Exploiting π-shielding interactions: A highly selective chiral auxiliary derived from a biogenic building block

Article abstract of DOI:10.1016/j.tetlet.2005.03.058

A chiral auxiliary template, designed on the basis of π-shielding capability has been prepared from readily available L-proline. Cycloaddition to an acrylate derivative gave high endo preference, and diastereoselectivity as high as 99% was attainable. The electronic factors contributing to selectivity were probed, and the technology successfully applied to a polymer supported variant.

Full text of DOI:10.1016/j.tetlet.2005.03.058

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3579–3582
Exploiting p-shielding interactions: a highly selective
chiral auxiliary derived from a biogenic building block
Longfei Xie and Graham B. Jones*
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry & Chemical Biology,
Northeastern University, Boston, MA 02115, USA
Received 21 July 2004; revised 9 March 2005; accepted 10 March 2005
Available online 1 April 2005
Abstract—A chiral auxiliary template, designed on the basis of p-shielding capability has been prepared from readily available
L-proline. Cycloaddition to an acrylate derivative gave high endo preference, and diastereoselectivity as high as 99% was attainable.
The electronic factors contributing to selectivity were probed, and the technology successfully applied to a polymer supported
variant.
Ó 2005 Elsevier Ltd. All rights reserved.
Of the many tactics employed to achieve facial selectiv-
ity in asymmetric cycloadditions, p-shielding of one face
of the dienophile to attack has become a common and
effective strategy.1 Examples include both chiral cata-
lysts and auxiliaries, where the interaction of the chiral
controller and dienophile range from passive (steric
shielding) through active (p–p stacking).1 We have been
engaged in the design of auxiliaries and catalysts where a
pendant aryl substituent interacts with a proximal acryl-
ate to establish a high degree of facial selectivity in
cycloaddition viz., 1.2 We further demonstrated that
variation of the electronic interactions between aryl
and vinyl groups can be modulated via the correspond-
ing arene chromium carbonyl complexes, where mixed
ligand derivatives provide access to a range of p basic
through p acidic characteristics 2.3,4 The basic criteria
for two entities to engage in a p stack are satisfied when
able and is also easily accessible from proline;6 (c) both
enantiomeric forms are available; and (d) the electronics
of the benzyl group could be modulated at ease.
X
OC
CO
Cr
OH
N
Y
X
O
Z
O
O
O
H
H
Z
H
H
1
2
3
To establish proof-of-principle, L-proline 4 was con-
verted to its prolinol derivative and a variety of benzyl
chlorides 5 were used to introduce the N-aryl substitu-
ents 6 (Scheme 1).7 Conversion to the corresponding
acrylates 7 allowed us to probe the efficiency and stereo-
selectivity of cycloaddition, investigated using a series
of Lewis acids with cyclopentadiene. Initial results
(Table 1) confirmed the viability of the design criteria with
moderate to good endo selectivity achieved and appre-
ciable diastereocontrol. Chemical yields ranged from
poor to excellent, and the auxiliary could be recovered
in good (ꢁ90% yield) by reduction of the ester linkage.
In all cases, the major product obtained was the endo
R isomer, confirmed by comparison with authentic
material.8 The most striking results were observed with
4-substituted derivatives of 7 where a strong correlation
between diastereoselectivity and electron donor ability
of the substituent X emerged. As the same trends were
p clouds interact through space at a distance between 3
5
˚
˚
and 3.5 A, with optimal overlap at ꢀ3.4 A. Based on
this criterion we wished to apply the concept of face
selection in a readily available auxiliary derived from
the chiral pool, and surveyed a variety of inexpensive
building blocks. We ultimately decided to pursue deriv-
atives of N-benzyl prolinol 3 based on the fact that: (a)
molecular modeling analysis suggested that derived
acrylate esters could position at p-stacking distance
from the aryl; (b) the ligand itself is commercially avail-
Keywords: Diels–Alder; Cycloaddition; p-shielding; Chiral auxiliary.
*
Corresponding author. Tel.: +1 617 373 8619; fax: +1 617 373
8795; e-mail: gr.jones@neu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.058

3580
L. Xie, G. B. Jones / Tetrahedron Letters 46 (2005) 3579–3582
1. LiAlH4, THF (54%)
2. K2CO3, THF
H
OH
a X = H 69%
N
COOH
N
b X = OCH3 77%
c X=CH3 91%
d X = NO2 90%
H
Cl
X
4
5
6
X
O
Et3N,
THF
Cl
H
H
a X = H 51%
CO2R
O
b X = OCH3 72%
c X=CH3 90%
d X = NO2 90%
N
8
O
CO2R
H
Lewis acid
7
X
Scheme 1. Synthesis and cycloaddition to N-benzyl-prolinol acrylates.
Table 1. Cycloaddition of acrylates 7/11 with cyclopentadiene
Entry
Substrate
Lewis acid (equiv)
% 8
Temp/°C (time/h)
endo/exo
de (%)
1
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (2.0)
SnCl4 (1.2)
<1
6
À78 (48)
À50 (12)
À25 (6)
À25 (6)
À25 (6)
À50 (12)
À25 (6)
À25 (6)
À25 (6)
À25 (6)
À25 (12)
À25 (12)
À25 (12)
À25 (24)
À25 (24)
À25 (24)
—
—
95
55
81
21
81
—
—
93
80
83
68
22
98
97
96
2
20:1
8.8:1
5.8:1
1.5:1
3.7:1
—
3
57
24
23
10
<1
<1
10
5
4
5
6
SnCl4 (1.2)
TiCl4 (1.2)
7
8
TiCl2 (OiPr)2 (1.2)
AlEt2Cl (1.2)
AlEtCl2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
BF3ÆOEt2 (1.2)
—
9
10:1
1:40
39:1
22:1
20:1
35:1
32:1
28:1
10
11
12
13
14
15
16
90
65
77
99
86
77
7d
11a
11b
11c
All cycloadditions were conducted in CH2Cl2. exo:endo ratios were determined by GC–MS (HP-5, evap temp. 220 °C; operating temp 60 °C, 5 min
then 4 °C/min ramp rate to 145 °C); endo 8 18.32 min exo 8 18.58 min; de was determined by HPLC (Chiralcel OD, 3% 2-propanol:97% hexanes
eluent, 1 mL/min flow rate) in comparison to reference standards (tR exo S = 4.84 min exo R = 5.48 min, tR endo S = 5.95 min endo R = 6.97 min).
Cycloadducts derived from 11 were decomplexed in Et2O and then analyzed.
not reflected in endo:exo ratios, we become interested in
preparing alternate variants where through space elec-
tronics could be modulated, and turned attention to
the arene chromium complexes.2 Thus, commencing
with 6a, complexation was achieved using conventional
conditions to give alcohol 9, presumably via intramolec-
ular delivery of the Cr(CO)3 tripod from an intermediate
oxo–Cr complex (Scheme 2).3 Ligand exchange was
effective without need for masking of the alcohol group,
allowing 9, 10a and b to be converted to the correspond-
ing acrylates 11. Cycloaddition was efficient with all
three substrates (Table 1) and expected correlations be-
tween p donor ability and endo preference/diastereo-
selectivity were observed within the series. Clearly,
substrate 11c presents a more electron deficient p face
than 7a suggesting that the steric bulk of the metal car-
bonyl tripod contributes substantively to diastereoselec-
tivity. A very high degree of diastereoselectivity was
obtained in the case of 11a, suggesting the platform to
be suitable for application in other areas. One such
avenue of interest to us lies in preparation of solid-sup-
ported variants of this system. Promoted by reports
from the Semmelhack and Thomas groups,9,10 we have
utilized the ꢀtraceless linkerꢀ approach for the prepar-
ation of polymer-bound mixed ligand phosphine–chro-
mium arene complexes, and sought to apply in this
series.11 Accordingly, irradiation of 9 in the presence
of polystyrene–diphenylphosphine complex resulted in
formation of the mixed ligand derivative, which was
converted to acrylate ester 12 without incident
(Scheme 3). Cycloaddition proceeded with essentially
complete diastereoselectivity, and the adduct 13 could be
uncoupled from the support merely by exposure to light.
In an attempt to rationalize these findings, spectroscopic
studies were undertaken using ligands 7 and 11. Assum-
ing s-trans enoate geometry is adopted in the Lewis acid
catalyzed cycloaddition, a p–p stacked/shielded model is
consistent with the observed endo R cycloadduct, which
implies approach of diene with the methylene group anti

L. Xie, G. B. Jones / Tetrahedron Letters 46 (2005) 3579–3582
3581
H
OH
Cr(CO)6,
nBu2O, THF
N
6a
∆ 12h 78%
OC
OC
9
Cr
CO
Et3N,
THF
O
PPh3 or P(OPh)3
Cl
PhH hν
O
H
H
OH
O
Cl
N
N
a X= PPh3 73%
b X=P(OPh)3 76%
c X=CO 48%
O
a X= PPh3 69%
b X=P(OPh)3 63%
OC
X
Et3N,
THF
OC
X
Cr
CO
Cr
CO
10
11
Scheme 2. Preparation of g6-arene chromium carbonyl complexed derivatives.
H
1. BF3.OEt2
1.
O
H
H
N
PPh2
PhH, hν
O
O
N
9
O
Ph
OC
2. hν, THF
Cr
PPh
2. acryloyl chloride
Et3N, THF
55%
12
13
>99:1
2 CO
78%
Scheme 3. Preparation and cycloaddition of polymer supported derivative.
References and notes
1. Jones, G. B. Tetrahedron 2001, 57, 7999.
LA
O
O
N
2. Jones, G. B.; Chapman, B. J.; Mathews, J. E. J. Org.
Chem. 1998, 63, 2928.
3. Weber, I.; Jones, G. B. Tetrahedron Lett. 2001, 42, 6983;
Jones, G. B.; Guzel, M. Tetrahedron Lett. 2000, 41, 4695;
Jones, G. B.; Guzel, M. Tetrahedron: Asymmetry 2000, 11,
1267; Jones, G. B.; Guzel, M.; Heaton, S. B. Tetrahedron:
Asymmetry 2000, 11, 4303; Jones, G. B.; Guzel, M.;
Chapman, B. J. Tetrahedron: Asymmetry 1998, 9, 901;
Jones, G. B.; Guzel, M. Tetrahedron: Asymmetry 1998, 9,
2023; Jones, G. B.; Huber, R. S.; Chapman, B. J.
Tetrahedron: Asymmetry 1997, 8, 1797; Jones, G. B.;
Heaton, S. B.; Guzel, M.; Chapman, B. J. Tetrahedron:
Asymmetry 1997, 8, 3625.
4. Nelson, S. G.; Hilfiker, M. A. Org. Lett. 1999, 9, 1379;
Bolm, C.; Muniz, K. Chem. Soc. Rev. 1999, 28, 51;
Englert, U.; Haerter, R.; Vasen, D.; Salzer, A.; Eggeling,
E. B.; Vogt, D. Organometallics 1999, 18, 4390; Son, S. U.;
Jang, H.-Y.; Lee, I. S.; Chung, Y. K. Organometallics
1998, 17, 3236; Son, S. U.; Jang, H.-Y.; Han, J. W.; Lee, I.
S.; Chung, Y. K. Tetrahedron: Asymmetry 1999, 10, 347;
Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78; Merlic, C.
A.; Walsh, J. C. Tetrahedron Lett. 1998, 39, 2083;
Pasquier, C.; Naili, S.; Pelinski, L.; Brocard, J.; Mortreux,
A.; Agbossou Tetrahedron: Asymmetry 1998, 9, 193;
Englert, U.; Salzer, A.; Vasen, D. Tetrahedron: Asymmetry
1998, 9, 1867; Taniguchi, N.; Uemura, M. Tetrahedron
Lett. 1997, 38, 7199; Ariffin, A.; Blake, A. J.; Li, W.-S.;
Simpkins, N. S. Synlett 1997, 1453; Cowton, E. L. M.;
Gibson, S. E.; Schneider, M. J.; Smith, M. H. J. Chem.
Soc., Chem. Commun. 1996, 839; Hayashi, Y.; Sakai, H.;
Kaneta, N.; Uemura, M. J. Organometal. Chem. 1995,
Figure 1.
to the (mobile) benzyl substituent (Fig. 1). However,
chemical shift analysis of the acrylate protons in 7 and
11 (CDCl3, 25 °C) revealed only minor perturbations
in the presence of Lewis acid. If pronounced p stacking
effects were operational, upfield shift of these protons
would be expected.1 Additional NOE experiments were
conducted on substrates and in the case of 7c irradiation
of the aryl methyl group resulted in <2% enhancement
of the acrylate vinyl protons. Based on these data, a
face-to-edge arrangement seems most plausible, a
hypothesis which will be investigated with in depth
fluorescence quenching studies.
In summary, a chiral auxiliary derived from inexpensive
L-proline has been designed and demonstrated excellent
selectivity in cycloaddition chemistry. A polymer sup-
ported variant has also been produced, extending the
versatility of this system. Application in the preparation
of chiral synthons is now expected, and the p-shielding
design criterion may lead to the development of addi-
tional auxiliary and catalyst families.12

3582
L. Xie, G. B. Jones / Tetrahedron Letters 46 (2005) 3579–3582
503, 143; Uemura, M.; Hayashi, Y.; Hayashi, Y. Tetra-
hedron: Asymmetry 1993, 4, 2291.
Tetrahedron Lett. 1990, 31, 7219; Berson, J. A.; Walia, J.
S.; Remanick, A.; Suzuki, S.; Reynolds-Warnhoff, P.;
Willner, D. J. Am. Chem. Soc. 1961, 83, 3986.
9. Semmelhack, M. F.; Hilt, G.; Colley, J. H. Tetrahedron
Lett. 1998, 39, 7683.
5. Jones, G. B.; Chapman, B. J. Synthesis 1995, 475.
6. S-N-benzyl prolinol: Fluka cat. #13839, 5g = $26.75. For
prior applications see: Itsuno, S.; Ito, K.; Hirao, A.;
Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1984, 2887;
Waldmann, H. J. Org. Chem. 1988, 53, 6133; Yamashita,
T.; Yasueda, H.; Nakamura, N. Chem. Lett. 1974, 585.
7. Satisfactory spectroscopic and analytical data were
obtained for all new compounds.
10. Gibson, S. E.; Hales, N. J.; Peplow, M. A. Tetrahedron
Lett. 1999, 40, 1417.
11. Jones, G. B.; Wright, J. M.; Hynd, G.; Wyatt, J. K.;
Yancisin, M.; Brown, M. A. Org. Lett. 2000, 2, 1863.
12. We thank the PRF (administered by the American
Chemical Society) for financial support of this work
(33920-AC1).
8. endo-R-Norbornene-2-methanol [a]D +95 (c = 0.6, 95%
EtOH)Janseen, A. M.; Klunder, A. H.; Zwanenburg, B.