Asymmetric crotylation reactions on solid support: Synthesis of stereochemically well-defined polypropionate-like subunits

Full text of DOI:10.1021/ja972877c

12022
J. Am. Chem. Soc. 1997, 119, 12022-12023
Asymmetric Crotylation Reactions on Solid
Support: Synthesis of Stereochemically
Well-Defined Polypropionate-Like Subunits
Scheme 1
James S. Panek* and Bin Zhu
Department of Chemistry, Metcalf Center for
Science and Engineering
5
90 Commonwealth AVenue
Boston UniVersity, Boston, Massachusetts 02215
ReceiVed August 15, 1997
Polymer-supported synthesis has rapidly emerged as an
important strategy in synthetic organic chemistry. This notion
is supported by the large body of literature associated with
polymer-supported reactions, which are aimed at generating
libraries of molecularly diverse compounds for biological
1
evaluation in either a lead discovery or an optimization process.
However, methods for stereoselective bond construction on solid
2,3
support remain highly underdeveloped.
Our interest in this
area is to extend our asymmetric crotylation bond construction
4
methodology to a solid phase format to achieve the synthesis
of stereochemically well-defined small molecules. Such bond
formation methodology holds enormous potential in constructing
stereochemically well-defined biopolymer-like molecules and
polypropionate-like subunits on solid support.
The purpose of this paper is to report the preliminary results
of our investigation concerning the development of chiral (E)-
crotylsilane-based bond construction methodology on solid
support. We have already established that chiral crotylsilane
reagents 1 and 2 are capable of providing excellent levels of
diastereo- and enantioselectivity in condensation reactions with
various acetals and aldehydes in solution phase.4 The reaction
of (E)-crotylsilanes with achiral/chiral acetals and aldehydes
alcohol 3,7 which was then coupled to the carboxylated
polystyrene 4 through the corresponding acid chloride 5 to afford
the immobilized chiral (E)-crotylsilane reagent (R)-6 with greater
than 90% loading yield (Scheme 1).
(
through in situ generated oxocarbenium ions) exhibit syn-
5
selectivity in homoallylic ether generation. Mechanistic con-
siderations have lead us to conclude that the silane reagents
may be ideally suited for asymmetric synthesis on solid phase.
Equation 1 illustrates these reactions with their accompanying
transition state, which may be used to explain the facial bias of
the silane reagents.
In order to evaluate the reactivity and stereoselectivity of the
polymer-supported silane reagent in the asymmetric crotylation
reaction, a range of aryl and alkyl acetals were surveyed. Silane
reagent (R)-6 when combined with excess acetal in the presence
of trimethylsilyl triflate (TMSOTf) at low temperature afforded
the polymer-supported homoallylic ether 7. Linker cleavage
was achieved by base hydrolysis (K2CO3, THF/MeOH) to
provide the functionalized homoallylic ether 8. The important
results of this study in the construction of homoallylic ethers
In our first series of experiments, the asymmetric crotylation
reaction was performed with polymer-supported chiral silane
reagents. The preparation of reagent 6 was initiated with the
6
LiAlH4 reduction of chiral silane reagent (R)-1 to primary
(1) For reviews, see: (a) Moos, W. H.; Green, G. D.; Pavia, M. R. Annu.
Rep. Med. Chem. 1993, 28, 315-324. (b) Thompsom, L. A.; Ellman, J. A.
Chem. ReV. 1996, 96, 555-600. (c) Hermkens, P. H. H.; Ottenheijm, H.
C. J.; Rees, D. C. Tetrahedron 1996, 52, 4527-4554. Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1997, 53, 5643-5678. (d)
Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M.
A. J. Med. Chem. 1994, 37, 1385-1401.
8
are summarized in Table 1 (8a-f). The crotylation reactions
of (E)-crotylsilanes with aldehydes via reaction with in situ
9
generated oxocarbenium ions were also successfully performed
with the immobilized silane reagent 6. In this three-component
reaction, immobilized silane reagent 6 with excess aldehyde and
methoxytrimethylsilane (TMSOMe) in CH2Cl2 was treated with
TMSOTf under similar conditions as those used for the acetal
reactions to provide functionalized homoallylic ethers 8g-i with
high yield and diastereo/enantioselectivity (Scheme 1). The
results of this reaction are summarized in Table 1. The ratio
(2) For recent reports concerning aldol reactions on solid support without
emphasizing diastereoselection, see: (a) Kobayashi, S.; Hachiya, I.; Yasuda,
M. Tetrahedron Lett. 1996, 37, 5569-5572. (b) Kurth, M. J.; Randall, L.
A. A.; Chen, C.; Melander, C.; Miller, R. B. J. Org. Chem. 1994, 59, 5862-
5
864. For examples of asymmetric aldol reactions on solid support, see:
(
c) Reggelin, M.; Brenig, V. Tetrahedron Lett. 1996, 37, 8651-6852. (d)
Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabla, F.; He,
Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature
1
of the syn- to anti-adduct was measured by H NMR analysis
1
997, 387, 268-272.
of the crude product 8 after linker cleavage with the diastereo-
(3) For recent reports concerning other stereoselective reactions on solid
1
0
support, see: (a) Reference 1c. (b) Chen, S.; Janda, K. D. J. Am. Chem.
Soc. 1997, 119, 8724-8725. (c) Wipf, P.; Henninger, T. C. J. Org. Chem.
selectivity ranging from 7:1 to 30:1 (syn/anti). The purity of
1
997, 62, 1586-1587.
(6) For the preparation of (R)- and (S)-(E)-crotylsilane reagent 1, see:
(a) Panek, J. S.; Yang, M. G.; Solomon, J. S. J. Org. Chem. 1993, 58,
1003-1010. (b) Beresis, R. T.; Solomon, J. S.; Yang, M. J.; Jain, N. F.;
Panek, J. S. Org. Synth. In press.
(
4) (a) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 6594-
6
600. (b) Panek, J. S.; Yang, M. J. Org. Chem. 1991, 56, 5755-5758. (c)
Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
(5) Our studies concerning the reactions of (E)-crotylsilane with achiral
(7) Panek, J. S.; Garbaccio, R. M.; Jain, N. F. Tetrahedron Lett. 1994,
35, 6453-6456.
and chiral acetals and aldehydes (through in situ generated oxocarbenium
ions) show universal syn-selectivity in homoallylic ether generation. For
examples of chiral acetals/aldehydes see: (a) Panek, J. S.; Xu, F. J. Am.
Chem. Soc. 1995, 117, 10587-10588. (b) Beresis, R. T. Ph.D. Thesis,
Boston University, 1997; Chapter II.
(8) Satisfactory spectroscopic data ( H NMR, 13C NMR, CIMS, CIHRMS,
1
and IR data) were obtained for all new compounds. Ratios of diastereomers
1
were determined by H NMR analysis.
(9) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-5792.
S0002-7863(97)02877-1 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 49, 1997 12023
Table 1. Reactions of Polymer-Supported (E)-Crotylsilane
Reagent (R)-6 with Acetals and Aldehydes
Scheme 2
2 2
Method A: Silane 6, acetal (2 equiv), TMSOTf (1 equiv), CH Cl ,
-
78 f -55 °C, 72 h. Method B: Silane 6, aldehyde (2 equiv),
TMSOMe (2 equiv), TMSOTf (1 equiv), CH Cl , -78 f -55 °C, 72
2
2
c
h. The yield is based on the initial loading level of carboxylic acid
on the polymer support (4 steps overall). The ratio is determined by
d
1
H NMR (400 MHz) analysis of the crude products.
1
the addition products 8 was also measured by H NMR analysis
to be greater than 90% (syn + anti). The yields reported for
the four-step process were based on the initial loading level of
carboxylic acid on the polymer support 4. The results show
that solid phase reactions gave similar or higher (for 8a, syn/
anti is 20:1 in solid phase reaction and 13:1 in solution phase
reaction ) level of diastereoselectivity compared to the solution
phase reactions.
Gratifyingly, we have successfully extended this methodology
to the synthesis of polypropionate-like subunits through an
iterative crotylation sequence (Scheme 2). Aldehydes 9 were
loaded on to the polymer support 5 through an ester linkage.
The polymer-supported aldehyde 10 with excess TMSOMe and
chiral silane reagent (R)-1 in CH2Cl2 was treated with TMSOTf
at low temperature to afford resin-bound homoallylic ether 11.
The expected homoallylic ether 12 could be hydrolytically
cleaved from the polymer support (K2CO3, THF/MeOH) in good
yield and high diastereoselectivity (Scheme 2). To perform the
iterative crotylation reaction, polymer-supported homoallylic
ether 11 was subjected to ozonolysis to generate the chiral
aldehyde 13. A two-step sequence which included the formation
of acetal 14 from aldehyde 13 [cat. pyridinium p-toluene-
sulfonate (PPTS), CH(OMe)3]11 followed by the crotylation
reaction with silane reagents (S)-1 or (R)-1 in the presence of
BF ‚OEt gave 15 or 17 after cleavage from the polymer
3
2
support. In order to conduct the third crotylation, the double
bond of the resin bound homoallylic ether 16a was oxidatively
cleaved (O , Me S, CH Cl /MeOH). The resulting resin bound
3
2
2
2
aldehyde 18a was then transformed to the dimethyl acetal 19a.
4a
12
This material was mixed with silane reagent (R)-2 and treated
with BF ‚OEt at low temperature, followed by linker cleavage
3
2
2 3
(K CO , THF/MeOH), to afford the final product 20a. It is
worth noting that this compound contains three propionate units
and six stereogenic centers, and the overall yield is 37% for 10
steps (based on the initial loading level of carboxylic acid on
the polystyrene support 4).
In conclusion, we have successfully applied the chiral (E)-
crotylsilane reagent-based asymmetric crotylation reaction in a
solid phase format. The reaction provides functionalized chiral
homoallylic ethers with high yield and diastereoselectivity. A
new and useful procedure has been developed for the preparation
of stereochemically well-defined polypropionate-like subunits
on solid support. The methodology shall be a powerful tool in
constructing complex molecules on solid support.
Acknowledgment. Financial suppport was obtained from the
Community Technology Fund of Boston University.
(
10) The syn/anti ratio refers to the stereochemical relationship of the
Supporting Information Available: General experimental proce-
dure and spectral data for all intermediates and final products (56 pages).
See any current masthead page for ordering and Internet access
instructions.
newly formed C-C bond. The stereochemistry was assigned by correlation
with authentic material derived from solution phase chemistry: For example,
the homoallylic ethers reported in ref 4a and 9 were reduced with LiAlH4
to their primary alcohols, which had identical spectroscopic properties with
the products from the solid phase reactions.
JA972877C
1
(
11) No change of the syn/anti ratio was observed by H NMR analysis
in the acetalization step under the described reaction conditions.
12) Jain, N. F.; Cirillo, P. F.; Shaus, J. V.; Panek, J. S. Tetrahedron
Lett. 1995, 36, 8723-8726.
(