Asymmetric Hydroformylation of Heterocyclic Olefins
J . Org. Chem., Vol. 62, No. 13, 1997 4291
Calcd for C10H19O3N: C, 59.68; H, 9.52; N, 6.96. Found: C,
59.94; H, 9.80; N, 6.94. Enantiomeric excess was determined
by HPLC analysis of the corresponding (R)-MTPA ester (Daicel
Chiralcel OD, hexane/2-propanol ) 99/1, 1.0 mL min-1 for
N-(tert-butoxycarbonyl)pyrrolidine-2-methanol; hexane/2-pro-
panol ) 49/1, 0.5 mL min-1 for N-(tert-butoxycarbonyl)-
pyrrolidine-3-methanol).
Det er m in a t ion of Ab solu t e Con figu r a t ion of (-)-5b.
Hydroformylation of 4b (675 mg, 3.99 mmol) was carried out
as described above using (R,S)-1b. The reaction mixture was
diluted with DMF (16 mL). To this was added PDC (4.5 g, 12
mmol), and the mixture was stirred for 20 h at room temper-
ature. The reaction mixture was diluted with water (300 mL)
and extracted with ether (2 × 150 mL). The aqueous phase
was acidified with concd HCl to pH 4 and further extracted
with ether (2 × 100 mL). The combined organic extracts were
washed with water (2 × 100 mL), concentrated to ca. 80 mL,
and extracted with an aqueous solution of Na3PO4‚12H2O (4.5
g/100 mL). The extract was acidified to pH 4 with concd HCl
at 0 °C and then stirred at this temperature for 3 h. The
precipitates were collected and dried over P2O5: yield 318 mg
(47% from 4b). [R]21D ) -12.1 (c 2.33, EtOH) (lit.22 (R)-N-(tert-
butoxycarbonyl)pyrrolidine-3-carboxylic acid [R]25D ) -16.0 (c
2.4, EtOH)).
2.4-2.6 (m, 1H), 3.6-3.8 (m, 2H), 4.00 (dd, J ) 12.54, 2.31
Hz, 1H), 4.11 (dd, J ) 12.54, 4.62 Hz, 1H), 9.77 (s, 1H); 13C
NMR δ 24.5, 24.7, 28.5, 51.4, 59.9, 60.5, 101.4, 202.5; [R]22
)
D
-38.0 (c 1.54, THF) at 67% ee. Anal. Calcd for C8H14O3: C,
60.74; H, 8.92. Found: C, 60.74; H, 8.91.
Deter m in a tion of Absolu te Con figu r a tion a n d En a n -
tiom er ic Excess of 10b. To a suspension of NaBH4 (1.5 eq
to 10b) in absolute EtOH (5 mL) was added the hydroformy-
lation reaction mixture at -10 °C. The resulting mixture was
stirred for 2 h. The reaction mixture was concentrated and
excess NaBH4 was destroyed with water. The product was
extracted three times with ether. The organic layers were
washed with brine, dried over MgSO4, and concentrated. The
residue was purified by bulb-to-bulb distillation to afford the
corresponding alcohol as a colorless oil: bp 75 °C (bath temp,
0.1 mmHg);
1H NMR (CDCl3) δ 1.33 (s, 3H), 1.34 (s, 3H), 1.4-
1.6 (m, 2H), 1.6-1.9 (m, 2H), 3.58 (d, J ) 6.26 Hz, 2H), 3.6-
3.8 (m, 4H); 13C NMR δ 24.8, 32.1, 41.4, 60.2, 63.4, 63.8, 101.2;
[R]21 ) +2.3 (c 1.47, MeOH) at 63% ee. Anal. Calcd for
D
C8H16O3: C, 59.98; H, 10.07. Found: C, 59.86; H, 10.17. The
enantiomeric excess was determined by HPLC analysis of the
corresponding (R)-MTPA ester (Daicel Chiralcel OJ , UV ) 230
nm, hexane/2-propanol ) 97/3, 1 mL‚min-1). Absolute con-
figuration of 10b was confirmed by converting it into (R)-14
(vide infra).
(-)-N-Acetylp yr r olid in e-3-ca r ba ld eh yd e [(-)-5c]: bp
105 °C (bath temp, 0.1 mmHg); 1H NMR (CDCl3) δ 1.99 (s,
1.5H), 2.04 (s, 1.5H), 2.0-2.15 (m, 1.5H), 2.2-2.45 (m, 0.5H),
2.9-3.1 (m, 1.0H), 3.3-3.6 (m, 3.0H), 3.7-3.9 (m, 1.0H), 9.62
(d, J ) 0.99 Hz, 1.0H); 13C NMR21 δ 22.3, 22.4, 24.8, 25.9, 44.4,
(3R)-3-(H yd r oxym et h yl)-2-m et h oxyt et r a h yd r ofu r a n
(11). To a 1% (w/v) solution of iodine in methanol (60 mL)
was added 10b (2.5 g, 16 mmol). The resulting solution was
heated at reflux for 4 h. The reaction mixture was treated
with Na2S2O3 and concentrated. Chloroform (60 mL) was
added to the residue, and the insoluble solid was removed by
filtration. The filtrate was concentrated and distilled in a
Kugelrohr apparatus to give 11 (1.9 g, 94%) as a cis/trans
mixture: bp 70 °C (bath temp, 1 mmHg);
44.8, 45.8, 46.2, 49.0, 50.7, 169.1, 169.3, 199.6, 200.1; [R]22
)
D
-27.2 (c 3.40, THF) at 56% ee. Anal. Calcd for C7H11O2N:
C, 59.56; H, 7.85; N, 9.92. Found: C, 59.58; H, 7.98; N, 9.80.
Deter m in a tion of En a n tiom er ic Excess of 5c. The
reaction mixture was concentrated under reduced pressure,
and the residue was dissolved in ethanol (3 mL). To this was
added 1.0 equiv of NaBH4 at -78 °C, and the mixture was
stirred overnight with gradually warming to room temperature
to preclude the racemization of 5c. The reaction mixture was
cooled to 0 °C and carefully treated with 1 N HCl. The
aqueous layer was extracted three times with CH2Cl2. The
combined organic layers were dried over MgSO4 and concen-
trated. The residue was distilled under reduced pressure to
give N-acetylpyrrolidine-3-methanol: bp 160 °C (bath temp,
1H NMR (CDCl3) δ
1.5-1.7 (m, 1H), 1.9-2.2 (m, 2H), 2.3-2.5 (m, 1H), 3.35 (s,
2.25H), 3.37 (s, 0.75 H), 3.4-3.6 (m, 1H), 3.8-4.1 (m, 2H), 4.88
(d, J ) 1.32 Hz, 0.75H), 4.98 (d, J ) 4.95 Hz, 0.25H);
13C NMR
major: δ 26.6, 47.9, 54.63, 63.7, 66.3, 107.2; minor: δ 24.9,
45.2, 54.59, 60.6, 66.9, 105.8. HRMS Calcd for C6H12O3:
132.0786. Found: 132.0747 (M).
(3R)-3-[(Ben zyloxy)m et h yl]-2-m et h oxyt et r a h yd r ofu -
r a n (12). Sodium hydride (60% in mineral oil, 0.7 g, 0.02 mol)
was washed with dry hexane and dried in vacuo. To this were
added DMF (80 mL), 11 (1.8 g, 14 mmol), and benzyl bromide
(3.4 mL, 29 mmol). The resulting mixture was stirred at room
temperature for 2 h. The reaction mixture was poured into
water (300 mL) and extracted three times with ether. The
extract was dried over MgSO4 and concentrated. The residue
was purified by silica-gel column chromatography (hexane/
AcOEt ) 2/1) to give 12 (2.7 g, 88%) as a cis/trans mixture. 1H
NMR (CDCl3) δ 1.5-1.7 (m, 0.8H), 1.7-1.9 (m, 0.2H), 2.0-2.2
(m, 1H), 2.4-2.6 (m, 1H), 3.31 (s, 0.6H), 3.33 (s, 2.4 H), 3.2-
3.4 (m, 1.6H), 3.4-3.5 (m, 0.2H), 3.6-3.7 (m, 0.2H), 3.8-4.0
(m, 2H), 4.51 (br s, 2H), 4.86 (d, J ) 0.99 Hz, 0.8H), 4.90 (d, J
) 4.62 Hz, 0.2H), 7.2-7.4 (m, 5H); 13C NMR major: δ 26.8,
45.6, 54.5, 66.1, 70.9, 72.9, 107.1, 127.51, 128.3, 138.1; minor:
δ 26.8, 44.4, 54.4, 66.4, 69.1, 73.0, 104.0, 127.46, 128.2, 138.4.
HRMS Calcd for C13H18O3: 222.1255. Found: 222.1389 (M),
191.1087 (M - CH3O), 191.1019 (M - CH3OH).
(R)-3-[(Ben zyloxy)m eth yl]-tetr a h yd r o-2-fu r a n on e [(R)-
13]. To a solution of 12 (2.7 g, 12 mmol) in CH2Cl2 (45 mL)
were added BF3‚OEt2 (900 µL) and m-CPBA (80% purity, 2.9g,
13 mmol). The resulting solution was stirred at room tem-
perature overnight. The reaction mixture was diluted with
ether (300 mL) and washed successively with 10% Na2S2O3-
(aq), saturated NaHCO3(aq), and brine. The organic layer was
dried over MgSO4 and concentrated. The residue was chro-
matographed on silica gel (ether) and then distilled under
reduced pressure to give (R)-13 (1.8 g, 72%).11a
1
0.1 mmHg); H NMR (CDCl3) δ 1.6-1.9 (m, 1H), 1.9-2.2 (m,
1H), 2.04 (s, 1.5H), 2.05 (s, 1.5H), 2.3 (br s, 1H), 2.35-2.6 (m,
1H), 3.25-3.35 (m, 1H), 3.35-3.8 (m, 5H); 13C NMR21 δ 22.3,
22.4, 26.8, 28.4, 39.9, 41.6, 44.9, 46.8, 48.1, 50.1, 64.0, 64.1,
169.4; [R]22 ) +17.1 (c 0.65, MeOH) at 65% ee. Anal. Calcd
D
for C7H13O2N: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.29;
H, 9.00; N, 9.71. Enantiomeric excess was determined by 19F
NMR spectroscopy of the corresponding (R)-MTPA ester 8 in
CDCl3 (δ 4.54 and 4.58; another rotamer δ 4.71, see text and
Figure 1). The chemical shift of 19F NMR is referred to CF3-
COOH as δ 0.00. When the reduction was carried out at
higher temperature, racemization of 5c took place to some
extent.
(-)-1,3-Dioxep a n e-5-ca r ba ld eh yd e [(-)-10a ]: bp 60 °C
1
(bath temp, 1.5 mmHg); H NMR (CDCl3) δ 1.87 (dddd, J )
14.51, 8.91, 5.94, 3.63 Hz, 1H), 2.14-2.25 (m, 1H), 2.62 (qd, J
) 5.28, 2.64 Hz, 1H), 3.73 (ddd, J ) 12.20, 8.91, 2.64 Hz, 1H),
3.85 (ddd, J ) 12.20, 5.28, 3.62 Hz, 1H), 4.04 (dd, J ) 12.20,
2.64 Hz, 1H), 4.27 (dd, J ) 12.20, 4.62 Hz, 1H), 4.74 and 4.71
(ABq, J ) 4.62 Hz, 2H), 9.78 (s, 1H); 13C NMR δ 28.3, 51.4,
64.7, 64.8, 94.5, 201.9; [R]22D ) -41.4 (c 1.91, THF) at 51% ee.
Anal. Calcd for C6H10O3: C, 55.37; H, 7.74. Found: C, 55.11;
H, 7.95. The enantiomeric excess of 10a was determined by
1H NMR of the crude reaction mixture in CDCl3 in the presence
of Eu(hfc)3 (δ 10.77 and 10.81). Distillation of the product (66%
ee) (at 60 °C, 1.5 mmHg) caused a decrease in the enantiomeric
excess (to 51% ee).
(R)-3-(H yd r oxym et h yl)-t et r a h yd r o-2-fu r a n on e [(R)-
14]. The benzyl ether (R)-13 (1.8 g, 8.7 mmol) was dissolved
in ethanol (40 mL) and hydrogenated for 8 h over 10%
palladium on carbon (40 mg). The reaction mixture was
filtered through Celite, and the filtrate was concentrated. The
residue was purified by bulb-to-bulb distillation to give (R)-
(R )-2,2-D i m e t h y l-1,3-d i o x e p a n e -5-c a r b a ld e h y d e
1
[(R)-10b]: bp 50 °C (bath temp, 1 mmHg); H NMR (CDCl3)
δ 1.27 (s, 3H), 1.33 (s, 3H), 1.6-1.8 (m, 1H), 2.0-2.2 (m, 1H),
(22) Yuki, H.; Okamoto, Y.; Kobayashi, Y. J . Polym. Sci., Polym.
Chem. Ed. 1979, 17, 3867.
14 (1.0 g, 99%):11a bp 120 °C (bath temp, 0.1 mmHg). [R]23
)
D