Synthesis of dipeptide isosteres by cross-metathesis

Article abstract of DOI:10.1016/j.tet.2012.06.004

This work describes the attachment of two amino acid derivatives by olefin cross-metathesis using Grubbs' second generation catalyst. They were connected at the carboxyl termini. In addition, a cyclic dilactam scaffold was used, which reacted with only a

Full text of DOI:10.1016/j.tet.2012.06.004

Tetrahedron 68 (2012) 6920e6927
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Tetrahedron
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Synthesis of dipeptide isosteres by cross-metathesis
*
J. Eric Enholm , Tammy Low, Daniel Cooper, Ion Ghivirija
Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This work describes the attachment of two amino acid derivatives by olefin cross-metathesis using
Grubbs’ second generation catalyst. They were connected at the carboxyl termini. In addition, a cyclic
dilactam scaffold was used, which reacted with only a fraction of the amino acid derivatives. The re-
maining fraction coupled directly coupled with no scaffold. This highly trans-selective double attach-
ment resulted in the cross-metathesis of a variety of amino acids in a single reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 9 March 2012
Received in revised form 30 May 2012
Accepted 1 June 2012
Available online 17 June 2012
Keywords:
Cross-metathesis
Amino acids
Dipeptide
Grubbs’ catalyst
Diketopiperazine
1. Introduction
bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricycl-
ohexylphosphine)ruthenium (1). In this reaction modified amino
Dipeptidomimetics and dipeptides linked by various non-
peptides are isosteres of diamino acids.1 These have been con-
structed by classic methods over the years.2 Each can avoid the
problems associated with poor stability, crossing the bloodebrain
barrier and polarity of the peptide bond.3 Moreover, the standard
dipeptide amide bond is easily broken by peptidase enzymes
making another mode of connectivity worthy of synthetic in-
vestigation. Previous investigators have focused on an amine-
linked alkene side chain of amino acids,4,5 but a carboxyl-linked
alkene chain on the amino acid has been little studied.6 Efforts in
this area are expected to useful, especially those coupling methods
that use new metathetical methods.7
acid 3 (protecting group¼Boc) and 4 (protecting group¼Fmoc),
were coupled with diketopiperazine scaffold 2 by cross-metathesis,
as shown in Scheme 1. This produced coupled products 5 and 6
This effort describes the attachment of two amino acid de-
rivatives by olefin cross-metathesis (CM), at the carboxyl termini. In
addition, a cyclic dilactam scaffold was used, which reacted with
only a fraction of the amino acid derivatives.8e11 The remaining
fraction coupled directly coupled by CM with no scaffold. This
highly trans-selective type of double attachment with a variety of
amino acids in a single reaction has not been examined prior to this
work to the best of our knowledge.
2. Results and discussion
We report on the synthesis of cyclic dipeptide derivatives using
Scheme 1.
Grubbs’ second generation ruthenium catalyst benzylidene[1,3-
with 7 and 8, which underwent cross-metathesis without the
scaffold. It should be noted that both sets of products we obtained
* Corresponding author. E-mail address: enholm@chem.ufl.edu (J.E. Enholm).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.004

J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
6921
Table 1
are synthetically important to report because of the rare amino acid
carboxyl end coupling by metathesis.6,12 In the cross-metathesis
bonds, trans alkenes were observed as a single product. This was
confirmed by 1H NMR and independent synthesis of two products.
Different lengths for the alkenes (n¼1, 2) lead to an allyl or
homoallyl chain at the carboxylate site on the amino acid. It was
believed that different tether lengths might give a variation in
yields based on that minimal distance and negative neighboring
group participation. Fmoc and Boc protected amino acids were
investigated to determine the influence of the protecting groups, if
any, on the cross-metathesis reaction. The ease of construction of
these protected amino acids was also a consideration.
Preparation and yields of the protected amino acids with olefin side chains
Entry
Amino acid
R1
3 and 4
Yield
1
2
3
4
5
6
7
8
Boc-Phe
Boc-Ala
Boc-Pro
Boc-Met
Boc-Phe
Boc-Ala
Boc-Pro
Boc-Met
Boc-Leu
Fmoc-Phe
Fmoc-Pro
Fmoc-Gly
Allyl
Allyl
Allyl
Allyl
Homoallyl
Homoallyl
Homoallyl
Homoallyl
Homoallyl
Homoallyl
Homoallyl
Homoallyl
3a
3b
3c
3d
3e
3f
3g
3h
3i
95
95
95
95
90
98
89
88
86
95
92
85
9
10
11
12
4a
4b
4c
2.1. Synthesis of the scaffold
argon to remove evolved ethylene. The reaction was quenched with
EVE and purification by column chromatography and gave the de-
sired products, as shown in Table 2.
To obtain the N-diallyl scaffold 2, NaH was added to a solution of
commercially available dilactam 913e15 in DMF as shown in
Scheme 2. Excess allyl bromide was added and the reaction heated
to 70 ꢀC gave the desired product over 4 h. However, workup of the
reaction was more cumbersome. Due to the polarity, some 2 would
remain in DMF during the aqueous workup even after numerous
extractions with organic solvents. The best method to obtain good
yields was to quench the reaction with H2O, then remove the DMF
and water in vacuo with heat. The residue was redissolved in EtOAc,
leaving behind the sodium salts, which were filtered. Concentration
and purification by flash chromatography gave the desired product
as a white solid in 77% yield.
Table 2
Preparation and yields of the CM reaction products
Entry
Precursor
5 and 6
Yield
7 and 8
Yielda
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5b
5c
5d
5e
5f
5g
5h
5i
37
40
42
0
44
39
35
0
30
42
46
30
7a
7b
7c
7d
7e
7f
7g
7h
7i
38
42
31
0
50
66
55
14
59
48
52
44
9
10
11
12
4a
4b
4c
6a
6b
6c
8a
8b
8c
Scheme 2.
a
Isolated yields except 8b, which is based on NMR.
2.2. Synthesis of the protected amino acids with alkene
chains
Two sets of compounds that included the scaffold, 5aei and
6aec, and those that were coupled directly by metathesis, 7aei and
8aec, were obtained. We were able to isolate compounds by flash
column chromatography. Based on thin layer studies, several CM
products were difficult to isolate and a gradient of solvents was
required for the column chromatography. We were also able to
obtain pure samples by flash column chromatography. Some
products, 7a, 7b, 7e, 8a, and 8c were isolated as crystalline solids.
The yields of products 5aei and 6aec were comparable to each
other, whether an allyl or homoallyl moiety was attached to the
amino acid. There was also little difference between the yields of
Fmoc protected 6a and Boc protected 5a and 5e. However, the
yields improved for the homodimerized products 7eeh and 8aeb,
which possess the homoallyl olefin chain, one methylene longer, in
comparison to homodimerized products 7aed with the allyl chain.
A possible reason for the higher yield is that the ruthenium catalyst
is less sterically hindered by the amino acid moiety and has better
access to the slightly longer chain terminal olefin.17 Again, we saw
little differences between the Fmoc 8aeb and Boc protected 7e and
7g. Interestingly, CM of sulfur-containing methionine derivatives
resulted in zero or low yields. Analysis by TLC showed that mostly
starting material 3h and unreacted 2 were present, even after 2 d at
reflux. Only the trans isomers for products 7 and 8 were isolated
and this was elucidated by NMR.
Various amino acid derivatives 3aei and 4aec were synthesized
by coupling 10 (protecting group¼Boc) or 11 (protecting group-
¼Fmoc) amino acid derivatives with allyl alcohol or 3-buten-1-ol,
as shown in Scheme 3. DIC (1,3-diisopropylcarbodiimide) was used
and HOBt was required to prevent racemization.16 The starting
material was typically consumed within 20 min as indicated on TLC.
The urea byproduct was filtered and purification by column chro-
matography affording the amino acid products 3aei and 4aec in
very good yields as shown in Table 1.
Scheme 3.
The CM reactivity of dimer scaffold 2 with amino acid de-
rivatives 3aei and 4aec was examined next. Thus, scaffold 2 was
reacted with amino acid derivatives using a catalytic amount
(10 mol %) of Grubbs’ second generation catalyst 1. The reaction was
stirred at reflux in CHCl3 for 10 h while flushing the headspace with
We examined the 1H and 13C NMR of the crude reaction mixture
to determine the cis/trans ratio of products 7 and 8. The chemical
shifts of the cis isomers were expected to be further downfield than
the trans isomers. Further confirmation was made by independent

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J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
synthesis of cis-7a and trans-7e. Careful examination of the crude
NMR and the isolated homodimerized products by column chro-
matography indicated the compounds were single pure trans iso-
mers (over 99%), rather than a mixture of cis and trans isomers. We
expected them to be mostly trans based on Grubb’s studies. How-
ever, experiments conducted by Miller group showed a mostly cis/
trans 3:1 ratio of but differed with the utilization of Grubbs’ first
generation catalyst4 and N-linked amino acids.
To ensure we properly assigned the cis/trans ratio of products,
we examined the satellites of the alkene protons using a 500 MHz
spectrometer with deuterated acetone as the solvent. These weak
satellites were formed from protons attached directly to the 13C (1%
natural abundance), rather than protons attached to the more
abundant 12C isotope.18 We expected the alkene protons of the
trans isomers to have a larger coupling constant (J¼15e17 Hz) than
the cis isomers (J¼9e11 Hz).19
J coupling of the weak satellites since we observed a doublet of
a triplet pattern with J¼16 and 7 Hz.
3. Conclusion
This work shows the attachment of two amino acid derivatives
by olefin cross-metathesis (CM), at the carboxyl termini. The
carboxyl-linked alkene chain on the amino acid we used has been
little studied, however, more light is shed on this mode of synthesis.
A cyclic dilactam scaffold was used, which reacted with only
a fraction of the amino acid derivatives. The remaining fraction
coupled directly with no scaffold. This type of attachment with
a variety of amino acids in a single reaction has not been examined
prior to this work to the best of our knowledge. The stereochem-
istry of the newly formed products was found to be trans.20
We independently synthesized two authentic homodimers,
where the stereochemistry was known, to confirm the predicted J
coupling values of the weak satellites. We first synthesized the cis
allyl homodimer 7a by coupling (Z)-2-butene-1,4-diol (12) with
3 equiv of N-(t-BOC)-phenylalanine (11a), DMAP, HOBt, DIPEA, and
EDCI in 95% yield as shown in Scheme 4. Homodimer cis-7a was
prepared as shown and the yield was 88%. NMR analysis of the
satellites of the cis alkene protons indicated a pattern of a doublet of
a triplet with J¼11 and 6 Hz.
4. Experimental section
4.1. General
All moisture and air-sensitive reactions were run under argon
with flame dried glassware. Solvents were distilled under N2 from
appropriate drying agents according to established procedures.
Analytical Thin Layer Chromatography (TLC) was performed using
0.25 mm silica gel plates. UV light, phosphomolybdic acid in
ethanol, anisaldehyde in ethanol, permanganate, and vanillin
were used as indicators. Yields reported refer to the isolated
materials. Proton nuclear magnetic resonance (1H NMR) spectra
were recorded on 300 MHz and 500 MHz spectrometers. Carbon
nuclear magnetic resonance (13C NMR) spectra were recorded at
75 MHz on the same spectrometers. Chemical shifts were
reported in parts per million downfield relative to tetrame-
thylsilane (TMS) as an internal standard. Infrared spectra were
reported in wavenumbers (cmꢁ1).
4.2. N-Allyl dimer scaffold 2
NaH (60% mass, 4.0 g, 100 mmol) was added in portions to
a stirred solution of glycine anhydride (10) (3.14 g, 27.5 mmol) and
anhydrous DMF (55 mL). After stirring for an additional 15 min,
TBAI (1.60 g, 4.33 mmol) and allyl bromide (12 mL, 140 mmol) were
added. The reaction mixture was maintained at room temperature
for 3.5 h, then quenched with H2O. DMF and H2O were removed in
vacuo, leaving behind an orange semi-solid. EtOAc was added to the
residue and the sodium salts filtered. The filtrate was concentrated
in vacuo. Column chromatography on silica gel with EtOAc/hexane
(7:3) afforded 2 (4.1 g, 77%) as a white solid, mp 98e99 ꢀC; Rf¼0.24
Scheme 4.
We also independently synthesized the trans homoallyl dimer
product by employing the same method as above, but starting from
trans-3-hexenedioic acid 14 as in Scheme 5. The acid was converted
to the diester, which was then reduced to the diol by LiAlH4. Amino
acid coupling with Boc protected -phenylalanine 11a afforded
L
trans homodimer product 7e. NMR analysis of trans-7e and the
weak satellites of the alkene protons indicated a doublet of a triplet
pattern with J¼16 and 7 Hz.
(EtOAc); 1H NMR (CDCl3)
d
5.82e5.63 (ddt, J¼17.1, 10.2, 6.3 Hz, 2H),
5.29e5.17 (m, 4H), 4.02e3.97 (m, 8H); 13C NMR (CDCl3)
d
163.4,
130.9, 119.8, 49.3, 48.3; IR (KBr) 3079, 2914, 1656, 1487, 1441, 1415,
1336, 1294, 1193, 1142, 1074, 1011 cmꢁ1; HRMS (EI pos) for
C10H14N2O2 [M]þ: calcd 194.1055, found 194.1047. Anal. Calcd for
C10H14N2O2: C, 61.84; H, 7.27; N, 14.42. Found C, 61.75; H, 7.42; N,
14.29%.
4.3. General amino acid esterification procedure for 3ae4c
To a cooled (0 ꢀC) solution of amino acid (7.7 mmol) and CH2Cl2
(13 mL) was added 1,3-diisopropylcarbodiimide (DIC) (15 mmol), 4-
(dimethylamino)pyridine (DMAP) (1.5 mmol), and hydroxybenzo-
triazole (HOBt) (8.0 mmol). After stirring the mixture for 5 min, the
alcohol (12 mmol) was slowly added. The mixture was allowed to
warm to room temperature while stirring for a total of 3 h. All solids
were filtered and the filtrate was concentrated under reduced
pressure. The crude product was purified on a silica gel column,
Scheme 5.
We conducted an NMR analysis of our homodimer samples from
Table 2 clearly indicated trans isomers. This was determined by the

J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
6923
eluting with hexane/EtOAc to provide the amino acid derivatives
3ae4c in Table 1.
4.8. t-Boc-homoallyl phenylalanine 3e
The protected amino acid t-Boc-
L
-phenylalanine (5.35 g,
20.2 mmol), DIC (5.2 mL, 33.6 mmol), DMAP (0.48 g, 3.93 mmol),
HOBt (2.96 g, 21.9), 3-buten-1-ol (2.7 mL, 31.4 mmol), and CH2Cl2
(40 mL) yielded 3e (5.8 g, 90%) as a white solid; mp¼79e80.5 ꢀC;
4.4. t-Boc-allylester phenylalanine 3a
The protected amino acid t-Boc-
7.69 mmol), CH2Cl2 (13 mL), DIC (2.4 mL, 15 mmol), DMAP (0.186 g,
1.52 mmol), HOBt (1.08 g, 7.99 mmol), and allyl alcohol (0.85 mL,
12 mmol) gave 3a (2.2 g, 92%) as a white solid, mp 71e72 ꢀC;
Rf¼0.40 (hexane/EtOAc, 4:1); ½a D25
ꢂ
ꢁ9.01 (c 1.00, MeOH); 1H NMR
L
-phenylalanine (2.04 g,
(CDCl3)
d
7.33e7.10 (m, 5H), 5.72 (ddt, J¼17.1, 10.6, 6.6 Hz, 1H),
5.14e5.03 (m, 2H), 4.99 (d, J¼8.2 Hz,1H), 4.57 (dt, J¼8.2, 6.4 Hz,1H),
4.14 (t, J¼6.8 Hz, 2H), 3.11 (dd, J¼13.6, 6.5 Hz, 1H), 3.03 (dd, J¼13.7,
Rf¼0.35 (hexane/EtOAc, 4:1); ½a D25
ꢂ
ꢁ8.05 (c 1.1, MeOH); 1H NMR
6.6 Hz, 1H), 2.40e2.29 (m, 2H), 1.41 (s, 9H); 13C NMR (CDCl3)
d 172.1,
(CDCl3)
d
7.08e7.32 (m, 5H), 5.84 (ddt, J¼17.2, 10.4, 5.2 Hz, 1H), 5.28
155.3, 136.21, 133.78, 129.50, 128.68, 127.15, 117.68, 80.01, 64.50,
54.6, 38.5, 33.0, 28.5; IR (KBr) 3355, 3077, 3030, 3006, 2973, 2930,
1735, 1708, 1645, 1516, 1455, 1391, 1365, 1288, 1220, 1187, 1086,
1054, 1020; Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N, 4.39.
Found: C, 67.83; H, 8.07; N, 4.36%.
(dq, J¼17.1, 1.4 Hz, 1H), 5.22 (dq, J¼10.3, 1.3 Hz, 1H), 4.98 (d,
J¼7.9 Hz, 1H), 4.63e4.54 (m, 3H), 3.11 (dd, J¼13.8, 6.3 Hz, 1H), 3.04
(dd, J¼13.8, 6.5 Hz, 1H), 1.40 (s, 9H); 13C NMR (CDCl3)
d 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; HRMS
(CI pos) for C17H24NO4 [MþH]þ: calcd 306.1705, found 306.1703.
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
4.9. t-Boc-homoallyl alanine 3f
66.65, H, 7.78; N, 4.52%; ½a D29
ꢂ
ꢁ10.2 (c 1.10, MeOH).12
The protected amino acid t-Boc-L-alanine (1.86 g, 9.83 mmol),
DIC (2.5 mL, 16 mmol), DMAP (0.240 g, 1.96 mmol), HOBt (1.45 g,
10.7 mmol), 3-buten-1-ol (1.3 mL, 16 mmol), and CH2Cl2 (20 mL)
yielded 3f (2.4 g, 98%) as a colorless oil; Rf¼0.35 (hexane/EtOAc,
4.5. t-Boc-allylester alanine 3b
The protected amino acid t-Boc-
4:1); ½a 2D5
ꢂ
ꢁ45.7 (c 1.11, MeOH); 1H NMR (CDCl3)
5.75 (ddt, J¼17.1,
d
L
-alanine (1.73 g, 9.14 mmol),
10.5, 6.8, 1H), 5.16e5.00 (m, 3H), 4.34e4.08 (m, 3H), 2.43e2.34 (m,
DIC (2.8 mL, 18 mmol), DMAP (0.230 g, 1.89 mmol), HOBt (1.27 g,
9.40 mmol), allyl alcohol (1.0 mL, 15 mmol), and CH2Cl2 (15 mL)
yielded 3b (2.0 g, 95%) as a colorless oil; Rf¼0.42 (hexane/EtOAc,
2H), 1.42 (s, 9H), 1.35 (d, J¼7.2 Hz, 3H); 13C NMR (CDCl3)
d 173.5,
155.2, 133.8, 117.6, 79.9, 64.3, 49.4, 33.2, 28.5, 18.9; IR (KBr) 3368,
2980, 1718, 1644, 1517, 1168, 1069; HRMS (CI pos) for C12H22NO4
[MþH]þ: calcd 244.1549, found 244.1549.
8:2); ½a 2D5
ꢂ
ꢁ35.0 (c 1.04, MeOH); 1H NMR (CDCl3)
5.89 (ddt, J¼17.0,
d
10.2, 5.6 Hz, 1H), 5.37e5.19 (m, 2H), 5.11 (br s, 1H), 4.69e4.54 (m,
2H), 4.39e4.26 (m, 1H), 1.43 (s, 9H), 1.38 (d, J¼7.1, 3H); 13C NMR
4.10. t-Boc-homoallyl proline 3g
(CDCl3)
d 173.2, 155.2, 131.8, 118.7, 80.0, 65.9, 49.4, 28.5, 18.8; IR
(neat) 3368, 2980, 2937, 1716, 1650, 1518, 1455, 1367, 1251, 1167,
1069; HRMS (ESI-FTICR) for [MþNa]þ, calcd 252.1206, found
252.1227. Anal. Calcd for C11H19NO4: C, 57.62; H, 8.35; N, 6.11.
Found: C, 57.88; H, 8.77; N, 6.47.
The protected amino acid t-Boc-L-proline (4.06 g, 18.9 mmol),
DIC (5.0 mL, 32 mmol), DMAP (0.730 g, 5.98 mmol), HOBt (2.82 g,
20.9 mmol), 3-buten-1-ol (2.7 mL, 32 mmol), and CH2Cl2 (31 mL)
yielded 3g (4.5 g, 89%) as a clear oil; Rf¼0.41 (hexane/EtOAc, 7:3);
½
a 2D5
ꢂ
ꢁ72.3 (c 1.24, MeOH); 1H NMR (CDCl3)
5.71 (ddt, J¼17.0, 10.2,
d
6.8 Hz, 1H), 5.11e4.96 (m, 2H), 4.27e4.01 (m, 3H), 3.54e3.26 (m,
4.6. t-Boc-allylester proline 3c
2H), 2.38e2.27 (m, 2H), 2.21e1.73 (m, 4H), 1.39 and 1.34 (s, 9H); 13C
NMR (CDCl3)
d 173.21e172.95 (2 lines), 153.87, 134.05e133.83 (2
The protected amino acid t-Boc-L-proline (4.15 g, 19.3 mmol),
lines), 117.46e117.23 (2 lines), 79.89e79.76 (2 lines), 63.93,
59.28e58.98 (2 lines), 46.63e46.41 (2 lines), 33.20, 31.03e30.08 (2
lines), 28.54e28.45 (2 lines), 24.37e23.67 (2 lines); IR (KBr) 3482,
3080, 2977, 1699, 1395, 1160; HRMS (CI pos) for C14H23NO4
[MþH]þ: calcd 270.1705, found 270.1701.
DIC (6.0 mL, 39 mmol), DMAP (0.707 g, 5.79 mmol), HOBt (2.74 g,
20.3 mmol), allyl alcohol (2.24 g, 38.6 mmol), and CH2Cl2 (32 mL)
yielded 3c (4.7 g, 95%) as a clear oil; Rf¼0.25 (hexane/EtOAc, 4:1);
½
a 2D5
ꢂ
ꢁ70.9 (c 1.00, MeOH); 1H NMR (CDCl3)
5.89 (ddt, J¼16.7, 10.5,
d
5.7 Hz, 1H), 5.37e5.15 (m, 2H), 4.68e4.51 (m, 2H), 4.36e4.18 (m,
1H), 3.58e3.30 (m, 2H), 2.28e2.09 (m, 1H) 2.02e1.71 (m, 3H), 1.43
and 1.38 (s, 9H); 13C NMR (CDCl3)
d 173.0, 153.9, 131.9, 118.7e118.2
4.11. t-Boc-homoallyl methionine 3h
(2 lines), 80.00e79.9 (2 lines), 65.6, 59.3e59.0 (s lines), 46.7e46.6
(2 lines) 31.1e30.1 (2 lines), 28.6e28.5 (2 lines), 24.5e23.8 (2 lines);
IR (KBr) 2978, 2882, 1749, 1702, 1397, 1258, 1162, 1122, 1089; HRMS
(CI pos) for C13H21NO4 [MþH]þ, calcd 256.1549, found 256.1541.
The protected amino acid t-Boc-L-methionine (5.59 g, 22.4 mmol),
DIC (5.2 mL, 34 mmol), DMAP (0.577 g, 4.72 mmol), HOBt (3.35 g,
24.8 mmol), 3-buten-1-ol (2.9 mL, 34 mmol), and CH2Cl2 (40 mL)
yielded 3h(6.0g, 88%)asaclearoil;Rf¼0.26(hexane/EtOAc,8:2); ½a D25
ꢂ
ꢁ23.8 (c 1.10, MeOH); 1H NMR (CDCl3)
5.76 (ddt, J¼17.5,10.3, 6.7 Hz,
d
4.7. t-Boc-allylester methionine 3d
1H), 5.16e5.05 (m, 3H), 4.44e4.33 (m,1H), 4.26e4.13 (m, 2H), 2.52 (t,
J¼7.6 Hz, 2H), 2.40 (qt, J¼6.7, 1.2, 2H), 2.18e1.86 (m, 5H); 1.44 (s, 9H);
13C NMR (CDCl3) 172.40, 155.46, 133.75, 117.74, 80.13, 64.59, 53.02,
33.16, 32.49, 30.15, 28.50,15.64; IR (KBr) 3362, 3079, 2978, 2919,1716,
1643, 1509, 1446, 1391, 1367, 1251; HRMS (CI pos) for C14H26NO4S
[MþH]þ, calcd 304.1582, found 304.1570.
The protected amino acid t-Boc-L-methionine (2.23 g,
8.94 mmol), DIC (2.8 mL, 18 mmol), DMAP (0.300 g, 2.46 mmol),
HOBt (1.26 g, 9.33 mmol), allyl alcohol (0.90 mL, 13 mmol), and
CH2Cl2 (15 mL) yielded 3d (2.5 g, 97%) as a colorless oil; Rf¼0.28
(hexane/EtOAc, 8:2); ½a D25
ꢂ
ꢁ32.4 (c 1.04, MeOH); 1H NMR (CDCl3)
d
5.88 (ddt, J¼17.1, 10.4, 5.7 Hz, 1H), 5.35e5.16 (m, 3H), 4.67e4.55
4.12. t-Boc-homoallyl leucine 3i
(m, 2H), 4.44e4.34 (m,1H), 2.51 (t, J¼7.5 Hz, 2H), 2.18e1.83 (m, 5H),
1.41 (s, 9H); 13C NMR (CDCl3)
d
172.1, 155.4, 131.7, 119.0, 80.1, 66.1,
The protected amino acid t-Boc-L-leucine (2.08 g, 8.99 mmol),
52.9, 32.3, 30.1, 28.4, 15.6; IR (neat) 3362, 2977, 2920, 1716, 1650,
1511, 1447, 1367, 1251, 1167, 1050; HRMS (CI pos) for C13H24NO4S
[MþH]þ, calcd 290.1426, found 290.1421.
DIC (2.0 mL, 13 mmol), DMAP (0.179 g, 1.47 mmol), HOBt (1.44 g,
10.6 mmol), 3-buten-1-ol (1.0 mL, 12 mmol), and CH2Cl2 (50 mL)
yield 3i (2.1 g, 83%) as a clear oil; Rf¼0.33 (hexane/EtOAc, 9:1); ½a D25
ꢂ

6924
J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
ꢁ39.2 (c 1.42, MeOH); 1H NMR (CDCl3)
d
5.72 (ddt, J¼17.3, 10.1,
The reaction was heated at reflux for 10 h while flushing the
6.7 Hz, 1H), 5.10e4.92 (m, 3H), 4.28e4.05 (m, 3H), 2.35 (qt, J¼6.7,
1.1 Hz, 2H), 1.71e1.39 (m, 12H), 0.90 (d, J¼1.2, 3H), 0.88 (d, J¼1.3 Hz,
3H); 13C NMR (CDCl3) 173.50, 155.48, 133.79, 117.48, 79.72, 64.17,
52.24, 41.97, 33.10, 28.40, 24.86, 22.87, 22.03; IR (neat) 3368, 3081,
2960, 2872, 1718, 1644, 1509, 1455, 1367, 1165, 1122, 1048, 1023;
Anal. Calcd for C15H27NO4: C, 67.69; H, 7.89; N, 4.39. Found: C,
67.83; H, 8.07; N, 4.36%.
headspace with argon to remove evolved ethylene. The reaction
was allowed to cool to room temperature and quenched with EVE
(ca. 0.5 mL). The solution was stirred for 30 min and concentrated
under reduced pressure. Purification by column chromatography
on silica gel with hexane/EtOAc yielded 5/6 and 7/8.
4.17. Cross-metathesis product t-Boc-allylester
phenylalanine-dimer 5a
4.13. Fmoc homoallyl phenylalanine 4a
A solution of catalyst 1 (46 mg, 0.054 mmol) and CHCl3
(0.50 mL) was added to a stirred solution of dimer 2 (105 mg,
0.541 mmol), amino acid 3a (825 mg, 2.70 mmol), and CHCl3
(0.50 mL). The reaction was heated at reflux for 10 h while flushing
the headspace with argon to remove evolved ethylene. The reaction
was allowed to cool to room temperature and quenched with EVE
(ca. 0.5 mL). The solution was stirred for 30 min and concentrated
under reduced pressure. Purification by column chromatography
on silica gel with hexane/EtOAc (9:1e4:6) yielded 5a as an oil
(150 mg, 37%) and homodimer 7a (301 mg, 38%) as a white solid.
The protected amino acid Fmoc-L-phenylalanine (1.00 g,
2.58 mmol), DIC (0.60 mL, 3.87 mmol), DMAP (60.0 mg, 0.491 mmol),
HOBt (422 mg, 3.12 mmol), 3-buten-1-ol (0.33 mL, 3.86 mmol), and
THF (5.0 mL) yielded 4a (1.1 g, 99%) as a white solid; mp¼52e54 ꢀC;
Rf¼0.44 (hexane/EtOAc, 7:3); ½a D25
ꢂ
ꢁ20.0 (c 1.06, MeOH); 1H NMR
(CDCl3)
d 7.85e7.16 (m, 13H), 5.86e5.72 (m, 1H), 5.46e5.09 (m, 3H),
4.80e4.20 (m, 6H), 3.25e3.15 (m, 2H), 2.48e2.32 (m, 2H); 13C NMR
(CDCl3) 171.61, 155.67, 143.98e143.88 (2 lines), 141.42,135.93, 133.67,
129.47,128.69,127.83,127.23e127.17(2lines),125.25e125.18(2lines),
120.11, 117.70, 67.05, 64.60, 54.94, 47.26, 38.38, 32.94; IR (KBr) 3327,
3064, 2962, 1696, 1605, 1536, 1450, 1388, 1263, 1104, 1086, 1045;
HRMS (CI pos) for C28H28NO4 [MþH]þ: calcd 442.2018, found
442.2025; Anal. Calcd for C28H27NO4: C, 76.17; H, 6.16; N, 3.17. Found:
C, 75.81; H, 6.22; N, 3.16%.
Compound 5a: Rf¼0.33 (EtOAc); 1H NMR (CDCl3)
d 7.35e7.09 (m,
10H), 5.78e5.57 (m, 4H), 5.03 (d, J¼7.9 Hz, 2H), 4.66e4.51 (m, 6H),
4.07e3.90 (m, 8H), 3.16e2.98 (m, 4H), 1.41 (s, 18H); 13C NMR
(CDCl3)
d 171.70, 163.08, 155.14, 135.99, 129.39, 128.80, 128.65,
127.40, 127.13, 80.07, 64.56, 54.57, 49.34, 47.03, 38.41, 28.40; IR
(KBr) 3324, 2978, 1666, 1498, 1366, 1169, 1022 cmꢁ1; HRMS (ESI-
FTICR) for [MþNa]þ: calcd 771.3576, found 771.3544.
4.14. Fmoc homoallyl proline 4b
The protected amino acid Fmoc-L-proline (1.04 g, 3.07 mmol), DIC
4.18. Homodimer t-Boc-allylester phenylalanine 7a
(0.71 mL, 4.6 mmol), DMAP (0.0749 g, 0.613 mmol), HOBt (0.502 g,
3.71 mmol), 3-buten-1-ol (0.40 mL, 4.7 mmol), and THF (7.0 mL)
yielded 4b (1.1 g, 92%) as a colorless oil; Rf¼0.35 (hexane/EtOAc, 7:3);
Compound 7a: Rf¼0.67 (hexane/EtOAc, 1:1); 1H NMR (CDCl3)
d
7.34e7.09 (m, 10H), 5.76e5.64 (m, 2H), 4.99 (d, J¼7.9 Hz, 2H),
½
a 2D5
ꢂ
ꢁ49.4 (c 1.25, MeOH); 1H NMR (CDCl3)
d
7.62e7.12 (m, 8H),
4.65e4.54 (m, 6H), 3.10 (dd, J¼13.6, 5.8 Hz, 2H), 3.03 (dd, J¼13.6,
5.69e5.50 (m, 1H), 5.00e4.84 (m, 2H) 4.33e3.89 (m, 6H), 3.55e3.29
5.8 Hz, 2H), 1.41 (s, 18H); 13C NMR (CDCl3)
d
171.76, 155.25, 136.07,
(m, 2H), 2.27e1.66 (m, 6H); 13C NMR (CDCl3)
d
172.43e172.36 (2
129.53, 128.76, 128.06, 127.26, 80.18, 64.70, 54.64, 38.54, 28.47; IR
(neat) 3367, 2977, 1715, 1498, 1455, 1367, 1252, 1166, 1054,
1022 cmꢁ1; HRMS (ESI-FTICR) for [MþNa]þ: 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%.
lines),154.67e154.27 (2 lines),144.10e143.68 (4 lines),141.18e141.13
(2 lines), 133.79e133.60 (2 lines)127.58, 126.94, 125.09e124.86 (3
lines), 119.86, 117.31e117.17 (2 lines), 67.31, 63.85, 59.20e58.75 (2
lines), 47.20e46.34 (4 lines), 32.96e32.91 (2 lines) 30.96e29.80 (2
lines) 24.19, 23.17; IR (KBr) 3068, 2957, 2884, 1745, 1705, 1451, 1417,
1349, 1194, 1120, 1089; HRMS (ESI-FTICR) for [MþNa]þ: calcd
414.1676,found414.1669;Anal. CalcdforC24H25NO4:C,73.64;H,6.44;
N, 3.58. Found: C, 73.28; H, 6.61; N, 3.54%.
4.19. Cross-metathesis product t-Boc-allylester alanine-dimer
5b
Following general CM procedures, dimer
2
(104 mg,
4.15. Fmoc homoallyl glycine 4c
0.533 mmol), amino acid 3b (600 mg, 2.62 mmol), Grubbs’ catalyst
1 (46 mg, 0.054 mmol), and CHCl3 (0.5 mL) gave a brown residue.
Purification by column chromatography on silica gel with hexane/
EtOAc (9:1 to 6:4, 2:8 to 0:10) yielded 5b (130 mg, 40%) as an oil and
homodimer 7b (180 mg, 42%) as a white solid, mp¼96e97 ꢀC.
The protected amino acid Fmoc-glycine (1.90 g, 6.39 mmol), DIC
(1.5 mL, 9.7 mmol), DMAP (0.318 g, 2.60 mmol), HOBt (1.38 g,
10.2 mmol), 3-buten-1-ol (0.85 mL, 9.9 mmol), and THF (15 mL)
yielded 4c (2.2 g, 85%) as a white solid; mp¼78.5e80 ꢀC; Rf¼0.40
Compound 5b: Rf¼0.21 (EtOAc); 1H NMR (CDCl3)
d 5.85e5.60
(hexane/EtOAc, 7:3); 1H NMR (CDCl3)
d
7.81e7.30 (m, 8H), 5.79 (ddt,
(m, 4H), 5.10 (d, J¼7.2 Hz, 2H), 4.65e4.55 (m, 4H), 4.35e3.89 (m,
J¼17.2,10.2, 6.7 Hz,1H), 5.49e5.41 (m,1H), 5.18e5.08 (m, 2H), 4.43 (d,
J¼7.0 Hz), 4.28e4.20 (m, 3H), 4.00 (d, J¼5.6 Hz, 2H), 2.42 (qt, J¼6.8,
1.3 Hz, 2H); 13C NMR (CDCl3) 170.15, 156.43, 143.93, 141.40, 133.63,
127.83, 127.19, 125.20, 120.10, 117.71, 67.28, 64.54, 47.21, 42.85, 33.02;
IR (KBr) 3335, 3065, 3017, 2947,1767,1685,1541,1451,1414,1389,1361,
1288, 1192, 1104, 1081, 1055; HRMS (CI pos) for C21H22NO4 [MþH]þ:
calcd 352.1549, found 352.1556; Anal. Calcd for C21H21NO4: C, 71.78;
H, 6.02; N, 3.99. Found: C, 71.62; H, 6.06; N, 3.98%.
10H), 1.40 (s, 18H), 1.35 (d, J¼7.3 Hz, 6H); 13C NMR (CDCl3)
d 173.13,
163.14,155.17,128.93,127.24, 79.95, 64.49, 51.52, 49.30, 47.03, 28.41,
18.61; IR (KBr) 3330, 2980, 2935, 2361, 2250,1666,1520,1478, 1366,
1252, 1165, 1070, 1023 cmꢁ1; HRMS (EI pos) for C28H44N4O4 [M]þ:
calcd 619.2950, found 619.2946.
4.20. Homodimer t-Boc-allylester alanine 7b
Compound 7b: Rf¼0.34 (hexane/EtOAc, 6:4); 1H NMR (CDCl3)
4.16. General procedure for cross-metathesis of dimer 2 with
an amino acid derivative
d
5.87e5.78 (m, 2H) 5.11 (d, J¼7.2 Hz, 2H), 4.64e4.57 (m, 4H),
4.35e4.22 (m, 2H), 1.40 (s, 18H), 1.36 (d, J¼7.2 Hz, 6H); 13C NMR
(CDCl3)
d 173.12, 155.19, 127.91, 79.95, 64.60, 49.32, 28.43, 18.67; IR
As shown in Scheme 1, a solution of catalyst 1 (0.05 mmol) and
CHCl3 (0.50 mL) was added to a stirred solution of dimer 2
(0.541 mmol), amino acid 3/4 (2.70 mmol), and CHCl3 (0.50 mL).
(KBr) 3370, 2983, 2938, 1737, 1685, 1522, 1456, 1369, 1274, 1163,
1085, 1024 cmꢁ1; HRMS (CI pos) for C20H35N2O8 [MþH]þ: calcd
431.2393, found 431.2379.

J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
6925
4.21. Cross-metathesis product t-Boc-allylester proline-dimer 5c
Following general CM procedures, dimer (95.5 mg,
18H), 1.36 (d, J¼7.7, 6H); 13C NMR (CDCl3)
d
173.20, 163.22, 155.10,
131.37, 125.49, 79.45, 63.73, 49.13, 48.87 47.15, 31.51, 28.24, 22.81,
18.20; IR (neat) 3327, 2979, 2934, 1666, 1521, 1478, 1391, 1367, 1335,
1250, 1166, 1115, 1068, 1023 cmꢁ1; HRMS (CI pos) for C30H49N4O10
[MþH]þ: calcd 625.3449, found 625.3450.
2
0.492 mmol), amino acid 3c (726 mg, 2.51 mmol), Grubbs’ catalyst 1
(42.0 mg, 0.0495 mmol), and CHCl3 (1.0 mL) gave a brown residue.
Purification by column chromatography on silica gel with hexane/
EtOAc (9:1 to 7:3, 2:8 to 0:10) yielded 5c (135 mg, 42% NMR yield)
as an oil and homodimer 7c (188 mg, 31%) as an oil.
4.26. Homodimer t-Boc-homoallylester alanine 7f
Compound 5c: Rf¼0.28 (EtOAc); 1H NMR (CDCl3)
d
5.88e5.65
Compound 7f: Rf¼0.39 (hexane/EtOAc, 7:3); 1H NMR (CDCl3)
(m, 4H), 4.66e4.58 (m, 4H), 4.36e4.20 (m, 2H), 4.07e3.92 (m, 8H),
3.60e3.35 (m, 4H), 2.30e2.13 (m, 2H), 2.02e1.82 (m, 6H), 1.46 and
1.41 (s, 18H).
d 5.47e5.39 (m, 2H), 5.15 (s, 2H), 4.28e4.02 (m, 6H), 2.38e2.24 (m,
4H), 1.37 (s, 18H), 1.30 (d, J¼7.3 Hz, 6H); 13C NMR (CDCl3)
d 173.41,
155.19, 131.70, 128.29, 127.39 (cis), 79.81, 64.47, 49.31, 32.01, 28.43,
18.73; IR 3366, 2979, 1715, 1518, 1455, 1392, 1367, 1251, 1166, 1069,
1025 cmꢁ1; HRMS (CI pos) for C22H39N2O8 [MþH]þ: calcd 459.2706,
found 459.2705.
4.22. Homodimer t-Boc-allylester proline 7c
Compound 7c: Rf¼0.37 (hexane/EtOAc, 5:5); 1H NMR (CDCl3)
d
5.94e5.60 (m, 2H), 4.76e4.52 (m, 4H), 4.36e4.18 (m, 2H), 3.58e3.32
4.27. Cross-metathesis product t-Boc-homoallylester proline-
(m, 4H), 2.29e2.10 (m, 2H), 2.02e1.77 (m, 6H), 1.44 and 1.38 (s, 18H);
dimer 5g
13C NMR (CDCl3)
d
172.92, 172.67, 154.48, 153.83, 128.46e127.61 (3
lines), 80.00, 64.41, 64.27, 59.22, 58.92, 46.68, 46.46, 31.04, 30.06,
28.55, 28.45, 24.47, 23.78 cmꢁ1; IR (neat) 3482, 2974,1950,1747,1698,
1399, 1259, 1170 cmꢁ1. HRMS (CI pos) for C24H39N2O8 [MþH]þ: calcd
483.2706, found 483.2724. Anal. Calcd for C24H38N2O8: C, 59.73; H,
7.94; N, 5.81. Found: C, 60.05; H, 8.20; N, 5.70%
Following general CM procedures, dimer 2 (90.0 mg, 0.463 mmol),
amino acid 3g (624 mg, 2.32 mmol), Grubbs’ catalyst 1 (41.2 mg,
0.048 mmol) and CHCl3 (1.0 mL) gave a brown residue. Purification by
chromatography on silica gel with hexane/EtOAc (100:0e0:100) gave
5g (140 mg, 45%) and homodimer 7g (325 mg, 55%) as an oil.
Compound 5g: Rf¼0.28 (EtOAc); 1H NMR (CDCl3)
d 5.68e5.31
4.23. Cross-metathesis product t-Boc-homoallylester
phenylalanine-dimer 5e
(m, 4H), 4.24e3.75 (m, 14H), 3.52e3.24 (m, 4H), 2.44e1.73 (m,
12H), 1.39 and 1.34 (s, 18H); 13C NMR (CDCl3)
d 173.13, 172.92,
163.24, 163.14, 154.36, 153.75, 131.75, 131.41, 125.60, 125.38, 79.83,
79.69, 63.62, 59.14, 58.81, 49.05, 47.35, 46.58, 46.34, 31.66, 30.93,
29.99, 28.46, 28.36, 24.32, 23.64; IR (neat) 3494, 2975, 1745, 1670,
1477, 1399, 1279, 1162 cmꢁ1; HRMS (CI pos) for C34H53N4O10
[MþH]þ: calcd 677.3762, found 677.3751.
Following general CM procedures, dimer
2
(103 mg,
0.530 mmol), amino acid 3e (908 mg, 2.84 mmol), catalyst 1
(45.9 mg, 0.0541 mmol) and CHCl3 (1.0 mL) gave a brown residue.
Purification by chromatography on silica gel with hexane/EtOAc
(100:0e0:100) gave 5e (180 mg, 44%) as a silver foam and homo-
dimer 7e (440 mg, 50%) as a gray solid, mp¼142e144 ꢀC.
4.28. Homodimer t-Boc-homoallylester proline 7g
Compound 5e: Rf¼0.27 (EtOAc); 1H NMR (CDCl3)
d 7.38e7.08 (m,
10H), 5.58 (dt, J¼15.2, 6.3 Hz, 2H), 5.42 (dt, J¼15.3, 6.3 Hz, 2H), 5.10
(d, J¼8.0 Hz, 2H), 4.63e4.47 (m, 2H), 4.18e3.83 (m, 12H), 3.15e2.96
Compound 7g: Rf¼0.33 (hexane/EtOAc, 7:3); 1H NMR (CDCl3)
d
5.50e5.32 (m, 2H), 4.26e3.92 (m, 6H), 3.54e3.20 (m, 4H),
(m, 4H), 2.39e2.25 (m, 4H), 1.41 (s, 18H); 13C NMR (CDCl3)
d
172.01,
2.36e1.74 (m, 12H), 1.39 and 1.34 (s, 18H); 13C NMR (CDCl3)
d 173.10,
163.28, 155.21, 136.22, 131.46, 129.39, 128.63, 127.09, 125.68, 79.92,
64.11, 54.62, 49.11, 47.40, 38.41, 31.56, 28.40; IR (KBr) 3328, 2976,
2249,1713,1664,1498,1366,1170,1052 cmꢁ1; HRMS (ESI-FTICR) for
[MþNa]þ: calcd 799.3889; found 799.3879.
172.82, 154.32, 153.73, 128.43, 128.22, 127.98, 79.71, 79.61, 64.07,
59.11, 58.81, 46.51, 46.28, 31.97, 30.89, 29.94, 28.40, 28.30, 26.86,
24.25, 23.55 IR (neat) 3522, 2976, 2882, 1747, 1700, 1478, 1455, 1397,
1258, 1162, 1122 cmꢁ1; HRMS (CI pos) for C26H43N2O8 [MþH]þ:
calcd 511.3019, found 511.3017.
4.24. Homodimer t-Boc-homoallylester phenylalanine 7e
Compound 7e: Rf¼0.30 (hexane/EtOAc, 7:3); 1H NMR (CDCl3)
4.29. Homodimer t-Boc-homoallylester methionine 7h
d
7.35e7.10 (m, 10H); 5.47e5.35 (m, 2H), 5.09 (d, J¼7.2 Hz, 2H), 4.56
Following general CM procedures, dimer 2 (86.0 mg, 0.443 mmol),
amino acid 3h (690 mg, 2.27 mmol), Grubbs’ catalyst 1 (39.9 mg,
0.0470 mmol) and CHCl3 (1.0 mL) gave a brown residue. Purification
by chromatography on silica gel with hexane/EtOAc (9:1) gave
homodimer 7h (94 mg, 14%) as an oil and 5h was not observed.
Compound 7h: Rf¼0.31 (hexane/EtOAc, 7:3); 1H NMR (CDCl3)
(dt, J¼7.6, 7.0 Hz, 2H) 4.08 (t, J¼6.8 Hz, 4H), 3.09 (dd, J¼13.6, 6.5 Hz,
2H), 3.02 (dd, J¼13.6, 6.2 Hz, 2H), 2.37e2.20 (m, 4H),1.40 (s,18H); 13C
NMR (CDCl3)
d 171.90, 155.13, 136.17, 129.34, 128.53, 128.24, 126.99,
79.80, 64.55, 54.52, 38.39, 31.81, 28.33; IR (KBr) 3365, 3003, 2971,
2931, 1709, 1517, 1456, 1391, 1365, 1222, 1184, 1087, 1053, 1019 cmꢁ1
;
HRMS (ESI-FTICR) for [MþNa]þ: calcd 633.3146, found 633.3156.
d 5.78e5.39 (m, 2H), 5.19 (s, 2H), 4.44e4.30 (m, 2H), 4.22e4.07 (m,
4H), 2.56e2.29 (m, 8H), 2.17e1.83 (m, 10H), 1.42 (s, 18H); 13C NMR
(CDCl3) 172.4, 155.5, 128.4e126.6 (3 lines), 80.1, 65.6e64.2 (4
4.25. Cross-metathesis product t-Boc-homoallylester alanine-
d
dimer 5f
lines), 53.0, 32.4e31.7 (4 lines), 30.1e29.8 (2 lines), 28.5, 27.2e27.0
(2 lines), 15.9; IR (neat) 3357, 2976, 1715, 1515, 1366, 1252, 1166,
1051 cmꢁ1; HRMS (CI pos) for C26H47N2O8S2 [MþH]þ: calcd
579.2774, found 579.2768.
Following general CM procedures, dimer 2 (200 mg, 1.03 mmol),
amino acid 3f (1200 mg, 4.94 mmol), Grubbs’ catalyst 1 (84.0 mg,
0.099 mmol) and CHCl3 (3.0 mL) gave a brown residue. Purification
by chromatography on silica gel with hexane/EtOAc (100:0e0:100)
gave 5f (250 mg, 39%) as a silver foam and homodimer 7f (750 mg,
66%) as an oil.
4.30. Cross-metathesis product t-Boc-homoallylester leucine-
dimer 5i
Compound 5f: Rf¼0.31 (EtOAc); 1H NMR (CDCl3)
d
5.65 (dt,
Following general CM procedures, dimer 2 (95.0 mg, 0.489 mol),
amino acid 3i (682 mg, 2.39 mmol), Grubbs’ catalyst 1 (43.5 mg,
0.0512 mmol) and CHCl3 (1.0 mL) gave a brown residue. Purification
J¼15.4, 6.8 Hz, 2H), 5.46 (dt, J¼15.3, 6.4 Hz, 2H), 5.16 (s, 2H),
4.28e4.07 (m, 6H), 4.01e3.90 (m, 8H), 2.44e2.37 (m, 4H), 1.43 (s,

6926
J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
by chromatography on silica gel with hexane/EtOAc (9:1e1:9) gave
5i (103 mg, 30%) and homodimer 7i (381 mg, 59%) as an oil.
Compound 5i: Rf¼0.42 (EtOAc/hexane, 8:2); 1H NMR (CDCl3)
4.35. Homodimer Fmoc-homoallylester proline 8b
Compound 8b: Rf¼0.37 (hexane/EtOAc, 1:1); 1H NMR (CDCl3)
d
5.72e5.41 (m, 4H), 5.03 (d, J¼7.6 Hz, 2H), 4.31e3.90 (m, 14H),
d 7.73e7.15 (m, 16H), 5.43e5.27 (m, 2H), 4.40e3.88 (m, 12H),
2.53e2.35 (m, 4H), 1.86e1.38 (m, 24H), 0.94 (d, J¼6.72, 12H); 13C
3.62e3.37 (m, 4H), 2.32e1.73 (m, 12H); 13C NMR (CDCl3)
d 172.6,
NMR (CDCl3)
d
173.6, 163.4, 155.6, 131.7, 125.7, 79.9, 64.0, 52.4, 49.2,
154.9e154.5 (2 lines), 144.2e143.9 (2 lines), 141.4, 128.4e128.1 (3
lines), 127.8, 127.1, 125.3e125.1 (3 lines), 120.1, 67.6, 64.4, 59.4e59.0
(2 lines), 47.4e46.6 (4 lines) 32.1, 31.2, 30.1, 24.5, 23.5; HRMS (ESI-
FTIR) for [MþNa]þ calcd 777.3148, found 777.3129.
47.5, 41.9, 31.8, 28.5, 25.0, 23.0, 22.1; IR 3325, 2960,1713,1665,1522,
1475, 1390, 1366, 1334, 1253, 1166, 1048, 1020 cmꢁ1; HRMS (CI pos)
for C36H60N4O10 [MþH]þ: calcd 709.4388, found 709.4390.
4.31. Homodimer t-Boc-homoallylester leucine 7i
4.36. Cross-metathesis product Fmoc-homoallylester glycine-
dimer 6c
Compound 7i: Rf¼0.29 (hexane/EtOAc, 8:2); 1H NMR (CDCl3)
d
5.53e5.36 (m, 2H), 4.97 (d, J¼6.4 Hz, 2H), 4.30e4.00 (m, 6H),
Following general CM procedures, dimer 2 (94.0 mg, 0.484 mol),
amino acid 4c (854 mg, 2.43 mmol), Grubbs’ catalyst 5 (67.5 mg,
0.0795 mmol) and CHCl3 (2.0 mL) gave a brown residue. Purifica-
tion by chromatography on silica gel with hexane/EtOAc (9:1e1:9)
gave 6c (120 mg, 30%) as a silver solid, mp¼52e54 ꢀC, and homo-
dimer 8c (357 mg, 44%) as a white solid, mp¼121e123 ꢀC.
2.41e2.26 (m, 4H), 1.73e1.37 (m, 24H), 0.90 (d, J¼6.3 Hz, 12H); 13C
NMR (CDCl3) d 173.5,155.5,128.3,127.4 (cis) 79.8, 64.4, 52.3, 42.0, 32.1,
28.5, 27.0e24.9 (2lines), 22.9e22.1 (2 lines); IR 3379, 2960, 1716, 1510,
1391, 1367, 1253, 1165, 1048 cmꢁ1. HRMS (CI pos) for C28H50N2O8
[MþH]þ calcd 543.3645, found 543.3630; Anal. Calcd for C28H50N2O8:
C, 61.97; H, 9.29; N, 5.16. Found: C, 62.13; H, 9.62; N, 5.04%
Compound 6c: Rf¼0.42 (EtOAc); 1H NMR (CDCl3)
d 7.67e7.15 (m,
16H), 5.86e5.20 (m, 6H), 4.32e3.72 (m, 22H), 2.37e2.18 (m, 4H); 13C
4.32. Cross-metathesis Fmoc-homoallylester phenylalanine-
dimer 6a
NMR (CDCl3) d 170.2, 163.5, 156.6, 143.9, 141.3, 131.8, 127.8, 127.13,
125.6,125.2,120.1, 67.1, 63.9, 48.9, 47.2, 42.8, 31.8; IR 3319, 3065, 2957,
1724,1662, 1534,1478, 1450,1333,1263,1193, 1104, 1051, 1008 cmꢁ1
;
Following general CM procedures, dimer 2 (61.0 mg, 0.314 mol),
amino acid 4a (614 mg, 1.39 mmol), Grubbs’ catalyst 1 (30.0 mg,
0.035 mmol) and CHCl3 (1.5 mL) gave a brown residue. Purification
by chromatography on silica gel with hexane/EtOAc (9:1e2:8) gave
6a (136 mg, 42%) as brown foam, and homodimer 8a (285 mg, 48%)
as a white solid, mp¼54e56 ꢀC.
HRMS (ESI-FTICR) for [MþH]þ: calcd 841.3443, found 841.3432.
4.37. Homodimer Fmoc-homoallylester glycine 8c
Compound 8c: Rf¼0.39 (hexane/EtOAc, 5:5); 1H NMR (CDCl3)
7.78e7.27 (m, 16H), 5.50e5.36 (m, 4H), 4.40 (d, J¼7.3 Hz, 4H),
d
Compound 6a: Rf¼0.35 (EtOAc/hexane, 8:2); 1H NMR (CDCl3)
4.26e4.14 (m, 6H), 3.98 (d, J¼5.7 Hz, 4H), 2.43e2.31 (m, 4H); 13C NMR
d
7.70e7.01 (m, 26H), 5.53e5.26 (m, 6H), 4.59e3.74 (m, 18H),
(CDCl3) d 170.2,156.5,144.0,141.5,128.5,127.9,127.3,125.3,120.2, 67.4,
3.09e2.92 (m, 4H), 2.34e2.17 (m, 4H); 13C NMR (CDCl3)
d
171.7,
67.4, 64.8, 47.3, 42.9, 32.0; IR 3319, 2950, 1758, 1691, 1541, 1450, 1411,
1361, 1287, 1191, 1105, 1082, 1053 cmꢁ1. HRMS (ESI-FTICR) for
[MþNa]þ calcd697.2520,found697.2528.Anal. CalcdforC40H38N2O8:
C, 71.20; H, 5.68; N, 4.15. Found: C, 70.83; H, 5.74; N, 4.12%
163.4, 155.8, 143.9, 141.7,136.0, 131.5, 129.4, 128.7,127.8, 127.2, 125.7,
125.2, 120.1, 67.0, 64.3, 55.1, 49.1, 48.3, 47.3, 38.3, 31.6; IR 3304,
2956, 1721, 1662, 1478, 1451, 1334, 1260 cmꢁ1; HRMS (ESI-FTICR) for
[MþNa]þ: calcd 1043.4202, found 1043.4214.
4.38. Independent synthesis of cis-7a
4.33. Homodimer Fmoc-homoallylester phenylalanine 8a
A flame dried flask under argon was charged with acid 11a
Compound 8a: Rf¼0.30 (hexane/EtOAc, 7:3); 1H NMR (CDCl3)
(2.07 g, 7.8 mmol), and CH2Cl2 (10 mL). The solution was cooled to
d
7.72e6.98 (m, 26H), 5.55e5.20 (m, 4H), 4.64e3.92 (m, 12H),
0
ꢀC, followed by the addition of EDCI (1.47 g, 7.67 mmol), HOBt
3.10e2.75 (m, 4H), 2.29e2.12 (m, 4H); 13C NMR (CDCl3)
d
171.6,
(1.05 g, 7.77 mmol), DMAP (0.095 g, 0.78 mmol), and DIPEA (1.8 mL,
10 mmol). After stirring for 20 min, (Z)-2-butene-1,4-diol (12) was
added drop-wise to the solution and maintained for 6 h. The sol-
vent was removed in vacuo, and the residue redissolved in EtOAc.
The organic layer was washed with 1 N KHSO4, 1 N NaHCO3, water,
and brine. The organic layer was then dried with Na2SO4 and
concentrated in vacuo to give cis-7a (1.7 g, 97%) as a white solid.
155.7, 144.0e143.9 (2 lines), 141.5, 136.0, 129.5, 128.7, 128.4, 127.9,
127.3e127.2 (2 lines), 125.3e125.2 (2 lines), 120.2, 67.1, 64.9e64.8
(2 lines), 55.0, 47.3, 38.4, 31.9; IR 3343, 2953, 1728, 1521, 1450, 1211,
1051 cmꢁ1; HRMS (ESI-FTICR) for [MþNa]þ calcd 877.3459, found
877.3485. Anal. Calcd for C54H50N2O8: C, 75.86; H, 5.89; N, 3.28.
Found: C, 75.46; H, 5.99; N, 3.26%
Compound 7a: 1H NMR (CDCl3)
d d 7.32e7.09
1H NMR (CDCl3)
4.34. Cross-metathesis product Fmoc-homoallylester proline-
dimer 6b
(m, 10H), 5.72e5.60 (m, 2H), 4.98 (d, J¼8.1 Hz, 2H), 4.72e4.54 (m,
6H), 3.15e2.96 (m, 4H), 1.39 (s, 18H); 13C NMR (CDCl3)
d 171.8, 136.1,
129.5, 128.8, 128.1, 127.3, 80.2, 60.7, 54.6, 38.6, 28.5.
Following general CM procedures, dimer 2 (63.0 mg, 0.324 mol),
amino acid 4b (558 mg, 1.42 mmol), Grubbs’ catalyst 1 (30.0 mg,
0.0353 mmol) and CHCl3 (1.5 mL) gave a brown residue. Purifica-
tion by chromatography on silica gel with hexane/EtOAc (9:1e2:8)
gave 6b (140 mg, 46% NMR yield) and homodimer 8b (280 mg, 52%
NMR yield) as a brown semi-solid.
4.39. Hex-3-ene-1,6-diol (15)
Following literature procedures,14 a solution of trans-
b-hydro-
muconic acid 13 (1.00 g, 6.94 mmol), concentrated sulfuric acid
(0.34 mL), and absolute methanol (50 mL) refluxed overnight under
an atmosphere of argon. The solution was cooled to room temper-
ature and the MeOH was removed by reduced pressure. Extraction
with ether, NaHCO3, H2O, and brine, and drying with MgSO4 gave the
diester (1.0 g, 85%). A solution of the diester (1.0 g, 5.8 mmol) and THF
(30 mL) was added to a reaction vessel containing LiAlH4 (925 mg,
24.4 mmol) and THF (12 mL) by an addition funnel, and the reaction
mixture stirred under argon at room temperature for 6 h. The
Compound 6b: Rf¼0.32 (EtOAc); 1H NMR (CDCl3)
d 7.67e7.18 (m,
16H), 5.58e5.27 (m, 4H), 4.41e3.38 (m, 24H), 2.31e1.80 (m, 12H);
13C NMR (CDCl3)
d 172.6, 163.3e163.2 (2 lines), 154.8e154.4 (2
lines), 144.2e143.8 (3 lines), 141.3, 131.5e131.8 (2 lines), 127.7, 127.1,
125.6e125.0 (4 lines), 120.0, 67.5, 63.8, 59.3e58.9 (2 lines), 49.1,
47.3e46.5 (4 lines), 31.6e31.6 (2 lines), 31.2, 30.0, 24.4, 23.4; HRMS
(ESI-FTIR-MS) for [MþNa]þ: calcd 943.3899, found 943.3900.

J.E. Enholm et al. / Tetrahedron 68 (2012) 6920e6927
6927
reaction was quenched with EtOAc. The white precipitate that was
References and notes
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organic layers was passed through a pad of Celite and concentrated
under reduced pressure to give diol 14 (0.44 g, 65%).
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2107e2111.
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(2.21 g, 16.4 mmol), DMAP (0.130 g, 1.06 mmol), and DIPEA (4.0 mL,
23 mmol). After stirring for 20 min, diol 14 was added drop-wise to
the solution and maintained for 16 h. The solvent was removed in
vacuo, and the residue redissolved in EtOAc. The organic layer was
washed with 1 N KHSO4, 1 N NaHCO3, water, and brine. The organic
layer was then dried with Na2SO4 and concentrated in vacuo to give
trans-7e (1.2 g, 54%) as a white solid. Analytical data are identical to
data from CM product 7e.
Acknowledgements
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 sponsorship of a Ph.D. program for T.L.20