2-Dibenzylaminobutane-l,4-diol: An Effective Chiral Building Block for the Synthesis of 1,2Amino Alcohols
Peter Gmeiner,
* Annerose Kartner
Pharmazeutisches Institut der Universitat Bonn, An der Immenburg 4, 53121 Bonn, Germany
Received 17 August 1994
Regioselective activation and protection of the chiral building block
1, readily available from L-aspartic acid, leads to the key intermediate 8. Employing classical nucleophiles, heterocyclic anions or
organocuprates, 8 could be transformed into the displacement products 9. Finally, hydrolysis affords the homochiral1,2-amino
alcohols 4 in 48- 77 % yield (based on 8).
Regioselective functionalization of proteinogenic ex-amino acids' has become a major method for the synthesis
of enantiomerically pure natural products and biologically active compounds.! Employing this strategy, we
have reported very recently that the enantiomerically
pure building block 1, readily accessible from L-aspartic
acid, can be selectively O-protected at position 4 (Scheme
1).2.3 The differentiation between the two primary hydroxyls is due to the benzyl groups which shield not only
the amine but also the HO-function in position 1 exerting
a "remote protecting group effect". Subsequent activation of position 1 (affording 2) followed by nucleophilic
displacement reactions lead to the chiral 1,3-amino alcohols 3. During the synthesis a two-fold migration of
the dibenzylamino group under complete preservation of
the optical purity was observed.
o
OH
1.
activation
2.
protection
3.
displacement
4.
O-deprotection
R
B"'N~
OH
formation of the side product 62 (8 %) and the cyclization
product 7 (25 %) (Scheme 3). The formation of 6 can be
explained by esterification of position 1 and subsequent
rearrangement of the dibenzylamino group through an
aziridinium cation. Furthermore, the bad mass balance
indicated that product could have been lost during the
workup. Since protection of position 1 was planned to
be the next reaction step it should be possible to circumvent these problems by treating the crude reaction mixture with tert-butyldimethylsilyl chloride (TBDMSCI) in
the presence of imidazole. As a consequence, the projected key intermediate 8 could be isolated in 57 % yield
(based on 1).
Mes CI / EtaN
CHCla" -20 'C, 2 h
--------C>
H'N~~:
--I> --I> B"'N~: --I> --I>
B"'N~M".
CI ~H
37 % (5), 8 % (6), 25 % (7)
OH
o
OH
5
6
NBn2
Asp
OTBDMS
--I> --I> x~
a: Mes CI / Et3N
CHCla" -20 'C, 3 h
OMes
b: TBDMSCI / imidazole
DMF, -20 ·C. 1.5 h
B"'N~
In connection with our program on the structure activity
relationships of selective dopamine autoreceptor agonists,4 1,2- and 1,3-amino alcohols served as valuable
intermediates for the synthesis of enantiomerically pure
aminoindolizine derivatives.5 Therefore, we envisioned
to extend our studies on the general EPC synthesis of
amino alcohols.
Following the route sketched in Scheme 2, we herein
describe the synthesis of the homochiral1 ,2-amino alcohols6 4 when performing activation and protection of
the diol 1 in a reversed sequence. 3
In order to selectively activate the position 4, the enantiomerically pure dioll? was treated with 1.1 equivalents
of methanesulfonyl chloride. However, the required sulfonate 5 could be isolated in only 37 % yield due to
For a nucleophilic displacement of the mesyloxy substituent, compound 8 was reacted with classical nucleophiles, organocuprates and heterocyclic anions (Scheme
4, Table 1). Thus, treatment of 8 with sodium cyanide,
resulted in quantitative formation of the amino nitrile
9a which is of potential interest as a y-amino acid
precursor. Furthermore, reaction of 8 with potassium
phthalimide or sodium azide gave the protected diaminobutanol derivatives 9b and 9c in 61 and 79 % yield, respectively. Introduction of alkyl or aryl substituents was
done by use of lower order Gilman cuprates.8 Thus, the
mesylate 8 was reacted with Me2CuLi and Ph2CuLi to
afford a 51 and 58 % yield of 9d and ge, respectively.
Finally, the heterocyclic derivatives 9f-h could be syn-
thesized upon treatment of 8 with potassium
pyrazolide and indolide (yield: 51-75 %).
pyrrolide,
O-Deprotection
of 9a-h was accomplished using acetic
acid or sodium hydroxide. Under these conditions, the
1,2-amino alcohols 4a-h were formed in 78-99% yield.
R
HOAc / THF / H20. r.t. 7d
see: Table
or NaOH / EtOH / H20, 50'C, 1d
---------~[>
78-99 %
~
-5-1--99-0-Yo~[>
Bn N ~
4
2
OTBDMS
Entry
Reaction Conditions
Product
Yield
(%)
1
2
3
4
5
6
7
8
NaCN, DMF, r. t. 1 d
phthalimide-K, DMF, r. t., 1 d
NaN3, DMF, r. t. 1 d
Me2CuLi, Et20, - 50°C, 22 h
Ph2CuLi, Et20, - 50°C, 22 h
pyrrole, (Me3Si)2K, THF,
-20°C,44h
pyrazole, (Me3Si)2K, THF,
-20°C,44h
indole, (Me3Si)2K, THF,
-20°C,44h
9a
9b
9c
9d
ge
9f
(R
9g
(R
9h
(R
(R
(R
(R
(R
(R
=
=
=
=
=
CN)
NPhth)
N3)
Me)
Ph)
99
61
79
51
58
51
= I-pyrrolyl)
62
= I-pyrazolyl)
75
= l-indolyl)
As an application of the method, it could be shown that
the N,N-dibenzyl protected amino alcohols can serve as
precursors for amino aldehydes9 and amino acids with
side chains different to those of the proteinogenic amino
acids. Employing the pyrazole derivative 9g Swern oxidation10 was performed to give the 1,2-amino aldehyde
10 (Scheme 5). Subsequent oxidation of 10 with sodium
chlorite11 resulted in the formation of the amino acid 11.
NaCI02• 2-methyl-2-butene.
NaH2P04,
CH3CN / t-BuOH
---------[>
In conclusion, a practical method for the synthesis of
chiral amino alcohols which can serve as valuable intermediates for unnatural 1,2 amino aldehydes, nonproteinogenic amino acids, bioactive compounds and natural
products could be elaborated.
THF was distilled from Na/benzophenone, DMF and CH2Cl2 from
CaH2, in all cases immediately before use. All liquid reagents were
also purified by distillation. Unless otherwise noted reactions were
conducted under dry N2. Evaporations of final product solutions
were done under vacuo with a rotary evaporator. Flash chromatography was carried out with 230-400 mesh silica gel. Melting
points: Biichi melting point apparatus. IR spectra: Perkin-Elmer
881 spectrometer. Mass spectra: Varian CH7 instrument, methane
was employed for CIMS. NMR spectra: leol lNM-GX 400 spectrometer at 400 MHz, spectra were measured as CDCl3 solutions
using TMS as internal standard. Elemental analyses: Heraeus CHN
Rapid instrument. Optical rotations were measured at 23 °c using
a Perkin-Elmer 241 polarimeter. Petroleum ether used had bp
40-60°C. For all new compounds satisfactory microanalyses were
obtained: C ± 0.39, H ± 0.45, N ± 0.47.
(S)-4-N,N-Dibenzylamino-5-hydroxy-l-pentanenitrile
(4a):
A solution of9a (1.27 g, 3.12 mmol) in THF/AcOH/H20
(150 mL,
1: 3: 1) was stirred for 7 d at r. t. Then, the reaction mixture was
basified with 2 N NaOH (650 mL) and extracted with Et20
(500 mL). The organic layer was dried (MgS04) and evaporated
and the residue was purified by flash chromatography (petroleum
ether/EtOAc, 65: 35) to give 4a (0.716 g, 78 %) as a colorless solid;
mp 55-57°C; [aID + 27 (c = 1, CHCI3).
1 H NMR (CDCI3): b = 1.56-1.65
(m, 1 H), 1.89-1.98 (m, 1 H),
2.22-2.35 (m, 2 H), 2.74-2.81 (m, 1 H), 3.52 (d, J = 13.2 Hz, 2 H),
3.56-3.51 (m, 2 H), 3.67 (d, J = 13.2 Hz, 2 H), 7.17-7.28 (m, 10 H).
IR (film): v = 3450, 3030, 2930, 2250, 1600 em -I.
MS (CI): m/z = 295 (M+ + 1).
(S)-1-(3-N,N-Dibenzylamino-4-hydroxy )butyl-N-phthalimide (4b):
A solution of 9b (19 mg, 0.036 mmol) in THF/AcOH/H20
(2 mL,
1: 3: 1) was reacted and worked up as described for 4a to give 4b
(12.8 mg, 86 %) as a colorless oil (solvent for flash chromatography:
petroleum ether/EtOAc, 7: 3); [aID + 64 (c = 0.45, CHCI3).
IHNMR (CDCI3): b = 1.46-1.55 (m, 1 H), 2.10-2.19 (m, 1 H),
2.68-2.79 (m, 1 H), 3.32 (d, J = 13.2 Hz, 2H), 3.49-3.67 (m, 4H),
3.73 (d, J = 13.2 Hz, 2 H), 7.07-7.19 (m, 10 H), 7.67 (dd, J = 7.3,
3.0 Hz, 2H), 7.75-7.78 (m, 2H).
MS (CI): m/z = 415 (M+ + 1).
(S)-4-Azido-2-N,N-dibenzylamino-l-butanol
(4c):
A solution of 9c (43 mg, 0.10 mmol) in EtOH (3.5 mL) and NaOH
(2 N, 3.5 mL) was stirred at 6O°C for 24 h. After addition of sat.
NaHC03 (10 mL), the mixture was extracted with Et20 (30 mL)
and the organic layer dried (MgS04) and evaporated. The residue
was purified by flash chromatography
(petroleum ether/EtOAc,
85: 15) to give 4c (29 mg, 90 %) as a colorless oil; [aID + 79 (c = 1,
CHCI3)·
1 H NMR (CDCI3): b = 1.39-1.46
(m, 1 H), 1.89-1.97 (m, 1 H),
2.79-2.86 (m, 1 H), 3.16-3.32 (m, 2 H), 3.40 (d, J = 13.2 Hz, 2 H),
3.44-3.49 (m, 2H), 3.73 (d, J = 13.2 Hz, 2H), 7.16-7.27 (m, 10H).
IR (film): v = 3420, 3030, 2930, 2100, 1600 em - 1.
MS (CI): m/z = 311 (M+ + 1).
(S)-2-N,N-Dibenzylamino-l-pentanol
(4d):
A solution of 9d (45 mg, 0.11 mmol) in EtOH (4 mL) and NaOH
(2 N, 4 mL) was reacted and worked up as described for 4c to give
pure 4d (30 mg, 94 %) as a colorless oil (solvent for flash chromatography: petroleum ether/EtOAc, 9: 1; [aID + 62 (c = 1, CHCI3).
IHNMR (CDCI3): b = 0.86 (t, J = 7.3 Hz, 3 H), 1.09-1.39 (m,
3H), 1.59-1.68 (m, 1 H), 2.68-2.75 (m, 1 H), 3.31-3.36 (m, 1 H),
3.33 (d, J = 13.2 Hz, 2H), 3.42 (dd, J = 11.0,5.1 Hz, 1 H), 3.74 (d,
J= 13.2 Hz, 2H), 7.15-7.29 (m, 10H).
IR (film): v = 3450, 3030, 2930, 1600 cm-1
MS (CI): m/z = 284 (M+ + 1).
(S)-2-N,N-Dibenzylamino-4-phenyl-l-butanol
(4e):
A solution of ge (55 mg, 0.12 mmo!) in EtOH (4 mL) and NaOH
(2N, 4 mL) was reacted and worked up as described for 4c to give
pure 4e (36 mg, 87 %) as a colorless oil (solvent for flash chromatography: petroleum ether/EtOAc, 9: 1); [aID + 102 (c = 1, CHCI3).
IHNMR (CDCI3): (j = 1.51-1.60 (m, 1 H), 2.00-2.09 (m, 1 H),
2.44-2.52 (m, 1 H), 2.63-2.70 (m, 1 H), 2.77-2.84 (m, 1 H), 3.34
(d, J = 13.9 Hz, 2H), 3.46 (dd, J = 11.0, 10.2 Hz, 1 H), 3.58 (dd,
J= 10.2, 5.8 Hz, 1 H), 3.79 (d, J= 13.9 Hz, 2H), 7.14-7.35 (m,
15H).
IR (film): v = 3440, 3030, 2930, 1600 em -I.
MS (CI): m/z = 346 (M + + 1).
(S)- 2-N,N-Dibenzylamino-4-(I-pyrrolyl)-I-butanol
(4t):
A solution of 9f (52 mg, 0.12 mmol) in EtOH (4 mL) and NaOH
(2N, 4 mL) was reacted and worked up as described for 4c to give
pure 4f (37 mg, 95 %) as a colorless oil (purification by flash chromatography was not necessary); [a]o + 68 (c = 0.5, CHCI3) [Lit. 5
[a]o + 67 (c = 1.0, CHCI3)].
Analytical data are in agreement with those reported in Ref. 5.
(S)-2-N,N-Dibenzylamino-4-(I-pyrazolyl)-I-butanol
(4g):
A solution of 9g (73 mg, 0.16 mmol) in EtOH (6 mL) and NaOH
(2 N, 6 mL) was reacted and worked up as described for 4c to give
pure 4g (54 mg, 99 %) as a colorless oil (purification by flash chromatography was not necessary); [a]o + 3 (c = 1, CHCI3).
IHNMR (CDCI3): (j = 1.66-1.74 (m, 1 H), 2.24-2.32 (m, 1 H),
2.63-': 2.70 (m, 1 H), 3.34 (d, J = 13.2 Hz, 2 H), 3.39 (dd, J = 11.0,
5.2 Hz, 1 H), 3.46 (dd,J = 11.7, 11.0 Hz, 1 H), 3.67 (d, J = 13.2 Hz,
2H), 3.94-4.07 (m, 2H), 6.12 (t, J = 2.2 Hz, 1 H), 7.09-7.24 (m,
11 H), 7.44 (d, J = 2.2 Hz, 1 H).
MS (CI): m/z = 336 (M+ + 1).
(S)-2-N,N-Dibenzylamino-4-(I-indolyl)-1-butanol
(4h):
A solution of9h (1.73 g, 3.47 mmol) in EtOH (120 mL) and NaOH
(2N, 120 mL) was reacted and worked up as described for 4c to
give pure 4h (1.26 g, 95 %) as a colorless solid; mp 82- 85°C (purification by flash chromatography was not necessary); [a]o + 99
(c = 1, CHCI3).
IHNMR (CDCI3): (j = 1.67-1.76 (m, 1 H), 2.27-2.35 (m, 1 H),
2.77-2.84 (m, 1 H), 3.33 (d, J = 13.2 Hz, 2 H), 3.58 (d, J = 7.3 Hz,
2 H), 3.75 (d, J = 13.2 Hz, 2 H), 4.02-4.11 (m, 1 H), 4.12-4.19 (m,
1 H), 6.46 (d, J = 2.9 Hz, 1 H), 6.94 (d, J = 2.9 Hz, 1 H), 7.09-7.42
(m, 13 H), 7.66 (d, J = 8.1 Hz, 1 H).
IR (KBr): v = 3390, 3030, 2930 cm -I.
MS (EI): m/z = 353 (M+ - 31).
(S)-I-(3-N,N-Dibenzylamino-4-hydroxy
)butylmethanesulfonate
(5),
(R)-I-N,N-Dibenzylamino-2-bromo-l-butanol
(6), and (S)-3-N,NDibenzylaminotetrahydrofuran
(7):
To a solution of 12,3 (500mg, 1.75mmol) and Et3N (213mg,
2.10 mmol) in CHCl3 (12.5 mL) was added MesCl (221 mg,
1.93 mmol) at - 20°e. After 3 h, the solvent was evaporated and
the residue purified by flash chromatography
(CH2CI2/EtOAc,
92: 8) to give the colorless oils 7 (117 mg, 25 %) followed by 6
(42mg, 8%) and 5 (240mg, 37%).
5:
IHNMR (CDCI3): (j = 1.67-1.77 (m, 1 H), 2.20-2.30 (m, 1 H),
2.74 (s, 3H), 2.95-3.05 (m, 1 H), 3.53-3.66 (m, 6H), 4.11-4.23
(m, 2H), 7.19-7.41 (m, 10H).
IR (film): A. = 3390, 3030, 2930 cm - I.
6: data are identical to those reported in Ref. 2.
7: [a]o + 12 (c = 0.5, CHCI3).
IHNMR (CDCI3): (j = 1.97 (g, J= 7.3 Hz, 2H), 3.51-3.57 (m,
1 H), 3.54 (dd, J = 13.9 Hz, 2H), 3.62-3.68 (m, 2H), 3.82 (dd,
J = 9.5, 5.1 Hz, 1 H), 3.95-4,00 (m, 1 H), 7.20-7.36 (m, 10 H).
IR (film): v = 3030, 2930, 1600 cm - I.
(S)-I-(3-N,N-Dibenzylamino-4-tert-butyldimethylsilyloxy
)butylmethanesulfonate (8):
To a solution of 1 (2.65 g, 9.23 mmol) and Et3N (1.13 g, 11.1 mmol)
in CHCl3 (65 mL) was added MesCl (1.17 g, 10.2 mmol) at - 20°e.
After 2 h the solvent was evaporated and DMF (75 mL), was added
were added. The mixture was stirred for 1.5 h and sat. ag NaHC03
(50 mL) and Et20 (100 mL) were added. The organic layer was
dried (MgS04) and evaporated and the residue was purified by flash
chromatography (petroleum ether/EtOAc, 9: 1) to give 8 (2.51 g,
57%) as a colorless oil; [a]o - 38 (c = 1, CHCI3).
1H NMR (CDCI3): (j = - 0.01 (s, 9 H), 0.83 (s, 6 H), 1.69-1.77 (m,
1 H), 1.84-1.90 (m, 1 H), 2.68 (s, 3 H), 2.75-2.80 (m, 1 H), 3.53 (d,
J= 13.2 Hz, 2H), 3.69 (d, J=4.4Hz, 2H), 3.73 (d, J= 13.2 Hz,
'2 H), 4.11-4.17 (m, 1 H), 4.23-4.28 (m, 1 H), 7.11-7.41 (m, 10 H).
IR (film): v = 3030, 2930, 1600 cm-1
(S)-4-N,N-Dibenzylamino-5-tert-butyldimethylsilyloxy-l-pentanenitrile (9a):
A mixture of 8 (1.62 g, 3.38 mmol) and NaCN (1.5 g, 30 mmol) in
DMF (80 mL) was stirred for 1 d at r. t. Then, sat. ag NaHC03
(200 mL) was added and the mixture was extracted with Et20
(3 x 200 mL). The organic fractions were dried (MgS04) and evaporated to leave pure 9a (1.37 g, 99 %) as a colorless oil; [a]o - 42
(c = 1, CHCI3).
1H NMR (CDCI3): (j = - 0.01 (s, 9 H), 0.83 (s, 6 H), 1.57 -1.62 (m,
1 H), 1.63-1.69 (m, 1 H), 2.02-2.11 (m, 1 H), 2.39-2.47 (m, 1 H),
2.60-2.66 (m, 1 H), 3.50 (d, J = 13.2 Hz, 2H), 3.64-3.70 (m, 2H),
3.74 (d, J = 13.2 Hz, 2 H), 7.15-7.24 (m, 10 H).
IR (film): v = 3030, 2950, 2250 cm -1.
MS (EI): m/z = 408 (M+).
(S)-I-(3-N,N-Dibenzylamino-4-tert-butyldimethylsilyloxy
)butyl-Nphthalimide (9b):
A mixture of 8 (65 mg, 0.14 mmol) and potassium phthalimide
(225 mg, 1.20 mmol) in DMF (3 mL) was reacted and extracted as
described for 9a to give 9b (45 mg, 61 %) as a colorless oil after
flash chromatography (petroleum ether/EtOAc, 93: 7); [a]o + 35
(c = 1, CHCI3).
1 H NMR (CDCI3): (j = - 0.01 (s, 9 H), 0.84 (s, 6 H), 1.66-1.72 (m,
1 H), 1.79-1.85 (m, 1 H), 2.65- 2.69 (m, 1 H), 3.32- 3.40 (m, 1 H),
3.58 (d, J = 13.9 Hz, 2 H), 3.66-3.74 (m, 2 H), 3.73 (d, J = 13.9 Hz,
2H), 3.82-3.90 (m, 1 H), 7.07 (t, J = 7.3 Hz, 2H), 7.16 (t, J =
7,3 Hz, 4 H), 7.29 (d, J = 7.3 Hz, 4 H), 7.60-7.63 (m, 2 H),
7.70-7.73 (m, 2H).
IR (film): v = 3030, 2930, 1770, 1710, 1600 cm -I.
MS (EI): m/z = 529 (M +).
(S)- N,N- Dibenzyl- 2-( 4-azido-l-tert-butyldimethylsilyloxy
)buty 1amine (9c):
A mixture of8 (120 mg, 0.25 mmol) and NaN3 (144 mg, 2.20 mmol)
in DMF (6 mL) was reacted and extracted as described for 9a to
give 9c (84 mg, 79 %) as a colorless oil after flash chromatography
(petroleum ether/EtOAc, 99: 1); [a]o - 16 (c = 1, CHCI3).
1H NMR (CDCI3): (j = - 0.1 (s, 9 H), 0.84 (s, 6 H), 1.50-1.58
(m,
1 H), 1.68-1.77 (m, 1 H), 2.67 - 2.74 (m, 1 H), 3.55 (d, J = 13.2 Hz,
2H), 3.67 (d,! = 5.2 Hz, 2H), 3.74 (d,! = 13.2 Hz, 2H), 7.12-7.25
(m,10H).
IR (film): v = 3030, 2930, 2100, 1600 cm - I.
MS (EI): m/z = 425 (M+).
(S)- N,N-Dibenzyl-2-(I-tert-butyldimethylsilyloxy
)pentylamine (9d):
To a stirred suspension of CuI (444 mg, 2.33 mmol) in Et20 (10 mL)
was added MeLi (2.9 mL, 1.6 molar in Et20) at - 50°C. Then the
mixture was allowed to warm up to - 20°C. After 30 min it was
cooled to - 50°C, and a solution of 8 (159 mg, 0.33 mmol) in Et20
(3.5 mL) was added. After stirring for 22 h at - 50°C, sat. ag
NaHC03 (10 mL) and Et20 (50 mL) were added. The organic layer
was dried (MgS04) and evaporated and the residue was purified
by flash chromatography (petroleum ether/EtOAc, 98: 2) to give
9d (68 mg, 51 %) as a colorless oil; [a]o - 31 (c = 1, CHCI3).
1H NMR (CDCI3): (j = 0.05 (s, 9 H), 0.79 (t, J = 7.4 Hz, 3 H), 0.92
(s, 6 H), 1.25-1.52 (m, 4 H), 2.64-2.70 (m, 1 H), 3.68 (d, J =
13.8 Hz, 2H), 3.68-3.74 (m, 2H), 3.78 (d, J = 13.8 Hz, 2H), 7.18
to the residue. Then, the mixture was cooled to - 20°C, and
(t, J
TBDMSCI (2.24 g, 14.8 mmol) and imidazole (2.02 g, 29.7 mmol)
4H).
= 7.3 Hz, 2 H), 7.27 (t, J = 7.3 Hz, 4 H), 7.36 (d, J = 7.3 Hz,
IR (film): v = 3030, 2550, 1600 cm -1.
MS (el):
mlz
=
398 (M+
+ 1).
(S)-N,N- Dibenzyl- 2-( I-tert-butyldimethylsilyloxy-4-phenyl)butylamine (ge):
CuI (428 mg, 2.25 mmol) and PhLi (2.25 mL, 2 molar in cyclohexane/Et20)
in Et20 (10 mL) and a solution of 8 (153 mg,
0.32 mmol) in Et20 (3.5 mL) were reacted and worked up as described for 9d to give ge (86 mg, 58 %) as a colorless oil; [aJo + 4
(c = 1, CHCI3).
1H NMR (CDCI3): b = - 0.01 (s, 9 H), 0.85 (s, 6 H), 1.51-1.57 (m,
1 H), 1.61-1.68 (m, 1 H), 2.37 -2.45 (m, 1 H), 2.65- 2.77 (m, 2 H),
3.64 (d, J = 13.9 Hz, 2H), 3.65-3.72 (m, 2H), 3.76 (d,J = 13.9 Hz,
2H), 7.00 (d, J=7.3Hz,
2H), 7.07-7.24 (m, 9H), 7.30 (d,
J = 7.3 Hz, 4H).
IR (NaCI): v = 3030, 2930, 1600 cm -1.
MS (CI): m/z = 460 (M+
+ 1).
(S)-N,N-Dibenzyl-2-[I-tert-butyldimethylsilyloxy-4-(I-pyrrolyl)jbutylamine (91):
To a stirred solution ofpyrrole (361 mg, 5.38 mmol) in THF (8 mL)
was added (Me3Si)2K (11.83 mL, 0.5 molar in toluene) at - 40°C.
Then the mixture was allowed to warm up to - 20°C. After 30
min it was cooled to - 78°C, when a solution of 8 (257 mg,
0.54 mmol) in THF (10 mL) was added. After stirring for 44 hat
- 20°C, sat. aq NaHC03 (30 mL) and Et20 (150 mL) were added.
The organic layer was dried (MgS04) and evaporated and the residue was purified by flash chromatography
(petroleum ether/
EtOAc, 9: 1) to give 9f (123 mg, 51 %) as a colorless oil; [aJo - 14
(c = 1.0, CHCI3)·
1H NMR (CDCI3): b = 0.02 (s, 9 H), 0.86 (s, 6 H), 1.70-1.79
(m
1 H), 1.86-1.95 (m, 1 H), 2.67-2.73 (m, 1 H), 3.60 (d, J = 13.9 Hz,
2H), 3.63-3.72 (m, 3 H), 3.77 (d, J = 13.9 Hz, 2H), 3.93-4.01 (m,
1 H), 5.99-6.00 (m, 2 H), 6.36-6.37 (m, 2 H), 7.13-7.30 (m, 10 H).
IR (film): v = 3030, 2930, 1600, 1490 cm - 1.
(S)-N,N-Dibenzyl-2-[I-tert-butyldimethylsilyloxy-4-(I-pyrazoly1)]butylamine (9g):
Pyrazole (76 mg, 1.12 mrnol), (Me3Si)2K (2.46 mL, 0.5 molar in
toluene), THF (2 mL) and a solution of 8 (54 mg, 0.11 mmol) were
reacted and worked up as described for 9f to give 9g (32 mg, 62 %)
as a colorless oil; [aJo - 34 (c = 0.5, CHCI3).
1 H NMR (CDCI3): b = 0.01 (s, 9 H), 0.84 (s, 6 H), 1.80-1.89
(m,
1 H), 1.93-2.01 (m, 1 H), 2.62-2.69 (m, 1 H), 3.59 (d, J = 13.2 Hz,
2H), 3.66 (dd, J = 11.0,5.1 Hz, 1 H), 3.71 (dd, J = 11.0,6.3,1 H),
3.77 (d, J = 13.2 Hz, 2 H), 3.91-3.98 (m, 1 H), 4.16-4.23 (m, 1 H),
6.00 (dd, J = 2.2, 1.5 Hz, 1 H), 6.73 (d, J = 2.2 Hz, 1 H), 7.15-7.27
(m, 10H), 7.37 (d, J = 1.5 Hz, 1 H).
IR (film): v = 3030, 2930, 1600 cm - 1.
(S)-N,N-Dibenzyl-2-[ I-tert-butyldimethylsilyloxy-4-(I-indolyl)lbutylamine (9h):
Indole (234 mg, 2.00 mmol), (Me3Si)2K (4.40 mL, 0.5 molar in toluene), THF (3 mL) and a solution of 8 (96 mg, 0.20 mmol) were
reacted and worked up as described for 9f to give 9h (74 mg, 75 %)
as a colorless oil; [aJo - 12 (c = 1.0, CHCI3)·
lHNMR (CDCI3): b = 0.01 (s, 9H), 0.84 (s, 6H), 1.78-1.87 (m,
1 H), 1.91- 2.00 (m, 1 H), 2.74-2.80 (m, 1 H), 3.62 (d, J = 13.9 Hz,
2H), 3.65 (dd, J = 10.2, 5.1 Hz, 1 H), 3.72 (dd, J = 10.2, 6.8, 1 H),
3.79 (d, J = 13.9 Hz, 2H), 3.87-3.94 (m, 1 H), 4.19-4.26 (m, 1 H),
6.30 (d, J = 3.0 Hz, 1 H), 6.62 (d, J = 3.0 Hz, 1 H), 7.01 (t, J =
7.3 Hz, 1 H), 7.09 (t, J = 7.3 Hz, 1 H), 7.17-7.31 (m, 11 H), 7.53
(d, J = 7.3 Hz, 1 H).
IR (film): v = 3030, 2930, 1600 cm - 1.
MS (EI): m/z = 499 (M +).
(S)- 2-N,N-Dibenzylamino-4-(I-pyrazolyl)butanal
(10):
To a solution of oxalyl chloride (0.075 mL, 0.88 mmol) in CHzClz
(2.2 mL) was added at - 60°C DMSO (0.125 mL, 1.76 mmol), dissolved in CH2CI2 (0.4 mL), and subsequently, 4g (234 mg,
0.70 mmol), also dissolved in CH2CI2 (2 mL). The mixture was
stirred for 15 min and Et3N (0.490 mL, 3.52 mrnol) was added.
After a further 90 min, sat. aq NaHC03 (5 mL) and Et20 (30 mL)
were added. The organic layer was dried (MgS04) and evaporated
and the residue was purified by flash chromatography (petroleum
ether/EtOAc, 4:1 and later 2:3) to give 10 (124mg, 53%, 67%
based on consumed starting material) followed by 4g (49 mg, 21 %),
both as colorless oils; [aJo - 55 (c = 1, CHCI3).
lHNMR (CDCI3): b=2.24-2.29
(m, 2H), 3.10-3.14 (m, IH),
3.62 (d, J= 13.2 Hz, 2H), 3.75 (d, J= 13.2 Hz, 2H), 4.09-4.17
(m, 1 H), 4.20-4.27 (m, 1 H), 6.14 (dd, J = 2.2, 1.5 Hz, 1 H), 7.10
(d, J = 2.2 Hz, 1 H), 7.22-7.34 (m, 10H), 7.49 (d, J = 1.5 Hz, 1 H),
9.68 (s, 1 H).
IR (film): v = 3030, 2930, 1730, 1600 cm -1.
MS (CI): m/z = 334 (M +).
(S)-2-N,N-Dibenzylamino-4-(I-pyrazolyl)butanoic
acid (11):
To a solution of 10 (112 mg, 0.34 mmol) and 2-methylbut-2-ene
(0.85 mL) in MeCN/t-BuOH (7 mL, 1: 1) was added a solution of
NaCl02 (307 mg, 3.4 mmol) and NaH2P04 . 2H20 in H20 (2 mL)
at O°C. The mixture was stirred for 30 min and the aqueous layer
was extracted with EtOAc (10 mL). The combined organic layers
were washed with aq Na2S204 (5 mL, 1 M), dried (MgS04) and
evaporated. The residue was purified by flash chromatography
(CH2CI2/MeOH, 9: 1) to give 11 (85 mg, 72 %) as a colorless solid;
[aJo - 26 (c = 0.5, CHCI3).
1 H NMR (CDCI3): b = 2.13-2.20
(m, 1 H), 2.30-2.38 (m, 1 H),
3.15-3.19 (m, 1 H), 3.68 (d, J = 13.5 Hz, 2H), 3.78 (d, J = 13.5 Hz,
2 H), 4.08-4.30 (m, 2 H), 6.08 (br s, 1 H), 7.03 (br s, 1 H), 7.15- 7.26
(m, 10 H), 7.42 (br s, 1 H).
IR (KBr): v = 3400, 3030, 2940, 2600, 1650, 1600 cm -1.
This work is supported by the Deutsche Forschungsgemeinschaft
the Fonds der Chemischen Industrie.
and
(1) For examples, see: Coppola, G.M.; Schuster, H. F. Asymmetric
Synthesis, Wiley: New York, 1987.
(2) Gmeiner, P; Junge, D.; Kartner, A. J. Org. Chem. 1994,59,
6764.
(3) Preliminary communication: Gmeiner, P; Kartner, A.; Junge,
D. Tetrahedron Leu. 1993, 34, 4325.
(4) Gmeiner, P; Sommer, J.; Mierau, J.; Horner, G. BioMed.
Chem. Leu. 1993, 3, 1477.
(5) Gmeiner, P.; Mierau, J.; Hofner, G. Arch. Pharm. (Weinheim)
1992, 325, 57.
(6) Previous syntheses of nonracemic 1,2-aminoalcohols: Sibi,
M.P; Li, B. Tetrahedron Leu. 1992,33,4115, and references
cited therein.
(7) The optical purity of 1 was proved according to the derivatization reactions described in Refs. 2 and 3.
(8) For recent studies on the reaction of organocuprates with an
N,N-dibenzyl protected fJ-homoserine derivative, see: Gmeiner, P. Tetrahedron Leu. 1990,31,5717.
Gmeiner, P. Arch. Pharm. (Weinheim) 1991, 324, 551.
(9) For review on the versatility of N,N-dibenzylamino aldehydes
as synthetic intermediates, see: Reetz, M. T. Angew. Chem.
1991,103,1559; Angew. Chem., Int. Ed. Engl. 1991,30, 1531.
(10) Manacuso, A.J.; Swern, D. Synthesis 1981, 165.
(11) Bal, B. S.; Childers, Jr., W. E.; Pinnick, H. W. Tetrahedron 1981,
37,2091.