Studies toward the total synthesis of GKK1032A2, a structurally unique antitumor compound: Stereoselective construction of the tricarbocyclic system

Article abstract of DOI:10.1055/s-2005-871549

The unique tricarbocyclic system in GKK1032A₂, an antitumor agent from Penicillium sp. GKK1032, was constructed in a highly stereoselective manner, starting from a readily available Hajos-Wiechert ketone analog. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871549

LETTER
1691
Studies toward the Total Synthesis of GKK1032A2, a Structurally Unique Anti-
tumor Compound: Stereoselective Construction of the Tricarbocyclic System
Stereoselective
Co
o
nstruction of
r
a
Tricar
i
bocylic
y
S
yste
m
oshi Arai,a Hideaki Ui,b Satoshi Omura,c Isao Kuwajima*a
a
Creation and Function of New Molecules and Molecular Assemblies, Core Research for Evolutional Science and Technology (CREST),
Japan Science and Technology Agency (JST), 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
Fax +81(42)7789931; E-mail: kuwajima@lisci.kitasato-u.ac.jp
b
c
School of Pharmaceutical Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received 15 April 2005
Abstract: The unique tricarbocyclic system in GKK1032A2, an
antitumor agent from Penicillium sp. GKK1032, was constructed in
a highly stereoselective manner, starting from a readily available
Hajos–Wiechert ketone analog.
Key words: antitumor agents, carbocycles, Diels–Alder reactions,
natural products, stereoselective synthesis
GKK1032A2 is a member of a novel class of antibiotic an-
titumor compounds recently isolated from Penicillium sp.
GKK1032 (Figure 1).1,2 These compounds exhibit potent
activity against bacteria including drug-resistant strain, as
well as antitumor activity against epithelioid cell HeLa
S3.1a He et al. isolated pyrrocidines A and B, 3,6-bisepi-3-
desmethyl analogues of GKK1032s, and reported that
they showed similar bioactivity.3 From a pharmaceutical
point of view, these bioactivities make GKK1032 family
an expecting candidate for a drug to control mutidrug-re-
sistant Staphylococcus aureus and other nosocomial in-
fections, and a new seed for anti-cancer drug. Structural
feature of the compound was elucidated by NMR tech-
niques and X-ray crystallographic analysis,1b which in-
cludes an unique 6-5-6 tricarbocyclic system and an
unusual 13-membered macrocyclic ether containing 1,4-
disubstituted phenyl moiety. Recently, Oikawa disclosed
that the unique backbone of GKK1032A2 is biosyntheti-
cally constructed from L-tyrosine and a nonaketide chain
with five methyl groups.4
Figure 1 Structures of GKK1032 family.
These biologically and synthetically attracting features of
GKK1032 family prompted us to embark on the total
synthesis of GKK1032A2.
The synthetic plan is shown in Scheme 1. The macrocy-
clic moiety of 1 could be constructed from an aldehyde 2
via carbon chain elongation followed by ring-closure. The
cyclohexene ring in 2 is expected to be formed by Diels–
Alder reaction between a diene 3 and an appropriate
dienophile which may occur from the upper face of the
diene taking advantage of a steric effect of the aromatic
ring. The diene 3 would be readily accessible from a
known bicyclic ketone 45 available with high optical
Scheme 1 Retrosynthetic analysis of GKK1032A2.
purity. We describe herein a method to construct the tri-
carbocyclic system of GKK1032s in a highly stereoselec-
tive manner, starting from a readily available Hajos–
Wiechert ketone analogue 4.
The bicyclic ketone 4 was regio- and stereoselectively re-
duced and protected with TBS group5 to afford an enone
5 (Scheme 2). For the trans selective reduction of 6–5
SYNLETT 2005, No. 11, pp 1691–1694
Advanced online publication: 14.06.2005
DOI: 10.1055/s-2005-871549; Art ID: U10005ST
© Georg Thieme Verlag Stuttgart · New York
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7
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7
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0
0
5

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N. Arai et al.
LETTER
bicyclic enone related to 5, we preferred a catalytic hydro-
genation procedure convenient for multi-gram scale prep-
aration at the early stage of the total synthesis. On the
catalytic hydrogenation of this type of compounds, it was
reported that the larger is a substituent at a-position of the
enone [corresponding to C(11)-Me in 5, GKK1032A2
numbering], the higher trans selectivity is observed,6
though unsubstituted substrates gave cis major product.7,8
Indeed, the hydrogenation of 5 proceeded with high trans
selectivity in THF to afford 6 via a subsequent epimeriza-
tion under basic conditions. Use of the dry solvent was
essential to achieve the high trans selectivity, otherwise
the selectivity was markedly decreased, and in some case
inverted. Methylation of 6 under kinetic conditions fol-
lowed by epimerization produced a ketone 7 in good
yield. A secondary alcohol 8 obtained by conventional
deoxygenation9 of 7 was converted into an enone 9 via
Swern oxidation10 and dehydrogenation under Tsuji’s
conditions.11
Scheme 3 Reagents and conditions: a) 2-lithio-2-methyl-1,3-di-
thiane, THF, –78 to –23 °C, 5 h, 97%; b) 0.5% H2SO4, aq THF, 0 °C
to r.t., 1 d, 77% (3 recycles), >20:1 stereoselectivity; c) NaH, h6-4-
FC6H4CH2OMOM-Cr(CO)3, THF, reflux, 7 h, 81%; d) CAN,
NaHCO3, MeCN, –23 °C, 20 min, 82%; e) Dess–Martin periodinane,
MeCN–CH2Cl2–H2O, r.t., 39 h, 70%; f) KHMDS, TBSCl, THF–
HMPA, –78 °C to r.t., 95%.
gave enone 12 in an acceptable yield. The diene 13 was
readily prepared by usual procedure from 12.
Thus, the stage was set for the formation of the third 6-
membered ring. In refluxing toluene, the [4+2]cycloaddi-
tion of dimethyl fumarate to the diene 13 took place selec-
tively from the opposite side of OAr to afford the desired
14a as a major product together with a small amount of its
epimer 14b (Scheme 4). The stereochemistry of each
product was determined by NOE experiments. Reduction
of 14a to a diol followed by treatment with TBAF afford-
ed a thermodynamically most favorable trans-fused ke-
tone. Protection of the diol moiety with TBS provided 15,
which was converted into an enone 16. A stereoselective
introduction of methyl on the C(3)-position to form a qua-
ternary carbon was a next critical aspect of our synthetic
study. While usual procedures for conjugate addition
(e.g., Me2CuLi,18 MeMgBr–cat.Cu(I)–TMSCl19) did not
work with the enone 16, a Cu(II)–salicylidene–iminato
complex 19 catalyzed reaction20 effected the addition to
afford methylation product in good yield. However, no
stereoselection was observed (Equation 1), and we had to
modify the structure of the substrate appropriate for the p-
facial selection.
Scheme 2 Reagents and conditions: a) ref. 5; b) H2, Pd/C, THF,
0 °C, 1 d, trans/cis = ca.9:1; c) NaOEt, EtOH, reflux, 6 h, 77% (2
steps); d) LDA, THF, –78 °C, 3 h, then MeI, –78 °C to r.t., 85%; e)
1,2-ethanedithiol, BF3·OEt2, neat, 0 °C to r.t., 1 d, 85%; f) Raney Ni
(W-2), EtOH, reflux, 14 h, 76%; g) (COCl)2, DMSO, Et3N, –78 to
0 °C, 1 h, 93%; h) LDA, THF, –78 °C, 3 h, then TMSCl; i) 10 mol%
Pd(OAc)2, allyl carbonate, MeCN, reflux, 67% (2 steps).
For the stereoselective introduction of an oxygen func-
tionality at C(13)-position, we decided to utilize Krafft’s
procedures: they reported a suprafacial 1,3-rearrangement
of the hydroxyl group of tertiary allylic alcohol obtained
by addition of 2-lithio-2-methyl-1,3-dithiane to cyclo-
pentenone moiety in a steroid derivative under dilute
acidic conditions.12 Their protocol worked well also in our
case: Addition of the lithiodithiane to the enone 9 took
place selectively from the opposite side of the angular
methyl group and a subsequent treatment with dilute
sulfuric acid afforded allylic alcohol 11 in excellent
stereoselectivity (Scheme 3). Introduction of the aryl
ether was effectively achieved by using aromatic SN2
reaction between a fluoroarene chromium complex and an
alkoxide of 11,13 followed by decomplexation with
CAN.14 The deprotection of the dithiane turned out to be
somewhat troublesome, probably due to a steric factor and
the instability of the aryl ether moiety under the reaction
conditions.15 After several trials, it was found that appli-
cation of Stork’s method16 as well as Panek’s protocol17
After various examinations, we found that the cyclic silyl
ether 17, easily available from 16 via a protective group
manipulation,21 was the substrate of choice for the stereo-
Equation 1
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LETTER
Stereoselective Construction of the Tricarbocyclic System
1693
selective 1,4-addition. When 17 was subjected to the GKK1032s with correct stereochemistry. Since 20 was
above conditions, the addition product 18 was obtained as isolated as a crystalline compound, the relative configura-
a sole product (Scheme 4). The complete stereoselectivity tion was unambiguously determined by X-ray crystallo-
observed in this conjugate addition could be explained by graphic analysis (Figure 3).25
considering the structural feature of 17 shown in Figure 2.
Figure 2 An optimized structure of the right half of 17.
Figure 3 ORTEP drawing of 20.
After deprotection of the silylene in 20 with TBAF, regio-
selective TBDPS ether formation was nicely carried out
under low temperature conditions to give 21a in prefer-
ence to 21b. Oxidation of the remaining hydroxy group in
21a followed by Wittig reaction26 led to 22, which was
converted into aldehyde 23 via usual protecting group ma-
nipulation. Thus, we established a highly stereoselective
synthetic route from the known ketone 4 to the aldehyde
23, which could be a useful common intermediate in the
total synthesis of GKK1032 family.
Scheme 4 Reagents and conditions: a) dimethyl fumarate, toluene,
reflux, 10 h, 14a 83%, 14b 17%; b) LiBH4, THF–MeOH, 0 °C to r.t.,
1 d, 91%; c) TBAF, THF, 0 °C to r.t., 2 h; d) TBSCl, imidazole, DMF,
r.t., 1 h, 97% (2 steps); e) LDA, TMSCl, THF, –78 °C, 3 h; f)
Pd(OAc)2, MeCN, 50 °C, 10 h; g) TBAF, THF, 0 °C to r.t., 2 h; h) (t-
Bu)2Si(OTf)2, 2,6-lutidine, CH2Cl2, –78 to –45 °C, 4 h, 58% (based
on 15); i) MeMgBr, TMSCl, 10 mol% 19, THF, –45 °C, 44 h, 84%
Scheme 5 Reagents and conditions: a) MeLi, THF, –78 °C to r.t., 2
(single stereoisomer).
h, then 24, –78 °C, 16 h, 86%; b) Me2Zn, Pd(PPh3)4, THF, 0 °C to r.t.,
28 h, 95%; c) TBAF, THF, r.t., 20 h; d) TBDPSCl, Et3N, 10 mol%
DMAP, CH2Cl2, –78 °C to –45 °C, 4 h, 21a 80%, 21b 13%; e)
(COCl)2, DMSO, Et3N, –78 °C to 0 °C, 1 h, 95%; f) MePh3PBr, BuLi,
THF, 0 °C, 2 h, 96%; g) 2 M HCl, aq THF, 35 °C, 8 h, 95% (3
recycles); h) ethyl vinyl ether, 10 mol% PPTS, CH2Cl2, r.t., 3 h; i)
TBAF, MS 4 Å, THF, 40 °C, 17 h, quant. (2 steps); j) SO3·pyridine,
Et3N, DMSO, r.t., 1.5 h, 89%.
The trimethylsiloxy group in 18 was replaced with methyl
group via three sequential steps, silyl–lithium exchange,22
triflation with Comins reagent,23 Pd(0)–Me2Zn reagents,24
affording 20 (Scheme 5). Compound 20 carries all
required functionalities in the tricarbocyclic core of
Synlett 2005, No. 11, 1691–1694 © Thieme Stuttgart · New York

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N. Arai et al.
LETTER
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Acknowledgment
The authors acknowledge Dr. M. Minoura in Department of
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Synlett 2005, No. 11, 1691–1694 © Thieme Stuttgart · New York