- Email: [email protected]
Asymmetric bromolactonization reaction: Synthesis of optically active 2-hydroxy-2-methylalkanoic acids from 2-methylenealkanoic acids
Tetrahedron Letters,Vo1.28,No.25,pp Printed in Great Britain
2801-2804,1987
oo40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
ASYMMETRIC BROMOLACTONIZATIONREACTION: SYNTHESIS OF OPTICALLY ACTIVE 2-RYDROXY-2-METHYLALKANOICACIDS FROM 2-METRYLENEAUANOIC ACIDS
Paul F. Corey
Central Research Services Division, Miles Laboratories, Inc. P. 0. Box 40, Elkhart, IN 46515
Abstract: Optically pure 2-hydroxy-2-methylalkanoicacids of either configuration may be obtained via an asymmetric bromolactonizationreaction using &-proline as a chiral auxilliary.
During the development of the antiulcer drug candidate Rioprostil (L)l there arose a need to prepare substantial quantities of the individual 16s and 163 isomers for pharmacological evaluation. Pappo and co-workers2 have previously described the synthesis of both isomers of the analogously prepared 2 beginning with chemically resolved (via chiral a-naphthylethylamine salts) hydroxy-acids g and 14.
The search for a more efficient synthesis of these chiral
acids led to the asymmetric bromolactonizationreaction pioneered by Terashima et al.3-5 These authors found that &.-prolineamides of a-methyl-B-alkyl-a,P_unsaturated acids undergo facile bromolactonizationwith stereoselective introduction of oxygen at the a-carbon. In cases where the 8-alkyl group is trans to the carbonyl the ratio of the two possible diastereomers is 95:5, but when the relationship is cis the ratio falls to E. 60:40. This reaction has here been extended to include the hitherto unexplored &-proline amides of 2-methylenealkanoicacids (a-alkylacrylicacids), which upon bromolactonizationafford a mixture of diastereomers in which the readily isolated major component has the opposite configuration from that obtained from the corresponding trans-a-methyl-8-alkyl-a.P_unsaturated acid. SCHEME I outlines the synthesis of (+)S and (-)R_-2-hydroxy-2-methylhexanoic acids 6 and 14 from 2-methylenehexanoicacid (2) and trans-2-methyl-2-hexenoicacid (g), respectively.
2801
2802
&-proline was first acetylated, under Schotten-Baumannconditions, with 2-methylenehexanoyl chloride (iJ6 to give amide 2 as a viscous oil. Treatment of 2 with N-bromosuccinimide (NBS) afforded the bromolactone 5 (63% yield; mp = 73.5-74.5'C; [a], = -134.3O (C = 2.08, CHC13)) and tributyltin hydride reduction of 2 gave the lactone 7 {86X yield; mp = 68-69.5OC; [a], = -160.4' (C = 1.26, CHC13)}. Upon hydrolysis of z in hot 48% aqueous HBr (+)S-2-hydroxy-2methylhexanoic acid (4) was obtained, identical to that prepared by chemical resolution of the racemate (67X yield; mp = 70.5-72.0°C; Ia]365 = +24.1° (C = 1.54, H20j]. Scheme I
Br
-
OH 8
Br
h OH
‘2 12
'I? a> 0.8 eq. L-proline, H O/Et O/NaOH pH = 10.5-10.7, 0.75 h 25'C; b) 2 eq. NBS, anhydrous Dk, 20 h 25O?!; c? 1.5 eq. (YJ-Bu)~SIIH~ 0.007 eq. bensoyl peroxide, CH2C12, hv, 18 h roeflux; d) 48XoHBr, 19.5 h 100 C; e> 1.5 eq. oxalyl chloride, Et20. 1.25 h at 0 C tdhen16 h 25 C; f> 0.95 eq. &-prooline,H20/Et20/NaOH pH = 10.5-10.7, 0.75 h 25 C; g) 2 eq. NBS, CC14, 17 h 25 C; h) 1.2 eq. (B-Bu13SnH. 0.007 eq. benzoyl peroxide, CH2C12, hv, 21 h reflux; i) cont. aq. HCl, 17 h 1ooOc.
2803
The (-)R_isomer 14 was prepared in a similar manner. Thus trans-2-methyl-2-hexenoicacid W7
was converted to its acid chloride g
(81% yield; bp = 70-2OC (24 torr)} and then reacted
with &-proline under Schotten-Baumann conditions to afford the amide 11 as a viscous oil. Treatment of 11 with NBS in CC14 yielded the bromolactone 12 (76% yield; mp = 116.5-117.2OC;
la],
= -58.2O (C = 2.36, CHCl )} and reduction of 12 with tributyltin hydride gave the lactone
12 (87% yield; mp = 79-8O'C; :a]D = -117.5O (C = 1.42, CHC13)}. Acid hydrolysis of 12 afforded (-)R_-2-hydroxy-2-methylhexanoic acid (141, identical to that prepared by resolution' (77% yield; mp = 71-2'C; [a]365 = -24.2' (C = 2.07, H20)}. Shorter chain 2-methylenealkanoicacids react similarly and SCHEME II outlines the synthesis of (+)R-2-methylhexane-1,2-diol(22) from methacryloyl chloride (15). The &-proline amide _168, upon treatment with NBS in dimethylformamideyielded bromolactone 17 {64X yield; mp = 157-8OC; [al, = -131.4' (C = 1.97, CHC13)) and hydrolysis of 17 gave hydroxy-acid E (88% yield; mp = 111.5-114°C; [a]365 = -31.2' (C = 1.4, CHC13)}. Borane reduction of 18 Scheme I I Br
a
C OH
b
e
Br
*
w
b
OH
OH
a) 2 eq. NBS, anhydrous DMF, 19.5 h 25OC; b) 48% HBr, 16 h 1OOOC; C) 31 eq. BH_,-THF,anhydrous THF, 22 h O°C to 25OC; d) 1.2 eq. 2,2-dimethoxypropane, acetone, cat. tosic acid, 15.5 h. 25OC; e) 3 eq. LiCu (H-Er)2-LiCN,Et20, 1 h O"ci f) 2N HCl/THF (1:l). 2.5 h 25OC.
2804
afforded bromodiol 19 (94% yield; bp = 63-4'C (0.14 torr); [al365 = +10.7 (C = 1.50, CHC13)), a chiral. bifunctional and potentially versatile tertiary alcohol synthon. Protection of _@ as the acetonide 20 {854 yield; bp = 176-9OC (760 torr); [a]365 = -55.0° (C = 1.91, acetone)} followed by reaction with lithium di-(g-propyl)cyanocuprate8gave 21 (65% yield; bp = ~a. 130°C (760 torr); [al365 = t6.27 (C_= 1.21, acetone)} and acid hydrolysis afforded (t)R-2-methylhexane-1,2-diol(22) {77% yield; kuglrohr distilled, bp = 40-90°C (0.1 torr);
[al 365 = t12.5' (C = 2.58, CHC13)) as a viscous oil identical to that obtained by lithium aluminum hydride reduction of 14. Based on these results, the bromolactonisationof &-proline amides 5 and 3
proceeds
predominately on the same face of the double bond, regardless of whether the attached alkyl 3-5 group is 1 or 4 carbons long. While Terashima -et al. have shown that the bromolactonizationdoes not proceed with absolute stereospecificity,the highly crystalline nature of lactones 6, 1, 12, 13 and 17 makes it possible to easily remove the minor diastereomers by recrystallization. The present method makes available optically pure 2-hydroxy-2-methylalkanoicacids of either configuration from a,B-unsaturated acids differing only in the geometry of the double bond.
Acknowledgements: The author wishes to thank Professor Charles .I.Sih and Dr. Harold C. Kluender for helpful discussions and support. Thanks also to Mr. Michael Bloczynski for performing the LAH reduction of 14.
REFERENCES 1.
Rioprostil; TR-4698; l6-Methyl-l,lla,16E-trihydroxyprost-13E_-en-g-one.H. C. Kluender, W. D. Woessner and W. G. Biddlecom, U.S. 4,132,738.
2.
R. Pappo, P. W. Collins, M. S. Bruhn, A. F. Gasiecki, C. T. Jung, I-I. W. Sause and J. A. Schulz in "Chemistry, Biochemistry and PharmacologicalActivity of Prostanoids," S. M. Roberts and F. Scheinmann, Eds., Pergamon Press, New York, 1978, p. 17.
3.
S. Terashima, S-s. Jew and K. Koga, Chemistry Letters, 1109 (1977).
4.
S. Terashima and S-s. Jew, Tetrahedron Letters, 1105 (1977).
5.
S-s. Jew, S. Terashima and K. Koga, Tetrahedron 35, 2337 (1979).
6.
Y. Ikakura. M. Sato and Y. Matsuo, Nippon Kagaku -Zasshi 80, 502 (1959).
7.
J. Cason and M. J. Calm, -Journal of Organic Chemistry l9, 1947 (1954).
8.
B. H. Lipshutz, R. S. Wilhelm and D. M. Floyd, 2. &. (Received
in USA 18 March
1987)
Chem. Sot. 103, 7672 (1981). --
2801-2804,1987
oo40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
ASYMMETRIC BROMOLACTONIZATIONREACTION: SYNTHESIS OF OPTICALLY ACTIVE 2-RYDROXY-2-METHYLALKANOICACIDS FROM 2-METRYLENEAUANOIC ACIDS
Paul F. Corey
Central Research Services Division, Miles Laboratories, Inc. P. 0. Box 40, Elkhart, IN 46515
Abstract: Optically pure 2-hydroxy-2-methylalkanoicacids of either configuration may be obtained via an asymmetric bromolactonizationreaction using &-proline as a chiral auxilliary.
During the development of the antiulcer drug candidate Rioprostil (L)l there arose a need to prepare substantial quantities of the individual 16s and 163 isomers for pharmacological evaluation. Pappo and co-workers2 have previously described the synthesis of both isomers of the analogously prepared 2 beginning with chemically resolved (via chiral a-naphthylethylamine salts) hydroxy-acids g and 14.
The search for a more efficient synthesis of these chiral
acids led to the asymmetric bromolactonizationreaction pioneered by Terashima et al.3-5 These authors found that &.-prolineamides of a-methyl-B-alkyl-a,P_unsaturated acids undergo facile bromolactonizationwith stereoselective introduction of oxygen at the a-carbon. In cases where the 8-alkyl group is trans to the carbonyl the ratio of the two possible diastereomers is 95:5, but when the relationship is cis the ratio falls to E. 60:40. This reaction has here been extended to include the hitherto unexplored &-proline amides of 2-methylenealkanoicacids (a-alkylacrylicacids), which upon bromolactonizationafford a mixture of diastereomers in which the readily isolated major component has the opposite configuration from that obtained from the corresponding trans-a-methyl-8-alkyl-a.P_unsaturated acid. SCHEME I outlines the synthesis of (+)S and (-)R_-2-hydroxy-2-methylhexanoic acids 6 and 14 from 2-methylenehexanoicacid (2) and trans-2-methyl-2-hexenoicacid (g), respectively.
2801
2802
&-proline was first acetylated, under Schotten-Baumannconditions, with 2-methylenehexanoyl chloride (iJ6 to give amide 2 as a viscous oil. Treatment of 2 with N-bromosuccinimide (NBS) afforded the bromolactone 5 (63% yield; mp = 73.5-74.5'C; [a], = -134.3O (C = 2.08, CHC13)) and tributyltin hydride reduction of 2 gave the lactone 7 {86X yield; mp = 68-69.5OC; [a], = -160.4' (C = 1.26, CHC13)}. Upon hydrolysis of z in hot 48% aqueous HBr (+)S-2-hydroxy-2methylhexanoic acid (4) was obtained, identical to that prepared by chemical resolution of the racemate (67X yield; mp = 70.5-72.0°C; Ia]365 = +24.1° (C = 1.54, H20j]. Scheme I
Br
-
OH 8
Br
h OH
‘2 12
'I? a> 0.8 eq. L-proline, H O/Et O/NaOH pH = 10.5-10.7, 0.75 h 25'C; b) 2 eq. NBS, anhydrous Dk, 20 h 25O?!; c? 1.5 eq. (YJ-Bu)~SIIH~ 0.007 eq. bensoyl peroxide, CH2C12, hv, 18 h roeflux; d) 48XoHBr, 19.5 h 100 C; e> 1.5 eq. oxalyl chloride, Et20. 1.25 h at 0 C tdhen16 h 25 C; f> 0.95 eq. &-prooline,H20/Et20/NaOH pH = 10.5-10.7, 0.75 h 25 C; g) 2 eq. NBS, CC14, 17 h 25 C; h) 1.2 eq. (B-Bu13SnH. 0.007 eq. benzoyl peroxide, CH2C12, hv, 21 h reflux; i) cont. aq. HCl, 17 h 1ooOc.
2803
The (-)R_isomer 14 was prepared in a similar manner. Thus trans-2-methyl-2-hexenoicacid W7
was converted to its acid chloride g
(81% yield; bp = 70-2OC (24 torr)} and then reacted
with &-proline under Schotten-Baumann conditions to afford the amide 11 as a viscous oil. Treatment of 11 with NBS in CC14 yielded the bromolactone 12 (76% yield; mp = 116.5-117.2OC;
la],
= -58.2O (C = 2.36, CHCl )} and reduction of 12 with tributyltin hydride gave the lactone
12 (87% yield; mp = 79-8O'C; :a]D = -117.5O (C = 1.42, CHC13)}. Acid hydrolysis of 12 afforded (-)R_-2-hydroxy-2-methylhexanoic acid (141, identical to that prepared by resolution' (77% yield; mp = 71-2'C; [a]365 = -24.2' (C = 2.07, H20)}. Shorter chain 2-methylenealkanoicacids react similarly and SCHEME II outlines the synthesis of (+)R-2-methylhexane-1,2-diol(22) from methacryloyl chloride (15). The &-proline amide _168, upon treatment with NBS in dimethylformamideyielded bromolactone 17 {64X yield; mp = 157-8OC; [al, = -131.4' (C = 1.97, CHC13)) and hydrolysis of 17 gave hydroxy-acid E (88% yield; mp = 111.5-114°C; [a]365 = -31.2' (C = 1.4, CHC13)}. Borane reduction of 18 Scheme I I Br
a
C OH
b
e
Br
*
w
b
OH
OH
a) 2 eq. NBS, anhydrous DMF, 19.5 h 25OC; b) 48% HBr, 16 h 1OOOC; C) 31 eq. BH_,-THF,anhydrous THF, 22 h O°C to 25OC; d) 1.2 eq. 2,2-dimethoxypropane, acetone, cat. tosic acid, 15.5 h. 25OC; e) 3 eq. LiCu (H-Er)2-LiCN,Et20, 1 h O"ci f) 2N HCl/THF (1:l). 2.5 h 25OC.
2804
afforded bromodiol 19 (94% yield; bp = 63-4'C (0.14 torr); [al365 = +10.7 (C = 1.50, CHC13)), a chiral. bifunctional and potentially versatile tertiary alcohol synthon. Protection of _@ as the acetonide 20 {854 yield; bp = 176-9OC (760 torr); [a]365 = -55.0° (C = 1.91, acetone)} followed by reaction with lithium di-(g-propyl)cyanocuprate8gave 21 (65% yield; bp = ~a. 130°C (760 torr); [al365 = t6.27 (C_= 1.21, acetone)} and acid hydrolysis afforded (t)R-2-methylhexane-1,2-diol(22) {77% yield; kuglrohr distilled, bp = 40-90°C (0.1 torr);
[al 365 = t12.5' (C = 2.58, CHC13)) as a viscous oil identical to that obtained by lithium aluminum hydride reduction of 14. Based on these results, the bromolactonisationof &-proline amides 5 and 3
proceeds
predominately on the same face of the double bond, regardless of whether the attached alkyl 3-5 group is 1 or 4 carbons long. While Terashima -et al. have shown that the bromolactonizationdoes not proceed with absolute stereospecificity,the highly crystalline nature of lactones 6, 1, 12, 13 and 17 makes it possible to easily remove the minor diastereomers by recrystallization. The present method makes available optically pure 2-hydroxy-2-methylalkanoicacids of either configuration from a,B-unsaturated acids differing only in the geometry of the double bond.
Acknowledgements: The author wishes to thank Professor Charles .I.Sih and Dr. Harold C. Kluender for helpful discussions and support. Thanks also to Mr. Michael Bloczynski for performing the LAH reduction of 14.
REFERENCES 1.
Rioprostil; TR-4698; l6-Methyl-l,lla,16E-trihydroxyprost-13E_-en-g-one.H. C. Kluender, W. D. Woessner and W. G. Biddlecom, U.S. 4,132,738.
2.
R. Pappo, P. W. Collins, M. S. Bruhn, A. F. Gasiecki, C. T. Jung, I-I. W. Sause and J. A. Schulz in "Chemistry, Biochemistry and PharmacologicalActivity of Prostanoids," S. M. Roberts and F. Scheinmann, Eds., Pergamon Press, New York, 1978, p. 17.
3.
S. Terashima, S-s. Jew and K. Koga, Chemistry Letters, 1109 (1977).
4.
S. Terashima and S-s. Jew, Tetrahedron Letters, 1105 (1977).
5.
S-s. Jew, S. Terashima and K. Koga, Tetrahedron 35, 2337 (1979).
6.
Y. Ikakura. M. Sato and Y. Matsuo, Nippon Kagaku -Zasshi 80, 502 (1959).
7.
J. Cason and M. J. Calm, -Journal of Organic Chemistry l9, 1947 (1954).
8.
B. H. Lipshutz, R. S. Wilhelm and D. M. Floyd, 2. &. (Received
in USA 18 March
1987)
Chem. Sot. 103, 7672 (1981). --