A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

Article abstract of DOI:10.3762/bjoc.7.32

A novel highly enantioselective two step access to a unit B precursor of cryptophycins in good yields from commercially available starting materials has been developed. The key step is an asymmetric hydrogenation using the commercially available [(COD)Rh-

Full text of DOI:10.3762/bjoc.7.32

A two step synthesis of a key unit B precursor of
cryptophycins by asymmetric hydrogenation
Benedikt Sammet, Mathilde Brax and Norbert Sewald*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 243–245.
Bielefeld University, Department of Chemistry, Organic and
Bioorganic Chemistry, Universitätsstraße 25, 33615 Bielefeld,
Germany
doi:10.3762/bjoc.7.32
Received: 02 November 2010
Accepted: 27 January 2011
Published: 22 February 2011
Email:
Norbert Sewald* - norbert.sewald@uni-bielefeld.de
Editor-in-Chief: J. Clayden
* Corresponding author
© 2011 Sammet et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amino acid; asymmetric hydrogenation; cryptophycin; DuPhos
Abstract
A novel highly enantioselective two step access to a unit B precursor of cryptophycins in good yields from commercially available
starting materials has been developed. The key step is an asymmetric hydrogenation using the commercially available [(COD)Rh-
(R,R)-Et-DuPhos]BF4 catalyst. The synthetic route provides the advantage of less synthetic steps, proceeds with high yields and
enantioselectivity, and avoids hazardous reaction conditions.
Introduction
Cryptophycins are macrocyclic depsipeptides, which show very
high cytotoxicity even against multidrug-resistant cell lines.
They inhibit mitosis of eukaryotic cells by interacting with the
β-subunit of α/β-tubulin heterodimers. Numerous natural and
artificial analogs have been analysed in structure–activity rela-
tionship (SAR) studies. The unit B of cryptophycins contains a
considerably modified D-tyrosine derivative (Figure 1).
Substituent variations at unit B are not well tolerated. Both the
methoxy and the chloro substituent are required for full bio-
logical activity [1-4].
Figure 1: The four building blocks (units) A–D of cryptophycin-1 (1)
and cryptophycin-52 (2).
The previously published synthetic route to unit B precursor 4
involves a three-step modification of D-tyrosine by chlorina-
243

Beilstein J. Org. Chem. 2011, 7, 243–245.
Scheme 1: Synthesis of the unit B precursor from D-tyrosine (3). Reagents and conditions [7]: a) SO2Cl2, AcOH, rt, 90 min, (75%); b) Boc2O, NaOH,
t-BuOH/H2O, rt, 16 h (quant.) c) Me2SO4, K2CO3, acetone, reflux, 4 h (99%); d) LiOH, H2O/THF/MeOH, rt, 1 h (93%).
tion, protecting group introduction and double methylation fol- Results and Discussion
lowed by a final saponification reaction to give carboxylic acid We envisaged a two step synthesis for the unit B precursor 4
5 (Scheme 1). A number of experimental procedures for this (Scheme 1) from commercially available non-toxic starting ma-
route have been published [5-7]. The selective monochlorina- terials based on an asymmetric hydrogenation approach to make
tion of D-tyrosine is quite cumbersome since the formation of the unit B precursor synthesis shorter and safer. In general,
the dichlorinated product must be minimized and the presence there is also a whole variety of possible stereoselective syn-
of unreacted D-tyrosine after the reaction must be completely thetic methods available to synthesize modified α-amino acids,
avoided. The dichlorinated by-product has to be separated by such as the classical Schöllkopf-method [10] or catalytic
column chromatography when purifying the desired methyl approaches [11,12]. The unit B precursor of cryptophycin is a
ester 4 [7,8]. In addition, another major drawback of this syn- phenylalanine derivative. An asymmetric hydrogenation ap-
thetic route is the use of highly toxic and carcinogenic dimethyl proach for the synthesis of such α-amino acids is well-estab-
sulfate.
lished [12]. In the first step of the developed synthesis 3-chloro-
4-methoxybenzaldehyde is reacted with rac-Boc-α-phosphono-
glycine trimethyl ester (9) [13,14] to yield olefin 10 in a
completely Z-selective Horner–Wadsworth–Emmons (HWE)
reaction (Scheme 3). Asymmetric hydrogenation using the
commercially available [(COD)Rh-(R,R)-Et-DuPhos]BF4 cata-
A completely different route to unit B precursor 8 (Scheme 2) is
based on a phase transfer catalyst (PTC) mediated asymmetric
alkylation. However, the required cinchonine derived chiral
catalyst is not commercially available [9].
Scheme 2: Unit B synthesis by a chiral PTC approach. Reagents and conditions [9]: a) N-(Diphenylmethylene)glycine tert-butyl ester, 50% KOH,
toluene/CHCl3, chiral phase transfer catalyst (0.01 equiv), 0 °C, 20 h (87%; 96% ee); b) 15% citric acid, THF, rt, 16 h; c) FmocCl, Na2CO3, THF, rt, 14
h, (72% over two steps).
Scheme 3: Unit B precursor 4 synthesis by asymmetric hydrogenation. Reagents and conditions: a) 3-Chloro-4-methoxybenzaldehyde, 1,1,3,3-
tetramethylguanidine, CH2Cl2, 0 °C to rt, 16 h (84%); b) [(COD)Rh-(R,R)-Et-DuPhos]BF4 (1.9 mol %), H2, dry and degassed MeOH, 3–6 bar, 21.5 h
(97%; 98% ee); c) 10% Pd/C, H2, MeOH, 16 h, (76%).
244

Beilstein J. Org. Chem. 2011, 7, 243–245.
8. Eißler, S. Synthese von Cryptophycinen für SAR-Studien. Ph.D.
Thesis, Bielefeld University, Bielefeld, Germany, 2008.
http://bieson.ub.uni-bielefeld.de/volltexte/2008/1301/
9. Danner, P.; Bauer, M.; Phukan, P.; Maier, M. E. Eur. J. Org. Chem.
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lyst [14,15] gave the anticipated methyl ester 4 (Scheme 1) in
97% yield with an ee exceeding 98% (determined by chiral
HPLC). Hydrogenation of 10 with 10% Pd/C was envisaged to
obtain rac-4 as a reference for the determination of the ee. Inter-
estingly, due to this more reactive catalyst a complete reductive
dehalogenation was observed to give rac-Boc-Tyr(Me)-OMe
(rac-11) as reported for a similar case [16]. Therefore, ent-4
was synthesized analogously also using the commercially avail-
able enantiomeric catalyst ([(COD)Rh-(S,S)-Et-DuPhos]BF4).
10.Lim, H. J.; Gallucci, J. C.; RajanBabu, T. V. Org. Lett. 2010, 12,
2162–2165. doi:10.1021/ol100663y
11.Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature
2009, 461, 968–970. doi:10.1038/nature08484
12.Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584–4671.
doi:10.1021/cr050580o
13.Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487–490.
doi:10.1055/s-1992-26143
Conclusion
A novel two step synthesis of the important cryptophycin unit B
precursor 4 is disclosed based on a HWE reaction followed by a
highly enantioselective [(COD)Rh-(R,R)-Et-DuPhos]BF4 medi-
ated asymmetric hydrogenation. This high-yielding access is
more convenient and avoids hazardous chemicals in contrast to
the established method.
14.Bower, J. F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005,
5793–5795. doi:10.1039/b510761j
15.Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.
J. Am. Chem. Soc. 1993, 115, 10125–10138. doi:10.1021/ja00075a031
16.Melillo, D. G.; Larsen, R. D.; Mathre, D. J.; Shukis, W. F.; Wood, A. W.;
Colleluori, J. R. J. Org. Chem. 1987, 52, 5143–5150.
doi:10.1021/jo00232a016
Supporting Information
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Supporting Information File 1
Full experimental procedures and detailed analytical data
for the synthesis of 10 and 4 including chiral HPLC spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-32-S1.pdf]
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Acknowledgements
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
We wish to thank F. Mertink, K.-P. Mester and G. Lipinski for
running the NMR spectra, and Dr. M. Letzel, O. Kollas and S.
Heitkamp for recording the mass spectra (all Bielefeld Univer-
sity). Financial support by Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged.
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.7.32
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