Access to macrocyclic endocyclic and exocyclic allylic alcohols by nickel-catalyzed reductive cyclization of ynals

Article abstract of DOI:10.1021/ja054590i

Ni-catalyzed reductive macrocyclizations of ynals are reported. Disubstituted alkynes afford either endocyclic or exocyclic allylic alcohols depending on the ligand. Phosphine ligands favor the formation of endocyclic olefins, whereas N-heterocyclic carbe

Full text of DOI:10.1021/ja054590i

Published on Web 08/31/2005
Access to Macrocyclic Endocyclic and Exocyclic Allylic Alcohols by
Nickel-Catalyzed Reductive Cyclization of Ynals
Beth Knapp-Reed, Gireesh M. Mahandru, and John Montgomery*,‡
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202
Received July 11, 2005; E-mail: jmontg@umich.edu
Table 1. Preparation of Macrocycles
Macrocyclic allylic alcohols are a common structural motif in
many natural products, and examples of both exocyclic and
endocyclic orientations of the alkene unit are frequently observed.
Among the known structures, endocyclic allylic alcohols with a
1,2-disubstitution pattern on the alkene are most common. Although
many routes to allylic alcohols are known, the reductive coupling
of alkynes and aldehydes is perhaps most attractive since the
stereogenic center, the alkene stereochemistry, and the carbon-
carbon bond that connects the two are simultaneously established.1-3
Early approaches to the reductive coupling of alkynes and aldehydes
involved the stoichiometric hydroboration or hydrozirconation of
an alkyne, followed by transmetalation with dimethylzinc and
addition to the aldehyde to generate an allylic alcohol.1 The variant
involving hydroboration has recently been applied in macro-
cyclizations.1c Other approaches, which utilize Ti, Zr, and Ta
complexes, have also been reported.2 Our group and Jamison have
recently developed nickel-catalyzed methods for the reductive
coupling of alkynes and aldehydes, and a broad range of procedures
have been reported.4-9 Alkylative couplings typically involve
catalysis with Ni(COD)2, whereas reductive couplings typically
involve catalysis with Ni(COD)2 and basic phosphines, such as
PBu3. A particularly challenging subset of this reaction class is the
intermolecular reductive coupling of terminal alkynes since
Ni(COD)2/PBu3 efficiently catalyzes the trimerization of terminal
alkynes. A recent report from our laboratory illustrates that the use
of N-heterocyclic carbene ligands largely avoids this limitation and
allows efficient reductive couplings of terminal alkynes.8c
The strategy of preparing macrocyclic allylic alcohols by the
nickel-catalyzed reductive exocyclization of ynals with an internal
alkyne was elegantly applied by Jamison in the total syntheses of
amphidinolides T1 and T4.9a A similar approach was examined in
the endocyclization of ynals with internal alkynes in an approach
to (-)-terpestacin; however, that strategy was not realized because
of the facility of the corresponding exocyclization.9b Given the
importance of accessing both endo- and exo-manifolds in macro-
cyclizations, as well as utilizing terminal alkynes to access the
important substructure that possesses a 1,2-disubstituted alkene, we
have examined macrocyclizations under a modification of our
recently reported conditions that involve catalysis with Ni(COD)2
and N-heterocyclic carbenes. This study thus provides the first
examples of nickel-catalyzed reductive macrocyclizations of ynals
that possess terminal alkynes and the first that provides ligand-
controlled selectivity for either the endocyclic or exocyclic manifold.
Our study began by examining the cyclization of 1b using the
conditions previously reported for the intermolecular coupling of
terminal alkynes and aldehydes.8c Treatment of 1b with a catalyst
system derived from Ni(COD)2, 2,10 and n-BuLi in THF provided
the desired 11-membered ring 4b in 31% yield. While the yield in
this initial experiment was modest, we were pleased to observe
entry
substrate
L
X
Y
m
n
ring size
yield (4:5)a
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
2
2
2
2
2
2
3
H2 CH2
H2 CH2
H2 CH2
1
1
1
7
7
7
7
1
3
6
1
5
8
8
9
11
14
15
19
22
22
33% (<1:99)
50% (>99:1)
62% (>99:1)
69% (>99:1)
70% (>99:1)
67% (>99:1)
67% (>99:1)b
O
O
O
O
O
O
O
O
1f
a Typical reaction conditions: Ni(COD)2 (20 mol %), KOt-Bu (20 mol
%), 2 or 3 (20 mol %), Et3SiH (5 equiv), toluene (0.006 M), 1 h. b Isolated
as a 10:1 ratio of endo- and exocyclic isomers.
that these conditions provided endocyclic E-olefin 4b as the sole
product. After screening several sets of conditions that varied the
base used to generate the carbene, solvent, and temperature, it was
determined that the optimal reaction conditions included using a
catalyst derived from Ni(COD)2, KOt-Bu, and 210 in toluene (Table
1, entry 2).
These optimized conditions were then used to generate macro-
cycles varying in size ranging from 14- to 22-membered rings
(Table 1). However, we were unable to form macrocycles smaller
than the 11-membered ring originally investigated (4b). Under our
optimized conditions, alkynal 1a provided only dimerized product
5a even when the ynal was added slowly to the catalyst solution
via syringe pump (entry 1). These dimerization products were not
observed with the longer chains, with the desired monomeric ring
being the only discernible product. Only the endocyclic E-olefins
were observed except when bulkier carbene 3 was employed.
Cyclization of 1f with this ligand produced 4f as the major product
along with a small amount of the exocyclic isomer (entry 7). Other
ligand variations were not studied with these substrates since
cyclization attempts with phosphine-based catalysts resulted in large
amounts of alkyne trimerization byproducts.
The cyclization of internal alkynes was also examined (Table
2). Under the optimized reaction conditions, phenyl-substituted ynal
6a provided exocyclic olefin 8a (entry 1). A catalyst system derived
from Ni(COD)2 and tributylphosphine was also highly selective
for exocyclization (entry 2). Results with methyl-substituted ynal
‡ Correspondence to this author should be addressed to: Department of
Chemistry, University of Michigan, 930 N. University, Ann Arbor, MI 48109.
9
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J. AM. CHEM. SOC. 2005, 127, 13156-13157
10.1021/ja054590i CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Preparation of Macrocycles from Internal Alkynes
in size, as with 2 and especially 3, interactions between the ligand
and RL force complexation to occur such that RL is placed distal to
the ligand (11), favoring formation of the exocyclization product
(entries 3 and 4).
In summary, this communication reports the first examples of
Ni-catalyzed macrocyclizations of ynals containing terminal alkynes
and the first examples that involve a ligand-controlled reversal in
regioselection with internal alkynes. Terminal alkynes and aryl
alkynes display substrate control in regioselection that overrides
ligand influences. With aliphatic internal alkynes, addition of the
most hindered alkyne terminus is favored by bulky ligands, whereas
addition of the least hindered alkyne terminus is favored by small
ligands. Application of this ligand-directed regioselection in total
synthesis will be reported in due course.
entry
substrate
conditionsa
R2
product
yield (7:8)
Acknowledgment. The authors wish to acknowledge receipt
of NIH Grant GM-57014. Mani Chaulagain, Kanicha Sa-ei, and
Vanessa Landry are thanked for their contributions.
1
2
3
4
5
6
6a
6a
6b
6b
6b
6b
a
c
a
b
c
d
TES
H
TES
TES
H
8a
8b
7c/8c
7c/8c
7d/8d
7d/8d
68%
48%
60% (1:1)
93% (1:5)
68% (3:1)
89% (4.5:1)
Supporting Information Available: Full experimental details and
copies of NMR spectra (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
H
a Conditions: (a) Ni(COD)2 (20 mol %), KOt-Bu (20 mol %), 2 (20
mol %), Et3SiH (5 equiv), toluene (0.006 M), 75 °C, 1 h; (b) Ni(COD)2
(20 mol %), KOt-Bu (20 mol %), 3 (20 mol %), Et3SiH (5 equiv), toluene
(0.006 M), 75 °C, 1 h; (c) Ni(COD)2 (20 mol %), Bu3P (20 mol %), Et3B
(3 equiv), toluene, 60 °C, 16 h; (d) Ni(COD)2 (20 mol %), Me3P (20 mol
%), Et3B (3 equiv), toluene (0.006 M), 60 °C, 16 h.
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(entry 3). Switching to a bulkier carbene (3) provided the exocyclic
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of tributylphosphine and triethylborane9 led to a reversal in
selectivity, with the endocyclic product 7d being favored in a 3:1
ratio (entry 5). This selectivity was further improved with tri-
methylphosphine and triethylborane, which boosted the endocyclic
selectivity to 4.5:1 (entry 6).
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Chem. Soc. 2003, 125, 11488.
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