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Enantioselective preparation of a C3 symmetrical triol
Tea-ahdm~ hymnWry
Vol. 5. No. 7, pi. 1161-1162,
1994
copy@t019!24Ek*scimc8w Ritlh?dillinEtfit4itt.AUIighblKMVd 0957416604
57.oo+o.00
0957-4166(94)00154-5
Enantiosektive
Reparation
of a C3 Symmetrical Trio1
HenningLiItjcnsand Paul Knochel* Fachbereich Cbemie der Philipps-Universitit
Marburg
D - 35032 Marburg. Germany
Swnmary: The new C3 symmcm’cal trio1 I has been prepared in optically pure fonn (> 98 %ee) using a catalytic enantioselective ethylation of a fimtionalized unsaturated aldehyde in an iterative way and a diastereoselective hy&oboration.
Chiral C2 symmetrical alcohols, amines. thiols or phospbines have found nutoerous applications as catalyst ligands for asymmetric synthesist CJ symmetrical ligands have been used far less for asymmttic synthesis,2 although such auxiliies should in principle lead to a beaca stereodSerentiation since the stereochernical information is concentrated in a space of 120 ’ cornpared to 180 ’ for a C2 symmetrical @and. Herein we report a stereoselective synthesis of a new C3 symmetrical trio1 1 using a catalytic asymtnetric addition of EtsZn to an unsaturated a-brorno-aldehyde 2 (eq 1). Et
OH
Br Et
HO Y Et
OH
Et/ +
ma
0
+
Et&
(1)
H
1
2
I Recently, we have shown that unsatutated a-bromoaldehydes react with functionalized dialkylxincs with excellent stereoselectivity using (1R. 2R)-1.2bis(trifluorosulfonamido)cyclohexane 34 (8 rnol %) as a catalyst. The treatment of my available (E)-2-petttenal successively with Brz (1 equiv. CH2Cl2.0 “C, 5 min) and Et3N (1.6 equiv, 0 “C) produces after filtration5 over silica gel tlte sensitive aldehyde 2 (59 % yield). Catalytic asynunetric addition ofEt2Zn (1.6 equiv) to 2 in the presence of ‘Ii(Oi-Pr)4 (1.7 equiv) and the catalyst 3 (5 mol%) in toluene (-60 “C, 2 h) affords the (S)-allylic alcohol 4 ([ah = -5.20 (c = 1.68, benzene)) in 88 % yield (50 mrnol scale reaction) and 94 %ee as determkd by tH NMR analysis of its ester derivative with (S)-(-)-0-acetylrnandelic acid6 (eq 2). The alcohol 4 was protected as a benyl aher (NaH (1 equiv); BnBr (2 equiv), lHF. rt, 12 h; 96 % yield) and amverted to tbe aldehyde 5 via a bromine-lithium exchange using r-BuLi (3 equiv, ether, -105 “C) and quenching the resulting alkenyllitltium with an excess of DMF (52 % yield). The addition of Et@ to 5 under our standard conditions affords tbe chiral1,3diol daivative 6 ([a]su = 46.5 (c = 1.70, benzene); 83 8 yi~W~iiastereoselectivity > 98 : 2; cq 3). Br
1) Br,, CH&I, c
Et&O
I H
lt
2) NEt3 59%
43) t-BuLi, -105 ‘C 4) DMF excess
Et&
Et
ONHTf u’,
2
1) NaH, THF
2) BnBr (2 equiv)
Etgrl, Ti(Oi’Pf)4 c
Et&O
(2)
AH NHTf 3 (5 mot%)
4: 66%; 94%ee
CHO Et&
Et
-
dBn
Eta,
Tipi-Pr), c
3 (5 Inor%)
5: 52%
Et &3n 6: 63%; d.r. > 982
1161
(3)
1162
H. LUTJWS
and P. KNOCHEL
To prove the relative swreochemistxy, the alcohol 7 prepared in the same way as 6 was benzylated (NaH, BnBr, THF, EQNI cat_, rt, 12 h; 83 4%yield) and submitted to ozonolysis (03, MeOH, 4 h) affording the C2 symmetrical ketone 87 ([a]=~ = +3 1.82 (c = 2.20, benzene); 69 8 yield; eq 4).
Pr
1) NaH. THF CBn 2) BnBr, DMF -
HOG.. ?Y Et
Et
Et4NI cat.
Pr 1) 03, MeOH
I
BnCL.. h Et
c
OBn Et
OBz
620 r,. Af Et
2) b2S
(4)
Et
8 9: 69% 7 Interestingly, the benzyloxy groups of 9 were oxidized to benzoates during the ozonolysis.8 The hydroboration of 6 with BH3-MezS (3 equiv. ether, rt. 12 h), followed by oxidation (35 % Hz02,O.l M NaOH, ether, rt, 2h) produces a mixture of two diastcreoisomers lOintheratio88:12.Themaprisomcrcouldbe~epara~by flash-chromatography and isolated in pure form ([a]“D = 18.4 (c = 1.25. benzene); 54 96 yield). After removal of the benzyl protecting group (Hz(l arm), Pd/C, rt, 24 h), the trio1 1 ([@b : -17.98 (c = 0.98. benzene); 90 8 yield) was obtained in pure form as indicated by IH and t3C NMR specuoscopy (eq 5).9 Applications of 1 and related molecules in asymmetric syntheses are currently underway.
1) BH&&S
H,, Pd/C
OH Et
H
2) 35% H202 0.1 M NaOH
OH
Et
t
AcOEt, 25 ‘C, 24h
10: 54%; d.r. = 88 : 12
6
Et
OH OH
(5)
Et
1:900/o
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFCi (SPP “Peroxidchemie”) research, BASF AG and Witco (Bergkamen) for generous gift of chemicals.
References and Notes. 1.
2.
3. 4.
5. 6. 7. 8. 9.
for generous support of this
(a) J. K. Whiscscll Chem Rev. 1989.89.1581; @) R. Noyti end M. Kitamin Modem Synrhrric M&ods R. Scbcff& Ed. Springer-Vexlag: Berlin, Heidelberg, 1989; Vol. 5 p. 114; (c) H. Brwmzr Top. Skmvchem 19J36.18.129; (d) H. Brmma ia The ckmisey of the meal-carbr bond, F. R. Hartley. Ed. J. Wiley and SCXIX Chichester,New-YorL 19sa. Vol. 5 p. 109. (a) B. Bogdanovic. B. Hex., B. Meistcx. H. Pauling and G. WiIke Angcw. Chewa.. I~I. Ed. Engl. 1972,ll,lU23; (b) C. BoIm. W. M. Davis, R. L. Hat-n and K. B. Shsrpleas Anger. Chem., Int. Ed. Engl. 1986.27.835; (c) C. Bolm aad K. B. Sharpless Tetrahedron fen. lm. 29.5101; (d) M. J. Bark and R. L. Harlow Angcw.Chum., In?. Ed Engl. 1990.29.1462; (e) M. J. Burk. J. E. Feuta and R. L. Harlow Tenahedron: Asymmeny 1991.2.569; (f) C. J. Tokar. P. B. Kettlcr and W. B. Tolman Organmne rallies 1992, II, 2737; (g) D. Seebach. J.M. Lapiarc. K. Skobridis and G. Greiveldingex Angcw.Chen 1994.106.457 (a) M. J. Rozema, S. AchyuthaRau and P. Knochel J. Org. Chem 1992.57.1956; (b) M. J. Roaema, C. Bisenberg, H. Llkjma, R. Gstwald, K. Belyk and P. Knochel Tetrahedron Lat. l993.34.3115. (a) M. Yoshhka. T. Kawakita and M. Ohno Tenakdron L&t. l989.30.1657; @) H. Takahashi. T. Kawakita. M. Yoshioka, S. Kobayashi and M. Ohno Terrahedron L.&f. 1989,30,7095; (c) H. Tabhbi. T. Kawakita, M Ohno, M. Yoshioka aud S. Kobayashi Tevohedron 1992.48.5691. For other Ti-catalyzed aunt&elective additiau of R2Zn tn aldehydcs. secz (d) B. Schmidt and D. Seebach Angew. Chem Int. Ed. Engl. 1991.30.99: (e) D. Seebach. L. Behrmdt and D. Felix Angew. Chem Int. Ed. Engl. 1991.30, 1008, (f) B. Schmidt and D. Seebach Aagew. Chen In!. Ed. Engf. 1991.30. 1321; (g) J. L. v. d. BusscheHttnnefeld and D. Sbebach Temzhedron 1992.48.5719; (h) D. Seebach, D. A. Plaamx. A. K. Beck. Y. M. Wang, D. Hunzikex and W. Peuex Helv. Chim. Aclcl1992.75,2171. C. J. Kowalski. A. E. Weber and K. W. Fields J. Org. Chem. 1932,47.5088. D. Parker/. Chum.SOL,Perkin Trans. 2.1983.83. For the preparation of related ketones. see: D. Endera, W. Gataweikx and U. Jegelka Synfhesis 1991.1137. F.G. Fischer Lkbigs. Ann. Ctum. 1929.476.233. Spectroscopic data for 1: tH NMR (CDC13.300 MHz) 6 4.08 (t, 3H. J = 6.4 Ha). 3.49 @ro. 3H). 1.98 - 1.63 (m. 3H). 1.48 1.35 (m, 3H), 1.18 (q, lH, J = 1.8 Hz), 0.89 (t, 3Y J = 7.4 Hz); 13C NMR (CDC13.75.5 MHz) 6 73.55.45.42. 28.13. 10.72. Anal.Calcd. forCtoH~@:C,63.12; H, 11.65.Found:C,63.31; H. 12.00.
(Received
in UK
9 April
1994)
Vol. 5. No. 7, pi. 1161-1162,
1994
copy@t019!24Ek*scimc8w Ritlh?dillinEtfit4itt.AUIighblKMVd 0957416604
57.oo+o.00
0957-4166(94)00154-5
Enantiosektive
Reparation
of a C3 Symmetrical Trio1
HenningLiItjcnsand Paul Knochel* Fachbereich Cbemie der Philipps-Universitit
Marburg
D - 35032 Marburg. Germany
Swnmary: The new C3 symmcm’cal trio1 I has been prepared in optically pure fonn (> 98 %ee) using a catalytic enantioselective ethylation of a fimtionalized unsaturated aldehyde in an iterative way and a diastereoselective hy&oboration.
Chiral C2 symmetrical alcohols, amines. thiols or phospbines have found nutoerous applications as catalyst ligands for asymmetric synthesist CJ symmetrical ligands have been used far less for asymmttic synthesis,2 although such auxiliies should in principle lead to a beaca stereodSerentiation since the stereochernical information is concentrated in a space of 120 ’ cornpared to 180 ’ for a C2 symmetrical @and. Herein we report a stereoselective synthesis of a new C3 symmetrical trio1 1 using a catalytic asymtnetric addition of EtsZn to an unsaturated a-brorno-aldehyde 2 (eq 1). Et
OH
Br Et
HO Y Et
OH
Et/ +
ma
0
+
Et&
(1)
H
1
2
I Recently, we have shown that unsatutated a-bromoaldehydes react with functionalized dialkylxincs with excellent stereoselectivity using (1R. 2R)-1.2bis(trifluorosulfonamido)cyclohexane 34 (8 rnol %) as a catalyst. The treatment of my available (E)-2-petttenal successively with Brz (1 equiv. CH2Cl2.0 “C, 5 min) and Et3N (1.6 equiv, 0 “C) produces after filtration5 over silica gel tlte sensitive aldehyde 2 (59 % yield). Catalytic asynunetric addition ofEt2Zn (1.6 equiv) to 2 in the presence of ‘Ii(Oi-Pr)4 (1.7 equiv) and the catalyst 3 (5 mol%) in toluene (-60 “C, 2 h) affords the (S)-allylic alcohol 4 ([ah = -5.20 (c = 1.68, benzene)) in 88 % yield (50 mrnol scale reaction) and 94 %ee as determkd by tH NMR analysis of its ester derivative with (S)-(-)-0-acetylrnandelic acid6 (eq 2). The alcohol 4 was protected as a benyl aher (NaH (1 equiv); BnBr (2 equiv), lHF. rt, 12 h; 96 % yield) and amverted to tbe aldehyde 5 via a bromine-lithium exchange using r-BuLi (3 equiv, ether, -105 “C) and quenching the resulting alkenyllitltium with an excess of DMF (52 % yield). The addition of Et@ to 5 under our standard conditions affords tbe chiral1,3diol daivative 6 ([a]su = 46.5 (c = 1.70, benzene); 83 8 yi~W~iiastereoselectivity > 98 : 2; cq 3). Br
1) Br,, CH&I, c
Et&O
I H
lt
2) NEt3 59%
43) t-BuLi, -105 ‘C 4) DMF excess
Et&
Et
ONHTf u’,
2
1) NaH, THF
2) BnBr (2 equiv)
Etgrl, Ti(Oi’Pf)4 c
Et&O
(2)
AH NHTf 3 (5 mot%)
4: 66%; 94%ee
CHO Et&
Et
-
dBn
Eta,
Tipi-Pr), c
3 (5 Inor%)
5: 52%
Et &3n 6: 63%; d.r. > 982
1161
(3)
1162
H. LUTJWS
and P. KNOCHEL
To prove the relative swreochemistxy, the alcohol 7 prepared in the same way as 6 was benzylated (NaH, BnBr, THF, EQNI cat_, rt, 12 h; 83 4%yield) and submitted to ozonolysis (03, MeOH, 4 h) affording the C2 symmetrical ketone 87 ([a]=~ = +3 1.82 (c = 2.20, benzene); 69 8 yield; eq 4).
Pr
1) NaH. THF CBn 2) BnBr, DMF -
HOG.. ?Y Et
Et
Et4NI cat.
Pr 1) 03, MeOH
I
BnCL.. h Et
c
OBn Et
OBz
620 r,. Af Et
2) b2S
(4)
Et
8 9: 69% 7 Interestingly, the benzyloxy groups of 9 were oxidized to benzoates during the ozonolysis.8 The hydroboration of 6 with BH3-MezS (3 equiv. ether, rt. 12 h), followed by oxidation (35 % Hz02,O.l M NaOH, ether, rt, 2h) produces a mixture of two diastcreoisomers lOintheratio88:12.Themaprisomcrcouldbe~epara~by flash-chromatography and isolated in pure form ([a]“D = 18.4 (c = 1.25. benzene); 54 96 yield). After removal of the benzyl protecting group (Hz(l arm), Pd/C, rt, 24 h), the trio1 1 ([@b : -17.98 (c = 0.98. benzene); 90 8 yield) was obtained in pure form as indicated by IH and t3C NMR specuoscopy (eq 5).9 Applications of 1 and related molecules in asymmetric syntheses are currently underway.
1) BH&&S
H,, Pd/C
OH Et
H
2) 35% H202 0.1 M NaOH
OH
Et
t
AcOEt, 25 ‘C, 24h
10: 54%; d.r. = 88 : 12
6
Et
OH OH
(5)
Et
1:900/o
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFCi (SPP “Peroxidchemie”) research, BASF AG and Witco (Bergkamen) for generous gift of chemicals.
References and Notes. 1.
2.
3. 4.
5. 6. 7. 8. 9.
for generous support of this
(a) J. K. Whiscscll Chem Rev. 1989.89.1581; @) R. Noyti end M. Kitamin Modem Synrhrric M&ods R. Scbcff& Ed. Springer-Vexlag: Berlin, Heidelberg, 1989; Vol. 5 p. 114; (c) H. Brwmzr Top. Skmvchem 19J36.18.129; (d) H. Brmma ia The ckmisey of the meal-carbr bond, F. R. Hartley. Ed. J. Wiley and SCXIX Chichester,New-YorL 19sa. Vol. 5 p. 109. (a) B. Bogdanovic. B. Hex., B. Meistcx. H. Pauling and G. WiIke Angcw. Chewa.. I~I. Ed. Engl. 1972,ll,lU23; (b) C. BoIm. W. M. Davis, R. L. Hat-n and K. B. Shsrpleas Anger. Chem., Int. Ed. Engl. 1986.27.835; (c) C. Bolm aad K. B. Sharpless Tetrahedron fen. lm. 29.5101; (d) M. J. Bark and R. L. Harlow Angcw.Chum., In?. Ed Engl. 1990.29.1462; (e) M. J. Burk. J. E. Feuta and R. L. Harlow Tenahedron: Asymmeny 1991.2.569; (f) C. J. Tokar. P. B. Kettlcr and W. B. Tolman Organmne rallies 1992, II, 2737; (g) D. Seebach. J.M. Lapiarc. K. Skobridis and G. Greiveldingex Angcw.Chen 1994.106.457 (a) M. J. Rozema, S. AchyuthaRau and P. Knochel J. Org. Chem 1992.57.1956; (b) M. J. Roaema, C. Bisenberg, H. Llkjma, R. Gstwald, K. Belyk and P. Knochel Tetrahedron Lat. l993.34.3115. (a) M. Yoshhka. T. Kawakita and M. Ohno Tenakdron L&t. l989.30.1657; @) H. Takahashi. T. Kawakita. M. Yoshioka, S. Kobayashi and M. Ohno Terrahedron L.&f. 1989,30,7095; (c) H. Tabhbi. T. Kawakita, M Ohno, M. Yoshioka aud S. Kobayashi Tevohedron 1992.48.5691. For other Ti-catalyzed aunt&elective additiau of R2Zn tn aldehydcs. secz (d) B. Schmidt and D. Seebach Angew. Chem Int. Ed. Engl. 1991.30.99: (e) D. Seebach. L. Behrmdt and D. Felix Angew. Chem Int. Ed. Engl. 1991.30, 1008, (f) B. Schmidt and D. Seebach Aagew. Chen In!. Ed. Engf. 1991.30. 1321; (g) J. L. v. d. BusscheHttnnefeld and D. Sbebach Temzhedron 1992.48.5719; (h) D. Seebach, D. A. Plaamx. A. K. Beck. Y. M. Wang, D. Hunzikex and W. Peuex Helv. Chim. Aclcl1992.75,2171. C. J. Kowalski. A. E. Weber and K. W. Fields J. Org. Chem. 1932,47.5088. D. Parker/. Chum.SOL,Perkin Trans. 2.1983.83. For the preparation of related ketones. see: D. Endera, W. Gataweikx and U. Jegelka Synfhesis 1991.1137. F.G. Fischer Lkbigs. Ann. Ctum. 1929.476.233. Spectroscopic data for 1: tH NMR (CDC13.300 MHz) 6 4.08 (t, 3H. J = 6.4 Ha). 3.49 @ro. 3H). 1.98 - 1.63 (m. 3H). 1.48 1.35 (m, 3H), 1.18 (q, lH, J = 1.8 Hz), 0.89 (t, 3Y J = 7.4 Hz); 13C NMR (CDC13.75.5 MHz) 6 73.55.45.42. 28.13. 10.72. Anal.Calcd. forCtoH~@:C,63.12; H, 11.65.Found:C,63.31; H. 12.00.
(Received
in UK
9 April
1994)