Stereoselective synthesis of cyclopropanes based on a 1,2-chirality transfer

Article abstract of DOI:10.1002/chem.200801002

A stereoselective route to enantiomerically enriched bicyclic cyclopropane derivatives 13 is described which is based on a conceptually novel 1,2-chirality transfer approach. The hyperconjugative interaction of an electronically excited carbonyl group with the σ* orbital of an adjacent C-X bond in the transition state of a hydrogen abstraction causes the preference of a certain conformation and consequently the differentiation between two diastereotopic methylene groups. The 1,2-chirality transfer is completed by a subsequent HX elimination which destroys the only stereogenic center in the reactants 12. Furthermore, it was found that contrary enthalpic and entropic influences result in the existence of an inversion temperature T₀. Upon crossing T₀ the stereoselectivity is reversed. Considering this temperature dependency, chirality transfer efficiencies of up to 83% could be achieved. The absolute configuration of most products could be unambiguously determined by VCD spectroscopy combined with DFT calculations.

Full text of DOI:10.1002/chem.200801002

FULL PAPER
DOI: 10.1002/chem.200801002
Stereoselective Synthesis of Cyclopropanes Based on a 1,2-Chirality Transfer
Olaf Muehling[a, b] and Pablo Wessig*[a]
Dedicated to Prof. Hans-Georg Henning in occasion of his 80th birthday
Abstract: A stereoselective route to
enantiomerically enriched bicyclic cy-
clopropane derivatives 13 is described
which is based on a conceptually novel
1,2-chirality transfer approach. The hy-
perconjugative interaction of an elec-
tronically excited carbonyl group with
quently the differentiation between
two diastereotopic methylene groups.
The 1,2-chirality transfer is completed
by a subsequent HX elimination which
destroys the only stereogenic center in
the reactants 12. Furthermore, it was
found that contrary enthalpic and en-
tropic influences result in the existence
of an inversion temperature T0. Upon
crossing T0 the stereoselectivity is re-
versed. Considering this temperature
dependency, chirality transfer efficien-
cies of up to 83% could be achieved.
The absolute configuration of most
products could be unambiguously de-
termined by VCD spectroscopy com-
bined with DFTcalculations.
ꢀ
the s* orbital of an adjacent C X
Keywords: asymmetric synthesis ·
chirality transfer · cyclopropanes ·
photochemistry · spin center shift
bond in the transition state of a hydro-
gen abstraction causes the preference
of a certain conformation and conse-
Introduction
memory effect”.[2] This term was introduced in 1991 by
Fuji[3] and describes the conservation of the chiral informa-
tion in the course of a reaction where a chiral sp3 center is
transformed into a new sp3 center via an achiral sp2 center
in the absence of an additional permanent chiral moiety.
In cyclization reactions between two sp3 carbon centers the
stereoselectivity of the ring closure is of particular interest
because up to two new stereogenic centers can be generat-
ed. In contrast to intermolecular coupling reactions, two
principles of diastereoselectivities can be distinguished:[1]
The non-induced “simple” diastereoselectivity is associated
with the relative arrangement of the two newly formed ste-
reogenic centers. In the case of facial diastereoselectivity the
main focus is on the relative configuration between a newly
formed stereogenic center and an “old” chiral moiety local-
ized in the substrate and controlling the stereoselectivity of
the ring closure (asymmetric induction via substrate or aux-
iliary control).
The Norrish–Yang cyclization,[4,5] an intramolecular C C
ꢀ
bond forming reaction, which results from intramolecular
hydrogen abstraction by a photoexcited carbonyl compound,
is an useful preparative tool to synthesize different homo-
and heterocyclic compounds. Many diastereoselective exam-
ples of this photocyclization reaction are known, which can
be classified according to the principles above men-
tioned.[6–9] Enantioselective variants of the Norrish–Yang
cyclization have been successfully performed in the solid
state,[10] but until quite recently no significant enantioselec-
tivities (>10% ee) have been recorded for a Norrish–Yang
cyclization in solution. No more than seven years ago, Bach
and co-workers achieved an essential breakthrough by using
chiral complexing agents capable of binding the prostereo-
genic Norrish–Yang substrate through hydrogen bonds.[11]
Based on the Norrish–Yang reaction, we developed the
concept of spin center shift[12] which allows a completely
new access to cyclopropanes.[13,14] In contrast to the classical
Norrish–Yang reaction, phenyl alkyl ketones 1 with a suita-
ble leaving group X in a-position (e.g. X=ꢀOSO2R) are
used. At the stage of triplet 1,4-diradicals 2 the b-elimina-
tion of HX occurs faster than the “classical” Norrish–Yang
reaction pathways (type II cleavage, cyclization). The result-
A novel strategy for asymmetric synthesis is based on a
phenomenon called “memory of chirality” or “chiral
[a] Dr. O. Muehling, Priv-Doz. Dr. P. Wessig
Institut für Chemie, Humboldt-Universität zu Berlin
Brook-Taylor-Str. 2, 12489 Berlin (Germany)
Fax : (+49)302093-7455
E-mail: pablo.wessig@chemie.hu-berlin.de
[b] Dr. O. Muehling
Current address:
Fraunhofer Institute of Applied Polymer Science (IAP)
Volmerstr. 7B, 12489 Berlin (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801002.
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ing oxoallyl 1,3-diradicals 3 cyclize with often complete dia-
stereoselectivity and good to excellent yields to give cyclo-
propanes 4 (Scheme 1).
Figure 1. Axial vs equatorial arrangement of the leaving group X.
straction (TS-A and TS-B) which differ in the arrangement
of the leaving group X (axial or equatorial). Based on quan-
tum chemical calculations,[13b] TS-A with X in the axial posi-
tion should be favored over TS-B. In TS-A the g1-methylene
group is attacked, whereas in TS-B the attack takes place at
the g2-methylene group. In other words, the carbonyl oxygen
atom has to distinguish between the two diastereotopic
methylene groups. During the photochemically induced hy-
drogen transfer and the following elimination of HX the en-
antiomeric diradicals DR-A and DR-B are formed, and the
chiral information of the a-C atom has been transferred to
the adjacent prostereogenic b-C atom (1,2-chirality trans-
fer). Consequently, after cyclization the enantiomeric cyclo-
propyl ketones (R)-6 and (S)-6 are obtained. For given rea-
sons the formation of (R)-6 should be favored over (S)-6.
Thus, during such a process a desymmetrization regarding to
the methylene groups (g1 and g2) takes place.
Scheme 1. Photochemical synthesis of cyclopropanes 4.
Herein, we report about an entirely new concept concern-
ing the synthesis of enantiomerically enriched cyclopropanes
based on a photochemically induced intramolecular 1,2-chir-
ality transfer.[15] In the case of an asymmetric induction the
chiral information is copied from a stereogenic to a proster-
eogenic moiety, that is, the chiral information is located
both at source and destination. During a chirality transfer
the prostereogenic moiety incorporates the chiral informa-
tion of a stereogenic moiety which simultaneously loses this
information. A distinguishing feature in the intramolecular
transfer of central chirality is the distance between the
source and the target of the chiral information (1,n-chirality
transfer). The term “chirality transfer” or “transfer of chiral-
ity” is mainly associated with stereoselective reactions
where the substrate loses a stereogenic center during the mi-
gration of one or more adjacent double bonds while a new
stereogenic center arises elsewhere in the molecule.[16] In
this context, concerted sigmatropic rearrangements are of
great interest because their mostly highly ordered transition
states assure an efficient generation of new stereogenic cen-
ters.[17] Consequently, relatively many examples of 1,3-chiral-
ity transfer exist but only a few examples of 1,2-chirality
transfer.[18]
Scheme 2. The concept of 1,2-chirality transfer in the synthesis of cyclo-
propanes (simplified representation). [a] The configuration corresponds
to C-b.
Results and Discussion
The concept shown in Scheme 2 should be applicable to
all enantiopure ketones of type 5 carrying two identical sub-
stituents in b-position. It can be expected that bridging be-
tween the substituents R, in other words a conformational
constraint in flexibility, creates the best situation for an effi-
cient 1,2-chirality transfer. Therefore, we chose systems in
which the atoms b, g1, and g2 (Scheme 2) are part of a five-
or six-membered ring.
The concept—A simple selectivity model: By extensive
quantum chemical calculations we could elucidate details of
the mechanism and found that the leaving group X already
has a significant impact on the first reaction step, the photo-
chemical hydrogen shift (1 ! 2, Scheme 1).[13] Due to hyper-
ꢀ
conjugation between the s* orbital of the C X bond and
the p system of the excited carbonyl group, X prefers a
pseudoaxial arrangement with respect to the approximately
chair-like six-membered transition state (Figure 1).[13b]
If we consider enantiopure ketones of type 5 (e.g. (R)-5)
with two identical substituents in b-position (Scheme 2), we
can formulate two different transition states for the g-H ab-
Synthesis of the enantiopure photochemical precursors: T o
verify the concept shown in Scheme 2 we first of all needed
an efficient method for the synthesis of enantiopure precur-
sors of type 5. As sulfonates were found to be suitable leav-
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Chem. Eur. J. 2008, 14, 7951 – 7960

Stereoselective Synthesis of Cyclopropanes
FULL PAPER
ing groups (X = -OSO2R),[13] a retrosynthetic analysis of 5
led to 2-hydroxy ketones. Various methods for the synthesis
of enantiomerically enriched 2-hydroxy ketones are known.
Oxidative methods starting from the ketones or their enol
ethers are the most common.[19] Based on the results of
Sharpless et al.[20] and Kirschning et al.,[21] we developed a
very efficient sequence for the synthesis of enantiomerically
enriched 2-hydroxy ketones (Scheme 3). This four-step syn-
Table 1. Synthesis of the enantiopure photo precursors (R)-12.
Alcohol
R
Yield [%][c] Yield [%] Yield [%]
10
(R)-11
(R)-12
(E/Z)[d]
(ee [%])[e]
7a
7b
7c
7d
7e
7 f
-CH2-CH
-CH2-CH
C
81
(95)
86
(55)
92
(91)
87
(99)
91
(93)
98
87
87
84
81
87
82
G
-CH2-O-CH2-
-CH2-N(Ts)-CH2-
-CH2-N
-C6H4-
A
(97)
[a] The tBu substituent is trans with respect to C-b. [b] The tBu substitu-
ent is cis with respect to C-b. [c] Yield over two steps (7 ! 8 ! 10).
[d] The E/Z ratio was determined by 1H NMR. [e] The enantiomeric
excess (ee) was determined by HPLC (Chiralcel-OD, Chiralpak-AD-H).
Scheme 3. Synthesis of the enantiopure precursors (R)-12. a) Dess–
Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-
N
one) (7a–c,e,f) or pyridinium chlorochromate (PCC) (7d), dichlorome-
thane, 08C ! room temperature (RT). b) THF, ꢀ788C, nBuLi, + 9, 16–
24 h at RT. c) tBuOH/H2O 1:1, AD-Mix-b, MsNH2, 6–24 h at RT. d)
Ts2O, pyridine, cat. dimethylamino pyridine (DMAP), 0.5–6 h at RT.
Table 2. Results of irradiation at 258C.
thesis started with alcohols 7 which were easily accessible
from the corresponding carboxylic acids.[13b] Dess–Martin
oxidation[22] or PCC oxidation[23] to aldehydes 8 and subse-
quent Horner–Wadsworth–Emmons coupling with phospho-
nate 9[24] gave the enol ethers 10. All enol ethers were isolat-
ed as E/Z mixtures (Z mostly predominating), a fact which
had almost no effect on the stereochemical outcome of the
following asymmetric dihydroxylation (AD, 10 ! (R)-11).
The configuration of the product is determined primarily by
the choice of the ligand during the AD. In accordance with
the results of Sharpless[20] application of AD-mix-a led to
the S configured, AD-mix-b to the R-configured product in
high enantiomeric excesses and generally unaffected by R.
Because AD-mix-b[25] had yielded better results with respect
to the enantiomeric excess, we chose the R configured 2-hy-
droxy ketone (R)-11 as starting material of our investiga-
tions. Finally, tosylation of (R)-11 with tosyl anhydride
(Ts2O) gave the photo precursors (R)-12. The results are
shown in Table 1.
(R)-12
(ee [%])
Solvent[a] Yield 13 Rel.
C-b
ee [%][f]
[g]
G
[%][b]
conf.
13
conf.
A
13[c]
a (95)
a (95)
b (55)
c (91)
c (91)
d (99)
d (99)
e (93)
e (93)
f (97)
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
79
n.d.
72
74
n.d.
78
n.d.
69
n.d.
78
exo
exo
exo
exo
exo
exo
exo
exo
exo
R
R
52 (55)
45 (47)
n.d.[d] 10 (18)
S
S
S
S
28 (31)
50 (55)
38 (38)
48 (48)
23 (25)
rac.
R[e]
–
80% exo 20% endo n.d.[d] 49 (51)
[a] Irradiation at 258C in dichloromethane in the presence of N-methyli-
midazole as acid scavenger or in methanol without acid scavenger. For
details see ref. [13b]. [b] Yield after conversion of the racemic precursors
12a,c–f. For details see ref. [13b]. Irradiations in MeOH were not per-
formed on a preparative scale. Therefore, the yield in MeOH was not de-
termined. [c] C-b Configuration of the excess enantiomer at 258C, as-
signed by VCD spectroscopy. [d] Not determined. [e] A complete assign-
ment with VCD spectroscopy was not possible. [f] The enantiomeric
excess (ee) was determined by HPLC (Chiralcel-OD, Chiralpak-AD-H).
[g] Chirality transfer according to ref. [17f]: CT=(ee [13]/ee [12])”100.
Photochemical investigations: The results of the irradiation
studies (258C, solvent: dichloromethane or methanol) are
summarized in Table 2. In addition to the relative configura-
tion of the bicylic products 13 (exo or endo), the absolute
configuration at C-b of the preferred product enantiomer (R
or S), and the enantiomeric excess (ee), a fourth stereo-
chemical term is given: The chirality transfer (CT, [%])
which is calculated according to the equation CT=(ee [13]/
ee[12])*100.[17f] The term CT is independent from the optical
purity of the photochemical precursor 12 and therefore an
expression for the efficiency of the 1,2-chirality transfer.
From some bicyclic products 13 the absolute configuration
of the excess enantiomer was determined using VCD spec-
troscopy.
The photochemical precursors (R)-12 delivered the bicy-
clic cyclopropyl ketones 13 in good yields and in part with
considerable enantiomeric excess. With one exception [(R)-
12 f] the photochemical cyclization occurred with complete
diastereoselectivity to the exo product due to an asymmetric
induction of the chirality center in b position of diradicals
DR-A and DR-B, respectively on the adjacent radical cen-
Chem. Eur. J. 2008, 14, 7951 – 7960
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7953

P. Wessig and O. Muehling
ters (Scheme 2).[13] Thus, the stereoselectivity obtained in
the formation of 13 exclusively reflects the efficiency of the
1,2-chirality transfer.
an inversion of selectivity by temperature. In this case, we
obtain an excess of one enantiomer at low temperature and
of the other one at high temperature. Figure 2 schematically
Compound 13 f contains a p-electronic system in conjuga-
tion with the cyclopropyl moiety. It is well known that upon
irradiation benzoyl cyclopropanes of such type undergo an
efficient cis/trans- and exo/endo-photoisomerization, respec-
tively, until a photostationary state is reached.[26] This iso-
merization proceeds with no loss of the chirality information
in b position because after photochemical excitation bond a)
is cleaved exclusively (Scheme 4).
Figure 2. Eyring Plots a) with and b) without selectivity reversal at T0
(according to ref. [29b]).
Scheme 4. exo/endo Photoisomerization of 13 f with no loss of the chirali-
ty information in b position.
shows the corresponding linear Eyring plots. Plot a crosses
the x axis (S=DDG° = 0) at a special temperature T0
=
The selectivity model depicted in Scheme 2 predicts the
preferred formation of (R)-13 from (R)-12. However, no
consistent picture emerges from our irradiation studies at
258C (Table 2): Irradiation of (R)-12a delivers predominant-
ly the expected R-configured exo-13a, whereas from (R)-
12c and (R)-12d the product enantiomer with S configura-
tion at C-b is mainly generated. To clarify this contradiction,
systematic examinations were carried out to investigate the
effect of temperature on the stereoselectivity.
DDH°/DDS°[29] where enantiomers A and B are formed as
a racemic mixture. Since the absolute temperature is always
greater than zero, an inversion of product configuration can
only be observed if DDH° and DDS° have the same sign.
Otherwise, enthalpy and entropy play in favor of the same
enantiomer (e.g. A, plot b, Figure 2) and a reversal of selec-
tivity by variation of the temperature cannot occur. At T0
the enthalpic and entropic contributions compensate each
other (DDH° = TDDS°) affording no stereodifferentiation.
Below T0 the enthalpy difference DDH° controls the selec-
tivity process (DDH° > TDDS°), while the entropic term
TDDS° is dominant at temperatures higher than T0 (DDH°
< TDDS°).
The roles of enthalpy and entropy on stereoselectivity: For
the first time, Scharf investigated in detail the temperature
dependence of the selectivity of photochemical processes by
means of the Paterno–Büchi reaction.[27] He found that the
reaction temperature has no uniform influence on the ste-
reoselectivity of the product formation. In contrast to the
prevalent opinion—the lower the reaction temperature, the
higher the stereoselectivity—a constant behavior or even a
decrease can also be observed. This appears contra-intuitive
at first but can be easily explained bearing in mind the rules
for temperature-dependent selectivity processes.
A couple of thermal[30] and photochemical[31] reactions ac-
companied by a reversal of selectivity at T0 are reported in
literature.[32] One of the best investigated photochemical re-
actions of this type is the enantiodifferentiating Z/E photoi-
somerization of (Z)-cyclooctene in the presence of a chiral
sensitizer (Scheme 5). By variation of temperature,[33] pres-
In a kinetically controlled unimolecular reaction leading
to two enantiomers A and B, the selectivity S is expressed
by S = ln(kA/kB) where kA and kB are the overall rate con-
G
Scheme 5. Enantiodifferentiating Z/E photoisomerization of cyclooctene.
stants for the formation of A and B, respectively. Then, the
temperature dependence of the stereoselectivity for the two
reaction channels can be analyzed according to the Eyring
sure[34] or solvent[35] it is possible to control which E enantio-
mer is formed preferentially.[36]
formalism[28] S = ln
A
ferred formation of one enantiomer (A or B) is based on
the difference between the free activation energies DDG°
of both reaction paths which in turn consists of an enthalpic
and an entropic term (DDG° = DDH°°TDDS°, Gibbs–
By means of (R)-12a,c–e the effect of temperature (and
solvent) on the stereoselectivity of the reaction (R)-12 ! 13
was investigated in detail. The corresponding Eyring plots
are given in Figure 3. The activation parameters calculated
from the Eyring plots are summarized in Table 3.
Helmholtz equation): S
DDS°/R. A special situation arises if enthalpy and entropy
With one exception (Table 3, entry 2) DDH° and DDS°
have the same sign leading to a temperature T0 where the
promote the formation of opposite enantiomers leading to
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Stereoselective Synthesis of Cyclopropanes
FULL PAPER
*
*
Figure 3. Eyring plots of (R)-12 ! exo-13: = CH2Cl2, = MeOH.
respective photo product exo-13 results as a racemic mix-
ture. In four of eight cases (Table 3, entries 3–6) T0 lies
below room temperature and at 258C the S enantiomer is
formed preferentially due to entropy control (positive
DDG° values). In contrast, photolysis of (R)-12a always
gives the enthalpic-favored exo-(R)-13a in excess (negative
DDG° values) and independently of the used solvent be-
cause T0 either is far above the
Moreover, the solvent has a uniform influence on the ste-
reochemical outcome of the investigated reactions.
A
change of the solvent from dichloromethane to methanol
causes a decrease of the difference of DH° and DS° (abso-
lute values) between both reaction channels and a shift of
T0 to lower temperatures [(R)-12c–e]. In the case of (R)-
12a photolysis in methanol induces a change of sign in
boiling point of the solvent (di-
chloromethane) or does not
exist (methanol). For similar
reasons, irradiation of (R)-12e
in dichloromethane yields pre-
dominantly the R enantiomer
within the investigated temper-
ature range. However, in meth-
anol selectivity reversal occurs
Table 3. Activation parameters (DDH°, DDS°, DDG°, T0) calculated from the Eyring plots.
Entry
12
a
Solvent[a]
DDH° [b]
DDS° [c]
DDG°[d]
C-b conf. exo-13[e]
T0 [8C]
1
2
3
4
5
6
7
8
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
CH2Cl2
MeOH
ꢀ1.89ꢁ0.08
ꢀ0.49ꢁ0.03
ꢀ1.92ꢁ0.06
ꢀ1.02ꢁ0.05
ꢀ2.67ꢁ0.12
ꢀ1.33ꢁ0.08
ꢀ2.64ꢁ0.13
ꢀ1.19ꢁ0.08
ꢀ3.94ꢁ0.28
0.40ꢁ0.10
ꢀ0.72ꢁ0.08
ꢀ0.60ꢁ0.03
0.38ꢁ0.06
0.74ꢁ0.05
0.48ꢁ0.12
0.62ꢁ0.08
ꢀ0.29ꢁ0.13
0.00ꢁ0.08
R
R
S
S
S
S
207ꢁ18
–
ꢀ7.71ꢁ0.23
ꢀ5.89ꢁ0.16
ꢀ10.58ꢁ0.45
ꢀ6.53ꢁ0.27
ꢀ7.90ꢁ0.50
ꢀ4.01ꢁ0.29
ꢀ24ꢁ2
ꢀ100ꢁ6
ꢀ20ꢁ2
ꢀ70ꢁ6
61ꢁ5
c
d
e
(R)[f]
rac.
25ꢁ3
near room temperature (T0
=
[a] Irradiation at 258C in dichloromethane in the presence of N-methylimidazole as acid scavenger or in meth-
anol without acid scavenger. [b] kcalmolꢀ1. [c] calmolꢀ1 Kꢀ1. [d] 258C, kcalmolꢀ1. [e] C-b configuration of the
excess enantiomer at 258C, assigned by VCD spectroscopy. [f] A complete assignment with VCD spectroscopy
was not possible.
25ꢁ38C) and exo-13e is
formed as racemic mixture.
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7955

P. Wessig and O. Muehling
DDS°. Consequentially, enthalpy and entropy play in favor
of the same enantiomer and a reversal of selectivity cannot
occur.
Determination of the absolute configuration via VCD spec-
troscopy: A couple of methods has been developed over the
years to determine the absolute configuration in chiral mol-
ecules, for example, anomalous X-ray scattering,[37] different
chiroptical methods (electronic circular dichroism [CD],[38]
vibrational circular dichroism (VCD),[39] optical rotation dis-
persion [ORD][40]
) and nuclear resonance spectroscopy
(NMR) in combination with chiral derivatizing agents
(CDAs).[41]
Particularly predestined for conformationally rigid mole-
cules of type 13 is vibrational circular dichroism (VCD).[39]
VCD is the extension of electronic CD[38] into (near-)infra-
red regions of the spectrum, namely the difference in the IR
absorption between left and right circularly polarized radia-
tion during a vibrational transition. Only chiral molecules
can display this difference. Pairs of enantiomers have VCD
spectra of identical magnitude but opposite sign at all fre-
quencies. Analogous to the comparison of UV/Vis and IR
spectra, VCD spectra are much richer in spectral features
than electronic CD spectra. The widths of vibrational transi-
tions are much narrower leading to more highly resolved
spectra.
VCD studies for absolute configuration determination
consist of a combination of spectral measurement and quan-
tum mechanical calculations. In this context, it is highly ad-
visable to calculate both IR and VCD spectrum. Only a
good agreement between observed and calculated IR spec-
trum allows a comparison of the respective VCD spectra.
For IR/VCD calculations the best compromise between ac-
curacy and computational cost is currently offered by using
density functional theory (DFT) with a hybrid functional
like B3LYP or B3PW91 and a 6-31G* basis set as a mini-
mum. All IR/VCD calculations were carried out at the DFT
level with the Gaussian 98 program package[42] using the
hybrid functional B3LYP[43] and the 6-31G* basis set. Based
on the optimized geometries, single point calculations were
accomplished with the same DFTmethod and a higher 6-
311++G** basis set. For comparison with experimental
spectra, the calculated frequencies were uniformly scaled
with the factor 0.9614 and the IR and VCD intensities were
represented as Pseudo-Voigt bands with 8 cmꢀ1 half width.
The calculation has been started with the selection of a spe-
cific absolute configuration of the particular photo product
exo-13 followed by an analysis of the conformational flexi-
bility to determine which conformers are significantly popu-
lated under the experimental measurement conditions.
Here, it was advantageous that the bicyclic products exo-13
are comparatively rigid molecules and so only few conform-
ers have to be taken into account. Afterwards, the exact rel-
ative energies of the remaining low-energy conformers were
determined to calculate the IR/VCD spectrum as a linear
combination of the computed spectral data.
Figure 4. Optimized geometries (B3LYP/6-311++G**//B3LYP/6-31G*).
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Chem. Eur. J. 2008, 14, 7951 – 7960

Stereoselective Synthesis of Cyclopropanes
FULL PAPER
In close collaboration with Bruker Optics (Ettlingen, Ger-
many) we succeeded in unambiguously determining the ab-
solute configuration of exo-13a,c,d. The optimized geome-
tries (B3LYP/6-311++G**//B3LYP/6-31G*) of all relevant
conformers are given in Figure 4. The resulting relative en-
For exo-13a only one of two ring conformers has to be
taken into account as well. The tert-butyl moiety in 3-posi-
tion acts as a conformational anchor and a pseudo equatori-
al arrangement (B) is highly favored (DErel =3.9 kcalmolꢀ1,
PA
A
E
VCD calculation of exo-(R)-13a-B (1R,3R,6R,7S) gave a
very good correlation with the corresponding experimental
spectra.
Table 4. Relative energies and fractional Boltzmann populations for con-
formers of exo-13a,c,d (B3LYP/6-311++G**//B3LYP/6-31G*).
The IR/VCD calculations of the 3-azabicyclo-
[4.1.0]heptanes exo-13d,e turned out to be slightly more
Conformer
Erel [kcalmolꢀ1
]
P(258C) [%]
G
G
exo-(R)-13a-A
exo-(R)-13a-B
exo-(S)-13c-A
exo-(S)-13c-B
exo-(S)-13d-A
exo-(S)-13d-B
exo-(S)-13d-C
exo-(S)-13d-D
1.9
0.0
3.9
0.0
0.2
0.0
1.3
1.1
3.9
96.1
0.1
99.9
36.0
50.5
5.6
complicated. In both cases four conformers (A–D) were
found because an additional degree of freedom, namely the
N-substituent (Ts or Boc), is involved. However, the respec-
tive conformers C and D are at least 1.0 kcalmolꢀ1 higher
than the corresponding lowest energy conformation. Conse-
quently, conformers C and D were not considered because
only a small contribution to the IR/VCD spectra was ex-
pected. Conformer A can be transformed into B by rotation
around the N,S- and N,C(=O)-bond, respectively. In rotamer
exo-(S)-13d-A the p-tolyl group of the angular tosyl moiety
is sticking out into the endo half space of the bicyclus.
Therefore, A is around 0.2 kcalmolꢀ1 less favored than B
7.9
ergies and fractional Boltzmann populations are summar-
ized in Table 4. The experimental and calculated IR and
VCD spectra, respectively, are shown in Figure 5.
The approach is illustrated
firstly by means of compound
exo-13c.
A
conformational
analysis of the enantiomer exo-
(S)-13c showed that the benzo-
yl group adopts a nearly bisect-
ed conformation with respect to
the cyclopropane ring due to a
stereoelectronic interaction be-
tween the carbonyl moiety and
the cyclopropane ring.[44] In
terms of the tetrahydropyrane
ring two half-chair conforma-
tions[45] (exo-(S)-13c-A and
exo-(S)-13c-B) have to be dis-
tinguished. In consequence of a
1,4-transannular
interaction
conformer A is 1.9 kcalmolꢀ1
less favored compared with B.
This correlates with a fractional
Boltzmann population of PA-
A
measurement conditions. Thus,
conformer A will not contribute
significantly to the IR/VCD
spectrum and has not to be con-
sidered. This conclusion was
impressively confirmed by
a
very good agreement with the
experimental IR and VCD
spectra, respectively (Figure 5).
The VCD study thus estab-
lished the configuration of the
excess enantiomer of exo-13c
as (1R,6S,7R) (~exo-(S)-13c).
Figure 5. Comparison of experimental and calculated IR and VCD spectra.
Chem. Eur. J. 2008, 14, 7951 – 7960
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7957

P. Wessig and O. Muehling
[2] H. Zhao, D. C. Hsu, P. R. Carlier, Synthesis 2005, 1–16.
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corresponding to fractional Boltzmann populations of PA-
(258C)=42% and PB(258C)=58%. The resulting compo-
site spectra exo-(S)-13d-A and exo-(S)-13d-B are in quite
good agreement with the experimental data. Thus, the VCD
analysis identified the configuration of the excess enantio-
mer of exo-13d as (1R,6S,7R) (~exo-(S)-13d).
However, in exo-13e the analogous conformers A and B
are of nearly equal energy. The hybrid spectra of 54% A
and 46% B have shown an inadequate correlation with the
observed spectra, and so no conclusion about the absolute
configuration of exo-13e could be made (see Supporting In-
formation).
A
ACHTREUNG
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Conclusion
In summary, we reported on a completely novel concept of
stereoselectivity based on a 1,2-chirality transfer. In the ini-
tial step of a photochemical cyclopropane synthesis,[13] which
is a special application of the concept of spin center shift,[12]
an electronically excited carbonyl group can interact with a
[6] Examples based on simple diastereoselectivity: a) A. Azzouzi, M.
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ꢀ
s* orbital of an adjacent C X bond causing a preferred ge-
ometry of the corresponding cyclohexane-like transition
state for the hydrogen abstraction (Scheme 2). In the conse-
quence of this interaction, the carbonyl group can distin-
guish between two diastereotopic methylene groups in g po-
sition. Because the initial chirality information is destroyed
in the next step by elimination of acid HX, an 1,2-chirality
transfer takes place. To our surprise, we found after careful
determination of the absolute configuration of the resulting
bicyclic cyclopropane derivatives 13 by VCD spectroscopy
that the stereochemical outcome of the reaction is not uni-
formly for different derivatives. An extensive investigation
of the temperature dependence of the stereoselectivity re-
vealed that contrary enthalpic and entropic contributions
are responsible for this unexpected behavior. In most cases,
[7] Examples based on asymmetric induction via substrate control:
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[29]
we could determine a temperature T0 at which these con-
tributions compensate each other and the stereoselectivity
vanishes. With these findings in hand we could obtain the
products 13 with partly impressive stereoselectivities by
proper choice of the irradiation temperature (e.g. ee 83%
for 13a at ꢀ568C). We hope that our results will inspire fur-
ther interesting stereoselective photochemical as well as
thermal reactions.
Acknowledgements
This work has been supported by the Deutsche Forschungsgemeinschaft.
We would like to especially give thanks to Dr. Hans-Hermann Drews at
Bruker Optics (Ettlingen) for measuring the VCD spectra and the valua-
ble discussions about VCD spectroscopy. Furthermore we thank Priv.-
Doz. Dr. Detlef Heller from Leibnitz-Institut für Organische Katalyse
(IfOK) (University Rostock) for his helpful advice about the temperature
dependency of selectivities.
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therein.
7958
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Chem. Eur. J. 2008, 14, 7951 – 7960

Stereoselective Synthesis of Cyclopropanes
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Received: May 25, 2008
Published online: July 18, 2008
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