Stereoselective synthesis of alicyclic ketones: A hydrogen borrowing approach

Article abstract of DOI:10.1016/j.tet.2019.130680

A highly diastereoselective annulation strategy for the synthesis of alicyclic ketones from diols and pentamethylacetophenone is described. This process is mediated by a commercially available iridium(III) catalyst, and provides efficient access to a wide range of cyclopentane and cyclohexane products with high levels of stereoselectivity. The origins of diastereoselectivity in the annulation reaction have been explored by a series of control experiments, which provides an explanation for how each stereocentre around the newly forged ring is controlled.

Full text of DOI:10.1016/j.tet.2019.130680

Journal Pre-proof
Stereoselective synthesis of alicyclic ketones: A hydrogen borrowing approach
Roly J. Armstrong, Wasim M. Akhtar, James R. Frost, Kirsten E. Christensen, Neil G.
Stevenson, Timothy J. Donohoe
PII:
S0040-4020(19)31054-3
https://doi.org/10.1016/j.tet.2019.130680
TET 130680
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 August 2019
Revised Date: 26 September 2019
Accepted Date: 4 October 2019
Please cite this article as: Armstrong RJ, Akhtar WM, Frost JR, Christensen KE, Stevenson NG,
Donohoe TJ, Stereoselective synthesis of alicyclic ketones: A hydrogen borrowing approach,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130680.
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Graphical Abstract
Stereoselective synthesis of alicyclic ketones:
a hydrogen borrowing approach
Leave this area blank for abstract info.
Roly J. Armstronga, Wasim M. Akhtara, James R. Frosta, Kirsten E. Christensena, Neil G. Stevensonb and
Timothy J. Donohoea
a Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom
b GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom.

1
Tetrahedron
journal homepage: www.elsevier.com
Stereoselective synthesis of alicyclic ketones: a hydrogen borrowing approach
Roly J. Armstronga, Wasim M. Akhtara, James R. Frosta, Kirsten E. Christensena, Neil G. Stevensonb and
Timothy J. Donohoea
a Chemical Research Laboratory, University of Oxford, Oxford, OX1 3TA, United Kingdom
b GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom.
In honour of Professor Steve Davies to recognize his many achievements in research and his service to Tetrahedron: Asymmetry
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly diastereoselective annulation strategy for the synthesis of alicyclic ketones from diols
and pentamethylacetophenone is described. This process is mediated by a commercially
available iridium(III) catalyst, and provides efficient access to a wide range of cyclopentane and
cyclohexane products with high levels of stereoselectivity. The origins of diastereoselectivity in
the annulation reaction have been explored by a series of control experiments, which provides an
explanation for how each stereocentre around the newly forged ring is controlled.
Available online
Keywords:
Hydrogen borrowing catalysis
Iridium
2009 Elsevier Ltd. All rights reserved
.
Diastereoselective
Cyclopentanes
Cyclohexanes
Corresponding author. Tel.: +44-1865 275 649; e-mail: timothy.donohoe@chem.ox.ac.uk

2
Tetrahedron
1. Introduction
Enolate alkylation is a cornerstone of organic synthesis,
representing a versatile method for the formation of C–C bonds.1
However, in practice, this methodology suffers from several
drawbacks. The formation of enolates and subsequent addition of
reactive alkylating agents typically requires cryogenic conditions,
rendering such processes energy-intensive.2 Moreover, the
alkylating agents employed are often highly toxic and lead to the
formation of stoichiometric quantities of metal halide by-
products which must be separated after the reaction is complete.
Finally, although alkylation with primary alkyl halides or
pseudohalides is generally an efficient process, the corresponding
reactions with secondary electrophiles are often sluggish and
suffer from competing side reactions such as elimination.1
Recently, hydrogen borrowing catalysis has emerged as a
powerful alternative strategy for C–C bond formation, enabling
the direct alkylation of enolates with unactivated alcohols.3 For
example, we have shown that pentamethylphenyl (Ph*) ketones
can be alkylated with primary or secondary alcohols to afford α-
and β-branched ketones (Scheme 1A).4 These reactions are
mediated by an iridium catalyst which oxidizes the alcohol to the
corresponding carbonyl compound along with concomitant
formation of iridium hydride. The in situ generated aldehyde or
ketone then undergoes aldol condensation with the Ph* ketone to
generate an intermediate enone, which is reduced by iridium
hydride to form the product and close the catalytic cycle.
The Ph* group is critical to the success of this chemistry; the
doubly ortho- substituted aromatic ring is oriented orthogonal to
the carbonyl group which shields the ketone against undesired
reduction and aldol homo-dimerization processes. Moreover, we
have previously shown that the Ph* group can be readily
converted to the corresponding acid bromide via a retro-Friedel-
Crafts acylation with Br2, greatly expanding the utility of the
reaction products.4
Scheme 1. Previous work and strategy for formation of alicyclic
ketones
2. Results and Discussion
It is also well established that hydrogen borrowing catalysis can
be employed for the construction of C–N bonds.3 We were
particularly attracted to several elegant reports in the literature
involving annulation reactions between primary amines and diols
(Scheme 1B).5 Mechanistically, these reactions are thought to
proceed via two sequential hydrogen borrowing cycles. The
reaction is initiated by oxidation of the diol to the
hydroxyaldehyde which undergoes imine formation followed by
reduction to liberate an amino alcohol. This intermediate then
undergoes a further sequence of oxidation, cyclization and
reduction to deliver the cyclic product. We speculated that it
might be possible to merge these strategies and develop a new
process for the synthesis of saturated carbocyclic products from
pentamethylacetophenone and a diol (Scheme 1C). The proposed
annulation reaction would enable the formation of two new C–C
bonds, liberating two equivalents of water as the sole by-product.
The products of this reaction would be multiply substituted
cyclopentanes and cyclohexanes, which are useful compounds
that are encountered in a range of pharmaceutical agents, natural
products and functional materials.6 Our aim was to develop a
method which could generate alicyclic ketones in high yields and
with stereochemical control at each position on the newly formed
ring. We have recently communicated our preliminary results in
this area, and here wish to provide full details of this work.7,8
2.1. Reaction Optimization
We initiated our study by investigating the reaction of
pentamethylacetophenone
1 with an excess (5 equiv) of
commercially available 1,4-butanediol 2a (for full details of
optimization, see Supporting Information). In the presence of
2 mol% [IrCp*Cl2]2 and 3 equiv of KOH in toluene at 105 oC we
isolated the desired cyclopentane 3a in only 4% yield along with
84% yield of unreacted starting material 1 (Table 1, entry 1). In
an attempt to improve conversion, we increased the concentration
of the reaction mixture to 2M and found that 3a was obtained in
an improved yield of 14% (Table 1, entry 2). Increasing the
concentration further to 4M provided 3a in 34% yield, but an
additional increase to 8M gave a slightly lower yield (Table 1,
entries 3-4). We were pleased to find that reducing the amount of
diol 2a to 2 equiv resulted in significantly improved efficiency
and 3a was isolated in 59% yield (Table 1, entry 5). Carrying out
the reaction with 1.1 equiv of diol gave an additional
improvement, providing 3a in 65% yield (Table 1, entry 6). We
also investigated various reaction temperatures, but found that
inferior results were obtained (Table 1, entries 7-8).
We then took the most promising reaction conditions (Table 1,
entry 6) and applied them to the analogous formation of
cyclohexane 3b from 1,5-pentanediol 2b. Under these conditions

3
Table 1. Optimization of cyclopentane formationa
Entry
1
Base (equiv)
KOH (3)
KOtBu (3)
NaOH (3)
LiOH (3)
NaHCO3 (3)
Cs2CO3 (3)
KOH (4)
KOH (5)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
Diol (equiv) T/oC
Yield 3/%b
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (1.1)
2b (2.0)
2c (1.1)
2c (2.0)
2c (2.0)
2c (2.0)
105
105
105
105
105
105
105
105
115
115
115
115
115
115
44
2
44
3
15
4
<5
T/oC
105
105
105
105
105
105
85
Yield 3a/%b
5
<5
Entry
[1]/M
Equiv 2a
6
<5
1
2
3
4
5
6
7
8
0.2
2
5
5
4 (+84% 1)
7
58
14
34
29
59
65
49
63
8
57
4
5
9
66
8
5
10
11
12
13c
14d
64
61; 85:15 d.r.
80; >95:5 d .r.
<5
4
2
4
1.1
1.1
1.1
4
4
125
<5
(a) reaction conditions: 1 (1.0 equiv), 2a (1.1-5 equiv),
[IrCp*Cl2]2 (2 mol%), KOH (3 equiv), PhMe (0.2-8 M), 24 h. (b)
Yields refer to isolated material after column chromatography.
(a) Reaction conditions: 1 (1.0 equiv), diol (1.1-2 equiv)
,
[IrCp*Cl2]2 (2 mol%), base (3-5 equiv), PhMe (4 M), 24 h. (b)
Yields refer to isolated material after column chromatography. (c) In
the absence of [IrCp*Cl2]2. (d) With acetophenone instead of 1.
we isolated 3b in 44% yield (Table 2, Entry 1). We next varied
the base and found that potassium tert-butoxide gave similar
results, but that other bases were less efficient (Table 2, entries 2-
6). Increasing the loading of KOH to 4 equiv provided an
increase in yield to 58%, but an additional increase to 5 equiv
resulted in no further improvement (Table 2, entries 7-8).
Increasing the temperature to 115 °C gave a further small
improvement and 3b was isolated in 66% yield (Table 2, entry
9). Employing an increased amount of diol 2b (2 equiv) gave a
similar result (Table 2, Entry 10). We next attempted annulation
with α-methyl substituted diol 2c and isolated the corresponding
cyclohexane 3c in 61% yield as
a 85:15 mixture of
diastereoisomers (Table 2, entry 11). We were delighted to find
that with 2 equiv of diol 2c, we obtained 3c in 80% yield as a
single trans-diastereoisomer (Table 2, entry 12). Based on
control experiments (vide infra) we believe that the relative
stereochemistry is established under thermodynamic control by
deprotonation α-to the ketone under the basic reaction
conditions.9 As expected, a control experiment in the absence of
iridium catalyst resulted in no conversion to cyclohexane 3c
(Table 2, Entry 13). Finally, we found that when Ph* ketone 1
was replaced with acetophenone, a complex mixture of products
containing <5% yield of the desired cyclohexane was observed.
This result highlights the key role that the Ph* group plays in
facilitating this chemistry.
Table 2. Optimization of cyclohexane formationa

4
Tetrahedron

5
X-ray crystallographic analysis. Trisubstituted cyclopentanes 3g
and 3h were formed in good to moderate yields with 90:10 d.r.
and 75:25 d.r. respectively (the relative stereochemistry could not
be assigned). A reaction with 1,2-benzenedimethanol afforded
aryl fused cyclopentane 3i in 26% yield.
methyl groups of the minor meso-diastereoisomer).12 This
methodology could also be employed for the synthesis of bicyclic
ketones such as 3am, 3an and 3ao (the two latter examples were
obtained with complete diastereocontrol). A symmetrical triol
underwent successful annulation followed by alkylation of the
exocyclic alcohol to afford cyclohexane 3ap in 74% yield and
88:12 d.r. An additional benefit of the Ph* group is its high
degree of crystallinity – the majority of alicyclic products
synthesized (3a-3ar) were crystalline solids. In the case of 3ap
this enabled us to increase the stereochemical purity to 94:6 d.r.
after a single recrystallization (See Supporting Information for
details). We also investigated annulation reactions with 1,6-diols
and found that cycloheptane products 3aq and 3ar could be
isolated, albeit with moderate yields.
At this point we turned our attention to the synthesis of
cyclohexanes. We found that an ether or amino group could be
introduced into the backbone of the 1,5-diol affording
heterocyclic products 3j and 3k in yields of 33% and 48%
respectively. We were delighted to find that a diol bearing a
geminal dimethyl group at the β-position cyclized to afford 3l in
79% yield. It is likely that this increase in yield is due to a
beneficial Thorpe-Ingold effect which promotes the desired
cyclization pathway.10 Geminal substitution at the γ-position also
proved to be similarly effective and cyclohexanes 3m-o were
obtained in excellent yields. Diols bearing a single α-substituent
underwent annulation to afford 1,2-disubstituted cyclohexanes 3c
and 3p in yields of 80% and 78% respectively with complete
diastereocontrol. We obtained crystals of 3c which were suitable
for single crystal X-ray diffraction, unambiguously establishing
that the relative configuration is trans. We hypothesized that the
relative stereochemistry results from epimerization α- to the
carbonyl under the basic reaction conditions to the
thermodynamically favored doubly equatorial product. In line
with this hypothesis, β-substituted diols reacted to generate 1,3-
disubstituted cyclohexanes 3q and 3r with high selectivity in
favour of the cis-diastereoisomer. This assignment of relative
stereochemistry was confirmed by single crystal X-ray
crystallographic analysis of 3q. A diol bearing a γ-methyl group
reacted smoothly to afford 1,4-disubstitued cyclohexane 3s as a
single trans-diastereoisomer (again verified by single crystal X-
ray diffraction). We were also able to introduce a range of
aromatic substituents at the C4 position and cyclohexanes
containing phenyl (3t), methoxyphenyl (3u), aryl fluoride (3v),
aryl chloride (3w) and naphthyl groups (3y) were all obtained in
high yields with complete diastereocontrol. Interestingly a diol
substituted with an aryl bromide cyclized to form 3x as a single
diastereoisomer, but a significant amount of protodebromination
was also observed. A diol obtained by reduction of homophthalic
acid reacted to afford a 1:1 mixture of tetrahydronaphthalene and
naphthalene products 3z (the latter likely arises via aerobic
oxidation).
To shed further light on the role of the Ph* group, we
investigated the effect of removing methyl substituents from the
aryl
ring.
Under
our
optimized
conditions,
2,6-
dimethylacetophenone reacted cleanly to afford alicyclic ketone
3as in 77% yield and 89:11 d.r. This result is very similar to the
corresponding result with pentamethylacetophenone (3c; 80%
yield; >95:5 d.r.) and confirms that the role of the Ph* group
arises predominantly from steric shielding of the carbonyl rather
than an electronic effect. In line with this hypothesis, o-
methylacetophenone reacted to afford ketone 3at in only 12%
yield along with 18% yield of 1-(o-tolyl)ethan-1-ol which
presumably arises by reduction of the aryl ketone by iridium
hydride. This result confirms that two ortho-substitutes are
required to protect the aryl ketone against reduction.
Not all of the diols we investigated underwent the desired
annulation reaction. For example, we found that modification of
the diol backbone to introduce multiple fluorine atoms (2au) was
unsuccessful and
a
mixture of unreacted diol and
pentamethylacetophenone were observed after 24 h. We
hypothesize that this diol is too electron deficient to undergo
oxidation by the iridium catalyst. Secondary amine groups (2av),
acetals (2aw), benzyl ethers (2ax) and 1,3-diols (2ay) were also
not tolerated in the reaction – in these cases the starting materials
were fully consumed but a complex mixture of products was
observed by 1H-NMR analysis of the crude reaction mixtures.
2.3. Mechanistic studies
We next set out to investigate how relative stereochemistry is
controlled in this reaction. Our hypothesis was that the C1
stereochemistry is set by epimerization under the basic reaction
conditions (vide supra). To directly test this theory, we set out to
synthesize contra-thermodynamic ketone cis-3t. To this end, we
began with trans-3t and attempted to carry out deprotonation
with methylmagnesium chloride followed by a kinetic quench at
Diols bearing more than one substituent could also be
employed in this chemistry. For example, dimethyl substituted
cyclohexanes 3aa-3ac were obtained as diastereoisomeric
mixtures in good yields.11 When one of the methyl groups was
exchanged for a phenyl substituent, the diastereoselectivity was
improved and 3ad and 3ae were isolated in 70:30 d.r. and 62:38
d.r. respectively and a diol bearing two phenyl groups reacted to
afford cyclohexane 3af as a single diastereoisomer in 24% yield.
α,γ-Disubstituted diols proved to be particularly effective
substrates for this chemistry. For example, 1,2,4-trisubstituted
cyclohexane 3ag was obtained with high levels of
diastereoselectivity in 74% yield. The relative stereochemistry of
the major diastereoisomer was unambiguously determined by
single crystal X-ray crystallography analysis. A range of
derivatives were prepared and aryl, ethyl and cyclopropyl
substituted products 3ah-3aj were obtained with excellent levels
of diastereocontrol. Cyclohexanes 3ak and 3al were formed in
yields of 81% and 87% respectively, both with a preference for
formation of the pseudo C2-symmetrical diastereoisomer (in
o
–78 C with methanol (Scheme 3A). Disappointingly, this only
resulted in a small amount of epimerization and 3t was obtained
in 87:13 d.r. in favour of the undesired trans-diastereoisomer. We
suspected that deprotonation may not have been complete under
these conditions and therefore carried out deprotonation under
t
more forcing conditions with 5 equiv of BuLi. After a low-
temperature methanolic quench, we isolated 3t in an improved
d.r. of 70:30 (trans/cis). A similar quench with MeOD resulted in
full deuteration, confirming that complete deprotonation is
achieved under these conditions. Pleasingly, we found that
employing 2,6-di-tert-butylphenol (4) as a bulky proton source
resulted in a further improvement to 48:52 d.r. (trans/cis).
t
1
Finally, we found that the stoichiometry of BuLi could be
both cases, the H NMR spectrum of the major diastereoisomer
exhibited a characteristic pair of resonances for the two non-
equivalent methyl groups as opposed to a single resonance for the
reduced to 3 equiv enabling the isolation of 3t in 95% yield as a
47:53 mixture of diastereomers (trans/cis). Pure cis-3t could be
isolated from this mixture by column chromatography. With this

6
Tetrahedron
material in hand, we resubjected it to our standard annulation
small change in regioselectivity during the first C-C bond
formation (see below).
conditions (Scheme 3B). Smooth epimerization was observed to
3t which was isolated in 94% yield as a single trans-
diastereoisomer. This result strongly suggests that the C1
stereochemistry is established under thermodynamic control.
Scheme 3. Experiments to investigate relative stereochemical
1
control at C1. (a) d.r. determined by H-NMR analysis of the
crude reaction mixtures. (b) After purification by column
chromatography, pure cis-3t (>95:5 d.r.) was isolated in 40%
yield. (c) Diol 2t (2 equiv), ketone cis-3t (1 equiv), [IrCp*Cl2]2
(2 mol%), KOH (4 equiv), PhMe (4 M), 115 oC, 24 h.
Scheme 4. Experiments to investigate stereochemical control at
C2, C3 and C4. (a) Diol (2 equiv), ketone (1 equiv), [IrCp*Cl2]2
(2 mol%), KOH (4 equiv), PhMe (4 M), 115 oC, 24 h.
(b) determined by HPLC using a chiral stationary phase. (c) For
full assignment and characterization of diastereomeric mixtures,
see Supporting Information.
To probe the origins of stereocontrol at the other positions around
the newly formed ring, we carried out annulation reactions with a
series of enantiopure diols (+)-2c, (-)-2q and (-)-2ah which
possess a stereogenic centre at the α, β and γ-positions
respectively (Scheme 4A). Enantiopure diol (+)-2c reacted under
our optimized conditions to afford 3c as a racemate. This is in
good agreement with our mechanistic hypothesis as we expect
the secondary alcohol to undergo oxidation to the corresponding
ketone, thereby ablating any stereochemistry. Interestingly, diol
(-)-2q also resulted in the formation of racemic material. In this
case it is probable that racemization occurs via oxidation of
(-)-2q to an aldehyde followed by formation of the corresponding
enolate. Finally, diol (-)-2ah reacted cleanly to afford (-)-3ah in
76% yield and >99:1 e.r. This result shows that any
stereochemical information present at the γ-position of the diol is
reproduced in the corresponding cyclohexane product with
complete fidelity.
The majority of trisubstituted cyclic products shown in Scheme
2 are derived from diols containing both a primary and secondary
alcohol. The regioselectivity of the first C–C bond formation is
therefore important: initial reaction of the secondary alcohol will
ultimately lead to an intermediate trisubstituted cyclic enone A
(Scheme 5A, red); whereas if the first C–C bond forms at the
primary end of the diol then tetrasubstituted enone B would be
anticipated (Scheme 5A, blue). Clearly, this has important
ramifications for the stereochemical outcome at the C2 position.
To test which pathway is operative, we designed a competition
experiment in which pentamethylacetophenone 1 was treated
with an equimolar excess of a primary and secondary alcohol
under our standard annulation conditions (Scheme 5B). The
major products we isolated from this reaction were 7 and 9, both
of which result from selective reaction with primary alcohol 5.
By extension, we infer that where there is competition, the
primary site of the diol reacts first and consequently
tetrasubstituted cyclic enones such as B are intermediates.
Similarly, we were also interested to investigate whether there
would be any selectivity when both positions of the diol are
primary, but one is branched at the β-position. This is particularly
pertinent for reactions of β,γ-disubstituted diols (e.g. reactions to
form cyclohexanes 3ac-3af). To avoid complications arising
from over-alkylation, we selected ethyl ketone 10 and reacted it
under our optimized conditions with an equimolar mixture of
unbranched and branched alcohols 5 and 11 (Scheme 5C). This
resulted in formation of ketones 12 and 13 in yields of 78% and
18% respectively. This result implies that in cases where there is
competition, some selectivity (~4:1) is expected for reaction of
We also investigated the effect of relative stereochemistry in the
diol starting materials (Scheme 4B). Diol 2am could be either
employed as a single diastereoisomer or as a diastereoisomeric
mixture (85:15 d.r.). In both cases, the cyclohexane product 3am
was obtained with essentially identical diastereoselectivity. This
result supports the conclusion that stereochemistry at the α-
position of the diol is ablated by oxidation to the corresponding
ketone during the reaction. With β,γ-disubstituted diol 2ad we
were able to independently synthesize diastereomerically pure
syn- and anti-starting materials (for details of diol synthesis, see
Supporting Information). In this case subjection of both anti- and
syn-2ad to our standard conditions afforded the same major
diastereoisomer of the corresponding cyclohexane 3ad with
similar levels of diastereoselectivity (70:30 and 60:40 d.r.
respectively). The small difference in diastereoselectivity may be
a consequence of experimental error, but could also reflect a

7
the unbranched end of the diol over the corresponding β-
thermodynamic control by epimerization under the basic
branched site.
reaction conditions. The stereochemistry at C2 is set by reduction
of a cyclic tetrasubstituted enone such as B by iridium hydride. In
general, the results are consistent with axial addition of iridium
hydride to a half-chair with other substituents occupying
equatorial positions.14 The stereochemistry at C3 can be
scrambled by enolate (or extended enolate) formation which
explains the generally low levels of stereocontrol at this position.
Finally, the stereochemistry at the C4 position is set in the diol
starting material and faithfully reproduced in the product.
Scheme 5. Competing pathways for cyclohexane formation. (a)
aryl ketone (1 equiv), 1-butanol (2 equiv), branched alcohol
(2 equiv), [IrCp*Cl2]2 (2 mol%), KOH (4 equiv), PhMe (4 M),
115 oC, 24 h. (b) Products were isolated as an inseparable
mixture, ratios were determined by H NMR spectroscopy (see
Supporting Information).
1
Scheme 6. Deuterium labelling experiment and rationalization of
the stereochemical outcome. (a) 14 (1 equiv), 15 (4 equiv),
o
[IrCp*Cl2]2 (2 mol%), KOH (4 equiv), PhMe (4 M), 115 C,
1
24 h. Extent of D-incorporation was determined by H NMR
To shed further light on the mechanism of the reduction process
we set out to carry out a deuterium labelling experiment. To this
end, cyclic enone 14 which is proposed to be an intermediate in
this chemistry was treated α-deuterated alcohol 15 under our
standard conditions for iridium catalyzed annulation (Scheme
6A). The desired transfer hydrogenation occurred smoothly to
deliver 3m in 87% yield. We expected to find that a single
deuterium had been incorporated at C2, but surprisingly 1H NMR
analysis revealed only 10% incorporation of deuterium at C2
along with similar levels of deuteration at the C1 and C3-
positions. The most likely explanation for this observation is that
the iridium deuteride species initially formed upon oxidation of
15 can undergo rapid H/D exchange with protic species (i.e.
alcohol, KOH and H2O) in the reaction mixture.13 This leads to
partial incorporation of deuterium at the C2 position by reduction
by either Ir-D or Ir-H. Deuterium is also incorporated statistically
at the C1 position by reversible enolate formation and
reprotonation. Presumably the C3 position is deuterated by either
formation of an extended enolate of 14 followed by reprotonation
or via a reversible retro-aldol process accompanied by α-
deuteration of the resulting aldehyde. We drew several
conclusions from this reaction: (i) The high yield of 3m suggests
that cyclic enones such as 14 are indeed intermediates in the
annulation chemistry; (ii) the absence of cross-over products
arising from alkylation with 15 implies that the formation of 14 is
not fully reversible; (iii) deuterium labelling experiments of this
type, which have frequently been employed to study hydrogen
borrowing processes must be interpreted with a great deal of
caution.
spectroscopy (See Supporting Information for details).
2.4. Derivatization of alicyclic products
We have previously shown that Ph* ketones can be converted to
the corresponding acid bromides by treatment with Br2 via a
retro-Friedel-Crafts acylation.4 However, it was not clear whether
the newly installed α-stereogenic centre would undergo
epimerization during the cleavage process. To investigate this,
we took a representative series of products from the hydrogen
borrowing reaction and treated them with bromine at –17 °C
followed by addition of n-butanol (Scheme 7A). We were
delighted to find that the corresponding butyl esters 16-22 were
formed in uniformly excellent yields with no evidence of
epimerization. It is also noteworthy that aryl containing products
underwent the desired esterification reaction to form 17 and 18
without any evidence of competing electrophilic aromatic
substitution.
We then selected Ph* substituted cyclohexane 3t (>95:5 d.r.) as
a representative example and investigated its conversion to a
range of different functional groups (Scheme 7B). Addition of
bromine followed by reduction with LiAlH4 delivered the
corresponding alcohol 23 in 95% yield as a single trans-
diastereoisomer. Alternatively, partial reduction of the acid
bromide with SnBu3H in the presence of catalytic Pd(PPh3)4
afforded aldehyde 24 in 88% yield without any epimerization.15
The acid bromide could also be hydrolyzed to the corresponding
carboxylic acid 25, reacted with amines to form amides such as
26 and 27 in high yields. Addition of a thiol afforded the
corresponding thioester 28 in 82% yield. It was also possible to
carry out an esterification with N-hydroxyphthalimide to generate
Based on all of these experiments it is possible to rationalize
the stereochemical outcome at each site around the newly formed
ring (Scheme 6B). The stereochemistry at C1 is set under

8
Tetrahedron
3. Conclusion
the corresponding NHP ester 29 in 89% yield as a single
diastereoisomer.
In summary, we have developed a new annulation process for the
synthesis of alicyclic products from diols and
pentamethylacetophenone. The reaction is promoted by a
commercially available iridium(III) catalyst and can generate
multiply substituted cyclopentane and cyclohexane products in
good to excellent yields often with high levels of
diastereoselectivity. A series of control experiments were carried
out, which explain how each stereocentre around the newly
formed ring is controlled. The Ph* group in the products can be
converted to a wide range of functionality without erosion of
stereochemistry. This methodology constitutes
a
novel
disconnection of carbocycles and we believe it will find
widespread application in the stereoselective synthesis of
alicyclic compounds.
4. Experimental section
4.1. General Experimental
All commercially available organic compounds were
purchased from major chemical suppliers. Unless otherwise
noted, all commercial reagents and solvents were used without
additional purification. NMR spectroscopy was carried out using
Bruker 400 MHz, 500 MHz, 600 MHz, 700 MHz or Cryo 500
MHz spectrometers in the deuterated solvent stated, using the
residual non-deuterated solvent signal as an internal reference.
Chemical shifts are quoted in ppm with signal splittings recorded
as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn),
sextet (sext), septet (sept), octet (oct), nonet (non) and multiplet
(m). The abbreviation br denotes broad. The abbreviations eq and
ax denote equatorial and axial respectively. Coupling constants,
J, are measured to the nearest 0.1 Hz and are presented as
observed. Infrared spectra were recorded neat on a Bruker Tensor
27 spectrometer. Electrospray ionization (ESI) HRMS were
recorded on a Thermo Exactive orbitrap spectrometer equipped
with a Waters Equity LC system. Electron impact ionization (EI)
HRMS were performed on an Agilent 7200 quadrupole time of
flight (Q-ToF) instrument. Optical rotations were recorded on a
Schmidt Haensch Unipol L2000 polarimeter. Chiral HPLC was
performed on an Agilent 1260 Series HPLC unit equipped with
UV-vis diode-array detector fitted with the appropriate Daicel
Chiralpak column. Detailed experimental procedures,
characterization data and NMR spectra for diols and alicyclic
products are provided in the Supporting Information. Single
crystal X-ray diffraction data were collected using a (Rigaku)
Oxford Diffraction SuperNova diffractometer and CrysAlisPro.
Structures were solved using 'Superflip’17 before refinement with
CRYSTALS18 as per the SI (CIF).
Scheme 7. Derivatization of alicyclic products (a) Br2 (2 equiv),
CH2Cl2, –17 oC then nBuOH (3 equiv), RT. (b) Br2 (2 equiv),
o
CH2Cl2, –17 C then LiAlH4 (5 equiv), THF, RT, 95%, >95:5 d.r.
o
(c) Br2 (2 equiv), CH2Cl2, –17 C then Bu3SnH (2 equiv), Pd(PPh3)4
(5 mol%), C6H6, RT, 88%, >95:5 d.r. (d) Br2 (2 equiv),
CH2Cl2, -17 oC then NaHCO3, THF/H2O, RT, 76%, >95:5 d.r. (e)
o
Br2 (2 equiv), CH2Cl2, –17 C then MeONHMe.HCl (2 equiv), Et3N
(4 equiv), RT, 81%, >95:5 d.r. (f) Br2 (2 equiv), CH2Cl2, –17 oC then
H-L-Phe-OtBu.HCl (2 equiv), iPrEt2N (4 equiv), RT, 88%, >95:5 d.r.
o
n
(g) Br2 (2 equiv), CH2Cl2, –17 C then PrSH (3 equiv), RT, 82%,
>95:5 d.r. (h) Br2 (2 equiv), CH2Cl2, –17 oC then
N-hydroxyphthalimide (2 equiv), iPrNEt2 (4 equiv), RT, 89%,
>95:5 d.r.
4.2. Representative procedure for diol synthesis: synthesis of
3-Phenylpentane-1,5-diol (2t)
This functional group represents a useful handle for further
functionalization.16 In all the cleavage reactions presented in
Schemes 7A and 7B, no evidence of any epimerization was
observed. However, these results do not definitively rule out a
scenario in which epimerization during the Ph* cleavage process
generates the same equilibrium mixture as that observed in the
hydrogen borrowing annulation. To disprove this, we took
contra-thermodynamic ketone cis-3t and converted it to the
corresponding Weinreb amide cis-26, which was isolated in 71%
yield as a single diastereoisomer (Scheme 7C). This result
confirms that the relative stereochemistry of the products is
preserved during Ph* cleavage.
To a stirred solution of 3-phenylglutaric acid (1.00 g, 4.80
mmol) in THF (15 mL) at 0 °C was added BH3·S(CH3)2
(1.37 mL, 14.4 mmol) dropwise over 10 mins. The mixture was
allowed to warm to RT slowly over 16 h. After this time, the
reaction was cooled to 0 °C and quenched with MeOH (3.6 mL)
and H2O (11.5 mL). The mixture was extracted three times with
EtOAc and the combined organics were dried (MgSO4), filtered
and concentrated in vacuo. Purification by column
chromatography (CH2Cl2:MeOH, 95:5) afforded the title
compound 2t as a colourless oil (795 mg, 92%). The spectral data
matched that previously reported in the literature.19 IR (film)
νmax/cm-1 3313, 3027, 2933, 1602, 1493, 1452, 1420, 1335, 1040,
1
889; H NMR (CDCl3, 400 MHz) δ = 7.35 – 7.29 (2H, m, Ph),
7.26 – 7.19 (3H, m, Ph), 3.62 – 3.55 (2H, m, CHAHBOH), 3.53 –

9
3.45 (2H, m, CHAHBOH), 2.95 (1H, tt, J = 9.9, 5.4 Hz, CHPh),
2.02 – 1.78 (6H, m, CH2CH2OH and OH). 13C NMR (CDCl3,
101 MHz) δ = 144.5, 128.6, 127.6, 126.4, 60.8, 39.3, 38.7.
HRMS (ESI+) Found [M+H]+ = 181.1223; C11H17O2 requires
181.1223, ꢀ –0.21 ppm.
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. R.J.A is also grateful to
University College, Oxford for a Junior Research Fellowship. We
thank Prof. Tim Claridge and Dr Nader Amin for helpful
discussions.
4.3. Representative procedure for hydrogen borrowing
annulation: synthesis of (2,3,4,5,6-pentamethylphenyl)(trans-4-
phenylcyclohexyl)methanone (3t)
References and notes
1. Smith, M. B. March’s Advanced Organic Chemistry, 7th Ed, John
Wiley & Sons: New York, 2013.
To a 2–5 mL Biotage microwave vial equipped with a stirrer
bar was added aryl ketone 1 (114 mg, 0.60 mmol), [Cp*IrCl2]2
(9.6 mg, 0.012 mmol), diol 2t (216 mg, 1.20 mmol), PhMe
(0.15 mL) and powdered KOH (135 mg, 2.40 mmol) sequentially
in the open atmosphere. The reaction vessel was sealed with a
microwave vial cap (containing a Reseal™ septum) and an Ar
2. (a) von Keutz, T.; Strauss, F. J.; Cantillo, D.; Kappe, C. O.
Tetrahedron 2018, 74, 3113–3117. (b) Bakker, W. I. I.; Wong, P.
L.; Snieckus, V.; Warrington, J. M.; Barriault, L. Lithium
Diisopropylamide. In e-EROS Encyclopedia of Reagents for
Organic Synthesis, John Wiley & Sons: Chichester, 2001.
3. For representative reviews of hydrogen borrowing catalysis, see:
(a) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Adv.
Synth. Catal. 2007, 349, 1555–1575. (b) Dobereiner, G. E.;
Crabtree, R. H. Chem. Rev. 2010, 110, 681. (c) Bahn, S.; Imm, S.;
o
balloon was fitted. The vial was heated to 115 C in a preheated
oil bath for 24 h and then the mixture was cooled to RT. The
crude reaction mixture was filtered through a SiO2 plug (eluting
with Et2O) and concentrated in vacuo. Purification by column
chromatography (Pentane:Et2O, 96:4) afforded the title
compound 3t as a white solid (167 mg, 83%, >95:5 d.r.). The
relative stereochemistry was determined by J-coupling constant
analysis. m.p. = 153–154 °C; IR (film) νmax/cm-1 2918, 2850,
1688, 1599, 1491, 1446, 1265, 1314, 1262, 1143, 1112, 1020,
Neubert, L.; Zhang, ̈ M.; Neumann, H.; Beller, M. ChemCatChem
2011, 3, 1853. (d) Pan, S.; Shibata, T. ACS Catal. 2013, 3, 704. (e)
Gunanathan, C.; Milstein, D. Science 2013, 341, 1229712. (f)
Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J.
Angew. Chem. Int. Ed. 2014, 53, 9142. (g) Obora, Y. ACS Catal.
2014, 4, 3972. (h) Yang, Q.; Wang, Q.; Yu, Z. Chem. Soc. Rev.
2015, 44, 2305. (i) Nandakumar, A.; Midya, S. P.; Landge, V. G.;
Balaraman, E. Angew. Chem. Int. Ed. 2015, 54, 11022. (j)
Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.;
Mulholland, K. R.; Newton, R. Org. Process Res. Dev. 2015, 19,
1400. (k) Corma, A.; Navas, J.; Sabater, M. J. Chem. Rev. 2018,
118, 1410–1459. (l) Holmes, M.; Schwartz, L. A.; Krische, M. J.
Chem. Rev. 2018, 118, 6026–6052. (m) Reed-Berendt, B. G.;
Polidano, K.; Morrill, L. C. Org. Biomol. Chem. 2019, 17, 1595–
1607.
1
988; H NMR (CDCl3, 400 MHz) δ = 7.24 – 7.08 (5H, m, Ph),
2.63 (1H, tt, J = 12.0, 3.3 Hz, CHCOPh*), 2.46 (1H, tt, J = 12.0,
3.4 Hz, CHPh), 2.17 (3H, s, Ar-CH3), 2.12 (6H, s, Ar-CH3), 2.05
(6H, s, Ar-CH3), 2.04 – 1.99 (2H, m, CHeqHaxCHCOPh*), 1.97 –
1.88 (2H, m, CHeqHaxCHPh), 1.56 (2H, qd, J = 13.0, 3.2 Hz,
CHeqHaxCHCOPh*), 1.39 (2H, qd,
J = 13.0, 3.2 Hz,
CHeqHaxCHPh); 13C NMR (CDCl3, 101 MHz) δ = 214.8, 147.0,
140.2, 135.6 , 133.2 128.5, 128.2, 126.9, 126.2, 52.8, 43.9, 33.7,
28.6, 18.1, 16.9, 16.2; HRMS (ESI+) Found [M+H]+ = 335.2369;
C24H31O requires 335.2369, ꢀ –0.29 ppm.
4. (a) Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F. J.;
Stevenson, N. G.; Donohoe, T. J. J. Am. Chem. Soc. 2015, 137,
15664–15667. (b) Akhtar, W. M.; Cheong, C. B.; Frost, J. R.;
Christensen, K. E.; Stevenson, N. G.; Donohoe, T. J. J. Am. Chem.
Soc. 2017, 139, 2577–2580.
4.4. Representative procedure for Br2 mediated Ph* cleavage:
Synthesis of butyl trans-4-phenylcyclohexane-1-carboxylate
(18)
5. (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai,
N. J. Chem. Soc. Chem. Commun. 1981, 12, 611–612. (b) Todd
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Saidi, O.; Blacker, A. J.; Lamb, G. W.; Marsden, S. P.; Taylor, J.
E.; Williams, J. M. J. Org. Process Res. Dev. 2010, 14, 1046–
1049. (f) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. J.
Org. Chem. 2011, 76, 2328–2331. (g) Cami-Kobeci, G.; Slatford,
P. A.; Whittlesey, M. K.; Williams, J. M. J. Bioorg. Med. Chem.
Lett. 2005, 15, 535–537. (h) Kawahara, R.; Fujita, K.; Yamaguchi,
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Moasser, B. J. Org. Chem. 2014, 79, 7553–7563. (j) Zhang, W.;
Dong, X.; Zhao, W. Org. Lett. 2011, 13, 5386–5389. (k) Yan, T.;
Feringa, B. L.; Barta, K. Nature Commun. 2014, 5, 5602. (l) Shan,
S. P.; Xiaoke, X.; Gnanaprakasam, B.; Dang, T. T.; Ramalingam,
B.; Huynh, H. V.; Seayad, A. M. RSC Adv. 2014, 5, 4434–4442.
(m) Yamaguchi, R.; Kawagoe, S.; Asai, C.; Fujita, K. Org. Lett.
2008, 10, 181–184. (n) Marichev, K. O.; Takacs, J. M. ACS Catal.
2016, 6, 2205–2210. (o) Apsunde, T. D.; Trudell, M. L. Synthesis
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Trudell, M. L. Org. Lett. 2009, 11, 1579–1582. For a related
process, see: (r) Zhao, Y.; Xu, G.; Yang, G.; Wang, Y.; Shao, P.-
L.; Yau, J. N. N.; Liu, B.; Zhao, Y.; Sun, Y.; Xie, X.; Wang, S.;
Zhang, Y.; Xia, L.; Zhao, Y. Angew. Chem. Int. Ed.
https://doi.org/10.1002/anie.201906199.
A stirred solution of Ph* ketone 3t (67 mg, 0.20 mmol) in
CH2Cl2 (1 mL) was cooled to –17 oC and Br2 (20 ꢁL, 0.40 mmol)
was added dropwise. The resulting solution was stirred at –17 °C
for 15 min and then n-butanol (45 mg, 0.60 mmol) was added.
The resulting solution was warmed to RT and stirred for 16 h.
After this time the reaction was diluted with Et2O and H2O. The
layers were separated and the aqueous layer was extracted three
times with Et2O. The combined organic extracts were washed
with sat. aq. NaHCO3, sat. aq. Na2S2O3, brine, dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography
(Pentane:Et2O, 97:3) afforded the title compound 18 as a
colourless oil (47 mg, 90%, >95:5 d.r.). The relative
stereochemistry was determined by J-coupling constant analysis.
IR (film) νmax/cm-1 2932, 1730, 1493, 1450, 1314, 1255, 1170,
1021, 752, 699. 1H NMR (CDCl3, 400 MHz) δ = 7.33 – 7.27 (2H,
m, Ph), 7.23 – 7.17 (3H, m, Ph), 4.10 (2H, t, J = 6.6 Hz, OCH2),
2.53 (1H, tt, J = 11.8, 3.5 Hz, CHPh), 2.36 (1H, tt, J = 12.1, 3.6
Hz, CHCO2Bu), 2.15 – 2.08 (2H, m, CHeqHaxCHCO2Bu), 2.02 –
1.95 (2H, m, CHeqHaxCHPh), 1.68
–
1.34 (8H, m,
OCH2CH2CH2CH3, CHeqHaxCHCO2Bu and CHeqHaxCHPh), 0.96
(3H, t, J = 7.4 Hz, OCH2CH2CH2CH3). 13C NMR (CDCl3, 101
MHz) δ = 176.1, 146.9, 128.4, 126.8, 126.1, 64.1, 43.6, 43.1,
6. (a) Ansell; M. F. in Rodd's Chemistry of Carbon Compounds,
Supplements to the 2nd Edition, Volume 2: Alicyclic Compounds;
Elsevier, Amsterdam, Netherlands, 1992. (b) Bravo, L.; Mico, J.
A.; Berrocoso, E. Expert Opin. Drug Discov. 2017, 12, 1281–
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Yang, J. Polym. Chem. 2015, 7, 44–53.
33.3, 30.8, 29.4, 19.2, 13.8. HRMS (ESI+) Found [M+H]+
=
261.1851; C17H25O2 requires 261.1849, ꢀ 0.7 ppm.
Acknowledgments
7. Akhtar, W. M.; Armstrong, R. J.; Frost, J. R.; Stevenson, N. G.;
Donohoe, T. J. J. Am. Chem. Soc. 2018, 140, 11916–11920.

10
Tetrahedron
8. We have also recently reported a catalytic asymmetric variant
axial methyl substituent (favoured due to minimization of 1,2-
strain). For a related example, see: Davies, S. G.; Durbin, M. J.;
Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.;
Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron:
Asymmetry 2008, 19, 2870–2881.
of this process, see: Armstrong, R. J.; Akhtar, W. M.; Young, T.
A.; Duarte, F.; Donohoe, T. J. Angew. Chem. Int. Ed. 2019, 58,
12558–12562.
9. Our working hypothesis is that the minor diastereoisomer results
from kinetic protonation of any remaining enolate upon workup
(see Scheme 3A). Increasing the stoichiometry of diol from 1.1 to
2.0 equiv attenuates the basicity of the reaction mixture and
ensures that only protonated ketone is present at the end of the
reaction.
15. Four, P.; Guibe, F. J. Org. Chem. 1981, 46, 4439–4445.
16. (a) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S.
Science 2016, 352, 801–805. (b) Fawcett, A.; Pradeilles, J.; Wang,
Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science 2017,
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11. With sterically hindered diols (3ab, 3al, 3am and 3ao), a mixture
of alicyclic product and cyclic enone intermediate was obtained.
In these cases the crude reaction mixtures were treated with
NaBH4 to affect complete reduction. See Supporting Information
for details.
19. Endo, Y.; Bäckvall, J.-E. Chem. Eur. J. 2011, 17, 12596–12601.
12. Sánchez-Chávez, A. C.; Elena Vargas-Díaz, M.; Ontiveros-
Rodríguez, J. C.; Pérez-Estrada, S.; Flores-Bernal, G. G.;
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M.; Fedorov, A.; Grubbs, R. H. Organometallics 2012, 31, 39–41.
14. In the case of 3ab and 3al the stereochemistry can be explained by
axial addition of iridium hydride to a half chair bearing an pseudo-
Supplementary Material
Supplementary data to this article can be found online at
(please insert link here). Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre
(CCDC 1944075-79) and can be obtained via www.
ccdc.cam.ac.uk/data_request/cif.

Highlights
A highly diastereoselective annulation strategy for the synthesis of alicyclic ketones from diols and
pentamethylacetophenone is described. This process provides efficient access to a wide range of
cyclopentane and cyclohexane products with high levels of stereoselectivity. The origins of
diastereoselectivity in the annulation reaction have been explored by a series of control
experiments, which provides an explanation for how each stereocentre around the newly forged
ring is controlled.