Total synthesis of (-)-basiliskamide B

Article abstract of DOI:10.1002/adsc.200700589

The total synthesis of the polyketide antibiotic (-)-basiliskamide B is described. The convergent asymmetric synthesis relies on the use of a diastereoselective ethyl ketone aldol reaction followed by a syn selective reduction of a β-hydroxy ketone and a

Full text of DOI:10.1002/adsc.200700589

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DOI: 10.1002/adsc.200700589
Total Synthesis of (À)-Basiliskamide B
Luiz C. Diasa,* and Caroline da Costa S. GonÅalvesa
a
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971, Campinas, SP, Brazil
Phone: (+55)-19-3521-3097; fax: (+55)-019-3521-3023; e-mail: ldias@iqm.unicamp.br
Received: December 14, 2007; Published online: March 17, 2008
Dedicated to Professor Andreas Pfaltz on the occasion of his 60th anniversary.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The total synthesis of the polyketide anti-
biotic (À)-basiliskamide B is described. The conver-
gent asymmetric synthesis relies on the use of a dia-
stereoselective ethyl ketone aldol reaction followed
by a syn selective reduction of a b-hydroxy ketone
and a Stille cross-coupling between a Z-vinylstan-
siliskamide Ashows toxicity against human diploid fi-
broblast cells in vitro at 100 mgmLÀ1 and amphotericin
B shows toxic effects at 12 mgmLÀ1, destroying the
cells at 100 mgmLÀ1.[1] The relative configurations of
basiliskamides A( 1) and B (2) were proposed by An-
dersen and co-workers and further supported by
means of NMR experiments.[1,3] The relative and ab-
solute configurations for basiliskamides A( 1) and B
(2) have been recently confirmed by their first total
synthesis, completed by the Panek group, as being
7S,8S,9R,10S.[4]
nane and an E-vinyl iodide to establish the (Z,E)-
A
dienamide moiety.
Keywords: aldol reaction; antitumor compounds;
Stille cross-coupling; total synthesis
To provide material for more extensive biological
evaluation, along with access to novel analogues, we
have undertaken the total synthesis of the polyketide
antibiotic basiliskamide B. Basiliskamide B is a pri-
The basiliskamides A( 1) and B (2) are two antifugal mary amide containing four contiguous stereogenic
polyketides isolated from the marine bacterium PNG- centers, a Z,E-diene system and a cinnamoyl ester at
276 from the coast of Papua New Guinea the less hindered oxygen.
(Scheme 1).[1,2] Both 1 and 2 show potent in vitro ac-
Not surprisingly, our first disconnection, summar-
ized in Scheme 2, involved cleavage of the Z,E-diene
À À
portion (C-3 C 4 bond) to give Z-vinylstannane 3
(C-1–C-3 fragment) and E-vinyl iodide 4 (C-4–C-12
fragment) bearing the 4 stereogenic centers of the ba-
siliskamides.[4,5] Of the available options, we speculat-
ed that the C-9 stereocenter could be constructed by
a selective hydroxy ketone reduction in 6, which may
be further dissected in a straightforward manner to
give aldehyde 7 and ethyl ketone 8. The C-1–C-3
fragment 3 is viewed as arising from a,b-acetylenic
ester 5, providing control for the Z geometry of the
Scheme 1. Basiliskamides Aand B.
tivity against Candida albicans and Aspergillus fumi- double bond.
gatus with MIC values of 1.0 and 2.5 mgmLÀ1, respec-
The Z-vinylstannane 3 corresponding to the C-1–C-
tively, for basiliskamide Aand MIC values of 3.1 and
3 fragment was easily prepared using a two-step pro-
5.0 mgmLÀ1 for basiliskamide B.[1] The only difference tocol from commercially available a,b-acetylenic ester
between basiliskamides Aand B is the relative posi-
5 (Scheme 3). Tributylstannylation of 5 under reflux
tion of the cinnamate ester (C-9 in basiliskamide A in benzene gave a mixture of 9-(Z) and 10-(E) vinyl-
and C-7 in basiliskamide B). The in vitro activities of stannanes, which were separated by column chroma-
basiliskamide A( 1) and B (2) are similar to that of tography.[6] Ester-amide exchange, was accomplished
amphotericin B. Basiliskamides Aand B also showed
by treatment of vinylstannane (Z)-9 with Me3Al and
at least 4-fold less cytotoxixity for normal human fi- NH4Cl in toluene at 408C, giving Z-vinylstannane 3
broblast cells when compared to amphotericin B. Ba-
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Luiz C. Dias and Caroline da Costa S. GonÅalves
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Scheme 3. Preparation of vinylstannane 3.
(Scheme 4).[8] Treatment of ester 11 with PMB-acet-
imidate and catalytic amounts of CSAin CH Cl2 gave
AHCTREUNG
2
ester 12 in 98% yield.[9] Ester 12 was then converted
to N-methoxy-N-methylamide 13 (83% yield), which
was reacted with ethyl magnesium bromide to provide
the desired chiral ethyl ketone 8 in 88% yield.[7,8]
It was with some gratification that enolization of
ketone 8 with (c-Hex)2BCl and Et3N in Et2O followed
by addition of aldehyde 7, provided the anti-aldol 6 in
78% isolated yield and 92:8 diastereomeric purity
(Scheme 5).[8,10] Stereoselective reduction of the anti-
aldol 6 under modified Narasakaꢁs conditions gave
the requisite 1,3-syn diol 14 in 65% yield (ds>
95:5).[11]
Scheme 2. Retrosynthetic analysis.
after purification by column chromatography (72%
yield).[7]
In order to determine the relative stereochemistry
of the aldol bond construction and b-hydroxy ketone
Our approach for the preparation of ethyl ketone 8 reduction steps, diol 14 was transformed to the corre-
was initiated with Roche ester 11 following the strat- sponding cyclic acetal (Scheme 6). Treatment of 1,3-
egy developed by Paterson and co-workers diol 14 with DDQ gave benzylidene acetal 15 in 65%
Scheme 4. Preparation of ethyl ketone 8.
Scheme 5. Aldol coupling of ethyl ketone 8.
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Total Synthesis of (À)-Basiliskamide B
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Scheme 6. Determination of the relative stereochemistry for diol 14.
yield.[12] The relative stereochemistry of C-9 and C-10 to give compound 19 in 56% overall yield for the
stereocenters was determined by analysis of the two-step sequence.[14]
1H NMR spectra of the acetal 15. The small coupling
With compound 19 in hand, only three synthetic
constants between Ha-Hc (2.0 Hz) and Hc-Hd operations remained to arrive at an intermediate suit-
(1.1 Hz), together with the small observed value be- able for coupling with Z-vinylstannane 3 (Scheme 7).
tween Hb-Hc (2.0 Hz), unambiguously established the Removal of the TBDPS protecting group at C-5 in 19
À
proposed relative stereochemistry for C-9 C-10 bond gave a primary alcohol, which was followed by TPAP
in 15.
oxidation to give the intermediate aldehyde.[15] All
The stereochemistry of the secondary alcohols at C- that remained was to carry out the necessary Takai
7 and C-9 was determined on the basis of the olefination reaction.[15] Treatment of the unpurified al-
13C NMR analysis of the corresponding 1,3-diol acet- dehyde with CrCl2 and CHI3 proceeded smoothly to
onide 16, prepared in 80% yield from diol 14 produce E-vinyl iodide 4 (E,Z=88:12), corresponding
(Scheme 4). 13C NMR resonances at 19.7, 26.8, and to the C-4–C-12 segment of basiliskamide B in 63%
97.7 ppm are characteristic of a syn acetonide.[13]
Asequence of PMB removal from 16 with DDQ
overall yield for the two-step sequence.[16]
With synthesis of the requisite C-1–C-3 and C-4–C-
(90% yield), followed by protection of the primary 11 fragments in hand, their coupling was undertaken.
OH function in 17 with Tf2O in the presence of 2,6-lu- This was done by using Stille cross-coupling condi-
tidine provided triflate 18 (Scheme 7).[14] The next tions (Scheme 8).[17,18] Treatment of a solution of E-vi-
step involved coupling of triflate 18 with MeLi/CuCN nylstannane 3 and E-vinyl iodide 4 in DMF with a
Scheme 7. Synthesis of (E)-vinyl iodide 4.
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Luiz C. Dias and Caroline da Costa S. GonÅalves
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Scheme 8. Total synthesis of basiliskamide B.
and stirring continued for 15 min before aging in the freezer
(À208C, 18 h). The reaction mixture was then partioned be-
tween Et2O (3”10 mL) and pH 7 buffer solution (20 mL),
the organic extracts were concentrated under vacuum to
give an oil, which was taken up in methanol (29 mL) and
pH 7 buffer solution (29 mL) and stirred at 08C. Hydrogen
peroxide (30% aqueous, 8,6 mL) was added dropwise. After
stirring for 2 h at 08C the mixture was diluted with H2O and
extracted with CH2Cl2. The combined extracts were dried
over anhydrous MgSO4, filtered and concentrated under
vacuum. Purification by flash chromatography (10%
EtOAc/hexanes) afforded 6; yield: 2.5 g (4.5 mmol, 78%;
ds=92:08).
catalytic amount of Pd(MeCN)2Cl2 at 258C afforded
A
20 in 69% yield after purification by silica gel column
chromatography.[17,18]
Removal of the isopropylidene acetal with 80%
AcOH followed by selective acylation of the less hin-
dered oxygen with E-cinnamoyl chloride gave basil-
A
spectroscopic and physical data [1H and 13C NMR,
IR, [a]D, Rf] were identical in all respects with the
published data.[1,4] The 12-step sequence starting from
8 proceeded in 6% overall yield and is amenable to a
multigram scale-up.
The total synthesis of basiliskamide B has been
completed. Notable features of this approach include
convergence, a boron enolate-mediated aldol reaction
to set up the desired C-8 and C-9 stereocenters and a
Stille cross-coupling between a Z-vinylstannane and a
vinyl iodide. The synthesis required 12 steps (longest
linear sequence) from ethyl ketone 8 and produced
the desired product in 6% overall yield. This ap-
proach compares very well with a previously pub-
lished route. As a result, the route to (À)-basilisk-
tert-Butyl-(2-{(4S,5S,6R)-6-[(S)-sec-butyl]-2,2,5-
trimethyl-1,3-dioxan-4-yl}ethoxy)diphenylsilane (19)
G
Asolution of alcohol 17 (56 mg, 0.13 mmol) in CH2Cl2
(2.6 mL) was treated with 2.6-lutidine (0.045 mL,
0.39 mmol) and cooled to À788C. The solution was treated
with triflic anhydride (0.032 mL, 0.195 mmol) and stirred at
À788C for 30 min. The reaction was then quenched with sa-
turated aqueous NaHCO3 (2.7 mL). The aqueous phase was
extracted with CH2Cl2, the combined organic extracts were
dried over MgSO4, filtered and concentrated under vacuum,
to provide triflate 18. Methyllithium (1.3 mmol, 1.0 mL of a
1M solution in ether) and CuCN (0.06 g, 0.67 mmol) were
stirred in dry THF (1 mL) at À788C for 30 min. Asolution
of the crude triflate 18 (0.13 mmol) in dry THF (0.5 mL)
was added, the mixture stirred at À788C for 1.5 h, and at
room temperature for 1 h. After cooling to 08C, aqueous sa-
turated NH4Cl solution was added, the layers were separat-
ed, and the organic layer was washed with brine, dried over
MgSO4 and concentrated. The residue was purified by silica
gel column chromatography (5% EtOAc/hexanes) to give
compound 19; yield: 34 mg (0.073 mmol).
U
cable for the preparation of additional novel structur-
al analogues. Further optimization of the synthesis as
well as application of this strategy to the synthesis of
basiliskamide Aand analogues is underway and the
results will be described in a full accout of this work.
Experimental Section
A
phenylsilyloxy)-5-hydroxy-2,4-dimethylheptan-3-one
(6)
A
trimethyl-1,3-dioxan-4-yl}hexa-2,4-dienamide (20)
To a stirred solution of dicyclohexylboron chloride (1.9 mL,
8.6 mmol) in Et2O (8.2 mL) at 08C was added Et3N (1.3 mL,
9.15 mmol). Ketone (S)-8 (1.4 g, 5.7 mmol) in Et2O (4 mL)
was added via cannula and the reaction mixture was stirred
for 1 h at 08C before cooling to À788C. Asolution of alde-
hyde 7 (11.4 mmol) in Et2O (2 mL) was added via cannula
Vinyl iodide 4 (0.17 g, 0.48 mmol) was treated with a solu-
tion of vinylstannane 3 (0.243 g, 0.672 mmol) in DMF
(8.2 mL). Dichloro(bis)acetonitrilepalladium(II) (6.2 mg,
0.024 mmol) in DMF (1.7 mL) was then added. The reaction
was protected from light and stirred at ambient temperature
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Total Synthesis of (À)-Basiliskamide B
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for 18 h. The mixture was diluted with EtOAc (5 mL) and
washed with water. The combined aqueous layers were ex-
tracted with EtOAc and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concen-
trated under vacuum. Purification by flash column chroma-
tography (50% EtOAc/hexanes) afforded diene 20; yield:
0.097 g (0.33 mmol, 69%).
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Basiliskamide B (2)
The diene 20 was dissolved in 80% acetic acid. The reaction
was protected from light and warmed to 608C for 3 h. The
reaction was then allowed to reach ambient temperature
and adjusted to pH 7.0 with NH4OH. The aqueous phase
was extracted with EtOAc (2”10 mL). The combined or-
ganic extracts were dried over MgSO4, filtered and concen-
trated under reduced pressure. Asolution of the corre-
sponding crude diol (0.14 mmol) in CH2Cl2 (3 mL) was
treated with Et3N (0.08 mL, 0.6 mmol) and DMAP (1.7 mg,
0.014 mmol) and cooled to 08C. The solution was treated
with of (E)-cinnamoyl chloride (46 mg, 0.28 mmol). The re-
action was protected from light and allowed to reach ambi-
ent temperature for 48 h. The reaction was then quenched
with water. The aqueous phase was extracted with CH2Cl2.
Purification by flash column chromatography (80% EtOAc/
CH2Cl2) afforded basiliskamide 2; yield: 36 mg (0.094 mmol,
67%).
Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP and CNPq
(Brazil) for financial support. We also thank Prof. Carol H.
Collins, from IQ-UNICAMP, for helpful suggestions about
English grammar and style and Leonardo JosØ Steil for help-
ful comments and suggestions.
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