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\begin{document}

\title{En Route to Diastereopure Polycyclic \selectlanguage{greek}γ-\selectlanguage{english}Lactones by Iridium-Catalyzed
Hydride Transfer\selectlanguage{english}}



\author[1]{yang chen}%
\author[1]{Jingyu Zhang}%
\author[1]{Yecheng Wang}%
\author[1]{Hongguang Du}%
\author[2]{Jiaxi Xu}%
\author[1]{Zhanhui Yang}%
\affil[1]{Beijing University of Chemical Technology}%
\affil[2]{Beijing Univ Chem Technol, State Key Lab Chem Resource Engn, Beijing 100029, Peoples R China}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
The reductive lactonization strategy provides an efficient access to
stereoenriched polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones. However, it is still a formidable
challenge to develop an efficient and versatile protocol with excellent
levels of diastereocontrol. Herein we provide a highly
diastereoselective and efficient route to diastereopure bi- and
polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones, by means of an iridium-catalyzed hy-dride
transfer strategy. This method features high levels of stereocontrol,
broad substrate scope, and high catalyst efficiency (S/C = up to 5000).
Mechanistic studies suggested that the iridium hydride formation be the
rate-determining step, and that the hydride transfer step be the
diastereo-determining step. The large steric hindrance of the iridium
hydride species and intramolecular hydro-gen bonding are critically key
to the diastereocontrol of the hydride transfer process. From the
perspectives of configurational anal-ysis and Duniz angles of attack,
the nature of diastereocontrol is well rationalized. A more general
empirical rule based on facial se-lectivity analysis for explaining and
predicting the stereochemistry is also proposed.%
\end{abstract}%



\sloppy


\textbf{Cite this paper:}\emph{Chin. J. Chem.} \textbf{2023} , \emph{41}
, XXX---XXX. \textbf{DOI: 10.1002/cjoc.202300XXX}

En Route to Diastereopure Polycyclic \selectlanguage{greek}γ-\selectlanguage{english}Lactones by Iridium-Catalyzed
Hydride Transfer

Yang Chen,\emph{\textsuperscript{a}}Jingyu
Zhang,\emph{\textsuperscript{a}} Yecheng
Wang,\emph{\textsuperscript{a}}Hongguang Du,\emph{\textsuperscript{a}}
Jiaxi Xu\emph{\textsuperscript{a}} and Zhanhui
Yang*\textsuperscript{,\emph{a}}

\textsuperscript{a} Department of Organic Chemistry, College of
Chemistry, Beijing University of Chemical Technology, Beijing 100029, P.
R. China.\textsuperscript{}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\textbf{Keywords}\tabularnewline
\midrule
\endhead
Iridium catalysis \textbar{} hydride transfer \textbar{} reductive
lactonization \textbar{} diastereoselectivity control \textbar{}
polycyclic \selectlanguage{greek}γ-\selectlanguage{english}Lactones\tabularnewline
\textbf{Comprehensive Summary}\tabularnewline
The reductive lactonization strategy provides an efficient access to
stereoenriched polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones. However, it is still a formidable
challenge to develop an efficient and versatile protocol with excellent
levels of diastereocontrol. Herein we provide a highly
diastereoselective and efficient route to diastereopure bi- and
polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones, by means of an iridium-catalyzed hydride transfer
strategy. This method features high levels of stereocontrol, broad
substrate scope, and high catalyst efficiency (\emph{S/C} = up to 5000).
Mechanistic studies suggested that the iridium hydride formation be the
rate-determining step, and that the hydride transfer step be the
diastereo-determining step. The large steric hindrance of the iridium
hydride species and intramolecular hydrogen bonding are critically key
to the diastereocontrol of the hydride transfer process. From the
perspectives of configurational analysis and Duniz angles of attack, the
nature of diastereocontrol is well rationalized. A more general
empirical rule based on facial selectivity analysis for explaining and
predicting the stereochemistry is also proposed.\tabularnewline
\bottomrule
\end{longtable}

\section*{}

{\label{section}}

Background and Originality Content

Stereoenriched polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones display a wide spectrum of
biological activities, and are important lead molecules for the
development of physiological and therapeutic agents. Representative
bioactive compunds containing \emph{cis} -\selectlanguage{greek}γ-\selectlanguage{english}lactone substructures are
listed in Figure 1, including\emph{Longilactone} ,\textsuperscript{1}
\emph{Merrilactone A}
,\textsuperscript{2}Ineleganolide,\textsuperscript{3}\emph{(+)-}
\emph{Strigol,} \textsuperscript{4}\emph{Artemisin A}
,\textsuperscript{5}and \emph{Mitchellene C.} \textsuperscript{6} The
2,3-\emph{cis} -bicyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones were also used as key intermediates
in the total synthesis of natural products Mitchellenes
B-H.\textsuperscript{7}

The importance of stereoenriched polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones has triggered
numerous efforts for their chemical
synthesis.\textsuperscript{8,9}Specifically, the reductive lactonization
of 2,3-fused 4-oxo-butanoic acids, with two stereocenters pre-installed,
represents a step-economic and diastereo-controllable stragegy. However,
very limited efforts have been made in this area.\textsuperscript{10} In
1983 Eisenbraun and coworkers investigated the diastereocontrol,
using\emph{cis} -2-benzoylcyclohexane-1-carboxylic acid (R = Ph,
(\selectlanguage{ngerman}±)-\emph{cis} -\textbf{1a} ) as the model substrate (Scheme 1a,
i).\textsuperscript{10a} They found that the diastereochemical outcomes
were dependent on the reducing agents. With strongly basic metal
hydrides, \emph{anti} -selectivity (\emph{syn:anti} = 21:79 to 5:95) was
favored. Notably, with sterically large hydrides, the\emph{anti}
-selectivity was highly enhanced (5:95 or 6:94). They also evaluated the
platinum oxide catalyzed hydrogenation, and a moderate\emph{syn}
-selectivity was observed (\emph{syn} :\emph{anti} = 74:26). In 2005,
Rovis and coworkers achived a good \emph{syn} -selectivity by means of
an acid-promoted transfer hydrogenation process
(PhMe\textsubscript{2}SiH/TFA) (Scheme 1a, ii).\textsuperscript{10b}This
protocol was limited to a variety of (±)-\emph{cis}
-2-propionylcycloalkane-1-carboxylic acid (\emph{syn} :\emph{anti} =
90:10 to \textgreater{}95:5). For example, the reaction of
2-propionylcyclohexane-1-carboxylic acid (R = Et, (±)-\emph{cis}
-\textbf{1b} ) yielded a \emph{syn} :\emph{anti} ratio of 93:7. However,
their protocol was not applicable to the 2-aroyl counterparts, as
exemplified by the unselective reaction of (±)-\emph{cis}
-\textbf{1a}(\emph{syn} :\emph{anti} = 50:50). Even now, controlling the
diastereochemistry of the reductive \selectlanguage{greek}γ-\selectlanguage{english}lactonization still remains a
formidable challenge, and an efficient and versatile protocol with
excellent diastereocontrol is in high demand.

\textbf{Figure 1} Bioactive structures with polycyclic\emph{cis}
-\selectlanguage{greek}γ-\selectlanguage{english}lactone substructures.

\textbf{Scheme 1} Previous and our reductive \selectlanguage{greek}γ-\selectlanguage{english}lactonization strategies.

The past several years have witnessed our efforts on developing new
synthetic methodologies by virtue of catalytic hydride transfer
processes catalyzed by a novel series of half-sandwiched
{[}Cp*Ir\textsuperscript{III}Cl/PyIm{]}\textsuperscript{+}Cl\textsuperscript{-}complexes
{[}PyIm = 2-(4,5-dihydro-1\emph{H} -imidazol-2-yl)pyridine, Cp* =
pentamethylcyclopentadiene{]}. With those complexes, a series of
reactions were realized under acidic conditions by our group, including
transfer hydrogenation of
aldehydes,\textsuperscript{11}ketones,\textsuperscript{12}
nitroalkenes,\textsuperscript{13}imines,\textsuperscript{14}
deoxygenation of alcohols,\textsuperscript{15} and other
reactions.\textsuperscript{16}The reduction of oximes and reductive
amination and beyond were also reported by Luo's group.
\textsuperscript{17} The key intermediates were identified as iridium
hydrides {[}Ir{]}--H, of which the hydride atom comes from the formyl
hydrogen of formic acid (Scheme 1b). Our systematic studies have
disclosed the special properties of the iridium hydride species: They
were mild hydride donors with weak Lewis basicity and nucleophilicity
and large steric hindrance. These properties rendered them as
acid-tolerant and stereo-discriminating transient reducing agents, as
evidenced by our previous highly diastereoselective hydride transfer
reductions of endocyclic sp\textsuperscript{2}-hybridized carbon centers
of cyclohexyl/cyclopentyl carbocations\textsuperscript{15b} and
1,5-benzodiazepines\textsuperscript{14} (Scheme 1b). Out of our
expertise, we envision to try our
{[}Cp*Ir\textsuperscript{III}Cl/PyIm{]}\textsuperscript{+}Cl\textsuperscript{-}catalysts
in solving the diastereocontrol challenge of reductive \selectlanguage{greek}γ-\selectlanguage{english}lactonization.
The key to the diastereocontrol lies on the sterically governed hydride
transfer to the exocyclic sp\textsuperscript{2}-hybridized carbon of
carbonyl group. Gratifyingly, our catalysts, even at \emph{S/C} = 5000
(\emph{S/C} = substrate/ catalyst molar ratio), showed good performance
in inducing the diastereocontrol, yielding (\selectlanguage{ngerman}±)-\emph{syn} -\textbf{2} in
99:1 dr in most cases. What is more, the substrate scope limitation in
previous studies was well overcome (Scheme 1c, R = aryl and alkyl).
Herein, we report our iridium-catalyzed highly diastereoselective
reductive lactonization strategy, and provide an efficient access to
diastereopure bicyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones with three continuous sterecenters.

Results and Discussion

Using (\selectlanguage{ngerman}±)-\emph{cis} -\textbf{1a} as the model substrate, we optimized
the reaction conditions, using ethanol and water as the green solvent
(Table 1).\textsuperscript{18} The relative configuration of\emph{syn}
-\textbf{2a} was assigned by analyzing the coupling constants of the
proton at the newly formed stereocenters and by comparing the NMR
spectra of \emph{syn} -\textbf{2a} with those reported. Catalysts were
first screened (entries 1-8). At \emph{S/C} = 1000, the
catalysts\textbf{C1} --\textbf{C7} gave 83-99\% yields (entries 1-7),
while N-Ts catalyst \textbf{C8} only resulted in a 39\% yield (entry 8).
The substituents on pyridine rings and the N-substituent on the
imidazoline ring imposed different effects on the yields, presumably by
affecting the basicity and nucleophilicy of the corresponding iridium
hydride intermediates. \textbf{C1} was selected as the optimal catalyst.
Decreasing its loadings to 2000 and 5000 \emph{S/C} ratios still gave
(±)-\emph{syn} -\textbf{2a} in \textgreater{}99 and 87\% yields (entry
9-10). Shortening the reaction time to 1 hour, the yield of
(±)-\emph{syn} -\textbf{2a} slightly decreased under the condition of
2000 \emph{S/C} ratio (entry 11). Upon lengthening time to 4 hours at
5000 \emph{S/C} ratio, 90\% yield of (±)-\emph{cis} -\textbf{1a} was
obtained (entry 12). Optimization of the equivalents of formic acid
revealed that 8 equivalents of formic acid or more was necessary for a
complete conversion (entries 9, 13, and 14).

\textbf{Table 1} Optimization of reaction conditons\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
entry & cat. & \emph{S/C \textsuperscript{a}} & time (h) & Yield
(\%)\emph{\textsuperscript{b}} &
\emph{syn}:\emph{anti\textsuperscript{c}}\tabularnewline
\midrule
\endhead
1 & \textbf{C1} & 1000 & 2 & \textgreater{}99 & 99:1\tabularnewline
2 & \textbf{C2} & 1000 & 2 & 83 & 99:1\tabularnewline
3 & \textbf{C3} & 1000 & 2 & 96 & 99:1\tabularnewline
4 & \textbf{C4} & 1000 & 2 & 96 & 99:1\tabularnewline
5 & \textbf{C5} & 1000 & 2 & 95 & 99:1\tabularnewline
6 & \textbf{C6} & 1000 & 2 & 90 & 99:1\tabularnewline
7 & \textbf{C7} & 1000 & 2 & 94 & 99:1\tabularnewline
8 & \textbf{C8} & 1000 & 2 & 39 & 99:1\tabularnewline
9 & \textbf{C1} & 2000 & 2 & \textgreater{}99 & 99:1\tabularnewline
10 & \textbf{C1} & 5000 & 2 & 87 & 99:1\tabularnewline
11 & \textbf{C1} & 2000 & 1 & 98 & 99:1\tabularnewline
12 & \textbf{C1} & 5000 & 4 & 90 & 99:1\tabularnewline
13\emph{\textsuperscript{d}} & \textbf{C1} & 2000 & 2 & 76 &
99:1\tabularnewline
14\emph{\textsuperscript{e}} & \textbf{C1} & 2000 & 2 & \textgreater{}99
& 99:1\tabularnewline
\bottomrule
\end{longtable}

\emph{\textsuperscript{a}} Molar ratio of substrate to
catalyst.\textsuperscript{\emph{b} 1}H NMR yield with
1,3,5-trimethoxybenzene as an internal standard.
\emph{\textsuperscript{c}} Determined by\textsuperscript{1}H
NMR.\emph{\textsuperscript{d}} HCO\textsubscript{2}H (4
equiv).\emph{\textsuperscript{e}} HCO\textsubscript{2}H (12 equiv).

A number of \emph{cis} -2-acyl cycloalkane-1-carboxylic acids were
synthesized via either AlCl\textsubscript{3}-catalyzed Friedel-Crafts
acylation\textsuperscript{19} or Ni-catalyzed cross-coupling of
anhydrides with organozinc reagents,\textsuperscript{20} followed by
submitting them to the optimal conditions (Table 2). The stereochemistry
of products was further demonstrated by the one-dimensional NOE (Nuclear
Overhauser Effects) spectra of four randomly selected representative
compounds (\textbf{2c} ,\textbf{2x} , \textbf{2aa} , and \textbf{2b} ).
We focused our substrate scope on 2-aroyl substrates (R = aryl,
\emph{cis} -\textbf{1} ), to which previously established \emph{syn}
-selective reductive lactonization protocols were not
applicable.\textsuperscript{10b} In addition to\emph{cis} -\textbf{1a} ,
other 2-aroyl substituted substrates were converted to the desired
diastereopure products in 60-99\% yields and 98:2 to \textgreater{}99:1
diastereoselectivity, strongly favoring the formation of \emph{syn}
-isomers (\textbf{2a} -\textbf{2u} ). The substituents, for instance,
alkyls, phenyl, phenyloxyl, benzenesulfenyl, and halogen atoms, on
phenyl rings, whether electron-donating or withdrawing, all uniformly
gave [?] 98:2 dr (\textbf{2a} -\textbf{2n} ), although the yields varied.
Substrates bearing more complex arene rings such as
5,6,7,8-tetrahydronaphthalen-2-yl (\textbf{2o} ),
4-methylnaphthalen-2-yl (\textbf{2p} ), naphthalen-2-yl and
naphthalen-1-yl (\textbf{2q} ), pyren-4-yl (\textbf{2r} ), 9\emph{H}
-fluoren-3-yl (\textbf{2s} ), and dibenzo{[}\emph{b} ,\emph{d}
{]}thiophen-2-yl (\textbf{2u} ) also transformed in \textgreater{}99:1
dr. The ketoacid with dibenzo{[}\emph{b} ,\emph{d} {]}furan-2-yl
(\textbf{2t} ) was reductively lactonized in [?] 98:2 dr values. Oxidation
of the sulfur atom of\emph{syn} -\textbf{2u} did not reduce its
diastereopurity.

We next examined the effects of backbone architectures on the
stereochemial results. Introduction of an endocyclic disubtituted
(\textbf{2w} ) or tetrasubstituted alkene moiety (\textbf{2x} ), being
fused with a bridged bicyclic {[}2.2.1{]} or {[}2.2.2{]} scaffold
(\textbf{2y} and \textbf{2z} ), or contraction of the cyclohexane ring
to cyclopentane (\textbf{2aa} ) or cyclobutane (\textbf{2ab} ), did not
affect the stereochemical outcomes. All products were produced in
\textgreater{}99:1 dr values, and \emph{syn} -products were formed
exclusively.

Substrates with alkanoyls (R = alkyl, \emph{cis} -\textbf{1} ) were also
amenable to the diastereocontrol. The reactions of\emph{cis}
-\textbf{1b} and \emph{cis} -\textbf{1ac} both gave \textgreater{} 99:1
dr values and reasonable yields.

\textbf{Table 2} Substrate scope\emph{\textsuperscript{a}}

\emph{\textsuperscript{a} cis} -\textbf{2a} , \textbf{2c} --\textbf{2h}
,\textbf{2k} --\textbf{2o} , \textbf{2q, 2w, 2ab} were isolated by
extraction. \emph{\textsuperscript{b}} The regioselective ratio (rr) of
ketoacid was 94:6 (\emph{para} :\emph{ortho} ), and it was inherited to
the next step. \emph{\textsuperscript{c}} The \emph{rr} of ketoacid and
product was 50:50. \emph{\textsuperscript{d}} 0.1 mmol of ketoacid was
used. \emph{\textsuperscript{e}} HCO\textsubscript{2}H (16
equiv.),\textbf{C1} (\emph{S/C} = 500), H\textsubscript{2}O/EtOH (1:1),
80\textsuperscript{o}C, 6 h. \emph{\textsuperscript{f}} The \emph{rr} of
ketoacid and product was 96:4.\emph{\textsuperscript{g}}
HCO\textsubscript{2}H (12 equiv.), \textbf{C1}(\emph{S/C} = 500),
H\textsubscript{2}O/EtOH (1:1), 80\textsuperscript{o}C, 6 h.

Mechanistic studies were performed (Scheme 2). The isotope tracing
experiments with HCO\textsubscript{2}D, DCO\textsubscript{2}D, and
D\textsubscript{2}O (Scheme 2a) demonstrated that (1) the transfered
hydride originated from the formyl group of formic acid, and (2) that
H--D exchange, both between iridium hydride ({[}Ir{]}--H) and
D\textsubscript{2}O and between iridium deteride ({[}Ir{]}--D) and
H\textsubscript{2}O, occurred before the hydride or deuteride
transfer.\textsuperscript{12, 15a, 21} The H--D exchange between
{[}Ir{]}--D and solvent was dramatically suppressed by using
DCO\textsubscript{2}D and D\textsubscript{2}O-EtOH as the respective
deteride source and solvent, and thereby a 95\% D-incorporation was
obtained. We also measured the kinetic isotope effect (KIE), and
a\emph{k\textsubscript{H}} /\emph{k\textsubscript{D}} = 4.8 was observed
(Scheme 2b). The primary KIE implied that the rate-determining step
should involve a C--H cleavage event.

The key intermediate during the reductive lactonization was observed
by\textsuperscript{1}H NMR of the crude reaction mixture (Scheme 2c). It
turned out to be an alcohol (\textbf{3a} ), which was generated from the
diastereospecific reduction of the ketone moiety. Treatment of this
alcohol under acidic conditions (AcOH) yielded lactone\emph{syn}
-\textbf{2a} with \textgreater{}99:1 \emph{syn} :\emph{anti}ratio. We
also found that the reduction of 4-ketoester\emph{cis} -\textbf{1m'} did
not occur (Scheme 2d), which indicated the important role of the
carboxylic acid group in facilitating the reduction. Similar carboxylic
acid effect was also observed by Rovis and
coworkers.\textsuperscript{10b}

\textbf{Scheme 2} Isotope labelling, KIE, and other mechanistic
expecriments.

\textbf{Scheme 3} Proposed mechanism and diastereocontrol models

On the basis of the mechanistic studies, a plausible mechanism was
proposed (Scheme 3a). In light of the KIE studies, the generation of
iridium hydride \textbf{B} via \selectlanguage{greek}β-\selectlanguage{english}hydride elimination was suggested to be
the rate-determining step.\textsuperscript{22} Subsequent hydride
transfer to the carbonyl group, which was activated by the carboxylic
group, served as the diastereo-determining step. Considering the
experimental results in Scheme 2d, we proposed that the hydrogen bonding
between the carboxylic acid and ketone moiety accounted for the
activation. In detail, protonation of the C=O bond of carboxylic
acid\textbf{1a} increased its acidity, and an intramolecular hydrogen
bonding between O--H and carbonyl C=O occurred, as designated by the
structure \textbf{C} . Although \textbf{C} could resonate with\textbf{D}
, it was suggested as the major contributor for explaining the
carboxylic effect. On the other hand, the intramolecular hydrogen
bonding, to some extent, fixed the configuration by connecting the
ketone and carboxylic acid moieties. The fixed and somewhat rigid
configuration of the molecule rendered the hydride transfer more
stereoselective. In this regard, it is the intramolecular hydrogen
bonding that holds responsibility for the excellent diastereocontrol in
the hydride transfer step. Once diastereospecifically formed,\textbf{3a}
immediately undergoes intramolecular esterification, following classic
acid-catalyzed addition-elimination mechanism, to form lactone
\emph{syn} -\textbf{2a} , without eroding the stereochemistry of the
newly generated stereocenter.

To better understand the diastereocontrol of the hydride transfer, we
performed the DFT calculations. The calculated fixed configurations and
B\selectlanguage{ngerman}ürgi-Dunitz angles of attack for hydride delivery to carbonyl were
shown in Scheme 3b and 3c.\textsuperscript{23} In the case that the
carboxylic assumes axial position and benzoyl equatorial position
(Scheme 3b), the frontside attack will encounter severe steric repulsion
against two axial hydrogen atoms and one axial carboxylic group.
However, the backside attack faces very little steric retardation.
Consequently, the hydride delivery in this direction kinetically
preferentially gave \emph{syn} -\textbf{2a} . Similar stereocontrol is
also applicable in the other configuration bearing an equatorial
carboxylic and an axial benzoyl (Scheme 3c). In one word, it is the
steric repulsion between sterically bulky iridium hydride and the
cycloalkyl ring that governs the diastereoselectivity.

To explain the backbone architecture effects in Table 2 and also to
predict the stereochemical outcomes of the potential reactions of
substrates with similar stereochemistry, we proposed a rule of thumb
(Scheme 3d). The hypothesis that the hydrogen bond form an additional
ring (ring B) leads to a \emph{cis} -fused bicyclic system, and thereby
the hydride reduction of the ``pseudo-endocyclic'' carbonyl was endowed
with facial selectivity---the hydride can attack from either convex or
concave face.\textsuperscript{24} Owing to the large steric hindrance of
the iridium hydride, it would preferentially donate its hydride from the
sterically much more accessible convex face, in this way generating a
configuration with all the hydrogen atoms on the three tertiary
stereocenters residing in the same convex face.

\textbf{Scheme 4} Gram-scale reactions and synthetic applications

In the two gram-scale reactions, \textbf{2a} and \textbf{2m} were both
isolated in excellent yields and \textgreater{} 99:1 dr (Scheme 4a). The
purification was very convenient. Column chromatography was not
required. Extraction with ethyl acetate followed by drying and
concentration afforded desired products in good NMR purities (see
Supporting Information). The 4-bromophenyl group in \textbf{2m} acted a
handle for further chemical manipulations (Scheme 4b). For examples, the
Suzuki coupling of \textbf{2m} with three aryl boric acids carrying
electron-withdrawing or electron-donating substituents delivered more
functionalized products \textbf{4a} -\textbf{4c} in 56-96\% yields, and
the stereochemistry of the three stereocenters was not affected.

\emph{trans} -2-Benzoylcyclohexane-1-carboxylic acid (\emph{trans}
-\textbf{1a} ) did not undergo the reductive lactonization (Scheme 4c),
highlighting the importance of the configurational effect of the
substrate. In other words, our iridium catalysts showed excellent
capability in discriminating the \emph{cis} - and\emph{trans}
-substrates, and highly selectively catalyzed the reactions of
\emph{cis} -substrates, leaving the \emph{trans} -ones intact. This
selectivity provides an easy procedure to separate the \emph{cis} -
and\emph{trans} -2-acylcycloalkane-1-carboxylic acids, which were
generated as a diasteremeric mixture in some cases and were difficult to
be separated due to their almost identical polarity. As shown in Scheme
4d, subjection of equimolar \emph{cis} -\textbf{1a} and\emph{trans}
-\textbf{1a} to standard reductive latonization conditions produced
\emph{cis} -\textbf{2b} in 94\% yield and\emph{trans} -\textbf{1a} in
92\% recovery. Due to the largely different polarities and water
solubility of \emph{cis} -\textbf{2b} and\emph{trans} -\textbf{1a} ,
they were easily separated.

Conclusions

We have developed a highly diastereoselective method for efficient
synthesis of diastereopure bi- and polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones,
using\emph{cis} -2,3-fused 4-oxo-butanoic acids as the starting
materials. This method features the use of a
{[}Cp*Ir\textsuperscript{III}Cl/PyIm{]}\textsuperscript{+}Cl\textsuperscript{-}catalyst
with formic acid as the hydride source. Advantages of this method
include excellent diastereoselectivity control, use of water-ethanol as
solvent, broad substrate scope, and high catalyst efficiency (\emph{S/C}
up to 5000). The gram-scale reactions take place efficiently in
excellent yields and diastereocontrol. Mechanistic studies suggested
that the iridium hydride formation be the rate-determining step, and
that the hydride transfer step be the diastereo-determining step. The
large steric hindrance of the iridium hydride species underlies the
success of diastereocontrol. The carboxylic acid group of substrates
plays important roles in activating the substrates and in rendering a
relatively rigid configuration to highly diastereoselectively receive
the hydride. DFT calculations provide detailed insights into the nature
of diastereocontrol, from the perspectives of configurational analysis
and Duniz angles of attack. An empirical rule based on facial
selectivity analysis for explaining and predicting the stereochemistry
is also proposed. Our iridium catalysts only work on \emph{cis}
-2,3-fused 4-oxo-butanoic acids, showing excellent level of molecular
recognization. This selectivity can be harnessed to separate the
diastereomeric mixtures of \emph{cis} - and\emph{trans}
-2-acylcycloalkane-1-carboxylic acids. Compared with previous methods,
our method shows superiority in terms of substrate scope, degree of
diastereocontrol, and sustainability.

Experimental

To a 10-mL reaction tube was sequentially added \emph{cis} -2-acyl
cycloalkane-1-carboxylic acids\textbf{1} (0.2 mmol), ethanol (0.5 mL), 1
mL of \textbf{C1} solution in deionized water (0.0001 mol/L, \emph{S/C}
= 2000). The tube was then sealed with a rubber cap. A syringe needle
was inserted into the cap to connect the inner to outer atmosphere. The
mixture was stirred for 3 minutes in an 80 \selectlanguage{ngerman}°C heating block, followed by
addition of formic acid (60 \selectlanguage{greek}μ\selectlanguage{english}L, 1.6 mmol, 8 equiv) in one portion via a
microsyringe. After stirring for 2 h, the reaction mixture was cooled to
room temperature, diluted with saturated brine (2 mL), and extracted
with ethyl acetate (2 mL \selectlanguage{ngerman}× 3). The organic phase was dried with
anhydrous Na\textsubscript{2}SO\textsubscript{4} and then removed under
reduced pressure. \textsuperscript{1}H NMR pure \emph{syn} -\textbf{2a}
,\textbf{2c} --\textbf{2h} , \textbf{2k} --\textbf{2o} , \textbf{2q}
,\textbf{2w} , \textbf{2ab} were obtained without further purification.
Other products were purified by silica gel column chromatography.

Supporting Information

The supporting information for this article is available on the WWW
under https://doi.org/10.1002/cjoc.2023xxxxx.

Acknowledgement (optional)

This research was supported by the National Key Research and Development
Program of China (No.2022YFF0709803), Natural Science Foundation of
Beijing Municipality (no. 2202041), and the High Performance Computing
Platform of Beijing University of Chemical Technology (BUCT).

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\begin{longtable}[]{@{}l@{}}
\toprule
Manuscript received: XXXX, 2023 Manuscript revised: XXXX, 2023
Manuscript accepted: XXXX, 2023 Accepted manuscript online: XXXX, 2023
Version of record online: XXXX, 2023\tabularnewline
\bottomrule
\end{longtable}

The Authors\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& After acceptance, please insert a group photo of the authors taken
recently. &\tabularnewline
& \textbf{Left to Right:} Authors Names &\tabularnewline
\bottomrule
\end{longtable}

\textbf{Entry for the Table of Contents}\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
\selectlanguage{greek}\textbf{En Route to Diastereopure Polycyclic γ-Lactones by
Iridium-Catalyzed Hydride Transfer}\selectlanguage{english} Yang Chen, Jingyu Zhang, Yecheng
Wang, Hongguang Du, Jiaxi Xu and Zhanhui Yang* \emph{Chin. J. Chem.}
\textbf{2023}, \emph{41}, XXX---XXX. \textbf{DOI:
10.1002/cjoc.202300XXX}\tabularnewline
An iridium-catalyzed highly diastereoselective and efficient route to
diastereopure bi- and polycyclic \selectlanguage{greek}γ-\selectlanguage{english}lactones is achieved, featuring high
levels of stereocontrol, broad substrate scope, and high catalyst
efficiency (\emph{S/C} up to 5000). The large steric hindrance of the
iridium hydride species and the intramolecular hydrogen bonding underlie
the success of the highly diastereoselective reductive lactonization. A
general empirical rule based on facial selectivity analysis is proposed
for explaining and predicting the stereochemistry.\tabularnewline
\bottomrule
\end{longtable}

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