Synthesis of oximidine II by a copper-mediated reductive ene-yne macrocyclization

Article abstract of DOI:10.1002/anie.201103081

Holy macro! An intramolecular copper-mediated reductive Castro-Stephens reaction furnished a key macrocyclic triene intermediate for the total synthesis of oximidine II (see scheme). The total synthesis of the natural product was completed and the mechanism of this unprecedented key reaction was deduced.

Full text of DOI:10.1002/anie.201103081

DOI: 10.1002/anie.201103081
Natural Product Synthesis
Synthesis of Oximidine II by a Copper-Mediated Reductive Ene–Yne
Macrocyclization**
Christopher M. Schneider, Kriangsak Khownium, Wei Li, Jared T. Spletstoser, Torsten Haack,
and Gunda I. Georg*
Oximidine II (1, Figure 1) was isolated in 1999 by Hayakawa
and co-workers and displays cytotoxicity at the ngmLÀ1 level
in mutant rat fibroblasts.[1] Oximidine II belongs to the
Porco[4a] and Molander[4b] groups demonstrated this difficulty.
Joining C9 and C10 of the macrocyclic core of 1 through
either ring-closing metathesis (Porco) or a Suzuki–Miyaura
coupling (Molander) proceeded with yields of 48% and 42%,
respectively. Other groups have reported similar challenges in
forming this strained macrocycle in model systems.[5] Our
retrosynthesis in Figure 1 utilizes an intramolecular Castro–
Stephens reaction,[4,5b] in which intermediate 4 is employed to
form the C9–C10 bond; a chemo- and stereoselective
reduction of the alkyne unit in the cyclization product 3
generates the triene macrocyclic core 2. The cyclization
precursor 4 would be derived from the chiral aliphatic
fragment 5 and aryl acetonide 6.
The synthesis of precursor 4 (Scheme 1) began with an
asymmetric Brown allylation[4,7] of aldehyde 7 with alkene 8,
followed by TBS protection of the newly formed secondary
hydroxy group to furnish the enantioenriched product 9 in
Figure 1. Retrosynthesis for oximidine II (1). TBS=tert-butyldimethyl-
silyl, TBDPS=tert-butyldiphenylsilyl, MOM=methoxymethyl.
benzolactone enamide family of natural products,[2] which
exert their biological activity through selective inhibition of
mammalian vacuolar-type H+-ATPases (V-ATPases).[3]
Intrigued by its promise as an anticancer agent, our group
sought a feasible synthetic route towards oximidine II.
The major challenge in the synthesis of oximidine II is the
formation of its strained 12-membered macrolactone core,
which contains nine contiguous sp2-hybridized carbon atoms.
The two previous total syntheses of oximidine II by the
Scheme 1. Synthesis of 4: a) sBuLi, (+)-Ipc2BOMe, BF3·OEt2, À78 to
08C, 81%, 94:6 e.r.; b) TBSOTf, 2,6-lutidine, CH2Cl2, quantitative;
c) O3, CH2Cl2, À788C, then Me2S; d) 1,3-bis(TIPS)-propyne, nBuLi,
THF À788C; e) TBAF, THF; 51% over three steps; f) TBDPSCl,
imidazole, DMAP, DMF, 80%; g) NaHMDS, THF, 08C, then 5, then
Me2SO4, 89%; Ipc=isopinocampheyl, OTf=trifluoromethanesulfo-
nate, TIPS=triisopropylsilyl, THF=tetrahydrofuran, TBAF=tetra-n-
butylammonium fluoride, DMAP=4-dimethylaminopyridine,
DMF=N,N-dimethylformamide, HMDS=hexamethyldisilazane.
[*] Dr. G. I. Georg
Department of Medicinal Chemistry and the Institute for Thera-
peutics Discovery and Development
University of Minnesota
717 Delaware Street SE, Minneapolis, MN 55414 (USA)
E-mail: georg@umn.edu
Dr. C. M. Schneider, Dr. K. Khownium, Dr. J. T. Spletstoser,
Dr. T. Haack
Department of Medicinal Chemistry, University of Kansas (USA)
81% yield as a single diastereoisomer (1H NMR analysis)
with 94:6 e.r. as determined by Mosher ester analysis.[8]
Ozonolysis of intermediate 9 yielded aldehyde 10, which
was treated with the lithium anion of 1,3-bis(TIPS)-propyne[9]
to afford the Peterson olefination product with a Z/E ratio of
10:1. Desilylation and reprotection of the alcohol as its
monosilyl ether provided the aliphatic building block 5.
Reaction of aryl acetonide 6[10] with the sodium alkoxide[4] of
5, followed by quenching of the resultant phenolate with
W. Li
Department of Chemistry, University of Minnesota (USA)
[**] We thank X. Gu for help in obtaining spectral data. C.M.S. was
supported by NIH Training Grant T32 GM008545 and K.K. by a
Royal Thai Government Fellowship; T.H. was the recipient of a
Postdoctoral Fellowship from the German Academic Exchange
Services. Support from the University of Minnesota through the
Vince and McKnight Endowed Chairs is also acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103081.
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Communications
Me2SO4 produced 4, the key intermediate for the macro-
cyclization step.
Similar to our previously reported results[4] reaction of
compound 4 under catalytic Castro–Stephens conditions[6]
(Scheme 2) afforded the energetically more stable macrocycle
Scheme 3. Synthesis of oximidine II (1): a) CuI, PPh3, K2CO3, HCO2Na,
DMF, 1208C, 67%; b) TBAF, THF, 94%; c) Dess–Martin periodinane,
CH2Cl2, 86%; d) IH2CPPh3I, NaHMDS, HMPA, DMF, THF, 08C to RT
to À788C, 80%; e) CBr4, iPrOH, 758C, 96%; f) BCl3, CH2Cl2, À788C,
94%; g) TBSOTf, pyridine, CH2Cl2, 08C to RT, 80%. HMPA=hexame-
thylphosphoramide.
Scheme 2. Castro–Stephens macrocyclization of 4: a) CuI, PPh3, K2CO3,
DMF, 1208C, 18% (Z-3) and 8% (2).
Z-3 in 18% yield and none of the kinetic product E-3. Careful
analysis of the reaction mixture surprisingly, revealed the
presence of a small amount (8%) of the partially reduced
triene macrocycle 2, featuring the required oximidine triene
system.
and protection of the resultant diol as its bis-TBS ether to
form known vinyl iodide 11. Following Porcoꢀs protocol, we
completed the synthesis of oximidine II (1) from intermediate
11.[4]
Given these findings, we concluded that the alkyne-
containing macrocycle E-3 was highly reactive and could
undergo subsequent transformations such as C8–C9 isomer-
ization to form the thermodynamically more stable Z-3
product, or reduction of the alkyne to furnish 2. We then
hypothesized that it might be possible to find reaction
conditions to optimize the conversion of reactive intermedi-
ate E-3 to generate triene 2. Our initial attempts involved
addition of excess Cu0 or CuI—potential reductant sources—
to the reaction mixture. However, these reactions resulted
only in the isolation of dienyne Z-3 and triene 2 in similar
ratios. We then hypothesized that a copper hydride species
could be responsible for the in situ reduction of the alkyne in
E-3.
Indeed, exposing 4 to the reaction conditions reported by
Stryker et al. for the generation of [CuH(PPh3)]6[12] led to
the isolation of only the reduced triene product 2 in 31%
yield. Dienynes Z-3 or E-3 were not detected in the
reaction mixture. The optimal source of hydride for this
one-flask macrocyclization/reduction transformation
proved to be sodium formate, which exclusively generated
the triene macrocycle 2 in a yield of 67% (Scheme 3). This
reductive cyclization was also mediated by Cu-
(OAc)2·H2O, albeit furnishing lower yields (55%) of the
desired triene 2 but producing cleaner reactions. In order
to exclude the possibility that reduction of Z-3 had
generated 2, we subjected macrocycle Z-3 to the optimized
reductive cyclization conditions but isolated only starting
material from the reaction mixture.
To investigate the mechanism of this novel transformation
from 4 to 2, we turned to deuterium-incorporation studies
using the readily accessible model compound 12
(Scheme 4).[10] Reaction of 12 with DCO2Na as the deuterium
source under the established reaction conditions led to a 9:1
mixture of monodeuterated products 13 and 14 [Eq. (1) in
Scheme 4]. Since we did not observe the bisdeuterated
product in the reaction mixture, we hypothesized that a
purported vinyl copper intermediate (i.e. 18 in Figure 2) was
likely quenched by protons present in solution (i.e. from
Cu(OAc)2·H2O, the alkynyl proton, or adventitious water).
This hypothesis is supported by the experiment performed
with 12 in the presence of HCO2Na and excess D2O [Eq. (2)
With a viable route to the triene core in hand, we
completed the total synthesis of oximidine II (1;
Scheme 3). Desilylation of triene 2, oxidation to the
corresponding aldehyde, and Z-selective iodo-olefination
under Stork–Zhao conditions[13] generated the corre-
sponding Z-vinyl iodide as the sole isomer (1H NMR
analysis) required for the penultimate amide coupling.
Completion of the formal synthesis of oximidine II was
Scheme 4. Mechanistic investigation of reductive macrocyclization: a) Cu-
(OAc)2·H2O, PPh3, K2CO3, DCO2Na, DMF, 1208C, 9:1 (13/14), 31%;
b) Cu(OAc)2·H2O, PPh3, K2CO3, HCO2Na, D2O, DMF, 1208C, 1:8 (14/15),
34%; Cu(OAc)2·H2O, PPh3, K2CO3, DCO2Na, DMF, 1208C, 5:3 ([11D]-
achieved after removal of the alkyl ether protecting group 2/[10D]-2), 65%.
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Angew. Chem. Int. Ed. 2011, 50, 7855 –7857

unprecedented Cu-mediated reductive Castro–Stephens mac-
rocyclization was the key step to form the triene macrocycle
in 67% yield. This methodology should prove useful in the
construction of other macrocycles. Studies are underway to
explore the scope of this chemistry.
Received: May 4, 2011
Published online: June 29, 2011
Keywords: anticancer agents · copper-mediated reactions ·
.
macrocyclization · natural products · total synthesis
Figure 2. Mechanistic proposal for the reductive macrocyclization.
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in Scheme 4], which generated monodeuterated product 14
and nondeuterated product 15 in a 1:8 ratio by 1H NMR
analysis. We also subjected intermediate 4 to the optimized
reductive cyclization conditions in the presence of DCO2Na
[Eq. (3) in Scheme 4] and observed the C11- and C10-
deuterated products [11D]-2 and [10D]-2 in a 5:3 ratio by
1H NMR analysis.[10] Since it is possible that protons could be
generated from the decomposition of DMF,[14] we carried out
the reaction in [D7]DMF as the solvent, but could not detect
any deuterium incorporation.
Based on the deuterium-labeling studies, we propose the
mechanism of this reductive macrocyclization to occur as
shown in Figure 2. The stereoselective ring closure of 12 by
means of a Castro–Stephens reaction[15] forms the alkyne-
containing 8E macrocycle 16, with the copper atom remaining
coordinated to the alkyne, thereby stabilizing the C8–C9 E-
olefin geometry and preventing double-bond isomerization.
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species 17, which then undergoes a 1,2-addition across the
triple bond to afford the vinyl copper intermediate 17 in
which the copper is preferentially bound to C10. As shown in
Scheme 4 [Eqs. (2) and (3)], a C11–Cu intermediate must
form as well since C11-deuterated products were formed also.
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influenced by the electronic properties of the alkyne since
model compound 12 and cyclization precursor 4 gave differ-
ent ratios of deuterium incorporation. Finally, protonation of
the copper metal species yields the reduced macrocycle 15.
The interception of reactive intermediate 16 with the hydride
species is presumably key to the success of the reaction,
because subjecting alkynyl macrocycle Z-3 to the same
reaction conditions led only to the recovery of starting
material.
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In summary, the synthesis of oximidine II was completed
in a total of 14 steps and in 9.2% overall yield. An
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