Claisen rearrangements of allylic and propargylic alcohols prepared by an N-Boc-2-acyloxazolidine methodology - Application to the synthesis of original chiral building blocks

Article abstract of DOI:10.1002/1099-0690(20021)2002:1<29::AID-EJOC29>3.0.CO;2-B

Stereodefined alkenols prepared in two steps from a Weinreb amide derived from (R)-phenylglycinol undergo highly stereoselective Claisen rearrangements. The masked aldehyde moiety of the produced N-Boc-alkenyloxazolidines can then be recovered and reduced without epimerization, to yield new enantiopure chiral building blocks. Alternatively, epoxidation of these N-Boc-2-alkenyloxazolidines by a well-established intramolecular bromocarbamation involving the Boc protecting group occurs stereoselectively. The resulting α,β-epoxyoxazolidines are then transformed into trisubstituted stereodefined cyclopropanes. Claisen rearrangements of propargylic alcohols, on the other hand, stereoselectively give α-allenyloxazolidines. These compounds follow a different pathway to α-alkenyloxazolidines as regards bromocarbamation. An original route to enantiopure 3-hydroxy-4-phenylpiperidine was found in the course of this study.

Full text of DOI:10.1002/1099-0690(20021)2002:1<29::AID-EJOC29>3.0.CO;2-B

FULL PAPER
Claisen Rearrangements of Allylic and Propargylic Alcohols Prepared by an
N-Boc-2-acyloxazolidine Methodology ؊ Application to the Synthesis of
Original Chiral Building Blocks
Claude Agami,[a] Francois Couty,*[a] and Gwilherm Evano[a]
¸
Keywords: Asymmetric synthesis / Claisen rearrangement / Cyclopropanes / Oxazolidines
Stereodefined alkenols prepared in two steps from a Weinreb
amide derived from (R)-phenylglycinol undergo highly ster-
eoselective Claisen rearrangements. The masked aldehyde
moiety of the produced N-Boc-alkenyloxazolidines can then
Boc protecting group occurs stereoselectively. The resulting
α,β-epoxyoxazolidines are then transformed into trisubsti-
tuted stereodefined cyclopropanes. Claisen rearrangements
of propargylic alcohols, on the other hand, stereoselectively
be recovered and reduced without epimerization, to yield give α-allenyloxazolidines. These compounds follow a differ-
new enantiopure chiral building blocks. Alternatively, epox- ent pathway to α-alkenyloxazolidines as regards bromocar-
idation of these N-Boc-2-alkenyloxazolidines by a well-es-
bamation. An original route to enantiopure 3-hydroxy-4-
tablished intramolecular bromocarbamation involving the phenylpiperidine was found in the course of this study.
Introduction
Enantiopure 2-acyl-1,3-oxazolidines are useful hetero-
cycles in asymmetric synthesis. Indeed, 1,2-asymmetric in-
ductions occurring during nucleophilic attack of the car-
bonyl moiety adjacent to the oxazolidine heterocycle result
with good stereocontrol in α-hydroxyoxazolidines.[1] These
compounds can be considered as protected forms of α-hy-
droxy aldehydes and have found applications in asymmetric
synthesis. In this field, we have previously developed a prac-
tical synthesis of N-Boc-2-acyloxazolidines; these com-
pounds were shown to be useful chiral substrates for the
synthesis of enantiopure 1,2-diols,[2] and also piperidinic
heterocycles including (Ϫ)-desoxoprosopinine, (ϩ)-pseudo-
conhydrine,[3] (ϩ)-conhydrine, and analogues.[4] These acy-
loxazolidines encompass a particularly interesting family of
ketones, of the general structure 2. These ynones are easily
prepared by treatment of the Weinreb amide 1 with a li-
thium acetylide and can be reduced in a highly stereoselec-
tive way (typically with de Ͼ 95%) by zinc borohydride. The
produced alkynol 3 can then be reduced to either of the
stereodefined (E)- or (Z)-allylic alcohols 4, with Red-Al or
H2 in the presence of Lindlar’s catalyst, respectively, while
their mesyloxy derivatives were shown to undergo a 1,3-
chirality transfer on reaction with organocuprates[5]
(Scheme 1).
Scheme 1
In this article[6] we wish to describe the Claisen re-
arrangement of allylic alcohols 4, followed by the recovery
of the masked aldehyde moiety present in the γ,δ-unsatur-
ated esters 5 produced. This methodology is also especially
well suited for the synthesis of trisubstituted cyclopropanes;
the synthesis in this case involves a diastereoselective epox-
idation of 5 to give α,β-epoxyoxazolidine 6, followed by in-
tramolecular nucleophilic opening of the epoxide, through
reaction with the ester enolate moiety (Scheme 2).
Furthermore, in this paper we also report the Claisen re-
arrangements of propargylic alcohols 3. This rearrange-
ment stereoselectively gives α-allenyloxazolidines, and the
chemical behavior of these allenic compounds was investig-
ated.
Finally, in the course of this study, an unexpected intram-
olecular nucleophilic opening of a carbamate by an ester
enolate resulted in an oxazoloazepinone. An intramolecular
version of this reaction allowed us to devise a route to an
oxazolopiperidinone. This was then transformed into
(2R,3R)-2-hydroxy-3-phenylpiperidine, featuring the substi-
[a]
`
´
´
Laboratoire de Synthese Asymetrique associe au CNRS, Case
´
courrier 47, Universite Pierre et Marie Curie,
4 place Jussieu, 75005 Paris, France
Fax: (internat.) ϩ 33-1/44272620
E-mail: couty@ccr.jussieu.fr
Eur. J. Org. Chem. 2002, 29Ϫ38
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1434Ϫ193X/02/0101Ϫ0029 $ 17.50ϩ.50/0
29

C. Agami, F. Couty, G. Evano
FULL PAPER
Scheme 2
tution pattern found in a new class of antihypertensive com-
pounds.
Scheme 3
Results and Discussion
I. Claisen Rearrangements of Allylic Alcohols Linked to
Oxazolidine Rings
The (E)-allylic alcohols 7Ϫ10 and the (Z)-allylic alcohols
11Ϫ14 were prepared from Weinreb amide 1 by our previ-
ously reported three-step sequence.[5] This sequence enabled
the hitherto unreported compounds 10, 13, and 14 to be
synthesized (38, 80, and 48% overall yields, respectively).
However, as regards the scope of this synthesis, it should be
mentioned that an (E)-aliphatic alkenol (4, R ϭ C6H13) was
obtained only in a prohibitive 15% yield on Red-Al reduc-
tion of the corresponding carbinol (3, R ϭ C6H13).
Claisen rearrangements were performed on these diaster-
eoisomerically pure compounds to afford alkenyloxazolid-
ines 15Ϫ22 with high levels of stereocontrol; no minor ste-
reoisomer could be detected by NMR in the crude reaction
product (Scheme 3). However, the yields of these reactions
were low in the cases of compounds 9 and 13 (R ϭ Ph).
The stereochemical course of this reaction is known to be
governed by an equatorially substituted chair-like transition
state[7] [depicted for an (E)-alkenol in Scheme 3], in which
the configuration of the double bond in the starting alkenol
dictates the configuration of the newly formed stereocenter.
Nevertheless, the sense of this 1,3-chirality transfer was
confirmed through the sequence shown in Scheme 4. Oxid-
ative cleavage of the alkenyl moiety in compound 17, fol-
lowed by reduction of the resulting aldehyde ester, gave diol
(ϩ)-23. Determination of the configuration of this diol[8]
by examination of its optical rotation thus confirmed the
stereochemical course of this reaction.
Scheme 4. Reagents and conditions: a. OsO4 (cat.), NaIO4, THF/
H2O; b. NaBH4, EtOH, 53% overall yield; c. CF3COOH, DCE; d.
THF, H2O; e. NaBH4, CeCl3·7H2O, EtOH, 0 °C; 24: 72%, ent-
24: 52%
sibility of racemization of these enals, they were immedi-
ately reduced to allylic alcohols (Ϫ)-24 and (ϩ)-24
(Scheme 4). The enantiomeric excesses of these alcohols
were determined by chiral GC analysis [Chirasil-DEX-CB,
160 °C, tR ϭ 9.6 and 10.7 min for (Ϫ)-24 and (ϩ)-24, re-
spectively] and found to be 98 and 93%, respectively. This
demonstrates that little or no racemization occurs during
these steps.
II. Claisen Rearrangements of Propargylic Alcohols Linked
to Oxazolidine Rings
The recovery of the aldehyde moiety masked as an oxazo-
lidine ring in the rearranged products was achieved with
alkenyloxazolidines 16 and 20. To this end, N-Boc deprotec-
We next turned our attention to Claisen rearrangements
tion (TFA) and mild hydrolysis of the produced ammonium of alkynols[9] of general structure 3. These substrates were
salts gave the corresponding enals, with a concomitant re- found to be slightly less reactive than the allylic alcohols
lease of (R)-phenylglycinol. In order to minimize the pos- discussed above, and they required 4 h of reflux in triethyl
30
Eur. J. Org. Chem. 2002, 29Ϫ38

Claisen Rearrangements of Allylic and Propargylic Alcohols
FULL PAPER
evant were the 3J values observed for the signals of the pro-
tons located on the bromine-substituted carbon atom; these
large coupling constants (8.5 and 10.9 Hz in compound 29,
for example: see Exp. Sect.) unambiguously attested to a
trans-diaxial geometry for this proton, which is in accord-
ance with the depicted relative configuration in these ureth-
anes. Epoxides 33Ϫ35 were then obtained in high yields
from the corresponding urethanes by treatment with so-
dium ethoxide.
In the course of this study, iodolactonization[12] of carb-
oxylic acid 36, prepared by saponification of ester 16, was
investigated. However, this reaction was not chemoselective,
and a mixture of uncharacterized compounds was pro-
duced, suggesting the occurrence of a competitive iodocar-
bamation.
As regards bromocarbamation, allenyloxazolidine 26 did
not react in the same way as alkenyloxazolidine. In fact,
treatment of 26 under the conditions described above gave
enal 37 in good yield. This compound results from an open-
ing of the bromonium ion Ϫ located on the double bond in
a β-position to the oxazolidine ring by the lone pair of the
oxygen atom[13] Ϫ followed by fragmentation, as depicted
in Scheme 7. It should be noted, however, that the (Z) or
(E) geometry of the enal in 37 was not proven unambigu-
ously. The (Z) stereochemistry depicted should indeed be
the result of the stereospecificity of this anti-nucleophilic
attack, but a subsequent (Z) to (E) isomerization in the
produced enal cannot be ruled out.
Scheme 5. Reagents and conditions: a. CH3C(OEt)3, propionic acid
(cat.), reflux, 4 h
orthoacetate to be converted into allenic oxazolidines.
However, the rearrangement was again highly stereoselec-
tive and gave diastereoisomerically pure allenic compounds
25Ϫ28 (Scheme 5). A very modest yield, though, was ob-
served when starting with the propargylic alcohol derived
from phenylacetylene (3, R ϭ Ph).
With the aim of recovering the aldehyde moiety from ox-
azolidine 25, attempts like those described above in the case
of alkenyloxazolidines were made. However, these experi-
ments only produced polymeric compounds, probably
because of the instability of the released allenal in acidic
media.
III. Diastereoselective Epoxidation of Alkenyloxazolidines
Resulting from Claisen Rearrangements
Epoxidation of alkenyloxazolidines 15, 16, 19, and 20 by
a two-step procedure was next studied.[10] This epoxidation
consisted of an intramolecular bromocarbamation of the
alkene moiety, followed by treatment of the resulting bicyc-
lic urethane with sodium ethoxide, as depicted in Scheme 6.
As previously reported with similar substrates,[5] the config-
uration of the stereocenter determined by the Claisen re-
arrangement does not influence the stereochemical course
of the bromocarbamation: Urethanes 29Ϫ32 were in all
1
cases obtained as unique stereoisomers, within H NMR
error limits. However, an unsatisfactory yield, most prob-
ably due to steric crowding, was obtained in the case of
substrate 19. The relative configurations of these urethanes
1
were deduced from their H NMR spectroscopic data and
were consistent with previous results.[10,11] Particularly rel- Scheme 7. Reagents and conditions: a. NBS, DME/H2O, 80%
Scheme 6. Reagents and conditions: a. NBS, DME/H2O; b. EtONa/EtOH
Eur. J. Org. Chem. 2002, 29Ϫ38
31

C. Agami, F. Couty, G. Evano
FULL PAPER
V. Synthesis of Azepinones and Piperidinones
As a matter of fact, of the four diastereofaces of the al-
lenyl moiety, only one gives a bromonium ion that would
react further to produce 37. No competitive intramolecular
bromocarbamation of the double bond adjacent to the ox-
azolidine ring occurs in this reaction. This can be attributed
to steric crowding of this double bond by the allene sub-
stituents, impeding the formation of the bromonium ion,
and the subsequent attack of the bulky carbamate.
Finally, treatment of the bicyclic urethane 29 with
LiHMDS was examined. This reaction gave oxazoloazepi-
none 41 through an intramolecular opening of the urethane
ring by the enolate, instead of the expected intramolecular
displacement of the bromine atom, which would yield com-
pound 42 (Scheme 10). Compound 41 was produced as a
single diastereomer in which the configuration of the newly
created stereogenic center was not determined with cer-
IV. Synthesis of Trisubstituted Cyclopropanes
3
tainty, although the value of the J coupling for H(6) [δ ϭ
3
Epoxy esters 33Ϫ35 were next transformed into trisubsti- 5.39, J H(6)ϪH(7) ϭ 5.5 Hz; see Exp. Sect.] strongly sug-
tuted cyclopropanes by treatment with LiHMDS at Ϫ50 °C gests a cis relationship between H(6) and H(7). AM1 calcu-
(Scheme 8). This 3-exo-trig cyclisation[14] was highly stereo- lations were performed to minimize the conformations of
selective: Again, no minor isomers could be detected by 1H both cis and trans isomers in 41. In these minimized con-
NMR spectroscopy, and the relative configurations of the formations, the values of the dihedral angle
produced cyclopropanes 38Ϫ40 were assigned on the basis H(6)ϪC(6)ϪC(7)ϪH(7) are 45° in the cis isomer and 90°
of the vicinal coupling values [3J(cis) ϭ 4Ϫ5 Hz, 3J(trans) ϭ in the trans isomer; the former angle matches well with the
3
9 Hz; see Exp. Sect.]. In this reaction, the configuration of observed J value. This reaction represents a new route to
the stereocenter created during the Claisen rearrangement polyhydroxylated azepanes, these compounds being good
governs the stereochemical outcome of the intramolecular candidates for evaluation as glycosidase inhibitors.[15]
cyclopropanation; the ethoxycarbonyl moiety and the R
group always show a trans relationship in the product. This
stereoselectivity can easily be understood in terms of min-
imization of A(1,3) strain. Indeed, such minimization favors
transition states A and C over B and D (Scheme 9.).
Scheme 10. Reagents and conditions: a. LiHMDS, THF, Ϫ50 °C,
61%
Scheme 8. Reagents and conditions: a. LiHMDS, THF, Ϫ50 °C
In order to examine the scope of this unexpected reac-
tion, an intermolecular version was then studied. To this
end, bicyclic urethane 43, easily prepared by bromocarbam-
ation of the corresponding cinnamaldehyde-derived N-Boc-
alkenyloxazolidine[10] was treated with the lithium enolate
of ethyl acetate to produce bromohydrin 44 in high yield,
and this compound was then readily transformed into epox-
ide 45 (Scheme 11). In order to prepare a six-membered ox-
azolopiperidinone ring, intramolecular nucleophilic open-
ing of this epoxide by the enolate of the β-amido ester was
studied. However, this reaction proved to be quite sluggish,
and among the numerous conditions investigated for this
transformation,[16] NaH in DMF at 110 °C was found to
be the best. Under these conditions, oxazolopiperidinone
46 could be isolated in a 41% yield, and deethoxycarbonyl-
ation of the ester moiety spontaneously occurred in the
same pot. Transformation of this compound into (3R,4R)-
3-hydroxy-4-phenylpiperidine (48) was effected in two steps:
Scheme 9
32
treatment with lithium aluminium hydride to afford 47, fol-
Eur. J. Org. Chem. 2002, 29Ϫ38

Claisen Rearrangements of Allylic and Propargylic Alcohols
FULL PAPER
General Procedure for the Zn(BH4)2-Mediated Reduction of Ynones
lowed by hydrogenolysis. The substitution pattern of this
heterocycle is currently of interest, since it has recently been
shown that piperidines deriving from this basic framework
display strong antihypertensive activity.[17]
2: See ref.[5]
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1S)-1-hydroxy-3-trimethylsilyl-
prop-2-ynyl]-4-phenyl-1,3-oxazolidine (3, R ؍ TMS): Yield: 92%;
Rf ϭ 0.65 (Et2O/PE, 1:1); m.p. 157 °C; [α]2D0 ϭ ϩ27 (c ϭ 1.2,
1
CHCl3). H NMR: δ ϭ 0.14 (s, 9 H), 1.25 (br. s, 9 H), 4.19Ϫ4.35
(m, 2 H), 4.79 (dd, J ϭ 8.9 and 2, 1 H), 4.84 (bm, 1 H), 4.87 (br.
s, 1 H), 5.59 (d, J ϭ 2, 1 H), 7.26Ϫ7.40 (m, 3 H), 7.48Ϫ7.57 (m, 2
H). 13C NMR: δ ϭ Ϫ0.1 (CH3), 27.6 (CH3), 61.0 (CH), 64.8 (CH),
65.3 (Cq), 74.0 (CH2), 81.5 (Cq), 91.2, 91.7 (Cq), 126.7, 127.2,
˜
128.0 (CH), 139.5 (Cq), 154.6 (Cq). IR: ν ϭ 3345, 2170, 1675.
C20H24NO4Si (375.5): C 63.97, H 7.78, N 3.73; found C 63. 94, H
7.91, N 3.62.
General Procedure for the Red-Al-Mediated Reduction of Propar-
gylic Alcohols 3: See ref.[5]
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1S,2E)-1-hydroxy-3-trimethyl-
silylprop-2-enyl]-4-phenyl-1,3-oxazolidine (10): Yield: 52%; Rf
ϭ
Scheme 11. Reagents and conditions: a. LiHMDS, EtOAc, Ϫ50 °C,
97%; b. EtONa/EtOH, quant. yield; c. NaH, DMF, 100 °C, 41%;
d. LiAlH4, Et2O, 63%; e. (i) HCl in EtOAc, (ii) Pd/C, MeOH, H2,
quant. yield
0.56 (Et2O/PE, 1:1); m.p. 131 °C; [α]2D0 ϭ ϩ40 (c ϭ 0.7, CHCl3).
1H NMR: δ ϭ 0.00 (s, 9 H), 1.23 (br. s, 9 H), 4.03 (dd, J ϭ 8.9
and 4.9, 1 H), 4.23 (dd, J ϭ 8.9 and 4.6, 1 H) 4.41 (br. s, 1 H),
4.63Ϫ4.79 (br. m, 1 H), 5.19 (br. s, 1 H), 6.00Ϫ6.19 (m, 2 H),
7.15Ϫ7.32 (m, 5 H). 13C NMR: δ ϭ Ϫ1.3 (CH3), 28.1 (CH3), 60.8
(CH), 73.5 (CH2), 74.7 (CH), 81.5 (Cq), 93.0 (CH), 128.0, 128.6,
In conclusion, we have shown that Claisen rearrange-
ments of allylic alcohols linked to N-Boc-oxazolidine rings
provide a new route to enantiopure original chiral building
blocks. When this rearrangement is combined with a dias-
tereoselective epoxidation, this methodology permits the
synthesis of trisubstituted cyclopropanes.
˜
129.4, 132.2 (CH), 140.6 (Cq), 143.3 (CH), 154.6 (Cq). IR: ν ϭ
3380, 1675, 1625.
General Procedure for the Lindlar-Catalyzed Hydrogenation of Yn-
ols 3: See ref.[5]
In the course of this work, during exploration of the re-
activity of the esters resulting from the Claisen rearrange-
ment, an unexpected intramolecular nucleophilic attack on
a cyclic carbamate by an ester enolate was observed. An
intermolecular version of this reaction was used as the key
step to devise an original synthesis of (3R,4R)-3-hydroxy-4-
phenylpiperidine, incorporating the basic skeleton of a new
class of antihypertensive molecules. This work extends the
scope of the use of N-Boc-acyloxazolidines in asymmetric
synthesis, and further applications of this methodology are
under study in our group.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1S,2Z)-1-hydroxy-3-phenylprop-
2-enyl]-4-phenyl-1,3-oxazolidine (13): Yield: 93%; Rf ϭ 0.63 (Et2O/
1
PE, 2:8); oil; [α]2D0 ϭ ϩ22 (c ϭ 0.6, CHCl3). H NMR: δ ϭ 1.24 (s,
9 H), 3.97 (dd, J ϭ 8.9 and 5.8, 1 H), 4.21 (dd, J ϭ 8.9 and 7.1, 1
H), 4.73Ϫ4.87 (bm, 2 H), 5.25 (br. s, 1 H), 5.79 (dd, J ϭ 11.7 and
9.9), 6.70 (d, J ϭ 11.7, 1 H), 7.13Ϫ7.40 (m, 5 H). 13C NMR: δ ϭ
28.4 (CH3), 60.9 (CH), 68.2 (CH), 73.3 (CH2), 81.5 (Cq), 93.0
(CH), 126.7, 127.5, 128.5, 128.6, 128.9, 134.2 (CH), 136.5, 140.2
˜
(Cq), 155.0 (Cq). IR: ν ϭ 3420, 1690, 1620.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1S,2Z)-1-hydroxy-3-trimethyl-
silylprop-2-enyl]-4-phenyl-1,3-oxazolidine (14): Yield: 65%; Rf
ϭ
1
0.75 (Et2O/PE, 1:1); m.p. 76 °C; [α]2D0 ϭ ϩ39 (c ϭ 1.0, CHCl3). H
NMR: δ ϭ 0.15 (s, 9 H), 1.33 (br. s, 9 H), 4.11 (dd, J ϭ 8.7 and
5.1, 1 H), 4.25 (dd, J ϭ 8.7 and 7.1, 1 H), 4.54Ϫ4.64 (br. m, 1 H),
4.84Ϫ4.93 (br. s, 1 H), 5.24 (br. s, 1 H), 5.85 (dd, J ϭ 14.2 and 0.9),
6.39 (dd, J ϭ 14.2 and 8.3, 1 H), 7.26Ϫ7.45 (m, 3 H), 7.47Ϫ7.53 (m,
2 H). 13C NMR: δ ϭ 0.5 (CH3), 28.2 (CH3), 60.9 (CH), 72.2 (CH2),
73.4 (CH), 81.6 (Cq), 93.1 (CH), 127.1, 127.6, 128.4, 134.8 (CH),
140.8 (Cq), 144.9 (CH), 154.8 (Cq). R: ν˜ ϭ 3400, 1692, 1622.
Experimental Section
General: 1H and 13C spectra (CDCl3 solution unless otherwise
stated) were recorded with 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
PerkinϪElmer 141 instrument. All reactions were carried out under
argon. Column chromatography was performed on silica gel
230Ϫ400 mesh with various mixtures of diethyl ether (Et2O), ethyl
acetate (EtOAc), and petroleum ether (PE). TLCs were run on
Merck Kieselgel 60 F254 plates. Melting points are uncorrected.
THF and ether were distilled from sodium/benzophenone ketyl.
Dichloromethane was distilled from calcium hydride. ‘‘Usual
workup’’ means: (i) decanting of the organic layer, (ii) extraction
of the aqueous layer with ether, (iii) drying of the combined organic
phases with MgSO4, and (iv) solvent evaporation under reduced
pressure. The compositions of stereoisomeric mixtures were deter-
mined by NMR analysis on crude products before any purification.
General Procedure for the Claisen Rearrangement of Propargylic Al-
cohols 3 and of Allylic Alcohols 7؊14: A solution of propargylic
alcohol or allylic alcohol (1.3 mmol) and propionic acid (3 drops)
in triethyl orthoacetate (5 mL) was heated under reflux
(DeanϪStark) while propionic acid (3 drops) was added every
hour. The reaction was monitored by TLC and required ca. 4 h to
reach completion for alkynols, and 3 h for allylic alcohols. At this
time, concentration under reduced pressure was followed by flash
chromatography to afford allenic or alkenyloxazolidines as clear
oils.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3R)-4-tert-butyldimethyl-
silyloxy-3-ethoxycarbonylmethylbut-1-enyl]-4-phenyl-1,3-oxazoli-
dine (15): Yield: 93%; flash chromatography: Et2O/PE, 1:9; oil;
General Procedure for the Synthesis of Ynones 2: See ref.[5]
Eur. J. Org. Chem. 2002, 29Ϫ38
33

C. Agami, F. Couty, G. Evano
FULL PAPER
1
Rf ϭ 0.73 (Et2O/PE, 1:1); [α]2D0 ϭ Ϫ7 (c ϭ 0.9; CHCl3). H NMR:
8.9 and 4.9, 1 H), 3.87Ϫ3.94 (m, 1 H), 3.99Ϫ4.09 (m, 2 H),
δ ϭ 0.00 (s, 6 H), 0.84 (s, 9 H), 1.18 (t, J ϭ 7.1, 3 H), 1.30 (s, 9 4.17Ϫ4.26 (m, 1 H) 4.80Ϫ4.95 (bm, 1 H), 5.50Ϫ5.75 (m, 2 H), 5.83
H), 2.27 (dd, J ϭ 15.5 and 8.2, 1 H), 2.58 (dd, J ϭ 15.5 and 5.8, 1 (dd, J ϭ 15.4 and 7.5, 1 H), 7.19Ϫ7.33 (m, 5 H). 13C NMIR: δ ϭ
H), 2.73Ϫ2.87 (m, 1 H), 3.49 (dd, J ϭ 9.8 and 6.8, 1 H), 3.61 (dd, Ϫ5.3, 14.2 (CH3), 18.3 (Cq), 25.9, 28.2 (CH3), 36.1 (CH2), 41.8
J ϭ 9.8 and 5.2, 1 H), 3.87Ϫ3.94 (m, 1 H), 3.99Ϫ4.09 (m, 2 H),
(CH), 60.2 (CH2), 60.6 (CH), 65.3, 73.2 (CH2), 80.4 (Cq), 89.6,
4.17Ϫ4.26 (m, 1 H), 4.80Ϫ4.95 (bm, 1 H), 5.50Ϫ5.75 (m, 2 H), 126.6, 127.4, 128.6, 128.9, 134.2 (CH), 140.6, 153.4, 172.3 (Cq). IR:
5.82 (dd, J ϭ 15.0 and 7.5, 1 H), 7.17Ϫ7.31 (m, 5 H). 13C NMIR:
δ ϭ Ϫ5.3, 14.2 (CH3), 18.3 (Cq), 25.9, 28.3 (CH3), 36.0 (CH2), 41.1
(CH), 60.2 (CH2), 60.6 (CH), 65.4, 73.2 (CH2), 80.4 (Cq), 89.6,
126.6, 127.4, 128.6, 128.9, 134.1 (CH), 140.7, 153.4, 172.3 (Cq). IR:
ν˜ ϭ 3030, 2930, 1720, 1700.
(2R,4R)-2-[(1E,3S)-4-Benzyloxy-3-ethoxycarbonylmethylbut-1-
enyl]-3-tert-butoxycarbonyl-4-phenyl-1,3-oxazolidine (20): Yield:
83%; flash chromatography: Et2O/PE, 2:8; oil; Rf ϭ 0.50 (Et2O/PE,
6:4); [α]2D0 ϭ ϩ8 (c ϭ 2.4; CHCl3). 1H NMIR: δ ϭ 1.20 (t, J ϭ 7.1,
3 H), 1.32 (s, 9 H), 2.37 (dd, J ϭ 15.5 and 7.8, 1 H) 2.38 (dd, J ϭ
15.5 and 6.2, 1 H), 2.99 (b sext, J ϭ 6.7, 1 H), 3.40 (dd, J ϭ 9.2
and 7.0, 1 H), 3.50 (dd, J ϭ 9.2 and 5.5, 1 H), 3.93 (dd, J ϭ 8.7
and 5.5, 1 H), 4.03Ϫ4.13 (m, 2 H), 4.24 (dd, J ϭ 8.7 and 6.7, 1 H)
4.47 (s, 2 H) 4.70Ϫ4.93 (br. s, 1 H), 5.58 (br. s, 1 H), 5.71 (dd, J ϭ
15.6 and 5.1, H), 5.86 (dd, J ϭ 15.6 and 7.5, 1 H), 7.16Ϫ7.33 (m,
10 H),. 13C NMIR: δ ϭ 14.3, 28.3 (CH3), 36.7 (CH2), 38.9 (CH),
60.3 (CH2), 60.4 (CH), 66.0, 72.6, 73.1 (CH2), 80.6 (Cq), 89.6,
126.7, 127.5, 127.6, 128.4, 128.5, 129.0, 134.2 (CH), 138.3, 140.7,
˜
ν ϭ 3030, 2930, 1720, 1700. Ϫ C28H45NO6Si (519.8): C 64.70, H
8.73, N 2.69; found C 64.61, H 8.82, N 2.71.
(2R,4R)-2-[(1E,3R)-4-Benzyloxy-3-ethoxycarbonylmethylbut-1-
enyl]-3-tert-butoxycarbonyl-4-phenyl-1,3-oxazolidine (16): Yield:
98%; flash chromatography: EtOAc/PE, 2:8; oil; Rf ϭ 0.5 (Et2O/
PE, 1:1); [α]2D0 ϭ Ϫ13 (c ϭ 2.6; CHCl3). 1H NMIR: δ ϭ 1.20 (t,
J ϭ 7.1, 3 H), 1.32 (s, 9 H), 2.37 (dd, J ϭ 15.4 and 8.0, 1 H), 2.61
(dd, J ϭ 15.4 and 6.5, 1 H), 2.99 (sext, J ϭ 6.5, 1 H), 3.40 (dd,
J ϭ 9.6, 6.9 Hz, 1 H), 3.50 (dd, J ϭ 9.6 and 5.4, 1 H), 3.93 (dd,
J ϭ 8.6 and 5.2, 1 H), 4.03Ϫ4.13 (m, 2 H), 4.23 (dd, J ϭ 8.6 and
6.8, 1 H), 4.47 (s, 2 H), 4.70Ϫ4.93 (br. s, 1 H), 5.54 (s, 1 H), 5.71
(dd, J ϭ 15.0 and 4.6, 1 H), 5.88 (dd, J ϭ 15.2 and 7.6, 1 H),
7.17Ϫ7.33 (m, 5 H). 13C NMIR: δ ϭ 14.3, 28.3 (CH3), 36.7 (CH2),
38.9 (CH), 60.3 (CH2), 60.4 (CH), 65.4, 72.7, 73.1 (CH2), 80.5 (Cq),
89.6, 126.7, 127.5, 128.4, 128.5, 129.0 134.2 (CH), 138.3, 140.7,
˜
153.5, 172.3 (Cq). IR: ν ϭ 3030, 2980, 1730, 1700. C29H37NO6
(495.6): C 70.28, H 7.52, N 2.83; found C 70.62, H 7.55, N 2.70.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3S)-4-ethoxycarbonyl-3-phen-
ylbut-1-enyl]-4-phenyl-1,3-oxazolidine (21): Yield: 39%; flash chro-
matography: EtOAc/PE, 1:9; oil; Rf ϭ 0.75 (Et2O/PE, 1:1); [α]2D0
ϭ
1
˜
153.5, 172.3 (Cq). IR: ν ϭ 3030, 2980, 1730, 1700.
ϩ15 (c ϭ 0.8; CHCl3). H NMIR: δ ϭ 1.05 (t, J ϭ 7.1, 3 H), 1.23
(s, 9 H), 2.68 (ABX, J ϭ 15.1 and 7.7, 1 H), 3.82Ϫ4.01 (m, 4 H),
4.16 (dd, J ϭ 8.8 and 6.9, 1 H), 4.70Ϫ4.90 (br. s, 1 H), 5.50Ϫ5.68
(m, 2 H), 6.00 (dd, J ϭ 14.9 and 7.2, 1 H), 7.09Ϫ7.24 (m, 10 H).
13C NMIR: δ ϭ 14.1, 28.2 (CH3), 40.3 (CH2), 44.1 (CH), 60.4
(CH2), 60.5 (CH), 73.3 (CH2), 80.5 (Cq), 89.4, 126.5, 126.8, 127.4,
127.6, 128.5, 128.6, 136.4 (CH), 140.6, 142.1, 153.4, 171.6 (Cq). IR:
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3R)-4-ethoxycarbonyl-3-
phenylbut-1-enyl]-4-phenyl-1,3-oxazolidine (17): Yield: 55%; flash
chromatography: EtOAc/PE, 1:9; oil; Rf ϭ 0.8 (Et2O/PE, 1:1); [α]
20
1
ϭ Ϫ8 (c ϭ 0.8; CHCl3). H NMIR: δ ϭ 1.05 (t, J ϭ 7.1, 3 H),
D
1.20 (s, 9 H), 2.68 (ABX, J ϭ 15.1 and 8.0, 1 H), 3.82Ϫ4.06 (m, 4
H), 4.15 (dd, J ϭ 8.6 and 6.8, 1 H), 4.70Ϫ4.90 (br. s, 1 H),
5.45Ϫ5.68 (m, 2 H), 6.00 (dd, J ϭ 14.9 and 6.9, 1 H), 5.88 (dd,
J ϭ 15.2 and 7.6, 1 H), 7.09Ϫ7.24 (m, 10 H). 13C NMIR: δ ϭ 14.1,
28.2 (CH3), 40.3 (CH2), 44.2 (CH), 60.4 (CH2), 60.5 (CH), 73.2
(CH2), 80.5 (Cq), 89.4, 126.5, 126.8, 127.4, 127.6, 128.5, 128.6,
˜
ν ϭ 3060, 3030, 1730.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3S)-4-ethoxycarbonyl-3-tri-
methylsilyl-but-1-enyl]-4-phenyl-1,3-oxazolidine (22): Yield: 79%;
flash chromatography: Et2O/PE, 1:9; oil; Rf ϭ 0.75 (Et2O/PE,
50:50); [α]2D0 ϭ ϩ11 (c ϭ 0.8; CHCl3). 1H NMIR: δ ϭ 1.19 (s, 9
H), 1.21 (t, J ϭ 7.1, 3 H), 1.31 (s, 9 H), 2.15 (q, J ϭ 7.7, 1 H), 2.42
(d, J ϭ 6.5, 2 H), 3.85 (dd, J ϭ 8.9 and 6.2, 1 H), 4.03Ϫ4.15 (m,
2 H), 4.28Ϫ4.31 (m, 1 H), 4.77Ϫ4.85 (br. m, 1 H), 5.39 (ddd, J ϭ
15.4, 5.6 and 1.2, 1 H), 5.57 (d, J ϭ 5.6, 1 H), 5.75Ϫ5.90 (br. m, 1
H), 7.17Ϫ7.26 (m, 5 H). 13C NMIR: δ ϭ Ϫ 3.0, 14.5, 28.5 (CH3),
29.3 (CH), 34.2, 60.6 (CH2), 60.9 (CH), 73.4 (CH2), 80.5 (Cq), 90.0,
125.7, 126.8, 127.6, 128.6, 134.9 (CH), 140.8, 154.2, 173.4 (Cq). IR:
˜
136.7 (CH), 140.7, 142.1, 153.4, 171.6 (Cq). IR: ν ϭ 3060, 3030,
1730.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3R)-4-ethoxycarbonyl-3-tri-
methylsilylbut-1-enyl]-4-phenyl-1,3-oxazolidine (18): Yield: 93%;
flash chromatography: Et2O/PE, 1:9; oil; Rf ϭ 0.76 (Et2O/PE, 1:1);
1
[α]2D0 ϭ Ϫ3 (c ϭ 0.8; CHCl3). H NMIR: δ ϭ Ϫ0.03 (s, 9 H), 1.13
(t, J ϭ 7.1, 3 H), 1.24 (s, 9 H), 2.11 (q, J ϭ 7.4, 1 H) 2.38 (d, J ϭ
7.1, 2 H), 3.87 (dd, J ϭ 8.8 and 6.0, 1 H), 3.95Ϫ4.08 (m, 2 H),
3.99Ϫ4.09 (m, 2 H), 4.21 (dd, J ϭ 8.8 and 6.9, 1 H), 4.78Ϫ4.88
(br. m, 1 H), 5.42 (dd, J ϭ 15.4 and 5.8, 1 H), 5.57 (d, J ϭ 5.8, 1
H), 5.83 (dd, J ϭ 15.4 and 8.3, 1 H), 7.19Ϫ7.28 (m, 5 H). 13C
NMIR: δ ϭ Ϫ3.1, 14.4, 28.4 (CH3), 29.4 (CH), 34.0, 60.5 (CH2),
60.7 (CH), 73.3 (CH2), 80.4 (Cq), 90.2, 125.6, 126.4, 127.6, 128.6,
˜
ν ϭ 3030, 2980, 1710.
(S)-2-Phenylbutane-1,4-diol (23): An aqueous solution of OsO4 (4
wt.%; 0.1 mL, 0.27 mmol) was added at 0 °C to a solution of 17
(120 mg, 0.27 mmol) in a THF/water mixture (1:1; 4 mL) . After
10 min, sodium periodate (300 mg, 1.4 mmol) was added and the
mixture was stirred at room temp. for 8 h. Addition of an aqueous
solution of sodium thiosulfate (10wt.%; 5 mL) was followed by the
usual workup (Et2O). The oily residue was then taken up in ethanol
(4 mL) and treated with sodium borohydride (52 mg, 1.38 mmol).
After 5 h, the reaction medium was hydrolyzed by addition of a
saturated aqueous solution of NH4Cl (5 mL) and the ethanol was
˜
135.2 (CH), 140.9, 153.6, 173.4 (Cq). IR: ν ϭ 3030, 2980, 1720,
1700. GC (OV17, 250 °C), tR ϭ 7.45 min. MS (CI; NH3): m/z (%):
464 (45), 392 (100), 348 (36), 302 (20), 258 (24), 236 (56), 148 (8),
60 (8). C24H37NO5Si (447.6): C 64.39, H 8.33, N 3.13; found C
64.46, H 8.29, N 3.04.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(1E,3S)-4-tert-butyldi- distilled off under reduced pressure. The usual workup (Et2O) was
methylsilyloxy-3-ethoxycarbonylmethylbut-1-enyl]-4-phenyl-1,3- followed by flash chromatography (Et2O/PE, 1:1) to give diol 23 as
oxazolidine (19): Yield: 73%; flash chromatography: Et2O/PE, 1:9;
a clear oil (24 mg, 53%). [α]2D0 ϭ ϩ29.0 (c ϭ 0.6; MeOH) {ref.[8] [α]
oil; Rf ϭ 0.73 (Et2O/PE, 1:1); [α]2D0 ϭ ϩ10 (c ϭ 1.9; CHCl3). 1H
20 ϭ ϩ29.4 (c ϭ 0.7; MeOH)}. 1H NMIR: δ ϭ 1.84Ϫ2.07 m, 4 H),
D
NMIR: δ ϭ 0.00 (s, 6 H), 0.84 (s, 9 H), 1.18 (t, J ϭ 7.1, 3 H), 1.31 2.95 (br. quint, J ϭ 7.5, 1 H), 3.56Ϫ3.79 (m, 4 H), 7.19Ϫ7.36 (m,
(s, 9 H), 2.29 (dd, J ϭ 15.7 and 8.1, 1 H), 2.60 (dd, J ϭ 15.7 and
5 H). 13C NMIR: δ ϭ 39.5 (CH2), 46.1 (CH), 61.3, 67.7 (CH2),
6.2, 1 H), 2.74Ϫ2.86 (m, 1 H), 3.50Ϫ3.63 (m, 1 H), 3.63 (dd, J ϭ 127.0, 127.8, 128.0, 128.9 (CH), 142.4 (Cq).
34
Eur. J. Org. Chem. 2002, 29Ϫ38

Claisen Rearrangements of Allylic and Propargylic Alcohols
FULL PAPER
Ethyl (R)-3-Benzyloxymethyl-6-hydroxyhex-3-enoate [(؊)-24]: Tri-
fluoroacetic acid (0.57 mL) was added to a solution of 16 (200 mg,
chromatography: EtOAc/PE, 1:9; Rf ϭ 0.5 (Et2O/PE, 5:5); [α]2D0
ϩ41 (c ϭ 0.6, CHCl3). H NMIR: δ ϭ 1.07 (t, J ϭ 6.9, 3 H), 1.21
ϭ
1
0.4 mmol) in 1,2-dichloroethane (3 mL). After 20 min, the solvent (s, 9 H), 3.42 (s, 2 H), 3.85Ϫ4.29 (m,4 H), 4.80 (br. s, 1 H),
was removed under reduced pressure and the crude oil was taken 5.77Ϫ5.82 (m, 2 H), 7.10Ϫ7.95 (m, 10 H). 13C NMIR: δ ϭ 14.3,
up in a mixture of THF and water (1:1; 4 mL). After 1 h of stirring,
the usual workup (Et2O) gave an oil that was dissolved in ethanol
28.3 (CH3), 37.0 (CH2), 60.4 (CH), 61.0, 73.6 (CH2), 80.9 (Cq),
87.7, 89.4 (CH), 94.7 (Cq), 126.3, 126.5, 127.5, 128.3, 128.8, 128.9
(3 mL). CeCl3 (7 H2O) was added to this solution at 0 °C (180 mg, (CH), 139.9, 140.5 (Cq), 154.1 (Cq), 170.8 (Cq), 205.8 (Cq).
0.48 mmol), followed after 10 min by sodium borohydride (18 mg,
0.48 mmol). After 1 h at 0 °C, the reaction medium was hydrolyzed
by addition of a saturated aqueous solution of NH4Cl (5 mL), and
the ethanol was distilled off under reduced pressure. The usual
(2R,4R)-3-tert-Butoxycarbonyl-2-[(2S)-4-ethoxycarbonyl-3-tri-
methylsilylbuta-1,2-dienyl]-4-phenyl-1,3-oxazolidine (28): Yield:
50%; flash chromatography: Et2O/PE, 1:9; Rf ϭ 0.7 (Et2O/PE, 4:6);
1
[α]2D0 ϭ ϩ53 (c ϭ 0.9, CHCl3). H NMIR: δ ϭ 0.16 (s, 9 H), 1.23
workup (Et2O) was followed by flash chromatography (EtOAc/PE,
(t, J ϭ 7.1, 3 H), 1.31 (s, 9 H), 2.99 (dd, J ϭ 15.4 and 2.1, 1 H),
3:7) and gave (Ϫ)-24 as a clear oil (81 mg, 72%). Rf ϭ 0.3 (Et2O/
3.08 (dd, J ϭ 15.4 and 2.4, 1 H), 3.96 (dd, J ϭ 8.8 and 6.9, 1 H),
4.10 (q, J ϭ 7.1, 2 H), 4.33 (dd, J ϭ 8.8 and 7.1, 1 H) 4.80Ϫ4.92
(br. m, 1 H), 5.25Ϫ5.29 (m, 1 H), 5.83 (d, J ϭ 5.2, 1 H), 7.25Ϫ7.29
(m, 5 H). 13C NMIR: δ ϭ Ϫ1.4, 14.2, 28.2 (CH3), 35.8 (CH2), 60.8
(2 CH), 73.6 (CH2), 80.4 (Cq), 86.9, 87.8 (CH), 94.0 (Cq), 126.5,
127.5, 128.3 (CH), 140.6 (Cq), 153.2 (Cq), 171.4 (Cq), 206.2 (Cq).
PE, 7:3); [α]D20 ϭ Ϫ12 (c ϭ 1.0; CHCl3). 1H NMIR: δ ϭ 1.20 (t, J ϭ
7.2, 3 H), 2.32 (dd, J ϭ 15.2 and 8.0, 1 H), 2.56 (dd, J ϭ 15.2 and
6.0, 1 H), 2.68 (br. s, 1 H), 2.90 (br. sext, J ϭ 6.8, 1 H), 3.37 (dd,
J ϭ 9.2 and 7.0, 1 H), 3.46 (dd, J ϭ 9.2 and 5.6, 1 H), 4.02Ϫ4.11
(m, 4 H), 4.48 (br. s, 2 H), 5.54Ϫ5.74 (m, 2 H), 7.25Ϫ7.33 (m, 5
H). 13C NMIR: δ ϭ 14.1 (CH3), 36.8 (CH2), 38.1 (CH), 60.3, 63.0,
72.7, 72.9 (CH2), 127.6, 128.3, 131.0, 131.5 (CH), 138, 172.5 (Cq).
(3R,7S,8S,9R)-8-Bromo-7-[(1S)-2-tert-butyldimethylsilyloxy-1-eth-
oxycarbonylmethylethyl]-3-phenyltetrahydrooxazolo[3,2-c][1,3]-
oxazin-5-one (29): N-Bromosuccinimide (90 mg, 0.5 mmol) was ad-
ded to a solution of 15 (200 mg, 0.38 mmol) in a mixture of DME/
water (1:1; 2 mL). After this had stirred for 2 h at room temp.,
water (10 mL) was added. The usual workup (CH2Cl2), followed
by flash chromatography (Et2O/PE, 1:1), gave 29 as a clear oil
(170 mg, 82%). Rf ϭ 0.1 (Et2O/PE, 1:1); [α]2D0 ϭ ϩ31 (c ϭ 1.5;
CHCl3). 1H NMIR: δ ϭ 0.03 (s, 6 H), 0.9 (s, 9 H), 1.25 (t, J ϭ 7.1,
3 H), 2.30Ϫ2.52 (m, 2 H), 2.92Ϫ3.05 (m, 1 H), 3.50 (dd, J ϭ 10.6
and 4.5, 1 H), 3.80 (dd, J ϭ 10.6 and 9.2, 1 H), 4.10Ϫ4.32 (m, 4
H), 4.51 (dd, J ϭ 10.9 and 1.2, 1 H), 4.69 (dd, J ϭ 10.9 and 8.7, 1
H), 4.94 (dd, J ϭ 6.8 and 1.5, 1 H), 4.98 (d, J ϭ 8.7, 1 H),
7.23Ϫ7.32 (m, 5 H). 13C NMIR: δ ϭ Ϫ5.3, 14.3 (CH3), 18.2 (Cq),
26.0 (CH3), 33.6 (CH2), 37.5, 44.5, 60.8 (CH), 60.9, 61.6, 73.9
(CH2), 79.6, 89.6, 126.5, 128.2, 128.8 (CH), 140.0, 149.0, 172.1
(Cq). IR: ν˜ ϭ 2927, 1730. C24H36NO6BrSi (542.5): C 53.13, H 6.69,
N 2.58; found C 53.15, H 6.83, N 2.46.
˜
IR: ν ϭ 3435, 2860, 1730. GC (OV 17, 120 °C then gradient of 5
°C/min): tR ϭ 17.2 min. Chiral GC (Chirasil-DEX-CB, 156 °C):
tR ϭ 9.6 min. MS (EI): m/z (%): 278 (3), 261 (100), 231 (18), 215
(3), 187 (6), 171 (47), 155 (88), 130 (31), 91 (35), 65 (16), 41 (3).
Ethyl (S)-2-Benzyloxymethyl-6-hydroxyhex-4-enoate [(؉)-24]: This
compound was prepared by the procedure described for (Ϫ)-24,
starting with 20 (1 g, 2.09 mmol), and was obtained as an oil
(305 mg, 52%). It displays the same spectroscopic data as described
for (Ϫ)-24. [α]2D0 ϭ ϩ13 (c ϭ 2.1; CHCl3). Chiral GC (Chirasil-
DEX-CB, 156 °C): tR ϭ 10.7 min. C16H22O4 (278.3): C 69.04, H
7.97; found C 68.89, H 8.14.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(2R)-3-ethoxycarbonyl-
methylnona-1,2-dienyl]-4-phenyl-1,3-oxazolidine (25): Yield: 67%;
flash chromatography: Et2O/PE, 1:9; Rf ϭ 0.5 (Et2O/PE, 4:6); [α]
20
1
ϭ ϩ26 (c ϭ 1.9, CHCl3). H NMIR: δ ϭ 0.79 (t, J ϭ 6.9, 3 H),
D
1.10Ϫ1.38 (m, 20 H), 2.00 (m, 2 H), 2.90 (dd, J ϭ 15.4 and 1.8, 1
H), 2.99 (dd, J ϭ 15.4 and 1.8, 1 H), 3.88 (dd, J ϭ 8.9 and 6.8, 1
H), 4.04 (q, J ϭ 6.9, 2 H), 4.25 (dd, J ϭ 8.9 and 6.8, 1 H),
4.75Ϫ4.88 (br. m, 1 H), 4.36Ϫ5.43 (m, 1 H), 5.70 (d, J ϭ 4.9, 1
H), 7.15Ϫ7.29 (m, 5 H). 13C NMIR: δ ϭ 14.2, 14.3 (CH3), 22.7,
27.3, 28.3, 29.0, 31.8, 32.0, 38.8 (CH2), 60.7 (CH), 60.8, 73.4 (CH2),
80.5 (Cq), 87.9 (CH), 92.4 (CH), 102.0 (Cq), 126.5, 127.2, 128.5
(CH), 140.4 (Cq), 153.3 (Cq), 171.0 (Cq), 202.7 (Cq). IR: ν˜ ϭ 2930,
2855, 1717. C27H39NO5 (457.6): C 70.87, H 8.59, N 3.06; found C
70.95, H 8.61, N 2.96.
(3R,7S,8S,9R)-7-[(1S)-2-Benzyloxy-1-ethoxycarbonylmethylethyl]-
8-bromo-3-phenyltetrahydrooxazolo[3,2-c][1,3]oxazin-5-one
(30):
This compound was prepared by the procedure described above,
but with a reaction time of 4 h, and starting with 16 (183 mg,
0.37 mmol). It was isolated by flash chromatography (EtOAc/PE,
3:7) as a clear oil (135 mg, 70%). Rf ϭ 0.5 (Et2O); [α]2D0 ϭ ϩ51 (c ϭ
1
1.1; CHCl3). H NMIR: δ ϭ 1.51 (t, J ϭ 7.0, 3 H), 2.65 (dd, J ϭ
16.7 and 5.7, 1 H), 2.80 (dd, J ϭ 16.7 and 8.2, 1 H), 3.37Ϫ3.49 (m,
1 H), 3.63 (dd, J ϭ 9.7 and 5.0, 1 H), 3.91 (t, J ϭ 9.2, 1 H),
4.35Ϫ4.44 (m, 3 H), 4.52 (dd, J ϭ 9.0 and 6.5, 1 H), 4.69 (dd, J ϭ
10.9 and 8.5, 1 H), 4.71 (AB syst., J ϭ 13.0, 2 H), 4.82 (dd, J ϭ
10.7 and 1.0, 1 H), 4.94 (dd, J ϭ 10.9 and 8.5, 1 H), 5.21 (dd, J ϭ
6.5 and 1.2, 1 H), 7.10Ϫ7.28 (m, 10 H). 13C NMIR: δ ϭ 14.2
(CH3), 33.9 (CH2), 35.4, 44.8, 60.7 (CH), 60.8, 68.6, 73.1, 73.8
(CH2), 79.6, 89.1, 126.6, 127.3, 127.7, 128.2, 128.5, 128.8 (CH),
137.8, 139.9, 148.7, 171.8 (Cq). IR: ν˜ ϭ 2925, 1710.
(2R,4R)-3-tert-Butoxycarbonyl-2-[(2S)-3-tert-butyldimethyl-
silyloxymethyl-4-ethoxycarbonylbuta-1,2-dienyl]-4-phenyl-1,3-
oxazolidine (26): Yield: 71%; flash chromatography: Et2O/PE, 1:9;
Rf ϭ 0.8 (Et2O/PE, 5:5); [α]2D0 ϭ ϩ44 (c ϭ 1.3, CHCl3). 1H NMIR:
δ ϭ 0.07 (s, 6 H), 0.89 (s, 9 H), 1.24 (t, J ϭ 7.1, 3 H), 1.32 (s, 9
H), 3.00 (dd, J ϭ 16.0 and 2.2, 1 H), 3.09 (dd, J ϭ 16.0 and 2.2, 1
H), 3.97 (dd, J ϭ 8.9 and 6.8, 1 H), 4.10 (q, J ϭ 7.1, 2 H), 4.27 (t,
J ϭ 2.3, 2 H), 4.31 (dd, J ϭ 8.9 and 6.8, 1 H), 4.75Ϫ4.88 (bm, 1
H), 5.43Ϫ5.50 (m, 1 H), 5.77 (d, J ϭ 4.6, 1 H), 7.22Ϫ7.36 (m, 5
H). 13C NMIR: δ ϭ Ϫ5.3, 14.3 (CH3), 18.5 (Cq), 26.0, 28.3 (CH3),
34.8 (CH2), 60.8 (CH), 60.9, 63.2, 73.5 (CH2), 80.5 (Cq), 87.6 (CH),
93.1 (CH), 102.0 (Cq), 126.7, 127.4, 128.6 (CH), 140.4 (Cq), 152.3
(3R,7S,8S,9R)-8-Bromo-7-[(1R)-2-tert-butyldimethylsilyloxy-1-eth-
oxycarbonylmethylethyl]-3-phenyltetrahydrooxazolo[3,2-c][1,3]-
oxazin-5-one (31): This compound was prepared by the procedure
described above, but with a reaction time of 5 h, and starting with
19 (330 mg, 0.63 mmol). It was isolated after flash chromatography
(EtOAc/PE, 2:8) as a clear oil (89 mg, 26%). Rf ϭ 0.3 (Et2O/PE,
(Cq), 170.9 (Cq), 202.7 (Cq). IR: ν˜
C28H43NO6Si (517.7): C 64.96, H 8.37, N 2.71; found C 64.82, H
8.71, N 2.51.
ϭ 2930, 1979, 1700.
1
1:1); [α]2D0 ϭ ϩ21 (c ϭ 0.5; CHCl3). H NMIR: δ ϭ 0.03 (s, 3 H),
(2R,4R)-3-tert-Butoxycarbonyl-2-[(2S)-4-ethoxycarbonyl-3-phenyl- 0.04 (s, 3 H), 0.86 (s, 9 H), 1.19 (t, J ϭ 7.1, 3 H), 2.18 (dd, J ϭ
buta-1,2-dienyl]-4-phenyl-1,3-oxazolidine (27): Yield: 17%; flash
16.0 and 7.4, 1 H), 2.31 (dd, J ϭ 16.0 and 5.4, 1 H), 2.79 (br. quint,
Eur. J. Org. Chem. 2002, 29Ϫ38
35

C. Agami, F. Couty, G. Evano
J ϭ 6.5, 1 H), 3.63 (d, J ϭ 7.4, 1 H), 4.01Ϫ4.15 (m, 4 H), 4.24 (dd, above, starting with 32 (90 mg, 0.17 mmol). It was obtained as an
FULL PAPER
J ϭ 9.2 and 6.5, 1 H), 4.69 (dd, J ϭ 11.1 and 1.2, 1 H), 4.91 (d,
oil (71 mg, 86%) after flash chromatography (EtOAc/PE, 2:8). Rf ϭ
1
J ϭ 5.8, 1 H), 5.03 (d, J ϭ 8.6, 1 H), 7.23Ϫ7.32 (m, 5 H). 13C 0.7 (Et2O/PE, 6:4); [α]2D0 ϭ Ϫ3 (c ϭ 1.1; CHCl3). H NMIR: δ ϭ
NMIR: δ ϭ Ϫ5.3, 14.2 (CH3), 18.3 (Cq), 26.0 (CH3), 30.3 (CH2), 1.05Ϫ1.18 (m, 6 H), 2.22 (b sext, J ϭ 6.3, 1 H), 2.50 (d, J ϭ 6.7,
38.8, 43.9, 60.8 (CH), 61.0, 62.4, 73.9 (CH2), 77.2, 89.3, 126.65, 2 H), 3.09 (dd, J ϭ 6.9 and 2.1, 1 H), 3.20 (t, J ϭ 2.0, 1 H),
˜
128.3, 128.9 (CH), 139.9, 148.7, 172.2 (Cq). IR: ν ϭ 2930, 1720.
3.46Ϫ3.57 (m, 2 H), 3.98Ϫ4.13 (m, 5 H), 4.27 (dd, J ϭ 8.7 and
7.0, 1 H), 4.42 (s, 2 H), 4.90 (t, J ϭ 6.9, 1 H), 5.45 (br. s, 1 H),
7.20Ϫ7.40 (m, 10 H). 13C NMIR: δ ϭ 14.2, 14.4 (CH3), 33.5 (CH2),
38.0, 56.0, 58.2 (CH), 60.5 (CH2), 60.8 (CH), 61.9, 69.8, 73.2, 73.9
(CH2), 88.4, 126.7, 127.5, 127.6, 127.7, 128.4, 128.6 (CH), 138.1
(3R,7S,8S,9R)-7-[(1R)-2-Benzyloxy-1-ethoxycarbonylmethylethyl]-
8-bromo-3-phenyltetrahydrooxazolo[3,2-c][1,3]oxazin-5-one
(32):
This compound was prepared by the procedure described above,
but with a reaction time of 0.5 h, and starting with 20 (500 mg,
1.0 mmol). It was isolated by flash chromatography (CH2Cl2) as a
˜
139.4, 154.9, 172.1 (Cq). IR: ν ϭ 2980, 1715. C27H33NO7 (483.6):
C 67.06, H 6.88, N 2.90; found C 67.08, H 6.81, N 2.84.
solid (356 mg, 68%). M.p. 139 °C; Rf ϭ 0.2 (Et2O/PE, 7:3); [α]2D0
ϭ
1
(2Z,4S)-4-Bromo-5-tert-butyldimethylsilyloxy-4-ethoxycarbonyl-
m et hy l -3 -{ [ ( 2R )- 2 -p he ny l -2 - N -te rt -b u t ox yc a r bo ny l -
ethyl]oxy}pent-2-enal (37): This compound was prepared by the
procedure described for the bromocarbamation of 15, starting with
allene 26 (310 mg, 0.59 mmol). It was obtained as an oil (290 mg,
80%) after flash chromatography (Et2O/PE, 3:7). Rf ϭ 0.4 (Et2O/
ϩ18 (c ϭ 0.5; CHCl3). H NMIR: δ ϭ 1.11 (t, J ϭ 7.0, 3 H), 2.17
(dd, J ϭ 16.0 and 7.2, 1 H), 2.31 (dd, J ϭ 16.0 and 5.5, 1 H),
2.89Ϫ3.01 (m, 1 H), 3.42Ϫ3.60 (m, 2 H), 3.91Ϫ4.15 (m, 5 H), 4.45
(AB syst. J ϭ 12.4, 2 H), 4.63 (dd, J ϭ 11.2 and 1.6, 1 H), 4.83
(dd, J ϭ 6.3 and 1.1, 1 H), 4.93 (d, J ϭ 8.5, 1 H), 7.16Ϫ7.28 (m,
10 H). 13C NMIR: δ ϭ 14.0 (CH3), 30.3 (CH2), 36.2, 43.5, 60.6
(CH), 60.8, 69.4, 72.9, 73.7 (CH2), 77.0, 89.0, 126.4, 127.5, 127.7,
1
PE, 4:6); [α]2D0 ϭ ϩ7 (c ϭ 1.5; CHCl3). H NMIR: δ ϭ 0.00 (s, 6
H), 0.82 (s, 9 H), 1.18 (t, J ϭ 7.1, 3 H), 1.34 (s, 9 H), 2.86 (AB
syst., J ϭ 15, 2 H), 3.66Ϫ3.83 (m, 2 H), 3.82 (AB syst., J ϭ 11.1,
2 H), 4.03Ϫ4.15 (m, 2 H), 4.77 (br. s, 1 H), 5.51 (d, J ϭ 6.5, 1 H),
6.50 (d, J ϭ 6.5, 1 H), 7.19Ϫ7.27 (m, 5 H), 9.73 (d, J ϭ 6.5, 1 H).
13C NMIR: δ ϭ Ϫ5.4, 14.1 (CH3), 18.1 (Cq), 25.8, 28.3 (CH3),
38.2 (CH2), 54.8 (CH), 61.2, 64.7 (CH2), 79.5, 85.8 (Cq), 126.2,
127.6, 128.6, 138.0 (CH), 139.6, 155.3, 168.9 (Cq), 191.0 (CH). IR:
˜
128.3, 128.5, 128.7 (CH), 137.9, 139.79, 148.3, 171.8 (Cq). IR: ν ϭ
2925, 1710. C25H28NO6Br (518.4): C 57.92, H 5.44, N 2.70; found
C 57.80, H 5.62, N 2.59.
(2R,4R)-2-[(1R,2R,3S)-4-tert-Butyldimethylsilyloxy-1,2-epoxy-3-
ethoxycarbonylmethylbutyl]-3-ethoxycarbonyl-4-phenyl-1,3-oxa-
zolidine (33): A solution of sodium ethoxide, prepared from sodium
(80 mg, 3.5 mmol) in ethanol (2.5 mL), was added at room temp.
to a solution of 29 (180 mg, 0.33 mmol) in ethanol (4 mL). The
mixture was stirred for 1.5 h at room temp. and hydrolyzed by addi-
tion of a saturated aqueous solution of NH4Cl (5 mL). The ethanol
was then distilled off under reduced pressure, and the usual workup
(Et2O) followed by flash chromatography (Et2O/PE, 6:4) gave epox-
˜
ν ϭ 3390, 3065, 2930, 1682.
(2R,4R)-2-{(R)-[(1S,2S,3R)-2-tert-Butyldimethylsilyloxymethyl-3-
ethoxycarbonylcyclopropyl](hydroxy)methyl}-3-ethoxycarbonyl-4-
phenyl-1,3-oxazolidine (38): A solution of lithium bis(trimethylsilyl-
amide) (1  solution in THF, 0.35 mL, 0.35 mmol) was added at
Ϫ78 °C to a solution of 32 (76 mg, 0.15 mmol) in THF (3 mL).
The solution was stirred for 6 h at Ϫ50 °C and hydrolyzed by addi-
tion of a saturated aqueous solution of NH4Cl (5 mL). The usual
workup, followed by flash chromatography (EtOAc/PE, 3:7) gave
cyclopropane 38 as an oil (56 mg, 74%). Rf ϭ 0.4 (Et2O/PE, 6:4);
ide 33 (162 mg, 97%) as a clear oil. Rf ϭ 0.8 (Et2O/PE, 6:4); [α]2D0
ϭ
1
ϩ10 (c ϭ 0.5; CHCl3). H NMIR: δ ϭ 0.01 (s, 6 H), 0.83 (s, 9 H),
1.18 (t, J ϭ 7.1, 3 H), 1.21 (t, J ϭ 7.1, 3 H), 1.86Ϫ1.96 (m, 1 H),
2.30 (dd, J ϭ 16.3 and 7.1, 1 H), 2.49 (dd, J ϭ 8.0 and 2.2, 1 H),
2.99 (dd, J ϭ 8.0 and 2.2, 1 H), 3.20 (t, J ϭ 2.3, 1 H), 3.69 (b dd,
J ϭ 4.3 and 0.9, 1 H), 3.99Ϫ4.10 (m, 5 H), 4.25 (dd, J ϭ 8.8 and
6.9, 1 H), 4.86 (t, J ϭ 6.9, 1 H), 5.37 (d, J ϭ 2.3, 1 H), 7.18Ϫ7.38
(m, 5 H). 13C NMIR: δ ϭ Ϫ4.9, 14.2, 14.5 (CH3), 18.3 (Cq), 25.9
(CH3), 32.8 (CH2), 39.1, 55.2, 58.3 (CH), 60.5, 61.1 (CH), 61.9,
62.7, 73.9 (CH2), 88.7, 126.8, 127.8, 128.6 (CH), 139.4, 155.2, 172.3
1
[α]2D0 ϭ ϩ32 (c ϭ 1.3; CHCl3). H NMIR: δ ϭ 0.00 (s, 6 H), 0.83
(s, 9 H), 1.07 (t, J ϭ 6.9, 3 H), 1.12 (t, J ϭ 6.9, 3 H), 1.47 (td, J ϭ
9.0 and 6.0, 1 H), 1.75 (dd, J ϭ 9.0 and 5.2, 1 H), 1.86 (br. quint,
J ϭ 5.2, 1 H), 3.53 (dd, J ϭ 10.7 and 5.2, 1 H), 3.80 (dd, J ϭ 10.7
and 4.9, 1 H), 3.85Ϫ4.09 (m, 6 H), 4.21 (dd, J ϭ 8.7 and 7.2, 1 H),
4.93 (t, J ϭ 6.6, 1 H), 5.23 (d, J ϭ 7.2, 1 H), 7.18Ϫ7.33 (m, 5 H).
13C NMIR: δ ϭ Ϫ5.2, 14.3, 14.4 (CH3), 18.4 (Cq), 22.4 (CH), 26.0
(CH3), 27.0, 28.1 (CH), 60.5 (CH2), 61.0 (CH), 62.4, 62.7 (CH2),
70.7 (CH), 73.7 (CH2), 93.1, 126.6, 127.7, 128.7 (CH), 139.7, 156.7,
173.0 (Cq). IR: ν˜ ϭ 3420, 2955, 1680. C26H41NO7Si (507.7): C
61.51, H 8.14, N 2.76; found C 61.79, H 8.57, N 2.56.
˜
(Cq). IR: ν ϭ 2955, 2930, 1710. C26H41NO7Si (507.7): C 61.51, H
8.14, N 2.76; found C 61.14, H 8.21, N 2.79.
(2R,4R)-2-[(1R,2R,3S)-4-Benzyloxy-1,2-epoxy-3-ethoxycarbonyl-
methylbutyl]-3-ethoxycarbonyl-4-phenyl-1,3-oxazolidine
(34): This compound was prepared by the procedure described
above, starting with 30 (140 mg, 0.27 mmol). It was obtained as an
oil (117 mg, 90%) after flash chromatography (EtOAc/PE, 2:8).
Rf ϭ 0.4 (Et2O/PE, 5:5); [α]2D0 ϭ Ϫ19 (c ϭ 1.0; CHCl3). 1H NMIR:
δ ϭ 1.05Ϫ1.18 (m, 6 H), 2.09 Ϫ2.20 (m, 1 H), 2.31 (dd, J ϭ 16.0
and 7.0, 1 H), 2.45 (dd, J ϭ 16.2 and 7.0, 1 H), 3.01 (dd, J ϭ 7.4
and 2.2, 1 H), 3.20 (t, J ϭ 2.2, 1 H), 3.49 (d, J ϭ 4.7, 1 H),
3.96Ϫ4.05 (m, 5 H), 4.22 (dd, J ϭ 8.7 and 7.0, 1 H), 4.43 (s, 2 H),
(2R,4R)-2-{(R)-[(1S,2S,3R)-2-Benzyloxymethyl-3-ethoxycarbonyl-
cyclopropyl](hydroxy)methyl}-3-ethoxycarbonyl-4-phenyl-
1,3-oxazolidine (39): This compound was prepared by the proced-
ure described above, starting with 34 (65 mg, 0.13 mmol). It was
obtained as an oil (53 mg, 81%) after flash chromatography
(EtOAc/PE, 1:1). Rf ϭ 0.2 (Et2O/PE, 6:4); [α]2D0 ϭ ϩ32 (c ϭ 1.2;
1
CHCl3). H NMIR: δ ϭ 1.04 (t, J ϭ 7.0, 3 H), 1.07 (t, J ϭ 7.0, 3
4.84 (b t, J ϭ 6.8, 1 H), 5.37 (br. s, 1 H), 7.17Ϫ7.34 (m, 10 H). 13
C
H), 1.39 (td, J ϭ 8.9 and 5.6, 1 H), 1.70 (dd, J ϭ 8.9 and 5.1, 1
H), 1.95 (br. quint, J ϭ 5.5, 1 H), 3.30 (dd, J ϭ 10.4 and 6.5, 1
H), 3.53 (dd, J ϭ 10.4 and 5.4, 1 H), 3.83Ϫ4.05 (m, 6 H), 4.16 (dd,
J ϭ 8.7 and 7.2, 1 H), 4.47 (s, 2 H), 4.89 (t, J ϭ 6.2, 1 H), 5.19 (d,
J ϭ 7.0, 1 H), 7.18Ϫ7.26 (m, 10 H). 13C NMIR: 14.2, 14.3 (CH3),
NMIR: δ ϭ 14.3, 14.5 (CH3), 33.2 (CH2), 37.8, 55.7, 58.0 (CH),
60.6 (CH2), 61.0 (CH), 62.0, 70.1, 73.3, 73.9 (CH2), 88.6, 127.6,
˜
127.8, 128.4, 128.6 (CH), 138.3 139.5, 155.0, 172.1 (Cq). IR: ν ϭ
2985, 1715.
(2R,4R)-2-[(1R,2R,3R)-4-Benzyloxy-1,2-epoxy-3-ethoxycarbonyl- 22.4, 24.5, 29.1 (CH), 60.5 (CH2), 61.0 (CH), 62.4 (CH2), 70.6
methylbutyl]-3-ethoxycarbonyl-4-phenyl-1,3-oxazolidine
(CH), 70.8, 73.6 (CH2), 93.0, 126.6, 127.6, 127.8, 128.4, 128.7 (CH),
˜
(35): This compound was prepared by the procedure described
138.3, 139.7, 156.6, 172.6 (Cq). IR: ν ϭ 3410, 2980, 1715.
36
Eur. J. Org. Chem. 2002, 29Ϫ38

Claisen Rearrangements of Allylic and Propargylic Alcohols
(2R,4R)-2-{(R)-[(1S,2R,3S)-2-Benzyloxymethyl-3-ethoxycarbonyl- 1 H), 4.32 (q, J ϭ 7.3, 2 H), 4.48 (dd, J ϭ 7.5 and 8.5, 1 H), 4.73
FULL PAPER
cyclopropyl)(hydroxy)methyl}-3-ethoxycarbonyl-4-phenyl-1,3-
(dd, J ϭ 6.7 and 8.5, 1 H), 5.25 (t, J ϭ 7, 0.8 H), 5.38 (d, J ϭ 6.7,
oxazolidine (40): This compound was prepared by the procedure
0.2 H), 5.75 (b t, J ϭ 6, 0.2 H), 6.23 (s, 0.8 H)7.52Ϫ7.73 (m, 10
described above, starting with 35 (72 mg, 0.15 mmol). It was ob- H). 13C NMR (major rotamer): δ ϭ 14.4 (CH3), 42.9 (CH2), 55.1
tained as an oil (52 mg, 72%) after flash chromatography (EtOAc/ (CH), 61.6 (CH2), 61.7, 62.2, 75.4, 88.0, 125.8, 126.4, 126.9, 127.8,
PE, 4:6). Rf ϭ 0.4 (EtOAc/PE, 4:6); [α]2D0 ϭ ϩ3 (c ϭ 0.5; CHCl3).
128.4, 128.6, 128.7, 129.3 (CH), 136.3, 137.8, 166.6, 166.8 (Cq). IR:
1H NMIR: δ ϭ 1.05 (t, J ϭ 7.0, 3 H), 1.06 (t, J ϭ 7.0, 3 H), 1.64 (Nujol) ν˜ ϭ 1658, 1733, 2924.
(t, J ϭ 4.7, 1 H), 1.81Ϫ1.95 (m, 2 H), 3.40Ϫ3.51 (m, 1 H),
(7R,8R,9R)-8-Hydroxy-3,7-diphenyloxazolo[3,2-a]pyridin-5-one
3.73Ϫ3.81 (m, 2 H), 3.83Ϫ4.15 (m, 5 H), 4.23 (dd, J ϭ 8.9 and 7.1,
1 H), 4.49 (AB syst., J ϭ 12.1, 2 H), 4.91 (dd, J ϭ 6.7 and 5.2, 1
H), 5.28 (d, J ϭ 5.0, 1 H), 7.18Ϫ7.33 (m, 10 H). 13C NMIR: δ ϭ
14.2, 14.5 (CH3), 23.9, 24.0, 27.8 (CH), 60.6 (CH2), 61.0 (CH),
62.1, 68.5 (CH2), 72.4 (CH), 73.1, 73.7 (CH2), 92.0, 126.8, 127.7,
(46): Sodium hydride (60 wt.%; 14 mg, 0.3 mmol) was added to a
solution of epoxide 45 (97 mg, 0.254 mmol) in dry DMF (3 mL).
The solution was stirred at 50 °C for 1 h and then at 100 °C for
2 h 15. The mixture was then cooled to room temp. and hydrolyzed
by addition of a saturated aqueous solution of NH4Cl. The usual
workup (CH2Cl2) was followed by flash chromatography (EtOAc/
PE, 4:6) and gave 46 as a white solid (32 mg, 41%). Rf ϭ 0.75
˜
128.0, 128.6 (CH), 137.6, 140.3, 156.1, 172.9 (Cq). IR: ν ϭ 3428,
2980, 1650.
1
(EtOAc/PE, 7:3); m.p. 215 °C; [α]2D0 ϭ Ϫ120 (c ϭ 1.6; CHCl3). H
(3R,7S,8S,9S,10R)-9-Bromo-7-tert-butyldimethylsilyloxymethyl-6-
ethoxycarbonyl-8-hydroxy-5-oxo-3-phenyloctahydrooxazolo[3,2-a]-
azepine (41): This compound was prepared by the procedure de-
scribed above, starting with 29 (317 mg, 0.58 mmol) and with a
reaction time of 1.5 h. It was obtained as an oil (191 mg, 61%) after
flash chromatography (EtOAc/PE, 2:8). Rf ϭ 0.5 (Et2O/PE, 6:4);
NMIR: δ ϭ 2.56 (dd, J ϭ 1.5 and 17.5, 1 H), 2.95 (dd, J ϭ 7.2
and 17.5, 1 H), 3.05 (br. s, 1 H), 3.50Ϫ3.55 (m, 1 H), 3.95 (dd, J ϭ
1.7 and 9.0, 1 H), 4.04 (dd, J ϭ 7.0 and 9.0, 1 H), 4.31 (br. s, 1 H),
4.46 (d, J ϭ 2.0, 1 H), 4.95 (b d, J ϭ 7.0, 1 H), 7.15Ϫ7.34 (m, 10
H). 13C NMIR: δ ϭ 32.1 (CH2), 42.2, 58.5, 69.3 (CH), 74.7 (CH2),
86.8, 126.2, 127.3, 127.4, 128.7, 128.8, 129.4 (CH), 140.2, 140.9,
167.4 (Cq). IR: (Nujol) ν˜ ϭ 1628, 2920, 3278. C19H19NO3 (309.4):
C 73.76, H 6.19, N 4.52; found C 73.60, H 6.39, N 4.37.
1
positive Beilstein test. H NMIR: δ ϭ Ϫ0.24 (s, 3 H), Ϫ0.09 (s, 3
H), 0.81 (s, 9 H), 1.32 (t, J ϭ 7.1, 3 H), 2.69Ϫ2.78 (m, 1 H), 2.94
(t, J ϭ 10.5, 1 H), 3.25 (br. s, 1 H), 4.07 (dd, J ϭ 10.3 and 5.0, 1
H), 4.13Ϫ4.19 (m, 5 H), 4.40 (d, J ϭ 9.0, 1 H), 4.55 (br. s, 1 H),
5.39 (d, J ϭ 5.5, 1 H), 5.59 (d, J ϭ 9.5, 1 H), 7.26Ϫ7.40 (m, 3 H),
7.53Ϫ7.57 (m, 2 H). 13C NMIR: δ ϭ 1.3, 1.9, 14.0, 25.7 (CH3),
43.7, 46.9, 55.9 (CH), 59.6 (CH2), 60.1 (CH), 61.4, (CH2), 69.3,
71.6, 89.4, 127.4, 128.2, 128.8 (CH), 139.2, 165.8, 169.0 (Cq). IR:
(1R,3R,4R)-1-(2-Hydroxy-1-phenylethyl)-4-phenylpiperidin-2-ol
(47): LiAlH4 (70 mg, 2 mmol) was added portionwise to a solution
of 46 (110 mg, 0.35 mmol) in THF (5 mL). The suspension was
stirred at room temp. for 3 h and quenched by pouring it into an
aqueous solution of NaOH (4 wt.%; 4 mL). Addition of water
(5 mL) with vigorous stirring was followed by filtration through a
Celite pad. Concentration under reduced pressure gave an oil that
was purified by flash chromatography (EtOAc/PE, 7:3). Diol 47
was obtained as a clear oil (67 mg, 63%). Rf ϭ 0.45 (EtOAc/PE,
˜
ν ϭ 3420, 1750, 1675.
(2R,4R)-2-[(1S,2R)-1-Bromo-2-hydroxy-2-phenylethyl]-3-(2-ethoxy-
carbonyl-1-oxoethyl)-4-phenyl-1,3-oxazolidine (44): A solution of
LiHMDS in THF (35 mL, 1  solution, 35 mmol) was added drop-
wise at Ϫ78 °C to a solution of ethyl acetate (3.9 mL, 40 mmol) in
THF (20 mL). The solution was warmed to Ϫ50 °C over 1 h and
recooled to Ϫ78 °C. To this solution was then added dropwise a
solution of 43 (3 g, 8.01 mmol) in THF (30 mL). The reaction mix-
ture was stirred at Ϫ50 °C for 1.5 h and hydrolyzed with an aque-
ous saturated solution of NH4Cl. The usual workup, followed by
flash chromatography (EtOAc/PE/CH2Cl2), gave bromohydrin 44
as a white solid (3.6 g, 97%). Rf ϭ 0.5 (EtOAc/PE, 1:1); m.p. 120
1
8:2); [α]2D0 ϭ ϩ21.4 (c ϭ 0.5; CHCl3). H NMIR: δ ϭ 1.97 (t, J ϭ
10.2, 1 H), 2.01Ϫ2.15 (m, 2 H), 2.41Ϫ2.52 (m, 1 H), 2.53Ϫ2.72 (m,
1 H), 2.90 (br. s, 2 H), 3.21 (b dd, J ϭ 1.5 and 10.7, 1 H), 3.45
(ddd, J ϭ 1.5, 4.2, and 10.7, 1 H), 3.91 (dd, J ϭ 4.5 and 9.7, 1 H),
4.00 (dd, J ϭ 4.5 and 9.7, 1 H), 4.01Ϫ4.10 (m, 1 H), 4.30 (t, J ϭ
9.9, 1 H), 7.46Ϫ7.67 (m, 10 H). 13C NMIR: δ ϭ 32.4 (CH2), 51.4
(CH), 52.8, 52.9, 60.3 (CH2), 69.8, 72.2, 127.1, 127.9, 128.1, 128.4,
128.8, 128.9 (CH), 135.2, 142.1 (Cq).
1
°C; [α]2D0 ϭ ϩ11 (c ϭ 0.7; CHCl3). H NMIR: δ ϭ 1.47 (t, J ϭ 7,
(3R,4R)-4-Phenylpiperidin-3-ol (48): Pd/C (10%; 10 mg) was added
to a solution of 47·HCl (56 mg, 0.168 mmol) in MeOH (3 mL), and
the suspension was stirred at room temp. under hydrogen for 24 h.
The suspension was then filtered through Celite (washed with hot
MeOH), and the filtrate was concentrated under reduced pressure
to give 48·HCl as crystals, which were washed with small portions
of acetone (38 mg, quant. yield). M.p. 186 °C; [α]2D0 ϭ ϩ40.2 (c ϭ
3 H), 3.28 (d, J ϭ 15.7, 1 H), 3.43 (d, J ϭ 15.7, 1 H), 3.59 (d, J ϭ
6.2, 1 H), 4.37 (q, J ϭ 7.0, 2 H) 4.61Ϫ4.73 (m, 2 H), 5.24 (t, J ϭ
7.2, 1 H), 5.41 (t, J ϭ 6.5, 1 H), 5.53 (dd, J ϭ 2 and 7.2, 1 H), 6.05
(d, J ϭ 2, 1 H), 7.29Ϫ7.60 (m, 10 H). 13C NMIR: δ ϭ 14.4 (CH3),
43.3 (CH2), 58.1, 61.8 (CH), 61.9, 75.2 (CH2), 76.8, 90.2, 127.1,
127.7, 128.7, 129.0, 129.6 (CH), 137.8, 141.4, 167.2, 167.9 (Cq). IR:
ν˜ ϭ 3420, 2955, 1680. C22H24NO5Br (462.3): C 57.15, H 5.23, N
3.03; found C 57.13, H 5.37, N 2.87.
1
0.5; CHCl3). H NMR (D2O): δ ϭ 2.08Ϫ2.23 (m, 2 H), 2.92Ϫ3.00
(m, 1 H), 3.07 (t, J ϭ 11.2, 1 H), 3.28 (td, J ϭ 12.0 and 2.0, 1 H),
3.63 (b d, J ϭ 12.5, 1 H), 3.74 (dd, J ϭ 3.5 and 12.2, 1 H), 4.21
(td, J ϭ 11.5 and 6.2, 1 H), 7.43Ϫ7.62 (m, 5 H). 13C NMIR: δ ϭ
29.1, 44.1 (CH2), 48.4 (CH), 48.5 (CH2), 67.9, 127.8, 128.1, 129.4
(2R,4R)-3-(2-Ethoxycarbonyl-1-oxoethyl)-2-[(1R,2R)-2-phenyl-1,2-
epoxyethyl]-4-phenyl-1,3-oxazolidine (45): Compound 44 (1 g,
2.16 mmol) was added to a solution of sodium ethoxide, prepared
from sodium (260 mg, 10.8 mmol) in ethanol (20 mL). The solution
was stirred for 15 min and quenched by addition of a saturated
aqueous solution of NH4Cl. The ethanol was then distilled off.
Addition of water and dichloromethane followed by the usual
workup gave epoxide 45 as a solid (820 mg, quant. yield). Rf ϭ
0.58 (EtOAc/PE, 1:1); m.p. 72 °C; [α]2D0 ϭ ϩ11.7 (c ϭ 1.1; CHCl3).
1H NMR (two rotamers, in a 82:18 ratio): δ ϭ 1.35 and 1.40 (2 t,
J ϭ 7, 3 H), 3.38 (d, J ϭ 15.7, 0.82 H), 3.51 (d, J ϭ 15.7, 1 H),
3.45 (t, J ϭ 1.5, 0.82 H), 3.85Ϫ4.05 (m, 0.36 H), 4.25 (d, J ϭ 1.7,
˜
(CH), 141.1 (Cq). IR: ν ϭ 2923, 1459, 1376. C10H15NO·HCl·H2O
(231.7): calcd. C 57.02, H 7.83, N 6.04; found C 57.01, H 7.36,
N 5.97.
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Received March 20, 2001
[O01138]
38
Eur. J. Org. Chem. 2002, 29Ϫ38