Modular evolution of a chiral auxiliary for the 1,3-dipolar cycloaddition of isomuenchnones with vinyl ethers.

Article abstract of DOI:10.1021/ol017263y

[reaction: see text]. The 1,3-dipolar cycloaddition reaction has long been recognized as a powerful methodology in organic synthesis. More recently, this reaction has become a popular manifold for the construction of chemical diversity. Herein, we report the development of a chiral template for the facially selective cycloaddition of isomuenchnones, a common class of 1,3-dipoles. The modular format of the asymmetric unit allowed a systematic optimization of selectivity. In addition, the chiral auxiliary was removed through an unusually facile ester aminolysis.

Full text of DOI:10.1021/ol017263y

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1415-1418
Modular Evolution of a Chiral Auxiliary
for the 1,3-Dipolar Cycloaddition of
Isomu1nchnones with Vinyl Ethers
Sergey N. Savinov and David J. Austin*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06511
daVid.austin@yale.edu
Received December 19, 2001 (Revised Manuscript Received March 19, 2002)
ABSTRACT
The 1,3-dipolar cycloaddition reaction has long been recognized as a powerful methodology in organic synthesis. More recently, this reaction
has become a popular manifold for the construction of chemical diversity. Herein, we report the development of a chiral template for the
facially selective cycloaddition of isomu1nchnones, a common class of 1,3-dipoles. The modular format of the asymmetric unit allowed a
systematic optimization of selectivity. In addition, the chiral auxiliary was removed through an unusually facile ester aminolysis.
Since its introduction, the 1,3-dipolar cycloaddition has
become an important reaction for the synthesis of hetero-
cyclic molecules.1 We utilize this approach for the construc-
tion of bicyclic diversity scaffold 1, which can serve as a
small-molecule probe for the chemical investigation of
cellular targets.2 To this end, we have previously reported
the endo diastereoselective 1,3-dipolar cycloaddition of
isomu¨nchnones with vinyl ethers.3 Herein we report the
design and optimization of a chiral auxiliary for their
enantioselective cycloaddition. The diastereomeric excess
(de) obtained with the optimized auxiliary exceeds 95%. In
addition, the auxiliary is efficiently removed under mild
aminolysis, furthering the synthetic utility of this approach.
Diazoimides such as 2 undergo chemoselective rhodium-
(II) perfluorobutyramidate [Rh2(pfbm)4] catalyzed cyclization
to isomu¨nchnone intermediates 3, which upon treatment with
a suitable dipolarophile undergoes a 1,3-dipolar cycloaddi-
tion, yielding bicyclic product 1 (Scheme 1).3 To use this
Scheme 1. Construction of the Diversity Scaffold (1)
(1) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-
909. (b) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 2,
123-41. (c) Padwa, A. Trends Org. Chem. 1993, 4, 139-60. (d) 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vols.
1 and 2.
(2) (a) Savinov, S. N.; Austin, D. J. Comb. Chem. High Throughput
Screen. 2001, 4, 593-7. (b) Sche, P. P.; McKenzie, K. M.; White, J. D.;
Austin, D. J. Chem. Biol. 1999, 6, 707-716. (c) Sche, P. P.; McKenzie, K.
M.; White, J. D.; Austin, D. J. J. Chem. Biol. 2001, 8, 399-400.
(3) Savinov, S. N.; Austin, D. J. J. Chem. Commun. 1999, 1813-4.
methodology for the synthesis of specific small-molecule
probes, the bimolecular cycloaddition step must be both
regio- and diastereoselective. Additionally, the methodology
should involve an enantioselective process, since drug-
biomolecule interactions are stereospecific,4 and the use of
10.1021/ol017263y CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/30/2002

mirror-image related molecules is one of the best methods
for assessing affinity-independent specificity.5
Scheme 2. Facial Selectivity at the Dipole Ester
Both the regio- and diastereoselective applications of this
method are accomplished by exploiting primary6 and second-
ary7 orbital effects, furnishing exclusively bicyclic constructs
of syn/endo topology.3 Therefore, manipulation of absolute
stereochemistry remains a challenge for the synthesis of these
molecules in a stereoselectiVe manner.
The catalytic enantioselective cycloaddition of some 1,3-
dipoles, such as nitrones, has been reported.8 The application
of a chiral rhodium(II) catalyst for the asymmetric induction
of a carbonyl ylide cycloaddition has also been reported with
moderate selectivity (ca. 50% ee).9 This low enantioselec-
tivity, in conjunction with the evidence of metal-free
dipoles,10 indicates the transient nature of metal coordination
with the isomu¨nchnone dipole. While several diastereo-
selective cycloadditions with chiral isomu¨nchnones have been
reported,11 the stereogenic center was an integral part of the
molecule, not allowing use as a removable auxiliary.
To fulfill the criteria for the stereospecific construction
of scaffold 1, we required a removable enantioselective 1,3-
dipolar cycloaddition auxiliary. By incorporating a chiral
substituent at the ester position of the dipole (OR3, Scheme
1), we hoped to create an inductive effect that would be
proximal to the dipole to induce facial selectivity, yet
sensitive enough for subsequent removal. A variety of
potential auxiliaries were evaluated by coupling the corre-
sponding chiral malonic acid ester with methylacetamide.12
Diazotransfer subsequently furnished the 1,3-dipole precur-
sors 4, 6, and 8, derivatized with (-)-menthol, (-)-borneol,
and (R)-(-)-pantalactone respectively (Scheme 2). Treatment
of R-diazoimides 4, 6, and 8 with a catalytic amount of Rh2-
(pfbm)4 in the presence of tert-butyl vinyl ether led to
formation of the corresponding cycloadducts 5, 7, and 9 in
good to excellent yield. While each chiral dipole underwent
efficient cycloaddition, the terpene-based chiral auxiliary
failed to exert the required π facial bias and provided only
a modest level of selectivity.13 Despite low diastereoselec-
tivity, these preliminary results were encouraging enough
to warrant further exploration of this approach. An amino
acid based chiral auxiliary would allow the introduction of
stereoelectronic bias,14 while providing a modular design for
systematic optimization. In addition, amino acids afford a
diverse array of functionality and are available in enantio-
meric pairs.
R-Diazoimide 10 was synthesized with a phenylalanine-
based chiral auxiliary. Interestingly, upon exposure to Rh2-
(pfbm)4 in the presence of tert-butyl vinyl ether, L-phenyl-
alanine derivative 10 led to a 50:50 mixture of bicyclic
adducts (2R,5S)-11 and (2S,5R)-11. It was postulated that
the lack of selectivity was due to the flexibility of the
methylene spacer between the dipole and the chiral center.
R-Diazoimide 12 contains a more sterically demanding
â-branched isopropyl group, thereby limiting flexibility
adjacent to the dipole. Treatment of R-diazoimide 12 with
Rh2(pfbm)4 in the presence of tert-butyl vinyl ether provided
cycloadduct 13 in a 84% de in excellent yield. The absolute
stereochemistry of the major isomer was determined via
single-crystal X-ray analysis, which identified the (2Re-5Re)
face of the dipole as the preferred approach of dipolarophile.
Fortunately, both the syn-regiocontrol and endo-diastereo-
control were maintained, despite the added steric congestion
from the auxiliary.
(4) The importance of chirality in drug design has been recently
reviewed: Beroza, P.; Suto, M. J. Drug DiscoVery Today 2000, 5, 364.
(5) Liu, F.; Johnson, E. F.; Austin, D. J.; Anderson, K. F. Submitted.
(6) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123.
(7) Savinov, S. N. Ph.D. Dissertation, Yale University, New Haven, CT,
2000.
(8) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 16, 1449-
58. (b) Jensen, K. B.; Roberson, M.; Jorgensen, Karl A. J. Org. Chem.
2000, 65, 9080-4.
(9) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett. 1997,
38, 6471.
(10) Padwa, A.; Snyder, J. P.; Curtis, E. A.; Sheehan, S. M.; Worsencroft,
K. J.; Kappe, C. O. J. Am. Chem. Soc. 2000, 122, 8155-67.
(11) (a) Padwa, A.; Prein, M. J. Org. Chem. 1997, 62, 6842. (b) Padwa,
A.; Prein, M. Tetrahedron 1998, 54, 6957. (c) Angell, R.; Fengler-Veith,
M.; Finch, H.; Harwood, L. M.; Tucker, T. T. Tetrahedron Lett. 1997, 38,
4517.
To better understand how amino acid substitution affects
the level of diastereofacial induction, a series of R-hydroxy
acids, readily accessible from their corresponding R-amino
acids,15 were used to construct R-diazoimides with incre-
mental substitution. In analogy with the parent system 12,
four diazo substrates, 14, 16, 18, and 21, were prepared from
(14) A π-complex is a feature common to many diastereofacially robust
chiral auxiliaries: (a) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. J.
Org. Chem. 1998, 63, 8397. (b) Mezrhab, B.; Dumas, F.; d'Angelo, J.; Riche,
C. J. Org. Chem. 1994, 59, 500. (c) Maddaluno, J. F.; Gresh, N.; Giessner-
Prettre, C. J. Org. Chem. 1994, 59, 793.
(12) Rigo, B.; Fasseur, D.; Cauliez, P.; Couturier, D. Tetrahedron Lett.
1989, 30, 3073.
(13) The percent diastereoselectivity (% de) was determined by 1H NMR
integration of the diastereomeric pairs.
(15) Johnson, R. L. J. Med. Chem. 1980, 23, 666.
1416
Org. Lett., Vol. 4, No. 9, 2002

L-alanine, L-leucine, L-phenylalanine, and L-tert-leucine,
respectively.16 Ethyl vinyl ether-derived cycloadducts 15, 17,
19, 20, and 22 were obtained in good yield from the
corresponding R-diazoimides through Rh2(pfbm)4-catalyzed
cyclization-cycloaddition, with the favored (2Re-5Re) ap-
proach in each case (Scheme 3).
The computational analysis predicts a hydrogen-bonded
seven-membered ring conformation (Figure 1). The aromatic
Scheme 3. Facial Selectivity at the Amino Acid Site
Figure 1. Computational models for the 1,3-dipole.
group is allowed free rotation, as noted in the existence of
two low-energy structures, with the aromatic moiety either
engaged in a π-stacking interaction with the dipole or
projected away. In one conformation the (2Si-5Si)-face is
blocked, while the second conformation leaves the dipole
free, allowing cycloaddition from the less favored (2Si-5Si)-
face.
The importance of hydrogen bond-mediated organization
was confirmed by screening substrates 23 and 25, which lack
the amide N-H (Scheme 4); in both cases the stereoselection
was greatly compromised. The contribution of π-stacking
toward selectivity is questionable, as shown by the similar,
if somewhat diminished, diastereoselectivity noted in 27 (cf.
12). Attempts to further probe the contribution of π-stacking
and to favor the blocked conformation (Figure 1, bottom)
R-diazoimides 29, 31, and 33 were constructed. As expected,
the absolute configuration of the benzylic center produced
little influence on either the sense or extent of the facial
selectivity. When treated with Rh2(pfbm)4 in the presence
of ethyl vinyl ether, R-diazoimide 35 provided the single
cycloadduct 36, with a de greater than 95%. This improved
diastereoselectivity is presumably due to the degenerate
nature of the possible conformations.
Although the level of diastereoinduction varied widely, it
could be correlated with the level of substitution. L-Alanine
derivative 14 gave the lowest diastereofacial selection, while
both the L-isoleucine 16 and L-phenylalanine 18 auxiliaries
provided a significantly higher level of induction, presumably
due to the bulkier isobutyl and benzyl substituents. However,
the diastereofacial bias appeared to reach saturation with
isopropyl derivative 20, since no additional effect was
observed with tert-butyl derivative 22.
A crystal structure of cycloadduct 1317 confirmed the
absolute stereochemistry of the cycloaddition. A molecular
mechanics (MM2 force field)18 based Monte Carlo19 con-
formational search, using the Macromodel20 software pack-
age, was used to establish the preferred structural arrange-
ment in the dipole. The auxiliary of 12 was conformationally
sampled (i.e., the geometry-optimized dipole was fixed), with
charges localized at N (“+”) and exocyclic O (“-”).
(16) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61,
4196. (b) Konradi, A. W.; Kemp, S. J.; Pedersen, S. F. J. Am. Chem. Soc.
1994, 116, 1316.
(17) See Supporting Information.
(18) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
(19) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989,
111, 4379.
(20) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440.
Substituents on the dipolarophile were found to have a
minimal effect on the overall facial selectivity. As shown in
Scheme 5, good yields and selectivities were observed for
bicyclic constructs 37-40, regardless of substitituion of the
Org. Lett., Vol. 4, No. 9, 2002
1417

Scheme 4. Facial Selectivity at the Auxiliary Amine
Scheme 5. Effect of Dipolarophile on Facial Selectivity
construction of chemically diverse libraries is currently under
investigation.
Scheme 6. Removal of the Chiral Auxiliary
vinyl ether dipolarophile. Notably, both a sterically demand-
ing tert-butyl vinyl ether and a hydrogen-bond donor
(guanidine) provided cycloadducts 37 and 40, respectively,
in excellent yield and high diastereofacial selectivity.
Removal of the chiral auxiliary can be achieved under
surprisingly mild conditions by treatment with primary
amines. Cleavage of cycloadducts 36-40 with methylamine
furnished amides 41-45, in excellent yield (Scheme 6).
Dimethylamine failed to cleave the auxiliary, even under
elevated temperature.
In conclusion, we have presented the systematic optimiza-
tion of a chiral auxiliary for diastereofacially selective 1,3-
dipolar cycloaddition in the presence of a variety of
dipolarophiles. This diastereofacial selectivity, when coupled
with the previously established regioselectivity and endo-
selectivity of this cycloaddition, ensures that only one of the
eight possible products is formed. In addition, the structure-
selectivity relationship established during the course of this
study demonstrates the power and flexibility of a modular
auxiliary design. The use of this methodology for the
Acknowledgment. The authors thank Susan de Gala for
X-ray structure analysis, Wolfgang Hinz and Viet-Anh
Nguyen for helpful discussion, and the National Institutes
of Health (R01 GM59673) for financial support. D.J.A. is
the recipient of an Alfred P. Sloan Foundation Fellowship.
Supporting Information Available: Experimental details
and characterization of compounds 4-45. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL017263Y
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Org. Lett., Vol. 4, No. 9, 2002