Using cross-metathesis to couple L-phenylalanine to a macrocyclic lactam

Article abstract of DOI:10.1021/jo052415e

Grubbs' second generation ruthenium catalyst was used to couple the amino acid L-phenylalanine to a 17-membered lactam, using cross-metathesis with an E-alkene favored in the process. The best coupling conditions gave the product in 48% yield. The reversi

Full text of DOI:10.1021/jo052415e

Using Cross-Metathesis to Couple L-Phenylalanine to a Macrocyclic
Lactam
Eric Enholm* and Tammy Low
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
enholm@chem.ufl.edu
ReceiVed NoVember 22, 2005
Grubbs’ second generation ruthenium catalyst was used to couple the amino acid L-phenylalanine to a
17-membered lactam, using cross-metathesis with an E-alkene favored in the process. The best coupling
conditions gave the product in 48% yield. The reversibility of the process was also confirmed. Ring-
closing metathesis was a key reaction used to form the macrocyclic lactam.
Introduction
Peptidomimetic research is a vital tool for the field of
medicinal chemistry. One approach toward the synthesis of
peptidomimetics is to use a molecular template or scaffold to
which important pharmacophoric groups such as amino acid
side chains are covalently anchored.1-4 These molecules have
an excellent potential for chiral discrimination and display
stabilization of functional groups. Macrocylic lactams have also
been used as scaffolds for biomolecules.5
During the course of our studies to link amino acids to
macrocyclic scaffolds using cross-metathesis (CM), we needed
to construct 1, shown in Figure 1. The compound is ideally
suited to a cross-metathesis reaction6 because it has a dumb-
bell shape with two halves connected together by an E-alkene
FIGURE 1. Phenylalanine on a Macrocylic Lactam.
tether. We believed that Grubbs’ well-defined second generation
catalyst would be an ideal choice to mediate this reaction.7
The left side of the molecule has a modified L-phenylalanine,
bearing a t-BOC protecting group. It is attached to the E-alkene
on the carboxylate side. The 17-membered macrocyclic lactam,
on the right side of the molecule, was to be assembled by using
ring-closing metathesis (RCM), using Grubbs’ second generation
catalyst. In addition, the reversibility of the CM reaction was
confirmed in these studies.8
In examining the viability of our approach to the synthesis
of 1, we decided that anchoring the amino acid to the nitrogen
atom of a large-ring lactam would function well, as shown in
Scheme 1. As just discussed, 1 could be prepared from protected
(1) Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789-854.
(2) Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57, 7431-48.
(3) Eguchi, M.; Shen, R. Y. W.; Shea, J. P.; Lee, M. S.; Kahn, M. J.
Med. Chem. 2002, 45, 1395-98.
(4) Le, G. T.; Abbenante, G.; Becker, B.; Grathwohl, M.; Halliday, J.;
Tometzki, G.; Zuegg, J.; Meutermans, W. Drug DiscoVery Today 2003, 8,
701-9.
(7) (a) Yun, J.; Marinez, E. R.; Grubbs, R. H. Organometallics 2004,
23, 4172-3. (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125 (33), 10103-9. (c) Trnka, T. M.; Morgan, J. P.;
Sanford, M. S.; Wilhelm, T. E.; Scholl, M.; Choi, T. L.; Ding, S.; Day, M.
W.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125 (9), 2546-58.
(8) (a) Fisher, R. A.; Grubbs, R. H. Makromol. Chem., Macromol. Symp.
1992, 63, 271-77. (b) Smith, A. B.; Adams, C. M.; Kozmin, S. A., J. Am.
Chem. Soc. 2001, 123, 990-91.
(5) Hu, X,; Nguyen, K. T.; Jiang, V. C.; Lofland, D.; Moser, H. E.; Pei,
D. J. Med. Chem. 2004, 47, 4941-9.
(6) (a) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360-70. (b) Love, J. A.; Morgan, J. P.; Trnka,
T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035-37. (c) Grubbs,
R. H. Tetrahedron 2004, 60, 7117-40. (d) Salim, S. S.; Bellingham, R.
K.; Brown, R. C. D. Eur. J. Org. Chem. 2004, 800-6.
10.1021/jo052415e CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/07/2006
2272
J. Org. Chem. 2006, 71, 2272-2276

Coupling of L-Phenylalanine to a Macrocyclic Lactam
TABLE 1. RCM To Obtain 12a and 12b
SCHEME 1
concn
(M)a
mol %
of 11
time
(h)
yield
(%)
E:Z
12a:12b
entry
1
2
3
4
5
6
7
8
0.001
10
10
10
10
8
14
8
5
25
21
24
16
19
3.5
2
59
45
46
61
60
48
35
18
97:3
98:2
92:8
96:4
93:7
NAb
NAb
NAb
0.0014
0.0016
0.0016
0.0018
0.003
0.007
0.013
20
a All reactions were run in dichloromethane. b Cis-isomer not isolated
due to small scale reaction.
SCHEME 4
SCHEME 2
SCHEME 3
of the terminal diene 10. Diene 10 was reacted with Grubbs’
2nd generation catalyst 11 under various conditions (Table 1
and Scheme 4) to give two 17-membered RCM lactams, 12a
and 12b, as geometric isomers.10 Prior to the addition of catalyst
11, a few crystals of butylated hydroxyl toluene (BHT) were
added to prevent atom transfer radical polymerization (ATRP).11
All reactions were refluxed in CH2Cl2 and monitored by TLC.
In every entry, 10 was never fully consumed. Moreover, data
showed that refluxing for longer periods of time did not improve
the yield of RCM products 12a and 12b. E-Isomer 12a was the
major product and was separated from Z-isomer 12b by
chromatography over silica gel.
phenylalanine 2 bearing an allyl ester and allyl lactam 3. Each
of these halves of the molecule contains a terminal alkene to
be used in the CM reaction. The 17-membered lactam contained
the allyl moiety attached at the nitrogen atom. Precursor 3 was
to be prepared by RCM and the alkene would later be removed
by hydrogenolysis. Eventually we envisioned 3 as emanating
from the SN2 coupling of bromo-amide 4 and alcohol 5.
After ring-closing metathesis, 12a and 12b were hydrogenated
with Pd on activated C (10% Pd) to give the corresponding
saturated lactam in good yields. NMR spectra and TLC showed
that it was pure enough for the next step without chromatog-
raphy. Addition of TBAI, and nucleophilic substitution of allyl
bromide, gave 3 in 62% yield. Two different conformations of
3, in roughly equal amounts, were present at ambient temper-
1
ature and readily detected by H NMR and 13C NMR by the
Results and Discussion
doubling of peaks.
We began our synthesis with a Williamson etherification
using commercially available 1,8-octanediol (6) and allyl
bromide, as shown in Scheme 2. The desired allyl ether 5 was
obtained in 70% yield, while the minor product, double
Williamson ether 7, was isolated in 25% yield. The use of
tetrabutylammonium iodide (TBAI) was essential in obtaining
good yields.9
N-Allyl-2-bromoacetamide (4) was next readily synthesized
in 73% yield from allylamine (8) and dibromide 9 followed by
recrystallization in hexane/ether, as shown in Scheme 3.
Deprotonation of 5 with NaH, addition of TBAI, and nucleo-
philic substitution of allyl-bromoacetamide 4 gave a 54% yield
The next step involved the cross-metathesis of the N-allyl
lactam 3 with 2, the allyl ester of t-BOC-phenylalanine (Scheme
5). Commercially available t-BOC-L-phenylalanine was reacted
with 1,3-diisopropylcarbodiimide (DIC), hydroxybenzotriazole
(HOBt), and allyl alcohol to afford amino acid derivative 2 in
95% yield. The starting material was completely consumed
within 20 min as indicated on TLC.12 Upon recrystallization in
hexane/Et2O, we obtained 2 as colorless needles with mp 70-
71 °C. We were pleased that the cross-metathesis of phenyl-
(10) Ivin, K. J. J. Mol. Catal. A: Chem. 1998, 133, 1-16.
(11) Sachinvala, N. D.; Winsor, D. L.; Hamed, O. A. J. Polym. Sci.,
Part A: Polym. Chem. 2000, 38, 1889-02.
(12) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.; Mizuno,
Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 10, 1063-66.
(9) Gibson, H. W.; Nagvekar, D. S.; Delaviz Y. Can. J. Chem. 1998,
76, 1429-36.
J. Org. Chem, Vol. 71, No. 6, 2006 2273

Enholm and Low
SCHEME 5
Experimental Section
General Experimental Procedures. See the Supporting Infor-
mation.
N-Allyl-2-bromoacetamide (4). Preparation is modified from
a published procedure.14 A flame-dried 250-mL round-bottom flask
was charged with bromoacetyl bromide (8.0 mL, 61 mmol) and
freshly distilled CH2Cl2 (80 mL) and cooled in an ice bath to 0 °C.
To the stirred solution was added a solution of allylamine (12 mL,
160 mmol) and CH2Cl2 (40 mL) dropwise and the mixture was
stirred at 0 °C for 4 h. Distilled H2O was added and the organic
layer was extracted and washed with 1 N HCl, followed by H2O.
After drying (anhydrous Na2SO4), concentration gave a crude
yellow-orange oil. Recrystallization from hexane and ethyl ether
(9:1) at 0 °C overnight gave 4 (8.0 g, 73%) as analytically pure
1
white crystals, mp 27 °C: Rf 0.39 (hexane/EtOAc, 1:1); H NMR
(CDCl3) δ 6.62 (s, 1H), 5.85 (ddt, J ) 17.2, 10.2, 5.3 Hz, 1H),
5.23 (dq, J ) 17.1, 1.5 Hz, 1H), 5.19 (dq, J ) 10.0, 1.5 Hz, 1H),
3.96-3.90 (m, 4H); 13C NMR (CDCl3) δ 165.9, 133.3, 116.8, 42.5,
29.1; IR (neat) 3285, 3082, 1654, 1552, 1430, 1309, 1211, 1132,
990, 925 cm-1. HRMS (CI pos) for C5H9BrNO [M + H]+: calcd
177.9868, found 177.9862.
SCHEME 6
8-Allyloxyoctan-1-ol (5). A flame-dried flask flushed with argon
was charged with sodium hydride (60% in oil) (1.1 g, 28 mmol).
The gray powder was washed three times with pentane to remove
the protective oil. To the NaH was added 1,8-octanediol (6) (3.55
g, 24.3 mmol) dissolved in THF (25 mL). Tetrabutylammonium
iodide (TBAI) (25 mg, 0.068 mmol) was added and the mixture
was stirred for 40 min. A solution of allyl bromide (1.9 mL, 22
mmol) and THF (25 mL) was added dropwise to the reaction flask
and heated at reflux for 12 h. The reaction mixture was cooled to
room temperature, neutralized with saturated ammonium chloride,
and extracted 3× with EtOAc. The combined organic layers were
washed with brine, dried with sodium sulfate (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel with CH2Cl2/MeOH (100:0
to 98:2) to give colorless oil 5 (2.9 g, 70%) and double Williamson
etherification product 7 (0.62 g, 25%).
alanine derivative 2 (2 equiv) and N-allyl lactam 3 was observed
with 5 mol % of catalyst 11 (Scheme 5). The reaction was heated
at reflux in CHCl3 for 21 h while continuously flushing out
ethylene with argon to drive the reaction forward. Additional
CHCl3 was added as needed, to keep the concentration to ca. 1
M. After the reaction was quenched with ethyl vinyl ether,
purification gave the desired product 1 in 48% yield with an
E:Z ratio of 1.2:1 and the amino acid dimer 13 in 45%. Similar
to the 13C NMR of N-allyl lactam 3, we also observed the
doubling of peaks for 1. Interestingly, the dimer of N-allyl
lactam 3 was not observed.
It is known that CM is reversible and this could be tested in
our system.8,13 We were able to confirm that 1 can be converted
back to allyl lactam 3 and amino acid derivative 2, as shown in
Scheme 6. Ethylene gas, used without purification, was admitted
via a balloon to a stirred solution of compound 1, catalyst 11
(2 mol %), in CH2Cl2. The solution was first maintained at room
temperature overnight. TLC showed the formation of N-allyl
lactam 3 and allyl ester 2. In an attempt to drive the reaction
further, the solution was refluxed in CH2Cl2 for 2.5 h under an
atmosphere of ethylene gas, then quenched with ethyl vinyl ether
upon cooling. Purification by chromatography gave 36% of
N-allyl lactam 3 and 37% of allyl ester 2. Both the amino acid
dimer 13 (4%) and unreacted starting material 1 (27%) were
recovered as well.
Allyl ether 5 (0.62 g, 25%): Rf 0.23 (CH2Cl2/MeOH, 96:4); 1H
NMR (CDCl3) δ 5.91 (ddt, J ) 17.1, 10.2, 5.6 Hz, 1H), 5.26 (dq,
J ) 17.2, 1.6 Hz, 1H), 5.16 (dq, J ) 10.7, 1.4 Hz, 1H), 3.95 (dt,
J ) 5.6, 1.3 Hz, 2H), 3.61 (t, J ) 6.5 Hz, 2H), 3.41 (t, J ) 6.7 Hz,
2H), 1.66 (s, 1H), 1.60-1.49 (m, 4H), 1.31 (s, 8H); 13C NMR
(CDCl3) δ 135.2, 116.9, 72.0, 70.6, 63.1, 32.9, 29.9, 29.6, 29.5,
26.3, 25.8; IR (neat) 3385 (broad), 2931, 2856, 1647, 1463, 1348,
1101 cm-1. HRMS (CI pos) for C11H23O2 [M + H]+: calcd
187.1698, found 187.1697.
1
Diether 7: Rf 0.74 (CH2Cl2/MeOH, 96:4); H NMR (CDCl3);
5.90 (ddt, J ) 17.2, 10.3, 5.65 Hz, 1H), 5.89 (ddt, J ) 17.2, 10.3,
5.65 Hz, 1H), 5.25 (dq, J ) 17.1, 1.7 Hz, 1H), 5.24 (dq, J ) 17.1,
1.8 Hz, 1H), 5.15 (dq, J ) 10.4, 1.5 Hz, 1H), 5.14 (dq, J ) 10.4,
1.5 Hz, 1H), 3.94 (dt, J ) 5.6, 1.5 Hz, 2H), 3.93 (dt, J ) 5.4, 1.5
Hz, 2H), 3.40 (t, J ) 6.7 Hz, 2H), 3.39 (t, J ) 6.7 Hz, 2H), 1.61-
1.50 (m, 4H), 1.30 (s, 8H); 13C NMR (CDCl3) δ 135.2, 116.8, 71.9,
70.6, 29.9, 29.6, 26.3; IR (neat) 3080, 2932, 2856, 1647, 1457,
1420, 1400, 1347, 1264, 1106 cm-1. HRMS (CI pos) for C14H27O2
[M + H]+: calcd 227.2011, found 227.2015.
Conclusion
N-Allyl-2-(8-allyloxyoctyloxy)acetamide (10). A flame-dried
25-mL round-bottom flask under argon was charged with alcohol
5 (2.97 g, 16.0 mmol) and THF (9.5 mL). NaH (60% in oil, 0.64
g, 16 mmol) was added portion wise slowly into the stirred solution
and the mixture continued to be stirred for 20 min. TBAI (26 mg,
0.070 mmol) and N-allyl-2-bromoacetamide (4) (2.20 g, 12.3 mmol)
were added and the mixture was heated at reflux for 4 h. The
mixture was diluted with CH2Cl2 and washed with brine. The
In summary, Grubbs’ second generation ruthenium catalyst
was used to couple the amino acid phenylalanine to a 17-
membered lactam by using cross-metathesis in 48% yield. Ring-
closing metathesis was a key reaction used to form the
macrocyclic lactam. The reversibility of the process was
confirmed.15
(13) Huc, I.; Nguyen, R. Comb. Chem. High Throughput Screening 2001,
4, 109-30.
(15) The views in this article are those of the authors and do not reflect
the official policy or position of the United States Air Force, Department
of Defense, or the U.S. Government.
(14) Casadei, M. A.; Cesa, S.; Inesi, A. Tetrahedron 1995, 51, 5891-
00.
2274 J. Org. Chem., Vol. 71, No. 6, 2006

Coupling of L-Phenylalanine to a Macrocyclic Lactam
organic layer was dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude oil was purified
by chromatography on silica gel with hexane/EtOAc (100:0 to 80:
20) to give 10 (1.9 g, 54%) as a colorless oil: Rf 0.53 (hexane/
EtOAc, 1:1); 1H NMR (CDCl3) δ 6.63 (s, 1H), 5.87 (ddt, J ) 17.2,
10.7, 5.4 Hz, 1H), 5.82 (ddt, J ) 17.0, 10.6, 5.3 Hz, 1H), 5.23 (dq,
J ) 17.2, 1.6 Hz, 2H), 5.12 (dq, J ) 10.5, 1.6 Hz, 2H), 3.94-3.86
(m, 6H), 3.46 (t, J ) 6.6 Hz, 2H), 3.38 (t, J ) 6.7 Hz, 2H), 1.61-
1.49 (m, 4H), 1.28 (s, 8H); 13C NMR (CDCl3) δ 169.9, 135.2, 134.1,
116.8, 116.5, 72.0, 71.9, 70.5, 70.3, 41.2, 29.8, 29.6, 29.5, 29.4,
26.2, 26.1; IR (neat) 3426, 3335, 3081, 2932, 2856, 1738, 1676,
1526, 1432, 1342, 1277, 1111, 997, 921 cm-1. HRMS (CI pos) for
C16H30O3N [M + H]+: calcd 284.2226, found 284.2225.
E-Cycloheptadecene (12a) and Z-Cycloheptadecene (12b). To
a stirred solution of diene 10 (377 mg, 1.33 mmol) and CH2Cl2
(750 mL) was added a few crystals of butylated hydroxytoluene
(BHT). A solution of Grubbs’ 2nd generation catalyst 11 (108 mg,
0.127 mmol) and CH2Cl2 (100 mL) was added then the solution
was heated at reflux for 16 h. The reaction was cooled to room
temperature, quenched with ethyl vinyl ether (ca. 3 mL), and
maintained for 1 h. The solution was concentrated under reduced
pressure and the residue was chromatographed on silica gel with
hexane/EtOAc (9:1 to 7:3) to give the E-isomer 12a (200 mg, 58%)
and Z-isomer 12b (8.2 mg, 3%) as a brown oil.
70.21, 70.15, 70.03, 70.00, 49.0, 48.0, 47.3, 45.0, 29.5, 28.71, 28.67,
28.5, 28.0, 27.5, 27.4, 27.1, 26.7, 26.6, 25.9, 25.7, 25.1, 24.3, 24.2;
IR (neat) 2931, 2858, 1651, 1459, 1352, 1282, 1232, 1118, 1038,
995, 922 cm-1. HRMS (CI pos) for C17H32NO3 [M + H]+: calcd
298.2382, found 298.2391. Anal. Calcd for C17H31NO3: C, 68.65;
H, 10.51; N, 4.71. Found: C, 68.31; H, 10.73; N, 4.94.
BOC-Allyl Ester of Phenylalanine 2. To a cooled (0 °C)
solution of BOC-L-phenylalanine (2.04 g, 7.69 mmol) and CH2Cl2
(13 mL) was added 1,3-diisopropylcarbodiimide (DIC) (2.4 mL,
15 mmol), 4-(dimethylamino)pyridine (DMAP) (0.186 g, 1.52
mmol), and hydroxybenzotriazole (HOBt) (1.08 g, 7.99 mmol).
After the mixture was stirred for 5 min, allyl alcohol (0.85 mL, 12
mmol) was slowly added. The mixture was allowed to warm to
room temperature with stirring for a total of 3 h. All solids were
filtered and the filtrate was concentrated under reduced pressure.
Purification by chromatography on silica gel with hexane/EtOAc
(10:1) gave 2 (2.2 g, 92%) as a white solid, mp 71-72 °C: Rf
0.35 (hexane/EtOAc, 4:1); [R]25D -8.05 (c 1.1, MeOH); 1H NMR
(CDCl3) δ 7.08-7.32 (m, 5H), 5.84 (ddt, J ) 17.2, 10.4, 5.2 Hz,
1H), 5.28 (dq, J ) 17.1, 1.4 Hz, 1H), 5.22 (dq, J ) 10.3, 1.3 Hz,
1H), 4.98 (d, J ) 7.9 Hz, 1H), 4.63-4.54 (m, 3H), 3.11 (dd, J )
13.8, 6.3 Hz, 1H), 3.04 (dd, J ) 13.8, 6.5 Hz, 1H), 1.40 (s, 9H);
13C NMR (CDCl3) δ 171.6, 155.1, 136.1, 131.6, 129.4, 128.6, 127.1,
118.9, 79.9, 66.0, 54.6, 38.4, 28.4; IR (neat) 3362, 3088, 2971,
1705, 1509, 1455, 1368, 1169, 1053 cm-1. HRMS (CI pos) for
C17H24NO4 [M + H]+: calcd 306.1705, found 306.1703. Anal.
Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.65,
H, 7.78; N, 4.52. Spectral data are in agreement with literature.12
E-isomer 12a: Rf 0.35 (EtOAc/hexane, 4:1); 1H NMR (CDCl3)
δ 6.59 (s, 1H), 5.80 (dd, J ) 14.8, 4.4 Hz, 1H), 5.72 (dd, J ) 14.8,
4.3 Hz, 1H), 3.99-3.89 (m, 6H), 3.53 (t, J ) 5.7 Hz, 2H), 3.46 (t,
J ) 5.7 Hz, 2H), 1.65-1.29 (m, 12H); 13C NMR (CDCl3) δ 170.0,
130.1, 127.9, 71.9, 70.2, 69.9, 69.3, 40.0, 29.2, 28.9, 28.4, 28.1,
26.1, 25.3; IR (neat) 3419, 2929, 2856, 1683, 1525, 1460, 1340,
1263, 1111 cm-1. HRMS (CI pos) for C14H26NO3 [M + H]+: calcd
256.1913, found 256.1911.
Lit.12 [R]29 -10.2 (c 1.1, MeOH).
D
Cross-Metathesis of BOC-Allyl Ester Phenylalanine 2 and
Lactam 3. To a stirred solution of 3 (140 mg, 0.469 mmol), 2
(290 mg, 0.950 mmol), and CHCl3 (0.50 mL) was added a solution
of catalyst 11 (19.9 mg, 23 mmol) in CHCl3 (0.40 mL). The solution
was heated at reflux for 21 h while flushing the headspace with
argon to remove evolved ethylene. The reaction was allowed to
cool to room temperature and quenched with ethyl vinyl ether (EVE,
ca. 0.75 mL). The solution was stirred for 30 min and concentrated
under reduced pressure. Purification by chromatography with
hexane/EtOAc (90:10-65:35) gave cross-metathesis product 1 (130
mg, 48%) as a colorless oil and homodimer 13 (120 mg, 45%) as
a white solid, mp 148-150 °C. Starting materials 2 (40 mg, 29%)
and 3 (71 mg, 25%) were recovered as well.
Z-isomer 12b: Rf 0.43 (EtOAc/hexane, 4:1); 1H NMR (CDCl3)
δ 6.65 (s, 1H), 5.89 (dd, J ) 10.6, 6.3 Hz, 1H), 5.81 (dd, J ) 10.3,
7.2 Hz, 1H), 4.03-3.90 (m, 6H), 3.55-3.45 (m, 4H), 1.70-1.23
(m, 12H); 13C NMR (CDCl3) δ 170.0, 130.3, 130.0, 71.2, 70.7,
70.4, 65.6, 35.4, 29.2, 28.4, 27.3, 27.2, 24.9, 24.6; HRMS (ESI-
FTICR) for [2M + Na]+: calcd 533.3561, found 533.3580.
Allyl Lactam 3. Palladium on activated carbon (10% Pd) (58
mg, 0.055 mmol) was added to a solution of 12 (507 mg, 1.99
mmol) and EtOAc (9 mL). Hydrogen was admitted via a balloon
and the reaction mixture was stirred for 45 min and the catalyst
removed by filtering through a small pipet column of Celite. The
column was rinsed with EtOAc (3 × 5 mL) and the combined
fractions were concentrated under reduced pressure leaving the
crude saturated lactam (500 mg, 98%) as a yellow-brown oil. The
hydrogenated saturated lactam product was used in the next step
without further purification.
To a stirred solution of the saturated lactam (570 mg, 2.22 mmol)
in THF (2.2 mL) under argon was added NaH (60% in oil, 270
mg, 6.7 mmol) slowly in portions. The mixture was stirred for 30
min. TBAI (8.18 mg, 0.022 mmol) and allyl bromide (0.97 mL,
11 mmol) were added and the reaction was heated at reflux for 9
h. The reaction mixture was cooled to room temperature, neutralized
with saturated ammonium chloride, and extracted with EtOAc. The
organic layer was washed with saturated NaCl, dried with MgSO4,
and concentrated under reduced pressure. Purification by chroma-
tography on silica gel with hexane/EtOAc (4:1) gave 3 (410 mg,
62%) as a slightly yellow oil.
1
Cross-metathesis product 1: Rf 0.26 (hexane/EtOAc, 1:1); H
NMR (CDCl3) δ 7.09-7.32 (m, 5H), 5.79-5.53 (m, 2H), 4.99 (d,
J ) 8.5 Hz, 1H), 4.62-4.53 (m, 3H), 4.19-3.94 (m, 4H), 3.59-
3.22 (m, 8H), 3.11 (dd, J ) 13.4, 6.3 Hz, 1H), 3.03 (dd, J ) 13.4,
6.5 Hz, 1H), 1.81-1.14 (m, 25H); 13C NMR (CDCl3) δ 171.8,
169.8, 169.4, 155.2, 136.1, 130.7, 130.5, 129.5, 129.4, 128.7, 127.2,
126.2, 125.4, 80.0, 71.8-70.0 (7 lines), 65.2-64.8 (2 lines), 54.6,
47.7-45.0 (4 lines), 38.5, 29.5-24.3 (13 lines); IR (neat) 3439,
2933, 2860, 2247, 1712, 1640, 1497, 1456, 1367, 1254, 1168, 1114,
910, 733 cm-1. HRMS (CI pos) for C32H51N2O7 [M + H]+: calcd
575.3696, found 575.3680. Anal. Calcd for C32H50N2O7: C, 66.87;
H, 8.77; N, 4.87. Found: C, 66.56; H, 9.00; N, 4.70.
Homodimer BOC-allyl ester phenylalanine 13: Rf 0.67 (hexane/
EtOAc, 1:1); 1H NMR (CDCl3) δ 7.34-7.09 (m, 10H), 5.76-5.64
(m, 2H), 4.99 (d, J ) 7.9 Hz, 2H), 4.65-4.54 (m, 6H), 3.10 (dd,
J ) 13.6, 5.8 Hz, 2H), 3.03 (dd, J ) 13.6, 5.8 Hz, 2H), 1.41 (s,
18H); 13C NMR (CDCl3) δ 171.7, 155.2, 136.0, 129.5, 128.7, 128.0,
127.2, 80.2, 64.7, 54.6, 38.5, 28.5; IR (neat) 3354, 2971, 1736,
1519, 1455, 1367, 1187, 1086, 1053 cm-1. HRMS (ESI-FTICR)
for [M + Na]+: calcd 605.2833, found 605.2859. Anal. Calcd for
C32H42N2O8: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.16, H, 7.53;
N, 4.77.
Saturated lactam: Rf 0.32 (EtOAc/hexane, 4:1); 1H NMR (CD-
Cl3) δ 6.63 (s, 1H), 3.83 (s, 2H), 3.43-3.21 (m, 8H), 1.66-1.21
(m, 16H); 13C NMR (CDCl3) δ 170.0, 71.6, 70.2, 70.1, 38.0, 29.0,
28.8, 27.5, 27.4, 26.7, 26.6, 25.1, 24.7; IR (neat) 3420, 2932, 2857,
1681, 1530, 1446, 1340, 1261, 1120 cm-1. HRMS (CI pos) for
C14H28NO3 [M + H]+: calcd 258.2069, found 258.2073.
Allyl lactam 3: Rf 0.37 (hexane/EtOAc, 1:1) 1H NMR (CDCl3)
δ 5.84-5.68 (m, 1H), 5.18-5.07 (m, 2H), 4.17-3.93 (m, 4H),
3.57-3.22 (m, 8H), 1.79-1.21 (m, 16H); 13C NMR (CDCl3) δ
169.9, 169.3, 133.5, 133.4, 117.2, 116.3, 71.7, 71.45, 71.41, 70.8,
General Procedure for the Reverse Metathesis of 1. A flame-
dried 5-mL round-bottom flask equipped with a reflux condenser
capped with a three-way stopcock was charged with 1 (110 mg,
0.191 mmol) and CH2Cl2 (95 µL). To the stirred solution was added
a solution of catalyst 11 (3.5 mg, 0.0041 mmol) in CH2Cl2 (95
J. Org. Chem, Vol. 71, No. 6, 2006 2275

Enholm and Low
µL). The headspace was evacuated with use of a water aspirator
attached to the stopcock. Ethylene gas, used without purification,
was admitted via a balloon also attached to the stopcock. The
solution was heated at reflux for 2.5 h, cooled to room temperature,
and quenched with EVE (ca. 0.5 mL). Concentration by reduced
pressure and purification of the residue by chromatography on silica
gel with hexane/EtOAc (10:0-8:2) gave 3 (20 mg, 36%) and 2
(22 mg, 37%) as a colorless oil. Starting material 1 (30 mg, 27%)
and amino acid dimer 13 (2.2 mg, 4%) were isolated as well. All
spectral and TLC data were identical with data for 2, 3, 13, and 1
as previously isolated.
Acknowledgment. We gratefully acknowledge support by
the National Science Foundation (grant CHE-0111210) for this
work. We would like to thank the USAF, Air Force Institute of
Technology (AFIT), and the USAF Academy for the sponsor-
ship of a Ph.D. program for T.L.
1
Supporting Information Available: General procedures, H
NMR, and 13C NMR for all compounds synthesized. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052415E
2276 J. Org. Chem., Vol. 71, No. 6, 2006