Communications
these strategies were either lengthy[6a] or unselective.[5b] We
Information), setting the stage for the aryl alkyl etherifica-
tion. Our initial attempts to form the Tyr-Ile ether followed
the JoulliØ conditions of phenol/aziridine (mol ratio 2:1)with
1% copper(I)acetate. [5d] However, these conditions produced
the desired product in only 18% yield. The majority of phenol
9 was recovered, but the aziridine was completely consumed.
Optimized conditions required stoichiometric inversion using
2 equiv of aziridine 8 and 1% copper(I)acetate to provide the
desired aryl alkyl ether 14 in 87% yield. The perfect
regioselectivity of the aziridine opening sets the vicinal
stereochemical centers at C2 and C3 in one step.
The next major hurdle in the synthesis involved appending
the tripeptide side chain and DVal. However, before these
unsaturated fragments could be incorporated, a redox adjust-
ment of the alkynyl group was required. We therefore
exchanged the C3-amine protecting group and exposed the
fully protected Tyr-Ile dipeptide to hydrogen and Pearlmanꢀs
catalyst to hydrogenate the alkyne and concomitantly remove
the two benzyl groups in 99% yield. We next installed an
orthogonal set of blocking agents to mask the newly liberated
envisioned that a recently described use of a phenolate to
open a copper(I)-activated alkynyl aziridine[5d] could be used
to construct this fragment. This convergent strategy would
reduce the complexity to aziridine 8, a derivative of a
published intermediate,[5d] and phenol 9 (Scheme 2). Phenol
9 could be formed using an aldol reaction between 3,4-
dihydroxybenzaldehyde derivative 10 and a glycine equiva-
lent that we used in our synthesis of ustiloxin D.[5b]
Our synthesis began with the reaction of benzaldehyde
derivative 10 with oxazole 11[8] using Evansꢀ chiral salen-Al
catalyst[9] to produce the cis-oxazoline 13 (Scheme 3). As
evidence of the versatility of this strategy, we had previously
used the opposite enantiomer of the Al catalyst to construct a
diastereomeric trans-oxazoline for the synthesis of ustilox-
in D.[5b] In contrast to ustiloxinꢀs robust trans-oxazoline,
however, phomopsinꢀs cis-oxazoline undergoes rapid isomer-
ization under alkaline conditions, mandating its early
unmasking to the underlying N-methyl amino alcohol.
Fluoride-labile groups were installed as part of a global
end-game deprotection strategy, followed by deacetylation
under mild conditions to furnish phenol 9 in excellent yield
over five steps. Gentle deacetylation conditions were required
to prevent epimerization of the C9 Teoc-protected secondary
amine.
oxygens. We could now selectively reveal the C17 carboxylic
[10]
acid by treatment with silica gel in toluene at 908C
and
produce intermediate 5, which is poised for further elabo-
ration with the dehydrated amino acids.
The preparation of tripeptide 6 has been outlined
previously.[6c] Using our methodology, the (E)-DIle residue
was synthesized by the anti elimination of cyclic sulfamidite
diastereomers. Carboxylic acid 5 and tripeptide 6 were
coupled in satisfactory yield to produce adduct 15
(Scheme 4). Following Troc deprotection the final amino
acid, Alloc-DVal-OH 7, was coupled to provide the complete
carbon skeleton. We next employed palladium to deprotect
the C8 allyl ester, the N7-Alloc-protected amine, and
phenolic allyl ether to reveal the desired macrocycle pre-
cursor in amino acid 4.[11] Macrocyclization was favored over
intermolecular coupling by using high-dilution conditions
(3 mm)to provide the desired macrocycle in moderate yield.
Saponification of the terminal methyl esters provided the
b-hydroxy-Asp intermediate 16. Model studies had shown
that use of acetic anhydride and pyridine successfully
dehydrated the b-hydroxyaspartic acid residue to produce a
mixture of the desired (E)-DAsp and the doubly dehydrated
cyclic anhydride. This mixture could be converged into the
desired (E)-DAsp species following brief exposure to lithium
hydroxide. Care was taken in the hydrolysis step because
prolonged alkaline exposure results in isomerization to the
undesired, thermodynamic (Z)-DAsp product. Finally, the
TBS and Teoc groups were removed in one step using
anhydrous fluoride conditions of TAS-F in DMF to yield
phomopsin B (3)following reverse-phase HPLC purifica-
tion.[12]
Minor modifications to published procedures enabled
facile construction of aziridine
8 (see the Supporting
Scheme 3. Reagents and conditions: a) Na2SO4, 12, AgSbF6, 3- MS,
PhCH3, 25 h, 96%, 98% ee; b) MeOTf, CH2Cl2, 2 h then NaBH4,
NaHCO3, H2O, 08C, 15 min, 72%; c) 0.1n (COOH)2, THF, 24 h, 99%;
d) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 30 min, 87%; e) Teoc-Cl,
NaHCO3, CH3CN, 16 h, 98%; f) NH2NH2·H2O, THF, 08C, 3 h, 98%;
g) 8, CuOAc, DBU, PhCH3, 08C, 12 d, 87%; h) PhSH, Cs2CO3, DMF,
1 h, 92%; i) 2,2,2-trichloroethyl chloroformate, Na2CO3, THF, 1 h, 96%;
j) H2, 20% Pd(OH)2/C, EtOAc, 4 d, 99%; k) allyl bromide, DBU, DMF,
5 h, 70%; l) SiO2, PhCH3, 908C, 20 h. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMF=N,N-dimethylformamide, MS=molecular
sieves, OTf=trifluoromethanesulfonate.
The identity of the synthetic phomopsin B was confirmed
by MS, HPLC, and NMR spectroscopy. Interestingly, the 1H,
1H-13C HSQC, and 1H-13C HMBC spectra of the HPLC-
purified synthetic and natural compounds were similar but
not identical.[13] Upon mixing equimolar amounts of the two
samples the spectra display one set of resonances, demon-
strating that both samples are phomopsin B (see the
Supporting Information). HPLC analysis supports this con-
8158
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8157 –8159