Montagnat et al.
JOCArticle
secondary structural motifs such as R-helices (some excep-
tions to this include the design of the unnatural tetrapeptide
Boc-(S)-γ-Ala-(S)-γ-Val-(S)-γ-Ala-(S)-γ-Val-TMSE by Ha-
nessian and co-workers,23 which was found to form a stable,
right-handed 2.61 helix in d5-pyridine, the design of Boc-
(ACHC)4-CO2Bn by Apella and co-workers,3 which was
found to adopt a 14-helical conformation in the solid state,
and the design of the 1,2,3-triazole tetramer: Boc-(S)-Lys-
(Cbz)-(S)-Lys(Cbz)-(S)-Bn-(S)-Bn-CO2Me by Angelo and
Arora,22 which was found to adopt a zigzag structure
reminiscent of β-strand conformations). Further investiga-
tions with these β-type 1,2,3-triazole oligomers are required
to determine if any stable secondary structures can be
formed, and if so, what minimum residue length and addi-
tional structural factors (such as the nature of side chains,
hydrogen bond donors/acceptors, electron donating/with-
drawing groups, etc.) control the nature of these confor-
mation(s).
842 cm-1; 1H NMR (300 MHz, CDCl3, T = 330 K) δ 0.10 (s,
9H, Si(CH3)3), 0.87 (d, 3H, J = 10.1 Hz, H6), 0.90 (d, 3H,
J = 10.0 Hz, H60), 1.72 (octet, 1H, J = 6.2 Hz, H5), 2.01 (s, 1H,
OH), 2.41 (2 ꢀ dd, 2H, J = 16.8 and 7.4 Hz, H3), 3.38-3.42
(m, 1H, H4); 13C NMR (75 MHz, CDCl3) -0.4 (Si(CH3)3),
17.2, 18.3 (C6, C60), 25.8 (C3), 32.2 (C5), 74.2 (C4), 86.8 (C1),
103.3 (C2).
General Procedure for the Synthesis of Chiral β3-Substituted
Trimethylsilyl-Homopropargyl Mesylates 27-29. Preparation of
(S)-2-Methyl-6-(trimethylsilyl)hex-5-yn-3-yl Methanesulfonate,
27. The alcohol 23 (133 mg, 0.72 mmol) was dissolved in
anhydrous CH2Cl2 (2 mL) and the solution was cooled to
0 °C. Triethylamine (1.08 mmol, 150 μL) was added via syringe
along with methanesulfonyl chloride (0.94 mmol, 58 μL) in one
portion. After 0.25 h, the reaction mixture was diluted with Et2O
(20 mL), washed with H2O (15 mL) and brine (15 mL), dried
with sodium sulfate, filtered, and evaporated under reduced
pressure to leave a yellow residue. The crude residue was
purified by column chromatography on silica gel, using 10%
ethyl acetate/hexane as the eluant, to afford (S)-2-methyl-
6-(trimethylsilyl)hex-5-yn-3-yl methanesulfonate 27 as a clear
residue (156 mg, 88%). Rf 0.54 (10% ethyl acetate/hexane); IR
Conclusion
1
(NaCl) νmax 2960, 2180, 1362, 1251, 1176, 914, 844 cm-1; H
In this paper, the synthesis of β3-substituted homopropar-
gyl alcohols and chiral β3-substituted trimethylsilyl-homo-
propargyl azides has been described in order to increase the
diversity of our set of small azido-alkyne precursors. It was
shown alkyl-substituted R-amino acids provide a chiral pool
for the synthesis of these fragments, using β3-substituted
trimethylsilyl-homopropargyl alcohols as a common syn-
thetic intermediate. One pure chiral 1,4-disubstituted-1,2,
3-triazole heterotetramer 45 was fully characterized and
investigated for the presence of organized secondary struc-
ture. NOESY/ROESY NMR along with computational
modeling studies showed that this heterotetramer existed in
a linear conformation in solution. Further modeling studies
are required to be conducted on alternative, enantiomeri-
cally pure 1,4-disubstituted-1,2,3-triazole oligomers in order
to assess if these molecules are capable of adopting ordered
secondary conformation(s) in solution.
NMR (300 MHz, CDCl3) δ 0.52 (s, 9H, Si(CH3)3), 1.36 (2 ꢀ d,
6H, J = 6.7 and 6.7 Hz, H6, H60), 2.45-2.56 (m, 1H, H5), 3.01
(2 ꢀ dd, 2H, 17.4 and 5.7 Hz, H3), 3.45 (s, 3H, H3CSO3), 4.95
(q, 1H, J = 5.5 Hz, H4); 13C NMR (75 MHz, CDCl3) δ -0.5
(Si(CH3)3), 16.7, 17.8 (C6, C60), 23.1 (C3), 31.1 (C5), 38.3
(H3CSO3), 85.0 (C4), 87.3 (C1), 101.4 (C2).
General Procedure for the Synthesis of Chiral β3-Substituted
Trimethylsilyl-Homopropargyl Azides 30-32. Preparation of
(S)-(4-Azido-5-methylhex-1-ynyl)trimethylsilane, 30. The mesy-
late 27 (559 mg, 2.18 mmol) was dissolved in dry DMF (13.6 mL)
along with sodium azide (283 mg, 4.36 mmol) and the mixture
was stirred at 40 °C. After 40 h, the reaction mixture was diluted
with Et2O (40 mL), washed with H2O (2 ꢀ 20 mL) and brine (20
mL), dried with sodium sulfate, filtered, and concentrated under
reduced pressure to leave a dark yellow oil. The crude oil was
purified by column chromatography on silica gel, using hexane
as the eluant, to afford (S)-(4-azido-5-methylhex-1-ynyl)tri-
methylsilane 30 as a slightly yellow oil (456 mg, 44%). Rf 0.55
(100% hexane); [R]D -4.5 (c, 1.78 in CH2Cl2); IR (NaCl) νmax
1
2964, 2901, 2180, 2124, 2100, 1250, 843 cm-1; H NMR (300
Experimental Section
MHz, CDCl3) δ 0.12 (s, 9H, Si(CH3)3), 0.90, 0.93 (2 ꢀ d, 6H, J =
9.5 Hz, H6, H60), 1.84 (octet, 1H, J = 6.3 Hz, H5), 2.43-2.49
(m, 2H, H3), 3.26 (q, 1H, J = 5.9 Hz, H4); 13C NMR (75 MHz,
CDCl3) δ -0.2 (Si(CH3)3), 17.5, 19.4 (C6, C60), 24.0 (C3), 31.7
(C5), 67.2 (C4), 87.5 (C1), 102.6 (C2); HRMS m/z for
C10H20N3Si [M þ H]þ calcd 210.1421, found 210.1425.
General Procedure for the Synthesis of Chiral β3-Substituted
Trimethylsilyl-Homopropargyl Alcohols 23-25. Preparation of
(S)-2-Methyl-6-trimethylsilanylhex-5-yn-3-ol, 23. The epoxide
20 was synthesized immediately before use and stored at -20 °C.
To a flame-dried, argon-filled, 25 mL three-necked round-
bottomed flask fitted with a stopper, septum, and argon line
was added dry THF (2.0 mL) and trimethylsilylacetylene (3.1
mmol, 442 μL) at -78 °C. nBuLi (1.9 mL of a 1.6 M solution in
hexanes, 3.1 mmol) and boron trifluoride etherate (3.1 mmol,
397 μL) were added at -78 °C and the mixture was left to stir for
0.5 h. The epoxide 20 was then added (270 mg, 3.1 mmol) at -78
°C and the reaction mixture was left to stir for 2 h. The reaction
mixture was then quenched with saturated NH4Cl solution
(4 mL) and diluted with Et2O (20 mL), washed with H2O
(15 mL) and brine (15 mL), dried with sodium sulfate, filtered,
and concentrated on a rotary evaporator to leave a yellow oil.
The crude oil was purified by column chromatography on silica
gel, using 10% ethyl acetate/hexane as the eluant, to afford (S)-
2-methyl-6-trimethylsilanylhex-5-yn-3-ol 23 as a clear oil (149
mg, 26%). Rf 0.52 (10% ethyl acetate/hexane); [R]D þ17.3 (c,
0.75 in CH2Cl2); IR (NaCl) νmax 3409, 2961, 2176, 1250,
1-Phenyl-pent-4-yn-2-(R)-ol, 26. The trimethylsilylbutynyl
alcohol 25 (336 mg, 1.4 mmol) was dissolved in dry MeOH (2
mL) and to this was added anhydrous K2CO3 (2.1 mmol, 299
mg) in one portion. The reaction mixture was left to stir at rt.
After 1 h, the reaction mixture was diluted with Et2O (30 mL),
washed with H2O (15 mL) and brine (15 mL), dried with
magnesium sulfate, filtered, and evaporated at reduced pressure
to leave 26 as a yellow oil (194 mg, 98%). 1H NMR spectroscopy
of the oil showed the desired product was obtained and it was
then used in the next reaction without further purification. Rf
0.46 (20% ethyl acetate/hexane); Rf 0.23 (10% ethyl acetate/
hexane); [R]D þ2.2 (c, 0.50 in CH2Cl2); IR (NaCl) νmax 3395,
1
3294, 3028, 2915, 1261, 1075, 1047, 701 cm-1; H NMR (300
MHz, CDCl3) δ 2.09 (t, 1H, J = 2.7 Hz, H1), 2.16 (s, 1H, OH),
2.37 (ddd, 1H, J = 2.7, 5.8, and 8.5 Hz, H3), 2.39 (ddd, 1H, J =
2.6, 5.0, and 7.6 Hz, H30), 2.82 (dd, 1H, J = 7.4 and 13.6 Hz,
H5), 2.92 (dd, 1H, J = 5.6 and 13.6 Hz, H50), 3.97 (quintet, 1H,
J = 5.7 Hz, H4), 7.22-7.34 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3) δ 26.1 (C3), 42.1 (C5), 70.5 (C4), 70.8 (C1), 80.4 (C2),
(23) Hanessian, S.; Luo, X.; Schaum, R.; Michnick, S. J. Am. Chem. Soc.
1998, 120, 8569–8570.
J. Org. Chem. Vol. 75, No. 2, 2010 397