Highly Diastereoselective Conjugate Addition of Lithium Dialkylamides to α,β-Unsaturated Esters Having a Chiral Center at the γ-Position

Article abstract of DOI:10.1021/jo970435d

The conjugate addition of lithium amides 2 to tert-butyl 4-(OR)-substituted-2-pentenoates 1 produced a mixture of the syn- and anrt-amino esters (3 and 4) in high yields. Sterically bulky OR groups, such as trityloxy and tert-butyldiphenylsilyloxy, gave t

Full text of DOI:10.1021/jo970435d

6274
J . Org. Chem. 1997, 62, 6274-6282
High ly Dia ster eoselective Con ju ga te Ad d ition of Lith iu m
Dia lk yla m id es to r,â-Un sa tu r a ted Ester s Ha vin g a Ch ir a l Cen ter
a t th e γ-P osition
Naoki Asao, Takashi Shimada, Tomoko Sudo, Naofumi Tsukada, Kazuhiko Yazawa,
Young Soo Gyoung, Tadao Uyehara, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-77, J apan
Received March 10, 1997X
The conjugate addition of lithium amides 2 to tert-butyl 4-(OR)-substituted-2-pentenoates 1 produced
a mixture of the syn- and anti-amino esters (3 and 4) in high yields. Sterically bulky OR groups,
such as trityloxy and tert-butyldiphenylsilyloxy, gave the syn diastereomer 3 either exclusively or
predominantly. The syn-selectivity may be explained by a modified Felkin-Anh model. The use
of tert-butyldimethylsilyloxy as an OR group afforded a nearly 1:1 mixture of diastereoisomers,
and the use of the smallest MeO group produced a 63:37 mixture of the syn 3 and anti isomer 4.
The presence of Me group at the R-position (C-2 position) of the enoate enhanced the syn
diastereoselectivity up to 100%; the conjugate addition to tert-butyl 4-methoxy-2-methyl-2-
pentenoate (17) gave the syn-isomer 18 exclusively. This enhancement may be explained by the
combination of chelation and allylic strain model 19 in which the smallest H orients inside to avoid
an allylic strain. A phenyl group at the γ-position enhanced the anti selectivity in the case of
γ-alkoxy-R,â-enoates such as isopropyl 4-[(tert-butyldimethylsilyl)oxy]-4-phenyl-2-butenoate (20),
and in the case of γ-alkyl-R,â-enoates such as tert-butyl 4-phenyl-2-pentenoate (27).
Sch em e 1
â-Amino acids are synthetic precursors of â-lactams
and are also present in certain peptides. In this respect,
enantioselective synthesis of â-amino acids is becoming
an important and challenging synthetic problem. Among
several methods for the synthesis of optically active
â-amino acids, the conjugate addition of amine nucleo-
philes to R,â-unsaturated carbonyl compounds is one of
the most popular and useful procedures.1
There are three possible ways for asymmetric induction
in the conjugate addition of amine nucleophiles to
Michael acceptors (Scheme 1): (1) the use of chiral
auxiliaries Y* (process A); (2) the use of chiral amine
nucleophiles Y*NM (process B); (3) the use of γ-chiral-
R,â-unsaturated esters (process C). The chiral auxiliary
method (A) has been studied widely and deeply,2 and a
high level of enantioselectivity has been accomplished.
More recently, the conjugate addition of chiral lithium
amides (B) was studied by Davies,3 Hawkins,4 Enders,5
and our group,6 and very high asymmetric induction has
been achieved. However, little was known about the
diastereoselectivity of 1,2-asymmetric induction in the
conjugate addition of metal amides to R,â-unsaturated
esters having a chiral center at the γ-position. We report
how to enhance the 1,2-asymmetric induction and how
to control the diastereoselectivity in the process C.
Resu lt a n d Discu ssion
Before we started to investigate the diastereoselectivity
of 1,2-asymmetric induction in the conjugate addition of
metal amides, the addition of amines,7 alkoxides,8 and
carbon nucleophiles9 to R,â-enoates bearing a chiral
center at the γ-position had been reported. The syn-
selectivity was reported previously for the conjugate
addition of benzylamine7a,b and various alkoxides8 to
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) For review articles; (a) Cole, D. C. Tetrahedron 1994, 50, 9517.
(b) J uaristi, E.; Quintana, D.; Escalante, J . Aldrichim. Acta 1994, 27(1),
3. (c) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 117.
(2) (a) d’Angelo, J .; Maddaluno, J . J . Am. Chem. Soc. 1986, 108,
8112. (b) Yamamoto,Y.; Asao, N.; Uyehara, T. J . Am. Chem. Soc. 1992,
114, 5427. (c) Mezrhab, B.; Dumas, F.; d’Angero, J .; Riche, C. J . Org.
Chem. 1994, 59, 500. (d) Asao, N.; Uyehara, T.; Tsukada, N.; Yama-
moto, Y.; Bull. Chem. Soc. J pn. 1995, 68, 2103. (e) Dumas, F.; Mezrhab,
B.; d’Angelo, J . J . Org. Chem. 1996, 61, 2293.
(3) (a) Davies, S. G.; Ichihara, O. Tetrahedron Asymmetry 1991, 2,
183. (b) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461.
(c) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J . Chem.
Soc., Chem. Commun. 1993, 1153. (d) Bunnage, M. E.; Davies, S. G.;
Goodwin, C. J . J . Chem. Soc., Perkin Trans. 1 1993, 1375. (e) Davies,
S. G.; Ichihara, O.; Walters, I. A. S. J . Chem. Soc., Perkin Trans. 1
1994, 1141. (f) Costello, J . F.; Davies, S. G.; Ichihara, O. Tetrahedron
Asymmetry 1994, 5, 1999. (g) Bunnage, M. E.; Burke, A. J .; Davies, S.
G.; Goodwin, C. J . Tetrahedron Asymmetry 1995, 6, 165. (h) Davies,
S. G.; Fenwick, D. R. J . Chem. Soc., Chem. Commun. 1995, 1109.
(4) (a) Hawkins, J . M.; Fu, G. C. J . Org. Chem. 1986, 51, 2820. (b)
Rudolf, K.; Hawkins, J . M.; Loncharich, J .; Houk, K. N. J . Org. Chem.
1988, 53, 3879. (c) Hawkins, J . M.; Lewis, T. A. J . Org. Chem. 1992,
57, 2114. (d) Hawkins, J . M.; Lewis, T. A. J . Org. Chem. 1994, 59,
649.
(6) (a) Asao, N.; Tsukada, N.; Yamamoto, Y. J . Chem. Soc., Chem.
Commun. 1993, 1660. (b) Tsukada, N.; Shimada, T.; Gyoung, Y. S.;
Asao, N.; Yamamoto, Y. J . Org. Chem. 1995, 60, 143.
(7) (a) Matsunaga, H.; Sakamaki, T.; Nagaoka, H.; Yamada, Y.
Tetrahedron Lett. 1983, 24, 3009. (b) Dondoni, A.; Boscarato, A.; Marra,
A. Synlett 1993, 256. (c) For the addition to 5-alkoxy-2(5H)-furanones,
de Lange, B.; van Bolhuis, F.; Feringa, B. L. Tetrahedron 1989, 45,
6799. (d) For the addition to 2-(hydroxyalkyl)propenoates, Perlmutter,
P.; Tabone, M. Tetrahedron Lett. 1988, 29, 949. (e) Asao, N.; Shimada,
T.; Tsukada, N.; Yamamoto, Y. Tetrahedron Lett. 1994, 35, 8425. (f)
Hausermann, U. A.; Linden, A.; Song, J .; Hesse, M. Helv. Chim. Acta
1996, 79, 1995.
(8) Mulzer, J .; Kappert, M.; Huttner, G.; J ibril, I. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 704.
(9) For the most recent article, Yamamoto, Y.; Chounan, Y.; Nishii,
S.; Ibuka, T.; Kitahara, H. J . Am. Chem. Soc. 1992, 114, 7652, and
references cited therein.
(5) (a) Enders, D.; Bettray, W.; Raabe, G.; Runsink, J Synthesis
1994, 1322. (b) Enders, D.; Walh, H.; Bettray, W. Angew. Chem., Int.
Ed. Engl. 1995, 34, 455.
S0022-3263(97)00435-0 CCC: $14.00 © 1997 American Chemical Society

Diastereoselective Conjugate Addition
J . Org. Chem., Vol. 62, No. 18, 1997 6275
Ta ble 1. Dia ster eoselectivity on th e Con ju ga te Ad d ition
of 2 to 1
tween the hydrogen at the â-position and that of the
γ-position. A similar method was used for the structural
determination of 3b-d (eq 2). The ester group of 4f was
reduced by LiAlH4, and the resulting alcohol was me-
thylated with NaH/MeI, giving 6 in good yield. Desilyl-
ation of 4d followed by lactonization, as mentioned above,
gave 5b-tr a n s. The reduction of 5b-tr a n s with LiAlH4
gave the corresponding diol, which was methylated with
NaH/MeI in 75% yield. The spectroscopic data of the
resulting dimethyl ether was completely identical to those
of 6, indicating the anti-stereochemistry of 4f. 3e was
lithium
diastereomer ratio
total yield
entry enoates 1 amides 2
syn-3:anti-4
(isolated)/%
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
2a
2a
2a
2b
2a
2b
54:46
89:11
90:10
91
99
95
79
77
83
30:70
∼100:-
63:37
acyclic R,â-enoates and their derivatives. A more com-
plex situation holds for the addition of organometallic
reagents (carbon nucleophiles) to acyclic γ-alkoxy-R,â-
enoates and enones;9 the anti-selectivity has been ob-
served frequently with organocopper reagents, but in
certain cases organolithium and copper reagents have
reacted with syn-selectivity. During our investigation,
it was reported that the Michael addition of chiral
γ-amino-substituted-R,â-unsaturated esters with nitro-
gen nucleophiles of the type Me3SiNHOSiMe3 and MeN-
HOH proceeded diastereoselectively.10
We first investigated the diastereoselectivity on the
addition of lithium amides LiNR1R2 2 to γ-silyloxy and
alkoxy-R,â-unsaturated esters 1 (eq 1). The results are
summarized in Table 1. The reaction of tert-butyldi-
converted to 7 in 77% yield by the three-component
coupling (TCC) procedure.6,7e Treatment of 7 with Et-
MgBr gave 8 in 81% yield. Detritylation of 8 gave 9 in
96% yield. Treatment of 9 with PPh3/CCl4 gave 10 in
good yield. The TCC method was used for 3b, giving 11
in 75% yield. Treatment of 11 with CF3CO2H followed
by PPh3/2,2′-dipyridyl disulfide gave 12 in 88% yield.
Desilylation of 12 gave 13 in 77% yield. The reaction of
13 with PPh3/CCl4 afforded 14 in 92% yield. The acetyl
group of 14 was removed, and the OH group was
protected with TBDMSCl. The spectroscopic data of the
resulting TBDMS derivative were completely identical
to those of 10, indicating the syn-stereochemistry of 3e
(Scheme 2).
The syn-selectivity for 1b-d can be accounted for by a
modified Felkin-Anh model 15, in which OR group
becomes anti, Me orients inside, and the nucleophile 2a
attacks from the less hindered outside position, as shown
by the arrow. The coordination of lithium amide 2a to
methylsilyl (TBDMS)-protected enoate 1a with lithium
benzyl(trimethylsilyl)amide 2a 2b,d gave an approximate
1:1 mixture of the syn-3a and anti-4a diastereomers
(entry 1). The syn-diastereoselectivity increased to 89-
90% with sterically bulkier tert-butyldiphenylsilyl 1b and
triisopropylsilyl protected enoate 1c (entries 2 and 3).
Chemical yields were very high in the reactions with 1b
and 1c. The syn-diastereoselectivity reached to ∼100%
using the trityloxy derivative 1d although the chemical
yield decreased to 77% (entry 5). It is clear from these
experiments that an increase of steric bulk at the OR
group produces high syn-diastereoselectivity.
an oxygen atom of the OR group followed by delivery of
the nitrogen nucleophile from the side of OR would not
take place; the chelation-controlled delivery of nucleo-
phile 2a is not conceivable due to the presence of
sterically very bulky silyloxy groups11 in addition to the
The syn-stereochemistry was confirmed by converting
the syn-adduct 3a , upon treatment with Bu4NF, into the
cis γ-butyrolactone 5a ; NOE effects were observed be-
(10) Reetz, M. T.; Ro¨hrig, D.; Harms, K.; Frenking, G. Tetrahedron
Lett. 1994, 35, 8765.
(11) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1991, 32,
6939, and references cited therein.

6276 J . Org. Chem., Vol. 62, No. 18, 1997
Asao et al.
Sch em e 2
would be most favorable owing to both the chelation
factor and minimum allylic strain, the presence of a small
methyl group at the outside position, and the anti OMe.
In the case of 16a , OMe is anti and this is stereoelec-
tronically satisfactory, but there is allylic strain between
the inside Me and an olefinic hydrogen. In the case of
16c there is steric repulsion between the incoming
reagent and Me group. Therefore, the reason for the syn-
preference in the case of 1e is presumably due to both
allylic strain and chelation factor.
To reduce ambiguous factors encountered when we
considered probable transition state geometries in 16, the
addition to the R-methyl-substituted enoate 17 was
investigated. Interestingly, the reaction of 17 with 2b
gave the syn-diastereomer 18 exclusively in 85% yield
(eq 3). No anti-isomer was detected. A 1:1 mixture of
diastereoisomers concerning the R-position to ester group
was obtained, although the stereochemistry at the R-po-
sition was not determined. The syn-stereochemistry of
18 was determined in the following way. Treatment of
3f with LDA/MeI gave a 1:1 diastereomeric mixture of
the corresponding R-methylated products (X and Y).
Each isomer was separated by a silica gel column
chromatography. The spectroscopic data of X and Y were
identical to those of two diastereomers (18a and 18b)
separated from 18. It is now clear that the reaction
proceeds through 19, in which the allylic strain is
minimized, leading to the syn-isomer 18 exclusively.
Furthermore, the above result suggests that chelation-
controlled delivery of 2b is involved in the reaction of 17.
Next, we investigated the reaction of γ-phenyl-substi-
tuted enoate 20 in order to determine the effect of a
substituent other than Me at the γ-position. The reaction
of 20 with 2a gave exclusively the anti-diastereoisomer
21 in 74% yield, with no detection of the syn-diastereo-
isomer (eq 4). Not only isopropyl ester 20, but also ethyl
and tert-butyl ester derivatives produced, upon treatment
with 2a , the corresponding anti-diastereoisomers exclu-
Sch em e 3
soft nature of the nucleophile. The addition of lithium
dibenzylamide 2b to 1c afforded a 30:70 mixture of 3d
and 4d in 79% yield, indicating that the diastereoselec-
tivity depended very much upon the structural difference
of lithium amide reagents, either 2a or 2b (entry 3 vs 4).
Although the precise reason for the anti-preference is not
clear, the participation of a chelation model is conceivable
in the case of 2b because of its hard characteristics in
comparison with 2a . Very interestingly, the reaction of
γ-methoxy-substituted enoate 1e with lithium dibenzyl-
amide 2b gave a 63:37 mixture of the syn-3f and anti-4f
diastereomers in 83% yield (entry 6). Among four pos-
sible transition state geometries (Scheme 3), 16d would
be most unfavorable due to the allylic strain between
OMe and vinylic hydrogen group, and due to the presence
of the Me group at the anti-position.12 Perhaps 16b
(12) (a) Anh, N. T.; Eisenstein, O. Nouv. J . Chem. 1977, 1, 61. (b)
Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987, 109, 3353. (c)
Wong, S. S.; Paddon-Row, M. N. J . Chem. Soc., Chem. Commun. 1990,
456.
(13) Yamamoto, Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W.
J . Am. Chem. Soc. 1986, 108, 7778.

Diastereoselective Conjugate Addition
J . Org. Chem., Vol. 62, No. 18, 1997 6277
Sch em e 4
conjugate addition of 2b to 32 afforded a 27:73 mixture
of syn-33b and anti-34b diastereomers in 84% yield (eq
6). The syn-configurations of 33a and 33b were deter-
sively although chemical yields were lower than reactions
of 20. The anti-stereochemistry of 21 was determined
by the similar method as mentioned above. Treatment
of 21 with Bu4NF gave trans-lactone (22-t r a n s). The
thermal reaction of 20 with benzylamine gave a 2:1
mixture of syn- and anti-(21) adducts. The syn-adduct
was converted to the corresponding cis-lactone (22-cis).
NOE effects (9%) between the hydrogens at the â-position
and that of the γ-position were observed for 22-cis, but
NOE effects of 22-tr a n s were less than 2%. The anti-
diastereoselectivity can be explained by an allylic strain
model 23. It should be noted that the reaction of 1a
(OTBDMS and Me substituent at the γ-position) with 2a
gave about 1:1 mixture of syn- and anti-diastereomers
(entry 1, Table 1). The phenyl substituent enhanced the
anti-selectivity dramatically. A possible explanation for
this difference is as follows (Scheme 4). A serious steric
repulsion (allylic strain) would arise between vinylic
hydrogen and the phenyl group in the transition state
geometry 24 which produces the syn-diastereomer. Ac-
cordingly, the reaction of 20 would proceed through 23
to afford the anti-diastereomer 21. On the other hand,
the steric repulsion between the Me group and vinylic
hydrogen would be not so serious, and thus the reaction
of 1a would proceed through both transition state geom-
etries 26 and 25.
mined by converting them into the reduction product 35
via hydrogenation with catalytic Pd(OH)2/C. The spec-
troscopic data of 35 were completely identical to those of
authentic 35,6b indicating the syn stereochemistry of 33a
and 33b. Similarly, the anti-configurations of 34a and
34b were determined by converting them into the 36 (eq
7). The predominant formation of the anti-isomer 34 can
Finally, we investigated the diastereoselectivity in the
reaction of enoates substituted with Ph and Me, and with
Me and CH2OTBDMS, at the γ-position. The reaction
of 27 with 2a gave a 3:97 mixture of syn-28 and anti-29
diastereomers in 79% yield (eq 5).
be explained by a modified Felkin-Anh model 37 (Scheme
5). Relatively low anti-selectivity is a reflection of weaker
stereoelectronic influence of the CH2OTBDMS group, in
comparison with phenyl group in 31, upon occupation at
the anti position. Perhaps, other transition state geom-
etries such as 38 and 39, which lead to the syn-isomer
33, would intervene in the reaction of 32. Although
relatively low diastereoselectivities were observed for the
conjugate addition of achiral lithium amide reagents 2a
and 2b to 32, the use of certain chiral reagents lead to
very high asymmetric induction. For example, the reac-
tion of 32 with lithium N-benzyl-N-((R)-phenylethyl)-
amide gave the syn-diastereomer with essentially 100%
de and the reaction with lithium N-benzyl-N-((S)-phen-
ylethyl)amide gave the anti-diastereomer exclusively.6b
Similarly, the addition of lithiated (R)-3,5-dihydro-4H-
dinapth[2,1-c:1′,2′-e]azepine to 32 afforded 100% de.4c
The anti-stereochemistry of 29 was confirmed by
converting it, upon treatment with LiAlH4 followed by
cyclization with TCF (trichloromethyl chloroformate),
into the cyclic carbamate 30. The configuration and
stereochemistry of 30 were reported previously (see
Experimental Section).13 The very high anti-selectivity is
a reflection of a modified Felkin-Anh model 31 in which
hydrogen orients outside, small Me group orients inside,
and the bulky and electron-withdrawing phenyl group
becomes anti. It is clear that not only an appropriate
OR substituent at the γ-position but also a stereoelec-
tronically suitable substituent (such as phenyl) produces
high 1,2-asymmetric induction.
The reaction of 32 with 2a gave a 27:73 mixture of syn-
33a and anti-34a diastereomers in 93% yield. The

6278 J . Org. Chem., Vol. 62, No. 18, 1997
Asao et al.
1) gave the E- and Z-methyl ester (4.70 g, 39%, E/Z ) 84/16).
To a THF (30 mL) solution of 2-methyl-2-propanol (3.8 mL,
40 mmol) under argon atmosphere at 0 °C was added dropwise
in 10 min a 1.65 M n-hexane solution of n-BuLi (17 mL, 28
mmol). The mixture was stirred for 1 h, and a THF (15 mL)
solution of E-methyl ester (3.4 g, 13.9 mmol) was added and
stirred overnight. The mixture was further stirred for 2 h at
room temperature. Addition of excess aqueous saturated
NH4Cl, extraction with ether, washing with brine, drying with
anhydrous MgSO4, concentration under reduced pressure, and
purification with column chromatography (silica gel; n-hexane/
ethyl acetate, 10/1) afforded 1a (3.40 g, 86%). Colorless oil:
1H NMR (CDCl3) δ 6.82 (dd, J ) 4.4, 15.3 Hz, 1H), 5.88 (dd, J
) 1.9, 15.3 Hz, 1H), 4.43 (ddq, J ) 1.9, 4.4, 6.4 Hz, 1H), 1.49
(s, 9H), 1.25 (d, J ) 6.4 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 6H); IR
(neat) 2978-2858, 1716, 1367, 1302, 1258, 1153 cm-1. Anal.
Calcd for C15H30O3Si (286.49): C, 62.89; H, 10.55. Found: C,
62.72; H, 10.42.
Sch em e 5
(E)-ter t-Bu tyl 4-((ter t-Bu tyld ip h en ylsilyl)oxy)-2-p en -
ten oa te (1b). 1b was prepared from ethyl lactate and
Ph2(tBu)SiCl as described above for 1a (56% yield from ethyl
lactate). Colorless oil: 1H NMR (CDCl3) δ 7.71-7.32 (m, 10H),
6.78 (dd, J ) 5.0, 16.0 Hz, 1H), 5.86 (dd, J ) 1.5, 16.0 Hz,
1H), 4.43 (ddq, J ) 1.5, 5.0, 6.5 Hz, 1H), 1.48 (s, 9H), 1.13 (d,
J ) 6.5 Hz, 3H), 1.08 (s, 9H); IR (CCl4) 3200-2885, 1723, 1380,
1314, 1168 cm-1
73.13; H, 8.35. Found: C, 72.85; H, 8.22.
. Anal. Calcd for C25H34O3Si (410.63): C,
Accordingly, the asymmetric induction at the â-position
of 32 is controlled completely by the chirality of the
lithium amide reagents, and the effect of the chirality at
the γ-carbon upon the asymmetric induction is very
small.
(E)-ter t-Bu tyl 4-((Tr iisop r op ylsilyl)oxy)-2-p en ten oa te
(1c). 1c was prepared from ethyl lactate and iPr3SiCl as
described above for 1a (58% yield from ethyl lactate). Colorless
oil: 1H NMR (CDCl3) δ 6.82 (dd, J ) 4.7, 15.6 Hz, 1H), 5.90
(dd, J ) 1.8, 15.6 Hz, 1H), 4.54 (ddq, J ) 1.8, 4.7, 6.3 Hz, 1H),
1.48 (s, 9H), 1.28 (d, J ) 6.3 Hz, 3H), 1.06 (br s, 21H); IR (neat)
2963-2868, 1717, 1367, 1300, 1153, 1094 cm-1. Anal. Calcd
for C18H36O3Si (328.57): C, 65.80; H, 11.04. Found: C, 65.86;
H, 11.27.
Con clu sion
Sterically bulky OR group at the γ-position of enoates,
such as trityloxy and tert-butyldiphenylsilyloxy, produces
a syn-diastereoisomer either exclusively or very predomi-
nantly. The syn-selectivity can be explained by a modi-
fied Felkin-Anh model 15. The reaction of 1e with
lithium dibenzylamide 2b gives a 63:37 mixture of the
syn-3f and anti-4f isomer, but the presence of Me group
at the R-position of enoate enhances the syn-diastereo-
selectivity up to 100%. This enhancement can be ex-
plained by the allylic strain in the transition state
geometry. A phenyl group at the γ-position enhances the
anti-diastereoselectivity in the case of γ-alkoxy-R,â-
enoates, and in the case of γ-alkyl-R,â-enoates.
(4S)-(E)-ter t-Bu tyl 4-(Tr ityloxy)-2-p en ten oa te (1d ). To
a CH2Cl2 (80 mL) solution of (S)-ethyl lactate (11.3 mL, 100
mmol) under argon atmosphere were added triethylamine
(20.9 mL, 150 mmol), 4-(dimethylamino)pyridine (0.49 g, 0.004
mmol), and trityl chloride (27.0 g, 110 mmol), and the mixture
was refluxed for 25 h and then cooled to room temperature.
Addition of excess H2O, extraction with CH2Cl2, washing with
brine, drying with anhydrous Na2SO4, concentration under
reduced pressure, and filtration through silica gel (using ethyl
acetate as a eluent) gave a crude product, which was used for
further manipulation as described above for 1a (80% yield from
ethyl lactate). Colorless oil: 1H NMR (CDCl3) δ 7.51-7.16 (m,
15H), 6.36 (dd, J ) 6.2, 15.4 Hz, 1H), 5.30 (dd, J ) 1.3, 15.4
Hz, 1H), 4.19 (ddq, J ) 1.3, 6.2, 6.6 Hz, 1H), 1.41 (s, 9H), 1.10
(d, J ) 6.6 Hz, 3H); IR (CCl4) 3012-2780, 1725, 1460, 1319,
Exp er im en ta l Section
1306, 1163 cm-1; [R]24 -43.4° (c 1.00, CHCl3). Anal. Calcd
for C28H30O3 (414.55): C, 81.13; H, 7.29. Found: C, 80.88; H,
7.53.
D
(E)-ter t-Bu tyl 4-((ter t-Bu tyld im eth ylsilyl)oxy)-2-p en -
ten oa te (1a ). To a CH2Cl2 (50 mL) solution of ethyl lactate
(5.7 mL, 50 mmol) at 0 °C were added imidazole (4.1 g, 60
mmol) and TBDMSCl (8.3 g, 55 mmol), and the mixture was
stirred overnight at room temperature. Water (50 mL) was
added, and the mixture was extracted with CH2Cl2, washed
with brine, dried with anhydrous MgSO4, and concentrated
under reduced pressure. The residue was dissolved in toluene
(50 mL), and a 1.5 M toluene solution of DIBAL (iBu2AlH, 33
mL, 50 mmol) was added dropwise in 15 min at -78 °C under
argon atmosphere. The mixture was stirred for 80 min, and
water (27 mL) was added slowly. The mixture was stirred
overnight at room temperature, dried with anhydrous MgSO4,
and concentrated under reduced pressure. The residue was
used for further manipulation without purification. To a
suspension of NaH (1.5 g, 37 mmol, 60% in mineral oil) in
n-hexane (70 mL) at 0 °C under argon atmosphere was added
trimethyl phosphonoacetate (7.2 mL, 44 mmol), and the
mixture was stirred for 30 min. An n-hexane (20 mL) solution
of the oil obtained above was added. The resulting mixture
was stirred for 15 min at 0 °C and stirred for 1 h at room
temperature. Addition of 100 mL of H2O, extraction with
ether, washing with brine, drying with anhydrous MgSO4,
concentration under reduced pressure, and purification with
column chromatography (silica gel; n-hexane/ethyl acetate, 20/
(E)-ter t-Bu tyl 4-Meth oxy-2-p en ten oa te (1e). To a sus-
pension of NaH (3.6 g, 120 mmol, 60% in mineral oil) in THF
(130 mL) at 0 °C under argon atmosphere was added ethyl
lactate (11.3 mL, 100 mmol), and the mixture was stirred for
30 min. MeI (9.3 mL, 120 mmol) was added, and the resulting
mixture was stirred for 4 h at room temperature. Addition of
excess aqueous saturated NH4Cl, extraction with ether, wash-
ing with brine, drying with anhydrous MgSO4, and concentra-
tion under reduced pressure gave a crude product, which was
used for further manipulation as described above for 1a (46%
yield from ethyl lactate). Colorless oil: 1H NMR (CDCl3) δ
6.72 (dd, J ) 6.2, 15.7 Hz, 1H), 5,89 (dd, J ) 1.1, 15.7 Hz,
1H), 3.89 (ddq, J ) 1.1, 6.2, 6.6 Hz, 1H), 3.31 (s, 9H), 1.27 (d,
J ) 6.6 Hz, 3H) ; IR (neat) 2980-2824, 1717, 1367, 1302, 1259,
1153 cm-1. Anal. Calcd for C10H18O3 (186.25): C, 64.49; H,
9.74. Found: C, 64,58; H, 9.58.
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition of 2a
or 2b to r,â-Un sa tu r a ted En on es 1a -e, 17, 20, 27, a n d
32.6b To a THF (20 mL) solution of a dialkylamine (4.2 mmol)
under argon atmosphere at -78 °C was added dropwise a 1.65
M n-hexane solution of n-BuLi (4.1 mmol). The mixture was
stirred for 30 min. A THF (3 mL) solution of the R,â-
unsaturated enone (2.0 mmol) was added, and the resulting

Diastereoselective Conjugate Addition
J . Org. Chem., Vol. 62, No. 18, 1997 6279
mixture was stirred for 1.5 h. Addition of excess aqueous
saturated NH4Cl, extraction with ether, washing with brine,
drying with anhydrous Na2SO4, concentration under reduced
pressure, and purification with silica gel column chromatog-
raphy (using n-hexane/ethyl acetate as an eluent) gave the
adducts. The reaction of 1a with 2a : 91% yield, 3a /4a ) 54/
46. The reaction of 1b with 2a : 99% yield, 3b/4b ) 89/11.
The reaction of 1c with 2a : 95% yield, 3c/4c ) 90/10. The
reaction of 1c with 2b: 79% yield, 3d /4d ) 30/70. The reaction
of 1d with 2a : 77% yield, 3e/4e ) 100/0. The reaction of 1e
with 2b: 83% yield, 3f/4f ) 63/37. The reaction of 17 with
2b: 85% yield, only 18 (1:1 mixture of diastereomers concern-
ing the R-position to ester group). The reaction of 20 with 2a :
74% yield, only 21. The reaction of 27 with 2a : 79% yield,
28/29 ) 3/97. The reaction of 32 with 2a : 93% yield, 33a /
34a ) 27/73. The reaction of 32 with 2b: 93% yield, 33b/34b
) 27/73.
1.14 (d, J ) 6.2 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s,
3H); IR (neat) 2976-2857, 1728, 1367, 1257, 1154, 1097 cm-1
.
Anal. Calcd for C22H39NO3Si (393.65): C, 67.13; H, 9.99; N,
3.56. Found: C, 66.76; H, 10.05; N, 3.58.
(3R*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((ter t-bu tyl-
d ip h en ylsilyl)oxy)p en ta n oa te (4b). Colorless oil: 1H NMR
(CDCl3) δ 7.68-7.18 (m, 15H), 4.01 (dq, J ) 2.8, 6.4 Hz, 1H),
3.69 (s, 2H), 3.03 (dt, J ) 2.8, 6.5 Hz, 1H), 2.38 (d, J ) 6.5 Hz,
2H), 1.39 (s, 9H), 1.04 (s, 9H), 1.01 (d, J ) 6.4 Hz, 3H); IR
(neat) 3070-2857, 1727, 1427, 1367, 1153 cm-1. Anal. Calcd
for C32H43NO3Si (517.79): C, 74.23; H, 8.37; N, 2.71. Found:
C, 74.23; H, 8.21; N, 3.02.
(3R*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((tr iisop r o-
pylsilyl)oxy)pen tan oate (4c). Colorless oil: 1H NMR (CDCl3)
δ 7.36-7.18 (m, 5H), 4.11 (dq, J ) 3.2, 6.2 Hz, 1H), 3.80 (s,
2H), 3.11 (ddd, J ) 3.2, 6.2, 7.3 Hz, 1H), 2.41 (dd, J ) 7.3,
14.6 Hz, 1H), 2.30 (dd, J ) 6.2, 14.6 Hz, 1H), 1.45 (s, 9H),
1.19 (d, J ) 6.2 Hz, 3H), 1.05 (br s, 21H); IR (neat) 2964-
2867, 1728, 1463, 1384, 1367, 1154, 1100 cm-1. Anal. Calcd
for C25H45NO3Si (435.73): C, 68.91; H, 10.41; N, 3.21.
Found: C, 68.88; H, 9.98; N, 3.10.
(3R*,4S*)-ter t-Bu tyl 3-(N,N-Diben zyla m in o)-4-((tr iiso-
p r op ylsilyl)oxy)p en ta n oa te (4d ). Colorless oil: 1H NMR
(CDCl3) δ 7.39-7.15 (m, 10H), 4.02 (d, J ) 13.6 Hz, 1H), 3.98
(dq, J ) 6.2, 6.2 Hz, 1H), 3.40 (d, J ) 13.6 Hz, 1H), 3.03 (ddd,
J ) 5.9, 6.2, 7.3 Hz, 1H), 2.75 (dd, J ) 7.3, 15.0 Hz, 1H), 2.61
(dd, J ) 5.9, 15.0 Hz, 1H), 1.46 (s, 9H), 1.20 (d, J ) 6.2 Hz,
3H), 0.98 (bs, 21H); IR (neat) 2943-2866, 1726, 1454, 1376,
1150, 1099 cm-1. Anal. Calcd for C32H51NO3Si (525.85): C,
73.09; H, 9.78; N, 2.66. Found: C, 72.73; H, 10.03; N, 2.70.
(3R*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-m eth oxyp en -
ta n oa te (4f). Colorless oil: 1H NMR (CDCl3) δ 7.38-7.19 (m,
10H), 3.98 (d, J ) 13.7 Hz, 2H), 3.36 (d, J ) 13.7 Hz, 2H),
3.32 (dq, J ) 5.3, 6.6 Hz, 1H), 3.24 (s, 3H), 3.04 (dt, J ) 5.3,
6.7 Hz, 1H), 2.58 (d, J ) 6.7Hz, 2H), 1.44 (s, 9H), 1.15 (d, J )
6.6 Hz, 3H) ; IR (neat) 2976-2822, 1724, 1367, 1256, 1148,
1103 cm-1. Anal. Calcd for C24H33NO3 (383.53): C, 75.16; H,
8.67; N, 3.65. Found: C, 75.46; H, 9.01; N, 3.75.
(3S*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((ter t-bu tyl-
d im eth ylsilyl)oxy)p en ta n oa te (3a ). Colorless oil: 1H NMR
(CDCl3) δ 7.36-7.18 (m, 5H), 3.90 (dq, J ) 4.5, 6.1 Hz, 1H),
3.87 (d, J ) 13.1 Hz, 1H), 3.77 (d, J ) 13.1 Hz, 1H), 2.96 (ddd,
J ) 4.5, 5.2, 7.2 Hz, 1H), 2.48 (dd, J ) 5.0, 15.0 Hz, 1H), 2.29
(dd, J ) 7.2, 15.0 Hz, 1H), 1.44 (s, 9H), 1.14 (d, J ) 6.1 Hz,
3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); IR (neat) 2976-
2857, 1727, 1367, 1257, 1153 cm-1. Anal. Calcd for C22H39
-
NO3Si (393.65): C, 67.13; H, 9.99; N, 3.56. Found: C, 67.02;
H, 10.08; N, 3.56.
(3S*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((ter t-bu tyl-
d ip h en ylsilyl)oxy)p en ta n oa te (3b). Colorless oil: 1H NMR
(CDCl3) δ 7.69-7.16 (m, 15H), 3.96 (dq, J ) 6.0, 6.0 Hz, 1H),
3.57 (d, J ) 13.0 Hz, 1H), 3.50 (d, J ) 13.0 Hz, 1H), 3.04 (ddd,
J ) 3.8, 6.0, 9.0 Hz, 1H), 2.68 (dd, J ) 3.8, 15.1 Hz, 1H), 2.22
(dd, J ) 9.0, 15.1 Hz, 1H), 1.42 (s, 9H), 1.04 (s, 9H), 1.02 (d, J
) 6.0 Hz, 3H); IR (neat) 2975-2857, 1727, 1367, 1154, 1147,
1111 cm-1. Anal. Calcd for C32H43NO3Si (517.79): C, 74.23;
H, 8.37; N, 2.71. Found: C, 74.16; H, 8.32; N, 2.71.
(3S*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((tr iisop r o-
pylsilyl)oxy)pen tan oate (3c). Colorless oil: 1H NMR (CDCl3)
δ 7.35-7.18 (m, 5H), 4.07 (dq, J ) 4.2, 6.1 Hz, 1H), 3.84 (d, J
) 13.2 Hz, 1H), 3.78 (d, J ) 13.2 Hz, 1H), 3.08 (ddd, J ) 3.8,
4.2, 8.7 Hz, 1H), 2.63 (dd, J ) 3.8, 15.4 Hz, 1H), 2.18 (dd, J )
8.7, 15.4 Hz, 1H), 1.44 (s, 9H), 1.14 (d, J ) 6.1 Hz, 3H), 1.04
(3S*,4S*)-3-(N-Ben zylam in o)-4-m eth yl-4-bu tan olide (5a).
To a THF (2 mL) solution of 3b (67.3 mg, 0.13 mmol) under
argon atmosphere at 0 °C was added dropwise a 1.0 M THF
solution of tetrabutylammonium fluoride (0.26 mL, 0.26 mmol),
and the mixture was stirred for overnight at room tempera-
ture. Addition of excess aqueous saturated NH4Cl, extraction
with ether, washing with brine, drying with anhydrous MgSO4,
concentration under reduced pressure, and purification with
column chromatography (silica gel; n-hexane/ethyl acetate, 10/
1) gave 5a (19 mg, 71%). Colorless oil: 1H NMR (CDCl3) δ
7.37-7.24 (m, 5H), 4.67 (dq, J ) 6.5, 5.6 Hz, 1H), 3.84 (d, J )
13.0 Hz, 1H), 3.72 (d, J ) 13.0 Hz, 1H), 3.56 (ddd, J ) 6.9,
5.6, 5.3 Hz, 1H), 2.66 (dd, J ) 17.0, 6.9 Hz, 1H), 2.48 (dd, J )
17.0, 5.3 Hz, 1H), 1.51 (broad s, 1H), 1.39 (d, J ) 6.5 Hz, 3H);
13C NMR (CDCl3) δ 175.29, 139.28, 128.63, 128.03, 127.43,
81.88, 60.32, 51.90, 36.12, 19.50; IR (neat) 3330, 3040-2860,
(br s, 21H); IR (neat) 2965-2867, 1729, 1367, 1157, 1102 cm-1
.
Anal. Calcd for C25H45NO3Si (435.73): C, 68.91; H, 10.41; N,
3.21. Found: C, 69.00; H, 10.44; N, 3.34.
(3S*,4S*)-ter t-Bu tyl 3-(N,N-Diben zyla m in o)-4-((tr iiso-
p r op ylsilyl)oxy)p en ta n oa te (3d ). Colorless oil: 1H NMR
(CDCl3) δ 7.34-7.11 (m, 10H), 4.13 (dq, J ) 5.7, 6.2 Hz, 1H),
3.72, 3.65 (2d, J ) 13.9 Hz, each 2H), 3.11 (ddd, J ) 4.8, 5.7,
7.6 Hz, 1H), 2.63 (dd, J ) 4.8, 15.0 Hz, 1H), 2.55 (dd, J ) 7.6,
15.0 Hz, 1H), 1.48 (s, 9H), 1.15 (d, J ) 6.2 Hz, 3H), 1.05 (bs,
21H); IR (neat) 2943-2866, 1728, 1454, 1367, 1256, 1157 cm-1
.
Anal. Calcd for C32H51NO3Si (525.85): C, 73.09; H, 9.78; N,
2.66. Found: C, 73.31; H, 10.02; N, 2.72.
1770, 1180, 1150 cm-1
.
(3S,4S)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-(tr ityloxy)p en -
ta n oa te (3e). Colorless oil: 1H NMR (CDCl3) δ 7.51-7.10 (m,
20H), 3.73 (dq, J ) 3.6, 6.1 Hz, 1H), 3.41 (s, 2H), 2.76 (dd, J
) 2.8, 15.6 Hz, 1H), 2.72 (ddd, J ) 2.8, 3.6, 10.6 Hz, 1H), 2.16
(dd, J ) 10.6, 15.6 Hz, 1H), 1.42 (s, 9H), 0.81 (d, J ) 6.1 Hz,
(3R*,4S*)-3-(N,N-Dib en zyla m in o)-4-m et h yl-4-b u t a n o-
lid e (5b-tr a n s). 5b-tr a n s was prepared from 4d as described
above for 5a (78% yield). Colorless oil: 1H NMR (CDCl3) δ
7.33-7.19 (m, 10H), 4.60 (dq, J ) 5.9, 5.9 Hz, 1H), 3.72, 3.48
(2d, J ) 13.9 Hz, each 2H), 3.33 (ddd, I ) 6.0, 7.0, 8.1 Hz,
1H), 2.65 (dd, J ) 7.0, 19.0 Hz, 1H), 2.57 (dd, J ) 8.1, 19.0
Hz, 1H), 1.31 (d, J ) 6.6 Hz, 3H); IR (neat) 2976-2806, 1782,
3H); IR (neat) 3086-2874, 1732, 1488, 1367, 1281, 1148 cm-1
;
[R]24 -8.88° (c 1.00, CHCl3). Anal. Calcd for C35H39NO3
D
(521.70): C, 80.58; H, 7.53; N, 2.68. Found: C, 80.37; H, 7.78;
N, 2.71.
1495, 1454, 1379, 1175 cm-1
. Anal. Calcd for C19H21NO2
(295.38): C, 77.26; H, 7.17; N, 4.74. Found: C, 76.91; H, 7.47;
N, 4.66.
(3S*,4S*)-ter t-Bu t yl 3-(N,N-Dib en zyla m in o)-4-m et h -
oxyp en ta n oa te (3f). Colorless oil: 1H NMR (CDCl3) δ 7.35-
7.20 (m, 10H), 3.98 (d, J ) 13.9 Hz, 2H), 3.38 (dq, J ) 6.2, 6.6
Hz, 1H), 3.23 (s, 3H), 3.06 (ddd, J ) 4.8, 6.6, 14.8 Hz, 1H),
2.62 (dd, J ) 4.8, 14.6 Hz, 1H), 2.27 (dd, J ) 8.0, 14.6 Hz,
1H), 1.44 (s, 9H), 1.11 (d, J ) 6.2 Hz, 3H); IR (neat) 2976-
2820, 1728, 1454, 1366, 1256, 1161, 1128 cm-1. Anal. Calcd
for C24H33NO3 (383.53): C, 75.16; H, 8.67; N, 3.65. Found:
C, 75.30; H, 8.90; N, 3.70.
(3S*,4S*)-3-(N,N-Dib en zyla m in o)-4-m et h yl-4-b u t a n o-
lid e (5b-cis). 5b-cis was prepared from 3d as described above
for 5a (71% yield). Colorless oil: 1H NMR (CDCl3) δ 7.38-
7.22 (m, 10H), 4.68 (dq, J ) 6.5, 6.5 Hz, 1H), 3.71 (d, J ) 14.1,
2H), 3.56 (ddd, J ) 6.5, 8.0, 4.8 Hz, 1H), 3.47 (d, I ) 14.1 Hz,
2H), 2.69 (dd, J ) 4.8, 18.0 Hz, 1H), 2.44 (dd, J ) 8.1, 18.0
Hz, 1H), 1.55 (d, J ) 6.5 Hz, 3H).
(3R*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((ter t-bu tyl-
d im eth ylsilyl)oxy)p en ta n oa te (4a ). Colorless oil: 1H NMR
(CDCl3) δ 7.35-7.18 (m, 5H), 3.97 (dq, J ) 3.9, 6.2 Hz, 1H),
3.79 (s, 2H), 2.97 (ddd, J ) 3.9, 6.0, 7.3 Hz, 1H), 2.38 (dd, J )
6.0, 14.7 Hz, 1H), 2.32 (dd, J ) 7.3, 14.7 Hz, 1H), 1.45 (s, 9H),
(3R*,4S*)-3-(N,N-Dib en zyla m in o)-1,4-d im et h oxyp en -
ta n e (6). To an ether (10 mL) solution of 3f (84 mg, 0.22
mmol) was added LiAlH4 (17 mg, 0.44 mmol) at 0 °C, and the
mixture was stirred for 2 h. Water (17 µL) and 15% aqueous
NaOH (17 µL) was added, and the mixture was dried with

6280 J . Org. Chem., Vol. 62, No. 18, 1997
Asao et al.
anhydrous MgSO4 and concentrated under reduced pressure.
The residue was used for further manipulation. To a suspen-
sion of NaH (53 mg, 1.32 mmol, 60% in mineral oil) in THF (5
mL) at 0 °C under argon atmosphere was added a THF (2 mL)
solution of the oil obtained above, and the mixture was stirred
for 30 min at room temperature. MeI (70 µL, 1.1 mmol) was
added and the resulting mixture was stirred for 12 h. Addition
of excess aqueous saturated NH4Cl, extraction with ether,
washing with brine, drying with anhydrous MgSO4, concentra-
tion under reduced pressure, and purification with column
chromatography (silica gel; n-hexane/ethyl acetate, 8/1) gave
6 (58 mg, 82%). Colorless oil: 1H NMR (CDCl3) δ 7.34-7.17
(m, 10H), 3.77, 3.52 (2d, J ) 13.9 Hz, each 2H), 3.48 (dq, J )
4.8, 6.2 Hz, 1H), 3.42 (dd, J ) 1.5, 7.0 Hz, 1H), 3.30 (s, 3H),
3.24 (s, 3H), 2.53 (ddd, J ) 4.8, 4.8, 7.7 Hz, 1H), 1.82 (dddd, J
) 1.5, 2.0, 4.8, 13.9 Hz, 1H), 1.60 (dddd, J ) 1.5, 2.0, 4.8, 13.9
Hz, 1H), 1.09 (d, J ) 6.2 Hz, 3H); IR (neat) 2970-2822, 1495,
pressure, and purification with column chromatography (silica
gel; n-hexane/ethyl acetate, 1/1) gave 9 (0.18 g, 96%). Colorless
oil: 1H NMR (CDCl3) δ 7.35-7.27 (m, 5H), 4.56 (d, J ) 15.2
Hz, 1H), 4.39 (d, J ) 15.2Hz, 1H), 4.16 (dq, J ) 5.4, 6.2 Hz,
1H), 3.73 (dq, J ) 7.2, 6.4 Hz, 1H), 3.48 (dd, J ) 7.2, 2.2 Hz,
1H), 2.79 (dd, J ) 5.4, 2.2 Hz, 1H), 1.24 (d, J ) 6.2 Hz, 3H),
1.13 (d, J ) 6.4 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.03 (s,
3H); IR (neat) 3595, 3448, 2990-2870, 1770, 1471, 1392, 1267,
1149, 1058 cm-1; [R]20 -12.1° (c 1.03, CHCl3). Anal. Calcd
D
for C20H33NO3Si (363.58): C, 66.07; H, 9.15; N, 3.85. Found:
C, 65.67; H, 9.20; N, 3.86.
(3S ,4S )-1-N -Be n zyl-3-[(R )-1-((t er t -Bu t yld im e t h ylsi-
lyl)oxy)eth yl]-4-[(R)-1-ch lor oeth yl]-2-azetidin on e (10). Syn-
thesis of 10 from 9: To a CCl4 (8 mL) solution of 9 (0.15 g,
0.41 mmol) was added PPh3 (0.31 g, 1.2 mmol), and the
mixture was refluxed for 24 h under argon atmosphere.
Concentration under reduced pressure gave 10 in good yield.
Synthesis of 10 from 14: To a MeOH (2 mL) and water (2 mL)
solution of 14 (0.36 g, 1.15 mmol) was added K2CO3 (0.5 g),
and the mixture was stirred for 2 h. The mixture was
quenched with water, extracted with ether, washed with brine,
dried with anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (2 mL), and
imidazole (0.09 g, 1.3 mmol) and TBDMSCl (0.18 g, 1.2 mmol)
were added at 0 °C, and the mixture was stirred overnight at
room temperature. Water was added, and the mixture was
extracted with CH2Cl2, washed with brine, dried with anhy-
drous MgSO4, and concentrated under reduced pressure.
Purification with column chromatography (silica gel; n-hexane/
ethyl acetate, 5/1) gave 10 (0.35 g, 80%). Colorless oil: 1H
NMR (CDCl3) δ 7.38-7.26 (m, 5H), 4.71 (d, J ) 15.0 Hz, 1H),
4.21 (dq, J ) 6.0, 6.4 Hz, 1H), 4.15 (d, J ) 15.0 Hz, 1H), 4.12
(m, 1H), 3.70 (dd, J ) 2.0, 3.2 Hz, 1H), 3.07 (dd, J ) 6.4, 2.0
Hz, 1H), 1.43 (d, J ) 6.9 Hz, 3H), 1.23 (d, J ) 6.0 Hz, 3H),
0.86 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); IR (CCl4) 3042-2870,
1454, 1371, 1117, 1086 cm-1
. Anal. Calcd for C21H29NO2
(327.47): C, 77.03; H, 8.93; N, 4.28. Found: C, 76.74; H, 8.80;
N, 4.26.
(2S,3S,4S)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-(tr ityloxy)-
2-[(R)-1-((ter t-bu t yld im et h ylsilyl)oxy)et h yl]p en t a n oa t e
(7). To a THF (50 mL) solution of a N-benzyl(trimethylsilyl)-
amine (4.1 mL, 21 mmol) under argon atmosphere at -78 °C
was added dropwise a 1.76 M n-hexane solution of n-BuLi (11
mL, 20 mmol). The mixture was stirred for 30 min, and a THF
(10 mL) solution of 1d (5.0 g, 12 mmol) was added at -78 °C.
After 1.5 h, MeOH (0.89 mL, 22 mmol) was added, and the
mixture was stirred for 20 min at -78 °C. To this mixture
under argon was added slowly in 10 min a THF (40 mL)
solution of LDA (100 mmol) precooled at -78 °C. After 20 min,
a 5 M THF solution of acetaldehyde (30 mL, 150 mmol) was
added slowly. The mixture was stirred for 1.5 h at -78 °C.
The mixture was quenched with excess aqueous saturated
NH4Cl, extracted with ether, washed with brine, dried with
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 (20 mL), and imidazole
(1.2 g, 17 mmol) and TBDMSCl (3.0 g, 20 mmol) were added
at 0 °C. The mixture was stirred overnight at room temper-
ature. Water (20 mL) was added, and the mixture was
extracted with CH2Cl2, washed with brine, dried with anhy-
drous MgSO4, and concentrated under reduced pressure.
Purification with column chromatography (silica gel; n-hexane/
ethyl acetate, 10/1) gave 7 (6.3 g, 77%). Colorless oil: 1H NMR
(CDCl3) δ 7.51-7.14 (m, 20H), 4.26 (d, J ) 6.0, 6.6 Hz, 1H),
3.74 (dq, J ) 3.5, 6.0 Hz, 1H), 3.44 (s, 2H), 2.98 (dd, J ) 5.0,
6.6 Hz, 1H), 2.86 (dd, J ) 3.5, 5.0 Hz, 1H), 1.42 (s, 9H), 1.22
(d, J ) 6.0 Hz, 3H), 0.91 (s, 9H), 0.76 (d, J ) 6.6 Hz, 3H), 0.09
(s, 3H), 0.08 (s, 3H); IR (CCl4) 2980-2885, 1732, 1462, 1382,
1772, 1470, 1415, 1392, 1264, 1159, 1076 cm-1; [R]23 -8.38°
D
(c 1.01, CHCl3). Anal. Calcd for C20H32ClNO2Si (382.02): C,
62.88; H, 8.44; N, 3.67. Found: C, 62.86; H, 8.43; N, 3.69.
(2S,3S,4S)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-((ter t-bu tyl-
d ip h e n ylsilyl)oxy)-2-[(R )-1-((t er t -b u t yld im e t h ylsilyl)-
oxy)eth yl]p en ta n oa te (11). TCC reaction of 3b (2.05 g, 5.0
mmol) as described above for 7 gave the aldol adduct. To a
pyridine (30 mL) solution of the aldol adduct was added acetic
anhydride (15 mL) at 0 °C, and the mixture was stirred for 1
h at room temperature. Concentration under reduced pressure
and purification with column chromatography (silica gel;
n-hexane/ethyl acetate, 15/1) gave 11 (2.28 g, 75%). Colorless
oil: 1H NMR (CDCl3) δ 7.70-7.15 (m, 15H), 5.29 (dq, J ) 8.0,
6.5 Hz, 1H), 4.02 (dq, J ) 5.0, 6.0 Hz, 1H), 3.66 (d, J ) 15.5
Hz, 1H), 3.61 (d, J ) 15.5 Hz, 1H), 3.01 (dd, J ) 8.0, 5.0 Hz,
1H), 2.91 (dd, J ) 5.0, 5.0 Hz, 1H), 1.93 (s, 3H), 1.45 (s, 9H),
1.29 (d, J ) 6.5 Hz, 3H), 1.05 (s, 9H), 1.04 (d, J ) 6.0 Hz, 3H);
IR (CCl4) 3100-2890, 1755, 1475, 1422, 1408, 1387, 1255,
1260, 1167, 1102 cm-1; [R]20 +2.80° (c 0.995, CHCl3). Anal.
D
Calcd for C43H57NO4Si (680.02): C, 75.95; H, 8.45; N, 2.06.
Found: C, 76.27; H, 8.81; N, 2.10.
(3S ,4S )-1-N -Be n zyl-3-[(R )-1-((t er t -Bu t yld im e t h ylsi-
lyl)oxy)eth yl]-4-[(S)-1-(tr ityloxy)eth yl]-2-a zetid in on e (8).
To a THF (15 mL) solution of 7 (0.43 g, 0.63 mmol) under argon
atmosphere at 0 °C was added 0.9 M THF solution of EtMgBr
(2.1 mL, 1.9 mmol), and the mixture was stirred for 2 h.
Addition of excess aqueous saturated NH4Cl, extraction with
ether, washing with brine, drying with anhydrous Na2SO4,
concentration under reduced pressure, and purification with
column chromatography (silica gel; n-hexane/ethyl acetate, 5/1)
gave 8 (0.31 g, 81%). Colorless oil: 1H NMR (CDCl3) δ 7.40-
7.08 (m, 20H), 4.24 (s, 2H), 4.22 (dq, J ) 3.5, 6.2 Hz, 1H), 3.51
(dd, J ) 3.5, 2.2 Hz, 1H), 3.46 (dq, J ) 3.5, 6.2 Hz, 1H), 2.96
(dd, J ) 2.2, 3.5 Hz, 1H), 1.14 (d, J ) 6.2 Hz, 3H), 0.85 (s,
9H), 0.70 (d, J ) 6.2 Hz, 3H), 0.06 (s, 3H), 0.02 (s, 3H); IR
1170, 1126, 1090 cm-1; [R]20 -8.66° (c 1.01, CHCl3); HRMS
D
(EI) calcd for C36H49NO5Si (603.3380), found 603.3380. Anal.
Calcd for C36H49NO5Si (603.88): C, 71.60; H, 8.18; N, 2.32.
Found: C, 71.37; H, 8.37; N, 2.49.
(3S,4S)-1-N-Ben zyl-3-[(R)-1-(a cetyloxy)eth yl]-4-[(S)-1-
((ter t-b u t yld ip h en ylsilyl)oxy)et h yl]-2-a zet id in on e (12).
To a CH2Cl2 (25 mL) solution of 11 (1.81 g, 3.0 mmol) was
added trifluoroacetic acid (20 mL), and the mixture was stirred
for overnight at room temperature. The mixture was quenched
with aqueous saturated NaHCO3, extracted with CH2Cl2,
washed with brine, dried with anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was dissolved
in acetonitrile (100 mL), PPh3 (1.57 g, 6.0 mmol) and 2,2′-
dipyridyl disulfide (1.32 g, 6.0 mmol) were added, and the
mixture was refluxed for 10 h. The mixture was concentrated
under reduced pressure. Purification with column chroma-
tography (silica gel; n-hexane/ethyl acetate, 2/1) gave 12 (1.41
g, 88%). Colorless oil: 1H NMR (CDCl3) δ 7.66-7.18 (m, 15H),
5.13 (dq, J ) 6.0, 7.3 Hz, 1H), 4.75 (d, J ) 15.0 Hz, 1H), 4.08
(d, J ) 15.0 Hz, 1H), 3.99 (dq, J ) 4.2, 6.3 Hz, 1H), 3.47 (dd,
J ) 2.0, 4.2 Hz, 1H), 3.08 (dd, J ) 2.0, 6.0 Hz, 1H), 1.90 (s,
3H), 1.20 (d, J ) 6.3 Hz, 3H), 1.05 (s, 9H), 0.97 (d, J ) 6.3 Hz,
3H); IR (neat) 3100-2890, 1745, 1246, 1111 cm-1; [R]21D +38.6°
(CCl4) 3062-2856, 1736, 1448, 1252, 1219, 1198, 1074 cm-1
;
[R]20 -12.1° (c 0.60, CHCl3). Anal. Calcd for C39H47NO3Si
D
(605.90): C, 77.31; H, 7.82; N, 2.31. Found: C, 76.92; H, 7.81;
N, 2.35.
(3S ,4S )-1-N -Be n zyl-3-[(R )-1-((t er t -Bu t yld im e t h ylsi-
lyl)oxy)eth yl]-4-[(S)-1-h yd r oxyeth yl]-2-a zetid in on e (9).
To a ether (4 mL) solution of 8 (0.31 g, 0.51 mmol) at room
temperature was added HCO2H (6 mL), and the mixture was
stirred for 7 min. Addition of ether, quenching with aqueous
saturated NaHCO3, extraction with ether, washing with brine,
drying with anhydrous Na2SO4, concentration under reduced

Diastereoselective Conjugate Addition
J . Org. Chem., Vol. 62, No. 18, 1997 6281
(c 0.965, CHCl3). Anal. Calcd for C32H39NO4Si (529.76): C,
72.55; H, 7.42; N, 2.64. Found: C, 72.29; H, 7.38; N, 2.72.
(3S,4S)-1-N-Ben zyl-3-[(R)-1-(a cetyloxy)eth yl]-4-[(S)-1-
h yd r oxyeth yl]-2-a zetid in on e (13). To a THF (10 mL)
solution of 12 (1.36 g, 2.57 mmol) under argon atmosphere at
0 °C was added dropwise a 1.0 M THF solution of tetrabutyl-
ammonium fluoride (5.13 mL, 5.13 mmol), and the mixture
was stirred for 4 h at room temperature. Addition of water,
extraction with ether, washing with brine, drying with anhy-
drous Na2SO4, concentration under reduced pressure, and
purification with column chromatography (silica gel; n-hexane/
ethyl acetate, 1/1) gave 13 (0.58 g, 77%). Colorless oil: 1H
NMR (CDCl3) δ 7.37-7.23 (m, 5H), 5.14 (dq, J ) 6.5, 7.5 Hz,
1H), 4.62 (d, J ) 15.0 Hz, 1H), 4.35 (d, J ) 15.0 Hz, 1H), 3.77
(dq, J ) 8.0, 6.5 Hz, 1H), 3.31 (dd, J ) 2.2, 8.0 Hz, 1H), 2.91
(dd, J ) 2.2, 7.5 Hz, 1H), 1.95 (s, 3H), 1.34 (d, J ) 6.5 Hz,
3H), 1.14 (d, J ) 6.5 Hz, 3H); IR (CCl4) 3375, 2978-2933, 1740,
Addition of water (250 mL), extraction with CH2Cl2, washing
with brine, drying with anhydrous MgSO4, concentration
under reduced pressure, and distillation gave the product (11.9
g, 92%: bp 46 °C/0.7 mmHg). To a MeOH (400 mL) solution
of the oil obtained above at -78 °C was bubbled ozone until
the color of the solution turned blue. Excess of ozone was
removed by bubbling of argon at -78 °C. After the color
disppeared, Me2S (7.5 mL) was added, and the mixture was
allowed to warm to room temperature and concentrated under
reduced pressure. Ether and water were added, and the
mixture was extracted with ether, washed with three times
of water and brine, dried with anhydrous MgSO4, and con-
centrated under reduced pressure. The residue was used for
further manipulation without purification as described above
for 1a , and i-PrOH was used instead of t-BuOH at the final
step (22% yield from benzaldehyde). Colorless oil: 1H NMR
(CDCl3) δ 7.35-7.27 (m, 5H), 6.93 (dd, J ) 4.5, 15.2 Hz, 1H),
6.06 (dd, J ) 1.7, 15.2 Hz, 1H), 5.30 (dd, J ) 1.7, 4.5 Hz, 1H),
5.03 (septet, J ) 6.3 Hz, 1H), 1.24 (d, J ) 6.3 Hz, 6H), 0.91 (s,
9H), 0.07 (s, 3H), -0.04 (s, 3H); IR (CCl4) 3000-2856, 1720,
1656, 1280, 1169 cm-1. Anal. Calcd for C19H30O3Si (334.53):
C, 68.22; H, 9.04. Found: C, 68.05; H, 9.42.
(3R*,4S*)-Isop r op yl 3-(N-ben zyla m in o)-4-((ter t-bu tyl-
d im et h ylsilyl)oxy)-4-p h en ylp en t a n oa t e (21). Colorless
oil: 1H NMR (CDCl3) δ 7.35-7.18 (m, 10H), 4.96 (qq, J ) 6.2,
6.2 Hz, 1H), 4.86 (d, J ) 4.3 Hz, 1H), 3.77 (s, 2H), 3.18 (ddd,
J ) 4.3, 5.0, 8.2 Hz, 1H), 2.43 (dd, J ) 5.0, 15.3 Hz, 1H), 2.37
(dd, J ) 8.2, 15.3 Hz, 1H), 1.20 (d, J ) 6.2 Hz, 3H), 1.18 (d, J
) 6.2 Hz, 3H), 0.90 (s, 9H), 0.05 (s, 3H), -0.18 (s, 3H); IR (neat)
2982-2858, 1719, 1472, 1375, 1256, 1107 cm-1. Anal. Calcd
for C26H39NO3Si (441.69): C, 70.70; H, 8.90; N, 3.17. Found:
C, 70.70; H, 8.78; N, 3.38.
1711, 1437, 1242, 1144 cm-1; [R]26 +65.6° (c 1.00, CHCl3).
D
Anal. Calcd for C16H21NO4 (291.35): C, 65.96; H, 7.27; N, 4.81.
Found: C, 65.92; H, 7.22; N, 4.93.
(3S,4S)-1-N-Ben zyl-3-[(R)-1-(a cetyloxy)eth yl]-4-[(R)-1-
ch lor oeth yl]-2-a zetid in on e (14). 14 was prepared from 13
as described above for 10 (92% yield). Colorless solid: 1H NMR
(CDCl3) δ 7.40-7.24 (m, 5H), 5.21 (dq, J ) 7.2, 6.5 Hz, 1H),
4.85 (d, J ) 15.3 Hz, 1H), 4.14 (dq, J ) 6.8, 3.5 Hz, 1H), 3.99
(d, J ) 15.3 Hz, 1H), 3.57 (dd, J ) 2.0, 3.5 Hz, 1H), 3.26 (dd,
J ) 7.2, 2.0 Hz, 1H), 1.99 (s, 3H), 1.45 (d, J ) 6.8 Hz, 3H),
1.38 (d, J ) 6.5 Hz, 3H); IR (CCl4) 3067-2876, 1767, 1454,
1381, 1236, 1177, 1132 cm-1; HRMS (EI) calcd for C16H20ClNO3
(309.1132), found 309.1123. Anal. Calcd for C16H20ClNO3
(309.80): C, 62.03; H, 6.51; N,4.52. Found: C, 61.58; H, 6.37;
N, 4.45.
(3R*,4S*)-3-(N-Ben zylam in o)-4-ph en yl-4-bu tan olide (22-
tr a n s). 22-tr a n s was prepared from 21 as described above
for 5a (52% yield). Colorless needles: mp 76.2-76.7 °C; H
(E)-ter t-Bu tyl 4-Meth oxy-2-m eth yl-2-p en ten oa te (17).
To a benzene (180 mL) solution of crude 2-methoxypropanal
(ca. 3.2 g, 37 mmol) which was prepared from ethyl lactate
and MeI as described above for 1e was added 2-methyl-2-
(triphenyphosphoranylidene)acetic acid tert-butyl ester, and
the mixture was refluxed for overnight. After concentration
under reduced pressure, the residue was dissolved in n-hexane
(20 mL) and ether (20 mL). Filtration, concentration under
reduced pressure and purification with column chromatogra-
phy (silica gel, n-hexane/ethyl acetate, 15/1) gave 17 (2.0 g,
27% from ethyl lactate). Colorless oil: 1H NMR (CDCl3) δ 6.51
(dq, J ) 1.5, 8.6 Hz, 1H), 4.12 (dq, J ) 6.6, 8.6 Hz, 1H), 3.28
(s, 3H), 1.83 (d, J ) 1.5 Hz, 3H), 1.54 (s, 9H), 1.25 (d, J ) 6.6
1
NMR (CDCl3) δ 7.41-7.25 (m, 10H), 5.25 (d, J ) 5.1 Hz, 1H),
3.82 (d, J ) 13.5 Hz, 1H), 3.78 (d, J ) 13.5 Hz, 1H), 3.54 (ddd,
J ) 7.1, 6.5, 5.1 Hz, 1H), 2.83 (dd, J ) 17.0, 7.1 Hz, 1H), 2.47
(dd, J ) 17.0, 6.5 Hz, 1H), 1.60 (broad s, 1H); 13C NMR (CDCl3)
δ 175.00, 139.13, 137.77, 128.84, 128.68, 128.60, 127.98,
127.44, 125.61, 84.04, 61.88, 51.94, 36.02; IR (CHCl3) 3335,
1775, 1165, 1140 cm-1. HRMS calcd for C17H17NO2 (267.1259),
found 267.1249.
(3S*,4S*)-3-(N-Ben zylam in o)-4-ph en yl-4-bu tan olide (22-
cis). To a EtOH (2 mL) solution of 20 (0.33 g, 1.0 mmol) was
added benzylamine (0.30 mL, 2.8 mmol), and the mixture was
stirred for 50 h at 50 °C. Concentration under reduced
pressure, and purification with column chromatography (silica
gel; n-hexane/ethyl acetate, 15/1) gave 21 (0.35 g, 79%, syn/
anti ) 2/1). 22-cis was prepared from syn-21 as described
above for 5a (78% yield). Colorless oil: 1H NMR (CDCl3) δ
7.43-7.06 (m, 10H), 5.58 (d, J ) 4.9 Hz, 1H), 3.73 (ddd, J )
3.0, 4.9, 6.0 Hz, 1H), 3.63 (d, J ) 13.8 Hz, 1H), 3.47 (d, J )
13.8 Hz, 1H), 2.77 (dd, J ) 16.0, 6.0 Hz, 1H), 2.61 (dd, J )
16.0, 3.0 Hz, 1H), 1.02 (broad s, 1H); 13C NMR (CDCl3) δ
175.67, 139.25, 134.29, 128.74, 128.70, 128.47, 127.76, 127.19,
125.15, 83.83, 56.87, 50.00, 36.48; IR (CHCl3) 3330, 1780, 1195,
Hz, 3H); IR (neat) 2989-2750, 1722, 1367, 1342, 1143 cm-1
.
Anal. Calcd for C11H20O3 (200.28): C, 65.97; H, 10.07.
Found: C, 66.08; H, 10.10.
(3S*,4S*)-ter t-Bu tyl 3-(N,N-Diben zylam in o)-4-m eth oxy-
2-m eth yl-2-p en ta n oa te (18a ). White solid: 1H NMR (CDCl3)
δ 7.35-7.15 (m, 10H), 3.89, 3.72 (2d, J ) 13.2 Hz, each 2H),
3.54 (dq, J ) 4.2, 6.0 Hz, 1H), 3.25 (s, 3H), 2.95 (dq, J ) 6.6,
8.6 Hz, 1H), 2.85 (dd, J ) 4.2, 8.6 Hz, 1H), 1.49 (s, 9H), 1.10
(d, J ) 6.0 Hz, 3H), 1.05 (d, J ) 6.6 Hz., 3H); IR (KBr) 2976-
2794, 1716, 1494, 1440, 1365, 1340, 1145, 1107 cm-1. Anal.
Calcd for C25H35NO3 (397.56): C, 75.53; H, 8.87; N, 3.52.
Found: C, 75.54; H, 9.05; N, 3.58.
1160 cm-1
(E)-ter t-Bu tyl 4-P h en yl-2-p en ten oa te (27). To a benzene
D,L-2-phenylpropionaldehyde (1.25 mL, 9.41
.
An oth er Dia ster eom er (18b). White solid: 1H NMR
(CDCl3) δ 7.33-7.16 (m, 10H), 3.98, 3.78 (2d, J ) 13.5 Hz,
each 2H), 3.40 (dq, J ) 3.3, 6.2 Hz, 1H), 3.19 (s, 3H), 2.99 (dq,
J ) 6.6, 9.5 Hz, 1H), 2.83 (dd, J ) 3.3, 9.5 Hz, 1H), 1.41 (s,
9H), 1.26 (d, J ) 6.6Hz, 3H), 1.12 (d,J ) 6.2 Hz, 3H); IR (KBr)
(20 mL) solution of
mmol) at 0 °C was added dropwise (triphenylphosphoranylide-
ne)acetic acid tert-butyl ester (3.22 g, 8.56 mmol). The mixture
was stirred for 30 min at 0 °C, stirred for 35 min at room
temperature, refluxed for 2.5 h, and then cooled to room
temperature. After concentration under reduced pressure,
purification with column chromatography (silica gel; n-hexane/
ethyl acetate, 30/1) gave 27 (1.62 g, 82%). Colorless oil: 1H
NMR (CDCl3) δ 7.44-7.17 (m, 5H), 7.00 (dd, J ) 6.5, 15.3 Hz,
1H), 5.72 (dd, J ) 1.8, 15.3 Hz, 1H), 3.58 (ddq, J ) 1.8, 6.5,
7.0 Hz, 1H), 1.47 (s, 9H), 1.42 (d, J ) 7.0 Hz, 3H); IR (neat)
2980-2933, 1713, 1649, 1368, 1316, 1290, 1154 cm-1. HRMS
(EI) calcd for C15H20O2 (232.1463), found 232.1466. Anal.
Calcd for C15H20O2 (232.32): C, 77.55; H, 8.68. Found: C,
77.26; H, 8.71.
2976-2878, 1720, 1440, 1367, 1148 cm-1
. Anal. Calcd for
C25H35NO3 (397.56): C, 75.53; H, 8.87; N, 3.52. Found: C,
75.94; H, 9.22; N, 3.63.
(E)-Isop r op yl 4-((ter t-bu tyld im eth ylsilyl)oxy)-4-p h en -
yl-2-bu ten oa te (20). To a THF (200 mL) solution of benzal-
dehyde (9.7 mL, 95 mmol) at -78 °C under argon atmosphere
was added dropwise 0.98 M THF solution of vinylmagnesium
bromide (80 mL, 78.4 mmol) in 30 min. The mixture was
stirred for 1 h. Addition of 1 N HCl (200 mL), extraction with
ether, washing with brine, drying with anhydrous Na2SO4,
concentration under reduced pressure, and distillation gave
the product (7.0 g, 67%: bp 74 °C/4 mmHg). To a CH2Cl2
(250 mL) solution of the oil obtained above at 0 °C were added
imidazole (6.8 g, 100 mmol) and TBDMSCl (9.0 g, 60 mmol),
and the mixture was stirred for 4 h at room temperature.
(3S*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-p h en ylp en -
ta n oa te (28). Colorless oil: 1H NMR (CDCl3) δ 7.34-7.15 (m,
10H), 3.82 (d, J ) 12.7 Hz, 1H), 3.74 (d, J ) 12.7 Hz, 1H),

6282 J . Org. Chem., Vol. 62, No. 18, 1997
Asao et al.
3.17 (ddd, J ) 4.9, 6.7, 8.1 Hz, 1H), 2.97 (dq, J ) 6.7, 7.0 Hz,
1H), 2.34 (dd, J ) 4.9, 15.0 Hz, 1H), 2.12 (dd, J ) 8.1, 15.0
Hz, 1H), 1.42 (s, 9H), 1.35 (d, J ) 7.0 Hz, 3H); IR (CCl4) 3086-
2876, 1726, 1495, 1454, 1367, 1256, 1153 cm-1. HRMS (EI)
calcd for C22H29NO2 (339.2198), found 339.2163. Anal. Calcd
for C22H29NO2 (339.48): C, 77.84; H, 8.61; N, 4.13. Found:
C, 77.33; H, 8.45; N, 4.05.
(3S,4R)-ter t-Bu tyl 3-(N-Ben zyla m in o)-5-((ter t-bu tyld i-
m et h ylsilyl)oxy)-4-m et h ylp en t a n oa t e (33a ). Colorless
oil: 1H NMR (CDCl3) δ 7.35-7.20 (m, 5H), 3.82 (d, J ) 12.9
Hz, 1H), 3.74 (d, J ) 12.9 Hz, 1H), 3.64 (dd, J ) 6.3, 9.9 Hz,
1H), 3.52 (dd, J ) 5.8, 9.9 Hz, 1H), 3.13 (m, 1H), 2.41 (dd, J )
6.2, 17.0 Hz, 1H), 2.36 (dd, J ) 7.2, 17.0 Hz, 1H), 1.86 (m,
1H), 1.44 (s, 9H), 0.90 (d, J ) 7.0 Hz, 3H), 0.87 (s, 9H), 0.03
(s, 6H); IR (CCl4) 2957-2856, 1728, 1471, 1367, 1255, 1153
cm-1; [R]24D +3.46° (c 1.07, CCl4). Anal. Calcd for C23H41NO3Si
(407.67): C, 67.76; H, 10.14; N, 3.44. Found: C, 67.90; H, 9.95;
N, 3.55.
(3R*,4S*)-ter t-Bu tyl 3-(N-Ben zyla m in o)-4-p h en ylp en -
ta n oa te (29). Colorless oil: 1H NMR (CDCl3) δ 7.33-7.16 (m,
10H), 3.78 (d, J ) 13.0 Hz, 1H), 3.68 (d, J ) 13.0 Hz, 1H),
3.17 (ddd, J ) 6.0, 6.7, 6.8 Hz, 1H), 2.97 (dq, J ) 6.7, 7.1 Hz,
1H), 2.37 (dd, J ) 6.8, 15.2 Hz, 1H), 2.31 (dd, J ) 6.0, 15.2
Hz, 1H), 1.45 (s, 9H), 1.29 (d, J ) 7.1 Hz, 3H); IR (CCl4) 3080-
(3S,4R)-ter t-Bu tyl 3-(N,N-Diben zyla m in o)-5-((ter t-bu -
tyld im eth ylsilyl)oxy)-4-m eth ylp en ta n oa te (33b). Color-
less oil: 1H NMR (CDCl3) δ 7.39-7.23 (m, 10H), 3.79 (d, J )
14.0 Hz, 2H), 3.50 (dd, J ) 4.3, 9.9 Hz, 1H), 3.41 (d, J ) 14.0
Hz, 1H), 3.36 (dd, J ) 7.6, 9.9 Hz, 1H), 3.06 (m, 1H), 2.63 (dd,
J ) 4.6, 15.1 Hz, 1H), 2.39 (dd, J ) 7.3, 15.1 Hz, 1H), 1.85 (m,
1H), 1.48 (s, 9H), 1.04 (d, J ) 6.6 Hz, 3H), 0.86 (s, 9H), 0.01
(s, 6H); IR (CHCl3) 3009-2856, 1714, 1454, 1367, 1198, 1088
2830, 1728, 1603, 1454, 1367, 1153 cm-1
. HRMS (EI) calcd
for C22H29NO2 (339.2198), found 339.2175. Anal. Calcd for
C22H29NO2 (339.48): C, 77.84; H, 8.61; N, 4.13. Found: C,
77.36; H, 8.43; N, 4.17.
(4R*)-P er h yd r o-3-ben zyl-4-((S*)-1-p h en yleth yl)-1,3-ox-
a zin -2-on e (30). To an ether (5 mL) solution of 29 (130 mg,
0.47 mmol) at 0 °C was added LiAlH4 (100 mg), and the
mixture was stirred for overnight at room temperature. Water
(0.4 mL) and 15% aqueous NaOH (0.1 mL) were added, and
the mixture was dried with anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was dissolved in
CH2Cl2 (5 mL), and trichloromethyl chloroformate (0.1 mL)
and iPr2NEt were added to the solution at room temperature,
and the mixture was stirred for 2 h. After low bp materials
were removed under reduced pressure, 5 mL of benzene was
added. The mixture was refluxed for overnight and then
cooled to room temperature. Concentration under reduced
pressure and purification with column chromatography (silica
gel; n-hexane/ethyl acetate, 10/1) gave 30 (30.6 mg, 25%).
Colorless oil: 1H NMR (CDCl3) δ 7.37-7.08 (m, 10H), 5.15 (d,
J ) 15.1 Hz, 1H), 4.40-4.30 (m, 1H), 4.24-4.15 (m, 1H), 3.36-
3.21 (m, 2H), 3.22 (d, J ) 15.1 Hz, 1H), 1.83-1.68 (m, 1H),
1.99 (m, 1H), 1.63 (m, 1H), 1.26(d, J ) 7.0 Hz, 3H); 13C NMR
(CDCl3) δ 154.83, 142.44, 136.98, 128.75, 128.69, 128.12,
127.68, 127.66, 127.11, 64.22, 50.08, 49.93, 40.25, 23.92, 14.31.
Another approach of 30 via the reaction which was already
reported about diastereoselectivity:13 To a CH2Cl2 (5 mL)
solution of the carbamate, which was obtained from allylation
of N-(2-phenylpropylidene)benzylamine followed by treatment
with ClCO2Me/K2CO3 (4:1 mixture of diastereomers), at -78
°C was bubbled ozone until the color of the solution turned
blue. Excess of ozone was removed by bubbling of argon at
-78 °C. After the color disappeared, Me2S (0.2 mL) was added,
and the mixture was allowed to warm to room temperature
and concentrated under reduced pressure. The residue was
dissolved in MeOH (3 mL), and sodium borohydride (100 mg)
was added at room temperature. Water (10 mL) was added.
The mixture was extracted with ether, washed with brine,
dried with anhydrous MgSO4, and concentrated under reduced
pressure. The residue was dissolved in THF (5 mL). Potas-
sium tert-butoxide (50 mg) was added at room temperature,
and the mixture was stirred for 3 h. Ether (20 mL) and
aqueous saturated NH4Cl/brine (1/1) were added. Extraction
with ether, washing with brine, drying with anhydrous MgSO4,
concentration under reduced pressure, and purification with
column chromatography (silica gel; n-hexane/ethyl acetate, 15/
1) gave 30 as a 4:1 mixture of diastereomers (21.1 mg, 18%).
Dia ster eom er of 30: Colorless oil: 1H NMR (CDCl3) δ 7.39-
7.08 (m, 10H), 5.53 (d, J ) 14.9 Hz, 1H), 4.13 (d, J ) 14.9 Hz,
1H), 4.08 (ddd, J ) 11.7, 5.8, 2.8 Hz, 1H), 3.95 (ddd, J ) 11.7,
11.5, 4.5 Hz, 1H), 3.42 (ddd, J ) 7.5, 5.4, 3.0 Hz, 1H), 3.25
(dq, J ) 7.5, 7.1 Hz, 1H), 1.83-1.68 (m, 1H), 1.65-1.56 (m,
1H), 1.41 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 154.23,
142.35, 137.05, 128.92, 128.81, 128.14, 127.78, 127.29, 127.18,
64.16, 57.82, 52.32, 41.49, 24.27, 18.98; IR (CHCl3) 1680, 1490,
1455, 705 cm-1. HRMS (EI) calcd for C19H21NO2 (295.1572),
found 295.1568.
cm-1; [R]23 +0.495° (c 2.03, CHCl3). Anal. Calcd for
D
C30H47NO3Si (497.80): C, 72.39; H, 9.52; N, 2.81. Found: C,
72.10; H, 9.59; N, 2.73.
(3R,4R)-ter t-Bu tyl 3-(N-Ben zyla m in o)-5-((ter t-bu tyld i-
m et h ylsilyl)oxy)-4-m et h ylp en t a n oa t e (34a ). Colorless
oil: 1H NMR (CDCl3) δ 7.35-7.20 (m, 5H), 3.77 (s, 2H), 3.56
(d, J ) 6.1 Hz, 1H), 3.09 (m, 1H), 2.43 (dd, J ) 4.1, 15.0 Hz,
1H), 2.24 (dd, J ) 8.5, 15.0 Hz, 1H), 1.93 (m, 1H), 1.43 (s, 9H),
0.88 (d, J ) 6.9 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H); IR (CCl4)
2957-2856, 1728, 1471, 1367, 1255, 1151 cm-1; [R]24 -1.75°
D
(c 1.03, CCl4). Anal. Calcd for C23H41NO3Si (407.67): C, 67.76;
H, 10.14; N, 3.44. Found: C, 67.67; H, 10.05; N, 3.40.
(3R,4R)-ter t-Bu tyl 3-(N,N-d iben zyla m in o)-5-((ter t-bu -
tyld im eth ylsilyl)oxy)-4-m eth ylp en ta n oa te (34b). Color-
less oil: 1H NMR (CDCl3) δ 7.36-7.20 (m, 10H), 3.97 (dd, J )
4.5, 10.0 Hz, 2H), 3.73 (d, J ) 13.5 Hz, 2H), 3.42 (d, J ) 13.5
Hz, 2H), 3.08 (dd, J ) 8.0, 10.0 Hz, 1H), 3.05 (ddd, J ) 4.5,
7.5, 13.0 Hz, 1H), 2.65 (dd, J ) 4.5, 15.5 Hz, 1H), 2.29 (dd, J
) 7.5, 15.5 Hz, 1H), 1.95 (m, 1H), 1.47 (s, 9H), 0.90 (s, 9H),
0.87 (d, J ) 6.5 Hz, 3H), 0.02 (s, 6H); IR (CHCl3) 3064-2856,
1713, 1454, 1367, 1159 cm-1; [R]22 -2.66° (c 2.10, CHCl3).
D
Anal. Calcd for C30H47NO3Si (497.80): C, 72.39; H, 9.52; N,
2.81. Found: C, 72.35; H, 9.58; N, 2.72.
(3S,4R)-ter t-Bu t yl 3-Am in o-5-((ter t-b u t yld im et h ylsi-
lyl)oxy)-4-m eth ylp en ta n oa te (35). To an ethyl acetate (3
mL) solution of 33a or 33b (0.3 mmol) was added Pearlman
catalyst (Pd(OH)2/C, 47 mg), and the mixture was stirred
vigorously for 24 h under H2 atomosphere. Filtration through
Celite, concentration under reduced pressure, and purification
with column chromatography (silica gel; ethyl acetate) gave
35 (80-85%). Colorless oil: 1H NMR (CDCl3) δ 3.58 (dd, J )
6.7, 10.1 Hz, 1H), 3.54 (dd, J ) 5.5, 10.1 Hz, 1H), 3.32 (ddd, J
) 4.0, 4.3, 9.1 Hz, 1H), 2.36 (dd, J ) 15.0, 4.3 Hz, 1H), 2.24
(dd, J ) 15.0, 9.1 Hz, 1H), 1.66 (m, 1H), 1.45 (s, 9H), 0.89 (s,
9H), 0.87 (d, J ) 7.1 Hz, 3H), 0.05 (s, 6H); IR (CCl4) 3410,
3020-2850, 1740, 1467, 1379, 1260, 1157 cm-1; [R]24 -6.43°
D
(c 1.68, CHCl3). Anal. Calcd for C16H35NO3Si (317.53): C,
60.52; H, 11.11; N, 4.41. Found: C, 60.22; H, 11.18; N, 4.33.
(3R,4R)-ter t-Bu t yl 3-Am in o-5-((ter t-b u t yld im et h ylsi-
lyl)oxy)-4-m eth ylp en ta n oa te (36). 36 was prepared from
34a or 34b as described above for 35 (80-85% yield). Colorless
oil: 1H NMR (CDCl3) δ 3.61 (dd, J ) 5.5, 10.4 Hz, 1H), 3.55
(dd, J ) 5.8, 10.4 Hz, 1H), 3.18 (ddd, J ) 3.3, 5.7, 9.6 Hz, 1H),
2.45 (dd, J ) 3.3, 15.5 Hz, 1H), 2.19 (dd, J ) 9.6, 15.5 Hz,
1H), 1.66 (m, 1H), 1.65 (br s, 2H), 1.46 (s, 9H), 0.89 (s, 9H),
0.89 (d, J ) 6.8 Hz, 3H), 0.05 (s, 6H); IR (CCl4) 3365, 2980-
2860, 1738, 1465, 1373, 1260, 1157 cm-1; [R]24D +13.4° (c 1.68,
CHCl3). Anal. Calcd for C16H35NO3Si (317.53): C, 60.52; H,
11.11; N, 4.41. Found: C, 60.32; H, 11.10; N, 4.42.
J O970435D