Investigations concerning the syntheses of TADDOL-derived secondary amines and their use to access novel chiral organocatalysts

Article abstract of DOI:10.1055/s-0032-1316804

A structurally carefully diversified library of novel TADDOL-derived chiral secondary amines was synthesized and investigated for their applicability to obtain new organocatalysts like chiral Lewis bases and chiral phase-transfer catalysts. The scope and limitations of the developed syntheses routes to access these catalysts as well their catalytic performance in different benchmark reactions were systematically investigated. The most powerful of the catalysts prepared was found to be highly useful for the phase-transfer catalyzed α-alkylation of glycine Schiff base (high yields and up to 93% ee). Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316804

PAPER
▌3661
paper
Investigations Concerning the Syntheses of TADDOL-Derived Secondary
Amines and Their Use To Access Novel Chiral Organocatalysts
Towards TADDOL-Derived Organocatalysts
Katharina Gratzer, Mario Waser*
Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstraße 69, 4040 Linz, Austria
Fax +43(732)24688747; E-mail: Mario.waser@jku.at
Received: 06.09.2012; Accepted after revision: 24.09.2012
scope and limitations of these synthetic routes. In addi-
tion, the catalytic potential and the structure-activity rela-
tionship of the newly acquired catalysts in important
benchmark reactions were investigated.
Abstract: A structurally carefully diversified library of novel
TADDOL-derived chiral secondary amines was synthesized and in-
vestigated for their applicability to obtain new organocatalysts like
chiral Lewis bases and chiral phase-transfer catalysts. The scope
and limitations of the developed syntheses routes to access these
catalysts as well their catalytic performance in different benchmark
reactions were systematically investigated. The most powerful of
the catalysts prepared was found to be highly useful for the phase-
transfer catalyzed α-alkylation of glycine Schiff base (high yields
and up to 93% ee).
Ar Ar
HO
HO
COOH
COOH
R1
R2
O
O
OH
OH
Ar Ar
Key words: chiral pool, tartaric acid, asymmetric phase-transfer
L-tartaric acid (1)
TADDOLs 2
catalysis, Lewis base catalysis, asymmetric alkylation
Ar Ar
O
The use of chiral small molecule organocatalysts to facil-
itate demanding stereoselective applications has attracted
considerable interest over the last decade.1 One of the
main prerequisites to develop this methodology further to-
wards new, more generally applicable transformations
with a broader reaction scope is the availability of power-
ful, easily obtainable and easily modified (fine-tuned) cat-
alysts. We have recently started a project targeting the use
of tartaric acid (1) or easily derived TADDOLs 2 to syn-
thesize novel organocatalysts. Although TADDOLs are
omnipresent as ligands in (transition) metal catalysis2 and
tartaric acid is a versatile starting material for preparing
important chiral compounds,3 the use of these easily avail-
able natural chiral pool-based starting materials to obtain
asymmetric organocatalysts has so far been limited to a
few (but often impressive) examples only.4–6 Whilst our
initial investigations on the syntheses of TADDOL-
derived sulfonimides failed,7 we recently created a small
library of novel TADDOL-derived N-spiro quaternary
ammonium salts 3, which were found to be powerful
phase-transfer catalysts (PTCs) for the stereoselective
α-alkylation of glycine Schiff bases.8 Encouraged by
these promising initial results we have now undertaken
systematic investigations concerning the syntheses and
applicability of TADDOL-derived secondary amines 42,9
and 5 to synthesize a variety of structurally diverse novel
chiral Lewis base catalysts10 6–9 and chiral phase-transfer
catalysts11 3, 10–12 (Scheme 1). The main focus in this
work was therefore on the development of reliable and
flexible synthetic strategies to achieve the key intermedi-
ates and a diverse library of catalysts and to elucidate the
R1
n
NH
phase-transfer
catalysts (PTCs)
R2
Lewis bases
O
n
Ar Ar
secondary
TADDamines
4 (n = 0)
5 (n = 1)
Lewis bases:
Ar Ar
Ar Ar
O
H
O
R1
O
R1
R2
O
O
n
n
P
NR2
NR2
N
N
R2
O
n
n
Ar Ar
Ar Ar
6 (n = 0)
7 (n = 1)
8 (n = 0)
9 (n = 1)
PTCs:
Ar Ar
Ar Ar
X
X
R1
O
R1
R2
O
O
n
R
R
n
N
N
Y
R2
O
n
n
Ar Ar
Ar Ar
10 (n = 0)
11 (n = 1)
12 (n = 0)
3 (n = 1)
Scheme 1 Targeted key intermediate secondary amines 4 and 5 and
envisaged asymmetric Lewis base and phase-transfer catalysts
Pyrrolidine 4-Based Catalysts
The syntheses of TADDOL derivatives have been careful-
ly investigated and described in the past, especially by
Seebach’s group.2,9 Whereas different acetal/ketal groups
and aryl substituents have to be introduced early in the
synthesis of TADDOLs from tartaric acid (1), functional-
izations of the hydroxyl groups are most commonly
SYNTHESIS 2012, 44, 3661–3670
Advanced online publication: 16.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316804; Art ID: SS-2012-T0707-OP
© Georg Thieme Verlag Stuttgart · New York

3662
K. Gratzer, M. Waser
PAPER
achieved via conversion of TADDOLs 2 into dichloro
compounds 13, which can then be reacted with different
Azepane 5-Based Phase-Transfer Catalysts
nucleophiles.7,9 With respect to the syntheses of the pyrro- We have recently succeeded in developing a four-step
lidine-containing catalysts the ‘standard’ TADDOL 2aa route to build a small library of azepane-based C2-sym-
(R1 = R2 = Me, Ar = Ph)2,9 was first converted into the metric acetonide-containing N-spiro catalysts 3a (based
known azabicyclo[3.3.0]octane 4aa according to the pub- on the classical acetonide moiety with R1 = R2 = Me)
lished procedure.9b With this easily available compound starting from known TADDOLs 2a (Scheme 3).8 Based
in hand we first investigated the formation of the chiral on this initial success we have now undertaken systematic
formamide Lewis base 6aa. However, we were not able to investigations concerning the scope and limitations of this
obtain this compound as the secondary amine 4aa was route to synthesize new PTCs and also to employ the key
found to be rather unreactive, even upon treatment with intermediate 5 to realize novel chiral Lewis bases.
Ar Ar
Ar Ar
highly reactive acetic formic anhydride. During the course
of our investigations we also became aware that the
Seebach group experienced similar problems in modify-
ing this compound and has also not been able to obtain
6aa.12 In addition, they also reported a surprisingly high
instability of the ketal group of this compound under
slightly acidic conditions, which fully corresponds to our
experience with this highly strained trans-azabicyc-
lo[3.3.0]octane. This enhanced instability of the normally
rather stable acetonide moiety is also in line with recent
results in our group obtained with an analogous trans-
thiabicyclo[3.3.0]octane based TADDOL-derivative.7
Also treatment with several alkyl halides like 1,4-dibro-
mobutane or bromobutane or methyl iodide under a vari-
ety of conditions never gave any quaternary ammonium
salts 10aa or 12aa at all. The only transformation we ob-
served was a very slow formation of traces of intermediate
tertiary amines 14aa, but absolutely no quaternization
could be achieved (Scheme 2). Moreover, the bicyc-
lo[3.3.0] skeleton was also found to be unstable under
harsher basic reaction conditions resulting in partial ace-
tonide cleavage again. Accordingly, the use of the long-
known secondary amine 4aa to prepare novel chiral Lewis
bases13 or PTCs is not only limited because of the reduced
reactivity of the nitrogen, but also because of an increased
instability of this compound. These observations also ra-
tionalize why this (on a first glance promising) compound
has never really been used in any demanding applications.
Ar Ar
O
O
O
O
O
O
X
c)
d)
NH
N
Y
X
Br
Ar Ar
Ar Ar
Ar Ar
5a
3a
2a (X = OH)
13a (X = Cl)
a)
b)
15a (X = CN)
Ar = Ph (a); 4-t-BuC6H4 (b); 4-FC6H4 (c); 3-MeC6H4 (d); 3,5-Me2C6H3 (e);
3-PhC6H4 (f); 4-PhC6H4 (g)
N
Y
N
N
N
=
(a)
(b)
(c)
Scheme 3 Successful syntheses of a first library of C2-symmetric ace-
tonide-containing azepane-based PTCs 3a.8 Reagents and conditions:
a) SOCl2, Et3N, CH2Cl2, 25 °C; b) TMSCN, SnCl4, 25 °C, 47–63%
(over two steps); c) LiAlH4, mesitylene, reflux, 30–43%; d) Br–Y–Br,
K2CO3, MeCN, reflux, 49–69%.
Initial route development was carried out using the parent
TADDOL 2aa (R1 = R2 = Me, Ar = Ph). Surprisingly,
elongation of the carbon chain of TADDOLs has so far
not been systematically investigated.14 Reacting dichloro
compound 13aa with TMSCN (>2.5 equiv) in the pres-
ence of catalytic amounts of SnCl4 (25%)15 was rewarded
with the formation of dinitrile 15aa in excellent yield on a
multigram scale. Conversion into the secondary amine
5aa was found to be rather tricky as dinitrile 15aa turned
out to be unreactive under a variety of different condi-
tions. Attempted saponification failed even under very
strong basic conditions (e.g., refluxing with 20% NaOH
resulted in the recovery of starting material accompanied
with a partial decomposition). Attempted conversion into
the corresponding dialdehyde upon treatment with
DIBAL-H failed as 15aa was found to be unreactive un-
der standard DIBAL-H reduction conditions or decom-
posed under more forcing conditions. Also other hydride
donors like NaBH4 (also in combination with different ad-
ditives), Red-Al, LiBH4, or LiAlH4 at room temperature
in different ethereal solvents did not affect the cyano
groups either. Interestingly, we discovered that refluxing
heterogeneous mixtures of 15aa and excess LiAlH4 (20
equiv) in high boiling aromatic solvents (mesitylene was
found best) for 30–45 minutes gave access to amine 5aa
in around 30–40% isolated yield. HRMS studies of this re-
Ph Ph
Ph Ph
NH
O
O
O
O
X
a)
b)
d)
6aa (not formed)
12aa (not formed)
X
Ph Ph
Ph Ph
2aa (X = OH)
4aa
a)
c)
13aa (X = Cl)
Ph Ph
N
O
O
c)
R
10aa (not formed)
Ph Ph
14aa (trace)
Scheme 2 Attempted syntheses of pyrrolidine 4aa based organocata-
lysts: Reagents and conditions: a) ref. 9b; b) acetic formic anhydride; c)
different RX, different conditions; d) 1,4-dibromobutane, different
conditions.
Synthesis 2012, 44, 3661–3670
© Georg Thieme Verlag Stuttgart · New York

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Towards TADDOL-Derived Organocatalysts
3663
action revealed the presence of amidine intermediates be- Direct dicyanation of TADDOLs 2a with TMSCN in the
sides other unidentified by-products. These by-products presence of a Lewis acid worked with modest yields in the
were found to be nonpolar, highly fluorescent condensed case of electron-neutral aromatic residues (e.g., 2aa was
aromatic compounds, containing no heterofunctionalities directly converted into 15aa in around 30% unoptimized
like the acetonide or cyano groups anymore. Attempts to yield) but again no conversion was observed in the case of
increase the yields by using other solvents or different ad- electron poor aryl group containing TADDOLs. Accord-
ditives did not improve the outcome. Attempted heteroge- ingly, transformations of the benzylic position of the
neous hydrogenation was also not successful so far.16 TADDOL-skeleton are highly dependent on the electron-
However, having established a reliable route for the syn- ic properties of the aromatic substituents. Interestingly,
theses of the chiral secondary amine 5aa, the introduction whereas the corresponding naphth-2-yl-substituted di-
of different aryl groups to modify the steric and electronic chloride was accessible, dicyanide formation was not pos-
properties of this skeleton was focused next. As depicted sible in this case and just decomposition products were
in Scheme 3, a variety of different electron-neutral aryl obtained. In contrast, the sterically demanding biphenyl-
substituents were introduced successfully during our ini- containing dicyanides 15af and 15ag could be obtained in
tial investigations. Besides aryl groups with electronic high yields.19 All the obtained acetonide-based dicyanides
properties similar to a phenyl group in amines 5a (and the 15a could be converted into the secondary amines 5a in
corresponding catalysts), other aromatic residues bearing moderate yields (see Table 1).
either electron-rich or electron-deficient groups also
aroused our interest. Interestingly, a very strong differ-
ence in the reactivity of these compounds was observed.
The presence of strong electron-donating groups like
The final quaternization step was first investigated target-
ing N-spiro ammonium salts 3aa. In contrast to amine
4aa, the azabicyclo[5.3.0]decane 5aa (Ar = Ph) was
found to be nucleophilic enough in the reaction with 1,4-
methoxy groups did not allow us to obtain the correspond-
dibromobutane, giving the targeted ammonium bromide
ing dichlorides 13a under a variety of different chlorina-
3aaa (see Scheme 3; R1 = R2 = Me, Ar = Ph, Y = group a)
tion conditions, but instead different elimination and also
in 60% isolated yield upon refluxing 5aa with 4 equiva-
Friedel–Crafts products were formed.17 On the other
lents dibromobutane (MeCN, K2CO3). Noteworthy,
hand, strong electron-withdrawing substituents like tri-
whereas only traces of the intermediate tertiary amine
fluoromethyl groups did not give the dichlorides either,
were observed, significant amounts of unreacted starting
but instead the stable cyclic sulfites 16a were formed18
material 5aa could be reisolated. Similar results were ob-
tained in the successful syntheses of catalysts 3aab
(Ar = Ph, Y = group b) and 3aac (Ar = Ph, Y = group c).
On the other hand, quaternization with 1,2-dibromoethane
(Scheme 4). Unfortunately, neither changing the reaction
conditions, nor using other chlorination agents like PCl5
or oxalyl chloride gave the targeted dichlorides 13a. At-
tempts to employ this sulfite further failed due to the high
resulted in the formation of a very unstable aziridinium-
stability of this compound.
based ammonium salt that could not be employed further.
R
R
Attempting the quaternization with BuBr or MeI to pre-
pare nonspiro ammonium salts 11, only the corresponding
monoalkylated tertiary amines, but no quaternary ammo-
nium compounds 11 could be obtained under a variety of
different conditions.20 Accordingly, it seems that once the
tertiary amine is formed, the final quaternization step only
takes place intramolecularly. This might be rationalized
by the fact that the lone pair of the tertiary nitrogen seems
to be shielded towards an external electrophile by the
bulky aryl substituents, making an intermolecular alkyla-
tion much more difficult than an intramolecular one. This
explanation is also supported by additional molecular
modeling studies.
R = H, 3-Me, 4-t-Bu,
O
O
Cl
Cl
4-F, 3-Ph, 4-Ph
R
R
R
R
13a
SOCl2
Et3N
O
O
R = 3-OMe, 4-OMe
OH
OH
elimination and
Friedel–Crafts products
CH2Cl2
R
R
Surprisingly, when attempts were made to carry out the
quaternization with 1,5-dibromopentane or bis(2-bromo-
ethyl) ether, only formation of the corresponding tertiary
amines, and not even traces of the corresponding piperi-
dine- or morpholine-based ammonium bromides could be
observed. To elucidate this striking difference in the qua-
ternization step additional calculations were carried out
using different force fields and DFT methods to obtain the
optimized structures for the pyrrolidinium-based catalyst
3aaa and the targeted piperidinium-based catalyst 3aad
(Figure 1). A careful analysis revealed no striking differ-
ences between the parent skeletons of these two ammoni-
R
R
2a
O
O
O
O
R = 3-CF3, 4-CF3
S
O
R
R
16a
Scheme 4 Representative overview on the influence of the nature of
different aryl groups on the chlorination reaction
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3661–3670

3664
K. Gratzer, M. Waser
PAPER
um salts. Interestingly, in both cases two of the bulky transformation and we found that just small structural
phenyl groups are in an unfavored syn-pentane interaction changes of the electrophile can be crucial whether ammo-
(1,3-diaxial strain) with the newly introduced CH2 group nium salt formation is possible or not.
adjacent to the spiro ammonium group. Having a closer
As already depicted above, the use of more rigid dihalo-
look on the calculated tertiary amine intermediate it be-
electrophiles (e.g., xylene- or naphthyl-based ones) made
comes obvious that the electrophile has to approach the
quaternization possible (Scheme 3). We therefore at-
nitrogen lone pair via a rather close channel between the
tempted to introduce an axially chiral group by either re-
acting amines 5aa with dibromobiphenyl 17 or with both
enantiomers of binaphthyl 18 (Scheme 5). In both cases
phenyl groups. The calculated distances between the near-
est carbon atoms of the phenyl rings is around 4.5 Å and
for the nearest protons around 3.7 Å. As the SN2-type 6-
the reaction proceeded quickly under the standard reac-
ring formation is supposed to proceed via a sterically
tion conditions. The isolated ammonium salt 3aae was
found to be a mixture of diastereomers containing addi-
more demanding chair-type transition state with addition-
al destabilizing 1,3-diaxial-type interactions between the
tional impurities that could hardly be separated. In addi-
large N-substituents and the axial β-hydrogens, and
tion it was found that the amount of these impurities
whereas the 5-ring formation should proceed via a more
increased upon standing in solution and when the catalyst
planar transition state with a significantly lower transition
was exposed to basic conditions. Formation of both dia-
state strain energy (resulting in a much faster cyclization
stereomers of the binaphthyl-based salt 3aaf proceeded
reaction),21 it seems reasonable that our rather tight and
easily with full consumption of starting materials within a
crowded structure disfavors 6-ring formation significant-
few hours. Crude NMR, TLC, and HRMS analyses con-
ly. Steric hindrance in the transition state was also ac-
firmed the formation of the targeted product accompanied
counted to be the main reason for the unsuccessful
by significant amounts of by-products. Column chroma-
cyclization of substituted 1,4-dibromobutanes like (R,R)-
tography allowed us to isolate the most polar spot (with Rf
values similar to those of other PTCs) solely. However,
although ESI-HRMS proved the formation of the product,
it was not possible to record a clean NMR spectrum of this
or (S,S)-1,4-dibromo-2,3-dimethoxybutane where again
absolutely no formation of quaternary ammonium salts
could be observed.
Thus, and in contrast to analogous high-yielding transfor- compound as within minutes the formation of a much less
mations in the syntheses of the powerful Maruoka cata- polar product was observed (detected by TLC). Isolation
lysts,22 the quaternization of amines 5 is a rather difficult of this compound (accompanied with other unidentified
by-products) and analysis indicated the formation of the
tertiary amine 19,23 most presumably via a Stevens type
rearrangement, which is a well-known reaction for bi-
naphthyl and biphenyl-based ammonium salts.24 Accord-
ingly these highly crowded compounds turned out to be
Br
Ph Ph
Br
Br
O
O
N
5aa
decomp.
Ph Ph
3aae
17
(mixture of diastereomers)
Br
Ph Ph
Br
Br
O
5aa
N
O
Ph Ph
(R)- or (S)-18
3aaf
Ph Ph
O
N
O
Ph Ph
19
(via Stevens-type
rearrangement)
Figure 1 Comparison of the optimized structures of pyrrolidinium
and piperidinium-based chiral ammonium salts and the tertiary inter-
mediate in their syntheses
Scheme 5 Attempted syntheses of the centro-chiral–axially-chiral hy-
brid catalysts 3aae and 3aaf
Synthesis 2012, 44, 3661–3670
© Georg Thieme Verlag Stuttgart · New York

PAPER
Towards TADDOL-Derived Organocatalysts
3665
far too unstable to be used as chiral phase-transfer cata- ever, as this compound was much more difficult to obtain
lysts in asymmetric reactions (this behavior was even than the others due to low yields and vast amounts of by-
more pronounced in the case of amines bearing bulkier products especially in the final steps we did not investi-
aryl groups).
gate it further. As most of the introduced substituents re-
duced the catalytic potential of our PTCs we also
attempted to synthesize acetal-based catalysts. However,
all attempts to obtain these ammonium salts (e.g., formal-
dehyde or benzaldehyde as the acetal group, entries 34
and 35) failed because the strong LiAlH4-reduction condi-
tions always cleaved off these acetal groups. In addition,
we also attempted to replace the dioxolane ring, for exam-
ple, by a dioxane ring or by two methoxy groups.27 How-
ever, in both cases we were not able to prepare the
corresponding dichlorides. Instead we observed forma-
tion of the corresponding tetrahydrofurans originating
from an intramolecular nucleophilic substitution reaction
on the monochloro intermediate.
It is worth noting that the quaternary ammonium salts 3
synthesized so far give rather broad H NMR peaks
1
(CDCl3), especially for the CH2 groups adjacent to the
quaternary ammonium group, thus indicating a certain
conformational flexibility of the N-spiro skeleton. Ac-
cordingly, it seems that these ammonium salts are struc-
turally less rigid than the axially chiral Maruoka catalysts.
Based on these investigations we were then able to syn-
thesize a carefully investigated and extended library of
acetonide containing catalysts 3a first and to identify the
best-suited aryl substituents, quaternary ammonium
group, and counter anion by testing these catalysts in the
asymmetric α-alkylation of glycine Schiff base 20 using
benzyl bromide (21) as the electrophile.25 Table 1 gives a
detailed overview on the acquired catalysts, the limita-
tions of the developed synthesis route, and the results of
the successfully obtained PTCs in the test reaction. After
identifying the p-biphenyl-containing pyrrolidinium am-
monium bromide 3aga as the most active amongst the
tested acetonide-based catalysts (Table 1, entries 1–27)
the influence of the ketal group on the catalytic potential
of these PTCs was investigated next. Inspired by interest-
ing results reported by the Shibasaki group about the in-
fluence of different ketal groups on the catalytic
performance of their tartaric acid-derived two-center cat-
alysts,6 we targeted a small library of C1- and C2-symmet-
ric catalysts based on the p-biphenyl azepane-N-
pyrrolidinium skeleton with different ketal moieties (en-
tries 28–35). With respect to the syntheses of these cata-
lysts it was found necessary to start from the
corresponding tartrates and bring them through the
sequence, as we have so far not been able to carry out a
selective transacetalization on one of the later stages. In-
terestingly, whereas different dialkyl ketals could easily
be transferred through the developed sequence, the aceto-
phenone-based catalyst 3fga was not that easily obtained,
as the dicyanation and reduction step were found to give
an increased amount of difficult to separate impurities.
Based on all these studies we finally identified the p-bi-
phenyl-containing pyrrolidinium ammonium bromide
3aga as the most active catalyst for the asymmetric α-al-
kylation of glycine Schiff base 20 (Table 1, entry 8). As
recently disclosed, the use of different electrophiles in this
reaction was well tolerated with up to 93% ee and isolated
yields of 70–80%,28 (for an overview, see Scheme 6, up-
per reaction scheme) thus making this compound a versa-
tile catalyst for asymmetric reactions using prochiral
nucleophiles. In addition the use of this catalyst was also
investigated for the asymmetric epoxidation of chalcone
23, thus employing an achiral nucleophile and a prochiral
electrophile (Scheme 6, lower reaction scheme).29 Unfor-
tunately, despite a thorough screening of different reac-
tion conditions it was not possible to obtain the epoxide 24
in any reasonable enantiomeric excess although the cata-
lyst promoted the reaction well giving the product in high
yield.30
(S,S)-3aga
(10 mol%)
Ph
N
CO2t-Bu
Ph
N
CO2t-Bu
RX (3 equiv)
toluene, KOH (50%)
–35 °C, 20 h
Ph
Ph
R
20
23
70–80%
76–93% ee
(S,S)-3aga
(10 mol%)
O
O
Testing the obtained ammonium salts in the asymmetric
α-alkylation of 20, a strong influence of the introduced ke-
tal groups was observed. Amongst the C2-symmetric cat-
alysts the parent compound 3aga was found to be the most
active one (Table 1, entry 8 vs. 28, 29). In the case of the
C1-symmetric ones, the tert-butyl containing catalyst
3ega (entry 31) was found to give by far the lowest selec-
tivity. Interestingly, in contrast to the other catalysts this
ammonium salt shows sharp NMR peaks, thus indicating
that the tert-butyl holding group forces the rest of the skel-
eton in a more rigid (but less selective) conformation. Use
of this catalyst in alternative solvents did not improve the
result. Whereas the corresponding isobutyl and benzyl an-
alogues (entries 30 and 33) performed slightly worse than
3aga, the acetophenone-based catalyst 3fga gave (S)-22
with the same enantioselectivity (entry 32 vs. 8).26 How-
Ph
Ph
Ph
Ph
H2O2 or NaOCl
different conditions
O
24
>80%, <7% ee
Scheme 6 Scope and limitation of TADDOL-derived PTC 3aga in
asymmetric applications
Azepane 5-Based Chiral Lewis Bases
Chiral Lewis bases have proven to be useful catalysts for
the activation of Lewis acids like, for example, organosil-
icon nucleophiles. We reasoned that the chiral secondary
amines 5 present versatile starting materials to prepare
chiral formamides 7 and chiral phosphoramides 9. Where-
© Georg Thieme Verlag Stuttgart · New York
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3666
K. Gratzer, M. Waser
PAPER
Table 1 Targeted and Obtained Catalysts and Their Performance in the Asymmetric α-Alkylation of Glycine Schiff Base 20
Ar Ar
R1
R2
O
O
N
Y
Ar Ar
X
O
O
(S,S)-3 (10 mol%)
Ph
N
Ph
N
+
PhCH2Br
Ot-Bu
Ot-Bu
toluene, KOH (50% aq)
20 h
Ph
Ph
Ph
20
21
22
Entry Cata
Catalyst structure
Ar
Catalyst synthesisb
Alkylation
R1/R2
Y
X–
13 15
5
3
21 (equiv) Temp Yieldc (Conv.)d ee (%)e
(°C)
(%)
(Conf.)f
1
2
3
4
5
6
7
8
3aaa
3aba
3aca
3ada
3aea
3afa
3aga
3aga
3aha
3aia
3aja
3aka
3ala
Ph
Me/Me
ag
Br–
+
+
+
+
+
+
+
+
+
+
+
–
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
1.2
–20
55 (~70)
30 (~50)
35 (~50)
77 (~90)
47 (~60)
45 (~60)
65 (~80)
81 (quant)
72 (~95)
65 (~80)
45 (~60)
–
45 (S)
61 (S)
34 (S)
55 (S)
5 (S)
7 (S)
79 (S)
87 (S)
76 (S)
80 (S)
47 (S)
–
4-t-BuC6H4
4-FC6H4
3-MeC6H4
3,5-Me2C6H3
3-PhC6H4
4-PhC6H4
4-PhC6H4
Me/Me
ag
Br–
3
–35
–20
–35
9
4-(4-MeOC6H4)C6H4
4-(3-F3CC6H4)C6H4
4-(2,4,6-Me3C6H2)C6H4
4-(naphth-2-yl)C6H4
4-F3CC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
–
–
–
–
–
–
–
–
–
–
–
–
3ama 3-F3CC6H4
3ana
3aoa
3apa
3aga
3aga
3agb
3agc
3aad
3agd
3aae
3age
3aaf
3agf
3bga
3cga
3dga
3ega
3fga
3gga
3hga
3iga
3-MeOC6H4
4-MeOC6H4
naphth-2-yl
4-PhC6H4
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
–
–
–
–
BF4
PF6
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
–
+
+
+
+
–
–
–
–
–
–
+
+
+
+
+
+
1.2
67 (~80)
61 (~80)
57 (~80)
21 (~30)
–
–
–
–
–
77 (S)
20 (S)
51 (S)
25 (R)
–
–
–
–
–
–
bg Br–
cg
dh
Ph
4-PhC6H4
Ph
4-PhC6H4
Ph
4-PhC6H4
ei
fi
–
–
n-Bu/n-Bu ag
(CH2)5
Me/i-Bu
Me/t-Bu
Me/Ph
Me/Bn
H/H
H/Ph
3
73 (~95)
69 (~90)
72 (~95)
75 (quant)
70 (~90)
79 (quant)
–
78 (S)
82 (S)
84 (S)
50 (S)
87 (S)
80 (S)
–
–
–
–
a The first alphabet denotes the ketal group, the second the aryl group, and the third the quaternary ammonium group.
b The sign + or – indicates whether formation of the respective product was possible or not.
c Isolated yields.
d Judged by NMR of the crude product.
e Determined by HPLC using a chiral stationary phase.
f Absolute configuration was determined by comparison of the HPLC retention time and optical rotation with literature values.22h,31
g See Scheme 3.
h See Figure 1, compound 3aad.
i See Scheme 5, compounds 3aae and 3aaf.
Synthesis 2012, 44, 3661–3670
© Georg Thieme Verlag Stuttgart · New York

PAPER
Towards TADDOL-Derived Organocatalysts
3667
as synthesis of 7aa was easily accomplished by the reac- ber of dihalo-electrophiles in an intramolecular fashion
tion of 5aa (Ar = Ph, R1 = R2 = Me) with acetic formic only, whereas sterically more demanding electrophiles or
anhydride (88% yield), synthesis of 9aa turned out to be intermolecular approaches stalled at the tertiary amines.
rather difficult. Although reaction of 5aa with PCl3 or Further applications of the PTCs are currently investigat-
POCl3 proceeded smoothly, further reaction with ed and will be reported in due course.
(di)amines was found to be problematic, especially due to
the observed good leaving group ability of 5aa, which of-
Melting points were measured on a Kofler melting point microscope
(Reichert, Vienna). H and 13C NMR spectra were recorded on a
Bruker Avance DRX 500 MHz spectrometer, a Bruker Avance III
300 MHz spectrometer, and on a Bruker Avance III 700 MHz spec-
trometer with TCI cryoprobe. All NMR spectra were recorded at
298 K and referenced on the solvent peak. High-resolution mass
spectra were obtained using an Agilent 6520 Q-TOF mass spec-
trometer with an ESI source and an Agilent G1607A coaxial spray-
er. IR spectra were recorded on a Shimadzu IR Affinity-1 FT IR
spectrometer. Optical rotations were recorded on a Perkin-Elmer
Polarimeter Model 241 MC. HPLC was performed using a Dionex
Summit HPLC system with a Chiralcel OD-H (250 × 4.6 mm) chi-
ral stationary phase. All chemicals were purchased from commer-
cial suppliers and used without further purification unless otherwise
stated. All reactions were performed under an argon atmosphere.
Starting TADDOLs were synthesized according and in analogy to
known methods.2,9,33 Molecular modeling studies of the ground
states were performed using the MMFF94 force field (Pcmodel) and
on the B3LYP/6-31G level (Gaussian).
1
ten resulted in the hydrolysis or P–N bond cleavage of the
intermediates. Direct reaction with POCl(NR2)2 was also
not possible. However, after some optimization, it was
found that a two-step reaction of 5aa with POCl3 first and
immediate reaction with N,N′-dimethylethylenediamine
was possible to obtain the phosphoramide 9aa in 86%
yield (Scheme 7). Interestingly, this compound tends to
partially hydrolyze upon standing in solution (e.g., 3 days
in aqueous MeOH). To test these compounds for their cat-
alytic potential the allylation of benzaldehyde (25) with
trichloroallylsilane (26) was chosen as a benchmark reac-
tion. Unfortunately, the homoallylic alcohol 27 was never
obtained in reasonable yield, even when stoichiometric
amounts of Lewis base activator were used, only racemic
product could be obtained under a variety of different con-
ditions with both activators (Scheme 7).32
Catalyst (S,S)-3aga
Ph Ph
Ph Ph
Dicyanide 15ag: SOCl2 (5.65 mL, 77.9 mmol) was added to a solu-
tion of 2ag (12.01 g, 15.6 mmol) in CH2Cl2 (280 mL) and stirred at
r.t. A solution of Et3N (15.1 mL, 109 mmol) in CH2Cl2 (140 mL)
was added dropwise over 30 min. The mixture was stirred for 1 h at
r.t., cooled to 5 °C and sat. aq NaHCO3 (400 mL) was added. The
biphasic mixture was vigorously stirred for 90 min, the layers were
separated, the organic phase was dried (Na2SO4), and evaporated to
dryness. Crude 13ag formed was directly dissolved in CH2Cl2 (400
mL), cooled to 5 °C and TMSCN (9.73 mL, 77.8 mmol) and SnCl4
(1.82 mL, 15.6 mmol) were added. The mixture was warmed to r.t.
over 1 h and stirred for 12 h. After quenching with sat. aq K2CO3
(200 mL), the phases were separated, and the organic phase washed
with sat. aq K2CO3 (2 × 200 mL) and brine (2 × 200 mL) (CAU-
TION! Aqueous phases contain residual cyanide!). After drying
(Na2SO4) and evaporation to dryness, the product was purified by
column chromatography (heptanes–EtOAc, 5:1) to give dicyanide
15ag in 59% (7.26 g, 9.2 mmol) as a light brown solid; mp >220 °C
(dec.); [α]D20 +104.6 (c 1.6, CHCl3).
O
P
N
Me
O
H
O
O
O
O
a
b,c
N
5aa
N
N
Me
Ph Ph
Ph Ph
7aa
9aa
OH
Lewis base
(0.1–1 equiv)
CHO
+
SiCl3
different
conditions
25
26
27
<15%, <5% ee
Scheme 7 Syntheses of chiral TADDOL-derived Lewis bases and at-
tempted application: Reagents and conditions: a) acetic formic
anhydride, Hünig’s base, CH2Cl2, 0–25 °C, 88%; b) POCl3, KH,
DMAP, 4 Å MS, toluene, 60 °C; c) N,N′-dimethylethylenediamine,
Et3N, CH2Cl2, 0–25 °C, 86% (over two steps).
IR (film): 3055, 3030, 1485, 1409, 1373, 1234, 1159, 1076, 1006,
835, 742, 694 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.65 (s, 6 H), 5.68 (s, 2 H), 7.24–
7.36 (m, 14 H), 7.39 (d, J = 8.4 Hz, 4 H), 7.43 (t, J = 7.6 Hz, 2 H),
7.52 (t, J = 7.3 Hz, 4 H), 7.65 (d, J = 8.8 Hz, 8 H), 7.63 (d, J = 7.8
Hz, 4 H).
13C NMR (125 MHz, CDCl3): δ = 28.0 (CH3), 56.6 (CCN), 81.9
(CH), 111.2 (CO2), 120.8 (CN), 126.9 (ArC), 127.1 (ArC), 127.2
(ArC), 127.4 (ArC), 127.5 (ArC), 127.6 (ArC), 127.7 (ArC), 128.8
(ArC), 128.9 (ArC), 135.0 (ArC), 138.4 (ArC), 139.5 (ArC), 140.1
(ArC), 140.6 (ArC), 140.7 (ArC).
In conclusion, we have found that the literature known
TADDOL-derived amine 4aa is not suitable as a starting
material for the syntheses of novel PTCs or chiral Lewis
bases due to a rather low reactivity of the nitrogen and an
increased sensitivity of this compound under acidic and
basic conditions. In contrast, the novel azepane-based
amines 5 could be successfully employed to synthesize
both PTCs and Lewis bases. Whereas the Lewis bases 7aa
and 9aa were found to be catalytically inactive in the cho-
sen test reaction, the N-spiro PTCs 3 were found to be
powerful catalysts for the asymmetric α-alkylation of gly-
cine Schiff base 20 (up to 93% ee). Noteworthy, the devel-
oped synthesis route proved to be suitable for the
synthesis of amines/catalysts containing electron-neutral
aromatic residues mainly. Surprisingly, the final quater-
nization step was found to be possible with a limited num-
HRMS (ESI): m/z calcd for C57H44N2O2: 806.3741 [M + NH4]+;
found: 806.3751.
Amine 5ag: A mixture of 15ag (2.13 g, 2.7 mmol) and LiAlH4 (2.05
g, 54 mmol) in mesitylene (100 mL) was refluxed for 30–45 min,
cooled in an ice bath, and carefully quenched with EtOAc (200 mL)
first, followed by the addition of H2O (150 mL). After phase sepa-
ration, the aqueous phase was extracted with EtOAc (2 × 150 mL)
and the combined organic layers were washed with brine (3 × 150
mL). After drying (Na2SO4) and evaporation to dryness, the product
was purified by column chromatography (heptanes–EtOAc, 5:1) to
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3661–3670

3668
K. Gratzer, M. Waser
PAPER
give 5ag (631 mg, 30%, 0.81 mmol) as a white foam; [α]D20 –143.4
(c 1.14, CHCl3).
Formamide 7aa
A solution of 5aa (123 mg, 0.258 mmol) and Hünig’s base (88 μL,
0.516 mmol) in CH2Cl2 (6 mL) was cooled to 0 °C and acetic formic
anhydride (38 μL, 0.516 mmol) was added. The mixture was
warmed to r.t. over 1 h and stirred for 2 h. After washing with brine
(5 mL), the organic layer was dried (Na2SO4), and evaporated to
dryness. The product was purified by column chromatography (hep-
tanes–EtOAc, 1:1) to give formamide 7aa as a white foam (115 mg,
88%, 0.228 mmol); [α]D20 –247.5 (c 2.3, CHCl3).
IR (film): 3028, 2983, 1732, 1598, 1485, 1369, 1240, 1215, 1166,
1072, 1006, 831, 763, 742 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.86 (s, 6 H), 3.54 (d, J = 14.5 Hz,
2 H), 3.89 (d, J = 14.5 Hz, 2 H), 5.21 (s, 2 H), 7.31–7.34 (m, 4 H),
7.41–7.44 (m, 12 H), 7.51–7.64 (m, 20 H).
13C NMR (125 MHz, CDCl3): δ = 27.0 (CH3), 53.7 (Ar2C), 63.1
(CH2N), 79.7 (CH), 109.6 (CO2), 125.7 (ArC), 126.9 (ArC), 127.1
(ArC), 127.2 (ArC), 127.3 (ArC), 127.4 (ArC), 128.8 (ArC), 128.9
(ArC), 131.7 (ArC), 139.0 (ArC), 139.1 (ArC), 140.9 (ArC), 141.0
(ArC), 142.8 (ArC), 147.6 (ArC).
1H NMR (500 MHz, CDCl3): δ = 0.51 (s, 3 H), 0.89 (s, 3 H), 3.03
(d, J = 14.8 Hz, 1 H), 4.28 (d, J = 15.0 Hz, 1 H), 4.36 (d, J = 15.0
Hz, 1 H), 4.91 (d, J = 8.6 Hz, 1 H), 5.18 (d, J = 14.8 Hz, 1 H), 5.26
(d, J = 8.6 Hz, 1 H), 7.20–7.35 (m, 18 H), 7.40–7.45 (m, 2 H), 7.54
(s, 1 H).
HRMS (ESI): m/z calcd for C57H49NO2: 818.3395 [M + K]+; found:
13C NMR (125 MHz, CDCl3): δ = 26.1 (CH3), 27.2 (CH3), 52.9
(Ar2C), 54.9 (Ar2C), 55.4 (CH2N), 59.1 (CH2N), 77.9 (CH), 78.5
(CH), 110.6 (CO2), 126.1 (ArC), 126.4 (ArC), 126.5 (ArC), 126.6
(2 × ArC), 127.0 (ArC), 127.5 (ArC), 127.8 (ArC), 128.1 (2 × ArC),
129.9 (ArC), 130.8 (ArC), 141.2 (ArC), 141.7 (ArC), 145.8 (ArC),
146.8 (ArC), 163.9 (NCHO).
818.3376.
Catalyst 3aga: A mixture of 5ag (134 mg, 0.172 mmol), 1,4-dibro-
mobutane (81 μL, 0.689 mmol), and K2CO3 (95 mg, 0.689 mmol)
in MeCN (10 mL) was refluxed for 2 days. The inorganic salts were
filtered off, the solvent evaporated, and the residue purified by col-
umn chromatography (CH2Cl2–MeOH, 10:1) to obtain ammonium
salt 3aga as a white solid (108 mg, 57%, 0.118 mmol); mp 163–
168 °C; [α]D20 –57.4 (c 0.74, CHCl3).
HRMS (ESI): m/z calcd for C34H33NO3: 504.2533 [M + H]+; found:
504.2543.
IR (film): 3028, 2931, 1736, 1487, 1371, 1247, 1213, 1161, 1078,
1006, 837, 765, 740, 696 cm–1.
Phosphoramide 9aa
A mixture of 5aa (52 mg, 0.109 mmol), KH (17 mg, 0.424 mmol),
DMAP (13 mg, 0.106 mmol), and activated 4 Å molecular sieves
(50 mg) in anhyd toluene (4 mL) was cooled to 0 °C and a solution
of POCl3 (40 μL, 0.429 mmol) in anhyd toluene (1 mL) was added
dropwise over 30 min. The mixture was warmed to 60 °C over 1 h
and stirred at this temperature for 40 h. After filtration over a pad of
Celite, the solvent was evaporated and the residue dissolved in an-
hyd CH2Cl2 (3 mL), followed by the addition of Et3N (58 μL, 0.418
mmol) and cooling to –10 °C. After dropwise addition of a solution
of N,N′-dimethylethylenediamine (23 μL, 0.212 mmol) in anhyd
CH2Cl2 (1 mL), the mixture was allowed to warm up to r.t. over 2 h,
and stirred for 16 h. The resulting mixture was evaporated to dry-
ness and the residue was purified by column chromatography
(EtOAc) to give phosphoramide 9aa (57 mg, 86%, 0.094 mmol) as
an oily residue (the compound tends to be sensitive to hydrolysis
upon standing in solution); [α]D20 –141.2 (c 2.85, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 6 H), 1.24 (br, 2 H), 1.62
(br, 2 H), 3.57 (br m, 2 H), 3.77 (br m, 2 H), 5.03 (br m, 2 H), 5.44
(br m, 2 H), 5.64 (s, 2 H), 7.31–7.41 (m, 8 H), 7.46 (t, J = 7.2 Hz, 4
H), 7.52–7.62 (m, 12 H), 7.67 (d, J = 7.8 Hz, 4 H), 7.74 (d, J = 7.5
Hz, 4 H), 7.97 (br s, 4 H).
13C NMR (125 MHz, CDCl3): δ = 20.7 (CH2), 25.8 (CH3), 52.6
(Ar2C), 66.8 (CH2N+), 70.6 (CH2N+), 79.2 (CH), 110.9 (CO2), 127.0
(2 × ArC), 127.1 (ArC), 127.5 (ArC), 127.7 (ArC), 127.8 (ArC),
129.0 (2 × ArC), 129.1 (ArC), 131.3 (ArC), 138.1 (ArC), 139.9
(ArC), 140.0 (ArC), 140.1 (ArC), 140.3 (ArC), 143.6 (ArC).
+
HRMS (ESI): m/z calcd for C61H56NO2 : 834.4306 [M+]; found:
834.4317.
Phase-Transfer Catalyzed α-Alkylation of Glycine Schiff Base
20; General Procedure
A mixture of 20 (0.2–1 mmol) and catalyst 3aga (10 mol%) in tol-
uene (6.5 mL/mmol 20) was cooled to 0 °C. Aq 50% KOH (2
mL/mmol 20) was added and the vigorously stirred mixture (>1200
rpm) cooled to –35 °C. After addition of the electrophile (3 equiv),
the biphasic mixture was stirred for 20 h at –35 °C. After extraction
with CH2Cl2 (2 × 15 mL) and washing the combined extracts with
H2O (5 mL) and brine (5 mL), the combined organic phases were
dried (Na2SO4), evaporated to dryness, and purified by column
chromatography. The alkylation products were isolated using hep-
tanes–EtOAc (15:1) as eluent whereas the catalyst could be recov-
ered in >85% by flushing with CH2Cl2–MeOH (10:1). The catalyst
could be reused several times without any decrease in yield or en-
antioselectivity.
1H NMR (500 MHz, CDCl3): δ = 0.69 (s, 6 H), 1.74 (d, J = 9.7 Hz,
3 H), 2.49 (m, 1 H), 2.52 (d, J = 9.7 Hz, 3 H), 2.84 (m, 1 H), 3.07
(m, 2 H), 3.60 (dd, J = 14.8, 8.3 Hz, 2 H), 4.58 (dd, J = 14.8, 8.3
Hz, 2 H), 5.10 (s, 2 H), 7.16–7.34 (m, 16 H), 7.52–7.58 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 26.8 (CH3), 30.2 (d, J = 4 Hz,
CH3), 31.3 (d, J = 5 Hz, CH3), 46.1 (d, J = 13 Hz, CH2), 48.2 (d,
J = 11 Hz, CH2), 53.8 (Ar2C), 53.9 (Ar2C), 61.5 (CH2N), 78.5 (CH),
109.9 (CO2), 126.2 (ArC), 126.6 (ArC), 121.1 (ArC), 128.1 (ArC),
128.9 (ArC), 131.6 (ArC), 142.7 (ArC), 148.0 (ArC).
31P NMR (81 MHz, CDCl3): δ = 31.6.
HRMS (ESI): m/z calcd for C37H42N3O3P: 608.3037 [M + H]+;
found: 608.3044.
Compound (S)-22
Obtained in 81% yield and with 87% ee upon reacting 20 with ben-
zyl bromide (21); colorless oil. Analytical data are in full accor-
Acknowledgment
20
dance with those reported in the literature;22h,31 [α]D –125.7 (c
This work was supported by the Austrian Science Funds (FWF):
Project No. P22508-N17. We are grateful to Dr. Manuela
Haunschmidt and Dr. Markus Himmelsbach for their support with
HRMS analysis and to Christian Rückl for his help with the HPLC
analysis. We are grateful to Dr. Christoph Etzlstorfer for assisting
with the molecular modeling studies. The used NMR spectrometers
were acquired in collaboration with the University of South Bohe-
mia (CZ) with financial support from the European Union through
the EFRE INTERREG IV ETC-AT-CZ program (project M00146,
‘RERI-uasb’).
1.53, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9 H), 3.11–3.23 (m, 2 H),
4.10 (dd, J = 9.0, 4.2 Hz, 1 H), 6.59 (d, J = 6.6 Hz, 2 H), 7.03–7.40
(m, 11 H), 7.61 (d, J = 8.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 28.0, 39.6, 68.0, 81.2, 126.2, 127.7,
127.9, 128.0, 128.1, 128.3, 128.8, 129.9, 130.1, 136.4, 138.4, 139.6,
170.3, 170.9.
HRMS (ESI): m/z calcd for C26H27NO2: 386.2115 [M + H]+; found:
386.2113.
Synthesis 2012, 44, 3661–3670
© Georg Thieme Verlag Stuttgart · New York

PAPER
Towards TADDOL-Derived Organocatalysts
3669
(e) Pichota, A.; Gramlich, V.; Bichsel, H.-U.; Styner, T.;
Knöpfel, T.; Wünsch, R.; Hintermann, T.; Schweizer, W. B.;
Beck, A. K.; Seebach, D. Helv. Chim. Acta 2012, 95, 1273.
(10) For reviews on chiral Lewis base catalysis, see:
(a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed.
2008, 47, 1560. (b) Denmark, S. E.; Stavenger, R. A. Acc.
Chem. Res. 2000, 33, 432.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are analytical data of catalyst analogues, precursors, alkylation pro-
ducts, and copies of NMR spectra, HPLC chromatograms, and
Tables with details of optimization and scope of the PT-catalyzed
α-alkylationSungIifo
maoirtnuSpgIri
r
p
t
o
pfo.nmatr.
(11) For reviews about asymmetric phase-transfer catalysis, see:
(a) Maruoka, K. Asymmetric Phase Transfer Catalysis;
Wiley-VCH: Weinheim, 2008. (b) Maruoka, K.; Ooi, T.
Chem. Rev. 2003, 103, 3013. (c) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506. (d) Lygo, B.; Andrews, B. I. Acc.
Chem. Res. 2004, 37, 518. (e) Hashimoto, T.; Maruoka, K.
Chem. Rev. 2007, 107, 5656. (f) Ooi, T.; Maruoka, K.
Angew. Chem. Int. Ed. 2007, 46, 4222.
(12) Weibel, D. Ph.D. Dissertation; ETH: Zürich, 2003, Nr.
1529.
(13) Due to the failed syntheses of catalysts 6, 10, and 12, the
synthesis of phosphoramides 8 was not exhaustively
investigated anymore after the failure of a few initial
experiments.
(14) Seebach et al. coincidentally observed the formation of trityl
derivatives upon treatment of dichloro compound 13 with
diphenylamine or methylaniline: Seebach, D.; Pichota, A.;
Beck, A. K.; Pinkerton, A. B.; Litz, T.; Karjalainen, J.;
Gramlich, V. Org. Lett. 1999, 1, 55.
(15) Reetz, M. T.; Chatzhosifidis, I.; Künzer, H.; Müller-Starke,
H. Tetrahedron 1983, 39, 961.
(16) BH3·DMS in refluxing THF was the only other reducing
agent that gave small amounts of 5aa (?20%).
(17) p-Methoxy-substituted TADDOL gave elimination and
Friedel–Crafts products in the chlorination step exclusively,
whereas the m-methoxy one gave at least small amounts of
the dichlorides, which then formed only Friedel–Crafts
products, but not dinitrile under the Lewis acidic cyanation
conditions.
(18) Synthesis of the TADDOL 2aa based sulfite 16aa was
reported by Seebach et al. in ref. 9b.
(19) In these two cases it was necessary to use 5 equiv of TMSCN
and 1 equiv SnCl4 to obtain the dicyanides in a reliable and
reproducible manner.
(20) Using MeI, trace amounts of the targeted ammonium iodide
could be detected by ESI-HRMS of the crude reaction
mixture, but no product could be isolated.
(21) For detailed investigations concerning the kinetics of SN2-
type cyclization reactions, see: (a) Freundlich, H.;
Kroepelin, H. Z. Physik. Chem. 1926, 122, 39. (b) Casadei,
M. A.; Galli, C.; Mandolini, L. J. Am. Chem. Soc. 1984, 106,
1051.
(22) (a) Shirakawa, S.; Liu, K.; Ito, H.; Maruoka, K. Chem.
Commun. 2011, 47, 1515. (b) Kano, T.; Yamamoto, A.;
Song, S.; Maruoka, K. Chem. Commun. 2011, 47, 4358.
(c) Shirakawa, S.; Terao, S. J.; He, R.; Maruoka, K. Chem.
Commun. 2011, 47, 10557. (d) Hashimoto, T.; Sakata, K.;
Maruoka, K. Adv. Synth. Catal. 2010, 352, 1653. (e) Lan, Q.;
Wang, X.; Shirakawa, S.; Maruoka, K. Org. Process Res.
Dev. 2010, 14, 684. (f) Ooi, T.; Kameda, M.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 5139. (g) Shirakawa, S.; Liu,
K.; Maruoka, K. J. Am. Chem. Soc. 2012, 134, 916. (h) Ooi,
T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121,
6519.
(23) This compound was not unambiguously proven by NMR
analysis due to the presence of other by-products (maybe
also due to the presence of other possible Stevens
rearrangement products), but could be clearly identified by
HRMS in the positive ion mode.
References
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From Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005. (b) Dalko, I.
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Natural Products; Vol. 96; Kinghorn, A.-D.; Falk, H.;
Kobayashi, J., Eds.; Springer: Berlin, 2012.
(2) For reviews on TADDOLs, see: (a) Seebach, D.; Beck, A.
K.; Heckel, A. Angew. Chem. Int. Ed. 2001, 40, 92.
(b) Pellissier, H. Tetrahedron 2008, 64, 10279.
(3) For a recent report describing the syntheses of tartaric acid
derived 1,4-ditertiary carbinols, see: Budragchaa, T.; Roller,
A.; Widhalm, M. Synthesis 2012, 44, 3238.
(4) For the application of TADDOLs and derived
organocatalysts as chiral H-bonding donors or Brønstedt
acids, see: (a) Huang, Y.; Unni, A. K.; Thadani, A. N.;
Rawal, V. H. Nature 2003, 424, 146. (b) McGilvra, J. D.;
Unni, A. K.; Modi, K.; Rawal, V. H. Angew. Chem. Int. Ed.
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M.; Fröhlich, R.; Paradies, J. Synthesis 2012, 44, 3209.
(e) Seebach, D.; Beck, A. K.; Bichsel, H.-U.; Pichota, A.;
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(5) For TADDOLs as PTCs, see: (a) Belokon, Y. N.;
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Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki,
M. Tetrahedron Lett. 2002, 43, 9539. (b) Ohshima, T.;
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(c) Ohshima, T.; Shibuguchi, T.; Fukuta, Y.; Shibasaki, M.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3661–3670

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PAPER
(28) For detailed scope, see the tables in the Supporting
Information and the preliminary results in our recent
communication (ref. 8).
(29) For a recent example using cinchona-based PTCs, see: Yoo,
M. S.; Kim, D. G.; Ha, M. W.; Jew, S.; Park, H.; Jeong, B.
S. Tetrahedron Lett. 2010, 51, 5601.
(24) Goncalves-Farbos, M.-H.; Vial, L.; Lacour, J. Chem.
Commun. 2008, 829.
(25) For optimization of the reaction conditions and catalyst
amount, please see the detailed tables in the Supporting
Information and the preliminary results in our recent
communication (ref. 8).
(26) We have also synthesized the corresponding 2-acetylnaph-
thalene-based derivative, which performed slightly better
(88% ee in the benchmark alkylation), but was even harder
to obtain as the last steps were significantly lower yielding
and vast amounts of difficult to remove impurities were
formed.
(30) No background reaction was observed in the absence of the
catalyst.
(31) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
(32) Also the use of more reactive p-nitrobenzaldehyde did not
result in a better conversion.
(27) For successful applications of acyclic TADDOL-backbone
containing ligands in asymmetric catalysis, see: (a) Teller,
H.; Flügge, S.; Goddard, R.; Fürstner, A. Angew. Chem. Int.
Ed. 2010, 122, 1993. (b) Teller, H.; Fürstner, A. Chem.–Eur.
J. 2011, 17, 7764.
(33) (a) Weber, E.; Dörpinghaus, N.; Wimmer, C.; Stein, Z.;
Krupitsky, H.; Goldberg, I. J. Org. Chem. 1992, 57, 6825.
(b) Voituriez, A.; Charette, A. B. Adv. Synth. Catal. 2006,
348, 2363. (c) Kelly, T. R.; Cai, X.; Elliott, E. L.;
Grossmann, G.; Laurent, P. Org. Lett. 2004, 6, 4953.
Synthesis 2012, 44, 3661–3670
© Georg Thieme Verlag Stuttgart · New York