A unified synthetic approach to polyketides having both skeletal and stereochemical diversity

Article abstract of DOI:10.1021/ol070405p

An efficient systematic approach to the diversity-oriented synthesis of polyketides has been developed to provide both skeletal and stereochemical diversity. Each synthetic intermediate is also a desired polyketide fragment and no protecting group manipul

Full text of DOI:10.1021/ol070405p

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1895-1898
A Unified Synthetic Approach to
Polyketides Having Both Skeletal and
Stereochemical Diversity
Shiying Shang,† Hayato Iwadare,‡ Daniel E. Macks,‡ Lisa M. Ambrosini,‡ and
Derek S. Tan*,†,‡,§
Pharmacology Program, Weill Graduate School of Medical Sciences of Cornell
UniVersity, Molecular Pharmacology & Chemistry Program, and Tri-Institutional
Research Program, Memorial Sloan-Kettering Cancer Center, 1275 York AVenue,
Box 422, New York, New York 10021
tand@mskcc.org
Received February 16, 2007
ABSTRACT
An efficient systematic approach to the diversity-oriented synthesis of polyketides has been developed to provide both skeletal and stereochemical
diversity. Each synthetic intermediate is also a desired polyketide fragment and no protecting group manipulations are required. A first-
generation synthesis provides a 74-membered polyketide library comprising six different skeletal classes, each in one to five steps from
propargylic alcohol precursors. A study of epoxyol opening reactions revealed unusual reactivity trends based on epoxide configuration.
Polyketide natural products exhibit a tremendous variety of
biological activities and chemical structures, making them
attractive starting points for the synthesis of natural product-
based libraries.1 Biologically, polyketides are known to bind
to a wide range of targets and, thus, can be considered an
empirically “privileged” family of structures.2 Chemically,
polyketides present significant challenges in diversity-
oriented synthesis, in that flexible, highly efficient synthetic
approaches are required to allow systematic modification of
biologically active compounds identified from the resulting
libraries. To access this biological and chemical diversity,
several approaches to polyketide libraries have been ad-
vanced.3 While efforts to date have focused primarily on
accessing the polypropionate 1,3-diol motif,4 an ideal
diversity-oriented synthesis would provide access to a wider
range of skeletal motifs found in polyketide natural products.
Indeed, generating libraries with both skeletal5 and stereo-
chemical diversity6 is a key current challenge in diversity-
oriented synthesis.7 Toward these ends, we report herein a
unified approach to the diversity-oriented synthesis of
polyketides and a first implementation that provides 74
stereochemically diverse polyketides falling into six different
structural classes.
† Weill Graduate School of Medical Sciences.
(3) (a) Paterson, I.; Donghi, M.; Gerlach, K. Angew. Chem., Int. Ed.
2000, 39, 3315-3319. (b) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E.
M. Angew. Chem., Int. Ed. 2001, 40, 2082-2085. (c) Smith, A. B., III;
Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett. 2005, 7, 139-142. (d)
Misske, A. M.; Hoffmann, H. M. R. Chem. Eur. J. 2000, 6, 3313-3320.
(e) Arjona, O.; Menchaca, R.; Plumet, J. J. Org. Chem. 2001, 66, 2400-
2413. (f) Reggelin, M.; Brenig, V. Tetrahedron Lett. 1996, 37, 6851-6852.
(4) Bode, S. E.; Wolberg, M.; Mueller, M. Synthesis 2006, 557-588.
‡ Molecular Pharmacology & Chemistry Program.
§ Tri-Institutional Research Program.
(1) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol. 2005, 9, 248-258.
(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-2246.
10.1021/ol070405p CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/17/2007

At the outset of our efforts, we noted that the polyketide
skeleton arises biosynthetically from reiterative couplings of
simple malonate building blocks, with tailoring reactions
generating most of the structural diversity, primarily through
variations in oxidation state and stereochemical configura-
tion.8 We envisioned a conceptually related synthetic ap-
proach in which simple precursors are transformed stereo-
selectively to a variety of polyketide structures through
formal alterations in oxidation state, with each synthetic
intermediate also representing a desired polyketide fragment.
Such an approach can be considered “biomimetic” under
Breslow’s original broad definition.9 Importantly, in contrast
to polyketide total synthesis, in which a variety of synthetic
approaches can be interchanged as necessary, diversity-
oriented synthesis requires that these various polyketide
motifs be accessed in a unified, systematic fashion.
Scheme 1. Unified Strategy for the Synthesis of 6-Carbon
Polyketide Fragments Having Skeletal and Stereochemical
Diversity (4-9)a
Thus, we formulated the general synthetic strategy outlined
in Scheme 1, using propargylic alcohols 3 as versatile
synthetic precursors10 that could be transformed to a variety
of polyketide structures. These key intermediates could be
generated from R-alkoxycarbonyl compounds 1 and alkynes
2, potentially bearing R1 and R3 substituents. Terminal benzyl
ether and dimethyl acetal groups were selected as function-
alities that are directly compatible with biological assays,11
and are also potential handles for further functionalization.
Subsequent reductive and oxidative transformations would
then provide six different polyketide skeletal motifs: allylic
alcohols (4), enones (5), epoxyols (6), epoxyketones (7),
1,3-diols (8), and â-hydroxyketones (9). R2 substituents could
potentially be installed in conjunction with any of the formal
reduction steps and the 1,3-diols 8 could be accessed from
a R1, R2, R3 ) H or Me; (*) ) site of stereochemical diversity.
either epoxyols 6 or â-hydroxyketones 9. Alcohol deoxy-
genation reactions can also be anticipated to provide corre-
sponding deoxypolyketide fragments (not shown).
To begin exploring this concept, we synthesized propar-
gylic alcohols 3 (R3 ) H) by coupling of Weinreb amides 1
(R1 ) H or Me, X ) N[Me]OMe) and 3-butynal dimethyl
acetal (2, R3 ) H), followed by stereoselective alkynone
reduction.12,13 We then investigated transformation of the key
intermediates 3 to various polyketide motifs (Scheme 2).
With a view toward future solid-phase implementations, we
sought homogeneous reaction conditions for stereospecific
alkyne reduction to Z-allylic alcohols 10. Gratifyingly, Sato’s
titanocene-catalyzed hydromagnesiation reaction provided an
effective solution.14 Alkyne reduction with Red-Al also
provided the complementary E-allylic alcohols 11.15
(5) (a) Lee, D.; Sello, J. K.; Schreiber, S. L. J. Am. Chem. Soc. 1999,
121, 10648-10649. (b) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett.
2000, 2, 709-712. (c) Kwon, O.; Park, S. B.; Schreiber, S. L. J. Am. Chem.
Soc. 2002, 124, 13402-13404. (d) Ding, S.; Gray, N. S.; Wu, X.; Ding,
Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1594-1596. (e)
Couladouros, E. A.; Strongilos, A. T. Angew. Chem., Int. Ed. 2002, 41,
3677-3680. (f) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003,
302, 613-618. (g) Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am.
Chem. Soc. 2004, 126, 14095-14104. (h) Taylor, S. J.; Taylor, A. M.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 1681-1685. (i) Oguri,
H.; Schreiber, S. L. Org. Lett. 2005, 7, 47-50. (j) Kumagai, N.; Muncipinto,
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Yeager, A. R.; Min, G. K.; Porco, J. A., Jr.; Schaus, S. E. Org. Lett. 2006,
8, 5065-5068.
We next sought to oxidize allylic alcohols 10 and 11 to
epoxyols 12 and 13, respectively, using stereoselective
epoxidation reactions. As hoped, syn epoxidation of Z-allylic
alcohols 10 with m-CPBA provided the cis,syn-epoxyols 12.16
Conversely, anti epoxidation of E-allylic alcohols 11a and
anti-11b under matched Sharpless conditions17 provided the
trans,anti-epoxyols 13, although syn-11b proved unreactive
in this case. Interestingly, however, syn-11b was amenable
to syn epoxidation with m-CPBA in unusually high stereo-
selectivity, providing one of the desired C2 epimeric ep-
oxyols directly (not shown).13,16 Alcohol inversions using
Mitsunobu or oxidation/re-reduction protocols then afforded
(6) (a) Sutherlin, D. P.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
9802-9803. (b) Annis, D. A.; Helluin, O.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1998, 37, 1907-1909. (c) Harrison, B. A.; Gierasch, T. M.; Neilan,
C.; Pasternak, G. W.; Verdine, G. L. J. Am. Chem. Soc. 2002, 124, 13352-
13353. (d) Kim, Y.-k.; Arai, M. A.; Arai, T.; Lamenzo, J. O.; Dean, E. F.,
III; Patterson, N.; Clemons, P. A.; Schreiber, S. L. J. Am. Chem. Soc. 2004,
126, 14740-14745. (e) Potuzak, J. S.; Moilanen, S. B.; Tan, D. S. J. Am.
Chem. Soc. 2005, 127, 13796-13797. (f) Moilanen, S. B.; Potuzak, J. S.;
Tan, D. S. J. Am. Chem. Soc. 2006, 128, 1792-1793.
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Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58. (c) Schreiber, S.
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(8) Fischbach, M. A.; Walsh, C. T. Chem. ReV. 2006, 106, 3468-3496.
(9) Breslow, R. Chem. Soc. ReV. 1972, 1, 553-580.
(10) The potential utility of propargylic alcohols in diversity-oriented
synthesis has been noted previously: Weber, L. Curr. Opin. Chem. Biol.
2000, 4, 295-302.
(12) Initial attempts to access 3a directly by various asymmetric alkyne
additions to the corresponding aldehydes (reviewed in: Pu, L. Tetrahedron
2003, 59, 9873-9886.) suffered from poor enantioselectivity.
(13) See the Supporting Information for full details.
(11) For examples of stable, biologically active dimethyl acetals, see:
(a) Cho, W.-J.; Kim, E.-K.; Park, I. Y.; Jeong, E. Y.; Kim, T. S.; Le, T. N.;
Kim, D.-D.; Lee, E.-S. Bioorg. Med. Chem. 2002, 10, 2953-2961. (b)
Springer, R. H.; Scholten, M. B.; O’Brien, D. E.; Novinson, T.; Miller, J.
P.; Robins, R. K. J. Med. Chem. 1982, 25, 235-242. (c) Kim, C. D.; Kim,
H. H.; Kim, Y. K.; Kwak, Y. K.; Kim, S.-O.; Yoo, S.-E.; Hong, K. W. J.
Pharmacol. Exp. Ther. 2001, 296, 1085-1090.
(14) Sato, F.; Ishikawa, H.; Watanabe, H.; Miyake, T.; Sato, M. J. Chem.
Soc., Chem. Commun. 1981, 718-720.
(15) Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy,
G. J. Org. Chem. 1976, 41, 3497-3505.
(16) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703-710.
(17) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299.
1896
Org. Lett., Vol. 9, No. 10, 2007

Scheme 2. Synthesis of Six Different Classes of Polyketide Skeletal Motifs with Stereochemical Diversification13
a Cp2TiCl2, i-BuMgBr, Et2O, 0 °C f rt, 8-48 h, 81-86%, g88:12 Z/E. bRed-Al, Et2O, 0 °C f rt, 3-8 h, 99%, g98:2 E/Z. cm-CPBA,
NaHCO3, CH2Cl2, 0 °C f rt (R1 ) H) or -4 °C (R1 ) Me), 8-24 h, 85-93%, g90:10 dr. dD- or L-diethyl tartrate (matched), Ti(Oi-Pr)4,
t-BuOOH, 4 Å MS, CH2Cl2, -20 °C (R1 ) H) or -4 °C (R1 ) Me), 2-3 d, 91-99%, 94:6 dr. en-BuLi, Me3Al, 1,2-dichloroethane, 0 °C
f
f rt, 2.5 h; then NaIO4, MeCN/H2O, 0 °C f rt, 2.5 h, 68-73% (two steps), g98:2 dr. MeMgCl, CuCl, THF/Et2O, -40 °C f rt, 4.5 h;
g
then NaIO4, MeCN/H2O, 0 °C f rt, 1 h, 68-69% (two steps), g91:9 dr. Dess-Martin periodinane, CH2Cl2, 0 °C f rt, 1.5-8 h, 85-
h
i
100%. SmI2, THF, -90 f -78 °C, 1.5 h, 65-93%. NaBH(OAc)3, AcOH, CH3CN, -20 °C, 1 h, 87-95%, g93:7 dr.
the remaining epoxyol C2 epimers (not shown).13 In total,
this approach provided serviceable access to all eight epoxyol
diastereomers for R1 ) H and 12 out of the 16 possible
diastereomers for R1 ) Me.
quite effective for these substrates, provided that at least 5
equiv of Me3Al were used to accommodate the five Lewis
basic sites in the substrates. Interestingly, we discovered that
We then explored nucleophilic epoxide-opening reactions
to provide canonical polypropionate 2-methyl-1,3-diols 14a
and 15a. Related epoxide-based approaches were pioneered
by Kishi18 and have also been developed by others.19 We
recognized that regioselectivity represented a key concern
in these transformations.20 To address this issue, we evaluated
a wide range of reaction conditions with both cis- and trans-
epoxyol substrates (Table 1). Notably, we discovered that
epoxide configuration had a pronounced effect upon reaction
outcome.
Table 1. Nucleophilic Ring Opening of Epoxyols to
2-Methyl-1,3-diols
product ratio (1,3-diol:1,2-diol)a
conditionsb
anti-12a
syn-12a
anti-13a
syn-13a
For cis-epoxyols anti-12a and syn-12a, epoxide opening
with methyl cuprate nucleophiles generally favored formation
of the undesired 1,2-diols and/or halogenated side products.
However, Miyashita’s n-BuLi/Me3Al combination21 proved
n-BuLi/Me3Al
MeMgCl/CuCl
MeMgBr/CuBr
MeMgBr/CuI
MeMgBr/CuCN
MeLi/CuI
79:9c
88:12
33:60f
33:62g
28:51g
21:58g
4:96
0:0d
77:23
68:32
48:26g
50:22g
48:52
58:42
4:20e
78:22
32:9f
26:7g
12:19g
17:3g
24:15h
17:12h
(18) (a) Johnson, M. R.; Nakata, T.; Kishi, Y. Tetrahedron Lett. 1979,
4343-4346. (b) Finan, J. M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719-
2722.
MeLi/CuCN
2:6e
(19) (a) Murphy, P. J.; Procter, G. Tetrahedron Lett. 1990, 31, 1059-
1062. (b) Miyashita, M.; Hoshino, M.; Yoshikoshi, A. J. Org. Chem. 1991,
56, 6483-6485. (c) Miyashita, M.; Yoshihara, K.; Kawamine, K.; Hoshino,
M.; Irie, H. Tetrahedron Lett. 1993, 34, 6285-6288. (d) Esumi, T.;
Fukuyama, H.; Oribe, R.; Kawazoe, K.; Iwabuchi, Y.; Irie, H.; Hatakeyama,
S. Tetrahedron Lett. 1997, 38, 4823-4826.
(20) Tius, M. A.; Fauq, A. H. J. Org. Chem. 1983, 48, 4131-4132.
(21) Sasaki, M.; Tanino, K.; Miyashita, M. Org. Lett. 2001, 3, 1765-
1767.
a Determined by 1H NMR. b 5 equiv of n-BuLi, 8 equiv of Me3Al,
1,2-dichloroethane, 0 °C f rt, 2.5 h; or 12 equiv of Me[M], 6 equiv of
CuX, 1:1 THF/Et2O, -40 °C f rt, 4.5 h. c Remainder 5-desmethoxy-2,5-
dimethyl-1,3-diol.13 d Debenzylated 13a (94%) and starting material (6%)
recovered. e Remainder starting material. f Remainder 2-chloro-1,3-diol side
product. g Remainder 2-bromo-1,3-diol side product and starting material.
h Remainder unidentified decomposition products.
Org. Lett., Vol. 9, No. 10, 2007
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the reaction required the use of chlorinated solvents, with
1,2-dichloroethane providing higher yields than methylene
chloride. Further studies of the mechanistic implications of
this intriguing finding are ongoing.
In conclusion, we have developed an efficient, unified
diversity-oriented synthesis of polyketides that provides both
skeletal and stereochemical diversity. Our first-generation
synthesis has provided a 74-membered polyketide library
comprising six different skeletal classes. Overall, this work
addresses three important current challeges in the field of
diversity-oriented synthesis. First, our synthesis provides
substantial skeletal diversity, and in an unusual context
involving acyclic molecules. Second, our route provides a
unified approach to these various polyketide motifs. Third,
the synthetic route is highly efficient, providing each
polyketide motif in only one to five steps from propargylic
alcohols 3, with each synthetic intermediate also representing
a desired polyketide motif and with no protecting group
manipulations required. While this has been accomplished
by strategic application of established chemistry, the exten-
sive synthetic investigations undertaken to achieve these high
yields and stereoselectivities required in diversity-oriented
synthesis have revealed interesting new avenues for further
chemical investigations. Further expansion of this synthetic
approach to provide more comprehensive access to these and
other polyketide motifs and screening of the resulting
polyketide libraries against a variety of targets is ongoing.
The availability of this unified synthetic approach will allow
systematic evaluation of skeletal and stereochemical modi-
fications to biologically active compounds identified therein.
Moreover, the results of these screens will provide important
insights into the effectiveness of natural product-based
libraries at addressing diverse biological targets.
In contrast, for trans-epoxyols anti-13a and syn-13a, the
n-BuLi/Me3Al combination was ineffective, leading only to
debenzylation of the starting material in the case of
anti-13a and to undesirable regioselectivity in the case of
syn-13a. However, examination of a variety of methyl
cuprates revealed that MeMgCl/CuCl provided effective
access to the desired 1,3-diol products for these substrates.
Interestingly, the choice of cuprate counterion had a signifi-
cant effect upon regioselectivity, with chloride providing
enhanced selectivity for 1,3-diol formation compared to
bromides, iodides, and cyanides.
In both the cis- and trans-epoxyol series, residual undesired
1,2-diols were then conveniently separated after NaIO4
cleavage.22 NMR analyses of 1,3-diol acetonide derivatives
using Rychnovsky’s 13C NMR method23 and NOESY experi-
ments were then used to confirm relative stereochemical
assignments for both the epoxyol precursors and 2-methyl-
1,3-diol products.13 Importantly, this approach provided
comprehensive access to all eight 2-methyl-1,3-diol diaster-
eomers in the R1 ) H series (14a, 15a).
Analogous efforts at nucleophilic opening of the more
hindered epoxyols in the R1 ) Me series (12b, 13b) were
thwarted by complete regioselectivity for 1,2-diol formation
under all conditions tested. However, expansion of the
synthetic route to include additional desired polyketide motifs
provided a useful alternative solution. Dess-Martin oxidation
of allylic alcohols 10 and 11 provided enones 17 and 18,
respectively, while oxidation of epoxyols 12 and 13 provided
epoxyketones 19 and 20, respectively. The epoxyketones
could then undergo reductive epoxide opening with SmI2 to
provide â-hydroxyketones 21.24 All three of these structural
classes represent desired polyketide motifs. NOESY analysis
of 1,2-diol cyclic carbonates derived from â-hydroxyketones
21b provided direct confirmation of relative stereochemical
assignments for the epoxyol precursors in the R1 ) Me
series.13 At this point, directed reductions of â-hydroxy-
ketones 21 provided anti-1,3-diols 16 and their syn-1,3-diol
congeners (not shown), representing all 12 possible 1,3-diol
diastereomers for R2 ) H.13,25,26
Acknowledgment. We thank Prof. Jae-Sang Ryu (Ewha
University) for helpful discussions and Dr. George Sukenick,
Hui Fang, Hui Liu, Sylvi Rusli, and Anna Dudkina for expert
mass spectral analyses. D.S.T. is a NYSTAR Watson
Investigator, H.I. is a Visiting Scientist from Daiichi Sankyo,
L.M.A. was a Summer Undergraduate Research Program
student. We gratefully acknowledge financial support from
the NIH (P41 GM076267), DOD (CM030085), William
Randolph Hearst Fund in Experimental Therapeutics,
William H. Goodwin and Alice Goodwin and the Com-
monwealth Foundation for Cancer Research, and MSKCC
Experimental Therapeutics Center.
Supporting Information Available: Detailed experi-
mental procedures and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Chakraborty, T. K.; Joshi, S. P. Tetrahedron Lett. 1990, 31, 2043-
2046.
(23) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945-948. (b) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc.
Chem. Res. 1998, 31, 9-17.
(24) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596-2599.
(25) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866-868.
OL070405P
(26) 1,3-Diol 16a and its C2 epimer could also be accessed directly by
reductive epoxide opening of 13a and its C2 epimer with Red-Al.13,18b
1898
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