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DOI: 10.1055/s-0031-1290123
New Routes to Lipophilic Amino Acids: Synthesis of Alkynyl and Fluoro-Containing Alanine Derivatives
Publication History
Publication Date:
22 December 2011 (online)
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Abstract
Branched α-amino acids incorporating an alkynyl group have been prepared by copper-catalysed reaction of a serine-derived organozinc reagent with bromoallenes. Substantial improvements to our previously reported Negishi cross-coupling of the serine-derived organozinc reagent with cycloalkenyl triflates are possible using a combination of LiCl and SPhos as ligand. Finally, we report a preliminary example of addition of HF to cycloalkenyl alanine derivatives, leading to the corresponding tertiary fluoride.
Key words
amino acids - alkynes - cross-coupling - fluorine - zinc
- 1
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References and Notes
General Method
for the Preparation of Alkynes 4:
The organozinc
reagent 1 was prepared from protected iodoalanine 9 (329 mg, 1 mmol) as a ca. 1 M solution
in DMF according to our previously reported method.¹¹ CuBr˙DMS
(20.6 mg, 0.1 mmol) was gently heated under vacuum in a dry flask
until the powder turned light green, and was then allowed to cool
under nitrogen. DMF (0.6 mL) and the bromoallene 8 (1.1
mmol) were added. The reaction mixture was cooled to -10 ˚C.
After 2 min stirring at -10 ˚C, a solution of
the organozinc reagent 1 (1 mL of a 1 M solution
in DMF, 1 mmol) was added dropwise via syringe over 10 min. The
reaction mixture was stirred for the time indicated at either -10 ˚C
or 0 ˚C. The reaction mixture was applied directly to a
silica gel column, which was eluted (5% Et2O
in toluene) to give the alkynes 4
¹9-²¹ and
the allenes 10 as light yellow oils.
General Method for the Preparation of Alkenes
12: The cycloalken-1-yl triflate 3 (1.3
mmol, 1.3 equiv), Pd2(dba)3 (22 mg, 2.5 mol%),
SPhos (21 mg, 5 mol%) and LiCl (1.8 mmol, 1.8 equiv), if
required, were added at r.t. to the organozinc reagent 1 (1 mL of a ca. 1 M solution in DMF). The
reaction mixture was stirred at r.t. overnight under a positive
pressure of nitrogen, and then applied directly to a silica gel
column, which was eluted (10% EtOAc in petroleum ether)
to give the cross-coupled product 12.
(
R
)-2-Amino-3-(1-fluorocyclopentyl)propionic Acid Methyl
Ester (5): Alkene ent-12a (492 mg, 1.83 mmol) was dissolved in
toluene (4 mL) in a Teflon bottle, cooled to 0 ˚C and stirred
vigorously. HF-pyridine (70% HF, 3.2 mL, CAUTION: very toxic) was added and the
bottle was sealed. After 2 h, the reaction mixture was carefully transferred
into a slurry of CaCO3 (12.8 g) in H2O (50
mL) and CH2Cl2 (35 mL) cooled to 0 ˚C.
The mixture was stirred while the pH was adjusted to ca. 10 by addition
of sat. aq Na2CO3, followed by stirring for
a further 30 min. Celite (6.4 g) was washed with Na2CO3 solution,
H2O, EtOH, EtOAc and CH2Cl2 in
sequence and added to the slurry. The suspension was filtered and
the filter cake was washed with CH2Cl2 (50
mL in portions) and H2O (25 mL). The phases were separated
and the aqueous layer was extracted with CH2Cl2 (2 × 20
mL). The combined organic phases were washed with sat. aq NaHCO3 (20
mL) and evaporated. The crude mixture of amino esters (0.253 g)
was dissolved in 1,4-dioxane (4 mL), aq sat. NaHCO3 (6
mL) was added and the mixture was cooled to 0 ˚C with stirring.
Boc2O (0.323 g, 1.48 mmol) in 1,4-dioxane (4 mL) was
added to the reaction mixture. The reaction mixture was allowed
to reach r.t. and stirred for 1 h. The reaction mixture was diluted
with Et2O (10 mL) and H2O (10 mL) and the
layers were separated. The aqueous phase was extracted with Et2O
(2 × 10 mL). The combined organic phases were washed with
H2O and brine (10 mL each) and evaporated. The product
was purified by gradient column chromatography [Column
40 mm i.d. × 82 mm, loaded with 50 g Biotage KP-Sil (silica
gel) 2-17% EtOAc in iso-hexane] to
give 5
²² (158
mg, 30% over two steps) and recovered ent-12a (160 mg, 32%).
Characterisation data for alkyne 4a: [α]D ²¹ +9.8 (c = 1.0, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.27 (s, 3 H), 1.42 (s, 9 H), 1.74 (dd, J = 9.1, 14.0 Hz, 1 H), 1.90 (dd, J = 4.3, 14.2 Hz, 1 H), 2.15 (s, 1 H), 3.71 (s, 3 H), 4.43-4.48 (m, 1 H), 5.17 (d, J = 7.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 28.4, 28.9, 29.8, 29.8, 44.3, 51.8, 52.2, 69.2, 79.9, 90.5, 155.2, 173.5. IR (ATR): 3293, 2973, 1744, 1705, 1508, 1436, 1391, 1366, 1279, 1246, 1209, 1160, 1048, 1028, 868, 779, 629 cm-¹. HRMS (ES): m/z [M + H+] calcd for C14H24NO4: 270.1705; found: 270.1716.
20Characterisation data for alkyne 4b: [α]D ²¹ +2.9 (c = 10.2, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 1.42 (s, 9 H), 1.45-1.54 (m, 2 H), 1.55-1.72 (m, 2 H), 1.73-1.89 (m, 3 H), 1.90-2.00 (m, 2 H), 2.04 (dd, J = 4.3, 14.2 Hz, 1 H), 2.18 (s, 1 H), 3.71 (s, 3 H), 4.43-4.56 (m, 1 H), 5.18 (d, J = 7.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 23.4, 23.8, 28.4, 40.2, 40.5, 41.1, 41.9, 52.2, 52.5, 70.1, 79.8, 89.8, 155.2, 173.5. IR (ATR): 3294, 2954, 2874, 1709, 1507, 1437, 1391, 1366, 1248, 1214, 1162, 1049, 1019, 868, 778, 630 cm-¹. HRMS (ES): m/z [M + H+] calcd for C16H26NO4: 296.1862; found: 296.1864.
21Characterisation data for alkyne 4c: mp 56-57 ˚C; [α]D ²¹ +2.0 (c = 7.0, CHCl3). ¹H NMR (500 MHz, CDCl3): δ = 1.04-1.27 (m, 3 H), 1.42 (s, 9 H), 1.56-1.70 (m, 5 H), 1.70-1.85 (m, 3 H), 1.89 (dd, J = 4.1, 14.1 Hz, 1 H), 2.33 (s, 1 H), 3.70 (s, 3 H), 4.45-4.51 (m, 1 H), 5.21 (d, J = 7.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 22.5, 22.6, 25.8, 28.4, 35.2, 37.0, 38.0, 44.3, 51.2, 52.2, 71.9, 79.8, 88.5, 155.2, 173.7. IR (ATR): 3306, 2930, 2857, 2360, 1744, 1712, 1506, 1449, 1391, 1366, 1252, 1206, 1165, 1048, 1023, 866, 776, 632 cm-¹. HRMS (ES): m/z [M + H+] calcd for C17H28NO4: 310.2018; found: 310.2017.
22Characterisation data for 5: mp 47-51 ˚C; [α]D
²¹ -5.2
(c = 1.0, CHCl3). ¹H
NMR (400 MHz, CDCl3): δ = 1.43 (s,
9 H), 1.50-1.70 (m, 4 H), 1.73-1.85 (m, 2 H),
1.93-2.07 (m, 2 H), 2.10-2.32 (m, 2 H), 3.72 (s,
3 H), 4.40-4.50 (m, 1 H), 5.21 (br d, J = 7.0
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 23.5,
23.6, 28.3, 37.65 (d, J = 13
Hz), 37.8 (d, J = 13 Hz), 39.9
(d, J = 23 Hz), 51.3, 52.3,
79.9, 105.9 (d, J = 172 Hz), 155.2,
173.1. ¹9F NMR (376 MHz, CDCl3): δ = -142.7.
IR
(ATR): 3364, 2974, 1750, 1718, 1508, 1367, 1167 cm-¹. HRMS
(ES): m/z [M + H+] calcd
for C14H25NO4F: 290.1768 (base
peak is 579 [M2H+]);
found: 290.1769.