Catalytic asymmetric synthesis of piperidines from pyrrolidine: Concisesynthesis of L-733,060

Article abstract of DOI:10.1021/ol900366m

Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of -hydroxy piperidines starting from W-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1 receptor antagonist, (+)-L-733,060.

Full text of DOI:10.1021/ol900366m

ORGANIC
LETTERS
2009
Vol. 11, No. 9
1935-1938
Catalytic Asymmetric Synthesis of
Piperidines from Pyrrolidine: Concise
Synthesis of L-733,060§
Julia L. Bilke,† Stephen P. Moore,† Peter O’Brien,*,† and John Gilday‡
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD, United
Kingdom, and AstraZeneca, Process R & D, AVlon Works, SeVern Road, Hallen,
Bristol, BS10 7ZE, United Kingdom
paob1@york.ac.uk
Received February 19, 2009
ABSTRACT
Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of
ꢀ-hydroxy piperidines starting from N-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1
receptor antagonist, (+)-L-733,060.
Chiral piperidines are widespread in natural products and are
common subunits in pharmaceutical lead compounds. One
important class of biologically active piperidine contains the
ꢀ-hydroxy piperidine motif. Selected examples are (-)-swain-
sonine, an inhibitor of lysosomal R-mannosidase and mannosi-
dase II and a potential anticancer drug,1 (+)-febrifugine, an
antimalarial agent,2 and (+)-L-733,060, a potent and selec-
tive neuronkinin-1 substance P receptor antagonist3 (Figure
1). Although the synthesis of these ꢀ-hydroxy piperidines has
§ Dedicated to Professor R. J. K. Taylor on the occasion of his 60th
birthday.
† University of York.
‡ AstraZeneca.
(1) (a) Liao, Y. F.; Lal, A.; Moremen, K. W. J. Biol. Chem. 1996, 271,
28348. (b) Elbein, A. D.; Solf, R.; Dorling, P. R.; Vosbeck, K. Proc. Natl.
Acad. Sci. U.S.A. 1981, 78, 7393. (c) Goss, P. E.; Baker, M. A.; Carver,
J. P.; Dennis, J. W. Clin. Cancer. Res. 1995, 1, 935.
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T. C. Science 1946, 103, 59. (b) Chou, T.-Q.; Fu, F. Y.; Kao, Y. S. J. Am.
Chem. Soc. 1948, 70, 1765. (c) Frederick, A. K.; Spencer, C. F.; Folkers,
K. J. Am. Chem. Soc. 1948, 70, 2091.
Figure 1. Biologically active ꢀ-hydroxy piperidines.
attracted recent attention,4-6 many of the synthetic approaches
are lengthy and not sufficiently flexible to allow stereose-
lective access to the different enantiomeric and diastereo-
meric structures required. To address this, we have developed
a new and general strategy for the stereoselective synthesis
of each stereoisomer of chiral ꢀ-hydroxy piperidines.
(3) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545.
(4) For the most recent syntheses of (-)-swainsonine, see: (a) Shi, G.-
F.; Li, J.-Q.; Jiang, X.-P.; Cheng, Y. Tetrahedron 2008, 64, 5005. (b)
Sharma, P. K.; Shah, R. N.; Carver, J. P. Org. Process Res DeV. 2008, 12,
831. (c) Guo, H.; O’Doherty, G. Tetrahedron 2008, 64, 304. (d) De´champs,
I.; Gomez Pardo, D.; Cossy, J. Tetrahedron 2007, 63, 9082. (e) Ceccon, J.;
Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 4739.
10.1021/ol900366m CCC: $40.75
Published on Web 04/01/2009
 2009 American Chemical Society

strategy for the synthesis of ꢀ-hydroxy piperidines 4 and a
transmetalation approach to allow selective access to each
diastereomer. Ultimately, we exemplify our methodology
with a five-step catalytic asymmetric synthesis of (+)-L-
733,060, which is half the length of the previous syntheses.6
We have previously reported a catalytic asymmetric protocol
for the Beak-style11 deprotonation of N-Boc pyrrolidine 1 using
s-BuLi in tandem with 0.1-0.3 equiv of (-)-sparteine.12 The
approach is only successful if a stoichiometric amount of an
additive is included to recycle and turnover the (-)-sparteine.
The optimum additive, a bis-i-Pr-bispidine, is not commercially
available and cannot be separated from the chiral ligand after
use (thus precluding reuse of the chiral ligand). To address these
two important limitations, we screened a range of commercially
available additives and ultimately discovered that lithiated
dimethylaminoethanol (LiDMAE13) worked well. Thus, lithia-
tion of N-Boc pyrrolidine 1 using 1.6 equiv of s-BuLi, 0.3 equiv
of (-)-sparteine and 1.3 equiv of LiDMAE (formed in situ by
lithiation of DMAE using an extra equivalent of s-BuLi) and
subsequent reaction with Me3SiCl delivered a 66% yield of
adduct (S)-5 of 88:12 er (Scheme 2). Notably, the (-)-sparteine
Scheme 1
Our approach to ꢀ-hydroxy piperidines 4 (Scheme 1)
comprises two key steps: (i) catalytic asymmetric deprotonation
of N-Boc pyrrolidine 1 using s-BuLi and substoichiometric
amounts of (-)-sparteine (in the presence of a stoichiometric
achiral additive) and subsequent trapping with an aldehyde to
give amino alcohols 2; (ii) ring expansion of amino alcohols 2
to the corresponding ꢀ-hydroxy piperidines 4 via formation and
ring-opening of an intermediate aziridinium ion 3 (R2 )
alkyl).7-9 Scheme 1 depicts the synthesis of ꢀ-hydroxy
piperidines 4 with (2S,3S) stereochemistry; other stereoiso-
mers of 4 would be available by changing the chiral ligand
(e.g., to a (+)-sparteine surrogate10) and/or the diastereose-
lectivity of the addition to the aldehyde. In this paper, we
report a new method for the catalytic asymmetric deproto-
nation step using a commercially available achiral additive,
implementation of the deprotonation-trapping-ring expansion
Scheme 2
(5) For syntheses of (+)-febrifugine, see: (a) Sieng, B.; Lozano Ventura,
O.; Bellosta, V.; Cossy, J. Synlett 2008, 1216. (b) Ashoorzadeh, A.; Caprio,
V. Synlett 2005, 346. (c) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T.
Tetrahedron Lett. 2004, 45, 6221. (d) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-
P. Synlett 2003, 1663. (e) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi,
Y.; Hatakeyama, S. Org. Lett. 2001, 3, 953. (f) Taniguchi, T.; Ogasawara,
K. Org. Lett. 2000, 2, 3193. (g) Takeuchi, Y.; Azuma, K.; Takakura, K.;
Abe, H.; Harayama, T. Chem. Commun. 2000, 1643. (h) Kobayashi, S.;
can be easily separated from the DMAE since the DMAE can
be extracted into NaOH(aq).
14 This means that the chiral ligand
Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett. 1999, 40, 2175
.
(6) For syntheses of (+)-L-733,060, see: (a) Liu, R.-H.; Fang, K.; Wang,
B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem. 2008, 73, 3307. (b) Emmanuvel,
L.; Sudalai, A. Tetrahedron Lett. 2008, 49, 5736. (c) Cherian, S. K.; Kumar,
P. Tetrahedron: Asymmetry 2007, 18, 982. (d) Oshitari, T.; Mandai, T.
Synlett 2006, 3395. (e) Kandula, S. R. V.; Kumar, P. Tetrahedron:
Asymmetry 2005, 16, 3579. (f) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim,
Y.-H.; Oh, C.-Y.; Ham, W.-H. Tetrahedron Lett. 2005, 46, 739. (g) Huang,
P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927. (h)
Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915. For synthesis of
(-)-L-733,060, see: (i) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron
can be recovered and reused.
We verified that it is necessary to have both the lithium
alkoxide and the dimethlyamino group in the additive: use of
lithium ethoxide gave (S)-5 in 90:10 er but in only 33% yield,
indicating that there was no turnover of (-)-sparteine and use
of N,N-dimethyl-2-methoxyethylamine gave rac-5 (74% yield),
reflecting a fast background deprotonation by the s-BuLi/amino
ether complex (Scheme 2). Next, with a view to optimizing
Lett. 2005, 46, 8927
(7) Fuson, R. C.; Zirkle, C. L. J. Am. Chem. Soc. 1948, 70, 2760
(8) Cossy, J.; Dumas, C.; Michel, P.; Gomez Pardo, D. Tetrahedron
Lett. 1995, 36, 549
.
.
.
(11) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
(9) For selected examples, see: (a) Calvez, O.; Chiaroni, A.; Langlois,
N. Tetrahedron Lett. 1998, 39, 9447. (b) Cossy, J.; Dumas, C.; Gomez
Pardo, D. Eur. J. Org. Chem. 1999, 1693. (c) Cossy, J.; Mirguet, O.; Gomez
Pardo, D.; Desmurs, J.-R. Tetrahedron Lett. 2001, 42, 5705. (d) Lee, J.;
Hoang, T.; Lewis, S.; Weissm an, S. A.; Askin, D.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 2001, 42, 6223. (e) Dechamps, I.; Gomez Pardo,
D.; Cossy, J. Synlett 2007, 263. (f) Drouillat, B.; Couty, F.; David, O.;
Evano, G.; Marrot, J. Synlett 2008, 1345. (g) Durrat, F; Vargas Sanchez,
(12) (a) McGrath, M. J.; O’Brien, P. J. Am. Chem. Soc. 2005, 127,
16378. (b) McGrath, M. J.; Bilke, J. L.; O’Brien, P. Chem. Commun. 2006,
2607. (c) Bilke, J. L.; O’Brien, P. J. Org. Chem. 2008, 73, 6452.
(13) For selected examples on the use of n-BuLi/LiDMAE in pyridine
lithiation, see: (a) Gros, P.; Fort, Y.; Queguiner, G.; Caube`re, P. Tetrahedron
Lett. 1995, 36, 4791. (b) Gros, P.; Fort, Y.; Caube`re, P. J. Chem. Soc.,
Perkin Trans. 1 1997, 3071. (c) Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002,
3375. (d) Gros, P. C.; Doudouh, A.; Woltermann, C. Chem. Commun. 2006,
2673.
M.; Couty, F.; Evano, G.; Marrot, J. Eur. J. Org. Chem. 2008, 3286
.
(10) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P.
J. Am. Chem. Soc. 2002, 124, 11870. (b) Dearden, M. J.; McGrath, M. J.;
O’Brien, P. J. Org. Chem. 2004, 69, 5789. (c) Dixon, A. J.; McGrath, M. J.;
O’Brien, P. Org. Synth. 2006, 83, 141. (d) O’Brien, P. Chem. Commun.
2008, 655.
(14) A solution of (-)-sparteine (10.0 mmol) and DMAE (33.3 mmol)
in Et2O (35 mL) was washed with 20% w/v NaOH(aq) solution (6 × 50
mL). Then, the Et2O layer was dried (Na2SO4) and evaporated under reduced
pressure to give pure (-)-sparteine (1H NMR spectroscopy).
1936
Org. Lett., Vol. 11, No. 9, 2009

surrogate 7 gave (R)-5 in 92:8 er (entry 12). We believe that
the success of the catalytic asymmetric deprotonation using
LiDMAE results from a negligible background rate of depro-
tonation by s-BuLi/LiDMAE (entry 1) and a ligand exchange
process (where the LiDMAE can displace the chiral ligand from
the lithiated N-Boc pyrrolidine to allow recycling of the chiral
ligand).
With an efficient catalytic asymmetric deprotonation protocol
in place, our attention then focused on the stereoselectivity of
the addition of the organolithium to the aldehyde16 and
subsequent ring expansion to the piperidines. Our intention was
to identify a simple way of accessing each diastereomeric
hydroxy piperidine and, for the initial studies, we used sto-
ichiometric s-BuLi and (-)-sparteine for the deprotonation of
N-Boc pyrrolidine 1. Direct trapping of the lithiated N-Boc
pyrrolidine with benzaldehyde was syn-selective, delivering a
75:25 mixture of alcohols syn- and anti-8 from which the major
diastereomer, syn-8 (95:5 er), was obtained in 74% yield after
chromatography (Scheme 3). The relative stereochemistry was
assigned by X-ray crystallography of alcohol anti-8.17
Figure 2. Chiral diamines.
the catalytic deprotonation conditions, we varied the stoichi-
ometry of the chiral ligand/LiDMAE and investigated the use
of other chiral ligands ((-)-sparteine surrogate 615 and (+)-
sparteine surrogate 7,10 Figure 2) (Table 1 and Scheme 2).
Table 1. Optimisation of the Catalytic Asymmetric
Deprotonation Using Lithiated Dimethylaminoethanol
(LiDMAE) for the Conversion of N-Boc Pyrrolidine 1 into
Adduct (S)- or (R)-5
equiva
s-BuLi
equiv chiral
ligand
equivb
Li DMAE
yield
(%)c
erd
S:R
Scheme 3
entry
1
2
3
4
5
6
7
8
1.3
2.6
1.6
1.6
1.6
1.4
1.4
1.3
1.3
1.25
1.3
1.3
0
1.3
1.3
1.3
1.3
1.3
1.2
1.2
1.2
1.2
1.2
1.0
1.0
4
62
66
60
70
53
74
58
43
36
58
74
-
98:2
88:12
93:7
11:89
88:12
13:87
88:12
2:98
77:23
97:3
8:92
1.3, (-)-sp
0.3, (-)-sp
0.3, 6
0.3, 7
0.2, (-)-sp
0.2,7
0.1, (-)-sp
0.1, 7
0.05, (-)-sp
0.3, (-)-sp
0.3, 7
9
10
11
12
a Amount of s-BuLi available after formation of LiDMAE. b Amount
of LiDMAE formed by premixing DMAE and s-BuLi. c Yield of adduct 5
after purification by column chromatography. d Er determined using chiral
GC.
We reasoned that different stereoselectivity could be obtained
using other metalated N-Boc pyrrolidines. Indeed, transmeta-
lation of lithiated N-Boc pyrrolidine to the corresponding
Grignard reagent using MgBr218,19 and then addition to
benzaldehyde gave a reversal in stereoselectivity: a 70:30
mixture of anti- and syn-8 was formed. In this way, alcohol
anti-8 (96:4 er) was obtained in 56% yield (Scheme 3). It is
notable that there is no loss of er during the transmetalation
of Li to Mg despite the fact that the reaction mixture was
stirred at 0 °C for 30 min. Clearly, the Grignard reagent has
a significantly higher barrier to enantiomerization than the
corresponding organolithium reagent.20,21
First, we showed that there was no appreciable background
deprotonation of N-Boc pyrrolidine 1 using s-BuLi in the
presence of LiDMAE: a 4% yield of rac-5 was obtained (entry
1). We also showed that lithiation using s-BuLi/(-)-sparteine
and stoichiometric LiDMAE gave adduct (S)-5 in high enan-
tioselectivity (62% yield, 98:2 er, entry 2). Use of 0.3, 0.2, or
0.1 equiv of (-)-sparteine all gave 88:12 er (entries 3, 6 and 8)
but use of 0.05 equiv of (-)-sparteine led to poor turnover (36%
yield) and lower enantioselectivity (77:23 er) (entry 10). Using
0.3 equiv of (-)-sparteine surrogate 6 worked especially well:
(S)-5 of 93:7 er was produced in 70% yield (entry 4). The
opposite enantiomeric series could be accessed with similar
enantioselectivity (87:13-92:8 er) using the (+)-sparteine
surrogate 7 (entries 5, 7 and 9). Finally, our optimum lithiation
conditions involved using 1.3 equiv of s-BuLi, 0.3 equiv of
chiral ligand and 1.0 equiv of LiDMAE: use of (-)-sparteine
gave (S)-5 in 97:3 er (entry 11) whereas use of (+)-sparteine
Although the ring expansion of a 2-chloromethylpyrrolidine
to a 3-chloropiperidine was first described by Fuson and Zirkle
(16) We are aware of only one example of the addition of a lithiated
N-Boc pyrrolidine to an aldehyde: Majewski, M.; Shao, J.; Nelson, K.;
Nowak, P.; Irvine, N. M. Tetrahedron Lett. 1998, 39, 6787.
(17) CCDC 696161 (anti-8) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre at http://www.ccdc.cam.ac.uk/
data_request/cif.
(18) Kise, N.; Urai, T.; Yoshida, J.-i. Tetrahedron: Asymmetry 1998, 9,
3125
.
(19) Zhang, P.; Gawley, R. E. Tetrahedron Lett. 1992, 33, 2945
(20) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716
.
(15) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
Org. Lett., Vol. 11, No. 9, 2009
.
1937

in 1948,7 it was not until 1995 that Cossy reported a useful
method for converting 2-hydroxymethyl pyrrolidines into ꢀ-hy-
droxy piperidines;8 subsequently, a range of synthetic applica-
tions have appeared.4d,9 Such a ring expansion is only possible
if the nitrogen lone pair is available to participate in
aziridinium ion formation. As a result, we needed to
transform the N-Boc group into an N-alkyl substituent. This
was readily achieved by treating alcohols syn-8 and anti-8
with TFA and then benzyl bromide to give syn-9 and anti-9
(Scheme 4). Cossy’s conditions for ring expansion
Scheme 5
Scheme 4
((CF3CO)2O, THF, Et3N, reflux, 48 h and then base-mediated
ester hydrolysis) were successful with both syn- and anti-9
giving piperidines syn-10 (84% yield) and anti-10 (96%
yield) respectively (Scheme 4). The high yield obtained for
both of these reactions is notable since it has previously been
reported that the N-Me version of syn-9 did not undergo the
ring expansion.9b
Finally, to validate the synthetic utility of the deprotonation-
trapping-ring expansion methodology, we chose (+)-L-733,060
as a suitable target since it has important biological activity and
previous syntheses are g10 steps.6 First, we carried out the
catalytic asymmetric deprotonation of N-Boc pyrrolidine 1 using
the optimized conditions (1.3 equiv of s-BuLi, 0.3 equiv of (-)-
sparteine and 1.0 equiv of LiDMAE) and then trapped the
organolithium reagent with benzaldehyde. The stereoselectivity
(syn:anti ) 75:25) was the same as the stoichiometric version
and, after chromatography, alcohol syn-8 of 90:10 er was
obtained in 64% yield; alcohol anti-8 (25% yield, 89:11 er)
was also isolated (Scheme 5).
Alcohol syn-8 was converted into N-allylated alcohol syn-
11 (58% yield) via Boc deprotection and allylation (Scheme 5)
since we needed an N-alkyl protecting group that could be
cleaved in the presence of the benzylic ether present in (+)-
L-733,060. Then, alcohol syn-11 was ring-expanded (using
(CF3CO)2O and subsequent base-mediated ester hydrolysis) to
piperidine syn-14 (83% yield). The remaining two steps
proceeded uneventfully and in high yield. O-Benzylation of syn-
12 was achieved by NaH deprotonation and alkylation with
functionalized benzyl bromide 13. Finally, treatment of syn-14
with Pd(0) and N,N′-dimethylbarbituric acid led to smooth
N-deallylation to give (+)-L-733,060 of 90:10 er (by chiral shift
NMR spectroscopy in the presence of (R)-2,2,2-trifluoro-1-(9-
anthryl)ethanol) which exhibited [R]D +55.0 (c 1.0 in CHCl3)
[lit.,6a [R]D +73.9 (c 0.64 in CHCl3)]. Our synthesis of (+)-
L-733,060 is five steps and proceeds in 30% overall yield,
making it the shortest synthesis to date.
In summary, we report a new two-ligand catalytic asymmetric
deprotonation of N-Boc pyrrolidine 1 utilizing a stoichiometric
additive that is commercially available and can be separated
from the chiral ligand. This protocol is combined with aldehyde
trapping and pyrrolidine f piperidine ring expansion to
selectively deliver chiral ꢀ-hydroxy piperidines such as syn-10
or anti-10 in just four steps. Either enantiomer of these
compounds can be accessed using (-)-sparteine or (+)-sparteine
surrogate 7 in the deprotonation step. The methodology provides
a concise entry to ꢀ-hydroxy piperidines as illustrated with a
five-step synthesis of (+)-L-733,060.
Acknowledgment. We thank The Leverhulme Trust, EPSRC
and AstraZeneca for funding, Graeme Barker (University of
York) for some data and Dr Adrian C. Whitwood (University
of York) for X-ray crystallography.
Supporting Information Available: Full experimental
1
procedures, characterization data and copies of H NMR and
13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(21) For a similar effect with O-alkyl carbamates, see: Tomooka, K.;
Shimizu, H.; Nakai, T. J. Organomet. Chem. 2001, 624, 364.
OL900366M
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Org. Lett., Vol. 11, No. 9, 2009