Asymmetric Oxidative Dimerization of Glycinates
J . Org. Chem., Vol. 62, No. 8, 1997 2481
assignment of 13C NMR spectra has been carried out with the
aid of the DEPT-135 pulse sequence. MS spectra were carried
out by electron impact at 70 eV. Compounds 1a ,26 1b,27 1c,28
and 1d 12 were prepared as previously described.
increase in enolate 2-E formation. In the presence of
DMPU as cosolvent or KOtBu an open transition state
should operate which rendered products 3 in expected
thermodynamical ratios.16 In Et2O as the solvent higher
aggregation of the lithium bases is expected. This
increases 1,3-diaxial interactions operating in intermedi-
ate Z*. This interaction overwhelms the A1,3-strain in
E* in the case of glycinate 1b favoring 2b-E enolate
formation and 3b -II production as compared with the
assays carried out in THF.
Dim er iza tion of th e Ch ir a l Glycin a te 1d . On the
basis of previous studies on alkylations of enolate 212,23
steric hindrance of the re face of Ca of 2d -Z as well as
hindrance of the si face of Ca of 2d -E is to be expected.
Recent studies on radical reactions have put forward the
applicability of models previously developed for ionic
reactions.24 Parallelism between enolates and carbonyl-
substituted radicals has been reported.25 Thus a lk
approach of enolate 2d -Z to radical 6d should take place
in a si+si fashion (matched pair, transition state A of
Scheme 5), affording (2S,3S)-3d -I. The ul approach of
enolate 2d -E to radical 6d should take place in a si+re
fashion (mismatched pair, transition state C of scheme
5), giving rise to 3d -II (meso).
Gen er a l P r oced u r e for th e Oxid a tive Cou p lin g of
Glycin a tes 1. Rea ction s w ith LDA (Meth od A). To a
i
solution of Pr2NH (1.06 mmol, 0.15 mL) in THF or Et2O (1.0
mL) at -78 °C was added a 1.6 M solution of BuLi in hexane
(1.1 mmol, 0.7 mL). After 30 min, a solution of 1a -d (0.96
mmol) in THF or Et2O (1.2 mL) was added, and the mixture
was stirred for 1 h. A solution of I2 (0.48 mmol, 122 mg) in
THF or Et2O (1.5 mL) was dropwise added at -78 °C with
vigorous stirring. The temperature was slowly raised to 25
°C and the mixture stirred at this temperature for 20 h. The
reaction mixture was hydrolyzed with brine (4 mL). The
organic layer was decanted and the aqueous one extracted with
Et2O (3 × 10 mL). The combined organic extracts were dried
over MgSO4. Evaporation under reduced pressure afforded
an oil which was purified by column chromatography on silica
gel, eluting with a mixture of hexane-ethyl acetate 80:20.
Gen er a l P r oced u r e for th e Oxid a tive Cou p lin g of
Glycin a tes 1. Rea ction s w ith tBu Li a n d sBu Li (Meth od
B). To a 1.7 M solution of tBuLi in pentane or a 1.3 M solution
of sBuLi in cyclohexane (1.06 mmol) in THF or Et2O (1.0 mL)
at -78 °C was added a solution of 1a -d (0.96 mmol) in THF
or Et2O (1.2 mL) and all operations continued as above.
Gen er a l P r oced u r e for th e Oxid a tive Cou p lin g of
Glycin a tes 1. Rea ction s w ith KOtBu (Meth od C). To a
solution of KOtBu (1.06 mmol, 120 mg) in THF or Et2O (1.0
mL) at -78 °C was added a solution of 1a -d (0.96 mmol) in
THF or Et2O (1.2 mL) and all operations continued as above.
Con clu sion s
The adequate selection of the starting material 1 and
the lithium base used for its deprotonation allowed for
the synthesis of the threo (C2 symmetry) products 3 under
kinetic-controlled conditions. On the other hand, the use
of KOtBu as the base afforded compounds 3 in ratios
corresponding to a thermodynamic control. Facial dias-
tereoselectivity was enforced starting from a homochiral
ester, albeit at the expense of simple diastereoselectivity.
The extension of this methodology to other substrates
could allow for the preparation of chiral ethylenediamine
derivatives with anticipated utility as pharmacologically
active compounds.
(2S*,3S*)-Eth yl 3-Am in o-N,N′-bis[bis(m eth ylth io)m e-
th ylen e]aspar tate (3a-I). Method A (THF) (55%): IR (CHCl3)
3
1740, 1680 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.23 (6H, t, J
) 7 Hz), 2.36 (6H, s), 2.55 (6H, s), 4.17 (4H, q, 3J ) 7 Hz),
5.05 (2H, s); 13C (75.5 MHz, CDCl3) δ 14.3, 15.0, 15.4, 61.1,
68.1, 162.2, 168.9. Anal. Calcd for C14H24N2O4S4: C, 40.76;
H, 5.86; N, 6.79. Found: C, 40.89; H, 5.99; N, 6.90.
(2S*,3R*)-Eth yl 3-Am in o-N,N′-bis[bis(m eth ylth io)m e-
th ylen e]a sp a r ta te (3a -II). Method C (THF) (50%): mp 82-
84 °C (hexane-ethyl acetate); IR (CHCl3) 1740, 1680 cm-1; 1H-
NMR (300 MHz, CDCl3) δ 1.25 (6H, t, 3J ) 7 Hz), 2.37 (6H, s),
2.56 (6H, s), 4.17 (4H, q, 3J ) 7 Hz), 5.00 (2H, s); 13C (75.5
MHz, CDCl3) δ 14.3, 15.1, 15.6, 61.2, 69.0, 162.4, 170.2. MS
413 (M + 1), 365, 339, 292, 206, 133. Anal. Calcd for
C14H24N2O4S4: C, 40.76; H, 5.86; N, 6.79. Found: C, 40.99;
H, 5.99; N, 6.66.
Exp er im en ta l Section
All starting materials were commercially available research-
grade chemicals and used without further purification. THF
was distilled after refluxing over Na/benzophenone. Diiso-
propylamine and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyri-
midinone (DMPU) were dried over CaH2 and freshly distilled
under Ar prior to use. Silica gel 60 F254 was used for TLC,
and the spots were detected either with UV or with ninhydrin
solution. Flash column chromatography was carried out on
silica gel 60. Ion exchange chromatography was performed
on Dowex-50(H). IR spectra have been recorded as CHCl3
solutions. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded at 300 and 75.5 MHz, respectively, in
CDCl3 solution with TMS as internal reference, and full
(2S*,3S*)-ter t-Bu tyl 3-Am in o-N,N′-bis[bis(m eth ylth i-
o)m eth ylen e]a sp a r ta te (3b-I). Method A (THF) (80%): mp
1
111-112 °C (MeOH); IR (CHCl3) 1740, 1690 cm-1; H-NMR
(300 MHz, CDCl3) δ 1.50 (18H, s), 2.36 (6H, s), 2.54 (6H, s),
4.90 (2H, s); 13C (75.5 MHz, CDCl3) δ 14.9, 15.3, 28.1, 67.8,
81.4, 162.1, 168.8. Anal. Calcd for C18H32N2O4S4: C, 46.13;
H, 6.88; N, 5.98. Found: C, 46.25; H, 6.67; N, 5.79.
(2S*,3R*)-ter t-Bu tyl 3-Am in o-N,N′-bis[bis(m eth ylth i-
o)m eth ylen e]a sp a r ta te (3b-II). Method C (THF) (40%): mp
1
101-103 °C (hexane); IR (CHCl3) 1740, 1690 cm-1; H-NMR
(300 MHz, CDCl3) δ 1.40 (18H, s), 2.27 (6H, s), 2.45 (6H, s),
4.84 (2H, s); 13C (75.5 MHz, CDCl3) δ 14.7, 15.4, 28.4, 67.5,
81.2, 161.9, 169.0; MS 469 (M+1), 421, 367, 234, 178. Anal.
Calcd for C18H32N2O4S4: C, 46.13; H, 6.88; N, 5.98. Found:
C, 46.05; H, 6.95; N, 6.05.
(23) For the use of (-)-8-phenylmenthol as chiral inducer see: (a)
Comins, D. L.; Guerra-Weltzien, L.; Salvador, J . M. Synlett 1994, 972
and references cited therein. In connection with π-facial diastereose-
lectivity in 8-phenylmenthyl derivatives, there is theoretical and
spectroscopic evidence of a π-π stabilizing interaction of the conformer
which has a cis relative disposition of the aromatic ring and the
conjugated system of the side chain. See: (a) Solladie´-Cavallo, A.;
Khiar, N. Tetrahedron Lett. 1988, 29, 2189. (b) Denmark, S. E.;
Schnute, M. E.; Senayake, C. B. W. J . Org. Chem. 1993, 58, 1859. (c)
Maddaluno, J . F.; Gresh, N.; Giessner-Prettre, C. J . Org. Chem. 1994,
59, 793. (d) Shida, N.; Kabuto, C.; Niwa, T.; Ebata, T.; Yamamoto, Y.
J . Org. Chem. 1994, 59, 4068.
(2S*,3S*)-Eth yl 3-Am in o-N,N′-bis(d ip h en ylm eth ylen e)-
a sp a r ta te (3c-I). Method B (tBuLi, THF) (90%): mp 134-
135 °C (ethyl acetate-MeOH); IR (CHCl3) 1670, 1640, 1600
cm-1
;
1H-NMR (300 MHz, CDCl3) δ 1.20 (6H, t, 3J ) 7 Hz),
3
4.10 (4H, q, J ) 7 Hz), 4.95 (2H, s), 7.20-7.62 (20H, m); 13C
(75.5 MHz, CDCl3) δ 14.1, 61.1, 67.9, 127.8, 127.9, 139.0, 139.4,
170.1, 171.9; MS 533 (M+1), 459, 351, 266, 193. Anal. Calcd
(24) (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1995. (b) Porter, N. A.; Giese,
B.; Curran, D. P. Acc. Chem. Res. 1991, 24, 296.
(25) Bulliard, M.; Zehnder, M.; Giese, B. Helv. Chim. Acta 1991,
74, 1600.
(26) Alvarez Ibarra, C.; Quiroga, M. L.; Mart´ın-Santos, E.; Toledano,
E. Org. Prep. Proc. Int. 1991, 23, 611.
(27) Alvarez Ibarra, C.; Csa´ky¨, A. G.; Maroto, M.; Quiroga, M. L. J .
Org. Chem.1995, 60, 6700.
(28) O’Donnell, M. J .; Polt, R. L. J . Org. Chem. 1982, 47, 2663.