Synthetic studies towards leiodermatolide: Rapid stereoselective syntheses of key fragments

Article abstract of DOI:10.1055/s-0030-1259286

The synthesis of three key fragments of the novel 16-membered macrolide leiodermatolide is described. The stereotetrad-containing building block was prepared via a Marshall-Tamaru reaction on an aldehyde obtained by organocatalysis. For a second building block, a Marshall-Tamaru reaction was used as well. The side-chain fragment containing a hydroxy δ-lactone could be obtained by intramolecular Reformatsky reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259286

LETTER
191
Synthetic Studies towards Leiodermatolide: Rapid Stereoselective Syntheses
of Key Fragments
Synthetic Studies
t
a
owards
L
ei
i
oderma
d
tolide otas Navickas, Christian Rink, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295137; E-mail: martin.e.maier@uni-tuebingen.de
Received 3 November 2010
H2N
O
Abstract: The synthesis of three key fragments of the novel 16-
membered macrolide leiodermatolide is described. The stereotet-
rad-containing building block was prepared via a Marshall–Tamaru
reaction on an aldehyde obtained by organocatalysis. For a second
building block, a Marshall–Tamaru reaction was used as well. The
side-chain fragment containing a hydroxy d-lactone could be ob-
tained by intramolecular Reformatsky reaction.
34
O
29
15
30
33
25
11
OH
18
8
HO
28
4
24
22
21
31
13
O
O
1
32
27
O
O
26
Key words: leiodermatolide, macrolide, Marshall–Tamaru reac-
tion, intramolecular Reformatsky reaction, Fráter–Seebach alkyla-
tion
leiodermatolide (1)
Sonogashira
O
25
O
O
OP
OP
9
S
N
8
O
18
N
19
7
N
N
O
+
Leiodermatolide (1) is a potent antimitotic agent, recently
isolated by the group of Amy Wright from the sponge
Leiodermatium, which belongs to the order Lithistida
(Scheme 1).1 It displays cytotoxicity at nanomolar level
against a variety of human tumor cell lines2 while show-
ing reduced toxicity to normal cell lines. Leiodermatolide
does not show much similarity to other cytotoxic
polyketides, however, it shares a carbamate function, for
example with palmerolide3 and discodermolide.4 This
novel polyketides features a 16-membered macrolide,
with a six-membered lactone ring on the side chain and
has nine stereocenters together with a Z,Z- and E,E-diene
system. Although, the initial report of Wright et al.1 just
contained a flat structure of this macrolide, more recently
additional data with stereochemical information as shown
in Scheme 1 appeared on the web.5
O
1
Ph
6
O
Reformatsky
O
3
RCM
2
Marshall–Tamaru
OPMB
11
O
18
O
2
OTBS
12
I
5
Marshall–Tamaru
4
4
Scheme 1 Proposed structure of leiodermatolide (1) together with
key retrosynthetic cuts; P = protecting group
reaction9,10 that would secure the anti stereochemistry at
Taking into account the remarkable potent antiprolifera-
tive activity and the unique structural features which are
calling for proof, leiodermatolide (1) deserves attention
for total synthesis. As outlined in the retrosynthetic plan
in Scheme 1, we decided to remove part of the side chain
by cutting the C18–C19 trans double bond (Julia–
Kocienski olefination).6 For macrolactone formation a
ring-closing metathesis approach was considered.7,8 Al-
ternatively, other C–C bond-forming reactions or lacton-
ization reactions (Yamaguchi/Mitsunobu) might be
options. The internal Z,Z-diene would come from an
enyne precursor. This way, a Sonogashira cross-coupling
followed by Z-selective reduction is obvious. This leads to
two building blocks 4 and 5, both having roughly equal
size. For these, we decided to apply a Marshall–Tamaru
C6/C7 and C14/C15 carbons.
The synthesis of alkyne 4 started from known aldehyde
(+)-6, which was obtained via L-proline-catalyzed cross-
aldol reaction of a-silyloxyacetaldehyde using a known
literature procedure (Scheme 2).11,12 With this aldehyde in
hand, which was used as a mixture of diastereomers, we
tested the Marshall–Tamaru conditions hoping for separa-
ble diastereomeric diols. To our surprise, when (R)-
mesylate13 7 (2.0 equiv) was added into the reaction mix-
ture containing Pd(OAc)2 (0.05 equiv), Ph3P (0.05 equiv)
and aldehyde 6 followed by slow addition of diethyl zinc
(3.0 equiv) and stirred for 48 hours, diol 8 was isolated as
a single isomer in 61% yield after chromatographic puri-
fication. This reaction outcome can be understood based
on Felkin–Anh-like transition state A which is akin to at-
tack of an E-enolate to an a-substituted aldehyde
(Scheme 2). Due to an angle of 120° between the C=O and
the OH-dipole this transition state also minimizes dipole
interactions.14 We assume that the major anti diastereo-
SYNLETT 2011, No. 2, pp 0191–0194
x
x.
x
x.
2
0
1
1
Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1259286; Art ID: G29910ST
© Georg Thieme Verlag Stuttgart · New York

192
V. Navickas et al.
LETTER
mer 6 reacts faster than the corresponding syn isomer.15
Subsequent diol protection as acetal 9 additionally proved
the 1,3-anti relationship. In particular, the two methyl
groups of the acetal appear at similar chemical shifts in the
13C NMR spectrum (d = 23.7 and 24.9 ppm, respective-
ly).16
O
O
Hg(OAc)2, PPTS
H2O, acetone (76%)
K2CO3, MeOH
(97%)
9
OTBDPS
H
10
O
OH
MsO
O
O
O
O
O
Ph3P, Pd(OAc)2
1. (Cp)2TiCH2ClAl(Me)2
THF, –40 °C (92%)
TMS
H
+
Et2Zn, THF, –10 °C
(61%)
OTBDPS
2. TBAF, THF
0 °C (85%)
(R)-7
6
OTBDPS
OH
11
12
OH OH
O
O
Me2C(OMe)2
O
O
1. Dess–Martin oxidation
CH2Cl2, 0 °C
CSA, CH2Cl2
(82%)
8
OTBDPS
OTBDPS
7
11
9
6
2. AcC(N2)PO(OMe)2
K2CO3, MeOH
(40% over 2 steps)
TMS
TMS
4
8
9
4
OH
H
Scheme 3 Synthesis of the C4–C11 fragment 4 featuring the
stereotetrad22 of leiodermatolide
OTBDPS
H
H
MsOZn
TMS
O
Me
•
sponding iodoalkyne, which was directly subjected to Z-
specific diimide reduction.25 Thus, slow addition (6 h) of
acetic acid to a solution of the iodoalkyne, potassium
azodicarboxylate and pyridine gave Z-iodoalkene 5 in
77% yield over two steps.
Me
H
A
Scheme 2 Synthesis of heptyne 9 via Marshall–Tamaru reaction
between aldehyde 6 and mesylate (R)-7
OPMB
For further functionalization of the triple bond we found
the Kutcheroff alkyne hydration17,18 and Tebbe
olefination19 to be optimal, since classical carbometala-
tion reactions on alkyne 10 were not successful. Accord-
ingly, the TMS group of 9 was removed using K2CO3 in
MeOH followed by reaction of alkyne 10 with mercu-
ry(II) acetate in wet acetone to give the corresponding me-
thyl ketone 11 which was then transformed to alkenol 12
via Tebbe olefination and cleavage of the silyl ether
(Scheme 3). This two-step sequence was achieved in 70%
overall yield. Alcohol 12 was then oxidized with Dess–
Martin reagent to the corresponding aldehyde followed by
MsO
Pd(OAc)2, Ph3P
H
+
TMS
Et2Zn, THF, –5 °C
(58%)
O
(R)-7
13
OPMB
1. AgNO3, NIS, DMF
TMS
OR
2. (KO2CN)2, MeOH
pyridine, AcOH
(77%, 2 steps)
14 R = H
TBSOTf, CH2Cl2
2,6-lutidine
–50 °C
I
OPMB
15 R = TBS
(70%)
15
18
12
14
16
OTBS
5
reaction
with
dimethyl-1-diazo-2-oxopropylphos-
phonate20 (Bestmann–Ohira protocol)21 in the presence of
K2CO3 to give the desired alkyne 4 in 40% yield over two
steps. One should mention that no epimerization was de-
tected during alkyne formation.
Scheme 4 Synthesis of Z-iodoalkene 5 (C12–C18 fragment)
After successful synthesis of Sonogashira coupling part-
ners 4 and 5 we then concentrated on the construction of
the side chain lactone 3. Here we started the synthesis
from known methyl (3S)-3-hydroxypentanoate26 (16),
which underwent a Fráter–Seebach alkylation27 with MeI
to give ester28 17 (Scheme 5). The diastereoselectivity of
this reaction could be determined from the 1H NMR to be
85:15. Subsequent protection of the free hydroxy function
as TBS ether followed by Weinreb amide formation29 al-
lowed us to prepare amide 19 in 82% yield and on a gram-
scale. Initial Grignard reaction to give enone 20 was fol-
lowed by Michael addition of benzyl alcohol induced by
1,1,3,3-tetramethylguanidine (1.0 equiv)30 resulting in ke-
tone 21 in 76% yield. After removal of the TBS group
For the synthesis of Z-iodoalkene 5 the same Marshall–
Tamaru reagent (R)-7 served as a perfect synthetic tool to
establish the desired C14/C15 anti stereochemistry
(Scheme 4). Starting from known aldehyde23 13 and ap-
plying the same conditions as for the synthesis of ho-
mopropargyl alcohol 8, alcohol 14 could be isolated in
58% as a single isomer. Subsequent alcohol protection
with TBSOTf in the presence of 2,6-lutidine furnished si-
lyl ether 15 in 70% yield. Further functionalization of the
triple bond called for terminal iodination and Z-selective
reduction. Thus, treatment of trimethylsilyl alkyne 15
with N-iodosuccinimide in the presence of silver nitrate24
resulted in almost quantitative conversion to the corre-
Synlett 2011, No. 2, 191–194 © Thieme Stuttgart · New York

LETTER
Synthetic Studies towards Leiodermatolide
193
(HCl, MeOH) resulting in hydroxyketone 22, esterifica- tertiary alcohol function was protected as trimethylsilyl
tion of the obtained alcohol function with bromoacetyl ether 25 (96% yield). At this stage the stereochemistry of
1
chloride delivered Reformatsky precursor 23 in high the tertiary alcohol function was deduced from the H
yield.
NMR NOESY spectrum (CDCl3). In particular the H-5–
4-CH2 (weak) correlation is only possible with the C-4
side chain in equatorial position. The absence of a H-6–4-
CH2 cross peak also supports this assignment. Surprising-
ly, the 13C chemical shifts of C-4 (d = 71.97 ppm) and C-
6 (d = 84.53 ppm) of hydroxy lactone 24 in CD3OD are
comparable to the corresponding shifts in the natural
product (d = 72.73, 85.56 ppm). This could mean that the
assigned stereochemistry at C-21 requires revision. Next,
the benzyl ether was cleaved via catalytic hydrogenation
to provide primary alcohol 26. A subsequent two-step
protocol involving Mitsunobu reaction of alcohol 26 with
tetrazole 27 gave thio ether 28 which upon oxidation with
hydrogen peroxide in the presence molybdate furnished
the desired sulfone 29 in 89% yield over two steps.
A smooth intramolecular Reformatsky reaction31,32 took
place when ester 23 was introduced to a SmI2 solution33 at
–78 °C giving alcohol 24 as a single isomer (Scheme 5).
The formation of hydroxylactone 24 is in accordance
with a chair-like transition state B with the keto group
adopting a pseudoaxial orientation to allow for intramo-
lecular chelation with the Sm(III) center. Thereafter, the
LDA, MeI, HMPA
MeONHMe•HCl
MeO2C
MeO2C
THF, –78 °C
(70%, dr = 85:15)
i-PrMgCl, THF
(88%)
OH
OR
16
17 R =H
TBSCl, DMAP
imid., DMF (93%)
18 R = TBS
In summary, the stereoselective synthesis of all three key
fragments of leiodermatolide (1) has been accomplished
utilizing a Marshall–Tamaru reaction as a key transforma-
tion for two units and an internal Reformatsky aldol reac-
tion for the side chain. Further work is currently underway
to achieve the total synthesis of 1.
OMe
N
BnOH
TMG
vinylMgCl, THF
Me
–10 °C to 0 °C
(90%)
(76%)
O
OTBS
O
OTBS
19
20
BrCH2COCl, Py
DMAP, CH2Cl2
(100%)
OBn
O
OR
OBn
O
O
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
21 R = TBS
23
HCl, MeOH
(89%)
Br
22 R = H
RO
Me3SiO
Acknowledgment
Sm, CH2I2
H2, Pd/C
THF (80%)
Financial support by the Deutsche Forschungsgemeinschaft (Grant
Ma 1012/25-1) and the Fonds der Chemischen Industrie is grateful-
ly acknowledged. This work was carried out within the framework
of COST action CM0804, Chemical Biology with Natural Products.
We also thank the state Baden-Württemberg for a fellowship to
C.R.
THF, –78 °C
(88%)
OBn
O
OH
O
O
O
Me3SiCl
imid., CH2Cl2
(96%)
24 R = H
26
25 R = SiMe3
Me3SiO
27, Ph3P
(NH4)6Mo7O24
References and Notes
DEAD, THF
(92%)
H2O2, EtOH
(97%)
S
O
N
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O
N
Ph
28
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Me3SiO
22
Ph
N
Sm(III)
O
OBn
19
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27
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N
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OP
4
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Synlett 2011, No. 2, 191–194 © Thieme Stuttgart · New York

194
V. Navickas et al.
LETTER
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