An approach to the core structure of leiodermatolide

Article abstract of DOI:10.1021/ol200584a

Chemical equations presented. The synthesis of the 16-membered core structure of leiodermatolide 40 has been achieved in 26 linear steps starting from (R)-Roche ester. The key steps in the synthesis of 40 are a Stille cross-coupling between two main fragm

Full text of DOI:10.1021/ol200584a

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2334–2337
An Approach to the Core Structure of
Leiodermatolide
Christian Rink, Vaidotas Navickas, and Martin E. Maier*
€
€
Institut fu€r Organische Chemie, Universitat Tubingen, Auf der Morgenstelle 18, 72076
Tu€bingen, Gemany
martin.e.maier@uni-tuebingen.de
Received March 4, 2011
ABSTRACT
The synthesis of the 16-membered core structure of leiodermatolide 40 has been achieved in 26 linear steps starting from (R)-Roche ester. The key
steps in the synthesis of 40 are a Stille cross-coupling between two main fragments 11 and 33 having roughly equal size. For the trisubstituted C4/
C5 double bond a carbometalation reaction followed by a Suzuki coupling was used. A Yamaguchi macrolactonization furnished macrolactone 39.
Leiodermatolide (1) was isolated by the Wright group
from the Harbor Branch Oceanographic Institution at
Florida University.1 The source is the sponge Leioderma-
tium, which grows in depths of 200ꢀ500 m. This novel
macrolide shows cytotoxicity at a nanomolar level against
a variety of human tumor cell lines.2 It features nine
stereocenters, a conjugated Z,Z-diene, and a conjugated
E,E-diene system, terminating in a 6-membered lactone as
part of the side chain. Initially, only the constitution of
leiodermatolide was published,1 but more recently addi-
tional data with stereochemical information was released on
the Internet (Figure 1).3 Because of its potent antiprolifera-
tive activity and its unique structural features, leiodermato-
lide appeared as an interesting target for a synthesis
program. Even though structure 1 was possibly not 100%
correct, we chose it as a starting point. Because of the 14-H/
15-H coupling constant of 10.3 Hz, the anti-configuration
seemed highly likely. Some doubts remained, however,
regarding the stereocenters C6ꢀC9 since force field calcula-
tions (MacroModel 7.0) on all stereoisomers of the simpler
model compound 2 (C14, C15 D,D configuration) showed
isomer 2a to have the highest energy (241.9 vs 230.3 kJ molꢀ1
for isomer 2b) (Figure 1) (for details, see the Supporting
Information). Application of the Kishi method4,5 to the 13
C
shifts of leiodermatolide for this region in CD3OD also did
not favor stereoisomer 1 as a likely candidate. Most recently,
a detailed NMR and calculation study by the Paterson and
(1) Wright, A. E.; Reed, J. K.; Roberts, J.; Longley, R. E. U.S. Pat. Appl.
Publ. (USA), US2008033035, 14 pp; Chem. Abstr. 2008, 148, 230104.
(2) The following IC50 values were reported in the patent: A549, P399 =
3.3 nM, PANC-1 = 5.0 nM, DLD-1 = 8.3 nM, NCI-ADR-Res = 233 nM.
(3) http://www.rsmas.miami.edu/groups/ohh/courses/23nov12wright
marinenaturalproductsdrugdiscovery.pdf. Accessed on March 25,
2011.
Figure 1. Proposed structure of leiodermatolide 1 and simplified
model 2 used for force field calculations.
r
10.1021/ol200584a
Published on Web 03/28/2011
2011 American Chemical Society

Wright groups found that the 6,8-epi-isomer of 1 (both
methyl-bearing stereocenters inverted) was the correct one.6
Even though we might not reach the correct stereostructure
with isomer 1, the developed route was envisioned to pave the
way for accessing natural leiodermatolide.
Preparation of stannane 11 started from the known
aldehyde11 7 and (R)-mesylate12 8 with a MarshallꢀTamaru
reaction13 followed by protection of the free hydroxyl func-
tion as a TBS ether (Scheme 2).10 Homopropargylic alcohol was
obtained as a single diastereomer with an ee of 94% (determined
by Mosher analysis).8,10 The triple bond was then functionalized
by terminal iodination with N-iodosuccinimide and silver
nitrate14 and Z-selective reduction to the vinyl iodide10 10 by
diimide reduction.15 In the following step, a Z-selective replace-
ment of the iodide with tributylstannane using tributyltin
chloride in THF and addition of t-BuLi delivered stannane
11. One should mention that the order of addition (tin chloride
before t-BuLi) turned out to be crucial. Using the chloride and
the base, the other way around, in this case, only induced
elimination leading to the corresponding alkyne as a byproduct.
Our retrosynthetic plan for the synthesis of the stereo-
isomer 1 of leiodermatolide is illustrated in Scheme 1. We
Scheme 1. Retrosynthetic Plan for Leiodermatolide (1)
(P = Protecting Group)
Scheme 2. Preparation of Vinylstannane 11 (C12ꢀC18
Fragment)
decided to remove part of the side chain by cutting the
C18ꢀC19 trans double bond, which would be installed, for
example, by JuliaꢀKocienski olefination.7 For macrolactone
formation, a macrolactonization reaction was planned.8 The
internal Z,Z-diene would come from a Stille cross coupling.
This led to two building blocks, stannane 5 and vinyl iodide 6,
both of roughly equal size.9 A precursor for stannane 5 was
already published during our synthesis of key fragments of
leiodermatolide,10 as well as a δ-lactone fragment 4 (P =
SiMe3). For vinyl iodide 6 we decided to use an Evans aldol
reaction to establish the syn-stereochemistry at C7/C8 and a
hydride-based stereoselective reduction in order to guarantee
the C7/C9 anti-stereochemistry. For the highly substituted
double bond at C4/C5 a carbometalation appeared expedient,
followed by a Suzuki coupling to attach the C1ꢀC3 section.
The synthesis of vinyl iodide 18 proceeded via alkyne 17,
which was obtained from (R)-Roche ester (12) using a known
literature sequence16 (Scheme 3). Methyl (R)-(þ)-hydroxyiso-
butyrate was protected as a TBS ether. This was followed by
reduction of the ester and oxidation of the alcohol 14 to the
corresponding aldehyde 15. Thereafter, a CoreyꢀFuchs reac-
tion via dibromide 16 led to alkyne 17. This five-step sequence
was achieved in 78% overall yield. Alkyne 17 was introduced
in a carbometalation using bis(cyclopentadienyl)zirconium-
(IV) dichloride (1.5 equiv) and Me3Al (2.2 equiv) followed by
quenching with iodine to provide vinyl iodide 18 in 66% yield.
One should note that comparable carbometalation reactions
on larger fragments were not successful. Vinyl iodide 18 was
then elongated by Suzuki coupling with PMB-protected allylic
alcohol17 using Pd(PPh3)4 (0.05 equiv) and K2CO3 (4.0 equiv)
in DMF/water, leading to the corresponding product 19 as a
single diastereomer in 81% yield. The TBS group of ether 19
was removed (TBAF, THF) prior to Swern oxidation of the
(4) (a) Kobayashi, Y.; Lee, J.; Tezuka, K.; Kishi, Y. Org. Lett. 1999,
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(6) Paterson, I.; Dalby, S. M.; Roberts, J. C.; Naylor, G. J.; Guzman,
E. A.; Isbrucker, R.; Pitts, T. P.; Linley, P.; Divlianska, D.; Reed, J. K.;
Wright, A. E. Angew. Chem., Int. Ed. 2011, 50, 3219–3223.
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2002, 2563–2585.
(8) A ring-closing metathesis strategy (formation of the C4ꢀC5
double bond) did not work in our hands. Vaidotas, N. Ph.D. Thesis,
€
University of Tubingen, 2011.
(9) Coupling of a C1ꢀC11 vinylstannane with a C12ꢀC18 vinyl
iodide (1-OTBS) did not give the corresponding conjugated diene.
(10) Navickas, V.; Rink, C.; Maier, M. E. Synlett 2011, 191–194.
(11) Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui,
Y.; Abe, S.; Kotake, Y. Angew. Chem., Int. Ed. 2007, 46, 4350–4355.
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Org. Lett., Vol. 13, No. 9, 2011
2335

Scheme 3. Preparation of Aldol Product 23 (C1ꢀC9 Fragment)
Scheme 4. Preparation of Vinyl Iodide 33 (C1ꢀC11 Fragment)
primary alcohol 20. The resulting aldehyde 21 was subjected to
an Evansꢀaldol18 reaction, which was carried out using
oxazolidinone19 22 (1.4 equiv), n-Bu2BOTf19 (1.4 equiv), and
i-Pr2NEt (1.6 equiv) in CH2Cl2 at ꢀ78 to ꢀ60 °C, which gave
rise to aldol product 23. The diastereoselectivity of this reaction
was determined from 1H NMR to be 92:8.
pH 7 buffer) and the TIPS-function (TBAF) was cleaved and
the primary hydroxy was protected as a pivaloyl ester (PivCl,
DMAP, pyridine) to obtain alkyne 30. This four-step sequence
was achieved in 63% yield. The 1,3-anti relationship of the two
acetal-protected hydroxyl functions in 30 was evident from the
chemical shift of the acetal C-atom in its 13C NMR spectrum
[measured 13C shift of C(CH3)2: desired diastereomer 100.4
ppm; undesired diastereomer 99.2 ppm].22
For further functionalization of the terminal triple bond
iodination and Z-selective reduction was evaluated. Thus,
treatment of alkyne 30 with N-iodosuccinimide in the presence
of silver nitrate resulted in iodoalkyne 31 in 97% yield, which
was then subjected to a Z-specific reduction using o-nitro-
benzenesulfonyl hydrazide23 (32) (1.6 equiv) and triethylamine
in THF/i-PrOH leading to vinyl iodide 33 in 95% yield.
However, this key fragment contained 12% of a byproduct,
resulting from over-reduction of the C10/C11 double to single
bond. All other common approaches [(KO2CN)2, Cy2BH] for
Z-selective reduction resulted in higher concentrations of this
byproduct. Fortunately, this impurity was not participating in
the subsequent coupling reaction.
In the next step, we converted aldol product 23 into the
Weinreb amide 24 using N,O-dimethylhydroxylamine hydro-
chloride (3.0 equiv) and Me3Al (2.9 equiv).20 This was followed
by addition of TIPS-acetylide (4.0 equiv) to obtain alkynone 25
in 69% yield over two steps (Scheme 4). Protection of the free
hydroxyl function was not necessary in this case. Because
diastereoselective reduction by the typical Noyori protocol
failed, a directed reduction with tetramethylammonium triace-
toxyborohydride was used.21 A solution of the hydride
(5.0 equiv) in acetonitrile and glacial acetic acid was treated
with alkynone 25 at ꢀ35 °C leading to diol 26 in high yield. The
diastereoselectivity of this reaction was determined by 1HNMR
to be 88:12. Separation of the isomers was possible at the stage of
the acetal 27. After protection of the diol 26 (2,2-dimethoxy-
propane, CSA) as acetal 27, the PMB-protecting group (DDQ,
(18) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83–91. Organic
Synthesis; Wiley: New York, 1993; Collect. Vol. VIII, pp 339343
(19) (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099–3111. (b) Vo, L.; Ciula, J.; Gooding, O. W.
Org. Process Res. Dev. 2003, 7, 514–520. (c) Guerlavais, V.; Carroll, P. J.;
Joullie, M. M. Tetrahedron: Asymmetry 2002, 13, 675–680. (d) Lu, C.-
D.; Zakarian, A. Org. Synth. 2008, 85, 158–171.
(20) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–
3818. (b) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000,
342, 340–347.
(22) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9–17.
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Soc. 1988, 110, 3560–3578.
(24) Substrate 33 with a TBS protecting group at 1-OH instead of the
pivaloyl group did not react in the Stille cross-coupling.
2336
Org. Lett., Vol. 13, No. 9, 2011

After successful synthesis of the two building blocks 11 and
33, we now concentrated on their cross coupling (Scheme 5).
Accordingly, we investigated a range of conditions for the Stille
coupling trying different catalysts (Pd(PPh3)4, Pd(MeCN)Cl2,
Pd(dba)3) and additives ([Ph2PO2ꢀ][NBu4þ], (2-furyl)3P,
i-Pr2NEt, Ph3As, Cu(I)Cl, CuTC).24 The only variation25 that
was effective involved Pd(PPh3)4 (0.1 equiv), Ph2PO2ꢀ]-
Scheme 5. Stille Cross-Coupling to Tetraene 34 and
Macrolactonization to the Core Structure 40 of Leiodermatolide
[NBu4þ 26 (1.1 equiv), and CuTC27 (1.5 equiv) in DMF at
]
room temperature, leading to pivaloyl-protected conjugated
diene 34 in 85% yield as a single Z,Z-stereoisomer.
After removal of the pivaloyl group (DIBAL-H), alcohol 35
was converted to acid 37 by Swern oxidation and further
Pinnick oxidation28 of the intermediate aldehyde. This three-
step sequence proceeded in 75% yield. Next, the TBS group
was cleaved (TBAF) to give seco acid 38 in reasonable yield
(60%) but represented the best result for deprotection in
comparison to other methods (HCl, MeOH; HF pyridine;
3
aqueous HF). With seco-acid 38 in hand, we tested different
lactonization methods (TrostꢀKita,29 Shiina30), but Yama-
guchi conditions31,32 offered the best results. Thus, 2,4,6-
trichlorobenzoyl chloride (5.0 equiv), triethylamine (6.0 equiv),
and DMAP (25.0 equiv) were used to obtain macrolactone 39
in 50% yield. Cleavage of the acetal-group protecting group
was realized under acidic conditions (HCl, MeOH) resulting in
diol 40. Unfortunately, the following selective carbamate form-
ation at C9 was not successful. Instead, we observed reaction of
diol 40 with Cl3C(CO)NCO33 at the more hindered 7-OH
group. This was evident from the downfield shift of 7-H (4.89
ppm). This is surprising, since electrophilic attack on related
precursors always took place selectively on 9-OH and not on
7-OH. Also, selective protection of the diol 40 was not possible
because moderate amounts of base always resulted in sub-
stantial elimination with formation of a C8ꢀC9 double bond.
The core structure 40 allowed us to compare its NMR
data with that from the natural product. Excellent agree-
1
ment was seen in the H and 13C NMR spectra for the
In summary, the synthesis of the core structure 40 of
leiodermatolide was achieved in a convergent way in 26 steps
(longest linear sequence) starting from (R)-Roche ester. While
structure 40 most likely does not represent the correct stereo-
chemistry, slight modifications of this route should allow for
preparation of the correct isomer. Further work is currently
underway to achieve the total synthesis of leiodermatolide (1).
chemical shifts of the stereocenters at C15 and C14. Also,
for the conjugated Z,Z-diene system the shifts and the
coupling constants are fitting quite well. From this we
assume that this stereochemical information suggested by
the Wright group3,6 is probably correct (see the table of
chemical shifts of the natural product and the synthesized
core structure 40 in the Supporting Information).
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft (Grant No. Ma 1012/25-1) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
€
(25) Furstner, A.; Funel, J.-A.; Tremblay, M.; Bouchez, L. C.;
Nevado, C.; Waser, M.; Ackerstaff, J.; Stimson, C. C. Chem. Commun.
€
We also thank the state Baden-Wurttemberg for a fellowship
2008, 2873–2875.
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1997, 119, 12376–12377.
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2091–2096.
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Y.-j.; Ibuka, R. Chem.;Eur. J. 2005, 11, 6601–6608.
(31) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
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Chem. Rev. 2006, 106, 911–939.
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to C.R. during the early stage of his graduate studies. In
addition, we thank Dr. Claudio Salvagnini, Kaneka Pharma
Europe, Brussels, for a generous gift of Roche ester. Finally,
we thank Dr. Dorothee Wistuba (Institute for Organic
Chemistry) for measuring the high-resolution mass spectra.
This work was carried out within the framework of COST
action CM0804 ꢀ Chemical Biology with Natural Products.
Supporting Information Available. Experimental pro-
cedures and characterization for all new compounds
reported and copies of NMR spectra for important
intermediates. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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