Crotylsilane reagents in the synthesis of complex polyketide natural products: Total synthesis of (+)-discodermolide

Article abstract of DOI:10.1021/ja043168j

An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6 (12), C7-C14 (13), and C15-C24 (11) subunits was intro

Full text of DOI:10.1021/ja043168j

Published on Web 03/26/2005
Crotylsilane Reagents in the Synthesis of Complex Polyketide
Natural Products: Total Synthesis of (+)-Discodermolide
Alexander Arefolov† and James S. Panek*
Contribution from the Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Metcalf Center for Science and Engineering, 590 Commonwealth AVenue,
Boston UniVersity, Boston, Massachusetts 02215
Received November 12, 2004; E-mail: panek@chem.bu.edu
Abstract: An efficient, highly convergent stereocontrolled synthesis of (+)-discodermolide has been achieved
with 2.1% overall yield (27 steps longest linear sequence). The absolute stereochemistry of the C1-C6
(12), C7-C14 (13), and C15-C24 (11) subunits was introduced using asymmetric crotylation methodology.
Key elements of the synthesis include the use of hydrozirconation-cross-coupling methodology for the
construction of C13-C14 (Z)-olefin, acetate aldol reaction to construct the C6-C7 bond and install the C7
stereocenter with high levels of 1,5-anti stereoinduction, and the use of palladium-mediated sp2-sp3 cross-
coupling reaction to join the advanced fragments, which assembled the carbon framework of discodermolide.
Introduction
These findings have stimulated considerable interest in disco-
dermolide as a possible immunosuppressant and suggested that
Discodermolide (1) is a polyketide natural product that was
first isolated in 1990 from extracts of the rare Caribbean marine
sponge Discodermia dissoluta by the researchers at Harbor
Branch Oceanographic Institution (HBOI).1 Its gross structure
was determined by extensive spectroscopic studies, including
a combination of 1-D and 2-D NMR techniques; the relative
stereochemistry was subsequently assigned by X-ray crystal-
lography.1 Structurally, discodermolide incorporates a linear 24-
membered polyketide backbone bearing 13 stereogenic centers,
a tetrasubstituted δ-lactone (C1-C5), one di- and one trisub-
stituted (Z)-double bond, an adjunct carbamate moiety (C19),
and a terminal (Z)-diene (C21-C24). The absolute configuration
of discodermolide was established by Schreiber and co-workers
later on by their initial syntheses of both (+)- and (-)-
antipodes.2
(+)-Discodermolide was initially found to be a potent
immunosuppressive agent, both in vivo and in vitro, as well as
displaying antifungal activity.3 It inhibited T-cell proliferation
with an IC50 of 9 nM and graft versus host disease in
transplanted mice. (+)-Discodermolide also suppressed both the
two-way mixed-lymphocyte reaction and the concanavalin
A-induced mitogenesis of murine splentocytes in vitro (IC50 0.24
and 0.19 mM, respectively) with no associated cytotoxicity.
it may be developed as an alternative drug to cyclosporine A,
which has demonstrated remarkable clinical success over the
past two decades in both organ and bone marrow transplantation.
Further biological studies revealed the remarkable cytotoxic
activity of (+)-discodermolide in a variety of human and murine
cell lines, causing cell cycle arrest in the G2/M phase by binding
and stabilizing mitotic spindle microtubules,4 thus resembling
the clinically proven anticancer agent paclitaxel5a (2)sanother
member of a small, but structurally diverse, family of micro-
tubule-stabilizing natural products (Figure 1) discovered over
the past decade. This family also includes epothilones A and B
(3, 4),5b eleutherobin (5),5c sarcodictyin (6),5d laulimalide (7),5e
and the most recently isolated (-)-dictyostatin (8),5f which is
thought to be biogenetically related to (+)-discodermolide.
Interestingly, the (-)-antipode of discodermolide was also
reported to possess considerable antiproliferative activity,
although acting by a different mechanismsblocking the cell
cycle in the S phase.6 The similarity between the cell growth
inhibitory effects of (+)-discodermolide and paclitaxel has been
confirmed by Day and co-workers.7 Significantly, the binding
(4) (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,
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† Current address: PTC Therapeutics, South Plainfield, NJ.
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Org. Chem. 1990, 55, 4912-4915. Additions and corrections: J. Org.
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E. U.S. Patent No. US5840750, Nov 24, 1998. (c) Gunasekera, S. P.; Paul,
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Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080.
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757-761. (b) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera,
M.; Gunasekera, S. P. Transplantation 1991, 52, 650-655. (c) Longley,
R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.; Gunasekera, S. P.
Transplantation 1991, 52, 656-661.
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W.; Fairchild, C. R. Cancer Res. 1998, 58, 1111-1115. (d) Ciomei, M.;
Albanese, C.; Pastori, W.; Grandi, M.; Pietra, F.; D′Ambrosio, M.;
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9
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J. AM. CHEM. SOC. 2005, 127, 5596-5603
10.1021/ja043168j CCC: $30.25 © 2005 American Chemical Society

Synthesis of Complex Polyketide Natural Products
A R T I C L E S
useful quantities of this compound for preclinical research and
development, stimulated considerable synthetic effort resulting
in six total syntheses2,10 and numerous fragment syntheses.11
In the present paper we report full details of the development
of a total synthesis of (+)-discodermolide based on an asym-
metric crotylation methodology developed in our laboratories.
Results and Discussion
Synthesis Plan. The synthetic plan developed for (+)-
discodermolide was guided by the principles of convergency,
flexibility of modifications in case of pitfalls, and the use of
similar precursors for the construction of key intermediates. At
the outset, we planned to take full advantage of the chiral
crotylsilane-based C-C bond construction methodology, de-
veloped earlier in our laboratories,12 allowing us to efficiently
build polypropionate-like stereochemical arrays. In the context
of acyclic stereocontrol, these reaction processes rely on the
(10) (a) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
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1826. (c) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654-8664. (d) Paterson, I.; Florence, G. J.; Gerlach, K.;
Scott, J. P. Angew. Chem., Int. Ed. 2000, 39, 377-380. (e) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereing, N. J. Am. Chem. Soc.
2001, 123, 9535-9544. (f) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles,
D. C. J. Org. Chem. 1997, 62, 6098-6099. (g) Marshall, J. A.; Johns, B.
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H.; Niederer, D.; Daeffler, R.; Osmani, A.; Schreiner, K.; Seeger-Weibel,
M.; Be´rod, B.; Schaer, K.; Gamboni, R.; Chen, S.; Chen, W.; Jagoe, C. T.;
Kinder, F. R.; Loo, M.; Prasad, K.; Repicˇ, O.; Shieh, W.-C.; Wang,
R.-M.; Waykole, L.; Xu, D. D.; Xue, S. Org. Process Res. DeV. 2004, 8,
92-100. (i) 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.; Liu, Y.; Lu, Y.; McKenna, J.; Prasad,
M.; Ramsey, T. M.; Repicˇ, O.; Rogers, L.; Shieh, W.-C.; Wang, R.-M.;
Waykole, L. Org. Process Res. DeV. 2004, 8, 101-106. (j) Mickel, S. J.;
Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Koch, G.; Kuesters, E.;
Daeffler, R.; Osmani, A.; Seeger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer,
K.; Gamboni, R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.;
Kinder, F. R.; Lee, G. T.; McKenna, J.; Ramsey, T. M.; Repicˇ, O.; Rogers,
L.; Shieh, W.-C.; Wang, R.-M.; Waykole, L. Org. Process Res. DeV. 2004,
8, 107-112. (k) Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch,
F.; Seger, M.; Schreiner, K.; Daeffler, R.; Osmani, A.; Bixel, D.; Loiseleur,
O.; Cercus, J.; Stettler, H.; Schaer, K.; Gamboni, R. Org. Process Res.
DeV. 2004, 8, 113-121. (l) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani,
A.; Kuesters, E.; Schmid, E.; Schaer, K.; Gamboni, R.; Chen, W.; Loeser,
E.; Kinder, F. R.; Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Repicˇ,
O.; Wang, R.-M. Org. Process Res. DeV. 2004, 8, 122-130. (m) Mickel,
S. J.; Daeffler, R.; Prikoszovich, W. Org. Process Res. DeV. 2005, 9, 113-
120.
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34, 8163-8166. (c) Paterson, I.; Schlapback, A. Synlett 1995, 498-500.
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1997, 1191-1192. (e) Miyazawa, M.; Oonuma, S.; Maruyama, K.;
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Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999, 40, 4461-4462.
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1999, 40, 5449-5453. (j) Paterson, I.; Florence, G. J. Tetrahedron Lett.
2000, 41, 6935-6939. (k) Paterson, I.; Delgado, O.; Florence, G. J.;
Lyothier, I.; Scott, J. P.; Sereing, N. Org. Lett. 2003, 5, 35-38. (l) Shin,
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Figure 1. Microtubule-stabilizing natural products.
activity to microtubules is higher for (+)-discodermolide. (+)-
Discodermolide also displays potent activity against multi-drug-
resistant carcinoma cell lines, including paclitaxel-resistant
ovarian and colon cancer cell lines, with an IC50 of 2.5 nM.8 In
the comparative studies of discodermolide, epothilones, and
eleutherobin against a paclitaxel-dependent human lung carci-
noma cell line (A549-T12),9 it was found that discodermolide
could not replace paclitaxel, whereas the natural products
epothilone A and B and eleutherobin could substitute for
paclitaxel and thus maintain the viability of the cell line.
Importantly, the paclitaxel-dependent cell line proved to be
almost 20-fold more sensitive to discodermolide in the presence
of low concentrations of paclitaxel than in its absence. This
synergistic effect, however, was not observed with combinations
of the epothilones or eleutherobin with paclitaxel.
The highly interesting biological profile of discodermolide
makes it a promising candidate for clinical development as a
chemotherapeutic agent, either on its own or in combination
with paclitaxel, for treatment of paclitaxel-resistant breast,
ovarian, and colon cancer, as well as other multi-drug-resistant
cancers. Currently, discodermolide is undergoing phase I clinical
trials for pancreatic cancer at the Cancer Therapy & Research
Center in San Antonio, TX, as it is being developed as an
anticancer drug by Novartis Pharmaceuticals Corp. (Francavilla,
C.; Chen, W. C.; Kinder, K. R. Org. Lett. 2003, 5, 1233-1236).
The remarkable biological activity and challenging structure
of discodermolide, as well as the growing interest in providing
(7) Balachandran, R.; ter Haar, E.; Welsh, M. J.; Grant, S. G.; Day, B. W.
Anti-Cancer Drugs 1998, 9, 67-78.
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E.; Panek. J. S. Chem. ReV. 1995, 95, 1293-1316. (d) Panek, J. S.; Beresis,
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T. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky, S. J.; Smith, A. B., III;
Horwitz, S. B. Clin. Cancer Res. 2000, 6, 1978-1987.
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A R T I C L E S
Arefolov and Panek
Scheme 1. Retrosynthetic Analysis of (+)-Discodermolide
Scheme 2. Synthesis of C1-C6 Subunit 12
Our retrosynthetic analysis yielded three principal fragments,
11, 12, and 13, of approximately equal complexity. Identification
of syn- and anti-related oxygen-methyl vicinal stereochemical
relationships at C2-C4, C10-C12, and C16-C20 suggested
that the three advanced polypropionate-like subunits 11, 12, and
13 could be constructed through double stereodifferentiating
crotylation reactions, a valuable extension of chiral organosilane
methodology developed in our laboratories.12
use and proper choice of the chiral crotylsilane reagents and
Lewis acids to deliver the anticipated relative and absolute
stereochemical relationships.
Synthesis of the C1-C6 Subunit 12. The reaction sequence
started with the formation of R-chiral silyl-protected aldehyde
15 from the commercially available methyl (S)-2-methyl-3-
hydroxypropionate, (S)-14 (Scheme 2). Protection as the tert-
butyldiphenylsilyl ether followed by DIBAL-H reduction with
subsequent Swern oxidation afforded aldehyde 15 (80% yield,
three steps). This aldehyde was used without further purification
in a diastereoselective condensation reaction with (S)-crotylsilane
16 promoted by TiCl4 as the Lewis acid. Treatment of the crude
product with a solution of 2% HCl in MeOH removed the
TBDPS protecting group to afford diol 17 with overall 85%
yield as a single diastereoisomer. This first asymmetric croty-
lation proceeds through a synclinical transition state (TS-1),
where the observed stereochemistry is consistent with the anti-
SE′ mode of addition with Felkin induction. The use of silane
16, bearing an additional methyl group, allowed for the
introduction of a trisubstituted olefin, which was used as a
methyl ketone equivalent through an oxidative cleavage. To this
end, diol 17 was protected as p-methoxybenzyl acetal 18 with
90% yield under standard conditions (p-methoxybenzaldehyde
dimethyl acetal in the presence of catalytic amounts of p-TsOH
in DMF).16 Ozonolytic cleavage of the double bond of acetal
18 furnished the desired methyl ketone subunit 12 with 95%
yield.
Our synthetic plan for (+)-discodermolide is outlined in
Scheme 1. Our strategy identifies methyl ester 9 as a key
intermediate from which (+)-discodermolide would be gener-
ated. Thus, it was anticipated that formation of the sensitive
lactone moiety would take place during the last step of the
synthesis in concert with total deprotection of the fully as-
sembled C1-C24 fragment 9. Our first retrosynthetic discon-
nection of the C14-C15 bond generated two fragments: the
C1-C14 vinyl iodide 10 and the C15-C24 alkyl iodide 11. In
the synthetic direction, this operation corresponds to a Pd(0)-
mediated sp2-sp3 type cross-coupling reaction.13 It was envi-
sioned that the sensitive vinyl iodide functionality would be
masked as a vinyl silane14 throughout the synthesis, allowing it
to be carried through a number of steps. The C8-C9 (Z)-double
bond would come from the Lindlar hydrogenation of the internal
acetylene. Further disconnection of the C6-C7 bond yield the
C1-C16 fragment 12 and the C7-C14 fragment 13. We
projected that the desired stereochemistry of the propargylic
alcohol at C7 could be realized utilizing an acetate aldol reaction
between the boron enolate of methyl ketone 12 and the
propargylic aldehyde 13 via 1,5-anti asymmetric induction.15
(13) (a) Hyashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu,
K. J. Am. Chem. Soc. 1984, 106, 158-163. (b) Negishi, E.; Valente, L. F.;
Kobayashi, M. J. Am. Chem. Soc. 1980, 102, 3298-3299. (c) Miyaura,
N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am.
Chem. Soc. 1989, 111, 314-321.
(14) A similar strategy was adopted in Nicolaou’s synthesis of rapamycin. See:
Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.;
Bertinato, P. J. Am. Chem. Soc. 1993, 115, 4419-4420. (b) Piscopio, A.
D.; Minowa, N.; Chakraborty, T. K.; Koide, K.; Bertinato, P.; Nicolaou,
K. C. J. Chem. Soc., Chem. Commun. 1993, 617-619. (c) Nicolaou, K.
C.; Bertinato, P.; Piscopio, A. D.; Chakraborty, T. K.; Minowa, N. J. Chem.
Soc., Chem. Commun. 1993, 619-622.
(15) (a) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788-
789. (b) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585-8588.
(16) The relative stereochemistry of the crotylation product was confirmed at
this point by the analysis of the vicinal coupling constant and NOE
measurements of PMB acetal 18:
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Synthesis of Complex Polyketide Natural Products
A R T I C L E S
Scheme 3. Synthesis of C7-C14 Subunit 13
Scheme 4. Synthesis of C7-C14 Subunit 13
Accordingly, hydrozirconation of silylacetylene 24 using
Schwartz’s reagent22 was followed by quenching of the resultant
alkenylzirconium species with iodine to afford the geminal
iodovinylsilane 25 as a single regio- and stereoisomer in 92%
yield. Subsequent coupling of 25 with methylzinc chloride in
the presence of a catalytic amount of tetrakis(triphenylphos-
phine)palladium(0) gave the (Z)-vinylsilane 26 in 88% yield.
In this approach, the vinylsilane functions as a masked vinyl
iodide23 throughout the synthesis until fragments 10 and 11 are
ready for the crucial palladium(0)-mediated cross-coupling
reaction. Lithium di-tert-butylbiphenyl radical anion (LDBB)
reagent24 in THF at -78 °C selectively removed the benzyl
ether without affecting the C13-C14 double bond nor the labile
C11 silyl ether, providing 27 in 95% isolated yield (Scheme
4). The resultant alcohol 27 was converted to aldehyde 28 using
Swern conditions25 in 90% yield. Aldehyde 28, prone to
epimerization, was immediately converted to vinyl dibromide
29 utilizing the Corey-Fuchs homologation protocol in 87%
yield. Subsequent treatment of 29 with n-BuLi was followed
by the addition of ethyl formate to furnish the propargylic
aldehyde 13 (C7-C14 fragment) in 77% yield.
Synthesis of the C15-C24 Subunit 11. Synthesis of the
C15-C24 fragment started with the diastereoselective addition
of (R)-silane 30 to the silyl-protected aldehyde 15 promoted by
TiCl4 as the Lewis acid (Scheme 5). In this situation, the reaction
partners represented a matched case, giving a syn,syn stereo-
chemical triad that is consistent with a Felkin mode of addition.
Treatment of the crude reaction mixture with methanolic HCl
promoted cleavage of the silyl protecting group, affording diol
31 as a single diastereoisomer with a 90% yield.26 This diol
was protected as di-tert-butylsilylene derivative 32 using tBu2-
Si(OTf)2 and 2,6-lutidine27 in CH2Cl2 at -78 °C with 95% yield.
Ozonolysis of the (E)-olefin of 32 successfully gave aldehyde
Synthesis of the C7-C14 Subunit 13. Synthesis of this
intermediate was initiated with the addition of (S)-silane 19 to
the benzyl-protected aldehyde 2017 in the presence of TiCl4 as
the Lewis acid (Scheme 3) to afford homoallylic alcohol 21
with 85% yield as a single stereoisomer.18 The high diastereo-
selectivity of the reaction results from the matched case19 of
chelation control and the syn addition mode of the crotylsilane.
Homoallylic alcohol 21 was protected as a TBS ether in
quantitative yield. Ozonolytic cleavage of the resultant alkene
furnished aldehyde 22 with 88% yield, which was then
converted to alkynylsilane 24 via a two-step reaction sequence.
First, 22 was subjected to Corey-Fuchs olefination20 to obtain
vinyl dibromide 23 with 86% yield. Second, treatment of the
vinyl dibromide 23 with n-butyllithium followed by trapping
of the intermediate lithium acetylide with trimethylsilyl chloride
afforded the desired silylacetylene 24 with 79% yield.
One of the most challenging problems in the synthesis of
(+)-discodermolide has been the efficient introduction of the
C13-C14 trisubstituted (Z)-olefin. Earlier approaches have used
conventional phosphorus-based olefination methods10c,g,i which
produced variable yields and selectivities. Our plan utilized a
hydrozirconation-cross-coupling approach21 which allows con-
vergent assembly of complex trisubstituted olefins.
(17) For the preparation of the (S)-3-(benzyloxy)-2-methylpropanal, see: (a)
Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc. 1988,
110, 5768-5779. (b) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org.
Chem. 1988, 48, 5180-5184.
(18) The relative stereochemistry of the addition product 21 was confirmed by
conversion to acetonide 21a and analysis of the 1H NMR vicinal coupling
constant:
(21) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 3281-3284.
(22) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115-8116. (b)
Buchwald, S. L.; La Maire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S.
M. Tetrahedron Lett. 1987, 28, 3895-3898.
(23) For the regio- and stereospecific transformations of vinylsilanes to vinyl
iodides, see: (a) Koenig, K. E.; Weber, W. P. J. Am. Chem. Soc. 1973, 95,
3416-3418. (b) Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986,
86, 857-873.
(24) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854-
860.
(19) Masamune, S.; Ali, S. A.; Snitman, D. L.; Garvey, D. S. Angew. Chem.,
Int. Ed. Engl. 1980, 19, 557-558.
(20) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1792, 13, 3769-3772.
(25) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
9
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A R T I C L E S
Arefolov and Panek
Scheme 5. Synthesis of C15-C24 Subunit 11
Scheme 6. Synthesis of C15-C24 Subunit 11
allylic alcohol 36 was further protected as triethylsilyl ether 37
utilizing (TES)OTf and 2,6-lutidine in CH2Cl2 with 96% yield.
Next, the C21-C24 terminal (Z)-diene was installed in a
three-step sequence (Scheme 6). First, olefin 37 was oxidatively
cleaved with ozone. The resultant aldehyde 38 was used
unpurified in the reaction with 2 equiv of 1-trimethylsilyl-1-
propene boronate 3931 in diethyl ether to afford anti-silyl-
hydroxyalkene 40 as a single diastereoisomer. Silyl alcohol 40
was used without purification to undergo a Peterson syn
elimination32 using sodium hydride in THF to give (Z)-diene
41 as a single isomer in 91% yield over three steps starting
from 37. The p-methoxybenzylidene acetal 41 was regioselec-
tively opened under reductive conditions33 (DIBAL-H at -50
°C) to afford alcohol 42 with 83% yield. The fragment synthesis
was completed by iodination of the primary hydroxyl using
Ph3P/I2/imidazole to produce iodide 11 in 95% yield.
33 in 91% yield. This material was used in a double stereo-
differentiating anti crotylation reaction with silane (S)-19. The
TiCl4-promoted condensation reaction between aldehyde 33 and
(S)-silane 19 produced the anti homoallylic alcohol 34 (dia-
stereoselection >30:1, 83% yield),28,29 which was deprotected
using HF‚Py reagent in THF to afford triol 35 with 83% yield.
This triol was selectively protected as p-methoxybenzyl acetal
36 with 90% yield under standard conditions (p-methoxy-
benzaldehyde dimethyl acetal in the presence of catalytic
amounts of p-TsOH in DMF).30 The selectivity of this reaction
resulted, presumably, from the difference in nucleophilicity
between the primary and secondary hydroxyl groups. Homo-
C6-C7 Bond Construction and Elaboration of the C1-
C14 Fragment. With efficient synthetic access to intermediates
12 and 13, we next examined their union via aldol bond
construction methodology (Scheme 7). At the inception of this
project, very few precedents existed for highly stereoselective
acetate aldol reactions where a methyl ketone component alone
is controlling the stereochemical outcome. In studies toward
the total synthesis of spongistatin 1, Paterson and co-workers
discovered that boron enolates of â-oxygenated methyl ketones
gave good to excellent levels of 1,5-anti asymmetric induction
with achiral aldehydes, leading to the efficient synthesis of 1,3-
polyol chains.34 In related studies directed toward the total
synthesis of altohyrtin C, Evans and co-workers reported similar
findings and extended these results to the additions with chiral
aldehydes.35
(26) The relative stereochemistry of the addition product 31 was confirmed by
conversion to acetonide 31a and analysis of the 1H NMR vicinal coupling
constant:
(27) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871-4874.
(28) The relative stereochemistry of the addition product 34 was confirmed by
conversion to acetonide 34a and analysis of the 1H NMR vicinal coupling
constant as well as 13C NMR analysis of the acetonide, which were
consistent with the reported data: see ref 29.
(31) Tsai, D. J. S.; Matteson, D. S. Tetrahedron Lett. 1981, 29, 2751-2752.
(32) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464-1468.
(33) (a) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593-1597. (b) Sviridov, A. F.; Ermolenko, M. S.; Yaskunsky, D. V.;
Borodkin, V. S.; Koshetkov, N. K. Tetrahedron Lett. 1987, 28, 3835-
3843. (c) Marotta, E.; Pagani, I.; Righi, P.; Rosini, G.; Bortolasi, V.; Medici,
A. Tetrahedron: Asymmetry 1995, 6, 2319-2324.
(34) (a) Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187-1191. (b)
Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37,
8585-8588.
(29) For the use of 13C NMR to assign the relative stereochemistry of 1,3-diols,
see: (a) Rychnovsky, S. D.; Roger, B.; Yang, G. J. J. Org. Chem. 1993,
58, 3511-3515. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron
Lett. 1990, 31, 7099-7103.
(30) For an example of a similar triol protection selectivity, see: Evans, D. A.;
Ng, H. P. Tetrahedron Lett. 1993, 34, 2229-2233.
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Synthesis of Complex Polyketide Natural Products
A R T I C L E S
Scheme 7. Synthesis of C1-C14 Subunit 10
Table 1. 1,5 Induction with Boron Enolates
In Paterson’s and Evans’ investigations, methyl ketone
components lacked substitution in the R-position to the carbonyl.
In the case of discodermolide, however, there is a methyl group
at the R-position to the C5 carbonyl of the C1-C6 subunit.
Having no precedent to help us anticipate the influence of this
substitution pattern on the stereochemical outcome of the aldol
condensation, we set out to investigate the levels and sense of
selectivity of boron enolates derived from subunit 12 in our
system (Table 1). Gratifyingly, the dialkylboron enolates
displayed good levels of asymmetric induction, consistently
favoring the 1,5-anti product 43. Dicyclohexylboron enolate
(entry 1) was less selective than dibutylboron enolate (entries
2-4), the latter providing the desired alcohol 43 as a single
diastereoisomer, as determined by 1H NMR analysis of the crude
reaction product.
After successful coupling of 12 and 13 subunits, we turned
our attention to the synthesis of the C1-C14 fragment (Scheme
7). First, Evans-Tischenko reduction36 of the â-hydroxy ketone
43 provided anti-1,3-diol 45 in 95% yield.37 Hydrolysis of
â-hydroxyisobutyrate 45 was carried out with KOH in methanol.
Unexpectedly, purification of the crude reaction mixture by
chromatography on SiO2 resulted in acetal rearrangement to
afford the internal acetal 46 in 80% yield along with the
expected 1,3-diol 47 (20% yield). The minor diol 47 could be
T
yieldb
(%)
entry
M/basea
(
°
C)
solvent
43/44c
1
2
3
4
Cy2B/Et3N
-78
-78
CH2Cl2
Et2O
CH2Cl2
CH2Cl2
83
76
86
88
90:10
>30:1
>30:1
>30:1
Bu2B/i-Pr2NEt
Bu2B/i-Pr2NEt
Bu2B/i-Pr2NEt
-78
-115
a The enolates were formed from the corresponding boron triflates.
b Yields of the unseparable mixture of diastereoisomers 43 + 44 isolated
after chromatography on SiO2. c Ratios determined by 1H NMR analysis
of the unpurified reaction mixture.
further converted into thermodynamically more stable internal
acetal 46 by stirring with SiO2 in hexanes or using a catalytic
amount of PPTS in CH2Cl2.38
Since we planned to deprotect the primary hydroxyl of the
anticipated acetal 47 at a later stage of the synthesis (for the
eventual conversion to a methyl ester for the subsequent
lactonization step), this acetal rearrangement could save a step
at this advanced point in the synthesis. To use this rearrangement
in our favor, however, we needed to selectively oxidize the
primary hydroxyl at C1 to an aldehyde in the presence of the
(35) (a) Evans, D. A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55, 8671-8726. (b)
Evans, D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788-789.
(36) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-6449.
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J. AM. CHEM. SOC. VOL. 127, NO. 15, 2005 5601

A R T I C L E S
Arefolov and Panek
C7 secondary propargylic alcohol. To determine the feasibility
of our approach, we screened a variety of conditions and
reagents. The use of modified Ley’s oxidation protocol39 (TPAP/
NMO, CH3CN, then H2O) as well as the use of 4-MeO-TEMPO/
NaOCl oxidation conditions40 caused undesirable side reactions.
Fortunately, selective oxidation of 46 was carried out using
ingly, hydrogenation under Lindlar conditions with a catalytic
amount of quinoline48,49 afforded (Z)-olefin 53 in 98% yield.
The use of Kishi iododesilylation conditions completed the
synthesis of the C1-C14 fragment 52 in 95% yield.
Coupling of the C1-C14 and C15-C24 Fragments. We
have now reached a crucial point in these synthetic studies:
formation of a σ-bond between subunits 11 and 52. At the outset,
we had planned to employ a palladium-catalyzed cross-coupling
reaction methodology. An analogous approach was employed
by Smith and co-workers, who coupled a C9-C14 vinyl iodide
with a C15-C21 vinyl iodide utilizing modified Negishi
conditions.10c Utilizing a similar strategy but at a later stage of
the synthesis, Marshall and Johns joined C1-C14 vinyl iodide
with C15-C24 alkyl iodide subunits under Suzuki conditions.10g
We attempted cross-coupling of alkyl iodide 11 and vinyl
iodide 52, trying both Negishi50 and Suzuki51 coupling condi-
tions (Scheme 8). To our disappointment, both coupling
conditionsfailed to afford the desired coupling product 54. After
considerable experimentation and further model studies, we
realized that the protecting group at C11 (TBS ether) was
preventing cross-coupling reaction, presumably by sterically
blocking the oxidative addition step of vinyl iodide 52. For this
reason, we decided to replace the C11 TBS ether with a smaller
protecting group. Removal of the C11 TBS ether proceeded
smoothly with TBAF/AcOH,52 while reprotection of the result-
ant alcohol as a MOM ether was achieved using standard
conditions (MOMCl, Hu¨nig’s base in the presence of DMAP
in CH2Cl2) to furnish 10 with 68% yield over two steps.
Fragment 10 was tried as a coupling partner with C15-C24
fragment 11 (Scheme 8). Alkyl iodide 11 was converted to the
trialkyl boronate 55 by lithiation and subsequent addition of
B-methoxy-9-BBN. Suzuki cross-coupling with vinyl iodide 10
in the presence of PdCl2(dppf) as a catalyst provided the desired
coupling product 57 in 82% yield. In an alternate approach, we
were also able to generate the C14-C15 bond through the
Negishi cross-coupling of the organozinc species 56 (derived
from iodide 11) with vinyl iodide 10. Thus, advanced intermedi-
ate 57 was produced in 64% yield in the presence of catalytic
amounts of tetrakis(triphenylphosphine)palladium (0). When the
two cross-coupling processes were compared, the Negishi
coupling gave minor amounts of impurities in the final product
and the reproducibility of the reaction was often a problem.
The Suzuki reaction, on the other hand, provided consistently
cleaner product with reproducibly higher yields.
41
Oshima’s reagentsRuCl2(Ph3P)3 in benzene. The crude al-
dehyde 48 was further treated with buffered sodium chlorite42
to afford a carboxylic acid, which, without purification, was
converted to methyl ester 49 utilizing (trimethylsilyl)diazo-
methane43 with 81% yield over three steps starting from diol
46. The choice of a protecting group for the C7 hydroxyl group
proved to be crucial for the following Lindlar reduction step.
Our initial choice of TES ether as a protecting group precluded
the hydrogenation of the C8-C9 alkyne under Lindlar condi-
tions. For this reason, the C7 hydroxyl was protected as MOM
ether 50 (83% yield).
Having only two steps left before the end of the fragment
synthesis, we initially decided to proceed with iododesilylation,
leaving the Lindlar reduction as the last step. We argued that
having a triple bond within the molecule during the iodode-
silylation (electrophilic addition of I+) was a safer option than
having the (Z)-olefin, which may be prone to isomerization.
To this end, we have screened several iododesilylation condi-
44
tions and learned that I2/CH2Cl2 promoted decomposition of
50, while the use of NIS/THF45 gave back unreacted starting
material. Fortunately, application of the modified Kishi protocol
(NIS, CH3CN)46 resulted in a clean transformation to vinyl
iodide 51 in a 95% yield. Subsequent Lindlar reduction47 of
the vinyl iodide 51, however, proved problematic, leading to
the decomposition of the substrate due to hydrogenolysis of the
vinyl iodide.
To circumvent this problem, the order of the iododesilylation/
Lindlar reduction sequence was reversed (Scheme 7). Accord-
(37) For assignment of the relative stereochemistry of aldol adduct 43, alcohol
45 was converted to acetal 45a. A C3-C5 syn relationship was confirmed
by NOE measurement. Since the relationship between C5 and C7 hydroxyl
groups is anti (see ref 36), the C3 and C7 hydroxy groups are also in an
anti relationship to each other.
(38) We assume that the observed thermodynamic stability of 46 over 47 results
from the C2-methyl in 47 adopting an axial position, whereas the C4-methyl
in 46 adopts an equatorial position.
After having solved the problems with our final cross-
coupling reaction, we were pleased to find that the final steps
of our synthesis proceeded uneventfully. Triethyl silyl ether 57
was cleanly deprotected using p-TsOH in MeOH to give alcohol
58 with 77% yield (Scheme 9). The carbamate derivative 9 was
(39) For a review, see: Ley, S.; Norman, J.; Griffith, W.; Marsden, S. Synthesis
1994, 639-666.
(40) For reviews, see: (a) DeNooy, A. E. J.; Basemer, A. C.; van Bekkum, H.
Synthesis 1996, 1153-1174. (b) Anelli, P. L.; Biffi, C.; Montanarie, F.;
Quici, S. J. Org. Chem. 1987, 52, 2559-2562. (c) Ireland, R. E.; Gleason,
J. L.; Gegnas, L. D.; Highsmith, T. K. J. Org. Chem. 1996, 61, 6856-
6872.
(41) Tomioka, H.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1981,
22, 1605-1608.
(42) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091-
2096.
(43) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29,
1475-1478. (b) Hirai, Y.; Aida, T.; Inoue, S. J. Am. Chem. Soc. 1989,
111, 3062-3064.
(44) Chan, T. H.; Fleming, I. Synthesis 1979, 10, 761-786.
(45) Piscopio, A. D.; Minowa, N.; Chakraborty, T. K.; Koide, K.; Bertinato,
P.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1993, 617-618.
(46) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8647-
8650.
(47) (a) Lindlar, H.; Dubuis, R. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. V, pp 880-883. (b) Rajaram, J.; Narula, A. P. S.; Chawla,
H. P. S.; Dev, S. Tetrahedron 1983, 39, 2315-2318. (c) McEven, A. B.;
Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem. 1983,
48, 4436-4438.
(48) In the absence of quinoline, over-reduction to an alkane was observed.
(49) For a powerful example of the use of quinoline as a Lindlar catalyst poison,
see: (a) Nicolaou, K. C.; Zipkin, R. E.; Petasis, N. A. J. Am. Chem. Soc.
1982, 104, 5558-5560. (b) Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.
J. Am. Chem. Soc. 1982, 104, 5560-5563.
(50) For a review, see: Negishi, E., Ed. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley: New York, 2002; Part III, pp
215-1119.
(51) For reviews, see: (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633-9695. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-
2483.
(52) (a) All other reagent systems surveyed including HF‚Py, TBAF, HF, and
LiBF4 failed to deprotect the C11 hydroxyl. (b) For an example of using
TBAF/AcOH to remove a TBS ether, see: Smith, A. B., III; Ott, G. R. J.
Am. Chem. Soc. 1998, 120, 3935-3948.
9
5602 J. AM. CHEM. SOC. VOL. 127, NO. 15, 2005

Synthesis of Complex Polyketide Natural Products
A R T I C L E S
Scheme 8. Cross-Coupling of C1-C14 and C15-C24 Fragments
Scheme 9. Completion of the Synthesis of (+)-Discodermolide
obtained through addition of trichloroacetyl isocyanate53 and
in situ cleavage of the derived trichloroacetyl derivative with
methanolic K2CO3 in 95% yield. Next, the PMB protecting
group at C17 was removed by oxidative cleavage utilizing DDQ
in aqueous CH2Cl2.54 Prolonged exposure (70 h) of the resultant
alcohol to 4 M HCl solution in THF effected cleavage of the
MOM protecting groups and the p-methoxybenzyl acetal with
concomitant lactonization, in accordance with the earlier
precedents.10e,g Purification of the crude product by flash
chromatography (10% CH3OH-CH2Cl2) afforded (+)-disco-
dermolide (1) as a stable amorphous solid in 60% yield over
the two steps. The spectroscopic and analytical properties of
this material (1H NMR, 13C NMR, [R]D, IR, FAB-HRMS)
proved identical in all respects with the data reported earlier.
Summary. An enantioselective total synthesis of (+)-
discodermolide has been achieved in a highly convergent
manner. A salient feature of the synthesis is that 11 out of 13
stereocenters within the target molecule were established using
asymmetric crotylation reactions. Highlights of the synthesis
include the use of hydrozirconation-cross-coupling methodol-
ogy for the construction of C13-C14 (Z)-olefin, acetate aldol
reaction to construct the C6-C7 bond and install the C7
stereocenter with high levels of 1,5-anti stereoinduction, and
the use of palladium-mediated sp2-sp3 cross-coupling reaction
to join the advanced fragments at the late stage of the synthesis.
Our synthetic strategy provides access to natural (+)-discoder-
molide in a total of 42 steps with 2.1% yield based on the longest
linear sequence (27 steps).
Acknowledgment. Financial support was obtained from NIH
Grant GM55740. J.S.P. is grateful to Johnson & Johnson, Merck
Co., Novartis, Pfizer, and GSK for financial support of our
program. Drs. Gwilherm Evano, Fredrik Lake, and Neil Langille
are acknowledged for their help with the manuscript preparation.
Supporting Information Available: Experimental procedures
and characterization data for all synthetic intermediates (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(53) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521-5524.
(54) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885-
888.
JA043168J
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