Itsuno reagent

Borane and aluminum hydrides modified by chiral diols or amino alcohols are well-known, effective reagents for the stoichiometric enan-tioselective reduction of prochiral ketones and related compounds (34). Reduction of prochiral aromatic ketones with the Itsuno reagent, which is prepared from a chiral, sterically congested /3-amino alcohol and borane, yields the corresponding secondary alcohols in 94-100% ee... 

Boranes have opened the door to asymmetric reduction of carbonyl compounds. The first attempt at modifying borane with a chiral ligand was reported by Fiaud and Kagan,75 who used amphetamine borane and desoxyephedrine borane to reduce acetophenone. The ee of the 1-phenyl ethanol obtained was quite low (<5%). A more successful borane-derived reagent, oxazaborolidine, was introduced by Hirao et al.76 in 1981 and was further improved by Itsuno and Corey.77 Today, this system can provide high stereoselectivity in the asymmetric reduction of carbonyl compounds, including alkyl ketones. 

For the preparation and use of this and related reagents, see Itsuno Nakano Miyazaki Masuda Ito Hirao Nakahama 7. Chem. Soc.. Perkin Trans. I 1985, 2039, and other papers in this series. 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of natural products. However, enantioselective methods for homoallylamine are quite undeveloped. In 1995, Itsuno and co-workers reported the first example of enantioselective allylation of an imine (Scheme 7) [13]. The reaction of N-trimethylsilylbenzaldimine 19 with a chiral allylboron reagent 20 in ether at -78 °C afforded the corresponding homoallylamine 22 in 73% ee. 

The use of oxazaborolidines as asymmetric reduction catalysts257 and the enantioselectivity of diphcnyloxazaborolidinc reduction of ketones have been reviewed.258 Large-scale practical enantioselective reduction of prochiral ketones has been reviewed with particular emphasis on the Itsuno-Corey oxazaborolidinc and Brown s 5-chlorodiisopinocampheylborane (Ipc2BCl) as reagents.259 Brown himself has also reviewed the use of Ipc2BCl.260 Indolinoalkylboranes in the form of dimers have been confirmed by 11B NMR as the products of the reduction of trifluoroacetylindoles by diborane.261... 

The pioneering studies by Itsuno [1] and Corey [2] on the development of the asymmetric hydroboration of ketones using oxazaborolidines have made it possible to easily obtain chiral secondary alcohols with excellent optical purity [3]. Scheme 1 shows examples of Corey s (Corey-Bakshi-Shibata) CBS reduction. When oxazaborolidines 1 were used as catalysts (usually 0.01-0.1 equiv), a wide variety of ketones were reduced by borane reagents with consistently high enan-tioselectivity [2]. The sense of enantioselection was predictable. Many important biologically active compounds and functional materials have been synthesized using this versatile reaction [2-4]. 

Itsuno etal. developed another borohydride-based strategy using amino acid derived reagents such as 11 in 1981. They can be obtained by treating the corresponding aminoalcohol such as 10 with BH3 in THF, and are applied in ketone reductions in a 1.25-fold excess together with 2.5 equivalents of BHs. ... 

The enantioselective asymmetric allylation of imines has been a synthetic challenge, the initial solutions of which required stoichiometric amounts of chiral allylbor on [87], allylsilane [88], allylzinc [89], or allylindium reagents [90]. Itsuno showed that a chiral B allyloxazaborolidine derived from norephedrine could add to the N trimethylsilyl imine prepared from benzaldehyde in high yield and enantiomeric excess (Scheme 1.22) [91]. Brown later reported that B allyldiisopinocamphenylbor ane is also very effective for the allylation of the same electrophiles, but the addition of a molar amount of water is necessary to obtain high yields [92]. The diastereo and... 

Midland MM (1983) Reductions with chiral boron reagents. In Morrison JD (ed) Asymmetric synthesis. Academic, New York, vol 2, chap 2, p 45 Itsuno S (1996) The Alembic, Morton Performance Chemicals 53 1 Fiaud JC, Kagan HB (1969) Bull Soc Chim Fr 2742 Borch RF, Levitan SR (1972) J Org Chem 37 2347 Grundon MF, McCleery DG, WUson JW (1976) Tetrahedron Lett 295 Grundon MF, McCleery DG, WUson JW (1981) J Chem Soc Perkin Trans 1 231 Johnson CR, Stark CJ (1979) Tetrahedron Lett 4713... 

The tremendous success in the catalytic asymmetric addition of organozinc reagents to aldehydes spurred Itsuno and co-workers to examine the reactivity of diethylzinc with silyl imines in the presence of chiral amino alcohols and diols. Unfortunately, this type of azomethine function failed to react [23a]. The use of activated N-acyl- and iV-phosphinoylimines turned out to be crucial as evidenced by the following reports on the alkylation of these functions using di-... 

The first example of enantioselective allylation of an azomethine function was reported in 1995 by Itsuno and co-workers [42a]. These researchers studied the addition of preformed chirally modified allylboranes to N -(trimethylsilyl)ben-zaldehyde imine (5a) (<2 g of imine, ca. 0.27 M). Of the wide range of chirally modified allylboron reagents reported in the literature, the use of chiral allylbo-ronates 42a-c and 5-allyldialkylborane 43 were logical first choices given their utility in the enantioselective addition to carbonyl substrates (Scheme 20). 

The chiral allylboration reagents employed by Itsuno et al. in this study were prepared by mixing triallylborane (1 equiv) with the appropriate chiral modifier in THE A variety of chiral modifiers, including chiral diols 47 and 48, chiral hydroxy acid 49, N-sulfonylated amino acid 50, and M-sulfonylamino alcohols 51--54 was evaluated (Scheme 21). The chiral modifiers 47-54 used in this study could be prepared easily and efficiently, and were easily recovered and recycled. 

Since the first asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [ 1 ], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey s oxazaborolidines are some of the most successful reagents [3 ]. The effect of fluorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, fluorine, and trifluoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). 

The first attempt to use a chiral ligand to modify borane was Kagan s attempt at enantioselective reduction of acetophenone using amphetamine-borane and desoxy-ephedrine-borane in 1969 [18]. However, both reagents afforded 1-phenyl ethanol in <5% ee. The most successful borane-derived reagents are oxazaborolidines, introduced by Hirao in 1981, developed by Itsuno, and further developed by Corey several years later (reviews [19,20]). Figure 7.2 illustrates several of the Hirao-Itsuno and Corey oxazaborolidines that have been evaluated to date. All of these examples are derived from amino acids by reduction or Grignard addition. Hirao... 

A major advance in the evolution of chiral boron reagents was reported initially by Itsuno and co-workers in 1981.5 Stereoselectivities up to 73% ee were observed using the 1,3,2-oxazaborolidine derived from p-amino alcohols. Thus (S)-valinol 5 in reaction with borane afforded 6. 

Enantiomerically pure boranes have a long history in the reduction of prochiral ketones/ Amongst the early results using stoichiometric oxazaborolidines, the work of Itsuno is of particular interest. For example, acetophenone (3.32) could be reduced with the oxazaborohdines (3.113) or (3.114) where the ratio of amino alcohol to borane was 1 2, implying that one equivalent of oxazaborolidine and one equivalent of borane were present in the transition state. Itsuno also reported that the oxazaborohdine reagent (3.114) could be used catalytically in the reduction of prochiral ketoxime ethers. ... 

Asymmetric reduction of ketimines to sec-aminesf Of the various hydride reagents found to achieve high enantioselective reduction of ketones, the oxazaborolidine 1 of Itsuno, prepared from BH3 and (S)-(—)-2-amino-3-methyl-I,l-diphenylbutane-l-ol, derived from (S)-valine, (12,31), is the most effective in terms of asymmetric induction. Like Corey s oxazaborolidines derived from (S)-proline, 1 can also be used in catalytic amounts. The highest enantioselectivities obtain in reduction of N-phenylimines of aromatic ketones (as high as 88% ee). The enantioselectivities are lower in the case of N-t-butylimines of aryl ketones (80% ee). Reduction of N-phenylimines of prochiral dialkyl ketones with 1 results in 10-25% ees. 

See also Itsuno, S, Ito, K, HIrao, A, Nakahama, S, Asymmetric Reduction of Aliphatic Ketones with the Reagent Prepared from (S)-(-)-2-Amino-3-methyl-1,1-dlphenylbutan-1-ol and Borane" J. Org. Chem. 1984,49,555-557. Fora review see Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986-2012,... 

Its1987 Itsuno, S., Sakurai, Y., Ito, K., Hirao, A. and Nakahama, S., Asymmetric Reduction of Acetophenone O-Methyloxime with the Reagent Prepared from Borane and Polymer-supported (S)-(-)-2-Amino-3-(4-hydroxyphenyl)-1,1 -diphenylpropan-1 -ol. Polymer, 28 (1987) 1005-1008. 

The first enantioselective allylation of imines [19-21, 39, 44] were reported by Itsuno only in 1995 [164]. Investigations of a range of chiral borane and boronate allylating reagents led to the identification of N-trimethylsilyl... 

---