Stereoselective condensation of bis-p-tolylthiomethane with lactic acid derivatives through an acylationndash;reduction strategy: synthesis of protected 4-deoxy-L-threose and 4-deoxy-L-erythrose

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 Stereoselective Condensation of Bis-p-tolylthiomethane with Lactic Acid Derivatives through an Acylation-Reduction Strategy: Synthesis of Protected 4-Deoxy-L-threose and 4-Deoxy-~-erythrose Giuseppe Guanti," Luca Banfi, Alberto Guaragna, and Enrica Narisano lstituto di Chimica Organica, Palazzo delle Scienze, corso Europa, I6132 Genova, Italy The condensation of lithium bis-p-tolylthiomethanide with protected ethyl-L-lactates gave a series of 3-alkoxy- (or 3-hydroxy-) 1,l -bis-p-tolylthiobutan-2-ones, which were stereoselectively reduced to the corresponding syn- or anti-alcohols with diastereoselectivities of up to 85:15 and 75: 25, respectively. These alcohols were then converted into variously protected 4-deoxy-~-threose and 4-deoxy-~- eryt h rose derivatives.In recent years, interest has grown in the synthesis of sugars from non-carbohydrate precursors. This goal has been accomplished via total asymmetric synthesis,'-3 and through stereospecific elaboration of simple chiral building blocks derived from natural sources. As building blocks of this type, protected 4-deoxy-~-threose and -L-erythrose are particularly useful, and have given rise to numerous rare sugars4 However, their utility is not limited to the field of sugars: they have also been employed in the preparation of pheromones5 and of the chemotactic factor LTB4.6 Protected 4-deoxy-~-threose has been prepared from D-thre~nine~~and from L-tartaric or through isomeriz- ation of the e~irner;~" 4-deoxy-~-erythrose has been synthesized via ozonolysis of a diol prepared from cinnamaldehyde in fermenting baker's Recently we reported some preliminary results on the synthesis of these important building blocks from ethyl L-lactate, a particularly cheap chiral precursor.8 Now we present our results in full.Our strategy (Scheme 1) was based on the 11) R'= PhCH;! (2) R' = MeOCH2CH20CH2 (3)R' = But Ph2Si (4)R' :Me2(MeO)CI ?R' I Me*CJO (61R1= MeOCH2CH20CH2 17) R'= Bu'Ph2Si stereoselective homologation of a protected ethyl lactate with bis-p-tolylthiomethane (5), the lithium salt of which can be regarded as a formyl anion equivalent. This conversion can be accomplished in two ways: (a)reduction of the protected ethyl lactates to the corresponding a-alkoxy aldehydes followed by condensation with lithiated (5), and (b) direct coupling of the lactates (1)-(4) with (5) followed by the reduction of the resulting ketones.We have already shown899 that the reaction of the lithium salt.of (5) with esters, in contrast with the same reaction of lithium 1,3-dithianides,lo gives ketones in excellent yields, without formation of undesired tertiary alcohols. These two approaches are equally straightforward and a choice between them must be made only on the basis of stereo-selectivity. Condensation of lithiated (5) with the protected lactaldehydes (6)and (7), prepared by known method~,"-'~ gave the adducts (14a and b) and (15a and b) in good yields, but with low stereoselectivity (syn:antiI4 36 :64 and 43 :57, respectively).This result was not unexpected since condensation of organo- (8) R'= PhCH2 (9) R' = MeOCH2CH20CH2 (10)R' = ButPh2Si (111R' = Me+MeO)C (12)R' = H bsol;L ?R' SAr Me bH OH a;syn (threo) b;unti (erythro) (13)R1=PhCH2 (14)R'= MeOCH2CH20CH2 (15)R' = But P h,Si (16)R' I H Scheme 1. 2370 J. CHEM. SOC. PERKIN TRANS. I 1988 Table 1. Diastereoselectivity in the reduction of 3-alkoxy- (or 3-hydroxy) l,l-bis-p-tolylthiobutan-2-ones Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 R' PhCH, PhCH, PhCH, MeOCH,CH,OCH, MeOCH,CH,OCH, MeOCH,CH,OCH, SiPh,Bu' SiPh,Bu' SiPh,Bu' SiPh, Bu' H H H H H MeOCMe, Reducing agent Conditions NaBH, Zn(BH4)2DIBAH NABH, LiAlH, DIBAH NaBH, MEAH DIBAH BH,-THF NaBH, Zn(BH4)2NaBH,/CeCl, Li AIH, MEAH DIBAH -50"C, MeOH -60"C, Et2O -78"C,CH2C12 -50"C,MeOH -78"C, EtZO -78"C, CH2C12 -78"C, MeOH -78'C, toluene -78 "C, toluene Room temp., THF, 7 days -50"C, MeOH -78 OC, Et2O -78OC, MeOH -78OC, Et2O -78"C,THF -78"C, CH,CI, syn :anti ratio a Yield () 42:58 80 65:35 75 77:23 80 42:58 80 52:48 90 78:22 80 34:66 83 40:60 90 85:15 75 85:15 75 25 :75 87 61:39 80 60:40 75 50:50 65 46:54 80 84:16' 70 'Determined by standardized spectrodensitometry (254nm) with diethyl ether-hexane as eluant except for R '=PhCH, when CH,CI,-hexane- diethyl ether was used; orders of elution (13a) (13b); (14b) (14s); (15a) (15b); (16b) (16a).DIBAH = di-isobutyl aluminium hydride; MEAH = sodium bis-(2-methoxyethoxy)aluminiumhydride. 'Compounds (16a and b) were obtained directly. Overall yield of (16a and b) from (4). 0 A rSASAr A rS*SAr / .H'H bsol; f} A rSamp;A, (20) (271 Scheme 2. lithium derivatives with simple r-alkoxy aldehydes is known to afford anti-compounds with low diastereoselectivity.' 5-1 We therefore focussed our attention on the acylation-reduction approach. The 3-alkoxy- l,l-bis-p-tolythiobutan-2-ones (8)-(11) were obtained in high yield through con-densation of (5) with the protected lactates (1)-(4); the a- hydroxy ketone (12) was synthesized by mild hydrolysis of the methoxy(methy1)ethoxy derivative (11).The stereoselectivity in the reduction of these a-alkoxy (or a-hydroxy) ketones with a series of reducing agents was then studied (Table 1). The stereochemical course of reduction was in some cases unexpected, on the basis of previous literature reports. For example, although reduction of a-diphenyl(t-buty1)silyloxy ketones with sodium bis(methoxyethoxy)aluminium hydride (MEAH) is known usually to afford syn-alcohols, according to the Felkin model," we found a reversed, albeit low, selectivity (entry 8). A similar deviation from the Felkin model had been reported by Oishi17 for the reduction of the ketone (17) with the same hydride.In these two cases the bulk of the bis-p- tolythiomethyl (or isopropyl) group, coupled with the steric hindrance of the diphenyl(t-buty1)silyloxy moiety, is likely to cause a distortion of the reactive conformation from (18) to (19) (Scheme 2). This explanation can account also for the slight anti preference in the reduction of the silyloxy ketone (10) with J. CHEM. SOC. PERKIN TRANS. I 1988 Me+-OH Hlsquo; (221 (23) Scheme 3. sodium borohydride (entry 7). In contrast, reduction with di- isobutylaluminium hydride (DIBAH) of the a-alkoxy ketones (8)-(11) led to the syn adducts with good diastereoselectivity, particularly in the case of bulky alkoxy groups (entries 3, 6, 9, and 16). It is likely that interaction with the two isobutyl groups disfavours the lsquo;distortedrsquo; conformation (21) with respect to the lsquo;normalrsquo; Felkin conformation (20) (Scheme 2).rsquo; **I9 A similar result was obtained with another Lewis acid, diborane (entry 10).However in this case the reaction was sluggish. When the reaction was quenched with water after 2h, the isomeric alcohols (15a and b) were obtained in 40 yield in a reversed syn :anti ratio of 35 :65, similar to that obtained with NaBH,. When quenching was effected after 2 or 7 days, this ratio had increased to 68: 32 or 85: 15, respectively (and the yields to 65 or 75). Since no equilibration of (15b)to (15a) was observed under the reaction conditions, this intriguing result is presumably due to reduction under quenching conditions.* The course of reduction of the a-hydroxy ketone (12) was also somewhat surprising.While sodium borohydride furnished preferentially the expected anti-diol (16b), according to Cramrsquo;s cyclic model (entry 1l), zinc borohydride and in situ-generated cerium borohydride2rsquo; gave opposite results (entries 12 and 13). The bulk of the p-tolylthiomethyl groups seems not to be responsible for this anomalous result, in the light of the high anti-selectivity obtained by Oishirdquo; in the zinc borohydride reduction of r-hydroxy ketones regardless of the steric hindrance of the alkyl group attached to carbonyl. A possible interpretation is based on the capacity of sulphur to co-ordinate zinc in the transition state (21) leading to the alternative chelated conformations (22) and (23).Oishi and his co-workers2rsquo; have recently demonstrated that in Zn(BH,), reduction of an r-alkylthio- P-hydroxy ketone the metal atom is chelated, in the preferred transition state, by the carbonyl oxygen and the hydroxy group (and not by the alkylthio group). In view of this finding, the transition state (22), in which, on the contrary, an alkylthio group rather than the hydroxy group contributes to the formation of a chelated transition state, * The use of BH,-Me,S leads to identical results. (160. b 1 12Ga.b 1 (26a. b) (25a,b1 P h-0 SAr Phno I I +C HO Me I I 0-Ph 27a, b 1 I28a) ButPh2Si0 I SAr I But PhZSiQ a;syn ( threo) b;anti erythro) Scheme 4. seems less likely. Nevertheless in that example the two types of co-ordination lead to differently sized rings (five-membered for sulphur and six-membered for oxygen), whereas in our case both kinds of co-ordination lead to five-membered rings. Thus we cannot definitely rule out the transition state (22).Reduction with DIBAH of the methoxy(methy1)ethoxy ketone (ll), followed by acidic work-up, led directly to the deprotected diols (16), and the silyloxy alcohols (15) were smoothly deprotected with Bu,NF to (16). The syn-and anti- diols (16a and b) were easily separated by flash chromato- graphy.** Thus we can conclude, from a synthetic point of view, that either (16a) or (16b) may be obtained in excellent yield and with good stereoselectivity by this acylation-reduction sequence, by employing the conditions of entry 9 (or 16) or 11, respectively. We next examined the transformation of these compounds into the protected 4-deoxy-~-threoses and 4-deoxy-~-erythroses.Conversion of (16a and b) into the acetonides (24a and b) (2-methoxypropene and toluene-p-sulphonic acid, 98 and 97 yield), followed by deblocking of the dithioacetal moiety (HgO and BF,-Et,O) '' gave isopropylidene-4-deoxy-~-threoseand -erythrose (25a and b), in situ reduction (NaBH,) of which furnished the known5a,23.24 isopropylidene-4-deoxy-~-threitol and -erythritol (26a and b) in, respectively, 40 and 60 overall yield from (24).*This conversion allowed unequivocal establishment of the relative configuration of (1621) and (16b).t Dibenzylation of (16a) NaH, PhCH,Br, and dimethyl- formamide (DMF); 65x1 followed by hydrolysis of the dithioacetal (HgO and BF,-Et,O, 75) gave the dibenzyl-4- deoxy-L-threose (28a).Finally a 4-deoxy-~-threose protected with two different groups was obtained in two steps (l) Ac,O, Et,N, and dimethylaminopyridine, 80; (2) HgO and BF,- Et,O, 70x1 from (15a). Access to variously protected a,P- dialkoxy aldehydes may well allow the development of high stereoselectivities in their addition reactions." Finally, use of D-lactic acid, which will be soon easily available through a biotechnological method,26 should allow us to obtain protected 4-deoxy-~-threose and 4-deoxy-~-erythrose; the latter is not available by previously known methods. Experimental N.m.r.spectra were recorded with a Varian FT 80 spectrometer (tetramethylsilane as internal standard). 1.r. spectra were measured with a Perkin-Elmer 257 instrument for CHCl, solutions. Optical rotations were measured at 20 "C (1 dm cell) with a JASCO DIP-181 polarimeter. Elemental analyses were performed with a Perkin-Elmer 240 instrument. Spectro-densitometry analyses were performed with a CAMAG t.1.c. scanner, with Hewlett-Packard 3390 A integrator. Samples were deposited automatically on silica gel 60 F254 plates (Merck) (CAMAG Linomat 111). Standardization was achieved by analyses of mixtures of known composition. Silica gel (Merck 270-400 mesh) was used for flash chromatography.22 Organic extracts were dried over Na,SO, and filtered before removal of the solvent under reduced pressure.All reactions in dry solvents were run under nitrogen. Protected ethyl lactates (1) and (2) were prepared by reported methods.' 1,12,27,28 (S)-( -)-Ethyl 2-Diphenyl( t-butyl)silyloxylpropanoate(3).-Diphenyl(t-buty1)silyl chloride (4 ml, 15.3 mmol) was added to a solution of (S)-ethyl lactate (1.788 ml, 16.0 mmol) and imidazole (2 g, 30 mmol) in dry dimethylformamide (DMF) (5 ml). The solution was stirred at 25 "C for 18 h, then treated with H,O and hexane; the phases were separated and the organic extracts evaporated to dryness. Flash chromatography (hexaneaiethyl ether) gave pure (3) as a colourless oil (5.8 g, 96) (Found: c, 71.05; H, 7.95. C,,H,,O,Si requires C, 70.7; H, 7.9); aID -41.1" (c 2 in CHCl,); vmax.1 740, 1 590, 1425, 1 140, 1 110, 1 020, and 820 cm-'; S,(CDCl,) 1.11 9 H, s, C(CH,),, 1.1 1 (3 H, t, J 7 Hz, CH,CH,), 1.40 (3 H, d, J 7 Hz, CH,CH), 4.00 (2 H, q, J 7 Hz, CH,CH,), 4.29 (1 H, q, J 7 Hz, CHCH,), and 6.95-7.80 (10 H, m, ArH).(S)-(-)-Ethyl 2-( 1-Methoxy-1 -methylethoxy)propanoate (4).-2-Methoxypropene (32.4 ml, 339 mmol) was slowly * The low yield in the hydrolysis of the dithioacetal moiety is due to partial hydrolysis of the acetonide under the reaction conditions. Better results could be probably obtained by the use of cyclohexylidene derivatives. t The relative configuration of the benzyl ethers (13a and b) was determined through their conversion into the bisbenzyl ethers (27a and b); the methoxyethoxymethyl ethers (14a and b) were correlated with the analogues through clear 'H n.m.r.analogies. J. CHEM. SOC. PERKIN TRANS. I 1988 added, at 0 "C, to (S)-ethyl lactate (19.2 ml, 169 mmol). A drop of POCl, was then added and the solution was stirred over- night at room temperature. After addition of few drops of triethylamine, the excess of 2-methoxypropene was evaporated off under reduced pressure to leave an oil which, after distillation, furnished pure (4) (27.5 g, 85), b.p. 93 "C at 15 mmHg (Found: C, 56.7; H, 9.75. C,HI8O, requires C, 56.8; H, 9.5); .ID -75.9 (c in CHCl,); v,,,, 2 830, 1 735, 1 445, 1 375, 1 180,l 110,l 095,1045, and 970 cm-'; GH(CDC1,) 1.27 (3 H, t, J 7.1 Hz, CH,CH,), 1.32 and 1.39 2 x 3 H, 2 x s, (CH,),C, 1.38(3 H, d, J6.9 Hz, CH,CH), 3.21 (3 H, s, CH,O), 4.18 (2 H, q, J 7.1 Hz, CH,CH,), and 4.33 (1 H, q, J 6.9 Hz, CH,CH).Bis-p-tolylthiomethane (5).-Sodium hydroxide (25.76 g, 644 mmol) was added to a cooled solution of p-thiocresol(80 g, 644 mmol) in absolute ethanol (300 ml). After 2 h, when nearly all the NaOH was dissolved, di-iodomethane (26.98 ml, 335 mmol) was slowly dropped in so that the temperature did not exceed 60 "C. The mixture was then heated at reflux for 2 h. Most of the ethanol was then evaporated off under reduced pressure; the residue was taken up with diethyl ether and water and the phases were separated. The organic extracts were washed with aqueous 5 KOH and brine, and evaporated to dryness to leave a yellowish oil which, after crystallization from hexane, afforded pure (5) as a white low-melting solid (70 g, 84), m.p.35 "C (Found: C, 69.1; H, 6.25. CI5Hl6S2 requires C, 69.2; H, 6.2); S,(CDCl,) 2.33 (6 H, s, CH,), 4.27 (2 H, s, CH,), and 7.15 and 7.36 (8 H, AB, J 8.5 Hz, ArH). 3- Alkoxy- (or 3-Hydroxy-) l,l-bis-p-tolylthiobutan-2-ones @)-(lo) and (12): General Procedure.-A 1.6~solution of butyl-lithium in hexane (6.87 ml, 11 mmol) was added, at -65 "C, to a solution of (5) (2.60 g, 10 mmol) in dry tetrahydrofuran (THF) (20 ml). After 15 min a solution of the ester (1-(4) (5 mmol) in THF (5 ml) was added at the same temperature. After 10 min the mixture was quenched with 3~ acetic acid in THF (5 ml, 15 mmol), stirred for 10 min at -65 "C, warmed to room temperature, and diluted with water and diethyl ether.The organic phase was separated and evaporated to dryness to leave a crude oil, which was purified by flash chromatography (hexane-diethyl ether) to give pure product (8)-(lo), and unchanged (5). The ketone (11) was quantitatively converted into (12) during silica gel chromato- graphy. Yields in parentheses that of unchanged (5) were (8) 75 (40) (Found: C, 70.8; H, 6.2. C25H2,02S, requires C, 71.05; H, 6.2); (9) 79 (41) (Found: C, 62.9; H, 6.85. C,,H,,O,S, requires c, 62.8; H, 6.7); (10) 85 (36) (Found: C, 71.45; H, 6.65. C,,H380,S,Si requires C, 71.5; H, 6.7); (12) 95 (32) (Found: C, 64.9; H, 6.05. C,8H2,02S, requires C, 65.0; H, 6.1).N.m.r. spectra showed SH(CDC13) (8) 1.33 (3 H, d, J6.8 Hz, CH,CH), 2.33 (6 H, s, CH,Ar), 4.23 (1 H, q, J6.8 Hz, CHCH,), 4.51 (2 H, s, CH,Ph), 5.33 (1 H, s, CHS), 7.29 (5 H, s, C6H5), and 7.00-7.50 (8 H, m, C6H,); (9) 1.35 (3 H, d, J6.8 Hz, CH,CH), 2.33 (6 H, s, CH,Ar), 3.36 (3 H, s, CH,O), 3.37-3.76 (4 H, m, OCH,CH,O), 4.47 (1 H, q, J6.8 Hz, CHCH,), 4.75 (2 H, s, OCH,O), 5.30 (1 H, s, CHS), and 7.05-7.50 (8 H, m, ArH); (10) 1.04 9 H, s, C(CH,),, 1.22(3 H, d, J6.8 Hz, CH,CH), 2.33 (6 H, s, CH,Ar), 4.43 (1 H, q, J 6.8 Hz, CHCH,), 5.65 (1 H, s, CHS), and 7.00-7.80 (18 H, m, ArH); (12) 1.30(3 H, d, J7.0 Hz, CH,CH), 2.34 (6 H, s, CH,), 3.04 (1 H, br s, OH), 4.56 (1 H, q, J 7.0 Hz, CHCH,), 5.07 (1 H, s, CHS), and 7.00-7.50 (8 H, m, ArH).General Procedure for Reduction with NaBH,.-A solution of the ketone in absolute methanol was added to a suspension of NaBH, (5 equiv.) in MeOH. After completion the mixture was quenched with aqueous HCI and evaporated to dryness; the residue was taken up with diethyl ether and water and worked up as usual. J. CHEM. SOC. PERKIN TRANS. I 1988 Table 2. Polarimetric and 'H n.m.r." data for compounds (13a and bH16a and b) CalDi" 6( l-H) 6(3-H) G(CH,CH) Compound (C, in CHCI,) G(CH,Ar) (Jl,z) 6(3-H) (J2J (13a) 2.32 4.51 3.50-3.80 4.10 (10.9) (m) (4.2)(13b) 2.31 4.82 3.50-3.78 3.91 (2.7) (m) (7.8)(14a) 2.32 4.41 3.50-3.80 4.23 (4.9) (m) (4.8)(14b) 2.33 4.62 3.50-3.80 4.08 (3.9) (m) (6.4)(154 -6.9 2.31 4.45 3.53 4.40 (6.0) (4.3)(15b) -87.0 2.32 4.82 3.70 4.27 (3.7) (6.9)(16a) + 102.0 2.33 4.40 3.44 4.25 (5.5) (4.4)(16b) -79.3 2.32 4.61 3.57 4.12 (4.3) (6.8) Solutions in CDCI,-D,O; coupling constants in Hz.General Procedure for Reduction with NaBH,-CeCl,.-The procedure of Gemal and Luche was followed.20 General Procedure for Reduction with Zn(BH,),.-A solution of zinc borohydride (2.5 equiv.) in ether was added to a solution of the ketone in ether. The reaction was quenched with saturated aqueous NH,Cl and worked up as usual. General Procedure for Reduction with Di-isobutylaluminium Hydride (DIBAH).-A solution of DIBAH (1.2-1.3 equiv.) in the appropriate solvent was added to a solution of the ketone in the same solvent. After 3 h the reaction was quenched with 3M acetic acid in diethyl ether (1.1 equiv.with respect to DIBAH) and, after 15 min, with water (0.2 ml per mmol of DIBAH). The suspension was stirred for 2 h at room temperature and then filtered through Celite; the filter cake was washed with CH,Cl,. The filtrate was then washed with dilute aqueous NaHCO, and evaporated to dryness to give a crude product, purified by flash chromatography. General Procedure for Reduction with Sodium Bis-(2-meth- o.xyethoxy)aluminiurn Hydride (MEAH).-A IM solution of the hydride in toluene (3 equiv.) was added to a solution of the ketone in THF for (12) or toluene for (lo). The mixture was quenched with saturated aqueous NH,Cl, filtered through Celite, and worked up as for the DIBAH reduction.General Procedure for Reduction with Diborane.-A solution of BH, in THF (5 equiv.) was added to a solution of the ketone at room temperature. After quenching with water, the reaction was worked up as usual. All the reduction products were purified by flash chromato- graphy hexane-diethyl ether for (14)-(16) and CH,Cl,- hexane-diethyl ether for (13) and gave correct elemental analyses. 'H N.m.r. data and polarimetric powers (when determined) are reported in Table 2. (2R,3S)-(+)-l,l-Bis-p-tolylthiobutane-2,3-diol(16a).-From (4). A solution of (5) (5 g, 19.2 mmol) in dry tetrahydrofuran (THF) (40 ml) was treated, at -78 "C, with a 1.6~ solution of BuLi in hexane (13.2 ml, 21.1 mmol). After 10 min, neat (4) (1 326 g, 1.8 13 ml, 9.6 mmol) was added; the solution was stirred for 15 min, then quenched with aqueous 15 (2.8~) NH,C1 (17.9 ml, 50 mmol).After warming to room temperature, extraction with diethyl ether and evaporation to dryness gave a (J3J G(aromatic) amp;(other) 1.21 6.90-7.55 4.50 (2 H, s, CH,Ph) 1.29(6.2) 6.90-7.55(m) 4.54 and 4.30 (2 H, AB, J 11.2 Hz, CH,Ph) 1.19 1.26 0.98 (5.6) (6.3) (6.1) 6.90-7.55 6.9C7.55 6.90-7.80 (m) (m) (m) 3.40-3.80 (4 H, m, CH,CH,), OCH,),4.79 (2 H, s, OCH,O) 3.40-3.80 (4 H, m, CH,CH,), OCH,),4.69 (2 H,s, OCH,O) 1.03 9 H, s, C(CH,), 3.38 (3 H, s, 3.35 (3 H, s, 1.10(6.0) 6.9G7.80(m) 0.93 9 H, s, C(CH,), 1.18(7.5) 6.s7.55(m) 1.25(6.3) 6.90-7.55(m) (6.3) (m) crude oil (6.82 g) which was taken up with dry CH,Cl, (30 ml); the solution was cooled to -80 "C, and treated with a 1.0~ solution of DIBAH in CH,Cl, (15.36 ml, 15.36 mmol).After 3.5 h, the solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with 3~ acetic acid in CH,Cl, (7.5 ml) and, after 20 min, with water (4 ml). After being stirred for 2 h, the suspension was filtered through Celite, and the filtrate washed with IM HCl, saturated aqueous NaHCO,, and brine, and evaporated to dryness. The crude product was purified by flash chromatography (hexane- diethyl ether) to give pure (Ma) (2.01 g, 63) (Found: C, 64.55; H, 6.7. C,,H2202S, requires C, 64.6; H, 6.6) and (16b) (337 mg, 10.5) (Found: C, 64.45; H, 6.75) as oils, as well as unchanged (5) (1.83 g, 37).(b) From (15a). To a solution of (15a) (67 mg, 0.12 mmol) in dry THF (1 ml), a IM solution of tetrabutylammonium fluoride trihydrate in THF (0.240 ml, 0.24 mmol) was added; the resulting solution was stirred for 2 h at room temperature. After quenching with water and dilution with diethyl ether, usual work-up gave, after flash chromatography (hexane-diethyl ether), pure (16a) (37 mg, 95); (16b) was obtained similarly from (15b). (4R,5S)-(-)-4-(Bis-p-tolylthiomethyl)-2,2,5-trimethyl-1,3-di-oxolane (24a).-2-Methoxypropene (0.295 ml, 3.075 mmol) was added to a cooled (O'C) solution of (16a) (412 mg, 1.23 mmol) in dry CH,Cl, (6 ml), followed by a 0.01~ solution of toluene-p-sulphonic acid in THF (0.2 ml, 0.002 mmol). The solution was stirred for 20 h, quenched with few drops of triethylamine, and evaporated to dryness.Flash chromato- graphy (hexanediethyl ether) gave pure (24a) as an oil (450 mg, 98) (Found: C, 67.2; H, 7.1. C,,H,,O,S, requires C, 67.3; H, 7.0). a,, (c 1 in CHCl,) -9.4O; G,(CDCl,) 1.33 (3 H, d, J 6.0 Hz, CH,CH), 1.41 and 1.46 (2 x 3 H, 2 x s, CH,CCH,), 2.32 (6 H, s, CH,Ar), 3.88 (1 H, dd, CHCHS, J4.0 and 7.6 Hz), 4.29 (1 H, dq, J5.9 and 7.7 Hz, CHCH,), 4.34 (1 H, d, J4.0 Hz, CHS), 7.09 (4 H, d, J 8.1 Hz, CH meta to S), and 7.30 (4 H, d, J 8.1 Hz, CH ortho to S); G,(CDCl,) 18.96 (CH,CH), 21.18 (CH,Ar), 26.94 and 27.62 (CH,CCH,), 61.68 (CHS), 74.84 and 83.57 (CHO), 109.06 (CH,CCH,), 130.73 and 130.66 (CCH,), 129.77 and 133.29 (ArCH), and 138.04 and 138.10 (CS).(4S,5S)-(-)-4-(Bis-p-tolylthiomethyl)-2,2,5-trimethyl-1,3-di-oxolane (24b).-This thioacetal was prepared in 97 yield from (16b) as described for (24a) (Found: C, 67.15; H, 7.05. C,,H2,02S2 requires C, 67.3; H, 7.0); rD (c 1.2 in CHCl,) -99.5"; 6,(CDC13) 1.36 (3 H, d, J 5.7 Hz, CH,CH), 1.33 and 1.54 (2 x 3 H, 2 x s, CH,CCH,), 2.34 (6 H, s, CH,Ar), 4.10 (1 H, dd, CHCHS, J5.3 and 7.6 Hz), 4.25 (1 H, d, J7.6 Hz, CHS), 4.37 (1 H, quint, J 5.5 Hz, CHCH,), and 6.90-7.55 (8 H, m, ArH); 6,(CDC13) 15.78 (CH,CH), 21.17 (CH,Ar), 25.65 and 27.81 (CH,CCH,), 59.49 (CHS), 74.02 and 78.28 (CHO), 108.31 (CH,CCH,), 129.79 (CCH,), 129.50, 129.79, 133.22, and 134.44 (ArCH), and 138.19 and 138.34 (CS).(4R,5S)-(+)-4-Hydroxymethyl-2,2,5-trimethyl-1,3-dioxolane (26b).-T0 a suspension of red mercury(I1) oxide (695 mg, 3.21 mmol) in THF-water (85 :15; 9 ml), boron trifluoride-diethyl ether complex (0.395 ml, 3.21 mmol) was added. After 5 min, the suspension was cooled to 0 "C and a solution of (24b) (800 mg, 2.14 mmol) in THF-water (85:15; 3.5 ml) was added. The mixture was stirred for 40 min at room temperature, diluted with diethyl ether, filtered through Celite, washed with dilute aqueous NaHCO,, and concentrated to a small volume. The white salts formed were filtered off and the filtrate was evaporated to dryness, without warming. The residue was taken up with absolute methanol (3 ml) and treated at 0deg;C with sodium borohydride (405 mg, 10.7 mmol).After 30 min the reaction was quenched with saturated aqueous NH4Cl, and most of the methanol was removed by careful evaporation under reduced pressure. The residue was taken up with diethyl ether and water; the phases were separated and the organic layer was evaporated to dryness to give a crude oil, which after flash chromatography (hexane4iethyl ether) furnished pure (26b) (178 mg, 57) (Found: C, 57.8, H, 9.45. C7HI4O3 requires C, 57.5, H, 9.65); RID (C 1 in CHCl,) 4-47.3" (w" +52"); GH(CDC1,) 1.24 (3 H, d, J 6.2 Hz, CH,CH), 1.36 and 1.47 (2 x 3 H, 2 s, CH,CCH3), 1.90 (1 H, br s, OH), 3.61 (2 H, br t, J5.4 Hz, CH,OH), 4.13 (1 H, q, J 5.8 Hz, CHCH,), and 4.36 (1 H, quint, J 6.2 Hz, CHCH,).(4S,5S)-4-Hydroxymethyl-2,2,5-trimethyl-1,3-dioxolane (26a).-This dioxolane was prepared as described for (26b), in 37 yield from (24a) (Found: C, 57.9; H, 9.4. C7H1403 requires C, 57.5; H, 9.65); 6,(CDCl,) 1.29 (3 H, d, J5.9 Hz, CH,CH), 1.41 and 1.42 (2 x 3 H, 2 x s, CH,CCH,), 2.30 (1 H, br s, OH), and 3.5W.20 (4 H, m, CH and CH,). (2R,3S)-(+)-2,3-Bis(phenylmethoxy)-1,l-bis-p-tolylthio-butane (27a).-(a) From (16a). Benzyl bromide (0.755 ml, 6.355 mmol) and sodium hydride (50 suspension in mineral oil; 268 mg, 5.59 mmol) were added in succession to a cooled (0deg;C) solution of (16a) (850 mg, 2.542 mmol) in dry dimethyl- formamide (DMF) (10 mol). After 1 h, the reaction was quenched with saturated aqueous NH,Cl, diluted with hexane- diethyl ether (8: 2; 150 ml) and water (70 ml), and the phases were separated.The organic extracts, evaporated to dryness, gave a yellow oil which was purified by flash chromatography (hexane-diethyl ether) to afford pure (27a) (908 mg, 69) (Found: C, 74.65; H, 6.6. C32H3402S2 requires C, 74.7; H, 6.7); .ID (c 2.72 in CHCl,) +9.6"; Q,~~(c 2.72 in CHC1,) +76.7"; a435 (c 2.72 in CHCl,) +31.7"; G,(CDCl,) 1.18 (3 H, d, J 6.1 Hz, CH,CH), 2.32 and 2.29 (2 x 3 H, 2 x s, CH,Ar), 3.76 (1 H, dd, J 2.7 and 6.1 Hz, CHCHS), 3.99 (1 H, quint, J 6.2 Hz, CHCH,),4.47 (2 H, s, CH2Ph),4.55 (1 H, d, J2.7 Hz, CHS),4.78 and 4.91 (2 H, AB, J 11.5 Hz, CH,Ph), and 6.95-7.50 (18 H, m, Arm (b) From (13a). Sodium hydride (50 suspension in mineral oil; 27 mg, 0.318 mmol) was added at room temperature to a solution of (13a) (90 mg, 0.212 mmol) in dry DMF (1 ml).After 5 min, benzyl bromide (0.030 ml, 0.254 mmol) was added to the stirred suspension. After 15 rnin the reaction was complete and was worked up as in (a) to give pure (27a) (89 mg, 82). J. CHEM. SOC. PERKIN TRANS. I 1988 (2S,3S)-(-)-2,3-Bis(phenylmethoxy)-1, l-bis-p-tolylthio- butane (27b).-This thioacetal prepared as described for (27a) either from (16b) (76 yield) or from (13b) (80 yield) (Found: C, 74.5; H, 6.8. C32H3402S2 requires C, 74.7; H, 6.7); .ID (c 1 in CHCI,) -74.6"; G,(CDCl,) 1.26 (3 H, d, J 5.7 Hz, CH,CH), 2.29 (6 H, s, CH,Ar), 3.79 (1 H, dd, J 1.8 and 7.8 Hz, CHCHS), 3.98 (1 H, dq, J5.7 and 7.8 Hz, CHCH,), 4.31 and 4.55 (2 H, AB, J 11.4 Hz, CH,Ph), 4.94 (1 H, d, J 1.8 Hz, CHS), 4.70 and 5.04 (2 H, AB, J 11.5 Hz, CH,Ph), and 6.95-7.50 (18 H, m, ArH). (2R,3S)-(+)-2,3-Bis( pheny1metha~~y)butanal (28a).-A sus-pension of red mercury(I1) oxide (515 mg, 2.38 mmol) in THF- H,O (85:15; 5 ml) was treated at room temperature with boron trifluoride-ether complex (0.293 ml, 2.38 mmol). After 5 min, a solution of (27a) (816 mg, 1.585 mmol) in THF-H,O (85:15; 5 ml) was added.The suspension was stirred at room temperature for 50 min, diluted with hexane (15 ml), and filtered. The phases were separated and the organic phase was kept in a freezer for 30 min and filtered again. After washings with aqueous 3 NaHCO, and concentration (to 7 ml), the resulting white suspension was kept at 0deg;C for 1 h and filtered.Evaporation to dryness left as a yellow oil, nearly pure (28a) (by n.m.r.), which upon flash chromatography (hexanediethyl ether) furnished pure (28a) (340 mg, 75) (Found: C, 75.75; H, 7.25. Cl8HzoO, requires C, 76.0; H, 7.1); .ID (c 1.93 in 95 EtOH) + 17.6"; G,(CDCl,) 1.25 (3 H, d, J 6.1 Hz, CH,CH), 3.654.15 (2 H, m, CHO), 4.47 and 4.60 (2 H, AB, J 12 Hz, CH,Ph), 4.55 and 4.79 (2 H, AB, J 12.2 Hz, CH,Ph), 7.29 and 7.33 (2 x 5 H, 2 x s, ArH), and 9.74 (1 H, s, CH=O). (2R,3S)-(+)-2-A ceto-xy- 1,1 -bis-p-tolylthiomethyl-3-di-phenyl(t-butyl)sil~lo.~~~but~ne(29a).-To an ice-cooled sol- ution of (15a) (650 mg, 1.13 mmol) in dry CH,Cl, (5 ml), triethylamine (0.261 ml, 1.87 mmol), acetic anhydride (0.161 ml, 1.70mmol), and 4-dimethylaminopyridine (14 mg, 0.1 13 mmol) were added in this order.After 1 h, the reaction was quenched with saturated aqueous ammonium chloride; the phases were separated and the organic layer was evaporated to dryness leave a crude oil, which, upon flash chromatography (hexane- diethyl ether) gave pure (29a) (560 mg, 80)(Found: C, 70.3; H, 6.9. C,6H,,0,S,Si requires C, 70.3; H, 6.976); .ID (c 1 in CHCl,) +4.4"; 6HO.96 (3 H, d, CH,CH), 1.02 9 H, S, (CH,),C, l.98(3H,s,CH3CO),2.33and2.35(23H,2 x s,CH,Ar),4.52x (1 H,quint,J5Hz,CHOSi),4.59(lH,d,J5.2Hz,CHS),5.19(1 H, t, J 5 Hz, CHOAc), and 6.95-7.80 (18 H, m, ArH). (2R,3S)-(-)-2- Aceto.xy-3-diphenyl( t-butyl)silyloxybutanal (30a).-This ester was prepared from (29a) (500 mg, 0.813 mmol) by the same method as employed for (28a) (reaction time 2 h) to give pure (30a) (219 mg, 70) (Found: C, 68.5; H, 7.5. C,,H,,O,Si requires C, 68.7; H, 7.3); .ID (c 1.38 in 95 EtOH) -7.7"; G"(CDC1,) 1.06 9 H, S, C(CH,)J, 1.12 (3 H, d, J 6.4 Hz, CH,CH), 2.13 (3 H, s, CH,CO), 4.37 (1 H, dq, J4.6 and 6.4 Hz, CHOSi).5.07 (1 H, d, J 4.6 Hz, CHOAc), 7.25-8.00 (10 H, m, ArH), and 9.78 (1 H, s, CH=O). Acknowledgements We thank the Progretto Finalizzato Chimica Fine e Secondaria for financial assistance. References 1 A. W. M. Lee, V. S. Martin, S. Masamune, K. B. Sharpless, and F. J. Walker, J. Am. 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