Practical synthesis of trans-tert-butyl-2-aminocyclopentylcarbamate and resolution of enantiomers

Article abstract of DOI:10.1021/jo061409v

Optically active trans-tert-butyl-2-aminocyclopentylcarbamate (1) has potential utility as a scaffold for chiral ligands and as a modified backbone unit for peptide nucleic acids (PNAs). We have developed a short and practical synthesis of 1 via aziridine

Full text of DOI:10.1021/jo061409v

compound 1 is air stable6 and can be easily converted to trans-
1,2-diaminocyclopentane. More importantly, 1 allows the step-
wise functionalization of amino groups to generate non-C2-type
chiral ligands or medicinal agents.7
Practical Synthesis of
trans-tert-Butyl-2-aminocyclopentylcarbamate and
Resolution of Enantiomers
Recently, we reported that incorporating trans-1,2-diami-
nocyclopentane into aminoethylglycine peptide nucleic acids
(aegPNAs) significantly increases binding affinity and sequence
specificity to complementary DNA.5 Related to this, we
developed an asymmetric synthetic route to (S,S)-1 relying on
Curtius rearrangement and multistep functional group transfor-
mations.5 The route was only serviceable for initial evaluation
of 1 as a building block. Its long sequence and low yield (10
steps, 10% yield) hindered its further application.
Qun Xu and Daniel H. Appella*
Laboratory of Bioorganic Chemistry, National Institute of
Diabetes and DigestiVe and Kidney Diseases, National Institute
of Health, DHHS, 9000 RockVille Pike, Bethesda,
Maryland 20892
appellad@niddk.nih.goV
ReceiVed July 6, 2006
Our ongoing interest in design and application of trans-
cyclopentane-constrained PNA prompted us to develop a more
efficient and practical process, which can provide multigram
quantities of both enantiomers of 1.8 We envisioned that a
straightforward approach to prepare such diamines would be
ring-opening of an appropriate aziridine with an azide nucleo-
phile in the presence of a promoter.9 In this way, two amine
groups or its equivalents are installed in one step, thus
circumventing the tedious functional group transformations.
Our synthesis begins with ring opening of tosyl-activated
aziridine 2 (Scheme 1, Table 1), which is readily accessible in
one step from commercially available cyclopentene.10 A litera-
ture search revealed four examples of ring-opening of 2 with
azides.11-14 However, our examination of these methods
revealed that none of them gave satisfactory results, especially
for large-scale (4 mmol scale) synthesis. For instance, attempted
opening of 2 with NaN3 using Oxone in aqueous acetonitrile
failed to provide any ring-opening products.11 The use of ceric
ammonium nitrate (CAN) instead of Oxone led to 15%
convension and 13% yield of 3.12 Similar results were observed
when TMSN3 in DMF was used.13 Fortunately, adding 5%
TBAF to TMSN3 significantly promoted the transformation
(entry 4, 80% conversion, 76% yield).14 However, the operation
requires laborious column chromatography to separate azido
amine product 3 from unreacted 2, which has an Rf value close
to that of 3. Complete conversion was achieved by increasing
the amount of TBAF to 20% (entry 5). If 1 equiv of TBAF is
Optically active trans-tert-butyl-2-aminocyclopentylcarba-
mate (1) has potential utility as a scaffold for chiral ligands
and as a modified backbone unit for peptide nucleic acids
(PNAs). We have developed a short and practical synthesis
of 1 via aziridine opening of tosyl-activated cyclopentene
aziridine 2 and optical resolution of racemic 1 with 10-
camphorsulfonic acid (CSA). The route provides ready access
to multigram quantities of both enantiomers without the need
for chromatography.
Optically active 1,2-diamines are important components of
many biologically active natural products and medicinal agents.1
Bidentate C2-symmetric ligands based on 1,2-diamine function-
ality have also found widespread applications in asymmetric
catalysis.2 For example, chiral salen ligands derived from trans-
1,2-diaminocyclohexane effect remarkable enantioselectivity for
a broad range of transformations.3 In contrast, the use of trans-
1,2-diaminocyclopentane as a chiral scaffold has received less
attention due to the limited availability of both enantiomers.4
In connection with our research on peptide nucleic acids
(PNAs),5 we felt that trans-tert-butyl-2-aminocyclopentylcar-
bamate (1) would be a versatile synthetic precursor and that
resolution of racemic 1 should be feasible. In our experience,
(6) When, exposed to air, 1,2-diamines react slowly with carbon dioxide
to produce carbamic acid derivatives. Berkessel, A.; Schro¨der, M., Sklorz,
C. A.; Tabanella, S.; Vogl, N.; Lex, J.; Neudo¨rfl, J. M. J. Org. Chem. 2004,
69, 3050.
(7) Non-C2-type diamine chiral ligands: (a) Mitchell, J. M.; Finney, N.
S. Tetrahedron Lett. 2000, 41, 8431-8434. (b) Christoffers, J.; Schulze,
Y.; Pickardt, J. Tetrahedron 2001, 57, 1765-1769. (c) Fujii, A.; Hashiguchi,
S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-
2522. Medicinal agents: (a) Szmuszkovicz, J.; Von Voigtlander, P. F. J.
Med. Chem. 1982, 25, 1125-1126. (b) Cheney, B. V.; Szmuszkovicz, J.;
Lahti, R. A.; Zichi, D. A. J. Med. Chem. 1985, 28, 1853-1864.
(8) Pokorski, J. K.; Nam, J.; Vega, R. A.; Mirkin, C. A.; Appella, D. H.
Chem. Commun. 2005, 2101-2102.
(1) For reviews, see: (a) Lucet, D.; Le, Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580-2627. (b) Kotti, S. R. S. S.; Timmons, C.;
Li, G. Chem. Bio. Drug Des. 2006, 67, 101-114.
(2) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691-1693.
(3) Larrow, J. F.; Jacobson, E. N. Top. Organomet. Chem. 2004, 6, 123-
152.
(4) (a) Luna, A.; Alfonso, L.; Gotor, V. Org. Lett. 2002, 4, 3627-3629.
(b) Toftlund, H.; Pedersen, E. Acta Chem. Scand. 1972, 26, 4019-4030.
(c) Ongeri, S.; Aitken, D. J.; Husson, H. Synth. Commun. 2000, 30, 2593-
2597. (d) Gouin, S. G.; Gestin, J.; Joly, K.; Loussouran, A.; Reliquet, A.;
Meslin, J. C.; Deniaud, D. Tetrahedron 2002, 58, 1131-1136. (e) Daly,
A. M.; Gilheany, D. G. Tetrahedron: Asymmetry. 2003, 14, 127-137.
(5) (a) Pokorski, J. K.; Witschi, M. A.; Purnell, B. L.; Appella, D. H. J.
Am. Chem. Soc. 2004, 126, 15067-15073. (b) Myers, M. C.; Witschi, M.
A.; Larionova, N. V.; Frank, J. M.; Haynes, R. D.; Hara, T.; Grakowski,
A.; Appella, D. H. Org. Lett. 2003, 5, 2695-2698.
(9) For recent reviews on ring-opening of aziridines with azides, see:
(a) Hu, X. E. Tetrahedron 2004, 60, 2701-2743; (b) Sweeney, J. B. Chem.
Soc. ReV. 2002, 31, 247-258.
(10) Jeong, J. K.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844-6845.
(11) Chandrasekhar, S.; Narsihmulu, C.; Sultana, S. S. Tetrahedron Lett.
2002, 43, 7361-7363.
(12) Sabitha, G.; Babu, R. S.; Reddy, S. K.; Yavad, J. S. Synthesis 2002,
2254-2258.
(13) Wu, J.; Sun, X.; Xia, H. Eur. J. Org. Chem. 2005, 4769-4772.
(14) Wu, J.; Hou, X.; Dai, L. J. Org. Chem. 2000, 65, 1344-1348.
10.1021/jo061409v This article not subject to U.S. Copyright. Published 2006 American Chemical Society
Published on Web 10/06/2006
J. Org. Chem. 2006, 71, 8655-8657 8655

SCHEME 1
SCHEME 2
were rapidly examined by a 1H NMR method as follows
(Scheme 2): the precipitated salts were converted to amine 1
and subsequently treated with optically pure (R)-(+)-1-phenyl-
ethyl isocyanate in CDCl3 to give corresponding urea disaste-
reomers 5.19 The Boc groups of the two disastereomers 5 showed
separated peaks at 1.30 and 1.44 ppm in the 1H NMR. Among
the different chiral acids that were screened, di-p-toluoyltartaric
acid, 2-phenylpropionic acid, and menthyloxyacetic acid showed
partial resolution. Fortunately, optimal results were obtained
when 10-camphorsulfonic acid (CSA) was used as a resolving
agent. The precipitate from rac-1 and CSA (1:1 or 1:0.5) in
acetone showed approximately 60% ee. After crystallizations
from acetonitrile, the optical purity of 1 was enhanced to over
99% ee, as determined by HPLC analysis (on a chiral stationary
phase) of the benzoylated derivative 6 (experimental section).
The configuration of 1 obtained from the resolution was assigned
based on the comparison of HPLC data of 6 (obtained on a
chiral stationary phase) to material obtained from previous
syntheses performed in our laboratory.5
TABLE 1. Ring Opening of Aziridine 2 with Azidesa
T
time convb yieldc
entry
reagents
solvent
(°C) (h)
(%)
(%)
1
2
3
4
5
6
7
NaN3, Oxone
NaN3, 10% CAN
TMSN3
TMSN3, 5% TBAF
TMSN3, 20% TBAF
TMSN3, 100% TBAF THF
CH3CN/H2O 23
CH3CN/H2O 23
5
20
16
16
16
4
0
15
34
0
13
30
76
93
96
95
DMF
THF
THF
40
40
40
40
40
81
100
100
100
30% TMSN3, 30%
TBAF, 100% NaN3
THF
20
a All reactions were conducted at 4 mmol scale, and entries 5-7 were
also conducted at ∼85 mmol scale. b Determined by 1H NMR. c Isolated
yield.
used, the reaction time can be shortened to 4 h and 3 can be
obtained in 96% yield (entry 6). Similar results can be obtained,
although with longer reaction times, by using 30% TMSN3, 30%
TBAF, and 100% NaN3 (entry 7). For our purposes, these final
conditions prove to be the most cost-effective and reliable for
preparation of 3.
Without further purification, 3 was reduced to the corre-
sponding amine by Pd-catalyzed hydrogenation or Staudinger
reduction (PPh3, THF/H2O).15 Subsequent Boc protection of the
resulting amine yielded 4 in 92% yield for two steps.
In conclusion, we have developed a short synthetic route to
optically enriched 1, a versatile building block for chiral ligands
and modified PNAs. The synthesis does not require column
chromatography and is amenable to large-scale preparation (10
g scale for rac-1), which can provide gram quantities of both
enantiomers.
The major drawback of tosyl-activated aziridine chemistry
is that harsh conditions are required for the cleavage of the
sulfonamide bond at a later stage of the synthesis.9b Recently,
milder conditions have been developed in this context, and
magnesium in methanol under ultrasonic conditions has been
successfully applied to a variety of substrates.16 Under these
conditions, 4 underwent clean but very sluggish conversion.
After considerable experimentation, the detosylation was achieved
with lithium and naphthalene in dimethoxyethane (DME) or
THF.17 The reaction was temperature-dependent: at low (-78
°C) or room temperature, either very slow conversion (10%)
was observed or low yield (40%) resulted. The reaction was
best performed at 0 °C for 5 h to afford 1 in 72% yield.
The resolution of primary amines with similar structures to
1 have been typically performed with tartaric acid or mandelic
acid.18 Our initial attempts to resolve 1 with these two acids
did not give precipitate under various conditions. Therefore, 20
other chiral resolving acids were screened. The resolution results
Experimental Section
2-Azido-N-tosylcyclopentanamine (3). To a mixture of 6-tosyl-
6-azabicyclo[3.1.0]hexane 210 (20.0 g, 84.4 mmol) and NaN3 (5.5
g, 84.4 mmol) in dry THF (300 mL) was added TMSN3 (2.9 g, 3.3
mL, 25.3 mmol), followed by the addition of TBAF (25.3 mL, 1
M in THF, 25.3 mmol). The solution was stirred at 40 °C for 20 h.
The reaction solution was cooled to room temperature, and saturated
NaHCO3 aqueous solution (200 mL) was added. The aqueous layer
was extracted with diethyl ether (100 mL × 3). Combined organic
layers were washed with brine (100 mL), dried over Na2SO4,
filtered, and concentrated under vacuum. The oil residue was filtered
through a pad of silica gel and washed with a mixture of ethyl
acetate/hexanes (1:2, 2000 mL). Solvents were removed under
vacuum to afford 3 (22.4 g, 95%) as a colorless oil. Spectroscopic
data of 3 were consistent with the literature data for this com-
pound.14
tert-Butyl 2-(Tosylamino)cyclopentylcarbamate (4). Triphen-
ylphosphine (40.3 g, 153.8 mmol) was added to a solution of 3
(21.5 g, 76.9 mmol) in THF/H2O (600/50 mL). The mixture was
stirred at room temperature for 16 h. HCl (1 M) solution (200 mL)
was added. The aqueous layer was separated, extracted with diethyl
(15) For large-scale synthesis (over 5 g) in laboratories, Staudinger
reduction is preferable.
(16) (a) Lee, G. H.; Choi, E. B.; Lee, E.; Pak, C. S. Tetrahedron Lett.
1993, 34, 4541-4542. (b) Alonso, D. A.; Andersson, P. G. J. Org. Chem.
1998, 63, 9465-9461. (c) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem.
Commun. 1997, 1017-1018.
(17) Cleavage of sulfonamides with sodium naphthalene: Ji, S.; Gortler,
L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D. J. Am. Chem.
Soc. 1967, 89, 5311-5312. In the presence of Boc group: (a) Henry, J.
R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, D.; Weinreb, S.
M. Tetrahedron Lett. 1989, 30, 5709-5712. (b) Alonso, E.; Ramo´n, D. J.;
Yus, M. Tetrahedron 1997, 53, 14355-14368.
(18) (a) Marino, S. T.; Stachurska-Buczek, D.; Huggins, D. A.; Krywult,
B. M.; Sheehan, C. S.; Nguyen, T.; Choi, N.; Parsons, J. G.; Griffiths, P.
G.; James, I. W.; Bray, A. M.; White, J. M.; Boyce, R. S. Molecules 2004,
9, 405-426. (b) Caiazzo, A.; Dalili, S.; Yudin, A. K. Org. Lett. 2002, 4,
2597-2600. (c) Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.;
Ripa, A.; Schu¨pfea, P.; Treptow, B.; Ku¨ndig, E. P. Chirality 2000, 12, 529-
539.
(19) Greiner, E.; Folk, J. E.; Jacobson, A, E.; Rice, K. C. Bioorg. Med.
Chem. 2004, 12, 233-238.
8656 J. Org. Chem., Vol. 71, No. 22, 2006

ether (200 mL × 3), and basified with 2 N NaOH solution to pH
12-14. The aqueous solution was extracted with ethyl acetate (200
mL × 5). Combined organic layers were washed with brine (100
mL), dried over Na2SO4, filtered, and concentrated under vacuum
to afford a light yellow oil (18.9 g, 97%). Without further
purification, the resulting oil was dissolved in dry methylene
chloride (360 mL), and di-tert-butyl dicarbonate (15.6 g, 71.6 mmol)
and triethylamine (10 mL) were added. The solution was stirred at
room temperature for 16 h. Most of the solvent was removed under
vacuum, and ethyl acetate (300 mL) was added. The mixture was
washed with 1 N HCl solution (50 mL × 3), dried over Na2SO4,
and concentrated to afford a white solid which crystallized from
diethyl ether to give white needles (24.9 g, 92% for two steps). Rf
) 0.36 (hexanes/EtOAc 2:1). Mp: 129-130 °C. IR (film): 3680,
precipitate was taken up in a mixture of ethyl acetate and 2 N NaOH
solution. The aqueous layer was extracted with ethyl acetate (30
mL × 3). The organic layers were combined and dried over Na2SO4.
The solvent was removed under vacuum to give a colorless oil (2.34
g, 11.7 mmol), which was dissolved in acetone and treated with a
solution of (S)-(+)-10-camphorsulfonic acid (2.71 g, 11.7 mmol)
in acetone (HPLC grade, 20 mL). After the mixture was stirred for
2 h, solvent was evaporated and solid was crystallized from
acetonitrile. The same workup procedure described above to make
the free base gave a colorless oil which solidified under vacuum
to give a white solid (S,S-1: 1.90 g, 51% based on one enantiomer).
[R]23D: +15.8 (c 1.0, EtOH). Mother liquid was basified and
extracted with ethyl acetate, resolved with (R)-(-)-10-camphor-
sulfonic acid following the procedure described above to afford
1
2973, 2844, 2866, 1685, 1346, 1160, 1055, 1012 cm-1. H NMR
(R,R)-1 (1.58 g, 46% based on one enantiomer): [R]23 -16.0 (c
D
(300 MHz, CDCl3): δ 7.75 (d, 2H), 7.26 (d, 2H), 6.19 (s, br, 1H),
4.55 (s, br, 1H), 3.70 (m, 1H), 3.03 (m, 1H), 2.42 (s, 3H), 2.02 (m,
2H), 1.65 (m, 3H), 1.42 (s, 9H), 1.30 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 156.9, 143.1, 137.4, 129.6, 127.2, 80.1, 61.7, 57.1, 31.3,
29.4, 28.4, 21.6, 20.2. HRMS (EI): m/z calcd for C17H27N2O4S
[M + 1]+ 353.1535, found 353.1554.
1.0, EtOH).
HPLC Analysis of tert-Butyl 2-(Benzamido)cyclopentylcar-
bamate (6). Benzoyl chloride (20 mg, 0.016 mL, 0.14 mmol) was
added to a solution of nonracemic 1 (28 mg, 0.14 mmol) and
triethylamine (28 mg, 0.038 mL, 0.28 mmol) in dry methylene
chloride (2 mL). The solution was stirred for 16 h and then washed
with 1 M HCl solution (1 mL × 3). The organic layer was dried
over Na2SO4, solvent was removed under vacuum, and the residue
was purified by preparative TLC (solvent: hexanes/EtOAc 2:1) to
afford 5 (38 mg, 85%) as a white solid. Rf ) 0.29 (hexanes/EtOAc
2:1). Mp: 190-192 °C. IR (film): 3314, 2974, 1638, 1621, 1541,
1302, 1170, 1033 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.75 (m,
2H), 7.34 (m, 3H), 4.75 (s, br, 1H), 3.85 (s, br, 2H), 2.33 (m, 1H),
2.04 (m, 1H), 1.72 (m, 2H), 1.39 (m, 2H), 1.34 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 168.0, 157.1, 134.3, 131.4, 128.5, 127.1, 80.0,
59.2, 56.5, 30.1, 29.8, 28.8, 28.4, 19.6. HRMS (EI): m/z calcd for
C17H27N2O4S [M + 1]+ 327.1685, found 327.1689.
tert-Butyl 2-Aminocyclopentylcarbamate (1). A mixture of
lithium granules (1.52 g, 226.6 mmol) and naphthalene (10.9 g,
85.0 mmol) in dry dimethoxyethane (350 mL) was stirred at room
temperature for 2 h. The deep blue solution was then cooled to 0
°C, and a solution of 4 (10.0 g, 28.33 mmol) in dry dimethoxyethane
(40 mL) was added dropwise over 20 min. The mixture was stirred
at 0 °C for 5 h. The undissolved lithium was filtered off, and 1 N
HCl solution (60 mL) was added to the filtrate. The organic layer
was separated and extracted with 1 N HCl (50 mL × 2). The
aqueous layers were combined, extracted with diethyl ether (50
mL × 3), and then basified with 2 N NaOH solution to pH 12-
14. The aqueous solution was extracted with ethyl acetate (50 mL
× 5). Organic layers were combined and dried over Na2SO4, and
solvent was removed under vacuum to afford rac-1 as a colorless
oil, which solidified under vacuum to a white solid (4.08 g, 72%).
Rf ) 0.31 (hexanes/EtOAc 2:1). Mp: 60-62 °C. IR (film): 3301,
2967, 1689, 1526, 1453, 1390, 1365, 1250, 1170, 1045, 1020, 870,
Compound 6 was dissolved in 2-propanol/hexanes (1:1) for
HPLC analysis. HPLC conditions: column: (S,S)-Whelk-O1, 250
mm × 4.6 mm, 10 µm; mobile phase: hexanes/2-propanol (95:5);
flow rate: 1.5 mL/min; absorbance 0.04; sample concentration: 1
mg/mL; injection volumn: 20 µL; retention time: (S,S)-1, 7.07
min; (R,R)-1, 9.53 min.
1
781 cm-1. H NMR (300 MHz, CDCl3): δ 4.48 (s, br, 1H), 3.48
(m, 1H), 2.99 (m, 1H), 2.14 (m, 1H), 1.98 (m, 1H), 1.70 (m, 2H),
1.45 (s, 9H), 1.38 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 156.1,
78.9, 60.5, 59.4, 33.0, 30.9, 28.4, 20.7. HRMS (EI): m/z calcd for
C10H21N2O2 [M + 1]+ 201.1603, found 201.1632.
Optical Resolution of tert-Butyl 2-Aminocyclopentylcarbam-
ate (1) Using (S)-(+)-10-Camphorsulfonic Acid. (S)-(+)-10-
Camphorsulfonic acid (8.24 g, 35.5 mmol) in acetone (HPLC grade,
20 mL) was added to a solution of rac-1 (7.1 g, 35.5 mmol) in
acetone (HPLC grade, 20 mL). The mixture was stirred for 6 h,
and the resulting white precipitate was collected by filtration. The
precipitate was recrystallized in acetonitrile twice. The white
Acknowledgment. We thank Dr. Kenner C. Rice, Dr.
Agniezka Sulima, and Dr. Josef Zezula for help with resolution
and HPLC analysis. Research support was provided by the
Intramural Research Program at NIDDK, NIH, DHHS.
Supporting Information Available: 1H and 13C NMR data for
compounds 1, 4, and 6. HPLC data (obtained on a chiral stationary
phase) for 6. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO061409V
J. Org. Chem, Vol. 71, No. 22, 2006 8657