Selective reduction of N-protected-α-amino lactones to lactols with lithium tri-tert-butoxyaluminohydride

Article abstract of DOI:10.1016/S0040-4039(00)02242-5

α-Amino lactols 3 can be prepared in good yield and high optical purity by reduction of α-amino lactones 2 with lithium tri-tert-butoxyaluminohydride (LiAlH(O-t-Bu)₃).

Full text of DOI:10.1016/S0040-4039(00)02242-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1329–1330
Selective reduction of N-protected-a-amino lactones to lactols
with lithium tri-tert-butoxyaluminohydride
Lee Tai Liu,* Hsiang-Ling Huang and Chia-Lin Jeff Wang
Development Center for Biotechnology, 102, Lane 169, Kang-Ning St., Hsi-Chih 221, Taipei, Taiwan, ROC
Received 21 July 2000; revised 27 November 2000; accepted 6 December 2000
Abstract—a-Amino lactols 3 can be prepared in good yield and high optical purity by reduction of a-amino lactones 2 with
lithium tri-tert-butoxyaluminohydride (LiAlH(O-t-Bu)3). © 2001 Elsevier Science Ltd. All rights reserved.
Optically active N-protected a-amino aldehydes are
important intermediates for the preparation of amino
alcohols and peptide analogues of biological interest.1
Moreover, recently published papers revealed that some
of the peptide C-terminal aldehydes are crucial compo-
nents of potent inhibitors of interleukin converting
enzyme and calpain.2 However, a-amino aldehydes can-
not be purified by chromatography nor be stored at
room temperature for some time because these com-
pounds racemize easily on silica gel and at room tem-
perature. In order to overcome these problems,
N-carbobenzyloxy a-amino lactols (hemiacetals) 3 have
been used as the precursor or equivalents of the corre-
sponding a-amino aldehydes by some research groups.
For example, Kim and Iyengar independently reported
the reduction and alkylation of various lactols to the
corresponding alcohols.3 Although diisobutylaluminum
hydride (DIBAL-H) and sodium borohydride have
been used by these chemists to prepare lactols from the
corresponding a-amino lactones, we found that these
two reagents and the reaction conditions were not
reproducible in our hands. Over-reduction and/or
unidentified compounds instead of the desired lactols 3
were the major products. Herein, we report that lithium
tri-tert-butoxyaluminohydride (LiAlH(O-t-Bu)3) is a
more efficient and selective reagent than DIBAL-H or
sodium borohydride for the reduction of lactones 2 to
lactols 3.
Lactones 2 were prepared according to a procedure in
the literature.4 Reduction of lactones 2 with 1.2 equiv.
of LiAlH(O-t-Bu)3 at −78°C for 10 min followed by
Scheme 1. Reagents and conditions: (a) see Ref. 4; (b) 1.0 M lithium tri-tert-butoxyaluminohydride in THF (1.2 equiv.),
tetrahydrofuran, −78°C, 10 min, then 0–18°C, 6–24 h, 80–87%; (c) acetic anhydride, N-methylmorpholine, dichloromethane,
0–18°C, 2 h, 90%; (d) methyl iodide, silver(I) oxide, 0–18°C, 4 days, 80–90%.
Keywords: chiral a-amino lactol; lithium tri-tert-butoxyaluminohydride.
* Corresponding author. Fax: 886-2-26953404; e-mail: ltliu@mail.dcb.org.tw
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02242-5

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L. T. Liu et al. / Tetrahedron Letters 42 (2001) 1329–1330
complete (monitored by TLC), the solution was
quenched with a 20% citric acid solution (5 mL) in an
ice bath. The suspension was concentrated to remove
tetrahydrofuran. The residue was extracted with ethyl
acetate several times. The organic layer was combined,
washed with brine, dried over magnesium sulfate,
filtered, and concentrated. Purification by chromatogra-
phy over silica gel (hexane/ethyl acetate 4:1) provided
0.20 g (80%) of pure lactol 3b as a pale yellow oil.5
stirring at 0–18°C for 6–24 h gave the desired lactols 3
(Scheme 1). The pure lactols 3 were obtained as a
viscous liquid in 80–90% yield after chromatography
over silica gel (Table 1).5 We observed that LiAlH(O-t-
Bu)3 is very mild and gives reproducible yields. No
lactone 2 was reduced if the reaction was performed at
−78°C overnight. The reductions were completed within
six hours at 0–18°C, but the yields were not influenced
even if the solution was stirred at this temperature
overnight. Only a trace amount of unreacted lactone 2
and/or overreduction product(s) were detected by TLC
under these reaction conditions. However, the amount
of the over-reduced compound(s) significantly increased
if LiAlH(O-t-Bu)3 was added to a lactone solution in
an ice bath or even at room temperature. No racemiza-
tion was observed during the chromatography process
because the specific rotation value of the lactol 3a
purified by chromatography is higher than that of the
crude compound. It is also noticeable that the lactols 3
obtained from the LiAlH(O-t-Bu)3 reduction in this
study have higher specific rotation values than those
obtained from the sodium borohydride reduction.3c
Although the optical purity of these lactols 3 did not
significantly change after storage at room temperature
for several days, however, cold storage is strongly rec-
ommended to avoid any possible deterioration and/or
oxidation. Of course, conversion of the hemiacetal (e.g.
3a) to the corresponding acetal (e.g. 4a or 4b) should be
more suitable for prolonged storage at room tempera-
ture. The specific rotation value of acetal 4b showed
that the optical purity was nearly unchanged after
storage at room temperature for several months.
Acknowledgements
Financial support from the Ministry of Economic
Affairs of ROC and the NMR analytical support pro-
vided by Ms. Ying Chen are greatly appreciated.
References
1. Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149.
2. (a) Mullican, M. D.; Lauffer, D. J.; Gillespie, R. J.;
Matharu, S. S.; Kay, D.; Porrititt, G. M.; Evans, P. L.;
Golec, J. M. C.; Murcko, M. A.; Luong, Y.-P.; Raybuck,
S. A.; Livingston, D. J. Bioorg. Med. Chem. Lett. 1994, 4,
2359; (b) Peet, N. P.; Kim, H.-O.; Marqwart, A. L.;
Angelastro, M. R.; Nieduzak, T. R.; White, J. N.;
Friedrich, D.; Flynn, G. A.; Webster, M. E.; Vaz, R. J.;
Linnik, M. D.; Koehl, J. R.; Mehdi, S.; Bey, P.; Emary,
B.; Hwang, K.-K. Bioorg. Med. Chem. Lett. 1999, 9, 2365.
3. (a) Hyum, S. I.; Kim, Y. G. Tetrahedron Lett. 1998, 39,
4299; (b) Ref. 2b; (c) Reddy, G. V.; Rao, G. V.; Iyengar,
D. S. Tetrahedron Lett. 1999, 40, 2653; (d) Reddy, G. V.;
Rao, G. V.; Sreevani, V.; Iyengar, D. S. Tetrahedron Lett.
2000, 41, 953.
In summary, we have demonstrated that LiAlH(O-t-
Bu)3 reduction of a-amino lactones 2 provided the
corresponding a-amino lactols 3 in good yield, selectiv-
ity, and optical purity. These lactols 3 were quite stable
and can be stored at low temperature for some time
without loss of optical purity.
4. Olsen, R. K.; Ramasamy, K. J. Org. Chem. 1985, 50, 2264.
5. Characterization data of lactols 3a–e:
3a: oil; [h]2D2 −19.4 (c 1, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.40–7.30 (m, 5H), 5.30 (s, 1H), 5.22–5.10 (m,
3H), 5.06 (s) and 4.96 (d, J=4.3 Hz, total 1H), 4.01 (m,
1H), 3.03 (br s, 1H), 1.33 and 1.28 (d, J=6.57 Hz and 7.05
Hz, total 3H). MS (EI) m/z 237.
General procedure
3b: oil; [h]2D2 −9.4 (c 1, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.40–7.30 (m, 5H), 5.31 (d, J=3.5 Hz, 1H),
5.20–5.10 (m, 3H), 4.96 (d, J=3.6 Hz, 1H), 3.97 (br s, 1H),
2.97 (br s, 1H), 1.65 (m, 1H), 1.50 (m, 1H), 1.32 (m, 1H),
0.92 (br s, 6H). MS (EI) m/z 279.
To a stirring tetrahydrofuran solution of 0.25 g (0.9
mmol) of lactone 2b in an acetone dry ice bath was
added dropwise a 1.0 M solution of LiAlH(O-t-Bu)3 in
THF (1.1 mL, 1 mmol). The solution was stirred at this
temperature for 10 min, then moved to an ice bath and
stirred at 0–18°C for 6–24 h. After the reduction was
3c: oil; [h]2D2 −23.8 (c 1, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.40–7.30 (m, 5H), 5.45 (d, J=3.1 Hz, 1H),
5.20–5.10 (m, 3H), 4.98 (d, J=3.5 Hz, 1H), 3.80 (br s, 1H),
2.96 (br s, 1H), 2.06 (m, 1H), 0.98 and 0.94 (d, J=6.16 and
6.83 Hz, 6H). MS (EI) m/z 265.
Table 1.
Entry
Compound
Yield of 3
from 2 (%)
[h]2D2 (c g/100 mL,
solvent)
3d: oil; [h]2D2 −51.6 (c 1, CHCl3); 1H NMR (500 MHz,
CDCl3) l 7.40–7.20 (m, 10H), 5.36 (d, J=3.1 Hz, 1H),
5.25–5.10 (m, 3H), 4.95 (m, 1H), 4.13 (m, 1H), 3.15 (br s)
and 2.78 (s, total 1H), 3.05 (m, 1H), 2.67 (dd, J=9.8, 13.7
Hz, 1H). MS (EI) m/z 313.
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
4a
4b
80
80
87
80
−19.4 (c 1, CHCl3)
−9.4 (c 1, CHCl3)
−23.8 (c 1, CHCl3)
−51.6 (c 1, CHCl3)
+9.4 (c 1, CHCl3)
−37.5 (c 2, CHCl3)
−35.4 (c 2, CHCl3)
3e: mp 77.0–78.0°C; [h]2D2 +9.4 (c 1, CHCl3); 1H NMR (500
MHz, CDCl3) l 7.50–7.10 (m, 10H), 5.45 (d, J=2.2 Hz,
1H), 5.35–5.25 (m, 2H), 5.25–5.05 (m, 2H), 4.90 (m, 1H),
3.04 (d, J=3.0 Hz, 1H). Anal. calcd for C17H17NO4: C,
68.21; H, 5.72; N, 4.68. Found: C, 67.97; H, 5.68; N, 4.64.
83
90 (from 3a)
90 (from 3a)