Angewandte
Communications
Chemie
two fragments.[7] By pursuing a unified strategy of site-
selective Stille cross-coupling reactions to rapidly install the
requisite stereodefined polyene motifs under suitably mild
conditions, we now report a concise and highly convergent
total synthesis of chivosazole F (1).
Building on the lessons learned from our earlier synthetic
efforts,[7] we proposed some major retrosynthetic disconnec-
tions and key fragments for assembling chivosazole F
(Scheme 1). An important consideration was how to best
handle the extremely labile and isomerization-prone
(2Z,4E,6Z,8E)-tetraenoate motif contained within the south-
ern hemisphere.[5a,7a] With this in mind, we first envisaged that
the macrocyclization step would involve an intramolecular
Horner–Wadsworth–Emmons-type olefination to form the
tetraenoate system, as outlined in Approach I. This would
avoid manipulating a vulnerable open-chain tetraenoate in
favor of a potentially more stable (4E,6Z,8E)-trienoate
moiety. Through judicious tuning of the reactivity of the
termini of each of the building blocks (3–6), it was reasoned
that a carefully designed sequence of site-selective Stille
cross-coupling reactions[8] would beneficially minimize the
need for the manipulation of sensitive intermediates.
Following Approach I, the linchpin fragment 3 was
required with a vinyl iodide at C14 and vinyl bromide at
C26. A modification to our existing synthetic route (Sche-
me 2A),[7b] starting from the known bromodienal 7[9] and the
chiral methyl ketone 8,[10] was used to prepare carboxylic acid
9 with efficient control (> 20:1 d.r.) over the installation of the
C20 and C22 oxymethine stereocenters. This entailed
a tandem boron-mediated aldol addition[11,12] [(À)-Ipc2BCl,
Et3N] and Sm-promoted reduction[13] (SmI2, EtCHO)
sequence, proceeding via the alcohol intermediates 10 and
11 (53%, 7 steps). The amine 12[14] was next coupled (EDC,
HOBt) with 9 and the resulting amide cyclized to the
oxazoline 3 (DAST, 73%).[15] At this point, the lack of an
electron-withdrawing substituent on the oxazoline ring pre-
sented a potential problem, since the oxidation of unactivated
oxazolines to the corresponding oxazoles can be challenging.
While this transformation can be accomplished using
MnO2,[16] the vinyl iodide in 3 proved incompatible with
these conditions, thus dictating that the installation of the
oxazole ring should be performed after fragment assembly.
The choice of an iodide at C14 in 3 necessitated the
controlled transformation of the C13 bromide in 13[7a]
(Scheme 2B) into the corresponding stannane. This was
achieved through lithium–halogen exchange at À788C and
stannylation (tBuLi, Bu3SnCl) to afford 19. Oxidation
(MnO2) and Stork–Zhao olefination[17] of the resulting
aldehyde then gave the (Z)-vinyl iodide 4 (Z/E > 20:1,
68%, 3 steps), which corresponds to the second linchpin
fragment envisaged in Approach I. A (Z)-vinyl stannane was
also required in the third fragment (5; Scheme 2C) and this
was readily accessed from 14[7a] using a Pd-catalyzed stanny-
lation [(Me3Sn)2, PdCl2(PPh3)2].[18] An Ando-type phospho-
nate[19] was then appended at the C30 hydroxy group through
esterification (15, DCC) to afford 5.
Scheme 2. A) Preparation of bis-vinyl halide 3. Reagents and condi-
tions: a) (À)-Ipc2BCl, Et3N, Et2O, 08C; 7, À788C, 84%, d.r. >20:1;
b) SmI2, EtCHO, THF, À208C, 96%, d.r. >20:1; c) Me3OBF4, Proton
Sponge, CH2Cl2, 08C, 92%; d) K2CO3, MeOH, 91%; e) TBSCl, imida-
zole, CH2Cl2, 96%; f) DDQ, pH 7 buffer, CH2Cl2, 79%; g) TEMPO,
PhI(OAc)2, MeCN, H2O, 95%; h) EDC, iPr2NEt, HOBt, 12, CH2Cl2,
98%; i) DAST, CH2Cl2 À788C, 75%. B) Preparation of vinyl stannane 4.
Reagents and conditions: a) tBuLi, Et2O À788C; Bu3SnCl, 68%;
b) MnO2, CH2Cl2; c) [PPh3CH2I]+IÀ, NaHMDS, THF, À788C, 99% (2
steps). C) Preparation of vinyl stannane 5. Reagents and conditions:
a) (Me3Sn)2, PdCl2(PPh3)2, Li2CO3, THF, 408C, 65%; b) 15, DCC,
CH2Cl2, 77%. DAST=diethylaminosulfur trifluoride, DCC=N,N-dicy-
clohexyl carbodiimide, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none, DMB=3,4-dimethoxybenzyl, EDC=1-ethyl-3-(3-dimethyl-amino-
propyl) carbodiimide, HMDS=hexamethyldisilazide, HOBt=1-hy-
droxybenzotriazole, Ipc=isopinocampheyl, Proton Sponge=1,8-bis(di-
methyl-amino)naphthalene, TEMPO=2,2,6,6-tetramethylpiperidine
1-oxyl.
employed in our earlier work,[7,20] we envisaged the forma-
À
À
À
tion, in turn, of the C5 C6, C13 C14, and C26 C27 bonds
with the controlled installation of a diene with alternating E/Z
geometry. We elected to initiate this demanding fragment
assembly process with the acrylate derivative 6,[21] which has
a a b-tributylstannyl substituent. It was anticipated that the
(E)-vinyl stannane in 6 would be more reactive for steric
reasons than the (Z)-vinyl stannane in 4, and that the C14
iodide in 3 would be more reactive than the C26 bromide,
With the three key fragments in hand, the planned Stille
cross-coupling chemistry in Approach I was explored
(Scheme 3). Based on the Pd/Cu-promoted conditions
À
thereby facilitating the site-selective construction of the C13
C14 bond. In practice, the first Pd/Cu-mediated Stille
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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