absolute configuration and synthesis of 2-hydroxy-2-(1-hydroxyethyl)-3-methyl-γ-butyrolactone, a...

S. Schulz 829

Absolute Configuration and Synthesis of 2-Hydroxy-2-( l-hydroxyethyl)-3- methyl-y-butyrolactone, a Presumed Pheromone of Ithomiine Butterflies Stefan Schulz

Institut fur Organische Chemie, Universitat Hamburg, Martin-Luther-King-Platz 6, W-2000 Hamburg 13, Germany

Received April 7, 1992

Key Words: Pheromones / Ithomiinae / Ithomiolide / Keto lactone / Butterflies

2-Hydroxy-2-(l-hydroxyethyl)-3-methyl-~-butyrolactone (1) is a constituent of scent glands of male ithomiine butterflies. All diastereomers and the respective (3R)-enantiomers were syn- thesized by starting from rac- or (3S)-3-methyl-y-butyrolactone 3. Their relative configurations were determined by difference NOE-NMR spectroscopy or by X-ray diffraction analysis. The absolute configuration of the natural product was determined

by gas chromatography on a chiral stationary phase of the respective dioxolane derivatives. The natural lactone could be shown to be the (lfS,2S,3R)-enantiomer [(l’S,2S,3R)-l a, ithomiolide A]. In addition, the corresponding ketone, (2S,3R)-2-acetyl-2-hydroxy-3-methyl-y-butyrolactone [(2S,3R)-5a, ithomiolide B], could be identified as a new natural product from k i t - twitzia hymaenea.

Males of the large tropical ithomiine butterflies (Lepi- doptera: Nymphalidae) possess scent glands in the form of fringes of long erectile hairs on their hindwings. These glands play a role in the chemical communication systems of the butterflies. Whereas in the closely related danaine butterflies (Lepidoptera: Nymphalidae) the males use similar organs during courtship“], the exact function of the volatile con- stituents of the scent glands in the ithomiines is still unclear. While Haber described exposed fringes to be somehow at- tractive to both sexes of several species[’%21, Pliske found indications for inter- and intraspecies male repellency, and postulated that in some species components of the scent gland secretion would be used as male territorial markersL3].

Scheme 1

g2 4 1

0 1

J$ HO

2

a: (l’S,2S,3RS) b: (1’R,2S,3RS) c: (1 ‘S,2R,3 RS) d: (l’R,2R,3RS)

a: (-)-viridifloric acid (2S,3S) b: (+)-trachelantic acid (2S,3R) c: (-)-trachelantic acid (2R,3S) d: (+)-viridifloric acid (2R,3R)

Several volatile compounds from the ithomiine scent glands have been identified so From the scent glands of seven species, Edgar et al. identified 2-hydroxy-2-( 1 -hydroxyethyl)-3-methyl-y-butyrolactone (1); however, no in- formation on the stereochemistry of this chiral compound could be obtainedL4]. This unique lactone is structurally closely related to both (- )- and (+ )-viridifloric acids 2a and 2d, and (+)- and (-)-trachelantic acids 2b and 2c, which

represent necic acids of naturally occurring pyrrolizidine alkaloids. Larvae or adult ithomiines are attracted to these alkaloids and ingest them presumably for their own defence[@. Therefore, they are believed to be the biosynthetic precursor of lL4]. In such a case, each one of the necic acids 2 would lead to a different diastereomer of 1. The overall configuration of the resulting stereoisomer of 1 would be determined by the configurations of C-2 and C-3 in 2 and the stereochemical outcome of the oxidation, necessary for the lactone formation, of one of the methyl groups of the isopropyl group. Thus, viridifloric acids 2a and 2d would lead to (l’S,2S,3RS)-l a and (l’R,2R,3RS)-l d, respectively, while trachelantic acids 2b and 2c would lead to (l’R,2S,3RS)-l b and (l’S,2R,3RS)-lc.

To clarify the role of 1 in the communication systems of ithomiine butterflies it was instrumental to assign the absolute configuration of naturally occurring 1, and to syn- thesize pure reference compounds for behavioral bioassays.

To assign the relative configurations of 1 all four possible diastereomers were needed. For later elucidation of the absolute configuration, the synthesis of respective enantiomers was also necessary. Therefore, a synthesis furnishing all four diastereomeric racemates of 1 was designed which allowed the use of an easily accessible chiral building block for the principle preparation of pure enantiomers (see Scheme 2).

Citraconic acid anhydride was reduced to 3-methyl-2-buten-4-olide by using lithium tetrahydridoaluminate[’] and subsequently hydrogenated to yield (& )-3-methyl-y-butyrolactone (rac-3). An a-ethylidene group was introduced by condensing diethyl oxalate with the sodium salt of rac-3, followed by deprotonation of the resulting oxaloester and reaction with acetaldehyde[*]. Final rearrangement gave reasonable yields of a mixture of (E/Z)-( +)-2-ethylidene-3- methyl-y-butyrolactone (rac-4) in almost equal amounts, which proved to be unseparable on a preparative scale. The reaction furnished better yields than the direct condensation

Liebigs Ann. Chem. 1992, 829- 834 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1992 0170-2O41/92/0808 -0829 $ 3S0+ .25/0

830 S. Schulz

Scheme 2

3 4 5a 5b

OH OH OH g++& OH OH OH

l a l b IC Id

6a 6b 6c 6d

Reagents: (a) NaH,(CO,Et),,THF. - (b) NaOH,MeCHO,H,O. - (c) KHCO,. - (d) KMnO,, CuSO,,CH,CI,,H,O,MeCN. - (e) Reducing agents see text. - (f) TsOH,(MeO),CMe,

of 3 with acetaldehyde or the procedure of Murray et al. which uses the sodium salt of an a-formyl lactone in the condensation step['].

Direct catalytic osmium tetroxide oxidation"'] of rac-4 yielded equal amounts of all stereoisomers of the dihydroxy lactones rue-1 which could not be completely separated. Therefore, it seemed advantageous to oxidize 4 first to the keto lactones 5 which, after separation, were expected to yield the different dihydroxy lactones 1 upon reduction.

Oxidation of 4 with CuS04/KMn04/H20/CH2C12 in the presence of small amounts of tert-butyl alcohol as polar modifier produced a mixture of equal amounts of cis- and trans-2-acetyl-2-hydroxy-3-methyl-y-butyrolactone (rac-5a and rac-5b)["I. The use of acetonitrile instead of tert-butyl alcohol furnished higher yields and purities of the products.

The keto lactones 5a and 5 b could be separated by column chromatography. Reduction of racda with sodium cyanotrihydroborate yielded a 2 : 3 mixture of ruc-la and rac- 1 b, while rac-5 b was converted into a 1 : 10 mixture of rac- 1 c and ruc-1 d. These mixtures could only partly be separated by column chromatography. However, pure samples could be obtained by using HPLC. A comparison of the 'H- NMR spectra of la -d with the 'H-NMR data reported for natural lL4] proved l a to be the naturally occurring diastereomer. Mass spectra of l p and the respective cyclic sulfite derivative (prepared by reaction with SOCl2) were similar to those reported.

For the elucidation of the absolute configuration of 1, it was necessary to obtain enantiomers of 1 for GLC analyses.

Using commercially available (S)-3 instead of rue-3, we obtained the (3R)-enantiomers of 1 by the sequence described above. Spectroscopic data and enantiomeric purity of the resulting products 1 and 5 are given in Table 1.

Because of the difficulty to separate the obtained dihydroxy lactones 1 it was desirable to improve the diastereo- selectivity in the reduction of 5. Various reducing agents other than sodium cyanotrihydroborate were tried. The re- sults are listed in Table 2. While the use of bulky reducing agents like potassium selectride did not improve selectivity, the use of sodium triacetoxyhydroborate showed marked improvements. This reagent, developed for the diastereose- lective reduction of 1,3-ketol~['~], is fixed to the substrate prior to hydride transfer by replacement of one acetoxy group by the hydroxyl group of the ketol. Thus, the hydride transfer takes place via a five-membered ring transition state. In the case of 5b, in which the two alkyl substituents of the lactone show cis configuration, obviously a strong influence of the 3-methyl group on the stability of the diastereomeric transition states occurs, leading to I d only. The trans-configurated keto lactone 5a shows less diastereose- lectivity, presumably because the methyl group is now at the opposite side of the molecule. In both cases preferentially the syn-product is obtained, in contrast to the anti-products formed in the reduction of 1,3-ketol~['~].

Another approach to the enantioselective synthesis of 1 would be the direct bishydroxylation of 4 by use of the Sharpless osmium tetroxide oxidation in the presence of dihydroquinidine 4-~hlorobenzoate['~~. Because (S)-4 was available only as a E / Z mixture, mixtures of diastereomers could be expected. The stereoselectivity of the reaction, using stoichiometric amounts of reagents, was similar to the values reported in the original paper for other substrates, and theEefore no higher selectivity than with the other reagents was achieved (see Table 2).

On the basis of the spectroscopical data obtained so far it was impossible to assign the correct configuration for each of the dihydroxy lactones 1. Difference NOE-NMR spectra of 1 and 5 showed no signals useful for interpretation. There- fore, each dihydroxy lactone (3R)-1 was converted into the

H 2 0 Hs n A H6l

H 6 2

H 7 3

Figure 1 . SCHAKAL plot of the X-ray crystallographic analysis of (I'R,2S,3R)-lb. The full set of data will be published elsewhere['']

Liebigs Ann. Chem. 1992, 829 - 834

2-Hydroxy-2-( l-hydroxyethyl)-3-methyl-y-butyrolactone

[(~]2D3 + 9.8 f 0.4 + 30.0 f 0.3 + 29.8 f 0.8 + 18.2 f 0.3 - 38.5 f 5.0 c 0.62, CHzClz 2.08, CH2C12 0.47, CIl2Clz 1.15, CHzClz 0.24, CHzClz ee (%) 98.2 f 0.5 98.0 f 0.5 97.0 f 0.5 97.5 f 0.5 97.2 f 0.5

831

- 53.1 f 3.8 0.42, CHzClz

97.3 f 0.5

Table 1. NMR data, rotation values, and ee values of compounds 5 and 1 (ee values determined as dioxolanes 6)

(1’S,2S,3R)-la (l’R,2S,3R)-lb (1’S,2R,3R)-lc (l’R,2R,3R)-ld

corresponding spirodioxolane 6, expecting that the reduced flexibility and the increase of steric constraints would allow the observation of NOES. The dioxolane 6d showed a 2% NOE between 1’-H and the 3-CH3 methyl group, thus in- dicating that the two alkyl substituents of the ring are cis- configurated. A small 1% NOE between one 4-H proton and the C-2’ methyl group indicated the (R)-configuration at C-1’. This leads to the assignment of the (l’R,2R,3R)- configuration to Id, while its 1’-epimer l c must show the (l’S,2R,3R)-configuration. Thus, the keto lactone 5 b, from which both 1 c and 1 d are obtained upon reduction, exhibits the (2R,3R)-configuration.

Unfortunately, both dioxolanes 6a and 6b showed no NOE, presumably due to still inherent flexibility of the mol- ecules. To elucidate the absolute configurations, an X-ray structural analysis of l b was performed. This compound

formed crystals more suitable for analysis than 1 a. Figure 1 shows a SCHAKAL plot of lb[*]. The expected trans- configuration of the two alkyl substituents leads to the assignment of the (I’R,2S,3R)-configuration for 1 b. The related products l a and 5a exhibit (1’S,2S,3R)- and (2S,3R)-configurations, respectively.

After the establishment of the relative configuration of the natural product, the absolute configuration was determined by GLC by using chiral cyclodextrine phases[”]. An extract obtained from scent glands of male Prittwitzia hymaenea (Lepidoptera: Ithomiinae) which had been shown to contain 1 was treated with small amounts of dimethoxypropane and p-toluenesulfonic acid to convert the dihydroxy lactone

[*I Further details of the crystal structure will be published elsewhere[’‘].


S. Schulz 832

1 into the corresponding dioxolane 6 for better separation in GLC. A comparison of gas chromatographic retention times with those of synthetic samples of 6a-d proved this dihydroxy lactone to be 1 a, too.

The absolute configuration of natural l a was determined by GLC by using a chiral 3-0-acetyl-2,6-0-pentyl-y-cyclodextrine phase[’51. In contrast to the dihydroxy lactones 1, the dioxolane derivatives 6 could be very well-separated on this phase. The derivatized extract of P. hymaenea showed some interferring peaks eluting in the region of 6 a - d. Mon- itoring the characteristic ions m/z = 56 and m/z = 185 in a GC/MS investigation, we could identify the natural product as (l’S,2S,3R)-2-hydroxy-2-(1 -hydroxyethyl)-3-methyl-y- butyrolactone [(l’S,2S,3R)-la] (see Figure 2) for which the name ithomiolide A is proposed.

Another ithomiine butterfly, Callithomia hezia hezia, showed small amounts of the lactone 1 in a GC/MS investigation. It was not possible to clarify the stereochemistry.

TIC

m/z=l85

300 400

TIC

m/z=l85

300 400

Figure 2. GC/MS separation of enantiomers of 6a and 6b on a 30-m 3-0-acetyl-2,6-di-0-pentyl-y-cyclodextrine fused-silica column. Total ion current (TIC) and selected traces. A Synthetic mixture of enantiomers of 6a and 6b. B Natural extract of P. hymaenea

treated with dimethoxypropane

In addition to ithomiolide A, small amounts of the keto lactone 5 could be identified by GC/MS in extracts of P. hymaenea. Mass spectra of 1 and 5 are very similar except for the ion mlz = 45 in 1 which is shifted to mlz = 43 in 5. The keto lactone could be identified to be (2S,3R)-2-acetyl- 2-hydroxy-3-methyl-y-butyrolactone [(2S,3R)-5a] by using GLC on the chiral phase described above. This compound, ithomiolide B, represents a new natural product.

The structure proposed by Edgar et al.[41 was confirmed and the relative and absolute configuration of ithomiolide A is now established. In addition, the new natural product, ithomiolide B, could be identified. The structures of the ithomiolides are closely related to that of (-)-viridifloric acid 2a which represents the necic acid in lycopsamine, the major pyrrolizidine alkaloid of the food plants of some ithiomiine butterflies[@. It seems reasonable to assume that the biosynthetic route to both ithomiolides in the butterflies would include hydrolysis of a pyrrolizidine alkaloid and stereo- specific hydroxylation at the methyl of the isopropyl group which furnishes the (3R)-configuration. Final lactonization would yield ithomiolide A, followed by oxidation to ithomiolide B.

The biological role of both ithomiolides in the ecology of ithomiine butterflies is currently under investigation.

I thank Prof. W. Francke, Universitat Hamburg, for helpful dis- cussions and his critical review of the manuscript, Prof. W. A. Kiinig, Universitat Hamburg, for the supply of the cyclodextrine columns, Dr. V. Sinnwell, Universitat Hamburg, for his help in measuring NMR spectra, Prof. D. Schneider, Max-Planck-Institut fur Verhal- tensforschung Seewiesen, for collecting P. hymaenea, and Prof. M . BopprP, Universitat Freiburg, for collecting C. hezia hezia. Financial support by the Deutsche Forschungsgemeinschaft is gratefully ac- knowledged.

Experimental ‘H-NMR and 13C-NMR spectra were obtained with Bruker WM

400 and AC 250P instruments and TMS as internal standard. - Mass spectra (70 eV) were recorded with a VG 70/250 S mass spec- trometer coupled to a Hewlett-Packard H P 5890 A gas chromatograph. - Analytical GLC analyses were carried out with a Carlo- Erba Fractovap 2101 gas chromatograph with a flame-ionization detector and on-column injection. Separations were performed by using a 30-m Rt,-5 (id = 0.32 mm, df = 0.25 p) fused-silica column with hydrogen as the carrier gas. For enantiomer separations a 30- m 3-0-acetyl-2,6-di-O-pentyl-y-cyclodextrine fused-silica column (id = 0.25 mm) and a 25-m Lipodex E (3-0-butyryl-2,6-di-O-pentyl-y-cyclodextrine) fused-silica column (id = 0.25 mm)[15] were used with helium (1.0 bar) as the carrier gas. - Melting points (uncorrected) were measured with an Ernst Leitz instrument. - Column chromatography was performed on silica gel (70 - 230 mesh, Merck). - Optical rotations were measured with a Perkin- Elmer 243 polarimeter. - HPLC separations were performed with a Merck-Hitachi L-6200 Intelligent Pump equipped with a Li- Chrochart 125-4 HPLC cartridge filled with LiChrosorb CN (7 pm). A Rheodyne injector and a Merck-Hitachi L-4000 UV- detector operating at 232 nm were used. - FTIR spectra were recorded by using a Hewlett Packard GC-FTIR combination con- sisting of a HP 5890 Series I1 gas chromatograph equipped with a 20-m HP-1 (id = 0.32 mm, df = 0.25 pm) fused-silica column with helium as the carrier gas and a H P 5965 A infrared detector. -


2-Hydroxy-2-(l-hydroxyethyl)-3-methyl-y-butyrolactone 833

Males of P. hymaenea (10 individuals) were caught in 1984 and 1985 in Argentine, and males of C . hezia hezia (6 individuals) were caught in 1989 in Costa Rica. Scent glands were dissected directly into pentane (Merck, Uvasol). The samples were stored at -70°C until workup. Scent glands were mazerated, and the mixture was filtrated through a cotton plug. The extracts were concentrated to an appropriate volume for use in GLC analyses.

(f)-3-Methyl-y-butyrolactone (3): To a solution of 1.6 g (16.7 mmol) of 3-methyl-2-buten-4-olide''' in 80 ml of ethanol 20 mg of 10% palladium/charcoal was added and the mixture hydrogenated until take up of one equivalent hydrogen. After filtration the solvent was removed in vacuo and the residue distilled under reduced pressure. Yield: 1.34 g (13.4 mmol, 80%) of a colourless oil, b.p. 84-86"C/18 Torr. - 'H NMR (250 MHz, CDCI,): 6 = 1.16 (d, 3H, CH3), 2.14 (m, l H , 2-H), 2.65 (m, 2H, 2-H and 3-H), 3.88 (q, 1 H, 4-H), 4.42 (q, 1 H, 4'-H). - I3C NMR (62.5 MHz, CDC13): 6 =

MS (70 eV): m/z (%) = 100 (18) [M'], 70 (2), 56 (49, 42 (loo), 41 17.90 (CH3), 30.36 (C-3), 36.20 (C-2), 74.69 (C-4), 177.30 (C-I). -

(77).

(3S)-2-Ethylidene-3-methyl-y-butyrolactone [(3S)-4]: According to a modified procedure by Ksander et al.[*], 0.9 g (30 mmol) of an 80% suspension of NaH in mineral oil (washed three times with hexane prior to use) was added to 150 ml of absolute diethyl ether in a three-necked vessel equipped with a mechanical stirrer. A mixture of 3 g (30 mmol) of (9-3 (Fluka) and 4.38 g(30 mmol) of diethyl oxalate was slowly added to the suspension under nitrogen. After the mixture was stirred for about 12 h, a thick yellowish mass was obtained. The solvent was removed under reduced pressure, then 90 ml of ethanol, 45 ml of water, and 1.2 g (30 mmol) of NaOH were added. Subsequently, 13.2 g (300 mmol) of freshly distilled acetaldehyde was added and the mixture stirred for 6 h. After the addition of 27 g (270 mmol) of KHCO,, the mixture was stirred for a further 30 rnin and then extracted four times with CH2C12. The combined organic phases were dried with MgS04, the solution was concentrated to ca. 20 ml, and the resulting solution filtered over a short pad of silica. Removal of the solvent from the filtrate furnished (E,3S)- and (Z,3S)-4 as a pale yellow oil sufficiently pure to be used for the next steps; yield 2.73 g (72%).

(E,3S)-4 'H NMR (250 MHz, CDCI,): 6 = 1.25 (d, J3,CH3 =

H), 3.21 (mc, J3A = 7.6 Hz, J3,4 = 2.8 Hz, J3,1, = 2.2 Hz, l H , 3-H), 7.2 Hz, 3H, 3-CH3), 1.91 (dd, J1:y = 7.2 Hz, J3,y = 1.4 Hz, 3H, 2'-

3.97 (dd, J4.4 = 9.0 Hz, l H , 4-H), 4.40 (dd, 1 H, 4-H), 6.80 (qd, 1 H, 1'-H). - 13C NMR (62.5 MHz, CDCI,): 6 = 14.84 (3-CH3), 19.30 (C-2'), 31.58 (C-3), 72.70 (C-4), 131.97 (C-2), 135.97 (C-l'), 171.08 (C-I). - MS (70 eV): m/z (%) = 126 (95) [M+], 111 (12), 97 (55), 96 (17), 83 (8), 81 (6), 79 (9, 69 (25), 68 (loo), 67 (91), 65 (6), 55 (8), 53 (38), 41 (54), 39 (49). - ee = 99 0.5% determined by GLC on the Lipodex E column at 120°C. Retention times: 17.9 rnin [(E,3R)-4], 19.5 min [(E,3S)-4].

(Z,3S)-4 'H NMR (250 MHz, CDC13): 6 = 1.21 (d, J3,CH, =

H), 3.08 (mc, J3,4 = 7.6 Hz, 4 4 = 6.8 Hz, J3,1, = 2.2 Hz, IH, 3-H),

1'-H). - I3C NMR (62.5 MHz, CDCl3): 6 = 13.69 (3-CH4, 18.17

((2-1). - MS (70 eV): m/z (%) = 126 (100) [M'], 111 (78), 97 (6),

6.6 Hz, 3H, 3-CH3), 2.19 (dd, J1,,2 = 7.0 Hz, 53,y = 1.2 Hz, 3H, 2'-

3.79 (dd, J4,4 = 8.6 Hz, IH, 4-H), 4.42 (dd, IH, 4-H), 6.24 (qd, IH,

(C-2'), 34.92 (C-3), 72.05 (C-4), 130.33 (C-2), 137.73 (C-l'), 170.37

(2S,3R)- and (2R,3R)-2-Acetyl-2-hydroxy-3-methyl-y-butyrolactone [(2S,3R)-Sa and (2R,3R)-Sb]: According to a modified procedure by Baskaran et al.["], 4 g of KMn04 and 2 g of CuS04. 5 H 2 0 were ground to a fine powder. Water (0.3 ml) was added and the mixture suspended in 20 ml of CH2Cl2. After the addition of 570 mg of (3S)-4 (4 mmol) 1 ml of acetonitrile was added and the mixture, which warmed slightly during the reaction, vigorously stirred for 3 h. After filtration over Celite the residue was thoroughly washed with dichloromethane. The solvent was removed and the resulting crude oil (530 mg) separated by column chromatography (CHC13/ ethanol, 50: 1, saturated with water) yielding 190 mg (30%, colourless oil) of (2S,3R)-5a and 180 mg (28%, colourless oil, solidifying upon cooling) of (2R,3R)-Sb.

For 'H- and ',C-NMR data, optical rotation and ee values see Table 1.

(2S,3R)-Sa: IR: T = 3557 cm-' (OH), 3487 (OH), 1804 (C=O), 1732 (C=O), 1185, 1149. - MS (70 eV): m/z (%) = 116 (65) [M+ - CH2=C0], 101 (22), 71 (18), 70 (28), 55 (36), 43 (100). - Using the Lipodex E column at 150"C, we determined the ee by GLC. Retention times: 30.9 rnin [(2S,3R)-Sa], 35.3 rnin [(2R,3S)-5a].

C7HI0O4 (158.2) Calcd. C 53.16 H 6.37 Found C 52.98 H 6.55

(2R,3R)-5b M.p. 52-53°C. - I R 3 = 3567 ~ m - ' (OH), 1802 (C=O), 1728 (C=O), 1216, 1146. - MS (70 eV): m/z (%) = 116 (56) [M' - CH2=C0], 103 (15), 71 (18), 70 (24), 55 (31), 43 (100). - Using the Lipodex E column at 150"C, we determined the ee by GLC. Retention times: 22.5 rnin [(2R,3R)-5 b], 23.6 rnin [(2S,3S)- 5 b].


(3 R) -2- H ydroxy-2- (i'-hydroxyethyl)-3-methyl- y-butyrolactones (3R)-la-d by Sodium Cyanotrihydroborate Reduction of Keto Lac- tones 5: According to the procedure of Borch et al.[l7], 47 mg (0.3 mmol) of keto lactone 5a or 5b and a trace of methyl orange was dissolved in 3 ml of methanol. Then 20 mg (0.3 mmol) of sodium cyanotrihydroborate was added to the solution. Roughly 0.5 ml of methanolic 2 N HCl (prepared from methanol and conc. aqueous HCl) was added dropwise to the stirred solution at a rate sufficient to keep the solution just red. When the red colour persisted, the mixture was stirred for an additional hour. The solution was acid- ified to pH 2 and the solvent removed under reduced pressure. The remainder was concentrated twice with methanol. The residue was dissolved in satd. brine and CH2C12 and the solution neutralized with triethylamine. The aqueous phase was extracted five times with CH2C12, and the combined organic phases were dried with MgS04. After evaporation of the solvent, 47 mg of a colourless oil was obtained. The resulting mixture of two diastereomeric diols could partly be separated by flash chromatography (hexane/ethyl acetate, 1 : 1, saturated with conc. aqueous ammonia) to yield 38 mg (80%). Pure compounds were obtained by HPLC (eluents: CH2CI2/hexane/ methanol, 28: 70: 2). - For 'H- and ',C-NMR data, optical rotation and ee values see Table 1.

(l'S,2S,3R)-la: M.p. 90-91°C. - MS (70 eV): m/z (%) = 116 (100) [M+ - CH2=CHOH], 101 (36), 71 (18), 70 (42), 56 (12), 55 (34), 45 (25), 43 (21), 42 (18), 41 (16).

93 (8), 83 (24), 81 (14), 80 (4), 79 55 (11), 53 (32), 41 (48), 39 (42). GLC on the Lipodex E column [(Z,3R)-4], 7.9 rnin [(Z,3S)-4].

(13), 69 (8), 68 (34), 67 (82), 65 (12), - ee = 99 f 0.5% determined by at 120°C. Retention times: 7.2 min


(l'R,2S,3R)-l b: M.p. 54-55°C (CH2Cl&exane, 4: 1). - MS similar to l a .

C7H1002 (126.2) Calcd. C 66.65 H 7.95 C7H12O4 (160.2) Calcd. C 52.49 H 7.55 Found C 66.23 H 8.09 Found C 52.32 H 7.62

Liebigs Ann. Chem. 1992, 829-834

834 S. Schulz

(I’S,2R,3R)-lc: Colourless oil. MS similar to l a . C7H1204 (160.2) Calcd. C 52.49 H 7.55

Found C 52.27 H 7.57

(I’R,2R,3R)-ld: Colourless oil. MS similar to l a . C7HI2O4 (160.2) Calcd. C 52.49 H 7.55

Found C 52.31 H 7.69

(3R) -2-Hydroxy-2- (1’-hydroxyethyl) -3-methyl-y-butyrolactones (3R)-1 a-d by Sodium Triacetoxyhydroborate Reduction of Keto Lactones 5: Each keto lactone 5 (20 mg) was converted to the respective compounds 1 according to the procedure of Romeyke et al.[’61; yield 70%.

(3R)-2-Hydroxy-2- (I‘-hydroxyethyl)-3-methyl-y-butyrolactones (3R)-la-d by Oxidation of 4 with Osmium Tetroxide: To a stirred solution of 0.465 g (1 mmol) of dihydroquinidine 4-chlorobenzoate (Aldrich) and 195 mg (60%, 1 mmol) of N-methylmorpholine N- oxide in 10 ml of acetone/water (10: 1) at 0°C was added 126 mg of (3S)-4L’31. After 1 h 50 ml of CH2C12 was added and the mixture washed three times with 1 N HCI saturated with brine. The solvent was removed after drying with K2C03, and the products were sub- jected to flash chromatography to yield 65 mg (40%) of a mixture of the diols 1.

2,2,9-Trimethyl-1,3,7-trioxaspiro[4.4]nonan-6-one (6): Roughly 10 mg of the respective lactone 1 was dissolved in 0.5 ml of freshly distilled 2,2-dimethoxypropane and a trace of p-toluenesulfonic acid was added to the solution. After stirring for 4 h the mixture was diluted with diethyl ether, washed with a saturated NaHC03 solution, and dried with MgS04. After filtration, the solvent was removed under reduced pressure leaving pure 6 as a colourless oil in quantitative yield.

6a: ‘H NMR (400 MHz, CDCI3): 6 = 1.14 (d, J3,CH) = 7.0 Hz, 3H, 3-CH3), 1.40 (d, 51,,2 = 6.2 Hz, 3H, 2’-H), 1.41 (s, 3H, CH,-C-CH3), 1.56 ( s , 3H, CHj-C-CH3), 2.32 (qdd, J3,4 = 7.6 Hz, 53,4 = 7.4 Hz, IH, 3-H), 3.93 (dd, 54.4 = 9.0 Hz, IH, 4-H), 4.20 (q, l H , 1’-H), 4.31 (dd, l H , 4-H). - 13C NMR (62.5 MHz, CDC13): 6 = 11.22 (3-CH3), 14.35 (C-2’), 26.38 (CH3-C-CH3), 27.18 (CH3-C-CH3), 35.82 (C-3), 71.22 (C-4), 75.86 (C-l’), 84.01 (C-2), 110.86 (CH3-C-CH3), 173.81 (C-1). - MS (70 eV): m/z (%) = 200 (1) [M’], 185 (88), 156 (lo), 143 (15), 142 (ll), 125 (6), 116 (S), 101 (9), 99 (25), 84 (28). 81 (23), 70 (48), 59 (39), 56 (loo), 55 (14), 45 (6), 43 (98): 41 (33).

Cl0Hl6O4 Calcd. 200.2355 Found 200.2403 (MS)

6 b ‘H NMR (400 MHz, CDCl3): 6 = 1.11 (d, J3,CH1 = 6.4 Hz, 3H, 3-CH3), 1.33 (d, J1,,2, = 6.4 Hz, 3H, 2’-H), 1.49 (s , 6H, CH3-C-CH3), 2.39 (qdd, J3,4 = 7.6 Hz, J3.4 = 8.6 Hz, 1 H, 3-H), 3.89 (dd, J4,4 = 8.6 Hz, l H , 4-H), 4.33 (dd, l H , 4-H), 4.66 (q, 1 H, 1’-H). - 13C NMR (100 MHz, CDCI3): S = 10.63 (3-CH4, 14.80 (C-2’), 25.30 (CH3-C-CH3), 26.54 (CH3-C-CHJ, 35.03 (C-3), 71.70 (C-4), 74.83 (C-l’), 82.24 (C-2), 109.85 (CH3-C-CH3), 175.89 (C-I). - MS similar to 6a.

Cl0HI6O4 Calcd. 200.2355 Found 200.2414 (MS)

6 ~ : ‘H NMR (400 MHz, CDCI,): 6 = 1.10 (d, J3,CH3 = 7.0 Hz, 3H, 3-CH3), 1.33 (d, Ji,,2 = 6.2 Hz, 3H, 2’-H), 1.45 (s, 3H, CH3-C-CH3), 1.50 (s, 3H, CH3-C-CH3), 2.61 (qdd, J3,4 = 6.8 Hz, J3,4 = 6.6 Hz,’lH, 3-H), 3.92 (dd, J4,4 = 8.6 Hz, IH, 4-H), 4.47 (dd, 1 H, 4-H), 4.49 (q, 1 H, 1’-H). - MS similar to 6a.

C10H1604 Calcd. 200.2355 Found 200.2398 (MS)

6 d ‘H NMR (400 MHz, CDC13): 6 = 1.14 (d, J3,CH3 = 7.0 Hz, 3H, 3-CH3), 1.35 (d, J1.,2. = 6.2 Hz, 3H, 2’-H), 1.43 (s , 3H, CH3-C-CH3), 1.65 (s, 3H, CH3-C-CH3), 2.84 (qdd, J3,4 = 10.4 Hz, J3 ,4 = 8.4 Hz, 1 H, 3-H), 3.72 (dd, J4,4 = 9.0 Hz, 1 H, 4-H), 4.34 (q, IH, 1’-H), 4.34 (dd, I H , 4-H). - 13C NMR (62.5 MHz, CDCI,): 6 = 10.64 (3-CH3), 15.16 (C-2’), 26.66 (CH3-C-CH3), 27.26 (CH3-C-CH3), 36.55 (C-3), 70.39 (C-4), 72.40 (C-l’), 85.09 (C-2), 109.82 (CH2-C-CH,), 174.89 (C-1). - MS similar to 6a.

C10H& Calcd. 200.2355 Found 200.2401 (MS)

[‘I M. Boppre in The Biology of Butterflies (Eds.: R. I. Vane-Wright, P. R. Ackery), Academic Press, London, 1984, p. 259-275.

121 W. A. Haber, Ph. D. Thesis, University of Minnesota, 1978. 13] T. E. Pliske, Ann. Entomol. SOC. Am. 1975, 68, 935-942. 14] J. A. Edgar, C. C. J. Culvenor, T. E. Pliske, J. Chem. Ecol. 1976,

Is] S. Schulz, W. Francke, J. Edgar, D. Schneider, Z. Naturforsch., Teil C 1988, 43, 99- 104. - S. Schulz, Dissertation, Universitat Hamburg, 1987.

16] K. S. Brown jr., Rev. Brasil. Bio. 1984, 44, 435-460. - K. S. Brown jr., Ann. Mass. Bot. Gard. 1985, 74, 359-391. - J. R. Trino. L. Witte. K. S. Brown ir.. T. Hartmann. L. E. S. Barata.

2, 263 - 270.

> I

J. Ehhem. Ecol., ’submitted. [71 M. M. Kavser. P. Morand. Can. J. Chem. 1980.58.2484-2490.

G. M. Kiander, J. E. McMurry, M. Johnson, J. Org. Chem.

19] A. W. Murray, R. G. Reid, J. Chem. SOC., Chem. Commun. 1984, 132-133. - A. W. Murray, R. G. Reid, Synthesis 1985,35-38.

I1O1 K. Akashi, R. E. Palermo, K. B. Sharpless, J. Org. Chem. 1978,

[‘‘l S. Baskaran, J. Das, S. Chandrasekaran, J. Org. Chem. 1989,54,

[‘*I D. A. Evans, K. T. Chapman, Tetrahedron Lett. 1986, 27, 5939-5942. - D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. SOC. 1988, fi0, 3560-3578.

[I3] J. S. M. Wai, I. Mark6, J. S. Svendsen, M. G. Finn, E. N. Jacobsen, K. B. Sharpless, J. Ant Chem. SOC. 1989, llf, 1123- 1125.

[I4] J. Kopf, S. Schulz, paper in preparation. W. A. Konig, R. Krebber, P. Mischnick, J. High Res. Chrom.

Y. Romeyke, M. Keller, H. Kluge, S. Grabley, P. Hammann, Tetrahedron 1991, 47, 3335 - 3346.

[”I R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc.

1977, 42, 1180-1185.

43, 2063 - 2066.

5182- 5184.

1978, 12, 732-138.

1971, 93, 2897 - 2904. B. Ganem, J. Org. Chem. 1975, 40, 146-147.

c73/921

CAS Registry Numbers

(I’S,2S,3R)-la: 141979-35-3 / (I’R,2S,3R)-l b: 141979-36-4: / (I’S,2R,3R)-lc: 141979-37-5 / (l’R,2R,3R)-ld: 141979-38-6 / (+)-3: 70470-05-2 /’ ( 9 3 : 64190-48-3 / (E,3S)-4: 141979-32-0 (Z,3$)-4: 141979-33-1 / (2S,3R)-5a: 141902-99-0 / (2R,3R)-5b: 141979-34-2 / 6a: 141903-00-6 / 6b: 141979-39-7 / 6c: 141979-40-0 / 6d: 141979- 41-1 / 3-methyl-2-buten-4-olide: 6124-79-4 / acetaldehyde: 75-07-0


absolute configuration and synthesis of 2-hydroxy-2-(1-hydroxyethyl)-3-methyl-γ-butyrolactone, a...

Documents