Checked by Carol M. Taylor and Amos B. Smith, III.
1. Procedure
A.
(S)-N-(9-Phenylfluoren-9-yl)alanine (2).
3 A
1-L, flame-dried, three-necked Morton flask (Note
1) equipped with an
overhead stirrer,
rubber septum, and
reflux condenser (equipped with a rubber septum) under a
nitrogen atmosphere is charged with
L-alanine (1, 13.5 g, 150 mmol, (Note 2)),
chloroform (375 mL, (Note 3)),
acetonitrile (75 mL, (Note 4)), and
chlorotrimethylsilane (19.04 mL, 150 mmol, (Note 5)). The rubber septum in the neck of the Morton flask is replaced with a
glass stopper, and the mixture is heated at reflux for 2 hr with vigorous stirring under an inert atmosphere (Note
6). The mixture is cooled to room temperature under a stream of
nitrogen,
triethylamine (46.0 mL, 330 mmol, (Note 7)) is added via syringe at a rate sufficient to maintain a gentle reflux, and the mixture is stirred for 15 min after which
Pb(NO3)2 (33.1 g, 100 mmol, (Note 8)) is added. The glass stopper is replaced with a rubber septum, and a solution of
9-bromo-9-phenylfluorene (57.8 g, 180 mmol, (Note 9)) in
chloroform (180 mL, (Note 3)) is added via a
Teflon cannula with a positive
nitrogen pressure. The reflux condenser is replaced with a glass stopper, and an
18-gauge syringe needle equipped with an argon-filled balloon is inserted in the rubber septum. The heterogeneous, off-white mixture is stirred vigorously under this inert atmosphere for 48 hr. After about 20 hr, the reaction mixture becomes orange and darkens over time.
Methanol (15.2 mL, 375 mmol, (Note 10)) is then added, and the mixture is stirred an additional 30 min.
The mixture is filtered using a sintered glass filter, the filter cake is washed by stirring with
chloroform (3 × 50 mL), and the dark orange filtrate is evaporated to a residue that is partitioned between
ether (750 mL, (Note 11)) and
aqueous 5% citric acid (750 mL, (Note 12)). The layers are separated, and the aqueous layer is extracted with
ether (4 × 250 mL). The combined organic solutions are extracted with
1 M sodium hydroxide (300 mL). The aqueous solution is washed with
300 mL of ether, cooled to 0°C with stirring using a magnetic stir bar, and the pH is adjusted to 7 by the dropwise addition of
glacial acetic acid (approximately 17 mL, (Note 13)). The mixture now containing an off-white precipitate is extracted with
25% 2-propanol (Note
14) in
chloroform (3 × 300 mL). The combined organic solutions are washed with
150 mL of saturated sodium chloride solution, dried (Na
2SO
4), filtered, and evaporated to a light yellow foam that is dried under reduced pressure to give
39.2 g (
80% yield) of
(S)-N-(9-phenylfluoren-9-yl)alanine (
2) (Note
15).
2. Notes
1. Use of a Morton flask and an overhead stirrer allows for better mixing of the heterogenous system and gives conversion to product faster than does use of a
standard round-bottomed flask with an overhead stirrer.
2.
L-Alanine was purchased from Fisher Scientific company and used without further purification.
3.
Chloroform was purchased from Fisher Scientific Company and distilled from
phosphorus oxide (P2O5) immediately before use and added to the reaction mixture via syringe.
4.
Acetonitrile was purchased from EM Science, distilled from
calcium hydride (CaH2) immediately before use and added to the reaction mixture via syringe.
5.
Chlorotrimethylsilane was purchased from Aldrich Chemical Company, Inc., distilled from CaH
2 immediately before use, and added to the reaction mixture via syringe.
6. A syringe needle equipped with an argon-filled balloon should be inserted through the rubber septum on the reflux condenser. In addition, while the mixture is refluxing, the apparatus should be checked frequently for leaks.
7.
Triethylamine was purchased from Fisher Scientific Company and distilled from
barium oxide (BaO) immediately before use and added to the reaction mixture via syringe.
8.
Lead nitrate (toxic!) was purchased from Fisher Scientific Company, dried in an
oven at 160°C for 4 days, and cooled in a
desiccator, yielding a freely-flowing, white granular solid. The checkers dried it at 100°C under 1.5 mm vacuum for 4 days.
10.
Methanol was purchased from Fisher Scientific Company and used without further purification.
11.
Ethyl ether was purchased from Fisher Scientific Company and used without further purification.
12. An insoluble brownish-orange polymer formed was carefully excluded from the organic extractions. Leaching of this material into the organic layer produces colored product.
13.
Glacial acetic acid was purchased from Fisher Scientific Company and used without further purification. Near pH 7, much of the product precipitated, and the off-white mixture became difficult to stir. Distribution of the
acetic acid was accomplished by manually swirling the flask.
14.
2-Propanol was purchased from Fisher Scientific Company and used without further purification.
15. Compound
23 thus obtained was of sufficient purity (>97%, as determined by elemental analysis) for direct use; but was contaminated by a small amount of highly colored impurities. IR cm
−1: 3070 (m), 3005 (m), 2905 (m), 1765 (m), 1735 (m), 1640 (m), 1590 (m), 1450 (s), 1390 (s), 1375 (s), 1355 (s), 690 (m), 605 (m).
2 can be recrystallized (1:1 EtOAc/hexane) to give a white solid,
3 mp
158–161°C. [α] −63.0° (EtOH,
c 1.4);
1H NMR δ: 1.09 (d, 3 H, J = 7.2), 2.70 (q, 1 H, J = 7.2), 7.36 (m, 11 H), 7.71 (m, 2 H);
13C NMR δ: 19.2, 52.9, 73.0, 120.19, 120.21, 125.5, 125.7, 125.9, 127.6, 128.2, 128.6, 129.1, 140.5, 140.6, 141.8, 145.9, 146.5, 176.5 (Four
13C NMR signals appear to be missing, possibly due to overlapping of signals.); TLC R
f 0.25 (

8:1 EtOAc/hexane); UV (EtOH) λ, nm (ε): 310 (9,600), 298 (5,000), 266 (14,000), 238 (23,000), 209 (47,000). Anal. Calcd for C
22H
19NO
2: C, 80.22; H, 5.81; N, 4.25. Found: C, 80.4; H, 5.6; N, 4.2.
16.
Potassium phosphate was obtained from Mallinckrodt Chemical and was dried at >500°C for > 12 hr, cooled in a
desiccator, ground to a
fine powder with a
mortar and pestle, and stored in a desiccator before use. It must be weighed quickly, as it is hygroscopic.
18.
Eight or nine 100-mL portions of chloroform, obtained from EM Science and used without further purification, were required.
19.
Silica gel of 230–400 mesh was obtained from EM Science. The checkers used
silica gel from J. T. Baker.
20. Both
ethyl acetate and hexanes were obtained from Fisher Scientific Company and used without further purification.
21. The physical properties of
9-methoxy-9-phenylfluorene are as follows:
7 mp
93–94°C (lit.
7 mp
94–95°C),
1H NMR δ: 2.96 (s, 3 H), 7.2–7.4 (m, 11 H), 7.7 (m, 2 H);
13C NMR δ: 51.3, 89.0, 119.9, 125.3, 125.5, 127.1, 128.0, 128.1, 128.9, 140,8, 143.4, 146.8; TLC (1/3 EtOAc/hexane,
aluminum backed silica) R
f 0.85.
22. The properties of
9-phenyl-9-fluorenol are as follows: TLC (1/3 EtOAc/hexane, aluminum backed
silica) R
f 0.67; see ref.
5 for additional spectral and physical data.
23. The physical properties of
(S)-dimethyl N-(9-phenylfluoren-9-yl)aspartate (
4) are as follows:
4 mp
58–59.5°C (sometimes
4 does not solidify);
[α]D −264° (CHCl
3, c 3.3); IR (CHCl
3) cm
−1: 3320 (w), 3005 (m), 2950 (m), 1740 (s), 1600 (w), 1440 (s), 1365 (m), 1340 (m), 1170 (m), 1010 (m), 1000 (m), 900 (w), 690 (m), 610 (w); UV (EtOH) λ (ε): 310 (9,600), 298 (8,700), 276 (22,100), 239 (43,700), 231 (50,700), 211 (66, 200);
1H NMR δ: 2.35 (dd, 1 H, J = 15, 5.4), 2.52 (dd, 1 H, J = 15, 6.8), 3.01 (m, 1 H), 3.3 (br s, 1 H), 3.34 (s, 3 H), 3.65 (s, 3 H), 7.15–7.4 (m, 11 H), 7.7–7.8 (m, 2 H);
13C NMR δ: 39.7, 51.5, 51.8, 52.7, 72.7, 119.7, 119.9, 125.4, 125.8, 125.9, 127.2, 127.4, 127.7, 128.2, 128.3, 139.7, 141.1, 144.4, 148.3, 148.5, 170.8, 174.6 (Note: Three
13C NMR signals appear to be missing, possibly due to overlapping of signals.); TLC (1/3 EtOAc/hexane,
aluminum backed silica) R
f 0.52. Anal. Calcd for C
25H
23NO
4: C, 74.8; H, 5.8; N, 3.5. Found: C, 74.6; H, 5.8; N, 3.4.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Procedures A and B illustrate the two current methods for preparation of N-9-phenylfluoren-9-yl derivatives of amino acids and amino acid esters. Free carboxylate (as in
alanine in Step A) or free hydroxyl (e.g.,
serine8) functions can be blocked for the duration of the reaction as trimethylsilyl (TMS) esters or ethers, respectively, by treatment with
chlorotrimethylsilane and
triethylamine. The TMS group(s) are then removed by methanolysis from carboxylic acids (as in Step A) and mild acidic hydrolysis from hydroxyl groups, both being accomplished during product isolation. In addition to
2, the N-9-phenylfluoren-9-yl derivatives of serine,
8 glutamic acid γ-methyl ester,
9 and aspartic acid β-methyl ester
4,10 have been prepared in this manner.
Both the stability
14 and rigid steric bulk of the 9-phenylfluoren-9-yl group have increased significantly the utility of amino acids N-protected in this way as chiral educts for asymmetric synthesis. N-(9-Phenylfluoren-9-yl)-α-amino aldehydes maintain configurational stability at the αcarbon during treatment with
silica gel or
triethylamine and on treatment with Wittig and organometallic reagents.
3,8,15,16 N-(9-Phenylfluoren-9-yl)-α-amino ketones and esters behave similarly under these conditions, and they can also be regioselectively enolized and subsequently alkylated with a variety of electrophiles in good to excellent yield with modest to excellent diastereoselectivity, no detectable racemization, and no detectable alkylation on
nitrogen or at the
carbon corresponding to the αcarbon of the starting amino acid.
4,9,10,11,12,13,15,16 Consequently, these N-(9-phenylfluoren-9-yl)-α-amino carbonyl compounds have enabled the enantiospecific syntheses of many important compounds, including cyclosporin's unique amino acid MeBmt,
16 other unusual amino acids,
9,10 α-amino aldehydes,
3,8,15,16 vinca alkaloids,
4,12 (−)-vindoline,
13,17 α-alkyl branched carboxylic acids,
15 and the core nuclei of two antineoplastic agents.
11
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