Exo-selective reductive macrocyclization of ynals

Article abstract of DOI:10.1021/acs.orglett.5b00381

A general protocol for the highly exo-selective macrocyclization of ynals using a nickel/N-heterocyclic carbene catalyst system has been developed. A series of 10- to 21-membered macrocycles bearing an exomethylene substituent was synthesized in good yields with excellent regioselectivity (exo/endo >95:5). Very high levels of long-range diastereocontrol can also be achieved for some classes of macrocycles. Complementary to previously reported endo-selective macrocyclizations, this method provides accesses to exoalkylidene macrocycles from simple ynals in high selectivity.

Full text of DOI:10.1021/acs.orglett.5b00381

Letter
pubs.acs.org/OrgLett
Exo-Selective Reductive Macrocyclization of Ynals
Hengbin Wang, Solymar Negretti, Allison R. Knauff, and John Montgomery*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: A general protocol for the highly exo-selective
macrocyclization of ynals using a nickel/N-heterocyclic
carbene catalyst system has been developed. A series of 10-
to 21-membered macrocycles bearing an exomethylene
substituent was synthesized in good yields with excellent
regioselectivity (exo/endo >95:5). Very high levels of long-
range diastereocontrol can also be achieved for some classes of
macrocycles. Complementary to previously reported endo-selective macrocyclizations, this method provides accesses to
exoalkylidene macrocycles from simple ynals in high selectivity.
In contrast to the ease of assembly of structure types 1 and 2,
simple exomethylene substituents are commonly observed in
numerous classes of macrolactones,1h,i but would require an
unfavorable exocyclization from a simple terminal alkyne
substrate to afford product 3. A single example of participation
of a terminal alkyne in an exo-selective reductive macro-
cyclization was described by our laboratory while pursuing the
total synthesis of 10-deoxymethynolide.4a However, the
procedure required an N-heterocyclic carbene (NHC) ligand
that was prepared in a multistep operation and that displays a
somewhat limited scope when conducted with minimally
functionalized ynal structural classes. Given the potential utility
of directly accessing macrocycles of structure type 3 by the
reductive exocyclization of simple ynals bearing terminal alkynes,
we have conducted studies to provide a more broadly applicable
method. As reported herein, a protocol that utilizes a readily
available ligand has now been developed that is effective across a
range of substrates and that additionally possesses unusual
capabilities in long-range diastereocontrol. Mechanistic insights
provide a basis for the highly exo-selective outcome of this
procedure.
acrocycles are common structural motifs in many classes
1
Mof natural products and bioactive molecules.
While
methods such as macrolactonization and ring-closing metathesis
are commonly employed in their preparation,2,3 alternative
strategies that allow fundamentally different disconnections and
precursor functional groups are highly desirable. Nickel-
catalyzed reductive coupling methods have proven to be useful
in the preparation of macrocycles, since these methods allow the
combination of functional groups not commonly employed in
macrocycle-forming processes, and both a stereogenic center and
a stereodefined alkene are established during assembly of the
macrocyclic ring. Reports from our laboratory and the Jamison
group have established highly selective reductive macrocycliza-
tion methods that were utilized in the synthesis of several natural
products.4 These applications have typically involved control of
regiochemistry by the electronic influence of the alkyne. For
example, terminal alkynes display a bias toward endocyclization
to provide internal 1,2-trans-disubstituted alkenes (Scheme 1,
structure 1), whereas aromatic alkynes display a bias toward
exocyclization to provide exobenzylidene structural elements
(structure 2).
We began the study of exomacrocyclization with ynal 4, by
applying reaction conditions that were developed in our recent
work with precursors leading to 10-deoxymethynolide.4a With
ligand DP-IPr and triethylsilane (Et3SiH) as the reducing agent
(Table 1, entry 1), the desired macrocycle 5 was successfully
synthesized with excellent regioselectivity (exo:endo 93:7) albeit
in low yield (21%). In the course of conducting recent
mechanistic studies of intermolecular aldehyde−alkyne reductive
couplings, we observed that high temperatures paired with bulky
silanes led to especially high levels of regiocontrol, where the
more hindered alkyne terminus undergoes addition to the
aldehyde.5a In exploring the options with DP-IPr, increasing the
reaction temperature did not lead to effective macrocyclizations
with substrate 4, and the Ni/DP-IPr catalyzed reaction with
Scheme 1. Regiocontrol in Nickel-Catalyzed Reductive
Macrocyclizations
Received: February 5, 2015
Published: March 6, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00381
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Organic Letters
Letter
a
Table 1. Optimization Study
Scheme 2. Scope of Macrocyclizations
a
b
temp
(°C)
C,
mM
rr
NMR
isolated
yield, %
entry
L·HX
R
(5:6)
yield, %
1
DP-IPr
DP-IPr
DP-IPr
SIPr
rt
Et
3
3
3
3
3
3
3
3
5
10
5
5
5
93:7
−
21
−
−
−
−
2
90
90
90
90
90
90
50
90
90
90
90
90
Et
−
−
trace
trace
27
18
35
67
30
−
3
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
4
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
65:35
>95:5
>95:5
5
IPr
6
IPrMe
IPrCl
−
66
7
8
IPrCl
−
9
IPrCl
69
−
51
10
11
IPrCl
32
c
IPrCl
−
17
−
d
12
IPrCl
IPrCl
i-Pr
−
63
a
rr is ratio of regioisomers.
e
13
i-Pr
a
b
Determined by 1H NMR analysis of the crude mixture. 1,3,5-
worked well in generating molecules having a ring size greater
than 11, and 12-, 13-, 18-, and 21-membered macrocycles 8b−8e
were produced in good yields. Under the standard conditions,
10-membered macrocycle 8a was also successfully synthesized in
moderate yield (45%). In addition to esters within the linear
precursor, ethers are also tolerated as shown by the synthesis of
macrocycle 8f. Unfortunately, further efforts to include an amide
functional group or purely aliphatic chains only resulted in low
yields. In these latter cases, dimers and higher oligomers were
observed as major products.
Trimethoxybenzene was used as the internal standard. Preparative
experiments were not conducted with an internal standard due to the
c
complexity of removing the internal standard. Combined yield.
d
Ni(COD)2 (23 mol %), IPrCl·HCl (20 mol %), KO-t-Bu (24 mol %).
e
Ni(COD)2 (43 mol %), IPrCl·HCl (40 mol %), KO-t-Bu (44 mol %).
In addition to terminal alkynes, the reaction of internal alkynes
was also explored. In our previous study on nickel-catalyzed
reductive macrocyclizations, a larger ring (21-membered)
exoalkylidene macrocycle was prepared using IPr as the ligand
and Et3SiH as the reducing reagent (exo/endo = 5:1).4b Based on
the high regioselectivity observed in this study, we envisioned
that higher selectivity toward the synthesis of exoalkylidene
macrocycles could be achieved with the IPrCl ligand. Indeed, only
exocyclization products 8g and 8h were obtained from the Ni/
IPrCl catalyzed reaction of ynal 7g (Scheme 2). In contrast to the
need for bulky silanes to achieve high levels of regiocontrol with
terminal alkynes, excellent regioselectivity was obtained with
both Et3SiH and (i-Pr)3SiH using IPrCl as the ligand.
Prior advances from Jamison and our laboratory have
described high levels of diastereoselectivity in macrocyclizations
utilizing chirality adjacent to the aldehyde or alkyne.4 The
Jamison approach to amphidinolides T1 and T4 in particular
described a detailed conformational analysis of the diastereose-
lectivity of macrocyclizations of aromatic alkynes.4e To more
fully explore the potential of diastereoselective macrocycliza-
tions, including those potentially involving long-range diaster-
eocontrol, we examined the reactivity of ynals 9a−9f (Scheme 3).
Interestingly, the 11-membered macrocycles 10a−10c were all
formed as single diastereomers. Remarkably, despite the remote
positioning of substituents, macrocycle 10d was generated with a
high level of 1,5-diastereocontrol (90:10).
either Et3SiH or (i-Pr)3SiH as the reducing agent (entries 2 and
3) failed to produce the desired macrocyclization product. Slight
improvement of the reaction yield, however, was observed with
the SIPr ligand (entry 4). Encouraged by this result, other NHC
ligands with 2,6-diisopropylphenyl substituents on nitrogen were
examined, and the highest yield of macrocycle 5 was obtained
with IPrCl as the ligand (entries 5−7). IPrCl is easily accessible,
highly stable, and known to provide highly active catalysts in
other catalytic processes.6,7 With IPrCl as a ligand, the reaction
temperature, concentration, and catalyst loading were then
investigated. It was found that conducting the reaction at
relatively high temperatures (90 °C) was indeed necessary, and
lowering the temperature to 50 °C decreased the yield of
compound 5 to 30% (entry 8). The concentration of the reaction
could be increased to 5 mM (entry 9), but a decrease in yield was
observed for the reaction performed at higher concentration
(entry 10). The use of bulky (i-Pr)3SiH was essential for the
regioselectivity (exo/endo), and large erosion of the regiose-
lectivity was observed with Et3SiH as the reducing agent (entry
11). The optimal catalyst loading for this reaction was 30 mol %
of nickel/IPrCl. Lowering the catalyst loading decreased the yield,
while increasing the catalyst loading to 40 mol % provided no
benefits (entries 12 and 13).
After identifying the optimal reaction conditions (entry 9), the
scope of ring size and functional groups tolerated in the exo-
selective macrocyclization was investigated (Scheme 2). In all
cases studied, high selectivity (>95:5) for the formation of
exoalkylidene macrocycles was observed. In general, the method
The stereochemistry of 10a−10c was deduced by COSY and
NOE experiments. The diol derived from 10d, by removing the
two triisopropylsilyl groups, was crystalline, and its structure was
unambiguously assigned by X-ray crystallography.8 Further study
showed that the diastereoselectivity of the macrocyclization
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Organic Letters
Letter
a
structure. The typical pathway for silane-mediated reductive
couplings involves rate-determining formation of a nickel
metallacycle, which thus governs the regioselectivity of the
process.9 Alternatively, the specific combination of a large NHC
ligand, a bulky silane, and high temperature was observed to
follow a different kinetic description, where formation of the
metallacycle leading to the minor product is reversible.5a This
outcome leads to very high regioselectivity for the product that
possesses the more hindered C−C bond. The conditions (large
ligand, bulky silane, high temperature, slow addition) favoring
formation of the more hindered exocyclization-derived macro-
cyclization products (Schemes 2−3) closely pattern the
conditions that favored reversible formation of the metallacycle
in our recent mechanistic investigations. On this basis, it is likely
that the procedure reported herein involves reversible formation
of the endocyclic metallacycle 15, but due to the more hindered
nature of the Ni−C bond, its capture by the bulky silane [i.e., (i-
Pr)3SiH] is inefficient (Scheme 5). Reversion back to the Ni(0)
Scheme 3. Diastereoselectivity Study
Scheme 5. Mechanistic Rationale
a
b
rr is the ratio of regioisomers. Combined yield.
strongly depends on the ring size formed. With a methyl
substituent at the homopropargylic position, 13- and 16-
membered macrocycles 10e and 10f were synthesized in good
yields employing the standard conditions. Compared to the 11-
membered macrocycle 10b (dr >95:5), the diastereoselectivity of
13-membered macrocycle 10e dropped to 76:24, and a
completely nonselective reaction was observed for the synthesis
of 16-membered macrocycle 10f (dr 50:50).
Coupled with the previously reported advances allowing
endoselective macrocyclizations of terminal alkynes,4b the
exocyclization protocol described herein now allows either
regioisomer to be effectively obtained from a common substrate.
To demonstrate the versatility of this feature, substrate 9d was
subjected to the macrocyclization conditions, allowing either
endo- or exocyclization to proceed (Scheme 4). Whereas the
ynal complex 14, reorientation of the alkyne to intermediate 12,
and then formation of exocyclic metallacycle 13 allows a
productive σ-bond metathesis leading to the preferred formation
of the exocyclic product.
According to the above mechanistic hypothesis, the
regioselectivity for the exocyclic product should erode as the
silane steric hindrance decreases. To address this question, the
macrocyclization of ynal 9b was conducted with (i-Pr)3SiH and
also with Et3SiH under otherwise identical conditions (Scheme
6). Compared to the highly regioselective synthesis of 10b using
Scheme 4. Regiochemical Alterations
Scheme 6. Influence of Silane Sterics on Regioselectivity
(i-Pr)3SiH, the reaction of 9b with Et3SiH generated the
products as a mixture of exo- and endocyclization products 16
and 17 with a ratio of 32:68 favoring macrocycle 17 derived from
endocyclization. These results support the above hypothesis for
the origin of regiocontrol since the use of a smaller silane
promotes a faster addition of silane to the hindered endocyclic
metallacycle 15, thus rendering the production of endocyclic
products more efficient.
exocyclization procedure requires a bulky ligand IPrCl and bulky
silane (i-Pr)3SiH to produce 10d, the endocyclization proceeds
best with IMes as the ligand and Et3SiH as the reductant to
produce 12-membered macrocycle 11.
Recent mechanistic investigations of intermolecular nickel-
catalyzed reductive couplings have elucidated the operative
mechanistic pathways according to the catalyst and silane
Whereas exocyclization products 10b or 16 were obtained
with high levels of diastereoselectivity regardless of silane
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Letter
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In conclusion, a general protocol for the exo-selective
macrocyclization of ynals has been developed. By employing a
Ni/IPrCl catalyst system paired with (i-Pr)3SiH as the reducing
agent, high selectivity for the synthesis of exoalkylidene
macrocycles was achieved. Although IPrCl has been successfully
applied to other chemical transformations,7 its use in reductive
coupling reactions of this type has not been previously described.
Under the optimized conditions, 10- to 21-membered macro-
cycles were prepared in synthetically useful yields with high
regioselectivity. Complementary to previously published endo-
selective macrocyclizations, this study provides access to
exoalkylidene macrocycles with high selectivity from similar
ynal substrates. Excellent diastereoselectivity of the exo-selective
macrocyclization was also observed for macrocycles of certain
ring sizes. High levels of diastereocontrol were obtained for
macrocycles with substituents quite remote from the reacting
alkyne and aldehyde functional groups. Future efforts will involve
increasingly complex illustrations of this macrocyclization
method and utilization of the novel structures obtained in
enzymatic oxidation processes.
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(5) For other regiochemistry reversals in nickel catalysis: (a) Jackson,
E. P.; Montgomery, J. J. Am. Chem. Soc. 2015, 137, 958. (b) Malik, H. A.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
Chem. Soc. 2014, 136, 17702. (e) Kopfer, A.; Sam, B.; Breit, B.; Krische,
̈
Synthetic details, spectral data, and CIF file for the X-ray
crystallographic data. These materials are available free of charge
via the Internet at http://pubs.acs.org.
M. J. Chem. Sci. 2013, 4, 1876. (f) Bausch, C. C.; Patman, R. L.; Breit, B.;
Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 5686. (g) Zhao, Y.; Weix,
D. J. J. Am. Chem. Soc. 2013, 136, 48. (h) Donets, P. A.; Cramer, N.
Angew. Chem., Int. Ed. 2015, 54, 633. (i) For a copper-catalyzed process:
Tani, Y.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2014, 136,
17706. (j) For a review of regiochemistry reversal reactions:
Mahatthananchai, J.; Dumas, A. M.; Bode, J. W. Angew. Chem., Int. Ed.
2012, 51, 10954.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jmontg@umich.edu.
Notes
(6) For the synthesis of IPrCl: (a) Gaillard, S.; Slawin, A. M. Z.; Bonura,
A. T.; Stevens, E. D.; Nolan, S. P. Organometallics 2009, 29, 394.
(b) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55,
14523.
(7) (a) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Chem.Eur. J. 2012,
18, 4179. (b) Arduengo, A. J., III; Davidson, F.; Dias, H. V. R.; Goerlich,
J. R.; Khasnis, D.; Marshall, W. J.; Prakasha, T. K. J. Am. Chem. Soc. 1997,
119, 12742. (c) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv.
Synth. Catal. 2012, 354, 1542. (d) Fujihara, T.; Xu, T.; Semba, K.; Terao,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grants GM-57014 (which
supports catalytic ligand-controlled regioreversals) and GM-
78553 (which supports the examination of novel macrolide
analogues in enzymatic hydroxylations). S.N. acknowledges
support from the NIH Chemistry-Biology Interface Training
Grant (GM008597). We thank Dr. Jeff Kampf (University of
Michigan) for the X-ray crystallographic structure determination.
Evan P. Jackson (University of Michigan) is thanked for the
initial synthesis of the IPrCl ligand.
Bhattacharyya, K. X.; Muller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2007,
̈
129, 7736.
(8) The crystal structure has been deposited at the Cambridge
Crystallographic Data Centre, and the deposition number CCDC
1045615 has been allocated.
(9) (a) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc. 2011,
133, 6956. (b) Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc. 2011,
133, 5728.
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