Stereoselective Synthesis of Cyclohexanes via an Iridium Catalyzed (5 + 1) Annulation Strategy

Article abstract of DOI:10.1021/jacs.8b07776

An iridium catalyzed method for the synthesis of functionalized cyclohexanes from methyl ketones and 1,5-diols is described. This process operates by two sequential hydrogen borrowing reactions, providing direct access to multisubstituted cyclic products with high levels of stereocontrol. This methodology represents a novel (5 + 1) strategy for the stereoselective construction of the cyclohexane core.

Full text of DOI:10.1021/jacs.8b07776

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Stereoselective Synthesis of Cyclohexanes via an Iridium Catalyzed
(5 + 1) Annulation Strategy
Wasim M. Akhtar,† Roly J. Armstrong,† James R. Frost,† Neil G. Stevenson,‡
and Timothy J. Donohoe*,†
†Department of Chemistry, Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom
‡GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom
S
* Supporting Information
of these strategies rely on the availability of appropriately
ABSTRACT: An iridium catalyzed method for the
synthesis of functionalized cyclohexanes from methyl
ketones and 1,5-diols is described. This process operates
by two sequential hydrogen borrowing reactions, provid-
ing direct access to multisubstituted cyclic products with
high levels of stereocontrol. This methodology represents
a novel (5 + 1) strategy for the stereoselective
construction of the cyclohexane core.
substituted precursors, and as a result new methods targeting
multisubstituted cyclohexanes are of great interest. A
complementary (5 + 1) strategy would involve double
alkylation of a C-1 building block with a C-5 bis-electrophile.
However, very few such examples have been reported in the
literature.5 Typically, multistep sequences such as malonate
alkylation/decarboxylation are required, and consequently, this
methodology has not been widely employed.6
We have recently reported that pentamethylphenyl (Ph*)
ketones can be alkylated with alcohols via hydrogen borrowing
catalysis (Scheme 1B).7 This process is mediated by an iridium
catalyst, which abstracts hydrogen from an alcohol to generate
the corresponding carbonyl compound in situ.8 After aldol
condensation with the aryl ketone, the catalyst “returns” the
abstracted hydrogen to provide the C−C coupled product and
complete the catalytic cycle. We wondered whether a related
approach could be used to construct substituted cyclohexane
rings by double alkylation of Ph* ketones with 1,5-diols
(Scheme 1C).9 This approach would form two new C−C
bonds in a direct manner, enabling the synthesis of a diverse
range of cyclohexane products due to the widespread
availability of functionalized 1,5-diols. However, we recognized
that, for this approach to prove fruitful, several challenges must
be addressed: (i) to identify conditions which favor cyclization
over competing oligomerization of the 1,5-diol; (ii) to control
the stereochemistry at each of the newly formed stereogenic
centers; (iii) straightforward conversion of the Ph* ketone to a
range of functional groups without loss of stereochemistry.
We commenced our study by investigating the reaction
between ketone 1 and unsubstituted pentanediol 2a. In the
presence of catalytic [IrCp*Cl2]2 and KOH in toluene at
105 °C, we were pleased to isolate the desired cyclohexane
product 3a in 44% yield (Table 1, entry 1). We investigated
various bases and found that KOtBu provided similar results,
while other bases (NaOH, LiOH, K3PO4) afforded 3a in
reduced yields (entries 2−5). With an increased amount of
base (4 equiv) we obtained 3a in a higher yield of 58%, but a
further increase to 5 equiv did not provide any further
improvement (entries 6−7). When the temperature was raised
by 10 °C, 3a was obtained in an improved 66% yield (entry 8).
Increasing the amount of diol to 2 equiv did not result in any
he substituted cyclohexane motif is encountered in a wide
Trange of natural products, pharmaceutical agents, and
materials.1 Consequently, methods which target the synthesis
of this scaffold, particularly those in which the regio- and
stereochemistry of the product can be controlled, are of great
importance.2 Previous approaches to substituted cyclohexanes
have primarily been based upon (6 + 0) or (4 + 2) strategies
involving hydrogenation of an aromatic precursor or Diels−
Alder cycloaddition followed by reduction (Scheme 1A).3
Several elegant (3 + 3) approaches based on cyclodimerization
of donor−acceptor cyclopropanes have also been reported.4 All
Scheme 1. Previous Work and Strategy for Stereoselective
Synthesis of Cyclohexanes via Hydrogen Borrowing
Catalysis
Received: July 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b07776
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Journal of the American Chemical Society
Communication
a
further enhancement (entry 9). We then applied these
conditions to a diol bearing an α-methyl substituent (2b). In
this case, the desired product 3b was isolated in 61% yield as
an 85:15 mixture of diastereoisomers (entry 10). We were
delighted to find that increasing the loading of diol to 2.0 equiv
resulted in a significant increase in yield and 3b was isolated in
80% yield (entry 11). Moreover, 3b was formed as a single
diastereomer. As expected, an experiment conducted in the
absence of [IrCp*Cl2]2 gave only unreacted starting materials
(entry 12). Finally, when 1 was replaced by acetophenone a
complex mixture of products was obtained (entry 13), which
confirms the key role that the Ph* group plays in minimizing
undesired side reactions.
With optimal conditions for double alkylation of Ph*
ketones in hand, we set out to investigate the generality of this
process (Table 2). We were pleased to find that diols
substituted with a geminal dimethyl group cyclized cleanly to
afford cyclohexanes 4 and 5 in 79% and 83% yield,
respectively. We were also able to access spirocyclic products
6 and 7 in excellent yields. The enhanced yields obtained with
geminally disubstituted diols are likely a consequence of the
Thorpe−Ingold effect which favors the desired cyclization
pathway.10 An α-phenyl substituted diol cyclized efficiently to
afford 8 in 78% yield as a single diastereoisomer. In both
Table 1. Optimization of Reaction Conditions
b
entry
base (equiv)
diol (equiv)
T/°C
yield 3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
KOH (3)
KOtBu (3)
NaOH (3)
LiOH (3)
K3PO4 (3)
KOH (4)
KOH (5)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (1.1)
2a (2.0)
2b (1.1)
2b (2.0)
2b (2.0)
2b (2.0)
105
105
105
105
105
105
105
115
115
115
115
115
115
44
44
15
<5
<5
58
57
66
64
61; 85:15 d.r.
80; >95:5 d.r.
<5
<5
c
d
a
Diol (1.1−2 equiv), 1 (1.0 equiv), [IrCp*Cl2]2 (2 mol %), base
b
(3−5 equiv), PhMe (4 M), 24 h. Yields refer to isolated material
c
after column chromatography. In the absence of [IrCp*Cl2]2.
d
Acetophenone instead of pentamethylacetophenone (1).
a b
,
Table 2. Scope of Formation of Cyclohexanes from Diols via Hydrogen Borrowing Catalysis
a
b
1 (1 equiv), diol (2 equiv), [IrCp*Cl2]2 (2 mol %), KOH (4 equiv), PhMe (4M), 115 °C, 24 h. Major diastereoisomer depicted. Yields refer to
c
d
isolated material after column chromatography. Reaction carried out with 2 equiv of KOH. The crude reaction mixture was filtered through a
plug of silica gel and then treated with NaBH4 in THF/MeOH to reduce unreacted enone (see Supporting Information for details). Reaction
carried out at 105 °C. The d.r. of 28 could be increased to 94:6 d.r. by recrystallization (see Supporting Information).
e
f
B
DOI: 10.1021/jacs.8b07776
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Journal of the American Chemical Society
Communication
a
compounds 3b and 8 the trans-diastereoisomer was obtained
as the major product which led us to speculate that the relative
stereochemistry is established by base-mediated epimerization
α- to the carbonyl. In line with this hypothesis, when β-
substituted diols were subjected to our optimized conditions
we isolated cyclohexanes 9 and 10 in good to excellent yields
with high selectivity in favor of the cis-diastereoisomer.
Pleasingly, γ-substituted diols also proved to be well tolerated
and products 11 and 12 were obtained in 76% and 83% yields
respectively, both as a single trans-diastereomer. We found that
substituents on the aromatic ring were well tolerated, including
electron-donating, electron-deficient, halogen-containing, and
sterically encumbered groups (13−16).
Scheme 2. Investigation of Stereochemical Control
We next turned our attention to the synthesis of more
complex cyclohexanes from multiply substituted diols.
Trisubstituted cyclohexanes 17, 18, and 19 were obtained in
good yields as mixtures of diastereoisomers (the factors
responsible for stereoselectivity are discussed later).11 Incor-
poration of a phenyl substituent was tolerated, and arylated
cyclohexane 20 was isolated in 72% yield and 70:30 d.r.
Symmetrical diols also participated in the desired reaction
providing products 21 and 22 in high yields with a preference
in both cases for the formation of the C2-symmetrical
diastereoisomer. When we evaluated an α,γ-substituted diol
we were pleased to obtain trisubstituted cyclohexane 23 in
74% yield with high diastereoselectivity (93:5:2 d.r.). With this
substitution pattern, we explored variation of the C2 and C4
substituents and found that cyclohexanes 24 and 25 could be
obtained in good yields again with excellent levels of
diastereoselectivity. A diol synthesized in two steps from
thujone cyclized to provide 6,3-fused product 26 in 90% yield
as a mixture of diastereoisomers, while a diol obtained by
reduction of camphoric acid afforded bicyclic product 27 in
75% yield as a single diastereoisomer. Finally, we subjected a
symmetrical triol to our optimized conditions and obtained
cyclohexane 28, resulting from cyclization followed by
exocyclic hydrogen borrowing alkylation in 74% yield with
good diastereoselectivity.
Having established that the relative stereochemistry at the
C1 position arises from equilibration,12 we were interested to
determine how the relative stereochemistry is controlled at
each of the other positions around the newly formed
cyclohexane. Therefore, we carried out cyclohexane formation
with enantioenriched diols bearing a stereogenic center at the
α-, β-, and γ-positions (Scheme 2). As expected, diol (+)-2b
reacted to give racemic 3b, a result which is consistent with a
mechanism involving oxidation of the alcohol to the
corresponding ketone. Interestingly, β-substituted diol
(−)-29 also cyclized to give cyclohexane 9 as a racemate.
We hypothesize that, after oxidation to the aldehyde,
racemization can occur under the basic reaction conditions.13
Pleasingly, γ-substituted diol (−)-30 cyclized cleanly to
provide (−)-25 without any erosion of enantioselectivity
(76% yield, >99:1 e.r.). This result demonstrates that a single
γ-stereocenter can serve as a reporter site, translating its chiral
information to new stereogenic centers on the cyclohexane
ring.
a
(a) 1 (1 equiv), diol (2 equiv), [IrCp*Cl2]2 (2 mol %), KOH
(4 equiv), PhMe (4 M), 115 °C, 24 h. (b) Determined by chiral
HPLC analysis. (c) 1 (1 equiv), 1-butanol (2 equiv), 2-pentanol
(2 equiv), [IrCp*Cl2]2 (2 mol %), KOH (4 equiv), PhMe (4 M),
115 °C, 24 h. (d) Products 33−35 were isolated as an inseparable
mixture; ratios were determined by 1H NMR (see Supporting
Information).
excess of a primary and secondary alcohol under our optimized
conditions (Scheme 2B). The major products obtained were
33 (73% yield) and 35 (18% yield) which both arise from
selective reaction of 1 with the primary alcohol. By extension,
we propose that diols which possess both primary and
secondary sites undergo preferential C−C bond formation at
the primary position.
Given these results, we propose that stereochemistry at each
position is controlled in the following manner: (i) The
stereochemistry at C1 is set under thermodynamic control by
base mediated epimerization; (ii) the stereochemistry at C2 is
dictated by the facial selectivity of attack on a cyclic enone
intermediate by iridium hydride; (iii) C3 is able to epimerize
after oxidation to the aldehyde; (iv) the stereochemistry at C4
is translated from the diol starting material with complete
fidelity (Scheme 2C).
For nonsymmetrical diols, the chemoselectivity of the initial
oxidation and aldol reaction governs the regiochemistry of the
final enone intermediate and is therefore expected to play a
significant role in determining the stereochemical outcome of
the reaction. To investigate this, we carried out a competition
reaction in which ketone 1 was alkylated with an equimolar
C
DOI: 10.1021/jacs.8b07776
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Journal of the American Chemical Society
Communication
With a robust method in hand for the stereoselective
synthesis of cyclohexanes, we set out to demonstrate the utility
of the Ph* ketone substituted cyclohexane products by
carrying out a series of derivatization reactions. It has
previously been demonstrated that Ph* ketones can be cleaved
to the corresponding acid bromide by a retro-Friedel−Crafts
acylation with bromine.7 However, we were uncertain if this
process would preserve the stereochemical integrity of the
cyclohexane products. We were delighted to find that upon
treatment of 8 with bromine at −17 °C followed by addition of
n-butanol the corresponding butyl ester 36 was obtained in
94% yield as a single diastereoisomer (Scheme 3A). A
representative series of reaction products were smoothly
converted to the butyl esters (37−41), and in all cases no
erosion of stereochemistry was observed.14
reduction provided aldehyde 43 in 88% yield without
epimerization.15 The acid bromide is a versatile intermediate,
which could be hydrolyzed to the corresponding acid 44 (76%
yield, >95:5 d.r.) or coupled with amine nucleophiles to afford
amides 45 and 46. Finally, coupling with N-hydroxy-
phthalimide afforded useful NHP-ester 47 in 89% yield as a
single diastereomer.16
In conclusion, we have developed an efficient method for the
synthesis of cyclohexanes by alkylation of ketones with diols
via hydrogen borrowing catalysis. A series of multiply
substituted cyclohexane products were obtained often with
high levels of control over relative stereochemistry. Several
control experiments were carried out, which established the
factors responsible for stereocontrol at each of the positions
around the newly formed cyclohexane ring. Finally, it was
demonstrated that the Ph* ketone substituted cyclohexanes
could be readily converted into a wide variety of functional
groups without epimerization. Given the extensive availability
of substituted diols, we believe that this methodology will find
widespread use for the stereoselective synthesis of function-
alized cyclohexanes.
Taking cyclohexane 12 as a representative example, a range
of different functional group interconversions were investigated
(Scheme 3B). After cleavage to the acid bromide, reduction
with LiAlH4 afforded cyclohexyl alcohol 42 in 95% yield as a
single diastereomer. Alternatively, palladium catalyzed partial
a
Scheme 3. Derivatization of Cyclohexane Products
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b07776.
■
S
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*timothy.donohoe@chem.ox.ac.uk
■
ORCID
Roly J. Armstrong: 0000-0002-3759-061X
James R. Frost: 0000-0002-4966-0419
Timothy J. Donohoe: 0000-0001-7088-6626
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank GlaxoSmithKline [W.M.A.] and the EPSRC [R.J.A.,
J.R.F., and T.J.D., Established Career Fellowship (EP/
L023121/1)] for financial support. We are grateful to Prof.
Tim Claridge and Dr. Nader Amin for helpful discussions.
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