Thio-mediated two-component coupling reaction of carboxylic acids and isonitriles under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2009.01.046

The coupling reaction between carboxylic acids and isonitriles in the presence of thiophenol as activator under mild conditions is described.

Full text of DOI:10.1016/j.tetlet.2009.01.046

Tetrahedron Letters 50 (2009) 1523–1525
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Tetrahedron Letters
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Thio-mediated two-component coupling reaction of carboxylic acids
and isonitriles under mild conditions
Xiangyang Wu a, Xuechen Li 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:
The coupling reaction between carboxylic acids and isonitriles in the presence of thiophenol as activator
under mild conditions is described.
Received 15 December 2008
Revised 5 January 2009
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Recently, our laboratory described some conceptually notewor-
thy and translationally promising results arising from reactions of
carboxylic acids (1) with isonitriles (2).1 Several notions and terms
have been suggested to help facilitate communication in this rap-
idly emerging chemistry. Eq. 1 describes the formation of formim-
idate carboxylate mixed anhydrides (FCMAs) in E- and/or Z-form
via the merger of 1 and 2 (Fig. 1). Eq. 2 corresponds to a 1,3-
O?N acyl migration to generate an N-formyl amide (4). This
migration is the key and terminating step in the overall two-com-
ponent coupling (2CC) process. Depending on how the experiment
is structured, the O?N acyl migration within FCMA 3 may be inter-
dicted by a resident nucleophile (NuH) to afford 5.2 Several re-
ports3 in the literature which did not appreciate the high
susceptibility of FCMAs to nucleophile attack have been corrected.4
We interpret the formation of 5 at room temperature, wherein the
formation of 2CC product 4 is not observed, to suggest that FCMA 3
(Z or E) is readily produced, albeit in low concentration. However,
the 1,3-O?N acyl transfer requires thermolysis (best done via
microwave heating at 150 °C). In earlier papers, we described some
of the high ‘value added’ chemistry, which accrues from readily
achievable transformations of the formyl group of 4 (see Fig. 1,
product types 6). Moreover, the 2CC chemistry, generalized above,
has been shown to be applicable to the synthesis of N-linked small
peptides and glycopeptides.1
That the FCMA is produced, albeit slowly, at room temperature,
had been established through interdiction experiments, resulting
in the formation of secondary amide 9, albeit in modest yield
(Fig. 2).1
We were also intrigued by the implications of our findings in
the context of an intended model experiment for achieving ‘serine
ligation.’ 4,5 Remarkably, reaction of
L-serine isonitrile 10 with acid
11 afforded 15 (Fig. 2). Although the yield is modest, we noted that
when the side chain hydroxyl of the serine was protected, no cou-
pling occurred at room temperature. However, the microwave
(150 °C) induced 2CC coupling in the –OTMS protected series oc-
curred normally (16?17?18). When the silyl ether of 18 was
cleaved, the same formate ester, 15, was smoothly produced, thus
corroborating the various structural assignments.
The mechanistic inferences to be drawn from the ‘serine’ exper-
iments are far from certain. Perhaps the free-hydroxyl group adds
to the imino linkage of the FCMA 12 to generate 13. Following this
line of reasoning, one would be obliged to conclude that the acyl
R2
O
N
O
R2
eq. 2
N
R1
O
R1
CHO
4
3-E-FCMA
O
eq. 1
+
C
N R2
Of course, the main disadvantage in the 1,3-O?N acyl transfer
step (cf. 3?4) is the requirement for thermolytic activation. Such
conditions may or may not be consistent with maintenance of a
sensitive polypeptidic or polypeptidic glycan structure.
The work described herein was motivated by the hope of realiz-
ing 2CC reactions, ideally at room temperature, but certainly well be-
low the current microwave (150 °C) conditions. As described below,
important progress in this regard has been realized.
R1
OH
O
2
1
R2
Nu– H
interdiction
N
O
Nu
R1
5
O
R1
Nu =
OR, NHR
3-Z-FCMA
O
O
R2
R2
N
R
R1
N
R1
CHO
4
6
R = H, Me,
CH2OH, et al
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.046

1524
X. Wu et al. / Tetrahedron Letters 50 (2009) 1523–1525
Table 1 8
NH2
O
O
O
NHFmoc
CO2t-Bu
O
O
+
NHFmoc
CO2t-Bu
conditions
R2
R2
MeO
+
+
–C N+ R2
R1
N
R1
PhS
N
:
+
NC
N
H
R1
O
OH
HO
rt
CHO
9
7
8
SPh
MeO
BnO2C
O
CO2Bn
O
ÀC„N+AR2
Conditions
RT
+
NPhth
NPhth
O
O
N
H
N
HO
C–
R2
R2
O
O
H
OH
R1
PhS
N
N
R1
OH
R1
11
10
15
CHO
SPh
CO2Bn
CO2Bn
BnO2C
O
+
MV
+
11
N
O
a
a
a
b
45%
32%
48%
23%
15%
23%
22%
18%
N
C–
N
BnO2C
OH
NC
TMSO
NPhth
TMSO
TMSO
CHO NPhth
O
16
BocHN
O
17
18
Possible Mechanistic Rationales:
CO2Bn
BnO2C
BocHN
OH
OH
OH
NC
HO
O
O
O
N
O
NPhth
O
12-Z-FCMA
CO2Bn
NH
BnO2C
BocHN
t-Bu-O2C
t-Bu-O2C
NC
O
RT
10
+ 11
?
15
O
O
CO2Bn
NPhth
13
BnO2C
BocHN
Ph
N
O
OH
NPhth
15
NC
O
12-E-FCMA
a
50%
25%
O
CO2Bn
NC
BnO2C
O
BnO2C
BocHN
OH
N
O
N
RT
O
10
+ 11
NPhth
15
H
H
O
O
O
NPhth
H
12 E-FCMA
14
Conditions: (a) 50 °C, 48 h.; (b) 80 °C, 48 h.
Figure 2.
The results of our survey investigations are shown in Table 1.
While the concurrent formation of N-formyl amides and their
‘thioacetals’ (see 21) is obviously awkward, the yields for convert-
ing type 21 products to 20 are high (88%), so that in the end the
2CC reaction is quite productive.
transfer in 13 is significantly faster than are its counterparts, 3 (see
3?4) or 17 (see 17?18). Alternatively, the role of the free hydro-
xyl group in the serine might be that of promoting (via 13) the for-
mation of FCMA 12-E required for acyl transfer.6 Still another
possibility to account for the serine acceleration focuses on the
‘late stage’ of the acyl transfer shown in Figure 2.7 It contemplates
intervention of a stabilizing hydrogen bond to the emerging imide
(at either the nitrogen or the formyl lone pairs), which helps to
facilitate the culminating O?N acyl transfer of the 2CC reaction
(see 12?14).
While a full understanding of the detailed mechanism of the
2CC serine reaction leading to 15 is a work in progress, the already
intriguing results reported above prompted us to explore the pos-
sibility of achieving a similar outcome through mediation by an
external nucleophile. Pursuing this admittedly speculative line of
thought, we studied the consequences of adding thiols to putative
2CC reactions.
As was suggested in the discussion of the serine ligation experi-
ment, we are tempted to propose the formation of the tetrahedral
intermediate B by combining the FCMA A with the thio nucleophile
(Scheme 2). As before, the tetrahedral intermediate might undergo
rapid acyl transfer or revert to the required E-FCMA for the acyl
transfer step leading to N-formyl amides. Alternatively, the inter-
molecular thiol SH bond could provide a hydrogen-bonding source
(as described above) to facilitate the culminating O?N transfer step.
Hoping to gain further insight into the thiol-mediated 2CC reac-
tion, we explored the possibility of generating a related tetrahedral
intermediate B (Scheme 2) by the reaction of an acid with a thioim-
idate. However, attempted aspartylation via the reaction of aspar-
tic acid with independently synthesized thioimidate9 led to no
observed coupling product (Scheme 2).
Happily, already in the opening experiment, it was found that in
the presence of 0.5 equiv of thiophenol, with 1,2-dichloroethane as
the solvent, coupling of 19 and 7 took place at room temperature to
provide 20 and 21 in the yields shown. The yields could be im-
proved (ca 60%) by conducting the reaction at 50 °C (Scheme 1).
O
R2
O
(a)
N
S
H
R1
N
Ph
O
R2
CHO
R2
HSPh
(b)
20
R1
OH
O
HN
(b)
RT
19
+
O
R1
O
SPh
R1
O
+
R2
B
A
R1
N
SPh
PhS
– C N+ R2
HO2C
CHO
N
a
CO2Bn
(a)
CO2Bn
NHBoc
PhS
SPh
+
7
7
N
+
BnO2C
NHBoc
21
O
NHBoc
O
21
(20%)
(45%)
20
19
20
(10%)
(15%)
O
RT
50 o
C
H
OH
CO2Bn
20 or 21
+
b
N
BocHN
88%
PhS
Scheme 1. Reagents: (a) CH2ClCH2Cl, PhSH; (b) TsOH, CH2Cl2.
Scheme 2.

X. Wu et al. / Tetrahedron Letters 50 (2009) 1523–1525
1525
In summary, we have described herein an improved method for
References and notes
coupling of isonitriles and carboxylic acids in the presence of thio-
phenol as an activator under mild conditions. This coupling method,
with appropriatefinetuning, couldbe utilizable inthepreparationof
important biomolecules.
1. Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446; Li, X.; Danishefsky, S. J.
Nat. Protocols 2008, 3, 1666.
2. Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13225.
3. (a) Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007, 48, 6137;
(b) Gloede, J.; Gross, H. Z. Chem 1968, 8, 219.
4. Li, X.; Yuan, Y.; Berkowitz, W. F.; Todaro, L. J.; Danishefsky, S. J. J. Am. Chem. Soc.
2008, 130, 13222.
Acknowledgments
5. A similar chemistry in comparable yield has been achieved with the threonine
isonitrile.
This work was supported by the NIH(CA103823 to S.J.D.).
Special thanks goes to Dana Ryan and Rebecca Wilson for assis-
tance with the preparation of the Letter. We thank Dr. Jianglong
Zhu, Dr. Yu Yuan, and Dr. Cindy Kan for their helpful discussions.
We thank Dr. George Sukenick, Ms. Hui Fang, and Ms. Sylvi Rusli
of the Sloan-Kettering Institute’s NMR core facility for mass spec-
tral and NMR spectroscopic analysis.
6. For this interpretation to explain the serine ligation, one would have to propose
that the kinetic product of the original insertion reaction between the carboxylic
acid and the isonitrile is the Z-FCMA, which does not undergo 1,3 O?N transfer.
The formation of tetrahedral intermediate 12 allows for equilibration of the
FCMA forms, enabling the E-form to rearrange. This formulation seems
counterintuitive, but is included as a formal possibility. See Marcelli, T.; Himo,
F. Eur. J. Org. Chem. 2008, 4751.
7. The eventual progression to formate ester 15 provides
a thermodynamic
advantage, but is unlikely to explain the sharply accelerated rate of the serine
ligation since it comes after the 1,3-N?O acyl transfer.
8. Attempts to use
L-a-amino acid derivatives in the thio-mediated 2CC reaction
Supplementary data
have not been rewarding.
9. Saegusa, T.; Kobayashi, S.; Hirota, K.; Okumura, Y.; Ito, Y. Bull. Chem. Soc. Jpn.
1968, 41, 1638.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.046.