Trifluoroacetic acid-mediated intramolecular formal N-H insertion reactions with amino-α-diazoketones: A facile and efficient synthesis of optically pure pyrrolidinones and piperidinones

Article abstract of DOI:10.1139/v00-066

Trifluoroacetic acid (TFA) was found to promote intramolecular formal N-H insertion reactions. Upon treatment with TFA, optically pure N-Boc-β′-amino-α-diazoketones (5a-c) and N-Boc-γ′-amino-α-diazoketones (10a-d) can be converted, with retention of chira

Full text of DOI:10.1139/v00-066

800
Trifluoroacetic acid-mediated intramolecular
formal N-H insertion reactions with amino-α -
diazoketones: a facile and efficient synthesis of
optically pure pyrrolidinones and piperidinones
Hua Yang, Valdas Jurkauskas, Nicole Mackintosh, Tobias Mogren,
Corey R. J. Stephenson, Katherine Foster, William Brown, and Edward Roberts
Abstract: Trifluoroacetic acid (TFA) was found to promote intramolecular formal N-H insertion reactions. Upon
treatment with TFA, optically pure N-Boc-β ′-amino-α-diazoketones (5a–c) and N-Boc-γ′-amino-α-diazoketones (10a–d)
can be converted, with retention of chirality, into pyrrolidinones (11a–c) and piperidinones (12a–d), respectively, with
concomitant removal of the Boc group, in good to excellent yields.
Key words: α-diazoketone, amino acid, pyrrolidinone, piperidinone, N-H insertion.
Résumé : Le TFA induit des réactions d’insertion formelle de N-H intramoléculaires. Par traitement avec du TFA, les
N-Boc-β ′-amino-α-diazocétones (5a–c) et les N-Boc-γ′-amino-α-diazocétones (10a–d) optiquement pures peuvent être
converties avec rétention de chiralité en pyrrolidinones (11a–c) et pipéridinones (12a–d) avec déprotection simultanée
de l’amine dans de bons à excellents rendements.
Mots clés : α-diazocétone, acide aminé, pyrrolidinone, pipéridinone, insertion de N-H.
Yang et al. 808
Introduction
examples of N-H insertion reactions to form piperidinone
derivatives see ref. (5) and also ref. (4a), (4c)), which have
been widely used in drug discovery processes (for selected
examples, see ref. (6)). These reactions with α-diazoketones
commonly employ metal catalysts, such as rhodium(II) and
copper(I). However, Rh(II) and Cu(I) catalyzed N-H inser-
tion reactions are sometimes accompanied with a significant
level of C-H insertion or other side reactions (2, 3d, 4a), de-
pending upon the structures of the α -diazoketones.
As part of the ongoing research program exploiting the
chemistry of α-diazoketones and its applications in medici-
nal chemistry at our laboratory, we have found that upon
treatment with trifluoroacetic acid (TFA), N-Boc-α -amino α ′-
diazoketones can be converted into 1,3-oxazine-2,5-diones
via an intramolecular oxygen insertion pathway with good to
excellent yields (Scheme 1).2 It is of interest to investigate if
the oxygen insertion reaction could also be conducted with
homolagated N-Boc-amino-α -diazoketones. Surprisingly,
C—N bond forming reactions are one of the most interest-
ing research areas in synthetic organic and medicinal chem-
istry (for recent reviews on the synthesis of C—N bond
containing heterocycles see ref. (1)). N-H insertion reactions
with α -diazoketones are one of the frequently utilized tech-
niques to form C—N bonds (for recent reviews on the appli-
cations of N-H insertion reactions with α -diazoketones in
organic synthesis, see ref. (2)). These N-H insertion reac-
tions can be performed either in an intermolecular or intra-
molecular fashion (2). The intramolecular N-H insertion
reactions give access to a variety of heterocyclic molecules,
including azetidinones (for selected examples of N-H inser-
tion reactions to generate azetidinone derivatives, see
ref. (3)), pyrrolidinones (for selected examples of N-H inser-
tion reactions to form pyrrolidinone derivatives, see ref. (4)
and also refs. (3e) and (5b)), and piperidinones (for selected
Received November 30, 1999. Accepted March 11, 2000. Published on the NRC Research Press website on June 7, 2000.
This paper is dedicated to Professor Stephen Hanessian on the occasion of his 65th birthday.
H. Yang,1 V. Jurkauskas, N. Mackintosh, T. Mogren, C.R.J. Stephenson, K. Foster, W. Brown, and E. Roberts. Chemistry
Department, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Ville St. Laurent, Quebec, Canada, H4S 1Z9
1Author to whom correspondence may be addressed. Telephone: (514) 832-3200 ext. 2404. Fax: (514) 832-3232.
e-mail: hua.yang@astrazeneca.com
2H. Yang, T. Mogren, C.R.J. Stephenson, V. Jurkauskas, W. Brown, and E. Roberts. Unpublished results. Upon treatment of the
N-Boc-α-amino-α′-diazoketones with TFA, 1,3-oxazine-2,5-diones were produced with good to excellent yields. Presumably the
reactions proceed through a six-membered ring oxonium intermediate, which was generated from an intramolecular oxygen
addition. In situ FTIR studies of the reactions suggested the presence of the oxonium intermediate before it cleaved the tert-butyl
to the final product.
Can. J. Chem. 78: 800–808 (2000)
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Yang et al.
801
Scheme 1.
Synthesis of the γ ′-amino-α -diazoketones
The synthesis of the N-Boc-γ ′-amino-α -diazoketones can
also be efficiently achieved starting from commercially
available N-Boc-α -amino-acids, as shown in Scheme 3.
DIBAL-H reduction of methyl esters 6a–d followed by in
situ Wittig reaction (8) gave the α , β -unsaturated methyl es-
ters 7a–d. Treatment of the esters 7a–d with a sequence of
reactions, involving hydrolysis, hydrogenation, mixed anhy-
dride generation, and diazomethane coupling, resulted in the
isolation of the desired precursors N-Boc-γ ′-amino-α -
diazoketones (10a–d). With both types of the precursors in
hand, we set the stage to examine the TFA mediated
intramolecular formal N-H insertion reactions with 5a–c and
10a–d.
treatment of the N-Boc-β-amino-α ′-diazoketones and N-Boc-
γ-amino-α ′-diazoketones with TFA, respectively, results in
the isolation of the corresponding pyrrolidinones and
piperidinones, presumably via an intramolecular formal N-H
insertion pathway. It has been documented in the literature
that protic acid and Lewis acid can also promote other
intramolecular reactions, such as C—C bond formation from
α -diazoketones (2a). Thus, the results we found would fur-
ther extend the utility of acid-mediated intramolecular
cyclization with α -diazoketones. In this paper, we would
like to report our research efforts on the synthesis of
pyrrolidinones and piperidinones using TFA-mediated for-
mal N-H insertion reactions with amino-α -diazoketones.
Results and discussion
First, we examined the TFA-mediated reactions with the
corresponding N-Boc-β ′-amino-α -diazoketones. Thus, these
N-Boc-β ′-amino-α -diazoketones (5a–c) were treated with
TFA in dichloromethane at –78°C. Interestingly, an
intramolecular formal N-H insertion reaction was observed
with concomitant removal of the Boc group, instead of the
oxygen insertion, resulting in the generation of five-
membered-ring pyrrolidinones 11a–c in good to excellent
yields (84–93%), as shown in Table 1.
All these reactions had gone to completion in less than
5 min. These reactions were very clean, and usually required
no further purification after evaporation and washing with
ether prior to subsequent chemical manipulations, such as
reductive amination. However, a low concentration is essen-
tial to ensure a clean and high-yielding formal intramole-
cular N-H insertion. It is noted that concentrations of
0.005 M were sufficient for most of the reactions tested thus
far. We reasoned that a low concentration might prevent side
reactions related to intermolecular couplings with the diazo
moiety. In contrast, N-Boc-α ′-amino-α -diazoketones can undergo
TFA-mediated intramolecular oxygen insertion reactions at
concentrations as high as 0.5 M, without compromising the
quality of the reaction.2 This difference implies that the six-
Results and discussion
Synthesis of the β ′-amino-α -diazoketones
Synthesis of the precursors of the N-Boc-β ′-amino-α -
diazoketones can be accomplished starting from commer-
cially available α -amino acids, as depicted in Scheme 2. The
commercially available N-Boc-α -amino acids (1a–c) were
treated with i-BuOCOCl followed by diazomethane (3b) to
afford α -diazoketones (2a–c). Silver benzoate-catalyzed
Wolff rearrangement reactions (7) with compounds 2a–c
followed by hydrolysis resulted in the formation of
homologated β ′-amino-acids (4a–c). Repetition of steps 1
and 2 with 4a–c furnished the desired precursors N-Boc-β ′-
amino-α -diazoketones (5a–c).
Scheme 2.
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Can. J. Chem. Vol. 78, 2000
Scheme 3.
Table 1.a TFA mediated reactions with N-Boc-β ′-amino-α-diazoketones.
a All reactions were run using the procedures as described in the experimental section (average of two runs for each reaction).
b TFA salt.
c Isolated yield.
d [α]Ds were measured as a TFA salt in methanol.
membered ring oxygen insertion may be a much more effi-
cient process than the five-membered ring nitrogen insertion
in the cases we have studied thus far. Presumably, the
nucleophilicity of the nitrogen atom was markedly reduced
by the Boc group.
Next, the N-Boc-γ ′-amino-α -diazoketones 10a–c were
treated with TFA in dichloromethane at –78°C. Not surpris-
ingly, six-membered ring piperidinones 12a–c were isolated
with good to excellent yields (62–88%), after removal of the
solvent and the excess TFA (entries 1–3, Table 2). Presum-
ably, a formal N-H insertion with concomitant cleavage of
the Boc group is involved, an observation similar to the five-
membered ring pyrrolidinone generation reactions. Interest-
ingly, the construction of the six-membered ring
piperidinones is as efficient as that of the five-membered
ring pyrrolidinones. They are all very clean, and no further
purification is required after removal of the solvent and the
excess TFA, provided that low concentrations are applied
while running the reactions. The fact that high concentra-
tions may increase the level of potential side reactions also
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Yang et al.
803
Table 2.a TFA mediated reactions with N-Boc-γ′-amino-α -diazoketones.
aAll reactions were run using the procedures as described in the experimental section (average of two runs for each reaction).
b TFA salt.
c Isolated yield.
d [α]Ds were measured as a TFA salt in dichloromethane.
e Prepared from the corresponding D-α-amino acid.
f [α]D was measured as a TFA salt in methanol.
same type of intermediate: nitronium species, as depicted in
Scheme 4. The neutralization of the cation intermediate may
constitute the driving force in the subsequent step of cleav-
ing the Boc group. In situ FTIR studies of the intramolecular
formal N-H insertion reactions with these amino-α ′-diazo-
ketones support this hypothesis. The poor nucleophilicity of
the TFA counteranion together with low concentration may
have suppressed the possible undesired intermolecular reac-
tions. The detailed results of the mechanistic studies of the
TFA-mediated intramolecular formal N-H insertion will be
reported in due course.
Scheme 4.
suggests that a six-membered ring formal N-H insertion
reaction is not as efficient as the six-membered ring oxygen
insertion in the cases we have studied thus far.2
We also examined the chemistry of N-Boc-γ ′-amino-α -
diazoketone 10d, derived from N-Boc-proline (Scheme 3)
under the reaction condition described above. Interestingly,
α-diazoketone 10d (entry 4, Table 2) underwent a formal
intramolecular N-H insertion reaction with concomitant Boc
removal to afford the expected azobicyclic molecule 12d.
This reaction continues to have enjoyed the characteristics of
the TFA-mediated intramolecular formal N-H insertion reac-
tion, being fast (<5 min) and clean at low concentrations.
We believe that all the intramolecular formal N-H inser-
tion reactions in Tables 1 and 2 may proceed through the
Conclusions
We have demonstrated that TFA is an efficient reagent to
promote intramolecular formal N-H insertion reactions with
N-Boc-β ′- and γ ′-amino-α-diazoketones. A nitronium spe-
cies might be involved in this transformation. Pyrrolidin-
ones, piperidinones, and azabicyclic molecules have been
readily prepared using this method. This method will find a
variety of applications in synthetic organic and medicinal
chemistry (9), complementary to the existing synthetic meth-
odology (2).
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Can. J. Chem. Vol. 78, 2000
(3S)-tert-Butyl 3-diazo-1-isopropyl-2-oxopropylcarbamate (2b):
Following the general procedure A. (2S)-N-Boc-valine 1b
(3.0 g, 13.8 mmol) in THF (100 mL) with triethylamine
(5.8 mL, 41.4 mmol) and isobutylchloroformate (2.2 mL,
16.5 mmol). Approximately 2 equiv. of diazomethane in
ether solution. MPLC (Silica gel 60, EtOAc–Heptane
(50:50)) gave 2b as a yellow oil (3.08 g, 92%). IR (NaCl
disc) υ : 3334, 2967, 2105, 1716, 1698, 1650, 1634, 1519,
1504, 1367, 1172 cm–1. 1H NMR (400 MHz, CDCl3) δ : 0.89
(3H, d, J = 7.3 Hz), 0.98 (3H, d, J = 6.6 Hz), 1.44 (9H, s),
2.08 (1H, q, J = 6.3 Hz), 4.06 (1H, brs), 5.13 (1H, brs), 5.42
(1H, brs).
Experimental part
General
Specific optical rotations ([α]D) were measured on a
Perkin–Elmer 243B Polarimeter using a 1 dm path length
micro cell and are reported in deg dm–1. The concentration
(c) is given in 10 mg mL–1 in the specified solvent. NMR
spectra were recorded on a Varian 400GX Fourier Transform
Spectrometer. The chemical shifts (δ ) are expressed in parts
per million (ppm) and coupling constants (J) are reported in
Hertz (Hz). Infrared spectra were recorded on a Perkin–
Elmer FTIR Spectrometer Paragon 1000 (ν in cm–1). Mass
spectroscopy data were obtained using either a Micromass
Quattro LC (LC–MS–MS) or a Micromass LCT (time of
flight) spectrometer; HRMS data were obtained by the Uni-
versity of Montreal mass spec. facility. Thin layer chroma-
tography was performed on Silica Gel 60 F254 precoated
plates and visualized with ultraviolet light and developed by
staining with either basic potassium permanganate solution
or acidic ammonium molybdate (IV). Column chromatogra-
phy was carried out using Silica Gel 60 (70–230 mesh).
Organic solvents were used as purchased in sure sealed
bottles and stored on molecular sieves. All reagents were
used as received from commercial suppliers unless otherwise
stated.
(3S)-tert-Butyl 1-benzyl-3-diazo-2-oxopropylcarbamate (2c):
Following the general procedure A. (2S)-N-Boc-phenyl-
alanine 1c (3.0 g, 11.3 mmol) in THF (100 mL) with
triethylamine (4.7 mL, 34.0 mmol) and isobutylchloro-
formate (1.8 mL, 13.5 mmol). Approximately 2 equiv. of
diazomethane in ether solution. MPLC (Silica gel 60,
EtOAc–Heptane (50:50)) gave 2c as a brown solid (3.30 g,
100%). IR (NaCl disc) υ : 3334, 2976, 2359, 2106, 1706,
1
1698, 1635, 1496, 1366, 1166 cm–1; H NMR (400 MHz,
CDCl3) δ : 1.41 (9H, s), 3.03 (2H, d, J = 6.6 Hz), 4.42 (1H,
brs), 5.09 (1H, brs), 5.22 (1H, brs), 7.17–7.34 (5H, m).
N-Boc-β-amino acid methyl esters
Diazomethane was prepared by dissolving Diazald® in di-
ethyl ether and the resulting solution was added dropwise to
a stirring solution of KOH in ethanol and water at 65°C.
Diazomethane solution in diethyl ether obtained by distilla-
tion from the reaction′s mixture is used without further puri-
fication (10).
General procedure B
A solution of silver benzoate in triethylamine was added
dropwise to a solution of α-diazoketone in MeOH at room
temperature under a nitrogen atmosphere. Upon addition of
the silver benzoate, bubbles were observed, the reaction
darkened in color. It was noted that the reaction was exother-
mic. The resulting mixture was allowed to stir for 18 h and
filtered through Celite® and concentrated to give a crude
sample which was purified by MPLC.
N-Boc-α -amino-α ′-diazoketones
General procedure A
The α -amino acid was dissolved in THF and cooled to
–10°C. Triethylamine was added followed by the dropwise
addition of isobutylchloroformate. The reaction was stirred
at –10°C, under a nitrogen atmosphere, for 20 min then the
white precipitate was filtered through celite. The filtrate was
cooled to –10°C and freshly prepared diazomethane was
added dropwise. The reaction was allowed to warm to room
temperature and stirred for 18 h. The reaction was quenched
with saturated aqueous NH4Cl and the resulting layers were
separated. The aqueous layer was extracted with EtOAc (3×)
and the combined organic layers were washed with H2O
(1×) and saturated aqueous NaCl (1×), dried over Na2SO4,
filtered, and concentrated.
Methyl (3S)-3-[(tert-butoxycarbonyl)amino]butanoate (3a):
Following the general procedure B. α -Diazoketone 2a
(2.84 g, 13.3 mmol) in MeOH (100 mL) and silver benzoate
(0.31 g, 1.33 mmol) in triethylamine (10 mL). MPLC (Silica
gel 60, EtOAc–Heptane (50:50)) gave 3a as a yellow solid
(2.77 g, 96%). H NMR (400 MHz, CDCl3) δ : 1.21 (3H, d,
J = 6.6 Hz), 1.44 (9H, s), 2.45–2.57 (2H, m), 3.69 (3H, s),
4.04 (1H, brs), 4.94 (1H, brs). MS (m/z): 218.16 (M + H).
1
Methyl (3R)-3-[(tert-butoxycarbonyl)amino]-4-methylpentanoate
(3b): Following the general procedure B. α -Diazoketone 2b
(3.07 g, 12.7 mmol) in MeOH (100 mL) and silver benzoate
(0.29 g, 1.27 mmol) in triethylamine (10 mL). MPLC (Silica
gel 60, EtOAc–Heptane (50:50)) gave 3b as a yellow oil
1
(2.92 g, 93%). H NMR (400 MHz, CDCl3) δ : 0.92 (6H, d,
(3S)-tert-Butyl 3-diazo-1-methyl-2-oxopropylcarbamate (2a):
Following the general procedure A. (2S)-N-Boc-alanine 1a
(3.0 g, 15.8 mmol) in THF (100 mL) with triethylamine
(6.6 mL, 47.0 mmol) and isobutylchloroformate (2.5 mL,
19.0 mmol). Approximately 2 equiv. of diazomethane in
ether solution. MPLC (Silica gel 60, EtOAc–Heptane
(50:50)) gave 2a as a yellow solid (2.84 g, 84%). IR (NaCl
disc) υ : 3334, 2978, 2106, 1701, 1636, 1517, 1453, 1366,
J = 6.6 Hz), 1.45 (9H, s), 1.72–1.86 (1H, m), 2.41–2.57
(2H, m), 3.68 (3H, s), 3.69–3.80 (1H, m), 4.86 (1H, brs).
MS (m/z): 246.15 (M + H).
Methyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-phenylbutanoate
(3c): Following the general procedure B. α -Diazoketone 2c
(3.20 g, 11.0 mmol) in MeOH (100 mL) and silver benzoate
(0.259 g, 1.10 mmol) in triethylamine (10 mL). MPLC (Sil-
ica gel 60, EtOAc–Heptane (50:50)) gave 3c as a yellow oil
(3.25 g, 100%). 1H NMR (400 MHz, CDCl3) δ : 1.41
(9H, s), 2.40–2.55 (2H, m), 2.75–2.98 (2H, m), 3.69 (3H, s),
1
1166 cm–1. H NMR (400 MHz, CDCl3) δ : 1.33 (3H, d, J =
6.6 Hz), 1.44 (9H, s), 4.22 (1H, brs), 5.11 (1H, brs), 5.43
(1H, brs).
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Yang et al.
805
1
4.06–4.21 (1H, m), 5.04 (1H, brs), 7.10–7.32 (5H, m). MS
(m/z): 294.14 (M + H).
immediately in the next step. H NMR (400 MHz, CDCl3)
δ : 1.41 (9H, s), 1.60–2.00 (4H, m), 3.34–3.59 (2H, m), 3.73
(3H, s), 4.37 (1H, brs), 5.83 (1H, d, J = 14.6 Hz), 6.78–6.90
(1H, m).
N-Boc-γ-amino-α ,β-unsaturated methyl esters
General procedure C
N-Boc-amino acids
0.5 M solution of DIBAL-H (2 equiv.) in toluene at –78°C
was added dropwise over 2 h to a solution of N-Boc-α-
amino acid methyl ester in toluene (0.1 M) at –78°C. The re-
action was monitored by TLC. Methanol was added at this
temperature and the resulting mixture stirred for additional
30 min. Then methyl (triphenylphosphoranylidene) acetate
(1.15 equiv.) was added at –78°C and the resulting mixture
stirred for 12 h allowing it to warm to room temperature.
The mixture was filtered over Celite®, washed with warm
ethyl acetate, concentrated in vacuo, and purified by chroma-
tography.
General procedure D
The N-Boc-amino acid methyl ester was dissolved in
MeOH and treated with 10% aqueous NaOH. The reaction
was stirred for 18 h at room temperature. The MeOH was re-
moved in vacuo and the remaining mixture was diluted with
H2O. The aqueous layer was washed with EtOAc (2×) and
acidified to pH 2 with 10% aqueous HCl. The aqueous layer
was extracted with EtOAc (3×) and the combined organic
layers washed with saturated aqueous NaCl (1×), dried over
Na2SO4, filtered, and concentrated.
Methyl (E,4R)-4-[(tert-butoxycarbonyl)amino]-2-pentenoate
(7a): Following the general procedure C. (2R)-N-Boc-alanine
methyl ester 6a (1.00 g, 4.92 mmol) in toluene (100 mL) at
–78°C and DIBAL-H (9.64 mL, 9.64 mmol, 1 M in toluene).
Reaction was quenched with MeOH (1 mL). Added methyl
(triphenylphosphoranylidene) acetate (1.90 g, 5.69 mmol).
Chromatography (Silica gel 60, EtOAc–Heptane (30:70))
gave unsaturated ester 7a as a colorless oil (0.812 g, 72%).
1H NMR (400 MHz, CDCl3) δ : 1.25 (3H, d, J = 6.6 Hz),
1.44 (9H, s), 3.77 (3H, s), 4.40 (1H, brs), 4.58 (1H, brs),
5.91 (1H, dd, J = 15.4, 1.5 Hz), 6.88 (1H, dd, J = 15.4,
4.4 Hz). 13C NMR (100 MHz, CDCl3) δ : 20.97, 29.02,
47.71, 52.31, 120.38, 150.39, 155.56, 167.51.
(3S)-3-[(tert-Butoxycarbonyl)amino]butanoic acid (4a):
Following the general procedure D. The β-amino acid
methyl ester 3a (2.73 g, 12.6 mmol) in MeOH (50 mL) and
10% aqueous NaOH (50 mL). Flash chromatography (silica
gel 60, 100% EtOAc) gave β-amino acid 4a as a pale yellow
viscous oil (2.60 g, 100%). H NMR (400 MHz, CDCl3) δ :
1.24 (3H, d, J = 6.6 Hz), 1.45 (9H, s), 2.46–2.62 (2H, m),
4.05 (1H, brs), 4.95 (1H, brs). MS (m/z): 204.10 (M + H).
1
(3R)-3-[(tert-Butoxycarbonyl)amino]-4-methylpentanoic acid
(4b): Following the general procedure D. The β-amino acid
methyl ester 3b (2.90 g, 11.8 mmol) in MeOH (50 mL) and
10% aqueous NaOH (50 mL). Flash chromatography (Silica
gel 60, 100% EtOAc) gave β-amino acid 4b as a pale yellow
1
Methyl (E,4R)-4-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate
(7b): Following the general procedure C. (2R)-N-Boc-valine
methyl ester 6b (2.11 g, 91.1 mmol) in toluene (100 mL) at
–78°C and DIBAL-H (18.22 mL, 18.22 mmol, 1 M in tolu-
ene). The reaction was quenched with MeOH (2 mL). Added
methyl (triphenylphosphoranylidene) acetate (3.66 g,
11.0 mmol). Chromatography (Silica gel 60, EtOAc–
Heptane (30:70)) gave unsaturated ester 7b as a white solid
viscous oil (2.80 g, 100%). H NMR (400 MHz, CDCl3) δ :
0.93 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 1.76–1.91 (1H, m),
2.40–2.65 (2H, m), 3.70–3.82 (1H, m), 4.92 (1H, d, J =
9.5 Hz). MS (m/z): 232.09 (M + H).
(3S)-3-[(tert-Butoxycarbonyl)amino]-4-phenylbutanoic acid
(4c): Following the general procedure D. The β-amino acid
methyl ester 3c (3.26 g, 11.1 mmol) in MeOH (50 mL) and
10% aqueous NaOH (50 mL). Flash chromatography (Silica
gel 60, 100% EtOAc) gave β-amino acid 4c as a pale yellow
1
(2.17 g, 93%). H NMR (400 MHz, CDCl3) δ : 0.83 (6H, t,
J = 6.6 Hz), 1.35 (9H, s), 1.72–1.81 (1H, m), 3.64 (3H, s),
4.07 (1H, brs), 4.71 (1H, d, J = 8.8 Hz), 5.84 (1H, d, J =
16.1 Hz), 6.78 (1H, dd, J = 15.4, 5.1 Hz).
1
solid (0.56 g, 19%). H NMR (400 MHz, CDCl3) δ : 1.40
(9H, s), 2.45–2.61 (2H, m), 2.80–3.00 (2H, m), 4.18 (1H,
brs), 5.06 (1H, brs), 7.17–7.33 (5H, m). MS (m/z) 280.21
(M + H).
Methyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-phenyl-2-
pentenoate (7c): Following the general procedure C. (2S)-N-
Boc-phenylalanine methyl ester 6c (4.59 g, 16.4 mmol) in
toluene (250 mL) at –78°C and DIBAL-H (33.0 mL,
33.0 mmol, 1 M in toluene). The reaction was quenched
with MeOH (2 mL). Added methyl (triphenylphosphor-
anylidene) acetate (6.30 g, 18.86 mmol). Usual work-up
gave unsaturated ester 7c as a crude sample that was used di-
rectly in the next step.
(E,4R)-4-[(tert-Butoxycarbonyl)amino]-2-pentenoic acid (8a):
Following the general procedure D. The unsaturated γ-
amino acid methyl ester 7a (0.65 g, 2.83 mmol) in MeOH
(5 mL) and 10% aqueous solution NaOH (5 mL). MPLC
(Silica gel 60, EtOAc–Heptane (40:60 – 60:40)) gave unsat-
urated acid 8a (367 mg, 61%). IR (NaCl disc) υ : 3330 (br),
2976, 1703, 1646 cm–1. 1H NMR (400 MHz, CDCl3) δ : 1.28
(3H, d, J = 6.6 Hz), 1.45 (9H, s), 4.44 (1H, brs), 4.56 (1H,
brs), 5.91 (1H, d, J = 15.4 Hz), 6.98 (1H, dd, J = 15.4,
4.4 Hz). 13C NMR (100 MHz, CDCl3) δ : 14.1, 20.1, 28.1,
28.2, 119.3, 151.8.
tert-Butyl (2S)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-pyrrolidinecar-
boxylate (7d): Following the general procedure C. (2S)-N-
Boc-proline methyl ester 6d (3.36 g, 14.65 mmol) in to-
luene (120 mL) at –78°C and DIBAL-H (15.0 mL, 15.0 mmol,
1 M in toluene). Reaction was quenched with MeOH (2 mL).
Added methyl (triphenylphosphoranylidene) acetate (5.63 g,
16.85 mmol). Chromatography (Silica gel 60, EtOAc–
Heptane (30:70)) gave unsaturated ester 7d which was used
(E,4R)-4-[(tert-Butoxycarbonyl)amino]-5-methyl-2-hexenoic
acid (8b): Following the general procedure D. The unsatu-
rated γ-amino acid methyl ester 7b (1.98 g, 7.73 mmol)
in MeOH (2 mL) and 10% aqueous NaOH (2 mL). MPLC
© 2000 NRC Canada

806
Can. J. Chem. Vol. 78, 2000
(Silica gel 60, EtOAc–Heptane (40:60 – 60:40)) gave unsat-
urated acid 8b (1.56 g, 83%) as a white foam. H NMR
2.33–2.46 (2H, m), 2.70–2.82 (2H, m), 3.80–3.90 (1H, m),
4.39 (1H, d, J = 10.2 Hz), 7.13–7.33 (5H, m).
1
(400 MHz, CDCl3) δ : 0.94 (6H, m), 1.45 (9H, s), 1.84–1.92
(1H, m), 4.23 (1H, brs), 4.60 (1H, brs), 5.94 (1H, d, J =
16.1 Hz), 6.96 (1H, dd, J = 15.4, 5.1 Hz).
3-[(2S)-1-(tert-Butoxycarbonyl)pyrrolidinyl]propanoic acid (9d):
Following the general procedure E. The unsaturated γ-amino
acid 8d (3.24 g, 13.4 mmol) in EtOAc (40 mL) and cat. 10%
Pd/C with H2. Washed with EtOAc (120 mL) to give γ-
amino acid 9d as a white solid (2.45 g, 74%). [α]D + 85.6°
(MeOH, c 0.74).
(E,4S)-4-[(tert-Butoxycarbonyl)amino]-5-phenyl-2-pentenoic
acid (8c): Following the general procedure D. The unsatu-
rated γ-amino acid methyl ester 7c in MeOH (30 mL) and
10% aqueous NaOH (30 mL). MPLC (Silica gel 60, EtOAc–
Heptane (40:60 – 60:40)) gave unsaturated acid 8c (1.40 g,
N-Boc-β-amino-α ′-diazoketones
1
29% over 2 steps) as a white solid. H NMR (400 MHz,
tert-Butyl (1S)-1-methyl-4-diazo-3-oxobutylcarbamate (5a):
Following the general procedure A. β-Amino acid 4a
(2.70 g, 13.3 mmol) in THF (100 mL) with triethylamine
(5.5 mL, 39.8 mmol) and isobutylchloroformate (2.07 mL,
15.9 mmol). Approximately 2 equiv. of diazomethane in
ether solution. MPLC (Silica gel 60, EtOAc–Heptane (20 –
50:80 – 50)) gave diazoketone 5a as a yellow solid (0.33 g,
10%). [α]D + 19.03° (MeOH, c 0.77). IR (NaCl disc) υ :
3370, 2976, 2100, 1710, 1694, 1681, 1633, 1519, 1371,
CDCl3) δ: 1.40 (9H, s), 2.90 (2H, brs), 4.12 (1H, q, J =
7.3 Hz), 4.60 (1H, m), 5.85 (1H, d, J = 15.4 Hz), 6.99 (1H,
dd, J = 16.1, 5.1 Hz), 7.15–7.39 (5H, m).
(E)-3-[(2S)-1-(tert-Butoxycarbonyl)pyrrolidinyl]-2-propenoic
acid (8d): Following the general procedure D. The unsatu-
rated γ-amino acid methyl ester 7d in MeOH (30 mL) and
10% aqueous NaOH (30 mL). MPLC (Silica gel 60, EtOAc–
Heptane (40:60 – 60:40)) gave unsaturated acid 8d (3.24 g,
1
1163 cm–1. H NMR (400 MHz, CDCl3) δ : 1.23 (3H, d, J =
1
92% over 2 steps) as a colourless oil. H NMR (400 MHz,
6.6 Hz), 1.44 (9H, s), 2.52 (2H, brs), 3.98 (1H, brs), 4.99
(1H, brs), 5.32 (1H, brs). MS (m/z): 228.2 (M + H). HRMS
calcd. for C10H17N3O3 + H: 228.1348; found: 228.1346.
CDCl3) δ : 1.39 (9H, s), 1.70–1.93 (4H, m), 3.22–3.48
(2H, m), 4.34 (3H, brs), 5.80 (1H, d, J = 16.1 Hz), 6.80–
6.96 (1H, m), 9.80 (1H, brs).
tert-Butyl (1R)-1-isopropyl-4-diazo-3-oxobutylcarbamate (5b):
Following the general procedure A. β-Amino acid 4b
(2.80 g, 12.1 mmol) in THF (100 mL) with triethylamine
(5.1 mL, 36.3 mmol) and isobutylchloroformate (1.88 mL,
14.5 mmol). Approximately 2 equiv. of diazomethane in ether
solution. MPLC (Silica gel 60, EtOAc–Heptane (20 – 50:80
– 50)) gave diazoketone 5b as a yellow solid (0.26 g, 9%).
[α]D + 28.23° (MeOH, c 0.58). IR (NaCl disc) υ : 3376,
3074, 2964, 2102, 1688, 1631, 1519, 1386, 1366, 1248,
N-Boc-γ-amino acids (9)
General procedure E
The N-Boc-γ-amino-α ,β-unsaturated acid was dissolved
in ethyl acetate followed by addition of 10% Pd/C (10% in
weight). The resulting mixture was shaken under the hydro-
gen atmosphere (45 psi) for 3 h. The catalyst was filtered
over Celite®, and the filtrate washed with ethyl acetate and
concentrated in vacuo to give the γ-amino acid which was
used in the next step without further purification.
1
1173 cm–1. H NMR (400 MHz, CDCl3) δ : 0.91 (6H, d, J =
6.6 Hz), 1.43 (9H, s), 1.86 (1H, brs), 2.51 (2H, brs), 3.68
(1H, brs), 4.92 (1H, brs). MS (m/z): 256.2 (M + H). HRMS
calcd. for C12H21N3O3 + H: 256.1661; found: 256.1649.
(4R)-4-[(tert-Butoxycarbonyl)amino]pentanoic acid (9a):
Following the general procedure E. The unsaturated γ-amino
acid 8a (0.36 g, 1.7 mmol) in EtOAc (20 mL) and cat. 10%
Pd/C with H2. Washed with EtOAc (120 mL) to give γ-
tert-Butyl (1S)-1-benzyl-4-diazo-3-oxobutylcarbamate (5c):
Following the general procedure A. β-Amino acid 4c
(0.58 g, 2.07 mmol) in THF (25 mL) with triethylamine
(0.87 mL, 6.22 mmol) and isobutylchloroformate (0.32 mL,
2.49 mmol). Approximately 2 equiv. of diazomethane in
ether solution. MPLC (Silica gel 60, EtOAc–Heptane
(20 – 50:80 – 50)) gave α-diazoketone 5c as a yellow solid
(80.1 mg, 13%). IR (NaCl disc) υ : 3364, 3076, 2979, 2102,
1
amino acid 9a (0.37 g, 100%) as a white solid. H NMR
(400 MHz, CDCl3) δ : 1.14 (3H, d, J = 3.6 Hz), 1.41 (9H, s),
1.60–1.71 (1H, m), 1.72–1.82 (1H, m), 2.39 (2H, t, J =
2.8 Hz), 3.69 (1H, brs), 4.40 (1H, brs).
(4S)-4-[(tert-Butoxycarbonyl)amino]-5-methylhexanoic acid
(9b): Following the general procedure E. The unsaturated γ-
amino acid 8b (1.28 g, 5.26 mmol) in EtOAc (10 mL) and
cat. 10% Pd/C with H2. Washed with EtOAc (120 mL) to
1
1691, 1633, 1523, 1386, 1366, 1249, 1171 cm–1. H NMR
(400 MHz, CDCl3) δ : 1.41 (9H, s), 2.48 (2H, brs), 2.78–
3.04 (2H, m), 4.04–4.15 (1H, m), 5.14–5.30 (2H, m), 7.17–
7.32 (5H, m). MS (m/z): 304.2 (M + H). HRMS calcd. for
C16H21N3O3 + H: 304.1661; found: 304.1673.
1
give γ-amino acid 9b (1.22 g, 95%) as a white solid. H
NMR (400 MHz, CDCl3) δ : 0.86 (6H, t, J = 6.6 Hz), 1.39
(9H, s), 1.50–1.58 (1H, m), 1.60–1.72 (1H, m), 1.74–1.87
(1H, m), 2.31–2.40 (2H, m), 3.30–4.46 (1H, m), 4.37 (1H, d,
J = 10.2 Hz). MS (m/z): 246.23 (M + H).
N-Boc-γ-amino-α ′-diazoketones
(4R)-4-[(tert-Butoxycarbonyl)amino]-5-phenylpentanoic acid
(9c): Following the general procedure E. The unsaturated γ-
amino acid 8c (1.39 g, 4.77 mmol) in EtOAc (10 mL) and
cat. 10% Pd/C with H2. Washed with EtOAc (120 mL) to
give γ-amino acid 9c (1.24 g, 87%) as a white solid. H
NMR (400 MHz, CDCl3) δ: 1.38 (9H, s), 1.82–1.91 (2H, m),
tert-Butyl (1R)-5-diazo-1-methyl-4-oxopentylcarbamate (10a):
Following the general procedure A. To a solution of γ-amino
acid 9a (0.373 g, 1.728 mmol) in 15 mL of THF was added
iBuOCOCl (0.27 mL, 2.07 mmol), triethylamine (0.73 mL,
5.18 mmol), followed by about 10-fold excess of diazome-
thane solution in ether. Compound 10a was obtained
1
© 2000 NRC Canada

Yang et al.
807
(0.135 g, 32%) as a yellow solid. [α]D –13.7° (MeOH, c
0.68). Rf = 0.30 in 30% of EtOAc in heptane. IR (NaCl disc)
ν: 3358, 3082, 2975, 2101, 1682, 1633, 1531, 1455,
3-Pyrrolidinones
(5S)-5-Methyl-3-pyrrolidinone trifluoroacetate (11a): Fol-
lowing the general procedure F. α -Diazoketone 5a (5.1 mg,
0.022 mmol) in CH2Cl2 (10 mL) with trifluoroacetic acid
(1 mL) gave cyclized product 11a as a yellow solid (4.1 mg,
86%). [α]D + 162.5° (MeOH, c 0.20). IR (NaCl disc) υ :
1
1389 cm–1. H NMR (400 MHz, CDCl3) δ : 1.05 (3H, d, J =
6.5 Hz), 1.45 (9H, s), 1.6–1.8 (2H, m), 2.40 (2H, brs), 3.70
(1H, brs), 4.20 (1H, brs), 5.25 (1H, brs). HRMS (FAB)
calcd. for C11H20O3N3 + H: 242.1505; found: 242.1498.
3391, 1694, 1446, 1318, 1179 cm–1. H NMR (400 MHz,
1
CDCl3) δ : 1.38 (3H, d, J = 6.6 Hz), 2.86–3.03 (2H, m),
3.88–3.98 (1H, m), 4.54 (1H, d, J = 16.9 Hz), 4.80 (1H, d,
J = 16.9 Hz), 6.99 (1H, s). HRMS calcd. for C5H9NO:
99.0685; found: 99.0709.
tert-Butyl (1S)- 5-diazo-1-isopropyl-4-oxopentylcarbamate (10b):
Following the general procedure A. To a solution of γ-amino
acid 9b (1.22 g, 4.97 mmol) in 40 mL of THF, was added
iBuOCOCl (0.78 mL, 5.96 mmol) and triethylamine
(2.10 mL, 14.9 mmol), followed by 10-fold excess of diazo-
methane in ether. Compound 10b (0.74 g, 55%) was ob-
tained as a yellow crystal. [α]D –20.1° (CH Cl2, c 0.74). Rf =
0.30 in 30% of EtOAc in heptane. IR (Na2Cl disc) ν : 3347,
2963, 2104, 1703, 1633, 1519, 1366, 1248, 1172, 1067 cm–1.
1H NMR (400 MHz, CDCl3) δ : 0.90 (6H, d, J = 6.5 Hz), 1.25
(9H, s), 1.6–1.8 (2H, m), 1.85 (1H, m), 2.40 (2H, brs), 3.40
(1H, m), 4.17 (1H, d, J = 6.5 Hz), 5.15 (1H, brs). HRMS
(FAB) calcd. for C13H24O3N3 + H: 270.1817; found:
270.1824.
(5R)-5-Isopropyl-3-pyrrolidinone trifluoroacetate (11b):
Following the general procedure F. α -Diazoketone 5b
(4.9 mg, 0.019 mmol) in CH2Cl2 (10 mL) with trifluoro-
acetic acid (1 mL) gave cyclized product 11b as a yellow
viscous oil (4.3 mg, 93%). [α]D + 84.40° (MeOH, c 0.25).
1
IR (NaCl disc) υ: 3417, 1766, 1682, 1201 cm–1. H NMR
(400 MHz, CDCl3) δ : 1.00 (3H, d, J = 6.0 Hz), 1.01 (3H, d,
J = 6.0 Hz), 1.83–1.94 (1H, m), 2.73–3.08 (2H, m), 3.63–
3.88 (1H, m), 4.50 (1H, d, J = 16.8 Hz), 4.70 (1H, d, J =
16.8 Hz), 6.74 (1H, s). HRMS calcd. for C7H13NO + H:
128.1076; found: 128.0322.
tert-Butyl (1R)-5-diazo-1-benzyl-4-oxopentylcarbamate (10c):
Following the general procedure A. To a solution of γ -
amino acid 9c (1.20 g, 4.09 mmol) in 40 mL of THF, was
added iBuOCOCl (0.64 mL, 4.90 mmol) and triethylamine
(1.73 mL, 12.26 mmol) followed by 10-fold excess of diazo-
methane in ether. Compound 10c (0.35 g, 27%) was ob-
tained as a yellow solid. [α] + 14.44° (MeOH, c 0.45). Rf =
0.30 in 35% of EtOAc in hDeptane. IR (NaCl disc) ν : 3352,
3083, 2979, 2357, 2101, 1682, 1633, 1524, 1447, 1385,
(5S)-5-Benzyl-3-pyrrolidinone trifluoroacetate (11c): Fol-
lowing the general procedure F. α-Diazoketone 5c (5.9 mg,
0.019 mmol) in CH2Cl2 (10 mL) with trifluoroacetic acid
(1 mL) gave cyclized product 11c as an off-white solid
(4.7 mg, 84%). [α]D + 41.60° (MeOH, c 0.25). IR (NaCl
1
disc) υ: 3390, 2931, 1770, 1682, 1455, 1319, 1172 cm–1. H
NMR (400 MHz, CDCl3) δ : 2.84–3.05 (4H, m), 3.90–3.99
(1H, m), 4.53 (1H, d, J = 16.8 Hz), 4.72 (1H, d, J = 16.8
Hz), 6.53 (s, 1H), 7.14–7.40 (m, 5H). MS (m/z): 176.2 (M +
H). HRMS calcd. for C11H13NO + H: 176.1075; found:
176.1079.
1
1348 cm–1. H NMR (400 MHz, CDCl3) δ : 1.45 (9H, s),
1.70–1.60 (1H, brs), 1.90–1.80 (1H, brs), 2.40 (2H, brs),
2.90–2.80 (2H, ddd), 3.80 (1H, brs), 4.40 (1H, brs), 5.15
(1H, brs), 7.40–7.20 (5H, m). HRMS (FAB) calcd. for
C17H24O3N3 + H: 318.1818; found: 318.1832.
3-Piperidinoes
(6R)-6-Methyl-3-piperidinone trifluoroacetate (12a): Fol-
lowing the general procedure F. To a solution of γ-amino-
α ′-diazoketone 10a (9 mg, 0.037 mmol) in CH2Cl2 (6 mL)
was added TFA (2 mL). Compound 12a (69%) was ob-
tained. [α]D –57.1° (CH2Cl2, c 0.21). IR (NaCl disc) ν :
tert-Butyl (2S)-2-(4-diazo-3-oxobutyl)-1-pyrrolidinecarboxylate
(10d): Following the general procedure A. To a solution of
γ-amino acid 9d (2.45 g, 10.2 mmol) in 80 mL of THF, was
added iBuOCOCl (1.72 mL, 13.2 mmol) and triethylamine
(4.65 mL, 32.9 mmol) followed by 10-fold excess of diazo-
methane in ether. Compound 10d (1.54 g, 56%) was ob-
tained as a yellow oil. [α]D + 91.80° (MeOH, c 0.74). Rf =
0.30 in 30% of EtOAc in heptane. IR (NaCl disc) ν : 2974,
1
3365, 2976, 1736, 1676, 1424, 1202, 1179, 1134 cm–1. H
NMR (400 MHz, CDCl3) δ : 1.5 (3H, d, J = 6.6 Hz), 2.0–1.9
(1H, m), 2.70–2.60 (1H, m), 3.20–3.10 (2H, m), 4.55 (1H,
m), 4.80 (2H, brs). MS (m/z): 114.1 (M + 1). HRMS calcd.
for C6H11NO + H: 114.0919; found: 114.0916.
1
2103, 1692, 1392, 1165 cm–1. H NMR (400 MHz, CDCl3)
δ : 1.40 (9H, d), 2.0–1.60 (6H, m), 2.30 (1H, brs), 3.30 (2H,
brs), 3.40 (2H, brs), 3.70 (1H, brs), 4.20 (1H, m), 5.20 (1H,
m). HRMS (FAB) calcd. for C13H22O3N3 + H: 268.1661;
found: 268.1666.
(6S)-6-Isopropyl-3-piperidinone trifluoroacetate (12b): Fol-
lowing the general procedure F. To a solution of γ-amino-α ′-
diazoketone 10b (8.0 mg, 0.030 mmol) in CH2Cl2 (10 mL)
was added TFA (1 mL). Compound 12b (6.0 mg, 79%) was
obtained. [α]D –30.68° (CH2Cl2, c 0.37). IR (NaCl disc) ν :
Intramolecular formal N-H insertion reactions
1
2967, 1770, 1673, 1504, 1192, 1080, 1014 cm–1. H NMR
General procedure F
(400 MHz, CDCl3) δ : 0.9 (3H, d, J = 6.6 Hz), 1.1 (3H, d),
2.2–2.0 (2H, m), 2.4 (1H, m), 3.1 (2H, m), 4.3 (1H, m), 4.8
(2H, m). HRMS (FAB) calcd. for C8H16ON + H: 142.1232;
found: 142.1229.
The α ′-diazoketone was dissolved in CH2Cl2 and cooled
to –78°C. Trifluoroacetic acid was added dropwise and the
reaction stirred under a nitrogen atmosphere for 5 min and
then concentrated in vacuo to give the desired product as a
TFA salt. The excess TFA could also be removed by wash-
ing with ether (2×).
(6R)-6-Benzyl-3-piperidinone trifluoroacetate (12c): Fol-
lowing the general procedure F. To a solution of γ -amino-
© 2000 NRC Canada

808
Can. J. Chem. Vol. 78, 2000
3. (a) J. Poldech and D. Seebach. Helv. Chim. Acta, 78, 1238
(1995); (b) S. Hanessian, J.-M. Fu, J.-L. Chiara, and R. Di
Fabio. Tetrahedron Lett. 34, 4157 (1993); (c) G. Emmer. Tetra-
hedron, 48, 7165 (1992); (d) M.P. Moyer, P.L. Feldman, and
H. Rapoport. J. Org. Chem. 50, 5223 (1985); (e) O.V. Isakova,
A.M. Sipyagin, and V.V. Kartsev. Zh. Org. Khim. 17, 1522
(1980).
4. (a) C.F. Garcia, M.A. McKervey, and T. Ye. J. Chem. Soc.
Chem. Commun. 1465 (1996); (b) E. Beausoleil, B.
L’Archeveque, L. Belec, M. Atfani, and W. Lubell. J. Org.
Chem. 61, 9447 (1996); (c) J.S. Clark and P.B. Hodgson. J.
Chem. Soc. Chem. Commun. 2701 (1994); (d) G. Bouthillier,
H. Mastalerz, and M. Menard. Tetrahedron Lett. 35, 4689
(1994); (e) K. Burger, M. Rudolph, and S. Fehn. Angew.
Chem. Int. Ed. Engl., 32, 285 (1993); ( f ) J.V. Heck, M.J.
Szymonifka, and B.G. Christensen. Tetrahedron Lett. 23, 1519
(1982); (g) J.V. Heck and B.G. Christensen. Tetrahedron Lett.
22, 5027 (1981).
5. (a) C.F. Garcia, M.A. McKervey, and T. Ye. J. Chem. Soc.
Chem. Commun. 1465 (1996); (b) F.G. West and B.N. Naidu.
J. Am. Chem. Soc. 116, 8420 (1994); (c) F.G. West and B.N.
Naidu. J. Am. Chem. Soc. 115, 1177 (1993); (d) K.-Y. Ko, K.-
I. Lee, and W.-J. Kim. Tetrahedron Lett. 33, 6651 (1992).
6. (a) P. Conti, M. De Amici, G. De Sarro, M. Rizzo, T.B.
Stensbol, M. Brauner-Osborne, U. Madsen, L. Toma, and C.
De Micheli. J. Med. Chem. 42, 4099 (1999); (b) M. Gerasimov,
D. Marona-Lewicka, D.M. Kurrasch-Orbaugh, A.M. Qandil,
and D.E. Nichols. J. Med. Chem. 42, 4257 (1999); (c) K.E.
Andersen, J.L. Sorensen, P.O. Huusfeldt, L.J.S. Knutsen, J.
Lau, B.F. Lundt, H. Petersen, P.D. Suzdak, and M.D.B.
Swedberg. J. Med. Chem. 42, 4281 (1999).
α ′-diazoketone 10a (9.8 mg, 0.031 mmol) in CH2Cl2
(10 mL) was added TFA (1 mL). Compound 12c (5.8 mg,
62%) was obtained. [α]D + 19.58° (MeOH, c 0.24). IR
(NaCl disc) ν: 2969, 2358, 1770, 1681, 1504, 1417, 1139,
1163, 1081 cm–1. 1H NMR (400 MHz, CDCl3) δ : 2.2
(1H, m), 2.5–2.4 (1H, m), 2.8–2.6 (1H, m), 2.9 (1H, m), 3.0
(1H, m), 3.2 (1H, m), 4.70–4.80 (3H, m), 7.4–7.2 (5H, m).
HRMS (FAB) calcd. for C12H16ON + H: 190.1232; found:
190.1226.
(8aS)-Hexahydro-6(5H)-indolizinone trifluoroacetate (12d):
Following the general procedure F. To a solution of γ-
amino-α ′-diazoketone 10d (11.8 mg, 0.044 mmol) in
CH2Cl2 (10 mL) was added TFA (1 mL). Compound 12d
(9.4 mg, 88%) was obtained. [α]D + 172.9° (CH2Cl2, c 0.36).
IR (NaCl disc) ν : 3417, 2988, 2555, 1782, 1673, 1446,
1326, 1177 cm–1. 1H NMR (400 MHz, CDCl3) δ : 1.3
(1H, m), 2.1–1.8 (4H, m), 2.4 (1H, m), 2.6 (1H, m), 3.4
(1H, m), 3.7 (2H, m), 4.1 (1H, m), 4.8–4.5 (2H, m). HRMS
(FAB) calcd. for C8H14ON + H: 140.1075; found: 140.1072.
Acknowledgments
We thank Dr. M. Evans for HRMS analysis, Dr. Chris
Walpole for helpful discussion.
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