Intramolecular [2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications

Article abstract of DOI:10.1002/chem.201901304

The intramolecular [2+2] photocycloaddition of 3-alkenyl-2-cycloalkenones was performed in an enantioselective fashion (nine representative examples, 54–86 % yield, 76–96 % ee) upon irradiation at λ=366 nm in the presence of an AlBr₃-activated oxazaborolidine as the Lewis acid. An extensive screening of proline-derived oxazaborolidines showed that the enantioface differentiation depends strongly on the nature of the aryl group at the 3-position of the heterocycle. DFT calculations of the Lewis acid–substrate complex indicate that attractive dispersion forces may be responsible for a change of the binding mode. The catalytic [2+2] photocycloaddition was shown to proceed on the triplet hypersurface with a quantum yield of 0.05. The positive effect of Lewis acids on the outcome of a given intramolecular [2+2] photocycloaddition was illustrated by optimizing the key step in a concise total synthesis of the sesquiterpene (±)-italicene.

Full text of DOI:10.1002/chem.201901304

A Journal of
Accepted Article
Title: Intramolecular [2+2] Photocycloaddition of Cyclic Enones:
Selectivity Control by Lewis Acids and Mechanistic Implications
Authors: Saner Poplata, Andreas Bauer, Golo Storch, and Thorsten
Bach
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: Chem. Eur. J. 10.1002/chem.201901304
Link to VoR: http://dx.doi.org/10.1002/chem.201901304
Supported by

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
Intramolecular [2+2] Photocycloaddition of Cyclic Enones:
Selectivity Control by Lewis Acids and Mechanistic Implications
Saner Poplata,[a] Andreas Bauer,[a] Golo Storch,[a] and Thorsten Bach[a]*
Abstract: The intramolecular [2+2] photocycloaddition of 3-alkenyl-
2-cycloalkenones was performed in an enantioselective fashion
(nine representative examples, 54-86% yield, 76-96% ee) upon
irradiation at  = 366 nm in the presence of an AlBr3-activated
oxazaborolidine as the Lewis acid. An extensive screening of
proline-derived oxazaborolidines showed that the enantioface
differentiation depends strongly on the nature of the aryl group at the
3-position of the heterocycle. DFT calculations of the Lewis acid-
substrate complex indicate that attractive dispersion forces may be
responsible for a change of the binding mode. The catalytic [2+2]
photocycloaddition was shown to proceed on the triplet hypersurface
with a quantum yield of 0.05. The positive effect of Lewis acids on
the outcome of a given intramolecular [2+2] photocycloaddition was
illustrated by optimizing the key step in a concise total synthesis of
the sesquiterpene (±)-italicene.
Scheme 1. The conversion of carvone (1) into carvonecamphor (2)
representing the first intramolecular [2+2] photocycloaddition reaction of a
cyclic enone.[6-9]
Despite the fact, that the reaction is so powerful, enantio-
selective variants of the enone [2+2] photocycloaddition have
relied, until very recently, on the covalent attachment of a chiral
auxiliary.[10] In 2013, our group presented the first enantio-
selective[11] enone [2+2] photocycloaddition reaction mediated
by chiral Lewis acids.[12,13] The substrates were 5,6-dihydro-4-
pyridones[14] to which an alkenyl chain was attached at the
nitrogen atom. The chiral Lewis acid acts by coordination to the
carbonyl carbon atom and lowers the energy difference between
the ground state (S0) and the first excited state (S1). The
chromophore is activated[15] and the allowed * absorption is
red-shifted to absorb at   360 nm. Although there is a weak
n* absorption of uncomplexed dihydropyridone at a similar
wavelength, the Lewis acid complex has a much higher
absorption coefficient and the reaction thus proceeds
enantioselectively. Despite the fact that the reaction could be
extended to the intramolecular [2+2] photocycloaddition of 3-
alkenyloxy-2-cycloalkenones,[16] the intermolecular reaction of
simple 2-cycloalkenones, such as 2-cyclohexenone, has
remained elusive until very recently.[17] In the context of the latter
topic, we had performed optimization reactions with 3-alkenyl-2-
cycloalkenones of general structure A (Figure 1) for which there
has not yet been a report on an enantioselective variant.
Introduction
The intramolecular [2+2] photocycloaddition[1] of appropriately
substituted 2-cycloalkenones is an enormously powerful
transformation which has been extensively used in the total
synthesis of natural products.[2] The reaction can be performed
by direct irradiation, typically at a wavelength () of 300-370 nm.
Since intersystem crossing in enones is fast (kISC  1011 s1),[3]
the reaction proceeds via the first excited triplet state (T1) which
has * character. Compared to intermolecular reactions, there
is an improved regioselectivity as the internal olefin is enforced
to approach the photoexcited enone via an initial cyclization to a
1,4-diradical.[4] Five-membered ring formation is preferred where
possible and dictates the regioselectivity of the reaction.[5]
Historically, the reaction belongs to one of the first
photochemical transformations known to organic chemists. In
1908, Ciamician and Silber reported on the formation of
carvonecamphor (2) upon exposure of carvone (1) to sunlight
(Scheme 1).[6] The same observation was made by Sernagiotto
a few years later.[7] In 1957, Büchi and Goldman isolated product
2 – still prepared by sunlight irradiation – and proved its
constitution and configuration.[8] Meinwald and Schneider
optimized the reaction employing an artificial light source with an
emission maximum at  = 355 nm and could isolate the desired
product with a maximum yield of 35%.[9]
Figure 1. General structure of [2+2] photocycloaddition substrates A and of
putative chiral catalysts B; structure of chiral [2+2] photocycloaddition
substrate rac-3.
The reaction was studied with a broad variety of chiral
oxazaborolidine Lewis acids[18] B (variation of X’ and Y’) and the
results of this study are disclosed in this full paper. In addition,
we could show with chiral substrate rac-3 that Lewis acid
coordination lends a significantly improved selectivity to the
reaction. This reaction was used in the total synthesis of
italicene and isoitalicene. Mechanistic studies confirm the fact
that the reaction proceeds on the triplet surface and
[a]
S. Poplata, Dr. A. Bauer, Dr. G. Storch and Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universität München
D-85747 Garching, Germany
E-mail: thorsten.bach@ch.tum.de
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/chem.201901304
Chemistry - A European Journal
FULL PAPER
computational studies offer an explanation for an unexpected
reversal in the enantioselectivity of the process.
The precursors are typically prepared from 3-ethoxy-2-
cycloalkenones by addition of the respective alkenyl metal
reagent and subsequent hydrolysis.[20] The previously unknown
compounds 5c and 5h were synthesized from the chloromethyl-
substituted olefinic acetal 4 which was obtained by a known
procedure[21] and which underwent nucleophilic substitution by
an allylic alcohol (Scheme 2).
Table 1 lists the substrates 5 and racemic products rac-6 which
were investigated in the present study. Irradiation was
performed with fluorescent lamps which exhibit an emission
maximum at  = 366 nm.[22] Typically, full conversion of 2-
cyclohexenones (5a-5d, 5f-5i) was achieved after a maximum
irradiation time of eight hours. The blue-shifted absorption of
cyclopentenones 5e and 5j required for substrate 5e a longer
irradiation time of 47 h while in the case of enone 5j a short-
wavelength emitter ( = 350 nm) was used to complete the
reaction in a reasonable period of time.
Results and Discussion
Synthesis of starting materials and racemic [2+2]
photocycloaddition. Our experiments focussed on 2-
cyclopentenones and 2-cyclohexenones, which carry an alkenyl
chain at position C-3. To the best of our knowledge, the first
intramolecular [2+2] photocycloaddition of
a
3-alkenyl-
substituted 2-cycloalkenone was mentioned in a communication
by Corey and Sestanj.[19] Since then, this compound class has
been extensively used and there are a plethora of examples for
their intramolecular [2+2] photocycloaddition.[1]
Scheme 2. Preparation of photocycloaddition substrates 5c and 5h from allylic
chloride 4.
Table 1. Racemic [2+2] photocycloaddition reactions of enones 5:
Substitution patterns, reaction times and yields.
substrate[a]
X
Y
CH2
CMe2
O
R
H
R1
H
t [h]
8
yield [%]
91
5a
5b
5c
5d
5e
5f
CH2CH2
CH2CH2
CH2CH2
CMe2CH2
CH2
H
H
3
87
H
H
5
87
CH2
CH2
CH2
CH2
O
H
H
5
79
Scheme 3. Synthesis of various diaryl-substituted prolinols 9 from N-benzyl
proline methyl ester (7).
H
H
47
5
56
CH2CH2
CH2CH2
CH2CH2
CMe2CH2
CH2
Me
H
H
68
51[b]
80
Oxazaborolidine Lewis acids of general formula B (Figure 1)
were prepared from the respective amino alcohols[23] by
oxazaborolidine formation and subsequent complexation with
AlBr3 as the activating Lewis acid. Other activators did not match
the enantioselectivity achieved with this Lewis acid neither did
other amino alcohol skeletons. In the optimization experiments,
we thus focussed on amino alcohols derived from proline.
Accordingly, the synthesis commenced with known L-proline
methyl ester 7[23] which was converted to amino alcohols 8 by
treatment with an excess (2.5 equiv.) of the respective Grignard
reagent (Scheme 3). The latter in turn was formed from aryl (Ar)
bromide by direct magnesiation in the presence of catalytic
amounts of iodine. Yields were high (>80%) both for the
formation of the alcohols and for the subsequent hydrogenolysis
5g
5h
5i
Me
H
5.5
8
Me
Me
Me
CH2
CH2
H
5
88
5j
H
8
63[c]
[a]
Unless noted otherwise, the reactions were performed under anhydrous
and oxygen-free conditions at an irradiation wavelength of  = 366 nm
(emission maximum of the light source) and at a substrate concentration of
20 mM in CH2Cl2 as the solvent at ambient temperature.
products were removed by ozonolysis. An irradiation wavelength of  =
[b]
Olefinic by-
[c]
350 nm (emission maximum of the light source) was used.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
of the N-benzyl group to the target compounds (see the
Supporting Information for more details).
allows this complex to harvest the respective long wavelength
photons and to suppress the racemic background reaction that
occurs upon excitation of the uncomplexed substrates via their
n* transition. Indeed, it was found for the reaction of compound
5a that several AlBr3-activated oxazaborolidines derived from
2,3,4-trifluoroboronic acid and amino alcohols 9 promoted an
enantioselective intramolecular [2+2] photocycloaddition to
product 6a (Scheme 4).
There was some concern regarding a possible racemization at
the stereogenic center of proline during the Grignard addition
which is the reason we attempted to determine the enantiomeric
excess (ee) of the amino alcohols after deprotection. However, a
satisfactory separation of the enantiomers by chiral HPLC could
not be achieved and an unambiguous ee determination was
impossible. Two representative amino alcohols were hence
converted into the respective oxazolidinones 10a and 10b which
were amenable to HPLC separation (Figure 2). Both compounds
turned out to be essentially enantiopure (98.8% ee for 10a,
99.9% ee for 10b). Oxazaborolidine 11 was prepared from
aminoalcohol 9i by condensation with 2,4,6-trifluorophenyl
boronic acid and it was characterized by NMR analysis (1H, 11B,
13C, 19F). The NMR data matched reported data of other
previously synthesized oxazaborolidines.[24] In the 11B NMR
there was a single signal for the oxazaborolidine boron atom at
30.2 ppm[24a] (for further details, see the Supporting Information).
In the catalytic experiments, the oxazaborolidines were freshly
prepared but not individually characterized. After thorough
removal of water they were directly activated by addition of AlBr3.
Figure 3. UV/Vis spectra of cyclic alkenone 5a in the absence (black line) and
in the presence of 20 equivalents of either EtAlCl2 (yellow) or BCl3 (red) (c =
0.5 mM in CH2Cl2).
Upon diastereoselective reduction to the respective secondary
alcohol, the absolute configuration of the major enantiomer 6a
was elucidated by Mosher analysis.[25] The selection of the aryl
boronic acid was based on a preliminary screen performed with
the 3,5-dimethylphenyl-substituted alcohol 9i and various
boronic acids. In this first set of experiments, the 2,3,4-
trifluorophenyl boronic acid performed the best (see Supporting
Information). Surprisingly, we found that the enantioface
differentiation in the reaction 5a → 6a was not consistent but
that it depended strongly on the aryl group Ar in catalyst 12. In
some cases, there was even a slight preference for the other
enantiomer ent-6a which is presented in Scheme 4 as a
negative enantiomeric excess (ee).
Figure 2. Structures of oxazolidinones 10 and of oxazaborolidine 11.
Enantioselective [2+2] photocycloaddition. As mentioned in the
introduction, Lewis acids display a profound influence on the
absorption properties of enones.[15] Figure
3 shows the
absorption spectrum of enone 5a in dichloromethane solution (c
= 0.5 mM). The strong * absorption of the compound appears
at short wavelength with an absorption maximum at max = 234
nm ( = 17010 M1 cm1). The n* absorption that is responsible
for the observed photocycloaddition reaction (Table 1) could not
be identified due to its low absorbance but it was clearly
detectable at higher concentration (c = 50 mM, see Supporting
Information). Its absorption maximum was found at max = 324
nm ( = 50 M1 cm1). Addition of Lewis acids led to a
bathochromic shift of the allowed * transition (Figure 3).
Assuming full complexation to occur with 20 equivalents of
Lewis acid, the respective UV/Vis absorption data are for
5a·EtAlCl2 max = 281 nm ( = 13750 M1 cm1) and for 5a·BCl3
max = 288 nm ( = 17830 M1 cm1). In both cases, there is a
significant absorption at longer wavelength that exceeds in
terms of quantitative absorbance the n* absorption of the
uncomplexed substrate 5a. In the presence of a Lewis acid there
is no n* transition.[15]
The above-mentioned scenario is typical for enones[15] and is the
prerequisite for the use of chiral Lewis acids in a subsequent
intramolecular [2+2] photocycloaddition reaction. The higher
absorption coefficient of the Lewis acid-substrate complex
Scheme 4. Evaluation of various oxazaborolidines 12 in the enantioselective
intramolecular [2+2] photocycloaddition to tricyclic product 6a.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
The highest enantioselectivity (78% ee) was recorded for
oxazaborolidine 12e derived from amino alcohol 9e (Ar = 2,3-
dimethylphenyl). Several other oxazaborolidines 12 with alkyl-
and methoxy-substituted aryl groups also led to selectivities
>50% ee (12d, 12g-12l, 12o). A substitution in para-position of
the aryl group and fluorine substituents led to low or negative
enantioselectivities (12f, 12m, 12n, 12p, 12r).
When searching for ways to optimize the enantioselectivity of
the intramolecular [2+2] photocycloaddition we initially turned
towards the irradiation conditions. The emission source that we
employed exhibits an emission maximum at  = 366 nm (Figure
4) but has a notable emission in the short wavelength ( < 360
nm) region. It was speculated that this emission might lead to a
direct excitation of substrate 5a and might favor the racemic
transformation by direct excitation. We could show that an
Fe2(SO4)3 filter solution[26] indeed suppresses the short
wavelength emission and the effect on the enantioselectivity was
clearly notable. Upon direct irradiation at  = 366 nm the
reaction with Lewis acid 12e·AlBr3 had provided product 6a
(Table 1) in 62% yield and with 78% ee. When the light was
filtered by an Fe2(SO4)3 solution (c = 600 mg L1) the yield
increased to 80% and the enantioselectivity increased to 84% ee.
This method thus paves – for the first time – an enantioselective
route to access typical intramolecular [2+2] photocycloaddition
products of 2-cyclohexenones (6a-6d, 6f, 6h, 6i) and 2-
cyclopentenones (6e, 6j). The product configuration was
assigned in analogy to major enantiomer 6a which was
dextrorotatory ([]D = +156). Likewise, all other cyclobutane
products showed a high positive specific rotation in CH2Cl2
solution ([]D = +98 to []D = +292).
Figure 4. Calculated emission profile of a 366 nm fluorescent lamp tuned by
Scheme 5. Enantioselective intramolecular [2+2] photocycloaddition of
enones 6 in the presence of AlBr3-activated oxazaborolidine 13. [a]Olefinic
side-products were removed by ozonolysis prior to purification.
an Fe2(SO4)3 filter solution (in 0.01 M HCl) of varying concentration.
Simultaneously to the emission experiments, we revisited the
aryl boronic acids and performed another screening of their
influence on the enantioselectivity now employing prolinol 9e (Ar
= 2,3-dimethylphenyl) as the amino alcohol. It was found that
2,4,6-trifluorophenyl boronic acid led to an improvement that
parallels the improvement achieved with the filter solution. When
catalyzed by AlBr3-activated oxazaborolidine 13, the yield for the
reaction 5a → 6a improved as compared to the reaction
promoted by catalyst 12e to 80% and the enantioselectivity to
83% ee (Scheme 5). Since direct irradiation at  = 366 nm is
operationally easier than irradiation through a filter solution,
alkenones 5a-5j were subsequently subjected to the former
conditions. Substrate consumption was complete after 24 hours
and the products were – with a single exception (vide infra) –
obtained in good to high yields (54-86%). More importantly, the
enantiocontrol was high and exceeded in eight out of ten
examples a level of 80% ee. Upon Lewis acid-promoted
conversion of enone 5g, a significant amount of olefinic side
products were identified which had to be removed from the
product by ozonolysis.
Computational and mechanistic studies. The coordination of
enones to acid-activated oxazaborolidines has been discussed
in previous work[27,28] and most commonly a weak non-classical
hydrogen bond between the -hydrogen atom of the enone
substrate and the oxygen atom of the oxazaborolidine is invoked.
This interaction avoids rotation around the strong coordinating
bond between the carbonyl group and the boron atom. In order
to visualize the reactive complex, we optimized the structure of
model substrate 3-methyl-2-cyclohexenone coordinated to Lewis
acid 12i·AlBr3. All computations were carried out with Gaussian
16[29] using the B3LYP-D3BJ functional[30] and the cc-pVTZ basis
set.[31] In order to match experimental conditions, computations
include thermal corrections at 75 °C and a PCM solvation
model for CH2Cl2 (for details see the Supporting Information). Si-
C was found to be the most stable conformation of complex C
with the above-mentioned non-classical hydrogen bond (2.46 Å)
clearly visible and the Si face of the -carbon atom being
exposed for an intramolecular attack. The lower aryl group
(Ardown) is slightly turned with one side pointing towards the
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
enone double bond thereby blocking this enantiotopic face. The
2,3,4-trifluorophenyl group shields the area above the enone -
carbon atom and is very likely responsible for the fact that
olefins with terminal substituents (substrate 5g) react poorly in
the intramolecular [2+2] photocycloaddition. Likewise, it was
found in the previously studied intermolecular variant of this
enone are perfectly parallel to each other (Figure 6) thereby
suggesting attractive dispersion interactions between the two
entities. Additionally, the aryl para-substituent and the substrate
-substituent are brought in close proximity in Re-D, which might
serve as a plausible hint towards the difference between C and
D. While this result should not be taken in any way as
reaction[17] that tri- and tetrasubstituted olefins reacted sluggishly. quantitative (the computed ground state energies for Re- and Si-
A
major difference between the former and the latter
complexes differ by less than 5 kJ mol1), it shows qualitatively
how cyclic enones can coordinate to certain Lewis acid-activated
photocycloaddition is the fact that the first C-C bond formation in
the former case will occur exclusively in the -position (“rule of
five”)[5] while in the latter case the -position is likely the position
of initial attack. In addition, the intramolecular reaction is faster
and thus outcompetes possible degradation pathways of the
photoexcited enone. Indeed, Lewis acids 11·AlBr3 and 12i·AlBr3
performed poorly in the intermolecular [2+2] photocycloaddition
which was ascribed to the fact that they underwent
decomposition by hydrogen abstraction from the enone.
oxazaborolidines in
enantioselectivity.
a way that explains a reversal in
Figure 6. Optimized complex conformer structure (right) of 3-methyl-2-
cyclohexenone and Lewis acid 12n·AlBr3 which displays the Re face of the -
carbon atom towards attack (Re-D, left).
Due to an efficient symmetry-allowed ISC from the n* singlet
state,[3,35] cyclic enones undergo [2+2] photocycloaddition
reactions from the * triplet state. We determined the quantum
yield for the racemic reaction 5a → rac-6a at  = 368 nm (LED)
and at 80 °C to be  = 0.38 (± 0.02). The high value which
compares well with quantum yields previously obtained for this
and related [2+2] photocycloaddition reactions[36] is a testimony
to the high efficiency with which both ISC and ring closure occur.
Under the same conditions it was attempted to determine the
quantum yield of the Lewis acid-promoted reaction employing
Lewis acid 13·AlBr3. The high sensitivity of the Lewis acid
towards air and moisture made it difficult to take samples at
given time intervals and to monitor the progress of the reaction.
Instead, the reaction was stopped after 10 min and the
conversion was determined (see the Supporting Information for
further details). The measurement was performed in triplicate
and delivered a quantum yield of  = 0.052 (± 0.007). Given that
ISC occurs in this case from a * singlet the quantum yield is
remarkably high. The value seems to support – as earlier
suggested by calculations[37] – the hypothesis that the Lewis
acids facilitates the forbidden ISC to the * triplet state. An
alternative explanation for the efficiency of the Lewis acid-
catalyzed process would be a rapid cyclization on the singlet
hypersurface prior to ISC. In order to distinguish between the
two pathways and to substantiate the fact that the catalyzed
reaction proceeds indeed on the triplet hypersurface, we turned
to a classical experiment that had been earlier performed with
substrates 5k by Becker and co-workers.[36a] Upon irradiation at
 > 330 nm (uranium glass filter), it had been found that both
diastereoisomers cis-5k and trans-5k gave in separate reactions
products rac-6k as a cis/trans mixture in a ratio of 50/50. The
Figure 5. Optimized structure (right) displaying the preferred conformation
within the complex of 3-methyl-2-cyclohexenone and Lewis acid 12i·AlBr3 (Si-
C, left).
The complex of 3-methyl-2-cyclohexenone and Lewis acid
12n·AlBr3 (complex D) was also studied computationally since
the latter is the least structurally different from 12i·AlBr3 but
nonetheless had led to an inverted enantioselectivity (Scheme 4,
29% ee). Although the ee shift from 75% ee (12i·AlBr3) to
29% ee (12n·AlBr3) corresponds only to a difference in free
enthalpies of approx. 4 kJ mol1 at 75 °C, we were curious
whether different conformational properties of the two
complexes C and D could be identified that would rationalize an
influence of the rather subtle changes in catalyst aryl group
substitution. We first explored enone binding to the opposite
concave side of the catalyst which has been discussed in the
context of cycloaddition reactions.[27,32] and obtained the
corresponding conformers for both C and D. However, both
structures were very similar and no apparent characteristics
were identified that would explain the strong influence of the aryl
para-substituent (see Supporting Information for details). In a
complimentary approach encouraged by computational studies
of complexes without Csp2H-O contacts but rather -interactions
with Ardown,
[33] we turned our attention to a coordination pattern in
which the substrate is rotated by 180° around the O–B bond
between enone and catalyst. This complex would also lead to
product of inverse absolute configuration through shielding of
the opposite enantiotopic face and, indeed, we identified
conformation Re-D in which the Re face of the -carbon atom is
exposed towards an attack.[34] In this conformation, Ardown and
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
reaction was not stereospecific and implied the intermediacy of
triplet diradical 14 which allows for free rotation around the
indicated single bond (Figure 7). Likewise, we studied the two
substrates cis-5k and trans-5k in separate reactions which were
performed with the Lewis acid 13·AlBr3 under the conditions of
Scheme 5. The reaction turned out to be also stereoconvergent
and led to a mixture of trans-6k and cis-6k in an almost identical
diastereomeric ratio (dr). When starting from cis-5k, the dr was
83/17 whereas the dr was 86/14 with trans-5k. In both reactions,
the trans compound trans-6k prevailed and was formed with
79% ee in the former and with 86% ee in the latter case.
Following a retrosynthetic [2+2] disconnection, 2-cyclohexenone
rac-3 seemed to be a reasonable starting material which would
allow the implementation of a photochemical key step in the
synthesis. Indeed, this reaction had been previously studied by
Hoye et al.[42] but the results were somewhat sobering (Scheme
6). At ambient temperature, not a single selectivity parameter
was satisfactorily controlled and the reaction delivered four
isomeric products in relative proportions of almost unity.
Optimization of the intramolecular [2+2] photocycloaddition in
our study rested on three parameters: choice of the irradiation
wavelength, temperature, and Lewis acid. There was a minor
improvement in yield at  = 366 nm but the dr (rac-15a/rac-15b)
remained low (67/33) and the formation of compounds rac-16
was not suppressed. As already found by Hoye et al., a
decrease of the reaction temperature to 75 °C enhanced the dr
to 78/22 but olefins rac-16 remained present. Eventually, we
discovered that with AlBr3 as the (achiral) Lewis acid there was a
perfect type selectivity and even an increase of the dr to 82/18
(Scheme 7).
Figure 7. Structures of irradiation precursors cis-5k and trans-5k, of
photocycloaddition products cis-6k and trans-6k, and of putative triplet
intermediate 14.
While the stereoconvergency of the reactions 5k → 6k supports
the intermediacy of 1,4-diradical 14, the high simple
diastereoselectivity is remarkable if compared to the non-
existent diastereoselectivity (dr = 50/50) observed for the
racemic reaction.[36a] The finding seems to indicate that
intermediate 14 remains in the coordination sphere of the
catalyst which forces the methyl group in the trans position of
the resulting cyclobutane ring. If intermediate 14 had dissociated
from the catalyst prior to ring closure[38] the dr should have been
similar to the racemic reaction. The observation parallels with
the sensitivity of the Lewis acid-mediated [2+2] photo-
cycloaddition towards steric hindrance (substrate 5g).
Scheme 7. Total synthesis of (±)-italicene (rac-19a) and (±)-isoitalicene (rac-
19b) via a selective Lewis-acid promoted [2+2] photocycloaddition.
Total synthesis of (±)-italicene and (±)-isoitalicene. The
sesquiterpenes italicene and isoitalicene[39] are the most
prominent natural products which feature the octahydro-
cyclopenta[1,4]cyclobuta[1,2]benzene skeleton that in turn is
built up in the intramolecular [2+2] photocycloaddition of 3-(pent-
4-enyl)-2-cyclohexenones. Synthetic approaches towards these
compounds have been reported[40] and to this date there exist
two completed total syntheses.[39,41]
The diastereomeric photocycloaddition products rac-15 were
separable and the relative configuration of the major isomer rac-
15a was confirmed.[42] Its preferred formation can be explained
by a chair-like transition state in which the methyl group at the
stereogenic center is in an equatorial position.[43] While it was
initially attempted to perform the -methylation and to follow a
known route towards italicene and isoitalicene,[39] we failed to
separate the isomers at the stage of the natural products. In
addition, the final dehydration step yielded repeatedly several
product isomers apart from the two natural products. As an
alternative, we decided to process the diastereoisomers
separately and devised an alternative sequence for the
introduction of the olefinic double bond. The -methylation
proceeded smoothly and with high diastereoselectivity for both
epimers rac-15a and rac-15b. The ketones rac-17a and rac-17b
were converted via the respective enolates into unstable
triflates[44] rac-18a and rac-18b which had to be purified on
deactivated neutral alumina. The reduction was eventually
performed with lithium formate employing Pd(OAc)2 (10 mol%)
as the catalyst.[45] The conditions were found to be superior to
other reported procedures which led to the formation of
Scheme 6. Low type selectivity and facial diastereoselectivity in the [2+2]
photocycloaddition of substrate rac-3.[42]
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
inseparable nonpolar side products.[46] Starting from 4-
bromoanisole as precursor for enone rac-3,[42] (±)-italicene (rac-
19a) was synthesized in seven steps with an overall yield of
15a increased. A concise and high-yielding synthesis of (±)-
italicene (rac-19a) could thus be achieved.
14%. The Lewis acid was responsible for
a significant
improvement in the selectivity of the photochemical stey step
which accounts for the high overall yield. (±)-Isoitalicene (rac-
19b) was obtained via the minor photocycloaddition diastereo-
isomer rac-15b with an overall yield of 3%.
Experimental Section
General Information: All air and moisture sensitive reactions were
carried out in heat gun-dried glassware under an argon atmosphere
using standard Schlenk techniques. Room temperature refers to 22-26
°C. Temperatures of 0 °C were obtained using an ice/water bath.
Temperatures of 78 °C were obtained using a dry ice/iso-propanol bath.
For moisture sensitive reactions, tetrahydrofuran (THF), diethyl ether
(Et2O) and dichloromethane (CH2Cl2) were dried using a MBSPS 800
MBraun solvent purification system. The following columns were used:
Tetrahydrofuran: 2 × MB-KOL-M type 2 (3 Å molecular sieve); Diethyl
ether: 1 × MB-KOL-A type 2 (aluminum oxide), 1 × MB-KOL-M type 2
Given that the starting alkene rac-3 is doubly substituted at the
terminal carbon atom, the chances were low to process the
compound in a kinetic photochemical resolution (cf. substrate
5g). Still, it was attempted to perform the [2+2] photo-
cycloaddition in the presence of Lewis acids 11·AlBr3, 12e·AlBr3,
12i·AlBr3, and 13·AlBr3 under standard conditions (Scheme 5).
The highest enantioselectivity was recorded with the Lewis acid
11·AlBr3 if the reaction was stopped after one hour. The major
diastereoisomer 15a that was formed with a dr of 84/16
displayed an enantiomeric excess of 42%. The conversion was
low, however, and 71% of the starting material 3 was recovered
(10% ee).
(3 Å molecular sieve); Dichloromethane: 2 × MB-KOL-A type
2
(aluminum oxide). The following dry solvents are commercially available
and were used without further purification: Toluene: Acros Organics,
99.8% extra dry, over molecular sieves. For photochemical reactions, dry
dichloromethane was degassed by three freeze-pump-thaw cycles and
stored over 4 Å molecular sieves. Technical solvents [pentane (P),
diethyl ether (Et2O), dichloromethane (CH2Cl2), methanol (MeOH),
n-hexane (nHex), ethyl acetate (EtOAc), cyclohexane (cHex)] were
distilled prior to column chromatography. Commercially available
chemicals were purchased from the suppliers ABCR, Acros, Alfa-Aesar,
Sigma-Aldrich (now Merck KGaA), and TCI, and were used without
further purification. For isomerizations of the photoproducts, basic
alumina (Merck, aluminum oxide 90 active basic, 0.063-0.200 mm) was
used.
Conclusions
In summary, this study provided new information about the
mode of action of Lewis acid-mediated [2+2] photocycloaddition
reactions. For the enantioselective intramolecular reaction of
substrates 5, it was found that the choice of substituents at the
chiral oxazaborolidine has a large influence on the degree of
enantioselecitivity. According to DFT calculations of complex
12i·AlBr3 with an enone, the lower aryl group (Ardown) at the
carbon atom and the aryl group at the boron atom control the
accessibility to the substrate. The enone encounters a high
enantioface differentiation at the -carbon atom at which the first
C-C bond formation occurs. Moreover, the aryl group at the
boron atom limits the available space in cis-position of the
terminal carbon atom in the alkenyl chain. It was found that a
reversal of enantioselectivity is possible by varying the aryl
groups Ar of the oxazaborolidine and a different binding mode of
the enone to the Lewis acid was identified. This discovery may
allow to access in the future opposite enantiomers of a given
photoproduct by alteration of the substituents. Regarding the
mechanism of the Lewis acid-catalyzed reaction, a reaction
pathway via the * triplet was substantiated. Although the
higher absorbance at  = 366 nm of the Lewis acid-enone
complex vs. the free enone facilitates its preferred excitation, the
faster ISC rate of the free enone compensates its lower
absorbance. As a consequence, the quantum yield of the Lewis
acid-mediated reaction is by a factor of 10 lower which in turn
requires a high catalyst loading of 50 mol% to achieve a high
degree of enantioselectivity. The effect of Lewis acids on the
selectivity of photochemical reactions is not limited to aspects of
enantioselectivity. We found an improved type selectivity in the
intramolecular [2+2] photocycloaddition of substrate rac-3.
Hydrogen abstraction products rac-16 were absent if the
reaction was performed in the presence of AlBr3 as the Lewis
acid and the facial diastereoselectivity in favor of product rac-
Analytical Methods and Equipment: Photochemical experiments were
carried out in heat gun-dried Duran tubes in a positive geometry setup
(cylindrical array of 16 fluorescent tubes, 8 W nominal power) with the
sample placed in the center of the illumination chamber. Fluorescent
tubes of the type Hitachi UV-A (BI-B) (max = 350 nm) and Philips Blue
Light (max = 366 nm) were employed. Enantioselective reactions were
carried out at 75 °C using a Duran cooling finger which was attached to
a high-performance cryostat (Huber CC80). Ozone was generated by a
FisherTechnology ozone-generator Type 502. Flash column
chromatography was performed with silica 60 (Merck, 230-400 mesh) as
the stationary phase with the indicated eluent mixtures. Deactivation of
neutral alumina (Merck, aluminum oxide 90 active neutral, 70-230 mesh)
was carried out by the addition of 36 wt% water in small portions.
Subsequently, the powder was spreaded in a petri dish and was allowed
to dry on air for at least two days. Thin Layer Chromatography (TLC) was
performed on silica coated glass plates (Merck, silica 60 F254) with
detection by UV-light (λ = 254 nm) and/or by staining with a potassium
permanganate solution [KMnO4] or with a cerium ammonium molybdate
solution [CAM] followed by heat treatment: KMnO4-staining solution:
potassium permanganate (3.00 g), potassium carbonate (20.0 g) and
aqueous sodium hydroxide solution (5 wt%, 5.00 mL) in water (300 mL).
CAM-staining solution: cerium sulfate tetrahydrate (1.00 g), ammonium
molybdate (25.0 g) and concentrated sulfuric acid (25.0 mL) in water
(250 mL). NMR-spectra were recorded at room temperature either on a
Bruker AVHD-300, AVHD-400, AVHD-500 or an AV-500 cryo. 1H NMR
spectra were referenced to the residual proton signal of chloroform-d1
(δ = 7.26 ppm), methanol-d4 (δ = 3.31 ppm), benzene-d6 (δ = 7.16 ppm)
or deuterium oxide (δ = 4.79 ppm). 13C NMR spectra were referenced to
the 13C-D triplet of CDCl3 (δ = 77.16 ppm), to the 13C-D septet of CD3OD
(δ = 49.00 ppm) or to the 13C-D triplet of C6D6 (δ = 128.06 ppm).
19F NMR spectra were referenced to the 19F signal of CCl3F (δ = 0 ppm).
Apparent multiplets which occur as a result of coupling constant equality
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
between magnetically non-equivalent protons are marked as virtual
(virt.). The following abbreviations for single multiplicities were used:
br-broad, s-singlet, d-doublet, t-triplet, q-quartet, quint-quintet,
sext-sextet, sept-septet. Assignment and multiplicity of the 13C NMR
signals were determined by two-dimensional NMR experiments (COSY,
HSQC, HMBC). Protons oriented above the molecular plane are labeled
as α and those oriented below as β. Infrared spectra were recorded on a
Perkin Elmer Frontier IR-FTR spectrometer by ATR technique. The
signal intensity is assigned using the following abbreviations: br (broad),
vs (very strong), s (strong), m (medium), w (weak). Low resolution and
high resolution mass spectra were recorded on a Thermo Scientific
LTQ-FT Ultra (ESI) or a Thermo Scientific DFS-HRMS spectrometer (EI).
All melting points were determined using a Büchi M-565 melting point
apparatus, with a range quoted to the nearest integer. UV/Vis spectra
were measured on a Perkin Elmer Lambda 35 UV/Vis spectrometer.
Spectra were recorded using a Hellma precision cell made of quartz
oxazaborolidine catalyst 13·AlBr3 (50.0 mol%) in dichloromethane
(1-3 mL) was transferred to the reaction mixture and the vessel was
washed with small portions of dichloromethane. Dichloromethane was
added until a concentration of 20 mM was reached. The solution was
cooled to 75 °C within 30 minutes and was subsequently irradiated at
 = 366 nm for 24 hours. The reaction mixture was poured into
suspended silica in dichloromethane and the solvent was removed in
vacuo. The dry-loaded product was purified by column chromatography
with
a given eluent mixture. The obtained cis/trans-mixture was
equilibrated over basic alumina in a small amount of dichloromethane
over night. The suspension was filtered, washed with small portions of
diethyl ether, and the filtrate was concentrated.
Photocycloaddition Product 6a: Racemic: Following GP1, enone 5a
(131 mg, 800 mol, 1.00 equiv) was irradiated in dichloromethane
(40 mL) for eight hours. After purification by column chromatography
(silica, P/Et2O = 4/1), ketone rac-6a (119 mg, 725 mol, 91%) was
obtained as a colorless oil. Enantioselective: Following GP2, enone 5a
(16.4 mg, 100 mol, 1.00 equiv) was irradiated in dichloromethane
(5 mL). After purification by column chromatography (silica, P/Et2O = 4/1),
ketone 6a (13.2 mg, 80.4 mol, 80%, 83% ee) was obtained as a
colorless oil. Rf = 0.42 (pentane/Et2O 6:4) [KMnO4]; [α]D25 = +156 (c = 1.0
in CH2Cl2); 1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 1.34 (virt. td,
2J ≈ 3J1 = 12.6 Hz, 3J2 = 6.8 Hz, 1 H, HH-1), 1.50-1.58 (m, 2 H, H-8),
1.58-1.64 (m, 3 H, HH-1, H-3), 1.77-1.93 (m, 3 H, H-2, HH-4), 1.93-2.04
(m, 2 H, H-7), 2.07 (ddd, 2J = 13.1 Hz, 3J1 = 9.7 Hz, 3J2 = 7.0 Hz, 1 H,
SUPRASIL® with
a pathway of 1 mm or 1 cm. Solvents and
concentrations are given for each spectrum. GC analysis was performed
on an Agilent 7890 B gas chromatograph using an Agilent HP-5 column
(30 m × 0.32 mm × 0.25 µm, SN: 19091J-413) with a flame ionization
detector. The temperature method is given for the corresponding
compounds. Chiral GC analysis was performed on an Agilent 7890 B gas
chromatograph
(30 m × 0.25 mm × 0.25 µm, SN: USF620714H) or a Macherey-Nagel
Lipodex E column (25 m × 0.25 mm, SN: 23393-92) with flame
ionization detector. The temperature method is given for the
corresponding compounds. Chiral HPLC was performed on
using
an
Agilent
Cyclosil-B
column
a
2
HH-4), 2.17 (dddd, J = 18.0 Hz, 3J1 = 11.4 Hz, 3J2 = 6.9 Hz, 4J = 1.1 Hz,
a
1 H, HH-6), 2.37-2.43 (m, 1 H, H-3a), 2.48 (virt. ddq, 3J1 = 11.4 Hz,
3J2 = 7.0 Hz, 4J1 ≈ 4J2 = 1.2 Hz, 1 H, H-4a), 2.57 ppm (virt. dddt,
2J = 18.0 Hz, 3J1 = 4.7 Hz, 3J2 = 3.4 Hz, 4J1 ≈ 4J2 = 1.2 Hz, 1 H, HH-6);
13C NMR (126 MHz, CDCl3, 27°C, TMS): δ = 21.2 (t, C-7), 25.1 (t, C-2),
26.9 (t, C-4), 32.9 (t, C-8), 33.1 (t, C-3), 39.6 (d, C-3a), 39.6 (t, C-6), 40.4
(t, C-1), 47.3 (d, C-4a), 50.0 (s, C-8a), 215.7 ppm (s, C-5); Chiral GC:
Thermo-Fisher HPLC system comprising a SR3000 solvent rack, a
LPG3400 SD pump, a WPS-3000 SL autosampler, a TCC-3000 SD
column compartment and a DAD-3000 UV/Vis detector fitted with the
appropriate Daicel column as chiral stationary phase (flow rate:
1.0 mL/min, Daicel column, time and eluent are given for the
corresponding compounds). Optical rotations were recorded on
a
Bellingham+Stanley ADP440+ polarimeter using a cuvette with a path
length of 0.05 dm. All measurements were performed using the sodium D
line ( = 589 nm) at room temperature. The specific rotation is reported
as follows: []DT = 100×/(l×c) [101 grad cm2 g1] (: optical rotation
[deg], l: path length [dm], c: concentration of sample [g/100 cm3]).

R (major) = 157.2 min, R (minor) = 161.8 min, [60 °C (1 min), 100 °C
(30 °C/min), 100 °C (157 min), 135 °C (3 °C/min), 200 °C (20 °C/min),
200 °C (3 min)], Cyclosil-B. The analytical data obtained matched those
reported in the literature.[47]
Photocycloaddition Product 6b: Racemic: Following GP1, enone 5b
(38.5 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for three hours. After purification by column chromatography
(silica, P/Et2O = 4/1), ketone rac-6b (33.5 mg, 174 mol, 87%) was
obtained as a colorless oil. Enantioselective: Following GP2, enone 5b
(38.5 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL). After purification by column chromatography (silica,
P/Et2O = 6/1), ketone 6b (33.0 mg, 172 mol, 86%, 86% ee) was
obtained as a colorless oil. Rf = 0.51 (pentane/Et2O 1:1) [KMnO4];
[α]D25 = +97.7 (c = 1.5 in CH2Cl2); 1H NMR (500 MHz, CDCl3, 25°C,
TMS): δ = 0.94 (s, 3 H, Me-2), 1.17 (s, 3 H, Me-2), 1.49 (dd, 2J = 13.4 Hz,
4J = 1.7 Hz, 1 H, HH-1), 1.51 (dd, 2J = 13.1 Hz, 3J = 6.2 Hz, 1 H, HH-3),
Preparation of Starting Materials, Calculations, and Mechanistic
Studies: The synthesis of the photocycloaddition precursors and of the
proline-derived amino alcohols
9 is described in the Supporting
Information (SI). In addition, the SI contains details on the preparation of
the oxazaborolidines and other amino alcohol derivatives, on the
preparation of the activated oxazaborolidines, on the DFT calculations,
and on the mechanistic studies.
Racemic Intramolecular [2+2] Photocycloaddition (General
Procedure 1):
A solution of the respective irradiation precursor
(1.00 equiv) in dichloromethane (1-3 mL) was transferred to a Duran
phototube. Dichloromethane was added until a concentration of 20 mM
was reached. The solution was irradiated at  = 366 nm for the
respective amount of time. After complete conversion, the solvent was
removed in vacuo. The residue was purified by column chromatography
with the given eluent mixture. The obtained cis/trans-mixture was
equilibrated over basic alumina in a small amount of dichloromethane
over night. The suspension was filtered, washed with small portions of
diethyl ether, and the filtrate was concentrated.
2
1.57 (ddd, J = 14.0 Hz, 3J1 = 11.1 Hz, 3J2 = 3.3 Hz, 1 H, HH-8), 1.70 (d,
2J = 13.4 Hz, 1 H, HH-1), 1.75 (dddd, 2J = 14.0 Hz, 3J1 = 6.4 Hz,
3J2 = 3.0 Hz, 4J = 1.1 Hz, 1 H, HH-8), 1.81-1.91 (m, 2 H, HH-3, HH-7),
1.94-2.07 (m, 2 H, HH-4, HH-7), 2.12-2.18 (m, 1 H, HH-4), 2.18-2.25 (m,
1 H, HH-6), 2.44-2.49 (m, 1 H, H-3a), 2.49-2.56 (m, 1 H, HH-6),
2.77-2.82 ppm (m, 1 H, H-4a); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 20.7 (t, C-7), 27.9 (t, C-4), 29.6 (q, Me-2), 30.0 (q, Me-2), 35.0 (t, C-8),
38.9 (t, C-6), 41.8 (d, C-3a), 43.2 (s, C-2)*, 49.4 (t, C-3), 50.9 (d, C-4a),
51.3 (s, C-8a)*, 56.6 (t, C-1), 216.7 ppm (s, C-5) [*Assignment of signals
is interconvertible.]; IR (ATR): ṽ = 2927 (s, sp3-CH), 2863 (m, sp3-CH),
1696 (vs, C=O), 1462 (m, sp3-CH), 907 cm1 (w); MS (EI, 70 eV): m/z
(%): 192 (33) [M]+, 177 (23) [MCH3]+, 164 (17) [MCO]+, 159 (11), 136
(15), 122 (30) [C8H10O]+, 110 (100) [MC6H10]+, 107 (58), 93 (20), 83 (23)
[C6H11]+, 67 (24), 55 (51) [C4H7]+, 41 (20); HRMS (EI, 70 eV): calcd for
Enantioselective Intramolecular [2+2] Photocycloaddition (General
Procedure 2):
A solution of the respective irradiation precursor
(1.00 equiv) in dichloromethane (1-3 mL) was transferred to a heat-gun
dried Duran phototube and the vessel was washed twice with small
portions of dichloromethane. Then,
a
solution of activated
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
C13H20O [M]+: 192.1509; found: 192.1504; calcd for C1213CH20O [M]+:
Photocycloaddition Product 6e: Racemic: Following GP1, enone 5e
(30.0 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for 47 hours. After purification by column chromatography (silica,
P/Et2O = 5/1), ketone rac-6e (16.6 mg, 111 mol, 56%) was obtained as
a colorless oil. Enantioselective: Following GP2, enone 5e (30.0 mg,
200 mol, 1.00 equiv) was irradiated in dichloromethane (10 mL). After
purification by column chromatography (silica, P/Et2O = 5/1), ketone 6e
(16.2 mg, 108 mol, 54%, 80% ee) was obtained as a colorless oil.
Rf = 0.26 (pentane/Et2O 5:1) [KMnO4]; [α]D25 = +292 (c = 1.1 in CH2Cl2);
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 1.42 (ddd, 2J = 13.0 Hz,
3J1 = 10.7 Hz, 3J2 = 9.1 Hz, 1 H, HH-7), 1.54-1.59 (m, 1 H, HH-5),
1.59-1.67 (m, 1 H, HH-5), 1.68-1.74 (m, 1 H, HH-7), 1.76-1.83 (m, 1 H,
HH-4), 1.83-1.91 (m, 4 H, HH-6, HH-4, H-1), 1.92 (virt. dq, 2J = 4.8 Hz,
3J1 ≈ 3J2 ≈ 3J3 = 2.2 Hz, 1 H, HH-6), 2.22 (ddd, 3J1 = 10.7 Hz, 3J2 = 4.4 Hz,
4J = 2.0 Hz, 1 H, H-3a), 2.35 (virt. ddt, 2J = 17.9 Hz, 3J1 = 7.8 Hz,
3J2 ≈ 4J = 2.0 Hz, 1 H, HH-2), 2.49-2.56 (m, 1 H, H-4a), 2.78 ppm
(virt. dddt, 2J = 17.9 Hz, 3J1 = 12.5 Hz, 3J2 = 9.6 Hz, 4J1 ≈ 4J2 = 0.8 Hz,
1 H, HH-2); 13C NMR (126 MHz, CDCl3, 27°C, TMS): δ = 25.8 (t, C-4),
26.0 (t, C-6), 32.1 (t, C-1), 33.4 (t, C-5), 37.4 (t, C-7), 38.2 (t, C-2), 40.6
(d, C-4a), 47.1 (d, C-3a), 53.0 (s, C-7a), 222.8 ppm (s, C-3); Chiral GC:
193.1542; found: 193.1541; Chiral GC:
R (major) = 173.4 min,
R (minor) = 174.0 min, [60 °C (1 min), 100 °C (30 °C/min), 100 °C
(157 min), 135 °C (3 °C/min), 200 °C (20 °C/min), 200 °C (3 min)],
Cyclosil-B.
Photocycloaddition Product 6c: Racemic: Following GP1, enone 5c
(16.6 mg, 100 mol, 1.00 equiv) was irradiated in dichloromethane
(5 mL) for five hours. After purification by column chromatography (silica,
P/EtOAc = 1/1), ketone rac-6c (14.4 mg, 86.6 mol, 87%) was obtained
as a colorless oil. Enantioselective: Following GP2, enone 5c (33.2 mg,
200 mol, 1.00 equiv) was irradiated in dichloromethane (10 mL). After
purification by column chromatography (silica, P/EtOAc = 1/1), ketone 6c
(22.6 mg, 136 mol, 68%, 82% ee) was obtained as a colorless oil.
Rf = 0.31 (pentane/Et2O 1:1) [KMnO4]; [α]D26 = +138 (c = 1.4 in CH2Cl2);
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 1.52 (ddd, 2J = 13.9 Hz,
3J1 = 11.9 Hz, 3J2 = 4.3 Hz, 1 H, HH-8), 1.70 (dddd, 2J = 13.9 Hz,
3J1 = 4.5 Hz, 3J2 = 3.2 Hz, 4J = 1.5 Hz, 1 H, HH-8), 1.94-2.13 (m, 4 H, H-4,
H-7), 2.18 (dddd, 2J = 17.4 Hz, 3J1 = 12.3 Hz, 3J2 = 6.0 Hz, 4J = 1.1 Hz,
1 H, HH-6), 2.54-2.61 (m, 2 H, H-3a, HH-6), 2.71 (dd, 3J1 = 10.7 Hz,
3J2 = 7.2 Hz, 1 H, H-4a), 3.28 (d, 2J = 9.3 Hz, 1 H, HH-1), 3.61 (dd,
2J = 9.3 Hz, 3J = 5.2 Hz, 1 H, HH-3), 3.86 (d, 2J = 9.3 Hz, 1 H, HH-1),
3.86 ppm (d, 2J = 9.3 Hz, 1 H, HH-3); 13C NMR (126 MHz, CDCl3, 27°C,
R (minor) = 82.4 min,
R (major) = 90.8 min, [60 °C (1 min), 100 °C
(30 °C/min), 100 °C (157 min), 135 °C (3 °C/min), 200 °C (20 °C/min),
200 °C (3 min)], Cyclosil-B. The analytical data obtained matched those
reported in the literature.[48]
TMS): δ = 21.3 (t, C-7), 26.8 (t, C-4), 28.6 (t, C 8), 39.9 (t, C-6), 40.9 (d,
-
C-3a), 46.6 (d, C-4a), 51.1 (s, C-8a), 74.4 (t, C-3), 78.9 (t, C-1),
214.1 ppm (s, C-5); IR (ATR): ṽ = 2938 (m, sp3-CH), 2843 (m, sp3-CH),
1697 (vs, C=O), 1107 (s, sp3-CO), 914 cm1 (vs, sp3-CO); MS (EI,
70 eV): m/z (%): 166 (58) [M]+, 137 (27) [MCO]+, 121 (84) [MC2H5O]+,
110 (100) [MC3H4O]+, 96 (82) [MC4H6O]+, 82 (78) [C5H6O]+, 79 (90), 67
(66), 55 (58) [C4H7]+, 41 (61) [C3H5]+; HRMS (EI, 70 eV): calcd for
C10H14O2 [M]+: 166.0988; found: 166.0985; calcd for C913CH14O2 [M]+:
Photocycloaddition Product 6f: Racemic: Following GP1, enone 5f
(35.7 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for five hours. After purification by column chromatography (silica,
P/Et2O = 5/1), ketone rac-6f (24.2 mg, 136 mol, 68%) was obtained as a
colorless oil. Enantioselective: Following GP2, enone 5f (35.7 mg,
200 mol, 1.00 equiv) was irradiated in dichloromethane (10 mL). After
purification by column chromatography (silica, P/Et2O = 5/1), ketone 6f
(29.5 mg, 165 mol, 83%, 86% ee) was obtained as a colorless oil.
Rf = 0.58 (pentane/Et2O 1:1) [KMnO4]; [α]D25 = +155 (c = 1.1 in CH2Cl2);
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 1.06 (s, 3 H, Me-3a),
1.29-1.36 (m, 1 H, HH-3), 1.36-1.42 (m, 1 H, HH-1), 1.45 (ddd,
2J = 13.7 Hz, 3J1 = 9.1 Hz, 3J2 = 4.2 Hz, 1 H, HH-8), 1.57-1.63 (m, 1 H,
HH-3), 1.71-1.83 (m, 4 H, HH-1, H-2, HH-8), 1.86 (ddd, 2J = 12.7 Hz,
3J = 7.2 Hz, 4J = 1.4 Hz, 1 H, HH-4), 1.88-1.98 (m, 2 H, H-7), 2.01 (dd,
2J = 12.7 Hz, 3J = 11.0 Hz, 1 H, HH-4), 2.21-2.28 (m, 1 H, HH-6),
2.37-2.44 ppm (m, 2 H, H-4a, HH-6); 13C NMR (126 MHz, CDCl3, 27°C,
TMS): δ = 22.0 (t, C-7), 22.9 (q, Me-3a), 23.9 (t, C-2), 29.5 (t, C-8), 35.1
(t, C-4), 40.0 (t, C-6), 41.7 (t, C-1), 42.0 (t, C-3), 44.6 (s, C-3a), 45.3 (d,
167.1022;
R (major) = 37.7 min, [60 °C (0 min), 245 °C (3 °C/min), 245 °C (3 min)],
Cyclosil-B.
found:
167.1022;
Chiral GC:
R (minor) = 37.5 min,

Photocycloaddition Product 6d: Racemic: Following GP1, enone 5d
(38.5 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for five hours. After purification by column chromatography (silica,
P/Et2O = 6/1), ketone rac-6d (30.4 mg, 158 mol, 79%) was obtained as
a colorless oil. Enantioselective: Following GP2, enone 5d (38.5 mg,
200 mol, 1.00 equiv) was irradiated in dichloromethane (10 mL). After
purification by column chromatography (silica, P/Et2O = 6/1), ketone 6d
(32.6 mg, 170 mol, 85%, 89% ee) was obtained as a colorless oil.
Rf = 0.63 (pentane/Et2O 1:1) [KMnO4]; [α]D25 = +156 (c = 1.3 in CH2Cl2);
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.98 (s, 3 H, Me-7), 1.06 (s,
3 H, Me-7), 1.36 (virt. td, 2J ≈ 3J1 = 12.3 Hz, 3J2 = 7.2 Hz, 1 H, HH-1),
C-4a),
51.3
(s,
C-8a),
216.5 ppm
(s,
C-5);
Chiral GC:
R (minor) = 131.9 min,
R (major) = 136.7 min, [60 °C (1 min), 100 °C
(30 °C/min), 100 °C (157 min), 135 °C (3 °C/min), 200 °C (20 °C/min),
200 °C (3 min)], Cyclosil-B. The analytical data obtained matched those
reported in the literature.[49]
2
3
1.52 (dd, J = 12.6 Hz, J = 6.0 Hz, 1 H, HH-3), 1.54-1.62 (m, 2 H, HH-3,
HH-8), 1.69 (d, 2J = 14.5 Hz, 1 H, HH-8), 1.72-1.78 (m, 1 H, HH-1),
1.78-1.89 (m, 3 H, H-2, HH-4), 2.15 (d, 2J = 14.8 Hz, 1 H, HH-6), 2.19
(ddd, 2J = 13.0 Hz, 3J1 = 9.5 Hz, 3J2 = 6.6 Hz, 1 H, HH-4), 2.25 (d,
2J = 14.8 Hz, 1 H, HH-6), 2.36 (dd, 3J1 = 11.6 Hz, 3J2 = 6.6 Hz, 1 H, H-4a),
2.38-2.43 ppm (m, 1 H, H-3a); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 24.8 (t, C-2), 27.3 (t, C-4), 28.5 (q, Me-7), 31.0 (q, Me-7), 33.0 (t, C-3),
34.6 (s, C-7), 42.7 (d, C-3a), 43.1 (t, C-1), 46.0 (d, C-4a), 47.7 (t, C-8),
49.6 (s, C-8a), 53.8 (t, C-6), 216.7 ppm (s, C-5); IR (ATR): ṽ = 2941 (s,
sp3-CH), 2895 (m, sp3-CH), 2868 (m, sp3-CH), 1700 (vs, C=O),
1467 cm1 (m, sp3-CH); MS (EI, 70 eV): m/z (%): 192 (40) [M]+, 177 (18)
[MCH3]+, 149 (41) [MC3H7]+, 136 (81) [MC4H8]+, 125 (35) [C8H13O]+,
108 (56) [C7H8O]+, 93 (44), 82 (100) [C6H10]+, 54 (30), 41 (18); HRMS (EI,
70 eV): calcd for C13H20O [M]+: 192.1509; found: 192.1513; Chiral GC:
Photocycloaddition Product 6g: Racemic: Following GP1, enone 5g
(38.5 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for 5.5 hours. After purification by column chromatography (silica,
P/Et2O = 6/1),
a product mixture was obtained, which contains
inseparable impurities. To facilitate purification, the mixture was
submitted to ozonolysis which was conducted at 78 °C in
dichloromethane (3 mL). Completion of the reaction was indicated by
blue coloration during ozon introduction. The blue color was removed by
an argon gasflow and dimethyl sulfide (1 mL) was added. Subsequently,
the mixture was warmed to room temperature and the solvent was
removed in vacuo. The residue was purified by column chromatography
(silica, P/Et2O = 6/1). After the work-up process, ketone 6g (19.7 mg,
102 mol, 51%) was obtained as a colorless oil. Enantioselective:
Following GP2, enone 5g (38.5 mg, 200 mol, 1.00 equiv) was irradiated
in dichloromethane (10 mL). After purification by column chromatography
R (minor) = 169.7 min, R (major) = 170.3 min, [60 °C (1 min), 100 °C
(30 °C/min), 100 °C (157 min), 135 °C (3 °C/min), 200 °C (20 °C/min),
200 °C (3 min)], Cyclosil-B.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
(silica, P/Et2O = 6/1), a product mixture was obtained, which contains
inseparable impurities. To facilitate purification, the mixture was
submitted to ozonolysis which was conducted at 78 °C in
dichloromethane (3 mL). Completion of the reaction was indicated by
blue coloration during ozon introduction. The blue color was removed by
an argon gasflow and dimethyl sulfide (1 mL) was added. Subsequently,
the mixture was warmed to room temperature and the solvent was
removed in vacuo. The residue was purified by column chromatography
(silica, P/Et2O = 6/1). After the work-up process, ketone 6g (6.20 mg,
32.2 mol, 16%, 55% ee) was obtained as a colorless oil. Rf = 0.66
(pentane/Et2O 1:1) [KMnO4]; [α]D25 = +140 (c = 1.1 in CH2Cl2); 1H NMR
(500 MHz, CDCl3, 25°C, TMS): δ = 1.03 (s, 3 H, Me-4), 1.05 (s, 3 H,
Me-4), 1.21-1.30 (m, 1 H, HH-1), 1.50-1.62 (m, 1 H, HH-3), 1.68-1.78 (m,
5 H, HH-1, HH-2, HH-3, HH-7, HH-8), 1.80-1.91 (m, 2 H, HH-2, HH-8),
1.91-1.98 (m, 1 H, HH-7), 1.98-2.00 (m, 1 H, H-3a), 2.17 (s, 1 H, H-4a),
2.18-2.33 ppm (m, 2 H, H-6); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 21.4 (t, C-7), 25.1 (q, Me-4), 26.9 (t, C-2), 27.6 (q, Me-4), 28.2 (t, C-3),
34.5 (t, C-8), 36.9 (s, C-4), 40.4 (t, C-1), 41.1 (t, C-6), 45.1 (s, C-8a), 52.0
(d, C-3a), 57.4 (d, C-4a), 214.3 ppm (s, C-5); Chiral GC:
(virt. td, 2J ≈ 3J1 = 12.2 Hz, 3J2 = 7.0 Hz, 1 H, HH-1), 1.62 (virt. ddt,
2J = 12.7 Hz, 3J = 6.2 Hz, 4J1 ≈ 4J2 = 1.5 Hz, 1 H, HH-3), 1.69-1.84 (m,
3 H, H-2, HH-4), 1.91 (d, 2J = 14.2 Hz, 1 H, HH-8), 1.93-1.99 (m, 1 H,
HH-1), 2.02 (dd, 2J = 12.5 Hz, 3J = 11.2 Hz, 1 H, HH-4), 2.12 (ddd,
2J = 16.1 Hz, 4J1 = 2.5 Hz, 4J2 = 1.3 Hz, 1 H, HH-6), 2.21 (dd,
2J = 16.1 Hz, 4J = 0.8 Hz, 1 H, HH-6), 2.36 ppm (ddd, 3J1 = 11.2 Hz,
3J2 = 7.7 Hz, 4J = 1.3 Hz, 1 H, H-4a); 13C NMR (126 MHz, CDCl3, 27°C,
TMS): δ = 24.3 (q, Me-3a), 24.3 (t, C-2), 28.0 (q, Me-7), 31.8 (q, Me-7),
33.9 (s, C-7), 34.8 (t, C-4), 40.8 (t, C-3), 42.8 (t, C-8), 43.7 (d, C-4a), 44.0
(t, C-1), 45.4 (s, C-3a), 50.0 (s, C-8a), 52.7 (t, C-6), 216.2 ppm (s, C-5);
Chiral GC: R (major) = 94.3 min, R (minor) = 95.0 min, [60 °C (0.5 min),
70 °C (10 °C/min), 114 °C (0.4 °C/min), 200 °C (10 °C/min), 200 °C
(3 min)], Lipodex E. The analytical data obtained matched those reported
in the literature.[49]
Photocycloaddition Product 6j: Racemic: Following GP1, enone 5j
(32.9 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for eight hours at  = 350 nm. After purification by column
chromatography (silica, P/Et2O = 5/1), ketone rac-6j (20.6 mg, 125 mol,
63%) was obtained as a colorless oil. Enantioselective: Following GP2,
enone 5j (32.9 mg, 200 mol, 1.00 equiv) was irradiated in
dichloromethane (10 mL). After purification by column chromatography
(silica, P/Et2O = 5/1), ketone 6j (20.2 mg, 123 mol, 61%, 76% ee) was
obtained as a colorless oil. Rf = 0.60 (pentane/Et2O 1:1) [KMnO4];
[α]D25 = +222 (c = 1.1 in CH2Cl2); 1H NMR (500 MHz, CDCl3, 25°C, TMS):
δ = 1.14 (s, 3 H, Me-4a), 1.30-1.38 (m, 1 H, HH-5), 1.44-1.52 (m, 1 H,
HH-7), 1.59-1.70 (m, 3 H, HH-4, HH-5, HH-7), 1.70-1.84 (m, 3 H, HH-1,
H-6), 2.01-2.09 (m, 2 H, HH-1, HH-4), 2.20 (ddd, 3J1 = 11.0 Hz,
3J2 = 4.7 Hz, 4J = 2.0 Hz, 1 H, H-3a), 2.34 (virt. ddt, 2J = 18.8 Hz,
3J1 = 9.8 Hz, 3J2 ≈ 4J = 2.0 Hz, 1 H, HH-2), 2.62-2.71 ppm (m, 1 H, HH-2);
13C NMR (126 MHz, CDCl3, 27°C, TMS): δ = 23.2 (q, Me-4a), 25.1 (t,
C-6), 27.1 (t, C-1), 34.5 (t, C-4), 38.5 (t, C-7), 38.8 (t, C-2), 42.3 (t, C-5),
43.8 (s, C-4a), 45.6 (d, C-3a), 53.6 (s, C-7a), 223.4 ppm (s, C-3);
Chiral GC: R (minor) = 14.8 min, R (major) = 14.9 min, [60 °C (0 min),
120 °C (30 °C/min), 120 °C (10 min), 240 °C (30 °C/min), 240 °C (2 min)],
Cyclosil-B. The analytical data obtained matched those reported in the
literature.[48]
R (minor) = 157.6 min, R (major) = 161.9 min, [60 °C (1 min), 100 °C
(30 °C/min), 100 °C (157 min), 135 °C (3 °C/min), 200 °C (20 °C/min),
200 °C (3 min)], Cyclosil-B. The analytical data obtained matched those
reported in the literature.[42]
Photocycloaddition Product 6h: Racemic: Following GP1, enone 5h
(18.0 mg, 100 mol, 1.00 equiv) was irradiated in dichloromethane
(5 mL) for eight hours. After purification by column chromatography
(silica, P/EtOAc = 2/1), ketone rac-6h (14.4 mg, 79.9 mol, 80%) was
obtained as a colorless oil. Enantioselective: Following GP2, enone 5h
(36.1 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL). After purification by column chromatography (silica,
P/EtOAc = 2/1), ketone 6h (25.8 mg, 143 mol, 72%, 84% ee) was
obtained as a colorless oil. Rf = 0.37 (pentane/Et2O 1:1) [KMnO4];
[α]D26 = +142 (c = 1.5 in CH2Cl2); 1H NMR (500 MHz, CDCl3, 25°C, TMS):
δ = 1.08 (s, 3 H, Me-3a), 1.45 (ddd, 2J = 14.4 Hz, 3J1 = 8.6 Hz,
3J2 = 5.9 Hz, 1 H, HH-8), 1.77 (virt. dt, 2J = 14.4 Hz, 3J1 ≈ 3J2 = 5.0 Hz,
1 H, HH-8), 1.87-2.02 (m, 3 H, HH-4, H-7), 2.20-2.31 (m, 2 H, HH-4,
HH-6), 2.46 (virt. dt, 2J = 16.6 Hz, 3J1 ≈ 3J2 = 5.2 Hz, 1 H, HH-6), 2.68 (dd,
3J1 = 11.0 Hz, 3J2 = 7.0 Hz, 1 H, H-4a), 3.26 (d, 2J = 9.1 Hz, 1 H, HH-3),
3.30 (d, 2J = 9.2 Hz, 1 H, HH-1), 3.83 (d, 2J = 9.1 Hz, 1 H, HH-3),
3.95 ppm (d, 2J = 9.2 Hz, 1 H, HH-1); 13C NMR (126 MHz, CDCl3, 27°C,
TMS): δ = 18.1 (q, Me-3a), 21.9 (t, C-7), 24.9 (t, C-8), 34.8 (t, C-4), 40.2
(t, C-6), 45.0 (d, C-4a), 45.5 (s, C-3a), 51.7 (s, C-8a), 80.0 (t, C-1), 81.1 (t,
C-3), 214.6 ppm (s, C-5); IR (ATR): ṽ = 2935 (m, sp3-CH), 2838 (m,
sp3-CH), 1699 (vs, C=O), 1054 (s, sp3-CO), 932 cm1 (s, sp3-CO); MS (EI,
70 eV): m/z (%): 180 (15) [M]+, 135 (55) [C9H11O]+, 122 (31), 109 (100)
[C7H9O]+, 95 (46), 79 (61), 67 (51), 55 (97) [C4H7]+, 41 (45) [C3H5]+;
HRMS (EI, 70 eV): calcd for C11H16O2 [M]+: 180.1145; found: 180.1143;
calcd for C1013CH16O2 [M]+: 181.1178; found: 181.1183; Chiral GC:
Photocycloaddition Products trans-6k and cis-6k: Racemic:
Following GP1, enone cis-5k (35.7 mg, 200 mol, 1.00 equiv) was
irradiated in dichloromethane (10 mL) for eight hours at a wavelength of
 = 366 nm. After purification by column chromatography (P/Et2O = 4/1),
a mixture of ketones rac-trans-6k and rac-cis-6k (32.7 mg, 183 mol,
92%, d.r. = 50/50) was obtained as a colorless oil. Following GP1, enone
trans-5k (35.7 mg, 200 mol, 1.00 equiv) was irradiated in
dichloromethane (10 mL) for eight hours at a wavelength of  = 366 nm.
After purification by column chromatography (P/Et2O = 4/1), a mixture of
ketones rac-trans-6k and rac-cis-6k (33.0 mg, 185 mol, 93%,
d.r. = 50/50) was obtained as a colorless oil. Enantioselective: Following
GP2, enone cis-5k (35.7 mg, 200 mol, 1.00 equiv) was irradiated in
dichloromethane (10 mL). After purification by column chromatography
(P/Et2O = 5/1), a mixture of ketones trans-6k (79% ee) and cis-6k (55%
ee) (13.5 mg, 75.7 mol, 38%, d.r. = 83/17) was obtained as a colorless
oil. Following GP2, enone trans-5k (35.7 mg, 200 mol, 1.00 equiv) was
irradiated in dichloromethane (10 mL). After purification by column
chromatography (P/Et2O = 5/1), a mixture of ketones trans-6k (86% ee)
and cis-6k (74% ee) (15.7 mg, 88.1 mol, 44%, d.r. = 86/14) was
obtained as a colorless oil. trans-6k: Rf = 0.58 (pentane/Et2O 1:1)
[KMnO4]; 1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.94 (d,
3J = 7.5 Hz, 3 H, Me-4), 1.29-1.39 (m, 1 H, HH-3), 1.49-1.63 (m, 5 H, H-1,
HH-3, H-8), 1.75-1.84 (m, 2 H, H-2), 1.89-1.98 (m, 2 H, H-7), 1.98-2.04
(m, 1 H, H-3a), 2.04-2.14 (m, 2 H, H-4, HH-6), 2.40 (virt. dt, 2J = 18.4 Hz,
3J1 ≈ 3J2 = 3.6 Hz, 1 H, HH-6), 2.52 ppm (d, 3J = 11.2 Hz, 1 H, H-4a);
13C NMR (126 MHz, CDCl3, 27°C, TMS): δ = 17.3 (q, Me-4), 21.3 (t, C-7),
R (minor) = 42.7 min,
R (major) = 43.3 min, [60 °C (0 min), 130 °C
(30 °C/min), 130 °C (38 min), 160 °C (5 °C/min), 240 °C (15 °C/min),
240 °C (2 min)], Cyclosil-B.
Photocycloaddition Product 6i: Racemic: Following GP1, enone 5i
(41.3 mg, 200 mol, 1.00 equiv) was irradiated in dichloromethane
(10 mL) for five hours. After purification by column chromatography (silica,
P/Et2O = 6/1), ketone rac-6i (36.4 mg, 176 mol, 88%) was obtained as a
colorless oil. Enantioselective: Following GP2, enone 5i (41.3 mg,
200 mol, 1.00 equiv) was irradiated in dichloromethane (10 mL). After
purification by column chromatography (silica, P/Et2O = 6/1), ketone 6i
(34.7 mg, 168 mol, 84%, 96% ee) was obtained as a colorless oil.
Rf = 0.62 (pentane/Et2O 1:1) [KMnO4]; [α]D25 = +228 (c = 1.3 in CH2Cl2);
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.90 (s, 3 H, Me-7), 1.01 (s,
3 H, Me-3a), 1.04 (s, 3 H, Me-7), 1.23-1.34 (m, 2 H, HH-3, HH-8), 1.39
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
25.2 (t, C-2), 32.5 (t, C-8)*, 33.0 (t, C-1)*, 33.3 (d, C-4), 40.6 (t, C-3), 41.1
(t, C-6), 45.8 (s, C-8a), 47.9 (d, C-3a), 51.3 (s, C-4a), 214.9 ppm (s, C-5)
C-4a), 214.7 ppm (s, C-5); Chiral GC:
R (minor) = 25.3 min,
R (major) = 25.9 min, [60 °C (0.5 min), 200 °C (4 °C/min), 200 °C
[*Assignment
of
signals
is
interconvertible.];
Chiral GC:
(5 min)], Lipodex E. 15b: Rf = 0.66 (pentane/Et2O 1:1) [CAM, KMnO4];
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.89 (d, 3J = 6.7 Hz, 3 H,
Me-1), 1.03 (s, 3 H, Me-4), 1.06 (s, 3 H, Me-4), 1.42 (virt. qd,
R (major) = 55.4 min,
R (minor) = 58.1 min, [60 °C (0 min), 115 °C
(15 °C/min), 115 °C (50 min), 160 °C (5 °C/min), 220 °C (30 °C/min),
220 °C (2 min)], Cyclosil-B. cis-6k: Rf = 0.58 (pentane/Et2O 1:1) [KMnO4];
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.98 (d, 3J = 6.8 Hz, 3 H,
Me-4), 1.24-1.38 (m, 1 H), 1.47-1.63 (m, 3 H), 1.56-1.75 (m, 1 H),
1.68-1.74 (m, 1 H), 1.75-1.86 (m, 2 H), 1.89-1.98 (m, 1 H), 2.03-2.21 (m,
3 H, H-4a), 2.33-2.46 (m, 2 H, H-3a, H-4), 2.57 ppm (virt. dt, 2J = 17.8 Hz,
3J1 ≈ 3J2 = 3.9 Hz, 1 H, HH-6); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 14.7 (q, Me-4), 20.9 (t), 26.7 (t), 26.9 (t), 31.3 (d, C-4), 32.5 (t), 39.0
(t), 39.6 (t), 43.3 (d, C-3a), 47.4 (s, C-8a), 56.0 (d, C-4a), 214.0 ppm (s,
3
2J ≈ 3J1 ≈ 3J2 = 12.3 Hz, J3 = 6.6 Hz, 1 H, HH-2), 1.48-1.73 (m, 4 H, H-1,
H-3, HH-8), 1.73-1.91 (m, 3 H, HH-2, HH-7, HH-8), 1.94-2.04 (m, 1 H,
HH-7), 2.06 (d, 3J = 8.0 Hz, 1 H, H-3a), 2.11-2.21 (m, 1 H, HH-6),
2.25-2.35 ppm (m, 2 H, H-4a, HH-6); 13C NMR (126 MHz, CDCl3, 27°C,
TMS): δ = 12.8 (q, Me-1), 21.5 (t, C-7), 24.9 (q, Me-4), 26.6 (t, C-3),
27.3 (q, Me-4), 33.0 (t, C-8), 35.4 (t, C-2), 36.3 (s, C-4), 41.1 (t, C-6),
44.7 (d, C-1), 46.5 (s, C-8a), 52.2 (d, C-4a), 53.1 (d, C-3a), 214.1 ppm (s,
C-5); Chiral GC:
R (major) = 24.3 min, R (minor) = 24.6 min, [60 °C
C-5); Chiral GC:

R (minor) = 56.8 min,

R (major) = 57.6 min, [60 °C
(0.5 min), 200 °C (4 °C/min), 200 °C (5 min)], Lipodex E. The analytical
data obtained matched those reported in the literature.[42]
(0 min), 115 °C (15 °C/min), 115 °C (50 min), 160 °C (5 °C/min), 220 °C
(30 °C/min), 220 °C (2 min)], Cyclosil-B. The analytical data obtained
matched those reported in the literature.[47]
Ketone rac-17a: A solution of n-butyllithium (2.50 M in hexane, 3.54 mL,
8.85 mmol, 6.00 equiv) was added to a solution of diisopropylamine
(955 mg, 1.33 mL, 9.44 mmol, 6.40 equiv) in tetrahydrofuran (15 mL,
630 mM) at 78 °C. The resulting mixture was stirred for one hour at
78 °C. A solution of ketone rac-15a (304 mg, 1.47 mmol, 1.00 equiv) in
tetrahydrofuran (15 mL, 100 mM) was added dropwise to the freshly
prepared lithium diisopropylamide solution at 78 °C. After six hours,
DMPU (2.27 g, 2.14 mL, 17.7 mmol, 12.0 equiv) and iodomethane
(1.67 g, 735 L, 11.8 mmol, 8.00 equiv) were added in sequence, during
which a colorless precipitate was formed. The suspension was allowed to
slowly warm to room temperature over the course of 15 hours. The
brown reaction mixture was transferred to a silica-packed column, the
reaction vessel was rinsed with dichloromethane and the reaction mixture
was filtered with a solvent mixture (P/Et2O = 5/1). The product containing
fractions were combined and after removal of the solvent in vacuo, the
residue was purified by column chromatography (silica, P/Et2O = 10/1).
Ketone rac-17a (305 mg, 1.38 mmol, 94%, d.r. = 90/10) was obtained as
a colorless oil. Rf = 0.77 (pentane/Et2O 1:1) [CAM, KMnO4]; 1H NMR
Photocycloaddition Products 15a and 15b: Racemic: Following GP1,
enone rac-3 (273 mg, 1.32 mmol, 1.00 equiv) was irradiated in
dichloromethane (66 mL) for 14 hours. Different from GP6, the reaction
mixture was treated with triethylamine (1 mL) instead of basic alumina
and the solvent was removed in vacuo. The residue was purified by
column chromatography (silica, P/Et2O = 5/1). Starting material rac-3 as
well as the product mixture, which was submitted to ozonolysis, were
isolated. The ozonolysis was conducted at 78 °C in dichloromethane
(3 mL). Completion of the reaction was indicated by blue coloration
during ozon introduction. The blue color was removed by an argon
gasflow and dimethyl sulfide (1 mL) was added. Subsequently, the
mixture was warmed to room temperature, the solvent was removed in
vacuo and the residue was purified by column chromatography (silica,
P/Et2O = 5/1). After the work-up process, ketones rac-15a and rac-15b
(211 mg, 1.02 mmol, 77%, d.r. = 67/33, rac-15a/rac-15b) were obtained
as a colorless oil and starting material rac-3 (17.7 mg, 85.8 mol, 6%)
was recovered. Racemic with in the presence of aluminum bromide: In
analogy to GP2, enone rac-3 (41.3 mg, 200 mol, 1.00 equiv) was
irradiated in dichloromethane (10 mL) using aluminum bromide as
catalyst for 24 hours. After purification by column chromatography (silica,
P/Et2O = 6/1), ketones rac-15a and rac-15b (25.5 mg, 124 mol, 62%,
3
(500 MHz, CDCl3, 25°C, TMS): δ = 0.82 (d, J = 7.2 Hz, 3 H, Me-1), 1.01
(s, 3 H, Me-4), 1.09 (s, 3 H, Me-4), 1.09 (d, 3J = 7.1 Hz, 3 H, Me-6),
2
3
1.33 (virt. tdd, J ≈ 3J1 = 13.5 Hz, J2 = 11.9 Hz, 3J3 = 2.3 Hz, 1 H, HH-7),
1.49-1.56 (m, 1 H, HH-2), 1.56-1.64 (m, 1 H, HH-3), 1.70 (virt. tt,
2J ≈ 3J1 = 13.0 Hz, 3J2 ≈ 3J3 = 7.6 Hz, 1 H, HH-3), 1.76-1.83 (m, 1 H,
HH-8), 1.84-1.92 (m, 2 H, H-1, HH-7), 1.94 (d, 3J = 8.2 Hz, 1 H, H-3a),
2.01 (virt. tt, 2J ≈ 3J1 = 13.1 Hz, 3J2 ≈ 3J3 = 6.9 Hz, 1 H, HH-2), 2.07-2.15
(m, 2 H, H-6, HH-8), 2.19 ppm (s, 1 H, H-4a); 13C NMR (126 MHz, CDCl3,
27°C, TMS): δ = 16.5 (q, Me-6), 16.9 (q, Me-1), 24.9 (t, C-3), 25.5 (q,
Me-4), 27.9 (q, Me-4), 29.0 (t, C-8), 29.3 (t, C-7), 34.6 (t, C-2), 37.2 (s,
C-4), 39.9 (d, C-1), 45.8 (d, C-6), 48.7 (s, C-8a), 51.9 (d, C-3a), 57.9 (d,
C-4a), 216.5 ppm (s, C-5); The analytical data obtained matched those
reported in the literature.[42]
d.r. = 82/18, rac-15a/rac-15b) were obtained as
a colorless oil.
Enantioselective: Following GP2, enone rac-3 (41.3 mg, 200 mol,
1.00 equiv) was irradiated in dichloromethane (10 mL) using activated
catalyst 11AlBr3 for one hour. After purification by column
chromatography (silica, P/Et2O = 6/1), ketones 15a and 15b [5.30 mg,
25.7 mol, 13%, d.r. = 84/16, 15a (43% ee)/15b (21% ee)] were obtained
as a colorless oil and starting material ent-3 (29.l mg, 141 mol, 71%,
10% ee) was recovered. Separation of diastereoisomers: A mixture of
diastereomers rac-15a and rac-15b (500 mg) was separated by column
chromatography (silica, P/Et2O = 30/1) with
a conventional column
Ketone rac-17b: A solution of n-butyllithium (2.50 M in hexane, 1.51 mL,
3.76 mmol, 6.00 equiv) was added to a solution of diisopropylamine
(406 mg, 566 L, 4.01 mmol, 6.40 equiv) in tetrahydrofuran (6.27 mL,
640 mM) at 78 °C. The resulting mixture was stirred for one hour at
78 °C. A solution of ketone rac-15b (129 mg, 627 mol, 1.00 equiv) in
tetrahydrofuran (6.27 mL, 100 mM) was added dropwise to the freshly
prepared lithium diisopropylamide solution at 78 °C. After six hours,
DMPU (965 mg, 910 L, 7.53 mmol, 12.0 equiv) and iodomethane
(712 mg, 312 L, 5.02 mmol, 8.00 equiv) were added in sequence,
during which a colorless precipitate was formed. The suspension was
allowed to slowly warm to room temperature over the course of 15 hours.
The brown reaction mixture was transferred to a silica-packed column,
the reaction vessel was rinsed with dichloromethane and the reaction
mixture was filtered with a solvent mixture (P/Et2O = 5/1). The product
containing fractions were combined and after removal of the solvent in
vacuo, the residue was purified by column chromatography (silica,
(36 mm diameter, 300 mm length). The collected fractions were analyzed
by gas chromatography and were combined to six fractions [(content of
rac-15b)]: [F1 (≥99.5%)], [F2 (90<99.5%)], [F3 (10<90%)]; [(content of
rac-15a)]: [F4 (90<99%)], [F5 (99<99.5)], [F6 (≥99.5%)]. The fractions F3,
F4 and F5 were purified under the same conditions iteratively
(subsequently from F3 to F5) until F3 contained less than 15 mg of the
product mixture. Finally, F2, F3, F4, F5 were purified subsequently. 15a:
Rf = 0.66 (pentane/Et2O 1:1) [CAM, KMnO4]; 1H NMR (500 MHz, CDCl3,
25°C, TMS): δ = 0.84 (d, 3J = 7.2 Hz, 3 H, Me-1), 1.03 (s, 3 H, Me-4),
1.07 (s, 3 H, Me-4), 1.48-1.55 (m, 1 H, HH-2), 1.59-1.76 (m, 4 H, H-3,
HH-7, HH-8), 1.84-2.07 (m, 5 H, H-1, HH-2, H-3a, HH-7, HH-8),
2.15-2.25 (m, 2 H, H-4a, HH-6), 2.28-2.36 ppm (m, 1 H, HH-6); 13C NMR
(126 MHz, CDCl3, 27°C, TMS): δ = 16.7 (q, Me-1), 20.5 (t, C-7), 25.1 (t,
C-3), 25.7 (q, Me-4), 27.6 (q, Me-4), 29.0 (t, C-8), 34.7 (t, C-2), 37.0 (s,
C-4), 40.9 (t, C-6), 41.0 (d, C-1), 47.8 (s, C-8a), 51.6 (d, C-3a), 58.4 (d,
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
P/Et2O = 10/1). Ketone rac-17b (119 mg, 540 mol, 86%) was obtained
as a colorless oil. Rf = 0.77 (pentane/Et2O 1:1) [CAM, KMnO4]; 1H NMR
in tetrahydrofuran (1.02 mL, 1.00 M) was added dropwise to the enolate
solution, during which the solution turned deep brown. After five minutes,
the reaction mixture was allowed to warm to room temperature in the
course of 30 minutes. The brown reaction mixture was transferred to a
column packed with deactivated, neutral alumina*, the reaction vessel
was rinsed with dichloromethane and the reaction mixture was filtered
3
(500 MHz, CDCl3, 25°C, TMS): δ = 0.90 (d, J = 6.7 Hz, 3 H, Me-1), 1.00
(s, 3 H, Me-4), 1.07 (d, 3J = 7.0 Hz, 3 H, Me-6), 1.09 (s, 3 H, Me-4),
3
1.41 (virt. qd, 2J ≈ 3J1 ≈ 3J2 = 12.3 Hz, J3 = 7.0 Hz, 1 H, HH-2), 1.49-1.67
(m, 4 H, H-1, H-3, HH-7), 1.75 (virt. dt, 2J = 12.4 Hz, 3J1 ≈ 3J2 = 6.2 Hz,
1 H, HH-2), 1.89 (ddd, 2J = 13.7 Hz, 3J1 = 5.6 Hz, 3J2 = 3.5 Hz, 1 H,
HH-8), 1.94-2.07 (m, 3 H, H-3a, HH-7, HH-8), 2.16-2.26 (m, 1 H, H-6),
2.31 ppm (s, 1 H, H-4a); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 13.2 (q, Me-1), 15.8 (q, Me-6), 24.9 (q, Me-4), 26.3 (t, C-3), 27.8 (q,
Me-4), 30.4 (t, C-7), 33.7 (t, C-8), 35.7 (t, C-2), 36.7 (s, C-4), 45.1 (d,
C-6), 45.9 (d, C-1), 47.0 (s, C-8a), 51.8 (d, C-4a), 54.2 (d, C-3a),
215.6 ppm (s, C-5); The analytical data obtained matched those reported
in the literature.[42]
with
a solvent mixture (P/CH2Cl2 = 15/1). The product containing
fractions were combined and after removal of the solvent in vacuo, the
residue was purified by column chromatography (deactivated neutral
alumina, P/CH2Cl2 = 15/1) three consecutive times in order to remove
residual Comins reagent. Triflate rac-18b (63.8 mg, 181 mol, 80%) was
obtained as a colorless oil. [*Deactivation is described in the general
information.] Rf = 0.47 (pentane) [CAM, KMnO4]; 1H NMR (500 MHz,
C6D6, 25°C, TMS): δ = 0.85 (d, 3J = 5.6 Hz, 3 H, Me-1), 0.95 (s, 3 H,
Me-4), 0.97 (s, 3 H, Me-4), 1.26-1.36 (m, 4 H, HH-1, HH-2, HH-3,
HH-8), 1.40-1.52 (m, 2 H, HH-3, HH-8), 1.55-1.61 (m, 2 H, HH-2, H-3a),
1.62 (s, 3 H, Me-6), 1.72 (virt. dt, 2J = 16.7 Hz, 3J1 ≈ 3J2 = 6.1 Hz, 1 H,
HH-7), 1.90 (virt. dt, 2J = 16.7 Hz, 3J1 ≈ 3J2 = 6.7 Hz, 1 H, HH-7),
2.49 ppm (br s, 1 H, H-4a); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 13.0 (q, Me-1), 17.2 (q, Me-6), 23.9 (q, Me-4), 26.5 (t, C-3), 26.7 (q,
Me-4), 30.5 (t, C-7), 31.0 (t, C-8), 35.7 (t, C-2), 35.8 (s, C-4), 43.2 (d,
C-4a), 44.6 (d, C-1), 48.1 (s, C-8a), 52.8 (d, C-3a), 119.1 (qs,
1JCF = 320 Hz, CF3), 128.6 (s, C-6)*, 145.5 ppm (s, C-5) [*The 13C signal
of C-6 overlaps with the solvent signal of C6D6. However, the signal can
be located with the help of a HMBC crosspeak with the proton signal of
Me-6 to assign the 13C signal of C-6.]; 19F NMR (376 MHz, C6D6, 25°C,
TMS): δ = 75.4 (s, 3 F, CF3); IR (ATR): ṽ = 2953 (m, sp3-CH), 2870 (m,
sp3-CH), 1410 (s, SO), 1201 (vs, sp3-CF), 1141 (vs, sp3-CF), 898 cm1
(vs, SO); MS (EI, 70 eV): m/z (%): 352 (51) [M]+, 308 (14), 281 (74), 266
(100), 252 (14), 220 (17), 205 (68), 187 (64), 159 (56), 145 (73), 109 (39),
82 (55), 55 (42) [C4H7]+; HRMS (EI, 70 eV): calcd for C16H23O3F332S [M]+:
352.1315; found: 352.1310; calcd for C1513CH23O3F332S [M]+: 353.1348;
found: 353.1344.
Triflate rac-18a: A solution of n-butyllithium (2.50 M in hexane, 363 L,
908 mol, 4.00 equiv) was added to a solution of diisopropylamine
(96.4 mg, 135 L, 953 mol, 4.20 equiv) in tetrahydrofuran (2.27 mL,
420 mM) at 78 °C. The resulting mixture was stirred for 30 minutes. A
solution of ketone rac-17a (50.0 mg, 227 mol, 1.00 equiv) in
tetrahydrofuran (2.27 mL, 100 mM) was added dropwise to the freshly
prepared lithium diisopropylamide solution at 78 °C. After seven and a
half hours, a solution of Comins reagent (401 mg, 1.02 mmol, 4.50 equiv)
in tetrahydrofuran (1.02 mL, 1.00 M) was added dropwise to the enolate
solution, during which the solution turned deep brown. After five minutes,
the reaction mixture was allowed to warm to room temperature in the
course of 30 minutes. The brown reaction mixture was transferred to a
column packed with deactivated, neutral alumina*, the reaction vessel
was rinsed with dichloromethane and the reaction mixture was filtered
with
a solvent mixture (P/CH2Cl2 = 15/1). The product containing
fractions were combined and after removal of the solvent in vacuo, the
residue was purified by column chromatography (deactivated neutral
alumina, P/CH2Cl2 = 15/1) three consecutive times in order to remove
residual Comins reagent. Triflate rac-18a (59.8 mg, 170 mol, 75%) was
obtained as a colorless oil. [*Deactivation is described in the general
information.] Rf = 0.47 (pentane) [CAM, KMnO4]; 1H NMR (500 MHz,
C6D6, 25°C, TMS): δ = 0.58 (d, 3J = 7.2 Hz, 3 H, Me-1), 1.00 (s, 3 H,
Me-4), 1.04 (s, 3 H, Me-4), 1.24-1.39 (m, 2 H, HH-2, HH-8), 1.41-1.51
(m, 3 H, H-3, HH-8), 1.51-1.74 (m, 7 H, H-1, H-3a, Me-6, H-7), 1.85
(virt. dtd, 2J = 13.3 Hz, 3J1 ≈ 3J2 = 9.5 Hz, 3J3 = 6.7 Hz, 1 H, HH-2),
2.39 ppm (br s, 1 H, H-4a); 13C NMR (126 MHz, CDCl3, 27°C, TMS):
δ = 15.9 (q, Me-1), 17.3 (q, Me-6), 24.8 (t, C-3), 24.9 (q, Me-4), 26.8 (q,
Me-4), 26.8 (t, C-8), 29.5 (t, C-7), 34.9 (t, C-2), 35.6 (s, C-4), 40.6 (d,
C-1), 48.7 (s, C-8a), 49.4 (d, C-4a), 51.1 (d, C-3a), 119.1 (qs,
1JCF = 320 Hz, CF3), 128.5 (s, C-6)*, 145.2 ppm (s, C-5) [*The 13C signal
of C-6 overlaps with the solvent signal of C6D6. However, the signal can
be located with the help of a HMBC crosspeak with the proton signal of
Me-6 to assign the 13C signal of C-6.]; 19F NMR (376 MHz, C6D6, 25°C,
TMS): δ = 75.4 (s, 3 F, CF3); IR (ATR): ṽ = 2953 (m, sp3-CH), 2870 (m,
sp3-CH), 1410 (s, SO), 1201 (vs, sp3-CF), 1141 (vs, sp3-CF), 898 cm1
(vs, SO); MS (EI, 70 eV): m/z (%): 352 (51) [M]+, 308 (14), 281 (74), 266
(100), 252 (14), 220 (17), 205 (68), 187 (64), 159 (56), 145 (73), 109 (39),
82 (55), 55 (42) [C4H7]+; HRMS (EI, 70 eV): calcd for C16H23O3F332S [M]+:
352.1315; found: 352.1310; calcd for C1513CH23O3F332S [M]+: 353.1348;
found: 353.1344.
Italicene (rac-19a): Palladium(II) acetate (3.91 mg, 17.0 mol,
10.0 mol%) was added to
a solution of triflate rac-18a (59.8 mg,
170 mol, 1.00 equiv), triphenylphosphine (13.4 mg, 50.9 mol,
30.0 mol%) and lithium formate monohydrate (59.4 mg, 848 mol,
5.00 equiv) in dimethylformamide (3.39 mL, 50.0 mM). The resulting
mixture was heated to 60 °C. The reaction mixture turned black in seven
minutes. After stirring for 20 minutes, the reaction mixture was allowed to
cool to room temperature. The suspension was transferred to a column
packed with deactivated, neutral alumina*, the reaction vessel was rinsed
with dichloromethane and the reaction mixture was filtered with pentane.
The product containing fractions were combined and after removal of the
solvent in vacuo, the residue was purified by column chromatography
(deactivated neutral alumina, pentane) three consecutive times to
remove residual triphenylphosphine. In order to remove pentane
completely without loosing too much of the volatile product rac-19a, the
vessel was evacuated at room temperature to 100 mbar and loaded with
air in sequence five times. The title compound rac-19a (31.5 mg,
154 mol, 91%) was obtained as a colorless oil. [*Deactivation is
described in the general information.] Rf = 0.71 (pentane) [CAM, KMnO4];
1H NMR (500 MHz, CDCl3, 25°C, TMS): δ = 0.78 (d, 3J = 7.2 Hz, 3 H,
Me-1), 0.91 (s, 3 H, Me-4), 0.96 (s, 3 H, Me-4), 1.46 (dd, 2J = 12.4 Hz,
3J = 6.9 Hz, 1 H, HH-2), 1.53-1.59 (m, 1 H, HH-3), 1.60-1.69 (m, 2 H,
HH-3, HH-8), 1.69-1.76 (m, 5 H, H-1, H-3a, Me-6), 1.76-1.81 (m, 2 H,
H-7), 1.84 (virt. dt, 2J = 12.8 Hz, 3J1 ≈ 3J2 = 3.5 Hz, 1 H, HH-8), 1.88 (br s,
1 H, H-4a), 2.02 (virt. tt, 2J ≈ 3J1 = 12.3 Hz, 3J2 ≈ 3J3 = 7.0 Hz, 1 H,
HH-2), 5.30-5.34 ppm (m, 1 H, H-5); 13C NMR (126 MHz, CDCl3, 27°C,
TMS): δ = 16.6 (q, Me-1), 24.5 (q, Me-6), 24.9 (t, C-3), 24.9 (q, Me-4),
27.2 (q, Me-4), 27.8 (t, C-7), 28.1 (t, C-8), 34.8 (s, C-4), 35.0 (t, C-2),
39.7 (d, C-1), 45.4 (s, C-8a), 48.0 (d, C-4a), 51.5 (d, C-3a), 121.1 (d, C-5),
Triflate rac-18b: A solution of n-butyllithium (2.50 M in hexane, 363 L,
908 mol, 4.00 equiv) was added to a solution of diisopropylamine
(96.4 mg, 135 L, 953 mol, 4.20 equiv) in tetrahydrofuran (2.27 mL,
420 mM) at 78 °C. The resulting mixture was stirred for 40 minutes. A
solution of ketone rac-17b (50.0 mg, 227 mol, 1.00 equiv) in
tetrahydrofuran (2.27 mL, 100 mM) was added dropwise to the freshly
prepared lithium diisopropylamide solution at 78 °C. After eight and a
half hours, a solution of Comins reagent (401 mg, 1.02 mmol, 4.50 equiv)
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
136.2 ppm (s, C-6); The analytical data obtained matched those reported
in the literature.[39]
[3]
a) O. Schalk, M. S. Schuurman, G. Wu, P. Lang, M. Mucke, R. Feifel, A.
Stolow, J. Phys. Chem. A 2014, 118, 2279-2287. b) E. Riedle, M.
Bradler, M. Wenninger, C. F. Sailer, I. Pugliesi, Faraday Discuss. 2013,
163, 139-158.
Isoitalicene (rac-19b): Palladium(II) acetate (4.06 mg, 18.1 mol,
[4]
[5]
D. I. Schuster, in CRC Handbook of Photochemistry and Photobiology
(Eds.: W. M. Horspool, F. Lenci), CRC Press, Boca Raton, 2004, pp.
72/1-72/24.
10.0 mol%) was added to
a solution of triflate rac-18b (63.8 mg,
181 mol, 1.00 equiv), triphenylphosphine (14.3 mg, 54.3 mol,
30.0 mol%) and lithium formate monohydrate (63.3 mg, 905 mol,
5.00 equiv) in dimethylformamide (3.62 mL, 50.0 mM). The resulting
mixture was heated to 60 °C. The reaction mixture turned black in ten
minutes. After stirring for 20 minutes, the reaction mixture was allowed to
cool to room temperature. The suspension was transferred to a column
packed with deactivated, neutral alumina*, the reaction vessel was rinsed
with dichloromethane and the reaction mixture was filtered with pentane.
The product containing fractions were combined and after removal of the
solvent in vacuo, the residue was purified by column chromatography
(deactivated neutral alumina, pentane) three consecutive times to
remove residual triphenylphosphine. In order to remove pentane
completely and avoid any loss of the volatile product rac-19b, the vessel
was evacuated at room temperature to 100 mbar and loaded with air in
sequence five times. The title compound rac-19b (35.8 mg, 175 mol,
97%) was obtained as a colorless oil. [*Deactivation is described in the
general information.] Rf = 0.71 (pentane) [CAM, KMnO4]; 1H NMR
D. J. Maradyn, A. C. Weedon, J. Am. Chem. Soc. 1995, 117, 5359-
5360.
[6]
[7]
G. Ciamician, P. Silber, Ber. Dtsch. Chem. Ges. 1908, 41, 1928-1935.
a) E. Sernagiotto, Gazz. Chim. Ital. 1917, 47, 153-159. b) E.
Sernagiotto, Gazz. Chim. Ital. 1918, 48, 52-61.
[8]
[9]
G. Büchi, I. M. Goldman, J. Am. Chem. Soc. 1957, 79, 4741-4748.
J. Meinwald, R. A. Schneider, J. Am. Chem. Soc. 1965, 87, 5218-5229.
[10] a) L. M. Tolbert, M. B. Ali, J. Am. Chem. Soc. 1982, 104, 1742-1744. b)
G. L. Lange, C. Decicco, S. L. Tan, G. Chamberlain, Tetrahedron Lett.
1985, 26, 4707-4710. c) H. Herzog, H. Koch, H.-D. Scharf, A. J.
Runsink, Tetrahedron 1986, 42, 3547-3558. d) Y. Inoue, Chem. Rev.
1992, 92, 741-770. e) C. Chen, V. Chang, X. Cai, E. Duesler, P. S.
Mariano, J. Am. Chem. Soc. 2001, 123, 6433-6434. f) S. Faure, S.
Piva-Le-Blanc, C. Bertrand, J.-P. Pete, R. Faure, O. Piva, J. Org. Chem.
2002, 67, 1061-1070. g) I. Inhülsen, N. Akiyama, K. Tsutsumi, Y.
Nishiyama, K. Kakiuchi, Tetrahedron 2013, 69, 782-790.
3
(500 MHz, CDCl3, 25°C, TMS): δ = 0.82 (d, J = 6.3 Hz, 3 H, Me-1), 0.90
[11] a) R. Brimioulle, T. Bach, Science 2013, 342, 840-843. b) R. Brimioulle,
A. Bauer, T. Bach, J. Am. Chem. Soc. 2015, 137, 5170-5176.
[12] For recent reviews covering enantioselective [2+2] photocycloaddition
reactions, see: a) Y. Xu, M. L. Conner, M. K. Brown, Angew. Chem. Int.
Ed. 2015, 54, 11918-11928; Angew. Chem. 2015, 127, 12086-12097.
b) R. Brimioulle, D. Lenhart, M. M. Maturi, T. Bach, Angew. Chem. Int.
Ed. 2015, 54, 3872-3890; Angew. Chem. 2015, 127, 3944-3963.
[13] For alternative approaches towards enantioselective intramolecular
[2+2] photocycloaddition reactions, see: a) C. Müller, A. Bauer, T. Bach,
Angew. Chem. Int. Ed. 2009, 48, 6640-6642; Angew. Chem. 2009, 121,
6767-6769. b) C. Müller, A. Bauer, M. M. Maturi, M. C. Cuquerella, M. A.
Miranda, T. Bach, J. Am. Chem. Soc. 2011, 133, 16689-16697. c) J. Du,
K. L. Skubi, D. M. Schultz, T. P. Yoon, Science 2014, 344, 392-396. d)
N. Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi, J. Sivaguru,
Angew. Chem. Int. Ed. 2014, 53, 5604-5608; Angew. Chem. 2014, 126,
5710-5714. e) K. L. Skubi, J. B. Kidd, H. Jung, I. A. Guzei, M.-H. Baik,
T. P. Yoon, J. Am. Chem. Soc. 2017, 139, 17186-17192.
(s, 3 H, Me-4), 0.91 (s, 3 H, Me-4), 1.39-1.67 (m, 5 H, H-1, HH-2, H-3,
HH-8), 1.68-1.77 (m, 5 H, HH-2, H-3a, Me-6), 1.82 (ddd, 2J = 14.9 Hz,
3J1 = 9.5 Hz, 3J2 = 5.5 Hz, 1 H, HH-8), 1.90 (virt. dt, 2J = 16.5 Hz,
3J1 ≈ 3J2 = 5.8 Hz, 1 H, HH-7), 1.94-2.02 (m, 2 H, H-4a, HH-7), 5.36-5.40
(m, 1 H, H-5); 13C NMR (126 MHz, CDCl3, 27°C, TMS): δ = 13.5 (q,
Me-1), 24.1 (q, Me-4), 24.5 (q, Me-6), 26.5 (t, C-3), 27.2 (q, Me-4),
28.6 (t, C-7), 33.1 (t, C-8), 35.2 (s, C-4), 36.3 (t, C-2), 41.0 (d, C-4a), 43.9
(s, C-8a), 45.0 (d, C-1), 53.6 (d, C-3a), 121.8 (d, C-5), 135.7 (s, C-6); The
analytical data obtained matched those reported in the literature.[39]
Acknowledgements
Financial support by the European Research Council under the
European Union’s Horizon 2020 research and innovation
programme (grant agreement No 665951 – ELICOS) and by the
Fonds der Chemischen Industrie (Liebig fellowship to G. S.) is
gratefully acknowledged. We thank O. Ackermann and J.
Kudermann for their help with the HPLC and GLC analyses. Dr.
C. Brenninger is acknowledged for his help in the preparation
and characterization of products cis-5k and trans-5k. The
authors gratefully acknowledge the computing and data
resources provided by the Leibniz Supercomputing Centre
(www.lrz.de).
[14] P. Guerry, P. Blanco, H. Brodbeck, O. Pasteris, R. Neier, Helv. Chim.
Acta 1991, 74, 163-178.
[15] C. Brenninger, J. D. Jolliffe, T. Bach, Angew. Chem. Int. Ed. 2018, 57,
14338-14349; Angew. Chem. 2018, 130, 14536-14547.
[16] R. Brimioulle, T. Bach, Angew. Chem. Int. Ed. 2014, 53, 12921-12924;
Angew. Chem. 2014, 126, 13135-13138.
[17] S. Poplata, T. Bach, J. Am. Chem. Soc. 2018, 140, 3228-3231.
[18] Review: E. J. Corey, Angew. Chem. Int. Ed. 2009, 48, 2100-2117;
Angew. Chem. 2009, 121, 2134-2151.
[19] W. L. Dilling, Chem. Rev. 1966, 66, 373-393.
[20] J. Mattay, A. Banning, E. W. Bischof, A. Heidbreder, J. Runsink, Chem.
Ber. 1992, 125, 2119-2127.
Keywords: cycloaddition • enantioselectivity • Lewis acids •
photochemistry • total synthesis
[21] a) T. Tsunoda, M. Suzuki, R. Noyori, Tetrahedron Lett. 1980, 21, 1357-
1358. b) R. Noyori, S. Murata, M. Suzuki, Tetrahedron 1981, 37, 3899-
3910.
[1]
[2]
Reviews covering intramolecular [2+2] photocycloaddition reactions: a)
D. Becker, N. Haddad, Org. Photochem. 1989, 10, 1-162. b) P.
Margaretha, in Synthetic Organic Photochemistry, Molecular and
Supramolecular Photochemistry, Vol. 12 (Eds.: A. G. Griesbeck, J.
Mattay), Dekker, New York, 2005, pp. 211-237. c) S. Poplata, A.
Tröster, Y.-Q. Zou, T. Bach, Chem. Rev. 2016, 116, 9748-9815.
Reviews: a) J. Iriondo-Alberdi, M. F. Greaney, Eur. J. Org. Chem. 2007,
4801-4815. b) N. Hoffmann, Chem. Rev. 2008, 108, 1052-1103. c) T.
Bach, J. P. Hehn, Angew. Chem. Int. Ed. 2011, 50, 1000-1045; Angew.
Chem. 2011, 123, 1032-1077.
[22] For the reaction set-up, see ref.[17]
.
[23] C. Sparr, E.-M. Tanzer, J. Bachmann, R. Gilmour, Synthesis 2010,
1394-1397.
[24] a) K. Mahender Reddy, E. Bhimireddy, B. Thirupathi, S. Breitler, S. Yu,
E. J. Corey, J. Am. Chem. Soc. 2016, 138, 2443-2453. b) R. Brimioulle,
H. Guo, T. Bach, Chem. Eur. J. 2012, 18, 7552-7560. c) M. L. Conner,
Y. Xu, M. K. Brown, J. Am. Chem. Soc. 2015, 137, 3482-3485.
[25] a) J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512-519. b) T.
R. Hoye, C. S. Jeffrey, F. Shao, Nat. Protoc. 2007, 2, 2451-2458.
[26] S. F. Pellicori, Appl. Opt. 1964, 3, 361-366.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
[27] a) D. H. Ryu, T. W. Lee, E. J. Corey, J. Am. Chem. Soc. 2002, 124,
9992-9993. b) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2003, 125,
6388-6390. c) J. M. Wiest, M. L. Conner, M. K. Brown, J. Am. Chem.
Soc. 2018, 140, 15943-15949.
[36] a) D. Becker, M. Nagler, Y. Sahali, N. Haddad, J. Org. Chem. 1991, 56,
4537-4543. b) R. Gleiter, E. Fischer, Chem. Ber. 1992, 125, 1899-1911.
[37] H. Wang, X. Cao, X. Chen, W. Fang, M. Dolg, Angew. Chem. Int. Ed.
2015, 54, 14295-14298; Angew. Chem. 2015, 127, 14503-14506..
[38] Lifetimes of 1,4-diradicals are in the range of 10-100 ns which appears
to be a tentative lower limit for the association of enone intermediates
to the Lewis acid: a) D. Becker, N. Haddad, Y. Sahali, Tetrahedron Lett.
1989, 30, 2661-2664. b) A. Rudolph, A. C. Weedon, Can. J. Chem.
1990, 68, 1590-1597. c) N. A. Kaprinidis, G. Lem, S. H. Courtney, D. I.
Schuster, J. Am. Chem. Soc. 1993, 115, 3324-3325.
[28] a) M. N. Paddon-Row, C. D. Anderson, K. N. Houk, J. Org. Chem. 2009,
74, 861-868. b) K. Sakata, H. Fujimoto, J. Org. Chem. 2013, 78, 3095-
3103.
[29] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H.
Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko,
R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov,
J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J.
Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G.
Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E.
Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N.
Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M.
Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R.
L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J. Fox,
Gaussian 16, Revision B.01, Gaussian, Inc., Wallingford CT, 2016.
[30] a) P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys.
Chem. 1994, 98, 11623-11627. b) A. D. Becke, J. Chem. Phys. 1993,
98, 5648-5652. c) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37,
785-789. d) S. Grimme, S. Ehrlich, L. Goerigk, J. Comp. Chem. 2011,
32, 1456-1465.
[39] J. Leimner, H. Marschall, N. Meier, P. Weyerstahl, Chem. Lett. 1984,
13, 1769-1772.
[40] a) M. Ihara, M. Ohnishi, M. Takano, K. Makita, N. Taniguchi, K.
Fukumoto, J. Am. Chem. Soc. 1992, 114, 4408-4410. b) M. Ihara, T.
Taniguchi, K. Makita, M. Takano, M. Ohnishi, N. Taniguchi, K.
Fukumoto, C. Kabuto, J. Am. Chem. Soc. 1993, 115, 8107-8115. c) P.
Weyerstahl, H. Marschall, C. Christiansen, I. Seelmann, Liebigs Ann.
1996, 1641-1644. d) Y. Harada, S. Maki, H. Niwa, T. Hirano, S.
Yamamura, Synlett 1998, 1313-1314. e) S. Faure, O. Piva, Tetrahedron
Lett. 2001, 42, 255-259.
[41] T. Honda, K. Ueda, M. Tsubuki, T. Toya, A. Kurozumi, J. Chem. Soc.,
Perkin Trans. 1 1991, 1749-1754.
[42] T. R. Hoye, S. J. Martin, D. R. Peck, J. Org. Chem. 1982, 47, 331-337.
[43] a) A. M. Birch, G. Pattenden, J. Chem. Soc., Chem. Commun. 1980,
1195-1197. b) W. Oppolzer, F. Zutterman, K. Bättig, Helv. Chim. Acta
1983, 66, 522-533.
[44] D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299-6302.
[45] Lithium formate was used as reducing agent in order to avoid partial
decomposition of triflates rac-18a and rac-18b which was observed
when using formic acid/trialkylamine salts as reducing agents: S.
Cacchi, E. Morera, G. Ortar, Tetrahedron Lett. 1984, 25, 4821-4824.
[46] A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006-3019.
[47] C. Brenninger, A. Pöthig, T. Bach, Angew. Chem. Int. Ed. 2017, 56,
4337-4341; Angew. Chem. 2017, 129, 4401-4405.
[31] R. A. Kendall, T. H. Dunning, R. J. Harrison, J. Phys. Chem. 1992, 96,
6796-6806.
[32] R. S. Paton, Org. Biomol. Chem. 2014, 12, 1717-1720.
[33] M. N. Paddon-Row, L. C. H. Kwan, A. C. Willis, M. S. Sherburn, Angew.
Chem. Int. Ed. 2008, 47, 7013-7017; Angew. Chem. 2008, 120, 7121-
7125.
[34] This coordination pattern of the enone substrate was observed to occur
concomitant to energetically favoring pyrrolidine ring inversion.
[35] a) M. A. El-Sayed, Acc. Chem. Res. 1968, 1, 8-16. b) P. Klán, J. Wirz,
Photochemistry of Organic Compounds; Wiley, Chichester, 2009, pp.
38-39.
[48] A. R. Matlin, C. F. George, S. Wolff, W. C. Agosta, J. Am. Chem. Soc.
1986, 108, 3385-3394.
[49] F. M. Hörmann, T. S. Chung, E. Rodriguez, M. Jakob, T. Bach, Angew.
Chem. Int. Ed. 2018, 57, 827-831; Angew. Chem. 2018, 130, 835-839.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901304
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Saner Poplata, Andreas Bauer, Golo
Storch and Thorsten Bach*
Page No. – Page No.
Intramolecular [2+2]
Photocycloaddition of Cyclic Enones:
Selectivity Control by Lewis Acids
and Mechanistic Implications
Lewis acids and [2+2] photocycloaddition: The intramolecular reaction to pro-
ducts such as 1 was promoted enantioselectively (76-96% ee) by a chiral oxaza-
borolidine Lewis acid. Its mode of action was studied by DFT calculations and an
achiral Lewis acid (AlBr3) was essential for a concise synthesis of italicene (2).
This article is protected by copyright. All rights reserved.