Robert S. Paley
List of Publications
[NOTE: Swarthmore College undergraduate co-workers denoted by*].
The sulfoxide functional group, readily available in enantiomerically pure
form, has long been used as a chiral auxiliary by synthetic organic chemists.
That is, it is readily attached, in a covalent manner, to an organic substrate
and is then utilized to control the absolute stereochemistry of incipient
stereogenic centers. The final step of this strategy involves removal
of the sulfoxide unit to afford a chiral organic unit in enantioenriched
form. While the use of enantiomerically pure sulfoxides in the context
of "classic" organic transformations is well-established, their use as
chiral auxiliaries in transition metal-mediated reactions remains rare.
Our group at Swarthmore has been involved in developing this area of research,
and our contribution is a still-evolving indirect approach in which the
sulfoxide is used in combination with diene iron(0) tricarbonyl complexes.
1. "Enantiomerically Pure Planar Chiral Organometallic Complexes
via Facially-Selective Pi-Complexation". R.S. Paley, Chem. Rev.,
2. "Enantiopure h4-(1-Sulfinyldiene)iron(0)
Tricarbonyl Complexes as Templates for Carbocycle Construction via Ring-Closing
Metathesis", R.S. Paley, L.A. Estroff,* J.-M. Gauguet,* D.K. Hunt,*
R.C. Newlin* Org. Lett., 2000, 2, 365-368.
3. "Diastereoselective Allylation of Enantiopure 3- and 4-Substituted h-4-(1Z)-(Sulfinyldienal)Iron(0)
Tricarbonyl Complexes", R. S. Paley, L. A. Estroff*, D. J. McCulley*, L.
Alfonso Martinez-Cruz, A. Jimenez Sanchez, F. H. Cano, Organometallics,
4. "Synthesis and Diastereoselective Complexation of Enantiopure Sulfinyl
Dienes: The Preparation of Sulfinyl Iron(0) Dienes", R. S. Paley, A. de
Dios, L. A. Estroff*, J. A. Lafontaine*, C. Montero, D. J. McCulley*, M.
Belen Rubio, M. P. Ventura, H. L. Weers*, R. Fernandez de la Pradilla,
M. Morente, R. Dorado, J. Org. Chem., 1997, 62, 6326-6343.
5. "Diastereoselective Formation Of An h-4-(1Z)-(Sulfinyldiene)Iron(0)
Tricarbonyl Complex. Diastereoselective Allylation Of The Derived Iron
Dienal", R. S. Paley, M. B. Rubio, R. Fernandez de la Pradilla, R. Dorado,
G. Hundal, M. Martinez-Ripoll, Organometallics, 1996, 15,
6. "Stereocontrolled Synthesis of Enantiomerically Pure 2-Dienyl Sulfoxides
via Palladium-Catalyzed Coupling Reactions", R. S. Paley, H. L. Weers,*
P. Fernandez, R. Fernandez de la Pradilla, S. Castro, Tetrahedron Letters,
7. "Synthesis of Enantiopure 2-Malonylvinyl Sulfoxides via Addition-Elimination
Reactions of 2-Halo- and 2-Mesyloxyvinyl Sulfoxides", J. P. Marino, E.
Laborde, C. F. Deering, R. S. Paley, M. P. Ventura, J. Org. Chem.,
8. "Enantiopure Enynyl Sulfoxides via Palladium-Catalyzed Coupling Reactions",
R. S. Paley, J. A. Lafontaine,* M. P. Ventura, Tetrahedron Letters,
9. "Stereocontrolled Synthesis of Enantiomerically Pure Dienyl Sulfoxides
via Palladium-Catalyzed Coupling Reactions", R. S. Paley, A. de Dios, R.
Fernandez de la Pradilla, Tetrahedron Letters, 1993, 34,
10. "Synthesis of Enantiomerically Pure (Z)-2-Haloalkenyl Sulfoxides",
R. Fernandez de la Pradilla, M. Morente, R. S. Paley, Tetrahedron Letters,
11. "Stereoselective Synthesis of N-Acyl-(E)-vinyl, -dienyl,
and -enynylsulfoximines", R.S. Paley and S.R. Snow*, Tetrahedron Letters,
12. "Stereospecific Replacement of Sulfur from Chiral g-Arylsulfanylbutyrolactones.
Synthesis of Optically Pure Ring-Fused g-Butyrolactones",
J.P. Marino, E. Laborde, and R.S. Paley, J. Am. Chem. Soc., 1988,
We have been the first to prepare sulfinyl diene iron(0) tricarbonyl
complexes (1, Figure 1). Placement of a chiral sulfoxide group
at the terminus of diene, with cis stereochemistry as shown, renders
the two faces of the diene distinct. Therefore upon pi-complexation
of an Fe(CO)3 fragment to the diene there are two possible diastereomeric
products that could be formed by coordination either above or below the
chiral plane defined by the diene. In our case, complexation to the
sulfinyl dienes is highly diastereoselective; attachment to one face is
greatly preferred as a result of conformational bias (Figure 1).
Thus we are able to control the installation of planar chirality, and considering
the paucity of reliable methods for controlling the facial preference in
complexations of acyclic diene systems as well as the well-known usefulness
of Fe(CO)3 fragments for the installation of new stereocenters
along the periphery of dienes, this methodology has great promise as a
novel strategy the construction of enantiomerically pure highly functionalized
natural product sub-units.
Having thus demonstrated that the chirality of the sulfoxide group could
be used to form "planar chiral" organometallic complexes, more elaborate
substrates were prepared (2). The planar chirality was then
used to direct the installation of new stereocenters along the periphery
of the diene (i.e., 3, Figure 2). New carbon chains added
during this process were then joined to form ring systems using "ring-closing
metathesis" chemistry; of particular interest was the unexpected ease in
synthesizing an eight-membered ring system, 4.
We have also been exploring the conversion of dialdehydes (5
and 6) into diols via an intramolecular pinacol coupling (Figure
3). This reaction is highly diastereoselective and allows us to prepare
more complex ring systems from our sulfinyl iron diene templates.
Current work in our laboratories includes synthesizing a variety of related
substrates in order to obtain crystals suitable for analysis by X-ray crystallography
(in order to establish the stereochemistry of the pinacol products).
Also, we are exploring further manipulations of the sulfinyl iron diene
Finally, planar chiral organometallic complexes can offer unique opportunities
for the design of catalysts for asymmetric reactions, or in the design
of transition metal ligands for asymmetric metal-catalyzed processes.
This is due to the potential for three-dimensional engineering about the
atom or atoms intimately involved in the reaction one seeks to control.
An advantage of such strategies, which can represent wholly synthetic mimics
of enzyme active sites, is the potential for precise spatial control of
the chiral environment about the transition state of the desired reaction.
Thus, there has been substantial recent interest in the development of
this area of synthetic methodology. Since we can now prepare sulfinyl
iron(0) diene complexes in which a sterically demanding functional group
can be essentially fixed in a defined position above a diene whose lower
face is blocked, some modifications of our complexes could lead to an entirely
new class of chiral bidentate ligands based on non-biaryl atropisomerism
and planar chirality.
Our initial focus would be to develop a ligand or ligands suitable for
use in the palladium-catalyzed asymmetric allylic alkylation reaction which
would proceed via an intermediate p-allyl complex,
(Figure 4). The challenge in this area has been to design a ligand
which would force the symmetrical p-allyl complex
to adopt a single position in order to allow only one of its two faces
to be accessible to the incoming nuclophile. Furthermore, one of
the two terminal carbon atoms of the p-allyl
complex must be distinguished from the other to avoid indiscriminate approach
of the nucleophile. The best successes in this area have been achieved
with the utilization of systems in which the chelating atoms are different
- typically N, P- or S, P-ligands, since it has been demonstrated
that nucleophile approach trans to the phosphorous atom is preferred.
At all stages of this work, high-field NMR is heavily utilized to identify
and characterize the synthesized compounds.
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