Job/Unit: O20652
/KAP1
Date: 25-06-12 11:45:48
Pages: 5
Enantioselective Synthesis of (R)-Homoboroproline
plicable in this case. Hence, under those conditions, reaction ation our studies so far concerning both enantiomeric
of iodide 6 with B2pin2, LiOtBu, and catalytic CuI gratify- forms of the homoboroproline catalyst, our proposed cata-
ingly gave pinacol boronate ester 5 directly in 48% yield lytic cycle can be reinforced as proposed in previous re-
with, importantly, 97%ee. Subsequent optimization re- ports.[6,7]
sulted in routine isolation of 5 in 65% yield by modifying
the workup procedure (Scheme 4).
Conclusions
In summary, we have developed an efficient, novel syn-
thetic route to amino boronic acid 4 via ammonium salt 10
by taking advantage of newly reported methodology for the
sp3-borylation of corresponding alkyl iodide 6. Subsequent
application of the boronate ester analogue of 10 in the stan-
dard aldol reaction highlighted the importance of the chiral
center present on the pyrrolidine ring for the asymmetric
induction of the aldol product. These studies in combina-
tion with results reported previously[6,7] have provided evi-
dence of our understanding the mode of action of catalysts
1 and 4 through a transition state resulting from the cooper-
ative relationship between the enamine and the boronate
function.
Scheme 4. Synthetic route towards the formation of homoboro-
proline catalyst 10.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, copies of the NMR spectra and HPLC
chromatograms.
The development of this simple, high-yielding, and repro-
ducible reaction meant that isolation of enantiomeric cata-
lyst 4 could be easily achieved as its HCl salt 10 through
this sequence from (S)-proline. Hence, cleavage of the Boc
and pinacol protecting groups of 5 was readily conducted
under the standard acidic conditions to afford deprotected
10 in near quantitative yield (Scheme 4).[4]
To demonstrate that the enantioselective aldol reaction
catalyzed by the chiral boronate ester analogues of 1 arises
from the chiral center present on the pyrrolidine ring of the
catalyst rather than from the chirality of the diol used for
the esterification of the boronic acid,[6,7] a standard aldol
reaction was carried out under the optimized reaction con-
ditions by using (R)-homoboroproline catalyst 10[7] neutral-
ized in situ. Hence, the aldol reaction between p-nitrobenz-
aldehyde and acetone in DMF was performed in the pres-
ence of (R,R)-hydrobenzoin (10, see Equation 3) and pro-
ceeded in full agreement with our expectations; aldol prod-
uct 3 was obtained with the expected absolute stereocontrol
(i.e., R) with 93%ee and in 89% yield after 7 h (Equa-
tion 3), which is opposite to that obtained from (S)-enantio-
mer 1.
Acknowledgments
We are grateful to One North East and the Department of Chemis-
try at Durham University for financial support. We acknowledge
Prof. T. B. Marder for assistance in the borylation reactions of the
alkyl halides and the EPSRC National Mass Spectrometry Service
Centre at Swansea.
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Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2005.
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These findings indicate that the enantiomeric excess of
the aldol product originates from the chiral center on the
pyrrolidine ring of the catalyst, because homoboroproline
catalyst 10 provides the opposite enantiomeric form of the
aldol adduct compared to catalyst 1. Taking into consider-
Eur. J. Org. Chem. 0000, 0–0
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