Chiral Lewis acid-Hydroxylamine Hybrid Reagent for enantioselective Michael addition reaction directed towards β-amino acids synthesis

Article abstract of DOI:10.1055/s-1998-1929

We have succeeded in introducing a chiral auxiliary tethered by an appropriate metal into the hydroxy group of N-benzylhydroxylamine. The thus-obtained recyclable chiral reagent can act as an amine nucleophile to give chiral isoxazolidinones (up to 71% ee

Full text of DOI:10.1055/s-1998-1929

November 1998
SYNLETT
1291
Chiral Lewis Acid-Hydroxylamine Hybrid Reagent for Enantioselective Michael Addition Reaction
Directed Towards β-Amino Acids Synthesis
Teruhiko Ishikawa,* Keita Nagai, Takayuki Kudoh, and Seiki Saito*
Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Tsushima, Okayama 700-8530, Japan
Fax: 81-86-251-8209; E-mail: seisaito@biotech.okayama-u.ac.jp
Received 29 July 1998
Abstract: We have succeeded in introducing a chiral auxiliary tethered
by an appropriate metal into the hydroxy group of N-benzylhydroxyl-
amine. The thus-obtained recyclable chiral reagent can act as an amine
nucleophile to give chiral isoxazolidinones (up to 71% ee) as a β-amino
acid synthon on the reaction with α,β-unsaturated carbonyl compounds.
(Lewis acid-Hydroxylamine Hybrid Reagent) because the tethered atom
(Al, B, etc.) can play the role of a Lewis acid as shown in Scheme 2.
This communication describes the first example of such chiral
hydroxylamine derivatives and reagent-controlled asymmetric synthesis
of isoxazolidinones as a precursor for β-amino acids6 via amino
Michael addition processes.
Recent physiological interests in a type of oligopeptide in which β-
amino acid units are incorporated as an important segment1 have
motivated synthetic organic chemists to develop methods for the
synthesis of such amino acids in an optically pure form.2 Among them
Michael addition of chiral metal amides (1,2a 2,2b 3,2c 4,2d 52e) to α,β-
unsaturated esters seems to be straightforward and approved as a
promising and efficient methods for chiral β-amino acid synthesis.
Scheme 2
We have also been involved in this field and recently reported that
Michael addition of chiral (N-α-methylbenzyl)hydroxylamine3 [(S)-
MBHA] to diisopropyl (R,R)-(O-crotonoyl)tartrate resulted in the
formation of isoxazolidinone 6 in 70% yield with 80% de as a result of
double stereo differentiation (Scheme 1).4
In the first place an achiral version of the LHHR (10—13) was prepared
in a conventional manner as a clear solution in THF, which was directly
used for the reaction with 14.7 For instance, 10 was prepared via two-
step transformation involving the reaction of 2,3-dimethyl-2,3-
butanediol (1 eq) with borane-THF complex (1 eq) (THF/0 °C, 30 min)
and subsequent reaction with N-benzylhydroxylamine (BHA: 1 eq; 0
°C, 30 min). For NMR diagnosis the THF was removed under reduced
pressure to give highly viscous gum, which was dissolved in CDCl3: a
cycle of evaporating the CDCl3 and dissolving the residue in fresh
CDCl3 was followed three times to give the desired NMR sample. The
structure of these LHHR was revealed on the basis of 1H- and 13C-NMR
spectra of this sample.8 It turned out that the LHHRs 10—13 exhibited
10 or more times as high reactivity as BHA itself when subjected to the
reaction with 14 and the expected conjugated addition took place even
at –78 — –50 °C to give the corresponding isoxazolidinones 8a in high
yield. The results pertinent to this reaction are summarized in Table 1.
Scheme 1
However, there exists a common drawback in these asymmetric
syntheses that the stereo centers of 1—4 or (S)-MBHA are to be
destroyed when submitted to any deprotection protocol to generate free
amines. Hence more economical chiral amine nucleophiles bearing
removable and recyclable chiral auxiliaries are desirable.5 This situation
strongly motivated us to answer this problem and we were intrigued by
the functionality of hydroxylamine again. If we can introduce the chiral
auxiliary tethered by an appropriate metal into its hydroxyl group, the
hydroxylamine can act as the chiral amine nucleophile as requested
above. This idea is illustrated below and referred to as LHHR concept
Particularly interesting is that dialkoxy-N-benzylaminoxyborane (10) or
aluminum (11) exhibited the highest reactivity as a Michael donor
amine nucleophile among those examined because we can easily change
these reagents into the corresponding chiral versions by replacing the
dialkoxy moieties of 10 or 11 with those containing chiral centers or
axes. Thus, chiral 2-boradioxolane- or 2-aluminadioxolane-type LHHRs

1292
LETTERS
SYNLETT
were prepared in a similar manner as that for achiral LHHRs employing
well-known C2-symmetric chiral diols such as diisopropyl tartrate,
N,N,N’,N’-tetramethyltartaramide, or trans-stilbenediol. The reactions of
these chiral LHHRs with 14 or 16a were, however, totally disappointing
in terms of enantioselectivity: for instance the reaction of 15Ac (1 eq)
with 16a (1 eq) (THF/22°C, 7 hr) gave 8a in 58% yield and the
enantioselectivity was 37% ee preferentially in (R)-configuration, which
was the best result among them. Other chiral reagents of this class
(15Aa,b and 15Bb) downgraded the degree of % ee significantly (≤1%
ee). Hence, we turned our attention to an aluminum- or boron-based
dioxepane-type LHHR such as 17Aa—e9 or 17Ba in the hope of
significant improvement in the enantioselectivity because of the flexible
nature of this type of LHHR as compared with the dioxolane-type
LHHR (15). Much better results with regard to the enantioselectivity,
though moderate (43—71% ee),10 have been achieved when aluminum-
based LHHRs such as 17Aa, 17Ab, or 17Ae were reacted with 14 and
16. These results are summarized in Table 2. On the other hand the
boron reagent such as 17Ba was far from satisfactory (<5% ee). This is
also the case for other aluminum reagents such as 17Ac and 17Ad
which led to very poor stereoselectivity (<5% ee).
The potency of dioxepane-type chiral LHHR 17 probably stemmed
from its conformationally more flexible nature than the dioxolane-type
one 15.11 Since stereogenic centers or chiral axes of the diol ligands
incorporated into 17 are located far from the nucleophilic nitrogen
center, the two phenyl groups (17a,b) or substituted aromatic ring (17e)
would play an important role in transmitting the chirality sphere to the
reaction sphere. In addition, the conformationally flexible seven-
membered rings in these LHHRs should be convenient to adjust
transition state assembly as appropriate as possible. Also the degeneracy
intrinsic to C2-symmetry of these ligands is capable of minimizing
diastereomeric turbulence leading to lower selectivity.11 We are now
making an effort to tune up this type of reagent-controlled asymmetric
synthesis in terms of % ee by elaborating LHHR, which will be
disclosed elsewhere.
Acknowledgment: This work was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (No. 07214221) from the Ministry
of Education, Science, Sports, and Culture, Japan. We are grateful to
"The SC–NMR Laboratory of Okayama University" for high field (500
and 200 MHz) NMR experiments.

November 1998
SYNLETT
1293
References and Notes
1H, NH), 7.24 (s, 5H, Ar-H); 13C-NMR (50 MHz, CDCl3) δ 24.5,
64.4, 82.6, 127.7, 128.3, 129.4, 136.0. On the other hand, for the
corresponding aluminum reagent 11 the proton-NMR exhibited
highly broadened signals at methyl, benzyl methylene linked to
the nitrogen, and NH and aromatic proton regions and the 13C-
NMR as well, suggesting the occurrence of random association
and disproportionation.
(1) For a recent review, see Cole, D. C. Tetrahedron 1994, 50, 9517.
(2) (a) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461;
(b) Bunnage, M. E.; Davies, S. G.; Goodwin, C. J. J. Chem. Soc.,
Perkin Trans. 1, 1994, 2385; (c) Rico, C. J.; Dindmark, R. J.;
Rogers, T. E.; Boby, P. R. J. Org. Chem. 1993, 58, 7948; (d)
Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1992, 57, 2114; (e)
Enders, D.; Wahl, F.; Bettray, W. Angew. Chem., Int. Ed. Engl.
1995, 34, 455; for enantio-selective synthesis of β-amino acids
from β-amino-α,β-unsaturated esters based on catalytic
hydrogenation with chiral metal complexes, see Lubell, W. D.;
Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543
and references cited therein.
(9) For chiral diols involved in these reagents, see Narasaka, K.;
Iwasawa, I.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J.
J. Am. Chem. Soc. 1989, 111, 5340 (for a), Seebach, D.; Beck, A.
K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. Helv. Chim. Acta
1987, 70, 954 (for b), Jacques, J.; Fouquey, C. Org. Syn. 1988, 67,
1 and Truesdale, L. K. ibid. 1988, 67, 13 (for d), and Maruoka, K.;
Itoh, T.; Shirasaka, H.; Yamamoto, H. J. Am. Chem. Soc. 1988,
110, 310 and Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, H.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 1988, 61, 2975 (for e). The
diol ligand c was prepared through the reaction of dimethyl (R,R)-
O-bis-(tert-butyldimethylsilyl)tartrate with CH3MgBr (> 4 eq):
neither EtMgBr nor PhMgBr reacted with this tartrate under the
same reaction conditions as those for the CH3MgBr.
(3) Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S. Synlett 1995, 1171:
the reaction of methyl crotonate with (S)-MBHA has been
reported so far from two laboratories: see Baldwin, J. E.;
Harwood, L. M.; Lombard, M. J. Tetrahedron, 1984, 40, 4363
(43% de) and Baldwin, S. E.; Aubé, J. Tetrahedron Lett. 1987, 28,
179 (60% de). Asymmetric syntheses of β-amino acid precursors
using O-benzylhydroxylamine as a nucleophile have recently been
developed: Cardillo, G.; Casolari, S.; Gentilucci, L.; Tomasini, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1848 (substrate control);
Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615 (chiral Lewis acid catalysis).
(10) The absolute configurations and % ee's for isoxazolidinones 8
listed in Table 2 were determined by chemical correlation and/or
NMR spectroscopy of Mosher esters. In the event, 8 was led to 3-
(N-acylated)aminobutanoate through
a series of reactions
(4) For the double stereo differentiation, see Masamune, S.; Choy, W.;
involving hydrogenolysis of the N—O bond to β-amino acid, N-
acylation with acid halides [benzoyl chloride, Mosher acid
chloride, or (Boc)2O], and final esterification of a carboxylic acid
group with TMSCHN2. Since the optical rotation values of methyl
(3S)-3-(N-benzoyl)aminobutanoate (Estermann, H.; Seebach, D.
Helv. Chim. Acta 1988, 71, 1824) and (3R)-4-phenyl-3-(N-tert-
butoxycarbonyl)aminobutanoic acid (Seki, M.; Matsumoto, K.
Tetrahedron Lett. 1996, 37, 3165) are known, 8a and 8b were able
to be correlated with these compounds. The absolute
configuration of 8c, however, was merely estimated on the
analogy of the relationship between the absolute structure and sign
of rotation of 8a and 8b. It turned out that the absolute
configuration of 8b obtained from 16d of (Z)-geometry was the
same as that obtained from the (E)-isomer 16b with a preference
for R-configuration.
Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24,
1.
(5) The compound [(S)-5] developed by Enders is the first example of
a chiral amine nucleophile in which the chiral auxiliary moiety is
removable and recyclable. For this purpose, however, two
chemical events after the conjugate addition have to be done and
the yields of β-amino acids are rather low (16—58%).
(6) Isoxazolidinone represents one of the N,O-protected form of β-
amino acids.
(7) The alkoxy moiety of 14 comes from optically pure pantolactone
in the hope of obtaining optically active product. However, the
product turned out to be 5% ee at most.
(8) Prepared by mixing borane·THF complex or trimethylaluminum
with 2,3-dimethylbutane-2,3-diol followed by the addition of
BHA. With regard to the boron reagent 10, for instance, a narrow-
(11) For this discussion, see Noyori, R., Asymmetric Catalysis in
1
lined simple NMR spectrum was observed: H-NMR (200 MHz,
Organic Synthesis, John Wiley & Sons, New York, 1994, pp 47–
CDCl3) δ 1.17 (s, 12H, 4 × CH3), 3.98 (s, 2H, CH2-Ar), 7.08 (s,
49.