Isothiourea-mediated asymmetric O- to C-carboxyl transfer of oxazolyl carbonates: Structure-selectivity profiles and mechanistic studies

Article abstract of DOI:10.1002/chem.201102847

The structural motif within a series of tetrahydropyrimidine-based isothioureas necessary for generating high asymmetric induction in the asymmetric Steglich rearrangement of oxazolyl carbonates is fully explored, with crossover and dynamic ¹⁹F NMR experiments used to develop a mechanistic understanding of this transformation. Copyright

Full text of DOI:10.1002/chem.201102847

DOI: 10.1002/chem.201102847
Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer of Oxazolyl
Carbonates: Structure–Selectivity Profiles and Mechanistic Studies
Caroline Joannesse,[a] Craig P. Johnston,[a] Louis C. Morrill,[a] Philip A. Woods,[a]
Madeleine Kieffer,[a] Tobias A. Nigst,[b] Herbert Mayr,[b] Tomas Lebl,[a] Douglas Philp,[a]
Ryan A. Bragg,[c] and Andrew D. Smith*[a]
Abstract: The structural motif within a series of tetrahydropyrimidine-based iso-
thioureas necessary for generating high asymmetric induction in the asymmetric
Steglich rearrangement of oxazolyl carbonates is fully explored, with crossover
and dynamic 19F NMR experiments used to develop a mechanistic understanding
of this transformation.
Keywords: asymmetric catalysis ·
isothioureas · Lewis bases · NMR
spectroscopy · reaction mechanisms
Introduction
(PPY) or 4-dimethylaminopyridine (DMAP) derivatives
such as 1–3, elegantly introduced by Fu et al.,[5] Vedejs
et al.[6] and Richards et al.,[7] respectively, deliver C-carboxy-
azlactones with up to 95% enantiomeric excess (ee). Alter-
native catalyst classes also deliver high enantioselectivity in
this process,[8] such as phosphine 4 utilised by Vedejs et al.,[6]
chiral ammonium betaine 5 introduced by Ooi et al.,[9] and
bicyclic imidazole 6 used by Zhang et al.[10] (Scheme 1).
In the literature, amidines and isothioureas have been
widely used to promote a range of asymmetric O- and N-
acylation protocols, building upon the pioneering work of
Birman[11] and Okamoto.[12] These readily prepared or com-
Lewis base-mediated catalysis encompasses a plethora of re-
actions, catalyst types and mechanisms that are widely appli-
cable in synthesis and asymmetric catalysis. This area has re-
ceived intensive coverage and has been extensively re-
viewed.[1] Among the most common organocatalytic reaction
types that belong to this subclass are those initiated through
the interaction of non-bonding lone pairs with a p* orbital
(n–p* interaction). Perhaps the most studied archetypal re-
action of this class is the Lewis base-catalysed acylation of
alcohols and amines,[2] with a multitude of achiral catalysts
having been developed that can promote acylation, and a
range of chiral catalysts allowing efficient kinetic resolution
procedures.[3] The Steglich rearrangement of oxazolyl car-
bonate derivatives[4] is a related Lewis base-promoted reac-
tion process that can be categorised as proceeding through
an initial n–p* interaction, and this transformation has been
widely probed to evaluate the stereodirecting ability of a
range of chiral Lewis bases in asymmetric catalysis. Within
this area, the development of chiral 4-pyrrolidinopyridine
[a] C. Joannesse, C. P. Johnston, L. C. Morrill, P. A. Woods, M. Kieffer,
Dr. T. Lebl, Prof. D. Philp, Dr. A. D. Smith
EaStCHEM, School of Chemistry
University of St Andrews, North Haugh
St Andrews, KY16 9ST (United Kingdom)
[b] Dipl.-Chem. T. A. Nigst, Prof. H. Mayr
Department Chemie
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F)
81377 Mꢁnchen (Germany)
[c] Dr. R. A. Bragg
AstraZeneca UK Ltd, Mereside
Alderley Park, Macclesfield
Cheshire, SK10 4TG (United Kingdom)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102847.
Scheme 1. Asymmetric Lewis base promoted O- to C-carboxyl transfer
(Steglich rearrangement) of oxazolyl carbonates.
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FULL PAPER
mercially available catalyst architectures have been widely
applied in kinetic resolution,[13] dynamic kinetic resolution[14]
and desymmetrisation processes.[15] In this area, Birman and
co-workers first introduced a range of dihydroimidazoACHTUNTRGNEUNG[1,2-
a]pyridine (DHIP) derivatives (such as CF3-PIP 7) for kinet-
ic resolutions,[11a,b] with a C(2)-aryl substituent essential for
high stereocontrol in these reactions.[11c] Birman et al. later
introduced isothioureas such as tetramisole 8[11d] and benzo-
tetramisole (BTM 9).[11d] Following the development of 3,4-
dihydro-2H-pyrimidoACTHNUGRTENUNG[2,1-b]benzothiazole 10 (DHPB) by
Okamoto,[12] and their own studies,[11e] the Birman group de-
veloped homobenzotetramisole 11 (HBTM)[11f] and 12[11g]
(HBTM 2) for kinetic resolutions. Concurrent with these
latter studies, we have shown that the nature of the stereodi-
recting groups within the tetrahydropyrimidine unit of iso-
thioureas such as HBTM markedly affects their reactivity
and stereoselectivity in kinetic resolution processes[16] and
the asymmetric C-acylation of silyl ketene acetals with anhy-
drides,[17] with 13 proving optimal in our hands (see below).
The synthetic utility of isothioureas has been expanded to
allow the generation of ammonium enolates from carboxylic
acids[18] with applications in desymmetrising aldol cyclisa-
tions,[19] as well as intra- and intermolecular Michael addi-
tion-lactonisation reactions.[20]
Figure 1. Schematic representation of previous transition-state modelling
of the isothiourea-promoted Steglich rearrangement.[22b]
stereodirecting unit to adopt a pseudo-axial conformation to
minimize 1,2-strain.[26] Facial selectivity of the enolate com-
ponent is controlled by a combination of steric factors and
charge matching, with the predicted lowest energy transition
state leading to the observed enantiomer of the product.
Building upon these precedents, this manuscript delin-
eates our full studies concerning the use of chiral isothiour-
eas in the Steglich rearrangement. Primarily, the structural
motif within a series of tetrahydropyrimidine-based iso-
thioureas necessary for high asymmetric induction in this
process is evaluated, and their catalytic activity compared.
In situ mechanistic studies of the course of this isothiourea-
promoted reaction process are also reported, and the scope
and limitations of the optimal catalysts for this process in-
vestigated.
Results and Discussion
Structure–selectivity relationships for tetrahydropyrimidine-
based isothioureas in the Steglich rearrangement: To evalu-
ate the structural motif within tetrahydropyrimidine based
isothioureas necessary for high asymmetric induction in the
Steglich rearrangement, variation of the stereodirecting
group(s), substitution pattern and conformational con-
straints within a series of catalysts were studied. In particu-
lar, the effect of changing the relative and absolute configu-
ration of substituents at C(2) and/or C(3) of these isothiour-
eas, in either combination or isolation, upon the stereoselec-
tivity observed in this process were probed.[27] To compare
directly the reactivity and stereoselectivity of isothioureas
11 and 14–17 containing a single stereogenic centre at either
C(2) or C(3), the enantioselective rearrangement of a stan-
dard series of three oxazolyl carbonates, containing diversity
in C(4)-substitution (Et, Bn, iBu) and either a reactive
phenyl or sterically encumbered 1,1,1-trichloro-2-methylpro-
pan-2-yl carbonate, to their C-carboxyazlactones were stud-
ied (Table 1, entries 1–17). Trends in product enantioselec-
tivity and reactivity within this series of isothioureas indicate
Building upon these precedents, and as part of our exist-
ing research programme focusing upon Lewis base cataly-
sis,[21] we have shown that isothioureas such as HBTM 11
and 13 promote the asymmetric O- to C-carboxyl rearrange-
ment of oxazolyl carbonates with high enantioselectivity (up
to 94% ee).[22,23] Notably, recent work by Okamoto has
probed the ability of a C(4)-stereodirecting unit within tetra-
hydropyrimidine-derived isothioureas to promote the asym-
metric Steglich rearrangement,[24] whereas Grçger and Dietz
have utilised isothioureas for related asymmetric O- to C-
acetyl transfer processes.[25] To understand the origins of
asymmetric induction in the O- to C-carboxyl transfer pro-
cess using HBTM 11 we have previously carried out molecu-
lar modelling calculations, allowing a simple model for
asymmetric induction in this process to be developed
(Figure 1). In this rationale, the N-carboxyl group of the iso-
thiouronium intermediate is assumed to lie approximately
co-planar with the heterocycle, forcing the adjacent C(2)-
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A. D. Smith et al.
Table 1. Evaluation of isothiourea catalysts.
Entry
Isothiourea
R1
R2
T
[8C]
Product
ratio[a]
ee
Yield
[%][c]
[%][b]
1
2
3
4
5
6
7
8
Bn
Bn
Et
iBu
Bn
Bn
Et
Ph
Ph
Ph
RT
À50
À50
RT
RT
À10
À10
40
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
NR
79
91
91
89
87 (ent)
91 (ent)
92 (ent)
–
95
96
91
88
94
94
92
–
11
14
C(Me)2CCl3
Ph
Ph
Ph
iBu
C(Me)2CCl3
9
10
11
Bn
Et
iBu
Ph
Ph
40
40
40
83:17
>98:<2
NR
79
82
–
57
–
–
15
C(Me)2CCl3
12
13
14
Bn[d]
Et[d]
Ph
Ph
40
40
40
93:7
58:42
NR
79 (ent)
71 (ent)
–
–
–
–
iBu[d]
C(Me)2CCl3
16
17
15
16
17
Bn
Et
iBu
Ph
Ph
RT
RT
40
>98:<2
>98:<2
>98:<2
23
24
18
90
95
82
C(Me)2CCl3
18
19
20
21
22
Bn
Bn
Et
Et
iBu
Ph
Ph
Ph
Ph
RT
À60
RT
À50
40
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
83
93
84
93
91
87
96
93
96
82
13
C(Me)2CCl3
23
18
19
Bn
Ph
RT
>98:<2
82
77
24
25
Bn
Et
Ph
Ph
RT
RT
>98:<2
>98:<2
64
82
–
–
26
27
28
Bn
Et
iBu
Ph
Ph
RT
RT
40
>98:<2
83:17
>98:<2
77
79
86
94
43
81
12 (HBTM-2)
C(Me)2CCl3
29
30
31
Bn
Me
Et
Ph
Ph
Ph
RT
RT
RT
>98:<2
>98:<2
>98:<2
81
84
78
95
93
96
20
21
32
33
34
Bn
Me
Et
Ph
Ph
Ph
RT
RT
40
0:13
0:14
0:10
–
–
–
–
–
–
[a] Product ratio of C-carboxyazlactone to azlactone calculated by 1H NMR spectroscopic analysis of the crude reaction product. [b] Determined by
chiral HPLC analysis. [c] Isolated product yield of homogeneous product. [d] 20 mol% of isothiourea 16 was used. NR=no reaction.
that C(2)-substitution (isothioureas 11, 14, 15 and 16) leads
to high enantioselectivity (>71% ee), with C(3)-substitution
(isothiourea 17) leading to good catalytic reactivity but only
modest enantioselectivity (<25% ee). C(2)-phenyl substitu-
tion (isothiourea 11) leads to optimal reactivity in this
series, allowing the reaction temperature to be lowered to
À508C to achieve optimal product ee values (91% ee,
Table 1, entries 1–4). Although C(2)-iPr-substituted iso-
thiourea 14 generates the highest ee value at RT, it is only
catalytically active at temperatures of À108C or above (up
to 92% ee) with phenyl carbonates (Table 1, entries 5–7).
Isothioureas 15 and 16 with sterically encumbered C(2)-
alkyl substituents (tBu and CHPh2) lead to decreased reac-
tivity, requiring high temperatures (408C) and increased cat-
alyst loading (up to 20 mol% for 16) to promote the rear-
rangement of reactive phenyl oxazolyl carbonates (deliver-
ing products in 71–82% ee), typically leading to significant
formation (up to 50%) of the corresponding azlactone and
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Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer
FULL PAPER
diphenylcarbonate (Table 1, entries 9, 10, 12, and 13). Iso-
thioureas 14, 15 and 16 all give no product conversion with
the sterically hindered 1,1,1-trichloro-2-methylpropan-2-yl
carbonate.
Mechanistic studies: Intermediate isolation, in situ reaction
monitoring and crossover reactions: To complement our
previous computational studies, mechanistic studies of the
isothiourea-mediated Steglich rearrangement were investi-
gated. In particular, these studies aimed to characterise and
observe potential reaction intermediates, monitor the evolu-
tion of product throughout the reaction, and decipher the
reversibility of any steps in this transformation through
crossover studies.
Further investigations probed the effect of 2,3-disubstitu-
tion within the isothiourea catalyst structure (Table 1, en-
tries 18–34). In comparison to HBTM 11, the incorporation
of an additional syn-configured C(3)-iPr substituent (iso-
thiourea 13) leads to marginally increased stereoselectivities
under optimised conditions (Table 1, entries 18–22), with the
incorporation of an electronegative Cl atom within the ben-
zothiazole unit (isothiourea 18) giving negligible change in
stereoselectivity (Table 1, entry 23). The inclusion of alterna-
tive C(2)-2-naphthyl or C(3)-methyl units (within 19 and
HBTM 2 12 respectively) gave slightly lower enantioselec-
tivities than 13 (Table 1, entries 24–28). The effect of both
stereochemical and cyclic constraints were also investigated,
with tetracyclic syn-20 proving highly reactive and enantio-
selective (Table 1, entries 29–31), whereas the diastereoiso-
meric isothiourea anti-21 gave no C-carboxylazlactone prod-
uct, returning mainly starting material and about 10% azlac-
tone (Table 1, entries 32–34).
19F NMR spectroscopic analysis was chosen to facilitate in
situ reaction monitoring, with C(2)-iPr isothiourea 14
chosen for these NMR studies. Initial investigations aimed
to independently synthesise a 19F-“tagged” N-carboxyl iso-
thiouronium ion intermediate, which was readily achieved
by treatment of isothiourea 14 with 4-fluorophenylchlorofor-
mate, giving N-carboxyl isothiouronium ion 22 (dF =À114.1)
in 74% isolated yield (Figure 2).[29] 1H NMR spectroscopy
was used to study the preferred solution-phase conformation
adopted by isothiouronium salt 22. Interestingly, optimal
resonance dispersion for 22 was observed in CD3OD, with
no noticeable acyl transfer to the solvent. The C(2)-H reso-
nance at d=4.96 ppm showed a distinctive ddd coupling pat-
1
Marked differences in catalyst reactivity are observed
using isothioureas 11–21 in these transformations, with C(2)-
aryl-substituted isothioureas 11 and 13 leading to optimal re-
activity and enantioselectivity, and C(2)-branched alkyl-sub-
stituted isothioureas 14, 15 and 16 leading to decreased cata-
lytic efficiency. These trends mirror the previously observed
reactivity of isothioureas (in terms of rate and catalytic effi-
ciency) in both kinetic resolution[18] and asymmetric C-acyla-
tion processes.[19] Notably, the observed reactivity profiles
for isothioureas 11, 13, 14, 15 and 16 in the Steglich rear-
rangement (reactivity 13ꢀ11>14>15>16) correlate well
to their relative nucleophilicities and Lewis basicities (13>
11>14ꢀ15>16) as measured photometrically by their reac-
tions with benzhydrylium ions,[28] although specifically relat-
ing these properties directly to their organocatalytic activity
is difficult. Simplistically, however, the following generalisa-
tions regarding these trends in reactivity may be proposed.
The reduced catalytic efficiency of branched C(2)-alkyl sub-
stituted isothioureas presumably results partly from their re-
duced nucleophilicities and Lewis basicities. This may lead
to reduced equilibrium concentrations of a putative N-car-
boxyl isothiouronium ion intermediate, formed from iso-
thiourea addition to the oxazolyl carbonate, in this reaction
process. Furthermore the requirement of the C(2)-substitu-
ent to adopt a pseudo-axial conformation to minimize 1,2
strain in an N-carboxyl isothiouronium ion intermediate is
also expected to be disfavoured with increased size of this
stereodirecting unit. Using this rationale, the inability of iso-
thiourea anti-21 to promote the Steglich rearrangement in
comparison with its diastereoisomer syn-20, which shows
good catalytic activity in this process, may be rationalised.
The anti-configuration within 21 presumably disfavours for-
mation of the N-carboxyl isothiouronium intermediate as
the C(2)-substituent cannot adopt a pseudo-axial conforma-
tion due to the constraints of the cyclohexyl ring.
tern (J=10.5, 3.2 and 3.2 Hz), with phase sensitive H,1H-
DQF-COSY indicating that the large (J=10.5 Hz) coupling
constant corresponds to coupling from C(2)-H to C(1’)H.[30]
Figure 2. Synthesis of N-carboxyl isothiouronium ion 22 and modelling of
its preferred conformation located using the pseudo-empirical RM1
method and refined at the B3LYP/6-31G** level of theory.
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A. D. Smith et al.
The coupling constants from C(2)-H to the adjacent methyl-
ene group correspond to 3.2 Hz, consistent with equatorial-
axial and equatorial-equatorial coupling, accordant with the
C(2)-iPr unit adopting the expected pseudo-axial position.
The minimum energy conformation of 22 represented in
Figure 2 was located using the pseudo-empirical RM1
method and refined at the B3LYP/6-31G** level of theory.
The energy of this conformer was found to be approximate-
ly 4 kJmolÀ1 lower than an alternative conformer with the
C(2)-iPr unit in a pseudo-equatorial position.[30] Further-
more, the corresponding coupling constants calculated using
the Altona equation[31] (J=10.8, 4.6 and 2.0 Hz) are also in
good agreement with those observed experimentally.
build up of the by-product di-(4-fluorophenyl)carbonate 25
(dF =À115.8 ppm) up to 2 mm over the course of the trans-
formation (Figure 3).
19F was also readily incorporated into a model oxazolyl
carbonate 23 (dF =À115.0 ppm),[32] with rearrangement
using achiral isothiourea DHPB 10 giving C-carboxyazlac-
tone 24 in 95% yield (dF =À115.7 ppm, Scheme 2). As dia-
rylcarbonates are a recognised by-product in the Steglich re-
arrangement of oxazolyl aryl carbonates,[22a] implying in situ
generation of phenoxide, di-(4-fluorophenyl)carbonate 25
was prepared by treatment of 22 with potassium 4-fluoro-
phenoxide (Scheme 2).[33]
Figure 3. Time course for the Steglich rearrangement of 23 to 24 as moni-
tored by 19F NMR spectroscopy: =23; =24; =22; =25. Reaction
conditions: 23 [100 mm], 14 [5 mm], 4-fluoronitrobenzene [20 mm],
CDCl3, 58C.
~
&
&
^
Having observed an N-carboxyl isothiouronium inter-
mediate in this process, its participation in a catalytic cycle
was further probed. Treatment of oxazolyl carbonate 26 and
N-phenoxycarboxyl isothiouronium ion 27[35] (10 mol%)
with achiral isothiourea DHPB 10 (5 mol%) gave
a
40:10:50 mixture of 26 to C-carboxyazlactones 28 and 29,
consistent with the phenoxycarbonyl unit from ion 27 being
incorporated into the C-carboxyazlactone product
(Scheme 3). This is consistent with an intermolecular reac-
tion step within the reaction mechanism, and an N-carboxyl-
isothiouronium ion such as 27 being a plausible intermediate
in the reaction.
Scheme 2. Synthesis of fluorinated products.
Further crossover studies showed that treatment of a
50:50 mixture of oxazolyl carbonates 30 and 31 with DHPB
10 gave a 28:22:23:27 ratio of four C-carboxyazlactone
products 34–37, again consistent with the reaction contain-
ing an intermolecular process (Scheme 4). However, treat-
ment of 30 and 31 with HBTM 11 gave, after five minutes
and incomplete conversion to product, a 64:36 mixture of
four oxazolyl carbonates 30–33 (in an approximate
14:10:36:4 ratio) to two C-phenoxycarbonylazlactone prod-
ucts 34 and 37 (in a 26:10 ratio). This product ratio is consis-
Having characterised likely products, by-products and in-
termediates, the conversion of oxazolyl carbonate 23 to C-
carboxyazlactone 24 using isothiourea 14 (5 mol%, 5 mm)
was readily observed at 58C using 4-fluoronitrobenzene as
an internal standard, with approximately 80% product con-
version reached in 6 h.[34] The presence of an N-carboxyl iso-
thiouronium ion 22 (dF =À114.1) at an approximate con-
stant concentration of 2.8 mm throughout the duration of
the reaction can be observed, along with the simultaneous
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Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer
FULL PAPER
Scheme 3. Crossover experiment using N-carboxyl isothiouronium ion 27.
tent with the reaction involving an initial rapid O-transcar-
boxylation process, resulting in scrambling of the carbonate
group within the starting materials to generate a mixture of
all four possible oxazolyl carbonates.
Further control experiments indicated that the C-carboxy-
azlactone products are configurationally stable under the re-
action conditions, as treatment of C-carboxyazlactone 37
(79% ee) with either enantiomerically pure or racemic iso-
thiourea 11 returned 37 in 79% ee. This is consistent with an
À
irreversible C C bond forming process that proceeds with
high enantiocontrol in the asymmetric process. These cross-
over and product stability experiments are consistent with
this O- to C-carboxyl group transfer process proceeding
through an initial rapid and reversible O-transcarboxylation
process (allowing for crossover of the oxazolyl carbonates),
followed by an irreversible C-carboxylation event that
occurs with high enantiocontrol (Scheme 5). This mechanis-
tic rationale is consistent with that observed in this process
by Fu using PPY* 1,[5] and ourselves with NHCs,[8c] in this
reaction manifold.
Scheme 4. Crossover experiments of oxazolyl carbonates 30 and 31.
Scope and limitations: Having probed the mechanism and
structural motifs within the iso-
thiourea catalyst architecture
necessary for efficient asym-
metric catalysis of the Steglich
rearrangement, its full scope
and limitations were delineated.
The effect of variation of the
carbonate group and C(2)-sub-
stitution of the oxazolyl carbon-
ate was initially probed, with a
C(4)-benzyl substitutent used as
standard (Table 2, entries 1–8).
At RT, rearrangement of
a
phenyl carbonate gave higher
enantioselectivity than a methyl
or benzyl carbonate, whereas Scheme 5. Mechanistic hypothesis for the isothiourea-mediated Steglich rearrangement.
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A. D. Smith et al.
Table 2. Effect of variation of C(2) substituent and carbonate group.
rangement of 53 catalysed by HBTM 11 proceeded in high
yield but only modest enantioselectivity (21% ee), while
similarly disappointingly low levels of enantioselectivity (up
to 39% ee) and up to ꢀ20% of the corresponding hydroin-
dole and diphenylcarbonate, were observed in the indolyl
series using 13 (Scheme 6).[41] It appears that benzannulation
of the heterocyclic carbonate leads to only modest enantio-
control in the isothiourea-mediated rearrangement of these
carbonates, consistent with the observations of Okamoto
and co-workers.[24]
Entry R1
R2
Cat.
T
[8C]
Product ee
Yield
[%][a] [%][b]
1
2
3
4
5
6
7
8
9
Me
Bn
Ph
Ph
PMP 11
PMP 11
PMP 11
RT
RT
RT
RT
RT
À208C 37
À508C 37
À408C 37
À608C 37
38
39
37
40
41
70
72
79
72
91
87
91
90
93
91
75
95
[c]
Me
11
13
–
C(Me)2CCl3 Ph
96
96
96
94
96
Ph
Ph
Ph
Ph
PMP 11
PMP 11
PMP 13
PMP 13
Conclusion
The ability of a series of tetrahydropyrimidine-based iso-
thioureas to promote the asymmetric Steglich reaction has
been evaluated. Good to excellent levels of enantioselectivi-
ty are generally observed for the rearrangement of oxazolyl
carbonates, with markedly different catalytic efficiencies ob-
served with variation of the stereodirecting group(s). Cross-
over and dynamic 19F NMR experiments have been used to
further the mechanistic understanding of this isothiourea-
mediated transformation, consistent with a rapid and rever-
sible initial O-transcarboxylation process followed by an ir-
reversible C-carboxylation event. Alternative applications of
[a] Determined by chiral HPLC analysis. [b] Isolated product yield of ho-
mogeneous product. [c] Isolation of 40 by chromatography proved diffi-
cult due to competitive decomposition although HPLC analysis on the
crude reaction product was possible.
variation from C(2)-PMP to C(2)-methyl substitution result-
ed in decreased enantioselectivity (Table 2, entries 1–4).[36]
Rearrangement of a sterically hindered 1,1,1-trichloro-2-
methylpropan-2-yl carbonate gave the highest ee value at
RT (Table 2, entry 5)[37] but proved recalcitrant to
rearrangement at lower temperatures, whereas
phenyl carbonates generally undergo asymmetric
Table 3. Scope and limitations of isothiourea O- to C-carboxyl transfer.
rearrangement at low temperatures (Table 2, en-
tries 6–9).
Subsequent studies varied the nature of the C(4)-
substituent of the oxazolyl carbonate using iso-
thioureas 11, 13 and 14. A range of linear C(4)-
alkyl substituents (R=Me, Et, nBu, allyl,
Entry R1
R2
Cat Product
T
ee
Yield
[%][b]
[8C] [%][a]
MeSCH2CH2,
4-BnOC6H4CH2,
4-
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Me
Me
Et
Et
Et
nBu
allyl
CH2CH2SMe
CH2CH2SMe
Ph
11
13
14
11
13
11
13
14
11
11
11
13
11
13
11
13
14
37
37
37
34
34
42
42
42
43
44
45
45
46
46
47
47
47
48
48
49
50
50
51
52
52
À50 91
À60 93
96
96
PhO2COC6H4CH2) are tolerated, with generally
high enantioselectivity (Table 3, entries 1–19, up to
94% ee). C(4)-phenyl substitution results in lower
enantioselectivity (Table 3, entries 13–14, 60% ee at
À208C), consistent with the work of Vedejs et al.[6]
and Zhang et al.[10] who have also reported lower
enantioselectivity with a C(4)-aryl substituted oxa-
zole. Rearrangement of leucine-derived carbonates
proceed with good ee values (Table 3, entries 20–22,
up to 91% ee), whereas C(4)-iPr substitution is also
tolerated although significant amounts (30–40%) of
the parent azlactone and diphenylcarbonate are
generated (Table 3, entries 23–25, up to 78% ee at
08C using 11, 77% ee at RT using 13).[38]
Having investigated thoroughly the scope and
mechanism of this rearrangement in the oxazolyl
series, the ability of chiral isothioureas 11 and 13 to
promote the rearrangement of benzofuranyl and in-
dolyl carbonates was probed,[39] using a series of
model benzofuranyl and indolyl carbonate sub-
strates prepared following standard methods.[40] In
À10 91 (ent) 94
À50 94
À30 94
À50 91
À50 93
68
94
91
96
À10 92 (ent) 92
9
À50 92
À50 89
À50 90
65
69
65
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
À10 92 (ent) 81
À20 60
RT 45
90
96
90
86
Ph
4-BnOC6H4CH2
4-BnOC6H4CH2
4-BnOC6H4CH2
4-PhO2COC6H4CH2 11
4-PhO2COC6H4CH2 13
À50 91
À30 86
À10 91 (ent) 93
À50 90
À30 87
À20 91
90
97
50
88
82
–
4-MeOC6H4 iBu
C(Me)2CCl3 iBu
C(Me)2CCl3 iBu
11
11
13
11
11
13
RT
40
RT
0
89
91
73
78
77
Ph
iPr
4-MeOC6H4 iPr
4-MeOC6H4 iPr
38
30
RT
[a] Determined by chiral HPLC analysis. [b] Isolated product yield of homogeneous
the benzofuranyl series, O- to C-carboxyl rear- product.
2404
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 2398 – 2408

Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer
FULL PAPER
centrated in vacuo. Purification by recrystallization (Et2O/hexanes) gave
23 (1.93 g, 70%) as a white solid. M.p. 136–1388C; 1H NMR (400 MHz,
CDCl3): d=2.18 (3H, s, CH3), 3.85 (3H, s, OCH3), 6.95 (2H, d, J=
9.2 Hz, 4-OMeAr
7.28 (2H, dd, J=9.2 Hz, 4.4, 4-FAr
8.8 Hz, 4-OMeAr
N
ACHTUNGTRENNUNG(3,5)H),
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
À
1789 (C=O), 1617 (Ar C=C), 1501 (C=N), 1260 (C O), 1225 (C O) and
832 cmÀ1 (Ar C-H); MS (CI): m/z (%): 344.1 (100) [M+H]; HRMS (CI):
m/z: calcd for C18H15NO5F: 344.0934 [M+H]; found 344.0934 (d=
À0.4 ppm); elemental analysis calcd (%) for C18H14FNO: C 63.0, H 4.1,
N, 4.1; found: C 62.7, H 4.0, N 4.0.
4-Fluorophenyl 2-(4-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydrooxazole-
4-carboxylate 24: To oxazolyl carbonate 23 (0.300 mmol, 102 mg) in
CH2Cl2 (3 mL) was added DHPB 10 (10 mol%, 5.7 mg). After 15 min
0.1m HCl was added, extracted with Et2O (3ꢃ100 mL), the combined or-
ganic layers dried (MgSO4) filtered and concentrated in vacuo to give 24
(97.0 mg, 95%) as a colourless oil. 1H NMR (400 MHz, CDCl3) d=1.86
(3H, s, CH3), 3.89 (3H, s, OCH3), 7.00–7.07 (6H, m, ArH) and 8.01 ppm
(2H, d, J=9.2 Hz, 4-OMeArACHTNUTGRNEUNG
(2,6)H); 13C NMR (100 MHz; CDCl3) d=
Scheme 6. [a] Isolated product yield of homogeneous product. [b] Deter-
mined by chiral HPLC analysis. [c] Product ratio of C-carboxyl product
to hydroindole 99:1. [d] Product ratio of C-carboxyl product to hydroin-
dole 87:13. [e] Product ratio of C-carboxyl product to hydroindole 74:26.
20.6, 55.6, 72.8, 114.4, 116.2 (d, 2J=23.7 Hz), 117.3, 122.6 (d, 3J=8.6 Hz),
130.4, 146.0 (d, 4J=2.8 Hz), 160.6 (d, 1J=243.9 Hz), 163.5, 163.9, 165.0,
174.9 ppm; 19F NMR (376 MHz; CDCl3) d=À115.70 ppm; IR (thin film):
n˜ =1810 (C=O), 1750 cmÀ1 (C=O); MS (CI): m/z (%): 344.1 (55) [M+
H]; HRMS (CI): m/z: calcd for C18H15NO5F: 344.0934 [M+H]; found
344.0934 (d=À0.1 ppm).
Bis(4-fluorophenyl) carbonate 25: To
a solution of 22 (100 mg,
chiral isothioureas in asymmetric catalysis are under investi-
gation in this laboratory.[42]
0.27 mmol) was added potassium 4-fluorophenoxide (0.27 mmol) in THF
(2 mL) at RT. After five minutes the solution was concentrated in vacuo.
Purification by chromatography gave 25 (67 mg, quant) as a colourless
solid. M.p. 108–1108C; 1H NMR (300 MHz; CDCl3) d=7.08–7.14 (4H,
(2,6)H); 13C NMR
m, 4-FArACHTUNTRGENN(UG 3,5)H), 7.23–7.28 ppm (4H, m, 4-FArACHTUNGTRENNUGN
Experimental Section
(100 MHz, CDCl3) d=116.4 (d, 2J=23.6 Hz), 122.5 (d, 3J=8.5 Hz), 146.9
(d, 4J=2.7 Hz), 152.3, 160.6 ppm (d, 1J=244.0 Hz); 19F NMR (376 MHz,
For general experimental details and spectroscopic and HPLC data see
the Supporting Information.
À
CDCl3) d=À115.83 ppm; IR (KBr): n˜ =3084 (C H), 1766 (C=O), 1504,
1277 (C O) and 825 cmÀ1; MS (EI): m/z (%): 250.2 (60) [M]+, 139.2 (18)
À
[CO2C6H4F]+, 111.2 (35) [OC6H4F]+, 95.2 (100) [C6H4F]+; HRMS (ESI):
Synthesis of 19F-substituted products and N-carboxyl isothiouronium
ions: 1-((4-Fluorophenoxy)carbonyl)-2-isopropyl-3,4-dihydro-2H-benzo-
+
m/z calcd for C13H8O3F2
:
250.0436 [M]+; found: 250.0438 (d= +
0.8 ppm).
ACHTUNGTRENNUNG[4,5]thiazoloACHTUNGTRENNUNG[3,2-a]pyrimidin-1-ium chloride 22: A solution of 4-fluoro-
2-Isopropyl-1-(phenoxycarbonyl)-3,4-dihydro-2H-benzoACTHNUTRGENN[UG 4,5]thiazoloACHTUNGTRENNUNG[3,2-
phenyl chloroformate (50% in toluene, 0.1 mmol, 26 mL) was added to a
solution of 14 (0.1 mmol, 23.0 mg) in Et2O (2 mL). After stirring for 1 h
at RT, the salt was filtered and washed with Et2O to give 22 as a white
solid (30 mg, 74%). M.p. 74–768C; 1H NMR (500 MHz, CD3OD): d=
1.18 (3H, d, J=7.5 Hz, CH3), 1.19 (3H, d, J=7.0 Hz, CH3), 2.16–2.24
(1H, m, CHACHTUNGTRENNUNG(CH3)2), 2.49–2.56 (1H, m, NCH2CHH), 2.81–2.86 (1H, m,
NCH2CHH), 4.53 (1H, app. td, J 13.5, 5.5, NCHH), 4.76 (1H, app. dd,
J=14.0 Hz, 6.0, NCHH), 4.96 (1H, app. dt, J=10.5, 3.0 Hz, CH2CH),
a]pyrimidin-1-ium chloride 27: A solution of phenyl chloroformate (50%
in toluene, 0.1 mmol, 25 mL) was added to a solution of isothiourea 14
(0.1 mmol, 23.0 mg) in Et2O (2 mL). After stirring for 1 h at RT, the salt
was filtered and washed with Et2O to give 27 as a white solid (29 mg,
75%). M.p. 72–748C; 1H NMR (300 MHz; CD3OD) d=1.19 (3H, d, J=
6.3 Hz, CH3), 1.20 (3H, d, J=6.6 Hz, CH3), 2.14–2.27 (1H, m, CH-
AHCUTNGERT(GNNUN CH3)2), 2.46–2.59 (1H, m, NCH2CHH), 2.81–2.88 (1H, m, NCH2CHH),
4.53 (1H, app. td, J=13.6, 5.3 Hz, NCHH), 4.76 (1H, app. dd, J=13.9,
6.0 Hz, NCHH), 4.97 (1H, app. dt, J=10.6, 3.1 Hz, CH2CH), 7.34–7.37
7.28 (2H, app. t, J=8.0 Hz, 4-FAr
ACHTUNGTRENN(UNG 3,5)H), 7.40 (2H, dd, J=9.0, 4.0 Hz, 4-
FAr(2,6)H), 7.72 (1H, t, J=7.5 Hz, ArH), 7.84 (1H, td, J=7.5 Hz, 1.0,
ACHTUNGTRENNUNG
(2H, m, Ph
ACHTUNGTREN(NUGN 2,6)H), 7.41–7.44 (1H, m, Ph(4)H), 7.51–7.67 (2H, m, Ph-
ArH), 8.01 ppm (1H, d, J=8.5 Hz, ArH) and 8.17 ppm (1H, d, J=
8.0 Hz, ArH); 13C NMR (75 MHz, CD3OD): d=19.1, 20.2, 21.4, 31.3,
43.7, 62.2, 115.8, 117.6 (d, 2J=24.2 Hz), 124.0 (d, 3J=8.8 Hz), 124.4,
127.3, 128.8, 130.2, 139.3, 147.3 (d, 4J=2.6 Hz), 152.9, 162.5 (d, 1J=
243.8 Hz), 164.1 ppm; 19F NMR (376 MHz, CDCl3) d=À114.09 ppm; IR
AHCTUNGERTG(NNUN 3,5)H), 7.71 (1H, td, J=7.7 Hz, 0.9, ArH), 7.84 (1H, td, J=7.5 Hz, 1.2,
ArH), 8.00 (1H, d, J=8.4 Hz, ArH) and 8.16 ppm (1H, d, J=7.8 Hz,
ArH); 13C NMR (75 MHz, CD3OD) d=19.1, 20.3, 21.4, 31.3, 43.7, 62.1,
115.8, 122.1, 124.4, 127.3, 128.5, 128.7, 130.2, 131.1, 139.3, 151.5, 152.9,
162.2 ppm; IR (KBr): n˜ =2964 (C-H), 1737 (C=O), 1546 (C=N), 1471,
À
(KBr): n˜ =2967 (C-H), 1731 (C=O), 1545 (C=N), 1504, 1284 (C O),
1278 (C O), 1191, 765 cmÀ1; MS (EI): m/z (%): 353.1 (40) [MÀCl], 233.1
1190, 761 cmÀ1; MS (ES+): m/z (%): 371.1 (100) [MÀCl]+, 233.1 (75)
[MÀClÀCO2C6H4F]+; HRMS (ESI): m/z calcd for C20H20O2N2FS+:
371.1224 [MÀCl]+; found: 371.1226 (d= +0.5 ppm).
À
(100) [MÀClÀCO2C6H5 +H]; HRMS (ESI): m/z: calcd for C20H21O2N2S+
: 353.1324 [MÀCl]; found: 353.1318 (d=À1.7 ppm).
4-Fluorophenyl (2-(4-methoxyphenyl)-4-methyloxazol-5-yl) carbonate 23:
General Procedure A: O- to C-carboxyl rearrangement of oxazolyl car-
bonates: The isothiourea was added to a solution of the desired carbon-
ate (1 equiv) in CH2Cl2 under nitrogen at the required temperature.
After the specified time, the desired product was obtained by concentra-
tion in vacuo. Purification by silica chromatography, or by acidic work-up
in which the crude reaction mixture was poured into aq. 0.1m HCl, ex-
NEt3 (8.90 mmol, 1.2 mL) was added to 4-methyl-2-(4-methoxyphenyl)-
oxazol-5ACHTUNGTRENNUNG(4H)-one (8.09 mmol, 1.66 g) in THF (15 mL), followed by the
addition of 4-fluorophenyl chloroformate (8.58 mmol, 1.1 mL) at 08C and
stirred for two hours. The resulting solution was poured into H2O, ex-
tracted with Et2O (3ꢃ100 mL), and the combined organic layer washed
successively with 0.1m HCl, sat. NaHCO3, brine, dried (MgSO4) and con-
Chem. Eur. J. 2012, 18, 2398 – 2408
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2405

A. D. Smith et al.
tracted with Et2O (ꢃ3), dried (MgSO4), filtered and concentrated in
vacuo, was used to isolate the product.
[3] For select examples, see: a) E. Vedejs, O. Daugulis, S. T. Diver, J.
Org. Chem. 1996, 61, 430–431; b) J. C. Ruble, G. C. Fu, J. Org.
Chem. 1996, 61, 7230–7231; c) J. C. Ruble, H. A. Latham, G. C. Fu,
J. Am. Chem. Soc. 1997, 119, 1492–1493; d) S. J. Miller, G. T. Cope-
land, N. Papaioannou, T. E. Horstmann, E. M. Ruel, J. Am. Chem.
Soc. 1998, 120, 1629–1630; e) C. E. Garrett, G. C. Fu, J. Am. Chem.
Soc. 1998, 120, 7479–7483; f) J. C. Ruble, J. Tweddell, G. C. Fu, J.
Org. Chem. 1998, 63, 2794–2795; g) E. Vedejs, O. Daugulis, J. Am.
Chem. Soc. 1999, 121, 5813–5814; h) T. Sano, K. Imai, K. Ohashi, T.
Oriyama, Chem. Lett. 1999, 265–266; i) E. R. Jarvo, G. T. Copeland,
N. Papaioannou, P. J. Bonitatebus, Jr., S. J. Miller, J. Am. Chem. Soc.
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J. Am. Chem. Soc. 1999, 121, 5091–5092; k) T. Sano, H. Miyata, T.
Oriyama, Enantiomer 2000, 5, 119–123; l) E. R. Jarvo, M. M. Vas-
binder, S. J. Miller, Tetrahedron 2000, 56, 9773–9779; m) A. C.
Spivey, T. Fekner, S. E. Spey, J. Org. Chem. 2000, 65, 3154–3159;
n) A. C. Spivey, A. Maddaford, D. Leese, A. J. Redgrave, J. Chem.
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Rozners, J. Am. Chem. Soc. 2001, 123, 2428–2429; q) G. T. Cope-
land, S. J. Miller, J. Am. Chem. Soc. 2001, 123, 6496–6502; r) E. R.
Jarvo, C. A. Evans, G. T. Copeland, S. J. Miller, J. Org. Chem. 2001,
66, 5522–5527; s) M.-H. Lin, T. V. RajanBabu, Org. Lett. 2002, 4,
1607–1610; t) K.-S. Jeong, S.-H. Kim, H.-J. Park, K.-J. Chang, K. S.
Kim, Chem. Lett. 2002, 1114–1115; u) E. Vedejs, O. Daugulis, J.
Am. Chem. Soc. 2003, 125, 4166–4173; v) A. C. Spivey, F. Zhu,
M. B. Mitchell, S. G. Davey, R. L. Jarvest, J. Org. Chem. 2003, 68,
7379–7385; w) G. Priem, B. Pelotier, S. J. F. Macdonald, M. S.
Anson, I. B. Campbell, J. Org. Chem. 2003, 68, 3844–3848; x) Y.
Matsumura, T. Maki, S. Murakami, O. Onomura, J. Am. Chem. Soc.
2003, 125, 2052–2053; y) S. Mizuta, M. Sadamori, T. Fujimoto, I. Ya-
mamoto, Angew. Chem. 2003, 115, 3505–3507; Angew. Chem. Int.
Ed. 2003, 42, 3383–3385; z) J. A. MacKay, E. Vedejs, J. Org. Chem.
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Davey, R. L. Jarvest, Tetrahedron 2004, 60, 4513–4525; ab) Y.
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T. Oriyama, Tetrahedron: Asymmetry 2005, 16, 1157–1165; ae) C. ꢄ.
Dꢅlaigh, S. J. Hynes, D. J. Maher, S. J. Connon, Org. Biomol. Chem.
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Angione, S. J. Miller, Tetrahedron 2006, 62, 5254–5261. For select re-
views see: ak) S. J. Miller, Acc. Chem. Res. 2004, 37, 601–610; al) E.
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107, 5759–5812.
(R)-1,1,1-Trichloro-2-methylpropan-2-yl 4-benzyl-5-oxo-2-phenyl-4,5-dihy-
drooxazole-4-carboxylate 41: Following general procedure A, 4-benzyl-2-
phenyloxazol-5-yl
(1,1,1-trichloro-2-methylpropan-2-yl)
carbonate
(0.440 mmol, 0.200 g), CH2Cl2 (2 mL) and 13 (10 mol%, 14.0 mg) gave,
after 1 h at RT and an acidic work-up, 41 (0.191 g, 96%) as a white solid.
M.p. 78–828C; [a]2D0 = +126.6 (c=0.47 in CHCl3); 1H NMR (300 MHz,
CDCl3) d=1.93 (3H, s, CH3), 1.96 (3H, s, CH3), 3.52 (1H, ABq, J=
14.1 Hz, CHH), 3.63 (1H, ABq, J=13.8 Hz, CHH), 7.15–7.21 (5H, m,
CH2PhH), 7.39–7.45 (2H, m, Ph
ACHTUNGTRENN(UNG 3,5)H), 7.52–7.58 (1H, m, Ph(4)H) and
7.84–7.87 ppm (2H, m, Ph
AHCTUNGTRENNUNG
39.0, 78.3, 91.1, 105.1, 125.1, 127.6, 128.1, 128.4, 128.8, 130.4, 132.9, 133.2,
163.2, 163.7, 173.5 ppm; IR (KBr): n˜ =1818 (C=O), 1753 (C=O), 1650
À1
À
À
(C=N), 1249 (C O), 980, 793 cm (C Cl); MS (EI): m/z (%): 476.0
(100) [M
N
(35Cl)3NO4Na:
18ACHTUGNTRENNNUG
476.0199 [MACHTUNGTRENNUNG
excess was determined by HPLC with ChiralPak AD-H column (2%
iPrOH in hexanes, flow rate=1.0 mLminÀ1), tR(S) 7.7 min and tR(R)
9.0 min, 91% ee.
(R)-4-Methoxyphenyl
drooxazole-4-carboxylate 49: Following general procedure A, 4-isobutyl-
2-(4-methoxyphenyl)oxazol-5-yl (4-methoxyphenyl) carbonate
4-isobutyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihy-
(0.100 mmol, 40.0 mg), CH2Cl2 (1 mL) and 11 (10 mol%, 2.6 mg) gave,
after 16 h at À208C and purification by silica chromatography (10:90,
Et2O/petrol), 49 (21 mg, 51%) as a colourless oil. [a]2D0 = +38.8 (c=0.57
in CHCl3); 1H NMR (400 MHz; CDCl3): d=0.95 (3H, d, J 6.8, CH3), 0.99
(3H, d, J=6.8 Hz, CH3), 1.80 (1H, app. sept, J=6.8 Hz, CH), 2.15 (1H,
ABX, JAB =14.0, JAX =7.2 Hz, CHH), 2.48 (1H, ABX, JBA =14.2, JBX
6.0 Hz, CHH), 3.78 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.86 (2H, d, J=
9.2 Hz, 4-OMe(3,5)ArH), 7.01 (2H, d, J=9.2 Hz, 4-OMe(3,5)ArH), 7.01
(2H, d, J=9.2 Hz, 4-OMe(2,6)ArH) and 8.03 ppm (2H, d, J=8.8 Hz, 4-
OMe
(2,6)ArH); 13C NMR (75 MHz, CDCl3) d=23.2, 24.0, 24.8, 42.9,
=
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENUNG
55.7, 80.5, 114.5, 114.6, 117.6, 122.0, 130.5, 143.9, 157.8, 162.9, 163.9,
À
165.3, 175.1 ppm; IR (thin film): n˜ =2961 (C H), 1821 (C=O), 1768 (C=
À1
À
À
O), 1648 (C=C), 1608 (C=N), 1506 (C C), 1261 cm (C O); MS (ES+):
m/z (%): 452.0 (100) [M+CH3OH+Na]; HRMS (ES+): m/z calcd for
C23H27NO7Na: 452.1685 [M+CH3OH+Na]; found: 452.1674 (d=
À2.4 ppm). Enantiomeric excess was determined by HPLC with Chiral-
Pak AD-H column (10% iPrOH in hexanes, flow rate=1.0 mLminÀ1),
tR(S) 15.4 min and tR(R) 20.6 min, 91% ee.
Acknowledgements
The authors would like to thank the Royal Society for a University Re-
search Fellowship (A.D.S.), the EPSRC (C.J.), AstraZeneca (P.A.W.),
Fonds der Chemischen Industrie (T.A.N.) and the EPSRC National Mass
Spectrometry Service Centre (Swansea).
[4] W. Steglich, G. Hçfle, Tetrahedron Lett. 1970, 11, 4727–4730.
[5] J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532–11533.
[6] a) S. A. Shaw, P. Aleman, E. Vedejs, J. Am. Chem. Soc. 2003, 125,
13368–13369; b) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P.
Va, E. Vedejs, J. Am. Chem. Soc. 2006, 128, 925–934.
[1] For an excellent review of Lewis base catalysed reaction processes,
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Chem. Eur. J. 2012, 18, 2398 – 2408

Isothiourea-Mediated Asymmetric O- to C-Carboxyl Transfer
FULL PAPER
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[27] The preparations of isothioureas 11–20 have previously been repor-
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[29] See Supporting Information for full experimental details, characteri-
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[30] For full experimental details and spectra see Supporting Informa-
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[32] See Supporting Information for full experimental details, characteri-
sation data and NMR spectra for 23.
[33] Di-(4-fluorophenyl)carbonate 25 was also isolated in the preparation
of oxazolyl carbonate 23 from the parent azlactone and 4-fluorophe-
nylchloroformate.
[34] The longitudinal relaxation time T1 of fluorinated products 22–25
and of the internal standard, 4-fluoronitrobenzene, were determined
in order to allow accurate quantitative data to be determined in
these experiments. See the Supporting Information for full experi-
mental details.
[35] See the Supporting Information for full experimental details, charac-
terisation data and NMR spectra for 27.
[36] The absolute configuration of 39 was unambiguously assigned by
comparison of the sign of its specific rotation with that of the litera-
ture.[5] The absolute configuration of 37 was also assigned by com-
parison of the HPLC data derived from its preparation employing
an authentic sample of (R)-TADMAP that was generously donated
by Prof. Edwin Vedejs. The absolute configuration of all other rear-
rangement products was assigned by analogy.
[37] We were unable to suitably assess the enantiomeric excess upon re-
arrangement of a C(4)-Bn, C(2)-PMP 1,1,1-trichloro-2-methylpro-
pan-2-yl carbonate derivative with 13 so rearrangement of a C(4)-
Bn, C(2)-phenyl derivative to give 41 (readily amenable to enantio-
meric excess determination by HPLC analysis) was assessed.
[38] Attempted rearrangement of a C(4)-iPr 1,1,1-trichloro-2-methylpro-
pan-2-yl carbonate derivative with either 11 or 13 returned only
starting material.
[20] D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin, A. D.
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[39] For previous asymmetric applications of this O- to C-carboxyl trans-
fer methodology to the enantioselective preparation of oxindole and
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2003, 115, 4051–4054; Angew. Chem. Int. Ed. 2003, 42, 3921–3924;
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Chem. Eur. J. 2012, 18, 2398 – 2408
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2407

A. D. Smith et al.
chards, Tetrahedron Lett. 2009, 50, 6332–6334; c) T. A. Duffey, S. A.
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[40] For full experimental details and spectra see the Supporting Infor-
mation.
[42] Note added in proof: During the consideration of this manuscript an
alternative dual catalysis approach has been reported: C. K. De, N.
Mittal, D. Seidel, J. Am. Chem. Soc. 2011, 133, 16802–16805.
[41] The absolute configurations within 54 and 58–60 have not been as-
signed due to the modest enantioselectivity observed in these pro-
cesses.
Received: September 12, 2011
Published online: January 19, 2012
2408
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Chem. Eur. J. 2012, 18, 2398 – 2408