Enhanced diastereoselectivity in the asymmetric Ugi reaction using a new 'convertible' isonitrile

Full text of DOI:10.1021/jo982186e

336
J . Org. Chem. 1999, 64, 336-337
Sch em e 1
En h a n ced Dia ster eoselectivity in th e
Asym m etr ic Ugi Rea ction Usin g a New
“Con ver tible” Ison itr ile
Russell J . Linderman,* Sophie Binet, and
Samantha R. Petrich
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received November 2, 1998
design of a “convertible" isonitrile, cyclohexenyl isocyanide.8
Armstrong has shown that the cyclohexenyl amide Ugi
product can be hydrolyzed to the free acid, or be converted
to a different amide, an ester, or a thioester derivative via
a munchnone intermediate. Although the “convertible” iso-
nitrile is a significant advance toward a solution for the post-
Ugi conversion problem, cyclohexenyl isocyanide introduces
additional difficulties. The isonitrile can be difficult to
prepare and is quite unstable, requiring storage at -30 °C.
We report here an alternative “convertible" isonitrile which
not only provides a means for milder hydrolysis of the Ugi
amide product, but results in improved diastereoselectivities
of both (R)- and (S)-amino acids via the asymmetric Ugi
reaction using the Kunz chiral auxiliaries.
Our design of a convertible isonitrile envisioned an acid-
catalyzed intramolecular conversion of an amide to an ester.
Evans and Takacs demonstrated that chiral amides obtained
via alkylation of a prolinol derivative were easily hydrolyzed
under acidic conditions without racemization of the adjacent
chiral center.9 We chose to prepare isonitrile 1, Scheme 1,
bearing a silyl ether functionality suitable for conversion of
the derived Ugi amide product to an ester via a six-centered
transition state. A potential advantage of isonitrile 1 com-
pared to cyclohexenyl isocyanide is the application of this
sterically demanding isonitrile in the asymmetric Ugi reac-
tion. Chemoselective O-silylation of 2-amino benzyl alcohol
2 was achieved using sodium hydride and tert-butyldimeth-
ylsilyl chloride. Formation of the N-formyl intermediate 4
via the mixed anhydride and subsequent dehydration with
DABCO and triphosgene8b generates 1. Isonitrile 1 can be
purified by chromotography on deactivated silica gel or by
Kugelrohr distillation. Although isonitrile 1 is quite stable
and can be prepared on a reasonable scale, we routinely
prepare and store larger quantities of formamide 4 rather
than the isonitrile. The Ugi reaction using isonitrile 1,
benzylamine, benzaldehyde, and formic acid at 0 °C to obtain
amide 5 was carried out. The amide exhibited an IR stretch
at 1670 cm-1 for the secondary amide CO. Upon treatment
with methanolic HCl, the silyl protecting group was cleaved,
and the expected amide/ester exchange reaction took place
to provide ester 6 in quantitative yield (after basification),
eq 1. The amide CO stretch was no longer present, and only
the ester CO stretch at 1722 cm-1 was observed.
Multicomponent condensation (MCC) reactions, and in
particular the Ugi four-component coupling reaction,1 have
recently appeared as efficient methods for the synthesis of
diverse libraries of small organic molecules such as benzo-
diazepines, pyrroles, lactams, and diketopiperazines.2 The
Ugi reaction has also been applied in the asymmetric
synthesis of amino acids. In early work, Ugi and co-workers
determined that use of a chiral acid or isonitrile in the Ugi
MCC reaction did not provide any degree of diastereoselec-
tivity.1,3 In contrast, chiral ferrocenylamine inputs resulted
in the synthesis of nonracemic amino acid derivatives with
low to modest levels of diastereoselectivity.4 Kunz and
Pfrengle developed more versatile chiral auxiliaries for the
Ugi MCC reaction using carbohydrate derivatives.5 High
diastereomeric ratios of (R)-amino acids were obtained in
reactions employing a galactosylamine derivative.5a A draw-
back of this asymmetric Ugi reaction was the fact that high
levels of diastereoselectivity were only observed for reactions
using tert-butyl isonitrile. The asymmetric synthesis of (S)-
amino acid acids via the Ugi reaction was achieved using
an arabinosylamine derivative; however, the diastereo-
selectivity was not as high as that observed in the synthesis
of the corresponding (R)-enantiomer.5b A single variant on
the chemistry developed by Kunz has been reported by Ugi.6
A 2-acetamido glucosylamine derivative provided high levels
of stereoselectivity for the (R)-amino acid derivative in the
Ugi reaction, even if nonsterically demanding isonitriles
were employed. However, no hydrolysis of the amide product
was reported, and a complementary method for the synthesis
of the (S)-amino acid was not achieved.
The chemical conversion of an Ugi product is a limitation
in the application of the Ugi reaction to the synthesis of
small molecules.2a Post-Ugi modification is restricted by the
need to selectively hydrolyze a secondary amide functional
group, a nontrivial task in functionalized substrates.7 Arm-
strong and co-workers have addressed this problem by the
* Corresponding author. Phone: 919-515-3616. Fax: 919-515-8920.
email: linderma@chemdept.chem.ncsu.edu.
(1) (a) Ugi, I. Angew. Chem., Intl. Ed. Engl. 1982, 21, 810-819. (b) Ugi,
I. J . Prakt. Chem. 1997, 339, 499-516.
(2) (a) Mjalli, A. M. M.; Sarshar, S.; Baiga, T. J . Tetrahedron Lett. 1996,
37, 2943-2946. (b) Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39,
2725-2728. (c) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38,
359-362. (d) Short, K. M.; Ching, B. W.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 7489-7492. (e) Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998,
39, 2735-2738. (f) Hulme, C.; Morrissette, M. W.; Volz, F. A.; Burns, C. J .
Tetrahedron Lett. 1998, 39, 1113-1116.
(3) (a) Bock, H.; Ugi, I. J . Prakt. Chem. 1997, 339, 385-389. (b) Ziegler,
T.; Schlomer, R.; Koch, C. Tetrahedron Lett. 1998, 39, 5957-5960.
(4) Sigmuller, F.; Herrmann, R.; Ugi, I. Tetrahedron 1986, 42, 5931-
5940.
(5) (a) Galactosylamine for (R)-amino acid synthesis: Kunz, H.; Pfrengle,
W. Tetrahedron 1988, 44, 5487-5494. (b) Arabinosylamine for (S)-amino
acid synthesis: Kunz, H.; Pfrengle, W.; Sager, W. Tetrahedron Lett. 1989,
30, 4109-4110.
(8) (a) Strocker, A. M.; Keating, T. A.; Tempest, P. A.; Armstrong, R. W.
Tetrahedron Lett. 1996, 37, 1149-1152. (b) Keating, T. A.; Armstrong, R.
W. J . Am. Chem. Soc. 1996, 118, 2574-2583. (c) Keating, T. A.; Armstrong,
R. W. J . Org. Chem. 1996, 61, 8935-8939.
(9) Evans, D. A.; Takasc, J . M. Tetrahedron Lett. 1980, 21, 4233-36.
For a recent example, see: Pippel, D. J .; Curtis, M. D.; Du, H.; Beak, P. J .
Org. Chem. 1998, 63, 2-3.
(6) Lehnhoff, S.; Goebel, M.; Karl, R. M.; Klosel, R.; Ugi, I. Angew. Chem.,
Intl. Ed. Engl. 1995, 34, 1104-1107.
(7) For selective hydrolysis of secondary amide Ugi products via initial
chemical conversion to an oxazolidinone, see ref 2a and Geller, J .; Ugi, I.
Chem. Scr. 1983, 22, 85-89.
10.1021/jo982186e CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/31/1998

Communications
J . Org. Chem., Vol. 64, No. 2, 1999 337
Ta ble 2. Asym m etr ic Syn th esis of 8c′ a n d 10c′ via th e
Sch em e 2
Ugi MCC Rea ction Usin g Silyl Eth er An a logs of Ison itr ile
1
yield (%)
yield (%)
isonitrile, OR )
(R)-8c′
dr
(S)-10c′
dr
SiEt3
Si(iPr)3
Si(Ph)2CH3
Si(Ph)2tBu
87
76
52
54
94:6
98:2
>99:1
98:2
75a
81
90:10
99:1
98:2
98:2
80a
69
a
Yield of amide corrected for isolated benzyl ester derivative
formed by amide/ester exchange under the Ugi reaction conditions.
Ta ble 1. Asym m etr ic Am in o Acid s via th e Ugi MCC
Rea ction u sin g Ison itr ile 1
reaction mixture. Purification of the amino acid can then
be accomplished by ion exchange chromatography. Yields
reported in Scheme 3 were determined by NMR integration
of the mixture of the free amino acid and 2-aminobenzyl
alcohol. Separation of the 2-aminobenzyl alcohol byproduct
can be problematic. More highly functionalized amino acid
products, such as diacid 11c, are easily separated by ion
exchange chromatography while separation of simpler prod-
ucts such as phenylalanine 11d is difficult. We are currently
examining several alternative aryl groups in the isonitrile
to alleviate this problem.
aldehyde, R )
yield (%)
dr
yield (%)
dr
Ph
CH(CH3)2
(CH2)4CO2CH3
CH2Ph
(CH2)2CFdCHC6H5
8a , 61
8b, 80
8c, 80
8d , 85
8e, 65
90:10
97:3
98:2
98:2
98:2
10a , 48
10b, 76
10c, 71
10d , 66
10e, 76
90:10
90:10
96:4
93:7a
95:5
a
Reaction temperature reached -70 °C resulting in a dimin-
ished dr.
The improvement realized by the incorporation of an
intramolecular amide/ester exchange process is illustrated
by the synthesis of the (R) and (S) vinyl fluoride containing
amino acid 11e.10 The acid-catalyzed hydrolysis of tert-butyl
amide amino acid derivatives required 6 N HCl at 80 °C for
6 days!5 We have found that vinyl fluorides are very
susceptible to acid-catalyzed hydrolysis. Normal hydrolysis
conditions for an amide (6 N HCl) result in complete
destruction of the vinyl fluoride within 12 h. We obtained
(R) vinyl fluoride 11e in 75% yield from amide 8e. The lower
yield for the (S) enantiomer of 11e was attributed to
solubility problems encountered during hydrolysis of the
arabinosyl derivative.
We have also been able to demonstrate that the size of
the silyl ether can influence the diastereoselectivity of the
reaction. We have prepared a series of silyl ether derivatives
of isonitrile 1 and carried out the asymmetric Ugi reaction
leading to amide 8c′ and 10c′, Table 2.
The triethyl silyl ether provided the lowest dr while all of
the other ether derivatives provided comparable dr. The
yield of the reaction is somewhat lower with the phenyl silyl
ether derivatives, but the yields in Table 2 have not been
optimized. For practical purposes, the tert-butyldimethyl
silyl ether isonitrile 1 is the reagent of choice for the
asymmetric Ugi reaction reported here. In all of the cases
examined, the Ugi product minor diastereomer is easily
removed by flash chromatography, and diastereomerically
pure products can be obtained prior to hydrolysis.
Sch em e 3
We then examined the application of isonitrile 1 in the
asymmetric Ugi reaction using the galactosylamine auxiliary
7 under the conditions reported by Kunz,5a Scheme 2. As
previously reported, the asymmetric Ugi reaction is fairly
slow, requiring up to 72 h at -78 °C. Nevertheless, we were
extremely gratified to note that the reaction did indeed
provide the (R)-valine derivative 8b in 80% yield with
excellent diastereoselectivity, 97:3 dr. The diastereoselec-
tivity of the reaction is rapidly degraded at increased
reaction temperatures. While benzaldehyde provided the
lowest yield and diastereoselectivity in the reaction, Table
1, the amino acid amides 8b-e are obtained with excellent
diastereomeric ratios. It is interesting to note that the
formamide proton is not only distinguishable as pairs of
diastereomers, but also as rotamers. Integration of the
formamide proton signal provides a reliable method for
determination of the diastereomeric ratio; however, all of
the ratios reported herein were verified by HPLC analysis.
In nearly all cases, the minor diastereomer is not observed
by NMR in reactions carried out at -78 °C, but can be
readily detected in reactions carried out at higher temper-
atures. More significantly, Ugi reaction of isonitrile 1 with
the arabinosylamine auxiliary 9, Scheme 2, provides the (S)-
amino acid in excellent yield with greater degrees of dia-
stereoselectivity than those reported by Kunz for similar
asymmetric Ugi reactions using tert-butyl isonitrile. The
results of the synthesis of several (S)-amino acids are also
given in Table 1.
In summary, we have developed an alternative easily
hydrolyzable isonitrile which can be applied to the asym-
metric Ugi reaction, providing functionalized unnatural
amino acids such as 11e in excellent dr.
Ack n ow led gm en t . The authors thank the NCSU
Department of Chemistry for partial funding of this work.
S.R.P. was a participant in the NCSU NSF-REU program
(CHE-9610196).
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures for isonitrile synthesis, the Ugi reaction, and hydrolysis of
the amide products; characterization data for all new compounds.
The amides 8a -e and 10a -e were converted to the free
amino acids 11 as shown in Scheme 3. The amides were
converted to the acid via hydrolysis without isolation of the
intermediate ester. Hydrolysis of the sugar and formyl
groups occurs concomitantly. The chiral auxiliary sugar is
isolated by pentane extraction of the crude hydrolysis
J O982186E
(10) Vinyl fluorides are potential peptide isosteres. See, (a) Allmendinger,
T.; Furet, P.; Hungerbuhler, E. Tetrahedron Lett. 1990, 31, 7297-7300. (b)
Bartlett, P. A.; Otake, A. J . Org. Chem. 1995, 60, 3107-3111.