Scalable, catalytic asymmetric synthesis of syn, anti stereotriad building blocks for polypropionate antibiotics

Article abstract of DOI:10.1021/ol0612612

Asymmetric catalysis and chirality transfer by the 2,3-Wittig rearrangement were combined to provide a syn, anti stereotriad-containing olefinic alcohol in five steps from inexpensive starting materials. Development of this compound, a versatile intermedi

Full text of DOI:10.1021/ol0612612

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3541-3544
Scalable, Catalytic Asymmetric
Synthesis of Syn, Anti Stereotriad
Building Blocks for Polypropionate
Antibiotics
Kathlyn A. Parker* and Huanyan Cao
Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
kparker@notes.cc.sunysb.edu
Received May 23, 2006
ABSTRACT
Asymmetric catalysis and chirality transfer by the 2,3-Wittig rearrangement were combined to provide a syn, anti stereotriad-containing olefinic
alcohol in five steps from inexpensive starting materials. Development of this compound, a versatile intermediate for polypropionate synthesis,
gave known building blocks for discodermolide.
The biosynthetic cascades controlled by the type I polyketide
synthases produce a large and diverse family of natural
products, in which the key structural feature is a long, methyl-
and oxygen-substituted carbon chain.1 Many of these me-
tabolites are important medicinals, and many more have
promising activity.
erythromycin, streptovaricin) and antifungal (amphotericin)
macrolides has been the subject of the most attention. It
appears three times in the structure of the important non-
macrolide (+)-discodermolide (1, Figure 1).
The construction of the long, multiply substituted chains
required for the chemical synthesis of the nonaromatic
polyketides is usually based on the iterative lengthening of
an acyclic substituted chain and/or the coupling of several
appropriately substituted chains. In this context, stereotriad-
containing building blocks2,3 have found widespread use. The
anti, syn stereotriad that appears in antibacterial (e.g.,
Figure 1. (+)-Discodermolide (1).
(1) McDaniel, R.; Welch, M.; Hutchinson, C. R. Chem. ReV. 2005, 105,
543.
(2) Related reviews: (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1987, 26, 489. (b) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W.
Synthesis 1994, 629. (c) Kolodiazhnyi, O. I. Tetrahedron 2003, 59, 5953.
(3) For a recent review on the occurrence of stereotetrads in natural
products and selected examples of stereotetrad building blocks, see:
Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677.
(+)-Discodermolide is a marine natural product, isolated
in truly meager amounts from the Caribbean sponge Disco-
derma dissolute.4 Originally identified in an immunosup-
10.1021/ol0612612 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/11/2006

pressant screen, discodermolide was later shown to have
antimitotic activity that results from its binding to microtu-
bules.5 Discodermolide is a particularly attractive drug
candidate because it maintains activity against multidrug
resistant organisms6 and because it demonstrates synergism
with taxol.7,8 Because of the difficulty in obtaining this
valuable compound from its deep-sea source, drug develop-
ment has necessitated its preparation by total synthesis.
Among the impressive total syntheses that have been
reported,9,10 Schreiber’s original synthesis,11 the “gram-scale”
preparation by Smith,12 and the subsequent “practical”
synthesis of Paterson13 are noteworthy for having supplied
materials for biological testing. Proceeding on the premise
that discodermolide will indeed become available in sub-
stantial amounts, the Novartis group has scaled up a “hybrid”
synthesis and, with synthetic material, advanced discoder-
molide to phase I clinical trials.14
on the chiral aldol strategy for the chain extension of an
aldehyde derived from the Roche ester 3 (Figure 3). For
Retrosynthesis of discodermolide quickly reveals probable
disconnects through or adjacent to the 8,9- and 13,14-olefinic
bonds. Consequently, the total syntheses of this target have
generally relied on strategies in which an anti, syn stereotriad-
containing building block, functionalized on both ends
(Figure 2), is parlayed into three more advanced intermedi-
Figure 3. Origins of key building blocks in the chiral pool.
example, Smith’s “common precursor” or “CP” 2 was
prepared in eight steps from the Roche ester 3.15 There are
two notable exceptions to this rule. In almost simultaneous
disclosures, Dias16 and Day17 and later the Novartis group18
have described the use of recoverable auxiliaries (see 6,
Figure 3) as the sources of chiral induction in Evans aldol
condensations with methacrolein. The resulting stereodiads
were then converted to the stereotriad-containing lactone 5.
Lactone 5 has been converted to the more advanced
discodermolide intermediate 4 (see 6 f 5 f 4), a precursor
to both the C-1-C-6 and C-9-C-14 synthons in the Smith19
and Novartis20 syntheses. It has also been employed in a total
synthesis of sanglifehrin A21 and converted to a useful
Horner-Wadsworth-Emmons reagent.22 Recently, Myles
Figure 2. Functionalized syn, anti stereotriad building blocks for
polypropionate construction.
ates, appropriately extended and/or activated for sequential
coupling.
In general, the stereotriad-containing building blocks for
discodermolide synthesis have been prepared by variations
(4) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K.
J. Org. Chem. 1990, 55, 4912. Additions and corrections: J. Org. Chem.
1991, 56, 1346.
(5) (a) 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. (b) Hung, D. T.; Chen J.; Schreiber S. L. Chem. Biol. 1996, 3,
287. (c) Klein, L. E.; Freeze, B. S.; Smith, A. B., III; Horwitz, S. B. Cell
Cycle 2005, 4, 501. (d) Escuin, D.; Kline, E. R.; Giannakakou, P. Cancer
Res. 2005, 65, 9021.
(6) Kowalski, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R.
E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613.
(7) Huang, G. S.; Lopez-Barcons, L.; Freeze, B. S.; Smith, A. B., III;
Goldberg, G. L.; Horwitz, S. B.; McDaid, H. M. Clin. Cancer Res. 2006,
12, 298.
(8) (a) Honore, S.; Kamath, K.; Braguer, D.; Horwitz, S. B.; Wilson, L.;
Briand, C.; Jordan, M. A. Cancer Res. 2004, 64, 4957. (b) Martello, L. A.;
McDaid, H. M.; Regl, D. L.; Yang, C.-P. H.; Meng, D.; Pettus, T. R. R.;
Kaufman, M. D.; Arimoto, H.; Danishefsky, S. J.; Smith, A. B., III; Horwitz,
S. B. Clin. Cancer Res. 2000, 6, 1978.
(11) (a) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1996, 118, 11054. (b) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.;
Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621.
(12) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.
(13) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
(14) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.; Kuesters, E.;
Schmid, E.; Schaer, K.; Gamboni, R.; Chen, W.; Loeser, E.; Kinder, F. R.,
Jr.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repic, O.; Wang, R.-M.;
Florence, G.; Lyothier, I.; Paterson, I. Org. Process Res. DeV. 2004, 8,
122.
(15) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.; LaMarche,
M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.
(9) A review of the total syntheses prior to 2003: Paterson, I.; Florence,
G. J. Eur. J. Org. Chem. 2003, 12, 2193.
(16) Dias, L. C.; Bau, R. Z.; de Sousa, M. A.; Zukerman-Schpector, J.
Org. Lett. 2002, 4, 4325.
(17) Day, B. W.; Kangani, C. O.; Avor, K. S. Tetrahedron: Asymmetry
2002, 13, 1161.
(18) Loiseleur, O.; Koch, G.; Wagner, T. Org. Process Res. DeV. 2004,
8, 597.
(19) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654.
(10) For contributions that describe improvements on the reports cited
in ref 9, see: (a) Smith, A. B., III; Freeze, B. S.; Xian, M.; Hirose, T. Org.
Lett. 2005, 7, 1825-1828. (b) Smith, A. B.; Freeze, B. S.; Brouard, I.;
Hirose, T. Org. Lett. 2003, 5, 4405. (c) Paterson, I.; Lyothier, I. J. Org.
Chem. 2005, 70, 5494. (d) Paterson, I.; Delgado, O.; Florence, G. J.;
Lyothier, I.; O’Brien, M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70,
150. (e) Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933.
3542
Org. Lett., Vol. 8, No. 16, 2006

and co-workers at Kosan prepared this key lactone by
chemical modification of a fermentation product (see 7 f
5, Figure 3) from a genetically engineered Streptomyces.23
In this paper, we describe the preparation of key disco-
dermolide intermediates 5 and 9 from the stereotriad-
containing alcohols 8 (Figure 4). Each of these chiral alcohols
Scheme 1. Asymmetric Catalysis Route to Chiral Stereotriad
Building Blocks
Figure 4. Examples of polypropionate building blocks available
from alcohols 8.
8 is readily available by the catalytic asymmetric synthesis
of a chiral cis allylic alcohol and then elaboration by the
remarkably efficient and totally overlooked “Midland se-
quence” (methallylation, 2,3-Wittig rearrangement, protec-
tion, and hydroboration).24
In 1984, when this efficient chemistry was demonstrated,
chiral cis allylic alcohols could be obtained only indi-
rectly.25,26 More recently introduced methodology for the
catalytic asymmetric synthesis of allylic alcohols in combi-
nation with the Midland sequence allows the preparation of
stereotriad building blocks 8 in only five steps from
inexpensive, commercially available starting materials (Scheme
1). In this work, we used cyclohexanecarboxaldehyde-derived
intermediates for convenience in handling.
Thus, treatment of cyclohexanecarboxyaldehyde (10) with
the complex prepared from Z-propenylzinc bromide and
lithiated (+)-N-methylephedrine, according to Oppolzer’s
asymmetric addition protocol,27 afforded the cis allylic
alcohol 11 in 82% yield (92% ee).28 Alkylation of the alcohol
11 gave the doubly allylic ether 12 which, on treatment with
the KOtBu/nBuLi reagent, underwent the 2,3-Wittig rear-
rangement to provide alcohol 13 with two chiral centers
established. The ratio of the syn/anti diastereomers of this
rearrangement product was, as judged by analysis of the 1H
NMR spectrum, 97:3.29 Silylation and hydroboration pro-
vided the key intermediate 8a. Alternatively, MOM alkyla-
tion followed by hydroboration gave alcohol 8b. This strategy
allows the preparation of these versatile intermediates in high
overall yield and high enantiomeric excess without the
sacrifice of a chiral starting material or the need to recycle
a chiral auxiliary.
Alcohols 8 are versatile stereotriad-containing building
blocks. To illustrate the potential of this approach for the
practical synthesis of complex polyketides, we have applied
it in the synthesis of lactone 5 and of vinyl iodide 9, which
are both intermediates in established syntheses of discoder-
molide.
(20) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Grimler,
D.; Koch, G.; Daeffler, R.; Osmani, A.; Hirni, A.; Schaer, K.; Gamboni,
R.; Bach, A.; Chaudhary, A.; Chen, S.; Chen, W.; Hu, B.; Jagoe, C. T.;
Kim, H.-Y.; Kinder, F. R., Jr.; Liu, Y.; Lu, Y.; McKenna, J.; Prashad, M.;
Ramsey, T. M.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.; Waykole,
L. Org. Process Res. DeV. 2004, 8, 101.
(21) Dias, L. C.; Salles, A. G., Jr. Tetrahedron Lett. 2006, 47, 2213.
(22) Kagani, C. O.; Bruckner, A. M.; Curran, D. P. Org. Lett. 2005, 7,
379.
The TBS monoprotected diol 8a was easily converted to
lactone 5 in two steps (Scheme 2). Ozonolysis with dimethyl
Scheme 2. Preparation of Lactone 5
(23) Burlingame, M. A.; Mendoza, E.; Ashley, G. W.; Myles, D. C.
Tetrahedron Lett. 2006, 47, 1209.
(24) (a) Tsai, D. J. S.; Midland, M. M. J. Org. Chem. 1984, 49, 1842.
(b) Tsai, D. J. S.; Midland, M. M. J. Am. Chem. Soc. 1985, 107, 3915.
(25) First, a propargyl alcohol was oxidized to an ynone that was then
reduced with a chiral reagent (Midland used R-alpine-borane); then
semihydrogenation provided the allylic alcohol. See: (a) Midland, M. M.;
McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980,
102, 867. (b) Midland, M. M.; Kazubski, A. J. Org. Chem. 1982, 47, 2814.
(26) Brinkmeyer, R. S.; Kapoor, V. M. J. Am. Chem. Soc. 1977, 99,
8339.
sulfide workup followed by MnO2 oxidation of the crude
(29) Careful integration of the 3-4 ppm region of the 1H NMR spectrum
(300 Hz) revealed the ratio of syn diastereomer (d, J ) 6.0 Hz centered at
3.87 ppm) to anti diastereomer (d, J ) 8.4 Hz, centered at 3.66 ppm) to be
97:3. For the assignment, see ref 24a.
(27) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(28) The ee was obtained by Mosher ester analysis; see Supporting
Information.
Org. Lett., Vol. 8, No. 16, 2006
3543

lactol 15 gave lactone 5 directly (recrystallized product, 80%
for two steps).
efficiently accessed by short schemes from inexpensive
starting materials. Asymmetric catalysis replaces the need
for the stoichiometric consumption of a chiral starting
material or a chiral reagent or the recycling of a chiral
auxiliary. Extension of this strategy to the preparation of
advanced intermediates for antibiotic synthesis will be
described in due course.
The MOM-protected diol 8b has been converted to vinyl
iodide 9, an intermediate in Smith’s later generation disco-
dermolide syntheses in which it serves as the precursor to
the C-9-C-14 moiety.10a,b Preparation of vinyl iodide 9 from
alcohol 8b was achieved in three steps (Scheme 3). Introduc-
Acknowledgment. The work described in this com-
munication was supported by the National Institutes of Health
(CA-87503), the Army Breast Cancer Initiative (BC 051816),
and the National Science Foundation (CHE-0131146, NMR
instrumentation).
Scheme 3. Preparation of Vinyl Iodide 9
Note Added after ASAP Publication. Figure 2 was
referenced in error twice in the version posted July 11, 2006;
this error was corrected July 13, 2006. Subsequently, an error
was discovered in the abstract graphic. A corrected version
was posted July 17, 2006.
Supporting Information Available: Detailed descrip-
tions of the experimental procedures and complete analytical
data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
tion of the PMB group was followed by ozonolysis to give
the aldehyde 17. Then, the Stork-Zhao procedure gave the
known building block 9.
Thus, chiral syn, anti stereotriad building blocks, useful
for the preparation of polypropionate antibiotics, may be
OL0612612
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Org. Lett., Vol. 8, No. 16, 2006