Synthesis of nitrogen-containing unsaturated carbohydratesviaan allyl cyanate-to-isocyanate rearrangement

摘要

'WSynthesis of nitrogen-containing unsaturated carbohydrates via man allyl cyanate-to-isocyanate rearrangement IIx Yoshiyasu Ichikawa,* Chie Kobayashi and Minoru Isobe Laboratory of Organic Chemistry, School of Agricultural Sciences, Nagoya University, Chikusa, Nagoya 464-01, Japan A new method for the synthesis of 4-amino-~-hex-2-enopyranosidesand %amino-~-hex-3- enopyranosides has been developed. The key feature in this method involves construction of the allylamine moiety in the pyranose framework by employing an allyl cyanate-to-isocyanate rearrangement. Introduction Over the last few years we have been concerned with the development of both the synthesis of allyl cyanate and the [3,3] sigmatropic rearrangement. This reaction offers an efficient transformation of allyl alcohols into allylamines in a highly stereospecific manner, as illustrated in Scheme 1.Starting from the allyl alcohols 1, dehydration of the allyl carbamates 2 provides the allyl cyanates 3. These allyl cyanates 3 undergo a concerted [3,3] sigmatropic rearrangement below ambient temperature to furnish the allyl isocyanates 4,2 which are successively transformed into either the allylureas 5 or the N-allylacetamides 6. As an application of this allyl cyanate-to- isocyanate rearrangement, we have initiated an investigation of the synthesis of nitrogen-containing unsaturated carbohy- drates. Several workers have reported the synthesis of nitrogen- containing unsaturated carbohydrates by using sigmatropic rearrangement; for example, the pioneer work of R.J. Ferrier in 1970employed the [3,3] sigmatropic rearrangement of the allyl thiocyanate. Similar strategies using the [3,3] sigmatropic rearrangement of allyl imidates has also a~peared.~ In this report, we present a full description of an allyl cyanate-to-isocyanate rearrangement for the synthesis of nitrogen-containing unsaturated carbohydrates. Results and discussion The starting unsaturated carbohydrates, hex-3- and hex-2- enopyranosides (9, 10, 13, 14), were prepared as shown in Scheme 2. Synthesis of the hex-3-enopyranosides 9 and 10 began with the isopropyl glycoside 7.6Treatment of compound 7 with lithium aluminium hydride and selective protection of the resulting diol 8 with tert-butyldimethylsilyl chloride (TBDMSCl) gave the hex-3-enopyranoside 9.Inversion of the C-2 hydroxy group of compound 9 by the Mitsunobu reaction and hydrolysis of the resulting benzoate furnished the inverted hex-3-enopyranoside 10. The hex-2-enopyranoside 12 was prepared from tri-o-acetyl-D-glucal 11 by employing Ferrier glycosidation. Selective protection of the diol 12 with TBDMSCl provided the hex-2-enopyranoside 13, which was further converted into its epimer 14 by the Mitsunobu reaction and hydrolysis. With the four enopyranosides in hand, their allyl cyanate-to-isocyanate rearrangement was undertaken. At the beginning of this study, we were most interested in the rearrangement of the hex-3-enopyranoside 9 to the 4-amino- 3-enopyranoside, because the 4-amino-3-enopyranoside is a structural unit found among the naturally occurring antifungal 1 2 3 4 5 6 Scheme 1 Reactions: i, dehydration; ii, rearrangement.Reagents: iii, pyrrolidine; iv, AlMe,. nucleoside antibiotics, such as blasticidin S 15' and mildiomycin 16.lo We expected that an allyl cyanate-to-isocyanate rearrange- ment of the hex-3-enopyranoside 9 would be difficult, because the C-2 hydroxy group of 9 adopts a pseudo-equatorial con- formation. In fact, a literature search revealed that rearrange- ment of hex-3-enopyranoside 174a with a pseudo-equatorial hydroxy group proceeded in moderate yield to give compound 18 (Scheme 3). On the other hand, rearrangement of compound 194a with a pseudo-axial hydroxy group proceeded smoothly in good yield to give compound 20 (Scheme 4).Scheme 5 illustrated an allyl cyanate-to-isocyanate rearrange- ment of compound 9. Treatment of the alcohol 9 with trichloroacetyl isocyanate and hydrolysis with potassium carbonate in aq. methanol provided the carbamate 21. Dehydration of the carbamate 21 with trifluoromethanesulfonic anhydride and diisopropylethylamine (DIPEA) at -78 "C for 2.5 h and successive treatment with pyrrolidine furnished no detectable rearrangement product. After a substantial amount of experimentation, we realized that the reaction time and temperature after dehydration of the carbamate 21 was crucial for the rearrangement. Subsequently, dehydration of the carbamate 21 with triphenylphosphine, tetrabromomethane and DIPEA was complete after 150 min at -20 "C, and gave the allyl cyanate 22.After dehydration, it was necessary for re- arrangement to occur, so that the reaction mixture was stirred at room temperature for 60 min. The resulting reaction mixture was recooled to -78 "C, and then was treated with pyrrolidine. J. Chem. SOC.,Perkin Trans. 1 377 OAc 7 OTBDMS OTBDMS iii, iv 011x!j -x!j'-or+ ! '*or? (89%,88%) 0" (638) 10 9 €lo.'& I v, vi __c AcO "OEt (67%, 71%) 11 12I ii OTBDMS 1106 -iii, iv "OEt 2* (64%,86%) (85%) 14 13 Scheme 2 Reagents and conditions: i, LiAlH,; ii, Bu'Me,SiCl, imidazole; iii, PhCO,H, Ph,P, DEAD; iv, KOH, MeOH; v, EtOH, BF,.OEt,; vi, Et,N, aq.MeOH BlasticidinS 15 y2 Mildiomycin 16 The urea 24 was isolated in 68% overall yield from the hex-3- enopyranoside 9 after chromatographic purification. When trimethylaluminium was employed for the transform- 378 J. Chem. Soc., Perkin Trans. 1 c'3cKb (1 38) NH 17 18 Scheme 3 Reagents and conditions: i, o-dichlorobenzene, 165 "C, 11 h K' (68%)NH 19 20 Scheme 4 Reagents and conditions: i, o-dichlorobenzene, 165 "C, 6 h 23 I ivorv 24 R= -N3 25 R=Mc Scheme 5 Reagents and conditions: i, CC1,CONCO; K2C03, aq. MeOH; ii, Ph,P, CBr,, Pr',NEt, -20 "C; iii, room temp., 60 min; iv, pyrrolidine;v, Me,Al, 2.5 min, 0 "C ation of the allyl isocyanate 23, the acetamide 25 was obtained in 59% overall yield from alcohol 9.In this transformation, the reaction time (2.5 min) and temperature (0°C) were both necessary to obtain the given yield. A prolonged reaction time as well as a low reaction temperature resulted in variable and often low yields (3040%). The stereochemistry of the acetamide 25 was determined by 'H NMR spectroscopy. Thus, the large vicinal coupling constant of 9 Hz between 4-H and 5-H (J4,Jof compound 25 indicated that these protons were trans. This J4,svalue was consistent with that of mildiomycin 16 (J4,510 Hz)." Other examples of the rearrangement are collected in Table 1 and the generality of this allyl cyanate-to-isocyanate rearrange- ment for the synthesis of nitrogen-containing unsaturated carbohydrates was evident from these results.The stereochemistry of entries A, B and C was determined by 'H NMR analysis. In case of entry A, the small J4,svalue of 3 Hz found for compound 27 was consistent with the cis-relationship. Ferrier reported an empirical relationship between 2-substituted hex-3-enopyranosides and the J, ,2 value in the 'H NMR spectra.* The generalization was that 2cc-isomers displayed a value for the coupling constant J, ,2 within the range 3-4 Hz, while the 2P-isomers had J1,2 z 0 Hz. This may be the result of the conformational difference between 2~-and 2P- substituted hex-3-enopyranosides which resulted in significantly different 'H NMR spectra Jl,2 values. We confirmed the Table 1 Synthesis of nitrogen-containing unsaturated carbohydrates from hexenopyranosides Entry Reactant Product (yield, %) A OTBDMS B 'OEt 2 OTBDMS C 14 --oE~ stereochemistry of entries B and C based on his empirical rule; that is, both compounds 28 and 29 had coupling-constant values of 4 Hz between 1-H and 2-H (J1 ,,).These values were in good agreement with the stereochemistry of a 2a-substituent. In the case of compounds 30and 31, we observed J1,, x0 Hz, which was consistent with the 2P-stereochemistry. Further stereochemical confirmation was obtained by transforming the acetamide 31 into the known mesyl derivative 32 as shown in Scheme 6. Desilylation of compound 31 with tetrabutylammo- nium fluoride (TBAF) and mesylation with methanesulfonyl chloride in pyridine provided the methanesulfonate 32.The spectroscopic data of our synthetic ester 32was in good agree- ment with those reported by R. D. Guthrie." fOTBDMS A: 8 h'lI Me,,NI1 8 (57%) 31 32 Scheme 6 Reagents and conditions: i, Bu,NF; ii, MsCl, Py Conclusions The stereochemistry of the rearranged product was consistent with our expectations for such suprafacial allyl rearrangements that the asymmetry at the initial allylic centre was transmitted into the new centre as a nitrogenous substituent. The better yields of compounds 10 and 14compared with those of 9 and 13 followed from the quasi-axial orientation of their C-2 and C-4 hydroxy substituents. This stereochemistry provided the consequent relative ease with which cyclic transition states involved in the allyl cyanate-to-isocyanate rearrangement could be formed.* Further transformation of the nitrogen-containing unsatu- rated carbohydrates prepared in this study into naturally occurring amino sugars is now under study. (OTBDMS 28 R= -Na (47) ! -'OEt 29 R= Me (47) 0 (OTBDMS 30 R= -Na (78) 'OEt 31 R= Me (58) II * 0 Experimental Mps were determined on a hot-stage melting apparatus and were uncorrected.IR spectra were recorded using a JASCO FT/TR- 7000s for KBr discs unless otherwise stated. 'H NMR spectra were determined using a JEOL EX 270 spectrometer operating at 270 MHz unless otherwise stated. I3C NMR spectra were determined using the JEOL EX 270 instrument, operating at 67.80 MHz unless otherwise stated. Dilute solutions in [2H]chloroform were used as solvent throughout unless stated otherwise, with tetramethylsilane as the internal standard.All J values are in Hz. Optical rotations were measured on a JASCO DIP-0181 digital polarimeter; [a],, values are given in units of lo-' deg cm2 g-'. All organic solutions from work-ups were dried by brief exposure to anhydrous sodium sulfate. Column chromatography was performed on silica gel supplied by Fuji Davison (BW-820MH). Preparative TLC was carried out on plates prepared with a 2 mm layer of silica gel PF254 obtained from E. Merck (Art #7747). Isopropyl6-0-(tert-butyldimethylsilyl)-3,4-dideoxy-a-~-erythro-hex-3-enopyranoside 9 To a solution of diol8 (1 -40g, 7.50 mmol) and imidazole (1 -54 g, 22.6 mmol) dissolved in a mixture of dichloromethane (33 cm3) and N,N-dimethylformamide (DMF) (14 cm3) was added TBDMSCl (I .36 g, 9.0 mmol) portionwise. After being stirred for 3.5 h at room temperature, the reaction mixture was poured into water.The separated aqueous layer was extracted with diethyl ether (three times). The combined extracts were washed successively with water and brine, dried, and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (silica gel 40 g) with a mixture of diethyl ether-hexane (1 :5, v/v) to provide the silyl ether 9 (1.42 g, 63%), [CX]~~-11.0 (c 0.49, CHC1,) (Found: C, 59.5; H, 10.2. C,,H,,04Si requires C, 59.56; H, 10.00%); v,,,(film)/cm 3427 (OH); 6,(270 MHz; CDCI,) 0.05 (6 H, s, SiMe,), 0.88 (9 H, s, Bu'), 1.19 (3 H, d, J6, CHMe,), 1.25 (3 H, d, J6, CHMe,), 3.57 (1 H, dd, J 10 and 6,6-H), 3.67 (1 H, dd, J 10 and 6,6-H), 3.99 (1 H, sept, J6, CHMe,), 4.10-4.19 (2 H, 2- and 5-H), 5.06 (1 H, d, J 4, 1 -H) and 5.68-5.84 (2 H, 3-and 4-H).J. Chem. SOC.,Perkin Trans. I 379 Ethyl 6-O-(tevt-butyldimethylsilyl)-2,3-dideoxy-~-~-erythro-hex-2-enopyranoside 13 Starting from diol 12 (300 mg, 1.72 mmol), TBDMSCl (452 mg, 3.0 mmol), imidazole (532 mg, 7.7 mmol), dichloromethane (7 cm3) and DMF (3 cm3), the silyl ether 13 (420 mg) was isolated in 85%yield after chromatographic purification, [a];' f22.6 (c 1.20, CHCl,) (Found: C, 58.3; H, 9.8. C,,H,,O,Si requires C, 58.29; H, 9.78%); v,,,(film)/cm-' 3442 (OH); 6,(270 MHz; CDCl,) 0.1 1 (6 H, s, SiMe,), 0.91 (9 H, s, Bu'), 1.23 (3 H, t, J 7, CH,), 3.53 (1 H, dq, J 10 and 7,OCH,CH,), 3.68-3.94 (4 H),4.16(1H,brd,J8),4.95(1 H,br,l-H),5.73(1H,dt,JlO and 2) and 5.93 (1 H, br d, J 10).Isopropyl6-O-(tert-butyldimethylsilyl)-3,4-dideoxy-~-~-thveo-hex-3-enopyranoside10 To a solution of erythro-isomer 9 (297 mg, 0.98 mmol), triphenylphosphine (1.16 g, 4.41 mmol) and benzoic acid (360 mg, 2.94 mmol) in tetrahydrofuran (THF) (7.5 cm3) cooled to 0 "C was added diethyl azodicarboxylate (DEAD) (0.76 cm3, 4.9 mmol) dropwise. After being stirred for 70 rnin at 0 "C, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether and washed successively with saturated aq.sodium hydrogen carbonate and brine. After being dried, evaporation of the solvent gave the crude product (1.6 g), which was purified by silica gel chromatography (50 g) with a mixture of diethyl ether-hexane (1 :10, v/v) to provide the benzoate (357 mg, 89%). A solution of the benzoate (870 mg, 2.14 mmol) in methanol (30 cm3) was treated with sodium methoxide (4.1 mol dm-, solution in methanol; 1.14 cm3, 4.7 mmol) at 0 "C for 15 min. Cracked solid CO, was added, and the solution was concentrated under reduced pressure. The resulting residue was diluted with water, and the aqueous layer was extracted with diethyl ether. The combined extracts were dried, and then concentrated under reduced pressure.Purification of the resulting residue by silica gel chromatography (24 g) with a mixture of diethyl ether-hexane (1 :2, vjv) furnished threo- isomer 10 (568 mg, 8873, [a];' +66.5 (c 0.95, CHCl,) (Found: C, 59.5; H, 10.0. C,,H3,0,Si requires C, 59.56; H, 10.00%); vmax(film)/cm-' 3447 (OH); 6,(270 MHz; CDC1,) 0.07 (6 H, s, SiMe,), 0.89 (9 H, s, Bu'), 1.16 (3 H, d, J6, CHMe,), 1.21 (3 H, d, J 6, CHMe,), 3.69-3.78 (3 H, 2-H and 6-H,), 3.97 (1 H, sept, J6, CHMe,), 4.19-4.27 (1 H, m, 5-H), 4.95 (1 H, s, 1-H), 5.89 (1 H,dd, J11 and2,4-H)and6.07(1 H, brd, J11,3-H). Ethyl 6-O-(tert-butyldimethylsilyl)-2,3-dideoxy-a-~-threo-hex-2-enopyranoside 14 The procedure described here was similar to that used for compound 10. Thus, starting from erythro-compound 13 (300 mg, 1.04 mmol), DEAD (0.82 cm3, 5.2 mmol), triphenylphos- phine (1.23 g, 4.7 mmol), benzoic acid (381 mg, 3.12 mmol) and THF (7.5 cm3), the benzoate (263 mg) was isolated in 64% yield.Starting from the benzoate (1.56 g, 4.27 mmol), sodium methoxide (4.1 mol dm-, solution in methanol; 0.93 cm3, 3.8 mmol) and methanol (50 cm3), the alcohol 14 (1.06 g) was obtained in 86% yield, [a];' -28.9 (c 0.42, CHC1,) (Found: C, 58.3; H, 9.8. C,,H,,O,Si requires C, 58.29; H, 9.78%); v,,,(film)/cm 3448 (OH); 6,(270 MHz; CDC1,) 0.09 (6 H, s, SiMe,), 0.90(9 H, s, Bur), 1.23 (3 H, t, J7, CH,), 2.03-2.17 (1 H, br d, OH), 3.53 (1 H, dq, J9 and 7,OCH,CH,), 3.78-3.94 (4H, OCH,CH,, 4-H and 6-H2), 4.04 (1 H, td, J 6 and 2, 5-H), 5.02 (1H,d,J3,l-H),5.90(1H,dd,J10and3,2-H)and6.15(1H, dd, J 10 and 5,3-H).General procedure for the synthesis of the urea derivative isopropyl6-0-(tert-butyldimethylsilyl)-2,3,4-trideoxy-(4-pyrrolidine-1-carboxamido)-u-~-erythro-hex-2-enopyranoside 24 To a solution of compound 9 (500 mg, 1.66 mmol) in dichloromethane (17 cm3) was added trichloroacetyl isocyanate 380 J. Chem. SOC.,Perkin Trans. 1 (0.24 cm', 1.99 mmol) dropwise at 0 "C. After the mixture had been stirred for 15 rnin at 0 "C, solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in a mixture of methanol (7 cm3) and water (5 cm3). To this solution, cooled to O"C, was added potassium carbonate (705 mg, 4.98 mmol) portionwise. After the solution had been stirred for 60 min at 0 "C, the cooling bath was removed, and stirring was continued for a further 120 rnin at room temperature. Methanol was evaporated off and the resulting aqueous phase was extracted with dichlorometh- ane (three times).The combined organic phases were dried, and then concentrated under reduced pressure to afford the carbamate 21 (552 mg, 9773, which was used for the next reaction without further purification. To a solution of the carbamate 21 (149 mg, 0.43 mmol), triphenylphosphine (283 mg, 1.08 mmol) and DIPEA (0.18 cm3, 1.1 mmol) in dichloromethane (4 cm3) was added a solution of tetrabromomethane (398 mg, 1.21 mmol) in dichloromethane (1 cm3) dropwise at -20 "C. After being stirred for 150 rnin at -20 "C, the cooling bath was removed, and the stirring was continued for 60 min at room temperature.The resulting solution was cooled to -78 "C and then treated with pyrrolidine (0.29 cm3, 3.5 mmol). After being stirred for 30 rnin at -78 "C and for 30 min at -20 "C, the reaction mixture was poured into water, and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried, and concentrated under reduced pressure to provide a crude oil (0.96 g), which was purified by silica gel chromatography with diethyl ether to afford the urea 24 (121 mg, 68% overall yield from 9), mp 93-96 "C (Found: C, 60.3; H, 9.5; N, 6.9. C,,H,,N,O,Si requires C, 60.26; H, 9.61; N, 7.03%); [@I;' +96.4 (c 0.93, CHC1,); v,,,(film)/cm-' 3304 (NH) and 1633 (C=O); 6,(270 MHz; CDCl,) 0.05 (6 H, s, SiMe,), 0.85 (9 H, s, Bu'), 1.17 (3 H, d, J 6, CHMe,), 1.26 (3 H, d, J 6, CHMe,), 1.86-1.94 (4 H, NCHZCH,), 3.22-3.37 (4 H, NCHZCH,), 3.66-3.80 (2 H, 5- and 6-H), 3.88 (1 H, d, J 11, 6-H), 4.06 (1 H, sept, J 6, OCHMe,), 4.13 (1 H, br d, J 10, NH), 4.33 (1 H, br d, J 10, 4-H).5.11 (1 H, d, J2, 1-H) and 5.80-5.87 (2 H, 2- and 3-H). General procedure for the synthesis of the acetamide isopropyl 4-acetamido-6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-erythvo-hex-2-enopyranoside 25 To a solution of the carbamate 21 (148 mg, 0.43 mmol), triphenylphosphine (283 mg, 1.08 mmol) and DIPEA (0.18 cm3, 1.1 mmol) in dichloromethane (4 cm3) was added a solution of tetrabromomethane (398 mg, 1.21 mmol) in dichloromethane (1 .O cm3) dropwise at -20 "C.After being stirred for 150 rnin at -20 "C and then for 60 rnin at room temperature, the solution was recooled to -20 "C. To this solution was added a solution of trimethylaluminium (1.3 mol dmP3 solution in hexane; 2.2 cm3, 2.8 mmol). After the solution had been stirred for 2.5 min at -20 "C, methanol was added cautiously. The reaction mixture was poured into saturated aq. potassium sodium tartrate, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, and concentrated under reduced pressure. Purification of the resulting residue (0.75 g) with silica gel chromatography with diethyl ether furnished the acetamide 25 (90 mg, 59% overall from 9), mp 99-100 "C (from diethyl ether-hexane) (Found: C, 59.4; H, 9.6; N, 4.0.C17H3,N04Si requires C, 59.44; H, 9.68; N, 4.08%); [a];'+56.0 (c 0.26, CHCl,); vmax(film)/cm-' 3259 (NH) and 1647 (0);6,(270 MHz; CDCl,) 0.06 (6 H, s, SiMe,), 0.89 (9 H, s, Bu'), 1.16 (3 H, d, J 6, CHMe,), 1.24 (3 H, d, J 6, CHMe,), 1.97 (3 H, s, Ac), 3.64-3.79 (3 H, 5-H and 6-H,), 4.03 (1 H, sept, J 6, CHMe,), 4.43 (1 H, t, J 9, 4-H), 5.09 (1 H, d, J2, 1-H), 5.45 (1 H, br d, J9, NH) and 5.72-5.83 (2 H, 2- and 3-H). Isopropyl6-0-(tert-butyldimethylsilyl)-2,3,4-trideoxy-4-(pyrrolidine-1-carboxamido)-a-~-threo-hex-2-enopyranos~de26 The procedure used here was similar to that used in the general procedure for the synthesis of the epimeric urea 24.Starting from compound 10 (568 mg, 1.88 mmol), trichloroacetyl isocyanate (0.27 cm3, 2.3 mmol), dichloromethane (19 cm3), potassium carbonate (780 mg, 5.64 mmol), methanol (9 cm3) and water (5 cm3), the corresponding carbamate (627 mg) was obtained in 97% yield.A portion of this carbamate was used for the next reaction without further purification. The carbamate (120 mg, 0.35 mmol) was transformed into the urea 26 (95 mg, 66% overall yield from substrate 10)by employing tetrabromomethane (325 mg, 0.98 mmol), triphenyl- phosphine (230 mg, 0.88 mmol), DIPEA (0.15 cm3, 0.88 mmol), dichloromethane (5 cm3) and pyrrolidine (0.23 cm3, 2.8 mmol), [a]:' -142 (c 0.42, CHC1,); vmax(film)/cm-l 3272 (NH) and 1626 (C=O); 6,(270 MHz; CDC1,) 0.04 (6 H, s, SiMe,), 0.87 (9 H, s, Bu'), 1.15 (3 H, d, J6, CHMe,), 1.24 (3 H, d, J 6, CHMe,), 1.841.91 (4 H, m, NCH,CH,), 3.23-3.33 (4 H, NCH,CH,), 3.67 (1 H, dd, J 10 and 7, 6-H), 3.81 (1 H, dd, J 10 and 4,6-H), 4.06 (1 H, sept, J6, OCHMe,), 4.14-4.22 (1 H, 5-H), 4.224.26 (2H,4-HandNH),5.09(1H,d,J3, l-H),5.77(1H,dd,JlOand 3, 2-H) and 6.07 (1 H, br d, J 10, 3-H) (Found: M', 398.2587. C,,H,,N,O,Si requires M, 398.2601).Isopropyl4-acetamido-6-tert-butyldimethylsilyl)-2,3,4-0-( trideoxy-a-~-threo-hex-2-enopyranoside27 The procedure used was similar to that used in the general procedure for the synthesis of the epimeric acetamide 25.The carbamate (150 mg, 0.43 mmol) was transformed into the acetamide 27 (97 mg, 63% overall yield from substrate LO) by using tetrabromomethane (398 mg, 1.20 mmol), triphenylphos- phine (283 mg, 1.08 mmol), DIPEA (0.18 cm3, 1.1 mmol), dichloromethane (5 cm3) and trimethylaluminium (1.3 mol dmp3 solution in hexane; 2.15 cm', 2.8 mmol), mp 52-54 "C; [a];' -96.8 (c 0.34, CHCl,) (Found: C, 59.2; H, 9.7; N, 4.0.C1,H3,NO4Si requires C, 59.44; H, 9.69; N, 4.08%); v,ax(film)/cm-l 3259 (NH) and 1647 (C=O); 6,(270 MHz; CDCI,) 0.05 (6 H, s, SiMe,), 0.88 (9 H, s, Bu'), I .16 (3 H, d, J6, CHMe,), 1.23 (3 H, d, J6, CHMe,), 1.96 (3 H, s, Ac), 3.63 (1 H, dd, J 11 and 7,6-H), 3.75 (1 H, dd, J11 and4,6-H),4.03 (1 H, sept, J6, Me,CHO), 4.17 (1 H, ddd, J7,4 and 3,5-H), 4.36 (1 H, ddd, J 9,6and 3,4-H), 5.09(1 H, d,J 3,1-H), 5.70(1 H,d,J9,NH), 5.81 (1 H, dd, J 10 and 3,2-H) and 6.02 (1 H, dd, J 10 and 6,3-H).Ethyl 6-0-(tert-butyldimethyIsilyl)-2,3,4-trideoxy-2-(pyrrolidine-1-carboxamido)-a-~-ery~hro-hex-3-enopyranoside 28 The procedure used was similar to that used in the general procedure for the synthesis of the ureas 24and 26.Starting from compound 13 (471 mg, 1.64 mmol), trichloroacetyl isocyanate (0.25 cm3, 2.1 mmol), dichloromethane (1 7 cm3), potassium carbonate (721 mg, 5.22 mmol), methanol (8 cm3) and water (5 cm3), the corresponding carbamate (550 mg) was obtained in 96% yield. The carbamate was used for the next reaction without further purification. The carbamate (1 50 mg, 0.45 mmol) was transformed into the urea 28(85 mg, 47% overall yield from alcohol 13)by employing tetrabromomethane (41 8 mg, 1.26 mmol), triphenylphosphine (295 mg, 1.13 mmol), DIPEA (0.20 cm3, 1.1 mmol), dichloro- methane (5 cm3) and pyrrolidine (0.30 cm3, 3.6 mmol), [a];' Ethyl 2-acetamido-6-O-(tert-butyldimethylsilyl)-2,3,4-h.ideoxy-a-~-erythro-hex-3-enopyranoside29 The procedure used was similar to that used in the general procedure for the synthesis of the acetamides 25 and 27.The carbamate (150 mg, 0.45 mmol) was transformed into the acetamide 29 (74 mg, 47% overall yield from alcohol 13) by using tetrabromomethane (41 8 mg, 1.26 mmol), triphenylphos- phine (295 mg, 1.13 mmol), DIPEA (0.20 cm3, 1.1 mmol), dichloromethane (5 cm3) and trimethylaluminium (1.3 mol dm-, solution in hexane; 2.3 cm3, 2.9 mmol), mp 90-91 "C; [a];' -18.1 (c 0.24, CHCl,) (Found: C, 58.6; H, 9.5; N, 4.3.C,,H,,NO,Si requires C, 58.32; H, 9.48; N, 4.25%); vmax(film)/ cm-I 3292 (NH) and 1652 (NHC=O); 6,(270 MHz; CDCl,) 0.07 (6 H, s, SiMe,), 0.88 (9 H, s, Bu'), 1.24 (3 H, t, J 7, CH,CH,), 2.00 (3 H, s, Ac), 3.51-3.64 (2 H, CH,CH,O and 6-H), 3.71 (1 H, dd, J 10 and 6,6-H), 3.76-3.90 (1 H, CH,CH,), 4.084.17 (1 H, m, 5-H), 4.67-4.77 (1 H, m, 2-H), 4.92 (1 H, d, J4, I-H), 5.57 (1 H, br d, J 10, CH=CH), 5.77-5.81 (1 H, NH) and 5.85 (1 H, dt, J 10 and 1, CHSH). Ethyl6-0-(tert-butyldimethylsilyl)-2,3,4-trideoxy-2-(pyrrolidine-l-carboxamido)-a-~-thre~-~e~-3-enopyranoside The procedure used was similar to that used in the general procedure for the synthesis of the ureas. Starting from compound 14 (500 mg, 1.74 mmol), trichloroacetyl isocyanate (0.25 cm3, 2.1 mmol), dichloromethane (1 7 cm3), potassium carbonate (721 mg, 5.22 mmol), methanol (8 cm3) and water (5 cm3), the corresponding carbamate (551 mg) was obtained in 96% yield.The resulting carbamate was used for the next reaction without further purification. The carbamate (127 mg, 0.38 mmol) was transformed into the urea 30 (1 13 mg, 78% overall yield from the alcohol 14)by using tetrabromomethane (3 15 mg, 0.95 mmol), triphenylphos- phine (252 mg, 0.96 mmol), triethylamine (0.18 cm3, 0.96 mmol), dichloromethane (4 cm3) and pyrrolidine (0.25 cm3, 3.0 mmol), [a];' +85.4 (c 0.74, CHCl,) (Found: C, 59.3; H, 9.6; N, 7.1. C19H,,N,0,Si requires C, 59.34; H, 9.44; N, 7.29%); v,,,(film)/cm-' 3313 (NH) and 1652 (C=O); 6,(270 MHz; CDCl,) 0.05 (6 H, s, SiMe,), 0.87 (9 H, s, Bur), 1.20 (3 H, t, J 7, CHZCH,), 1.79-1.92 (4 H, NCHZCH,), 3.17-3.36 (4 H, NCH,CH,), 3.48-3.84 (4 H, CH,CH,O and 6-H,), 4.1-4.23 (3 H, 2- and 5-H, NH), 4.82 (1 H, s, 1-H) and 5.78-5.95 (2 H, 3- and 4-H).Ethyl2-acetamido-6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-a-D-threo-hex-3-enopyranoside31 The procedure used was similar to that used in the general procedure for the synthesis of the acetamides. The carbamate (122 mg, 0.36 mmol) was transformed into the acetamide 31 (73 mg, 58% overall yield from the alcohol 14) by using tetrabromomethane (334 mg, 1.01 mmol), triphenylphosphine (236 mg, 0.90 mmol), DIPEA (0.16 cm3 0.90 mmol), dichloromethane (4 cm3) and trimethylaluminium (1.3 mol dm-, solution in hexane; 1.8 cm3, 2.4 mmol), [a]:' +52.1 (c 0.13, CHCl,); v,,,(film)/cm-' 3281 (NH) and 1653 (W);6,(270 MHz; CDCl,) 0.08 (6 H, s, SiMe,), 0.90 (9 H, s, Bur), 1.22(3 H, t, J 7, CH,CH,), 1.96 (3 H, s, Ac), 3.51-3.85 (4 H, CH3CH,0 and 6-H,), 4.19 (I H, br, 5-H), 4.33 (1 H, dd, J9 and 6,2-H), 4.78 (1 H, s, 1 -H), 5.59 (1 H, br d, J 9, NH) and 5.79-5.98 (2 H, 3- and 4-H) (Found: Mf , 329.2014.C,,H,,NO,Si requires M, 329.2022). -40.7(~0.46,CHCI,)(Found:C,59.3;H,9.5;N,7.3.C,,H,,-Ethyl 2-acetamido-2,3,4-tr~deoxy-6-O-methylsulfonyl-a-~-N204Si requires C, 59.34; H, 9.44; N, 7.29%); vmax(film)/cm-' 3344 (NH) and 1652 (C=O); 6,(270 MHz; CDCl,) 0.06 (6 H, s, SiMe,), 0.89 (9 H, s, Bu'), 1.22 (3 H, t, J 7, CH,CH,), 1.84-1 -95 (4 H, NCHZCH,), 3.25-3.39 (4 H, NCHZCH,), 3.51-3.64 (2 H, CH,CH,O and 6-H), 3.71 (1 H, dd, J 10 and 6,6-H), 3.83 (1 H, dq, J10and7,CH3CH2O),4.08-4.16(1H, br, 5-H),4.56-4.69 (2 H, 2-H and NH), 4.94 (1 H, d, J4, 1-H), 5.64 (1 H, br d, J 10, CH=CH) and 5.83 (1 H, br d, J 10, CH=CH).threo-hex-3-enopyranoside 32 A solution of TBAF (1 mol dmp3 solution in THF; 0.14 cm3, 0.14 mmol) was added to a solution of the silyl ether 31 (70 mg, 0.21 mmol) in acetonitrile (2.3 cm3) at room temperature. The resulting reaction mixture was stirred for 90 min and then concentrated under reduced pressure. Purification of the resulting residue by silica gel chromatography (3 g) with ethyl acetate afforded the alcohol (38 mg).This alcohol (38 mg, 0.18 J. Chem. Soc., Perkin Trans. 1 381 mmol) was dissolved in pyridine (2.7 cm3), and then treated with methanesulfonyl chloride (0.15 cm3, 2.0 mmol) at room temperature. After being stirred for 90 min, the reaction mixture was concentrated under reduced pressure to provide a residue (0.14 g), which was purified by silica gel chromatography (2 g) with ethyl acetate to furnish the mesyl derivative 32(36 mg, 57% overall yield from substrate 31), mp 92-93 "C (lit.," 89-91 "C); [a];' + 121 (c 1.78, CHCl,) [lit.," + 132 (c 2.0 in CHCI,)] (Found: C, 44.9; H, 6.5; N, 4.8. Calc. for C11HigN06S: C, 45.04; H, 6.53; N, 4.77%); 6,(270 MHz; CDCl,) 1.23 (3 H, t, J7, CH,CH,j, 1.98 (3 H, s, Ac), 3.08 (3 H, s, CH,SO,), 3.60 (1 H, dq, J 10 and 7, OCH,CH,j, 3.79 (1 H, dq, J 10 and 7, OCH,CH,), 4.28 (1 H, dd, J 11 and 4, 6-H), 4.32-4.46 (2 Hj, 4.54 (1 H, dd, J 11 and 3), 4.83 (1 H, s, 1-H), 5.82-6.04 (2 H, 3- and 4-H) and 6.19 (I H, d, J 9, NH) [lit., * zH 3.8-4.2 (3 H, m), 5.2(1 H, s), 5.48-5.96(4H, m), 6.17-6.58 (2 H, m), 6.94 (3 H, s), 8.2 (3 H, s) and 8.76 (3 H, t)].Acknowledgements We appreciate the support of two Grants-In-Aid for Scientific Research from the Ministry of Education, Science and Culture. We also thank Mr. Kitamura (Analytical Laboratory, School of Agriculture, Nagoya University) for elemental analyses. References 1 Y. Ichikawa, Synlett, 1991, 238; Y. Ichikawa, H. Yamazaki and M. Isobe, J. Chem. Soc., Perkin Trans.I, 1993,2429. 2 Y. Ichikawa, K. Tsuboi and M. Isobe, J. Chem. SOC.,Perkin Trans. I, 1994,2429. 3 R. J. Ferrier and N. Vethaviyasar, Chem. Commun., 1970, 1385; R. J. Ferrier and N. Prasad, J. Chem. Soc. C,1969,570. 4 (a)I. Dyong, J. Weigand and H. Merten, Tetrahedron Lett., 1981,22, 2965; I. Dyong, J. Weigand and J. Thiem, Liebigs Ann. Chem., 1986, 577; (b)M. Isobe, Y. Fukuda, T. Nishikawa, P. Chabert, T. Kawai and T. Goto, Tetrahedron Lett., 1990, 31, 3327; (c) K. Takeda, E. Kaji, Y. Konda, N. Sato, H. Nakamura, N. Miya, A. Morizane, Y. Yanagisawa, A. Akiyama, S. Zen and Y. Harigaya, Tetrahedron Lett., 1992,33, 7145. 5 Y. Ichikawa, C. Kobayashi and M. Isobe, Synlett, 1994,919. 6 M. Isobe, Y. Ichikawa and T. Goto, Tetrahedron Lett., 1985, 26, 5199; Y. Ichikawa, M. Isobe, D.-L.Bai and T. Goto, Tetrahedron, 1987,43,4737. 7 G. Grynkiewicz and H. Burzynska, Tetrahedron, 1976, 32, 2109; D. L. Hughes, in Organic Reactions, Wiley, New York, 1992; vol. 42, p. 335. 8 R. J. Ferrier and N. Vethaviyaser, J. Chem. Soc. C, 1971, 1907. 9 N. Otake, S. Takeuchi, T. Endo and H. Yonehara, Tetrahedron Lett., 1965, 1405. 10 S. Harada, E. Mizuta and T. Kishi, Tetrahedron, 1981, 37,1317. 11 R. S. Guthrie and G. J. Williams, J. Chem. Soc., Perkin Trans. 1, 1972,2619. Puper 5/046451 Received 14th July 1995 Accepted 15th August 1995 382 J. Chem. SOC.,Perkin Trans. 1