Abstract
Abstract -Stereoselectivities in reactions for the introduction of an ct hydroxyethyl group to 4-uloses via 4-C-vinyl and 4-C-ethylidene derivatives were examined, and the results were used for the stereoselective synthesis of methyl 6-deoxy-4-C-(hydroxymethyl)-5-O-methyl_2,3_O_methylene_L_idonate which was obtained by methanolysis of everninomicin B and D. In addition, the configuration of methyl eurekanate (methyl 4-C-.acetyl-6-.deoxy-2,3-Omethylene-hexonate) from flambamycin was determined to be D-galacto by synthesi .
Abstract
As an extension of knowledge in the chemistry of branched-chain sugars to chiral syntheses of natural products, 4-amino-2-(hydroxymethyl)-tetrahydrofuran-4-carboxylic acid found in acid hydrolysate of diabetic urine, and thiazol.4-carboxylic acids having an optically active substituent at C-2 found in thiostrepton and nosiheptide were studied.
INTRODUCTION
Significant parts of over thirty kinds of naturally occurring branched-chain sugars Fiave been synthesized during the last two decades, mainly by the nucleophilic 1,2-addition to uloses. The development of newer methods (Ref. 1) and accumulated data for prediction of the stereoselectivity in this field accelerated recent advances in chiral syntheses of natural products of widely diverse structures by the use of carbohydrates as intermediates . However, in spite of strong demands for higher stereoselectivities and higher yields, the control of absolute stereochemistry at the branching point remains as the crucial problem, even in such simple molecules as cyclohexanone derivatives (Ref. [5] [6] [7] . Starting point of our research in this field was to discover the factors controlling the complementary stereoselectivities between diazomethane and the Grignard reactions. In addition to the wellknown non-bonded interaction, an attractive electrostatic interaction between the diazomethyl cation and a neighbouring axial oxygen in the transition state of the diazomethane reaction (Ref. 8 & 9) , and thermodynamic control in such an equilibration reaction as the nitromethane reaction (Ref. 10 & 11) were shown to be important factors.
INTRODUCTION
Recently, our keen interest has been in the synthesis of five new branched-chain sugars found in oligosaccharide antibiotics of the orthosomycin family, everninomicins (Ref. 12 ) and flambamycin (Ref. 13 ). Thus, we have reported on synthesis of three of them; D-evermicose (Ref. 14) , D-evalose (Ref. 15) , and L-evernitrose (Ref. 16 ). In the present lecture I would like to present the synthesis of the remaining two at first, and then of a few nonsugar natural products from sugar precursors.
SYNTHESIS OF BRANCHED-CHAIN SUGARS
The configuration of terminal 6-deoxy-4-C-(hydroxymethyl )-5-O-methyl-2,3-O-methylene-hexono-1,4'-lactone in everninomicin B and 0, which links with a characteristic orthoester interlinkage, was determined to be (1R)-L-ido by the X-ray analysis of the partially hydrolyzed pentasaccharide, olgose (Ref. 17) . This lactone was chemically characterized as the corresponding methyl L-idonate (1) (Ref. 18) . Besides, a similar lactone (4-acetyl-6-deoxy-2, 3-O-methylene-hexono-1,5-lactone) is included in flambamycin, and the corresponding aldonate was named as 'methyl eurekanate" of unknown configuration (2) (Ref. 13) . In this section synthesis of (1) and configurational determination of (2) by synthesis are described.
JUJI YOSHIMURA

P11 larose
Me.. OMe The above compounds, (1) and (2), are of a branched-chain sugar kind having a two-carbon branch. To date, two-carbon branched sugars such as aldgarose (Ref. 19 & 20) from aldgamycin E and pillarose (Ref. 21 & 22) from pillaromycin A have been synthesized via the corresponding C-vinyl or C-(2-methyl-or 2-hydroxymethyl-l,3-dithian-2-yl) derivatives, and L--y-octose from quinocyclin B via the corresponding C-vinyl derivative (Ref. 23) . From these results, it was deduced that the 1,2-addition of carbanions to 3-or 4-uloses gave preponderantly equatorially C-substituted products and osmium tetroxide oxidation of C-alkylidene derivatives obtained from a 4-ulose gave predominantly axially 4-C-substituted products (Ref. 22) . However no proper methods for the stereoselective introduction, and a'so for the determination of the chirality in the branched carbon (for example in the case of the 3-C-ahydroxyethyl group of aldgarose) are known (Fig. 1 ).
P11 larose
As shown in Fig. 2 , it was considered that the comparison of the diols obtained from the corresponding C-vinyl derivatives by epoxidation and reduction (route A) with those obtained from the corresponding C-ethylidene derivative by osmium tetroxide oxidation or epoxidation followed by alkaline ring-opening in dimethyl sulfoxide (route B or C) should give the unambiguous configuration of the branched carbon, when the configuration of the ethylidene group is obvious. By the use of this principle the configurations of most of the diols synthesized were determined, and the stereoselectivities in reactions used were examined. Moreover, it was shown that the simultaneous inversion of the configurations at the branching point and the branching a-carbon in diols via the corresponding epoxides were possible. Preparation of 4-C-ethylidene and 4-C-vinyl derivatives for syntheses of (1) and (2). For the synthesis of (1), two patWways; i.e. the introduction of an equatorially oriented twocarbon unit to benzyl 2,3-O-methylene-L-threo-pentopyranosid-4-ulose (4) and that of an axially oriented one-carbon unit into benzyl 6-deoxy-2,3-O-methylene-L-]-hexopyranosid-4-ulose, were considered. However, the former was chosen because of the difficulty in the preparation of the latter. In addition, benzyl-6-deoxy-2,3-O-methylene-a-D-yj-hexopyranosid-4-ulose (6) and the corresponding 2,3-di-O-benzyl derivatives (3 and 5) of (4) and (6) were synthesized as the substrates for the examination of stereoselectivities in reactions to be used here.
I,
The precursors (7) (8) (9) (10) 25 R1=OH, R2=2-methyl-117 benzyl 4-O-(methy1thio)methy1--L-arabinopyranoside in 50% overall yield. The free hydroxyl groups at C-2 and C-3 of the above product were protected with benzyl and methylene groups (Ref. 26 ). De-O-(rnethylthio)methylation with mercuric chloride and calcium carbonate gave benzyl 2,3-di-O-benzyl-(7) and 2,3-O-.methylene--L-arabinopyranoside (8) In the cases of (7) and (9), oxidations into the corresponding 4-uloses proceeded even with dimethyl sulfoxide (DMSO)-acetic anhydride, however, those of (8) and (10) gave only the corresponding 4-0-(methylthio)methyl derivatives in low yields. Oxidation of (8) and (10) with Jones' reagent were accompanied with epimerization at C-3, indicating the strained state of the 2,3-0-methylene ring. Configuration of the product (13), benzyl 6-deoxy-2,3-0-methylenea-D-ribo-hexopyranosid-4-ulose, from (6) On the other hand, the above uloses (3-6) were converted into the corresponding 4-C-ethylidene derivatives by the reaction with ethyltriphenylphosphonium bromide and butyllithium in ether. In the case of (3), (E)-and (Z)-isomers (14) were obtained in 22% and 25% yields, respectively. Their configurtions could be clearly assigned from their C1(J1 2=3.0, J2,3=
I,
9.0 Hz) and 1C (J1 2=1.5, J2 3=4.0 Hz) conformations. The conformation of (Z)-16 obtained from (5) wasdeducd to be flattened Cl (J1 2=3.0, J2 3=6.0 Hz), and the configuratinal determination will be described in the followirg paragra3h, together with those of other ethylidene derivatives from (4) 
and (6). It is interesting that (E)-isomers showed commonly larger dextro-rotational values than (Z)-isomers.
The results in the synthesis of 4-C-vinyl derivatives are summarized in Table 1 . The corigurations of products were determined from the chemical shifts of branched ct-carbons in C n.m.r. spectra (Ref. [29] [30] [31] [32] . The complemental stereoselectivity in the reaction of (3) with methylmagnesium iodide and methyllithium in ether at a lower temperature is the same that reported by Miljkovic etal. in the reaction of methyl 2,
and (6). It is interesting that (E)-isomers showed commonly larger dextro-rotational values than (Z)-isomers.
It is interetting that the tendency to give an equatorially substituted product is stronger in the reaction of hexos-4-uloses (5,6) than (4), though the axial attack product predominates in the case of (3). 
JUJI YOSFIIMURA Stereoselectivities in reactions for the introduction of 4-C-(oc-hydroxyethyl) group
From 4-C-ethylidene derivatives (14-17) and 4-C-vinyl derivatives (18) (19) (20) (21) (22) (23) (24) shown in Fig. 3 , 4-C-(o-hydroxyethy1) derivatives were synthesfed (Fig. 5) , and the stereoselectivities in reactions used were examined ( Table 2) . First of all, determination of the configurations of 4-C-(-hydroxyethyl) groups by the principle shown in Fig. 2 were ascertained by use of (18), (19) , (E)-14 and (Z)-14 ( Fig. 4) . Peracid oxidation of (18) and (19) gave a mixture of the corresponding epoxides in the ratios of 1:14 and 1.2:1, respectively. Reduction of each epoxide with lithium aluminium hydride gave the corresponding diols (26) (27) (28) (29) in good yields (route A). Oxidation of (E)-14 and (Z)-14 with osmium tetroxide and N-methylmorpholine-N-oxide gave a 1:4.8 mixture of (27) and (29) and a 1:2 mixture of (26) and (28), respectively (route B). These interrelations were further confirmed by the route C. Peracid oxidation of (E)-14 and (Z)-14 gave the corresponding epoxides in the ratios of 2.3:1 and 1:1.5, respectively. Treatment of the former and the Thtter epoxides with 2M potassium hydroxide in dimethyl sulfoxide gave reversely a mixture of (26) and (28) and a mixture of (27) and (29), respectively. Thus, the configurations of°-hydroxyethyl groups in (26), (27) , (28) and (29) were unambiguously determined to be (R), (S), (S) and (R) respectively. The similar relationships between diols (30-37) and 4-C-vinyl(20-21, 23-24) or 4-C-ethylidene derivatives (15 and 17) were also examined by the routes A and B, and (E)-and (Z)-configurations of (15) and (17) were determined. In the case of (Z)-16, the minor product (38) in the osmium tetroxide oxidation was identical with that obtained by the reduction of (R)-epoxide from (22) , whose configuration was deduced on the supposition of a similar stereoselectivity in the epoxidation of (22) and (23), and consequently, the configuration of major product (40) was also determined.
JUJI YOSFIIMURA Stereoselectivities in reactions for the introduction of 4-C-(oc-hydroxyethyl) group
In Table 2 , it is characteristic that osmium tetroxide oxidation of 4-C-ethylidene derivatives gave predominantly 4-C-axial derivatives in good yields. The exclusive formation of equatorial-attack products in cases of hexose derivatives (17) indicates a decisive effect of steric hindrance. Thus, the selectivity in the reaction of (Z)-16, was reversed, reflecting the respective presence of two and one axial substituents in ct-and s-positions of the olefinic function. Besides, epoxidation with peracids does not usually proceed selectively (Ref. 37) , except for cis-epoxidation of cyclohexenols. However, the results in Fig. 4 and Table 2 *The ratio of (S) to (R) was determined after conversion into 4-C-(ct-hydroxyethyl) derivatives, and others were determined by the separation of epoxides. **These yields indicate (S) and (R) diols, respectively. hexose derivatives (22 and 23) gave preferentially (S)-and (R)-epoxides (namely, (S)-and (R)-ct-hydroxyethyl derivatives), respectively, but, axial 4-C-vinyl groups gave (S)-epoxides regardless of pentose or hexose derivatives (19,21 and 24) . These results will be explained by deductions that the conformation of an equatorial vinyl group shown in (A) of Fig. 6 is preferable in cases of pentosides (R=H) but not hexosides (R=CH3) and that the conformation of an axial one shown in (B) is commonly preferable by the electrostatic repulsion between electrons of the ring-oxygen and vinyl group. 
39
OBn
39
The weak effect of tertiary hydroxyl group in the peracid oxidation of 4-C-vinyl derivatives was noticed in the following experiments (Fig. 7) . 
R=Me
In the next experiment, a simultaneous inversion of the configurations of 4-C and branched acarbon was examined (Fig. 8) . Acetylation of the secondary hydroxyl group of (29) followed by mesylation of tertiary hydroxyl group with methanesulfonyl chloride gave the corresponding diest8r in 46% yield. Treatment of the diester in dimethyl sulfoxide with sodium methoxide at 80 C for 18 hours gave 4-0-methyl derivative of (27) , which was also prepared by the partial 0-methylation of (27) , in 82% yield. In a similar manner, (28) was converted into 4-0-methyl derivative of (26). (44) and (45) were deduced from the analogy of the rotational values of (31) and (30),respectively. Compounds (44) and (45) (49) in 60 and 69% overall yields, respectively, by 0-methylation with sodium hydride and methyl iodide followed hydrogenolysis in the presence of palladium-charcoal (Fig. 9) . Oxidation of (48) and (49) in 85% aqueous methanol with bromine, treatment of the reaction mixture with silver oxide, and separation of the products by preparative t.l.c. gave respectively (1) and the corresponding D-gluco isomer (50) in low yields, together with the dimethyl acetals (51 and 52) of the parent free sugars (48 and 49).
-> MsO

R=H 0 BnO
Stereoselective synthesis of branched-chain sugar derivatives 121 As was expected, rotational value ([c1D_26.1°) and 'H n.m.r. parameters of (1) were consistent with those reported aD_28°) (Ref. On the configuration of methyl eurekanate, it was postulated that the structure of the characteristic 2,3-0-methylene ring of the trans-diequatorial diols is the same as (1), and D-galacto (57) and D-gluco isomers (58) were synthesized as follows (Fig. 10) . Oxidation of (34) or (35) with N-chlorosuccinimide and dimethyl sulfide (Ref. 39) gave benzyl 4-C-acetyl-6-deoxy-2,3-O-methylene-D-galactopyranoside (53) in a good yield. This compound was also obtained from (25) by treatment with mercuric oxide and mercuric chloride in aqueous methanol in 50% yield. Besides, thegjjç.Q isomer (54) of (53) was obtained from (36) or (37) by a similar oxidation. Hydrogenation of (53) and (54) in the presence of palladium-charcoal gave the free sugars (55 and 56) each in 96% yield. Oxidation of (55) and (56) with bromine and barium carbonate in water followed by deionization in methanol with ion-exchanger (IR12O) gave the corresponding methyl aldonates (57); [cID -52.1° and (58); [cJD -39.8°) in 37% and 36% yields, respectively. Comparison of 1H and 13C n.m.r. parameters (Table 3) of (57) In conclusion, it can be said that two carbon branches in naturally occurring branched-chain sugars known so far have an equatorial orientation in pyranoses such as in aldgarose, pillarose, and y-octose and that (1) and (2) seem to originate from such branched-chain sugars. Stereoselective synthesis of branched-chain sugar derivatives 123 0.05M sulfuric acid under reflux for 5 h to give 5-O-benzyl-2,3-di-0-methyl-D-ribose (65) in 90% yield. The same s-elimination reaction of (65) afforded (61) also in a good yield.
R=H 0 BnO
At first, conversion of (61) into a furan derivative keeping the enol ether function was attempted. Sodium borohydride reduction of (61) gave the corresponding pent-2-enitol derivative (66) in quantitative yield. The structure was confirmed by disappearance of the anomeric protons in its n.m.r. spectrum and by i.r. absorption at 1670 cm'. Acetylation of (66) with acetic anhydride in pyridine afforded unexpectedly a mixture of 1-0-acetyl derivative (67) and (E)-1-acetoxy-5-benzyloxy-3-pentene-2-one (68). The structure of (67) was deduced the intensity of acetyl signal and the down-field shift of methylene protons at C-i in the n.m.r. spectrum, and that of (68) from the i.r. absorption at 1740 cm' (acetyl), and 1690 and 1640 cm 1 (a,-unsatured ketone) as well as the large coupling constant (16 Hz) between two olefinic protons. Aiming at a intramolecular cyclization, selective 1-0-tosylation of (66) with tolysulfonyl chloride in pyridine was performed but failed because of rapid conversion into 5-O-benzyl-3-deoxy-D-glycero-2-pentulose (69), which was also obtained directly from (61) by sodium borohydride reduction followed by treatment with weak acidic ionexchange resin, in 45% yield together with 3-penten-2-one derivative (70, ca. 10% yield).The structure of (69) could be ascertained by i.r. absorption at 1720 cm 1 and C-3 deoxymethylene jessica20@example.org and 2.68 in the n.m.r. spectrum. Selective 1-0-tosylation again and direct dehydrolytic cyclization of (69) at high temperature and by orthophosphoric acid failed due to the instability of (69). Thus it became clear that cyclization of the acyclic compound having an enol ether or carbonyl function was not possible. (71) with tosyl chloride in pyridine at -15°C followed by addition of triethylamine gave cyclized compounds (72 and 73), which were separated by preparative t.1.c. in 74% and 18% yields, respectively. In the latter cyclization reaction the complete formation of (72) took 3 days after the addition of triethylamine, while (73) was formed quickly. The intermediate 1-0-tosyl derivative mixture was observed on t.l.c. butits isolation in a pure state could not be done, presumably due to its easy conversion to (72) and (73). Then the mixture of (72) and (73) was oxidized with dimethyl sulfoxidetrifluoroacetic anhydride to give the 4-oxo derivative (74) in 86% yield.
R=H
On the other hand, the enantiomer of (74) was prepared also from (71) in the following manner. Treatment of (71) with acetone and anhydrous cupric sulfate afforded 1,2-0-isopropylidene derivative mixture (75) in 81% yield, and its 4-0-mesyl derivative mixture (76) was obtained in the usual manner in quantitative yield. The down-field shift of H in the n.m.r. spectrum of (76) confirmed the position of mesyl as well as isopropylidene groups. Hydrolysis of (76) gave de-O-isopropylidenated product (77) which was cyclized with sodium methoxide (accompanied by inversion at C-4) to give a mixture of (78) and (79). The mixture was successfully converted into the corresponding ketone (80), the enantiomer of (74), in the same manner as described above. data, a definite conclusion on the stereochemistry of the spiro-carbon could not be drawn. However, the succeeding chemical conversion ascertained the structure. Both epimers hydrolyzed in barium hydroxide solution under ref lux for 1 day gave the corresponding amino acid derivatives (83 and 84) in 68% and 65% yield, respectively. Hydrogenolysis of (83) and (84) in methanol in the presence of palladium-carbon and acetic acid gave an aminolactone derivative (85) and an amino acid [(2S,4S)-59] both in quantitative yield. The former shows a six-membered lactone absorption at 1740 cm 1 in the i.r. spectrum. In the same manner the enantiomers of (85) and (2S,4S)-59 were synthesized from the (2R)-4-oxo-derivative (80). As shown in Table 4 , (2S,4)-59 was identical with the amino acid isolated from the acid hydrolysate of diabetic urine in most respects including n.m.r. spectrum and behaviour on liquid chromatography, but not in the magnitude of the optical rotation value.
R=H
The differences in the absolute values of specific rotation between enantiomers of (59) and (85) may imply the presence of 5N1 mechanism to some extent in the 5N2 cyclization of (77). It is not known whether (85) exists in the acid hydrolysate of diabetic urine, probably due to much different behaviour of (85) from (59) on liquid chromatography. The evidence of this point will be an important clue in the elucidation of the formation pathway of (59). (Fig. 14) . It was considered that 2-azido-2,3-dideoxy-D-threo penturonic acid (88) and 2-azido-2,5-dideoxy-3-C-methyl-Darabino-pentose (89) are key intermediates for synthesis of (86) and (87) converted into methyl 1-O-acetyl-2-azido-2,3-dideoxy-D-threo'-pentofuranuronate (96) by successive reactions (periodate oxidation, permanganate oxidation, and esterification with diazomethane) in 55% overall yield. De-O-acetylation of (96) in methanol with sodium methoxide gave (97), methyl ester of (88), quantitatively. Condensation of (97) with methyl Lcysteinate proceeded smoothly to give the corresponding thiazolidine derivative (98) in 60% yield (Ref. 54) , and the structure was confirmed by n.m.r. spectra of derivatives. Analogous derivatives from (92) and (93) were also obtained. Conversion of (98) into (86) is under investigation.
R=H
Attempted synthesis of (89). Reaction of methyl 2,3-anhydro-6-deoxy-a-D-allopyranoside (99, Ref. 23) with sàdiüñi azidi gave two products, which were separated on a silica gel column after acetonation to give methyl 3-azido-3,6-dideoxy-o-D-glucopyranoside (100) and methyl 2-azido-2,6-dideoxy-3,4-O-isopropylidene-oc-D-altropyranoside (101) in 60% and 27% yields, respectively. The next step is the introduction of axial 4-C-methyl group into (100) via the corresponding 4-ulose. However, the selective protection of the 2-hydroxyl group of (T5) with the benzoyl group (102, 80%) followed by oxidation with dimethyl sulfoxide-trifluoracetic anhydride gave the corresponding enolone (103) in 92% yield (Ref. 55) . Therefore, (100) was hydrolyzed to (104) followed by acetonation with dimethoxypropane to give the corresponding 1,2-0-isopropylidene derivative (105) in 87% yield. Oxidation of (105) with dimethyl sulfoxide-trifluoroacetic anhydride was unexpectedly accompanied by the epimerization of the 3-azido group to give 3-azido-3,6-dideoxy-1,2-O-isopropylidene-o-D-ribohexopyranos-4-ulose (106) in 87% yield. The configuration of (106) was confirmed from the n.m.r. spectrum of 1,2,3-tri-O-acetyl-3-azido-3,6-dideoxy-a,-D-allopyranose (107) obtained by reduction of (106) with sodium borohydride followed by acetolysis. The reason for epimerization of the equatorial 3-azido group is attributed to a twist-boat conformation (J1 2= 5.0, J3,=7.O Hz) of (105) or the expected 4-ulose, caused by the formation of 1,2-0-isopropylidene ring. Because it became clear that a reasonable introduction of Cmethyl group into the pyranose ring of (100) is impossible, other pathways via a ketonic thiazole derivative (108) and a pentofuranosid-3-ulose (109) The pioneering work on the chemistry of branched-chain sugars made easy the synthesis of those having a one-carbon branch, unless there are strict requirements for high stereoselectivity and yield. In connection with the synthesis of (1) having an optically active two-carbon branch,, the possibilities of configurational control of not only the tertiary carbon but also the branching a-carbon by the proper use of three routes shown in Fig. 2 were indicated in the present work. As an addition to this work, the configuration of (2) could be determined by synthesis. Synthesis of four diastereomers of (59) illustrates that synthesis of optically active compounds having two asymmetric carbons is not too difficult. However, the results in the attempted synthesis of (87) indicate the shortage of knowledge on 4-uloses, in spite of their important role in biosynthesis of various sugars. The use of carbohydrates as sources for asymmetric synthesis of optically active compounds will become common in organic chemistry. Various other reactions will be applied to carbohydrates as organic substrates, and their selectivities will be disclosed.

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