A practical sulfenylation of 2,5-diketopiperazines

Article abstract of DOI:10.1002/anie.201107623

Sulfurs in action: A practical and simple method has been developed for the introduction of sulfur atoms into 2,5-diketopiperazines (I) under mild conditions. The reaction provides more or less complex epidithiodiketopiperazines (II) and bis-methylthiodik

Full text of DOI:10.1002/anie.201107623

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DOI: 10.1002/anie.201107623
Natural Product Synthesis
A Practical Sulfenylation of 2,5-Diketopiperazines**
K. C. Nicolaou,* Denis Giguꢀre, Sotirios Totokotsopoulos, and Ya-Ping Sun
Sulfenylated 2,5-diketopiperazine structural motifs are found
abundantly in nature as domains of a wide range of natural
products.[1] Among them, the bis-methylthiodiketopipera-
zines [for example, epicoccin G (1), Figure 1][2] and epidi-
droxydiketopiperazine[9] derivatives. These methods require
either harsh conditions or multistep sequences, or both, and
they lack in generality and efficiency. Faced with such
difficulties in our total synthesis approach toward some of
these natural products (i.e. 1 and 2, Figure 1),[10] we opted to
explore the use of elemental sulfur in the presence of
NaHMDS. As we describe below, these explorations led to
a general and practical sulfenylation method of 2,5-diketopi-
perazines that is simple to perform at ambient temperature in
common organic solvents.
The new sulfenylation method involves three sequential
steps from 2,5-diketopiperazine substrates (I, Table 1) to
epidithiodiketopiperazines (II, Table 1) or bis-methylthiodi-
ketopiperazines (III, Table 2) with no purification in between
steps. Thus 2,5-diketopiperazine I was added to a freshly
prepared solution of elemental sulfur and NaHMDS in THF
at room temperature. After a short period of stirring,
additional NaHMDS was added and the reaction mixture
was stirred at the same temperature until the sulfenylation
was complete, at which time the reaction was quenched with
aq. NH4Cl. The crude product was transferred to a THF–
EtOH (1:1) solution through extraction with CH2Cl2, drying,
evaporation and dissolution, and then reduced with NaBH4 to
the corresponding dithiolate, which was oxidized with KI3 to
afford epidithiodiketopiperazines (II), or methylated with
MeI to give the corresponding bis-methyldithiodiketopiper-
azines (III).
Table 1 demonstrates the generality and scope of the
developed sulfenylation method for the preparation of a
range of epidithiodiketopiperazines. Thus, 3,6-unsubstituted
diketopiperazines (e.g. 3, entry 1) enter the reaction to
provide the expected epidithiodiketopiperazine product,
albeit in modest yield (40%). This result may be attributed
to unhindered intermolecular reactions of the generated
sulfur species, as supported by the higher yields obtained from
3,6-mono- (entry 2) and 3,6-disubstituted (entries 3–7) di-
ketopiperazines. Furthermore, the present method accom-
modates equally well both syn (entries 4–6) and anti (entries 3
and 7) 3,6-disubstituted diketopiperazines, as well as poly-
cyclic diketopiperazines (entries 8–10). It should be noted
that sulfenylation through this protocol proceeds from the
same side of the molecule even in the case of the anti
diketopiperazines (entries 3 and 7). As a consequence of
enolate formation, the epidithio products obtained in Table 1
are racemic. Product 21 is formed as a mixture of two
diastereoisomers (ca. 1.4:1 d.r.) as previously demon-
strated.[10]
Figure 1. Molecular structures of epicoccin G (1) and aranotin (2).
thiodiketopiperazines [for example, aranotin (2), Figure 1][3]
are the most common and important. These natural products
are often endowed with important biological properties such
as cytotoxic, antibacterial, antiviral, antiallergy and antima-
larial activities.[4] Full biological investigations of several of
these promising compounds are lacking, primarily due to their
natural scarcity and difficulties associated with their chemical
synthesis. The latter problems stem from the sensitivity of
their sulfur moieties and the deficiencies of methods for their
installation within the growing diketopiperazine scaffolds.[5]
Herein we report a simple and practical method for the
sulfenylation of 2,5-diketopiperazines to afford either epidi-
thiodiketopiperazines or bis-methylthiodiketopiperazines
through the use of elemental sulfur and sodium hexamethyl-
disilazide (NaHMDS).
Previous sulfenylation methods of 2,5-diketopiperazines
involved installation of sulfur, either directly (i.e. NaNH2, S8,
liq. NH3)[6] or indirectly through their 3,6-dibromodiketopi-
perazine,[7] 3,6-dimethoxydiketopiperazine[8] and 3,6-dihy-
[*] Prof. Dr. K. C. Nicolaou, Dr. D. Giguꢀre, S. Totokotsopoulos,
Dr. Y.-P. Sun
Department of Chemistry and The Skaggs Institute for Chemical
Biology, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
[**] We thank Drs. D. H. Huang and L. Pasternack for NMR spectro-
scopic assistance, Dr. R. Chadha for X-ray crystallographic assis-
tance and Dr. G. Siuzdak for mass spectrometric assistance. This
work was supported by the Skaggs Institute for Research and grants
from the National Institutes of Health (USA) and National Science
Foundation (USA), as well as a postdoctoral fellowship from Fonds
de Recherche Quꢁbec (to D.G.).
With the generality and scope of the newly developed
sulfenylation method for the synthesis of epidithiodiketo-
piperazines demonstrated, we then proceeded to explore its
application to the preparation of bis-methylthiodiketopiper-
azines (III, Table 2) from diketopiperazine substrates (I). The
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107623.
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Table 1: Preparation of epidithiodiketopiperazines from 3,6-diketopiper-
Table 2: Preparation of bis-methylthiodiketopiperazines from 3,6-dike-
topiperazines (DKPs).[a]
azines (DKPs).[a]
Product[b]
Overall
Entry
1
Substrate
Product[b]
Overall
Entry
1
Substrate
yield [%][c]
yield [%][c]
40
63
70
72
2
3
2
63
3
4
70
69
4
5
64
58[d]
5
65
[a] Reactions were performed on 100 mg scale of DKP. [b] Racemic
mixture unless otherwise stated. [c] Yield of isolated products after flash
column chromatography. [d] ca. 1.4:1 d.r.
6
45
tives, namely methylation of the generated sulfenylated
species after the sodium borohydride reduction with MeI.
Table 2 summarizes the conditions used and shows a number
of examples involving monocyclic, tricyclic and pentacyclic
diketopiperazines as substrates. All bis-methylthiodiketo-
piperazines were obtained in good yields as single syn
diastereoisomers (racemic mixtures) except for compound
26, which was isolated as a mixture of diastereoisomers (ca.
1.4:1 d.r.) by virtue of the additional stereogenic centers
present in the starting substrate.[10] The absence of any anti
products in these reactions provides support for an intra-
molecular attachment of the second sulfur moiety within the
diketopiperazine scaffold and stands in contrast to the
classical Schmidt method that provides mixtures of syn and
anti products in much lower yields.[6]
7
47
8
65
9
68
10
55[d]
Having developed this new sulfenylation method using
the [NaHMDS-S8] reagent combination, we then sought to
gain some mechanistic insight as to the chemistry involved. To
this end, we attempted to analyze the products obtained by
the initial mixing of elemental sulfur (S8) and NaHMDS as
described above. High resolution mass spectrometry showed
a major signal at m/z C12H36N2O2S4H+ [M+H+] which
corresponded to (TMS)2N-SSSS-N(TMS)2 (calcd: 449.0911;
[a] Reactions were performed on 100 mg scale of DKP. [b] Racemic
mixture unless otherwise stated. [c] Yield of isolated products after flash
column chromatography. [d] ca. 1.4:1 d.r.
protocol for the preparation of the latter compounds required
modification of only the last step of the sequence employed
for the preparation of the epidithiodiketopiperazine deriva-
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found: 449.0908).[11] Flash column chromatography with silica
gel led to the isolation of this rather labile compound whose
NMR spectroscopic data provided further support for its
presumed structure noted above [1H NMR (CDCl3,
600 MHz): d = 0.26 ppm; 13C NMR (CDCl3, 150 MHz): d =
2.4 ppm]. A possible scenario for the formation of this species
is depicted in Scheme 1. Thus, it is postulated that the first
Scheme 1. Proposed mechanism for the formation of N,N’-tetrathio-
bis-trimethylsilyl compound 29 from S8 (27) and NaHMDS.
equivalent of NaHMDS opens the eight-membered-ring
sulfur cluster (27) to an open-chain mono-TMS sulfenamide
species (28) which suffers further attack from a second
equivalent of NaHMDS preferentially at the middle of the
sulfur chain (presumably due to electronic and steric repul-
sion at each end, respectively) to afford the observed N,N’-
tetrathio-bis-TMS derivative (29) and disodium tetrasulfide
(30). Indeed, freshly prepared and isolated species 29 served
as a successful sulfenylating reagent of diketopiperazine 6 in
the presence of 3.0 equiv of NaHMDS under the same
conditions as those described in Table 1 to afford epidithio-
diketopiperazine 16 in similar yield (57% yield) to the
original protocol. The crude mixture [NaHMDS-S8] also
exhibited mass spectrometric peaks corresponding to
Scheme 2. A postulated mechanism for the formation of epidithiodi-
ketopiperazine 16 and bis-methylthiodiketopiperazine 23 from diketo-
piperazine 6. Only one diastereoisomer of 6c and related compounds
is shown.
16, whereas methylation affords bis-methylthiodiketopiper-
azine 23. Pure tetrasulfide 31 was also converted to 16 under
the same NaBH4-KI3 conditions (94% yield).
(TMS)2N-SSS-N(TMS)2
(calcd
for
C12H36N2O2S3H+
[M+H+]: 417.1190; found: 417.1186) and (TMS)2N-SSSSS-
N(TMS)2 (calcd for C12H36N2O2S5H+ [M+H+]: 512.0280;
found: 512.0241).
In order to explore further the usefulness of this new
sulfenylation procedure, we decided to capture the inter-
mediate dithiolate species with other electrophiles. As shown
in Scheme 3, quenching of the resulting dithiolate derived
from 33 after NaBH4 reduction with pivaloyl chloride (PivCl)
led to bis-pivalate 34 in 35% yield (syn isomer, unoptimized).
Exposure of the latter to Mg(OMe)2, followed by bubbling of
oxygen through the solution led to epidithiodiketopiperazine
35 (87% yield). On the other hand, employment of tri-
methylsilyl ethoxymethyl chloride (SEMCl) instead of PivCl
to capture the dithiolate species generated from 33 and
NaHMDS led to the formation of bis-SEM derivative 36 in
40% yield (syn isomer, unoptimized). Attempts to deprotect
compound 36 with fluoride reagents failed; at best, only trace
amounts of epidithiodiketopiperazine 35 were obtained upon
oxidation of the derived mixture of products. However, the
most interesting transformation of compound 36 was
observed when this compound was treated with SnCl4 in
THF at 258C in an attempt to cleave the SEM groups. Under
these conditions, product 37, possessing the S-CH2-O bridge,
Given the possibility of several sulfenylation agents within
the reaction mixture, this sulfenylation reaction may be rather
complex. However, using tetrasulfide species 29, the tentative
mechanism shown in Scheme 2 for the case of diketopiper-
azine 6 as a substrate may be proposed. Thus, enolate
formation[12] from 6 under the basic conditions employed may
allow stepwise installation of sulfur at positions 3 and 6
through sequential inter- and intramolecular carbon–sulfur
bond formations. This sequence furnishes intermediates 6b–
6d as a mixture of oligosulfides from which the epitetrasulfide
31 was isolated as the major product (43% yield) together
with epidisulfide 16 (8% yield), as well as several other
unidentified products. An X-ray crystallographic analysis of
31 proved its tetrasulfide nature unambiguously (see X-ray
derived ORTEP in Scheme 2).[13] Reduction of this oligosul-
fide mixture with NaBH4 then leads to the corresponding bis-
thiolate species, whose oxidation with KI3 (after quenching
with NH4Cl) furnishes the epidithiodiketopiperazine product
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SEM group may lead to trichlorotin alkoxide 36b,[15] whose
decomposition to iminium species 36c by expulsion of a
trichlorotinthio-SEM species may be facilitated by intra-
molecular activation of the departing S atom as shown on 36b.
The latter species (36c) may then undergo ring closure to the
observed product 37.
The described chemistry offers a general, practical and
simple method for the introduction of sulfur into cyclic 2,5-
diketopiperazines under mild conditions. This method has
already proven its value in the total synthesis of epicoccin G
(1),[10] 8,8’-epi-ent-rostratin B,[10] and acetylaranotin,[16] where
it was proven superior to previously known methods, and is
expected to facilitate future expeditions in similarly complex
and challenging molecules containing the epidithiodiketo-
piperazine and bis-methylthiodiketopiperazine structural
motifs, as well as other diketopiperazine natural products
featuring cyclic tetrasulfide moieties.
Experimental Section
Scheme 3. Synthesis of bis-sulfenylated diketopiperazine derivatives 34
and 36 and formation of O,S-acetal diketopiperazine 37. Reagents and
conditions: a) NaHMDS (0.6m in PhMe, 3.0 equiv), S8 (1.0 equiv),
THF, 258C, 1 min; then 33 (1m in THF, 1.0 equiv) 1 min; then
NaHMDS (0.6m in PhMe, 2.0 equiv), 258C, 0.5 h; b) NaBH4
(25 equiv), THF/MeOH (1:1), 0!258C, 0.75 h; c) PivCl (50 equiv),
258C, 15 h, 35%; d) Mg(OMe)2 (20 equiv), MeOH, 258C, 15 h, 87%;
e) SEMCl (50 equiv), 258C, 15 h, 40%; f) SnCl4 (1.0m in CH2Cl2,
14 equiv), CH2Cl2, 258C, 15 min, 93%.
Preparation of epidithiodiketopiperazines: To
a suspension of
elemental sulfur (8.0 equiv) in THF (0.2m) at 258C under argon
was added NaHMDS (0.6m in PhMe, 3.0 equiv; LiHMDS and
KHMDS gave comparable yields) dropwise over a period of 2 min.
During the addition, the insoluble yellow S8 quickly changed color,
initially into a dark blue, then dark orange, and finally light orange
solution. This solution was stirred for an additional 1 min, and DKP
(1.0 equiv) dissolved in THF (0.2m) was added dropwise at 258C over
a 2 min period, at which time the reaction mixture turned light brown.
The mixture was stirred for an additional 1 min, then additional
NaHMDS (0.6m in PhMe, 2.0 equiv) was added, and the resulting
mixture was stirred for 0.5 h at 258C. The reaction mixture was
quenched with sat. aq. NH4Cl solution and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered, and
concentrated to afford a brownish residue which was taken to the next
step without purification. The residue was dissolved in a mixture of
degassed THF:EtOH (1:1, 0.05m) at 08C, and to the stirred solution
under argon was added NaBH4 (25 equiv) in small portions over a
period of 1 min. The resulting mixture was stirred for 45 min while it
was allowed to reach ambient temperature. After this time, the
solution was cooled to 08C and quenched by careful addition of sat.
aq. NH4Cl solution. The resulting mixture was extracted with EtOAc,
and to the combined organic extracts was added an aq. solution of KI3
(1.4m). This mixture was stirred for 10 min and then quenched with
sat. aq. Na2S2O3 solution; the resulting mixture was extracted with
EtOAc. The combined organic layers were dried (MgSO4), filtered,
and concentrated to give an oily residue. The crude product was
purified by flash silica gel column chromatography or preparative thin
layer chromatography.
was obtained in 93% yield. The assigned structure of the
latter was consistent with its spectroscopic data and was
unambiguously proven through X-ray crystallographic anal-
ysis (see X-ray derived ORTEP, Scheme 3).[14]
A plausible mechanism for this unusual reaction is shown
in Scheme 4. Thus, rapid cleavage of the tail end of the first
Preparation of bis-methylthiodiketopiperazines: The DKP was
processed through steps a and b as described in Table 1. To the
mixture obtained after NaBH4 reduction (step b) at 08C was added
MeI (50 equiv), and the resulting mixture was stirred at 258C for 15 h.
After this time, the solution was quenched by careful addition of sat.
aq. NH4Cl solution and extracted with CH2Cl2. The combined organic
layers were dried (MgSO4), filtered, and concentrated to give an oily
residue. The crude product was purified by flash silica gel column
chromatography or preparative thin layer chromatography.
Scheme 4. Postulated mechanism for the formation of mixed thio-
acetal 37 from bis-SEMthiodiketopiperazine 36. Reagents and condi-
tions: a) SnCl4 (1.0m in CH2Cl2, 14 equiv), CH2Cl2, 258C, 15 min, 93%.
Received: October 28, 2011
Published online: December 7, 2011
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Keywords: bis-methylthiodiketopiperazines ·
epidithiodiketopiperazines · natural product synthesis ·
sulfenylation
.
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