close

Вход

Забыли?

вход по аккаунту

?

Hydrogen Bond Mediated Enantioselectivity of Radical Reactions.

код для вставкиСкачать
Angewandte
Chemie
Asymmetric Synthesis
Hydrogen Bond Mediated Enantioselectivity of
Radical Reactions**
Tobias Aechtner, Martina Dressel, and Thorsten Bach*
The renaissance in radical chemistry during the last years and
decades can be explained in large part by the improved
prediction and control of the important parameters chemo-,
regio-, and stereoselectivity.[1] Recent investigations show that
radical reactions can be carried out enantioselectively without
an auxiliary being attached covalently to the substrate.[2] Two
different strategies have been reported. On the one hand, it is
possible to differentiate the enantiotopic faces of a prochiral
radical with chiral reagents (reagent control). For this purpose
chiral hydrogen-atom donors have been used most often.[3]
On the other hand, face differentiation is possible by a Lewis
acid, which forms a chelate complex with the substrate, and
which is in turn coordinated to chiral ligands.[4] Alternative
chiral templates that are based upon noncovalent interactions
and are similarly effective have, to the best of our knowledge,
not yet been established. In a recent study we were able to
show that high enantioselectivity (up to 84 % ee) in radical
reactions can be achieved with the help of a hydrogenbonding chiral template. Our preliminary results are presented in this communication.
We investigated the enantioselectivity of the reductive
radical cyclization of 3-(w-iodoalkylidene)piperidin-2-ones
(1). These compounds can be synthesized by the aldol
condensation of N-tert-butyloxycarbonyl(Boc)piperidin-2one with w-tert-butyldimethylsilyl(TBDMS)oxyaldehydes
followed by conversion of the protected hydroxy group into
an iodo group (1. tetrabutylammonium fluoride (TBAF),
THF; 2. PPh3, imidazole, I2).[5]
In the presence of an initiator and Bu3SnH the alkenyl
iodides reacted in a 5- or 6-exo-trig-cyclization[1, 6] (e.g. 2 a!
3 a, Scheme 1). The intermediate radicals 3 exhibit a prostereogenic center in a-position to the carbonyl function which is
transformed by an intermolecular reaction with Bu3SnH to a
stereogenic saturated carbon atom. In the case of the alkenyl
iodide 1 a both enantiomeric cyclization products 4 a and ent4 a are formed during the reaction.
The reaction proceeded smoothly for the three substrates
investigated. The appropriate cyclization products were
[*] Dr. T. Aechtner, Dipl.-Chem. M. Dressel, Prof. Dr. T. Bach
Lehrstuhl fr Organische Chemie I
Technische Universit$t Mnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+ 49) 89-28913315
E-mail: thorsten.bach@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemeinschaft (Ba 1372-4/4) and by the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. 2004, 43, 5849 –5851
DOI: 10.1002/anie.200461222
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5849
Communications
Scheme 1. Mechanism of the radical cyclization 1 a!4 a/ent-4 a. The
hydrogen transfer is the enantioselectivity-determining step.
obtained in good yields (77–83 %) albeit in racemic form. The
two enantiotopic faces of the radical center in a-position to
the carbonyl function become diastereotopic when linked to a
chiral environment. We hoped to achieve such face differentiation by using the chiral complexing reagent 5,[7, 8] which
coordinates to lactams through hydrogen bonds.[9] For that
purpose the radical cyclization of 1 a to give 4 a and ent-4 a was
carried out in a series of experiments in the presence of
compound 5. BEt3 was used as the
initiator as it allowed the reactions
to be carried out at low temperature.
The reaction was indeed enantioselective.
The
enantiomeric
excess of product 4 a in the radical
cyclization[10] of iodide 1 a was dependent on three parameters
(Table 1). 1) The temperature should be as low as possible
since this leads to a remarkable increase of selectivity (e.g.
entries 5 and 9). 2) The amount of initiator BEt3 must be held
to a minimum to achieve optimum enantioselectivity
(entries 2 and 3, entries 4–6). 3) The amount of complexing
reagent used should preferably be high (entries 7 and 9).
These observations are reasonable considering the fact that
the enantiomeric excess directly reflects the ratio of bound to
unbound substrate.[9a,d] The association by means of hydrogen
Table 1: Enantioselective radical reaction (cf. Scheme 1) of substrate 1 a
to give the products 4 a and ent-4 a using the chiral complexing reagent
5.[10]
Entry
T [8C][a]
Equiv.[b]
BEt3 [mol %]
Yield [%]
ee [%][c]
1
2
3
4
5
6
7
8
9
25
25
25
10
10
10
78
78
78
–
2.5
2.5
1.0
2.5
2.5
1.0
2.5
2.5
50
20
10
50
20
10
20
50
20
83
84
72
78
82
79
91
84
81
–
38
44
20
40
55
40
41
84
[a] Reaction temperature. The reaction was carried out at the cited
temperature in toluene with Bu3SnH (2 equiv). The concentration of
substrate was 5 E 102 mol L1. The initiation occurred by addition of the
cited amount of BEt3.[10] [b] Equivalents of chiral complexing reagent 5.
The reagent was completely (> 90 %) recovered. [c] The ee values were
calculated from the enantiomeric ratios determined by HPLC analysis
(Daicel ChiralCel OD).
5850
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
bonding is ideal if the reaction is run in nonpolar solvents and
at low temperatures. Unfortunately, the reaction did not take
place at 78 8C with only 10 mol % BEt3. Despite good
reproducibility the results are not completely coherent. Thus
the minimal increase in selectivity upon decreasing the
temperature is hard to explain (entries 2 and 5). The
interactions of BEt3 and its decomposition products with
the substrate, complexing reagent, and product are apparently
complex and must be investigated in further experiments.
Selectivity in the reaction 1 a!4 a did not improve upon
photochemical initiation (Original Hanau TQ 150, duran
filter, 65 8C).
Compounds 1 b and 1 c were also reductively cyclized
under optimized conditions (Scheme 2). For the reaction of
Scheme 2. Enantioselective reductive cyclization of substrates 1 b and
1 c.
1 b we observed an insignificant increase of enantioselectivity
upon photochemical initiation (c = 5 ? 102 mol L1, light
source: Original Hanau TQ 150, duran filter). In the reaction
of 1 c under the same conditions[10] as those used for the
reaction of 1 a!4 a, initiation catalyzed by BEt3 was preferred. In every case we obtained the dextrorotatory 3cycloalkylpiperin-2-ones as products. The ee values were
calculated from HPLC analysis (for 4 b) or chiral shift
experiments (for 4 c).[11]
The comparison with literature data shows that dextrorotatory a-monoalkyl-substituted five to seven membered
ring lactams with the priority order CONH > alkyl > CH2 > H
are R configurated.[12] This configuration assignment corroborates the hypothesis that the hydrogen transfer from Bu3SnH
to radical 3, which is linked to template 5 by means of
hydrogen bonding, occurs from the Si side. The Re side is
shielded by the tetrahydronaphthalene residue. This is
illustrated in Figure 1 for the enantioselective hydrogen
transfer from Bu3SnH to the prochiral radical 3 a.
Figure 1. Model to explain the face differentiation in the intermediate
radicals 3.
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 5849 –5851
Angewandte
Chemie
In ongoing studies we are trying to apply the concept of an
enantioselective radical reaction to other model systems and
to use it in synthesis.
Received: July 7, 2004
.
Keywords: asymmetric synthesis · cyclization ·
enantioselectivity · hydrogen bonds · radical reactions
[1] General reviews: a) Radicals in Organic Synthesis (Eds.: P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001; b) T. Linker,
M. Schmittel, Radikale und Radikalionen in der Organischen
Synthese, Wiley-VCH, Weinheim, 1998; c) D. P. Curran, N. A.
Porter, B. Giese, Stereochemistry of Radical Reactions, VCH,
Weinheim, 1996.
[2] Reviews on enantioselective radical reactions: a) M. P. Sibi, S.
Manyer, J. Zimmerman, Chem. Rev. 2003, 103, 3263 – 3295; b) G.
Bar, A. Parsons, Chem. Soc. Rev. 2003, 32, 251 – 263; c) M. Sibi,
N. A. Porter, Acc. Chem. Res. 1999, 32, 163 – 171; d) P. Renaud,
M. Gerster, Angew. Chem. 1998, 110, 2704 – 2722; Angew. Chem.
Int. Ed. 1998, 37, 2562 – 2579.
[3] a) D. Nanni, D. P. Curran, Tetrahedron: Asymmetry 1996, 7,
2417 – 2422; b) M. Blumenstein, K. Schwarzkipf, J. O. Metzger,
Angew. Chem. 1997, 109, 245 – 247; Angew. Chem. Int. Ed. Engl.
1997, 36, 235 – 236; c) D. Dakternieks, K. Dunn, V. T. Perchyonok, C. H. Schiesser, Chem. Commun. 1999, 1665 – 1666; d) D.
Dakternieks, V. T. Perchyonok, C. H. Schiesser, Tetrahedron:
Asymmetry 2003, 14, 3057 – 3068; e) M. Blumenstein, M. Lemmler, A. Hayen, J. O. Metzger, Tetrahedron: Asymmetry 2003, 14,
3069 – 3077, and references therein.
[4] First original reports: a) M. Murakata, H. Tsutsui, O. Hoshino, J.
Chem. Soc. Chem. Commun. 1995, 481 – 482; b) H. Urabe, K.
Yamashita, K. Suzuki, K. Kobayashi, F. Sato, J. Org. Chem. 1995,
60, 3576 – 3577; c) J. H. Wu, R. Radinov, N. A. Porter, J. Am.
Chem. Soc. 1995, 117, 11 029 – 11 030; d) M. Nishida, H. Hayashi,
A. Nishida, N. Kawahara, Chem. Commun. 1996, 579 – 580;
e) M. P. Sibi, J. Ji, J. H. Wu, S. GHrtler, N. A. Porter, J. Am.
Chem. Soc. 1996, 118, 9200 – 9201; f) A.-R. Fhal, P. Renaud,
Tetrahedron Lett. 1997, 38, 2661 – 2664.
[5] a) J. L. GarcIa Ruano, M. M. Cifuentes, A. Lorente, J. H.
RodrIguez Ramos, Tetrahedron: Asymmetry 1999, 10, 4607 –
4618; b) A. P. Kozikowski, P. W. Shum, A. Basu, J. S. Lazo, J.
Med. Chem. 1991, 34, 2420 – 2430.
[6] a) A. L. J. Beckwith, Tetrahedron 1981, 37, 3073 – 3100;
b) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41,
3925 – 3941; c) B. Giese, B. Kopping, T. GJbel, J. Dickhaut, G.
Thoma, K. J. Kulicke, F. Trach, Org. React. 1996, 48, 301 – 856.
[7] T. Bach, H. Bergmann, B. Grosch, K. Harms, E. Herdtweck,
Synthesis 2001, 1395 – 1405.
[8] For the use of similar amides as chiral auxiliaries in radical
reactions, see J. G. Stack, D. P. Curran, S. V. Geib, J. Rebek, Jr.,
P. Ballester, J. Am. Chem. Soc. 1992, 114, 7007 – 7018.
[9] Examples: a) T. Bach, H. Bergmann, K. Harms, Angew. Chem.
2000, 112, 2391 – 2393; Angew. Chem. Int. Ed. 2000, 39, 2302 –
2304; b) T. Bach, H. Bergmann, B. Grosch, K. Harms, J. Am.
Chem. Soc. 2002, 124, 7982 – 7990; c) T. Bach, T. Aechtner, B.
NeumHller, Chem. Eur. J. 2002, 8, 2464 – 2475; d) T. Bach, B.
Grosch, T. Strassner, E. Herdtweck, J. Org. Chem. 2003, 68,
1107 – 1116; e) B. Grosch, C. N. Orlebar, E. Herdtweck, M.
Kaneda, T. Wada, Y. Inoue, T. Bach, Chem. Eur. J. 2004, 10,
2179 – 2189.
[10] Representative experimental procedure: Compund 1 a (15.0 mg,
0.05 mmol) and the chiral complexing reagent 5 (44.1 mg,
0.125 mmol) were dissolved in toluene (1 mL, Merck Uvasol).
The solution was cooled to 78 8C, and Bu3SnH (26.9 mL,
Angew. Chem. Int. Ed. 2004, 43, 5849 –5851
29.6 mg, 0.10 mmol) and BEt3 (10.0 mL, 0.01 mmol, 1m in
hexane) were added. When the reaction was complete (3 h)
silica gel was added, the solvent removed on a rotatory
evaporator, and the crude product purified by flash chromatography (silica, pentane/ethyl acetate 50:50!ethyl acetate). The
cyclization product 4 a was obtained as a colorless solid (6.8 mg,
81 %, 84 % ee). Rf = 0.16 (ethyl acetate); [a]20
D = + 45.8 (c = 0.6 in
MeOH); IR (KBr): ñ = 3190 cm1 (m, NH), 1654 (vs, C=O);
1
H NMR (360 MHz, CDCl3): d = 1.08–1.22 (m, 1 H), 1.23–1.38
(m, 1 H), 1.42–1.90 (m, 10 H), 2.22–2.43 (m, 2 H, CH-CH), 3.16–
3.30 (m, 2 H, CH2NH), 6.33 (s, 1 H, NH); 13C NMR (90 MHz,
CDCl3): d = 21.3 (CH2), 23.3 (CH2), 25.1 (CH2), 25.4 (CH2), 28.7
(CH2), 30.3 (CH2), 40.7 (CH), 42.4 (CH2NH), 44.3 (CH), 175.1
(CO); MS (EI, 70 eV): m/z (%): 167 (6) [M+], 99 (100)
[M+C5H8]; Elemental analysis for C10H17NO (167.248) (%):
calcd. C 71.81, H 10.25; found C 71.91, H 10.25.
[11] H. Bergmann, B. Grosch, S. Sitterberg, T. Bach, J. Org. Chem.
2004, 69, 970 – 973.
[12] a) D. Enders, R. Groebner, G. Raabe, J. Runsink, Synthesis 1996,
941 – 948; b) M. Brenner, D. Seebach, Helv. Chim. Acta 1999, 82,
2365 – 2379; c) Y.-G. Suh, S.-A. Kim, J.-K. Jung, D.-Y. Shin, K.-H.
Min, B.-A. Koo, H.-S. Kim, Angew. Chem. 1999, 111, 3753 – 3755;
Angew. Chem. Int. Ed. 1999, 38, 3545 – 3547.
www.angewandte.org
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5851
Документ
Категория
Без категории
Просмотров
0
Размер файла
122 Кб
Теги
hydrogen, bond, reaction, enantioselectivity, radical, mediated
1/--страниц
Пожаловаться на содержимое документа