1051
J. Org. Chem. 1987,52. 1051-1056 A, 288,278,270,228,220 nm; IR (KBr) v(C=N) 2250, v(C=O) 1740,vC=N) 1668 cm-'; EIMS (70 eV) m/e 352 ([MI+, 15%), 284 (33%), 258 (31%), 252 (49%), 210 (28%), 185 ([CiiHgNzO]+, loo%), 169 (74%), 168 ([C11H8N2]+,84%; exact mass for C19HZ0N4O3,calcd 352.1535, found 352.1543; 'H NMR (90 MHz, CDC1,) 6 8.35 (s br, 1H, N(11) H), 7.55-7.05 (m, 4 H, C(7)-C(10) H), 6.20 (s, 1 H, C(1lb) H), 4.35 and 4.32 (2 q, 2 H, OCHzCH3), 3.80 (X part of ABX spectrum, 3 J m = 10.0 Hz, 3 J B X = 5.0 Hz, 1 H, C(5) H), 3.15 and 3.05 (AB part of ABX spectrum, ,JAx = 10.0 Hz, 3 J ~= x 5.0 Hz, 'JAB = 12.5 Hz, 2 H, C(6) Hz), 1.70 (s, 6 H, C(CH,),), 1.35 (t, 3 H, OCH,CH,). Anal. Calcd for ClgHmN403(MW 352.394): C, 64.76;, H, 5.72; N, 15.90. Found: C, 64.74; H, 5.73; N, 15.70. 2-( l-Cyano-2-phenylvinyl)-5-(ethoxycarbonyl)-9-methoxy-4,5,6,1 lb-tetrahydro-A4-1,2,4-oxadiazolino[3,2-a 1-8carboline (14c). A solution of the nitrone 9 (lmmol, 288 mg) and the nitrile l2cZ7(2.16 mmol, 330 mg) dissolved in toluene (15 mL) was kept at 65 "C for 7 h. The reaction was monitored by TLC (MeOH/CHCl,, 7/93, v/v). Evaporation of the solvent, flash column chromatography of the residue (MeOH/CH,Cl,, 0.8/99.2, v/v, and recrystallization gave 400 mg of 14c: 95%; mp 188-190 "C; R, 0.60 (CH2Cl,/n-hexane); UV (MeOH) ,A, 307 (sh), 299, 228 nm; Amin 251 nm; IR (KBr) v(C=N) 2200, v(C=O) 1725, v(C=N) 1642 cm.'; EIMS (70 eV) m/e 442 ([MI+, 42%), 369 ([CzzHi7N,0zlf, 20%), 314 ([C11$16N3041+, l o % ) , 198 ([C12Hl&0]+, 100%); exact mass for CwHzzN404, calcd 442.1641, found 442.1635; 'H NMR (90 MHz, CDC13)6 8.27 (s br, 1 H, NH), 7.97-6.71 (m, 9 H, C(7)-C(8) H, C(10) H, C&, C=CH), 6.34 (9, 1 H, C(l1b) H), 4.35 (q, 2 H, OCH,CH3), 3.90 (X part of ABX spectrum, 1 H, C(5) H-C(6) H,), 3.83 (s, 1 H, OCH,), 3.18 and 3.04 (AB part of ABX spectrum, 2 H, ,J = 3.3 Hz, 3J = 11.7 Hz, 2J = 12.6 Hz, C(6) Hz-C(5) H), 1.35 (t, 3 H, OCH,CH3). Anal. Calcd for CEHzZN4O4 (MW 442.476): C, 67,86; H, 5.01; N, 12.66. Found: C, 67.56; H, 4.85; N, 12.50. 2-Methyl-3-phenyl-5-(1-cyano-1-methylethy1)-A4-1,2,4-oxadiazoline (15d). A solution of the nitrone l O l 9 (0.8 mmol, 108 mg) and the nitrile 12d (0.81 mmol, 76 mg) in dry toluene (5 mL) was kept at 110 "C for 10 days. evaporation of the solvent and flash column chromatography of the residue (MeOH/CH,Cl,, 0.5/99.5 v/v) gave 156 mg of 15d (85%) as an oil, which was homogeneous on TLC: R, 0.35 (MeOH/CDCl,, 7/93); CIMS (100 eV) m/e 230 ([M + l),28%), 161 ([CgHgNzO], 100%); exact mass for C13H15N30,calcd 229.1215, found 229.1211; 'H NMR (90MHz,
CDClJ 6 7.23 (s,5 H, CCHS), 5.61 (9, 1 H,C(3) H), 2.89 N(2) CH3), 1.71 ( 8 , 6H, C(1) (CHJZCN).
(9,
3 H,
2-(7-Cyanonorcaran-7-yl)-4,5,6,10b-tetrahydro-A41,2,4oxadiazolino[3,2-a Iisoquinoline (16b). The nitrone 1114(0.5 mmol, 74 mg) and the nitrile 12b27(0.55 mmol, 80 mg) were dissolved in CHzClz (1.5 mL). The solution was placed in a high-pressure vessel, which was placed in a high-pressure apparatus (12 kbar) for 7 days. After evaporation of the solvent and flash column chromatography (MeOH/CHzCl2,1/99, v/v) 16b was obtained as an oil in 86% yield: 126 mg; R, 0.30 (MeOH/ CHzC1,, 1/99, v/v); EIMS (70 eV) m/e 293 ([MI+, 6%), 147 ([CgHgNO]+, 100%); exact mass for Cl8HlgN30,calcd 293.1528, found 293.1517; H NMR (90 MHz, CDC1,) 6 7.60-7.00 (m, 4 H, C(77)-C(10) H), 5.95 (s, 1H, C(1Ob) H), 3.70-2.50 (m, 4 H, C(5) Hz-C(6) Hz, 2.40-1.10 (m, 10 H, cyclohexyl H). 1-[[(7-Cyanonorcaran-7-yl)carbonyl]amino]-3,4-dihydroisoquinoline (17b). The nitrone 1114(0.5 mmol, 74 mg) and the nitrile l2bZ7(0.55 mmol, 80 mg) were dissolved in toluene and heated (110 "C) for 2 days. Evaporation of the solvent and flash column chromatographyof the residue (MeOH/CHzCl2,2/98, v/v) gave 17b [115 mg (78%)], which was recrystallized from CH,Cl,/n-hexane: R, 0.7 (MeOH/CHZClz,1/99, v/v); mp 128-130 282,210 nm; A(, 230 nm; IR (KBr) v(C=N) "C; UV (MeOH) A, 2218 cm-'; EIMS (70 eV) m/e 293 ([MI+,37%), 173 ([Cld-IgN,O]+, loo%), 130 ([cgH8N]+,18%); exact mass for C18H19N30,calcd 293.1528, found 293.1524; 'H NMR (90 MHz, CDC13)6 11.10 (s br, 1 H, CONH), 8.50-7.10 (m, 4 H, C75)-C(8) H), 3.60 (dt, 2 H, C(3) Hz), 2.95 (t,2 H, C(4) H), 2.20-1.10 (m, 10 H, cyclohexyl H). Anal. Calcd for C18H19N30(MW 293.370): C, 73.69; H, 6.53; N, 14.32. Found: C, 73.50; H, 6.54; N, 14.32.
Acknowledgment. We gratefully acknowledge Dr. J. W. Scheeren for advice and making available the highpressure apparatus. Registry No. 2, 3189-13-7;5,106544-16-5; 7,106544-17-6; 8, 106544-20-1;9, 106544-18-7; 10, 3376-23-6; 11, 24423-87-8; 12a, 6904-17-2;12b, 29782-28-3; 1212, 2700-22-3; 12d, 7321-55-3; 12e, 6914-79-0; 12f, 5500-21-0; 13a (isomer l),106544-19-8;13a (isomer a), 106622-86-0; 13b, 106544-21-2; 1 3 ~ ,106544-22-3; 13d, 106544-23-4;1 4 ~106544-24-5; , 15d, 106544-25-6;16b, 106568-14-3; 17b, 106544-26-7; 18, 74214-62-3; BrCHzC(=NOH)COZEt, 73472-94-3.
Anthracyclinones. 2. Isosaccharinic Acid as Chiral Template for the Synthesis of ( )-4-Demethoxy-9-deacetyl-9-( hydroxymethy1)daunomycinone and (-)-4-Deoxy-y-rhodomycinone'
+
J. C. Florent, J. Ughetto-Monfrin, and C. Monneret* DZpartement de Pharmacognosie associZ au CNRS, U.A. no. 484, FacultZ des Sciences Pharmaceutiques et Biologiques, 75270 Paris CZdew 06, France Received January 22, 1986 Chiral aldehyde derivatives 12, 19, and 22 were prepared in few steps from a-D-isosaccharino-l,4 lactone (la). These derivative precursors of ring A of the title anthracyclinones were condensed with leucoquinizarin (28), the component of the BCD rings. Aldolization reactions afforded alkylanthraquinones 29,33, and 34, respectively. After suitable transformations of 29 and ring closure, the protected anthracyclinone 27 was obtained. Acetal (5). Similarly suitable cleavage of 27 led to the (+)-4-demethoxy-9-deacetyl-9-(hydroxymethyl)daunomycinone transformations of 33 or 34 followed by ring closure gave the (-)-4-deoxy-y-rhodomycinone (30).
Rearrangement of hexoses by prolonged treatment with aqueous alkali leads primarily to the formation of "saccharinicacids" or deoxyaldonic acids, usually isolated as their crystalline lactones which are isomeric with the parent monosaccharides.2
In this way, for instance, a-D-isosaccharino-1,4-lactones la,b and a-~-glucosaccharino-1,4-ladone(2) were prepared or xylotriose,4 and in high yield from l a c t o ~ exylobiose ,~ f r u ~ t o s erespectively. ,~
(1) Paper 1: Bennani, F.; Florent, J. C.; Koch, M.; Monneret,-E Tetrahedron 1984,40,4669. (2) Rodd's Chemistry of Carbon Compounds;Coffey, S., Ed.; Elsevier:
(3) Whistler, R. L.;BeMiller, J N Mpthodp in C'orhnhvdmto f'homistry Academic: New York 196.7 . ____, __ Vol. 11, p 477. (4) Whistler, R.L.;BteMiller, J. N. Adu. Carbohydr. Res. 1958,13, 289.
Amsterdam, 1967; Vol. IF, p 251.
0022-3263/87/1952-1051$01.50/0
-d;
(5) Cf. ref 3, p 484.
0 1987 American Chemical Society
1052 J . Org. Chem., Vol. 0‘2, No. 6, 1987
Florent et al.
Scheme I
.
Scheme I1
1 .. ”
i
-k R,
HO,
4
t2q
-
e
‘i’
0
x
5c
/
PI
=
a
0
0
X
4 :r O Y ?
,
C 3 Y e , CCSH2;P
LHiOLi
9 RIOH
Interestingly, although such highly elaborated “chirons” as 1 and 2 are easily obtained from abundant and cheap starting materials by this well-known rearrangement, its potential in synthesis has been seldom
JH
l a R
z CHzOH
1b R -
k
2
0
2
3
91 - 0 ‘ e
d Ri 5
R
10 R r C l -
Scheme 111 OR
OR,
OH R2
1
0‘4*R z
1
.t
r COY? :C O C t i 2 O H
q2 r C V 2 C i - l
In our work toward the synthesis of analogs of daunomycinone 3 and adriamycinone 4, the nonsugar moieties of the antitumour agents, daunorubicin, and doxorubicin? it appeared attractive to use these compounds as precursor of ring A carbons 7-10 as the transfer of chirality of C-2 (sugar numbering) to C-9 (anthracycline numbering) would give rise to enantiomerically pure compounds. Construction of the tetracyclic nucleus of 3 or 4 or of analogues can be achieved by two routes as illustrated in Scheme I by assembling the subunits A + BCD or AB + CD. Following route I we have recently reported1 a synthesis of 4-demethoxy-9-deacetyl-9-(hydroxymethyl)daunomycinone (5) from isosaccharino-1,4-lactone(la) and from leucoquinizarin as the BCD ring component. In this present paper we wish to describe as an extension of the route I (Scheme I),the synthesis of (-)-4-deoxy-y-rhodomycinonelO while following route I1 a new synthesis of 5 from hydroxytetralin intermediate will be presented in the accompanying paper. Results and Discussion Syntheses of Aldehyde Derivatives. (a) Aldehyde 12. First, the 0-isopropylidene lactone 6 derived from la was transformed into the iodo derivative 8 in an overall yield of 62% in a two-step sequence involving reaction with tosyl chloride in pyridine to afford the tosylate 7 followed by reflux with sodium iodide in 2-butanone. Bernet and Vasella’* reported that 6-deoxy-6-haloglycosidesreact with (6) Hanessian, S.; Roy, R. Tetrahedron Lett. 1981,22, 1005; Can. J . Chem. 1985,63, 163. (7) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983, 105, 1988. (8) Hoffmann, R. W.; Ladner, W. Chem. Ber. 1983, 116, 1631. (9) Arcamone, F. Dororubicin; Medicinal Chemistry 17; Academic: New York, 1981. (10) Krohn, K.; Behnke. Liebigs Ann. Chem. 1983, 1818. (11) Genot, A.; Florent, J. C.; Monneret, C. J . Org. Chem. 1987, following paper in this issue.
4
OR
Y OH
1
OR
zinc dust under mild conditions with glycoside cleavage and formation of hex-5-enoses. Later on l3 they also reported that under the same conditions fragmentation of a 6-bromo lactone gives an unsaturated acid in good yield (70%). As expected, application of the same procedure to 8 afforded a mixture containing the unsaturated carboxylic compound 9. Formation of side products could be largely avoided, however, by replacing preactivated Zn and THF by nonpreactivated Zn and THF + HOAc as solvent. Lithium aluminum hydride reduction of 9 followed by oxidation of alcohol 11 with pyridinium dichromate according to Czernecky’s procedure14 gave the desired aldehyde 12 (overall yield 8 12, 42%). An alternative route was also attempted which consists in preparing aldehyde 12 from the corresponding acid chloride 10 according to Fleet.15 However under these conditions, 10 reacts slowly and a mixture of 11 and 12 was obtained in a 1:l ratio after 24 h. The sequence of reactions is summarized in Scheme 11. (b) Aldehydes 19 and 22. The triol compound 13l obtained by LAH reduction of la was protected as its tri-0-benzyl derivative 14 and the isopropylidene ring was cleaved by acid hydrolysis giving 15 in 50% overall yield. Transformation of the hydroxymethyl side chain into an ethyl group as occur in ring A of rhodomycins, involved
-
(12) Bernet, B.; Vasella, A. Helu. Chim. Acta 1979, 62, 1990, 2400, 2411. (13) Bernet, B.; Vasella, A. Helu. Chim. Acta 1984, 67, 1328. (14) Czernecki, S.; Georgoulis, C.; Stevens, C. L.; Vijayakumaran. Tetrahedron Lett. 1985, 26, 1699. (15) Fleet, G. S.; Harding P. J. C. Tetrahedron Lett. 1979, 975.
J. Org. Chem., Vol. 52, No. 6, 1987 1053
Anthracyclinones
Scheme VI
Scheme IV
18
-F
&To O%-
@&y* OH
OR
\
R
OH
0
20 -
0
33, R = R' = H
30, R = H
31, R =
OH
OH
34,R,R1 =
32, R = OMe
Scheme VI1 0
OH
0
OH
0
OH
0
OH
DH
desired compound 24, unsaturated aldehyde 12 appeared to be an appropriate starting material since the terminal double bond could act as a masked aldehyde. Actually on reacting 12 with leucoquinizarin 28 under Marschalklg (KOH, NazS204),Lewis" (piperidinium acetate) or ShawZ1 (DBU or DBN in THF) conditions, the alkylanthraquinone 29 was isolated in 75-80% yield (Scheme V). Ozonolysis of 29 afforded aldehyde 26 in 75-80% yield, which was then converted stereospecifically in 75% yield into the cis aglycon 27 (overall yield for the last three steps 42-48%). Acidic hydrolysis afforded in nearly quantitative yield 5. In planning an extension of the usefulness of saccharinic acids as precursors of other aglycons, we focused our attention toward y-rhodomycinone. Closely related to the antitumour drugs daunorubicin and doxorubicin, the rhodomycins were isolatedzzfrom strains of Streptomyces purpurascens. In spite of their widespread occurence, relative few syntheses of the rhodomycinones, nonsugar moieties of rhodomycins have been published. (fI-4-Deoxy-y-rhodomycinone (30) was elaborated first by means of Diels-Alder reactionsz3or as for (f)-y-rhodomycinone (31) and its corresponding methyl ether 32 by intramolecular Marschalk r e a c t i ~ n l (Scheme ~ , ~ ~ VI). According to our general strategy as described in a previous publication,l the aldehydes 19 and 22 were precursors of optically active 30. Their condensation with leucoquinizarin 28 afforded the alkylanthraquinones 33 and 34 in 10% and 45% yields, respectively. The low yield observed for the formation of 34 is understandable since, as mentioned above, the aldehyde 18 is very unstable. In fact, as hydrolysis of 34 giving 33 was almost quantitative, 33 can be prepared via 34. Moffatt oxidation of 33 gives the aldehyde 35 (60%) (Scheme VII). Conversion of this a-hydroxy aldehyde to the tetracyclic (-)-4-deoxy-y-rhodomycinone 30 and to a small amount of its cis epimer 36 was achieved at 0 "C under Marschalk conditions. The mp and spectroscopic data for 30 were in full agreement
* *; OH
J )t;., I1 2
OH
, /
OH
OH
----+
\
"
o
/
on
E
reaction of 15 with mesyl chloride in pyridine and reaction of the resultant mesylate 16 with Me2CuLi in ether.le Compound 17 obtained in 65% yield was then treated under hydrogenolysis conditions, giving 18 in quantitative yield. Periodate oxidation of 18 led to the rather unstable aldehyde derivative 19 which exists as its hemiketal form as shown by examination of its IR and 'H NMR spectra (Scheme 111). Alternatively (Scheme IV) acetalation of 18 followed by regioselective hydrolysis of the bisacetonide compound 20 led to 21 and subsequent periodate oxidation gave the aldehyde 22, which was more stable than the corresponding unprotected analogue 19. Syntheses of Anthracyclinones. Since several glycosides of 5 have shown interesting cytotoxic activity" and original electrochemical behavior,l* our efforts were turned toward a large-scale synthesis of this aglycon. Previous route to 5 or its monoisopropylidene derivative 27 included a regioselective hydrolysis of the diisopropylidene derivative 23 to give 24, which, after periodate oxidation, led to aldehyde 26 as precursor of 27. UnfQrtunatly when repeated on a larger scale, less regioselectivity was observed which led to a mixture of starting material 23 and monoacetal derivative 24 and also a large amount of tetrol25. To avoid such a delicate chromatography to isolate the (16) Johnson, C. R.;Dutra, G. A. J.Am. Chem. SOC.1973,95, 7777. (17) Monneret, C.;Florent, J. C.; Genot, A. Fr. Patent 85 10063,1985. (18) Anne, A.; Bennani, F.; Florent, J. C.; Moiroux, J.; Monneret, C. Tetrahedron Lett. 1985,26, 2641.
(19) Marschalk, C.;Koenig, J.; Ouroussof. Bull. SOC. Chim. Fr. 1936, 1545. (20) Lewis, C. E.J. Org. Chem. 1970, 35, 2938. (21) Qureshi, S.;Shaw, G.;Burgess, G. E. J.Chem. SOC.Perkin Trans. 1 1985,1557. (22) Brockmann, H.Fortschr. Chem. Org. Naturst. 1963,21 121. (23) Kende, A. S.;Tsay, Y. J. Chem. SOC.,Chem. Commun. 1977,140. Krohn, K.; RBsner, A. Tetrahedron Lett. 1978, 353. (24) Krohn, K.; Behnke, B. Chem. Ber. 1980, 113, 2994. Krohn, K.; Priyono, W.Tetrahedron 1984,40,4609.
1054
J. Org. Chem., Vol. 52, No. 6, 1987
Florent e t al.
"c;
+
solid: mp 65 [aI2'D 52" (c0.6, CHCl,); IR (KBr) 1780 cm-'; 'H NMR 6 4.58 (m, 1 H, 4-H), 4.36 (d, 1 H, J = 9) and 4.01 (d, 1 H, J = 9) (AB, 2'-H), 3.40 (dd, 1 H, J = 10, S = 5) and 3.29 Conclusions (dd, 1 H, J = 10, J' = 7) (ABX, 5-H), 2.62 (dd, 1 H, J = 15, S The foregoing results are significant in several respects: = 6) and 2.01 (dd, 1H, J = 15, J' = 8) (ABX, 3-H), 1.45 (9, 3 H) First, the starting material, isosaccharino- l,4-lactone which and 1.43 (s, 3 H) (CMe,); EIMS; m / z (relative intensity) 297 ( M + already incorporates t h e desired functionality present at - 15, loo), 255 (16), 237(13), 141(39). Anal. Calcd for CgHl3O4I: C, 34.6; H, 4.19. Found: C, 34.35; H, 4.22. C-9 of the anthracyclinone products is prepared in a single ( - ) - ( 2 5 )-2-Hydroxy-2-(h y d r o x y m e t h y l ) - 2 , 2 ' - 0 -isostep from readily available materials. Second, these propylidenepent-4-enoic Acid (9). To a solution of iodo comsyntheses avoid the delicate introduction of the labile pound 8 (55 g, 176 mmol) in THF (300 mL), water (10 mL), and 9-OH. Third, t h e aldol-type ring-closure step encountered acetic acid (10 mL) at 0 "C was added zinc powder (20 g). The in the synthesis of 5 is highly stereoselective giving t h e cis mixture was stirred vigorously at room temperature for 1h. After derivative 27 precursor of biologically active drugs. filtration through a pad of Celite, the filtrate was diluted with The value of our synthetic approach is further enhanced water (500 mL) and neutralized with aqueous NaOH (1 N) and by the fact that 4-demethoxydaunorubicin and doxorubicin washed with dichloromethane (2 X 300 mL). The aqueous layer cannot be produced by fermentation. was then acidified with aqueous HC1 (1N) and extracted with Transformation of cu-D-glucosaccharino-l,4-lactone (2) ethyl acetate to give after evaporation under reduced pressure 26 g of compound 9 in a semicrystalline form (70%):DO,].[ -17" into ~ t e f f i m y c i n o n eand ~ ~ aranciamycinone26 analogues is (c 2, CHCl,); IR (film) 1750 cm-'; 'H NMR 6 5.74 (m, 1 H, 4-H), now under investigations. 5.14 (d, 2 H, 5-H), 4.31 (d, 1 H, J = 9) and 3.92 (d, 1 H, J = 9) (AB, 2'-H), 2.64 (dd, 1 H, J = 15, J' = 7, 3a-H) and 2.49 (dd, 1 Experimental S e c t i o n H, J = 15, J' = 7, 3b-H), 1.44 (s, 3 H) and 1.42 (s, 3 H) (CMe,). General Methods. Melting points (Kofler hot stage microAnal. Calcd for CgHl4O4:C, 58.05; H, 7.57. Found: C, 58.25; scope) were uncorrected. IR spectra were recorded on a PerH, 7.48. kin-Elmer Model 257 spectrophotometer, calibrated against (-)-(2R )-2-Hydroxy-2-(hydroxymethyl)-2,2'0 -isopolystyrene film, and were expressed in cm-'. 'H NMR spectra propylidenepent-4-enol(ll). To a solution of 9 (27 g, 145 mmol) at 270 MHz were obtained on a Brucker HX 270 in CDC1, except in THF (500 mL) was added portionwise and at 0 "C LAH (8.26 when signaled. Chemical shifts were expressed in ppm downfield g, 220 mmol). The suspension was stirred under reflux, overnight. from internal Me,Si with the notations indicating the multiplicity The reaction mixture was then cooled and treated sequentially of the signal (s, singlet; d, doublet; t, triplet; q, quartet; m, with 8 mL of water, 8 mL of 15% aqueous NaOH, and 24 mL multiplet). The coupling constants are expressed as J values in of water. The mixture was stirred at room temperature for 2 h units of hertz. Mass spectra (DCI/NH, or EI) were recorded on and filtered. Solids were washed with ether and the filtrate was a Nermag R 1010 (E.N.S.C.P.). For E1 they were obtained at an concentrated under reduced pressure to give 24.9 g (80%)of 11 ionizing voltage of 70 eV. as a colorless oil: [a]"D -3" (c 3 CHCl,); IR (film) 3450 cm-l; 'H Silica gel for column chromatography or flash chromatography NMR 6 5.74 (m, 1 H, 4-H), 5.11 (d, 1 H, J = 3) and 5.07 (br s) was Merck Silica Gel H 60 No. 7736. Analytical thin-layer (5-CH,), 3.88 (d, 1 H, J = 9) and 3.78 (d, 1H, J = 9) (AB, 2'-H), chromatographies were performed on Merck Silica Gel 60 F254. 3.50 (m, 2 H, 1-H), 2.40 (m, 2 H, 3-H), 1.98 (dd, J = 5 , OH), 1.41 Ether solvents (THF, ether, etc.) were dried over sodium (s, 6 H, CMe,); EIMS, m / z (relative intensity) 173 (M + 1, 20), benzophenone and distilled, while dry CH2C12was prepared by 157 (M" - 15, lo), 141 (20), 131 (25), 117 (42), 83 (loo), 59 (100). distillation over CaH2. Anal. Calcd for C9H1603: C, 61.31; H, 9.15. Found: C, 61.48; Microanalyses were performed by the Laboratoire de MicroH, 9.32. analyse du CNRS, Gif sur Yvette and Lyon. (-)-( 2 5 )-2-Hydroxy-2-(hydroxymethy1)-2,2'- 0 -iso2,2'-O-Isopropylidene-5-0-tosyl-a-~-isosaccharino-1,4- propylidenepent-4-enal (12). (1) From Alcohol 11. To a lactone (7). To a solution of 6 (735 g, 3.7 mol) in pyridine (2500 solution of alcohol 11 (20 g, 116 mmol) in dry dichloromethane mL) cooled at -25 "C was slowly added 900 g (4.7 mol) of p (500 mL) at 0 "C were added 93 g of molecular sieves (3 A); toluenesulfonyl chloride. The reaction was allowed to reach room (activated 5 h at 320 "C) and pyridinium dichromate (65 g, 174 temperature and stirred for 72 h. The reaction mixture was then mmol). After dropwise addition of 10 mL of acetic acid,14the poured into crushed ice ( 5 kg) and water (10 L) with vigorous mixture was stirred at room temperature for 0.5 h. Ether (1000 stirring. The white precipitate was filtered, washed with hot water, mL) was then added, the suspension was filtered through a pad and washed quickly with cold ether. This affords 975 g of 7 (75%) of Celite, and the filtrate was evaporated. The residue was as white crystals. Recrystallization from ether-CH2C1, gave an dissolved in ether (500 mL) and the ethereal solution was filtered analytical sample: mp 110 "C; [aI2OD+ 57" (c 1,CHC1,); IR (KBr) through silica gel (20 g, 230-400 mesh). Evaporation of ether 1780 cm-'; 'H NMR 6 7.71 (d, 2 H, Ar), 7.31 (d, 2 H, Ar), 4.73 under reduced pressure gave 14.8 g of aldehyde 12 (75%) as a (m, 1 H, 4-H), 4.28 (d, 1 H, J = 9) and 4.02 (d, 1 H, J = 9) (AB, pale yellow syrup: ),'2I.[ -3" (c 3.2, CHCI,); IR (film) 1730 cm-'; 2'-H), 4.19 (dd, 1 H, J = 11,J' = 4) and 4.09 (dd, 1 H, J = 11, 'H NMR 6 9.59 (s, 1H, 1-H),5.70 (m, 1H, 4-H), 5.14 (s, 1H, 5a-H), J' = 4) (ABX, 5-H), 2.43 (s, 3 H, Me), 2.55-2.13 (m, 2 H, 3-H), 5.06 (d, 1 H, J = 10, 5b-H), 4.15 (d, 1 H, J = 9) and 3.78 (d, 1 1.45 (s, 3 H) and 1.41 (s, 3 H) (CMe,); EIMS; m / z (relative H, J = 9) (AB, 2'-H), 3.17 (dd, 1H, J = 15, J' = 7) and 2.62 (dd, intensity) 357 (M 1,
