α-aminoallylation of aldehydes with ammonia: Stereoselective synthesis of homoallylic primary amines

Article abstract of DOI:10.1021/ja049689o

Three-component reactions of aldehydes, ammonia, and allylboronates were found to provide homoallylic primary amines in high yields with high chemo- and stereoselectivities. A two-step, one-pot, stereoselective synthesis of an uncommon α-amino acid, alloisoleucine, was achieved utilizing this reaction. Copyright

Full text of DOI:10.1021/ja049689o

α-Aminoallylation of Aldehydes with Ammonia:
Stereoselective Synthesis of Homoallylic Primary Amines
_
Masaharu Sugiura, Keiichi Hirano and Shu Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Supporting Information
Table of Contents
Pages
S-1
Experimental Details and Physical Data
General Methods
S-1
Chemicals
S-2
General procedures for α-aminoallylation of aldehydes 1a-l (Table 1)
Diastereoselective α-aminoallylation of (S)-1m (Scheme 2)
Diastereoselective α-aminoallylation of (2S,3S)-1n (Scheme 2)
Transformation of Boc-3n to a L-acosamine derivative (Scheme 2)
α-Aminocrotylation of aromatic aldehydes (Scheme 3)
Synthesis of alloisoleucine (Scheme 4)
S-2
S-6
S-8
S-9
S-9
S-10
S-11
S-11
S-12
Enantioselective α-aminoallylation of benzaldehyde (Scheme 5)
Detection of an N-unsubstituted imine by 1H NMR analysis
References and notes
Experimental Details and Physical Data
1
13
General Methods: Melting points are uncorrected. H and C NMR spectra were recorded
on a JEOL JNM-LA300 or JNM-LA400 spectrometer in CDCl3 unless otherwise noted.
Tetramethylsilane (TMS) served as internal standard (δ = 0) for 1H NMR and CDCl3 was used
13
as internal standard (δ = 77.0) for C NMR. High-resolution electron impact mass spectra
(HR-EIMS) were measured with JEOL JMX-SX-102A mass spectrometer. High-resolution
electrospray ionization mass spectra (HR-ESIMS) were measured with BRUKER
DALTONICS BioTOF II mass spectrometer. Preparative thin-layer chromatography (PTLC)
S-1

was carried out using Wakogel B-5F. Ethanol was distilled from sodium and stored over 3Å
MS. Distilled water was employed for the aqueous reactions. All other solvents were
purified based on standard procedures.
Chemicals: Aldehydes 1a and 1d-k were purified by distillation prior to use. Aldehydes 1b
and 1c were purified by recrystallization from aqueous ethanol and ethanol, respectively.
Glyoxylic acid monohydrate (1l) was purchased from Tokyo Kasei Kogyo Co., Ltd. and used
without further purification. Aldehyde (S)-1m1 and (2S,3S)-1n2 were prepared according to
the literature procedures. Allylboronate 2,3 (E)- and (Z)-crotylboronate 5,4 and chiral
allylboronate 75 were prepared according to the literatures. Liquid ammonia (99.999%,
Nippon Sanso Corporation) and aqueous ammonia (28.0-30.0 wt%, Wako Pure Chemical
Industries, Ltd.) were used without purification. Palladium on carbon (5 wt%, PH-type, wet,
Kawaken Fine Chemicals Co., Ltd.) were used for hydrogenation. All other chemicals were
purified based on standard procedures.
General procedures for α-aminoallylation of aldehydes 1a-l (Table 1)
Method A (entries 1 and 3-9): To a dry two-neck flask with an argon balloon and a
rubber septum cooling at –78 °C, gaseous ammonia was introduced via a needle to obtain
liquid ammonia (ca. 0.5 mL). After addition of ethanol (0.5 mL), aldehyde 1 (0.5 mmol) was
added to ammonia at –78 °C and rinsed with ethanol (0.5 mL). In the case of 1b and 1c (solid
aldehydes), aldehyde was first placed in the flask before addition of liquid ammonia (ca. 0.5
mL) and ethanol (1.0 mL). The mixture was warm to –10 °C and was stirred at that
temperature for 2 h. During that, excess ammonia was vaporized in the balloon.
Allylboronate 2 (0.6 mmol) in ethanol (0.5 mL) was then added dropwise to the solution.
Colorless precipitates were formed on addition of 2. The mixture was stirred at –10 °C for 3
h and at rt for 1 h. The balloon and the septum were then removed to vaporize most of
ammonia and 1 N aqueous HCl was added to acidify the solution (pH ca. 1). The mixture was
washed with diethyl ether (3×), alkalized with 6 N aqueous NaOH (pH ca. 10) and extracted
with dichloromethane (3×). The dichloromethane layers were dried over anhydrous Na2CO3,
filtered and evaporated to give almost pure amine 3. The crude product was purified by
preparative TLC (hexane/isopropylamine = 10/1) to give amine 3. Meanwhile, non-basic
components including alcohol 4 was obtained from the ethereal extracts. The extracts were
S-2

dried over anhydrous MgSO4, filtered and concentrated in vacuo. The yield of alcohol 4 was
estimated by 1H NMR analysis using 1,2,4,5-tetramethylbenzene as an internal standard.
Method B (entries 2 and 13): Aldehyde 1a or 1l (0.5 mmol) in 28-30 wt% aqueous
ammonia (0.74 mL, ca. 20 equiv) and ethanol (1 mL) was stirred at rt for 30 min.
Allylboronate 2 (0.6 mmol) was added to the solution and rinsed with ethanol (0.5 mL). The
mixture was stirred at rt for 2 h (entry 2) or 3 h (entry 13) and worked up in the same way as
Method A for the reaction of 1a (entry 2). In the case of glyoxylic acid (1l) (entry 3), the
reaction mixture was concentrated in vacuo and the residue was charged on a cationic ion
exchange resin column (DOWEX 50W-X2, 50-100 mesh, H+ form; ca. 7 g/wet) with water.
After washing with a sufficient amount of water, the product was eluted with 0.2 N aqueous
ammonia. The fractions were checked by silica gel TLC plates without development using
0.1 wt% ninhydrine in acetone/water (80/20 v/v%). Fractions including product 3l were
collected and concentrated to dryness.
Method C (Table 1, entries 10-12): Allylboronate 2 (0.6 mmol) in ethanol (0.5 mL)
was added to liquid ammonia (ca. 0.5 mL, see Method A) at –78 °C and rinsed with ethanol
(0.5 mL). Colorless precipitates were formed during addition of 2. After being stirred at rt
for 30 min, aldehyde 1 (0.5 mmol) was added to the suspension and rinsed with ethanol (0.5
mL). The mixture was stirred at rt for 2 h and worked up in the same way as Method A.
1
1-Phenylbut-3-en-1-amine (3a):6 84% (Method A), 80% (Method B); H NMR (300 MHz,
CDCl3) δ 7.34-7.21 (m, 5H), 5.76 (dddd, J = 17.0, 10.1, 8.0, 6.5 Hz, 1H), 5.05-5.16 (m, 2H),
3.99 (dd, J = 8.0, 5.3 Hz, 1H), 2.52-2.42 (m, 1H), 2.41-2.30 (m, 1H), 1.55 (brs, 2H); 13C NMR
(75 MHz, CDCl3) δ 145.8, 135.4, 128.4, 127.0, 126.3, 117.6, 55.4, 44.2; HR-ESIMS calcd for
C10H14N (M+H+) 148.1126, found 148.1126.
1
1-(4-Nitrophenyl)but-3-en-1-amine (3b):6 96% (Method A); H NMR (400 MHz, CDCl3)
δ 8.14 (apparent d, J = 8.8 Hz, 2H), 7.50 (apparent d, J = 8.8 Hz, 2H), 5.69 (dddd, J = 15.9,
9.6, 7.9, 6.5 Hz, 1H), 5.13-5.06 (m, 2H), 4.12 (dd, J = 7.8, 5.4 Hz, 1H), 2.43 (dddt, J = 13.6,
13
6.5, 5.4, 1.2 Hz, 1H), 2.32 (ddd, J = 13.6, 7.9, 7.8 Hz, 1H), 1.59 (brs, 2H); C NMR (100
MHz, CDCl3) δ 153.3, 147.0, 134.2, 127.3, 123.6, 118.6, 54.8, 44.1; HR-ESIMS calcd for
C10H13N2O2 (M+H+) 193.0977, found 193.0973.
1
1-(4-Bromophenyl)but-3-en-1-amine (3c):7 92% (Method A); H NMR (400 MHz, CDCl3)
δ 7.45 (apparent d, J = 8.5 Hz, 2H), 7.23 (apparent d, J = 8.5 Hz, 2H), 5.73 (dddd, J = 17.1,
S-3

10.3, 8.0, 6.4 Hz, 1H), 5.14-5.08 (m, 2H), 3.97 (dd, J = 7.8, 5.6 Hz, 1H), 2.46-2.38 (m, 1H),
2.36-2.27 (m, 1H), 1.54 (brs, 2H); 13C NMR (100 MHz, CDCl3) δ 144.8, 134.9, 131.4, 128.1,
120.6, 118.0, 54.8, 44.1; HR-ESIMS calcd for C10H13BrN (M+H+) 226.0231, found 226.0234.
1
1-(4-Methoxyphenyl)but-3-en-1-amine (3d):6 91% (Method A); H NMR (300 MHz,
CDCl3) δ 7.26 (apparent d, J = 8.6 Hz, 2H), 6.87 (apparent d, J = 8.6 Hz, 2H), 5.75 (dddd, J =
17.2, 10.1, 7.9, 6.3 Hz, 1H), 5.16-5.04 (m, 2H), 3.95 (dd, J = 7.9, 5.5 Hz, 1H), 3.80 (s, 3H),
2.44 (dddt, J = 13.7, 6.3, 5.5, 1.4 Hz, 1H), 2.34 (dddt, J = 13.7, 7.9, 7.9, 0.9 Hz, 1H), 1.54 (brs,
2H); 13C NMR (75 MHz, CDCl3) δ 158.5, 138.0, 135.6, 127.3, 117.5, 113.7, 55.3, 54.8, 44.3;
HR-ESIMS calcd for C11H16NO (M+H+) 178.1226, found 178.1225.
1
2-(1-Aminobut-3-enyl)phenol (3e): 76% (Method A); H NMR (400 MHz, CDCl3) δ 7.15
(ddd, J = 8.1, 7.3, 1.7 Hz, 1H), 6.96 (dd, J = 7.6, 1.7 Hz, 1H), 6.84 (dd, J = 8.1, 1.2 Hz, 1H),
6.78 (ddd, J = 7.3, 7.3, 1.2 Hz, 1H), 5.78 (dddd, J = 16.8, 10.3, 8.8, 5.8 Hz, 1H), 5.24-5.17 (m,
13
2H), 4.13 (dd, J = 9.0, 4.9 Hz, 1H), 2.57-2.43 (m, 2H), NH2, OH (unassignable); C NMR
(75 MHz, CDCl3) δ 157.7, 134.7, 128.5, 127.7, 126.7, 119.0, 118.9, 117.3, 55.4, 41.5; HR-
EIMS calcd for C10H13NO (M+) 163.0997, found 163.1001.
1
1-(Pyridin-2-yl)but-3-en-1-amine (3f):8 85% (Method A); H NMR (300 MHz, CDCl3)
δ 8.56 (ddd, J = 4.9, 1.8, 1.1 Hz, 1H), 7.65 (ddd, J = 7.9, 7.5, 1.8 Hz, 1H), 7.31 (d, J = 7.9 Hz,
1H), 7.16 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 5.77 (dddd, J = 17.0, 10.2, 7.9, 6.4 Hz, 1H), 5.16-
5.06 (m, 2H), 4.06 (dd, J = 7.9, 5.3 Hz, 1H), 2.60 (dddt, J = 13.7, 6.4, 5.3, 1.4 Hz, 1H), 2.41
13
(dddt, J = 13.7, 7.9, 7.9, 1.0 Hz, 1H), 1.88 (brs, 2H); C NMR (75 MHz, CDCl3) δ 164.0,
149.1, 136.4, 135.1, 121.9, 120.9, 117.7, 56.5, 43.2; HR-ESIMS calcd for C9H13N2 (M+H+)
149.1079, found 149.1080.
1
1-(Thiophen-2-yl)but-3-en-1-amine (3g):9 77% (Method A); H NMR (400 MHz, CDCl3)
δ 7.19 (dd, J = 5.0, 1.4 Hz, 1H), 6.96-6.91 (m, 2H), 5.79 (dddd, J = 17.1, 10.2, 7.8, 6.4 Hz,
1H), 5.18-5.10 (m, 2H), 4.28 (dd, J = 7.9, 5.2 Hz, 1H), 2.61-2.53 (m, 1H), 2.46-2.38 (m, 1H),
13
1.68 (brs, 2H); C NMR (75 MHz, CDCl3) δ 150.7, 134.8, 126.5, 123.6, 122.7, 118.2, 51.3,
44.7; HR-ESIMS calcd for C8H12NS (M+H+) 154.0690, found 154.0687.
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1
(E)-1-Phenylhexa-1,5-dien-3-amine (3h):10 75% (Method A); H NMR (300 MHz, CDCl3)
δ 7.40-7.18 (m, 5H), 6.52 (d, J = 15.8 Hz, 1H), 6.20 (dd, J = 15.8, 6.8 Hz, 1H), 5.82 (dddd, J
= 17.0, 10.2, 7.7, 6.6 Hz, 1H), 5.19-5.09 (m, 2H), 3.58 (dddd, J = 7.3, 6.8, 5.7, 1.1 Hz, 1H),
2.36 (dddt, J = 13.7, 6.6, 5.7, 1.3 Hz, 1H), 2.24 (dddt, J = 13.7, 7.7, 7.3, 1.1 Hz, 1H), 1.48 (brs,
13
2H); C NMR (75 MHz, CDCl3) δ 137.1, 135.0, 134.2, 129.0, 128.6, 127.3, 126.3, 117.8,
53.2, 42.5; HR-ESIMS calcd for C12H16N (M+H+) 174.1283, found 174.1284.
1-Phenylhex-5-en-3-amine (3i):11 78% (Method C); 1H NMR (300 MHz, CDCl3) δ 7.32-7.24
(m, 2H), 7.22-7.14 (m, 3H), 5.79 (dddd, J = 17.6, 9.6, 8.0, 6.4 Hz, 1H), 5.12-5.06 (m, 2H),
2.83 (tt, J = 8.0, 4.9 Hz, 1H), 2.76 (ddd, J = 13.7, 10.0, 5.9 Hz, 1H), 2.64 (ddd, J = 13.7, 10.0,
6.4 Hz, 1H), 2.27 (dddt, J = 13.7, 6.4, 4.7, 1.4 Hz, 1H), 2.03 (dddt, J = 13.7, 7.9, 7.9, 1.0 Hz,
1H), 1.76 (dddd, J = 13.5, 10.0, 6.4, 4.9 Hz, 1H), 1.61 (dddd, J = 13.5, 10.0, 7.9, 5.9 Hz, 1H),
1.26 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 142.2, 135.6, 128.36, 128.34, 125.8, 117.4, 50.2,
42.7, 39.4, 32.6; HR-ESIMS calcd for C12H18N (M+H+) 176.1439, found 176.1435.
1
1-Cyclohexylbut-3-en-1-amine (3j): 80% (Method C); H NMR (300 MHz, CDCl3) δ 5.80
(dddd, J = 16.9, 10.4, 8.3, 6.1 Hz, 1H), 5.13-5.05 (m, 2H), 2.57 (ddd, J = 9.0, 5.3, 3.9 Hz, 1H),
2.34-2.24 (m, 1H), 1.96 (apparent ddd, J = 13.7, 9.0, 8.3 Hz, 1H), 1.82-1.61 (m, 5H), 1.32-
0.93 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 136.6, 117.0, 55.3, 43.4, 39.4, 29.7, 28.3, 26.6,
26.5, 26.4; HR-ESIMS calcd for C10H20N (M+H+) 154.1596, found 154.1593.
1
2-Phenylhex-5-en-3-amine (3k): 69% (syn/anti = 73/27) (Method C); H NMR (400 MHz,
CDCl3) syn-isomer δ 7.34-7.15 (m, 5H), 5.75 (dddd, J = 17.8, 9.4, 8.3, 6.0 Hz, 1H), 5.08-5.02
(m, 2H), 2.93 (ddd, J = 9.0, 6.8, 3.9 Hz, 1H), 2.69 (dq, J = 6.8, 7.1 Hz, 1H), 2.16 (dddt, J =
13.8, 6.0, 3.9, 1.6 Hz, 1H), 1.86 (dddt, J = 13.8, 9.0, 8.3, 1.0 Hz, 1H), 1.31 (d, J = 7.1 Hz, 3H),
1.20 (brs, 2H); anti-isomer (representative peaks) δ 5.84 (dddd, J = 17.1, 10.2, 8.5, 6.1 Hz,
5H), 5.17-5.09 (m, 2H), 2.64 (apparent quint, J = 7.2 Hz, 1H), 2.44 (m, 1H), 1.86 (dddt, J =
13
13.9, 9.0, 8.3, 1.0 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) syn-
isomer δ 145.2, 136.2, 128.3, 127.7, 126.2, 117.3, 56.0, 45.6, 40.0, 16.4; HR-ESIMS calcd
for C12H18N (M+H+) 176.1439, found 176.1444.
Assignment of the relative configuration of 3k: A mixture of 3k (20.6 mg), propionyl
chloride (15 µL, 1.5 equiv) and triethylamine (2 equiv) in dichloromethane (2 mL) was stirred
at rt for 5 h. The resultant was purified by preparative TLC (hexane/ethyl acetate = 1/1) to
give the corresponding propionamide (26.2 mg). Then, a mixture of propionamide (24.3 mg)
and Pd/C (5 wt%, wet) in ethanol (2 mL) was stirred at rt for 29 h under hydrogen atmosphere
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using a balloon (ca. 1 atm). The mixture was filtered through a Celite pad and concentrated in
vacuo to dryness. The crude hydrogenated product was then treated with lithium aluminum
hydride (10.3 mg, 2 equiv) in THF (2 mL) at 80 °C for 6 h. The mixture was cooled to rt and
quenched by a careful addition of powdered Na2SO4•10H2O (89.5 mg). After being mixed
until colorless precipitates were formed, the mixture was filtered through a Celite pad,
concentrated in vacuo and purified by preparative TLC (hexane/isopropylamine = 10/1) to
give 2-phenyl-N-propylhexan-3-amine (12.3 mg). 1H NMR analysis of this amine (10%
CDCl3 in CCl4) showed two sets of doublets [δ 1.27 (J = 7.1 Hz) (major), 1.23 (J = 7.1 Hz)
(minor)]. According to the literature,12 this indicates that the major diastereomer is syn isomer.
1
2-Aminopent-4-enoic acid (3l):13 Quant. (Method B); decomp. 247-248 °C; H NMR (300
MHz, D2O, 1,4-dioxane as an internal standard: δ 3.75 ppm) δ 5.77 (ddt, J = 17.2, 10.0, 7.3
Hz, 1H), 5.27 (brd, J = 17.2 Hz, 1H), 5.26 (brd, J = 10.0 Hz, 1H), 3.80 (brt, J = 6.0 Hz, 1H),
2.66 (br ddd, J = 14.7, 7.3, 6.0 Hz, 1H), 2.59 (br ddd, J =14.7, 7.3, 6.0 Hz, 1H); 13C NMR (75
MHz, D2O, 1,4-dioxane as an internal standard: δ 67.19 ppm) δ 174.7, 131.9, 121.1, 54.6,
35.4, 20.9. Anal. Calcd for C5H9NO2: C, 52.16; H, 7.88; N, 12.17. Found: C, 51.88; H, 7.72;
N, 11.97.
Diastereoselective α-aminoallylation of (S)-1m (Scheme 2)
Allylboronate 2 (106.0 mg, 0.6 mmol) in ethanol (0.5 mL) was added to a mixture of
liquid ammonia (ca. 0.5 mL) and ethanol (0.5 mL) at –78 °C (see Method A). After being
stirred at 0 °C for 30 min, aldehyde (S)-1m (132.5 mg, 0.5 mmol, >94% ee) in ethanol (0.5
mL) was added to the suspension. The mixture was stirred at 0 °C for 12 h and concentrated
in vacuo. The crude was purified by preparative TLC (hexane/isopropylamine = 100/7) to
give amine 3m (102.6 mg, 67%, syn/anti = 85/15) as colorless oil.
(2S)-2-(tert-Butyldimethylsilyloxy)-1-phenylhex-5-en-3-amine (3m): [α]26 –12.7 (c 1.05,
D
1
MeOH, 95% ee, syn/anti = 85/15); H NMR (400 MHz, CDCl3) syn-isomer δ 7.31-7.15 (m,
5H), 5.72 (dddd, J = 15.3, 11.9, 7.8, 6.1 Hz, 1H), 5.08-5.00 (m, 2H), 3.80 (apparent dt, J = 2.7,
6.8 Hz, 1H), 2.97 (dd, J = 13.4, 7.1 Hz, 1H), 2.71 (dd, J = 13.4, 6.4 Hz, 1H), 2.71 (dd, J =
13.4, 6.4 Hz, 1H), 2.62 (ddd, J = 9.0, 4.4, 2.7 Hz, 1H), 2.27 (dddt, J = 13.9, 6.1, 4.4, 1.4 Hz,
1H), 2.01 (apparent dt, J = 13.9, 8.5 Hz, 1H), 1.31 (brs, 2 H), 0.89 (s, 9H), 0.02 (s, 3H), -0.15
S-6

(s, 3H); anti-isomer (representative peaks) δ 5.82 (dddd, J = 17.2, 10.0, 7.1, 7.0 Hz, 1H),
5.18-5.08 (m, 2H), 2.87 (ddd, J = 8.8, 5.2, 3.5 Hz, 1H), 2.12 (apparent dt, J = 13.9, 8.2 Hz,
13
1H), 0.83 (s, 9H), -0.09 (s, 3H), -0.40 (s, 3H); C NMR (100 MHz, CDCl3) syn-isomer δ
138.9, 136.4, 129.6, 128.3, 126.1, 116.9, 76.5, 53.1, 40.2, 39.5, 25.90, 18.08, -4.6; anti-isomer
δ 139.3, 136.0, 129.8, 128.1, 126.0, 117.2, 77.1, 55.0, 37.74, 37.71, 25.84, 17.98, -4.8, -5.3;
HR-ESIMS calcd for C18H32NOSi (M+H+) 306.2253, found 306.2259.
Assignment of the stereochemistry:
(1) (S)-1m was prepared from L-phenylalanine.1 The enantiomeric excess of (S)-1m was
determined by HPLC analysis to be 94% ee after its conversion to the corresponding
primary alcohol by NaBH4-reduction. HPLC (CHIRALCEL OD-H, 0.46 cmø × 25 cmL,
hexane/2-propanol = 9/1, flow rate 1.0 mL/min, UV detection at 254 nm) tR = 4.1 min (S),
9.5 min (R).
(2) The authentic racemic product (±)-3m was prepared from (±)-1m in 72% (syn/anti =
85/15) according to the above procedure. By HPLC analysis using (±)-3m, the
enantiomeric excess of (2S)-3m was determined to be 95% ee. HPLC (double
CHIRALCEL OD columns, 0.46 cmø × 25 cmL each, hexane/2-propanol = 9/1, flow rate
0.3mL/min, UV detection at 254 nm) tR = 26.3 min (2S,3S), 27.6 min (2S,3R), 32.4 min
(2R,3S), 61.7 min (2R,3R).
(3) The relative configuration of 3m was determined as follows (Table S-1). To a solution of
(±)-3m (72.2 mg, dr = 85/15) in dry THF (2 mL) was added TBAF (1.0 M THF solution,
354 µL) at rt. The mixture was stirred at rt for 45 h, diluted with ethyl acetate, washed
with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated
to dryness. The residue was dissolved in dry THF (1.0 mL) and treated with 1,1’-
carbonyldiimidazole (42 mg) in THF (0.5 mL) at rt. The mixture was stirred at rt for 4 h,
concentrated and purified preparative TLC (hexane/ethyl acetate 1/1) to give
oxazolidinone 8 (28.9 mg, 2 steps 56%, trans/cis = 85/15). NOE difference spectroscopy
with 8 determined the relative configuration of the major diastereomer to be trans.
4-Allyl-5-benzyloxazolidin-2-one (8): 1H NMR (400 MHz, CDCl3) trans-isomer δ 7.35-7.19
(m, 5H; Ph), 6.28 (brs, 1H; NH), 5.58 (ddt, J = 17.1, 10.3, 7.1 Hz, 1H; H5), 5.14-5.02 (m, 2H,
H6), 4.44 (dt, J = 5.6, 6.5 Hz, 1H; H2), 3.59 (dt, J = 5.6, 6.4 Hz, 1H; H3), 3.09 (dd, J = 14.0,
6.5 Hz, 1H; H1a), 2.91 (dd, J = 14.0, 6.5 Hz, 1H; H1b), 2.16 (dt, J = 14.4, 6.4 Hz, 1H; H4),
2.13 (dt, J = 14.4, 6.4 Hz, 1H; H4); cis-isomer (representative peaks) δ 6.15 (brs, 1H), 5.75
(dddd, J = 16.7, 10.5, 7.7, 6.0 Hz, 1H), 5.24-5.17 (m, 2H), 4.88 (ddd, J = 9.6, 7.6, 4.6 Hz, 1H),
S-7

13
3.86 (ddd, J = 9.6, 7.4, 4.0 Hz, 1H), 2.45-2.37 (m, 1H), 2.35-2.25 (m, 1H); C NMR (100
MHz, CDCl3) trans-isomer δ 159.0, 135.2, 131.9, 129.4, 128.6, 127.1, 119.3, 81.7, 56.1, 40.4,
39.3; cis-isomer δ 159.1, 136.4, 132.7, 129.0, 126.9, 119.5, 80.1, 54.7, 35.5, 34.7; HR-ESIMS
calcd for C13H16NO2 (M+H+) 218.1181, found 218.1183.
Table S-1. NOE Difference Spectroscopy with 8
O
NH2
a) TBAF, THF
O
2
NH
3
Ph
TBSO
(±)-3m
b) CDI, THF
5
Ph
(56%, 2 steps)
1
4
6
8
trans/cis = 85/15
syn/anti = 85/15
irradiated
enhanced (%)
H1a (3.09 ppm)
H1b (24.4), H2 (4.0), H3 (2.2), Ph (23.3)
H1a (21.8), H2 (6.7), H3 (5.7), Ph (35.8)
H1a (3.1), H1b (3.6), H3 (2.2), H4 (5.9)
H1a (2.3), H1b (3.4), H3 (1.8), H4 (6.8)
H2 (4.6), H3 (4.1)
H1b (2.91 ppm)
H2
H3
H4
Diastereoselective α-aminoallylation of (2S,3S)-1n (Scheme 2)
(2S,3S)-1n was prepared from L-chinovose and used without further purification
according to the literature.2 A solution of crude (2S,3S)-1n (67.2 mg, obtained from 164 mg
of L-chinovose) in liquid ammonia (ca. 0.5 mL) and ethanol (1 mL) was stirred at 0 °C for 1 h
(see Method A). Allylboronate 2 (84 mg, 0.5 mmol) in ethanol (0.5 mL) was added to the
mixture. After being stirred at 0 °C for 24 h, the cloudy solution was collected with methanol
and evaporated. The residue was charged on a DOWEX 50W-X2 column (ca. 5g/wet, pre-
treated with 1N aq. HCl, water and methanol) with methanol, washed with methanol (ca. 100
mL) and eluted with 0.2 N ammonia in methanol. The fractions were checked by TLC plates
without development using a phosphomolybdic acid indicator. Positive fractions were
concentrated to dryness and the residue was dissolved in dichloromethane (1 mL) and treated
with Boc2O (125 µL) at rt for 4 h. The mixture was evaporated and purified by flash silica gel
column chromatography to give Boc-3n (62.2 mg, 51% based on 2, >98% syn, the minor
isomer was not detected by 1H NMR analysis).
N-tert-Butoxycarbonyl-4-aminohept-6-ene-2,3-diol (Boc-3n): [α]27 –8.7 (c 0.52, MeOH,
D
>98% syn); 1H NMR (300 MHz, CDCl3) δ 5.79 (ddt, J = 17.0, 10.1, 7.0 Hz, 1H), 5.17-5.04 (m,
2H), 4.75 (brd, J = 7.7 Hz, 1H), 3.97 (apparent q, J = 7.2 Hz, 1H), 3.49 (dq, J = 8.3, 6.2 Hz,
1H), 3.26 (dd, J = 8.3, 1.4 Hz, 1H), 3.90 (brs, 2H), 2.42-2.23 (m, 2H), 1.43 (s, 9H), 1.27 (d, J
S-8

= 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.5, 134.5, 117.7, 80.3, 77.4, 67.5, 50.2, 36.6,
28.3, 19.2; HR-ESIMS calcd for C12H24NO4 (M+H+) 246.1705, found 246.1711.
Transformation of Boc-3n to a L-acosamine derivative (Scheme 2)
Ozone/oxygen gas was bubbled into a solution of Boc-3n (63 mg, 0.26 mmol) in
methanol (4 mL) at –78 °C until the solution turned purple. After removal of excess ozone,
dimethyl sulfide (97 µL) was added dropwise to the solution at – 78 °C. The mixture was
wormed to rt and stirred at rt for 2 h. The mixture was recovered with methanol and
concentrated to dryness. The residue was dissolved in dry methanol (2.5 mL) and treated
with sat. HCl/MeOH (ca. 0.5 mL). After being stirred at rt for 6 h, the mixture was
concentrated in vacuo. The residue was then treated with acetic anhydride (194 µL) in
pyridine (1 mL) at rt for 9 h. After removal of pyridine under reduced pressure at 50 °C, the
residue was purified by preparative TLC (ethyl acetate) to give 1-O-methyl-3-N-acetyl-4-O-
acetyl-L-acosamine (27.7 mg, 3 steps 44%) as colourless solid. Recrystallization from
dichloromethane/hexane gave colourless needles (18.1 mg, α-anomer).
1-O-Methyl-3-N-acetyl-4-O-acetyl-L-acosamine:14 α-anomer mp 159-161 °C, [α]26 –190.3
D
(c 0.38, MeOH); 1H NMR (400 MHz, CDCl3) δ 5.57 (brd, J = 8.3 Hz, 1H), 4.70 (dd, J = 10.2,
8.8 Hz, 1H), 4.46 (dd, J = 10.2, 8.8 Hz, 1H), 4.40 (dddd, J = 11.8, 10.2, 8.3, 4.5 Hz, 1H), 3.89
(dq, J = 8.8, 6.4 Hz, 1H), 3.33 (s, 3H), 2.21 (ddd, J = 13.2, 4.5, 1.2 Hz, 1H), 2.07 (s, 3H), 1.90
(s, 3H), 1.58 (ddd, J = 13.2, 11.8, 3.5 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.8, 169.7, 97.5, 75.7, 65.6, 54.6, 47.0, 36.4, 23.4, 20.9, 17.7; HR-ESIMS calcd
for C11H20NO5 (M+H+) 246.1341, found 246.1342.
α-Aminocrotylation of aromatic aldehydes (Scheme 3)
(E)- or (Z)-Crotylboronate 5 (0.75 mmol) in ethanol (0.5 mL) was added to liquid
ammonia (ca. 0.5 mL, see Method A) at –78 °C and rinsed with ethanol (0.5 mL). Colorless
precipitates were formed during addition of 5. After being stirred at rt for 30 min, aldehyde
1a (0.5 mmol) or a 1,4-dioxane solution of aldehyde 1b (0.5 mmol in 0.5 mL of the solvent)
was added to the suspension and rinsed with ethanol (0.5 mL) or 1,4-dioxane (0.5 mL),
respectively. The mixture was stirred at rt for 2 h and worked up in the same way as Method
A.
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1
(1S*,2R*)-2-Methyl-1-phenylbut-3-en-1-amine (syn-6a):15 85% (syn/anti = >99/<1); H
NMR (400 MHz, CDCl3) δ 7.35-7.19 (m, 5H), 5.69 (ddd, J = 17.8, 9.7, 7.3 Hz, 1H), 5.06-
4.97 (m, 2H), 3.88 (d, J = 5.5 Hz, 1H), 2.50 (ddq, J = 7.3, 5.5, 6.8 Hz, 1H), 1.52 (brs, 2H),
13
0.98 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 144.3, 141.0, 128.0, 127.1, 126.8,
115.0, 60.0, 44.7, 15.0; HR-ESIMS calcd for C11H16N (M+H+) 162.1283, found 162.1279.
(1S*,2S*)-2-Methyl-1-phenylbut-3-en-1-amine (anti-6a):15 79% (syn/anti = 7/93); 1H NMR
(400 MHz, CDCl3) δ 7.34-7.22 (m, 5H), 5.75 (ddd, J = 17.1, 10.3, 8.5 Hz, 1H), 5.17 (dq, J =
17.1, 1.0 Hz, 1H), 5.12 (dd, J = 10.3, 1.7 Hz, 1H), 3.65 (d, J = 8.5 Hz, 1H), 2.38 (ddq, J = 8.5,
13
8.5, 6.8 Hz, 1H), 1.75 (brs, 2H), 0.82 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ
144.6, 141.7, 128.3, 127.3, 127.1, 115.8, 60.7, 46.3, 17.7; HR-ESIMS calcd for C11H16N
(M+H+) 162.1283, found 162.1278.
(1S*,2R*)-2-Methyl-1-(4-nitrophenyl)but-3-en-1-amine (syn-6b): 90% (syn/anti
=
>99/<1); 1H NMR (300 MHz, CDCl3) δ 8.18 (apparent d, J = 8.3 Hz, 2H), 7.47 (apparent d, J
= 8.3 Hz, 2H), 5.66 (ddd, J = 17.0, 10.6, 7.3 Hz, 1H), 5.05 (apparent d, J = 10.6 Hz, 1H), 5.03
(apparent d, J = 17.0 Hz, 1H), 4.03 (d, J = 5.5 Hz, 1H), 2.52 (ddq, J = 7.3, 5.5, 6.8 Hz, 1H),
13
1.55 (brs. 2H), 0.98 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 152.0, 146.9, 140.0,
128.0, 123.2, 115.9, 59.5, 44.7, 14.6; HR-ESIMS calcd for C11H15N2O2 (M+H+) 207.1134,
found 207.1136.
(1S*,2S*)-2-Methyl-1-(4-nitrophenyl)but-3-en-1-amine (anti-6b): 92% (syn/anti = 2/98);
mp 43-44 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (apparent d, J = 8.8 Hz, 2H), 7.51 (apparent
d, J = 8.8 Hz, 2H), 5.69 (ddd, J = 17.1, 10.2, 8.6 Hz, 1H), 5.16 (apparent d, J = 17.1 Hz, 1H),
5.15 (apparent d, J = 10.2 Hz, 1H), 3.82 (d, J = 8.1 Hz, 1H), 2.38 (ddq, J = 8.6, 8.1, 6.8 Hz,
13
1H), 1.89 (brs. 2H), 0.85 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3) δ 152.2, 147.1,
140.3, 128.2, 123.4, 116.7, 60.1, 46.1, 17.3; HR-EIMS calcd for C11H15N2O2 (M+H+)
207.1134, found 207.1142.
Synthesis of alloisoleucine (Scheme 4)
(Z)-Crotylboronate 5 (137.5 mg, 0.75 mmol) in ethanol (0.5 mL) was added to liquid
ammonia (ca. 0.5 mL, see Method A) at –78 °C and rinsed with ethanol (0.5 mL). After
being stirred at –10 °C for 30 min, glyoxylic acid (1l) (46.5 mg, 0.5 mmol) in water (0.5 mL)
was added to the suspension and rinsed with ethanol (0.5 mL). The mixture was stirred at
–10 °C for 3 h. Most of the ammonia was removed by aspiration. After addition of Pd/C (5
S-10

wt%, wet, 15.2 mg), the mixture was stirred at rt for 12 h under hydrogen atmosphere using a
balloon (ca. 1 atm). The mixture was filtered through a Celite pad and concentrated in vacuo.
The residue was purified by ion exchange resin chromatography (see the method for isolation
of 3l, Method B) to give (±)-alloisoleucine (60 mg, 91%). The above one-pot procedure
(subsequent hydrogenation) was important to suppress the undesired isomerization of the syn-
crotylated product to the linear isomer. This isomerization was observed when we tried to
isolate the crotylated product, i. e. concentration with heating.
(±)-Alloisoleucine:16 Colorless plates (recrystallized from 90% aqueous ethanol); decomp.
238 °C; 1H NMR (400 MHz, D2O, 1,4-dioxane as an internal standard: δ 3.75 ppm) δ 3.73 (d,
J = 3.6 Hz, 1H), 2.06 (dtq, J = 3.6, 7.3, 6.6 Hz, 1H), 1.43 (ddt, J = 14.0, 7.3, 7.6 Hz, 1H), 1.32
13
(ddt, J = 14.0, 7.3, 7.6 Hz, 1H), 0.95 (t, J = 7.6 Hz 3H), 0.93 (d, J = 6.6 Hz, 3H); C NMR
(100 MHz, D2O, 1,4-dioxane as an internal standard: δ 67.19 ppm) δ 175.2, 59.1, 36.2, 26.1,
13.9, 11.6; HR-ESIMS calcd for C6H14NO2 (M+H+) 132.1025, found 132.1024.
Enantioselective α-aminoallylation of benzaldehyde (Scheme 5)
A mixture of benzaldehyde (52.4 mg, 0.49 mmol) in liquid ammonia (ca. 0.5 mL) and
dichloromethane (1.0 mL) was stirred at –30 °C for 30 min (see Method A). Allylboronate 75
(177.2 mg, 0.6 mmol) in dichloromethane (0.5 mL) was then added to the mixture and rinsed
with dichloromethane (0.5 mL). The clear solution was stirred at that temperature for 4 h and
worked up in the same way as Method A to give (R)-1-Phenylbut-3-en-1-amine (3a) (53.4 mg,
74% yield, 34% ee).
(R)-1-Phenylbut-3-en-1-amine (3a):17 [α]27 +15.9 (c 1.30, CHCl3, 34% ee (R)); HPLC
D
(CHIRALCEL OD-H, 0.46 cmø × 25 cmL, hexane/2-propanol/diethylamine = 96.7/3.3/0.05,
flow rate 0.7 mL/min, UV detection at 254 nm) tR = 11.0 min (R), tR = 16.0 min (S).
Detection of an N-unsubstituted imine by 1H NMR analysis
The following preliminary 1H NMR experiments support involvement of N-
1
unsubstituted imines in the present reaction system.18 First, a H NMR spectrum of
benzaldehyde (0.2 mmol) in ammonia saturated THF-d8 (0.6 mL) at –78 °C showed two
broad doublets at 10.96 and 8.70 ppm (J = 16.0 Hz) and a singlet at 10.00 ppm. These
doublets could correspond to the N-unsubstituted benzaldimine with a cis geometry of the
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imino hydrogens and the singlet to benzaldehyde. The ratio of imine/aldehyde was 15/85.
Next, trimethyl borate (0.22 mmol) was added to this solution at –78 °C, and the spectrum at
that temperature showed a broad doublet at 10.87 ppm (J = 15.8 Hz, corresponding to the
imine) and a singlet at 10.00 ppm (benzaldehyde) in a 76/24 ratio. A trace amount of a
doublet was also observed at 11.12 ppm (J = 25.4 Hz). These signals were broadened at
–10 °C, but became sharp again when re-cooled to –78 °C. The coupling partner of the
doublet at 10.87 ppm appeared around at 8.7 ppm (confirmed by a decoupling), though the
exact value was unclear due to overlapping of unknown signals. Assignment of the imine was
further confirmed by similarity of a 1H NMR spectrum of the imine prepared by the Brown’s
method.19 Thus, a spectrum of a mixture of N-(trimethylsilyl)benzaldimine (0.15 mmol),
trimethyl borate (1.1 equiv), and methanol (1.1 equiv) in THF-d8 (0.6 mL) at –78 °C showed
two doublets at 10.74 and 8.71 ppm (J = 16.0 Hz). The above experiments suggest that N-
unsubstituted imines are involved under the conditions of α-aminoallylation and that
conversion of aldehydes to imines appears to be assisted by boron agents. Further
investigation concerning the reaction mechanism is now in progress.
References and notes
(1) Humphrey, A. J.; Turner, N. J.; McCague, R.; Taylor, S. J. C. J. Chem. Soc., Chem.
Commun. 1995, 2475 and references therein.
(2) (a) Bilík, V.; Voelter, W.; Bayer, E. Angew. Chem. Int. Ed. 1971, 10, 909. (b) Snyder, J.
R.; Serianni, A. S. Carbohydrate Res. 1987, 163, 169.
(3) Roush, W. R.; Walts, A. E. Tetrahedron Lett. 1985, 26, 3427.
(4) (a) Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem. Soc. 1986, 108,
3422. (b) Hoffmann, R. W.; Ladner, W.; Ditrich, K. Liebigs Ann. Chem. 1989, 883.
(5) Herold, T.; Schrott, U.; Hoffmann, R. W. Chem. Ber. 1981, 114, 359.
(6) van Maarseveen, J. H.; Meester, W. J. N.; Veerman, J. J. N.; Kruse, C. G.; Hermkens, P.
H. H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2001, 994.
(7) Yamada, K.; Hashihayata, T. JP 2002047289, 2002.
(8) (a) Alvaro, G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7, 2083. (b) Aiqiao, M.; Xun,
X.; Lanjun, W.; Yaozhong, J. Synth. Commun. 1991, 21, 2207.
(9) Andreoli, P.; Billi, L.; Cainelli, G.; Panunzio, M.; Martelli, G.; Spunta, G. J. Org. Chem.
1990, 55, 4199.
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(10) Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem. 1983, 48, 289.
(11) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610.
(12) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. J. Am. Chem. Soc. 1986,
108, 7778.
(13) Yeh, T.-L.; Liao, C.-C.; Uang, B.-J. Tetrahedron 1997, 53, 1141.
(14) Ginesta, X.; Pastó, M.; Pericas, M. A.; Riera, A. Org. Lett. 2003, 5, 3001.
(15) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1987, 215.
(16) Lloyd-Williams, P.; Monerris, P.; Gonzalez, I.; Jou, G.; Giralt, E. J. Chem. Soc., Perkin
Trans. 1 1994, 1969.
(17) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766.
1
(18) H NMR experiments were performed in THF-d8 because assignment of the N-
unsubstituted imine was difficult when the experiments were carried out in ethanol-d6
probably due to the proton-deuterium exchange.
It was confirmed that α-
aminoallylation of benzaldehyde (1a) with allylboronate 2 in THF (Table 1, Method C)
afforded a mixture of amine 3a and alcohol 4a (3a/4a = 55/45) in quantitative yield
1
(determined by H NMR analysis using 1,2,4,5-tetramethylbenzene as an internal
standard).
(19) Chen, G.-M.; Brown, H. C. J. Am. Chem. Soc. 2000, 122, 4217.
S-13