Reaction of Diisopropoxytitanium(III) Tetrahydroborate
J . Org. Chem., Vol. 61, No. 3, 1996 829
Ta ble 5. Red u ction of N-P r otected Am in o Acid s w ith
Tetr a h yd r obor a te 2
corresponding saturated and unsaturated alcohols were
obtained in a 1:1 ratio (78% yield). Although cinnamyl
alcohol (1 equiv) when treated with 2 (1 equiv) at -20
°C for 0.5 h gave back the starting material, the same
reaction carried out at room temperature (25 °C, 1 h) gave
3-phenylpropanol in 15% yield involving reduction of the
carbon-carbon double bond. When 10-undecen-1-ol (1
equiv) was treated with 2 (1 equiv) at -20 °C for 10 min,
it was recovered unchanged. However, when the reaction
was allowed to proceed at -20 °C for 1 h, 1-undecanol
was obtained in 55% yield. Hence it is apparent that
longer reaction time affects the C-C double bond during
the reduction of undecylenic acid.
yieldc
(%)
[RD]
(c, solvent)
entry
substrate
producta,b
1.
2.
3.
4.
5.
6.
7.
Boc-L-Gly-OH Boc-L-Gly-ol
Boc-L-Ala-OH Boc-L-Ala-ol
Boc-L-Val-OH Boc-L-Val-ol
Boc-L-Leu-OH Boc-L-Leu-ol
88
70
64d
83
59
61
75
-11.2 (0.6, CHCl3)
-16.0 (1.0, MeOH)
-28.0 (1.0, MeOH)
-18.7 (0.2, CHCl3)
-47.0 (1.0, CHCl3)
-27.8 (1.0, MeOH)
Boc-L-Ile-OH
Boc-L-Ile-ol
Boc-L-Pro-OH Boc-L-Pro-ol
Boc-L-Phe-OH Boc-L-Phe-ol
a
All the products were identified by direct comparison of
b
physical data with those of authentic samples. Reaction time 4
h (25 °C). c Yield refers to pure isolated products. Yield based
d
on recovered starting material.
Reduction of R-amino acids19 with 2 afforded â-amino
alcohols in poor yields (≈10%). This may be due to the
poor solubility of amino acids in CH2Cl2.
Con clu sion
The present study confirms the versatility of the
reagent system. The reagent has unique and unusual
reducing properties and is shown to be exceptionally
powerful but highly selective. The advantages of this
reagent system are (i) the reagent can be prepared very
easily in CH2Cl2, (ii) the reactions are carried out under
mild conditions, (iii) the reaction period is very short and
(iv) generally the yields are very high.
N-Protected amino alcohols and N-protected peptide
alcohols have received considerable attention in recent
years. N-Protected amino alcohols have been utilized as
intermediates in the preparation of amino aldehydes,20
which are inhibitors of proteolytic enzymes21 and are
important synthetic intermediates.22
Several procedures for the reduction of N-protected
R-amino acids and esters have been reported.23 Lithium
aluminum hydride and diisobutylaluminum hydride,
which are generally used for the reduction of the carboxyl
group, were found unsuitable for reduction of N-protected
R-amino acids and esters because of their reactivity with
many protecting groups. Reduction of N-Boc-protected
amino acids by a borane-THF complex is reported as
smooth,17 but the optical rotations of N-Boc-protected
amino alcohols24 obtained revealed that the enantiomeric
homogeneity was lost. In exploring further the utility
of our reagent, a number of N-Boc-protected R-amino
acids were treated with 2 (-20 to 25 °C, 4 h) and it was
found that it led to the formation of the corresponding
N-Boc-protected amino alcohols in moderate to good
yields (61-89%) without any racemization. The results
are summarized in Table 5.
Exp er im en ta l Section
Gen er a l Rem a r k s. 1H NMR spectra were recorded at 60,
90, or 300 MHz in CDCl3. 13C NMR spectra were recorded at
75 MHz in CDCl3. TLC were performed on 0.25-mm precoated
silica plates (60F-254). Gas chromatographic (GLC) analyses
of product mixtures and purified samples were performed on
5% OV-17 on a Chromosorb W-HP 80/100 (3 mm × 6 m)
column. All glasswares were dried in a drying oven and cooled
under nitrogen. All reduction experiments were carried out
under nitrogen. 2-Methylcyclohexanone,25 3-methylcyclohex-
anone,26 4-tert-butylcyclohexanone,27 cholestan-3-one,28 3,3,5-
trimethylcyclohexanone,29 2-methylcyclopentanone,30 2,4,4-
trimethylcyclopentanone,31 and N-Boc-protected amino acids32
were prepared according to the literature procedures. The
aldehydes, carboxylic acids, and camphor were commercially
available and were used without further purification. All the
acid chlorides were prepared according to the literature
procedure and freshly distilled before use.33 A stock solution
of diisopropoxytitanium dichloride in dry CH2Cl2 (11.8% w/v)
was used.6
P r ep a r a tion of Ben zyltr ieth yla m m on iu m Tetr a h y-
d r obor a te.34 To a stirred solution of benzyl triethylammo-
nium chloride (22.7 g, 0.1 mol) in 5 M aqueous sodium
hydroxide solution (20 mL) was added a solution of NaBH4
(4.5 g, 0.12 mol) in 5 M aqueous sodium hydroxide (10 mL) at
room temperature (25 °C). The resulting mixture was stirred
at rt for 0.5 h and then extracted with CH2Cl2 (3 × 100 mL).
The combined organic layers were dried (K2CO3), and the
solvent was evaporated under vacuum to afford a crystalline
Red u ction of Miscella n eou s F u n ction a l Gr ou p s.
The reaction of diisopropoxytitanium tetrahydroborate,
2 was studied with a number of other substrates. For
example, benzyl azide, ethyl benzoate, benzaldoxime,
benzyl cyanide, and octanamide on treatment with 2 (1-2
equiv, -20 to 25 °C, 1-4 h) were recovered unchanged.
(19) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517.
Dickmann, D. A.; Meyers, A. I.; Smith, G. A.; Gawley, R. E. Organic
Syntheses; Wiley: New York, 1993; Collect. Vol. 7, p 528. Giannis, A.;
Sandhoff, K. Angew. Chem., Int. Ed. Engl. 1989, 28, 218. McKennon,
M. J .; Meyers, A. I.; Drauz, K.; Schwarm, M. J . Org. Chem. 1993, 58,
3568.
(20) Stanfield, C. F.; Parker, J . E.; Kanellis, P. J . Org. Chem. 1981,
46, 4797. Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 1921.
Sharma, R. P.; Gore, M. G.; Akhtar, M. J . Chem. Soc., Chem. Commun.
1979, 875.
(25) Brown, H. C.; Garg, C. P. J . Am. Chem. Soc. 1961, 83, 2951.
(26) Vogel’s Text Book of Practical Organic Chemistry, 5th ed.;
Wiley: New York, 1991, 1098.
(27) Flatt, S. J .; Fleet, G. W. J .; Taylor, B. J . Synthesis 1979, 815.
(28) Bruce, W. F.; Ralls, J . O. Organic Syntheses, Wiley: New York,
1943; Collect. Vol. II, p 191. Bruce, W. F. Organic Syntheses: Wiley:
New York, 1943; Collect. Vol. II, p 139.
(21) Umezawa, H. Enzyme Inhibitors of Microbial Origin; University
of Tokyo Press: Tokyo, 1972.
(22) Nakamura, E. Tetrahedron Lett. 1981, 663. Newmann, H. J .
Am. Chem. Soc. 1973, 95, 4098.
(29) Pyysalo, H. Acta Chem. Scand., Ser. B 1976, 30, 235.
(30) Mislow, K.; Simmons, T.; Melillo, J . T.; Ternay, A. L, J r. J . Am.
Chem. Soc. 1964, 86, 1452.
(31) House, H. O.; Wasson, R. L. J . Am. Chem. Soc. 1957, 79, 1488.
Wasson, R. L; House, H. O. Org. Synth. 1957, 37, 58.
(32) Keller, O.; Keller, W. E.; Look, G. V.; Wersin, G. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, p 70.
(33) Tietze, L. F.; Eicher, Th. Reactions and Syntheses in the Organic
Chemistry Laboratory; University Science Books: Mill Valley, CA 1989.
(34) Baskaran, S.; Gupta, V.; Chidambaram, N.; Chandrasekaran,
S. J . Chem. Soc., Chem. Commun. 1989, 903. Brandstrom, A.;
J unggren, U.; Lamm, B. Tetrahedron Lett. 1972, 3173.
(23) Karrer, P.; Portmann, P.; Suter, M. Helv. Chim. Acta. 1949,
32, 1156. Ito, A.; Takahashi, R.; Baba, Y. Chem. Pharm. Bull. 1975,
23, 3081. Stanfield. C. F.; Parker, J . E.; Kanellis, P. J . Org. Chem.
1981, 46, 4799. Hamada, Y.; Shiori, T. Tetrahedron Lett. 1982, 23,
1193. Luly, J . R.; Dellaria, J . F.; Plattner, J . J .; Soderquist, J . L.; Yi,
N. J . Org. Chem. 1987, 52, 1487. Soai, K.; Oyamada, H.; Takase, M.
Bull. Chem. Soc. J pn. 1984, 57, 2372.
(24) (a) Soucek, W.; Urban, J .; Saman, D. Collect. Czech. Chem.
Commun. 1990, 55, 761. (b) Hamada, Y.; Shibata, M.; Sugiura, T.;
Kato, S.; Shioiri, T. J . Org. Chem 1987, 52, 1252.