α-Oxygenated crotyltitanium and dyotropic rearrangement in the total synthesis of discodermolide

Article abstract of DOI:10.1002/anie.200604629

(Chemical Equation Presented) A complete strategy: The total synthesis of discodermolide relies on the elaboration of syn-anti stereotriads linked to a Z-O-enecarbamate group, its direct transformation into the terminal Z diene, and stereocontrolled gener

Full text of DOI:10.1002/anie.200604629

Angewandte
Chemie
DOI: 10.1002/anie.200604629
Natural Product Synthesis
a-Oxygenated Crotyltitanium and Dyotropic Rearrangement in the
Total Synthesis of Discodermolide**
Elsa de Lemos, François-Hugues PorØe, Alain Commerçon, Jean-François Betzer,*
Ange Pancrazi, and Janick Ardisson*
Discodermolide is a polyketide natural product that was first
isolated in 1990 from extracts of the rare Caribbean marine
[
1]
sponge Discodermia dissoluta by Gunasekera et al. This
compound has been shown to inhibit the proliferation of cells
[
2]
by arresting the G /M phase of the cell cycle. Discodermo-
2
lide belongs to the class of antimitotic agents known to act by
microtubule stabilization, whose members used clinically
include taxol and taxotere. This product is more potent in
stabilizing microtubules, more water-soluble than taxoid
[
3]
compounds, and exhibits synergy with taxol. The marine
sponge cannot provide the quantities of discodermolide
needed for drug development. Therefore, efficient and
highly convergent syntheses are needed, and studies in the
[
4]
area are increasing.
Herein, we report a new total synthesis of discodermolide
that relies on three particular points: elaboration of syn–anti
stereotriads linked to a Z-O-enecarbamate group, direct
transformation of this core into the terminal Z diene, and
stereocontrolled generation of the trisubstituted Z double
bond by dyotropic rearrangement. Our convergent synthetic
strategy, which is outlined in Scheme 1, relies on the
preparation of the three subunits C1–C7 (2), C8–C14 (3),
Scheme 1. Retrosynthetic analysis of discodermolide (1).
[
4h]
and C15–C24 (4). Each subunit, or its precursors, possesses
a syn–anti methyl–hydroxy–methyl triad (in C2–C4, C12–C10,
and C18–C20, respectively, for fragments 2, 3, and 4) with
adjacent unsaturation (Scheme 2). Therefore, we developed a
convenient and scalable elaboration of this core motif. A
[
5]
crotyltitanation reaction, developed by Hoppe and widely
[
6]
used in total synthesis by us, was selected.
[*] E. de Lemos, Dr. F.-H. PorØe, Dr. J.-F. Betzer, Dr. A. Pancrazi,
Prof. Dr. J. Ardisson
UniversitØ de Cergy-Pontoise
CNRS UMR 8123
5
Mail Gay Lussac, 95031 Cergy Pontoise Cedex (France)
Fax: (+33)1-3425-7381
E-mail: jean-francois.betzer@u-cergy.fr
janick.ardisson@u-cergy.fr
Dr. A. Commerçon
DØpartement des Sciences Chimiques
Chimie des Produits Naturels, Sanofi-Aventis
Centre de Recherche de Vitry-Alfortville
Scheme 2. Preparation of the syn–anti methyl–hydroxy–methyl triad
cores and subsequent use of the Z-O-enecarbamate function.
13 Quai Jules Guesde, 94403 Vitry-sur-Seine Cedex (France)
[
**] We thank Sanofi–Aventis for a fellowshipfor E.d.L. Technical
support from Paris XI University (Châtenay-Malabry and Orsay
centers) is gratefully acknowledged (elemental analysis and high-
resolution mass spectrometry).
The enantioenriched (R)-a-(N,N-diisopropylcarbamoyl-
oxy)crotyltitanium (5) was readily prepared in situ from
crotyl diisopropylcarbamate, an equimolar mixture of nBuLi/
Supporting information including experimental details for this
article is available on the WWW under http://www.angewandte.org
or from the author.
[
7]
(ꢀ)-sparteine, and tetra(isopropoxy)titanium.
Matched
reactions between a-(S)-methyl aldehydes 6a–c and R-
Angew. Chem. Int. Ed. 2007, 46, 1917 –1921
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1917

Communications
crotyltitanium 5 should yield homoaldol adducts 7a–c with
A very large number of oxidation conditions were tested
high diastereoselectivities. The stereocenters of these alcohols
have the correct absolute configurations linked to a Z-O-
enecarbamate group.
on alcohol 10, but only the use of TEMPO/PhI(OAc) led to
2
[
13]
the expected aldehyde 6b. Subsequent allylation of 6b with
the R-crotyltitanium 5 delivered the pure adduct 7b in 84%
yield for two steps (no other isomers were detected by NMR
analysis). A Fritsch–Buttenberg–Wiechell rearrangement
allowed the transformation of the O-enecarbamate 7b into
Moreover, we wanted to take advantage of this Z-O-
enecarbamate function to set up the required unsaturation.
The alkyne function in C8–C9 of subunit 3 could result from a
carbenoid rearrangement, the a,b-unsaturated Weinreb
amide in C7 of subunit 2 from a cross-metathesis reaction,
and the terminal Z diene in C21–C24 of subunit 4 from a
nickel-catalyzed cross-coupling reaction. For this strategy, we
had to prepare suitable aldehydes for each subunit.
[
14]
the terminal alkyne by treatment with tBuLi. Notably, this
a-elimination reaction, which used two equivalents of tBuLi,
was faster than the tin/lithium exchange. Subunit 3 was
obtained in 26.4% overall yield for eight steps.
To elaborate subunit2, the optically pure aldehyde 6a was
needed (Scheme 4). This compound could be obtained by
classical chemistry in three steps from commercially available
The crucial central subunit 3 possesses the C13–C14
trisubstituted Z double bond and a terminal alkyne group.
The C8–C9 triple bond should be accessible by an O-
enecarbamate rearrangement. For stereocontrolled building
of the C13–C14 trisubstituted functionalized Z double bond,
we considered focusing on a dyotropic rearrangement of 5-
[
8]
lithiodihydrofuran, which was first examined by Fujisawa
and developed by Kocienski and us.
[
9]
[10]
This attractive
reaction should allow the construction of various trisubsti-
tuted Z or E double bonds, in good yields and with total
control of their geometry.
The synthesis of subunit 3 began with commercially
available bromo alcohol 8 (Scheme 3). A reaction sequence
involving cyanide displacement of the bromide, partial
[
11]
reduction of the resulting hydroxynitrile compound, and
direct dehydration provided the optically pure (S)-3-methyl-
2
,3-dihydrofuran (9) in 64% overall yield for three steps. The
stereochemical control of the C13–C14 trisubstituted func-
tionalized Z double bond was based on 1,2-cuprate transfer
between the 5-lithio derivative of 9 and a cyano-Gilman
Scheme 4. Synthesis of the C1–C7 subunit 2. a) TBSCl, imid, DMF,
08C!RT, 18 h, 98%; b) DIBAL-H, CH
Cl
, ꢀ208C, 30 min, 92%;
2
2
c) (COCl) , DMSO, Et N, CH Cl , ꢀ558C!RT, 1 h; d) 5, pentane/
2
3
2
2
cyclohexane, ꢀ788C, 3 h, 66% (two steps); e) O , sudan III, CH Cl ,
3
2
2
dimethyl cuprate, Me CuLi·LiCN. The use of various addi-
2
ꢀ
788C, 1 h then PPh
3
, ꢀ788C!RT, 3 h, 87%; f) (EtO)
2 2
P(O)CH C(O)-
tives, and in particular those containing sulfur, allowed the
efficient installation of a methyl group, which remained the
NMe(OMe), NaH, THF, 08C!RT, 45 min, 86%; g) PhCHO, KHMDS,
THF, ꢀ208C, 45 min, 79%. TBS=tert-butyldimethylsilyl, imid=imida-
zole, KHMDS=potassium bis(trimethylsilyl)amide.
[
12]
most difficult to introduce.
After tri-n-butyltin chloride
trapping, the unique Z-vinyltin derivative 10 was obtained in
an optimized yield of 68%.
(
2S)-3-hydroxy-2-methylpropionic acid methyl ester (11;
[
15]
Roche ester). The crotyltitanation reaction between alde-
hyde 6a and R-crotyltitanium 5 furnished homoaldol com-
pound 7a in 66% yield for two steps with total diastereose-
lectivity. The O-enecarbamate function of 7a has been
deoxygenated under reducing conditions using isopropyl-
[
16]
magnesium chloride and a nickel catalyst. To our surprise,
all attempts to transform this terminal alkene into an a,b-
unsaturated Weinreb amide function by cross-metathesis
[
17]
reaction using Grubbs II or Hoveyda catalyst failed, and
[
18]
only the starting material was recovered. Therefore, we
undertook an oxidation of O-enecarbamate 7a with ozone;
the resulting aldehyde was used in a Horner–Wadsworth–
Emmons reaction with the commercially available diethyl (N-
methoxy-N-methylcarbamoylmethyl)phosphonate to provide
the expected a,b-unsaturated Weinreb amide 12 as a single
stereomer. A hetero-Michael reaction, with benzaldehyde
under anionic conditions, introduced the stereocenter in
position C5 and simultaneously protected the C3 and C5
hydroxy functions as a benzylidene group (diastereomeric
Scheme 3. Synthesis of the C8–C14 subunit 3. a) NaCN, DMSO, 608C,
2
4 h, 92%; b) DIBAL-H, CH Cl , ꢀ788C, 2 h, 82%; c) p-TSA
2
2
(
0.2 mol%), quinoline, 160!2108C, 30 min, 85%; d) tBuLi,
Me CuLi ·LiCN, Et O/DMS (4:1), 08C!RT, 18 h, then nBu SnCl,
2
2
2
3
ꢀ
208C!RT, 4 h, 68%; e) TEMPO (10 mol%), PhI(OAc) , CH Cl , RT,
2
2
2
2
h; f) 5, pentane/cyclohexane, ꢀ788C, 3 h, 84% (two steps); g) tBuLi,
Et O, ꢀ40!ꢀ208C, 20 min, 78%; h) MOMCl, TBAI, Hünig’s base,
2
CH Cl , 18 h, 92%. DIBAL-H=diisobutylaluminum hydride, p-TSA=
2
2
p-toluenesulfonic acid, DMS=dimethyl sulfide, TEMPO=2,2,6,6-tetra-
methyl-1-piperidinyloxy free radical, MOM=methoxymethyl, TBAI=
tetra-n-butylammonium iodide, Hünig’s base=diisopropylethylamine.
1
918
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 1917 –1921

Angewandte
Chemie
[
19]
ratio > 95:5).
This sequence resulted in the effective
catalyzed allylation reaction using achiral tri-n-butylcrotyl-
stannane under simple asymmetric induction conditions (the
formation of subunit 2, in 35.2% overall yield for seven steps.
The same Roche ester 11 was used for the preparation of
the third subunit 4 (Scheme 5). This starting material was
transformed into aldehyde 13 by successive protection,
reduction, and TEMPO/sodium chlorite oxidation.
C16–C18 syn–syn stereotriad was installed by a BF ·OEt -
[
21]
diastereomeric ratio was optimized to 95:5). Protection of
the C17 hydroxy group allowed the isolation of the expected
major isomer 14 (74% yield for two steps). An oxidative
cleavage of this alkene then delivered the desired aldehyde
6c.
[
20]
The
3
2
In a single step, both the C18–C20 syn–anti stereotriad
and the C21–C22 Z double bond were set up by an allylation
reaction of 6c with R-crotyltitanium 5. Therefore, carbamate
7
c was elaborated in 77% yield and total selectivity from
alkene 14. Protection of the C19 hydroxy group and
subsequent direct vinylation by a cross-coupling [Ni(acac) ]-
2
[
22]
catalyzed reaction between the Z-O-enecarbamate moiety
and commercially available vinylmagnesium bromide fur-
[
23]
nished the Z diene 15 in 85% yield. After regeneration of
the C15 primary hydroxy group, the clean transformation into
alkyl iodide 4 was realized under optimized Garegg con-
ditions in a benzene/diethyl ether mixture under high
[
24]
dilution.
In this way, the final subunit 4 bearing five
stereocenters and the terminal diene was obtained in 16.5%
overall yield for 11 steps.
The first coupling reaction of the subunits was achieved by
nucleophilic addition of an organometallic species derived
from 3 on Weinreb amide 2 (Scheme 6). Reaction of 2 with
the lithio derivative of 3, generated by metalation with tBuLi,
afforded the ynone 16 in 80% yield. Reduction of 16 with the
CBS reagent allowed generation of the C7 stereocenter
Scheme 5. Synthesis of the C15–C24 subunit 4. a) CCl C(N)OPMB,
3
PPTS (5 mol%), CH Cl /cyclohexane, 208C, 40 h, 88%; b) LAH, THF,
2
2
0
8C!RT, 3 h, 95%; c) TEMPO (2 mol%), NaOCl, KBr, NaHCO ,
3
CH Cl /H O; d) tri-n-butylcrotylstannane, BF ·OEt , Et O, ꢀ1008C, 2 h,
2
2
2
3
2
2
[
25]
(diastereomeric ratio > 95:5). After protection of the C7
7
4% (two steps); e) TBSOTf, 2,6-lutidine, CH Cl , 08C!RT, 2 h, 92%;
2
2
f) O , sudan III, CH Cl /MeOH, ꢀ788C, 2 h then Me S, ꢀ788C!RT,
hydroxy group, regeneration of the primary alcohol at C1, and
3
2
2
2
1
6 h; g) 5, pentane/cyclohexane, ꢀ788C, 3 h, 77% (two steps);
oxidation under TEMPO/PhI(OAc) conditions, the crude
2
h) TESOTf, 2,6-lutidine, CH Cl , 08C!RT, 1.5 h, 78%; i) vinylmagne-
[26]
2
2
aldehyde was treated with sodium chlorite
to afford a
sium bromide, [Ni(acac) ] (10 mol%), Et O, 08C, 16 h, 85%; j) DDQ,
2
2
carboxylic acid, which was readily converted into its methyl
CH Cl /H O, 08C!RT, 40 min, 72%; k) I , PPh , imid, C H /Et O,
2
2
2
2
3
6
6
2
[27]
ester with TMS-diazomethane. The partial reduction of the
0
8C!RT, 2 h, 79%. PMB=p-methoxybenzyl, PPTS=pyridinium p-
[
28]
triple bond at C8–C9 was realized with PtO2.
Finally,
toluenesulfonate, LAH=lithium aluminum hydride, Tf=trifluorome-
thanesulfonyl, TES=triethylsilyl, acac=acetylacetonate, DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
iododestannylation gave the required vinyl iodide 18 in
30.6% overall yield for nine steps.
Scheme 6. Coupling reactions and total synthesis of (+)-discodermolide (1). a) 3, tBuLi, Et O, ꢀ788C, 30 min, then 2, 08C, 3 h, 80%; b) (S)-(ꢀ)-
2
2
4
-methyl-CBS-oxazaborolidine, BH ·Me S, THF, ꢀ308C, 2 h, 95%; c) MOMCl, TBAI, Hünig’s base, CH Cl , RT, 18 h, 86%; d) HF/py, py/THF, RT,
3
2
2
2
h, 96%; e) TEMPO (10 mol%), PhI(OAc) , CH Cl , RT, 3 h; f) NaClO , NaH PO , 2-methylbut-2-ene, tBuOH/H O, RT, 1 h; g) TMS-CHN , C H /
2
2
2
2
2
4
2
2
6
6
MeOH, RT, 15 min, 66% (three steps); h) H , PtO (30 mol%), AcOEt, RT, 12 h; i) I , CH Cl , 08C, 10 min, 71% (two steps); j) 4, tBuLi, Et O,
2
2
2
2
2
2
ꢀ
788C, 5 min, B-methoxy-9-BBN, THF, ꢀ788C!RT, then 18, CsCO , [Pd(dppf)Cl ], AsPh , DMF, H O, 18 h, 60%; k) p-TSA, MeOH, 08C, 1 h,
3
2
3
2
7
7%; l) Cl CC(O)NCO, CH Cl , RT, 15 min, then K CO , MeOH, RT, 1.5 h, 64%; m) HCl (4n), THF, RT, 72 h, 70%. CBS=Corey–Bakshi–Shibata
3 2 2 2 3
reagent, py=pyridine, TMS=trimethylsilyl, BBN=borabicyclo[3.3.1]nonane, dppf=(diphenylphosphino)ferrocene.
Angew. Chem. Int. Ed. 2007, 46, 1917 –1921 ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1919

Communications
The s bond between the major fragment 18 and subunit 4
was formed by a B-alkyl Suzuki–Miyaura cross-coupling
reaction. The reactive trialkyl boronate species, prepared
Smith III, S. B. Horwitz, Chem. Biol. 2001, 8, 843 – 855; g) M.
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[
29]
from alkyl iodide 4 with tBuLi and B-methoxy-9-BBN,
[
30]
reacted with 18 under [Pd(dppf)Cl ] and AsPh conditions
2
3
to give the fully elaborated discodermolide carbon skeleton
[
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1
9 in 60% yield.
After cleavage of the C19 triethylsilyl group and installa-
[
31]
tion of the carbamate moiety, the final global deprotection
of all protecting groups, with concomitant lactonization, was
performed in a 4n HCl solution in THF. Purification of the
crude product by flash chromatography (CH Cl /MeOH
[
4] For major publications on total synthesis, see: a) J. B. Nerenberg,
D. T. Hung, P. K. Somers, S. L. Schreiber, J. Am. Chem. Soc.
2
2
8
0:20) afforded (+)-discodermolide (1) in 70% yield.
The spectroscopic data observed for our synthetic 1 ( H
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1
Schreiber, J. Am. Chem. Soc. 1996, 118, 11054 – 11080; c) A. B.
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1
3
and C NMR spectroscopy and high-resolution mass spec-
trometry) were identical in all respects with those reported for
the natural material or another synthetic discodermolide. The
specific optical rotation, [a] = + 16.2 degcm g dm (c =
1
2
D
0
3
ꢀ1
ꢀ1
ꢀ
3
.0 gcm , MeOH), was very close to previously reported
values. In addition, in vitro cytotoxicity levels comparable to
[
1,2]
literature data
were obtained.
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In conclusion, the total synthesis of discodermolide was
achieved in 21 linear steps with 1.6% overall yield from
commercially available compounds (8 or 11). We have shown
homoallylic Z-O-enecarbamate alcohols to be powerful tools
in the total synthesis of multifunctional compounds. Allyla-
tion reaction of a-(S)-methyl aldehydes 6a–c with enantioen-
riched R-a-oxygenated crotyltitanium 5, conveniently pre-
pared in situ, ensured the stereocontrolled elaboration, for
each subunit, of syn–anti methyl–hydroxy–methyl triads
connected to a Z-O-enecarbamate. This particular group
allowed direct and easy access to either a triple bond or
terminal Z diene functions. This efficient and versatile syn-
thesis delivered the natural product, and we are currently
looking to extend this methodology to the preparation of
original, unnatural discodermolide analogues.
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Keywords: allylation · metalation · natural products ·
rearrangement · total synthesis
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