Biocatalytic Conversion of Cyclic Ketones Bearing α-Quaternary Stereocenters into Lactones in an Enantioselective Radical Approach to Medium-Sized Carbocycles

Article abstract of DOI:10.1002/anie.201800121

Cyclic ketones bearing α-quaternary stereocenters underwent efficient kinetic resolution using cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus. Lactones possessing tetrasubstituted stereocenters were obtained with high enantioselectivi

Full text of DOI:10.1002/anie.201800121

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Biocatalytic conversion of cyclic ketones bearing alpha-
quaternary stereocenters to lactones in an enantioselective
radical approach to medium-sized carbocycles
Authors: Charlotte Morrill, Chantel Jensen, Xavier Just-Baringo,
Gideon Grogan, Nicholas Turner, and David John Procter
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800121
Angew. Chem. 10.1002/ange.201800121
Link to VoR: http://dx.doi.org/10.1002/anie.201800121
http://dx.doi.org/10.1002/ange.201800121

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
Biocatalytic conversion of cyclic ketones bearing α-quaternary
stereocenters to lactones in an enantioselective radical approach
to medium-sized carbocycles
Charlotte Morrill,[a] Chantel Jensen,[a] Xavier Just-Baringo,[a] Gideon Grogan,[b] Nicholas J. Turner*[a]
and David J. Procter*[a]
Abstract: Cyclic ketones bearing α-quaternary stereocenters
undergo efficient kinetic resolution using cyclohexanone
monooxygenase (CHMO) from Acinetobacter calcoaceticus.
Lactones possessing tetrasubstituted stereocenters are obtained
with high enantioselectivity (up to >99% ee) and complete
chemoselectivity. Preparative scale biotransformations were
exploited in conjunction with a SmI2-mediated cyclization process to
access complex, enantiomerically enriched cycloheptan- and
cycloctan-1,4-diols. In a parallel approach to structurally distinct
products, enantioenriched ketones from the resolution bearing an α-
all carbon quaternary stereocenter were used in a SmI2-mediated
cyclization process to give cyclobutanol products (up to >99% ee).
1A).[9] The synthetic reach of biocatalytic reactions is greatly
extended when enzymatic processes are integrated into synthetic
sequences involving chemical catalysts and reagents.[10] Herein, we
describe a highly enantioselective and chemoselective, biocatalytic
Baeyer-Villiger approach to unsaturated lactones II bearing
tetrasubstituted stereocenters that proceeds by the kinetic resolution
of cyclic ketones I bearing α-quaternary stereocenters. Crucially,
lactones II are not easily accessible in enantiomerically enriched
form using state-of-the-art chemical methods.[11] Lactones II are
excellent substrates for SmI2–H2O-mediated[12] cyclization reactions
that complete an enantioselective biocatalytic-chemical approach to
important and complex cycloheptan- and cycloctan-1,4-diols III
(Scheme 1B): Structural motifs that are notoriously hard to prepare
and that are prevalent in many biologically-relevant targets
(Schemes 1B and 1C).[13]
The Baeyer-Villiger (BV) reaction[1] transforms ketones into
esters or lactones with predictable regioselectivity and as such is a
valuable tool for synthesis. Metal-based catalysts[2] and
organocatalysts[3] have been developed for catalytic enantioselective
variants of the BV reaction, however, high enantioselectivities are
generally limited to the transformation of activated cyclobutanone
substrates in which the release of ring strain drives the BV
reaction.[4] Baeyer-Villiger monooxygenases (BVMOs) offer an
attractive alternative to the use of chemical reagents for
enantioselective BV reactions. These flavin-dependent enzymes
exploit atmospheric oxygen and catalyze the transformation through
an enzyme-bound flavin-(hydro)peroxy intermediate.[5] The use of
A. Biocatalytic kinetic resolution of cyclic ketones using BVMOs
O
O
O
R2 = H – many examples
R1
R2
R1
R2
BVMOs
O
*
+
R1
*
R2 ≠ H – unknown
kinetic resolution
R2
n
n
n
rac
R1 = aryl, alkyl
B. A biocatalytic-chemical approach to complex, medium-sized cycloalkanols
OH
O
chemical
reagent
biological
reagent
O
R2
Me
O
R3
R3
II
CHMO
Acinetobacter
sp.
SmI2–H2O
I
III
1,2
1,2
Me
17 examples
up to >99% ee
1,2
OH
5 examples
BVMOs
promises
distinct
advantages
in
terms
of
Me
rac
n biocatalytic BV reaction
n reductive radical cyclization
enantioselectivities, substrate scope, and chemoselectivity not
possible using chemical reagents.[6]
n tetrasubstituted stereocenters n quaternary all-carbon stereocenters
n high enantioselectivity n high chemoselectivity n good substrate scope
BV transformations of α,α-dialkyl cyclic ketones have the
potential to deliver enantioenriched lactones with tetrasubstituted
stereocenters and cyclic ketones bearing α-all-carbon quaternary
centers. Such products possess hard-to-build stereocenters[7] and
are high value chiral building blocks for synthesis.[8] To our
knowledge, there are no reports of the enantioselective BV reaction
C. Biologically significant targets possessing complex medium-sized cycloalkanols
OH
O
AcO
O
OH
Ph
OH
HO
O
NH
O
H
OH
HO
O
H
AcO
Ph
O
H
OH
O
O
H
H
O
HO
O
OH
O
HO
2g]
of α,α-dialkyl cyclic ketones using chemical reagents.[2b,
(+)-pleuromutilin
n antibacterial
phorbol
n tumour promotor
paclitaxel (Taxol)
n anticancer
Ph
Furthermore, the ability of BVMOs to catalyze the kinetic resolution
of α,α-dialkyl cyclic ketones was, until now, unexplored (Scheme
Scheme 1. A. BVMOs in the kinetic resolution of cyclic ketones: lack of
precedent for the resolution of substrates bearing α-quaternary stereocenters.
B. An approach to complex, medium-sized cycloalkanols that exploits the
synergy between a biocatalytic and a chemical process. C. The biological
importance of molecules containing cycloheptanol and cyclooctanol motifs.
[a]
[b]
C. Morrill, Dr. C. Jensen, Dr. X. Just-Baringo, Prof. N. J. Turner,
Prof. D. J. Procter
School of Chemistry, University of Manchester
Manchester, M13 9PL (UK)
E-mail: david.j.procter@manchester.ac.uk
Prof. G. Grogan
The biocatalytic kinetic resolution was explored using the
purified CHMOActineto enzyme from Acinetobacter calcoaceticus
(NCIMB 9871). A glucose/glucose dehydrogenase (GDH) recycling
system was employed for catalytic regeneration of the NADPH
cofactor[14] and the feasibility of the biotransformation was initially
Department of Chemistry, University of York
Heslington, York, YO10 5DD (UK)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
assessed on an analytical scale using ketone 1a (R1 = Me, R2 = H).
Pleasingly, despite the lack of precedent for the resolution of
substrates bearing α-quaternary centers, lactone 2a was efficiently
formed in >99% ee at a conversion of 50% (Table 1). A control
reaction, in which 1a was exposed to the reaction conditions in the
absence of CHMO, resulted in no conversion to the product. In order
to assess the scope of the transformation, a range of lactones
bearing various aryl groups on the alkene unit was prepared in one
straightforward step from 1a (see Supporting Information). Despite
the presence of the bulky aryl substituents and the α-quaternary
center, we were pleased to observe unprecedented tolerance on the
part of CHMO and all six-membered ketones 1 were transformed to
less efficiently by the enzyme and lower conversions were exhibited,
however, enantioselectivity remained high. Variation of the reaction
pH and use of an alternative biocatalyst, cyclododecanone
monooxygenase (CDMORhodo) from Rhodococcus, did not lead to
improved conversions.[17] Ketone 1i, in which the R1 group was an
ethyl rather than a methyl substituent, was transformed inefficiently,
although
a small amount of product was formed with high
enantiocontrol. Following assessment of the process on an analytical
scale, transformations were performed on a preparative scale (0.2
mmol) (formation of 2a-c, 2f). Facile separation of the product from
the ketone afforded pure samples of the enantioenriched lactone
products. For substrates, 1a-c, 1f, high value ketones bearing α- all
carbon quaternary stereocenters 2a-c, 2f were obtained in high
enantiopurity after the kinetic resolution (vide infra).
seven-membered lactones
2 with very high enantioselectivities
(selectivity factors, E > 200) (Table 1).
We also explored the scope of the biocatalytic kinetic resolution
with respect to the formation of six-membered lactones. A range of
five-membered ketones 3 was prepared and subjected to the
CHMO-catalysed transformation (Table 2). Although the
biotransformations were typically less efficient than those involving
Table 1. Biotransformations of six-membered cyclic ketones bearing α-
quaternary all-carbon stereocenters catalyzed by CHMOAcineto
.
CHMO
O
O
NADPH
R1
Glucose/GDH
O
R2
R2
Tris/HCl Buffer pH 7.0
25 °C, 250 rpm, 24 h
R1
Table 2. Biotransformations of five-membered cyclic ketones bearing α-
1
2
quaternary all-carbon stereocenters catalyzed by CHMOAcineto
.
O
O
O
O
F
O
O
CHMO
O
O
NADPH
Me
Me
Me
Me
Glucose/GDH
O
R3
2a 50%a (47%)b
>99% ee (R)
E > 200
2b 50%a (43%)b
>99% ee (R)
E > 200
2c 44%a (32%)b
>99% ee (R)
E > 200
R3
Tris/HCl Buffer pH 7.0
25oC, 250 rpm, 24 h
Me
4
3
O
O
O
O
O
O
O
O
Cl
O
F
O
O
O
Br
Me
Me
Me
Me
Me
Me
2d 13%a
>99% ee (R)
E > 200
2e 19%a
>99% ee (R)
E > 200
2f 44%a (34%)b
>99% ee (R)
E > 200
4a 48%a
78% ee (R)
E = 17
4b 52%a (46%)b
80% ee (R)
4c 17%a
96% ee (R)
E = 25
O
E = 59
O
O
O
O
O
O
Br
Cl
O
CF3
Me
O
O
O
O
Me
Me
Me
Me
Me
Et
4d 0%a
4e 4%a
ee n.d.
4f 34%a
72% ee (R)
E = 9
2g 34%a
>99% ee (R)
E > 200
2h 29%a
>99% ee (R)
E > 200
2i 3%a
>99% ee
E > 200
O
O
CF3
Me
Conditions for analytical scale biotransformations: Ketone 1 mg mL-1, CHMO
0.25 mg mL-1, NADPH 0.7 mM, GDH 0.25 mg mL-1, glucose 5.5 mM, Tris/HCl
buffer 100 mM. a Values shown are conversions determined by GC or 1H NMR
analysis of crude reaction mixtures. b Isolated yields in brackets for preparative
scale transformations. For a detailed description of the procedure for the
preparative scale biotransformations see the Supporting Information.
Enantiomeric excesses determined by chiral stationary phase GC or HPLC
analysis.
O
O
Me
Me
4g 2%a
4h 39%a
88% ee (R)
E = 28
ee n.d.
Conditions for analytical scale biotransformations: Ketone 1 mg mL-1, CHMO
0.25 mg mL-1, NADPH 0.7 mM, GDH 0.25 mg mL-1, glucose 5.5 mM, Tris/HCl
buffer 100 mM. a Values shown are conversions determined by GC or 1H NMR
analysis of crude reaction mixtures. b Isolated yields in brackets for preparative
scale transformations. For a detailed description of the procedure for the
preparative scale biotransformations see Supporting Information. Enantiomeric
excesses determined by chiral phase GC or HPLC analysis.
Selective formation of the (R) enantiomer of the lactone products
was confirmed for 2a-c and inferred for the remainder.[15] For
substrates bearing a methyl substituent at the α-quaternary center,
conversions up to 50% (the maximum theoretical value for an ideal
kinetic resolution) were observed. In stark contrast to chemical
oxidation of 1b to 2b, no side products resulting from competing
oxidation of the alkene in the starting material and product were
observed.[16] Thus, the biocatalytic process exhibits complete
chemoselectivity. Substitution was tolerated at all positions on the
aromatic ring, with halogen, methyl and trifluoromethyl substituents
all accepted by the enzyme active site. Substrates 1d and 1e,
bearing bulky naphthyl and 3-bromo substituents, were transformed
six-membered cyclic ketones, in some cases lactone products 4
were formed with selectivity factors (E 17-59) indicative of useful
synthetic procedures. For example, cyclopentanones 3c and 3h
underwent significant conversion and lactones 4c and 4h were
obtained in 96% ee and 88% ee, respectively. Five-membered cyclic
ketones 3d, 3e and 3g, containing larger aromatic substituents,
showed very little or no conversion to lactone products (Table 2).
This article is protected by copyright. All rights reserved.

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
Selective formation of the (R) enantiomer of the lactone products
was confirmed for 4a-c and inferred for the remainder.[15] Analogous
seven-membered ketone substrates were incompatible with the
biocatalytic process.[15]
lactones to complex seven- and eight-membered cycloalkanols,
however, until now the process could only deliver racemic products
as enantioenriched starting lactones could not easily be
prepared.[12g, 12j] Achieving enantiocontrol in SmI2-mediated reactions
of achiral or racemic substrates is challenging[23] and the use of
enantioenriched substrates in diastereoselective processes is a
more general approach to access enantioenriched products.
Berghuis and co-workers have previously determined the
structure of CHMORhodo, a homolog of CHMOActineto, in its ‘tight’
conformation in complex with ε-caprolactone, the product of BV
oxidation of cyclohexanone (PDB code 4RG3)[18] and suggest that
this is the conformation of the enzyme in which stereoselectivity of
the reaction is determined. CHMOAcineto used here, shares 55%
amino acid sequence identity with CHMORhodo and the majority of
residues within the active site are conserved, allowing the
construction of a model of CHMOAcineto such as that previously
presented by Reetz and co-workers.[19] The model was used as the
input for an in silico docking experiment with the enantiomers of
lactone product 2a. Figure 1 shows the (R)-enantiomer of 2a, the
preferred product of reaction, beneath the FAD coenzyme with its
alkenyl substituent accommodated in the hydrophobic pocket formed
by the side chains of L435, F505, and F432, the latter having been
shown through mutation to have a profound influence on the
The enantioenriched lactones 2/4 formed by the biocatalytic
Baeyer-Villiger
reaction
were
excellent
substrates
for
diastereoselective radical cyclizations mediated by SmI2–H2O. Upon
treatment with SmI2–H2O, lactones 2/4 underwent efficient 5-exo-trig
radical cyclization to give seven- and eight-membered cycloalkanols
5 in good yield. Oxidation of the crude product mixtures simplified
the diastereoisomeric mixtures and afforded the cycloalkanoid
products 6 with up to 6:1 dr. The reaction proceeded with no loss of
enantioenrichment and important cyclooctanol motifs were obtained
in >99% ee.
The radical cyclization proceeds by electron transfer from
Sm(II) to the carbonyl group of the enantioenriched lactones formed
by the biocatalytic BV reaction. The resultant radical anions IV (see
Table 3) undergo intramolecular addition to the alkene acceptor to
give hemiketal intermediates that are reduced in situ by SmI2–H2O to
give enantioenriched seven- and eight-membered cycloalkanol
products 5 in good yield.
enantioselectivity of CHMO
catalyzed reactions.[20] The pose
Acineto
would also permit the accommodation of larger side chains such as
those in the (R)-lactone products 2b and 2c. The role of this region
in the accommodation of bulky side chains, such as that of 2-phenyl
cyclohexanone, has previously been demonstrated.[19] Interestingly,
the 2a lactone carbonyl in the top pose superimposes well with the
equivalent atom in the 4RG3-ε caprolactone complex, at a distance
of 3.3 Å from the ribose 1- hydroxyl and 2.7 Å from the side chain of
R327, which is thought to stabilise the oxyanion in the Criegee
intermediate in the same position.
Table 3. Radical cyclization of enantioenriched lactones using SmI2–H2O
completes an enantioselective approach to cycloheptanols and cyclooctanols.
OH
OH
O
DMP
SmI2–H2O
THF, rt
O
Ar
Ar
O
1,2
1,2
Ar
CH2Cl2, rt
1,2
Me
2b,c,f,g, 4b
Me OH
5
6
Me
OH
OH
OH
Cl
O
O
O
F
Me
Me
Me
6a 73%a
72:28 dr
>99% ee
6b 87%a
75:25 dr
>99% ee
6c 70%a
80:20 dr
>99% ee
(from 2b, >99% ee)
(from 2c, >99% ee)
(from 2f, >99% ee)
OH
OH
SmIII
O
O
O
CF3
O
Me
Me
Ar
1,2
Me
IV
6d 58%a
75:25 dr
6e 76%a
86:14 dr
>99% ee
80% ee
(from 4b, 80% ee)
(from 2g, >99% ee)
Conditions: Lactone (1 equiv.), SmI2 (8 equiv.), H2O (800 equiv.).
Diastereoisomeric ratios were determined from 1H NMR of crude reaction
2 steps. Enantiomeric excesses were
determined by chiral phase GC or HPLC analysis. DMP = Dess-Martin
Figure 1. Model of CHMOAcineto in complex with lactone product (R)-2a
created using Autodock-Vina.[21] Backbone and side chains of the enzyme are
shown in light blue, carbon atoms of FAD, NADP+ and 2a are shown in grey,
green and yellow, respectively. Selected interactions are indicated by black
dashed lines with distance in Ångstroms.
mixtures. aIsolated yields after
periodinane.
The biocatalytic transformation of α,α-dialkyl cyclic ketones delivers
not only enantioenriched lactones 2 but also enantioenriched cyclic
ketones 1 recovered from the kinetic resolution (Scheme 2). For
example, the biocatalytic transformation to give lactone 2b (43%
isolated yield, >99% ee) also gave ketone 1b (39% isolated yield,
Radical approaches to challenging medium sized carbocycles
are highly prized.[22] In particular, radical cyclizations to give
cyclooctanes are scarce and are mostly limited to 8-endo cyclization
modes. We recently reported
a 5-exo-trig radical cyclization
approach that converts unsaturated six and seven-membered
This article is protected by copyright. All rights reserved.

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
C. Baccin, F. Pinna, G. Strukul, Organometallics 1994, 13, 3442-3451;
f) N. Yang, Z. Su, X. Feng, C. Hu, Chem. Eur. J. 2015, 21, 7264-7277.
g) L. Zhou, X. Liu, J. Ji, Y. Zhang, W. Wu, Y. Liu, L. Lin, X. Feng, Org.
Lett. 2014, 16, 3938-3941.
>99% ee) bearing an α- all-carbon quaternary stereocenter.
Pleasingly, SmI2-mediated radical cyclization of 2b gave enantiopure
cyclobutanol 7a with complete diastereocontrol in 84% yield.[24]
Cyclobutanols 7b and 7c could be similarly be obtained from
resolved ketones bearing α- all-carbon quaternary stereocenters, 1f
and 3f. Thus, biocatalytic kinetic resolution of racemic ketones 1 and
3, when used in combination with metal-mediated radical
cyclizations, allows divergent access to important carbocyclic
products with very different molecular architectures in enantiopure
[3]
a) P. P. Poudel, K. Arimitsu, K. Yamamoto, Chem. Commun. 2016, 52,
4163-4166; b) D. K. Romney, S. M. Colvin, S. J. Miller, J. Am. Chem.
Soc. 2014, 136, 14019-14022; c) M. W. Giuliano, C.-Y. Lin, D. K.
Romney, S. J. Miller, E. V. Anslyn, Adv. Synth. Catal. 2015, 357, 2301-
2309; d) S. Xu, Z. Wang, X. Zhang, X. Zhang, K. Ding, Angew. Chem.
Int. Ed. 2008, 47, 2840-2843.
[4]
[5]
[6]
B. Mao, M. Fañanás-Mastral, B. L. Feringa, Chem. Rev. 2017, 117,
10502-10566.
form.
OH
O
1. SmI2–H2O
THF, rt
D. Sheng, D. P. Ballou, V. Massey, Biochemistry 2001, 40, 11156-
11167.
Ph
O
Ph
O
Ph
a) H. Leisch, K. Morley, P. C. K. Lau, Chem. Rev. 2011, 111, 4165-
4222; b) G. de Gonzalo, M. D. Mihovilovic, M. W. Fraaije,
ChemBioChem 2010, 11, 2208-2231; c) V. Alphand, G. Carrea, R.
Wohlgemuth, R. Furstoss, J. M. Woodley, Trends Biotechnol. 2003, 21,
318-323; d) M. Bučko, P. Gemeiner, A. Schenkmayerová, T. Krajčovič,
F. Rudroff, M. D. Mihovilovic, Appl. Microbiol. Biotechnol. 2016, 100,
6585-6599; e) G. de Gonzalo, W. J. H. van Berkel, M. W. Fraaije (Ed.
K. Faber, W-D. Fessner, N. J. Turner) in Science of Synthesis:
Biocatalysis in Organic Synthesis, Thieme, New York, 2015, 187-234.
a) Y. Minko, M. Pasco, L. Lercher, M. Botoshansky, I. Marek, Nature
2012, 490, 522-526; b) J. P. Das, I. Marek, Chem. Commun. 2011, 47,
4593-4623; c) J. P. Das, H. Chechik, I. Marek, Nat. Chem. 2009, 1,
128; d) S. F. Martin, Tetrahedron 1980, 36, 419-460; e) K. Fuji, Chem.
Rev. 1993, 93, 2037-2066; f) D. C. Behenna, B. M. Stoltz, J. Am.
Chem. Soc. 2004, 126, 15044-15045; g) M. Seto, J. L. Roizen, B. M.
Stoltz, Angew. Chem. Int. Ed. 2008, 47, 6873-6876.
CHMO
NADPH
2. DMP
CH2Cl2, rt
O
Me
2b 43%, >99% ee
Me
Me
Glucose/GDH
6a 73%, >99% ee
72:18 dr
Tris/HCl Buffer
pH 7.0
O
OH
rac-1b
Me
25 °C
SmI2, HMPA
Ph
Ph
250 rpm, 24 h
THF
–78 °C to rt
Me
1b 39%, >99% ee
7a 84%, >99% ee
>95:5 dr
Cl
[7]
OH
OH
7b 73%
87:13 e.r.
7c 66%
85:15 e.r.
Me
Me
Scheme 2. Biocatalytic kinetic resolution of rac-1b in a divergent, metal-
mediated radical cyclization approach to structurally distinct, enantiopure
molecular architectures.
[8]
[9]
a) A. Y. Hong, B. M. Stoltz, Eur. J. Org. Chem. 2013, 2013, 2745-2759;
b) Y. Liu, S.-J. Han, W.-B. Liu, B. M. Stoltz, Acc. Chem. Res. 2015, 48,
740-751.
In summary, racemic cyclic ketones bearing α-quaternary
G. Ottolina, G. de Gonzalo, G. Carrea, B. Danieli, Adv. Synth. Catal.
2005, 347, 1035-1040.
stereocenters
undergo
efficient
kinetic
resolution
using
cyclohexanone monooxygenase (CHMO) from Acinetobacter
calcoaceticus. The new biocatalytic process has been used in
combination with new radical cyclizations to access important
enantioenriched carbocyclic scaffolds. In particular, lactones
possessing tetrasubstituted stereocenters are obtained with high
enantioselectivity (up to >99% ee) and are exploited in SmI2-
mediated cyclization processes to access complex, enantiomerically
[10] a) M. Hönig, P. Sondermann, N. J. Turner, E. M. Carreira, Angew.
Chem. Int. Ed. 2017, 56, 8942-8973; b) M. T. Reetz, J. Am. Chem. Soc.
2013, 135, 12480-12496; c) R. O. M. A. de Souza, L. S. M. Miranda, U.
T. Bornscheuer, Chem. Eur. J. 2017, 23, 12040-12063.
[11] For example, Stoltz’s enantioselective approach to cyclic ketones I
does not embrace substrates in which R3 ≠ H. Furthermore, even if I
were available in enantioenriched form using such an approach,
chemical Baeyer-Villiger oxidation is unselective (see ref. 16). a) D.
Behenna, J. T. Mohr, N. H. Sherden, S. C. Marinescu, A. M. Harned, K.
Tani, M. Seto, S. Ma. Z. Novák, M. R. Krout, R. M. McFadden, J. L.
Roizen, J. A. Enquist Jr, D. E. White, S. R. Levine, K. V. Petrova, A.
Iwashita, S. C. Virgil, B. M. Stoltz, Chem. Eur. J. 2011, 17, 14199-
14223; b) U. Kazmaier, D. Stolz, K. Krämer, F. L. Zumpe, Chem. Eur. J.
2008, 14, 1322-1329.
enriched cycloheptan- and cycloctan-1,4-diols. In
a divergent
approach to structurally distinct molecular architectures,
enantioenriched cyclic ketones from the resolution, bearing an α- all-
carbon quaternary stereocenter, were used in a SmI2-mediated
cyclization process to give cyclobutanol products (up to >99% ee).
[12] a) P. Girard, J. L. Namy, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,
2693-2698; b) J. L. G. Namy, P. Kagan, H.B, Nouv. J. Chim. 1977, 1, 5-
7; c) X. Just-Baringo, D. J. Procter, Acc. Chem. Res. 2015, 48, 1263-
1275; d) L. A. Duffy, H. Matsubara, D. J. Procter, J. Am. Chem. Soc.
2008, 130, 1136-1137; e) D. Parmar, L. A. Duffy, D. V. Sadasivam, H.
Matsubara, P. A. Bradley, R. A. Flowers, D. J. Procter, J. Am. Chem.
Soc. 2009, 131, 15467-15473; f) D. Parmar, H. Matsubara, K. Price, M.
Spain, D. J. Procter, J. Am. Chem. Soc. 2012, 134, 12751-12757; g) D.
Parmar, K. Price, M. Spain, H. Matsubara, P. A. Bradley, D. J. Procter,
J. Am. Chem. Soc. 2011, 133, 2418-2420; h) M. Szostak, K. D. Collins,
N. J. Fazakerley, M. Spain, D. J. Procter, Org. Biomol. Chem. 2012, 10,
5820-5824; i) X. Just-Baringo, C. Morrill, D. J. Procter, Tetrahedron
2016, 72, 7691-7698; j) X. Just-Baringo, J. Clark, M. J. Gutmann, D. J.
Procter, Angew. Chem. Int. Ed. 2016, 55, 12499-12502.
Acknowledgements
We thank the EPSRC (EPSRC Established Career Fellowship to
D.J.P.), the BBSRC DTP (Studentship to C.M.), and the ERC (ERC
Advanced Grant to N. J. T.).
Keywords: biocatalysis • lactones • samarium • radical • cyclization
[1]
[2]
A. Baeyer, V. Villiger, Ber. Dtsch. Chem. Ges. 1899, 32, 3625-3633.
a) C. Bolm, G. Schlingloff, K. Weickhardt, Angew. Chem. Int. Ed. 1994,
33, 1848-1849; b) L. Zhou, X. Liu, J. Ji, Y. Zhang, X. Hu, L. Lin, X.
Feng, J. Am. Chem. Soc. 2012, 134, 17023-17026; c) A. Cavarzan, G.
Bianchini, P. Sgarbossa, L. Lefort, S. Gladiali, A. Scarso, G. Strukul,
Chem. Eur. J. 2009, 15, 7930-7939; d) C. Paneghetti, R. Gavagnin, F.
Pinna, G. Strukul, Organometallics 1999, 18, 5057-5065; e) A. Gusso,
[13] For selected total syntheses of biologically important natural products,
see: a) R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J. Biediger, P.
D. Boatman, M. Shindo, C. C. Smith, S. Kim, J. Am. Chem. Soc. 1994,
This article is protected by copyright. All rights reserved.

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
116, 1597-1598; b) K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G.
Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros,
K. Paulvannan, E. J. Sorensen, Nature 1994, 367, 630-634; c) S. J.
Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V.
Magee, D. K. Jung, R. C. A. Isaacs, W. G. Bornmann, C. A. Alaimo, C.
A. Coburn, M. J. Di Grandi, J. Am. Chem. Soc. 1996, 118, 2843-2859;
d) K. Morihira, R. Hara, S. Kawahara, T. Nishimori, N. Nakamura, H.
Kusama, I. Kuwajima, J. Am. Chem. Soc. 1998, 120, 12980-12981; e)
H. Kusama, R. Hara, S. Kawahara, T. Nishimori, H. Kashima, N.
Nakamura, K. Morihira, I. Kuwajima, J. Am. Chem. Soc. 2000, 122,
3811-3820; f) T. Doi, S. Fuse, S. Miyamoto, K. Nakai, D. Sasuga, T.
Takahashi, Chem. Asian. J. 2006, 1, 370-383; g) A. Mendoza, Y.
Ishihara, P. S. Baran, Nat. Chem. 2012, 4, 21-25; h) E. G. Gibbons, J.
Am. Chem. Soc. 1982, 104, 1767-1769; i) R. K. Boeckman, D. M.
Springer, T. R. Alessi, J. Am. Chem. Soc. 1989, 111, 8284-8286; j) N.
J. Fazakerley, M. D. Helm, D. J. Procter, Chem. Eur. J. 2013, 19,
6718-6723; k) S. K. Murphy, M. Zeng, S. B. Herzon, Science 2017,
356, 956-959; l) S. Kawamura, H. Chu, J. Felding, P. S. Baran, Nature
2016, 532, 90–93.
[14] C. H. Wong, D. G. Drueckhammer, H. M. Sweers, J. Am. Chem. Soc.
1985, 107, 4028-4031.
[15] See the Supporting Information.
[16] Oxidation of ketone 1b using mCPBA gives rise to a mixture of Baeyer-
Villiger product, the epoxide of the starting material, and the epoxide of
the product. See supporting information.
[17] M. J. Fink, D. V. Rial, P. Kapitanova, A. Lengar, J. Rehdorf, Q. Cheng,
F. Rudroff, M. D. Mihovilovic, Adv. Synth. Catal. 2012, 354, 3491-3500.
[18] E. Romero, J. R. G. Castellanos, A. Mattevi, M. W. Fraaije, Angew.
Chem. Int. Ed. 2016, 55, 15852-15855.
[19] F. Schulz, F. Leca, F. Hollmann, M. T. Reetz, Beilstein J. Org. Chem.
2005, 1, No. 10.
[20] M. T. Reetz, B. Brunner, T. Schneider, F. Schulz, C. M. Clouthier, M. M.
Kayser, Angew. Chem. Int. Ed. 2004, 43, 4075-4078.
[21] O. Trott, A. J. Olson, J. Comput. Chem. 2010, 31, 455-461.
[22] a) D. L. Boger, R. J. Mathvink, J. Org. Chem. 1992, 57, 1429-1443; b)
A. G. Myers, K. R. Condroski, J. Am. Chem. Soc. 1995, 117, 3057-
3083; c) A. J. Blake, A. R. Gladwin, G. Pattenden, A. J. Smithies, J.
Chem. Soc., Perkin Trans. 1 1997, 1167-1170; d) S. Hashimoto, S.-i.
Katoh, T. Kato, D. Urabe, M. Inoue, J. Am. Chem. Soc. 2017, 139,
16420-16429.
[23] N. Kern, M. P. Plesniak, J. J. W. McDouall, D. J. Procter, Nat. Chem.
2017, 9, 1198-1204.
[24] For a review of the use of SmI2 to form small carbocyclic rings, see: H.
Y. Harb, D. J. Procter, Synlett 2012, 23, 6-20.
This article is protected by copyright. All rights reserved.

10.1002/anie.201800121
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Ph
OH
Me
CHMO
NADPH
O
SmI2–H2O
THF, rt
Charlotte Morrill, Chantel Jensen, Xavier
Just-Baringo, Gideon Grogan, Nicholas
J. Turner* and David J. Procter*
O
Ph
Glucose/GDH
Ph
Me
O
H
O
Tris/HCl Buffer
pH 7.0
Me
25 °C
250 rpm, 24 h
43%, >99% ee
rac
73%, >99% ee
n combined biocatalytic-chemical approach to complex, medium-sized cycloalkanols
Page No. – Page No.
Biocatalytic conversion of cyclic
ketones bearing α-quaternary
stereocenters to lactones in an
enantioselective radical approach to
medium-sized carbocycles
Racemic cyclic ketones bearing α-quaternary stereocenters undergo kinetic
resolution using cyclohexanone monooxygenase (CHMOActineto) to give lactones
possessing tetrasubstituted stereocenters (up to >99% ee). Preparative scale
biotransformations were exploited in conjunction with a SmI2-mediated cyclization
process to access complex, enantiomerically enriched cycloheptan- and cycloctan-
1,4-diols. In a parallel approach to structurally distinct products, enantioenriched
cyclic ketones from the resolution were converted to cyclobutanols bearing a
quaternary stereocenter (>99% ee) using a SmI2 cyclization.
This article is protected by copyright. All rights reserved.