Cyclic hydroboration of geraniol derivatives: a synthesis of the left-hand portion of X-14547A

Department of Chemistry, Queen's University, Kingston, Ont., Canada K7L 3N6 Received June 26, 1985

RALPH ALLEN WHITNEY. Can. J. Chem. 64, 803 (1986). The stereochemical consequences of the cyclic hydroboration-oxidation of geraniol derivatives have been examined;

moderately high selectivity (85-88%) for the formation of one major diastereomer has been observed, presumably as a consequence of remote asymmetric induction in the cyclic hydroboration of these 1,5-dienes. An approach to the synthesis of the left-hand portion of the ionophore antibiotic X-14547A is described.

RALPH ALLEN WHITNEY. Can. J. Chem. 64, 803 (1986). On a CvaluC les consCquences stCrCochimiques de I'hydroboration-oxydation cyclique de dCrivCs du gkraniol. On a observe

des sClCctivitCs relativement ClevCes (85-88%) pour la formation du diastCrCoisom~re prCpondCrant; ce rCsultat est probablement la consCquence d'une induction asymktrique a distance qui se fait sentir lors de l'hydroboration cyclique de ces dienes-1,5. On dCcrit une approche ?i la synthese de la portion de gauche de I'antibiotique ionophore X-14547A.

[Traduit par la revue]

One of the major objectives in the synthesis of complex natural products is to transform stereochemically simple com- pounds into topologically complex structures in the most efficient manner possible. In this regard, reactions that allow the formation and relative control of a number of asymmetric centres in one synthetic step are extremely important; intramolecular cycloaddition reactions have been particularly useful in achiev- ing this objective, with the Diels-Alder reaction (for recent reviews, see ref. 1) having received notable attention. Other recent examples of specific reactions that generate multiple

1 asymmetric centres are the permanganate oxidation of dienes 1 ( 2 ) , arene-olefin cycloadditions (3), and diene cyclic hydro-

boration-oxidation (4). In this last case, the hydroboration of 1,4- and 1,5-dienes was examined and moderate to high levels

I of stereochemical control were obtained in the formation of 1 acyclic 1,4- and 1,5-diols containing two remote asymmetric I centres. : X-14547A, 1, is an ionophore antibiotic possessing interest-

ing and unusual structural features (5); the left-hand portion of I the molecule, 2, contains a trisubstituted tetrahydropyran ring

with trans substituents across the ring oxygen, while the right-hand portion, 3, contains a trans-fused tetrahydroindan with an appended ketopyrrole unit, an unusual structural feature

2o,R=H,X = E t b, R=Me,X =OH c, R=Me,X= OMe

for this type of antibiotic. Several synthetic approaches to the left-hand (6) and right-hand (7) portions of X-14547A have been reported, as well as three total syntheses (8) of the compound. Interestingly, the intramolecular Diels-Alder route to the right-hand portion has allowed a high degree of relative stereochemical control in establishing four additional centres of asymmetry from one pre-existing asymmetric centre in the triene substrate. In considering the possibility of establishing four centres of relative asymmetry in one step from an achiral precursor through cyclic hydroboration, it was decided that the left-hand portion 2 of X-14547A was a suitable synthetic target upon which to test this notion.

Results and discussion Geraniol tetrahydropyranyl ether 14a was the first diene

examined; hydroboration was performed with borane-tetrahy- drofuran complex at low temperature to suppress elimination in the P-alkoxyalkyborane intermediate (13). Subsequent oxida- tion followed by alcoholysis of the tetrahydropyranyl group provided 3,7-dimethyl-l,2,6-octanetriol(9) as a mixture of the diastereomers 5 and 6 in a 73% yield. Examination of the proton decoupled 13C nmr spectrum indicated the presence of the two diastereomers in approximately an 85: 15 ratio, by integration, but gave no indication as to the stereochemistry of the major isomer. Elucidation of the stereochemistry of the major diaste- reomer was accomplished using a precedented sequence (6a, b; 8d) in which the configuration at C-2 of 5 and 6 was inverted during the formation of the tetrahydropyran ring in 7 a and 8a . The trio1 was selectively sulfonated at the primary hydroxyl group with p-toluenesulfonyl chloride to give a P-hydroxy- tosylate that, on treatment with base, afforded an epoxide. Intramolecular alcoholysis of the epoxide under acidic condi- tions proceeded to give a mixture of tetrahydropyranyl alcohols 7 a and 8 a with precedented inversion of configuration at C-2 (6a,b; 8d). Proton nmr data on the corresponding acetate indicated the presence of predominantly one stereoisomer, 7b or 8b, but did not unambiguously indicate which one of the two was the predominant isomer; mass spectral data showed fragment ions arising from a-cleavage of the C-2 and C-6 substituents as is characteristic of tetrahydropyrans (14). The 13c nmr data on the alcohols were, however, very informative; 7 a and 8 a differ only in the axial versus equatorial disposition of the hydroxymethyl group at C-2 and the equatorial versus axial disposition of the methyl group at C-3. In general, axial sub-

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CAN. J. CHEM. VOL. 64. 3986

- Me OH

OMe OMe

lOa,R=Bn

stituents in tetrahydropyranyl rings show a large upfield chemi- cal shift compared to equatorial substituents (10); the nmr spectrum of the mixture of 7 a and 8a showed the major isomer having chemical shifts of 64.7 and 12.1 ppm, respectively, for the C-2 hydroxymethyl and C-3 methyl groups, while the minor isomer had chemical shifts of 57.7 and 16.2 ppm, respectively. On this basis, 8a was the major diastereomer obtained and hence triol 6 was the major stereoisomer obtained from the cyclic hydroboration-oxidation of geraniol tetrahydropyranyl ether. Subsequent experiments showed that direct hydroboration of geraniol 4b with 2.5 molar equivalents of borane-tetra- hydrofuran complex also gave triol 6 as the major diastereomer, obviating the need for an alcohol-protecting group during the hydroboration.

The use of thexylborane (13) as the reagent for hydroboration of 4a substantially altered the stereochemical outcome in that the mixture of triols obtained, on subsequent oxidation then alcoholysis of the tetrahydropyranyl group, showed a small predominance (60:40) of the diastereomer 5 over 6 , as evi-

denced by the proton decoupled I3C nmr spectrum of the triol mixture. Conversion of this triol mixture to the mixture of tetrahydropyranylalcohols 7 a and 8a showed the major isomer having chemical shifts of 57.7 and 16.2ppm, respectively, for the C-2 hydroxymethyl and C-3 methyl groups, as expected for 7 a .

Attention was next turned to diene 9, prepared by selenium dioxide oxidation of 0-benzylgeraniol (Sharpless catalytic procedure (11)) and subsequent methylation. The use of borane-tetrahydrofuran complex at low temperature as the cyclic hydroborating reagent led, on oxidation, to a mixture of nearly equal amounts of diols 10a and l l a , as determined by the proton decoupled 13C nmr spectrum of the diol mixture. The use of thexylborane resulted in a substantial increase in diastereo- selectivity (88:12 ratio of isomers) when the reaction was performed at 5 - 10°C; however, a competing p-elimination rehydroboration reaction led to the formation of a substantial amount of the diol 12 as well; we were unable to suppress the p-elimination without suppressing cyclic hydroboration. AS a

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consequence, the mixture of diastereomers 10a and l l a was obtained in only 3 1 % yield upon chromatographic purification.

The mixture of diols was hydrogenolysed over palladium to give a mixture of triols l o b and l l b , which was converted to a mixture of the tetrahydropyranylalcohols 13 and 14 as de- scribed previously. The proton nmr spectrum did not readily identify the major diastereomer, while mass spectral data again showed typical fragment ions arising from a-cleavage of a tetrahydropyran. The 13c nmr spectrum of the mixture of 13 and 14 showed the major diastereorner having a chemical shift of 57.4 ppm for the carbon of the hydroxymethyl group at C-2 and 16.3 ppm for the C-3 methyl group, clearly indicating (vide supra) 13 to be the major stereoisomer. The minor isomer 14 showed a hydroxymethyl group at 64.5 ppm and a C-3 methyl group at 12.1 ppm. That the stereochemistry of the major product was identical to that of the left-hand portion 2 of X-14547A was confirmed by oxidation of 13 to 2 b with ruthenium tetroxide (Sharpless catalytic procedure (12)); treat- ment with ethereal diazomethane afforded the diester 2c. Both 2b and 3 c have recently been reported (8b) as degradation products of X-14547A; comparison of the proton nmr spectra of our synthetic samples with spectra for samples obtained by degradation confirmed the structural assignment.

The difference in the stereoselectivities observed in the hydroboration-oxidation of dienes 4alb and 9 can be rational- ized as arising from opposite chemoselectivity in the initial site of hydroboration, followed subsequently by either an endo- cyclic or exocyclic intramolecular hydroboration step in which

1 nonbonded interactions control the stereochemistry observed in i the oxidation products. In the case of 4alb it is well known that , electrophilic reagents (e.g. ozone (15) and N-bromosuccini-

mide (16)) preferentially added to the C-6 double bond of 1 geraniol; furthermore, recent studies by Nelson and Brown (17)

have shown that an electronegative allylic heteroatom (chlorine) reduces the relative rate of reactivity of the alkene towards hydroboration. This strongly suggests that the first hydrobora- tion of 4alb is at the C-6 double bond, giving 17, which undergoes an endocyclic hydroboration in a subsequent step that controls the stereochemical outcome. In the diene 9, however, both double bonds are trisubstituted and have an allylic heteroatom substituent; again, the results of Nelson and Brown on allylic halogen substituent effects indicate that the relative rate of addition of boron to an alkene is slower when the site of boron addition is y rather than P to the allylic heteroatom. This suggests that the initial site of hydroboration is reversed for diene 9; that is, intermediate 18 is formed followed by an exocyclic ring-forming reaction. This latter case was verified experimentally by reacting diene 9 with 9-BBN (9-borobicy-

clo13.3. I Inonane); the major hydroboration-oxidation product obtained was the alcohol 15 arising from hydroboration, P- elimination, then rehydroboration, prior to oxidation.

In summary, the cyclic hydroboration-oxidation of geraniol and certain of its derivatives has been shown to proceed to give moderately high levels of remote asymmetric induction in the formation of acyclic diols with the generation of up to four centres of relative asymmetry; the apparent importance of endocyclic versus exocyclic reaction pathways has been noted, as has the effect of electronegative allylic heteroatoms on relatives rates of alkene reactivity.

Experimental General

Unless otherwise stated, sodium sulfate was used as the drying agent for organic solutions; organic solutions were concentrated by rotary evaporation at water aspirator pressure and temperatures below 40°C. All aqueous-organic partitioning was followed by a wash of the separated aqueous layer with an additional portion of the same organic solvent. Dry organic solvents were prepared by distillation from the following desiccants: magnesium (methanol), calcium hydride (pyri- dine, tetrahydrofuran). Column chromatography was performed with Merck silica gel 60 (70-230 mesh), while high performance liquid chromatography was performed on Merck Lobar columns. Melting points were determined on a Fisher-Johns or a Thomas Hoover melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 528 instrument. Proton and carbon magnetic resonance spectra were recorded on Varian EM360, Bruker WH60, Bruker HX60, Bruker CXP200, or Bruker AM400 spectro- meters; chemical shifts are recorded in 6 values relative to tetramethyl- silane, while coupling constants are generally reported to values of k0.5 Hz. Mass spectra were recorded on an AEI MS12 at Trent University, Peterborough, Ontario, or on a V.G. 7070F at McMaster University, Hamilton, Ontario.

(2 RS ,3RS,6RS)-3,7-Dimethyloctane-I ,2,6-trio1 6 and its diastereo- mer 5

A solution of borane in tetrahydrofuran (1 M, 16 mL, 16 mmol) under a nitrogen atmosphere was cooled in a Dry Ice - isopropanol bath to -65"C, then geraniol tetrahydropyranyl ether (3 g, 12.6 mmol) was added neat by syringe. The resulting reaction mixture was allowed to warm to 0°C over 2 h, then aqueous sodium hydroxide (3 M, 16 mL), followed by 30% hydrogen peroxide (1 6 mL), was added. After stirring several hours the solution was extracted with methylene chloride (3 times) and the combined organic solutions were dried, filtered, then concentrated under reduced pressure. The residue obtained was dissolved in methanol (100 mL), a few crystals of p-toluenesulfonic acid were added, then the solution was stirred 24 h; addition of solid sodium carbonate, dilution with methylene chloride, filtration, and concentration under reduced pressure afforded an oil that was purified by kugelrohr distillation to give the triols 5 and 6 (bp 1 3O0C/0. 1 Torr; 1 Torr = 133.3Pa) (lit. bp (9) 142"CIO.l Ton) (1.73g, 9.2mmol,73%); 'H nmr (CDC13/D20): 3.8-3.3 (4H, m), 1.75-1.15 (6H, m), 0.91 (6H, d, J = 7 Hz); "C nmr (CDC13): 76.3, 76.1, 64.7, 35.3, 33.8, 30.3, 28.4, 18.8, 17.8, 15.5 (major isomer).

(2SR,3RS,6RS)-2 -Hydroxymethyl-3-methyl-6-methylethyltetrahydro- pyran 8a and acetate 8b, and their diastereomers 7a and 7b

The mixture of triols (1.73 g, 9.2 mmol) was dissolved in methylene chloride (20 mL) and pyridine (8 mL) in a round-bottomed flask protected by a calcium chloride guard tube, then cooled in an ice-salt bath. p-Toluenesulfonyl chloride (2.0 g, 10.5 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was then partitioned between methylene chloride and dilute hydrochloric acid, with the organic layer being separated, dried, filtered, then concentrated under reduced pressure followed by high

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806 CAN. 1. CHEM. VOL. 64, 1986

vacuum to give the monotosylate: IH nmr (CDCl,): 7.82 (2H, d, J = 9 Hz)7.36(2H,d,J=9Hz),4.16(1H,dofd,J=10.5and3Hz),3.98 ( lH,dofd , J = 10.5and7Hz), 3.63 ( lH, m),3.32(1H, m), 2.45 (3H, s), 1.9- 1.2 (8H, m including OH), 0.88 (6H, d, J = 7 Hz), 0.84 (3H, d, J = 7 Hz); ',c nmr (CDCI,): 145.0, 133.3, 130.0, 128.0,77.2,73.5, 72.8, 35.6, 33.8, 30.9, 28.4, 21.6, 18.8, 17.4, 15.4 (major isomer).

The tosylate was dissolved in methanol, then freshly prepared sodium methoxide in methanol was added dropwise until the reaction mixture was basic. After stirring for an additional 15 min, the solution was concentrated under reduced pressure. The crude epoxide was dissolved in glacial acetic acid (8 mL), then stirred 2 days at room temperature. The reaction mixture was partitioned between ether and aqueous sodium carbonate, and the organic layer was separated, dried, filtered, then concentrated under reduced pressure. Purification by kugelrohr distillation (100"C/0.07 Torr) afforded a mixture of alcohols 7a and 8a (0.767 g, 4.5 mmol, 49%); 'H nmr (CDCI,): 3.75-3.4 (3H, m), 3.03 (lH, m), 1.99 (IH, br s), 1.81-1.31 (6H, m), 0.95 (3H, d, J = 7 Hz), 0.89 (6H, d, J = 7.5 Hz); 13C nmr (CDCI,): 83.4, 80.7, 64.7, 33.2, 31.3, 28.9, 22.9, 18.5, 18.3, 12.2 (major isomer); 76.7, 74.6, 57.7, 32.4, 31.7, 27.7, 27.7, 18.7, 18.5, 16.2 (minor isomer).

Treatment with acetyl chloride in pyridine gave the acetate 86 (bp 125"C115 Torr); 'H nmr(CDCI3):4.12 ( lH, ABX, J = 12and 8.7Hz), 4.03(1H, ABX, J = 12and4.5Hz), 3 .68(1H,dofdofd , J = 8.7, 4.5, and 2 Hz, H-2), 3.06 ( lH, m, H-6), 2.12 (3H, s), 1.9-1.3 (6H, m), 1.0 (6H, d, J = 7 Hz), 0.95 (3H, d, J = 7 Hz); ms mle: 215 (M+ +1)(23%),214(Mf) (12%), 213 (Mf -1)(31%), 171 (73), 154(91), 141 (52), 123(67), 111 (72),93(60), 82(98),55(100). Signalsat2.12 (s) and 4.58 (d of d) in the proton nrnr spectrum were assigned to the acetate methyl group and one of the two diastereotopic hydrogens on the exocyclic methylene group, respectively, of the minor diastereomer 7b.

(2E,6E)-1 -Benzyloxy-8-methoxy-3,7-dimethylocta-2,6-diene 9 Following the procedure of Umbreit and Sharpless (1 l ) , a solution of

tert-butyl hydroperoxide (from 42 mL of 70% aqueous), salicylic acid (1.2 g, 8.7 mmol), and seleniumdioxide (0.22 g, 2 mmol) in methylene chloride (54 mL) was prepared. To this solution was added slowly 0-benzylgeraniol (18 g, 73.8 mmol), then the reaction mixture was stirred 2 days at room temperature after which time it was diluted with ether (200 mL), washed with aqueous sodium hydroxide (3 M, 30 mL, 3 times), dilute aqueous sodium bisulfite (twice), dried, filtered, then concentrated under reduced pressure. The crude product was dissolved in 95% ethanol (200 mL), then sodium borohydride (2 g) was added and the reaction mixture stirred overnight. After concentration under reduced pressure, the reaction mixture was partitioned between ether (350 mL) and water (100 mL). The ether layer was separated, dried, filtered, then concentrated under reduced pressure to give, after drying under high vacuum, an oil (16.3 g). The oil was dissolved in dry ether (l00mL) and then added to a stirred suspension of sodium hydride (7.5 g, 50% dispersion in oil, hexane washed, 156 mmol) in dry ether (150 mL):Methyl iodide (8 mL, 128 mmol) was added, then the reaction mixture was refluxed overnight under a calcium chloride guard tube. The organic solution was then washed with water, dried, filtered, and concentrated under reduced pressure. The crude product was purified by vacuum distillation to give the diether (bp 120-125"CIO.Ol Torr, 8.3 g, 30.3 mmol, 41%); ir (neat): 2910, 2840, 1490, 1450, 1370, 1190, 1090 cm-'; 'H nmr (CDC13): 7.35 (5H, m), 5.45 (2H, m), 4.5 (2H, s), 4.05 (2H, d, J = 6 Hz), 3.8 (2H, s), 3.3 (3H, s), 2.4-1.4 (lOH, m).

(2SR ,3SR ,6RS, 7SR)-1 -Benzyloxy-8-methoxy-S,7-dimethyloctane- 2,6-diol lOa and its diastereomer I l a

The diether 9 (1.8 g, 6.57 mmol) was dissolved in dry tetrahydro- furan (10 mL) under a nitrogen atmosphere, then cooled in an ice-salt bath to - 10 to - 15°C. A solution of thexylborane (13) (1 M, 10 mL) was then added dropwise via a double-tipped cannula; the resulting reaction mixture was stirred for 2 h at - 10°C. Aqueous NaOH (3 M, 20 mL) was added, followed by 50% aqueous hydrogen peroxide (10 mL); the resulting solution was stirred overnight, then partitioned between ether (100 mL) and water. The organic layer was separated, washed with aqueous sodium metabisulfite, dried, filtered, and concentrated

under reduced pressure. Thin-layer chromatography (silica, ether) showed two major components, Rf 0.4 and 0.3. Chromatographic purification (Lobar, ether) gave a mixture of diols IOU and l l a (0.63 g, 31%) as the higher Rfcomponent; ir (CHCI,): 3600-3200,2860,1450, 1200, 1100 cm-'; 'H nmr (CDCl,): 7.35 (5H, s), 4.58 (2H, s), 3.72-3.16 (9H, m including s at 3.36), 2.62 ( lH, br s), 1.95-1.14 (7H, m), 0.90 (6H, d, J = 7 Hz); I3c nmr (CDCI,): 138.31, 128.41, 127.67, 77.22, 76.39, 74.31, 73.49, 72.82, 58.95, 38.35, 36.35, 32.35, 28.31, 15.62, 14.04 (major diastereomer).

The lower Rf component was the diol 12 (0.58 g, 44%) as an equal mixture of a pair of diastereomers, as evidenced by proton decoupled 13c nmr; ir (CHCl,): 3610, 3600-3100, 2920, 1450, 1090 cm-'; 'H nmr (CDCl,): 3.75-2.85 (lOH, m, including s at 3.34 and br -OH), 1.88-2.05 (8H, m) 0.98-0.82 (6H, m); I3C nmr (CDC13): 77.51 77.45, 76.24175.7 1, 60.63160.58, 59.00, 39.99139.64, 38.25138.21, 32.54132.07, 32.03131.79, 29.78129.17, 19.88119.64, 13.93113.85 (carbon chemical shifts have not been unambiguously assigned for each of the diastereomers).

(2SR ,3SR ,6RS, 7SR)-8-Methoxy-3,7-dimethyloctane-l,2,6-triol lob and its diastereomer 11 b

The mixture of diols (0.490 g, 1.58 mmol) was dissolved in methanol (20 mL) containing glacial acetic acid (2 drops) and 5% palladium on charcoal (100 mg), then hydrogenolysed at atmospheric pressure until thin-layer chromatography (silica, ethyl acetate) showed no remaining starting material. The solution was then filtered through Celite, concentrated under reduced pressure, and dried under high vacuum to give the trio1 as a mixture of stereoisomers (0.338 g, 1.55 mmol, 98%); ir (CHCI,): 3600-3100, 3000, 2930, 1450, 1190, 1090 cm-'; 'H nmr (CDCl,): 3.82-3.30 (9H, m including s at 3.37), 3.3-1.9 (3H, br), 1.9-1.28 (6H, m), 0.9-0.8 (6H, pair ofoverlapping doublets); ms mle: 201 (Mf -H30) (7%), 187(17), 171(25), 139(48), 129(72), 103(95), 71(100). Exact Mass calcd. for C1 1H2404 - CH50: 187.1334; found: 187.1343.

(ZRS,SSR,6RS,l 'SR)-6-(2-Methoxy-1 -methylethyl)-2-hydroxymethyl- 3-methyltetrahydropyran 13 and its diastereomer 1 4

The mixture of triols (0.339 g, 1.55 mrnol) was dissolved in dry pyridine (10 mL) under a nitrogen atmosphere, then cooled in an ice-salt bath to - 10°C. p-Toluenesulfonyl chloride (0.325 g, 1.70 mmol) was added, then the reaction mixture was stirred 2 h at - 1O0C, followed by 2 h at room temperature. The solvent was then removed under high vacuum and the residue partitioned between methylene chloride (50 mL) and water (25 mL). The organic layer was separated, washed with dilute aqueous HCl, dried, filtered, and concentrated under reduced pressure to give the monotosylate; ir (CHCl,): 3600-3300, 2960, 1450, 1350, 1160, 1085, 890 cm-I; I H nmr (CDCI,): 7.82 (2H, d, J = 6 HZ), 7.36 (2H, d, J = 6 Hz), 4.17-3.92 (2H, m, AB portion of ABX), 3.70-3.30 (7H, m including s at 3.36), 2.46 (3H, s), 2.4-2.00 (2H, br s), 1.86- 1.20 (6H, m), 0.88 (3H, d, J = 7 Hz), 0.87 (2H, d, J = 7 Hz).

The tosylate was dissolved in dry methanol (25 mL), then freshly prepared sodium methoxide in methanol was added dropwise until thin-layer chromatography (silica, ether) showed complete consump- tion of the starting material. The reaction mixture was concentrated under reduced pressure, then partitioned between methylene chloride (50 mL) and water (25 mL). The organic layer was separated, dried, filtered, and concentrated under reduced pressure to give the epoxide, which was used without purification. The 'H nmr spectrum showed multiplets centred at 2.73 and 2.48 6 in a 2:l ratio, indicative of an epoxide structure.

The epoxide was dissolved in glacial acetic acid (4 mL), then stirred 3 days at room temperature, after which time the reaction mixture was partitioned between methylene chloride (50 mL) and aqueous NaOH (3 M, 25 mL). The organic layer was dried, filtered, then concentrated under reduced pressure to give the crude product. Purification by Lobar chromatography (ether-hexanes, 1 : 1 ; ether) gave a mixture of dia- stereomeric tetrahydropyrans with 13 as the major component and 14 as the minor component (0.13 g, 49%); ir (CHCI,): 3650-3 150,2900, 1450, 1220, 1085, 1065, 1050,900 cm-I; 'H nmr (CDCI,): 4.0-3.84 (2H, m), 3.72(1H, dd, J = 9and5 Hz), 3.51-3.26(5H, mincludings

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WHITNEY 807

at3.34),3.22(1H,dd,J=9,3Hz),3.15(1H,brOH),2.06-1.18(6H, m), 0.95 (3H, d, J = 7 Hz), 0.82 (3H, d, J = 7 Hz); doublets at 0.94 and 0.91 were attributed to the minor diastereomer; I3C nmr (CDC13): 76.67, 75.24, 70.24, 58.93, 57.37, 38.13, 31.83, 28.54, 27.88, 16.27, 14.22 (major diastereomer); 80.88, 79.88, 75.16, 64.46, 58.78, 38.89, 3 1.32, 28.88, 22.92, 13.19, 12.09 (minor diasterwmer); ms rnle: 203 (M' + 1) (13%), 184 (1 l ) , 171(57), 139(53), 129(55), 11 1(53), 99(71), 93(60), 81(86), 69(97), 55(100). Exact Mass calcd. for CllH2203 - CH20H: 171.1385; found: 171.1385.

Methyl (2RS,5SR,6RS, aRS)-6-Carboxy-a,5-dimethyltetrahydro- pyran-2-acetate 2b and dimethyl ester 2c

Following the procedure of Sharpless and co-workers (12), to a solution of the alcohols 13 and 14 (30 mg, 0.15 mmol) in carbon tetrachloride (2 mL) and acetonitrile (2 mL) were added water (3 mL), ruthenium trichloride trihydrate (10 mg), and sodium periodate (360 mg, 1.68 mmol). The resulting reaction mixture was stirred 18 h at room temperature, then partitioned between methylene chloride (25 mL) and water (10 mL). The aqueous layer was separated, dried, filtered, and concentrated under reduced pressure to give the half-ester 26 (20 mg, 58%) on purification by Lobar chromatography (ether): ir (CHC13): 3700-3000,2920, 1715 (br), 1450, 1430, 1310,1200,1170, 1080 cm-I; 'H nmr (CDC13): 8.25 ( lH, br s, C02H), 4.35 (lH, d, J = 5Hz,H-C6), 3.89 ( lH, ddd, J = l l ,9and2 .5 Hz, H-C2),3.75 (3H, s, methyl ester), 2.65 ( lH, d of q, J = 9 and 7 Hz, H-Ca), 2.18-0.9 (1 lH, m including doublets at 1.16 and 1.15 with J = 7 Hz); 13c nmr (CDCI,): 175.26, 172.16,76.28,75.07, 51.86,43.95, 32.35, 27.02, 26.20, 16.09, 13.27; ms rnle: 231 (M' + 1) (lo%), 212 (21), 199(21), 185(45), 170(36), 153(54), 143(49), 125(72), 1 15(68), 97(75), 88(67), 69(78), 55(100). Exact Mass calcd. for CllH1805 - C02H: 185.1176; found: 185.1169.

Treatment of the half-ester 2b with ethereal diazomethane afforded the diester 2c; ir (CHC13): 2940, 1725, 1450, 1435, 1170, 1085 cm-I; 'H nmr (CDC13): 4.33 ( lH, d, J = 5.6 Hz), 4.27 ( lH, ddd, J = 2.9, 8.5, 10.8 Hz), 3.71 (3H, s), 3.68 (3H, s), 2.57 ( lH, dq, J = 7.1, 8.2 Hz),2.2-1.2(5H,m),l.ll(3H,d,J=7Hz),0.92(3H,d,J=7Hz).

Reaction of 9 with 9-borabicyclo[3.3.1]nonane The diene 9 (0.36 g, 1.3 mmol) was dissolved in dry tetrahydrofuran

(2 mL) under a dry nitrogen atmosphere in a round-bottomed flask. The flask was placed in a room-temperature bath, then 9-BBN (0.5 M in tetrahydrofuran, 5 mL) was added to the flask by syringe. After stirring the reaction mixture overnight, aqueous sodium hydroxide (3 M, 5 mL) was added, followed by hydrogen peroxide (30%, 5 mL). The resulting mixture was stirred several hours, then partitioned between methylene chloride and water. The organic layer was separated, dried, filtered, then concentrated under reduced pressure to give an oil that was chromatographed (Lobar; ether-hexanes, 1: 1) to give recovered diene (0.19 g) and the alcohol 15 (0.054 g); ir (CHC13): 3610, 3600-3100, 2990,2910, 1445,1370, 1200, 1085 cm-'; 'H nmr (C~C1~) : 5.42 (lH, t, J=7Hz)3.81(2H,s),3.68(2H,m),3.28(3H,s),2.55-1.13(11H, m including s at 1.66), 0.92 (3H, d, J = 7 Hz); I3C nmr (CDC13): 131.83, 128.63, 78.75, 60.88, 57.29, 39.84, 36.83, 29.24, 25.13, 19.52, 13.75. The alcohol 16 was detected by proton nmr as a minor and unquantifiable component in another fraction (5 mg).

Acknowledgements Financial assistance of the Natural Sciences and Engineering

Research Council is gratefully acknowledged, as is the technical assistance of Ms. S . Blake of the Queen's University Magnetic Resonance Laboratory, Nuclear Division. The author is in- debted to Professor Steven V. Ley, Imperial College of Science and Technology, for providing copies of spectra for compounds 2b and 2c for the purpose of comparison.

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