Total synthesis of discodermolide: Optimization of the effective synthetic route

Article abstract of DOI:10.1002/chem.200801478

An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including related alternative synthetic approaches. Particularly notable is the repeated application of a crotyltitanation reaction to yield homoallylic (Z)-O-ene-carbamate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled building of the syn-anti methyl-hydroxy- methyl triads of DDM, but also for the direct construction of the terminal (Z)diene. Of particular interest is also the installation of the C13=C14 (Z)-double bond through a highly selective dyotropic rearrangement. The preparation of the middle C8-C14 fragment in two sequential stages and its coupling to the C1-C7 moiety was a real challenge and required careful optimization. Several synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a systematic structural variation of DDM and, therefore, the elaboration and exploration of novel discodermolide structural analogues.

Full text of DOI:10.1002/chem.200801478

DOI: 10.1002/chem.200801478
Total Synthesis of Discodermolide:
Optimization of the Effective Synthetic Route
Elsa de Lemos,[a] FranÅois-Hugues Porꢀe,[a] Arnaud Bourin,[a] Julien Barbion,[a]
Evangelos Agouridas,[a] Marie-Isabelle Lannou,[a] Alain CommerÅon,[b]
Jean-FranÅois Betzer,*[a] Ange Pancrazi,*[a] and Janick Ardisson*[a]
Abstract: An efficient and modulable
total synthesis of discodermolide
(DDM), a unique marine anticancer
polyketide is described including relat-
ed alternative synthetic approaches.
Particularly notable is the repeated ap-
plication of a crotyltitanation reaction
to yield homoallylic (Z)-O-ene-carba-
mate alcohols with excellent selectivity.
Advantage was taken of this reaction
not only for the stereocontrolled build-
ing of the syn–anti methyl–hydroxy–
methyl triads of DDM, but also for the
direct construction of the terminal (Z)-
diene. Of particular interest is also the
installation of the C13=C14 (Z)-double
bond through a highly selective dyo-
tropic rearrangement. The preparation
of the middle C8–C14 fragment in two
sequential stages and its coupling to
the C1–C7 moiety was a real challenge
and required careful optimization. Sev-
eral synthetic routes were explored to
allow high and reliable yields. Due to
the flexibility and robust character of
this approach, it might enable a sys-
tematic structural variation of DDM
and, therefore, the elaboration and ex-
ploration of novel discodermolide
structural analogues.
Keywords:
cross-coupling
allylation
discodermolide
·
·
·
nickel · total synthesis
Introduction
that, like Taxol (Paclitaxel), arrests cells at the G2/M boun-
dary of the cell cycle.[2] The cytotoxicity values reported for
discodermolide against breast, prostate, colon, lung, and
ovarian cancer cell lines are generally in the low nm range.
Comparative studies showed that DDM was 1000-fold more
potent than Taxol in promoting the same microtubule poly-
merization/bundling. This product is also more water-soluble
than taxoid compounds, and acts synergistically in combina-
tion with paclitaxel.[3] Extensive investigation of the site and
mode of binding of DDM to b-tubulin as well as the deter-
mination of its bioactive conformation led to the proposal of
a pharmacophore model.[2d] Due to the potential therapeutic
applications and the extreme scarcity of this compound, con-
siderable synthetic efforts directed towards DDM were pro-
vided, culminating in several total syntheses,[4] including the
development of a preparative-scale approach.[5] Phase I clin-
ical trials were initiated from Novartis Pharma AG; howev-
er, despite encouraging results, trials were suspended due to
adverse toxicity at high doses.[6] Owing to the remarkable
profile of DDM and its potential as a lead structure, concep-
tion and synthesis of analogues have to be developed.
In 1990, Gunasekera and co-workers reported the isolation
of discodermolide (DDM) (1),[1] a unique polyketide marine
metabolite obtained in low yields from the Caribbean deep-
water sponge Discodermia dissoluta. Biological studies re-
vealed DDM to be a potent microtubule-stabilizing agent
[a] Dr. E. de Lemos, Dr. F.-H. Porꢀe, Dr. A. Bourin, Dr. J. Barbion,
Dr. E. Agouridas, Dr. M.-I. Lannou, Dr. J.-F. Betzer, Dr. A. Pancrazi,
Prof. J. Ardisson
Universitꢀ Paris Descartes
Facultꢀ de Pharmacie, CNRS UMR 8638
4 avenue de l’Observatoire
75270 Paris Cedex (France)
Fax : (+33)143291403
E-mail: jean.francois.betzer@icsn.cnrs-gif.fr
ange.pancrazi@parisdescartes.fr
janick.ardisson@parisdescartes.fr
[b] Dr. A. CommerÅon
Chemical&Analytical Sciences
Natural Product Chemistry, Sanofi-Aventis
Centre de Recherche de Vitry-Alfortville
13 Quai Jules Guesde
In this full account, we report synthetic details of our
total synthesis of DDM (1), including related alternative
synthetic approaches that enabled us to develop the final ef-
fective synthetic route.[7] The modulable character of this ap-
94403 Vitry-sur-Seine Cedex (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801478.
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FULL PAPER
proach might allow structural modifications of DDM and,
therefore, the elaboration and investigation of novel disco-
dermolide structural analogues.
Results and Discussion
Retrosynthetic and strategic considerations: Our synthetic
strategy relies upon the disassembly of DDM into three
fragments of similar size and stereochemical complexity (A
C15–C24, B C8–C14, C C1–C7; Scheme 1). The linkage of
these subunits appears to us to be optimally convergent, the
two internal (Z)-alkenes C8=C9 and C13=C14 being pivotal
in the choice of disconnection strategies either in acetylide
addition in the aldehyde/reduction sequence or Pd-catalyzed
sp2–sp3 coupling.
Scheme 2. Crotyltitanation of aldehyde 4. Insaturation setup from (Z)-
acyclic or cyclic enol ether.
figure the terminal C21–C24 (Z)-diene 6 of fragment A,[11]
whereas a carbenoid rearrangement would install the termi-
[12]
ꢀ
nal C8 C9 alkyne 7 of subunit B in one step.
Another highlight of our strategy was the stereocontrolled
building of the C13=C14 trisubstituted (Z)-double bond.
ꢀ
With our C14 C15 disconnection, elected by several re-
search groups, the elaboration of the pivotal segment B,
which encompassed a (Z)-vinyl halide at the C14-position,
was needed for the sp2–sp3 cross-coupling reaction between
A and B. A (Z)-vinyl iodide can be obtained in one step, by
Zhao aldehyde olefination,[13] but the yields were modest
and the Z/E stereoselectivity remained disappointing.[14] To
circumvent this reaction, we considered focusing on a dyo-
tropic rearrangement of the 5-lithiodihydrofurans 10 and 11,
obtained by metalation of cyclic enol ethers 8 and 9 leading
to (Z)-alkenes 12 and 13. This attractive reaction, first ex-
amined by Fujisawa[15] and developed by Kocienski[16] and
our group,[17] would allow the construction of various (Z) or
(E)-trisubstituted double bonds, in expected good yields and
with total control of their geometry.
Scheme 1. Retrosynthetic analysis of discodermolide.
A central feature of our approach was the repeated
matched addition of the chiral secondary (R)-crotyltitanium
reagent 2 to a-(S)-methyl aldehyde 4. As exemplified in
Scheme 2, this crotyltitanation reaction initially developed
by Hoppe,[8] and widely used in total syntheses by our
group,[9] yielded homoallylic adducts 5 encompassing a syn–
anti methyl–hydroxy–methyl triad linked to a (Z)-O-enecar-
bamate group, with excellent diastereoselectivity. The enan-
tioenriched (R)-a-(N,N-diisopropylcarbamoyloxy)crotyltita-
nium 2 could easily be prepared in situ from deprotonation
of crotyl diisopropylcarbamate 3 with nBuLi/(ꢀ)-sparteine
and tetra(isopropoxy)titanium.[10]
This retrosynthetic plan should ultimately allow for modi-
fications of every substructure embedded into the frame of
the natural compounds.
Preparation of the building blocks: The recent determina-
tion of the DDM bioactive “U”-shaped conformation
strongly supports the crucial role of the middle part of the
DDM molecule.[2b] The preparation of this C8–C14 fragment
region B was a real challenge; the strategy involved two
main stages, a crotyltitanation for the setup of the C10–C12
anti–syn stereotriad and a dyotropic rearrangement to build
the C13=C14 trisubstituted (Z)-double bond. Two alterna-
Our plan was precisely to take advantage of the reactivity
of this terminal (Z)-O-enecarbamate function in two ways.
First, a nickel-catalyzed cross-coupling reaction would con-
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J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
tive routes were examined, which differed in the ordering of
the two key steps.
The first sequence started with the commercially available
(S)-(+)-Roche ester 14 (Scheme 3). Protection of 14 as a p-
methoxybenzyl ether[18] was followed by reduction of the
berg–Wiechell rearrangement.[12] Enol ether 18 was readily
available from 17, after PMB ether cleavage with DDQ,
IBX oxidation of the resulting alcohol, and subsequent alde-
hyde homologation with the commercially available (me-
thoxymethyl)triphenylphosphonium ylide. Aqueous acidic
hydrolysis of the resulting enol ether 18, accompanied by re-
moval of the TES group afforded lactol 19.
The next step should allow us to build the C13=C14 tri-
substituted functionalized (Z)-double bond by means of a
dyotropic rearrangement. However, the envisaged transfor-
mation of lactol 19 into the 2,3-dihydrofuran (DHF) deriva-
tive 21, turned out to be more difficult than expected. Spe-
cifically, all attempts to effect a direct elimination (PTSA,[20]
PPTS,[21] CuSO4,[22] NH4NO3,[23] or Burgess reagent)[24] from
compound 19 failed to give the expected DHF 21. However,
lactol 19 could be smoothly converted to hemithioketal 20.
Upon DBU pyrolysis of 20 with concomitant distillation of
the elimination product,[25] the desired dihydrofuran 21 was
obtained in 30% yield. Attempts to improve this outcome
by conversion of phenyl sulfide 20 into the corresponding
sulfoxide derivative[26] and subsequent elimination delivered
DHF 21 in only 19% yield. Application to 21 of dyotropic
rearrangement conditions (1,2-cuprate transfer from cyano-
Gilman dimethylcuprate followed by tri-n-butyltin trapping)
led to the expected C8–C14 segment 22 in 20% yield. Un-
fortunately, this 15 step sequence afforded the C8–C14 subu-
nit 22 in a very poor yield and thus could not provide suffi-
cient quantities to carry on the synthesis.
The formation of the DHF ring with an alkyne part was a
critical step in the synthesis. The strategy was reconsidered
and an alternative tactic was suggested based on an earlier
formation of the DHF ring. By using the same approach, we
inverted the order of the crotyltitanation–dyotropic rear-
rangement sequence. This required the introduction of a
C13=C14-functionalized double bond bearing a metallic or
halide function at a very early stage of synthesis. According
to the literature, vinyl iodide hydrogenolysis occurred in the
subsequent Lindlar reduction step,[41] and, therefore, we
choose to introduce a vinyl tin function as the precursor of
the vinyl halide core at the C14 position.
Stability of the vinyl stannane function during C8–C14
subunit elaboration was a challenging problem. With the
aim to determine the chemical compatibility of this moiety,
we decided to prepare a C12-desmethyl model (ꢁ)-25
(Scheme 4). While the formation of alkene 12 in one step by
metallate rearrangement with a cyano-Gilman dimethylcup-
rate from commercially available 2,3-dihydrofuran 8 pro-
ceeded smoothly,[27] significant problems were encountered
during conversion of homoallylic alcohol 12 into aldehyde
23. Extensive screening was performed. Classical oxidation
methods, such as Swern,[28] Doering–Parikh,[29] or the use of
PCC[30] led to decomposition with loss of the tin function.
On the other hand, milder reagents, such as tetrapropylam-
monium perruthenate (TPAP)/N-methylmorpholine N-oxide
(NMO)[31] or IBX[32] resulted in recovery of the starting ma-
terial. The Saigo–Mukaiyama protocol,[33] employing 1,1’-
(azodicarbonyl)dipiperidine (ADD) as a hydride acceptor
Scheme 3. a) CCl3C(N)OPMB, PPTS (5 mol%), CH2Cl2/cyclohexane 1:2,
RT, 40 h, 88%; b) LAH, THF, 08C!RT, 3 h, 95%; c) TEMPO
(2 mol%), NaOCl, KBr, NaHCO3, CH2Cl2/H2O; d) (R)-2, cyclohexane/
pentane 1:7, ꢀ788C, 2 h, 85% (2 steps, c–d), d.r. 97:3; e) TESOTf, 2,6-lu-
tidine, CH2Cl2, 08C!RT, 2 h, 97%; f) tBuLi, Et2O, ꢀ308C!ꢀ208C,
45 min, 84%; g) nBuLi, THF, ꢀ788C!08C, 1 h, then TMSCl, ꢀ788C!
RT, overnight, 92%; h) DDQ, CH2Cl2/H2O 95:5, 08C!RT, 30 min, 86%;
i) IBX, DMSO, RT, 3 h; j) (methoxymethyl)triphenylphosphonium chlo-
ride, LiHMDS, ꢀ108C, 1 h, 85%; k) acetone/H2O 9:1, HCl, 658C, 1 h,
61% (3 steps, h–k); l) PTSA, PPTS, CuSO4, NH4NO3 or Burgess reagent;
m) PhSH, BF3·OEt2, 4 ꢂ MS, Et2O, 1 h, 80%; n) DBU, neat, 2458C,
30%; o) mCPBA, NaHCO3, PhH, 08C, 1 h, then, reflux, 1 h, 19%;
p) tBuLi, Me2CuLi·LiCN, THF/Et2O/1:2, 08C!RT, 3 h, then nBu3SnCl,
ꢀ308C!RT, 5 h, 20%. mCPBA=3-chloroperbenzoic acid; DBU=1,8-
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene; DDQ=2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone; d.r.=diasteromeric ratio; HMDS=hexamethyldisilazane;
IBX=2-iodoxybenzoic acid; MS=molecular sieves; PMB=p-methoxy-
benzyl; PPTS=pyridinium p-toluenesulfonate; PTSA=p-toluenesulfonic
acid; TEMPO=tetramethylpiperdinyloxy free radical; TES=triethylsil-
yl; TMS=trimethylsilyl.
methyl ester to the primary alcohol and subsequent oxida-
tion to aldehyde 15.[19] The crotyltitanation reaction of chiral
aldehyde 15, with enantioenriched reagent (R)-2 led to the
desired diastereomer 16 in good yield and with an excellent
diastereomeric ratio (97:3) (Scheme 3). Obtention of a O-
enecarbamate moiety by the crotyltitanation process al-
lowed for the generation of alkyne 17 by a Fritsch–Butten-
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Total Synthesis of Discodermolide
FULL PAPER
DHF 9 was subjected to metallate rearrangement under
the standard laboratory conditions with a cyano-Gilman di-
methylcuprate to afford the expected trisubstituted (Z)-
alkene 13 in a disappointing 27% yield (Scheme 6; Table 1,
Scheme 4. a) tBuLi, Me2CuLi·LiCN, THF/Et2O/1:2, 08C!RT, 3 h, then
nBu3SnCl, ꢀ308C!RT, 5 h, 61%; b) TEMPO (10 mol%), BAIB,
CH2Cl2, RT, 2 h; c) (ꢁ)-2 (from 3, nBuLi/TMEDA, Et2O), Et2O, ꢀ788C,
2 h, 63% (2 steps b and c); d) tBuLi, Et2O, ꢀ308C!ꢀ208C, 30 min,
Scheme 6. Cuprate rearrangement with methyl transfer from DHF 8 or 9.
a) 1) tBuLi (1.2 equiv), THF, ꢀ608C 10 min then 08C 50 min; 2) MeLi
(5 equiv), CuCN (2 equiv), Et2O, additive (see Table 1), 08C!RT;
3) nBu3SnCl, ꢀ30C!RT, 5 h.
70%. BAIB=[bisACHTUNGTRENNUNG(acetoxy)iodo]benzene.
failed, resulting only in the recovery of the starting material,
despite encouraging Marshall precedent.[34]
Table 1. Results of cuprate rearrangement with methyl transfer from
Finally, we were pleased to find that the use of TEMPO-
free radicals and a suitable co-oxidant led to a significant
improvement. Recourse to BAIB as a co-oxidant delivered
cleanly the oxidation product.[35] Unfortunately, fast proto-
destannylation of 23 upon purification or even shelf storage
was observed. Therefore, the crude product was directly
subjected to crotyltitanation conditions with racemic (ꢁ)-2.
The O-enecarbamate (ꢁ)-24 was then converted into termi-
nal alkyne (ꢁ)-25 by tBuLi treatment. After the difficulties
encountered during the oxidation step, it was gratifying to
find that the (Z)-vinyl stannane function was sufficiently
stable toward crotyltitanation conditions and especially
upon tBuLi treatment. Thus, the 12-desmethyl C8–C14 frag-
ment (ꢁ)-24 could be obtained in only four steps, from com-
mercially available 2,3-dihydrofuran 8, in 26.9% overall
yield.
DHF 8 or 9.
Entry Starting Additive
material
Conditions Yield of
(Z)-12 or
(Z)-13
[%]
1
2
3
4
5
6
7
8
8
9
8
8
8
8
8
8
8
8
8
none[a,b]
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 3 h
RT, 12 h
RT, 12 h
61
27
13
46
29
0
none[a,b]
BF3·OEt2 (2.5 equiv)[a,b]
TMSCl (4 equiv)[a,b]
HMPA (5 equiv)[a,b]
DMPU (5 equiv)[a,b]
DMF (20 equiv)[a,b]
TMEDA (10 equiv)[a,b]
pyridine (10 equiv)[a,b]
thiophene (20 equiv)[a,b]
tetrahydro-thiophene
(20 equiv)[a,b]
0
45
16
55
67
9
10
11
12
13
14
8
8
9
DMS (Et2O/DMS 4:1)[b]
none[a,c]
RT, 12 h
RT, 3 h
RT, 12 h
76
22
68
With secured information on the C14 tin function stability
in hand, the stage was set for the synthesis of DHF 9 bear-
ing a methyl group at the C12-position (Scheme 5). Prepara-
DMS (Et2O/DMS 4:1)[b]
[a] THF/Et2O 1:2. [b] MeLi/CuCN. [c] MeMgBr (4 equiv), CuBr·Me2S
(2 equiv). DMPU=N,N’-dimethylpropyleneurea; HMPA=hexamethyl-
phosphoramide.
entry 2). To improve this result, it was decided to investigate
the influence of different reaction parameters. To this end,
the solvent and/or cuprate ligands were modified with
regard to the classical 1:2 THF/Et2O solvent mixture. The
results, from commercial DHF 8 as a model, are summar-
Scheme 5. a) NaCN, DMSO, 608C, 24 h, 92%; b) DIBAL-H, CH2Cl2,
ꢀ788C, 2 h, 82%; c) PTSA, quinoline, 1608C!2458C, 45 min, 85%.
DIBAL-H=diisobutylaluminium hydride.
ꢀ
ized in Table 1. It was envisaged to activate the C O bond
of the dihydrofuran ring by addition of Lewis acids (Table 1,
entries 3–4), to promote organometallic dissociation
(Table 1, entries 5–7) or to modify the cuprate ligands in
presence of TMEDA or pyridine (Table 1, entries 8–9), but
without significant effect. However, the use of sulfur addi-
tives resulted in appreciable yields (Table 1, entries 10–12).
Thereby, a 4:1 mixture of Et2O and DMS (Table 1, entry 12)
allowed the formation of the expected (Z)-alkene 12 in a
satisfactory 76% yield. It was noted, however, that the mag-
nesio-cuprates prepared from MeMgBr and CuBr·Me2S
(Table 1, entry 13), versus cyanocuprates, gave disappointing
results and yields remained below 22%.
tion of DHF 9 was achieved from commercially available
(R)-3-bromo-2-methyl-1-propanol (26). Cyanide displace-
ment of the bromide and partial reduction of the nitrile
function led to lactol 27 after spontaneous cyclization of the
g-hydroxy aldehyde.
After several attempts, a straightforward dehydration with
PTSA in quinoline with simultaneous distillation of the vol-
atile elimination product from the reaction mixture cleanly
afforded the desired DHF 9 in 85% yield (Scheme 5).[36]
This expeditious three-step sequence furnished the enantio-
pure DHF 9 in 64% overall yield.
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J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
Application of optimized conditions to DHF 9 led to the
(Z)-tin derivative 13 in a substantial 68% yield (Table 1,
entry 14).
followed by crotyltitanation delivered the required Felkin–
Anh homoallylic alcohols 29 in 42% yield and a minor dia-
stereomer 31 in 14% yield. At this stage of the synthesis, it
is important to point out that these C12-epimeric com-
pounds 29/31 were easily separated by flash chromatogra-
phy.
From carbamate 29, a-elimination reaction upon a tBuLi
treatment and subsequent C11 secondary alcohol protection
as the methoxymethyl ether furnished alkyne 32 (Scheme 8).
Subunit 32 was obtained in eight steps in 13.9 or 26.3%
yields, respectively, from pentenoate (ꢁ)-30 (with a kinetic
resolution step) or enantiopure propanol 26. However,
taking into account the cost of the starting material 26 and
the convenient separation of the C12-epimeric compounds,
we preferred using the racemic DHF (ꢁ)-9 to produce C8–
C14 subunit 32 on a multigram scale.
We developed a useful and efficient dimethylsulfide-pro-
moted methyl transfer in the 1,2-cuprate rearrangement
leading to (Z)-trisubstituted olefins. With an efficient supply
of alkene 13 being assured, the synthesis of the C8–C14 sub-
unit B was tackled. In agreement with the model C12-des-
methyl series, compound 13 was converted to carbamate 29
as a single diastereomer in 87% yield after oxidation to al-
dehyde 28 with TEMPO/BAIB and crotyltitanation
(Scheme 7). To confirm the (S)-C11 secondary hydroxy
center configuration, 29 was derivatized to the (R)- and (S)-
a-methoxy-phenylacetic acid (MPA) ester (see the Experi-
mental Section for details).[37]
The synthesis of the C15–C24 subunit A started with the
C16–C18 syn–syn motif preparation, planned by a substrate-
based crotylation reaction. The addition of the achiral tri-
nbutylcrotylstannane on chiral aldehyde 15 under Keckꢃs
conditions (BF3·OEt2 in CH2Cl2),[38] led to a 85:15 mixture
of diastereomers 33 and 34. Felkin–Anh selectivity was opti-
mized to 95:5 when replacing CH2Cl2 by Et2O and perform-
ing the reaction at a lower temperature (Scheme 9). Howev-
Scheme 7. a) TEMPO (10 mol%), BAIB, CH2Cl2, RT, 2 h; b) (R)-2, cy-
clohexane/pentane 1:7, ꢀ788C, 3 h, 87% (2 steps, a and b).
DHF 9 was also prepared in racemic form. After some ex-
perimentation, it was found that the most effective approach
started from commercially available ethyl 2-methyl-4-pente-
noate ((ꢁ)-30) (Scheme 8). Reduction of ester function fol-
lowed by ozonolysis of the terminal double bond and dehy-
dration of the corresponding lactol led to the desired DHF
(ꢁ)-9. Oxidation of the 1,2-cuprate transfer product (ꢁ)-13
Scheme 9. a) Tri-n-butylcrotylstannane, BF3·OEt2, Et2O, ꢀ1008C, 2 h,
74%, d.r. 95:5; b) (Z)-2-butene, nBuLi, tBuOK, [(ꢀ)-Ipc]2BOMe,
BF3·OEt2, 65%, d.r. 100:0; c) TBSOTf, 2,6-lutidine, CH2Cl2, 08C!RT,
2 h, 92%; d) DDQ, CH2Cl2/H2O 95:5, 08C!RT, 2 h, 75%; e) O3, Sudan
III, Py, CH2Cl2/MeOH 1:1, ꢀ788C, 2 h then DMS, ꢀ788C!RT, over-
night; f) (R)-2, cyclohexane/pentane 1:7, ꢀ788C, 3 h, 77%, d.r. 100:0.
Ipc=isopinocampheyl, Py=pyridine.
er, large-scale production of 33 was impeded by difficulties
associated with diastereomer separation. This difficulty was
readily overcome by using the chiral crotylborane procedure
developed by Brown.[39] The desired homoallylic alcohol 33
was cleanly formed in a stereospecific manner from the (Z)-
crotyldiisopinocampheylborane reagent derived from (ꢀ)-
Scheme 8. a) LAH, Et2O, 0 8C!RT, 3 h; b) O3, Sudan III, CH2Cl2/MeOH
1:1, ꢀ788C, 7 h then PPh3, ꢀ788C!RT, overnight, 80% (2 steps, a and
b), anomeric ratio 2:1; c) PTSA, quinoline, 160!2458C, 45 min, 85%;
d) tBuLi, Me2CuLi·LiCN, Et2O/DMS 4:1, 08C!RT, 18 h, then nBu3SnCl,
ꢀ308C!RT, 5 h, 68%; e) TEMPO (10 mol%), BAIB, CH2Cl2, RT, 2 h;
f) (R)-2, cyclohexane/pentane 1:7, ꢀ788C, 3 h, compound 29 42%
(2 steps, e and f), compound 31 14% (2 steps, e and f; g) tBuLi, THF,
ꢀ40!ꢀ208C, 20 min, 78%; h) MOMCl, TBAI, Hunigꢃs base, CH2Cl2,
RT, 18 h, 92%. DMS=dimethyl sulfide; Hunigꢃs base=diisopropylethyl-
amine; LAH=lithium aluminum hydride; MOM=methoxymethyl;
TBAI=tetra-n-butylammonium iodide.
Ipc2BACTHNUTRGENUG(N OMe).
The absolute configuration of the stereogenic centers of
33 was confirmed by chemical correlation. Cleavage of the
PMB moiety was accomplished to provide the known triol
36. The NMR spectroscopic data and the specific optical ro-
tation were in agreement with the literature.[40]
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Total Synthesis of Discodermolide
FULL PAPER
For the construction of the second C18–C20 syn–anti ste-
reotriad, we selected a crotyltitanation reaction. After pro-
tection of the C17 hydroxy group of 33 as TBS ether, an oxi-
dative cleavage of corresponding alkene 35 by ozonolysis
delivered the aldehyde 37. When the crotyltitanation reac-
tion was realized with the chiral, non-racemic (R)-2, the de-
sired isomer 38 was provided in 77% yield with total stereo-
control.
On the basis of extensive precedent, we predicted that the
unique isomer from this addition would be the C18–C20
syn–anti stereoisomer 38. This assignment was confirmed by
applying the Rychnovsky method[41] and analysis of the
1H NMR vicinal coupling constants of the corresponding
acetonides (see the Experimental Section for details).
Application of this crotyltitanation reaction was also in-
strumental in the preparation of the required terminal (Z)-
diene. As previously described by our group,[11] the direct vi-
nylation of a (Z)-O-enecarbamate moiety was carried out in
nylmagnesium bromide solution was unreliable for this
cross-coupling. Furthermore, even with the same batch, the
selectivity between the cross-coupled product and the re-
duced compound decreased during the time of storage. We
decided to prepare ourselves the vinylmagnesium bromide.
Three methods were explored. First, direct insertion of mag-
nesium into vinyl bromide[42] led to reliable results but with
a modest selectivity in favor of the desired compound 40,
that is, 80:20 (Table 2, entry 2). The vinylmagnesium reagent
was also generated in situ, by transmetallation of the vinyl-
lithium derivative with magnesium bromide.[43] When the vi-
nyllithium was produced from vinyl bromide by metal–halo-
gen exchange,[44] no reaction occurred (Table 2, entry 3). On
the other hand, the preparation of the vinyllithium from tet-
ravinyltin and MeLi,[45] cleanly afforded the cross-coupled
product 40 in modest yield (Table 2, entry 4).
The reaction with solely vinyllithium species (without
magnesium salts) produced from tetravinyltin and MeLi,[45]
led to a significant improvement (Table 2, entry 5). This
method allowed the selective formation of the cross-coupled
product 42 in a reproducible 80% yield (no reduction prod-
uct was recovered). Use of tetravinylstannane and MeLi al-
lowed the scaling up the cross-coupling reaction to 2.5 g. To
the best of our knowledge, it is the first example of a C-
the presence of [NiACHTUNGTRENNUNG(acac)2] with commercially available vi-
nylmagnesium bromide. In this way, from carbamate 39, this
reaction gave highly variable but mostly disappointing low
yields (Scheme 10, see Table 2 entry 1). The cross-coupled
product 40 was generated solely or as a mixture with the
corresponding inseparable reduced compound 41 (selectivity
varying from 100:0 to 0:100). The quality of commercial vi-
ACHUTNGRENNUG CAHTUNGTRENNUGN
(sp2)–C(sp2) cross-coupling between a vinyllithium and a vi-
nylic electrophilic species.[46]
To achieve the synthesis of subunit 43, the PMB ether was
removed by treatment with DDQ and the resulting alcohol
42 was transformed into alkyl iodide 43 under optimized
Garegg conditions in a benzene/diethyl ether mixture under
high dilution.[47] The C15–C24 subunit 43, bearing five con-
tiguous stereogenic centers and a terminal diene, was ob-
tained in 13.7% overall yield for 11 steps.
Our initial approach to the synthesis of the third building
block C1–C7 C started with standard Brown crotylation of
aldehyde 44 (derived from (S)-Roche ester 14), to afford the
desired syn–anti homoallylic alcohol 45 in 76% yield
(Scheme 11). It was envisaged to rely upon a substrate-di-
rectable epoxidation/oxirane regioselective ring-opening se-
quence for the installation of the missing C5 chiral center.
The epoxidation of homoallylic alcohol 45 turned out to be
more difficult than expected. The use of mCPBA,
Scheme 10. a) TESOTf, 2,6-lutidine, CH2Cl2, 08C!RT, 1.5 h, 76%;
b) [NiACHTUNGTRENNUNG(acac)2], Et2O, 0 8C, overnight, vinylmagnesium bromide, see
[Mo(CO)6]/TBHP[48] or [VO
more than 40% selectivity, whereas recourse to [VO-
AHCTUNGTRENNUNG
(acac)2]/TBHP[49] led to a significant improvement (78%
ACHTUNGTNER(NNUG OiPr)3]/TBHP never gave
Table 1; c) DDQ, CH2Cl2/H2O 95:5, 08C!RT, 40 min, 72%; d) I2, PPh3,
imid, C6H6/Et2O, 0 8C!RT, 2 h, 79%. acac=acetylacetonate; imid=imi-
dazole.
yield of oxiranes 46 and 47 as a 90:10 mixture of separable
diastereomers). However, upon attempted optimization and
scaling up, this reaction was not reproducible. Pure 46 was
then subjected to a regioselective ring opening by a cyano-
Gilman divinyl cuprate, (CH2=CH)2CuLi·LiCN,[50] to ensure
the formation of the alkene 48 in 86% yield. Finally, cleav-
age of the OBn group with lithium in liquid ammonia fol-
lowed by silylation afforded the C1–C7 subunit 49.
An alternative route allowed the generation of the C5
chiral center by hetero-Michael addition on a,b-unsaturated
Weinreb amide 53, which in turn could be derived from al-
dehyde 50 through a crotyltitanation reaction and homolo-
Table 2. Results of direct vinylation of a (Z)-O-enecarbamate by a [Ni-
ACHTUNGTRENNUNG
Yield [%][a]
[b]
ꢀ
1
2
3
4
5
CH2=CH MgBr
100!0 0!100 35!80
ꢀ
CH2=CH Br, Mg
CH2=CH Br, tBuLi, MgBr2·OEt2
(CH2=CH)4Sn, MeLi, MgBr2·OEt2 100
(CH2=CH)4Sn, MeLi
80
–
20
–
65
[c]
ꢀ
–
G
0
50[d]
80
C
100
0
[a] Isolated yield of the 40 and 41 mixture. [b] Commercial reagent.
[c] Only the starting material was recovered. [d] 10% of starting material
was recovered.
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11097

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
ic reasons. Thus, the vinylic function of compound 51 was
deoxygenated by hydride reduction with iso-propylmagnesi-
um chloride in a nickel-catalyzed reaction to furnish 52.[52]
More surprisingly, the CM reactions between N-methoxy-N-
methylacrylamide or methyl acrylate and terminal olefinic
compound 52 failed when using Grubbs 2nd-generation or
Hoveyda catalyst. Gratifyingly, a two-step sequence involv-
ing an oxidative cleavage of the double bond, followed by a
Horner–Wadsworth–Emmons reaction (HWE) with com-
mercially available diethyl (N-methoxy-N-methylcarbamoyl-
methyl)phosphonate, gave the a,b-unsaturated Weinreb
amide 53. Reaction of 53 with benzaldehyde mediated by
KHMDS afforded benzylidene 54 in 79% yield with an ex-
cellent diastereoselectivity (d.r.>95:5).[53] After reduction of
54 into aldehyde 55 by treatment with DIBAL-H,[54] the last
C1–C7 subunit, bearing four stereocenters, was obtained in
32.7% overall yield for eight steps.
Scheme 11. a) CCl3C(N)OBn, TfOH (5 mol%), CH2Cl2/cyclohexane 1:2,
08C!RT, 40 h, 84%; b) LAH, THF, 08C!RT, 3 h, 94% c) IBX, DMSO,
RT, 3 h, 92%; d) (E)-2-butene, nBuLi, tBuOK, [(ꢀ)-Ipc]2BOMe,
BF3·OEt2, 76%, d.r. 90:10; e) [VOACHTUNGRTNEUNG(acac)2], TBHP, CH2Cl2, 78%, d.r.
ꢀ
90:10; f) CH2=CH Br, tBuLi, CuCN, THF, ꢀ78!08C, overnight, 86%;
g) Li, NH3, THF, ꢀ788C, 1 h; h) TBSOTf, 2,6-lutidine, CH2Cl2, 08C!RT,
3 h, 99% (2 steps, g and h). TBHP=tert-butyl hydroperoxide.
Completion of the total synthesis of discodermolide: With
access to the required fragments now reliable, the stage was
set for the coupling. The first coupling reaction involved an
addition of the C8–C14 acetylenic compound 32 to C1–C7
aldehyde 55 (Scheme 13). Previous observations on the sta-
gation (Scheme 12). Thus, crotyltitanation of aldehyde 50
(which was prepared from (S)-Roche ester 14) cleanly led to
the syn–anti homoallylic alcohol 51. A cross-metathesis
(CM) reaction between alkene 51 and N-methoxy-N-methyl-
acrylamide was tested.[51] None of the desired product was
formed and most of the starting material was recovered. We
suspected that the N,N-diisopropyl-O-enecarbamate func-
tion could have deleterious effects for steric or/and electron-
Scheme 13. a) 32, tBuLi, THF, ꢀ788C, 30 min, then 55, ꢀ78!08C, 3 h,
50%, d.r. 1:2.
bility of the sterically hindered trisubstituted (Z)-vinyl stan-
nane provided encouraging precedent with regard to the
chemoselectivity issue. Although the lithiated acetylide of
32 was chemoselectively produced by action of tBuLi at low
temperature, its reaction with aldehyde 55 afforded a 2:1
mixture of separable C7 diastereomers 56 and 57 in a
modest 50% yield.
To assign the C7 stereochemistry of both these epimers,
each C7 isomeric secondary alcohol was independently sub-
jected to the formation of (R)- and (S)-MPA ester deriva-
tives (see the Experimental Section for details). To our sur-
prise, the desired and expected 5,7-anti diol 56 was the
minor product (Scheme 13).[55]
Scheme 12. a) TBSCl, imid, DMF, RT, 3 h, 94%; b) DIBAL-H, CH2Cl2,
ꢀ208C, 30 min, 92%; c) (COCl)2, DMSO, Et3N, ꢀ558C!RT, 1 h; d) (R)-
2, cyclohexane/pentane 1:7, ꢀ788C, 3 h, 66% (2 steps, c and d); e) [Ni-
ACHTUNGTRENNUNG(acac)2] (10 mol%), iPrMgBr, THF, RT overnight, 50%; f) O3, Sudan III,
CH2Cl2, ꢀ788C, 1 h, then PPh3, ꢀ788C!RT, 3 h, 87%;
g) (EtO)2P(O)CH2C(O)NMe
G
A more appropriate solution was found with the addition
of acetylenic derivative 32 to Weinreb amide 54 followed by
h) PhCHO, KHMDS, THF, ꢀ208C, 45 min, 79%; i) DIBAL-H, CH2Cl2,
ꢀ788C, 1 h, 93%.
11098
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
stereoselective reduction of ynone 58 (Scheme 14). Prelimi-
nary assays were conducted by using tBuLi as a metallating
agent and afforded cleanly the desired adduct 58 in 80%
yield. However, upon attempted optimization and scale up,
Scheme 14. a) 32, nBuLi/Et2O, THF, ꢀ408C, 50 min, then 54, ꢀ40!
>08C, 1 h, 81%; b) (S)-(ꢀ)-2-methyl-CBS-oxazaborolidine, BH3·Me2S,
THF, ꢀ308C, 2 h, 95%, d.r. 98:2. CBS=Corey–Bakshi–Shibata.
Scheme 15. a) MOMCl, TBAI, Hunigꢃs base, CH2Cl2, RT, 18 h, 86%;
b) HF/Py, Py/THF, RT, 4 h, 96%; c) TEMPO (10 mol%), BAIB, CH2Cl2,
RT, 3 h; d) NaClO2, NaH2PO4, 2-methyl-but-2-ene, tBuOH/H2O, RT, 1 h ;
e) TMSCHN2, C6H6/MeOH, RT, 15 min, 66% (3 steps, c–e); f) H2, PtO2
(30 mol%), AcOEt, RT, 12 h; g) I2, CH2Cl2, 08C, 10 min, 71% (2 steps, f
and g); h) 43, tBuLi, Et2O, ꢀ788C, 5 min, B-methoxy-9-BBN, THF,
this reaction was not reproducible. During these initial at-
tempts, however, it was noticed that Weinreb amide 54 was
totally consumed with the production of a significant
amount of benzaldehyde, which indicated a probable retro-
hetero-Michael reaction, followed by a vinylogous retro-
aldol reaction. After careful optimization, it was found that
this addition reaction proceeded best when using a solution
of nBuLi generated by treatment of butyl bromide by lithi-
um metal in Et2O,[56] whereas protocols involving commer-
cial nBuLi, LDA, or LiHMDS did not bring any significant
improvement. This procedure led cleanly and faster to the
desired ynone 58 in a reliable 81% yield. Subsequent re-
agent-controlled stereoselective reduction of 58 with (S)-
CBS reagent[57] provided alcohol 56 in high yield (95%) and
diastereoselectivity (d.r.>98:2).
The coupling of the two C1–C7 and C8–C14 fragments
now in hand required the consecutive formation of vinyl
iodide 60, in view of an alkyl-Suzuki reaction with the C15–
C24 subunit 43. Alcohol 56 was smoothly converted to
methyl ester 59 by a two-step MOM-protection reaction and
TBS-ether cleavage protocol followed by oxidation of the
resulting alcohol and esterification (Scheme 15). Subsequent
standard Lindlar hydrogenation of the alkyne 59 seemed op-
timal relative to the discodermolide C8=C9 semi-reduction
cases previously reported in the literature.[4] However, this
reduction only resulted in recovery of the starting material.
After some experimentation, it was found that the reaction
preceded best when using a PtO2 protocol without overre-
duction. Consecutive iododestannylation furnished the de-
sired (Z)-vinyl iodide 60 in 71% for two steps.
ꢀ788C!RT, then 60, Cs2CO3, [PdCl2CAHTUNGTREN(UNNG dppf)], AsPh3, DMF, H2O, 18 h,
60%; i) PSA, MeOH, 08C, 1 h, 77%; j) Cl3CC(O)NCO, CH2Cl2, RT,
15 min, then K2CO3, MeOH, RT, 1.5 h, 64%; k) HCl 4n, THF, RT, 72 h,
70%. BBN=borabicycloACTHNUTRGNE[NUG 3.3.1]nonane; dppf=(diphenylphosphino)ferro-
cene.
Selective cleavage of the C19 TES-ether followed by reac-
tion with trichloroacetylisocyanate furnished the corre-
sponding carbamate.[59] Final total deprotection with con-
comitant lactonization by following the procedure estab-
lished in the previous total syntheses[4] afforded discodermo-
lide 1 in 70% yield. The spectroscopic and analytical data of
the synthetic samples of 1 and their in vitro cytotoxicity
levels were in full accord with those of the natural product
reported in the literature.
Conclusions
The investigation outlined above resulted in a total synthesis
of the anticancer marine metabolite discodermolide (1) in
1.6% overall yield for 21 linear steps. The chosen approach
bears witness to the maturity of the crotyltitanation reaction
with an enantiomerically defined secondary crotyltitane re-
agent. The repeated application of this reaction yielded ho-
moallylic (Z)-O-enecarbamate alcohols 16, 29, 38, and 51
with excellent diastereoselectivity. Moreover, advantage was
taken of these alkenyl carbamates to form the next carbon–
carbon bond. Particularly notable is the direct construction
of the terminal C21–C24 (Z)-diene 40, with high geometric
control, utilizing an original cross-coupling nickel-catalyzed
reaction. Another highlight of our strategy was the 1,2-cup-
rate rearrangement of the dihydrofuran 9 leading to the ste-
reocontrolled building of the C13=C14 trisubstituted (Z)-
alkene 13 with total selectivity.
The stage was set for the coupling of the vinyl iodide 60
and C15–C24 subunit 43. An alkyl-Suzuki reaction was per-
formed according to the Marshall et al. procedure,[58] by
using trialkyl boronate species prepared from alkyl iodide
43 with tBuLi and B-methoxy-9-BBN under [PdCl2ACTHNUTRGNEU(GN dppf)]
and AsPh3 conditions to afford the discodermolide back-
bone 60 in 60% yield.
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11099

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
CH3), 1.60–1.40 (m, 6H; 3CH2), 1.39–1.20 (m, 6H; 3CH2), 1.02–0.84 ppm
(m, 15H; 3CH2, 3CH3).
For the key steps employed en route to 1, the most signifi-
cant problems were posed by the methyl transfer during the
C13=C14 trisubstituted (Z)-double bond installation and the
construction of the middle C8–C14 fragment in two sequen-
tial stages (dyotropic rearrangement/crotyltitanation). After
careful optimization, these reactions allowed high and relia-
ble yields. Hence, this study illustrates the notion that the
total synthesis of complex target molecules remains the ulti-
mate test for the performance, scope and limitations of any
newly development methodology.
(1Z,6Z,3R/S,4R/S)-1-[(N,N-Diisopropyl)carbamoyloxy]-4-hydroxy-3-
methyl-7-(tributylstannyl)oct-1,6-diene ((ꢁ)-24):
A solution of nBuLi
(1.6m in hexane, 44 mL, 70.0 mmol, 2.04 equiv) was added to a quick-
stirred solution of the (E)-crotyl (diisopropyl)carbamate (11.7 g,
59.0 mmol, 2.0 equiv) and TMEDA (6.8 g, 59.0 mmol, 2.0 equiv) in Et2O
(70 mL) at ꢀ788C. After 30 min at ꢀ788C, Ti
ACHTUNGTERN(NUNG OiPr)4 (52.0 mL,
176.0 mmol, 6.0 equiv) was quickly added by cannula to the reaction mix-
ture of lithio carbamate, which turned orange. After 30 min at ꢀ788C, al-
dehyde 23 (10.9 g, 29.3 mmol, 1.0 equiv) in Et2O (15 mL) was slowly
added to the orange solution, and the mixture was stirred for 3 h at
ꢀ788C. The solution was then poured into a mixture of Et2O-saturated
aqueous NH4Cl solution. After extraction with Et2O, the organic layer
was washed with brine, dried over MgSO4, filtered, and the solvent was
removed under reduced pressure. The residue was purified by chroma-
tography on silica gel (cyclohexane/Et2O 95:5 to 60:40) to give the title
compound (ꢁ)-24 (7.4 g, 44% for 2 steps). 1H NMR (400.0 MHz,
The strategy is flexible enough to accommodate systemat-
ic structural variations and, therefore, to provide novel dis-
codermolide structural analogues.
CDCl3): d=7.12 (d, J=6.4 Hz, 1H), 6.10 (ddq, J=5.9, 5.5, 1.4, J1H,117
=
Sn
Experimental Section
J1H,119Sn =131.0 Hz, 1H), 4.67 (dd, J=9.9, 6.4 Hz, 1H), 4.19–4.11 (brs,
1H), 3.80–3.75 (brs, 1H), 3.51 (dddd, J=8.6, 5.0, 3.4, 3.0 Hz, 1H), 2.81
(ddq, J=9.9, 8.6, 7.3 Hz, 1H), 2.30–2.15 (m, 1H), 2.10–2.06 (m, 1H), 1.92
(d, J=1.4, J1H,117Sn =J1H,119Sn =41.7 Hz, 3H; CH3), 1.78 (brd, J=3.0 Hz, 1H;
OH), 1.58–1.38 (m, 6H; 3CH2), 1.38–1.17 (m, 18H; 3CH2, 4CH3), 1.07
(d, J=7.3 Hz, 3H; CH3), 0.96–0.85 ppm (m, 15H; 3CH2, 3CH3);
General: All reactions were carried out in oven or flame-dried glassware
under an argon atmosphere by employing standard techniques in han-
dling air-sensitive materials. All solvents employed were reagent grade.
THF and diethyl ether (Et2O) were freshly distilled from sodium/benzo-
phenone under nitrogen immediately prior to use. Dichloromethane, cy-
clohexane and pentane were freshly distilled over calcium hydride. All
other reagents were used as supplied. Reactions were magnetically
stirred and monitored by TLC with 0.20 mm SDS 60F254 pre-coated
silica-gel plates. Visualization was accomplished with UV light then treat-
ment with a 10% ethanolic phopshomolybdic acid solution followed by
heating. Flash chromatography was performed with silica gel 60 (particle
size 0.040–0.063 mm) supplied by SDS. Yield refers to chromatography
and spectroscopically pure compounds, unless otherwise noted. 1H NMR
spectra were recorded by using an internal deuterium lock at ambient
temperature on a JEOL JNM-ECX 270 or 400 MHz spectrometer. Inter-
nal references of dH =7.26 and 1.96 ppm were used for CDCl3 and
CD3CN, respectively. Spectroscopic data are represented as follows:
chemical shift (in ppm), multiplicity (s=single, d=doublet, t=triplet,
q=quartet), integration, coupling constant (J/Hzꢀ1). 13C NMR spectra
were recorded on a Jeol 67.5 or 100.5 MHz spectrometer. Internals refer-
ences of dC =77.16 and 118.26 ppm were used for CDCl3 and CD3CN, re-
spectively. IR spectra were recorded on a Nicolet Impact-400 and wave-
length (n˜) is given in cmꢀ1. Mass spectra were recorded on a GC/MS cou-
pling unit with a MSD 5973 spectrometer and a Hewlett–Packard HP-
GC 6890 chromatograph. Ionization was obtained either by electronic
impact (EI) or chemical ionization with methane (CI, CH4). Mass spec-
tral data are reported as m/z. Optical rotations were recorded on a Jasco
13C NMR (100.5 MHz, CDCl3): d=152.3 (C), 141.9 (C), 136.4 (J
=
13C,117Sn
J
Sn =28.1 Hz; CH), 135.3 (CH), 111.9 (CH), 74.1 (CH), 45.4 (CH),
13C,119
45.2 (CH), 39.6 (J
Sn =J
13C,117
Sn =30.7 Hz; CH2), 35.4 (CH), 28.8
13C,119
(J
Sn =J
13C,117
Sn =19.2 Hz; 3CH2), 27.5 (J
13C,119
Sn =J
13C,117
Sn =56.5 Hz;
13C,119
3CH2), 26.8 (J
Sn =J
13C,117
Sn =46.0 Hz; CH3), 21.1 (2CH3), 20.3 (2CH3),
13C,119
17.0 (CH3), 13.2 (3CH3), 9.6 ppm (J
Sn =313.4,
13C,117
J
Sn =326.8 Hz;
13C,119
3CH2); IR (film): n˜ =3470, 2957, 2925, 2872, 2855, 1712, 1705, 1679, 1642,
1456, 1444, 1371, 1306, 1211, 1147, 1134, 1065, 1001, 961, 903, 885, 865,
762 cmꢀ1
.
(3R/S,4R/S,6Z)-4-Hydroxy-3-methyl-7-(tributylstannyl)oct-6-en-1-yne
((ꢁ)-25): A solution of tBuLi (1.5m in pentane, 27.2 mL, 40.8 mmol,
3.0 equiv) was slowly added to a solution of the preceding carbamate
(ꢁ)-24 (8.4 g, 13.6 mmol, 1.0 equiv) in Et2O (100 mL) at ꢀ408C. The so-
lution was stirred for 20 min at ꢀ208C and was then quenched by the ad-
dition of a saturated aqueous NH4Cl solution, and extracted with Et2O.
The combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
residue was purified by chromatography on silica gel (cyclohexane/Et2O
90:10 to 80:20) to give (ꢁ)-25 (4.7 g, 78%). 1H NMR (270.0 MHz,
CDCl3): d=6.00 (ddq, J=7.7, 6.5, 1.7, J1H,117Sn =J1H,119Sn =129.0 Hz, 1H),
3.47–3.42 (m, 1H), 2.54 (qdd, J=6.9, 4.0, 2.6 Hz, 1H), 2.26 (m, 1H), 2.16
(m, 1H), 2.14 (d, J=2.3 Hz, 1H), 1.86 (d, J=1.7, J1H,117Sn =J1H,119
=
Sn
P-1010 digital polarimeter at 589 nm and are reported as follows: [a]D20
,
41.6 Hz, 3H; CH3), 1.50–1.33 (m, 6H; 3CH2), 1.32–1.11 (m, 10H; 1OH,
1CH3, 3CH2), 0.98–0.74 ppm (m, 15H, 3CH2, 3CH3); 13C NMR
concentration (c in g100 mL), and solvent. Elemental analysis were per-
formed on a CHN 240 Perkin–Elmer instrument by the Service de Micro-
analyses, Centre d’Etudes Pharmaceutiques, Chatenay-Malabry, F-92296.
HRMS were obtained on a Thermo-Electron MAT-95 spectrometer in
the ICMMO, Mass Spectrometry Laboratory, Orsay University, 91405
Orsay. IUPAC nomenclature was used for all compounds. RN refers
CAS registration numbers. See Supporting Information for further exper-
imental procedures.
(67.5 MHz, CDCl3): d=142.8 (C), 136.1 (J
Sn =J
13C,117
Sn =26.8 Hz; CH),
13C,119
85.1 (C), 74.0 (CH), 71.0 (CH), 40.1 (CH2), 32.2 (CH), 29.2 (J
=
13C,117Sn
J
Sn =19.5 Hz; 3CH2), 27.4 (J
13C,119
Sn =J
13C,117
Sn =56.2 Hz; 3CH2), 17.3
13C,119
(CH3), 13.7 (3CH3), 9.6 ppm (J
Sn =314.4, J
13C,117
Sn =328.8 Hz; 3CH2);
13C,119
IR (film): n˜ =3311, 2956, 2926, 2871, 2854, 1712, 1463, 1376, 1260, 1192,
1072, 1039, 960 cmꢀ1
.
(2R/S,4R/S)-4-Methyltetrahydrofuran-2-ol ((ꢁ)-27): A solution of com-
mercial ethyl 4-methylpentenoate (ꢁ)-30 (30 g, 211 mmol, 1.0 equiv) in
Et2O (200 mL) was added to a solution of LiAlH4 (6.4 g, 169 mmol,
0.8 equiv) in Et2O (100 mL) at 08C over 30 min. After the reaction mix-
ture had been stirred for 4 h at 208C, the mixture was cooled at 08C and
H2O (6.5 mL), an aqueous NaOH 15% solution (6.5 mL), and further
H2O (19.5 mL) were added successively. The mixture was stirred for 2 h,
and filtered through a pad of Celite. The filtrate was dried over MgSO4
and the solvent was removed under reduced pressure. The crude 2-meth-
ylpent-4-en-1-ol was directly used in the next step. 1H NMR (400.0 MHz,
CDCl3): d=5.75 (dddd, J=17.0, 10.1, 7.3, 6.9 Hz, 1H), 4.97 (dd, J=17.0,
1.4 Hz, 1H), 4.94 (dd, J=10.1, 1.4 Hz, 1H), 3.55 (ddd, J=6.9, 6.0, 4.6 Hz,
1H), 3.45 (ddd, J=6.4, 6.0, 4.6 Hz, 1H), 2.10 (ddd, J=8.2, 6.9, 6.0 Hz,
(3Z)-4-(Tributylstannyl)pent-3-en-1-al (23): BAIB (10.4 g, 32.2 mmol,
1.1 equiv) was added to a solution of alcohol 12 (11.0 g, 29.3 mmol,
1.0 equiv) and TEMPO (457 mg, 2.93 mmol, 0.1 equiv) in CH2Cl2
(100 mL). The mixture was stirred until the starting material had disap-
peared (2 h). After this time, the mixture was diluted with cyclohexane,
washed with an aqueous saturated Na2S2O3 solution and extracted with
cyclohexane. The combined organic phases were washed with a saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, and the solvent
was removed under reduced pressure. The crude aldehyde 23 was directly
used in the next step. 1H NMR (400.0 MHz, CDCl3): d=9.67 (t, J=
2.1 Hz, 1H), 6.16 (tq, J=7.3, 1.9, J1H,117Sn =J1H,119Sn =122.1 Hz, 1H), 2.89
(dd, J=7.3, 2.1 Hz, 2H), 1.98 (d, J=1.9, J1H,117Sn =J1H,119Sn =38.9 Hz, 3H;
11100
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
1H), 1.88 (ddd, J=8.2, 7.3, 6.4 Hz, 1H), 1.66 (quinttd, J=6,9, 6.4, 6.0 Hz,
1H), 1.40 (t, J=4.6 Hz, 1H; OH), 0.85 ppm (d, J=6.9 Hz, 3H; CH3);
13C NMR (100.5 MHz, CDCl3): d=136.9 (CH), 116.0 (CH2), 67.7 (CH2),
37.7 (CH2), 35.5 (CH), 16.3 ppm (CH3); MS (GC, EI): m/z: 82 [Mꢀ18]+,
67, 58.
(dd, J=8.7, 6.4 Hz, 1H), 3.03 (dqdt, J=9.6, 6.9, 6.4, 2.3 Hz, 1H),
1.07 ppm (d, J=6.9 Hz, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=
145.3 (CH), 106.6 (CH), 76.8 (CH2), 36.6 (CH), 20.8 ppm (CH3).
Preparation of (ꢁ)-9: (ꢁ)-9 was obtained from racemic lactol (ꢁ)-27
using the procedure described for the preparation of 9 from lactol 27.
A stream of ozone was bubbled into a solution of the preceding 2-
methyl-pent-4-en-1-ol (24.2 g, 241.5 mmol, 1.0 equiv) and Sudan III
(small amount) in CH2Cl2/MeOH (1:1, 200 mL) at ꢀ788C until the pink
solution became colorless (ca. 7 h). Then PPh3 (63.3 g, 241.5 mmol,
1.0 equiv) was cautiously added (over 30 min), the cold bath was re-
moved and the mixture was stirred at 208C for one night. After this time,
the solvents were removed under reduced pressure (20 mmHg) and the
product was distilled out of the reaction mixture by using a microdistilla-
tion apparatus under reduced pressure (0.2 mmHg) at 708C to give lactol
(ꢁ)-27 (19.7 g, 80%) as a colorless oil and a 1:2 mixture of two diaste-
reomers. RN: 34314-85-7; first anomer: 1H NMR (400.0 MHz, CDCl3):
d=5.46 (d, J=5.0 Hz, 1H), 4.09 (t, J=7.8 Hz, 1H; Ha-11), 3.32 (dd, J=
7.8, 7.3 Hz, 1H; Hb-11), 2.80 (brs, 1H; OH), 2.24 (dddqd, J=9.2, 7.8, 7.3,
6.9, 6.9 Hz, 1H), 1.97 (dd, J=12.8, 6.9 Hz, 1H), 1.51 (ddd, J=12.8, 9.2,
5.0 Hz, 1H), 1.03 ppm (d, J=6.9 Hz, 3H; CH3); second anomer:
1H NMR (400.0 MHz, CDCl3): d=5.46 (d, J=4.6 Hz, 1H), 3.95 (dd, J=
8.2, 6.6 Hz, 1H), 3.55 (dd, J=8.7, 8.2 Hz, 1H), 2.92 (brs, 1H; OH), 2.58–
2.48 (m, 1H), 1.76–1.70 (m, 1H), 1.47–1.40 (m, 1H), 1.09 ppm (d, J=
6.4 Hz, 3H; CH3); first anomer: 13C NMR (100.5 MHz, CDCl3): d=98.9
(CH), 74.4 (CH2), 41.8 (CH2), 31.4 (CH), 17.8 ppm (CH3); second
anomer: 13C NMR (100.5 MHz, CDCl3): d=99.4 (CH), 73.5 (CH2), 41.8
(CH2), 33.3 (CH), 17.3 ppm (CH3); IR (film): n˜ =3406, 2960, 2935, 2875,
1455, 1379, 1346, 1290, 1122, 1095, 1056, 1002, 927 cmꢀ1; MS (GC, EI):
m/z: 101, 84, 72, 56.
AHCTUNGTERG(NNUN 2S,3Z)-2-Methyl-4-tributylstannyl-pent-3-en-1-ol (13): MeLi (1.6m solu-
tion in Et2O, 94.4 mL, 151.0 mmol, 5.0 equiv) was added to a suspension
of CuCN (5.41 g, 60.4 mmol, 2.0 equiv) in dry Et2O (10 mL) and DMS
(40 mL) at ꢀ308C. The solution was stirred at ꢀ308C for 5 min and then
allowed to warm up to 08C for 20 min (pale-yellow color). tBuLi (1.5m
solution in pentane, 24.2 mL, 36.2 mmol, 1.2 equiv) was added to a solu-
tion of dihydrofuran 9 (2.54 g, 30.2 mmol, 1.0 equiv) in dry Et2O (50 mL)
at ꢀ608C. The mixture was stirred at 08C for 50 min. After this time, the
solution of the lithio-dihydrofuran prepared above was added by cannula
to the cyanocuprate (Et2O/DMS 4:1) and the reaction mixture was al-
lowed to warm up to 208C (strong orange color) over 12 h. The mixture
was cooled at ꢀ308C and tri-n-butyltin chloride (49.1 mL, 181.2 mmol,
5.0 equiv) was added. The reaction mixture was allowed to warm up to
208C over 5 h. Finally, the reaction mixture was poured into a mixture of
a saturated aqueous NH4Cl solution and concentrated ammonia (4:1) at
08C and stirred for 1 h at 208C before extraction with Et2O. The organic
layer was washed with water and brine, dried over MgSO4, and the sol-
vent was removed under reduced pressure. The crude residue was puri-
fied by chromatography on silica gel (cyclohexane/Et2O 100:0 to 60:40)
to give the title compound 13 (8.21 g, 68%). 1H NMR (400.0 MHz,
CDCl3): d=5.78 (dq, J=9.6, 1.8, J1H,117Sn =J1H,119Sn =128.7 Hz, 1H), 3.47
(ddd, J=10.5, 8.7, 6.0 Hz, 1H), 3.36 (ddd, J=10.5, 8.2, 3.7 Hz, 1H), 2.16
(dddq, J=9.6, 8.7, 8.2, 6.9 Hz, 1H), 1.92 (d, J=1.8, J1H,117Sn =J1H,119
=
Sn
41.7 Hz, 3H; CH3), 1.55–1.45 (m, 6H; 3CH2), 1.39–1.28 (m, 7H; OH,
(4S)-3-Methyl-2,3-dihydrofuran (9) and (4R/S)-3-methyl-2,3-dihydrofuran
[(ꢁ)-9]
3CH2), 0.95 (d, J=6.4 Hz, 3H; CH3), 0.99–0.91 (m, 6H; 3CH2), 0.90 ppm
(m, 9H; 3CH3); 13C NMR (100.5 MHz, CDCl3): d=143.0 (J
=
=
=
13C,117Sn
13C,119Sn
13C,117Sn
Preparation of optically pure 9: Sodium cyanide (4.62 g, 94.4 mmol,
1.2 equiv) was added to a solution of commercially available (R)-3-
bromo-2-methyl-propanol 26 (13.1 g, 85.8 mmol, 1.0 equiv) in DMSO
(140 mL). The reaction was stirred for 24 h at 208C. After this time, the
solution was poured out into water and extracted three times with
EtOAc. To extract the remainder of the compound, the aqueous solution
was carefully acidified to pH 5 by using 10% sulfuric acid. After extract-
ing the aqueous layer three more times, the combined organic layers
were washed with brine, dried over MgSO4, and the solvent was removed
under reduced pressure. (2S)-3-Cyano-2-methyl propan-1-ol (7.6 g, 89%)
was collected and used directly in the next step. 1H NMR (400.0 MHz,
CDCl3): d=3.65 (ddd, J=10.5, 5.0, 4.6 Hz, 1H), 3.50 (ddd, J=10.5, 7.3,
5.0 Hz, 1H), 2.62 (t, J=5.0 Hz, 1H; OH), 2.50 (dd, J=16.7, 5.5 Hz, 1H),
2.37 (dd, J=16.7, 6.9 Hz, 1H), 2.06 (dquintdd, J=7.3, 6.9, 5.5, 4.6 Hz,
1H), 1.08 ppm (d, J=6.9 Hz, 3H; CH3); 13C NMR (100.5 MHz, CDCl3):
d=118.7 (C), 65.6 (CH2), 32.8 (CH), 20.8 (CH2), 15.8 ppm (CH3); IR
(film): n˜ =3416, 2967, 2933, 2880, 2251, 1644, 1464, 1424, 1387, 1350,
1044, 993 cmꢀ1; MS (GC, EI): m/z: 99, 69, 59, 54.
J
Sn =27.8 Hz; CH), 140.9 (C), 67.3 (CH), 42.4 (J
13C,119
Sn =J
13C,117
33.6 Hz; CH), 29.3 (J
Sn =J
13C,117
Sn =20.4 Hz; 3CH2), 27.5 (J
13C,119
J
Sn =57.5 Hz; 3CH2), 27.2 (J
13C,119
Sn =J
13C,117
Sn =46.0 Hz; CH3), 17.4
13C,119
(CH3), 13.7 (3CH3), 10.1 ppm (J
Sn =314.4, J
13C,117
Sn =329.7 Hz; 3CH2);
13C,119
IR (film): n˜ =3327, 2956, 2928, 2920, 2871, 2853, 1678, 1623, 1483, 1456,
1377, 1340, 1292, 1072, 1037, 996, 864, 690, 668 cmꢀ1; MS (GC, CI, NH3):
m/z: 373 [MHꢀH2O]+, 359 [MHꢀH2OꢀBu]+, 291 [Bu3Sn]+, 261, 249,
235, 141, 113, 101, 85, 57; elemental analysis calcd (%) for C18H38OSn: C
55.55, H 9.84; found: C 55.73, H 10.02.
AHCTUNGTERG(NNUN 2S,3Z)-2-Methyl-4-tributylstannyl-pent-3-en-1-al (28): BAIB (6.09 g,
18.9 mmol, 1.1 equiv) was added to a solution of alcohol 13 (6.7 g,
17.2 mmol, 1.0 equiv) and TEMPO (538 mg, 3.45 mmol, 0.2 equiv) in
CH2Cl2 (40 mL). The mixture was stirred until the starting material had
disappeared (2 h), and was then diluted with cyclohexane, washed with
an aqueous saturated Na2S2O3 solution, and extracted with cyclohexane.
The combined organic phases were washed with a saturated aqueous
NaHCO3 solution and brine, dried over MgSO4, and the solvent was re-
moved under reduced pressure until the volume was approximately equal
to 20 mL. This solution can be kept only for a few hours before use (the
neat product 28 is more unstable). 1H NMR (400.0 MHz, CDCl3): d=
9.48 (d, J=1.7 Hz, 1H), 5.72 (dq, J=9.7, 1.6, J1H,117Sn =J1H,119Sn =122.1 Hz,
A solution of DIBAL-H (1m in CH2Cl2, 86 mL, 86 mmol, 2.5 equiv) was
added to a solution of the preceding nitrile derivative (3.4 g, 34 mmol,
1.0 equiv) in CH2Cl2 (60 mL) at ꢀ788C. The mixture was stirred at
ꢀ788C until the starting material had disappeared and it was then diluted
1H), 2.89 (dqd, J=9.7, 6.4, 1.7 Hz, 1H), 1.89 (d, J=1.6, J1H,117Sn =J1H,119
=
Sn
with AcOEt and poured into
a
solution of Rochelleꢃs salt
40.7 Hz, 3H; CH3), 1.47–1.37 (m, 6H; 3CH2), 1.24 (sext, J=7.3 Hz, 6H;
3CH2), 1.08 (d, J=6.4 Hz, 3H; CH3), 0.91–0.86 (m, 6H; 3CH2), 0.83 ppm
(t, J=7.3 Hz, 9H; 3CH3); 13C NMR (100.5 MHz, CDCl3): d=202.1 (CH),
(C4H4KNaO6·4H2O, 78 g, 8.0 equiv). After the reaction mixture had been
stirred for 12 h, it was extracted with AcOEt, and the combined organic
phases were washed with brine, dried over MgSO4, and the solvent was
removed under reduced pressure. (2R/S,4S)-4-Methyl tetrahydrofuran-2-
ol 27 was obtained as a 1:2 diastereomeric mixture (2.87 g, 82%). RN:
34314-85-7 (see above for analytical data for racemic 4-methyltetrahydro-
furan-2-ol (ꢁ)-27).
146.0 (J
24.9 Hz; CH), 53.1 (J
Sn =346.0,
J
13C,117
Sn =362.3 Hz, C), 136.2 (J
Sn =J
Sn =J
=
13C,117
13C,119
13C,117
13C,119Sn
Sn =31.6 Hz; CH), 29.1 (J
13C,119 13C,117Sn
=
J
Sn =19.2 Hz; 3CH2), 27.4 (J
13C,119
Sn =J
13C,117
Sn =40.3 Hz; CH3, CH3), 27.3
13C,119
(J
(J
Sn =J
Sn =58.5 Hz; 3CH2), 14.4 (CH3), 13.7 (3CH3), 10.1 ppm
13C,119
13C,117
Sn =317.3, J
13C,117
Sn =332.6 Hz; 3CH2); IR (film): n˜ =2958, 2927, 2872,
13C,119
A
solution of the above optically active lactol 27 (5.0 g, 49 mmol,
2854, 2809, 1726, 1614, 1463, 1426, 1377, 1072, 999, 854, 689 cmꢀ1; MS
(GC, CI, NH3): m/z: 331 [MꢀBu]+, 291 [Bu3Sn]+, 275, 255, 235, 217, 189,
177, 159, 147, 135, 121, 97.
1.0 equiv) and PTSA (25 mg, 0.11 mmol, 0.0022 equiv) in quinoline
(2.5 mL) was heated from 160 to 2458C. Distillation of a mixture of the
title compound with water was achieved in 45 min (b.p. 80–908C). After
separation of water, dihydrofuran 9 was obtained (3.5 g, 85%). RN:
1708-27-6; 1H NMR (400.0 MHz, CDCl3): d=6.30 (dd, J=2.8, 2.3 Hz,
1H), 4.94 (dd, J=2.8, 2.3 Hz, 1H), 4.38 (dd, J=9.6, 8.7 Hz, 1H), 3.85
(2R/S,3Z)-2-Methyl-4-tributylstannyl-pent-3-en-1-ol ((ꢁ)-13): The same
protocol used before for the synthesis of 13 was employed to prepare
(ꢁ)-13 (16.5 g, 67%) from (ꢁ)-9 (5 g). See above for data.
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11101

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
A
3H; CH3), 0.99–0.92 (m, 6H, 3CH2), 0.89 ppm (t, J=7.3 Hz, 9H; 3CH3);
protocol used before for the synthesis of 28 was employed to prepare
(ꢁ)-28 from (ꢁ)-13 (2.5 g). See above for data.
(1Z,3S,4S,5S,6Z)-1-[(N,N-Diisopropyl)carbamoyloxy]-3,5-dimethyl-7-tri-
butylstannyl-octa-1,6-dien-4-ol (29) and (1Z,3S,4S,5R,6Z)-1-[(N,N-diiso-
propyl)carbamoyloxy]-3,5-dimethyl-7-tributylstannyl-octa-1,6-dien-4-ol
(31)
13C NMR (100.5 MHz, CDCl3): d=152.6 (C), 144.3 (J
Sn =J
13C,117
=
13C,119Sn
28.8 Hz, CH), 142.2 (J
Sn =355.1, J
13C,117
Sn =372.4 Hz, C), 135.3 (CH),
13C,119
111.0 (CH), 77.7 (CH), 46.6 (CH), 46.0 (CH), 44.0 (J
Sn =J
13C,117
=
13C,119Sn
29.8 Hz; CH), 32.1 (CH), 29.1 (J
Sn =J
13C,117
Sn =20.2 Hz; 3CH2), 27.4
13C,119
(J
Sn =J
13C,117
Sn =57.6 Hz; 3CH2), 27.2 (J
13C,119
Sn =J
13C,117
Sn =42.2 Hz; CH3),
13C,119
21.4 (2CH3), 20.3 (2CH3), 18.7 (CH3), 17.3 (CH3), 13.6 (3CH3), 10.1 ppm
(J Sn =315.7, J Sn =330.1 Hz; 3CH2).
13C,117
13C,119
From optically pure aldehyde 28: A solution of nBuLi (1.6m in hexanes,
2.4 mL, 3.95 mmol, 3.0 equiv) was added to a quick-stirred solution of the
(E)-crotyldiisopropylcarbamate (787 mg, 3.95 mmol, 3.0 equiv) and (ꢀ)-
sparteine (925 mg, 3.95 mmol, 3.0 equiv) in pentane (6 mL) and cyclohex-
ane (1 mL) at ꢀ788C. After 10 min, white crystals appeared. After 3 h of
(3S,4R,5S,6Z)-3,5-Dimethyl-4-[(methoxymethyl)oxy]-7-(tributylstannyl)-
oct-6-en-1-yne (32): A solution of tBuLi (1.5m in pentane, 27.2 mL,
40.8 mmol, 3.0 equiv) was slowly added to a solution of carbamate 29
(8.4 g, 13.6 mmol, 1.0 equiv) in Et2O (100 mL) at ꢀ408C. The solution
was stirred for 20 min at ꢀ208C, and was then quenched by the addition
of a saturated aqueous NH4Cl solution and extracted with Et2O. The
combined organic phases were washed with brine, dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude residue was
purified by chromatography on silica gel (cyclohexane/Et2O 90:10 to
80:20) to give (3S,4R,5S,6Z)-3,5-dimethyl-4-hydroxy-7-(tributylstannyl)-
oct-6-en-1-yne (4.7 g, 78%). [a]2D0 =ꢀ26.8 (c=1.0 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=5.87 (dq, J=9.6, 1.8, J1H,117Sn =J1H,119Sn =133.3 Hz,
1H), 3.17 (ddd, J=9.0, 7.5, 3.2 Hz, 1H), 2.73 (dqd, J=7.5, 6.9, 2.3 Hz,
1H), 2.16 (dqd, J=9.6, 6.9, 3.2 Hz, 1H), 2.14 (d, J=2.3 Hz, 1H), 1.90 (d,
J=1.8, J1H,117Sn =J1H,119Sn =40.8 Hz, 3H; CH3), 1.74 (d, J=9.0 Hz, 1H; OH),
1.53–1.42 (m, 6H; 3CH2), 1.34 (sext, J=7.3 Hz, 6H; 3CH2), 1.26 (d, J=
6.9 Hz, 3H; CH3), 1.08 (d, J=6.9 Hz, 3H; CH3), 0.98–0.91 (m, 6H;
3CH2), 0.89 ppm (t, J=7.3 Hz, 9H; 3CH3); 13C NMR (100.5 MHz,
crystallization at ꢀ788C, a pre-cooled (ꢀ408C) solution of Ti
(3.5 mL, 11.9 mmol, 9.0 equiv) in pentane (7 mL) was quickly added by
cannula to the reaction mixture of lithio carbamate, which became limpid
and turned orange. After 1 h at ꢀ788C, aldehyde 28 (513 mg, 1.30 mmol,
1.0 equiv) in cyclohexane (5 mL) was slowly added to the orange solu-
tion, and the mixture was stirred for 3 h at ꢀ788C. The solution was then
poured into a mixture of Et2O-saturated aqueous NH4Cl solution. After
extraction with Et2O, the organic layer was washed with brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure.
The residue was purified by chromatography on silica gel (cyclohexane/
AcOEt 95:5 to 80:20) to give the title compound 29 (669 mg, 87% for
2 steps) as
1H NMR (400.0 MHz, CDCl3): d=7.15 (d, J=6.4 Hz, 1H), 6.17 (dq, J=
9.9, 1.4, J1H,117Sn =J1H,119Sn =134.0 Hz, 1H), 4.66 (dd, J=9.8, 6.4 Hz, 1H),
4.19–4.02 (brs, 1H), 3.78–3.61 (brs, 1H), 3.25 (dt, J=8.0, 2.8 Hz, 1H),
2.86 (ddq, J=9.8, 8.0, 6.9 Hz, 1H), 2.18 (dqd, J=9.9, 6.8, 2.8 Hz, 1H),
1.90 (d, J=1.4, J1H,117Sn =J1H,119Sn =42.6 Hz, 3H; CH3), 1.72 (brd, J=2.8 Hz,
1H; OH), 1.55–1.45 (m, 6H; 3CH2), 1.38–1.16 (sext, J=7.3 Hz, 6H;
3CH2), 1.20–1.12 (m, 12H; 4CH3), 1.00 (d, J=6.9 Hz, 3H; CH3), 0.98 (d,
J=6.8 Hz, 3H; CH3), 0.99–0.92 (m, 6H; 3CH2), 0.89 ppm (t, J=7.3 Hz,
9H; 3CH3); 13C NMR (100.5 MHz, CDCl3): d=152.9 (C), 144.3
CDCl3): d=142.8 (J
Sn =J
13C,117
Sn =28.8 Hz; CH), 138.8 (C), 84.8 (C),
13C,119
78.0 (CH), 71.5 (CH), 43.2 (J
Sn =J
13C,117
Sn =33.6 Hz; CH), 30.4 (CH),
13C,119
29.0 (J
Sn =J
13C,117
Sn =19.2 Hz; 3CH2), 27.1 (J
13C,119
Sn =J
13C,117
Sn =58.7 Hz;
13C,119
3CH), 27.0 (J
Sn =J
13C,117
Sn =44.0 Hz; CH3), 18.4 (CH3), 17.0 (CH3), 13.4
13C,119
(3CH3), 9.7 ppm (J
Sn =314.4, J
13C,117
Sn =328.8 Hz; 3CH2); IR (film): n˜ =
13C,119
3560, 350, 3456, 3310, 2957, 2926, 2872, 2854, 1463, 1455, 1376, 1247,
1115, 1070, 1050, 997, 981, 960, 873, 862, 690, 663, 631 cmꢀ1; elemental
analysis calcd (%) for C22H42OSn: C 59.88, H 9.59; found: C 59.99, H
9.77.
(J
C), 136.7 (CH), 113.2 (CH), 78.6 (CH), 47.1 (CH), 45.7 (CH), 41.3
Diisopropylethylamine (27.7 mL, 159 mmol, 20 equiv) and MOMCl
(6.9 mL, 79.5 mmol, 10 equiv) were added to a solution of the above alco-
hol (3.51 g, 7.95 mmol, 1.0 equiv), dimethylaminopyridine (194 mg,
1.59 mmol, 0.2 equiv), and TBAI (294 mg, 0.795 mmol, 0.1 equiv) in dried
CH2Cl2 (40 mL) at 08C. After the reaction mixture had been stirred for
12 h at 208C, it was quenched with a saturated aqueous NaHCO3 solution
and extracted with Et2O. The organic layers were washed with brine,
dried over MgSO4, filtered, and the solvent was removed under reduced
pressure. The crude residue was purified by chromatography on silica gel
(cyclohexane/Et2O 98:2 to 90:10) to give the title compound 32 (3.53 g,
(J
Sn =J
Sn =32.6 Hz; CH), 34.5 (CH), 29.3 (J
Sn =J
=
=
13C,117
13C,119
13C,117
13C,119Sn
Sn =57.5 Hz; 3CH2), 27.2 (J
13C,119 13C,117Sn
19.2 Hz; 3CH2), 27.5 (J
Sn =J
13C,117
J
Sn =46.0 Hz; CH3), 21.7 (2CH3), 20.4 (2CH3), 17.6 (CH3), 14.2
13C,119
(CH3), 13.8 (3CH3), 10.0 ppm (J
Sn =313.4, J
13C,117
Sn =326.8 Hz; 3CH2);
13C,119
IR (film): n˜ =3490, 2957, 2929, 2872, 2851, 1705, 1463, 1455, 1441, 1370,
1301, 1289, 1210, 1135, 1065, 997, 862, 762 cmꢀ1; MS (GC, CI, NH3): m/z:
530, 385, 327, 291 [Bu3Sn]+, 257, 235, 199, 177, 12, 86, 69; elemental anal-
ysis calcd (%) for C29H57NO5Sn: C 59.39, H 9.802, N 2.39; found: C
59.51, H 9.90, N 2.30.
From racemic aldehyde (ꢁ)-28: A solution of nBuLi (1.6m in hexane,
23 mL, 36.8 mmol, 2.14 equiv) was added to a quick-stirred solution of
the (E)-crotyldiisopropylcarbamate (6.84 g, 34.4 mmol, 2.0 equiv) and
(ꢀ)-sparteine (8.30 g, 35.4 mmol, 2.06 equiv) in pentane (36 mL) and cy-
clohexane (6 mL) at ꢀ788C. After 10 min, white crystals appeared. After
3 h of crystallization at ꢀ788C, a pre-cooled (ꢀ408C) solution of Ti-
92%) as
a
yellow oil. [a]2D0 =ꢀ20.6 (c=0.98 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=5.87 (d, J=9.6, J1H,117Sn =J1H,119Sn =133.3 Hz, 1H),
4.80 (d, J=7.3 Hz, 1H), 4.72 (d, J=7.3 Hz, 1H), 3.45 (s, 3H; CH3), 3.19
(dd, J=7.8, 3.6 Hz, 1H), 2.74 (qdd, J=7.3, 3.6, 2.7 Hz, 1H), 2.33 (ddq,
J=9.6, 7.8, 6.9 Hz, 1H), 2.09 (d, J=2.7 Hz, 1H), 1.88 (s, J1H,117Sn =J1H,119
=
Sn
40.8 Hz, 3H; CH3), 1.52–1.42 (m, 6H; 3CH2), 1.32 (sext, J=7.3 Hz, 6H;
3CH2), 1.25 (d, J=7.3 Hz, 3H; CH3), 1.02 (d, J=6.9 Hz, 3H; CH3), 0.97–
0.93 (m, 6H; 3CH2), 0.89 ppm (t, J=7.3 Hz, 9H; 3CH3); 13C NMR
ACHTUNGTRENNUNG(OiPr)4 (30.5 mL, 103.2 mmol, 6.0 equiv) in pentane (30 mL) was quickly
added by cannula to the reaction mixture of lithio carbamate, which
became limpid and turned orange. After 1 h at ꢀ788C, aldehyde (ꢁ)-28
(6.66 g, 17.2 mmol, 1.0 equiv) in cyclohexane (5 mL) was slowly added to
the orange solution, and the mixture was stirred for 3 h at ꢀ788C. The
solution was then poured into a mixture of Et2O-saturated aqueous
NH4Cl solution. After extraction with Et2O, the organic layer was
washed with brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/AcOEt 95:5 to 80:20) to give the title
compound 29 (8.50 g, 42% for 2 steps; see above for data) and its 12R
minor isomer 31 (1.41 g, 14%). 1H NMR (400.0 MHz, CDCl3): d=7.10
(d, J=6.9 Hz, 1H), 5.88 (dq, J=9.8, 1.7, J1H,117Sn =J1H,119Sn =128.0 Hz, 1H),
4.86 (dd, J=10.1, 6.9 Hz, 1H), 4.12–3.99 (brs, 1H), 3.91–3.78 (brs, 1H),
3.19 (dd, J=8.4, 2.6 Hz, 1H), 2.92 (dqd, J=10.1, 6.9, 2.6 Hz, 1H), 2.00
(dqd, J=9.8, 8.4, 6.4 Hz, 1H), 1.92 (d, J=1.7, J1H,117Sn =J1H,119Sn =40.3 Hz,
3H; CH3), 1.55–1.45 (m, 6H; 3CH2), 1.38–1.16 (sext, J=7.3 Hz, 19H;
3CH2 +OH+4CH3), 1.13 (d, J=6.9 Hz, 3H; CH3), 0.96 (d, J=6.4 Hz,
(100.5 MHz, CDCl3): d=143.6 (J
Sn =J
13C,117
Sn =28.7 Hz, CH), 138.5
13C,119
(C), 98.4 (CH2), 86.1 (C), 85.9 (CH), 70.0 (CH), 56.3 (CH3), 42.8
(J
Sn =J
Sn =30.1 Hz; CH), 30.0 (CH), 27.3 (J
Sn =J
=
13C,117
13C,119
13C,117
13C,119Sn
Sn =59.4 Hz; 3CH2), 27.2 (J
13C,119 13C,117Sn
20.1 Hz; 3CH2), 27.3 (J
Sn =J
13C,117
=
J
Sn =40.2 Hz; CH3), 18.8 (CH3), 17.7 (CH3), 13.7 (3CH3), 9.9 ppm
13C,119
(J
Sn =314.4, J
Sn =328.7 Hz; 3CH2); IR (film): n˜ =3312, 2956, 2926,
13C,119
13C,117
2872, 2823, 1458, 1376, 1146, 1096, 1035, 996, 668, 634 cmꢀ1; elemental
analysis calcd (%) for C24H46O2Sn: C 59.39, H 9.55; found: C 59.55, H
9.73.
AHCTUNGTERG(NNUN 3R,4S,5S)-3,5-Dimethyl-6-(4-methoxybenzyloxy)hex-1-en-4-ol (33) and
(3S,4R,5S)-3,5-dimethyl-6-(4-methoxybenzyloxy)hex-1-en-4-ol (34)
Brown reaction: A solution of cis-2-butene (12.5 mL) in THF (10 mL)
was slowly added to a solution of freshly sublimed potassium tert-butox-
ide (7.56 g, 67.4 mmol, 1.2 equiv) in THF (100 mL) at ꢀ788C. nBuLi
(1.6m in hexane, 44 mL, 70.3 mmol, 1.25 equiv) was then added dropwise
11102
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
and the resulting yellow mixture was stirred at ꢀ788C for 5 min and at
ꢀ458C for 20 min. The resulting orange solution was cooled to ꢀ788C,
Compound 34: 1H NMR (400.0 MHz, CDCl3): d=7.26 (d, J=8.9 Hz,
2H), 6.88 (d, J=8.9 Hz, 2H), 5.86 (ddd, J=17.9, 10.1, 7.3 Hz, 1H), 5.07
(dd, J=17.9, 1.4 Hz, 1H), 4.99 (dd, J=10.1, 1.4 Hz, 1H), 4.46 (d, J=
11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.82 (s, 3H), 3.67–3.60 (m, 1H),
3.55–3.45 (m, 2H), 2.70 (d, J=3.0 Hz, 1H; OH), 2.25–2.22 (m, 1H), 1.92–
1.79 (m, 1H), 1.04 (d, J=6.9 Hz, 3H; CH3), 0.96 ppm (d, J=6.6 Hz, 3H;
CH3).
and
a
solution of (ꢀ)-B-methoxydiisopinocamphenylborane (25 g,
78.7 mmol, 1.4 equiv) in Et2O (46 mL) was added dropwise over ca.
15 min. The resulting white solution was stirred at ꢀ788C for 40 min.
BF3·OEt2 (11.8 mL, 95.5 mmol, 1.7 equiv) was added dropwise followed
after 5 min by the addition of a solution of the aldehyde 13 (11.7 g,
56.2 mmol, 1.0 equiv) in THF (25 mL). The resulting solution was stirred
at ꢀ788C for 5 h and the reaction was then quenched by the successive
addition of an aqueous NaOH solution (2.5N, 66 mL) and an aqueous
H2O2 solution (30%, 20 mL). The acetone/dry ice bath was then re-
moved, and the mixture was heated at 458C for 45 min. The cloudy solu-
tion was cooled to 208C, diluted with Et2O (45 mL), washed with brine,
dried over MgSO4, filtered, and the solvent was removed under reduced
pressure. The crude residue was distilled (85–908C, 3.3 mmHg) to
remove most of the byproduct isopinocampheol. The remaining oil was
then purified by chromatography on silica gel to give title compound 33,
which was used in the next step.
AHCTUNGTERG(NNUN 3R,4S,5S)-4-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-6-(4-methoxyben-
zyloxy)hex-1-ene (35): 2,6-Lutidine (6.9 g, 7.5 mL, 64 mmol, 3.0 equiv)
and TBSOTf (8.5 g, 7.35 mL, 32 mmol, 1.5 equiv) were added to a solu-
tion of alcohol 33 (5.64 g, 21.3 mmol, 1.0 equiv) in dried CH2Cl2 (90 mL)
at 08C. After the reaction mixture had been stirred for 2 h at 208C, it
was partitioned between Et2O and a saturated aqueous solution of
NH4Cl and extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, filtered, and the solvent was removed under re-
duced pressure. The residue was purified by chromatography on silica gel
(cyclohexane/ethyl acetate 98:2 to 95:5) to give the title compound 35
(6.30 g, 78%) as a yellow oil. [a]2D0 =+1.3 (c=1.5 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=7.25 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H),
5.79 (ddd, J=17.6, 10.2, 7.8 Hz, 1H), 4.96 (dd, J=17.6, 1.7 Hz, 1H), 4.92
(dd, J=10.2, 1.7 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 4.38 (d, J=11.6 Hz,
1H), 3.81 (s, 3H), 3.63 (dd, J=6.9, 2.3 Hz, 1H), 3.35 (dd, J=8.9, 7.9 Hz,
1H), 3.19 (dd, J=8.9, 6.3 Hz, 1H), 2.34 (dqd, J=7.8, 6.9, 6.9 Hz, 1H),
1.97 (dqdd, J=7.9, 6.6, 6.3, 2.3 Hz, 1H), 0.99 (d, J=6.9 Hz, 3H; CH3),
0.89 (s, 9H; 3CH3), 0.85 (d, J=6.6 Hz, 3H; CH3), 0.04 (s, 3H; CH3),
0.02 ppm (s, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=159.0 (C),
142.0 (CH), 130.8 (C), 129.1 (2CH), 113.6 (2CH), 113.4 (CH2), 75.5
(CH), 73.4 (CH2), 72.4 (CH2), 55.2 (CH3), 42.6 (CH), 36.5 (CH), 26.1
(3CH3), 18.4 (C), 16.9 (CH3), 11.0 (CH3), ꢀ3.6 ppm (2CH3); IR (film):
n˜ =2959, 2855, 1653, 1615, 1513, 1462, 1360, 1301, 1246, 1172, 1103, 1039,
911, 836 cmꢀ1; MS (GC, CI, CH4): m/z: 407 [M+29]+, 377, 363, 323, 271,
241, 199, 187, 161, 145, 121, 109, 89, 75; elemental analysis calcd (%) for
C22H38O3Si: C 69.79, H 10.12; found: C 70.16, H 10.35.
Crotylation reaction with crotylstannane—crotylstannane preparation
Method 1: nBuLi (1.4m in hexane, 49 mL, 69 mmol, 1.0 equiv) was added
to a solution of diisopropylamine (8.0 mL, 79 mmol, 1.15 equiv) in THF
(130 mL) at 08C. After 10 min, HSnBu3 (20.0 g, 69 mmol, 1.0 equiv) was
added over 10 min to the LDA solution, and after stirring for 20 min at
08C, the mixture was cooled to ꢀ408C and a solution of (E)-crotylchlor-
ide (6.2 g, 69 mmol, 1.0 equiv) in THF (70 mL) was added by cannula.
The mixture was stirred for 15 min at ꢀ208C and then treated with a sa-
turated aqueous NH4Cl solution. After extraction with Et2O, the organic
layer was washed with water and brine, dried over MgSO4, and the sol-
vent was removed under reduced pressure. The residue was then distilled
under reduced pressure (154–1588C, 0.3 mbar) to give a mixture of
(E/Z)-crotylstannane 50:50 (19.0 g, 81%).
Method 2: A solution of trans-butene (7 mL) in THF was added by can-
nula to freshly sublimed potassium tert-butoxide (4.0 g, 36 mmol,
1.2 equiv) in THF (70 mL) at ꢀ788C. nBuLi was then added dropwise
(1.4m in hexane, 26.6 mL, 37.2 mmol, 1.25 equiv). After the reaction mix-
ture had been stirred for 1 h at ꢀ458C, tributyltin chloride (9.7 g,
30 mmol, 1.0 equivalent) was added slowly and the resulting mixture was
allowed to warm to 208C for 12 h. The reaction was then quenched by
the addition of a saturated aqueous NH4Cl solution. After extraction
with Et2O, the organic layer was washed with water and brine, dried over
MgSO4, and the solvent was removed under reduced pressure. The resi-
due was then distilled under reduced pressure (154–1588C, 0.3 mbar) to
give a mixture of (E/Z)-crotylstannane 75:25 (3.25 g, 32%).
AHCTUNGTERG(NNUN 2S,3S,4R)-2,4-Dimethyl-hex-5-ene-1,3-diol (36): At 08C, a solution of
compound 33 (100 mg, 0.38 mmol, 1.0 equiv) in CH2Cl2 (3 mL) was treat-
ed with water (0.15 mL) and DDQ (72 mg, 0.317 mmol, 1.2 equiv). The
mixture was stirred for 10 min at 08C, warmed to 208C and then stirred
for an additional 30 min. The mixture was quenched with a saturated
aqueous NaHCO3 solution, diluted with CH2Cl2, and washed with water
and brine. The combined organic layers were dried over MgSO4, filtered,
and the solvent was removed under reduced pressure. The crude residue
was purified by chromatography on silica gel (cyclohexane/ethyl acetate
60:40 then 50:50) to give the title compound 36 as white crystals (41 mg,
75%). RN: 108867-45-4; [a]2D0 =+40 (c=1.5 in CHCl3); 1H NMR
(270.0 MHz, CDCl3): d=6.03–5.49 (m, 1H), 5.03–4.89 (m, 2H), 3.69–3.57
(m, 2H), 3.51 (dd, J=9.2, 2.3 Hz, 1H), 2.49 (brs, 1H; OH), 2.28–2.19 (m,
1H), 1.79–1.73 (m, 1H), 1.03 (d, J=6.6 Hz, 3H; CH3), 0.87 ppm (d, J=
6.9 Hz, 3H; CH3); 13C NMR (67.5 MHz, CDCl3): d=140.8 (CH), 114.7
(CH2), 76.5 (CH), 67.8 (CH2), 42.2 (CH), 36.5 (CH), 17.1 (CH3), 8.9 ppm
(CH3); IR (film): n˜ =3464, 2957, 1655, 1264, 1105, 1094, 1023, 1016,
798 cmꢀ1; MS (GC, CI, CH4): m/z: 127 [MHꢀH2O]+, 125, 109, 97, 89, 83,
71, 57; elemental analysis calcd (%) for C8H16O2: C 66.63, H 11.18; found
C 66.46, H 11.07.
BF3·OEt2 (9.0 g, 8.1 mL, 63.8 mmol, 2.2 equiv) was added to a solution of
aldehyde 13 (6.0 g, 28.9 mmol, 1.0 equiv) in Et2O (90 mL) at ꢀ1008C.
After the reaction mixture had been stirred for 10 min, crotyltributylstan-
nane (13.3 g, 38.6 mmol, 1.1 equiv) was added and the resulting mixture
was stirred for 3 h at ꢀ100/ꢀ958C. After this time, a saturated aqueous
NaHCO3 solution was added and the resulting mixture was extracted
with Et2O. The organic layer was washed with water and brine, dried
over MgSO4, and the solvent was removed under reduced pressure. The
residue was purified by chromatography on silica gel (cyclohexane/ethyl
acetate 90:10 to 70:30) to give the title compound 33 as a yellow oil
(5.64 g, 74%) and its diastereomer 34 (d.r. 91:9).
AHCTUNGTERG(NNUN 2S,3R,4S)-3-(tert-Butyldimethylsilyloxy)-2,4-dimethyl-5-(4-methoxyben-
zyloxy)pentanal (37): A stream of ozone was bubbled through a solution
of compound 35 (6.3 g, 16.6 mmol, 1.0 equiv), pyridine (4 mL, 50 mmol,
3.0 equiv), and a small amount of Sudan III in MeOH/CH2Cl2 (1:1,
200 mL) at ꢀ788C until the pink solution became colorless. The solution
was treated with DMS (36.5 mL, 498 mmol, 30 equiv) and was then
warmed to 208C for 12 h. The solution was concentrated under reduced
pressure, diluted with Et2O, washed with water (3ꢄ), dried over MgSO4,
and the solvent was removed under reduced pressure. The crude 37 pro-
duced (6.0 g, 95%) was used in the next step without further purification.
1H NMR (400.0 MHz, CDCl3): d=9.87 (d, J=0.8 Hz, 1H), 7.25 (d, J=
8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.41 (d, J=11.6 Hz, 1H), 4.36 (d,
J=11.6 Hz, 1H), 4.24 (dd, J=5.1, 3.4 Hz, 1H), 3.82 (s, 3H), 3.37 (dd, J=
9.0, 7.3 Hz, 1H), 3.24 (dd, J=9.0, 5.9 Hz, 1H), 2.54 (qdd, J=6.9, 5.1,
0.8 Hz, 1H), 1.94 (dqdd, J=7.3, 6.9, 5.9, 3.4 Hz, 1H), 1.05 (d, J=6.9 Hz,
Compound 33: [a]2D0 =ꢀ2.7 (c=9.6 in CHCl3); 1H NMR (400.0 MHz,
CDCl3): d=7.26 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 5.63 (ddd,
J=17.2, 10.2, 8.6 Hz, 1H), 5.07 (dd, J=17.2, 2.0 Hz, 1H), 4.99 (dd, J=
10.2, 2.0 Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H),
3.82 (s, 3H), 3.55–3.45 (m, 2H), 3.43 (dd, J=9.1, 5.0 Hz, 1H), 2.70 (d, J=
3.0 Hz, 1H; OH), 2.23 (dqd, J=8.6, 7.3, 6.6 Hz, 1H), 1.92–1.79 (m, 1H),
1.10 (d, J=6.6 Hz, 3H; CH3), 0.96 ppm (d, J=6.6 Hz, 3H; CH3);
13C NMR (100.5 MHz, CDCl3): d=159.2 (C), 141.3 (CH), 130.3 (C),
129.2 (2CH), 114.5 (CH2), 113.8 (2CH), 75.4 (CH), 73.1 (CH2), 72.0
(CH2), 55.3 (CH3), 42.1 (CH), 35.4 (CH), 17.2 (CH3), 9.8 ppm (CH3); IR
(film): n˜ =2960, 2907, 2870, 1612, 1513, 1462, 1365, 1302, 1210, 1173,
1093, 1037, 982, 914 cmꢀ1; MS (GC, CI, CH4): m/z: 293 [M+29]+, 264,
246, 190, 161, 149, 137, 121, 109, 69, 57.
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11103

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
3H; CH3), 0.91 (s, 9H; 3CH3), 0.86 (d, J=6.9 Hz, 3H; CH3), 0.07 (s, 3H;
CH3), 0.05 ppm (s, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=205.5
(C), 129.2 (2CH), 113.7 (2CH), 72.6 (CH2), 72.5 (CH2), 72.3 (CH), 55.2
(CH3), 51.3 (CH), 37.0 (CH), 25.9 (3CH3), 18.2 (C), 12.1 (CH3), 9.3
(CH3), ꢀ4.0 ppm (2CH3), one C atom was not detected; MS (GC, EI):
m/z: 323 [MꢀtBu]+, 251, 199, 187, 137, 121, 107, 98, 89, 73, 59; elemental
analysis calcd (%) for C21H36O4Si: C 66.67, H 9.53; found: C 66.60, H
9.67.
was purified by chromatography on silica gel (cyclohexane/ethyl acetate
70:30) to give the title product (59 mg, 84%). [a]2D0 =+29.6 (c=2.9 in
CHCl3); 1H NMR (270.0 MHz, CDCl3): d=7.18 (d, J=8.6 Hz, 2H), 6.93
(d, J=6.3 Hz, 1H), 6.79 (d, J=8.6 Hz, 2H), 4.49 (dd, J=8.9, 6.3 Hz, 1H),
4.33 (s, 2H), 4.16–4.02 (brs, 1H), 3.75–3.58 (brs, 1H), 3.72 (s, 3H), 3.51
(dd, J=9.6, 2.0 Hz, 1H), 3.36 (dd, J=9.6, 2.0 Hz, 1H), 3.24 (d, J=4.6 Hz,
2H), 2.78–2.63 (m, 1H), 1.83–1.73 (m, 1H), 1.50–1.42 (m, 1H), 1.27–1.16
(m, 12H; 4CH3), 1.27 (s, 3H; CH3), 1.25 (s, 3H; CH3), 0.96 (d, J=
6.6 Hz, 3H), 0.81 (d, J=6.9 Hz, 3H), 0.75 ppm (d, J=6.9 Hz, 3H);
13C NMR (67.5 MHz, CDCl3): d=159.0 (C), 153.2 (C), 134.9 (CH), 130.5
(C), 129.0 (2CH), 114.6 (CH), 113.6 (2CH), 98.8 (C), 77.5 (CH), 75.7
(CH), 72.7 (CH2), 71.1 (CH2), 55.1 (CH3), 46.1 (2CH), 34.9 (CH, C-16),
31.8 (CH), 30.9 (CH), 29.8 (CH3), 21.0 (4CH3), 19.4 (CH3), 15.8 (CH3),
14.8 (CH3), 4.9 ppm (CH3); IR (film): n˜ =2968, 2936, 1708, 1513, 1462,
1439, 1377, 1310, 1288, 1248, 1135, 1057, 1012 cmꢀ1; MS (GC, CI, CH4):
m/z: 534 [M+29]+, 506 [M+1]+; elemental analysis calcd (%) for
C29H47NO6: C 68.88, H 9.37, N 2.77; found: C 68.75, H 9.32, N 2.85.
(1Z,3S,4S,5R,6R,7S)-6-(tert-Butyldimethylsilyloxy)-1-[(N,N-diisopropyl)-
carbamoyloxy]-8-(4-methoxybenzyloxy)-3,5,7-trimethyl oct-1-en-4-ol (38)
(E)-Crotyldiisopropylcarbamate preparation: A solution of 2-buten-1-ol
(E/Z mixture, 18.4 g, 255 mmol, 1.0 equiv) in THF (50 mL) was added to
a suspension of NaH (60%, 12.2 g, 306 mmol, 1.2 equiv) in THF (50 mL)
at 08C over 20 min. After the reaction mixture had been stirred for
20 min at 208C, it was cooled to 08C and a solution of N,N-diisopropyl-
carbamoyl chloride (50 g, 306 mmol, 1.2 equiv) in THF (70 mL) was
slowly added. The reaction mixture was stirred for 3 h at 208C, and was
then poured into an aqueous HCl 1n solution (150 mL) and extracted
with Et2O. The combined organic layers were washed with a saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and the
solvent was removed under reduced pressure. The crude residue was dis-
tilled (648C, 0.1 mbar) to give (E)-crotyldiisopropylcarbamate (50.0 g,
98%).
2,4-Acetonide of 38: A stream of ozone was bubbled into a cooled
(ꢀ788C) solution of the carbamate 38 (100 mg, 172 mmol, 1.0 equiv), pyri-
dine (40 mL), and a small amount of Sudan III in MeOH/CH2Cl2 (1:1,
10 mL) until the pink solution became colorless. Sodium borohydride
(39 mg, 1.03 mmol, 6.0 equiv) was added at ꢀ788C, the mixture was al-
lowed to warm to 208C and was then stirred for 6 h. After this time, the
reaction mixture was cooled, treated with a saturated aqueous solution of
NH4Cl and extracted with Et2O. The organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated. The residue was pu-
rified by flash chromatography on silica gel (cyclohexane/ethyl acetate
70:30) to give (2S,3R,4R,5S,6S)-3-(tert-butyldimethylsilyloxy)-5,7-dihy-
droxy-1-(4-methoxy-benzyloxy)-2,4,6-trimethyl heptane (60 mg, 79%).
[a]2D0 =ꢀ0.73 (c=1.1 in CHCl3); 1H NMR (270.0 MHz, CDCl3): d=7.22–
7.18 (m, 2H), 6.85–6.79 (m, 2H), 4.36 (s, 2H), 3.75 (s, 3H), 3.86–3.67 (m,
3H), 3.80–3.70 (m, 1H; OH), 3.60–3.50 (m, 1H; OH), 3.50 (t, J=
10.6 Hz, 1H), 3.40–3.31 (m, 1H), 3.22–3.16 (m, 1H), 2.06–2.01 (m, 1H),
1.90–1.65 (m, 2H), 0.83 (s, 9H; 3CH3), 0.87–0.70 (m, 9H; 3CH3),
0.03 ppm (s, 6H; 2CH3); 13C NMR (67.5 MHz, CDCl3): d=159.0 (C),
130.7 (C), 129.1 (2CH), 113.6 (2CH), 77.6 (CH), 73.9 (CH2), 73.6 (CH),
72.4 (CH2), 68.4 (CH2), 55.2 (CH3), 38.5 (CH), 35.8 (CH), 32.8 (CH), 26.1
(3CH3), 18.4 (C), 12.1 (CH3), 10.5 (CH3), 9.6 (CH3), ꢀ3.6 ppm (2CH3);
IR (film): n˜ =2958, 2933, 2856, 1653, 1618, 1559, 1514, 1423, 1344, 1270,
Crotylation reaction with optically active crotyltitane: A solution of nBuLi
(1.4m in hexanes, 25.5 mL, 35.5 mmol, 2.1 equiv) was added to a quick-
stirred solution of the (E)-crotyl diisopropylcarbamate (6.6 g, 33.2 mmol,
2.0 equiv) and (ꢀ)-sparteine (8.01 g, 34.2 mmol, 2.1 equiv), in pentane
(30 mL) and cyclohexane (5 mL) at ꢀ788C, and after 10 min white crys-
tals appeared. After 3 h of crystallization at ꢀ788C,
a
pre-cooled
(ꢀ408C) solution of Ti
ACHTUNGTRENNUNG(OiPr)4 (29.5 mL, 99.6 mmol, 6.0 equiv) in pentane
(30 mL) was quickly added by cannula to the reaction mixture of lithio
carbamate, which became limpid and turned orange. After 1 h at ꢀ788C,
a
solution of aldehyde 37 (6.32 g, 16.6 mmol, 1.0 equiv) in pentane
(10 mL) was slowly added to the orange solution, and the mixture was
stirred for 3 h at ꢀ788C. The solution was then poured into a mixture of
Et2O (250 mL) and aqueous HCl (0.5n, 250 mL). After extraction with
Et2O, the organic layer was washed with brine, dried over MgSO4, fil-
tered, and the solvent was removed under reduced pressure. The crude
residue was purified by chromatography on silica gel (cyclohexane/ethyl
acetate 90:10 to 80:20) to give the title compound 38 (7.1 g, 77%) as a
single diastereomer.
1103, 1037, 837 cmꢀ1
.
2,2-Dimethoxypropane (180 mL, 1.50 mmol, 12 equiv) and PPTS (10
mol%) were added to a solution of the preceding diol (55 mg, 125 mmol,
1.0 equiv) in CH2Cl2 (3 mL) at 208C. The reaction mixture was stirred for
2 h and then the solution was cooled to 08C and triethylamine (1 mL)
was added. The reaction mixture was concentrated under reduced pres-
sure. The crude residue was purified by chromatography on silica gel (cy-
clohexane/ethyl acetate 90:10 to 60:40) to give the title product, the 2,4-
acetonide of 38, (46 mg, 78%) and the starting diol (22 mg). [a]2D0 =+12.2
(c=1.2 in CHCl3); 1H NMR (270.0 MHz, CDCl3): d=7.21 (d, J=8.6 Hz,
2H), 6.82 (d, J=8.6 Hz, 2H), 4.36 (s, 2H), 3.76 (s, 3H), 3.72 (dd, J=7.6,
1.3 Hz, 1H), 3.63–3.49 (m, 2H), 3.43 (t, J=11.3 Hz, 1H), 3.36–3.30 (m,
1H), 3.22–3.16 (m, 1H), 1.86–1.70 (m, 3H), 1.38–1.19 (m, 6H; 2CH3),
0.87 (d, J=5.3 Hz, 3H; CH3), 0.84 (s, 9H; 3CH3), 0.80 (d, J=6.9 Hz, 3H;
CH3), 0.63 (d, J=6.6 Hz, 3H; CH3), 0.00 ppm (s, 6H; 2CH3); 13C NMR
(67.5 MHz, CDCl3): d=159.5 (C), 131.5 (C), 129.5 (2CH), 114.5 (2CH),
98.5 (C), 75.2 (CH), 74.2 (CH2), 73.6 (CH), 72.8 (CH2), 67.0 (CH2), 55.8
(CH3), 38.2 (CH), 36.8 (CH), 31.3 (CH), 29.3 (CH3), 26.7 (3CH3), 19.4
(CH3), 19.0 (C), 12.8 (CH3), 11.0 (CH3), 10.5 (CH3), ꢀ3.6 ppm (2CH3);
IR (film): n˜ =3256, 1684, 1653, 1550, 1501, 1445, 1359, 1248, 1101, 1032,
846 cmꢀ1; MS (GC, CI, CH4): m/z: 481 [M+H]+; elemental analysis calcd
(%) for C27H48O5Si: C 67.45, H 10.06; found: C 67.32, H 10.24.
4,6-Acetonide derivative of 38: A solution of tetrabutylammonium fluo-
ride (1.0m in THF, 345 mL, 345 mmol, 2.0 equiv) was added to a solution
of compound 38 (100 mg, 172 mmol, 1.0 equiv) in THF (0.6 mL) at 208C.
The reaction mixture was stirred for 4 h, quenched by the addition of
water, and extracted with ethyl acetate. The organic layer was washed
with brine, dried over MgSO4, filtered, and concentrated. The residue
was purified by chromatography on silica gel (cyclohexane/ethyl acetate
80:20 to 70:30) to give the corresponding (2S,3R,4R,5S,6S)-3,5-dihydroxy-
8-{[(N,N-diisopropyl)carbamoyloxy]-1-(4-methoxy-benzyloxy)-2,4,6-tri-
methyl oct-7-ene (73 mg, 91%). [a]2D0 =+0.8 (c=0.75 in CHCl3);
1H NMR (270.0 MHz, CDCl3): d=7.18 (d, J=8.6 Hz, 2H), 7.08 (d, J=
6.3 Hz, 1H), 6.80 (d, J=8.6 Hz, 2H), 4.53 (dd, J=9.9, 6.3 Hz, 1H), 4.35
(s, 2H), 4.13–3.97 (brs, 1H), 3.73 (s, 3H; CH3), 3.72–3.60 (brs, 1H), 3.66–
3.63 (m, 1H), 3.35–3.33 (m, 2H), 3.32–3.28 (m, 1H), 2.88–2.73 (m, 1H),
2.00–1.85 (m, 1H; OH), 1.94–1.85 (m, 2H), 1.57–1.48 (m, 1H; OH),
1.21–1.16 (m, 12H; 4CH3), 0.98 (d, J=6.9 Hz, 3H; CH3), 0.88 (d, J=
6.9 Hz, 3H; CH3), 0.85 ppm (d, J=6.9 Hz, 3H; CH3); 13C NMR
(67.5 MHz, CDCl3): d=158.9 (C), 152.5 (C), 137.2 (CH), 130.2 (C), 129.1
(2CH), 113.7 (2CH), 112.9 (CH), 78.5 (CH), 77.9 (CH), 73.9 (CH2), 72.3
(CH2), 55.2 (CH3), 45.7 (2CH), 36.1 (CH), 35.6 (CH), 34.2 (CH), 21.0
(4CH3), 16.2 (CH3), 13.1 (CH3), 5.8 ppm (CH3); IR (film): n˜ =2969, 2934,
(1Z,3S,4S,5R,6S,7S)-6-(tert-Butyldimethylsilyloxy)-1-[(N,N-diisopropyl)-
carbamoyloxy]-8-(4-methoxybenzyloxy)-4-(triethylsilyloxy)-3,5,7-trimeth-
yl oct-1-ene (39): 2,6-Lutidine (0.9 mL, 7.50 mmol, 4.0 equiv) and
TESOTf (0.9 mL, 3.76 mmol, 2.5 equiv) were added to a solution of 38
(1.09 g, 1.88 mmol, 1.0 equiv) in dried CH2Cl2 (15 mL) at 08C. After the
reaction mixture had been stirred for 2 h at 208C, it was partitioned be-
tween Et2O and a saturated aqueous solution of NH4Cl and was extract-
2873, 1708, 1692, 1513, 1441, 1370, 1305, 1247, 1210, 1135, 1063, 971 cmꢀ1
.
2,2-Dimethoxypropane (210 mL, 1.67 mmol, 12 equiv) and PPTS (10%)
were added to a solution of the above diol (65 mg, 0.14 mmol, 1.0 equiv)
in CH2Cl2 at 208C. The reaction mixture was stirred for 2 h. Then the so-
lution was cooled to 08C and triethylamine (1 mL) was added. The reac-
tion mixture was concentrated under reduced pressure. The crude residue
11104
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
ed with Et2O. The organic layer was washed with brine, dried over mag-
nesium sulfate, filtered, and the solvent was removed under reduced
pressure. The residue was purified by chromatography on silica gel (cy-
clohexane/ethyl acetate 95:5 to 90:10) to give the title compound 39
(985 mg, 76%) of as a colorless oil. [a]2D0 =+14.4 (c=0.8 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.22 (d, J=8.6 Hz, 2H), 6.90 (d, J=
6.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 5.01 (dd, J=9.2, 6.6 Hz, 1H), 4.38
(d, J=11.1 Hz, 1H), 4.35 (d, J=11.1 Hz, 1H), 4.11–3.95 (brs, 1H), 3.82–
3.69 (brs, 1H), 3.78 (s, 3H), 3.67 (dd, J=6.3, 2.3 Hz, 1H), 3.53 (dd, J=
6.3, 5.3 Hz, 1H), 3.37 (dd, J=8.6, 5.6 Hz, 1H), 3.16 (t, J=8.6 Hz, 1H),
2.78–2.72 (m, 1H), 1.87–1.80 (m, 1H), 1.74–1.67 (m, 1H), 1.28–1.14 (m,
12H; 4CH3), 1.01 (d, J=7.2 Hz, 3H; CH3), 0.97–0.87 (m, 12H; 4CH3),
0.85 (s, 9H; 3CH3), 0.80 (d, J=7.2 Hz, 3H; CH3), 0.60 (q, J=7.6 Hz, 6H;
3CH2), 0.02 (s, 3H; CH3), 0.01 ppm (s, 3H; CH3); 13C NMR (100.5 MHz,
CDCl3): d=159.0 (C), 153.0 (C), 133.7 (CH), 130.7 (C), 129.2 (2CH),
113.6 (2CH), 112.7 (CH), 77.0 (CH), 73.9 (CH), 73.6 (CH2), 72.6 (CH2),
55.2 (CH3), 45.4 (2CH), 42.9 (CH), 38.7 (CH), 32.4 (CH), 26.1 (3CH3),
21.5 (4CH3), 20.3 (CH3), 18.4 (C), 12.2 (CH3), 11.1 (CH3), 7.0 (3CH3),
5.5 (3CH2), 3.2 ppm (2CH3); IR (film): n˜ =2966, 2937, 2877, 1710, 1514,
1460, 1439, 1306, 1249, 1060, 1042, 1005, 837 cmꢀ1; elemental analysis
calcd (%) for C38H71NO6Si2: C 65.75, H 10.31, N 2.02; found: C 65.72, H
10.27, N 1.97.
4.35 (d, J=11.9 Hz, 1H), 3.80 (s, 3H), 3.68 (dd, 1H, J=5.9, 3.2 Hz), 348
(dd, J=5.0, 4.8 Hz, 1H), 3.38 (dd, J=8.7, 6.4 Hz, 1H), 3.18 (dd, J=8.7,
7.3 Hz, 1H), 2.34 (dqd, J=8.2, 6.9, 5.0 Hz, 1H), 1.93 (dqdd, J=7.3, 6.9,
6.4, 3.2 Hz, 1H), 1.69 (qdd, J=6.9, 5.9, 4.8 Hz, 1H), 0.99 (d, J=6.9 Hz,
3H; CH3), 0.93 (t, J=7.8 Hz, 9H; 3CH3), 0.88 (s, 9H; 3CH3), 0.86 (d,
J=6.9 Hz, 3H; CH3), 0.85 (d, J=6.9 Hz, 3H; CH3), 0.59 (q, J=7.8 Hz,
6H; 3CH2), 0.03 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz, CDCl3): d=
159.0 (C), 141.2 (C), 131.2 (CH), 129.3 (2CH), 114.6 (CH2), 113.6 (2CH),
77.0 (CH), 73.3 (CH2), 73.2 (CH), 72.6 (CH2), 55.3 (CH3), 39.6 (CH), 37.9
(CH), 33.5 (CH), 26.2 (3CH3), 18.5 (C), 18.5 (CH3), 11.7 (CH3), 11.5
(CH3), 7.2 (3CH3), 5.6 (3CH2), ꢀ3.4 ppm (2CH3).
(3Z,5S,6S,7R,8S,9S)-8-(tert-Butyldimethylsilyloxy)-10-hydroxy-6-(triethyl-
silyloxy)-5,7,9-trimethyl deca-1,3-diene (42): DDQ (117 mg, 0.52 mmol,
1.1 equiv) was added to a solution of compound 40 (249 mg, 0.43 mmol,
1.0 equiv) in CH2Cl2 (6 mL)/H2O (300 mL) at 08C. The mixture was
stirred for 10 min at 08C, warmed to 208C and was then stirred for an ad-
ditional 30 min. The mixture was quenched with a saturated aqueous
NaHCO3 solution, diluted with Et2O, and washed with water and brine.
The combined organic layers were dried over MgSO4, filtered, and the
solvent was removed under reduced pressure. The crude residue was pu-
rified by chromatography on silica gel (cyclohexane/ethyl acetate 95:5 to
80:20) to give the title compound 42 (142 mg, 72%). [a]2D0 =+11.4 (c=
1
(3Z,5S,6S,7R,8S,9S)-8-(tert-Butyldimethylsilyloxy)-10-(4-methoxybenzyl-
1.2 in CHCl3); H NMR (400.0 MHz, CDCl3): d=6.58 (ddd, J=16.9, 11.0,
oxy)-6-(triethylsilyloxy)-5,7,9-trimethyl
(3Z,5S,6S,7R,8S,9S)-6-(tert-butyldimethylsilyloxy)-8-(4-methoxybenzyl-
oxy)-6-(triethylsilyloxy)-3,5,7-trimethyl-1-decene (41)
deca-1,3-diene
(40)
and
10.5 Hz, 1H), 6.02 (t, J=11.0 Hz, 1H), 5.60 (dd, J=11.0, 10.1 Hz, 1H),
5.22 (d, J=16.9 Hz, 1H), 5.13 (d, J=10.5 Hz, 1H), 3.68 (t, J=3.9 Hz,
1H), 3.60–3.56 (m, 1H), 3.51 (dd, J=7.3, 3.9 Hz, 1H), 3.45–3.40 (m, 1H),
2.88 (dqd, J=10.1, 7.3, 3.9 Hz, 1H), 2.86 (m, 1H), 1.75 (dd, J=5.5,
5.0 Hz, 1H; OH), 1.64 (dqd, J=7.3, 6.9, 3.9 Hz, 1H), 1.04 (d, J=7.3 Hz,
3H; CH3), 0.98 (t, J=7.8 Hz, 9H; 3CH3), 0.94 (d, J=6.9 Hz, 3H; CH3),
0.85 (s, 9H; 3CH3), 0.83 (d, J=6.9 Hz, 3H; CH3), 0.65 (q, J=7.8 Hz, 6H;
3CH2), 0.11 ppm (s, 3H; CH3), 0.08 ppm (s, 3H; CH3); 13C NMR
(100.5 MHz, CDCl3): d=134.6 (CH), 132.5 (CH), 129.2 (CH), 117.7
(CH2), 78.0 (CH), 73.7 (CH), 66.2 (CH2), 40.8 (CH), 40.2 (CH), 35.9
(CH), 26.2 (3CH3), 19.2 (CH3), 18.5 (C), 12.5 (CH3), 11.9 (CH3), 7.4
(3CH3), 5.8 (3CH2), ꢀ3.5 (CH3), ꢀ3.7 ppm (CH3); IR (film): n˜ =3405,
Reaction with vinylmagnesium bromide: A solution of the vinyl carba-
mate 39 (700 mg, 1.01 mmol, 1.0 equiv) in Et2O (10 mL, 3 mL rinse) and
vinylmagnesium bromide (sol. 1m in THF, 15.1 mL, 15.1 mmol, 15 equiv)
were added to a stirred suspension of [NiACTHNUTRGNEN(UG acac)2] (26 mg, 0.10 mmol,
0.1 equiv) in Et2O (10 mL) at 08C. The resulting mixture was stirred for
24 h at 08C. After this time, a saturated aqueous NH4Cl solution was
added and the solution was extracted with Et2O. The organic layer was
washed with brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/ethyl acetate 100:0 to 90:10) to give
diene 40 (460 mg, 80%) and compound 41 (less than 5% yield).
2956, 2930, 2878, 2858, 1461, 1252, 1096, 1076, 1006, 837, 772, 737 cmꢀ1
;
elemental analysis calcd (%) for C25H52O3Si2: C 65.73, H 11.47; found: C
65.56, H 11.62.
Reaction with vinyllithium: MeLi (1.6m in Et2O, 18 mL, 28.8 mmol,
10 equiv) was added to a solution of tetravinyltin (1.7 g, 7.48 mmol,
2.6 equiv) in Et2O (12 mL) at 08C. After the reaction mixture had been
stirred for 30 min, it was added by cannula to a stirred solution of the car-
bamate 39 (2.0 g, 2.88 mmol, 1.0 equiv) and [Ni
0.288 mmol, 0.1 equiv) in Et2O (4 mL) at ꢀ5/08C. After the reaction mix-
ture had been stirred for a further 6 h, the same amount of [Ni(acac)2]
was added and the resulting mixture was stirred for another 12 h at 08C.
Then a saturated aqueous NH4Cl solution was added and the solution
was extracted with Et2O. The organic layer was washed with brine, dried
over MgSO4, filtered, and the solvent was removed under reduced pres-
sure. The residue was purified by chromatography on silica gel (cyclohex-
ane/ethyl acetate 98:2 to 80:20) to give 40 (1.33 g, 80%).
Compound 40: [a]2D0 =+8.9 (c=2.1 in CHCl3); 1H NMR (400.0 MHz,
CDCl3): d=7.24 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 6.57 (dt, J=
16.9, 10.0 Hz, 1H), 5.97 (t, J=10.0 Hz, 1H), 5.48 (t, J=10.0 Hz, 1H),
5.14 (d, J=10.0 Hz, 1H), 5.07 (d, J=16.9 Hz, 1H), 4.40 (d, J=11.4 Hz,
1H), 4.35 (d, J=11.4 Hz, 1H), 3.80 (s, 3H), 3.63 (dd, J=5.5, 3.0 Hz, 1H),
3.51 (t, J=4.0 Hz, 1H), 3.38 (dd, J=16.5, 9.0 Hz, 1H), 3.16 (dd, J=16.5,
9.0 Hz, 1H), 2.82 (m, 1H), 1.99–1.88 (m, 1H), 1.73–1.58 (m, 1H), 1.03–
0.85 (m, 27H; 9CH3), 0.59 (q, J=7.8 Hz, 6H; 3CH2), 0.04 ppm (s, 6H;
2CH3); 13C NMR (100.5 MHz, CDCl3): d=159.0 (C), 135.0 (CH), 132.5
(CH), 130.8 (C), 129.2 (2CH), 129.0 (CH), 117.1 (CH2), 113.6 (2CH),
77.5 (CH), 73.2 (CH2), 73.1 (CH), 72.5 (CH2), 55.2 (CH3), 40.2 (CH), 38.0
(CH), 36.5 (CH), 26.2 (3CH3), 18.7 (C), 18.5 (CH3), 11.9 (CH3), 11.5
(CH3), 7.2 (3CH3), 5.6 (3CH2), ꢀ3.3 ppm (2CH3); IR (film): n˜ =2957,
2857, 1616, 1490 cmꢀ1; elemental analysis calcd (%) for C33H60O4Si2: C
68.69, H 10.48; found: C 68.48, H 10.67.
(3Z,5S,6S,7R,8S,9S)-8-(tert-Butyldimethylsilyloxy)-10-iodo-6-(triethylsilyl-
oxy)-5,7,9-trimethyl deca-1,3-diene (43): A solution of iodine (167 mg,
0.66 mmol, 1.5 equiv) in Et2O (2 mL) was added slowly to a solution of
compound 42 (200 mg, 0.44 mmol, 1.0 equiv), triphenylphosphine (PPh3,
218 mg, 0.83 mmol, 1.9 equiv), and imidazole (57 mg, 0.83 mmol,
1.9 equiv) in a benzene/Et2O mixture (1.5 mL:3 mL) at 08C. After the re-
action mixture had been stirred for 2 h at 208C, a 1m Na2S2O3 solution
was added and the reaction mixture was extracted with Et2O. The organic
layers were washed with, brine, dried over MgSO4, filtered, and the sol-
vent was removed under reduced pressure. The residue was purified by
chromatography on silica gel (cyclohexane/Et2O 100:0 to 80:20) to give
the title compound 43 (197 mg, 79%). [a]2D0 =+11.3 (c=0.68 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=6.58 (ddd, J=16.9, 11.0, 10.1 Hz, 1H),
6.02 (t, J=11.0 Hz, 1H), 5.55 (dd, J=11.0, 10.1 Hz, 1H), 5.21 (d, J=
16.9 Hz, 1H), 5.12 (d, J=10.1 Hz, 1H), 3.58 (t, J=4.6 Hz, 1H), 3.50 (dd,
J=6.4, 3.7 Hz, 1H), 3.32 (dd, J=9.6, 4.6 Hz, 1H), 2.98 (dd, J=9.6,
9.2 Hz, 1H), 2.84 (dqd, J=10.1, 6.9, 4.6 Hz, 1H), 1.97 (dqdm, J=9.2, 6.9,
4.6 Hz, 1H), 1.65 (qdm, J=6.9, 4.6 Hz, 1H), 1.01 (d, J=6.9 Hz, 3H;
CH3), 0.98 (t, J=7.8 Hz, 9H; 3CH3), 0.98 (d, J=6.9 Hz, 3H; CH3), 0.91
(s, 9H; 3CH3), 0.90 (d, J=6.9 Hz, 3H; CH3), 0.64 (q, J=7.8 Hz, 6H;
3CH2), 0.10 (s, 3H; CH3), 0.09 ppm (s, 3H; CH3); 13C NMR (100.5 MHz,
CDCl3): d=134.1 (CH), 132.5 (CH), 129.0 (CH), 117.4 (CH2), 77.1 (CH),
75.0 (CH), 41.9 (CH), 40.4 (CH), 35.8 (CH), 25.9 (3CH3), 18.8 (CH3),
18.4 (C), 15.0 (CH3), 13.4 (CH2), 11.9 (CH3), 7.0 (3CH3), 5.5 (3CH2),
ꢀ3.8 ppm (2CH3); IR (film): n˜ =2950, 2930, 2877, 2857, 1461, 1097, 1028,
1005, 836 cmꢀ1; elemental analysis calcd (%) for C25H51IO2Si2: C 52.98, H
9.07; found: C 53.17, H 9.25.
ACHTUNGTERN(NUNG acac)2] (74 mg,
AHCTUNGTRENNUNG
Compound 41: 1H NMR (400.0 MHz, CDCl3): d=7.24 (d, J=8.7 Hz,
2H), 6.86 (d, J=8.7 Hz, 2H), 5.80 (ddd, J=15.1, 11.9, 8.2 Hz, 1H), 4.97
(d, J=11.9 Hz, 1H), 4.96 (d, J=15.1 Hz, 1H), 4.41 (d, J=11.9 Hz, 1H),
(1Z,3S,4S,5S)-6-(tert-Butyldimethylsilyloxy)-1-[(N,N-diisopropyl)carba-
moyloxy]-3,5-dimethyl-hex-1-en-4-ol (51): A solution of nBuLi (1.37m in
hexanes, 30.6 mL, 41.9 mmol, 2.1 equiv) was added to a quick-stirred so-
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11105

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
lution of the (E)-crotyl diisopropylcarbamate (7.80 g, 39.2 mmol,
2.0 equiv) and (ꢀ)-sparteine (9.50 g, 40.4 mmol, 2.1 equiv) in pentane
(36 mL) and cyclohexane (6 mL) at ꢀ788C. After 10 min, white crystals
appeared, and after 3 h of crystallization at ꢀ788C, a pre-cooled (ꢀ408C)
acetate 90:10 to 60:40) to give (2R,3R,4S)-5-(tert-butyldimethylsilyloxy)-
2,4-dimethyl-3-hydroxy-pentanal (590 mg, 87%). RN: 209251-54-7;
1H NMR (400.0 MHz, CDCl3): d=9.83 (d, J=2.3 Hz, 1H), 4.06 (dt, J=
9.6, 1.8 Hz, 1H), 3.84 (dd, J=9.8, 3.4 Hz, 1H), 3.73 (dd, J=9.8, 4.3 Hz,
1H), 3.49 (d, J=1.8 Hz, 1H; OH), 2.52 (dqd, J=9.6, 7.3, 2.3 Hz, 1H),
1.77 (qddd, J=6.9, 4.3, 3.4, 1.8 Hz, 1H), 1.01 (d, J=7.3 Hz, 3H; CH3),
0.98 (d, J=6.9 Hz, 3H; CH3), 0.90 (s, 9H; 3CH3), 0.08 ppm (s, 6H;
2CH3); 13C NMR (100.5 MHz, CDCl3): d=205.9 (CH), 75.4 (CH), 67.8
(CH2), 49.7 (CH), 35.8 (CH), 26.0 (3CH3), 18.3 (C), 10.6 (CH3), 9.4
(CH3), ꢀ5.5 ppm (2CH3).
solution of TiACHTUNGTRENNUNG(OiPr)4 (34.7 mL, 117.6 mmol, 6.0 equiv) in pentane
(30 mL) was quickly added by cannula to the reaction mixture of lithio
carbamate, which became limpid and turned orange. After 1 h at ꢀ788C,
aldehyde 50 (3.96 g, 19.6 mmol, 1.0 equiv) in pentane (10 mL) was slowly
added to the orange solution, and the mixture was stirred for 3 h at
ꢀ788C. The solution was then poured into a mixture of Et2O (250 mL)/
aqueous HCl (0.5n, 250 mL). After extraction with Et2O, the organic
layer was washed with brine, dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The residue was purified by chro-
matography on silica gel (cyclohexane/ethyl acetate 95:5 to 70:30) to give
the title compound 51 (4.30 g, 58%) and its 3,4-bis-epi diastereomer
(de=95:5; de=diastereomeric excess).
Compound 51: [a]2D0 =+20.1 (c=1.0 in CHCl3); H RMN (400.0 MHz,
CDCl3): d=7.13 (d, J=6.4 Hz, 1H), 4.73 (dd, J=9.6, 6.4 Hz, 1H), 4.22–
4.11 (brs, 1H), 3.82–3.70 (brs, 1H), 3.71 (d, J=4.6 Hz, 2H), 3.54 (dt, J=
8.2, 2.3 Hz, 1H), 2.86 (ddq, J=9.6, 8.2, 6.9 Hz, 1H), 2.69 (d, J=2.3 Hz,
1H; OH), 1.84 (qtd, J=6.9, 4.6, 2.3 Hz, 1H), 1.28–1.10 (m, 12H; 4CH3),
0.97 (d, J=6.9 Hz, 3H; CH3), 0.94 (d, J=6.9 Hz, 3H; CH3), 0.90 (s, 9H;
3CH3), 0.08 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz, CDCl3): d=153.0
(C), 135.9 (CH), 113.9 (CH), 77.0 (CH), 68.0 (CH2), 47.0 (CH), 45.2
(CH), 36.6 (CH), 34.0 (CH), 26.0 (3CH3), 21.6 (2CH3), 20.5 (2CH3), 18.3
(C), 17.4 (CH3), 9.4 (CH3), ꢀ5.50 ppm (2CH3); IR (film): n˜ =3493, 2959,
2930, 2858, 1708, 1472, 1439, 1370, 1304, 1290, 1256, 1211, 1156, 1134,
1092, 1061, 837 cmꢀ1; MS (GC, EI): m/z: 344 [MꢀtBu]+, 326, 302, 228,
212, 199, 184, 145, 128, 115, 86, 73; elemental analysis calcd (%) for
C21H43NO4Si: C 62.80, H 10.79, N 3.49; found: C 62.61, H 10.87, N 3.35.
3,4-bis-epi isomer of 51: 1H NMR (400.0 MHz, CDCl3): d=7.07 (d, J=
6.4 Hz, 1H), 4.97 (dd, J=9.6, 6.4 Hz, 1H), 4.25–4.05 (brs, 1H), 4.20 (s,
1H; OH), 3.85–3.67 (brs, 1H), 3.75 (dd, J=10.1, 4.1 Hz, 1H), 3.60 (dd,
J=10.1, 9.4 Hz, 1H), 3.47 (dd, J=8.7, 2.3 Hz, 1H), 2.85 (ddq, J=9.6, 8.7,
6.9 Hz, 1H), 1.77 (dqdd, J=9.4, 6.9, 4.1, 2.3 Hz, 1H), 1.33–1.19 (m, 12H;
4CH3), 1.14 (d, J=6.9 Hz, 3H; CH3), 0.90 (s, 9H; 3CH3), 0.76 (d, J=
6.9 Hz, 3H; CH3), 0.09 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
CDCl3): d=153.5 (C), 135.1 (CH), 111.5 (CH), 80.5 (CH), 69.5 (CH2),
46.9 (CH), 45.5 (CH), 38.1 (CH), 33.5 (CH), 25.9 (3CH3), 21.6 (2CH3),
20.5 (2CH3), 18.3 (C), 18.2 (CH3), 13.2 (CH3), ꢀ5.5 ppm (2CH3).
A solution of commercial diethyl N-methoxy-N-methylphosphonoaceta-
mide (3.9 mL, 19.1 mmol, 2.0 equiv) was added to a suspension of sodium
hydride (powder, 60% in oil, 763 mg, 19.1 mmol, 2.0 equiv) in dry THF
(80 mL) at 08C. The solution was stirred at 208C for 1 h (until hydrogen
evolution was not observed). The solution was cooled to 08C, and the
preceding aldehyde (2R,3R,4S)-5-(tert-butyldimethylsilyloxy)-2,4-dimeth-
yl-3-hydroxy-pentanal (2.48 g, 9.52 mmol, 1.0 equiv) in dry THF (20 mL)
was added dropwise. After 5 min, the mixture was allowed to warm to
208C for 1 h and was then quenched by the addition of a saturated aque-
ous NH4Cl solution. The aqueous layer was separated and extracted with
Et2O (2ꢄ). The combined organic phases were washed with water and
brine, dried over MgSO4, filtered, and the solvent was removed under re-
duced pressure. The crude residue was purified by chromatography on
silica gel (cyclohexane/ethyl acetate 70:30 to 40:60) to give 53 (2.83 g,
86%) as a pale-yellow oil. [a]2D0 =ꢀ3.3 (c=1.0 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=6.99 (dd, J=15.6, 8.7 Hz, 1H), 6.49 (d, J=
15.6 Hz, 1H), 3.76 (dd, J=9.8, 3.9 Hz, 1H), 3.71 (s, 3H; CH3), 3.69 (dd,
J=6.4, 5.0 Hz, 1H), 3.68 (dd, J=9.8, 5.0 Hz, 1H), 3.24 (s, 3H; CH3), 2.84
(brs, 1H; OH), 2.50 (dqd, J=8.7, 6.9, 6.4 Hz, 1H), 1.82 (qddd, J=7.3,
5.0, 5.0, 3.9 Hz, 1H), 1.01 (d, J=6.9 Hz, 3H; CH3), 0.96 (d, J=7.3 Hz,
3H; CH3), 0.90 (s, 9H; 3CH3), 0.09 ppm (s, 6H, 2CH3); 13C NMR
(100.5 MHz, CDCl3): d=167.0 (C), 150.9 (CH), 119.1 (CH), 77.3 (CH),
68.6 (CH2), 61.8 (CH3, CH3), 40.9 (CH), 36.2 (CH), 32.4 (CH3), 26.0
(3CH3), 18.3 (C), 16.6 (CH3), 9.5 (CH3), ꢀ5.5 ppm (2CH3); IR (film): n˜ =
3444, 2958, 2930, 2857, 1650, 1627, 1471, 1417, 1385, 1255, 1093, 1004,
850 cmꢀ1; MS (GC, EI): m/z: 288 [MꢀtBu]+, 267, 246, 227, 203, 187, 172,
145, 115, 89, 75, 55; elemental analysis calcd (%) for C17H35NO4Si: C
59.09, H 10.21, N 4.05; found: C 58.95, H 10.28, N 3.94.
(2S,4S,5S,6R)-2-{6-[2-(tert-Butyldimethylsilyloxy)-1-methyl
ethyl]-5-
methyl-2-phenyl-1,3-dioxinan-4-yl}-N-methoxy-N-methyl-acetamide (54):
KHMDS (0.5m solution in toluene, 175 mL, 87.5 mmol, 0.1 equiv) was
added to a solution of compound 53 (300 mg, 0.87 mmol, 1.0 equiv) and
freshly distilled benzaldehyde (97 mL, 0.96 mmol, 1.1 equiv) in dry THF
(9 mL) at 08C. The yellow solution obtained was stirred for 15 min. This
sequence (addition of KHMDS/stirring) was repeated twice, after which
the solution was quenched by the addition of a saturated aqueous NH4Cl
solution. The organic layer was washed with water and brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure.
The crude residue was purified by flash chromatography on silica gel (cy-
clohexane/ethyl acetate 95:5 to 50:50) to give 54 (311 mg, 79%) as a
pale-yellow oil. [a]2D0 =+21.9 (c=0.6 in CHCl3); 1H NMR (400.0 MHz,
CDCl3): d=7.46–7.43 (m, 2H), 7.36–7.29 (m, 3H), 5.58 (s, 1H), 4.12
(ddd, J=10.0, 9.6, 3.0 Hz, 1H), 3.74 (dd, J=9.8, 1.7 Hz, 1H), 3.69 (dd,
J=9.6, 9.2 Hz, 1H), 3.65 (s, 3H; CH3), 3.50 (dd, J=9.6, 5.5 Hz, 1H), 3.22
(s, 3H), 2.92 (dd, J=15.6, 9.6 Hz, 1H), 2.64 (dd, J=15.6, 3.0 Hz, 1H),
2.01 (dqdd, J=9.2, 6.9, 5.5, 1.7 Hz, 1H), 1.77 (ddq, J=10.0, 9.8, 6.9 Hz,
1H), 0.90 (d, J=6.9 Hz, 3H; CH3), 0.89 (s, 9H; 3CH3), 0.85 (d, J=
6.9 Hz, 3H; CH3), 0.03 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
CDCl3): d=172.2 (C), 139.1 (C), 128.4 (CH), 128.0 (2CH), 126.1 (2CH),
100.0 (CH), 80.3 (CH), 79.2 (CH), 65.0 (CH2), 61.6 (CH3), 36.7 (CH2),
36.0 (CH), 35.4 (CH), 32.2 (CH3), 26.0 (3CH3), 18.4 (C), 12.0 (CH3), 9.8
(CH3), ꢀ5.3 ppm (2CH3); IR (film): n˜ =2956, 2930, 2857, 1666, 1483,
1403, 1387, 1256, 1149, 1090, 1029, 837 cmꢀ1; MS (GC, EI): m/z: 394
[MꢀtBu]+, 330, 288, 258, 243, 221, 199, 185, 172, 145, 115, 89, 75, 55; ele-
mental analysis calcd (%) for C24H41NO5Si: C 63.82, H 9.15, N 3.10;
found: C 63.79, H 9.21, N 3.01.
ACHTUNGTRENNUNG(2S,3S,4S)-1-(tert-Butyldimethylsilyloxy)-2,4-dimethyl-hex-5-en-3-ol (52):
A solution of isopropylmagnesium chloride in THF (1.55m, 8.0 mL,
12.4 mmol, 10 equiv) was slowly added to a solution of carbamate 51
(500 mg, 1.24 mmol, 1.0 equiv) and [NiACHTNUTRGNEUNG(acac)2] (32 mg, 0.12 mmol, 10
mol%) in THF (5 mL) at 208C. After the reaction mixture had been
stirred for 12 h, a saturated aqueous NH4Cl solution was added, and the
reaction mixture was extracted with Et2O. The combined organic layers
were washed with water and brine, dried over MgSO4, filtered, and the
solvent was removed under reduced pressure. The crude residue was pu-
rified by chromatography on silica gel (cyclohexane/ethyl acetate 98:2 to
85:15) to give the title compound 52 (162 mg, 50%). RN: 106296-58-6;
1H NMR (400.0 MHz, CDCl3): d=5.84 (ddd, J=16.5, 10.5, 8.2 Hz, 1H),
5.12 (dd, J=16.5, 1.8 Hz, 1H), 5.09 (dd, J=10.5, 1.8 Hz, 1H), 3.74 (dd,
J=9.8, 4.1 Hz, 1H), 3.71 (dd, J=9.8, 5.0 Hz, 1H), 3.55 (ddd, J=8.7, 2.3,
1.8 Hz, 1H), 2.89 (d, J=2.3 Hz, 1H; OH), 2.27 (ddq, J=8.7, 8.2, 6.9 Hz,
1H), 1.80 (qddd, J=6.9, 5.0, 4.1, 1.8 Hz, 1H), 0.95 (d, J=6.9 Hz, 6H;
2CH3), 0.90 (s, 9H; 3CH3), 0.07 ppm (s, 6H; 2CH3); 13C NMR
(100.5 MHz, CDCl3): d=142.3 (CH), 115.3 (CH2), 77.2 (CH), 68.8 (CH2),
42.0 (CH), 36.1 (CH), 26.0 (3CH3), 18.4 (C), 16.9, 9.5 (2CH3), ꢀ5.4
(CH3), ꢀ5.5 ppm (CH3).
(2E,4S,5S,6S)-N-Methyl-N-methoxy-7-(tert-butyldimethylsilyloxy)-4,6-di-
methyl-5-hydroxy-hept-2-enamide (53): A stream of ozone was bubbled
into a cooled (ꢀ788C) solution of 51 (1.05 g, 2.61 mmol, 1.0 equiv) and a
small amount of Sudan III in CH2Cl2 (50 mL) until the pink solution
became colorless. The solution was treated with triphenylphosphine
(686 mg, 2.61 mmol, 1.0 equiv) and the mixture was allowed to warm to
208C for 2 h. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel (cyclohexane/ethyl
(2S,4S,5S,6R)-2-{6-[2-(tert-Butyldimethylsilyloxy)-1-methyl
ethyl]-5-
methyl-2-phenyl-1,3-dioxinan-4-yl}acetaldehyde (55): DIBAL-H (1m so-
11106
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
lution in CH2Cl2, 10.0 mL, 9.96 mmol, 3.0 equiv) was added to a solution
of Weinreb amide 54 (1.50 g, 3.32 mmol, 1.0 equiv) in CH2Cl2 (20 mL) at
ꢀ788C. The yellow solution was stirred at ꢀ788C for 1 h. After this time,
the mixture was quenched by the addition of ethyl acetate (15 mL). The
mixture was allowed to warm to 208C and a solution of Rochelleꢃs salt
(17.0 g, 60.2 mmol, 18.1 equiv, in 20 mL water) was added. The mixture
was stirred at 208C for 2 h and then the organic layer was extracted with
Et2O (2ꢄ). The combined organic extracts were washed with brine, dried
over MgSO4, filtered, and the solvent was removed under reduced pres-
sure. The crude residue was purified by chromatography on silica gel (cy-
clohexane/ethyl acetate 95:5 to 80:20) to give 55 (1.21 g, 93%) as a pale-
yellow oil. [a]2D0 =+12.3 (c=1.0 in CHCl3); 1H NMR (400.0 MHz,
CDCl3): d=9.83 (dd, J=2.3, 1.8 Hz, 1H), 7.48–7.43 (m, 2H), 7.40–7.31
(m, 3H), 5.58 (s, 1H), 4.07 (ddd, J=9.6, 7.8, 3.7 Hz, 1H), 3.75 (dd, J=
10.6, 1.8 Hz, 1H), 3.66 (t, J=9.2 Hz, 1H), 3.47 (dd, J=9.2, 6.0 Hz, 1H),
2.74 (ddd, J=10.5, 3.7, 1.8 Hz, 1H), 2.71 (ddd, J=10.5, 7.8, 2.3 Hz, 1H),
2.02 (dqdd, J=9.2, 7.3, 6.0, 1.8 Hz, 1H), 1.78 (ddq, J=10.6, 9.6, 6.9 Hz,
1H), 0.90 (s, 9H; 3CH3), 0.90 (d, J=7.3 Hz, 3H; CH3), 0.88 (d, J=
6.9 Hz, 3H; CH3), 0.04 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
CDCl3): d=201.6 (C), 138.6 (C), 128.7 (CH), 128.2 (2CH), 126.1 (2CH),
100.3 (CH), 80.1 (CH), 77.4 (CH), 64.9 (CH2), 47.0 (CH2), 36.6 (CH),
35.1 (CH), 26.0 (3CH3), 18.4 (C), 11.8 (CH3), 9.7 (CH3), ꢀ5.3 ppm
(2CH3); IR (film): n˜ =2955, 2929, 2882, 2856, 1728, 1471, 1462, 1402,
1256, 1101, 1073, 1029, 837 cmꢀ1; MS (GC, EI): m/z: 335 [MꢀtBu]+, 281,
263, 243, 229, 211, 199, 185, 171, 157, 145, 131, 115, 101, 89, 75.
663, 661 cmꢀ1; elemental analysis calcd (%) for C46H82O6SiSn: C 62.93, H
9.41; found: C 63.10, H 9.55.
Compound 57: 1H NMR (400.0 MHz, CDCl3): d=7.47–7.24 (m, 2H),
7.39–7.30 (m, 3H), 6.00 (dq, J=9.6, 1.4, J1H,117Sn =J1H,119Sn =137.4 Hz, 1H),
5.53 (s, 1H), 4.81 (d, J=6.9 Hz, 1H), 4.77–4.70 (m, 1H), 4.71 (d, J=
6.9 Hz, 1H), 3.78–3.65 (m, 3H), 3.49 (dd, J=9.6, 6.0 Hz, 1H), 3.43 (s,
3H; CH3), 3.26 (t, J=5.5 Hz, 1H), 2.89 (d, J=3.2 Hz, 1H; OH), 2.74
(qdd, J=6.9, 5.5, 2.7 Hz, 1H), 2.23 (dqd, J=9.6, 6.9, 5.5 Hz, 1H), 2.12
(ddd, J=13.7, 6.0, 1.8 Hz, 1H), 2.06–1.96 (m, 2H; H-2), 1.90 (d, J=1.4,
J1H,117Sn =J1H,119Sn =42.6 Hz, 3H; CH3), 1.80–1.71 (m, 1H), 1.53–1.45 (m,
6H; 3CH2), 1.32 (sext, J=7.3 Hz, 6H; 3CH2), 1.21 (d, J=6.9 Hz, 3H;
CH3), 1.00 (d, J=6.9 Hz, 3H; CH3), 1.00–0.86 (m, 18H; 4CH3, 3CH2),
0.90 (s, 9H; 3CH3), 0.82 (d, J=6.9 Hz, 3H), 0.04 ppm (s, 6H; 2CH3);
13C NMR (100.5 MHz, CDCl3): d=144.2 (CH), 138.7 (C), 137.8 (C),
128.7 (CH), 128.2 (2CH), 126.0 (2CH), 100.5.1 (CH), 98.3 (CH2), 87.4
(CH), 85.7 (C), 82.5 (C), 81.7 (CH), 80.4 (CH), 65.0 (CH2), 61.8 (CH),
56.3 (CH3), 42.3 (CH), 41.2 (CH2), 36.7 (CH), 35.2 (CH), 30.3 (CH), 29.3
(J
Sn =J
13C,117
Sn =20.1 Hz; 3CH2), 27.6 (J
13C,119
Sn =J
13C,117
Sn =57.5 Hz;
13C,119
3CH2), 27.3 (J
Sn =J
13C,117
Sn =46.0 Hz; CH3), 26.1 (3CH3), 18.8 (CH3),
13C,119
18.5 (C), 16.5 (CH3), 13.9 (3CH3), 11.9 (CH3), 10.1 (J
Sn =312.5,
13C,117
J
Sn =329.8 Hz; 3CH2), 9.8 (CH3), ꢀ5.5 ppm (2CH3).
13C,119
Reduction of ynone 58 (vide infra): A solution of (S)-CBS-oxazaboroli-
dine in toluene (1m, 8.22 mL, 8.22 mmol, 2.0 equiv) and BH3·Me2S (2m in
THF, 10.3 mL, 20.5 mmol, 5.0 equiv) were added to a solution of com-
pound 58 (3.6 g, 4.1 mmol, 1.0 equiv) in THF (20 mL) at ꢀ308C. The re-
sulting mixture was stirred for 2 h at ꢀ308C and was then quenched with
EtOH and extracted with Et2O. The organic layers were washed with
water and brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/AcOEt 95:5 to 70:30) to give the title
compound 56 (6.88 g, 95%).
ACHTUNGTRENNUNG
and [2S,4R(1S),5S,6S(2R,5S,6R,7S,8Z)]-4-[2-(tert-butyldimethylsilyloxy)-
1-methyl ethyl-1-yl]-6-{5,7-dimethyl-2-hydroxy-6-[(methoxymethyl)oxy]-
9-tributylstannyl-dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (57)
Compound 57 was also obtained by enantioselective reduction of ynone
58: A solution of (R)-CBS-oxazaborolidine in toluene (1m, 171 mL,
0.171 mmol, 2.0 equiv) and BH3·Me2S (2m in THF, 214 mL, 0.43 mmol,
5.0 equiv) were added to a solution of ynone 58 (75 mg, 0.085 mmol,
1.0 equiv) in THF (0.5 mL) at ꢀ308C. The resulting mixture was stirred
for 2 h at ꢀ308C and was then quenched with EtOH and extracted with
Et2O. The organic layers were washed with water and brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure.
The residue was purified by chromatography on silica gel (cyclohexane/
AcOEt 95:5 to 70:30) to give 57 (63 mg, 90%).
Coupling reaction between B fragment 32 and C aldehyde 55: A solution
of tBuLi (1.5m in pentane, 295 mL, 0.44 mmol, 1.98 equiv) was added to a
solution of alkyne 32 (305 mg, 0.62 mmol, 2.5 equiv) in THF (3 mL) at
ꢀ788C. The resulting mixture was stirred for 30 min at ꢀ788C and then a
solution of aldehyde 55 (100 mg, 0.25 mmol, 1.0 equiv) in THF (1 mL)
was slowly added. After the reaction mixture had been stirred for 3 h at
08C, a saturated aqueous NH4Cl solution was added and the reaction
mixture was extracted with Et2O. The organic layers were washed with
water and brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/Et2O 98:2 to 80:20) to furnish the title
compound 56 (30 mg, 14%), its diastereomer 57 (74 mg, 34%), and the
starting aldehyde 55 (14 mg, 14%).
AHCTUNGTRENNUNG
stannyl-2-oxo-dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (58)
Compound 56: [a]2D0 =ꢀ1.33 (c=0.64 in CHCl3); 1H NMR (400.0 MHz,
CDCl3): d=7.49–7.43 (m, 2H), 7.39–7.30 (m, 3H), 5.97 (dq, J=9.6, 1.4,
J1H,117Sn =J1H,119Sn =132.8 Hz, 1H), 5.59 (s, 1H), 4.80 (d, J=6.9 Hz, 1H),
4.70 (d, J=6.9 Hz, 1H), 4.70–4.67 (ddd, J=7.8, 7.3, 2.7 Hz, 1H), 4.03
(ddd, J=10.1, 10.1, 2.3 Hz, 1H), 3.73 (dd, J=10.1, 1.4 Hz, 1H), 3.69 (dd,
J=9.6, 9.2 Hz, 1H), 3.50 (dd, J=9.6, 6.0 Hz, 1H), 3.43 (s, 3H; CH3), 3.23
(dd, J=5.9, 5.0 Hz, 1H), 2.98 (d, J=7.3 Hz, 1H; OH), 2.77 (qdd, J=6.9,
5.0, 1.8 Hz, 1H), 2.24 (dqd, J=9.6, 6.9, 5.9 Hz, 1H), 2.12 (ddd, J=14.6,
7.8, 2.3 Hz, 1H), 2.10 (dddm, J=9.2, 6.0, 1.4 Hz, 1H), 1.95 (ddd, J=14.6,
10.1, 2.7 Hz, 1H), 1.89 (d, J=1.4, J1H,117Sn =J1H,119Sn =44.8 Hz, 3H; CH3),
1.76 (ddq, J=10.1, 10.1, 6.4 Hz, 1H), 1.54–1.43 (m, 6H; 3CH2), 1.33–1.29
(sext, J=7.8 Hz, 6H; 3CH2), 1.22 (d, J=6.9 Hz, 3H; CH3), 1.02 (d, J=
6.9 Hz, 3H; CH3), 1.0–0.81 (m, 18H; 4CH3, 3CH2), 0.89 (s; 3CH3), 0.81
(d, J=6.4 Hz, 3H; CH3), 0.04 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
Coupling reaction with tBuLi: A solution of tBuLi (1.5m in pentane,
295 mL, 0.44 mmol, 1.98 equiv) was added to a solution of alkyne 32
(215 mg, 0.44 mmol, 2.0 equiv) in THF (3 mL) at ꢀ788C. The resulting
mixture was stirred for 30 min at ꢀ788C and then a solution of amide 54
(100 mg, 0.22 mmol, 1.0 equiv) in THF (1 mL) was slowly added. After
the reaction mixture had been stirred for 3 h at 08C, a saturated aqueous
NH4Cl solution was added and the reaction mixture was extracted with
Et2O. The organic layers were washed with water and brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure.
The residue was purified by chromatography on silica gel (cyclohexane/
Et2O 98:2 to 80:20) to furnish the title compound 58 (156 mg, 81%).
Coupling reaction with nBuLi—preparation of nBuLi in Et2O: Small
pieces of lithium (wire containing 0.5–1% Na, 4.3 g, 619 mmol,
2.48 equiv) were introduced to a four-necked flask (500 mL) containing
dry Et2O (100 mL) and equipped with a thermometer, a mechanical stir-
CDCl3): d=143.9 (J
Sn =J
13C,117
Sn =26.8 Hz; CH), 138.6 (J
13C,119
=
13C,117Sn
J
Sn =385.3 Hz; C), 137.7 (C), 128.3 (CH), 127.9 (2CH), 125.7 (2CH),
13C,119
rer, and
a dropping funnel under argon. After starting the stirrer,
99.8 (CH), 98.1 (CH2), 87.0 (CH), 85.5 (C), 82.5 (C), 80.1 (CH), 79.6
(CH), 64.7 (CH2), 60.0 (CH), 59.6 (CH3), 42.2 (J Sn =J Sn =30.6 Hz;
30 drops of a nbutylbromide (27 mL, 250 mmol, 1.0 equiv) solution in
Et2O (50 mL) were added from the dropping funnel. After a few minutes,
the solution became slightly cloudy and bright spots appeared on the lith-
ium. The reaction mixture was then cooled to ꢀ108C by immersing in a
ꢀ308C nitrogen/acetone bath. The remainder of the n-butylbromide solu-
tion was added over 20 min while keeping the internal temperature
below ꢀ108C. After the addition was complete, the reaction mixture was
allowed to warm up gradually to 0 and then 108C with stirring over 1.5 h.
13C,117
13C,119
CH), 42.1 (CH2), 36.4 (CH), 34.7 (CH), 30.0 (CH), 29.1 (J
=
13C,117Sn
J
Sn =19.1 Hz; 3CH2), 27.3 (J
13C,119
Sn =J
13C,117
Sn =57.5 Hz; 3CH2), 26.7
13C,119
(J
Sn =J
13C,117
Sn =44.1 Hz; CH3), 25.8 (3CH3), 18.6 (CH3), 18.1 (C), 16.6
13C,119
(CH3), 13.6 (3CH3), 11.5 (CH3), 9.8 (J
Sn =313.4, J
13C,117
Sn =327.8 Hz;
13C,119
3CH2), 9.5 (CH3), ꢀ5.5 ppm (2CH3); IR (film): n˜ =2956, 2928, 2855,
2360, 2341, 1594, 1455, 1404, 1375, 1255, 1149, 1095, 1050, 836, 775, 695,
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11107

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
The pale-blue solution was then filtered whilst being transferred to a
flask by cannula, titrated by a standard method (1.23m, 74%), and kept
under argon at 48C.
3CH2), 25.9 (3CH3), 18.5 (CH3), 18.3 (C), 16.3 (CH3), 13.7 (3CH3), 11.6
(CH3), 9.9 (J
Sn =313.4,
13C,117
J
Sn =327.8 Hz; 3CH2), 9.6 (CH3),
13C,119
ꢀ5.4 ppm (2CH3); IR (film): n˜ =2956, 2928, 2380, 2341, 1456, 1402, 1375,
1350, 1250, 1158, 1098, 1015, 920, 837, 775, 690, 663 cmꢀ1; elemental anal-
ysis calcd (%) for C48H86O7SiSn: C 62.53, H 9.40; found: C 62.33, H 9.59.
A solution of nBuLi in Et2O (1.23m, 2.8 mL, 3.44 mmol, 1.98 equiv) was
added to a solution of alkyne 32 (1.7 g, 3.5 mmol, 2.0 equiv) in THF
(25 mL) at ꢀ408C. The resulting mixture was stirred for 50 min at ꢀ408C
and then a solution of amide 54 (789 mg, 1.75 mmol, 1.0 equiv) in THF
(12 mL) was slowly added. After the reaction mixture had been stirred
for 1 h at 08C, a saturated aqueous NH4Cl solution was added and the re-
action mixture was extracted with Et2O. The organic layers were washed
with water and brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/Et2O 98:2 to 80:20) to furnish the title
compound 58 (1.22 g, 81%). [a]2D0 =+13.4 (c=0.94 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=7.43–7.40 (m, 2H), 7.38–7.34 (m, 3H), 5.92 (dq,
J=6.9, 1.4 Hz, 1H), 5.54 (s, 1H), 4.71 (d, J=6.9 Hz, 1H), 4.66 (d, J=
6.9 Hz, 1H), 4.20 (ddt, J=9.6, 6.4, 5.9 Hz, 1H), 3.73 (dd, J=9.6, 1.4 Hz,
1H), 3.69 (dd, J=9.6, 9.2 Hz, 1H), 3.51 (dd, J=9.6, 5.9 Hz, 1H), 3.39 (s,
3H; CH3), 3.27 (dd, J=6.4, 4.1 Hz, 1H), 2.87 (qd, J=6.9, 4.1 Hz, 1H),
2.85 (d, J=5.9 Hz, 2H), 2.22 (dqd, J=9.6, 6.9, 6.4 Hz, 1H), 1.98 (dddm,
J=9.2, 5.9, 1.4 Hz, 1H), 1.88 (d, J=1.4, J1H,117Sn =J1H,119Sn =41.2 Hz, 3H;
CH3), 1.72 (ddq, J=9.6, 9.6, 6.9 Hz, 1H), 1.54–1.43 (m, 6H; 3CH2), 1.32
(sext, J=7.3 Hz, 6H; 3CH2), 1.24 (d, J=6.9 Hz, 3H; CH3), 1.00 (d, J=
6.9 Hz, 3H; CH3), 0.95–0.87 (m, 27H; 7CH3 +3CH2), 0.80 (d, J=6.9 Hz,
3H; CH3), 0.04 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz, CDCl3): d=
185.3 (C), 143.4 (CH), 138.8 (C), 138.7 (C), 128.4 (CH), 128.0 (2CH),
126.0 (2CH), 99.9 (CH), 98.3 (CH2), 96.5 (C), 85.2 (CH), 83.0 (C), 80.3
A
HF·pyridine stock solution (500 mL, prepared from commercial
HF·pyridine 2 mL/pyridine 4 mL/THF 10 mL) was added to a solution of
the preceding di-MOM ether (100 mg, 0.108 mmol, 1.0 equiv) in THF
(1 mL) at 08C. After the reaction mixture had been stirred for 4 h at
208C, the resulting mixture was quenched with a saturated aqueous
NaHCO3 solution and extracted with Et2O. The organic layers were
washed with brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (cyclohexane/AcOEt 70:30 to 40:60) to give
[2S,4R(1S),5S,6S(2S,5S,6R,7S,8Z)]-4-(2-hydroxy-1-methyl
ethyl-1-yl)-6-
{5,7-dimethyl-2,6-bis[(methoxymethyl)oxy]-9-tributylstannyl-dec-8-en-3-
yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (84 mg, 96%). [a]2D0 =ꢀ35.9 (c=
1.19 in CHCl3); 1H NMR (400.0 MHz, CDCl3): d=7.46–7.43 (m, 2H),
7.38–7.33 (m, 3H), 6.01 (dq, 1H, J=9.6, 1.4, J1H,117Sn =J1H,119Sn =132.8 Hz),
5.58 (s, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.79 (d, J=6.4 Hz, 1H), 4.76 (d, J=
11.0 Hz, 1H), 4.70 (d, J=6.4 Hz, 1H), 4.59 (d, J=6.9 Hz, 1H), 3.83–3.73
(m, 4H), 3.44 (s, 3H; CH3), 3.34 (s, 3H; CH3), 3.24 (t, J=5.5 Hz, 1H),
2.72 (qd, J=6.9, 5.5 Hz, 1H), 2.28–2.23 (dqd, J=9.6, 6.9, 5.5 Hz, 1H),
2.28–2.23 (m, 1H), 2.06–2.02 (m, 1H), 1.89 (d, J=1.4, J1H,117Sn =J1H,119
=
Sn
43.0 Hz, 3H; CH3), 1.89–1.85 (m, 1H), 1.83 (dqd, J=6.9, 6.4, 3.4 Hz,
1H), 1.49–1.38 (m, 6H; 3CH2), 1.37–1.28 (sext, J=7.3 Hz, 6H; 3CH2),
1.18 (d, J=6.9 Hz, 3H; CH3), 1.43 (d, J=6.9 Hz, 3H; CH3), 1.03 (d, J=
6.9 Hz, 3H; CH3), 1.02–0.88 (m, 15H; 3CH2 +3CH3), 0.85 ppm (d, J=
6.9 Hz, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=144.1 (CH), 138.5
(C), 137.5 (C), 128.5 (CH), 128.1 (2CH), 125.7 (2CH), 99.9 (CH), 98.0
(CH2), 93.6 (CH2), 87.7 (C), 85.2 (CH), 83.5 (CH or CH2), 80.3 (C), 77.5
(CH or CH2), 66.7 (CH or CH2), 60.9 (CH), 56.1 (CH3), 55.4 (CH3), 41.9
(CH), 78.2 (CH), 65.0 (CH2), 56.4 (CH3), 49.5 (CH2), 42.8 (J
=
13C,117Sn
J
Sn =30.6 Hz; CH), 36.7 (CH), 35.0 (CH), 30.8 (CH), 29.4 (3CH2),
13C,119
27.5 (J
Sn =J
13C,117
Sn =58.4 Hz; CH3, 3CH2), 26.0 (3CH3), 18.4 (C), 17.8
13C,119
(CH3), 17.1 (CH3), 13.8 (3CH3), 11.9 (CH3), 10.1 (J
Sn =313.4,
13C,117
J
Sn =328.8 Hz; 3CH2), 9.7 (CH3), ꢀ5.2 ppm (2CH3); IR (film): n˜ =
13C,119
2956, 2855, 2212, 1678, 1465, 1403, 1376, 1345, 1255, 1215, 1147, 1092,
1032, 837, 758, 699 cmꢀ1; elemental analysis calcd (%) for C46H80O6SiSn:
C 63.08, H 9.21; found: C 63.18, H 9.32.
(J
Sn =J
13C,117
Sn =34.4 Hz; CH), 39.8 (CH2), 35.5 (CH), 35.3 (CH), 30.1
13C,119
(CH), 29.2 (J
Sn =J
13C,117
Sn =19.2 Hz; 3CH2), 27.4 (J
13C,119
Sn =J
13C,117
=
13C,119Sn
58.5 Hz; 3CH2), 27.2 (J
Sn =J
13C,117
Sn =46.0 Hz; CH3), 18.5 (CH3), 16.3
13C,119
(CH3), 13.6 (3CH3), 11.5 (CH3), 9.8 (J
Sn =314.4, J
13C,117
Sn =327.8 Hz;
13C,119
ACHTUNGTRENNUNG[2S,4R(1R),5S,6S(2S,5S,6R,7S,8Z)]-4-(2-Methoxycarbonyl-1-methyl
3CH2), 9.5 ppm (CH3); IR (film): n˜ =3380, 2956, 2927, 2872, 2852, 1590,
1454, 1436, 1376, 1351, 1154, 1098, 1029, 699 cmꢀ1; elemental analysis
calcd (%) for C42H72O7Sn: C 62.46, H 8.98; found: C 62.58, H 9.00.
ethyl-1-yl)-6-{5,7-dimethyl-2-hydroxy-2,6-bis[(methoxymethyl)oxy]-9-tri-
butylstannyl-dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (59): Di-
isopropylethylamine (34.1 mL, 196 mmol, 20 equiv) and MOMCl
(5.95 mL, 78.4 mmol, 10 equiv) were added to a solution of compound 56
BAIB (1.44 g, 4.46 mmol, 1.1 equiv) and TEMPO (160 mg, 0.81 mmol,
0.2 equiv) were added to a solution of the preceding alcohol (3.3 g,
4.05 mmol, 1.0 equiv) in dried CH2Cl2 (20 mL). After the reaction mix-
ture had been stirred for 3 h at 208C, a 1m Na2S2O3 solution was added,
and the reaction mixture was extracted with Et2O. The organic layers
were washed with a saturated aqueous NaHCO3 solution, brine, dried
over MgSO4, filtered, and the solvent was removed under reduced pres-
sure. The crude [2S,4R(1R),5S,6S(2S,5S,6R,7S,8Z)]-4-(2-formyl-1-methyl
ethyl-1-yl)-6-{5,7-dimethyl-2,6-bis[(methoxymethyl)oxy]-9-tributylstannyl-
dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan was used without fur-
(6.88 g, 7.84 mmol,
1.0 equiv), dimethylaminopyridine
(192 mg,
1.57 mmol, 0.2 equiv) and TBAI (290 mg, 0.784 mmol, 0.1 equiv) in dried
CH2Cl2 (35 mL) at 08C. After the reaction mixture had been stirred for
12 h at 208C, it was quenched with a saturated aqueous NaHCO3 solution
and extracted with Et2O. The organic layers were washed with brine,
dried over MgSO4, filtered, and the solvent was removed under reduced
pressure. The residue was purified by chromatography on silica gel (cy-
clohexane/AcOEt
[2S,4R(1S),5S,6S(2S,5S,6R,7S,8Z)]-4-[2-(tert-butyldimethylsilyloxy)-1-
methyl ethyl-1-yl]-6-{5,7-dimethyl-2,6-bis[(methoxymethyl)oxy]-9-tribu-
95:5
to
80:20)
to
give
1
ther purification for the next step. H NMR (400.0 MHz, CDCl3): d=9.80
tylstannyl-dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan
(6.2 g,
(s, 1H), 7.42–7.32 (m, 5H), 6.00 (dq, J=8.2, 1.4, J1H,117Sn =J1H,119 =
Sn
86%) as
a
yellow oil. [a]2D0 =ꢀ17.2 (c=1.52 in CHCl3); 1H NMR
135.1 Hz, 1H), 5.59 (s, 1H), 5.03 (d, J=6.9 Hz, 1H), 4.80–4.76 (m, 1H),
4.78 (d, J=6.9 Hz, 1H), 4.69 (d, J=6.9 Hz, 1H), 4.58 (d, J=6.9 Hz, 1H),
4.15 (dd, J=10.1, 2.3 Hz, 1H), 3.84 (ddd, J=9.6, 9.2, 1.4 Hz, 1H), 3.43 (s,
3H; CH3), 3.35 (s, 3H; CH3), 3.23 (t, J=5.5 Hz, 1H), 2.72 (qd, J=7.3,
5.5 Hz, 1H), 2.64 (qd, J=6.9, 2.3 Hz, 1H), 2.28–2.18 (dqd, J=8.2, 6.9,
5.5 Hz, 1H), 2.28–2.18 (m, 1H), 1.89 (d, J=1.4, J1H,117Sn =J1H,119Sn =41.2 Hz,
3H; CH3), 1.89–1.84 (m, 1H), 1.84 (ddq, J=10.1, 9.6, 6.4 Hz, 1H), 1.51–
1.44 (m, 6H; 3CH2), 1.33 (sext, J=7.3 Hz, 6H; 3CH2), 1.23 (d, J=
6.9 Hz, 3H; CH3), 1.19 (d, J=7.3 Hz, 3H; CH3), 0.99 (d, J=6.9 Hz, 3H;
CH3), 0.96–0.88 (m, 15H; 3CH2 +3CH3), 0.90 ppm (d, J=6.4 Hz, 3H);
(400.0 MHz, CDCl3): d=7.49–7.47 (m, 2H), 7.37–7.30 (m, 3H), 6.00 (d,
1H, J=9.6, J1H,117Sn =J1H,119Sn =133.7 Hz), 5.51 (s, 1H), 5.04 (d, J=6.4 Hz,
1H), 4.82–4.78 (m, 1H), 4.78 (d, J=6.9 Hz, 1H), 4.70 (d, J=6.9 Hz, 1H),
4.70 (d, J=6.4 Hz, 1H), 3.75–3.67 (m, 3H), 3.51 (dd, J=9.6, 5.9 Hz, 1H),
3.43 (s, 3H; CH3), 3.36 (s, 3H; CH3), 3.24 (t, J=5.5 Hz, 1H), 2.72 (qd,
J=6.9, 5.5 Hz, 1H), 2.28–2.18 (dqd, J=9.6, 6.9, 5.5 Hz, 1H), 2.28–2.18
(m, 1H), 2.04–1.98 (m, 1H), 1.89 (s, J1H,117Sn =J1H,119Sn =41.7 Hz, 3H; CH3),
1.87–1.83 (m, 1H), 1.66–1.63 (m, 1H), 1.52–1.45 (m, 6H; 3CH2), 1.33
(sext, J=7.3 Hz, 6H; 3CH2), 1.18 (d, J=7.3 Hz, 3H; CH3), 0.98 (d, J=
6.9 Hz, 3H; CH3), 0.98–0.85 (m, 18H; 4CH3 +3CH2), 0.89 (s, 9H;
3CH3), 0.81 (d, J=6.4 Hz, 3H; CH3), 0.05 ppm (s, 6H; 2CH3); 13C NMR
13C NMR (100.5 MHz, CDCl3): d=204.0 (C), 144.0 (J
Sn =J
13C,117
=
13C,119Sn
32.6 Hz; CH), 137.9 (C), 137.2 (C), 128.0 (2CH), 127.3 (CH), 125.6
(2CH), 99.6 (CH), 98.0 (CH2), 94.2 (CH2), 87.7 (C), 86.2 (CH), 80.6
(CH), 80.2 (C), 77.0 (CH), 60.7 (CH), 56.1 (CH3), 55.4 (CH3), 47.2 (CH),
(100.5 MHz, CDCl3): d=144.2 (J
Sn =J
13C,117
Sn =29.7 Hz; CH), 139.1
13C,119
(C), 137.5 (C), 128.3 (CH), 128.0 (2CH), 125.8 (2CH), 99.6 (CH), 98.1
(CH2), 93.6 (CH2), 87.7 (C), 85.3 (C), 80.1 (C), 80.0 (CH), 77.6 (CH),
65.0 (CH2), 61.0 (CH), 56.1 (CH3), 55.5 (CH3), 42.0 (CH), 39.9 (CH2),
41.9 (J
Sn =J
13C,117
Sn =34.4 Hz; CH), 39.7 (CH2), 34.9 (CH), 30.1 (CH),
13C,119
29.1 (J
Sn =J
13C,117
Sn =21.0 Hz; 3CH2), 27.3 (J
13C,119
Sn =J
13C,117
Sn =57.4 Hz;
13C,119
36.6 (CH), 35.2 (CH), 30.2 (CH), 29.2 (J
Sn =J
13C,117
Sn =20.1 Hz; 3CH2),
3CH2), 27.2 (J
Sn =J
13C,117
Sn =46.0 Hz; CH3), 18.4 (CH3), 16.3 (CH3),
13C,119
13C,119
27.4 (J
Sn =J
13C,117
Sn =58.4 Hz; CH3), 26.9 (J
13C,119
Sn =J Sn =53.6 Hz;
13C,117 13C,119
13.6 (3CH3), 13.5 (CH3), 9.8 (3CH2), 6.8 (CH3).
11108
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
A solution of NaClO2 (549 mg, 6.07 mmol, 1.5 equiv) and NaH2PO4
(729 mg, 6.07 mmol, 1.5 equiv) in H2O (21 mL) was added to a solution
of the preceding aldehyde (3.26 g, 4.05 mmol, 1.0 equiv) in tert-butanol
(245 mL) and 2-methyl-2-butene (55 mL). After the reaction mixture had
been stirred for 1 h at 208C, the same quantity of NaClO2 and NaH2PO4
solution was added. The resulting mixture was stirred for 1 h and was
then quenched by the addition of a 0.1n HCl solution. The mixture was
extracted with CH2Cl2 and the organic layers were washed with brine,
dried over MgSO4, filtered, and the solvent was removed under reduced
pressure. The crude [2S,4R(1R),5S,6S(2S,5S,6R,7S,8Z)]-4-(2-carboxy-1-
methyl ethyl-1-yl)-6-{5,7-dimethyl-2,6-bis[(methoxymethyl)oxy]-9-tribu-
tylstannyl-dec-8-en-3-yn-1-yl}-5-methyl-2-phenyl-1,3-dioxinan was used in
the next step without further purification. 1H NMR (400.0 MHz, CDCl3):
d=7.43–7.40 (m, 2H), 7.33–7.28 (m, 3H), 6.00 (d, J=8.2 Hz, 1H,
J1H,117Sn =J1H,119Sn =133.3 Hz), 5.54 (s, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.79 (d,
J=6.4 Hz, 1H), 4.80–4.78 (m, 1H), 4.69 (d, J=6.4 Hz, 1H), 4.09 (dd, J=
10.1, 2.3 Hz, 1H), 4.00 (d, J=6.9 Hz, 1H), 3.79 (td, J=9.6, 1.4 Hz, 1H),
3.43 (s, 3H; CH3), 3.35 (s, 3H; CH3), 3.23 (t, J=5.5 Hz, 1H), 2.86 (qd,
J=6.9, 2.3 Hz, 1H), 2.72 (qd, J=6.9, 5.5 Hz, 1H), 2.20 (dqd, J=8.2, 6.4,
5.5 Hz, 1H), 2.22–2.18 (m, 1H), 1.89 (s, J1H,117Sn =J1H,119Sn =42.6 Hz, 3H;
CH3), 1.89–1.85 (m, 1H), 1.64 (ddq, J=10.1, 9.6, 6.4 Hz, 1H), 1.53–1.42
(m, 6H; 3CH2), 1.31 (d, J=6.9 Hz, 3H; CH3), 1.30 (sext, J=7.3 Hz, 6H;
3CH2), 1.17 (d, J=6.9 Hz, 3H; CH3), 0.98 (d, J=6.4 Hz, 3H; CH3), 0.94–
0.85 ppm (m, 18H; 3CH2, 4CH3); 13C NMR (100.5 MHz, CDCl3): d=
The crude [2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z)]-4-(2-methoxycarbonyl-1-
methyl ethyl-1-yl)-6-{5,7-dimethyl-2,6-bis[(methoxymethyl)oxy]-9-tribu-
tylstannyl-deca-3,8-dien-1-yl}-5-methyl-2-phenyl-1,3-dioxinan was used
without further purification in the next step. 1H NMR (400.0 MHz,
CDCl3): d=7.49–7.44 (m, 2H), 7.35–7.29 (m, 3H), 5.93 (dq, J=8.2, 1.4,
J1H,117Sn =J1H,119Sn =136.0 Hz, 1H), 5.60 (s, 1H), 5.55 (t, J=10.5 Hz, 1H),
5.25 (dd, J=10.5, 10.1 Hz, 1H), 4.87 (dd, J=10.1, 9.2 Hz, 1H), 4.72 (d,
J=6.9 Hz, 1H), 4.54 (s, 2H), 4.49 (d, J=6.9 Hz, 1H), 4.05 (dd, J=10.1,
3.2 Hz, 1H), 3.82 (dd, J=10.1, 9.2 Hz, 1H), 3.74 (s, 3H; CH3), 3.32 (s,
6H; 2CH3), 3.14 (dd, J=6.9, 4.1 Hz, 1H), 2.85–2.79 (qd, J=6.4, 3.2 Hz,
1H), 2.85–2.79 (dqd, J=10.9, 6.9, 6.9 Hz, 1H), 2.17 (dqd, J=8.2, 6.9,
4.1 Hz, 1H), 2.00–1.91 (m, 1H), 1.85 (d, J=1.4, J1H,117Sn =J1H,119Sn =42.1 Hz,
3H; CH3), 1.70–1.60 (m, 2H), 1.51–1.44 (m, 6H; 3CH2), 1.32 (sext, J=
7.3 Hz, 6H; 3CH2), 1.23 (d, J=6.9 Hz, 3H; CH3), 0.98 (d, J=6.9 Hz, 3H;
CH3), 0.94 (d, J=6.4 Hz, 3H; CH3), 0.92–0.82 ppm (m, 18H; 3CH2 +
4CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8 (C), 144.7 (CH), 138.7
(CH), 137.3 (C), 136.5 (C), 129.0 (CH), 128.2 (CH), 127.9 (2CH), 125.7
(2CH), 99.5 (CH), 97.9 (CH2), 93.1 (CH2), 86.3 (CH), 82.2 (CH), 77.3
(CH), 66.2 (CH), 56.1 (CH3), 55.2 (CH3), 51.9 (CH3), 41.0 (2CH), 39.1
(CH2), 35.9 (CH), 35.8 (CH), 29.2 (J
Sn =J
13C,117
Sn =19.2 Hz; 3CH2),
13C,119
27.4 (J
Sn =J
13C,117
Sn =57.5 Hz; 3CH2), 27.2 (J
13C,119
Sn =J
13C,117
Sn =42.2 Hz;
13C,119
CH3), 17.7 (CH3), 15.6 (CH3), 14.2 (CH3), 13.7 (3CH3), 11.6 (CH3),
9.9 ppm (J Sn =313.4, J Sn =326.8 Hz; 3CH2).
13C,117
13C,119
An iodine solution (48 mg, 0.19 mmol, 0.98 equiv) in CH2Cl2 (16 mL) was
added to a solution of the preceding compound (168 mg, 0.2 mmol,
1.0 equiv) in CH2Cl2 (4 mL) at 08C over 30 min. The resulting solution
was immediately added to a 1m Na2S2O3 solution and the organic phase
was then concentrated under reduced pressure. The residue was taken up
with Et2O (3 mL) and a 0.7m KF solution (600 mL). After the reaction
mixture had been stirred for 3 h at 208C, the solution was filtered and ex-
tracted with Et2O. The organic layers were washed with brine, dried over
MgSO4, filtered, and the solvent was removed under reduced pressure.
The residue was purified by chromatography on silica gel (cyclohexane/
Et2O 80:20 to 50:50) to give the title compound 60 (96 mg, 71% for
178.0 (C), 144.2 (J
Sn =J
13C,117
Sn =29.0 Hz; CH), 138.2 (C), 137.6 (C),
13C,119
128.5 (CH), 128.1 (2CH), 125.7 (2CH), 99.7 (CH), 98.1 (CH2), 93.7
(CH2), 88.0 (C), 85.3 (CH), 81.8 (CH), 80.0 (C), 77.0 (CH), 61.0 (CH),
56.2 (CH3), 55.5 (CH3), 42.1 (CH), 40.7 (CH), 39.8 (CH2), 35.5 (CH), 30.2
(CH), 29.2 (J
Sn =J
13C,117
Sn =19.2 Hz; 3CH2), 27.3 (J
13C,119
Sn =J
13C,117
=
13C,119Sn
57.4 Hz; 3CH2), 27.2 (J
Sn =J
13C,117
Sn =36.4 Hz; CH3), 18.6 (CH3), 16.4
13C,119
(CH3), 15.2 (CH3), 13.7 (3CH3), 11.5 (CH3), 9.9 ppm (J
Sn =310.6,
13C,117
J
Sn =331.8 Hz; 3CH2).
13C,119
A
(trimethylsilyl)diazomethane solution (2m in hexane, 4.05 mmol,
solution of the preceding acid (3.3 g,
1.0 equiv) was added to
a
1
4.05 mmol, 1.0 equiv) in benzene (160 mL)/MeOH (45 mL) until a yellow
tint persisted. The resulting mixture was stirred for 15 min and was then
concentrated in vacuum. The residue was purified by chromatography on
silica gel (cyclohexane/AcOEt 90:10 to 80:20) to give the expected prod-
uct 59 (2.32 g, 69% over 3 steps). [a]2D0 =ꢀ34.5 (c=0.96 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.45–7.42 (m, 2H), 7.37–7.31 (m, 3H),
6.00 (dq, J=9.6, 1.8, J1H,117Sn =J1H,119Sn =132.8 Hz, 1H), 5.55 (s, 1H), 5.03
(d, J=6.4 Hz, 1H), 4.81–4.77 (m, 1H), 4.79 (d, J=6.9 Hz, 1H), 4.70 (d,
J=6.9 Hz, 1H), 4.56 (d, J=6.4 Hz, 1H), 4.05 (dd, J=10.5, 3.2 Hz, 1H),
3.78 (ddd, J=9.6, 9.1, 1.8 Hz, 1H), 3.72 (s, 3H; CH3), 3.43 (s, 3H; CH3),
3.36 (s, 3H; CH3), 3.23 (t, J=5.5 Hz, 1H), 2.82 (qd, J=7.3, 3.2 Hz, 1H),
2.72 (qd, J=6.9, 5.5 Hz, 1H), 2.30–2.17 (dqd, J=9.6, 6.9, 5.5 Hz, 1H),
2.30–2.17 (m, 1H), 1.89 (d, J=1.8, J1H,117Sn =J1H,119Sn =42.1 Hz, 3H; CH3),
1.87–1.83 (m, 1H), 1.75 (ddq, J=10.5, 9.6, 6.9 Hz, 1H), 1.57–1.51 (m,
6H; 3CH2), 1.37 (sext, J=7.3 Hz, 6H; 3CH2), 1.24 (d, J=7.3 Hz, 3H;
CH3), 1.19 (d, J=6.9 Hz, 3H; CH3), 1.00–0.80 (m, 15H; 3CH2, 3CH3),
0.85 (d, J=6.9 Hz, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8
2 steps). [a]2D0 =+3.70 (c=0.78 in CHCl3); H NMR (400.0 MHz, CDCl3):
d=7.49–7.44 (m, 2H), 7.35–7.30 (m, 3H), 5.60 (t, J=10.5 Hz, 1H), 5.59
(s, 1H), 5.28 (t, J=10.5 Hz, 1H), 5.24 (dq, J=8.2, 1.4 Hz, 1H), 4.83 (ddd,
J=10.5, 9.2, 1.8 Hz, 1H), 4.72 (d, J=6.9 Hz, 1H), 4.57 (s, 2H), 4.51 (d,
J=6.9 Hz, 1H), 4.08 (dd, J=10.1, 3.2 Hz, 1H), 3.84 (dd, J=9.6, 9.2,
1.8 Hz, 1H), 3.74 (s, 3H; CH3), 3.35 (s, 6H; 2CH3), 3.26 (t, J=5.5 Hz,
1H), 2.86–2.78 (dqd, J=10.5, 6.9, 5.5 Hz, 1H), 2.86–2.78 (qd, J=6.9,
3.2 Hz, 1H), 2.47 (dqd, J=8.2, 6.9, 5.5 Hz, 1H), 2.36 (d, J=1.4 Hz, 3H;
CH3), 1.99 (ddm, J=11.0, 1.8 Hz, 1H), 1.70 (ddq, J=10.1, 9.6, 6.9 Hz,
1H), 1.72–1.64 (m, 1H), 1.25 (d, J=6.9 Hz, 3H; CH3), 1.08 (d, J=6.9 Hz,
3H; CH3), 0.96 (d, J=6.9 Hz, 3H; CH3), 0.89 ppm (d, J=6.9 Hz, 3H;
CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8 (C), 138.8 (C), 137.9 (C),
135.8 (CH), 129.4 (CH), 128.2 (2CH), 127.9 (2CH), 125.7 (CH), 100.4
(CH), 99.4 (CH2), 97.9 (C), 93.1 (CH2), 85.6 (CH), 82.1 (CH), 77.6 (CH),
66.1 (CH), 56.1 (CH3), 55.2 (CH3), 51.9 (CH3), 43.9 (CH), 41.0 (CH), 39.2
(CH or CH2), 35.7 (CH), 35.3 (CH3), 33.6 (CH or CH2), 18.4 (CH3), 14.7
(CH3), 11.7 (CH3), 9.2 ppm (CH3); IR (film): n˜ =3428, 2952, 2928, 2880,
2821, 1744, 1454, 1435, 1398, 1207, 1152, 1090, 1045 cmꢀ1; elemental anal-
ysis calcd (%) for C31H47IO8: C 55.19, H 7.02; found: C 55.31, H 7.15.
(C), 144.4 (J
Sn =J
13C,117
Sn =27.8 Hz; CH), 138.6 (C), 137.7 (J
13C,119
=
13C,117Sn
J
Sn =369.0 Hz; C), 128.6 (CH), 128.5 (2CH), 125.8 (2CH), 99.7 (CH),
13C,119
98.2 (CH2), 93.8 (CH), 87.9 (C), 85.4 (C), 82.2 (CH), 80.5 (C), 77.0 (CH),
61.1 (CH), 56.2 (CH3), 55.7 (CH3), 52.1 (CH3), 42.2 (J Sn =J
AHCTUNGTRENNUNG
=
13C,119Sn
13C,117
42.6 Hz; CH), 41.1 (CH), 39.9 (CH2), 35.8 (CH), 30.3 (CH), 29.4
(J Sn =J Sn =19.2 Hz; 3CH2), 27.6 (J Sn =J Sn =57.4 Hz;
5,7,9,11,13,15-hexamethyl-2,6-bis[(methoxymethyl)oxy]-14-(triethylsilyl-
oxy)nonadeca-3,8,16,18-tetraen-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (61):
tBuLi (1.5m in pentane, 355 mL, 0.53 mmol, 3.8 equiv) was rapidly added
to a solution of the alkyliodide 43 (145 mg, 0.26 mmol, 1.8 equiv) in Et2O
(3.7 mL) at ꢀ808C. After 2 min, 9-MeOBBN (1m in hexane, 602 mL,
0.60 mmol, 4.3 equiv) followed by THF (3.7 mL) was added. The result-
ing mixture was stirred 10 min at ꢀ788C and was then allowed to warm
to 208C over a period of 1 h 15 min. An aqueous 3.5m Cs2CO3 solution
was then added (220 mL, 0.77 mmol, 5.5 equiv), followed by the addition
of the vinyliodide 60 (96 mg, 0.14 mmol, 1.0 equiv) in DMF (3.7 mL). Fi-
13C,117
13C,119
13C,117
13C,119
3CH2), 27.4 (J
Sn =J
13C,117
Sn =44.1 Hz; CH3), 18.7 (CH3), 16.5 (CH3),
13C,119
13.8 (3CH3), 11.6 (CH3), 10.0 (J
Sn =312.4, J
13C,117
Sn =327.8 Hz; 3CH2),
13C,119
9.3 ppm (CH3); IR (film): n˜ =2955, 2927, 2872, 2853, 1745, 1454, 1403,
1349, 1375, 1207, 1154, 1110, 1029, 700 cmꢀ1; elemental analysis calcd
(%) for C43H72O8Sn: C 61.80, H 8.68; found: C 61.92, H 8.83.
ACHTUNGTRENNUNG[2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z)]-4-(2-Methoxycarbonyl-1-methyl
ethyl-1-yl)-6-{5,7-dimethyl-9-iodo-2,6-bis[(methoxymethyl)oxy]deca-3,8-
dien-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (60): PtO2 (20 mg, 0.088 mmol,
0.35 equiv) was added to a solution of the preceding ester (200 mg,
0.24 mmol, 1.0 equiv) in AcOEt (2.5 mL). The resulting suspension was
stirred for 12 h at 208C under a H2 atmosphere. After this time, the mix-
ture was filtered and the solvent was removed under reduced pressure.
nally, [PdCl2ACTHNUTRGNEUG(N dppf)] (12 mg, 0.014 mmol, 0.10 equiv) and triphenylarsine
(7 mg, 0.021 mmol, 0.12 equiv) were added, and the resulting dark solu-
tion was stirred at 208C for 16 h. After extraction with Et2O, the organic
layers were washed with brine, dried over MgSO4, filtered, and the sol-
Chem. Eur. J. 2008, 14, 11092 – 11112
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11109

J.-F. Betzer, A. Pancrazi, J. Ardisson et al.
vent was removed under reduced pressure. The residue was purified by
chromatography on silica gel (cyclohexane/Et2O 80:20 to 60:40) to give
the title compound 61 (87 mg, 60%). [a]2D0 =+13.8 (c=0.90 in CHCl3);
1H NMR (400.0 MHz, CDCl3): d=7.47–7.44 (m, 2H), 7.35–7.30 (m, 3H),
6.57 (ddd, J=16.9, 11.0, 10.5 Hz, 1H), 6.03 (dd, J=11.0, 10.5 Hz, 1H),
5.58 (s, 1H), 5.54 (dd, J=11.9, 10.5 Hz, 1H), 5.54 (t, J=10.5 Hz, 1H),
5.20 (d, J=16.9 Hz, 1H), 5.22 (dd, J=10.5, 10.1 Hz, 1H), 5.11 (d, J=
10.5 Hz, 1H), 4.97 (d, J=10.1 Hz, 1H), 4.84 (dd, J=11.0, 10.1 Hz, 1H),
4.71 (d, J=6.9 Hz, 1H), 4.54 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.06 (dd,
J=10.1, 3.2 Hz, 1H), 3.82 (dd, J=10.1, 8.7 Hz, 1H), 3.74 (s, 3H, CH3),
3.55 (dd, J=6.9, 3.2 Hz, 1H), 3.44 (dd, J=4.6, 4.1 Hz, 1H), 3.34 (s, 3H;
CH3), 3.33 (s, 3H; CH3), 3.07 (t, J=5.5 Hz, 1H), 2.91–2.76 (m, 3H), 2.54
(dqd, J=10.1, 6.4, 5.5 Hz, 1H), 2.08–1.55 (tq, J=10.1, 6.4 Hz, 1H), 2.08–
1.55 (m, 6H), 1.55 (s, 3H; CH3), 1.22 (d, J=6.9 Hz, 3H; CH3), 1.06–0.83
(m; 8CH3), 0.91 (s, 9H; 3CH3), 0.68 (q, J=7.8 Hz, 6H; 3CH2), 0.63 (d,
J=6.4 Hz, 3H; CH3), 0.07 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz,
CDCl3): d=174.8 (C), 138.8 (C), 136.8 (CH), 134.4 (CH), 132.3 (C),
132.1 (CH), 130.4 (CH), 128.9 (3CH), 128.2 (CH), 127.9 (2CH), 125.8
(CH), 117.4 (CH2), 99.6 (CH), 97.8 (CH2), 92.5 (CH2), 86.9 (CH), 82.2
(CH), 78.0 (CH), 77.0 (2CH), 66.4 (CH), 56.0 (CH3), 55.2 (CH3), 51.9
(CH3), 41.9, 41.0, 40.3, 39.0, 36.2, 35.8, 35.3, 35.0, 34.4 (7CH, 2CH2), 26.9
(3CH3), 23.1 (CH3), 18.5 (C), 18.5, 17.4, 16.5, 14.2, 11.6, 11.3, 9.3 (7CH3,
CH3-2), 7.2 (3CH3), 5.7 (3CH2), ꢀ3.1 (CH3), ꢀ3.2 ppm (CH3); IR (film):
n˜ =3383, 2957, 2931, 2878, 2857, 2821, 2359, 2340, 1747, 1733, 1657, 1455,
1462, 1435, 1396, 1374, 1328, 1252, 1143, 1094, 1045, 919, 835, 772, 739,
701 cmꢀ1; HRMS (ESI): m/z: calcd for C56H98O10NaSi2: 1009.6591; found:
1009.6591.
washed with water, brine, dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The residue was purified by chro-
matography on silica gel (cyclohexane/AcOEt 90:10 to 50:50) to give
[2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z,11S,12R,13S,14S,15S,16Z)]-4-(2-me-
thoxycarbonyl-1-methyl ethyl-1-yl)-6-{12-(tert-butyldimethylsilyloxy)-14-
(carbamoyloxy)-5,7,9,11,13,15-hexamethyl-2,6-bis[(methoxymethyl)oxy]-
nonadeca-3,8,16,18-tetraen-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (76 mg,
64%) as a pale colorless oil. [a]2D0 =+17.4 (c=0.80 in CHCl3); 1H NMR
(400.0 MHz, CDCl3): d=7.50–7.44 (m, 2H), 7.34–7.30 (m, 3H), 6.60 (dt,
J=16.9, 10.5 Hz, 1H), 6.02 (dd, J=11.0, 10.5 Hz, 1H), 5.58 (s, 1H), 5.58–
5.52 (m, 1H), 5.53 (dd, J=12.8, 10.5 Hz, 1H), 5.38 (dd, J=11.0, 10.5 Hz,
1H), 5.28–5.18 (m, 3H), 5.14 (d, J=10.5 Hz, 1H), 4.99 (d, J=10.1 Hz,
1H), 4.82 (dd, J=10.1, 9.2 Hz, 1H), 4.74–4.70 (m, 1H), 4.72 (d, J=
6.9 Hz, 1H), 4.54 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.06 (dd, J=10.1,
3.2 Hz, 1H), 3.81 (dd, J=9.6, 9.2 Hz, 1H), 3.73 (s, 3H; CH3), 3.43 (dd,
J=4.6, 4.1 Hz, 1H), 3.32 (s, 6H; 2CH3), 3.06 (t, J=5.5 Hz, 1H), 2.99
(dqd, J=10.5, 6.9, 3.7 Hz, 1H), 2.83–2.79 (qdm, J=7.3, 5.5 Hz, 1H), 2.81
(dqd, J=10.1, 6.9, 5.5 Hz, 1H), 2.52 (dqd, J=10.1, 6.4, 5.5 Hz, 1H), 2.15–
1.79 (m, 5H), 1.74–1.52 (m, 2H), 1.57 (s, 3H; CH3), 1.25 (d, J=7.3 Hz,
3H; CH3), 1.01 (d, J=6.9 Hz, 3H; CH3), 0.94–0.85 (m, 12H; 4CH3), 0.91
(s, 9H; 3CH3), 0.73 (d, J=6.9 Hz, 3H; CH3), 0.07 (s, 3H; CH3), 0.05 ppm
(s, 3H; CH3); 13C NMR (100.5 MHz, CDCl3): d=174.9 (C), 156.9 (C),
138.8 (CH), 137.0 (C), 133.6 (CH), 132.5 (CH), 132.1 (C), 130.1 (CH),
129.8 (CH), 129.0 (CH), 128.2 (CH), 127.9 (2CH), 125.8 (2CH), 117.9
(CH2), 99.7 (CH), 97.8 (CH2), 93.2 (CH2), 86.9 (CH), 82.1 (CH), 78.8
(CH), 77.0 (2CH), 66.4 (CH), 56.0 (CH3), 55.2 (CH3), 51.9 (CH3), 41.2
(CH), 39.2 (CH2), 37.8 (CH), 36.3 (CH), 35.9 (CH2), 35.3 (CH), 35.1
(CH), 34.4 (CH), 29.7 (CH), 26.2 (3CH3), 23.0 (CH3), 18.5 (C), 18.5
(CH3), 17.5, 16.5, 11.7, 10.1 (4CH3), 13.7 (CH3), 9.4 (CH3), ꢀ3.3 (CH3),
ꢀ3.6 ppm (CH3);. IR (film): n˜ =3359, 2981, 2930, 2884, 2857, 1728, 1598,
1455, 1435, 1395, 1363, 1326, 1258, 1214, 1146, 1094, 1035, 836, 773,
757 cmꢀ1; HRMS (ESI): m/z: calcd for C51H85O11NaSi: 938.5784; found:
938.5793.
Discodermolide 1: PTSA (3 mg, 0.015 mmol, 0.28 equiv) was added to a
solution of compound 61 (53 mg, 0.054 mmol, 1.0 equiv) in MeOH
(6.5 mL) at 08C. After the reaction mixture had been stirred for 1 h at
08C, triethylamine was added (0.3 equiv), and the solvent was removed
under reduced pressure. The residue was purified by chromatography on
silica gel (cyclohexane/AcOEt, 95:5 to 70:30) to give the
[2S,4R(1R),5S,6S(2S,3Z,5S,6R,7S,8Z,11S,12R,13S,14S,15S,16Z)]-4-(2-me-
HCl (4n, 1.5 mL) was added to a solution of the preceding compound
(14 mg, 0.015 mmol, 1.0 equiv) in THF (1.5 mL). The resulting mixture
was stirred for 72 h at 208C and then solid NaHCO3 was added and the
mixture extracted with AcOEt (3ꢄ). The organic layers were washed
with water, brine, dried over MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The residue was purified by chromatog-
raphy on silica gel (CH2Cl2/MeOH 95:5 to 90:10) to give the title com-
thoxycarbonyl-1-methyl
5,7,9,11,13,15-hexamethyl-14-hydroxy-2,6-bis[(methoxymethyl)oxy]nona-
deca-3,8,16,18-tetraen-1-yl}-5-methyl-2-phenyl-1,3-dioxinan (36 mg,
ethyl-1-yl)-6-{12-(tert-butyldimethylsilyloxy)-
77%). [a]2D0 =+11.0 (c=0.90 in CHCl3); 1H NMR (400.0 MHz, CDCl3):
d=7.47–7.43 (m, 2H), 7.33–7.30 (m, 3H), 6.64 (ddd, J=16.9, 11.0,
10.1 Hz, 1H), 6.16 (dd, J=11.0, 10.5 Hz, 1H), 5.59 (s, 1H), 5.54 (dd, J=
11.0, 10.1 Hz, 1H), 5.33 (dd, J=10.5, 10.1 Hz, 1H), 5.23 (dd, J=10.1,
9.6 Hz, 1H), 5.20 (d, J=16.9 Hz, 1H), 5.16 (d, J=10.1 Hz, 1H), 4.99 (d,
J=10.1 Hz, 1H), 4.84 (dd, J=10.1, 9.6 Hz, 1H), 4.71 (d, J=6.9 Hz, 1H),
4.54 (s, 2H), 4.50 (d, J=6.9 Hz, 1H), 4.06 (dd, J=10.5, 3.2 Hz, 1H), 3.82
(t, J=9.6 Hz, 1H), 3.74 (s, 3H; CH3), 3.63 (dd, J=5.5, 2.8 Hz, 1H), 3.33
(s, 6H; 2CH3), 3.35–3.33 (m, 1H), 3.09 (t, J=5.5 Hz, 1H), 2.86–2.75
(dqd, J=11.0, 7.3, 5.5 Hz, 1H), 2.86–2.75 (m, 2H), 2.54 (dqd, J=10.1,
6.4, 5.5 Hz, 1H), 2.19 (t, J=12.4 Hz, 1H), 2.05–1.71 (m, 4H), 1.58 (s, 3H;
CH3), 1.65–1.55 (ddq, J=10.5, 9.6, 6.4 Hz, 1H), 1.65–1.55 (m, 1H), 1.44
(s, 1H; OH), 1.22 (d, J=7.3 Hz, 3H; CH3), 1.01 (d, J=6.9 Hz, 3H; CH3),
0.96 (d, J=6.4 Hz, 3H; CH3), 0.95–0.91 (m, 6H; 2CH3), 0.91 (s, 9H;
3CH3), 0.87 (d, J=6.4 Hz, 3H; CH3), 0.70 (d, J=6.9 Hz, 3H; CH3),
0.10 ppm (s, 6H; 2CH3); 13C NMR (100.5 MHz, CDCl3): d=174.8 (C),
138.8 (C), 137.0 (CH), 134.7 (CH), 132.7 (C), 132.1 (CH), 131.1 (CH),
130.0 (CH), 129.1 (CH), 128.2 (2CH), 127.9 (2CH), 125.8 (CH), 118.5
(CH2), 99.6 (CH), 97.9 (CH2), 93.2 (CH2), 86.8 (CH), 82.0 (CH), 79.0
(CH), 77.8 (CH), 76.7 (CH), 66.4 (CH), 56.1 (CH3), 55.3 (CH3), 51.9
(CH3), 41.1, 39.1, 38.0, 36.7, 36.3, 35.9, 35.3, 34.7, 34.4 (7CH, 2CH2), 26.3
(3CH3), 23.3 (CH3), 18.5 (C), 17.6, 17.1, 16.4, 13.4, 11.7, 9.5, 9.3 (7CH3),
ꢀ3.1 (CH3), ꢀ3.6 ppm (CH3); IR (film): n˜ =2377, 2957, 2929, 2883, 2857,
1591, 1462, 1434, 1395, 1257, 1153, 1093, 1036, 874 cmꢀ1; HRMS (ESI):
m/z: calcd for C50H84O10NaSi: 895.5726; found: 895.5721.
pound (+)-discodermolide (1) (6.2 mg, 70%) as a white solid. [a]D20
=
+16.2 (c=1.0 in MeOH); 1H NMR (400.0 MHz, CDCl3): d=6.61 (ddd,
J=16.9, 11.0, 10.5 Hz, 1H), 6.03 (t, J=11.0 Hz, 1H), 5.53 (dd, J=11.0,
7.8 Hz, 1H), 5.42 (dd, J=11.0, 10.5 Hz, 1H), 5.36 (dd, J=11.0, 10.5 Hz,
1H), 5.23 (d, J=16.9 Hz, 1H), 5.14 (d, J=10.5 Hz, 1H), 5.12 (d, J=
11.0 Hz, 1H), 4.79–4.70 (m, 4H), 4.63 (ddd, J=10.1, 8.2, 1.8 Hz, 1H),
3.73 (t, J=3.7 Hz, 1H), 3.28 (dd, J=5.0, 4.6 Hz, 1H), 3.21 (dd, J=8.9,
5.0 Hz, 1H), 3.00 (dqd, J=10.5, 6.9, 3.2 Hz, 1H), 2.79 (m, 1H), 2.70 (qd,
J=7.3, 3.7 Hz, 1H), 2.61–2.54 (m, 1H; OH), 2.58 (m, 1H), 2.00–1.81 (m;
4H+2OH), 1.72–1.60 (m; 3H+OH), 1.64 (s, 3H; CH3), 1.32 (d, J=
7.3 Hz, 3H; CH3), 1.08 (d, J=6.9 Hz, 3H; CH3), 1.01 (d, J=7.3 Hz, 3H;
CH3), 0.98 (d, J=6.4 Hz, 3H; CH3), 0.98 (d, J=6.4 Hz, 3H; CH3), 0.95
(d, J=6.4 Hz, 3H; CH3), 0.83 ppm (d, J=5.9 Hz, 3H; CH3); 13C NMR
(100.5 MHz, CDCl3): d=174.3 (C), 157.4 (C), 134.5 (CH), 133.8 (CH),
133.6 (C), 133.0 (CH), 132.2 (CH), 130.1 (CH), 129.8 (CH), 118.1 (CH2),
79.1 (CH), 78.8 (CH), 77.7 (CH), 75.7 (CH), 73.4 (CH), 64.5 (CH), 43.4
(CH), 41.1 (CH2), 37.5 (CH), 36.4 (CH), 35.9 (CH2), 35.6 (CH), 35.0
(CH), 33.2 (CH), 30.0 (CH), 23.6 (CH3), 18.6 (CH3), 17.7 (CH3), 16.1
(CH3), 16.0 (CH3), 13.9 (CH3), 12.9 (CH3), 9.3 ppm (CH3); 1H NMR
(400.0 MHz, CD3CN): d=6.69 (ddd, J=16.9, 11.0, 10.1 Hz, 1H), 6.10 (t,
J=11.0 Hz, 1H), 5.56 (dd, J=10.5, 9.6 Hz, 1H), 5.45 (dd, J=10.5, 9.2 Hz,
1H), 5.41 (dd, J=11.0, 10.5 Hz, 1H), 5.27 (d, J=16.9 Hz, 1H), 5.17 (d,
J=10.1 Hz, 1H), 5.15–5.04 (m, 2H), 4.98 (d, J=10.1 Hz, 1H), 4.74 (dd,
J=8.2, 4.1 Hz, 1H,), 4.56–4.41 (m, 2H), 3.64 (t, J=4.1 Hz, 1H), 3.16 (dd,
J=7.3, 3.2 Hz, 1H), 3.16–3.14 (m, 1H; OH), 3.09 (dd, J=6.9, 3.7 Hz,
1H), 2.67–2.56 (m, 3H; OH), 2.35–2.10 (m, 4H; OH), 1.90–1.45 (m, 3H),
1.59 (s, 3H; CH3), 1.21 (d, J=7.3 Hz, 3H; CH3), 1.03 (d, J=6.4 Hz, 3H;
CH3), 1.01 (d, J=6.4 Hz, 3H; CH3), 0.97 (d, J=6.9 Hz, 3H; CH3), 0.90
(d, J=6.9 Hz, 3H; CH3), 0.82 (d, J=6.9 Hz, 3H; CH3), 0.75 ppm (d, J=
Trichloroacetylisocyanate (16 mL, 0.14 mmol, 1.05 equiv) was added to a
solution of the preceding alcohol (114 mg, 0.13 mmol, 1.0 equiv) in
CH2Cl2 (10 mL). After the reaction mixture had been stirred for 15 min
at 208C, the resulting mixture was concentrated in vacuo and the residue
taken up in MeOH (13 mL). K2CO3 (99 mg, 0.71 mmol, 5.5 equiv) was
added and the resulting solution was stirred for 1 h 15 min and then con-
centrated in vacuo and extracted with AcOEt. The organic layers were
11110
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 11092 – 11112

Total Synthesis of Discodermolide
FULL PAPER
5.9 Hz, 3H; CH3); 13C NMR (100.5 MHz, CD3CN): d=174.7 (C), 158.3
(C), 134.0 (CH), 133.8 (CH), 133.7 (CH), 133.2 (CH), 131.1 (CH), 130.5
(CH), 118.1 (CH2), 79.7 (CH), 79.2 (CH), 77.4 (CH), 75.9 (CH), 73.1
(CH), 63.3 (CH), 44.0 (CH), 42.1 (CH2), 38.4 (CH), 37.1 (CH), 36.5
(CH2), 36.2 (CH), 36.1 (CH), 34.4 (CH), 34.2 (CH), 23.3 (CH3), 19.7
(CH3), 18.1 (CH3), 17.6 (CH3), 15.8 (CH3), 15.6 (CH3), 13.1 (CH3),
9.2 ppm (CH3); HRMS (ESI): m/z: calcd for C33H55O8NNa: 616.3820
[M+Na]+; found: 616.3816.
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Published online: October 30, 2008
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Chem. Eur. J. 2008, 14, 11092 – 11112