Development of a Strategy for Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral γ-Hydroxyaldehyde Equivalents

Article abstract of DOI:10.1021/acs.orglett.9b02973

We report the development of a stereoselective method for the allylation of ketones utilizing N-substituted allyl equivalents generated from a chiral allenamide. By choice of the appropriate ligand for the Cu-catalyst, high linear selectivity can be obtai

Full text of DOI:10.1021/acs.orglett.9b02973

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development of a Strategy for Linear-Selective Cu-Catalyzed
Reductive Coupling of Ketones and Allenes for the Synthesis of
Chiral γ‑Hydroxyaldehyde Equivalents
Raphael K. Klake, Samantha L. Gargaro, Skyler L. Gentry, Sharon O. Elele, and Joshua D. Sieber*
Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, Virginia 23284-3028, United
States
*
S Supporting Information
ABSTRACT: We report the development of a stereoselective method for
the allylation of ketones utilizing N-substituted allyl equivalents generated
from a chiral allenamide. By choice of the appropriate ligand for the Cu-
catalyst, high linear selectivity can be obtained with good diastereocontrol.
This methodology allows access to chiral γ-hydroxyaldehyde equivalents
that were applied in the synthesis of chiral γ-lactones and 2,5-disubstitued
tetrahydrofurans.
hiral alcohols are ubiquitous in organic molecules
C
prepared both naturally and synthetically for a desired
biological function. Therefore, development of synthetic
methods to access chiral alcohols has been an intense area of
1
research in the field of organic chemistry. One of the most
highly studied areas of stereoselective alcohol synthesis is in
the controlled addition of an allylmetal reagent to an aldehyde
2
or ketone electrophile. Pioneering work in stereoselective
allylation typically employed the generation of a stoichiometric
chiral allylmetal nucleophile in a separate step to be used in the
allylation reaction with an aldehyde or ketone to generate the
3
chiral alcohol. Over the years, catalytic methods to generate
the reactive allylmetal in situ from an unreactive allyl source
4
−7
and metal catalyst have emerged.
In particular, reductive
8
coupling strategies that generate the reactive allylmetal from
unsaturated hydrocarbons via hydrometalation are extremely
powerful, atom-economical approaches for the synthesis of
9
chiral homoallylic alcohols.
Recently, an elegant catalytic method for the allylation of
ketone and imine electrophiles was developed by Buchwald
1
0
employing hydrocupration of carbon-substituted allenes (2)
1
1
or 1,3-dienes by a Cu−H catalyst to generate the reactive
allylmetal reagent in situ (Figure 1A). In the ketone version of
this process, the anti-diastereomer of the branched product
anti-b-3) was formed as the major product in high diastereo-
1
0a
(
and enantioselectivity when using chiral bis(phosphine)
ligands. However, the linear product l-3 was not formed.
Our group became interested in developing a method to
generate linear products utilizing this approach, which has not
been reported with ketones. While Buchwald demonstrated
that both linear and branched products could be obtained
Figure 1. Cu-catalyzed reductive coupling of allenes and ketones.
Hydrometalation of allenes typically occurs trans to the R′-
12
substituent of the allene due to steric reasons. Therefore,
initial hydrocupration of 2 would be expected to afford the Z-
isomer of the linear (allyl)Cu species l-Z-5. Buchwald has
1
0c
when using imine electrophiles
by changing the N-
substituent on the imine, this is not possible with ketone
electrophiles.
Our working mechanistic hypothesis for regio- and
diasteroselectivity for this reaction is given in Figure 1B.
Received: August 20, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Copper-Catalyzed Reductive Coupling
1
0a
would be derived from anti-b-7 from reaction between l-E-5
and 1 via 6c. The preference for this isomer can be easily
rationalized by steric effects. Arguably, l-E-5 would be the least
sterically hindered of the three possible (allyl)Cu intermediates
b
c
d
d
entry
ligand
TEP
θ
% l-15a (dr)
l/b
(
5) causing it to be the dominant species in the reaction.
1
2
3
4
5
6
7
8
9
PCy3
2056
−
2056
2052
−
170
142
182
−
68 (84:16)
14 (84:16)
61 (93:7)
71 (93:7)
80:20
23:77
76:24
71:29
9:91
12:88
26:74
70:30
83:17
92:8
Therefore, if this mechanistic hypothesis is correct, then to
obtain the linear product (E-l-7), conditions would need to be
designed to either stabilize the branched (ally)Cu intermediate
b-5 relative to l-5 or make it more reactive.
Dcpe
P(t-Bu)3
P(adam)3
SPhos
e
−
−
−
7 (68:32)
Our strategy to stabilize (allyl)Cu intermediate b-5 is shown
in Figure 1C. Use of allene 8 containing a heteroatom tethered
ligand should initially generate linear (allyl)Cu species l-9 after
hydrocupration. The tethered ligand could then help stabilize
the branched (allyl)Cu intermediate b-9 through coordination
to Cu. Reaction of b-9 with a ketone would then generate
linear product l-10 with an enol (X = O) or enamine (X = NR)
group representing a masked aldehyde functionality to provide
useful chiral γ-hydroxyaldehyde equivalents. Additionally, use
of a chiral tethered ligand in allene 8 could enable
stereocontrol of the newly formed stereocenter of 10. Overall,
we envisioned that this methodology could be a valuable entry
XPhos
−
−
5
5
t-BuXPhos
P(o-tol)3
P(NMe2)3
P(OEt)3
16
2067
2062
2076
−
194
157
109
−
14 (81:19)
79 (87:13)
90 (83:17)
97 (90:10)
89 (92:8)
76 (89:11)
12 (85:15)
10
11
12
13
14
97:3
97:3
99:1
99:1
17
−
−
P(OPh)3
P(C F )
5 3
2085
2091
128
184
6
a
1
a (0.25 mmol) and 14 (0.30 mmol) in 0.5 mL of toluene. See the
Supporting Information for details. Tolman electronic parameter
from ref 19. Ligand cone angle obtained from ref 19a. Determined
by HNMR spectroscopy on the unpurified reaction mixture. dr of b-
5a.
b
c
d
15
16
into chiral lactone or tetrahydrofuran containing natural
1
e
products (Scheme 1) through lactol 11 obtained by hydrolysis
1
Scheme 1. Chiral Lactone and THF Containing Natural
Products
the oxazolidinone carbonyl group (i.e., noncoordinating
solvents, monodentate ligands).
Trialkyl monodentate phosphines favored the formation of
linear product l-15a with modest l/b selectivity (entries 1, 3,
and 4). Furthermore, use of dcpe, a bidentate ligand
commonly employed in Cu−H catalyzed reductive coupling
10,11
reactions,
also gave preferentially the branched product
(
entry 2). A further survey of monodentate phosphine ligands
19
19a
of varying electronic and steric properties revealed that the
linear selectivity was largely influenced by the electron-
donating ability of the ligand employed with less electron-
donating ligands affording higher linear selectivities (compare
entries 1, 3, 4, and 8−14). There was a rough correlation
between ligand cone angle and diasterocontrol with larger
ligands affording higher diastereoselectivity (compare entries 1,
3, 4, 9, 10, 12, and 13). Ultimately, phosphoramidite ligand 16
afforded the highest reaction yield with excellent linear
selectivity and good diastereoselectivity.
of the enol or enamine functionality of 10. Herein, we report
our findings on the development of a diastereoselective
copper-catalyzed reductive coupling of a chiral allenamide
with ketones to access the linear isomer (10) of product.
To identify an allene that fit the requirements of 8, we
initially chose to investigate allenamide 14 derived from Evans’
auxiliary because it has been synthesized previously (Table
The substrate scope for the linear-selective reductive
coupling of ketones and allene 14 is given in Scheme 2. In
general, high linear selectivity was obtained in good to
excellent reaction yield for halogenated (l-15f,i), electron-
rich (l-15b,c,j,k), and electron-poor (l-15e,m) arenes.
Hindered ketones bearing ortho-substitution on the aryl
group required heating to achieve full conversion; however,
this did not severely reduce the diastereoselectivity (l-15c,h,i).
Additionally, diastereoselectivity and linear selectivity were
reduced when the steric bias between the two R-groups of
ketone 1 was reduced (e.g. l-15d,l,n,o,p,u). Notably, a nitrile
1
7
1
). Furthermore, we had hoped that the carbonyl group of
the oxazolidinone would serve as a sufficient coordinating
1
8
group for Cu. Additionally, based on our design in Figure
C, we focused on reaction conditions where Cu would have a
low coordination number to facilitate potential coordination of
1
B
DOI: 10.1021/acs.orglett.9b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Linear Selective Copper(phosphoramidite)
Catalyzed Reductive Coupling
Scheme 3. Effect of Oxazolidinone Structure on
Regioselectivity
a
selectivity in the reaction when the optimized ligand 16 was
used. Additionally, use of PCy in the reaction employing
3
allenamide 18 led to a turnover in the reaction selectivity and
favored formation of the branched product b-19. In contrast,
with chiral allenamide 14, use of PCy as a ligand afforded
3
linear selectivity (Scheme 3 and Table 1, entry 1). Based on
these observations, and the results of our ligand optimization
survey (Table 1), a model to rationalize regio- and stereo-
control in these reactions could be developed (Figure 2).
a
Percent yield represents isolated yield of linear product as a mixture
Figure 2. Stereo- and Regiochemical model.
of two diastereomers on 0.5 mmol scale of 1 using 1.2 equiv of 14; see
the Supporting Information for further details. Diastereomeric ratios
1
Mechanistically, hydrocupration of allene 14 or 18 is expected
to initially form the Z-linear (σ-allyl)Cu complex (l-Z-20; vide
supra) that will be in equilibrium with the branched (σ-
allyl)Cu complex (b-σ-20) through the intermediacy of the (π-
allyl)Cu complex π-20. The π-allyl geometry and coordination
of the oxazolidinone group to Cu in complex π-20 are
proposed based on structural information determined by X-ray
crystallography and NMR spectroscopy for related anions of
(
dr) and linear:branched ratios (l:b) were determined by H NMR
b
spectroscopy on the unpurified reaction mixture. Reaction
performed at 60 °C. Reaction performed at 40 °C. 4.0 equiv of
Me(MeO) SiH used.
c
d
2
group was not reduced under the reaction conditions (l-15q),
and both amino (l-15s) and a free hydroxyl group (l-15k) was
also tolerated.
In regards to factors dictating branched/linear selectivity and
stereocontrol in these reactions, studies employing achiral
allenamide 18 were informative (Scheme 3). Use of 18 lacking
substitution on the oxazolidinone ring afforded reduced linear
20
this type found in the literature. Considering the turnover-
limiting step in Cu-catalyzed reductive coupling of ketones and
allenes is believed to be the addition of the (allyl)Cu reagent to
1
0
the ketone electrophile, this would allow for a pre-
C
DOI: 10.1021/acs.orglett.9b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
equilibrium between l-Z-20 and b-σ-20 to be established before
reaction with the ketone. Therefore, a model to rationalize
regioselectivity in the reaction could be developed based on
considering the stability of these two intermediates whereby a
preference for l-Z-20 would result in a branched selective
process while preference for b-σ-20 in the reaction would result
Scheme 4. Synthetic Applications
21
in linear selectivity.
Due to the Z-olefin geometry formed in the initial
hydrocupration event, reaction regioselectivity could be
explained by a competition between the strength of the
1
,3
oxazolidinone coordination versus the size of the A -strain
present in l-Z-20 (Figure 2). The high linear selectivity
obtained as the electron-donating ability of the phosphine
ligand decreases (Table 1) can be explained by an increase in
the preference for complex b-σ-20 due to the enhanced
1
,3
electrophilicity at Cu. Additionally, the magnitude of the A -
strain in l-Z-20 would be expected to affect the overall
equilibrium between the (allyl)Cu complexes. As a result,
when the poorly electron-donating ligand 16 is employed,
coordination of the oxazolidinone to the electrophilic Cu atom
leads to a preference for b-σ-20 leading to linear selectivity
when using either allenamide 14 or 18. A reduction in linear
selectivity with ligand 16 when using allenamide 18 in place of
1
4 can be rationalized by the presence of increased amounts of
1
,3
l-Z-20 due to the reduction in the magnitude of the A -strain
present in l-Z-20 when R = H. In contrast, when the electron-
rich ligand PCy is used, the branched product (b-19) is
3
preferred when the unsubstituted allenamide 18 was used. This
may result from a shift in the equilibrium of the (allyl)Cu
complexes to favor l-Z-20 because of the reduced coordinating
ability of the oxazolidinone to the more electron-rich Cu atom.
23
diastereocontrol in the Et Zn addition. Finally, the linear
2
selective reductive coupling reaction was performed on a 1.0 g
scale to complete a three-step asymmetric synthesis of the
1,3
When the magnitude of the A -strain present in l-Z-20 is
15a−c
natural product (S)-(−)-boivinianin A
methylacetophenone.
starting from 4′-
increased by utilizing the chiral allenamide 14 with PCy as
3
ligand, the oxazolidinone coordination is presumably enhanced
by destabilizing l-Z-20 leading to preferential linear selectivity
in the reaction. Furthermore, it is important to point out that if
In conclusion, we have disclosed a strategy for the
stereoselective reductive coupling of ketones and a chiral
allenamide to selectively generate the linear reaction products
providing useful chiral γ-hydroxyaldehyde equivalents. This
method employs simple starting materials and a readily
available catalyst system to furnish chiral products with
increased complexity in an efficient manner. Further develop-
ment of this reaction to enable stereocontrol by a chiral
catalyst is currently under investigation and will be reported in
due course.
1
,3
the A -strain present in l-Z-20 is involved in governing
regiochemical control in this reaction, then the alkene moiety
22
in b-σ-20 likely remains coordinated to Cu. If the alkene of b-
σ-20 were to disassociate from Cu, isomerization of the Z-
alkene to the E-isomer l-E-20 could occur that would remove
1
,3
this A -interaction that is proposed to be important.
Additionally, it is possible that b-σ-20 may not be a discrete
intermediate in these reactions, and rather, π-20 may be the
dominant species that reacts directly with ketone 1a to afford
22
ASSOCIATED CONTENT
linear product l-15a/19. However, this scenario is also
consistent with the model described above for regiocontrol.
Finally, the absolute stereochemistry and the Z-olefin geometry
of the linear product l-15a can be rationalized by the reaction
of b-σ-20 or π-20 with ketone 1a through chair-transition state
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02973.
2
1 with the oxazolidinone group in an axial position and
Experimental procedures and characterization data for
all compounds and NMR spectra (PDF)
complexed with Cu for selective reaction to the Si-face of 1a.
Transition state model 21 is supported by literature
precedent
2
0b,c
and further supports oxazolidinone coordination
in these processes.
AUTHOR INFORMATION
■
*
Demonstration of the synthetic potential of the reductive
coupling products is outlined in Scheme 4. Reduction of the
oxazolidinone of l-15a with excess DIBAL afforded lactol 22
after hydrolysis of the resultant eneamine formed in the
reduction to unmask the chiral γ-hydroxyaldehyde equivalent.
Lactol 22 could then be converted to chiral γ-lactone 23 by
oxidation with TPAP/NMO or converted to the 2,5-
substituted tetrahydrofuran 24 in good yield albeit with poor
Corresponding Author
jdsieber@vcu.edu
ORCID
Joshua D. Sieber: 0000-0001-6607-5097
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b02973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
−
100.degree. Under New, Salt-Free Conditions. J. Org. Chem. 1991,
6, 401−404. (d) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H.
ACKNOWLEDGMENTS
■
5
Startup funding from the Virginia Commonwealth University
and the Bill and Melinda Gates Foundation (The Medicines
for All Institute, Grant Number OPP#1176590) is gratefully
acknowledged. We thank Dr. Joseph Turner (VCU) for
assistance in collecting HRMS data.
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Organic Letters
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consistent with the model proposed for regiocontrol in this
transformation.
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G
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