Domino primary alcohol oxidation-wittig reaction: Total synthesis of ABT-418 and (E)-4-oxonon-2-enoic acid

Article abstract of DOI:10.1055/s-2004-829123

Domino oxidation of primary alcohols to α,β-unsaturated compounds using the combination of PCC-NaOAc and stabilized Wittig reagent and its application towards total synthesis of ABT-418 and 4-oxonon-2-enoic acid is described.

Full text of DOI:10.1055/s-2004-829123

PAPER
1859
Domino Primary Alcohol Oxidation-Wittig Reaction: Total Synthesis of
ABT-418 and (E)-4-Oxonon-2-enoic Acid
Total
Syn
y
A
BT
o
-
418
a
nd (
E
t
)-4-Ox
i
onon-2-enoic
S
A
cid het, Vidya Desai, Santosh Tilve*
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
Fax +91(832)2451184; E-mail: santoshtilve@yahoo.com
Received 2 March 2004; revised 7 April 2004
the handling of intermediate aldehyde during the synthe-
sis. It appeared that we could easily achieve the synthesis
of this compound by Wittig condensation of 1-triphe-
nylphosphorylidine-2-propanone with N-substituted pro-
linol using the above ‘in situ’ procedures. However,
application of the above two procedures3a–c as well as use
of PDC as an oxidant did not give the desired product of
the reaction of 1-triphenylphosphorylidine-2-propanone
with N-methyl, N-ethoxycarbonyl or N-BOC-prolinol in
our hand. The third procedure available3g was not used,
since we thought that its harsh conditions may result in ra-
cemization.
Pyridinium chlorochromate6 (PCC) is one of the most eas-
ily available reagents for the oxidation of primary alcohol
to aldehydes. However, this reagent along with stable
Wittig reagent has, to our knowledge, not been used for
‘in situ’ homologation. This prompted us to investigate its
possible application toward this end. In order to check the
feasibility of this domino approach, we took benzyl al-
cohol as the substrate and treated it with PCC and stable
Wittig reagent [(carboethoxymethylene) triphenylphos-
phorane] in molar ratios and stirred in CH2Cl2. No
homologated product was observed. Pyridinium chloro-
chromate, being an acidic reagent has been buffered with
NaOAc effectively. Using the buffered PCC (1.5 molar
ratio) along with one mole of stable Wittig reagent [(car-
boethoxymethylene) triphenylphosphorane] and benzyl
alcohol, we got ethyl cinnamate in excellent yield of 96%
(Scheme 1). Further studies using long chain as well as
branched aliphatic alcohols (Table 1) with different Wit-
tig reagents revealed the usefulness of this method. Reac-
tion of ethylene glycol using the same one-pot approach
gave the corresponding, a,b-unsaturated diester3h in 39%
yield. Interestingly, the product obtained from diethylene
glycol was also the same as that for ethylene glycol. The
reaction with sensitive alcohols such as 2-phenylethanol
and 3-chloropropanol (entries 2 and 10) gave the desired
products.
Abstract: Domino oxidation of primary alcohols to a,b-unsaturat-
ed compounds using the combination of PCC-NaOAc and stabi-
lized Wittig reagent and its application towards total synthesis of
ABT-418 and 4-oxonon-2-enoic acid is described.
Keywords: primary alcohols, oxidation, PCC, olefination, domino
reaction
Domino reactions1 have attracted considerable attention
as they lead to reduction in the amount of byproducts, sol-
vents, eluents, time and energy, thereby contributing to
the protection of the environment. The sequence of oxida-
tion of a primary alcohol and its condensation with a sta-
ble Wittig reagent is a routinely used step in organic
synthesis. The most common problem associated with this
sequence is the handling of intermediate aldehydes. The
isolation of intermediate aldehyde is difficult due to vola-
tility, toxicity or high reactivity. This problem has been
overcome to a great extent by the ‘one pot’ oxidation
approach2 or by more convenient way via the recently re-
ported excellent ‘in situ’ procedures.3 One of these proce-
dures uses3a,b Dess–Martin periodinane reagent as an
oxidant with a stable Wittig reagent in the presence of
benzoic acid to expedite the reaction in DMSO–CH2Cl2
(1:6) solvent mixture. The second procedure3c uses IBX in
DMSO for 21 hours to give homologated nucleosides.
The third procedure uses MnO2 as an oxidant to oxidize
activated alcohols3d–f such as allylic, benzylic and propar-
gylic alcohols in presence of a carbonyl stabilized Wittig
reagent for 5 hours to 3.5 days or N-protected b-amino
alcohols3g with the Wittig reagent by refluxing in MeCN
for 15 hours. In another similar procedure,3h allylic alco-
hols were converted to dienyl esters by using barium per-
manganate as an oxidant in presence of stable Wittig
reagent. These authors reported failure of PDC and Dess–
Martin periodinane reagent for such conversions.
Our main objective of looking towards synthesis of a,b-
unsaturated compounds in a domino approach was to ob-
tain large amount of 1-[1-methyl-2(S)-pyrrolidinyl]-1-
butene-3-one for extending our method4 of synthesis of
3,5-disubstitued isoxazole to synthesize 3-methyl-5-[1-
methyl-2(S)-pyrrolidinyl]isoxazole (ABT-418) (1), a po-
tent cholinergic agent5 and also the difficulties faced in
Ph3P=CR1-COR2
R-CH=CR1-COR2
R-CH2OH
R1= H, CH2-CH=CH2
PCC-NaOAc
CH2Cl2
R2= OEt, Me, CH2-COOMe
Scheme 1
SYNTHESIS 2004, No. 11, pp 1859–1863
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829123; Art ID: Z03404SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
4
ABT-418 (1) is a potent and selective ligand for the neu-
ronal nicotinic acetylcholine receptor and used effectively
for the treatment of Alzheimer’s disease.8 There are five

1860
J. Shet et al.
PAPER
Table 1 In situ PCC-NaOAc Oxidation-Wittig Reaction in CH2Cl2
Entry
17a
Alcohol
Product
Time, Yield (%)
COOEt
COOEt
COOEt
COOEt
1 h, 96 (E:Z = 9:1)
2 h, 70
Ph
Ph
OH
OH
OH
Ph
Ph
27b
37c
4 h, 55
47d
57a
67e
77f
4 h, 85
3 h, 70
3.5 h, 70
5 h, 60
n-C4H9-CH2OH
n-C6H13-CH2OH
n-C7H15-CH2OH
n-C13H27-CH2OH
n-C4H9
COOEt
COOEt
COOEt
n-C6H13
n-C7H15
n-C13H27
83h
93h
3 h, 39
4 h, 30
4 h, 65
1 h, 90
5 h, 72
HO
OH
COOEt
COOEt
COOEt
COMe
EtOOC
EtOOC
Cl
HO
O
OH
107g
117h
12
Cl
OH
Ph
OH
H
Ph
H
OH
N
N
COOEt
COOEt
O
137i
1 h, 50
COCH2COOMe
Ph OH
Ph
reports5 available for the synthesis of ABT-418. All these isolate the expected product. When N-ethoxycarbonyl
approaches require strongly basic conditions, which re- prolinol, prepared from L-proline in two steps was used, it
quire cryogenic conditions to avoid the problem of racem- gave the corresponding product ethyl (2S)-2-[(1E)-3-oxo-
ization or side product formation. Keeping this in mind, but-1-enyl]pyrrolidine-1-carboxylate in 72% yield. Ethyl
following Scheme 2 was visualized for the synthesis of (2S)-2-[(1E)-3-oxobut-1-enyl]pyrrolidine-1-carboxylate
ABT-418 (1). As depicted in the scheme, we use 1-tri- was then converted to oxime and the crude oxime when
phenylphosphorylidine-2-propanone for our projected subjected to our oxidative cyclization method4 failed to
synthesis of ABT-418. Therefore, we initially checked the get converted to isoxazole. Ethyl (2S)-2-[(1E)-3-oxobut-
reactivity of this Wittig reagent with benzyl alcohol. 1-enyl]pyrrolidine-1-carboxylate was then directly con-
Herein, we got the corresponding condensation product verted to 3-methyl-5-(carboethoxy)-pyrrolidine isoxazole
benzalacetone in 90% yield (entry 11).7h This was then by one pot experiment of the reported two step method9 of
converted to its oxime which without isolation was con- preparing isoxazoles in 69% yield. The conversion to
verted to 3-methyl-5-phenylisoxazole in 75% yield by ox- ABT-418 was achieved by LiAlH4 reduction of 3-methyl-
idative cyclization method using DDQ as reagent reported 5-(carboethoxy)-(S)-pyrrolidine isoxazole in 62% yield.
in our laboratory.4
The salient features of this synthesis are: i) direct conver-
sion of N-ethoxycarbonyl prolinol to ethyl (2S)-2-[(1E)-3-
oxobut-1-enyl]pyrrolidine-1-carboxylate without isola-
tion of the sensitive aldehyde, ii) no cryogenic conditions
required at any step, and iii) the one-pot conversion of
a,b-unsaturated ketones to isoxazole.
H
H
H
OH
N
R
N
R
N
NOH
O
R
After the successful synthesis of ABT-418, we decided to
use the product ethyl-(E)-non-2-enoate (entry 5) obtained
via one-pot approach towards synthesis of (E)-4-oxonon-
2-enoic acid (2), a natural antibiotic isolated from Strep-
tomyces olivaceus. There are only two reported methods
for the preparation of this compound and both these ap-
proaches require drastic conditions as well as costlier re-
agents.10,11 Our approach from n-heptanol in three steps
gave the (E)-4-oxonon-2-enoic acid (2) in 68% yield
(Scheme 3).
H
H
N
N
O
N
O
Me
N
EtOOC
1
Scheme 2
After having successfully carried out model studies, we
subjected N-methylprolinol and N-BOC-prolinol to the
same set of experiments but unfortunately, we could not
Synthesis 2004, No. 11, 1859–1863 © Thieme Stuttgart · New York

PAPER
Scheme 3
Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid
1861
K2CO3/EtOH
CrO3
56%
COOH
COOEt
COOEt
68%
O
O
2
Ethyl-2(E)-4-phenylbutenoate (Entry 2)
This protocol can also be used with other stable Wittig re-
agents for such homologations (entries 11–13). In all cas-
es except for one (entry 1), the products obtained have
exclusively E-geometry.
1H NMR (300 MHz, CDCl3, TMS): d = 1.28 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 3.54 (br d, J = 6.8 Hz, 2 H, CH2), 4.18 (q, J = 7.1 Hz, 2
H, OCH2CH3), 5.80 (d, J = 15.0 Hz, 1 H, CH=CHCO), 7.00–7.50
(m, 6 H, ArH, CH=CHCO).
In conclusion, we have developed a mild and general
method for domino primary alcohol oxidation-Wittig re-
action for the synthesis of a,b-unsaturated compounds.
The easy availability of PCC and comparatively milder
Wittig reaction conditions of this protocol should provide
a powerful alternative for the preparation of fuctionalized
a,b-unsaturated compounds and may find widespread use
in organic synthesis. The synthesis of enantiopure12 ABT-
418 (1) and (E)-4-oxonon-2-enoic acid (2) illustrates the
usefulness of this method. We are presently exploring this
reaction and its intramolecular version for the synthesis of
pyrrolizidine alkaloids.
Ethyl-2(E)-4-methylpentenoate (Entry 3)
1H NMR (300 MHz, CDCl3, TMS): d = 1.00 (t, J = 6.9 Hz, 3 H,
CH3CHCH3), 1.05 (t, J = 6.9 Hz, 3 H, CH3CHCH3), 1.30 (t, J = 7.1
Hz, 3 H, OCH2CH3), 2.22 (m, 1 H, CH3CHCH3), 4.20 (q, J = 7.1 Hz,
2 H, OCH2CH3), 5.78 (dt, J = 16.0, 1.5 Hz, 1 H, CH=CHCO), 6.95
(td, J = 16.0, 7.0, 1.5 Hz, 1 H, CH=CHCO).
Ethyl-2(E)-heptenoate (Entry 4)
1H NMR (300 MHz, CDCl3, TMS): d = 0.91 (t, J = 7.2 Hz, 3 H,
CH2CH3), 1.29 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.33–1.50 (m, 4 H,
2 × CH2), 2.02 (m, 2 H, CH2CH=CH), 4.20 (q, J = 7.0 Hz, 2 H,
OCH2CH3), 5.82 (dt, J = 15.6, 1.5 Hz, 1 H, CH=CHCO), 6.97 (td,
J = 15.6, 6.7, 1.5 Hz, 1 H, CH=CHCO).
Ethyl-2(E)-nonenoate (Entry 5)
All melting points are uncorrected and measured by normal thiels
tube (paraffin) method. Column chromatography was performed on
silica gel 60–120 mesh size and TLC on silica gel G (13% CaSO4 as
binder). IR spectra were recorded on a Shimadzu FT-IR spectro-
phometer (KBr pellet or neat sample). 1H NMR and 13C NMR were
recorded on a Brucker-300 MHz instrument. The multiplicities of
carbon signals were obtained from DEPT experiments.
1H NMR (300 MHz, CDCl3, TMS): d = 0.89 (t, J = 6.8 Hz, 3 H,
CH2CH3), 1.29 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.23–1.50 (m, 8 H,
4 × CH2), 2.20 (m, 2 H, CH2CH=CH), 4.19 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 5.81 (dt, J = 15.6, 1.4 Hz, 1 H, CH=CHCO), 6.97 (td,
J = 15.6, 6.7, 1.4 Hz, 1 H, CH=CHCO).
Ethyl-2(E)-decenoate (Entry 6)
1H NMR (300 MHz, CDCl3, TMS): d = 0.90 (t, J = 6.7 Hz, 3 H,
CH2CH3), 1.10–1.65 (m, 10 H, 5 × CH2), 1.21 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.18 (m, 2 H, CH2CH=CH), 4.20 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 5.80 (dt, J = 17.1, 1.6 Hz, 1 H, CH=CHCO), 6.97 (td,
J = 17.1, 7.0, 1.6 Hz, 1 H, CH=CHCO).
Synthesis of 3-Methyl-5-phenylisoxazole; Typical Procedure
Benzalacetone oxime (0.5 g, 3.1 mmol) and DDQ (1.4 g, 6.2 mmol)
mixture was stirred for 5 h in MeOH (5mL). The reaction mixture
was then concentrated and adsorbed on silica gel. The column chro-
matographic separation using EtOAc–hexanes (1:9) as eluent gave
the product as a colourless solid (0.372 g, 75%); mp 67 °C.
Ethyl-2(E)-hexadecenoate (Entry 7)
1H NMR (300 MHz, CDCl3, TMS): d = 2.32 (s, 3 H, CH3), 6.35 (s,
1 H, 4-H), 7.41 (m, 3 H, Ar-H), 7.75 (m, 2 H, ArH).
1H NMR (300 MHz, CDCl3, TMS): d = 0.95 (t, J = 6.7 Hz, 3 H,
CH2CH3), 1.20–1.70 (m, 22 H, 11 × CH2), 1.22 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.19 (m, 2 H, CH2CH=CH), 4.20 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 5.80 (dt, J = 15.9, 1.8 Hz, 1 H, CH=CHCO), 6.97 (td,
J = 15.9, 7.3, 1.8 Hz, 1 H, CH=CHCO).
Domino Primary Alcohol Oxidation–Wittig Reaction; General
Procedure (Table 1, Entries 1–13)
To a magnetically stirred suspension of pyridinium chlorochromate
(1.5 mmol) and sodium acetate (1.5 mmol) in anhyd CH2Cl2 (10
mL), alcohol (1 mmol) in anhyd CH2Cl2 (5 mL) was added, fol-
lowed by the Wittig reagent (1 mmol) in one portion. Et2O (5 mL)
was added after the completion of the reaction and the supernatant
solution was decanted from the black granular solid. The combined
organic solutions were filtered through a short pad celite and the fil-
trate obtained was evaporated to give a residue. Purification of the
residue by column chromatography using hexanes as eluent gave
the product.
Diethylhexa-2(E),4(E)-diene-1,6-dioate (Entries 8 and 9)
1H NMR (300 MHz, CDCl3, TMS): d = 1.29 (t, J = 7.2 Hz, 6 H, 2 ×
OCH2CH3), 4.22 (q, J = 7.1 Hz, 4 H, 2 × OCH2CH3), 6.16–6.21 (m,
2 H, 2 × CH=CHCO), 7.26–7.33 (m, 2 H, 2 × CH=CHCO).
Ethyl-2(E)-5-chloropentenoate (Entry 10)
1H NMR (300 MHz, CDCl3, TMS): d = 1.23 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 2.63 (q, J = 6.7 Hz, 2 H, ClCH2CH2), 3.57 (t, J = 6.7
Hz, 2 H, ClCH2CH2), 4.17 (q, J = 7.1 Hz, 2 H, OCH2CH3), 5.87 (dt,
J = 15.7, 1.7 Hz, 1 H, CH=CHCO), 6.83 (td, J = 15.7, 6.8, 1.7 Hz,
1 H, CH=CHCO).
Ethyl Cinnamate (Entry 1, E and Z)
1H NMR (300 MHz, CDCl3, TMS): d = 1.26 (t, J = 7.2 Hz, 3 H,
OCH2CH3), 1.33 (t, J = 7.2 Hz, 3 H, OCH2CH3), 4.17 (q, J = 7.2 Hz,
2 H, OCH2CH3), 4.26 (q, J = 7.2 Hz, 2 H, OCH2CH3), 5.93, 6.43 (2
d, J = 12.0, 15.9 Hz, 1 H, CH=CHCO), 6.95, 7.90 (2 d, J = 12.0, 15.9
Hz, 1 H, CH=CHCO).
Ethyl (2S)-2-[(1E)-3-Oxobut-1-enyl]pyrrolidine-1-carboxylate
(Entry 12)
[a]D25 –89.78 (c = 2.3, CHCl3).
1H NMR (300 MHz, CDCl3, TMS): d = 1.26 (t, J = 6.9 Hz, 3 H,
COOCH2CH3), 1.85–1.93 (m, 3 H), 2.13–2.2 (m, 2 H), 2.26 (s, 3 H,
COCH3), 3.47 (t, J = 7.5 Hz, 1 H), 4.11 (q, J = 6.9 Hz, 2 H,
Synthesis 2004, No. 11, 1859–1863 © Thieme Stuttgart · New York

1862
J. Shet et al.
PAPER
COOCH2CH3), 4.5 (m, 1 H, CH), 6.07 (d, J = 15.9 Hz, 1 H,
CH=CHCO), 6.69 (d, J = 15.9 Hz, 1 H, CH=CHCO).
13C NMR (75 MHz, CDCl3, TMS): d = 14.7, 23.18, 27.28, 31.07,
46.61, 57.99, 61.13, 129.75, 140.87, 155.0, 198.04.
was stirred for 2 h at ambient temperature. Benzene (5 mL) was
added and the mixture cooled in an ice-bath and cautiously neutral-
ized with concd KOH solution. The two-phase mixture was then
poured into water (20 mL) and extracted with Et2O (4 × 15 mL). The
combined Et2O extracts were washed with sat. NaHCO3 (3 × 5 mL)
and then with brine solution. The organic extracts were dried over
anhyd Na2SO4 and evaporated. The residue obtained was further pu-
rified by column chromatography using EtOAc–hexanes (1:9) as an
eluent, which gave the product as colourless oil (0.3 g, 1.5 mmol,
56.60%).
1H NMR (300 MHz, CDCl3, TMS): d = 0.88 (t, J = 6.7 Hz, 3 H,
COOCH2CH3), 1.23–1.47 [m, 6 H, (CH2)3], 1.29 (t, J = 7.3 Hz, 3 H,
CH2CH3), 2.62 (t, J = 7.5 Hz, 2 H, CH2C=O), 4.26 (q, J = 7.3 Hz, 2
H, COOCH2CH3), 6.62 (d, J = 16.07 Hz, 1 H, CH=CHCO), 7.06 (d,
J = 16.07 Hz, 1 H, CH=CHCO).
EIMS: m/z (%) = 212 (8.7) [M + 1], 169 (22.5), 142 (100), 96 (20),
70 (83.7), 29 (100).
Methyl (4E)-3-Oxo-5-phenylpent-4-enoate (Entry 13)
1H NMR (300 MHz, CDCl3, TMS): d = 3.67, 5.14, 11.87 (3 s, 2 H,
CH2, HC=COH, HC=COH), 3.71, 3.72 (2 s, 3 H, OCH3), 6.37 (dd,
J = 15.9, 1.2 Hz, 1 H, CH=CHCO), 6.42 (d, J = 16.2 Hz, 1 H,
CH=CHCO). 7.27–7.57 (m, 5 H, ArH).
Synthesis of 3-Methyl-5-(carboethoxy)pyrrolidinylisoxazole;
Typical Procedure
To ethyl (2S)-2-[(1E)-3-oxobut-1-enyl]pyrrolidine-1-carboxylate
(0.718 g, 3.4 mmol) was added hydroxylamine hydrochloride
(0.284 g, 4.1 mmol) in THF–H2O (9:1) and the reaction mixture was
stirred for 2 h. Then, KI (1.97 g, 11.9 mmol), iodine (0.863 g, 3.4
mmol), and NaHCO3 (1.13 g, 13.6 mmol) was added and refluxed
for 16 h. The mixture was then cooled to r.t. and diluted with 1.7 M
sodium bisulphite solution (10 mL) and extracted with Et2O (3 × 15
mL). The combined Et2O extracts were washed with brine solution
and dried with anhyd Na2SO4. The solvent was evaporated off and
the product obtained was further purified by column chromatogra-
phy using EtOAc–hexanes (1:9) as eluent, which gave the product
(0.525 g, 69%) as a colourless oil; [a]D25 –123.92 (c = 1.19, CHCl3).
Synthesis of (E)-4-Oxonon-2-enoic Acid (2); Typical Procedure
To a solution of ethyl-2-(E)-4-oxononate (0.1 g, 0.5 mmol) in EtOH
(5 mL) was added K2CO3 (1 mmol) and stirred for 2 h. The reaction
mixture was concentrated under vacuum. Water (5 mL) was added
followed by acidification with dilute HCl acid. The aq layer was ex-
tracted with Et2O (3 × 10 mL). The crude solid product obtained af-
ter drying and evaporation of the solvent was purified by column
chromatography using EtOAc–hexanes (1:4) as an eluent to give the
white solid (0.058 g, 68.23%); mp 104 °C.
1H NMR (300 MHz, CDCl3, TMS): d = 0.9 (t, J = 7.3 Hz, 3 H,
CH2CH3), 1.25–1.66 (m, 6 H, 3 × CH2), 2.66 (t, J = 7.3 Hz, 2 H,
CH2CO), 6.66 (d, J = 16.0 Hz, 1 H, CH=CHCO), 7.12 (d, J = 16.0
Hz, 1 H, CH=CHCO), 10.60 (br s, 1 H, exchangeable with D2O,
COOH).
1H NMR (300 MHz, CDCl3, TMS): d = 1.24 (t, J = 6.9 Hz, 3 H,
COOCH2CH3), 1.86–2.12 (m, 3 H), 2.12–2.18 (m, 2 H, CH2), 2.24
(s, 3 H, CH3), 3.48 (t, J = 7.5 Hz, 1 H), 4.10 (q, J = 6.9 Hz, 2 H,
COOCH2CH3), 4.9 (m, 1 H, CH), 5.98 (s, 1 H, =CH).
13C NMR (75 MHz, CDCl3, TMS): d = 11.50, 14.47, 24.34, 31.78,
46.00, 62.00, 102, 154, 160.
Acknowledgment
We thank the CSIR (New Delhi) for support of this work, Prof. S.
Chandrasekaran IISc, Bangalore for providing HPLC facilities and
Dr. A. R. A. S. Deshmukh NCL, Pune for recording [a]D values and
NIO, Dona Paula, Goa for spectral analysis.
EIMS: m/z (%) = 223 (12.5) [M + 1], 151 (25), 123 (12.5), 110 (10),
82 (30), 41 (41.2), 29 (100).
Synthesis of 3-Methyl-5-[1-methyl-2(S)-pyrrolidinyl]isoxazole
(1) (ABT-418); Typical Procedure
To a stirred solution of 3-methyl-5-(carboethoxy)-pyrrolidinyl isox-
azole (0.2 g, 0.89 mmol) in anhyd THF (20 mL) cooled at 0 °C, was
added LiAlH4 (1.78 mmol) in small portions and the mixture was
stirred for 15 min. The reaction was quenched by adding few drops
of EtOAc followed by aq sat. Na2SO4 (10 mL) and extracted with
EtOAc (3 × 10 mL) and the solvent concentrated. The crude residue
was dissolved in dilute HCl acid (1 N, 30mL) and washed with
EtOAc (2 × 10 mL). The aq layer was then neutralized with sat.
NaHCO3 solution (10 mL) and then further extracted with EtOAc (3
× 10 mL). The organic extracts were dried over anhyd Na2SO4.
Concentration under vacuum gave the compound (0.076 g) as a
light yellow oil (0.11 g, 62%); [a]D25 –111.80 (c = 1.57, CHCl3).
1H NMR (300 MHz, CDCl3, TMS): d = 1.76–2.04 (m, 3 H,), 2.11–
2.34 (m, 2 H, CH2), 2.22 (s, 3 H, CCH3), 2.26 (s, 3 H, NCH3), 3.07–
3.12 (m, 1 H), 3.36 (t, J = 7.5 Hz, 1 H, CH), 6.00 (s, 1 H, =CH).
13C NMR (75 MHz, CDCl3, TMS): d = 11.03, 22.51, 31.38, 40.30,
56.22, 61.88, 101.12, 159.17, 173.83.
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Synthesis of Ethyl-(E)-4-oxonon-2-enoate; Typical Procedure
A mixture of an oxidizing solution of chromium trioxide (100
mmol) in acetic anhydride (1 mL) and glacial HOAc (2 mL) was
added dropwise with cooling to a stirred solution of ethyl-2-(E)-
nonate (0.5 g, 2.7 mmol) in benzene (5 mL). The reaction mixture
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Synthesis 2004, No. 11, 1859–1863 © Thieme Stuttgart · New York

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Total Synthesis of ABT-418 and (E)-4-Oxonon-2-enoic Acid
1863
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C.; Bhat, N. G.; Campbell, B. Jr. J. Org. Chem. 1986, 51,
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(12) Enantiomeric purity of the products ethyl (2S)-2-[(1E)-3-
oxobut-1-enyl]pyrrolidine-1-carboxylate, 3-methyl-5-
(carboethoxy)pyrrolidinyl isoxazole, 3-methyl-5-[1-methyl-
2-(S)-pyrrolidinyl] isoxazole (ABT-418) were determined
on chiral AD-column as reported in an earlier synthesis (see
reference 5b).
(8) Arneric, S. P.; Anderson, D. J.; Bannon, A. W.; Briggs, C.
A.; Buccafusco, J. J.; Brioni, J.; Cannon, J. B.; Decker, M.
Synthesis 2004, No. 11, 1859–1863 © Thieme Stuttgart · New York