TiCl4-promoted multicomponent reaction: A new entry to functionalized α-amino acids

Article abstract of DOI:10.1021/ol048302j

(Chemical Equation Presented) TiCl₄-promoted multicomponent reactions involving N-tosyl imino ester, cyclic enol ether, and silane reagents in a single one-pot operation provide functionalized α-amino acids with multiple stereogenic centers in

Full text of DOI:10.1021/ol048302j

ORGANIC
LETTERS
2005
Vol. 7, No. 1
7-10
TiCl4-Promoted Multicomponent
Reaction: A New Entry to
Functionalized
r-Amino Acids
Arun K. Ghosh,* Chun-Xiao Xu, Sarang S. Kulkarni, and Donald Wink
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received August 25, 2004 (Revised Manuscript Received November 30, 2004)
ABSTRACT
TiCl4-promoted multicomponent reactions involving N-tosyl imino ester, cyclic enol ether, and silane reagents in a single one-pot operation
provide functionalized -amino acids with multiple stereogenic centers in good to excellent yields. Cis/trans selectivities with optically active
r
substituted dihydrofurans have been investigated.
The biological relevance of unnatural R-amino acids con-
tinues to foster immense interest in their design and synthesis.
As a consequence, a number of effective methodologies have
been developed over the years.1 In continuation of our interest
in probing enzyme active sites with designed ligands, we
required a range of R-amino acids with cyclic ether templates.
The use of such amino acids, particularly those that contain
a tetrahydrofuran or tetrahydropyran ring, has been limited
by the lack of effective and practical methodologies for their
synthesis.2 Our interest in this area has now led us to devise
a straightforward approach to these heterocyclic amino acids
using multicomponent reactions.
amino acids in a single one-pot operation. Herein, we report
TiCl4-promoted multicomponent reactions with an N-tosyl
imino ester that provide rapid access to functionalized R-
amino acids containing up to three contiguous chiral centers
in good to excellent isolated yields. Asymmetric reactions
with optically active substituted dihydrofurans are also
reported; these proceed with excellent diastereoselectivities.
Our basic strategy for the synthesis of functionalized
heterocyclic amino acids is depicted in Scheme 1. Since our
previous multicomponent reactions with glyoxalates and
pyruvates were remarkably efficient, we initially investigated
the reaction of the N-benzyl imine of ethyl glyoxalate with
dihydrofuran and triethylsilane. However, the desired con-
densation product could not be obtained under a variety of
reaction conditions. Since N-tosyl imines of ethyl glyoxalate
are much more stable and can be prepared readily, we
examined subsequent multicomponent reactions with the
N-sulfonyl imino ester 1. Weinreb and co-workers were the
first to show the utility of such imino esters in thermal ene
reactions.4 More recently, Lectka et al.5 have shown the
application of this imino ester in enantioselective alkylation
reactions leading to R-amino acids.
Recently, we developed syntheses of a variety of substi-
tuted tetrahydrofurans and tetrahydropyrans by a novel
multicomponent coupling reaction.3 We now plan to develop
this reaction further so as to provide functionalized, complex
(1) For recent reviews of amino acid synthesis: (a) Bloch, R. Chem.
ReV. 1998, 98, 1407. (b) Williams, R. M. Synthesis of Optically ActiVe
R-Amino Acids; Pergammon, New York, 1989. (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. (d) Hegadus, L. Acc. Chem. Res. 1995, 28,
299. (e) Boger, D. L.; Patane, M. A.; Zhou, J. J. J. Am. Chem. Soc. 1994,
116, 8544.
(2) Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.; Lyle,
T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.;
Huff, J. R.; Anderson, P. S. J. Med. Chem. 1993, 36, 292.
(4) (a) Tschaen, D. M.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984,
49, 5058. (b) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
(5) Ferraris, D.; Young, B.; Cox, C.; Dudding, C.; Drury, W. J.; Ryzhkow,
L.; Taggi, A.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67.
(3) (a) Ghosh, A. K.; Kawahama, R.; Wink, D. Tetrahedron Lett. 2000,
41, 8425. (b) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40,
1083. (c) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40, 4751.
10.1021/ol048302j CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/14/2004

Scheme 1. Multicomponent Reactions with N-Tosyl Imino
Ester and Dihydrofuran and Silanes
Figure 1. ORTEP drawing of X-ray structure of 5a.
The feasibility of this multicomponent reaction was
examined with dihydropyran and the substituted optically
enriched dihydrofurans 11 and 12 in the presence of a number
of nucleophiles. The results are summarized in Table 1.
Reaction of dihydrofuran-derived oxocarbenium ion with
trimethylsilyl cyanide provided the corresponding nitrile 5b
with excellent selectivity (99:1, entry 3). Reaction with 3,4-
dihydro-2-H-pyran and triethylsilylsilane as the nucleophile
proceeded with excellent diastereoselectivity (entry 4). The
corresponding reactions with allyltrimethylsilane provided
a 3:1 mixture of diastereomers in excellent yield (entry 5).
Unlike dihydrofuran, reaction of the dihydropyran-derived
oxocarbenium ion with trimethylsilyl cyanide provided
significantly lower selectivity (4:1, entry 6).
We have investigated the stereochemical outcome of our
multicomponent reaction with dihydrofurans having aryl
substituents at the 5-position. Multicomponent reactions of
N-tosyl imino ester with racemic phenyl dihydrofuran in the
presence of triethylsilane as the nucleophile and CH3CN as
an additive provided a single diastereomer 13 in 71% yield
(entry 7). The presence of CH3CN prevented the formation
of an unidentified byproduct. The scope of this additive effect
is being investigated in detail. The assignment of the relative
stereochemistry of the three chiral centers of 13 was made
by X-ray crystallography.6 As can be seen in Figure 2, the
relative stereochemistry of the R-tosylamine and â-tetrahy-
drofuranyl chiral centers in 13 is the same as that in
derivative 5a. Encouraged by this stereochemical outcome,
we subsequently prepared phenyl and naphthyl dihydrofurans
in optically active form and investigated the issue of
diastereoselection with a variety of nucleophiles. The phenyl
and 2-naphthyl dihydrofurans 11 and 12 were prepared using
asymmetric Heck reactions7 in optically enriched form.8 As
shown, when the above reaction was carried out with
optically active phenyl dihydrofuran in the presence of
After surveying a number of Lewis acids, we found that
the multicomponent reactions could be carried out effectively
with TiCl4. Accordingly, freshly distilled N-tosyl imino ester
(1, 1 equiv) and 2,3-dihydrofuran (1.2 equiv) in CH2Cl2 were
treated with TiCl4 (1 M in CH2Cl2, 1.2 equiv) at -78 °C for
1 h. Triethylsilane (3 equiv) was added, and the resulting
reaction mixture was allowed to stir at -78 °C for 2 h. After
this period, the reaction was quenched with saturated aqueous
NaHCO3 solution at -78 °C and warmed to 23 °C. Standard
workup and flash chromatography over silica gel provided
a single condensation product 3 in 71% yield as a single
1
diastereomer (by H and 13C NMR analysis).
When the presumed oxocarbenium ion derived from the
reaction of N-tosyl imino ester (1) and 2,3-dihydrofuran was
reacted with allyltrimethylsilane as a nucleophile, the reaction
proceeded smoothly (-78 °C for 2 h). However, multicom-
ponent products 5a and 6a were obtained as a 2.4:1 mixture,
which were separable by silica gel chromatography. As
depicted in Figure 1, the relative stereochemistry of the major
diastereomer 5a was determined by X-ray crystallography.6
The major diastereomer 5a was converted to amino acid 7a
by a two-step sequence involving saponification by aqueous
LiOH followed by exposure of the resulting acid to Na-Hg
in methanol at reflux. Functionalized amino acid 7a was
obtained in 98% for the two-step sequence.
(6) Crystal data for 5a: C18H25NO5S; MW ) 367.45; colorless crystal;
crystal system, block; space group, P21/c; cell parameters, a ) 23.9477 Å,
b ) 9.0234 Å, c ) 18.1405 Å, â ) 104.100(2)°, V ) 3801.9(5) Å3, Z )
8; Mo KR radiation (λ ) 0.71073 Å, T ) 173(2) K, R1 ) 0.0542, wR2 )
0.1053 (I > 2σ(I)); R1 ) 0.1264, wR2 ) 0.1214 (all data). Crystallographic
data have been deposited with the Cambridge Crystallographic Data Center
(deposition no. 252667). Crystal data for 13: C21H25 NO5S; MW ) 403.48;
colorless crystal; crystal system, block; space group, P21/c; cell parameters,
a ) 17.9352 Å, b ) 6.2661 Å, c ) 18.4264 Å, â ) 93.710(2)°, V ) 2066.5-
(3) Å3, Z ) 4; Mo KR radiation (λ ) 0.71073 Å, T ) 298(2) K, R1
)
0.0657, wR2 ) 0.1747 (I > 2σ(I)); R1 ) 0.1049, wR2 ) 0.1988 (all data).
Crystallographic data have been deposited with the Cambridge Crystal-
lographic Data Center (deposition no. 252668). These data can be obtained
free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif, by
email to data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033.
(7) (a) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett. 1992, 33,
1485. (b) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417.
(8) Optical purities of 5-phenyl and 5-naphthyl dihydrofuran were 89
and 88% ee, respectively.
8
Org. Lett., Vol. 7, No. 1, 2005

Table 1. TiCl4-Promoted Multicomponent Reactions of N-Tosyl Imino Ester with Vinyl Ethersa
a All reactions were carried out as described in the text. b Determined by 1H NMR for entries 1-12 and by LCMS for entries 7-9. c Isolated yield. d Ring
stereochemistry was assigned after NOESY experiment. e CH3CN (5 equiv) was added as an additive; see Supporting Information for experimental details.
trimethylsilyl cyanide, it afforded diastereomer 14 as a major
product (mixture ratio 95:5, entry 8). The corresponding
reaction with allyltrimethylsilane as a nucleophile provided
single product 15 in excellent yield (entry 9). Optical purities
of compounds 14 and 15 were determined by reduction of
these compounds with LiAlH4 in ether at 0 °C followed by
conversion of the respective alcohol to the Mosher ester.9
The 19F NMR analysis of the Mosher esters established
optical purities of 84 and 86% ee for 14 and 15, respectively.
The depicted absolute and relative stereochemistry was
assigned on the basis of the X-ray structure of 13 as well as
extensive NOESY experiments on compounds 14 and 15
(Figure 3). We have also investigated stereoselection in the
multicomponent reactions with naphthyl dihydrofuran (en-
tries 10-12). These reactions also proceeded with excellent
diastereoselectivities and isolated yields.
To rationalize the stereoselectivities observed, we propose
stereochemical models A and B. In these we postulate that
one of the electron pairs of the ethoxy oxygen is donated to
the oxo carbenium ion from the pseudoaxial side for
stabilization of the transition state (Figure 4). Titanium metal
chelation with sulfonyl oxygen is also proposed. Walsh and
co-workers have documented such metal chelation by X-ray
Figure 2. ORTEP drawing of X-ray structure of 13.
(9) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
Org. Lett., Vol. 7, No. 1, 2005
9

Figure 3. Observed NOE effects on 14 and 15.
crystallography.10 Multicomponent reaction with N-tosyl
imino ester 1 and dihydrofuran presumably proceeds through
transition state model B (exo) as opposed to model A (endo).
Model B is preferred because of the absence of the
developing nonbonded interaction between the tetrahydro-
furan ring and the chelated titanium metal. The observed
stereochemical outcome in various reactions is consistent
with the proposed models.
In summary, the TiCl4-promoted multicomponent coupling
reaction of N-tosyl imino ester, cyclic enol ethers, and carbon
nucleophiles has provided stereocontrolled access to un-
natural THP- and THF-containing amino acids with multiple
stereocenters. The overall protocol is practical and quite
efficient. Further studies and applications are currently under
investigation.
Figure 4. Stereochemical models.
Acknowledgment. Financial support by the National
Institutes of Health (GM 53386) is gratefully acknowledged.
We thank Mr. Bhushan Surve for assistance in the X-ray
structure determination.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for compounds 3-10
and 13-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am.
Chem. Soc. 1998, 120, 6423.
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