Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment.

Article abstract of DOI:10.1021/ol026139r

[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight ste

Full text of DOI:10.1021/ol026139r

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2397-2400
Studies Directed toward the Total
Synthesis of Discodermolide:
Asymmetric Synthesis of the C1−C14
Fragment
,†
Alexander Arefolov and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis,
Metcalf Center for Science and Engineering, 590 Commonwealth AVenue,
Boston UniVersity, Boston, Massachusetts 02215
panek@chem.bu.edu
Received May 6, 2002
ABSTRACT
A convergent and stereoselective assembly of the C1−C14 subunit of marine natural product (+)-discodermolide has been completed. The
approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling
is achieved via an efficient stereoselective acetate aldol reaction between C1−C6 and C7−C14 subunits.
(+)-Discodermolide 1 is a polypropionate-derived marine
metabolite, isolated from the Caribbean deep sea sponge
Discodermia dissoluta.1,2 The structure of discodermolide,
determined through a combination of spectroscopic tech-
niques, was shown to possess a tetrasubstituted δ-lactone
ring, a side chain containing four double bonds, and a total
of 13 stereocenters. The relative stereochemistry was as-
signed by X-ray crystallography, while the absolute config-
uration remained unidentified until Schreiber and co-workers3
synthesized both antipodes. (+)-Discodermolide was initially
shown to be a potent immunosuppressive agent, both in vitro
and in vivo, and also an antifungal agent.4 Further biological
studies revealed remarkable cytotoxic activity in a variety
of human and murine cell lines. This cytotoxicity is due to
binding and stabilizing mitotic spindle microtubules causing
cell cycle arrest in the M phase.5
The striking biological profile as well as its structural
complexity prompted substantial synthetic effort toward the
total synthesis of (+)-discodermolide.6 To date, six total
† Recipient of a 2002 Cope-Scholar Award.
(1) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K.
J. Org. Chem. 1990, 55, 4912-4915. Additions and corrections: J. Org.
Chem. 1991, 56, 1346.
(2) Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E. U.S. Patent
US5840750, Nov 24, 1998.
(4) (a) Gunasekera, S. P.; Cranick, S.; Longley, R. E. J. Nat. Prod. 1989,
52, 757-761. (b) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera,
M.; Gunasekera, S. P. Transplantation 1991, 52, 656-661. (c) Longley,
R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.; Gunasekera, S. P.
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Am. Chem. Soc. 1993, 115, 12621-12622. (b) Hung, D. T.; Nerenberg, J.
B.; Schreiber, S. L. Chem. Biol. 1994, 1, 67-71. (c) Hung, D. T.; Nerenberg,
J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080.
(5) (a) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R.
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3, 287-293.
10.1021/ol026139r CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/06/2002

syntheses of discodermolide have been reported.3,7 Herein
we report our approach to the C1-C14 fragment 2, which
sets the stage for a convergent synthesis of (+)-discoder-
molide and its analogues for further structural and biological
study.
projected that the desired stereochemistry of the propagylic
alcohol 4 at C7 could be realized utilizing an acetate aldol
reaction between the boron enolate of methyl ketone 5 and
the propargylic aldehyde 6. Finally, the stereogenic centers
of the polypropinate fragments 5 and 6 could be constructed
using chiral (E)-crotylsilane bond construction methodology,
developed earlier in our laboratories.8
Our retrosynthetic analysis of (+)-discodermolide 1 is
outlined in Figure 1. The first key disconnection at C14-
Assembly of the methyl ketone 5 started with the double
stereodifferentiating crotylation between readily available9
aldehyde 7 and (S)-silane 8 (Scheme 1). Acidic workup
Scheme 1
removed the silyl protecting group in situ to afford homoal-
lylic alcohol 9 in 85% yield with dr > 30:1 anti:syn. The
resulting diol 9 was converted to the p-methoxybenzyl acetal
10 in 90% yield. Subsequent ozonolysis of the double bond
in the presence of pyridine provided C1-C6 fragment 5 in
95% yield.
Figure 1. Retrosynthetic analysis of (+)-discodermolide.
Synthesis of propargylic aldehyde 6 is outlined in Scheme
2 and was initiated by a double stereodifferentiating reaction
between aldehyde 11 and the (S)-crotylsilane reagent 12 to
give the homoallylic alcohol 13 (85%, dr > 30:1 syn:anti).
Protection of the homoallylic alcohol as the TBS ether (94%
yield), followed by the oxidative cleavage of the double bond,
and Corey-Fuchs10 homologation, afforded vinyl dibromide
15 in 84% yield (two steps). Treatment with n-BuLi and
TMSCl led to acetylene 16 in 79% yield. Hydrozirconation
of silylacetylene 16 using Schwartz’s reagent11 [Cp2Zr(H)-
Cl] (2.5 equiv, THF, 55 °C, 1 h), followed by quenching
with iodine affored iodovinylsilane 17 as a single isomer in
92% yield. Subsequent coupling of 17 with methylzinc
species in the presence of a catalytic amount of Pd(0) gave
the (Z)-vinyl silane 18 in 88% yield. Due to the inherent
stability, the vinylsilane functions as a masked vinyl iodide
throughout the synthesis until fragments 2 and 3 are ready
for the crucial palladium(0)-mediated cross-coupling reaction.
C15 envisions an sp2-sp3 type palladium(0)-mediated cross-
coupling reaction between C1-C14 vinyl iodide 2 and C15-
C24 alkyl iodide 3 fragments. Fragment 2 is derived from
propargylic alcohol 4 via Lindlar reduction of the C8-C9
internal acetylene and iododesilylation. Our second discon-
nection of 4 at C6-C7 yields two subunits 5 and 6. We
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Wren, S. P. J. Chem. Soc., Chem. Commun. 1993, 1790-1792. (b) Clark,
D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5878-5879. (c) Golec, J.
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Tetrahedron 1999, 40, 4461-4462. (n) Filla, S. A.; Song, J. J.; Chen, L.
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2398
Org. Lett., Vol. 4, No. 14, 2002

Scheme 2
Scheme 3
The reaction sequence based on the formation (and use)
of the geminally substituted iodovinylsilane has been docu-
mented12 to be a useful strategy for the convergent assembly
of complex trisubstituted olefins. Our approach provides
access to the configurationally pure C13-C14 (Z)-olefin of
the (+)-discodermolide.
The selective deprotection of the benzyl group (in the
presence of the vinylsilane functionality) in 18 was carried
out using LDBB reagent13,14 in 95% yield. Swern oxidation15
of the deprotected alcohol 19, followed by the Corey-Fuchs
homologation, afforded vinyl dibromide 20 (81% yield, two
steps). Subsequent treatment of 20 with n-BuLi followed by
the addition of ethyl formate furnished the propargylic
aldehyde 6 (C7-C14 fragment) in 78% yield.
Cl2 17 at -78 °C), produced the desired adduct 21 as a single
1
diastereoisomer18 (as determined by H NMR analysis) in
76% yield.
A modified Tischenko reduction19 of the â-hydroxy ketone
21 provided anti-1,3 diol 22 in 95% yield, differentiated as
the hydroxyisobutyrate. After hydrolysis of the isobutyrate
(KOH/MeOH), chromatography on silica gel unexpectedly
resulted in acetal rearrangement to afford diol 23 in 80%
yield along with the expected diol 24 (20% yield). Diol 24
could be further converted into thermodynamically more
stable 23 by stirring with SiO2 in hexanes or by performing
silica gel chromatography with the same conversion (80%).
With the efficient synthetic access to intermediates 5 and
6, we next examined their union via aldol bond construction
(Scheme 3). Analysis of this process dictated the use of
enolborinates to establish the desired stereochemistry at C7
via 1,5-anti asymmetric induction.16
(17) Optimizing the reaction conditions, we found that while the use of
both CH2Cl2 and Et2O produced good results on a small scale (70-80%
yield on a 20-40 mg scale), increasing the reaction scale using Et2O led to
considerable decrease in yields, due to decomposition of methyl ketone.
Use of CH2Cl2 as a solvent allowed us to upscale the aldol reaction and
run it with reproducibly good yields on a 20-500 mg scale.
(18) The relative stereochemistry was assigned by NOE analysis of the
acetal, derived from 22:
Gratifyingly, the aldol reaction between the dibutylboron
enolate, derived from methyl ketone 5 and aldehyde 6 (CH2-
(12) Arefolov, A.; Lagille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 3281-
3284.
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854-860.
(14) Other debenzylation conditions, such as hydrogenation, transfer
hydrogenation, or metal in liquid ammonia reduction either gave back
starting material or caused decomposition of the substrate.
(15) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(16) (a) Evans, D. A.; Coleman, P. J.; Coˆte, B. J. Org. Chem. 1997, 62,
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1996, 37, 8585-8588.
.
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6449.
Org. Lett., Vol. 4, No. 14, 2002
2399

Since we planned to deprotect the primary hydroxyl of the
anticipated acetal 24 later (for eventual conversion to a
methyl ester for the subsequent lactonization step), this
rearrangement could save a step at this advanced point in
synthesis. To use the acetal rearrangement in our favor,
however, we needed to find the reagent system able to
selectively oxidize the primary hydroxyl to an aldehyde, in
the presence of the secondary propargylic alcohol. To
determine the feasibility of this approach, a variety of
oxidative conditions were explored at this point. The use of
modified Ley’s oxidation protocol20 (TPAP/NMO, CH3CN;
then H2O) as well as the use of 4-MeO-TEMPO/NaOCl
oxidation conditions21 caused decomposition of the substrate.
Fortunately, selective oxidation of 23 worked extremely well
Scheme 4
22
using RuCl2(Ph3P)3 in benzene. Treatment with buffered
sodium chlorite,23 followed by (trimethylsilyl)diazomethane,
furnished methyl ester 25 with 90% overall yield. The choice
of protecting group for the C7 hydroxyl proved to be crucial
for the subsequent Lindlar reduction step. Our preliminary
studies indicated that bulky protecting groups inhibited the
hydrogenation of the alkyne in a similar system. For this
reason, we protected the C7 hydroxyl as MOM ether 26 (83%
yield).
nately, the Lindlar reduction of this product led to hydro-
genolysis of the vinyl iodide. To circumvent this problem,
the order of the iododesilylation/Lindlar reduction sequence
was reversed (Scheme 4). Hydrogenation under Lindlar
conditions afforded (Z)-olefin 28 in 98% yield. The use of
Kishi iododesilylation conditions (95% yield) completed the
synthesis of the C1-C14 fragment 2.
In conclusion, the synthesis of the fully elaborated C1-
C14 fragment of (+)-discodermolide was completed in 21
steps in approximately 14% yield. The approach is conver-
gent and proceeds with high levels of stereocontrol through-
out. With the vinyl iodide 2 in hand, we are now in position
to explore the final steps of the synthesis. Progress toward
the total synthesis continues and will be reported in due
course.
Having only two steps left before the end of the fragment
synthesis, we initially decided to proceed with iododesily-
lation first, leaving the Lindlar reduction as the last step.
We argued that having a triple bond within the molecule
during the iododesilylation (electrophilic addition of the I+)
was a safer option than having the (Z)-olefin, which may be
prone to isomerization. To this end, we have screened several
24
iododesilylation conditions and learned that I2/CH2Cl2
promoted decomposition of 26 while the use of NIS/THF25
gave back the starting material. Application of Kishi
protocol26 (NIS, CH3CN/ClCH2CN) resulted in a clean
transformationto vinyl iodide 27 in a 95% yield. Unfortu-
Acknowledgment. This work has been financially sup-
ported by the National Institute of Health (GM55740).
(20) For a review of Ley’s oxidation, see: Ley, S.; Norman, J.; Griffith,
W.; Marsden, S. Synthesis 1994, 639-666.
(21) (a) For review, see: DeNooy, A. E. J.; Basemer, A. C.; VanBekkum,
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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-
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Supporting Information Available: Experimental pro-
1
cedures and spectroscopic characterization (IR, HRMS, H
NMR and 13C NMR data) of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.
OL026139R
(26) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37,
8647-8650.
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