Stereoselective syntheses of the C1-C5, C7-C15 and C17-C24 fragments of (+)-discodermolide using a catalytic and asymmetric vinylogous Mukaiyama reaction

Article abstract of DOI:10.1055/s-2004-817744

The stereoselective syntheses of C1-C5, C7-C15 and C17-C24 fragments of (+)-discodermolide are described from a common intermediate: an α,β-unsaturated six-membered lactone obtained in one step using a catalytic and asymmetric vinylogous Mukaiyama (CAVM)

Full text of DOI:10.1055/s-2004-817744

720
LETTER
Stereoselective Syntheses of the C1-C5, C7-C15 and C17-C24 Fragments
of (+)-Discodermolide Using a Catalytic and Asymmetric Vinylogous
Mukaiyama Reaction
Stereoselective
S
e
l
the
C
1
é
-
C5, C7-C1
n
5 and C17-C24 Fr
B
a
gments of (+)-D
a
iscodermol
z
ide án-Tejeda, Marie Georgy, Jean-Marc Campagne*
ICSN-CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France
Fax +33(1)69077247; E-mail: campagne@icsn.cnrs-gif.fr
Received 10 November 2003
Different accesses to this stereotriad have been developed
using efficient asymmetric aldol,5,8,9 crotylation,4,10 or
allenylmetal7 methodologies. We have recently reported12
a stereoselective access to lactone 2, which possesses the
correct syn/anti stereotriad and interestingly, a well-posi-
tioned Z-double bond (Scheme 1). We thus embarked on
a total synthesis of (+)-discodermolide. In this communi-
cation, we would like to disclose the syntheses of C1-C5,
C7-C15 and C17-C24 fragments of (+)-discodermolide
starting from lactone 2.
Abstract: The stereoselective syntheses of C1-C5, C7-C15 and
C17-C24 fragments of (+)-discodermolide are described from a
common intermediate: an a,b-unsaturated six-membered lactone
obtained in one step using a catalytic and asymmetric vinylogous
Mukaiyama (CAVM) reaction.
Key words: asymmetric, lactones, stereoselectivity, catalysis,
copper
Discodermolide (1), isolated in 1990, by Gunasekera1
from the marine sponge Discodermia dissoluta, is a po-
tential anti-cancer agent. Discodermolide was found to
bind to tubulin with a 100 fold greater affinity than taxol
and also to act synergistically with taxol.2,3 This natural
product also possesses an original structure bearing 13
stereogenic centers and 3 Z-double bonds. Owing to its bi-
ological properties, original structure and scarcity from
the natural source (0.002% w/w from frozen sponges),
considerable synthetic efforts have been undertaken cul-
minating in 5 total syntheses,4–8 a formal synthesis,9 a
great number of different synthetic approaches,10 and the
design11 of simplified potent analogues.2,3
Scheme 2
Lactone 2 was synthesized in four steps starting from
commercially available enantiomerically pure ester 3
(Scheme 2). Aldehyde 4 was first obtained using standard
procedures13 in three steps and 66% overall yield.
Scheme 1
From a retrosynthetic point of view, it has been previously
shown that discodermolide could be divided in three main
fragments possessing the same syn/anti stereotriad.
Scheme 3
Starting from aldehyde 4, a catalytic and asymmetric vi-
nylogous Mukaiyama (CAVM) reaction in the presence
of Carreira’s catalyst14 (10%) led to lactone 2 as a single
diastereoisomer in a 68% yield.
SYNLETT 2004, No. 4, pp 0720–0722
Advanced online publication: 29.01.2004
DOI: 10.1055/s-2004-817744; Art ID: G30103ST
© Georg Thieme Verlag Stuttgart · New York
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9.
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3.
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LETTER
Stereoselective Syntheses of the C1-C5, C7-C15 and C17-C24 Fragments of (+)-Discodermolide
721
In order to construct fragment C17-C24, lactone 2 was
first partially reduced to the corresponding lactol, which
was not purified but directly engaged in a Wittig reac-
tion with methyl(triphenyl)phosphonium bromide
(Scheme 3). Initial attempts (using different amounts of
phosphonium bromide and NaHMDS in THF) were quite
disappointing leading to the expected diene 5 in low
yields (18–26%).
Scheme 6
Fragment C1-C5 (Scheme 6) was finally obtained in two
steps by oxidative cleavage20 of the double bond in lac-
tone 2. A mixture of compounds 10 and 1121 was ob-
tained. Further basic treatment of the crude mixture led to
fragment C1-C521 in 68% yield (2 steps).
In conclusion, we have developed short accesses to C1-
C5, C7-C15 and C17-C24 fragments of (+)-discoder-
molide in 2, 5 and 2 steps, respectively, starting from a
common intermediate: the lactone 2. Our current work on
assembling these fragments will be reported in due
course.
Scheme 4
Careful examination of the by-products generated in the
Wittig reaction led us to isolate compound 6,15 which is
probably resulting from a Wittig reaction on the retro-vi-
nylogous-aldol product of the lactol (Scheme 4). This ob-
servation led us to reconsider the amount of base in this
reaction. Indeed, using 2.5 equivalents of phosphonium
bromide and 2 equivalents of NaHMDS in THF, com-
pound 516 could be isolated in 70% yield (2 steps). Frag-
ment C17-C24 5 was thus obtained in two steps and 70%
yield from lactone 2.
Acknowledgment
We thank CNRS and CONACYT-Mexico (fellowship to B. B.-T.)
for financial support.
References
(1) Gunasereka, S. P.; Gunasereka, M.; Schulte, G. K. J. Org.
Chem. 1990, 55, 4912; corrigendum: J. Org. Chem. 1991,
56, 1346.
(2) For a review, see: Kalesse, M. ChemBioChem 2000, 1, 171.
(3) For a review, see: Paterson, I.; Florence, G. J. Eur. J. Org.
Chem. 2003, 2193.
The synthesis of fragment C7-C15 (Scheme 5) started
with the partial reduction of the lactone to the correspond-
ing lactol, followed by its protection as acetal 7.
(4) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1996, 118, 11054.
(5) 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.
(6) (a) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J.
Org. Chem. 1997, 62, 6098. (b) Harried, S. S.; Lee, C. P.;
Yang, G.; Lee, T. I. H.; Myles, D. C. J. Org. Chem. 2003, 68,
6646.
(7) (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
7885. (b) Marshall, J. A.; Lu, Z. H.; Johns, B. A. J. Org.
Chem. 1998, 63, 817.
(8) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.;
Sereining, N. J. Am. Chem. Soc. 2001, 123, 9535.
(b) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.;
Scott, J. P.; Sereining, N. Org. Lett. 2003, 5, 35.
(9) Francavilla, C.; Chen, W.; Kinder, F. R. Jr. Org. Lett. 2003,
5, 1233.
Scheme 5
Treatment of the silylether with TBAF, which after subse-
quent oxidation using a Swern reaction led to aldehyde 8
in 82% yield. Olefination using the Still–Gennari17,18
modification of the Horner–Wadsworth–Emmons reac-
tion ultimately led (75% yield) to the selective formation
of 919 with the requisite C13-C14 Z-trisubstituted double
bond. Fragment C7-C1519 was thus obtained in 5 steps
(55% overall yield from 2).
(10) Bouzbouz, S.; Cossy, J. Org. Lett. 2003, 5, 3029; and
references cited therein.
(11) Choy, N.; Shin, Y.; Nguyen, P. Q.; Curran, D. P.;
Balachandran, R.; Madiraju, C.; Day, B. W. J. Med. Chem.
2003, 46, 2846; and references cited therein.
(12) Bluet, G.; Bazan-Tejeda, B.; Campagne, J. M. Org. Lett.
2001, 3, 3807.
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722
B. Bazán-Tejeda et al.
LETTER
in an ice-water bath, starting aldehyde has disappeared
(CCM monitoring). After quenching using sat. NH4Cl (15
min) and classical work-up, the crude residue is purified by
column chromatography (heptane/EtOAc 7:3) to give 9 (20
mg, 75%) as a colorless oil.
Analytical data: Rf = 0,66 (heptane/EtOAc 7:3). IR: 2965,
2930, 2865, 2821, 1705, 1602 cm–1. 1H NMR (CDCl3): d =
0.98 (3 H, d, J = 7.2 Hz, H12). 1.03 (3 H, d, J = 6.8 Hz,
H13), 1,07 (3 H, dd, J = 1.6 and 6.7 Hz, H11), 1.30 (3 H, t,
J = 7.2 Hz, H16), 2.24–2.35 (1 H, m, H5), 3.38 (3 H, s, H14),
3.45–3.61 (2 H, m, H6-H7), 4.20 (2 H, q, J = 7.2 Hz, H15),
4.85 (1 H, bs, H2), 5.68 (1 H, dt, J = 2.6 and 10 Hz, H3), 5.79
(1 H, bd, J = 10 Hz, H4), 6.14 (1 H, dd, J = 1.4 and 8.4 Hz,
H8). 13C NMR (CDCl3): d = 13.05 (C12), 14.2 (C16), 16.3
(C13), 20.8 (C11), 30.9 (C5), 33.3 (C7), 55.0 (C14), 60.0
(C15), 75.3 (C6), 95.4 (C2), 124.0 (C3), 136.2 (C4), 140.5
(C9), 146.6 (C8), 167.7 (C10), [a]D25 +138.9 (c 0.58,
CHCl3). Anal. Calcd for (%): C, (67.14); H, (9.01). Found
(%): C, (67.23); H (9.11).
(13) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am.
Chem. Soc. 2002, 124, 10396.
(14) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
(15) Konno, K.; Fujishima, T.; Maki, S.; Liu, Z.; Miura, D.;
Chokki, M.; Ishizuka, S.; Yamaguchi, K.; Kan, Y.; Kurihara,
M.; Miyata, N.; Smith, C.; DeLuca, H. F.; Takayama, H. J.
Med. Chem. 2000, 43, 4247.
(16) Experimental Procedure for Fragment C17-C24 5.
DIBAL-H (0.55 mL, 1 M in hexanes) is added to a solution
of 2 (200 mg, 0,49 mmol) in toluene (6 mL) at –78 °C. After
15 min at –78 °C, sat. NH4Cl (10 mL) is added and the
reaction mixture is allowed to warm up to r.t. After
extraction with CH2Cl2 and classical work-up, lactol (196
mg) is obtained without further purification as a colorless
oil. Triphenylmethylphosphonium bromide (59 mg, 0,16
mmol) is suspended in THF (0.5 mL) at 0 °C. NaHMDS (63
mL, 0,127 mmol, 2 M in THF) is then added dropwise. After
2.5 h at 0 °C, the reaction mixture is cooled to –78 °C and a
solution of crude lactol (26 mg, 0.063 mmol) in THF (0.6
mL) is added. The reaction mixture is allowed to warm up to
r.t. and after 15 h the solvent is evaporated. The crude
residue is purified by column chromatography (pentane/
CH2Cl2 8:2 to 6:4). Diene 5 is obtained (18 mg, 70% yield)
as a colorless oil.
(20) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(21) Experimental Procedure for Fragment C1-C5 11. To a
solution of lactone 2 (60 mg, 0.15 mmol) in CCl4 (0.15 mL),
CH3CN (0.15 mL) and H2O (0.27 mL) are added. RuCl3·H2O
(15 mL, 6% in H2O) and NaIO4 (135 mg, 0.6 mmol) are then
added and the reaction is stirred at r.t. for 24 h. The reaction
mixture is diluted with H2O (1 mL) and extracted with
CH2Cl2. Organic phases are discarded and the aqueous phase
is acidified with 1 N HCl and extracted with CH2Cl2.
Organic phases are dried over MgSO4, filtered and
Analytical data: Rf = 0.38 (heptane/EtOAc 9:1). IR: 3503,
3071, 3049, 2999, 2961, 2930, 2858 cm–1. 1H NMR
(CDCl3): d = 0.95 (3 H, d, J = 6.7 Hz, H10), 0.97 (3 H, d,
J = 7.0 Hz, H9), 1.07 (9 H, s, t- Bu), 1.81–1.93 (1 H, m, H7),
2.27 (1 H, d, J = 2.6 Hz, OH), 2.73–2.85 (1 H, m, H5), 3.63
(1 H, dt, J = 2.5 and 8.1 Hz, H6), 3.72 (2 H, d, J = 2 Hz, H8),
5.12 (1 H, d, J = 10.1 Hz, H1), 5.22 (1 H, d, J = 16.8 Hz,
H1¢), 5.42 (1 H, t, J = 10.4 Hz, H4), 6.12 (1 H, d, J = 11 Hz,
H3), 6.61 (1 H, dt, J = 10.4 and 16.8 Hz, H2), 7.36–7.46 (6
H, m, Ph), 7.66–7.72 (4 H, m, Ph). 13C RMN (CDCl3): d =
9.67 (C9), 17.41 (C10), 19.20 (t-Bu), 26.98 (3 C, t-Bu),
35.79 (C5), 36,82 (C7), 68.12 (C8), 76.38 (C6), 117.89 (C1),
127.64 (4 C, Ph), 129.65 (2 C, Ph), 130.20 (C3), 132.25
(C2), 133.31 (Ph), 133.45 (Ph), 135.50 (C4), 135.67 (4 C,
Ph). [a]D25 +43.5 (c 1, CHCl3). HRMS (ESI+) [MNa]+: calcd
m/z = 431.2382, found m/z = 431.2379.
evaporated to give a mixture of compounds 10 and 11. The
crude product is dissolved in MeOH (2 mL) and a solution
of NaOH (2 mL) is then added. After 1 h stirring at r.t., the
reaction mixture is evaporated. The residue is taken up in
H2O and then acidified (1 N HCl). Extraction with CH2Cl2
and classical work-up gave acid 11 (42 mg, 68%).
Analytical data: IR: 3435, 2929, 1713, 1112 cm–1. 1H NMR
(CDCl3): d = 0.95 (3 H, d, J = 7.0 Hz, H6), 1.07 (9 H, s, t-
Bu), 1.15 (3 H, d, J = 7.1 Hz, H7), 1.73–1.84 (1 H, m, H4),
2.61 (1 H, m H2), 3.60 (1 H, dd, J = 5.7 and 10 Hz, H5), 3.82
(1 H, dd, J = 3.9 and 10 Hz, H5¢), 4.12 (1 H, d, J = 10.1 Hz,
(17) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(18) The same reaction carried out under ‘regular’ HWE
conditions led to a 95:5 Z/E mixture.
(19) Experimental Procedure for Fragment C7-C15 9. To a
solution of fluorophosphonate22 (70 mg, 0.2 mmol) and 18-
C-6 (64 mg, 0.24 mmol) at –78 °C, is added KHMDS (0.4
mL, 0.5 M in toluene). After 15 min, a solution of aldehyde
8 (18 mg, 0.1 mmol) in THF (0.2 mL) is added. After 8 min,
H3), 7.36–7.46 (6 H, m, Ph), 7.66–7.72 (4 H, m, Ph). 13
C
NMR (CDCl3): d = 9.3 (C6), 17.4 (C7), 19.2 (1 C, t-Bu), 26.9
(3 C, t-Bu), 36.8 (C4), 43.7 (C2), 68.3 (C5), 74.8 (C3), 127.7
(4 C, Ph), 129.7 (2 C, Ph), 133.3 (1 C, Ph), 134.7 (1 C, Ph),
135.6 (4 C, Ph), 179.0 (C=O). HRMS (ESI+) [MNa]+: calcd
m/z = 423.197, found m/z = 423.200.
(22) Patois, C.; Savignac, P. Synth. Commun. 1991, 21, 2391.
Synlett 2004, No. 4, 720–722 © Thieme Stuttgart · New York