S(N)2' regio and stereoselective alkylation of allylic and propargylic mesylates linked to a N-Boc oxazolidine using organocuprates

Article abstract of DOI:10.1016/S0040-4020(99)00949-7

N-Boc-oxazolidines derived from (R)-phenylglycinol and bearing a stereodefined propargylic or allylic alcohol side chain were transformed into the corresponding mesylates. Alkylation of these allylic mesylates by means of organocuprate reagents effected a regio and stereoselective 1,3-transfer of chirality. Similarly, alkylation of the propargylic mesylate gave a chiral allenyl oxazolidine. The N-Boc-2-alkenyl oxazolidines resulting from an anti S(N)2' addition underwent an intramolecular bromocarbamoylation with a high level of stereocontrol upon treatment with NBS. After reaction with sodium alkoxide, the resulting cyclic urethanes gave the corresponding epoxy oxazolidines whose reactivity towards organocuprates was studied. The sequence represents an efficient synthesis of enantiopure protected aldehydes bearing three contiguous chiral centers. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)00949-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 367–376
SN20 Regio and Stereoselective Alkylation of Allylic and
Propargylic Mesylates Linked to a N-Boc Oxazolidine
using Organocuprates
*
´ `
Claude Agami, Franc¸ois Couty, Gwilherm Evano and Helene Mathieu
`
´
´
´
Laboratoire de Synthese Asymetrique associe au CNRS, Universite Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France
Received 2 August 1999; accepted 20 October 1999
Abstract—N-Boc-oxazolidines derived from (R)-phenylglycinol and bearing a stereodefined propargylic or allylic alcohol side chain were
transformed into the corresponding mesylates. Alkylation of these allylic mesylates by means of organocuprate reagents effected a regio and
stereoselective 1,3-transfer of chirality. Similarly, alkylation of the propargylic mesylate gave a chiral allenyl oxazolidine. The N-Boc-2-
alkenyl oxazolidines resulting from an anti SN20 addition underwent an intramolecular bromocarbamoylation with a high level of stereo-
control upon treatment with NBS. After reaction with sodium alkoxide, the resulting cyclic urethanes gave the corresponding epoxy
oxazolidines whose reactivity towards organocuprates was studied. The sequence represents an efficient synthesis of enantiopure protected
aldehydes bearing three contiguous chiral centers. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
1,3-Oxazolidines 3 are easily prepared by condensation of
an aldehyde with a chiral b-amino alcohol 1. These hetero-
cycles can be considered as a chiral protected form of the
starting aldehyde 2, and when R4 is a prostereogenic group,
its diastereoselective transformation, followed by hydroly-
sis eventually produces optically enriched aldehydes
(Scheme 1).
These could be transformed into two enantiomerically
pure 1,2-diols by using a straightforward procedure
(Scheme 2).2 Furthermore, subsequent manipulation of
these compounds allowed the asymmetric synthesis of
piperidinic amino acids3 or alkaloids.4 On the other hand,
when R4 was an olefin, it underwent an efficient epoxidation
via a two-step sequence involving treatment with N-bromo-
succinimide followed by a sodium alkoxide-mediated
cleavage of the resulting cyclic urethane 7. The resulting
epoxy oxazolidines 8 turned out to be very valuable
synthons, as shown by their conversion into pheromones,5
or into the anti isomer of the Taxol side chain.6
Numerous applications of this strategy have been
published.1 Still the method relies upon an efficient stereo-
control during the first step, namely the formation of the C-2
stereocenter of the oxazolidine ring. We had previously
shown that this new stereogenic center could be controlled
efficiently to give diastereoisomerically pure N-Boc-cis-2,4
oxazolidines 3 (R3ˆCO2t-Bu). In the same context, our
group recently developed two sets of diasteroselective trans-
formations. On the one hand, diastereoisomerically pure
a-hydroxy oxazolidines 5, could be obtained from the
reduction (or organometallic addition) of compound 4.
In order to extend the scope of these methodologies, we
have combined them through an efficient 1,3-transfer of
chirality7 starting from an allylic alcohol such as 9, the latter
being synthesized through the diastereoselective reduction
of an acyl oxazolidine. This transfer of chirality gives rise to
an N-Boc-2-alkenyl oxazolidine 10, which in turn, can be
Scheme 1.
Keywords: oxazolidine; asymmetric synthesis; organocuprates; epoxidation.
* Corresponding author. Tel.: ϩ1-44-27-30-13; fax:ϩ33-1-44-27-26-20; e-mail: couty@ccr.jussieu.fr
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00949-7

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C. Agami et al. / Tetrahedron 56 (2000) 367–376
Scheme 2.
Scheme 3.
stereoselectively epoxidized, thus allowing the control of
three contiguous stereogenic centers on the protected
aldehyde 11 (Scheme 3).
with lithium acetylides 13–16 gave the desired 2-acyl
oxazolidines 17–20 with yields ranging from 75 to 90%.4
A reverse quench into a phosphate buffer was crucial to
obtain good yields.8 Reduction of these ynones by zinc
borohydride in ether at Ϫ30ЊC gave carbinols 21–24 (de
Ͼ95%).9 These high selectivities can be rationalized by a
model involving coordination of the metal cation with both
oxygen atoms of the carbonyl and carbamate groups.
Stereoselective reduction of these carbinols using Red-Al
gave E allylic alcohols 25–27, whereas hydrogenation in the
presence of Lindlar’s catalyst gave the Z isomers 28 and 29.
Alcohols 25–28 were then quantitatively converted into the
corresponding mesylates 30–32. The mesylate derived from
alcohol 27 proved to be unstable at room temperature (RT)
and could not be isolated. On the other hand, carbinol 24
could be converted into a stable mesyloxy derivative 33
This article describes: (i) the stereocontrolled synthesis of
the required allylic alcohols 9, (ii) a 1,3-transfer of chirality
effected on the sulfonated allylic alcohols using organo-
copper reagents, (iii) the diastereoselective epoxidation of
the resulting alkenyl oxazolidines, and (iv) a brief examina-
tion of the reactivity of the resulting epoxides.
Synthesis of the a-hydroxy b-alkenyl oxazolidines
Allylic alcohols 25–29 linked to an N-Boc oxazolidine were
synthesized as follows. Reaction of the Weinreb amide 12
Scheme 4.

C. Agami et al. / Tetrahedron 56 (2000) 367–376
369
Table 1.
Entry
1
Substrate
Conditions
Yield (%)a
30
Product
30
Me2Cu(CN)(ZnCl)2,
THF
2
3
30
30
Me2CuLi,
THF
79
61
34
Bu2Cu(CN)(ZnCl)2,
THF
4
5
30
31
Bu2CuLi,
THF
0b
35
Me2CuLi,
THF
78
6
7
32
33
Me2CuLi,
THF
72
80
Me2CuLi,
THF
a Yield of isolated product.
1
b No product 35 could be detected in H NMR spectum of the crude material.
Scheme 5.
(Scheme 4: Reagents and conditions: a. LiuCH2OTBS
(13), LiuCH2OBn (14), LiuPh (15) or LiuC6H13 (16),
THF, Ϫ78ЊC to RT, 77% (17), 75% (18), 80% (19),
quant. crude yield (20). b. Zn(BH4)2, Et2O, Ϫ30ЊC, 95%
(21), 94% (22), 95% (23), 62% (24). c. Red-Al, THF, RT;
85% (25), 80% (26), 75% (27). d. H2, Lindlar’s catalyst,
EtOH, 90% (28), 80% (29). e. MsCl, Et3N, CH2Cl2, quant.
crude yields).
and various experimental conditions have been described
in order to improve the regioselectivity10d and/or the chemi-
cal yield,10f which is often low due to a competing reductive
elimination. Experiments effected on oxazolidine 30–33 are
listed in Table 1. Yamamoto’s procedure which uses a
higher order zinc cuprate reagent was unsatisfactory when
it came to introducing a methyl group (entry 1), and simple
Gilman’s cuprates proved to be more reactive (entries 2 and
5–7). A butyl group was however successfully introduced
using Yamamoto’s reagent (compare entries 3 and 4).
Having in hand the required mesylates, we next studied their
alkylation using organocuprates.
The anti stereochemical outcome of this reaction was
proved by a chemical correlation with known alkenol
39.12 With this objective, diastereomeric oxazolidines 36
and 37 were treated with trifluoroacetic acid in order to
effect N-Boc deprotection. The corresponding enantiomeric
aldehydes were then released by hydrolysis and reduced
Action of organocuprate reagents
The anti SN20 displacement of allylic10 or propargylic11
sulfonates by organocuprates is a well-known procedure

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C. Agami et al. / Tetrahedron 56 (2000) 367–376
Table 2.
with sodium borohydride. These reactions finally led to
alkenols 39 and ent-39 whose configurations were deduced
from their optical rotation.The SN20 substitution has there-
fore occurred with an anti stereochemical course (Scheme 5:
Reagents and conditions: a. (i) CF3CO2H, CH2Cl2, (ii) THF,
H2O, (iii) NaBH4, EtOH, 57% (39), 50% (ent-39)).
Consequently, it is possible to choose the nature of the
protecting carbamate on the epoxy oxazolidine (Table 2).13
Unexpectedly, aldehyde 47 resulted from the bromo-
carbamation of the allenyl oxazolidine 38. This compound
is produced by a nucleophilic opening of the intermediate
bromonium ion 46 by the oxygen atom14 of the oxazolidine
ring. Ring fragmentation followed by hydrolysis of the
intermediate acyliminium ion then led to the diastereo-
isomerically pure enal 47 (Scheme 6).
Epoxidation of the N-Boc alkenyl oxazolidines
The previously described6 two-step epoxidation was next
applied to alkenyl oxazolidines 34, 36 and 37. Treatment
of these alkenyl oxazolidines with N-bromosuccinimide in a
DME/water mixture provoked a regio and stereoselective
intramolecular bromocarbamation and led to bicyclic
urethanes 40–42. From a mechanistical point of view, it
should be noted that whereas bromocarbamation of 34 and
36 was complete after 10 min at RT, the reaction involving
37 was more sluggish and required 2 h to reach completion.
This shows that reactivity is affected by the absolute config-
uration of the stereocenter a to the alkenyl moiety.
However, high stereoselectivity was always observed,
Finally, epoxy oxazolidines 44 and 45 were reacted with
Me2CuLi in order to obtain a nucleophilic opening of their
epoxide moieties (Scheme 7). Substrate 44 led to hydroxy
oxazolidine 48 in an acceptable yield but, in the case of
substrate 45, both regioisomeric oxazolidines 49 and 50
were produced in low yield. High regioselectivity as
observed in the first case has already been reported5,6in
similar substrates devoid of an extra stereogenic center a
to the epoxide.
The above difference of reactivity between compounds
44 and 45 can be rationalized by considering a chelation
of the metal cation by the oxygen atom of the epoxide
and of the benzylic ether (Fig. 1). Due to this chelation,
the SN2 approach is hindered by the methyl group in
substrate 45, thus lowering both its reactivity and
regioselectivity.
1
since no minor stereoisomer was ever detected in the H
NMR spectra of the crude products. Reaction of these bicyc-
lic carbamates with sodium ethoxide in ethanol (compounds
41, 42) or with sodium phenylmethoxide in DMF
(compound 40) cleanly opened the urethane to give
diastereoisomerically pure epoxy oxazolidines 43–45.
Scheme 6.

C. Agami et al. / Tetrahedron 56 (2000) 367–376
371
Scheme 7.
(25 mL). The reaction medium was slowly warmed to ca.
Ϫ10ЊC (2 h). At this time, the reaction was quenched by
pouring it with vigorous stirring into a biphasic layer
made of 10 wt.% aqueous KH2PO4 (140 mL) and ether
(140 mL), precooled at 0ЊC. Usual workup, followed by
flash chromatography gave the following ynones.
(2R,4R)-3-tert-Butoxycarbonyl-2-(4-tert-butyldimethyl-
silyloxy-but-2-ynoil)-4-phenyl-1,3-oxazolidine 17. This
compound was obtained as an oil (77%). Rf: 0.4 (E/EP:
20/80); IR (film): 1805, 1680; [a]d20: ϩ10 (c 1.2, CHCl3);
1H NMR: Ϫ0.05 (bs, 6H), 0.78 (bs, 9H), 1.04 and 1.14 (two
bs, 9H), 3.90–3.95 (bm, 1H), 4.27–4.40 (bm, 3H), 4.70–
4.78 (bm, 1H), 5.40 (s, 1H), 7.11–7.24 (m, 3H), 7.40 (dd,
Jˆ8.3 and 1.7, 2H); 13C NMR: Ϫ5.0 (CH3), 18.1 (Cq), 25.6
(CH3), 27.9 (CH3), 51.5 (CH2), 60.7 (CH), 74.9 (CH2), 81.4
(Cq), 82.2 (Cq), 90.4 (Cq), 92.8 (CH), 126.8 (CH), 127.6
(CH), 128.4 (CH), 138.6 (Cq), 153.0 (Cq), 182.2 (Cq). Anal.
Calcd for C24H35NSiO5: C, 64.69; H, 7.92; N 3.15. Found:
C, 64.80; H, 7.89; N, 3.08.
Figure 1.
In conclusion, this efficient 1,3-transfer of chirality invol-
ving organocopper reagents considerably enhances the
usefulness of N-Boc-2-acyl oxazolidines in asymmetric
synthesis. Explorations of other 1,3-transfers of chirality
starting from enantiopure allylic alcohols linked to an
oxazolidine ring are underway in our group.
Experimental
General comments
(2R,4R)-3-tert-Butoxycarbonyl-2-(4-benzyloxy-but-2-
ynoil)-4-phenyl-1,3-oxazolidine 18. This compound was
obtained as an oil (75%). Rf: 0.55 (E/EP: 40/60); IR
1H and 13C spectra (CDCl3 solution unless otherwise stated)
were respectively recorded on a Bruker ARX 250 spectro-
meter at 250 and 62.9 MHz; chemical shifts are reported in
ppm from TMS. Optical rotations were determined with a
Perkin–Elmer 141 instrument. All reactions were carried
out under argon. Column chromatography was performed
on silica gel, 230–400 mesh by using various mixtures of
diethyl ether (E) and petroleum ether (EP). TLC was 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, and (iv) solvent evaporation
under reduced pressure. Composition of stereoisomeric
mixtures was determined by NMR analysis on crude
products before any purification.
1
(film): 1805, 1680; [a]d20: ϩ3.1 (c 1.2, CHCl3); H NMR:
1.3 (bs, 9H), 3.87–4.02 (bm, 1H), 4.22 (s, 2H), 4.38 (dd,
Jˆ7.1 and 8.9, 1H), 4.49 (s, 2H), 4.75–4.84 (bm, 1H), 5.44
(bs, 1H), 7.15–7.45 (m, 10H); 13C NMR 29.4 (CH3), 58.3
(CH2), 63.2 (CH), 71.2 (CH2), 73.4 (CH2), 81.0 (Cq), 81.2
(Cq), 81.6 (Cq), 91.9 (CH), 128.2 (CH), 128.3 (CH), 129.2
(CH), 129.5 (CH), 129.9 (CH), 137.9 (Cq), 140.1 (Cq),
153.4 (Cq), 183.7 (Cq).
(2R,4R)-3-tert-Butoxycarbonyl-2-(3-phenyl-prop-2-
ynoil)-4-phenyl-1,3-oxazolidine 19. This compound was
obtained as a pale yellow solid (80%). Rf: 0.6 (E/EP:
50/50); IR (CHCl3): 1805, 1670; [a]d20: ϩ5.3 (c 1, CHCl3);
1H NMR: 1.22 (bs, 9H), 4.02 (t, Jˆ7.2, 1H), 4.36 (dd, Jˆ7.2
and 8.7, 1H), 4.84 (bs, 1H), 5.50 (bs, 1H), 7.15–7.25 (m,
6H), 7.34–7.42 (m, 4H, Ph); 13C NMR: 28.0 (CH3), 60.7
(CH), 75.1 (CH2), 81.5 (Cq), 86.5 (Cq), 90.6 (CH), 95.3
(Cq), 119.7 (Cq), 126.9 (CH), 127.6 (CH), 128.4 (CH),
128.5 (CH), 129.7 (CH), 131.1 (CH), 133.2 (Cq), 138.9
(Cq), 153.1 (Cq), 182.3 (Cq).
General procedure for the syntheses of ynones 17–20
To a solution of the required alkyne (27 mmol) in THF
(50 mL) cooled to Ϫ78ЊC, was added dropwise n-butyl-
lithium (1.6N solution in hexanes, 14.5 mL, 23 mmol).
The solution was allowed to reach 0ЊC within 1 h and was
cooled again at Ϫ78ЊC. To this solution was added dropwise
a solution of Weinreb amide 12 (6 g, 17.8 mmol) in THF
(2R,4R)-3-tert-Butoxycarbonyl-2-(non-2-ynoil)-4-phenyl-
1,3-oxazolidine 20. This compound was obtained as an oil
(quantitative crude yield). Rf: 0.6 (E/EP: 40/60); IR (film):
1
1805, 1680; [a]d20: ϩ8.3 (c 0.52, CHCl3); H NMR: 0.78 (t,

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C. Agami et al. / Tetrahedron 56 (2000) 367–376
Jˆ6.8, 3H), 1.25 (bs, 9H), 1.2–1.55 (m, 8H), 2.24 (bt,
Jˆ6.9, 2H), 3.80–3.95 (bm, 1H), 4.30 (dd, Jˆ7.2 and 8.9,
1H), 4.78 (bs, 1H), 5.40 (bs, 1H), 7.10–7.22 (m, 4H), 7.37
(dd, Jˆ8.1 and 1.2, 2H); 13C NMR: 14.4 (CH3), 19.2 (CH2),
22.6 (CH2), 27.5 (CH2), 28.1 (CH3), 28.6 (CH2), 31.2 (CH2),
60.8 (CH), 75.2 (CH2), 79.5 (Cq), 81.4 (Cq), 90.8 (CH), 99.5
(Cq), 127.1 (CH), 127.7 (CH), 128.5 (CH), 139.1 (Cq),
153.2 (Cq), 182.9 (Cq).
[2R,2(1S),4R]-3-tert-Butoxycarbonyl-2-(1-hydroxy-non-
2-ynyl)-4-phenyl-1,3-oxazolidine 24. Overall yield from
12 62%; mp 73ЊC; Rf: 0.7 (E/EP: 60/40); IR (CHCl3):
1
3150, 2110, 1680; [a]d20: ϩ8.3 (c 1.1, CHCl3); H NMR:
0.75 (t, Jˆ6.8, 3H), 1.16 (bs, 9H), 1.05–1.30 (m, 8H), 2.04
(bt, Jˆ6.9, 2H), 4.08 (dd, Jˆ6 and 8.9, 1H), 4.19 (bt, Jˆ8.6,
1H), 4.64–4.75 (bm, 1H), 5.15 (d, Jˆ1.5, 1H), 7.10–7.22
(m, 3H), 7.38 (dd, Jˆ6.9 and 1, 2H); 13C NMR: 14.4 (CH3),
19.3 (CH2), 22.9 (CH2), 28.4 (CH3), 28.8 (CH2), 29.0 (CH2),
31.7 (CH2), 61.5 (CH), 65.0 (CH), 74.5 (CH2), 82.0 (Cq),
87.8 (Cq), 92.8 (CH), 127.3 (CH), 127.9 (CH), 128.6 (CH),
140.5 (Cq), 154.3 (Cq).
General procedure for the reduction of ynones 17–20 by
zinc borohydride
To a solution of ynone (2.13 mmol) in ether (30 mL) was
added dropwise at Ϫ30ЊC a solution of freshly prepared zinc
borohydride in ether (0.5 M solution, 8.6 mL, 4.3 mmol).
The mixture was warmed to 0ЊC and stirred for 1 h at this
temperature. Hydrolysis by dropwise addition of a saturated
aqueous solution of NH4Cl (20 mL) was followed by usual
workup to give carbinols 21–23 as solids that were washed
with small portions of cold petroleum ether and used with-
out further purification in the following steps. Analytical
samples were purified by flash chromatography. Carbinol
24 was obtained as an oil and was purified by flash chroma-
tography (E/EP: 40/60). It then crystallized on standing.
General procedure for the Red-Al-mediated reduction of
carbinols 21–23
To a solution of carbinol (5 mmol) in THF (35 mL), was
added dropwise at RT a solution of Red-Al in toluene
(3.5 M solution, 2.25 mL, 7.9 mmol). Completion of the
reduction was ascertained by TLC and required ca. 0.5 h.
The mixture was then hydrolyzed by dropwise addition of a
saturated aqueous solution of NH4Cl (10 mL). Addition of
water and ether, followed by usual workup gave (E)-allylic
alcohols 25–27 as oils that were further purified by flash
chromatography.
[2R,2(1S),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyldi-
methylsilyloxy-1-hydroxy-but-2-ynyl)-4-phenyl-1,3-
oxazolidine 21. Yield 95%; mp 121ЊC; Rf: 0.6 (E/EP:
70/30); IR (CHCl3): 3200, 2200, 1678; [a]d20: ϩ7 (c 0.8,
[2R,2(1S,2E),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyl-
dimethylsilyloxy-1-hydroxy-but-2-enyl)-4-phenyl-1,3-
oxazolidine 25. Yield 85%. Oil. Rf: 0.55 (E/EP: 70/30); IR
1
CHCl3); H NMR: 0.01 (s, 6H), 0.79 (s, 9H), 1.18 (bs,
1
(CHCl3): 3400, 1620, 1690; [a]d20: Ϫ21 (c 0.9, CHCl3); H
9H), 4.10 (dd, Jˆ6 and 8.5, 1H), 4.18–4.22 (m, 3H), 4.7–
4.80 (bm, 3H), 5.18 (d, Jˆ1.1, 1H), 7.15–7.25 (m, 3H), 7.40
(d, Jˆ7.8, 2H); 13C NMR: Ϫ5.2 (CH3), 18.1 (Cq), 25.7
(CH3), 28.0 (CH3), 51.7 (CH2), 60.9 (CH), 64.5 (CH),
74.2 (CH2), 81.6 (Cq), 82.5 (Cq), 85.0 (Cq), 92.0 (CH),
126.8 (CH), 127.4 (CH), 128.2 (CH), 139.8 (Cq), 154.6
(Cq). Anal. Calcd for C24H37NSiO5: C, 64.39; H, 8.34; N
3.13. Found: C, 63.90; H, 8.28; N, 3.00.
NMR: 0.01 (s, 6H), 0.76 (s, 9H), 1.18 (bs, 9H), 3.85 (bs,
1H), 4.00 (dd, Jˆ5.4 and 8.5, 1H), 4.15 (d, Jˆ3.8, 2H), 4.21
(t, Jˆ7.8, 1H), 4.42 (bm, 1H), 4.82 (bm, 1H), 5.15 (d,
Jˆ2.9, 1H), 5.74 (dd, Jˆ5.4 and 15.7, 1H), 5.86 (dt,
Jˆ3.9 and 15.7, 1H) 7.15–7.25 (m, 3H), 7.29 (d, Jˆ7.8,
2H); 13C NMR: Ϫ5.2 (CH3), 18.1 (Cq), 25.7 (CH3), 28.0
(CH3), 60.5 (CH), 63.1 (CH2), 72.5 (CH), 73.5 (CH2), 81.1
(Cq), 92.6 (CH), 126.5 (CH), 127.3 (CH), 127.6 (CH), 128.2
(CH), 132.2 (CH), 139.8 (Cq), 154.6 (Cq). Anal. Calcd for
C24H39NSiO5: C, 64.11; H, 8.74; N 3.11. Found: C, 64.09;
H, 8.78; N, 3.01.
[2R,2(1S),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-1-
hydroxy-but-2-ynyl)-4-phenyl-1,3-oxazolidine 22. Yield
94%; mp 93ЊC; Rf: 0.55 (E/EP: 60/40); IR (CHCl3): 3200,
1
2200, 1680; [a]d20: ϩ4.2 (c 0.6, CHCl3); H NMR:1.21 (bs,
[2R,2(1S,2E),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
1-hydroxy-but-2-enyl)-4-phenyl-1,3-oxazolidine 26. Yield
80%. Oil. Rf: 0.59 (E/EP: 70/30); IR (CHCl3): 3410, 1622,
1692; [a]d20: Ϫ26.3 (c 0.52, CHCl3); 1H NMR: 1.24 (bs, 9H),
3.8–4.0 (bs, 1H), 3.97–4.06 (m, 3H), 4.21 (t, Jˆ7.8, 1H),
4.43 (bs, 3H), 4.42 (bm, 1H), 4.84 (bs, 1H), 5.15 (d, Jˆ2.5,
1H), 5.78 (dd, Jˆ5.4 and 16, 1H), 5.90 (dt, Jˆ5.4 and 16, 1H)
7.15–7.35 (m, 10H); 13C NMR: 27.6 (CH3), 60.1 (CH), 69.1
(CH2), 71.7 (CH2), 72.0 (CH), 72.9 (CH2), 80.9 (Cq), 92.2
(CH), 126.2 (CH), 127.1 (CH), 127.3 (CH), 128.0 (CH),
129.0 (CH), 130.2 (CH), 137.8 (CH), 139.8 (Cq), 154.5 (Cq).
9H), 1.55 (bs, 1H), 4.08 (bs, 2H), 4.13 (dd, Jˆ6 and 8.5,
1H), 4.23 (t, Jˆ8.5, 1H), 4.48 (s, 2H), 4.78–4.90 (bm, 2H),
5.23 (s, 1H), 7.10–7.25 (m, 8H), 7.45 (d, Jˆ7.6, 2H); 13C
NMR: 28.1 (CH3), 57.8 (CH2), 61.2 (CH), 63.1 (CH), 71.5
(CH2), 74.8 (CH2), 82.5 (Cq), 82.0 (Cq), 84.9 (Cq), 85.0
(Cq), 92.5 (CH), 126.7 (CH), 126.8 (CH), 127.6 (CH),
128.2 (CH), 128.6 (CH), 128.8 (CH), 139.8 (Cq), 141.4
(Cq), 154.6 (Cq). Anal. Calcd for C25H29NO5: C, 70.90;
H, 6.90; N 3.31. Found: C, 70.85; H, 6.89; N, 3.30.
[2R,2(1S),4R]-3-tert-Butoxycarbonyl-2-(1-hydroxy-3-
phenyl-prop-2-ynyl)-4-phenyl-1,3-oxazolidine 23. Yield
95%; mp 101ЊC; [a]d20: ϩ19 (c 1.1, CHCl3); 1H NMR:
1.21 (bs, 9H), 4.15 (dd, Jˆ6 and 8.6, 1H), 4.27 (dd, Jˆ7.4
and 8.5, 1H), 4.79 (bs, 1H), 4.93 (bd, Jˆ7.8, 1H), 5.15 (bs,
1H), 5.31 (s, 1H), 7.10–7.44 (m, 10H); 13C NMR: 28.0
(CH3), 61.2 (CH), 63.1 (CH), 65.3 (CH), 74.2 (CH2), 81.9
(Cq), 86.5 (Cq), 87.4 (Cq), 85.0 (Cq), 92.4 (CH), 122.5
(CH), 126.9 (CH), 127.9 (CH), 127.6 (CH), 128.1 (CH),
128.3 (CH), 128.4 (CH), 131.8 (Cq), 139.9 (Cq), 154.7 (Cq).
[2R,2(1S,2E),4R]-3-tert-Butoxycarbonyl-2-(1-hydroxy-3-
phenyl-prop-2-enyl)-4-phenyl-1,3-oxazolidine 27. Yield
75%. Oil. Rf: 0.5 (E/EP: 70/30); IR (CHCl3): 3420, 1620,
1
1690; [a]d20: Ϫ28 (c 0.7, CHCl3); H NMR: 1.18 (bs, 9H),
4.01 (dd, Jˆ4.8 and 8.8, 1H), 4.19 (t, Jˆ7.6, 1H), 4.52 (bs,
1H), 4.82 (bs, 1H), 5.21 (bs, 1H), 6.18 (dd, Jˆ6.1 and 16,
1H), 6.64 (d, Jˆ16, 1H) 7.09–7.25 (m, 10H); 13C NMR:
28.1 (CH3), 60.7 (CH), 73.3 (CH), 73.5 (CH2), 81.6 (Cq),

C. Agami et al. / Tetrahedron 56 (2000) 367–376
373
93.1 (CH), 126.7 (CH), 127.6 (CH), 128.5 (CH), 132.2
(CH), 136.8 (CH), 140.3 (Cq), 154.8 (Cq).
and 15, 1H), 6.18–6.24 (m, 1H), 7.15–7.23 (m, 3H), 7.29 (d,
Jˆ7.8, 2H); 13C NMR: Ϫ5.3 (CH3), 18.3 (Cq), 25.9 (CH3),
28.1 (CH3), 38.8 (CH3), 60.6 (CH), 62.5 (CH2), 72.8 (CH2),
81.2 (CH), 81.5 (Cq), 90.7 (CH), 122.5 (CH), 126.9 (CH),
127.7 (CH), 128.5 (CH), 137.3 (CH), 139.2 (Cq), 154.6
(Cq).
General procedure for the Lindlar-catalyzed
hydrogenation of carbinols 21 and 22
In a solution of carbinol (2.3 mmol) in ethanol (20 mL), was
suspended Lindlar’s catalyst (155 mg, 15 wt. % of palla-
dium). The vessel was flushed with hydrogen, and the
mixture was vigorously stirred for 0.5 h. The mixture was
then filtered over a short pad of Celite, and the catalyst was
washed with ethanol. Evaporation of the solvent gave
Z-allylic alcohols 28 and 29 as oils that were further purified
by flash chromatography.
[2R,2(1S,2E),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
1-methanesulfonyloxy-but-2-enyl)-4-phenyl-1,3-oxazoli-
dine 31. Yield quant. Oil. Rf: 0.59 (E/EP: 70/30); [a]d20:
1
ϩ60.5 (c 0.5, CHCl3); H NMR: 1.23 (bs, 9H), 2.66 (s,
3H), 3.8–4.0 (bs, 1H), 4.01 (d, Jˆ3.7, 2H), 4.09 (dd,
Jˆ6.2 and 9, 1H), 4.26 (t, Jˆ9, 1H), 4.45 (bs, 2H), 4.90
(bs, 1H), 5.20 (d, Jˆ4.5, 1H), 5.90 (dd, Jˆ4.5 and 16, 1H),
6.03 (dt, Jˆ4 and 16, 1H), 7.15–7.35 (m, 10H); 13C NMR:
28.1 (CH3), 39.7 (CH3), 60.6 (CH), 69.2 (CH2), 71.5 (CH2),
73.0 (CH2), 80.8 (CH), 81.6 (Cq), 92.0 (CH), 125.1 (CH),
127.4 (CH), 127.3 (CH), 128.1 (CH), 128.2 (CH), 128.8
(CH), 128.9 (CH), 130.2 (CH), 134.3 (CH), 137.8 (Cq),
139.8 (Cq), 153.8 (Cq).
[2R,2(1S,2Z),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyl-
dimethylsilyloxy-1-hydroxy-but-2-enyl)-4-phenyl-1,3-
oxazolidine 28. Yield 90%. Oil. Rf: 0.53 (E/EP: 70/30); IR
1
(CHCl3): 3400, 1620, 1690; [a]d20: ϩ16 (c 0.7, CHCl3); H
NMR: 0.04 (s, 6H), 0.83 (s, 9H), 1.26 (bs, 9H), 3.62 (bs,
1H), 4.04 (dd, Jˆ5.8 and 8.7, 1H), 4.12–4.21 (m, 2H), 4.31
(dd, Jˆ6 and 13.5, 1H), 4.65 (bd, Jˆ5.7, 1H), 4.80 (bm,
1H), 5.09 (d, Jˆ2.6, 1H), 5.54 (dd, Jˆ5.6 and 5.9, 1H), 5.
63–5.72 (m, 1H) 7.13–7.25 (m, 3H), 7.31–7.35 (m, 2H);
13C NMR: Ϫ5.5 (CH3), 17.9 (Cq), 25.5 (CH3), 27.7 (CH3),
59.5 (CH), 60.4 (CH2), 68.1 (CH), 73.2 (CH2), 80.7 (Cq),
92.4 (CH), 126.5 (CH), 127.1 (CH), 127.9 (CH), 128.2
(CH), 133.1 (CH), 140.0 (Cq), 155.4 (Cq).
[2R,2(1S,2Z),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
1-methanesulfonyloxy-but-2-enyl)-4-phenyl-1,3-oxazoli-
dine 32. Yield quant. Oil. Rf: 0.52 (E/EP: 70/30); [a]d20:
1
ϩ58 (c 0.3, CHCl3); H NMR: 1.23 (bs, 9H), 2.65 (s, 3H),
4.0–4.22 (m, 4H), 4.42 (d, Jˆ2.5, 2H), 4.85 (bs, 1H), 5.12
(d, Jˆ2.8, 1H), 5.70 (bs, 1H), 5.76 (bt, Jˆ7.2, 1H),
5.90–6.01 (m, 1H), 7.15–7.40 (m, 10H); 13C NMR: 28.1
(CH3), 38.6 (CH3), 60.4 (CH), 66.0 (CH2), 72.7 (CH2),
72.8 (CH2), 76.1 (CH), 81.3 (Cq), 90.4 (CH), 125.2 (CH),
127.0 (CH), 128.8 (CH), 128.0 (CH), 128.8 (CH), 128.3
(CH), 128.4 (CH), 133.0 (CH), 137.8 (Cq), 139.2 (Cq),
153.5 (Cq).
[2R,2(1S,2Z),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
1-hydroxy-but-2-enyl)-4-phenyl-1,3-oxazolidine 29. Yield
80%. Oil. Rf: 0.55 (E/EP: 70/30); IR (CHCl3): 3405, 1622,
1
1695; [a]d20: ϩ24 (c 0.54, CHCl3); H NMR: 1.24 (bs, 9H),
3.8–4.0 (bs, 1H), 3.9–4.18 (m, 3H), 4.18 (t, Jˆ7.9, 1H), 4.43
(bs, 2H), 4.62 (bs, 1H), 4.84 (bs, 1H), 5.10 (bd, Jˆ2.5, 1H),
5.60–5.82 (m, 2H) 7.15–7.30 (m, 10H); 13C NMR: 28.1
(CH3), 60.6 (CH), 66.2 (CH2), 68.4 (CH2), 72.3 (CH), 73.3
(CH2), 81.4 (Cq), 92.7 (CH), 126.8 (CH), 127.1 (CH), 127.3
(CH), 127.9 (CH), 129.1 (CH), 130.1 (CH), 130.2 (CH),
138.1 (CH), 140.2 (Cq), 154.4 (Cq). Anal. Calcd for
C25H31NO5: C, 70.56; H, 7.34; N 3.29. Found: C, 69.61; H,
7.53; N, 3.15.
[2R,2(1S),4R]-3-tert-Butoxycarbonyl-2-(1-methane-
sulfonyloxy-non-2-ynyl)-4-phenyl-1,3-oxazolidine
33.
Yield quant. Oil. Rf: 0.7 (E/EP: 60/40); [a]d20: ϩ15 (c 1.5,
CHCl3); 1H NMR: 0.81 (t, Jˆ6.8, 3H), 1.20–1.51 (bm,
17H), 2.21 (td, Jˆ7.1 and 2.1, 2H), 2.93 (s, 3H), 4.04 (dd,
Jˆ7.5 and 8.7, 1H), 4.31 (dd, Jˆ7.9 and 8.6, 1H), 4.90 (bs,
1H), 5.34 (d, Jˆ2.9, 1H), 5.52 (bs, 1H), 7.10–7.40 (m, 5H);
13C NMR: 14.4 (CH3), 19.3 (CH2), 22.9 (CH2), 28.4 (CH3),
28.5 (CH2), 28.6 (CH2), 31.6 (CH2), 39.4 (CH3), 53.9 (CH),
61.3 (CH), 71.6 (CH), 73.2 (CH2), 74.7 (CH2), 81.9 (Cq),
91.0 (CH), 91.9 (Cq), 127.2 (CH), 128.1 (CH), 128.9 (CH),
139.3 (Cq), 154.1 (Cq).
General procedure for the mesylation of allylic alcohols
25–28 and of carbinol 24
To a solution of the allylic alcohols 25–28 or of carbinol 24
(2.6 mmol) and triethylamine (0.5 mL, 3.5 mmol), in
dichloromethane (30 mL) cooled at 0ЊC was added
methanesulfonyl chloride (0.25 mL, 3.2 mmol). The solu-
tion was stirred at RT for 0.5 h and water was then added.
Usual workup (dichloromethane) gave mesylates 30–33 as
oils that were used without further purification. Mesylate
derived from 27 proved to be unstable and could not be
isolated.
General procedure for the organocuprate alkylation of
mesylates 30–32 with Me2CuLi
To a suspension of copper iodide (1.56 g, 8.22 mmol) in
THF (25 mL) was added dropwise at Ϫ78ЊC a solution of
methyllithium (1.4N solution in ether, 9.4 mL, 13.2 mmol).
The solution was allowed to reach Ϫ20ЊC and was then
cooled again to Ϫ78ЊC. To this solution was added the
required mesylate (3.3 mmol) in THF (10 mL). The mixture
was stirred at ca. Ϫ60ЊC for 1 h and hydrolyzed by addition
of a saturated aqueous solution of NH4Cl (10 mL) and
ammonia (30% aqueous solution, 3 mL). Addition of
water and ether was followed by usual workup. Crude
alkenyl oxazolidines were then purified by flash chromato-
graphy and were obtained as oils.
[2R,2(1S,2E),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyl-
dimethylsilyloxy-1-methanesulfonyloxy-but-2-enyl)-4-
phenyl-1,3-oxazolidine 30. Yield 98%. Oil. Rf: 0.55 (E/EP:
1
70/30); [a]d20: ϩ75 (c 0.6, CHCl3); H NMR: 0.01 (s, 6H),
0.84 (s, 9H), 1.14 (bs, 9H), 2.70 (s, 3H), 4.10 (dd, Jˆ6.4 and
8.9, 1H), 4.17 (bs, 2H), 4.27 (dd, Jˆ7.3 and 8.9, 1H), 4.87
(bs, 1H), 5.20 (d, Jˆ3.7, 1H), 5.35 (bs, 1H), 5.90 (dd, Jˆ7.8

374
C. Agami et al. / Tetrahedron 56 (2000) 367–376
[2R,2(1E,3S),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyl-
dimethylsilyloxy-3-methyl-but-1-enyl)-4-phenyl-1,3-
oxazolidine 34. Yield 79%. Oil. Rf: 0.5 (E/EP: 20/50); IR
Yield 61%.Rf: 0.35 (E/EP: 20/80); IR (CHCl3): 2980, 1730;
1
[a]d20 Ϫ3.7 (c 0.65, CHCl3); H NMR: 0.35 (s, 6H), 1.04–
1.15 (m, 12H), 1.40–1.91 (m, 15H), 2.4–2.6 (m, 1H), 3.77
(dd, Jˆ6.4 and 9.8, 1H), 3.85 (dd, Jˆ6.4 and 9.8, 1H), 4.25
(dd, Jˆ5.6 and 8.7, 1H), 4.55 (dd, Jˆ6.9 and 8.7, 1H), 5.05–
5.30 (bm, 1H), 5.82–5.92 (m, 2H), 6.03 (dd, Jˆ8 and 15.7,
1H), 7.50–7.70 (m, 5H); 13C NMR: Ϫ5.6 (CH3), 14.1
(CH3), 18.4 (Cq), 23.4 (CH2), 26.5 (CH2), 28.8 (CH3),
29.3 (CH2), 30.7 (CH2), 45.1 (CH), 60.6 (CH), 66.4
(CH2), 73.2 (CH2), 80.4 (Cq), 90.1 (CH), 126.5 (CH),
127.4 (CH), 128.1 (CH), 128.3 (CH), 136.6 (CH), 140.6
(Cq), 153.5 (Cq). Anal. Calcd for C28H47NSiO4: C, 68.52;
H, 9.65; N 2.85. Found: C, 68.60; H, 9.83; N, 2.78.
1
(CHCl3): 2980, 1730; [a]d20: Ϫ19 (c 0.7, CHCl3); H NMR:
Ϫ0.02 (s, 6H), 0.83 (s, 9H), 0.99 (d, Jˆ6.7, 3H), 1.30 (bs,
9H), 2.32–2.38 (m, 1H), 3.36 (dd, Jˆ7.1 and 9.7, 1H), 3.51
(dd, Jˆ5.8 and 9.7, 1H), 3.91 (dd, Jˆ5.2 and 8.7, 1H), 4.20
(dd, Jˆ6.8 and 8.7, 1H) 4.86 (bs, 1H), 5.54 (bs, 1H), 5.59
(dd, Jˆ5.8 and 14.7, 1H), 5.81 (dd, Jˆ7.1 and 14.7, 1H),
7.19–7.30 (m, 5H); 13C NMR: Ϫ5.3 (CH3), 16.5 (CH3), 18.3
(Cq), 25.9 (CH3), 28.3 (CH3), 38.9 (CH3), 60.5 (CH), 67.6
(CH2), 73.1 (CH), 80.4 (Cq), 90.1 (CH), 126.6 (CH), 127.1
(CH), 127.3 (CH), 128.4 (CH), 137.8 (CH), 140.8 (Cq),
153.4 (Cq). Anal. Calcd for C25H41NSiO4: C, 67.07; H,
9.23; N 3.13. Found: C, 67.01; H, 9.40; N, 3.16.
[2R,2(2R),4R]-3-tert-Butoxycarbonyl-2-(3-methylnona-
1,2-dienyl)-4-phenyl-1,3-oxazolidine 38. To a solution of
copper bromide (430 mg, 3 mmol) and lithium bromide
(260 mg, 3 mmol) in THF (15 mL) cooled at Ϫ78ЊC, was
added dropwise a solution of methylmagnesium bromide in
ether (3N solution, 1 mL, 3 mmol). The mixture was
warmed to Ϫ20ЊC within 0.5 h and cooled again at
Ϫ78ЊC. To this solution was then added mesylate 33
(700 mg, 1.5 mmol) in THF (5 mL). The mixture was
allowed to slowly reach 0ЊC (1 h) and then quenched by
addition of a saturated aqueous solution of NH4Cl
(10 mL) and ammonia (30% aqueous solution, 3 mL). Addi-
tion of water and ether was followed by usual workup.
Crude allenyl oxazolidine was then purified by flash chro-
matography (E/EP: 20/80) and was obtained as an oil
(463 mg: 80%). Rf: 0.70 (E/EP: 40/60); IR (CHCl3): 2925,
[2R,2(1E,3S),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
3-methyl-but-1-enyl)-4-phenyl-1,3-oxazolidine 36. Yield
78%. Oil. Rf: 0.3 (E/EP: 20/80); IR (CHCl3): 2980, 1730;
[a]d20: Ϫ15.3 (c 1.1, CHCl3); 1H NMR: 1.02 (d, Jˆ6.8, 3H),
1.27 (bs, 9H), 2.52 (hept, Jˆ6.7, 1H), 3.25–35 (ABX, 2H),
3.90 (dd, Jˆ5.2 and 8.7, 1H), 4.18 (dd, Jˆ6.8 and 8.7, 1H),
4.43 (s, 2H), 4.85 (bs, 1H), 5.54 (bs, 1H), 5.57 (dd, Jˆ15
and 5, 1H), 5.82 (dd, Jˆ15 and 7, 1H), 7.15–7.28 (m, 10H);
13C NMR: 17.4 (CH3), 28.8 (CH3), 37.0 (CH), 61.0 (CH),
73.5 (CH2), 73.6 (CH2), 75.3 (CH2), 80.9 (Cq), 90.4 (CH),
127.1 (CH), 127.5 (CH), 127.9 (CH), 128.0 (CH), 128.1
(CH), 128.9 (CH), 138.1 (CH), 139.0 (Cq), 141.3 (Cq),
153.9 (Cq). Anal. Calcd for C26H33NO4: C, 73.73; H,
7.85; N 3.31. Found: C, 73.58; H, 7.88; N, 3.32.
1
1997, 1703, 1370; [a]d20: Ϫ8.5 (c 1, CHCl3); H NMR: 0.80
[2R,2(1E,3R),4R]-3-tert-Butoxycarbonyl-2-(4-benzyloxy-
3-methyl-but-1-enyl)-4-phenyl-1,3-oxazolidine 37. Yield
72%. Oil. Rf: 0.3 (E/EP: 20/80); IR (CHCl3): 2980, 1730;
[a]d20: Ϫ18.6 (c 1.2, CHCl3); 1H NMR: 1.05 (d, Jˆ6.8, 3H),
1.28 (bs, 9H), 2.55 (hept, Jˆ6.7, 1H), 3.60–3.75 (ABX,
2H), 3.93 (dd, Jˆ5.2 and 8.7, 1H), 4.21 (dd, Jˆ6.0 and
8.7, 1H), 4.35 (s, 2H), 4.76 (bs, 1H), 5.46 (bs, 1H), 5.50
(dd, Jˆ15 and 5, 1H), 5.76 (dd, Jˆ15 and 7, 1H), 7.15–7.30
(m, 10H); 13C NMR: 17.0 (CH3), 28.7 (CH3), 36.5 (CH),
60.6 (CH), 73.1 (CH2), 73.2 (CH2), 75.0 (CH2), 80.4 (Cq),
90.1 (CH), 126.4 (CH), 127.0 (CH), 127.4 (CH), 127.5
(CH), 128.5 (CH), 128.6 (CH), 138.1 (CH), 138.9 (Cq),
141.2 (Cq), 153.9 (Cq).
(t, Jˆ6.9, 3H), 1.20–1.70 (m, 17H), 1.65 (d, Jˆ 2.8, 3H),
1.9–2.0 (m, 2H), 3.87 (dd, Jˆ6.7 and 8.8, 1H), 4.22 (dd,
Jˆ6.9 and 8.8, 1H), 4.81 (bs, 1H), 5.19–5.23 (bm, 1H), 5.64
(bd, Jˆ5, 1H), 7.10–7.40 (m, 5H); 13C NMR: 14.5 (CH3),
19.3 (CH3), 23.0 (CH2), 27.8 (CH2), 28.6 (CH3), 29.4 (CH2),
32.1 (CH2), 34.3 (CH2), 61.1 (CH), 73.5 (CH2), 80.7 (Cq),
88.8 (CH), 90.9 (CH), 103.6 (Cq), 126.9 (CH), 128.8 (CH),
140.7 (Cq), 153.8 (Cq), 202.3 (Cq). Anal. Calcd for
C24H35NO3: C, 74.76; H, 9.15; N 3.63. Found: C, 74.94;
H, 9.28; N, 3.72.
(4S) and (4R) 5-Benzyloxy-4-methyl-pent-2-enol 39 and
ent-39. To a solution of 36 or 37 (0.7 mmol) in dichloro-
ethane (5 mL) was added at rt trifluoroacetic acid (1 mL).
The solution was stirred for 0.5 h and concentrated under
reduced pressure. The crude deprotected oxazolidine was
then taken up in THF (4 mL) and water (4 mL) and stirred
for 1 h. Usual workup gave an oil that was dissolved in
EtOH (10 mL) and sodium borohydride (54 mg,
1.4 mmol) was added portionwise at 0ЊC. After 0.5 h, the
mixture was hydrolyzed by addition of a saturated aqueous
solution of NH4Cl (5 mL), and the ethanol was evaporated
under reduced pressure. Addition of water and ether,
followed by usual work up and flash chromatography
(E/EP: 50/50) gave title alkenols as oils. 39: 83 mg, 57%.
Rf: 0.2 (E/EP: 50/50); [a]d20: Ϫ9.3 (c 2.25, CHCl3); GC
(OV17, 60 to 220ЊC, rate: 10ЊC/mn): tr 11.3 mn (98%);
1H NMR: 0.95 (d, Jˆ6.8, 3H), 1.90 (bs, 1H), 2.42 (hept,
Jˆ6.5, 1H), 3.22 (dd, Jˆ6.5 and 9.1, 1H), 3.29 (dd, Jˆ6.5
and 9.1, 1H), 3.98 (d, Jˆ4.2, 2H), 4.42 (s, 2H), 5.56–5.90
(m, 2H), 7.22–7.35 (m, 5H); 13C NMR: 17.3 (CH3), 36.8
(CH), 63.9 (CH), 73.3 (CH2), 75.4 (CH2), 127.9 (CH), 128.0
[2R,2(1E,3S),4R]-3-tert-Butoxycarbonyl-2-(4-tert-butyl-
dimethylsilyloxy-3-butyl-but-1-enyl)-4-phenyl-1,3-oxa-
zolidine 35. To a solution of zinc chloride in THF (0.63N,
9.5 mL, 6 mmol) was added dropwise at Ϫ78ЊC a solution
of n-butyllithium in hexanes (1.58N solution, 3.8 mL,
6 mmol). The solution was warmed to 0ЊC, cooled again
at Ϫ78ЊC, and cannulated into a suspension of copper
cyanide (270 mg, 3 mmol) in THF (4 mL) at Ϫ78ЊC. The
mixture was warmed at 0ЊC and the resulting greenish solu-
tion was cooled again at Ϫ78ЊC. To this solution was added
mesylate 30 (527 mg, 1 mmol) in THF (3 mL). The reaction
mixture was allowed to progressively reach 0ЊC and was
stirred for 2 h at this temperature. Hydrolysis was effected
by addition of a saturated aqueous solution of NH4Cl
(10 mL) and ammonia (30% aqueous solution, 3 mL).
Addition of water and ether was followed by usual workup.
Crude alkenyl oxazolidine was then purified by flash
chromatography (E/EP: 15/85) and was obtained as an oil.

C. Agami et al. / Tetrahedron 56 (2000) 367–376
375
(CH), 128.7 (CH), 129.2 (CH), 135.5 (CH), 138.7 (Cq). ent-
39: 73 mg, 50%; [a]d20: ϩ8.2 (c 0.8, CHCl3).
cooled at 0ЊC, was added dropwise benzyl alcohol
(0.155 mL, 1.5 mmol). After 0.5 h, a solution of 38
(471 mg, 1 mmol) in DMF (4 mL) was added dropwise
and the mixture was stirred for 0.5 h at 0ЊC. Addition of
water and ether was followed by usual workup and purifica-
tion by flash chromatography (E/EP: 15/85). Epoxide 43
was obtained as an oil (338 mg, 68% overall yield from
General procedure for the bromocarbamation of
alkenyloxazolidines 34, 36 and 37
To a solution of alkenyl oxazolidine (1 mmol) in a mixture
of water (5 mL) and dimethoxyethane (5 mL) was added
N-bromosuccinimide (202 mg, 1.15 mmol). The mixture
was stirred for 45 min (2 h in case of substrate 37) and
water was added. Usual workup (dichloromethane) gave
40 and 41 as solids that were triturated with small portions
of petroleum ether and used as such in the following step.
Analytical samples were purified by flash chromatography.
Compound 42 was obtained as an oil and was purified by
flash chromatography (E/EP: 60/40).
1
34). Rf: 0.6 (E/EP: 70/30); [a]d20: Ϫ8 (c 0.5, CHCl3); H
NMR: Ϫ0.01 (bs, 6H), 0.82 (bs, 9H), 0.91 (d, Jˆ7, 3H),
1.62–1.70 (m, 1H), 2.92 (dd, Jˆ2 and 6, 1H), 3.21 (bs, 1H),
3.40–3.50 (m, 2H), 4.01 (dd, Jˆ7.5 and 8.7, 1H), 4.26 (dd,
Jˆ7 and 8.8, 1H), 4.88 (bt, Jˆ6.8, 1H), 4.98 and 5.04 (AB,
Jˆ11, 2H), 5.48 (bs, 1H), 6.85–7.38 (m, 10H); 13C NMR:
Ϫ5.5 (CH3), 12.9 (CH3), 18.2 (CH3), 25.8 (CH3), 37.5 (CH),
57.2 (CH), 57.4 (CH), 61.4 (CH), 67.3 (CH2), 74.0 (CH2),
88.7 (CH), 126.7 (CH), 127.7 (CH), 127.9 (CH), 128.4
(CH), 128.6 (CH), 135.9 (Cq), 139.1 (Cq), 154.7 (Cq).
Anal. Calcd for C28H39NSiO5: C, 67.57; H, 7.90; N 2.81.
Found: C, 67.73; H, 7.82; N, 2.73.
[3R,7S,7(1R),8S,9R]-8-Bromo-7-(2-tert-butyldimethyl-
silyloxy-1-methylethyl)-3-phenyl-tetrahydrooxazolo [3,2-c]
[1,3]oxazin-5-one 40. Yield 93%. mp: 136ЊC; Rf: 0.30
1
(E/EP: 70/30); [a]d20: ϩ15 (c 0.4, CHCl3); H NMR: 0.02
[2R,2(1R,2R,3R),4R]-3-Ethyloxycarbonyl-2-(4-benzyl-
oxy-1,2-epoxy-3-methylbutyl)-4-phenyl-1,3-oxazolidine
44. To a suspension of 39 (364 mg, 0.82 mmol) in ethanol
(10 mL) was added at RT a solution of sodium ethoxide
(prepared from sodium: 188 mg, 8.2 mmol) in ethanol
(6 mL). The mixture was stirred at RT for 1 h, and quenched
by addition of an aqueous saturated solution of NH4Cl
(5 mL). The ethanol was evacuated under reduced pressure
followed by addition of water and ether then usual workup
and flash chromatography (E/EP: 60/40) to give title epox-
ide 44 as an oil (280 mg, 83%). Rf: 0.5 (E/EP: 70/30); [a]d20:
(s, 6H), 0.76 (d, Jˆ6.8, 3H), 0.82 (s, 9H), 2.35–2.41 (m,
1H), 3.44 (dd, Jˆ5.8 and 9.9, 1H), 3.59 (t, Jˆ9.8, 1H), 3.92
(dd, Jˆ8.7 and 11, 1H), 4.09 (t, Jˆ9.2, 1H), 4.20 (dd, Jˆ6.6
and 9.2, 1H), 4.61 (dd, Jˆ1.6 and 11, 1H), 4.88 (d, Jˆ6.4,
1H), 5.01 (d, Jˆ8.7, 1H), 7.20–7.43 (m, 5H); 13C NMR:
Ϫ5.5 (CH3), 8.2 (CH3), 18.1 (Cq), 25.8 (CH3), 36.2 (CH),
43.6 (CH), 60.5 (CH), 63.8 (CH2), 73.7 (CH2), 77.2 (CH),
89.1 (CH), 126.3 (CH), 128.0 (CH), 128.6 (CH), 139.8 (Cq),
149.0 (Cq). Anal. Calcd for C21H32NSiBrO4: C, 53.61; H,
6.86; N 2.98. Found: C, 54.10; H, 7.14; N, 3.04.
1
Ϫ4.8 (c 0.5, CHCl3); H NMR: 0.94 (d, Jˆ6.3, 3H), 1.10
(bs, 3H), 1.74 (hept, Jˆ6.8, 1H), 2.88 (dd, Jˆ2 and 7, 1H),
3.16 (t, Jˆ2.2, 1H), 3.23–3.42 (m, 2H), 3.87–4.01 (m, 2H),
4.17 (dd, Jˆ7 and 8.6, 1H), 4.32 (d, Jˆ3, 2H), 4.80 (bt,
Jˆ6.8, 2H), 5.37 (bs, 1H), 7.20–7.41 (m, 10H); 13C
NMR: 13.6 (CH3), 11.4 (CH3), 35.7 (CH), 57.6 (CH), 57.7
(CH), 60.8 (CH), 61.7 (CH2), 72.4 (CH2), 73.0 (CH2), 73.8
(CH2), 88.5 (CH), 127.1 (CH), 127.9 (CH), 128.1 (CH),
128.8 (CH), 128.9 (CH), 138.9 (Cq), 139.8 (Cq), 155.3
(Cq). Anal. Calcd for C24H29NO5: C, 70.05; H, 7.10; N,
3.40. Found: C, 68.87; H, 7.22; N, 3.35.
[3R,7S,7(1R),8S,9R]-8-Bromo-7-(2-benzyloxy-1-methyl-
ethyl)-3-phenyl-tetrahydrooxazolo[3,2-c][1,3] oxazin-5-
one 41. Yield 89%. mp: 140ЊC; Rf: 0.24 (E/EP: 70/30);
1
[a]d20: ϩ18 (c 0.5, CHCl3); H NMR: 0.81 (d, Jˆ 7, 3H),
2.49–2.60 (m, 1H), 3.33 (dd, Jˆ5.5 and 9.9, 1H), 3.49 (t,
Jˆ9.9, 1H), 3.90 (dd, Jˆ8.6 and 11, 1H), 4.05 (dd, Jˆ9.2
and 1.2, 1H), 4.15 (dd, Jˆ6.5 and 9.2, 1H), 4.41 (d, Jˆ12,
1H), 4.43 (d, Jˆ12, 1H), 4.62 (dd, Jˆ11 and 2, 1H), 4.88
(dd, Jˆ6.5 and 1.2, 1H), 4.99 (d, Jˆ8.6, 1H), 7.25–7.55 (m,
10H); 13C NMR: 9.1 (CH3), 34.4 (CH), 43.9 (CH), 61.1
(CH), 71.5 (CH2), 73.5 (CH2), 74.3 (CH2), 77.6 (CH),
89.6 (CH), 126.8 (CH), 128.0 (CH), 128.6 (CH), 128.8
(CH), 138.6 (Cq), 140.3 (Cq), 149.5 (Cq).
[2R,2(1R,2R,3S),4R]-3-Ethyloxycarbonyl-2-(4-benzyl-
oxy-1,2-epoxy-3-methylbutyl)-4-phenyl-1,3-oxazolidine
45. Following the procedure for the preparation of 44, epox-
ide 45 was obtained as an oil (70%). Rf: 0.5 (E/EP: 70/30);
[3R,7S,7(1S),8S,9R]-8-Bromo-7-(2-benzyloxy-1-methyl-
ethyl)-3-phenyl-tetrahydrooxazolo[3,2-c][1,3] oxazin-5-
one 42. Yield 70%. Oil. Rf: 0.17 (E/EP: 70/30); [a]d20:
ϩ13 (c 0.4, CHCl3); 1H NMR: 0.96 (d, Jˆ7, 3H),
2.65–2.75 (m, 1H), 3.23 (dd, Jˆ4.5 and 9.9, 1H), 3.54 (t,
Jˆ9.9, 1H), 4.03 (dd, Jˆ1.2 and 8.9, 1H), 4.15 (dd, Jˆ8.6
and 11, 1H), 4.24 (dd, Jˆ1.2 and 10, 1H), 4.33 (s, 2H), 4.70
(dd, Jˆ8.9 and 10, 1H), 4.87 (dd, Jˆ1.2 and 8.6, 1H), 4.90
(d, Jˆ9, 1H), 7.25–7.55 (m, 10H); 13C NMR: 9.1 (CH3),
34.4 (CH), 43.9 (CH), 61.1 (CH), 71.5 (CH2), 73.5 (CH2),
74.3 (CH2), 77.6 (CH), 89.6 (CH), 126.8 (CH), 128.0 (CH),
128.6 (CH), 128.8 (CH), 138.6 (Cq), 140.3 (Cq), 149.5 (Cq).
1
[a]d20: Ϫ2.5 (c 0.7, CHCl3); H NMR: 0.95 (d, Jˆ6.8, 3H),
1.10 (bs, 3H), 1.78 (hept, Jˆ6.8, 1H), 2.97 (dd, Jˆ2 and 7,
1H), 3.16 (t, Jˆ2.2, 1H), 3.40–3.50 (m, 2H), 3.98–4.06 (m,
2H), 4.25 (dd, Jˆ7 and 8.6, 1H), 4.46 (s, 2H), 4.83 (bt,
Jˆ6.8, 2H), 5.41 (bs, 1H), 7.15–7.40 (m, 10H); 13C
NMR: 13.9 (CH3), 14.8 (CH3), 36.2 (CH), 57.6 (CH), 57.7
(CH), 61.2 (CH), 62.2 (CH2), 72.9 (CH2), 73.5 (CH2), 74.3
(CH2), 88.9 (CH), 127.1 (CH), 127.9 (CH), 128.1 (CH),
128.8 (CH), 128.9 (CH), 138.9 (Cq), 139.8 (Cq), 155.4 (Cq).
[2Z, 4R, 3(3R)]-4-Bromo-4-methyl-3-(3-phenyl-3-N-tert-
butoxycarbonyl-ethyloxy)-dec-2-enal 47. To an emulsion
of allenyl oxazolidine 38 (162 mg, 0.42 mmol) in a mixture
of water (3 mL) and dimethoxyethane (3 mL) was added
N-bromosuccinimide (89 mg, 0.54 mmol). The mixture
was stirred for 45 mn and water was added. Usual workup
[2R,2(1R,2R,3R),4R]-3-Benzyloxycarbonyl-2-(4-tert-
butyldimethylsilyloxy-1,2-epoxy-3-methylbutyl)-4-
phenyl-1,3-oxazolidine 43. To a suspension of sodium
hydride (60 wt. %, 60 mg, 1.5 mmol) in DMF (5 mL),

376
C. Agami et al. / Tetrahedron 56 (2000) 367–376
moiety). (a) Scolastico, C. Pure Appl. Chem. 1988, 60, 1689–1698.
(b) Bernardi, A.; Scolastico, C.; Villa, R. Tetrahedron Lett. 1989,
30, 3733–3734. (c) Belvisi, L.; Gennari, C.; Poli, G.; Scolastico,
C.; Salom, B. Tetrahedron: Asymmetry 1993, 4, 273–280. (d)
Bernardi, A.; Cardoni, S.; Scolastico, C.; Villa, R. Tetrahedron
1990, 46, 1987–1998. (e) Isobe, M.; Hirose, Y.; Shimokawa, K.
J.; Nishikawa, T.; Goto, T. Tetrahedron Lett. 1990, 31, 5499–
5502. (R4: carbonyl moiety). (f) Ukaji, Y.; Yamamoto, K.;
Fukui, M.; Fujisawa, T. Tetrahedron Lett. 1991, 32, 2919–2922.
(g) O’Brien, P.; Warren, S. Tetrahedron Lett. 1996, 37, 3051–
(dichloromethane) gave 47 as an oil that was purified by
flash chromatography (E/EP: 50/50).The title compound
was obtained as an oil (112 mg, 55%): Rf: 0.5 (E/EP:
70/30); [a]d20: Ϫ10.4 (c 0.25, CHCl3) IR (film): 2980,
1
1722; H NMR: 0.81 (t, Jˆ6.1, 3H), 1.18 (bs, 8H), 1.34
(bs, 9H), 1.43 (s, 3H), 1.55–1.73 (m, 2H) 3.59 (bd, Jˆ5,
2H), 4.75 (bs, 1H), 4.92–5.02 (bm, 1H), 6.39 (d, Jˆ6.5,
1H), 7.20–7.42 (m, 5H), 9.82 (bd, Jˆ6.5, 1H); 13C NMR:
14.1 (CH3), 22.6 (CH2), 23.3 (CH2), 25.1 (CH3), 28.3 (CH3),
28.8 (CH2), 29.2 (CH2), 39.5 (CH2), 54..8 (CH), 66.6 (CH2),
79.9 (Cq), 85.0 (Cq), 126.5 (CH), 127.8 (CH), 128.7 (CH),
135.6 (CH), 139.6 (Cq), 152.2 (Cq), 155.2 (Cq), 191.3 (CH).
Anal. Calcd for C24H36NBrO4(H2O): C, 57.79; H, 7.65; N,
2.79. Found: C, 57.70; H, 7.39; N, 2.53.
¨
3054. (h) Harder, T.; Lohl, T.; Bolte, M.; Wagner, K.; Hoppe, D.
Tetrahedron Lett. 1994, 35, 7365–7368. (i) Garcia-Valverde, M.;
Pedrosa, R.; Vicente, M.; Garcia-Granda, S.; Guttierrez-Rodri-
guez, A. Tetrahedron 1996, 52, 10761–10773. (j) Eliel, E. L.;
He, X. C. J. Org. Chem. 1990, 55, 2114–2119. (k) Conde-Frieboes,
K.; Harder, T.; Aulbert, D.; Strahringer C.; Bolte, M.; Hoppe, D.
Synlett 1993, 921–923.
[2R,2(1R,2R,3S),4R]-3-Ethyloxycarbonyl-2-(4-benzyl-
oxy-1-hydroxy-2,3-dimethylbutyl)-4-phenyl-1,3-oxazo-
lidine 48. To a suspension of copper iodide (304 mg,
1.6 mmol) in ether (5 mL) cooled at Ϫ78ЊC was added drop-
wise a solution of methyllithium (1.4N solution in ether,
2.3 mL, 3 mmol). The mixture was allowed to slowly
reach 0ЊC and a solution of epoxide 44 (220 mg,
0.53 mmol) in ether (5 mL) was then added. The solution
was stirred for 12 h at 0ЊC and hydrolyzed by addition of a
saturated aqueous solution of NH4Cl (10 mL) and ammonia
(30% aqueous solution, 3 mL). Addition of water and ether
was followed by usual workup. Flash chromatography of the
residue (E/EP: 20/80) gave two fractions. The first fraction
eluted was the title compound (50 mg, 22%), the second one
consisted of a mixture of the title compound and starting
material in a respective 80/20 ratio (85 mg). First fraction:
2. Agami, C.; Couty, F.; Lequesne, C. Tetrahedron 1995, 51,
4043–4056.
3. Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996, 37,
4000–4002.
4. Agami, C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998,
54, 8783–8796.
5. Agami, C.; Couty, F.; Venier, O. Synlett 1996, 511, 512.
6. Agami, C.; Couty, F.; Venier, O.; Hamon, L. J. Org. Chem.
1997, 62, 2107–2113.
7. For some recent examples, see Clayden, J.; McCarthy, C.;
Cumming, J. G. Tetrahedron: Asymmetry 1998, 9, 1427–1440
and references cited therein. (b) Liang, J.; Hoard, D. W.; Khau,
V. V.; Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. J.
Org. Chem. 1999, 64, 1459–1463. (c) Suginome, M.; Iwanami, T.;
Ito, Y. J. Org. Chem. 1998, 63, 6096–6097.
8. Journet, M.; Cai, D.; Dimichele, L.; Larsen, R. D. Tetrahedron
Lett. 1998, 39, 6427–6428.
1
oil; Rf: 0.70 (E/EP: 70/30); [a]d20 Ϫ17.7 (c 1.5, CHCl3); H
9. This reduction was previously reported (Ref. 3) using sodium
borohydride in the presence of CeCl3, 7H2O, but the stereoselec-
tivity (de 86%) was lower with this reagent. Reduction with
sodium borohydride alone gave only 40% de. The diastereo-
isomeric excesses were determined by examination of the 1H
NMR spectra of the crude reaction product. For example, in case
of compound 22, the amount of minor stereoisomer was deter-
mined by integration of the doublet at 5.29 ppm, corresponding
to the H-2 proton.
10. (a) Yamamoto, Y.; Chounan, Y.; Tanaka, M.; Ibuka, T. J. Org.
Chem. 1992, 57, 1024–1026. (b) Fujii, N.; Nakai, K.; Habashita,
H.; Yoshizawa, H.; Ibuka, T.; Garrido, F.; Mann, A.; Chounan, Y.;
Yamamoto, Y. Tetrahedron Lett. 1993, 34, 4227–4230. (c)
Pradilla, R. F.; Rubio, M. B.; Marino, J. P.; Viso, A. Tetrahedron
Lett. 1992, 33, 4985–4988. (d) Yamamoto, Y.; Yamamoto, S.;
Yatagai, H.; Maruyama, K. J. Am. Chem. Soc. 1980, 102, 2318–
2325. (e) Ibuka, T.; Yoshizawa, H.; Habashita, H.; Fujii, N.;
Chounan, Y.; Tanaka, M.; Yamamoto, Y. Tetrahedron Lett.
1992, 33, 3783–3786. (f) Marino, J. P.; Viso, A. J. Org. Chem.
1991, 56, 1349–1351.
NMR: 0.89 (d, Jˆ8, 3H), 0.98 (d, Jˆ8, 3H), 1.05 (t, Jˆ7.9,
3H), 1.42 (d, Jˆ6.5, 0.6H), 1.63 (bs, 0.4H), 1.79–1.90 (m,
1H), 2.20–2.35 (m, 1H), 3.18 (dd, Jˆ5 and 9, 1H), 3.46 (bt,
Jˆ9.2, 1H), 3.53 (bq, Jˆ 6.8, 1H), 3.94 (dd, Jˆ6.8 and 8.6,
1H), 4.00 (q, Jˆ7.9, 2H), 4.23 (t, Jˆ8, 1H), 4.45 (s, 2H),
4.98 (bt, 1H), 5.40 (d, Jˆ7.4, 1H), 7.15–7.35 (m, 10H);
13C NMR: 11.8 (CH3), 14.8 (CH3), 17.4 (CH3), 32.9 (CH),
40.0 (CH), 61.2 (CH), 62.3 (CH), 72.6 (CH2), 73.7 (CH2),
76.4 (CH2), 73.8 (CH2), 91.9 (CH), 126.6 (CH), 127.8
(CH), 128.1 (CH), 128.2 (CH), 128.8 (CH), 138.3 (Cq),
140.6 (Cq), 156.9 (Cq).
[2R,2(1R,2R,3R),4R]-3-Ethyloxycarbonyl-2-(4-benzyl-
oxy-1-hydroxy-2,3-dimethylbutyl)-4-phenyl-1,3-oxazo-
lidine 49 and [2R,2(1S,2S,3S),4R]-3-Ethyloxycarbonyl-2-
(4-benzyloxy-1,3-dimethyl-2-hydroxy-butyl)-4-phenyl-
1,3-oxazolidine 50. Following the procedure for the
preparation of 48 and starting from 45 (230 mg,
0.56 mmol), an inseparable mixture of 49 and 50 was
obtained (30 mg, 17%) Rf: 0.70 (E/EP: 70/30). The ratio
of 49 and 50 was determined by integration of the
following signals: 1H NMR: 0.86 (d, Jˆ8, 2.46H),
0.90 (d, Jˆ8, 2.46H), 0.97 (d, Jˆ8, 0.54H), 0.98 (d,
Jˆ8, 0.54H), 1.05 (t, Jˆ7.9, 2.46H), 1.14 (t, Jˆ7.9,
0.54H).
11. Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36,
186–204.
12. Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873–3888.
[a]d20 for ent-38: ϩ9.9 (c 1.3, CHCl3).
13. A Cbz group allows the recovery of the aldehydic moiety
under mild conditions. See for example Colombo, L.; Gennari,
C.; Poli, G.; Scolastico, C.; De Murani, S. Tetrahedron Lett.
1985, 26, 5459–5462.
14. For a similar behaviour involving an acetal instead of an
oxazolidine ring, see: Fujioka, H.; Nagatomi, Y.; Kitagawa, H.;
Kita, Y. J. Am. Chem. Soc. 1997, 119, 12016–12017.
References
1. For previous relevant references in this field, see (R4: olefinic