Asymmetric synthesis of a hydroxylated nine-membered lactone from tartaric acid using the claisen rearrangement

Article abstract of DOI:10.1071/CH09637

The synthesis of a hydroxylated vinyl-appended lactone, in five synthetic steps from tartaric acid, is reported. The C2-symmetrical bis-vinyl diol 12 was converted into the ketene acetal 14 via methylenation of the cyclic carbonate 13 or thermal elimination of benzeneselenenic acid from the selenoxide 17. In both cases, the in situ generated ketene acetal 14 underwent spontaneous Claisen rearrangement to give the nine-membered lactone (+)-15. Lactones of this type are potentially advanced precursors to simplified eleutherobin analogues or other medium-ring lactone natural products.

Full text of DOI:10.1071/CH09637

Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 529–532
Asymmetric Synthesis of a Hydroxylated Nine-membered
Lactone from Tartaric Acid using the Claisen Rearrangement
Leon S.-M. Wong,A,B Kathleen A. Turner,A Jonathan M. White,B
Andrew B. Holmes,A,B and John H. RyanA,C
ACSIRO Molecular and Health Technologies, Bag 10, Clayton South, Vic. 3169, Australia.
BSchool of Chemistry, Bio21 Institute, The University of Melbourne,
30 Flemington Road, Parkville, Vic. 3010, Australia.
CCorresponding author. Email: jack.ryan@csiro.au
The synthesis of a hydroxylated vinyl-appended lactone, in five synthetic steps from tartaric acid, is reported. The C2-
symmetrical bis-vinyl diol 12 was converted into the ketene acetal 14 via methylenation of the cyclic carbonate 13 or
thermal elimination of benzeneselenenic acid from the selenoxide 17. In both cases, the in situ generated ketene acetal
14 underwent spontaneous Claisen rearrangement to give the nine-membered lactone (+)-15. Lactones of this type are
potentially advanced precursors to simplified eleutherobin analogues or other medium-ring lactone natural products.
Manuscript received: 8 December 2009.
Manuscript accepted: 14 January 2010.
O
Eleutherobin (1) is an oxygenated diterpene glycoside first iso-
lated from a rare alcyonacean soft coral, Eleutherobia sp., off
O
the coast from Exmouth in Western Australia (Fig. 1).[1,2] Sub-
NMe
H
N
sequent investigations by Andersen et al. suggested that the
B
O C
A
methylacetal 1 was an artefact of isolation due to the use
of methanol as the extraction solvent,[3] and that the hemi-
acetal analogue of 1 is a more potent antimitotic agent than
eleutherobin in cell-based assays.[4] Eleutherobin (1) displays
microtubule-stabilizing properties by binding to the paclitaxel-
binding site, with IC50 values of 10–15 nM.[1] The complex
structure of 1, together with its potent activity, has attracted
much attention from the synthetic community.[5] The groups of
Nicolaou[6] and Danishefsky[7] have completed total syntheses
of 1, and formal syntheses have been reported by the groups
of Metz[8] and Gennari.[9] Many other groups have reported
synthetic efforts towards the eleutherobin core,[10] as well as
towards the synthesis and evaluation of simplified eleutherobin
analogues.[11] Furthermore, the Nicolaou group has prepared,
and evaluated for biological activity, analogues based on the
closely related sarcodictyin family of natural products.[12]
In previous investigations we reported that the highly sim-
plified eleutherobin B-C core analogue 2 possessed signifi-
cantmicrotubule-stabilizingproperties(ED90 = 3 µM), whichis
only slightly less active than paclitaxel (ED90 = 0.5 µM).[13–15]
Incorporation of the urocanic acid side-chain to give 3 resulted in
decreased activity in this series (Fig. 1). In order to elucidate the
minimum structural requirements for biological activity[16] in
analogues such as 2, we required a shorter route towards the 11-
oxabicyclo[6.2.1]undecane framework. This paper describes the
efficient preparation of a novel nine-membered lactone, which
could be applied towards simplified analogues of eleutherobin
and other related bioactive natural products.
H
OMe
O
OAc
OH
OH
1
O
OR
O
2 R ꢀ H
3 R ꢀ
ED90 ꢀ 3 µM
H
ED90 ꢀ 6 µM
O
NMe
N
ED90 ꢀ 0.5 µM
Paclitaxel
H
Fig. 1. Structure of eleutherobin (1) and promising simplified analogues 2
and 3.[13]
would allow synthesis of a library of similar compounds to be
evaluated for structure–activity relationships. A general retro-
synthesis of these newly designed eleutherobin analogues 4 is
outlined in Scheme 1.
Bicyclic ethers 4 could be prepared by Barbier-type ring-
closure[17] of derivatives of the key intermediate lactone 5. This
method of ring closure would also allow access to the hemi-
acetal moiety (R = H), which is believed to be important for
biological activity. Lactone 5 would in turn be produced from
Claisen rearrangement[18] of a symmetrical divinyl-appended
ketene acetal 6. Incorporation of a group on the ketene acetal (R6
in Scheme 1) would introduce an additional functional group at
the position adjacent to the hemiacetal. Ketene acetal 6 could
be derived from diol 7 by Tebbe[19] or Petasis[20] olefination
of cyclic carbonate derivatives of 7[21] or by elimination of
In designing a new route to simplified eleutherobin-core ana-
logues we chose inexpensive starting materials readily available
in a range of stereochemistry and substitution patterns. This
© CSIRO 2010
10.1071/CH09637
0004-9425/10/030529

530
L. S.-M. Wong et al.
benzeneselenenic acid from selenoxide-substituted cyclic acetal
derivatives of 7.[22] Bis-vinyldiols 7 could be obtained by addi-
tionofvinylzincreagenttodialdehydes, themselvesderivedfrom
readily available 1,4-dicarboxylic acid derivatives 8. A range
of 1,4-dicarboxylic acids are commercially available (e.g. R1,
R2 = H, alkyl, amino, hydroxy, etc.) or are readily synthesized.
Differing substitution patterns on the bicyclic ether 4 could be
introduced at various stages of the synthesis, as indicated by the
positions of R1–R6 (Scheme 1).
Our planned synthesis of medium-ring lactones,[23] such as 5
is analogous to our previously described methodology,[21,24–27]
where we have used the Claisen rearrangement to synthesize
marine-derived natural products such as ascidiatrienolide,[28]
laurencin,[29] octalactins,[30] eunicellins,[15] and obtusenyne.[31]
Such an approach to medium-ring lactone synthesis could prove
useful for the preparation of complex marine natural products
such as the brevetoxins.[27] Furthermore, lactone 5 forms the
core carbon framework of structures like the halicholactones[32]
and the topsentolides,[33] both of which are nine-membered
lactone marine natural products with unsaturated side chains.
As proof-of-principle of this new approach, we chose l-
tartaric acid as a starting material[34] that would translate
into a dihydroxy-substituted nine-membered lactone 5 (R1,
R2 = OH in Scheme 1). l-Tartaric acid 9 underwent one-pot bis-
esterification and diol protection by treatment with methanol
and 2,2-dimethoxypropane, respectively, to give diester ace-
tonide 10 (Scheme 2).[35] Reduction of the diester 10 with
diisobutylaluminium hydride (DIBAL) at low temperature pro-
duced dialdehyde 11, which was treated in situ with divinylzinc
to afford a 10:1 diastereomeric mixture of diols. Flash chro-
matographic separation of the diols allowed for isolation of the
major C2-symmetric diol 12 in reasonable yield and with high
diastereomeric purity.[36]
R1
R2
R5
R2
R1
O
R4
H
R3
R4
R5
Barbier
O
R3
R3
R3
O
OR
R4
R4
R6
R5
R5 R6
4
5
R2
O
R1
R3
R3
PhSeOH
elimination
or
Claisen
rearrangement
R4
R4
R5
R5
O
Tebbe/Petasis
R6
6
Vinylzinc
addition
R1
R3
R3
R2
R2
CO2H
R1
HO2C
R4
R4
R5
R5
OH
OH
7
8
Initially, we attempted to transform the diol 12 into the
required ketene acetal 14 by carbonate formation (12 → 13)
Scheme 1. A new approach to simplified eleutherobin analogues.
O
O
OH
CO2H
HO
HO2C
O
O
O
O
(i)
(ii)
H
H
O
CO2Me
O
MeO2C
OH
OH
9
10
11
12
C10
C11
O4
C9
O3
O
O
O
C12
O
O
C7
O
O
O
C13
H
H
H
O
C8
O1
C1
C2
H
H
(iv) or (v)
C6
(iii)
O
O2
12
O
O
C5
C4
(vi)
O
C3
13
14
15
O
O
O
O
O
H
H
H
H
(vii)
(viii)
O
O
O
H
H
ꢂ
SePh
SePh
O
16
17 ꢁ
Scheme 2. Synthesis of lactone 15. Reagents and conditions: (i) dimethoxypropane, p-TsOH, MeOH, C6H12, reflux, 17 h, 67%; (ii) DIBAL, PhMe, −78◦C;
then divinyl zinc,THF, −78◦C to 25◦C, 10:1, 69%; (iii) triphosgene, pyridine, NaHCO3, CH2Cl2, −78◦C to 25◦C, 72% (+ 18% recovered 12); (iv) Cp2TiMe2,
THF, 130◦C microwave, 30 min, 15–28%; or (v)Tebbe reagent, DMAP, 4 Å molecular sieves, THF, 0◦C to 25◦C, 4 h, 35–57%; (vi) PhSeCH2CH(OEt)2, PPTS,
PhMe, reflux; (vii) NaIO4, NaHCO3, CH2Cl2/MeOH/H2O; (viii) 1,8-diazabicycloundecane, PhMe, reflux (53% from 12). Inset: Thermal ellipsoid plot (20%
probability) of lactone 15; hydrogen atoms from the methyl groups have been omitted for clarity; absolute configuration was established by chemical means,
using l-tartaric acid as starting material.

Asymmetric Synthesis of a Hydroxylated Nine-membered Lactone
531
followed by methylenation with either the Tebbe[19] or
Petasis[20] reagents, according to previously developed
methodology.[21,25–27,30] Under both conditions, ketene acetal
14 was not observed; instead, a rapid Claisen rearrangement
occurred to afford the desired lactone 15. However, it was
found that carbonate 13 was unstable towards chromatographic
purification and the yields of 15 from one-pot methylenation-
Claisen rearrangement could not be reproduced on larger scale
(see Accessory Publication for details). For this sequence, and
consistent with previous work where we have compared both
routes,[26,27,30] we prefer the method involving selenoacetal 16,
whichwasmorereliable.Thus, condensationofdiol 12with(2,2-
diethoxyethylselanyl)benzene[37] afforded the phenylseleno-
acetaldehyde acetal 16 in 70% yield after chromatography. The
selenide 16 was oxidized with sodium periodate to give the
selenoxide 17. The polar nature of this compound rendered
it unsuitable to normal phase chromatography so the crude
selenoxide 17 was subjected to elimination/rearrangement in
dilute refluxing toluene, with 1,8-diazabicycloundecane as an
additive to scavenge the by-product benzeneselenenic acid.[38]
Cyclic ketene acetal 14 was not isolated under these conditions
due to fast Claisen rearrangement, resulting in the chiral nine-
membered lactone (+)-15. We found in optimizing the sequence
towards lactone 15, that the use of either pure or crude seleno-
acetal 16 gave similar results. Thus, lactone 15 was obtained in
53% yield over three chemical steps from diol 12 (an average
of 85% yield for each transformation), without chromato-
graphic purification of the intermediates. Medium-ring lactone
15 crystallized from a concentrated solution of chloroform,
allowing examination by X-ray crystallography. This confirmed
the Z-double bond geometry of the alkene, as well as the s-cis-
conformation of the ester moiety. The relative stereochemistry
of the vinyl group was also confirmed to be anti to the adjacent
acetonide C–O bond (Scheme 2, inset).
In summary, we have developed an efficient, asymmetric
route to vinyl-appended dihydroxy nine-membered lactones
starting from l-tartaric acid. The key step in this route involves
a stereoselective Claisen rearrangement of a C2-symmetrical
ketene acetal into a Z-alkene containing lactone. We have con-
verted 15 into an iodoethyl derivative; however, initial attempts
at Barbier-type ring closure of the iodoethyl derivative, using
samarium iodide, have resulted in a side-reaction involving
reductive cleavage of the iodoethyl group. Further work will be
towards: optimization of the ring closing reaction, exploration
of the scope of the chemistry using other 1,4-dicarboxylic acid
starting materials, and application of the chemistry to the prepa-
ration of bicyclic ether analogues of eleutherobin and related
natural products systems.
References
[1] T. Lindel, P. R. Jensen, W. Fenical, B. H. Long, A. M. Casazza,
J. Carboni, C. R. Fairchild, J. Am. Chem. Soc. 1997, 119, 8744.
doi:10.1021/JA9717828
[2] W. H. Fenical, P. R. Jensen, T. Lindel, US Patent 5 473 057 1995
[Chem. Abstr. 1996, 124, 194297].
[3] R. Britton, M. Roberge, H. Berisch, R. J. Andersen, Tetrahedron Lett.
2001, 42, 2953. doi:10.1016/S0040-4039(01)00347-1
[4] M. Roberge, B. Cinel, H. J. Anderson, L. Lim, X. Jiang, L. Xu,
C. M. Bigg, M. T. Kelly, R. J. Andersen, Cancer Res. 2000,
60, 5052.
[5] For a recent review on synthetic efforts towards eleutherobin,
see: T. Busch, A. Kirschning, Nat. Prod. Rep. 2008, 25, 318.
doi:10.1039/B705652B
[6] (a) K. C. Nicolaou, F. van Delft, T. Ohshima, D. Vourloumis, J. Xu,
S. Hosokawa, J. Pfefferkorn, S. Kim, T. Li, Angew. Chem. Int. Ed.
1997, 36, 2520. doi:10.1002/ANIE.199725201
(b) K. C. Nicolaou, T. Ohshima, S. Hosokawa, F. L. van Delft,
D. Vourloumis, J. Y. Xu, J. Pfefferkorn, S. Kim, J. Am. Chem. Soc.
1998, 120, 8674. doi:10.1021/JA9810639
[7] (a) X.-T. Chen, B. Zhou, S. K. Bhattacharya, C. E. Gutteridge,
T. R. R. Pettus, S. J. Danishefsky, Angew. Chem. Int. Ed. 1998,
37, 789. doi:10.1002/(SICI)1521-3773(19980403)37:6<789::AID-
ANIE789>3.0.CO;2-3
(b) X.-T. Chen, S. K. Bhattacharya, B. Zhou, C. E. Gutteridge,
T. R. R. Pettus, S. J. Danishefsky, J. Am. Chem. Soc. 1999, 121, 6563.
doi:10.1021/JA990215C
[8] P. Metz, N. Ritter, Synlett 2003, 2422. doi:10.1055/S-2003-42467.
This formal synthesis intercepts Nicolaou’s route (ref. 6) 15 steps
away from eleutherobin.
[9] (a) D. Castoldi, L. Caggiano, L. Panigada, O. Sharon, A. M. Costa,
C. Gennari, Angew. Chem. Int. Ed. 2005, 44, 588. doi:10.1002/
ANIE.200461767
(b) D. Castoldi, L. Caggiano, L. Panigada, O. Sharon, A. M. Costa,
C. Gennari, Chem. Eur. J. 2006, 12, 51. doi:10.1002/CHEM.
200500749. This formal synthesis intercepts Danishefsky’s route
(ref. 7) 13 steps away from eleutherobin.
[10] (a) For synthetic efforts towards the core of eleutherobin, not included
in ref. 5, see: A. Baron, V. Caprio, J. Mann, Tetrahedron Lett. 1999,
40, 9321. doi:10.1016/S0040-4039(99)01956-5
(b) G. Scalabrino, X.-W. Sun, J. Mann, A. Baron, Org. Biomol. Chem.
2003, 1, 318. doi:10.1039/B207800G
(c) P. Kim, M. M. Olmstead, M. H. Nantz, M. J. Kurth, Tetrahedron
Lett. 2000, 41, 4029. doi:10.1016/S0040-4039(00)00581-5
(d) P. Kim, M. H. Nantz, M. J. Kurth, M. M. Olmstead, Org. Lett.
2000, 2, 1831. doi:10.1021/OL005886Q
(e) K. By, P. A. Kelly, M. J. Kurth, M. M. Olmstead, M. H.
Nantz, Tetrahedron 2001, 57, 1183. doi:10.1016/S0040-4020(00)
01117-0
(f) M. E. Jung, A. Huang, T. W. Johnson, Org. Lett. 2000, 2, 1835.
doi:10.1021/OL000104E
(g) K. P. Kaliappan, N. Kumar, Tetrahedron Lett. 2003, 44, 379.
doi:10.1016/S0040-4039(02)02510-8
(h) K. P. Kaliappan, N. Kumar, Tetrahedron 2005, 61, 7461.
doi:10.1016/J.TET.2005.05.045
Accessory Publication
(i) A. Rosales, R. E. Estevez, J. M. Cuerva, J. E. Oltra, Angew. Chem.
Int. Ed. 2005, 44, 319. doi:10.1002/ANIE.200461210
(j) M. Friedel, G. Golz, P. Mayer, T. Lindel, Tetrahedron Lett. 2005,
46, 1623. doi:10.1016/J.TETLET.2005.01.080
(k) S. Dhulut, A. Bourin, M.-I. Lannou, E. Fleury, N. Lensen,
E. Chelain, A. Pancrazi, J. Ardisson, J. Fahy, Eur. J. Org. Chem. 2007,
5235. doi:10.1002/EJOC.200700490
The crystallographic information file has been deposited at
the Cambridge Crystallographic Data Centre (CCDC-753692).
This information, experimental procedures for 12 → 15 (both
and 13C JMOD NMR data for 15 are available in the Accessory
Publication on the Journal’s website.
1
routes), characterization data for all new compounds, and H
[11] (a) For synthetic efforts towards simplified eleutherobin analogues,
see: J. D. Rainier, Q. Xu, Org. Lett. 1999, 1, 27. doi:10.1021/
OL990532O
Acknowledgements
The authors thank CSIRO (Australia), the Australian Research Council and
the Victorian Endowment for Science, Knowledge and Innovation (VESKI)
for financial support. We also thank Dr Roger Mulder and Dr Jo Cosgriff
for assistance with collection of NMR data and Dr Carl Braybrook for
interpretation of MS data.
(b) J. D. Rainier, Q. Xu, Org. Lett. 1999, 1, 1161. doi:10.1021/
OL990795I
(c) Q. Xu, M. Weeresakare, J. D. Rainier, Tetrahedron 2001, 57, 8029.
doi:10.1016/S0040-4020(01)00778-5

532
L. S.-M. Wong et al.
(d) J. Telser, R. Beumer, A. A. Bell, S. M. Ceccarelli, D. Monti,
C. Gennari, Tetrahedron Lett. 2001, 42, 9187. doi:10.1016/S0040-
4039(01)02045-7
(e) R. Beumer, P. Bayon, P. Bugada, S. Ducki, N. Mongelli,
F. R. Sirtori, J. Telser, C. Gennari, Tetrahedron Lett. 2003, 44, 681.
doi:10.1016/S0040-4039(02)02646-1
[18] Fora recentreviewoftheClaisenrearrangement, see:A. M. M. Castro,
Chem. Rev. 2004, 104, 2939. doi:10.1021/CR020703U
[19] F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978, 100,
3611. doi:10.1021/JA00479A061
[20] N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112, 6392.
doi:10.1021/JA00173A035
(f)L. Caggiano, D. Castoldi, R. Beumer, P. Bayon, J.Telser, C. Gennari,
TetrahedronLett. 2003, 44, 7913. doi:10.1016/J.TETLET.2003.09.010
(g) R. Beumer, P. Bayon, P. Bugada, S. Ducki, N. Mongelli,
F. R. Sirtori, J. Telser, C. Gennari, Tetrahedron 2003, 59, 8803.
doi:10.1016/J.TET.2003.08.057
[21] E. A. Anderson, J. E. P. Davidson, J. R. Harrison, P. T. O’Sullivan,
J. W. Burton, I. Collins, A. B. Holmes, Tetrahedron 2002, 58, 1943.
doi:10.1016/S0040-4020(02)00049-2
[22] M. Petrzilka, Helv. Chim. Acta 1978, 61, 3075. doi:10.1002/HLCA.
19780610833
(h) D. Castoldi, L. Caggiano, P. Bayon, A. M. Costa, P. Cappella,
O. Sharon, C. Gennari, Tetrahedron 2005, 61, 2123. doi:10.1016/
J.TET.2004.12.039
[23] (a) For reviews on the biological occurrence and synthesis of
medium-ring lactones, see: G. Rousseau,Tetrahedron 1995, 51, 2777.
doi:10.1016/0040-4020(94)01064-7
(i)G.A.Tolstikov, I. P.Tsypysheva,A. M. Kunakova, F.A.Valeev, Russ.
Chem. Bull., Int. Ed. 2001, 50, 1699. doi:10.1023/A:1013071510133
(j) C. Sandoval, E. Redero, M. A. Mateos-Timoneda, F. A. Bermejo,
Tetrahedron Lett. 2002, 43, 6521. doi:10.1016/S0040-4039(02)
01475-2
(b) I. Shiina, Chem. Rev. 2007, 107, 239. doi:10.1021/CR050045O
[24] (a) R. W. Carling, A. B. Holmes, Chem. Commun. 1986, 325.
(b) M. A. M. Fuhry, A. B. Holmes, D. R. Marshall, J. Chem. Soc.,
Perkin Trans. 1 1993, 2743. doi:10.1039/P19930002743
(c) J. R. Harrison, A. B. Holmes, I. Collins, Synlett 1999, 972.
(d) E. A. Anderson, A. B. Holmes, I. Collins, Tetrahedron Lett. 2000,
41, 117. doi:10.1016/S0040-4039(99)01988-7
(k) C. Sandoval, J. L. Lopez-Perez, F. Bermejo, Tetrahedron 2007, 63,
11738. doi:10.1016/J.TET.2007.08.099
(l) S. Chandrasekhar,V. Jagadeshwar, C. Narsihmulu, M. Sarangapani,
D. R. Krishna, J.Vidyasagar, D.Vijay, G. NarahariSastry, Bioorg. Med.
Chem. Lett. 2004, 14, 3687. doi:10.1016/J.BMCL.2004.05.017
(m) S. Chandrasekhar, C. Narsihmulu, V. Jagadeshwar, S. Shameem
Sultana, ARKIVOC 2005, 92.
[25] J. E. P. Davidson, E. A. Anderson, W. Buhr, J. R. Harrison, P. T.
O’Sullivan, A. B. Holmes, I. Collins, R. H. Green, Chem. Commun.
2000, 629. doi:10.1039/B000299M
[26] J.W. Burton, P.T. O’Sullivan, E.A.Anderson,A. B. Holmes, I. Collins,
Chem. Commun. 2000, 631. doi:10.1039/B000303O
(n) A. M. Montaña, S. Ponzano, Tetrahedron Lett. 2006, 47, 8299.
doi:10.1016/J.TETLET.2006.09.103
(o) A. M. Montaña, S. Ponzano, G. Kociok-Kohn, M. Font-Bardia,
X. Solans, Eur. J. Org. Chem. 2007, 4383. doi:10.1002/EJOC.
200700172
[27] J. W. Burton, E. A. Anderson, P. T. O’Sullivan, I. Collins, J. E. Davies,
A. D. Bond, N. Feeder, A. B. Holmes, Org. Biomol. Chem. 2008, 6,
693. doi:10.1039/B715354F
[28] M. S. Congreve, A. B. Holmes, A. B. Hughes, M. G. Looney, J. Am.
Chem. Soc. 1993, 115, 5815. doi:10.1021/JA00066A056
[29] J. W. Burton, J. S. Clark, S. Derrer, T. C. Stork, J. G. Bendall,
A. B. Holmes, J. Am. Chem. Soc. 1997, 119, 7483. doi:10.1021/
JA9709132
[30] P. T. O’Sullivan, W. Buhr, M. A. M. Fuhry, J. R. Harrison, J. E. Davies,
N. Feeder, D. R. Marshall, J. W. Burton, A. B. Holmes, J. Am. Chem.
Soc. 2004, 126, 2194. doi:10.1021/JA038353W
[31] (a) S. Y. F. Mak, N. R. Curtis, A. N. Payne, M. S. Congreve,
C. L. Francis, J. W. Burton, A. B. Holmes, Synthesis 2005, 3199.
(b) S. Y. F. Mak, N. R. Curtis, A. N. Payne, M. S. Congreve,
A. J. Wildsmith, C. L. Francis, J. E. Davies, S. I. Pascu, J. W.
Burton, A. B. Holmes, Chem. Eur. J. 2008, 14, 2867. doi:10.1002/
CHEM.200701567
(p) L. Zhang, Y. Wang, C. Buckingham, J. W. Herndon, Org. Lett.
2005, 7, 1665. doi:10.1021/OL050416N
[12] (a) K. C. Nicolaou, J.-Y. Xu, S. Kim, T. Ohshima, S. Hosokawa,
J. Pfefferkorn, J. Am. Chem. Soc. 1997, 119, 11353. doi:10.1021/
JA973000G
(b) K. C. Nicolaou, J. Y. Xu, S. Kim, J. Pfefferkorn, T. Ohshima,
D. Vourloumis, S. Hosokawa, J. Am. Chem. Soc. 1998, 120, 8661.
doi:10.1021/JA981062G
(c) K. C. Nicolaou, S. Kim, J. Pfefferkorn, J. Xu, T. Ohshima,
S. Hosokawa, D. Vourloumis, T. Li, Angew. Chem. Int. Ed. 1998, 37,
1418. doi:10.1002/(SICI)1521-3773(19980605)37:10<1418::AID-
ANIE1418>3.0.CO;2-5
(d)K. C. Nicolaou, N.Winssinger, D.Vourloumis,T. Ohshima, S. Kim,
J. Pfefferkorn, J.-Y. Xu, T. Li, J. Am. Chem. Soc. 1998, 120, 10814.
doi:10.1021/JA9823870
[32] H. Niwa, K.Wakamatsu, K.Yamada,Tetrahedron Lett. 1989, 30, 4543.
doi:10.1016/S0040-4039(01)80740-1
[33] X. Luo, F. Li, J. Hong, C.-O. Lee, C. J. Sim, K. S. Im, J. H. Jung,
J. Nat. Prod. 2006, 69, 567. doi:10.1021/NP0503552
[34] For a review on tartaric acid and tartrates as starting materials for the
synthesis of bioactive compounds, see: A. K. Ghosh, E. S. Koltun,
G. Bilcer, Synthesis 2001, 1281. doi:10.1055/S-2001-15217
[35] E. A. Mash, K. A. Nelson, S. Van Deusen, S. B. Hemperly, Org. Synth.
1990, 68, 92. This compound is also commercially available from
Sigma-Aldrich as either D- or L-tartrate esters.
[13] G. C. H. Chiang, A. D. Bond, A. Ayscough, G. Pain, S. Ducki,
A. B. Holmes, Chem. Commun. 2005, 1860. doi:10.1039/B413426E
[14] S. Y. F. Mak, G. C. H. Chiang, J. E. P. Davidson, J. E. Davies,
A. Ayscough, G. Pain, J. W. Burton, A. B. Holmes, Tetrahedron
Asymmetry 2009, 20, 921. doi:10.1016/J.TETASY.2009.03.010
[15] J. E. P. Davidson, R. Gilmour, S. Ducki, J. E. Davies, R. Green,
J. W. Burton, A. B. Holmes, Synlett 2004, 1434.
[16] For an in depth discussion on the elements believed to be important for
biological activity in eleutherobin and other microtubule-stabilizing
natural products, see: I. Ojima, S. Chakravarty,T. Inoue, S. Lin, L. He,
S. Band Horwitz, S. D. Kuduk, S. J. Danishefsky, Proc. Natl. Acad.
Sci. USA 1999, 96, 4256. doi:10.1073/PNAS.96.8.4256
[17] (a) P. Knochel, W. Dohle, N. Gommermann, F. F. Kneisel, F. Kopp,
T. Korn, I. Sapountzis,V.A.Vu,Angew. Chem. Int. Ed. 2003, 42, 4302.
doi:10.1002/ANIE.200300579
[36] (a) M. Jørgensen, E. H. Iversen, A. L. Paulsen, R. Madsen, J. Org.
Chem. 2001, 66, 4630. doi:10.1021/JO0101297
(b)C. Gaul, J.T. Njardarson, D. Shan, D. C. Dorn, K.-D.Wu,W. P.Tong,
X.-Y. Huang, M. A. S. Moore, S. J. Danishefsky, J. Am. Chem. Soc.
2004, 126, 11326. doi:10.1021/JA048779Q
[37] R. Baudat, M. Petrzilka, Helv. Chim. Acta 1979, 62, 1406.
doi:10.1002/HLCA.19790620505
[38] (a) P. A. Evans, A. B. Holmes, R. P. McGeary, A. Nadin, K. Russell,
P. J. O’Hanlon, N. D. Pearson, J. Chem. Soc., Perkin Trans. 1 1996,
123. doi:10.1039/P19960000123
(b) M. S. Baird, V. M. Boitsov, A. V. Stepakov, A. P. Molchanov,
J. Kopf, M. Rajaratnam, R. R. Kostikov, Tetrahedron 2007, 63, 7717.
doi:10.1016/J.TET.2007.04.104
(c) A. Krief, A.-M. Laval, Chem. Rev. 1999, 99, 745. doi:10.1021/
CR980326E
(b) N. R. Curtis, A. B. Holmes, M. G. Looney, Tetrahedron 1991, 47,
7171. doi:10.1016/S0040-4020(01)96169-1