aldehyde 10 by a series of reactions: (1) diastereoselective
alkynylation, (2) stereoselective reduction of alkyne, and (3)
1,3-chirality transfer of (E)- and (Z)-allylic alcohols (Scheme
5), wherein we selected a PMB (p-methoxybenzyl) protecting
group as a regio- and stereocontroller.
Table 2. Allylic Substitution of anti- and syn-5 with
Nucleophilesa
entry
product
R
conditions
yieldb (%)
1
2
3
4
5
6
anti-6
anti-7
anti-8
syn-6
syn-7
syn-8
CH(CO2Me)2
BnNH
Bn2N
CH(CO2Me)2
BnNH
Bn2N
rt, 30 min
rt, 30 min
reflux, 23 h
rt, 30 min
rt, 30 min
reflux, 3 h
93 (tr)c
83 (10)c
34 (45)d
98 (tr)c
84 (15)
46 (23)d
Scheme 5
a Reactions were carried out using anti-5 (1.0 equiv), nucleophile (2
equiv), and Pd(PPh3)4 (10 mol %) in THF under Ar. b Isolated yield. c Yield
in parentheses is the yield of compound 2. d Yield in parentheses is the
yield of compound 9.
The results are summarized in Table 2. Benzylamine also
exclusively attacked distal to the TBSO group at room
temperature, giving 1,4-anti isomer anti-7 (entry 2). The
reaction was stereospecific, and no 1,4-syn isomer was
obtained. The regiochemistry was controlled completely.11
In the case of bulky dibenzylamine, the reaction became
sluggish and no allylic substitution reaction product was
produced at room temperature. When the reaction mixture
was refluxed, the material disappeared, giving the adduct
anti-8 in 34% yield along with 45% yield of diene 9 (ca.
2.7:1 E/Z mixture) probably formed by â-hydride elimination
(entry 3).12 The syn adduct syn-5 also afforded the corre-
sponding 1,4-syn compounds syn-6 and syn-7 in good yields
with high regio- and diastereoselectivity (entries 4 and 5).
Although the reaction of syn-5 with dibenzylamine was
sluggish as in the case of anti-5, the yield of the allylic
substitution reaction was higher than that in the anti isomer
(entry 6). Thus, two kinds of diastereomeric 1,4-bifunctional
compounds were synthesized in an enantiomerically pure
form.
(S)-2-(p-Methoxybenzyloxy)propanal (10)13 was reacted
with the lithium acetylide of 1-hexyne in the presence of
ZnBr2 in ether14 to give the syn adduct syn-11 mainly in a
ratio of 87:13. The diastereoselectivity was further improved
by employing Carreira’s conditions.15 The adduct syn-11 was
obtained in 84% yield as the sole product. Then, syn-11 was
reduced selectively to (E)-allylic alcohol (E)-12 with LiAlH4
in THF, and subsequent trifluoroacetylation with (CF3CO)2O
in pyridine afforded trifluoroacetate (E)-12 in 80% yield in
two steps.
Next, we examined the stereodivergent synthesis of 1,4-
bifunctional compounds starting from a common R-oxy-
The corresponding (Z)-isomer (Z)-12 was synthesized via
hydrogenation of syn-11 with Lindlar catalyst in MeOH
followed by trifluoroacetylation, giving (Z)-12 in 83% in two
steps.
(5) Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron: Asymmetry
1998, 9, 1427-1440.
(6) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983,
48, 5180-5182.
(7) Chen, M.-J.; Narkunan, K.; Liu, R.-S. J. Org. Chem. 1999, 64, 8311-
8318.
(8) Optical purity of anti-2 was confirmed by 1H NMR spectral data
after conversion into the MTPA ester. The relative configurations of anti-
and syn-2 were assigned by comparison with the reported 1H NMR spectral
data of a related compound. The assignment was confirmed by applying a
modified Mosher method to anti-2. For data of the related compound, see:
Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T. Tetrahedron
1998, 54, 15589-15606. For the modified Mosher method, see: Ohtani,
I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092-4096.
Scheme 6
(9) Vitagliano, A.; AÄ kermark, B.; Hansson, S. Organometallics 1991,
10, 2592-2599.
(10) Absolute configuration of anti-6 was confirmed by comparison of
the specific rotation with that reported after conversion into known (S)-4-
butyldihydrofuran-2-one by subsequent reactions: (1) ozonolysis of the
double bond followed by NaBH4 reduction of the resulting aldehyde, (2)
demethoxycarbonylation of the R-methoxycarbonyl γ-lactone with NaCl
in aqueous DMSO. [R]24D -5.72 (c 0.25, CHCl3). lit. [R]20D -6.00 (c 0.32,
CHCl3). For the specific rotation of (S)-4-butyldihydrofuran-2-one, see:
Kosugi, H.; Tagami, K.; Takahashi, A.; Kanna, H.; Uda, H. J. Chem. Soc.,
Perkin Trans. 1 1989, 935-943.
(11) Absolute configuration of the amine anti-7 was determined by a
modified Mosher method; see: Kusumi, T.; Fukushima, T.; Ohtani, I.;
Kakisawa, H. Tetrahedron Lett. 1991, 32, 2939-2942.
Org. Lett., Vol. 6, No. 13, 2004
2179