Total synthesis and structural elucidation of (-)-delactonmycin

Article abstract of DOI:10.1002/anie.200351347

The key steps in the total synthesis of delactonmycin (1) involved a Wittig olefination, a Negishi coupling, and an aldol reaction. The polyketide, which was isolated from Streptomyces sp., displays potent inhibitory activity of the nucleocytoplasmic tran

Full text of DOI:10.1002/anie.200351347

Angewandte
Chemie
Total Synthesis
configurations were established by spectroscopic methods
and total synthesis.[4,5]
Total Synthesis and Structural Elucidation of
Our interest in the synthesis of delactonmycin stemmed
from its greater structural simplicity relative to that of other
members of this class, which renders it an interesting model
compound for structure–activity studies.[6] Additionally, the
implementation of a successful approach to 1 would pave the
way to the total synthesis of other polyketides whose structures
have not yet been confirmed by total synthesis. Herein, we
disclose our approach and results toward the first total synthesis
and structural elucidation of (ꢀ)-delactonmycin (1, Scheme 1).
(ꢀ)-Delactonmycin**
Ivan R. CorrÞa, Jr. and Ronaldo A. Pilli*
Dedicated to Professor Albert J. Kascheres
on the occasion of his 60th birthday
ꢀ
In recent years, a number of highly cytotoxic polyketides with
similar chemical structures, including the leptomycins, kazu-
samycins, anguinomycins, and leptolstatins, were isolated as
secondary metabolites from Streptomyces strains.[1] In 1997,
Wang et al. identified two novel polyketides, named delac-
tonmycin and dilactonmycin, in the extracts from Streptomy-
ces strain A92-308902 with very potent inhibitory activity of
the nucleo-cytoplasmic translocation of the HIV-1 regulatory
protein Rev.[2] The planar structure of delactonmycin was
established by spectroscopic methods, but its relative as well
as its absolute configuration remained unknown. In our
synthetic studies towards the elucidation of the relative
configuration of delactonmycin (1), we were led to presume
that it is the same as that of leptomycin B and callystatin A—
a structurally related polyketide isolated from the marine
sponge Callyspongia truncata[3]—whose relative and absolute
The installation of the C4 C5 bond through E-selective
Wittig olefination between aldehyde 2 and phosphonium
bromide 3 was left to a late stage of the synthesis in our
retrosynthetic analysis. In turn, 3 could be obtained from a
Wittig olefination of aldehyde 4 with ethyl triphenylphos-
phoranylidene propionate. It was envisaged that aldehyde 4
could be prepared from the syn aldol adduct obtained from
the reaction between ethyl ketone 5 and g,d-unsaturated
aldehyde 6. The fragments 2, 5, and 6 are available from the
methyl (R)- and (S)-3-hydroxy-2-methylpropionates, which
we have already used in the total synthesis of the aglycon of
the macrolide antibiotic 10-deoxymethymycin.[7]
Aldehyde 6 was readily obtained through the sequence
shown in Scheme 2. A palladium-catalyzed cross-coupling
reaction between the chiral zinc homoenolate 8[8,9] and cis-2-
bromo-2-butene (both commercially available) led to the
formation of 11, which was carefully
reduced with diisobutylaluminum hy-
dride at ꢀ908C to afford 6 in 86%
overall yield. Ketone 5 was prepared
as described by Paterson et al.[10] in
three steps and 57% overall yield.
Conversion of (R)-7 into the Weinreb
amide 9 was followed by protection as
its p-methoxybenzyl ether 10. Subse-
quent addition of ethyl magnesium
bromide provided ethyl ketone 5.
Treatment of 5 with stannous triflate
and Et3N at ꢀ788C in CH2Cl2 gen-
erated the corresponding Z enolate,
which reacted with the g,d-unsatu-
rated aldehyde 6 to afford the syn
aldol adduct 12 in 75% yield (92% based on consumed
starting material) and 96:4 diastereomeric ratio. The stereo-
chemical control observed in the formation of 12 is ultimately
derived from the tin(ii) enolate of ketone 5.[11]
[*] Prof. R. A. Pilli, I. R. CorrÞa, Jr.
Instituto de Química
Universidade Estadual de Campinas – UNICAMP
Campinas, SP – C.P. 6154, 13084-971 (Brazil)
Fax: (+55)19-3788-3023
As depicted in Scheme 1, we planned to postpone the
installation of the ketone at C9 to a late stage in our synthetic
sequence in order to carry out the requisite functional-group
manipulation and chain extension. The stereoselective for-
mation of 1,3-diol 13 was explored using metal-chelation
control and intermolecular hydride transfer. The best 1,3-syn
diastereofacial selectivity (d.r. 95:5) was achieved in the
reduction of b-hydroxyketone 12 with DIBAL-H at ꢀ788C
(Scheme 3).[12] The diastereomeric ratio was determined by
GC/MS analysis of acetonide 14.
E-mail: pilli@iqm.unicamp.br
[**] This work was supported by the Fundaç¼o de Amparo à Pesquisa do
Estado de S¼o Paulo (FAPESP) and the Conselho Nacional para o
Desenvolvimento Científico e Tecnológico (CNPq). We are grateful
to Dr. Y. Wang, Novartis Pharma for providing us with 1H and
13C NMR spectra of natural delactonmycin and to Prof. Dr. A.
de Meijere, Georg-August Universität, Göttingen for critical reading
of the manuscript.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author (spectro-
scopic and analytical data for compounds (ꢀ)-13,(ꢀ)-20, and (ꢀ)-1,
including a CD curve for (ꢀ)-1).
Having secured the diastereoselective preparation of syn-
diol 13, we proceeded to its oxidative conversion with DDQ
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DOI: 10.1002/anie.200351347
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Communications
into the corresponding p-methoxyben-
zylidene acetal 15 under anhydrous
conditions[14] and protection of the
secondary hydroxy group at C11 as
the tert-butyldimethylsilyl ether 16
(Scheme 4). Regioselective cleavage
of the PMP acetal[14] efficiently pro-
vided the primary alcohol 17, and its
subsequent oxidation with Dess–
Martin periodinane led to the aldehyde
4. An E-selective Wittig olefination of
¼
4 with Ph3P C(Me)CO2Et in toluene
afforded a,b-unsaturated ester 18 as
the only product. Reduction of the
ester moiety in 18 with DIBAL-H
provided the allylic alcohol 19, which
was converted with CBr4 and PPh3 in
the presence of 2,6-lutidine into the
corresponding bromide 20 in 31%
overall yield from b-hydroxyketone
12. The all-syn configuration in bro-
mide 20 was established after analysis
of the 1H and 13C NMR spectra and
NOESY experiments carried out with
acetonide 14 and p-methoxybenzyl-
idene acetal 15 (Figure 1).
Scheme 1. Retrosynthetic analysis of the putative stereostructure of delactonmycin.
At this stage, a final Wittig olefina-
tion was used to join the known
aldehyde 2[15] and the tributylphospho-
nium salt derived from allylic bromide
20 (Scheme 5). The coupling was car-
ried out under the conditions described
by Tamura et al.[16] to provide 21 (d.r.
E/Z 8:1). Next we sought the chemo-
selective deprotection of the PMB
ethers at C1 and C9. Attempts to
deprotect 21 with DDQ invariably
gave complex reaction mixtures.[17] In
fact, closer inspection of the literature
revealed that several authors have
been unable to remove methoxybenzyl
groups in the presence of conjugated
dienes.[18] Several alternative methods
(hydrogenolysis, reduction with dis-
solved metal, as well as Lewis acid
conditions)[19,20] were investigated for
model compounds without much suc-
cess. After extensive experimentation,
the PMB group of 21 was selectively
cleaved with TFA in CH2Cl2 to give
diol 22, albeit in low yield.[21]
The synthesis was completed with
the double oxidation of 22 (oxidation
with Dess–Martin periodinane[22] fol-
lowed by Pinnick oxidation to the
carboxylic acid[23]) and deprotection
of the secondary TBS ether with HF/
pyridine complex in THF. The spectro-
scopic data of the synthetic (ꢀ)-delac-
Scheme 2. Synthesis of 12. Reagents and conditions: a) MeONHMe·HCl, AlMe3, CH2Cl2,
¼
08C!RT, 18 h; b) PMBOC( NH)CCl3, CSA, CH2Cl2, room temperature, 18 h; c) EtMgBr, Et2O,
08C, 1 h; d) cis-2-bromo-2-butene, [PdCl2(PPh3)2], THF, 08C!RT, 24 h; e) DIBAL-H, hexane,
ꢀ908C, 1 h; f) Sn(OTf)2, Et3N, CH2Cl2, ꢀ788C; then 5, 2 h; then 6, ꢀ788C, 2 h and ꢀ508C,
1 h. PMB=p-methoxybenzyl, CSA=camphor-10-sulfonic acid, Tf=trifluoromethanesulfonyl.
DIBAL-H=diisobutylaluminium hydride.
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Angewandte
Chemie
tonmycin (1) (IR, HRMS,
1H and 13C NMR)
nicely
matched those reported for the
natural product,[2] thus allowing
us to confirm their identity and
unambiguously establish its rel-
ative configuration. Unfortu-
nately, the lack of a sample of
natural delactonmycin (1) or its
chiroptical data precluded the
determination of its absolute
configuration at this point. Stud-
ies directed towards the total
synthesis of other members of
Scheme 3. Synthesis of 13 and determination of its d.r. Reagents and conditions: a) DIBAL-H, THF,
ꢀ788C, 3 h; b) Me2C(OMe)2, PTSA, CH2Cl2, room temperature, 12 h. PTSA=p-toluenesulfonic acid.
Scheme 4. Synthesis of 20. Reagents and conditions: a) DDQ, molecular sieves (3 Š), CH2Cl2, room temperature, 30 min; b) TBSOTf, 2,6-lutidine,
¼
08C!RT, 1 h; c) DIBAL-H, CH2Cl2, 08C!RT, 2 h; d) Dess–Martin periodinane, CH2Cl2/H2O, room temperature, 15 min; e) Ph3P C(Me)CO2Et, tol-
uene, room temperature, 36 h; f) DIBAL-H, CH2Cl2, ꢀ788C, 1 h; g) CBr4, PPh3, 2,6-lutidine, CH3CN, room temperature, 15 min. DDQ=2,3-
dichloro-5,6-dicyanobenzoquinone, TBS=tert-butyldimethylsilyl, PMP=p-methoxyphenyl.
this family of polyketides are
now underway in our laboratory
and will be reported in due
course.
Received: March 7, 2003 [Z51347]
Keywords: antiviral agents ·
.
natural products · structure
elucidation · total synthesis ·
Wittig reactions
Figure 1. Configurational assignment of acetonide 14 and p-methoxybenzylidene acetal 15.
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Communications
Scheme 5. Completion of 1. Reagents and conditions: a) PBu3, MeCN, room temperature, 2 h; b) 2, KOtBu, toluene, 08C, 2 h; c) TFA, CH2Cl2,
room temperature, 20 min; d) Dess–Martin periodinane, CH2Cl2/H2O, room temperature, 30 min; e) NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH/H2O, room temperature, 2 h; f) HF·pyridine, THF, room temperature, 64 h. TFA=trifluoroacetic acid.
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