The sonogashira cross-coupling reaction of alkenyl chlorides with aliphatic acetylenes

Article abstract of DOI:10.1055/s-0028-1088208

The Sonogashira cross-coupling reaction between amino acid based alkenyl chlorides and aliphatic acetylenes is reported. The present approach can be used in natural product synthesis and as an alternative to usually more expensive and unstable vinyliodide

Full text of DOI:10.1055/s-0028-1088208

LETTER
1063
The Sonogashira Cross-Coupling Reaction of Alkenyl Chlorides with
Aliphatic Acetylenes
The Sonogashira
C
oup
a
ling of Alk
t
i
loride
j
a Gredičak, Ivanka Jerić*
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, 10002 Zagreb, Croatia
Fax +385(1)4680195; E-mail: ijeric@irb.hr
Received 22 January 2009
lenging task. We have recently describe the synthesis and
characterization of three types of the Sonogashira reaction
products obtained from amino acid derived acetylenes
(Scheme 1).7
Abstract: The Sonogashira cross-coupling reaction between amino
acid based alkenyl chlorides and aliphatic acetylenes is reported.
The present approach can be used in natural product synthesis and
as an alternative to usually more expensive and unstable vinyl-
iodides.
In this context we decided to apply the described approach
to even more demanding ‘chemical cases’ with the ulti-
mate aim to decrease limitations of the Sonogashira reac-
tion in respect of alkenyl chlorides and aliphatic reactants.
Key words: acetylenes, alkenyl halides, Sonogashira cross-
coupling , amino acids, enediynes
Our initial studies were undertaken on the cross-coupling
reaction of chloroenyne-substituted amino acid deriva-
tives 4 carrying the oNbs protecting group at the N-termi-
nus with propargyl alcohol. Under the conditions applied
to the synthesis of 4, no traces of the desired enediyne
compound were detected (Scheme 2). We then turned our
attention back to Boc-protected N-substituted amino acid
derivatives. The Sonogashira reaction of Boc-protected
amino acids has been described; however, it involved cou-
pling with different aryl and heteroaryl bromides8,9 or 4-
iodophenylalanine.10 When coupled with cis-1,2-dichlo-
roethene (cis-DCE), glycine derivative 511 yielded 40% of
the corresponding Sonogashira product 6.12 Contrary to
our previous findings, optimization of reaction conditions
required usage of piperidine instead of BuNH2; 4 equiva-
lents were mixed with Pd catalyst and CuI, while addition-
The Sonogashira reaction, first described in 1975, still
represents one of the most valuable synthetic methods for
the cross-coupling of sp2-carbon halides and sp-carbon
terminal acetylenes.1 The majority of Sonogashira cou-
pling reactions described in the literature involve one or
both reactants to be aromatic compounds, which makes
them relatively reactive partners in the cross-coupling re-
action.2 Nevertheless, different approaches have been ex-
amined, including variations in the catalyst system,3
solvent,4 and base,5 indicating high interdependence of
the Sonogashira reaction conditions and the nature of
reactants involved.
We have studied the Sonogashira reaction of amino acid
derivatives as a crucial step in the synthesis of amino acid
derived enediynes. Finding out optimal conditions for the
coupling of aliphatic acetylenes with alkenyl chlorides,
far less reactive than bromides and iodides,6 was a chal-
HO
Cl
O
O
H
H
N
(i)
N
P
N
P
N
O
H
O
40–57% (P = Boc)
30–54% (P = oNbs)
H
R
(i) or (iii)
R
N
N
oNbs
1
2
O
oNbs
O
Cl
R
R
R = H, Me, Bn
Cl
4
HO
O
O
Cl
(ii)
N
N
30–50%
oNbs
O
oNbs
O
O
R
R
(ii)
40%
O
(iii)
O
3
R = amino acid side chain
4
N
N
50%
Boc
OH
N
Boc
OH
Boc
OH
Scheme 1 Our previous work. Reagents and conditions: (i)
(PhCN)2PdCl2 (0.05 mmol), CuI (0.05 mmol), cis-ClCH=CHCl (1.00
mmol), BuNH2 (1.00 mmol) in THF (1 mL), then 1 (0.5 mmol),
BuNH2 (1.00 mmol) in THF (2 mL); (ii) (PhCN)2PdCl2 (0.05 mmol),
CuI (0.05 mmol), cis-ClCH=CHCl (1.00 mmol), BuNH2 (1.00 mmol)
in THF (1 mL), then 3 (0.5 mmol) in THF (2 mL).
5
6
7
Scheme 2 Reagents and conditions: (i) (PhCN)2PdCl2 (0.05 mmol),
CuI (0.05), BuNH2 (1 mmol) and 4 (0.5 mmol) in THF (1 mL), then
propargyl alcohol (1 mmol) in THF (1 mL); (ii) (PhCN)2PdCl2 (0.035
mmol), CuI (0.053 mmol), cis-ClCH=CHCl (0.70 mmol), piperidine
(1.40 mmol) in THF (1 mL), then 5 (0.35 mmol) and piperidine (0.70
mmol) in THF (2 mL); (iii) (PhCN)2PdCl2 (0.011 mmol), CuI (0.041
mmol), 6 (0.164 mmol), piperidine (0.41 mmol) in THF (1 mL), then
propargyl alcohol (0.328 mmol) in THF (1 mL).
SYNLETT 2009, No. 7, pp 1063–1066
Advanced online publication: 16.03.2009
DOI: 10.1055/s-0028-1088208; Art ID: G01509ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9

1064
M. Gredičak, I. Jerić
LETTER
al 2 equivalents were added to the solution of acetylene Table 1 A Cross-Coupling Reaction between Chloroenynes 2a–f
and Glycine-Derived Acetylene 5a
component.
Further, chloroenyne derivative 6 was subjected to the
O
cross-coupling reaction with propargyl alcohol and gave
H
enediyne–amino acid conjugates 7 in 50% yield.13 The
N
Boc
N
H
O
Sonogashira coupling of 4 with propargyl alcohol, under
the described reaction conditions again failed to give ene-
diyne compound. It seems that the reactivity of N-propar-
gylated amino acid derivatives is influenced by the nature
of an additional group attached at the N-terminus (aromat-
ic oNbs or aliphatic Boc). While oNbs-related N-propar-
gylated derivatives gave the corresponding chloroenynes
in fair yields with BuNH2 as a base, Boc-related N-prop-
argylated derivatives required piperidine as a stronger
base. Also, oNbs-related chloroenynes turned out to be
poorly reactive partners in the Sonogashira cross-
coupling reaction with propargyl alcohol, while Boc-
related chloroenyne derived from glycine gave the ene-
diyne product in fair yield. Possible explanation can be
sought in sterical factors and interaction between two
electron-rich systems, aromatic (oNbs) and chloroenyne,
which prevents efficient bounding to the catalyst and con-
sequently coupling to another partner.
Boc
N
NH
R
N
O
Boc
OH
Cl
O
R
5
2a–f
OH
Boc NH
8a–f
Compound R
Yield (%)b
Yield (%)c
8a
8b
8c
8d
8e
8f
CH2C6H4OBoc
35
30
40
15
30
25
51
58
64
37
77
69
Bn
i-Pr
H
Me
(CH2)4NHBoc
a Reagents and conditions: (PhCN)2PdCl2, (0.02 mmol), CuI (0.02
mmol), 2 (0.20 mmol), and base (0.40 mmol) in dry THF (1 mL), then
solution of 5 (0.40 mmol) and base (0.80 mmol) in dry THF (2 mL).
b BuNH2 was used as a base.
Encouraged by the obtained results, we decided to exploit
the Sonogashira reaction for the synthesis of enediyne-
bridged peptide motifs. In particular, we have published a
general strategy comprising usage of amino acids carrying
different protecting groups.14 This approach is suitable
when selective deprotection is required, however, its effi-
ciency is highly dependent on the structure of amino
acids. Alternatively, when single-step deprotection is an
advantage, the presence of the Boc group can simplify the
reaction procedure. Thus, we carried out a number of
cross-coupling reactions between amino acid derived
chloroenynes and N-propargylated amino acid (Table 1).
c Piperidine was used as a base.
MS spectra of compounds 8a–f showed consecutive loss-
es of 100 Da fragment originating from the cleavage of
two or three Me3COCO moieties. More interesting, all
MS/MS spectra display relatively abundant ions arising
from the combined loss of Me3COCO and Me3C moieties
(156 Da).
Only a limited number of amino acid and peptide-related
enediyne structures are reported in the literature,16 though
such conjugates show promising DNA cleavage abili-
ties.16c,d In this respect, it is important to note that depro-
tected derivatives of enediyne-bridged dipeptide mimetics
8 showed a biologically relevant response in preliminary
antimicrobial activity. Anticancer activity of these com-
pounds is currently under investigation and will be pub-
lished in due course.
A cross-coupling reaction between chloroenynes derived
from various amino acids (Tyr, Phe, Val, Gly, Ala, and
Lys) and N-propargylated Boc-protected glycine deriva-
tive 5 was performed with BuNH2 and piperidine as a
base. As clearly seen from Table 1, considerably higher
yields were obtained with piperidine. It was also found
that 4 equivalents of piperidine added to acetylene compo-
nent are essential for a successful coupling.15
Compounds 8a–f were characterized by spectroscopic
analysis, mass spectrometry, and HRMS. Optical purity
was checked by acid hydrolysis (6 M HCl) at 105 °C for
24 hours and analysis on chiral plates for enantiomeric
resolution by TLC. Purity was also checked by the RP
HPLC under isocratic conditions (71.5% MeOH in 0.1%
TFA, flow rate 0.5 mL/min). NMR spectra were recorded
in CD3OD and exhibit the presence of two conformers
owing to the cis–trans isomerization of the tertiary pep-
tide bond (Figure 1). Two sets of signals displayed both
carbons and protons of the glycine residue and the ene-
diyne moiety, with the approximate ratio 60:40 (Figure 1).
Additionally, vinyl protons were found equivalent and
Figure 1 The cis–trans isomerization of 8b (R = Bn) and enediyne
present as a singlet at approximately d = 5.88 ppm. MS/ part of the 13C NMR spectrum
Synlett 2009, No. 7, 1063–1066 © Thieme Stuttgart · New York

LETTER
The Sonogashira Coupling of Alkenyl Chlorides
1065
(7) Gredičak, M.; Kolonić, A.; Jerić, I. Amino Acids 2008, 35,
185.
(8) López-Deber, M. P.; Castedo, L.; Granja, J. R. Org. Lett.
2001, 3, 2823.
(9) Brea, R. J.; López-Deber, M. P.; Castedo, L.; Granja, J. R.
J. Org. Chem. 2006, 71, 7870.
(10) Hoffmanns, U.; Metzler-Nolte, N. Bioconjugate J. 2006, 17,
204.
(11) Boc-(prop-2-yne-1-yl)-Gly-OH (5) was prepared according
to the procedure described in ref. 8. Yield 74%; yellow oil;
Rf = 0.44 (toluene–EtOAc–AcOH, 10:2:0.5). 1H NMR (300
MHz, CDCl3, trans and cis): d = 1.45, 1.49 (s, 9 H, CH3
Boc), 2.28 (br t, 1 H, H3 propargyl), 4.17 (m, 4 H, H11¢
propargyl, a Gly). 13C NMR (75 MHz, CDCl3, trans and
cis): d = 28.2 (CH3 Boc), 36.6, 37.3 (C1 propargyl), 47.1 (a
Gly), 72.7, 73.0 (C3 propargyl), 78.5 (C Boc), 81.4, 81.6 (C2
propargyl), 154.6, 154.8 (CO Boc), 175.3 (CO Gly). HRMS
(MALDI): m/z [M + Na]+ calcd for C10H15NNaO4: 236.0893;
found: 236.0887.
In summary, we have demonstrated that aliphatic amino
acid derived acetylenes and chlorides can be successfully
applied in the Sonogashira type of cross-coupling reac-
tions. Although reactions must be performed under rigor-
ous conditions and yields are lower than those obtained
with aromatic substituents, the presented results encour-
age further utilization of the Sonogashira reaction. This is
especially important for the synthesis of natural products,
since many metabolites contain alkyne or enyne moi-
eties.17 Although aryl- and vinyl-chlorides have been rare-
ly exploit so far, under defined reaction conditions they
can be favorable alternatives to the usually more expan-
sive and unstable aryl- and vinyl-iodides.
Acknowledgment
This work was supported by the Croatian Ministry of Science, Edu-
cation and Sports, Grant No. 0098-0982933-2936. We thank Dr.
Tanja Poljak for assistance and useful discussions regarding the set-
ting up experiments and Dr. Mario Cindrić for performing HRMS
analyses.
(12) Synthesis of Boc-[penta-5-chloro-4-(Z)-ene-2-yne-1-yl]-
Gly-OH (6)
A mixture of Pd(Ph3P)4 (12 mg, 0.035 mmol), CuI (12 mg,
0.053 mmol), cis-DCE (65 mL, 0.7 mmol), and piperidine
(136 mL, 1.40 mmol) dissolved in dry THF (1 mL) was
stirred for 30 min under argon. A solution of Boc-(prop-2-
yne-1-yl)-Gly-OH (5, 75 mg, 0.35 mmol) and piperidine (68
mL, 0.70 mmol) in THF (2 mL) was added dropwise by the
syringe, and the reaction was stirred at r.t. overnight. Solvent
was evaporated, and the residue purified by flash chroma-
tography. Yield 59% (56 mg); yellow oil; Rf = 0.54
(toluene–EtOAc–AcOH, 10:2:0.5). 1H NMR (300 MHz,
DMSO-d6, trans and cis): d = 1.36, 1.41 (s, 9 H, CH3 Boc),
2.69 (s, 1 H, H3 chloroenyne), 3.91, 3.93 (br s, 2 H, a Gly),
4.26, 4.28 (H11¢ chloroenyne), 6.19 (br td, 1 H, H4 chloro-
References and Notes
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Cassar, L. J. Organomet. Chem. 1975,
93, 253. (c) Dieck, H. A.; Heck, F. R. J. Organomet. Chem.
1975, 93, 259. (d) Sonogashira, K.; Yatake, T.; Tohda, Y.;
Takahashi, S.; Hagihara, N. J. Chem. Soc., Chem. Commun.
1977, 291.
(2) (a) Arnautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.; Witulski,
B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695. (b) Nakano,
Y.; Ishizuka, K.; Muraoka, K.; Ohtani, H.; Takayama, Y.;
Sato, F. Org. Lett. 2004, 6, 2373. (c) Bosshart, E.;
Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003, 5,
2441. (d) Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002,
32, 1489. (e) Mohamed Ahmed, M. S.; Mori, A.
Tetrahedron 2004, 60, 9977. (f) König, B.; Pitsch, W.;
Klein, M.; Vasold, R.; Prall, M.; Schreiner, P. R. J. Org.
Chem. 2001, 66, 1742. (g) Suzuki, I.; Uno, S.; Tsuchiya, Y.;
Shigenaga, A.; Nemoto, H.; Shibuya, M. Bioorg. Chem.
Lett. 2004, 14, 2959.
enyne), 6.79 (d, 3J4,5 = 7.3 Hz, 1 H, H5 chloroenyne). 13
C
NMR (75 MHz, DMSO-d6, trans and cis): d = 27.8, 27.9
(CH3 Boc), 37.3, 38.03 (C1 chloroenyne), 47.4, 47.7 (a Gly),
77.6, 77.9 (C Boc), 79.9, 80.0 (C2 chloroenyne), 93.4, 93.5
(C3 chloroenyne), 112.0 (C4 chloroenyne), 129.1 (C5
chloroenyne), 154.6, 154.2 (CO Boc), 170.7 (CO Gly).
HRMS (MALDI): m/z [M + Na]+ calcd for C12H16ClNNaO4:
296.0660; found: 296.0652.
(13) Synthesis of Boc-[octa-8-hydroxy-2,6-diyne-4-(Z)-ene-1-
yl]-Gly-OH (7)
A mixture of Pd(Ph3P)4 (13 mg, 0.011mmol), CuI (10 mg,
0.041 mmol), Boc-[penta-5-chloro-4-(Z)-ene-2-yne-1-yl]-
Gly-OH (6, 45 mg, 0.164 mmol), and piperidine (38 mL, 0.41
mmol) dissolved in dry THF (1 mL) was stirred for 30 min
under argon. A solution of propargyl alcohol (20 mL, 0.328
mmol) in THF (1 mL) was added dropwise by the syringe,
and the reaction was stirred at r.t. overnight. Solvent was
evaporated and the residue purified by flash chromatog-
raphy. Yield 67% (32 mg); yellow oil; Rf = 0.60 (EtOAc–
toluene–AcOH, 10:5:0.5). 1H NMR (300 MHz, DMSO-d6):
d = 1.37 (s, 9 H, CH3 Boc), 3.94 (br s, 2 H, a Gly), 4.27 (br
d, 4 H, H11¢, H88¢ enediyne), 6.00 (br td, 1 H, H4 enediyne),
6.04 (br td, 1 H, H5 enediyne). 13C NMR (75 MHz, DMSO-
d6): d = 27.8 (CH3 Boc), 37.2 (C1 enediyne), 47.4 (a Gly),
49.4 (C8 enediyne), 79.5 (C Boc), 79.8 (C2 enediyne), 81.3
(C7 enediyne), 92.4 (C3 enediyne), 97.5 (C6 enediyne),
119.0 (C4 enediyne), 120.1 (C5 enediyne), 154.2 (CO Boc),
170.8 (CO Gly). HRMS (MALDI): m/z [M + H]+ calcd for
C15H19NO5: 294.1336; found: 294.1322.
(3) (a) Fukuyama, T.; Shinmen, M.; Nashitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691. (b) Köllhofer, A.; Pullman,
T.; Plenio, H. Angew. Chem. Int. Ed. 2003, 42, 1056.
(c) Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron
2005, 61, 9839. (d) Rollet, P.; Kleist, W.; Dufaud, V.;
Djakovitch, L. J. Mol. Catal. A: Chem. 2005, 241, 39.
(e) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Eur. J. Org. Chem.
2005, 4256. (f) Doucet, H.; Hierso, J. C. Angew. Chem. Int.
Ed. 2007, 46, 834.
(4) (a) Deng, C.; Xie, Y.; Yin, D.; Li, Y. Synthesis 2006, 20,
3370. (b) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.;
Fathi, R.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097.
(c) Colacino, E.; Daïch, L.; Martinez, J.; Lamaty, F. Synlett
2007, 1279.
(5) (a) Batchu, V. R.; Subramanian, V.; Parasuraman, K.;
Swamy, N. K.; Kumar, S.; Pal, M. Tetrahedron 2005, 61,
9869. (b) Kim, J. H.; Lee, D. H.; Jun, B. H.; Lee, Y. S.
Tetrahedron Lett. 2007, 48, 7079.
(6) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(14) Jerić, I.; Chen, H.-M. Tetrahedron Lett. 2007, 48, 4687.
Synlett 2009, No. 7, 1063–1066 © Thieme Stuttgart · New York

1066
M. Gredičak, I. Jerić
LETTER
(15) General Procedure for the Synthesis of 8
(PhCN)2PdCl2, (0.02 mmol), CuI (0.02 mmol), 2 (0.2
mmol), and piperidine (0.40 mmol) were dissolved in dry
THF (1 mL), and the reaction was stirred for 30 min under
argon. A solution of 5 (0.40 mmol) and piperidine (0.80
mmol) in 2 mL of dry THF was added dropwise by the
syringe, and the reaction was stirred at r.t. until all acetylene
was consumed. Solvent was evaporated and the residue
purified by flash column chromatography.
Boc-Gly-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl](Boc)-Gly-
OH (8d)
Yield 37%; yellow oil; Rf = 0.27 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 9.14 min. 1H NMR (600 MHz, CD3OD):
d = 1.45 (s, 18 H, CH3 Boc), 3.72 (br s, 2 H, a Gly1), 4.09,
4.12 (br s, 2 H, H88¢ enediyne), 4.20 (br s, 2 H, a Gly2), 4.34,
4.36 (br s, 2 H, H11¢ enediyne), 5.87 (s, 2 H, H4,5 enediyne).
13C NMR (150 MHz, CD3OD, trans and cis): d = 28.6, 28.7,
28.8 (CH3 Boc), 30.5 (C1 enediyne), 38.6, 39.3 (C8
enediyne), 44.7 (a Gly1) 48.2 (a Gly2), 80.9 (C Boc), 82.4,
82.5, 82.9 (C2, C7 enediyne), 92.6, 92.7, 94.0 (C3, C6
enediyne), 120.3, 120.4 (C4 enediyne), 120.8, 121.0 (C5
enediyne), 156.8, 157.7 (CO Boc), 172.4 (CO Gly1), 173.4
(CO Gly2). HRMS (MALDI): m/z [M + Na]+ calcd for
C22H31N3NaO7: 472.2054; found: 472.2066.
Boc2-Tyr-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl](Boc)-
Gly-OH (8a)
Yield 51%; yellow oil; Rf = 0.64 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 11.54 min. 1H NMR (300 MHz, CD3OD):
d = 1.37, 1.44, 1.48, 1.52 (s, 27 H, CH3 Boc), 2.87, 3.08 (dd,
3Ja,b = 8.4 Hz, 3Ja,b¢ = 5.9 Hz, 2Jb,b¢ = 13.5 Hz, 2 H, bb¢ Tyr),
4.12 (m, 5 H, a Tyr, a Gly, H88¢ enediyne), 7.04 (d, 3Jd,e
=
Boc-Ala-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl](Boc)-Gly-
OH (8e)
8.4 Hz, 2 H, e Tyr), 4.35 (br d, 2 H, H11¢ enediyne), 5.89 (s,
2 H, H4,5 enediyne), 7.26 (d, 3Jd,e = 8.4 Hz, 2 H, d Tyr). 13
C
Yield 77%; yellow oil; Rf = 0.40 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 9.40 min. 1H NMR (600 MHz, CD3OD):
d = 1.30 (d, 3Ja,b = 7.2 Hz, 3 H, b Ala), 1.44 (s, 18 H, CH3
Boc), 4.11 (m, 3 H, a Ala, a Gly), 4.18 (br d, 2 H, H88¢
enediyne), 4.34 (br d, 2 H, H11¢ enediyne), 5.88 (s, 2 H, H4,5
enediyne). 13C NMR (150 MHz, CD3OD, trans and cis):
d = 18.5 (d Ala), 28.6, 28.7, 28.8 (CH3 Boc), 30.6 (C1
enediyne), 38.6, 39.3 (C8 enediyne), 48.1 (a Gly), 51.7 (a
Ala), 80.8, 80.9, 81.0 (C Boc), 82.4, 82.5, 83.0 (C2, C7
enediyne), 92.5, 94.0 (C3, C6 enediyne), 120.3, 120.4 (C4
enediyne), 120.9, 121.0 (C5 enediyne), 156.8, 157.7 (CO
Boc), 173.3 (CO Gly), 175.7, 175.7 (CO, Ala). HRMS
(MALDI): m/z [M + Na]+ calcd for C23H3N3NaO7: 486.2211;
found: 486.2233.
NMR (75 MHz, CD3OD, trans and cis): d = 28.0, 28.6, 28.7,
28.8 (CH3 NHBoc, OBoc), 30.5 (C1 enediyne), 38.6 (b Tyr),
38.9, 39.3 (C8 enediyne), 48.1 (a Gly), 57.4 (a Tyr), 80.9,
81.0, 84.4 (C Boc), 82.4, 82.5, 82.9, 83.00 (C2, C7
enediyne), 92.6, 92.7, 93.8, 93.9 (C3, C6 enediyne), 120.4,
120.5 (C4 enediyne), 120.9, 121.1 (C5 enediyne), 122.3 (e
Tyr), 131.6 (d Tyr), 136.2 (g Tyr), 151.6, 153.6 (CO Boc),
156.8, 157.7 (z Tyr), 173.2, 173.3 (CO Gly), 173.9 (CO Tyr).
HRMS (MALDI): m/z [M + Na]+ calcd for C34H45N3NaO10:
678.2997; found: 678.2980.
Boc-Phe-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl](Boc)-Gly-
OH (8b)
Yield 58%; yellow oil; Rf = 60 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 10.59 min. 1H NMR (300 MHz, CD3OD):
d = 1.36, 1.44, 1.47 (s, 18 H, CH3 Boc), 2.85, 3.08 (dd,
3Ja,b = 8.7 Hz, 3Ja,b¢ = 5.7 Hz, 2Jb,b¢ = 13.5 Hz, 2 H, bb Phe),
4.10 (m, 4 H, H88¢ enediyne, a Gly), 4.27 (m, 1 H, a Phe),
4.35 (br d, 2 H, H11¢ enediyne), 5.88 (s, 2 H, H4,5 enediyne),
7.22 (m, 5 H, arom. Phe). 13C NMR (75 MHz, CD3OD, trans
and cis): d = 28.6, 28.7, 28.8 (CH3 Boc), 30.5 (C1 enediyne),
38.6, 39.2 (C8 enediyne), 39.5 (b Phe), 48.2 (a Gly), 57.4 (a
Phe), 80.8, 81.0 (C Boc), 82.4, 82.5, 82.9, 83.0 (C2, C7
enediyne), 92.6, 92.7, 93.8, 93.9 (C3, C6 enediyne), 120.3,
120.4 (C4 enediyne), 120.9, 121.0 (C5 enediyne), 127.8 (z
Phe), 129.5 (e Phe), 130.6 (d Phe), 138.5 (g Phe), 156.8,
157.6 (CO Boc), 173.2 (CO Gly), 174.1 (CO Phe). HRMS
(MALDI): m/z [M + Na]+ calcd for C29H37N3NaO7:
562.2523; found: 562.2509.
Boc-Lys(Boc)-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl]-
(Boc)-Gly-OH (8f)
Yield 69%; yellow oil; Rf = 0.24 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 10.07 min. 1H NMR (300 MHz, CD3OD):
d = 1.43, 1.44 (br d, 31 H, CH3 Boc, gg¢, dd¢ Lys), 1.75 (m,
2 H, bb¢ Lys), 3.03 (t, 3Jd,e = 6.6 Hz, 2 H, ee¢ Lys), 3.99 (br
d, 1 H, a Lys), 4.15 (m, 4 H, H88¢ enediyne, a Gly), 4.35 (br
d, 2 H, H11¢ enediyne), 5.88 (s, 2 H, H4,5 enediyne). 13
C
NMR (75 MHz, CD3OD, trans and cis): d = 24.3 (g Lys),
28.6, 28.7, 28.9, 29.0 (CH3 Boc), 30.6 (C1 enediyne), 30.7
(d Lys), 33.2 (b Lys), 38.6, 39.3 (C8 enediyne), 41.2 (e Lys),
48.1 (a Gly), 56.1 (a Lys), 80.0, 80.8, 81.0 (C Boc), 82.4,
82.5, 82.9, 83.0 (C2, C7 enediyne), 92.6, 92.7, 94.0 (C3, C6
enediyne), 120.4, 120.5 (C4 enediyne), 120.9, 121.0 (C5
enediyne), 156.7, 156.8, 158.0, 158.7 (CO Boc), 173.2,
173.3 (CO Gly), 175.1 (CO Lys). HRMS (MALDI): m/z
[M + Na]+ calcd for C31H48N4NaO9: 643.3314; found:
643.3296.
Boc-Val-N-[octa-2,6-diyne-4-(Z)-ene-1,8-diyl](Boc)-Gly-
OH (8c)
Yield 64%; yellow oil; Rf = 0.57 (toluene–EtOAc–AcOH,
5:5:0.5); tR = 10.22 min. 1H NMR (300 MHz, CD3OD):
d = 0.94 (br t, 6H, g Val), 1.44 (br s, 18 H, CH3 Boc), 2.01
(s, 1 H, b Val), 3.85 (d, 3Ja,b = 6.9 Hz, 1 H, a Val), 4.14 (m,
4 H, H88¢ enediyne, a Gly), 4.36 (br d, 2 H, H11¢ enediyne),
5. 87 (s, 2 H, H4,5 enediyne). 13C NMR (75 MHz, CD3OD,
trans and cis): d = 18.7, 19.8 (g Val), 28.6, 28.7, 28.8 (CH3
Boc), 30.4 (C1 enediyne), 32.4 (b Val), 38.6, 39.2 (C8
enediyne), 48.1 (a Gly), 61.6 (a Val), 80.7, 80.9 (C, Boc),
82.4, 82.5, 82.8, 83.0, (C2, C6 enediyne), 92.5, 92.6, 93.9,
94.0 (C3, C7 enediyne), 120.3, 120.4 (C4 enediyne), 120.8,
120.9 (C5 enediyne), 156.8 (CO Boc), 173.3 (CO Gly),
174.4 (CO Val). HRMS (MALDI): m/z [M + Na]+ calcd for
C25H37N3NaO7: 514.2524; found: 514.2537.
(16) (a) Basak, A.; Bag, S. S.; Bdour, H. M. M. Chem. Commun.
2003, 2614. (b) Basak, A.; Bag, S. S.; Basak, A. Bioorg.
Med. Chem. 2005, 13, 4096. (c) Breiner, B.; Schlatterer,
J. C.; Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V.
Angew. Chem. Int. Ed. 2006, 45, 3666. (d) Du, Y.;
Creighton, C. J.; Yan, Z.; Gauthier, D. A.; Dahl, J. P.; Zhao,
B.; Belkowski, S. M.; Reitz, A. B. Bioorg. Med. Chem. 2005,
13, 5936.
(17) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
Synlett 2009, No. 7, 1063–1066 © Thieme Stuttgart · New York

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