Thio FCMA intermediates as strong acyl donors: A general solution to the formation of complex amide bonds

Article abstract of DOI:10.1021/ja906005j

(Chemical Equation Presented) Novel methodology for the formation of amide bonds under neutral conditions is described. Evidence is presented that the active acyl donors are thio FCMA intermediates, generated from the reactions of thioacids with isonitril

Full text of DOI:10.1021/ja906005j

Published on Web 08/21/2009
Thio FCMA Intermediates as Strong Acyl Donors: A General Solution to the
Formation of Complex Amide Bonds
Yu Rao,† Xuechen Li,† and Samuel J. Danishefsky*,†,‡
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10065, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027
Received July 22, 2009; E-mail: s-danishefsky@ski.mskcc.org
Following explorations into the chemistry of isonitriles,1 we were
recently able to develop a new line of methodology which we
consolidate in the expression, two-component coupling (2CC).2 The
2CC progression presumably commences via the reaction of an
Figure 2
isonitrile (2) with a carboxylic acid (1), thereby generating a
formimidate carboxylate mixed anhydride (3).3 For ease of com-
munication, we refer to such a structure as an “FCMA”. While no
FCMA has been fully characterized, Rebek has brought to bear
impressive evidence as to their existence4 in special settings. It
seems that, under the usual reaction conditions, the oxy FCMA (3)
is produced slowly and is disfavored at equilibrium. However, at
higher temperatures under microwave mediation, the oxy FCMA,
as its Z stereoisomer (3-Z), apparently undergoes a 1,3-OfN acyl
transfer to generate an N-formylamide (4),2b the end point of the
2CC reaction.
room temperature, interdiction was, indeed, faster than 1,3 OfN
intramolecular acyl transfer (i.e., 8 dominates over 4). However in
the oxyacid experiments, the interdiction leading to 8 was quite
slow and inefficient.2b As the temperature was raised, the apparent
rates of intramolecular 1,3-OfN acyl transfer become competitive
with interdiction and a mixture of products ensued. Accordingly,
attempts at efficient bimolecular acylation via oxy FCMA inter-
mediates (3) were frustrated. Thus in our current modalities, the
ultimate product of the 2CC reaction reflects only the functionality
of the acid and that of the isonitrile in the end products delivered,
i.e., N-formylamide 4 or N-thioformylamide 7.2a,d
In the short time since its discovery, the 2CC reaction has been
adapted to the generation of a variety of biology related structures
including secondary and tertiary amides and is already a valuable
resource in the increasingly important field of chemoglycobiology.5
As described above, both the formation of thio FCMA 6 and its
1,3-SfN intermolecular acyl transfer leading to 7 are much more
rapid than they are for their oxy counterparts (3f4).2d Accordingly,
a rather fascinating possibility presented itself. To evaluate this
matter, it would first be necessary to explore the relative rates of
rearrangement of the thio FCMA intermediates (see 6f7 vs 6f8).
If per chance interdiction (6f8) were faster than its already rapid
rearrangement possibility (6f7), an opportunity for accomplishing
bimolecular acylation Via an isonitrile would be at hand. In such
a setting, we could envision a new acylation reaction where the
formation of the active acylating agent (6) and its intramolecular
acyl transfer product (see 8) were conducted under particularly mild
conditions, giving rise to neutral “debris” (i.e., thioformamide 9).
In this proposed new bimolecular acylation format, structure 2
would now represent a simple, “throwaway” isonitrile (vide infra).8
This isonitrile would serve as a neutral dehydrothiolating agent
enabling an acylation event (see 8) with extrusion of the neutral
debris product 9. It was hoped that the proposed chemistry advanced
in Figure 3 would be applicable to the establishment of sensitive
acyl products such as those found in biological level target systems.
We began the exploration by investigating the reaction of
differentiated thioacid 10 and cyclohexylisonitrile 11. Indeed, as
anticipated by precedent, a two component coupling (2CC) reaction
occurred to afford the expected product 12 in 55% yield. We next
investigated the reaction of 10 and 11, but now in the presence of
aniline (2 equiv) as the hypothetical nucleophile (NuH). It was found
that anilide 13 was produced in 75% yield.9 Indeed under these
conditions, we could find no clear indication for the formation of
the preViously obserVed 2CC product 12. Accordingly, we had to
surmise that, at least with aniline as the nucleophile, interdiction
was much faster than intramolecular 1,3-SfN transfer, which would
have led to the 2CC product 12.
Figure 1
In probing the matter further, it was discovered that the overall
thio counterpart of the 2CC reaction, unlike the oxa version, occurs
at room temperature.2d,6 The throughput of thio FCMA (6)
intermediates generated from reactions of 2 with thioacids (5)7 is
much greater than is the case for their oxy FCMA (3) counterparts.
Moreover, the corresponding SfN rearrangement (see 6f7) is far
more rapid than is its oxy counterpart (3f4). Indeed transformation
6f7 apparently takes place at room temperature. Early findings
concerning the scope and limitations of the thio FCMA version of
the 2CC reaction have been charted.2d
The value of the above-described 2CC and thio 2CC chemistry
was much enhanced as we learned how to synthesize, often for the
first time, high value added isonitriles.2f Application of the 2CC
chemistry to merge “valuable” acids (as well as thioacids) with
“valuable” isonitriles, provides access to useful peptide and
glycopeptide substructural motifs.2a-c
Earlier we had considered the possibility of exploiting oxy FCMA
intermediates (3) as potential bimolecular acylating agents (see 3
+ NuHf8).2d,e For such a prospectus to be feasible, bimolecular
acylation had to dominate over monomolecular 1,3-OfN acyl
transfer (leading to 4). In our initial reaction survey, conducted at
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
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C O M M U N I C A T I O N S
Figure 3
We also addressed the potential competition between intramo-
lecular 1,3-SfN acyl transfer and intermolecular acyl transfer as
a function of the structure of the isonitrile. In an introductory
experiment,2h it was found that the recourse to tert-butylisonitrile
(14) strongly retarded the formation of the 2CC coupling product.
In fact, with 14 as the governing isonitrile, there was obtained a
high yield of tert-butylthioformamide 16, rather than 17. Presumably
compound 16 arose from the reaction of the corresponding thio
FCMA with unreacted acid (10). This proposal as to the origin of
16 further served to reinforce the notion that thio FCMA intermedi-
ates (6) are very strong bimolecular acylating agents.10
Figure 5
Figure 4
We now launched our proposed program in earnest. When the
tert-butylisonitrile (14) mediated reaction was conducted in the
presence of primary amine nucleophiles, anilides were smoothly
produced. The formation of anilides 18 and 19, notwithstanding
the relatiVely weak reactiVity of anilino nucleophiles, was encourag-
ing. Even more impressive was the success of the method in
producing hindered anilides 20 and 21. Remarkably, the method
works well for the formation of doubly hindered amides (see 22
and 23).9 The formation of cinnamanilide 24 demonstrated that the
potential difficulty of conjugate addition need not be a complication.
The power of the new acylation method is perhaps best seen by
the fact that it can be used to produce tertiary amides (see
compounds 28 to 37).11 Particular attention should be drawn to
the formation of products 28 and 29 wherein both flanking sides
of the amide bond are highly hindered. The ability to produce such
products under mild neutral conditions is a strong virtue of the
Figure 6
method. Finally, we also note the formation of cinnamic acid amides
32 and 37 without any apparent complication from Michael
additions.
Remarkably as shown in Figure 7, the chemistry also works very
nicely for the production of esters. Even isopropyl esters 38 and
39 are produced smoothly from the reactions of the corresponding
thioacids with isopropanol. These data strongly support the notion
that an intermediate with exceptionally powerful acyl donor
capacities is generated in the reaction of thioacid and isonitrile.
Thus, in the formation of 38, it is proposed, but not proven, that
the Fmoc-alanine thioacid reacts with tert-butylisonitrile to give
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C O M M U N I C A T I O N S
40, which acylates isopropanol to yield ester 38. It will be noted
that the transformation is achieved without recourse to the usual
acylation catalysis by tertiary amines.12 In Figure 7, we suggest
that, perhaps, concurrent proton transfer from the alcohol to the
nitrogen of the emerging tert-butylthioformamide helps to drive
the acylation.
back to the beginnings of organic chemistry. The amide forming
construction described here could, in principle, have been conducted
in 1909 without difficulty. It is not unlikely that careful mechanisti-
cally based revisitation of the foundations of organic chemistry
might yield additional surprises of considerable value.
Acknowledgment. Support was provided by the NIH (CA103823
to S.J.D.). We thank Prof. W. F. Berkowitz for helpful discussions.
Special thanks to Ms. Rebecca Wilson for editorial advice and
consultation and to Ms. Dana Ryan for assistance with the
preparation of the manuscript. 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
Supporting Information Available: Experimental procedures,
copies of spectral data, and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 7
References
Finally we emphasize the straightforward formation of the highly
hindered tertiary amide 46. This product must have arisen by
interdiction of thio FCMA intermediate 44 with N-methyl valine
42.13 We further note that this reaction essentially fails when
conducted on N-methyl valine methyl ester 43. Accordingly it is
proposed that the thio FCMA 44 first acylates the carboxyl group
of 42, giving rise to mixed anhydride 45. The latter proceeds to
product 46 by a novel OfN acyl transfer.14
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(8) Of course, the resulting formamide can be recycled to amine and isonitrile,
thus completing the cycle.
(9) This compound was purified, and its structure is defined by infrared, NMR
(1H and 13C), and high resolution mass spectra. All data are provided in
the Supporting Information.
(10) The cognate product, which we don’t isolate, is almost certainly the (syn)
mono thio anhydride. It seems unlikely (but not impossible) that such an
anhydride is performing acylation. The rapidity of our observed acylation
in less hindered settings renders such an interpretation highly unlikely.
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(12) The electronic depiction suggested in going from 40f38 is not intended
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Figure 8. Key: (a) TMSCH2N2, THF/MeOH, RT, 90%.
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reactivity of this substrate. The reaction efficiently proceeded in DCM,
DMF, or DCM/DMF (1:1/v:v) solvent systems without additional base.
(14) Brown, Z. Z.; Schafmeister, C. E. J. Am. Chem. Soc. 2008, 130, 14382.
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In summary, we have presented above a notable advance in the
construction of amide bonds, including highly hindered cases.15,16
The chemistry is easily executed. The reactions are currently
conducted under neutral conditions at room temperature in dichlo-
romethane. Subsequent disclosures will deal with the applicability
of this chemistry to the fashioning of biologic-level molecules. The
prognosis, at this time, is quite promising.
In this and earlier papers, we have attempted to delineate the
various conjectures, mechanistic analyses, and experiments which
enabled these discoveries. We note in passing that amines,
isonitriles, and thioacids are very old functional groups which go
(16) While quantitative comparisons are not yet available, we believe that the
rate of interdiction relative to rearrangement of the thio FCMA renders it
a superior acylating device relative to intermediates arising in carbodiimide
methodology.
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