Visible Light-Mediated Synthesis of Enantiopure g-Cyclobutane Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids

Article abstract of DOI:10.1002/adsc.201801413

A visible light-mediated [2+2] photocycloaddition of amide-linked dienes using [Ir(dtb-bpy)(dF(CF₃)ppy)₂]PF₆ as triplet sensitizer was applied to generate a variety of N-tert-butyl, N-benzyl- and N-tert-butoxycarbonyl-protected 3-aza-bicyclo[3.2.0]heptan-2-ones in good yields and with good diastereoselectivity. Density functional theory calculations shed light on the conformational prerequisites for the [2+2] photocycloaddition. The bicyclic key structures could be readily transformed into g-cyclobutane amino acids. For the obtained racemic 3-phenyl-2-aminocyclobu-tane-1-carboxylic acid the resolution with chiral oxazolidin-2-one is demonstrated to allow access to both enantiomers. Alternatively, a chiral auxiliary approach led as well to the enantiomerically pure target compound. Finally, the synthesis of either enantiomer of 3-(aminomethyl)-5-phenylpentanoic acid, the racemate being described as an anticonvulsant is described.

Full text of DOI:10.1002/adsc.201801413

Title: Visible Light-Mediated Synthesis of Enantiopure γ-Cyclobutane
Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
Authors: Sabine Kerres, Eva Plut, Simon Malcherek, Julia Rehbein,
and Oliver Reiser
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801413
Link to VoR: http://dx.doi.org/10.1002/adsc.201801413

10.1002/adsc.201801413
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Visible Light-Mediated Synthesis of Enantiopure γ-Cyclobutane
Amino and 3-(Aminomethyl)-5-phenylpentanoic Acids
Sabine Kerres,a Eva Plut,a Simon Malcherek,a Julia Rehbein,a* and Oliver Reisera*
a
Institut für Organische Chemie, Universität Regensburg, Universitätstrasse 31, 93053 Regensburg, Germany
Fax: (+49)-941-943-4121; phone: (+49)-941-943-4631; email: oliver.reiser@chemie.uni-regensburg.de;
julia.rehbein@chemie.uni-regensburg.de
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Herein, we demonstrate a “green” synthesis towards
addition of amide-linked dienes using [Ir(dtb- new γ-amino-cyclobutane-carboxylic acid derivatives.
Abstract. A visible light-mediated [2+2] photocyclo-
bpy)(dF(CF3)ppy)2]PF6 as triplet sensitizer was applied to
generate a variety of N-tert-butyl, N-benzyl- and N-tert-
butoxycarbonyl-protected 3-azabicyclo[3.2.0]heptan-2-ones
in good yields and with good diastereoselectivity. Density
functional theory calculations shed light on the
conformational prerequisites for the [2+2] photocyclo-
addition. The bicyclic key structures could be readily
transformed into γ-cyclobutane amino acids.
For the obtained racemic 3-phenyl-2-aminocyclobutane-1-
carboxylic acid the resolution with chiral oxazolidin-2-one
is demonstrated to allow access to both enantiomers.
Alternatively, a chiral auxiliary approach led as well to the
enantiomerically pure target compound. Finally, the
synthesis of either enantiomer of 3-(aminomethyl)-5-
phenylpentanoic acid, the racemate being described as an
anticonvulsant, is described.
Established procedures for the installation of the
cyclobutane moiety in amino acid derivatives have
made use of a UV-mediated [2+2] photocycloaddition
as key step.[7] More recently, a variety of [2+2]
photocycloaddition using visible light have been
established.[8] These cycloadditions are either
promoted by an electron transfer[9] or based on an
energy-transfer-mechanism.[10] In 2012, an intra-
molecular energy transfer-mediated [2+2] photo-
cycloaddition of tethered bisstyrenes whose oxidation
potential has precluded its ability to participate in a
radical cation cycloaddition was developed by Yoon
and coworkers.[11] The iridium-based catalyst, Ir[(dtb-
bpy)(dF(CF3)ppy)2]PF6 was a suitable triplet sensitizer
for this [2+2] photocycloaddition via visible light. This
method could also be applied to 1,3-dienes.[12] The
intramolecular variant afforded mostly carbocycles or
oxygen-containing heterocycles 2 (Scheme 1). In
contrast to this metal-based photocatalytic process,
also flavin derivatives can serve as triplet sensitizer for
this reaction type,[13] being demonstrated for the
cyclization of nitrogen- and sulfur-containing aryl
dienes to the corresponding aryl-bicyclo[3.2.0]-
heptanes 4.[14] Already in 1976, Oppolzer et al.[15] have
observed in the thermolysis of N-benzyl-substituted
cinnamyl cinnamide the corresponding aza-bicyclo-
[3.2.0]-heptanone as byproduct, whose generation was
confirmed afterwards by an UV-mediated [2+2]
photocycloaddition. An elegant example of utilizing
UV light for the triplet-sensitized intramolecular [2+2]
photocycloaddition was later reported by Bach et al.,
who described the stereoselective preparation of 3-
azabicyclo[3.2.0]heptanes from N,N-diallylamines
with acetophenone as the sensitizer.[16] More recently,
Mykhailiuk and coworkers irradiated N-benzyl-
substituted amide-linked dienes at 366 nm in the
presence of acetophenone as photosensitizer in order
to build up 3-azabicylo[3.2.0]heptanes, which are
attractive building blocks for drug discovery.[17]
Keywords: amino acids, cycloaddition, energy transfer,
green chemistry, photocatalysis
γ-Amino acids play an important role in the clinical
treatment of diseases related to the central nervous
system such as epilepsy, neuropathic pain or anxiety.[1]
The most prominent representative of this family is γ-
aminobutyric acid (GABA), which is the major inhi-
bitory neurotransmitter in the mammalian central ner-
vous system.[2] A wide variety of GABA derivatives
have been synthesized and investigated over recent
years.[3] Amongst these, cyclic GABA analogues have
proven to be of significant therapeutic value, as
exemplary shown with the commercial therapeutic
gabapentin.[4] Besides their inherent biological activity,
γ-amino acids have been in the focus due to their
potential for application in the design of oligopeptides
with well-defined secondary structures.[5] Especially,
cyclic γ-amino acids are promising building blocks for
such peptides due to the limitation of their backbone
torsional mobility with potential applications in
medicinal and material chemistry.[6]
1
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
Having the synthesis of novel cyclobutane containing
amino acids in mind, we investigated the extension of
the iridium-based triplet sensitized reaction to amide
linked dienes 5 (Scheme 1).
5a-H and 5a-tBu: Stability of the reactive ground state
conformation NAC and barriers and reaction free
energies associated with its reactive triplet state after
the energy transfer by the excited photocatalyst (Table
2, Figure 1). To cover for expected dispersion inter-
actions the D3-corrected (u)B3lYP hybrid functio-
nal[18a-c] was applied with a 6-311+G** basis set[18d,e]
(see SI for further details).
This analysis is based on the assumption that the
conformational changes of the substrate are occurring
prior to the bimolecular activation step (energy trans-
fer) as indicated by the computed activation barriers
associated with conformational changes and bond
reorganizations (Figure 1). Hence, the concentration of
the reactive conformation of 5, the so-called near-
attack conformation (NAC), plays a key role in
understanding why 5a-tBu gives rise to 6a-tBu via a
formal [2+2] cyclization and 5a-H does prefer the
competitive quenching path of the excited state via
double bond isomerization. From the excited triplet
state of the substrate in principle two chemical
quenching pathways can be envisioned: The desired
cyclization and the double bond isomerization. The
latter is known for stilbenes to proceed via conical
intersections (CoI), hence a very efficient and quick
reaction path.[19] Therefore, if the linear substrate is
activated it probably will not undergo conformational
changes in order to allow a cyclization, but rather will
follow the CoI path of the double bond isomerization.
Scheme 1. Visible light-mediated synthesis of
bicyclo[3.2.0] cores.
The seemingly small change from substrate of type 1
to 5 poses a challenge since a near attack conformation
(NAC) favorable for cyclization has to be adopted that
involves the rotation around an amide bond (Scheme
1). Our study therefore focused initially on screening
different substituents R (Table 1), which indeed
proved to be crucial for the success of the desired
photocyclization. While hydrogen, methyl or phenyl
(5a-H, 5a-Me, 5a-Ph) did not result in any cyclization
product even after 48 h of irradiation, a tert-butyl
substituent allowed the smooth conversion of 5a-tBu,
giving rise to 6a-tBu in 79% yield after only 3 h. 6a-
tBu was obtained as a 4:1 diastereomeric mixture in
favor for exo-diastereomer, having the phenyl groups
oriented on the sterically favored convex face of the
bicycle.
Figure 1. Reaction coordinate diagram of the key-elemental
steps describing the cyclisation of NAC-5a-H (italic
numbers) and NAC-5a-tBu and in its triplet state (B3LYP-
D3/6-311+G**) on the contrary there is the preferred
pathway of 5a-H featuring the double bond isomerization
after energy transfer.
Table 1. Screening of substituents R on the amide bond.
entry
R
H
Me
Ph
tBu
time h
yield %
In case of 5a-tBu it was expected that in analogy to the
Thorpe-Ingold effect the formation of the near-attack
conformation (NAC) is facilitated by the tert-butyl
group.[20] Although the comparison of both NAC (5a-
H, 5a-tBu) conformers did not show any significant
differences in their geometries (see SI) the higher
stability of NAC-5a-tBu by 6 kcal/mol compared to
NAC-5a-H (Table 1) supports this hypothesis.
Barriers of interconverting the linear 5 to the NAC
conformation were estimated based on a relaxed PES
scan (Table 2, see SI for details) indicating a facile
1
2
3
4
48
48
48
3
-
-
-
79 (dr 81/19)a
1
a) Diastereomeric ratio was estimated by crude H-NMR, major
diastereomer shown.
Two aspects were addressed by computational
chemistry to understand the different reactivity of
2
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
population of the NAC conformer at room temperature
with barriers of 17.0 kcal/mol (5a-tBu) and
13.4 kcal/mol (5a-H). The interconversion of NAC
back to the linear conformer (19.9 kcal/mol NAC-5a-
tBu to 5a-tBu; 16.5 kcal/mol NAC-5a-H to 5a-H)
indicate that the NAC-5a-tBu has a 300-fold longer
life-time than NAC-5a-H. In combination with the
thermodynamic preference of NAC-5a-tBu over its
linear conformer, it is NAC-5a-tBu that will almost
exclusively take part in the energy transfer activation
by 3[Ir] than 5a-tBu and the reversed situation would
be true for 5a-H and NAC-5a-H.
show that styrene part of the substrate interacts with
the excited-state photocatalyst and quenches its
luminescence.
Table 2. Overview of the calculated energy values.
Figure 2. Stern-Volmer plot for the fluorescence quenching
of photocatalyst [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 with 5c-tBu
(▲, N-(tert-butyl)-N-cinnamylamine (■), and ethyl acrylate
(●).
entry energies in [kcal/mol]
R= tert- R= H
butyl
1
2
ΔRG(5
-2.9
3.1
NAC
to
to
)
The triplet excited state energy of an amide-linked
diene 5a-tBu was attempted to be experimentally
determined from its phosphorescence spectrum, but
the substrate is not emissive, thus no information about
the triplet energy was obtained. To exclude a single-
electron transfer mechanism of the reaction, the redox
potential of starting material 5c-tBu (E1/2 = + 1.57 V
vs SCE; see SI for further details) was measured and
compared with the redox potential of photocatalyst (E
= + 1.21 V vs SCE)[23]. Additionally, from the
ΔEA(
17.0
13.4
5
NAC
)
∆푅퐺(
∆퐺(≠
∆퐺(≠0
3
4
5
ퟑ
ퟑ
-25.0
5.2
-17.4
7.9
퐍퐀퐂 to 퐈퐧퐭)
ퟑ
ퟑ
퐍퐀퐂 to 퐈퐧퐭)
ퟑ
ퟑ
15.1
15.6
퐍퐀퐂 to 퐈퐧퐭)
Starting from the 3NAC the barriers for a formal [2+2]-
cycloaddition were calculated (Table 2, Figure 1).[21]
This C-C bond formation is more favorable both in
activation free energy and driving force for ³NAC-5a-
tBu than for ³NAC-5a-H, but still both processes are
feasible and fast at room temperature. To close the
cyclobutane a second C-C bond formation must take
place. This is only possible if a quick ISC occurs
between the two states ³Int and Int. As soon as Int
is populated it is believed to react without a barrier to
the annulated cyclobutane 6.[22] Interestingly, the
overall reaction free energy 5 to 6 is slightly
endergonic in case of 5a-H (+ 3.9 kcal/mol) and
considerably exergonic for 5a-tBu (– 9.0 kcal/mol).
In conclusion, the difference in reactivity and
selectivity of 5a-H and 5a-tBu is best explained to be
a ground state phenomenon. Analysis of equilibria and
lifetimes of reactive conformations are key to the
understanding of the unexpected failure of substrates 5
with sterically undemanding R (= H, Me) to not
undergo the desired cycloaddition reaction via energy
transfer.
comparison of triplet state energy of the photocatalyst
[23]
used (ET = 61 kcal/mol)
and the calculated triplet
energy of starting material NAC-5a-tBu (ET = 57.8
kcal/mol), it can be concluded that the reaction pro-
ceeds through energy transfer.
Variation of the catalyst, light source and reaction
temperature the optimized reaction conditions were
established: 1 mol% [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6,
DMSO as solvent at 40 °C and a blue LED-setup (λmax
= 455 nm) as light source (see SI), with which the
substrate scope of the title reaction was evaluated
(Table 3).
Besides N-tert-butyl, also N-benzyl and N-Boc pro-
tected amide derivatives cyclize to the cyclobutane
containing compounds in moderate to good yields
(Table 3), the N-Boc derivates however needed longer
reaction times. Depending on the location of the
phenyl group on the involved double bonds, the
reaction times varied dramatically. If the aromatic
substituent is placed on the amine moiety (5c-tBu, 5c-
Bn) the [2+2] reaction is complete within 3-4 h (entries
5, 6), whereas in the case of 5d-tBu or 5c-Bn the [2+2]
photocycloaddition takes approximately five times
longer to reach full conversion (entries 8, 9). The
electron-rich heterocycles thiophene and furan on the
carbonyl side also accelerate the [2+2] photocyclo-
addition with respect to the phenyl substituent (entry 8,
12,13). Additionally, if the aromatic substituent is
1
1
To gain insight into which part of the substrate is
sensitized, we performed a Stern-Volmer emission
quenching study (Figure 2). The fluorescence intensity
of the excited-state photocatalyst was decreasing upon
titration with substrates 5c-tBu and N-(tert-butyl)-N-
cinnamylamine (I) in a linear fashion. On the contrary,
the emission intensity of photocatalyst stayed constant
upon titration with ethyl acrylate (II). These results
3
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
located on the carbonyl side (R2) a better diastereo-
selectivity is achieved (entries 8-10, 12-14). The [2+2]
cycloaddition of substrates with two aromatic
substituents (entry 1-4, 16) resulted in a diastereomeric
mixture, from which a minor compound could not be
isolated and thus its stereochemistry cannot be
assigned with certainty. However, the 13C NMR
signals for a methylene carbon and to methylene
adjacent carbon in cyclobutane ring of minor isomer
are shifted by approximately 5 ppm upfield, which is a
common shift for the endo- with respect to the exo
isomer in all azabicyclo[3.2.0]heptanes.[16]
In the case of the ester-linked derivative 5j, an
increase in the reaction temperature to 80 °C was
necessary, nevertheless, the cyclobutane 6j was only
obtained in a yield of 29% (entry 16). The low yield,
as well as the need for higher temperatures, can be
explained by the favorable s-trans-conformation of the
ester moiety.[24]
Table 3. Substrate scope of the [2+2] photocatalyzed cycloaddition.a
R1
R2
R1
R2
[Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 (1 mol%)
DMSO, hn (455 nm), 40°C
O
+
R1
R2
X
O
O
X
X
exo-6
(major)
endo-6
(minor)
5
entry
1
2
3
4
5
6
7
8
R1
R2
X
5/6
time
3 h
4 h
24 h
7 h
3 h
yield [%]b
Ph
Ph
Ph
4-MeOPh
Ph
Ph
Ph
H
H
H
CO2Me
H
H
H
H
Ph
Ph
Ph
Ph
H
H
H
Ph
Ph
Ph
Ph
N-tBu
N-Bn
N-Boc
N-tBu
N-tBu
N-Bn
N-Boc
N-tBu
N-Bn
N-Boc
N-tBu
N-tBu
N-tBu
N- tBu
N-tBu
O
85 (dr 81/19)
75 (dr 72/28)
61 (dr 78/22)
63 (dr 72/28)
78 (dr 76/24)
72 (dr 85/15)
73 (dr 81/19)
60 (dr >99/1)
83c (dr 93/7)
47 (dr >99/1)
67 (dr 76/24)
73 (dr >99/1)
78 (dr >99/1)
35 (dr >99/1)
0
5a-/6a-tBu
5a-/6a-Bn
5a-/6a-Boc
5b-/6b-tBu
5c-/6c-tBu
5c-/6c-Bn
5c-/6c-Boc
5d-/6d-tBu
5d-/6d-Bn
5d-/6d-Boc
5e-/6e-tBu
5f-/6f-tBu
5g-/6g-tBu
5h-/6h-tBu
5i-/6i-tBu
5j-/6j
4 h
48 h
23 h
19 h
14 d
48 h
3 h
9
10
11
12
13
14
15
16d
2-furanyl
2-thiophenyl
N-acetyl-3-indolyl
H
Ph
3 h
48 h
48 h
48 h
Ph
29 (dr 72/28)
a) 1 mmol substrate (0.04 M in DMSO), 1 mol% [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6, 40 °C. b) Diastereomeric ratio was estimated by crude 1H-
NMR. c) Yield of the major isomer. d) 80 °C reaction temperature.
Table 4. Catalyst loading of the [2+2] photocycloaddition
Keeping the desired synthesis of cyclic -amino acids
in mind, we investigated the scale up of the [2+2]-
cycloaddition of 5c-tBu (Table 4).
of compound 5c-tBu.a
Ph
Ph
O
[Ir(dtb-bpy)(dF(CF3)ppy2)]PF6
The best result from a practical point of view was
obtained by applying 0.1 mol% of catalyst with a
substrate concentration of 0.16 M giving rise to 79%
overall yield of the cyclobutane containing substrate
(entry 4). A further decrease of catalyst amount led to
a prolonged reaction time and concurrently, the yield
dropped to 41% and 56%, respectively (entry 6,7).
Ph
N
+
O
O
DMSO, 40 °C, hn
N
N
5c-tBu
exo-6c-tBu
endo-6c-tBu
5c-tBu
catalyst
6c-tBu
yield [%] a
entry amount
[mol%]
time [h]
Conc.
[M]
Thus, employing 5c-tBu (110 mmol),
a
1
2
3
4
5
6
7
1
0.04
0.04
0.08
0.04
0.16
0.16
0.16
3
3
3
5
5
48
43
78
73
75
80
79
41
56
conversion of 95% was achieved after 7 d, allowing
the production of 6c-tBu on an 18 g scale (70% yield).
The prolonged reaction time was most likely a
consequence of the batch reactor that was applied,
nevertheless, also under these conditions the catalyst
stability was sufficient to achieve the yield that was
projected by the optimization studies (Table 4).
0.5
0.5
0.1
0.1
0.01
0.05
a)
Diastereomeric ratio (exo/endo 82:18 to 84:16) was
estimated by crude 1H-NMR.
4
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
Aiming at the synthesis of the target molecules in
enantiopure form, we replaced the tBu group on
nitrogen for (S)-phenylethyl ((S)-PE). Thus, the [2+2]
photocycloaddition of the enantiomerically pure
amide linked diene 5c-(S)-PE gave rise to a mixture of
four diastereomers 6c-(S)-PE (dr 43:43:7:7) in an
overall yield of 83% (Scheme 2), reflecting well the
diastereomeric ratio obtained with achiral 5c-tBu.
Obviously, no asymmetric induction is executed from
the chiral auxiliary, nevertheless, the major exo-
diastereomers 6c1-(S)-PE und 6c2-(S)-PE could be
readily separated by column chromatography and
isolated in pure form. The absolute stereochemistry
could be established by X-Ray analysis of 6c2-(S)-PE.
From here, both enantiomers of 7 could be obtained by
removing the chiral auxiliary under Birch conditions,
followed by N-Boc protection and lithium hydroxide-
mediated ring opening in high yield.
Scheme 3. Three different synthetic routes towards racemic
(rac)-7. Reaction conditions: a) Na, NH3 (li), tert-BuOH, –
33 °C, 1 h; b) Boc2O, NEt3, DMAP, MeCN, 0 °C to rt, 2 d;
c) LiOH, THF/H2O (1:1), rt, 1 d; d) LiOH, THF/H2O (1:1),
rt, 2 d; e) HCl (25% aq), reflux, 5 d; f) Boc2O, NaHCO3,
dioxane/H2O (1:1), 0 °C to rt, 2 d.
The (rac)-7 was subsequently resolved in its
enantiomers following a protocol developed by Aitken
and coworkers[25] (Scheme 4). An X-ray structure of
10a could be obtained, which allowed the correlation
of the absolute stereochemistry of the final amino
acids of either enantiomer 7.
6c2-(S)-PE
Scheme 2. Stereoselective strategy for the synthesis of γ-
cyclobutane amino acids 7. Reaction conditions: a) [Ir(dtb-
bpy)(dF(CF3)ppy2)]PF6 (1 mol%), DMSO, 40 °C, hν, 5 h,
83% (dr 43:43:7:7); b) Na, NH3 (li.), tert-BuOH, -33 °C, 1
h; c) Boc2O, NEt3, DMAP, MeCN, 0°C to rt, 2 d; d) LiOH,
THF/H2O (1:1), rt, 22 h.
Alternatively, the racemic derivatives 6c-Bn, 6c-Boc,
or 6c-tBu could be converted by deprotection / ring
opening sequences into (rac)-7 in high yields (Scheme
3).
Analogously to transformation of 6c-tBu to exo-
8c, bicyclic compounds 6-(a-g) with N-tert-butyl
group were heated in 25% aqueous HCl to obtain
corresponding cyclobutane amino acids (Scheme 3).
As a result, amino acids with a single (endo-8c, 8d) as
well as two phenyl groups (8a) were prepared in
moderate to good yields. Upon the treatment of 6e-tBu
in acidic solution, both ester and amide groups were
hydrolysed, and N-tert-butyl group was cleaved
simultaneously to afford 8e. Other N-tert-butyl
derivatives, such as 6f-and 6g-tBu decomposed under
the same reaction conditions. Purification of amino
acid, derived from 6b-tBu, was not possible. All amino
acids were obtained as chloride salts with the
exception of 8a, which required purification by elution
through an ion exchange resin (H+-form).
Scheme 4. Chiral resolution of the racemic cyclobutane
amino acids 7. Reaction conditions: a) PivCl, NEt3, THF,
0 °C, 1 h; b) lithium (4S,5R)-4-methyl-2-oxo-5-phenyloxa-
zolidin-3-ide, THF, -78 °C, 1 h; c) H2O2, LiOH, THF/H2O,
0 °C, 5 h, (4S,5R)-4-methyl-2-oxo-5-phenyloxazolidine was
almost quantitatively recovered; d) i) DCM, TFA, rt, 24 h,
ii) dioxane/H2O (1:1), FmocOSu, NaHCO3, 0 °C to rt, 24 h.
To be compatible with solid phase peptide synthesis
using the Fmoc strategy, the exchange of Boc to Fmoc
5
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
could be readily performed, giving rise to either
enantiomer of 7 in high yield and enantiopurity of 99%
ee. Protecting group was performed yielding 84% of
enantiomer (1S,2R,3S)-9 (R=Fmoc) and 91% of
enantiomer (1R,2S,3R)-9 (R=Fmoc) each with an
unrelieved enantiomeric excess of 99% (Scheme 4).
A sequence analogous to the one shown in
Scheme 2 was also attempted with 5d-(S)-PE, in
which the phenyl group is connected to the enone
rather than to the allyl fragment. The exo-
diastereomers 6d1-(S)-PE and 6d2-(S)-PE were
formed with high preference over the corresponding
endo-diastereomers, but again, the chiral auxiliary did
not exert an influence on the newly formed
stereocenters (Scheme 5).
In conclusion, we have developed a visible light-
mediated, intramolecular [2+2] photocycloaddition of
amide-linked dienes catalyzed by [Ir(dtb-bpy)-
(dF(CF3)ppy)2]PF6 as triplet sensitizer. The protecting
group at the amide nitrogen atom plays a key role for
a successful cyclization, which was elucidated by DFT
calculations. The resulting azabicycloheptanones
could be converted in an enantiomerically manner into
γ-cyclobutane amino acids. Furthermore, this
methodology was applied for the enantioselective
synthesis of both enantiomers of anticonvulsant 3-
(aminomethyl)-5-phenylpentanoic acid.
Experimental Section
Typical Procedure for the [2+2] Photocycloaddition:
Synthesis of (±)-3-(tert-butyl)-6-phenyl-3-azabicyclo-
[3.2.0]heptan-2-one (exo-6c-tBu and endo-6c-tBu):
The amide linked diene 5c-tBu (241 mg, 990 µmol, 1
equiv.) was dissolved in DMSO (25 mL, 0.04 M) together
with [Ir(dtb-bpy)(dF(CF3)ppy)2]PF6 (11.2 mg, 0.010 mmol).
The reaction mixture was stirred at 40 °C for 3 h with a blue
LED-setup. After completion, the reaction mixture was
diluted with H2O (10 mL) and DEE (30 mL). Then the
phases were separated, and the aqueous phase was extracted
three times with DEE (each 30 mL). The combined organic
phases were washed twice with H2O (each 10 mL) and once
with brine (20 mL). Finally, the combined aqueous phases
were back-extracted with DEE (30 mL). The combined
organic phases were dried over MgSO4, filtered and the
solvent was removed under reduced pressure. By silica gel
column chromatography (hexanes/EtOAc 3:1) both
diastereomers of compound 6c-tBu were separated and were
obtained in an overall yield of 78% (dr 83:17; exo-6c-tBu:
yellow oil, 157.5 mg, 647 µmol; endo-6c-tBu: yellow solid,
32.4 mg, 133 µmol). exo-6c-tBu: Rf = 0.33 (hexanes/EtOAc
2:1); 1H-NMR (400 MHz, CDCl3) δ = 7.36 – 7.29 (m, 2H),
7.24 – 7.18 (m, 3H), 3.66 (dd, J = 10.2, 6.3 Hz, 1H), 3.48 –
3.35 (m, 2H), 3.03 – 2.86 (m, 2H), 2.66 – 2.41 (m, 2H), 1.47
(s, 9H); 13C-NMR (75 MHz, CDCl3) δ = 177.4, 144.1, 128.5,
126.4, 126.3, 54.0, 51.6, 44.4, 39.5, 38.2, 31.8, 27.7; IR
(neat) ν [cm-1] = 3060, 3020, 2970, 2870, 1669, 1401, 1364,
1289, 1222, 749, 700; HRMS: (APCI-MS) calc. for
[C16H22NO]+ [M+H]+ 244.1696, found 244.1700; endo-6c-
6d2-(S)-PE
Scheme 5. Synthetic route towards (S)- and (R)-3-
(aminomethyl)-5-phenylpentanoic acid 12. Reaction con-
ditions: a) [Ir(dtb-bpy)(dF(CF3)ppy2)]PF6 (1 mol%), DMSO,
40 °C, hν, 24 h, 76%; b) Na, NH3 (li), tert-BuOH, –33 °C, 1
h; c) HCl (25% aq), reflux, 24 h, d) EDC•HCl, NEt3, DCM,
rt, 24 h.
Unexpectedly, under Birch reduction conditions to
remove the N-protecting group in 6d-(S)-PE also the
regioselective ring opening of the cyclobutane core
was observed giving rise to phenyl ethyl pyrrolidinone
11. While 6d1-(S)-PE could be isolated in pure form
by column chromatography, 6d2-(S)-PE contained
minor impurities of the corresponding endo-diastere-
omers, which explains the slight decrease to 90% ee
that is observed for (R)-11.
1
tBu: Rf = 0.2 (hexanes/EtOAc 2:1); mp = 51-52 °C; H-
NMR (400 MHz, CDCl3) δ = 7.33 (t, J = 7.5 Hz, 2H), 7.28
– 7.14 (m, 3H), 3.91 (dd, J = 16.5, 9.6 Hz, 1H), 3.31 (dd, J
= 10.5, 8.2 Hz, 1H), 3.17 – 3.00 (m, 2H), 2.92 (d, J = 10.9
Hz, 1H), 2.87 – 2.75 (m, 1H), 2.53 (ddd, J = 11.2, 6.6, 4.2
Hz, 1H), 1.22 (s, 9H); 13C-NMR (101 MHz, CDCl3) δ =
177.4, 139.7, 128.3, 128.1, 126.5, 53.8, 46.8, 40.1, 39.9,
32.7, 28.3, 27.7, 27.6, 27.5; HRMS: (APCI-MS) calc. for
[C16H22NO]+ [M+H]+ 244.1696, found 244.1707, calc for
[C32H43N2O2]+ [2•(M+H)]+ 488.3352, found 488.3355.
Refluxing either enantiomer of pyrrolidinones 11 in
a 25% aqueous solution of HCl gives rise to (S)-12
(99% ee) and (R)-12 (90% ee) being independently
confirmed by X-ray structure analysis, the racemate
being described as an anticonvulsant with good
biological activity[26]. No erosion of stereochemistry is
observed in this ring-opening reaction, which was
confirmed by converting back (R)-12 to (R)-11 upon
treatment with EDC. So far, only the group of Wu et
al. had developed an asymmetric synthesis for the (R)-
enantiomer (R)-12.[26], [27], [28]
6
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
Acknowledgements
[8] S. Poplata, A. Trꢀster, Y.-Q. Zou, T. Bach, Chem. Rev.
2016, 116, 9748−9815.
This work was supported by the Friedrich-Ebert-Stiftung and the
DFG (Graduiertenkolleg 1626 Photocatalysis and RE948-9). The
authors thank the Department of Crystallography, Universität
Regensburg, for carrying out the X-Ray crystal structure analyses,
Marsel Shafikov for phosphorescence measurements and Regina
Hoheisel for cyclic voltammetric measurements.
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7
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
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–
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These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
8
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10.1002/adsc.201801413
Advanced Synthesis & Catalysis
UPDATE
Visible Light-Mediated Synthesis of Enantiopure γ-
Cyclobutane Amino and 3-(Aminomethyl)-5-
phenylpentanoic Acids
Adv. Synth. Catal. Year, Volume, Page – Page
Sabine Kerres, Eva Plut, Simon Malcherek, Julia
Rehbein,* and Oliver Reiser*
9
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