Predicting the R/S absolute configuration in asymmetric bifunctional catalysis (ABC)

Article abstract of DOI:10.1016/j.tetlet.2007.05.131

A predictive model for assigning the R/S absolute configuration in chiral Lewis base-dependent asymmetric bifunctional catalysis (ABC) has been developed. Chiral Lewis base (LB^*)-dependent ABC abolishes the chiral Lewis acid (LA^*) co

Full text of DOI:10.1016/j.tetlet.2007.05.131

Tetrahedron Letters 48 (2007) 5275–5278
Predicting the R/S absolute configuration in
asymmetric bifunctional catalysis (ABC)
Yun-Ming Lin,* Zhongtao Li and Julie Boucau
Department of Chemistry, University of Toledo, MS 602, 2801 W. Bancroft Street, Toledo, OH 43606, United States
Received 6 May 2007; accepted 21 May 2007
Available online 25 May 2007
Abstract—A predictive model for assigning the R/S absolute configuration in chiral Lewis base-dependent asymmetric bifunctional
catalysis (ABC) has been developed. Chiral Lewis base (LB*)-dependent ABC abolishes the chiral Lewis acid (LA*) component as
the stereochemical determining factor in asymmetric catalysis. By correlating the constant LB* chirality to the facial preference for
the LA*-bound carbonyl group for nucleophile delivery, the R/S absolute configuration of the products can be predicted a priori.
Ó 2007 Elsevier Ltd. All rights reserved.
The addition of nucleophiles to a carbonyl group is an
important C–C bond forming reaction. In the absence
of a chiral environment, the nucleophile attacks the car-
bonyl group from either enantiomeric face with equal
opportunity, thus affording a racemic product (Scheme
1). Because chirality plays an essential role in molecular
recognition between small molecules and their biological
targets, differentiating the two enantiomeric faces of the
carbonyl groups in order to achieve asymmetric induc-
tion (ideally >99% ee) is highly desirable. One contem-
porary approach to impart asymmetric induction in
the addition of carbon nucleophiles is to employ a chiral
group and imparts chirality transfer from the LA* to
the product (i.e., LA*-dependent asymmetric induction).
While the ee from the LA*-catalyzed reactions can be
readily determined (e.g., using chiral HPLC), predicting
the R/S absolute configuration of the product prior to
reaction execution is very challenging.1d In addition to
the dynamic equilibrium between the two structurally
different LA*-aldehyde complexes 3 and 4, the steric
and electronic properties of the LA* fluctuate during
catalysis (Scheme 1). Addition of the nucleophile
(Nuc) to the LA*-activated C@O generates a more Le-
wis basic alkoxide ligand that can coordinate to the
LA* to form a modified LA* 5. In addition to inhibiting
catalyst turnover, this coordination event could lead to
the replacement of hemiliable chiral ligands that are
indispensable for asymmetric induction. To date, devel-
oping a reliable model for predicting the R/S absolute
configuration prior to the reactions remains a consider-
able challenge in asymmetric catalysis.2
Lewis acid (LA*, denotes chirality).1 Coordination of
*
the LA* to the carbonyl oxygen activates the carbonyl
Nuc
top face
R
2
HO
HO
H
Nuc
R
H
+
O
R
H
ent-2
bottom face
1
Nuc
We have designed a Lewis acid–Lewis base (LA*–LB*)
bifunctional catalytic system 6 that features a planar
LA*, aiming at abolishing its role as a determining
factor in chiral induction (Fig. 1).3,4 Because both apical
coordination sites in bifunctional catalyst 6 are openly
accessible and the bound carbonyl group can freely
rotate, asymmetric induction is impossible for the
background reaction, catalyzed by the LA* alone. In
contrast, the LB* moiety of catalyst 6 converts the
Nuc into a transient chiral species, and it is this
LB*-bound chiral species that ultimately determines
LA*
R
LA*
Nuc
R
H
R
H
O
5
H
O
O
LA*
LA*
3
4
Nuc
Scheme 1. The LA* catalyzed carbonyl addition reaction.
*
Corresponding author. Tel.: +1 419 530 1501; fax: +1 419 530
4033; e-mail: Yun-Ming.Lin@Utoledo.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.131

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Y.-M. Lin et al. / Tetrahedron Letters 48 (2007) 5275–5278
If the LB*-dependent asymmetric induction hypothesis
Chiral LB* for asymmetric Induction
is correct, switching the LB* chirality in bifunctional
catalyst 9 from quinine to quinidine should reverse the
facial selectivity of the LA*-activated carbonyl group
and produce the other enantiomeric b-lactone.6 Employ-
ing the (R)-2,3-diaminopropionic acid as the linker, we
subsequently synthesized the quinidine-derived bifunc-
tional catalyst 13 from its corresponding ligand and
Co(II) (Scheme 3). Indeed, substituting bifunctional cat-
alyst 13 for 9 completely reversed the facial selectivity of
the bound carbonyl group. Employing 1 mol % of cata-
lyst 13 in the Wynberg reaction between aldehyde 7 and
ketene afforded the R enantiomeric b-lactone 8R in 86%
yield and >99% ee. This result provides additional
experimental evidence to support the LB*-dependent
asymmetric induction hypothesis.4
Nuc
R
Nuc (background reaction)
LB*
O
H
t-Bu
t-Bu
t-Bu
N
N
6
M
O
O
t-Bu
Planar LA* for electrophilic activation only
Figure 1. Design of a predictable asymmetric bifunctional catalytic
system.
the stereochemical outcome of the reactions. Because
the LB* chirality remains unchanged during the entire
catalytic cycle, it is possible to predict the R/S absolute
configuration of the product based on the LB* utilized.
Herein, we report the development of such a predictive
model and apply this model to determine the b-lactone
configurations in the asymmetric Wynberg reaction.5
Because the absolute configurations of both b-lactones
8S/8R have been established by Evans and Janey,7 the
relationship between the LB* chirality of catalysts 9/13
and their corresponding si-/re-facial preference to the
LA*-bound carbonyl group can be deduced. By correlat-
ing the LB* chirality in bifunctional catalysts 9/13 to the
corresponding si-/re-facial selectivity for delivering the
nucleophile (i.e., the ammonium enolates) in the stereo-
determining step,5a a predictive model for the R/S abso-
lute configurations has been developed. For the sake of
simplicity, we formulated the following conventions to
predicting the absolute configuration of the newly cre-
ated chiral center from achiral aldehydes (Scheme 4).
Based on the design principle outlined in Figure 1, we
recently reported the discovery of an active catalyst 9
(Scheme 2).4 Its remarkable bifunctional catalytic activ-
ity was demonstrated using the asymmetric Wynberg
reaction between aldehyde 7 and ketene. We have also
proposed a plausible catalytic cycle. Steric consideration
favors the coordination of the planar Co(II) to the car-
bonyl lone pair electrons that are cis to the H (i.e.,
11 > 10, Scheme 2). This selective coordination differen-
tiates the two enantiomeric faces of the bound carbonyl
group by the ammonium enolate derived from ketene
and the LB*. Thus, free rotation of the bound carbonyl
group becomes irrelevant in the stereodifferentiating C–
C bond forming step, in which the LB* delivers the eno-
late and defines the stereochemistry of the product (12,
Scheme 2).4
(1) Place the aldehyde on a horizontal plane by orienting
the carbonyl oxygen pointing to the left and the hydro-
gen to the front. (2) As discussed in Scheme 2, both cat-
alysts 9/13 coordinate their planar LA* to the lone pair
electrons cis to the H atom (in the front) of the carbonyl
group and are depicted as 15A/15B. The quinine-derived
bifunctional catalyst delivers the nucleophile from the
bottom face (15A) of the bound carbonyl group, thus
giving the new chiral center having the configuration
O
O
H2C C O
O
BnO
OMe
H
LA*-LB*
(1 mol %)
BnO
7
8S
N
> 99% ee
O
N
O
O
LA*-LB*
R
N
N
LB*
Co
O
H
O
t-Bu
t-Bu
O
t-Bu
t-Bu
t-Bu
N
N
N
t-Bu
9
t-Bu
Co
O
O
RCHO
t-Bu
12
LB*
(7)
H
R
LB*
H2C C O
t-Bu
t-Bu
O
O
R
N
H
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
N
N
Co
10
O
O
Co
O
O
t-Bu
11
Scheme 2. LB*-dependent asymmetric bifunctional catalysis. Notes: The ester linkage and the LB* are simplified for clarity.

Y.-M. Lin et al. / Tetrahedron Letters 48 (2007) 5275–5278
5277
OMe
N
O
O
H2C
C O
O
O
BnO
H
N
LA*-LB* (13)
BnO
O
7
(1 mol %)
8R
N
N
O
> 99% ee
Co
t-Bu
t-Bu
O
t-Bu
t-Bu
13
Scheme 3. An active bifunctional catalyst from quinidine.
(e.g., masked aldols)9 manifests to the current research
effort directed towards the development of new catalytic
systems for their efficient syntheses. The catalytic, asym-
metric Wynberg reaction between aldehydes and ketenes
is among the most elegant approaches.7,10 After much
experimentation, we were pleased to find that LA*–
LB* bifunctional catalyst 9 promoted the asymmetric
Wynberg reaction between ketene and aromatic alde-
hydes 16 efficiently to furnish the expected b-lactones
17 in good to excellent yields and excellent ee (Table
1, entries 1–6).11 Their S configurations were assigned
based on the predictive model in Scheme 4.
R
R
O
favors si-face
LA*–LB* 9
HO
H
H
LA
Nuc
LB*
Co
LB*
Nuc
O
ent-2
15A
N
N
O
t-Bu
t-Bu
O
LB*
Nuc
t-Bu
t-Bu
14
Nuc
R
H
O
LA*–LB* 13
favors re-face
R
HO
H
LA
15B
2
Scheme 4. A predictive model for assigning the R/S absolute
configuration.
For comparisons, the asymmetric Wynberg reaction cat-
alyzed by the LA*–LB* bifunctional catalyst 13 was
examined (entries 7–10). In contrast to the uniformly
excellent ee achieved by catalyst 9, the ee of the reactions
catalyzed by 13 varied from excellent (entry 7) to mod-
erate (entries 8–10). The R configurations of the major
enantiomers (entries 8–10) were predictable based on
model 15B, regardless of the level of asymmetric induc-
tion. Taken together, these results not only demonstrate
the substrate scope of our LA*–LB* bifunctional cata-
lysts 9/13, but also illustrate their predictable asymmet-
ric induction in which an excellent level of ee is not a
shown in ent-2 while the quinidine-derived catalyst
delivers the nucleophile from the top face (15B) to give
the absolute configuration depicted in 2.
The model was subsequently applied to the asymmetric
Wynberg reaction for assigning the R/S absolute config-
urations of the resulting b-lactones. The synthetic signif-
icance of optically pure b-lactones as versatile synthons8
Table 1. A predictable asymmetric Wynberg reactiona
O
O
O
LA*–LB* 9
(S)-17
O
R
R
+
H2C C O
ketene
O
CH2Cl2
R
H
LA*–LB* 13
(R)-17
16
Entry
Aldehydes 16 (R-)
LA*–LB* (mol %)
17 (% yield)b
17 (% ee)c
17 (R/S)
1
2
3
4
5
6
7
8
9
2-NO2–Ph–
3-NO2–Ph–
4-NO2–Ph–
4-CN–Ph–
2-F–Ph–
9 (10)
9 (10)
9 (10)
9 (10)
9 (20)
9 (5)
13 (1)
13 (10)
13 (10)
13 (10)
90
62
87
96
44
60
86
18
42
21
>99
>99
>99
>99
>99
>99
>99
78
S
S
S
S
S
2-Cl–Ph–
S
BnOCH2–
3-NO2–Ph–
4-NO2–Ph–
4-CN–Ph–
Rd
R
R
R
67
74
10
a All reactions were carried out at À78 °C except for entry 5, which was carried out at À20 °C.
b Isolated yields.
c ee Determined by chiral HPLC using a CHIRACEL OD-H column.
d Absolute configuration known.7

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Y.-M. Lin et al. / Tetrahedron Letters 48 (2007) 5275–5278
prerequisite.12 They also attest to the practical advan-
tage of the LB*-dependent asymmetric catalytic pro-
cesses over other catalytic systems. For aromatic
aldehydes, the drastic difference between catalysts 9
and 13 in asymmetric induction is presumably due to
the internal ‘matched–mismatched’ scenario between
the LA* and the LB*.13
4. Lin, Y.-M.; Boucau, J.; Li, Z.; Casarotto, V.; Lin, J.;
Nguyen, A. N.; Ehrmantraut, J. Org. Lett. 2007, 9, 567–570.
5. (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982,
104, 166–168; (b) Wynberg, H.; Staring, E. G. J. J. Chem.
Soc., Chem. Commun. 1984, 1181–1182; (c) Wynberg, H.;
Staring, E. G. J. J. Org. Chem. 1985, 50, 1977–1979.
6. For an overview on reversible stereoselectivity based on
quinine/quinidine cinchona alkaloids, see: Frances, S.;
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003,
103, 2985–3012.
7. Evans, D. A.; Janey, J. M. Org. Lett. 2001, 3, 2125–2128.
8. For reviews, see: (a) Wang, Y.; Tennyson, R. L.; Romo,
D. Heterocycles 2004, 64, 605–658; (b) Yang, H. W.;
Romo, D. Tetrahedron 1999, 55, 6403–6434.
9. For catalytic enantioselective aldol reactions, see: Carre-
ira, E. M.; Fettes, A.; Marti, C. In Organic Reactions;
Overman, L. E., Ed.; Wiley & Sons: New York, 2006; Vol.
67, pp 1–216, and references cited therein.
10. (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am.
Chem. Soc. 2001, 123, 7945–7946; (b) Nelson, S. G.; Zhu,
C.; Shen, X. J. Am. Chem. Soc. 2004, 126, 14–15; (c) Zhu,
C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126,
5352–5353; (d) Wilson, J. E.; Fu, G. C. Angew. Chem., Int.
Ed. 2004, 43, 6358–6360; (e) Calter, M. A.; Tretyak, O. A.;
Flascheriem, C. Org. Lett. 2005, 7, 1809–1812; (f) Gna-
nadesikan, V.; Corey, E. J. Org. Lett. 2006, 8, 4943–4945.
11. Experimental procedure: To a solution of 4-nitrobenzal-
dehyde (45 mg, 0.3 mmol), LA*–LB* bifunctional catalyst
9 (32 mg, 0.03 mmol) in methylene chloride (9 mL) at
À78 °C, was added diisopropylethylamine (0.2 mL,
1.2 mmol) under argon. A solution of acetyl chloride
(0.07 mL, 1.0 mmol) in methylene chloride (1 mL) was
added slowly (ca. 0.5 h) to the above solution and the
reaction was stirred at À78 °C for 1 h. The reaction was
quenched with saturated sodium bicarbonate solution and
extracted with methylene chloride. The combined extracts
were washed with brine, dried (Na2SO4), filtered, concen-
trated, and separated by flash column chromatography on
silica gel (8:1 to 4:1 hexanes/ethyl acetate) to give 50 mg
(87%) of (4S)-4-(4-nitrophenyl)-oxetan-2-one as a single
enantiomer. 1H NMR (600 MHz, CDCl3): d 8.26 (d,
J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 5.61 (dd,
J = 6.0, 4.8 Hz, 1H), 4.02 (dd, J = 16.2, 6.0 Hz, 1H),
3.42 (dd, J = 16.2, 4.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 166.7, 148.5, 144.5, 126.6, 124.4, 69.6, 47.0; IR
(neat): 1829.0, 1606.2, 1521.9, 1349.1; MS calcd. for
C9H8NO4 (MH+): 194.2, found: 194.3.
In summary, using the LA*–LB* catalyzed asymmetric
Wynberg reaction in a case study, we have developed
a predictive model that foretells the R/S absolute config-
uration in LB*-dependent asymmetric bifunctional
catalysis. By placing the stereodetermining factor solely
on the LB*, the LB*-dependent asymmetric induction
abolishes the planar LA* as the stereodetermining fac-
tor. Thus, restricted rotation of substrates is not a
requirement for excellent ee in our catalytic system.
Our LA*–LB* bifunctional catalysts complement other
bifunctional catalytic systems.14 Furthermore, the con-
stant LB* chirality is transcribed into that of the product
in a predictable manner. The predictive model thus
serves as a valuable guide in reaction planning and a
practical tool for absolute configuration determination.
Although this predictive model was born out of the
LA*–LB* catalyzed asymmetric Wynberg reaction, it
would be interesting to see if it is generally applicable
to other reactions amenable for LA*–LB* bifunctional
catalysis. Investigation of its generality is currently
underway in our laboratory.
Acknowledgments
Acknowledgment is made to the donors of the American
Chemical Society Petroleum Research Fund (PRF
42754-G1) for support of this research. We thank the
undergraduate teaching laboratory for the use of HPLC.
We are grateful to Ms. Tamam Baiz of our department
for assistance with the manuscript.
References and notes
12. The difference in activation energy between two diastereo-
meric transition states that gives 60% ee is too small (ca.
0.8 kcal/mol at rt) to be reliably predicted by theoretical
calculations. See Ref. 5a for additional discussion.
13. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
1. (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH: New York, 1999; Vol. 1–2; (b) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol. I–
III; (c) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000; For strategies to
enable reversible enantioselectivity using LA*, see: (d) Sibi,
M. P.; Liu, M. Cur. Org. Chem. 2001, 5, 719–755, and
references cited therein.
14. For reviews, see: (a) Shibasaki, M.; Kanai, M.; Funabashi,
K. Chem. Commun. 2002, 1989–1999; (b) Ma, J.-A.;
Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566–4583;
For examples of LA*–LB bifunctional catalysts, see: (c)
Sibi, M. P.; Cook, G. R.; Liu, P. Tetrahedron Lett. 1999,
40, 2477–2480; (d) Josephsohn, N. S.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 11594–11599; (e) DiMauro, E. F.; Kozlowski, M. C.
Org. Lett. 2001, 3, 3053–3056; (f) Lundgren, S.; Wing-
strand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc.
2005, 127, 11592–11593; For earlier examples of LA–LB*,
see: (g) France, S.; Wack, H.; Hafez, A. M.; Taggi, A. E.;
Witsil, D. R.; Lectka, T. Org. Lett. 2002, 4, 1603–1605; (h)
France, S.; Shah, M. H.; Weatherwax, A.; Wack, H.;
Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206–
1215.
2. For examples of predictive models in asymmetric catalysis,
see: (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.;
Schroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988,
110, 1968–1970; (b) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547; (c)
Davies, H. M. L.; Jin, Q. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5472–5475; (d) Trost, B. M.; Toste, F. D. J.
Am. Chem. Soc. 1999, 121, 4545–4554; (e) Trost, B. M.;
Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39,
747–760.
3. For an example of planar-LA* having excellent stereo-
selectivity, see: Liu, S. Y.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 15352–15353.