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Preparation of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether and epi-dill ether
W.L.P. Bredie and M.A. Petersen (Editors) Flavour Science: Recent Advances and Trends 9 2006 Elsevier B.V. All rights reserved.
209
Preparation of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether and epi-dill ether Stefano Serra and Claudio Fuganti C.N.R. Istituto di Chimica del Riconoscimento Molecolare, presso Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, 20133 Milano, Italy
ABSTRACT A concise synthesis of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether and epi-dill ether has been accomplished starting from the enantiomeric forms of p-mentha- 1,8(10)-diene-3,9-diol. 1. I N T R O D U C T I O N Recently, we have reported [1] the enzyme-mediated preparation of a number of enantiomerically pure p-menthan-3,9-diols and their use for the synthesis of some pmenthane lactones and ethers. In connection with our continuing interest in the developing of synthetic approaches to enantiopure flavour and fragrances, we extended our studies on the preparation of p-mentha-l-ene lactones and ethers showing cis stereochemistry at 3,4 position of the p-menthane framework [2]. The latter kind of compounds was found in Nature and different researches have demonstrated that both character and intensity of their odour are related to their relative and absolute stereochemistry [3]. This is the case of wine lactone 1, which was first identified as an animal metabolite [4] and then recognised as a key flavour compound of different white wines [5]. The olfactory evaluation [6] revealed that natural 1 is the more powerful isomer with an odour threshold <0.04 pg/1 whereas the weakest isomers show a threshold > 106 pg/1. A similar case is that of the dill ether 2 which is the most important constituent of dill essential oil from a sensory standpoint [7]. It is noteworthy that 1 and 2 show the same absolute configuration and cis stereochemistry at 3,4 position. Moreover, wine lactone and dill ether share the difficult accessibility by chemical synthesis, particularly in enantiomerically pure form.
210 Although different enatioselective synthesis as been reported, it seemed desirable to develop a new synthetic method to the enantiomerically pure forms of 1 and 2 by means of a procedure not involving troublesome separation, low yielding steps or the use of expensive catalyst and enantiopure starting materials. According to the retrosynthetic analysis (Figure 1), diol 5 could be a useful building block for the preparation of both wine lactone and dill ether. 1 was obtained in high enantiomeric purity by lipase-mediated acetylation of the racemic material [1 ].
I
Carbonyl
, reduction>~
I
%9
reductionr , .
~
'
-
4 0
.
%
Dill e t h e r
~ Double bond Ureduction I Lipase mediated resolution| 9, ~ )/~
%
[
2
Wine Lactone
%
Double bond
Oxidation
~
,
Wittig ~ .eaction~/~
z //"'OH ~5-~ OH
Diels-Alder creaction' ~
""~"v/oAc O~6"~ OAc
8
~ '~'"OAc O7"~OAc
Figure I. Retrosynthetic analysis of wine lactone l and dill ether 2. 2. RESULTS Oxidation. The preparation of wine lactone 1 by our synthetic pathway required the preparation of a,13-unsaturated lactone 4. The chemioselective oxidation of 5 is an intriguing synthetic step since both hydroxyl functional groups are allylic (Figure 2). We found that employing transition metal reagents, the reaction afforded a mixture of lactone 4 and keto-aldehyde 10 without formation of the lactols 8 and 9. Pyridinium chlorochromate (PCC) gave mainly the compound 10 whilst MnO2 and AgzCO3 on celite showed reverse selectivity. Otherwise, hypervalent iodine oxidants demonstrated a considerably different behaviour over the previous mentioned reagents. The use of o-iodoxybenzoic acid (IBX) in DMSO proceeded without regiochemical control affording predominantly a mixture of lactols 8 and 9 close to the keto-aldehyde 10, unreacted 5 and a trace of lactone 4. Further, the use of Dess-Martin periodinane (DMP) gave selectively 10 free of any lactol isomers. Surprisingly enough, we found that the use of catalytic TEMPO and bisacetoxyiodobenzene (BAIB) as the co-oxidant was the best methodology for the preparation of 4. The wanted product was obtained in yield up to 97% with complete transformation of the starting diol.
211
oxidation .
//"OH
~/__A..v/OH
5
4%'_ o+ + d'o + . ++o l. double bond reduction
~
-"
-
1+
'"*o 11 \,,...~ 0
0 Figure 2. Oxidation of diol 5 and reduction of lactone 4.
vi, vii, iv ~ 73%
"'*O
"
+
/~"OH 94 ~
%0 ~
(+)-5
(-)-4 0
~
(-)-1
%'0
-
93%
(+)-11 0
i
+ (+)-1
OH OH
92o/o-
11/1>7:1
(+)-4 o
~o
+
(-)-11
....iv m,
~
(+5
(+)-11
(-)-1 0
ii
91~
+
"
(-)-11 o v, iv182%
1/11>4:1
(+)-1 o v, iv175%
~i,~ii,iv 67% (+)-12
o (-)-13
..,,,..
(+)-2
i) BAIB, CHzC12, TEMPO (cat.). ii) Mg, MeOH. iii) tBuOK, tBuOH, iv) 3% aq. HC1 soln. v) LiA1H4, Et20. vi) 70% aq. HC104 soln. (cat.), THF/H20 2:l.vi/) NaBH 4. Figure 3. Preparation of wine lactone, epi-wine lactone, dill ether and epi-dill ether.
Reduction. According
to our retrosynthetic analysis, we studied the reduction of 4 to wine lactone 1 and/or its C(8)-epimer 11. Some problems of regio and diastereoselectivity arose. We found that all the reducing agents tested leave unaffected the double bond at C(1) whereas the main product of reduction was the epi-wine lactone 11. The use of magnesium turnings in methanol was the more effective procedure since all the starting 4 was reduced with the smallest amount of unidentified side products (<1%). Different results have been obtained using the hydrides as reducing agents. Either NaBH4 in ethanol and in situ formed copper hydride (Bu3SnH/LiC1/CuI) in THF
212 reduced efficiently 4. Otherwise, the reduction with silicon and tin hydrides afforded, closed to the lactone 11 and 1, a considerable amount of isomerised products. Preparation of the isomeric forms of wine lactones and dill ethers. The enantiopure (+) and (-)-5 were oxidised with BAIB/TEMPO to afford enantiopure (-) and (+)-4 respectively (Figure 3). The selective reduction of the latter lactones by mean of magnesium in methanol afforded epi-wine lactones (+) and (-)-11 respectively close to a small amount of isomeric (-) and (+)-1 respectively. The enantiomeric forms of 11 were easily separated from their epimers by chromatography. Furthermore, we found that treatment of either pure 11 or the mixture of 11/1 (>7:1) obtained as above with tBuOK in tBuOH gave a new mixture of 1/11 (>4:1) where 1 was the main component. By mean of the latter synthetic sequence natural (-)-wine lactone 1 and lactone (+)-1 were prepared from (-) and (+)-4 respectively in enantiopure form and with an overall yield of about 55%. The LiA1H4 reduction of the lactones (-) and (+)-1 affords smoothly the corresponding diastereoisomeric diols that were cyclised by treatment with diluted aq. HCI to give the natural (-)-dill ether 2 and its enantiomer (+)-2, respectively. This ring closure affords stereospecifically the bicyclic ethers with cis configuration at the 3,4 position in chemically and isomerically pure form. Analogously, the same procedure was applied to (+) and (-)-11 to afford pure (+) and (-)-epi dill ether 13 respectively. Finally, we transformed the diols (+) and (-)-5 in the ethers (-) and (+)-12 respectively by treatment with catalytic HCI and following isomerisation by mean of rhodium hydride catalyst [1]. The latter compounds were dissolved in a THF/water mixture and treated with catalytic HC104. The starting materials were smoothly converted in the corresponding lactols, which were treated with an excess of NaBH4. The mixtures were quenched with diluted HCI and the isolation procedure afforded diastereoselectively (+) and (-) epi-dill ether 13 respectively. 3. CONCLUSION A new enantiospecific approach to the isomeric forms of natural wine lactone and dill ether is described in this work. The enantiomeric forms ofp-mentha-l,8(10)-diene-3,9diol were the common building blocks for this divergent synthesis. The key steps were a number of chemio and diastereoselective reactions that we have studied and optimised. References
1. 2. 3. 4. 5. 6. 7.
S. Serra and C. Fuganti, Helv. Chim. Acta, 85 (2002) 2489. S. Serra and C. Fuganti, Helv. Chim. Acta, 87 (2004) 2100. E. Brenna, C. Fuganti and S. Serra, Tetrahedron-Asymmetr., 14 (2003) 1. I.A. Southwell, Tetrahedron Lett., 24 (1975) 1885. H. Guth, J. Agric. Food Chem., 45 (1997) 3022. H. Guth, Helv. Chim. Acta, 79 (1996) 1559. M. Wrist and A. Mosandl, Eur. Food Res. Technol., 209 (1999) 3.
209
Preparation of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether and epi-dill ether Stefano Serra and Claudio Fuganti C.N.R. Istituto di Chimica del Riconoscimento Molecolare, presso Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, 20133 Milano, Italy
ABSTRACT A concise synthesis of the enantiomeric forms of wine lactone, epi-wine lactone, dill ether and epi-dill ether has been accomplished starting from the enantiomeric forms of p-mentha- 1,8(10)-diene-3,9-diol. 1. I N T R O D U C T I O N Recently, we have reported [1] the enzyme-mediated preparation of a number of enantiomerically pure p-menthan-3,9-diols and their use for the synthesis of some pmenthane lactones and ethers. In connection with our continuing interest in the developing of synthetic approaches to enantiopure flavour and fragrances, we extended our studies on the preparation of p-mentha-l-ene lactones and ethers showing cis stereochemistry at 3,4 position of the p-menthane framework [2]. The latter kind of compounds was found in Nature and different researches have demonstrated that both character and intensity of their odour are related to their relative and absolute stereochemistry [3]. This is the case of wine lactone 1, which was first identified as an animal metabolite [4] and then recognised as a key flavour compound of different white wines [5]. The olfactory evaluation [6] revealed that natural 1 is the more powerful isomer with an odour threshold <0.04 pg/1 whereas the weakest isomers show a threshold > 106 pg/1. A similar case is that of the dill ether 2 which is the most important constituent of dill essential oil from a sensory standpoint [7]. It is noteworthy that 1 and 2 show the same absolute configuration and cis stereochemistry at 3,4 position. Moreover, wine lactone and dill ether share the difficult accessibility by chemical synthesis, particularly in enantiomerically pure form.
210 Although different enatioselective synthesis as been reported, it seemed desirable to develop a new synthetic method to the enantiomerically pure forms of 1 and 2 by means of a procedure not involving troublesome separation, low yielding steps or the use of expensive catalyst and enantiopure starting materials. According to the retrosynthetic analysis (Figure 1), diol 5 could be a useful building block for the preparation of both wine lactone and dill ether. 1 was obtained in high enantiomeric purity by lipase-mediated acetylation of the racemic material [1 ].
I
Carbonyl
, reduction>~
I
%9
reductionr , .
~
'
-
4 0
.
%
Dill e t h e r
~ Double bond Ureduction I Lipase mediated resolution| 9, ~ )/~
%
[
2
Wine Lactone
%
Double bond
Oxidation
~
,
Wittig ~ .eaction~/~
z //"'OH ~5-~ OH
Diels-Alder creaction' ~
""~"v/oAc O~6"~ OAc
8
~ '~'"OAc O7"~OAc
Figure I. Retrosynthetic analysis of wine lactone l and dill ether 2. 2. RESULTS Oxidation. The preparation of wine lactone 1 by our synthetic pathway required the preparation of a,13-unsaturated lactone 4. The chemioselective oxidation of 5 is an intriguing synthetic step since both hydroxyl functional groups are allylic (Figure 2). We found that employing transition metal reagents, the reaction afforded a mixture of lactone 4 and keto-aldehyde 10 without formation of the lactols 8 and 9. Pyridinium chlorochromate (PCC) gave mainly the compound 10 whilst MnO2 and AgzCO3 on celite showed reverse selectivity. Otherwise, hypervalent iodine oxidants demonstrated a considerably different behaviour over the previous mentioned reagents. The use of o-iodoxybenzoic acid (IBX) in DMSO proceeded without regiochemical control affording predominantly a mixture of lactols 8 and 9 close to the keto-aldehyde 10, unreacted 5 and a trace of lactone 4. Further, the use of Dess-Martin periodinane (DMP) gave selectively 10 free of any lactol isomers. Surprisingly enough, we found that the use of catalytic TEMPO and bisacetoxyiodobenzene (BAIB) as the co-oxidant was the best methodology for the preparation of 4. The wanted product was obtained in yield up to 97% with complete transformation of the starting diol.
211
oxidation .
//"OH
~/__A..v/OH
5
4%'_ o+ + d'o + . ++o l. double bond reduction
~
-"
-
1+
'"*o 11 \,,...~ 0
0 Figure 2. Oxidation of diol 5 and reduction of lactone 4.
vi, vii, iv ~ 73%
"'*O
"
+
/~"OH 94 ~
%0 ~
(+)-5
(-)-4 0
~
(-)-1
%'0
-
93%
(+)-11 0
i
+ (+)-1
OH OH
92o/o-
11/1>7:1
(+)-4 o
~o
+
(-)-11
....iv m,
~
(+5
(+)-11
(-)-1 0
ii
91~
+
"
(-)-11 o v, iv182%
1/11>4:1
(+)-1 o v, iv175%
~i,~ii,iv 67% (+)-12
o (-)-13
..,,,..
(+)-2
i) BAIB, CHzC12, TEMPO (cat.). ii) Mg, MeOH. iii) tBuOK, tBuOH, iv) 3% aq. HC1 soln. v) LiA1H4, Et20. vi) 70% aq. HC104 soln. (cat.), THF/H20 2:l.vi/) NaBH 4. Figure 3. Preparation of wine lactone, epi-wine lactone, dill ether and epi-dill ether.
Reduction. According
to our retrosynthetic analysis, we studied the reduction of 4 to wine lactone 1 and/or its C(8)-epimer 11. Some problems of regio and diastereoselectivity arose. We found that all the reducing agents tested leave unaffected the double bond at C(1) whereas the main product of reduction was the epi-wine lactone 11. The use of magnesium turnings in methanol was the more effective procedure since all the starting 4 was reduced with the smallest amount of unidentified side products (<1%). Different results have been obtained using the hydrides as reducing agents. Either NaBH4 in ethanol and in situ formed copper hydride (Bu3SnH/LiC1/CuI) in THF
212 reduced efficiently 4. Otherwise, the reduction with silicon and tin hydrides afforded, closed to the lactone 11 and 1, a considerable amount of isomerised products. Preparation of the isomeric forms of wine lactones and dill ethers. The enantiopure (+) and (-)-5 were oxidised with BAIB/TEMPO to afford enantiopure (-) and (+)-4 respectively (Figure 3). The selective reduction of the latter lactones by mean of magnesium in methanol afforded epi-wine lactones (+) and (-)-11 respectively close to a small amount of isomeric (-) and (+)-1 respectively. The enantiomeric forms of 11 were easily separated from their epimers by chromatography. Furthermore, we found that treatment of either pure 11 or the mixture of 11/1 (>7:1) obtained as above with tBuOK in tBuOH gave a new mixture of 1/11 (>4:1) where 1 was the main component. By mean of the latter synthetic sequence natural (-)-wine lactone 1 and lactone (+)-1 were prepared from (-) and (+)-4 respectively in enantiopure form and with an overall yield of about 55%. The LiA1H4 reduction of the lactones (-) and (+)-1 affords smoothly the corresponding diastereoisomeric diols that were cyclised by treatment with diluted aq. HCI to give the natural (-)-dill ether 2 and its enantiomer (+)-2, respectively. This ring closure affords stereospecifically the bicyclic ethers with cis configuration at the 3,4 position in chemically and isomerically pure form. Analogously, the same procedure was applied to (+) and (-)-11 to afford pure (+) and (-)-epi dill ether 13 respectively. Finally, we transformed the diols (+) and (-)-5 in the ethers (-) and (+)-12 respectively by treatment with catalytic HCI and following isomerisation by mean of rhodium hydride catalyst [1]. The latter compounds were dissolved in a THF/water mixture and treated with catalytic HC104. The starting materials were smoothly converted in the corresponding lactols, which were treated with an excess of NaBH4. The mixtures were quenched with diluted HCI and the isolation procedure afforded diastereoselectively (+) and (-) epi-dill ether 13 respectively. 3. CONCLUSION A new enantiospecific approach to the isomeric forms of natural wine lactone and dill ether is described in this work. The enantiomeric forms ofp-mentha-l,8(10)-diene-3,9diol were the common building blocks for this divergent synthesis. The key steps were a number of chemio and diastereoselective reactions that we have studied and optimised. References
1. 2. 3. 4. 5. 6. 7.
S. Serra and C. Fuganti, Helv. Chim. Acta, 85 (2002) 2489. S. Serra and C. Fuganti, Helv. Chim. Acta, 87 (2004) 2100. E. Brenna, C. Fuganti and S. Serra, Tetrahedron-Asymmetr., 14 (2003) 1. I.A. Southwell, Tetrahedron Lett., 24 (1975) 1885. H. Guth, J. Agric. Food Chem., 45 (1997) 3022. H. Guth, Helv. Chim. Acta, 79 (1996) 1559. M. Wrist and A. Mosandl, Eur. Food Res. Technol., 209 (1999) 3.