Chemoenzymatic synthesis of the C10-C23 segment of dictyostatin

Article abstract of DOI:10.1021/ol052917e

Employing enzymatic desymmetrization and resolution, respectively, the two aldehydes 8 and 20 were prepared. The precursor to aldehyde 8, meso-2,4-dimethylglutaric anhydride 3, could be obtained by base treatment of the diastereomeric mixture. Aldehyde 8

Full text of DOI:10.1021/ol052917e

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1025-1028
Chemoenzymatic Synthesis of the
C10 C23 Segment of Dictyostatin
−
Evgeny Prusov, Hartmut Ro1hm, and Martin E. Maier*
Institut fu¨r Organische Chemie, UniVersita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received December 1, 2005
ABSTRACT
Employing enzymatic desymmetrization and resolution, respectively, the two aldehydes 8 and 20 were prepared. The precursor to aldehyde
8, meso-2,4-dimethylglutaric anhydride 3, could be obtained by base treatment of the diastereomeric mixture. Aldehyde 8 was extended to
alkyne 10 by a Marshall reaction introducing four carbon atoms. Lithiation of the derived iodide 15 and trapping of the anion with amide 22
gave ketone 23. This compound led to the C10−C23 fragment 27 of dictyostatin.
A range of cytotoxic natural products confer their biological
activity through stabilization of the microtubule during cell
division. The taxol and epothilone cases show that this mode
of action can be of enormous clinical relevance.1 Neverthe-
less, undesired toxicity or sensitivity toward the P-glyco-
protein efflux pump can render compounds unsuitable for
further clinical development. The polyketide dictyostatin (1)
also turned out to be an inducer of tubulin polymerization
(Figure 1). Most interestingly, it retains this activity in cells
expressing the P-glycoprotein pump.2 The 22-membered
macrolide was originally isolated by Pettit and co-workers.3
Later, Wright et al. found the same compound in a different
sponge.2 Although the constitution was known, the stereo-
chemistry was reported only recently by Wright and Pater-
son.4 A striking feature of dictyostatin is its structural
similarity to discodermolide. In fact, the 10 stereocenters in
the overlapping regions all have the same configuration. This
similarity was first recognized and exploited by Curran for
the synthesis of discodermolide/dictyostatin hybrids.5 So far,
total syntheses of dictyostatin have been achieved by the
(1) (a) Myles, D. C. Ann. Rep. Med. Chem. 2002, 37, 125-132. (b)
Myles, D. C. Curr. Opin. Biotechnol. 2003, 14, 627-633.
(2) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.;
Wright, A. E. Biochem. Pharmacol. 2003, 66, 75-82.
(3) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M.
J. Chem. Soc., Chem. Commun. 1994, 1111-1112.
Figure 1. Structures of dictyostatin (1) and discodermolide (2).
10.1021/ol052917e CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/11/2006

groups of Curran6 and Paterson.7 In addition, the synthesis
of the C9-C19 subunit was described by Philipps.8 Biologi-
cal studies are consistent with the hypothesis that the
macrocyclic structure of dictyostatin resembles the bioactive
conformation of the more flexible discodermolide.9 Most
recently, an analogue, 16-normethyldictyostatin, turned out
to have an activity profile toward several cell lines different
from that of dictyostatin.10
The macrolactone of dictyostatin features a dienoate, a
dienyl side chain, and several clusters of stereocenters that
are commonly found in polyketides.11,12 Proven strategies
to reach the stereotriads of discodermolide are based on aldol
reactions with the Roche aldehyde13-16 or with methacrolein
followed by hydroboration.17 To combine the various sub-
units, the Paterson group employed Wittig-Horner reactions.
The Curran synthesis features an acetylide addition to a
Weinreb amide and a Wittig-Horner coupling as key steps
for connecting the subunits.
Figure 2. Retrosynthetic cuts for dictyostatin (1).
We devised a strategy to dictyostatin on the basis of an
intramolecular Nozaki-Hiyama-Kishi reaction (Figure 2,
structure A).18-20 Building block B containing a Z-vinyl
iodide can be traced back to the 2,4-pentane diol C which is
available from the corresponding diol by enzymatic sym-
metry breaking.21 As an alternative, building block D could
also be considered. Finally, we wanted to circumvent the
use of the Roche ester because of its prohibitive costs. In
this paper, we illustrate the realization of these goals.
The meso-diol 4 is available by reduction of the anhydride
meso-3 (Scheme 1). Unfortunately, the synthesis produces
a mixture of diastereomeric anhydrides that has to be
separated by repeated recrystallization leading to a low yield
for meso-3.22 However, we found that the diastereomeric
mixture of meso-3/dl-3 could be converted more or less
completely to meso-3 by stirring the mixture with Hu¨nig’s
base in ethyl acetate. One crystallization provided the meso-
anhydride in excellent yield. The derived diol 4 was then
converted to the acetate 5 using lipase Amano AK in the
presence of vinyl acetate.23 This reaction could be run on a
multigram scale in high ee (98%). Silylation and basic
cleavage of the acetate gave alcohol 7.24 This operation could
be performed without chromatography. Oxidation25 of alco-
hol 7 with bis(acetoxy)iodobenzene in the presence of
catalytic amounts of tetramethyl-1-piperidinyloxyl (TEMPO)
(4) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Chem. Commun.
2004, 632-633.
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Fukui, Y.; Brueckner, A. M.; Curran, D. P.; Day, B. W. Biochemistry 2005,
44, 15053-15063.
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C. E.; Pettus, T. R. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
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M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
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Chen, S.; Chen, W.; Jagoe, C. T.; Kinder, F. R., Jr.; Loo, M.; Prasad, K.;
Repic, O.; Shieh, W.-C.; Wang, R.-M.; Waykole, L.; Xu, D. D.; Xue, S.
Org. Process Res. DeV. 2004, 8, 92-100 and the following four papers in
the same issue.
(15) For reviews, see: (a) Kalesse, M. ChemBioChem 2000, 1, 171-
175. (b) Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193-2208.
(16) This short route to stereotriads allowed for the synthesis of various
discodermolide analogues: (a) Johns, S. J.; Sundermann, K. F.; Burlingame,
M. A.; Myles, D. C.; Freeze, B. S.; Xian, M.; Brouard, I.; Smith, A. B., III.
J. Am. Chem. Soc. 2005, 127, 6532-6533. (b) Smith, A. B., III; Xian, M.
Org. Lett. 2005, 7, 5229-5232. (c) Smith, A. B., III; Rucker, P. V.; Brouard,
I.; Freeze, B. S.; Xia, S.; Horwitz, S. B. Org. Lett. 2005, 7, 5199-5202.
(d) Smith, A. B., III; Xian, M.; Liu, F. Org. Lett. 2005, 7, 4613-4616. (e)
Smith, A. B., III; Freeze, B. S.; LaMarche, M. J.; Hirose, T.; Brouard, I.;
Xian, M.; Sundermann, K. F.; Shaw, S. J.; Burlingame, M. A.; Horwitz, S.
B.; Myles, D. C. Org. Lett. 2005, 7, 315-318. (f) Smith, A. B., III; Freeze,
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(19) For a review, see: Fu¨rstner, A. Chem. ReV. 1999, 99, 991-1046.
(20) For an intermolecular Nozaki-Hiyama-Kishi reaction of a Z-vinyl
iodide, see: Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D.
C. J. Org. Chem. 2003, 68, 6646-6660.
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(24) For the enantiomer of 7, see: Nagamitsu, T.; Takano, D.; Fukuda,
T.; Otoguro, K.; Kuwajima, I.; Harigaya, Y.; Oˆ mura, S. Org. Lett. 2004, 6,
1865-1867.
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anathan, R. J. Org. Chem. 1999, 64, 310-312.
1026
Org. Lett., Vol. 8, No. 6, 2006

was obtained. Instead of extension of 14 via aldol or related
technologies in a linear approach, we opted for a coupling
with a more elaborate right-hand fragment. For this purpose,
alcohol 14 was converted to iodide 15 using I2 and Ph3P.30
As a suitable right-hand building block, we initially chose
the known Weinreb amide 22.13a However, aldehyde 20 was
not prepared from the Roche ester but rather from diol 16
(Scheme 2). Because an enzymatic desymmetrization is not
Scheme 1. Synthesis of the C10-C18 Fragment of
Dictyostatin
Scheme 2. Synthesis of the Weinreb Amide 22 from the Diol
16
very efficient with this diol, resolution of the racemic mono-
tert-butyldimethylsilyl ether rac-17 was performed.31 Via a
lipase-mediated acetylation followed by chromatographic
separation of alcohol and acetate, the alcohol 17 could be
obtained in 37% yield and 96% ee. Two further steps,
namely, etherification with the PMB imidiate followed by
cleavage of the silyl ether under acidic conditions using
camphorsulfonic acid (CSA), delivered alcohol 19. As was
checked by Mosher analysis, these protecting group ma-
nipulations proceeded without loss of optical purity. After
oxidation of 19, the derived aldehyde 20 was extended by
an Evans aldol reaction32 using the propionyl oxazolidinone
21 as described in the literature, leading to building block
22.13a
The combination of iodide 15 and Weinreb amide 22 could
be achieved in an efficient manner via lithiation of iodide
15 with t-BuLi (2 equiv) followed by addition of amide 22
to produce ketone 23 (Scheme 3). At this point, the
trimethylsilyl-protected alkyne was converted to the (Z)-vinyl
iodide by treatment of 23 with N-iodosuccinimide (NIS)
followed by diimide reduction of the resulting iodoalkyne.33
This way, vinyl iodide 24 could be secured in excellent yield.
led to aldehyde 8. For the introduction of the stereocenters
at C-12 and C-13, an anti-aldol reaction or an equivalent
thereof was required. Although chain extension turned out
to be possible with the Abiko reagent,26 the subsequent
functional group manipulations to introduce an alkyne were
too elaborate. We therefore turned to the Marshall reaction
which is characterized by addition of a chiral allenyl metal
to an aldehyde.27 The corresponding starting material,
4-trimethylsilyl-3-butyn-2-ol, is available by lipase-catalyzed
resolution. In the event, reaction of the allenyl zinc reagent
derived from mesylate28 9 introduced the necessary stereo-
centers and all required four carbon atoms. The diastereo-
selectivity of the reaction was greater than 90:10. Although
the reaction is rather slow, its great advantage is that four
carbons are introduced in one operation. After protection of
the secondary hydroxyl function as its p-methoxybenzyl
ether,29 the primary silicon ether was cleaved. Through the
classical sequence of oxidation, Wittig reaction with (meth-
oxymethylene)(triphenyl)phosphorane to give the enol ethers
13, hydrolysis, and reduction, the homologated alcohol 14
(30) Wiley, G. A.; Hershkowitz, R. L.; Rein, B. M.; Chung, B. C. J.
Am. Chem. Soc. 1964, 86, 964-965.
(31) Grisenti, P.; Feraboschi, P.; Manzocchi, A.; Santaniello, E. Tetra-
hedron 1992, 48, 3827-3834.
(32) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 83-91.
(33) (a) Hamersma, J. W.; Snyder, E. I. J. Org. Chem. 1965, 30, 3985-
3988. (b) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138-
2152. (c) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126,
12432-12440.
(26) Abiko, A. Acc. Chem. Res. 2004, 37, 387-395.
(27) Marshall, J. A.; Schaaf, G. M. J. Org. Chem. 2001, 66, 7825-
7831.
(28) Marshall, J. A.; Yanik, M. M.; Adams, N. D.; Ellis, K. C.;
Chobanian, H. R. Org. Synth. 2005, 81, 157-170.
(29) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139-4142.
Org. Lett., Vol. 8, No. 6, 2006
1027

selective silylation was easily possible,7 completing the
synthesis of the C10-C23 segment 27.
Scheme 3. Combination of the Iodide 15 and the Weinreb
Amide 22 and Transformation of the Resulting Ketone 23 to the
C10-C23 Building Block 27
In summary, we could illustrate the use of meso-diol 4
for the synthesis of an important dictyostatin subunit. This
diol is now easily available by equilibration of the diaster-
eomeric dimethylglutaric anhydride. After enzymatic resolu-
tion of 4, the derived aldehyde 8 was extended in one step
to alkyne 10 via a Marshall reaction. Subsequently, homolo-
gation of 12 and coupling of the derived iodide 15 with
Weinreb amide 22 led to ketone 23. A syn-selective reduction
on hydroxyketone 25 and a selective silylation completed
the synthesis of the C10-C23 dictyostatin fragment 27. Out
of the eight stereocenters, five were ultimately derived by
chemoenzymatic methods.
Acknowledgment. Financial support by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. In addition, we ac-
knowledge partial support by COST D28. We also thank
Dr. Andrey Gavryushin (LMU Mu¨nchen) for many helpful
discussions.
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.
Subsequently, the silyl ether was cleaved using the HF‚
pyridine complex.34 Treatment of the hydroxy ketone 25 with
DIBALH in THF induced a syn-selective reduction furnish-
ing the 1,3-diol 26.35 Among the two hydroxyl groups of
26, the left one (OH-19) is less hindered, and in fact, a
OL052917E
(34) According to: Liu, Z.-Y.; Chen, Z.-C.; Yu, C.-Z.; Wang, R.-F.;
Zhang, R.-Z.; Huang, C.-S.; Yan, Z.; Cao, D.-R.; Sun, J.-B.; Li, G. Chem.-
Eur. J. 2002, 8, 3747-3756.
(35) (a) Kiyooka, S.-i.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986,
27, 3009-3012. (b) Solsona, J. G.; Nebot, J.; Romea, P.; Urp´ı, F. 2004,
2127-2130.
1028
Org. Lett., Vol. 8, No. 6, 2006