9-(4-Bromophenyl)-9-fluorenyl as a safety-catch nitro gen protecting group

Article abstract of DOI:10.1021/jo0521910

The 9-(4-bromophenyl)-9-fluorenyl (BrPhF) group has been developed as a novel safety-catch amine protection. This relatively acid-stable protecting group can be successfully activated by palladium-catalyzed cross-coupling reaction of the aryl bromide with morpholine and then cleaved effectively under mild conditions using dichloroacetic acid and triethylsilane. Complementary conditions are reported for selective removal of the BrPhF group in the presence of tert-butyl esters and carbamates as well as deprotection of tert-butyl esters and carbamates in the presence of BrPhF amines.

Full text of DOI:10.1021/jo0521910

tonation and epimerization.6 The PhF group is usually removed
by hydrogenolysis7 and by solvolysis with treatment under
strongly acidic conditions.8 Alternatively, the PhF group has
been removed using sodium or lithium in liquid ammonia,9
TMSOTf in the presence of triethylsilane,10 and iodine in
MeOH.11
Perceiving the advantages of having a chemical means for
rendering the PhF group cleavable under mildly acidic condi-
tions, we considered that p-aminophenylfluorenyl cations would
be significantly more stable than the parent PhF cation.
Strategies have been conceived for generating p-aminobenzylic
intermediates from suitable para-substituted benzyl derivatives.
For example, the p-nitrobenzyl ester has been used in the
synthesis of carbapenems and removed by nitro group reduction
and solvolysis.12 More recently, p-halobenzyl ethers were
reported to be as stable as normal benzyl ethers yet cleavable
using a two-step process featuring catalytic amination of the
aryl halide and solvolysis with acid.13
9-(4-Bromophenyl)-9-fluorenyl as a Safety-Catch
Nitrogen Protecting Group
Simon Surprenant and William D. Lubell*
De´partement de Chimie, UniVersite´ de Montre´al, C. P. 6128,
Succursale Centre Ville, Montre´al, Que´bec, Canada H3C 3J7
lubell@chimie.umontreal.ca
ReceiVed October 20, 2005
In our previous work, we used the 9-(4-bromophenyl)-9-
fluorenyl (BrPhF) group in a linking-protecting group strategy
for the synthesis of enantiopure norephedrines on solid support.14
The BrPhF group proved tolerant to similar chemistry previously
developed with PhF-protected amino acids before it reacted in
a palladium-catalyzed cross-coupling with bis(pinacolato)-
diboron ester to give a suitable boronate for attaching the PhF-
protected substrate to aryl halide resins. Pursuing the develop-
ment of this protecting group, we demonstrate now that the
BrPhF group can be employed as a safety-catch15 amine
protecting group which can be released by catalytic amination
followed by treatment with mild acid.
The relative acid stability of the PhF group and an analogue
bearing a p-aminophenyl substituent was studied by the synthesis
of N-(9-(4-morpholinophenyl)-9-fluorenyl)alanine methyl ester
2 and comparison of its reactivity under acid conditions with
N-(PhF)alanine methyl ester (Scheme 1, MPF ) 9-(4-morpholi-
nophenyl)-9-fluorenyl).
The 9-(4-bromophenyl)-9-fluorenyl (BrPhF) group has been
developed as a novel safety-catch amine protection. This
relatively acid-stable protecting group can be successfully
activated by palladium-catalyzed cross-coupling reaction of
the aryl bromide with morpholine and then cleaved ef-
fectively under mild conditions using dichloroacetic acid and
triethylsilane. Complementary conditions are reported for
selective removal of the BrPhF group in the presence of tert-
butyl esters and carbamates as well as deprotection of tert-
butyl esters and carbamates in the presence of BrPhF amines.
Both N-(PhF)- and N-(BrPhF)alanine methyl esters were
synthesized as previously described.14,16 Amination of BrPhF-
Ala-OMe (1) with morpholine using 5 mol % of Pd(OAc)2, (()-
BINAP, and excess Cs2CO3 provided N-(MPF)alanine methyl
ester (2) in 81% yield. Competitive cleavage of N-(PhF)alanine
Protecting groups have been essential for controlling the
reactivity of amines in organic synthesis, peptide science, and
medicinal chemistry.1,2 In the context of our research on the
synthesis of peptide mimics,3 the 9-phenyl-9-fluorenyl (PhF)
group has been used to prevent the loss of enantiomeric purity
during the employment of various amino carbonyl compounds.4
The PhF group offers several advantages as amine protection.
The steric bulk created by the PhF group acts as a barrier that
prevents deprotonation of R-amino carbonyl compounds at the
R-carbon. The PhF group is significantly more stable under acid
conditions relative to the trityl group because of the anti-
aromatic character of the 9-phenyl-9-fluorenyl carbocation.5
Furthermore, if deprotonation of the R-carbon occurs under
severe conditions, the PhF anion can act as a leaving group
and eliminate to furnish an imine intermediate prior to repro-
(6) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236-
239.
(7) Campbell, J. A.; Lee, W. K.; Rapoport, H. J. Org. Chem. 1995, 60,
4602-4616.
(8) Christie, B. D.; Rapoport, H. J. Org. Chem. 1985, 50, 1239-1246.
(9) Lubell, W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990, 55,
3511-3522.
(10) Hurt, C. R.; Lin, R. H.; Rapoport, H. J. Org. Chem. 1999, 64, 225-
233.
(11) Kim, J. H.; Lee, W. S.; Yang, M. S.; Lee, S. G.; Park, K. H. Synlett
1999, 614-616.
(12) Kumagai, T.; Abe, T.; Fujimoto, Y.; Hayashi, T.; Inoue, Y.; Nagao,
Y. Heterocycles 1993, 36, 1729-1734.
(13) Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem. Soc.
2000, 122, 7148-7149.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe groups in organic synthesis,
3rd ed.; Wiley: New York, 1999.
(2) Kocienski, P. J. Protecting groups, 3rd ed.; Thieme: Stuttgart, 2004.
(3) Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers 2000, 55, 101-
122.
(4) Cluzeau, J.; Lubell, W. D. J. Org. Chem. 2004, 69, 1504-1512.
(5) Bolton, R.; Chapman, N. B.; Shorter, J. J. Chem. Soc. 1964, 1895.
(14) Gosselin, F.; Van Betsbrugge, J.; Hatam, M.; Lubell, W. D. J. Org.
Chem. 1999, 64, 2486-2493.
(15) Kenner, G. W.; McDermott, J. R.; Sheppard, R. C. J. Chem. Soc.,
Chem. Commun. 1971, 12, 636-637.
(16) (a) Jamison, T. F.; Rapoport, H. Org. Synth. 1993, 71, 226. (b)
Jamison, T. F.; Lubell, W. D.; Dener, J. M.; Krische´, M. J.; Rapoport, H.
Org. Synth. 1993, 71, 220.
10.1021/jo0521910 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/15/2005
848
J. Org. Chem. 2006, 71, 848-851

SCHEME 1. Synthesis and Solvolysis of N-(MPF)alanine
SCHEME 2. Synthesis and Solvolysis of N-(MPF)-Protected
Estersa
Dipeptidesa
a Key: (a) Pd(OAc)2, (()-BINAP, Cs2CO3, morpholine, PhCH3, reflux;
(b) CHCl2CO2H, Et3SiH, CH2Cl2; (c) LiOH, H2O/dioxane; (d) O-tert-butyl
trichloroacetamidate, CH2Cl2; (e) Boc2O, Et3N, CH2Cl2.
a Key: (a) DCC, HOBt, DIEA, CH2Cl2; (b) Pd(OAc)2, (()-BINAP,
Cs2CO3, morpholine, PhCH3, reflux; (c) (i) CHCl2CO2H, Et3SiH, CH2Cl2,
(ii) Et3N, ClCO2Me; (d) (i) CHCl2CO2H, Et3SiH, CH2Cl2, (ii) Et3N,
FmocOSu.
methyl ester and N-(MPF)alanine methyl ester (2) was per-
formed by treating an equimolar mixture of the protected amino
acids in CH2Cl2 with trichloroacetic acid and triethylsilane.
Under these conditions, the 9-(4-morpholinophenyl)-9-fluorenyl
group was cleaved within 5 min as monitored by HPLC, which
detected 9-(4-morpholinophenyl)-9-fluorene (3). The PhF-
protected methyl ester remained stable and no trace correspond-
ing to PhFH was observed by HPLC. Employing the milder
dichloroacetic acid under the same conditions, complete sol-
volysis of N-(MPF)alanine methyl ester (2) occurred within 30
min.
The selective removal of the BrPhF group from an amino
tert-butyl ester was next studied to establish cleaving conditions
tolerant to a more acid-labile group. N-(BrPhF)Alanine 4 was
synthesized as previously described by hydrolysis of methyl
ester 1 using LiOH.14 N-(BrPhF)alanine tert-butyl ester (5) was
then prepared in 81% yield by treating the amino acid with
O-tert-butyl trichloroacetimidate17 in dichloromethane followed
by chromatography. The conversion of N-(BrPhF)alanine tert-
butyl ester (5) to N-(MPF)alanine tert-butyl ester (6) was
achieved in 79% yield using the palladium-catalyzed reaction
conditions mentioned above. Exposure of a 1:1 mixture of
N-(PhF)alanine tert-butyl ester18 and N-(MPF)alanine tert-butyl
ester (6) to dichloroacetic acid and triethylsilane in CH2Cl2
caused selective deprotection in 30 min as monitored by HPLC
which indicated the appearance of morpholine 3 and no traces
of 9-phenylfluorene nor any corresponding acids after 30 min.
Treatment of N-(MPF)alanine tert-butyl ester (6) with 20 equiv
of dichloroacetic acid and 2 equiv of triethylsilane in CH2Cl2
for 30 min followed by addition of 22 equiv of triethylamine
and Boc2O provided N-(Boc)alanine tert-butyl ester in 84%
yield. Alternatively, alanine tert-butyl ester could be isolated
as its hydrochloride salt in 89% yield after MPF deprotection,
extraction with dilute aqueous HCl, and lyophilization.
To explore more deeply the strengths and limitations of this
protection group N-(BrPhF)alaninyl(ω-Boc)lysine tert-butyl
ester (11) was synthesized by coupling acid 4 with (ω-Boc)-
lysine tert-butyl ester using DCC and HOBt in 75% yield
(Scheme 2).
Conversion to the N-(MPF) dipeptide 12 was effected as
previously described in 78% yield. The MPF-protected amine
was selectively deblocked using CHCl2CO2H and Et3SiH and
the free amine was subsequently converted in situ to a methyl
carbamate using methylchloroformate and Et3N in 82% yield.
The 1H NMR spectrum of the crude mixture showed a one-to-
three ratio of singlets corresponding to the methyl and tert-
butyl protons for the carbamates indicating that no deprotection
of the Boc-protected amine had occurred. The LC-MS analysis
of the crude mixture also confirmed that Boc-deprotection did
not occur during the sequence. Using a similar protocol,
N-(Fmoc)alaninyl(ω-Boc)lysine tert-butyl ester (14) was syn-
thesized by deprotecting the MPF-amine and reprotecting using
FmocOSu and Et3N in 86% yield.
Selective removal of tert-butyl esters in the presence of PhF
amines has been recently reported to be effectively accomplished
using ZnBr2 in CH2Cl2.18 When BrPhF-Ala-OtBu (5) was
submitted to these conditions, N-(BrPhF)alanine was obtained
in 82% yield (Scheme 3). The acid stability of the BrPhF group
was demonstrated by the selective removal of the Boc group
using Cl2CHCO2H which afforded dipeptide 15 in 72% yield,
as well as by removal of both the tert-butyl ester and carbamate
groups using the stronger acid Cl3CCO2H to give dipeptide 16
in 73% yield. These results demonstrated that the orthogonal
nature of the BrPhF/tert-Bu combination of protecting groups
can be utilized in both directions.
In sum, we have demonstrated the utility of the 9-(4-
bromophenyl)-9-fluorenyl group as safety-catch amine protec-
tion. Similar to the PhF group, the BrPhF group may be used
to ensure the configurational stability of amino carbonyl
compounds. This relatively acid stable group can then be
rendered susceptible to mild acid solvolysis by palladium-
catalyzed amination. The potential of this strategy has been
illustrated by the palladium-mediated selective cleavage of the
BrPhF-amine in the presence of the acid labile tert-butyl ester
and carbamate groups and complementary removal of either Boc
(17) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc. Chem.,
Perkin Trans. 1 1985, 2247-2250.
(18) Kaul, R.; Brouillette, Y.; Sajjadi, Z.; Hansford, K. A.; Lubell, W.
D. J. Org. Chem. 2004, 69, 6131-6133.
J. Org. Chem, Vol. 71, No. 2, 2006 849

SCHEME 3. Selective tert-Butyl Ester and Carbamate Cleavage
give the unprotected amine as a hydrochloride salt. Alternatively,
after complete solvolysis of MPF-amine was observed by TLC,
the reaction mixture was treated with 22 equiv of Et3N followed
by 200 mol % of either Boc2O, methyl chloroformate or FmocOSu,
stirred overnight, diluted with CH2Cl2, washed with H2O, 0.5 N
HCl, and brine, dried over MgSO4, and concentrated. The crude
residue was purified by flash chromatography20 to give, respectively,
the Boc-, methyl carbamoyl- or Fmoc-protected amino ester.
(2S)-Alanine tert-Butyl Ester Hydrochloride (9). Lyophilization
of aqueous layer after solvolysis of 6 (190 mg, 0.4 mmol) gave 9
(65 mg, 89% yield) as a white solid: mp 170 °C dec (lit.19 mp 168
°C dec); [R]20 6.1 (c ) 1.0, EtOH) [lit.19 [R]20 3.0 (c ) 2.0,
group or both Boc and tert-butyl ester groups in the presence
of the BrPhF-amine. Considering the need for selective methods
for removing acid labile protecting groups, the BrPhF group
should find general utility in the synthesis of amines.
Experimental Section
(2S)-N-(BrPhF)alanine tert-Butyl Ester (5). To a stirred
suspension of (2S)-N-(BrPhF)alanine (540 mg, 1.32 mmol, prepared
according to ref 14) in CH2Cl2 (4 mL) was added O-tert-butyl
trichloroacetimidate (578 mg, 2.64 mmol). The mixture was stirred
for 1 day, filtered, evaporated, and resubmitted to the same
conditions as above for 2 days. Filtration and evaporation, followed
D
D
EtOH)]; HRMS calcd for C7H15NO2Na [M + Na]+ 168.0995, found
168.0987.
by chromatography (5% EtOAc in hexanes) gave ester 5 (495 mg,
1
81%) as a clear oil: [R]20 -51.3 (c 1.5, CH3OH); H NMR δ
N-(Fmoc)alaninyl-ω-(Boc)lysine tert-Butyl Ester (14). Chro-
matography of the product from 12 (30 mg, 0.11 mmol) using 30%
EtOAc/hexanes as eluant gave 14 as a white powder (22.0 mg,
86% yield): mp 67-69 °C; [R]20D -16.5 (c 1.0, CHCl3); 1H NMR
δ 7.76 (d, J ) 7.5 Hz, 2H), 7.59 (d, J ) 7.4 Hz, 2H), 7.39 (t, J )
7.2 Hz, 2H), 7.31 (tt, J ) 7.5, 1.2 Hz, 2H), 6.59 (d, J ) 6.7 Hz,
1H), 5.59 (s, 1H), 4.69 (s, 1H), 4.45 (m, 1H), 4.38 (d, J ) 7.0 Hz,
2H), 4.29 (m, 1H), 4.22 (t, J ) 7.0 Hz, 1H), 3.06 (d, J ) 5.5 Hz,
1H), 1.84 (m, 2H), 1.65 (m, 1H), 1.52-1.27 (m, 6H), 1.46 (s, 9H),
1.42 (s, 9H); 13C NMR δ 171.8, 171.0, 156.0, 155.8, 143.6, 141.1,
127.6, 126.9, 125.0, 119.8, 82.1, 79.0, 67.0, 52.4, 50.3, 47.0, 39.9,
33.5, 29.2, 28.3, 27.8, 21.9, 18.6; HRMS calcd for C33H45N3O7
[M + Na]+ 618.31389, found 618.31389.
4-[4-(9H-Fluoren-9-yl)phenyl]morpholine (3). The N-arylamine
3 was isolated by flash chromatography as the second eluting
compound of the crude residue in the solvolysis of the MPF-
protected amine 5: 1H NMR δ 7.82 (d, J ) 7.5 Hz, 2H), 7.42-
7.26 (m, 6H), 7.03 (d, J ) 8.5 Hz, 2H), 6.84 (d, J ) 8.3 Hz, 2H),
5.02 (s, 1H), 3.87 (t, J ) 4.8 Hz, 4H), 3.15 (t, J ) 4.8 Hz, 4H);
13C NMR δ 149.7, 147.9, 140.5, 128.7, 126.9, 126.8, 124.9, 119.4,
115.5, 66.6, 53.3, 49.0; MS (ESI, m/z) 328.3 (MH)+.
D
7.72 (d, J ) 7.8 Hz, 2H) 7.40-7.26 (m, 10H), 3.09 (s, 1H), 2.69
(q, J ) 7.1 Hz, 1H), 1.23 (s, 9H), 1.13 (d, J ) 7.1 Hz, 3H); 13C
NMR δ 175.4, 148.9, 148.6, 143.7, 140.3, 139.7, 130.9, 127.99,
127.96, 127.7, 127.6, 127.5, 125.4, 124.8, 120.7, 119.7, 119.5, 80.1,
72.3, 51.6, 27.5, 21.8; HRMS calcd for C26H27BrNO2 [M + H]+
464,1227, found 464.1219.
General Procedure for N-(MPF)amine Synthesis. The BrPhF-
protected amine (2.5 mmol) was dissolved in 5 mL of dry and
degassed toluene and treated with Pd(OAc)2 (28 mg, 0.13 mmol),
BINAP (79 mg, 0.13 mmol), and dry Cs2CO3 (4.07 g, 12.5 mmol),
followed by morpholine (257 µL, 3.0 mmol). The mixture was
heated at reflux and stirred for 24 h, filtered on Celite, washed
with CH2Cl2, and the combined filtrate and washings were
evaporated. The residue was chromatographed to afford the MPF-
protected amine.
(2S)-N-(MPF)alanine Methyl Ester (2). Chromatography of the
product from 1 (1.00 g, 2.4 mmol) using 20% EtOAc in hexanes
as eluant gave 2 (820 mg, 81% yield) as a yellowish solid: mp
62-64 °C; [R]20D -121.1 (c 2.2, CH3OH); 1H NMR δ 7.68 (dd, J
) 7.5 Hz, 2.5 Hz, 2H), 7.33 (m, 5H), 7.23 (m, 3H), 6.77 (d, J )
8.9 Hz, 2H), 3.82 (t, J ) 4.8 Hz, 4H), 3.30 (s, 3H), 3.10 (t, J ) 4.8
Hz, 4H), 2.77 (q, J ) 7.0 Hz, 1H), 1.12 (d, J ) 7.0 Hz, 3H); 13C
NMR δ 177.1, 150.1, 149.4, 148.8, 140.6, 139.9, 135.6, 128.0,
127.6, 127.2, 126.9, 125.8, 124.8, 119.8, 119.7, 115.1, 72.4, 66.7,
51.4, 51.2, 49.0, 21.4; HRMS calcd for C27H28N2O3Na [M + Na]+
451.1989, found 451.1992.
(2S)-N-(BrPhF)alanine (4). A stirred solution of N-(BrPhF)-
alanine tert-butyl ester (6) (45 mg, 0.1 mmol) in 0.5 mL of
dichloromethane was treated with ZnBr2 (110 mg, 0.5 mmol) at rt,
(19) Csanady, G.; Medzihradszky, K. Org. Prep. Proced. Int. 1988, 20,
180-184.
General Procedure for MPF-Solvolysis. The MPF-protected
amine (0.4 mmol) was dissolved in 4 mL of CH2Cl2, treated with
dichloroacetic acid (660 µL, 8 mmol) and triethylsilane (128 µL,
0.8 mmol), stirred at rt for 30 min, and evaporated on a rotary
evaporator. The residue was dissolved in 10 mL of Et2O and treated
with 10 mL of 0.5 M HCl solution. The aqueous phase was
separated, washed twice with 5 mL of Et2O, and lyophilized to
(20) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(21) Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero, L.; Sanchez-
Obregon, R.; Walls, F.; Ruano, J. L. G. Tetrahedron: Asymmetry 2000,
11, 3079-3090.
(22) Zeggaf, C.; Poncet, J.; Jouin, P.; Dufour, M. N.; Castro, B.
Tetrahedron 1989, 45, 5039-5050.
(23) Barton, D. H. R.; Herve, Y.; Potier, P.; Thierry, J. Tetrahedron 1988,
44, 5479-5486.
850 J. Org. Chem., Vol. 71, No. 2, 2006

stirred for 24 h, treated with water (2 mL), stirred for 2 h, and
treated with CH2Cl2 (5 mL). The organic phase was separated. The
aqueous layer was extracted twice with CH2Cl2 (2 mL). The organic
portions were combined, dried, filtered, and evaporated. The residue
was chromatographed (50% EtOAc:hexanes containing 1% AcOH)
to afford 32.5 mg (82% yield) of N-(BrPhF)alanine as a white
7.1 Hz, 1H), 1.73 (m, 1H), 1.64 (m, 3H), 1.53 (s, 9H), 1.29 (m,
2H), 1.08 (d, J ) 7.1 Hz, 3H); 13C NMR (CD3OD) δ 178.6, 172.5,
150.5, 149.3, 145.3, 142.4, 141.6, 132.3, 129.9, 129.7, 129.3, 128.4,
127.2, 125.8, 122.0, 121.1, 83.5, 74.2, 53.8, 53.3, 40.5, 33.1, 28.3,
28.0, 23.5, 21.5; HRMS calcd for C32H39BrN3O3Na [M + H]+
592.21693, found 592.21666.
solid: mp 116-118 °C; [R]20 -16.5 (c 1.1, CH3OH). The
N-(BrPhF)alaninyllysine (16). The BrPhF-protected dipeptide
11 (40 mg, 0.058 mmol) was dissolved in 300 µL of CH2Cl2, treated
with Cl3CCO2H (236 mg, 1.44 mmol), and stirred for 72 h. The
mixture was diluted with 5 mL of CH2Cl2, washed with 0.1 N HCl
(2 × 3 mL), lyophilized, triturated with Et2O, and purified on
D
spectroscopic data were identical to those reported.14
N-(BrPhF)alaninyl-ω-(Boc)lysine tert-Butyl Ester (11). N-
(BrPhF)alanine (4), (514 mg, 1.26 mmol), DCC (311 mg, 1.51
mmol), and HOBt (204 mg, 1.51 mmol) were dissolved in 13 mL
of CH2Cl2, treated with ω-(Boc)lysine tert-butyl ester (380 mg, 1.26
mmol), stirred for 24 h, filtered, washed with a 10% HCl solution,
saturated NaHCO3, and brine, dried over MgSO4, filtered, and
concentrated to a residue that was purified by chromatography (50%
EtOAc/hexanes) to afford 651 mg (75% yield) of 11 as a white
powder: mp 83-85 °C; [R]20D -20.8 (c 1.0, CH3OH); 1H NMR δ
7.96 (d, J ) 7.6 Hz, 1H), 7.72 (d, J ) 7.5 Hz, 1H), 7.62 (d, J )
7.5 Hz, 1H), 7.44-7.25 (m, 9H), 7.05 (t, J ) 7.5 Hz, 1H), 4.68
(m, 1H), 4.27 (q, J ) 7.2 Hz, 1H), 3.10 (m, 2H), 2.47 (q, J ) 7.1
Hz, 1H), 2.25-1.80 (bs, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 1.54 (s,
9H), 1.43 (s, 9H), 1.54-1.43 (m, 2H), 1.29 (m, 2H), 1.09 (d, J )
7.1 Hz, 3H); 13C NMR δ 175.1, 171.8, 156.1, 148.9, 147.3, 143.5,
141.4 140.0, 131.6, 128.9, 128.8, 128.2, 128.1, 127.7, 126.1, 124.3,
121.4, 120.4, 120.2, 82.2, 79.1, 73.0, 52.8, 51.9, 40.4, 33.0, 29.5,
28.5, 28.1, 22.2, 21.8; HRMS calcd for C37H46BrN3O5Na [M +
Na]+ 714.25131, found 714.25002.
N-(BrPhF)alaninyllysine tert-Butyl Ester (15). N-(BrPhF)-
alaninyl(ω-Boc)lysine tert-butyl ester 11 (50 mg, 0.072 mmol) was
dissolved in 150 µL of CH2Cl2, treated with 150 µL of Cl2CHCO2H,
and stirred for 21 h. The mixture was diluted with 5 mL of CH2-
Cl2, washed with saturated NaHCO3 (2 × 3 mL), dried over MgSO4,
concentrated, and purified by chromatography (5% MeOH/CHCl3
+ 1% Et3N) to give amine 15 (30.7 mg, 72% yield) as a brownish
oil: [R]20D 39.7 (c 2.6, CHCl3); 1H NMR (CD3OD) δ7.80 (d, J )
7.5 Hz, 1H), 7.73 (d, J ) 7.5 Hz, 1H), 7.46-7.26 (m, 9H), 7.08
(dt, J ) 1.0, 7.6 Hz, 1H), 4.06 (m, 1H), 2.90 (m, 2H), 2.44 (q, J )
reversed-phase preparative HPLC to afford 16 (22.6 mg, 73% yield)
1
as a white gum: [R]20 -3.1 (c 1.1, CH3OH); H NMR (D2O) δ
D
7.78 (d, J ) 7.5 Hz, 1H), 7.66 (d, J ) 7.4 Hz, 1H), 7.47 (t, J ) 7.2
Hz, 1H), 7.32 (m, 3H) 7.21 (d, J ) 8.5 Hz, 2H), 7.12 (m, 2H),
6.98 (d, J ) 8.6 Hz, 2H), 3.47 (t, J ) 6.6 Hz, 1H), 3.12 (q, J ) 6.6
Hz, 1H), 2.87 (m, 2H), 1.51 (m, 2H), 1.33 (m, 2H), 1.19 (d, J )
7.1 Hz, 3H), 1.01 (m, 2H);13C NMR (D2O) δ 175.5, 170.1, 140.8,
140.3, 140.1, 131.6, 130.8, 130.6, 129.0, 127.9, 126.9, 126.8, 124.9,
122.0, 120.9, 120.4, 73.3, 53.2, 52.7, 38.6, 29.5, 26.0, 21.6, 16.9;
HRMS calcd for C28H31BrN3O3 [M + H]+ 536.15433, found
536.15304.
Acknowledgment. This work was supported by grants from
Fonds Que´becois de la Recherche sur la Nature et les Technolo-
gies (FQRNT) and the Natural Sciences and Engineering
Research Council of Canada (NSERC). We thank Mr. Dalbir
Sekhon and Dr. Alexandra Fu¨rto¨s for mass spectral analysis.
Supporting Information Available: General Experimental
1
Section, H and 13C NMR data for compounds 6, 8, 10, 12, and
1
13, copies of H and 13C NMR spectra of compounds 2, 3, 5, 6,
and 11-16, and HPLC traces of competitive cleavage experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0521910
J. Org. Chem, Vol. 71, No. 2, 2006 851