 6H), 4.88 (t, J = 3.8 Hz,1H), 3.64 (t, J = 6.5 Hz, 2H), 1.67 - 1.76 (m, 2H), 1.27 (br, 1H), 1.14 - 1.21 (m, 2H); 13 C-NMR (125 MHz, CDCl3 ) 135.1, 134.2, 129.7, 128.1, 64.9, 27.5, 8.1. * (R)-N-1-[(3-hydroxypropyl)diphenylsilyl]-4-(methoxymethoxy)butyl-4-methylbenzene sulfonamide (6) To a mixture of lithium (1.73 g, 247 mmol) in THF (20 mL) at 0 ◦ C in dry argon gas was added by-compound 8 (3.0 g, 12.4 mmol). The mixture was stirred at 0 ◦ C until the reduction was completed. The progress of reaction was monitored by NMR. The solution then was cooled to -78 ◦ C, transferred via a cannula to a solution of sulfinimine 7 (0.73 g, 4.1 mmol) in THF (10 mL) at -78 ◦ C for more than 15 min. The resulting solution was stirred at -78 ◦ C for 5 hr, gradually warmed up to room temperature and stirred for overnight. The reaction was quenched by water (100 mL), and extracted by ethyl acetate (3 × 30 mL). The organic combination phase was washed by water (3 × 50 mL), and then dried over with Na2 SO4 , concentrated in vacou. Flash column chromatography gave crude sulfinamide 11 (1.3 g, 76%). The sulfinamide 11 (1.3 g, 3.1 mmol) was dissolved in DCM (20 mL) at 0 ◦ C was added 77% m-CPBA (0.83 g, 3.72 mmol). The progress of reaction was monitored by TLC. The excess m-CPBA was quenched by saturated Na2 SO3 . The mixture was extracted with DCM (3 × 30 mL). Combination of organic phases was dried over with Na2 SO4 , concentrated in vacou. Flash column chromatography gave sulfone 6 (1.45 g, 89%) as a colorless oil. Rf = 0.58 (hexane/ethyl acetate 1:2); [α]20 D = +9.4 (c 0.085, CHCl3 ); IR: 3289, 3068, 2926, 2874, 1598, 1540, 1155, 1111, 702 cm−1 ; 1 H-NMR 5
Duong Quoc Hoan and Scott McN. Sieburth (400 MHz, CDCl3 ): δ 7.66 (d, J = 7.4 Hz, 2H), 7.5 - 7.3 (m, 10H), 7.2 (d, J = 8.0 Hz, 2H), 3.56 - 3.50 (m, 1H), 3.46 (t, J = 6.5 Hz, 2H), 3.25 - 3.20 (m, 2H), 3.21 (s, 3H), 2.4 (s, 3H), 1.87 (br, 1H), 1.72 - 1.62 (m, 1H), 1.5 - 1.3 (m, 5H), 1.0 (m, 2H); 13 C-NMR (100 MHz, CDCl3 ): δ 143.2, 138.7, 135.7, 135.5, 132.6, 131.9, 130.1, 129.6, 128.3, 127.2, 96.2, 67.3, 65.2, 55.2, 42.0, 29.8, 29.1, 27.3, 26.6, 21.6, 7.45. Exact mass: [M - Na]+ calcd. for [C28 H37 NNaO5 SSi]+ 550.2054, found 550.2035. * (R)-3-[4-(Methoxymethoxy)-1-(4-ethylphenylsulfonamido)butyl] diphenylsilyl propa- -noic acid (22) To a solution of sulfonamide 6 (1.0 g, 1.9 mmol) in a mixture of solvent DCM/CH3 CN/ water (1/1/1, 50 mL) was added RuCl3 (3.9 mg, 0.019 mmol), and then NaIO4 (1.6 g, 7.6 mmol). The resulting solution was stirred at room temperature for an hour. The progress of reaction was monitored by TLC. The mixtures reaction was extracted with DCM (3 × 30 mL), then the combination of organic phase was dried over Na2 SO4 , concentrated in vacou. Flash column chromatography gave acid 22 (0.7 g, 68%) as a colorless oil. Rf = 0.4 (tail) (hexane/ethyl acetate 2/1). [α]20 D = +12.0 (c 0.05, CHCl3 ). IR: 3205 - 2560 (br), 3284, 3070, 2883, 1705, 1592, 1111, 734 cm−1 ; 1 H-NMR (500 MHz, CDCl3 ): δ 7.66 (d, J = 8.2 Hz, 2H), 7.5 - 7.3 (m, 10H), 7.2 (d, J = 7.8 Hz, 2H), 4.56 (d, J = 9.4 Hz, 1H), 4.44 (s, 3H), 3.57 - 3.51 (m, 1H), 3.17 - 3.19 (m, 2H), 3.22 (s, 3H), 2.3 (s, 3H), 2.22 - 2.17 (m, 1H), 1.71 - 1.62 (m, 1H), 1.46 - 1.40 (m, 1H), 1.37 (dd, J = 8.6, 4.2 Hz, 1H), 1.36 - 1.30 (m 3H); 13 C-NMR (125 MHz, CDCl3 ): δ 179.5, 143.4, 138.6, 135.6, 135.5, 131.7, 131.1, 130.4, 129.7, 128.5, 127.1, 96.2, 67.3, 55.2, 41.9, 29.1, 28.2, 27.3, 21.6, 6.5; Exact mass: [M - Na]+ calcd. for [C28 H35 NNaO6 SSi]+ 564.1847, found 564.1819. * (R)-2-[3-(Methoxymethoxy)propyl]-3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one (5) To solution of acid 22 (0.1 g, 0.18 mmol) in THF (4mL) at -20 ◦ C was added triethyl amine (63 µL, 0.45 mmol) followed by PivCl (22 µL, 0.18 mmol). The solution was stirred at -20 ◦ C for an h, and then added LiCl (11.3 mg, 0.27 mmol) followed (S)-oxazolidione (25.5 mg, 0.2 mmol). The mixture was stirred at the same temperature for an hour, and then at 0 ◦ C for 2 h, quenched with saturated NH4 Cl (5 mL), extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed brine (10 mL), dried over with Na2 SO4 , and concentrated in vacou. Column chromatography gave 5 (90 mg, 92%). Rf = 0.7 (hexane/ethyl acetate 1/1); [α]20 D = +47.0 (c 0.39, CHCl3 ); IR: 3070, 3012, 2926, 2883, 1694, 1591, 1343, 1107, 715 cm−1 ; 1 H-NMR (400 MHz, CDCl3 ): δ 7.7 (d, J = 8.0 Hz, 2H), 7.6 - 7.3 (m, 10H), 6.98 (d, J = 8.0 Hz, 2H), 4.89 - 4.84 (m, 1H), 4.5 (s, 2H), 3.48 - 3.40 (m, 2H), 3.22 (s, 3H), 2.93 - 2.79 (m, 2H), 2.3 (s, 3H), 1.86 - 1.72 (m, 3H), 1.65 (ddd, J = 15.3, 6.0, 4.0 Hz, 1H), 1.62 - 1.54 (m, 1H), 1.36 (ddd, J = 15.3, 13.3, 7.2 Hz, 1H); 13 C-NMR (100 MHz, CDCl3 ): δ 173.2, 144.2, 136.4135.2, 135.2, 132.6, 132.3, 130.7, 129.1, 128.9, 128.8, 128.6, 96.3, 67.0, 55.2, 45.2, 33.8, 30.4, 28.3, 21.7, 4.3; Exact mass: [M - Na]+ calcd. for [C28 H33 NNaO5 SSi]+ 546.1741, found 546.1724. 6
Asymmetric synthesis of (R)-2-[3-(methoxymethoxy)propyl]- 3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one 2.2. Synthesis, results and discussion Alcohol 8 was synthesized from diphenylsilane (9) and allylic alcohol in 80% yield. It is noteworthy that the synthesis of alcohol 8 can be scaled up to 100 g of diphenylsilane (9) (Scheme 2). Scheme 2. Radical chain hydrosilylation of allylic alcohol In general, radical chain hydrosilylation of alkenes using R3 SiH is not very helpful, since the hydrogen abstraction step is slow under standard experimental conditions; however these reactions can be promoted under milder conditions by the presence of catalytic amounts of a thiol [12]. Thus, the thiol acts as the catalyst and the H transfer agent in propagation steps (Scheme 3). Under high temperature of the initiation step, AIBN (azobisisobutyronitrile) is decomposed to eliminating a molecule of nitrogen gas to form two 2-cyanoprop-2-yl radicals (reaction 1, Scheme 3). The radical reacts with thiol XSH to yield thiyl radical (reaction 2, Scheme 3), and then the thiyl radical abstract a hydrogen atom from the R3 SiH. The resulting R3 Si radical adds to the double bond to give a radical adduct, which then reacts with the thiol and gives the addition product together with ‘fresh’ XS radicals to continue the chain. Chain reactions are terminated by radical-radical combination or disproportionation reactions, Scheme 3. Scheme 3. Propagation steps for radical-based hydrosilylation catalyzed by thiol With large amount of the alcohol 8 in hand, the alcohol 8 was treated with lithium metal at -78 ◦ C in tetrahydrofuran (THF) to make (Si,O)-dianion 10. The reaction mixture was turned in black and released hydrogen gas. The addition of (Si,O)-dianion to sulfinimine 7 gave sulfinamide 11 in 75% yield as a crude product. Due to instability of sulfinamide 11 on silica gel, it was oxidized by m-CPBA (meta-chloroperoxybenzoic acid) to give a stable sulfonamide 6 in 89% yield, Scheme 4. 7
Duong Quoc Hoan and Scott McN. Sieburth Scheme 4. Synthesis of sulfonamide 6 Mechanism of lithium (Si, O)-dianion 10 formation and similarities is still unclear. Yingjian Bo and Scott Sieburth [10] proved that the first step of the lithiation of 12 (Scheme 5, part A) is a reduction of Si-O bond and open up the ring to form (Si-O)-dianion 13. After 4 h, an asymmetric and a symmetric alcohols, hydrolysis products of (O, O)-dianion and (Si, O)-dianion, were separated by a flash column chromatography. To explain the formation of these two alcohols, the either (Si)-anion or (O)-anion substitutes alkoxy of silicon following two path ways a and b and form two correlative dianions 14, and 15. These two dianions were reduced by lithium to yield only (Si, O)-dianion 16 [13]. In our case (Scheme 5, part B), Li reacted with hydroxyl group of alcohol 8 to release hydrogen gas and (O)-anion 17 then cyclized (pathway a’) to form silafuran 18. The silafuran 18 was converted to (Si, O)-dianion 10 following the same manner of chemistry in Scheme 5, part A. On the other hand, lithium reacted with both hydroxyl group and Si-H to produce the same (Si, O)-dianion 10 (path way b’), Scheme 5, part B. Scheme 5. Lithiation of Si-O and Si-H bond cleavages Absolute stereochemical assignment of the major isomer was inferred by analogy upon X-ray diffractions studies of many related single crystals such as compound 19, and 8
Asymmetric synthesis of (R)-2-[3-(methoxymethoxy)propyl]- 3,3-diphenyl-1-tosyl-1,3-azasilinan-6-one 20 [14-20]. Both structures showed that the major isomer is the opposite isomer than the one predicted via the closed transition-state model suggested by Ellman for the majority of organometallic additions. Therefore, an open, acyclic transition state was proposed to explain the stereochemical results where the nucleophin attacks to the lest sterically hindered effect (Figure 2, 21). Figure 2. Absolute stereochemical assignment of the major isomer and proposed acyclic transition state Alcohol 6 was oxidized by a stoichiometric amount of NaIO4 and catalytic amount of RuCl3 to give acid 22 in 68% yield. Carboxylic group was activated by PivCl (Pivaloyl chloride) in basic condition of triethylamine to form 1,3-azasilinan-6-one 5 in 92% yield. Scheme 6. Synthesis of 1,3-azasilinan-6-one A proposed mechanism of cyclization is shown in Scheme 7. In the presence of triethyl amine, carboxylic and tosyl amine were deprotonated, therefore carboxylate reacts easily with pivaloyl chloride (PivCl) to yield anhydride 23 following cyclization to give 1,3-azasilinan-6-one 5 in high yield. Scheme 7. Proposed mechanism of cyclization reaction 9
Duong Quoc Hoan and Scott McN. Sieburth 3. Conclusion In conclusion, (R)-2-(3-(methoxymethoxy)propyl)-3,3-diphenyl-1-tosyl-1,3- azasili nan-6-one (5) was synthesized successfully in five linear steps in 33% yield. This is an approach for the synthesis of 1,3-azasilaheterocycles with a substituent in the 2-position as analogs of cyclic alkaloids. The synthesis involves hydridosilane lithiation and sulfinimine addition with good diastereoselectivity at the silicon bearing a stereogenic center, producing the desired compounds in excellent yield. This result can be applied for synthesis of a sila analogue of natural product mimics. REFERENCES [1] Annaliese K. Franz, Sean O. Wilson, 2013. Organosilicon Molecules with Medicinal Applications. J. Med. Chem., 56, pp. 388-405. [2] Cooper J. C., Gutbrod O., Witzemann V., Methfessel C., 1966. Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes. Eur. J. Pharmacol, 309, p. 287. [3] El Nemr A., 2000. Synthetic Methods for the Stereoisomers of Swainsonine and its Analogues. Tetrahedron, 56, p. 8579. [4] Johansson T., Weidolf L., Popp F., Tacke R., Jurva U., 2010. In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange. Drug Metab. Dispos, 38, 73. [5] Lukevics E. I. S., Germane S., Zablotskaya A., 1997. Silyl modification of biologically active compounds. Chem. Heterocycl.Compd., 33, p. 234. [6] Stromberg V. L., Horning E. C., 1955. Pinus Alkaloids. The Alkaloids of P. sabiniana Dougl. and Related Species. J. Am. Chem. Soc., 77, p. 6361. [7] Tacke R., Handmann V. I., Bertermann R., Burschka C., Penka M., Seyfried C., 2003. Sila-Analogues of High-Affinity, Selective σ Ligands of the Spiro[indane-1,4-piperidine] Type: Syntheses, Structures and Pharmacological Properties. Organometallics, 22, p. 916. [8] Vivet B., Cavelier, F., Martinez J., 2000. Synthesis of Silaproline, a New Proline Surrogate. Eur. J. Org. Chem., pp. 807-811. [9] Wannagat U., Wiese D., Struckmeier G., Thewalt U., Debaerdemaeker T., 1988. Sila-Pharmaca, 38 - Structure and Pharmacological Effectiveness of Sila-Substituted Analogues of the Psychopharmacological Agent Dimetacrine. Liebigs Ann. Chem., pp. 241-248. [10] Yingjian Bo, Swapnil Singh, Hoan Quoc Duong, Cui Cao and Scott McN. Sieburth, 2011. Efficient, Enantioselective Assembly of Silanediol Protease Inhibitors. Org. Lett., 13 (7), pp. 1787-1789. 10