Synthesis of Strained 1,3-Diene Macrocycles via Copper-Mediated Castro-Stephens Coupling/Alkyne Reduction Tandem Reactions

Article abstract of DOI:10.1021/acs.orglett.5b01892

A copper-mediated macrocyclization involving the reaction of a vinyl iodide and a terminal alkyne followed by an in situ reduction of the enyne intermediate is reported. The reaction generates a conjugated Z-double bond within a strained medium-size lacto

Full text of DOI:10.1021/acs.orglett.5b01892

Letter
pubs.acs.org/OrgLett
Synthesis of Strained 1,3-Diene Macrocycles via Copper-Mediated
Castro−Stephens Coupling/Alkyne Reduction Tandem Reactions
Wei Li,† Christopher M. Schneider,‡ and Gunda I. Georg*,†
†Department of Chemistry, Department of Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development,
University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
‡Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: A copper-mediated macrocyclization involving the
reaction of a vinyl iodide and a terminal alkyne followed by an in
situ reduction of the enyne intermediate is reported. The reaction
generates a conjugated Z-double bond within a strained medium-size
lactone, lactam, or ether macrocycle. A variety of macrocyclic
compounds bearing different ring sizes and functionalities were synthesized. A complementary stepwise procedure was also
developed for less strained ring systems.
ighly functionalized macrocycles are prevalent structural
reactions. A sequential RCM/intramolecular palladium-cata-
Hfeatures in natural products and are present in more lyzed cross-coupling reaction between an alkenyl iodide and a
than 100 marketed drugs.1 We are particularly interested in
siloxane also provided access to an oximidine-like macrocyclic
structure and related analogues in good yields.6 For the
macrocycles possessing conjugated E,Z-polyene units within
synthesis of lactimidomycin, the E,Z-configuration of the 1,3-
diene was established using a RCM reaction; however, a silyl
directing group was needed for regio- and stereocontrol.3f
Despite these successful total syntheses, methods to prepare
conjugated polyene macrocycles are underexplored, and new
efficient methods that are tolerant of diverse functional groups
would be important to further explore these types of
structures for biomedical applications.
the ring since this motif is present in a number of natural
products with diverse and potent bioactivities such as
latrunculin A, oximidine II, lactimidomycin, and radicicol
(Figure 1).2
We pursued an alternative approach to this structural motif
via a two-step ene−yene macrocyclization7/alkyne reduction
sequence en route to the total synthesis of oximidine II
(Scheme 1). Initial attempts were disappointing. The highly
strained cyclic dienyne intermediate was obtained in very low
yield, and the double bond underwent E−Z isomerization to
release ring strain.8 Further investigations revealed that the
ene−yne coupling reaction performed in the presence of the
Scheme 1. Ene−Yne Coupling/Reduction Approach in the
Total Synthesis of Oximidine II
Figure 1. Selected examples of polyunsaturated macrocyclic natural
products.
Most reported total syntheses of these natural products rely
on variants of ring-closing metathesis (RCM) reactions,3
which exhibited low efficiency for highly strained ring systems
such as oximidine II3c and could potentially generate E/Z
isomers and ring contraction products.3f,4 A palladium-
catalyzed Suzuki cross-coupling reaction was also employed
for the synthesis of oximidine II,5 but the yield for the
macrocyclization was similar to those achieved with RCM
Received: July 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01892
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reducing reagent sodium formate allowed the in situ reduction
of the dienyne to afford the desired triene macrocycle in a
single step.9 The 67% yield compared favorably to the 40−
50% yields reported for the ring-closing steps in the two
previous total syntheses.3c,5 Encouraged by this success, we
decided to explore this coupling/reduction tandem trans-
formation as a general method for the construction of
conjugated polyunsaturated macrocycles.
reaction significantly (entry 9). Finally, we were pleased to
find that high yields of over 70% could be achieved with
bidentate ligands under catalytic conditions (HCO2Na (4
equiv), K2CO3, (1.5 equiv), Cu(OAc)2 (0.33 equiv), and
bidentate ligand (0.5 equiv) at 120 °C in DMF for 2 h,
entries 1012). Among them, phanephos afforded the best
selectivity for diene 2a, and the efficiency was not diminished
under lower catalyst loading (0.2 equiv of Cu(OAc)2 0.3
equiv of phanephos, entry 13). Further lowering the catalyst
loading (0.1 equiv of Cu(OAc)2 0.15 equiv of phanephos,
entry 14) resulted in incomplete reaction (70% conversion)
even after 4 h. N- or O-ligands exhibited inferior reactivities
(entries 15 and 16).
For optimization studies, we initially examined the
coupling/reduction tandem reaction with vinyl iodide 1a
(Table 1) under conditions similar to those reported for the
a
Table 1. Optimization of the Reaction Conditions
We next applied this coupling/reduction tandem reaction to
the synthesis of a diverse set of substrates (Table 2). We
found that 11- to 13-membered rings 2a, 2b, and 2d with an
E,Z-1,3-diene moiety were obtained in good yields (Table 2,
entries 1, 2, and 4). A more strained 10-membered
homologue 2c was also accessible, albeit only in 26% yield
(entry 3). The alkyne reduction step was clearly driven by the
release of ring strain from the enyne intermediate, which in
case of the 13-membered ring analogue (entry 4) was
observed after 2 h but converted to 2d after 22−24 h. 14-
Membered (entry 5) or larger rings formed the enyne but
were not reduced to produce dienes even after prolonged
reaction time. A phenylvinyl iodide with an ether linkage
(entry 7) worked equally as the ester linkages. An
unprotected phenol and a secondary amide (entries 8 and
9) were not well tolerated. In contrast, a protected amide
(entry 10) provided the desired lactam 2j in 79% yield. Both
vinyl iodide and terminal alkyne coupling partners can be
aromatic or aliphatic (entries 11 and 12). Vinyl iodide double-
bond isomerization was observed for substrate 1l (entry 12A
and Scheme 2), which furnished an inseparable mixture
(11:1) of 2l and enyne 4. When dppe was used as the ligand,
2l was obtained in 82% as the sole product (entry 12 B). Z,Z-
Diene macrocycles were difficult to access with this method
since the Z-enyne intermediate is much less strained than its
E-counterpart, and thus, the alkyne reduction did not take
place (entry 13). When the ring system was strained enough
to afford the desired diene product 2n in 30% yield (entry
14), significant amounts of the dimer 5 (34%) were formed
concomitantly (Scheme 2). In the majority of the above
examples, the undesired deiodinated product 3 was negligible.
For those substrates that produced a significant quantity of
compound 3, the use of stoichiometric amounts of copper
and ligand could completely suppress the side reaction
(entries 4 and 6).
Ring systems that were not strained enough to trigger the
in situ alkyne reduction afforded macrocyclic enynes. This
transformation is worth noting, since the intramolecular ene−
yne C−C couplings (Sonogashira or Castro−Stephens) have
not been widely applied to macrocyclizations,8,11 and most of
them employed phenyl iodide substrates. In addition, the
desired diene macrocycles could be obtained from the enynes
through a sequential reduction step (Scheme 3). Thus, the
iodides were subjected to the ene−yne coupling conditions in
the absence of HCO2Na, and the crude enyne was then
treated with in situ formed Cu−H.12 The 14-membered
macrocycle 2e and 17-membered macrocycle 2p were
synthesized using these conditions. Double-bond isomer-
ization as seen in Pd-catalyzed transhydrogenation13 of enynes
was not detected herein.
b
temp
yield
(%)
ratio (2a/
c
entry
(°C)
solvent
ligand
PPh3
3a)
1
2
3
4
5
6
7
8
120
100
140
120
120
120
120
120
120
120
120
120
120
120
120
120
DMF
DMF
DMF
DMSO
toluene
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
34
0
20:1
N/A
6:1
PPh3
PPh3
19
31
0
PPh3
20:1
N/A
N/A
20:1
18:1
90:1
11:1
25:1
44:1
44:1
28:1
4:1
PPh3
PPh3
PtBu3
0
49
53
64
73
72
71
73
N/A
30
39
P(OEt)3
PPh3
d
9
10
11
12
dppe
rac-BINAP
(R)-phanephos
(R)-phanephos
(R)-phanephos
L-proline
DMEDA
e
13
f
14
15
16
20:1
a
Reaction conditions unless otherwise specified: 1a (0.005 M),
Cu(OAc)2 (0.33 equiv), ligand (P/Cu = 3), HCO2Na (4 equiv),
b
c
K2CO3 (1.5 equiv) under N2 for 2 h. Isolated yield. Calculated from
d
1H NMR. Cu(OAc)2 (1 equiv) and PPh3 (1 equiv) were used.
e
Cu(OAc)2 (0.2 equiv) and phanephos (0.3 equiv) were used.
Cu(OAc)2 (0.1 equiv), phanephos (0.15 equiv) and reaction time (4
h); 70% conversion. Dppe = 1,2-bis(diphenylphosphinoethane;
BINAP = bis(diphenyl-phosphino)-1,1′-binaphthalene; phanephos =
4,12-bis(diphenylphosphino)[2.2]paracyclophane; DMEDA = N,N′-
dimethylethylenediamine.
f
total synthesis of oximidine II (HCO2Na (4 equiv), K2CO3,
(1.5 equiv), Cu(OAc)2 (0.33 equiv), and PPh3 (1 equiv) at
120 °C in DMF for 2 h). We employed Cu(OAc)2 as the
metal source instead of the previously reported CuI because
we observed better reproducibility of the reaction on large
scale with Cu(OAc)2.10 When these conditions were
employed, vinyl iodide 1a furnished the expected 12-
membered E,Z-diene lactone 2a in a modest 34% yield
along with the undesired acylic product 3a (entry 1). At 100
°C (Table 1, entry 2), no conversion was observed, while at
140 °C (Table 1, entry 3) both yield and selectivity
decreased. The reaction performed best at 120 °C (entries
1 and 4). Next, DMF was identified as the optimal solvent
(entries 46). Less polar solvents (entries 5 and 6) were
inefficient. Using other monodentate phosphorus ligands
(entries 7 and 8) slightly improved the yields. Stoichiometric
amounts of Cu(OAc)2 and 3 equiv of PPh3 facilitated the
B
DOI: 10.1021/acs.orglett.5b01892
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Reaction Scope
a
Reaction conditions unless otherwise specified: 1 (0.005 M), HCO2Na (4 equiv), K2CO3 (1.5 equiv) under N2; (A) Cu(OAc)2 (0.2 equiv),
phanephos (0.3 equiv); (B) Cu(OAc)2 (0.33 equiv), BINAP (0.5 equiv); (C) Cu(OAc)2 (1 equiv), PPh3 (3 equiv); (D) Cu(OAc)2 (0.33 equiv),
b
c
d
1
dppe (0.5 equiv). Reaction times were not fully optimized. Isolated yield. Calculated from H NMR. Cu(OAc)2 (0.1 equiv), phanephos (0.15
e
f
g
h
equiv) were used. Cu(OAc)2 (0.33 equiv), phanephos (0.33 equiv) were used. Only enyne was isolated. Decomposed. Combined yield of
inseparable mixture of diene 2l and enyne 4 (ratio 11:1). 34% of dimerized product 5 was also isolated.
i
membered rings. The synthesis of larger and thus less
strained macrocycles can be realized through a complementary
stepwise sequence. This methodology has been previously
used in the total synthesis of the natural product oximidine II,
and very recently, we have completed a concise formal total
synthesis of lactimidomycin employing the improved con-
ditions that we have discussed in this report.14 Further
investigations on applications in natural product synthesis are
in progress.
Scheme 2. Reactions of Substrates 1l and 1n
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 3. Stepwise Coupling/Reduction Synthesis of 14-
and 17-Membered Macrocycles
S
Experimental section, characterization data, and NMR spectra.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01892.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: georg@umn.edu.
Notes
The authors declare no competing financial interest.
In summary, a tandem reaction involving an intramolecular
Castro−Stephens coupling and in situ alkyne semireduction
has been developed for the construction of macrocycles
containing conjugated E,Z-diene units. The reaction is ring-
strain dependent and particularly efficient for 11−13-
ACKNOWLEDGMENTS
■
This work was supported by the University of Minnesota
through the Vince and McKnight Endowed Chairs.
C
DOI: 10.1021/acs.orglett.5b01892
Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.5b01892
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