Enantioselective C-H Lactonization of Unactivated Methylenes Directed by Carboxylic Acids

Article abstract of DOI:10.1021/jacs.9b12239

The formidable challenges of controlling site-selectivity, enantioselectivity, and product chemoselectivity make asymmetric C-H oxidation a generally unsolved problem for nonenzymatic systems. Discrimination between the two enantiotopic C-H bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed C-H oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%) using hydrogen peroxide as oxidant and a Br?nsted acid additive under mild conditions and short reaction times. Coordination of the carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γsite-selectivity. When the substrate contains nonequivalent γ-methylenes, the site-selectivity for lactonization can be rationally predicted on the basis of simple C-H activation/deactivation effects exerted by proximal substituents. In addition, discrimination of diastereotopic C-H bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]nonane enabled by two key, sequential γ-C-H lactonizations, with the latter that fixes the chirality of five stereogenic centers in one step with 96% ee.

Full text of DOI:10.1021/jacs.9b12239

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Article
Enantioselective C-H lactonization of unactivated
methylenes directed by carboxylic acids
Marco Cianfanelli, Giorgio Olivo, Michela Milan, Robertus J.M.
Klein Gebbink, Xavi Ribas, Massimo Bietti, and Miquel Costas
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12239 • Publication Date (Web): 27 Dec 2019
Downloaded from pubs.acs.org on December 28, 2019
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Enantioselective C-H lactonization of unactivated methylenes
directed by carboxylic acids
Marco Cianfanelli,§‡ Giorgio Olivo, §‡ Michela Milan, § Robertus J. M. Klein Gebbink,¶ Xavi Ribas, §
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Massimo Bietti,ǂ* and Miquel Costas§*
§ QBIS Research Group, Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de
Girona, Campus Montilivi, Girona E-17071, Catalonia, Spain.
ǂ Dipartimento di Scienze e Tecnologie Chimiche, Universitꢀ “Tor Vergata”, Via della Ricerca Scientifica, 1, I-00133 Rome,
Italy
¶ Organic Chemistry & Catalysis, Debye Institute for Nanomaterial Science, Utrecht University, Universiteitsweg 99,
3584CG Utrecht, The Netherlands
KEYWORDS C-H oxidation, enantioselectivity, Manganese catalysts, lactones, bioinspired oxidation, bicyclo[3.3.1]nonane
ABSTRACT: The formidable challenges of controlling site-selectivity, enantioselectivity and product chemoselectivity, make asym-
metric CH oxidation a generally unsolved problem for non-enzymatic systems. Discrimination between the two enantiotopic CH
bonds of an unactivated methylenic group is particularly demanding and so far unprecedented, given the similarity between their
environments and the facile overoxidation of the initially formed hydroxylation product. Here we show that a Mn-catalyzed CH
oxidation directed by carboxylic acids can overcome these challenges to yield γ-lactones in high enantiomeric excess (up to 99%)
using hydrogen peroxide as oxidant and a Brønsted acid additive under mild conditions and short reaction times. Coordination of the
carboxylic acid group to the bulky Mn complex ensures the rigidity needed for high enantioselectivity and dictates the outstanding γ
site-selectivity. When the substrate contains non-equivalent γ-methylenes, the site-selectivity for lactonization can be rationally pre-
dicted on the basis of simple CH activation/deactivation effects exerted by proximal substituents. In addition, discrimination of
diastereotopic CH bonds can be modulated by catalyst design, with no erosion of enantiomeric excess. The potential of this reaction
is illustrated in the concise synthesis of a tetrahydroxylated bicyclo[3.3.1]nonane enabled by two key, sequential γ-CH lactoniza-
tions, with the latter that fixes the chirality of five stereogenic centres in one step with 96% ee.
INTRODUCTION
translates into a meager toolbox of methodologies for asymmet-
ric aliphatic CH bond oxidation, with the available examples
that are essentially limited to the oxidation of relatively weak,
activated CH bonds (benzylic or -to-heteroatom).2–7 The
only example of asymmetric, unactivated C-H oxidation is the
recently described enantioselective desymmetrization of mono-
substituted cyclohexane derivatives via ketonization of enanti-
otopic methylenic carbons (Figure 1).8 To the best of our
knowledge, there are no reports for non-enzymatic asymmetric
hydroxylation of enantiotopic CH bonds in a prochiral meth-
ylenic group (Figure 1a). Even in the broader context of
C(sp3)H functionalization, there are only few examples of en-
antioselective methylene CH discrimination, limited to the
realm of late, noble transition metals9,10 (Pd,11 Rh,12 Ru,13
Ir14,15).
The increasing complexity of bioactive molecules, featuring a
large number of stereogenic centers, continuously demands for
the development of novel and effective enantioselective cata-
lytic transformations. In this regard, functionalization of ali-
phatic CH bonds represents the most straightforward ap-
proach, as it directly introduces a novel functionality on ubiqui-
tous CH bonds of the starting material.1 Given the relevance
of chiral oxygenated motifs in natural and bioactive products,
enantioselective C(sp3)H oxidation is particularly attractive in
this respect. However, such reaction requires highly reactive
species to cleave strong, unactivated secondary CH bonds and
yet a very fine control over three key challenging features: dis-
crimination of one among many C-H bonds, typically charac-
terized by similar bond strengths and steric environments (site-
selectivity or intramolecular chemoselectivity); discrimination
between two enantiotopic CH bonds (enantioselectivity); and
prevention of the facile oxidation of the first formed chiral sec-
ondary alcohol product to an achiral ketone (product chemose-
lectivity). The difficulty of addressing all these issues at once
Over the last decade, bioinspired nonheme Fe and Mn com-
plexes have emerged as catalysts for site-selective and stereose-
lective oxidations.16–18 These complexes activate H2O2
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Figure 1. A) Overview of the strategies for asymmetric oxidation of unactivated aliphatic CH bonds. B) State of the art for directed
CH oxidation, with the relative open challenges. C) Design of the present work.
to generate a powerful yet selective oxidant, an electrophilic
high- valent metal-oxo species, competent for challenging CH
hydroxylations via a stereospecific Hydrogen Atom Transfer
(HAT)/hydroxyl rebound mechanism, akin to the enzymatic
path.17 Remarkably, their structure can be modulated to ration-
ally tune enantioselectivity both in olefin epoxidations and syn-
dihydroxylations17 and, more recently, in CH oxidations via
enantioselective desymmetrization (Fig. 1A).8 In the latter case,
key to high enantioselectivity has been the development of a
well-defined pocket (cavity) around the catalytic center to pre-
cisely define substrate orientation.
shown to act as directing groups,20–23 enabling selective intra-
molecular hydroxylation of tertiary CH bonds to provide val-
uable -lactones (albeit with low stereoinduction, max 35% ee
in the kinetic resolution of a racemate),21 with a -selectivity
orthogonal to Pd catalyzed β-CH functionalization.24–26 Of no-
tice, such a predictable -lactonization is a Fe-catalyzed CH
oxidation that has found application in total synthesis.27–31 How-
ever, when applied to secondary γ-CH bonds the reaction is
not very efficient, leading to very low lactone yields32 or
overoxidation, to the ketoacid product.21
Within this framework, we hypothesized that the use of fluori-
nated alcohols as strong hydrogen bond donor (HBD) solvents
may reduce or prevent such overoxidation, preserving the chi-
rality.33–35 Furthermore, fluorinated alcohols may assist H2O2
activation36 as well as the subsequent spontaneous cyclization
of the hydroxyacid21 to afford the enantioenriched γ-lactone act-
ing as hydrogen bond donors. Following this design, we herein
describe the first example of Mn catalyzed enantioselective di-
rected oxidation of non-activated C(sp3)-H bonds on adaman-
taneacetic acids as a case study.
We envisioned that this versatile class of catalysts may consti-
tute a promising option to pursue enantioselective CH oxida-
tion of unactivated methylenic groups, provided that a far
higher degree of control over the transition state geometry is
exerted. We surmised that the use of a directing group could
supply such control by fixing substrate orientation to the cata-
lyst and rigidifying the transition state, as observed with heavier
metals.9,19 Carboxylic acids are known to bind the metal center
in Fe and Mn catalyzed CH oxidation where they have been
shown to act as co-ligands assisting in the cleavage of H2O2 to
give a high-valent metal-oxo carboxylate species.17 Moreover,
in Fe catalyzed CH oxidations, carboxylic acids have been
RESULTS AND DISCUSSION
Adamantaneacetic acid 1 was selected as a model substrate for
its rigidity and the presence of three accessible γ-methylenes for
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directed oxidation. Moreover, the defined shape, steric bulki-
Conv. Yield ee
Entry Catalyst
Additive
1
2
3
4
5
6
7
8
ness, lipophilicity and chemical inertness of the adamantane
core make this structural motif particularly attractive in multiple
fields, from drug design to catalyst development and material
science.37 From an organic synthesis perspective, the appeal of
adamantane cores could be even greater after the realization that
their deconstruction via CC bond cleavage pathways38,39 can
provide an easy entry into complex and densely functionalized
bicyclic [3.3.1] structures that are found in molecules with no-
table biological activity .39–42 Directed lactonization of 1 would
enable challenging functionalization of secondary γ-CH
bonds, with a selectivity orthogonal to common bridgehead
derivatizations that target the more reactive tertiary sites.9,16,17
(%)
(%)
(%)
1
Fe(pdp)
Fe(mcp)
-
59
6
75
2
-
53
75
72
81
74
54
89
38
85
86
97
80
5
67
84
89
94
95
93
95
65
90
90
94
96
9
Fe(TIPSpdp)
Mn(pdp)
Mn(TIPS pdp)
Mn(TIBSpdp)
“
-
12
26
28
29
14
28
8
3
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4
-
5
-
Optimization of the oxidation of 1: Oxidation of 1 (25 mM) with
1 equivalent of H2O2, delivered over 30 minutes by syringe
pump, was performed in 2,2,2-trifluoroethanol (TFE), employ-
ing 1 mol% of catalyst, at 0 °C, in the absence of an external
carboxylic acid co-ligand (Table 1). The catalysts used are chi-
ral Fe and Mn tetradentate complexes of general formula (S,S)-
[M(L)(OTf)2] (L = (S,S)-pdp and (S,S)-mcp, pdp = N,N′-bis(2-
pyridylmethyl)-2,2′-bipyrrolidine, mcp = N,N′-dimethyl N,N′-
bis(2-pyridylmethyl)-1,2-trans-diamino cyclohexane, OTf =
CF3SO3, Fig. 2a).8 At first, we tested the Fe(pdp) complex, pre-
viously shown to promote tertiary CH lactonization on a num-
ber of carboxylic acids.20,21 We were pleased to observe the for-
mation of the corresponding chiral -lactone 1a with good en-
antioselectivity (75% ee) albeit in poor yield (6%, entry 1).
Modification of the diamine backbone from
6
-
7b
8c
9
-
“
-
Mn(TIPSmcp)
Mn(dMM pdp)
Mn(NMe2pdp)
Fe(TIPSpdp)
Mn(pdp)
-
10
11
12d
13d
-
38
43
36
-
TfOH
TfOH
56
(64)e,f
Mn(NMe2pdp)
Mn(dMMpdp)
Mn(TMSpdp)
Mn(TIPSpdp)
Mn(TIBSpdp)
TfOH
TfOH
TfOH
TfOH
TfOH
60
>99
89
35
63
51
52
91
93
96
97
98
14
15d
16
17
18d
88
85
70
(68)e
a
Reaction conditions: substrate (25 mM) and (S,S)-cat. 1
mol% were dissolved in TFE, 1.0 eq. of H2O2 (and, when indi-
cated, a 0.09 M TfOH solution (0.1 eq.), delivered inde-
pendently) was added as a 0.9 M TFE solution over 30 minutes
by syringe pump, at 0°C. Workup as described in the SI. Con-
version, yield and ee were determined by chiral GC analysis of
two or three different runs with biphenyl as internal standard.
n.d. = not detected. Traces (<5%) of hydroxyacids have been
detected in the oxidations. bCH3CN solvent. cHFIP solvent. dAd-
ditional 30 minutes of stirring to promote lactonization. eIsolated
yield. f 0.8 g (4.5 mmol) scale. gee determined by chiral GC anal-
ysis after LiAlH4 reduction and acetylation of the resulting diol.
Absolute configuration was determined by X-Ray diffraction
(see SI).
bipyrrolidine to 1,2-cyclohexanediamine (entry 2) decreases the
enantioselectivity, while increase of the catalyst steric bulk43
(which leads to a more structured cavity around the metal,
Fe(TIPSpdp), entry 3) slightly improves product yield (up to
12%) and enantioselectivity (up to 84% ee). Considering that
Fe and Mn may operate via common mechanisms,44 we turned
our attention to the corresponding Mn catalysts, which lead to a
net improvement in both yield and ee (Mn(pdp),45 entry 4, 26%
and 89%, respectively). Again, increase of the catalyst steric
bulk improves the reaction up to 28% yield and 94% ee (Mn(TIP-
Spdp), entry 5). To further pursue this effect, we designed and
synthesized a novel catalyst with a greater steric hindrance:
complex Mn(TIBSpdp) (Fig. 2b). Its solid state structure is very
similar to those reported for other Mn(pdp) catalysts,8 but its
Figure 2. a, Schematic representation of the catalysts used in
this work (see SI for their synthesis and characterization). Sub-
stituents on position 5 of the pyridines, highlighted in red, mod-
ulate the catalyst steric bulk. b, ORTEP diagram of the solid
state structure of (S,S)-(MnTIBSpdp). Note the structured cavity
defined by the TIBS substituents. With the exception of the Mn
bound oxygen atoms, triflate groups are omitted for clarity.
Table 1. Optimization of adamantaneacetic acid (1) directed
oxidation.a
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larger triisobutylsilyl substituents define an even more steri-
Page 4 of 11
1
cally restricted cavity around the catalytic center. Accordingly,
the new catalyst Mn(TIBSpdp) furnished lactone 1a in slightly
improved yield and ee (entry 6, 29% and 95%, respectively).
Inversion of the chirality of the catalyst affords the opposite en-
antiomer (see Table S2). The use of CH3CN or HFIP
(1,1,1,3,3,3-hexafluoro-2-propanol) solvents leads to worse or
comparable results (entries 7-8), respectively, while change of
the diamine backbone from pdp to mcp or ecp has a detrimental
effect, as observed with Fe catalysts (entry 9 and Table S2). All
of these reactions suffer however from a low mass balance,
where high conversions are accompanied by modest product
yields, as previously observed in analogous Fe-catalyzed CH
lactonization reactions.21,27–32 Interestingly, increase in the cat-
alyst electron density significantly improves the efficiency of
the reaction, up to 43% yield for MnMe2Npdp (entries 10-11). We
attribute this increase in yield to a more efficient generation of
the active metal-oxo species, since electron-rich complexes
have been proposed to facilitate heterolytic OO cleavage via a
push-pull mechanism.46 Along this line, we reasoned that addi-
tion of a Brønsted acid could further improve the reaction out-
come (vide infra), as protons are also known to facilitate heter-
olytic OO cleavage in stoichiometric reactions.47–49 Indeed, we
were pleased to observe that slow addition of 0.1 eq of trifluo-
romethanesulfonic acid (triflic acid, TfOH), whose conjugate
base is the same as the counteranion of the complex, proved to
be key to significantly enhance product yield and, to a lower
extent, reaction enantioselectivity in a general manner (entries
12-20 and Table S2. The beneficial effect of TfOH eliminates
the requirement of electron-rich catalysts for efficient H2O2 ac-
tivation (entries 14-15). Systematic increase in size of the pyri-
dine substituent in position 5 (entries 16-18) enhances product
yield and enantioselectivity up to a 68% isolated yield and an
outstanding 98% ee for Mn(TIBSpdp) (entry 18 and Table S2).
The reaction can be easily scaled up to 0.8 g of substrate (4.5
mmol) without any loss in efficiency and selectivity (entry 13).
The optimized conditions were then applied to the oxidation of
2,2-dimethyladamantaneacetic acid 2 (Figure 3A). To our de-
light, oxidation led to the exclusive formation of γ-lactone 2a in
very high isolated yield (88%) and excellent ee (97% ee).
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Mechanistic considerations: In all cases, this directed oxidation
shows an excellent site-selectivity that overrides the innate re-
activity pattern of the substrate, with γ-lactone as the only prod-
uct. For instance, while oxidation of 2 exclusively furnishes lac-
tone 2a, with the corresponding methyl ester 3 oxidation selec-
tively occurs at the most activated tertiary sites to give hydrox-
yester 3a in 76% yield (Figure 3A). Along the same line, in the
oxidation of 1, traces of oxidized lactone, likely at the tertiary
CH bonds, are detected only when employing excess H2O2
(Table S4), suggesting that intermolecular overoxidation occurs
only after the lactonization.
Figure 3. A: Oxidation of 2,2-dimethyladamantaneacetic acid
2. B) Oxidation of the corresponding methyl ester 3 with differ-
ent amounts and types of acid additives (GC yields and conver-
sions). C) Isotope labelling experiments to ascertain the origin
of the O-atom incorporated into the lactones (GC-MS analysis
via chemical ionization with CH4). The reported 18O incorpora-
tions are obtained after correction of the isotopic purity of the
labelled reactants.
additives in H2O2 activation for the intermolecular oxidation of
3 (Figure 3B) to avoid any possible interference from the car-
boxylic acid moiety. With no external acids, 3a is formed in 4%
yield in CH3CN. In TFE, the yield increases up to 36%, sug-
gesting an assistance of the hydrogen bond donor solvent in
H2O2 activation.36 Addition of TfOH (0.1 eq) improves the yield
up to 43% and 41% in CH3CN and TFE, respectively, consist-
ently with our hypothesis of a more facile H2O2 activation with
Brønsted acid additives. Replacement of TfOH for AcOH (1
eq), known to facilitate O-O cleavage via the carboxylic acid
Then, we elucidated in further detail the influence of the acid
additive on reaction efficiency. It has to be remarked that an
acid environment is known to catalyze the lactonization of hy-
droxy acids, which occurs spontaneously even in CH3CN.21 Be-
sides this effect, we investigated the assistance of acid
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two paths are in competition (1:1 ratio) but lead to the same
assisted pathway,17 leads to 3a in 21% and 81% yield in CH3CN
1
2
3
4
5
6
7
8
and TFE, respectively. While in CH3CN a higher carboxylic
acid loading is required for efficient oxidation,8,45 the assistance
of TFE in H2O2 activation enables the reaction to proceed in
high yield even at low AcOH loadings. Moreover, TfOH, TFE
and the carboxylic acid can act synergistically to improve reac-
tion efficiency up to an 85% yield of 3a (Figure 3B), a scenario
that is fully consistent with that observed in the intramolecular
oxidation of 2 (Figure 3A), suggesting an effective H2O2 acti-
vation under these experimental conditions.
At last, we undertook 18O labelling experiments to gain more
insight into the oxidation mechanism. 88% of O-atom incorpo-
ration from H2O2 has been previously reported for Fe-catalyzed
lactonization.21 However, when the experiment was carried out
employing the Mn(TIBSpdp) catalyst, O-incorporation dropped
to 50%, with the remainder 50% of the O-atom that derives
from the carboxylic moiety (Figure 3C). These results imply
that as compared to the Fe system a different mechanism is op-
erating in the lactonization promoted by the Mn one. After ini-
tial HAT,8,17 the carbon centered radical can undergo competi-
tive rebound of either the OH or the carboxylate ligand. These
enantiomer of the final γ-lactone product.
Oxidation of 3’-hydroxy adamantaneacetic acid 4: With these
results in hand, we set out to study the oxidation of substituted
adamantaneacetic acids. Insertion of a substituent at position 3’
breaks the C3 symmetry of the adamantane core, differentiating
the three γ methylenic groups into one proximal and two distal
sites (see Fig. 4, where the substituent is OH, substrate 4). Each
of the distal methylenes bears, in turn, two diastereotopic C-H
bonds, pointing towards (endo, Hc and Hc’) or away (exo, Hb and
Hb’) from the substituent. Therefore, three possible enantio-
meric pairs can be formed upon lactonization, one proximal, 4a,
and two diastereomeric distal exo and endo lactones, 4b and 4c,
respectively, with the simultaneous formation of up to five ste-
reogenic centers in the latter cases (the indication of all possible
products is displayed in Figure S1). 3’-Substituted adaman-
taneacetic acids thus provide a unique set of six non-equivalent
C-H bonds to investigate the interplay between catalyst and sub-
strate structure over enantio-, diastereo- and site-selectivity.
Oxidation of 4 under optimized conditions with complex
Mn(TIBSpdp) furnishes the three lactones 4a, 4b and 4c in a
1:2.7:1 ratio, each
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60
Figure 4. Oxidation of 3’-hydroxyadamantaneacetic acid (4), showing the three lactone products formed and the impact of catalyst
steric bulk on selectivity. Diastereomeric ratio (d.r.) corresponds to exo:endo (4b:4c) ratio. Regioisomeric ratio (r.r.) refers to the
ratio of proximal over distal oxidation products (4a):(4b + 4c). Conversions, yields and ee of minor products are shown in Table S7.
Absolute chirality of 4b was assigned by its X-ray structure; taking into account that the oxidation does not occur on the same carbon,
absolute configuration of 4c can be also assigned, while that of 4a is assigned for similarity to 2a.
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O
O
O
(S,S)-Mn (TIBSpdp)
or (S,S)-Mn (pdp) (1 mol%)
H2O2 (1 eq.)
proximal
C-H
O
1
2
3
4
HO
O
O
O
*
*
TfOH (0.1 eq.)
+
+
*
*
*
*
*
distal
C-H
X
X
X
*
*
TFE, 0 ˚C or RT, 1h
X
*
*
5
6
7
c
b
a
X
= HBA or non-HBA
major product for
(S,S)-Mn (pdp)
generally major product for
major product for
X = Alkyl, Ar
(S,S)-Mn (TIBSpdp)
8
9
A
X
= HBA - Distal Lactones
(S,S)-Mn(TIBSpdp)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Cl
OH
O
NH
N
H
8cb
(+)-9cb
(+)-4b
(+)-5b
6b
7b
55% (a:b:c 1:2.7:1)
4b 32%, >99% ee
67% (a:b:c 1:6:10)
8c 40%, 92% ee)
82% (a:b:c 1:2.2:1.1)
5b 42%, 96% ee
79% (a:b:c 1:9:2.4)
6b 57% 95% ee
75% (a:b:c 1:7.4:2.5)
7b 51%, 96% ee
50% (a:b:c 1:1:2.5)
9c 28%, 88% ee
(S,S)-Mn(pdp)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
O
N
N
O
Cl
H
H
4c
5c
6c
7c
8c
(+)-9c
50% (a:b:c 1:2:5)
4c 31%, 89% ee
39% (a:b:c 1:2:5)
5c 23%, 88% ee
57% (a:b:c 1:1.4:4)
6c 36%, 94% ee
54% (a:b:c 1:4:13)
8c 39%, 94% ee
47% (a:b:c 1:1:3)
9c 28%, 88% ee
60% (a:b:c 1:3:6)
7c 35%, 94% ee
B
X
= non-HBA - Proximal Lactones
(S,S)-Mn(pdp)
X = Alkyl
X = Aryl
O
O
O
O
O
O
O
O
O
O
10a
(+)-12a
(+)-13a
(+)-14a
15a
64% ( r.r. 1.5:1)
10a 95% ee
58% ( r.r. 4.7:1)
12a 95% ee
48% ( r.r. 4.5:1)
13a 97% ee
60% ( r.r. 4.3:1)
14ac 56%, 96% ee
65% ( r.r. 2.8:1)
15a 95% ee
O
O
O
O
O
O
O
O
O
O
O
Br
NO2
O
N
H
16a
17a
18a
(+)-19a
11a
70% ( r.r. 3.7:1, d.r. 1:1.1)
proximalsd 95%, 96% ee
73% ( r.r. 2.2:1)
16a 95% ee
64% ( r.r. 5.4:1)
17a 96% ee
46% ( r.r. 0.9:1)
18a >99% ee
66% ( r.r. 3.9:1)
19a 95% ee
Figure 5. Enantioselective lactonization of bridgehead substituted adamantaneacetic acids (conditions as described in Typical Oxi-
dation Procedure). For each reaction, the major product is drawn (with its ee displayed in the second row, along with its GC yield for
section A), and the total yield of the three lactones is displayed in the first row (GC yield for section A, isolated yield for section B),
together with the distribution of products in the crude mixture (a:b:c ratio or r.r. ratio). Further details, such as conversions, yields
and ee of minor products, whenever determined, and results with Mn(TIBSpdp) catalyst are reported in Table S8 and Figure S3. bWith
substituents OAc and Cl the main product is the endo lactone c with both catalysts. cTwo diastereomeric proximal lactones are formed.
dIsolated single lactone yield.
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ents the endo lactone product c was favored over the exo prod-
one with good to excellent enantioselectivity (91, 99 and 67%
1
2
3
4
5
6
7
8
ee, respectively), without formation of non-directed oxidation
products (Fig. 4). Distal lactonization (4b + 4c) is favored over
proximal (4a), giving a regioisomeric ratio (r.r.) of 1:3.9, likely
due to deactivation of the proximal site by solvent hydrogen
bonding to the hydroxyl group33 and, to a lesser extent, by steric
effects. Exo-product 4b, is formed in larger amount than its
endo counterpart 4c, as a result of the slightly favored steric ac-
cessibility. Most importantly, the main product 4b (32% yield)
is formed with the highest enantioselectivity (99% ee). Dia-
stereomers 4b and 4c derive from oxidation of two different
carbons (see Figure S2). Remarkably, the exo:endo diastereose-
lectivity can be tuned by manipulation of catalyst structure. Sys-
tematic decrease of steric bulk on position 5 of the pyridine moi-
eties in the catalyst regularly decreases the exo:endo ratio
(4b:4c) from 2.7:1 with Mn(TIBSpdp) (Fig. 4) up to a complete
inversion with Mn(pdp) (1:2.5), whilethe enantioselectivity of
the main product 4c remains high (89% ee), thus implementing
a rare example of catalyst-controlled selectivity.
uct b, and, in line with the results obtained with the other sub-
strates, a decrease in d.r. was observed upon catalyst switch.
The steric bulk of these substituents alone cannot account for
this difference in diastereoselectivity, since groups with similar
sizes, such as hydroxyl (4) and chlorine (9) or acetamido (6) and
acetoxy (8), influence the d.r. to a significantly different extent.
We hypothesize that solvent hydrogen bonding to the substitu-
ent can affect not only its electronics, but also its size, thus in-
fluencing diastereoselectivity. In line with this hypothesis, in
the oxidation of 4 the use of a non-HBD solvent such as
CH3CN, depletes any exo:endo selectivity, while the use of
HFIP gives results that are similar to those found in TFE (Table
S7).
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
33
34
35
36
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46
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60
We then moved to alkyl substituents (Figure 5, section B, left),
which display a weak electron-donating character via inductive
effects. Accordingly, we observed that the presence of an ethyl
substituent at 3’ (10) favors proximal oxidation, with a r.r. of
1.5:1 and an excellent enantioselectivity for the proximal lac-
tone product 10a (95% ee). The distal lactones are now formed
in nearly equal amounts, irrespective of the catalyst used. Alt-
hough the same preference is observed for Mn(TIBSpdp), the
bulky trialkylsilyl moieties attenuate the proximal selectivity
probably because of steric clash. For this reason, we selected
the less hindered Mn(pdp) as the catalyst of choice for proximal
lactonization (the results for Mn(TIBSpdp) are reported in Figure
S3). The insertion of two methyl substituents (11) does not
change the reaction outcome, with the two diastereomeric prox-
imal lactones 11a representing again the main products.
Oxidation of 3’-substituted adamantaneacetic acids: We then
extended our study to other adamantaneacetic acids substituted
at 3’ (Figure 5). Ether, amide, ester and halogen substituents are
all well tolerated, affording lactones in modest to good yields
and excellent enantioselectivities (Figure 5, section A). The use
of Mn(TIBSpdp), generally provides the best results. In all cases,
distal lactonization is favored over proximal one, and the pref-
erence for the exo b or endo c diastereomer can be tuned by
changing catalyst structure from Mn(TIBSpdp) (in red) to
Mn(pdp) (in blue), respectively. Amide substituents, as previ-
ously observed in other CH oxidation reactions,8 give high
yields and selectivities (up to 79% yield and a d.r. of 3.7:1, with
95-96% ee and r.r.  1:9.9 for 6 (X = NHCOCH3) and 7
(NHCOC(CH3)3). Catalyst tuning allows complete inversion of
the exo:endo ratio for hydroxyl (4), methoxy (5) and amido (6
and 7) substituents. With acetoxy (8) and chlorine (9) substitu-
Replacement of ethyl (11) for phenyl (12) greatly enhanced the
proximal selectivity up to a 4.7:1 r.r., without altering the enan-
tioselectivity (95% ee), a behavior that can be explained on the
basis of proximal CH bond activation via stereoelectronic ef-
fects. These bonds benefit from homobenzylic stabilization that
slightly decreases their BDE as compared to non-activated
O
O
O
(R,R)-Mn(TIBSpdp) (1 mol%)
1. LiAlH4
2. KMnO4,NaOH
(S,S)-Mn(pdp) (1 mol%)
O
HO
OH
H2O2 (1 eq.)
H2O2 (1 eq.)
O
O
O
TfOH (0.1 eq.)
TFE
O
TfOH (0.1 eq.)
TFE
recycled1x
1
1a
20
20b (EXO)
64%
56% (96% ee)
d.r. 6.5 : 1
76%
HO
HO
OH
*
HO
O
O
O
*
*
*
*
H2O2 (30% v/v)
AcOH
OH
LiAlH4
O
HO
20b (EXO)
*
HO
*
*
*
*
21
OH
(+)-22
81%
(+)-22
75%
Chiral bicyclo[3.3.1]nonane
Figure 6. Synthesis of chiral tetrahydroxylated bicyclo[3.3.1]nonane core (22) via stepwise directed C-H oxidations with full enan-
tiocontrol. Absolute configuration of (+)-22 could not be unequivocally assigned by X-ray diffraction. Results for Mn(pdp) catalyzed
oxidation of 20 are shown in Figure S5.
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Page 8 of 11
CH bonds.50 Encouraged by this result, we expanded the scope
of proximal γ-lactonization to a series aryl-substituted adaman-
taneacetic acids (substrates 13-19 in Figure 5b). In all cases the
proximal lactone is the main product, obtained in good yield
(33-61%) and excellent ee (95-97%). The reaction is com-
pletely chemoselective for the lactonization of unactivated γ-
CH bonds, with no traces of products deriving from aromatic
oxidation even with electron-rich arene substituents. Moreover,
no competitive oxidation on benzylic primary (13) or secondary
(14) C-H bonds is observed, in spite of their significantly lower
BDE as compared to adamantane CH bonds.50 This is indeed
one of the few cases in which oxidation occurs selectively at
non-activatedH bonds over intrinsically more activated ben-
zylic ones.51,52 Increase of the steric bulk of the p-substituent of
the aryl ring leads to a regular erosion of the proximal selectiv-
ity (r.r. decreases from 4.7 for 13 to 4.5 for 14 up to 2.8 for 15).
Along a similar line, the insertion of meta substituents in 16 af-
fords an even lower proximal selectivity (r.r. 2.2; see also the
lower r.r. obtained with Mn(TIBSpdp), Figure S3). On the other
hand, increase of the electron-density of the aryl ring improves
the proximal selectivity, with a r.r. that decreases from 5.4 for
17 to 4.7 for 13 to 3..9 for 19 up to 0.9 for the strong electron-
withdrawing p-nitrophenyl group (18). To sum up, these reac-
tions disclose a rational impact of substrate and catalyst struc-
ture over site- and diastereoselectivity in asymmetric Mn-cata-
lyzed γ-lactonization of carboxylic acids, setting the stage for
prediction of the reaction selectivity.
moiety in 20b offers in turn a useful handle for the deconstruc-
1
2
3
4
5
6
7
8
tion of the adamantane core, with retention of configuration at
all the chiral centers.39 Baeyer-Villiger oxidation41 of 20b yields
bis-lactone product 21 by selective insertion of an oxygen atom
into the most electron rich CC bond. Reductive ring-opening
of the tetracycle affords tertahydroxylated chiral bicy-
clo[3.3.1]nonane 22 in a combined 75% yield over three steps.
Its carbon skeleton is found in several biologically active prod-
ucts/metabolites. It is an intermediate along the biosynthetic
pathway of sesquiterpenes, and represents as well a portion of a
simplified analogue of taxol.39–42,54 Summarizing, directed Mn-
catalyzed lactonization enables a novel synthetic route to this
structure with two key CH lactonization steps, the latter of
which fixes the chirality of 5 stereocenters with 96% ee.
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13
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17
18
19
20
21
22
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CONCLUSIONS
Herein, we describe the first enantioselective CH oxidation of
unactivated methylenic groups to yield γ-lactones by means of
a novel catalytic system that addresses the multiple selectivity
challenges associated with this reaction. Our strategy entails a
HAT-based CH bond oxidation , promoted by a chiral Mn cat-
alyst, a carboxylic acid directing group in combination with hy-
drogen peroxide, a fluorinated alcohol solvent and triflic acid in
catalytic amount to obtain chiral γ-lactones as the exclusive
products. Key to the high enantioselectivity is the combination
of a carboxylic acid and a rigid adamantane core, which act syn-
ergistically to define the spatial orientation of the γ-methylenic
CH bonds to the catalytic center. The reaction is robust and
tolerates several functional groups. When the three methylenic
sites are rendered non-equivalent by introduction of substitu-
ents in the tertiary sites, multiple lactone products become ac-
cessible. Remarkably, in these cases site-selectivity can be pre-
dicted on the basis of activating and deactivating effects exerted
by the substituents as well as their interaction with the hydrogen
bond donor solvent. In addition, the diastereoselectivity of the
reaction can be systematically manipulated in a predictable
manner by rational choice of the catalyst. We envision that the
principles for effective, asymmetric lactonization presented in
this work will be a starting point for the development of novel
enantioselective CH functionalizations and for the implemen-
tation of stereoselective γ-CH lactonization in organic synthe-
sis.
Functionalization of lactones and synthesis of (+)-22: The pro-
pensity of γ-lactones to undergo a vast array of different trans-
formations makes such compounds versatile intermediates in
organic synthesis. Their main reactivity path consists in a nu-
cleophilic addition to the carbonyl group, followed by ring
opening to furnish hydroxyacids, hydroxyesters, hydroxy-
amides and 1,4-diols, without affecting the chirality of the first
formed γ-CHOH bond. As an example of the viability of these
derivatizations with our oxidation products, we reduced lac-
tone2a to the corresponding 1,4-diol in excellent 95% yield and
97% ee (see Figure S4). To further demonstrate the synthetic
potential of our directed lactonization procedure, we prepared
2-oxo-1-adamantaneacetic acid 20 (bearing a valuable 1,2-di-
substituted adamantane motif, Figure 6) from commercial 1 in
three steps, to be compared with its shortest 7 step synthesis
reported so far.53 Lactonization of 1 to yield 1a is followed by
ring-opening reduction and re-oxidation to provide 20 in a com-
bined 53% yield over the three steps. The CH2CO2H motif can
be regarded as a handle to sequentially forge a novel -CO
bond on a different methylenic group with high enantioselectiv-
ity, increasing molecular complexity in a stepwise fashion. In
fact, ketoacid 20 can undergo a second round of directed γ-CH
lactonization, where the presence of the ketone function now
restricts oxidation to two positions, with formation of two dia-
stereomeric exo and endo lactones (20b and 20c, respectively).
Mn(TIBSpdp) shows the highest diastereoselectivity, providing
20b and 20c in a combined 56% yield, a 6.8:1 d.r. and an excel-
lent enantioselectivity for 20b (96% ee), with 5 stereogenic cen-
tres again formed in a single step. The increased level of dia-
stereoselectivity likely derives from the closer proximity of the
oxo group to the carboxylic acid moiety compared to the bridge-
head substituted adamantanes displayed in Figure 5. The ketone
ASSOCIATED CONTENT
The Supporting Information is available free of charge via the In-
ternet at http://pubs.acs.org.
Experimental details for the preparation and characterization of lig-
ands and metal complexes, substrates, catalytic reactions, and for
product isolation and characterization. NMR spectra and crystallo-
graphic information files (cif 1, cif 2, cif 3, cif 4 and cif 5).
AUTHOR INFORMATION
Orcid iD
Giorgio Olivo 0000-0003-4053-7673. Robertus J. M. Klein
Gebbink 0000-0002-0175-8302. Xavi Ribas 0000-0002-2850-
4409. Massimo Bietti 0000-0001-5880-7614. Miquel Costas
0000-0001-6326-8299.
Corresponding Author
* bietti@uniroma2.it
* miquel.costas@udg.edu
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1
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3
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5
6
7
8
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Support by the Spanish Ministry of Science (PGC2018-101737-B-
I00 to M.C. and J.d.C. grant to G.O., FJCI-2016-30243), and Gen-
eralitat de Catalunya (ICREA Academia Award to M.C. and
2014SGR 862), and from EU (MSCA-ITN-2015 Action
NoNoMeCat, 675020) is acknowledged. The authors thank M. Bor-
rell for providing an H218O2 sample.
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SYNOPSIS TOC A Mn-catalyzed method for the enantioselective lactonization of rigid carboxylic acids via asymmetric C-H
oxidation is presented. Lactones can be obtained in good yields and excellent ees, with a high, predictable site-selectivity and,
whenever possible a catalyst-controlled diastereoselectivity.
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