635
`
`above was treated with 0.5 N NaOH solution (80 mL) and ex-
`tracted with three 50-mL portions of chloroform. The combined
`chloroform layer was washed with water (100 mL) and dried over
`Na2S04. Evaporation of the solvent gave (S)-(-)-5 (1.11 g, 36%
`based on the initially used (S)-(-)-5), mp 225-232 "C, [a]2g -107"
`(e 1.1, chloroform). (S)-(-)-5: 'H NMR (CDClJ 6 1.19 (s,6 CHJ,
`1.37 (9, 6 CH,), 6.50 (d, 2 H, J = 7.9 Hz), 6.92 (t, 2 H, J = 7.0
`Hz), 6.96-7.03 (m, 4 H), 7.06-7.14 (dd, 4 H, J = 7.6 and 12.5 Hz),
`7.33-7.40 (m, 2 H), 7.44-7.53 (dd, 2 H, J = 8.6 and 13.1 Hz),
`7.61-7.67 (m, 4 H), 7.75-7.84 (m, 6 H), 7.97 (d, 2 H, J = 7.0 Hz);
`31P NMR (CDC1,) 29.5 ppm; IR (KBr) u 3050 (m), 2950 (s), 2900
`(m), 2870 (m), 1598 (m), 1553 (w), 1502 (m), 1462 (m), 1392 (m),
`1363 (m), 1302 (w), 1265 (m), 1195 (s), 1133 (m), 1112 (w), 1018
`(w), 869 (w), 815 (m), 810 (m), 751 (4,740 (m), 693 (w), 683 (w),
`650 (m), 607 (s), 581 (w), 568 (w), 557 (m), 522 (m), 489 (m) cm-';
`233 (z 130000), 273 (sh, 12000), 287 (12000),
`UV (ethanol) A,,
`300 (sh, lOOOO), 316 (sh, 36001, 332 (3500) nm.
`The purification of the antipode (R)-(+)-5, which went to the
`mother liquor of recrystallization of the (S)-(-)-5-(-)-7 complex
`was not carried out.
`Reduction of (S)-(-)-5 into 2,2'-Bis[bis(p-tert -butyl-
`pheny1)phosphinyll-1,l'-binaphthyl [p -tert-BuC8H4BINAP]
`[(S)-(-)-91. To a mixture of (S)-(-)-5 (1.50 g, 1.71 mmol) and
`triethylamine (1.65 mL, 1.20 g, 11.9 mmol) in xylene (25 mL) was
`added dropwise a solution of trichlorosilane (1.40 g, 10.3 mmol)
`in xylene (5 mL) at 20 "C. After the addition was completed, the
`mixture was heated with stirring at 100-110 "C for 3 h. Workup
`as described above gave 0.75 g (52%) of (S)-(-)-9, mp 263-265
`"C, [a]24D -83" (c 1.0, benzene). (S)-(-)-9: 'H NMR (CDCl,) 6
`1.24 (9, 6 CH,), 1.26 (s, 6 CH,), 6.65 (d, 2 H, J = 8.5 Hz), 6.74 (t,
`with fine splitting, 2 H, J = 7.6 Hz), 6.92-6.98 (m, 4 H), 7.06 (d,
`4 H, J = 7.9 Hz), 7.08-7.16 (m, 4 H), 7.20-7.32 (m, 6 H), 7.47 (d,
`with fine splitting, 2 H, J = 7.0 Hz), 7.78 (d, 2 H, J = 8.2 Hz),
`7.87 (d, 2 H, J = 8.2 Hz); 31P NMR (CDC1,) -16.4 ppm; IR (KBr)
`Y 3050 (w), 2950 (s), 2895 (w), 2860 (w), 1596 (w), 1551 (w), 1495
`(m), 1461 (m), 1392 (m), 1361 (m), 1307 (w), 1264 (s), 1200 (w),
`1082 (s), 1015 (s), 946 (w), 865 (w), 825 (s), 815 (s), 776 (w), 745
`(s), 697 (w), 645 (w), 581 (w), 556 (m), 515 (w), 456 (w), cm-'; LRMS
`(70 eV), m/z (% intensity) 846 (M', 0.14), 552 (ll), 551 (481,550
`1.31, 298 ((C4H9-C6H4)2P1 2.3);
`(loo), 549 (M' - (C4H&&)2P,
`HRMS (70 eV), m / z 846.4464, calcd for CmHMP2 846.4482. UV
`221 (e 125000), 237 (sh, 100000) nm. Anal. Calcd
`(ethanol) A,
`for CmHMP2: C, 85.07; H, 7.62. Found: C, 84.95; H, 8.03.
`X-ray Analysis of the Complex of (S)-(-)-3, (lR)-(-)-6, and
`
`J. Org. Chem. 1986,51,635-648
`Acetic Acid. Crystal data for the title complex are given in Table
`I. Single crystals were grown from a solution of the complex (0.25
`g, 0.38 mmol) in a mixture of ethyl acetate (8.5 mL) and acetic
`acid (0.1 mL). A suitable crystal was sealed in a thin-walled glass
`capillary. Diffraction data were collected with graphite-mono-
`chromated Cu Ka radiation. Fifty accurately centered reflections
`in the range 4O0<2O<6O0 were used for determination and
`least-squares refinement of the unit cell parameters. A total of
`8589 reflections were collected and 7842 reflections had IFoI >
`3u(F0), in which 5062 are independent. Three standard reflections,
`measured after every 50 reflections, showed neither indication
`of any misalignment nor deterioration of the crystal. The in-
`tensities were empirically corrected for Lorents and polarization
`factors and used in the structure determination. The structure
`solution by the use of the direct method (MULTAN 78 program)
`for 5062 reflections revealed positions for 48 non-hydrogen atoms,
`containing two phosphorus atoms. Three cycles of blockdiagonal
`least-squares refinement converged to R = 0.27 and R, = 0.34.
`The remaining non-hydrogen atoms and hydrogen atoms were
`located after carrying out a series of blockdiagonal least-squares
`refinement and Fourier and difference Fourier syntheses. Total
`123 atoms were refined by use of anisotropic thermal parameters
`for non-hydrogen atoms and isotropic thermal parameters for
`hydrogen atoms. Least-squares refinement based on 7842 ob-
`served reflections led to a final R = 5.96% and R, = 7.08%. The
`bond parameters in crystal solvent ethyl acetate have fairly large
`estimated standard deviations as is often observed for solvate
`molecules. Ten hydrogen atoms were not located from final
`difference Fourier maps. Selected bond lengths and angles appear
`in Table 11. Coordinates and thermal parameters for 123 atoms,
`observed and calculated structure factor amplitudes, all bond
`lengths and angles, and best planes (14 pages) are included as
`supplementary material.
`Acknowledgment. We thank Dr. C. Katayama, Na-
`goya University, for valuable contribution in X-ray crystal
`structure analysis. W e gratefully acknowledge financial
`support from the Ministry of Education, Science, and
`Culture, Japan (No. 59540331 and 60219012).
`Supplementary Material Available: Lists of atomic coor-
`dinates, thermal parameters, bond distances, bond angles, and
`best planes (14 pages). Ordering information is given on any
`current masthead page.
`
`Approach to the Total Synthesis of Chlorothricolide: Synthesis of
`(&)-19,2O-Dihydro-24-0 -methylchlorothricolide, Methyl Ester, Ethyl
`Carbonate+'
`
`Robert E. Ireland* and Michael D. Varney2
`The Chemical Laboratories, California Institute of Technology, Pasadena, California 91 125
`Received September 3, 1985
`An approach to the total synthesis of the macrolide antibiotic aglycone chlorothricolide (la) is presented. Herein
`is described the synthesis of the advanced intermediate (f)-19,20-dihydro-24-O-methylchlorothricolide, methyl
`ester, ethyl carbonate (34) from the "bottom half" acid 4 and the "top half" alcohol 3 by the sequence esterification,
`macrolactonization, ester enolate Claisen rearrangement, and decarboxylation.
`
`Chlorothricin (la), one of some 500 known macrolide
` antibiotic^,^ was isolated in 1969 by W. Keller-S~hierlein.~
`Active. against gram-positive bacteria, i t functions as a
`noncompetitive inhibitor of pyruvate c a r b ~ x y l a s e . ~ The
`aglycone chlorothricolide methyl ester (1 b) has been the
`subject of intense study by many synthetic chemists in
`recent years.6 In previous reports6a~b from this group, a
`convergent synthetic strategy was presented for the con-
`
`+ Contribution No. 7249.
`
`struction of chlorothricolide (lb). Central to the proposal
`was the joining of two nearly equal halves along the C12-
`
`(1) Grateful acknowledgment is made for support of this investigation
`by a grant from NSF (CHE-82-03494). Acknowledgment is also made for
`the use of the Southern California Regional NMR Facility (National
`Science Foundation Grant No. CHE-79-16324) and for use of the Midwest
`Center for Mass Spectrometry, University of Nebraska, Lincoln, NE
`(National Science Foundation Regional Instrumentation Facility) for all
`high-resolution mass spectra.
`(2) Atlantic Richfield Foundation Research Fellow, 1984.
`0022-3263/86/1951-0635$01.50/0 0 1986 American Chemical Society
`
`Illumina Ex. 1063
`IPR Petition - USP 10,435,742
`
`

`

`636 J. Org. Chem., Vol. 51, No. 5, 1986
`
`Ireland and Varney
`
`Chart 1.' Attempted Decarboxylation of the Seleno Ester 5b
`
`n-Eu,SnH, p-xylene
`130'C
`
`MOM0
`
`Ib R,: C H I
`R2: ti
`R3: H
`
`IC R , : CH3
`R z = CH)
`R3: H
`
`or
`II (62%)
`
`COpH
`
`&OM
`
`12
`
`Id R, : CH3
`R Z : CH,
`R 3 = COzC2H5
`C17 side chain followed finally by lactone formation. An
`equally convergent, but alternate, approach to this mac-
`rocycle is presented herein (Scheme I). This plan hinges
`on the preparation of the dilactone 2 from the "top half"
`alcohol 3 and "bottom half" acid 4 by initial esterification
`across the C1 and C25 carbons followed by macro-
`lactonization. Subsequent ester enolate Claisen rear-
`rangement7 and decarboxylation would then yield the in-
`tact monolactone.
`Such a strategy change was deemed necessary as a result
`of two key experiments. The first, as reported previously,6b
`
`(3) Berdy, J. "Handbook of Antibiotic Compounds", Val. 2 CRC Press
`Inc.: Boca Raton, FL, 1980.
`(4) (a) Keller-Schierlein, W.; Muntwyler, R.; Pache, W.; Zahner, H.
`Helu. Chim. Acta 1969, 52, 127-142. (b) Muntwyler, R.; Widmer, J.;
`Keller-Schierlein, W. Ibid. 1970, 53, 1544-1547. (c) Muntwyler, R.;
`Keller-Schierlein, W. Ibid. 1972,55, 2071-2094. (d) Brufani, M.; Cerrini,
`S.; Fedeli, W.; Mama, F.; Muntwyler, R. Ibid. 1972,55, 2094-2102.
`(5) (a) Schindler, P. W.; Zaehner, H. Arch. Microbiol. 1972,82,66-75.
`(b) Pache, W.; Chapman, D. Biochem. Biophys. Acta 1972,255,348. (c)
`Schindler, P. W.; Zaehner, H. Eur. J. Biochem. 1973, 39, 591-600. (d)
`Schindler, P. W. Ibid. 1975, 51, 579-585.
`(6) (a) Ireland, R. E.; Thompson, W. J. J. Org. Chem. 1979, 44,
`3041-3052. (b) Ireland, R. %.; Thompson, W. J.; Srouji, G. H.; Etter, R.
`J. Org. Chem. 1981,46, 4863-4873. (c) Hall, S. E.; Roush, W. R. J. Org.
`Chem. 1982,47,4611-4621. (d) Snider, B. B.; Burbaum, B. W. J. Org.
`Chem. 1983, 48, 4370-4374. (e) Schmidt, R. R.; Hirsenkorn, R. Tetra-
`hedron Lett. 1984, %, 4357-4360. (0 Marshall, J. A.; Audia, J. E.; Grote,
`J. J. Org. Chem. 1984,49, 5277-5279.
`(7) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. SOC.
`1976, 98, 2868-2877.
`
`6MOM
`
`4
`"(a) p-TsOH, CH30H, HzO, 85 "C; (b) CH3C(OCH3),CH3, p -
`TsOH, CHZClz; (c) MezSO, ClCOCOCl, Et3N, CHzC1,; (d) NaBH,,
`CH3CH(OH)CH3, 0 O C ; ( e ) CH30CH2C1, (i-C3H7)2C2H5N, CH,Cl,;
`(f) CH30H, HzO, PyHOTs; (g) Me2S0, PhH, (i-C3H7N),C, C1,CH-
`C0,H; (h) T H F , H20, 10% aqueous KOH, 30% H,O.
`was attempted decarbonylation of the aldehyde 5a with
`Wilkinson's catalyst.
`In this case, cyclopropane and
`isomerized olefin products were obtained (for details see
`ref 6b). The second, as shown in Chart I, was the radical
`decomposition8 of the seleno ester 5b. In this exploratory
`experiment, the pentacycle 7 and the aldehyde 5a were
`obtained together with the desired decarboxylated product
`6. Modification of the reaction conditions never resulted
`in exclusive formation of compound 6. It was felt that
`tying the side chain back, that is, making it part of a
`macrolactone, might restrict its motion enough to either
`reduce metal participation of the side-chain olefin to the
`point where no cyclopropanes were formed or, in the case
`of the seleno ester, allow for trapping of the intermediate
`radical before it could cyclize onto the C10 olefin. Results
`in this report bear this hypothesis as correct.
`
`(8) Pfenninger, J.; Heuberge, C.; Graf, W. Helu. Chim. Acta 1980,63,
`2328-2337.
`(9) The structures shown in these schemes depict one enantiomer of
`a racemic mixture for graphic simplicity, but in all cases only the race-
`mate was obtained. No resolution of these racemates was affected.
`
`

`

`Total Synthesis of Chlorothricolide
`
`J. Org. Chem., Vol. 51, No. 5, 1986 637
`
`Scheme 111: Synthesis of the Top Half 3"
`
`OBn
`
`17
`
`OB"
`
`OBn
`
`OH
`3
`19
`18
`" (a) CHz=CHCH=CH2, PhH, pyrogallol, A; (b) CH,OH, A; (c) ether, CHzN2; (d) LiHMDA, THF, -30 OC; (e) HMPA, CH,OSO,F;
`(0 catalytic NaOCH,, CH30H, A; (g) LiEt3BH, THF, 0 OC; (h) t- BuMezSiC1, pyridine, DMAP, CH2C12; (i) MCPBA, LiC104, Et20, 0°C;
`(i) LiMezCu, Et20, hexane, 0 "C; (k) SEMCl, (i-C3H7)2C2H5N,CHZC12;
`(1) 10% Pd/C, H2, CzH50H.
`late, CH,OH, HzO, 80 "C) of the acetonide gave the 1,Zdiol
`12 in 90% yield. Oxidation of the 1,2-diol to the corre-
`sponding 1,2-dione13 followed by treatment with basic
`hydrogen peroxide14 (KOH, HzOz, THF, HzO) afforded the
`diacid 4 in excellent yield. The lH NMR spectrum of the
`dimethyl ester of the synthetic diacid 4 and that of the
`one-carbon homologue obtained from natural chloro-
`thricidb were superimposable.
`11. Synthesis of the Top Half Alcohol 3. After de-
`ciding upon the alcohol 3 as our key intermediate, we
`investigated two approaches for its construction. The first,
`shown in Scheme 111, is an extension of earlier work re-
`ported from this group.6a A benzyl-protecting group was
`chosen in place of the previously used methyl group to
`insure selective deprotection. The starting material (a-
`(benzy1oxy)acetoxy)maleic anhydride (13), was prepared
`by acylation of the pyridine salt of hydroxymaleic anhy-
`dride with (benzy1oxy)acetyl chloride.16 Diels-Alder re-
`action of the anhydride 13 with 1,3-butadiene (autoclave,
`90 "C, 5 days) gave, after methanolysis and diazomethane
`treatment, the triester 14 in 82% yield.
`After extensive experimentation, improved conditions
`for the cyclization of the triester 14 to the spirobutenolide
`15 were found. In the case of lithium diisopropylamide
`(LDA), 0-elimination was the major reaction pathway. The
`use of a weaker base, lithium hexamethyldisilazide
`
`The current effort can be divided into four distinct parts.
`First, a synthesis of the diacid 4 from the previously re-
`ported intermediate 8 was developed. Second, with some
`modifications, construction of the appropriately protected
`top half alcohol 3 was completed by a route similar to that
`developed earlier.6a Third, a successful scheme for the
`synthesis of the lactone 29 was realized through decar-
`boxylation of the ester enolate Claisen rearrangement
`product 28. Fourth, functionalization of the top portion
`of the ketone 32 is explored.
`I. Inversion of the C-7 Alcohol and Synthesis of the
`Bottom Half Diacid 4. In a previous paper? the syn-
`thesis of "7-epi-bottom half" was outlined. Epimerization
`of the C-7 center was delayed because, at the time, its
`configuration had no effect on the outcome of the studies
`presented. For the sake of convergency, we felt that in-
`version of this center to the natural configuration would
`best be completed as early as possible. In Scheme I1 the
`inversion of the C-7 alcohol is presented together with a
`more efficient method of converting the 1,Zdiol 12 to the
`diacid 4.
`Aqueous acid treatment of the tricyclic acetal 86b fol-
`lowed by reketalization with 1,2-dimethoxypropane pro-
`vided the alcohol 9 in 95% yield. SwernlO oxidation af-
`forded the ketone 10 (97%) which when treated with so-
`dium borohydride" in dry isopropyl alcohol yielded a se-
`parable mixture of the a- and 0-alcohols ll and 9 in a 2.6:l
`ratio. Protection of the C7-hydroxy as a methoxymethyl
`e t h e P followed by selective hydrolysis (pyridinium tosy-
`
`(10) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
`(11) (a) Wigfield, D. C.; Phelps, D. J. J. Org. Chem. 1976, 41,
`2396-2401. (b) Wigfield, D. C. Tetrahedron 1974,35, 449-462.
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~~~~~~~~
`
`~
`
`~
`
`(12) Stork, G.; Takahashi, T. J. Am. Chem. SOC. 1977,99,1275-1276.
`(13) Corey, E. J.; Shimoji, K. J. Am. Chem. SOC. 1983,105,1662-1664.
`(14) Corey, E. J.; Pearce, H. L. J. Am. Chem. SOC. 1979, 101,
`5841-5843.
`(15) Roberts, J. C. J. Chem. SOC. 1952, 3315-3316.
`(16) Manhas, M. S.; Amin, S. G.; Chawla, H. P. S.; Bobe, A. K. J.
`Heterocycl. Chem. 1978, 15, 601-604.
`
`

`

`638 J . Org. Chem., Vol. 51, No. 5, 1986
`
`Scheme IV? Tartrate Approach to the Top Half 3"
`0
`e n 0 4
`
`COpCH,
`Dimethyl L- tartrate 4 H k O H b,c
`H 55*-
`34%
`TSO
`I
`C02CH3
`
`2o
`
`d /
`
`
`
`J
`
`A
`
`0
`
`
`
`21
`
`A
`
`23
`22
`(a) p-TsC1, pyridine, DMAP, CH2C12; (b) BnOCH,COCl, pyri-
`dine, DMAP, CH,Cl,; (c) THF, (CZH&N, DBU; (d) CH,=CHC-
`H=CH,, PhH, pyrogallol, 4 (e) LiHMDA, THF, 0 "C; (f) CH,N,.
`
`U
`
`(LiHMDA), along with low temperatures and long reaction
`times allowed for both improved yield and reproducibility.
`Thus, inverse addition of 2 equiv of LiHMDA in tetra-
`hydrofuran (THF) at -78 "C to the triester 14 in THF at
`-78 "C and warming to -30 "C for 5 h afforded, after
`trapping with methyl fluorosulfonate, the desired spiro-
`butenolide 15 in 78% yield. Equilibration of the pseu-
`doaxial carbomethoxy group provided a 79% yield of 15
`and 16 as an inseparable 1:7 mixture. Superhydride re-
`duction (2 equiv of LiEt3BH, THF, 0 "C) followed by
`protection with tert-butyldimethylsilyl chloridels (t-
`BuMe2SiC1) afforded the protected alcohol 17 in 94%
`overall yield. Selective epoxidation of the cyclohexene
`double bond was accomplished in 61% yield with m-
`chloroperbenzoic acid (MCPBA) in ether containing 1
`equiv of anhydrous lithium perchlorate.6a Treatment of
`the epoxide 18 with the higher order cuprates as described
`by Lipshutzlg in various solvents failed to give any of the
`desired alcohol, giving instead starting material or de-
`composition products. Alternately, when the epoxide 18
`was exposed to 10 equiv of lithium dimethylcuprate in
`hexane,2O the alcohol was obtained in 62% yield, together
`with 17% of a ketonic product. Hexane was critical to the
`success of this reaction. Protection of the alcohol with
`p-(trimethylsily1)ethoxymethyl chloride21 (SEMC1) pro-
`vided the ether 19 in 92% yield. Selective removal of the
`benzyl group (H, 10% Pd/C, EtOH) gave the crystalline
`"top half' alcohol 3 in essentially quantitative yield.
`Subsequent to the synthesis of the alcohol 3, a shorter
`alternative route to the intermediate 16 was pursued
`(Scheme IV). This plan entailed the use of the relative
`stereochemistry of the hydroxy groups in natural tartaric
`acid to generate stereospecifically the trans dienophile 21.
`Diels-Alder reaction and intramolecular Claisen conden-
`sation was to yield the spirolactone 16. In the event,
`monotosylationz2 of dimethyl L-tartrate afforded the al-
`cohol 20. The moderate yield of this reaction was of no
`consequence since both starting materials were readily
`available. Treatment of this alcohol with (benzyoxy)acetyl
`chloride followed by elimination of the tosylate group
`provided the olefin 21 in 55% yield. The Diels-Alder
`reaction of olefin 21 with 1,3-butadiene gave adduct 22 in
`
`(17) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979,35,567-607.
`(18) Chaudhary, S. K.; Hernandez, 0. Tetrahedron Lett. 1979, 99.
`(19) Lipshutz, B. H.; Kozlowski, J.; Wilhelm, R. S. J. Am. Chem. SOC.
`1982, 104, 2305-2307.
`(20) Hicks, D. R.; Fraser-Reid, B. Can. J. Chem. 1975,53,2017-2023.
`(21) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21,
`3343-3346.
`(22) Seebach, D.; Hungerbuhler, E. "Modern Synthetic Methods";
`Otto Salle Verlag: Frankfurt, West Germany, 1980; pp 93-171.
`
`Ireland and Varney
`
`high yield (autoclave, 150 "C, 3 days). All that remained
`was the cyclization of the triester 22 to the spirobutenolide
`16. However, addition of the triester 22 to 2 equiv of
`LiHMDA in THF at -78 "C followed by warming afforded,
`after treatment with diazomethane, the &lactone 23 as the
`only cyclization product. The remainder of the material
`consisted of products resulting from @-elimination. Re-
`versing the order of addition of the reagents and changing
`the trapping agent from diazomethane to methyl fluoro-
`sulfonate affected only the relative yields of 23 and 0-
`eliminated products. This result, though unexpected, is
`not without precedent. In Dieckmann cyclizations of re-
`lated triesters, small modifications in backbone structure
`resulted in drastic changes in product cornp~sition.~~
`Inspection of molecule models of 14 and 22 was of little
`help, and it is possible that because of the kinetic nature
`of the reaction conditions, the proximity of the two reacting
`centers is the controlling factor. However, further studies
`are needed.
`111. Formation of Macrolactone 29. With the two
`appropriately functionalized intermediates 3 and 4 in hand,
`the construction of the macrolactone 29 was pursued. The
`methyl ester acid chloride 24 was prepared in situ by se-
`lective esterification of the diacid chloridez4 of acid 4.
`Connection of the two pieces was accomplished by adding
`a solution of the top half alcohol 3 and 4-(dimethyl-
`amino)pyridinez5 in CH2C12 to the bottom half acid chlo-
`ride 24 in CHzCl, at 0 OC and then allowing the mixture
`to warm to room temperature (Scheme V). After aqueous
`workup, the ester 25 could be obtained in 77% overall
`yield.26
`The methyl ester function of compound 25 was con-
`verted to the thiophenol ester by hydrolysis and reester-
`ifi~ation.~~ This two-step sequence was necessary in light
`of the fact that selective esterification using the thiophenol
`of the diacid chloride of 4 was not successfuL2* Intro-
`duction of the vinyl group required removal of the t-
`BuMezSi protecting group (HF,.pyridine),z9 and it was at
`this stage that the two diastereomers, produced in the
`esterification step, became separable. A 1:1.26 ratio of the
`alcohols 26A,B was obtained with the more mobile one (by
`chromatography) being the minor component 26A. Since
`comparison with the natural product was impossible at this
`stage, all subsequent reactions were performed on both
`diastereomers individually. Oxidation of the alcohol 26
`
`with pyridinium chloro~hromate~~ (PCC) yielded the
`corresponding aldehyde which was immediately treated
`with vinyl-Grignard to provide the vinyl alcohol 27 in 65%
`overall yield.
`The macrolactonization of the alcohol 27 and related
`compounds was studied in some detail. The "double
`
`(23) (a) Schaefer, J. P.; Bloomfield, J. J. Org. React. 1N.Y.) 1967,15,
`1-203. (b) Augustine, R. L.; Zelawski, Z. S.; Malarek, D. H. J. Org. Chem.
`1967,32, 2257-2260.
`(24) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R., Toye, J.;
`Ghosez, L. Org. Synth. 1979,59, 26-34.
`(25) Hassner, A.; Krepski, L. R.; Alexanian, V Tetrahedron 1978,34,
`2069-2076.
`(26) Since the alcohol 3 and the diacid 4 are racemates, the connection
`of the two compounds produces a diastereomeric mixture. For the sake
`of clarity only one diastereomeric racemate is shown, but up to alcohol
`26 the materials prepared were indeed inseparable mixtures of diaste-
`reoisomeric racemates.
`(27) Neises, B.; Steglich, W. Agneur. Chem., Int. E d . Engl. 1978, 17,
`522-524.
`(28) Attempted selective esterification of the diacid chloride of acid
`4 with thiolphenol and pyridine at -90 "C gave only a 2:l mixture of the
`side-chain thio ester over the ring thio ester.
`(29) (a) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org.
`C h e n . 1979,44,4011-4013. (b) Trost, B. A,; Curran, D. P. J. Am. Chem.
`SOC. 1981, 103, 7380-7381.
`(30) Corey, E. J.; Suggs, J. W.; Tetrahedron Lett. 1975, 2647-2650.
`
`

`

`Total Synthesis of Chlorothricolide
`
`J. Org. Chem., Vol. 51, No. 5, 1986 639
`
`Scheme V? Formation of Maorolactone 2 9 O
`
`OSEM
`
`+
`
`C02CH3
`
`7 7 O/O
`
`.OY0
`
`24
`
` MOM
`
`c.f /
`
`9
`
`PhSCO
`
`-
`
`75%
`
`-
`GMOM
`
`27 A,B
`
`' OSEM
`
`+
`
` MOM
`
` MOM
`
`28 A,B
`
` MOM
` MOM
`3 0 A 0-0%
`2 9 A , B 70-76%
`(I (a) DMAP, CH,Cl,; (b) LiOH, CH30H, H,O; (c) PhSH, DCC,DMAP, CH,Cl,; (d) HF,.pyridine, THF; (e) PCC, CHzC1,; (f)
`CH2=CHMgBr, THF, 0 "C; (9) Ag(02CCF3), Na2HP04, PhH, 82°C; (h) KHMDS, THF, HMPA, -78 "C; (i) HMPA, (C2H5)3SiC1,
`(CZH5)3N, THF; 0) C12POOPh, (C2H,),N, THF, 0 "C; (k) PhSeH, (C,H,),N, THF, 0 "C; (1) (n-C,H9)3SnH, AIBN, p-Xylene, 130 "C.
`activation" methods of Corey3l failed to produce any lac-
`dilution conditions, afforded the 14-membered macrodi-
`tone as did Masamune's3' mixed phosphate anhydride
`lactone 2 in 75% yield together with -20% of the corre-
`method. However, silver-promoted oxidation of the thio-
`sponding hydroxy acid hydrolysis product. This hydroxy
`acid could be recycled back to the thio ester 27 in 7040%
`phenol ester 27, as described by M a ~ a m u n e ~ ~
`under high
`yield with diethyl chlorophosphate3* and thiophenol.
`
`(31) (a) Carey, E. J.; Nicolaou, K. C. J. Am. Chem. Sac. 1974, 96,
`5614-5616. (b) Carey, E. J.; Brunelle, D. J. Tetrahedron Lett. 1976,
`3409-3412.
`(32) Kaiho, T.; Maaamune, S.; Toycda, T. J. Org. Chem. 1982, 47,
`1612-1614.
`
`(33) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates, B.
`S. J. Am. Chem. SOC. 1977,99, 6756-6758.
`(34) Masamune, S.; Kamata, S.; Diakur, J.; Sugihara, Y.; Bates, G. S.
`Can. J. Chem. 1975,53, 3693-3695.
`
`

`

`640 J. Org. Chem., Vol. 51, No. 5, 1986
`Enolization of the dilactone 2 with potassium hexa-
`methyldisilazide6",b followed by trapping with triethylsilyl
`chloride gave, after being allowed to warm to room tem-
`perature for 2-4 h and aqueous workup, the 14-membered
`macrolactone Claisen acid 28 in 60-7270 yield. When
`t-BuMe2SiC1 was employed as the trapping agent, yields
`of only 40-50% resulted. Analysis of the 400-MHz 'H
`NMR spectrum of the acid 28 and its decarboxylation
`product 29 revealed that the newly formed C16-Cl7
`double bond was exclusively the trans isomer (see Ex-
`perimental Section).
`The hypothesis, as put forth earlier, concerning the re-
`stricted motion of the carboxylate-containing side chain
`could now be readily tested. The seleno ester of the acid
`28 was prepared, in 80% yield, by using the method de-
`scribed previou~ly.~~ Radical decompositions was per-
`formed by preheating the seleno ester in p-xylene at 130
`"C and then adding the tributyltin hydride and AIBN. In
`this manner, the decarboxylated product 29 could be ob-
`tained in 88-95% yield with no evidence of radical cy-
`clization on the C10 olefin. Produced as a byproduct from
`one of the diastereomers was the aldehyde 30A, which
`
`when treated with Wilkinson'~~~ catalyst also afforded the
`lactone 29. In this case no evidence of cyclopropane for-
`mation or olefin isomerization was found. These results
`are in stark contrast to those obtained in both the pre-
`viously discussed open-chain cases.6b
`IV. Functionalization of the Top Half of Lactone
`29. With the macrolactone now intact, functionalization
`of the top portion of the molecule was explored. The first
`requirement was distinction of the C7 and C20 hydroxy
`functions. As can be seen in compound 29 this problem
`had theoretically been solved by having two different
`protecting groups. However, attempted selective removal
`of the SEM group under the conditions described by
`LipshutzZ1 (TBAF, THF, or HMPA) and those developed
`in this group (CsF, HMPA)37 led to concomitant removal
`of the tetronic methyl group and extensive decomposition.
`Both the SEM and the MOM group could, however, be
`removed in one step38 (LiBF4, CH3CN, HzO, 70 "C) to give
`the diol 31 (Scheme VI) in quantitative yield. Conditions
`for selective reprotection of the less hindered C7 hydroxy
`group were eventually found39 (pyridine, CzH,OCOC1, 0
`"C) and, after oxidation, the ketone 32 could be obtained
`in 60% yield. Model studies indicated that this ketone
`was not only very unreactive toward nucleophiles but also
`very susceptible to epirneri~ation.~~ The only carbon
`nucleophile found that would add successfully, without
`epimerizing the adjacent methyl group, was the modified
`Still4I reagent (tributylstannyl)(2-methoxyisopropoxy)-
`methane.42 Unfortunately, treatment of the resultant 3"
`alcohol with thionyl chloride in pyridine gave the dehy-
`drated product with the double bond exclusively in the
`
`(35) Ireland, R. E.; Norbeck, D. W.; Mandel, G. S.; Mandel, N. S. J.
`Am. Chem. SOC. 1985, 107, 3285-3294.
`(36) Tsuji, J.; Ohno, D. Tetrahedron Lett. 1965, 3969-3971.
`(37) Ireland, R. E.; Norbeck, D. W. J. Am. Chem. SOC. 1985, 107,
`3279-3285.
`(38) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982,12,267-277.
`(39) Fieser, L. F.; Herz, J. E.; Klohs, M. W.; Romero, M. A.; Utne, T.
`J. Am. Chem. SOC. 1952, 74, 3309-3313.
`(40) The keto derivative of compound 19 was used as a model for
`functionalization studies. Acidic removal of the trimethylsilyl group from
`its corresponding trimethylsilyl cyanohydrin yielded the starting ketone.
`Attempted addition of numerous disubstituted one-carbon acyl anion
`equivalents gave no reaction. Addition of both trimethylsulfonium me-
`thylide and trimethylsulfoxonium methylide resulted in extensive epim-
`erization of the methyl group.
`(41) Still, W. C. J. Am. Chem. SOC. 1978, 100, 1481-1487.
`(42) First prepared in this group by D. W. Norbeck from (tributyl-
`stanny1)methanol and 2-methoxypropene.
`
`Scheme VI? Functionalization of the Top HalF
`
`Ireland and Varney
`
`o b
`L
`60%
`
`f , 9
`28%
`
`6COzCzHs
`~ C O Z C Z H C ,
`3 4 A , B
`33 A,B
`"(a) C2H50COC1, pyridine; (b) PCC, Celite, CH2C12; (c) (n-
`C,H,)3SnCH20C(OCH,)(CH3)2, n-BuLi, THF, -78 "C; (d) 10%
`HC1, THF; (e) TosIm, NaH, THF; (f) Me3SiTrf, 2,6-lutidine, DBU,
`PhCH3; (9) PDC, DMF.
`
`undesired C20-C21 position. Dehydration using other
`known methods (POCl, or mesylchloride and base) on
`similar systems always occurred to the more substituted
`side. Available methods for converting epoxides to allylic
`alcohols are numerous43 and, therefore, intermediate 33
`was prepared. Treatment of the epoxide 33 with tri-
`methylsilyl trifluoromethanesulfonate as described by
`Noyori4 resulted unexpectedly in formation of the isomeric
`aldehyde. A trace of allylic alcohol could be found in the
`reaction, but it had the undesired C20-C21 olefin. Al-
`ternate attempts to convert the epoxide to the desired
`allylic
`or to improve the yield of isomerization
`to the corresponding aldehyde43 were uniformly unsuc-
`cessful. However, after oxidation of the aldehyde to the
`carboxylic acid and treatment with diazomethane, the
`protected dihydrochlorothricolide 34 was obtained in
`moderate yield.
`For the purpose of comparison, chlorothricolide6b IC was
`
`treated with ethyl chlor~formate~~ to provide the carbonate
`Id. Study of the 400-MHz 'H NMR spectra of esters 34
`and Id revealed that the minor diastereomer from the
`connection reaction (see Scheme V) corresponded to the
`natural product.45
`The find transformation necessary to complete the total
`synthesis was the regioselective dehydrogenation of the
`ester 34. The two preparative useful methods available
`for this reaction, decomposition of a ele en oxide^^^ or oxi-
`
`(43) Gorzynski-Smith, J. Synthesis 1984, 629-656.
`(44) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. SOC. 1979,101,
`2738-2739.
`(45) This conclusion is based on the chemical shifts of the C16 and C17
`protons. The natural material had the C16 proton at 5.42 ppm and the
`C17 proton at 5.14 ppm, and the minor component had the C16 proton
`at 5.37 ppm and the C17 proton at 5.21 ppm. In contrast, the major
`component had the C16 proton at 5.19 ppm and C17 proton at 5.26 ppm.
`(46) (a) Reich, H. J.; Wollowitz, S.; Trend, 3. E.; Chow, F.; Wendel-
`born, D. F. J. Org. Chem. 1978,43,1697-1705. (b) Tsuji, J.; Takahashi,
`K.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1984, 25, 4783-4786.
`
`

`

`Total Synthesis of Chlorothricolide
`dation of a silyl ketene acetal,46b both required initial
`enolate formation. Attempted enolization with up to 5
`equiv of LDA, KHMDS, and KDA47 followed by trapping
`with diphenyl diselenide, phenylselenyl chloride, and
`tert-butyldimethylsilyl trifluoromethanesulfonate gave
`only starting material and decomposition products. Hy-
`drogenation of the natural carbonate Id to the hexahydro
`derivative4 and subjection of this to numerous enolization
`conditions also were unsuccessful. Thus, while the con-
`struction of the macrolactone has been efficiently accom-
`plished, modification of the strategy is necessary such that
`functionalization of the top half is performed prior to the
`connection of t h e two halves. The results of this effort,
`currently under way, will be the subject of a future report.
`Experimental Section
`Melting points are uncorrected. Proton nuclear magnetic
`resonance ('H NMR) spectra were recorded at 90 MHz except
`where designated "500 MHz". Data are reported as follows:
`chemical shift (multiplicity, integrated intensity, coupling con-
`stants, assignment). Optical rotations were measured in 1-dm
`cells of 1-mL capacity; chloroform, when used as a solvent for
`optical rotations, was filtered through neutral alumina (activity
`I) immediately prior to use. Reaction solvents and liquid reagents
`were purified by distillation or drying shortly before use. Reactions
`were run under an argon atmosphere arranged with a mercury
`bubbler so that the system could be alternately evacuated and
`filled with argon and left under a positive pressure. Reported
`temperatures were measured externally. Syringes and reaction
`flasks were dried at least 12 h in an oven (120-140 "C) and cooled
`in a dessicator over anhydrous CaS04 prior to use. If feasible,
`reaction flasks were also flame-dried in vacuo. Analytical samples
`of crystalline compounds were in all cases prepared by recrys-
`tallization from ether/petroleum.
`1 a,2a-( Isopropylidenedioxy)-8~-hydroxy- 1 1 ba-met hyl-
`5aa,7aa,8,9,10,11,1 laP,1 l