Computer-aided design of chiral ligands. Part III. A novel ligand for asymmetric allylation designed using computational techniques.

Article abstract of DOI:10.1021/ol026971w

[reaction: see text] Computer-aided design protocols to identify new chiral ligands for reactions proceeding through well-defined transition states are outlined. Ligand families are discovered via computational screening of large structural databases such as the Cambridge Structural Database. Using this method, a novel cis-decalin ligand has been identified as a chiral auxiliary for the allylboration of aldehydes. Synthesis, resolution, and evaluation revealed that this new auxiliary provided the aldehyde facial approach upon which the design was predicated.

Full text of DOI:10.1021/ol026971w

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4391-4393
Computer-Aided Design of Chiral
Ligands. Part III. A Novel Ligand for
Asymmetric Allylation Designed Using
Computational Techniques
Marisa C. Kozlowski,* Stephen P. Waters, Jason W. Skudlarek, and
Catherine A. Evans
Department of Chemistry, Roy and Diana Vagelos Laboratories, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104
marisa@sas.upenn.edu
Received September 26, 2002
ABSTRACT
Computer-aided design protocols to identify new chiral ligands for reactions proceeding through well-defined transition states are outlined.
Ligand families are discovered via computational screening of large structural databases such as the Cambridge Structural Database. Using
this method, a novel cis-decalin ligand has been identified as a chiral auxiliary for the allylboration of aldehydes. Synthesis, resolution, and
evaluation revealed that this new auxiliary provided the aldehyde facial approach upon which the design was predicated.
Diastereo- and enantioselective chemical reactions have
become essential for the efficient synthesis of complex chiral
targets. Much progress has been made in developing non-
enzymatic asymmetric methodology; however, good stereo-
selective versions of many reactions remain unavailable. One
driving force for the development of effective chiral auxil-
iaries and catalysts for asymmetric reactions is the identifica-
tion of the appropriate chiral ligands. To this end, we have
developed a computational method to identify new chiral
ligand classes by screening large numbers of potential ligands
motifs.
Numerous auxiliaries and catalysts have been developed for
the boron allylation reaction,1 but some variants, particularly
anti crotyl additions, remain problematic.
Only a single reaction step needs to be modeled in the
allylation reactions of unsubstituted alkenes; the product
ratios are controlled by the free energies of the illustrated
transition states (Figure 1). The rational design of asymmetric
boron allylation reactions has been aided by the development
of a molecular mechanics force field;2d,e however, prior
computational efforts have been restricted to the prediction
of stereoselectivity for given systems.3 In this communica-
tion, the use of computational methods for the generation,
as well as for the evaluation, of novel chiral auxiliaries is
addressed.
We chose to examine the boron allylation in this context
because it has been examined extensively experimentally and
theoretically.1,2 The absence of turnover as well as elements
past the second row simplifies any computational analysis.
Org. Chem. 1991, 56, 6472-6475. (d) Vulpetti, A.; Gardner, M.; Gennari,
C.; Bernardi, A.; Goodman, J. M.; Paterson, I. J. Org. Chem. 1993, 58,
1711-1718. (e) Gennari, C.; Fioravanzo, E.; Bernardi, A.; Vulpetti, A.
Tetrahedron 1994, 50, 8815-8826.
(1) For lead references: ComprehensiVe Organic Synthesis, Trost, B.
M.; Fleming, I. Eds.; Pergamon Press: Oxford, 1991; Vol. 2.
(2) (a) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1988,
110, 3684-3686. (b) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J. Org.
Chem. 1990, 55, 481-493 and references therein. (c) Bernardi, F.; Robb,
M. A.; Suzi-Valli, G.; Tagliavini, E.; Tromboni, C.; Umani-Ronchi, A. J.
(3) For examples in other systems, see: Transition State Modeling for
Catalysis; Truhlar, D. G., Morokuma, K., Eds.; ACS Symposium Series
721; American Chemical Society: Washington, DC, 1999; and references
contained therein.
10.1021/ol026971w CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/21/2002

generated around the desired transition state by functionality
mapping. The intent is to design ligands that place a key
stereodiscriminating moiety to incur favorable (or at least
no disfavorable) nonbonded interactions in one enantiomeric
transition state and to incur disfavorable nonbonded interac-
tions in the other enantiomeric transition state. The positions
of these “stereodiscriminating groups” (in this case, methanes
that stand in for a methyl substituent on a ligand) were
determined by functionality mapping4 of the enantiomeric
transition states (A1 and A2). This allowed the selection of
methane positions (Me1 and Me2) that would disfavor A2
sterically and complement A1 (Figure 3).
Figure 1. Boron allylation reaction.
Computational methods can aid in the generation of chiral
auxiliaries and catalysts by providing increased efficiency,
an improved rational basis, and leads usually available only
by intuitive leaps. The multiple step design procedure for
chiral ligands 2 and 3, designed to control the absolute
stereochemistry in the allylation reaction, is outlined in Figure
2 and the following paragraphs. Well-defined monomeric
Figure 3. (a) Step 2 in the design procedure. Illustration of the
Me1 and Me2 groups selected from the functionality mapping. (b)
Overlay of the Me1 and Me2 groups used in the CAVEAT search
(purple spheres) with the new ligand 3 appended to the A1 transition
state.
In the third and fourth steps, three-dimensional databases
such as the Cambridge Structural Database and the Chemical
Abstracts Service (CAS) three-dimensional database are
searched using CAVEAT5,6 for molecules that can position
the two methanes and the boron with the indicated placement
and orientation. This methodology could also be applied to
other databases such as the Fine Chemicals Directory or
corporate databases allowing for selection of readily aVail-
able ligands. The resultant lead compounds are classified
into structural subgroups and then analyzed. The enantiomer
of CAS structure 122522-13-8 represents a typical lead that
satisfies the design criteria. This lead could not be used
directly, but the basic scaffold (cis-decalin) provided the
insight for the design of decalin-based ligand 1 (step 5). Since
ligand 1 is not readily synthesized, several modifications
were incorporated resulting in analogues 2 and 3. The
resultant compounds 1-3 were examined with respect to the
initial search parameters used, namely, the initial methane
groups Me1 and Me2. Overall, ligand 3 places the two methyl
groups very close to the desired positions (Figure 3b).
In an encouraging affirmation of the validity of this
strategy, lead structures corresponding to the Masamune
dimethyl-borolane7 and the Corey stein reagent8 were also
Figure 2. Design procedure illustrated for ligands 2 and 3.
boat and chair transition states2 have been postulated to
account for the product distributions in boron allylation
reactions. As a first step, the more stable chair A was chosen
as a starting point.
In the second step, stereodiscriminating groups are selected
from models of previously successful chiral ligands or are
(4) Kozlowski, M. C.; Panda, M. J. Org. Chem. ASAP.
(5) Kozlowski, M. C.; Panda, M. J. Mol. Graphics Model. 2002, 20,
399-409.
(6) (a) Lauri, G.; Bartlett, P. A. J. Comput.-Aided Mol. Des. 1993, 8,
51. (b) Bartlett, P. A.; CAVEAT V2.2; University of California-
Berkeley: Berkeley, CA, 1995.
(7) Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892-
1894.
4392
Org. Lett., Vol. 4, No. 25, 2002

found when a different set of input stereodiscriminating
groups was used.5
The decalin ligands could have been envisioned as a ligand
for boron allylation reactions without the intervention of this
design protocol. However, the benefit of this method lies in
the large number of potential scaffolds that can be rapidly
and efficiently screened by the end user. Furthermore, the
databases of compounds employed allow the user to identify
structure types with which the user may not necessarily be
familiar.
Finally, the ligands are evaluated theoretically for potential
selectivity. Analysis of simple stereochemical models based
on six-membered transition states reveals that these com-
pounds possess asymmetric environments (Figure 4). Fur-
Figure 5. Synthesis of allyl boronates 6.
occupancy of the positions indicated in Figure 3 by the
pendant ethyl substituents compared to the n-butyl substit-
uents. Nevertheless, the designed ligands fulfilled the basic
criteria stipulated in the design process: favoring one reactive
pathway (si facial attack) over another (re facial attack).
Furthermore, the observed selectivity (71:29 si:re, ∆∆G )
0.36 kcal/mol) is within the error (0.2-0.5 kcal/mol) of the
transition structure calculations (85:15 si:re, ∆∆G ) 0.68
kcal/mol). As such, refinements in these calculations will
be instrumental in expanding the utility of this approach.
In summary, a protocol for the design of new chiral ligands
has been identified that uses transition structures as the
starting input. In the particular case described above, ligands
1-3 were identified for boron allylation reactions. The
designed compounds were anticipated to impart si selectivity
in these reactions, which has been corroborated experimen-
tally. Although the selectivity observed was only modest, a
new ligand motif with a well-defined chiral environment has
been identified that is finding utility in a variety of contexts.11
In addition to identifying new ligands, several other
applications of the functionality mapping and database
screening are possible. The functionality mapping can be
used to determine which groups/interactions in stereoselective
reactions are important. The database screening can be used
to find alternate scaffolds for ligands that either perform well
or are costly. Similarly, many ligand variants can be rapidly
identified for reaction optimization if there is a lead in hand.
Efforts are currently underway to examine such applications.
Figure 4. Stereochemical boron allylation models of 3.
thermore, transition states in which the prochiral aldehyde
is approached from the re face contained disfavorable
nonbonded interactions between the ligand and the six-
membered transition state core, which are largely absent in
transition states involving approach from the si face.
To determine if ligands such as 2 and 3 can control the
stereochemical course of these reactions as envisioned, the
synthesis of compound 3 was undertaken.9 The synthesis of
diol 3 is straightforward and employs the strategy of
Lautens10 for the nucleophilic ring-opening of oxabicyclic
compound 4 (Figure 5). Directed hydrogenation of 5
provided the requisite diols 3, which were resolved using
chiral chromatography. An X-ray crystal structure indicated
that 3b adopted the indicated conformation with axially
1
disposed hydroxyls. From the H NMR spectra, this con-
formation persisted in solution.
Treatment of 3 with trisallylborane provided the requisite
Acknowledgment. Financial support was provided by the
National Institutes of Health (GM-59945), Merck Research
Laboratories, and DuPont. Computing support was provided
by the NCSA in the form of a supercomputing grant. The
invaluable assistance of Dr. Patrick Carroll in obtaining the
X-ray structure is gratefully acknowledged.
1
allylboronates 6 cleanly as judged by H and 11B NMR
spectroscopy (Figure 5). These reagents were anticipated to
display si facial selectivity (g85:15 si:re) in additions to
aldehydes on the basis of the stereochemical models depicted
in Figure 4 and transition state calculations (MM2*, AM1,
HF). Upon treatment of 6a and 6b with dihydrocinnamal-
dehyde, si facial selectivity was indeed observed (55:45 and
71:29 si:re, respectively). The lower selectivity of 6a
compared to 6b likely arises from a lower degree of
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111,
5495-5496.
OL026971W
(9) Allyl boronates are reactive in aldehyde allylation reactions. For a
review of reactivity: Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org.
Chem. 1990, 55, 1868-1874.
(11) (a) Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett. 2000, 2,
875-878. (b) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137-
1140.
(10) Lautens, M.; Fillion, E. J. Org. Chem. 1998, 63, 647-656.
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