An efficient route to either enantiomer of trans-2-aminocyclopentanecarboxylic acid

Full text of DOI:10.1021/jo010279h

J . Org. Chem. 2001, 66, 5629-5632
5629
ond, (S,S)-ACPC derivatives are not available via this
route. Inability to prepare (S,S)-ACPC and derivatives
is a serious limitation in terms of biological applications
because the 12-helix promoted by this ACPC enantiomer
has the same helical sense as an R-helix formed by
conventional peptides. 12-Helical â-peptides containing
(S,S)-ACPC residues may serve as antagonists of protein-
protein interactions that depend on R-helix recognition.
Several alternative asymmetric routes to ACPC have
been reported,8,9 but none is efficient enough for our long-
term goals, which require that we be able to prepare
multigram quantities of enantiomerically pure material
in a few days from commerically available precursors.
Work by Bartoli et al.10 (eq 1) inspired the first new route
An Efficien t Rou te to Eith er En a n tiom er of
tr a n s-2-Am in ocyclop en ta n eca r boxylic Acid
Paul R. LePlae, Naoki Umezawa, Hee-Seung Lee, and
Samuel H. Gellman*
Department of Chemistry, University of Wisconsin,
Madison, Wisconsin 53706-1396
gellman@chem.wisc.edu
Received March 12, 2001
Oligomers of â-amino acids (â-peptides) can be de-
signed to adopt a variety of secondary structures, helix,
sheet, or turn, by proper choice of residue substitution
pattern.1 â-Peptide helices have proven to be very stable
conformationally, with oligomers containing as few as six
residues displaying high helix populations in aqueous
solution.2 The predictability and stability of â-peptide
conformations have led recently to the design of specific
â-peptides with useful biological activities.3 Further
exploration of â-peptide function will be facilitated by
improvements in the synthesis of the requisite â-amino
acids.4
We have shown that oligomers composed of trans-2-
aminocyclopentanecarboxylic acid (ACPC) adopt a helical
conformation that contains a network of 12-membered
ring hydrogen bonds between backbone CdO and N-H
groups (12-helix).5 Use of a pyrrolidine-based analogue
of ACPC allowed us to generate short water-soluble
â-peptides and to demonstrate that these oligomers fold
to the 12-helix in aqueous solution.2 We have recently
shown that an ACPC-containing â-peptide displays in-
teresting antibiotic activity.3c The synthesis of protected
ACPC derivatives we originally employed5 was service-
able for moderate quantities of only the R,R enantiomer.
Here, we report a more efficient synthesis of ACPC
derivatives that gives access to either enantiomeric series
in large quantities (> 20 g).
we explored. These workers demonstrated that the
reduction of the cyclic â-enamino esters with sodium
metal results in formation of trans γ-amino alcohols in
high yield and with excellent diastereoselectivity. We
hypothesized that replacement of benzylamine with
enantiomerically pure R-methylbenzylamine11 would re-
sult in reduction to produce predominantly trans dia-
stereomeric γ-amino alcohols, which could be separated
by simple recrystallization of the corresponding HCl salts.
It seemed likely that, after purification, the desired
γ-amino alcohol could be carried on to enantiomerically
pure Fmoc-ACPC.
The results of this synthetic endeavor are summarized
in Scheme 2. â-Ketoester 1 was allowed to react with (S)-
R-methylbenzylamine in refluxing benzene with a cata-
lytic amount of toluenesulfonic acid. The resulting enam-
ine 6 was isolated as a yellow oil after distillation. The
enamine was reduced with sodium in THF/iPrOH to a
diastereomeric mixture of four γ-amino alcohols. Unfor-
tunately, this reaction also produced significant amounts
of Birch reduction side products. Nevertheless, after HCl
was added to the reaction mixture, the HCl salt of the
desired amino alcohol could be obtained in 20% yield by
multiple recrystallizations. The configuration of the
desired diastereomer was confirmed by X-ray cystallog-
Scheme 1 shows our previous route to (R,R)-ACPC
derivatives,5 which is closely based on work of Tilley et
al.6 This route suffers from two major drawbacks. First,
the scale is limited by the need for large volumes of water
for the baker’s yeast reduction7 and by the tedious
filtration, extraction and chromatography required. Sec-
(1) (a) DeGrado, W. F.; Schneider, J . P.; Hamuro, Y. J . Peptide Res.
1999, 54, 206. (b) Gademann, K.; Hintermann, T.; Schreiber, J . V. Curr.
Med. Chem. 1999, 6, 905. (c) Recently reported â-peptides: Winkler,
J . D.; Piatnitski, E. L.; Mehlmann, J .; Kasparec, J .; Axelsen, P. H.
Angew. Chem., Int. Ed. 2001, 40, 743. Motorina, I. A.; Huel, C.;
Quiniou, E.; Mispelter, J .; Adjadj, E.; Grierson, D. S. J . Am. Chem.
Soc. 2001, 123, 8.
(8) Review: Fu¨lo¨p, F. Stud. Nat. Prod. Chem. 2000, 22, 273.
(9) (a) Yamazaki, T.; Zhu, Y.-F.; Probstl, A.; Chadha, R. K.; Good-
man, M. J . Org. Chem. 1991, 56, 6644. (b) Davies, S. G.; Ichihara, O.;
Lenoir, I.; Walters, L. A. S. J . Chem. Soc., Perkin Trans. 1 1994, 1411.
(c) Kanerva, L. T.; Csomo´s, P.; Sundholm, O.; Berna´th, G.; Fu¨lo¨p, F.
Tetrahedron: Asymmetry 1996, 7, 1705. (d) Enders, D.; Wiedemann,
J . Liebigs Ann./ Recueil 1997, 699. (e) No¨teberg, D.; Brånalt, Kvarn-
stro¨m, I.; Classon, B.; Samuelsson, B.; Nillroth, U.; Danielson, U. H.;
Karle´n, A.; Hallberg, A. Tetrahedron 1997, 53, 7975.
(10) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini,
M. J . Org. Chem. 1994, 59, 5328.
(11) Reviews on the use of R-methylbenzylamine to prepare enan-
tiomerically pure molecules: J uaristi, E.; Escalante, J .; Leo´n-Romo,
J . L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715. J uaristi, E.;
Leo´n-Romo, J . L.; Reyes, A.; Escalante, J . Tetrahedron: Asymmetry
1999, 10, 2441.
(2) Wang, X.; Espinosa, J . F.; Gellman, S. H. J . Am. Chem. Soc.
2000, 122, 4821.
(3) (a) Werder, M.; Hausre, H.; Abele, S.; Seebach, D. Helv. Chim.
Acta 1999, 82, 1774. (b) Hamuro, Y.; Schneider, J . P.; DeGrado, W. F.
J . Am. Chem. Soc. 1999, 121, 12200. (c) Porter, E. A.; Wang, X.; Lee,
H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404, 565.
(4) For the current state of â-amino acid synthesis, see: J uaristi,
E.; Lo´pez-Ruiz, H. Curr. Med. Chem.1999, 6, 983 and references
therein.
(5) Appella, D. H.; Christianson, L. A.; Klein, D. A.; Richards, M.
R.; Powell, D. R.; Gellman, S. H. J . Am. Chem. Soc. 1999, 121, 7574.
(6) Tilley, J . W.; Danho, W.; Shiuey, S.; Kulesha, I.; Swistok, J .;
Makofske, R.; Michalewsky, J .; Triscari, J .; Nelson, E.; Weatherford,
S.; Madison, V.; Fry, D.; Cook, C. J . Med. Chem. 1992, 35, 3774.
(7) Herrado´n, B.; Seebach, D. Helv. Chim. Acta 1989, 72, 690.
10.1021/jo010279h CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/11/2001

5630 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
Sch em e 1
Sch em e 2
raphy. Removal of the chiral auxiliary was accomplished
by transfer hydrogenation, and the resulting primary
γ-ammonium alcohol was protected with Fmoc-OSu.
Finally, oxidation of the primary alcohol provided (S,S)-
Fmoc-ACPC.
Although the route in Scheme 2 gives access to either
enantiomer of ACPC, it suffers from low yields in the
enamine reduction. In addition, when this reaction was
run on a larger scale the yields declined because of Birch
reduction. The reduction step could probably be improved
with careful attention, but we decided to investigate
another route.
Scheme 3 but starting with (R)-(+)-R-methylbenzylamine
provided (1R,2R)-5.
In summary, we have developed two new asymmetric
routes that provide either enantiomer of Fmoc-ACPC,
which is a building block for the solid-phase synthesis of
â-peptides. The better of these syntheses allows prepara-
tion of multigram quantities of enantiomerically pure
Fmoc-ACPC in four steps without the need for chroma-
tography. This route will facilitate investigation of the
conformational and biological properties of 12-helical
â-peptides.
The route in Scheme 3 was inspired by our recent
success with reductive amination of â-ketoester 9 to
â-aminoester 10 (eq 2).12 Subjecting â-ketoester 1 to
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined on a
capillary melting point apparatus and are uncorrected. Optical
rotations were measured using sodium light (D line, 589.3 nm).
THF was distilled from sodium/benzophenone ketyl under N2.
All commercially available reagents and solvents were purchased
from Aldrich and used without further purification, with the
exception of 4 N HCl in dioxane, which was purchased from
Pierce, and Fmoc-OSu, which was purchased from Advanced
ChemTech. Analytical thin-layer chromatography (TLC) was
carried out on Whatman TLC plates precoated with silica gel
60 (250 µm layer thickness). Visualization was accomplished
using either UV lamp or potassium permanganate stain (2 g of
KMnO4, 13.3 g of K2CO3, 3.3 mL of 5% (w/w) NaOH, 200 mL of
H2O). Column chromatography was performed on EM Science
silica gel 60 (230-400 mesh). Solvent mixtures used for TLC
and column chromatography are reported in v/v ratios. Diaster-
eomeric excesses were determined using 1H NMR.
Eth yl 2-[(1′S)-P h en yleth yla m in o]-cyclop en t-1-en e Ca r -
boxlyla te (6). To a stirred solution of â-ketoester 1 (31 mL, 209
mmol) in benzene (135 mL) under N2 atmosphere was added
(S)-(-)-R-methylbenzylamine (25 mL, 194 mmol) and TsOH (25
mg). The resulting solution was heated to reflux for 16 h, during
which time water was azeotropically removed via a Dean-Stark
trap. After removal of the benzene under reduced pressure, the
resulting orange oil was distilled (135 °C, 1 mmHg) to give 6
(42.7 g, 85%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.82
(d, J ) 6.4 Hz, 1H), 7.33-7.18 (m, 5H), 4.53 (p, J ) 7.1), 4.17
(m, 2H), 2.56-2.4 (m, 3H), 2.21 (m, 1H), 1.81-1.58 (m, 2H), 1.49
(d, J ) 7.0 Hz, 3H), 1.28 (t, J ) 7.2 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 168.4, 164.0, 145.1, 128.6, 126.9, 125.3, 93.4, 58.3, 54.2,
32.2, 28.8, 24.8, 20.8, 14.6.
reductive amination provided the â-aminoester 12 in 40%
yield after chromatography. Alternatively we found that
a three-step recrystallization of the HCl salt of the crude
product afforded â-ammonium ester in 29% yield. Reduc-
tive removal of the chiral auxiliary followed by saponi-
fication and protection of the amine with Fmoc-OSu
resulted in the desired (1S,2S)-Fmoc-ACPC in 25%
overall yield from 1 without need for chromatography.
1H NMR indicated that (1S,2S)-5 prepared in this way
was identical to (1S,2S)-5 synthesized via the previous
route (Scheme 2) as well as (1R,2R)-5 from our original
synthesis. Finally, the optical rotation of (1S,2S)-5 was
of the same magnitude as but opposite in sign to the
optical rotation of (1R,2R)-5. Following the route in
(12) Lee, H.-S.; LePlae, P. R.; Porter, E. A.; Gellman, S. H. J . Org.
Chem. 2001, 66, 3597.

Notes
J . Org. Chem., Vol. 66, No. 16, 2001 5631
Sch em e 3
(1S,2S)-2-Hydr oxym eth yl-cyclopen tyl-[(1′S)-ph en yleth yl]-
NaCl (30 mL) was added dropwise over 25 min. One hour after
the final addition, the yellow solution was acidified with 1 N
HCl to pH 3 and extracted with EtOAc. The organic layer was
dried over MgSO4 and concentrated under reduced pressure, and
the resulting oil was subjected to silica gel chromatography (6:
3:0.5 hexane/EtOAc/AcOH, Rf ) 0.33). Concentration of the
appropriate fractions yielded 390 mg (70%) of (1S, 2S)-5: mp
a m in e Hyd r och lor id e (7). â-Enamino ester 6 (7.6 g, 29.3
mmol) was dissolved in a mixture of THF (75 mL) and i-PrOH
(30 mL) under N2. Sodium was added in 1 g portions until all of
the starting material was consumed (5-7 h) according to TLC
(6% MeOH in CH2Cl2, Rf ) 0.9). The excess sodium was re-
moved, and the reaction was quenched with 75 mL of saturated
NH4Cl. The organic layer was concentrated, and the residue was
shaken with CH2Cl2. The organic layer was separated, washed
with brine, and dried with K2CO3. After concentration, the
orange oil was passed through a plug of silica, eluting with 10%
MeOH in CH2Cl2. The eluted solution was concentrated to afford
a yellow oil. The yellow oil was dissolved in 200 mL of EtOAc,
and 7.5 mL of 4 N HCl in dioxane was added dropwise with
stirring. The solution was stored at 0 °C for 2 h, and the resulting
white solid was isolated by filtration and washed with ether.
Multiple recrystallizations from MeOH/ether gave 1.49 g (20%
yield) of γ-ammonium alcohol 7 as a white crystalline solid: mp
230-231 °C; 1H NMR (300 MHz, D2O) δ 7.55-7.49 (m, 5H), 4.53
(q, J ) 6.8 Hz, 1H), 3.55 (m, 1H), 3.37 (m, 1H), 2.31 (m, 1H),
2.04-1.84 (m, 2H), 1.80-1.58 (m, 3H), 1.79 (d, J ) 6.9 Hz, 3H),
1.52-1.42 (m, 1H); 13C NMR (75 MHz, D2O) δ 137.8, 131.0,
130.9, 128.9, 64.6, 61.4, 58.8, 46.3, 31.7, 28.8, 24.5, 20.1.
(1S,2S)-2-Hyd r oxym eth yl-cyclop en tyl-(9H-flu or en -9-yl-
m eth oxy)-ca r ba m a te (8). γ-Ammonium alcohol 7 (1.1 g, 4
mmol) was dissolved in 35 mL of MeOH. 10% Pd/C (1.1 g) and
HCO2NH4 (5.2 g, 83 mmol) were added, and the reaction mixture
was heated at reflux until the starting material was completely
consumed (3-4 h) according to TLC (20% MeOH in CH2Cl2, Rf
) 0.22). After the reaction mixture had cooled to room temper-
ature, the mixture was filtered through a pad of Celite, and the
filtrate was concentrated to yield a white solid (0.6 g). The white
solid was dissolved in a mixture of acetone (24 mL) and water
(12 mL), and NaHCO3 (1.5 g, 17.9 mmol) and Fmoc-OSu (1.48
g, 4.4 mmol) were added. The reaction mixture was stirred under
N2 for 24 h. The acetone was removed under reduced pressure,
the residue was diluted with water, and the product was
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and concentrated. The resulting white solid was purified
via chromatography (1:1 hexane/EtOAc, Rf ) 0.28) to yield 1.1
g (85%) of 8 as a white solid: mp 140-141 °C (recrystallized
from hexane/CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J )
7.4 Hz, 2H), 7.57 (d, J ) 7.4 Hz, 2H), 7.39 (t, J ) 7.2 Hz, 2H),
7.30 (td, J ) 7.4 Hz, 1.4 Hz), 5.00 (d, J ) 7.0 Hz, 1H), 4.41 (d,
J ) 6.8 Hz, 2H), 4.18 (t, J ) 6.7 Hz, 1H), 3.73 (m, 1H), 3.59 (m,
1H), 3.48 (m, 2H), 2.03 (m, 1H), 1.79 (m, 2H), 1.59 (m, 2H), 1.5-
1.3 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 157.0, 143.8, 141.3,
127.7, 127.1, 125.0, 120.0, 66.7, 64.3, 55.2, 49.9, 47.2, 33.1, 27.6,
22.6.
164-165 °C (recrystallized from heptane/methanol); [R]23
)
D
36.3 (c 1.21, MeOH); 1H NMR (DMSO-d6, 300 MHz) δ 7.87 (d, J
) 7.2 Hz, 2H), 7.73-7.61 (m, 2H), 7.50-7.26 (m, 4H), 4.35-15
(m, 3H), 4.08-3.94 (m, 1H), 2.56 (q, 1H), 2.04-1.78 (m, 2H),
1.77-1.35 (m, 4H); 13C NMR (DMSO-d6, 75.4 MHz) δ 175.98,
155.53, 143.97, 143.88, 140.75, 127.63, 127.09, 125.16, 120.13,
65.26, 55.41, 49.39, 46.76, 32.61, 28.48, 22.92; HRMS FAB m/z
374.0 [M + Na]+.
Eth yl (1S,2S)-2-[(1′S)-P h en yleth yl]-a m in ocyclop en ta n e
Ca r boxyla te Hyd r och lor id e (11). To a stirred solution of
â-ketoester 1 (40 mL, 270 mmol) in absolute ethanol (320 mL)
under N2 was added (S)-(-)-R-methylbenzylamine (69.6 mL, 540
mmol) and glacial acetic acid (30.8 mL, 540 mmol). The reaction
mixture was stirred at room temperature until the formation of
the enamine was complete (2 h; monitored by TLC, 7:3 hexane/
EtOAc, Rf ) 0.22). The reaction mixture was diluted with 640
mL of absolute ethanol and heated to 72 °C, and sodium
cyanoborohydride (42.4 g, 675 mmol) was then added to the
reaction mixture in five portions over
a 5 h period. The
disappearance of enamine was monitored by TLC. Through the
course of the reaction a solid formed on the surface that hindered
efficient mixing of additional sodium cyanoborohydride. This
solid could be broken up with a spatula or by use of a mechanical
stirrer. When the reaction was complete (6-8 h), 200 mL of H2O
was added, and the ethanol was removed via rotary evaporation
in a well ventilated hood (Ca u tion : P ossible HCN evolu -
tion !!). The resulting mixture was extracted with diethyl ether
(700 mL). The ethereal solution was passed through a plug of
silica, eluting with an additional 1.5 L of ether. The filtrate was
concentrated, the resulting oil was dissolved in EtOAc (1.2 L),
and 4 N HCl in dioxane (65 mL) was added dropwise at room
temperature with stirring. The resulting solution was stored at
0 °C for 1 h. A white precipitate formed during this time. The
solid was isolated by filtration and washed with EtOAc (200 mL).
(The EtOAc filtrate was used to obtain a small amount of the
1R,2R diastereomer, as described below.) This solid could be
purified by recrystallization from ethanol (75 g of solid in 450
mL ethanol). The resulting solid was filtered and washed with
acetonitrile and then recrystallized from acetonitrile (27 g in 400
mL). After filtration and drying, 23 g of 11 was obtained as a
white crystalline solid (29% yield from 1). 1H NMR of the
corresponding free amine (12) indicated the diastereomeric
excess to be > 99%. Characterization of 11: mp 240-241 °C;
1H NMR (300 MHz, CD3OD) δ 7.53-7.40 (m, 5H), 4.44 (q, J )
6.6 Hz, 1H), 4.14 (m, 2H), 3.80 (dt, J ) 8.1 Hz, 6.4 Hz, 1H), 3.11
(m, 1H), 2.27-2.00 (m, 2H), 1.89-1.59 (m, 7H), 1.24 (t, J ) 7.2
Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 137.8, 130.6, 130.5, 128.7,
62.4, 60.4, 59.1, 48.6, 31.8, 31.1, 25.1, 20.2, 14.4.
(1S,2S)- 2-(9H-F lu or en -9-ylm eth oxyca r bon yla m in o)-cy-
clop en ta n e Ca r boxyla te [(1S,2S)-5] fr om Alcoh ol 8. Alcohol
8 (535 mg, 1.59 mmol) was dissolved in CH2Cl2 (20 mL). To the
resulting solution was added TEMPO (10 mg, 0.064 mmol), satu-
rated NaHCO3 (10 mL), KBr (50 mg, 0.42 mmol), and nBu4NBr
(60 mg 0.19 mmol). The reaction mixture was cooled to 0 °C,
and a solution of bleach (24 mL, 5.25% NaOCl by weight),
saturated aqueous NaHCO3 (15 mL), and saturated aqueous
Eth yl (1S,2S)-2-[(1′S)-P h en yleth yl]-a m in ocyclop en ta n e
Ca r boxyla te (12). A sample of 11 was mixed with an excess of

5632 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
saturated NaHCO3 solution, extracted into diethyl ether, dried
over MgSO4, and concentrated under reduced pressure to give
12 as a clear oil: Rf ) 0.24, 7:3 hexane/EtOAc; 1H NMR (300
MHz, CDCl3) δ 7.33-7.19 (m, 5H), 4.18-4.03 (m, 2H), 3.83 (q,
J ) 6.6 Hz, 1H), 3.21 (q, J ) 7.1 Hz, 1H), 2.56 (dt, J ) 8.9 Hz,
7.0 Hz, 1H), 1.95 (m, 1H), 1.79 (m, 2H), 1.61 (m, 3H), 1.32 (d, J
) 6.6 Hz, 3H), 1.29 (m, 1H), 1.23 (t, J ) 7.1 Hz); 13C NMR (75
MHz, CDCl3) δ 175.8, 145.8, 128.1, 126.6, 126.4, 61.5, 56.5, 51.2,
34.2, 26.7, 24.5, 23.5, 14.0.
mixture was shaken under H2 (50 psi) for 48 h. After the reaction
was complete (the disappearance of starting material was
monitored by TLC), the mixture was filtered through Celite, and
the filtrate was concentrated to obtain the HCl salt of (1S,2S)-
aminocyclopentanecarboxylic acid as a white solid, which was
used for the next step without further purification: 1H NMR
(DMSO-d6, 300 MHz) δ 8.68 (br s, 2H), 3.62-3.49 (q, 1H), 2.94-
2.80 (m, 1H), 2.11-1.37 (m, 6H); 13C NMR (DMSO-d6, 75 MHz)
δ 174.96, 53.38, 48.26, 30.85, 29.48, 23.49; HRMS FAB m/z 152.1
[M + Na]+.
The diastereomer of 12, ethyl (1R,2R)-2-[(1′S)-phenylethyl]-
aminocyclopentane carboxylate, was obtained in the following
way for use as a standard in the NMR-based determination of
the de of 12. The EtOAc filtrate mentioned in the procedure for
11 was shaken with solid NaHCO3, and the NaHCO3 was then
removed by filtration. The solution was concentrated, and the
residue was purified by chromatography to give ethyl (1R,2R)-
2-[(1′S)-phenylethyl]-aminocyclopentane carboxylate as a clear
oil: Rf ) 0.15, 7:3 hexane/EtOAc; 1H NMR (300 MHz, CDCl3) δ
7.35-7.20 (m, 5H), 4.10 (m, 2H), 3.79 (q, J ) 6.7 Hz, 1H), 3.02
(q, J ) 8.0 Hz, 1H), 2.50 (q, J ) 8.4 Hz, 1H), 1.99-1.86 (m, 2H),
1.82-1.50 (m, 4H), 1.41 (m, 1H), 1.35 (d, J ) 6.7 Hz, 3H), 1.23
(t, J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 175.2, 145.3, 128.2,
126.7, 126.2, 60.1, 60.1, 51.0, 32.6, 27.9, 24.7, 23.0, 14.1.
(1S,2S)-2-(9H-F lu or en -9-ylm eth oxyca r bon yla m in o)-cy-
clop en ta n e Ca r boxyla te [(1S,2S)-5] fr om â-Am m on iu m
Ester 11. Compound 11 (6.27 g, 21.0 mmol) was dissolved in
THF/MeOH/H2O (6:3:1, 100 mL), and the solution was cooled
to 0 °C. LiOH‚H2O (4.41 g, 105 mmol) was added. The mixture
was stirred at 0 °C for 9 h. Aqueous HCl (1 N, 110 mL) was
added at 0 °C. The solvent was then removed on a vacuum rotary
evaporator to give (1S,2S)-2-[(1′S)-phenylethyl]-aminocyclopen-
tanecarboxylic acid as a white solid, which was used for the next
step without further purification: 1H NMR (DMSO-d6, 300 MHz)
δ 10.12 (br s, 2H), 7.68-7.57 (m, 2H), 7.38-7.25 (m, 3H), 4.21
(m, 1H), 3.37-3.20 (m, 2H), 2.15-1.99 (m, 1H), 1.94-1.68 (m,
3H), 1.58 (d, J ) 6.6 Hz, 3H), 1.64-1.47 (m, 1H), 1.45-1.28 (m,
1H); 13C NMR (DMSO-d6, 75 MHz) δ 175.21, 137.40, 128.89,
128.77, 128.29, 58.57, 56.76, 46.22, 31.13, 30.86, 24.44, 20.95;
HRMS FAB m/z 256.3 [M + Na]+.
This solid was dissolved in acetone/H2O (2:1, 300 mL) and
cooled to 0 °C, and Fmoc-Osu (8.92 g, 26.4 mmol) and NaHCO3
(17.1 g, 203 mmol) were added. The reaction mixture was stirred
at 0 °C for 1 h and was then allowed to stir at room temperature
overnight. Water (100 mL) was added. The acetone was removed
under reduced pressure. The aqueous residue was diluted with
water (300 mL) and stirred for 1 h with diethyl ether (300 mL).
The layers were separated, and the aqueous layer was acidified
with 1 N aqueous HCl and extracted with ethyl acetate. The
organic layer was dried over MgSO4 and concentrated to give a
white solid. The crude product was purified by crystallization
from n-hexane/CH2Cl2 to afford 6.31 g (85%) of (1S,2S)-5 as a
white solid. This material was identical to the material produced
from alcohol 8 (characterization above).
Ack n ow led gm en t. This research was supported by
the National Institutes of Health (GM56414) and the
Leukemia Society of America. P.R.L. was supported in
part by a fellowship from Kodak. N.U. was supported
in part by a Research Fellowship for Young Scientists
from the J apan Society for the Promotion of Science.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR for
compounds 5-7, 11, and 12, as well as some additional
intermediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
The white solid was dissolved in 300 mL of 95% ethanol in a
hydrogenation flask; 10% Pd-C (2.0 g) was added. The resulting
J O010279H