Remarkable Lewis acid mediated enhancement of enantioselectivity during free-radical reductions by simple chiral non-racemic stannanes

Article abstract of DOI:10.1039/a904700j

Additions of 1 equiv, of achiral and chiral Lewis acids to free-radical reduction reactions involving (1S,2S,5R)-menthyldiphenyltin hydride 1, bis[(1S,2S,5R)-menthyl]phenyltin hydride 2, bis[1S,2S,5R)-menthyl][8-(N,N-dimethylamino)naphthyl]tin hydride 3, bis[(1R,2S,5R-menthyl] {1-(S)-N,N-dimethylaminoethyl]phenyl}tin hydride 4 or 3α-dimethylstannyl-5α-cholestane 5 result in remarkable increases in enantioselectivity.

Full text of DOI:10.1039/a904700j

Remarkable Lewis acid mediated enhancement of enantioselectivity during
free-radical reductions by simple chiral non-racemic stannanes
Dainis Dakternieks,a Kerri Dunn,a V. Tamara Perchyonokb and Carl H. Schiesser*b
a
Centre for Chiral and Molecular Technologies, Deakin University, Geelong, Victoria, Australia, 3217
School of Chemistry, The University of Melbourne, Parkville, Victoria, Australia, 3052.
b
E-mail: c.schiesser@chemistry.unimelb.edu.au
Received (in Cambridge, UK) 14th June 1999, Accepted 16th July 1999
Additions of 1 equiv. of achiral and chiral Lewis acids
to free-radical reduction reactions involving (1S,2S,5R)-
menthyldiphenyltin hydride 1, bis[(1S,2S,5R)-menthyl]-
phenyltin hydride 2, bis[1S,2S,5R)-menthyl][8-(N,N-
dimethylamino)naphthyl]tin hydride 3, bis[(1R,2S,5R-
used by Curran and Nanni;6 in this manner a direct comparison
with previous work is possible.
In this study, reductions were carried out at concentrations of
approximately 0.1 M of the substrate in to which 1.0 equiv. of
the Lewis acid† of choice and 1.1 equiv. of the stannane were
added in toluene at 278 °C, initiated using 9-BBN.11 Reactions
were carried out until TLC analysis indicated the absence of
starting material (ca. 1–2 h) at which time the reaction mixtures
were examined by chiral-phase gas chromatography (GC)‡ and
the percentage conversion and enantiomeric ratios determined
by integration of the signals corresponding to the mixture of
reduced compounds 6 and 7 (X = H) against an internal
standard (either octane or undecane). Reduced compounds 6
and 7 (X = H) were identified by comparison of their GC
retention times with those of the authentic compounds. The
absolute configuration of the dominant isomer in each case was
assigned by comparison with the GC retention times of the (S)-
products 6 and 7 prepared and resolved following literature
procedures.12
Table 1 lists enantioselectivity data for the model substrates
6 and 7 reacting with bis[(1S,2S,5R)-menthyl]phenyltin hydride
2 at 278 °C in toluene in the absence of any additive and in the
presence of 1 equiv. of BF3, zirconocene dichloride 8, (S,S)-
(2)- and (R,R)-(+)-N,NA-bis(3,5-di-tert-butylsalycidene)-1,2-
diaminocyclohexanemanganese(iii) chloride 9 or 10.13
Inspection of Table 1 reveals some interesting features which
aid in our understanding of the factors which goven the
menthyl]{1-(S)-N,N-dimethylaminoethyl]phenyl}tin
hy-
dride 4 or 3a-dimethylstannyl-5a-cholestane 5 result in
remarkable increases in enantioselectivity.
Despite there being numerous reports of free-radical reactions
proceeding with diastereocontrol,1,2 there are relatively very
few examples of free-radical reactions which proceed with
genuine enantiocontrol.2 The majority of examples that demon-
strate enantioselective outcomes involve the use of chiral
auxiliaries and, as a result, are further examples of diastereo-
selectivity in free-radical chemistry.1,2 Of the remaining few
reports, the introduction of asymmetry in the substrate through
the use of chiral Lewis acid mediation,3,4 and in the reagent
through the use of chiral ligands on the tin atom in suitably
constructed stannanes5–8 have been the methods of choice for
achieving enantioselectivity in radical chemistry.
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. Here we report that significant improvements in
enantioselectivity during asymmetric reductions involving
chiral non-racemic stannanes are achieved by the addition of
Lewis acids.
(1S,2S,5R)-Menthyldiphenyltin hydride 1, bis[(1S,2S,5R)-
menthyl)phenyltin hydride 2 and 3a-dimethylstannyl-5a-chol-
estane 5 were prepared previously within our group.9 The
remaining hydrides 3 and 4 were prepared by reaction of the
appropriate aryllithium with bis[(1S,2S,5R)-menthyl]phenyltin
chloride followed by LiAlH4 reduction.9,10 Substrates chosen
for this work include bromides 6 (X = Br) employed by
Metzger and co-workers in their recent study8 and the ketone 7
Table
1 Enantioselectivities observed for reactions involving bis-
[(1S,2S,5R)-menthyl]phenyltin hydride 2 in toluene at 278 °Ca
Entry
Substrate
Lewis acid
Eea (%)
Conversionb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6c
6c
6c
6c
6c
6d
6d
6d
6d
6d
7
None
BF3
8
9
10
None
BF3
8
9
10
None
BF3
8
9
10
None
BF3
8
9
10
2
32
36
60
55
4
20
46
86
84
9
30
35
80
78
6
10
60
80
83
16
12
52
52
50
80
64
58
81
59
81
68
52
75 (71)c
69
81
79
74
82 (70)c
75
82
76
68
72
52
81
69
92
None
BF3
8
9
10
7
7
7
7
76
60
a All reductions gave the (S)-product. b GC conversion. c Isolated yield.
Chem. Commun., 1999, 1665–1666
1665

Table 2 Enantioselectivities observed for reactions involving zirconocene
dichloride 8 and (S,S)-(2)-N,NA-bis(3,5-di-tert-butylsalycidene)-1,2-di-
aminocyclohexanemanganese(iii) chloride 9 and its enantiomer 10 in
toluene at 278 °C
the highest-ever reported enantioselectivities in stannane reduc-
tion chemistry,1,4,14§ the 96% ee observed for the reaction of 6c
(X = Br) with 4 in the presence of 9 being truly remarkable;
indeed, this result exceeds the highest ee achieved in any free-
radical reaction.1,15,16 We believe that, consistent with previous
models proposed to account for diastereoselective outcomes in
radical reactions,1–4 the profound increases in enantioselectivity
observed upon addition of the Lewis acids in this study are a
result of the significant increases in steric bulk17 associated with
the ester group during coordination of the carbonyl moiety of
the boron or metal centre in BF3, 8–10.
In order to explore the synthetic utility of the use of these
reagents and catalysts, we repeated the reduction of several
substrates in the presence of 9 (entries 9, 14 in Table 1; 5, 14, 22
in Table 2). We were delighted to isolate the reduction products
6 (X = H) in 67–71% yield after workup and chromatography;
GC analysis provided ees as listed.¶
Entry
Substrate
Lewis acid
Stannane
Ee (%)
Yielda (%)
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
6b
6b
6c
6d
6d
6d
6d
6d
6d
6d
6d
7
8
8
8
9
9
9
8
8
8
9
9
9
10b
9
8
8
8
8
9
9
9
9
8
8
8
9
9
9
9
1
3
5
1
4
5
1
3
5
2
4
5
36 (S)
38 (S)
60 (S)
60 (S)
90 (R)
34 (S)
42 (S)
52 (S)
54 (S)
70 (S)
72 (S)
62 (S)
86 (R)
96d (S)
0 (—)
58 (S)
62 (S)
76 (S)
8 (S)
72 (S)
80 (S)
82 (S)
50 (S)
56 (S)
42 (S)
58 (S)
46 (S)
62 (S)
52 (S)
59
77
82
82
73 (68)e
58
51
79
54
78
68
67
72
75 (67)c
—
63
87
96
—
74
76
72 (68)e
68
62
79
81
85
74
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
a
ent-2c
4
Bu3SnH
1
3
5
We are currently exploring immobilisation of these chiral
reagents onto polymer support and the use of catalytic chiral
stannane reductions. We thank the Australian Research Council
for financial support.
Bu3SnH
Notes and references
† The use of less than 1.0 equiv. results in noticeably lower ees, while
greater amounts provide no increases in ee.
‡ Enantioselectivities were determined by gas chromatographic analyses of
the reaction mixtures using a chiral trifluoroacteylated g-cyclodextrin
(Chiraldex™ G-TA, 30 m 3 0.25 mm) capillary column purchased from
Alltech.
§ To the best of our knowledge, the value of 61% reported by Hoshino and
co-workers represents the previous record, see ref. 1, 4, 13. Roberts has
reported recently some enantioselective hydrosilation reactions which
proceed with ees approaching 95%, see ref. 16.
1
4
5
1
3
5
1
3
4
5
c
7
7
7
7
7
7
b
GC conversion. The enantiomer of 9. Bis[(1R,2R,5S)-menthyl]phe-
¶ 96% ee for entry 14 in Table 2 represents a GC-determined lower limit.
nyltin hydride. d See footnote ¶. e Isolated yield.
1 For excellent reviews, see: D. P Curran, N. A. Porter and B. Giese,
Stereochemistry of Radical Reactions, VCH, Weinheim, 1995; W.
Smadja, Synlett., 1994, 1; N. A. Porter, B. Giese and D. P. Curran, Acc.
Chem. Res., 1991, 24, 296.
2 M. Sibi and N. A. Porter, Acc. Chem. Res., 1999, 32, 163.
3 For early examples, see: Y. Guindon, C. Yoakim, R. Lemieux, L.
Boisvert, D. Delorme and J.-F. Lavelle´e, Tetrahedron Lett., 1990, 31,
2845; Y. Guindon, J.-F. Lavalle´e, M. Llinas-Brunet, G. Horner and J.
Rancourt, J. Am. Chem. Soc., 1991, 113, 9701.
4 For a comprehensive review, see: P. Renaud and M. Gerster, Angew.
Chem., Int. Ed., 1998, 37, 2563.
5 H. Schumann, B. Pachaly and B. C. Schu¨tze, J. Organomet. Chem.,
1984, 265, 145.
6 D. P. Curran and D. Nanni, Tetrahedron: Asymmetry, 1996, 7, 2417.
7 M. Blumenstein, K. Schwartzkopf and J. O. Metzger, Angew. Chem.,
Int. Ed. Engl., 1997, 36, 235.
8 K. Schwartzkopf, M. Blumenstein, A. Hayen and J. O. Metzger, Eur. J.
Chem., 1998, 177.
9 D. Dakternieks, K. Dunn, D. J. Henry, C. H. Schiesser and E. R. T.
Tiekink, Organometallics, in press; C. H. Schiesser and M. A.
Skidmore, Phosphorus Sulfur Silicon Relat. Elem., in press.
10 J. B. T. H. Jastrzebski, G. van Koten, K. Goubitz, C. Arlen and M.
Pfeffer, J. Organomet. Chem., 1983, 246, C75; G. van Koten and
J. B. T. H. Jastrzebski, Tetrahedron, 1989, 45, 569.
11 V. T. Perchyonok, C. H. Schiesser, Tetrahedron Lett., 1998, 39,
5437.
12 A. Campbell and S. Kenyon, J. Chem. Soc., 1946, 25; C. Aaron, D. Dull,
S. L. Schmiegel, D. Jaeger, J. Ohashi and H. S. Mosher, J. Org. Chem.,
1967, 32, 2797; F. A. A. Elhafez and D. J. Cram, J. Am. Chem. Soc.,
1952, 74, 5846.
stereochemical outcome in the reactions of interest. Firstly, a
Lewis acid is crucial in obtaining reasonable enantioselectiv-
ities. Experiments carried out in the absence of these Lewis
acids give significantly poorer ees. For example, addition of 1
equiv. of BF3 to the reaction involving 6b (X = Br) results in
an increase in enantioselectivity from 4 to 20%. Increasing
Lewis acid bulk results 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%.
It is interesting to note that the (S)-isomer of the product
dominates in all of the reductions listed in Table 1. It is also
important to note, when the reduction of 6b (X = Br) was
repeated with the enantiomer of 2, bis[(1R,2R,5S)-menthyl]phe-
nyltin hydride, in the presence of 10, (R)-6b (X = H) was
obtained with an ee of 86% under the same reaction condi-
tions.
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,NA-bis(3,5-
di-tert-butylsalicylidene)-1,2-diaminocyclohexanemangane-
se(iii) chloride, namely 9 and 10, result in enantioselectivities
within a few percent of each other and with the same
enantiomeric form of the reduced substrate dominating.
Table 2 lists the effect that different stannanes have on the
observed enantioselectivities at 278 °C for reactions involving
Lewis acids 8, 9 and (for one example) 10. It should be noted
that the achiral stannane, tributyltin hydride, reacts with 6d (X
= Br) in the presence of Lewis acids 8 and 9 to afford 6d (X =
H) with 0 and 8% ee, respectively. The former result is
expected; the latter result demonstrates, one again, that chirality
in the stannane is more important than that in the Lewis acid.
The reader’s attention is drawn to the numerous examples
provided in Tables 1 and 2 where the observed enantioselectiv-
ity exceeds 80% and the two examples (entries 5 and 14, Table
2) of ees ! 90%. These results are significant as they represent
13 Jacobson’s catalyst: E. N. Jacobsen, W. Zhang, A. R. Muci, J. R. Ecker
and L. Deng, J. Am. Chem. Soc., 1991, 113, 7063.
14 M. Murakata, H. Tsutsui and O. Hoshino, J. Chem. Soc., Chem.
Commun., 1995, 481.
15 M. Murakata, T. Jono, Y. Mizuno and O. Hoshino, J. Am. Chem. Soc.,
1997, 119, 11713.
16 M. B. Haque, B. P. Roberts and D. A. Tocher, J. Chem. Soc., Perkin
Trans. 2, 1998, 2881.
17 D. Dakternieks, D. J. Henry and C. H. Schiesser, J. Phys. Org. Chem.,
1999, 12, 233.
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Chem. Commun., 1999, 1665–1666