Asymmetric skeletal rearrangement of symmetrically α,α-disubstituted α-amino aldehydes: A new entry to optically active α-hydroxy ketones

Article abstract of DOI:10.1021/ja0292851

A unique asymmetric skeletal rearrangement of symmetrically α,α-disubstituted α-amino aldehydes has been accomplished for the first time using a chiral organoaluminum Lewis acid 1. For instance, treatment of (S)-2,2′-bis(trifluoromethanesulfonylamino)-1,1′-binaphthyl with Me₃Al (1.0 equiv) in toluene at room temperature for 15 min and at 110 °C for an additional 15 min produced (S)-1, and a subsequent reaction with α -amino aldehyde 2a (R = CH₂Ph) at -78 °C for 4 h and at -40 °C for 12 h resulted in the smooth rearrangement to the zwitterionic iminium intermediate A, which furnished the α-hydroxy ketone 3a (R = CH₂Ph) in 93% isolated yield with 95% ee (S) after acidic hydrolysis. This result, together with other representative examples, clearly demonstrates the effectiveness of the present method for the hitherto difficult asymmetric synthesis of acyloins. Furthermore, we found that the treatment of the in situ generated A with DIBAH afforded the corresponding anti amino alcohol exclusively without loss of enantiomeric excess. Our approach casts light on the previously unexplored yet potential utility of α-amino aldehydes as synthetic building blocks and also provides a new entry to optically active α-hydroxy ketones and 1,2-amino alcohols. Copyright

Full text of DOI:10.1021/ja0292851

Published on Web 02/22/2003
Asymmetric Skeletal Rearrangement of Symmetrically r,r-Disubstituted
r-Amino Aldehydes: A New Entry to Optically Active r-Hydroxy Ketones
Takashi Ooi, Akira Saito, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received November 9, 2002 ; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Scheme 2
R-Amino aldehydes have been employed as useful building
blocks in organic synthesis, taking advantage of the ready avail-
ability of both enantiomers from the corresponding R-amino acids,1
particularly for the preparation of optically active 1,2-amino
alcohols,2 a pharmaceutically and biologically intriguing class of
compounds.3 As shown in extensive studies on this subject, most
of the transformations of R-amino aldehydes reported to date have
been categorized as the addition of external nucleophiles to aldehyde
carbonyls,1-4 and hence the transformations involving their skeletal
rearrangement are extremely rare, contrary to the case with R-amino
ketones.5 Although R-amino aldehydes are known to undergo
ligand, assuming a sufficient Lewis acidity of the corresponding
isomerization by treatment with strong acids to furnish several
products depending on the reaction conditions,6 there have been
no reports on controlling the stereochemical outcome as well as
the reaction pathways. Herein we wish to disclose the asymmetric
skeletal rearrangement of symmetrically R,R-disubstituted R-amino
aldehydes (Scheme 1). This unique reaction was found to be
smoothly facilitated by a chiral organoaluminum Lewis acid of type
17 and, upon acidic hydrolysis, afforded the corresponding R-hy-
droxy ketones with high enantiomeric purities.8
chiral organoaluminum Lewis acid (S)-1. Treatment of (S)-4 with
Me3Al (1.0 equiv) in toluene at room temperature for 15 min and
at 110 °C for an additional 15 min produced (S)-1,7 and, as expected,
subsequent reaction with R-amino aldehyde 2aa in CH2Cl2 at -78
°C for 4 h resulted in the smooth rearrangement to furnish, after
acidic hydrolysis, the R-hydroxy ketone 3a in 66% yield. The
enantiomeric excess of 3a was shown to be 91% ee by chiral HPLC
analysis (entry 1 in Table 1). Use of toluene as solvent greatly
improved the chemical yield (83%) and also enhanced the enan-
tioselectivity to 94% ee (entry 2).12 Furthermore, we examined the
effect of the aromatic moiety (Ar) of the N-substituent of 2 on the
reactivity and selectivity under similar reaction conditions. Although
the reactions with 2ba and 2ca did not lead to the expected
improvement (entries 3 and 4), an appreciable increase of chemical
yield and enantioselectivity was observed in the rearrangement of
2da possessing an R-naphthylmethyl group on nitrogen (entry 5),13
and, consequently, the optically active R-hydroxy ketone 3a was
obtained in 93% yield with 95% ee by conducting the reaction at
-40 °C (entry 6).
Scheme 1
Other selected examples of this asymmetric skeletal rearrange-
ment with 2d are also listed in Table 1. The electronic property of
the benzylic side chain of R-amino aldehyde slightly affected the
reactivity and selectivity (entries 7 and 8). Excellent enantioselec-
tivities were attained in the reactions involving the migration of
allylic R-substituents (entries 9 and 10). These results clearly
demonstrate the effectiveness of the present method for the hitherto
difficult asymmetric synthesis of acyloins.14 In addition, exposure
of an R,R-diphenyl-R-amino aldehyde derivative to the optimized
conditions afforded a facile access to an optically active benzoin
(entry 11).
To gain insight into the reaction mechanism, we performed the
1H NMR study of the mixture of 2da and (S)-1 in CDCl3 at room
temperature, which confirmed the formation of zwitterionic iminium
intermediate A. This result indicates that the rearrangement is
primarily facilitated by the activation of aldehyde carbonyl with
the chiral Lewis acid, being responsible for the stereochemistry of
the newly created stereogenic center in the 1,2-migration of the
R-substituent as shown in Scheme 3.
Our initial examination was focused on the possibility of effecting
selective rearrangement of R,R-dialkyl-R-amino aldehydes by using
an appropriate Lewis acid under mild conditions. Several common
Lewis acids were evaluated as promoters under identical conditions
with N-benzyl R-amino aldehyde 2aa as a representative substrate
(Scheme 2).9 Although both BF3‚OEt2 and TiCl4 mediated the
rearrangement selectively, the reactions proceeded sluggishly to give
the R-hydroxy ketone 3a in 20 and 23% isolated yields, respectively,
after hydrolysis with 1 N HCl. Trimethylsilyl triflate (Me3SiOTf)
exhibited comparable reactivity, and SnCl4 provided only a trace
amount of the product. In sharp contrast, however, the use of Me2-
AlCl as promoter led to clean formation of 3a (94%), indicating
the suitability of organoaluminum Lewis acids for this transforma-
tion.10
On the basis of these results, we next pursued the stereochemical
control of this unique skeletal rearrangement in an absolute sense.
For this purpose, we employed the optically active (S)-2,2′-bis-
(trifluoromethanesulfonylamino)-1,1′-binaphthyl [(S)-4]11 as a chiral
This observation suggested that the treatment of the in situ
generated iminium intermediate with certain nucleophiles would
9
3220
J. AM. CHEM. SOC. 2003, 125, 3220-3221
10.1021/ja0292851 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Skeletal Rearrangement of Symmetrically
R,R-Disubstituted R-Amino Aldehydesa
Supporting Information Available: Representative experimental
procedures as well as spectroscopic characterization of all new
compounds and the reaction intermediates (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
c
condition
(°C, h)
%ee
% yieldb (config)d
entry
R
Ar
1
2
3
4
5
6
PhCH2
Ph (2aa)
-78, 4
-78, 4
-78, 4
66
83
81
77
87
93
91 (S)e
94 (S)
93 (S)
94 (S)f
95 (S)
95 (S)
References
p-Cl-Ph (2ba)
p-MeOPh (2ca) -78, 4
R-Np (2da)
(1) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
(2) Tramontini, M. Synthesis 1982, 605.
(3) Reviews: (a) Paleo, M. R.; Cabeza, I.; Sardina, F. J. J. Org. Chem. 2000,
65, 2108. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996,
96, 835. (c) Blaser, H.-U. Chem. ReV. 1992, 92, 935.
(4) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149.
(5) For an excellent review on the thermal rearrangement of R-amino ketones,
see: Stevens, C. L.; Pillai, P. M.; Munk, M. E.; Taylor, K. G. Mech.
Mol. Migr. 1971, 3, 271 and references therein.
-78, 4
-78, 4;
-40, 12
-78, 4;
-40, 12
-78, 5;
-40, 13
-78, 3;
-40, 12
-78, 4;
-40, 15
-78, 4;
-40, 12
7
8
9
p-Cl-PhCH2
94
80
73
62
80
86
p-MeO-PhCH2
(CH3)2CdCHCH2
94
(6) (a) Duhamel, L.; Duhamel, P.; Jarry, A. Tetrahedron Lett. 1970, 1053.
(b) Kirrmann, A.; Nouri-Bimorghi, R.; Elkik, E. Bull. Soc. Chim. Fr. 1969,
2385.
97
10 PhCHdCHCH2
96
(7) Noyori, R.; Kitamura, M.; Takemoto, K. Jpn. Kokai Tokkyo Koho 1992,
JP0491093.
11 Ph
78 (S)
(8) For asymmetric synthesis of R-hydroxy ketones, see: (a) (asymmetric
dihydroxylation of enol ethers) Hashiyama, T.; Morikawa, K.; Sharpless,
K. B. J. Org. Chem. 1992, 57, 5067. (b) (asymmetric oxidation of ketone
enolates with chiral oxaziridines) Davis, F. A.; Sheppard, A. C.; Chen,
B.-C.; Haque, M. S. J. Am. Chem. Soc. 1990, 112, 6679. (c) (asymmetric
oxidation of ketones by chiral phase-transfer catalysis) Masui, M.; Ando,
A.; Shioiri, T. Tetrahedron Lett. 1988, 29, 2835.
(9) The starting symmetrically R,R-disubstituted R-amino aldehydes can be
prepared by simple reduction of the corresponding amino acid esters, which
were readily synthesized either by the Strecker reaction of symmetric
ketones17 or by the double alkylation of glycine Schiff base.
(10) The 1H and 13C NMR analyses of an equimolar mixture of 2aa and Me2-
AlCl in CD2Cl2 revealed the formation of the neutral imine 6; thus, the
reaction might be driven by coordination of the aluminum on aldehyde
carbonyl and the N-H proton abstraction in this case.
a Unless otherwise specified, the reaction was carried out with 1.1 equiv
of (S)-1 in toluene under the given reaction conditions. b Isolated yield.
c Enantiopurity was determined by HPLC analysis of the hydroxy ketones
using a chiral column with hexane-2-propanol or ethanol as solvent.
d Determined by 1H NMR analysis of the corresponding (R)- and (S)-MTPA
esters (Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092). The absolute configuration of the product of entry
11 was also confirmed by comparison with the optical rotation of the
commercially available (S)-benzoin. e Use of CH2Cl2 as solvent. f Use of
CH2Cl2 as cosolvent (toluene/CH2Cl2 ) 4:1) because of the insolubility of
the starting aldehyde.
Scheme 3
(11) (a) Shi, M.; Sui, W.-S. Chirality 2000, 574. (b) Mikami, K.; Kotera, O.;
Motoyama, Y.; Sakaguchi, H. Synlett 1995, 975.
(12) The results of the attempted rearrangements of 2aa with other representa-
tive chiral organoaluminum Lewis acids in toluene at -78 °C for 4 h are
as follows.18,19
Scheme 4
afford the corresponding optically active 1,2-amino alcohols,
expanding the synthetic utility of our approach. Indeed, the reaction
of 2da with (S)-1 in toluene followed by the addition of DIBAH at
-78 °C gave rise to anti amino alcohol 5 exclusively in 90% yield
with 95% ee,15 allowing an asymmetric synthesis of pharmaceuti-
cally useful 2-hydroxy-3-amino-1,4-diphenylbutane (Scheme 4).16
In conclusion, we have developed a highly enantioselective
skeletal rearrangement of symmetrically R,R-disubstituted R-amino
aldehydes using a chiral organoaluminum Lewis acid 1. This
method casts light on the previously unexplored yet potential utility
of R-amino aldehydes as synthetic building blocks and also provides
a new entry to optically active R-hydroxy ketones and 1,2-amino
alcohols.
(13) R,R-Disubstituted R-amino aldehydes are stable and easy to handle as
compared to R-monosubstituted aldehydes, and, particularly, 2d is
generally obtained as a solid with enhanced stability.
(14) (a) Guo, Z.; Goswami, A.; Nanduri, V. B.; Patel, R. N. Tetrahedron:
Asymmetry 2001, 12, 571. (b) Gill, M.; Kiefel, M. J.; Lally, D. A.
Tetrahedron Lett. 1986, 27, 1933.
(15) The stereochemistry of 5 was assigned by 1H NMR analysis after
conversion to the oxazolidin-2-one derivative. See the Supporting
Information.
(16) For example, see: Howarth, J.; Lloyd, D. G. J. Antimicrob. Chemother.
2000, 46, 625.
(17) (a) Dyker, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 1700. (b) Wysong,
C. L.; Yokum, T. S.; Morales, G. A.; Gundry, R. L.; McLaughlin, M. L.;
Hammer, R. P. J. Org. Chem. 1996, 61, 7650.
(18) Maruoka, K.; Banno, H.; Yamamoto, H. Tetrahedron: Asymmetry 1990,
112, 7791.
(19) Pikul, S.; Corey, E. J. Org. Synth. 1993, 71, 30.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
JA0292851
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