Toward the combinatorial synthesis of polyketide libraries: Asymmetric aldol reactions with α-chiral aldehydes on solid support

Article abstract of DOI:10.1021/ol026046+

(Matrix presented) The viability of performing stereocontrolled aldol additions with α-chiral aldehydes attached by a silyl linker to a hydroxymethylpolystyrene resin is demonstrated for boron and titanium enolates. Subsequent ketone reduction and manipul

Full text of DOI:10.1021/ol026046+

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2473-2476
Toward the Combinatorial Synthesis of
Polyketide Libraries: Asymmetric Aldol
Reactions with r-Chiral Aldehydes on
Solid Support
Ian Paterson* and Taoues Temal-La1ıb
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cus.cam.ac.uk
Received April 19, 2002
ABSTRACT
The viability of performing stereocontrolled aldol additions with r-chiral aldehydes attached by a silyl linker to a hydroxymethylpolystyrene
resin is demonstrated for boron and titanium enolates. Subsequent ketone reduction and manipulation on the solid support leads to elaborate
stereopentad sequences, as occur in 6-deoxyerythronolide B and discodermolide.
The polyketides represent an important reservoir of molecular
diversity for drug discovery.1 By applying the methods of
combinatorial chemistry,2 the synthesis of libraries of novel
polyketide-type structures are possible.3,4 For synthetic
purposes, it is desirable to assemble such compounds by
chain extension on solid support, enabling the permutation
of the stereochemistry and substitution pattern in the nascent
carbon skeleton. However, the controlled solid-phase syn-
thesis of the characteristic sequences of contiguous stereo-
centers that occur in structurally complex polyketides is
highly challenging. By starting from simple aldehydes on
solid support, we have recently developed iterative aldol
procedures3,5 to generate libraries of polyketide-type se-
quences of increasing stereochemical complexity, as in 1 f
2 (Scheme 1).3e
As part of a general program to expand polyketide
diversity,6,7 we now demonstrate the use of more elaborate
Scheme 1
(1) (a) O’Hagan, D. The Polyketide Metabolites; Ellis Harwood: Chi-
chester, 1991. (b) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1.
(2) (a) Balkenhohl, F.; Bussche-Hu¨nnefeld, C. v. d.; Lansky, A.; Zechel,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. (b) MacLean, D.; Baldwin,
J. J.; Ivanov, V. T.; Kato, Y.; Shaw, A.; Schneider, P.; Gordon, E. M. J.
Comb. Chem. 2000, 2, 562. (c) An, H. Y.; Cook, P. D. Chem. ReV. 2000,
100, 3311.
(3) (a) Paterson, I.; Scott, J. P. Tetrahedron Lett. 1997, 38, 7441. (b)
Paterson, I.; Scott, J. P. Tetrahedron Lett. 1997, 38, 7445. (c) Gennari, C.;
Ceccarelli, S.; Piarulli, U.; Aboutayab, K.; Donghi, M.; Paterson, I.
Tetrahedron 1998, 54, 14999. (d) Paterson, I.; Scott, J. P. J. Chem. Soc.,
Perkin Trans. 1 1999, 1003. (e) Paterson, I.; Donghi, M.; Gerlach, K. Angew.
Chem., Int. Ed. 2000, 39, 3315.
10.1021/ol026046+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/22/2002

By employing a diisopropylsilyl linker,9,10 the required
chiral aldehyde 3 was prepared on solid support (Scheme
3). Reduction of the ketone (R)-4,3e which is also used as a
Scheme 2
Scheme 3
chain-extending module, with LiAlH4 gave the alcohols 9
(92%, 1.4:1 diastereomeric mixture in favor of the syn
isomer). As this hydroxyl center is later oxidized back to a
ketone, both epimeric series were conveniently processed
together; providing a check for any difference in reactivity
and/or selectivity. A modification of Danishefsky’s silyl
linking protocol,9 as introduced for glycopeptide synthesis,
allowed attachment of the sterically hindered secondary
alcohol 9 to the polystyrene support.10 This involved silyl-
ation of the alcohol 9 with diisopropyldichlorosilane (1 equiv)
in the presence of imidazole (6 equiv, 1 h) in DMF to
generate a solution of intermediate 10, followed by treatment
of pre-swollen hydroxymethyl Merrifield resin11 (0.87 mmol/g
loading) with 10 (6 equiv) for 36 h (2 cycles). This two-
step sequence gave the silyl ether 11 with a high loading
value (0.75 mmol/g, as determined by cleavage with TBAF).
Deprotection of the PMB ether in 11 with DDQ,12 followed
by Dess-Martin oxidation, then proceeded cleanly to provide
resin-bound aldehydes 3 (Scheme 2), attached through a
secondary alcohol by a novel silyl linker to a polystyrene
support. Aldol chain extension with chiral ketone modules,
such as (R)- and (S)-4, leads to the expedient construction
of defined sequences of stereocenters. This is illustrated here
by the solid-phase synthesis of tetrapropionates 5 and 6 that
correspond configurationally to the indicated segments of
the seco-acid of 6-deoxyerythronolide B (7) and the anti-
cancer agent discodermolide (8).8 By suitable structural
permutation3d,e in 3 and 4, this methodology should facilitate
the parallel synthesis of diverse polyketide-type libraries.
(4) For other approaches to solid-phase polyketide synthesis, see: (a)
Reggelin, M.; Brenig, V. Tetrahedron Lett. 1996, 37, 6851. (b) Panek, J.
S.; Zhu, B. J. Am. Chem. Soc. 1997, 119, 12022. (c) Reggelin, M.; Brenig,
V.; Welcker, R. Tetrahedron Lett. 1998, 39, 4801. (d) Hanessian, S.; Ma,
J.; Wang, W. Tetrahedron Lett. 1999, 40, 4631.
(5) For the modular synthesis of polyketide building blocks by nitrile
oxide cycloadditions, see: Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E.
M. Angew. Chem., Int. Ed. 2001, 40, 2082.
(6) For reviews on polyketide synthesis, see: (a) Paterson, I.; Mansuri,
M. M. Tetrahedron 1985, 41, 3569. (b) Bode, J. W.; Carreira, E. M. In
The Chemical Synthesis of Natural Products; Hale, K. J., Ed.; Sheffield
Academic Press: London, 2000; pp 40-62. (c) Paterson, I.; Cowden, C.
J.; Wallace, D. J. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; pp 249-297.
(7) For structural diversification by the reconstruction of polyketide
biosynthetic pathways, see: (a) Cortes, J.; Wiesmann, K. E. H.; Roberts,
G. A.; Brown, M. J. B.; Staunton, J.; Leadlay, P. F. Science 1995, 268,
1487. (b) Rohr, J. Angew. Chem., Int. Ed. Engl. 1995, 34, 881. (c) Katz, L.
Chem. ReV. 1997, 97, 2557. (d) Cane, D. E.; Walsh, C. T.; Khosla, C.
Science 1998, 282, 63.
(8) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G.
K. J. Org. Chem. 1990, 55, 4912. (b) ter Haar, E.; Kowalski, R. J.; Hamel,
E.; Lin, C. M.; Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day,
B. W. Biochemistry 1996, 35, 243. (c) Hung, D. T.; Chen, J.; Schreiber, S.
L. Chem. Biol. 1996, 3, 287. (d) Balachandran, R.; ter Haar, E.; Welsh, M.
J.; Grant, S. G.; Day, B. W. Anti-Cancer Drugs 1998, 9, 67.
(9) Savin, K. A.; Woo, J. C. G.; Danishefsky, S. J. J. Org. Chem. 1999,
64, 4183.
(10) It was not possible to attach alcohol 9 directly to the chloro-
diisopropylsilylpolystyrene resin used in our earlier work (ref 3e), neces-
sitating the introduction of this new silyl linker protocol.
(11) The hydroxy-modified Merrifield resin (1% DVB, 100-200 mesh)
was purchased from Novabiochem and used without further manipulation.
(12) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
2474
Org. Lett., Vol. 4, No. 15, 2002

Scheme 4
the required aldehyde 3. To develop the chemistry and assist
of 16 with LiBH4 led to reductive removal of the acetate,
generating the corresponding resin-bound 1,3-anti-diol 18.
characterization (gel-phase 13C NMR, FT-IR) of the subse-
quent resin-bound intermediates, aldehyde 12 was prepared
as a solution model from benzyl alcohol in an analogous
manner, thus permitting a direct comparison of the reaction
yields and diastereoselectivities.
Transformation of resin-bound alcohol 18 to the acetonide
derivative 21 permitted confirmation of the 1,3-anti relation-
ship from diagnostic 13C NMR resonances (100.2, 23.5, 25.1
ppm).16 Subsequent cleavage of the resin 21 (HF‚pyr/pyr)
provided the separable epimeric alcohols 23a and 23b (ca.
1.4:1) in 47% yield over seven steps, with high selectivity
for the newly generated stereocenters (>95:5 dr). This
represents an average yield of 90% for each step performed
on the resin. In comparison, a 22% overall yield of 23a and
23b was obtained for the corresponding solution phase
synthesis (12 f 14 f 15 f 20 f 22 f 23a,b), which
required chromatographic purification of several intermedi-
ates. By regenerating the aldehyde functionality in resin 21,
further chain extension cycles can be potentially performed
to access even more elaborate polyketide sequences. For our
present purposes, Dess-Martin oxidation of the epimeric
alcohols 23a and 23b led to isolation of the stereopentad 5
(88%) as a single isomer, which is configurationally related
to two tetrapropionate fragments of 6-deoxyerythronolide B.
Suitable conditions for the aldol chain extension of resin-
bound aldehyde 3 with ketone (R)-4 were first developed
(Scheme 4). Reaction of aldehyde 3 (-78 to -27 °C, 17 h)
with a preformed solution of the (E)-enol dicyclohexyl-
borinate13 derived from (R)-4 (6 equiv, two cycles) in Et2O
gave the anti-anti adduct 13 after standard oxidative workup
(H2O2, MeOH, DMF, pH 7 buffer). At this stage, gel-phase
13C NMR and FT-IR analysis indicated essentially complete
conversion,14 with the resulting resin 13 displaying diagnostic
carbonyl resonances (216.6 and 216.9 ppm). Additionally,
comparison of the gel-phase 13C NMR spectrum of adduct
13 with that obtained for the corresponding solution-phase
model 14 suggested a high level of diastereoselectivity, as
expected from a matched relationship of the aldol coupling
partners.
To achieve an efficient anti-selective reduction of the
â-hydroxy ketone 13, a modified Evans-Tishchenko15
protocol was developed for the solid-phase reaction. Initial
experiments with the solution model 14 using a stoichio-
metric amount of SmI2 and acetaldehyde at 0 °C gave acetate
15 in 87% yield (97:3 dr, where the two epimers at the
linking center were separated by chromatography). Reaction
of the resin-bound adduct 13 with this reagent system over
two cycles (-20 to 0 °C, 16 h) gave resin 16 with complete
conversion. At this stage, cleavage from the resin 16 gave
alcohol 17 in 72% yield over four steps from 11. Treatment
To expand polyketide diversity, other stereochemical
permutations need to be developed as the chain is extended.
For the solid-phase synthesis of tetraketide sequence 6,
relevant to discodermolide and 6-deoxyerythronolide B, a
more challenging syn-selective addition of ketone (S)-4 to
the resin-bound aldehyde 3 was required. Previous studies
in solution showed that such ethyl ketones provide syn-syn
aldol adducts when enolized with Sn(OTf)2 and Et3N.17 In
the present case, these Lewis acidic conditions were found
to partly cleave the silyl linker in the aldehyde component.18
(16) (a) Rychnovsky, S. D.; Skalitzky, D. Tetrahedron Lett. 1990, 31,
945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990,
31, 7099. (c) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993,
58, 3511.
(17) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(18) While boron-mediated anti-aldol reactions work well on solid
support, the use of suitable boron reagents (9-BBNOTf, Bu2BOTf, (+)-
Ipc2BOTf) to promote Z-enolization and syn-aldol additions of ketone (S)-4
led only to poor yields and stereoselectivities with resin-bound aldehyde 3.
(13) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121. (b) Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister,
M. A. J. Am. Chem. Soc. 1994, 116, 11287. (c) Paterson, I.; Arnott, E. A.
Tetrahedron Lett. 1998, 39, 7185.
(14) Attempts to determine the yield and the diastereoselectivity at this
stage by cleavage of the resin with HF‚pyr/pyr gave only complex mixtures
due to hemiacetal formation with the ketone group.
(15) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
Org. Lett., Vol. 4, No. 15, 2002
2475

However, mild Ti(OiPr)2Cl2-mediated enolization19 of ketone
(S)-4 proved to be compatible, leading to the isolation of
the syn-syn aldol adducts 24 (Scheme 5) in high yields and
on the resin-bound ketone 25 to provide 1,3-diol 27.21
Acetonide protection of the resin-bound alcohol 27 proved
demanding and required special conditions (2-methoxy-
propene, CSA, DMF) to prevent any cleavage of the silyl
linker. The 1,3-syn relationship of the acetonide resin 29 was
confirmed by gel-phase 13C NMR spectroscopy (98.5, 29.8,
19.4 ppm)16 and TBAF cleavage led to the isolation of the
epimeric alcohols 30 in 24% overall yield over six steps (79%
average yield). Dess-Martin oxidation of the released
alcohols 30 then proceeded in 94% yield. At this stage, the
overall diastereoselectivity of the solid-phase synthesis was
determined as 90:10 dr in favor of isomer 6, which is con-
figurationally identical to major segments of discodermolide
and 6-deoxyerythronolide B.
Scheme 5
In conclusion, we have completed highly stereocontrolled
solid-phase syntheses of tetraketides 5 and 6, related to
sizable fragments of 6-deoxyerythronolide B and discoder-
molide. This clearly demonstrates the efficiency of our
methodology for solid-phase polyketide synthesis, along with
the general suitability of the silyl linker9 for attachment of
hindered secondary alcohols to the resin. By mimicking the
stereoregulated chain growth involved in the biosynthesis
of polyketides,3de,7 a variety of starting aldehydes may be
combined with various ketone extension modules in an
iterative fashion, enabling extensive diversification and
library generation. Efforts are now directed toward extending
this methodology and applying it to the synthesis of natural
and unnatural polyketides.
Acknowledgment. We thank the EC (Marie Curie
Postdoctoral Fellowship for T.T.-L. and IHP Network RTN1-
1999-00054), Merck, and Pfizer for support.
diastereoselectivities (90%, 95:5 dr) from 12. Gratifyingly,
this protocol when applied to the resin-bound aldehyde 3 (5
h, -78 °C) enabled complete conversion into the adducts
25 with comparable selectivity in a single cycle.
In solution phase, the stereocontrolled reduction of 24 was
best performed using Zn(BH4)2 in CH2Cl2 to afford the 1,3-
syn-diol 26 (90:10 dr).20 This reaction was then performed
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
information is available free of charge via the Internet at
http://pubs.acs.org.
OL026046+
(20) Alternative reducing systems explored (c-Hex2BCl/LiBH4, Et3B/
LiBH4, catecholborane, DIBAL) gave lower or overturned selectivities.
(21) After TBAF cleavage of resin 27, triol 28 was isolated in 30% yield
over four steps.
(19) (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047. (b) Perkins, M. V.; Sampson, R. A. Org. Lett.
2001, 3, 123.
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Org. Lett., Vol. 4, No. 15, 2002