Diastereoselective synthesis of functionally diverse substituted pipecolic acids

Article abstract of DOI:10.1055/s-0028-1087477

The synthesis of cis-4-substituted pipecolic acids, 4,5-disubstituted pipecolic acids, and their 6-oxo analogues starting from enantiopure L-aspartic acid is reported. The synthetic strategy involves as key steps, Suzuki-Miyaura and related Pd-mediated co

Full text of DOI:10.1055/s-0028-1087477

LETTER
71
Diastereoselective Synthesis of Functionally Diverse Substituted Pipecolic
Acids
Synthesis of
F
t
unction
e
a
lly
D
iver
s
p
e
Substitute
d
h
Pipecolic
A
e
cids n Hanessian,* Ludivine Riber, Julien Marin
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
E-mail: stephen.hanessian@umontreal.ca
Received 23 September 2008
Treatment of BocO-tert-butyl L-aspartate with Meldrum’s
acid according to Marin10e and Murray11 followed by cy-
clization and decarboxylation, afforded the 4-oxo deriva-
tive 1 in 77% yield over two steps (Scheme 1).
Abstract: The synthesis of cis-4-substituted pipecolic acids, 4,5-
disubstituted pipecolic acids, and their 6-oxo analogues starting
from enantiopure L-aspartic acid is reported. The synthetic strategy
involves as key steps, Suzuki–Miyaura and related Pd-mediated
couplings, followed by a catalytic hydrogenation with excellent Conversion into the enol triflate 2 allowed the application
of the Suzuki–Miyaura reaction,12 and to functionalize at
yields and diastereoselectivities. Enolate alkylations provide 4,5-
trans-oriented functionalization.
C-4 giving the corresponding 4-substituted 4,5-unsatu-
Key words: Suzuki–Miyaura coupling, lactam enolate alkylations,
arylpiperidine, piperidinone, pipecolic acid
rated-6-oxopipecolic acid Boc-t-Bu esters 3a–l
(Table 1).13,14 Aryl, olefinic, and heteroaryl boronic acids
(Table 1, entries 1–9, 12–14) were found to be excellent
reacting partners to 2. Pyridyl or 2-thiophenyl boronic ac-
Pipecolic acids are important components of a number of ids led to lower yields for 3j and 3k (entries 10 and 11).
natural products as peptidic subunits,1 or as embedded While to our best knowledge, no Suzuki reactions have
substructures.2 Many applications in medicinal chemistry been tested on an enol triflate of a b-dicarbonyl substrate
based on the inclusion of pipecolic acids and their deriva- such as 2 with a 3-pyridyl boronic acid or boronate, 2-
tives have been reported.3 Substituted piperidines, and in thienyl boronic acid is known to give lower yields with
particular 4-arylpiperidines, have been extensively used phenolic triflates.15
as components of enzyme inhibitors such as paroxetine,4
Suzuki–Miyaura coupling for the methyl 3o compound
also gave a lower yield. This corroborates previous obser-
vations with alkylboronic species where better yields
as inhibitors of human dopamine transporter,5 as DPP4 in-
hibitors,6 or as CCR2 antagonists.7
Although the literature abounds with methods for the syn- were achieved by the use of reactants such as 40 mol% of
thesis of substituted piperidines8 and pipecolic acids9 in triphenylarsine.16 The low reactivity is explained by a dif-
enantiomerically pure form, relatively few methods are ficult transmetalation step between the organoboron spe-
available for derivatives of 6-oxopipecolic acids such as 4 cies and the Pd intermediate.17 The use of the more
(Scheme 1).10 In this paper we report on a practical syn- nucleophilic potassium methyltrifluoroborate according
thesis of enantiopure substituted pipecolic acids and their to Molander18 with PdCl2(dppf·CH2Cl2)2 improved the
6-oxo analogues starting from the readily available L-as- yield only moderately up to 40% (Scheme 2).
partic acid.
Catalytic hydrogenation in the presence of Pd/C was high-
ly selective due to the presence of the bulky ester group,
OTf
O
N
NHBoc
CO2t-Bu
a
Ref. 10e
HO2C
(77%, 2 steps)
O
N
CO2t-Bu
O
CO2t-Bu
Boc
Boc
1
2
R
R
b
c
O
N
CO2t-Bu
O
N
CO2t-Bu
Boc
Boc
3a–l
4a–l
Scheme 1 Reagents and conditions: a) DIPEA, Tf2O, CH2Cl2, 0 °C, 30 min; b) PdCl2(PPh3)4, 2 M Na2CO3, R1B(OR2)2, THF, 40 °C 16 h (see
Table 1).
SYNLETT 2009, No. 1, pp 0071–0074
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087477; Art ID: S09008ST
© Georg Thieme Verlag Stuttgart · New York

72
S. Hanessian et al.
LETTER
Me
Me
OTf
NHAc
b
a
c
O
N
CO2t-Bu
O
N
CO2t-Bu
O
N
CO2t-Bu
O
N
CO2t-Bu
Boc
4o
Boc
3o
Boc
2
Boc
3p
Scheme 2 Reagents and conditions: a) PdCl2(PPh3)2, 2 M Na2CO3, MeB(OH)2, THF, 40 °C, 16 h, 31%, (40% with MeBF3K); b) H2, Pd/C,
EtOAc, 16 h, 69%, de >99%; c) Pd2(dba)3, Cs2CO3, AcNH2, Xantphos, dioxane, 40 °C, 16 h, 44%.
affording the cis-substituted products 4a,b,k,o as con- yield (Scheme 2). To the best of our knowledge, a cou-
firmed by X-ray structural analysis of 4a (Figure 1).14 pling between an enol triflate and an acetamide has not
However, over-reductions occurred for the heteroaryls 4i been described with a 6-oxopipecolic acid core.
and 4j giving inseparable mixtures (Table 1).
The attempted reductive amination of 1 with benzylamine
Other types of functionalizations were also possible with and p-anisidine in the presence of NaBH4·NiCl2,
the triflate intermediate 2. Thus, treatment with acetamide NaBH(OAc)3, NaBH3CN, or under high pressure hydro-
in the presence of Pd2(dba)3 according to Buchwald19 or genation (80 psi) afforded instead the 4-enamino ana-
Wallace,20 gave the 4-acetamido analogue 3p in 44%
Table 1 Synthesis of 4-Substituted 4,5-Unsaturated 6-Oxopipecolic Acid Boc-t-Bu Esters 3a–l and Reduction to Compounds 4a–l
R1
OTf
R1
a
b
O
N
CO2t-Bu
O
N
CO2t-Bu
O
N
CO2t-Bu
Boc
2
Boc
4a–l
Boc
3a–l
a) PdCl2(PPh3)4, 2 M Na2CO3, R1B(OR2)2, THF, 40 °C 16 h
b) H2, Pd/C, EtOAc, 2 h
Entry
1
Aryl
Compound
Yield (%)
90
Compound
Yield (%)a
>98
90
Ph
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
2
4-MeOC6H4
3-MeOC6H4
p-tolyl
91
3
82
94
4
84
93
5
3-CHOC6H4
4-FC6H4
3-NO2C6H4
3-CNC6H4
2-furyl
82
90c
6
89
>98
>98
86
7
3g
3h
3i
90
8
93
d
9
86
–
d
10
11
12
13
14
15
3-pyridyl
2-thiophene
vinyl
3j
58
4j
4k
–
–
3k
3l
40
40
–
92
trans-styryl
allyl
3m
3n
3ob
84
–
–
63
–
–
Me
31
4o
69
a In all cases de >98% as determined by 1H NMR at 400 MHz, see ref. 13, 14.
b See Scheme 2.
c Yield of alcohol.
d Inseparable mixture of partially saturated products.
Synlett 2009, No. 1, 71–74 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionally Diverse Substituted Pipecolic Acids
73
In summary, we have reported practical methods to access
2,4-cis-substituted 6-oxo-pipecolic acids in enantiopure
form from a common and readily available precursor Boc-
Asp-Ot-Bu. These functionalized intermediates are useful
scaffolds to access a variety of more complex monocyclic
and polycyclic compounds of relevance in medicinal
chemistry and in natural product synthesis.23
Acknowledgment
The authors wish to thank NSERC and FQRNT for financial assi-
stance and Dr. Michel Simard for X-ray analysis.
References and Notes
(1) See, for example: (a) Rapamycin: Vézina, C.; Kudelski, A.;
Sehgal, S. N. J. Antibiotics 1975, 28, 721. (b) Swindells, D.
C. N.; White, P. S.; Findlay, J. A. Can. J. Chem. 1978, 56,
2491. (c) Findlay, J. A.; Radics, L. Can. J. Chem. 1981, 59,
49. (d) McAlpine, J. B.; Swanson, S. J.; Jackson, M.;
Whittern, D. N. J. Antibiotics 1991, 44, C-3.
Figure 1 ORTEP of 4a
O
NHR
a
(e) Tetrazomine: Scott, J. D.; Tippie, T. N.; Williams, R. M.
Tetrahedron Lett. 1998, 39, 3659. (f) Homophymine A:
Zampella, A.; Sepe, V.; Luciano, P.; Bellotta, F.; Monti,
M. C.; D’Auria, M. V.; Jepsen, T.; Petek, S.; Adeline, M.-T.;
Laprévôte, O.; Aubertin, A.-M.; Debitus, C.; Poupat, C.;
Ahond, A. J. Org. Chem. 2008, 73, 5319.
O
N
CO2t-Bu
O
N
CO2t-Bu
Boc
1
Boc
3q: R = Bn, 48%
3r: R = 4-MeOC6H4, 46%
Scheme 3 Reagents and conditions: a) benzylamine or anisidine,
MS, CH2Cl2, r.t., 1 h.
(2) See, for example: (a) Mersinines A and B: Kam, T.-S.;
Subramaniam, G.; Lim, T.-M. Tetrahedron Lett. 2001, 42,
5977. (b) Sanguinones: Peters, S.; Spiteller, P. J. Nat. Prod.
2007, 70, 1274. (c) Bipleiophylline: Kam T.-S., Tan S.-J.,
Ng S.-W., Komiyama K.; Org. Lett.; 2008, in press
logues 3q and 3r in modest yields (48% and 46%,
respectively; Scheme 3).
(3) (a) For argatroban, see: Okamoto, S.; Hijikata, A.;
Kikumoto, R.; Tonomura, S.; Hara, H.; Ninomiya, K.;
Maruyama, A.; Sugano, M.; Tamao, Y. Biochem. Biophys.
Res. Commun. 1981, 101, 440. (b) For other examples of
inhibitors see: For palinavir, see for example: Beaulieu, P.
L.; Lavallée, P.; Abraham, A.; Anderson, P. C.; Boucher, C.;
Bousquet, Y.; Duceppe, J. S.; Gillard, J.; Gorys, V.; Grand-
Maitre, C.; Grenier, L.; Guindon, Y.; Guse, I.; Plamondon,
L.; Soucy, F.; Valois, S.; Wernic, D.; Yoakim, C. J. Org.
Chem. 1997, 62, 3440. (c) Trujillo, J. I.; Meyers, M. J.;
Anderson, D. R.; Hegde, S.; Mahoney, M. W.; Vernier,
W. F.; Buchler, I. P.; Wu, K. K.; Yang, S.; Hartmann, S. J.;
Reitz, D. B. Bioorg. Med. Chem. Lett. 2007, 17, 4657.
(d) Yao, W.; Zhuo, J.; Burns, D. M.; Xu, M.; Zhang, C.; Li,
Y. L.; Qian, D. Q.; He, C.; Weng, L.; Shi, E.; Lin, Q.; Agrios,
C.; Burn, T. C.; Caulder, E.; Covington, M. B.; Fridman,
Enolate alkylations were also possible for the representa-
tive products 4a and 4c (Scheme 4).
Thus, treatment of the lithium enolate with electrophiles
such as allyl iodide and m-methoxybenzyl bromide gave,
as expected, the anti adducts 5–7 with excellent diastereo-
selectivities.21 Decarbonylation of the 4-aryl analogues
4a, 4b, and 4d was achieved by reduction with BH3·SMe2
to give the 4-aryl pipecolic esters 8–10.22 Simultaneous
deprotection of the N-Boc amine and tert-butyl ester was
achieved under acidic conditions to afford the hydrochlo-
ride salts 11 and 12 with excellent yields.
R1
R1
R1
R1
a
c
b
R2
N
CO2t-Bu
N
CO2H
O
N
CO2t-Bu
O
N
CO2t-Bu
H•HCl
Boc
Boc
Boc
4a–d
5: R1 = H; R2 = H2C=CH, 77%
8: R1 = H, 93%
11: R1 = H, >99%
6: R1 = H; R2 = 3-MeOC6H4, 79%
7: R1 = 3-MeO; R2 = H2C=CH, 81%
9: R1 = 4-MeO, 52%
10: R1 = Me, 57%
12: R1 = 4-MeO, 96%
Scheme 4 Reagents and conditions: a) LiHMDS, THF, –78 °C, 1 h then allyl iodide or 3-methoxybenzylbromide, –78 °C, 2 h; b) BH3·SMe2,
THF, 0 °C then r.t., 16 h; c) HCl 6 M in MeOH, r.t., 3 h.
Synlett 2009, No. 1, 71–74 © Thieme Stuttgart · New York

74
S. Hanessian et al.
LETTER
over Na2SO4. After filtration, the solvent was evaporated
J. S.; Friedman, S.; Katiyar, K.; Hollis, G.; Li, Y.; Liu, C.;
Liu, X.; Marando, C. A.; Newton, R.; Pan, M.; Scherle, P.;
Taylor, N.; Vaddi, K.; Wasserman, Z. R.; Wynn, R.;
Yeleswaram, S.; Jalluri, R.; Bower, M.; Zhou, B. B.;
Metcalf, B. J. Med. Chem. 2007, 50, 603.
under reduced pressure. The resulting residue was purified
by flash chromatography (generally hexane–EtOAc, 8:2).
(14) Data for Selected Compound: (2S,4S)-Di-tert-butyl
6-Oxo-4-phenylpiperidine-1,2-dicarboxylate (4a)
From 3a (119 mg, 0.32 mmol) was obtained 4a as a white
solid (120 mg, 100%); [a]D –28.6 (c 1.04, CHCl3); mp
142.5–147.5 °C. IR (KBr): 2982, 2934, 1731, 1703, 1605,
1495, 1473, 1459, 1392, 1365, 1283, 1270, 1237, 1153,
1135, 1099, 1042, 1029, 1015 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.37 (t, 2 H, J = 7.2 Hz), 7.29 (t, 1 H, J = 7.4
Hz), 7.21 (d, 2 H, J = 7.2 Hz), 4.60 (dd, 1 H, J = 10.0, 6.6
Hz), 3.17–3.08 (m, 1 H), 2.85–2.79 (m, 1 H), 2.64 (dd, 1 H,
J = 16.8, 13.0 Hz), 2.59–2.52 (m, 1 H), 2.03–1.94 (m, 1 H),
1.56 (s, 9 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 170.2, 169.6, 152.1, 141.7, 128.6, 126.9, 126.1,
83.4, 81.9, 58.7, 41.5, 36.7, 33.4, 27.5 ppm. HRMS: m/z
calcd for C21H29NO5: 398.20457; found: 398.19487 [M +
Na]+.
(15) (a) Knor, S.; Laufer, B.; Kessler, H. J. Org. Chem. 2006, 71,
5625. (b) Torrado, M.; Masaguer, C. F.; Raviña, E.
Tetrahedron Lett. 2007, 48, 323.
(16) Mu, Y.; Gibbs, R. A. Tetrahedron Lett. 1995, 36, 5669.
(17) Molander, G. A.; Yun, C.-S. Tetrahedron 2002, 58, 1465.
(18) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
(19) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
(20) Wallace, D. J.; Klauber, D. J.; Chen, C. Y.; Volante, R. P.
Org. Lett. 2003, 5, 4749.
(21) Data for Selected Compound: (2S,4S,5R)-Di-tert-butyl
5-Allyl-6-oxo-4-phenylpiperidine-1,2-dicarboxylate (5)
From 4a (1.06 g, 2.82 mmol) was obtained 5 as a white solid
(904 mg, 77%); [a]D –133.1 (c 1.41, CHCl3); mp 115–
117 °C. IR (KBr): 2980, 1728, 1707, 1457, 1366, 1283,
1248, 1225, 1145, 1028 cm–1. 1H NMR (300 MHz, CDCl3):
d = 7.36–7.28 (m, 2 H), 7.28–7.20 (m, 1 H), 7.18–7.08 (m,
2 H), 5.70 (dddd, 1 H, J = 17.0, 10.1, 8.6, 5.7 Hz), 4.97 (d,
1 H, J = 10.1 Hz), 4.85 (d, 1 H, J = 17.1 Hz), 4.47 (dd, 1 H,
J = 10.3, 6.2 Hz), 2.92 (dt, 1 H, J = 11.8, 11.8, 3.9 Hz), 2.73
(td, 1 H, J = 11.9, 4.5, 4.5 Hz), 2.66–2.51 (m, 1 H), 2.38
(ddd, 1 H, J = 13.7, 6.1, 4.0 Hz), 2.06–1.93 (m, 2 H), 1.51 (s,
9 H), 1.42 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): d =
171.8, 170.1, 152.3, 141.3, 134.0, 128.4, 126.9, 126.7,
117.4, 83.0, 81.6, 58.4, 49.0, 40.5, 33.5, 32.3, 27.4, 27.4
ppm. HRMS: m/z calcd for C24H33NO5: 438.23587; found:
438.22464 [M + Na]+.
(4) For selected references, see: (a) Barnes, R. D.; Wood-
Kaczmar, M. W.; Curzons, A. D.; Lynch, I. R.; Richardson,
J. E.; Buxton, P. C. US 24721723, 1986. (b) Murthy,
K. S. K.; Rey, A. W.; Tjepkema, M. Tetrahedron Lett. 2003,
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C. Jr.; Mák, M. Eur. J. Org. Chem. 2004, 3336.
(d) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.;
Jørgensen, K. A. Angew. Chem. Int. Ed. 2006, 45, 4305.
(e) Bower, J. F.; Riis-Johannessen, T.; Szeto, P.; Whitehead,
A. J.; Gallagher, T. Chem. Commun. 2007, 728.
(5) Feng, X.; Fandrick, K.; Johnson, R.; Janowsky, A.;
Cashman, J. R. Bioorg. Med. Chem. 2003, 11, 775.
(6) Pei, Z.; Li, X.; vonGeldern, T. W.; Longenecker, K.; Pireh,
D.; Stewart, K. D.; Backes, B. J.; Lai, C.; Lubben, T. H.;
Ballaron, S. J.; Beno, D. W. A.; Kempf-Grote, A. J.; Sham,
H. L.; Trevillyan, J. M. J. Med. Chem. 2007, 50, 1983.
(7) Xia, M.; Hou, C.; Pollack, S.; Brackley, J.; DeMong, D.;
Pan, M.; Singer, M.; Matheis, M.; Olini, G.; Cavender, D.;
Wachter, M. Bioorg. Med. Chem. Lett. 2007, 17, 5964; and
references cited therein.
(8) See, for example: (a) Bailey, P. D.; Millwood, P. A.; Smith,
P. D. Chem. Commun. 1998, 633. (b) Kumareswaran, R.;
Balasubramanian, T.; Hassner, A. Tetrahedron Lett. 2000,
41, 8157. (c) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009.
(d) Amat, M.; Perez, M.; Llor, N.; Bosch, J.; Lago, E.;
Molins, E. Org. Lett. 2001, 3, 611. (e) Touré, B. B.; Hall,
D. G. Angew. Chem. Int. Ed. 2004, 43, 2001. (f) Escolano,
C.; Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198.
(g) Larivee, A.; Charette, A. B. Org. Lett. 2006, 8, 3955.
(9) For recent reviews, see: (a) Couty, F. Amino Acids 1999, 16,
297. (b) Kadouri-Puchot, C.; Comesse, S. Amino Acids
2005, 29, 101. (c) See also: Agami, C.; Comesse, S.;
Kadouri-Puchot, C. J. Org. Chem. 2000, 65, 4435.
(10) (a) Muller, M.; Schoenfelder, A.; Didier, B.; Mann, A.;
Wermuth, C.-G. Chem. Commun. 1999, 683. (b) Acherki,
H.; Alvarez-Ibarra, C.; de Dios, A.; Gutierrez, M.; Quiroga,
M. L. Tetrahedron: Asymmetry 2001, 12, 3173.
(c) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett.
2002, 43, 1991. (d) Hanessian, S.; van Otterlo, W. A. L.;
Nilsson, I.; Bauer, U. Tetrahedron Lett. 2002, 43, 1995.
(e) Marin J., Didierjean C., Aubry A., Casimir J. R., Briand
J. P., Guichard G.; J. Org. Chem.; 2004, 69: 130.
(22) Data for Selected Compound: (2S,4R)-Di-tert-butyl
4-Phenylpiperidine-1,2-dicarboxylate (8)
(f) Acherki, H.; Alvarez-Ibarra, C.; Luján, J. F. C.; Quiroga-
Feijóo, M. L. Tetrahedron: Asymmetry 2005, 16, 4034.
(11) Murray, P. J.; Starkey, I. D. Tetrahedron Lett. 1996, 37,
1875.
(12) For recent reviews, see: (a) Miyaura, N.; Suzuki, A. Chem.
Rev. 1995, 95, 2457. (b) Chemler, S. R.; Trauner, D.;
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58, 9633.
(13) General Procedure for Suzuki–Miyaura Coupling
Under argon, to a solution of 2 (1 equiv) in THF (0.04 M)
were added the boronic acid (1.5 equiv), (Ph3P)PdCl2 (0.05
equiv) and a 2 M Na2CO3 solution (1.5 mL for 0.11 mmol of
2). The mixture was stirred at 40 °C overnight. The reaction
generally turned black at completion. H2O was added, and
the aqueous layer was extracted three times with Et2O. The
combined organic layers were washed with brine and dried
From 4a (30 mg, 0.08 mmol) was obtained 8 as a colorless
gum (25 mg, 93%); [a]D –15.6 (c 0.95, CHCl3). IR (NaCl):
2976, 1738, 1699, 1602, 1478, 1454, 1393, 1366, 1249,
1150, 1028 cm–1. 1H NMR (400 MHz, CDCl3): d (rotamers)
= 7.35–7.31 (m, 2 H), 7.26–7.21 (m, 3 H), 4.25–4.21 (m,
1 H), 3.75–3.56 (m, 2 H), 2.88–2.80 (m, 1 H), 2.28–2.22 (m,
1 H), 2.14–2.02 (m, 2 H), 1.87–1.78 (m, 1 H), 1.49 (s, 9 H),
1.42 (s, 9 H). 13C (100 MHz, CDCl3): d = 171.3, 155.4,
144.6, 128.2, 126.6, 126.0, 80.6, 79.7, 56.1, 37.1, 32.4, 29.8,
28.0, 27.6 ppm. HRMS: m/z calcd for C21H31NO4:
361.22531; found: 362.23232 [M + H]+.
(23) (a) Hanessian, S.; Ma, J. Tetrahedron Lett. 2001, 42, 8785.
(b) Hanessian, S.; Papeo, G.; Angiolini, M.; Fettis, K.;
Beretta, M.; Munro, A. J. Org. Chem. 2003, 68, 7204.
(c) Hanessian, S.; Tremblay, M.; Marzi, M.; Del Valle, J. R.
J. Org. Chem. 2005, 70, 5070.
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