Stereoselective synthesis of 1,4-bifunctional compounds by regioselective Pd-catalyzed allylic substitution reaction

Article abstract of DOI:10.1021/ol049374d

Highly stereoselective synthesis of 1,4-bifunctional compounds was accomplished via 1,2-asymmetric induction to α-oxyaldehyde followed by regio- and diastereoselective Pd-catalyzed allylic substitution reaction.

Full text of DOI:10.1021/ol049374d

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2177-2180
Stereoselective Synthesis of
1,4-Bifunctional Compounds by
Regioselective Pd-Catalyzed Allylic
Substitution Reaction
Naoyoshi Maezaki, Yuki Hirose, and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received April 7, 2004
ABSTRACT
Highly stereoselective synthesis of 1,4-bifunctional compounds was accomplished via 1,2-asymmetric induction to r-oxyaldehyde followed by
regio- and diastereoselective Pd-catalyzed allylic substitution reaction.
Palladium-catalyzed 1,3-chirality transfer of readily available
chiral 1,2-diol derivatives is a fascinating strategy for
synthesizing olefins flanking two stereogenic centers, which
are synthetically useful chiral building blocks.1 Two methods
have been developed so far: Pd-catalyzed allylic substitution
reactions of cyclic carbonates2 and 1,3-diene monoepoxides.3
We planned an asymmetric synthesis of 1,4-bifunctional
alkenes via diastereoselective alkenylation of R-hydroxy
aldehydes followed by Pd-catalyzed allylic substitution4 as
shown in Scheme 1. The stereogenic center at the protected
Scheme 1
(1) For application of olefins flanking two stereogenic centers to a
synthesis of natural products, see: Block, O.; Klein, G.; Altenbach, H.-J.;
Brauer, D. J. J. Org. Chem. 2000, 65, 716-721. Carretero, J. C.; Arrayas,
R. G. J. Org. Chem. 1998, 63, 2993-3005. Rigby, J. H.; Mateo, M. E. J.
Am. Chem. Soc. 1997, 119, 12655-12656. Hudlicky, T.; Olivo, H. F. J.
Am. Chem. Soc. 1992, 114, 9694-9696. Takeda, K.; Kaji, E.; Konda, Y.;
Sato, N.; Nakamura, H.; Miya, N.; Morizane, A.; Yanagisawa, Y.; Akiyama,
A.; Zen, S.; Harigaya, Y. Tetrahedron Lett. 1992, 33, 7145-7148.
Ba¨eckvall, J.-E.; Schink, H. E.; Renko, Z. D. J. Org. Chem. 1990, 55, 826-
831.
(2) (a) Kang, S.-K.; Kim, S.-G.; Lee, J.-S. Tetrahedron: Asymmetry 1992,
3, 1139-1140. (b) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393.
(3) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981, 22,
2575-2578.
chiral secondary alcohol not only works as a stereocontroller
in the first step but also controls the regiochemistry in the
diastereoselective Pd-catalyzed allylic substitution reaction.
The whole transformation is formally equivalent to 1,4-
asymmetric induction. The method has some advantages: (1)
a variety of substrates for the allylic substitution reaction
can be readily synthesized from chiral R-oxyaldehydes and
vinylic anions; (2) the protecting group (PG) is adjustable
so as to control the regiochemistry efficiently in the allylic
(4) For selected recent reviews for Pd-catalyzed allylic substitutions,
see: Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921-2943.
Kazmaier, U. Curr. Org. Chem. 2003, 7, 317-328. Trost, B. M. Chem.
Pharm. Bull. 2002, 50, 1-14; van Leeuwen, P. W. N. M.; Kamer, P. C. J.;
Reek, J. N. H.; Dierkes, P. Chem. ReV. 2000, 100, 2741-2769. Moberg,
C.; Bremberg, U.; Hallman, K.; Svensson, M.; Norrby, P.-O.; Hallberg,
A.; Larhed, M.; Cso¨regh, I. Pure Appl. Chem. 1999, 71, 1477-1483. Poli,
G.; Scolastico, C. Chemtracts 1999, 12, 822-836. Trost, B. M.; van
Vranken, D. L. Chem. ReV. 1996, 96, 395-422. Reiser, O. Angew. Chem.
1993, 105, 576-578. Sawamura, M.; Ito, Y. Chem. ReV. 1992, 92, 857-
871. See also ref 2b.
10.1021/ol049374d CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/05/2004

substitution reaction; and (3) the reactivity of the leaving
group can also be tuned depending on the reactivity of the
nucleophiles, in contrast to the previous methods. Clayden
and co-workers reported the Pd-catalyzed rearrangement of
allylic esters controlled by a dibenzylamino group.5 However,
the regioselectivity depends on the acyl groups and is not
sufficiently high.
Herein, we describe a novel method for synthesizing chiral
1,4-bifunctional compounds using regio- and diastereo-
selective Pd-catalyzed allylic substitution reactions.
The allylic alcohol 2 was prepared by alkenylation of (S)-
2-(tert-butyldimethylsilyloxy)propanal (1)6 with (E)-1-
hexenyllithium generated in situ by iodine-lithium exchange
reaction from (E)-1-iodohexene7 (Scheme 2).
Table 1. Effect of Leaving Group and Amount of Nucleophilea
yield (%)b
anti-6 anti-2
Nu
entry acylates
R
(equiv)
conditions
1
2
3
4
5
6c
anti-3
anti-4
anti-5
anti-5
anti-5
anti-5
Me
3
3
3
2
1.5
3
reflux, 5 h
reflux, 2 h
rt, 0.5 h
rt, 0.5 h
rt, 5 h
0
32
74
93
72
0
0
5
23
trace
14
78
CCl3
CF3
CF3
CF3
CF3
rt to reflux, 6 h
a Reactions were carried out using Pd(PPh3)4 (10 mol %) in THF under
Ar. b Isolated yield. c Without Pd catalyst.
equiv of dimethyl sodiomalonate exhibited a sharp contrast
to each other (entries 1-3).
Scheme 2
Use of the allylic acetate anti-3 resulted in recovery of
the starting material even under refluxing conditions (entry
1). The corresponding allylic trichloroacetate anti-4 furnished
the products anti-6 in refluxing THF, but the yield was poor
(32%). Nucleophilic attack to the ester moiety afforded 5%
yield of the alcohol anti-2 (entry 2). We found that the use
of the most reactive trifluoroacetate anti-5 afforded better
results than the acetate and the trichloroacetate,9 but a
considerable amount of anti-2 (23%) was formed (entry 3).
The problem was overcome by using 2 equiv of dimethyl
sodiomalonate (entry 4). The reaction proceeded quickly even
at room temperature in an excellent yield. However, when
1.5 equiv of nucleophile was used, the reaction time was
prolonged and the yield of anti-6 was reduced (entry 5). It
is noteworthy that nucleophilic attack took place exclusively
at the position distal to the TBSO group with retention of
the stereochemistry via double stereoinversion, giving 1,4-
anti adduct as the sole product.10 SN2′-type reaction in the
absence of Pd-catalyst did not occur; instead, nucleophilic
attack took place at the ester moiety (entry 6).
The reaction proceeded under Felkin-Anh control, giving
the adduct anti-2 as a major product in a ratio of 75:25.8
With the two diastereomeric isomers in hand, the 1,3-
asymmetric transfer reaction was examined. The anti-adduct
2 was converted into acetate anti-3 (87%, Ac2O, pyridine,
DMAP), trichloroacetate anti-4 (86%, Cl3CCOCl, pyridine),
and trifluoroacetate anti-5 (86%, (CF3CO)2O, pyridine). The
adduct syn-2 was also converted into the trifluoroacetate
syn-5 in 79% yield.
Subsequently, 1,3-chirality transfer of anti- and syn-5 was
investigated using the optimized conditions (Scheme 4).
Scheme 4
Scheme 3 and Table 1 show the Pd-catalyzed allylic
substitution reaction of allylic acylates anti-3-5 with di-
methyl sodiomalonate. The reactions of anti-3-5 with 3
Scheme 3
2178
Org. Lett., Vol. 6, No. 13, 2004

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

Conversion of these geometric isomers into the diastereo-
meric isomers of 1,4-bifunctional compounds was conducted
by using 10 mol % Pd(PPh3)4 in THF at room temperature
(Scheme 6). Thus, the geometric isomer (E)-12 underwent
regioselective substitution in good yield with high dia-
stereoselectivity, giving the adducts syn-13 and syn-14 in
96 and 84% yields, respectively. On the other hand, the
geometric isomer (Z)-12 was converted into the (E)-isomers
via π-σ-π isomerization16 to give anti-13 and anti-14 in
93 and 85% yields, respectively. Despite the comparatively
small steric demand, the PMB-protected hydroxy group
controlled the regiochemistry causing exclusive nucleophilic
attack distal to the protected alcohol. Thus, two diastereo-
isomers were synthesized stereodivergently.17
In conclusion, we have developed a convenient method
for synthesizing chiral 1,4-bifunctional compounds, which
are synthetically useful. In principle, the method could be
applied to other R-functionalized aldehydes and nucleophiles,
giving a variety of 1,4-bifunctional compounds. Examination
of other protecting groups and nucleophiles is now under
way.
Supporting Information Available: General procedures
for Pd-catalyzed allylic substitution reaction and specific
(12) Absolute configuration of anti-8 was deduced by analogy to the
reaction with benzylamine.
(13) Roush, W. R.; Bennett, C. E.; Roberts, S. E. J. Org. Chem. 2001,
66, 6389-6393.
1
rotations of new chiral compounds and H and 13C NMR
spectral data for anti- and syn-6-8, 13, and 14. This material
(14) Mead, K. T. Tetrahedron Lett. 1987, 28, 1019-1022.
(15) For the Carreira’s asymmetric alkynylation, see: Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688. Frants, D. E.;
Fa¨ssler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33,
373-381. Frants, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807.
is available free of charge via the Internet at http://pubs.acs.org.
OL049374D
(17) Absolute configuration of anti-13 and anti-14 was determined by
conversion into anti-6 and anti-7, respectively by deprotection of PMB ether
followed by TBS protection.
(16) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem. 1986, 51,
723-727.
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Org. Lett., Vol. 6, No. 13, 2004