Total synthesis of (-)-Acetylaranotin

Article abstract of DOI:10.1002/anie.201207307

Epidithiodiketopiperazines are an important class of natural products because of their unique structural and biological properties. Among them, acetylaranotin (1), SCH64874 (2), compound 3, emethallicin A (4), MPC1001 (5), and emestrin (6) feature a dihydrooxepine moiety fused to a pyrrolidine/ epidithiodiketopiperazine (Figure 1). They also display a range of intriguing biological activities, such as: inhibitory activity against viral RNA polymerase, antagonistic activity of epidermal growth factor receptor, potent antituberculous activity, inhibitory activity against histamine release, antiproliferative activity against DU145 human prostate cancer cell line, and antagonistic activity of chemokine receptor (CCR2). While numerous synthetic approaches were investigated, only a limited number of successful preparations of the characteristic dihydrooxepine ring have been reported. During the synthetic studies on MPC1001, Peng and Clive established a synthetic method for a pyrrolidinone-fused dihydrooxepine through tetrahydrooxepine formation followed by selenoxide elimination.

Full text of DOI:10.1002/anie.201207307

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Angewandte
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DOI: 10.1002/anie.201207307
Natural Product Synthesis
Total Synthesis of (ꢀ)-Acetylaranotin**
Hideto Fujiwara, Taichi Kurogi, Shun Okaya, Kentaro Okano, and Hidetoshi Tokuyama*
Epidithiodiketopiperazines are an important class of natural
products because of their unique structural and biological
properties.[1] Among them, acetylaranotin (1),[2] SCH64874
(2),[3] compound 3,[4] emethallicin A (4),[5] MPC1001 (5),[6]
and emestrin (6)[7] feature a dihydrooxepine moiety fused to
a pyrrolidine/epidithiodiketopiperazine (Figure 1). They also
Recently, Reisman and co-workers accomplished the first
total synthesis of (ꢀ)-acetylaranotin (1), using a rhodium-
catalyzed formation of tetrahydrooxepine and subsequent
elimination of hydrogen chloride, providing the dihydroox-
epine.[11] Herein, we report the total synthesis of (ꢀ)-
acetylaranotin (1) through the efficient formation of the
proline-fused dihydrooxepine ring by unusual vinylogous
Rubottom oxidation and regioselective Baeyer–Villiger oxi-
dation.
Our retrosynthetic analysis is shown in Scheme 1. We
planned to introduce the base- and reduction-labile epidisul-
fide moiety, which is bridged to the diketopiperadine, at the
final stage of the synthesis. Disconnection of the two amide
Figure 1. Natural products containing dihydrooxepine moiety.
display a range of intriguing biological activities, such as:
inhibitory activity against viral RNA polymerase,[2] antago-
nistic activity of epidermal growth factor receptor,[3] potent
antituberculous activity,[4] inhibitory activity against hista-
mine release,[5] antiproliferative activity against DU145
human prostate cancer cell line,[6a] and antagonistic activity
of chemokine receptor (CCR2).[7c] While numerous synthetic
approaches were investigated, only a limited number of
successful preparations of the characteristic dihydrooxepine
ring have been reported.[8,9] During the synthetic studies on
MPC1001, Peng and Clive established a synthetic method for
a pyrrolidinone-fused dihydrooxepine through tetrahydroox-
epine formation followed by selenoxide elimination.[10]
Scheme 1. Retrosynthetic analysis of acetylaranotin (1). P/P’=protect-
ing group. R=alkyl group.
bonds divides the C2-symmetric acetylaranotin (1) to mono-
mer 7 with a dihydrooxepine ring fused to a proline moiety.
The dihydrooxepine skeleton would be formed by Baeyer–
Villiger oxidation[12] of cyclohexenone 9 followed by the
reduction of enol lactone 8 via the enol triflate. If the oxygen
functionality at the g position of a,b-cyclohexenone 9 is
introduced by an allylic oxidation of 10, compound 9 would be
synthesized from b,g-unsaturated ketone 12 by isomerization
of the double bond, epoxidation of the resultant enone, and
Wharton rearrangement.[13] Thus, we set known compound 12
as a starting material, which is prepared from l-tyrosine (13)
according to the method reported by Wipf et al.[14]
The synthesis of enone 16 commenced with the prepara-
tion of the known b,g-unsaturated ketone 14 through
oxidative cyclization of l-Cbz-tyrosine[14] (Scheme 2). Treat-
ment of 14 with catalytic DBU provided a,b-unsaturated
ketone, which was then subjected to basic H2O2 to give a,b-
epoxyketone 15 almost quantitatively. Subsequent Wharton
[*] Dr. H. Fujiwara, T. Kurogi, S. Okaya, Dr. K. Okano,
Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
[**] This work was financially supported by the Funding Program for
Next Generation World-Leading Researchers (LS008), the
KAKENHI, and Grant-in-Aid for Scientific Research (B) (20390003).
We thank Dr. M. Isaka (BIOTEC, NSTDA, Thailand) for providing
a sample of the natural product and valuable discussion. We
appreciate Prof. Y. Iwabuchi (Tohoku University) for the generous
gift of 9-azanoradamantane N-oxyl (nor-AZADO).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207307.
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Scheme 3. Synthesis of dihydrooxepine 23. Reagents and conditions:
a) TFAA, UHP, CH2Cl2, ꢀ208C, 53% total yield after 4 reaction cycles
(19% of 20 recovered; after a single reaction cycle: 23% yield, 65%
yield based on recovered starting material); b) KHMDS, PhNTf2, THF,
ꢀ788C, 77%; c) cat. Pd(OAc)2, PPh3, HCO2H, nBu3N, DMF, 658C,
94%. DMF=N,N-dimethylformamide, KHMDS=potassium hexame-
thyldisilazide, TFAA=trifluoroacetic anhydride, UHP=urea hydrogen
peroxide.
exclusively as a single isomer. After conversion to enol triflate
22, subjection to the palladium-catalyzed reduction condi-
tions gave dihydrooxepine 23 in excellent yield with the Cbz
group intact.
The stage was now set for dimerization of monomer 23
(Scheme 4). First, the Cbz group was removed by the
palladium-catalyzed hydrogenolysis to give secondary amine
Scheme 2. Synthesis of substrate 20 for Baeyer–Villiger oxidation.
Reagents and conditions: a) cat. DBU, CH2Cl2, RT, quant.; b) H2O2,
cat. NaOH, MeOH, 08C, 97%; c) NH2NH2·H2O, AcOH, CH2Cl2, 08C!
RT, 55%; d) DMP, CH2Cl2, 08C, 97%; e) TMSOTf, iPr2NEt, CH2Cl2, RT;
f) DMDO, CH2Cl2/acetone, ꢀ788C; evaporation; acidic silica gel, 56%
(over 2 steps); g) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 75%. Ac=acetyl,
Cbz=benzyloxycarbonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DMDO=dimethyldioxirane, DMP=Dess–Martin periodinane,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, TMS=tri-
methylsilyl.
rearrangement and Dess–Martin oxidation of the resulting
allyl alcohol proceeded smoothly to afford enone 16.
At this point, we investigated the oxidation of the allylic
position. Since the conventional oxidation reactions using
SeO2 or brominating agent[15] resulted in a complex mixture,
we devised an alternative method for this transformation. To
this end, we have successfully established a stepwise protocol,
including regioselective dienol silyl ether formation and
vinylogous Rubottom oxidation. Thus, treatment of 16 with
TMSOTf and Hꢀnigꢁs base gave dienol silyl ether 17 as an
exclusive product. Subsequent DMDO oxidation followed by
acidic workup with silica gel gave the desired g-hydroxyenone
19 as a sole product,[16] which was then protected as its TBS
ether 20. In contrast to the conventional Rubottom oxidation
that gives a-hydroxyketones, the result indicated that the
epoxidation occurred at the b,g-double bond to generate
epoxide 18.
Scheme 4. Dimerization of monomer. Reagents and conditions:
a) Et3SiH, cat. Pd(OAc)2, cat. Et3N, CH2Cl2, 458C, 91%; b) KOH, THF/
MeOH/H2O, RT, quant.; c) BOPCl, Et3N, CH2Cl2, RT, 83%; d) Et3SiH,
cat. Pd(OAc)2, cat. Et3N, CH2Cl2, 458C, 78%; e) TBAF, THF, RT, 74%.
BOPCl=bis(2-oxo-3-oxazolidinyl)phosphonyl chloride, TBAF=tetrabu-
tylammonium fluoride.
Surprisingly, the protected hydroxy group of compound 20
is located on the concave face, as determined by X-ray
crystallographic analysis for the advanced intermediate 27.[17]
Since further experiments showed unsuccessful condensation
of monomer units possessing the same configurations as
natural product 1,[18] we decided to invert the stereochemistry
of the hydroxy-bearing carbon center after dimerization and
continued further transformations using 20.
24, and the methyl ester was hydrolyzed to provide carboxylic
acid 25. The crucial condensation of 24 and 25 was then
carried out using BOPCl to afford amide 26 in high yield. The
diketopiperazine ring was then formed by removal of the Cbz
group and subsequent reaction of the generated amine with
the ester to give the corresponding amide. Finally, two TBS
groups were removed to give unprotected diol 28.
We then focused on the construction of the dihydroox-
epine skeleton using a Baeyer–Villiger oxidation[12] to form
enol lactone (Scheme 3). Thus, we examined a variety of
oxidants and found that a combination of TFAA/UHP
systems[12c] gave the best results. Gratifyingly, the expected
Baeyer–Villiger oxidation proceeded to give enol lactone 21
The remaining tasks for the total synthesis of acetylar-
anotin (1) were stereochemical inversion of the hydroxy-
bearing carbon centers at positions 5 and 13, and introduction
of the disulfide moiety (Scheme 5). Since the Mitsunobu
conditions provided a complex mixture of products, we
examined an oxidation–reduction sequence. Among a variety
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Scheme 5. Total synthesis of (ꢀ)-acetylaranotin (1). Reagents and
conditions: a) nor-AZADO, PhI(OAc)2, CH2Cl2, RT, 93%; b) NaBH4,
CeCl3·7H2O, CH2Cl2–EtOH, ꢀ788C, 69%; c) NaHMDS, S8, THF, RT,
31%; d) AcCl, DMAP, CH2Cl2, RT, 44%; e) propanedithiol, Et3N,
MeCN, then O2, RT, 40%. nor-AZADO=9-azanoradamantane N-oxyl,
DMAP=N,N-dimethyl-4-aminopyridine, NaHMDS=sodium hexame-
thyldisilazide.
of conditions tested, oxidation of diol 28 with nor-AZADO[19]
proceeded smoothly to provide vinylogous lactone 29. Sub-
sequent reduction was best effected by a combination of
NaBH4 and CeCl3 at ꢀ788C to provide known diol 30[11] as
a sole isomer. This facial selectivity was consistent with the
result of the Rubottom oxidation; the oxidant approached on
the opposite side to the adjacent bridgehead hydrogen.
Finally, following the synthetic route developed by Reisman
and co-workers,[11] introduction of the tetrasulfide moiety to
the diketopiperazine skeleton using the protocol reported by
Nicolaou and co-workers,[20] and subsequent acetylation
provided 32, the tetrasulfide moiety of which was reduced
to a disulfide moiety to give (ꢀ)-acetylaranotin (1).
[9] Tetrahydrooxepine formation: U. Gross, M. Nieger, S. Brꢃse,
Chem. Eur. J. 2010, 16, 11624 – 11631.
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In conclusion, we have accomplished the total synthesis of
(ꢀ)-acetylaranotin (1) in 22 steps (0.06% overall yield) from
commercially available l-Cbz-tyrosine (Reisman: 19 steps
(0.5% overall yield) from commercially available trans-
cinnamaldehyde). The approach features the efficient forma-
tion of the proline-fused dihydrooxepine ring through
unusual vinylogous Rubottom oxidation, and successful
dimerization of the monomer unit, which possesses an
unnatural stereochemistry.
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Received: September 10, 2012
Published online: November 19, 2012
Keywords: aranotin · diketopiperazine · oxidation ·
.
rearrangement · total synthesis
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[17] For details, see the Supporting Information.
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[18] Interestingly, the stereochemistry of the hydroxy-bearing carbon
center was found to be important for the condensation. Thus,
epi-24 and epi-25, the stereochemistry of which corresponds with
that of natural acetylaranotin (1), were subjected to the same
condensation conditions as described in Scheme 4, providing epi-
26 in low yield, even after prolonged reaction time.
[19] M. Hayashi, Y. Sasano, S. Nagasawa, M. Shibuya, Y. Iwabuchi,
Chem. Pharm. Bull. 2011, 59, 1570 – 1573.
[20] K. C. Nicolaou, D. Giguꢂre, S. Totokotsopoulos, Y.-P. Sun,
Angew. Chem. 2012, 124, 752 – 756; Angew. Chem. Int. Ed. 2012,
51, 728 – 732.
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