as a colorless oil; [R]22 -30.3 (c 1.78, CHCl3); >95% ee
D
(determined by 1H NMR in the presence of 40 mol % of Eu(hfc)3);
ν
max/cm-1(film) 1841 (CdO lactone), 1754 (CdO); δH (400 MHz,
CDCl3) 4.93 (1H, d, J ) 6.9 Hz), 4.32 (2H, dq, J ) 14.2, 7.1 Hz),
4.08 (1H, app quin, J ) 7.2 Hz), 1.31 (3H, t, J ) 7.1 Hz), 1.27
(3H, d, J ) 7.8 Hz); δC (100 MHz, CDCl3) 169.9, 167.2, 70.4,
62.0, 50.2, 14.2, 9.4; m/z (%) (CI, NH3) 176 (100) [M + NH4]+,
found [M + NH4]+ 176.0924. C7H14NO4 requires 176.0923.
General Procedure for Azide Opening. To a solution of sodium
azide (2 equiv) in anhydrous DMSO (half solvent volume), at 40
°C, was added â-lactone (1 equiv) in DMSO (half solvent volume).
The solution was stirred for 4 h, or until the starting material had
been consumed as judged by TLC. The reaction was cooled to room
temperature and saturated aqueous NaHCO3 was added to give a
heterogeneous solution that was then triturated with water until all
precipitate dissolved. The resulting mixture was extracted with ethyl
acetate (2 × 15 mL) and the aqueous layer was acidified to pH 0
with 1 M HCl. The acidic aqueous layer was extracted with ethyl
acetate (3 × 15 mL). The combined organics were then washed
with water (2 × 10 mL) and saturated NaCl (2 × 10 mL) and
dried over Na2SO4. The solvent was removed in vacuo to afford
the â-azido acid.
FIGURE 3. Model for C2-stereoselectivity.
explanation may be advanced by drawing an analogy with the
related ketene/imine condensation. In that process, molecular
modeling studies led Lectka to suggest the most favorable
conformations leading to cis-and trans-â-lactams are II and III,
respectively (Figure 2).22 Possibly, these are favored since they
maximize the indicated dipole-dipole repulsions, with the
former being more effective in this regard, leading to the
observed cis-selectivity. The assumption of analogous preferred
conformations IV and V in the â-lactone synthesis (Figure 3)
would again explain the observed cis-selectivity. It is then
reasonable to suggest that replacement of the glyoxylate’s ester
group with the more bulky trichloromethyl group of chloral
would disfavor TS-IV due to steric interactions with the
ammonium substituent, thus favoring TS-V and hence the trans-
product.13,23 However, we cannot rule out the possibility that
product epimerization is responsible for the reported trans-
selectivity in the chloral case.
8a: Lactone (2S,3S)-2a (0.14 g, 0.89 mmol) in DMSO (1.5 mL
(half solvent volume)) was used as described to afford the (2R,3S)-
product (0.11 g, 0.55 mmol, 60%) as a pale yellow oil in a >9:1
ratio of diastereomers; [R]22 +62.9 (c 0.35, CHCl3); νmax/cm-1
D
(film) 2116 (N3), 1742 (CdO), 1741 (CdO); δH (400 MHz, CDCl3)
9.49 (1H, s), 4.31-4.25 (2H, dq, J ) 14.4, 7.2 Hz), 4.18 (1H, d,
J ) 6.1 Hz), 3.11-3.04 (1H, app. dq, J ) 6.1, 7.1 Hz), 1.31 (3H.
t, J ) 7.2 Hz), 1.27 (3H, d, J ) 7.1 Hz); δC (100 MHz, CDCl3)
178.6, 168.6, 63.7, 62.4, 41.6, 14.1, 13.2; m/z (%) (CI, NH3) 219
(100) [M + NH4]+, found [M + NH4]+ 219.1087. C7H15N4O4
requires 219.1093.
In conclusion, we have developed a short, diastereo- and
enantioselective route to â-alkyl aspartates employing cinchona
alkaloid organocatalysis. The method has been used for the
synthesis of â-methyl aspartic acid 10, a component of the
phosphatase inhibitor motuporin.
General Procedure for Azide Reduction. To a solution of azido
acid (1 equiv) in methanol (10 mL) was added Pd/C (10% by mass).
The reaction was stirred under a positive pressure of hydrogen,
using a H2 balloon, for 3 h, then filtered through celite and washed
with methanol (25 mL). The solvent was removed in vacuo to afford
the â-amino acid.
9a: Azido acid (2R,3S)-8a (0.12 g, 0.59 mmol) was used as
described to afford the (2R,3S)-product (0.10 g, 0.57 mmol, 99%)
Experimental Section
as a white solid in a >9:1 ratio of diastereomers; [R]22 -8.5 (c
D
General Experimental Details. General experimental procedures
are provided in the Supporting Information. The ethyl glyoxylate
used in the lactonization reaction was obtained commercially as a
quoted 50% solution in toluene. By 1H NMR analysis, it was
estimated to be ca. 1.4 M in glyoxaldehyde and the quantity used
in the reactions was calculated on this basis. Racemic samples of
â-lactones were prepared for chiral HPLC comparison, using
triethylamine (1 equiv) and Hu¨nigs base (1 equiv) (see the
Supporting Information). rac-2a was also carried through to the
N-Fmoc-dimethyl ester of rac-10a for chiral HPLC comparison.
General Procedure for Catalytic Enantioselective â-Lactone
Synthesis. To a rapidly stirred solution of triethylamine (14 µL,
0.10 mmol, Hu¨nig’s base (0.35 mL, 2.0 mmol) and catalyst (47
mg, 0.10 mmol) in chloroform (1 mL), at -60 °C, was added a
mixture of ethyl glyoxylate (0.71 mL of 1.4 M in toluene, 1 mmol)
and acid chloride (1.5 equiv) in chloroform (1 mL) over 0.5 h.
The reaction was then stirred for 2.5 h at which point most of the
solvents were removed in vacuo. The crude product was purified
by flash column chromatography (2:1 petrol:ether eluant) to afford
â-lactone.
3.28, MeOH); mp 150-151 °C; νmax/cm1(neat) 3390 (O-H/N-H
br), 1739 (CdO); δH (400 MHz, D2O) 4.30-4.16 (2H, m), 4.09
(1H, d, J ) 4.3 Hz), 3.07-3.00 (1H, dq, J ) 4.3, 7.6 Hz), 1.22
(3H, d, J ) 7.6 Hz); 1.21 (3H, t, J ) 7.1 Hz); δC (100 MHz, D2O/
20 mol % MeOH) 180.4, 171.9, 64.0, 56.1, 42.3, 14.5, 13.8; m/z
(%) (CI, NH3) 176 (100) [M + H]+, found [M + H]+ 176.0928.
C7H14NO4 requires 176.0923.
Hydrolysis of 9a To Give 10. To a solution of amino acid 9a
(0.85 g, 4.9 mmol) in water (100 mL) was added 1 M NaOH (15
mL). The reaction was stirred at room temperature for 24 h after
which time the solution was acidified to pH 0 with 1 M HCl. The
solvent was removed in vacuo and the resulting white solid freed
from the HCl salt by using a column of Dowex 50WX8-100 ion-
exchange resin to afford (2R,3S)-102 (0.48 g, 3.3 mmol, 69%) as a
colorless thick oil; [R]22D -31.0 (c 2.00, 5M HCl); νmax/cm-1 (nujol)
3429-2854 (O-H/N-H br), 1588 (N-H); δH (400 MHz, D2O)
3.65 (1H, d, J ) 5.3 Hz), 2.87 (1H, app. qd, J ) 7.5, 5.3 Hz), 1.26
(3H, d, J ) 7.5 Hz); δC (100 MHz, D2O/20 mol % MeOH) 181.4,
174.3, 58.0, 42.1, 15.6; m/z (ES-) found [M - H]-, 146.0446. C5H8-
NO4 requires 146.0453.
Enantiomeric Excess Determination for 10. To a solution of
amino acid 10 (20 mg, 0.14 mmol) in water (0.5 mL) was added
NaHCO3 (23 mg, 0.27 mmol) with stirring. The resulting solution
was cooled to 5 °C and FmocCl (50 mg, 0.20 mmol) is added slowly
as a solution in dioxane (0.5 mL). The mixture was then stirred at
0 °C for 1 h and allowed to warm to room temperature overnight.
2a: Propionyl chloride (0.13 mL, 1.5 mmol) was used as
described to afford the (2S,3S)-lactone (0.09 g, 0.52 mmol, 55%)
(22) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.;
Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626-6635.
(23) Weatherwax, A.; Abraham, C. J.; Lectka, T. Org. Lett. 2005, 7,
3461-3463.
J. Org. Chem, Vol. 72, No. 21, 2007 8093