Highly enantioselective organocatalytic addition of aldehydes to N-(Phenylmethylene)benzamides: Asymmetric synthesis of the paclitaxel side chain and its analogues

Article abstract of DOI:10.1002/chem.200900078

A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected α-hydroxy-β- benzoylami-noaldehydes (92-99% ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.

Full text of DOI:10.1002/chem.200900078

DOI: 10.1002/chem.200900078
Highly Enantioselective Organocatalytic Addition of Aldehydes to N-
(Phenylmethylene)benzamides: Asymmetric Synthesis of the Paclitaxel Side
Chain and Its Analogues
Pawel Dziedzic,[a] Patric Schyman,*[b] Martin Kullberg,[a] and Armando Cꢀrdova*[a]
Abstract: A simple highly enantioselective organocatalytic addition of aldehydes
to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as
the catalyst and subsequent oxidation of the protected a-hydroxy-b-benzoylami-
noaldehydes (92–99% ee) gives access to esterification-ready phenylisoserine de-
rivatives such as the protected paclitaxel (taxol) side chain. Esterification of these
derivatives with baccatin III gives access to the cancer chemotherapeutic substance
paclitaxel and its analogues that do not exist in nature.
Keywords: aldehydes · asymmetric
catalysis (phenylmethylene)-
benzamides · organocatalysis · taxol
·
AHCTUNGTRENNUNG
Introduction
valuable a-hydroxy-b-amino acids, which are present in nat-
ural products such as paclitaxel (taxol).[10] Moreover, there
are only a few examples of the employment of protected a-
oxyacetaldehydes as donors in organocatalytic Mannich-
type reactions.[7u,v,8e]
Esterification of the furnished derivative of the (2R,3S)-
phenylisoserine side chain with a protected form of deace-
tylbaccatin III, an abundant natural product obtained from
various Taxus species, would give access to paclitaxel and its
analogues.[11]
Mannich reactions rank among the most versatile class of
transformations in organic chemistry.[1,2] Development of ef-
ficient and practical catalytic asymmetric variants of such re-
actions is a critical aim in chemical synthesis.[3] In particular,
organometallic complexes have been used successfully as
catalysts for indirect catalytic asymmetric Mannich-type re-
actions.[4] Direct catalytic Mannich-type reactions between
ketones and preformed imines are also catalyzed by organo-
metallic complexes with high enantioselectivity.[5] In the
field of organocatalysis,[6] List and co-workers reported the
first direct metal-free catalytic Mannich reaction in 2000.[7a]
However, despite the intense research on the catalytic enan-
tioselective Mannich reaction,[7–9] the organocatalytic enan-
tioselective addition of aldehydes to N-(phenylmethylene)-
benzamide has not been reported. This transformation
would be important and useful since according to retrosyn-
thetic analysis (Scheme 1) it would provide a direct entry to
[a] P. Dziedzic, Dr. M. Kullberg, Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)8-154-908
E-mail: acordova@organ.su.se
acordova1a@netscape.net
[b] Dr. P. Schyman
Division of Physical Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
E-mail: patric.schyman@gmail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900078.
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FULL PAPER
Proline derivatives also cata-
lyzed the transformation. For
example,
(S)-hydroxyproline
gave the corresponding prod-
uct ent-3a in 65% yield with
90:10 d.r. and 97% ee. Encour-
aged by these results, protected
2-hydroxy-3-benzoylamino-3-
phenylpropanals
3 with the
same stereochemistry as the
phenylisoserine side chan of
paclitaxel were prepared by
using (R)-proline as the cata-
lyst and CH3CN as the solvent
(Table 1).
The aldehyde products
3
were assembled in an asym-
metric fashion with good to
high
(75:25–95:5 d.r.) and high
enantioselectivity (92–99%
diastereoselectivity
Scheme 1. Retrosynthetic analysis for a three-step synthesis of protected paclitaxel.
ee). Both protected a-oxyalde-
hydes and aliphatic aldehydes
While deacetylbaccatin III can be obtained from Taxus
species, the side chains of paclitaxel and taxane derivatives
are prepared by chemical synthesis.[11,12] Asymmetric induc-
tion in the industrial transformations is generally achieved
by employing chiral auxiliaries. Thus, catalytic methods[11]
and in particular organocatalytic methods[6] that avoid the
use of toxic catalysts would be highly desirable for the syn-
thesis of paclitaxel side chain analogues. Herein, we report
the first example, to the best of our knowledge, of a highly
enantioselective amino acid-catalyzed addition of aldehydes
to N-(phenylmethylene)benzamides.
were successfully used as substrates. The reaction was also
performed on a large scale without loss of stereoselectivity
but a slight decrease in yield. Subsequent oxidation of the
protected 2-hydroxy-3-benzoylamino-3-phenylpropanals
3
gave the corresponding protected esterification-ready
(2R,3S)-phenylisoserine derivatives 4 in high yields. For ex-
ample, protected a-hydroxy-b-aminoaldehyde 3a was oxi-
dized to the corresponding paclitaxel side chain 4a[13h] in
82% yield (Scheme 2). We next embarked on the semisyn-
thesis of paclitaxel,[13] which is currently used to treat pa-
tients with lung, ovarian, breast cancer, head and neck
cancer, advanced forms of Kaposiꢂs sarcoma, and the pre-
vention of restenosis.[14] Esterification of 4a with protected
7-triethylsilylbaccatin III 5[11] produced the corresponding
orthogonally protected C-2’,C-7-protected paclitaxel 7,
which can be readily deprotected, in 60% yield. All structur-
al and characterization data were in agreement with known
literature values.[13h] The employment of orthogonal protec-
tive groups is advantageous since it allows further controlled
modification of the taxol to give analogues. Finally, paclitax-
el was synthesized after deprotection of 7 in 76% yield. The
(2R,3S)-phenylisoserine derivative 4a was also converted to
the corresponding methyl ester 6a, which is an excellent
precursor for the coupling with protected 7-triethylsilylbac-
catin III 5.[13h]
Results and Discussion
In an initial catalyst and solvent screen for the chiral amine-
catalyzed reaction between N-(phenylmethylene)benzamide
(1a) and a-benzyloxyacetaldehyde (2a), we found that
amino acid derivatives catalyzed the formation of 2-benzyl-
oxy-3-benzoylamino-3-phenylpropanals 3a (syn isomer) and
3a’ (anti isomer) (see the Supporting Information). To our
delight, (R)-proline catalyzed the formation of 2-benzyloxy-
3-benzoylamino-3-phenylpropanal 3a in 68% yield with
95:5 (syn:anti) d.r. and 99% ee in CH3CN at room tempera-
ture using nearly stoichiometric amounts of acceptor and
donor ([Eq. (1)]).
To shed more light on the initial step of the (R)-proline-
catalyzed reaction between
imines 1 and protected a-oxy-
aldehydes, we performed den-
sity functional theory (DFT)
calculations by using the Gaus-
sian 03 software package[15]
and the B3LYP functional.[16]
Geometries were optimized
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A. Cꢀrdova, P. Schyman et al.
Table 1. Catalytic assembly of 2-hydroxy-3-benzoylamino-3-phenylpropanals 3.[a]
zero-point effects obtained
from the frequency calcula-
tions. The transition state
search was conducted by using
the QST3 algorithm.[17] The
effect of solvation in CH3CN
was calculated by using an
IEF-PCM model with the di-
electric constant of acetoni-
Entry
R
Ar
R1
Product
Yield
[%][b]
d.r.[c]
ee [%][d]
1
2
OBn
OBn
3a
3b
68
64
95:5
99
99
trile.[18] As
a representative
case for the calculations, we
considered the initial step of
the (R)-proline-catalyzed reac-
tion between N-(phenylmethy-
88:12
3
OBn
3c
65
95:5
99
lene)benzamide
methyl-protected
(1a)
a-oxyalde-
and
4
5
6
OBn
OBn
OBn
3d
3e
3 f
50
61
60
85:15
90:10
90:10
94
98
96
hyde.[19] A favorable six-mem-
bered metal-free Zimmer-
mann–Traxler transition state
(TS) with an energy of
9.1 kcalmolÀ1 in CH3CN rela-
tive to that of the reactant was
found that gives the correct
stereochemistry of the product
(Figure 1). The six-membered
transition state is stabilized by
hydrogen bonding between the
nitrogen of the N-(phenylme-
7
OBn
3g
66
75:25
96
8
9
Me
3h
3i
68
85:15
80:20
92
98
OTBS
68[e]
thylene)benzamide
with
a
[a] Experimental conditions: A mixture of 1 (0.25 mmol), 2 (0.27 mmol), and (R)-proline (20 mol%) was
stirred at room temperature in CH3CN (1.0 mL). [b] Isolated yield of 3 after silica gel column chromatography.
[c] Determined by H1 NMR analysis of the crude reaction mixture. [d] Determined by chiral-phase HPLC
analysis. [e] Reaction run for 23 h. Bn=benzyl, TBS=tert-buthyldimethylsilyl.
trans-configuration and the car-
boxylic acid group of (R)-pro-
line. Hence, the reaction
worked best in polar aprotic
solvents.
with the double-zeta basis set 6–31G
with frequency calculations. Final energies were obtained
with the larger basis set 6–311+G(2d,2p) and corrected for
ACHTUNGERTN(NUNG d,p), and characterized
N
Conclusion
In summary, we have developed a highly enantioselective
catalytic asymmetric addition of aldehydes to N-(phenylme-
thylene)benzamides. This transformation was employed in
the short synthesis of phenylisoserine derivatives and the
cancer chemotherapeutic substance paclitaxel. Analogues of
the paclitaxel side chain that do not exist in nature could be
readily made following this modular route. We are continu-
ing to explore the potential of this method in structure–ac-
tivity relationship tests of paclitaxel analogues and in diver-
sity oriented synthesis. The results of these investigations
will be reported in due course.
Acknowledgement
We gratefully acknowledge the Swedish National Research Council, the
Swedish Governmental Agency for Innovation Systems (VINNOVA)
and the Carl Trygger Foundation for financial support.
Figure 1. DFT-optimized geometries of the initial reaction steps (kcal
molÀ1).
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Asymmetric Synthesis of the Paclitaxel Side-Chain and Its Analogues
FULL PAPER
Scheme 2. Synthesis of protected paclitaxel 7. Ac=acetyl, Bn=benzyl, DPC=di(2,2’-pyridyl)carbonate, DMAP=4-dimethylaminopyridine, TES=tri-
ethylsilyl, TMS=trimethylsilyl.
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À
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Received: January 12, 2009
Published online: February 26, 2009
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