Total synthesis of (±)-γ-rubromycin on the basis of two aromatic pummerer-type reactions

Article abstract of DOI:10.1002/anie.200702382

(Chemical Equation Presented) Double or nothing: In a convergent synthesis of the title compound, a potent inhibitor of human telomerase, two different aromatic Pummerer-type reactions were employed to construct the pivotal bisbenzannelated spiroketal ske

Full text of DOI:10.1002/anie.200702382

Communications
DOI: 10.1002/anie.200702382
Natural Products Synthesis
Total Synthesis of (ꢀ )-g-Rubromycin on the Basis of Two Aromatic
Pummerer-Type Reactions**
Shuji Akai, Keisuke Kakiguchi, Yuka Nakamura, Ikumi Kuriwaki, Toshifumi Dohi,
Shusaku Harada, Ozora Kubo, Nobuyoshi Morita, and Yasuyuki Kita*
The antibiotics b-rubromycin (1) and g-rubromycin (2)[1]
contain a highly oxygenated naphthoquinone moiety (A,B
rings) and an 8-hydroxyisocoumarin moiety (E,F rings) linked
through a 5,6-spiroketal (C,D rings). They exhibit activity
against the reverse transcriptase of human immunodeficiency
virus-1,[2] and their inhibition of human telomerase, reported
in 2000,[3] has made these compounds attractive lead com-
pounds for the development of new types of anticancer drugs.
The spiroketal unit is essential for their inhibitory activity
towards telomerase: The related compound a-rubromycin
(3), which lacks the spiroketal moiety, exhibits decreased
activity. Other natural products have a similar bisbenzanne-
lated spiroketal framework. Typical examples include heli-
quinomycin (4),[4] an inhibitor of DNA helicase,[5] and
purpuromycin (5),[6] a potential topical agent for vaginal
infections (Scheme 1).[7]
Much effort has been devoted to the synthesis of these
compounds,[8–16] and special attention has been focused on the
preparation of the vital bisbenzannelated spiroketal core
structure I.[8–13] The reported methods are based on the acid-
catalyzed spiroketalization of ketones[10–12] or a hemiketal,[9b]
the haloetherification of a benzofuran,[9a] or the oxidative
[3+2] cycloaddition of an enol ether with a b-diketone.[13]
However, multiple steps were required to build up the ketals I
from smaller fragments, and the applicability of these
methods to a wide range of analogues has not been
demonstrated. Furthermore, the total synthesis of the racemic
aglycone of 4 by Danishefsky and co-workers[9] is the only
successful synthesis that has been reported to date for this
[*] Prof. Dr. S. Akai,[+] Dr. K. Kakiguchi, Y. Nakamura, I. Kuriwaki,
Dr. T. Dohi, S. Harada, O. Kubo, Dr. N. Morita,[#] Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8229
Scheme 1. Some typical natural products with bisbenzannelated spiro-
ketal moieties and related compounds.
E-mail: kita@phs.osaka-u.ac.jp
[+] Current Address:
class of natural products. Therefore, there is a need for the
development of more efficient methods for the total synthesis
of these natural products and the preparation of diverse
analogues with the bisbenzannelated spiroketal moiety I. We
present herein a convergent synthesis of I and the first total
synthesis of (ꢀ )-g-rubromycin (2).
School of Pharmaceutical Sciences, University of Shizuoka
52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526 (Japan)
[#] Current Address:
Showa Pharmaceutical University
3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543
(Japan)
First, we developed an effective, convergent route to the
pentacyclic ketal 6a, the core structure of these natural
products, on the basis of an unprecedented rearrangement
reaction of the spiroketal 10a. The key precursor 10a was
prepared readily from the sulfoxide 7a and 2-methylenechro-
man (8a)[17] by an aromatic Pummerer-type reaction that we
had developed previously.[18–21] The conversion of the “bent”
[**] This research was supported by Grants-in-Aid for Scientific Research
(S and A) from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. We thank Dr. Axel Zeeck of the Universität
Göttingen (Germany) for generously providing an authentic sample
of g-rubromycin.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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ketal 10a into the linearly condensed
ketal 6a with a quinone structure at the
B ring would complete the preparation of
the core structure in a limited number of
steps. However, attempts with various
acids, such as sulfuric acid, trifluorome-
thanesulfonic acid, trifluoroacetic acid
(TFA), and BF3.Et2O, resulted in no
transformation. In contrast, when we
tried to prepare the orthoquinone 13a
from the sulfoxide derivative 12a by a
second aromatic Pummerer-type reac-
tion[20] in the presence of trifluorometha-
nesulfonic anhydride (Tf2O), we observed
the unexpected direct formation of 6a in
57% yield along with 13a (27% yield).
We investigated the reaction pathway in
detail and found that the similar treat-
ment of 12a with trifluoroacetic anhy-
dride (TFAA) gave 13a in 82% yield as a
single product. We also discovered that
the subsequent treatment of 13a with a
strong acid, such as trifluoroacetic acid,
afforded 6a in 87% yield. Probably, the
protonation of one carbonyl group in 13a
with the assistance of electron donation
by the oxygen atom at the b position (to
give intermediate B) promotes the cleav-
age of the ketal, and the oxonium inter-
mediate C formed in this way undergoes
recyclization to form 6a (Scheme 2).[22]
Having developed this successful pro-
tocol, we began the total synthesis of 2
with the attempted functionalization of
the Ering to build up the F ring. Reported
methods for the installation of the F ring
include carbon–carbon bond formation of
Scheme 2. Preparation of 6a by two aromatic Pummerer-type reactions: a) 1) methyl tri-
methylsilyl dimethylketene acetal, MeCN, RT; 2) 8a, Tf2O, 2,4,6-collidine, MeCN, ꢁ408C;
b) iPrNH2, MeCN, RT; c) MCPBA, CH2Cl2, ꢁ78!ꢁ358C; d) Tf2O, CH2Cl2, 08C; e) TFAA,
CH2Cl2, 08C; f) TFA, CH2Cl2, 08C. MCPBA=m-chloroperbenzoic acid.
phthalaldehyde derivatives with malonates[14] or Horner–
Wadsworth–Emmons reagents,[9,15] and the Heck reaction of
an aryl iodide.[16] However, our attempts to use these methods
for the functionalization of 2-methylenechroman (8a) were
unsuccessful, and we took a different approach based on the
benzyne intermediate D. Thus, the commercially available
bromophenol 14 was converted into the bromolactone 16 by
using the method described by Panetta and Rapoport,[23] and
16 was then treated with the Tebbe reagent[17] to give the 2-
methylenechroman 17. The treatment of 17 with dimethyl
malonate in the presence of lithium 2,2,6,6-tetramethylpiper-
idide afforded the highly functionalized bicyclic compound
8b as a single regioisomer. This exclusive regioselectivity is
probably a result of the strong inductive effect of the methoxy
group (Scheme 3).[24,25]
The functionalized AB-ring fragment 7b was prepared
from the known compound 18[26] and subjected to spiroketal
formation with 8b by the aromatic Pummerer-type reaction to
give the pentacyclic ketal 9b. The sulfoxide 10b derived from
9b by treatment with iPr2NH and oxidation underwent a
second aromatic Pummerer-type reaction in the presence of
TFAA, and the resulting orthoquinone was converted into the
Scheme 3. Preparation of the DE-ring moiety 8b: a) 1) triethyl ortho-
acrylate, tBuCO2H, toluene, reflux; 2) HCl (1n), Et2O, RT; 3) 10%
KOH, MeOH, RT; b) Ac2O, reflux; c) Tebbe reagent, THF, ꢁ78!
ꢁ408C; d) lithium 2,2,6,6-tetramethylpiperidide, dimethyl malonate,
THF, ꢁ788C.
linearly condensed paraquinone 6b with concomitant
removal of the MOM group. After reprotection of the
phenol with a MOM group, the quinone 6c was converted
into the corresponding dihydroquinone dimethyl ether 22,
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Scheme 4. Completion of the total synthesis of 2: a) 1) BCl3, CH2Cl2, 08C; 2) MOMCl, iPr2NEt, CH2Cl2, 08C; b) NaOMe, MeOH, reflux;
c) 1) PhICl2, Pb(SCN)2, CH2Cl2, RT; 2) PhLi, THF, ꢁ788C; d) 1) ClCO2Me, iPr2NEt, CH2Cl2, 08C; 2) MCPBA, CH2Cl2, ꢁ78!ꢁ58C; e) 1) methyl
trimethylsilyl dimethylketene acetal, MeCN, RT; 2) 8b, Tf2O, 2,4,6-collidine, MeCN, ꢁ788C; f) 1) iPr2NH, MeCN, RT; 2) MCPBA, CH2Cl2, ꢁ78!
ꢁ208C; g) 1) TFAA, CH2Cl2, 08C; 2) TFA, CH2Cl2, 08C; h) MOMCl, iPr2NEt, CH2Cl2, 08C; i) Na2S2O4, Me2SO4, K2CO3, acetone, reflux; j) TFA,
CH2Cl2, 08C; k) [Co(salen)2], O2, DMF, RT; l) 10% KOH, MeOH, RT; m) (triphenylphosphoranylidene)acetonitrile, EDCI, DMAP, CH2Cl2, RT;
n) dimethyldioxirane, MeOH, 08C; o) BBr3, CH2Cl2, ꢁ78!08C. DMAP=4-(dimethylamino)pyridine, DMF=N,N-dimethylformamide,
EDCI=N-ethyl-N’-(3-(dimethylamino)propyl)carbodiimide hydrochloride, MOM=methoxymethyl.
and the MOM group was removed to give 23. The [Co-
(salen)2]-catalyzed oxidation[13a] of the A ring of 23 gave the
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of 26 with (triphenylphosphoranylidene)acetonitrile gave 27,
which was oxidized by dimethyldioxirane. The intermediate
28 underwent immediate cyclization to produce the lactone
29. Final deprotection by BBr3 delivered 2, which was
identical to authentic natural g-rubromycin by direct compar-
ison (1H NMR, IR, TLC; Scheme 4).
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Received: June 1, 2007
Published online: August 14, 2007
Keywords: natural products · Pummerer reaction ·
.
rearrangement · spiroketals · total synthesis
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