Enantioselective synthesis of linear polypropionate arrays using anthracene-tagged organosilanes

Article abstract of DOI:10.1021/ol0516723

(Chemical Equation Presented) Preparation and use of anthracene-tagged organosilanes in an iterative, resin-capture-release protocol for the stereocontrolled synthesis of polypropionate arrays are described.

Full text of DOI:10.1021/ol0516723

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4435-4438
Enantioselective Synthesis of Linear
Polypropionate Arrays Using
Anthracene-Tagged Organosilanes
Sarathy Kesavan, Qibin Su, Jian Shao, John A. Porco Jr.,* and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu; panek@bu.edu
Received July 15, 2005
ABSTRACT
Preparation and use of anthracene-tagged organosilanes in an iterative, resin-capture-release protocol for the stereocontrolled synthesis of
polypropionate arrays are described.
Polyketides represent a rich source of natural products
possessing a broad spectrum of biological activity.1 Repre-
sentative examples of important polyketide-derived natural
products and their derivatives include the antibiotic erythry-
nolide (1),2 the immunosuppressant discodermolide (3),3 and
the antitumor geldanamycin (2)4 (Figure 1). As a potential
source of molecular diversity, polyketides have also served
as inspiration for the synthesis of complex chemical libraries.
Recently we5 and others6 have developed solid-phase meth-
ods that may be applicable for generation of polyketide
libraries. To expand the scope of these initial studies, we
have considered an iterative, parallel solution-phase protocol
employing anthracene-tagged7 crotylsilanes featuring the use
of our chiral silane-based bond construction methodology
Figure 1. Representative polyketide natural products.
(1) (a) O’Hagan, D. The Polyketide Metabolites; Ellis Harwood: Chich-
ester, 1991. (b) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1.
(2) Flynn, E. H.; Sigal, M. V., Jr.; Wiley: P. F.; Gerzon, K. J. Am. Chem.
Soc. 1954, 76, 3121.
(3) Gunasekera, S. P.; Cranick, S.; Longley, R. E. J. Nat. Prod. 1989,
52, 757.
(4) Rinehart, K. L. Acc. Chem. Res. 1972, 5, 57.
(5) Panek, J. S.; Zhu, B. J. Am. Chem. Soc. 1997, 119, 12022.
(Scheme 1). The sequence involves enantioselective crotyl-
ation, followed by [4 + 2] cycloaddition-removal7a of the
tagged product, to afford a resin-bound adduct. Oxidative
cleavage to afford an aldehyde may be followed by further
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Scheme 1. Strategy for Synthesis of Polypropionate Arrays
Using Resin Capture-Release
Figure 2. Anthracene-tagged organosilanes.
Scheme 2
iterations of crotylation, cycloaddition-removal, and oxidative
release. This overall strategy, combining synthesis and
purification, represents a specific application of resin-capture-
release involving asymmetric synthesis of complex stereo-
chemical arrays.8 Herein, we report our initial studies on the
synthesis of stereochemically well-defined, polyproprionate-
like molecules using anthracene-tagged, enantioenriched
silane reagents.
We first established that enantioselective crotylations9 may
be performed using anthracene-tagged organosilanes (Figure
2).10 Results of initial experiments involving enantioenriched
organosilanes (R)-4 are shown in Scheme 2. Reaction of
silane (R)-4 with benzaldehyde in the presence of triflic acid
and methoxytrimethylsilane resulted in the formation of syn-
homoallylic ether 6. Without further purification, crude 6
was sequestered to polystyrene maleimide resin 711 (loading
) 1.54 mmol/g) by microwave irradiation (150 °C, 200 W,
15 min) to afford resin 8. Subsequent oxidative cleavage12
of the olefin resulted in release of a mixture of dimethyl
acetal and aldehyde, which was converted to dimethyl acetal
9 (65% yield, four steps, dr > 30:1)13 using montmorillonite
K10 clay/CH(OMe)314 in greater than 95% purity (determined
using LC/evaporative light scattering detection (ELSD)
analysis). The corresponding enantiomer ent-9 was prepared
using an identical procedure starting with silane (S)-4.
We next evaluated the second iteration of the crotylation
sequence (Scheme 3). Crotylation of acetal 9 afforded an
anthracene-tagged product, which was sequestered using PS-
maleimide resin 7 as previously described. Subsequent
oxidative cleavage and workup afforded dimethyl acetal 10a
(dr > 20:1). Stereoisomer 10b was also prepared by an
analogous procedure from (S)-4. We found that the diastereo-
selectivity of the all-syn product 10a was greater than that
of the syn-anti-syn product 10b. The erosion in selectivity
may arise from a set of mismatched reaction partners;
addition of silane (S)-4 to acetal 9 occurs with syn-bond
(6) For approaches to polyketide library synthesis, see: (a) Reggelin,
M.; Brenig, V. Tetrahedron Lett. 1996, 37, 6851. (b) Paterson, I.; Scott, J.
P. Tetrahedron Lett. 1997, 38, 7441. (c) Paterson, I.; Scott, J. P. Tetrahedron
Lett. 1997, 38, 7445. (d) Gennari, C.; Ceccarelli, S.; Piarulli, U.; Aboutayab,
K.; Donghi, M.; Paterson, I. Tetrahedron 1998, 54, 14999. (e) Reggelin,
M.; Brenig, V.; Welcker, R. Tetrahedron Lett. 1998, 39, 4801. (f) Hanessian,
S.; Ma, J.; Wang, W. Tetrahedron Lett. 1999, 40, 4631. (g) Paterson, I.;
Scott, J. P. J. Chem. Soc., Perkin Trans. 1 1999, 1003. (h) Paterson, I.;
Donghi, M.; Gerlach, K. Angew. Chem., Int. Ed. 2000, 39, 3315. (i) Paterson,
I.; Temal-laib, T. Org. Lett. 2002, 4, 2473.
(7) (a) Wang, X.; Parlow, J. J.; Porco, J. A., Jr. Org. Lett. 2000, 2, 3509.
(b) Lan, P.; Berta, D.; Porco, J. A., Jr.; South, M. S.; Parlow, J. J. J. Org.
Chem. 2003, 68, 9678. (c) Lan, P.; Porco, J. A., Jr.; South, M. S.; Parlow,
J. J. J. Comb. Chem. 2003, 5, 660. (d) Andrews, S. P.; Ladlow, M. J. Org.
Chem. 2003, 68, 5525. (e) Lei, X.; Porco, J. A., Jr. Org. Lett. 2004, 6, 795.
(f) Li, X.; Abell, C.; Congreve, M. S.; Warrington, B. H.; Ladlow, M. Org.
Biomol. Chem. 2004, 2, 989.
(8) For resin-capture-release involving a resin-bound chiral auxiliary,
see: Kerrigan, N, J.; Hutchinson, P. C.; Heightman, T, D.; Procter, D, J.
Chem. Commun. 2003, 1402.
(9) (a) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117, 10587. (b)
Beresis, R. T. Ph.D. Thesis, Boston University, 1997; Chapter II. (c) Jain,
N. F.; Takenake N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475. (d)
Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron Lett. 1995,
36, 8727.
(10) Prepared from the corresponding (R)- and (S)-crotylsilane methyl
esters using microwave-mediated transesterification with 3-(anthracen-10-
yl)propan-1-ol.7e See Supporting Information for experimental details. For
preparation of the crotylsilanes, see: (a) Panek, J. S.; Yang. M. G.; Solomon,
J. S. J. Org. Chem. 1993, 58, 1003. (b) Beresis, R. T.; Solomon, J. S.;
Yang, M. J.; Jain, N. F.; Panek, J. S. Org. Synth. 1997, 75, 78. (c) Jain, N.
F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron Lett. 1995, 36,
8727.
(11) See Supporting Information for complete experimental details.
(12) (a) Frechet, J. M.; Schuerch, C. Carbohydr. Res. 1972, 22, 399. (b)
Sylvain, C.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 1997, 38, 1043.
(13) Diastereomeric ratios (dr’s) were determined by 1H NMR analysis
(400 MHz).
(14) (a) Taylor, E. C.; Chiang, C.-S. Synthesis 1977, 467. (b) Nikalje,
M. D.; Phukan, P.; Sudalai, A. Org. Prep. Proc. Int. 2000, 32, 1.
4436
Org. Lett., Vol. 7, No. 20, 2005

Scheme 3a
Scheme 5a
a Diastereomeric ratios (dr’s) were determined by 1H NMR
b
analysis (400 MHz). HPLC purity (ELSD).
a Diastereomeric ratios (dr’s) were determined by 1H NMR
analysis (400 MHz).b HPLC purity (ELSD).
Scheme 4a
Scheme 6a
a Diastereomeric ratios (dr’s) were determined by 1H NMR
b
analysis (400 MHz). HPLC purity (ELSD).
construction but with an anti-Felkin stereochemical relation-
ship between the existing methyl-bearing center and the
emerging methoxy groups.15 As anticipated, the chiral silane
reagent was capable of overriding the chirality of acetal 9,
thus determining the stereochemistry in this double-stereo-
differentiating reaction.
a Diastereomeric ratios (dr’s) were determined by 1H NMR
analysis (400 MHz). HPLC purity (ELSD).
b
elimination-crotylation sequence (Scheme 6).16 Diene 16 was
sequestered using polystyrene maleimide resin 7 and was
subsequently released as methyl ester 17a (Scheme 6). The
corresponding diastereoisomer 17b was prepared using a
similar procedure starting with silane (S)-4. Although
unexpected, the elimination-crotylation sequence provides
novel access to 1,5-diene-containing polyketide motifs found
in complex natural products including geldanamycin (2,
Figure 1).4
We next evaluated the synthesis of backbone-modified
polypropionates using the iterative crotylation/resin-capture/
release sequence (Scheme 7). Treatment of cyclohexanecar-
boxaldehyde with silane reagent (R)-4 in the presence of
triflic acid and silyl ether 18 resulted in production of a syn-
homoallylic ether, which was taken through a resin-capture/
release sequence to afford acetal 19 (59%, four steps). Acetal
19 was further advanced along the same lines to primary
alcohol 20. To establish additional diversity elements, we
next evaluated installation of functionalized ethers at various
To further increase the utility of the resin-capture/release
strategy as well as the diversity of end group functionality,
resin-captured product 11 was cleaved from the resin using
O3/NaBH4 to afford primary alcohol 12 (Scheme 4). Alter-
natively, treatment of 11 with NaOMe/MeOH resulted in the
release of methyl ester 13.
A third sequential crotylation of acetal 10a with silane
(R)-5 afforded syn-homoallylic ether 14 bearing a trans-
trisubstituted olefin (Scheme 5). This material, when sub-
jected to the Diels-Alder capture/oxidative cleavage se-
quence, afforded methyl ketone 15a (dr ) 10:1, 52% yield
from 10a). However, reaction of 10a with silane (S)-5
(mismatched addition) led to the production of 15b (Scheme
5) with severe erosion in diastereoselectivity (dr ) 2:1). An
additional diastereomer (15c) was also prepared using the
methodology. In contrast, treatment of acetal 10a with the
less reactive silane (R)-4 afforded the syn-homoallylic ether
16 bearing a trans-trisubstituted olefin through a tandem
(16) Further studies on this unexpected transformation are currently under
investigation. For asymmetric crotylation of R,â-unsaturated aldehydes,
see: Panek, J. S.; Xu, F.; Rondon, A. C. J. Am. Chem. Soc. 1998, 120,
4113.
(15) For a review on matched and mismatched reaction partners, see:
Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. Angew. Chem., Int.
Ed. Engl. 1985, 24, 1.
Org. Lett., Vol. 7, No. 20, 2005
4437

Scheme 7a
Scheme 8
a Diastereomeric ratios (dr’s) were determined by 1H NMR
b
analysis (400 MHz). HPLC purity (ELSD).
alcohol 13 with ester 26 under microwave conditions using
fluorous tin oxide 2719 led to the isolation of ester 28 (92%
yield, > 95% ELSD purity) after removal of the tin catalyst
using fluorous solid-phase extraction (SPE).20
positions along the polypropionate backbone. Treatment of
cyclohexanecarboxaldehyde with (S)-4 in the presence of
triflic acid and methoxytrimethylsilane produced a syn-
homoallylic ether. Sequestration of the product to resin 7,
followed by oxidative-cleavage using O3/PMe3, afforded
aldehyde 21 (dr > 20:1). Use of PMe3 as the reducing agent
greatly simplified the workup procedure. Filtration of the
crude reaction mixture through an Isolute cartridge led to
the removal of trimethylphosphine oxide via supported-liquid
extraction17 to provide aldehyde 21. Unlike Me2S, use of
PMe3 as the reducing agent led to the isolation of aldehyde
21 without formation of the dimethyl acetal. Crotylation of
aldehyde 21 with (S)-4 in the presence of triflic acid and
silyl ether 18 resulted in a syn-homoallylic ether, which was
sequestered using maleimide resin 7 and subsequently
cleaved from the resin using O3/NaBH4 to provide alcohol
22.
In summary, we have developed an iterative resin capture-
release strategy for the synthesis of stereochemically well
defined polypropionate arrays using anthracene-tagged or-
ganosilanes. Further applications of the methodology are
currently in progress and will be reported in due course.
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) is gratefully acknowl-
edged. We thank Drs. Aaron Beeler and Sivaraman Danda-
pani (Boston University) for helpful discussions and Ms.
Dawn Troast (Boston University) for initial experimental
studies. We thank Synthematix, Inc. for assistance with
chemical reaction planning software, and CEM Corp. (Mat-
thews, NC) for assistance with microwave instruments.
Derivatives bearing modified backbones were further
functionalized as shown in Scheme 8. Resin-captured ho-
moallylic ether 23 was subjected to Stille coupling conditions
using tributylphenyltin or tributylfuryltin to give function-
alized polypropionates, which were subsequently released
as methyl esters from the resin to yield 25a and 25b. Finally,
we sought to expand the utility of our methodology through
convergent fragment coupling18 to produce highly complex,
polypropionate-like molecules (Scheme 8). Coupling of
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0516723
(18) (a) Chen, C.; Li, X.; Newmon, C. S.; Lo, M. C.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2005, 44, 2249. (b) Su, S.; Acquilano, D. E.;
Arumugasamy, J.; Beeler, A. B.; Eastwood, E. L.; Giguere, J. R.; Lan, P.;
Lei, X.; Min, G. K.; Yeager, A. R.; Zhou, Y.; Panek, J. S.; Snyder, J. K.;
Schaus, S. E.; Porco, J. A., Jr. Org. Lett. 2005, 7, 2751.
(19) Bucher, B.; Curran, D. P. Tetrahedron Lett. 2000, 41, 9617.
(20) Curran, D. P. Synlett 2001, 9, 1488.
(17) (a) Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager,
K. M. Tetrahedron 1998, 54, 4097. (b) Breitenbucher, J. G.; Arienti, K.
L.; McClure, K. J. J. Comb. Chem. 2001, 3, 528.
4438
Org. Lett., Vol. 7, No. 20, 2005