Asymmetric synthesis of β2,3-amino acids by InI-Pd(0)-promoted metalation and addition of chiral 2-vinylaziridines

Article abstract of DOI:10.1016/S0040-4020(02)00499-4

The reaction of optically active 3-alkyl-2-vinylaziridines with various aldehydes in the presence of InI and Pd(PPh₃)₄ gives rise to chiral syn,syn-2-vinyl-1,3-amino alcohols possessing three contiguous chiral centers stereoselectively. The ratio of the syn,syn-isomer to the other three isomers is significantly affected by the C3-substituents of aziridines as well as the alkyl groups of aldehydes. In addition, the obtained 1,3-aminoalcohols can be converted into biologically important β^2,3-amino acid derivatives.

Full text of DOI:10.1016/S0040-4020(02)00499-4

TETRAHEDRON
Pergamon
Tetrahedron 58,2002) 5231±5239
Asymmetric synthesis of b2,3-amino acids by InI±Pdꢀ0)-promoted
metalation and addition of chiral 2-vinylaziridines
Miyuki Anzai, Reiko Yanada, Nobutaka Fujii, Hiroaki Ohno, Toshiro Ibuka
and Yoshiji Takemotop
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 18March 2002; accepted 10 May 2002
AbstractÐThe reaction of optically active 3-alkyl-2-vinylaziridines with various aldehydes in the presence of InI and Pd,PPh3)4 gives rise
to chiral syn,syn-2-vinyl-1,3-amino alcohols possessing three contiguous chiral centers stereoselectively. The ratio of the syn,syn-isomer to
the other three isomers is signi®cantly affected by the C3-substituents of aziridines as well as the alkyl groups of aldehydes. In addition, the
obtained 1,3-aminoalcohols can be converted into biologically important b2,3-amino acid derivatives. q 2002 Elsevier Science Ltd. All
rights reserved.
1.Introduction
reaction of the resultant allylmetals with aldehydes proceeds
regio- and stereoselectively ,A!C), b2,3-amino acid
derivatives, which are very important compounds as
peptidomimetics, could be easily prepared from a-amino
acids as shown in Scheme 1. Herein, we describe in detail
an InI/Pd,0)-mediated allylation of aldehydes with the
N-activated vinylaziridines 1, which proceeds with regio-
and stereoselectivity to provide the syn,syn-2-vinyl-1,3-
amino alcohols 2a and 5a±7a in good yield, and transfor-
mation of the obtained products into b2,3-amino acid
derivatives.5
Due to their very high reactivity and ability to function as
carbon electrophiles, vinylaziridines and their analogues
have been used as intermediates for the synthesis of azino-
mycin, b-lactams, ,R)-,2)-dysidazirine, azacycles such as
2,6-disubstituted
tetrahydropyridines,
indolizidine
alkaloids, pyrrolizidine alkaloids, and 3,7-disubstituted
tetrahydroazepinone.1 In the course of our studies on chiral
aziridines, we have developed several unique syntheses and
reactions of 2-alkenylaziridines such as Pd,0)-catalyzed
isomerization of trans-isomers into cis-ones and organo-
copper-mediated anti-SN20 substitution, aimed at stereo-
selective synthesis of alkene dipeptide isosteres.2 In
contrast to the reactions of aziridines used as electrophiles,
there are few reactions where 2-alkenylaziridines were
employed as nucleophiles.3 Recently, several umpolung
reactions of allylic alcohol derivatives and vinylic epoxides
with various reducing agents via the p-allylpalladium
complexes have been developed.4 Therefore, anticipating
a dramatic increase in their synthetic versatility, we started
to explore an ef®cient synthetic method of chiral allylmetals
bearing an amino group at the d-position from 2-alkenyl-
aziridines with a reducing agent and a Pd,0) catalyst. If the
2.Results and discussion
Diastereoselective addition of chiral allylmetals possessing
a stereogenic center at the d-position with aldehydes plays
an important role in stereoselective synthesis, since
contiguous stereogenic centers can be created in a single
operations and the resulting homoallylic alcohols can be
used for further chemical transformation into various
types of natural and synthetic compounds.6,7 Although
there are numerous reports concerning the preparation and
utilization of 4-hydroxy- or 4-alkoxyallyl metals,7 few
Scheme 1. General synthetic strategy of b2,3-amino acids from a-amino acids.
Keywords: vinylaziridines; b2,3-amino acids; metalation.
Corresponding author. Tel.: 181-075-753-4610; fax: 181-075-753-4569; e-mail: takemoto@pharm.kyoto-u.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00499-4

5232
M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
Scheme 2.
2.1. Synthesis of N-Mts-2-vinyl-1,3-amino alcohols from
N-Mts-2-vinylaziridines
Table 1. Synthesis of 2-vinyl-1,3-amino alcohols 2 from 2-vinylaziridine 1
with various reducing agents
Entry
Reaction conditions
Yielda ,%)
,2±3)
It is known that a strong electron-withdrawing protecting
group on the nitrogen atom is required for the Pd-catalyzed
ring-opening of aziridines. Hence, we chose a 2,4,6-
trimethylbenzenesulfonyl ,Mts) group for that purpose.
The requisite N-arylsulfonylated 2,3-trans- and 2,3-cis-3-
alkyl-2-vinylaziridines trans-1 and cis-1 were prepared
from natural a-amino acids with high optical purity accord-
ing to our recently published procedures.2d We initially
examined the umpolung reaction for generating the desired
allylmetal reagent from 1. The reactions of 1 and benzalde-
hyde ,2 equiv.) were carried out at room temperature using
various reducing agents ,2±3 equiv.) and a catalytic amount
of a Pd-catalyst under argon atmosphere ,Scheme 2). The
representative results are shown in Table 1. It is revealed
that the reactivity of the allylmetal reagent bearing an amino
group at the d-position is strongly affected by the reducing
reagent employed. When Et2Zn4a was used as a reducing
agent ,entry 1), the desired 1,3-amino alcohols 2 were
obtained as minor products together with 1,5-amino
1
2
3
4
Et2Zn, Pd,PPh3)4, THF, 2 h
16:17
32:0
±
SnCl2, PdCl2,CH3CN)2, DMF/H2O, 23 h
Et3B, Pd,PPh3)4, THF, 8h
InI ,2), Pd,PPh3)4 ,5), THF, 6 h
83:3
All reactions were carried out with 2 equiv. of benzaldehyde in the presence
of palladium catalyst and reducing agent at room temperature.
Isolated yields.
a
reactions of chiral allylmetals bearing an amino group at the
d-position have been reported.8 We have already found that
trans-N-activated 2-vinylaziridines were ef®ciently
isomerized into the corresponding cis-isomers via a p-allyl-
palladium complex by the reaction with a catalytic amount
of Pd,PPh3)4.2d Then we examined various reducing agents
for the Pd,0)-promoted metalation of optically active
3-alkyl-2-vinylaziridines 1 and the subsequent nucleophilic
addition with several aldehydes.
4b
alcohols 3. A similar reaction of 1 with SnCl2 produced
2 without other products, but the yield of 2 was low due to
decomposition of the starting material ,entry 2).
Although addition of Et3B4c resulted in a complex
mixture of products, the choice of InI4d as a reducing
agent promoted the transmetalation and nucleophilic
addition with benzaldehyde to give 2 in 83% yield ,entries
3 and 4).
The synthesis of b-amino acids has attracted considerable
attention in recent years.9 Among various substituted
b-amino acids, b0-hydroxy derivatives constitute an
important class of molecules with interesting chemical
and biological properties due to their similarity to serine
and other unusual amino acids.
Scheme 3.
Table 2. The InI±Pd,0)-mediated allylation of 2-vinyl-aziridines 1 and allylic carbonate 4 with various aldehydes
Entry
Substrate
Aldehyde R ,RCHO)
Reaction time ,h)
Yielda ,%)
Ratiob ,a±b±others)
1
2
3
4
5
6
7
8
trans-1
cis-1
4
cis-1
cis-1
cis-1
cis-1
cis-1
Ph
Ph
Ph
6
2 ,76)
2 ,88)
2 ,52)
5 ,86)
6 ,77)
7 ,88)
8 ,80)
9 ,92)
89:11:0
90:10:0
85:15:0
90:10:0
91:9:0
93:7:0
51:14:35
38:25:37
5
7 ,408C)
26
3
23
2
1
p-MeOC6H4
p-ClC6H4
i-Pr
Et
Me
All reactions were carried out with 2 equiv. of aldehyde in the presence of Pd,PPh3)4 ,5 mol%) and InI ,2 equiv.) in dry THF at room temperature.
Total yields.
Calculated from isolated yield.
a
b

M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
5233
Scheme 4.5 : Rˆp-MeOC6H4, 6: Rˆp-ClC6H4, 7: Rˆi-Pr, 8: RˆEt, 9: RˆMe.
Scheme 5.
Having established the conditions for giving 2, we next
examined the effect of the C-2 chirality of 1 on diastereo-
selectivity ,2a/2b) ,Scheme 3). Treatment of cis-1 and
trans-1 with benzaldehyde in the presence of InI and
Pd,PPh3)4 gave the same syn,syn-1,3-amino alcohols 2a as
a major product in a similar ratio of 2a/2b ,Table 2, entries 1
and 2). In addition, although reaction of the methyl carbon-
ate 4,2a bearing no chirality on the C2 position, proceeded
slowly even if at 408C, similar results were obtained except
for the moderate yield ,entry 3). From these results, it is
revealed that the allylation of these compounds proceeds
via the same intermediate, and the stereoselectivity is only
affected by the substituent of the C3 position, but not that of
the C2 position. These facts are reasonable by considering
that the isomerization of trans-1 and cis-1 proceeds quickly
via a p-allylmetal complex. Therefore, the following reac-
tions were carried out with the 2,3-cis-vinylaziridines. We
next investigated the Pd-mediated allylation with several
aldehydes ,Scheme 4). As shown in Table 2 ,entries 4±8),
all entries afforded the syn,syn-1,3-amino alcohols 5a±9a as
a major product among four possible diastereomers,
irrespective of aromatic aldehydes having an electron-with-
drawing or electron-donating group on the aromatic ring and
aliphatic ones. In this reaction, the substituents of the alde-
hydes play an important role on the selectivity. Whereas the
bulky substituents such as aryl and secondary alkyl groups
tend to afford the syn,syn-adducts with good diastereo-
selectivity, the reactions with propionaldehyde and acetal-
dehyde gave rise to the four diastereomers with low to
moderate selectivity. This result is in sharp contrast to that
of allyltitanium reagents, where another syn,anti-diastereo-
mer was obtained predominantly and the diastereo-
selectivity dramatically changed depending on the
aldehydes employed.8c In particular, the Ti-mediated
reaction with aryl aldehyde resulted in poor stereo-
selectivity. Furthermore, the reaction rate of the In-mediated
allylation was signi®cantly in¯uenced by the substituents of
the aldehydes. The electron-donating and/or bulky substitu-
ents tend to retard the allylation reaction ,entries 4 and 6).
2.2. Synthesis of N-Boc-2-vinyl-1,3-amino alcohols from
N-Boc-2-vinylaziridines and their applications
It would be desirable to employ a Boc group for protection
of the amino moiety in place of the Mts group. Therefore,
we next examined the umpolung of the N-Boc-aziridines 10
and 11, N-Boc-allylic acetates 12 and 13,2f and oxazolidi-
nones 14 and 1510 under identical transmetalation condi-
tions ,Scheme 5). The reaction of 10 and 11 with
benzaldehyde gave the corresponding N-Boc-syn,syn-1,3-
amino alcohols 16a and 17a as a major product with a little
bit lower yield than that of the N-Mts-aziridine 1 ,Table 3,
entries 1 and 2). Furthermore, the same treatment of 11 with
cinnamaldehyde resulted in lesser diastereoselectivity
,entry 3). On the other hand, on employing the acetate 12
and N-Boc-oxazolidinone 14 as a substrate, both the chemi-
cal yield and diastereoselectivity of 16a were increased
,entries 4 and 6). In contrast, unprotected oxazolidinone
15 afforded none of the desired 1,3-amino alcohols.
Comparison with the diastereoselectivity obtained from
the reactions of 10, 11 and 12, 13 ,entries 1±2, 4 and 5)
revealed that bulkiness of the alkyl group ,R) of the
substrates would be crucial to achieve good diastereo-
selectivity.
Table 3. The InI±Pd,0)-mediated allylation of 2-vinyl-aziridines 10 and 11,
allylic acetates 12 and 13, and carbonate 14
Entry Substrate Aldehyde R0 ,R0CHO) Yielda ,%) Ratiob ,a±b)
1
2
3
4
5
6
10
11
11
12
13
14
Ph
Ph
16 ,51)
17 ,58)
18 ,51)
16 ,84)
19 ,55)
16 ,89)
90:10
88:12
69:31
93:7
80:20
93:7
PhCHvCH
Ph
Ph
Ph
All reactions were carried out with 2 equiv. of aldehyde in the presence of
Pd,PPh3)4 ,5 mol%) and InI ,2 equiv.) in dry THF at room temperature.
a
Total yields.
Calculated from isolated yield.
b

5234
M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
Scheme 6.
The con®guration at the newly created stereocenters of the
major and minor diastereomers 16a and 16b was determined
by the chemical transformation and NOE experiment
,Scheme 6). Namely, treatment of 16a and 16b with NaH
afforded the tetrahydro-1,3-oxazin-2-ones 20 and 21, which
were analyzed by NOE difference spectroscopy. In 20, the
strong interaction between H-1 and H-3 ,6.7%), H-1 and
H-2 ,6.2%), and H-2 and H-3 ,5.7%) clearly indicated the
syn,syn-con®guration. Similarly, in 21, the distinct interac-
tion between H-1 and H-2 ,6.6%), and H-3 and vinyl proton
,3.9%) clearly indicated the syn,anti-con®guration. The
stereochemistry of the major N-Mts adduct 2a was
con®rmed by conversion of the assigned major product
16a into 2a. The other diastereomers were deduced by
ing on the allylindium intermediates bearing neutral and
anionic species of the N-protecting groups, in terms of
stereoselectivity and reaction rate. In any event, both T.S.
models gave the syn,syn-1,3-amino alcohols as a major
product. On the contrary, when the aziridine and allylic
acetate bearing a smaller alkyl group such as 11 and 13
was used for the allylation, another six-membered chair-
like T.S.-model C, where the amino moiety ,NHR2) is
located at the anti-position, would gradually prevailed,
resulting in low stereoselectivity.
Finally, we transformed the obtained syn,syn-1,3-amino
alcohols into b-amino-b0-hydroxycarboxylic acid deriva-
tives, which are versatile intermediates for unnatural
amino acids, b-lactams, and b-lactones ,Scheme 7).
Ozonolysis of the alcohols 2a, 5a and 6a, followed by
reduction with dimethyl sul®de to afford the aldehydes,
which were subjected to the NaClO2 oxidation, gave the
corresponding carboxylic acids in good yield. After esteri-
®cation with TMSCHN2, the methyl b-amino-b0-hydroxy-
esters 22±24 were obtained in 58±89% yields from the
alcohols 2a, 5a and 6a.
1
comparison of their TLC behavior and H NMR spectra
with that of 16a and 16b.
The stereoselectivity attained in the allylation reaction can
be explained reasonably by consideration of the three tran-
sition states ,A±C, Fig. 1).7c,11 The six-membered chair-like
T.S.-models A where the most sterically demanding alkyl
moiety ,R1) is located at the anti-position, seem to be the
most favorable according to the Felkin±Ahn model.
However, a similar six-membered boat-like T.S.-model B,
where the allylindium reagents possess ,Z)-con®guration
and coordinate to the amido group, could not be ruled out.
In practice, we could not ®nd any differences between the
reaction of 10 and 12 via the T.S.-models A and B depend-
3.Conclusion
In conclusion, we have demonstrated a novel utility of
N-activated 2-vinylaziridines as a precursor of chiral
Figure 1. Plausible transition state model ,A, B and C).
Scheme 7.

M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
5235
allylmetals by umpolung with an indium,I) salt in the
presence of a Pd,0) catalyst. The allylindium reagents bear-
ing a protected amino group ,Mts and Boc) possess a differ-
ent character from the reported allyltitanium8c,d and
allenylindium reagents8a,b in terms of stereochemistry of
the major products ,2a vs. 2b) and the stereodetermined
chiral centers ,C-2 vs C-3), respectively.
,17 mg, 0.015 mmol) and InI ,140 mg, 0.579 mmol) in dry
THF ,1 ml) under an argon atmosphere was added a solution
of benzaldehyde ,59 ml, 0.58mmol) in dry THF ,1 ml), and
the mixture was stirred at room temperature for 6 h. The
same workup procedure as described for 2 ,Table 1, entry
4) gave 2b ,9.8mg, 8%) and 2a ,79 mg, 68%). Entry 2. The
same treatment of cis-1 ,40 mg, 0.136 mmol) as described
above ,entry 1) gave 2b ,5.0 mg, 9%) and 2a ,43 mg, 79%).
Entry 3. The same treatment of 4 ,43.0 mg, 0.116 mmol) as
described above ,entry 1) except for the reaction tempera-
ture ,at 408C for 7 h) gave 2b ,3.5 mg, 8%) and 2a ,21 mg,
44%). 2a. Colorless crystals from Et2O±hexane. Mp 108±
4.Experimental
4.1. General
28
1
1108C; [a]D ˆ248.1 ,c 1.44, CHCl3); H NMR ,CDCl3,
270 MHz) d: 0.62 ,d, Jˆ6.8Hz, 6H), 1.57 ,m, 1H), 2.28,d,
Jˆ2.7 Hz, 1H), 2.30 ,s, 3H), 2.55 ,ddd, Jˆ3.2, 7.0, 10.0 Hz,
1H), 2.62 ,s, 6H), 3.16 ,ddd, Jˆ3.2, 5.4, 9.8Hz, 1H), 4.50
,d, Jˆ9.8Hz, 1H), 4.60 ,dd, Jˆ2.7, 7.0 Hz, 1H), 5.13 ,dd,
Jˆ1.6, 17.3 Hz, 1H), 5.32 ,dd, Jˆ1.6, 10.0 Hz, 1H), 5.87
,dt, Jˆ10.0, 17.3 Hz, 1H), 6.95 ,s, 2H), 7.17±7.35 ,m, 5H);
13C NMR ,CDCl3, 67.8MHz) d: 18.3, 19.2, 21.1, 23.4, 32.7,
53.6, 59.4, 74.9, 121.9, 127.4, 128.0, 128.4, 132.2. 134.9,
135.7, 138.7, 142.2; LRMS ,FAB) m/z 402 ,MH1), 400,
384, 254 ,100), 183, 119; HRMS ,FAB) m/z calcd. for
C23H32NO3S ,MH1) 402.2103; found: 402.2107. 2b. A
Melting points are uncorrected. 1H NMR spectra were
recorded in CDCl3 using a JEOL EX-500 spectrometer.
Chemical shift are reported in parts per million down®eld
from internal Me4Si. Nominal ,LR-MS) and exact mass
,HRMS) spectra were recorded on a JEOL JMS-01SG-2
or JMS-HX/HX 110A mass spectrometer. Optical rotations
were measured in CHCl3 with a JASCO DIP-360 digital
polarimeter. For ¯ash chromatography, silica gel 60 H
,silica gel for thin-layer chromatography, Merck) was
employed.
34
1
colorless oil; [a]D ˆ241.9 ,c 0.983, CHCl3); H NMR
,CDCl3, 270 MHz) d: 0.43 ,d, Jˆ7.0 Hz, 3H), 0.76 ,d,
Jˆ7.0 Hz, 3H), 1.91 ,dqq, Jˆ2.7, 7.0, 7.0 Hz, 1H), 2.26
,dt, Jˆ2.4, 9.2 Hz, 1H), 2.30 ,s, 3H), 2.65 ,s, 6H), 3.28
,d, Jˆ4.6 Hz, 1H), 3.39 ,dt, Jˆ3.0, 9.7 Hz, 1H), 4.60 ,dd,
Jˆ1.6, 17.0 Hz, 1H), 4.84 ,d, Jˆ10.3 Hz, 1H), 4.90 ,dd,
Jˆ1.6, 10.3 Hz, 1H), 5.22 ,dd, Jˆ3.2, 4.3 Hz, 1H), 5.67
,dt, Jˆ10.0, 17.0 Hz, 1H), 6.95 ,s, 2H), 7.17±7.32 ,m,
5H); LRMS ,FAB) m/z 402 ,MH1), 400 ,100), 198;
HRMS ,FAB) m/z calcd. for C23H30NO3S ,M2H2)
400.1946; found: 400.1951.
4.1.1. Alcohol 2. Table 1, entry 1. To a stirred solution of 1
,40.0 mg, 0.136 mmol), Pd,PPh3)4 ,8mg, 6.8 mmol) and
benzaldehyde ,27.7 ml, 0.273 mmol) in dry THF ,1 ml)
was added a 1.1 M toluene solution of En2Zn ,0.25 ml,
0.273 mmol) under an argon atmosphere, and the mixture
was stirred for 2 h at room temperature. After quenching
with 0.1N HCl, the resulting mixture was extracted with
AcOEt. The extract was washed with water and brine, and
dried over MgSO4. The ®ltrate was concentrated in vacuo,
and the obtained residue was puri®ed by ¯ash chromato-
graphy over silica gel with hexane±AcOEt ,6:1) gave the
g-adduct 2 ,9.0 mg, 16%) and a-adduct 3 ,9.5 mg, 17%) as
diastereomixtures. Entry 2. To a stirred solution of 1
4.1.3. syn,syn-Alcohol 5a. Table 2, entry 4. To a stirred
solution of cis-1 ,45.0 mg, 0.153 mmol), Pd,PPh3)4
,9.0 mg, 7.7 mmol) and InI ,74 mg, 0.31 mmol) in dry
THF ,1 ml) under an argon atmosphere was added a solution
of p-anisaldehyde ,37 ml, 0.31 mmol) in dry THF ,0.5 ml),
and the mixture was stirred at room temperature for 26 h.
The same workup and ¯ash chromatography over silica gel
with hexane±AcOEt ,5:1) gave 5b as a diastereomixture
,5.8mg, 9%) and 5a ,51 mg, 77%). 5a. Colorless crystals
,15.0 mg,
0.051 mmol),
PdCl2,CH3CN)2
,1.0 mg,
3.0 mmol) and benzaldehyde ,11 mg, 0.102 mmol) in a
mixture of DMF ,0.3 ml) and water ,0.1 ml) was added
SnCl2 ,29 mg, 0.15 mmol) under an argon atmosphere,
and the mixture was stirred at room temperature for 23 h.
After quenching with 0.1N HCl, the resulting mixture was
extracted with AcOEt. The extract was washed with water
and brine, and dried over MgSO4. Usual workup followed
by ¯ash chromatography over silica gel with hexane±
AcOEt ,7:1) gave the diastereomeric g-adduct 2 ,6.3 mg,
32%) as the sole product. Entry 4. To a stirred solution of 1
,15 mg, 0.051 mmol), Pd,PPh3)4 ,3.0 mg, 2.6 mmol) and InI
,25 mg, 0.10 mmol) in dry THF ,0.5 ml) under an argon
atmosphere was added a solution of benzaldehyde ,11 mg,
0.10 mmol) in dry THF ,0.5 ml), and the mixture was stirred
at room temperature for 7 h. After 0.1N HCl was added to
the mixture, the resulting mixture was extracted with ether.
The extract was washed with water and brine, and dried over
MgSO4. The ®ltrate was concentrated in vacuo, and the
obtained residue was puri®ed by ¯ash chromatography
over silica gel with hexane±AcOEt ,7:1) to give 3
,0.6 mg, 3%) and 2 ,17 mg, 83%) as diastereomeric
mixture.
29
from Et2O±hexane. Mp 105±1078C; [a]D ˆ243.1 ,c 0.35,
CHCl3); 1H NMR ,CDCl3, 270 MHz) d: 0.62 ,d, Jˆ6.8Hz,
6H), 1.55 ,m, 1H), 2.18,d, Jˆ2.4 Hz, 1H), 2.30 ,s, 3H),
2.54 ,m, 1H), 2.61 ,s, 6H), 3.10 ,ddd, Jˆ2.7, 5.4, 10.0 Hz,
1H), 3.80 ,s, 3H), 4.48±4.53 ,m, 2H), 5.17 ,dd, Jˆ1.6,
17.0 Hz, 1H), 5.36 ,dd, Jˆ1.6, 10.3 Hz, 1H), 5.87 ,dt,
Jˆ10.3, 17.0 Hz, 1H), 6.82 ,d, Jˆ8.6 Hz, 2H), 6.95 ,s,
2H), 7.11 ,d, Jˆ8.6 Hz, 2H); 13C NMR ,CDCl3,
67.8MHz) d: 18.5, 19.2, 21.3, 23.4, 32.8, 53.5, 55.5,
59.2, 74.3, 113.8, 121.9, 128.7, 132.2, 134.2, 135.2, 135.8,
138.7, 142.2, 159.4. Anal. calcd for C24H33NO4S: C, 66.79;
H, 7.71; N, 3.25. Found: C, 66.90; H, 7.68; N, 3.19.
4.1.4. syn,syn-Alcohol 6a. Table 2, entry 5. To a stirred
solution of cis-1 ,45.0 mg, 0.153 mmol), Pd,PPh3)4
,9.0 mg, 7.7 mmol) and InI ,74 mg, 0.31 mmol) in dry
THF ,1 ml) was added a solution of p-chlorobenzaldehyde
,43 mg, 0.31 mmol) in dry THF ,0.5 ml) under an argon
4.1.2. syn,syn-Alcohol 2a. Table 2, entry 1. To a stirred
solution of trans-1 ,85.0 mg, 0.290 mmol), Pd,PPh3)4

5236
M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
atmosphere, and the mixture was stirred at room tempera-
ture for 3 h. The same workup and ¯ash chromatography
over silica gel with hexane±AcOEt ,4:1) gave 6b ,4.5 mg,
7%) and 6a ,47 mg, 70%). 6a. Yellow crystals from Et2O±
solution of cis-1 ,13.8mg, 0.047 mmol), Pd,PPh 3)4
,2.7 mg, 2.4 mmol) and InI ,23 mg, 0.094 mmol) in dry
THF ,1 ml) was added a solution of propionaldehyde
,6.8 ml, 0.094 mmol) in dry THF ,0.5 ml) under an argon
atmosphere, and the mixture was stirred at room tempera-
ture for 2 h. The same workup and ¯ash chromatography
over silica gel with hexane±AcOEt ,4:1) gave a mixture of
8b and other isomer ,3.2 mg, 19%, 3:2) and a mixture of 8a
and other isomer ,10.1 mg, 61%, 2:1). 8a. 1H NMR ,CDCl3,
500 MHz) d: 0.61 ,d, Jˆ6.7 Hz, 1.02H), 0.72±0.88 ,m,
7.98H), 0.88±2.0 ,m, 3H), 2.18 ,m, 1H), 2.29 ,s, 3H),
2.64 ,s, 2.04H), 2.66 ,s, 3.96H), 3.38,m, 1.32H), 3.44 ,m,
0.34H), 3.57 ,m, 0.34H), 4.44 ,d, Jˆ9.2 Hz, 0.66H), 4.94 ,d,
Jˆ10.1 Hz, 0.34H), 5.02±5.28,m, 2H), 5.54 ,ddd, Jˆ10.1,
10.4, 17.1 Hz, 0.34H), 5.69 ,ddd, Jˆ10.1, 10.1, 17.4 Hz,
0.66H), 6.93 ,s, 2H); LRMS ,FAB) m/z 354 ,MH1, 45),
29
1
hexane. Mp 1408C; [a]D ˆ253.9 ,c 0.34, CHCl3); H
NMR ,CDCl3, 270 MHz) d: 0.60 ,d, Jˆ4.6 Hz, 3H), 0.63
,d, Jˆ4.6 Hz, 3H), 1.55 ,dqq, Jˆ5.4, 4.6, 4.6 Hz, 1H), 2.30
,s, 3H), 2.44±2.52 ,m, 2H), 2.61 ,s, 6H), 3.15 ,ddd, Jˆ3.0,
5.4, 9.7 Hz, 1H), 4.53 ,d, Jˆ9.7 Hz, 1H), 4.65 ,d, Jˆ6.5 Hz,
1H), 5.09 ,dd, Jˆ1.6, 17.3 Hz, 1H), 5.20 ,dd, Jˆ1.6,
10.3 Hz, 1H), 5.87 ,dt, Jˆ17.3, 10.3 Hz, 1H), 6.95 ,s,
2H), 7.15±7.29 ,m, 4H); 13C NMR ,CDCl3, 67.8MHz) d:
18.4, 19.3, 21.1, 23.4, 32.7, 53.7, 59.6, 74.3, 122.2, 128.5,
128.8, 132.2, 133.6, 134.3, 135.6, 138.6, 140.8, 142.3. Anal.
calcd for C23H30NO3S: C, 63.36; H, 6.94; N, 3.21. Found: C,
33
63.10; H, 6.92; N, 3.07. 6b. A colorless oil. [a]D ˆ241.2
1
,c 0.42, CHCl3); H NMR ,CDCl3, 270 MHz) d: 0.36 ,d,
1
336, 254, 119 ,100). 8b. H NMR ,CDCl3, 500 MHz) d:
Jˆ7.0 Hz, 3H), 0.73 ,d, Jˆ7.0 Hz, 3H), 1.89 ,dqq, Jˆ2.7,
7.0, 7.0 Hz, 1H), 2.19 ,dt, Jˆ2.4, 10.3 Hz, 1H), 2.30 ,s, 3H),
2.66 ,s, 6H), 3.41 ,dt, Jˆ2.7, 10.3 Hz, 1H), 3.52 ,d,
Jˆ5.1 Hz, 1H), 4.58,dd, Jˆ1.6, 17.3 Hz, 1H), 4.76 ,d,
Jˆ10.3 Hz, 1H), 4.91 ,dd, Jˆ1.6, 10.3 Hz, 1H), 5.26 ,dd,
Jˆ2.4, 5.1 Hz, 1H), 5.63 ,dt, Jˆ10.3, 17.3 Hz, 1H), 6.96 ,s,
2H), 7.17±7.27 ,m, 4H); LRMS ,FAB) m/z 436 ,MH1), 434
,100), 198, 168, 153; HRMS ,FAB) m/z calcld. for
C23H29ClNO3S ,M2H2) 434.1557; found: 434.1556.
0.36 ,d, Jˆ7.1 Hz, 1.8H), 0.54 ,d, Jˆ6.7 Hz, 1.2H), 0.71
,d, Jˆ7.0 Hz, 1.8H), 0.79 ,d, Jˆ6.7 Hz, 1.2H), 0.92 ,m,
3H), 1.2±1.7 ,m, 2.4H), 1.86 ,m, 0.6H), 1.98 ,m, 0.6H),
2.25 ,m, 0.4H), 2.29 ,s, 3H), 2.64 ,s, 2.4H), 2.65 ,s,
3.6H), 3.10 ,d, Jˆ5.2 Hz, 0.6H), 3.18,d, Jˆ4.9 Hz,
0.4H), 3.37 ,ddd, Jˆ3.1, 9.8, 9.8 Hz, 0.6H), 3.44 ,m,
0.4H), 3.54 ,m, 0.4H), 3.93 ,m, 0.6H), 4.49 ,d,
Jˆ10.1 Hz, 0.4H), 4.58,d, Jˆ10.1 Hz, 0.6H), 4.9±5.3 ,m,
2H), 5.55 ,ddd, Jˆ9.8, 10.4, 17.4 Hz, 0.4H), 5.67 ,ddd,
Jˆ10.1, 10.4, 17.4 Hz, 0.6H), 6.94 ,s, 2H); LRMS ,FAB)
m/z 354 ,MH1, 56), 336, 254, 119 ,100).
4.1.5. syn,syn-Alcohol 7a. Table 2, entry 6. To a stirred
solution of cis-1 ,45.0 mg, 0.153 mmol), Pd,PPh3)4
,9.0 mg, 7.7 mmol) and InI ,74 mg, 0.31 mmol) in dry
THF ,1 ml) was added a solution of isobutylaldehyde
,29 ml, 0.31 mmol) in dry THF ,0.5 ml) under an argon
atmosphere, and the mixture was stirred at room tempera-
ture for 23 h. The same workup and ¯ash chromatography
over silica gel with hexane±AcOEt ,5:1) gave 7b ,3.5 mg,
6%) and 7a ,46 mg, 82%). 7a. Orange crystals from Et2O±
4.1.7. syn,syn-Alcohol 9a. Table 2, entry 8. To a stirred
solution of cis-1 ,38.6 mg, 0.132 mmol), Pd,PPh3)4
,7.6 mg, 6.6 mmol) and InI ,64 mg, 0.26 mmol) in dry
THF ,1 ml) was added a solution of acetaldehyde ,15 ml,
0.26 mmol) in dry THF ,0.5 ml) under an argon atmosphere,
and the mixture was stirred at room temperature for 1 h. The
same workup and ¯ash chromatography over silica gel with
hexane±AcOEt ,5:1) gave a mixture of 9b and other isomer
,15.0 mg, 34%, 2.2:1) and a mixture of 9a and other isomer
,26.1 mg, 58%, 1.4:1). 9a1isomer. 1H NMR ,CDCl3,
500 MHz) d: 0.58, 0.75, 0.76, 0.78, 1.08, 1.10 ,each d,
Jˆ7.0, 6.7, 7.1, 7.3, 6.1, 5.8Hz, total 9H), 1.70 and 1.81
,each m, total 1H), 2.09 ,ddd, Jˆ4.9, 4.9, 9.8Hz, 0.58H),
2.16 ,ddd, Jˆ7.3, 7.3, 9.8Hz, 0.42H), 2.29 ,s, 3H), 2.64 and
2.65 ,each s, total 6H), 3.34 and 3.39 ,each m, total 1H),
3.66 and 3.89 ,each m, total 1H), 4.49 ,d, Jˆ9.5 Hz, 0.58H),
5.01 ,d, Jˆ9.8Hz, 0.42H), 5.05±5.35 ,m, total 2H), 5.53
,ddd, Jˆ10.1, 10.1, 17.1 Hz, 0.58H), 5.71 ,ddd, Jˆ10.1,
10.1, 17.1 Hz, 0.42H), 6.93 ,s, 2H); LRMS ,FAB) m/z 340
,MH1, 100), 254, 119. 9b1isomer. 1H NMR ,CDCl3,
500 MHz) d: 0.32 ,d, Jˆ6.8Hz, 1.98H), 0.51 ,d,
Jˆ10.2 Hz, 1.02H), 0.70 ,d, Jˆ7.0 Hz, 1.98H), 0.78 ,d,
Jˆ6.8Hz, 1.02H), 1.14 ,d, Jˆ6.8Hz, 1.98H), 1.15 ,d,
Jˆ6.4 Hz, 1.02H), 1.53 ,m, 0.34H), 1.85 ,m, 0.66H), 1.90
,ddd, Jˆ1.9, 9.8, 10.1 Hz, 1H), 2.19 ,ddd, Jˆ2.4, 9.5,
9.8Hz, 1H), 2.29 ,s, 3H), 2.63 ,s, 2.04H), 2.65 ,s, 3.96H),
3.34 ,ddd, Jˆ3.1, 10.1, 10.1 Hz, 0.66H), 3.42 ,m, 0.34H),
3.89 ,m, 0.66H), 4.36 ,m, 0.34H), 4.54 ,d, Jˆ10.1 Hz,
0.34H), 4.68,d, Jˆ10.1 Hz, 0.66H), 4.95±5.25 ,m, 2H),
5.57 ,ddd, Jˆ10.1, 10.1, 17.4 Hz, 0.34H), 5.68,ddd,
Jˆ10.1, 10.1, 17.4 Hz, 0.66H), 6.94 ,s, 2H); LRMS
,FAB) m/z 340 ,MH1, 100), 254, 119.
hexane. Mp 100±1058C; [a]D ˆ235.2 ,c 0.29, CHCl3); 1H
30
NMR ,CDCl3, 270 MHz) d: 0.72 ,d, Jˆ7.0 Hz, 3H), 0.78,d,
Jˆ7.0 Hz, 3H), 0.83 ,d, Jˆ7.0 Hz, 3H), 0.89 ,d, Jˆ7.0 Hz,
3H), 1.61 ,m, 1H), 1.73 ,m, 1H), 1.77 ,d, Jˆ4.9 Hz, 1H),
2.29 ,s, 3H), 2.35 ,dt, Jˆ5.4, 10.3 Hz, 1H), 2.64 ,s, 6H),
3.07 ,dt, Jˆ4.9, 6.2 Hz, 1H), 3.40 ,dt, Jˆ5.4, 9.2 Hz, 1H),
4.39 ,d, Jˆ9.2 Hz, 1H), 5.13 ,dd, Jˆ1.6, 17.0 Hz, 1H), 5.22
,dd, Jˆ1.6, 10.3 Hz, 1H), 5.67 ,dt, Jˆ10.3, 17.0 Hz, 1H),
6.93 ,s, 2H); 13C NMR ,CDCl3, 67.8MHz) d: 17.4, 18.1,
19.4, 20.0, 21.1, 23.4, 30.9, 31.8, 49.3, 60.4, 77.0, 120.5,
132.1, 134.9, 136.2, 138.4, 142.0. Anal. calcd for
C20H33NO3S: C, 65.36; H, 9.05; N, 3.81. Found: C, 64.90;
30
H, 8.82; N, 3.68. 7b. A colorless oil; [a]D ˆ228.1 ,c
1
0.401, CHCl3); H NMR ,CDCl3, 270 MHz) d: 0.41 ,d,
Jˆ7.0 Hz, 3H), 0.73 ,d, Jˆ6.8Hz, 3H), 0.80 ,d,
Jˆ6.8Hz, 3H), 0.98,d, Jˆ6.5 Hz, 3H), 1.63 ,dqq, Jˆ6.8,
6.8, 9.6 Hz, 1H), 1.88 ,dqq, Jˆ3.4, 6.5, 7.0 Hz, 1H), 2.21
,dt, Jˆ1.6, 10.0 Hz, 1H), 2.92 ,s, 3H), 2.65 ,s, 6H), 2.98,d,
Jˆ5.3 Hz, 1H), 3.37 ,dt, Jˆ3.4, 10.0 Hz, 1H), 3.43 ,ddd,
Jˆ1.6, 5.3, 9.6 Hz, 1H), 4.62 ,d, Jˆ10.0 Hz, 1H), 5.04 ,dd,
Jˆ1.9, 17.0 Hz, 1H), 5.09 ,dd, Jˆ1.9, 10.0 Hz,1H), 5.69 ,dt,
Jˆ10.0, 17.0 Hz, 1H), 6.94 ,s, 2H); LRMS ,FAB) m/z 368
,MH1) 350, 254, 252, 183, 151, 119 ,100); HRMS ,FAB)
m/z calcd for C20H34NO3S ,MH1) 368.2259; found:
368.2250.
4.1.6. syn,syn-Alcohol 8a. Table 2, entry 7. To a stirred
4.1.8. Boc-Aziridine 10. To a stirred solution of ,3RS,4S)-4-

M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
5237
[N-,tert-butoxycarbonyl)amino]-5-methylhexene-3-ol ,340
mg, 0.1.48mmol) in THF ,4 ml) were added PPh 3
,468mg, 1.78mmol) and diethyl azodicarboxylate ,40%
solution in toluene, 807 ml, 1.78 mmol) at 08C, and the
mixture was stirred for 5 h. The mixture was concentrated
in vacuo to give an oily residue, which was puri®ed by SiO2
¯ash chromatography. Elution with hexane±AcOEt ,5:1)
gave 10 ,175 mg, 56%). 10 ,cis±transˆ6:1). A colorless
was concentrated in vacuo and the residue was extracted
with ether, the extract was washed with a 10% citric acid
solution, a saturated NaHCO3 solution and brine, and then
dried over MgSO4. Usual workup followed by ¯ash chro-
matography over silica gel with hexane±AcOEt ,5:1) gave
14 ,166 mg, 72%) and cis-adduct ,24 mg, 10%). 14. A
colorless oil; [a]D ˆ221.9 ,c 0.366, CHCl3); H NMR
,CDCl3, 270 MHz) d: 0.94 ,d, Jˆ7.0 Hz, 3H), 0.96 ,d,
Jˆ7.0 Hz, 3H), 1.54 ,s, 9H), 2.29 ,dq, Jˆ7.0, 4.1 Hz, 1H),
3.89 ,dd, Jˆ4.1, 3.0 Hz, 1H), 4.46 ,dd, Jˆ5.5, 3.0 Hz, 1H),
5.31 ,d, Jˆ10.3 Hz, 1H), 5.41 ,d, Jˆ16.7 Hz, 1H), 5.85
,ddd, Jˆ16.7, 10.3, 5.5 Hz, 1H). LRMS ,FAB) m/z 256
,MH1), 200 ,100); HRMS ,FAB), m/z calcd. for
C13H22NO4 ,MH1) 256.1549, found: 256.1557.
17
1
1
oil; H NMR ,CDCl3, 270 MHz) d: 0.88 ,d, Jˆ6.8Hz,
18/7H), 0.98 ,d, Jˆ6.8Hz, 3/7H), 1.06 ,d, Jˆ6.8Hz,
3/7H), 1.13 ,d, Jˆ6.8Hz, 18/7H), 1.3±1.5 ,m, 1H), 1.45
,s, 9H), 2.16 ,dd, Jˆ9.6, 6.8Hz, 6/7H), 2.22 ,dd, Jˆ7.7,
6.1 Hz, 1/7H), 2.80 ,dd, Jˆ7.6, 3.2 Hz, 1/7H), 2.98,t,
Jˆ6.8Hz, 6/7H), 5.24±5.30 ,m, 1H), 5.39±5.47 ,m, 1H),
5.67 ,m, 1H). Anal. calcd for C12H21NO2: C, 68.21; H,
10.02; N, 6.63. Found: C, 67.95; H, 10.16; N, 6.37.
4.1.12. syn,syn-Alcohol 16a. Table 3, entry 1. The same
treatment of 10 ,40.0 mg, 0.189 mmol) and benzaldehyde
,29 ml, 0.31 mmol) as described for 2a afforded the oily
residue, which was puri®ed by SiO2 ¯ash chromatography
with hexane±AcOEt ,5:1) gave 16b ,3.2 mg, 5%) and 16a
,28mg, 46%). Entry 4. The same treatment of 12 ,60.0 mg,
0.221 mmol) and benzaldehyde ,50 ml, 0.44 mmol) as
described above gave 16b ,4.2 mg, 6%) and 16a ,55 mg,
78%). Entry 6. The same treatment of 14 ,48.0 mg,
0.188 mmol) and benzaldehyde ,38 ml, 0.38mmol) as
described above gave 16b ,3.8mg, 6%) and 16a ,50 mg,
4.1.9. Boc-Aziridine 11. The same treatment of ,3RS,4S)-4-
[N-,tert-butoxycarbonyl)amino]-5-tert-butyldimethylsiloxy-
penten-3-ol ,200 mg, 0.603 mmol) as described for 10 gave
1
11 ,143 mg, 76%). 11 ,cis±transˆ6:1). A colorless oil; H
NMR ,CDCl3, 270 MHz) d: 0.06 ,s, 3H), 0.07 ,s, 3H), 0.90
,s, 9H), 1.45 ,s, 9H), 2.57 ,dt, Jˆ4.5, 3.0 Hz, 1/7H), 2.71 ,dt,
Jˆ6.5, 5.4 Hz, 6/7H), 2.94 ,m, 1/7H), 3.03 ,t, Jˆ6.5 Hz,
6/7H), 3.53 ,dd, Jˆ8.5, 6.5 Hz, 6/7H), 3.69 ,dd, Jˆ11.3,
4.9 Hz, 1/7H), 3.80 ,dd, Jˆ8.5, 5.4 Hz, 6/7H), 3.89 ,dd,
Jˆ11.3, 4.0 Hz, 1/7H), 5.26±5.31 ,m, 1H), 5.38±5.48 ,m,
1H), 5.69 ,ddd, Jˆ16.7, 10.3, 6.5 Hz, 1H); 13C NMR
,CDCl3, 67.8MHz) d ,major): 24.8, 24.5, 18.5, 26.1,
28.1, 42.8, 44.3, 61.2, 81.5, 119.8, 131.9, 162.3; LRMS
,FAB) m/z 314 ,MH1), 258, 200, 73 ,100); HRMS ,FAB),
m/z calcd. for C16H32NO3Si ,MH1) 314.2152, found:
314.2165.
26
83%). 16a. A colorless oil; [a]D ˆ288.8 ,c 0.965, CHCl3);
1H NMR ,CDCl3, 270 MHz) d: 0.82 ,d, Jˆ6.8Hz, 6H), 1.46
,s, 9H), 1.61 ,dqq, Jˆ6.8, 6.8, 7.8 Hz, 1H), 2.58 ,ddd,
Jˆ3.0, 6.5, 10.0 Hz, 1H), 2.82 ,br, 1H), 3.33 ,ddd, Jˆ3.0,
7.8, 10.0 Hz, 1H), 4.42 ,d, Jˆ10.0 Hz, 1H), 4.73 ,d,
Jˆ6.5 Hz, 1H), 5.06 ,dd, Jˆ1.6, 17.3 Hz, 1H), 5.26 ,dd,
Jˆ1.6, 10.0 Hz, 1H), 5.81 ,dt, Jˆ10.0, 17.3 Hz, 1H),
7.23±7.35 ,m, 5H); 13C NMR ,CDCl3, 67.8MHz) d: 18.6,
19.9, 28.6, 32.0, 54.2, 57.0, 75.5, 79.5, 120.7, 127.1, 127.7,
128.3, 134.2, 142.7, 156.4; LRMS ,FAB) m/z 320 ,MH1),
246, 116 ,100); HRMS ,FAB) m/z calcd for C19H30NO3
,MH1) 320.2225; found: 320.2214. 16b. A colorless oil;
4.1.10. Acetate 12. To a stirred solution of ,3RS,4S)-4-[N-
,tert-butoxycarbonyl)amino]-5-methylhexen-3-ol ,500 mg,
2.18mmol) in CH 2Cl2 ,1 ml) were added pyridine
,4.4 ml), DMAP ,13 mg, 0.11 mmol) and Ac2O ,2.0 ml,
21.8mmol), and the mixture was stirred at room tempera-
ture for 1 h. After quenching with citric acid, the mixture
was extracted with ether. The extract was washed with
water, a saturated NaHCO3 solution and brine, and dried
over MgSO4. Usual workup followed by ¯ash chromato-
graphy over silica gel with hexane±AcOEt ,8:1) gave 12
,425 mg, 72%). 12 ,syn±antiˆ6:1). A colorless oil; 1H
NMR ,CDCl3, 270 MHz) d: 0.89 ,d, Jˆ6.5 Hz, 3/7H),
0.92 ,d, Jˆ7.2 Hz, 18/7H), 0.95 ,d, Jˆ7.2 Hz, 18/7H),
0.99 ,d, Jˆ6.5 Hz, 3/7H), 1.44 ,s, 9H), 1.71 ,m, 1H), 2.07
,s, 3/7H), 2.09 ,s, 18/7H), 3.37 ,m, 1/7H), 3.55 ,ddd,
Jˆ10.9, 7.2, 3.9 Hz, 6/7H), 3.70 ,m, 1/7H), 4.37 ,d,
Jˆ10.5 Hz, 1/7H), 4.58,d, Jˆ10.3 Hz, 6/7H), 5.1±5.6 ,m,
3H), 5.6±6.0 ,m, 1H); 13C NMR ,CDCl3, 67.8MHz) d
,major): 18.4, 20.1, 21.2, 28.6, 30.0, 58.5, 74.6, 79.4,
118.0, 134.4, 156.3, 170.2; LRMS ,FAB), m/z 272
,MH1), 216, 172, 156 ,100); HRMS ,FAB), m/z calcd. for
C14H26NO4 ,MH1) 272.1862, found: 272.1857.
[a]D ˆ235.6 ,c 0.358, CHCl3); 1H NMR ,CDCl3,
33
270 MHz) d: 0.80 ,d, Jˆ6.8Hz, 3H), 0.98,d, Jˆ6.8Hz,
3H), 1.47 ,s, 9H), 2.06 ,dqq, Jˆ3.0, 6.8, 6.8 Hz, 1H), 2.18
,dt, Jˆ1.9, 10.4 Hz, 1H), 3.77 ,dt, Jˆ1.9, 10.4 Hz, 1H), 4.27
,d, Jˆ4.3 Hz, 1H), 4.56 ,dd, Jˆ1.9, 17.3 Hz, 1H), 4.63 ,d,
Jˆ10.4 Hz, 1H), 4.89 ,dd, Jˆ1.9, 10.4 Hz, 1H), 4.94 ,m,
1H), 5.69 ,dt, Jˆ10.4, 17.3 Hz, 1H), 7.15±7.32 ,m, 5H);
LRMS ,FAB) m/z 320 ,MH1), 246, 116 ,100); HRMS
,FAB) m/z calcd for C19H30NO3 ,MH1) 320.2225; found:
320.2235.
4.1.13. syn,syn-Alcohol 17a. Table 3, entry 2. The same
treatment of 9 ,111 mg, 0.354 mmol) and benzaldehyde
,72 ml, 0.71 mmol) as described for 2a afforded the oily
residue, which was puri®ed by SiO2 ¯ash chromatography
with hexane±AcOEt ,5:1) to give 17b as a diastereomixture
,10.4 mg, 7%) and 17a as a single isomer ,76 mg, 51%).
32
1
17a. A colorless oil; [a]D ˆ215.9 ,c 0.508, CHCl3); H
NMR ,CDCl3, 500 MHz) d: 0.02 ,s, 3H), 0.04 ,s, 3H), 0.88
,s, 9H), 1.44 ,s, 9H), 2.70 ,m, 1H), 3.20 ,br, 1H), 3.50 ,m,
1H), 3.64 ,m, 1H), 3.75 ,m, 1H), 4.67 ,m, 1H), 4.87 ,br, 1H),
4.96 ,d, Jˆ16.5 Hz, 1H), 5.16 ,d, Jˆ10.0 Hz, 1H), 5.84 ,dt,
Jˆ10.0, 16.5 Hz, 1H), 7.24±7.32 ,m, 5H); LRMS ,FAB)
m/z 422 ,MH1), 322, 308, 218 ,100); HRMS ,FAB) m/z
calcd. for C23H40NO4Si ,MH1) 422.2727; found: 422.2721.
4.1.11. Oxazolidinone 14. To a stirred solution of a mixture
of ,4R,5S)- and ,4R,5R)-4-isopropyl-5-vinyloxazolidin-2-
one 15 ,140 mg, 0.902 mmol) in THF ,3 ml) were added
Et3N ,137 ml, 0.992 mmol), DMAP ,110 mg, 0.902 mmol)
and Boc2O ,216 mg, 0.992 mmol), and the resulting mixture
was stirred at room temperature for 15 h. After the mixture

5238
M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
4.1.14. syn,syn-Alcohol 18a. Table 3, entry 3. The same
treatment of 11 ,65 mg, 0.207 mmol; cis±transˆ7:1) and
trans-cinnamaldehyde ,39 ml, 0.31 mmol) as described for
2a afforded the oily residue, which was puri®ed by SiO2
¯ash chromatography with hexane±AcOEt ,7:1) to give
18b as a diastereomixture ,10 mg, 11%) and 18a as a single
Jˆ17.1 Hz, 1H), 5.16 ,d, Jˆ10.4 Hz, 1H), 5.41 ,d,
Jˆ3.3 Hz, 1H), 5.47 ,ddd, Jˆ8.8, 10.4, 17.1 Hz, 1H), 5.67
,br s, 1H), 7.25±7.40 ,m, 5H); LRMS ,FAB) m/z 246
,MH1), 149, 116 ,100); HRMS ,FAB) m/z calcd for
C15H20NO2 ,MH1) 246.1494; found: 246.1491.
19
isomer ,32 mg, 35%). 18a. A colorless oil; [a]D ˆ122.3 ,c
4.1.18. Ester 22. A solution of 2a ,10 mg, 0.025 mmol) in a
mixture of MeOH ,2 ml) and CH2Cl2 ,1 ml) was treated
with a stream O3/O2 at 2788C until blue color persisted.
After the solution was purged with O2 to remove excess
O3, Me2S ,5.5 ml, 0.074 mmol) was added and the mixture
was stirred at 2788C for 0.5 h and then at room temperature
for 1 h. The mixture was concentrated in vacuo and the
residue was used for the following reaction. To a solution
of the crude aldehyde and 2-methyl-2-butene ,5.0 ml,
0.10 mmol) in t-BuOH ,1 ml) was added a solution of
NaClO2 ,4.5 mg, 0.050 mmol) and NaH2PO4 ,7.5 mg,
0.062 mmol) in water, and the resulting mixture was stirred
vigorously for 40 min. After addition of a 10% HCl solution
for acidi®cation, the mixture was extracted with CHCl3 and
the organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was dissolved in a mixture of benzene±
MeOH ,4:1, 1.25 ml) and TMSCHN2 ,10% solution in
n-hexane, 77 ml, 0.068mmol) was added to the solution,
and the mixture was stirred at room temperature for 1 h.
After concentration in vacuo, the residue was puri®ed by
column chromatography over silica gel with hexane±AcOEt
,5:1) to give 22 ,9.6 mg, 89%). 22. A colorless oil;
1.47, CHCl3); 1H NMR ,CDCl3, 270 MHz) d: 0.08,s, 6H),
0.91 ,s, 9H), 1.44 ,s, 9H), 2.56 ,ddd, Jˆ4.8, 4.8, 10.0 Hz,
1H), 3.60 ,dd, Jˆ5.1, 10.0 Hz, 1H), 3.74 ,dd, Jˆ4.0,
10.0 Hz, 1H), 3.92 ,m, 1H), 4.45 ,dd, Jˆ4.8, 6.2 Hz, 1H),
4.68,br d, Jˆ8.1 Hz, 1H), 5.17 ,d, Jˆ17.1 Hz, 1H), 5.26 ,d,
Jˆ10.0 Hz, 1H), 5.86 ,td, Jˆ10.0, 17.1 Hz, 1H), 6.23 ,dd,
Jˆ6.2, 15.9 Hz, 1H), 6.61 ,d, Jˆ15.9 Hz, 1H), 7.20±7.39
,m, 5H); 13C NMR ,CDCl3, 67.8MHz) d: 24.8, 24.5, 18.4,
26.1, 28.6, 51.8, 53.1, 63.6, 72.5, 79.9, 120.1, 126.8, 127.7,
128.7, 130.7, 131.0, 134.2, 137.2, 156.0; LRMS ,CI) m/z
448,MH 1), 446, 374, 346, 294 ,100); HRMS ,CI) m/z calcd
for C25H42NO4Si ,MH1) 448.2883; found: 448.2866.
4.1.15. syn,syn-Alcohol 19a. Table 3, entry 5. The same
treatment of 13 ,39 mg, 0.160 mmol) and benzaldehyde
,33 ml, 0.32 mmol) as described for 2a afforded the oily
residue, which was puri®ed by SiO2 ¯ash chromatography
with hexane±AcOEt ,5:1) to give 19b as a diastereomixture
,4.9 mg, 11%) and 19a as a single isomer ,21 mg, 44%).
21
1
19a. A colorless oil; [a]D ˆ268.8 ,c 1.61, CHCl3); H
NMR ,CDCl3, 500 MHz) d: 1.08,d, Jˆ6.4 Hz, 3H), 1.45
,s, 9H), 2.30 ,ddd, Jˆ3.4, 6.4, 9.8Hz, 1H), 2.69 ,br s, 1H),
3.78,br s, 1H), 4.38,br s, 1H), 4.82 ,br s, 1H), 5.05 ,d,
Jˆ17.4 Hz, 1H), 5.28,d, Jˆ9.8Hz, 1H), 5.84 ,td, Jˆ9.8,
17.4 Hz, 1H), 7.24±7.43 ,m, 5H); LRMS ,FAB) m/z 292
,MH1), 236, 218, 154, 88 ,100); HRMS ,FAB) m/z calcd
for C17H26NO3 ,MH1) 292.1913; found: 292.1921.
[a]D ˆ244.6 ,c 0.552, CHCl3); 1H NMR ,CDCl3,
15
270 MHz) d: 0.72 ,d, Jˆ7.0 Hz, 6H), 1.83 ,dq, Jˆ5.4,
7.0 Hz, 1H), 2.31 ,s, 3H), 2.47 ,d, Jˆ5.1 Hz, 1H), 2.63 ,s,
6H), 3.03 ,dd, Jˆ3.2, 8.6 Hz, 1H), 3.22 ,ddd, Jˆ3.2, 5.4,
8.8 Hz, 1H), 3.68 ,s, 3H), 4.71 ,dd, Jˆ4.3, 8.6 Hz, 1H), 6.17
,d, Jˆ8.8 Hz, 1H), 6.97 ,s, 2H), 7.00±7.04 ,m, 2H), 7.26±
7.30 ,m, 3H); 13C NMR ,CDCl3, 67.8MHz) d: 17.6, 18.8,
21.1, 23.1, 32.9, 51.6, 52.4, 58.1, 74.2, 126.9, 128.8, 128.9,
132.1, 137.0, 138.3, 141.0, 141.8, 174.9; LRMS ,FAB) m/z,
434 ,MH1), 254 ,100); HRMS ,FAB) m/z calcd for
C23H32NO5S ,MH1) 434.2002, found: 434.2009.
4.1.16. Oxazinone 20. To a stirred suspension of NaH ,60%
suspension, 2.0 mg, 0.046 mmol) in DMF ,0.5 ml) was
added a solution of 16a ,9.7 mg, 0.030 mmol) in THF
,1 ml) at 08C under an argon atmosphere, and the mixture
was stirred at room temperature for 3 h. After quenched
with a 10% citric acid solution, the mixture was extracted
with AcOEt. The extract was washed with a saturated
NaHCO3 solution, water and brine, and dried over
MgSO4. Usual workup followed by ¯ash chromatography
with hexane±AcOEt ,1:1) gave 20 ,5.4 mg, 72%). 20.
Colorless crystals from Et2O±hexane. Mp 154±1568C;
4.1.19. Ester 23. The same treatment of 5a ,9.3 mg,
0.022 mmol) as described for 22 gave the crude product,
which was puri®ed by column chromatography over silica
gel with hexane±AcOEt ,3:1) to give 23 ,6.3 mg, 63%). 23:
16
1
A colorless oil; [a]D ˆ239.4 ,c 0.360, CHCl3); H NMR
,CDCl3, 270 MHz) d: 0.72 ,d, Jˆ6.8Hz, 6H), 1.79 ,dq,
Jˆ5.4, 6.8Hz, 1H), 2.23 ,d, Jˆ4.6 Hz, 1H), 2.32 ,s, 3H),
2.63 ,s, 6H), 3.00 ,dd, Jˆ3.0, 9.3 Hz, 1H), 3.16 ,ddd, Jˆ3.0,
5.4, 8.6 Hz, 1H), 3.71 ,s, 3H), 3.81 ,s, 3H), 4.66 ,dd, Jˆ4.6,
9.3 Hz, 1H), 6.25 ,d, Jˆ8.6 Hz, 1H), 6.78±6.82 ,m, 2H),
6.90±6.97 ,m, 4H); 13C NMR ,CDCl3, 67.8MHz) d: 17.5,
19.0, 21.1, 23.1, 33.1, 51.4, 52.5, 55.5, 58.1, 73.9, 114.2,
128.3, 132.1, 133.0, 137.0, 138.3, 139.4, 141.8, 175.1;
LRMS ,FAB) m/z 464 ,MH1), 254 ,100), 154; LRMS
,FAB) m/z calcd for C24H34NO6S ,MH1) 464.2106, found:
464.2112.
[a]D ˆ243.1 ,c 0.252, CHCl3); 1H NMR ,CDCl3,
32
500 MHz) d: 0.92 ,d, Jˆ6.4 Hz, 3H), 1.04 ,d, Jˆ6.7 Hz,
3H), 1.65 ,qqd, Jˆ6.4, 6.7, 10.5 Hz, 1H), 2.73 ,ddd, Jˆ1.8,
3.6, 10.5 Hz, 1H), 3.33 ,dd, Jˆ3.6, 10.5 Hz, 1H), 4.76 ,dd,
Jˆ1.3, 17.0 Hz, 1H), 5.11 ,dd, Jˆ1.3, 10.5 Hz, 1H), 5.42 ,br
s, 1H), 5.49 ,d, Jˆ1.8Hz, 1H), 5.67 ,ddd, Jˆ10.5, 10.5,
17.0 Hz, 1H), 7.26±7.35 ,m, 5H); LRMS ,FAB) m/z 246
,MH1), 116 ,100); HRMS ,FAB) m/z calcd for
C15H20NO2 ,MH1) 246.1494; found: 246.1497.
4.1.17. Oxazinone 21. The same treatment of 16b ,9.0 mg,
0.0282 mmol) as described for 20 and puri®cation by SiO2
column chromatography with hexane±AcOEt ,3:1) gave 21
4.1.20. Ester 24. The same treatment of 6a ,9.8mg,
0.023 mmol) as described for 22 gave the crude product,
which was puri®ed by column chromatography over silica
gel with hexane±AcOEt ,5:1) to give 24 ,6.1 mg, 58%). 24:
32
,3.3 mg, 48%). 21. A colorless oil; [a]D ˆ232.6 ,c 0.291,
CHCl3); 1H NMR ,CDCl3, 500 MHz) d: 1.01 ,d, Jˆ6.8Hz,
6H), 1.86 ,sepd, Jˆ6.8, 6.7 Hz, 1H), 2.82 ,ddd, Jˆ3.3, 5.8,
8.8 Hz), 3.07 ,ddd, Jˆ2.1, 5.8, 6.7 Hz, 1H), 5.11 ,d,
17
1
A colorless oil; [a]D ˆ255.3 ,c 0.235, CHCl3); H NMR
,CDCl3, 270 MHz) d: 0.70 ,d, Jˆ6.8Hz, 3H), 0.71 ,d,

M. Anzai et al. / Tetrahedron 58 *2002) 5231±5239
5239
Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.;
Yamamoto, Y. Angew. Chem. Int. Ed. Engl. 1994, 33, 652±
654. ,f) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi,
Y.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1991, 56,
4370±4382.
Jˆ6.8Hz, 3H), 1.77 ,dqq, Jˆ5.4, 6.8, 6.8 Hz, 1H), 2.31 ,s,
3H), 2.63 ,s, 6H), 2.97 ,dd, Jˆ3.2, 8.4 Hz, 1H), 3.23 ,ddd,
Jˆ3.2, 5.4, 8.6 Hz, 1H), 3.68 ,s, 3H), 4.79 ,dd, Jˆ5.0,
8.4 Hz, 1H), 6.15 ,d, Jˆ8.6 Hz, 1H), 6.96 ,s, 2H), 7.03±
7.07 ,m, 2H), 7.26±7.30 ,m, 2H); 13C NMR ,CDCl3,
67.8MHz) d: 17.8, 18.8, 21.1, 23.1, 32.7, 51.9, 52.5, 58.2
73.5, 128.3 129.0, 132.1, 134.4, 136.8, 138.3, 139.7, 141.9,
174.6; LRMS ,FAB) m/z 468,MH 1), 254 ,100), 119;
HRMS ,FAB) m/z calcd for C23H31ClNO5S ,MH1)
468.1611, found: 468.1592.
3. ,a) Alezra, V.; Bonin, M.; Micouin, L.; Husson, H.-P.
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Acknowledgements
This work was supported in part by The Japan Health
Sciences Foundation and Grant-in-Aid for Scienti®c
Research ,C) from the Ministry of Education, Science,
Sports, and Culture, Japan.
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