A formal total synthesis of dictyostatin

Article abstract of DOI:10.1016/j.tet.2009.04.073

A convergent formal synthesis of the antimitotic macrolide dictyostatin has been achieved. The C11-C26 fragment of dictyostatin was prepared via convergent assembly of the central deoxypropionate motif utilizing a site- and stereoselective titanium-mediated reductive cross-coupling and an asymmetric hydrogenation of the resulting stereodefined 1,3-diene.

Full text of DOI:10.1016/j.tet.2009.04.073

Tetrahedron 65 (2009) 5908–5915
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A formal total synthesis of dictyostatin
,
1
*
Heidi L. Shimp, Glenn C. Micalizio
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent formal synthesis of the antimitotic macrolide dictyostatin has been achieved. The C11–C26
fragment of dictyostatin was prepared via convergent assembly of the central deoxypropionate motif
utilizing a site- and stereoselective titanium-mediated reductive cross-coupling and an asymmetric
hydrogenation of the resulting stereodefined 1,3-diene.
Received 24 November 2008
Received in revised form 13 April 2009
Accepted 20 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Following the isolation of dicytostatin, its planar structure was
determined to include 11 stereogenic centers, a cis-1,2-disubstituted
(ꢀ)-Dictyostatin (1, Fig. 1), an antimitotic macrolide, was first
isolated in 1994 by Pettit and co-workers from a Maldives marine
sponge1,2 and subsequently from a Caribbean sponge (Corallistidae
sp.) by Wright and co-workers in 2003.3,4 The 22-membered mac-
rolactone has been shown to exhibit potent anticancer properties,
similar or superior to its open-chain analogue discodermolide (2).4
Displaying a Taxol-like mechanism of action by binding to tubulin
and inducing microtubule assembly, dictyostatin inhibits human
cancer cell proliferation at nanomolar concentrations (ED50
0.38 nM, P338 leukemia cells).5 Importantly, both discodermolide
and dictyostatin retain activity against multi-drug resistant cell-
lines as they do not bind to P-glycoprotein, a principal mediator of
taxane resistance.6 With the withdrawal of discodermolide from
clinical development in 2005,7 interest in dictyostatin has increased,
particularly as the natural supply is extremely scarce.
olefin, an endocyclic 2Z,4E-dienoate and a pendant Z-diene.1 Relative
stereochemical assignment was later reported through the use of
extensive high field NMR studies and molecular modeling,5 with the
absolute stereochemistry proposed based on a common biogenesis
for dictyostatin and discodermolide.8 Concurrent total syntheses by
the Paterson9 and Curran groups10 in 2004 confirmed the proposed
structure of dictyostatin, inwhich the10 stereocentersthatare shared
withdiscodermolidehavethesameabsoluteconfiguration. Following
these initial synthetic efforts, the significant therapeutic potential of
dictyostatinhas ledseveralgroupstotargetits synthesisinadditionto
several related analogues.11–13
Efficient construction of the functionalized deoxypropionate-con-
taining fragment of dictyostatin (C11–C26) persists as a challenging
synthetic goal.13,14 In an extension of our prior work on the convergent
assembly of trisubstituted (E,E)-1,3-dienes,15 we anticipated that the
C11–C26 subunit of dictyostatin (3) could arise from the regio-, stereo-,
and chemoselective cross-coupling of homopropargylic ether 5 with
terminal alkyne 6 (Scheme 1). From the resulting polyene, hydroxyl-
directed reduction16 of the central diene was expected to set the remote
C16 stereocenter en route to triol 3, an intermediate in the synthesis of
dictyostatin reported by Paterson and co-workers.9
Me Me
Me Me
Me
OH
O
OH
O
HO
HO
Me
O
Me Me
Me
O
Targeting the synthesis of dictyostatin through an un-
conventional C16–C17 bond construction, we sought to expand the
utility of our alkyne–alkyne cross-coupling methodology in the
context of complex polyketide synthesis. In this case, sequential
reductive cross-coupling and hydroxyl-directed reduction was
expected to provide a means for the convergent stereoselective
synthesis of deoxypropionates.
Me Me
Me Me
OH NH2
Me
OH
O
OH OH
O
dictyostatin (1)
discodermolide (2)
Figure 1. Dictyostatin and discodermolide.
2. Results and discussion
2.1. Titanium-mediated cross-coupling
* Corresponding author. Tel.: þ1 203 432 9043.
E-mail address: micalizio@scripps.edu (G.C. Micalizio).
1
As depicted in Scheme 2, preparation of terminal alkyne frag-
The Scripps Research Institute, Scripps Florida130 Scripps Way #3A2, Jupiter,
FL 33458, USA. Tel.: þ1 561 228 2463; fax: þ1 561 228 3092.
ment 6 commenced from the known homoallylic alcohol 7,17
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.073

H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
5909
Me
26
Me
26
OH
OH
16
Paterson
HO
11
TBSO
Me Me
Me
O
Me Me
Me
O
OH
Me
Me Me
2004
11
Me
3
HO
OH OH
dictyostatin (1)
TESO
Me
Me Me
Me Me
O
titanium-
mediated
hydroxyl-
Me
+
Me Me
5
directed
HO
BnO
reductive
reduction
O
cross-coupling
Me
BnO
PMP
4
O
O
PMP
Scheme 1. Retrosynthesis of dictyostatin 1: application of a titanium-mediated cross-coupling/hydroxyl-directed reduction sequence.
6
accessed in four steps from commercially available (2S)-3-hydroxy-
Me
Me Me
O
2-methyl-propionate. Oxidation with DDQ followed by site-selec-
tive opening of the PMP acetal (DIBALH)18 and protection of the
primary alcohol (TBDPSCl, imid.) provided the homoallylic ether 8
in 80% overall yield. Oxidative cleavage of the terminal olefin (OsO4,
NMO, then NaIO4) afforded aldehyde 9, which was employed in
a double asymmetric addition reaction with TMS–acetylene19 to
deliver propargyl alcohol 10 in 89% yield (d.s.¼5:1). Oxidative for-
mation of the corresponding PMP acetal (DDQ), followed by desi-
lylation with TBAF and oxidation20 supplied aldehyde 11. Finally,
TESO
BnO
+
Me
O
Me
PMP
6
5
1) ClTi(OiPr)3, cC5H9MgCl,
PhMe, –78 °C to –30 °C;
then -78 °C, 6
2) TBAF, THF
Me
Me Me
allylation with (E)-g-trimethylsilylallylboronic ester 12 and base-
Me Me
Me
Me Me
O
Me
induced Peterson elimination (KH, THF) provided the stereodefined
1,3-(Z)-diene 6 in 64% yield as a single isomer.21 Confirmation of the
desired syn–syn stereochemistry was established using NOE
analysis.
HO
+
Me
O
O
O
OH
PMP
13
BnO
PMP
BnO
Reductive cross-coupling of 5 (available from well established
propargylation chemistry)22 with 6 (ClTi(Oi-Pr)3, c-C5H9MgCl,
PhMe), followed by desilylation (TBAF, THF) provided the 1,3-di-
ene 4 in 78% yield as a 7:1 mixture of regioisomers (Scheme 3).23
We were delighted to observe both regioselectivity for the
formation of the desired product (4), as well as high levels of
chemoselectivity in this reductive cross-coupling reaction; com-
petitive reaction of the preformed titanium–alkyne complex of 5
with the 1,3-(Z)-diene of 6 was not observed. With a suitable
convergent coupling reaction established, we set out to in-
vestigate the site- and stereoselective functionalization of the
4
78%, 7:1 r.r.
Scheme 3. Titanium-mediated reductive cross-coupling in the preparation of tetra-
ene 4.
2.2. Hydroxyl-directed hydrogenation
Numerous studies have demonstrated the ability of proximal
hydroxyl groups to influence the stereochemical course of transi-
tion metal-catalyzed olefin hydrogenation reactions.25 Despite
significant precedent for hydroxyl-directed hydrogenation of allylic
and homoallylic alcohols with either the cationic iridium catalyst,
Ir(COD)(py)(PCy3)PF6 (Crabtree’s catalyst, 14)26,27 or the cationic
central (E,E)-diene of
4
using substrate-directed hydro-
genation.16,24
Et Zn, Ti(OiPr
)
4
1) OsO4, NMO
THF, acetone,
OTBDPS
pH 7 buffer
2
1) DDQ, 4Å M.S.,
(R)-BINOL,
PMBO
OHC
OTBDPS
PMBO
OH OPMB
CH2Cl2, 82%
TMS
PhMe, Et2O,
89%, (3 steps)
d.s. = 5:1
2) DIBALH, PhMe, 97%
3) TBDPSCl, Et3N,
DMAP, CH2Cl2, 95%
2) NaIO4, THF
pH 7 buffer,
Me Me
Me Me
Me Me
8
7
9
Me
R
PMP
PMP
12
O
B
PMB
O
1)
1) DDQ, 4Å M.S.,
O
H
TMS
O
O
OH
OR
O
CH2Cl2, 93%
O
O
O
O
Ar
H
5%
nOe
H
H
2) TBAF, THF, 94%
3) (COCl)2, DMSO
Et3N, CH2Cl2
H
4Å M.S., PhMe
2) KH, THF, 64%
(3 steps)
Me Me
6
TMS
Me Me
10
R = TBDPS
Me Me
11
7% nOe
5% nOe
Scheme 2. Synthesis of terminal alkyne coupling partner 6.

5910
H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
rhodium catalyst [Rh(nbd)(dppb)]BF4 (15),28,29 to the best of our
knowledge, hydroxyl-directed reduction of 1,3-dienes has not been
reported. As such, we set out to investigate chemo- and stereo-
selective directed reduction of the central diene of 4 with the intent
to: (1) extend the utility of our reductive cross-coupling reaction of
alkynes in organic synthesis, (2) provide access to the C11–C26
fragment of dictyostatin, and (3) add to the body of literature as-
sociated with directed hydrogenation methodology (Scheme 1).
Initial attempts aimed at the selective functionalization of tetra-
ene 4 using the cationic rhodium catalyst [Rh(nbd)(dppb)]BF4 (15)
in CH2Cl2 at 700 psi led to complete reduction of both the central
and terminal diene, with 17 isolated in 76% yield (Scheme 4). Efforts
to modify the reaction conditions to achieve site-selectivity in the
reduction included varying temperature (ꢀ78 ꢁC to 23 ꢁC), H2
pressure (1 atm to 700 psi), and use of either the rhodium catalyst
15 or Crabtree’s iridium catalyst 14.26 In all cases, site-selective
hydrogenation of the central trisubstituted diene was not possible.
Therefore, despite the success of our reductive cross-coupling
process to deliver tetra-ene 4 in a regio- and chemoselective
manner, limitations in site selective hydroxyl-directed hydrogena-
tion led us to redesign our synthetic route.
Through an efficient eight-step sequence, terminal alkyne 20
was prepared in an overall 45% yield from the commercially
available (2S)-3-hydroxy-2-methyl-propionate (21). As shown in
Scheme 6, the auxiliary-controlled enolborane syn-aldol reaction30
with aldehyde 22 provided known aldol adduct 24 in 93% yield.31
Conversion to the Weinreb amide32 followed by ynone formation
gave acetylenic ketone 25. Diastereoselective reduction (DIBALH,
THF) then afforded a syn-diol (92%, ꢂ20:1 d.s.),33 which was pro-
tected as its corresponding PMP acetal (20).
O
O
N
Et
1) TBDPSCl, Et3N,
DMAP, CH2Cl2
23
O
O
N
OH
O
OR
Bn
MeO
H
Bu2BOTf, Et3N,
CH2Cl2,
2) DIBALH, CH2Cl2
3) (COCl)2, DMSO,
Et3N, CH2Cl2
Me
21
Me
22
R = TBDPS
93% (4 steps)
O
OH OR
1) MeNHOMe•HCl
O
O
O
OH OR
Me3Al, THF, 85%
2)
MgBr, THF
69%
Me Me
24
Me Me
25
R = TBDPS
Bn
R = TBDPS
Me Me
Me Me
PMP
1) DIBALH,
THF, 92%
HO
O
O
OR
OMe
OMe
O
O
2)
Me
BnO
PMP
Me Me
MeO
20
4
PPTS, CH2Cl2,
90%
R = TBDPS
Rh+ cat.
(15)
Rh+ cat.
(15)
H2, CH2Cl2
76%
Scheme 6. Synthesis of terminal alkyne fragment 20.
As expected, regioselective reductive cross-coupling of internal
alkyne 5 with terminal alkyne 20 provided a functionalized 1,3-di-
ene in 66% isolated yield (r.r.ꢂ20:1; Scheme 7). Selective desilylation
(TBAF, THF) then delivered the secondary carbinol 19 in 72% yield.
While we were pleased to have secured a convergent and ster-
eoselective synthesis of 19, all attempts to accomplish a stereo-
selective directed hydrogenation of this substrate were
unsuccessful. In fact, only inseparable mixtures of products were
obtained on exposure of 19 to either hydrogenation catalyst (14 or
15; CH2Cl2, 700 psi H2).
Me Me
Me Me
O
Me Me
Me Me
HO
HO
O
O
O
Me
Me
BnO
PMP
BnO
PMP
16
17
Scheme 4. Hydroxyl-directed reduction of polyene 4.
2.3. Revised route
To avoid the site selectivity problems observed in our attempted
directed hydrogenation, we targeted hydroxyl-directed hydroge-
nation of 19, a substrate that lacks the terminal (Z)-diene found in
dictyostatin. Employing a titanium-mediated reductive cross-cou-
pling reaction, 19 was thought to derive from the union of alkyne 5
with the terminal alkyne 20 (Scheme 5).
2.4. Exploring hydroxyl-directed reduction
Based on the lack of literature precedent for hydroxyl-directed
hydrogenation of conjugated dienes, we set out to further in-
vestigate this type of reduction in the context of polyketide syn-
thesis. Various directing groups have been shown to participate in
the catalytic reduction of endo- or exo-cyclic olefins (including
ethers, esters and amides).24 As such, we were concerned that the
allylic acetal in substrate 19 may competitively coordinate to
the cationic rhodium catalyst and adversely affect selectivity in the
reduction. Therefore, the Lewis basic dienylic PMP acetal of 19 was
converted to the corresponding TIPS ether 26 (Scheme 8). Un-
fortunately, attempted hydrogenation of 26 was similarly un-
successful, as exposure to the cationic Rh catalyst 15 and 750 psi H2
led once again to an inseparable mixture of products.
In an attempt to dissect the problems that we were experi-
encing in directed hydrogenation of 1,3-dienes, we focused our
attention on a substrate lacking some of the molecular complexity
associated with the C11–C26 fragment of dictyostatin. As illus-
trated in Scheme 9, directed reduction of diene 27 proceeded
with low selectivity, providing a separable mixture of four prod-
ucts in 85% yield: two fully-saturated diastereomers (29 and 30),
as well as (E)- and (Z)-olefin isomers (31 and 32, respectively;
29:30:31:32¼2:1:1:1).34
Me
26
Me Me
Me Me
OH
OH
HO
TBSO
Me Me
Me
3
Me
O
O
OR
Me
11
BnO
PMP
18
HO
Me
TESO
BnO
Me Me
Me Me
titanium-
hydroxyl-
directed
Me
HO
Me
+
5
mediated
O
O
OR
Me Me
cross-
Me
reduction
coupling
BnO
PMP
19
O
O
OR
PMP 20
R = TBDPS
Scheme 5. Revised retrosynthetic analysis for the C11–C26 fragment of dictyostatin.

H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
5911
Me
Me
Me Me
Me Me
1) ClTi(OiPr)3, cC5H9MgCl,
TESO
BnO
HO
PhMe, –78 °C to –30 °C;
Me
O
O
OR
then –78 °C,
Me Me
Me
19
R = TBDPS
BnO
PMP
66%
5
20
O
O
OTBDPS
Rh+ cat. (15)
H2, CH2Cl2
PMP
2) TBAF, THF, 0 °C, 72%
complex mixture
of products
Scheme 7. Regioselective titanium-mediated cross-coupling and hydroxyl-directed reduction sequence.
While standard hydrogenation catalysts (i.e., Pd/C, PtO2,
RhCl(PPh3)3) typically led to nonselective reduction of 19, the chiral
ruthenium catalyst Ru(OAc)2[(R)-BINAP]36 provided the desired
intermediate 33 as the major product (50 ꢁC, 1450 psi, 6 days, 53%
yield; Scheme 10). Unfortunately, the long reaction time (6 days)
and high pressure required to generate 33 in only modest yield
were seen as a barrier to material throughput and an alternative
pathway to establish this central deoxypropionate unit was
pursued.
Me Me
TIPS
O
1) DIBALH (12 eq.),
PhMe, 61%
HO
OR
Me
19
2) TIPSOTf, 2,6-lut.,
CH2Cl2, 57%
Me
Me
BnO
OPMB
26
Rh+ cat. (15)
H2, CH2Cl2
complex mixture
of products
Scheme 8. Preparation of diene 21 and subsequent hydroxyl-directed reduction.
Me Me
Me
Me Me
Me Me
Me
Me Me
HO
HO
a
O
O
OR
O
O
OR
The non-selective reduction of 27 suggested that olefin isom-
erization was partially responsible for the mixture of products
observed in our attempted hydrogenation reactions toward a dic-
tyostatin synthesis. Although isomerization is known to occur in
rhodium-catalyzed hydroxyl-directed reductions of allylic alcohols
at low H2 pressures,25 olefin isomerization of homoallylic alcohols
where allylic and homoallylic stereogenic centers are present has
not been reported.29 To confirm that the conjugated diene was
responsible for the low levels of selectivity observed in the re-
duction of 27, we studied the directed hydrogenation of homoallylic
alcohol 28.35 Interestingly, use of the cationic rhodium catalyst 15
resulted in a highly selective hydrogenation, in this case delivering
29 as essentially a single diastereomer in 88% yield.
53%
BnO
PMP
BnO
PMP
19
R = TBDPS
33
R = TBDPS
a) Reaction conditions: Ru(OAc)2[(R)-BINAP], 1450 psi H2, 50 °C, 6 d
Scheme 10. Partial hydrogenation of 19.
2.5. Asymmetric hydrogenation
Recently, the Burgess group has highlighted the utility of the chiral
iridium carbene catalyst 34 (Fig. 2) in diastereoselective hydrogenation
reactions leading to deoxypropionate architecture.37,38 As shown in
Scheme 11, catalyst control provided a pathway for conversion of the
homoallylic alcohol 35 to either the anti or syn isomer (in 9:1 and 4:1
selectivity, respectively).38 In a related series of experiments, the 1,3-
diene 37 was selectively reduced to deliver either the anti,syn stereo-
isomer (d.s.¼11:1) with D-34, or the syn,syn isomer (d.s.¼3:1) with
Based on these findings, a potential synthetic solution to the
problems associated with advancing our conjugated diene-con-
taining substrates to the northern fragment of dictyostatin could
include partial hydrogenation of the trisubstituted diene followed
by directed hydrogenation of the remaining trisubstituted olefin.
Me Me
Me Me
HO
BnO
HO
HO
BnO
HO
R
R
Me
Me
Rh+ cat.
Me Me
Me
8
(15, 30 mol%),
a
a
HO
29
30
R
7
800 psi H2,
CH2Cl2
Me Me
Me Me
BnO
R
R = (CH2)2OTBDPS
Me
Me
R
BnO
BnO
b
b
31
32
:
:
:
29 30 31 32
)
yield (%)
ratio (
2:1:1:1
27 C7-C8: C=C
28 C7-C8: C-C
85
88
≥20:1 (29:all others)
a = stereochemistry at C6 assigned based on literature precedent for diastereoselectivity: see Ref. 29.
b = olefin stereochemistry determined by nOe analysis: see Supplementary data.
Scheme 9. Hydroxyl-directed reduction of diene 27 versus homoallylic alcohol 28.

5912
H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
control43 was anticipated to favor production of the undesired anti
O
N
diastereomer. As such, selection of D-34 was based on the desire to
accomplish a stereoselective functionalization in which catalyst con-
trol would dominate over the inherent substrate-based selectivity
(Scheme 12).38 Success in related mismatched double asymmetric
hydrogenation reactions reported by Burgess (Scheme 11) led to our
optimistic assignment of the C14–C16 syn stereochemical relationship
in the major product (18). Our tentative assignment was one that
would require conversion to dictyostatin in order to confirm the C16
stereochemistry resulting from this asymmetric hydrogenation.
(cod)Ir
iPr
N
N
BARF-
iPr
D-34
BARF = tetrakis(3,5-bis(trifluoro-
methyl)phenyl)borate
2.6. Completion of a formal synthesis of dictyostatin
Figure 2. Burgess’ iridium carbene–oxazoline complex.
Planning on a late stage deprotection of the C11 alcohol, we
opted to exchange the benzyl ether protecting group on the in-
ternal alkyne component for a PMB ether (40, Scheme 13), a de-
cision that was anticipated to facilitate deprotection in the presence
of the terminal diene (i.e., 39/3). This strategic consideration re-
quired a slight modification of our original synthetic pathway to the
stereodefined internal alkyne coupling partner.22 The often harsh
Lewis acidic conditions required for propargylation of aldehydes
with allenylsilanes (i.e., TiCl4)44 were expected to be incompatible
with aldehyde 41. As such, we opted to employ the related organ-
ometallic reagent 42, as chiral allenylstannanes are known to un-
dergo propargylation with chiral aldehydes under more mild
reaction conditions (BF3$OEt2, MgBr2$OEt2).45,46
50 atm H2
*
cat. (0.2 mol%)
OH
TBDPSO
OH
TBDPSO
Me
Me Me
36
Me
35
CH2Cl2, 25 ºC, 4 h
anti,syn
D-34
L-34
9:1
1:4
as above
*
*
OH
TBDPSO
OH
TBDPSO
Me Me Me
37
Me Me Me
38
83%
anti,syn: syn,syn
D-34
L-34
11:1
1:3
Toward this end, the double asymmetric43 propargylation re-
action of a-chiral aldehyde 41 with allenylstannane 42 (MgBr2$OEt2,
Scheme 11. Asymmetric hydrogenation reactions of allylic and dienylic alcohols with
34 leading to deoxypropionates.
CH2Cl2) afforded the homopropargylic alcohol 40 in 79% yield
(d.s.ꢂ20:1). Following TES-protection of the homopropargylic al-
cohol, titanium-mediated reductive cross-coupling with terminal
alkyne 20 afforded the (E,E)-1,3-diene in 65% yield with 7:1 regio-
selection (entry 1, Table 1). Subsequent selective desilylation of the
TES ether (TBAF or HF$py) provided 44 in only moderate yields (43–
60%), prompting us to examine the cross-coupling of terminal al-
kyne 20 with 40, a substrate bearing an unprotected C13 hydroxy
group.15 Unfortunately, repeated attempts to accomplish this cross-
coupling reaction led to mixtures of products in which the desired
diene 44 was isolated in ꢃ23% yield. While the origin of this poor
efficiency remains unclear, we opted to investigate the related re-
ductive cross-coupling of TMS-ether 45. To our delight, regiose-
lective coupling of 45 with the terminal alkyne 20 provided the
trisubstituted 1,3-diene in 76% isolated yield (r.r.ꢂ20:1). Selective
deprotection under mild conditions (K2CO3, MeOH) then delivered
the fully functionalized substrate 44 in 71% yield.
L-34. Based on these observations, we shifted our attention to the ap-
plication of the Burgess catalyst to our synthetic problem.
Hydrogenation of diene 27 with catalyst D-34 resulted in the
formation of 29 in 86% yield (4 mol % D-34, 725 psi, CH2Cl2, 3 h,
Scheme 12).39 Notably, products related to olefin isomerization or
incomplete reduction were not observed. Encouraged by this result,
we subjected our fully functionalized fragment 19 to related
reduction conditions (8 mol % D-34, 750 psi H2, CH2Cl2). To our
delight, we isolated the desired deoxypropionate 18 in 62% yield
(d.s.¼5:1)40 accompanied by a minor product resulting from
deprotection of the PMP acetal.41
At this point, rigorous stereochemical assignment of C16 was not
possible. Considering the intrinsic facial selectivity of 19 dictated by
minimization of 1,3-allylic strain,42 hydrogenation under substrate
Me Me
4 mol % D-34,
725 psi H2,
Me Me
HO
HO
OR
OR
CH2Cl2, 25 °C
86%
Me
Me
BnO
BnO
27
29
Me Me
Me Me
Me Me
Me Me
8 mol % D-34,
HO
HO
750 psi H2,
14
16
CH2Cl2, 25 °C
62%, 5:1 d.s.
O
O
OR
O
O
OR
Me
Me
BnO
PMP
BnO
PMP
19
18
substrate
R = TBDPS
favors addition
OH
from α-face
H
Me
R
BnO
H
Me
H
Me
catalyst controls
addition to β-face
D-34
Scheme 12. Diastereoselective hydrogenation reactions of dienes 27 and 19 with Burgess’ catalyst.

H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
5913
O
H
steps). Following oxidation with Dess–Martin periodinane,48 in-
stallation of the terminal diene was achieved through the standard
protocol used previously in the syntheses of discodermolide49 and
dictyostatin.9,10,12 Accordingly, Nozaki–Hiyama–Kishi allylation50
with 1-bromo-1-trimethylsilyl-2-propene provided a mixture of
Me
Me
Me
OH
OH
HO
PMBO
41
TBSO
RO
Me Me
Me
Me
Me
Me
anti-b-hydroxysilanes (48), which upon treatment with KH un-
Me
Me
PMBO
•
derwent 1,2-syn-elimination51 to provide the (Z)-diene 49 in 67%
yield over the three-step sequence.
Bu3Sn
H
R = PMB, 39
R = H, 3
40
DDQ
42
Completion of the formal total synthesis of dictyostatin was ac-
complished in two additional steps. Deprotection of the PMP acetal
Scheme 13. Revised strategy for the preparation of 3.
Table 1
Me Me
Me
Me Me
O
Me
Me
1) reductive cross-coupling
HO
with 20
RO
O
OTBDPS
Me
2) deprotection
PMBO
PMP
44
PMBO
Entry
Internal alkyne
Cross-coupling yield
Deprotection yield
1
2
3
R¼TES (43)
R¼H (40)
65% (7:1 r.s.)
ꢃ23%
43–60% (TBAF or HF$py)
n/a
71% (K2CO3, MeOH)
R¼TMS (45)
76% (ꢂ20:1 r.r.)
Seeking totake advantage of the labilityof the TMS ether, wenext
examined conditions for a one-pot cross-coupling/deprotection
sequence. Following titanium-mediated reductive cross-coupling,
successful removal of the TMS-ether was possibleusing avarietyof acidic
or basic conditions in thework-up (1 N HCl, TBAFor K2CO3), with NaOMe
in MeOH providing the highest yield of diene 44 (63%, Scheme 14).
under acidic conditions (PPTS, MeOH) provided diol 39 in 42% yield
accompaniedbytriol50in23%yield. Finally, removalofthePMBether
with DDQ afforded the desired fragment 3 (72% yield), which was
previously converted to dictyostatin over nine steps.9 Comparison of
our 1H and 13C NMR data tothat provided by Paterson and co-workers
verified the identity of triol 3 and confirmed the validity of this tita-
Me Me
Me Me
Me Me
Me
Me Me
Me Me
8 mol % D-34,
ClTi(OiPr)3, cC5H9MgCl,
HO
TMSO
PMBO
HO
750 psi H2, 4Å M.S.,
PhMe, then
+
O
O
OR
Me
O
O
OR
O
O
OR
NaOMe, MeOH,
CH2Cl2, 25 °C, 4 h
72%, 4:1 d.s.
Me
Me
Me
63%, ≥20:1 r.r.
PMP
PMBO
PMP
PMBO
PMP
46
R = TBDPS
45
44
R = TBDPS
20
R = TBDPS
Me Me
Me Me
Me Me
Me
Me Me
1) Dess-Martin
periodinane
1) TBSOTf, 2,6-lut.,
∗
∗
TBSO
PMBO
TBSO
KH, THF
CH2Cl2, –78 °C, 75%
TMS
O
O
OH
Br
2)
O
O
OH
67% (3 steps)
2) TBAF, THF, 25 °C,
12 h, 90%
Me
Z:E ≥20:1
TMS
CrCl2, THF
PMP
PMBO
PMP
47
48
(mixture of anti-β-hydroxysilanes)
Me
OH
Me
OH
OH
Me Me
TBSO
Me Me
DDQ, pH 7 buffer,
PPTS, MeOH,
65 °C, 8 h,
TBSO
RO
Me Me
OH
Me
Me Me
Me
PMBO
39 R = TBS 42% b.r.s.m.
50 R = H 23%
Me
CH2Cl2, 25 °C, 2 h,
72%
O
O
Me
Me
PMBO
PMP
HO
3
49
Scheme 14. Completion of a formal total synthesis of dictyostatin.
Next, asymmetric reduction employing the Burgess iridium
carbene–oxazoline catalyst D-34 provided the deoxypropionate
fragment 46 in 72% yield (d.s.¼4:1, separable by HPLC). The prob-
lematic partial deprotection of the PMP acetal previously observed
in the reduction of 19, presumably due to the Lewis acidic nature of
the cationic iridium catalyst, was circumvented through the addi-
tion of 4 Å molecular sieves to the reaction mixture.47 Subsequent
protection with TBSOTf and selective removal of the TBDPS ether
(TBAF, THF) provided the primary alcohol 47 (73% yield over two
nium-mediated cross-coupling/asymmetric reductionprocess for the
convergent assembly of the C11–C26 fragment of dictyostatin.
3. Conclusion
In our planned synthesis of the C11–C26 fragment of dictyos-
tatin, we targeted an unconventional bond construction for the
convergent assembly of the central deoxypropionate motif. This
strategy, based on initial application of a titanium-mediated

5914
H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
reductive cross-coupling reaction between an internal alkyne and
terminal alkyne followed by stereoselective hydrogenation of the
resulting 1,3-diene, led to the successful completion of a formal
total synthesis of dictyostatin. Our initial investigations demon-
strated notable chemoselectivity in the titanium-mediated re-
ductive cross-coupling reaction (5þ6/4); however, limitations
associated with site- and stereoselective hydroxyl-directed
hydrogenation ultimately prohibited the use of this pathway to
dictyostatin. In the search to avoid the problems associated with
selective hydrogenation, we arrived at a solution that: (1) employed
a reductive cross-coupling reaction of a simplified terminal alkyne
coupling partner to obviate the need for site-selective hydrogena-
tion (removal of the terminal (Z)-diene), and (2) embraced a cata-
lyst-controlled diastereoselective hydrogenation to establish the
stereodefined central deoxypropionate. Overall, through in-
vestigations culminating in a formal total synthesis of dictyostatin,
we have demonstrated the utility of our titanium-mediated re-
ductive cross-coupling between an internal and terminal alkyne for
the convergent assembly of deoxypropionate architecture.
2H), 1.70–1.68 (m, 1H), 1.69 (d, J¼0.95 Hz, 3H), 1.06 (s, 9H), 1.04 (d,
J¼6.9 Hz, 3H), 1.03 (d, J¼6.6 Hz, 3H), 1.01 (d, J¼7.3 Hz, 3H), 0.98 (d,
J¼6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3)
d 159.8,159.4,136.4,135.8,
135.60, 135.56, 133.94, 133.90, 131.9, 131.7, 129.9, 129.5, 129.4, 127.6,
127.5, 125.6, 113.9, 113.5, 101.1, 82.0, 80.5, 80.0, 77.2, 73.9, 73.3, 64.8,
55.34, 55.30, 36.8, 36.7, 35.7, 34.2, 26.9, 19.4, 15.5, 15.0, 12.5, 12.4,
6.3; IR (thin film, NaCl) 3494, 2962, 2931, 2857, 1615, 1515, 1457,
1362, 1250, 1112, 1034, 824, 757, 703 cmꢀ1; LRMS (EI, Na) calcd for
C50H66O7SiNa m/z 829.45 (MþNa); observed m/z 829.4 (MþNa)þ.
4.3. Asymmetric hydrogenation
4.3.1. (2S,3R,4S,6S)-8-((2R,4R,5S,6S)-6-((S)-1-(tert-Butyldiphenyl-
silyloxy)propan-2-yl)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-
4-yl)-1-(4-methoxybenzyloxy)-2,4,6-trimethyloctan-3-ol, 46
To a Schlenk flask containing 44 (660 mg, 0.82 mmol) in 5 mL of
dry CH2Cl2 was added D-34 (100 mg, 0.065 mmol). The resulting
solution was degassed by three cycles of freeze–pump–thaw and
transferred via cannula to a flame-dried glass liner equipped with
a rubber septum containing activated 4 Å molecular sieves (30 mg,
powder). The glass liner was quickly transferred to a Parr bomb
hydrogenator, which was flushed with H2 for 1 min without stirring.
The reaction mixture was then stirred rapidlyat 750 psi. After 4 h, the
crude reaction mixture was transferred to a short silica gel column
and eluted with 10%/20% EtOAc/hexanes to provide 475 mg (72%) of
46 as a viscous, clear and colorless oil (d.s.¼4:1 by 1H NMR). A small
sample was further purified by HPLC [EtOAc/hexanes: 13% (28 mL/
4. Experimental section
4.1. General
All reactions were conducted in flame-dried glassware under ni-
trogen using anhydrous solvents. Toluene was distilled from sodium/
benzophenone ketyl or passed through and activated alumina col-
umn followed by a copper column before using. Diethyl ether and
tetrahydrofuran were passed through an activated alumina column.
Et3N was distilled from calcium hydride immediately prior to use.
Ti(Oi-Pr)4 was used after distillation of the commercially available
reagent. ClTi(Oi-Pr)3 waspurchased asa1 Msolution inhexanesfrom
AldrichÒ and was used without further analysis or purification. All
other commercially available reagents were used as received.
min) on a Microsorb (Si 80-120-C5 H410119) column] to obtain 46 as
20
a single diastereomer: [
a
]
þ13.3ꢁ (c 0.83, CHCl3); 1H NMR
589
(500 MHz, CDCl3)
d
7.67–7.61 (m, 4H), 7.42–7.38 (m, 1H), 7.36–7.33
(m, 5H), 7.26–7.20 (m, 4H), 6.88–6.84 (m, 4H), 5.45 (s, 1H), 4.47 (A of
AB, J¼11.4 Hz, 1H), 4.43 (B of AB, J¼11.7 Hz, 1H), 3.96 (dd, J¼9.5,
4.4 Hz,1H), 3.84(dd, J¼10.1,1.9 Hz,1H), 3.81 (s, 3H), 3.80(s, 3H), 3.80–
3.76 (m, 1H), 3.66 (dd, J¼9.5, 2.5 Hz, 1H), 3.57 (dd, J¼8.8, 4.1 Hz, 1H),
3.48–3.44 (m, 2H), 3.39 (ddd, J¼8.8, 2.5, 2.5 Hz, 1H), 1.99–1.84 (m,
2H), 1.73–1.49 (m, 6H), 1.46–1.41 (m, 1H), 1.15–1.07 (m, 2H), 1.05 (s,
9H), 1.04 (d, J¼7.3 Hz, 3H), 0.93 (d, J¼6.6 Hz, 3H), 0.90 (d, J¼6.6 Hz,
3H), 0.85 (d, J¼6.6 Hz, 3H), 0.81 (d, J¼6.9 Hz, 3H); 13C NMR (126 MHz,
4.2. Titanium-mediated cross-coupling
4.2.1. (2S,3R,4S,5E,7E)-8-((2R,4R,5S,6S)-6-((S)-1-(tert-
Butyldiphenylsilyloxy)propan-2-yl)-2-(4-methoxyphenyl)-5-
methyl-1,3-dioxan-4-yl)-1-(4-methoxybenzyloxy)-2,4,6-
CDCl3)
d 159.7, 159.3, 135.60, 135.56, 134.0, 133.9, 131.9, 129.9, 129.5,
129.40, 129.36, 127.6, 127.5, 127.4, 113.9, 113.5, 101.1, 81.9, 80.9, 78.6,
77.2, 76.2, 73.2, 64.9, 55.34, 55.27, 41.7, 36.8, 36.0, 32.5, 32.1, 30.00,
29.99, 29.97, 26.9, 19.4, 13.6, 12.8, 12.4, 5.9; IR (thin film, NaCl) 3496,
2959, 2932, 2856, 1615, 1516, 1463, 1361, 1249, 1113, 1035, 825, 757,
704, 505 cmꢀ1; LRMS (EI, Na) calcd for C50H70O7SiNa m/z 833.48
(MþNa); observed m/z 834.0 (MþNa)þ.
trimethylocta-5,7-dien-3-ol, 44
To a ꢀ78 ꢁC solution of alkyne 45 (4.36 g, 12.5 mmol) in 80 mL of
PhMe were added sequentially 19.0 mL of ClTi(Oi-Pr)3 (1.0 M in
hexanes, 18.8 mmol) and 19.0 mL of c-C5H9MgCl (2.0 M in Et2O,
37.5 mmol) dropwise via a gas-tight syringe. The resulting clear,
yellow solution turned black while warming slowly to ꢀ30 ꢁC over
1 h. The reaction mixture was stirred at ꢀ30 ꢁC for 1 h and then
cooled to ꢀ78 ꢁC. Terminal alkyne 20 (4.63 g, 8.8 mmol) in 10 mL of
PhMe was added slowly dropwise via a gas-tight syringe and
warmed to ꢀ30 ꢁC over 1 h. After stirring at ꢀ30 ꢁC for 1 h, the
reaction mixture was concentrated in vacuo to ca. 10 mL, and 50 mL
of NaOMe (0.5 M in MeOH, 25.0 mmol) was added. The mixture was
stirred at room temperature for 24 h and poured into 100 mL of
H2O. The aqueous layer was extracted with Et2O (3ꢄ50 mL), and the
combined organics were washed with satd NaHCO3 solution
(1ꢄ80 mL), brine (1ꢄ80 mL), and dried over anhydrous Na2SO4.
4.4. Completion of a formal synthesis
4.4.1. (2S,3R,4S,6S,9R,10S,11S,12S,Z)-3-(tert-Butyldimethylsilyloxy)-
2,4,6,10,12-pentamethylhexadeca-13,15-diene-1,9,11-triol, 3
Diol 39 (17 mg, 0.029 mmol) was dissolved in 330
mL of CH2Cl2
and 83 L of pH 7 buffer. To the solution, DDQ (7 mg, 0.032 mmol)
m
was added and the resulting dark green mixture was stirred at
room temperature. After 1 h, an additional 7 mg (0.032 mmol) of
DDQ was added. The mixture was stirred for 30 min, quenched
with satd NaHCO3 solution (1 mL), and extracted with CH2Cl2
(3ꢄ1 mL). The combined extracts were washed with satd NaHCO3
solution (1 mL) and dried over anhydrous Na2SO4. Purification
using flash column chromatography (10%/30% EtOAc/hexanes)
provided 14 mg (95%) of 3 as a clear, colorless oil. Analytically pure
3 was obtained using HPLC [EtOAc/hexanes (30%, 9 mL/min) on
a Microsorb (Si 80-120-C5 F310135) column, refractive index de-
Purification using silica gel chromatography (10% EtOAc/hexanes)
20
provided 4.42 g (63%) of 44 as a clear, colorless oil: [
a]
ꢀ7.1ꢁ
589
(c 0.85, CHCl3); 1H NMR (500 MHz, CDCl3)
d
7.67–7.62 (m, 4H), 7.42–
7.33 (m, 6H), 7.25–7.21 (m, 4H), 6.89–6.85 (m, 4H), 6.30
(d, J¼16.1 Hz, 1H), 5.62 (dd, J¼16.1, 5.7 Hz, 1H), 5.50 (s, 1H), 5.41 (d,
J¼9.8 Hz, 1H), 4.49–4.48 (m, 1H), 4.46 (A of AB, J¼11.7 Hz, 1H), 4.39
(B of AB, J¼11.4 Hz, 1H), 3.96 (dd, J¼9.5, 4.1 Hz, 1H), 3.92 (dd, J¼10.1,
1.9 Hz,1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.66 (dd, J¼9.5, 2.5 Hz,1H), 3.58
(dd, J¼9.1, 3.8 Hz, 1H), 3.37 (dd, J¼9.1, 5.4 Hz, 1H), 3.31 (dd, J¼12.0,
6.0 Hz, 1H), 3.23 (d, J¼5.7 Hz, 1H), 2.61–2.54 (m, 1H), 1.91–1.82 (m,
tector]. The spectral data obtained for 3 was identical in all re-
20
spects to that provided by Paterson and co-workers:9 [
a]
589 ꢀ12.3ꢁ
(c 0.17, CHCl3); 1H NMR (500 MHz, CDCl3)
d
6.64 (ddd, J¼16.7, 10.4,
10.4 Hz, 1H), 6.20 (t, J¼11.0 Hz, 1H), 5.29–5.23 (m, 2H), 5.18 (d,

H.L. Shimp, G.C. Micalizio / Tetrahedron 65 (2009) 5908–5915
5915
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23. Regioisomeric ratio (r.r.) was determined by 1H NMR analysis of the product
mixture after flash column chromatography. Regioisomers 4 and 13 were
separable by HPLC: see Supplementary data for details.
J¼10.1 Hz, 1H), 3.77 (app. t, J¼5.4 Hz, 1H), 3.60 (d, J¼4.7 Hz, 2H),
3.48–3.45 (m, 2H), 2.86–2.78 (m, 1H), 1.89–1.82 (m, 1H), 1.76–1.69
(m, 3H), 1.57–1.46 (m, 4H), 1.36 (ddd, J¼13.2, 7.9, 4.7 Hz, 1H), 1.09–
1.04 (m, 1H), 0.95 (d, J¼7.3 Hz, 3H), 0.95 (d, J¼6.9 Hz, 3H), 0.94 (d,
J¼6.6 Hz, 3H), 0.92 (s, 9H), 0.91 (d, J¼7.3 Hz, 3H), 0.89 (d, J¼6.6 Hz,
3H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (126 MHz, CDCl3)
d 134.3,
131.9, 131.8, 119.0, 81.0, 80.6, 66.1, 41.3, 38.0, 37.0, 36.3, 35.3, 32.4,
32.2, 30.4, 26.1, 20.5, 18.2, 16.6, 16.2, 15.4, 4.1, ꢀ3.9, ꢀ4.1; IR (thin
film, NaCl) 3374, 2958, 2929, 2856, 1616, 1517, 1457, 1379, 1258,
1030, 836, 773 cmꢀ1; HRMS (EI, Na) calcd for C27H54O4SiNa m/z
493.36891 (MþNa); observed m/z 493.36919 (MþNa)þ.
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35. See Supplementary data for experimental details on the preparation of homoallylic
alcohol 28.
We gratefully acknowledge financial support of this work by the
American Cancer Society (RSG-06-117-01), the Arnold and Mabel
Beckman Foundation, Boehringer Ingelheim, Eli Lilly & Co., Bristol-
Myers Squibb (for a graduate fellowship to H.L.S.). The authors also
thank Professor Kevin Burgess for helpful discussions, Professor Ian
Paterson for providing spectral data for compound 3, and Holly
Reichard for assistance in preparing the Supplementary data sec-
tion that accompanies this manuscript.
Supplementary data
36. Takaya, H.; Ohta, T.; Inoue, S. i.; Tokunaga, M.; Masato, K.; Noyori, R. Org. Synth.
1995, 72, 74–85.
37. Perry, M. C.; Cui, X. H.; Powell, M. T.; Hou, D. R.; Reibenspies, J. H.; Burgess, K.
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39. Diastereoselectivity could not be determined due to overlapping peaks in the
crude 1H NMR spectrum.
Complete experimental details for all preparative procedures
along with spectral data for all products are provided. Supple-
mentary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2009.04.073.
40. Diastereomer 18 was separable by HPLC: see Supplementary data for details.
41. As the chiral iridium catalyst does not require a coordinating functional group,
we also examined the hydrogenation with the protected homoallylic ether 38.
Although 38 was completely consumed upon exposure to D-34 (725 psi H2,
CH2Cl2, 3 h), significant amounts of products resulting from PMP deprotection
and low levels of diastereoselectivity (ca. 1.3:1) were observed.
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