Reduction of Prochiral Cyclic Imines to Alkaloid Derivatives
J . Org. Chem., Vol. 64, No. 23, 1999 8477
Ta ble 5. Asym m etr ic Red u ction of 3 or 5 to 4 or 6 w ith
Red u cin g Agen t 2a in Solid Sta te Con d ition s
-232.5 (c 1.1. THF). Anal. Calcd for C51H37BNaN3O12
: C,
66.75; H, 4.06; N, 4.58. Found: C, 66.70; H, 4.20; N, 4.50.
[R]25
chemica
yield (%) (%)
ee
Asym m etr ic Red u ction of Cyclic Im in es 3 a n d 5 to 4
a n d 6 w ith 2a . Gen er a l P r oced u r e: Meth od A. A solution
of cyclic imine (1.0 mmol) in THF (10 mL) was added to a
stirred solution of 2a (0.45 g, 1.2 mmol), and the whole was
stirred at ambient temperature for the time specified in Table
1. After concentration, the residue was treated with 5%
aqueous HCl (20 mL, 50 °C for 1 h) and then made basic with
KHCO3. The reaction mixture was extracted with ethyl acetate
(2 × 10 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by preparative TLC
(EtOAc-MeOH, 9:1) to afford 4 or 6 (Table 1).
reaction
time (min) (c 1, CHCl3)
D
entry product
1
2
3
4
5
6
7
8
4a
4b
4c
4d
6a
6b
6c
6d
60
55
60
50
50
60
50
50
-59.5
-21.4
-32.3
+36.3a
-51.0
-15.4
-80.8
-79.1
90
80
81
83
90
89
93
90
100
93
95
98
98
94
100
99
a
25
[R]D (c 1, H2O.
Meth od B. The procedure is as described except 1.2 equiv
of dried ZnCl2 was added. The yield and ee of the products
are listed in Table 2.
The advantage of these methods over conventional
homogeneous reactions is that they provide greater
selectivity, enhanced reaction rates, cleaner products, and
manipulative simplicity. We anticipated that the reduc-
tion of the prochiral cyclic imine 3 or 5 in the solid state
under solvent-free conditions may be stereoselective. We
repeated the above reduction reaction in the solid state
under solvent-free conditions and have found that the
alkaloids 4 or 6 were formed in higher chemical yield and
enantiomeric purity in less than 60 min. The process
involves a simple mixing of supported 2a on alumina15
with an appropriate prochiral cyclic imine in a mortar,
followed by grinding the mixture for the time specified
in Table 5. The chemical yields and enantioselectivity of
the reactions are excellent (80-92%, ee 93-100%), and
the reaction times are exceedingly short (50-60 min).
In conclusion, because these cyclic imines are easily
accessible by the Bishler-Napieraski reaction,16 the
synthesis of the new chiral nonracemic reducing agent 2
provides a very effective route to various enantiomerically
enriched alkaloids. Moreover, the reagents are quite
inexpensive, since N,N-phthaloylamino acid 1 can be
recovered in nearly quantitative yield after the reduction.
Meth od C. A mortar was charged with cyclic imine (1
mmol), alumina (0.3 g) and 2a (0.45 g, 1.2 mmol). The reaction
mixture was ground with a pestle in the mortar. When TLC
showed no remaining cyclic imine, the reaction mixture was
poured into a mixture of ethyl acetate (20 mL) and 1 N HCl (5
mL) and made basic with KHCO3. The organic layer was
separated, dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by preparative TLC
(EtOAc-MeOH, 9:1) to afford 4 or 6 (Table 5).
(S)-(-)-Sa lsolid in e 4a . Meth od A: slightly yellowish oil;
[R]25 -44.6 (c 2.1, CHCl3) (ee 75%) [lit.7 [R]25 -59.5 (c 4.39,
D
D
EtOH)]; IR (Nujol) 3552 cm-1; 1H NMR δ (CDCl3) 6.62 (s, 1 H,
ArH), 6.57 (s, 1 H, ArH), 4.07 (q, 1 H, J ) 6.6 Hz), 3.84 (s, 6
H, 2xOMe), 3.2 (t, 4 H), 2.25 (s, 1 H, NH, exchange with D2O),
1.45 (d, 3 H, J ) 6.6 Hz, Me); Ms m/z 208 (56, M+H+). Anal.
Calcd for C12H17NO2: C, 69.50; H, 8.30; N, 6.80. Found: C,
69.40; H, 8.50; N, 6.60.
(S)-(-)-Nor cr yp tostylin e I 4b. Meth od A: mp 117-119
°C; [R]25 -15.0 (c 1.3, CHCl3) (ee 65%) [lit.8 mp 122-123 °C;
D
[R]25 -23.0 (c 1.0, CHCl3)]; IR (Nujol) 3556 cm-1; H NMR δ
1
D
(CDCl3) 6.59-6.20 (5 H, ArH), 5.90 (s, 2 H, OCH2O), 4.96 (s,
1 H), 3.85 (s, 3 H, OMe), 3.65 (s, 3 H, OMe), 3.25 (t, 4 H), 2.10
(s, 1 H, NH, exchange with D2O); MS m/z 313 (64, M+H+).
(S)-(-)-Nor cr yp tostylin e II 4c. Meth od A: mp 108-111
°C; [R]25 -23.8 (c 1.1, CHCl3) (ee 70%) [lit.7 mp 114-115 °C;
D
[R]25 -34.0 (c 1.0, CHCl3)]; IR (Nujol) 3554 cm-1; H NMR δ
1
D
Exp er im en ta l Section
(CDCl3) 6.55 (s, 1 H, ArH), 6.42 (s, 1 H, ArH), 4.99 (s, 1 H),
3.89 (s, 6 H, 2 × OMe), 3.68 (s, 6 H, 2 × OMe),3.20 (t, 4 H),
2.45 (s, 1 H, NH, exchange with D2O); MS m/z 330 (75, M+H+)
328, and 192.
Gen er a l Meth od s. The N,N-phthaloyl-(S)-amino acid 1 was
prepared from (S)-amino acid and phthalic anhydride by a
known method.6 All products were identified by comparison
with an authentic sample (IR, NMR, mp). Elemental analysis
was performed by the Research Institute of Petroleum Indus-
(S)-(+)-Nor la u d a n osin e 4d Hyd r och lor id e. Meth od A:
colorless prisms; mp 210-212 °C; [R]25D +25.2 (c 1.0, H2O) (ee
68%) [lit.9,10 mp 215 °C; [R]25 +37.0 (c 1.0, H2O)]; IR (Nujol)
D
1
try, Tehran, IR, Iran. The H NMR spectra were measured in
3100 cm-1; 1H NMR δ (D2O) 7.90-6.70 (m, 4 H, ArH), 6.39 (s,
1 H, ArH), 5.47 (dd, 1 H, J ) 3.2, 6.0 Hz), 4.80 (dd, 1 H, J )
3.6, 13.6), 4.68 (dd, 1 H, J ) 6.0, 13.6), 3.88 (s, 3 H, OMe),
3.85 (s, 3 H, OMe), 3.80 (s, 6 H, 2 × OMe), 2.85 (t, 4 H).
CDCl3 unless otherwise stated, relative to TMS (0.00 ppm).
Syn t h esis of Ch ir a l Non r a cem ic R ed u cin g Agen t 2.
Gen er a l Meth od . (S)-N,N-phthaloylamino acid 1 (6 mmol)
in THF (10 mL) was added to a suspension of NaBH4 (76 mg,
2 mmol) in THF (15 mL) at room temperature. After vigorous
hydrogen evolution ceased, the mixture was stirred at ambient
temperature for 10 h and then concentrated under reduced
pressure. The residue was digested with n-hexane and filtered
to give 2.
1-Meth yltetr a h yd r o-â-ca r bolin e 6a . Meth od A: semi-
solid; [R]25 -36.9 (c 0.98, CHCl3) (ee 71%) [lit.5 [R]25 -52 (c
D
D
1.0, EtOH)]; IR (Nujol) 3325 cm-1; 1H NMR δ (CDCl3) 7.75 (s,
1 H, NH), 7.48 (d, 1H, J ) 7.6 Hz, ArH), 7.31 (dd, 1 H, J )
1.0, 8.0 Hz, ArH), 7.20 (dt, 1 H, J ) 1.2, 8.0 Hz, ArH), 7.10
(dt, J ) 1.0, 8.0 Hz, ArH), 4.20 (q, 1H, J ) 6.8), 2.92 (t, 2H,
J ) 5.6, CH2), 2.72 (t, 2 H, J ) 5.6, CH2). 1.58 (s, 1 H, NH),
1.46 (d, 3 H, J ) 6.8, Me); MS m/z 187 (45, M+H+) 172 (100).
Sod iu m t r is[(S)-N,N-P h t h a loylleu cin e]b or oh yd r id e:
white powder (1.58 g, 96%); mp 193-194 °C dec; [R]25 -28.5
D
(c 1.4. THF). Anal. Calcd for C39H37BNaN3O12: C, 60.56; H,
1-P h en yltetr a h yd r o-â-ca r bolin e 6b. Meth od A: semi-
4.82; N, 5.48. Found: C, 60.40; H, 4.90; N, 5.40.
solid; [R]25 -11.3 (c 0.90, CHCl3) (ee 69%) [lit.5 [R]25 -16.4
D
D
Sod iu m t r is[(S)-N,N-p h t h a loyla la n in e]b or oh yd r id e:
(c 0.38, EtOH)]; IR (Nujol) 3330 cm-1;, 1H NMR δ (CDCl3)
7.75-6.85 (m, 9 H, ArH), 5.28 (s, 1 H, NH), 5.10 (s, 1 H), 3.25
(t, 2H, J ) 5.4, CH2), 2.90 (t, 2H, J ) 5.4, CH2), (1.73 (s, 1 H,
NH); MS m/z 249 (100, M+H+).
white powder (1.27 g, 94%); mp 178-191 °C dec; [R]25 -26.4
D
(c 1.2. THF). Anal. Calcd for C33H25BNaN3O12: C, 58.40; H,
3.72; N, 6.19. Found: C, 58.30; H, 3.90; N, 6.10.
Sod iu m tr is[(S)-N,N-p h th a loylp h en yla la n in e]bor oh y-
1-Bu tyltetr a h yd r o-â-ca r bolin e 6c. Meth od A: oil; [R]25
D
d r id e: white powder (1.80 g, 98%); mp 223-225 °C dec; [R]25
D
-59.8 (c 0.65, CHCl3) (ee 74%) [lit.5 [R]25 -80.86 (c 0.55,
D
EtOH)]; IR (Nujol) 3345 cm-1; 1H NMR δ (CDCl3) 7.70 (s, 1 H,
NH), 7.45 (d, 1H, J ) 7.6 Hz, ArH), 7.36 (dt, 1 H, J ) 1.0, 8.0
Hz, ArH), 7.28 (dt, 1 H, J ) 1.0, 8.0 Hz, ArH), 7.14 (d, J ) 7.6
(15) Alumina, type 507 C neutral: 100-125 mesh, Fluka.
(16) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74.