Conformationally restricted nonchiral pipecolic acid analogues

Article abstract of DOI:10.1021/jo900842w

(Chemical Equation Presented) Practical syntheses of 2-azabicyclo[3.1.1] heptane-1-carboxylic (2,4-methanopipecolic), 2-azabicyclo [2.2.2]octane-1- carboxylic (2,5-ethanopipecolic), and 9-azabicyclo[3.3.1]nonane-1-carboxylic (2,6-propanopipecolic) acids a

Full text of DOI:10.1021/jo900842w

pubs.acs.org/joc
Conformationally Restricted Nonchiral Pipecolic Acid Analogues
Dmytro S. Radchenko,†,‡ Nataliya Kopylova,† Oleksandr O. Grygorenko,*,†,‡ and
Igor V. Komarov†,‡
†Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street 64,
Kyiv 01033, Ukraine, and ‡Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
gregor@univ.kiev.ua
Received April 23, 2009
Practical syntheses of 2-azabicyclo[3.1.1]heptane-1-carboxylic (2,4-methanopipecolic), 2-azabicyclo
[2.2.2]octane-1-carboxylic (2,5-ethanopipecolic), and 9-azabicyclo[3.3.1]nonane-1-carboxylic (2,6-
propanopipecolic) acids are reported. The synthetic schemes are short (five, seven, and five steps,
respectively) and result in reasonably high yields of the title compounds. The key step in the syntheses
is the tandem Strecker reaction and intramolecular nucleophilic cyclization of ketones possessing a
leaving group at the δ-position.
Introduction
is very important for drug design: development of new drugs
often requires the use of chiral building blocks. The funda-
mental reason behind this lies in the fact that almost all
biological targets are chiral, and drug-receptor interaction
requires strict matching of chirality. However, chirality also
causes serious problems in drug design as a result of the cost
of synthesis of chiral nonracemic compounds and their
analysis and the strengthening of regulatory guidelines for
submitting new drug applications in many countries. There-
fore, the synthesis of novel nonchiral building blocks, in-
cluding amino acids, capable of generating drug candidates
has taken on increased importance.4
A design concept for bicyclic nonchiral R-amino acids
consists of the incorporation of -(CH2)n- bridges between
the C(2) and C(n+3) atoms of parent monocyclic scaffolds.
For example, the proline nonchiral family includes the
known 2,4-methanoproline 45 and 7-azabicyclo[2.2.1]hep-
tane-1-carboxylic acid 5.6 Recently, we used an analogous
concept for a nonchiral analogue of R-aminoadipic acid,
7-azabicyclo [2.2.1]heptane-1,4-dicarboxylic acid 6.7
Conformationally restricted amino acids (CRAAs) have
been the subject of considerable interest in the past decade
due to their importance for drug design. Incorporation of
the CRAA in peptidomimetics can lead to improvement
of their pharmacokinetic and pharmacodynamic character-
istics.1
Most of the natural and unnatural CRAAs used for this
purpose are cyclic; the presence of cycles in a molecule
considerably restricts its conformational flexibility.2 For
example, three natural cyclic CRAAs, 2-azetidinecarboxylic
acid (1), proline (2) and pipecolic acid (3), are frequently used
either nonderivatized or as scaffolds in the design of con-
formationally restricted peptidomimetics.2b,3
Application of this design concept to the pipecolic acid
scaffold 3generates three less explored analogues, the nonchiral
It should be noted that compounds 1-3 and many of their
non-natural analogues known to date are chiral. This property
(4) (a) Reddy, R. B. et al. PCT Int. Pat. WO 2005113518, 2005. (b) Jacob,
M.; Killgore, J. K. PCT Int. Pat. WO 0140184, 2001. (c) Brighty, K. E.; PCT Int.
Pat. WO 9102526, 1991.
(5) Rammeloo, T.; Stevens, C. V.; De Kimpe, N. J. Org. Chem. 2002, 67,
6509–6513.
(1) Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford
University Press: New York, NY, 2005; pp 210-213.
(2) (a) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1–24.
(b) Komarov, I. V.; Grygorenko, O. O.; Turov, A. V.; Khilya, V. P. Russ.
ꢀ
(6) Avenoza, A.; Cativiela, C.; Busto, J. H.; Fernandez-Recio, M. A.;
Chem. Rev. 2004, 73, 785–810. (c) Cativiela, C.; Dı
Tetrahedron: Asymmetry 2000, 11, 645–732.
(3) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241–1251.
´
az-de-Villegas, M. D.
Peregrina, J. M.; Rodrıgues, F. Tetrahedron 2001, 57, 545–548.
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(7) Kybyshkin, V. S.; Mikhailiuk, P. K.; Komarov, I. V. Tetrahedron
Lett. 2007, 48, 4061–4063.
DOI: 10.1021/jo900842w
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Published on Web 06/11/2009
J. Org. Chem. 2009, 74, 5541–5544 5541
2009 American Chemical Society

Radchenko et al.
JOCArticle
CRAAs 7-9. Herein, we wish to report expedient syntheses
of these compounds.
SCHEME 1
described in the literature.13 All these procedures are easy to
scale up, thus allowing multigram quantities of the corre-
sponding functionalized ketones to be obtained. Com-
pounds 12, 17, and 21 smoothly underwent the Strecker
reaction and cyclization in the presence of acetone cyanohy-
drin (ACH) and benzylamine, giving the aminonitriles 13,
18, and 22. Their hydrolysis in aqueous HCl and deprotec-
tion by hydrogenolysis proceeded in reasonable yields.
The overall yields for the syntheses were 14% (7, five steps),
14% (8, seven steps), and 15% (9, five steps), so the proce-
dures can be used to obtain multigram quantities of the
amino acids.
Results and Discussion
To the best of our knowledge, none of the compounds 7-9
are described in the open literature in the free form. Synth-
eses of O-benzyl8a and N-benzyl8b derivatives of 2-azabicyclo
[2.2.2]octane-1-carboxylic acid (2,5-ethanopipecolic acid)
have already been reported. The key transformation of
the latter synthesis was the intramolecular cyclization of
1-aminocyclohexane-1,4-dicarboxylic acid dimethyl ester.
Another synthesis of a 2,5-ethanopipecolic acid deriva-
tive (N-benzoyl-2-azabicyclo[2.2.2]octane-1-carboxylic acid
methyl ester) through an intramolecular cyclization of
methyl 1-(benzoylamino)-4-(mesyloxymethyl)cyclohexane-
carboxylate has been published recently.8c Compounds with
the core skeleton of 9 have also been described in the
literature. They have been prepared by an intramolecular
reductive radical cyclization of corresponding alkynes.9
In our syntheses of 7-9 we used a different approach,
which had been recently developed by our group10 and
utilizes a tandem Strecker reaction-cyclization sequence
followed by hydrolysis and deprotection, as shown in the
Scheme 1. Advantages of this approach are generality, the
simplicity of the synthetic procedures, short reaction paths,
and good yields. As the final compounds are nonchiral,
the synthetic strategy avoids the use of expensive chiral
auxiliaries, reagents, or catalysts, as well as tedious separa-
tion of stereoisomers. Corresponding functionalized cyclic
ketones can be easily synthesized from commercially avail-
able compounds.
Conclusions
In summary, a set of nonchiral, conformationally re-
stricted pipecolic acid analogues has been designed. An
approach to their synthesis utilizing a tandem Strecker
reaction-cyclization sequence has been developed. The
procedure is a modification of a method previously reported
by our group10 and can be applied for the synthesis of
other cyclic amino acids starting from corresponding
functionalized ketones. These amino acids can be used as
building blocks in the search for biologically active com-
pounds and as model compounds in structural studies of
peptides.
Experimental Section
2,2-Dichloro-3-(2-chloroethyl)cyclobutanone 11. Compound
10 (4.45 g, 49.1 mmol), Zn-Cu couple (3.51 g, 54 mmol), and
dry ether (80 mL) were placed in a pre-dried three-necked flask
under an argon atmosphere. A solution of trichloroacetyl
chloride (5.75 mL, 51.5 mmol) and POCl3 (4.81 mL, 51.5 mmol)
in dry ether (40 mL) was added over a period of 30 min. The
reaction mixture was refluxed for 1 day under argon, and
the solution was filtered over Celite and washed with ether.
The filtrate was evaporated to 60 mL and extracted with pentane
(3Â45 mL). The clear yellow upper solution was decanted from
the brown residue into a separating funnel. The organic layer
was washed with water (3Â30 mL) and brine (1Â30 mL) and
dried over MgSO4. Removal of the solvent in vacuo afforded
crude 11 (6 g, 29.8 mmol) as a pale yellow oil (79.4% purity by
GCMS), which was used in the next step without further
purification: IR (cm-1) 1815 (ν(CdO)); MS (m/z) 200(M+),
158(M+-CH2dCdO), 122, 109; 1H NMR (CDCl3) δ 3.69 (m,
2H, CH2CH2Cl), 3.43 (dd, J=17.2 and 9.2 Hz, 1H, 4-CH2),
3.18 (m, 1H, 3-CH), 3.08 (dd, J=17.4 and 9.3 Hz, 1H, 4-CH2),
2.44 (m, 1H, CH2CH2Cl), 2.11 (m, 1H, CH2CH2Cl); 13C NMR
(CDCl3) δ 191.9 (CdO), 88.7 (CCl2), 47.9 (4-CH2), 43.7
(3-CH), 42.2 (CH2CH2Cl), 34.1 (CH2CH2Cl).
Details of the syntheses are outlined in the Scheme 2.
The functionalized ketone 12 was obtained from commer-
cially available 10 by [2+2] cycloaddition of dichloroketene
followed by reduction, utilizing the procedure described for
an analogous compound.11 Starting ketone 17 was synthe-
sized from 2-trimethylsilyloxy-1,3-butadiene 14 by a method
reported elsewhere.12 Finally, ketone 21 was obtained as
(8) (a) Bright, G. M.; Dee, M. F.; Kellogg, M. S. Heterocycles 1980, 14,
1251–1254. (b) Casabona, D.; Cativiela, C. Tetrahedron 2006, 62, 10000–
10004. (c) Carreras, J.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. J. Org.
Chem. 2007, 72, 3112–3115.
(9) Sato, T.; Yamazaki, T.; Nakanishi, Y.; Uenishi, J.; Ikeda, M. J. Chem.
Soc., Perkin Trans. 1 2002, 1438–1443.
(10) (a) Grygorenko, O. O.; Artamonov, O. S.; Palamarchuk, G. V.;
Zubatyuk, R. I.; Shishkin, O. V.; Komarov, I. V. Tetrahedron: Asymmetry
2006, 17, 252–258. (b) Grygorenko, O. O.; Kopylova, N. A.; Mikhailiuk, P.
K.; Meissner, A.; Komarov, I. V. Tetrahedron: Asymmetry 2007, 18, 290–
297.
3-(2-Chloroethyl)cyclobutanone 12. Zinc powder (10.5 g,
161 mmol) was added in small portions to a stirred solution of 11
(5 g, 24.8 mmol) in HOAc (50 mL) at 90 °C. The suspension was
(11) Kabalka, G. W.; Yao, M.-L.; Navarane, A. Tetrahedron Lett. 2005,
46, 4915–4917.
(12) Yin, T.-K.; Lee, J. G.; Borden, W. T. J. Org. Chem. 1985, 50, 531–
534.
(13) Crandall, J. K.; Huntington, R. D.; Brunner, G. L. J. Org. Chem.
1972, 37, 2911–2913.
5542 J. Org. Chem. Vol. 74, No. 15, 2009

Radchenko et al.
JOCArticle
SCHEME 2. Synthesis of Amino Acids 7-9
heated at 90 °C for 2 h, cooled to rt, filtered over Celite, and
washed with dichloromethane (100 mL). The resulting solu-
tion was washed with water (1Â50 mL) and saturated NaHCO3
solution until basic, dried over Na2SO4, and evaporated. Dis-
tillation of the crude product afforded 12 (2.58 g, 19.5 mmol,
79% yield) as a colorless oil: bp 98 °C/15 mmHg; IR (cm-1) 1785
(ν(CdO)); MS (m/z) 132(M+), 104, 55. Anal. Calcd for
C6H9ClO: C 54.35, H 6.84, Cl 26.74. Found: C 54.72, H 6.79,
Cl 26.83. 1H NMR (CDCl3) δ 3.57 (t, J=6.5 Hz, 2H, CH2Cl),
3.19-3.24 (m, 2H), 2.75-2.80 (m, 2H), 2.64 (sept, J=7.5 Hz,
1H, 3-CH), 2.10 (q, J = 7.0 Hz, 2H, CH2CH2Cl); 13C NMR
(CDCl3) δ 206.8 (CdO), 52.5 (CH2), 43.3 (CH2), 38.7 (CH2),
21.8 (3-CH).
128.0 (o-C6H5), 128.8 (m-C6H5), 128.6 (p-C6H5), 120.5 (CN), 58.7
(1-C), 57.5 (CH2C6H5), 43.0 (3-CH2), 37.4 (6- and 7-CH2), 31.5 (5-
CH), 27.9 (4-CH2).
2-Azabicyclo[3.1.1]heptane-1-carboxylic Acid 7. A solution of
13 (0.2 g, 0.9 mmol) in 6 N HCl (5 mL) was heated under reflux
for 18 h. After evaporation of the solvent, the residue was
dissolved in water and hydrogenated over 10% Pd/C at 70 bar
and rt for 12 h. Evaporation of the solvent and purification by
ion-exchange chromatography (Amberlite IR-120(plus) ion-
exchange resin (20 g), 3.5% aqueous ammonia as an eluent)
gave 7 (0.090 g, 0.6 mmol, 68%) as a white solid: mp 150 °C
(dec); IR (KBr, cm-1) 3394 (νas(NH2+)), 3187 (νs(NH2+)), 1686,
1639, and 1608 (δ(NH2), νas(COO-) and νs(COO-)). Anal.
Calcd for C7H11NO2: C 59.56, H 7.85, N 9.92. Found:
C 59.43, H 7.86, N 9.61. 1H NMR (D2O) δ 3.54 (t, J=7.2 Hz,
2H, 3-CH2), 2.64 (m, 3H, 5-CH, 6-CHH and 7-CHH), 2.14 (m,
2H, 4-CH2), 1.92 (m, 2H, 6-CHH and 7-CHH); 13C NMR
(DMSO-d6) δ 172.3 (COOH), 65.1 (1-C), 36.7 (3-CH2), 34.8
(6- and 7-CH2), 29.2 (5-CH), 26.7 (4-CH2).
2-Benzyl-2-azabicyclo[3.1.1]heptane-1-carbonitrile 13. Acet-
one cyanohydrin (5.13 mL, 56.1 mmol) and benzylamine (2.06 mL,
18.9 mmol) were added to a solution of 12 (2.5 g, 18.9 mmol)
in dry methanol (20 mL). The mixture was refluxed for 80 h,
evaporated, diluted with 10% sodium hydroxide solution
(25 mL), and extracted with ether. The combined organic
extracts were dried over MgSO4 and evaporated under redu-
ced pressure. The residue was chromatographed (hexane/
ethylacetate/triethyamine (15:5:1) as an eluent) to give 13 (1.69 g,
7.96 mmol, 42%) as a white crystalline solid: mp 55-57 °C; IR
(KBr, cm-1) 2235 (ν(CtN)); MS (m/z) 212(M+), 184, 171, 91
(C7H7+). Anal. Calcd for C14H16N2: C 79.21, H 7.60, N 13.20.
2-benzyl-2-azabicyclo[2.2.2]octane-1-carbonitrile 18. Acetone
cyanohydrin (32 mL, 0.354 mol) and benzylamine (12.9 mL,
0.118 mol) were added to a solution of 17 (33.3 g, 0.118 mol) in
dry methanol (140 mL). The mixture was refluxed for 80 h,
evaporated, diluted with 10% sodium hydroxide solution
(150 mL), and extracted with ether. The combined extracts were
dried over MgSO4 and evaporated under reduced pressure.
The residue was recrystallized from MeOH to give 18 (9.66 g,
0.043 mol, 36%) as a white crystalline solid: mp 96-98 °C; IR
(KBr, cm-1) 2235 (ν(CtN)); MS (m/z) 226(M+), 197,
91(C7H7+). Anal. Calcd for C15H18N2: C 79.61, H 8.02,
1
Found: C 79.05, H 7.57, N 12.98. H NMR (CDCl3) δ 7.38 (d,
J=7.1 Hz, 2H, o-C6H5), 7.34 (t, J=7.1 Hz, 2H, m-C6H5), 7.27 (t,
J=7.0 Hz, 1H, p-C6H5), 3.87 (s, 2H, CH2C6H5), 2.88 (t, J=6.8 Hz,
2H, 3-CH2), 2.52 (m, 1H, 5-CH), 2.44 (t, J = 6.8 Hz, 2H,
4-CH2), 2.27 (dd, J=7.3 and 2.2 Hz, 2H, 6- and 7-CHH), 1.93
(m, 2H, 6- and 7-CHH); 13C NMR (CDCl3) δ 139.0 (ipso-C6H5),
1
N 12.38. Found: C 79.36, H 7.79, N 12.43. H NMR (CDCl3)
J. Org. Chem. Vol. 74, No. 15, 2009 5543

Radchenko et al.
JOCArticle
δ 7.38 (d, J=7.1 Hz, 2H, o-C6H5), 7.34 (t, J=7.4 Hz, 2H,
m-C6H5), 7.26 (t, J = 7.0 Hz, 1H, p-C6H5), 3.98 (s, 2H,
CH2C6H5), 2.64 (s, 2H, 3-CH2), 2.40 (m, 2H, 6- and 7-CHH),
2.01 (td, J=12.1 and 4.4 Hz, 2H, 6- and 7-CHH), 1.68 (m, 5H);
13C NMR (CDCl3) δ 138.8 (ipso-C6H5), 129.0 (o-C6H5), 128.5
(m-C6H5), 127.3 (p-C6H5), 122.3 (CN), 59.1 (CH2C6H5), 55.2
(3-CH2), 52.6 (1-C), 30.4 (6- and 7-CH2), 25.1 (4-CH), 24.3 (5-
and 8-CH2).
2-Azabicyclo[2.2.2]octane-1-carboxylic Acid 8. A solution
of 18 (0.220 g, 1.0 mmol) in 6 N HCl (5 mL) was heated under
reflux for 72 h. After evaporation of the solvent, the residue was
dissolved in water and hydrogenated over 10% Pd/C at 70 bar
and rt for 12 h. Removal of the solvent and purification by
ion-exchange chromatography (Amberlite IR-120(plus) ion-
exchange resin (20 g), 3.5% aqueous ammonia as an eluent)
gave 8 (0.095 g, 0.6 mmol, 63%) as a white solid: mp 260 °C
(dec); IR (KBr, cm-1) 3361 (νas(NH2+)), 3204 (νs(NH2+)), 1653
and 1600 (δ(NH2+), νas(COO-) and νs(COO-)). Anal. Calcd
for C8H13NO2: C 61.91, H 8.44, N 9.03. Found: C 62.13% H
8.27, N 8.86. 1H NMR (D2O) δ 3.22 (s, 2H, 3-CH2), 2.04 (td, J=
13.1 and 5.2 Hz, 2H), 1.98 (s, 1H, 4-CH), 1.90 (m, 2H), 1.83 (m,
2H), 1.75 (m, 2H); 13C NMR (D2O) δ 177.7 (COOH), 58.2 (1-C),
45.8(3-CH2), 25.9 (CH2), 22.7 (CH2), 22.3 (4-CH).
9-Benzyl-9-azabicyclo[3.3.1]nonane-1-carbonitrile 22. Acet-
one cyanohydrin (0.31 mL, 3.4 mmol) and benzylamine (0.13
mL, 1.19 mmol) were added to a solution of 21 (0.340 g,
1.15 mmol) in 1 mL of dry CH3CN. The mixture was heated
at 90 °C for 18 h with an air condenser to allow the solvent
to evaporate gradually, cooled, diluted with 10% sodium
hydroxide solution (5 mL), and extracted with ether (3Â5 mL).
The combined extracts were dried over MgSO4 and evapo-
rated under a reduced pressure to give crude 22 (0.190 g,
0.79 mmol, 69%), which was used in the next step without
further purification. The analytical sample was obtained by
flash chromatography (hexane/ethyl acetate (90:10 to 60:40
gradient) as an eluent, detection at 254 nm) as a white solid:
mp 68-70 °C; IR (KBr, cm-1) 2235 (ν(CtN)); MS (m/z, CI) 241
(MH+). Anal. Calcd for C16H20N2: C 79.96, H 8.39, N 11.66.
Found: C 79.64, H 7.98, N 11.40. 1H NMR (CDCl3) δ 7.38 (d,
J=6.1 Hz, 2H, o-C6H5), 7.32 (t, J=7.3 Hz, 2H, m-C6H5), 7.25
(dd, J=6.7 and 5.9 Hz, 1H, p-C6H5), 4.10 (s, 2H, CH2C6H5),
2.79 (s, 1H, 5-CH), 2.40 (2m, 2H, 2- and 8-CHH), 2.10 (m, 2H, 3-
and 7-CHH), 1.91-2.07 (m, 4H, 2- and 8-CHH, 4-and 6-CHH),
1.77 (m, 2H, 3- and 7-CHH), 1.40 (m, 2H, 4- and 6-CHH); 13
C
NMR (CDCl3) δ 139.2 (ipso-C6H5), 128.4 (CH), 128.3 (CH),
127.1 (CH), 123.2 (CN), 55.6 (1-C), 53.7 (CH2C6H5), 47.2
(5-CH), 32.4 (2-CH2), 25.0 (4-CH2), 20.3 (3-CH2).
9-Azabicyclo[3.3.1]nonane-1-carboxylic Acid 9. A solution of
22 (0.160 g, 0.67 mmol) in 6 N HCl (5 mL) was heated under
reflux for 80 h. After evaporation of the solvent, the residue was
dissolved in water and hydrogenated over 10% Pd/C at 70 bar
and rt for 12 h. Evaporation of the solvent and purification
by ion-exchange chromatography (Amberlite IR-120(plus) ion-
exchange resin (20 g), 3.5% aqueous ammonia as an eluent) gave
9 (0.061 g, 0.36 mmol, 54%) as a white solid: mp 252 °C (dec); IR
(KBr, cm-1) 3378 (νas(NH2+)), 3333 (νs(NH2+)), 1642, 1617,
and 1589 (δ(NH2+), νas(COO-) and νs(COO-)). Anal. Calcd
for C9H15NO2: C 63.88, H 8.93, N 8.28. Found: C 64.11, H 8.92,
N 8.34. 1H NMR (D2O) δ 3.73 (s, 1H, 5-CH), 2.19 (m, 4H), 1.98
(m, 2H), 1.89 (m, 4H), 1.74 (m, 2H); 13C NMR (D2O) δ 178.3
(COOH), 59.4 (1-C), 48.7 (5-CH), 30.5 (CH2), 26.1 (CH2), 18.9
(3- and 7-CH2).
Supporting Information Available: Copies of NMR spectra
and LS-MS/GS-MS chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org.
5544 J. Org. Chem. Vol. 74, No. 15, 2009