The quest for single-enantiomer outcomes in free-radical chemistry

Article abstract of DOI:10.1071/CH01042

A significant challenge facing free-radical chemists is in the area of stereocontrol, specifically the ability to control the direction of reagent attack at a prochiral radical. While significant inroads have been made in the area of diastereoselective ra

Full text of DOI:10.1071/CH01042

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Current Chemistry
Aust. J. Chem. 2001, 54, 89–91
The Quest for Single-Enantiomer Outcomes in Free-Radical Chemistry
Dainis DakternieksA,C and Carl H. SchiesserB,C,D
A Centre for Chiral and Molecular Technologies, Deakin University, Geelong, Victoria, Australia, 3217.
B School of Chemistry, The University of Melbourne, Victoria, Australia, 3010.
C Chirogen Pty Ltd.
D Author to whom correspondence should be addressed (e-mail: carlhs@unimelb.edu.au).
A significant challenge facing free-radical chemists is in the area of stereocontrol, specifically the ability to control
the direction of reagent attack at a prochiral radical. While significant inroads have been made in the area of
diastereoselective radical chemistry, less successful have been attempts to provide truly enantioselective processes.
This article highlights recent efforts in the area of enantioselective free-radical reduction chemistry and describes
how single-enantiomer outcomes are possible when simple enantiopure stannanes are used in conjunction with
large, sterically-demanding Lewis acids. Selectivities in excess of 90% are now possible, with one example in
excess of 99.5% ee provided.
Manuscript received: 4 May 2001.
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Free-radical chemistry is a relative newcomer in the
synthetic chemistry arena. It is fair to say that during the
twenty-year period 1970–1990, free-radical chemistry
underwent a series of remarkable transformations that
effectively drew to a close the era in which free-radicals were
considered to give rise only to intractable tars or polymers.
This period revolutionized synthetic chemists’ attitudes
toward free radicals.[1–7]
Controlling the stereochemical outcomes of free-radical
reactions presented a more difficult problem.[8] Despite
advances made in the control of diastereoselectivity by the
late eighties, only low levels of enantiocontrol had been
achieved by the mid-nineties. Indeed, the majority of
examples that claimed to be ‘enantioselective’ involved the
use of chiral auxiliaries and were mostly further examples of
diastereoselectivity.[7–10] Of the remaining few reports, the
introduction of asymmetry, in the substrate through the use
of chiral Lewis-acid mediation,[11,12] and in the reagent
through the use of chiral ligands on suitably constructed
stannanes[13–16] and thiols,[17] were the methods of choice for
achieving enantioselectivity in radical chemistry. Selected
examples from the work of Metzger [14] and Hoshino[18] are
provided in Scheme 1. The reader is referred to excellent
recent reviews for further examples.[7,8,11]
were estimated to have a market value of $US18 billion. This
year they are worth over $US100 billion.[19] The
development of improved methods to provide single-
enantiomer compounds is therefore a topical objective and
several groups around the world have been actively engaged
in seeking methods to achieve this aim—enantioselective
free-radical chemistry, at first glance, would appear to offer
a solution.
Our approach to the development of synthetically useful
chiral stannanes primarily involves the judicious choice of
ligand from the multitude of compounds available in the
natural-chiral pool. Unfortunately, our initial foray in this
area was met with limited success. For example, reactions of
(1S,2S,5R)-menthyl-substituted stannanes (1–3)[20] with a
wide cross-section of substrates (4–6; X = Br) at –78°C
The importance of single-enantiomer outcomes in
synthesis cannot be overstated; 80 per cent of new drugs
entering development are enantiomerically pure,
a
consequence of the ever-tightening restrictions on the
composition of pharmaceutical preparations imposed by
regulatory authorities.[19] From a commercial perspective,
this has led to growth in both the number and value of single-
enantiomer drugs. In 1992, chiral pharmaceuticals, alone,
© CSIRO 2001
10.1071/CH01042
0004-9425/01/020089

90
CurrentChemistry
Fig. 1. MP2/DZP calculated transition-state geometries for the
delivery of a hydrogen atom from trimethylstannane to a methyl
radical (UHF/DZP data in parentheses) [AM1 data in square
brackets].
the ability of the ligand on tin to impart chiral information to
the prochiral radical during the reduction process. How then
do we improve the situation? One approach would be to
construct stannanes bearing very bulky chiral substitutents
able to induce asymmetry across the 3.5 Å transition-state
distance. This approach is somewhat limited if we choose to
restrict ourselves to cheap, readily available ligands from the
chiral pool. Alternatively, we might be able to ‘bulk up’ the
radical by the addition of a sterically-demanding co-reagent
or catalyst capable of coordination to the reacting species.
Bulky Lewis acids seemed appropriate and we next set about
examining the effect of Lewis acids on enantioselectivity
during free-radical reduction by simple chiral, non-racemic
stannanes such as (2).
Scheme 3 depicts some enantioselectivity data for the re-
duction of substrate (6e) with bis((1S,2S,5R)-menthyl)phe-
nyltin hydride (2) at –78°C in toluene in the absence of any
additive, and in the presence of one equivalent of BF3, zir-
conocene dichloride (8) and (S,S)-(–)- and (R,R)-(+)-N,N′-
bis(3,5-di-tert-butylsalycidene)-1,2-cyclohexanediamino-
manganese(III) chloride (9,10). Further data for other sub-
strates and reagents can be found in our recent publi-
cation.[23]
afforded reduced compounds (4–6;
X = H) with
enantioselectivities of less than 16%, a result with little
synthetic utility (Scheme 2).[21] These results compare
favorably with similar selectivities reported by Metzger and
Curran on related systems.[13–15]
Why should stannane-based free-radical chemistry be
expected to give rise to low levels of enantioselectivity in
reduction chemistry and how might we systematically go
about engineering reagents to improve the outcome? In an
attempt to answer these questions, we determined the relative
Arrhenius parameters for the reduction of (6g) with
tris((1S,2S,5R)-menthyl)tin hydride (3) by monitoring the
enantioselectivity as a function of temperature in the usual
way. In this manner, the difference in activation energy
(∆∆Eꢀ) for attack of the chiral reagent (3) at the re or si face
of the prochiral radical (7) was determined to be only
0.7 0.1 kJ mol–1.[21] Clearly, this value needs to be
increased if synthetically viable outcomes are to be achieved;
values in excess of about 10 kJ mol–1 are desirable.
As low values of ∆∆Eꢀ ultimately have their origins in the
diastereomeric transition states for hydrogen transfer to the
two faces of the prochiral radicals in question, we chose to
examine in detail the geometric requirements of the
transition states involved in the delivery of a hydrogen atom
from several types of stannane to a variety of alkyl
radicals.[22] Ab initio techniques provided overall Sn–C
distances of about 3.50 Å in these transition states that
proved to be largely independent of substitution, an example
is depicted in Fig. 1.[22] It would appear that the relatively
large CTS–Sn separations in these structures severely restrict
It is apparent that a Lewis acid is crucial in obtaining
reasonable enantioselectivities. For example, addition of one
equivalent of BF3 to the reaction involving (6e; X = Br)
resulted in an increase in enantioselectivity from 4 to 20%.

Current Chemistry
91
Increasing Lewis-acid bulk resulted in further increases;
46% ee is observed with the addition of zirconocene
dichloride (8), while addition of (9) results in a remarkable
improvement in ee to a value of 86%.
Acknowledgment
We thank the Australian Research Council for financial
support.
Despite the obvious benefit derived by the presence of the
Lewis acid, chirality transfer appears to originate with the
ligand on tin because the achiral Lewis acid (8) itself has a
remarkable effect on the stereochemistry of the reaction in
question. In addition, both enantiomeric forms of N,N′-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
manganese(III) chloride (9,10) result in enantioselectivities
within a few percent of each other and with the same enanti-
omeric form of the reduced substrate dominating, namely
(S). It is interesting to note that the value of ∆∆Eꢀ for the re-
action of (6e; X = Br) with (2) in the presence of (9) is now
12 2 kJ mol–1.[24]
References
[1] B. Giese, ‘Radicals in Organic Synthesis: Formation of Carbon–
Carbon Bonds’ (Pergamon Press: Oxford 1986).
[2] W. P. Neumann, Synthesis 1987, 665.
[3] D. P. Curran, Synthesis 1988, 417.
[4] D. P. Curran, Synthesis 1988, 489.
[5] C. P. Jasperse, D. P. Curran , T. L. Fevig, Chem. Rev. 1991, 91,
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[6] C. H. Schiesser, L. M. Wild, Tetrahedron 1996, 52, 13265.
[7] P. Renaud, M. P. Sibi (Eds), ‘Radicals in Organic Synthesis’ Vols
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[8] M. P. Sibi, N. A. Porter, Acc. Chem. Res. 1999, 32, 163.
[9] W. Smadja, Synlett. 1994, 1.
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[13] D. P. Curran, D. Nanni, Tetrahedron Asym. 1996, 7, 2417.
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[18] M. Murakata, H. Tsutsui, N. Takeuchi, O. Hoshino, Tetrahedron
1999, 55, 10295.
We have explored the use of other structurally-related
chiral stannanes[25–27] and can report that (11) and (12) react
with (13) and (6e), respectively, in toluene at –78°C to afford
the reduced products with 96 and >99.5% ee,
respectively;[23,24] single-enantiomer outcomes in free-
radical chemistry are possible!
[19] S. C. Stinson, Chem. Eng. News 1999, 77 (41), 101.
[20] D. Dakternieks, K. Dunn, D. J. Henry, C. H. Schiesser, E. R. T.
Tiekink, Organometallics 1999, 18, 3342.
[21] V. T. Perchyonok, C. H. Schiesser, Phosphorus, Sulfur Silicon
Relat. Elem. 1999, 150–151, 193.
[22] D. Dakternieks, D. J. Henry, C. H. Schiesser, J. Chem. Soc. Perkin
Trans. 2 1997, 1665.
[23] D. Dakternieks, K. Dunn, V. T. Perchyonok, C. H. Schiesser,
Chem. Commun. 1999, 1665.
[24] V. T. Perchyonok, Ph.D. Thesis, The University of Melbourne,
2000.
[25] C. H. Schiesser, M. A. Skidmore, Phosphorus, Sulfur Silicon
Relat. Elem. 1999, 150–151, 177.
[26] D. Dakternieks, K. Dunn, C. H. Schiesser, E. R. T. Tiekink, J.
Orgamomet. Chem. 2000, 605, 209.
In conclusion, we have successfully tackled an important
frontier confronting synthetic free-radical chemistry, namely
that of producing synthetically-acceptable levels of
enantioselectivity during free-radical transformations. Work
in our laboratories has developed new techniques that control
hydrogen transfer reactions to the extent that single-
enantiomer outcomes are now possible.
[27] D. Dakternieks, K. Dunn, C. H. Schiesser, E. R. T. Tiekink, J.
Chem. Soc., Dalton Trans. 2000, 3693.