Efficient solution phase parallel synthesis of norstatine analogs

Article abstract of DOI:10.1016/j.tet.2004.07.085

The reaction of glycidic amides with various functionalized nitriles to afford norstatine analogs in a regio- and diastereoselective fashion (43-99% yield) is described. Utilizing this chemistry, a 20 membered solution phase library was prepared in two st

Full text of DOI:10.1016/j.tet.2004.07.085

Tetrahedron 60 (2004) 9043–9048
Efficient solution phase parallel synthesis of norstatine analogs
b
c
a
Michael V. Voronkov,a, Alexander V. Gontcharov, Zhi-Min Wang, Paul F. Richardson
*
and Hartmuth C. Kolbd
aMedicinal Chemistry, Lexicon Pharmaceuticals, 350 Carter Road, Princeton, NJ 08540, USA
bWyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965, USA
cRhodia Chirex, 56 Roland Street, Boston, MA 02129, USA
dDepartment of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 8 April 2004; revised 29 June 2004; accepted 29 July 2004
Available online 27 August 2004
Abstract—The reaction of glycidic amides with various functionalized nitriles to afford norstatine analogs in a regio- and diastereoselective
fashion (43–99% yield) is described. Utilizing this chemistry, a 20 membered solution phase library was prepared in two steps featuring three
points of diversity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
describe the preparation of a small library of norstatine
analogs.4
Since the discovery of the inhibitory activity of (hydroxy-
methyl)carbonyl isosteres against aspartyl proteases, the
norstatine analogs 1 have become a popular target for
medicinal chemists.1,2 Amongst the various synthetic
approaches to these analogs, the reaction of glycidic esters
3 with acetonitrile to afford the desired 3-N-acylamino-2-
hydroxy compounds 2 via the oxazoline intermediate 4,
appears to be the most straightforward (Fig. 1).3 Surpris-
ingly, the scope of this reaction has been largely unexplored:
glycidic esters have been reported to react with only a few
simple unfunctionalized nitriles (i.e. acetonitrile and
propionitrile), and only a single glycidic amide3c has been
described as an alternative to the ester. However, in all of
the published examples, the transformation proceeds with
remarkably high regio- and diastereoselectivity, which
would be a crucial feature for the efficient preparation of a
diverse solution phase library. Herein, we present our
investigations into expanding the reaction scope and
2. Results and discussion
2.1. Chemical approaches
Our initial approach to the library synthesis was based on
the results published by Zvonkova and others.3 For our
initial synthetic studies, we used racemic glycidic acid 5a
available via a simple mCPBA epoxidation of the
commercially available olefin.5 When the epoxy-acid 5a
reacted with acetonitrile in the presence of an excess of
BF3$OEt2, the corresponding 3-N-acyl-2-hydroxyacid 6a
was isolated upon base hydrolysis of the oxazoline 4a
(Fig. 2). We found that this transformation can be efficiently
performed using only a single equivalent of the nitrile and
also that a number of functionalities on the nitrile are
tolerated. However, numerous attempts to couple the
Figure 1. Proposed synthesis of norstatine analogues.
Keywords: Epoxide; Nitrile; Norstatine; Solution phase combinatorial chemistry.
* Corresponding author. Tel.: C1-609-466-5500; fax: C1-609-466-3562; e-mail: mvoronkov@lexpharma.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.085

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M. V. Voronkov et al. / Tetrahedron 60 (2004) 9043–9048
Figure 2. Initial route to norstatine analogues.
product 6a with amines in the presence of resin-bound DCC
and HOBt according to published procedures6,7 failed to
produce the desired norstatine analog 1.
We then studied the influence of various conditions on the
epoxide opening of glycidic amides 7 and 8. Use of a
stoichiometric amount of BF3$OEt2 and nitrile in
dichloroethane afforded 1 in low yield accompanied by
considerable amounts of recovered starting material. This
can be rationalized by formation of an amine–borane
complex, leaving only a small amount of the uncomplexed
Lewis acid available in solution to mediate the desired
transformation.
To circumvent the deleterious influence of the functional-
ities in 6 on the DCC coupling step, the sequence of steps
was reversed (Fig. 3). The amides 7 and 8 were prepared in
35–81% yields (Table 1) from the epoxy-acids 5 and the
corresponding amines via resin-bound DCC coupling in the
presence of HOBt.
In addition, the nitrile opening of the glycidic amides 7 and
8 mediated by an excess of BF3$OEt2 proceeded consider-
ably more slowly than the previously examined reactions of
the glycidic acids 5. The desired products 1 were isolated in
low yields, after NaHCO3 hydrolysis3cof the oxazoline
intermediates, and no starting material was detected in the
reaction mixture. This suggested that competing reactions
such as the facile opening of the epoxide by other
nucleophiles present in the reaction mixture such as traces
of water were effectively competing with the desired
reaction leading to the observed attrition in yield. In fact,
Figure 3. Resin bound amide bond formation.
Table 1. Preparation of glycidic amides 7 and 8
Entry
Product
Epoxide
NHR3R4
Yield (%)
74
1
7a
5a
2
3
7b
7c
5a
5a
81
62
4
7d
5a
35
5
6
8a
8b
5b
5b
66
85
7
8
8c
5b
5b
48
8d
Traces

M. V. Voronkov et al. / Tetrahedron 60 (2004) 9043–9048
9045
2.2. Library synthesis and analysis
For library preparation, chiral glycidic amides 7a,b and 8b,c
were prepared from commercial optically active precursors.
The reaction of these glycidic amides with a series of nitriles
in dichloroethane in the presence of the excess BF3$OEt2
afforded the desired products 1 (Table 2). The adducts
formed utilizing cyclohexanecarbonitrile and acetonitrile
were isolated by simple removal of excess reagent under
reduced pressure. When non-volatile nitriles were used, the
final products were captured on acidic SCX resin and then
released with methanolic ammonia to afford 1 in yields
ranging from 43–99%. Generally, secondary amides gave
both higher yield and purity than tertiary amides. Amongst
the tertiary amides, both glycidic amides 7d and 8d gave
low purity of the corresponding products 1, and as such were
discarded. As expected, adducts of chiral nitriles (entries 4,
10 and 15) were obtained as equimolar mixtures of
diastereomers. Similarly, adducts of glycidic amide 7a
also afforded diastereomeric mixtures.
Figure 4. Synthesis of a library of norstatine analogues.
LC/MS analysis identified the corresponding diol as the
major impurity. Use of other chlorinated solvents (CH2Cl2,
CHCl3) gave similar results, while reactions in ethers (Et2O,
THF) or NMP resulted in multiple products. Other Lewis
acids (TfOH, Mg(ClO4)2 and LiClO4) gave also inferior
results.
The optimized conditions for the desired transformation was
found to be the reaction of glycidic amides 7 and 8 with a 5-
fold excess of the nitrile in the presence of an excess of
BF3$OEt2 in dichloroethane under strictly anhydrous
conditions. This consistently put the yields of the desired
product in 90% range with little or no undesired by-products
being formed (Fig. 4). After 24 h, the reaction mixture was
quenched with saturated aqueous NaHCO3 and stirred for an
additional 12 h to break the trifluoroborane–amine com-
plexes and hydrolyze the oxazoline ring.3c The products
were isolated by utilizing the ‘catch-and-release’ technique
with acidic SCX resin taking advantage of the basicity of the
tertiary amine moiety within the target molecules.8
The purity of all the library members was ascertained by
LC/MS analysis (UV and LSD detection). The structures of
the representative library members was further confirmed
by proton and carbon NMR experiments. According to
LC/MS analysis, compounds 1c, 1j, 1g and 1q cyclize
spontaneously upon isolation and exist as equilibrium
mixtures of the corresponding oxazolines with the open-
chain amido-alcohols; compounds 1d, 1i and 1o were
isolated as the corresponding oxazolines. All compounds
analyzed by 1H NMR consistently showed the H2 signal as a
doublet at 4.71–5.15 ppm with a coupling constant JH2
Z
6.4–6.7 Hz. This is consistent with the expected anti
geometry of the norstatine analogues. There were no other
regioisomers observed.
The relative stereochemistry of the C2 and C3 substituents
was established by NMR analysis of oxazoline 4a isolated
1
from the reaction mixture.3c The H NMR spectrum of 4a
revealed the characteristic JH2Z9.4 Hz coupling constant
for a doublet at 5.01 ppm (H2 signal) which is consistent
with a syn geometry of the substituents.3b,c
In conclusion, the scope of the epoxide ring opening with
nitriles in the presence of BF3$OEt2 has been significantly
extended to reactions of functionalized nitriles with glycidic
acids, and secondary and tertiary amides. These reactions
proceed with high regio and diastereoselectivity and afford 1
in 43–99% yields. This transformation was used as the key
step in a solution-phase preparation of a 20-membered
combinatorial library of norstatine analogs.
Therefore, upon base hydrolysis of oxazoline 4a, the
resulting 3-N-acylamino-2-hydroxyamide 1a would have
the desired anti-relationship between the substituents at C2
and C3 positions. Indeed, the characteristic anti (JH2Z
6.6 Hz) coupling constant for H2 was observed in the H
1
NMR spectrum of isolated 1a (a doublet at 5.04 ppm)
(Fig. 5).
3. Experimental
Thus, the stereoselectivity of reaction of nitriles with
glycidic amides is thought to arise from preferential SN2
attack on the C3 position since the C2 positive charge is
somewhat destabilized by the adjacent carboxylate group
similarly to the reaction with glycidic esters.3b,c,10
3.1. General comments
NMR experiments were conducted with a Bruker ARX300
spectrometer at 75 MHz for 13C and 300 MHz for 1H
Figure 5. Confirmation of stereochemistry via hydrolysis of the oxazoline.

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M. V. Voronkov et al. / Tetrahedron 60 (2004) 9043–9048
Table 2. Characterization of solution phase library of norstatine analogues, 1
Entry
Product
Amide
R2CN
Puritya
(%)
ES-MS
calc’d
Anal.
obs’d
Yield
(%)
MeCN
BnCN
286.1
362.2
1
2
1a
1b
7a
7a
91
97
286.1
362.2
99
90
354.3,
336.4
3
4
1c
7a
7a
93
95
354.3
99
60
1d
370.2b
352.2
366.2
5
1e
7a
96
366.2
95
MeCN
BnCN
320.2
396.1
6
7
1f
7b
7b
93
95
320.2
396.1,
378.1
99
85
1g
8
1h
7b
95
388.1
388.1
382.1
77
9
1i
1j
7b
7b
78
97
400.1b
548.2
78
60
548.2,
530.2
10
MeCN
BnCN
347.6
423.6
11
12
1k
1l
8b
8b
91
75
347.6
423.6
71
68
435.6
415.6
13
14
1m
1n
8b
8b
83
93
435.6
415.6
61
58
15
1o
8b
91
427.5b
409.5
43
MeCN
BnCN
376.2
452.2
16
17
1p
1q
8c
8c
86
77
376.2
452.2,
434.2
46
52
18
19
1r
1s
8c
8c
83
85
464.2
444.3
464.2
444.3
67
61
20
1t
8c
86
604.2
604.2
43
a
Determined by UV at 220 nm.
Isolated as corresponding oxazolines.
b
spectra. Samples were dissolved in CDCl3 with TMS as the
internal reference. Affinity chromatography was carried out
using Bondesil (SCX 40 mm). Reactions were carried out
under dry nitrogen with magnetic stirring. LC/MS analysis
was conducted on HP1100 with Polaris C18 A-5m column.
Thin layer chromatographic (TLC) analyses were
performed using 10!20 cm Analtech Silica Gel GF plates
(25 mm thick). The TLC plate was developed in the
appropriate EtOAc/hexanes mixture and visualized by UV
light (254 nm).
Ethyl (2S)-trans-2,3-epoxybutanoate was purchased from

M. V. Voronkov et al. / Tetrahedron 60 (2004) 9043–9048
9047
Acros. (2S)-trans-2,3-epoxyhexanol [lit.11 bp 100 8C/
17 mm] was prepared in accordance with the literature
methods. 1-Methyl-2-piperidinoethylamine (a), N-3-propyl-
1-benzyl-3-azetanamine (c), N1,N1-dimethyl-N2-(3-pyri-
dylmethyl)-2,1-cyclopentanediamine (d), 2-hydroxy-1-
cyclo hexanecarbonitrile (E) and N-1-(2-cyano-1-methyl-
ethyl)-3-nitro-1-benzenesulfonamide (G) were obtained as
single racemic diastereomers from Coelacanth Corpor-
ation’s available inventory of building blocks. All other
chemicals were obtained from commercial sources and were
used without further purification.
(dq, 1H, JZ6.5, 7.2 Hz), 4.56 (d, 1H, JZ6.5 Hz); 13C
(75 MHz; DMSO-d6): d 16.8, 17.9, 46.9, 84.2, 170.1, 175.6.
3.2.2. Compound 6b. Colorless oil. 1H (300 MHz; CDCl3):
d 1.16 (t, 3H, JZ7.4 Hz), 1.39–1.71 (m, 4H), 3.64 (s, 2H),
4.03 (d, 1H, JZ6.5 Hz), 4.62 (d, 1H, JZ6.5 Hz), 7.18–7.34
(m, 5H); 13C (75 MHz; CDCl3): d 14.7, 18.5, 32.3, 46.8,
83.1, 127.5, 128.5, 129.4, 137.7, 169.8, 172.7.
3.3. General procedure for preparation of epoxy amides
7 and 8
3.1.1. Preparation of (2S)-trans-2,3-epoxybutanoic acid
(5a). To a cooled solution of ethyl (2S)-trans-2,3-epoxy-
butanoate (2.8 g, 24 mmol) in ethanol (25 mL) was added
ethanolic KOH (1.8 g, 26 mmol, 25 mL of ethanol) drop-
wise at 0 8C over 30 min. The reaction mixture was stirred at
room temperature for 6 h. Potassium trans-2,3-epoxy-
butanoate was isolated by filtration, washed with cold
ethanol (25 mL) and dried in vacuo overnight. The
potassium salt was mixed with dichloroethane (20 mL)
cooled to 0 8C and HCl (1,4-dioxane solution, 4 M, 5.5 mL)
was added dropwise over 10 min. The reaction mixture was
stirred for an additional 2 h, filtered and concentrated to
yield 5a (1.4 g, 58%) as a viscous oil which solidified upon
standing. 1H (300 MHz; CDCl3): d 1.41 (d, 3H, JZ6.2 Hz),
3.22 (d, 1H, JZ2.2 Hz), 3.31–3.37 (m, 1H), 9.80 (br s, 1H);
13C (75 MHz; CDCl3): d 17.5, 53.9, 55.5, 175.2.
To a solution of the glycidic acid 5 (4.8 mmol) in THF
(10 mL) was added PS-DCC (14.4 mmol) and HOBt
(4.8 mmol). The mixture was shaken for 20 min, and then
a solution of the corresponding amine (4 mmol) in 10 mL of
THF was added. The reaction was monitored by LC/MS.
Depending on the nature of the amine, the reaction went to a
completion in 12–36 h. Upon completion, the reaction was
diluted with 20 mL of ethyl acetate and filtered. The filtrate
was washed with saturated NaHCO3 solution, dried over
magnesium sulfate and concentrated in vacuo to yield the
desired glycidic amides 7 or 8 in 46–92% yields.
3.3.1. Compound 7a. Colorless oil.9 1H (300 MHz;
CDCl3): d 1.22 (d, 3H, JZ7.4 Hz), 1.32 (d, 3H, JZ
6.2 Hz), 1.54–1.62 (m, 6H), 2.16–2.45 (m, 6H), 2.98–3.05
(m, 1H), 3.17 (d, 1H, JZ1.5 Hz), 6.32 (br s, 1H); 13C
(75 MHz; CDCl3): d 17.9, 19.5, 24.7, 26.3, 42.6, 54.9, 56.0,
56.7, 63.8, 168.7.
3.1.2. Preparation of (2S)-trans-2,3-epoxyhexanoic acid
(5b). (2S)-trans-2,3-Epoxyhexanol (10 mmol) was dis-
solved in acetonitrile (20 mL) and CCl4 (20 mL) followed
by addition of water (40 mL). To the vigorously stirred
solution, RuCl3 (0.03 g) and NaIO4 (8 g) were added at
room temperature. The reaction was monitored by TLC (9:1
hexanes/EtOAc, developed in PMA). After 10 h, TLC
indicated full consumption of the starting material and the
reaction mixture was diluted with 100 mL of dichloro-
ethane. The aqueous phase was saturated with NaCl, and
extracted twice with dichloromethane. The organic phases
were combined, filtered through Celite, dried over mag-
nesium sulfate and concentrated to give 5b as a clear oil. 1H
(300 MHz; CDCl3): d 1.12 (d, 3H, JZ6.2 Hz), 1.64–1.82
(m, 4H), 3.28–3.30 (m, 1H), 3.37 (d, 1H, JZ1.5 Hz), 10.22
(br s, 1H); 13C (75 MHz; CDCl3): d14.1, 19.2, 33.7, 52.9,
59.2, 175.3.
3.3.2. Compound 7b. Amorphous solid. 1H (300 MHz;
CDCl3): d 1.32 (d, 3H, JZ7.2 Hz), 2.31–2.45 (m, 4H), 3.15
(dq, 1H, JZ1.5 Hz, 7.2 Hz), 3.27 (d, 1H, JZ1.5 Hz), 3.52
(s, 2H), 3.59–3.74 (m, 4H), 7.16–7.32 (m, 5H); 13C
(75 MHz; CDCl3): d 17.7, 45.3, 52.9, 53.5, 55.3, 63.2,
127.7, 128.8, 129.5, 137.9, 166.3.
3.3.3. Compound 7c. Amorphous solid. 1H (300 MHz;
CDCl3): d 1.12 (t, 3H, JZ7.2 Hz), d 1.32 (d, 3H, JZ
6.8 Hz), 1.64–1.82 (m, 2H), 3.17–3.30 (m, 2H), 3.31–3.52
(m, 6H), 3.57 (d, 1H, JZ1.5 Hz), 3.72 (s, 2H) 7.25–7.47 (m,
5H); 13C (75 MHz; CDCl3): d 14.2, 19.6, 23.9, 33.9, 48.0,
48.8, 53.9, 58.6, 62.7, 128.1, 128.9, 129.3, 137.9, 168.7.
3.3.4. Compound 8a. Colorless oil.9 1H (300 MHz;
CDCl3): d 1.25 (t, 3H, JZ7.2 Hz), 1.32 (d, 3H, JZ
6.2 Hz), 1.58–1.82 (m, 10H), 2.16–2.45 (m, 6H), 3.11–3.17
(m, 1H), 3.21 (d, 1H, JZ1.7 Hz), 6.22 (br s, 1H); 13C
(75 MHz; CDCl3): d 17.9, 19.4, 20.3, 24.1, 24.7, 26.3, 42.6,
54.9, 56.2, 56.7, 63.9, 167.1.
3.2. General procedure for the preparation of
compounds 6
To a vigorously stirred solution of 2 (0.1 mmol) in 2 mL of
dichloroethane, the corresponding nitrile (0.1 mmol) was
added, followed by dropwise addition of BF3$OEt2
(0.1 mmol) over 5 min at 0 8C. After stirring at room
temperature for 12 h, TLC indicated that no starting
material remained, and the reaction mixture was quenched
with 2 mL of saturated aqueous NaHCO3 and stirred for an
additional 12 h. The organic layer was separated, dried over
magnesium sulfate and concentrated in vacuo to afford the
desired product 6.
3.3.5. Compound 8b. Amorphous solid. 1H (300 MHz;
CDCl3): d 1.26 (t, 3H, JZ7.4 Hz), 1.59–1.81 (m, 4H), 2.33–
2.47 (m, 4H), 3.12 (dq, 1H, JZ1.5 Hz, 7.4 Hz), 3.21 (d, 1H,
JZ1.5 Hz), 3.42 (s, 2H), 3.44–3.64 (m, 4H), 7.18–7.31 (m,
5H); 13C (75 MHz; CDCl3): d 17.7, 19.6, 20.3, 44.6, 52.7,
53.5, 54.8, 63.1, 127.5, 128.5, 129.4, 137.7, 167.3.
3.3.6. Compound 8c. Amorphous solid. 1H (300 MHz;
CDCl3): d 1.02 (t, 3H, JZ7.4 Hz), d 1.24 (d, 3H, JZ
6.2 Hz), 1.59–1.82 (m, 6H), 3.07–3.21 (m, 2H), 3.32–3.49
(m, 6H), 3.52 (d, 1H, JZ1.5 Hz), 3.69 (s, 2H) 7.22–7.42 (m,
3.2.1. Compound 6a. Colorless oil. 1H (300 MHz; DMSO-
d6): d 1.12 (d, 3H, JZ7.4 Hz), 1.32 (d, 3H, JZ7.2 Hz), 4.11

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M. V. Voronkov et al. / Tetrahedron 60 (2004) 9043–9048
5H); 13C (75 MHz; CDCl3): d 14.1, 19.7, 23.3, 34.0, 48.0,
48.8, 53.9, 58.6, 62.7, 128.2, 128.9, 129.1, 137.8, 167.7.
1.75 (m, 8H), 2.33–2.47 (m, 5H), 3.42 (s, 2H), 3.44–3.51
(m, 1H), 3.59–3.74 (m, 4H), 4.95 (d, 1H, JZ6.5 Hz), 7.22–
7.35 (m, 5H); 13C (75 MHz; CDCl3): d 17.2, 19.6, 20.3,
23.9, 26.4, 27.4, 42.2, 44.6, 52.7, 53.5, 63.8, 64.1, 81.1,
127.5, 128.5, 129.4, 137.7, 167.3, 177.7.
3.4. Preparation of oxazoline 4a
To a vigorously stirred solution of 7a (23 mg, 0.1 mmol) in
2 mL of acetonitrile was added BF3$OEt2 (0.5 mmol) over
5 min at 0 8C. The resulting solution was stirred at room
temperature for 7 h, at which point TLC indicated that no
starting material remained. The reaction mixture was
concentrated, re-dissolved in 10 mL of ethanol, heated at a
gentle reflux for 3 h, then filtered through a silica gel plug
and concentrated in vacuo to yield 24 mg (89%) of 4a.
3.5.4. Compound 1r. Amorphous solid. 1H (300 MHz;
CDCl3): d 0.81–1.24 (m, 6H), 1.58–1.74 (m, 6H), 3.07–3.36
(m, 4H), 3.49–3.82 (m, 3H), 3.69 (s, 2H), 4.23–4.50 (m,
2H), 4.71 (d, 1H, JZ6.7 Hz), 6.56 (d, 1H, JZ14.2 Hz),
7.25–7.41 (m, 7H), 7.51–7.65 (m, 3H); 13C (75 MHz;
CDCl3): d 14.6, 17.3, 23.9, 34.4, 47.3, 48.5, 58.9, 59.8, 63.4,
68.9, 78.5, 114.9, 127.6, 127.9, 128.5, 128.8, 128.9, 129.0,
135.6, 137.5, 141.2, 167.9, 193.2.
3.4.1. Compound 4a. Clear oil.9 1H (300 MHz; DMSO-d6):
d 0.92–1.27 (m, 6H), 1.35–1.61 (m, 6H), 1.72 (s, 3H), 2.24–
2.72 (m, 6H), 3.41–3.47 (m, 1H), 4.19 (dt, 1H, JZ6.6,
7.4 Hz), 5.04 (d, 1H, JZ6.6 Hz); 13C (75 MHz; DMSO-d6):
d 13.9, 17.9, 19.2, 19.7, 23.7, 26.8, 43.2, 54.6, 54.7, 63.8,
71.5, 75.4, 171.2, 174.1.
References and notes
1. (a) Rich, D. H.; Sun, C. Q.; Prasad, J. V. N. V.; Pathiasseril, A.;
Toth, M. V.; Marshall, G. R.; Clare, M.; Mueller, R. A.;
Houseman, K. J. Med. Chem. 1991, 34, 1222. (b) Mimoto, T.;
Imai, J.; Kisanuki, S.; Enomoto, H.; Hattori, N.; Akaji, K.;
Kiso, Y. Chem. Pharm. Bull. 1992, 40, 2251.
3.5. General procedure for the preparation of the library
set 1
To a vigorously stirred solution of 7 or 8 (0.1 mmol) in 2 mL
of dichloromethane, 0.5 mmol of the corresponding nitrile
was added, followed by dropwise addition of 0.5 mmol of
BF3$OEt2 over 5 min at 0 8C. The reaction mixture was
stirred at room temperature for 24 h, at which point TLC
indicated no starting glycidic amides remained. The
reaction mixture was quenched with 2 mL of saturated
aqueous NaHCO3 and stirring was continued for 12 h. The
organic layer was separated, dried over magnesium sulfate
and concentrated in vacuo. Purification of the product was
accomplished ‘catch and release technique’: the solution of
the crude product mixture in methanol was passed through a
column packed with SCX modified silica. The non-basic
impurities were washed off the column with excess of
methanol and the retained product was then released with
1 M methanolic ammonia.
2. (a) Tam, T. F.; Carriere, J.; MacDonald, I. D.; Castelhano,
A. L.; Pliura, D. H.; Dewdney, N. J.; Thomas, E. M.; Bach, C.;
Barnett, J.; Chan, H.; Krantz, A. J. Med. Chem. 1992, 35, 1318.
(b) Chen, J. J.; Coles, P. J.; Arnold, L. D.; Smith, R. A.;
MacDonald, I. D.; Carriere, J.; Krantz, A. Bioorg. Med. Chem.
Lett. 1996, 6, 435. (c) Cardillo, G.; Tolomelli, A.; Tomasini, C.
Eur. J. Org. Chem. 1999, 155. (d) Takashiro, E.; Hayakawa, I.;
Nitta, T.; Kasuya, A.; Miyamoto, S.; Ozawa, Y.; Yagi, R.;
Yamamoto, I.; Shibayama, T.; Nakagawa, A.; Yabe, Y.
Bioorg. Med. Chem. 1999, 7, 2063. (e) Semple, J. E.; Owens,
T. D.; Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769.
3. (a) Zvonkova, E. N.; Bushnev, A. S.; Aksenov, N. E.;
Golovanova, N. K.; Evstigneeva, R. P. J. Org. Chem. USSR
1974, 10, 1621. (b) Legters, J.; Van Dienst, E.; Thijs, L.;
Zwanenburg, B. Recl. Trav. Chim. Pays-Bas 1992, 111, 69.
(c) Ruano, J. L. G.; Paredes, C. G. Tetrahedron Lett. 2000, 41,
5357.
3.5.1. Compound 1a. Colorless amorphous solid.9 1H
(300 MHz; DMSO-d6): d 0.98–1.32 (m, 6H), 1.54–1.67
(m, 6H), 1.98 (s, 3H), 2.24–2.72 (m, 6H), 3.41–3.47 (m,
1H), 3.97–4.11 (m, 1H), 4.91 (br s, 1H), 5.04 (d, 1H, JZ
6.6 Hz), 8.11 (br s, 1H); 13C (75 MHz; DMSO-d6): d 13.2,
17.9, 19.5, 19.6, 23.8, 25.4, 42.0, 54.6, 54.7, 63.5, 71.5,
74.2, 170.2, 171.3.
4. Maly, D. J.; Huang, L.; Ellman, J. A. ChemBiochem 2002, 3,
16.
5. Glabe, A. R.; Sturgeon, K. L.; Ghizzoni, S. B.; Musker,
W. K.; Takahashi, J. N. J. Org. Chem. 1996, 61, 7212.
6. Under various coupling conditions (resin-bound-DCC,
PyBROP, etc.) LC/MS consistently indicated the correspond-
ing (M-74) fragment, which corresponds to the formal loss of
hydroxyacetic acid fragment, as a major component of the
reaction mixture.
3.5.2. Compound 1j. Off-white amorphous solid.9 1H
(300 MHz; CDCl3): d 1.17 (d, 3H, JZ6.4 Hz), 1.37 (d,
3H, JZ6.2 Hz), 1.31–1.38 (m, 1H), 1.92–1.98 (m, 1H),
2.37–2.46 (m, 4H), 3.52 (s, 2H), 3.49–3.70 (m, 4H), 3.79
(dq, 1H, JZ6.6 Hz, 6.2 Hz), 4.31–4.39 (m, 1H), 5.08 (d, 1H,
JZ6.6 Hz), 7.18–7.27 (m, 5H), 7.65–7.72 (m, 2H), 7.81–
7.84 (m, 1H), 8.14–8.19 (m, 1H); 13C (75 MHz; CDCl3): d
17.6, 20.7, 34.9, 42.3, 46.2, 54.6, 63.9, 64.5, 78.6, 125.4,
127.8, 128.8, 129.5, 133.5, 133.6, 137.9, 148.2, 166.3,
171.2.
7. Weinshenker, N. M.; Shen, C.-M. Tetrahedron Lett. 1972, 13,
3281.
8. Lawrence, R. M.; Biller, S. A.; Fryszman, O. M.; Poss,
M. A. Synthesis 1997, 553.
9. Due to racemic nature of the amine moiety, the product was
isolated as 1:1 mixture of diasteriomers.
10. However, excessive stabilization of positive charge on this
carbon (i.e. by aryl substituent) apparently leads to SN1 attack
and results in multiple products.
3.5.3. Compound 1n. Amorphous solid. 1H (300 MHz;
CDCl3): d 1.02 (t, 3H, JZ7.4 Hz), 1.22–129 (m, 6H), 1.52–
11. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.