Catalytic asymmetric deprotonation using a ligand exchange approach

Article abstract of DOI:10.1021/ja056026d

A novel ligand exchange approach to catalytic asymmetric deprotonation-electrophilic trapping has been developed that uses 1.3 equiv of s-BuLi, 0.06-0.2 equiv of chiral diamine ((-)-sparteine or a (+)-sparteine surrogate), and 1.2 equiv of achiral bispidine. The methodology is illustrated with a range of examples and gives access to either enantiomer of useful chiral products in good yields using substoichiometric amounts of chiral diamines. Copyright

Full text of DOI:10.1021/ja056026d

Published on Web 11/03/2005
Catalytic Asymmetric Deprotonation Using a Ligand Exchange Approach
Matthew J. McGrath and Peter O’Brien*
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, U.K.
Received September 1, 2005; E-mail: paob1@york.ac.uk
Scheme 1
(-)-Sparteine is a widely utilized chiral diamine for stoichio-
metric asymmetric synthesis,1,2 but reports of catalytic applications
are rare. Notable exceptions, which proceed with high enantiose-
lectivity using substoichiometric amounts of (-)-sparteine, include
additions to imines,3 carbolithiations,4 conjugate addition to enoates,5
and Pd-mediated oxidation.6 In the area of asymmetric deprotonation
reactions,7 use of substoichiometric (-)-sparteine has had mixed
success. Whereas the R-lithiation rearrangement of an epoxide gave
similar yield and enantioselectivity under both stoichiometric and
catalytic conditions,8 lithiation trapping of N-Boc pyrrolidine 1 or
O-alkyl carbamate 3 was far less successful (Scheme 1). For
example, in our hands, use of 1.3 equiv of s-BuLi and 0.2 equiv of
(-)-sparteine on 1 gave (S)-2 of 75:25 er in 34% yield9 (stoichio-
metric: 87% yield, 95:5 er10), and use of 1.4 equiv of s-BuLi and
0.2 equiv of (-)-sparteine on 3 gave (S)-4 of 85:15 er in 17% yield
(stoichiometric: 73% yield, 99:1 er). In these substoichiometric
examples, the yield and enantioselectivity obtained from 1 and 3
suggest that the diamine does not readily dissociate from the
Scheme 2
lithiated complexes 5 so that the reactive s-BuLi/(-)-sparteine
complex is not regenerated.
Thus, we set out to devise a conceptually different catalytic
approach in which a ligand exchange process would enable the
chiral ligand to be recycled from the lithiated complexes 5 such
that high yield and enantioselectivity should be possible. An outline
of our proposed approach is shown in Scheme 2 for N-Boc
pyrrolidine 1. We envisaged that a stoichiometric achiral diamine
8 would displace (-)-sparteine from 7 (≡ 5, X ) NR) thus
producing a new organolithium/diamine complex 10 and regenerat-
ing the active s-BuLi/(-)-sparteine complex 6, which could re-
enter the catalytic cycle. Subsequent electrophilic trapping of either
7 or 10 (or both) with Me3SiCl after the usual lithiation time would
then produce (S)-2. For such an approach to work, several criteria
Scheme 3
must be met: (i) ligand exchange must occur;11 (ii) organolithiums
7 and 10 must be configurationally stable12 during the ligand
exchange; and (iii) deprotonation of 1 using s-BuLi/(-)-sparteine
complex 6 must be faster than that using the achiral s-BuLi/diamine
complex 9.13 Wu and Chong have recently reported a related ligand
exchange concept for conjugate addition to enones using orga-
respectively. Hence, s-BuLi/bispidine 13 was investigated with
either (-)-sparteine or (+)-11 in three catalytic reactions: 1 f 2,
3 f 4, and 14 f 15 (Scheme 3).
To our delight, when the lithiation-Me3SiCl trapping of N-Boc
pyrrolidine 1 was attempted using 1.3 equiv of s-BuLi, 0.2 equiv
of (-)-sparteine, and 1.2 equiv of bispidine 13, adduct (S)-2 of
90:10 er was obtained in 76% yield (entry 1) (stoichiometric: 87%,
95:5 er). Even better enantioselectivity was obtained using 0.2 equiv
noboron reagents.14 We now report the application of a ligand
exchange strategy to s-BuLi/diamine-mediated catalytic asymmetric
deprotonation.
To implement the projected ligand exchange approach, a suitable
achiral diamine 8 needed to be designed. For this, our ligand
variation study on the lithiation trapping of N-Boc pyrrolidine 115
was a useful guide. Thus, whereas N-Me diamine 11 behaved as a
(+)-sparteine surrogate, the sterically hindered N-i-Pr diamine 12
of (+)-sparteine surrogate 11 in combination with 1.2 equiv of
failed to deprotonate 1 (even though s-BuLi/diamine 12 has been
used in other reactions16). This suggested that s-BuLi complexes
of structurally similar achiral diamines, such as bispidine 13,17 might
be slow lithiators and thus suitable for catalysis. Consistent with
this idea, lithiation trapping of 1 and 3 using excess s-BuLi/diamine
13 furnished adducts rac-2 and rac-4 in 5 and 15% isolated yields,
9
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J. AM. CHEM. SOC. 2005, 127, 16378-16379
10.1021/ja056026d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalytic Asymmetric Deprotonation-Electrophilic
Trapping
Scheme 4
entry
SM
diamine
equiv
producta
yield (%)
erb
1
2
3
4
5
6
7
8
1
1
3
3
3
3
14
14
(-)-sp
(+)-11
(-)-sp
(+)-11
(-)-sp
(+)-11
(-)-sp
(+)-11
0.2
0.2
0.2
0.2
0.1
0.06
0.2
0.2
(S)-2
(R)-2
(S)-4
(R)-4
(S)-4
(R)-4
(S)-15
(R)-15
76
66
77
72
54
63
67
68
90:10
6:94
92:8
6:94
In summary, a novel ligand exchange approach to catalytic
asymmetric deprotonation-electrophilic trapping has been devel-
oped. Using (-)-sparteine and our previously reported (+)-sparteine
surrogate 11, this methodology allows access to either enantiomer
of useful products in good yields using substoichiometric amounts
of chiral diamines.
81:19
15:85
83:17
11:89
a Reaction conditions: 1.3 equiv of s-BuLi, 1.2 equiv of bispidine 13,
0.06-0.2 equiv of (-)-sparteine ((-)-sp) or (+)-11, Et2O, -78 °C, 5 h for
1 and 3 or 3 h for 14 then add electrophile (Me3SiCl for 1, Bu3SnCl for 3,
Ph2CO for 14). b Enantiomeric ratio determined by chiral GC (Betadex 120)
for 2 and by chiral HPLC (Chiracel OD) for 4 and 15.
Acknowledgment. We thank the EPSRC for funding.
Supporting Information Available: Full experimental procedures
and characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
bispidine 13; the antipode (R)-2 of 94:6 er was formed in 66%
yield (entry 2), approaching the stoichiometric result (84% yield,
95:5 er10). Deprotonation of O-alkyl carbamate 3 with 1.3 equiv of
s-BuLi, 0.2 equiv of (-)-sparteine, and 1.2 equiv of bispidine 13
and trapping gave stannane (S)-4 of 92:8 er in 77% yield (entry 3)
(stoichiometric: 73% yield, 99:1 er). Similarly, use of Me3SiCl in
place of Bu3SnCl gave the (S)-trimethylsilyl adduct18 of 89:11 er
in 69% yield (stoichiometric: 64% yield, 98:2 er). As with 1, (+)-
11 performed better than (-)-sparteine in the deprotonation of 3
under otherwise identical conditions; (R)-4 of 94:6 er was generated
in 72% yield (entry 4), which is almost identical to the stoichio-
metric result (84%, 96:4 er10).
An investigation into lower chiral diamine loadings was carried
out using O-alkyl carbamate 3 (entries 5 and 6). Use of 0.1 equiv
of (-)-sparteine and 1.2 equiv of bispidine 13 with 3 gave (S)-4 of
81:19 er (54% yield), whereas use of just 0.06 equiv of (+)-11
under the same conditions gave (R)-4 of 85:15 er (63% yield). The
reduced enantioselectivity with <0.2 equiv of chiral diamine
suggests that background deprotonation by free s-BuLi or s-BuLi/
bispidine 13 is significant. Indeed, reaction of O-alkyl carbamate
3 with s-BuLi alone or s-BuLi/bispidine 13 gave adduct rac-4 in
17 and 15% yields, respectively.
Similar success was obtained in the catalytic asymmetric
lithiation trapping of phosphine borane 14.16,19 Lithiation of 14 with
1.3 equiv of s-BuLi, 0.2 equiv of (-)-sparteine, and 1.2 equiv of
bispidine 13 followed by benzophenone quench gave (S)-15 of 83:
17 er in 67% yield (entry 7). This compares well with 83% yield
of (S)-15 of 88:12 er under stoichiometric conditions.16 The antipode
(R)-15 was prepared in 68% yield and 89:11 er using 0.2 equiv of
(+)-11 and 1.2 equiv of bispidine 13 (entry 8) (stoichiometric
result: 78% yield, 96:4 er16).
Finally, to showcase our catalytic asymmetric deprotonation
methodology, we applied it to the synthesis of bis-phosphine
boranes (R,R)- and (S,S)-16, precursors of useful chiral bis-
phosphines for asymmetric hydrogenation.19b Thus, lithiation of
phosphine borane 14 using 1.3 equiv of s-BuLi, 0.2 equiv of (+)-
11, and 1.2 equiv of bispidine 13 followed by Cu(II)-promoted
dimerization of the intermediate organolithium gave (R,R)-16 (53%
yield, >99:1 er by chiral HPLC) and meso-16 (15% yield) (Scheme
4). This catalytic asymmetric synthesis of (R,R)-16 is the shortest
and most direct approach to date.20 The analogous reaction with
(-)-sparteine gave (S,S)-16 of >99:1 er in 46% yield (with 12%
meso-16).
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