Mechanistic Studies of the TRIP-Catalyzed Allylation with Organozinc Reagents

Article abstract of DOI:10.1021/acs.joc.0c00992

3,3-Bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) catalyzes the asymmetric allylation of aldehydes with organozinc compounds, leading to highly valuable structural motifs, like precursors to lignan natural products. Our previously reported mechanistic proposal relies on two reaction intermediates and requires further investigation to really understand the mode of action and the origins of stereoselectivity. Detailed ab initio calculations, supported by experimental data, render a substantially different mode of action to the allyl boronate congener. Instead of a Br?nsted acid-based catalytic activation, the chiral phosphate acts as a counterion for the Lewis acidic zinc ion, which provides the activation of the aldehyde.

Full text of DOI:10.1021/acs.joc.0c00992

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Article
Mechanistic Studies of the TRIP Catalyzed
Allylation with Organozinc Reagents
Peter E. Hartmann, Mattia Lazzarotto, Jakob Pletz, Stefan Tanda, Philipp
Neu, Walter Goessler, Wolfgang Kroutil, A. Daniel Boese, and Michael Fuchs
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00992 • Publication Date (Web): 10 Jul 2020
Downloaded from pubs.acs.org on July 13, 2020
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The Journal of Organic Chemistry
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Mechanistic Studies of the TRIP Catalyzed Allylation with Organozinc
Reagents
†,‡
†
†
§
†
Peter E. Hartmann, Mattia Lazzarotto, Jakob Pletz, Stefan Tanda, Philipp Neu, Walter
§
†
‡,
†,
Goessler, Wolfgang Kroutil, A. Daniel Boese, * Michael Fuchs *
† University of Graz, Institute of Chemistry, Bioorganic and Organic Chemistry, Heinrichstrasse 28/II, 8010 Graz,
Austria, Europe.
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‡ University of Graz, Institute of Chemistry, Physical and Theoretical Chemistry, Heinrichstrasse 28/IV, 8010 Graz,
Austria, Europe.
§ University of Graz, Institute of Chemistry, Analytical Chemistry, Universitätsplatz 1/I, 8010 Graz, Austria, Europe.
Keywords: Chiral Phosphoric Acids, Asymmetric Allylation, Ab Initio Calculations, Reaction Mechanisms, Organocatalysis
ABSTRACT: 3,3-Bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) catalyzes the
asymmetric allylation of aldehydes with organozinc compounds leading to highly valuable structural motifs, like
precursors to lignan natural products. Our mechanistic proposal previously reported relies on two reaction intermediates
and requires further investigation in order to really understand the mode of action and the origins of stereoselectivity.
Detailed ab initio calculations, supported by experimental data, render a substantially different mode of action to the allyl
boronate congener. Instead of a Brønsted acid based catalytic activation, the chiral phosphate acts as a counterion for the
Lewis acidic zinc ion, which provides the activation of the aldehyde.
reagent, whereas the required rigidity for the alignment is
reasoned by a formyl-H interaction with the P=O oxygen
Lewis base.
Introduction
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Computational efforts have become a frequent tool in
the elucidation of mechanistic scenarios and
understanding the course of chemical reactions.1-3 They
allow the evaluation of different events by the comparison
of their energetic profiles and deliver useful information in
order to understand and improve the chemistry behind the
process of interest.1-4 Especially in combination with
asymmetric synthesis, density functional theory (DFT)
calculations have facilitated the finding of asymmetric
induction and have delivered or confirmed the accepted
mechanistic concept of activation and stereopreference.
Regarding asymmetric synthesis, allylation reactions have
a pronounced foundation and are an indispensable
methodology when it comes to the creation of chiral
molecules.5-10 One of these examples is the asymmetric
preparation of dibenzylbutyrolactones, which proceeds via
the asymmetric allylation of an aldehyde precursor with an
organozinc reagent.11-12 The catalyst – namely 3,3-bis(2,4,6-
triisopropylphenyl)-1,1-binaphthyl-2,2-diyl
For the zinc-based reaction, the absence of the pinacol
system renders this activation impossible, and our initial
mechanistic proposal was based on the energetical
assessment of two reaction intermediates. Therefore,
additional investigations are required to understand the
differences of these allylation reactions.
iPr
3 11
Asymmetric Allylation using allyl-zinc reagent
:
iPr
(R)-TRIP
iPr
O
P
O
iPr
O
OH
(2, 20 mol-%),
Zn0, NH4Cl
(R)
MeO
MeO
BnO
O
P
O
O
O
(S)
O
O
+
=
*
OH
OH
toluene/iPr2O 4/1,
-30°C
BnO
1
O
O
71% yield,
98% ee
Br
3
(R)-TRIP (2) iPr
iPr
O
Previously proposed mechanisms for zinc and boron reagents:
4.6Å
3.2Å
O
P
2.6Å
O
H
O
H
2.4Å
O
O
Br-
Br-
H
O
O
H
Zn2+
O
O
Zn2+
O
S
R
O
O
Ph
O
O
O
O
O
Ralc
Salc
Sax
Sax
P
P
B
O-
H
H
O-
H
H
O
proposed
transition state
for the
hydrogenphosphate (TRIP, 2)13
–
shows high
correspodning
allylboration15,17
SaxRalcS-Int1 (favored)
SaxSalcR-Int1 (disfavored)
stereoinduction on the process and delivers the natural
product precursor with an enantiomeric excess as high as
98%. Important to note is the fact, that the reaction has a
boron congener, using allyl boronate reagents and the
same catalyst.14 Some effort has been undertaken to explain
the stereoselectivity in case of these reagents, and yielded
a mechanistic mode of action as depicted in Figure 1.15-17
The decrease of the activation barrier is explained by the
hydrogen bond to the pinacol oxygen, activating the
previously proposed reaction intermediates for the stereoinduction in case of zinc reagents11
Figure 1. Asymmetric allylation of aldehydes with
bromolactone 3 and previously reported rationales for the
reactivity and the stereoselectivity of catalyst 2 for the zinc-
and boron-based reagents.
Results and Discussion
In order to investigate the reactivity of the TRIP acid (2)
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under reaction conditions, we probed the acid in the This observed quench of 2 by zinc organyls has even
1
2
3
4
5
6
7
8
presence of compound 3 and zinc dust (see Scheme 1). The
NMR spectra show strong peak broadening due to the
unfavorable properties of the NMR-active zinc. The
resolution of the recorded spectra slightly improves when
the allylic bromide was changed to compound 4 (see
Scheme 1a). The reaction with this open-chain, allylic
bromide (4) yields the allylated product 6 under TRIP
catalysis too, albeit with significantly reduced
stereoselectivity [99% conv., 60% isolated yield for product
7 (over 2 steps), 28% ee, see Scheme 1a]. Alternatively, the
initially envisaged complex 8b was prepared via the
preformed zinc salt 10 and its subjection to the in-situ
formed reagent 9 (see Scheme 1d). The observed shift in
the 31P NMR spectrum is in almost perfect agreement with
precedence in literature and has been documented even by
a crystal structure of a homologue phosphate.19 Important
to note is that within the homologue zinc complex, both
oxygen atoms of the phosphate interact with the zinc
species forming a dimeric zinc salt – a fact that our
calculations suggest for the outlined transition states
herein too (vide infra).19 Finally, the question remained
which complexes of the observed ones are catalytically
active: under resubmission to reaction conditions all
complexes (namely acid 2, zinc salt 10 and complex 8b)
proved active and provided the homoallylic alcohol
product with 86-88% conversion and close to perfect
selectivity (96% ee).
These findings, in combination with the fact that educt
complexes involving a mono-zinc phosphate complex are
energetically significantly higher in energy (see supporting
information, chapter 3.9.2), render a dinuclear catalytic
species with respect to zinc the most likely one. All
experimental data as well as the theoretical results point to
complex 8 to be the product of the treatment of 2 with
reagent 4/9 (see Scheme 1b). It results from a quench of the
first reagent equivalent by the acidic proton of TRIP (2) and
the subsequent coordination of a second equivalent to the
chiral zinc phosphate salt.
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the one observed for complex 8a
– a reasonable
observation due to their highly similar environment for the
zinc core [4.63 ppm (8a) and 4.54 ppm (8b)]. The
formation of a zinc phosphate salt under reaction
conditions finds additional support in the detection of
protodemetalated reagent 9 via headspace GC-MS analysis.
Whereas only little amounts of the quenched reagent 9
form in the absence of TRIP (presumably via a quench by
the ammonium salt), significantly higher amounts were
detected in the presence of the chiral phosphoric acid
reflecting the 20 mol-% used in the experiment (for details
see experimental section and supporting information,
chapter 2.5).
Nonetheless, our computational efforts support this
hypothesis of a coordinated allyl-zinc species and the
involvement of two zinc atoms in the active species, as the
formation of such is thermodynamically and kinetically
highly favored (see Scheme 1d). Note that the subscripts of
Scheme 1. a) asymmetric allylation with reagent 4 and b)
31P-NMR studies of the catalyst under reaction conditions
in the absence of benzaldehyde (5); c) rendered structures
of the most stable conformers B1 and B1h;18 d) preparation
of zinc salt 10 and complex 8b; e) calculations of the
quench and coordination of TRIP (2) and reagent 9 at the
DLPNO-CCSD(T)/cc-pVTZ G+COSMO level [compare to
G(edfav.) = -88.3 kJ/mol].
훥퐺
훥훥퐺
values give the point of reference (“ed” refers
and
to educts; “ISR” stands for “infinitely separated reactants”).
Phosphoric acid 2 is quenched with zinc reagent 9
(formed by the zinc insertion into allylic bromide 3) with a
푇푆
Δ퐺푒푑푢푐푡
∆∆퐺
negligible barrier [
= -3.6 kJ/mol;
= +6.7
퐼푆푅
푒푑
훥퐺푍푛 ― 푠푎푙푡
kJ/mol;
= -85.3 kJ/mol; obtained from RI-PBE20-
single point
퐼푆푅
21-D3/def222-TZVPPD22-23+COSMO24-25
calculations]. Subsequently, the formed zinc salt can
coordinate another equivalent of reagent 9, leading to
structures B1 and B1h. Whereas B1 represents the local
minimum, the formation of the final educt complex edfav.
requires severe geometrical rearrangements and thus B1 is
regarded as an off-cycle intermediate which leads to a non-
productive pathway (see supporting information, chapter
3.9.1.; pathways leading to the favored and disfavored
enantiomers are labelled with the subfixes “fav.” and “dis.”,
respectively). B1h however – which resembles assumed
structure 8 (except the double coordination of the lactone
carbonyl) – demonstrates a perfect starting point for the
formation of edfav.: Following the reaction trajectory, the
most likely subsequent event is the coordination of the
aldehyde oxygen to the Lewis acidic zinc salt of B1h (see
Figure 2: mechanistic cycle, B1h to edfav.). This weakens
and finally breaks the coordination of the lactone-carbonyl
group.
a) Asymmetric allylation with reagent 4:
O
O
OH
O
Br
O
(S)-2 (10 mol-%),
Zn, NH4Cl
7
*
*
OEt
+
+
[60% isolated
yield (2 steps)
28% ee]
OEt
4
toluene, rt, 16h,
full conversion
5
6
O
pTSA (cat.), CHCl3
b) NMR studies in the absence of 5:
4 (5 eq.),
c) rendered structures of B1 and B1h:
Br
O
O
O
O
Zn, NH4Cl
Zn
P
O
P
*
*
O
OH
O
CDCl3,
rt, 2h
O
Zn
OEt
2
Br
31P: 3.37 ppm
8a, assumed structure
31P: 4.63 ppm
B1
B1h
d) Preparation of zinc salt 10 and complex 8b:
3 (2 eq.),
Zn, NH4Cl
Br
O
P
O
O
P
O
O
O
O
O
Zn(CO3)2
Zn
ZnX
P
*
*
*
O
OH
O
10
O
O
CDCl3,
RT, 16h
toluene,
RT, 16h
O
Zn
2
8b, assumed structure
31P: 4.54 ppm
(X = O(CO)OZn)
31P: 6.67 ppm
Br
31P: 3.37 ppm
e) Calculations regarding the formation of B1 or B1h:
Br
Br
Br
O
O
Zn
O
O
O
P
O
O
O
P
O
O
O
O
Zn
Zn
or
+
P
*
*
O
*
O
O
Zn
Br
OZnBr
O
Zn
O
Br
2
9
B1
G = -105.7 kJ/mol
zinc salt of
B1h
G = -74.8 kJ/mol
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Figure 2. Left side: energy diagrams for the catalyzed and the uncatalyzed allylation step (■ blue = catalyzed reaction
leading to the observed enantiomer; ■ red = catalyzed reaction leading to the non-observed enantiomer; ■ gray =
uncatalyzed reaction); right side: reactants, products and transition state structures of the corresponding pathway (newly
formed bond in the transition states is marked in dark blue).18 Only the energetically lowest pathways are shown, for all
others see the supporting information. All presented data are given on the DLPNO-CCSD(T)/cc-pVTZ G+COSMO level;
the refence point (0 kJ/mol) represents the indefinitely separated reactants [the zinc salt of TRIP, reagent 9 and
benzaldehyde (5)].
O
P
O
[see edfav. and eddis. in Figure 2 and 3; note that all
O
O
O
Br
Zn
O
calculated transition states with reasonable energies
require this double coordination (for additional transition
states see supporting information, chapter 3)].
*
product
9
Zn
Br
zinc
2
salt of
The latter structures (edfav. and eddis.) were originally
computed from the coordination of the educt complex of
the uncatalyzed reaction edunc. to the zinc salt of the
catalyst. Thus, they represent perfect starting points for the
asymmetric catalysis.
Br
Br
O
O
H
O
O
P
O
O
P
O
O
O
O
Zn
Zn
*
*
O
O
Zn
Br
O
Ph
Zn
Br
pfav.
B1h
Complex edfav. readily transforms into the product
∆∆퐺푇푆
complex pfav. via an energetic barrier of
= +39.0
푒푑
H
Br
O
H
kJ/mol (see Figure 2, left side). This compares to the lowest
O
P
O
O
O
Zn
O
Ph
5
energy barrier for the formation of the experimentally
*
O
Zn
Br
푇푆
O
∆∆퐺
disfavored enantiomer of
= +51.0 kJ/mol, giving a
푒푑
Ph
difference of 12.0 kJ/mol in favor of the experimentally
observed results. This difference very well reflects the
observed enantiomeric excess, which has been determined
to be 94% at 4°C.11
edfav.
proposed
catalytic cycle
Figure 3. Mechanistic proposal of the catalytic cycle.
The obtained mono-coordination of the allylating
reagent provides the possibility of an interaction of the
aldehyde with both zinc atoms, increasing the aldehyde’s
polarization and translating to a more reactive electrophile
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chapter 3.9.1). Important to note is that the catalysis
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2
3
4
5
6
7
provides the stereoinduction, but the experimental data
suggests, that the preceding in-situ formation of the allyl-
zinc reagent demonstrates the rate determining step of the
overall process, as at no time of the reaction the level of
active zinc reagent exceeds the catalyst loading (see
supporting information, chapter 2.3-2.4, for details).
Finally, the energies of the formed product complexes
deserve some attention, as all reactions are endergonic (for
energies of products see supporting information, chapter
3.8). This fact may reveal the role of the NH4Cl additive,
which has been either believed to activate the zinc dust or
quench the obtained zinc alcoholate product yielding the
free protonated alcohol and ZnX2 (please note, that
without the ammonium salt no reaction is observed
regarding the catalyzed and the uncatalyzed reaction).
With the reaction(s) being endergonic, the latter role of
the additive seems to be supported by our calculations, as
it provides the final pull the equilibrium to the product
side. An alternative for this shift of the equilibrium would
be a cluster formation of the zinc alcoholate product
molecules, as described for Noyori’s DAIB catalyzed,
asymmetric alkylation of aldehydes with dialkylzinc
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Figure 4. TS structures,18 overall dipole moment (gray
arrow) and dipole moment of the lactone (yellow arrow);
the overall dipole moment is given in brackets. All
presented data are given on the DLPNO-CCSD(T)/cc-
pVTZ level.
The rationale for the difference in the transition states
may be found in the minimization of the dipole moment,
especially with consideration of the apolar reaction
medium (toluene). Whereas the favored TSfav. exhibits a
dipole moment of 4.13 D, the disfavored TSdis. yields 6.85
D. This is reasoned by a different alignment of the lactone
moiety and its dipole, which is positioned along the overall
dipole moment in TSdis.. In contrast to structure TSdis., the
dipole moment of the lactone subunit is almost orthogonal
to the overall dipole in TSfav. (see Figure 4). Furthermore,
the dipole moment of edfav. was calculated to be 5.10 D,
while the one of eddis. was determined to be 4.74 D. Hence,
for the favored pathway, the polarity of the complex
decreases along the reaction coordinate towards the
transition state, while for the disfavored pathway it
increases significantly, reflecting in the complementary
educt energies (eddis. is slightly favored over edfav., see
Figure 2). This adds to the energetic barriers and further
favors the pathway of the observed stereoselectivity.
In addition, the experimental observation that allyl
bromide leads to no detected stereoinduction may be
rationalized by this hypothesis, as allyl bromide exhibits a
significantly lower dipole moment.
+
reagents.26 Nevertheless, the presence of the NH4 proton
and the significant bulk around the zinc-oxygen cluster
favor the equilibrium push by the quenching scenario.
Conclusion
We have shown that the TRIP catalyzed asymmetric
allylation via zinc reagents proceeds via the zinc salt of the
chiral phosphoric acid. Addition of a second equivalent of
the in situ formed reagent yields complex B1h, which –
upon an approaching aldehyde – gives educt complex
edfav., an ideal precursor for the final C-C bond formation.
The catalysis is rationalized by the double coordination of
the aldehyde oxygen by both Lewis acidic zinc atoms (see
structure of TSfav.) and the required rigidity of the catalytic
system stems from the Lewis basic interaction of the P=O
oxygen to the allylzinc reagent. Perfectly aligned in edfav.
,
the favorable enantiomer is formed via an energetic barrier
Moreover, the alignment of the aldehyde carbon and the
β-carbon of the lactone forming the future C-C bond is
∆∆퐺푇푆
of 39.0 kJ/mol (
푒푑). Thus, the formation of the
experimentally non-observed enantiomer and the
uncatalyzed reaction are outrun by 12.0 kJ/mol and 36.5
kJ/mol, respectively. The energetic difference in the
transition states can be rationalized by the dipole moment
of the corresponding complexes, which is minimized for
the favored enantiomer. Important to note is the
endergonic character of the final reaction step, which
requires an external pull to the reaction system. This pull
can be found in the protonic quench of the zinc alcoholate
by the ammonium chloride additive. All these findings
render a rather clear picture of the asymmetric catalysis in
the case of this allylation process and provide another
example for a counterion directed asymmetric catalytic
much more favorable in structure edfav. than in eddis.
,
which can be attributed to unfavorable steric interactions
with the isopropyl groups of the catalyst in the latter educt
complex. Attempts to improve the alignment in eddis.
reverted to the original geometry when optimized. Hence,
we conclude that the pathway leading to the
experimentally
disfavored
enantiomer
requires
significantly more reorganization, contributing to the
higher energetic barrier of TSdis. additionally.
The uncatalyzed reaction is disfavored by 36.5 kJ/mol (
푇푆
∆∆퐺
= +75.5 kJ/mol). Other coordination patterns of the
푒푑
educt complexes to the zinc salt of the TRIP catalyst
yielded unfavorable pathways (see supporting information,
process. Additionally, they may lead to
a better
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understanding of the Lewis acidic/basic interactions of this TOF LC/MS using ESI (positive mode, capillary voltage
1
2
3
4
5
6
7
8
3.5 kV) or APCI (negative mode, 5.0 kV) methods. Chiral
HPLC analysis was performed on a Shimadzu HPLC system
[DGU-20A (degasser), LC-20A (pump), SIL-20A
(autosampler), CTO-20AC (column oven), SPD-M20A
(detector), CBM-20AC (controller)] with n-heptane/2-
PrOH as eluent using Daicel columns [dimension: 4.6 x 250
mm, 5 µm particle size, except Chiralpak AD (10 µm) and
Chiralcel OJ (10 µm)] and conditions as specified below. All
GC-MS measurements were carried out with an Agilent
7890A GC system, equipped with an Agilent 5975C mass-
selective detector (electron impact, 70 eV), a HP-5-MS
column (30m x 0.25 mm x 0.25 µm film) and an Agilent
7697A headspace autosampler using He as carrier gas at a
flow of 0.7 mL/min. The following temperature program
was used in all GC-MS headspace measurements: initial
temperature 40°C, hold for 5 min, 10 °C/min, to 200 °C.
Headspace parameters: vial pressurization gas: He; loop
size: 1 mL; transfer line: DB-ProSteel (0.53 mm diameter);
oven temperature: 50°C; loop temperature: 55°C; transfer
line: 60°C; vial equilibration time: 4 min; Injection
duration: 0.5 min; vial size: 20 mL; vial shaking: level 5, 71
shakes per min with acceleration of 260 cm/s2; fill pressure:
15 psi.
outstanding catalyst and stimulate new catalytic
procedures of a similar type.
Experimentals
General. All chemicals were purchased from Sigma
Aldrich or Acros Organics and were used as received,
unless otherwise noted. All solvents were purchased from
Roth, except Dioxane (Alfa Aasar) and dry toluene (Sigma
Aldrich). Moisture sensitive reactions were performed
using standard Schlenk techniques with argon 5.0.
Analytical thin layer chromatography (TLC) was carried
out on Merck TLC silica gel aluminum sheets (silica gel 60,
F254, 20 x 20 cm) and spots were visualized by UV light (λ =
254 nm) and by staining with cerium ammonium
molybdate solution [50 g (NH4)6Mo7O24 were dissolved in
400 mL H2O and 50 mL conc. H2SO4 was added followed
by 2.0 g Ce(SO4)2] or KMnO4 solution (1 g KMnO4 and 2 g
Na2CO3 were dissolved in 100 mL H2O) and developed by
heating with a heat gun. Column chromatography was
performed on silica gel 60 from Merck with particle sizes
40-63 µm. A 30- to 100-fold excess of silica gel was used
with respect to the mass of dry crude product, depending
on the separation problem. For sticky crude products, the
crude material was dissolved in MeOH and subsequently
adsorbed on the 2.5-fold excess of silica gel. Afterwards the
solvent was removed in vacuum and the adsorbed crude
material was dried in oil pump vacuum. The dimension of
the column was adjusted to the required amount of silica
gel and formed a pad between 20 and 40 cm of height. In
general, the silica gel was mixed with the eluent and
charged into the column before equilibration.
Subsequently, the dissolved or adsorbed crude material
was loaded onto the top of the silica gel and the mobile
phase was forced through the column by pressure exerted
by a rubber bulb pump.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
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59
60
3-Methylene-5-phenyldihydrofuran-
O
2(3H)-one (7). A 5 mL screw cap vial with
O
magnetic stirring bar was charged with zinc
(33.0 mg, 500 µmol, 5 eq.), ammonium
chloride (43.0 mg, 800 µmol, 8 eq.) and (S)-
*
7
3,3′-bis(2,4,6triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl
hydrogenphosphate (TRIP, 7.5 mg, 10.0 µmol, 0.1 eq.)
followed by toluene (1.0 mL), benzaldehyde (10.6 mg,
100 µmol) and allyl bromide 4 (29.0 mg, 150 µmol, 1.5 eq.).
The mixture was stirred (720 rpm) at room temperature for
16 h and was consecutively quenched by the addition of
saturated aqueous NH4Cl solution (5 mL). The mixture was
extracted with EtOAc (3 x 10 mL) and the combined
organic phase was dried over Na2SO4, filtered and
concentrated under reduced pressure. The obtained crude
product [mixture of compound 6 (free alcohol) and 7
(lactone)] was dissolved in CH2Cl2 and para-
toluenesulfonic acid hydrate (4 mg, 20 µmol, 20 mol-%)
was added. The reaction mixture was stirred for 16 h,
quenched with NaHCO3 aqueous solution (saturated) and
extracted with CH2Cl2 (3 x 10 mL). The combined organic
phase was dried over Na2SO4, filtered and concentrated.
The crude product was purified via flash chromatography
(SiO2, hexanes/EtOAc 5/1) to give product 7 (20 mg, 60
µmol, 60%) as a colorless oil.
1
Instrumentation. H-, 13C-, and 31P-NMR spectra were
recorded on a Bruker AVANCE III 300 spectrometer (1H:
300.13 MHz; 13C: 75.47 MHz; 31P: 121.49 MHz) with an
autosampler. Chemical shifts were referenced to the
residual proton and carbon signal of the deuterated solvent
[CDCl3: δ = 7.26 ppm (1H), 77.16 ppm (13C)]. Chemical shifts
δ are given in ppm (parts per million) and coupling
constants J in Hz (Hertz). Deuterated solvents for nuclear
resonance spectroscopy were purchased from Roth.
Melting points were determined on
MPD350.BM2.5 apparatus with
a
an
Gallenkamp
integrated
microscopical support. They were measured in open
capillary tubes with a mercury-in-glass thermometer and
were not corrected. IR-spectra were recorded neat on a
Bruker Alpha-P (ATR) instrument. The specific optical
rotation was determined on a Perkin Elmer Polarimeter 341
with an integrated sodium vapor lamp. All samples were
measured in CHCl3 and CH2Cl2 (both were purchased from
Sigma Aldrich, ACS spectrophotometric grade, ≥99.8%) at
the D-line of the sodium light (λ = 589 nm) under non-
tempered conditions between 22 °C and 27 °C. High
resolution mass spectra were recorded on an Agilent 6230
20
1
[]D = +4.4 (c = 2.0, CHCl3); H-NMR (300.13 MHz,
CDCl3): 7.46 – 7.28 (m, 5H), 6.31 (t, J = 2.8 Hz, 1H), 5.69 (t,
J = 2.5 Hz, 1H), 5.53 (dd, J1 = 7.9, J2 = 6.6 Hz, 1H), 3.41 (ddt,
J1 = 17.1, J2 = 8.1, J3 = 2.5 Hz, 1H), 2.91 (ddt, J1 = 17.1, J2 = 6.4, J3
= 2.9 Hz, 1H); 13C{1H}-NMR (75.47 MHz, CDCl3): 170.3,
139.9, 134.3, 129.0, 128.7, 125.5, 122.6, 78.1, 36.4; IR (film) ῦ =
3093, 3066, 3050, 3037, 2974, 2919, 2853, 1752, 1602, 1551,
1496, 1459, 1437, 1402, 1375, 1319, 1277, 1240, 1215, 1126, 1080,
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Page 6 of 10
31
1020, 985, 962, 938, 818, 761, 701, 639, 562 cm-1; HPLC
analysis on chiral stationary phase {Daicel Chiralpak OD-
H, n-heptane/2-propanol 90/10, 1.0 mL/min, 30 °C, UV
215 nm, tret(enantiomer 1) = 8.7 min, tret(enantiomer 2) =
9.8 min}: tret(major isomer) = 8.7 min, 28% ee; HRMS(ESI):
was added to reference the P-NMR, which was recorded
subsequently.
1
2
3
4
5
6
7
8
Time study of the zinc insertion reaction forming
reagent 9. Zinc dust (10.1 mg, 155 µmol, 5 eq.) and
ammonium chloride (13.3 mg, 248 µmol, 8 eq.) were
combined in a 1 mL HPLC vial. A stock solution (200 µL
toluene and 50 µL 2-iPr2O) containing the bromolactone 3
(6.5 mg, 37 µmol, 1.2 equiv.) was added and the reaction
mixture was stirred at room temperature. Samples of 50 µL
were withdrawn after the times given below, applied to a
syringe with filter, diluted with 500 µL of toluene and
filtered. The filtrate was quenched with aqueous HCl (1 M,
100 µL), the phases were separated, the organic phase was
dried over Na2SO4 and subjected to GC-FID analysis [for
conditions and instrumentation see general part;
tret(quenched 9) = 6.65 min, tret(3) = 11.20 min].
+
m/z: calc. for C11H11O2 : 175.0754 [M+H]+, found: 175.0755.
General procedure for the preparation of racemic
reference material. A HPLC vial with magnetic stirring
bar was charged with the ketone or aldehyde (25.0 µmol,
1 eq.), zinc (8.0 mg, 125 µmol, 5 eq.), NH4Cl (11.0 mg,
200 µmol, 8 eq.) and diphenyl phosphate (2.0 mg,
8.0 µmol, 0.3 eq.). Allylic bromide 4 (36.0 µmol, 1.5 eq.)
dissolved in toluene (200 µL) was added and the reaction
mixture was stirred at room temperature for 16 h. The
suspension was filtered through a plug of silica gel (~1 g),
the plug was rinsed with additional EtOAc (ca. 1 mL) and
the combined filtrates were concentrated. The residue was
dissolved in a small amount of EtOAc (ca. 100 µL) and half
of the solution was adsorbed on the starting line of a silica
gel TLC plate (~8 cm wide). The plate was developed in the
solvent indicated for flash chromatography for the specific
compound (indicated below) and the product band was
scratched off. The obtained silica gel with the adsorbed
product was transferred into a HPLC vial with magnetic
stirring bar and was extracted by stirring with 2-propanol
(800 µL) for 30 min at 22 °C. The suspension was filtered
through a syringe filter (Nylon, 0.2 µm) and subjected to
HPLC-MS and HPLC-UV analysis on a chiral stationary
phase.
9
10
11
12
13
14
15
16
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60
Time study of the catalytic reaction with regard to
the accumulation of 9 over time. Zinc dust (10.1 mg, 155
µmol, 5 eq.) and ammonium chloride (13.3 mg, 248 µmol, 8
eq.) were combined in a 1 mL HPLC vial. A stock solution
(200 µL toluene and 50 µL 2-iPr2O) containing the
bromolactone 3 (6.5 mg, 37 µmol, 1.2 equiv.), benzaldehyde
(5, 3.3 mg, 31 µmol, 1 eq.) and (R)-TRIP (2, 2.3 mg, 3.1 µmol,
0.1 eq., 10 mol-%) was added and the reaction mixture was
stirred at room temperature. Samples of 50 µL were
withdrawn after the times given below, applied to a syringe
with filter, diluted with 500 µL of toluene and filtered. The
filtrate was quenched with aqueous HCl (1 M, 100 µL), the
phases were separated, the organic phase was dried over
Na2SO4 and subjected to GC-FID analysis [for conditions
and instrumentation see general part; tret(quenched 9) =
6.65 min, tret(3) = 11.20 min, tret(SI01) = 18.41 min]. The final
sample (after 23 h reaction time) was dried by a positive
stream of air, redissolved in 2-PrOH (500 µL) and subjected
to HPLC-UV analysis on a chiral stationary phase {Daicel
Chiralpak AD, n-heptane/2-propanol 85/15, 0.7 mL/min, 18
Mechanistic Studies
General. All reactions were performed in dry and
degassed CDCl3. All samples were prepared under a dry
argon atmosphere in flame-dried glass ware. 31P-NMR
spectra were referenced to dimethyl methylphosphonate
( = +33.8 ppm) unless otherwise noted. The reference was
filled into a small capillary (50 µL volume), which was
sealed by flame and added to the corresponding sample to
avoid interaction of the standard with the reaction
mixture. 1H- and 13C-spectra were referenced to the residual
solvent peak of CDCl3 [ = 7.26 ppm (1H) and 77.16 ppm
(13C)].
°C, UV 215 nm, tret(enantiomer 1)
tret(enantiomer 2) = 14.1 min}: tret(major isomer) = 13.7 min,
92% ee.
=
13.0 min,
GC-MS headspace measurements for the indirect
detection of the zinc phosphate salt of 2. Zinc dust (33
mg, 500 µmol) ammonium chloride (43 mg, 800 µmol) and
TRIP (2, 22.5 mg, 30 µmol) and a magnetic stirring bar were
placed into an agilent headspace vial. The vial was capped
and crimped, evacuated and refilled with dry N2. A solution
of 4 (29 mg, 150 µmol, 21 µL) in dry dichloromethane (200
µL) was added. The reaction mixture was stirred at room
temperature for 3 h and subjected directly to the GC-MS
headspace sampling under the conditions outlined in the
general section. t(ret)(quenched reagent 9) = 6.03 min.
TRIP (2) spectra in the
4 (5 eq.),
Zn, NH4Cl
Br
O
P
O
O
O
O
presence of allylic
OEt zinc reagent derived
from 4. (S)-TRIP [(S)-2,
Zn
P
*
*
O
OH
O
CDCl3, RT, 2 h
O
Zn
2
Br
31P: 3.37 ppm
8a
, assumed structure
31P: 4.63 ppm
22.5 mg,
zinc
30.0 µmol),
(98.1 mg,
1.50 mmol, 50 eq.) and ammonium chloride (128 mg,
2.40 mmol, 80 eq.) were combined in a Schlenk tube with
magnetic stirring bar and suspended in CDCl3 (600 µL). 4
(29.0 mg, 150 µmol, 21.0 µL, 5 eq.) was added and the
reaction mixture was stirred for 1 h. The reaction mixture
was filtered through a syringe filter (PVDF, 0.45 µm, 33 mm
diameter) and the filtrate was filled into a NMR tube and
analysed. After 1H-, 13C- and a NOESY spectra were
recorded, the capillary with dimethyl methylphosphonate
O
P
O
O
O
Preparation
phosphate 10. TRIP (2, 26
mg, 34 µmol) and
[ZnCO3]2.[Zn(OH)2]3 (26 mg,
of
zinc
O
Zn(CO3)2
P
ZnX
*
*
O
OH
O
10
toluene,
RT, 16h
2
(X = O(CO)OZn)
31P: 6.67 ppm
31P: 3.37 ppm
>58% zinc basis, 230 µmol zinc) were combined in a
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The Journal of Organic Chemistry
Schlenk tube and dry, degassed CDCl3 (700 µL) was added. Computational Methods.
1
The slurry was stirred for 16 h at room temperature, and
transferred via syringe, canula and syringe filter (PVDF,
0.45 µm, 33 mm diameter) into a NMR tube under argon
protective gas atmosphere. A capillary with dimethyl
methylphosphonate was added to reference the 31P-NMR
and the tube was capped and subjected to NMR analysis.
After the analysis, 70 µL were withdrawn from the sample
in order to test its catalytic activity. The remaining 630 µL
were directly subjected to the next reaction step. 1H-NMR
(CDCl3, 300 MHz):  = 7.87 (d, J = 8.2, 2H), 7.46 (ddd, J1 =
8.1, J2 = 6.3, J3 1.5 Hz, 2H), 7.33 – 7.20 (m, 4H), 7.01 (d, J = 1.7
Hz, 2H), 6.94 (d, J = 1.7 Hz, 2H), 2.88 (p, J = 6.9 Hz, 2H),
2.66 (tt, J1 = 13.5, J2 = 6.8 Hz, 4H), 1.26 (d, J = 4.5 Hz, 6H),
1.23 (d, J = 4.4 Hz, 6H), 1.07 (d, J = 6.8 Hz, 6H), 0.97 (d, J =
6.7 Hz, 6H), 0.91 (d, J = 6.8 Hz, 6H), 0.79 (d, J = 6.7 Hz, 6H);
13C{1H}-NMR (CDCl3, 75 MHz):  = 148.6, 148.5, 147.9, 146.8,
146.6, 132.7, 132.5, 132.3, 132.2, 130.8, 128.2, 127.3, 126.2, 125.4,
122.3, 121.0, 120.3, 34.3, 31.0, 30.8, 26.3, 25.1, 24.3, 24.1, 23.4,
23.3; 31P{1H}-NMR (CDCl3, 121.5 MHz):  = 6.67.
2
3
4
5
6
7
8
9
Conformational searches of the catalyst and the substrates
were performed with the COSMO-conf program27 at the
BP8628-29/def-SVP22-23 level and single points were
calculated at the BP86/def-TZVP level. All calculations
were run with the TURBOMOLE program (version 6.6),30
while the DLPNO-CCSD(T)/cc-pVTZ calculations were
performed with ORCA 4.0.1.2.31 The geometries were
optimized using the PBE functional,20-21 the def2-SVP basis
set and D3-dispersion correction. To reduce computational
cost, the RI-approximation was utilized. To model solvent
effects, the geometries were reoptimized at the RI-PBE-
D3/def2-SVP level employing the COSMO-solvation model
for toluene (εr = 2.438 at 0 °C).24-25 Transition states were
located by using TURBOMOLE’s woelfling-program32
followed by subsequent geometry optimization. Analytical
normal modes were determined using TURBOMOLE’s
aoforce-program for confirmation of the stationary points
and transition state search. After scaling of the
frequencies33 the rigid-rotor-harmonic-oscillator (RRHO)
approximation was used to calculate zero point vibrational
energies and thermal properties (at 4 °C). Single points of
the transition states and minima were calculated with RI-
PBE-D3/def2-TZVPPD (with and without computing
solvation effects), B3LYP-D3/def2-TZVPPD and DLPNO-
CCSD(T)/cc-pVTZ (without solvation effects). Zero-point
energies and thermal corrections for the COSMO-
reoptimized structures and the single point calculations
were taken from the RI-PBE-D3/def2-SVP gas phase
calculations. COSMO corrected energies for the B3LYP28, 34-
35-D3/def2-TZVPPD and DLPNO-CCSD(T)36/cc-pVTZ37-38
were obtained from the RI-PBE-D3/def2-TZVPPD single
point calculations. All presented data are given on the
DLPNO-CCSD(T)/cc-pVTZ G+COSMO level unless
otherwise noted.
10
11
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60
3 (2 eq.),
Zn, NH4Cl
Br
Preparation
of
O
P
O
O
O
O
Zn
ZnX
P
*
*
O
O
10
O
complex 8b from
zinc phosphate 10.
Zinc dust (10 mg, 153
O
CDCl3
,
O
Zn
RT, 16h
8b, assumed structure
(X = O(CO)OZn)
31P: 6.67 ppm
Br
31P: 4.54 ppm
µmol, 5 eq.) and ammonium chloride (13 mg, 243 µmol, 8
eq.) were combined in a flame dried Schlenk tube. The
solution containing zinc phosphate 10 in CDCl3 (ca. 630
µL) was added, followed by bromolactone 3 (6.8 µL, 11.6
mg, 66 µmol) and the reaction mixture was stirred for 16 h
at room temperature. Subsequently, it was transferred via
syringe, canula and syringe filter (PVDF, 0.45 µm, 33 mm
diameter) into a NMR tube under argon protective gas
atmosphere. A capillary with dimethyl methylphosphonate
was added to reference the 31P-NMR and the tube was
capped and subjected to NMR analysis. As the solubility of
the complex proved low, 100 µL of DMSO-d6 were added
and the NMR analysis was repeated. Subsequently, 70 µL
of this reaction mixture were used to test the catalytic
potential of complex 8b as described below.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Testing the catalytic activity of salt 10 and complex
8b. Zinc dust (10 mg, 153 µmol, 5 eq.) and ammonium
chloride (13 mg, 243 µmol, 8 eq.) were combined in a flame
dried Schlenk tube. Dry toluene (1 mL) was added,
followed by the catalyst preparation (3.4 µmol in 70 µL
CDCl3), benzaldehyde (5, 3.0 µL, 2.9 mg, 30 µmol) and
bromolactone 3 (3.5 µL, 5.8 mg, 33 µmol). The remaining
slurry was stirred for 16 h at room temperature, filtered
through a pad of silica and concentrated to dryness. The
residue was dissolved in 2-PrOH and subjected to HPLC-
UV analysis on a chiral stationary phase {Daicel Chiralpak
IA, n-heptane/2-PrOH 95/5, 1.0 mL/min, 30°C, UV 215 nm,
t(ret)(enantiomer 1) = 26.4 min, t(ret)(enantiomer 2) = 28.3}:
t(ret)(major isomer) = 28.7 min (catalyst 2), 28.7 min
(catalyst 10), 28.7 min (catalyst 8b); ee = 96% for all
catalysts. All other physical data has been reported
previously.11
NMR- and HPLC spectra, and additional data to the
performed calculations (PDF)
Coordinates of calculated structures (PDF)
AUTHOR INFORMATION
Corresponding Author
* Michael Fuchs, University of Graz, Institute of Chemistry,
Bioorganic and Organic Chemistry, Heinrichstrasse 28/II,
8010 Graz, Austria, Europe; mail to: michael.fuchs@uni-
graz.at.
* A. Daniel Boese, University of Graz, Institute of Chemistry,
Physical and Theoretical Chemistry, Heinrichstrasse 28/IV,
8010 Graz, Austria, Europe; mail to:
adrian_daniel.boese@uni-graz.at.
ACKNOWLEDGMENT
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Benzaldehydes: Synthetic Applications and Factors Governing the
M. Lazzarotto and M. Fuchs are grateful for a grant of the
Austrian Science Fund (FWF, P 31276-B21). K. Faber, K.
Zangger, B. Werner, E. Schwarz, J. Schachner and R. Fischer
are acknowledged for fruitful discussion. J. Goodman, J.
Antilla, K. N. Houk and M. Grayson are acknowledged for
discussion of the content prior to submission.
Enantioselectivity. ACS Catal. 2016, 6, 2506-2514.
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2013, 78, 1208-1215.
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Page 10 of 10
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TOC Graph
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O
OH
H
Active
O Species
H
O
O
+
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65.39
30
Zn
Zinc
O
Br
Lewis acidic
based mechanism
Chiral counterion
phosphate
Detailed ab
initio calculations
TS and dipole moments
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