Enantioselective total synthesis of (-)-acetylaranotin, a dihydrooxepine epidithiodiketopiperazine

Article abstract of DOI:10.1021/ja209354e

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (-)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (-)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family.

Full text of DOI:10.1021/ja209354e

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pubs.acs.org/JACS
Enantioselective Total Synthesis of (À)-Acetylaranotin, a
Dihydrooxepine Epidithiodiketopiperazine
Julian A. Codelli, Angela L. A. Puchlopek, and Sarah E. Reisman*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
S Supporting Information
b
ABSTRACT: The first total synthesis of the dihydroox-
epine-containing epidithiodiketopiperazine (ETP) (À)-
acetylaranotin (1) is reported. The key steps of the
synthesis include an enantioselective azomethine ylide
(1,3)-dipolar cycloaddition reaction to set the absolute
and relative stereochemistry, a rhodium-catalyzed cycloi-
somerization/chloride elimination sequence to generate
the dihydrooxepine moiety, and a stereoretentive dike-
topiperazine sulfenylation to install the epidisulfide. This
synthesis provides access to (À)-1 in 18 steps from
inexpensive, commercially available starting materials.
We anticipate that the approach described herein will
serve as a general strategy for the synthesis of additional
members of the dihydrooxepine ETP family.
he epidithiodiketopiperazine (ETP) natural products are a
large and structurally diverse family of biologically active
T
fungal metabolites that beautifully exemplify the interplay be-
tween molecular structure and function in nature (Figure 1).1
One structural subgroup of the ETPs is characterized by the
presence of a seven-membered dihydrooxepine ring and includes
acetylaranotin (1),2 MPC1001B (2),3 and emethallicin A (3).4
Compounds 1À3 exhibit an array of biological activities, ranging
from the inhibition of viral RNA polymerase2,5 to antipro-
liferative3 and apoptotic6 activity against various human cancer
cell lines. The labile ETP core, in combination with the complex
peripheral structures, renders these molecules challenging can-
didates for chemical synthesis. Indeed, ETPs containing the
dihydrooxepine ring at their periphery have remained elusive
as synthetic targets,7 despite the fact that 1 was first isolated over
40 years ago and that the first synthesis of the biosynthetically
related compound gliotoxin (4) was reported in 1976.8 As part of
a research program aimed at advancing the chemistry and biology
of ETP natural products, we sought to develop a general strategy
for the synthesis of the dihydrooxepine ETPs. In this commu-
nication, we report the results of our synthetic efforts, which have
culminated in the first enantioselective total synthesis of (À)-
acetylaranotin (1).
Figure 1. Epidithiodiketopiperazine (ETP) natural products.
dihydrooxepine moiety. The recent syntheses of pyrroloindoline
ETPs (such as 5, 6, and 7 in Figure 1) have utilized strategies
involving diketopiperazine oxidation and thiol trapping of pre-
sumed acyliminium intermediates under acidic conditions to
achieve late-stage CÀS bond formation.9 Because of the sensi-
tivity of dihydrooxepines to both oxidative and acidic conditions,
this strategy was not expected to be feasible for the preparation of
1. Since the dihydrooxepines of 8 were anticipated to be stable
under basic conditions, we instead envisioned utilizing a mod-
ification of Schmidt’s protocol for diketopiperazine enolization
and trapping with S8.10
Diketopiperazine 8 was envisioned to arise from the dimeriza-
tion of two equivalents of protected amino ester 9 through a standard
peptide coupling sequence. The preparation of 9 raises the
second key tactical consideration: construction of the dihydroox-
epine moiety. Relatively few general methods for dihydrooxepine
Our synthetic planning began with the retrosynthetic simpli-
fication of (À)-acetylaranotin (1) to a C2-symmetric diketopi-
perazine intermediate, 8 (Scheme 1). In the forward sense, this
disconnection reserves installation of the redox-active epidisul-
fide for the final stage of the synthesis and highlights the first
tactical consideration: identification of conditions for oxidation
of the diketopiperazine CÀH bonds in the presence of the
Received: October 4, 2011
Published: October 24, 2011
r
2011 American Chemical Society
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formation have been disclosed, and these methods are typically
constrained to substitution patterns that are undesirable in the
context of preparing 1.11,12 Inspired by recent examples of
transition metal-catalyzed heterocycloisomerization reactions
of alkynes,13 we envisioned preparing dihydrooxepine 9 from
alkynal 10 (or an aldehyde surrogate) through a metal vinyli-
dene-mediated 7-endo cycloisomerization.14,15 Alkynal 10 was
expected to arise from pyrrolidine 11, the product of a catalytic
asymmetric (1,3)-dipolar cycloaddition reaction between tert-
butyl acrylate (12) and the azomethine ylide derived from ethyl
glycinate (14) and cinnamaldehyde (13).
In the forward sense, exposure of cinnamaldimine 15, which
was pregenerated from ethyl glycinate (14) and cinnamaldehyde
(13), to tert-butyl acrylate (12) in the presence of catalytic
copper iodide and brucin-OL16 as the chiral ligand provided
the corresponding endo-pyrrolidine in 50% yield with 96% ee
(Scheme 2). Subsequent cleavage of the tert-butyl group using
trifluoroacetic acid (TFA) furnished TFA salt 16. Notably,
during the trituration process utilized to isolate 16, the enantio-
meric excess was enriched to >98%. Although the yield of the
(1,3)-dipolar cycloaddition reaction was modest, the inexpensive
starting materials and catalyst system employed in this transfor-
mation meant that it could be routinely conducted on a multi-
gram scale to furnish ample quantities of 16. Protection of the
amine as the trimethylsilylethyl carbamate and ozonolytic clea-
vage of the alkene delivered hydroxylactone 17 in 77% yield over
two steps.
To incorporate the required alkyne for the cycloisomeriza-
tion reaction, hydroxylactone 17 was treated with excess
ethynylmagnesium bromide; a standard acidic workup resulted
in spontaneous lactonization. Unfortunately, the major lactone
diastereomer (not shown) possessed the undesired stereo-
chemistry at C13 (acetylaranotin numbering) for elaboration
to the natural product.17 Whereas efforts to override the
observed diastereoselectivity by varying the reaction para-
meters failed to produce synthetically useful quantities of 18,
a procedure involving in situ Mitsunobu lactonization18 of the
transiently formed hydroxy acid was more fruitful, delivering 18
in 76% isolated yield. Lactone 18 was then reduced to diol 19
with NaBH4 in EtOH, and bis-silylation with TBSOTf followed
by selective cleavage of the primary silyl ether furnished alcohol
20. Finally, oxidation of the primary alcohol with DessÀMartin
periodinane (DMP)19 afforded aldehyde 10 (see Scheme 1) in
excellent yield.20
With access to aldehyde 10, we were poised to study the key
cycloisomerization reaction. Unfortunately, dihydrooxepine for-
mation was not observed under any of the conditions screened;
in all cases, the substrate was either recovered as a mixture with its
C16a epimer or underwent complete decomposition.21 We
therefore set out to design an aldehyde surrogate that would
demonstrate the desired reactivity but would also incorporate the
correct oxidation state for conversion to the dihydrooxepine.
Given that alkynols have been shown to undergo vinylidene-
mediated cycloisomerization under a variety of conditions,14 we
turned our attention to chlorohydrin 21 as a potential substrate.
Treatment of aldehyde 10 with N-chlorosuccinimide (NCS) and
Scheme 1. Retrosynthetic Analysis for Acetylaranotin (1)
pyrrolidine TFA gave the α-chloroaldehyde as a single diaster-
3
eomer, which was reduced in situ with NaBH4 to deliver alkynol
21 in excellent yield (Scheme 2). After screening several catalysts
and solvents, we were pleased to find that exposure of a solution
of 21 in N,N-dimethylformamide (DMF) to catalytic [Rh(cod)-
Cl]2 and tris(4-fluorophenyl)phosphine at 85 °C provided the
corresponding chlorotetrahydrooxepine 22 in 88% yield
(Scheme 3).22 After considerable experimentation, elimination
of the chloride was achieved using LiCl and Li2CO3 at 100 °C in
DMF, yielding the desired dihydrooxepine 9.
What remained in the synthesis of 1 was diketopiperazine
formation, acetylation, and installation of the epidisulfide. Our
original plan called for conversion of 9 to the corresponding
amino acid and dimerization of two identical monomers. To this
end, chemoselective cleavage of the Teoc group in the presence
Scheme 2. Enantioselective Synthesis of Pyrrolidine 21
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Scheme 3. Completion of the Synthesis of Acetylaranotin (1)
of the TBS ether was necessary. Unfortunately, exposure of 9 to a
variety of conditions provided mixtures of mono- and bis-
desilylated products. In contrast, treatment of chlorotetrahy-
drooxepine 22 with tetrabutylammonium fluoride (TBAF) at
0 °C cleanly provided the free amine (Scheme 3). Subjection of
the amine to the previously optimized chloride elimination
conditions delivered dihydrooxepine 23 in 65% yield. Hydrolysis
of the ethyl ester using lithium hydroxide in methanol gave the
corresponding amino acid, but attempts to form the diketopiper-
azine by direct dimerization were unfruitful.
currently unclear, and understanding this process is the subject of
ongoing research in our laboratory. Regardless, the high diastereos-
electivity observed in the formation of diketopiperazine 26 is
impressive considering the seemingly flat nature of the pentacyclic
ring system. Moreover, the high apparent diastereoselectivity of the
dihydroxylation suggested that the analogous dithiolation might
also proceed stereoselectively.24
With diketopiperazine 26 in hand, our attention turned to the
epidisulfide formation. In the event, a solution of 26 in tetra-
hydrofuran (THF) was treated with sodium hexamethyldisila-
zide (NaHMDS), and the resulting solution was added to a
mixture of NaHMDS and S8, after which additional NaHMDS
was added (Scheme 3).25 1H NMR analysis of the crude reaction
mixture indicated that the major product was a C2-symmetric
compound. Upon isolation of this compound, single-crystal XRD
determined it to be tetrasulfide 28, in which CÀS bond forma-
tion had occurred to give the relative stereochemistry found in 1.
Tetrasulfide 28 was unstable to most standard reductants; for
example, exposure to NaBH4 produced a complex mixture of
decomposition products. Instead, bisacetylation of 28 using
acetyl chloride furnished the diacetate, and the tetrasulfide was
reduced under mild conditions using propanedithiol and triethy-
lamine in acetonitrile. Aerobic oxidation of the resulting dithiol
delivered the natural product, 1. The spectroscopic data for
synthetic (À)-acetylaranotin were identical to the original
isolation data.
In conclusion, we have achieved the enantioselective total
synthesis of (À)-acetylaranotin (1), the first total chemical
synthesis of any dihydrooxepine-containing ETP natural pro-
duct, in 18 steps from inexpensive, commercially available
materials. Essential to the development of this route was the
successful execution of a rhodium-catalyzed cycloisomeriza-
tion/chloride elimination sequence to furnish the dihydroox-
epine ring and complete the monomer subunit (9). This
strategy allowed us to exploit the power of an azomethine ylide
(1,3)-dipolar cycloaddition reaction in order to enantio- and
diastereoselectively construct the densely functionalized pyr-
rolidine scaffold of the requisite alkynyl alcohol substrate 21.
Instead, a stepwise approach was pursued in which amine 23
was coupled with carboxylic acid 24 using standard peptide
coupling conditions to give 25 (Scheme 3). After a survey of
fluoride sources, we were pleased to find that treatment of
23
dipeptide 25 with TBAF (t-BuOH)4 in acetonitrile at 70 °C
3
effected global desilylation and cyclization to deliver a C2-
symmetric compound as the major product (isolated in 27%
yield). Interestingly, initial characterization of this compound
using standard NMR techniques and high-resolution mass
spectrometry suggested that it was a syn-diol, the result of a
double CÀH oxidation process. On the basis of the hypothesis
that the oxidant was oxygen in the ambient atmosphere, the
reaction was repeated under a nitrogen atmosphere using
rigorously degassed solvent, which provided diketopiperazine
26 as a single diastereomer in 76% yield. The structure of 26 was
confirmed by single-crystal X-ray diffraction (XRD). Notably, the
(S,S)-stereochemistry of the central diketopiperazine is the result
of epimerization at both of the diketopiperazine methine posi-
tions under the cyclization conditions. At this time, it is uncertain
whether epimerization occurs prior to cyclization of the dipeptide—
cyclization of the (S,S)-configured dipeptide could potentially be
more facile than that of the starting (R,R)-diastereomer—or
subsequent to diketopiperazine formation to give a thermodyna-
mically favored product. Isolation and resubjection of 26 to TBAF
3
(t-BuOH)4 in deuterated acetonitrile at 70 °C under air provided
the same oxidation product observed previously, which was con-
firmed by XRD analysis to be syn-diol 27. Whether this double
CÀH oxidation proceeds through a radical or anionic mechanism is
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Furthermore, we determined that upon global deprotection,
dipeptide 25 could be readily cyclized with concomitant
epimerization to afford diketopiperazine 26. Notably, direct
sulfenylation of diketopiperazine 26 occurs with complete
retention of stereochemistry to provide epitetrathiodiketopiper-
azine 28. Investigations directed toward the implementation of
these strategies and methods for the synthesis of related
dihydrooxepine-containing ETP natural products are ongoing.
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’ ASSOCIATED CONTENT
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acterization and spectral data for all compounds, and crystal-
lographic data (CIF). This material is available free of charge via
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’ AUTHOR INFORMATION
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(17) See the Supporting Information for details.
(18) Mitsunobu, O. Synthesis 1981, 1.
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required aldehyde 10.
Corresponding Author
reisman@caltech.edu
’ ACKNOWLEDGMENT
We thank Dr. Michael Day and Mr. Larry Henling for X-ray
crystallographic structure determination and Dr. David Vander-
Velde for assistance with NMR structure determination. We
thank Prof. Brian Stoltz, Dr. Scott Virgil, and the Caltech Center
for Catalysis and Chemical Synthesis for access to analytical
equipment. The Bruker KAPPA APEXII X-ray diffractometer
was purchased through an award to the California Institute of
Technology by the National Science Foundation (NSF) CRIF
program (CHE-0639094). NMR spectra were obtained on a
spectrometer funded by the National Institutes of Health (NIH)
(RR027690). J.A.C. was supported by the Department of
Defense (DoD) through the National Defense Science &
Engineering Graduate Fellowship Program and by the NSF
Graduate Research Fellowship Program (Grant DGE-07032
67). Financial support from the California Institute of Tech-
nology and the NIH (NIGMS RGM097582A) is gratefully
acknowledged.
(21) Several transition metal catalysts in the presence and absence of
ligands and additives were evaluated under a variety of conditions, including
[Rh(cod)Cl]2, [Rh(cod)(MeCN)2]BF4, CpRuCl[(4-FC6H4)3P]2, (CO)5-
WdC(OMe)Me, AuCl, Pd(OAc)2, CuI, and AgOTf.
(22) Conditions were adapted from Trost’s conditions for the
preparation of indoles and benzofurans: Trost, B. M.; McClory, A.
Angew. Chem., Int. Ed. 2007, 46, 2074.
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