On the preparation of enantiomerically pure isonitriles from amino acid esters and peptides

Article abstract of DOI:10.1016/j.tetlet.2008.11.069

An improved method for the synthesis of enantiomerically pure isonitriles from amino acid esters and dipeptides is described.

Full text of DOI:10.1016/j.tetlet.2008.11.069

Tetrahedron Letters 50 (2009) 577–579
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On the preparation of enantiomerically pure isonitriles from amino acid
esters and peptides
Jianglong Zhu a, Xiangyang Wu a, Samuel J. Danishefsky a,b,
*
a Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
b Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An improved method for the synthesis of enantiomerically pure isonitriles from amino acid esters and
dipeptides is described.
Received 7 November 2008
Accepted 19 November 2008
Available online 24 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Initially discovered in 1867 by Gautier1 and Hofmann2, isoni-
triles have emerged as a synthetically useful class of organic com-
pounds. A number of important isonitrile-based methods had been
developed, including the Passerini reaction3 and the Ugi 4-compo-
nent coupling reaction,4 among others.5 We recently reported a no-
vel thermally induced two-component coupling reaction between
isonitriles and carboxylic acids, which provides ready access to
various N-formyl imides.6 Importantly, this coupling methodology
has been extended to the preparation of peptides bearing N-formyl
imides. We envision that these peptides could be further elongated
through iterative isonitrile–carboxylic acid coupling reactions.
The feasibility of such a peptide coupling strategy is predicated
on our ability to gain access to enantiomerically pure amino acid-
and N-terminal peptide-derived isonitriles. The typical literature-
based approach to the preparation of isonitriles involves dehydration
of N-alkyl or N-arylformamides.7 A number of reagents (cf. phos-
gene,6,8 diphosgene,9 triphosgene,10 and POCl311) and tertiary
amine bases (triethylamine and N-methyl morpholine [NMM])
have been employed to accomplish such dehydrations. In 1977,
Ugi and co-workers described the syntheses of several optically ac-
Table 1
Ph
O
Ph
O
O
conditions
OMe
OMe
H
N
CN
H
1
2
Entry Conditions
Yield
(%)
er
1
2
3
4
POCl3/Et3N (1.2 equiv, 5.0 equiv), ꢀ78 to 0 °C
80
51
75
79
1:1
1.2:1
NA
Phosgene/NMM (1.2 equiv, 3.5 equiv), ꢀ30 °C12
Diphosgene/NMM (0.5 equiv, 2.1 equiv), ꢀ30 °C9
Triphosgene/NMM (0.35 equiv, 2.0 equiv), ꢀ40 to
18:1
ꢀ30 °C
5
Triphosgene/NMM (0.35 equiv, 2.0 equiv), ꢀ78 to
ꢀ30 °C
82
>99:1
In our initial studies, we focused on the enantioselective prepa-
ration of isonitrile 2 from N-formyl phenylalanine methyl ester (1).
As shown in Table 1, treatment of 1 with POCl3/Et3N gave the race-
mized product 2 in good yield (entry 1). Postulating that racemiza-
tion may be caused by use of overly strong dehydrating conditions,
we turned to the use of milder protocols, with particular emphasis
on the maintenance of a neutral or slightly acidic reaction environ-
ment. In the event, treatment of a mixture of 1 and NMM (2.0 equiv)
at ꢀ40 °C with solid triphosgene (0.35 equiv) followed by warming
to ꢀ30 °C furnished 2 in 79% yield with slight racemization
(er = 18:1, entry 4). The enantiomeric ratio was further improved
when the reaction was conducted at a lower temperature (entry 5).
We next sought to explore the scope of the reaction with re-
spect to the nature of the particular amino acid residue. Thus, as
outlined in Table 2 (entries 1–6), a variety of amino ester isonitriles
could be prepared in good yield and with high levels of optical pur-
ity from the corresponding N-formyl amino esters. The synthesis of
tive a-isocyanocarboxylic acid derivatives, including 2, which was
prepared from 1 through exposure to either phosgene/NMM12 or
diphosgene/NMM.9 However, under these conditions, we observed
significant racemization of the N-formyl amino acid esters (Table 1,
entries 2 and 3).12 Others have since reported the preparation of
various
a-isocyano carboxylic esters; however, in these cases,
either limited or no information on the enantiomeric excess of
the
a
-chiral center was provided.13 In some instances, syntheses
of racemates were reported.14 Herein, we describe the develop-
ment of an effective protocol for the preparation of a variety of
enantiomerically pure isonitriles from amino acid esters and N-ter-
minal peptides. With enantiomerically enriched isonitriles in hand,
we investigated the conditions required for their racemization.
CN-
L
-Asp-(OBn)2 was accompanied by slight racemization of the
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
a-chiral center (entry 4). The preparation of methyl
a-isocyano-
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.069

578
J. Zhu et al. / Tetrahedron Letters 50 (2009) 577–579
Table 2
Table 3
triphosgene (0.35 equiv)
NMM (2.0 equiv), CH2Cl2
Ph
CN
2, >99:1 er
Me
R
O
R
OBn
OMe
X
X
CN
3, >99:1 er
CN
H
N
–78 °C to –30 °C
H
O
O
O
O
Entry
1
Conditions
Yield (%)
er
Entry
Starting isonitrile
Racemization conditions
Results (er)
Me
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
1.0 equiv Et3N, CH2Cl2, ꢀ30 °C, 1.5 h
1.0 equiv Et3N, CH2Cl2, rt, 20 min
1.0 equiv NMM, CH2Cl2, ꢀ30 °C, 1 h
1.0 equiv NMM, CH2Cl2, rt, 20 min
1.0 equiv Et3N, CH2Cl2, ꢀ30 °C, 1 h
1.0 equiv Et3N, CH2Cl2, rt, 20 min
1.0 equiv NMM, CH2Cl2, ꢀ30 °C, 1 h
1.0 equiv NMM, CH2Cl2, rt, 20 min
1.25:1
1:1
>99:1
7.3:1
4.5:1
1:1
OBn
75
90
>99:1
>99:1
CN
O
3
Me
Me
2
3
4
>99:1
13.5:1
OBn
CN
O
OTMS
4
63
62
>99:1
32:1
purity of the
rather readily racemizable isonitrile amino esters—CN-
(2) and CN- -Ala-OBn (3)—and subjected them to a variety of con-
a
-isocyano amino ester is eroded. We selected two
OBn
CN
CN
L
-Phe-OMe
5
O
L
CO2Bn
ditions which might induce racemization. As shown in Table 3, we
found that, while treatment of these two isonitriles with 1.0 equiv
NMM at ꢀ30 °C for 1 h did not lead to detectable racemization
(entries 3 and 7), exposure to 1.0 equiv NMM at room temperature
resulted in partial racemization (entries 4 and 8). Furthermore,
treatment with triethylamine led to significant levels of racemiza-
tion (entries 1, 2, 5, and 6), indicating that the choice of base is
indeed very crucial.
In summary, we have described herein an improved method for
the preparation of enantiomerically pure isonitriles from the corre-
sponding a-amino acid esters and N-terminal dipeptide substrates.
This coupling method could potentially be utilized in the prepara-
tion of peptides through our newly developed two-component
isonitrile–carboxylic acid coupling chemistry. Such applications
have been realized.
OBn
O
6
5
79
ND
OMe
CN
CN
O
7
SEt
Me
S
O
6
7
52
>99:1
O
8
Me
O
H
N
70a
Single diastereomer
Single diastereomer
Acknowledgments
CN
CN
OBn
O
Me
9
This work was supported by the NIH (CA28824 to S.J.D.). Special
thanks go to Rebecca Wilson for editorial consultation and Dana
Ryan for assistance with the preparation of the manuscript. We
thank Dr. Xuechen Li, Dr. Yu Yuan and Dr. Cindy Kan for their help-
ful discussions. We thank Dr. George Sukenick, Ms. Hui Fang, and
Ms. Sylvi Rusli of the Sloan-Kettering Institute’s NMR core facility
for mass spectral and NMR spectroscopic analysis.
Ph
O
H
N
58a
OMe
Me
8
O
10
Me
a
Conditions: 2,6-lutidine, ꢀ50 °C.
Supplementary data
phenylacetate had been previously reported to be very challeng-
ing.15 Under our optimal conditions, this isonitrile was obtained
in good yield and in optically active form (½aꢁD) +96.0; however,
the compound was found to be very unstable to chromatography
and all attempts to obtain an HPLC-based enantiomeric ratio were
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.069.
References and notes
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J. Zhu et al. / Tetrahedron Letters 50 (2009) 577–579
579
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