C O M M U N I C A T I O N S
Table 1. CDR of 2 at -45 °C for 3 h Using Ligand 8 (or 9 Where
Noted)
Scheme 3. Synthesis of (S)-(+)-Pelletierine and (S)-(-)-Coniine
and Formal Synthesis of (-)-Lasubine II and (+)-Cermizine Ca12
a (i) Pd(OH)2 (1.0 equiv), H2 (1 atm), MeOH, rt, 48 h; (ii) CF3CO2H,
CH2Cl2, 0 °C, 2 h, then NaOH; (iii) PdCl2 (1.0 equiv), CuCl (10 mol %),
O2, 10:1 DMF/H2O, rt, 10 h; (iv) CF3CO2H, CH2Cl2, 0 °C, 2 h, then NaOH.
Scheme 4. Synthesis of (S)-(-)-Ropivacainea
a (i) s-BuLi (1.2 equiv), Et2O, TMEDA (4.0 equiv), -78 °C, 3 h, then
9 (10 mol %), -45 °C, 3 h, -78 °C, 2,6-dimethylphenyl isocyanate, 2 h,
>99:1 er; (ii) CF3COOH, CH2Cl2, rt, 10 h, then NaOH; (iii) isopropyl
alcohol, 1-bromopropane (3.0 equiv), K2CO3 (3.0 equiv), H2O, 100 °C, 6 h.
CDR of 2 with ligand 9 and electrophilic quenching with 2,6-
dimethylphenyl isocyanate afforded enantiopure (>99:1 er) (S)-21
in 69% yield (Scheme 4). After deprotection, alkylation with
1-bromopropane in the presence of K2CO3 yielded (S)-(-)-
ropivacaine in 61% overall yield for three steps.
In summary, the discoveries of ligands 8 and 9 coupled with
their ability to resolve N-Boc-2-lithiopiperidine catalytically have
provided an efficient route for the highly enantioselective syntheses
of 2-substituted piperidines having either absolute configuration.
a Using ligand 9. b Via Negishi cross-coupling. c Major diastereomer
illustrated.
er (entry 8). When CDR using ligand 9 was employed, (S)-14 was
obtained in 59% yield and 96:4 er (entry 9). A similar protocol
using ligand 8 and Negishi coupling with benzyl bromide gave
enantiopure (R)-15 in 65% yield (entry 10).
CDR of rac-2 followed by addition to aldehydes and ketones was
also investigated, and the results are summarized in Table 1, entries
11-14. Not surprisingly,11 the adducts from addition to cyclohexanone,
benzaldehyde, and 1-naphthaldehyde cyclized to oxazolidinones in situ,
the latter two as mixtures of diastereomers. Nevertheless, the config-
uration at the lithium-bearing carbon of 2 was maintained, with all
adducts exhibiting high er’s. Quenching with acetaldehyde provides a
convenient way to prepare the enantiopure alcohol 19 in 78% yield as
a mixture of diastereomers (85:15 dr; entry 14).
When (S)-2 was quenched with propionaldehyde, alcohol 20 was
obtained as a 70:30 mixture of diastereomers, both of which had
96:4 er. Separation of the diastereomers by column chromatography
and hydrolysis of the carbamate from the major diastereomer
afforded the alkaloid (+)-ꢀ-conhydrine (Scheme 2).
Acknowledgment. This work was supported by the Arkansas
Biosciences Institute and the National Science Foundation (CHE
0616352 and 1011788). Core facilities were funded by the National
Institutes of Health (R15569) and the Arkansas Biosciences
Institute. The authors are grateful to Professors Dieter Seebach and
Iain Coldham for helpful discussions.
Supporting Information Available: Full experimental details and
spectroscopic data. This material is available free of charge via the
References
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Scheme 2. Synthesis of (+)-ꢀ-Conhydrinea
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(8) A mechanistic study of the DTR and CDR of rac-2 will be published
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Hydrogenation of (S)-14 and deprotection afforded (S)-(-)-
coniine; Wacker oxidation and deprotection afforded (S)-(+)-
pelletierine (Scheme 3). Cheng and co-workers12 recently prepared
(S)-14 from glutaraldehyde in six steps and showed that (S)-14 can
be readily converted to (-)-lasubine II and (+)-cermizine C via
(S)-(+)-pelletierine.
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