One-pot syntheses of dissymmetric diamides based on the chemistry of cyclic monothioanhydrides. Scope and limitations and application to the synthesis of glycodipeptides

Article abstract of DOI:10.1021/jo900532e

(Chemical Equation Presented) Opening cyclic monothioanhydrides by amines provides a convenient entry into amido thioacids that can be trapped in situ by 2,4-dinitrobenzenesulfonamides, by electron-deficient azides, or by amines in the presence of Sanger's reagent leading, in each case, to dissymmetric diamides in what can be considered a one-pot, three-component coupling sequence. The use of monothiomaleic anhydride and bifunctional nucleophiles such as amino thiols provides access to heterocyclic amides. The low reactivity of cyclic monothioanhydrides toward alcohols enables the use of methanol as solvent and obviates the need for the protection of alcohols in the various reaction components. Reaction of N-benzyloxycarbonyl-L-aspartic monothioanhydride with unprotected glycosyl amines, followed by capture of the thioacid intermediate with N-sulfonyl amino acid derivatives results in a three-component convergent synthesis of glycosylated peptides.

Full text of DOI:10.1021/jo900532e

One-Pot Syntheses of Dissymmetric Diamides Based on the
Chemistry of Cyclic Monothioanhydrides. Scope and Limitations
and Application to the Synthesis of Glycodipeptides
David Crich,*,†,‡,§ Kaname Sasaki,‡ Md Yeajur Rahaman,‡ and Albert A. Bowers§
Centre de Recherche CNRS de Gif-sur-YVette, Institut de Chimie des Substances Naturelles, AVenue de la
Terrasse, 91198 Gif-sur-YVette, France, Department of Chemistry, Wayne State UniVersity, 5101 Cass
AVenue, Detroit, Michigan 48202, and Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607
dcrich@icsn.cnrs-gif.fr
ReceiVed March 13, 2009
Opening cyclic monothioanhydrides by amines provides a convenient entry into amido thioacids that
can be trapped in situ by 2,4-dinitrobenzenesulfonamides, by electron-deficient azides, or by amines in
the presence of Sanger’s reagent leading, in each case, to dissymmetric diamides in what can be considered
a one-pot, three-component coupling sequence. The use of monothiomaleic anhydride and bifunctional
nucleophiles such as amino thiols provides access to heterocyclic amides. The low reactivity of cyclic
monothioanhydrides toward alcohols enables the use of methanol as solvent and obviates the need for
the protection of alcohols in the various reaction components. Reaction of N-benzyloxycarbonyl-L-aspartic
monothioanhydride with unprotected glycosyl amines, followed by capture of the thioacid intermediate
with N-sulfonyl amino acid derivatives results in a three-component convergent synthesis of glycosylated
peptides.
Introduction
coupling of thioacids with amines,3 their condensation with
azides,4 their condensation with electron-deficient sulfonamides,
Monothiocarboxylic acids [RsC(dO)sSH]1 have an inter-
esting and varied chemistry,2 some of the more fascinating
aspects of which pertain to their use in amide bond forming
reactions. Such amide bond forming reactions include the direct
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† Institut de Chimie des Substances Naturelles.
‡ Wayne State University.
§ University of Illinois at Chicago.
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Murai, T.; Kanda, T. J. Am. Chem. Soc. 1996, 118, 1262–1267. (b) Hadad, C. M.;
Rablen, P. R.; Wiberg, K. B. J. Org. Chem. 1998, 63, 8668–8681.
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3886 J. Org. Chem. 2009, 74, 3886–3893
10.1021/jo900532e CCC: $40.75 2009 American Chemical Society
Published on Web 04/22/2009

One-Pot Syntheses of Dissymmetric Diamides
again leading to amides,5 their use as precursors to thioesters
for native chemical ligation,6 and their application as compo-
nents of Ugi-type reactions leading to thioamides.7 Monosele-
nocarboxylic acids undergo analogous reactions,8 as do dithio-
acids albeit with the provision of thioamides in the latter
case.5a,b,9 Despite the obvious utility of this broad range of
chemistry thioacids have found relatively little application in
organic synthesis, perhaps due to the very limited range of
commercially available thioacids and the consequent need to
prepare all but the simplest members of the family.
Cyclic monthioanhydrides are a group of readily prepared
thioacid derivatives10 that exhibit a considerable range of
interesting chemistry,10c,11 but which are also underemployed
in organic synthesis. We reasoned that perhaps the simplest of
reactions of cyclic monothioanhydrides, their ring-opening with
competent nucleophiles, would provide a facile, practical means
of generation of thioacids for subsequent use within the one
reaction pot, thereby affording a series of multicomponent
coupling reactions,12 by the union of two underappreciated
functional groups. Dervan and co-workers had previously
studied the ring-opening of monothiosuccinic anhydride with
amines, coupled with subsequent alkylation by benzyl bromide
to give a thioester for eventual use in native chemical ligation,13
but as we outlined previously14 and set out here in full, this
simple trick has a much broader scope when the range of easily
prepared cyclic monothioanhydrides and the breadth of thioacid
chemistry is taken into consideration.
1 and 2).15 This reaction sequence worked extremely well at
room temperature both in DMF and, more surprisingly at first,
in methanol indicating the monothioanhydride to be more
reactive toward an approximately stoichiometric amount of
aniline than to the bulk solvent, methanol. When aniline was
replaced by benzylamine as nucleophile and the N-phenyl 2,4-
dinitrobenzenesulfonamide employed as a trap for the thioacid,
leading overall to the same bisamide 2 (Table 1, entry 3), a
notable drop in yield was observed. This is attributed to the
weaker nucleophilicity of the aniline released on reaction of
the thioacid with the sulfonamide and its consequent slower
reaction with the activated thioacid generated in this step. The
ability of a relatively modest nucleophile to function in the first
step of the protocol is, however, underlined by entry 4 of Table
1, which illustrates how this chemistry may be directed toward
glycoconjugate synthesis. With the tetra-O-acetyl derivative of
glucosamine as the nucleophile the ring-opening is much more
difficult, perhaps owing to the electron-withdrawing effect of
the esters reducing the nucelophilicity of the already only weakly
nucelophilic glucosylamine (Table 1, entry 5).16 Entry 6 of Table
1 illustrates the employment of 1-glucosamine17 as the initiating
nucleophile, with ultimate capture of the thioacid by an amino
acid-based sulfonamide, leading overall to a simple neoglyco
conjugate,18 while entry 7 (Table 1) extends the concept to the
use of an amino deoxy sugar as the first nucleophile. Table 1
(entries
8
and 9) serves to illustrate how an
aminoglycoside19based sulfonamide may be productively em-
ployed as the third coupling partner in this three-component
sequence, whether in DMF or in methanol as solvent. Self-
evidently, given the established compatibility with methanol,
the lack of protecting groups on this sulfonamide was not
detrimental to the overall process. In entry 10 of Table 1 both
the first and third reaction partners are carbohydrate-derived,
with the use of 2-acetylamino-2-deoxy-1-glucosamine 13 being
particularly noteworthy,20 while in entry 11 the union between
an amino acid and a carbohydrate is again established, this time
with the amino acid initiating the cascade and a sugar-based
sulfonamide serving to capture the intermediate thioacid. The
final two entries of Table 1 demonstrate the extension of this
chemistry beyond the commercially available monothiosuccinic
anhydride to readily prepared malonic and adipic analogues,
giving rise to 1,3- and 1,5-bisamides, respectively. The last two
examples of Table 1 also feature the use of an N-sulfonyl
morpholine derivative, resulting in the inclusion of tertiary amide
units in the final three-component coupled products.
Results and Discussion
Saturated Monothio Anhydrides. We first investigated the
reaction of commercially available monothiosuccinic anhydride,
studying ring-opening with the relatively modest nucleophile,
aniline, and subsequent capture of the resulting thioacid
with N-benzyl 2,4-dinitrobenzenesulfonamide (Table 1, entries
(5) (a) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O. Tetrahedron Lett.
1998, 39, 1673–1676. (b) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O.
Tetrahedron Lett. 1998, 39, 1669–1672. (c) Crich, D.; Sana, K.; Guo, S. Org.
Lett. 2007, 9, 4423–4426.
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1994, 266, 776–779. (b) Dawson, P. E.; Kent, S. B. H. Annu. ReV. Biochem.
2000, 69, 923–960. (c) Yeo, D. S. Y.; Srinivasan, R.; Chen, G. Y. J.; Yao, S. Q.
Chem.sEur. J. 2004, 10, 4664–4672. (d) Macmillan, D. Angew. Chem., Int.
Ed. 2006, 45, 7668–7672.
(7) Gulevich, A. V.; Balenkova, E. S.; Nenajdenko, V. G. J. Org. Chem.
2007, 72, 7878–7885.
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L. J. Org. Chem. 2007, 72, 765–774.
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2006, 47, 1163–1166.
(15) All sulfonamides employed herein were prepared from the amine by
reaction with 2,4-dinitrobenzenesulfonyl chloride; see the Supporting Information
for details.
(10) (a) Kates, M. J.; Schauble, J. H. J. Org. Chem. 1995, 60, 6676–6677.
(b) Kates, M. J.; Schauble, J. H. J. Heterocycl. Chem. 1995, 32, 971–978. (c)
Verbeek, M.; Scharf, H. D.; Korte, F. Chem. Ber. 1969, 102, 2471–2477. (d)
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M.; Itabashi, K. Nippon Kagaku Kaishi 1973, 4, 867–869. (d) Schlessinger, R. H.;
Ponticello, I. S. J. Chem. Soc., D 1969, 101, 3–1014. (e) Alberti, A.; Hudson,
A.; Pedulli, G. Tetrahedron 1982, 38, 3749–3752. (f) Baasov, T.; Fuchs, B.
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3605.
(16) In our preliminary communication14 we reported a yield of 69% for
this reaction but we have been unable to reproduce this yield despite considerable
effort. Acetylation of the desacetyl compound 4 gave an authentic sample of 6
whose spectra were in every way consistent with those provided in the supporting
information to the original communication14 (see the Supporting Information),
forcing us to the conclusion that the original result was obtained with the
assistance of an unknown catalyst perhaps present as an impurity in either the
nucleophile or the thiosuccinic anhydride employed. Efforts are continuing toward
the resolution of this issue.
(17) Kovacs, J.; Pinter, I.; Messmer, A.; Toth, G. Carbohydr. Res. 1985,
141, 57–65.
(18) (a) Nicotra, F.; Cipolla, L.; Peri, F.; La Ferta, B.; Redaelli, C. AdV.
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Chemistry; Boons, G.-J. , Ed.; Blackie Academic and Professional: London, UK,
1998; pp 243-321. (c) Lee, Y. C.; Lee, R. T., Eds. Neoglycoconjugates:
Preparation and Applications; Academic Press: San Diego, CA, 1994. (d) Haase,
C.; Seitz, O. Top. Curr. Chem. 2007, 1, 36.
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Tsukamoto, H. Carbohydr. Res. 1970, 14, 355–364.
(12) Zhu, J.; Bienayme´, H., Eds. Multicomponent Reactions; Wiley: Wein-
heim, Germany, 2005.
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Sci., U.S.A. 2000, 97, 3930–3935.
(14) Crich, D.; Bowers, A. A. Org. Lett. 2007, 9, 5323–5325.
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Crich et al.
TABLE 1. Three-Component Coupling of Cyclic Thioanhydrides with Amines and 2,4-Dinitrobenzenesulfonamides
a Ar ) 2,4-dinitrophenyl. b Conditions: (i) 1-1.2 equiv of thioanhydride, 1 equiv of amine, DMF, 30 min; (ii) 1 equiv of Cs2CO3, 1 equiv of sulfonamide,
DMF 1 h. c CsHCO3 was the base in this reaction.
3888 J. Org. Chem. Vol. 74, No. 10, 2009

One-Pot Syntheses of Dissymmetric Diamides
Thiomaleic Anhydride. Subsequently, we turned our atten-
tion to monothiomaleic anhydride, for which several prepara-
tions are available with the optimal in our hands being reaction
of the maleic anhydride/furan cycloadduct with sodium
sulfide,10b followed by retro Diels-Alder reaction and con-
comitant distillation of the product. In extending the basic
concept to monothiomaleic anhydride we anticipated that vicinal
aminothiols would undergo reaction first by conjugate addition
of the softer, more nucelophilic thiol, and that this would be
followed up by cyclization of the amine onto the thioanhydride
moiety. The viability of this concept is evident from entries
1-3 of Table 2, in which 2-mercaptoaniline is employed as
the doubly nucleophilic first reaction component. Particularly
noteworthy here is the use of the piperidine sulfonamide 24
and of the R-aminoisobutyric acid-derived sulfonamide 26
(Table 2, entries 2 and 3) leading to the formation of a tertiary
and a somewhat hindered amide bond, respectively. The
remaining four examples of Table 2 illustrate the use of
L-cysteine and D-penicillamine derivates as the initial reaction
partner. These four reactions, in which a second stereogenic
center was generated, were moderately diastereoselective pro-
viding in each case an approximately 3:1 mixture of epimers
favoring the cis-isomers as determined by NOE studies.
[4+2]-Cycloaddition of thiomaleic anhydride with 2-tert-
butyloxycarbamoylmethylfuran 34 afforded the cycloadduct 35
in 68% yield, as a single diastereoisomer, after 4 days at room
temperature in benzene. Hydrogenation over Raney nickel, as
described by Dauben et al. for the adduct with furan itself,21
afforded the dihydro analogue 36 in 94% yield, whose exo-
stereochemistry was readily ascertained by NOE measurements,
thereby confirming the stereochemistry of the initial adduct
(Scheme 1). Both 35 and 36, on treatment with trifluoroacetic
acid followed by collidine, underwent the anticipated cyclization
with generation of a thioacid that was immediately captured
TABLE 2. Three-Component Coupling of Thiomaleic Anhydrides with Aminothiols and 2,4-Dinitrobenzenesulfonamides
a Ar ) 2,4-dinitrophenyl. b Conditions: (i) 1.2 equiv of thioanhydride, 1 equiv of aminothiol, DMF; (ii) 1.2 equiv of Cs2CO3, 1 equiv of sulfonamide,
DMF 3 h.
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Crich et al.
TABLE 3. Three-Component Coupling of Thiomaleic Anhydrides with Aminothiols and Amines Promoted by Sanger’s Reagent
a Conditions: (i) 1.2 equiv of thioanhydride, 1 equiv of aminothiol, DMF; (ii) 1.2 equiv of Cs2CO3, 1 equiv of Sanger’s reagent, 1 equiv of amine,
DMF 3 h.
SCHEME 1. Intramolecular Ring-Opening of Cyclic
Thioanhydrides Generated by Diels-Alder Reaction
zenesulfonamides involves nucleophilic aromatic substitution
of the sulfonamide by the thioacid, giving a S-(2,4-dinitrophenyl)
thioester and a free amine, which then react to give the final
amide.5c,7 On this basis, as we have established elsewhere in
the course of work directed at the synthesis of peptides, the
sulfonamide may be productively replaced by a simple amine
and either Sanger’s reagent (2,4-dinitrofluorobenzene), its iodo
analogue, or Mukaiyama’s reagent (2-chloro-N-methylpyri-
dinium iodide),22 and doubtless other electron-deficient arenes
capable of undergoing nucleophilic aromatic substitution. The
proof of this was established by the reaction of vicinal
aminothiols with monothiomaleic anhydride followed by the
addition of Sanger’s reagent and a second amine, as illustrated
in Table 3.
Although we have not made an extensive study, the thioacid
may also be productively trapped by electron-deficient azides
according to the Williams and Liskamp protocol,4 as illustrated
by the two examples of Scheme 2. Particularly noteworthy here
is the illustration of the use of an unprotected amino acid as
the nucleophile initiating the entire sequence.
with a 2,4-dinitrobenzenesulfonamide leading, overall, to 37 and
38 in 84% and 63% yield, respectively (Scheme 1).
Thioacid Capture by Other Electrophilic Species. The
mechanism of the condensation of thioacids with 2,4-dinitroben-
(21) Kawamura, N.; Li, Y. M.; Engel, J. L.; Dauben, W. G.; Casida, J. E.
Chem. Res. Toxicol. 1990, 3, 318–324.
(22) Crich, D.; Sharma, I. Angew. Chem., Int. Ed. 2009, 48, 2355–2358.
3890 J. Org. Chem. Vol. 74, No. 10, 2009

One-Pot Syntheses of Dissymmetric Diamides
SCHEME 2. Nucleophilic Ring-Opening of Thiosuccinic
Anhydride with Subsequent Thioacid Capture by
p-Toluenesulfonyl Azide
isolated yield, by a process involving the liberation of a first thioacid
and its cyclization onto the remaining thioester.
Reaction of N-Cbz-monothioaspartic anhydride 43 with
aniline in DMF followed by addition of the N-sulfonyl mor-
pholine derivative 19 led to the isolation of the asparagines
derivative 45 in 48% isolated yield as a single regioisomer
(Table 4, entry 1). No evidence was found by NMR spectros-
copy for the formation of a second regioisomer in the crude
reaction mixture. Subsequently, 1-glucosylamine 3 was allowed
to react with the monothioaspartic anhydride, followed by
trapping of the thioacid with the morpholine-based sulfonamide
resulting in the formation of a N-glycosyl asparagine derivative
46 in 44% yield (Table 4, entry 2). Gratifyingly, this chemistry
could be extended to the use of an amino acid-based sulfonamide
7, thereby coupling the introduction of the N-glycosyl aspar-
agines unit with the formation of a peptide bond (Table 4, entry
3). Moreover, ꢀ-cellobiosylamine27 48 and ꢀ-maltosylamine28
50 also served as productive nucleophiles in this chemistry
(Table 4, entries 4 and 5). The ability to conduct this chemistry
with unprotected glycosylamines is stressed. It should also be
noted that the isolation of the various products in this table as
single diastereomers indicates not only a very high degree of
regioselectivity in the initial ring-opening reaction, but also the
absence of racemization both in the formation and the reaction
of the monothioaspartic anhydride. Unfortunately, we have been
unable so far to translate this chemistry to 2-acetamido-2-
deoxyglucosylamine derivates as nucleophiles.
SCHEME 3. First-Generation Synthesis of a Thioaspartic
Anhydride
SCHEME 4. Second-Generation Synthesis of a Thioaspartic
Anhydride
The regioselectivity of the reactions presented in Table 4 was
predicted on the basis of the known reactivity of the corre-
sponding carboxylic anhydride, which was known to undergo
preferential nucelophilic attack at the γ-carbon in the polar
solvent DMSO, but at the R-carbon in the nonpolar solvent
benzene, with aniline as nucleophile.23b The regiochemistry of
the initial attack of aniline on the monothioanhydride is
supported by a strong HMBC correlation of the anilide NH to
the γ-carbonyl carbon. For proof of the rather more important
cases of the formation of the N-glycosylasparagine derivatives,
we resorted to unambiguous synthesis of authentic samples, as
set out in Scheme 5 starting from the known γ-allyl aspartate
derivative 52,29 passing through the known dipeptide 54,30 and
resulting in the formation of samples that were chromatographi-
cally and spectroscopically homogeneous with those obtained
in Table 4. In addition to establishing firmly the regiochemistry
of the ring-opening reaction in DMF as solvent the somewhat
longer authentic syntheses highlight the efficiency of the
monothioanhydride protocol for the preparation of this class of
compounds.
Glycopeptide Synthesis. An intriguing facet of this chemistry
was the possibility of extending it to unsymmetrically substituted
monothioanhydrides, particularly those based on aspartic acid.
Toward this end, N-benzyloxycarbonyl-L-aspartic acid 41 was
converted to the known cyclic anhydride 42 by heating with
acetic anhydride according to a literature protocol,23 followed
by reaction with sodium sulfide10b (Scheme 3). Although this
last step results only in an isolated yield of 47% of the cyclic
thioanhydride 43, it has to be remembered that this is close to
the theoretical 50% owing to the consumption of half of the
initial anhydride as dehydrating reagent for the intermediate
monothio diacid.
An improved synthesis of the thioaspartic anhydride 43, based
on the literature observation24 that aspartic and glutamic mono-
thioesters undergo facile cyclization to anhydrides, involved
activation of N-benzyloxycarbonyl-L-aspartic acid with the PyBOP
reagent, under the Kajihara conditions for nonracemizing synthesis
of thioesters at the C-terminus of peptides,25 in the presence of
2,4,6-trimethyloxybenzylthiol (TmobSH)26 to give the bisthioester
44 in essentially quantitative yield (Scheme 4). Treatment with
trifluoroacetic acid in the presence of triethylsilane as cation
scavenger then gave the desired cyclic thioanhydride in 71%
In a more general sense unsymmetrically substituted succinic
anhydrides frequently undergo preferential attack at the carbonyl
group adjacent to the least substituted carbon. Thus, for example,
2,2-dimethylsuccinic anhydride undergoes reaction with orga-
nonickel reagents31 and phosphorus ylides32 with a significant
preference for reaction at the carbonyl group distal to the
quaternary center. On the other hand metal hydride reduction
of 2,2-dimethylsuccinic anhydride takes place predominantly
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(29) Baldwin, J. E.; Moloney, M. G.; North, M. Tetrahedron 1989, 45, 6319–
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26B, 201–208.
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(32) Kayser, M. M.; Breau, L. Can. J. Chem. 1989, 67, 1401–1410.
(25) (a) Kajihara, Y.; Yoshihara, A.; Hirano, K.; Yamamoto, N. Carbohydr.
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Crich et al.
TABLE 4. Three-Component Coupling Centered on Monothioaspartic Anhydride
a Ar ) 2,4-dinitrophenyl. b Conditions: (i) 1 equiv of thioanhydride, 1 equiv of amine, DMF, 30 min; (ii) 1 equiv of Cs2CO3, 1 equiv of sulfonamide,
DMF 1 h.
SCHEME 5. Synthesis of Authentic Glycopeptide Samples
Burgi-Dunitz approach vector is only blocked by the solvated
carbamate group on a single face of the molecule leaving the second
open for productive interaction.
Experimental Section
General Procedure for Multicomponent Coupling Reaction
in Table 1. The reactions in Table 1 were carried out as follows
unless particular conditions were specified. To a stirred solution of
thioanhydride (∼1.0 mmol, 1.2 equiv) in DMF (∼1 mL; ∼1 M in
thioanydride) was added 1.0 equiv of amine (∼0.8 mmol) in an
equal volume of DMF (∼1 mL) at room temperature. The reaction
mixture was allowed to stir for 30 min to 1 h, after which time the
color of the reaction had turned a faint yellow. Cs2CO3 (1.0 equiv)
was added followed immediately by 1.0 equiv of sulfonamide. Upon
addition of the sulfonamide the reaction mixture became dark red,
which further deepened as the reaction continued. The reaction
mixture was allowed to stir ∼1 h, after which the DMF was
removed under high vacuum and the crude mixture was dissolved
in EtOAc and washed with NaHCO3 and brine and dried over
Na2SO4. Evaporation of the solvent, followed by column chroma-
tography provided the diamide products in the yields described
below. When the products were water-soluble the extraction was
omitted and the crude mixture submitted directly to chromatography
after the removal of DMF.
R to the quaternary center,33 something that it has in common
with the 2,2-dimethylsuccinimides.34
Presumably, the regioselectivity of these reactions for the simple
aspartic anhydrides reported in the literature and the monothioan-
hydride described here, with preferential nucleophilic attack at the
γ-center in polar solvents, is due to simple hydrogen bonding of
the carbamate group to the solvent thereby significantly hindering
access to the R-position. Self-evidently, and unlike the case of 2,2-
dimethylsuccinic anhydride and the corresponding succinimdes the
(33) Kayser, M. M.; Wipff, G. Can. J. Chem. 1982, 60, 1192–1198.
(34) Wunberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron
1978, 34, 179–187.
Methyl 2-Amino-2-deoxy-N-(N-phenylsuccinamyl)-r-D-glu-
copyranoside (12). Pale yellow oil. [R]24D +64.8 (c 0.8, CH3OH).
3892 J. Org. Chem. Vol. 74, No. 10, 2009

One-Pot Syntheses of Dissymmetric Diamides
1H NMR (500 MHz, CDCl3/CD3OD) δ 7.51-7.54 (m, 2H),
7.26-7.30 (m, 2H), 7.06 (t, J ) 7.0 Hz, 1H), 4.64 (d, J ) 3.0 Hz,
1H), 3.90-3.95 (m, 1H), 3.82 (dd, J ) 3.0, 12.5 Hz, 1H), 3.64-3.70
(m, 2H), 3.52-3.56 (m, 1H), 3.34-3.37 (m, 4H), 2.65-2.70 (m,
2H), 2.60-2.63 (m, 2H). 13C NMR (125.9 MHz, CDCl3/CD3OD)
δ 173.8, 171.7, 138.5, 128.4, 123.7, 119.8, 98.5, 72.3, 71.7, 70.8,
61.3, 54.2, 54.0, 31.7, 30.5. ESIHRMS: m/z calcd for C17H24N2O7
(M + Na)+ 391.14760, found 391.14741.
Method A: General Procedure for Three-Component Cou-
pling of Thiomaleic Anhydrides with Aminothiols and 2,4-
Dinitrobenzenesulfonamides (Table 2). Aminothiol (0.41 mmol,
1.0 equiv) was added to a stirred solution of maleic thioanhydride
(0.5 mmol, 1.2 equiv) in 1 mL of DMF at 0 °C. The reaction
mixture turned purple and further deepened in color as it was
warmed to room temperature. The reaction mixture was allowed
to stir for 1 h then cooled to 0 °C and Cs2CO3 (0.5 mmol, 1.2
equiv) was added, followed immediately by the sulfonamide (0.4
mmol, 1.0 equiv). The reaction mixture was allowed to warm to
room temperature and stirred for a further 3 h. The solvent was
then removed under vacuum and the crude reaction mixture was
dissolved in EtOAc, washed with saturated aqueous NaHCO3
solution followed by brine, and dried over Na2SO4. The product
was purified by silica gel column chromatography.
2-(2,3-Dihydrobenzo-1,4-thiazin-3-on-2-yl)acetylpiperidine (25).
Chromatographic purification eluting with 70% EtOAc/hexanes
afforded a light yellow oil in 59% yield (method A) or 51% yield
(method B, which employed 2.0 equiv of Cs2CO3 instead of 1.2
equiv to liberate amine from the corresponding hydrochloride salt).
1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 7.29 (dd, J ) 1.6,
8 Hz, 1H), 7.15 (dt, J ) 1.6, 9 Hz, 1H), 6.99 (dt, J ) 1.6, 7.4 Hz,
1H), 6.89 (dd, J ) 1.6, 8 Hz, 1H), 4.19 (dd, J ) 4.8, 8 Hz, 1H),
3.65-3.50 (m, 2H), 3.41-3.32 (m, 2H), 3.10 (dd, J ) 4.8, 16 Hz,
1H), 2.57 (dd, J ) 8, 16 Hz, 1H), 1.67-1.58 (m, 2H), 1.58-1.52
(m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.0, 167.3, 136.2, 128.2,
127.4, 124.0, 120.0, 117.3, 46.8, 43.4, 38.5, 32.6, 26.6, 25.7, 24.7.
ESIHRMS: m/z calcd for C15H18N2O2S (M + Na)+ 313.0987, found
313.0995.
Method B: General Procedure for Three-Component Cou-
pling of Thiomaleic Anhydrides with Aminothiols and Amines
Promoted by Sanger’s Reagent (Table 3). Aminothiol (0.4 mmol,
1.0 equiv) was added to a stirred solution of maleic thioanhydride
(0.5 mmol, 1.2 equiv) in 1 mL of DMF at 0 °C. The reaction
mixture turned purple, and further deepened in color as it was
warmed to room temperature. The reaction mixture was allowed
to stir for 1 h and cooled to 0 °C then (0.5 mmol, 1.2 equiv) Cs2CO3
was added, followed immediately by Sanger’s reagent (1-fluoro-
2,4-dinitrobenzene) (0.4 mmol, 1.0 equiv). The reaction mixture
was allowed to warm to room temperature and then was stirred for
5 min before the amine (0.4 mmol, 1.0 equiv) was added and stirring
continued for 3 h. The solvent was then removed under vacuum
and the crude reaction mixture was dissolved in EtOAc, washed
with saturated aqueous NaHCO3 solution followed by brine, and
dried over Na2SO4. The product was purified by silica gel column
chromatography.
(dd, J ) 4, 12 Hz, 1H), 3.00-2.90 (m, 2H), 2.41 (dd, J ) 5.6,
15.8 Hz, 1H), 1.53 (s, 6H), 1.30 (t, J ) 7.4, 3H). 13C NMR (100
MHz, CDCl3) δ 175.1, 169.8, 169.2, 168.9, 62.9, 56.8, 55.4, 52.8,
37.9, 37.6, 29.9, 24.9, 14.3. ESIHRMS: m/z calcd for C14H22N2O6S
(M + Na)+ 369.1096, found 369.1103. Trans: [R]24D -19.8 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.60 (br s, 1H), 6.30 (br s,
1H), 4.44-4.40 (m, 1H), 4.26 (q, J ) 6.8 Hz, 2H), 3.89 (t, J ) 6
Hz, 1H), 3.73 (s, 3H), 3.18 (dd, J ) 4, 13.6 Hz, 1H), 3.00 (dd, J
) 9, 13.8 Hz, 1H), 2.91 (dd, J ) 5.6, 15.6 Hz, 1H), 2.60 (dd, J )
6.4, 14.8 Hz, 1H), 1.54 (s, 6H), 1.30 (t, J ) 7 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 175.2, 169.0, 62.7, 58.0, 56.8, 52.9, 39.1,
28.2, 24.9, 24.9, 14.3. ESIHRMS: m/z calcd for C14H22N2O6S (M
+ Na)+ 369.1096, found 369.1107.
N-Benzyloxycarbonyl-L-aspartic Thioanhydride (43). To a
solution of 44 (29.0 mg, 0.044 mmol) in 40% TFA in CH2Cl2 (300
µL) was added Et3SiH (56.2 µL, 0.35 mmol), and the reaction
mixture was stirred for 4 h. The volatiles were removed in vacuo,
and the residue was dissolved in CHCl3 (5 mL) and washed with
sat. NaHCO3 aq (10 mL) and brine (10 mL). The organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue was
recrystallized from CHCl3/hexanes to give a white solid (8.2 mg,
1
71%). Mp 87.5-88.4 °C. [R]24 +3.0 (c 1.15, CHCl3). H NMR
D
(500 MHz, CDCl3) δ 7.26-7.37 (m, 5H), 6.03 (d, J ) 6.5 Hz,
1H), 5.08 (s, 2H), 4.66-4.71 (m, 1H), 3.25 (dd, J ) 8.5 Hz, 1H),
3.10 (dd, J ) 9.0 Hz, 1H). 13C NMR (125.9 MHz, CDCl3) δ 199.2,
195.2, 156.0, 135.7, 128.8, 128.6, 128.4, 128.3, 67.7, 60.4, 45.4.
Elemental anal. calcd for C12H11NO4S: C, 54.33; H, 4.18; N, 5.28;
S, 12.09. Found: C, 54.51; H, 4.10; N, 5.24; S, 12.05.
General Procedure for Table 4. To a solution of N-benzyloxy-
carbonyl-L-aspartic thioanhydride (43, 20.0 mg, 0.075 mmol) in
DMF (150 µL) was added a suspension or a solution of amine
(0.075 mmol) in DMF (150 µL) dropwise. The reaction mixture
was stirred for 1 h, then Cs2CO3 (24.5 mg, 0.075 mmol) was added,
immediately followed by sulfonamide (0.075 mmol). The reaction
mixture was stirred for further 1 h. After removal of DMF under
high vacuum, the residue was purified by column chromatography
to give the corresponding peptide.
Nr-Benzyloxycarbonyl-Nγ-{4-(ꢀ-D-glucopyranosyl)-ꢀ-D-glu-
copyranosyl}-L-asparaginyl-L-phenylalanine Methyl Ester (49).
1
[R]24 +8.7 (c 0.70, DMF); H NMR (300 MHz, DMF-d7 with
D
drops of D2O) δ 7.37-7.14 (m, 10H), 5.01 (s, 2H), 4.86 (d, J )
9.3 Hz, 1H), 4.60-4.51 (m, 2H), 4.39 (d, J ) 7.2 Hz, 1H), 3.83
(dd, J ) 11.7, 1.8 Hz, 1H), 3.78-3.72 (m, 2H), 3.61 (s, 3H), 3.54
(dd, J ) 12.0, 6.3 Hz, 1H), 3.50-3.42 (m, 2H), 3.42-2.98 (m,
7H), 2.76-2.58 (m, 2H). 13C NMR (75 MHz, DMF-d7) δ 172.5,
172.4, 170.8, 156.8, 138.0, 138.0, 130.0, 129.0, 129.0, 128.4, 128.3,
127.3, 104.5, 81.7, 80.5, 78.0, 77.8, 77.6, 74.6, 73.4, 71.3, 66.4,
62.3, 61.7, 54.8, 52.2, 38.3, 37.7. ESIHRMS: m/z calcd for
C34H45N3O16Na (M + Na)+ 774.2689, found 774.2704.
Acknowledgment. K.S. and A.A.B. thank the Japan Society
for the Promotion of Science for a postdoctoral fellowship
(18.6013) and the University of Illinois at Chicago for a Moriarty
Graduate fellowship, respectively.
N-(1-Ethoxycarbonyl-1-methylethyl) 2-(5-Ethoxycarbonyl-
2,3,5,6-tetrahydro-1,4-thiazin-3-on-2-yl)acetamide (30). Chro-
matographic purification eluting with 3% methanol in dichlo-
romethane afforded a light yellow oil in 63% yield (method A) or
70% yield (method B, with 2.0 equiv of Cs2CO3 instead of 1.2
equiv to liberate the amine from the corresponding hydrochloride
salt) with 3:1 cis/trans selectivity. Cis: [R]24D +28.4 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3) δ 6.62 (br s, 1H), 6.44 (br s, 1H),
4.34-4.24 (m, 3H), 3.94 (t, J ) 6.4 Hz, 1H), 3.72 (s, 3H), 3.27
Supporting Information Available: Details of the preparation
of compounds 2, 4, 6, 8, 10-12, 14, 15, 17, 19, 20, 22, 24, 25, 27,
29, 30, 32, 33, 35-40, 43-47, 49, 51, 53, and 54, and copies of
1
their H spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900532E
J. Org. Chem. Vol. 74, No. 10, 2009 3893