Selective catalytic hydrogenations and hydrogenolyses VIII [1]: Stereoselective synthesis of the stereomeric pilopyl alcohols

Article abstract of DOI:10.1007/s00706-002-0484-9

The stereoselective synthesis of pilopyl- and isopilopyl alcohol is reported. The reaction of dimethyldioxanone and diethoxyphosphoryl-butyric acid ethyl ester afforded the corresponding dioxanylidenbutyric acid ester as the key intermediate. Upon treatme

Full text of DOI:10.1007/s00706-002-0484-9

Monatshefte fur Chemie 133, 1285±1290 ꢀ2002)
DOI 10.1007/s00706-002-0484-9
Selective Catalytic Hydrogenations
and Hydrogenolyses VIII [1]:
Stereoselective Synthesis of the
Stereomeric Pilopyl Alcohols
Ã
Eberhard Reimann , Manfred Renz [2], and Helene Unger

Department Pharmazie ± Zentrum fur Pharmaforschung,


Ludwig-Maximilians-Universitat Munchen, D-81377 Munchen, Germany

Received April 3, 2002; accepted April 9, 2002
Published online July 15, 2002 # Springer-Verlag 2002
Summary. The stereoselective synthesis of pilopyl- and isopilopyl alcohol is reported. The reaction
of dimethyldioxanone and diethoxyphosphoryl-butyric acid ethyl ester afforded the corresponding di-
oxanylidenbutyric acid ester as the key intermediate. Upon treatment with mineral acid it cyclized giving
3-ethyl-4-hydroxymethylfuran-2-one which in turn could be converted either to 3-ethyl-4-methyl-
furanone or pilopyl alcohol with excellent stereoselectivity and quantitative chemical yield. On the other
hand, hydrogenation and subsequent cyclization of the same key compound furnished isopilopyl
alcohol with good stereomeric purity and yield.
Keywords. Horner-Wadsworth-Emmons carbonyl ole®nation; Selective catalytic hydrogenation;
Pilopyl and isopilopyl alcohol.
Introduction
A considerable number of natural products such as pheromones, sesquiterpenes,
cardiac glycosides, tetronic acids, or pilocarpine exhibiting important biological
activities were found to contain the butyrolactone moiety. Their activities fre-
quently depends on the con®guration of this subunit. Thus, in connection with
researches concerning structure=activity relationships, extensive work has been
devoted to the stereoselective synthesis of differently substituted butyrolactones.
Unexpectedly, a corresponding approach to pilopyl alcohol ꢀ6a) and isopilopyl
alcohol ꢀ8a) has not been reported hitherto [3]. As part of our current interest in the
synthesis of protoberberines, we required 6a and 8a as starting materials. Herein
we present an ef®cient approach to the title compounds.
Ã
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de

1286E. Reimann et al.
Results and Discussion
The ®rst preparation of pilopyl derivatives was based on a malonic acid ester
synthesis with ꢀ-bromobutyric acid, affording a mixture of the stereomeric pilopic
acid esters as the key compounds ꢀScheme 2, 6a, 8a: CO2R instead of CH2OR),
which in turn were separated by fractionation and freezing procedures and ®nally
converted to the corresponding pilopyl alcohols [4±6]. However, the use of this
route ± being the only one to our knowledge ± was little attractive especially because
of the troublesome separation procedures of the stereomeric acids. This prompted
us to develop a more direct and high-yield strategy depicted in Schemes 1 and 2.
The key step involved a Horner-Wadsworth-Emmons ole®nation of the easy
available dioxanone 1 [7] with the phosphonate 2 [8], providing the dioxanylidene
derivative 3 in good yield which in turn represented the perfect starting material to
Scheme 1
Scheme 2

Synthesis of Pilopyl Alcohols
1287
form our target compounds 6a and 8a. Thus, treatment of 3 with dilute mineral acid
resulted in cyclization to furnish the unsaturated furanone 4 in quantitative yield.
The result of subsequent catalytical hydrogenation depended on the catalyst used.
Employing palladium±charcoal, the hydroxy function was smoothly and selectively
hydrogenolized, giving the known ethylmethylfuranone 5 [9]. In contrast, the cyclic
double bond was hydrogenated by Adams catalyst affording the cis-con®gured pilo-
pyl alcohol 6a in excellent stereoselectivity. Carrying out the hydrogenation under
elevated pressure and ambient temperature proved to be the most suitable conditions
and afforded a cis=trans stereomer ratio of ꢀ 99:1. Normal pressure was found both
to decrease the stereomer ratio to about 88:12 and to extend the reaction time.
Using the same reactions, but in an inverted order, the isopilopyl alcohol 8a
could be also prepared in two steps starting from the dioxanylidene derivative.
Thus, 3 ®rst was hydrogenated affording the saturated compound 7 in quantitative
yield. Then, consecutive treatment with dilute acid caused cyclization, providing
mainly the trans-con®gured isopilopyl alcohol 8a. The ratio of trans=cis stereo-
mers was 92:8.
Both the con®gurations and the cis=trans stereomeric ratios of 6a and 8a could be unequivocally
assigned by 13C NMR spectroscopy. Because of the more extended mutual sterical hindrance of C-10
and C-100 in the cis-stereomer, their signals should occur at higher ®elds compared to those of the trans-
compound. The ꢁ-values found ꢀ59.87=18.17 vs. 6 2.32=22.63 ppm) con®rmed this presumption and
were in line with those observed in related furanones [10±12].
Separation of the stereomers to upgrade the stereomeric ratio of 8a was desir-
able but failed. Using a mixture of the 3,5-dinitrobenzoates 6b and 8b and multiple
development, however, separation could be achieved by TLC. Thus, the small
portions of the opposite stereomers occuring in 6a and 8a were detectable.
In conclusion, we have established an ef®cient stereoselective route to the title
compounds. In comparison with the ®rst synthesis mentioned above [4±6], the
overall yield could be increased from ca. 18% to 67 and 76% of the trans- and
cis-product. Furthermore, our method should give an easy access to functional
derivatives of 6a and 8a, which should be valuable as starting materials in natural
product synthesis.
Experimental
Melting points were measured with a Reichert hot-stage microscope and are uncorrected. IR: Perkin
Elmer FT-IR Paragon 1000; NMR: Jeol GSX 400 ꢀ1H: 400 MHz, 13C: 100MHz, CDCl3, TMS as
internal reference); MS ꢀ70 eV): Hewlett Packard MS-Engine. Elemental analyses: Heraeus CHN-
Rapid; the results were in good agreement with the calculated values. Thin layer chromatography
ꢀTLC): aluminum sheets Kieselgel 60 F254 ꢀMerck), thickness of layer 0.2 mm. Flash chromatography
ꢀFC): ICN-Silica 32±3660 A. 2,2-Dimethyl-[1,3]-dioxan-5-one ꢀ 1) and 2-ꢀdiethoxyphosphoryl)-butyric
acid ethyl ester ꢀ2) were prepared according to Refs. [7] and [8].
2-ꢀ2,2-Dimethyl-[1,3]dioxan-5-ylidene)-butyric acid ethyl ester ꢀ3; C12H20O4)
To a suspension of 3.1 g NaH ꢀ60% in paraf®n; 77mmol) in 150cm3 anhydrous THF, 29.0g
ꢀ115 mmol) 2 [8] were added dropwise under N2 and stirring at ambient temperature. Stirring was
continued until dissolution of NaH was completed. After heating to re¯ux temperature, 10.0g

1288
E. Reimann et al.
ꢀ77 mmol) 1 [7] were added dropwise. The mixture was re¯uxed for 1 h under N2, poured into
1000 cm3 H2O, and extracted with diethyl ether ꢀ3Â 250 cm3). The combined ether extracts were dried
over Na2SO4 and concentrated in vacuo. The residue ®rst was destillated in vacuo ꢀb.r.: 97±114ꢁC=
20Pa) and then puri®ed by FC ꢀn-hexane:EtOAc ˆ 17:3).
Yield: 13.3g ꢀ76%); colourless oil; TLC ꢀeluent: see FC): Rf ˆ 0.50; IR ꢀ®lm): ꢂ~ ˆ 1709 ꢀCˆO),
1642 ꢀCˆC) cmÀ 1; MS ꢀEI): m=z ꢀ%) ˆ 228 ꢀM‡ ꢂ, 10), 178 ꢀ55), 149 ꢀ65), 145 ꢀ69), 127 ꢀ100), 97
ꢀ81); 1H NMR ꢀCDCl3; for numbering of atoms: see formula 3=Scheme 1): ꢁ ˆ 4.60, 4.30 ꢀeach s, 40-H
and 60-H), 4.12, 2.14 ꢀeach q, J ˆ 6.8=7.3 and 7.7=7.3 Hz, 100-H and 3-H), 1.31 ꢀs, 2 CH3), 1.22, 0.92
ꢀeach t, each J ˆ 7.3 Hz, 200-H and 4-H) ppm; 13C NMR ꢀCDCl3): 166.83 ꢀC-1), 149.20 ꢀC-2), 125.92
ꢀC-50), 99.75 ꢀC-20), 62.04 ꢀC-100), 60.34 ꢀC-60), 59.97 ꢀC-40), 23.73 ꢀC[CH3]2), 21.13 ꢀC-3), 14.25
ꢀC-200), 13.41 ꢀC-4) ppm.
3-Ethyl-4-hydroxymethyl-5H-furan-2-one ꢀ4; C7H10O3)
A solution of 3.0 g ꢀ13.2mmol) 3 in 30 cm3 EtOH was slightly acidi®ed with 2 N HCl ꢀca. 3 drops)
and stirred at ambient temperature until the reaction was completed ꢀ18±20h; TLC monitoring).
After diluting with 50cm3 H2O and saturating with NaCl, the mixture was extracted with CHCl3
ꢀ4Â 100 cm3). The combined organic extracts were dried over Na2SO4 and evaporated in vacuo.
Yield: 1.8 g ꢀ100%); colourless oil which crystallized on cooling in the refrigator ꢀ18±20h); m.p.:
49ꢁC; TLC ꢀEtOAc:CHCl3 ˆ 1:1): Rf ˆ 0.4 ꢀeduct: Rf ˆ 0.9); IR ꢀFilm): ꢂ~ ˆ 3438 ꢀbr, OH), 1731
ꢀCˆO), 1671 ꢀCˆC) cmÀ 1; MS ꢀEI): m=z ꢀ%) ˆ 142 ꢀM‡ ꢂ, 5), 125 ꢀ98), 124 ꢀ100), 97 ꢀ63);
1H NMR ꢀCDCl3): ꢁ ˆ 4.79 ꢀs, CH2OCO), 4.56ꢀs, C H2OH), 3.41 ꢀbr s, OH), 2.21 ꢀq, 2H, J ˆ 7.7 Hz,
CH2CH3), 1.05 ꢀt, J ˆ 7.7 Hz, CH2CH3) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 175.57 ꢀCO), 159.70 ꢀC-3),
127.86ꢀC-4), 70.73 ꢀC-5), 57.30 ꢀCH OH), 16.91 ꢀCH2CH3), 12.59 ꢀCH2CH3) ppm.
2
3-Ethyl-4-methyl-5H-furan-2-one ꢀ5; C7H10O2)
To a suspension of 285 mg prehydrogenated 10% Pd±C catalyst in 7.0 cm3 MeOH p.a., 285 mg
ꢀ2mmol) 4 were added, and the mixture was hydrogenated at ambient temperature under normal
pressure. After 10min, 50cm3 ꢀtheory: 44.8 cm3) H2 were absorbed. The catalyst was centrifuged
off, and the solvent was removed in vacuo.
Yield: 240 mg ꢀ95%); colourless oil; TLC ꢀCHCl3:EtOAcˆ 1:1): Rf ˆ 0.69 ꢀeduct: Rf ˆ 0.44); IR
1
ꢀ®lm): ꢂ~ ˆ 2972, 1744, 1678cmÀ 1; H NMR ꢀCDCl3): ꢁ ˆ 4.54 ꢀs, OCH2), 2.19 ꢀq, J ˆ 7 Hz, CH2),
1.95 ꢀs, ˆC±CH3), 0.99 ꢀt, J ˆ 7 Hz, CH3) ppm [8].
ꢀ3R,4R=3S,4S)-3-Ethyl-4-hydroxymethyldihydrofuran-2-one
ꢀpilopyl alcohol, 6a; C7H12O3)
A mixture of 427 mg ꢀ3mmol) 4, 220 mg Adams catalyst ꢀPtO2±H2O), and 65 cm3 EtOAc p.a. was
hydrogenated for 2.5h at ambient temperature and 6.8 Â 106 Pa initial pressure of H2. The catalyst was
centrifuged off, and the solvent was removed in vacuo.
Yield: 426mg ꢀ100%); colourless oil; TLC ꢀCHCl3:EtOAcˆ 1:1): Rf ˆ 0.38 ꢀdetection with KMnO4
dissolved in acetone); IR ꢀ®lm): ꢂ~ ˆ 3440 ꢀOH), 2939, 1757 ꢀCˆO) cmÀ 1; MS ꢀCI): m=z ꢀ%) ˆ 145
‡ ꢂ
1
ꢀM ‡ 1, 100), 127 ꢀ24), 99 ꢀ10); H NMR ꢀCDCl3): ꢁ ˆ 4.43±4.38 and 4.28±4.23 ꢀeach m, 5-H),
3.85±3.76and 3.65±3.59 ꢀeach m, CH 2±O), 2.74±2.64 ꢀm, 4-H), 2.57±2.50 ꢀm, 3-H), 2.23 ꢀbr s, OH),
1.91±1.82 and 1.56±1.47 ꢀeach m, CH2), 1.15±0.99 ꢀm, CH3) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 179.46
ꢀCˆO), 69.28 ꢀC-5), 59.87 ꢀCH2OH), 43.11 ꢀC-3), 39.56ꢀC-4), 18.17 ꢀCH 2), 12.46ꢀCH 3) ppm.
ꢀR,S)-2-ꢀ2,2-dimethyl-[1,3]dioxan-5-yl)-butyric acid ethyl ester ꢀ7; C12H22O4)
To a suspension of 340 mg 5% Pd±C catalyst, ca. 500 mg NaHCO3, and 5 drops of aqueous saturated
NaHCO3 in 10 cm3 EtOH, 15.0g ꢀ66 mmol) 3 were added, and the mixture was hydrogenated for 24h

Synthesis of Pilopyl Alcohols
1289
at ambient temperature and 8.0Â 106 Pa initial pressure of H2. The solids were ®ltered off and washed
with EtOH. After removing the solvent in vacuo, the remaining colourless oil was used for the next
step without further puri®cation.
Yield: 15.0g ꢀ100%); TLC ꢀCHCl3:n-hexane:MeOH ˆ 1:1:0.1): Rf ˆ 0.8 ꢀdetection with KMnO4
‡ ꢂ
dissolved in acetone); IR ꢀ®lm): ꢂ~ ˆ 1731 ꢀCˆO) cmÀ 1; MS ꢀCI): m=z ꢀ%) ˆ 231 ꢀM ‡ 1, 2), 173
1
ꢀ100), 79 ꢀ49); H NMR ꢀCDCl3; for numbering of atoms see formula 3=Scheme 1): ꢁ ˆ 4.09 ꢀq,
J ˆ 7.1 Hz, 100-H), 3.86±3.82, 3.77±3.72, 3.67±3.59 ꢀeach m, 40-H and 60-H), 2.15 ꢀdt, J ˆ 2.4=6.2Hz,
2-H), 2.00 ꢀm, 50-H), 1.53 ꢀm, 3-H), 1.34, 1.32 ꢀeach s, 2 CH3), 1.20 ꢀt, J ˆ 7.1 Hz, 200-H), 0.82
ꢀt, J ˆ 7.3 Hz, 4-H) ppm; 13C NMR ꢀCDCl3): ꢁ ˆ 174.39 ꢀCˆO), 97.99 ꢀC-20), 62.82, 62.53 ꢀC-40 and
0
C-60), 60.41 ꢀC-100), 46.56 ꢀC-2), 35.88 ꢀC-5 ), 26.46 ꢀacetal±CH3), 22.53 ꢀC-3), 21.36ꢀacetal±CH ),
3
14.36ꢀC-2 00), 11.61 ꢀC-4) ppm.
ꢀ3R,4S=3S,4R)-3-Ethyl-4-hydroxymethyldihydrofuran-2-one
ꢀisopilopyl alcohol, 8a; C7H12O3)
To a solution of 15.0g ꢀ65.2 mmol) 7 in 50 cm3 EtOH, 1 cm3 2 N HCl and 3 cm3 H2O were added. The
mixture was stirred at ambient temperature for 5.5 h and then rendered alkaline by addition of solid
NaHCO3. After evaporating the EtOH in vacuo, the mixture was diluted with 250 cm3 H2O and
extracted with CHCl3 ꢀ3Â 200 cm3). The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The residue was puri®ed by FC ꢀsilica gel, n-hexane:CHCl3:EtOH ˆ 5:5:1).
Yield: 8.36g ꢀ88%); colourless oil; TLC ꢀeluent: see FC): Rf ˆ 0.5 ꢀdetection with KMnO4
dissolved in acetone; one spot, no separation of the stereomer 6a; educt: Rf ˆ 0.95); IR ꢀ®lm):
ꢂ~ ˆ 3431 ꢃOH†, 2968, 1758 ꢀCˆO), 1182, 1017 cmÀ 1; MS ꢀEI): m=z ꢀ%) ˆ 116ꢀ28), 85 ꢀ100);
‡ ꢂ
1
ꢀCI): 145 ꢀM ‡ 1, 100); H NMR ꢀCDCl3): ꢁ ˆ 4.39, 4.14 ꢀeach dd, J ˆ 7.8=1.5 and 7.1=2.2 Hz,
CH2OH), 3.78±3.72, 3.69±3.61 ꢀeach m, CH2OCO), 3.40 ꢀpseudo-t, J ˆ 5.0Hz, OH), 2.56±2.46 ꢀm,
4-H), 2.44±2.38 ꢀm, 3-H), 1.83±1.62 ꢀm, CH2), 1.02 ꢀt, J ˆ 7.4 Hz, CH3) ppm; 13C NMR ꢀCDCl3):
ꢁ ˆ 180.15 ꢀCˆO), 69.33 ꢀC-5), 62.32 ꢀCH2OH), 42.75 ꢀC-3), 42.29 ꢀC-4), 22.63 ꢀCH2), 11.06ꢀCH 3)
ppm ꢀthe spectrum contained small peaks revealing ca. 8% of the cis-stereomer 6a).
3,5-Dinitrobenzoic acid ꢀ3R,4S=3S,4R)-4-ethyl-5-oxo-tetrahydrofuran-3-ylmethyl ester
ꢀpilopyl 3,5-dinitrobenzoate, 6b; C14H14N2O8)
To a solution of 110 mg ꢀ0.76mmol) 6a in 0.35 cm3 anhydrous pyridine, a solution of 250 mg
ꢀ1.09 mmol) 3,5-dinitrobenzoyl chloride in 1.5 cm3 pyridine was added. The mixture was heated for
10min at 60ꢁC, then diluted with 6cm3 H2O and cooled in an ice bath for 4 h. The crystalline product
was ®ltered off, washed with ice-cold H2O, dried in vacuo, and recrystallized from MeOH.
Yield: 216mg ꢀ84%); colourless platelets; m.p.: 111±112ꢁC; TLC ꢀCHCl3:EtOAc:petroleum
ether ˆ 11:4:1, developing twice over a path of 6cm): Rf ˆ 0.65 ꢀan additional very small spot at
Rf ˆ 0.74 indicated the presence of 8b).
3,5-Dinitrobenzoic acid ꢀ3R,4R=3S,4S)-4-ethyl-5-oxo-tetrahydrofuran-3-ylmethyl ester
ꢀisopilopyl 3,5-dinitrobenzoate, 8b; C14H14N2O8)
Preparation from 110 mg 8a according to 6b.
Yield: 229 mg ꢀ89%); m.p.: 101±102ꢁC ꢀMeOH); TLC ꢀsee 6b): Rf ˆ 0.74 ꢀa small spot at Rf ˆ
0.65 indicated the presence of 6b).
References
[1] VII: Reimann E, Erdle W, Unger H ꢀ1999) Pharmazie 54: 418

[2] Renz M ꢀ2001) Part of PhD Thesis, LMU Munchen, Germany
[3] Zhu G, Lu X ꢀ1995) Tetrahedron Asymm 6: 1657 and further lit. cited therein

1290
E. Reimann et al.: Synthesis of Pilopyl Alcohols
[4] Preobrashenski NA, Poljakowa AM, Preobrashenski WA ꢀ1934) Ber Dtsch Chem Ges 67: 710
[5] Preobrashenski NA, Poljakowa AM, Preobrashenski WA ꢀ1935) Ber Dtsch Chem Ges 68: 844
[6] Brochmann-Hanssen E, Jenkins GL, Data JB ꢀ1951) JAm Pharm Assoc=Scienti®c Edition 40: 6 1
[7] Hoppe D, Schmincke H, Kleemann H-W ꢀ1989) Tetrahedron 45: 6 87
[8] Berry IP, Isbell AF, Hunt GE ꢀ1972) J Org Chem 37: 4396
[9] Woo EP, Cheng FCW ꢀ1986) J Org Chem 51: 3704
[10] Ozegowski R, Kunath A, Schick H ꢀ1995) Tetrahedron Asymm 6: 1191
[11] Brunner M, Alper H ꢀ1997) J Org Chem 62: 7565
[12] Abe N, Fujisaki F, Sumoto K, Miyano S ꢀ1991) Chem Pharm Bull 39: 1167