Enantioselective synthesis of arglabin

Article abstract of DOI:10.1002/anie.200701584

(Chemical Equation Presented) Closing the ring: The first enantioselective synthesis of the guanianolide natural product arglabin and its dimethylamino adduct, which shows promising results in the treatment of various tumors, has been achieved. Key steps

Full text of DOI:10.1002/anie.200701584

Angewandte
Chemie
DOI: 10.1002/anie.200701584
Natural Products
Enantioselective Synthesis of Arglabin**
Srinivas Kalidindi, Won Boo Jeong, Andreas Schall, Rakeshwar Bandichhor, Bernd Nosse, and
Oliver Reiser*
Dedicated to Professor Lutz-F. Tietze on the occasion of his 65th birthday
A prominent member of the widely distributed class of
guaianolides is arglabin,[1] which inhibits farnesyl transferase
and thus activation of the RAS proto-oncogene, a process that
is believed to play a pivotal role in 20–30% of all human
tumors. The natural product shows promising antitumor
activity and cytotoxicity against different tumor cell lines
(human tumor cell lines IC50 = 0.9–5.0 mgmLÀ1).[2] Arglabin is
isolated from Artemisia glabella and is transformed into the
hydrochloride salt of the dimethylamino adduct 1·HCl to
increase bioavailability. This compound 1·HCl has been
successfully used in Kazakhstan for the treatment of breast,
colon, ovarian, and lung cancers.[3,4]
The heart of arglabin consists of a cycloheptane ring with
five contiguous stereocenters, to which two five-membered
rings are trans-annulated. The resulting strain can be released
by ring opening of the g-butyrolactone at C-2, which makes
arglabin and its derivatives prone to attack by nucleophiles—
a mode of action that plays an integral role in its biological
activity.[2,5]
Scheme 1. Retrosynthetic analysis of arglabin. PG=protecting group,
The absence of other control factors should cause the
planned epoxidation of 2 described in our retrosynthetic
analysis (Scheme 1) to preferably occur from the top face of
the tricycle to afford a less-strained but undesirable cis junc-
tion between the five- and seven-membered rings. Consider-
ing this, we reasoned that a hydroxy function at C-8 could
direct a suitable epoxidation reagent to the desired lower face,
and subsequently allow the installment of the double bond
between C-8 and C-9 by elimination of water. Compound 2
should be accessible from 3 by allylation and subsequent ring-
closing metathesis (RCM); the latter requires the formation
of a tetrasubstituted double bond within a medium-sized
seven-membered ring. Following the strategy developed in
TMS=trimethylsilyl.
our research group for the enantioselective synthesis of trans-
4,5-disubstituted g-butyrolactones,[6,7] the allylation of cyclo-
propane 4 with the allylsilane 5 should lead to the first key
intermediate 3.
Cyclopropanecarbaldehyde 8 was prepared in diastereo-
and enantiomerically pure form in two steps from methyl-2-
furoate (6) on a 50 g scale (Scheme 2) following an analogous
[*] M.Sc. S. Kalidindi, Dr. W. B. Jeong, Dipl.-Chem. A. Schall,
Dr. R. Bandichhor, Dr. B. Nosse, Prof. Dr. O. Reiser
Institut für Organische Chemie
Universität Regensburg
Universitätsstrasse 31, 93053 Regensburg (Germany)
Fax: (+49)941-943-4121
E-mail: oliver.reiser@chemie.uni-regensburg.de
Homepage: http://www-oc.chemie.uni-regensburg.de/reiser/
index.html
[**] This work was supported by the DAAD (fellowship for S.K. and R.B.),
the Studienstiftung des Deutschen Volkes (fellowshipfor B.N.), and
the Fonds der Chemischen Industrie (fellowshipfor A.S. and
Sachbeihilfe). We thank Dr. M. Zabel, Regensburg, for carrying out
the X-ray analyses.
Scheme 2. a) 1. Ethyl diazoacetate (2.67 equiv), Cu(OTf)2 (0.66 mol%),
(R,R)-iPr-box[8] (0.84 mol%), PhNHNH2 (0.70 mol%), CH2Cl2, 85–
90% ee; 2. recrystallization (pentane), >99% ee, 38%; b) 1. O3,
CH2Cl2, À788C 2. dimethylsulfide, 94%; c) CH3MgCl, TMSCl, CuI, LiCl,
THF, À788C, 4 h, 90%; d) TMSCH2MgCl, [Ni(acac)2], Et2O, reflux,
16 h, 72%. Tf=trifluoromethanesulfonyl, acac=acetylacetonate,
PMB=para-methoxybenzyl.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
strategy previously developed by us for its enantiomer.[9] The
allylsilane 11 was obtained starting from enantiomerically
pure 9,[10] by trans-selective methyl cuprate addition and NiII-
catalyzed cross coupling[11] with trimethylsilylmethylenemag-
nesium chloride.
Borontrifluoride-mediated formation of 12 proceeded
with excellent double stereocontrol (Scheme 3). The carbonyl
group of 8 was attacked in accordance with the Felkin–Anh
Scheme 4. Synthesis of the guaianolide core. a) 1. 2-methylallylsilane,
BF3·OEt2, À788C, 16 h, 70% (4:1 epimeric mixture at C-4); 2. Ac2O,
Et3N, DMAP, RT, 24 h, 85% (4:1 epimeric mixture at C-4); b) 1. cat. G-
II (3”5 mol%), toluene, sparging with Ar, 958C, 6 h; 2. separation of
C-4 epimers by chromatography: 18 (70%), epi-18 (16%); c) DDQ,
CH2Cl2, 4 h, RT, 90%. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none, DMAP=4-dimethylaminopyridine.
Deprotection of the PMB group was uneventful to give rise to
19 upon treatment with DDQ in 90% yield (Scheme 4).
The X-ray structure of 19[14] (Scheme 4) revealed that
both faces of the seven-membered ring for the subsequently
planned epoxidation are equally exposed. In particular, it
became clear that for the desired attack from the a face
(bottom) the upward but pseudoequatorial-pointing acetoxy
group at C-8 would provide little steric shielding. Moreover,
the hydroxy group at C-3 that was envisioned to serve as a
directing substituent, which is known not only for the
epoxidation of allylic but also for homoallylic alcohols,[15]
rather unfavorably was in a pseudoequatorial position and
pointed away from the double bond that was to be attacked.
Furthermore, epoxidation from the b face (top) yielded the
product with the more stable cis annulation between the five-
and seven-membered ring.
Indeed, simple undirected epoxidation of 19 with dime-
thyldioxirane occurred with a preference of 7:1 (Table 1,
entry 1) from the undesired b face to give 20, which supports
the rational put forward above. Disappointingly, m-CPBA,
which is known to be directed by homoallylic alcohols, still
gave the b-epoxide with a ratio of 3:1 (Table 1, entry 4), which
again demonstrates the preference for the cis annulation of
the five- and seven-membered rings.[16]
Consequently, we attempted the epoxidation by initial
bromohydrine formation with the rational that the bromo-
nium ion should also be formed from the b face followed by
backside attack of water and elimination of HBr. Indeed, by
using this strategy, the overall epoxidation took place in high
yields without the isolation of intermediates, and gave only
one product, although unfortunately again the unwanted b-
epoxide (Table 1, entries 2 and 3). However, employing
catalytic amounts of [V(O)(acac)2] and tert-butylhydroper-
oxide (TBHP) as the stoichiometric oxidant[17] gave the
desired a-epoxide 21 with a preference of 9:1 (Table 1,
Scheme 3. Stereoselective allylation/retroaldol/lactonization cascade
for the synthesis of the outer five-membered rings in arglabin. 8
(1.0 equiv), 11 (1.04 equiv), BF3·OEt2, À788C, 4 h; Ba(OH)2·8H2O,
08C, 2 h.
paradigm[12] by the allylsilane 11, which reacts from the face
opposite its methyl group. Without isolation, 12 was directly
subjected to a base, which caused saponification of the labile
oxalic ester. As a result, the now-unmasked donor-acceptor
cyclopropane[13] underwent ring opening followed by lactoni-
zation to give 15 as a single stereoisomer.
A second Sakurai allylation of 15 with 2-methylallylsilane
smoothly yielded 16 as a 4:1 mixture of diastereomers
(Scheme 4). The latter is, in principle, without consequence,
since in the synthesis of the target compound the newly
created hydroxy group is removed at a later stage in the
sequence. Acylation of 16 set the stage for subsequent ring-
closing metathesis, which not unexpectedly proved to be
challenging because of the medium-size ring and the tetra-
substituted double bond that had to be formed. Nevertheless,
the combination of Grubbs second-generation (G-II) catalyst
and inert-gas sparging at a reaction temperature of 958C gave
the desired 18 and its C-4-epimer epi-18 in a total of 86%
yield, although 15 mol% of G-II split into 3 portions of
5 mol% each had to be employed to achieve complete
conversion. To develop the stereoselective epoxidation on
C-6/C-6a it turned out to be advantageous to continue
working with only the major diastereomer 18, which was
readily separated from epi-18 by column chromatography.
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Angewandte
Chemie
Table 1: Epoxidation of 19.
nation. This product corresponded in all spectroscopic data
with an authentic sample.[20]
In conclusion, we have developed the first enantioselec-
tive synthesis of the guaianolide arglabin and its dimethyl-
amino adduct 1. The latter, as its hydrochloride salt, is
currently under clinical evaluation for the treatment of
various cancers. Key steps to build up the guaianolide
framework include a copper(I)-catalyzed asymmetric cyclo-
propanation, a stereoselective Sakurai allylation followed by
a retroaldol/lactonization cascade, a second Sakurai allyla-
tion, and ring-closing metathesis. This strategy should also
open access to related tricyclic 5,7,5-guaianolide natural
products, which we are currently investigating.
Entry Method
Conditions[a]
20/
Yield [%][c]
65
21[b]
1
2
dimethyl-
dioxirane
KHSO5, acetone, CH2Cl2/H2O, 88:12
pH 7.2 buffer, [18]crown-6,
08C, 6 h
halohydrine NaBrO3/NaHSO3 (1:2),
CH3CN/H2O (1:2), 48 h, RT
>99:1
80
Received: April 11, 2007
Published online: July 16, 2007
3
4
halohydrine NBS, THF/H2O (2:1), 15 h, RT >99:1
peracid
72
85
m-CPBA, CH2Cl2, À108C to
75:25
RT, 6 h
Keywords: arglabin ·asymmetricsynthesis ·farnesyl transferase·
5
vanadium
[V(O)(acac)2] (2 mol%),
TBHP, CH2Cl2, 08C to RT, 16 h
10:90
78[d]
.
natural products · total synthesis
[a] NBS=N-bromosuccinimide, m-CPBA=meta-chloroperoxybenzoic
acid. [b] Determined by 1H NMR and GC. [c] Yields of isolated products.
[d] Yield of isolated purified 21.
[1] S. M. Adekenov, M. N. Mukhametshanov, A. N. Kupriyanov,
Khim. Prir. Soedin. 1982, 565.
[2] T. E. Shaikenov, S. Adekenov, R. M. Williams, N. Prashad, F.
Baker, T. L. Madden, R. Newman, Oncol. Rep. 2001, 8, 173.
[3] T. E. Shaikenov, S. Adekenov, Arglabin. Its structure, properties
and usage, Pourtmouth, Virginia, 1997.
[4] N. S. Zhangabylov, L. Y. Dederer, L. B. Gorbacheva, S. V.
Vasilꢀeva, A. S. Terekhov, S. M. Adekenov, Pharm. Chem. J.
2004, 38, 651.
[5] A. Z. Abilꢀdaeva, R. N. Pak, A. T. Kulyyasov, S. M. Adekenov,
Eksp. Klin. Farmakol. 2004, 67, 37.
[6] R. B. Chhor, B. Nosse, S. Soergel, C. Böhm, M. Seitz, O. Reiser,
Chem. Eur. J. 2003, 9, 260.
entry 5), which demonstrates the extraordinary affinity for
precoordination of the vanadium reagent to hydroxy groups
before the epoxidation occurs. Epoxide 21 was isolated in
78% yield after chromatographic separation from the minor
b-epoxide product.
Treatment of 21 with trifluorosulfonic acid anhydride and
pyridine afforded a clean elimination product 22 as a single
regioisomer, which was confirmed by X-ray analysis
(Scheme 5).[14] Deoxygenation at C-4 was achieved by acetate
deprotection followed by the Barton–McCombie protocol[18]
to give rise to 23. Alkylation with the Eschenmoser salt,[19]
yielded 1, which could then be transformed to arglabin itself
by quaternization with methyliodide/trimethylamine elimi-
[7] B. Nosse, R. B. Chhor, W. B. Jeong, C. Boehm, O. Reiser, Org.
Lett. 2003, 5, 941.
[8] (+)-(R,R)-Bis(4-isopropyloxazoline)[4R,4R’)-2,2’-(2,2’-pro-
panediyl)bis(4-isopropyl-4,5-dihydrooxazole)]: D. A. Evans,
K. A. Woerpel, B. Nosse, A. Schall, Y. Shinde, E. Jezek, M. M.
Haque, R. B. Chhor, O. Reiser, P. Wipf, N. Jayasuriya, Org.
Synth. 2006, 83, 97.
[9] E. Jezek, A. Schall, P. Kreitmeier, O. Reiser, Synlett 2005, 915.
[10] Prepared in analogy to the reported O-benzyl derivative: T. T.
Curran, D. A. Hay, C. P. Koegel, J. C. Evans, Tetrahedron 1997,
53, 1983.
[11] T. Hayashi, T. Fujiwa, Y. Okamoto, Y. Katsuro, M. Kumada,
Synthesis 1981, 1001.
[12] A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191.
[13] H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151.
[14] CCDC-648651 (for 19) and CCDC-648653 (for 22) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif;
see also the Supporting Information.
[15] A. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307.
[16] For a similar result, see: M. Ando, A. Akahane, K. Takase,
Chem. Lett. 1978, 727.
[17] K. B. Sharpless, T. R. Verhoeven, Aldrichimica Acta 1979, 12, 63.
[18] S. W. McCombie in Comprehensive Organic Synthesis, Vol. 8
(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 811.
[19] E. F. Kleinman in Encyclopedia of Organic Reagents (Ed.: L.
Paquette), Wiley, New York, 2004.
Scheme 5. a) Tf2O, pyridine, CH2Cl2, À108C to RT, 18 h, 62%.
b) 1. K2CO3, MeOH, 08C to RT, 4 h, 70%; 2. 1,1’-thiocarbonyldiimada-
zole, DMAP, CH2Cl2, RT, 4 h, 80%; 3. Bu3SnH, AIBN, toluene, 908C,
5 h, 77%. c) 1. LiHMDS, THF, À788C; 2. Eschenmoser salt, THF,
À788C to RT, 4 h, 75%; d) MeI, MeOH, NaHCO3, CH2Cl2, 80%.
AIBN=azobisisobutyronitrile, LiHMDS=lithium hexamethyldisilaza-
nide.
[20] We thank Dr. K-D. Göhler, CAC Chemnitz GmbH, for a sample
of natural arglabin.
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