Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven

Article abstract of DOI:10.1002/anie.200602011

(Chemical Equation Presented) Antitumor agents (-)-acylfulvene and (-)-irofulven are prepared in an approach that employs the powerful enyne ring-closing metathesis reaction to secure the spiro-bicyclic AB rings. Other key features of this synthesis include an efficient aldol-based introduction of the stereocenter at C2, a diazene-mediated reductive allylic transposition, and a ring-closing metathesis/oxidation sequence.

Full text of DOI:10.1002/anie.200602011

Angewandte
Chemie
Asymmetric Synthesis
DOI: 10.1002/anie.200602011
Enantioselective Total Synthesis of
(ꢀ)-Acylfulvene and (ꢀ)-Irofulven**
Mohammad Movassaghi,* Grazia Piizzi,
Dustin S. Siegel, and Giovanni Piersanti
While sesquiterpene illudins M and S (1 and 2, respectively)
are highly cytotoxic compounds isolated from Omphalotus
illudens, a semisynthetic derivative, (ꢀ)-irofulven (4; hydroxy-
methyl acylfulvene (HMAF)), has recently demonstrated far
superior efficacy as an antitumor agent.[1,2] (ꢀ)-Irofulven (4)
is currently in phase II clinical trials for the treatment of
ovarian, prostate, and thyroid cancers both as monotherapy
and combination therapy.[2] Significantly, it has demonstrated
activity against a variety of solid tumors. Prior syntheses of
irofulven using the Padwa carbonyl ylide 1,3-dipolar cyclo-
addition reaction and the Pauson–Khand reaction have been
reported.[3] Herein, we describe a convergent enantioselective
total synthesis of (ꢀ)-acylfulvene (3) and (ꢀ)-irofulven
(4).
The inhibition of DNA synthesis and S-phase arrest in
cells treated with these compounds stems from sequential
nucleophilic addition at C8 and cyclopropyl ring opening, thus
[*] Prof. Dr. M. Movassaghi, Dr. G. Piizzi, D. S. Siegel, Dr. G. Piersanti[+]
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-254-1504
E-mail: movassag@mit.edu
Homepage: http://web.mit.edu/movassag/www/index.htm
[+] Currentaddress:
Universitµ degli Studi di Urbino “Carlo Bo”
Istituto di Chimica Farmaceutica
Piazza Rinascimento 6, 61029 Urbino (Italy)
[**] M.M. is a Dale F. and Betty Ann Frey Damon Runyon Scholar
supported by the Damon Runyon Cancer Research Foundation
(DRS-39-04). M.M. is a Firmenich Assistant Professor of Chemistry.
G.P. acknowledges partial support for a postdoctoral fellowship
from Universitµ degli Studi di Urbino “Carlo Bo”. We are grateful to
Professors A. H. Hoveyda and E. N. Jacobsen for generous samples
of their silylcyanation catalysts. We acknowledge financial support
by MIT, Paul M. Cook Fund, and Boehringer Ingelheim Pharma-
ceutical Inc.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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leading to B-ring aromatization.[3a] In light of their potent
Scheme 2). The stereochemistry at C2 of 14 was secured by
X-ray analysis (a related salt with (ꢀ)-brucine)[7] and was
found to be consistent with the predicted sense of carbonyl
addition.[6a]
antitumor activity, we sought to develop a general solution to
the synthesis of the fully functional spirocyclic AB-ring
system common to these antitumor agents by employing a
versatile enyne ring-closing metathesis reaction (EYRCM;
Scheme 1).[4] A convergent assembly of trienyne 8 by addition
Under optimal conditions, the methyl ketone 15 was
efficiently prepared by the cross-coupling of thiol ester 14
with methylzinc iodide using SPhos as a supporting ligand.[8]
Methods employing more nucleophilic reagents were plagued
by significant decomposition of the reactive cyclopropyl
ketone 15. Methylenation of the sensitive and sterically
hindered ketone 15 was achieved using CH2I2/Zn/TiCl4 in the
presence of catalytic PbCl4[9] to provide multigram batches of
the methyl ester 16. The conversion of ester 16 into the
corresponding aldehyde (+)-11 afforded the key building
block for the synthesis of the spirocyclic AB-ring system of 1–
4. Given the presence of this substructure in a number of
natural illudins, the efficiency of this aldol-based approach in
securing the 2R stereochemistry of the intermediates in large
quantities is noteworthy.[10]
The proposed EYRCM cascade (8!6; Scheme 1) would
require the formation of a tetrasubstituted alkene on a
sterically congested and fully substituted B ring.[11] We
examined the EYRCM of dienynes 17a–f (Table 1) to quickly
Scheme 1. Retrosynthetic analysis of (ꢀ)-irofulven (4). Ru=1,3-dimesityl-4,5-
dihydroimidazol-2-ylidene ruthenium dichloride, X=SiR2 or Si(O)R2.
Table 1: Evaluation of the EYRCM strategy.[a]
of a lithium acetylide to a suitable a-alkoxy aldehyde 11
followed by temporary introduction of an allyl group was
envisioned. The planned EYRCM cascade of trienyne 8
would provide rapid access to the fully functional tricycle 6,
which contains the core structure of compounds 1–4, via the
ruthenium alkylidene 7. Deconjugation of the newly formed
diene 6 would set the stage for the final ring-closing meta-
thesis (RCM)/oxidation sequence to complete the synthesis of
the target compounds.[4,5]
An enantioselective route to aldehyde 11 (R = TMS) was
developed based on the Evans copper-catalyzed aldol addi-
tion reaction (Scheme 2).[6] The addition of the strained
ketene hemithioacetal 12[7] to a solution of methyl pyruvate
13 and (R,R)-2,2’-isopropylidene-bis(4-tert-butyl-2-oxazo-
line)-copper(II) triflate (10 mol%) in THFat ꢀ788C gave
the desired O-trimethylsilyl diester 14 (95%, 92% ee;
Entry
Substrate
R
Yield [%][b]
1
2
3
4
5
6
a
b
c
d
e
f
CH2CHMe2
(CH2)2CH CMe2
CH2OPiv
(CH2)4OPiv
(CH2)2CHO
(CH2)4I
76[c]
64
66
=
66
59
52[d]
[a] Uniform reaction conditions (unless noted): G2 (10 mol%), benzene,
658C, [17]=0.02m, 1 h. [b] Yield of the isolated product 20 after
purification. [c] Toluene, 808C, 40 min. [d] t=6 h.
probe the potential generality of this approach in the
synthesis of the B ring. The dienyne substrates 17 were
prepared by allyldimethylsilylation of the corresponding diol
obtained by addition of the lithium acetylide of an appro-
priate alkyne to the key aldehyde 11.[12] Gratifyingly, treat-
ment of the dienynes 17 with the Grubbs second generation
catalyst (G2)[13] afforded the desired corresponding tricyclic
dienes 20 (Table 1).[14]
Scheme 2. Enantioselective synthesis of (+)-aldehyde 11. Reagents
and conditions: a) (R,R)-2,2’-isopropylidene-bis(4-tert-butyl-2-oxazo-
line), Cu(OTf)2, THF, ꢀ788C, 12 h (95%, 92% ee); b) MeZnI,
[Pd2dba3], SPhos, THF, NMP, 658C, 2 h (83%); c) CH2I2, TiCl4, Zn,
PbCl4, CH2Cl2, THF, 238C, 4 h (89%); d) DIBAl-H, Et2O, ꢀ788C;
Dess–Martin periodinane, CH2Cl2, 238C (91%). dba=dibenzylidene-
acetone, Dess–Martin periodinane=1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3-(1H)-one, DIBAl-H=diisobutylaluminumhydride,
NMP=N-methylpyrrolidinone, OTf=trifluoromethane sulfonate,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxy-1,1’-biphenyl,
TMS=trimethylsilyl.
Interestingly, this strategy not only provides the fully
functional and substituted AB-ring system of many illudins,[15]
but it also tolerates sensitive functional groups, such as an
aldehyde or a primary iodide (Table 1, entries 5 and 6,
1
respectively). Monitoring these reactions by H NMR spec-
troscopic analysis in situ ([D6]benzene) revealed excellent
conversion of the starting dienynes into the EYRCM
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Table 2: Implementation of the EYRCM cascade.[a]
products. The yield of the isolated dienes 20 (Table 1) is
diminished as a result of their sensitivity to chromatography
on silica and alumina gel. Attempted protodesilylative trans-
position of the dienes 20 (namely, 6!5 in Scheme 1) to
provide the vinyl group necessary for the final RCM was
plagued by extensive decomposition. Additionally, tricycles
20 were found to be sensitive toward oxidative breakdown;
for example, Tamao oxidation of product 20a (Table 1,
entry 1) gave the corresponding triol in poor yield (27%).[16]
We reasoned that the use of an allyloxydialkylsilyl tether in
the EYRCM cascade (8!6; Scheme 1) would not only
obviate the need for the isolation of dienes 20, but also
permit alternative methods for the synthesis of the key triene
5 (Scheme 1).[17,18]
Entry
1
Substrate
Product
Yield [%]
74–79
23a
25a
The successful synthesis of (ꢀ)-acylfulven and (ꢀ)-
irofulven by using the above EYRCM strategy began with
the rapid assembly of the key trienyne 23a through the
multigram scale coupling of the readily available aldehyde
(+)-11, enyne 21, and allyloxydiethylchlorosilane (Scheme 3).
25b
26
52
2
23b
<20
[a] Reaction conditions: G2 (15 mol%), toluene, 908C, [23]=0.01m,
30 min, then TBAF, AcOH, THF, 238C, 10 min.
isolation of sensitive intermediates, but also led to a marked
increase in the overall efficiency of the process.[19] The key
triol 25a contained all the necessary functional groups and the
carbon skeleton needed for completion of the synthesis.
Importantly, both C3 diastereomers of 23a were equally
effective substrates for this key EYRCM cascade. While this
EYRCM cascade provided the desired triol with a range of
dienyne substrates, a minor EYRCM by-product (26, Table 2,
entry 2) was observed when employing trienyne 23b.[20]
Careful inspection of this transformation revealed that triol
26 was formed by sequential RCM involving the C7 alkene of
23b, EYRCM, and C7 olefin isomerization.[7] Significantly,
the by-product 26 is not observed when the C7–C8 segment is
appropriately masked as in trienyne 23a (also see Table 1,
entry 2). Guided by this insight and using 23a, multigram
quantities of the desired triol 25a (Table 2, entry 1) were
prepared.
Sequential exposure of the key triol 25a to TBSOTf
(1 equiv) followed by triphosgene (1.5 equiv) and tetrabutyl-
ammonium fluoride (TBAF) afforded the desired alcohol 27
(Scheme 4), thus setting the stage for the planned reductive
allylic transposition and RCM steps. The Mitsunobu displace-
ment of alcohol 27 with 2-nitrobenzene-sulfonylhydrazide
(NBSH) in N-methylmorpholine (ꢀ30!238C) gave the
triene 30 (6S/6R = 3:1) through a sigmatropic loss of dini-
trogen from the intermediate monoalkyldiazene 29.[21] The
poor solubility of 27 in optimal solvents for this transforma-
tion and the required high concentration of reagents
(ꢁ 0.3m) led to variable yields of product 30 (35–54%). We
found that use of the more stable acetone hydrazone of
NBSH gave the (isolable) hydrazone 28 through an efficient
Mitsunobu reaction at a more dilute concentration (ꢁ 0.1m in
Scheme 3. Synthesis of the trienyne 23a. For clarity, the major diaste-
reomer of the intermediates is shown. Reagents and conditions: a) 21,
LHMDS, THF, ꢀ78!ꢀ408C; (+)-11; TBAF, AcOH (75%);
=
b) (Et)2Si(Cl)OCH2CH CH2, 2,6-lutidine, CH2Cl2; TMSOTf, ꢀ788C
(83%). LHMDS=lithium hexamethyldisilazide, TBAF=tetrabutylam-
monium fluoride, TMSOTf=trimethylsilyltrifluoromethane sulfonate.
Addition of the corresponding lithium acetylide of enyne 21
(two steps from a-methylcinnamyl alcohol)[7] to (+)-11
provided the diol 22 in 75% yield after desilylation of the
immediate product from silyl migration (C2!C3) as a
mixture of C3 diastereomers (3S/3R ꢁ 6:1), thus favoring
the Felkin–Ahn mode of carbonyl addition (Scheme 3).
Given the final stage oxidation of the hydroxy group at C3
to the corresponding carbonyl group of the target compounds,
both diastereomers were moved forward in the optimized
synthetic sequence without chromatographic separation. The
diastereomeric mixture of diol 22 was subjected to sequential
secondary alcohol allyloxydiethylsilylation followed by tri-
methylsilylation of the tertiary alcohol at C2 to give trienyne
23a (3S/3R = 6:1) in 83% yield in a single step (Scheme 3).[7]
Protection of the tertiary hydroxy group of 22 was found to
increase the stability of these trienynes during purification.
We were delighted to find that the treatment of 23a with
the Grubbs G2 catalyst (15 mol%) in toluene (0.01m) at 908C
afforded the desired dihydrodioxasilepine 24a (ꢂ 90%;
Table 2, entry 1) in 30 min, which was directly converted
into the key triol 25a (3S/3R = 6:1) in 74–79% yield of the
isolated product. Thus, use of the allyloxysilyl tether in the
key EYRCM cascade not only removed the need for the
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Scheme 4. Synthesis of 3 and 4. For clarity, the major diastereomer of the compounds 25a–32 is shown. Reagents and conditions: a) TBSOTf,
=
2,6-lutidine, CH2Cl2, ꢀ788C; triphosgene; TBAF (67%); b) 2-NO2C6H4SO2NHN CMe2, DEAD, Ph3P, THF, 0!238C; TFE, H2O (71%); c) Grubbs
G2 catalyst (15 mol%), PhH, 788C; NaOMe; AcOH; DDQ (30!3, 30%)—or use chloranil to isolate 32 (70% from 30) then IBX, DMSO (83%);
d) H2SO4, CH2Oaq (63%). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DEAD=diethylazadicarboxylate, DMSO=dimethyl sulfoxide,
IBX=ortho-iodoxybenzoic acid, TBSOTf=tert-butyldimethysilyltrifluormethane sulfonate, TFE=2,2,2-trifluoroethanol.
THF) and without requiring sub-zero reaction temperatures
or additives. Importantly, the addition of trifluoroethanol and
water following the Mitsunobu displacement step led to in situ
hydrolysis and fragmentation of 28 to give the desired triene
30 in 71% yield of the isolated product (6S/6R = 3:1) from 27
(Scheme 4).
This synthetic route is expected to provide ready access to
derivatives of 3 and 4 not available through semisynthesis.
Received: May 21, 2006
Published online: August 4, 2006
Keywords: aldol reaction · antitumor agents ·
The G2-catalyzed RCM reaction of triene 30 afforded the
sensitive tricyclic diene carbonate 31 (70%, 6S/6R = 3:1).
Initially, 31 was isolated and converted into the stable diol
fulvene 32 by sequential dehydrogenation with DDQ fol-
lowed by hydrolysis of the cyclic carbonate. We later
discovered that addition of sodium methoxide upon comple-
tion of the RCM reaction, followed by treatment with
chloranil gave the desired diol 32 with greater overall
efficiency (70%). Treatment of 32 with IBX in DMSO
provided the target compound (ꢀ)-acylfulvene (3) in 83%
yield.[3a] Importantly, simple exchange of chloranil with DDQ
provided 3 from 30 without isolation of the intermediates in
30% yield in a sequence that involved RCM, methanolysis,
and two consecutive dehydrogenation reactions. (ꢀ)-Acylful-
vene (3) was converted into (ꢀ)-irofulven (4) based on
conditions described by McMorris and co-workers.[3a] Spec-
troscopic data of our synthetic (ꢀ)-3 and (ꢀ)-4 matched those
in the literature.[7]
The powerful EYRCM and RCM reactions play key roles
in our enantioselective total synthesis of 3 and 4. Only five
intermediates (22, 23a, 25a, 27, and 30) need to be isolated in
the conversion of the readily available aldehyde (+)-11 and
alkyne 21 to (ꢀ)-acylfulvene (3), the direct precursor to the
potent anticancer agent (ꢀ)-irofulven (4). Noteworthy fea-
tures of this chemistry include an aldol addition strategy that
uses new reagent 12 to secure the stereochemistry at C2, a
general EYRCM cascade to introduce the AB-ring system of
these compounds, and the development of new conditions for
the generation of a transient monoalkyldiazene species for
reductive allylic transposition. The application of this chemis-
try to the synthesis of other cytotoxic illudins is underway.
.
asymmetric catalysis · metathesis · total synthesis
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[18] Initial EYRCM reactions to test the new allyloxydiethylsilyl
tether were successfully carried out on dienynes related to those
described in Table 1.
[19] The EYRCM reaction of the C2 hydroxy variants of trienynes
23a–b exclusively gave the desired triols 25a–b, respectively, in
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