Garner aldehyde (8)7 derived from L-serine did react with
the enolate of compound 7 generated with LDA at -78 °C
to produce condensation product 9. This molecule possesses
a â-hydroxyl group which was removed by Barton deox-
genation6,8 to provide the deoxygenated product 10 with
Scheme 2. Synthesis of a Phenyl Analogue of Monatin (13)
1
excellent diastereoselectivity (17:3) as determined by H
NMR spectroscopy. Selective deprotection with PPTS in
refluxing ethanol9 afforded the Boc-protected â-amino
alcohol 11 in good yield. The primary alcohol 11 was
oxidized to carboxylic acid 12 with PDC without epimer-
ization at the C4 position.9 Compound 12 and the small
amount of diastereomer were separable, and optically pure
product 12 was obtained. We established by NMR spectros-
copy that the major product 12 possessed the (2S,4R)
configuration.4,5 Final deprotection of the Boc and pivalidene
protections of compound 12 was afforded by allowing the
reaction to reflux in 0.1 N HCl/HCO2H for 3 h. Subsequent
purification provided the (2S,4R) phenyl analogue of Monatin
(13) which did not possess a sweet taste.
Since separation of the diastereomers of the phenyl
analogue 12 was successful, we applied this strategy to the
preparation of Monatin (1, Scheme 3). This synthesis
commences with commercially available racemic indolelactic
acid (3). The pivalidene derivatives 2 were obtained in good
yield by following the same procedure as that reported above
for the preparation of compound 7. Reaction of the appropri-
ate enantiomer of the Garner aldehyde (14) with the enolates
of intermediates 2 produced compounds 15. In this reaction,
dimerization of intermediates 2 can readily occur. To avoid
this side reaction, it was necessary to maintain the reaction
temperature below -76 °C. Deoxygenation of isomers 15
produced the diastereomeric pair 16.10 Deprotection of the
pivalidene group gave the hydroxymethylene molecules 17a
and 17b11 which were readily oxidized to the carboxylic acid
structures 18a and 18b12 using PDC. These reactions were
successfully carried out using reaction conditions similar to
those described above for the preparation of a phenyl
analogue of Monatin, compound 13.
a (a) (CH3)3CCHO (1.2 equiv), BF3‚Et2O (1.2 equiv), Et2O, -20
°C, 2 h; (b) 7 (1.0 equiv), 8 (1.1 equiv), LDA (1.2 equiv), THF,
-78 °C, 2 h; (c) NaH (3.0 equiv), THF, -15 °C f rt, 40 min, CS2
(3.0 equiv), 0 °C, 20 min, MeI (3.0 equiv), rt, 30 min; (d) n-Bu3SnH
(6.0 equiv), AIBN (3.0 equiv), Ph-CH3, ∆, 2 h, Ar; (e) PPTS (1.0
equiv × 3), EtOH/H2O (95:5), ∆, 6 h; (f) PDC (6.0 equiv), DMF,
rt, 24 h; (g) 0.1 N HCl/HCO2H, ∆, 3 h. LDA ) lithium
diisopropylamide, AIBN ) 2,2′-azobis(isobutyronitrile), PPTS )
pyridinium p-toluenesulfonate, PDC ) pyridinium dichromate,
DMF ) N,N′-dimethylformamide.
prepared from R-hydroxycarboxylic acids and pivalaldehyde
through the Li-enolate.3 This reaction has been applied to
many total syntheses.4 We used this method as a key step in
the synthesis of a phenyl analogue of Monatin (13). The
optically pure cis-dioxolanone 7 was obtained in 95% yield.5
Alkylation at the R-carbon of compound 7 was unsuccessful
using iodoalanine derivatives. We believe that the sterically
hindered enolate of compound 7 cannot react with the bulky
iodoalanine derivatives in a displacement reaction.6 The
The final deprotection steps used for the phenyl analogue
could not be applied to Monatin (1) because decomposition
of the indole group occurs under the acidic conditions
employed. Compounds 18a and 18b were successfully
converted to the diastereomeric mixture of lactams 19a and
(6) (a) Forsyth, C. J.; Sabes, S. F.; Urbanek, R. A. J. Am. Chem. Soc.
1997, 119, 8381-8382. (b) Sabes, S. F.; Urbanek, R. A.; Forsyth, C. J. J.
Am. Chem. Soc. 1998, 120, 2534-2542.
(7) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361. (b) Garner,
P.; Park, J. M. Org. Synth. 1991, 70, 18.
(8) Barton, D. H. R.; McCombie,S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574.
(3) (a) Seebach, D.; Naef, R. HelV. Chim. Acta 1981, 64, 2704. (b)
Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40(8), 1313-1324.
(4) (a) Hiwa, H.; Ogawa, T.; Yamada, K. Bull. Chem. Soc. Jpn. 1990,
63, 3707-3709. (b) Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K.
J. Am. Chem. Soc. 1991, 113, 9682-9684. (c) Bojack, G.; Bornowski, H.
Tetrahedron 1991, 47(44), 9179-9186. (d) McPherson, D. W.; Knapp, F.
F., Jr. J. Org. Chem. 1996, 61, 8335-8337. (e) Visser, T. J.; Waarde, A.
V.; Jansen, T. J. H.; Visser, G. M.; Mark, T. W. V. D.; Kraan, J.; Ensing,
K.; Vaalburg, W. J. Med. Chem. 1997, 40, 117-124.
(5) (a) Farines, M.; Soulier, J. Bull. Soc. Chim. Fr. 1970, 332. (b) Hoye,
T. R.; Peterson, B. H.; Miller, J. D. J. Org. Chem. 1987, 52, 1351. (c)
Pearson, W. H.; Cheng, M. J. J. Org. Chem. 1987, 52, 1353. (d) Ortholand,
J. Y.; Greiner, A. J. Bull. Soc. Chim. Fr. 1993, 130, 133. (e) Nicos, A. P.;
Shao-Po, L. J. Am. Chem. Soc. 1995, 117, 6394-6395.
(9) (a) Jako, I.; Uiber, P.; Mann, A.; Wermuth, C.-G.; Boulanger, T.;
Norberg, B.; Evard, G.; Durand, F. J. Org. Chem. 1991, 56, 5729. (b) Muller,
M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 3289. (c) D’Aniello,
F.; Mann, A.; Taddei, M.; Wermuth, C.-G. Tetrahedron Lett. 1994, 42,
7775. (d) D’Aniello, F.; Falorni, M.; Mann, A.; Taddei, M. Tetrahedron:
Asymmetry 1996, 7(4), 1217-1226.
(10) The diastereomeric ratio was not established.
(11) The ratio of diastereomers was approximately 3:2 as determined
1
by H NMR spectroscopy.
(12) The ratio of diastereomers was approximately 4:3 as determined
by HPLC.
2968
Org. Lett., Vol. 2, No. 19, 2000