Y. Saito et al. / Tetrahedron Letters 47 (2006) 3099–3102
Table 3. Esterification of 1a with BBDI in the coexistence of alcohols
3101
Acknowledgements
beforehand
This work was supported in part by a Grant-in-Aid for
Scientific Research (No. 15590019) and High Techno-
logy Research Program from the Ministry of Education,
Sciences, Sports and Culture of Japan and the Sasakawa
Scientific Research Grant from The Japan Science Soci-
ety (Y.S).
Entry
N-PG-AA
R0
Ester
Yield (%)a
1
2
3
1a
1a
1a
Allyl
C6H5CH2
(CH3)2CH
2a
2i
94
96
92
2n
a Isolated yield.
References and notes
Table 4. Esterification of 1a with allyl alcohol in the absence of BBDI
under several conditionsa,b
1. (a) Otera, J. Esterification. Methods, Reaction, and
Applications; Wiley-VCH: WeinHiem, 2003; (b) Multzer,
J. Carboxylic Esters and Lactione. In Comprehensive
Organic Functional Group Transformations; Moody, C.
J., Ed.; Pergamon: Oxford, 1995; Vol. 6, p 121; (c)
Sutherland, I. O.. In Comprehensive Organic Chemistry;
Barton, D. H. R., Ollis, W. D., Eds.; Pergamon Press:
Oxford, 1979; Vol. 2, pp 869–956; (d) Multtzer, J. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 323.
2. Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
1999.
3. (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J.
Org. Chem. 2004, 69, 1822–1830; (b) Disadee, W.;
Watanabe, T.; Ishikawa, T. Synlett 2003, 115–117; (c)
Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6988;
(d) Nagarajan, M.; Kumar, S. V.; Rao, B. V. Tetrahedron
Lett. 1997, 38, 5835–5838; (e) Zacharie, B.; Connolly, T.
P.; Penney, C. L. J. Org. Chem. 1995, 60, 7072–7074; (f)
Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yama-
guchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
4. Saito, Y.; Yamaki, T.; Kohashi, F.; Watanabe, T.; Ouchi,
H.; Takahata, H. Tetrahedron Lett. 2005, 46, 1277–1279.
5. Ouchi, H.; Saito, Y.; Yamamoto, Y.; Takahata, H. Org.
Lett. 2002, 4, 585–587.
Entry
Catalyst
(10 mol %)
Additive
(10 mol %)
Ester
Yield
(%)c
1
2
3
4
Isoquinoline
Quinoline
Isoquinoline
—
—
—
DMAP
DMAP
2a
2a
2a
2a
66
16
81
4
a Reaction time (24 h).
b Use of Boc2O (110 mol %).
c Isolated yield.
The issue of whether the amounts of BBDI in the esteri-
fication of 1b with allyl alcohol could be further re-
duced was next examined. The use of 5 mol % and
1 mol % of BBDI provided yields of 92% and 84% of
2d, respectively. However, to achieve this, it was neces-
sary to extend the reaction times to 48 h and 10 days,
respectively.
The data presented herein show that no significant
racemization of the chiral center on the a-carbon atom
occurred during the synthesis.10
In conclusion, we developed a novel BBDI-catalyzed
esterification of N-protected amino acids in the presence
of Boc2O under simple and mild conditions. Although a
variety of methods for acid-catalyzed esterification reac-
tions have been reported,11 the use of a nearly neutral
catalyst such as BBDI has not been extensively investi-
gated.12 This procedure has several advantages includ-
ing the use of nearly equimolar amounts of alcohols,
no requirement for additives, and no racemization
occurs.
6. General procedure for esterification of N-protected amino
acids with BBDI. BBDI (0.1 mmol) was added to a
solution of N-protected amino acid (1 mmol) and Boc2O
(1.1 mol) in CH2Cl2 (5 mL) with stirring at room temper-
ature. The reaction mixture was stirred for 30 min.
Alcohol (1 or 1.1 mmol) was added to the reaction
mixture and after the addition, the reaction mixture was
stirred for 24 h, and then concentrated. After the addition
of ethyl acetate, the organic phase was washed twice with
5% HCl and brine. The organic layers were dried (MgSO4)
and the solvent evaporated to give the crude compound,
which was purified by chromatography on a short column
using a mixture of n-hexane and ethyl acetate as eluant to
yield N-protected amino acid ester.
7. N-Protected amino acid esters were used as chiral educts
(a) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96,
1825–1872; (b) Coppola, G. M.; Schuster, H. F. Asym-
metric Synthesis. Construction of Chiral Molecules Using
Amino Acids; John Wiley & Sons: New York, 1987.
8. The exposure of quinoline to Boc2O gave no adduct (tert-
butyl 2-tert-butoxyquinoline-1(2H)-carboxylate) similar to
BBDI. Unpublished result.
OCOR
RCOOH
OtBu
N
OtBu
N
OtBu O
tBuO
O
H
regeneration
N
+
Boc2O
9. Accordingly, DMAP, quinoline, and isoquinoline would
be weak as bases for tert-butoxylation of carboxylic acid.
10. In fact, the enantiomeric purities of 2a, 2b and 2h were
>99% ee, as determined by chiral HPLC analysis (Chiral-
cel OD column, 95:5 hexane/2-propanol, 1.0 mL/min) for
2a,b and (Chiralcel OJ column) for 2h.
tBuOH
O
R
O
RCOOR'
O
OtBu
+
tBuOH + CO2
11. (a) Ishihara, K.; Ohhara, S.; Yamamoto, H. Sciences 2000,
290, 1140–1142; (b) Manabe, K.; Sun, X.-M.; Kobayashi,
S. J. Am. Chem. Soc. 2001, 123, 10101–10102; (c) Shiina, I.
R'OH
Scheme 2. Postulated mechanism of BBDI-catalyzed esterification.