authers used an asymmetric Strecker amino acid approach
for the preparation of the key tryptophan 2 starting with the
aldehyde 6. One of our two routes to 2 involves the aldehyde
6. Our synthesis of 6 is one step from N-methylindole, and
our version of an asymmetric Strecker synthesis complements
that of Vedejs group.
mixture of R-cyano amines; chromatographic separation gave
the desired isomer 7 in 70% yield. The auxiliary was
removed via Pb(OAc)4 in MeOH:CH2Cl2, and the resultant
chiral R-aminonitrile 8 was hydrolyzed in refluxing concen-
trated hydrochloric acid. The amino acid thus obtained was
capped as the Boc derivative and methylated with NaH/CH3I
to afford 2. The overall yield of 2 from N-methylindole was
16%. The HPLC purity of the corresponding deprotected
amino acid was 96%. The absolute stereochemistry was
assigned on the basis of analogy with the synthesis of tert-
butylglycine from pivalaldehyde via this route.7a
The sequence for the first route is shown in Scheme 1.
Tin tetrachloride mediated ring opening of the cyanoepoxide
Scheme 1a
To illustrate the potential for analogue synthesis, the spiro
epoxynitrile 9 and N-methylindole were converted to the
tryptophan derivative 10 in 20% overall yield using the same
synthetic sequence (Scheme 2). Coupling of 4a or 9 to
Scheme 2
indoles substituted in the benzenoid ring should readily lead
to additional analogues of 2 and 10.
In an alternative approach, racemic N-methyl-â,â-di-
methyltryptophan methyl ester hydrochloride 14 was pre-
pared as shown in Scheme 3. Acid-catalyzed ring opening
a Reagents and conditions: (a) SnCl4, CH2Cl2, -78 °C, 70%;
(b) NaOH, EtOH 95%; (c) (R)-phenylglycinol, CH2Cl2, TMSCN;
(d) Pb(OAc)4, MeOH/CH2Cl2; (e) 3 N HCl, Et2O, 55% over two
steps; (f) concentrated HCl reflux; (g) (Boc)2O, Na2CO3, THF/H2O;
(h) NaH, MeI, DMF, 65% over three steps.
Scheme 3. Synthesis of rac-N-
4a5 in CH2Cl2 at -78 °C in the presence of N-methylindole,
3, gave the 3-indoyl-substituted cyanohydrin 5 in 72% yield.
Exposure of 5 to NaOH provided aldehyde 6 in quantitative
yield. The same aldehyde could be obtained directly in 52%
yield via the SnCl4-catalyzed ring opening of the epoxy-
sulfone 4b6 in the presence of 3. The stage was now set to
transform 6 into the highly methylated, enantiomerically
enriched tryptophan derivative 2. There have been a number
of reports outlining asymmetric versions of the classic
Strecker R-amino acid synthesis.7 We chose to use (R)-
phenylglycinol7a as chiral auxiliary to accomplish this goal.
Aldehyde 6 was reacted with (R)-phenylglycinol to give the
expected imine which was captured with TMSCN. This
sequence led to the formation of an 85:15 diastereomeric
Methyl-ss,ss-dimethyltryptophan Methyl Ester‚HCl (14)a
a Reagents and conditions: (a) SnCl4, CH2Cl2, -78 °C, 70%;
(b) DEAD/Ph3P, DPPA, pyridine, CH2Cl2, 0 °C, 85%; (c) Ph3P,
H2O, THF, 65%.
(4) Vedejs, E.; Kongkittingam, C. J. Org. Chem. 2001, 22, 7355.
(5) Ayi, A. I., Guedz. R. M. R. Tetrahedron Lett. 1981, 22, 1505.
(6) (a) Vogt, P. F.; Travers, D. F. Can. J. Chem. 1969, 47, 2875. (b)
Durst, T.; Tin, K.-C. Tetrahedron Lett. 1970, 2369.
(7) (a) Chakraborty, T. K.; Azhar Hussain.; Venkat Reddy, G. Tetra-
hedron. 1995, 51, 9179. (b) Weinges, K.; Gries, K.; Stemmle, B.; Schrank,
W. Chem. Ber. 1977, 110, 2098. (c) Davis, F. A.; Reddy, R. E.; Portonovo,
P.S. Tetrahedron Lett. 1994, 35, 9351. (d) Ishitani, H.; Komiyama, S.;
Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762. (e) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315. (f) Inaba, T.;
Kozono, I.; Fujita, M.; Ogura, K. Bull. Chem. Soc. Jpn. 1992, 65, 2359.
(g) Kunz, H.; Sager, W. Angew Chem, 1987, 99, 595. Angew Chem., Int.
Ed. Engl. 1987, 26, 557.
of the glycidic ester 11 with SnCl4 in CH2Cl2 at -78 °C in
the presence of N-methylindole afforded the tryptol 12 in
70% yield. We were pleased with the 70% yield obtained in
the reaction of 11 with N-methylindole, as earlier reports
using 3-methylglycidates with various indoles and SnCl4
typically displayed yields under 40%.6
Mitsunobu azidation of 12 gave the azide 13 which was
reduced with triphenylphosphine in wet THF to afford the
696
Org. Lett., Vol. 4, No. 5, 2002