N-Boc-2-acyl oxazolidine methodology combined with ring-closing metathesis: A new approach towards the enantioselective synthesis of α-(1-hydroxyalkyl) nitrogen heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)00458-6

A synthetic methodology, based on N-Boc-2-acyloxazolidine chemistry combined with ring-closing metathesis, allows the preparation of enantiopure piperidinic heterocycles showing a 2-(1-hydroxyalkyl) side-chain, a pattern commonly found in natural alkaloids. Synthesis of Δ-3,4-2,6-disubstituted piperidinic rings can thus be achieved with a good 2,6-cis or -trans stereocontrol, unless the substituent located at C₂ is not a phenyl group. Diastereoselective functionnalization of the Δ-3,4 alkene moiety and access to seven or eight-membered nitrogen rings are also key features of this methodology.

Full text of DOI:10.1016/S0040-4020(01)00458-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 5393±5401
N-Boc-2-acyl oxazolidine methodology combined with
ring-closing metathesis: a new approach towards
the enantioselective synthesis of a-ꢀ1-hydroxyalkyl)
nitrogen heterocycles
Claude Agami, FrancËois Coutyp and Nicolas Rabasso
Á Â Â
Laboratoire de Synthese Asymetrique ꢀUMR CNRS 7611), Universite Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
Received 9 February 2001; accepted 26 April 2001
AbstractÐA synthetic methodology, based on N-Boc-2-acyloxazolidine chemistry combined with ring-closing metathesis, allows the
preparation of enantiopure piperidinic heterocycles showing a 2-(1-hydroxyalkyl) side-chain, a pattern commonly found in natural alkaloids.
Synthesis of D-3,4-2,6-disubstituted piperidinic rings can thus be achieved with a good 2,6-cis or -trans stereocontrol, unless the substituent
located at C2 is not a phenyl group. Diastereoselective functionnalization of the D-3,4 alkene moiety and access to seven or eight-membered
nitrogen rings are also key features of this methodology. q 2001 Elsevier Science Ltd. All rights reserved.
Nitrogen heterocycles a-substituted by a (1-hydroxyalkyl)
side-chain constitute a framework frequently encountered in
natural alkaloids.1 This is the case in (2)-b-conhydrine 1, a
piperidinic alkaloid isolated from the seeds of the toxic
Conium maculatum L.,2 or in palustrine 23, the toxic prin-
ciple of Equisetum paluster L. This pattern is also found in
indolizidinic alkaloids, such as (2)-castanospermine 3, or
(2)-slaframine 4; due to their potent glycosidase inhibitory
activity4 they are intensively studied, among other aza-
sugars, by the synthetic community. The improvement of
the biological activity and selectivity of this class of
compounds still calls for new synthetic strategies.
This paper reports a new approach5 for the enantioselective
synthesis of nitrogen heterocycles possessing the general
structure depicted in Figure 1.
This methodology is based on the combination of the
chemistry of N-Boc-2-acyl oxazolidines developed in our
group,6 and ring-closing metathesis.7 The scope of this
method includes: (i) an ef®cient syn stereocontrol of the
C6±C7 amino alcohol moiety, (ii) the possibility of further
diastereoselective functionalization of the C3±C4 alkene,
(iii) a cis or trans (when nˆ1) stereocontrol of the C2 and
C6 disubstituted piperidine, and (iv) an access (when R0ˆH)
to larger unsaturated nitrogen rings.
The retrosynthetic scheme of our method is depicted in
Scheme 1 for nˆ1. Unsaturated piperidinol A is accessible
through alkaline hydrolysis of bicyclic oxazolidinone B,
itself prepared by ring-closing metathesis of diole®nic
compound C. The latter arises from alcohol D through an
oxidation/Wittig ole®nation sequence. A trans C6±C7
stereocontrol results in D from the allylation of bicyclic
oxazolidinone
chemistry.8 Finally, oxazolidinone E derives via a trans-
carbamation of N-Boc-a-hydroxy oxazolidine F, easily
E through precedented acyl iminium
Keywords: heterocycles; alkaloids; stereoselective.
Corresponding author. Tel.: 133-1-44-273013; fax: 133-1-44-272620;
e-mail: couty@ccr.jussieu.fr
p
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00458-6

5394
C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
Scheme 1.
obtained by diastereoselective reduction of the starting
N-Boc-2-acyl oxazolidine G.
Treatment of 7a with NaH in THF gave oxazolidinone 8,
that was reacted with allyltrimethylsilane, in the presence of
titanium tetrachloride, in order to afford 9 with high stereo-
selectivity. Transformation of this alcohol into the diole®nic
substrate required for the ring-closing step (transfomation
D ! C in Scheme 1), requires its prior oxidation into 10.
Among the various conditions tested for this oxidation, only
Dess±Martin periodinane gave a satisfactory result, afford-
ing unstable aldehyde 10 in good yield. However, Wittig
ole®nation of this aldehyde failed to produce the required
alkene, presumably because of an undesired enolisation.
The less basic carboethoxy triphenyl phosphorane9 led to
unsaturated ester 11 in a reasonable yield, but with an
isomerized alkene moiety, conjugated with the phenyl
ring. This emphasizes the ease of enolization of the benzylic
position in this substrate (Scheme 3).
In order to test the viability of the above synthetic scheme,
this study was initiated with our previously described
phenyl glycinol-derived Weinreb amide 5 (R0ˆPh), and
although a wide range of acyl oxazolidines can be prepared
starting from 5, we choose to introduce an ethyl group
(RˆEt), aiming to synthetize (2)-b-conhydrine 1.
1. Synthesis of a-ꢀ1-hydroxyalkyl) substituted nitrogen
heterocycles
As shown in Scheme 2, reaction of ethylmagnesium bro-
mide with 5 gave ketone 6 in good yield. NaBH4-mediated
reduction of 6 then gave diateroisomeric a-hydroxy oxazo-
lidines 7a and 7b in a 86/14 ratio. Major stereoisomer 7a
was conveniently isolated pure after ¯ash chromatography.
When this reduction was conducted in the presence of
cerium trichloride, the ratio of 7a and 7b was reversed
(20/80), and major isomer 7b was now isolated. The
observed diastereoselectivity is in agreement with previous
results6 and is explained on the basis of a Felkin±Ahn
control (NaBH4 alone), or a chelated model (NaBH4 in the
presence of CeIII).
On the other hand, treatment of isomeric alcohol 7b with
NaH did not lead to any transcarbamation product, and this
was ascribed5 to a steric crowding between the ethyl group
and the C4 phenyl ring substituent. In order to synthetise
diole®nic substrates required to test the RCM step, oxazo-
lidinone 9 was reductively debenzylated to give 12, and
transformed into diole®nic oxazolidinones 13±16 by
treatment with NaH and alkylation with the appropriate
halogenoalkene. Ring-closing metathesis of these
Scheme 2. Reagents and conditions: a Ethylmagnesium bromide, Et2O, rt. b NaBH4, EtOH, 2788C, 71% overall for 7a. c NaBH4, EtOH, CeCl3 (7H2O),
2788C, 69% overall for 7b.
Scheme 3. Reagents and conditions: a NaH, THF, re¯ux, 98%. b allyltrimethylsilane, TiCl4, 2788C, CH2Cl2, 71%. c Dess±Martin periodinane, CH2Cl2.
d (C6H5)3PˆCHCO2Et, benzene, 40% overall from 9.

C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
5395
Scheme 4. Reagents and conditions: a Na (3.5 equiv.), EtOH, THF, NH3, 93%. b NaH, DMF, C3H7Br, 74%; 13: C4H9Br, 42%; 14:, C5H10Br, 72%, 15; C4H7Cl,
54%, 16. c Grubbs' catalyst (2.5 molar ratio), CH2Cl2, re¯ux, 17: 79%, 18: 80%, 19: 86%, 20: 74%.
compounds then occured in the presence of Grubbs' catalyst
(2.5% molar ratio), and yielded bicyclic oxazolidinones 17±
20 (Scheme 4).
Still remains unsolved the formation of a stereogenic center
at C2 (R0 other than H, in Fig. 1). In order to circumvent the
failure of the Wittig ole®nation of 10 (R0ˆPh), possessing a
relatively acidic hydrogen in a position both to a carbonyl
and phenyl groups, we decided to start with another
b-amino alcohol.
Reactivity of the above bicyclic oxazolidinones was next
studied. AM1 calculations performed on compound 17
shows a signi®cant steric crowding of the endo diastereo-
face of the alkene moiety in this bicyclic compound.5
Indeed, dihydroxylation of 17 gave exo diol 21 as a unique
stereoisomer, and the relative con®guration of the newly
created stereocenters was secured by X-ray radiocrystal-
lography. On the other hand, hydrogenation of compound
20 afforded 22 with a 72% de, and the structure of the major
isomer was assigned on the basis of the previous result (i.e.
exo hydrogenation). Finally, hydrogenation of 17, followed
by alkaline hydrolysis gave (2)-b-conhydrine 1, whereas
hydrolysis of 17 afforded the unsaturated analog 24
(Scheme 5).
2. Synthesis of a,a0-disubstituted-a-ꢀ1-hydroxyalkyl)
nitrogen heterocycles
(S)-Phenylalaninol-derived Weinreb amide 27 was prepared
following our reported procedure. No loss of selectivity was
observed for the C2 stereocontrol, compared to 5. Ketone 28
was then stereoselectively reduced to give 29a (de: 76%), or
29b (de: 58%). In these steps, similar selectivities were
observed, compared to the phenyl-substituted substrate.
However, an important difference of reactivity appeared
during the next step, i.e. the transcarbamation. Indeed, in
this case, both stereoisomers 29a and 29b could be con-
veniently cyclized to give the corresponding bicyclic oxazo-
lidinones 30 and 31 whereas substrate 7b was unreactive
under similar conditions. As a matter of fact, the larger
conformational mobility of the benzyl group compared to
the phenyl group in 7b, induces less steric crowding in the
course of the cyclization of 29b (Scheme 6).
Allylation of compounds 30 and 31 stereoselectively gave
trans adducts 32 and 33. Since it was previously demon-
strated9 that this reaction proceeds through an intermediate
acyliminium ion, these results show that the stereocenter
bearing the benzylic substituent on the oxazolidine ring
has a negligible stereodirecting effect in this allylation,
compared to the a-ethyl substituent. Oxidation of 32 and
33 afforded aldehydes 34 and 35 which were now ole®nated
without problems to give 36 and 37. The overall yield of this
Scheme 5. Reagents and conditions: a OsO4, NMO, acetone/water, 45%.
b Pd/C, EtOH, 92% (24), 88% (22). c LiOH, EtOH, THF, re¯ux, 45% (1),
54% (24).
Scheme 6. Reagents and conditions: a (i) Ethyl glyoxylate, (ii) (Boc)2O, (iii) LiOH, 77% overall. b Isobutyl chloroformiate, NHMe(OMe), HCl, 79%.
c Ethylmagnesium bromide, Et2O, rt, 72%. d NaBH4, EtOH, 2788C, 72%. e NaBH4, CeCl3, EtOH, 2788C, 54%. f NaH, THF, re¯ux, 71% (30), 68% (31).

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C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
Scheme 7. Reagents and conditions: a allyltrimethylsilane, TiCl4, 2788C, CH2Cl2, 77% (32), 65% (33). b Dess±Martin periodinane, CH2Cl2. c Ph3PCH3Br,
nBuLi, THF, 2208C, 80% overall (36), 40% overall (37). d Grubbs' catalyst (2.5 molar ratio), CH2Cl2, re¯ux, 83% (38), 74% (39).
sequence was nevertheless lower in case of substrate 32.
Finally, ring-closing metathesis of these diole®nic
substrates yielded cis and trans disubstituted piperidinic
compounds 38 and 39 (Scheme 7).
followed by usual workup to give crude 6 as an oil (11 g)
that was used without further puri®cations for the next step.
An analytical sample was puri®ed by ¯ash chromatography
20
(E/PE: 2/8). Rf: 0.53 (E/PE: 4/6); [a]D ˆ221.5 (c 0.5,
CHCl3); IR (®lm): 1812, 1708 cm21;1H NMR: 1.06 (t,
Jˆ7.5 Hz, 3H), 1.21 (bs, 9H), 2.58±2.65 (m, 2H), 3.93 (t,
Jˆ8.5 Hz, 1H), 4.34 (t, Jˆ8.5 Hz, 1H), 4.80 (bs, 1H), 5.13
(bs, 1H), 7.17±7.38 (m, 5H); 13C NMR: 7.3, 28.2 (CH3),
30.1 (CH2), 59.2 (CH), 69.6 (CH2), 84.3 (Cq), 89.8, 126.9,
127.1, 128.6, (CH), 140.9, 154.8 (Cq); Anal. calcd for
C17H23NO4: C: 66.86; H: 7.59; N: 4.59. Found: C: 66.69;
H: 7.88; N: 4.50.
In conclusion, the above reported procedure allows a
general access to enantiopure stereode®ned nitrogen hetero-
cycles. Application to the synthesis of bioactive alkaloids
showing more complex squeletton is currently under study
in our group.
3. Experimental
3.1.2. [2S,2ꢀ1S),4S]-3-tert-Butoxycarbonyl-2-ꢀ1-hydroxy-
propyl)-4-phenyl-1,3-oxazolidine 7a and [2S,2ꢀ1R),4S]-3-
tert-butoxycarbonyl-2-ꢀ1-hydroxy-propyl)-4-phenyl-1,3-
oxazolidine 7b. To a solution of crude acyl oxazolidine 6
(11 g, 36 mmol), in ethanol (240 mL), cooled to 2788C,
was added in one portion sodium borohydride (2.7 g,
72 mmol). The mixture was stirred for 0.5 h at 2788C and
hydrolyzed by addtion of a saturated aqueous solution of
NH4Cl (50 mL). After warming to rt, the ethanol was
distilled off under reduced pressure. Addition of water and
ether to the residue was followed by usual workup. Crude
hydroxy oxazolidine (de: 72%) was puri®ed by ¯ash
chromatography (E/PE: 2/8) to give pure title compound
7a as an oil (7.86 g, 71% overall yield from 5). Rf: 0.54
3.1. General comments
1H- and 13C spectra (CDCl3 solution unless otherwise stated)
were recorded on a Bruker ARX 250 spectrometer at 250
and 62.9 MHz, respectively; chemical shifts are reported in
ppm from TMS. Optical rotations were determined with a
Perkin±Elmer 141 instrument. GC analysis were run on a
Hewlett±Packard 5890 instrument using a capillary column
(OV 17) of 30 m. Mass spectra were recorded on a GC/MS
Varian Saturn 2000. Elemental analysis were performed by
Â
the `Sevice Regional de Microanalyses de l'Universite P. et
M. Curie'. All reactions were carried out under argon.
Column chromatography were performed on silica gel
230±400 mesh by using various mixtures of diethyl ether
(E), ethyl acetate (AcOEt) and petroleum ether (PE). TLC
were run on Merck Kieselgel 60F254 plates. Melting points
are uncorrected. THF and ether were distilled from sodium/
benzophenone ketyl. Dichloromethane was distilled from
calcium hydride. Mention of `usual workup' means: (i)
decantation of the organic layer, (ii) extraction of the
aqueous layer with ether, (iii) drying of the combined
organic phases over MgSO4, (iv) solvent evaporation
under reduced pressure. Composition of stereoisomeric
mixtures was determined by NMR analysis on crude
products before any puri®cation.
20
(E/PE: 4/6); [a]D ˆ13.7 (c 0.7, CHCl3); IR (®lm): 3441,
3030, 1709 cm21 1H NMR: 0.98 (t, Jˆ7.5 Hz, 3H), 1.22 (bs,
9H), 1.36±1.55 (m, 1H), 1.63±1.79 (m, 1H), 3.61±3.70 (m,
1H), 3.88 (dd, Jˆ8.5 and 6.8 Hz, 1H), 4.22 (dd, Jˆ6.8 and
8.6 Hz, 1H), 4.85 (t, Jˆ6.8 Hz, 1H), 5.04 (d, Jˆ7.7 Hz 1H),
7.19±7.28 (m, 5H); 13C NMR: 9.3 (CH3), 26.4 (CH2), 28.1
(CH3), 61.0 (CH), 73.6 (CH2), 75.1 (CH) 81.9 (Cq), 92.6,
126.4, 127.7, 128.6, (CH), 140.3, 154.5 (Cq); Anal. Calcd
for C17H25NO4: C: 66.43; H: 8.20; N: 4.56. Found: C: 66.68;
H: 8.09; N: 4.29. When the same reaction was conducted in
the presence of CeCl3 (7H2O) (1.5 equiv.), added prior to
the addition of sodium borohydride, crude hydroxy oxazo-
lidine 7b (de 60%) was now obtained. Pure 7b was isolated
20
as above (69%). Rf: 0.36 (E/PE: 4/6); oil; [a]D ˆ130.5 (c
3.1.1.
ꢀ2S,4S)-3-tert-Butoxycarbonyl-2-ꢀpropionyl)-4-
1
0.8, CHCl3); H NMR: 1.05 (t, Jˆ7.5 Hz, 3H), 1.37 (bs,
phenyl-1,3-oxazolidine 6. To a solution of Weinreb
amide 5 (13.5 g, 40 mmol) in ether (130 mL), cooled to
58C, was added dropwise a solution of ethylmagnesium
bromide (3N solution in ether, 20 mL, 60 mmol). At the
end of the addition, the suspension was stirred for 0.5 h
and hydrolyzed by addition of a saturated aqueous solution
of NH4Cl (50 mL). Addition of water (100 mL) was
9H), 1.55±1.70 (m, 2H), 3.82±3.92 (m, 1H), 4.10 (dd,
Jˆ8.9 and 5.5 Hz, 1H), 4.32 (dd, Jˆ7.4 and 8.9 Hz, 1H),
4.88±5.02 (m, 1H), 5.13 (d, Jˆ3.7 Hz 1H), 7.25±7.39 (m,
5H); 13C NMR: 10.9 (CH3), 26.0 (CH2), 28.6 (CH3), 61.0
(CH), 73.3 (CH2 and CH), 81.9 (Cq), 92.9, 126.9, 127.9,
128.9, (CH), 140.9, 154.9 (Cq).

C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
5397
3.1.3. ꢀ3S,6S,7S)-6-Ethyl-3-phenyltetrahydro-1,5-dioxa-
3a-aza-pentalen-4-one 8. To a solution of alcohol 7a
(3.2 g, 10.4 mmol) in THF (150 mL) was added sodium
hydride (60% wt, 833 mg, 20.8 mmol). When hydrogen
evolution had ceased, the mixture was re¯uxed for 2 h and
hydrolyzed by addition of a saturated aqueous solution of
NH4Cl (50 mL). Usual workup gave a pale yellow solid that
was washed with small portions of petroleum ether.
Compound 8 was obtained as a white solid (2 g, 82%); Rf:
15/85). Title compound was obtained as a clear oil
(78 mg, 40% overall yield from 9): Rf: 0.78 (AcOEt/PE:
20
3/7); [a]D ˆ241.3 (c 1.4, CHCl3); IR (®lm): 2977, 2934,
1
1744 cm21; H NMR: 0.95 (t, Jˆ7.5 Hz, 3H), 1.21 (t, Jˆ
7.5 Hz, 3H), 1.52±1.73 (m, 2H), 1.99±2.25 (m, 2H), 3.15
(dd, Jˆ8.5 and 19.0 Hz, 1H), 3.30 (dd, Jˆ5.2 and 19.0 Hz,
1H), 3.40±3.45 (m, 1H), 4.05±4.18 (m, 3H), 4.95±5.05 (m,
2H), 5.40±5.47 (m, 1H), 6.07 (dd, Jˆ5.3 and 8.5 Hz, 1H),
7.21±7.33 (m, 5H); 13C NMR: 9.5, 14.6 (CH3), 28.4, 34.3,
37.9 (CH2), 59.7 (CH), 61.2 (CH2), 80.6 (CH), 120.1 (CH2),
123.3, 127.4, 129.2, 131.8 (CH), 135.2, 135.7, 155.5, 171.5
(Cq).
20
0.42 (E/PE: 8/2); mp: 106±1088C; [a]D ˆ283.6 (c 0.6,
1
CHCl3); H NMR: 1.10 (t, Jˆ7.5 Hz, 3H), 1.84±1.87 (m,
2H), 4.29±4.33 (m, 2H), 4.51 (td, Jˆ3.0 and 6.5 Hz, 1H),
4.70 (dd, Jˆ3.4 and 6.5 Hz, 1H), 5.03 (d, Jˆ2.5 Hz, 1H),
7.37±7.40 (m, 5H); 13C NMR: 8.7 (CH3), 26.4 (CH2), 61.1
(CH), 75.8 (CH2), 80.6, 94.9, 127.9, 128.6, 128.7 (CH),
136.8 (Cq); Anal. calcd for C13H15NO3: C: 66.94; H: 6.48;
N: 6.00. Found: C: 64.82; H: 6.58; N: 5.51.
3.1.7. ꢀ4S,5S)-4-Allyl-5-ethyl-oxazolidin-2-one 12. To a
solution of 7a (926 mg, 3.36 mmol) in THF (5 mL), EtOH
(2 mL) and ammonia (40 mL), cooled at 2408C was added
sodium portionwise (271 mg, 11.8 mmol). After 20 min, the
mixture was quenched by addition of solid ammonium chlo-
ride (2 g), and stirred at rt for 1 h. The residue was taken up
in water, and usual workup (dichloromethane) gave an oil
that was puri®ed by ¯ash chromatography (E/PE: 1/1). Title
oxazolidinone was obtained as an oil (486 mg, 93%). Rf:
0.40 (E); GC (70±2208C, rate of 108C/min): trˆ8.46 min;
3.1.4. ꢀ4S,5S,6S)-4-Allyl-5-ethyl-3-ꢀ2-hydroxy-1-phenyl-
ethyl)-oxazolidin-2-one 9. To a solution of 8 (2.36 g,
10 mmol) in dichloromethane (50 mL) was added allyl-
trimethylsilane (6.4 mL, 40.5 mmol). The solution was
cooled to 2788C and a solution of TiCl4 (1 M solution in
dichloromethane, 20 mL, 20 mmol) was added dropwise.
The solution was warmed to rt and hydrolyzed with a
saturated aqueous solution of NaHCO3. Usual workup
(dichloromethane) gave a pale yellow solid that was washed
with small portions of petroleum ether. Compound 9 was
obtained as a white solid (1.94 g, 71%); Rf: 0.62 (E); mp:
20
[a]D ˆ259.7 (c 2.4, CHCl3); IR (®lm): 3220, 3019,
1
1747 cm21; H NMR: 0.94 (t, Jˆ7.5 Hz, 3H), 1.58±1.70
(m, 2H), 2.20±2.27 (m, 2H), 3.36±3.49 (m, 1H), 3.99±
4.12 (m, 1H), 5.05±5.13 (m, 2H), 5.59±5.74 (m, 1H), 6.65
(bs, 1H); 13C NMR: 9.4 (CH3), 28.0, 38.1 (CH2), 57.2, 83.5
(CH), 119.7 (CH2), 132.6 (CH), 160.0 (Cq); Anal. calcd for
C8H13NO2: C: 61.91; H: 8.44; N: 9.03. Found: C: 61.70; H:
8.35; N: 8.72.
20
1
74±768C; [a]D ˆ11.5 (c 0.6, CHCl3); H NMR: 0.80 (t,
Jˆ7.5 Hz, 3H), 1.41±1.53 (m, 2H), 2.17±2.22 (m, 2H),
3.08±3.15 (m, 1H), 3.81 (dd, Jˆ3.3 Hz, 1H), 4.00±4.07
(m, 1H), 4.24±4.29 (m, 1H), 4.35±4.39 (m, 1H), 4.66 (s,
1H), 5.02±5.10 (m, 2H), 5.47±5.54 (m, 1H), 7.16±7.29 (m,
5H); 13C NMR: 9.2 (CH3), 28.2, 36.3 (CH2), 59.8, 61.6
(CH), 64.1 (CH2), 79.9 (CH), 120.5 (CH2), 127.6, 128.7,
129.3, 131.5 (CH), 136.7, 157.8 (Cq); IR (Nujol): 3378,
1704 cm21; Anal. calcd for C16H21NO3: C: 69.79; H: 7.69;
N: 5.09. Found: C: 69.71; H: 7.54; N: 5.03.
3.2. General procedure for the N-alkylation of
oxazolidinone 12
To a solution of oxazolidinone 12 (330 mg, 2.13 mmol) in
dry DMF (8 mL) was added sodium hydride (60% wt,
102 mg, 2.55 mmol). After 10 min, the required bromo
alkene (4.25 mmol) was added in one portion. The solution
was stirred at rt for 0.5 h and hydrolized by addition of a
saturated aqueous solution of NH4Cl. Usual workup was
followed by ¯ash chromatography (E/PE: 8/2) and gave
oxazolidinones 13±16 as clear oils.
3.1.5. ꢀ2S,4S,5S)-ꢀ4-Allyl-5-ethyl-2-oxo-oxazolidin-3-yl)-
phenyl-acetaldehyde 10. To a solution of 9 (158 mg,
0.57 mmol) in dichloromethane (5 mL) was added Dess±
Martin Periodinane (485 mg, 1.14 mmol). The suspension
was stirred at rt for 2 h, and then diluted with ether (25 mL)
and petroleum ether (50 mL). Filtration over a pad of Celite
and concentration gave crude aldehyde 10 as an oil
(180 mg) that was used without further puri®cations. Rf:
3.2.1. ꢀ4S,5S)-3,4-Diallyl-5-ethyl-oxazolidin-2-one 13.
20
Yield: 74%; Rf: 0.67 (E/PE: 7/3); [a]D ˆ16.8 (c 1.0,
CHCl3); GC (100±2208C, rate of 108C/min): trˆ6.41 min;
1
IR (®lm): 3054, 1741 cm21; H NMR: 0.92 (t, Jˆ7.5 Hz,
1
0.77 (AcOEt/PE: 1/1); IR (®lm): 1730 cm21; H NMR:
3H), 1.55±1.61 (m, 2H), 2.18±2.34 (m, 2H), 3.33±3.40 (m,
1H), 3.58 (dd, Jˆ7.7 and 15.7 Hz, 1H), 4.01±4.09 (m, 1H),
4.13±4.15 (m, 1H), 5.08±5.23 (m, 4H), 5.53±5.73 (m, 2H);
13C NMR: 9.3 (CH3), 28.2, 36.6, 44.9 (CH2), 58.9, 79.6
(CH), 118.8, 120.2 (CH2), 131.9, 132.6 (CH), 157.8 (Cq).
0.89 (t, Jˆ7.5 Hz, 3H), 1.53±1.74 (m, 2H), 1.77±1.99 (m,
2H), 3.06 (s, 1H), 3.39 (q, Jˆ5.0 Hz, 1H), 4.12 (q, Jˆ
5.0 Hz, 1H), 4.90±5.17 (m, 2H), 5.37±5.65 (m, 1H),
7.20±7.39 (m, 5H), 9.74 (s, 1H); 13C NMR: 8.9 (CH3),
27.8, 36.8 (CH2), 58.4, 66.2, 80.9 (CH), 120.1 (CH2),
128.9, 129.3, 129.5, 131.8 (CH), 136.3, 158.3 (Cq), 195.1
(CH).
3.2.2. ꢀ4S,5S)-4-Allyl-3-but-3-enyl-5-ethyl-oxazolidin-2-
20
one 14. Yield: 42%; Rf: 0.50 (E/PE: 7/3); [a]D ˆ216.6
(c 0.7, CHCl3); IR (®lm): 3019, 1734 cm21 1H NMR:
;
3.1.6. ꢀ4S,5S)-4-ꢀ4-Allyl-5-ethyl-2-oxo-oxazolidin-3-yl)-
4-phenyl-but-3-enoic acid ethyl ester 11. To a solution
of the above crude aldehyde 10 (180 mg) in benzene
(7 mL) was added carboethoxytriphenyl phosphorane
(344 mg, 1 mmol). After 1 h, usual workup gave an oil
that was puri®ed by ¯ash chromatography (AcOEt/PE:
0.98 (t, Jˆ7.5 Hz, 3H), 1.58±1.70 (m, 2H), 2.27±2.48 (m,
4H), 3.03±3.13 (m, 1H), 3.42±3.49 (m, 1H), 3.60 (td, Jˆ7.7
and 14.2 Hz, 1H), 4.05±4.12 (m, 1H), 5.02±5.24 (m, 4H),
5.61±5.86 (m, 2H); 13C NMR: 9.3 (CH3), 28.2, 32.2, 36.8,
41.1 (CH2), 59.1, 79.6 (CH), 117.8, 120.5 (CH2), 131.9,
135.2 (CH), 158.4 (Cq).

5398
C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
3.2.3. ꢀ4S,5S)-4-Allyl-5-ethyl-3-pent-4-enyl-oxazolidin-2-
3.3.4. ꢀ1S,4S)-1-Ethyl-6-methyl-1,5,8,8a-tetrahydro-oxa-
zolo[3,4-a]pyridin-3-one 20. Yield: 74%; Rf: 0.56 (E/PE:
20
one 15. Yield: 72%; Rf: 0.75 (E/PE: 7/3); [a]D ˆ29.3
1
20
(c 0.6, CHCl3); H NMR: 1.00 (t, Jˆ7.5 Hz, 3H); 1.58±
8/2); [a]D ˆ2161.9 (c 0.3, CHCl3); IR (®lm): 3015,
1
1.73 (m, 4H), 2.08 (q, Jˆ5 Hz, 2H) 2.24±2.47 (m, 2H),
2.98±3.09 (m, 1H), 3.39±3.54 (m, 2H), 4.09 (q,
Jˆ5.0 Hz, 1H), 4.97±5.23 (m, 4H), 5.60±5.89 (m, 2H);
13C NMR: 9.3 (CH3), 26.9, 28.3, 31.2, 36.8, 41.6 (CH2),
59.3, 79.5 (CH), 115.8, 120.2 (CH2), 131.9, 137.8 (CH),
158.0 (Cq).
1749 cm21; H NMR: 0.95 (t, Jˆ7.5 Hz, 3H), 1.60±1.73
(m, 4H), 2.10 (s, 3H), 3.29 (quint., Jˆ4.9 Hz, 1H), 3.45
(d, Jˆ15.0 Hz, 1H), 3.89 (d, Jˆ15.0 Hz, 1H), 4.02 (q, Jˆ
7.1 Hz, 1H), 5.40±5.44 (m, 1H); 13C NMR: 9.4, 20.7 (CH3),
27.8, 30.4, 44.7 (CH2), 55.5, 83.0, 118.0, 131.5 (CH), 157.2
(Cq).
3.2.4. ꢀ4S,5S)-4-Allyl-5-ethyl-3-ꢀ2-methyl-allyl)-oxazoli-
3.3.5. ꢀ1S,4S,6R,7S)-1-Ethyl-6,7-dihydroxy-hexahydro-
oxazolo[3,4-a]pyridin-3-one 21. To a solution of 17
(79 mg, 0.47 mmol) in a (1/8) mixture of water and acetone
(2 mL) and cooled at 2208C was added an aqueous solution
of osmium tetroxide (4% wt. solution, 0.6 mL, 0.024 mmol)
and N-methyl morpholine N-oxide (110 mg, 0.95 mmol).
The reaction medium was warmed to rt (0.5 h) and
quenched by addition of sodium thiosulfate (23 mg). The
mixture was then saturated with sodium chloride and
extracted thouroughly with dichloromethane. Drying of
the organic layer over MgSO4 and concentration under
reduced pressure gave a residue that was puri®ed by ¯ash
chromatography (E/EtOH:9/1). Diol 21 was obtained as a
20
din-2-one 16. Yield: 54%; Rf: 0.54 (E/PE: 7/3); [a]D
ˆ
1
258.3 (c 0.8, CHCl3); H NMR: 1.00 (t, Jˆ 7.5 Hz, 3H),
1.63±1.69 (m, 2H), 1.72 (s, 3H), 2.21±2.42 (m, 2H), 3.32±
3.39 (m, 1H), 3.54 (d, Jˆ17.5 Hz, 1H), 4.08±4.15 (m, 2H),
4.90 (s, 1H), 4.95 (s, 1H), 5.14±5.22 (m, 2H), 5.59±5.75 (m,
1H); 13C NMR: 9.4, 20.3 (CH3), 28.5, 36.5, 48.3 (CH2),
58.8, 79.6 (CH), 114.3, 120.2 (CH2), 131.9 (CH) 140.2,
158.1 (Cq).
3.3. General procedure for the metathesis of diole®nic
oxazolidinones 13±16
white solid (43 mg, 45%). Slow evaporation of
methanolic solution gave crystals. Rf: 0.33 (E/EtOH: 9/1);
a
To a solution of oxazolidinone (1.13 mmol) in dichloro-
methane (20 mL) was added Grubbs' catalyst (23 mg,
2.5% molar ratio). After 2 h of re¯ux, the solvent was
evaporated under reduced pressure and the residue was puri-
®ed by ¯ash chromatography (E/PE: 4/6). Bicyclic oxazo-
lidinones 17±20 were obtained as oils.
20
1
mp: 165±1688C; [a]D ˆ23.5 (c 0.06, MeOH) H NMR
(CD3OD): 0.90 (t, Jˆ7.5 Hz, 3H), 1.46±1.68 (m, 3H),
1.93 (td, Jˆ3.6 and 13.6 Hz, 1H), 2.90±3.05 (m, 1H),
3.44±3.61 (m, 3H), 3.92±3.95 (m, 1H), 3.97 (q,
Jˆ6.1 Hz, 1H); 13C NMR (CD3OD): 9.6 (CH3), 28.6,
37.4, 42.6 (CH2), 55.0, 68.9, 69.0, 83.5 (CH), 157.1 (Cq).
Crystal data:10 C9H15NO4, orthorhombic, no centro-
symmetric P21 space group, Zˆ4, Dcˆ1.41 g/cm3, m (Mo
3.3.1. ꢀ1S,4S)-1-Ethyl-1,5,8,8a-tetrahydro-oxazolo[3,4-a]-
pyridin-3-one 17. Yield: 79%; Rf: 0.39 (E/PE: 7/3); GC
(100 to 2208C, rate 108C/min): tr 6.73 min (98%);
Ka)ˆ1.04 cm21
,
aˆ5.1132(8) A, bˆ110.332(2) A,
Ê 3
Ê
Ê
20
[a]D ˆ13 (c 0.5, CHCl3); IR (®lm): 3020, 1744 cm21
;
cˆ16.336(2) A, bˆ908, Vˆ947.9(3) A . The ®nal re®ne-
ment of 129 variables using 1620 re¯exions (with
(Fo)2.3s(Fo)2) were used to solve the structure to
Rˆ0.0444 and Rwˆ0.0517.
Ê
1H NMR: 0.96 (t, Jˆ7.0 Hz, 3H), 1.65±1.78 (m, 2H),
2.14±2.23 (m, 2H), 3.34 (quint., Jˆ7.0 Hz, 1H), 3.56±
3.65 (m, 1H), 3.98±4.08 (m, 2H), 5.69±5.78 (m, 2H); 13C
NMR: 9.4 (CH3), 27.7, 30.4, 41.2 (CH2), 55.5, 83.1, 125.5,
124.2 (CH), 157.4 (Cq); MS (EI, 70 eV): m/z 167 (M1, 40),
122 (30), 108 (44), 95 (30), 80 (41), 54 (100); Anal. calcd
for C9H13O2N, C, 64.65; H, 7.84; N, 8.33. Found. C, 65.04;
H, 7.72; N, 8.02.
3.3.6. ꢀ1S,4S)-1-Ethyl-hexahydro-oxazolo[3,4-a]pyridin-
3-one 23. A suspension of 17 (81 mg, 0.48 mmol) and
palladium on carbon (20% wt., 30 mg) in ethanol (7 mL)
was vigorously stirred under an hydrogen atmosphere
for 2 h. Filtration over a pad of Celite and concentration
under reduced pressure gave title compound as an oil
3.3.2. ꢀ1S,4S)-1-Ethyl-5,6,9,9a-tetrahydro-oxazolo[3,4-a]-
azepin-3-one 18. Yield: 80%; Rf: 0.36 (E/PE: 7/3);
20
(75 mg, 92%). Rf: 0.50 (E); [a]D ˆ233.2 (c 0.4, CHCl3);
[a]D ˆ285.2 (c 0.3, CHCl3); 1H NMR: 1.02 (t, Jˆ
IR (®lm): 1740 cm21; H NMR: 1.01 (t, Jˆ7.5 Hz, 3H),
20
1
7.0 Hz, 3H), 1.64±1.76 (m, 2H), 2.17±2.41 (m, 4H),
2.81±2.92 (m, 1H), 3.24±3.32 (m, 1H), 3.85±3.98
(m, 2H), 5.78±5.97 (m, 2H); 13C NMR: 9.2 (CH3), 27.3,
28.8, 34.9, 42.8 (CH2), 60.5, 80.9, 128.1, 132.7 (CH),
157.5 (Cq).
1.24±1.93 (m, 8H), 2.80 (td, Jˆ3.4 and 12.6 Hz, 1H),
3.19±3.28 (m, 1H), 3.81±3.88 (m, 1H), 4.00 (q, Jˆ
6.5 Hz, 1H); 13C NMR: 9.4 (CH3), 23.0, 24.7, 27.4, 31.0,
41.5 (CH2), 59.8, 82.2 (CH), 157.3 (Cq).
3.3.7. ꢀ1S,2S)-Piperidin-2-yl-propan-1-ol ꢀꢀ2)-b-con-
hydrine) 1. To a solution of 23 (66 mg, 0.39 mmol) in
2 mL of ethanol and 2 mL of water was added lithium
hydroxide (115 mg, 2.7 mmol). After 5 h of re¯ux, the
mixture was concentrated under reduced pressure, the resi-
due was taken up in water and ether. Usual workup gave an
oil that crystallized on standing (25 mg, 45%). Rf: 0.05 (E);
3.3.3. ꢀ1S,4S)-1-Ethyl-1,4,5,6,9a-hexahydro-2-oxa-3a-aza-
cyclopentacycloocten-3-one 19. Yield: 86%; Rf: 0.36
20
(E/PE: 7/3); [a]D ˆ255.5 (c 0.3, CHCl3); IR (®lm):
1
3010, 1729 cm21; H NMR: 1.01 (t, Jˆ7.5 Hz, 3H), 1.42±
1.56 (m, 1H), 1.60±1.77 (m, 2H), 1.93±2.14 (m, 2H), 2.17±
2.37 (m, 3H), 2.72±2.85 (m, 1H), 3.28 (q, Jˆ5.8 Hz, 1H),
3.77 (ddd, Jˆ14.5, 4.6 and 2.4 Hz, 1H), 4.00 (q, Jˆ6.5 Hz,
1H), 5.64±5.92 (m, 2H); 13C NMR: 8.6 (CH3), 26.4, 26.6,
27.4, 31.7, 41.3 (CH2), 63.3, 78.6, 124.4, 133.5 (CH), 158.5
(Cq).
[a]D ˆ234.1 (c 0.4, CHCl3); mp: 678C (Lit.2a: 728C), H
NMR: 0.92 (t, Jˆ7.5 Hz, 3H), 1.02±1.50 (m, 8H), 2.29
(ddd, Jˆ2.5, 7.5 and 10.0 Hz, 1H), 2.52 (td, Jˆ2.7 and
11.7 Hz, 1H), 2.98±3.05 (m, 1H), 3.15 (td, Jˆ3.4 and
20
1

C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
5399
7.7 Hz, 1H); 13C NMR: 10.5 (CH3), 24.8, 26.8, 26.9, 29.5,
46.9 (CH2), 61.3, 75.9 (CH).
reaction mixture was then stirred at rt for 1 h, and hydro-
lyzed by addition of a saturated aqueous solution of NH4Cl.
Usual workup gave a residue that was puri®ed by ¯ash
3.3.8. ꢀ1S,4S)-1-ꢀ1,2,3,6-tetrahydro-pyridin-2-yl)-propan-
1-ol 24. Following the above procedure and starting with 17
(67 mg, 0.40 mmol), title compound was obtained as an oil
that cristallyzed on standing (31 mg, 54%). Rf: 0.05 (E);
[a]D ˆ237.5 (c 0.6, CHCl3); mp: 65±668C, H NMR:
0.93 (t, Jˆ7.5 Hz, 3H), 1.18±1.37 (m, 1H), 1.46±1.64 (m,
1H), 1.73±1.83 (m, 1H), 1.90±1.99 (m, 1H), 2.47±2.56 (m,
1H), 2.72 (bs, 2H), 3.17 (td, Jˆ3.1 and 8.0 Hz, 1H), 3.30
(bs, 2H), 5.69 (bs, 2H); 13C NMR: 10.1 (CH3), 26.4, 28.3,
45.3 (CH2), 57.6, 75.7, 125.3, 127.7 (CH).
chromatography (E/PE: 2/8). Title compound was obtained
20
as an oil (650 mg, 72%). Rf: 0.60 (E/PE: 2/8); [a]D
ˆ
273.8 (c 0.8, CHCl3); IR (®lm): 3020, 2925, 2881, 1811,
1711 cm21; 1H NMR: 1.15 (t, Jˆ7.5 Hz, 3H), 1.51 (s, 9H),
2.55±2.85 (m, 3H), 3.41 (bs, 1H), 3.98 (bs, 2H), 4.21 (bs,
1H), 5.26 and 5.43 (two bs, 1H), 7.27±7.40 (m, 5H); 13C
NMR: 7.6, 28.6 (CH3), 32.0 (broadened), 39.5 (broadened)
(CH2), 58.5 (CH), 66.2 (broadened) (CH2), 81.6 (Cq), 89.6,
127.0, 129.0, 129.7 (CH), 138.1, 153.2, 206.1 (Cq); MS (CI,
NH3): m/z 246 (8), 220 (MH1, ±CO2, ±C4H8, 69), 206 (77),
162 (100), 117 (68), 91 (26).
20
1
3.3.9. ꢀ1S,4S,6RS)-1-Ethyl-6-methyl-hexahydro-oxazolo-
[3,4-a]pyridin-3-one 22. Following the procedure reported
above for the hydrogenation of 17, title compound was
prepared from 20 (25 mg, 0.138 mmol) and was obtained
as an oil (22 mg, 88%). This compound consisted in a 86/14
3.3.13. ꢀ2S,4S,9S)-4-Benzyl-2-ꢀ1-hydroxy-propyl)-oxazo-
lidine-3-carboxylic acid tert-butyl ester 29a and ꢀ2S,
4S,9R)-4-benzyl-2-ꢀ1-hydroxy-propyl)-oxazolidine-3-
carboxylic acid tert-butyl ester 29b. Following the pro-
cedure described for the reduction of 6, and starting with
28 (3.1 g, 9.7 mmol), title compound 29a was obtained as an
oil (2.3 g, 72%) after puri®cation by ¯ash chromatography
(E/PE: 5/95 and then 12/88). Minor stereoisomer 29b was
eluted in second (306 mg, 10%). Compound 29a: Rf: 0.66
1
mixture of stereoisomers at C6. Rf: 0.46 (E/PE: 8/2); H
NMR (major stereoisomer): 0.95±0.99 (m, 6H), 1.54±1.73
(m, 6H), 1.90±1.96 (bm, 1H), 3.91 (dd, Jˆ4 and 13.2 Hz,
1H), 3.09±3.17 (m, 1H), 3.50 (d, Jˆ13.0 Hz, 1H), 3.95 (q,
Jˆ6.5 Hz, 1H); 13C NMR: 9.5, 16.7 (CH3), 25.4 (CH2), 27.0
(CH), 27.6, 28.8, 46.7 (CH2), 60.4, 82.4 (CH) 157.8 (Cq).
20
(E/PE: 4/6), [a]D ˆ253.8 (c 0.7, CHCl3); IR (®lm): 3415,
1
The amount of minor stereoisomer was determined by H
NMR on the following resonance: 2.97 (dd, Jˆ3.5 and
2978, 2946, 1684, 1391 cm21; 1H NMR: 0.96 (t, Jˆ7.5 Hz,
3H), 1.34 (s, 9H), 1.56±1.75 (m, 2H), 2.62 (dd, Jˆ8.7 and
13.0 Hz, 1H), 2.96 (dd, Jˆ13.0 and 5.0 Hz, 1H), 3.45±3.54
(m, 1H), 3.70 (dd, Jˆ6.2 and 8.9 Hz, 1H), 3.79 (dd, Jˆ2.8
and 8.6 Hz, 1H), 4.02±4.15 (m, 1H), 4.88 (d, Jˆ6.7 Hz,
1H), 7.10±7.23 (m, 5H); 13C NMR: 9.8 (CH3), 26.1
(CH2), 28.7 (CH3), 40.5 (CH2), 59.1 (CH), 70.3 (CH2),
76.6 (CH), 81.4 (Cq), 92.5, 127.0, 129.0, 129.0 (CH),
137.7, 158.6 (Cq). Compound 29b: Rf: 0.58 (E/PE: 4/8),
13.0 Hz, 0.14H).
3.3.10. ꢀ4S,2S)-4-Benzyl-oxazolidine-2,3-dicarboxylic
acid-3-tert-butyl ester 26. Following the procedure
reported6 for the preparation of 5, and starting with (S)-
phenylalaninol 25 (3.5 g, 23.1 mmol), title compound 26
20
was obtained as a white solid (5.45 g, 77%): [a]D
295.1 (c 0.9, CHCl3); mp 1428C; IR (nujol): 3163, 1751,
ˆ
20
mp: 658C; [a]D ˆ281.4 (c 0.7, CHCl3); IR (nujol):
1638 cm21; H NMR: 1.36 (bs, 9H), 2.71 (dd, Jˆ8.7 and
3383, 3010, 2920, 1672 cm21
;
1H NMR: 0.70 (t, Jˆ
1
13.2 Hz, 1H), 3.07 (bs, 1H), 3.84±4.28 (m, 3H), 5.39 (bs,
1H), 7.12±7.27 (m, 5H), 9.34 (bs, 1H); 13C NMR: 28.5
(CH3), 39.7, (CH2), 58.6 (CH), 72.6 (CH2), 82.6, 127.2,
129.1, 129.7 (CH), 137.7, 157.0, 171.0 (Cq).
7.5 Hz, 3H), 1.40 (s, 9H), 1.50±1.60 (bm, 2H), 2.67 (bt,
Jˆ9.1 Hz, 1H), 2.95 (bs, 1H), 3.02 (dd, Jˆ4.0 and 9.1 Hz,
1H), 3.50±4.10 (m, 4H), 4.95 (bs, 1H), 7.05±7.30 (m, 5H);
13C NMR: 10.8 (CH3), 25.8 (CH2), 28.7 (CH3), 40.4 (CH2),
59.0 (broadened) (CH), 70.0 (CH2), 73.0 (CH), 81.4 (Cq),
92.5, 127.0, 129.0, 129.0 (CH), 137.7, 158.6 (Cq); Anal.
calcd for C18H27O4N, C, 67.26; H, 8.47; N, 4.36. Found C,
67.26; H, 8.53; N, 4.25.
3.3.11. ꢀ4S,2S)-4-Benzyl-2-ꢀmethoxy-methyl-cabamoyl)-
oxazolidine-3-carboxylic acid-3-tert-butyl ester 27.
Following the procedure reported6 for the preparation of
Weinreb amide 5, and starting with 26 (5.45 g,
17.7 mmol), title compound was obtained as a white solid
When CeCl3, 7H2O (1.5 equiv.) was added to the reaction
mixture, prior to the addition of sodium borohydride, the
produced ratio of 29a and 29b was 24/76, and compound
29b was isolated pure after ¯ash chromatography, with a
54% yield.
20
(4.9 g, 79%): [a]D ˆ236.5 (c 0.4, CHCl3); mp: 103±
1
1048C; IR (nujol): 1956, 1889, 1715 cm21; H NMR: 1.38
(bs, 9H), 2.79 (broad dd, Jˆ10.5 and 12.5 Hz, 1H), 3.20 (bs,
3H), 3.28±3.50 (bm, 1H), 3.73 (bs, 3H), 3.92 (bs, 2H),,4.09
(bs, 1H), 5.79 and 5.92 (two bs, 1H), 7.13±7.21 (m, 5H); 13C
NMR: 27.8, 31.7 (CH3), 39.0 (broadened) (CH2), 59.0
(broadened) (CH), 61.4 (CH3), 80.3 (Cq), 83.0, 125.8,
128.0, 129.7 (CH), 137.7, 157.0 (broadened) (Cq). MS
(EI, 70 eV): m/z 251 (13), 206 (100), 162 (70), 117 (50),
91 (26), 57 (55); Anal. calcd for C18H26O5N2, C, 61.70; H,
7.48; N, 7.99. Found. C, 61.95; H, 7.75; N, 7.97.
3.3.14. ꢀ3S,6S,7S)-3-Benzyl-6-ethyl-tetrahydro-1,5-dioxa-
3a-aza-pentalen-4-one 30. Following the procedure
described for the preparation of 8, with a time of re¯ux of
0.5 h, and starting with 29a (470 mg, 1.46 mmol), title
compound was obtained as a white solid (258 mg, 71%)
after ¯ash chromatography (E/PE: 15/85); Rf: 0.36 (E/PE:
20
4/6); mp: 658C; [a]D ˆ221.2 (c 0.6, CHCl3); IR (nujol):
3.3.12. ꢀ4S,2S)-4-Benzyl-2-propionyl-oxazolidine-3-carb-
oxylic acid-3-tert-butyl ester 28. To a solution of Weinreb
amide 27 (987 mg, 2.82 mmol) in ether (10 mL) and cooled
to 08C, was added dropwise a solution of ethylmagnesium
bromide (3N solution in ether, 1.4 mL, 4.23 mmol). The
2973, 2937, 2870, 1761, 1684 cm21 1H NMR: 1.26
;
(t, Jˆ7.5 Hz, 3H); 1.88±2.08 (m, 2H), 3.13 (dd, Jˆ11.2
and 15.2 Hz, 1H), 3.87 (t, Jˆ7.7 Hz, 1H), 4.00±4.18 (m,
3H), 4.55 (td, Jˆ6.7 and 1.7 Hz, 1H), 5.09 (d, Jˆ1.7 Hz,
1H), 7.43±7.57 (m, 5H); 13C NMR: 9.2 (CH3), 26.4, 34.2

5400
C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
(CH2), 60.8 (CH), 71.4 (CH2), 81.6, 95.1, 127.2, 129.2,
129.3 (CH), 138.4, 158.7 (Cq); Anal. calcd for
C14H17NO3: C: 68.00; H: 6.93; N: 5.66. Found: C: 68.15;
H: 7.07; N: 5.61.
then gave aldehyde 34 as a solid that was not further puri®ed
(138 mg), Rf: 0.63 (AcOEt/PE: 1/1), mp: 104±1058C,
20
[a]D ˆ2136.8 (c 0.3, CHCl3); IR (Nujol): 2968, 2920,
1
2848, 1733 cm21; H NMR: 0.70 (t, Jˆ7.5 Hz, 3H), 1.02±
1.32 (m, 2H), 2.11±2.24 (m, 2H), 2.52 (bq, Jˆ5.0 Hz, 1H),
3.12±3.33 (m, 2H), 3.75 (dd, Jˆ5 and 11 Hz, 1H), 3.93 (bq,
Jˆ5.2 Hz, 1H), 5.00±5.12 (m, 2H), 5.40±5.60 (m, 1H),
7.12±7.29 (m, 5H), 9.66 (s, 1H); 13C NMR: 8.8 (CH3),
27.4, 33.0, 37.2 (CH2), 60.9, 63.2, 80.9 (CH) 120.2 (CH2),
127.3, 128.9, 129.2, 131.3 (CH), 137.2, 157.1 (Cq), 198.3
(CH).
3.3.15. ꢀ3S,6S,7R)-3-Benzyl-6-ethyl-tetrahydro-1,5-dioxa-
3a-aza-pentalen-4-one 31. Following the procedure
described for the preparation of 8, with a time of re¯ux of
0.5 h, and starting with 29b (319 mg, 0.99 mmol), title
compound was obtained as a white solid (220 mg, 90%)
after ¯ash chromatography (E/PE: 15/85); Rf: 0.58 (E/PE:
20
4/6); mp: 708C; [a]D ˆ19.3 (c 1.0, CHCl3); IR (®lm):
1
3019, 2973, 2870, 1761, 1684 cm21; H NMR: 0.94 (t,
3.3.19. ꢀ2S,4S,5R)-2-ꢀ4-Allyl-5-ethyl-2-oxo-oxazolidin-3-
yl)-3-phenyl-propionaldehyde 35. Following the above
procedure and starting with 33 (123 mg, 0.43 mmol), alde-
hyde 35 was obtained as an oil that was not further puri®ed
Jˆ7.5 Hz, 3H); 1.69±1.82 (m, 2H), 2.85 (dd, Jˆ10.5 and
15.5 Hz, 1H), 3.48 (t, Jˆ7.5 Hz, 1H), 3.68±3.82 (m, 3H),
4.33 (bq, Jˆ5.0 Hz, 1H), 5.05 (d, Jˆ4.8 Hz, 1H), 7.40±7.55
(m, 5H); 13C NMR: 10.1 (CH3), 22.2, 34.0 (CH2), 61.7 (CH),
71.3 (CH2), 91.9, 127.0, 127.2, 129.1 (CH), 138.5, 158.9
(Cq); MS (CI, NH3): m/z 248 (MH1, 27), 134 (17), 100
(65), 88 (84), 71 (100).
20
(103 mg). Rf: 0.43 (AcOEt/PE: 4/6), [a]D ˆ250.7 (c 0.1,
1
CHCl3); H NMR: 0.74 (t, Jˆ7.5 Hz, 3H), 1.18±1.36 (m,
2H), 1.75±1.87 (m, 1H), 1.91±2.01 (m, 1H), 3.07 (dd,
Jˆ11.4 and 15.1 Hz, 1H), 3.19±3.26 (m, 1H), 3.40 (dd,
Jˆ5.2 and 15.1 Hz, 1H), 3.93±4.00 (m, 1H), 4.32 (dd, Jˆ
5.2 and 11.4 Hz, 1H), 4.94±5.07 (m, 2H), 5.26±5.46 (m,
1H), 7.15±7.29 (m, 5H), 9.67 (s, 1H); 13C NMR: 9.1
(CH3), 27.9, 30.1, 32.4 (CH2), 59.5, 63.4, 80.7 (CH) 120.4
(CH2), 127.5, 129.2, 131.6 (CH), 136.7, 158.2 (Cq), 199.1
(CH).
3.3.16. ꢀ4S,5S,6S)-4-Allyl-3-ꢀ1-benzyl-2-hydroxy-ethyl)-
5-ethyl oxazolidin-2-one 32. Following the procedure
reported for the preparation of 9, and starting with 30
(239 mg, 0.97 mmol), title compound was obtained as a
white solid (238 mg, 85%) after ¯ash chromatography
20
(E/PE: 9/1); Rf: 0.68 (E); mp: 768C; [a]D ˆ287.4 (c 0.9,
1
CHCl3); IR (nujol): 3430, 1709 cm21; H NMR: 1.01 (t,
3.3.20. ꢀ4S,5S,6S)-4-Allyl-3-ꢀ1-benzyl-allyl)-5-ethyl oxazo-
lidin-2-one 36. To a suspension of triphenylmethyl-
phosphonium bromide (388 mg, 1.09 mmol) in THF
(7 mL), cooled at 2788C, was added dropwise butyllithium
(1.6N solution in hexanes, 0.68 mL, 1.02 mmol). The reac-
tion mixture was warmed to rt and then recooled at 2308C.
Crude aldehyde 34 (142 mg, 0.49 mmol), in THF (7 mL)
was then added dropwise. The resulting white suspension
was warmed to rt (1 h), and hydrolized by addition of a
saturated aqueous solution of NH4Cl (10 mL). Usual
workup gave an oil that was puri®ed by ¯ash chroma-
tography (AcOEt/PE: 7/93) to afford title compound as a
white solid (113 mg, 80%): Rf: 0.37 (AcOEt/PE: 2/8), mp:
Jˆ7.5 Hz, 3H); 1.29±1.60 (m, 2H), 2.39±2.67 (m, 2H),
2.88±3.00 (m, 1H), 3.20 (dd, Jˆ5.5 and 13.5 Hz, 1H),
3.52 (dd, Jˆ10.2 and 13.5 Hz, 1H), 3.65±3.88 (m, 1H),
4.06±4.32 (m, 4H), 5.24±5.46 (m, 2H), 5.72±5.93 (m,
1H), 7.43±7.61 (m, 5H); 13C NMR: 9.3 (CH3), 28.0, 34.7,
37.8 (CH2), 59.2, 62.5 (CH), 64.8 (CH2), 80.7 (CH), 120.3
(CH2), 127.1, 129.1, 129.7, 131.9 (CH),138.7, 157.5 (Cq);
MS (CI, NH3): m/z 290 (MH1,19), 248 (87), 230 (15), 209
(24), 198 (70), 178 (10), 154 (26), 114 (26), 91 (100); Anal.
calcd for C17H23NO3 (0.5 H2O): C: 68.45; H: 8.05; N: 4.69.
Found: C: 68.67; H: 7.97; N: 4.65.
3.3.17. ꢀ4R,5R,6S)-4-Allyl-3-ꢀ1-benzyl-2-hydroxy-ethyl)-
5-ethyl oxazolidin-2-one 33. Following the procedure
reported for the preparation of 9, and starting with 31
(161 mg, 0.65 mmol), title compound was obtained as an
oil (123 mg, 65%) after ¯ash chromatography (E/PE: 1/1);
68±708C; IR (Nujol): 3063, 2925, 1735, 1639 cm21
;
[a]D ˆ215.5 (c 0.5, CHCl3); 1H NMR: 0.67 (t, Jˆ
7.5 Hz, 3H), 0.80±1.15 (m, 2H), 2.12±2.23 (m, 2H),
2.62±2.70 (m, 1H), 2.83 (dd, Jˆ6.0 and 13.5 Hz, 1H),
3.39 (dd, Jˆ10.2 and 13.7 Hz, 1H), 3.79±3.83 (m, 2H),
4.94±5.18 (m, 4H), 5.42±5.58 (m, 1H), 6.08±6.22 (m,
1H), 7.14±7.22 (m, 5H); 13C NMR: 9.2 (CH3), 28.0, 38.1,
38.7 (CH2), 59.8, 62.5, 79.6 (CH) 117.2, 120.1 (CH2), 127.7,
129.6, 130.4, 132.8,137.3 (CH), 139.3 157.1 (Cq); Anal.
calcd for C18H23NO2: C: 75.76; H: 8.12; N: 4.91. Found:
C: 75.56; H: 8.44; N: 4.45.
20
20
Rf: 0.42 (E); [a]D ˆ233.1 (c 0.1, CHCl3); IR (®lm): 3404,
1
1730 cm21; H NMR: 0.83 (t, Jˆ7.5 Hz, 3H); 1.30±1.47
(m, 2H), 1.73±1.86 (m, 1H), 2.02±2.13 (m, 1H), 2.35±
2.45 (m, 1H), 3.05 (dd, Jˆ3.5 and 7.3 Hz, 1H), 3.30±3.37
(m, 1H), 3.58±3.68 (m, 1H), 3.68±3.78 (m, 1H), 3.90±3.97
(m, 2H), 4.97±5.08 (m, 2H), 5.35±5.45 (m, 1H), 7.18±7.30
(m, 5H); 13C NMR: 8.5 (CH3), 27.5, 34.2, 37.4 (CH2), 58.1,
60.7, 63.2, 79.8 (CH), 119.8 (CH2), 126.5, 128.4, 129.0,
131.8 (CH),138.2, 157.8 (Cq).
3.3.21. ꢀ4R,5R,6S)-4-Allyl-3-ꢀ1-benzyl-allyl)-5-ethyl oxazo-
lidin-2-one 37. Following the above procedure and starting
with 34 (108 mg, 0.38 mmol) title compound was obtained
as a white solid (40 mg, 37%): Rf: 0.43 (AcOEt/PE: 2/8),
3.3.18. ꢀ2S,4S,5S)-2-ꢀ4-Allyl-5-ethyl-2-oxo-oxazolidin-3-
yl)-3-phenyl-propionaldehyde 34. To a solution of alcohol
32 (137 mg, 0.48 mmol) in dichloromethane (7 mL) was
added Dess±Martin periodinane (307 mg, 0.72 mmol).
The suspension was stirred for 1 h at rt, and ether (20 mL)
was added. The suspension was then treated with a (1/1)
mixture of saturated aqueous solution of NaHCO3 and satu-
rated aqueous solution of Na2S2O3 (10 mL). Usual workup
mp: 45±478C; IR (Nujol): 1735 cm21; [a]D ˆ229.2 (c 1.0,
20
1
CHCl3); H NMR: 0.76 (t, Jˆ7.5 Hz, 3H), 1.14±1.37 (m,
2H), 1.83±1.97 (m, 1H), 2.04±2.17 (m, 1H), 3.05 (dd,
Jˆ6.2 and 14.1 Hz, 1H), 3.17±3.23 (m, 1H), 3.25 (dd,
Jˆ10.1 and 14.1 Hz, 1H), 3.88 (td, Jˆ10.5 and 5.5 Hz,
1H), 4.11±4.24 (m, 1H), 5.00±5.21 (m, 4H), 5.29±5.47
(m, 1H), 6.01 (ddd, Jˆ7.0, 10.5 and 17.2 Hz, 1H),

C. Agami et al. / Tetrahedron 57 ꢀ2001) 5393±5401
5401
7.11±7.30 (m, 5H); 13C NMR: 9.1 (CH3), 27.9, 37.8, 38.0
References
(CH2), 58.2, 59.4, 79.7 (CH) 117.4, 119.8 (CH2), 127.1,
128.9, 129.5, 132.3,136.7 (CH), 139.7 157.4 (Cq).
1. Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. Rev.
1995, 95, 1677±1716.
3.3.22. ꢀ1S,4S,5S)-5-Benzyl-1-ethyl-1,5,8,8a-tetrahydro-
oxazolo[3,4-a]pyridin-3-one 38. Following the procedure
described for the metathesis of 13±16 and starting with 36
(20 mg, 0.07 mmol), title compound was obtained after
¯ash chromatography (AcOEt/PE: 5/95), as an oil that
crystallized on standing (15 mg, 83%): Rf: 0.43 (E); mp:
2. For asymmetric syntheses of b-conhydrine see: (a) Ratovelo-
manana, V.; Royer, J.; Husson, H. P. Tetrahedron Lett. 1985,
32, 3803±3806. (b) Comins, D. L.; Williams, A. L.
Tetrahedron Lett. 2000, 41, 2839±2842.
3. For an asymmetric synthesis of (2)-methyl palustramate, see:
Angle, S. R.; Henry, R. M. J. Org. Chem. 1998, 63, 7490±
7497.
20
98±1008C; [a]D ˆ199.3 (c 0.7, CHCl3); IR (®lm): 2972,
1
1739, 1162 cm21; H NMR: 0.96 (t; Jˆ7.5 Hz, 3H), 1.37±
4. Elbein, A. D.; Molyneux, R. J. Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1986; Vol. 5, pp 1±54.
1.49 (m, 2H), 1.57±1.75 (m, 1H), 1.94±2.08 (m, 1H), 3.13
(dd, Jˆ3.0 and 13.0 Hz, 1H), 3.20±3.35 (m, 2H), 3.78 (ddd,
Jˆ5.5, 7.0 and 10.0 Hz, 1H), 4.16±4.26 (m, 1H), 5.55 (td,
Jˆ3.1 and 10.2 Hz, 1H), 5.69 (ddt, Jˆ1.5, 6.8 and 10.2 Hz,
1H), 7.07±7.24 (m, 5H); 13C NMR: 9.9 (CH3), 26.2, 28.8,
38.5 (CH2), 53.8, 58.8, 82.6, 123.8, 126.8, 128.2, 128.6,
130.7 (CH), 135.8, 156.4 (Cq).
5. Preliminary communication: Agami, C.; Couty, F.; Rabasso,
N. Tetrahedron Lett. 2000, 41, 4113±4116.
6. Agami, C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron
1998, 54, 8783±8796.
7. For some examples of RCM applied to the synthesis of nitro-
gen heterocycles see (a) Philips, A. J.; Abell, A. D. Aldrichim.
Acta 1999, 32, 75±89. (b) Eunyoung, J.; Yongim, N.; Sukbok,
C. Tetrahedron Lett. 1999, 40, 5581±5582. (c) Sauers, A. J.;
Ellman, J. A. J. Org. Chem. 2000, 65, 1222±1224.
(d) Wallace, D. J.; Cowden, C. J.; Kennedy, D. J.; Ashwood,
M. S.; Cottrell, I. F.; Dolling, U. H. Tetrahedron Lett. 2000,
41, 2027±2029. (e) Lennartz, M.; Steckhan, E. Tetrahedron
2001, 57, 675±680.
3.3.23. ꢀ1S,4S,5R)-5-Benzyl-1-ethyl-1,5,8,8a-tetrahydro-
oxazolo[3,4-a]pyridin-3-one 39. Following the procedure
described for the metathesis of 13±16 and starting with 37
(35 mg, 0.101 mmol), title compound was obtained after
¯ash chromatography (AcOEt/PE: 5/95), as an oil (23 mg,
20
74%): Rf: 0.54 (AcOEt/PE: 4/6); [a]D ˆ1267.8 (c 0.2,
CHCl3); IR (®lm): 3015, 2962, 1749, 1649, 1601, 1500,
1
1415 cm21; H NMR: 0.85 (t, Jˆ7.5 Hz, 3H), 1.38±1.65
8. Agami, C.; Amiot, F.; Couty, F.; Dechoux, L.; Kaminsky, C.;
Venier, O. Tetrahedron: Asymmetry 1998, 9, 3955±3958.
9. Analogous problems of epimerization were observed in the
course of a synthesis of castanospermine using this ole®-
nation/RCM sequence: Overkleeft, H. S.; Pandit, U. K.
Tetrahedron Lett. 1996, 37, 547±550.
(m, 2H), 1.80±2.05 (m, 2H), 2.68±2.80 (m, 1H), 2.85±
3.00 (m, 2H), 3.90 (bq, Jˆ5.7 Hz, 1H), 4.32±4.42 (m,
1H), 5.64 (td, Jˆ2.2 and 10.7 Hz, 1H), 5.65±5.70 (m,
1H), 7.08±7.25 (m, 5H); 13C NMR: 8.9 (CH3), 27.4, 29.7,
39.6 (CH2), 51.4, 53.1, 82.5, 123.7, 126.6, 127.8, 128.2,
129.9 (CH), 136.8, 157.4 (Cq); Anal. calcd for
C16H19NO2: C: 74.68; H: 7.44; N: 5.44. Found: C: 73.88;
H: 7.63; N: 5.26.
10. Crystallographic data have been deposited at the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, and copies can be
obtained, free of charges, by quoting the publication citation 5.