Convenient synthesis of alcoholO-hemiesters using isopropenyl esters as acylating reagents: synthesis of hydrophilic oxaunomycin 10-O-hemiester derivatives

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1993 Convenient Synthesis of Alcohol 0-Hemiesters using lsopropenyl Esters as Acylating Reagents: Synthesis of Hydrophilic Oxaunomycin 10-0-Hemiester Derivatives Yasuyuki Kita," Hiroshi Maeda, Fumie Takahashi and Seiji Fukui Faculty of PharmaceuticalSciences, Osaka University, 7 -6, Yamada-oka, Suita, Osaka 565, Japan Various types of alcohol 0-hemiesters7a-m were synthesized conveniently ingood yield by reaction with isopropenyl esters 4a-f in the presence of a catalytic amount of conc. H,SO, or toluene-p-sulfonic acid followed by selective deprotection of the terminal esters. This method was applied to a preparation of hydrophilic oxaunomycin 10-0-hemiester derivatives 14a, b and 19a-c. Considerable efforts have been devoted to the synthesis of hydrophilic 0-hemiester derivatives of various clinically effica-cious drugs, notably in the fields of steroids,' tocopherols,2 anthracycline antibiotics and tax01.~Currently, they are prepared by (i) treatment of alcohols with cyclic acid anhydrides, (ii) treatment of alcohols with acid chlorides in the presence of a base, followed by deprotection of the terminal esters which are prepared by method (i) or from only simple alcohols and dicarboxylic acids, or (iii) conversion of alcohols into halogeno compounds followed by nucleophilicsubstitution with dicarboxylic monoanions, and are used to create less toxic drugs.These methods, however, have several restrictions: (i) medium to large unstable anhydrides cannot be employed in the direct acylation of alcohols, (ii) bulky secondary or tertiary alcohols do not react easily with acid anhydrides or acid chlorides, (iii) alcohols bearing some base-sensitive functional groups cannot be allowed to react with acid anhydrides or acid halides in the presence of the base and (iv) bulky alcohols may be troublesome to transform into the halogeno compounds. In a previous communication, we reported a novel and convenient method for the acylation of bulky alcohols using isopropenyl esters and selective deprotection of the terminal ester leading to the monoesters.6 We now report a full account of these studies and their applications to hydrophilic oxaunomycin 10-0-hemi-esters and related derivatives.Results and Discussion The isopropenyl esters 4a-f were prepared from the half-esters la-f bearing terminal esters as the protecting groups (Scheme 1).The known half-esters la,8 lc,' ldl' and If were prepared by standard methods. The unknown half-esters lb, e bearing 2-(trimethylsily1)ethyl(TMSE) ester groupings were synthesized from the benzyl esters la, d or from succinic anhydride 3. Thus, the half-esters la, d were converted into the diesters 2a, d by chlorination with oxalyl dichloride at below room temperature t followed by alcoholysis with 2-(trimethylsily1)ethanol in the presence of pyridine. Catalytic hydrogenation of diesters 2a, d afforded compounds lb, e in good yield. Alternatively, hemi-ester lb was obtained conveniently from succinic anhydride 3 by treatment with 2-(trimethy1silyl)ethanol in the presence of pyridine.The desired isopropenyl esters 4a-f were prepared by two different methods. Similarly to the reported methods,12 half-esters la-f reacted with isopropenyl acetate in the presence of a t Although the acid chloride could not be obtained from compound la under reflux in CHCl, in the presence of thionyl dichloride according to ref. 10 because of thermal instability, it was obtained at below room temperature in CH,CI, in the presence of oxalyl dichloride. i, ii H02CCHZ,C02CH2Ph TMSEOCOCH2amp;02CH2Ph la;n= 2 2a; n= 2 (56)d;n= 5 d; n = 5 (56) iii ii 1 OQO TMSEOCOCH2InC02H lb; n= 2 (82 from 2a) 3 (77from 3) e; n= 5 (95) B) ivR'OCOCHzInCO2H (route A) i, " R'OCOCH2,C02 04 1a-f 4a-f a; n = 2, R' = CH,Ph route A route B b; n = 2, R' = CH,,SiMe, 4a; 51 35 c; n = 2, R' = Me b; 45 d; n = 5, R' = CH,Ph c; 58 38 e; n = 5, R' = CH,,SiMeJ d; 51 40 r; n = 5, R' = Me e; 60 34 r;74 44 Scheme 1 Reagents: i, (COCI),, CH,CI,; ii, 2-(trimethylsilyl)-ethanol, pyridine; iii, H,/Pd, 1,Cdioxane; iv, isopropenyl acetate, cat. BF,*Et,O, cat.Hg(OAc),; v, acetone, KH, DME catalytic amount of BF,.Et20 and mercury(I1) acetate to give diesters 4a-f in moderate yield (route A). The esters 4a and 4c-f were also prepared by direct acylation of the potassium enolate generated from acetone and potassium hydride in 1,2-di-methoxyethane (DME) with the corresponding acid chloride $ at 0 "C (route B).Physical data of these isopropenyl esters are summarized in Table 1. All acylations were performed in the presence of a catalytic amount of acid to give a high yield of diesters 6a-y. When conc. H2S04was used as catalyst, the acylation was over in a short time through the use of a slight excess of the reagent (Table 2, runs 1, 5, 7, 9 and 11). Use of p-TsOH (PTSA) as catalyst required two mole equivalents of the reagents to consume the alcohol completely (runs 2, 4, 6, 8, 10 and 12). This acylation method is quite useful not only for the bulky alcohols such as tertiary alcohols 5e, f (runs 22-27), endo-trinorborneol5d (run 21) and pantolactone 5i (runs 31-33), but also for phenol 5j (runs 34-36). Furthermore, olefin and nitrile groups were not affected under these reaction conditions (runs 28-30).In the $These acid chlorides were prepared according to the preceding footnote.t The acid chloride derived from compound lb was unstable and we were unable to isolate it. 2640 J. CHEM. SOC. PERKIN TRANS. 1 1993 Table 1 Physical data of isopropenyl esters 4 V,,,y3C13)/ m-Found () B.p.PC (Required) Compound (mmHg) GQ C=C G,(CDC13) Formula C H 4a 165-1 68 1735 1670 1.89 (3 H, s), 2.72 (4 H, s), 4.67 and 4.69 (1 H each, 2 s), 5.14 Cl4Hl6O4 67.4 6.45 (2.0) (2 H, s), 7.35 (5 H, s) (67.72) (6.50)4b 122-124 1725 1670 0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.93 (3 H, s), 2.5-2.8 (4 H, m), Cl,H,20,Si 55.6 8.55 (0.60) 4.1-4.3 (2 H, m), 4.65-4.75 (2 H, m) (55.78) (8.58) 4c 104106 1735 1670 1.92 (3 H, s), 2.62.8 (4 H, m), 3.71 (3 H, s), 4.65-4.75 (2 H, m) C8H1204 55.45 7.15) (55.80) (7.03)(14)4d 168-171 1735 1670 1.3-1.5 (2 H, m), 1.5-1.8 (4 H, m), 1.91 (3.H, s), 2.37 (4 H, (0.30) brt,J7.3),4.66and4.69(1Heach,2~),5.11(2H,s),7.3-7.5 (5 H, m)4e I28 1720 1670 0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.3-1.5 (2 H, m), 1.5-1.8 (4 H, (0.38) m), 1.92 (3 H, s), 2.29 and2.38 (2 H each, 2 t, J7.3), 4.1-4.3 (2 H, m), 4.65-4.75 (2 H, m) 4f 121-1 23 1730 1670 1.3-1.5 (2 H, m), 1.61.8 (4 H, m), 1.92 (3 H, s), 2.25-2.45 (2.5) (4 H, m), 3.67 (3 H, s), 4.67 and 4.70 (1 H each, 2 s) CI7H22O4 70.25 7.5 (70.32) (7.64) C,,H2,0,Si 60.05 (59.96) 9.45 (9.39) CllH1804 61.5 8.3 (61.66) (8.47) work-up of the reaction, an excess of acylating reagent was quenched by treatment with several drops of conc.hydrochloric acid under ice-cooling. All results of the acylation and the physical data of acylation products (diesters) are summarized in Tables 2 and 3, respectively. For the purpose of obtaining alcohol 0-hemiesters 7, a terminal ester of diester 6 must be removed selectively. Three types of deprotection methods were examined with substrates 6m-0 as representative examples (Table 2): (i) catalytic hydro- genation of the benzyl ester 6m (method A), (ii) desilylative fragmentation of the 2-(trimethylsily1)ethyl (TMSE) ester 6n by treatment of tetrabutylammonium fluoride (TBAF) l3 (method B) and (iii) selective saponification of the methyl ester 60 by treatment with alkali (method C).High yields of the alcohol 0-hemiester 7f were obtained in every case. Various other types of alcohol 0-hemiesters 7a-e and 7g-m were prepared from the corresponding diesters by one of the above methods. In the case of the diesters obtained from primary or secondary alcohols and phenol, methods A and B gave satisfactory results. Method B is the best for removal of the terminal ester having an olefin or a nitrile moiety in the molecule. Method C is effective in deprotecting the terminal methyl ester, especially in the case of the bulky esters obtained from tertiary alcohols. All results of deprotections of the terminal esters and physical data of alcohol 0-hemiesters are summarized in Tables 2 and 4, respectively.In this way, we have developed a quite general and convenient synthesis of alcohol 0-hemiesters. Finally, we applied this method to the 0-hemiesterification of the anthracycline antibiotic, oxa~nomycin,'~ which was found to be about 100-fold more active than adriamycin against leukaemic L-1210 cultures.15 The acylating reagents 4a, c, f smoothly reacted with 7,9-0-phenylboranediyl-~-rhodomycin-one 8l4 in the presence of a catalytic amount of conc. H2S0, to afford diesters 9a-c in 8047 yield without any acylation of phenolic hydroxy groups. The boronate moiety in diesters 9was removed by treatment with 2-methylpentane-2,4-dioland acetic acid in acetone to give the desired 10-0-acyl-P-rhodomycinones 10a-c in high yield.For the preparation of hemiesters 14a, b glycosidation of 1,3-diols 10a, b with the 1,4-bis-O-(p-nitrobenz- oy1)-L-daunosamine derivative 11using trimethylsilyl trifluoro- methanesulfonate (TMSOTf) and molecular sieves (MS) 4 8, in a mixed solvent of anhydrous dichloromethane and diethyl ether at -15 "C l6 gave the 7-0-a-glycosides 12a, b in 79 and 77 yield, respectively. The glycosides 12a, b were deprotected with 1.2 mole equivalents of 0.1 mol dm-3 NaOH at 0 "C in dichloromethane-MeOH to afford 4'-hydroxy compounds 13a, b, which were further treated with an excess of 0.1 mol dmP3 NaOH at room temperature to give the desired N-(trifluoro- acety1)oxaunomycin 1 0-0-hemisuccinate 14a and 1 0-0-hemi- pimelate 14b in 51 and 41 yield, respectively (Scheme 2).Furthermore, we synthesized the oxaunomycin derivatives 19a-c in which the L-daunosamine residue was replaced by not only 2-deoxy-~-erythro-pentopyranosebut also 2,6-dideoxy-2- fluoro-L-talopyranose. This is because of the amount of attention that has been paid to the antitumour activities of anthracycline derivatives containing a sugar which has an axial 2'-fluoro substituent. ' The glycosidations of compounds lob, c with the protected sugars 15 l8 and 16 under Koenigs-Knorr conditions afforded the corresponding P-glycosides 17a and a-glycosides 17b, c in 5740 yield. These diacetates were deprotected by treatment with 3 mole equivalents of 0.1 mol dm-3 NaOH to give the 3',4'-dihydroxy compounds 18a-c, which were further treated with an excess of 0.1 mol dmP3 NaOH at room temperature to yield the desired derivatives 19a-c in 5662 yield from 17a-c (Scheme 3).The preparation of other oxaunomycin 10-0-hemiester derivatives and biological testing for activity against tumour cells is in progress. The present acylation and deprotection method opens up a potentially useful method for the O-hemi- esterification of other natural products. Experimental All b.p.s and m.p.s are uncorrected; m.p.s were measured on a Yanagimoto micro melting point apparatus. Optical rotations were measured with a Perkin-Elmer 241 polarimeter using a 10 cm cell and are given in lo-' deg cm2 g-'. IR spectra were recorded on a JASCO HPIR- 102 spectrophotometer. 'H NMR spectra were measured on a Varian VXR-200 (200 MHz), a Hitachi R-250HT (250 MHz), or a JEOL JNM-GXSOO (500 MHz) spectrometer with Me4Si as internal standard.J-and w3-values are given in Hz. Mass spectra were obtained on a JEOL JMS-D300 for electron impact (EI) MS or a JEOL HX-100 for fast atom bombardment (FAB) MS mass Spectrometer. E. Merck silica gel 60 (70-230 mesh ASTM) was used for column chromatography and E. Merck precoated TLC plates, silica gel 60 F254, were used for preparative TLC (PLC). Benzyl 2-(Trimethylsi1yl)ethyl Succinate 2a.4xalyl di-chloride (9.20 cm3, 104 mmol) was added to a solution of hemiester la8 (7.30 g, 35.1 mmol) in dry CH2C12 (40cm3) at 0deg;C and the mixture was stirred below 25 "C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in dry CH,C12 (40cm3).A solution of 2-(trimethylsilyl)ethanol(5.00 g, 42.4 mmol) in dry pyridine (50 cm3) was added to the above solution at -30 "C.J. CHEM. SOC. PERKIN TRANS. 1 1993 0 0 0 OH OH i w ii OH 0 OH 0-BPh 0-BPh OH 8 9a;n = 2, R' = Me (86Yo) 10a;n = 2, R1= Me (92) b;n = 5, R' = Me (87) b;n = 5, R' = Me (83) C; n = 2, R' = CH2Ph (80) C;n = 2, R' = CH2Ph (85) 0 OH 0 OH 0 R30 NHCOC F3 + 12a;n = 2, R' = Me, R3= PNB (79) b;n = 5, R1 = Me, R3= PNB (77) 13a;n = 2, R' = Me,R3= H (90) b;n = 5, R'= Me, f?=H (97) 14a;n = 2, R' = R3= H (51) b;n = 5, R' = R3= H (41) PNB = pnitrobenzoyl Scheme 2 Reagents: i, 4a, 4c or 4f, cat.H,SO,, CH,Cl,; ii, 2-methylpentane-2,4-diol,AcOH-acetone-CH,CI,; iii, TMSOTf, MS 4 A, CH,CI,-Et,O; ivy0.1 mol dm-3 NaOH (1.2 mol equiv.), CH,CI,-MeOH; v, 0.1 rnol dm--3 NaOH (20 rnol equiv.), DME i, p7-1 Adlob 15 lOb,c 8' Or Ii'Adlob 16 w 7-04 HOoH R4 17a; n = 5, R' = Me, R4= R5= H (80) 18a; n = 5, R' = Me, R4 = R5 = H (77) b; n = 5, R' = Me, R4= F (75) b;n = 5, R' = Me, R4 = F(84) C; n = 2, R' = CH2Ph, = F,Ff' = Me (57) C; n = 2, R' = CH2Ph, R4= F,R5= Me (75"/) 0 0 OW OACHJ,,C02H OH 0 OH 0 R5amp; HOoH R4 19a;n = 5, R4 = R5 = H (75) b; n = 5, R4 = F, R5= Me (74) c;n = 2, = F, R5= Me (74) Scheme 3 Reagents: i, yellow He, HgBr,, MS 4 A, CH,Cl,; ii, yellow HgO, HgBr,, MS 3 A, CH,CI,; iii, 0.1 rnol dm-3 NaOH (3 rnol equiv.),MeOH; iv, 0.1 rnol dm-3 NaOH (40 mol equiv.), MeOH J.CHEM. soc. PERKIN TRANS. 1 1993 Table 2 Acylation of alcohols 5 with reagents 4 and subsequent deprotection of diesters 6 to 0-hemiesters 7 4a-f deprotectionR20H-R20COCH2,C0,R' -R20COCH2,C02H 5a-j 6a-y 71- Conditions Run Alcohol 4 (mol equiv.), catalyst, time Yield" of 6 (R') () Deprotection method' Structure of 0-hemiester Yield" of 7 ( 1 2 3 4 5 6 7 8 9 10 11 PhCH,CH,OH 5a 4a (1.2), c. H,S04, 0.5 h (2.0), p-TsOH, 4 H 4b (2.0), C. H,S04, 11 h (2.0), p-TsOH, 12 h 4c (1.2), c. H2S0,, 2 h (2.0), p-TsOH, 7 h 4d (1.2), C. H,S04, 0.3 h (2.0), p-TsOH, 1 h 4e (1.2), C. H,S04, 0.8 h (2.0), p-TsOH, 1.5 h 4f (1.2), C. H2S04, 1.5 h PhCH,CH,0COCH2 5C02H 12 (2.0), P-TsOH, 7 h 13 14 15 PhCH20H 5b 4b (2.0),p-TsOH, 10 hd (2.0), p-TsOH, 4 h 4f (1.2), C.H2S04, 0.7 h 6g"(TMSE) (67) 6h (Me) (70) (Me) (79) B 16 17 18 19 20 -OH 5c 4a (2.0), c. H,S04, 2 h (2.0), P-TsOH, 9 h 4b (2.0), p-TsOH, 8 hd (2.0), p-TsOH, 3 h 4f (2.0), H,S04, 0.7h 6i (Bn) (72) (Bn) (70) (Me) (88) 6j (TMSE) (75) 6k (Me) (82) A B 21 4OH 4n (2.0), p-TsOH, 4 h 4 5d 22 23 24 25 PhCH2C Me20H 5. 4a (2.0), p-TsOH, 6 h 4b (2.0), p-TsOH, 13 hd 4c (2.0), p-TsOH, 3 h 4f (2.0), p-TsOH, 3 h 6m(Bn)(86) 6n (TMSE) (73) 60(Me) (70) 6P (Me) (75) A B C C 26 21 4d (2.0),p-TsOH, 4 he 0: 4f (2.0), p-TsOH, 4 he 28 29 0""" 5f 59 4b (2.0), p-TsOH, 8 hd 4e (2.0), p-TsOH, 1 h 6s (TMSE) (65) 6t (TMSE) (92) B B 30 NCCHamp;OH 4b (2.0), p-TsOH, 8 hdgq 6u (TMSE) (65) B 5h 31 4a (2.0), c.H,S04, 1 h 6v (Bn) (92) A 500cH22c02H32 (2.0), p-TsOH, 4 h (Bn) (94)33 4b (2.0), p-TsOH, 12 hd 6w (TMSE) (70) B 34 PhOH 4a (2.0), c. H,S04, 2 h PhOCOCH,,CO,H 35 5j (2.0), p-TsOH, 3 h 36 4f (2.0), p-TsOH, 1.3 h " Isolated yields are given. Abbreviations: Bn = CH,Ph, TMSE = Me,SiCH,I2. 'Method A: H,/Pd, 1,Cdioxane; method B: TBAF, DMF; method C: NaOH, aq. MeOH. Carried out at 40 "C. This compound is identical with 2a. This compound is identical with la. In the work-up, the treatment with conc. HCl was omitted. After being stirred for 1 h the mixture was concentrated under Benzy1 2-( Trimethy lsilyl )e thy 1 Pimela te 2d.-Compound 2d reduced pressure.The residue was acidified with 5 aq. HCl (781 mg,56) was prepared from half-ester Id lo (1.00 g, 4.00 and extracted with EtOAc. The extract was washed with mmol), oxalyl dichloride (1.52 g, 12.0 mmol), 2-(trimethylsily1)- saturated aq. NaHCO,, dried (Na,SO,), and concentrated ethanol (520 mg, 4.40 mmol) and pyridine (350 mg, 4.40 under reduced pressure. The residue was chromatographed on mmol), as an oil, b.p. 165-175 "C/0.28 mmHg (bath silica gel hexane-Et,O (14:1) to give the title compound 2a temperature); v,,,(CHCl,)/cm-' 1720; 6,(200 MHz; CDCI,) (6.0 g, 56) as an oil. Physical data are shown in Table 3 0.03 (9 H, s, SiMe,), 0.9-1.05 (2 H, m, SiCH,), 1.2-1.5 (2 H, m, (6g = 2a). CH,), 1.5-1.8 (4 H, m, CH, x 2), 2.26 and 2.36 (2 H each, 2 t, J J.CHEM. SOC. PERKIN TRANS. 1 1993 Table 3 Physical data of diesters 6 Found rk)(Required) Formula C H 6a 6b 6c 6d b 140-150 (0.30) 150-1 55 (0.30) (0.18) 155-165 1725 1720 1720 1725 2.5-2.75 (4 H, m), 2.91 (2 H, t, J7.0), 4.29 (2 H, t, J7.0), 5.12 (2 H, s), 7.1-7.4 (10 H, m) 0.04 (9 H, s), 0.9-1.1 (2 H, m), 2.5-2.7 (4 H, m), 2.94 (2 H, t, J7.0),4.1-4.3(2H,m),4.31 (2H,t,J7.0),7.1-7.4(5H,m) 2.61 (4 H, s), 2.94 (2 H, t, J7.0), 3.68 (3 H, s), 4.31 (2 H, t, J 7.0), 7.1-7.4 (5 H, m) 1.2-1.4 (2 H, m), 1.5-1.8 (4 H, m), 2.2-2.4 (4 H, m), 2.92 (2 H, t,J7.0),4.28(2H, t,J7.0), 5.11 (2H,s),7.1-7.5(10H, C19H2004 C17H2604Si 1JH 16O4 C22H2604 3 12.1352' (3 12.1359) 63.45 8.0 (63.31) (8.13) 65.85 7.0 (66.08) (6.83) 74.3 7.45 (74.55) (7.39) 6e 6f 135-145 (0.30) 160-170 (0.40) 1725 1725 m)0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.2-1.4 (2 H, m), 1.5-1.7 (4 H, m), 2.2-2.4 (4 H, m), 2.93 (2 H, t, J 7.0), 4.14.25 (2 H, m),4.29(2H,t,J7.0),7.1-7.4(5H,m) 1.2-1.4 (2 H, m), 1.5-1.7 (4 H, m),2.29 (4 H, t, J7.1), 2.93 (2 H, t, J7.0), 3.66 (3 H, s), 4.29 (2 H, t, J6.9), 7.1-7.3 (5 H, C20H3204Si C16H2204 364.2071 (364.2070) 68.95 8.05 (69.04) (7.97) 6g (=2a) 6h 6i 140-150 (0.45) 150-1 55 (0.35) 180-190 (0.50) 1720 1725 1725 m)0.03(9H,s),0.9-1.1 (2H,m),2.5-2.8(4H,m),4.1-4.3(2 H, m), 5.14 (2 H, s), 7.35 (5 H, s)1.2-1.4 (2 H, m), 1.5-1.7 (4 H, m), 2.2-2.4 (4 H, m), 3.66 (3 H, s), 5.1 1 (2 H, s), 7.35 (5 H, s) 0.85 (9 H, s), 0.9-2.1 (9 H, m), 2.55-2.75 (4 H, m), 4.55- 4.70($H,m),5.00-5.05(fH,m),5.13(2H,s),7.3-7.4(5H, C16H2404Si C15H2004 c2 lH3004 62.15 (62.30) 68.05 (68.16) 72.55 (72.80) 7.75 (7.84) 7.5 (7.63) 8.7 (8.73) 6i 6k 120-130 (0.30) 120-130 (0.28) 1720 1720 m)0.04(9H,s),0.85($ x 9H,s),0.86(+ x 9H,s)0.9-2.1(11H,m),2.56-2.65(4H,m),4.12-4.24(2H,m),4.55-4.73($ H, m), 4.99-5.07 (f H, m) 0.85($ x 9H,s),0.86(f x 9H,s),0.9-2.1(15H,m),2.2-2.35(4H,m),3.67(3 H,s),4.554.65($H,m),4.96-5.04(f C19H3604Si C18H3204 63.95 (64.00) 69.05 (69.19) 10.05 (1 0.18) 10.25 (10.32) 61 180-190 (0.23) 1720 H, m) 0.85-1.05 (1 H, m), 1.2-1.45 (4 H, m), 1.45-1.80 (2 H, m), 1.85-2.05 (1 H, m), 2.1-2.3 (1 H, m), 2.35-2.5 (1 H, m),2.65-2.75(4H,m),4.85-5.00(1H,m),5.13(2H,s),7.35(5 C18H2204 302.1479' (302.15 18) 6m 6n 60 6P 6q b 130-140 (0.40) (0.30) 150-170 (0.50) (0.20) 185-190 165-1 70 1720 1715 1715 1715 1725 1.42 (6 H, s), 2.5-2.7 (4 H, m), 3.03 (2 H, s), 5.13 (2 H, s), 7.1-7.4 (10 H, m) 0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.45 (6 H, s), 2.55 (4 H, s), 3.06 (2 H, s), 4.1-4.3 (2 H, m), 7.1-7.4 (5 H, m) 7.4 (5 H, m) 1.2-1.4(2H,m), 1.44(6H,s), 1.5-1.7(4H,m),2.22(2H,t, 7.35 (5 H, m) 1.0-2.0 (14 H, m), 1.45 (3 H, s), 2.05-2.20 (2 H, m), 2.24 (2 H, s) 1.44 (6 H, s), 2.56 (4 H, s), 3.05 (2 H, s), 3.68 (3 H, s), 7.1-J7.4), 2.30 (2 H, t, J7.4), 3.05 (2 H, s), 3.66 (3 H, s), 7.15-H, t, J7.3),2.37(2H, t, J7.3), 5.11 (2H,~),7.3-7.4(5H, c2 1 24O4 C19H3004Si ClSH2O04 C18H2604 C21H3004 74.0 (74.09) 65.0 (65.10) 67.95 (68.16) 70.35 (70.56) 72.4 (72.80) 7.2 (7.1 1) 8.65 (8.63) 7.65 (7.63) 8.45 (8.55) 8.8d (8.73) 6r 6s 140-145 (0.36) 125-135 (0.51) 1720 1720 m)1.2-1.7 (14 H, m), 1.46 (3 H, s), 2.05-2.4 (6 H, m), 3.67 (3 H, s)0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.2-2.2 (7 H, m), 2.5-2.7 (4 H, m), 4.00 (2 H, d, J6.4), 4.1-4.3 (2 H, m), 5.65.8 (2 H, cl SH2604 c16H2804Si 66.5 (66.63) 61.25 (61.50) 9.75 (9.69) 9.0 (9.03) 6t 6u 6v 6w 6x 6Y 145-150 (0.32) 140-145 (0.32) 170-1 80 (0.50) (0.35) 160-170 (0.20)140-150 (0.20) 135-145 1720 1725 1790, 1735 1790, 1750, 1725 1730 1720 m)0.04(9 H, s), 0.9-1.05 (2 H, m), 1.2-2.4 (13 H, m), 2.28 and 2.32 (2 H each, 2 t, J 7.1), 3.97 (2 H, d, J6.4), 4.14.3 (2 H, m), 5.6-5.7 (2 H, m) 0.04(9H,s),0.9-1.1 (2H,m), 1.9-2.2(2H,m),2.47(2H,t, J 7.1), 2.61 (4 H, s), 4.1-4.3 (2 H, m), 4.23 (2 H, t, J6.0) 1.09 (3 H, s), 1.18 (3 H, s), 2.6-2.9 (4 H, m), 4.02 (2 H, s), 5.14(2H,s), 5.36(1 H,s),7.34(5H,s) 0.04 (9 H, s), 0.9-1.1 (2 H, m), 1.13 and 1.21 (3 H each, 2 s), 2.6-2.9(4H,m),4.04(2H,d),4.14.3(2H,m),5.38(1H, s)2.7-3.0 (4 H, m), 5.16 (2 H, s), 7.0-7.5 (10 H, m) 1.35-1.5(2H,m),1,6-1.9(4H,m),2.35(2H,t,J7.4),2.56 (2 H, t, J 7.4), 3.67 (3 H, s), 7.07 (2 H, d, J 8.6), 7.15-7.30 (1 cl 9H3404Si C, ,Hz3NO4Si c1 7H2006 C15H2606Si cl 7H1604 C14H1804 64.0 (64.36) 54.5 (54.71) 63.45 (63.74) 54.15 (54.52) 71.8 (71.82) 66.9 (67.18) 9.55 (9.67) 8.0 (8.12) 6.3 (6.29) 7.8 (7.93) 5.6 (5.67) 7.3 (7.25) H, m), 7.37 (2 H, t, J 7.9) Bath temperature. * Oil.Partial decomposition occurred on distillation. 'High-resolution (EI) data. High-resolution (FAB, positive) data (Found: M+ + H, 347.2249. C2,H3,04 requires M + H, 347.2222). (Found: N, 4.85. Requires N, 4.91).High-resolution (EI) data (Found: M', 330.1524. C,sH260,Si requires M, 330.1499). M.p. 47-48 "C. 2644 J. CHEM. soc. PERKIN TRANS. 1 1993 Table 4 Physical data of alcohol 0-hemiesters 7 Vmax(CHC1,)I Found () B.p./T (mmHg)" a-' (Required) or m.p./T Compound (recrystalln. solvent) C--O amp;(CDCl,) Formula C H 7a 70-70.5 1720 2.5-2.7 (4 H, m), 2.94 (2 H, t, J7.0), 4.32 (2 H, t, J C12H 14'4 64.4 6.45' (hexane) 7.0), 7.1-7.4 (5 H, m) (64.85) (6.35) 7b 125-135 1710 1.2-1.4 (2 H, m), 1.5-1.7 (4 H, m), 2.2-2.4 (4 H, C15HZ004 67.7 7.35' (0.22) m), 2.93 (2 H, t, J7.0), 4.29 (2 H, t, J7.0), 7.1-7.4 (68.16) (7.63) (5 H, m) 7c (=la) 57-58d 1715 2.69 (4 H, s), 5.14 (2 H, s), 7.35 (5 H, s) C11H1204 (hexane) 7d 13C135 1710 0.85 (q x 9 H, s), 0.86 ($ x 9 H, s), 0.9-2.1 (9 H, C14H2404 65.35 9.3 (0.30) m), 2.5-2.8 (4 H, m), 4.5-4.8 (q H, m), 5.0-5.1 ($ (65.60) (9.44) H, m) 7e 95-105 1720 0.9-1.1 (1 H, m), 1.2-1.5 (4 H, m), 1.5-1.9 (2 H, cl lH 16O4 61.8 7.55" (0.22) m), 1.9-2.1 (1 H,m),2.1-2.3(1 H,m),2.4-2.5(1 (62.25) (7.60) H,m), 2.5-2.8 (4H,m), 4.9-5.1 (1 H,m) 7f 65-66 1705 1.44 (6 H, s), 2.5-2.7 (4 H, m), 3.06 (2 H, s), 7.1-C14H1804 66.95 7.3 (hexane) 7.4 (5 H, m) (67.18) (7.25) 7g 185-95 1700 1.2-1.4 (2 H, m), 1.44 (6 H, s), 1.5-1.8 (4 H, m), c1 7H2404 292.1655 (0.50) 2.22 (2 H, t, J7.6), 2.29 (2 H, t, J7.6), 3.05 (2 H, (292.1672) s), 7.1-7.4 (5 H, m) 7h g 1710 1.1-1.8 (14 H, m), 1.46 (3 H, s), 2.0-2.2 (2 H, m), C14H2404 65.15 9.35h 2.26(2H, t, J7.4),2.36(2H, t, J7.4) (65.59) (9.44) 7i 140-150 1710 1.15-1.45 (1 H, m), 1.6-2.2 (6 H, m), 2.5-2.8 (4 C11H1604 212.1075 (0.50) H, m), 4.01 (2 H, d, J6.4), 5.55-5.8 (2 H, m) (2 12.1049) 7j 135-145 1710 1.2-2.2 (13 H, m), 2.33 and 2.36 (2 H each, 2 t, J C14H2204 254.1525 (0.30) 7.1), 3.98 (2 H, d, J6.2), 5.5-5.8 (2 H, m) (254.15 18) 7k g 1730' 1.9-2.1 (2H,m),2.47(2H,t, J7.1),2.5-2.8(4H, C8H1 lNo4 185.0683 m), 4.24 (2 H, t, J6.0), 6.6-7.4 (1 H, br) (1 85.0685) n 170-180 1790, 1.11 and 1.20 (3 H each, 2 s), 2.6-2.9 (4 H, m), C10H1406 230.0780 (0.40) 1750, 4.04 (2 H, d, J 1.8), 5.39 (1 H, s) (230.0788) 1720 7m 96.5-97.5 1755, 2.7-3.0 (4 H, m), 7.0-7.5 (5 H, m) CIOH 10deg;4 (hexane) 1715 Bath temperature.High-resolution (EI) data (Found: M', 222.0908. C12H1404 requires M, 222.0892).High-resolution (EI) data (Found: M', 264.1376. C15HZoO4 requires M, 264.1361). Lit.,* m.p. 58-59 "C. " High-resolution (EI) data (Found: M+,212.1064. CllHl6O4 requires M, 212.1049. High-resolution (EI) data. CJ Oil. Partial decomposition occurred on distillation. High-resolution (FAB, positive) data (Found: M++ H, 257.1775. C14H2@4 requires M + H, 257.1753). Lit.,lg 97-98 OC. 7.5, COCH, x 2), 4.1-4.25 (2 H, m, OCH,), 5.1 1 (2 H, s, benzyl 2-(Trimethylsi1yl)ethyl Hydrogen Pimelate 1e.-Compound le CH,) and 7.3-7.5 (5 H, m, ArH) (Found: C, 65.05; H, 8.65. (7.90 g, 95) was prepared from diester 2d (14.0 g, 40.0 mmol) C19H3004 requires C, 65.10; H, 8.62). and Pd-black (550 mg), as an oil, b.p. 170-1 75 "C/0.30 mmHg; v,,(CHCl,)/m-' 1720-1705; amp;(200 MHz; CDCl,) 0.03 2-(Trimethylsi1yl)ethyl Hydrogen Succinate 1b.-Pd-black (9 H, s, SiMe,), 0.9-1.05 (2 H, m, SiCH,), 1.25-1.5 (2 H, m, (70.0 mg) was added to a solution of compound 2a (6.00 g, 19.5 CH,), 1.55-1.75 (4 H, m, CH, x 2), 2.28 and 2.35 (2 H each, 2 t, mmol) in 1,4-dioxane (40 cm3), and the mixture was subjected J7.3, COCH, x 2) and4.05-4.25 (2 H, m, OCH,) Found: M + to catalytic hydrogenation under hydrogen for 15 h.The (EI), 260.1438. C12H2,04Si requires M, 260.141 13. catalyst was filtered off and the filtrate was concentrated under reduced pressure to give an oil, which was distilled to General Procedures for Formation of Isopropenyl Ester: from give the title compound lb (3.30 g, 82) as an oil, b.p. Half-esters la-f and Isopropenyl Acetate (Route A).-Benzyl 132-1 33 OC/O.6 mmHg; v,,(CHCl,)/cm-' 17 10; amp;(200 MHz; isopropenylsuccinate 4a. A mixture of compound la (20.1 g, 96.6 CDCl,) 0.04 (9 H, s, SiMe,), 0.9-1.1 (2 H, m, SiCH,), mmol), isopropenyl acetate (53.1 g, 53 1 mmol), Hg(OAc), (920 2.5-2.8 (4 H, m, CH,CH,) and 4.1-4.3 (2 H, m, OCH,) mg, 2.90 mmol) and BF,.Et,O (0.50 cm3,4.1 mmol) was stirred Found: M+ (EI), 218.0975; C, 49.05; H, 8.25.C9H1,O4Si at 30 "C for 2 h. The reaction mixture was cooled to 0 "C and requires C,H,,O,Si requires M, 218.0981; C, 49.51; H, Et,N (0.6 cm3) was added. After concentration under reduced 8.31 I. pressure, the residue was filtered through Florisil (200 cm3) in a Compound lb was also obtained by the following method.A short column with the aid of hexane. After concentration under mixture of succinic anhydride 3 (1 1.5 g, 115 mmol), 2-(tri- reduced pressure, the residual oil was distilled to give the title methy1silyl)ethanol (10.0 g, 84.7 mmol) and pyridine (6.70 g, isopropenyl ester 4a (12.3 g, 51) as an oil. Data are given in 84.8 mmol) was heated at 100 OC for 5 h. After concentration Table 1. of the reaction mixture under reduced pressure, saturated aq. Compounds4c and 4f were obtained similarly as described for NaHCO, was added to the residue. The separated oil was the preparation of compound 4a. Compound 4b was purified by acidified to pH 1 with 10 aq. HCl and extracted with EtOAc. the preceding Florisil short-column chromatography mexane- The extract was dried (MgSO,), and concentrated under Et20(2 :l), silica1 gel column chromatography hexane-Et,O reduced pressure.CHCl, was added to the residue and the (7 :l), and distillation under reduced pressure. Compound 4d mixture was filtered. The filtrate was concentrated under was purified by theprecedingFlorisi1 short-columnchromatogra-reduced pressure to give an oil, which was distilled to give the phy (hexane), silica gel column chromatography hexane-Et,O title compound lb (14.2 g, 77) as an oil. (10: l), and distillation under reduced pressure. Compound 4e J. CHEM. SOC. PERKIN TRANS. I 1993 was purified by theprecedingFlorisi1 short-columnchromatogra-phy (hexane), silica gel column chromatography hexane-Et,O (5 :l), and distillation under reduced pressure.From Acid Chlorides of Hemiesters la, c-f and Potassium Enolate of Acetone (Route B).-Isopropenyl methyl succinate 4c. Under nitrogen, KH (727 mg, 18.2 mmol) was suspended in dry DME (16 cm3) below 0 "C. To this stirred suspension was added dropwise a solution of anhydrous acetone (1.33 cm3, 18.1 mmol) in dry DME (1 6 cm3) with cooling below 0 OC. The mixture was stirred at the same temperature for 30 min. A solution of this potassium enolate was added slowly to a solution of the respective acid chloride prepared from the reaction of compound lc (2.26 g, 17.1 mmol) and oxalyl dichloride (3.70 cm3, 42.4 mmol) in dry CH,Cl, (25 cm3) below room temperature and successive removal of excess of (COCI), and CH,Cl, below 30 "C under reduced pressure in DME (15 cm3) with cooling below 0 "C.The reaction mixture was allowed to warm to room temperature during 2 h and was stirred for 7 h. Et,O and water were added to the mixture and the organic layer was separated, dried (MgSO,), concentrated under reduced pressure, and purified by chromatography on silica gel hex- ane-Et,O (7 :1 ) to give the title isopropenyl ester 4c (1.12 g, 38) as an oil. Compounds4a, d-f were purified by column chromatography on silica gel (4a hexane-Et,O (5:1),4d hexane-EtOAc (10:l), 4e hexane-Et,O (7:l), 4f pexane-Et,O (4:l)). Physical data for compounds 4a-f are summarized in Table 1. General Procedures for Acylation Reaction: by using a Catalytic Amount of conc.H,SO,.-Benzyl 2-phenylethyl succinate 6a. To a solution of compound 4a (244 mg, 0.980 mmol) and phenethyl alcohol 5a (1 00 mg, 0.820 mmol) in dry CH,Cl, (10 cm3) was added a drop of conc. H2S04 (d 1.84 g ern-,) and the mixture was stirred for 30 min at room temperature. After the mixture had been concentrated under reduced pressure, MeCN (0.2 cm3) and a drop of conc. HCl were added to the residue at 0 "C. The mixture was stirred for 20 min and partitioned between EtOAc and saturated aq. NaHCO,. The organic layer was dried (MgSO,) and evaporated to give a residue, which was purified by column chromatography on silica gel hexane-Et,O (3:l) to give the title diester 6a (194 mg, 76) as an oil. Physical data for compounds 6 are given in Table 3.By using a Catalytic Amount of p-TsOH.-2-Phenylethyl2-(trimethylsily1)ethyl succinate 6b. To a solution of compound 4b (550 mg, 2.13 mmol) and the alcohol 5a (130 mg, 1.07 mmol) in dry CH,Cl, (8 cm3) was added anhydrous p-TsOH (37.0 mg, 0.210 mmol) and the mixture was stirred at 40 "Cfor 12 h. After the mixture had been concentrated under reduced pressure, MeCN (0.1 cm3) and three drops of conc. HCl were added to the residue at 0 "C. The mixture was stirred for 30 min and then partitioned between EtOAc and saturated aq. NaHCO,. The organic layer was dried (MgSO,) and evaporated to give a residue, which was purified by column chromatography on silica gel pexane-Et,O (8 :l) to give the title diester 6b (256 mg, 75) as an oil.Reaction conditions of the synthesis of compounds 6a-y are shown in Table 2. Products 6c-y were purified by column chromatography on silica gel (6c,g (=2a), i,l hexane-Et,O (5: l), 6d hexane-Et,O (7:l),6e,t pexane-Et,O (10: l), 6f, w hexane-Et,O (2:1), 6h, k hexane-Et,O (3:1), 6j, s mexane-Et,O (9: l), 6m hexane-EtOAc (20: l), 6n mexane-Et,O (1 1 :l), 60 hexane-EtOAc (2:l), 6p pexane-EtOAc (8:l),6q mexane-EtOAc (15: l), 6r hexane-Et,O (4: l), 6u Bexane-Et,O (3:2), 6v bexane-Et,O (2:3), 6x hexane-benzene-Et,O (8 :6 :l),6y Pexane-CHCl, (1 :2)}. 2645 General Procedures for Synthesis of Alcohol 0-Hemiesters: By Catalytic Hydrogenat ion (Method A).-2-Phenyle th y 1 hydrogen succinate7a.Pd-black (30mg) was added to a solution of diester 6a (250mg, 0.800mmol) in 1,4-dioxane (2cm'), and the mixture was subjected to catalytic hydrogenation under hydrogen for 4 h.The catalyst was filtered off and the filtrate was concentrated under reduced pressure. To the crude product was added a mixture of saturated aq. NaHCO, and EtOAc. The aqueous layer was separated, acidified with 10 aq. HCl, and extracted with EtOAc. The extract was dried (MgSO,), and concentrated under reduced pressure to give the title 0-hemiester 7a (156 mg, 88) as an oil. Physical data for compounds7 are summarized in Table 4. By using TBAF (Method B).-2-Phenylethyl hydrogen pimelate 7b.To a solution of compound 6e (300 mg, 0.820 mmol) in dimethylformamide (DMF) (4 an3)was added TBAF-3H20(517 mg, 1.64 mmol) and the mixture was stirred at room temperature for 1.5 h.A mixture of saturated aq. NaHCO, and EtOAc was added to the reaction mixture. The aqueous layer was separated, acidified with 10 aq. HCl, and extracted with EtOAc. The extract was dried (MgSO,), and concentrated under reduced pressure to give the title 0-hemiester 7b(185 mg, 85) as an oil. By Alkaline Hydrolysis (Method C).-l, 1-Dimethyl-2-phenyl-ethyl hydrogen succinate 7f. To a solution of compound 60(1 50 mg, 0.570 mmol) in MeOH (6 an3)at 5 "C was added 0.38 mol dmP3 NaOH (3.00 cm3, 1.14 mmol) and ihe mixture was stirred at room temperature for 2.5 h. After the reaction mixture had been washed with EtOAc, the aqueous layer was acidified with 10 aq.HCl and extracted with EtOAc. The extract was dried (MgSO,), and concentrated under reduced pressure to give the title 0-hemiester 7f (120 mg, 85) as an oil. Reaction conditions for the synthesis of half-esters 7a-m are shown in Table 2. 1O-O-3-(Methoxycarbonyl)propionyl-7,9-O-phenylborane-diyl-P-rhodomycinone 9a.-Under nitrogen, a drop of conc. H2S04 (d 1.84 g cm-,) was added to a stirred solution of compound 8l4 (33.0 mg, 0.064 mmol) and diester 4c (44.0 mg, 0.250 mmol) in dry CH2Cl, (7 cm3) at room temperature. After being stirred at room temperature for 2 h, the reaction mixture was quenched with saturated aq. NaHCO, and extracted with CH,Cl,. The extract was dried (Na,SO,), and concentrated under reduced pressure. The residue was washed with hexane and purified by PLC CH2Cl,-Et,O (9: l) to give the title compound 9a (32.0 mg, 86) as red crystals, m.p.209-21 1 "C (from CHC1,-Et,O); a;' +314 (c 0.10, CHC1,); v,-(CHCl,)/an-l 1735 and 1600; 44500 MHz; CDCl,) 1.11 (3 H, t, J7.3, 14-H3), 1.69 and 2.03 (1 H each, 2 sextet, J7.3, 13-H2), 2.20 (1 H, dd, J 14.5 and 2.4,8-H), 2.35 (1 H, dd, J 14.5 and 1.2, 8-H), 2.55-2.80 (4 H, m, CH,CH,), 3.69 (3 H, s, CO,Me), 5.75 (1 H, br t, J2.5,7-H), 6.36 (1 H, d, J 1.2, 10-H), 7.20-7.45 (4 H, m, 3-H and ArH), 7.70 (1 H, t, J8.0,2-H), 7.77 (2H,d,J6.7,ArH),7.86(1 H,d, J8.0,1-H), 12.12(1 H,s,4-OH), 12.80 (1 H, s, 6-OH) and 13.38 (1 H, s, 1 1 -OH) (Found: C, 63.3; H, 4.6. C31H27BOll requires C, 63.50; H, 4.64). 10-0-6-(Methoxycarbonyl)hexanoyl -7,9-O-phenylborane-diyl-P-rhodomycinone 9b.-Compound 9b (23.0 mg, 87) was prepared from compound 8 (20.0 mg, 0.0420 mmol), diester 4f (40.0 mg, 0.187 mmol) and a drop of conc.H,S04, as red crystals, m.p. 7amp;74 "C (from CHC1,-hexane); a;5 +360 (c 0.1 1, CHCI,); v,,,,(CHCl,)/cm-' 1730 and 1600; 44500 MHz; CDCl,) 1.11 (3 H, t, J 7.3, 14-H,), 1.32-1.45 (2 H, m, CH,), 1.55-1.75 (5 H, m, 13-H and CH, x 2), 2.05 (1 H, sextet, J7.3, 13-H), 2.20 (1 H, dd, J 14.0 and 1.8,8-H), 2.25-2.40 (5 H, m, 8-H and CH, x 2), 3.64 (3 H, s, CO,Me), 5.74 (1 H, br s, w3 6.0,7-H), 6.36 (1 H, s, 10-H), 7.25-7.43 (4 H, m, 3-H and ArH), 7.68 (1 H, t, J8.0,2-H), 7.78 (2 H, d, J6.7, ArH), 7.84(1 H, d, J 8.0, I-H), 12.10 (1 H, s, 4-OH), 12.78 (I H, s, 6-OH) and 13.38 (1 H, s, 11-OH) (Found: C, 64.8; H, 5.2.C3,H3,B01 requires C, 64.98; H, 5.29). 10-0-3-(Benzyloxycarbonyl)propionyl-7,9-O-phenylbor-anediyl-P-rhodomycinone 9c.-Compound 9c (28.0 mg, 80) was prepared from compound 8 (25.0 mg, 0.0530 mmol), diester 4a (65.0 mg, 0.260 mmol) and a drop of conc. H2S04, as red crystals, m.p. 86-89 "C (from CHC1,-hexane); Cali5 + 181 (c 0.097, CHCl,); v,,,(CHCl,)/cm-' 1735 and 1600; 6,(500 MHz; CDCl,) 1.09 (3 H, t, J 7.3, 14-H3), 1.68 and 2.03 (1 H each, 2 sextet, J7.3, 13-H,), 2.17 (1 H, dd, J 14.0 and 2.0, 8-H), 2.32 (1 H, d, J 14.0, 8-H), 2.63-2.85 (4 H, m, CH,CH,), 5.12 (2 H, br s, benzyl CH,), 5.72 (1 H, s, w3 7.5, 7-H), 6.35 (1 H, s, 10-H),7.25-7.40(9H7rn,3-HandArH),7.67(1H,t, J8.0,2-H), 7.77 (2 H, d, J7.3, ArH), 7.81 (1 H, d, J8.0, 1-H), 12.08 (1 H, s, 4-OH), 12.76 (1 H, s, 6-OH) and 13.35 (1 H, s, 11-OH) (Found: C, 67.25; H, 4.7.C37H31BOll requires C, 67.08; H, 4.72). 10-0-3-(Methoxycarbonyl)propionyl-~-rhodomycinone 10a.-A mixture of boronate 9a (28.0 mg, 0.0480 mmol), 2- methylpentane-2,4-diol (0.12 cm3), AcOH (0.06 cm3), acetone (1.8 cm3) and CH,Cl, (2.4 cm3) was stirred at room temperature for 24 h. The reaction mixture was poured into a mixture of EtOAc and saturated aq. NaHCO,. The organic layer was separated, washed with water, dried (Na,SO,), and concentrated under reduced pressure. The residue was washed with hexane and recrystallized from CHC1,-hexane to give the title compound 10a (22.0 mg, 92) as red crystals, m.p.241- 243 "C (from CHC1,-hexane); a;' -75.5 (c 0.10, CHCl,); v,,,(CHCl,)/crn-' 1730 and 1600; 6,(500 MHz; CDCl,) 1.08 (3 H, t, J7.3, 14-H,), 1.57 and 1.75 (1 H each, 2 sextet, J 7.3, 13-H2), 2.02 (1 H, dd, J 14.6 and 5.2, 8-H), 2.36 (1 H, d, J 14.6,8-H), 2.50-2.75 (4 H, m, CH,CH,), 3.39 (1 H, br s, 9-OH), 3.66(3 H, s, CO,Me), 5.27 (1 H, br s, w+ 10.5,7-H), 6.29 (1 H, s, J. CHEM. SOC. PERKIN TRANS. 1 1993 4.9, 8-H), 2.33 (1 H, d, J 14.7, 8-H), 2.55-2.78 (4 H, m, CH,CH,), 3.37 (1 H, S, 9-OH), 3.63 (1 H, d, J5.5, 7-OH), 5.09 (2 H, d, J 1.8, benzyl CH,), 5.25 (1 H, t, J4.5,7-H), 6.28 (1 H, d, J 1.2, 10-H), 7.24-7.45 (6 H, m, 3-H and ArH), 7.69 (1 H, t, J 8.0,2-H), 7.82(1 H, d, J8.0, 1-H), 12.03 (1 H, s,~-OH), 12.84(1 H, s, 6-OH) and 13.3 1 (1 H, s, 1 1 -OH) (Found: C, 64.35; H, 4.8.C31H2801 requires C, 64.58; H, 4.89). 10-0-3-(Methoxycarbonyl)propiony/-4'-0-(p-nitrobenzo-yl)-3'-N-(triJluoroacetyl)oxaunomycin 12a.-Under nitrogen, TMSOTf (0.023 cm3, 0.13 mmol) was added to a stirred mixture of compound 11 (35.0 mg, 0.063 mmol) and MS 4 8, in dry CH,Cl, (7 cm3)-dry Et,O (2.6 cm3) at -40 "C. The mixture was stirred at -5 "C for 1 h and was then cooled to -15 "C, and a solution of compound 10a (25.0 mg, 0.050 mmol) in dry CH,Cl, (7 cm3) was added. After being stirred for 6 h under the same conditions, the mixture was poured into a vigorously stirred mixture of EtOAc and saturated aq. NaHCO,. The organic layer was separated, and the aqueous layer was extracted with EtOAc.The combined organic layer was washed with brine, dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC CH,Cl,-Et,O (9 :l) gave the title compound 12a (34.5 mg, 79) as red crystals, m.p. 158-160 "C (from CHC1,-hexane); a;' -79.4 (c 0.10, CHCl,); v,,,(CHCl,)/cm-' 1735, 1600 and 1530; 6,(500 MHz; CDC1,) 1.08 (3 H, t, J 7.3, 14-H,), 1.27 (3 H, d, J 6.1, 6'-H3), 1.54 and 1.70 (1 H each, 2 sextet, J7.3,13-H2), 2.02-2.20 (3 H, m, 8-H and 2'-H,), 2.41 (1 H, d, J 15.3, 8-H), 2.50-2.75 (4 H, m, CH,CH,), 3.49 (1 H, br, 9-OH), 3.67 (3 H, s, CO,Me), 4.46(1 H,m,3'-H),4.49(1 H,q, J6.1, 5'-H), 5.24(1 H, brd, J 2.4, 7-H), 5.48 (1 H, br s, 4'-H), 5.65 (1 H, br d, J3.7, 1'-H), 6.26 (1 H, br d, J7.3, 3'-NH), 6.32 (1 H, d, J 1.2, 10-H), 7.34 (1 H, d, J8.0, 3-H), 7.74 (1 H, t, J8.0, 2-H), 7.91 (1 H, d, J 8.0, 1-H), 8.29 and 8.35 (2 H each, 2 d, J 8.8, ArH), 12.09 (1 H, s, 4-OH), 12.90 (1 H, s, 6-OH) and 13.43 (1 H, s, 11-OH) Found: M-(FAB, negative), 874.201 1.C,oH,,F,N2017 requires M, 874.20451. 10-H),7.28(1H,d,J8.0,3-H),7.69(1H,t,J8.0,2-H),7.81(1H, d, J 8.0, I-H), 12.04 (1 H, s, 4-OH), 12.86 (1 H, s, 6-OH) and 13.32 (1 H, s, 11-OH) (Found: C, 59.65; H, 4.85. C25H24011 requires C, 60.00; H, 4.83). 10-0-6-(Methoxycarbonyl)hexanoyl-~-rhodomycinone l0b.-Compound 10b (36.0 mg, 83) was prepared from compound 9b (50.0 mg, 0.0800 mmol), 2-methylpentane-2,4- diol(0.2 cm3), AcOH (0.1 cm3), acetone (3.1 an3),and CH,Cl, (4.1 cm3), as red crystals, m.p.210-213 "C (from CHC1,- hexane); Calk5 + 124 (c 0.043, CHCl,); v,,,(CHCl,)/cm-' 1720 and 1600; 6,(500 MHz; CDCl,) 1.09 (3 H, t, J7.3, 14-H,), 1.28- 1.40 (2 H, m, CH,), 1.50-1.70 (5 H, m, 13-H and CH, x 2), 1.74 (1 H, sextet, J7.3, 13-H), 2.00 (1 H, dd, J 14.7 and 4.9, 8-H),2.20-2.32(4H,m,CH2 x 2),2.35(1 H,d, J14.7,8-H), 3.39 (1 H,s,9-OH),3.63(3 H, s, CO,Me),3.66(1 H,d,J5.5,7-OH), 5.27 (1 H, t, J4.5,7-H), 6.29 (1 H, S, 10-H), 7.28 (1 H, d, J8.0,3- H), 7.69 (1 H, t, J8.0,2-H), 7.82 (1 H, d, J8.0, 1-H), 12.05 (1 H, s, 4-OH), 12.87 (1 H, s, 6-OH) and 13.34 (1 H, s, 11-OH) (Found: C, 61.65; H, 5.5. C,,H3oO11 requires C, 61.98; H, 5.57). 10-0-13-(Benzyloxycarbonyl)propionyl-P-rhodomycinone l0c.-Compound 1Oc (20.0 mg, 85) was prepared from boronate 9c (27.0 mg, 0.0410 mmol), 2-methylpentane-2,4-diol (0.1 cm3), AcOH (0.05 cm3), acetone (1.6 cm3), and CH,C1, (2 cm3), as red crystals, m.p. 213-215 "C (from CHC1,-hexane); Cali5 +27.8 (c 0.036, CHCl,); v,,,(CHCl,)/cm-' 1730 and 1600;6,(500 MHz; CDCl,) 1.06 (3 H, t, J 7.3, 14-H,), 1.55 and 1.74 (1 H each, 2 sextet, J7.3, 13-H,), 2.00 (1 H, dd, J 14.7 and 10-0-6-(Methoxycarbonyl)hexanoyl-4'-0-(p-nitrobenzo-yl)-3'-N-(triJluoroacetyI)oxaunomycin 12 b .-Compound 12b (39.0 mg, 77) was prepared from compound 11 (38.0 mg, 0.0700 mmol), TMSOTf (0.026 cm3, 0.14 mmol), and compound 10b (30.0 mg, 0.0560 mmol) in the presence of MS 4 A (220 mg), as red crystals, m.p.144-147 "C (from CHC1,-hexane); a;' -33.0 (c 0.10, CHCl,); vmm,,(CHCl,)/cm-' 1730, 1600 and 1530; 6,(500 MHz; CDCI,) 1.08 (3 H, t, J 7.3, 14-H,), 1.27 (3 H, d, J6.7,6'-H,), 1.25-1.40 (2 H, m, CH,), 1.49 (1 H, sextet, J 7.3, 13-H), 1.55-1.70 (4 H, m, CH, x 2), 1.70 (1 H, sextet, J 7.3, 13-H),2.05-2.20(3H,m, 8-Hand2'-H2),2.27(4H, t, J7.3, CH2 x 2), 2.41 (1 H, d, J 15.3, 8-H), 3.48 (1 H, S, 9-OH), 3.62 (3 H, s, CO,Me), 4.434.53 (2 H, m, 3'- and 5'-H), 5.24 (1 H, br d, J2.4, 7-H), 5.48 (1 H, br s, 4'-H), 5.65 (1 H, br d, J3.7, 1'-H), 6.29 (1 H, br d, J 7.3, 3'-NH), 6.30 (1 H, s, 10-H), 7.33 (1 H, d, J8.0, 3-H), 7.73 (1 H, t, J8.0, 2-H), 7.90 (1 H, d, J 8.0, 1-H), 8.29 and 8.35 (2 H each, 2 d, J 8.8, ArH), 12.08 (1 H, s, 4-OH), 12.89 (1 H, s, 6-OH) and 13.43 (1 H, s, 11-OH) Found: M-(FAB, negative), 916.2502.C,,H,,F,N,O, requires M, 916.25141. 10-0-3-(Methoxycarbonyl)propionyl-3'-N-(trifuoroacet-y1)oxaunomycin 13a.-A solution of nitrobenzoate 12a (23.0 mg, 0.0260 mmol) in CH,Cl, (1.4 cm3)-MeOH (1.4 cm3) was treated with 0.1 mol dm-3 NaOH (0.310 cm3, 0.0310 mmol) at 0deg;C. The mixture was stirred for 30 min under the same conditions, then a drop of 10 aq. HCl was added. The result- ing mixture was partitioned between CH,Cl, and water. The separated organic layer was dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC J. CHEM. SOC. PERKIN TRANS. 1 1993 CH,Cl,-Et20 (3 :l) gave the title compound 13a (17.0 mg, 90) as red crystals, m.p. 142-145 "C (from CHC1,-hexane); a;' +209 (c 0.096, CHC1,); v,,,(CHCl,)/~rn~~ 1730 and 1600; amp;(SO0 MHz; CDCl3) 1.05 (3 H, t, J 7.3, 14-H,), 1.32 (3 H, d, J6.7, 6'-H3), 1.51 and 1.79 (1 H each, 2 sextet, J7.3, 13-H2), 1.83 (1 H, dt, J 13.0 and 3.7,2'-H), 1.98 (1 H, br d, J9.0, 4'-OH), 2.00-2.10 (2 H, m, 8-and 2'-H), 2.38 (1 H, d, J 15.3, 8-H), 2.50-2.75 (4 H, m, CH,CH,), 3.61 (1 H, s, 9-OH), 3.65- 3.75 (1 H, m, 4'-H), 3.66 (3 H, s, CO,Me), 4.154.25 (1 H, m, 3'-H), 4.30 (1 H, q, J6.7, 5'-H), 5.17 (1 H, br d, J2.4,7-H), 5.46 (1 H, br d, J 3.7, 1'-H), 6.30 (1 H, s, 10-H), 6.65 (1 H, d, J 8.6, 3'-NH), 7.33 (1 H, d, J8.0, 3-H), 7.72 (1 H, t, J8.0, 2-H), 7.90 (1 H, d, J8.0, 1-H), 12.08 (1 H, S, 4-OH), 12.84 (1 H, S, 6-OH) and 13.42 (1 H, s, 11-OH) Found: M- (FAB, negative), 725.1956.C3,H3,F3NO14 requires M, 725.19311. 10-0-6-(Methoxycarbonyl)hexanoyl-3'-N-(triJluoroacet-y1)oxaunomycin 13b.-Compound 13b (19.0 mg, 97) was prepared from nitrobenzoate 12b (23.5 mg, 0.0260 mmol) and 0.1 mol dm-3 NaOH (0.310 cm3, 0.03 10 mmol), as red crystals, m.p. 108-111 "C (from CHC1,-hexane); ai5 +255 (c 0.081, CHCl,); v,,,(CHCl,)/cm-' 1725 and 1600; 6,(500 MHz; CDCI,) 1.05 (3 H, t, J7.3, 14-H,), 1.25-1.40 (2 H, m, CH,), 1.32 (3 H, d, J6.7, 6'-H3), 1.45 (1 H, sextet, J7.3, 13-H), 1.55-1.70 (4 H, m, CH, x 2), 1.78 (1 H, sextet, J7.3, 13-H), 1.83 (1 H, dt, J 13.0 and 3.7,2'-H), 1.98 (1 H, d, J7.9,4'-0H), 2.00-2.10 (2 H, m, 8-and2'-H),2.27(4H, t, J7.3,CH2 x 2),2.38(1 H,d, J14.7, S-H), 3.59 (1 H, s, 9-OH), 3.63 (3 H, s, CO,Me), 3.65-3.70 (1 H, m, 4'-H), 4.154.25 (1 H, m, 3'-H), 4.31 (1 H, q, J6.7,5'-H), 5.17 (1 H, brd, J2.4,7-H), 5.46(1 H, brd, J3.7,1'-H), 6.29(1 H,d, J 1.2, 10-H), 6.64(1 H, d, J8.6, 3'-NH), 7.32(1 H, d, J8.0, 3-H), 7.72 (1 H, t, J8.0, 2-H), 7.90 (1 H, d, J8.0, 1-H), 12.09 (1 H, S, 4-OH), 12.85 (1 H, s, 6-OH) and 13.44 (1 H, s, 11-OH) Found: M- (FAB, negative), 767.2374.C3,H4,F,NOl4 requires M, 767.240 11. 10-0-(3-Carboxypropionyl)-3'-N-(trijluoroacety1)oxauno-mysin 14a.-A solution of ester 13a (10.0 mg, 0.0140 mmol) in DME (2 cm3) was treated with a mixture of 0.1 mol dmP3 NaOH (2.80 cm', 0.280 mmol) and DME (1 cm3) at 0 "C. The mixture was stirred at room temperature for 30 min, then a drop of 5 aq. AcOH was added.The resulting mixture was partitioned between EtOAc and water. The separated organic layer was dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC CHCl,-MeOH (95:5) gave hemiester 14a (5.0 mg, 51) as red crystals, m.p. 169- 172 "C (from CHC1,-MeOH-hexane); aif5 +305 (c 0.01 1, acetone); v,,,(KBr)/crn-' 1720 and 1600; 6,500 MHz; (CD,),SO 0.95 (3 H, t, J 7.3, 14-H,), 1.13 (3 H, d, J 6.7, 6'- H,), 1.40-1.52 (2 H, m, 13- and 2'-H), 1.56 (1 H, sextet, J 7.3, 13-H), 1.89 (1 H, dd, J 14.7 and 4.9, 8-H), 2.09 (1 H, dt, J 13.0 and 3.7, 2'-H), 2.26 (1 H, d, J 14.7, 8-H), 2.48-2.55 (4 H, m, CH,CH,), 3.51 (1 H, br d, J 9.4, 4'-H), 3.95-4.02 (1 H, m, 3'-H), 4.21 (1 H, 9, J 6.7, 5'-H), 4.39 (1 H, S, 9-OH), 4.97 (1 H, br d, J4.9, 7-H), 5.00 (1 H, d, J 2.4, 4'-OH), 5.27 (1 H, br d, J 3.1, 1'-H), 6.10 (1 H, S, 10-H), 7.42 (1 H, d, J 7.9, 3-H), 7.80-7.90 (2 H, m, 1- and 2-H), 9.06 (1 H, d, J 7.3, 3'-NH), 11.96 (1 H, br s, 4-OH), 12.10-12.24 (1 H, br, CO,H), 12.77 (1 H, br s, 6-OH) and 13.36 (1 H, s, 11-OH) Found: M- (FAB, negative), 71 1.1815.C,,H,,F,NOl, requires M, 711.17761. 10-0-(6- Carboxyhexanoyl)-3'-N-( trz~uoroacety1)oxaunomy-cin 14b.-Compound 14b (2.0 mg, 41) was prepared from ester 13b (5.0 mg, 0.0065 mmol) and 0.1 mol dm-3 NaOH (1.30 cm3, 0.130 mmol), as red crystals, m.p. 147-149 "C (from CHC1,- hexane); Calk5 +250 (c 0.010, CHCl,); v,,,(KBr)/cm-' 1720 and 1605; 6,500 MHz; (CD,),SO 0.96 (3 H, t, J 7.3, 2647 14-H3),1.12(3H,d,J6.7,6'-H,),1.20-1.30(2H,m,CH2),1.38-1.54(6H,m, 13-,2'-HandCH, x 2), 1.58(1 H,sextet, J7.3,13- H), 1.87 (1 H, dd, J 14.8 and 4.6,8-H), 2.08 (1 H, dt, J 13.0 and 3.7, 2'-H), 2.13 (2 H, t, J7.3, CH,), 2.19-2.21 (3 H, m, 8-H and CH,), 3.51 (1 H, br d, J3.7,4'-H), 3.954.02 (1 H, m, 3'-H), 4.22 (1 H,q, J6.7,5'-H), 4.41 (1 H, ~,9-OH),4.97(1 H, d, J3.7,7-H), 5.00(1H,d,J5.5,4'-OH),5.27(1H,brd,J3.1,1'-H),6.11(1H, s, 10-H), 7.42(1 H,d, J7.9,3-H),7.80-7.90(2H,m, l-and2-H), 9.05 (1 H, d, J7.3, 3'-NH), 11.83-11.95 (1 H, br, CO,H), 11.96 (1 H, s, 4-OH), 12.77 (1 H, s, 6-OH) and 13.39 (1 H, s, 11-OH) Found: M-(FAB, negative), 753.2274.C,5H,,F,NOl, requires M, 753.22451. 7-0-( 3' ,4'- Di-O-acetyl-2'-deoxy-P-~-erythro-pentopyrano-sy1)-10-0-6-(methoxycarbonyl)hexanoyl-~-rhodomycinone 17a.-Under nitrogen, a mixture of compound 10b (42.0 mg, 0.0770 mmol), yellow HgO, (42.0 mg, 0.194 mmol), HgBr, (34.0 mg, 0.0940 mmol), and MS 4 A (500 mg) in dry CH,Cl, (20 cm3) was stirred at room temperature for 1 h.A solution of the chloride 15 (0.23 1 mmol) derived from 1,3,4-tri-O-acetyl-2-de-oxy-D-erythro-pentopyranose(60.1 mg, 0.23 1 mmol) according to the reported method ' in dry CH,Cl, (1 0 cm3) was added, and the mixture was stirred for 24 h in the dark. After filtration with the aid of CHCl,, the organic solution was washed successively with aq. 30 KI and saturated aq. NaHCO,, dried (Na,SO,), and concentrated under reduced pressure. Purific- ation of the residue by PLC CH,Cl,-Et,O (9 :l) gave the title compound 17a (46.0 mg, 80) as red crystals, m.p.6245 "C (from CHC1,-hexane); a;' + 106 (c 0.073, CHCl,); v,,,(CHC13)/cm-' 1740 and 1605; 6,(500 MHz; CDCI,) 1.06 (3 H, t, J7.3, 14-H3), 1.25-1.40 (2 H, m, CH,), 1.46 (1 H, sextet, J 7.3, 13-H), 1.50-1.70 (4 H, m, CH, x 2), 1.75 (1 H, sextet, J 7.3, 13-H), 1 .SO-1.90 (1 H, m, 2'-H), 1.90-2.20 (2 H, m, 8- and 2'-H), 1.98 and 2.15 (3 H each, 2 s, OAc x 2), 2.20-2.30 (4 H, m, CHI x 2), 2.45 (1 H, d, J 15.3, 8-H), 3.62 (3 H, s, CO,Me), 3.89 (1 H, dd, J 13.0 and 3.1, 5'-H), 4.16 (1 H, dd, J 13.0 and 1.8, 5'-H), 5.05-5.35 (3 H, m, 3'-, 4'- and 7-H), 5.55 (1 H, br t, J2.5, 1'-H), 6.29 (1 H, s, 10-H), 7.33 (1 H, dd, J8.5 and 1.2, 3-H), 7.72 (1 H, t, J8.5,2-H), 7.90 (1 H, dd, J8.5 and 1.2, 1-H), 12.10 (1 H, s, 4-OH), 12.88 (1 H, s, 6-OH) and 13.43 (1 H, s, 11-OH) Found: M- (FAB, negative), 742.2505.C37H42016 requires M, 742.24731. 7-0-( 3 ',4'-Di-O-acetyl-2',6'-dideoxy-2'-~uoro-a-~-talopyran-osy1)-1O-O-6-(methoxycarbonyl)hexanoyl-~-rhodomycinone 17b.-Under nitrogen, a mixture of compound 10b (28.0 mg, 0.0520 mmol), yellow HgO (45.0 mg, 0.208 mmol), HgBr, (19.0 mg, 0.0520 mmol), and MS 3 8, (260 mg) in dry CH2C1, (10 cm3) was stirred at room temperature for 30 min. A solution of the fluoride 16 (0.103 mmol) derived from 1,3,4-tri-O-acetyl-2,6- dideoxy-2-fluoro-a-~-talopyranose(30.1 mg, 0.103 mmol) according to the reported method l7 in dry CH,Cl, (2 cm3) was added, and the mixture was stirred for 48 h in the dark.After filtration with the aid of CHCl,, the organic solution was washed successively with aq. 30 KI and saturated aq. NaHCO,, dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC CH,Cl,-Et,O (9 :l) gave the title compound 17b (30.0 mg, 75) as red crystals, m.p. 109-1 11 "C (from CHC1,-hexane); Calk5 + 146 (c 0.24, CHCl,); v,,(CHCl,)/cm-' 1740 and 1605; 6,(500 MHz; CDCl,) 1.06 (3 H, t, J 7.3, 14-H3), 1.29 (3 H, d, J 6.7, 6'-H3), 1.25-l.38(2H,m,CH2), 1.47(1 H,sextet, J7.3,13-H), 1.55-1.68 (4H,m,CH, x 2), 1.77(1 H,sextet, J7.3, 13-H),2.01 and2.19 (3 H each, 2 s, OAc x 2), 2.07 (1 H, dd, J 15.0 and 4.3, 8-H), 2.23-2.30 (4 H, m, CH, x 2), 2.43 (1 H, d, J 15.0, 8-H), 3.03 (1 H, s, 9-OH), 3.63 (3 H, s, CO,Me), 4.38 (1 H, q, J6.7, 5'-H), 4.60 (1 H, br d, J49.4,2'-H), 4.97 (1 H, dt, J32.5 and 3.2,3'-H), 5.18-5.28 (2 H, m, 7-and 4'-H), 5.61 (1 H, d, J9.7, 1'-H), 6.28 (1 H,d, J1.2,10-H),7.34(1 H,d, J8.0,3-H), 7.73(1 H, t, J8.0,2- H),7.90(1 H,d, J8.0,1-H), 12.08(1 H,s,~-OH), 12.87(1 H,s,~- OH) and 13.41 (1 H, s, 11-OH) Found: M- (FAB, negative), 774.2507.C,,H4,FO16 requires M, 774.25361. 10-0-3-(Benzyloxycarbonyl)propionyl)-7-0-(3',4'-di-O-acetyl-2',6'-dideoxy-2'-~uoro-a-~-talopyranosyl)-~-rhodomy-cinone 17c.-Compound 17c (20.0 mg, 57) was prepared from compound 1Oc (25.0 mg, 0.0430 mmol), yellow HgO (38.0 mg, 0.176 mrnol), HgBr, (1 6.0 mg, 0.0440 mmol), MS 3 A (230 mg), and the fluoride 16 (0.103 mmol), as red crystals, m.p.118- 121 "C (from CHC1,-hexane); a;' + 142 (c 0.13, CHCl,); v,,,(CHCl,)/cm-' 1735 and 1600; 6,(500 MHz; CDCl,) 1.04 (3 H, t, J7.3, 14-H,), 1.29 (3 H, d, J 6.5, 6'-H3), 1.52 and 1.76 (1 H each, 2 sextet, J 7.3, 13-H,), 2.03 and 2.19 (3 H, each, 2s,OAc x 2), 2.04(1 H,dd, J15.3and4.3,8-H),2.40(1 H,d, J 15.3, 8-H), 2.52-2.78 (4 H, m, CH,CH,), 3.03 (1 H, s, 9-OH), 4.37 (1 H, q, J 6.5, 5'-H), 4.59 (1 H, br d, J 49.5, 2'-H), 4.96 (1 H, dt, J 33.0 and 3.5, 3'-H), 5.09 (2 H, s, benzyl CH,), 5.19 (1 H, d, J 3.1, 4'-H), 5.23 (1 H, d, J 3.7, 7-H), 5.60 (1 H, d, J 9.2, 1'-H), 6.28 (1 H, s, 10-H), 7.21-7.39 (6 H, m, 3-H and ArH), 7.73 (1 H, t, J8.0, 2-H), 7.89 (1 H, d, J8.0, 1-H), 12.07 (1 H, s, 4-OH), 12.85 (1 H, s, 6-OH) and 13.38 (1 H, s, 11-OH) Found: M-(FAB, negative), 808.2402.C41H4,FO16 requires M, 808.23791. 7-O-(2'-Deoxy-P-~-erythro-pentopyranosyl)-1 O-O-6-(meth- oxycarbonyl)hexanoyl-P-rhodomycinone18a.-A solution of diacetate 17a (56.0 mg, 0.0750 mmol) in MeOH (4 cm3) was treated with 0.1 rnol dm-, NaOH (2.25 cm3, 0.225 mmol) at 10deg;C. The mixture was stirred at room temperature for 10 min, then three drops of AcOH were added. The resulting mixture was partitioned between CH,Cl, and water. The separated organic layer was dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC CHCl,- MeOH (9: l) gave the title compound 18a (38.0 mg, 77) as red crystals, m.p. 196-199 "C (from CHC1,-Et,O); a;' +89.9 (c 0.1 1, CHCI,); V,,,,(CHC~~)/C~-~ 1735 and 1605; SH(5O0 MHz; CDC1,) 1.06 (3 H, t, J 7.3, 14-H,), 1.25-1.40 (2 H, m, CH,), 1.46 (1 H, sextet, J 7.3, 13-H), 1.50-1.70 (4 H, m, CH, x 2), 1.87 (1 H, ddd, J 13.4, 5.0 and 3.0, 2-H), 1.95-2.05 (2 H, m, 8-and 2'-H), 2.20-2.45 (4 H, m, CH, x 2), 2.47 (1 H, d, J.CHEM. soc. PERKIN TRANS. 1 1993 (1 H, s, 11-OH) Found: M-(FAB, negative), 690.2298. C34H,,F0,4 requires M, 690.23241. 10-0-3-(Benzyloxycarbonyl)propionyl-7-0-(2',6'-dideoxy-2'-flu0r0-a-~-talopyran0~yl)-~-rhodomycinone lamp;.-Com-pound 1(10.0 mg, 75) was prepared from diacetate 17c (1 5.O mg, 0.019 mmol) and 0.1 mol dm-, NaOH (0.600 cm3, 0.0600 mmol), as red crystals, m.p. 251-254 "C (from CHC1,-Et,O); Cali5 +43.8 (c 0.089, CHCl,); v,,(CHCl,)/cm-' 3520, 1730 and 1600; dH(500 MHz; CDCl,) 1.03 (3 H, t, J 7.3, 14-H3), 1.40 (3 H, d, J 6.7, 6'-H3), 1.53 and 1.75 (1 H each, 2 sextet, J7.3, 13-H2), 1.88 (1 H, dd, J 11.6 and 7.9,4'-OH), 2.04 (1 H,dd, J15.3and4.3,8-H),2.40(1 H,d, J15.3,8-H),2.53-2.79 (4 H, m, CH,CH,), 2.87 (1 H, d, J 11.0, 3'-OH), 3.15 (1 H, s, 9-OH), 3.55-3.70 (2 H, m, 3'- and 4'-H), 4.21 (1 H, q, J 6.7, 5'-H), 4.61 (1 H, br d, J 49.4, 2'-H), 5.09 (2 H, s, benzyl CH,), 5.20 (1 H, br d, J 3.1, 7-H), 5.56 (1 H, d, J 8.6, 1'-H), 6.27 (1 H, d, J 1.2, 10-H), 7.24-7.40 (6 H, m, 3-H and ArH), 7.73 (1 H, t, J 8.0, 2-H), 7.90 (1 H, d, J 8.0, 1-H), 12.07 (1 H, s, 4-OH), 12.87 (1 H, s, 6-OH) and 13.39 (1 H, s, 1 1-OH) Found: M--(FAB, negative), 724.2192.C3 7H3 ,FO requires M, 724.21681.10-0-(6-Carboxyhexanoyl)-7-0-(2'-deoxy-~-~-erythro-pentopyranosy1)-P-rhodomycinone19a.-A solution of ester 18a (8.0 mg, 0.012 mmol) in MeOH (2 cm3) was treated with 0.1 mol dm-, NaOH (4.80 cm3,0.480 mmol) at 10 "C. The mixture was stirred at room temperature for 1 h, then four drops of AcOH were added at 0deg;C. The resulting mixutre was partitioned between EtOAc and water. The separated organic layer was dried (Na,SO,), and concentrated under reduced pressure. Purification of the residue by PLC CHCI,-MeOH (9 :l) gave the title compound 19a (6.0 mg, 75) as red crystals, m.p. 178- 181 "C (from CHC1,-Et,O); a;' +235 c 0.021, CHC1,- MeOH (9:l); v,,,(KBr)/cm-' 3300, 1735 and 1600; 6H500 MHz; (CD,),SO 0.95 (3 H, t, J7.3, 14-H,), 1.20-1.30 (2 H, m, CH,), 1.35-1.60 (6 H, m, 13-H, and CH, x 2), 1.85-1.95 (2 H, m,8-and2'-H),2.12(2H, t, J7.3,CH2),2.15-2.30(3H,m,2'-H and CH,), 2.30 (1 H, d, J 15.3, 8-H), 3.55-3.65 (2 H, m, 4'- and5'-H),3.70(1 H,ddd,J8.6,4.0and2.5,3'-H),3.92(1 H,dd, J 13.1 and 3.4, 5'-H), 5.00 (1 H, dd, J4.0 and 1.0, 7-H), 5.29 (1 5'-H), 4.07 (1 H, d, J 10.4, 5'-H), 5.19 (1 H, dd, J4.0 and 1.8, 7-H),5.50(1H,dd,J3.3and3.0,1'-H),6.27(1H,d,J1.2,10-H), 7.32 (1 H, dd, J8.0 and 1.2, 3-H), 7.71 (1 H, t, J8.0, 2-H), 7.89 (1 H, dd, J8.0 and 1.2,1-H), 12.10 (1 H, s, 4-OH), 12.87 (1 H, s, 6-OH) and 13.44 (1 H, s, 11-OH) Found: M- (FAB, negative), 658.2284; C, 59.75; H, 5.95.C33H38014 requires M, 658.2262; C, 60.17; H, 532x1. 7-0-(2',6'-Dideoxy-2'-fluoro-a-L-talopyranosy1)-10-0-6-(methoxycarbonyl)hexanoyl-P-rhodomycinone 18b.-Com-pound 18b (21.0 mg, 84) was prepared from compound 17b (28.0 mg, 0.0360 mmol) and 0.1 mol din-, NaOH (1.08 cm3, 0.108 mmol), as red crystals, m.p.208-210 "C (from CHC1,- Et,O); a~' + 102 (c 0.10, CHCI,); v,,,(CHCl,)/cm-' 3550, 1730 and 1605; 6,(500 MHz; CDC1,) 1.06 (3 H, t, J 7.3, 14-H,), 1.25-1.38 (2 H, m, CH,), 1.40 (3 H, d, J6.7,6'-H,), 1.48 (1 H, sextet, J7.3,13-H), 1 S3-1.68 (4 H, m, CH, x 2), 1.77 (1 H, sextet, J7.3, 13-H), 1.89 (1 H, dd, J 11.3 and 8.0, 4'-OH), 2.06 (1 H, dd, J 15.3 and 4.6, 8-H), 2.27 (4 H, br t, J7.3, CH, x 2), 2.43(1H,d,J15.3,8-H),2.88(1H,d,J11.0,3'-OH),3.16(1H, s, 9-OH), 3.63 (3 H, s, CO,Me), 3.56-3.70 (2 H, m, 3'- and 4'-H), 4.22 (1 H, q, J6.7,5'-H), 4.62 (1 H, br d, J48.8,2'-H), 5.23 (1 H, d, J2.4,7-H), 5.57(1 H,d, J9.8, 1'-H),6.27(1 H,d, J1.2,10-H), 7.34 (1 H, d, J 8.0, 3-H), 7.73 (1 H, t, J8.0,2-H), 7.90 (1 H, d, J 8.0, 1-H), 12.08 (1 H, s, 4-OH), 12.89 (1 H, s, 6-OH) and 13.41 H, br t, J3.0, I'-H), 6.08 (1 H, d, J 1.0, 10-H), 7.42 (1 H, dd, J J15.3,8-H).3.62(3H,s,CO,Me),3.80-4.00(3H,m,3'-,4'-and8.0 and 1.2,3-M), 7.82 (1 H, dd, J8.0 and 1.2, 1-H), 7.86 (I H, t, J8.0,2-H), 11.94 (1 H, s, 4-OH), 12.79 (1 H, s, 6-OH) and 13.37 (1 H, s, 11-OH) Found: M- (FAB, negative), 644.2081.C32H36014 requires M, 644.21051. 10-0-(6-Carboxyhexanoy1)-7-0-(2',6'-dideoxy-2'-fluoro-~-~-talopyranosy1)-P-rhodomycinone19b.-Compound 19b (6.5 mg, 74) was prepared from ester 18b (9.0 mg, 0.01 3 mmol) and 0.1 mol dm-3 NaOH (5.20 cm3, 0.520 mmol), as red crystals, m.p.233-236 "C (from CHC1,-Et,O); a;' +99.3 c 0.028, CHC1,-MeOH (9 :l); v,,(KBr)/cm-' 3350, 1705 and 1600; 6,500 MHz; (CD,),SO 0.95 (3 H, t, J7.3, 14-H,), 1.19 (3 H, d,J6.7,6'-H,), 1.18-1.29(2H,m,CH2), 1.35-1.52(5H,m, 13-H and CH, x 2), 1.57 (1 H, sextet, J 7.3, 13-H), 1.90 (1 H, dd, J 15.3 and4.9, 8-H), 2.12(2 H, t, J7.3, CH,), 2.19-2.32 (3 H, m, 8-H and CH,), 3.45-3.60 (2 H, m, 3'- and 4'-H), 4.21 (1 H, q, J 6.7,5'-H), 4.32 (1 H, br d, J49.4,2'-H), 4.35 (1 H, s, 9-OH), 5.01 (1 H,d, J4.9,7-H),5.32(1 H,d, J9.2, l'-H),6.10(1 H,s, 10-H), 7.44 (1 H, d, J7.9, 3-H), 7.80-7.90 (2 H, m, 1-and 2-H), 11.97 (1 H, s, 4-OH), 12.79 (1 H, s, 6-OH) and 13.37 (1 H, s, 11-OH) Found: M-(FAB, negative), 676.21 72.C33H,7FOl, requires M, 676.21671. 10-0-(3-CarboxypropionyZ)-7-0-(2',6'-dideoxy-2'-fluoro-a-~-talopyranosy1)-P-rhodomycinone19c.-Compound 19c (6.5 mg, 74) was prepared from ester 1 (7.0 mg, 0.0096 mmol) and J. CHEM. SOC. PERKIN TRANS. 1 1993 0.1 mol dm-, NaOH (4.0 cm3,0.40 mmol), as red crystals, m.p. 264-267 OC (from CHC1,-Et,O); a$rsquo; +90.9 c 0.01 1, CHC1,-MeOH (9 :l); v,,(KBr)/cm-rsquo; 3480, 1720 and 1595; amp;500 MHz; (CD,),SO 0.94 (3 H, t, J 7.3, 14-H,), 1.19 (3 H, d, J 6.7,6lsquo;-H,), 1.48 and 1.58 (1 H each, 2 sextets, J 7.3, 13-H,), 1.91 (1 H, dd, J 15.3 and 4.3, 8-H), 2.23 (1 H, d, J 15.3, 8-H), 2.40-2.58 (4 H, m, CH,CH,), 3.45-3.60 (2 H, m, 3lsquo;-and 4rsquo;43, 4.22(1 H, q, J6.7,5rsquo;-H), 4.32(1 H, br d, J49.4,2rsquo;-H), 4.33 (1 H, s,9-OH), 5.02(1 H,d, J4.3,7-H), 5.32(1 H,d, J9.8, 1rsquo;-H), 6.09 (1 H,s, 10-H),7.44(1 H,d, J8.0,3-H),7.80-7.90(2H,m,1-and 2-H),11.97(1H,s,4-OH),12.80(1H,s,6-OH)and13.33(1H,s, 11-OH) Found: M- (FAB, negative), 634.1678. C30H31F014 requires M, 634.16981.References 1 R. Yamamoto, S. Fujisawa and M. Kawamura, Yakugaku Zasshi, 1971,91, 855; H. Minlon, U.S. Pat. 2 656 366, 1953 (Chem. Abstr., l954,48,10794b). 2 J. G. Baxter,C. D. Robeson, J. D. Taylor and R. W. Lehman, J. Am. Chem. SOC.,1943,65,918. 3 M. Israel, P. G. Potti and R. Seshadri,J. Med. Chem., 1985,28,1223; T. Tsuchiya, Y. Takagi, S. Umezawa, T. Takeuchi, K. Komuro, C. Nosaka, H. Umezawa, S. Fukatsu and T. Yoneta, J.Antibiot., 1988,41,988. 4 N. F. Magri and D. G. I. Kingston, J. Nat. Prod., 1988, 51, 298; H. M. Deutsch, J. A. Glinski, M. Hernandez, R. D. Haugwitz, V. L. Narayanan, M. Suffness and L. H.Zalkow, J. Med. Chem., 1989,32,788. 5 J. W. Hill and W. H. Carothers, J. Am. Chem. SOC.,1933,55,5023. 6 Y. Kita, H. Maeda, F. Takahashi and S. Fukui, J. Chem. Soc., Chem. Commun., 1993,410. 7 For similar acylating reagents, see: Y. Tamura, J. Haruta, S. Okuyama and Y. Kita, Tetrahedron Lett., 1978, 3737; Y. Kita, J. Haruta, H. Tagawa and Y. Tamura, J. Org. Chem., 1980,45,4519; Y. Kita, J. Haruta, H. Yasuda, K. Fukunaga, Y. Shirouchi and Y. Tamura, J. Org. Chem., 1982, 47, 2697; Y. Kita, S. Akai, N. Ajimura, M. Yoshigi, T. Tsugoshi, H. Yasuda and Y. Tamura, J. Org. Chem., 1986, 51, 4150; Y. Kita, S. Akai, M. Yamamoto, M. Taniguchi and Y. Tamura, Synthesis, 1989,334. 8 R. P. Linstead, B. C. L. Weedon and B. Wlandislaw, J. Chem. SOC., 1955, 1097. 9 J. Cason, Org. Synth., 1955, Coll. Vol. 3, p. 169. 10 J. H. Short and U. Biermacher, Chim. Ther., 1966,456. 11 G. T. Morgan and E. Walton, J. Chem. SOC.,1935,290. 12 E. S. Rothman, S. Serota and D. Swern, J. Org. Chem., 1966,31,629. 13 P. Sieber, Helv. Chim. Acta, 1977,60,2711; H. Gerlach,Helv. Chim. Acta, 1977,60, 3039. 14Y. Kita, H. Maeda, M. Kirihara, Y. Fujii, T. Nakajima, H. Yamamoto and H. Fujioka, Tetrahedron Lett., 1990, 31, 7173; Y. Kita, H. Maeda, M. Kirihara, Y. Fujii, T. Nakajima, H. Yamamoto, Y. Tamura and H. Fujioka, Chem. Pharm. Bull., 1992,40,61. 15 A. Yoshimoto, S. Fujii, 0. Johdo, K. Kubo, T. Ishikura, H. Naganawa, T. Sawa, T. Takeuchi and H. Umezawa, J. Antibiot., 1986,39,902. 16 Y. Kimura, M. Suzuki, T. Matsumoto, R. Abe and S. Terashima, Bull. Chem. SOC.Jpn., 1986,59,423. 17 K.-D. Ok, T. Takagi, T. Tsuchiya, S. Umezawa and H. Umezawa, Carbohydr. Rex, 1987, 169,69. 18 J. Davoll and B. Lythgoe, J. Chem. SOC.,1949,2526. 19 F. G. Baddar and L. S. El-Assal,J. Chem. Soc., 1950,3606. Paper 3/024701 Received 29th April 1993 Accepted 30th June 1993