New synthetic routes to optically active α-quaternary α-aryl amino acid derivatives via the diastereoselective Stevens and Sommelet-Hauser rearrangements

Article abstract of DOI:10.1039/b811162f

The Stevens rearrangement of N-allylic α-aryl amino acid-derived ammonium salts and the Sommelet-Hauser rearrangement of N-benzylic α-alkyl amino acid-derived ammonium salts are shown to proceed with remarkably high levels of diastereoselectivity. The met

Full text of DOI:10.1039/b811162f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
New synthetic routes to optically active a-quaternary a-aryl amino acid
derivatives via the diastereoselective Stevens and Sommelet–Hauser
rearrangements†
Eiji Tayama,* Kiwako Orihara and Hiroshi Kimura
Received 1st July 2008, Accepted 17th July 2008
First published as an Advance Article on the web 27th August 2008
DOI: 10.1039/b811162f
The Stevens rearrangement of N-allylic a-aryl amino acid-derived ammonium salts and the
Sommelet–Hauser rearrangement of N-benzylic a-alkyl amino acid-derived ammonium salts are
shown to proceed with remarkably high levels of diastereoselectivity. The methods presented in this
work provide new routes to optically active a-quaternary a-aryl amino acid derivatives.
Introduction
Optically active a-quaternary a-aryl amino acid derivatives are
a class of the most attractive target compounds in organic
synthesis due to their interesting biological properties but limited
routes for synthesis. The most well-studied synthetic method
for a-quaternary a-aryl amino acid derivatives involves enantio-
or diastereoselective cyanation of ketoimines to produce op-
tically active a-quaternary a-aryl a-amino nitriles as amino
acid precursors.1,2 While several methods or chiral catalysts for
Scheme 1 Previous report of the asymmetric Sommelet–Hauser rear-
rangement of N-benzylic ammonium salts 1
asymmetric cyanation have been developed, other routes to a-
quaternary a-aryl amino acid derivatives have been limited.
Recently, we reported that the asymmetric Sommelet–Hauser
rearrangement of N-benzylic glycine-derived ammonium salts 1
proceeds with high levels (2S : 2R = >20 : 1) of diastereoselectivity
to afford the optically active a-arylglycine esters 2 (Scheme 1).3
With this method, we have examined two routes to a-quaternary
a-aryl amino acid esters 5 (Scheme 2). One route (path A) is the
diastereoselective Stevens or Sommelet–Hauser rearrangement of
the a-arylglycine-derived ammonium salt 3, which was prepared
by quaternization of 2 with allylic or benzylic halides (R¢X).4,5
The other route (path B) is the Sommelet–Hauser rearrangement
of a-alkyl-substituted ammonium salts 4, which were prepared
by quaternization of a-amino acid esters. We now report that
the rearrangement of 3 or 4 with potassium tert-butoxide in
Scheme 2 Two routes to optically active a-quaternary a-aryl amino
acid derivatives 5 via the diastereoselective Stevens and Sommelet–Hauser
rearrangements.
THF provides the corresponding a-quaternary a-aryl amino acid
derivatives 5 with high diastereoselectivities.
Results and discussion
quantitative yield.6 After treatment of 6a with potassium tert-
butoxide in THF at -40 ◦C (Table 1, entry 1), the corresponding
[2,3] rearrangement product 7a was obtained in 83% yield (2R :
2S = >20 : 1,7 9 : 1 dr for the b-position8), together with 17%
of the [1,2] rearrangement product 8a (2R : 2S = >20 : 1, E :
Z = 1 : 1),9 respectively. Next, we examined the rearrangement
of an N-(Z)-crotyl derivative 6b (E : Z = 15 : 85) under the
same conditions as described above (entry 2). Interestingly, the
yield of the [2,3] rearrangement product 7b was decreased (52%
yield, 2R : 2S = >20 : 1, 3 : 7 dr for the b-position), and
the yield of the [1,2] rearrangement product 8b10 was increased
(42% yield, 2R : 2S = >20 : 1, E : Z = 1 : >20). The [2,3] and [1,2]
rearrangements proceeded stereospecifically. The diastereomeric
First, we carried out the Stevens rearrangement of the N-(E)-
crotyl-a-arylglycine-derived ammonium salt 6a (E : Z = 85 : 15)
prepared by quaternization of 2 with (E)-crotyl bromide in
Graduate School of Science and Technology, Niigata University, Niigata 950-
2181, Japan. E-mail: tayama@gs.niigata-u.ac.jp; Fax: +81 25 262 7741;
Tel: +81 25 262 7741
† Electronic supplementary information (ESI) available: Details of the
determinations of absolute configuration; table summarizing the 1H
NMR data of the rearrangement products; further experimental and
characterization details. CCDC reference number 693575. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b811162f
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Table 1 Diastereoselective Stevens rearrangement of N-allylic a-aryl amino acid-derived ammonium salts 6a
7
8
Entry
R1
R2
R3
Temp/◦C, time/h
Yield (%)b
dr (a)c,d
dr (b)c,e
Yield (%)b
dr (a)c,d
E : Zc
1
2
3
4
5
Me
H
H
H
Ph
H
Me
H
H
H
H
H
Me
H
H
af
bg
c
-40, 4
-40, 4
-40, 4
-78, 1
-78, 6
83
52
95
91
0
> 20 : 1
> 20 : 1
> 20 : 1
> 20 : 1
—
9 : 1
3 : 7
—
—
—
17
42
0
0
69
> 20 : 1
> 20 : 1
—
—
> 20 : 1
1 : 1
1 : >20
—
—
> 20 : 1
d
e
a Reactions were conducted using 1.5 equiv. of t-BuOK. b Isolated yield. c The ratios were determined by 1H NMR assay. d 2R : 2S. e The absolute
configuration was not determined. f E : Z = 85 : 15 mixture. g E : Z = 15 : 85 mixture.
ratios of product 7 or 8 (b-position or E : Z) are determined by
the E : Z ratio of the starting material 6a or 6b. To define the
scope and limitations of the present method, we prepared a series
of substrates 6c–e and carried out their reactions with potassium
tert-butoxide. The rearrangement of N-methallyl- (entry 3, 6c)
and N-allyl (entry 4, 6d) derivatives provided the corresponding
rearrangement products 7c and 7d in excellent yields with equally
high a-diastereoselectivities (2R : 2S = >20 : 1). However, in the
rearrangement of an N-(E)-cinnamyl derivative 6e (entry 5) at
a-diastereoselectivity (9 : 1 dr).11 No detectable amount of the
Sommelet–Hauser product 10 was observed.
To explore another synthetic route to optically active a-
quaternary a-aryl amino acid derivatives, we prepared N-benzylic
a-alkyl amino acid-derived ammonium salts 12a from L- and
D-alanine and examined their Sommelet–Hauser rearrangement
(Scheme 4). The rearrangements of L-12a and D-12a in THF at
◦
-60 C were found to produce the same rearrangement product
13a (a-arylalanine ester) in good yields (80% yield from L-12a; 92%
yield from D-12a) with excellent a-diastereoselectivities (2S : 2R =
>20 : 1).7 Though the exact origin is unclear at present, the high a-
selectivity suggests that the rearrangement proceeds via the same
intermediate A (ammonium ylide12) generated from ammonium
salts L-12a and D-12a by deprotonation with potassium tert-
butoxide. The (-)-8-phenylmenthol moiety would block the re-face
(front side of A) of the ammonium ylide, thus leading exclusively
to the 2S-isomer of 13a.
◦
-78 C, the [1,2] Stevens product 8e was obtained exclusively in
69% yield with high a- and E/Z- selectivities (2R : 2S = >20 : 1, E :
Z = >20 : 1). The [2,3] Stevens product 7e was not detected. The
radical stabilization group (Ph) on the allylic substituent might
accelerate the [1,2] Stevens rearrangement.
Next, we attempted the Sommelet–Hauser rearrangement of N-
benzylic a-aryl amino acid-derived ammonium salt 9 to produce
a,a-diaryl amino acid derivative 10 (Scheme 3). Unfortunately,
however, when the rearrangement of 9 with potassium tert-
butoxide was carried out in THF at -60 ◦C, the [1,2] Stevens
rearrangement proceeded to give exclusively the a-benzylic
a-aryl amino acid ester 11 in 91% yield with reasonable
Scheme 3 Rearrangement of an N-benzylic a-aryl amino acid-derived
ammonium salt 9
Scheme
4
Diastereoselective Sommelet–Hauser rearrangement of
N-benzylic L- and D-a-alanine-derived ammonium salts 12a
3674 | Org. Biomol. Chem., 2008, 6, 3673–3680
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Table 2 Diastereoselective Sommelet–Hauser rearrangement of various types of N-benzylic a-alanine-derived ammonium salts 12b–12ga
Entry
R1
R2
R3
Temp/◦C, time/h
Yieldb (%)
drc (2S : 2R)
1d
2
3
CN
H
H
COOMe
CF3
H
H
H
CN
H
H
H
H
H
CN
H
H
H
H
H
b
c
d
e
f
g
g
-60, 4
-60, 4
-60, 4
-60, 4
-60, 8
-60, 12
-40, 12
80
82
82
57
98
0e
9 : 1
6 : 1
> 20 : 1
> 20 : 1
> 20 : 1
—
4
5d
6
7
H
0e
—
a Reactions were conducted using 1.5 equiv. of t-BuOK. b Isolated yield. c The ratios were determined by 1H NMR assay. d The reactions were carried out
in THF–CH2Cl2 (2 : 1) because of the low solubility of the ammonium salts. e The corresponding [1,2] Stevens rearrangement product was obtained (19%
yield for entry 6, 81% yield for entry 7) with no diastereoselectivity (2 : 1 dr). The spectroscopic data is noted in the experimental section.
The scope of substrates was further explored as shown in Table 2.
The reactions of para- and ortho-cyano-N-benzylic ammonium
salts 12b and 12c were found to afford the corresponding
Sommelet–Hauser rearrangement products in good yields (entries
1, 2) with moderate a-diastereoselectivities (9 : 1 dr for 13b,
6 : 1 dr for 13c). However, the rearrangement of meta-cyano
ammonium salt 12d proceeded with high diastereoselectivity
to produce the 2,4-disubstituted regioisomer 13d13 as the only
detectable rearrangement product (entry 3, 82% yield, >20 : 1 dr).
The reaction of para-methoxycarbonyl (12e) and trifluoromethyl
(12f) derivatives also afforded the corresponding products 13e
(entry 4, 57% yield) or 13f (entry 5, 98% yield) respectively, with
equally high diastereoselectivities (>20 : 1 dr). In the absence of an
electron-withdrawing substituent on the aromatic ring such as in
12g (entries 6, 7), the reaction did not give the Sommelet–Hauser
product 13g; the [1,2] Stevens rearrangement product was the only
detectable product obtained.
Scheme 5 Diastereoselective Sommelet–Hauser rearrangement of an
a-allylglycine-derived ammonium salt 15
Finally, we attempted the rearrangement of an a-allylglycine
derivative 15 (3 : 2 dr mixture) prepared via the [2,3] Stevens
rearrangement of 14 (Scheme 5). Unfortunately, however, the re-
Experimental
arrangement did not proceed smoothly under the same conditions
as described in Scheme 4. The Sommelet–Hauser rearrangement
product 7d and the [1,2] Stevens rearrangement product 16 were
obtained in 18% (2R : 2S = 1 : 1) and 36% yield (3 : 2 dr),
respectively.
General
Infrared (IR) spectra were recorded on a HITACHI infrared
spectrometer 270–30. H and 13C NMR spectra were measured
1
on JEOL JMN–Excalibur (1H: 270 MHz, 13C: 68 MHz) and
Varian UNITY plus-500SW (1H: 500 MHz, 13C: 125 MHz)
spectrometers. Splitting patterns are indicated as s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. Specific
rotations were recorded on a JASCO Polarimeter P-1010. For
thin layer chromatography (TLC) analysis throughout this work,
Merck TLC plates (silica gel 60F254) were used. The products
were purified by preparative column chromatography on silica
gel (silica gel 60 N, spherical neutral, KANTO Chemical Co.,
Inc., Japan). The elemental analyses were recorded on a Yanaco
CHN corder, MT-3. Reactions involving air- or moisture-sensitive
Conclusions
We have shown that the Stevens rearrangement of N-allylic a-aryl
amino acid-derived ammonium salts 6 and the Sommelet–Hauser
rearrangement of N-benzylic a-alanine-derived ammonium salts
12 proceeded with remarkably high levels of diastereoselectivity.
The scope and limitations of these two synthetic methods were
defined. The present method provides new routes to optically
active a-quaternary a-aryl amino acid derivatives, and expands
the synthetic scope of the Sommelet–Hauser rearrangement.
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compounds were conducted in an appropriate round-bottomed
flask with a magnetic stirring bar under an atmosphere of dry
argon. Tetrahydrofuran (THF) was purchased from KANTO
Chemical Co., Inc., Japan as an anhydrous solvent.
8-Ph-Men-CH3(Z)), 1.23 (1.5H, s, 8-Ph-Men-CH3(E)), 1.15–0.75
(6H, m, 8-Ph-Men-H and 8-Ph-Men-CH3); dC (68 MHz, CDCl3,
CHCl3) 167.5(E), 167.4(Z), 166.3, 151.3(E), 151.1(Z), 141.1(E), 141.0(Z)
,
139.0(E), 138.9(Z), 131.7, 130.8(E), 130.7(Z), 128.6(Z), 128.5(E), 128.1,
127.8(E), 127.4(Z), 127.3(E), 125.7(Z), 125.6(E), 125.42(Z), 125.40(Z)
125.37(E), 124.8(Z), 80.4(Z), 80.3(E), 77.4(Z), 77.2(E), 72.0(E), 71.7(Z)
50.2(Z), 49.9(E), 44.2(Z), 44.1(E), 40.3(Z), 40.1(E), 39.8(Z), 39.7(E), 35.7(E)
34.6(E), 34.5(Z), 34.1(E), 31.5(Z), 30.3(Z), 29.6(Z), 28.3(E), 28.2, 27.5(Z)
,
,
,
,
Representative procedure for the diastereoselective Stevens rearr-
angement of N-allylic a-aryl amino acid-derived ammonium salt
A solution of 6a (136 mg, 0.212 mmol) in THF (2.1 mL) was cooled
27.4(E), 25.6(E), 24.4(Z), 22.3, 21.9, 18.0(E), 12.8(Z)
.
◦
to -40 C and treated with a 1.0 M THF solution of potassium
tert-butoxide (0.32 mL, 0.32 mmol). The mixture was stirred for
4 h at the same temperature under an argon atmosphere. The
resulting mixture was added to stirred ice-cold saturated aqueous
ammonium chloride and the mixture was extracted with ether. The
combined extracts were washed with saturated aqueous sodium
hydrogen carbonate and brine, dried over sodium sulfate, and
concentrated. Purification of the residue by chromatography on
silica gel (hexane–ethyl acetate = 20 : 1 to 10 : 1 as the eluent) gave
7a (99 mg, 83% yield) as a white solid and 8a (20 mg, 17% yield)
as a white solid.
(2R)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethyla-
mino-3-methylpent-4-enoic acid (-)-8-phenylmenthol ester (7b)
3 : 7 Mixture of stereoisomers; white solid (found: C, 77.0; H,
9.4; N, 2.4. Calc. for C36H51NO4: C, 77.0; H, 9.15; N, 2.5%);
v
max(film)/cm-1 3056, 2964, 2868, 2796, 1706, 1608, 1454, 1392,
1368, 1300, 1256, 1206, 1160, 1140, 1094, 1030, 978, 910, 850,
762, 732, 700; dH (270 MHz, CDCl3, Me4Si) 8.16 (1H, s, Ar-H),
7.76–7.68 (1H, m, Ar-H), 7.34–7.06 (6H, m, Ar-H), 5.78 (0.3H,
ddd, J = 17.3, 10.1, 7.8 Hz, 4-H), 5.61 (0.7H, ddd, J = 17.0, 10.7,
6.8 Hz, 4-H), 5.06–4.80 (3H, m, 5-H and COOCH), 3.40–3.24 (1H,
m, 3-H), 2.51 (0.9H, s, Ar-CH3), 2.48 (2.1H, s, Ar-CH3), 2.41–2.24
(1H, m, 8-Ph-Men-H), 2.34 (1.8H, s, (CH3)2N), 2.32 (4.2H, s,
(CH3)2N), 2.17–1.95 (1H, m, 8-Ph-Men-H), 1.64–0.72 (6H, m, 8-
Ph-Men-H), 1.60 (6.3H, s, t-Bu), 1.59 (2.7H, s, t-Bu), 1.37 (0.9H, s,
8-Ph-Men-CH3), 1.28 (0.9H, s, 8-Ph-Men-CH3), 1.23 (2.1H, s, 8-
Ph-Men-CH3), 1.20 (2.1H, s, 8-Ph-Men-CH3), 0.91 (2.1H, d, J =
7.0 Hz, 3-CH3 or 8-Ph-Men-CH3), 0.87 (3H, d, J = 7.6 Hz, 8-
Ph-Men-CH3), 0.82 (0.9H, d, J = 6.8 Hz, 3-CH3); dC (68 MHz,
CDCl3, CHCl3) 168.4 (0.7C), 167.8 (0.3C), 166.2 (0.7C), 166.1
(0.3C), 150.7 (0.3C), 150.5 (0.7C), 143.8 (0.3C), 143.6 (0.7C), 140.1
(0.7C), 140.0 (0.3C), 135.2 (0.3C), 135.0 (0.7C), 133.6 (1.0C), 132.5
(0.3C), 132.3 (0.7C), 128.0 (0.6C), 127.9 (1.4C), 127.8 (0.3C), 127.5
(0.7C), 127.25 (0.3C), 127.19 (0.7C), 125.64 (0.6C), 125.58 (1.4C),
125.3 (0.3C), 125.2 (0.7C), 115.8 (0.7C), 114.9 (0.3C), 80.35 (0.3C),
80.31 (0.7C), 78.6 (0.3C), 78.0 (0.7C), 50.3 (0.3C), 50.2 (0.7C),
43.2 (0.3C), 42.2 (0.7C), 41.5 (0.7C), 40.9 (0.3C), 40.2 (1.0C),
40.1 (0.7C), 39.8 (0.6C), 34.4 (0.3C), 34.1 (0.7C), 31.5 (0.7C),
31.4 (0.3C), 31.1 (0.7C), 30.3 (0.7C), 30.1 (0.3C), 28.3 (2.1C),
28.2 (0.9C), 27.9 (0.3C), 27.5 (0.7C), 23.8 (0.7C), 23.7 (0.3C),
23.5 (0.3C), 23.4 (0.7C), 22.0 (1.4C), 21.9 (0.6C), 18.7 (0.3C), 14.6
(0.7C).
(2R)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethylamino-
3-methylpent-4-enoic acid (-)-8-phenylmenthol ester (7a)
White solid (found: C, 77.2; H, 9.3; N,◦2.2. Calc. for C36H51NO4:
23
589
C, 77.0; H, 9.15; N, 2.5%); mp 49–51 C; [a] -30.9 (c 1.00 in
CHCl3); vmax(film)/cm-1 3016, 2968, 2924, 2872, 2796, 1708, 1608,
1454, 1368, 1304, 1272, 1256, 1210, 1160, 1142, 1030, 978, 960,
914, 848, 758, 700; dH (270 MHz, CDCl3, Me4Si) 8.14 (1H, s,
Ar-H), 7.72 (1H, dd, J = 7.8, 1.6 Hz, Ar-H), 7.36–7.19 (4H, m,
Ar-H), 7.19–7.10 (2H, m, Ar-H), 5.78 (1H, ddd, J = 17.3, 10.0,
7.8 Hz, 4-H), 5.05–4.86 (3H, m, 5-H and COOCH), 3.30 (1H,
dq, J = 7.8, 6.5 Hz, 3-H), 2.51 (3H, s, Ar-CH3), 2.40–2.24 (1H,
m, 8-Ph-Men-H), 2.34 (6H, s, (CH3)2N), 2.17–2.03 (1H, m, 8-Ph-
Men-H), 1.64–0.75 (6H, m, 8-Ph-Men-H), 1.59 (9H, s, t-Bu), 1.37
(3H, s, 8-Ph-Men-CH3), 1.28 (3H, s, 8-Ph-Men-CH3), 0.87 (3H, d,
J = 7.6 Hz, 8-Ph-Men-CH3), 0.82 (3H, d, J = 6.5 Hz, 3-CH3); dC
(68 MHz, CDCl3, CHCl3) 167.8, 166.1, 150.8, 143.8, 140.0, 135.2,
133.6, 132.5, 128.0, 127.8, 127.3, 125.7, 125.4, 114.9, 80.4, 78.6,
50.4, 43.3, 40.9, 40.2, 39.9 (2C), 34.4, 31.5, 30.2, 28.3 (3C), 27.9,
23.7, 23.5, 22.0 (2C), 18.8.
(2R)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-
dimethylaminohex-4-enoic acid (-)-8-phenylmenthol ester (8a)
(2R, 4Z)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-
E : Z = 1 : 1 mixture; white solid (found: C, 76.7; H, 9.2; N, 2.4.
Calc. for C36H51NO4: C, 77.0; H, 9.15; N, 2.5%); vmax(film)/cm-1
2924, 2870, 2792, 1710, 1608, 1452, 1390, 1366, 1304, 1254, 1208,
1160, 1136, 1092, 1012, 972, 895, 850, 762, 736, 700; dH (270 MHz,
CDCl3, Me4Si) 8.24 (0.5H, d, J = 1.9 Hz, Ar-H(Z)), 8.18 (0.5H, d,
J = 1.4 Hz, Ar-H(E)), 7.74–7.66 (1H, m, Ar-H), 7.39–7.21 (4H, m,
Ar-H), 7.19–7.08 (2H, m, Ar-H), 5.31 (0.5H, dq, J = 10.9, 6.5 Hz,
5-H(Z)), 5.15 (0.5H, dtd, J = 10.9, 6.5, 1.6 Hz, 4-H(Z)), 5.07–4.89
(2H, m, 4-H(E), 5-H(E), and COOCH), 2.83 (0.5H, dd, J = 16.1,
6.5 Hz, 3-H(Z)), 2.64 (0.5H, dd, J = 16.7, 4.9 Hz, 3-H(E)), 2.35 (3H, s,
(CH3)2N(Z)), 2.33 (3H, s, (CH3)2N(E)), 2.32 (1.5H, s, Ar-CH3(Z)),
2.28 (1.5H, s, Ar-CH3(E)), 2.26–2.10 (2.5H, m, 3-H and 8-Ph-Men-
H), 2.01–1.89 (0.5H, m, 3-H(E) or 8-Ph-Men-H(E)), 1.64–1.19 (6H,
m, 8-Ph-Men-H and 6-H), 1.58 (9H, s, t-Bu), 1.46 (1.5H, s, 8-
Ph-Men-CH3(Z)), 1.39 (1.5H, s, 8-Ph-Men-CH3(E)), 1.27 (1.5H, s,
dimethylaminohex-4-enoic acid (-)-8-phenylmenthol ester (8b)
Colorless crystals (found: C, 77.2; H, 9.4; N, 2.4. Calc. for
◦
24
589
C36H51NO4: C, 77.0; H, 9.15; N, 2.5%); mp 147–149 C; [a]
-11.6 (c 1.00 in CHCl3); vmax(film)/cm-1 2952, 2924, 2868, 2792,
1710, 1608, 1454, 1368, 1308, 1262, 1210, 1160, 1138, 1014, 978,
958, 850, 762, 736, 700; dH (270 MHz, CDCl3, Me4Si) 8.24 (1H,
d, J = 1.9 Hz, Ar-H), 7.71 (1H, dd, J = 7.7, 1.9 Hz, Ar-H), 7.43–
7.25 (4H, m, Ar-H), 7.22–7.10 (2H, m, Ar-H), 5.31 (1H, dq, J =
10.9, 6.5 Hz, 5-H), 5.21–5.09 (1H, m, 4-H), 4.99 (1H, td, J =
10.5, 3.8 Hz, COOCH), 2.83 (1H, dd, J = 16.1, 6.5 Hz, 3-H), 2.35
(6H, s, (CH3)2N), 2.32 (3H, s, Ar-CH3), 2.26–2.10 (3H, m, 3-H and
8-Ph-Men-H), 1.64–1.21 (3H, m, 8-Ph-Men-H), 1.58 (9H, s, t-Bu),
1.46 (3H, s, 8-Ph-Men-CH3), 1.28 (3H, d, J = 6.5 Hz, 6-H), 1.27
(3H, s, 8-Ph-Men-CH3), 1.15–0.75 (3H, m, 8-Ph-Men-H), 0.88
3676 | Org. Biomol. Chem., 2008, 6, 3673–3680
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(3H, d, J = 5.9 Hz, 8-Ph-Men-CH3); dC (68 MHz, CDCl3, CHCl3)
167.4, 166.4, 151.1, 141.1, 138.9, 131.7, 130.8, 128.6, 128.1, 127.5,
125.7, 125.43, 125.41, 124.8, 80.4, 77.4, 71.7, 50.2, 44.2, 40.3, 39.8,
34.5, 31.5, 30.3, 29.6, 28.2, 27.5, 24.4, 22.3, 21.9, 12.8.
(CH3)2N), 2.05–1.91 (1H, m, 8-Ph-Men-H), 1.64–0.67 (6H, m, 8-
Ph-Men-H), 1.57 (9H, s, t-Bu), 1.27 (3H, s, 8-Ph-Men-CH3), 1.17
(3H, s, 8-Ph-Men-CH3), 0.90 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3);
dC (68 MHz, CDCl3, CHCl3) 172.0, 165.7, 151.1, 142.1, 138.5,
134.9, 132.2, 130.4, 128.9, 128.0, 127.6, 125.4, 125.2, 116.3, 80.5,
77.6, 74.3, 50.6, 42.1, 40.4, 40.2, 39.5, 34.5, 31.5, 29.7, 28.2, 27.6,
23.5, 21.8, 21.6.
(2R)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethyla-
mino-4-methylpent-4-enoic acid (-)-8-phenylmenthol ester (7c)
White solid (found: C, 77.1; H, 9.45; N,◦2.4. Calc. for C36H51NO4:
(2R, 4E)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethyla-
mino-5-phenylpent-4-enoic acid (-)-8-phenyl-menthol ester (8e)
24
589
C, 77.0; H, 9.15; N, 2.5%); mp 57–59 C; [a] +37.1 (c 1.00 in
CHCl3); vmax(film)/cm-1 3056, 2964, 2792, 1708, 1608, 1454, 1392,
1368, 1304, 1264, 1206, 1160, 1136, 1096, 1032, 992, 954, 896,
850, 762, 736, 700; dH (270 MHz, CDCl3, Me4Si) 8.17 (1H, d, J =
1.9 Hz, Ar-H), 7.68 (1H, dd, J = 7.8, 1.9 Hz, Ar-H), 7.40–7.22
(4H, m, Ar-H), 7.16–7.06 (2H, m, Ar-H), 4.96 (1H, td, J = 10.5,
4.1 Hz, COOCH), 4.44 (1H, s, 5-H), 4.17 (1H, s, 5-H), 2.64 (1H,
d, J = 15.4 Hz, 3-H), 2.39 (6H, s, (CH3)2N), 2.30–2.17 (2H, m, 8-
Ph-Men-H), 2.28 (3H, s, Ar-CH3), 1.87 (1H, d, J = 15.4 Hz, 3-H),
1.66–1.20 (3H, m, 8-Ph-Men-H), 1.57 (9H, s, t-Bu), 1.44 (3H, s,
4-CH3 or 8-Ph-Men-CH3), 1.43 (3H, s, 4-CH3 or 8-Ph-Men-CH3),
1.23 (3H, s, 8-Ph-Men-CH3), 1.17–0.83 (3H, m, 8-Ph-Men-H),
0.89 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3); dC (68 MHz, CDCl3,
CHCl3) 167.1, 166.3, 151.4, 141.0, 140.9, 138.6, 131.4, 131.2, 128.4,
128.2, 127.2, 125.5, 125.3, 115.1, 80.3, 77.5, 72.9, 49.7, 44.2, 40.4,
40.0, 38.2, 34.6, 31.5, 28.2, 27.7, 27.3, 26.5, 24.1, 22.5, 21.9.
White solid (found: C, 78.9; H, 8.8; N,◦2.0. Calc. for C41H53NO4:
24
589
C, 78.9; H, 8.6; N, 2.25%); mp 61–64 C; [a] +82.0 (c 1.00 in
CHCl3); vmax(film)/cm-1 3020, 2964, 2868, 2796, 1708, 1606, 1494,
1452, 1392, 1368, 1306, 1256, 1214, 1160, 1136, 966, 900, 848, 756,
698; dH (270 MHz, CDCl3, Me4Si) 8.25 (1H, d, J = 1.6 Hz, Ar-H),
7.70 (1H, dd, J = 7.8, 1.6 Hz, Ar-H), 7.40–7.08 (11H, m, Ar-H),
5.99 (1H, d, J = 15.9 Hz, 5-H), 5.79 (1H, dt, J = 15.9, 6.5 Hz,
4-H), 4.98 (1H, td, J = 10.5, 4.1 Hz, COOCH), 2.76 (1H, dd, J =
15.7, 6.5 Hz, 3-H), 2.36 (6H, s, (CH3)2N), 2.31 (3H, s, Ar-CH3),
2.27–2.16 (2H, m, 8-Ph-Men-H), 2.03 (1H, dd, J = 15.7, 6.5 Hz,
3-H), 1.67–0.82 (6H, m, 8-Ph-Men-H), 1.54 (9H, s, t-Bu), 1.42
(3H, s, 8-Ph-Men-CH3), 1.24 (3H, s, 8-Ph-Men-CH3), 0.90 (3H, d,
J = 7.0 Hz, 8-Ph-Men-CH3); dC (68 MHz, CDCl3, CHCl3) 167.2,
166.2, 151.5, 141.0, 138.8, 137.8, 132.2, 131.9, 130.6, 128.6, 128.3,
128.2, 127.6, 126.8, 125.9, 125.8, 125.5, 125.4, 80.4, 77.4, 72.1,
49.8, 44.1, 40.0, 39.8, 35.8, 34.6, 31.5, 28.2, 27.5, 27.3, 26.5, 22.3,
21.9.
(2R)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethyla-
minopent-4-enoic acid (-)-8-phenylmenthol ester [(R)-7d]
White solid (found: C, 77.0; H, 9.15; N,◦2.4. Calc. for C35H49NO4:
2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-3-(4¢¢-cyanophenyl)-2-
dimethylaminopropionic acid (-)-8-phenylmenthol ester
[11 (major isomer)]
24
589
C, 76.7; H, 9.0; N, 2.6%); mp 140–143 C; [a] +12.4 (c 1.00 in
CHCl3); vmax(film)/cm-1 3064, 2952, 2872, 2796, 1712, 1608, 1454,
1392, 1368, 1304, 1256, 1218, 1162, 1140, 990, 956, 912, 850, 756,
700; dH (270 MHz, CDCl3, Me4Si) 8.21 (1H, d, J = 1.9 Hz, Ar-H),
7.71 (1H, dd, J = 7.8, 1.9 Hz, Ar-H), 7.40–7.20 (4H, m, Ar-H),
7.18–7.08 (2H, m, Ar-H), 5.38 (1H, ddt, J = 17.0, 10.5, 6.8 Hz,
4-H), 4.96 (1H, td, J = 10.5, 4.2 Hz, COOCH), 4.81 (1H, dd, J =
10.5, 1.4 Hz, 5-H), 4.74 (1H, dd, J = 17.0, 1.4 Hz, 5-H), 2.61 (1H,
dd, J = 15.8, 7.0 Hz, 3-H), 2.40–2.12 (2H, m, 8-Ph-Men-H), 2.33
(6H, s, (CH3)2N), 2.28 (3H, s, Ar-CH3), 1.97 (1H, dd, J = 15.8,
6.2 Hz, 3-H), 1.67–0.78 (6H, m, 8-Ph-Men-H), 1.58 (9H, s, t-Bu),
1.40 (3H, s, 8-Ph-Men-CH3), 1.22 (3H, s, 8-Ph-Men-CH3), 0.89
(3H, d, J = 5.9 Hz, 8-Ph-Men-CH3); dC (68 MHz, CDCl3, CHCl3)
167.3, 166.3, 151.4, 141.1, 138.9, 133.6, 131.8, 130.6, 128.6, 128.2,
127.5, 125.5, 125.3, 117.1, 80.4, 77.3, 71.7, 49.8, 44.1, 40.0, 39.7,
36.7, 34.6, 31.5, 28.2, 27.5, 27.3, 26.5, 22.3, 21.9.
White solid (found: C, 77.1; H, 8.4; N, 4.2. Calc. for C40H50N2O4:
◦
23
589
C, 77.1; H, 8.1; N, 4.5%); mp 88–91 C; [a] +126.1 (c 1.00 in
CHCl3); vmax(film)/cm-1 3052, 2960, 2868, 2796, 2224, 1710, 1608,
1454, 1392, 1368, 1304, 1266, 1208, 1178, 1160, 1130, 1000, 954,
898, 850, 824, 762, 734, 700; dH (270 MHz, CDCl3, Me4Si) 7.57
(1H, dd, J = 7.8, 1.6 Hz, Ar-H), 7.431 (1H, d, J = 1.6 Hz, Ar-
H), 7.430 (2H, d, J = 7.8 Hz, Ar-H), 7.28–7.16 (4H, m, Ar-H),
7.04 (1H, d, J = 8.1 Hz, Ar-H), 6.92 (1H, t, J = 7.2 Hz, Ar-H),
6.58 (2H, d, J = 7.8 Hz, Ar-H), 5.01 (1H, td, J = 10.5, 3.8 Hz,
COOCH), 3.03 (1H, d, J = 15.1 Hz, CH2Ar), 2.47–2.21 (2H, m,
CH2Ar and 8-Ph-Men-H), 2.40 (6H, s, (CH3)2N), 2.15 (3H, s, Ar-
CH3), 1.87–1.67 (3H, m, 8-Ph-Men-H), 1.51 (9H, s, t-Bu), 1.47
(3H, s, 8-Ph-Men-CH3), 1.33–0.85 (4H, m, 8-Ph-Men-H), 1.20
(3H, s, 8-Ph-Men-CH3), 0.94 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3);
dC (68 MHz, CDCl3, CHCl3) 167.0, 165.6, 151.9, 142.7, 141.0–
140.7 (m), 137.1, 131.6, 131.3, 131.1, 130.7, 128.3, 128.2, 127.4,
125.4, 125.3, 119.0, 109.5, 80.4, 77.8, 49.1, 43.9, 40.28, 40.23, 39.7,
36.9–36.6 (m), 34.6, 31.5, 29.4, 28.1, 26.9, 24.9, 22.1, 22.0.
(2S)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethyla-
minopent-4-enoic acid (-)-8-phenylmenthol ester [(S)-7d]
White solid (found: C, 77.0; H, 9.1; N,◦2.6. Calc. for C35H49NO4:
22
589
C, 76.7; H, 9.0; N, 2.6%); mp 45–47 C; [a] -36.1 (c 1.00 in
CHCl3); vmax(film)/cm-1 3052, 2956, 2924, 2868, 2788, 1708, 1610,
1454, 1390, 1368, 1302, 1278, 1254, 1190, 1164, 1138, 982, 952,
912, 850, 760, 736, 700; dH (270 MHz, CDCl3, Me4Si) 7.90 (1H, d,
J = 1.6 Hz, Ar-H), 7.69 (1H, dd, J = 7.8, 1.6 Hz, Ar-H), 7.28–7.07
(6H, m, Ar-H), 5.52 (1H, ddt, J = 16.9, 10.4, 6.9 Hz, 4-H), 5.00
(1H, td, J = 10.4, 3.8 Hz, COOCH), 4.79 (1H, d, J = 16.9 Hz,
5-H), 4.77 (1H, d, J = 10.4 Hz, 5-H), 2.82–2.61 (2H, m, 3-H),
2.51 (3H, s, Ar-H), 2.48–2.26 (1H, m, 8-Ph-Men-H), 2.37 (6H, s,
2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-3-(4¢¢-cyanophenyl)-2-
dimethylaminopropionic acid (-)-8-phenylmenthol ester
[11 (minor isomer)]
White solid (elemental analysis was not performed due to the
◦
23
589
small amount); mp 65–68 C; [a] -55.9 (c 1.00 in CHCl3);
v
max(film)/cm-1 3048, 2952, 2920, 2792, 2224, 1708, 1608, 1494,
1456, 1392, 1368, 1300, 1266, 1178, 1132, 1050, 1002, 952, 930,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3673–3680 | 3677
©

View Article Online
906, 848, 762, 736, 700; dH (270 MHz, CDCl3, Me4Si) 7.60 (1H,
dd, J = 7.8, 1.6 Hz, Ar-H), 7.43 (1H, s, Ar-H), 7.26 (2H, d, J =
8.1 Hz, Ar-H), 7.20–7.10 (4H, m, Ar-H), 7.09–6.96 (1H, m, Ar-H),
7.00 (1H, d, J = 7.8 Hz, Ar-H), 6.77 (2H, d, J = 8.1 Hz, Ar-H), 4.91
(1H, td, J = 10.4, 3.8 Hz, COOCH), 3.27 (1H, d, J = 13.8 Hz,
CH2Ar), 3.11 (1H, d, J = 13.8 Hz, CH2Ar), 2.62–2.51 (1H, m,
8-Ph-Men-H), 2.45 (6H, s, (CH3)2N), 2.16 (3H, s, Ar-CH3), 2.12–
1.98 (1H, m, 8-Ph-Men-H), 1.64–1.44 (2H, m, 8-Ph-Men-H), 1.52
(9H, s, t-Bu), 1.37–0.76 (4H, m, 8-Ph-Men-H), 1.21 (3H, s, 8-Ph-
Men-CH3), 1.05 (3H, s, 8-Ph-Men-CH3), 0.93 (3H, d, J = 5.9 Hz,
8-Ph-Men-CH3); dC (68 MHz, CDCl3, CHCl3) 169.4, 165.2, 151.2,
143.2, 136.8, 132.2, 131.7, 131.0, 130.7, 128.8, 128.5, 128.0, 127.7,
125.3, 125.2, 119.1, 109.6, 80.7, 78.9, 50.9, 42.3, 41.8, 40.0, 34.6,
31.6, 28.9, 28.13, 28.10, 27.8, 26.9, 24.0, 21.9, 20.9.
7.09 (6H, m, Ar-H), 4.88 (1H, td, J = 10.5, 4.3 Hz, COOCH), 2.61
(2.7H, s, Ar-CH3), 2.45 (0.3H, s, Ar-CH3), 2.29 (0.6H, s, (CH3)2N),
2.23 (5.4H, s, (CH3)2N), 2.14–2.00 (0.2H, m, 8-Ph-Men-H), 2.00–
1.85 (0.9H, m, 8-Ph-Men-H), 1.79–1.67 (0.9H, m, 8-Ph-Men-H),
1.56–0.83 (5H, m, 8-Ph-Men-H), 1.34 (3H, s, 8-Ph-Men-CH3),
1.19 (6H, s, 3-H and 8-Ph-Men-CH3), 0.78 (3H, d, J = 6.5 Hz, 8-
Ph-Men-CH3), 0.66 (1H, td, J = 12.0, 11.1 Hz, 8-Ph-Men-H); dC
(68 MHz, CDCl3, CHCl3) 171.6, 150.8, 144.2, 141.8, 133.1, 131.7,
130.4, 128.1, 125.5, 125.3, 119.2, 109.4, 76.5, 70.5, 49.7, 41.1, 40.0,
39.7, 34.2, 31.2, 28.4, 27.2, 25.2, 21.7, 21.6, 16.3.
2-(3¢-Cyano-2¢-methylphenyl)-2-dimethylaminopropionic acid
(-)-8-phenylmenthol ester (13c)
(2S) : (2R) = 6 : 1 mixture; colorless gum (found: C, 77.7; H, 8.8; N,
6.1. Calc. for C29H38N2O2: C, 78.0; H, 8.6; N, 6.3%); vmax(film)/cm-1
3052, 2948, 2868, 2784, 2220, 1716, 1598, 1440, 1370, 1264, 1224,
1182, 1154, 1110, 1088, 1048, 974, 908, 846, 764, 734, 700; dH
(270 MHz, CDCl3, Me4Si) 7.76 (0.14H, d, J = 8.1 Hz, Ar-H), 7.56–
7.44 (1.86H, m, Ar-H), 7.33–7.06 (6H, m, Ar-H), 4.89 (1H, td, J =
10.5, 4.3 Hz, COOCH), 2.81 (2.58H, s, Ar-CH3), 2.62 (0.42H, s,
Ar-CH3), 2.28 (0.84H, s, (CH3)2N), 2.25 (5.16H, s, (CH3)2N), 2.14–
1.96 (0.28H, m, 8-Ph-Men-H), 1.95–1.74 (1.72H, m, 8-Ph-Men-
H), 1.62–0.83 (5H, m, 8-Ph-Men-H), 1.39 (3H, s, 8-Ph-Men-CH3),
1.20 (3H, s, 3-H or 8-Ph-Men-CH3), 1.19 (3H, s, 3-H or 8-Ph-Men-
CH3), 0.80 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3), 0.69 (1H, q, J =
11.5 Hz, 8-Ph-Men-H); dC (68 MHz, CDCl3, CHCl3) 171.9, 150.8,
142.2, 142.1, 132.0, 131.7, 128.1, 125.9, 125.5, 125.3, 118.6, 115.4,
76.7, 70.8, 49.9, 40.0, 39.8, 39.7, 34.2, 31.2, 28.8, 27.3, 24.7, 21.8,
19.0, 17.3.
Representative procedure for the diastereoselective Sommelet–
Hauser rearrangement of N-benzylic a-alkyl amino acid-derived
ammonium salt
A solution of L-12a (97 mg, 0.16 mmol) in THF (1.6 mL) was
cooled to -60 ◦C and treated with a 1.0 M THF solution of
potassium tert-butoxide (0.27 mL, 0.27 mmol). The mixture was
stirred for 6 h at the same temperature under an argon atmosphere.
The resulting mixture was added to stirred ice-cold saturated
aqueous ammonium chloride and the mixture was extracted with
ether. The combined extracts were washed with saturated aqueous
sodium hydrogen carbonate and brine, dried over sodium sulfate,
and concentrated. Purification of the residue by chromatography
on silica gel (dichloromethane–methanol = 30 : 1 to 10 : 1 as the
eluent) gave 13a (67 mg, 80% yield) as a white solid.
(2S)-2-(5¢-tert-Butoxycarbonyl-2¢-methylphenyl)-2-dimethylamin-
opropionic acid (-)-8-phenylmenthol ester (13a)
(2S)-2-(4¢-Cyano-2¢-methylphenyl)-2-dimethylaminopropionic acid
(-)-8-phenylmenthol ester (13d)
White solid (found: C, 76.2; H, 9.2; N, ◦2.55. Calc. for C33H47NO4:
Colorless gum (found: C,78.3; H, 8.7; N, 6.1. Calc. for C29H38N2O2:
23
589
25
C, 76.0; H, 9.1; N, 2.7%); mp 41–44 C; [a] +24.5 (c 1.00 in
C, 78.0; H, 8.6; N, 6.3%); [a]
-19.6 (c 1.00 in CHCl3);
589
CHCl3); vmax(film)/cm-1 2952, 2784, 1708, 1608, 1452, 1392, 1368,
1304, 1276, 1244, 1222, 1166, 1142, 1086, 1050, 976, 954, 918,
848, 752, 700; dH (270 MHz, CDCl3, Me4Si) 7.94 (1H, d, J =
1.6 Hz, Ar-H), 7.73 (1H, dd, J = 7.7, 1.6 Hz, Ar-H), 7.30–7.20
(4H, m, Ar-H), 7.18–7.10 (2H, m, Ar-H), 4.91 (1H, td, J = 10.5,
4.6 Hz, COOCH), 2.61 (3H, s, Ar-CH3), 2.24 (6H, s, (CH3)2N),
1.94–1.74 (2H, m, 8-Ph-Men-H), 1.60 (9H, s, t-Bu), 1.53–1.17 (3H,
m, 8-Ph-Men-H), 1.44 (3H, s, 8-Ph-Men-CH3), 1.22 (6H, s, 3-H
and 8-Ph-Men-CH3), 1.02–0.83 (2H, m, 8-Ph-Men-H), 0.77 (3H,
d, J = 6.2 Hz, 8-Ph-Men-CH3), 0.68 (1H, td, J = 12.2, 11.1 Hz,
8-Ph-Men-H); dC (68 MHz, CDCl3, CHCl3) 172.4, 165.9, 151.0,
143.4, 140.4, 132.3, 129.2, 128.9, 128.0, 127.9, 125.6, 125.3, 80.6,
76.0, 70.7, 49.9, 41.1, 40.1, 39.8, 34.3, 31.2, 29.2, 28.2, 27.3, 24.5,
21.7, 21.3, 16.7.
v
max(film)/cm-1 2948, 2868, 2784, 2224, 1714, 1600, 1492, 1444,
1368, 1264, 1222, 1178, 1090, 1046, 974, 952, 886, 844, 758, 734,
698; dH (500 MHz, DMSO-d6, Me4Si) 7.65 (1H, d, J = 8.5 Hz,
Ar-H), 7.63 (1H, s, Ar-H), 7.44 (1H, d, J = 8.5 Hz, Ar-H), 7.30–
7.19 (4H, m, Ar-H), 7.13 (1H, t, J = 6.5 Hz, Ar-H), 4.76 (1H, td,
J = 10.3, 4.0 Hz, COOCH), 2.51 (3H, s, Ar-CH3), 2.16 (6H, s,
(CH3)2N), 1.90 (1H, td, J = 11.3, 3.0 Hz, 8-Ph-Men-H), 1.72–1.64
(1H, m, 8-Ph-Men-H), 1.48–1.41 (1H, m, 8-Ph-Men-H), 1.40–
1.20 (2H, m, 8-Ph-Men-H), 1.34 (3H, s, 8-Ph-Men-CH3), 1.14
(3H, s, 3-H or 8-Ph-Men-CH3), 1.13 (3H, s, 3-H or 8-Ph-Men-
CH3), 0.99–0.89 (1H, m, 8-Ph-Men-H), 0.75 (3H, d, J = 6.5 Hz,
8-Ph-Men-CH3), 0.73–0.64 (2H, m, 8-Ph-Men-H); dC (68 MHz,
CDCl3, CHCl3) 171.6, 150.8, 145.9, 139.5, 135.6, 129.2 128.5,
128.1, 125.5, 125.3, 118.8, 110.9, 76.6, 70.9, 49.8, 41.1, 40.0, 39.7,
34.2, 31.2, 28.8, 27.3, 24.8, 21.7, 21.1, 16.9.
2-(5¢-Cyano-2¢-methylphenyl)-2-dimethylaminopropionic acid
(-)-8-phenylmenthol ester (13b)
(2S)-2-Dimethylamino-2-(5¢-methoxycarbonyl-2¢-methylphenyl)-
propionic acid (-)-8-phenylmenthol ester (13e)
(2S) : (2R) = 9 : 1 mixture; colorless gum (found: C, 78.2; H, 8.8; N,
6.0. Calc. for C29H38N2O2: C, 78.0; H, 8.6; N, 6.3%); vmax(film)/cm-1
2948, 2868, 2784, 2224, 1718, 1600, 1488, 1444, 1370, 1226, 1204,
1162, 1086, 1048, 974, 952, 904, 820, 764, 732, 698; dH (270 MHz,
CDCl3, Me4Si) 7.87 (0.1H, d, J = 1.6 Hz, Ar-H), 7.59 (0.9H, d,
J = 1.6 Hz, Ar-H), 7.42 (1H, dd, J = 7.8, 1.6 Hz, Ar-H), 7.33–
Colorless gum (found: C, 75.4; H, 8.8; N, 2.9. Calc. for C30H41NO4:
25
589
C, 75.1; H, 8.6; N, 2.9%); [a]
v
+11.2 (c 1.00 in CHCl3);
max(film)/cm-1 3048, 2948, 2780, 1720, 1608, 1572, 1492, 1434,
1370, 1296, 1266, 1242, 1218, 1172, 1108, 1050, 972, 906, 834,
756, 698; dH (270 MHz, CDCl3, Me4Si) 7.93 (1H, s, Ar-H), 7.81
3678 | Org. Biomol. Chem., 2008, 6, 3673–3680
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
(1H, dd, J = 8.0, 1.6 Hz, Ar-H), 7.31–7.10 (6H, m, Ar-H), 4.94
(1H, td, J = 10.5, 4.6 Hz, COOCH), 3.90 (3H, s, COOCH3),
2.63 (3H, s, Ar-CH3), 2.26 (6H, s, (CH3)2N), 1.98–1.81 (2H, m,
8-Ph-Men-H), 1.56–1.15 (3H, m, 8-Ph-Men-H), 1.44 (3H, s, 8-Ph-
Men-CH3), 1.23 (6H, s, 3-H and 8-Ph-Men-CH3), 1.07–0.60 (3H,
m, 8-Ph-Men-H), 0.80 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3); dC
(68 MHz, CDCl3, CHCl3) 172.5, 167.1, 150.9, 143.9, 140.8, 132.7,
128.8, 128.2, 128.0, 127.4, 125.5, 125.3, 76.2, 71.0, 51.9, 49.8, 41.2,
40.1, 39.7, 34.3, 31.2, 29.1, 27.3, 24.6, 21.8, 21.4, 17.6.
2-(4¢-tert-Butoxycarbonylbenzyl)-2-dimethylaminopent-4-enoic
acid (-)-8-phenylmenthol ester (16)
3 : 2 Mixture of stereoisomers; white solid (found: C, 76.45;
H, 9.0; N, 2.5. Calc. for C35H49NO4: C, 76.7; H, 9.0; N, 2.6%);
v
max(film)/cm-1 3056, 2952, 2868, 2788, 1708, 1610, 1454, 1390,
1368, 1292, 1254, 1210, 1168, 1116, 1046, 1020, 956, 910, 848,
732, 700; dH (270 MHz, CDCl3, Me4Si) 7.87 (0.8H, d, J =
8.4 Hz, Ar-H), 7.86 (1.2H, d, J = 8.4 Hz, Ar-H), 7.33–7.02 (7H,
=
m, Ar-H), 5.94–5.66 (1H, m, CH2CH CH2), 5.18–4.84 (3H, m,
=
CH2CH CH2 and COOCH), 3.38 (0.4H, d, J = 13.5 Hz, CH2Ar),
(2S)-2-Dimethylamino-2-(2¢-methyl-5¢-trifluoromethylphenyl)-
propionic acid (-)-8-phenylmenthol ester (13f)
2.92 (0.6H, d, J = 14.3 Hz, CH2Ar), 2.71 (0.6H, d, J = 14.3 Hz,
CH2Ar), 2.66 (0.4H, d, J = 13.5 Hz, CH2Ar), 2.46 (0.6H, dd, J =
=
14.7, 6.6 Hz, CH2CH CH2), 2.39 (3.6H, s, (CH3)2N), 2.37 (2.4H, s,
Colorless gum (found: C, 71.35; H, 7.9; N, 2.8. Calc. for
C29H38F3NO2: C, 71.1; H, 7.8; N, 2.9%); [a]25869 -14.5 (c 1.00 in
CHCl3); vmax(film)/cm-1 2952, 2870, 2784, 1718, 1618, 1598, 1494,
1452, 1406, 1370, 1328, 1288, 1220, 1162, 1120, 1050, 976, 954,
904, 824, 760, 736, 698; dH (270 MHz, CDCl3, Me4Si) 7.52 (1H, s,
Ar-H), 7.38 (1H, d, J = 7.8 Hz, Ar-H), 7.32–7.10 (6H, m, Ar-H),
4.93 (1H, td, J = 10.5, 4.3 Hz, COOCH), 2.62 (3H, s, Ar-CH3), 2.28
(6H, s, (CH3)2N), 1.99–1.83 (2H, m, 8-Ph-Men-H), 1.60–1.15 (3H,
m, 8-Ph-Men-H), 1.40 (3H, s, 8-Ph-Men-CH3), 1.21 (3H, s, 3-H or
8-Ph-Men-CH3), 1.20 (3H, s, 3-H or 8-Ph-Men-CH3), 1.05–0.63
(3H, m, 8-Ph-Men-H), 0.80 (3H, d, J = 6.2 Hz, 8-Ph-Men-CH3);
dC (68 MHz, CDCl3, CHCl3) 172.2, 150.9, 142.2 (q, J = 1 Hz),
141.5, 132.9, 128.0, 127.7 (q, J = 32 Hz), 125.5, 125.3, 124.6 (q,
J = 4 Hz), 124.4 (d, J = 270 Hz), 123.7 (q, J = 4 Hz), 76.5, 71.1,
49.8, 41.2, 40.1, 39.7, 34.3, 31.2, 28.9, 27.3, 24.7, 21.6, 21.3, 17.9.
=
(CH3)2N), 2.23 (0.4H, dd, J = 16.2, 6.9 Hz, CH2CH CH2), 2.15–
=
1.93 (2.6H, m, CH2CH CH2 and 8-Ph-Men-H), 1.82 (0.4H, dd,
J = 16.2, 6.1 Hz, CH2CH CH2), 1.68–0.68 (6H, m, 8-Ph-Men-H),
=
1.58 (5.4H, s, t-Bu), 1.57 (3.6H, s, t-Bu), 1.36 (1.2H, s, 8-Ph-Men-
CH3), 1.21 (1.8H, s, 8-Ph-Men-CH3), 1.09 (1.2H, s, 8-Ph-Men-
CH3), 1.02 (1.8H, s, 8-Ph-Men-CH3), 0.87 (1.2H, d, J = 7.8 Hz,
8-Ph-Men-CH3), 0.85 (1.8H, d, J = 6.5 Hz, 8-Ph-Men-CH3); dC
(68 MHz, CDCl3, CHCl3) 171.9 (0.6C), 171.1 (0.4C), 165.8 (1.0C),
151.10 (0.4C), 151.08 (0.6C), 142.7 (0.4C), 142.5 (0.6C), 134.0
(0.6C), 133.5 (0.4C), 130.8 (0.8C), 130.7 (1.2C), 130.1 (0.4C), 129.9
(0.6C), 129.0 (0.8C), 128.8 (1.2C), 128.1 (1.2C), 128.0 (0.8C), 125.5
(1.2C), 125.4 (0.8C), 125.2 (0.6C), 125.1 (0.4C), 118.3 (0.6C), 118.0
(0.4C), 80.68 (0.4C), 80.64 (0.6C), 76.73 (0.4C), 76.65 (0.6C), 68.4
(0.4C), 68.2 (0.6C), 49.6 (0.4C), 49.5 (0.6C), 43.0 (0.4C), 42.4
(0.6C), 40.0 (0.6C), 39.8 (0.4C), 39.7 (1.2C), 39.5 (0.8C), 37.9
(0.4C), 36.8 (0.6C), 36.0 (0.6C), 34.5 (0.4C), 34.4 (0.6C), 34.1
(0.4C), 31.4 (0.4C), 31.3 (0.6C), 28.2 (3.0C), 28.1 (0.6C), 27.7
(0.4C), 27.2 (0.6C), 27.1 (0.4C), 26.0 (0.6C), 25.7 (0.4C), 21.83
(0.4C), 21.77 (0.6C).
2-Dimethylamino-2-methyl-3-phenylpropionic acid
(-)-8-phenylmenthol ester ([1,2] Stevens rearrangement product
in Table 2, entries 6 and 7)
2 : 1 Mixture of stereoisomers; colorless oil (found: C, 79.7;
H, 9.6; N, 3.3. Calc. for C28H39NO2: C, 79.8; H, 9.3; N, 3.3%);
v
Acknowledgements
max(film)/cm-1 3052, 2948, 2868, 2784, 1708, 1600, 1492, 1452,
1370, 1260, 1212, 1154, 1130, 1088, 1046, 1030, 978, 958, 906, 844,
762, 740, 696; dH (270 MHz, CDCl3, Me4Si) 7.43–7.05 (10H, m,
Ar-H), 4.99–4.81 (1H, m, COOCH), 3.26 (0.33H, d, J = 13.1 Hz,
CH2Ph), 2.89 (0.67H, d, J = 13.6 Hz, CH2Ph), 2.70 (0.33H, d,
J = 13.1 Hz, CH2Ph), 2.66 (0.67H, d, J = 13.6 Hz, CH2Ph), 2.40
(1.98H, s, (CH3)2N), 2.38 (4.02H, s, (CH3)2N), 2.17–1.85 (1.33H,
m, 8-Ph-Men-H), 1.85–1.70 (0.67H, m, 8-Ph-Men-H), 1.57–1.15
(3H, m, 8-Ph-Men-H), 1.35 (2H, s, 2-CH3 or 8-Ph-Men-CH3),
1.21 (2H, s, 2-CH3 or 8-Ph-Men-CH3), 1.10–0.58 (3H, m, 8-Ph-
Men-H), 1.07 (1H, s, 2-CH3 or 8-Ph-Men-CH3), 1.04 (2H, s, 2-
CH3 or 8-Ph-Men-CH3), 0.99 (1H, s, 2-CH3 or 8-Ph-Men-CH3),
0.95 (1H, s, 2-CH3 or 8-Ph-Men-CH3), 0.85 (1H, d, J = 5.9 Hz,
8-Ph-Men-CH3), 0.81 (2H, d, J = 6.5 Hz, 8-Ph-Men-CH3); dC
(68 MHz, CDCl3, CHCl3) 173.4 (0.67C), 172.2 (0.33C), 151.1
(0.67C), 151.0 (0.33C), 137.6 (0.33C), 137.4 (0.67C), 131.0 (0.66C),
130.9 (1.34C), 128.1 (1.34C), 127.9 (0.66C), 127.9 (0.66C), 127.7
(1.34C), 126.3 (0.33C), 126.2 (0.67C), 125.5 (1.34C), 125.4 (0.66C),
125.3 (0.67C), 125.1 (0.33C), 76.1 (0.33C), 75.8 (0.67C), 66.2
(0.33C), 66.0 (0.67C), 42.7 (0.33C), 42.0 (0.33C), 41.9 (0.67C), 41.7
(0.67C), 40.03 (0.67C), 39.98 (0.33C), 39.7 (1.33C), 39.6 (0.67C),
34.4 (0.33C), 34.3 (0.67C), 31.4 (0.33C), 31.2 (0.67C), 28.9 (0.33C),
28.4 (0.67C), 27.2 (0.33C), 27.1 (0.67C), 25.5 (0.67C), 24.4 (0.33C),
21.8 (0.33C), 21.7 (0.67C), 18.8 (0.67C), 18.5 (0.33C).
This work was supported by a Grant-in-Aid for Young Scientists
(19750029) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan and The Asahi Glass Foundation.
Notes and references
1 For a review, see: C. Spino, Angew. Chem., Int. Ed., 2004, 43, 1764 and
references therein.
2 Previous examples of optically active a-quaternary a-aryl amino
nitriles by asymmetric cyanation of ketoimines: J. Wang, X. Hu, J.
Jiang, S. Gou, X. Huang, X. Liu and X. Feng, Angew. Chem., Int. Ed.,
2007, 46, 8468; J. Huang, X. Liu, Y. Wen, B. Qin and X. Feng, J. Org.
Chem., 2007, 72, 204; N. Kato, T. Mita, M. Kanai, B. Therrien, M.
Kawano, K. Yamaguchi, H. Danjo, Y. Sei, A. Sato, S. Furusho and M.
Shibasaki, J. Am. Chem. Soc., 2006, 128, 6768; X. Huang, J. Huang,
Y. Wen and X. Feng, Adv. Synth. Catal., 2006, 348, 2579; N. Kato,
M. Suzuki, M. Kanai and M. Shibasaki, Tetrahedron Lett., 2004, 45,
3153; N. Kato, M. Suzuki, M. Kanai and M. Shibasaki, Tetrahedron
Lett., 2004, 45, 3147; S. Masumoto, H. Usuda, M. Suzuki, M. Kanai
and M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 5634; P. Vachal and
E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 10012; P. Vachal and
E. N. Jacobsen, Org. Lett., 2000, 2, 867; J. J. Byrne, M. Chavarot, P.-Y.
Chavant and Y. Valle´e, Tetrahedron Lett., 2000, 41, 873.
3 E. Tayama and H. Kimura, Angew. Chem., Int. Ed., 2007, 46, 8869.
4 For reviews, see: I. E. Marko´, in Comprehensive Organic Synthesis, ed.
B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 3, chap. 3.10;
J. A. Vanecko, H. Wan and F. G. West, Tetrahedron, 2006, 62, 1043.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3673–3680 | 3679
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5 Recent examples of base-induced diastereoselective Stevens and
Sommelet–Hauser rearrangements: J. B. Sweeney, A. Tavassoli and
J. A. Workman, Tetrahedron, 2006, 62, 11506; S. Hanessian, C. Talbot
and P. Saravanan, Synthesis, 2006, 723; E. Tayama, S. Nanbara and T.
Nakai, Chem. Lett., 2006, 35, 478; J. A. Workman, N. P. Garrido, J.
Sanc¸on, E. Roberts, H. P. Wessel and J. B. Sweeney, J. Am. Chem. Soc.,
2005, 127, 1066.
position was determined as R because the absolute configuration of the
Z-isomer 8b was determined as R by a single crystal X-ray diffraction
(see ref. 10). For experimental details, see the ESI†.
10 The absolute configuration of 8b at the a-position was determined as
R by a single crystal X-ray diffraction. CCDC-693575 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
6 For details, see the ESI†.
7 The absolute configurations at the a-position of 7, 8, and 13 were
determined by analogy between their 1H NMR chemical shifts and
those of such known compounds as (2R)-8a and (2R)-8b. For more
details, see the ESI†.
8 The absolute configurations at the b-position of 7a and 7b were not
determined.
11 The absolute configuration of the a-benzylic product 11 at the a-
position was not determined.
12 The geometries of the carbonyl-stabilized ammonium ylides were
similar to those of phosphonium ylides, see: N. A. Bailey, S. E.
Hull, G. F. Kersting and J. Morrison, J. Chem. Soc. D, 1971,
1429.
9 Hydrogenation of 8a afforded the corresponding reduced compound
(a-n-butyl derivative) as a single stereoisomer. Thus, 8a was found to be
a 1 : 1 mixture of E- and Z-isomer. The absolute configuration at the a-
13 The assignment of the 2,4-disubstituted regioisomer 13d was made by
1H NMR analysis; 13d showed a singlet peak for an aromatic proton
(3-H: dH 7.63 in DMSO-d6).
3680 | Org. Biomol. Chem., 2008, 6, 3673–3680
This journal is
The Royal Society of Chemistry 2008
©