RSS-Feed abonnieren
DOI: 10.1055/s-0028-1088150
Synthesis of Highly Functionalized Proline Derivatives via a One-pot Michael/Aldol Addition-Cyclization Approach
Publikationsverlauf
Publikationsdatum:
20. März 2009 (online)
![](https://www.thieme-connect.de/media/synlett/200907/lookinside/thumbnails/10.1055-s-0028-1088150-1.jpg)
Abstract
Chelated enolates undergo Michael addition towards halogenated α,β-unsaturated esters in a highly stereoselective fashion. The enolates formed can be trapped with aldehydes in a stereoselective aldol reaction, before subsequent cyclization gives rise to substituted proline derivative. Up to for stereogenic centers can be formed in this new one-pot reaction.
Key words
aldol reaction - amino acids - chelates - cyclization - Michael addition - one-pot reaction
-
1a
Shimamoto K.Ohfune Y. J. Med. Chem. 1996, 39: 407 ; and references cited therein -
1b
Shimamoto K.Ohfune Y. Synlett 1993, 919 -
1c
Ornstein PL.Bleisch TJ.Arnold MB.Wright RA.Johnson BG.Schoepp DD. J. Med. Chem. 1998, 41: 346 -
1d
Pellicciari R.Costantino G. Curr. Opin. Chem. Biol. 1999, 3: 433 -
1e
Moloney MG. Nat. Prod. Rep. 1999, 16: 485 ; and references cited therein - 2
Nitta I.Watase H.Tomiie Y. Nature (London) 1958, 181: 761 - 3 For a recent review, see:
Wang Q.Yu S.Simonyi A.Sun G.Sun A. Mol. Neurobiol. 2005, 31: 3 ; and references cited therein - 4
Sperk G. Prog. Neurobiol. 1994, 42: 1 -
5a
Goodenough S.Schleusner D.Pietrzik C.Skutella T.Behl C. Neuroscience 2005, 132: 581 -
5b
Mohmmad A.Sultana R.Keller J.St. Clair D.Markesbery W.Butterfield D. J. Neurochem. 2006, 96: 1322 -
6a
Coyle JT.Schwarcz R. Nature (London) 1976, 263: 244 -
6b
McGeer EG.McGeer PL. Nature (London) 1976, 263: 517 - 7
Yoo S.Lee S.Kim N. Tetrahedron Lett. 1988, 29: 2195 - 8
Carpes MJS.Miranda P.Correira CR. Tetrahedron Lett. 1997, 38: 1869 - 9
Sabol J.Flynn G.Friedrich D.Huber EW. Tetrahedron Lett. 1997, 38: 3687 - 10
Karoyan P.Chassaing G. Tetrahedron Lett. 2002, 43: 253 - Reviews:
-
11a
Kazmaier U. Amino Acids 1996, 11: 283 -
11b
Kazmaier U. Liebigs Ann./Recl. 1997, 285 ; and references cited therein -
12a
Pohlman M.Kazmaier U. Org. Lett. 2003, 5: 2631 -
12b
Pohlman M.Kazmaier U.Lindner T. J. Org. Chem. 2004, 69: 6909 -
12c
Mendler B.Kazmaier U.Huch V.Veith M. Org. Lett. 2005, 7: 2643 -
12d
Mendler B.Kazmaier U. Synthesis 2005, 2239 -
13a
Kazmaier U.Zumpe FL. Eur. J. Org. Chem. 2001, 4067 -
13b
Kazmaier U. Curr. Org. Chem. 2003, 317 -
13c
Kazmaier U.Pohlman M. Synlett 2004, 623 -
13d
Kazmaier U.Lindner T. Angew. Chem. Int. Ed. 2005, 44: 3303 ; Angew. Chem. 2005, 117, 3368 -
13e
Bauer M.Kazmaier U. Recent Res. Devel. Org. Chem. 2005, 9: 49 - 14
Schmidt C.Kazmaier U. Org. Biomol. Chem. 2008, 6: 4643 - 15
Schmidt C.Kazmaier U. Eur. J. Org. Chem. 2008, 887 -
16a
Grandel R.Kazmaier U.Nuber B. Liebigs Ann. 1996, 1143 -
16b
Grandel R.Kazmaier U. Tetrahedron Lett. 1997, 38: 8009 -
16c
Grandel R.Kazmaier U. J. Org. Chem. 1998, 63: 4524 -
16d
Kummeter M.Kazmaier U. Eur. J. Org. Chem. 2003, 3325 - 18 No epimerization of the ester 7a was observed. According to Seebach et
al. LHMDS is not able to deprotonate amino acid esters except glycine
and sarcosine, see:
Seebach D.Beck AK.Studer A. In Modern Synthetic Methods Vol. 7:Ernst B.Leumann C. Verlag Helvetica Chimica Acta; Basel: 1995. p.1-178 ; and references cited therein -
20a
Weygand F.Frauendorfer E. Chem. Ber. 1970, 103: 2437 -
20b
Bergeron RJ.McManis JS. J. Org. Chem. 1988, 53: 3108 -
20c
Kazmaier U.Krebs A. Tetrahedron Lett. 1999, 40: 479
References and Notes
In some cases the reactions of chelated enolates with aromatic aldehydes proceed with low diastereoselectivicity, probably because of the reversibility of the aldol process.
19It should be mentioned, that NMR is not a suitable method for determination of the isomeric ratios, because in addition to the signals of the different isomers, in general a double set of signals is observed caused by rotamers (hindered rotation around the secondary amide bond).
21
General Procedure
for Domino Michael-Aldol Additions-Cyclizations
In a Schlenk flask
HMDS (0.3 mL, 1.42 mmol) was dissolved in THF (2 mL). The solution
was cooled to -78 ˚C before n-BuLi
(1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath was removed
and the solution was allowed to warm up for 15 min, before it was
cooled again to -78 ˚C. In a second Schlenk
flask ZnCl2 (80 mg, 0.57 mmol) was dried with a heat
gun in high vacuum, before it was dissolved in THF (3 mL). After
addition of TFA-Gly-Ot-Bu (115 mg, 0.5 mmol)
the solution was cooled to -78 ˚C, before
the fresh prepared LHMDS solution was added. Then, 15 min later, the
Michael acceptor (0.45 mmol) was added in THF (2 mL). After 2 h
the corresponding aldehyde (1-1.5 mmol) was added and the
reaction mixture was allowed to r.t. overnight. The solution was
diluted with Et2O before 1 N KHSO4 was added.
The layers were separated, the aqueous phase was washed twice with
CH2Cl2, and the combined organic layers were
dried (Na2SO4). After evaporation of the solvent
in vacuo the crude product was purified by flash chromatography
(SiO2, hexanes-EtOAc).
Spectroscopic
and Analytical Data of Selected Products 9
Compound 9a
Major rotamer, (2S,3S,4R,5R)-9a: ¹H NMR (500 MHz, CDCl3): δ = 0.91
(d, J = 6.6
Hz, 2 H), 1.00 (d, J = 6.5
Hz, 2 H), 1.45 (s, 9 H), 1.56 (m, 1 H), 1.94 (m, 1 H), 2.24 (m,
1 H), 2.54 (dd, J = 11.6,
2.6 Hz, 1 H), 3.01 (m, 1 H), 3.21 (ddd, J = 12.2,
9.9, 2.4 Hz, 1 H), 3.29 (br s, 1 H), 3.63 (m, 1 H), 3.75 (s, 3 H),
3.98 (dd, J = 9.8,
9.8 Hz, 1 H), 4.38 (d, J = 7.9 Hz,
1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.2,
19.8, 27.6, 27.7, 33.1, 40.2, 46.1 (J = 3.0
Hz), 47.5, 52.0, 62.9, 77.4, 83.0, 115.8 (J = 287.6
Hz), 157.3 (J = 37.4
Hz), 168.8, 172.2.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 1.44
(s, 9 H), 1.78 (m, 1 H), 2.53 (dd, J = 11.5, 2.5
Hz, 1 H), 3.12 (m, 1 H), 3.77 (s, 3 H), 3.83 (dd, J = 11.9, 10.0
Hz, 1 H), 4.48 (dd, J = 7.4,
1.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 24.4,
32.0, 42.8, 47.9, 52.0, 61.8 (J = 2.7 Hz),
83.3, 168.9, 172.5.
Major rotamer, (2S,3S,4R,5S)-9a: ¹H
NMR (500 MHz, CDCl3): δ = 0.89
(d, J = 6.8
Hz, 2 H), 1.02 (d, J = 6.7
Hz, 2 H), 1.43 (m, 1 H) 1.44 (s, 9 H), 1.80 (m, 1 H), 2.04 (m, 1
H), 2.57 (dd, J = 7.8,
2.5 Hz, 1 H), 2.62 (br s, 1 H), 3.02 (m, 1 H), 3.56-3.65
(m, 2 H), 3.71 (s, 3 H), 3.98 (dd, J = 10.1,
9.4 Hz, 1 H), 4.61 (d, J = 7.8
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.1,
19.7, 27.9, 28.0, 34.2, 39.6, 46.0 (J = 3.5 Hz),
47.7, 51.9, 62.8, 75.6, 83.1, 168.1, 174.4.
Minor rotamer
(selected signals): ¹H NMR (500 MHz, CDCl3): δ = 1.45
(s, 9 H), 3.11 (m, 1 H), 3.72 (s, 3 H), 4.65 (dd, J = 7.4,1.4
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.0,
19.7, 47.1, 61.6 (J = 2.8
Hz), 83.6, 168.0, 174.2. GC (isothermic, 170 ˚C): t
R [(±)-(2S,3S,4R,5S)-9a] = 39.96 min; t
R [(±)-(2S,3S,4R,5R)-9a] = 49.87
min. HMRS (CI):
m/z [M + H]+ calcd
for C18H29F3NO6: 412.1947;
found: 412.1991. Anal. Calcd for C18H28F3NO6 (411.42):
C, 52.55; H, 6.86; N, 3.40. Found: C, 52.37; H, 6.71; N, 3.42.
Compound 9b
Major rotatmer, (2S,3S,4R,5R)-9b: ¹H NMR (500 MHz, CDCl3): δ = 0.89
(s, 9 H, 15-H), 1.46 (s, 9 H, 7-H), 1.50 (br s, 1 H), 2.02 (m, 1
H), 2.29 (m, 1 H), 2.58 (dd, J = 11.2,
2.3 Hz, 1 H), 2.92 (m, 1 H), 3.32 (dd, J = 10.3,
2.1 Hz, 1 H), 3.64 (m, 1 H), 3.74 (s, 3 H), 3.97 (dd, J = 9.8, 9.8
Hz, 1 H), 4.34 (d, J = 7.6
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 26.0, 27.7,
27.8, 35.8, 42.1, 44.8, 46.0 (J = 3.5
Hz), 52.1, 62.8, 79.1, 82.9, 115.8 (J = 287.6
Hz), 157.3 (J = 37.4
Hz), 168.6, 174.4.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 0.89
(s, 9 H), 1.45 (s, 9 H), 1.87 (m, 1 H), 2.56 (dd, J = 11.3,
2.2 Hz, 1 H), 3.03 (m, 1 H), 3.35 (dd, J = 10.0, 2.0
Hz, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 11.5,
10.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.7,
35.8, 45.0, 45.4, 79.1, 83.3, 169.7, 174.2. GC (isothermic, 180 ˚C): t
R [(±)-(2S,3S,4R,5S)-9b] = 32.33
min; t
R [(±)-(2S,3S,4R,5R)-9b] = 35.17
min. Anal. Calcd for C19H30F3NO6 (425.44):
C, 53.64; H, 7.11; N, 3.29. Found: C, 53.76; H, 6.85; N, 3.41.
Compound 9e
Major rotamer, (2S,3S,4R,5R)-9e: ¹H NMR (500 MHz, CDCl3): δ = 0.96
(t, J = 7.4
Hz, 3 H), 1.43 (s, 9 H), 1.50 (m, 2 H), 1.87 (br s, 1 H), 1.94 (m,
1 H), 2.25 (m, 1 H), 2.54 (dd, J = 11.6,
2.7 Hz, 1 H), 3.00 (m, 1 H), 3.59-3.66 (m, 2 H), 3.74 (s,
3 H), 3.97 (dd, J = 9.7,
9.7 Hz, 1 H), 4.45 (d, J = 8.0 Hz,
1 H). ¹³C NMR (125 MHz, CDCl3): δ = 10.5,
27.7, 27.8, 29.1, 39.7, 46.2 (J = 3.4
Hz), 49.9, 51.9, 62.9, 72.9, 83.0, 116.1 (J = 287.4
Hz), 155.9 (J = 37.4
Hz), 168.8, 172.3.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 1.42
(s, 9 H), 1.78 (m, 1 H), 2.33 (dd, J = 11.6, 2.7
Hz, 1 H), 3.11 (m, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 10.0, 10.0
Hz, 1 H), 4.50 (dd, J = 7.4,
1.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 42.7,
47.2, 61.8 (J = 2.7
Hz), 72.8, 83.4, 168.9, 172.2. The signals of the minor diastereomer
could not be separated from these of the major isomers.
GC
(155 ˚C, 60 min; 5˚/min; 180 ˚C,
3 min): t
R [(±)-(2S,3S,4R,5S)-9e] = 66.10
min; t
R [(±)-(2S,3S,4R,5R)-9e] = 75.16
min. Anal. Calcd for C17H26F3NO6 (397.39):
C, 51.38; H, 6.56; N, 3.52. Found: C, 50.98; H, 6.37; N, 3.56.
Unfortunately the aldol products obtained with aromatic aldehydes could not be analyzed by GC; NMR has to be used in this case. Therefore, we were not able to determine exact ratios, but the NMR spectra indicated that the isomers were formed in comparable amounts.