Study of Stereoselectivity in Organometallic Additions to 1,2-O-Isopropylidene-O-R-α-D-xylopentodialdo-1,4-furanose

Tibor Gracza* and Peter SzolcsanyiDepartment of Organic Chemistry, Faculty of Chemical Technology, Slovak University ofTechnology, Sk-812 37 Bratislava, Slovakia. Tel. (0421) 7 59325 167, Fax (0421) 7 529 68 560,http://www.chtf.stuba.sk/KATEDRY/koch/new_gracza.htm* Author to whom correspondence should be addressed. ?-mail gracza@chtf.stuba.sk.Received: 2 August 2000 / Accepted: 8 December 2000 / Published: 21 December 2000Abstract: Diastereofacial selectivity of the addition of organometallic reagents to 1,2-O-isopropylidene-O-R-α-D-xylopentodialdo-1,4-furanoses (6) was studied.Keywords: Organometallic reagents, stereoselectivity, addition to carbonyl.IntroductionGoniofufurone (+)-1 and 7-epi-goniofufurone (+)-2 were recently isolated from the stem bark ofThai Goniothalamus giganteus Hook f., Thomas (Annonaceae) and shown to exhibit cytotoxicactivity in tests with several human tumor cell lines [1,2]. We have developed a total synthesis of bothdiastereomers (+)-1 and (+)-2 starting from D-glucose [3]. The key steps are the phenyl magnesiumbromide addition to 1,2-O-isopropylidene-α-D-xylopentodialdo-1,4-furanose and palladium(II)-catalyzed oxycarbonylation of the corresponding 1-phenyl-5-hexene-1,2,3,4-tetrols. Whilst the Pd(II)-catalyzed formal O-cyclization and carbon monoxide addition yielded the required bicyclic skeletonswith high regio-preference and excellent threo-selectivity (concerning the newly formed stereocentreat C-3) [4,5], Grignard addition of phenyl magnesium bromide to 6a in tetrahydrofuran led to twodiastereomeric alcohols 7a and 8a in a 1:3 ratio favouring formation of the L-ido diastereomer 8a,possessing the correct stereochemistry for less cytotoxic 7-epi-goniofufurone (+)-2 (Scheme 1).


Results and Discussion
In connection with the above-mentioned synthesis, we were interested in obtaining a more reliable access to alcohol 7 while at the same time improving the ratio of this component to 8, therefore we decided to investigate the diastereoselectivity of additions of organometallic reagents to aldehydes 6 in a more detail.The design of addition of C-nucleophiles to aldehydes 6 could be based on models of either chelation-control: We have prepared 3-O-R-substituted aldehydes 6a-d from D-glucose (Scheme 3) with diverse protecting groups (R = H [6,7], Bn [6,8], TBDMS, Ms) in order to examine the effects of changes in the nature of the alkoxy group on the selectivity of the reaction.Treatment of aldehydes 6 with phenyl magnesium bromide in THF (see Table 1, Entry 1) or diethylether (Entries 2-4) gave in all cases the Lido diastereomer 8 as a major product as a result of 1,2-chelation-control.The highest degree of selectivity found for 6b is in accordance with the literature [6,[9][10][11][12], whilst aldehydes 6c and 6d with silyl (known for its non-chelation nature) and mesyl group (with opposite effect) gave about equal amounts of both diastereomers 7 and 8.
Generally, addition of polyethers to the reaction mixture to suppress chelation usually causes a reversal in the stereoselectivity, yielding a Cram , s product [13].Addition of 18-C-6 and.dibenzo-18-C-6 crown-ether to the reaction of aldehyde 6b with phenylmagnesium bromide inhibits chelation leading to a decrease of selectivity from 14:1 to 1:1.2 (comparison of entries 5 and 6).[6][7][8], (v) PhM, solvent and reaction conditions see Table 1.b The yields refer to pure isolated products.
c Probable assignments, may eventually be reversed.
The reversal of diastereofacial selectivity was also achieved by use of phenylceriumdichloride [14,15] (Entry 7), indicating the probability that model B was operating in this case.
Turning from chelation-to non-chelation-control, we reacted 6b with phenyltitanium-tris-Oisopropoxide [16,17], which is known to have only weakly Lewis acid properties [18,19].Obviously, phenyltitanium-tris-O-isopropoxide is incapable of effective chelation, so that carbonyl group in 6 is free to rotate.The fact that diastereoselectivity is nevertheless observed may be related to Anh , s model of 1,2-asymmetric induction in addition reactions of chiral aldehydes having electronegative substituents at the α-position.Accordingly, the most reactive conformation is the one having the alkoxy group positioned in such a way that the σ C-OR orbital overlaps with the π C=O orbital, providing a low laying LUMO.Antiperiplanar attack at an angle larger than 90 o (Burgi-Dunitz trajectory) according to model C results in the Felkin-Anh-product.
The prepared compounds were identified by elemental analyses, optical rotations, 1 H-NMR, 13 C-NMR, and IR spectra (see Experimental).The absolute configuration at the newly formed stereocentre, and hence the configuration of alcohols 7b and 8b, was established by comparison of 1 H-, 13 C-NMR data, and specific rotations with those described in the literature [6,[9][10][11][12].The structures of 7a/ 8a were established by total synthesis of (+)-1, (+)-2 [3].Assignment of the absolute configuration at C-5 in 7c,d/ 8c,d was not deemed of interest in view of low degree of selectivity observed.

General
Solvents and reagents were purified and dried according to standard procedures.TLC analyses were carried out with Si60F 254 -coated aluminium sheets (E.Merck) using ethylacetate/ i-hexane mixtures; detection by UV at 254 nm, phosphomolybdic acid (10% in ethanol) or sulfuric acid (40% in water).Silica gel 32-63 µm (Woelm) was used for flash chromatography, eluents as above.Melting points were determined on a Kofler hot block and are uncorrected.The optical rotations were measured on a POLAR L-µP (IBZ Messtechnik) polarimeter at 589 nm.IR spectra were recorded on a PU 9800 FTIR spectrometer (Philips Analytical) in film or KBr discs (0.5 mg of sample and 300 mg of KBr). 1 H-NMR and 13 C NMR spectra were obtained on a Varian model VXR 300 spectrometer (at 300.3 MHz and 75.12 MHz, respectively).In the NMR experiments deuterochloroform solutions with tetramethylsilane as internal standard were measured; evaluation of 1 H-NMR spectra was according to 1 st order interpretation; and multiplicity of 13 C-NMR signals was deduced from broad-decoupled or DEPT spectra.The ratios of diastereomers 7 and 8 were established by comparison of the integrals of H-1 signals in 1 H NMR experiments performed on crude reaction mixtures.
Prepared from aldehydes 6a-d according to lit.[4,6].The crude aldehydes 6a-d were dissolved in dry ether and added dropwise to a solution of phenylmagnesium bromide in ether, prepared from bromobenzene and magnesium at -10 o C during 2 h.The mixtures were stirred at 0 o C for 4 h, and at r.t. for 24 h, then quenched with cold, saturated aqueous ammonium chloride and extracted with ether.After drying (Na 2 SO 4 ) and solvent removal a yellow oils were obtained, whose were purified by flash chromatography on silica gel.
The mixture was stirred at 0 o C for 4 h, and at r.t. for 24 h, then quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ether.After drying (Na 2 SO 4 ) and solvent removal a yellow oil was obtained; yield 950 mg (89 %) resp.920 mg (86 %) as a 1.2:1 mixture of D-gluco/L-ido 7b/8b diastereomers.
To a stirred solution of aldehyde 6b (1.0 g, 3.59 mmol) in dry ether (20 mL) was added a solution of PhTi(O i Pr) 3 (1.195 g, 3.95 mmol, 1.1 equiv) in ether (20 mL) at -30 o C during 20 min.The mixture was stirred at -30 o C for 4 h and at r.t. for 48 h, then quenched with saturated aq.ammonium chloride (20 mL), extracted with ether (3 x 20 mL), dried with Na 2 SO 4 .After removal of solvent a yellow oil was obtained.Yield 383 mg (30 %).The product consists of a 14:1 mixture of 7b/ 8b diastereomers according to 1 H-NMR data.

Table 1 .
Addition of Organometallic Reagents to Aldehyde.
a Assignments of reaction ratios are based on the 1 H-NMR spectra of crude reaction mixtures.