A new enantiodivergent synthesis of the Geissman-Waiss lactone

Article abstract of DOI:10.1016/j.tet.2007.03.056

Intramolecular Michael reaction of methyl (R)-6-(tert-butoxycarbonylamino)oxy-4-hydroxy-2-hexenoate, in turn obtained from tert-butyl (R)-3-hydroxy-4-pentenoate, paved the way to the synthesis of both enantiomers of 2-oxa-6-azabicyclo[3.3.0]octan-3-one (the Geissman-Waiss lactone), a precursor for necine bases. Key intermediates in this approach were represented by enantiomeric bicyclic lactones incorporating a [1,2]-oxazinane nucleus, which has been conveniently used to install the pyrrolidine framework of the target compounds through a synthetic scheme featuring the reduction of the nitrogen-oxygen bond and an intramolecular S_N2 reaction.

Full text of DOI:10.1016/j.tet.2007.03.056

Tetrahedron 63 (2007) 4278–4283
A new enantiodivergent synthesis of the Geissman–Waiss lactone
Achille Barco,a Nikla Baricordi,a Simonetta Benetti,a Carmela De Risi,b,
*
b
Gian P. Pollinib, and Vinicio Zanirato
*
aDipartimento di Chimica, University of Ferrara, Via Luigi Borsari 46, 44100 Ferrara, Italy
bDipartimento di Scienze Farmaceutiche, University of Ferrara, Via Fossato di Mortara 19, 44100 Ferrara, Italy
Received 5 December 2006; revised 16 February 2007; accepted 8 March 2007
Available online 13 March 2007
Abstract—Intramolecular Michael reaction of methyl (R)-6-(tert-butoxycarbonylamino)oxy-4-hydroxy-2-hexenoate, in turn obtained from
tert-butyl (R)-3-hydroxy-4-pentenoate, paved the way to the synthesis of both enantiomers of 2-oxa-6-azabicyclo[3.3.0]octan-3-one (the
Geissman–Waiss lactone), a precursor for necine bases. Key intermediates in this approach were represented by enantiomeric bicyclic lac-
tones incorporating a [1,2]-oxazinane nucleus, which has been conveniently used to install the pyrrolidine framework of the target compounds
through a synthetic scheme featuring the reduction of the nitrogen–oxygen bond and an intramolecular SN2 reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
namely trans-4-hydroxy-L-proline,4 cis-(2R,3S)-3-hydroxy-
proline,5 D-ribose,6 D-erythrose,6,7 L-diethyl tartrate,8 L-malic
acid,8,9 and (S)-pyroglutamic acid.10 Alternatively, chiral
urethanes,11 1,4:3,6-dianhydrohexitols,12 enantiomerically
pure 2,5-dihydropyrroles,13 chiral oxazolidinones,14 ene-
carbamates bearing a chiral auxiliary,15 and a protected (S)-
maleimide16 served as versatile building blocks to achieve
the chirospecific synthesis of Geissman–Waiss lactone.
(+)- and (ꢀ)-Geissman–Waiss lactones 11 have emerged as
key intermediates in the synthesis of a number of pyrrolizi-
dine alkaloids, including the necine bases (+)-retronecine 2
and (ꢀ)-platynecine 3,2 which possess a wide range of bio-
logical activities, such as carcinogenic, antitumor, antispas-
modic, hypotensive, and anti-inflammatory (Fig. 1).3
The biological importance of this group of compounds has
evoked a widespread interest in the development of new
methodologies for the enantioselective synthesis of bicyclic
lactone 1.
Moreover, a number of methods have been developed to
prepare N-protected derivatives of 1 as suitable starting
materials for the synthesis of necine-based alkaloids.17
As a continuation of our interest in devising convenient
synthetic entries to polyfunctionalized heterocyclic systems,
we wish to report in this paper a new simple approach to both
(+)- and (ꢀ)-Geissman–Waiss lactones 1.
This compound has been obtained in optically pure form by
several groups, taking advantage of classical chiral sources,
O
O
O
O
N
H
N
H
2. Results and discussion
(+)-1
(-)-1
Central to our plan was the use of a chiral bicyclic lactone 7
as the key intermediate (Scheme 1). This compound would
represent a convenient precursor of the target compounds,
since cleavage of the [1,2]-oxazinane nitrogen–oxygen
bond would unmask an amino alcohol moiety to be consec-
utively used as the starting substrate for an intramolecular
SN2 reaction providing the pyrrolidine framework of 1.
OH
OH
HO
H
H
HO
N
N
2
3
Figure 1.
Keywords: Asymmetric synthesis; Michael addition; [1,2]-Oxazinanes;
Aminooxy compounds.
* Corresponding authors. Tel.: +39 0532 291285; fax: +39 0532 291296
(C.D.R.); tel.: +39 0532 291286; fax: +39 0532 291296 (G.P.P.); e-mail
addresses: drc@unife.it; pol@unife.it
The crucial step in this scheme would be represented by the
intramolecular Michael reaction of a chiral g-hydroxy a,b-
unsaturated ester 8, endowed with a suitably located amino-
oxy group acting as the nitrogen-centered nucleophile: to the
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.056

A. Barco et al. / Tetrahedron 63 (2007) 4278–4283
4279
O
O
O
O
*
*
*
*
*
*
OH
X
1
O
O
O
NH
P
N
P
NH
P
4
5
6
intramolecular SN2
reaction
P = protecting group
X = leaving group
lactonization
*
O
O
N
P
*
HO
*
O
7
HN
P
RO2C
intramolecular
Michael reaction
8
Scheme 1.
best of our knowledge, this approach has never been reported
in the literature, intramolecular conjugate addition of C-
linked nitrogen nucleophiles (e.g., amides and carbamates)
to activated olefins being conventionally used to obtain
five- or six-membered heterocyclic systems.8,9a,18
A different approach was eventually found through a two-
step procedure: thus, reduction of the ester group with diiso-
butylaluminum hydride formed the required aldehyde,20,21
which was directly treated with sodium borohydride to
efficiently provide (+)-1122 in 90% yield over two steps.
Having established the essential features of the synthetic
project, preparation of a convenient aminooxy derivative
to be used in the intramolecular Michael reaction was under-
taken.
Treatment of (+)-11 with an iodine/triphenylphosphine
system, in the presence of imidazole, proceeded smoothly
at room temperature to afford the iodide (+)-12, which was
subsequently treated with N-(tert-butoxycarbonyl)hydroxyl-
amine and 1,8-diazabicyclo[5.4.0]undec-7-ene23 to afford
the corresponding aminooxy ether (ꢀ)-13, in 72% overall
yield.
We reasoned that tert-butyl (R)-3-hydroxy-4-pentenoate (+)-
9, in turn obtained by kinetic resolution of the corresponding
racemic compound via PS-C lipase (Pseudomonas cepacia
immobilized on ceramic particles) catalyzed esterification
with vinyl acetate,19 would represent a useful starting chiral
source (Scheme 2).
Ozonolysis of the vinyl group, followed by quenching with
dimethyl sulfide, and subsequent removal of the silyl pro-
tecting group gave the hemiaminal 14 as a mixture of two
1
anomers, as evidenced by its H NMR spectrum showing
a complete absence of the aldehyde proton and suggesting
that the expected a-silyloxyaldehyde had undergone a spon-
taneous cyclization reaction.
b,c
a
HO
TBDMSO
t
t
CO2 Bu
CO2 Bu
94%
90%
(+)-9
(+)-10
Treatment of the hemiaminal 14 with methyl (triphenylphos-
phoranylidene)acetate, followed by chromatographic purifi-
cation of the crude reaction mixture, yielded a,b-unsaturated
ester 15 (Z:E¼1:9) and an inseparable 70:30 mixture of di-
astereomers, which were identified as the cyclized hydroxy
ester 16 arising from an intramolecular Michael reaction
(Scheme 3).24
I
OH
TBDMSO
TBDMSO
e
d
90%
80%
(+)-12
(+)-11
TBDMSO
HO
HO
f,g
O
O
60%
N
HN
Boc
Boc
On treatment of the alkene 15 with tetramethylguanidine, we
observed a clean transformation of the starting material into
a 70:30 mixture of ester (+)-16 and lactone (ꢀ)-17,24 which
could be easily separated by column chromatography. It
is likely that the base-induced intramolecular conjugate
addition gives rise to an intermediate mixture of cis- and
trans-16, the cis-isomer taking part in a smooth lactonization
reaction to afford the bicyclic compound.
(-)-13
14
Scheme 2. Reagents and conditions: (a) imidazole, TBDMS-Cl, CH2Cl2,
rt, 4 h; (b) DIBALH, toluene, ꢀ78 ꢁC, 15 min; (c) NaBH4, MeOH, 0 ꢁC,
10 min; (d) I2, PPh3, imidazole, Et2O/CH3CN/THF, rt, 15 min; (e)
(HO)NHBoc, DBU, CH2Cl2, rt, 12 h; (f) O3, CH2Cl2, ꢀ78 ꢁC, then Me2S,
rt, 12 h; (g) TBAF, THF, rt, 4 h.
Protection of secondary alcohol (+)-9 as tert-butyldimethyl-
silyl ether (+)-1020 anticipated the conversion of the ester
moiety into a hydroxymethyl functionality to be used for
the introduction of the aminooxy residue.
Similarly, exposure of diastereomers 16 to the same basic
treatment resulted in the formation of (ꢀ)-17, which could
be easily separated from unreacted (+)-16, thus allowing
for a clean separation of cis- and trans-16.
Initial attempts to reduce (+)-10 with lithium aluminum
hydride proved unsuccessful, giving a complex mixture in
which only traces of the desired reduction product were
present.
No epimerization at C-4 occurred during the Wittig/intra-
molecular Michael reaction sequence, as shown by the high

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A. Barco et al. / Tetrahedron 63 (2007) 4278–4283
14
enantiomer of (ꢀ)-17 should represent a convenient precur-
sor to be used in a same synthetic sequence as that reported
in Scheme 4.
a
60%
HO
20%
O
The most straightforward access to (+)-17 would be based on
the use of ester (+)-16, since its functionalities at C-3 and C-
4 should be elaborated according to the procedure reported
by Shishido et al.8 for the assemblage of a five membered
lactone nucleus condensed with a protected pyrrolidine
framework. As the key step in this approach was represented
by an intramolecular mesylate displacement promoted by
a suitably located carboxylate function, we treated (+)-16
with methanesulfonyl chloride and triethylamine in the pres-
ence of 4-dimethylaminopyridine to obtain the intermediate
mesylate (+)-21 (Scheme 5).
HO
O
HN
Boc
N
MeO2C
15
Boc
MeO2C
16
HO
O
O
b
b
O
O
+
N
N
90%
100%
Boc
Boc
MeO2C
O
HO
MsO
a
b
O
(+)-16
(-)-17
O
O
O
80%
80%
N
N
N
Boc
MeO2C
Boc
MeO2C
Boc
Scheme 3. Reagents and conditions: (a) Ph3P]CH–CO2Me, toluene,
80 ꢁC, 8 h; (b) TMG, CH2Cl2, rt, 12 h.
(+)-16
(+)-21
(+)-17
Scheme 5. Reagents and conditions: (a) CH3SO2Cl, Et3N, DMAP, CH2Cl2,
0 ꢁC, 1 h; (b) LiOH, dioxane/H2O, rt, 12 h.
enantiomeric excess of the lactone derivative (ꢀ)-17, which
was estimated to be >98% through chiral gas chromato-
graphy performed on a Megadex diethyl tert-butylsilyl
b-cyclodextrine column.
The ester of methanesulfonate (+)-21 was then hydrolyzed in
order to liberate the corresponding carboxylic acid, which
was the nucleophile in the subsequent intramolecular SN2
reaction.
The stage was now set for us to examine the feasibility of the
conversion of (ꢀ)-17 into the Geissman–Waiss lactone. To
this end, reductive cleavage of the nitrogen–oxygen bond
was the first goal. After extensive experimentation, we found
that the reduction could be conveniently achieved by treat-
ment of (ꢀ)-17 with molybdenum hexacarbonyl25 in wet
acetonitrile, leading to the formation of amino alcohol (+)-
18 in 80% yield (Scheme 4).
Gratifyingly, basic treatment of (+)-21 took place with con-
comitant mesylate displacement and inversion of configura-
tion at C-4, allowing us to gain (+)-17 in a very good yield.
Lactone (+)-17 was spectroscopically identical to (ꢀ)-17
except for the sign of the optical rotation and thus a route
to the formal synthesis of (ꢀ)-1 was established.
O
O
a
b
OMs
OH
(-)-17
O
O
80%
80%
NH
NH
Boc
Boc
3. Conclusion
(+)-18
(+)-19
In summary, we have demonstrated that the intramolecular
conjugate addition of an aminooxy group to an activated
olefin represents a convenient tool for the synthesis of
[1,2]-oxazinane derivatives.26 Reductive cleavage of the
nitrogen–oxygen bond allows for a clean conversion of the
heterocyclic nucleus to a pyrrolidine framework through in-
tramolecular nucleophilic displacement of a leaving group
conveniently introduced in the released amino alcohol.
O
O
c
d
98%
O
O
.HCl
N
H
N
Boc
90%
(-)-20
(+)-1
Scheme 4. Reagents and conditions: (a) Mo(CO)6, CH3CN, H2O, reflux,
4 h; (b) CH3SO2Cl, Et3N, CH2Cl2, 0 ꢁC, 10 min; (c) TMG, CH2Cl2, rt,
12 h; (d) HCl, Et2O, rt, 8 h.
This approach provided a new entry to both enantiomers of
Geissman–Waiss lactone 1 and could be used to prepare op-
tically active precursors of hydroxylated pyrrolidine-based
alkaloids.
Mesylation of (+)-18 with methanesulfonyl chloride/tri-
ethylamine system gave rise to (+)-19, which underwent
the planned intramolecular SN2 reaction by treatment with
tetramethylguanidine to afford the known N-Boc protected
Geissman–Waiss lactone (ꢀ)-20.12,14
4. Experimental
4.1. General
Subsequent acidic deprotection gave (+)-1 as the hydrochlo-
ride, whose physical and spectral data were consistent with
those reported in the literature.4b,14,16
Solvents were distilled prior to use, following standard pro-
cedures, and reactions were performed under nitrogen or
argon atmosphere, except ozonolysis. Silica gel 60 F254
Based on these results, we turned our attention to the syn-
thesis of (ꢀ)-Geissman–Waiss lactone, reasoning that the

A. Barco et al. / Tetrahedron 63 (2007) 4278–4283
4281
plates were used to monitor synthetic transformations, visu-
alization being done under UV light or using 2% KMnO4
solution. Organic solutions were dried over anhydrous mag-
nesium sulfate and evaporated with a rotary evaporator.
Chromatographic purifications were carried out using 70–
230 mesh silica gel. Melting points were determined on a
(100 MHz, CDCl3): d ꢀ4.6 (CH3), ꢀ4.1 (CH3), 2.7 (CH2),
18.2 (C), 25.9 (3CH3), 41.7 (CH2), 73.8 (CH), 114.9 (CH2),
140.5 (CH). Anal. Calcd for C11H23IOSi: C, 40.49; H,
7.10. Found: C, 40.36; H, 7.12.
4.1.3. (L)-(R)-3-(tert-Butyl-dimethylsilyl)oxy-5-(tert-but-
oxycarbonylamino)oxy-1-pentene (13). DBU (2.30 mL,
15.5 mmol) was added dropwise to a cooled (0 ꢁC) solution
of iodide (+)-12 (1.00 g, 3.10 mmol) and N-(tert-butoxycar-
bonyl)hydroxylamine (2.06 g, 15.5 mmol) in CH2Cl2
(10 mL). After being stirred for 12 h at room temperature,
water was added and the two phases separated. The aqueous
layer was washed several times with CH2Cl2, and the or-
ganic fractions were collected, dried, and evaporated. The
crude residue was purified by column chromatography
(Et2O/hexanes 1:6) to give (ꢀ)-13 (0.82 g, 80%) as a yellow-
ish oil. [a]2D0 ꢀ4.3 (c 1.78, CHCl3); IR (neat): 3287, 2958,
2930, 2857, 1723, 1700, 1367, 1255, 1086, 1017, 835,
€
Buchi–Tottoli apparatus and were uncorrected. Infrared (IR)
spectra were recorded with an FTIR PARAGON-100 spec-
trometer. Nuclear magnetic resonance spectra (1H NMR
and 13C NMR) were taken on a Mercury Plus spectrometer
at 400 MHz and 100 MHz, respectively. Variable-tempera-
1
ture H NMR spectra were recorded at 200 MHz with a
Varian VXR-200 spectrometer. Chemical shifts (d values)
are given in parts per million downfield from tetramethyl-
silane as the internal standard. Optical rotations were mea-
sured with a Perkin–Elmer 241 MC Polarimeter. Elemental
analyses were effected by the microanalytical laboratory
of Dipartimento di Chimica, University of Ferrara.
1
775 cmꢀ1; H NMR (400 MHz, CDCl3): d 0.03 (s, 3H),
The starting tert-butyl (R)-3-hydroxy-4-pentenoate (+)-9
and its tert-butyldimethylsilyl ether (+)-10 have been previ-
ously described and were characterized by comparison with
reported data.19,20
0.06 (s, 3H), 0.89 (s, 9H), 1.48 (s, 9H), 1.72–1.92 (m, 2H),
3.92 (t, J¼6.6 Hz, 2H), 4.22–4.32 (m, 1H), 5.04 (dt,
J¼10.4, 1.2 Hz, 1H), 5.17 (dt, J¼17.2, 1.2 Hz, 1H), 5.80
(ddd, J¼17.2, 10.4, 6.0 Hz, 1H), 7.12 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d ꢀ5.0 (CH3), ꢀ4.4 (CH3), 18.2 (C),
25.8 (3CH3), 28.2 (3CH3), 36.2 (CH2), 70.6 (CH), 73.1
(CH2), 81.6 (C), 114.0 (CH2), 114.1 (CH), 156.8 (C).
Anal. Calcd for C16H33NO4Si: C, 57.97; H, 10.03; N, 4.22.
Found: C, 58.01; H, 10.00; N, 4.23.
4.1.1. (D)-(R)-3-(tert-Butyl-dimethylsilyl)oxy-pent-4-en-
1-ol (11). tert-Butyldimethylsilyl ether (+)-10 (1.50 g,
5.23 mmol) was reduced with DIBALH (6.30 mL, 1 M in
hexane, 6.30 mmol) according to the protocol described by
Tan and Holmes.20 The obtained crude aldehyde21 was dis-
solved in MeOH (20 mL) and the resulting solution cooled at
0 ꢁC. NaBH4 (0.22 g, 5.75 mmol) was added portionwise
and the mixture stirred at room temperature for 10 min.
Removal of the solvent in vacuo was followed by column
chromatography (Et2O/hexanes 2:8) of the residue to furnish
(+)-11 (1.02 g, 90%) as a yellowish oil. [a]2D0 +4.0 (c 1.17,
CHCl3);27 spectral data were in close agreement with the lit-
erature,22 1H NMR (400 MHz, CDCl3): d 0.06 (s, 3H), 0.09
(s, 3H), 0.90 (s, 9H), 1.65–1.77 (m, 1H), 1.78–1.92 (m, 1H),
3.66–3.75 (m, 1H), 3.76–3.87 (m, 1H), 4.36–4.45 (m, 1H),
5.10 (dt, J¼9.6, 1.2 Hz, 1H), 5.22 (dt, J¼17.2, 1.2 Hz,
1H), 5.85 (ddd, J¼17.2, 9.6, 5.8 Hz, 2H). Anal. Calcd for
C11H24O2Si: C, 61.05; H, 11.18. Found: C, 61.15; H, 11.02.
4.1.4. Mixture of (3R,4R)- and (3S,4R)-3,4-dihydroxy-
[1,2]-oxazinane-2-carboxylic acid tert-butyl ester (14).
An ozone-enriched stream of oxygen was bubbled through
a ꢀ78 ꢁC cold solution of (ꢀ)-13 (1.00 g, 3.02 mmol) in
CH2Cl2 (50 mL) until it turned light blue. Excess ozone
was removed by flushing the solution with nitrogen, Me2S
(0.22 mL, 3.02 mmol) was successively added, and the mix-
turewas kept overnight at room temperature. The solvent was
removed in vacuo, the residue dissolved in CH2Cl2, and
passed through a short path of silica gel to give a crude prod-
uct, which was immediately dissolved in THF (20 mL). The
resulting solution was cooled at 0 ꢁC, then TBAF (1.90 g,
6.04 mmol) was added portionwise and stirring continued
at room temperature for 4 h. The solvent was evaporated
and the crude product purified by column chromatography
(EtOAc) to furnish the hemiaminal 14 (0.40 g, 60%) as a
white amorphous solid. This was an inseparable mixture of
anomers in a 60:40 ratio, based on the integrals of the anome-
ric H-3; IR (neat): 3335, 2963, 1723, 1680, 1258, 1068, 1014,
995, 792 cmꢀ1; 1H NMR (400 MHz, CD3OD): d 1.49 (s, 9H),
1.67–1.74 (m, 1H), 2.04–2.16 and 2.26–2.36 (m, 1H), 3.68–
3.88 (m, 2H), 4.02–4.10 and 4.18–4.26 (m, 1H), 5.28–5.32
and 5.45–5.48 (m, 1H). Anal. Calcd for C9H17NO5: C,
49.31; H, 7.82; N, 6.39. Found: C, 49.20; H, 7.84; N, 6.42.
4.1.2. (D)-(R)-3-(tert-Butyl-dimethylsilyl)oxy-5-iodo-1-
pentene (12). A solution of (+)-11 (1.00 g, 4.62 mmol) in
THF (10 mL) was added dropwise to a cooled (0 ꢁC) solution
of PPh3 (1.83 g, 7.00 mmol) and imidazole (0.50 g,
7.40 mmol) in Et2O (13 mL) and MeCN (7 mL). The mixture
was kept at the same temperature for 1 h, then I2 (2.03 g,
8.0 mmol) was added and stirring was continued for
15 min. The reaction mixture was diluted with Et2O
(20 mL) and washed with satd NaHSO3 (20 mL) until color-
less. The two phases were separated and the aqueous layer
extracted several times with Et2O. The combined organic
phases were dried and evaporated to a crude product, which
was purified by column chromatography (hexanes) to yield
(+)-12 (1.35 g, 90%) as a colorless oil. [a]2D0 +7.5 (c 0.75,
CHCl3); IR (neat): 2955, 2929, 2894, 2857, 1643, 1471,
4.1.5. Wittig reaction of 14. A suspension of 14 (0.50 g,
2.30 mmol) in toluene (20 mL) was heated at 80 ꢁC
for 30 min. Methyl (triphenylphosphoranylidene)acetate
(1.15 g, 3.45 mmol) was then added and stirring continued
for 8 h. The mixture was concentrated in vacuo, the residue
triturated with Et2O, and filtered. Evaporation of the solvent
and column chromatography (EtOAc/hexanes 1:1) of the
crude product furnished, in order of elution, the unsaturated
ester 15 (0.38 g, 60%) as an inseparable E/Z mixture in a 9:1
1361, 1257, 1089, 926, 835, 776 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 0.04 (s, 3H), 0.09 (s, 3H), 0.89 (s,
9H), 1.90–2.07 (m, 2H), 3.10–3.27 (m, 2H), 4.18 (app q, J¼
6.4 Hz, 1H), 5.08 (dt, J¼10.6, 1.6 Hz, 1H), 5.20 (dt, J¼17.2,
1.6 Hz, 1H), 5.77 (ddd, J¼17.2, 10.6, 6.4 Hz, 1H); 13C NMR

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A. Barco et al. / Tetrahedron 63 (2007) 4278–4283
ratio, and 16 (0.13 g, 20%) as an inseparable mixture of cis-
and trans-isomers in a 1:2 ratio. Compound 15: colorless oil;
IR (neat): 3500, 3300, 2954, 2930, 2857, 1723, 1660, 1367,
and refluxed for 4 h. The cooled mixture was filtered through
Celite and the filtrate evaporated. The residue was purified by
column chromatography (EtOAc/hexanes 1:1 increasing to
EtOAc) to give (+)-18 (0.16 g, 80%) as a white solid, mp
128–130 ꢁC. [a]D20 +78.0 (c 0.86, CH3OH); IR (neat): 3518,
3328, 2978, 1775, 1703, 1685, 1533, 1362, 1256, 1169, 1042,
1006, 939, 806 cmꢀ1; 1H NMR (400 MHz, CD3OD): d 1.44
(s, 9H), 1.78–1.92 (m, 2H), 2.39 (A part of ABX system,
J¼18.0, 2.4 Hz, 1H), 3.00 (B part of ABX system, J¼18.0,
8.0 Hz, 1H), 3.64–3.76 (m, 2H), 4.40–4.46 (m, 1H), 4.70–
4.80 (m, 1H); 13C NMR (100 MHz, CD3OD): d 28.6 (3CH3),
33.5 (CH2), 36.6 (CH2), 51.1 (CH), 59.3 (CH2), 80.5 (C), 82.1
(CH), 157.8 (C), 177.7 (C). Anal. Calcd for C11H19NO5: C,
53.87; H, 7.81; N, 5.71. Found: C, 53.95; H, 7.70; N, 5.70.
1250, 1164, 1086, 835, 776 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): only the resonances for the E-isomer are clearly de-
tectable, d 1.47 (s, 9H), 1.63–1.74 (m, 1H), 1.88–2.00 (m,
1H), 3.73 (s, 3H), 3.98–4.10 (m, 2H), 4.60–4.70 (m, 1H),
6.16 (A part of ABX system, J¼15.6, 2.0 Hz, 1H), 6.95 (B
part of ABX system, J¼15.6, 4.0 Hz, 1H), 7.37 (br s, 1H);
13C NMR (100 MHz, CDCl3): d 28.2 (3CH3), 34.4 (CH2),
51.7 (CH3), 68.3 (CH), 74.0 (CH2), 82.7 (C), 119.7 (CH),
150.0 (CH), 157.7 (C), 174.7 (C). Anal. Calcd for
C12H21NO6: C, 52.35; H, 7.69; N, 5.09. Found: C, 52.20;
H, 7.71; N, 5.11. Compound 16: colorless oil; IR (neat):
3456, 2978, 1738, 1720, 1695, 1367, 1255, 1161, 1094,
1020, 991 cmꢀ1; 1H NMR (400 MHz, CDCl3): major isomer
d 1.48 (s, 9H), 1.58–1.68 (m, 1H), 2.04–2.18 (m, 1H), 2.62
(A part of ABX system, J¼16.0, 7.0 Hz, 1H), 2.84 (B part
of ABX system, J¼16.0, 7.0 Hz, 1H), 2.66–2.78 (br s,
1H), 3.67 (s, 3H), 3.79 (app dd, J¼11.4, 5.6 Hz, 1H),
3.88–3.94 (m, 1H), 4.25–4.36 (m, 1H), 4.54–4.64 (m, 1H);
most of the resonances for the minor isomer are superim-
posed to those of the major isomer, except for the following
ones: 1.80–1.95 (m, 2H), 2.75 (d, J¼6.0 Hz, 2H), 3.84–4.05
(m, 2H), 4.65–4.73 (m, 1H). Anal. Calcd for C12H21NO6: C,
52.35; H, 7.69; N, 5.09. Found: C, 52.20; H, 7.71; N, 5.11.
4.1.8. (D)-(4R,5R)-4-(tert-Butoxycarbonyl)amino-5-[2-
(methanesulfonyl)oxy]ethyl-dihydrofuran-2-one (19).
An ice-cooled (0 ꢁC) solution of (+)-18 (0.21 g, 0.86 mmol)
in CH2Cl2 (10 mL) was treated with Et3N (0.19 mL,
1.30 mmol) and MeSO2Cl (0.10 mL, 1.30 mmol), and the
mixture stirred at room temperature for 10 min. Brine was
added, the organic phase separated, dried, and evaporated.
The crude product was purified by column chromatography
(Et2O) to give (+)-19 (0.22 g, 80%) as a white solid, mp
108–110 ꢁC. [a]D20 +124.0 (c 1.00, CHCl3); IR (neat): 3356,
1
2980, 1770, 1680, 1514, 1339, 1248, 1160, 910 cmꢀ1; H
NMR (400 MHz, CDCl3): d 1.42 (s, 9H), 2.00–2.20 (m,
2H), 2.46 (A part of ABX system, J¼18 Hz, 1H), 2.94 (B
part of ABX system, J¼18.0, 8.0 Hz, 1H), 3.03 (s, 3H),
4.30–4.47 (m, 2H), 4.50–4.60 (m, 1H), 4.68 (dt, J¼9.6,
4.4 Hz, 1H), 5.12 (br d, J¼8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 28.3 (3CH3), 29.3 (CH2), 36.3 (CH2),
37.4 (CH3), 49.9 (CH), 66.3 (CH2), 79.6 (CH), 80.6 (C),
155.2 (C), 174.5 (C). Anal. Calcd for C12H21NO7S: C,
44.57; H, 6.55; N, 4.33. Found: C, 44.60; H, 6.52; N, 4.35.
4.1.6. (D)-(3S,4R)-4-Hydroxy-3-(methoxycarbonyl)-
methyl-[1,2]-oxazinane-2-carboxylic acid tert-butyl ester
(16) and (L)-(1R,5R)-6-tert-butoxycarbonyl-2,7-dioxa-6-
azabicyclo[4.3.0]nonan-3-one (17). A solution of alkene 15
(0.50 g, 1.82 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 12 h in the presence of 1,1,3,3-tetramethyl-
guanidine (0.23 mL, 1.82 mmol), then the solvent was evap-
orated. Column chromatography of the residue (EtOAc/
hexanes 1:1) gave (+)-16 (0.30 g, 60%) and (ꢀ)-17 (0.13 g,
30%). Compound (+)-16: colorless oil. [a]2D0 +63.0 (c 1.66,
CHCl3); IR (neat): 3456, 2978, 1738, 1720, 1695, 1367,
4.1.9. (L)-(1R,5R)-6-tert-Butoxycarbonyl-2-oxa-6-azabi-
cyclo[3.3.0]octan-3-one (20). A solution of (+)-19 (0.15 g,
0.46 mmol) and 1,1,3,3-tetramethylguanidine (64 mL,
0.51 mmol) in CH2Cl2 (5 mL) was stirred at room tempera-
ture for 12 h, then the solvent was evaporated. Column chro-
matography (Et2O) of the residue gave (ꢀ)-20 (90 mg, 90%)
as a white solid, mp 110–111 ꢁC (lit.12 mp 111–112 ꢁC; lit.14
mp 111 ꢁC). [a]2D0 ꢀ150.0 (c 0.50, CHCl3) {lit.12 [a]3D0
ꢀ141.4 (c 0.44, CHCl3); lit.14 [a]D27 ꢀ131.1 (c 1.00,
1
1255, 1161, 1094, 1020, 991 cmꢀ1; H NMR (400 MHz,
CDCl3): d 1.48 (s, 9H), 1.58–1.68 (m, 1H), 2.04–2.18 (m,
1H), 2.62 (A part of ABX system, J¼16.0, 7.0 Hz, 1H),
2.84 (B part of ABX system, J¼16.0, 7.0 Hz, 1H), 2.66–
2.78 (br s, 1H), 3.67 (s, 3H), 3.79 (app dd, J¼11.4, 5.6 Hz,
1H), 3.88–3.94 (m, 1H), 4.25–4.36 (m, 1H), 4.54–4.64 (m,
1H); 13C NMR (100 MHz, CDCl3): d 27.1 (CH2), 28.3
(3CH3), 34.2 (CH2), 52.0 (CH3), 57.4 (CH), 64.5 (CH),
65.7 (CH2), 81.9 (C), 155.7 (C), 171.4 (C). Anal. Calcd for
C12H21NO6: C, 52.35; H, 7.69; N, 5.09. Found: C, 52.20;
H, 7.71; N, 5.11. Compound (ꢀ)-17: white solid, mp 72–
73 ꢁC. [a]D20 ꢀ135.0 (c 1.00, CHCl3); IR (neat): 2975,
1774, 1712, 1689, 1365, 1324, 1305, 1259, 1160, 1081,
1
CHCl3)}; H NMR (200 MHz, CDCl3 at 50 ꢁC): d 1.48 (s,
9H), 1.90–2.13 (m, 2H), 2.29 (part of ABX system,
J¼14.0, 6.0 Hz, 1H), 2.70–2.90 (m, 1H), 3.37 (dt, J¼11.0,
6.0 Hz, 1H), 3.60–3.90 (m, 1H), 4.35–4.50 (m, 1H), 5.05
(app t, J¼5.0 Hz, 1H). Anal. Calcd for C11H17NO4: C,
58.14; H, 7.54; N, 6.16. Found: C, 58.25; H, 7.51; N, 6.18.
1
1017, 980, 840 cmꢀ1; H NMR (400 MHz, CDCl3): d 1.49
(s, 9H), 2.00–2.20 (m, 2H), 2.80 (d, J¼6.4 Hz, 2H), 4.00–
4.20 (m, 2H), 4.76–4.90 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 25.3 (CH2), 28.2 (3CH3), 32.2 (CH2), 54.2 (CH),
65.9 (CH2), 73.2 (CH), 82.8 (C), 154.6 (C), 174.7 (C).
Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76.
Found: C, 54.40; H, 7.01; N, 5.78.
4.1.10. (D)-(1R,5R)-2-Oxa-6-azabicyclo[3.3.0]octan-3-
one hydrochloride (1$HCl). Urethane (ꢀ)-20 (0.10 g,
0.44 mmol) was deprotected with HCl as described by
Kouyama et al.14 to furnish (+)-1$HCl (70 mg, 98%) as
white needles, mp 184–185 ꢁC (lit.4b mp 185–186 ꢁC; lit.8
mp 185–186.5 ꢁC). [a]D20 +48.5 (c 0.20, MeOH) {lit.4b [a]D
+48.5 (c 1.5, MeOH); lit.8 [a]D25 +48.8 (c 0.20, MeOH)}.
Spectral data were in good agreement with those reported
in the literature,16 1H NMR (400 MHz, D2O): d 2.20–2.40
(m, 2H), 2.90 (dd, J¼19.5, 1.4 Hz, 1H), 3.30 (dd, J¼8.8,
19.5 Hz, 1H), 3.40 (dt, J¼11.4, 6.6 Hz, 1H), 3.50–3.60 (m,
4.1.7. (D)-(4R,5R)-4-(tert-Butoxycarbonyl)amino-5-(2-
hydroxy)ethyl-dihydrofuran-2-one (18). A solution of
(ꢀ)-17 (0.2 g, 0.82 mmol) in MeCN (12 mL) containing wa-
ter (0.4 mL) was treated with Mo(CO)6 (0.32 g, 1.23 mmol)

A. Barco et al. / Tetrahedron 63 (2007) 4278–4283
4283
5. Cooper, J.; Gallagher, P. T.; Knight, D. W. J. Chem. Soc., Perkin
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6. Buchanan, J. G.; Jigajinni, V. B.; Singh, G.; Wightman, R. H.
J. Chem. Soc., Perkin Trans. 1 1987, 2377.
1H), 4.60–4.80 (m, 1H), 5.42 (br t, J¼5.0 Hz, 1H). Anal.
Calcd for C6H10ClNO2: C, 44.05; H, 6.16; N, 8.56. Found:
C, 44.10; H, 6.13; N, 8.58.
7. Buchanan, J. G.; Singh, G.; Wightman, R. H. J. Chem. Soc.,
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8. Shishido, K.; Sukegawa, Y.; Fukumoto, K.; Kametani, T.
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36, 8127.
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1996, 7, 3327.
14. Kouyama, T.; Matsunaga, H.; Ishizuka, T.; Kunieda, T.
Heterocycles 1997, 44, 479.
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4.1.11. (D)-(3S,4R)-4-(Methanesulfonyl)oxy-3-(methoxy-
carbonyl)methyl-[1,2]-oxazinane-2-carboxylic acid
tert-butyl ester (21). To an ice-cooled (0 ꢁC) solution of
the hydroxy ester (+)-16 (0.23 g, 0.83 mmol) in CH2Cl2
(10 mL) were successively added Et3N (0.18 mL,
1.24 mmol), MeSO2Cl (0.10 mL, 1.24 mmol), and a catalytic
amount of DMAP. After being stirred at room temperature for
1 h, the mixture was diluted with brine and the organic layer
separated. The aqueous phase was further extracted with
CH2Cl2, the organic fractions were collected, dried, and evap-
orated. The crude product was purified by column chromato-
graphy (EtOAc/hexanes 1:2) to afford (+)-21 (0.23 g, 80%) as
a colorless oil. [a]2D0 +40.1 (c 1.00, CHCl3); IR (neat): 2979,
1717, 1355, 1170, 1091, 926, 846 cmꢀ1; 1H NMR (400 MHz,
CDCl3):d 1.51(s, 9H), 1.90–2.00(m, 1H), 2.22–2.38(m, 1H),
2.75 (A part of ABX system, J¼16.6, 8.8 Hz, 1H), 2.84 (B
part of ABX system, J¼16.6, 6.0 Hz, 1H), 3.13 (s, 3H),
3.71 (s, 3H), 3.90 (app dd, J¼11.6, 5.6 Hz, 1H), 4.18–4.28
(m, 1H), 4.76–4.82 (m, 1H), 4.85–4.90 (m, 1H); 13C NMR
(100 MHz, CDCl3): d 26.3 (CH2), 28.3 (3CH3), 33.9 (CH2),
38.6 (CH3), 52.3 (CH3), 65.3 (CH2), 73.6 (2CH), 82.4 (C),
154.5 (C), 170.7 (C). Anal. Calcd for C13H23NO8S: C,
44.18; H, 6.56; N, 3.96. Found: C, 44.30; H, 6.54; N, 3.98.
16. Du, J.-X.; Huang, H.-Y.; Huang, P.-Q. Tetrahedron: Asymmetry
2004, 15, 3461.
17. (a) Niwa, H.; Okamoto, O.; Miyachi, Y.; Uosaki, Y.; Yamada,
K. J. Org. Chem. 1987, 52, 2941; (b) Nagao, Y.; Dai, W.-M.;
Ochiai, M.; Shiro, M. J. Org. Chem. 1989, 54, 5211; (c) Wee,
A. G. H. J. Org. Chem. 2001, 66, 8513.
ˆ
18. (a) Hirama, M.; Iwakuma, T.; Ito, S. J. Chem. Soc., Chem.
4.1.12. (D)-(1S,5S)-6-tert-Butoxycarbonyl-2,7-dioxa-6-
azabicyclo[4.3.0]nonan-3-one (17). A solution of (+)-21
(0.24 g, 0.68 mmol) and LiOH$H2O (33 mg, 0.78 mmol) in
a mixture of dioxane (4 mL) and water (1 mL) was stirred
at room temperature for 12 h. The solvent was stripped off,
then water and Et2O were added. The organic layer was sep-
arated, the aqueous phase was extracted several times with
Et2O, and the combined organic extracts were dried. Evapo-
ration of the solvent gave (+)-17 (0.13 g, 80%) as a white
solid, mp 71–72 ꢁC. [a]D20 +134.0 (c 1.00, CHCl3). Spectral
data were identical to those of (ꢀ)-17. Anal. Calcd for
C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found: C, 54.38;
H, 7.02; N, 5.77.
Commun. 1987, 1523; (b) Nagasaka, T.; Yamamoto, H.;
Hayashi, I.; Watanabe, M.; Hamaguchi, F. Heterocycles
ˆ
1989, 29, 155; (c) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S.
Synlett 1995, 404.
19. Pollini, G. P.; De Risi, C.; Lumento, F.; Marchetti, P.; Zanirato,
V. Synlett 2005, 164.
20. Tan, C.-H.; Holmes, A. B. Chem.—Eur. J. 2001, 7, 1845.
21. Thecrudealdehydeobtaineduponwork-upwassufficientlypure
to be used in the next step without further purification, analytical
and spectroscopic data matching those reported in Ref. 20.
22. Hatakeyama, S.; Hokano, T.; Maeyama, J.; Esumi, T.;
Hiyamizu, H.; Iwabuchi, Y.; Nakagawa, K.; Ozono, K.;
Kawase, K.; Kawase, A.; Kubodera, N. Bioorg. Med. Chem.
2001, 9, 403.
23. Jones, D. S.; Hammaker, J. R.; Tedder, M. E. Tetrahedron Lett.
2000, 41, 1531; For preparation of O-substituted hydroxyl-
amines from alcohols, see also: Albrecht, S.; Defoin, A.;
Tarnus, C. Synthesis 2006, 1635.
Acknowledgements
We thank MIUR (PRIN 2006) and the University of Ferrara
for financial support.
1
24. The 70:30 ratio was estimated by H NMR spectrum of the
crude reaction mixture.
25. Marradi, M. Synlett 2005, 1195.
References and notes
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addition/intramolecular Wittig reaction sequence allowing
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Kumarn, S.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V.
Org. Lett. 2005, 7, 4189; (b) Kumarn, S.; Shaw, D. M.; Ley,
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ble, owing to an apparent misreporting. While describing the
synthesis of both (S)- and (R)-3-(tert-butyldimethylsilyl)oxy-
4-penten-1-ol, the authors omitted the optical value for the
(R)-enantiomer, [a]2D0 +3.3 (c 0.94, CHCl3) being given for
the (S)-configured alcohol.
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