Stereoselective synthesis of α-arylalkylamines by glycosylation-induced asymmetric addition of organometallic compounds to imines

Article abstract of DOI:10.1515/znb-2009-0609

Activation of imines of aromatic aldehydes by N-glycosylation with O-pivaloyl-galactopyranosyl bromide (pivalobromogalactose) and subsequent addition of organotin, organolithium, Grignard, or organozinc reagents afforded α-arylalkylamines with moderate to

Full text of DOI:10.1515/znb-2009-0609

Stereoselective Synthesis of α-Arylalkylamines by Glycosylation-induced
Asymmetric Addition of Organometallic Compounds to Imines
Petra Allef and Horst Kunz
Institut fu¨r Organische Chemie, Universita¨t Mainz, Duesbergweg 10 – 14, 55128 Mainz, Germany
Reprint requests to Prof. Dr. Horst Kunz. Fax: +49 6131 3924786. E-mail: hokunz@uni-mainz.de
Z. Naturforsch. 2009, 64b, 646 – 652; received April 8,2009
Dedicated to Professor Gerhard Maas on the occasion of his 60th birthday
Activation of imines of aromatic aldehydes by N-glycosylation with O-pivaloyl-galactopyranosyl
bromide (pivalobromogalactose) and subsequent addition of organotin, organolithium, Grignard, or
organozinc reagents afforded α-arylalkylamines with moderate to high diastereoselectivity.
Key words: Iminium Salts, Galactosylamine, Carbohydrate Auxiliaries, Arylalkylamines,
Organometallic Reagents
Introduction
proach described here, we tried to utilize the enhanced
reactivity of iminium salts in combination with the
stereodifferentiating potential of glycosyl substituents,
demonstrated already in a number of diastereoselective
Mannich-type reactions of glycosyl imines [14, 15],
for the stereoselective synthesis of arylalkylamines.
Glycosyl imines themselves proved to be not suf-
ficiently reactive for the addition of Grignard com-
pounds, although Takahashi et al. [16] had reported
on successful conversions of imines into branched
amines using Grignard reagents. For reactions with
organometallic reagents, N-ethyl benzaldimine (or N-
benzylidene ethylamine) (1) was used as the model
substrate (Scheme 1). It was reacted with 2,3,4,6-tetra-
O-pivaloyl-α-D-galactopyranosyl bromide [17] (2) in
dichloromethane in the presence of silver trifluo-
romethanesulfonate (triflate) and 2,6-lutidine at 0 ◦C to
give the N-galactosyliminium salt 3. After completion
of the iminium salt formation, the solution was cooled
Arylalkylamines are of interest as building blocks
for the synthesis of biologically active compounds
and as chiral ligands or chiral auxiliaries in stereo-
selective syntheses [1]. Their stereoselective synthe-
sis has been achieved by enantioselective reduction
of ketimines using chiral reagents [2], as for exam-
ple Corey’s oxaborolidines [3], or proline-derived tri-
acyloxyborohydrides [4]. Particularly efficient asym-
metric syntheses of chiral arylalkylamines have been
accomplished by Noyori et al. [5] through enantiose-
lective catalysis of hydrogen transfer reactions using
a chiral 1,2-diphenyl-ethylenediamine ruthenium cata-
lyst. Enantioselective transferhydrogenationshave also
been achieved using a chiral titanocene catalyst [6] or
sterically demanding BINOL phosphates [7]. Asym-
metric hydrogenation of imines using transition metal
catalysts has successfully been used to produce chiral
branched amines [8, 9]. An alternative to these reduc-
tive procedures consists of the stereoselective addition
of organometallic compounds to aldimines [10, 11].
We here report on a new asymmetric addition of
organometallic reagents to imines, which is based
on the principle of glycosylation-induced asymmetric
synthesis [12].
◦
to −20 C. At this temperature, the organometallic
reagent was added.
Reaction of iminium salt 3 with tetra-n-butyltin gave
α-phenylamylamine 4 in a low yield, but the diastere-
omers were formed in a ratio of 15 : 1. Usually, organo-
tin reagents are of low nucleophilicity. Their reac-
tion with electrophiles needs the promotion by Lewis
acids [18]. In absence of a Lewis acid, which, for
example, may also activate the stannane via a chlo-
ride bridge, the reactivity of the stannane towards the
iminium salt obviously is low and does not lead to a
smooth conversion.
Results and Discussion
Iminium salts exhibit distinctly higher reactivity to-
wards nucleophiles compared to imines [13]. In the ap-
c
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P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
647
Scheme 1.
Scheme 2.
Scheme 3.
Scheme 4.
On the other hand, application of the much more re- tions of the galactosyl iminium salt 3 in the solvent
active butyllithium is not sufficiently tolerated by the dichloromethane. As a consequence, the highly reac-
solvent required for the iminium salt formation. The tive nucleophile butyllithium was substituted by less
reaction also produced a low yield, but proceeded with reactive Grignard compounds (Scheme 3).
excellent diastereoselectivity (ratio of diastereomers
28 : 1). The diastereoselectivity of these reactions was
detected from the crude product by H NMR spec-
troscopy or by analytical reversed phase HPLC.
Reaction of the iminium salt 3 with tributylstannyl
cyanide gave the phenylglycinonitrile 5 in distinctly
higher yield (Scheme 2). However, in this case the dia-
stereoselectivity was low displaying a diastereomeric
ratio of only 3 : 1.
In these reactions, the α-arylalkylamines 6 were
formed in ca. 50 % yield (after purification) and with
moderate to good diastereoselectivity (diastereomeric
ratio 10 : 1 in case of 6a).
In further extension of these investigations, the re-
activity of the nucleophile was even more reduced, and
diethylzinc was applied (Scheme 4).
1
In this process, the α-phenylpropylamine 7 was
formed in 77 % yield and 82 % diastereoselectivity.
We concluded from the results shown in Schemes 1 The diastereomers, although distinguishable by analyt-
and 2 that the reactivity of the organometallic reagent ical HPLC, could not be separated by chromatographic
is of strong influence on the result of the reac- procedures. Repeated recrystallization from dichloro-
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648
P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
Scheme 5.
Scheme 6.
Scheme 7.
methane/methanolresulted in an enrichment of the ma- companied by a prevailing E to Z isomerization at the
jor (S) diastereomer.
C=N double bond.
To overcome this disadvantage, the structure of
The nucleophilic attack at the iminium ions, 3 or 9,
the model imine was modified, and N-benzylidene-p- respectively, is sterically hindered at the front side, and
methoxy-aniline [19] (8) was investigated as the sub- therefore should preferentially proceed at the Si (back)
strate (Scheme 5).
side (Scheme 6) to afford the α-arylalkylamines 4, 6,
The iminium salt 9 was prepared in dichlorometh- 7 and 10 in (S)-configuration as the major diastere-
ane under the conditions described for the formation omers. The electron-delocalizing effect of the N-(4-
of 3. Conversion of 9 with diethylzinc proceeded un- methoxy)phenyl substituent supports the E to Z iso-
der identical conditions as given for the formation of 7 merization during the galactosylation of imine 8. As a
with high yield and excellent diastereoselectivity. The consequence, the iminium salt 9 is more easily formed
obtained diastereomers of α-phenylpropyl aniline 10 and can undergo the reaction with the nucleophile di-
were separated giving 79% of the (S)-diastereomerand ethylzinc more readily and with higher diastereoselec-
3.5 % of the (R)-diastereomer. The amine 10 offers the tivity compared to the iminium salt 3, although the lat-
advantage that the N-(methoxy)phenyl group can be ter contains the smaller N-substituent.
removed by oxidative processes if this is desired.
Further evidence for the stereochemical course
As has been shown and proven by X-ray analysis of these addition reactions to imines was achieved
of the products for the galactosylation-induced Man- by transformation of the major diastereomer of N-
nich [12a] and Pictet-Spengler reactions [12b], the N- galactosylamine 10 into a known chiral amine. Treat-
glycosylation of imines, as for example 1 or 8, is ac- ment of N-glycosylamines with diluted aqueous HCl
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P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
649
in methanol results in the cleavage of the N-glycosidic ray detection); flow rate: 1 cm3 min−1. Preparative HPLC
was performed using two Knauer Ministar K500 pumps.
Columns: A: Eurospher 100, C8, 5 µ, 250×4 mm2, Knauer,
B: Kromasil C18, 5 µ, 250 × 4 mm2, Knauer; flow rate:
1 cm3 min−1. Thin layer chromatography (TLC) was per-
formed on Merck silica gel 60F254, column chromatography
on silica gel 60 (0.6 – 0.2 mm, Baker), flash chromatography
on silica (0.0063 – 0.04 mm, Merck, Darmstadt, Germany).
FAB mass spectra were measured on a Finnigan MAT 95
spectrometer, ESI mass spectra on a Thermoquest Navigator
instrument. Melting points were taken on a Bu¨chi Dr. Tot-
toli apparatus and are uncorrected. 1H and 13C NMR spec-
tra were recorded on a Bruker AC-200 or a Bruker AC-400
NMR instrument. Optical rotation values were measured
with a Perkin-Elmer 241 polarimeter.
bond [20, 21]. In case of N-galactosyl aniline 10,
the deglycosylation reaction was carried out with
1N HCl/acetonitrile (1 : 10). After neutralization, the
N-(4-methoxy-phenyl) group was removed from the
arylalkylamine 11 by subsequent oxidation with ceric
ammonium nitrate to afford α-phenylpropylamine 12
in high yield (Scheme 7).
Comparison of the optical rotation value of the ob-
tained product 12 ([α]2D2 = +5.82 (c = 2, EtOH)) with
that given in the literature [22] ([α]2D2 = +5.1 (c = 2.0,
EtOH)) confirmed that the major diastereomer of 10
had (S) configuration.
Conclusion
Reaction of arylaldimines via N-galactopyranosyl iminium
salts with organometallic reagents – General procedure
N-Glycosylation of arylaldimines provides a strong
activation the C=N double bond in the interme-
diate N-glycosyl iminium salts and, at the same
time, an efficient diastereodifferentiation in their re-
actions with organometallic nucleophiles to afford α-
arylalkylamines. As the N-glycosylation is accom-
panied by E to Z isomerization at the C=N dou-
ble bond, π-delocalizing N-substituents in the imine
substrates favor both reactivity and diastereodiffer-
entiation in these glycosylation-induced asymmetric
addition reactions to imines. The reactivity of the
organometallic reagent must be compatible with the
solvent used for the formation of the N-glycosyl im-
minium salt. Diethylzinc gave the best results in these
glycosylation-induced asymmetric syntheses of aryl-
Under argon atmosphere, the imine 1 or 8 (0.75 mmol),
2,3,4,6-tetra-O-pivaloyl-a-D-galactopyranosyl bromide [17]
(0.45 g, 0.8 mmol) and 2,6-lutidine (0.18 mL, 1.6 mmol)
were stirred in dichloromethane (10 mL) at 0 ◦C for 10 min.
Silver trifluoromethanesulfonate (0.5 g, 1.6 mmol) was
added, and the mixture was stirred at r. t. for 12 h. After di-
lution with dichloro◦methane (10 mL) the reaction mixture
was cooled to −20 C. At this temperature, 5 mmol of the
organometallic reagent (either neat or in the solvent given)
was added dropwise. Stirring was continued while the reac-
tion mixture was allowed to warm up to r. t. After 3 d the
solvents were evaporated in vacuo, and the ratio of diastere-
omers was recorded either by 1H NMR spectroscopy (ma =
major, mi = minor diastereomer) or by analytical HPLC. Pu-
alkylamines in terms of yield and diastereoselectivity. rification was carried out by flash chromatography in light
petroleum-ethyl acetate (15 : 1).
Using O-pivaloylated D-galactosyl bromide afforded
the stereoselective formation of arylalkylamines with
(S)-configuration. According to the principle of quasi-
enantiomeric carbohydrates [23], the O-pivaloylated
arabinopyranosyl bromide should offer an analogous
access to the corresponding (R)-enantiomers of the
arylalkylamines.
N-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyrano-
syl)-(1-phenyl-amyl)amine (4)
Method a) N-Benzylidene-ethylamine [24] (1) (0.1 g) was
used as the imine component and reacted with 1.7 mL of
tetrabutylstannane. The ratio of diastereomers detected by
1H NMR spectroscopy of the crude product was 15 : 1. The
mixture of diastereomers 4 was isolated by flash chromatog-
raphy and by preparative HPLC on a Knauer Kromasil C18
column in MeCN-H2O = 93 : 7 to 100 : 0 within 90 min.
Experimental Section
General procedures
◦
Reagents and solvents were distilled before use: Tetrahy-
drofuran, dioxane, and Et2O were distilled from potas-
sium/benzophenone ketyl. CH2Cl2 was◦distilled from CaH2.
Light petroleum refers to b. p. 60 – 80 C. All reactions and
distillations were carried out in flame-dried glassware under
argon atmosphere.
Yield: 82 mg, (16 %); colorless solid, m. p. 67 – 69 C, Rf =
0.69 (light petroleum-ethyl acetate 4 : 1), Rt = 28.20 min. –
C39H63NO9 (689.9): calcd. C 67.90, H 9.20, N 2.03; found
C 67.84, H 9.26, N 1.99. – 1H NMR (400 MHz, CDCl3):
δ = 7.23 (m, 5H, arom. (ma, mi)); 5.39 (t, J2,3 = 9.7 Hz, 1H,
H-2 (ma, mi)); 5.32 (d, J4,3 = 2.9 Hz, 1H, H-4 (mi)); 5.25
Analytical HPLC was carried out using a Knauer system (d, J4,3 = 2.9 Hz, 1H, H-4 (ma)); 4.97 (dd, J3,4 = 2.9 Hz,
(Knauer MaxiStar K1000 pump and DAD2062 for diode ar- J3,2 = 9.7 Hz, 1H, H-3 (mi)); 4.92 (dd, J3,4 = 2.9 Hz, 1H,
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P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
H-3 (ma)); 4.37 (d, J1,2 = 9.4 Hz, 1H, H-1 (mi)); 4.20 (d, (t, J = 7.4 Hz; 3H, -CH3 (ma)). – 13C NMR (100.6 MHz,
J1,2 = 9.1 Hz, 1H, H-1 (ma)); 3.86 (m, 1H, H-5 (ma, mi)); CDCl3): δ = 177.71, 177.67, 177.12, 177.06, 176.85, 176.51
3.79 (m, 1H, H-6 (ma, mi)); 3.72 (m, 1H, H-6ꢀ (ma, mi)); (Piv-C=O); 133.67, 133.28 (arom. Cquart); 128.08, 128.88,
3.52 (t, J = 7.0 Hz, 1H, α-CH (ma, mi)); 2.92 (m, 1H, - 128.58, 128.55, 128.27, 128.16 (arom. C); 118.25, 117.60,
CH2-N- (ma, mi)); 2.65 (m, 1H, -CH2-N- (ma, mi)); 1.74 (CN); 90.84, 87.79, (C-1); 72.22, 72.13, 72.10, 71.78 (C-3,
(m, 2H, β-CH2- (ma, mi)); 1.25 – 1.02 (m, 40H, Piv-CH3 C-5); 66.97, 66.89, 65.70, 64.92 (C-2, C-4); 61.12, 61.04
+ -CH2- (ma, mi)); 0.99 (t, J = 7.0 Hz; 3H, -CH3 (ma, (C-6); 56.59, 52.94 (α-C); 41.03, 40.40, (-CH2-N); 38.98,
mi)); 0.78 (t, J = 7.0 Hz, 3H, -CH3 (ma, mi)). – 13C NMR 38.94, 38.71, 38.65, 38.62, 38.59 (Piv-Cquart); 27.14, 27.11,
(100.6 MHz, CDCl3): δ = 177.71, 177.25, 176.77 (Piv- 26.98, 26.62 (Piv-CH3); 14.08, 13.49 (-CH3).
C=O); 141.87 (arom. Cquart); 128.53, 127.80, 126.99 (arom
C); 89.12 (C-1); 72.75, 71.93 (C-3, C-5); 67.22, 65.86 (C-2,
C-4); 62.80 (α-C); 61.04 (C-6); (-CH2-N); 38.91, 38.62,
38.58 (Piv-Cquart); 34.00, 28.92 (-CH2-); 27.18, 27.11, 27.01
(Piv-CH3); 22.63 (-CH2-); 14.60, 13.85 (CH3).
N-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyrano-
syl)-(1-phenyl)butylamine (6a)
N-Benzylidene-ethylamine [24] (1) (0.1 g) was sub-
jected to glycosylation and reacted with 2.5 mL n-propyl-
magnesium chloride (2 M in diethyl ether). The diastere-
omeric excess was determined by 1H NMR spectroscopy
of the crude product 6a (de 82 %). The mixture of diastere-
omers 6a was purified by flash chromatography and prepar-
ative HPLC in MeCN-H2O = 93 : 7 on a Knauer Kromasil
C18 column. Yield: 264 mg (52 %); colorless solid, m. p.
98 – 101 ◦C, Rf = 0.73 (light petroleum-ethyl acetate = 4 : 1),
Rt = 15.57 min. – C38H61NO9 (675.9): calcd. C 67.53,
Method b) N-Benzylidene-ethylamine [24] (1) (0.1 g) was
subjected to glycosylation and reacted with 3.2 mL of n-
butyllithium (1.6 M in n-hexane). The ratio of diastereomers
detected by 1H NMR spectroscopy of the crude product
amounted to 28 : 1. The diastereomers 4 were isolated by
flash chromatography and by preparative HPLC on a Knauer
Kromasil C18 column in MeCN-H2O = 93 : 7 to 100 : 0
within 90 min. Yield: 114 mg (22 %); colorless solid, m. p.
◦
69 – 70 C, Rf = 0.70 (light petroleum-ethyl acetate 4 : 1),
1
H 9.10, N 2.07; found C 67.44, H 9.09, N 2.01. – H NMR
Rt = 27.55 min. According to its NMR spectra the compound
(400 MHz, CDCl3): δ = 7.22 (m, 5H, arom. (ma, mi)); 5.39
(t, J2,3 = 9.8 Hz, J2,1 = 9.3 Hz, 1H, H-2 (ma, mi)); 5.32 (d,
J4,3 = 2.9 Hz, 1H, H-4 (mi)); 5.24 (d, J4,3 = 2.9 Hz, 1H,
H-4 (ma)); 4.98 (dd, J3,4 = 2.9 Hz, J3,2 = 9.7 Hz, 1H, H-3
(mi)); 4.91 (dd, J3,4 = 2.9 Hz, J3,2 = 10.1 Hz, 1H, H-3 (ma));
4.37 (d, J1,2 = 9.3 Hz, 1H, H-1 (mi)); 4.18 (d, J1,2 = 9.1 Hz,
1H, H-1 (ma)); 4.10 – 3.66 (m, 3H, H-5, 6, 6ꢀ (ma, mi)); 3.
51 (t, J = 7.3 Hz, 1H, α-CH (ma, mi)); 2.97 – 2.59 (m, 2H,
-CH2-N- (ma, mi)); 1.72 (m, 2H, β-CH2- (ma, mi)); 1.22 –
0.95 (m, 41H, Piv-CH3 + -CH2- + -CH3 (ma, mi)); 0.79 (t,
J = 7.3 Hz, 3H, -CH3 (ma, mi)). – 13C NMR (100.6 MHz,
CDCl3): δ = 177.71, 177.25, 176.77, 176.63 (Piv-C=O);
141.87 (arom. Cquart); 128.53, 127.80, 126.99 (arom. C);
89.12 (C-1); 72.75, 71.03 (C-3, C-5); 67.22, 65.86 (C-2,
C-4); 62.80 (α-C); 61.04 (C-06); 39.33 (-CH2-N); 38.91,
38.62, 38.58 (Piv-Cquart); 26.82 (-CH2-); 27.18, 27.11, 27.01
(Piv-CH3); 22.63 (-CH2-); 14.60, 13.85 (-CH3).
is identical with the substance obtained by procedure a).
N-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyrano-
syl)-phenylglycinonitrile (5)
According to the general procedure, 0.1 g of N-
benzylidene-ethylamine (1) was glycosylated and reacted
with tributyltin cyanide (1.6 g, 5 mmol). The formed di-
astereomers 5 were detected by analytical HPLC in MeCN-
H2O = 88 : 12 on a Knauer Kromasil C18 column (Rt =
24.99 min (R) and 23.87 min (S)), but could not be sepa-
rated. The mixture of diastereomers 5 was purified by flash
chromat◦ography. Yield: 311 mg (63 %); colorless solid, m. p.
59 – 62 C, Rf = 0.61 (light petroleum-ethyl acetate 4 : 1). –
C36H54N2O9 (658.9): calcd. C 65.62, H 8.26, N 4.24; found
C 65.66, H 8.19, N 4.18. – 1H NMR (400 MHz, CDCl3):
δ = 7.45 (m, 2H, arom. (ma, mi)); 7.34 (m, 3H, arom. (ma,
mi)); 5.42 (m, J2,3 = 9.8 Hz, J2,1 = 9.4 Hz, 1H, H-2 (ma,
mi)); 5.33 (d, J4,3 = 2.7 Hz, 1H, H-4 (ma, mi)); 5.12 (s,
N-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyrano-
syl)-(1-phenyl)ethylamine (6b)
1H, α-CH (mi)); 5.08 (s, 1H, α-CH (ma)); 5.03 (dd, J3,4
3.1 Hz, J3,2 = 10.2 Hz, 1H, H-3 (ma)); 4.99 (dd, J3,4 = 3.1 Hz,
=
In analogy to the synthesis of 6a, N-benzylidene-
J3.2 = 9.8 Hz, 1H, H-3 (mi)); 4.31 (d, J1,2 = 9.4 Hz, 1H, H-1 ethylamine [24] (1) (0.1 g) was glycosylated and subse-
(ma)); 4.22 (d, J1,2 = 9.4 Hz, 1H, H-1 (mi)); 4.16 (dd, J6,5
=
quently reacted with 1.7 mL of a methylmagnesium chlo-
ꢀ
6.4 Hz, J6,6 = 11.0 Hz, 1H, H-6 (mi)); 4.03 (t, J5,6 = 6.4 Hz, ride solution (3 M in THF). The diastereomeric ratio was
J6,6 = 11.0 Hz, 1H, H-6 (mi)); 3.98 (dd, J6,5 = 6.7 Hz, J6 ,6
=
measured by 1H NMR spectroscopy of the crude product 6b
ꢀ
ꢀ
11.3 Hz, 1H, H-6 (ma)); 3.88 (m, 1H, H-6ꢀ (ma, mi)); 3.76 (de 63 %). Purification of the diastereomeric mixture 6b was
(t, J5,6 = 6.7 Hz, 1H, H-5 (ma)); 2.97 (m, 1H, -CH2-N- (ma, achieved by flash chromatography and preparative HPLC in
mi)); 2.82 (m, 1H, -CH2-N- (ma, mi)); 1.24 – 1.04 (m, 36H, MeCN-H2O = 93 : 7 on a Knauer Kromasil C18 column.
Piv-CH3 (ma, mi)); 1.01 (t, J = 7.4 Hz; 3H, -CH3 (mi)); 0.95 Yield: 267 mg, (55 %); colorless solid, m. p. 80 – 82 ◦C, Rf =
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P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
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0.70 (light petroleum-ethyl acetate = 4 : 1), Rt = 16.20 min. – 89.32, 88.81 (C-1); 72.89, 72.77, 71.36, 71.06, (C-3, C-5);
C36H57NO9 (647.9): calcd. C 66.74, H 8.87, N 2.16; found 67.06, 67.22, 65.95, 65.63 (C-2, C-4); 64.81, 64.33 (α-C);
C 67.08, H 8.76, N 2.02. – 1H NMR (400 MHz, CDCl3): 62.03, 61.11 (C-6); 39.47, (-CH2-N); 38.87, 38.57, 38.53
δ = 7.26 (m, 5H, arom. (ma, mi)); 5.43 (2t, J2,3 = 9.8 Hz, (Piv-Cquart); 27.15, 27.08, 26.97, 26.94 (Piv-CH3); 24.05 (-
J2,1 = 9.8 Hz, 1H, H-2 (ma, mi)); 5.31 (d, J4,3 = 3.1 Hz, CH2-); 14.62, 14.37, 11.67, 11.28 (-CH3).
1H, H-4 (mi)); 5.27 (d, J4,3 = 2.7 Hz, 1H, H-4 (ma)); 4.99
N-(4-Methoxyphenyl)-N-(2,3,4,6-tetra-O-pivaloyl-β-D-
galactopyranosyl)-(1-phenyl)propylamine (10)
(dd, J3,4 = 3.1 Hz, J3,2 = 9.8 Hz, 1H, H-3 (mi)); 4.92 (dd,
J3,4 = 3.1 Hz, J3,2 = 9.8 Hz, 1H, H-3 (ma)); 4.32 (d, J1,2
=
9.4 Hz, 1H, H-1 (mi)); 4.16 (m, J1,2 = 9.4 Hz, 3H, H-1
(ma), H6 (ma, mi)); 3.94 (m, 1H, α-CH (mi)); 3.90 (m,
2H, α-CH (ma) H-6ꢀ (mi)); 3.81 (m, 2H, H-6ꢀ (ma)); 3.57
(m, 1H, H-5 (ma)); 2.92 (m, 1H, -CH2-N- (ma, mi)); 2.78
(m, 1H, -CH2-N- (ma, mi)); 1.42 (d, J = 6.7 Hz, 3H, β-
CH3 (mi)); 1.38 (d, J = 6.7 Hz, 3H, β-CH3 (mi)); 1.24 –
0.97 (m, 39H, Piv-CH3 + -CH3). – 13C NMR (100.6 MHz,
CDCl3): δ = 177.78, 177.80, 176.28, 176.84, 176.80, 176.77
(Piv-C=O); 144.16, 143.97 (arom. Cquart); 128.17, 128.02,
127.79, 127.75, 127.04, 126.74 (arom. C); 89.89, 88.98
(C-1); 72.97, 72.85, 71.52, 71.33, (C-3, C-5); 67.62, 67.42,
66.18, 65.69 (C-2, C-4); 62.07 (C-6); 58.06, 56.50 (α-C);
39.27 (-CH2-N); 39.02, 38.99, 38.69 (Piv-Cquart); 27.24,
27.19, 27.08 (Piv-CH3); 26.79 (-CH2-); 21.20, 17.98, 14.82,
14.21 (-CH3).
In this case, 0.16 g (0.75 mmole) N-benzylidene-(4-
methoxyphenyl)amine [19] (8) was glycosylated with 2
and the intermediate glycosyl iminium salt 9 reacted with
5 mL of a diethylzinc solution (1 M in n-heptane) according
to the general procedure. The diastereomers 10 were sepa-
rated by analytical HPLC in MeCN-H2O = 93 : 7 to 100 : 0
within 30 min on a Knauer Kromasil C18 column (diastere-
omeric excess de 91 %) and purified by preparative HPLC in
MeCN-H2O = 93 : 7 to 100.0 within 90 min on a Knauer Kro-
masil C18 column. Yield: 19 mg (R)-10 (3.6 %) and 419 mg
(S)-10 (79 %); mixture of diastereomers 10: colorless solid,
m. p. 69 – 72 ◦C, Rf = 0.66 (light petroleum-ethyl acetate
4 : 1). – C42H61NO10 (740.0): calcd. C 68.17, H 8.31, N 1.89;
found C 67.84, H 8.26, N 1.79.
(R)-diastereomer, (R)-10: [α]2D2 = +71.7 (c = 1, CHCl3);
Rt = 16.71 min. – 1H NMR (400 MHz, CDCl3): δ = 7.25
(m, 5H, arom.); 7.15 (d, J = 9.0 Hz, 2H, arom.); 5.29 (d,
J4,3 = 3.1 Hz, 1H, H-4); 5.19 (t, J2,3 = 9.4 Hz, 1H, H-2);
4.89 (dd, J3,4 = 3.1 Hz, J3,2 = 9.8 Hz, 1H, H-3 ); 4.52
(d, J1,2 = 9.4 Hz, 1H, H-1); 4.22 (m, 1H, H-6); 4.13 (m,
1H, H-5); 4.00 (m, 1H, H-6ꢀ); 3.82 (t, J = 6.7 Hz, 1H,
α-CH); 3.73 (s, 3H, -OCH3); 1.98 (m, 2H, -CH2-); 1.21 –
0.98 (4, 36H, Piv-CH3); 0.68 (t, J = 7.0 Hz; 3H, -CH3). –
13C NMR (100.6 MHz, CDCl3): δ = 177.98, 177.38, 176.79,
175.72 (Piv-C=O); 156.95, 140.47, 138.15 (arom. Cquart);
129.80, 129.11, 128.02, 127.26, 113.32 (arom. C); 88.95
(C-1); 73.12, 71.32 (C-3, C-5); 70.29 (α-C); 67.55, 65.92
(C-2, C-4); 62.34 (C-6); 55.11 (-OCH3); 38.94, 38.75, 38.62,
38.47 (Piv-Cquart); 27.17, 27.14, 27.01 (Piv-CH3); 25.63 (-
CH2-); 11.62 (-CH3).
N-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyrano-
syl)-(1-phenyl)-propylamine (7)
According to the general procedure 0.1 g of N-
benzylidene-ethylamine (1) was glycosylated and reacted
with 5 mL of a solution of diethylzinc (1M in n-heptane,
5 mmol). The diastereomeric ratio was recorded by 1H NMR
spectroscopy of 7 (de 93 %). The product 7 was purified by
preparative HPLC in MeCN-H2O = 93 : 7 to 100 : 0 in 30 min
on a Knauer Kromasil C18 column and by recrystallization
from CH2Cl2-MeOH =◦1 : 2. Yield: 377 mg (77 %); color-
less solid, m. p. 45 – 47 C, Rf = 0.70 (light petroleum-ethyl
acetate 4 : 1), Rt = 21.60 min. – C37H59NO9 (661.2): calcd.
C 67.21, H 8.99, N 2.12; found C 67.25, H 8.93, N 2.03. –
1H NMR (400 MHz, CDCl3): δ = 7.24 (m, 5H, arom. (ma,
(S)-diastereomer, (S)-10: [α]2D2 = +60.2 (c = 1, CHCl3);
mi)); 5.39 (t, J2,3 = 9.7 Hz, 1H, H-2 (ma, mi)); 5.32 (d, J4,3
=
Rt = 18.26 min. – 1H NMR (400 MHz, CDCl3): δ = 7.27
2.9 Hz, 1H, H-4 (mi)); 5.24 (d, J4,3 = 2.9 Hz, 1H, H-4 (ma)); (m, 5H, arom.); 7.16 (d, J = 9.6 Hz, 2H, arom.); 6.76 (d,
4.97 (dd, J3,4 = 3.2 Hz, J3,2 = 9.7 Hz, 1H, H-3 (mi)); 4.91 J = 9.0 Hz, 2H, arom.); 5.18 (d, J4,3 = 2.7 Hz, 1H, H-4);
(dd, J3,4 = 2.9 Hz, J3,2 = 10.0 Hz, 1H, H-3 (ma)); 4.37 (d, 4.91 (t, J2,1 = 9.4 Hz, 1H, H-2); 4.79 (dd, J3,4 = 2.7 Hz,
J1,2 = 9.1 Hz, 1H, H-1 (mi)); 4.18 (m, J1,2 = 9.4 Hz, 1H, 1H, H-2); 4.79 (dd, J3,4 = 2.7 Hz, J3,2 = 9.8 Hz, 1H, H-3);
H-1 (ma)); 4.04 (m, 1H, H-5 (mi)); 3.94 (m, 1H, H-6 (mi)); 4.31 (d, J1,2 = 9.0 Hz, 1H, H-1); 4.18 (m, 1H, H-6); 4.11
3.77 (m, 3H, H-5, 6,6ꢀ (ma), H-6ꢀ (mi), α-CH (mi)); 3.52 (m, 1H, H-5); 3.92 (m, 1H, H-6ꢀ); 3.76 (s, 3H, -OCH3);
(t, J = 7.0 Hz, 1H, α-H (ma)); 2.92 (m, 1H, -CH2-N- (ma, 3.76 (t, J = 6.7 Hz, 1H, α-CH); 1.46 (m, 2H, -CH2-); 1.19 –
mi)); 2.72 (m, 1H, -CH2-N- (ma, mi)); 1.86 (m, 1H, β-CH2- 0.98 (4s, 36H, Piv-CH3); 0.50 (t, J = 7.0 Hz; 3H, -CH3). –
(ma, mi)); 1.74 (m, 1H, β-CH2- (ma, mi)); 1.21 – 0.97 (m, 13C NMR (100.6 MHz, CDCl3): δ = 177.84, 177.28, 176.64,
39H, Piv-CH2-CH3 + -N-CH2-CH3); 0.67 (t, J = 7.0 Hz; 175.85 (Piv-C=O); 157.93, 141.76, 136.62 (arom. Cquart);
3H, -CH3). – 13C NMR (100.6 MHz, CDCl3): δ = 177.77, 131.67, 128.66, 128.02, 127.29, 113.18 (arom. C); 89.17
177.19, 176.70, 176.56 (Piv-C=O); 141.76, 141.63 (arom. (C-1); 73.08, 71.08 (C-3, C-5); 67.42 (α-C); 67.22, 66.45
Cquart); 128.56, 127.94, 127.80, 126.99, 126.77 (arom. C); (C-2, C-4); 61.89 (C-6); 55.13 (-OCH3); 38.80, 38.65, 38.54
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652
P. Allef – H. Kunz · Stereoselective Synthesis of α-Arylalkylamines
(Piv-Cquart); 28.19 (-CH2-); 27.23, 27.07, 26.94 (Piv-CH3); solution was filtered, the solvents were evaporated from
10.83 (-CH3).
the filtrate in vacuo, and the remainder was dissolved in
1N HCl (10 mL). This solution was extracted three times
with CH2Cl2 (20 mL). The aqueous solution was made
alkaline by addition of K2CO3 and extracted three times
with CH2Cl2 (20 mL). The organic solution was extracted
three times with 1N HCl (10 mL), and the combined acidic
aqueous solutions were evaporated to dryness to give the
amine hydrochloride 12. Yield: 80 mg (94 %); colorless
1-Phenyl-propylamine hydrochloride (12)
(S)-N-(4-Methoxyphenyl)-N-(2,3,4,6-tetra-O-pivaloyl-β-
D-galactopyranosyl)-(1-phenyl)-propylamine (10) (370 g,
0.5 mmol) was dissolved in 50 mL of MeCN. To this
solution, 1N HCl (5 mL) was added, and the mixture was
stirred at r. t. for 10 h. This solution containing tetra-O-
pivaloyl-D-galactopyranose and N-(4-methoxy-phenyl)-(1-
phenyl)-propylamine (11) was neutralized with 1N NaOH.
To the neutral solution 0.825 g (1.5 mmol) of ceric ammo-
nium nitrate was added. After stirring for 1 h, the black
◦
solid, m. p. 194 C, [α]2D2 = +5.82 (c = 2, EtOH) lit. [22]:
[α]2D2 = +5.1 (c = 2.0, EtOH), m. p. 191 – 194 ◦C. – 1H NMR
(200 MHz, D2O): δ = 7.35 (m, 5H, arom.); 4.15 (t, J =
7.3 Hz, 1H, α-CH); 1.95 – 1.86 (m, 2H, -CH2); 0.75 (t,
J =7.3 Hz; 3H, -CH3).
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