Stereochemical Control of Skeletal Diversity

Article abstract of DOI:10.1021/ol035773h

(Equation presented) Substrates having appendages that pre-encode skeletal information (σ-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (σ-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the a-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity.

Full text of DOI:10.1021/ol035773h

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4125-4127
Stereochemical Control of Skeletal
Diversity
Jason K. Sello, Peter R. Andreana, Daesung Lee,† and Stuart L. Schreiber*
Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute,
HarVard Institute of Chemistry & Cell Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
sls@slsiris.harVard.edu
Received September 13, 2003
ABSTRACT
Substrates having appendages that pre-encode skeletal information (σ-elements) can be converted into products having distinct skeletons
using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation
of a chiral amino alcohol appendage (σ-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the σ-element
and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to
the challenging problem of skeletal diversity.
Diversity-oriented synthesis (DOS) aims to yield collections
of products having many distinct molecular skeletons with
controlled variation of stereochemistry in a small number
(between three and five) of steps.1 The primary strategy for
accomplishing skeletal diversity thus far has been to treat a
substrate having potential for diverse reactivity with different
reagents that produce different skeletons.2 A second strategy
was recently demonstrated to generate skeletal diversity
combinatorially.3 This strategy involves the conversion of a
collection of substrates having different appendages that pre-
encode skeletal information (named “σ-elements”) into
products having distinct skeletons using a common set of
reaction conditions. Here we report the characterization of
a σ-element on the basis of stereochemistry rather than
constitution. As such, it illustrates the potential of linking
stereochemical control, for which many methods exist, to
the challenging problem of skeletal diversity.
Tricyclic compounds resulting in “one pot” from consecu-
tive Ugi and intramolecular Diels-Alder reactions4 can be
readily converted to 4-pentenoic acid esters and amides
(amide depicted in Figure 1). Related compounds have been
found to be conformationally well-suited to undergo efficient
12-membered ring-forming reactions.5
In this case, we envisioned forming such rings via ring-
opening/ring-closing metathesis reactions,4b,6 although the
indicated substrates are also candidates for 17-membered
ring-forming metathesis reactions. We were attracted to this
(4) (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851-1854. (b) Lee,
D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-712.
(5) Lee, D.; Sello, J. K.; Schreiber, S. L. J. Am. Chem. Soc. 1999, 121,
10648-10649.
(6) (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 6634-6640. (b) Zuercher, W. J.; Scholl, M.; Grubbs, R.
H. J. Org. Chem. 1998, 63, 4291-4298. (c) Stragies, R.; Blechert, S.
Tetrahedron 1999, 55, 8179-8188. (d) Arjona, O.; Csa´ky¨, A. G.; Murcia,
M. C.; Plumet, J. J. Org. Chem. 1999, 64, 9739-9741. (e) Weatherhead,
G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 1828-1829.
† Current address: University of Wisconsin-Madison, Madison, WI.
E-mail: dlee@chem.wisc.edu.
(1) (a) Schreiber, S. L. Science 2000, 287, 1964-1968. (b) Burke, M.
D.; Schreiber, S. L. Angew. Chem., Int. Ed., in press.
(2) Schreiber, S. L. Chem. Eng. News 2003, 81, 51-61.
(3) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science, in press.
10.1021/ol035773h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/07/2003

and 3, were first examined as tests of the proposed chemistry.
Under the actions of a ruthenium-based catalyst7 in refluxing
CH2Cl2 (4 h), 2 was converted into the fused macrocycle 5
(65%), while 3 was converted (4 h) to the bridged macrocycle
6 (87%, E/Z ) 10:1; X-ray crystallography) (Figure 3). The
Figure 1. Previously, the sequential use of complexity-generating
reactions, the Ugi 4CC-IMDA, was shown to produce complex
molecules efficiently.4 Here we show that the orientation of a single
substituent R3, denoted as a σ-element, leads to products having
different skeletal arrays.
Figure 3. Two examples of N-Me pentenamides illustrating the
role of stereochemistry in determining the direction followed in
ring-closing vs ring-opening/ring-closing reactions.
pathway for its potential to yield highly complex products
having different skeletons efficiently. We found that a single
stereocenter in the otherwise similar substrates dictates the
resulting reaction pathway.
(()-Tricyclic ester 1, available in one step from p-
methoxybenzylamine, furfural, fumaric acid monoethyl ester,
and benzyl isocyanide (MeOH, 48 h; 90% yield, 11:1
(structure of major diastereomer 1 ascertained by X-ray
crystallography),4 was converted into the resolved acids (+)-4
and (-)-4 (Figure 2). Two intermediates in this process, 2
pathway selectivity is uniformly high: in the reactions of 2
and 3, the product resulting from the alternative pathway
was not observed to the limits of our detection (>100:1;
HPLC-MS).
To harness the potential of these reactions in DOS, we
sought to understand the structural basis of the pathway
selectivity. A systematic study of ring-closing reactions of
substrates prepared from (+)-4 and (-)-4 and bearing chiral
amino alcohols that are structurally reminiscent of pseu-
doephedrine was performed. The six examples of substrates
having an NH in place of the N-Me group are shown in
Figure 4. Substrates 7 and 9 illustrate the dominant role of
the amino alcohol-derived side chain (compare to 2 and 3).
11 and 13 illustrate the dominant role played by the
stereochemistry of the carbon adjacent to the ester rather than
the amide of the amino alcohol moiety (compare to 7 and
9). The simpler substrates 15 and 17 reinforce this point and
reveal that the stereochemistry and not the nature of the
substituent (Ph vs Me) controls the reaction pathway.8
Finally, 19 and 21, which have the orientation of their
amino alcohol moieties reversed (Figure 5), reveal that the
location of ester and amide groups does not override the
stereocontrol element (though increased yields are observed
(7) Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimi-
dazol-2-ylidene] [benzylidene]ruthenium(IV) dichloride: (a) Scholl, M.;
Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. (b)
Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. (c) Huang,
J. K.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem. Soc. 1999,
121, 2674-2678. (d) Huang, J. E.; Schanz, H.-J.; Stevens, E. D.; Nolan, S.
P. Organometallics 1999, 18, 5375-5380.
(8) Remote stereocenters have been reported to impact the stereoselec-
tiVity of ring-closing metathesis reactions (Meng, D.; Su, D.-S.; Balog, A.;
Bertinato, P.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-
C.; He, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997, 119, 2733-2734) and
the diastereoselectiVity of other types of ring-closing reactions (review:
Tokoroyama, T. Chem. Eur. J. 1998, 4, 2397-2404).
Figure 2. Racemic tricycle 1 was acylated with 4-pentenoyl-(R,R)-
pseudoephedrine, yielding diastereomers that were purified using
silica gel chromatography. Following saponification, the resolved
acids (+)-4 and (-)-4 were used in subsequent experiments.
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Org. Lett., Vol. 5, No. 22, 2003

ways and, more generally, to plan short reaction sequences
that lead to complex small molecules having different
skeletons.
Figure 5. Two examples of pentenoate esters illustrating the
independence of amino alcohol orientation in determining the
direction followed in ring-closing vs ring-opening/ring-closing
reactions.
Encouragingly, catalysts that induce high enantioselectivity
in the initial 4CC reaction have been developed, and the
macrocyclizations described herein have been determined to
proceed efficiently on macrobead supports (unpublished
results of P.R.A.). Finally, we note that this study also
illustrates how DOS research can uncover new and subtle
facets of reactivity in organic chemistry.
Acknowledgment. We thank Dr. Richard Staples for
performing X-ray crystallographic analysis. J.K.S. acknowl-
edges predoctoral fellowships from the National Science
Foundation and the ACS Division of Organic Chemistry,
Pharmacia & Upjohn. D.L. and S.L.S. are Research Associate
and Investigator, respectively, at the Howard Hughes Medical
Institute at Harvard University.
Figure 4. Six examples of NH pentenamides illustrating the role
of a single stereogenic center in determining the direction followed
in ring-closing vs ring-opening/ring-closing reactions.
Supporting Information Available: Representative ex-
perimental procedure and characterization data and an X-ray
cryatallographic file (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
in the latter orientation).9 This study suggests ways to exploit
the influence of stereocenters on alternative reaction path-
(9) (a) Fu¨rstner, A. Top. Organomet. Chem. 1998, 1, 37-72. (b) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043.
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