8902
J. Org. Chem. 1997, 62, 8902-8906
Iodomethylation of Chiral r-Amino Aldehydes by Means of Samarium/Diiodomethane. Application to the Synthesis of Various Enantiomerically Pure Compounds Jose´ M. Concello´n* Departamento de Quı´mica Orga´ nica e Inorga´ nica and Instituto Universitario de Quı´mica Organometa´ lica, Facultad de Quı´mica, Universidad de Oviedo, Julia´ n Claverı´a, 8, 33071 Oviedo, Spain
Pablo L. Bernad and Juan A. Pe´rez-Andre´s Departamento de Quı´mica Orga´ nica e Inorga´ nica, Facultad de Quı´mica, Universidad de Oviedo, Julia´ n Claverı´a, 8, 33071 Oviedo, Spain Received February 19, 1997
Chiral iodohydrins 2 have been obtained from R-amino aldehydes 1 and Sm/CH2I2. Treatment of compound 2 with acetic anhydride, NaH, or AgBF4 affords, with high diastereoselectivity, O-protected 3-(dibenzylamino)-1-iodoalkan-2-ol 3, amino epoxides 4, or azetidinium salts 5, respectively. The synthesis of enantiomerically pure allylamines 6 is also described by metallation of 3 with zinc. The reaction of R-amino aldehydes 1 with Sm/CH2I2 and further treatment with organocuprates affords chiral amino alcohols 7 in a one-pot process. Introduction Chiral R-amino aldehydes are important compounds widely used in organic synthesis owing to their ready availability from R-amino acids1 and pronounced versatility. In recent years, several basic organic reactions using R-amino aldehydes have been described to prepare enantiomerically pure compounds such as organometallic addition to carbonyl groups,2 aldol condensations,3 [4 + 2] cycloadditions with activated 1,3-dienes,4 and trans* To whom correspondence should be addressed. Fax: 34-8-5103446. E-mail:
[email protected]. X Abstract published in Advance ACS Abstracts, November 15, 1997. (1) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149. (2) (a) Reezt, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987, 26, 1141. (b) Hanson, G. J.; Lindberg, T. J. Org. Chem. 1985, 50, 5399. (c) Reezt, M. T.; Drewes, M. W.; Harms, K.; Reif, W. Tetrahedron Lett. 1988, 29, 3295. (d) Reetz, M. T.; Reif, W.; Holdgru¨n Heterocycles 1989, 28, 707. (e) Holladay, M. W.; Rich, D. H. Tetrahedron Lett. 1983, 24, 4401. (f) Fray, A. H.; Kaye, R. L.; Kleiman, E. F. J. Org. Chem. 1986, 51, 4828. (g) Newman, H. J. Am. Chem. Soc. 1973, 95, 4098. (h) Saitoh, Y.; Moriyama, Y.; Takahashi, T.; Khuong-Huu, Q. Tetrahedron Lett. 1980, 21, 75. (3) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1983, 13, 1. (b) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3B, p 111. (c) Narita, M.; Otsuka, S.; Kobayashi, S.; Ohno, M.; Umezawa, Y.; Morishima, H.; Saito, S; Takita, T.; Umezawa, H. Tetrahedron Lett. 1982, 23, 525. (d) Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 1921. (e) Pyne, S. G.; Hensel, M. J.; Fuchs, P. L. J. Am. Chem. Soc. 1982, 104, 5719. (f) Ohfune, Y.; Nishio, H. Tetrahedron Lett. 1984, 25, 4133. (g) Andersson, L.; Wolfenden, R. Anal. Biochem. 1982, 124, 150. (h) Reetz, M. T. Wu¨nsch, T.; Harms, K. Tetrahedron Asymm. 1990, 1, 371. (4) (a) Danishefsky, S.; Larson, E.; Askin, D.; Kato, N. J. Am. Chem. Soc. 1985, 42, 5045. (b) Garner, P.; Ramakanth, S. J. Org. Chem. 1986, 56, 2609. (c) Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 1. (d) Midland, M. M.; Alfonso, M. M. J. Am. Chem. Soc. 1989, 111, 4368. (e) Jurzak, J.; Golebiowsky, A.; Raczko, J. J. Org. Chem. 1989, 54, 2495. (f) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 51, 2609. (g) Danishefsky, S.; Kobayashi, S.; Kerwin, J. F., Jr. J. Org. Chem. 1982, 47, 1981. (5) (a) Reetz, M. T.; Ro¨hring, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1706. (b) Kozikowski, A. P.; Nieduzak, T. R.; Konoike, T.; Springer, J. P. J. Am. Chem. Soc. 1987, 109, 5167. (c) Kozikowski, A. P.; Nieduzak, T. R.; Springer, J. P. Tetrahedron Lett. 1986, 27, 819. (d) Kozikowski, A. P.; Konoike, T.; Nieduzak, T. R. J. Chem. Soc., Chem. Commun. 1986, 1350. (e) Itaya, T.; Fujii, T.; Evidente, A.; Randazzo, G.; Surico, G.; Iacobellis, N. S. Tetrahedron Lett. 1986, 27, 6349. (f) Sodano, G.; Spinella, A. Tetrahedron Lett. 1986, 27, 2505. (g) Komiyama, K.; Urano, Y.; Kobayashi, S.; Ohno, M.; Tetrahedron Lett. 1987, 28, 3123. (h) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16, 1285. (i) Kogen, H.; Nishi, T. J. Chem. Soc., Chem. Commun. 1987, 311.
S0022-3263(97)00318-6 CCC: $14.00
formations into other functionalities such as aminoalkenes5 or R-amino aldimines.6 On the other hand, the halomethylation of carbonyl compounds is known to be difficult to achieve under ordinary reaction conditions due to the instability of (halomethyl)lithium compounds.7 As an alternative, this kind of reaction proceeds smoothly at room temperature using samarium metal8 or samarium(II) iodide9 and diiodomethane. However, to the best of our knowledge, iodomethylation of chiral carbonyl compounds has not been reported in the literature to date, and consequently, there is no information about the utility of this methodology in the synthesis of optically pure compounds.10 The halomethylation of chiral R-amino aldehydes would afford iodohydrins, which could be easily transformed into R-amino epoxides, azetidines, β-amino alcohols, or allylic amines. These compounds are important because of their biological properties and synthetic applications. As examples, chiral R-amino epoxides are highly useful intermediates in the synthesis of protease inhibitors11 and other pharmaceutically interesting compounds;12 the azetidine ring is present in an important number of molecules with biological activity;13 β-amino (6) Reetz, M. T.; Jaeger, R.; Drewlies, R.; Hu¨bel, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 103. (7) Aube´, J. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; p 260. (8) (a) Imamoto, T.; Takeyama, T.; Koto, H. Tetrahedron Lett. 1986, 27, 3243. (b) Imamoto, T.; Hatajima, T.; Takiyama, W.; Takeyama, T.; Kamiya, Y.; Yoshizawa, T. J. Chem. Soc., Perkin Trans. 1 1991, 3127. (9) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693. (b) Tabuchi, T.; Inanaga, J.; Yamaguchi, J. Tetrahedron Lett. 1986, 27, 3891. (c) For a recent review about reactions with samarium(II) iodide, see: Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (10) While this manuscript was being reviewed, preliminary results about the reaction of diiodoalkanes with aldehydes using samarium diiodide were reported, including two examples with chiral substrates: Matsubara, S.; Yoshioka, M.; Utimoto, K. Angew. Chem., Int. Ed. Engl. 1997, 36, 617. Synthetic applications of this reaction are not described. (11) (a) Pegorier, L.; Petit, Y.; Larcheveˆque, M. J. Chem. Soc., Chem. Commun. 1994, 633. (b) Evans, E. V.; Rittle, E. K.; Homnicik, C. F.; Springer, J. P.; Hirshfield, J.; Veber, D. F. J. Org. Chem. 1985, 50, 4615. (c) Luly, J. R.; Plattner; J. J.; Stein, H.; Yi, N.; Cohen, J.; Tricarico, K.; Dellaria, J. F. Pharmacologist 1985, 27, 260. (12) Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987, 52, 1487.
© 1997 American Chemical Society
Iodomethylation of Chiral R-Amino Aldehydes
J. Org. Chem., Vol. 62, No. 25, 1997 8903
Scheme 1a
Table 1. Synthesis of Compounds 3-6 entry 1 2 3 4 5 6 7 8 9 10 11 12
a Reagents and conditions: (i) Sm0/CH I , THF, 0 °C, 40 min, 2 2 then H3O+; (ii) Ac2O, pyridine, rt; (iii) NaH, CH2Cl2, rt; (iv) AgBF4, Et2O, rt; (v) H2O.
alcohols are biologically important,14 and the allylic amine moiety appears in many natural and bioactive compounds.15 Moreover, R-amino epoxides,16 azetidines,17 and allylamines18 can be used as chiral building blocks for a wide variety of compounds, and β-amino alcohols can be used as chiral auxiliaries.19 In this paper, we describe the preparation of enantiomerically pure, protected 3-amino-1-iodo 2-alcohols from chiral R-amino aldehydes and Sm/CH2I2, which are appropriate starting compounds for a simple and direct entry to amino epoxides, 3-hydroxy azetidinium salts, allylamines, and β-amino alcohols. Results and Discussion Treatment of a mixture of diiodomethane and different N,N-dibenzylated R-amino aldehydes 1 with samarium metal at 0 °C gave, after hydrolysis, the corresponding iodohydrins 2 (Scheme 1). When iodohydrins were taken to dryness they became unstable and decomposed to a mixture of several products. Therefore, these compounds were identified by NMR spectroscopy of the crude reaction mixture before the solvent was completely removed.20 In order to characterize compounds 2 they were transformed into their O-acetyl derivatives 3 by treatment with acetic anhydride at room temperature, and these (13) (a) Antibacterial: Jacquet, J. P.; Bouzard, D.; Kiechel, J. R.; Remuzon, P.; Tetrahedron Lett. 1991, 32, 1565. (b) Fungicidal: Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490. (c) Monoamine oxidase inhibitory activity: Wells, J. N.; Tarwater, O. R. J. Pharm. Bull. 1974, 22, 1490. (d) Actomyosin ATPase activating activities: Takikawa, H.; Maeda, T.; Mori, K. Tetrahedron Lett. 1995, 36, 7689. (14) Gladych, J. M. Z.; Hartley, D. In Comprehensive Organic Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon: Oxford, 1979; Vol. 2, p 99. (15) Hutchins, R. O.; Wei, J.; Rao, S. J. J. Org. Chem. 1994, 59, 4007 and references cited therein. (16) For applications of epoxides in organic synthesis, see: Behrens, C. H.; Sharpless, K. B. Aldrichim. Acta 1993, 16, 67. (17) For reactivity of azetidines: (a) Davies, D. E.; Stor, R. C. In Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7, pp 238-284. Other recent synthetic applications of azetidines: (b) Jung, M. E.; Choi, Y. M. J. Org. Chem. 1991, 56, 6729. (c) Viallm, L.; Reinand, O.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1995, 36, 4787. (18) For a review on the asymmetric isomerization of allylamines, see: Akutagawa, S.; Tani, K. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp 41-61. (19) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835. (20) 13C-NMR of compounds 2 were recorded in the presence of THF (20-50%). 2a: 130.9-128.2, 66.5 (CH), 59.0 (CH), 54.6 (CH2), 54.2 (CH2), 7.7 (CH3), 5.7 (CH2). 2b: 132.1-126.7, 66.5 (CH), 60.8 (CH) , 55.0 (CH2), 54.5 (CH2), 31.8 (CH2), 29.2 (CH), 22.6 and 21.0 (2 × CH3), 7.2 (CH2).
R
producta
yieldb (%)
dec (%)
Me
3a 3b 3c 4a 4b 4ce 5a 5b 5c 6a 6be 6c
72 65 70 81 77 (48d) 74 62 60 59 87f 84f 82f
81 79 81 82 80 (61d) 81 81 80 82
iBu
Bn Me iBu Bn Me iBu Bn Me iBu Bn
a All reactions were carried out at room temperature. b Isolated yield after purification based on the starting R-amino aldehyde 1. c Diastereomeric excess determined by 1H NMR (300 MHz) and/ or quantitative 13C NMR analysis of the crude products. d Reaction temperature -50 °C. e ee > 99% HPLC (Chiracel OD-H; 0.8 mL/ min; UV detector; 4c, 225 nm; 50:1 hexane/2-propanol; tR ) 17.15 min; 6b, 235 nm; 400:1 hexane/2-propanol; tR ) 6.15 min). f Isolated yield after purification based on the starting compound 3.
could be isolated and purified by flash column chromatography (Scheme 1 and Table 1, entries 1-3). Despite their instability, iodohydrins 2 could be converted to different compounds using the crude product (see the Experimental Section). Reaction of iodohydrins 2 with NaH at room temperature led to erythro amino epoxides 4 (Scheme 1 and Table 1). The stereochemistry of amino epoxides 4 was established unambiguously by comparison of their NMR spectra with those previously reported.21 The iodomethylation of amino aldehydes 1 with Sm/CH2I2 took place with good diastereoselectivity. The diastereomeric excess (de) of compounds 4a-c was higher than 80%, as determined by 300-MHz 1H NMR and quantitative 13C NMR spectroscopy. Interestingly, when the reaction was carried out at lower temperature the de of 4b decreased (entry 5 in Table 1).22 Iodomethylation of 1 proceeds with no detectable racemization. The enantiomeric purity of the major diastereomer of compound 4c23 was determined by chiral HPLC analysis (Chiracel OD-H) showing an enantiomeric excess (ee) >99%; for comparison, a racemic mixture of 4c was prepared and HPLC analysis excluded the possibility of coelution of both enantiomers. The observed stereochemistry of 4 can be explained by assuming a nonchelation control model in the iodomethylation reaction of aldehyde 1. This diastereofacial preference is the same as that previously reported for the addition of other organometallic compounds to dibenzylated amino aldehydes.21 Reaction of compounds 2 with AgBF4 at room temperature afforded the corresponding azetidinium salts 5 with high diastereoselectivity, in agreement with the de of compounds 4 (Scheme 1 and Table 1, entries 7-9). Configurational assignments of products 5 were estab(21) (a) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1995, 60, 6696. (b) Reetz, M. T.; Binder, J. Tetrahedron Lett. 1989, 30, 5425. (22) Similar diastereoselection temperature dependence has been reported for other reactions induced by SmI2: (a) Kawatsura, M.; Matsura, F.; Shirahawa, H. J. Org. Chem. 1994, 59, 6900. (b) Kawatsura, M.; Hosaka, K.; Matsura, F.; Shirahawa, H. Synlett 1995, 729. (c) Kawatsura, M.; Dekura, F.; Shirahawa, H.; Matsura, F. Synlett 1996, 373. (d) Fallis, A. G.; Sturino, C. F. J. Am. Chem. Soc. 1994, 116, 7447. (23) The high tendency of the N,N-dibenzylated aldehyde 4c (obtained from phenylalanine) to racemize has been documented: Rittle, K. E.; Homnick, C. F.; Ponciello, G. S.; Evans, B. E. J. Org. Chem. 1982, 47, 3016.
8904 J. Org. Chem., Vol. 62, No. 25, 1997
Concello´n et al.
amino alcohols than direct reaction of R-amino aldehydes with organolithium compounds or Grignard derivatives, for instance, to obtain 7d,e.27 In conclusion, iodomethylation of chiral carbonyl compounds using Sm/CH2I2 is an easy, rapid, and mild methodology for the transformation of R-amino aldehydes into optically pure amino epoxides, 3-hydroxy azetidinium salts, allylamines, and β-amino alcohols.
Scheme 2
Experimental Section
Scheme 3a
a Reagents and conditions: (i) Sm/CH I , THF, 0 °C; (ii) 2 2 Me2CuLi, 0 °C or (CH2dCHCH2)CuCNMgBr or CH2dCHCH2MgBr, -78 °C f rt; then NH4OH.
Table 2. Synthesis of Amino Alcohols 7a-e entry 1 2 3 4 5 6
R
R′
product
yielda (%)
deb (%)
Me
Mec Mec Mec allyld allyle allyld
7a 7b 7c 7d 7d 7e
60 58 56 56 46 54
87 87 90 76 76 77
iBu
Bn Me Me iBu
a Isolated yield after purification based on the starting R-amino aldehyde 1. b Diastereomeric excess determined by 1H NMR (300 MHz) and/or quantitative 13C NMR analysis of the crude products. c Lithium dimethylcuprate was used. d Magnesium allylcyanocuprate bromide was used. e Allylmagnesium bromide was used.
lished by NOESY experiments in the case of compound 5a, showing the trans relative configuration for methyl and hydroxyl groups. On the other hand, allylamines 6 were obtained by the treatment of 3 with zinc powder in the presence of aqueous acetic acid24 (Scheme 2 and Table 1, entries 1012). Compounds 6a-c were synthesized with no detectable racemization; chiral HPLC analysis of 6b using a racemic mixture as reference indicated an ee of 99%. The formation of these amines can be explained by formation of the corresponding organozinc compounds that undergo a β-elimination process to give the carbon-carbon double bond.25 Finally, secondary amino alcohols were prepared in a one-pot synthesis starting from R-amino aldehydes 1. Succesive treatment of N,N-dibenzylated R-amino aldehydes 1 with Sm/CH2I2 and Grignard or organocuprate reagents led to β-amino alcohols 7a-e (Scheme 3 and Table 2). Diastereoisomeric excesses, between 76 and 87%, were determined using either 300 MHz 1H NMR or quantitative 13C NMR spectroscopy of crude products.26 This methodology is a better strategy to prepare some (24) Florent, J. C.; Ughetto-Monfrin, J.; Monneret, C. J. Org. Chem. 1987, 52, 1051. (25) House, H. O.; Ro, R. S. J. Am. Chem. Soc. 1958, 80, 182. (26) NMR data of 6a-c are available: Andre´s, J. M.; Barrio, M.; Martı´nez, M. A.; Pedrosa, R.; Pe´rez-Encabo, A. J. Org. Chem. 1996, 61, 4210.
General Methods. Reactions requiring an inert atmosphere were conducted under dry nitrogen, and the glassware was oven dried (120 °C). THF and ether were distilled from sodium/benzophenone ketyl immediately prior to use. All reagents were purchased from Aldrich or Acros and were used without further purification. Amino aldehydes 1 were prepared according to literature procedures.2a Powdered zinc was washed successively with aqueous HCl, H2O, MeOH, and ether and then dried in vacuo. Pyridine was stored over NaOH. Silica gel for flash chromatography was purchased from Scharlau or Merck (200-450 mesh), and compounds were visualized on analytical thin-layer chromatograms (TLC) by UV light (254 nm). 1H NMR spectra were recorded at 200, 300, or 400 MHz. 13C NMR spectra and DEPT experiments were determined at 50 or 75 MHz. Chemical shifts are given in ppm relative to tetramethylsilane (TMS), which is used as an internal standard, and coupling constants (J) are reported in Hz. The diastereomeric excesses were obtained using 1HNMR analysis of crude products or by inverse gated decoupling experiments using chromium acetylacetonate (1 mg) as additive (namely quantitative 13C NMR). GC-MS and HRMS were measured at 70 eV or using FAB conditions. When HRMS could not be measured on the molecular ion the HRMS of a significant fragment is given. Only the most important IR absortions (in cm-1) and the molecular ions and/or base peaks in MS are given. The enantiomeric purity was determined by chiral HPLC analysis using a Chiracel OD-H (0.46 × 25 cm, Diacel) column. General Procedure for the Preparation of Protected Iodohydrins 3. Under a nitrogen atmosphere, samarium powder (300 mg, 2 mmol) was placed in a Schlenk tube at 0 °C. A solution of CH2I2 (0.24 mL, 3 mmol) and the corresponding amino aldehyde 1 (1 mmol) in THF (6 mL) were added dropwise with stirring over 20 min. After stirring at the same temperature for 20 min, the mixture was quenched with 1 M HCl (30 mL) and extracted with CH2Cl2 (4 × 10 mL). The combined organic layers were dried (Na2SO4), and to the resulting solution were added pyridine (10 mL), acetic anhydride (10 mL), and a catalytic amount of DMAP (5 mg). The reaction mixture was then stirred at room temperature overnight. Finally, the solution was carefully quenched with water/ice. The organic layer was separated, and the aqueous layer was extracted with ether (3 × 20 mL). The combined extracts were dried over (Na2SO4) and the solvents removed under reduced pressure (bath temperature 40 °C). Flash column chromatography over silica gel (hexane/triethylamine 75/1) provided erythro-3-amino-1-iodo-2-acetoxyalkanes 3. (2S,3S)-3-(N,N-Dibenzylamino)-1-iodobutan-2-yl acetate (3a): Rf ) 0.4 (hexane/ethyl acetate 10/1); [R]22D ) +4.74 (c 2.3, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.41-7.23 (10 H, m), 4.89 (1 H, ddd, J ) 9.2, 6.7, 3.5), 3.81 and 3.43 (4 H, AB syst, J ) 13.5), 3.68 (1 H, dd, J ) 6.7, 3.9), 3.29 (1 H, dd, J ) 3.9, 3.5), 2.96 (1 H, dq, J ) 9.2, 6.7), 2.11 (3 H, s), 1.11 (3 H, d, J ) 6.7); 13C NMR (CDCl3, 75 MHz) δ 170.11 (C), 139.0 (C), 128.7, 128.2 and 127.0 (3 × CH), 73.2 (CH), 55.8 (CH), 54.0 (CH2), 20.9 (CH3), 8.3 (CH3), 7.9 (CH2); IR (neat) 1742; MS m/z 437.1 (M+,
