Total synthesis of the potent antifungal agents bengazole C and E

Article abstract of DOI:10.1135/cccc2009016

The bengazoles are marine natural products with unique structure, containing two oxazole rings flanking a single carbon. They show very potent antifungal activity. The total syntheses of bengazole C and E are described following a convergent route which involves diastereoselective cycloaddition of an appropriately substituted nitrile oxide with a butane-1,2-diacetal-protected alkenediol as the key step.

Full text of DOI:10.1135/cccc2009016

Potent Antifungal Agents Bengazole C and E
887
TOTAL SYNTHESIS OF THE POTENT ANTIFUNGAL AGENTS
BENGAZOLE C AND E
1
2,
Álvaro ENRÍQUEZ-GARCÍA and Steven V. LEY *
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK;
1
2
e-mail: ae285@cam.ac.uk, svl1000@cam.ac.uk
Received February 20, 2009
Accepted April 3, 2009
Publish ed on lin e May 14, 2009
Dedicated to Dr. Alfred Bader on the occasion of his 85th birthday.
Th e ben gazoles are m arin e n atural products with un ique structure, con tain in g two oxazole
rin gs flan kin g a sin gle carbon . Th ey sh ow very poten t an tifun gal activity. Th e total syn -
th eses of ben gazole C an d E are described followin g a con vergen t route wh ich in volves
diastereoselective cycloaddition of an appropriately substituted n itrile oxide with a butan e-
1,2-diacetal-protected alken ediol as th e key step.
Keyw ord s: An tifun gal agen ts; Cycloaddition ; Oxazoles; Natural products; Total syn th esis;
Ben gazoles; Marin e com poun ds.
Th e ben gazoles are poten t an tifun gal com poun ds isolated from various m a-
rin e sources1. To date 22 m em bers of th is fam ily are kn own an d th eir struc-
tures an d biological profiles h ave been well docum en ted2. Total syn th eses
of ben gazole A an d B 3 togeth er with a deacylated derivative h ave also been
reported4. Neverth eless, th e syn th esis in th is area h as been com plicated by
th e lability an d ease of epim erisation of th e C-10 stereogen ic cen tre located
between th e oxazole rin gs. For exam ple, a previous syn th esis of ben gazole A
an d its C-10 epim er was previously described by Molin ski et al. as an in -
separable m ixture of diastereoisom eres5. Durin g our work on ben gazoles A
an d B we defin ed a route th at allowed con trol on th is im portan t stereo-
gen ic cen tre an d provided access to key buildin g blocks for an alogue prepa-
ration . Here we describe th e exten sion an d furth er optim isation of th is
process to syn th esise two addition al m em bers of th e series ben gazole C (1)
an d ben gazole E (2) (Ch art 1).
Wh ile th e n ew syn th esis reported h ere closely follows our previous stud-
ies, we h ave n ow optim ised a large n um ber of th e steps with th e aim of pro-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 887–900
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009016

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Enríquez-García, Ley:
CHART 1
vidin g larger quan tities of m aterial. In very gen eral term s th e syn th esis
requires efficien t preparation of two im portan t fragm en ts n am ely th e
oxazole aldeh yde 3 an d th e butan e-1,2-diacetal (BDA)-protected pen t-
4-en e-2,3-diol (4). Followin g elaboration of 3 to a suitable precursor 5
for n itrile oxide gen eration an d subsequen t stereoselective couplin g of
th is with 4 rapidly assem bles th e carbon con tain in g backbon e of all th e
ben gazole n atural products (Sch em e 1).
SCHEME 1
Oxazole-5-carbaldeh yde (3) can be m ost easily obtain ed from eth yl gly-
oxylate (6) th rough in itial reaction with tosyl m eth ylisocyan ide (TosMIC)
usin g DBU as a base to afford th e ester 7. Th is can be reduced on scale, us-
in g sodium boroh ydride in th e presen ce of lith ium ch loride in a m ixture of
THF/MeOH at 0 °C to provide th e alcoh ol 8. Th e product can be stored or
SCHEME 2
Syn th esis of oxazole-5-carbaldeh yde (3)
Reagen ts an d con dition s: (a) TosMIC, DBU, CH2Cl2, 0 °C, 92%; (b) NaBH4, LiCl, THF, MeOH,
0 °C to r.t., 71%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, –78 to 0 °C, 64%
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Potent Antifungal Agents Bengazole C and E
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con verted by oxidation un der Swern con dition s to provide th e aldeh yde 3
(Sch em e 2). Th e n ew optim ised con dition s give 3 in 42% overall yield
wh ich com pares favourably with our previous route (29%).
Next th e BDA alken ediol 4 was obtain ed from th e previously syn th esised
buildin g block 9 via direct reduction with DIBAL-H in CH2Cl2 to afford an
in term ediate aldeh yde wh ich un dergoes essen tially a quan titative con version
to th e protected alken ediol 4 usin g a Wittig couplin g process (Sch em e 3).
Again th is route proceeds with a 7% im provem en t over our previous route.
SCHEME 3
Syn th esis of BDA alken ediol 4
Reagen ts an d con dition s: (a) DIBAL-H, CH2Cl2, 78 °C, 93%; (b) NaBH4, LiCl, THF, MeOH, 0 °C
to r.t., 71%; (c) MePPh 3Br, KHMDS, Et2O, –78 °C to r.t., 99%
For th e n ext steps of th e syn th esis again several im provem en ts to th e
yield were realised upon scalin g-up of th e reaction process. Firstly upon
treatm en t of th e aldeh yde 3 with trim eth ylsilyl cyan ide th e cyan oh ydrin
10 can be obtain ed in an excellen t 98% yield. Th is can be furth er tran s-
form ed in two steps to th e tert-butyldiph en ylsilyl-protected ester 11 in 99%
yield on batch es over 8 g. Followin g ester h ydrolysis an d couplin g with
L-Ser-OMe a readily separated m ixture of diastereom eric products 12 an d 13
was obtain ed (Sch em e 4).
SCHEME 4
Syn th esis of am ides 12 an d 13
Reagen ts an d con dition s: (a) TMSCN, Et3N, CH2Cl2, 0 °C, th en 2 M HCl aqueous, 98%; (b) 2 M
HCl in MeOH, reflux to r.t., 89%; (c) TBDPSCl, Et3N, DMAP, DMF, r.t., 99%; (d) 1. LiOH, H2O,
THF, 0 °C to r.t.; 2. TBTU, H-L-Ser-OMe, i-Pr2NEt, DMF
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Th e un wan ted diastereoisom er 13 is n ot wasted as th is can be used for
an alogue program m es an d by in version of th e C-10 stereogen ic cen tre, to
oth er ben gazoles.
Com poun d 12 was th en processed followin g our previously establish ed
route an d progresses un even tfully to th e alcoh ol 14 in th e yields an d con di-
tion s sh own in Sch em e 5.
SCHEME 5
Syn th esis of alcoh ol 14
Reagen ts an d con dition s: (a) TBSCl, im idazole, DMAP, DMF, r.t., 92%; (b) NaBH4, LiCl, THF,
MeOH, 0 °C to r.t., 80%; (c) Dess–Martin periodin an e, NaHCO3, CH2Cl2, 0 °C; (d) PPh 3,
C2Br2Cl4, CH2Cl2, 2,6-di-tert-butylpyridin e, 0 °C, th en Et3N, MeCN, 0 °C to r.t., 89% over
2 steps, >98% ee; (e) PPTS, MeOH, r.t., 93%
Sim ilarly th is alcoh ol 14 serves as th e precursor for th e oxim e 15 wh ich
upon treatm en t with N-ch lorosuccin im ide an d th en Cs2CO3 provides th e
correspon din g n itrile oxide wh ich un dergoes stereoselective cycloaddition
with 4 to give th e readily separated diastereoisom ers 16 an d 17 in 7:2 ratio
(Sch em e 6). Th ese steps are reproducible an d m im ic our previously reported
yields an d observation s.
SCHEME 6
Syn th esis of th e ben gazole backbon e 16
Reagen ts an d con dition s: (a) Dess–Martin periodin an e, NaHCO3, CH2Cl2, 0 °C; (b) NH2OH·
HCl, K2CO3, MeOH, H2O, r.t., 93% over 2 steps; (c) alken ediol 4, Cs2CO3, DME, r.t., 77%
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Potent Antifungal Agents Bengazole C and E
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Next we were able to cleave th e N–O bon d in 16 an d affect a h ydrolysis
to give keton e 17 in 71% yield wh ich also con stitutes a 10% im provem en t
over our origin al studies. However, th is reaction is still capricious an d we
are still seekin g altern ative solution s. Neverth eless it was suitable to prog-
ress to th e n ext an d fin al steps of th e syn th esis towards th e two ben gazoles
C an d E. Diastereoselective reduction of β-h ydroxy keton e 17 gave alcoh ol
18 after acetal protection usin g 2,2-dim eth oxybutan e an d cleavage of th e
silyl eth er (Sch em e 7).
SCHEME 7
Syn th esis of alcoh ol 18
Reagen ts an d con dition s: (a) Ran ey n ickel, H2, B(OH)3, EtOH, H2O, r.t., 71%; (b) Et2BOMe,
NaBH4, THF, –78 °C (dr 14:1); (c) 2,2-dim eth oxypropan e, TsOH, 89% over 2 steps; (d) TBAF,
THF, 0 °C, 99%
To com plete th e total syn th esis, alcoh ol 18 was treated with th e corre-
spon din g acid ch loride to afford th e im m ediate ben gazole precursors.
Cleavage of both aceton ide an d BDA groups un der acidic con dition s af-
forded ben gazole C (1) an d ben gazole E (2) wh ose spectral data agreed with
th e literature values1a,5 (Sch em e 8).
SCHEME 8
Syn th esis of ben gazole C (1) an d ben gazole E (2)
Reagen ts an d con dition s: (a) RCOCl, Et3N, CH2Cl2, 0 °C, R = -(CH2)11CH3 88% an d R =
-(CH2)13CH3 75%; (b) TFA, H2O, r.t., R = -(CH2)11CH3 91% an d R = -(CH2)13CH3 69%
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In sum m ary, we h ave com pleted a stereocon trolled total syn th esis of
ben gazole C an d E by an optim ised syn th esis route wh ich poten tially could
also provide access to m an y oth er m em bers of th e ben gazole fam ily an d
oth er an alogue com pon en ts.
EXPERIMENTAL
Gen eral
Solven ts were purified by filtration on dryin g colum n s usin g Solvtek system . An h ydrous
N,N-dim eth ylform am ide, dim eth oxyeth an e an d pyridin e were used as supplied. Trieth yl-
am in e an d diisopropyleth ylam in e were distilled from calcium h ydride an d stored over 4Å
m olecular sieves. All n on -aqueous reaction s were perform ed un der an atm osph ere of argon
an d carried out usin g oven -dried glassware. Reagen ts were used as supplied or purified usin g
stan dard procedures as n ecessary.
Flash colum n ch rom atograph y was carried out usin g silica gel (Merck or Brecklan d
(230–400 m esh )) un der pressure. Collection was m on itored by UV absorption at 220 an d
254 n m . An alytical th in layer ch rom atograph y (TLC) was perform ed usin g precoated glass-
backed plates an d visualised by ultraviolet radiation (254 n m ) an d/or by oxidative stain in g
with aqueous acidic am m on ium m olybdate(VII) solution .
Optical rotation s were m easured usin g a Perkin –Elm er Polarim eter 343 over a path len gth of
10 cm with th e sam ple tem perature m ain tain ed at 25 °C. [α ]2D5 values are given in 10–1 cm 2 g–1
,
con cen tration (c) in g per 100 m l. Meltin g poin ts were perform ed on a Reich ert h ot stage
apparatus an d are un corrected. In frared spectra were recorded as th in film s on a Perkin –
Elm er Spectrum On e FT-IR spectrom eter. On ly selected absorban ces (νm ax in cm –1) are re-
ported an d peak sh ape in dicated (s, stron g; br, broad; w, weak) followed by assign m en t.
1H NMR spectra were recorded at 25 °C (un less stated oth erwise) on Bruker DPX-400, Bruker
DRX-500 (VT or Cryoprobe) an d Bruker DPX-600 spectrom eters an d are reported as follows:
ch em ical sh ift δ in ppm (n um ber of proton s, m ultiplicity, couplin g con stan t J in Hz, assign -
m en t). Residual protic solven t was used as th e in tern al referen ce (CHCl3 δH 7.27 ppm ).
13C NMR spectra were recorded at 100, 125 an d 150 MHz on Bruker DPX-400, Bruker
DRX-500 Cryoprobe an d Bruker DPX-600 spectrom eters, respectively. Th e reson an ce CDCl3
(δC 77.0 ppm , t) was used as th e in tern al referen ce. Assign m en ts were m ade usin g a ran ge of
NMR experim en ts an d th ese assign m en ts are m ade accordin g to th e n atural product n um -
berin g of ben gazole A 1 to allow direct com parison of NMR data between com poun ds. Mass
spectra were recorded on Waters LCT Prem ier, Bruker Daltron ics Bioapex II or Kratos Con cept
spectrom eters at th e Departm en t of Ch em istry, Un iversity of Cam bridge. Ch iral HPLC was
perform ed on an Agilen t 1100 series HPLC usin g Ch iralcel colum n s, HPLC grade solven ts
an d UV detection (λ = 215 an d 254 n m ) at room tem perature. Ch iral SFC (supercritical fluid
ch rom atograph y) was perform ed on a Berger Min igram , usin g a Ch iralcel AS colum n with
7% m eth an ol/carbon dioxide, 3 m l m in –1 at 100 bar an d UV detection (λ = 210 n m ) at 35 °C.
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(2S,3R,5S,6S)-5,6-Dim eth oxy-3,5,6-trim eth yl-[1,4]dioxan e-2-carbaldeh yde
DIBAL-H (1 M in h exan es, 7.46 m l, 7.46 m m ol) was added dropwise to a solution of ester 9
(1.30 g, 5.30 m m ol) in CH2Cl2 (43 m l) at –78 °C, via syrin ge pum p over 2 h 30 m in . Th e
m ixture was stirred for furth er 1 h 30 m in , th en m eth an ol (1.24 m l) was added dropwise
at –78 °C. Th e reaction m ixture was warm ed to room tem perature, th en saturated aqueous
Roch elle’s salt (12 m l) an d eth er (10 m l) were added an d th e m ixture stirred overn igh t.
Water (12 m l) was added an d th e layers separated. Th e aqueous layer was extracted with
eth er (2–20 m l) an d th e com bin ed organ ic extracts were dried (MgSO4) an d th e solven t re-
m oved in vacuo. Purification by flash ch rom atograph y (10 to 20 to 40% eth yl acetate/petrol
eth er, 30–40 °C) afforded title com poun d as a wh ite solid (1.08 g, 93%); m .p. 72–74 °C; RF
0.63 (50% eth yl acetate/petrol eth er, 30–40 °C); [α ]2D5 +107.2 (c 1.6, CHCl3). IR: 2951, 1738
(C=O), 1120 s, 1036, 908 s, 727 s. 1H NMR (400 MHz, CDCl3): 9.64 (1 H, s, 4-H), 3.87 (2 H,
m , 2-H an d 3-H), 3.29 (3 H, s, OCH3), 3.27 (3 H, s, OCH3), 1.38 (3 H, s, BDA CH3), 1.30
(3 H, s, BDA CH3), 1.26 (3 H, d, J = 5.8, 1-H3). 13C NMR (100 MHz, CDCl3): 199.8 (C-4), 98.9
(BDA quatern ary C), 98.6 (BDA quatern ary C), 77.7 (C-3), 63.1 (C-2), 48.2 (OCH3), 48.1
(OCH3), 17.7 (BDA CH3), 17.3 (BDA CH3), 16.4 (C-1). MS (ESI+), m/z: foun d 241.1048, [M +
Na]+ C10H18NaO5 requires 241.1046.
Oxazol-5-ylcarboxylic Acid Eth yl Ester (7)
TosMIC (73.2 g, 375 m m ol) was dissolved in dry CH2Cl2 (700 m l) un der an argon atm o-
sph ere. At 0 °C, DBU (56.1 m l, 375 m m oL) an d a solution of eth yl glyoxylate (10) (99.54 m l,
487 m m ol, 50% in toluen e) in dry CH2Cl2 (345 m l) were added sim ultan eously over a pe-
riod of 2.5 h . Furth er DBU (28.1 m l, 187 m m ol) was added an d th e dark solution was al-
lowed to stir for furth er 30 m in . Th e organ ic layer was th en wash ed with aqueous 1.5 M HCl
(300 m l) an d saturated aqueous Na2CO3 (300 m l), dried (MgSO4) an d evaporated un der re-
duced pressure. Th e crude m aterial was purified by flash ch rom atograph y (eluen t: 10 to 25
to 33% dieth yl eth er/petrol eth er, 30–40 °C) to give th e desired com poun d as a colourless
liquid (48.7 g, 92%). 1H NMR (400 MHz, CDCl3): 7.99 (1 H, s, Ar-H), 7.74 (1 H, s, Ar-H),
4.37 (2 H, q, J = 7.2, CH2), 1.36 (3 H, t, J = 7.1, CH3). 13C NMR (100 MHz, CDCl3): 157.9,
153.6, 143.3, 133.6, 62.0, 14.6. Th e an alytical data are con sisten t with th ose reported in th e
literature6.
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Enríquez-García, Ley:
Oxazol-5-ylm eth yl Alcoh ol (8)
Ester 7 (14.0 g, 100.0 m m ol) was dissolved in a m ixture of dry THF (180 m l) an d dry MeOH
(380 m l) un der an argon atm osph ere. Lith ium ch loride (25.5 g, 600.0 m m ol) was added an d
th e suspen sion cooled to –10 °C. Subsequen tly, sodium boroh ydride (22.7 g, 600 m m ol) was
added in sm all portion s over a period of 20 m in un der vigorous stirrin g an d th e tem perature
kept below –5 °C. After stirrin g for furth er 60 m in at –5 °C, th e suspen sion was slowly
warm ed to room tem perature. If n ecessary, th e tem perature was adjusted with a water bath
to 20–25 °C (caution: due to the strong H2 evolution at room temperature, a thermal runaway is
possible). Th e suspen sion was stirred for 21 h at room tem perature an d th en quen ch ed with
water (1 l). Sodium potassium tartrate (180 g) was added an d th e solution th en extracted
with eth yl acetate (1 × 600 m l, 4 × 400 m l an d 5 × 300 m l). Th e com bin ed organ ic extracts
were wash ed with brin e (200 m l) an d dried with MgSO4. Th e solven t was rem oved un der re-
duced pressure an d th e resultin g liquid dried in vacuo. Th e product (7.4 g, 71%) was suffi-
cien tly clean by NMR but can be furth er purified by flash ch rom atograph y (eluen t: dieth yl
eth er). 1H NMR (400 MHz, CDCl3): 7.83 (1 H, s, Ar-H), 6.97 (1 H, s, Ar-H), 4.66 (2 H, s,
CH2), 3.40 (1 H, br s, OH). 13C NMR (100 MHz, CDCl3): 151.7, 151.6, 124.4, 55.4. Th e an a-
lytical data are con sisten t with th ose reported in th e literature6.
Oxazole-5-carbaldeh yde (3)
To a solution of oxalyl ch loride (3.5 m l, 40.0 m m ol) in dry CH2Cl2 (64 m l) un der an argon
atm osph ere was added a solution of dry DMSO (7.2 m l, 100 m m ol) in dry CH2Cl2 (17 m l) at
–78 °C over 15 m in . After stirrin g for 30 m in , a solution of alcoh ol 8 (2.00 g, 20 m m ol) in
dry CH2Cl2 (12 m l) was added over a period of 15 m in . Th e m ixture was allowed to stir for
furth er 30 m in an d was th en treated with dry Et3N (12.2 m l, 80 m m ol). Stirrin g was con tin -
ued for 30 m in at –78 °C, th en th e m ixture was warm ed up to 0 °C an d allowed to stir for
65 m in . After h ydrolysis with pH 7 buffer solution (100 m l), th e aqueous layer was extracted
with CH2Cl2 (3 × 40 m l) an d th e com bin ed organ ic layers were dried (MgSO4). Th e solven t
was evaporated un der reduced pressure (t < 25 °C, p > 400 m bar) to a volum e of 12 m l. Th e
crude m aterial was th en purified by flash ch rom atograph y (eluen t: 50% dieth yl eth er/petrol
eth er, 30–40 °C) to yield aldeh yde 3 (1.3 g, 56%) as colourless solid; m .p. 30–32 °C; RF 0.17
(50% eth er/petrol eth er, 30–40 °C). IR: 3100 (C–H), 1681 (C=O), 1568 (oxazole), 1477
(oxazole). 1H NMR (400 MHz, CDCl3): 9.86 (1 H, s, C=O), 8.11 (1 H, s, 13-H), 7.88 (1 H, s,
12-H). 13C NMR (100 MHz, CDCl3): 177.2 (CHO), 154.7 (C-13), 150.3 (C-11), 136.3 (C-12).
MS (ESI+), m/z: foun d 97.0159, [M]+ C4H3NO2 requires 97.0164. Th e an alytical data are
con sisten t with th ose reported in th e literature5a,7
.
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Hydroxyoxazol-5-yl Aceton itrile rac-10
Triethylam ine (1.00 m l, 7.16 m m ol) was added to a solution of aldehyde 3 (7.00 g, 72.11 m m ol)
in CH2Cl2 (290 m l) at 0 °C. Trim eth ylsilyl cyan ide (7.14 g, 51.50 m m ol) was added an d th e
reaction m ixture was stirred at 0 °C for 2 h 30 m in . Aqueous 2 M HCl (70 m l) was added
dropwise to th e ven ted flask with vigorous stirrin g. After 30 m in , furth er aqueous 2 M HCl
(70 m l) was added, stirred for 30 m in an d th e layers separated. Th e organ ic layer was
wash ed with aqueous 2 M HCl (70 m l) an d th e com bin ed aqueous layers extracted with
eth yl acetate (7 × 150 m l). Th e com bin ed organ ic extracts were dried (MgSO4) an d th e
solven t rem oved in vacuo to give cyan oh ydrin rac-10 as a yellow solid (8.81 g, 98%); m .p.
106–107 °C; RF 0.40 (80% eth yl acetate/petrol eth er, 30–40 °C). IR: 3134, 3043 br (O–H),
2839, 2716, 1507, 1123 s, 1056 s, 971 s. 1H NMR (400 MHz, CD3OD): 8.30 (1 H, s, 13-H),
7.31 (1 H, s, 12-H), 5.87 (1 H, s, 10-H). 13C NMR (100 MHz, CD3OD): 154.8 (C-13), 149.4
(C-11), 126.1 (C-12), 118.6 (CN), 56.2 (C-10). MS (ESI+), m/z: foun d 124.0271, [M]+
C5H4N2O2 requires 124.0273.
2-[(tert-Butyldiph en ylsilyloxy)-2-oxazol-5-yl]acetic Acid Meth yl Ester (11)
Im idazole (7.01 g, 103 m m ol) was added to a solution of m eth yl 2-h ydroxy-2-(oxazol-5-yl)-
acetate (8.10 g, 65.3 m m ol) in DMF (28 m l) at room tem perature, followed by th e addition
of TBDPSCl (16.9 m l, 64.9 m m ol) an d DMAP (79.2 m g, 0.65 m m ol) at room tem perature.
After 1 h 45 m in , water (260 m l) was added to th e stirred solution an d th e aqueous m ixture
extracted with eth er (3 × 200 m l). Th e com bin ed organ ic extracts were wash ed with brin e,
dried (MgSO4) an d th e solven t rem oved in vacuo. Purification by flash ch rom atograph y
(25% dieth yl eth er/petrol eth er) afforded silyl-protected 11 as a colourless oil (24.6 g, 99%);
RF 0.58 (50% eth yl acetate/petrol eth er (30–40 °C)). IR: 2955, 2859, 1764 s (C=O), 1112 s.
1H NMR (400 MHz, CDCl3): 7.79 (1 H, s, 13-H), 7.71 (2 H, d, J = 7.2, Ph -H), 7.65 (2 H, d, J =
6.8, Ph -H), 7.47–7.33 (6 H, m , Ph -H), 6.88 (1 H, s, 12-H), 5.25 (1 H, s, 10-H), 3.63 (3 H, s,
OCH3), 1.10 (9 H, s, C(CH3)3). 13C NMR (100 MHz, CDCl3): 169.2 (C-9), 151.0 (C-13), 148.8
(C-11), 135.9 (Ph -C), 135.6 (Ph -C), 132.3 (Ph quatern ary C), 132.2 (Ph quatern ary C), 130.13
(Ph -C), 130.06 (Ph -C), 127.75 (Ph -C), 127.72 (Ph -C), 125.1 (C-12), 67.0 (C-10), 52.4 (OCH3),
26.6 (C(CH3)3), 19.3 (C(CH3)3). MS (ESI+), m/z: foun d 396.1624, [M + H]+ C22H26NO4Si re-
quires 396.1624.
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(S)-3-(tert-Butyldim eth ylsilyloxy)-2-[(S)-2-(tert-butyldiph en ylsilyloxy)-
2-oxazol-5-ylacetylam in o]propion ic Acid Meth yl Ester
Im idazole (1.30 g, 18.98 m m ol) was added to a solution of serin e am ide 12 (4.60 g, 9.48 m m ol)
in DMF (28 m l), followed by th e addition of TBSCl (1.72 g, 11.38 m m ol) an d a catalytic
am oun t of DMAP (30 m g, 0.25 m m ol) at room tem perature. Th e m ixture was stirred for
45 m in an d th en quen ch ed by th e addition of saturated aqueous sodium bicarbon ate (75 m l)
an d water (40 m l). Th e aqueous solution was extracted with eth er (2 × 110 m l) an d th e com -
bin ed organ ic extracts wash ed with 10% w/v aqueous LiCl (75 m l), dried (MgSO4) an d th e
solven t rem oved in vacuo. Purification by flash ch rom atograph y (40 to 50% eth yl acetate/
petrol eth er, 30–40 °C) afforded th e title com poun d as a colourless gum (5.21 g, 92%); RF
0.30 (50% eth yl acetate/petrol eth er, 30–40 °C); [α ]2D5 +63.7 (c 1.3, CHCl3). IR: 3430 (N–H),
2955, 2859, 1751 (C=O ester), 1694 s (C=O am ide), 1509, 1107 s, 837 s, 702 s. 1H NMR
(400 MHz, CDCl3): 8.06 (1 H, d, J = 8.8, N-H), 7.69 (2 H, d, J = 7.3, Ph -H), 7.65 (1 H, s,
13-H), 7.48 (3 H, m , Ph -H), 7.41 (3 H, t, J = 7.4, Ph -H), 7.30 (2 H, t, J = 7.4, Ph -H), 6.53
(1 H, s, 12-H), 5.21 (1 H, s, 10-H), 4.76 (1 H, ddd, J = 8.8, 2.8, 2.4, 7-H), 4.17 (1 H, dd, J =
10.1, 2.4, 8-H), 3.89 (1 H, dd, J = 10.1, 2.8, 8-H′), 3.80 (3 H, s, OCH3), 1.13 (9 H, s, TBDPS
C(CH3)3), 0.91 (9 H, s, TBS C(CH3)3), 0.10 (3 H, s, TBS CH3), 0.07 (3 H, s, TBS CH3).
13C NMR (100 MHz, CDCl3): 170.2 (C-6), 168.2 (C-9), 150.6 (C-13), 148.8 (C-11), 135.8
(Ph -C), 135.4 (Ph -C), 131.8 (Ph quatern ary C), 131.8 (Ph quatern ary C), 131.2 (Ph -C), 130.4
(Ph -C), 128.1 (Ph -C), 127.7 (Ph -C), 125.8 (C-12), 68.1 (C-10), 63.8 (C-8), 54.2 (C-7), 52.4
(OCH3), 26.8 (TBDPS C(CH3)3), 25.7 (TBS C(CH3)3), 19.2 (TBDPS C(CH3)3), 18.2 (TBS
C(CH3)3), –5.6 (TBS CH3), –5.7 (TBS CH3). MS (ESI+), m/z: foun d 597.2816, [M + H]+
C31H45N2O6Si2 requires 597.2814.
(R)-1-{2-[(S)-(tert-Butyldiph en ylsilyloxy)oxazol-5-ylm eth yl]oxazol-4-yl}-
3-[(2R,3R,5S,6S)-5,6-dim eth oxy-3,5,6-trim eth yl-[1,4]dioxan -2-yl]-
3-h ydroxypropan -1-on e (17)
Boric acid (264 m g, 4.26 m m ol) was added to a solution of isoxazolin e 16 (55 m g, 0.084 m m ol)
in eth an ol (5.5 m l) an d water (0.55 m l) at room tem perature. Ran ey n ickel (~1 m l as an
aqueous slurry) was added an d th e m ixture stirred un der an atm osph ere of h ydrogen . After
3 h th e m ixture was filtered th rough a plug of celite an d th e solven t rem oved in vacuo,
azetropin g with toluen e. Th e crude product was purified by flash ch rom atograph y (20 to
80% eth yl acetate/petrol eth er, 30–40 °C) to afford β-h ydroxy keton e 17 as a colourless oil
(39 m g, 71%); RF 0.26 (60% eth yl acetate/petrol eth er); [α ]2D5 +56.6 (c 0.6, CHCl3). IR: 3420 br
(O–H), 2935, 2860, 1691 (C=O), 1127 s. 1H NMR (400 MHz, CDCl3): 8.14 (1 H, s, 8-H), 7.80
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Potent Antifungal Agents Bengazole C and E
897
(1 H, s, 13-H), 7.59 (4 H, t, J = 7.8, Ph -H), 7.48–7.41 (2 H, m , Ph -H), 7.39–7.32 (4 H, m ,
Ph -H), 6.97 (1 H, s, 12-H), 5.97 (1 H, s, 10-H), 4.19 (1 H, m , 4-H), 3.70 (1 H, m , 2-H), 3.62
(1 H, dd, J = 9.6, 4.6, 3-H), 3.23 (3 H, s, OCH3), 3.23 (3 H, s, OCH3), 3.10 (2 H, m , 5-H2),
1.28 (3 H, s, BDA CH3), 1.24 (3 H, s, BDA CH3), 1.22 (3 H, d, J = 6.2, 1-H3), 1.08 (9 H, s,
C(CH3)3). 13C NMR (100 MHz, CDCl3): 194.8 (C-6), 161.0 (C-9), 151.3 (C-13), 148.7 (C-11),
142.7 (C-8), 140.6 (C-7), 135.67 (Ph -C), 135.61 (Ph -C), 131.8 (Ph quatern ary C), 131.8 (Ph
quatern ary C), 130.25 (Ph -C), 130.23 (Ph -C), 127.86 (Ph -C), 127.82 (Ph -C), 125.2 (C-12),
98.8 (BDA quatern ary C), 98.6 (BDA quatern ary C), 75.1 (C-3), 68.0 (C-4), 65.9 (C-2), 63.7
(C-10), 47.9 (OCH3), 47.8 (OCH3), 42.1 (C-5), 26.6 (C(CH3)3), 19.3 (C(CH3)3), 17.7 (BDA
CH3), 17.4 (BDA CH3), 17.1 (C-1). MS (ESI+), m/z: foun d 687.2710, [M
+
Na]+
C35H44N2NaO9Si requires 687.2714.
Tridecan oic Acid (S)-{4-[(4S,6R)-6-((2S,3R,5S,6S)-5,6-Dim eth oxy-3,5,6-trim eth yl-
[1,4]dioxan -2-yl)-2,2-dim eth yl-[1,3]dioxan -4-yl]oxazol-2-yl}oxazol-5-ylm eth yl Ester
Trieth ylam in e (339 µl, 2.43 m m ol) was added to a solution of th e bisoxazole alcoh ol 18
(38 m g, 0.081 m m ol) in CH2Cl2 (4.3 m l) at 0 °C. Tridecan oyl ch loride (31 µl, 0.12 m m ol)
was added dropwise to th e stirred solution an d after 20 m in m eth an ol (85 µl) was added an d
th e m ixture stirred for furth er 5 m in . Saturated aqueous sodium bicarbon ate (35 m l) was
added an d th e m ixture extracted with eth er (5 × 35 m l). Th e com bin ed organ ic extracts were
wash ed with saturated aqueous am m on ium ch loride (35 m l), th en dried (Na2SO4) an d th e
solven t rem oved in vacuo. Purification by flash ch rom atograph y (20 to 40% eth yl acetate/
petrol eth er, 30–40 °C) afforded acetal-protected ben gazole C as a colourless oil (47 m g,
88%); RF 0.47 (40% eth yl acetate/petrol eth er, 30–40 °C); [α ]2D5 +56 (c 1.73, CHCl3). IR: 2923 s
(C–H), 2854, 1751 (C=O), 1461, 1378, 1156 s. 1H NMR (500 MHz, CDCl3): 7.88 (1 H, s,
13-H), 7.60 (1 H, s, 8-H), 7.21 (1 H, s, 12-H), 7.07 (1 H, s, 10-H), 4.92 (1 H, dd, J = 11.9,
2.01, 6-H), 3.98 (1 H, ddd, J = 9.4, 7.2, 4.9, 4-H), 3.71 (1 H, dq, J = 9.5, 6.4, 2-H), 3.39 (1 H,
dd, J = 9.5, 7.2, 3-H), 3.26 (3 H, s, OCH3), 3.20 (3 H, s, OCH3), 2.38 (2 H, t, 7.0, 15-H2), 2.16
(1 H, ddd, J = 12.2, 2.5, 1.9, 5-Heq), 1.63–1.58 (3 H, m , 16-H2 an d 5-Hax), 1.48 (3 H, s,
aceton ide CH3eq), 1.41 (3 H, s, aceton ide CH3ax), 1.29 (3 H, s, BDA CH3), 1.27 (3 H, s, BDA
CH3), 1.28–1.20 (18 H, m , 17-H2 to 25-H2), 1.19 (3 H, d, J = 5.9, 1-H3), 0.86 (3 H, t, J = 6.8,
26-H3). 13C NMR (125 MHz, CDCl3): 171.9 (C-14), 157.5 (C-9), 151.8 (C-13), 145.9 (C-11),
142.9 (C-7), 136.2 (C-8), 126.9 (C-12), 99.0 (aceton ide quatern ary C), 98.4 (BDA quatern ary
C), 98.3 (BDA quatern ary C), 74.5 (C-3), 69.6 (C-4), 67.5 (C-2), 65.5 (C-6), 61.3 (C-10), 47.93
(OCH3), 47.88 (OCH3), 33.8 (C-15), 32.6 (C-5), 31.9 (C-17), 29.9 (aceton ide CH3eq), 29.59,
29.58, 29.54, 29.38, 29.31, 29.14, 28.94 (C-18 to C-24), 24.8 (C-15), 22.7 (C-25), 19.7
(aceton ide CH3ax), 17.9 (C-1), 17.7 (BDA CH3), 17.5 (BDA CH3), 14.1 (C-26). MS (ESI+), m/z:
foun d 687.3833, [M + Na]+ C35H56N2NaO10 requires 687.3833.
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898
Enríquez-García, Ley:
Ben gazole C (1)
Acetal-protected ben gazole C (46 m g, 0.069 m m ol) was dissolved in TFA/water (1:1 m ixture,
2.2 m l) an d stirred for 10 m in at room tem perature, th en water was added (1.1 m l, to give a
1:2 TFA/water m ixture). Th e reaction m ixture was stirred for 30 m in at room tem perature,
th en stirred un der reduced pressure for 15 m in (reducin g th e reaction volum e by about
h alf). Saturated aqueous sodium bicarbon ate (55 m l) was added dropwise an d th e m ixture
extracted with eth yl acetate (4 × 55 m l). Th e com bin ed organ ic extracts were dried (Na2SO4)
an d th e solven t rem oved in vacuo. Purification by flash ch rom atograph y (5% m eth an ol/
CH2Cl2) afforded ben gazole C (1) as a colourless oil (32 m g, 91%); RF 0.23 (10% m eth an ol/
CH2Cl2); [α ]2D5 +7 (c 0.83, MeOH). IR: 3351 br (O–H), 2923, 2853, 1750 (C=O). 1H NMR
(600 MHz, CD3OD): 8.25 (1 H, s, 13-H), 7.85 (1 H, s, 8-H), 7.30 (1 H, s, 12-H), 7.10 (1 H, s,
10-H), 4.90 (1 H, t, J = 6.9, 6-H), 3.92 (1 H, dq, J = 6.4, 3.4, 2-H), 3.66 (1 H, ddd, J = 9.2, 6.8,
2.5, 4-H), 3.17 (1 H, dd, J = 6.7, 3.3, 3-H), 2.42 (2 H, t, J = 7.4, 15-H2), 2.22 (1 H, ddd, J =
14.1, 6.9, 2.7, 5-H), 1.89 (1 H, ddd, J = 14.1, 9.5, 7.0, 5-H′), 1.61 (2 H, t, J = 7.0, 16-H2),
1.33–1.24 (18 H, br m , 17-H2 to 25-H2), 1.14 (3 H, d, J = 6.8, 1-H3), 0.88 (3 H, t, J = 6.7,
26-H3). 13C NMR (150 MHz, CD3OD): 173.3 (C-14), 159.7 (C-9), 154.4 (C-13), 147.7 (C-11),
145.6 (C-7), 138.0 (C-8), 127.6 (C-12), 78.8 (C-3), 71.2 (C-4), 67.7 (C-2), 66.3 (C-6), 62.8
(C-10), 40.4 (C-5), 34.5 (C-15), 33.1, 30.77, 30.76, 30.71, 30.59, 30.49, 30.34, 30.0 (C-17 to
C-24), 25.8 (C-16), 23.7 (C-25), 19.9 (C-1), 14.5 (C-26). MS (ESI+), m/z: foun d 533.2863,
[M + H]+ C26H42N2NaO8 requires 533.2839. Th e observed data was con sisten t with th at pre-
viously reported1a,5
.
Pen tadecan oic Acid (S)-{4-[(4S,6R)-6-((2S,3R,5S,6S)-5,6-dim eth oxy-3,5,6-trim eth yl-
[1,4]dioxan -2-yl)-2,2-dim eth yl-[1,3]dioxan -4-yl]oxazol-2-yl}oxazol-5-ylm eth yl Ester
Trieth ylam in e (196 µl, 1.41 m m ol) was added to a solution of th e bisoxazole alcoh ol 18
(22 m g, 0.047 m m ol) in CH2Cl2 (2.5 m l) at 0 °C. Pen tadecan oyl ch loride (20 µl, 0.07 m m ol)
was added dropwise to th e stirred solution an d after 20 m in m eth an ol (0.05 m l) was added
an d th e m ixture stirred for furth er 5 m in . Saturated aqueous sodium bicarbon ate (20 m l)
was added an d th e m ixture extracted with eth er (5 × 20 m l). Th e com bin ed organ ic extracts
were wash ed with saturated aqueous am m on ium ch loride (20 m l), th en dried (Na2SO4) an d
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Potent Antifungal Agents Bengazole C and E
899
th e solven t rem oved in vacuo. Purification by flash ch rom atograph y (20 to 40% eth yl acetate/
petrol eth er, 30–40 °C) afforded acetal-protected ben gazole A as a colourless oil (24 m g,
75%); RF 0.55 (50% eth yl acetate/petrol eth er, 30–40 °C); [α ]2D5 +52 (c 1.13, CHCl3). IR: 2923 s
(C–H), 2853, 1752 (C=O), 1464, 1379, 1124 s. 1H NMR (500 MHz, CDCl3): 7.88 (1 H, s,
13-H), 7.61 (1 H, s, 8-H), 7.22 (1 H, s, 12-H), 7.07 (1 H, s, 10-H), 4.93 (1 H, dd, J = 11.9, 2.1,
6-H), 3.98 (1 H, ddd, J = 11.4, 7.3, 2.3, 4-H), 3.72 (1 H, dq, J = 9.5, 6.4, 2-H), 3.39 (1 H, dd, J
= 9.4, 7.2, 3-H), 3.23 (3 H, s, OCH3), 3.21 (3 H, s, OCH3), 2.41 (2 H, t, 7.6, 15-H2), 2.18 (1 H,
ddd, J = 13.2, 2.3, 1.9, 5-Heq), 1.66–1.57 (3 H, m , 16-H2 an d 5-Hax), 1.49 (3 H, s, aceton ide
CH3eq), 1.41 (3 H, s, aceton ide CH3ax), 1.28 (3 H, s, BDA CH3), 1.26 (3 H, s, BDA CH3),
1.26–1.19 (22 H, m , 17-H2 to 27-H2), 1.21 (3 H, d, J = 6.4, 1-H3), 0.86 (3 H, t, J = 6.7, 28-H3).
13C NMR (125 MHz, CDCl3): 172.0 (H-14), 157.5 (C-9), 151.8 (C-13), 146.0 (C-11), 142.9
(C-7), 136.2 (C-8), 127.1 (C-12), 99.0 (aceton ide quatern ary C), 98.4 (BDA quatern ary C),
98.4 (BDA quatern ary C), 74.6 (C-3), 69.6 (C-4), 67.5 (C-2), 65.6 (C-6), 61.4 (C-10), 47.91
(OCH3), 47.86 (OCH3), 33.8 (C-15), 32.6 (C-5), 31.9 (C-17), 29.9 (aceton ide CH3eq), 29.67,
29.65, 29.63, 29.61, 29.55, 29.4, 29.3, 29.2, 28.9 (C-18 to C-25), 24.7 (C-16), 22.7 (C-27),
19.7 (aceton ide CH3ax), 17.9 (C-1), 17.7 (BDA CH3), 17.5 (BDA CH3), 14.1 (C-28). MS (ESI+),
m/z: foun d 715.4147, [M + Na]+ C37H60N2NaO10 requires 715.4146.
Ben gazole E (2)
Acetal-protected ben gazole E (23 m g, 0.033 m m ol) was dissolved in TFA/water (1:1 m ixture,
1 m l) an d stirred for 10 m in at room tem perature, th en water was added (0.5 m l, to give a
1:2 TFA/water m ixture). Th e reaction m ixture was stirred for 30 m in at room tem perature,
th en stirred un der reduced pressure for 15 m in (reducin g th e reaction volum e by about
h alf). Saturated aqueous sodium bicarbon ate (25 m l) was added dropwise an d th e m ixture
extracted with eth yl acetate (4 × 25 m l). Th e com bin ed organ ic extracts were dried (Na2SO4)
an d th e solven t rem oved in vacuo. Purification by flash ch rom atograph y (5% m eth an ol/
CH2Cl2) afforded ben gazole C (2) as a colourless oil (12 m g, 69%); RF 0.17 (10% m eth an ol/
CH2Cl2); [α ]2D5 +8 (c 0.25, MeOH). IR: 3377 br (O–H), 2918, 2851, 1751 (C=O), 1468. 1H NMR
(500 MHz, CD3OD): 8.25 (1 H, s, 13-H), 7.85 (1 H, s, 8-H), 7.31 (1 H, s, 12-H), 7.11 (1 H, s,
10-H), 4.90 (1 H, t, J = 6.9, 6-H), 3.91 (1 H, dq, J = 6.4, 3.4, 2-H), 3.65 (1 H, ddd, J = 9.2, 6.8,
2.5, 4-H), 3.17 (1 H, dd, J = 6.8, 3.3, 3-H), 2.43 (2 H, t, J = 7.4, 15-H2), 2.22 (1 H, ddd, J =
14.1, 11.4, 7.0, 5-H), 1.89 (1 H, ddd, J = 16.5, 9.6, 6.9, 5-H′), 1.62 (2 H, t, J = 7.1, 16-H2),
1.32–1.22 (22 H, br m , 17-H2 to 27-H2), 1.15 (3 H, d, J = 6.5, 1-H3), 0.88 (3 H, t, J = 6.7,
28-H3). 13C NMR (125 MHz, CD3OD): 173.3 (C-14), 159.6 (C-9), 154.4 (C-13), 147.7 (C-11),
145.6 (C-7), 138.0 (C-8), 127.5 (C-12), 78.8 (C-3), 71.2 (C-4), 67.7 (C-2), 66.3 (C-6), 62.8
(C-10), 40.4 (C-5), 34.5 (C-15), 33.1, 30.85, 30.83, 30.81, 30.79, 30.75, 30.63, 30.5, 30.4,
30.8 (C-17 to C-26), 25.8 (C-16), 23.7 (C-27), 19.9 (C-1), 14.4 (C-28). MS (ESI+), m/z: foun d
561.3145, [M + H]+ C28H46N2NaO8 requires 561.3152. Th e observed data was con sisten t with
th at previously reported1a,5
.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 6, pp. 887–900

900
Enríquez-García, Ley:
The authors would like to thank Syngenta for a support (S. V. Ley) and the Swiss National
Foundation for a postdoctoral fellowship (A. Enríquez-García).
REFERENCES
1. a) Adamczeski M., Quinoa E., Crews P.: J. Am. Chem. Soc. 1988, 110, 1598; b) Rodríguez J.,
Nieto R. M., Crews P.: J. Nat. Prod. 1993, 56, 2034; c) Rudi A., Kashman Y., Benayahu Y.,
Schleyer M.: J. Nat. Prod. 1994, 57, 829; d) Groweiss A., Newcomer J. J., O’Keefe B. R.,
Blackman A., Boyd M. R.: J. Nat. Prod. 1999, 62, 1691; e) Fernández R., Dherbomez M.,
Letourneux Y., Nabil M., Verbist J. F., Biard J. F.: J. Nat. Prod. 1999, 62, 678; f) Searle
P. A., Richter R. K., Molinski T. F.: J. Org. Chem. 1996, 61, 4073.
2. a) Molinski T. F.: J. Nat. Prod. 1993, 56, 1; b) Antonio J., Molinski T. F.: J. Nat Prod.
1993, 56, 54.
3. a) Bull J. A., Balskus E. P., Horan R. A. J., Langner M., Ley S. V.: Angew. Chem. Int. Ed.
2006, 45, 6714; b) Bull J. A., Balskus E. P., Horan R. A. J., Langner M., Ley S. V.: Chem.
Eur. J. 2007, 13, 5515.
4. a) Chittari P., Hamada Y.; Shioiri T.: Synlett 1998, 1022; b) Chittari P., Hamada Y., Shiori T.:
Heterocycles 2003, 59, 465.
5. a) Mulder R. J., Shafer C. M., Molinski T. F.: J. Org. Chem. 1999, 64, 4995; b) Shafer
C. M., Molinski T. F.: Tetrahedron Lett. 1998, 39, 2903; c) Shafer C. M., Molinski T. F.:
Heterocycles 2000, 53, 1167.
6. a) Vedejs E., Luchetta L. M.: J. Org. Chem. 1999, 64, 1011; b) Webb M. R., Donald C.,
Taylor R. J. K.: Tetrahedron Lett. 2006, 47, 549.
7. Kende A. S., Kawamura K., DeVita R. J.: J. Am. Chem. Soc. 1990, 112, 4070.
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