Enantioselective synthesis of a chiral C 3-symmetric bridgehead amine

Article abstract of DOI:10.1021/ol100426m

An efficient enantioselective synthesis of the above C₃- symmetric chiral quinuclidine starting with N-tert-butoxycarbonyl-4-pyridone has been developed.

Full text of DOI:10.1021/ol100426m

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1812-1814
Enantioselective Synthesis of a Chiral
C3-Symmetric Bridgehead Amine
Xuri Gao, Ravi P. Singh, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received February 19, 2010
ABSTRACT
An efficient enantioselective synthesis of the above C3-symmetric chiral quinuclidine starting with N-tert-butoxycarbonyl-4-pyridone has been
developed.
The use of C2-symmetric compounds as chiral reagents or
ligands for metal complexes has had a major impact on the
field of enantioselective synthesis. In contrast, there has been
little attention to C3-symmetric compounds.1,2 We describe
herein an enantioselective route to the C3-symmetric bridge-
head tertiary amine 1 (see below), a hitherto unknown
quinuclidine derivative that is potentially useful for a number
of catalytic enantioselective applications. For instance, as a
quaternary ammonium salt, it could serve as phase transfer
catalyst for enantioselective C-C bond formation by enolate
alkylation, adol reaction or Micheal addition. The possible
effectiveness of this approach is suggested by the mechanistic
model that has been developed for the enantioselective
Figure 1. X-ray crystallographic structure for the salt of the (+)-
enantiomer of 1 with Tf2NH.
reactions catalyzed by N-9-anthracenylmethylcinchona al-
kaloid salts.3
Some time ago we described the synthesis of a related
diphenylquinuclidine 2 by the process summarized in Scheme
1, which utilizes a Diels-Alder reaction to form the
intermediate 3. The enantiomers of the racemic amine 2 were
readily separated by recrystallization of the diastereomeric
salt mixture formed with 1 equiv of (-)-camphor-10-
sulfonic acid.4 An enantioselective synthesis of quinuclidine
2 was not investigated in this earlier work.
We now report an efficient enantioselective synthesis of
1 by the pathway that is outlined in Scheme 2. The
4-piperidone 4 (prepared from 4-hydroxypyridine and (t-
BuOCO)2O in t-BuOH)5 and RhCl(S)-BINAP in THF at
-40 °C were treated with PhZnCl and Me3SiCl, and the
(1) For a review see: Moberg, C. Angew. Chem., Int. Ed. 1998, 37, 248
(2) C3-Symmetric compounds have one three-fold axis of rotation and
no other axis of rotation.
.
(3) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (b) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347. (c) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett.
1999, 40, 3843. (d) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2001, 3, 639. (e)
Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287.
(4) Corey, E. J.; Yuen, P.-W. Tetrahedron Lett. 1988, 30, 5825.
10.1021/ol100426m  2010 American Chemical Society
Published on Web 03/23/2010

Scheme 1
.
Synthesis of Diphenylquinicidine 2
Scheme 2. Synthesis of (-)-Triphenylquinicidine 1
mixture was brought to 0 °C and maintained there for 48 h.
Extractive isolation and chromatography on silica gel (1:2
EtOAc-hexanes) afforded 5 in 91% yield and 98.7% ee.6
Addition of the R,ꢀ-enone 5 in THF to a THF solution of
the reagent from 2 equiv of PhMgBr and 1 equiv of CuI at
0 °C gave after 2 h at 0 °C, extractive isolation, and column
chromatography on silica gel the trans-2,6-diphenyl piperi-
done derivative 6 in 82% yield as a colorless solid, mp
178-179 °C, [R]23 +117 (c 0.70, CHCl3).7 Reaction of
D
phenylethynyl-cerium with 6 at -78 °C provided alcohol 7
in 95% yield as a yellow foam (515 mg, yield 95%) after
silica column chromatographic purification. The alcohol 7
was then treated with a catalytic amount of MoO2(acac)2,
AuCl(PPh3), and AgOTf in toluene at rt for 5 h.8 Extractive
isolation and chromatography on silica gel (1:6 EtOAc-hexanes)
produced the conjugated ketone 8 in 92% yield. Reduction of
8 with NaBH4 in the presence of CoCl2 in methanol at 23 °C
for 20 h afforded the saturated alcohol 9 in 81% yield as a
colorless foam. Treatment of the Boc-protected amino alcohol
9 with 48% hydrobromic acid at 23 °C for 18 h led to amino-
bromide 10 in 88% yield as a mixture of two diastereomers.
Both isomers underwent cyclization by heating with sodium
bicarbonate in toluene at 115 °C for 12 h and then, after addition
of tetrabutyl ammonium iodide, further heating at 115 °C for
6 h to form (-)-1 in 76% yield; colorless solid, mp 208-209
The absolute configuration of 1 obtained by the process
outlined in Scheme 2 follows from the established enantio-
preference in closely related examples.6 The assignment was
confirmed by X-ray crystallographic analysis (see Figure 1).
We have also synthesized the racemate corresponding
to 1 from the previously prepared Diels-Alder adduct
(()-3 (see below and Scheme 1) by the process outlined
in Scheme 3.
°C, [R]23 -437 (c 0.53, CHCl3).
D
(5) Lim, U. H.; Curtis, M. D.; Beak, P. Org. Lett. 2002, 3, 711.
(6) (a) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem.
Soc. 2004, 126, 6240. (b) Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi,
T. Org. Lett. 2005, 7, 5317.
(7) Hamblett, C. L.; Sloman, D. L.; Kliman, L. T.; Adams, B.; Ball,
R. G.; Stanton, M. G. Tetrahderon Lett. 2007, 48, 2079.
(8) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008, 10,
1867.
The enantiomeric forms of 1 are readily separated by
column chromatography on an chiral OD column (Chiral
Technologies) using 98:2 hexanes-i-PrOH for elution. The
Org. Lett., Vol. 12, No. 8, 2010
1813

Scheme 3. Synthesis of (()-Triphenylquinicidine 1
Figure 2. HPLC separation of (()-1.
This general approach described for the enantioselective
synthesis of 1 can be extended to a large number of
analogous C3-symmetric amines, some of which are expected
to be useful for application to catalytic enantioselective
synthesis.
Acknowledgment. We are grateful to Richard Staples,
Patrick B. Morrissey, and Travis Remarchuk (Department
of Chemistry and Chemical Biology, Harvard University)
for the X-ray crystallographic analysis. X.G. is a postdoctoral
fellowship recipient from NSERC of Canada.
results of a typical separation are shown in Figure 2. The
measured optical rotation of 1 were [R]23 -432 ( 5 (c 1,
D
CHCl3) and [R]23 +432 ( 5 (c 1, CHCl3). The dextroro-
D
Supporting Information Available: Detailed experimen-
tal procedures and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
tatory enantiomer was converted to the crystalline 1:1 salt
with triflimide (CF3SO2)2NH. X-ray crystallographic analysis
of salt of dextrorotatory 1 confirmed the structure and
absolute configuration as shown in Figure 1.
OL100426M
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Org. Lett., Vol. 12, No. 8, 2010