Isothiourea-catalyzed enantioselective carboxy group transfer

Article abstract of DOI:10.1002/anie.200904333

Transferable skills: Enantiomerically pure isothioureas promote the 0-to C-carboxyl group transfer of oxazolyl carbonates with excellent levels of enantiocontrol (see scheme). The origin of the enantioselectivity of this process was probed mechanistically and rationalized computationally.

Full text of DOI:10.1002/anie.200904333

Communications
DOI: 10.1002/anie.200904333
Synthetic Methods
Isothiourea-Catalyzed Enantioselective Carboxy Group Transfer**
Caroline Joannesse, Craig P. Johnston, Carmen Concellꢀn, Carmen Simal, Douglas Philp, and
Andrew D. Smith*
The rational design and mechanistic understanding of cata-
lytic systems capable of generating quaternary stereocenters
in an asymmetric fashion is a recognized challenge in
synthesis.[1] A number of asymmetric Lewis base mediated
processes have been developed within this area,[2] in which
enantiomerically pure derivatives of 4-(pyrrolidino)pyridine
(PPY) and 4-dimethylaminopyridine (DMAP) are elegantly
employed by the Fu,[3] Vedejs,[4] and Richards groups,[5] as
asymmetric catalysts for the rearrangement of 5-oxazolyl
carbonates into 4-carboxyazlactones (Scheme 1).[6] This pro-
cess delivers C-carboxyazlactones bearing a quaternary
stereocenter with excellent enantiocontrol.[7]
Scheme 2. Evolution of isothiourea catalysts.
DHPB,[10] before Birman and Li developed HBTM (1) for the
kinetic resolution of aryl cycloalkanols.[11] Building upon
these studies,[12,13] Dietz and Grꢀger have utilized tetramisole
(32 mol%) to promote a modestly enantioselective rear-
rangement of an oxazolyl acetate (63% ee at 80% conver-
sion),[14] and we have shown that DHPB represents the
optimal catalyst substructure for the carboxyl group transfer
reaction of oxazolyl carbonates in the racemic series.[15]
As part of a research program concerned with utilizing
Lewis bases as catalysts,[16] we hoped to build upon these
precedents by using chiral isothioureas, such as 1, to promote
the Steglich rearrangement with high enantioselectivity. The
incorporation of a stereodirecting group at C4, adjacent to the
nucleophilic nitrogen atom, is imperative in these catalyst
architectures; this contrasts the recognized derogatory effect
of the 2-substitution of DMAP or PPY derivatives upon
catalytic turnover in acylation reactions.[4a,17] Upon formation
of an N-carboxy derivative within the Steglich reaction, this
stereodirecting group was predicted to adopt a pseudoaxial
conformation.[18] It was anticipated that asymmetric induction
would arise from discrimination between the prochiral faces
of an azlactone enolate upon addition to this intermediate,
preferably anti to the C4 stereodirecting unit, with the axial
Scheme 1. The asymmetric Steglich rearrangement.
Among the recent developments in Lewis base catalysis,
the ability of isothioureas to efficiently promote alcohol
acylation has been demonstrated. Birman and Li first showed
that tetramisole and its benzannulated analogue BTM could
catalyze effective kinetic resolution[8] and desymmetrization
protocols (Scheme 2).[9] Independent studies by Kobayashi
and Okamoto, and Birman et al. subsequently introduced
À
C3 H aiding differentiation between the planar aromatic and
aliphatic quadrants (Figure 1).
Initial studies evaluated isothiourea 1 to promote the
asymmetric O- to C-carboxyl group transfer of a range of
alkyl and aryl oxazolyl carbonates 2–4, with the transfer of the
[*] C. Joannesse, C. P. Johnston, Dr. C. Concellꢀn, C. Simal,
Prof. D. Philp, Dr. A. D. Smith
EaStCHEM, School of Chemistry
University of St. Andrews
North Haugh, St. Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
[**] We thank the Royal Society (ADS), the EPSRC (C.J.), and the
Ministerio de Educaciꢀn y Ciencia (C.S. and C.C.) for funding and
the EPSRC Mass Spectrometry Centre. Prof. Edwin Vedejs is
gratefully acknowledged for supplying an authentic sample of
(R)-TADMAP to allow unambiguous stereochemical assignments.
Figure 1. Proposed stereodefined N-carboxy intermediate. The stereo-
directing unit at C4 is imperative; the stereodefined N-carboxy
intermediate has a pseudoaxial directing substituent; and discrimina-
tion between the aliphatic and planar quadrants leads to high ee.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904333.
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phenoxycarbonyl group proceeding with the highest ee
(Table 1).[19] The observed ee value of the product 7 proved
insensitive to a variety of solvents, with the exception of THF
proved less reactive than either 1 or 8, showing only
reasonable catalytic activity between room temperature and
À108C (Table 2, entries 7 and 8).
The generality of this process was additionally examined
using isothioureas 1 and 8. Rearrangement of the C4-
alkyloxazolyl phenyl carbonates (R = Me, Et, nBu, allyl,
CH2CH2SMe) with either 1 or 8 proceeded with uniformly
excellent enantioselectivities to deliver products 10–13
(Table 3, entries 3–8). Tyrosine-derived carbonates also
Table 1: Optimization studies.[a]
Table 3: Scope of the enantioselective carboxyl group transfer of oxazolyl
carbonates with isothioureas 1 and 8.[a]
Entry
R
1 (mol%)
T [8C]
Product
ee [%][b]
1
2
3
4
5
6
Me
Bn
Ph
Ph
Ph
Ph
10
10
10
2
10
10
RT
RT
RT
5
6
7
7
7
7
70
72
79
79
87
91
Entry Cat.
R
R1
Prod. Yield ee
RT
[%][b] [%][c]
À20
À50
1
1
8
1
8
1
8
1
1
1
1
8
1
8
1
8
1
1
8
Bn
Bn
Me
Me
Et
Et
nBu
allyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
7
7
96
96
68
94
91
96
65
69
65
90
86
90
97
88
82
–
91
2
3
4
5
93[d]
94
[a] Reaction conditions: 2–4 (1 mmol), CH2Cl2 (1 mL), 1 h (RT) or 16 h
(À208C or À508C). [b] Determined by HPLC analysis.
10
10
11
11
12
13
14
15
15
16
16
94[e]
91
93
92
89
which gave 7 with a reduced ee value.[20] The loading of 1
could be reduced to 2 mol% at room temperature without
affecting the product ee value. For optimal enantioselectivity,
lowering the reaction temperature to À508C was necessary,
giving 7 in 91% ee and 96% yield.[21]
Additional studies probed the ability of isothioureas 8 and
9 to promote the carboxyl group transfer of 4 (Table 2).[22]
Isothiourea 8 showed similar reactivity and enantioselectivity
to 1 (Table 2, entries 4–6). Isopropyl-substituted isothiourea 9
delivered 7 with high a ee value at room temperature but
6
7
8
9
CH2CH2SMe
4-BnOC6H4CH2
4-BnOC6H4CH2
4-PhO2COC6H4CH2 Ph
4-PhO2COC6H4CH2 Ph
iBu
iBu
iPr
iPr
iPr
90
10
11
12
13
14
15
16
17
18
91
86[e]
90
87[e]
89[f]
91[g]
73[f]
78[h]
78[f]
C(Me)2CCl3 17
C(Me)2CCl3 17
Ph
4-MeOC6H4 19
4-MeOC6H4 19
18
38
30
[a] Reaction conditions: oxazolyl carbonate (1 mmol), CH2Cl2 (1 mL),
16 h. [b] Yield of isolated product. [c] Determined by HPLC analysis.
[d] Reaction temperature À608C. [e] Reaction temperature À308C.
[f] Reaction temperature RT. [g] Reaction temperature 408C. [h] Reaction
temperature 08C.
Table 2: Evaluating chiral isothioureas for the carboxyl group transfer.[a]
undergo carboxyl group transfer with good enantioselectivity
to give products with up to 91% ee (Table 3, entries 10–13).
Carboxyl group transfer in the leucine series proceeded at
room temperature with 1 to give 17 in 88% yield and 89% ee,
whereas using 8 at 408C gave 17 in 82% yield and 91% ee
(Table 3, entries 14 and 15). Rearrangement of the C4-
isopropyl-substituted oxazolyl phenyl carbonate with 1 pro-
ceeded readily to give 18 at room temperature, although
significant amounts (30–40%) of the parent azlactone,
formally corresponding to hydrolysis of the carbonate
group, precluded the isolation of homogeneous product
(Table 3, entry 16). However, reaction of the corresponding
4-methoxyphenyl carbonate using 8 allowed the isolation of
19, albeit in modest yield (Table 3, entries 17 and 18), thereby
representing, to the best of our knowledge, the first asym-
metric rearrangement of C4-a-alkyl-branched oxazolyl car-
bonates.[4c]
Entry
Cat. (mol%)
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1 (2)
RT
À20
À50
RT
À25
À60
RT
95
96
96
93
92
96
94
94
79
87
91
83
87
93
87 (ent)
91 (ent)
1 (10)
1 (10)
8 (10)
8 (10)
8 (10)
9 (10)
9 (10)
À10
[a] Reaction conditions: 4 (1 mmol), CH2Cl2 (1 mL), 1 h (RT) or 16 h
(À108C to À608C). [b] Yield of isolated product. [c] Determined by HPLC
analysis.
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To exemplify the utility of the reaction products, 17
position. As predicted, N-carboxylation of 1 to give 23 results
in a reversal of the conformational bias—a pseudoaxial Ph
group in 23 is 4.62 kcalmolÀ1 more favorable than the
corresponding pseudoequatorial conformation, presumably
reflecting minimization of 1,2-strain in this intermedi-
ate. Within 23, the N-phenoxycarbonyl group prefer-
entially lies approximately co-planar with the iso-
thiourea heterocycle, giving two rotameric forms of
(91% ee) was derivatized with l-alanine methyl ester, giving
dipeptide 20 as a single diastereoisomer after purification
(Scheme 3).[3]
=
intermediate 23, with the C O group either syn
=
(preferred) or anti with respect to the C N bond.
Enolate 24 is therefore predicted to preferentially
approach 23 anti to the face blocked by the axial Ph
group.
This facial selectivity alone is not enough to
generate high enantioselectivity in this transforma-
tion, as the lateral orientation of prochiral enolate 24
with respect to 23 must also be controlled. The two
possible orientations of enolate 24, combined with the two
rotamers of 23, gives rise to four possible combinations
(Figure 2). We calculated the structures and the relative
energies of the favored transition state for each permutation.
Revealingly, all possible transition-states A–D placed the C2-
phenyl group of enolate 24 over the planar aromatic portion
of the isothiourea, thereby minimizing interactions with the
Scheme 3. Derivatization of C-carboxyazlactone product 17.
Preliminary mechanistic studies show that nonlinear
effects are not observed between the ee of the product
(R)-7 and catalyst 1, of known ee, upon rearrangement of
carbonate 4;[23] this result is consistent with only one molecule
of 1 being involved in the stereochemical-determining step of
this reaction. Furthermore, control experiments indicate that
the C-carboxyazlactone products are configurationally stable
under the reaction conditions,[24] consistent with the C C
axial C3 H of the tetrahydropyrimidinium ring. Both tran-
À
À
bond-forming event being irreversible. To understand the
factors that govern the observed stereocontrol in this
reaction, we performed calculations on the rearrangement
of oxazolyl carbonate 21 using isothiourea 1, which exper-
imentally generates (R)-22 in 84% ee at room temperature,[25]
at the B3LYP/6-31G(d,p) level of theory.[26] For these
calculations, it was assumed that the formation of C-carbox-
yazlactone (R)-22 is initiated through nucleophilic attack of 1
at the carbonate carbonyl group of 21 which generates, after
collapse of the corresponding tetrahedral intermediate,
N-carboxy intermediate 23 and azlactone enolate 24. Sub-
sequent preferential C-carboxylation upon the Re face of
enolate 24 gives (R)-22 (Scheme 4).
sition states leading to the major (R)-product enantiomer
(TSA and TSB, Figure 2a) are lower in energy than the two
transition states leading to the minor (S)-product enantiomer
(TSC and TSD, Figure 2a). The lowest energy transition state
=
is that accessed from the rotamer of 23 in which the C O
=
group is syn with respect to the C N bond, permitting
À
additional stabilizing C H···O interactions between the
enolate and both the tetrahydropyrimidinium ring and the
ortho-hydrogen atoms of the aromatic ring of the phenoxy-
carbonyl group (Figure 2b).[27] The molecular electrostatic
potentials of 23 and 24 were computed next to further
understand the origins of this orientational selectivity.[26]
These calculations indicated a significant area of positive
charge associated with the surface of 23 centered on the
tetrahydropyrimidinium ring. In enolate 24 there is consid-
erable charge asymmetry associated with the oxazole ring,
with the enolate oxygen atom carrying significant negative
charge. Matching of these two areas of opposite charge gives
rise to the correct orientation of enolate 24 with respect to 23
at the transition state.
A key question in understanding stereocontrol in this
rearrangement reaction is identification of the lowest energy
conformation of the N-carboxy intermediate 23. Calculation
of the relative conformational energies of (S)-1 revealed that
the Ph group preferentially adopts a pseudoequatorial
In conclusion, isothioureas 1, 8, and 9 promote the
rearrangement of a range of oxazolyl carbonates with
excellent levels of enantiocontrol (up to 94% ee). The factors
leading to high stereocontrol in this process have been studied
computationally, with a number of discrete features identified
as important. Firstly, the preference of the C4-stereodirecting
group of N-carboxy intermediate 23 to adopt a pseudoaxial
conformation directs the incipient enolate anti to the stereo-
directing unit. Secondly, electrostatic complementarity
À
between N-carboxy 23 and enolate 24, assisted by C H···O
interactions and minimization of steric interactions with the
À
axial C3 H, ensures that facial control of the enolate with
=
respect to the C O group is achieved. Current studies are
Scheme 4. Proposed catalytic cycle for the asymmetric carboxyl group
transfer from the O to C of 21 to generate (R)-22 using (S)-1.
focused upon probing fully the mechanism of this trans-
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[1] For a review, see C. J. Douglas, L. E. Overman, Proc. Natl. Acad.
Sci. USA 2004, 101, 5363.
[2] For an excellent recent review, see S. E. Denmark, G. L.
Beutner, Angew. Chem. 2008, 120, 1584; Angew. Chem. Int.
Ed. 2008, 47, 1560.
[3] a) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 11532; for
the application of this methodology to the rearrangement of
indolyl and benzofuranyl carbonates, see b) I. D. Hills, G. C. Fu,
Angew. Chem. 2003, 115, 4051; Angew. Chem. Int. Ed. 2003, 42,
3921.
[4] Vedejs et al. have also shown that PBO, a chiral phosphine, can
promote this reaction with good enantioselectivity; see a) S. A.
Shaw, P. Aleman, E. Vedejs, J. Am. Chem. Soc. 2003, 125, 13368;
b) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va, E.
Vedejs, J. Am. Chem. Soc. 2006, 128, 925. Vedejs et al. have
recently developed an alternative catalyst system for the
rearrangement of indolyl carbonates and acetates which can
tolerate a-branched substituents; c) T. A. Duffey, S. A. Shaw, E.
Vedejs, J. Am. Chem. Soc. 2009, 131, 14.
[5] H. Y. Nguyen, D. C. D. Butler, C. J. Richards, Org. Lett. 2006, 8,
769.
[6] W. Steglich, G. Hꢀfle, Tetrahedron Lett. 1970, 11, 4727.
[7] For other enantioselective approaches, see a) J. G. Seitzberg, C.
Dissing, I. Søtofte, P.-O. Norrby, M. Johannsen, J. Org. Chem.
2005, 70, 8332; b) E. Busto, V. Gotor-Fernꢁndez, V. Gotor, Adv.
Synth. Catal. 2006, 348, 2626.
[8] V. B. Birman, X. Li, Org. Lett. 2006, 8, 1351.
[9] V. B. Birman, H. Jiang, X. Li, Org. Lett. 2007, 9, 3237.
[10] a) M. Kobayashi, S. Okamoto, Tetrahedron Lett. 2006, 47, 4347;
b) V. B. Birman, X. Li, Z. Han, Org. Lett. 2007, 9, 37.
[11] For the previous preparation of chiral isothiourea 1 and its use in
kinetic resolution, see V. B. Birman, X. Li, Org. Lett. 2008, 10,
1115.
À
[12] For asymmetric C C bond-forming reactions employing cata-
lytic quantities of an amidine, see a) A. E. Taggi, A. M. Hafez, T.
Dudding, T. Lectka, Tetrahedron 2002, 58, 8351; for an alter-
native use of tetramisole, see b) V. C. Purohit, A. S. Matla, D.
Romo, J. Am. Chem. Soc. 2008, 130, 10478.
[13] For select examples of amidines as catalysts, see a) S. Kim H.
Chang, Bull. Chem. Soc. Jpn. 1985, 58, 3669; b) V. K. Aggarwal,
A. Mereu, Chem. Commun. 1999, 2311; c) W.-C. Shieh, S. Dell,
O. Repic, J. Org. Chem. 2002, 67, 2188; d) B. G. G. Lohmeijer,
R. C. Pratt, F. Leibfarth, J. W. Logan, D. A. Long, A. P. Dove, F.
Nederberg, J. Choi, C. Wade, R. M. Waymouth, J. L. Hedrick,
Macromolecules 2006, 39, 8574; e) W. Zhang, M. Shi, Org.
Biomol. Chem. 2006, 4, 1671.
[14] F. R. Dietz, H. Grꢀger, Synlett 2008, 663. In our hands,
tetramisole did not promote the carboxyl group transfer of 4.
[15] C. Joannesse, C. Simal, C. Concellꢂn, J. E. Thomson, C. D.
Campbell, A. M. Z. Slawin, A. D. Smith, Org. Biomol. Chem.
2008, 6, 2900.
[16] a) J. E. Thomson, K. Rix, A. D. Smith, Org. Lett. 2006, 8, 3785;
b) J. E. Thomson, C. D. Campbell, C. Concellꢂn, N. Duguet, K.
Rix, A. M. Z. Slawin, A. D. Smith, J. Org. Chem. 2008, 73, 2784;
c) J. E. Thomson, A. F. Kyle, C. Concellꢂn, K. A. Gallagher, P.
Lenden, L. C. Morrill, A. J. Miller, C. Joannesse, A. M. Z.
Slawin, A. D. Smith, Synthesis 2008, 2805; d) C. D. Campbell,
N. Duguet, K. A. Gallagher, J. E. Thomson, A. G. Lindsay, A. C.
OꢃDonoghue, A. D. Smith, Chem. Commun. 2008, 3528.
[17] For reviews of the chemistry of DMAP and PPY derivatives, see
a) G. Hꢀfle, W. Steglich, H. Vorbrꢄggen, Angew. Chem. 1978, 90,
602; Angew. Chem. Int. Ed. Engl. 1978, 17, 569; b) A. C. Spivey,
S. Arseniyadis, Angew. Chem. 2004, 116, 5552; Angew. Chem.
Int. Ed. 2004, 43, 5436. For asymmetric synthesis employing a 2-
substituted DMAP derivative, see c) E. Vedejs, X. Chen, J. Am.
Chem. Soc. 1996, 118, 1809.
Figure 2. a) Relative transition-state energies (B3LYP/6-31G(d,p)) for
the four possible transition states of the reaction of N-carboxy
intermediate 23 and enolate 24. Energies given in kcalmolÀ1. b) Ball-
and-stick representation of the lowest energy transition state (B3LYP/
6-31G(d,p)) accessed by N-carboxy intermediate 23 and enolate 24
À
which leads to (R)-22. Dashed lines indicate C H···O interactions and
À
the solid black line indicates the C C bond forming. Carbon atoms are
light gray, nitrogen and oxygen atoms are dark gray, and hydrogen
atoms are white.
formation and developing alternative applications of enan-
tiomerically pure isothioureas in asymmetric catalysis.
Received: August 3, 2009
Published online: October 15, 2009
Keywords: asymmetric catalysis · carboxy group transfer ·
.
heterocycles · isothioureas · organocatalysis
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[18] For representative examples that demonstrate the preference of
tion; see J. W. Yang, M. Stadler, B. List, Nat. Protoc. 2007, 2,
1937. (R)-9 was derived from (R)-3-amino-4-methyl-pentanoic
acid (> 99% ee, Fluorochem).
substituents adjacent to an N-acyl group in heterocyclic com-
pounds to adopt a pseudoaxial position, see a) P. J. Sinclair, D.
Zhai, J. Reibenspies, R. M. J. Williams, J. Am. Chem. Soc. 1986,
108, 1103; b) J. F. Dellaria, B. D. Santarsiero, J. Org. Chem. 1989,
54, 3916; c) M. G. B. Drew, L. M. Harwood, G. Park, D. W. Price,
S. N. G. Tyler, C. R. Park, S. G. Cho, Tetrahedron 2001, 57, 5641.
[19] The absolute configuration of (R)-6 was assigned by comparison
of the sign of its specific rotation with that reported in the
literature.[3] The absolute configuration of (R)-7 was unambig-
uously assigned by comparison of the HPLC data derived from
rearrangement of 4 into (R)-7 employing an authentic sample of
(R)-TADMAP that was generously donated by Prof. Edwin
Vedejs. The configuration of all other rearrangement products
was assigned by analogy.
[23] For reviews of nonlinear effects in asymmetric catalysis, see
a) H. B. Kagan, T. O. Luukas in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, New York, 1999, chap. 4.1; b) H. B. Kagan, Adv.
Synth. Catal. 2001, 343, 227.
[24] Treatment of (R)-7 (79% ee) with either (S)-1 or ( Æ )-1
(10 mol%) in CH2Cl2 at ambient temperature returned (R)-7
(79% ee); treatment of ( Æ )-7 with (S)-1 similarly returned ( Æ )-
7.
[25] Oxazolyl carbonate 21 was treated with (S)-1 (10 mol%) in
CH2Cl2 at room temperature, giving (R)-22 in 84% ee. See the
Supporting Information for details. Fu and co-workers have
previously shown that a 4-methoxyphenyl oxazolyl substituent
offers the highest rate of rearrangement in this process (see
reference [3])and so this substituent was used throughout.
Comparable product ee values were obtained from the rear-
rangement of 21 (4-Ph) and the corresponding 4-methoxyphenyl
oxazolyl carbonate in our hands.
[20] See the Supporting Information for full details.
[21] As well as giving the highest enantioselectivity, phenoxycarbonyl
substrates rearrange at a faster rate than the corresponding
methoxy- and benzyloxycarbonyl derivatives, and also allow the
reaction temperature to be lowered significantly from room
temperature to optimize product ee values.
[22] The stereochemical integrity of 1, 8, and 9 were all unambigu-
ously assessed as greater than 99% ee by HPLC analysis and
comparison with racemic standards. 1, 8, and 9 were easily
synthesized from the corresponding enantiomerically pure
g-amino alcohol derivatives in three simple steps (see the
Supporting Information for full experimental details). (S)-1 was
prepared directly from commercially available (S)-3-amino-3-
phenylpropan-1-ol hydrochloride (> 99% ee, Fluorochem);
(3R,4S)-8 was readily derived from (1S,2S)-2-methyl-3-oxo-1-
phenylpropylcarbamate (> 98% de, > 99% ee) which was pre-
pared using an asymmetric l-proline-catalyzed Mannich reac-
[26] The Supporting Information contains full computational details,
coordinates corresponding to the four lowest energy transition-
states A–D and the electrostatic potential surfaces of N-carboxy
23 and enolate 24.
[27] The observation of the ortho-hydrogen atoms of the phenoxy-
À
carbonyl intermediate participating in stabilizing C H···O
interactions in the preferred transition state may explain the
trend observed in Table 1 in which the highest levels of
enantioselectivity are observed with the phenoxycarbonyl,
rather than methoxy- or benzyloxycarbonyl substrates.
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