Rh-catalyzed kinetic resolution of enynes and highly enantioselective formation of 4-alkenyl-2,3-disubstituted tetrahydrofurans

Article abstract of DOI:10.1021/ja0351950

Rh-catalyzed cycloisomerization of enynes ether with a substituent at the allylic position was examined using (rac)-BINAP, and excellent selectivity was observed. When enantiomerically pure BINAP was used as the ligand, a process that combines kinetic res

Full text of DOI:10.1021/ja0351950

Published on Web 08/30/2003
Rh-Catalyzed Kinetic Resolution of Enynes and Highly Enantioselective
Formation of 4-Alkenyl-2,3-disubstituted Tetrahydrofurans
Aiwen Lei, Minsheng He, and Xumu Zhang*
Department of Chemistry, 152 DaVey Laboratory, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
Received March 17, 2003; E-mail: xumu@chem.psu.edu
Scheme 1
To obtain enantiomerically pure compounds has been a long
journey begun hundreds years ago, and has been continually targeted
by organic chemists.1 The kinetic resolution has been established
as a strategy for asymmetric synthesis to reach the enantiomerically
pure compounds.2 With extensive studies and developments in
metal-catalyzed asymmetric reactions during the past 30 years, the
metal-catalyzed kinetic resolution has been expanded and considered
as a synthetically useful method.3 If a process combines kinetic
resolution and diastereoselectivity together, an enantiomeric product
with multiple stereogenic centers can be obtained from racemic
starting materials via single step. Obtaining this type of enantio-
merically pure product along with enantiomerically pure unreacted
starting materials through the process will be useful for organic
syntheses. In this communication, we described a kinetic resolution
process coupled with a high diastereoselectivity in Rh-catalyzed
cycloisomerization of enynes, in which excellent stereoselectivity
(over 99% ee for both products, which contain two adjacent
stereogenic centers, and unreacted starting materials) was observed.
The transition metal-catalyzed cycloisomerization of enynes has
been extensively studied as an elegant method to construct
heterocyclic and carbocyclic compounds.4 However, the asymmetric
Scheme 2
5
version of the reaction has not been fully developed. Recently,
we successfully achieved highly enantioselective Rh-catalyzed
cycloisomerization of enynes.6 To examine the reactivity of the
substrates with substituents at the allylic position in the cyclo-
isomerization, the reaction of racemic 1 was carried out in the
presence of (rac)-BINAP, [Rh(COD)Cl]2, and AgSbF6 at room
temperature for 2 min. The trans-(()-2 was obtained as the sole
product. Exploration of the functional group tolerance revealed that
the alkenyl ether substituted tetrahydrofuran trans-(()-4 can be
prepared from readily available allylic ether 3 under the similar
conditions. When the unprotected allylic alcohol 5 was used under
the similar reaction condition, the tetrahydrofuran with an aldehyde
side chain, trans-(()-6, was formed in 92% yield. Further explora-
tion of the substrates scope indicated that the tetrahydrofurans with
a ketone functional group, trans-(()-8a and trans-(()-8b, can also
be formed under the catalytic condition.7
A detailed analysis of these results in Scheme 1 reveals some
very interesting phenomena. For example, the reaction of (()-3a
in the presence of (rac)-BINAP as the ligand yields trans-(()-4a
which is the mixture of (2R,3S)-4a and (2S,3R)-4a. However, the
theoretical analysis of the reaction shown as Scheme 2, which
contained the diastereoselectivity and competition between path A
and path B, should generate four products, which are (2R,3R)-4a,
(2S,3S)-4a, (2R,3S)-4a, and (2S,3R)-4a. Although it is easy to
understand that the ratio of these products are closely related with
the corresponding diastereoselectivity of each equation in Scheme
2, and the competition between path A and path B, only that
(2R,3S)-4a, (2S,3R)-4a were selectively obtained is unusual. To
explain the excellent selectivity under above reaction condition,
we have to assume two prerequisites for the reaction. The first
prerequisite is 100% selectivity between path A and path B in
Scheme 2. The second prerequisite is 100% diastereoselectivity in
each of the equations in Scheme 2.
The selectivity between paths A and B is particularly interesting.
It means that the reactants have excellent recognization of enan-
tiomerically pure BINAP from (rac)-BINAP. Although we do not
know which enantiomer of (rac)-BINAP will be matched by (R)- or
(S)-reactants in this stage, we envision that the reaction path can
be elucidated by using enantiomerically pure BINAP as the ligand.
One enantiomer of the racemic starting materials will be converted
into the corresponding product in excellent ee values, and the other
enantiomer will be remained as the starting materials in highly
enantiomeric purity because the corresponding enantiomerically
pure BINAP matched with the substrate does not exist. Therefore,
the whole process represents a perfect example of kinetic resolution!
The other interesting observation is the reactions of 7a and 7b.
Although the starting materials 7 are mixtures of four enantiomers,
the reactions yield only two enantiomers of a racemic compound
as the products. The regiospecific â-hydride-elimination is the key
for the transformation because it eliminates a stereogenic carbon
center and simplifies the reaction. Thus, it will be possible to
obtained enantiomerically pure compounds 7, which contained two
stereogenic carbon centers if the interesting proposal of kinetic
resolution is applied for these types of substrates.
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10.1021/ja0351950 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
as the ligand, the reaction of (2S,5R)-7a provided the desired cyclo-
isomerization product (2R,3S)-8a in 100% conversion and over 99%
ee in 2 min. Reaction of (2R,5S)-7a did not occur under the same
conditions. These results reveal that the stereoselectivity of the kine-
tic resolution is outstanding. In addition, the reactions confirm the ex-
cellent recognization between the ligand and substrates. On the basis
of the results, we conclude that that the path B is preferred over
path A in Scheme 2, which means (R)-reactants match (S)-BINAP.
Scheme 4
To distinguish the controlling factor of the excellent stereose-
lectivity, we examine the reaction of 9 under the similar reaction
conditions. The kinetic resolution result is poor. A diastereoisomeric
mixture was obtained, and both the ee values of the diastereoisomers
are over 99%.
In summary, a highly stereoselective kinetic resolution of enynes
and Rh(I)-catalyzed intramolecular cycloisomerization reaction were
developed. Polyfunctionalized tetrahydrofurans with two adjacent
stereogenic centers and high ee values of enynes were obtained in
this process. Syntheses of more complex molecules are currently
under investigation in our laboratory, and the results will be
published in due course.
To examine the hypothesis, we carried out the reaction of 7a,
which is syn- and anti-mixtures, using enantiomerically pure BINAP
(see Scheme 3). The high efficient kinetic resolution of 7a was
investigated in the presence of (S)-BINAP, [Rh(COD)Cl]2, and
AgSbF6 at 15 °C for 2 min. The corresponding cycloisomerization
product (2R,3S)-8a, which contained two of continual stereogenic
carbon centers, was obtained in 49% yield and over 99% ee, while
a mixture of (2R,5S)-7a (>99% ee) and (2S,5S)-7a (>99% ee) in
48% yields remained as the starting material. The other corre-
sponding enantiomer (2S,3R)-8a was formed with a mixture of
(2S,5R)-7a (>99% ee), and (2R,5R)-7a was obtained from the
reaction of 7a using (R)-BINAP as the ligand (see Scheme 4).8
To further clarify this reaction and obtain all of the enantio-
merically pure enantiomers of 7a, we prepared syn-(()-7a, and anti-
(()-7a, respectively.9 The reaction of syn-(()-7a in the presence
of 5 mol % (S)-BINAP, 2.5 mol % [Rh(COD)Cl]2 and 10 mol %
AgSbF6 at 15 °C for 2 min provided the desired cycloisomerization
product (2R,3S)-8a in 49% isolated yield and >99% ee along with
(2R,5S)-7a in 48% isolated yield and >99% ee. When the reaction
of syn-(()-7a was carried out using (R)-BINAP as the ligand, the
corresponding (2S 3R)-8a (>99% ee) and (2S,5R)-7a (>99% ee)
were obtained in 47% and 49% yield, respectively. With (S)-BINAP
as the ligand, the reaction of anti-(()-7a under the same condition
generates (2R,3S)-8a (>99% ee) in 48% isolated yield and (2S,5S)-
7a (>99% ee) in 49% yield. With (R)-BINAP as the ligand, the
reaction produced (2S,3R)-8a (>99% ee) and (2R,5R)-7a (>99%
ee) in 49% and 49% yield, respectively.10
Acknowledgment. This work was supported by NSF grant. We
thank Dr. A. Daniel Jones for his help in obtaining the mass spectral
data. We also thank the National Natural Science Foundation of
China.
Supporting Information Available: Spectroscopic data, GC, HPLC
spectra, and experimental details (PDF). This material is available free
of charge via the Internet at http://pubs.acs. org.
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To understand the nature of the reaction, controlling reactions
were examined as shown in Scheme 5. When (S)-BINAP was used
Scheme 5
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(10) During the investigation of substrate scopes, substrates 3a and 3c were
successfully employed in the kinetic resolution protocol with (S)-BINAP.
Some others substrates S1, S3, S5 (in Supporting Information 2) were
examined, and the excellent selectivity was observed as expected. Please
see details in Supporting Information 2.
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