α-Bromo-β,γ-unsaturated ketenes for the synthesis of α-benzylamino-β,γ-unsaturated acids

Article abstract of DOI:10.1016/j.tetasy.2003.12.029

The synthesis of α-benzylamino-β,γ-unsaturated acids has been developed starting from α-bromo-α,β-unsaturated chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the deconjugated ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine, followed by acid hydrolysis, allowed to us obtain enantiomerically enriched α-benzylamino-β,γ-unsaturated acids.

Full text of DOI:10.1016/j.tetasy.2003.12.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 593–601
a-Bromo-b,c-unsaturated ketenes for the synthesis of
a-benzylamino-b,c-unsaturated acids
Giuliana Cardillo,* Serena Fabbroni, Luca Gentilucci, Rossana Perciaccante and
Alessandra Tolomelli
Dipartimento di Chimica ÔG. CiamicianÕ, Universitꢀa di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 11 July 2003; accepted 17 December 2003
Abstract—The synthesis of a-benzylamino-b,c-unsaturated acids has been developed starting from a-bromo-a,b-unsaturated
chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the decon-
jugated ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine,
followed by acid hydrolysis, allowed to us obtain enantiomerically enriched a-benzylamino-b,c-unsaturated acids.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
R
O
R
O
TEA (1.1 equiv)
THF
R'
R'
C
Cl
Over the last few years, extensive studies have been
undertaken regarding the synthesis of unusual amino
acids.1 Among them a,b-unsaturated amino acids have
attracted high interest as valuable intermediates in the
synthesis of bioactive dehydropeptides and as starting
materials for the synthesis of uncommon enantiomeri-
cally pure amino acids.2 Synthetic and naturally occur-
ring b,c-unsaturated amino acids3 are known to
function as specific enzyme inhibitors of pyridoxal
phosphate-dependent enzymes.4 In addition, it has been
demonstrated that the introduction of alkyl, alkenyl or
aryl groups in the backbone or at the nitrogen of amino
acid residues, allows the synthesis of conformationally
constrained peptides with a rigidified secondary struc-
ture and an improved bioactivity and selectivity.5
R" Br
R" Br
1
(R)-Pantolactone
a: R = R' = R" = H
(1 equiv)
b: R = Me, R' = R" = H,
c: R = H, R' = H, R" = Et
d: R = Me, R' = H, R" = n-Pr
R
O
O
O
*
R'
O
R" Br
2
Scheme 1. Diastereoselective synthesis of a-bromo ester 2.
ester in high yield and selectivity. In a similar way, we
treated the a,b-unsaturated a-bromo acyl chlorides with
triethylamine in order to obtain the simultaneous
deconjugation of the double bond and the formation of
the ketenes9 that were in turn trapped by (R)-pantolac-
tone. The unsaturated a-halo esters were obtained in
good yield and good to excellent diastereomeric excess
(Scheme 1).
As part of a program directed to preparing b,c-unsat-
urated amino acids, we envisaged starting from a-bro-
mo-b,c-unsaturated ketenes,6 which are well known as
intermediates in the synthesis of organic molecules and
have been widely employed for the preparation of dia-
stereomeric esters.7 The generation of saturated a-hal-
ogenated ketenes from a-halo acid halides, as precursors
of a-amino acids, has already been reported.8 The in situ
preparation of the labile ketene and its treatment with
an enantiomerically pure alcohol, afforded a-bromo
2. Results and discussion
The preparation of chloride 1 involved simple treatment
of the a,b-dibromo acid with piperidine to obtain the
monobromo unsaturated derivative.10 The a-bromo acid
* Corresponding author. Tel.: +39-051-2599570; fax: +39-051-20994-
56; e-mail: cardillo@ciam.unibo.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.029

594
G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
Table 1. Synthesis of a-bromo-b,c-unsaturated esters 2a–d
Entry
Acyl chloride 1
TEA
(equiv)
T (ꢁC)
Time (h)
Yield of
2 (%)
Ratio of diastereomersa
2R/2S
Ee (%)
1
2
3
4
5
6
7
1a
1a
1b
1b
1c
1d
1d
1.1
1.1
1.1
2
)70 ꢁC fi )40 ꢁC
)70 ꢁC
)70 ꢁC
)50 ꢁC fi )20 ꢁC
)50 ꢁC fi )20 ꢁC
)50 ꢁC fi )20 ꢁC
)50 ꢁC fi )r.t.
2
2
60
60
50
85
65b
60
60
85:15
92:8
70
84
2.5
2.5
3
>95:5
92:8
>90
84
1.1
1.1
1.1
72:28
>95:5
50:50
44
7
14
>90
0
a Determined on the basis of 1H NMR signals.
b A 15% amount of the conjugated bromo ester was observed in the crude mixture.
was then converted to the corresponding acid halide,
which was purified by distillation under reduced pres-
sure.
the ester 2 with benzylamine and triethylamine in THF
(Scheme 2).
The subsequent reaction was performed by adding
dropwise the a-bromo halide 1 in dry THF and a solu-
tion of triethylamine in THF, to a stirred solution of
chiral alcohol for two hours at low temperatures. The
reaction proceeded with good to excellent diastereo-
selectivity in the presence of (R)-pantolactone. However,
using either ethyl lactate or (1S,2R)-N-Ts-ephedrine as
the chiral source, lowered the diastereomeric excess.6a
Some selected results of the reaction performed with
pantolactone are given in Table 1.
R'
O
R'
O
Benzylamine,
TEA
O
O
O
O
*
*
R
R
O
O
Ph
THF, r.t.
R" Br
R" HN
3b (yield 90%, d.r.92/8)
3c (yield 64%, d.r.61/39)
3d (yield 80%, d.r.94/6)
2b (d.r. 92/8)
2c (d.r.72/28)
2d (d.r.>95/5)
Scheme 2. Substitution with benzylamine on bromo derivative 2.
The displacement of bromine occurred easily on 2b
affording the corresponding benzylamino derivatives 3b
in 92:8 d.r., as determined from the H NMR signals of
The reaction of 1a with 1.1 equiv of TEA, from )70 to
)40 ꢁC for 2 h, afforded 2a with good yield and 85/15
d.r. (entry 1). Increased diastereoselectivity (92:8) was
observed while maintaining the temperature at )70 ꢁC
(entry 2). When the reaction was performed with 2 equiv
of TEA, the exclusive formation of the a-bromo-croto-
nyl ester was observed. For 2-bromo-3-methyl-but-2-
enoyl chloride 1b, high diastereoselectivity and moder-
ate yield were obtained at )70 ꢁC with 1.1 equiv of TEA
(entry 3), while the use of 2 equiv of base at higher
temperatures showed an increase in yield while still
maintaining a good d.r. (entry 4). In the same temper-
ature range, the reaction performed with 2-bromo-hex-
2-enoyl chloride 1c and an equimolar amount of base,
furnished 2c with good diastereoselectivity, although
15% of the corresponding conjugate bromo-ester was
detected (entry 5). Under the same reaction conditions,
compound 2d was obtained in 60% yield as a single
diastereoisomer from the reaction performed on 2-bro-
mo-3-methyl-hex-2-enoyl chloride 1d (entry 6). On
warming the reaction mixture at r.t. overnight, complete
epimerisation was observed (entry 7). The diastereo-
meric ratios of a-bromo esters 2a–d were determined
1
the C30 pantolactone proton (5.45 ppm for the major
isomer, 5.41 ppm for the minor one) and by GC–MS
analysis. In a similar way, 2d gave 3d in 94:6 d.r.,
established on the 1H NMR signals at 5.48 ppm (major)
and 5.43 ppm (minor). The substitution of the benzyl-
amine on the bromoderivative 2c afforded 3c with 61:39
d.r. Therefore the reaction occurred with appreciable
epimerisation. On the other hand, treatment of 2a under
the same conditions afforded a mixture of compounds
deriving both from the substitution and the 1,4-addition
of benzylamine on the reconjugated derivative.
The configuration of the newly generated stereogenic
centre in the predominant isomer of 3b, was easily pro-
ven by conversion to valine methyl ester 6 (Scheme 3).
Compound 3b was refluxed in 6 M HCl for 2 h. (R)-
pantolactone was recovered after purification of the
unsaturated benzyl amino acid 4b with a cation exchange
resin. Acid 4b was then treated with CH2N2/Et2O to give
the corresponding methyl ester 5b in a quantitative yield.
Compound 5b was purified by flash chromatography
with HPLC analysis on chiral column showing the same
enantiomeric excess as the diastereomeric excess of the
starting pantolactone ester 3b.
1
through the H NMR spectrum of the crude mixture,
based on the signal of the proton at the stereogenic
centre of pantolactone.7a
The unsaturated esters 2 were quite stable at low tem-
perature. However, slow racemisation was observed
when the temperature was raised to room temperature.
Furthermore, during the purification by flash chroma-
tography on silica gel, some epimerisation occurred. For
this reason the substitution of the bromine was per-
formed on the crude diastereomeric mixture by treating
The absolute configuration was established by reduction
of 5b with Pd(OH)2 in methanol for two hours. Under
these conditions the removal of the benzyl group and the
reduction of the double bond furnished valine methyl
ester 6 in quantitative yield. The specific rotation
{½aꢀ ¼ 11.7, (c ¼ 0:8, MeOH)} compared with the data
D
in literature11 allowed us to assign an (S) absolute

G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
595
Finally, the hydrolysis of 3d gave the N-benzyl-b,c-
unsaturated amino acid 4d in 88% ee, as established by
the HPLC analysis of the corresponding methyl ester 5d
(Scheme 5).
O
O
O
O
HCl 6M
OH
Ph
O
Ph
reflux, 2h
80%
HN
HN
4b
3b
CH2N2
MeOH
95%
O
O
HCl 6M
O
O
R*
Ph
OH
Ph
Pd(OH)2
OMe
OMe
Ph
reflux, 2h
HN
HN
MeOH, 2h
55%
NH2
HN
4d
3d
5b
L-valine methyl ester 6
[α]D = +11.7 (c 0.8, MeOH)
lit. [α]D = +14.9 (c 1.2, MeOH)
O
CH2N2
MeOH
e.e. 82%
OMe
Ph
HN
Scheme 3. Conversion of 3b into L-valine methyl ester.
5d
[α]D20= +44.6 (c 1, CHCl3).
configuration to the major isomer. On the basis of these
results we could attribute an (R)-configuration to the
major isomer of the starting a-bromo panctolactone
ester 2b.
Scheme 5. Transformation of 3d into a-benzylamino-b,c-unsaturated
ester 5d.
1
Since the comparison of the H NMR spectra of the
bromoderivatives 2a–d showed the same trend of
chemical shifts for the hydrogens on C2 and C30, we
assigned the (R)-configuration to the major isomers of
the other bromo derivatives.
Interesting papers by Koh, Ben and Durst demonstrated
that starting from 1:1 diastereomeric mixtures of (S,R)
and (R,R) a-haloesters, the synthesis of enriched
a-amino esters can be achieved via treatment with
benzylamine through a dynamic kinetic resolution. The
enhanced yield of one diastereomer was attributed to a
dynamic process, in which the (R,R) isomer reacted
more quickly with the amine than the (S,R) isomer with
the released bromide isomerising the slower to the faster
reacting isomer.
To obtain 2-benzylamino-hex-3-enoic acid 4c, 3c was
hydrolysed by treatment with HCl (6 M) at reflux.
Unfortunately, the HPLC analysis of the corresponding
methyl ester 5c showed a decreased enantiomeric excess
(11%). The reduction of 4c with H2 in the presence of
Pd/C catalyst allowed the removal of the benzylic pro-
tecting group and the reduction of the double bond, to
afford norleucine 7 in 75% yield. The HPLC analysis, in
In a similar way, we treated a 1:1 diastereomeric mixture
of 2b, 2c or 2d with benzylamine. The reaction per-
formed on 2b afforded 3b in 62:38 d.r. while 3d was
obtained in 78:22 d.r. starting from 2d. For 3c, the d.r.
observed at the equilibrium is the same obtained starting
from a mixture of 2c with 72:28 d.r. (see Scheme 2),
suggesting that an epimerisation at the C2 stereogenic
centre occurred during the substitution. However, for 3b
and 3d, the diastereomeric ratios at the equilibrium were
lower than the ones observed starting from diastereo-
merically enriched derivatives. These results seem to
indicate that 3,3-disubtituted-a-bromo-esters are more
stable during the substitution reaction with benzyl-
amine, than the corresponding hexenoyl or crotonyl
derivatives.
comparison with the commercially available
cine, confirmed the enantiomeric excess (11%) and the
L-norleu-
(2S)-configuration of the major isomer (Scheme 4).
O
O
HCl 6M
OH
Ph
R*
Ph
reflux, 2h
63%
HN
HN
4c
3c
CH2N2
MeOH
95%
O
R* = (R)-Pantolactone
OMe
Ph
HN
With the aim of extending this methodology to the
synthesis of N-unsubstituted unsaturated amino acids,
we performed the bromine displacement with other
nitrogen nucleophiles, such as p-MeO-benzylamine and
allylamine, whose dealkylation occurs under non-hy-
drogenolytic conditions (Scheme 6). The substitution
reactions were performed under the conditions reported
above for benzylamine.
5c e.e. 11%
O
O
Pd/C
OH
OH
HN
Ph
H2, MeOH
75%
NH2
4c
L-norleucine
7
Although the substitution reactions gave excellent
results in yields and good diastereomeric ratios, the
Scheme 4. Conversion of 3c into 2-benzylamino-hex-3-enoic acid 4c
and -norleucine 7.
L

596
G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
3. Conclusion
O
O
O
O
R-NH2, TEA
THF, r.t.
O
O
*
*
O
O
The asymmetric synthesis of b,c-unsaturated a-benz-
ylamino acids 4 has been reported starting from
a-bromo-a,b-unsaturated chlorides 1. The treatment of
the acyl chlorides with (R)-pantolactone in the presence
of TEA, allowed the in situ formation of the deconju-
gated ketenes and their direct transformation into chiral
esters 2. The reactions occurred with good yields and
high diastereomeric ratios. The substitution of bromine
with benzylamine, followed by acid hydrolysis, allowed
us to synthesise enantiomerically enriched a-benzyl-
amino-b,c-unsaturated acids 4. The displacement of the
bromine with other nitrogen nucleophiles also allowed
us to synthesise N-unsubstituted-b,c-unsaturated amino
acids in good yield with complete diastereoselectivity.
Br
NH
R
2b
8 R = PMB (yield 70%, d.r. 81: 19)
9 R = CH2CH=CH2 (yield 70%,
d.r. 80 : 20)
Scheme 6. Substitution on bromo derivative 2b with p-MeO-benzyl-
amine and allylamine.
transformation of the adducts 8 and 9 into the corre-
sponding unsaturated amino acids proved troublesome
with any attempt to remove the amine protection with
previously reported methods failed.12
When the bromine displacement was performed with
O-benzylhydroxylamine, starting either from a 1:1 dia-
stereomeric mixture or from an enriched one, compound
10 was obtained as a single diastereoisomer in 55% yield
(Scheme 7). In the literature, several methods for the
reduction of hydroxylamine N–O bond have been
reported.13 We envisaged the Mo(CO)6 method13a;b to be
the more suitable for our purposes, since it does not
affect double bonds. When we submitted 10 to acidic
conditions, in order to remove the chiral auxiliary, we
4. Experimental
4.1. General procedures
Unless stated otherwise, chemicals were obtained from
commercial sources and used without further purifica-
tion. Flash chromatography was performed on Merck
silica gel 60 (230–400 mesh). NMR spectra were
recorded with a INOVA Varian spectrometer 300 MHz
or with a Gemini Varian spectrometer 200 MHz.
Chemical shifts are reported as d values relative to the
solvent peak of CDCl3 set at d ¼ 7:27 (1H NMR) or
d ¼ 77:0 (13C NMR). GC–MS analysis were performed
on HP5890 series II chromatograph with HP5971 mass
detector, HP-5 column (ultra low-bleed 5%-phenyl col-
umn based on diphenyl methylsiloxane chemistry), 50–
250 ꢁC programmed analysis. Optical rotations were
recorded with Perkin Elmer Polarimeter 343. HPLC
analysis of N-benzyl methyl esters 5 were performed on
HP1090 liquid chromatograph equipped with UV
detector, CHIRALCEL-OD chiral column, isocratic
analysis with 90:10 hexane/isopropanol as eluent,
0.5 mL/min solvent flow, UV detector at 214.4 and
220.4 nm. HPLC analysis of norleucine 7 was performed
on HP1090 liquid chromatograph equipped with UV
detector, CHIROBIOT chiral column, isocratic analysis
with 95:5 water/methanol as eluent, 0.5 mL/min solvent
flow. MS analyses were performed with a HP1100 series
mass spectrometer single quadrupole electrospray ion-
isation interface (ESI).
obtained directly the unsaturated amino acid
L-isode-
hydrovaline 11 in 33% yield,14 together with compound
12,15 deriving from the rearrangement of an a-imino
intermediate. Better results were observed in the
Mo(CO)6 reaction on 10, which allowed us to simulta-
neously remove the pantolactone with cleavage of the
N–O bond, affording isodehydrovaline 11 in 80% yield.
The comparison of the analytical data of 11 and of the
corresponding BOC derivative, with the data reported in
the literature14c;16 allowed us to assign an (S) configu-
ration to the stereogenic centre in position 2.
NH2OBn
O
O
O
THF
O
O
O
O
*
*
O
O
r.t.
55 %
Br
HN
2b
10 d.r. >95 :5
O
O
*
OH
OH
Method a: HCl 6N,
2h, reflux
+
O
4.1.1. General procedure for the preparation of a-bromo-
a,b-unsaturated chlorides 1a–c from a,b-unsaturated
acids. To a stirred solution of a,b-unsaturated acid
(10 mmol) in CH2Cl2 (10 mL), bromine (11 mmol,
0.56 mL) was added dropwise at 0 ꢁC. The mixture was
stirred overnight and then washed with a saturated
solution of Na2S2O3 to remove unreacted bromine. The
organic layer was dried over Na2SO4 and concentrated
to give the dibromo acid as a white powder. The product
was dissolved in THF (10 mL) after which piperidine
(40 mmol, 3.9 mL) was added in one portion at 0 ꢁC. The
NH2
L-isodehydrovaline 11
12
66%
33%
10
O
*
OH
Method b: Mo(CO)6,
CH3CN, 5h, reflux
NH2
80%
Scheme 7. Synthesis of L-isodehydrovaline.

G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
597
solution was stirred for 24 h at room temperature and
then quenched with HCl 6 M (10 mL). After removing
THF under reduced pressure, the aqueous acid layer
was extracted twice with EtOAc (20 mL). The collected
organic layers were dried over Na2SO4 and concentrated
to give the a-bromo acid as a white powder. SOCl2
(60 mmol, 4.4 mL) was then added to the neat product at
0 ꢁC and the mixture then refluxed for 2 h. The a-bromo-
a,b-unsaturated chlorides 1a–c were isolated as E=Z
unseparable mixtures by stilling under reduced pressure.
4.1.3. General procedure for the preparation of a-bromo-
b,c-unsaturated esters 2a–d from a,b-unsaturated chlo-
rides 1a–d. To a stirred solution of (R)-pantolactone
(2 mmol, 260 mg) in dry THF (10 mL), chloride 1
(2.1 mmol) in THF (1 mL) and TEA (1.1 or 2 equiv, see
Table 1) in THF (1 mL) were added dropwise separately
but simultaneously, at low temperatures under inert
atmosphere. The mixture was stirred at the temperature
and the time as reported in Table 1, with the exclusion of
light. The reaction was quenched with a saturated
solution of NH4Cl (5 mL) and THF then removed under
reduced pressure. The residue was diluted with Et2O
(20 mL) and washed twice with water. The organic layer
was dried over Na2SO4 and solvent removed under
reduced pressure. The crude reaction was analysed by
1H NMR with the a-bromo-b,c-unsaturated ester uti-
lised without further purification.
4.1.1.1. 2-Bromo-but-2-enoyl chloride 1a. Yield 82%
(major isomer) 1H NMR (CDCl3) d 2.05 (d, 3H,
J ¼ 7:8 Hz), 6.80 (q, 1H, J ¼ 7:8 Hz). (minor isomer) 1H
NMR (CDCl3) d 2.13 (d, 3H, J ¼ 6:9 Hz), 7.89 (q, 1H,
J ¼ 6:9 Hz).
4.1.1.2. 2-Bromo-3-methyl-but-2-enoyl chloride 1b.
Yield 55% 1H NMR (CDCl3) d 2.11 (s, 3H), 2.13 (s, 3H).
4.1.3.1. 2-Bromo-but-3-enoic acid 4,4-dimethyl-2-oxo-
tetrahydro-furan-3-yl ester 2a. (2R,30R): 1H NMR
(CDCl3) d 1.18 (s, 3H), 1.25 (s, 3H), 4.10 (s, 2H), 4.94 (d,
1H, J ¼ 9:3 Hz), 5.41 (s, 1H), 5.38–5.57 (m, 2H), 6.22
(dt, 1H, J ¼ 16:2 Hz, 9.3 Hz).
4.1.1.3. 2-Bromo-hex-2-enoyl chloride 1c. Yield 49%
(major isomer) 1H NMR (CDCl3) d 1.02 (t, 3H,
J ¼ 7:2 Hz), 1.58–1.68 (m, 2H), 2.47 (m, 2H), 7.8 (t, 1H,
J ¼ 6:9 Hz). (minor isomer) 1H NMR (CDCl3) d 0.95 (t,
3H, J ¼ 7:2 Hz), 1.48–1.57 (m, 2H), 2.40 (m, 2H), 6.68
(t, 1H, J ¼ 7:8 Hz).
1
(2S,30R): H NMR (CDCl3) d 1.19 (s, 3H), 1.26 (s, 3H),
4.10 (s, 2H), 4.99 (d, 1H, J ¼ 9:3 Hz), 5.41 (s, 1H), 5.38–
5.57 (m, 2H), 6.22 (dt, 1H, J ¼ 16:2 Hz, 9.3 Hz).
4.1.2. Preparation of a-bromo-a,b-unsaturated chlorides
1d from ethyl 3-methyl-hex-2-enoate. To a stirred solu-
tion of ethyl 3-methyl-hex-2-enoate (10 mmol) in
CH2Cl2 (10 mL) at 0 ꢁC, bromine (11 mmol, 0.56 mL)
was added dropwise. The mixture was stirred overnight
and then washed with a saturated solution of Na2S2O3
to remove unreacted bromine. The organic layer was
dried over Na2SO4 and concentrated to give the di-
bromo ester as a yellow oil. The product was dissolved
in THF (10 mL) and then piperidine (40 mmol, 3.9 mL)
added in one portion at 0 ꢁC. The solution was stirred
for 24 h at room temperature and then quenched with
HCl 6 M (10 mL). After removing THF under reduced
pressure, the acid aqueous layer was extracted twice
with EtOAc (20 mL). The collected organic layers were
dried over Na2SO4 and concentrated to give the a-bro-
mo ester as a yellow oil. The product was refluxed in a
1:1 solution of 1 M NaOH/MeOH (10 mL) for 3 h and
then, after removing methanol under reduced pressure,
1 M HCl was added to the aqueous residue to pH ¼ 3.
The solution was extracted twice in EtOAc (20 mL), the
collected organic layers dried over Na2SO4 and con-
centrated to give the a-bromo acid as a white powder.
SOCl2 (60 mmol, 4.4 mL) was then added to the neat
product at 0 ꢁC and the solution then refluxed for 2 h.
The a-bromo-a,b-unsaturated chloride 1d was distilled
under reduced pressure.
4.1.3.2. 2-Bromo-3-methyl-but-3-enoic acid 4,4-di-
methyl-2-oxo-tetrahydro-furan-3-yl ester 2b. (2R,30R):
1H NMR (CDCl3) d 1.15 (s, 3H), 1.28 (s, 3H), 2.02 (s,
3H), 4.07 (s, 2H), 5.07 (d, 1H, J ¼ 1 Hz), 5.17 (m, 1H),
5.33 (s, 1H), 5.38 (s, 1H).
1
(2S,30R): H NMR (CDCl3) d 1.15 (s, 3H), 1.28 (s, 3H),
1.99 (s, 3H), 4.07 (s, 2H), 5.07 (d, 1H, J ¼ 1 Hz), 5.17
(m, 1H), 5.31 (s, 1H), 5.40 (s, 1H).
4.1.3.3. 2-Bromo-hex-3-enoic acid 4,4-dimethyl-2-oxo-
1
tetrahydro-furan-3-yl ester 2c. (2R,30R): H NMR (CD-
Cl3) d 1.04 (t, 3H, J ¼ 9:5 Hz), 1.20 (s, 3H), 1.25 (s, 3H),
2.23 (br t, 2H, J ¼ 9:6 Hz), 4.18 (s, 2H), 4.93 (d, 1H,
J ¼ 9:6 Hz), 5.36 (s, 1H), 5.76–6.05 (m,2H).
1
(2S,30R): H NMR (CDCl3) d 1.04 (t, 3H, J ¼ 9:5 Hz),
1.20 (s, 3H), 1.25 (s, 3H), 2.23 (br t, 2H, J ¼ 9:6 Hz),
4.18 (s, 2H), 4.97 (d, 1H, J ¼ 9:6 Hz), 5.39 (s, 1H), 5.76–
6.05 (m, 2H).
4.1.3.4. 2-Bromo-3-methyl-hex-3-enoic acid 4,4-di-
methyl-2-oxo-tetrahydro-furan-3-yl ester 2d. (2R,30R):
1H NMR (CDCl3) d 0.84 (t, 3H, J ¼ 7:8 Hz), 1.18 (s,
3H), 1.24 (s, 3H), 1.55–1.62 (m, 2H), 2.22–2.36 (m, 2H),
4.07 (s, 2H), 5.03 (br s, 1H), 5.20 (br s, 1H), 5.37 (s, 1H),
5.45 (s, 1H).
4.1.2.1. 2-Bromo-3-methyl-hex-2-enoyl chloride 1d.
1
Yield 49% (major isomer) H NMR (CDCl3) d 0.99 (t,
3H, J ¼ 7:5 Hz), 1.50–1.60 (m, 2H), 2.08 (s, 3H), 2.40 (m,
1
1
2H). (minor isomer) H NMR (CDCl3) d 0.94 (t, 3H,
(2S,30R): H NMR (CDCl3) d 0.84 (t, 3H, J ¼ 7:8 Hz),
J ¼ 7:2 Hz), 1.50–1.60 (m, 2H), 2.05 (s, 3H) 2.40 (m, 2H).
1.18 (s, 3H), 1.24 (s, 3H), 1.55–1.62 (m, 2H), 2.22–2.36

598
G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
(m, 2H), 4.07 (s, 2H), 5.03 (br s, 1H), 5.20 (br s, 1H),
5.40 (s, 1H), 5.45 (s, 1H).
J ¼ 1 Hz), 5.14 (d, 1H, J ¼ 1 Hz), 5.48 (s, 1H), 7.24–7.31
(m, 5H). 13C NMR (CDCl3) d 13.8, 19.7, 20.7, 23.0,
35.4, 40.4, 51.5, 64.9, 75.2, 76.1, 113.3, 127.1, 128.3,
128.4, 139.5, 146.0, 171.9, 172.4.
4.1.4. General procedure for the preparation of a-
benzylamino-b,c-unsaturated esters 3a–d from a-bromo-
b,c-unsaturated esters 2a–d. A solution of 2 (2 mmol),
TEA (2.2 mmol, 0.3 mL) and benzylamine (2.4 mmol,
0.26 mL) in dry THF (10 mL) was stirred overnight at
room temperature. After removing THF under reduced
pressure, the residue was diluted with EtOAc (20 mL)
and washed twice with water (10 mL). Compound 3 was
isolated pure by flash chromatography on silica gel
(cyclohexane/EtOAc, 8:2).
1
(2R,30R): H NMR (CDCl3) d 0.97 (t, 3H, J ¼ 7:8 Hz),
1.13 (s, 3H), 1.25 (s, 3H), 1.47–1.58 (m, 2H), 2.04 (br s,
1H), 2.05–2.27 (m, 2H), 3.77 (d, 1H, J ¼ 12:8 Hz), 3.84
(d, 1H, J ¼ 12:8 Hz), 4.00 (s, 1H), 4.07 (s, 2H), 5.09 (d,
1H, J ¼ 1 Hz), 5.17 (d, 1H, J ¼ 1 Hz), 5.43 (s, 1H),
7.24–7.31 (m, 5H). 13C NMR (CDCl3) d 13.8, 19.8, 20.7,
23.0, 35.1, 40.2, 51.4, 65.2, 75.3, 76.1, 113.2, 127.1,
20
D
128.3, 128.4, 139.5, 145.2, 171.6, 172.4. ½aꢀ ¼ +17.2 (c
0.8; CHCl3).
4.1.5. Transformation of ester 3b into
L-Valine methyl
4.1.4.1. 2-Benzylamino-3-methyl-but-4-enoic acid 4,4-
dimethyl-2-oxo-tetrahydro-furan-3-yl ester 3b. (2S,30R):
1H NMR (CDCl3) d 1.09 (s, 3H), 1.20 (s, 3H), 1.83 (s,
3H), 3.77 (s, 2H), 4.03 (s, 1H), 4.06 (s, 2H), 5.10 (m, 2H),
5.45 (s, 1H), 7.20–7.40 (m, 5H). 13C NMR (CDCl3) d
18.9, 19.6, 22.9, 40.4, 65.7, 75.1, 76.4, 115.5, 126.9,
128.1, 128.2, 139.2, 141.0, 171.7; GC–MS r.t. 24.76 min,
m=z 317 (1), 204 (2), 160 (100), 91 (58), 65 (6).
ester 6. A solution of 3b (1 mmol, 317 mg) in HCl 6 M
(5 mL) was refluxed for 2 h. After cooling to r.t., the
aqueous mixture was concentrated and the residue dis-
solved in methanol (1 mL). The solution was adsorbed
on a cation exchange resin (Dowex 50). (R)-pantolac-
tone was recovered from the methanol eluate in almost
quantitative yield. The resin was washed with distilled
water until the washing came out neutral, then with
1.5 M NH4OH. After evaporation of the aqueous solu-
tion, 4b was isolated in 80% yield. The product was then
diluted in MeOH and treated with an ethereal solution
of CH2N2 until persistence of a yellow colour. Elimi-
nation of the solvents under reduced pressure allowed us
to obtain 5b in 95% yield. Pd(OH)2 (40 mg) was added to
a solution of 5b in MeOH (15 mL). The reaction flask
was evacuated, purged with hydrogen five times, and
then stirred under a hydrogen atmosphere (40 psi) for
2 h. The solution was filtered over celite and concen-
(2R,30R): 1H NMR (CDCl3) d 1.09 (s, 3H), 1.20 (s, 3H),
1.86 (s, 3H), 3.77 (s, 2H), 3.97 (s, 1H), 4.06 (s, 2H), 5.10
(m, 2H), 5.41 (s, 1H), 7.20–7.40 (m, 5H). 13C NMR
(CDCl3) d 18.9, 19.7, 22.9, 40.1, 65.8, 75.2, 76.4, 115.2,
126.9, 128.1, 128.2, 139.2, 140.9, 171.3; GC–MS r.t.
24.58 min, m=z 317 (2), 204 (2), 160 (100), 91 (100), 65
20
D
(8). ½aꢀ ¼ +30.7 (c 1; CHCl3).
4.1.4.2. 2-Benzylamino-hex-3-enoic acid 4,4-dimethyl-
1
trated to give L-valine methyl ester 6 in 55% yield.
2-oxo-tetrahydro-furan-3-yl ester 3c. (2S,30R): H NMR
(CDCl3) d 1.01 (t, 3H, J ¼ 7:6 Hz), 1.11 (s, 3H), 1.21 (s,
3H), c 3.76 (d, 1H, J ¼ 12:8 Hz), 3.88 (d, 1H,
J ¼ 12:8 Hz), 4.01 (s, 1H), 4.07 (s, 2H), 5.44 (s, 1H),
5.46–5.56 (m, 1H), 5.86 (dt, 1H, J ¼ 6 Hz, 13 Hz), 7.28–
7.37 (m, 5H). 13C NMR (CDCl3) d 14.1, 20.8, 26.3, 41.3,
52.3, 63.5, 76.2, 77.1, 125.6, 128.1, 129.3, 129.4, 137.8,
140.4, 172.9, 173.5; GC–MS r.t. 38.63 min, m=z 331 (1),
218 (2), 174 (100), 91 (62), 65 (5).
4.1.5.1. (2S)-2-Benzylamino-3-methyl-but-4-enoic acid
4b. 1H NMR (D2O) d 1.77 (s, 3H), 3.93 (s, 1H), 3.96 (d,
1H, J ¼ 13:5 Hz), 4.01(d, 1H, J ¼ 13:5 Hz), 5.01 (br s,
1H), 5.09 (br s, 1H), 7.26 (br s, 5H). 13C NMR (D2O) d
19.4, 51.2, 65.8, 122.4, 129.8, 130.7, 131.8, 136.5, 137.5,
20
D
169.3; ½aꢀ ¼ +44 (c 1.4; H2O).
(2R,30R): H NMR (CDCl3) d 1.01 (t, 3H, J ¼ 7:6 Hz),
1
4.1.6. (2S)-Methyl 2-benzylamino-3-methyl-but-4-enoate
5b. H NMR (CDCl3) d 1.81 (s, 3H), 2.16 (br s, 1H),
3.74–3.76 (m, 5H), 3.88 (s, 1H), 5.05–5.07 (m, 2H), 7.31–
7.40 (m, 5H). 13C NMR (CDCl3) d 18.7, 51.0, 51.9, 66.0,
115.0, 127.0, 128.2, 128.4, 139.5, 141.4, 173.0; GC–MS
r.t. 16.7 min, m=z 219 (1), 160 (51), 128 (3), 91 (100), 65
(6); HPLC (isocratic 9:1 hexane/isopropanol) ee 82%,
1.13 (s, 3H), 1.25 (s, 3H), 2.03–2.19 (m, 2H), 3.76 (d, 1H,
J ¼ 12:8 Hz), 3.88 (d, 1H, J ¼ 12:8 Hz), 4.01 (s, 1H),
4.07 (s, 2H), 5.42 (s, 1H), 5.46–5.56 (m, 1H), 5.94 (dt,
1H, J ¼ 6 Hz, 13 Hz), 7.28–7.37 (m, 5H). 13C NMR
(CDCl3) d 14.1, 20.6, 26.3, 41.0, 52.1, 63.1, 76.2, 77.1,
126.0, 128.1, 129.3, 129.4, 138.3, 140.4, 172.8, 173.4;
1
GC–MS r.t. 38.21 min, m=z 331 (3), 218 (13), 174 (4), 91
20
D
r.t. major enantiomer: 8.36 min, r.t. minor enantiomer:
(100), 65 (5). ½aꢀ ¼ +4.8 (c 1; CHCl3).
20
D
9.12 min; ½aꢀ ¼ + 41 (c 1; CHCl3).
4.1.4.3. 2-Benzylamino-3-methyl-hex-2-enoic acid 4,4-
dimethyl-2-oxo-tetrahydro-furan-3-yl ester 3d. (2S,30R):
1H NMR (CDCl3) d 0.97 (t, 3H, J ¼ 7:8 Hz), 1.11 (s,
3H), 1.23 (s, 3H), 1.47–1.58 (m, 2H), 2.04 (br s, 1H),
2.05–2.27 (m, 2H), 3.77 (d, 1H, J ¼ 12:8 Hz), 3.84 (d,
1H, J ¼ 12:8 Hz), 4.02 (s, 1H), 4.07 (s, 2H), 5.06 (d, 1H,
4.1.7. L
-Valine methyl ester. 1H NMR (CDCl3) d 1.11 (d,
3H, J ¼ 5:4 Hz), 1.13 (d, 3H, J ¼ 5:4 Hz), 2.40 (m, 1H),
3.81 (s, 3H), 3.94 (br s, 1H). 13C NMR (CDCl3) d 18.3,
18.7, 30.1, 52.8, 58.6, 169.1; GC–MS r.t. 7.2 min, m=z
20
D
131 (1), 88 (36), 72 (100), 55(24); ½aꢀ ¼ +11.7 (c 0.8;
CHCl3).

G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
599
4.1.8. Transformation of ester 3c into 5c. A solution of 3c
(1 mmol, 0.33 g) in HCl 6 M (5 mL) was refluxed for 2 h.
The aqueous reaction mixture was concentrated and the
residue dissolved in methanol (1 mL). The solution was
adsorbed on cation exchange resin (Dowex 50) and (R)-
pantolactone was recovered from the methanol layer in
quantitative yield. The resin was washed with distilled
water until the washing came out neutral, then with
1.5 M NH4OH. 4c was isolated after evaporation of the
aqueous solution in 63% yield and then diluted in
MeOH and treated with an ethereal solution of CH2N2
until persistence of the yellow colour. Elimination of the
solvents under reduced pressure allowed to isolate 5c in
95% yield.
of the aqueous solution in 76% yield, then diluted in
MeOH and treated with an ethereal solution of CH2N2
until persistence of a yellow colour. Elimination of the
solvents under reduced pressure allowed us to isolate 5d
in 95% yield.
4.1.10.1.
(2S)-2-Benzylamino-3-methyl-hex-2-enoic
acid 4d. 1H NMR (CDCl3) d 0.93 (t, 3H, J ¼ 7:2 Hz),
1.45–1.55 (m, 2H), 2.09–2.13 (m, 2H), 3.71 (s, 1H), 3.76
(s, 2H), 5.04 (br s, 1H), 5.08 (br s, 1H), 7.31–7.37 (br s,
5H). 13C NMR (CDCl3) d 13.9, 20.7, 34.6, 52.0, 67.4,
113.4, 127.3, 128.1, 128.5, 130.0, 146.9, 174.6;
20
D
½aꢀ ¼ +13.1 (c 0.7; CHCl3).
4.1.8.1. (2S)-2-Benzylamino-hex-3-enoic acid 4c. 1H
NMR (D2O) d 0.85 (t, 3H, J ¼ 7:2 Hz), 1.93–2.03 (m,
2H), 5.29–5.37 (m, 1H), 5.93 (br t, 1H, J ¼ 6:3 Hz,
13.5 Hz), 7.31 (br s, 5H). 13C NMR (D2O) d 11.7, 24.6,
4.1.10.2. (2S)-Methyl 2-benzylamino-3-methyl-hex-2-
enoate 5d. 1H NMR (CDCl3) d 0.95 (t, 3H, J ¼ 7:5 Hz),
1.45–1.54 (m, 2H), 1.99–2.17 (m, 3H), 3.75 (s, 5H), 3.85
(s, 1H), 5.04 (br s, 1H), 5.08 (br s, 1H), 7.31–7.37 (m,
5H). 13C NMR (CDCl3) d 13.8, 20.7, 34.9, 51.4, 52.0,
65.4, 113.1, 127.0, 128.3, 128.4, 139.6, 145.9, 173.5; GC–
MS r.t. 18.6 min, m=z 247 (2), 188 (60), 91 (100), 65 (9);
HPLC (isocratic 95:5 hexane/isopropanol) ee 88%, r.t.
48.6, 63.4, 118.4, 128.3, 128.7, 129.3, 130.3, 143.9, 172.2;
20
D
½aꢀ ¼ +9.9 (c 1.9; H2O).
major enantiomer: 8.75 min, r.t. minor enantiomer:
10.12 min; ½aꢀ ¼ +44.6 (c 1; CHCl3).
4.1.8.2. (2S)-Methyl 2-benzylamino-hex-3-enoate 5c.
1H NMR (CDCl3) d 1.03 (t, 3H, J ¼ 6:5 Hz), 1.90 (br s,
1H), 2.10 (dr t, 2H, J ¼ 6:1 Hz, 6.5 Hz), 3.75 (s, 2H),
3.77 (s, 3H), 3.85 (d, 1H, J ¼ 7:5 Hz), 5.45 (dd, 1H,
J ¼ 7:5 Hz, 15.3 Hz), 5.81 (dr t, 1H, J ¼ 15:3 Hz,
6.1 Hz), 7.25–7.37 (m, 5H). 13C NMR (CDCl3) d 13.1,
25.3, 51.3, 51.9, 62.6, 125.2, 127.0, 128.3, 128.4, 136.7,
139.6, 173.9; GC–MS r.t. 16.7 min, m=z 233 (1), 188 (14),
174 (49), 91 (100), 65 (11); HPLC (isocratic 95:5 hexane/
isopropanol) ee 11%, r.t. major enantiomer: 9.99 min,
r.t. minor enantiomer: 11.65 min.
20
D
4.1.11. Preparation of compounds 8 and 9 from a-bromo-
b,c-unsaturated ester 2b. A solution of 2b (2 mmol,
0.58 g), TEA (2.2 mmol, 0.3 mL) and amine (2.4 mmol)
in dry THF (10 mL) was stirred overnight at room
temperature. After removing THF under reduced pres-
sure, the residue was diluted with EtOAc (20 mL) and
washed twice with water (10 mL). Compounds 8 and 9
were isolated pure by flash chromatography on silica gel
(cyclohexane/EtOAc, 8:2).
4.1.9. Transformation of acid 4c into norleucine 7. Pd/C
(10%, 50 mg) was added to a solution of 4c (1 mmol,
0.219 g) in MeOH (15 mL). The reaction flask was
evacuated, purged with hydrogen five times, and then
stirred under a hydrogen atmosphere (40 psi) for 2 h.
The solution was filtered over celite and concentrated to
4.1.11.1. 2-(p-Methoxy)benzylamino-3-methyl-but-4-
enoic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester
1
8. (2S,30R): H NMR (CDCl3) d 1.08 (s, 3H), 1.19 (s,
3H), 1.81 (s, 3H), 3.70 (s, 2H), 3.80 (s, 3H), 4.00 (s, 1H),
4.04 (br s, 2H), 5.01–5.04 (m, 2H), 5.43 (s, 1H), 6.84–
6.89 (m, 2H), 7.25–7.29 (m, 3H). 13C NMR (CDCl3) d
19.0, 19.7, 23.0, 40.5, 50.5, 55.2, 65.6, 75.1, 76.4, 113.7,
115.5, 129.5, 131.3, 141.2, 171.8; GC–MS r.t. 27.86 min,
m=z 347 (2), 189 (24), 121 (100), 77 (8).
give L-norleucine 7 in 75% yield.
4.1.9.1.
-norleucine 7. 1H NMR (D2O) d 0.75 (t, 3H,
L
J ¼ 7:5 Hz), 1.21–1.26 (m, 4H), 1.71–1.78 (m, 2H), 3.76
(t, 1H, J ¼ 6:6 Hz). 13C NMR (D2O) d 12.7, 21.3, 26.0,
29.7, 54.4, 174.9. HPLC (isocratic 95:5 water/methanol)
ee 11%, r.t. major enantiomer: 4.78 min, r.t. minor
enantiomer: 5.51 min.
(2R,30R): 1H NMR (CDCl3) d 1.10 (s, 3H), 1.21 (s, 3H),
1.84 (s, 3H), 3.70 (s, 2H), 3.82 (s, 3H), 3.94 (s, 1H), 4.05
(br s, 2H), 5.01–5.04 (m, 2H), 5.40 (s, 1H), 6.84–6.89 (m,
2H), 7.25–7.29 (m, 3H). 13C NMR (CDCl3) d 19.0, 19.8,
23.2, 40.4, 50.7, 55.2, 65.7, 75.1, 76.0, 113.8, 115.5,
129.4, 131.2, 141.2, 171.6; GC–MS r.t. 27.89 min, m=z
4.1.10. Transformation of ester 3d into 5d. A solution of
3d (1 mmol, 0.319 g) in HCl 6 M (5 mL) was refluxed for
2 h. The aqueous reaction mixture was concentrated and
the residue dissolved in methanol (1 mL). The solution
was absorbed on a cation exchange resin (Dowex 50)
and (R)-pantolactone recovered from the methanol layer
in a quantitative yield. The resin was washed with dis-
tilled water until the washing came out neutral, then
with 1.5 M NH4OH. 4d was isolated after evaporation
20
D
347 (2), 189 (21), 121 (100), 77 (6). ½aꢀ ¼ +30.8 (d.r. 81/
19, c 1; CHCl3).
4.1.11.2. 2-Allylamino-3-methyl-but-4-enoic acid 4,4-
dimethyl-2-oxo-tetrahydro-furan-3-yl ester 9. (2S,30R):
1H NMR (CDCl3) d 1.08 (s, 3H), 1.18 (s, 3H), 1.80 (s,
3H), 3.21 (dd, 2H, J ¼ 7:2, 1.6 Hz), 4.02–4.04 (m, 1H);

600
G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
4.03 (br s, 2H), 5.04–5.14 (m, 4H), 5.42 (s, 1H), 5.81–
5.99 (m, 1H). 13C NMR (CDCl3) d 18.8, 19.6, 22.8, 40.3,
49.7, 65.7, 75.1, 76.0, 115.5, 116.7, 135.8, 141.2, 171.9;
GC–MS r.t. 19.98 min, m=z 267 (2), 110 (100).
the residue dissolved in methanol (1 mL). The solution
was absorbed on a cation exchange resin (Dowex 50).
(R)-pantolactone and benzyl alcohol were recovered
from the methanol layer in a quantitative yield. The
resin was washed with distilled water until the washing
came out neutral, then eluted with 1.5 M NH4OH.
(2R,30R): 1H NMR (CDCl3) d 1.12 (s, 3H), 1.22 (s, 3H),
1.86 (s, 3H), 3.21 (dd, 2H, J ¼ 7:2, 1.6 Hz), 4.02–4.04
(m, 1H); 4.03 (br s, 2H), 5.04–5.14 (m, 4H), 5.41 (s, 1H),
5.81–5.99 (m, 1H). 13C NMR (CDCl3) d 18.8, 19.8, 22.8,
40.1, 49.7, 65.8, 75.3, 76.0, 115.1, 116.7, 135.9, 140.9,
L
-isodehydrovaline 11 was isolated after evaporation of
the ammonia solution in 80% yield (>95% ee). The
spectroscopic data was then compared with literature
values.14c
172.6; GC–MS r.t. 19.82 min, m=z 267 (3), 110 (100).
½aꢀ ¼ +28.5 (c 1; CHCl3).
20
D
The transformation into the N-BOC derivative follow-
ing a known procedure and the comparison with liter-
ature data for this compound,16 further confirmed the
attribution.
4.1.12. Preparation of compound 10 from a-bromo-b,c-
unsaturated ester 2b. A solution of 2b (2 mmol, 0.58 g),
and O-benzylhydroxylamine (2 equiv, 4 mmol, 8 mL of
solution 0.5 M in CH2Cl2) in dry THF (20 mL), was
stirred at room temperature for 40 h. After removing
THF under reduced pressure, the residue was diluted
with CH2CL2 (20 mL) and washed twice with water
(10 mL). Compound 10 was isolated pure by flash
chromatography on silica gel (cyclohexane/EtOAc, 8:2).
20
-isodehydrovaline 11. ½aꢀ ¼ +110.7 (c 0.8 H2O).
L
D
20
D
{Lit.14c ½aꢀ ¼ +113 (c 3.64 H2O)}.
20
-N(-tert-Butyloxycarbonyl)isodehydrovaline ½aꢀ ¼ +53.7
L
D
20
D
(c 0.8 MeOH). {Lit.16b ½aꢀ ¼ +56.2 (c 1.0 MeOH)}.
Acknowledgements
4.1.12.1. 2-Benzyoxylamino-3-methyl-but-4-enoic acid
We thank MURST (Cofin 2002 and FIRB), ISOF-CNR
and the University of Bologna (funds for selected topics)
for financial support.
4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl
ester
10.
(2S,30R): 1H NMR (CDCl3) d 1.08 (s, 3H), 1.18 (s,
3H), 1.82 (s, 3H), 4.05 (s, 2H), 4.30 (s, 1H), 4.74 (s, 2H),
5.06 (br s, 2H), 5.46 (s, 1H), 5.96 (br s, 1H), 7.29–7.35
(m, 5H). 13C NMR (CDCl3) d 19.6, 20.6, 22.9, 40.6,
60.3, 68.8, 75.2, 75.6, 116.0, 127.8, 128.2, 128.5, 137.4,
References and notes
138.2, 170.5, 171.8; GC–MS r.t. 17.84 min, m=z 225 (2),
20
D
114 (36), 99 (100), 68 (48), 55 (20). ½aꢀ ¼ +30.9 (c 0.9;
1. (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789–12854; (b)
Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699–
1720; (c) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetra-
hedron 1999, 55, 585–615.
2. (a) Balsamini, C.; Duranti, E.; Mariani, L.; Salvatori, A.;
Spadoni, G. Synthesis 1990, 779–781; (b) Yim, A. M.;
Vidal, Y.; Viallefont, P.; Martinez, J. Tetrahedron: Asym-
metry 2002, 13, 503–510; (c) Pena, D.; Minnaard, A. J.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Lett.
2003, 4, 475–478; (d) Evans, D. A.; Michael, F. E.;
Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003,
125, 3534–3543.
3. (a) Baldwin, J. E.; Christie, M. A.; Haber, S. B.; Kruse, L. I.
J. Am. Chem. Soc. 1976, 98, 3045–3047; (b) Baldwin, J. E.;
Haber, S. B.; Hoskins, C.; Kruse, L. I. J. Org. Chem. 1977,
42, 1239–1241; (c) Chari, R. V. J.; Wemple, J. Tetrahedron
Lett. 1979, 2, 111–114; (d) Baldwin, J. E.; Moloney, M. G.;
North, M. Tetrahedron 1989, 45, 6319–6330.
4. (a) Rando, R. R. Nature 1974, 250, 586–587; (b) Relyea,
N.; Rando, R. R. Biochem. Biophys. Res. Commun. 1975,
67, 392–402; (c) Owens, L. D.; Thompson, J. F.; Pitcher,
R. G.; Williams, T. J. Chem. Soc., Chem. Commun. 1972,
12, 714; (d) Walsh, C. Tetrahedron 1982, 38, 871–909.
5. (a) Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org.
Chem. 2002, 67, 1399–1402; (b) Schmidt, R.; Kalman, A.;
Chung, V. N.; Lemieux, C.; Horvath, C.; Schiller, P. W.
Int. J. Pept. Prot. Res. 1995, 46, 47–55; (c) Thormann, M.;
Hofmann, H. J. Theochem 1998, 431, 79–96.
CHCl3).
4.1.13. Transformation of compound 10 into (L)-isodehy-
drovaline 11. Method a: A solution of 10 (1 mmol, 0.33 g)
in HCl 6 M (5 mL) was refluxed for 2 h. The aqueous
reaction mixture was concentrated and the residue dis-
solved in methanol (1 mL). The solution was absorbed
on a cation exchange resin (Dowex 50). (R)-pantolac-
tone, benzyl alcohol and compound 12 were recovered
from the methanol layer in quantitative yield. The resin
was washed with distilled water until the washing came
out neutral, then eluted with 1.5 M NH4OH.
L-isode-
hydrovaline 11 was isolated after evaporation of the
ammonia solution in 33% yield (>95% ee). The spec-
troscopic data was then compared with the literature
values.14c
The transformation into an N-BOC derivative following
a known procedure and the comparison with literature
data for this compound,16b further confirmed the attri-
bution.
Method b: A solution of 10 (1 mmol, 0.33 g) in H2O
(5 mL) and CH3CN (0.3 mL) was refluxed for 5 h. The
reaction mixture was diluted with MeOH (5 mL) and
filtered over celite. The solution was concentrated and
6. (a) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273–279; (b)
Hyatt, J. A.; Raynolds, P. W. In Organic Reactions;

G. Cardillo et al. / Tetrahedron: Asymmetry 15 (2004) 593–601
601
^
Lemaire-Audoire, S.; Savignac, M.; Genet, J. P.; Bernard,
J.-M. Tetetrahedron Lett. 1995, 36, 1267–1270.
Paquette, L. A. , Ed.; John Wiley: New York, 1994, Vol.
45, pp 159–646; (c) Orr, R. K.; Calter, M. A. Tetrahedron
2003, 59, 3545–3565.
13. (a) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin 1 1985,
1401–1406; (b) Cicchi, S.; Goti, A.; Brandi, A.; Guarna,
A.; De Sarlo, F. Tetrahedron Lett. 1990, 31, 3351–3354; (c)
Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37,
8997–9000; (d) Amoroso, R.; Cardillo, G.; Sabatino, P.;
Tomasini, C.; Trere, A. J. Org. Chem. 1993, 58, 5615–
5619; (e) Momiyama, N.; Yamamoto, H. J. Am. Chem.
Soc. 2003, 125, 6038–6039; (f) Keck, G. E.; McHardy, S.
F.; Wager, T. T. Tetrahedron Lett. 1995, 36, 7419–
7422.
14. (a) Baldwin, J. E.; Au, A.; Christie, M.; Haber, S. B.;
Hesson, D. J. Am. Chem. Soc. 1975, 97, 5957–5958; (b)
Baldwin, J. E.; Christie, M. A.; Haber, S. B.; Kruse, L. I.
J. Am. Chem. Soc. 1976, 98, 3045–3047; (c) Baldwin, J. E.;
Haber, S. B.; Hoskins, C.; Kruse, L. I. J. Org. Chem. 1977,
42, 1239–1241.
7. (a) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.;
Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650–
7651; (b) Cannizzaro, C. E.; Strassner, T.; Houk, K. N. J.
Am. Chem. Soc. 2001, 123, 2668–2669.
8. (a) Durst, T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799–
6802; (b) OÕ Meara, J.; Jung, M.; Durst, T. Tetrahedron
Lett. 1995, 36, 2559–2562; (c) Calmes, M.; Daunis, J.; Mai,
N.; Natt, F. Tetrahedron Lett. 1996, 37, 379–380; (d)
OÕ Meara, J.; Gardee, N.; Jung, M.; Ben, R. N.; Durst, T.
J. Org. Chem. 1998, 63, 3117–3119.
9. Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C.
Synlett 1995, 1131–1132.
10. McDonald, I. A.; Lacoste, J. M.; Bey, P.; Wagner, J.;
Zreika, M.; Palfreyman, G. M. J. Am. Chem. Soc. 1984,
106, 3354–3356.
11. Jackson, A. E.; Johnstone, R. A. W. Synthesis 1976, 685–
687.
15. Ottinger, H.; Soldo, T.; Hofmann, T. J. Agric. Food.
Chem. 2001, 49, 5383–5390.
12. (a) Bull, S. D.; Davies, S. G.; Epstein, S. W.; Ouzman, J.
V. A. J. Chem. Soc., Chem. Commun. 1998, 659–660; (b)
Bull, S. D.; Davies, S. G.; Kelly, P. M.; Gianotti, M.;
Smith, A. D. J. Chem. Soc., Perkin 1 2001, 3106–3111; (c)
16. (a) Porter, J. R.; Wirschum, W. G.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 2657–2658; (b) Yonezawa, Y.; Shimizu, K.; Yoon, K.;
Shin, C. Synthesis 2000, 634–636.