Checked by P. B. Madan, A. Schwartz, and David L. Coffen.
1. Procedure
A.
Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl[2S,3S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine (Bicyclic lactam). To a warm solution of
(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (32.4 g, 194 mmol) (Note
1) in
toluene (800 mL),
5-oxohexanoic acid (25 g, 912 mmol) (Note
2) is added with stirring. The stirred mixture is heated to reflux under
argon with azeotropic removal of water for 18 hr. The reaction mixture is cooled, washed with
0.5 N hydrochloric acid (100 mL) and with saturated
sodium bicarbonate solution (50 mL), dried over
magnesium sulfate, and evaporated to dryness. The residue is crystallized from
methylene chloride/hexane in the cold. The crystals are collected by filtration and washed with cold
ether to give
35.9–37.2 g (
71–74% yield) of the bicyclic lactam in two crops (Note
3).
To an
oven-dried, 200-mL, conical flask (Note
6) with air replaced by
argon, containing
50 mL of dry tetrahydrofuran (THF) and sealed with a rubber septum,
13.9 g (19.3 mL, 137.4 mmol) of diisopropylamine (Note
7) is added with a syringe. The flask is placed in an
ice–water bath. After 15 min,
84 mL (134.4 mmol) of 1.6 M butyllithium in hexane (Note
8) is slowly added with a syringe and with gentle swirling of the flask. The solution is kept for 5 min at this temperature.
The
lithium diisopropylamide solution prepared as described above is transferred dropwise, via a cannula, into the bicyclic lactam solution. The
dry ice–acetone bath is replaced by an ice–water bath, where the reaction mixture is kept for 40 min to complete formation of the lithium enolate. The reaction mixture is cooled again (30 min) with a dry ice–acetone bath. Freshly distilled
ethyl iodide (25.8 g, 13.4 mL, 165.4 mmol) (Note
9) is added slowly, via syringe, to the mixture and stirring is continued for 55 min in a dry ice–acetone bath. The cooling bath is replaced by an ice–water bath, and the mixture is stirred for exactly 40 min (Note
10) and is poured immediately into a separatory funnel containing
400 mL of 1.0 N hydrochloric acid. The resulting emulsion is extracted once with
400 mL of ether and the organic layer is washed with
200 mL of a 1 : 1 mixture of brine and a saturated solution of sodium bicarbonate. The
ether extract is dried over
magnesium sulfate and evaporated to dryness in a 500-mL round-bottomed flask. The residue is dissolved in
60 mL of dry toluene and evaporated again using a
water bath (60°C for 45 min) to remove all traces of water and
toluene. The product (17.2 g, > 100%) is used in the next step without further purification.
The 500-mL flask containing the crude dry product (17.2 g) is filled with
argon and dry
tetrahydrofuran (150 mL), a magnetic stirring bar is added, the flask is sealed with a rubber septum, and
argon is introduced once again. The flask is gently swirled until the viscous oil is totally dissolved and then the flask is immersed in a dry ice–acetone bath.
Another portion of LDA is prepared as described above except that this time
12.6 g of diisopropylamine (17.6 mL, 124.6 mmol) in
THF (50 mL) and
78.0 mL (124.8 mmol) of 1.6 M butyllithium/hexane are used. The LDA solution is added, through a cannula, to the ethylated bicyclic lactam solution and the mixture is allowed to warm to 0°C; it is kept at this temperature for 3.0 hr (Note
11). The solution is cooled to −75° to −80°C in a dry ice–acetone bath. A solution of
9.4 g of freshly distilled allyl bromide (6.8 mL, 77.6 mmol) (Note
12) in dry
THF (50 mL) is prepared in a
100-mL, oven-dried conical flask flushed with
argon and sealed with a rubber septum. This solution is cooled in a dry ice–acetone bath and slowly added to the reaction mixture through a cannula (Note
13). After addition of the
allyl bromide, the mixture is kept in a dry ice–acetone bath for 2.5 hr; then the bath is replaced by
acetone at −50°C, which is allowed to warm to −30°C within a period of 45 min (Note
14). The reaction is terminated by pouring it into
1 N hydrochloric acid (as above), extracting with
ether, washing with
sodium bicarbonate–
brine, drying over
magnesium sulfate, and evaporating the solvents. The viscous or solid residue is dissolved in
methylene chloride (10 mL), and
petroleum ether (30–60°C) (140 mL) is added. The product is allowed to crystallize at room temperature for 1 hr, then at −15°C overnight, to give
13.5 g (
74%, mp
90–92°C) of a 9 : 1 mixture of diastereoisomers.
This mixture is recrystallized three times with the same mixture of solvents and the product is collected after 1 hr at 0°C to give
8.7 g (
47.9%, mp
101–103°C) of a 25 : 1 mixture of diastereoisomers (values based on the 8a-methyl signal integration on NMR spectra) (Note
15).
C.
(R)-4-Ethyl-4-allyl-2-cyclohexen-1-one. In an oven-dried, 500-mL, round-bottomed flask, containing dry
toluene (300 mL) and a magnetic stirring bar, is placed the dialkylated lactam (7.8 g, 23.7 mmol). The solution is cooled in a dry ice–acetone bath and a
1 M solution of Red-Al in
toluene (55 mL, 55.0 mmol) is slowly added (Note
16). The flask is flushed with
argon and sealed with a rubber septum which is connected by a hypodermic needle to a rubber balloon filled with
argon. The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The septum is removed, the reaction mixture is cooled to 0°C, and
methanol (10 mL) is cautiously added with stirring to destroy excess
Red-Al. The solution is poured over
1 M aqueous potassium hydroxide (500 mL) in a
2-L separatory funnel and thoroughly shaken with
ether (200 mL) until both layers become almost clear. The aqueous layer is extracted twice more with
ether (2 × 100 mL), and, after the ethereal layers are combined, the ethereal solution is dried over
magnesium sulfate and evaporated to dryness in a 500-mL flask.
The residue is dissolved in
ethanol (250 mL), a
1 M aqueous solution of tetrabutylammonium dihydrogen phosphate (80 mL) (Note
17) is added, and the mixture is stirred under reflux for 24 hr. After the solution is cooled, it is partly evaporated on a
rotary evaporator with a bath temperature not exceeding 40°C (Note
18) to remove most of the
ethanol. Water is added (500 mL) and the solution is extracted twice with
chloroform (200 mL). The
chloroform extracts are washed with a
1 : 1 mixture of brine and 1 N hydrochloric acid and then with
brine and saturated
sodium bicarbonate solutions. Both aqueous phases are extracted twice with
chloroform and the extracts are combined, dried over
magnesium sulfate, and evaporated to dryness to give
5.8 g of crude 4,4-disubstituted cyclohexenone. The product is distilled rapidly in a Kugelrohr apparatus at 3.5 mm and 115°C to give
3.0 g (
77%) of highly pure cyclohexenone (Note
19).
2. Notes
1. The
amino diol was purchased from Aldrich Chemical Company, Inc. and was recrystallized before use from
methanol/ethyl acetate (the material used had mp
111–113°C).
2.
5-Oxohexanoic acid was purchased from Aldrich Chemical Company, Inc. and was used without further purification.
3. The bicyclic lactam thus prepared has the following physical properties: mp
98–99°C;
[α]D21 + 13.54° (EtOH, c 1.55); IR (KBr) cm
−1: 3360, 2950, 1625, 1500, 1395;
1H NMR (270 MHz, CDCl
3) δ: 3.75 (dd, C
10H,
J = 11.3, 8.5), 3.90 (dd, C
10H,
J = 11.3, 1.9), 4.07 (dt, C
3H,
J = 8.5, 1.9), 4.79 (d, C
2H,
J = 8.6), 4.89 (br s, 1 H, OH), 7.38 (s, 5 H, phenyl) and unresolved signals.
4. THF was distilled from a blue solution of
benzophenone ketyl obtained by refluxing THF in the presence of a
sodium dispersion in paraffin and
benzophenone.
5. All reactions were done under
argon atmosphere. The
argon was introduced through hypodermic needles at a pressure below 50 mm across the rubber septum. An exhaust line was also provided to remove air or excess pressure.
6. A conical flask was used in order to allow efficient transfer of the LDA solution.
10. If the reaction mixture is kept for longer than 40 min in the ice-water bath, undesirable amounts of the diethylated product are produced.
11. This is the minimum time to allow complete enolate formation.
13. The
allyl bromide solution was allowed to cool efficiently by dripping it against the cold walls of the flask. It is important that
allyl bromide reach the reaction mixture at the lowest possible temperature in order to obtain an optimal stereo-selective alkylation. The cannula was protected against heat exchange with air by coating it with a fine rubber tubing.
14. Dry ice was removed, leaving only
acetone in the
Dewar vessel. The temperature was then adjusted to −50°C by adding warm (room temperature)
acetone; the temperature was allowed to rise slowly to −30°C by adding small portions of
acetone.
15. The physical properties for the dialkylated bicyclic lactam are as follows:
[α]D21 +38.89° (EtOH, c 1.77); IR (KBr) cm
−1: 3250, 2490, 1600, 1450, 1370, 1330, 1070, 890, 750;
1H NMR (270 MHz, CDCl
3) δ: 0.91 (t, 3 H, C
12H,
J = 7.3), 1.57 (s, 3 H, C
9H); 2.42 (ddd, 2 H, C
13H,
J = 63.6, 13.4, 7.4), 3.65 (br, 1 H, OH), 3.75 (dd, C
10H,
J = 11.3, 8.8), 3.90 (dd, C
10H,
J = 11.2, 2.5), 4.13 (dt, C
3H,
J = 8.8, 2.5), 4.78 (d, C
2H,
J = 8.5), 5.11–5.16 (m, 2 H, C
15H), 5.73–5.88 (m, C
14H), 7.37 (s, 5 H, phenyl) and unresolved signals. Anal. calcd. for C
20H
27NO
3: C, 72.91: H, 8.26; N, 4.25. Found: C, 72.77; H, 8.25; N, 4.24.
16.
1 M Red-Al is prepared, by diluting to 100 mL with
toluene,
29.5 mL of commercially available 3.4 M Red-Al solution in toluene (Aldrich Chemical Company, Inc.; the checkers used Vitride brand supplied by Hexcel Corp.). Before use, this solution should be warmed to room temperature since it tends to separate into two layers at low temperatures. The first milliliter of
Red-Al produces a vigorous evolution of gas; therefore, the flask should be kept open until the
Red-Al addition is complete. Then the reaction vessel is sealed as described.
18. The product has a high vapor pressure and can easily be lost by evaporation. Thus, the yields will vary because of this property. The more caution exerted in the evaporation and distillation step, the higher will be the yield of product.
19. If the distillation is performed slowly, a substantial amount of the product may polymerize, resulting in lower yield. The physical data are as follows:
[α]D21 −23.12° (EtOH, c, 1.67); IR (film) cm
−1: 2960, 1680, 1450, 1380, 1210;
1H NMR (270 MHz, CDCl
3) δ: 0.95 (t, 3 H, C
8H,
J = 7.6), 1.49–1.57 (m, 2 H, C
3H), 1.87 (t, 2H, C
5H,
J = 6.8), 2.23 (d, 2 H, C
9H,
J = 6.6), 2.45 (t, 2 H, C
6H,
J = 6.8), 5.07–5.14 (m, C
11H), 5.65–5.82 (m, C
10H), 5.94 (d, C
2H,
J = 10.3), 6.71 (d, C
3H,
J = 10.3). Anal. calcd. for C
11H
16O: C, 80.45; H, 9.82. Found: C, 79.67; H, 10.05. By GLC analysis, the product is 93–95% pure with 5–7% of diethylcyclohexenone detectable by GLC–MS.
3. Discussion
Chiral bicyclic lactams such as those described here are useful in reaching a variety of chiral quaternary carbon derivatives. Thus,
1 can be doubly alkylated to the bicyclic lactam
2 in high diastereoselectivity. Acidic hydrolysis leads to α,α-substituted γ-keto acids
3,
2 whereas reduction and hydrolysis furnish the chiral keto aldehydes
4. Base-catalyzed aldolization affords chiral cyclopentenones
5.
3 In addition, several total syntheses of natural products have been accomplished, further demonstrating the synthetic usefulness of these bicyclic lactams
1. Thus, (−)-α-cuparenone
(6),
4 (−)-grandisol
(7),
5 (+)-mesembrine
(8),
6 and (−)-silphiperfol-6-ene (
9)
7 have been prepared in high enantiomeric excess.
Furthermore, in place of reduction of
10 it was possible to add organolithium reagents such that the resulting alkyl carbinolamine, after hydrolysis, gave either
12 or
13 depending on hydrolysis conditions.
6 In summary, these bicyclic lactams have provided a route to a variety of chiral, nonracemic cyclohexenones and cyclopentenones containing quaternary stereocenters.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
benzophenone ketyl
brine
Red-Al
Hexahydro-3-(hydroxymethyl)-8a-methyl-2-phenyl[2S,3S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine (Bicyclic lactam)
ethanol (64-17-5)
potassium carbonate (584-08-7)
hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
Allyl bromide (106-95-6)
allyl (1981-80-2)
copper turnings (7440-50-8)
acetone (67-64-1)
potassium hydroxide (1310-58-3)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
Ethyl iodide (75-03-6)
butyllithium (109-72-8)
Tetrahydrofuran,
THF (109-99-9)
hexane (110-54-3)
calcium hydride (7789-78-8)
argon (7440-37-1)
lithium diisopropylamide (4111-54-0)
diisopropylamine (108-18-9)
5-oxohexanoic acid (3128-06-1)
tetrabutylammonium dihydrogen phosphate (5574-97-0)
(R)-4-Ethyl-4-allyl-2-cyclohexen-1-one (122444-62-6)
(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol
Hexahydro-6-ethyl-3-(hydroxymethyl)-6-allyl-2-phenyl[2S,3S,6S,8aR]-5-oxo-5H-oxazolo[3,2-a]pyridine
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