Catalytic asymmetric synthesis of the docetaxel (Taxotere) side chain: organocatalytic highly enantioselective synthesis of esterification-ready α-hydroxy-β-amino acids

Article abstract of DOI:10.1016/j.tetlet.2008.09.038

A highly enantioselective catalytic route to protected β-amino-α-hydroxy acids, such as the side chain of Taxotere, is presented. The organocatalytic asymmetric reactions between unmodified protected α-oxyaldehydes and N-Boc-protected aryl imines give the corresponding compound with up to >19:1 dr and 99-99% ee.

Full text of DOI:10.1016/j.tetlet.2008.09.038

Tetrahedron Letters 49 (2008) 6631–6634
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Tetrahedron Letters
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Catalytic asymmetric synthesis of the docetaxel (Taxotere) side chain:
organocatalytic highly enantioselective synthesis of esterification-ready
a-hydroxy-b-amino acids
*
Pawel Dziedzic, Jan Vesely, Armando Córdova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective catalytic route to protected b-amino-a-hydroxy acids, such as the side chain of
Received 3 August 2008
Revised 26 August 2008
Accepted 5 September 2008
Available online 11 September 2008
Taxotere, is presented. The organocatalytic asymmetric reactions between unmodified protected
a-
oxyaldehydes and N-Boc-protected aryl imines give the corresponding compound with up to >19:1 dr
and 99–99% ee.
Ó 2008 Elsevier Ltd. All rights reserved.
The b-amino-
a
-hydroxy acid moiety is a common structural
step synthesis of the Taxotere side chain based on a direct zinc
organometallic complex-catalyzed Mannich reaction between an
N-Boc imine and 2-hydroxy-2’-methoxyacetophenone.4
component in a vast group of naturally occurring as well as phar-
maceutically active molecules.1 In this context, docetaxel (Taxo-
tere), a synthetic derivative of paclitaxel (Taxol), which is one of
the most outstanding cancer chemotherapeutic substances, con-
tains a (2R,3S)-phenylisoserine side chain.2
Recently, organocatalysis was added to the synthetic repertoire
of the direct Mannich reaction.5–7 For example, we have reported
amino acid-catalyzed Mannich reactions between protected
a
-oxyaldehydes, para-anisidine, and aldehydes (Eq. 1).8
The corresponding N-p-methoxyphenyl (PMP)-protected
a-
HO
Boc
oxy-b-amino aldehydes are excellent precursors for the synthesis
O
OH
NH O
OH
of -hydroxy-b-amino acids. However, removal of the PMP group
a
requires oxidative conditions, can be low yielding, and requires
Boc protection as an additional step. Enders recently reported ele-
gant examples of Mannich-type reactions between ketones and
Boc imines.9 List10 and our group11 have also reported that alde-
hydes can be employed as donors in organocatalytic reactions with
Boc imines. Moreover, we recently showed that proline catalyzes
O
C6H5
H
HO
O
O
O
Taxotere
OCOCH3
C6H5
the highly enantioselective addition of a,b-unsaturated aldehydes
to Boc imines.12 Based on our previous results and retro-synthetic
analysis, we envisioned a short route to the important Taxotere
side chain via an amino acid-catalyzed direct Mannich-type
The importance of
a-hydroxy-b-amino acid derivatives has
inspired chemists to develop a number of methods for their prep-
aration.1,3 Among them, Shibasaki and co-workers reported a four-
MeO
COOH
N
O
H
NH2
NH
O
O
ð1Þ
(10-30 mol%)
+
+
H
R
H
R
H
MeO
OP
OP
* Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908.
E-mail addresses: acordova@organ.su.se, acordova1a@netscape.net (A. Córdova).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.038

6632
P. Dziedzic et al. / Tetrahedron Letters 49 (2008) 6631–6634
reaction between protected
benzaldimine (Eq. 2).
a-oxyaldehydes and N-Boc-protected
responding a-oxy-b-amino aldehyde 3a in poor to good yields but
with excellent diastereomeric ratios and ees (Table 1).13
Boc
Boc
Boc
NH
O
NH
O
O
N
C6H5
OH
ð2Þ
C6H5
H
+
H
Ph
H
OP
OP
OP
Taxotere side-chain
P = Protective Group
Herein, we report a highly enantioselective synthesis of the
esterification-ready side chain of Taxotere (>19:1 dr, 99% ee). The
(S)-Proline-catalyzed the formation of protected
a
-oxy-b-amino
aldehyde 3a in 12–36% yield with >19:1 dr (syn:anti) and 99–99%
ee in DMF, NMP, and CH3CN, respectively, at 4 °C (entries 1–3).
The optically active aldehyde 3a was quite stable but was stored
at ꢀ20 °C. The highest yield was obtained when CH3CN was used
as the solvent. Performing the catalytic reaction at room tempera-
ture increased the yield of 3a to 48% without affecting the stereose-
lectivity (entry 6). Inspired by these excellent results, we decided
reaction is
a direct route to Boc-protected a-hydroxy-b-
aminoaldehydes.
In an initial screen, we found that (S)-proline 4 and hydroxypro-
line 5 catalyzed the reaction between phenyl N-Boc-imine 1a
(0.25 mmol) and tert-butyldimethylsilyl (TBS)-protected
a-oxyal-
dehyde 2a (0.27 mmol) with high stereoselectivity to give the cor-
Table 1
Catalyst screen for the enantioselective reactions between 1a and 2aa
R
COOH
N
H
4: R = H
5: R = OH
Catalyst
(20 mol%)
Boc
Ar
Boc
O
NH
O
N
+
H
H
Ar
H
Solvent, 48 h
OTBS
2a (1.1 equiv)
OTBS
3a
1a: Ar = C6H5
Entry
Catalyst
Time (h)
Solvent
Temperature (°C)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
4
4
4
4
4
4
5
4
48
48
48
48
48
16
16
48
DMF
CH3CN
NMP
CHCI3
CH2CI2
CH3CN
CH3CN
Toluene
4
4
4
4
4
rt
rt
4
12
36
24
Trace
Trace
48
>19:1
>19:1
>19:1
n.d.
99
>99
99
n.d.
n.d.
99
n.d.
>19:1
>19:1
n.d.
6
95
n.d.
Trace
a
Experimental conditions: A mixture of 1a (0.25 mmol), aldehyde 2a (0.50 mmol), and catalyst (20 mol %) in 1.0 mL of solvent was stirred under the conditions displayed
in the table.
b
c
Isolated yield of pure compound 3a.
Determined by 1H NMR of the crude reaction mixture.
d
Determined by chiral-phase HPLC analysis. n.d. = not determined. TBS = tert-butyldimethylsilyl.
Table 2
Direct organocatalytic asymmetric Mannich reactions between N-Boc-protected imines 1 and
a
-oxyaldehydes 2a
(R)-proline
(20 mol%)
Boc
Ar
Boc
H
O
NH
O
N
+
H
H
Ar
CH3CN, rt
OP
OP
1
2
ent-3
Entry
Ar
X
Product
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
Ph
Ph
TBS
Bn
Bn
Bn
ent-3a
ent-3b
ent-3c
ent-3d
40
5
16
16
56
60
56
52
>19:1
>19:1
3:1
99
99
99
99
4-MeC6H4
4-MeOC6H4
9:1
a
Experimental conditions: A mixture of 1a (0.25 mmol),
Isolated yield of pure compound 3.
a-oxyaldehyde 2 (0.27 mmol), and (R)-proline (20 mol %) in 1.0 mL of CH3CN was stirred at room temperature.
b
c
syn/anti ratio determined by 1H NMR analysis.
d
Determined by chiral-phase HPLC analyses. TBS = tert-butyldimethylsilyl. Bn = benzyl.

P. Dziedzic et al. / Tetrahedron Letters 49 (2008) 6631–6634
6633
Boc
Ar
Boc
Boc
H
O
NH
O
NH
O
N
(b)
(a)
+
H
OH
Ar
H
Ar
OBn
2b
OBn
4b
OBn
ent-3b
1a: Ar = C6H5
Scheme 1. Reagents and conditions: (a) (R)-proline (20 mol %), CH3CN, rt, 16 h, 60%; (b) NaClO2, iso-butene, KHPO4, t-BuOH/H2O 2:1, 85%.
to investigate the catalytic asymmetric Mannich reaction between
H
O
various N-Boc-protected imines 1 and different a-oxyaldehydes 2
N
H
(Table 2).14 In order to achieve the same configuration (2R,3S) as
that of the Taxotere side chain, (R)-proline was selected as the
organocatalyst.
Boc
H
O
N
H
Ar
The (R)-proline-catalyzed Mannich reactions proceeded with
OP
excellent enantioselectivity, and the corresponding a-oxy-b-amino
I
aldehydes ent-3a–ent-3d were obtained in good yields with 99% ee.
To our delight, the reaction was highly syn-selective (>19:1 dr)
when imine 1a was used as the acceptor (entries 1 and 2). In fact,
this is the key transformation for the synthesis of the Taxotere side
chain (Eq. 2). For example, (R)-proline-catalyzed the asymmetric
Boc
Ar
NH
O
reaction between imine 1a and benzyl-protected
2b with high diastereo- and enantioselectivity to give the corre-
sponding orthogonally protected -oxy-b-amino aldehyde ent-
3b14 in 60% yield with >19:1 dr and 99% ee (entry 2). Moreover,
the reactions were readily scaled up. Next, the -oxy-b-amino
a-oxyaldehyde
H
a
OP
Figure 1. Transition-state model evoked to account for the enantioselectivity of the
(R)-proline-catalyzed reactions.
a
aldehyde ent-3b was oxidized to the corresponding (2R,3S)-phen-
ylisoserine (Taxotere) side chain 4b3g in high yield (Scheme 1).15
This reaction can also be performed as a one-pot operation.
transformation in total synthesis as well as mechanistic studies is
ongoing in our laboratory.
Notably, the benzyl-protected b-amino-a-hydroxy acid 4b is
esterification-ready for reaction with 10-deacetylbaccatin III, an
abundant natural product obtained from the yew tree, which after
deprotection gives Taxotere (Eq. 3).3g
Acknowledgments
We gratefully acknowledge the Swedish National Research
Council and Carl-Trygger Foundation for financial support.
PO
Boc
O
OP
NH
O
Ref. 3g
References and notes
+
Taxotere
OH HO
C6H5
OBn
2b
1. (a) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3; (b) Cardillo,
G.; Tomasini, C. Chem. Soc. Rev. 1996, 29, 117; (c) Bergmeier, S. C. Tetrahedron
2000, 56, 2561.
2. For selected reviews on these compounds see: (a) Nicolaou, K. C.; Dai, W.-M.;
Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15; (b) Blechert, S.; Guénard, D..
In Brossi, A., Ed.; The Alkaloids, Chemistry and Pharmacology; Springer: Berlin,
1990; Vol. 39, p 195; (c) Potier, P.; Guénard, D.; Guéritte-Voegelein, F. Acc.
Chem. Res. 1993, 26, 160.
H
HO
O
O
O
OCOCH3
C6H5
P = Protective Group
ð3Þ
3. For selected examples, see: (a) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int.
Ed. 1997, 36, 2637; (b) Upadhya, T. T.; Sufalai, A. Tetrahedron: Asymmetry 1997,
8, 3685; (c) Hanessian, S.; Sancéau, J.-Y. Can. J. Chem. 1996, 74, 621; (d) Gennari,
C.; Carcano, M.; Dongi, M.; Mongelli, N.; Vanotti, E.; Vulpetti, A. J. Org. Chem.
1997, 62, 4746; (e) Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. J. Org. Chem. 1993, 58,
1287; (f) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe, L. R. J. Org. Chem.
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1994, 59, 1238; (h) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1990, 55,
1957; (i) Montiel-Smith, S.; Cervantes-Mejía, V.; Dubois, J.; Guénard, D.;
Guéritte, ; Sandoval-Ramírez, J. Eur. J. Org. Chem. 2002, 2260; (j) Kudyaba, I.;
Raczko, J.; Jurczak, J. J. Org. Chem. 2004, 69, 2844. and references cited therein.
4. Matsunaga, S.; Yishida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2004, 126, 8777.
5. For reviews see: (a) Córdova, A. Acc. Chem. Res. 2004, 37, 102; (b) Rios, R.;
Córdova, A. Amino Group Chemistry. In Ricci, A., Ed.; Wiley-VCH: Weinheim,
2008, Chapter 5, p 185; (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
6. For selected examples of the use of amino acids as catalysts see: (a) List, B. J.
Am. Chem. Soc. 2000, 122, 9336; (b) Córdova, A.; Watanabe, S.-i.; Tanaka, F.;
Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866; (c) Münch, A.;
Wendt, B.; Christmann, M. Synlett 2004, 2751; (d) Zhuang, W.; Saaby, S.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476; (e) Fustero, S.; Jimenez,
D.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Esteban, E.; Simon-Fuentes, A. Org.
Lett. 2005, 7, 3433; (f) Córdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43,
7749; (g) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077; (h)
Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2005, 46, 3363; (i) Enders, D.; Grondal,
C.; Vrettou, M.; Raabe, G. Angew. Chem., Int Ed. 2005, 44, 4079; (j) Cobb, A. J. A.;
On the basis of the absolute configuration, we propose transi-
tion-state model I to account for the diastereo- and enantioselec-
tivity of the (R)-proline-catalyzed formation of
a-oxy-b-amino
aldehydes 3 (Fig. 1). Hence, the (R)-proline forms an enamine with
the aldehyde, which is attacked by the N-Boc-protected imine from
its Re-face providing (2R,3S)-b-amino-a-hydroxy acid derivatives.
This is in accordance with the opposite established transition
states of previously reported (S)-proline-catalyzed Mannich reac-
tions5,6 with -oxyaldehydes.8
a
In summary, we have reported a simple, highly enantioselec-
tive, organocatalytic asymmetric Mannich-type reaction with
-oxyaldehydes as nucleophiles and Boc-protected imines as
a
acceptors. The corresponding orthogonally protected -oxy-b-ami-
a
noaldehydes were formed in good yields with 99% ee. The impor-
tance of this transformation as an entry to the synthesis of
-hydroxy-b-amino acids was further exemplified by the highly
stereoselective (>19:1 dr, 99% ee) synthesis of the esterification-
a
ready Taxotere side chain. Further elaboration of this novel

6634
P. Dziedzic et al. / Tetrahedron Letters 49 (2008) 6631–6634
Shaw, D. M.; Ley, S. V. Synlett 2004, 558; (k) Cobb, A. J. A.; Shaw, D. M.;
(100 MHz, CDCl3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6,
28.5, 25.8, ꢀ5.1, ꢀ5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4SiNa) requires
m/z 402.2071, found 402.2074. The enantiomeric excess was determined by
HPLC with an AD column n-hexane/i-PrOH = 98:2, k = 220 nm), 0.5 mL/min;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84; (l)
Ibrahem, I.; Córdova, A. Chem. Commun. 2006, 1760; (m) Ibrahem, I.; Casas, J.;
Córdova, A. Angew. Chem., Int. Ed. 2004, 43, 6528; (n) Ibrahem, I.; Zou, W.;
Casas, J.; Sundén, H.; Córdova, A. Tetrahedron 2006, 62, 357; (q) Rodriguez, B.;
Bolm, C. J. Org. Chem. 2006, 71, 2888; (r) Ibrahem, I.; Zou, W.; Engqvist, M.; Xu,
Y. Chem. Eur. J. 2005, 11, 7024; (s) Córdova, A. Synlett 2003, 1651; (t) Córdova, A.
Chem. Eur. J. 2004, 10, 1987; (u) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima,
T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677; (v) Hayashi, Y.;
Urushima, T.; Shoji, M.; Uchimary, T.; Shiina, I. Adv. Synth. Catal. 2005, 347,
1595.
major enantiomer tR = 16.6 min, minor enantiomer = 24.1 min; ½a D25
ꢀ10.5 (c
ꢁ
1.0, CHCl3).
14. Typical experimental procedure: To a stirred solution of imine 1a (1.0 equiv,
0.25 mmol) and aldehyde 2b (1.1 equiv, 0.27 mmol) in CH3CN (1.0 mL) at room
temperature was added (R)-proline (20 mol %). The reaction mixture was
stirred vigorously for the reported time. Next, the reaction mixture was
directly loaded on
a silica-gel column, and immediate chromatography
7. For the use of organic catalysts see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566; (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356; (c) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. J. Am.
Chem. Soc. 2005, 127, 11256; (d) Wenzel, E. N.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 12964.
8. (a) Ibrahem, I.; Córdova, A. Tetrahedron Lett. 2005, 46, 2839; (b) Liao, W.-W.;
Ibrahem, I.; Córdova, A. Chem. Commun. 2006, 674.
9. (a) Enders, D.; Grondal, C.; Vrettou, M. Synthesis 2006, 2155.
10. (a) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46, 609; (b) Yang,
J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453.
11. Vesely, J.; Rios, R.; Ibrahem, R.; Córdova, A. Tetrahedron Lett. 2007, 48, 421.
12. Vesely, J.; Dziedzic, P.; Córdova, A. Tetrahedron Lett. 2007, 48, 6900.
13. Typical experimental procedure: To a stirred solution of imine 1a (1.0 equiv,
0.25 mmol) and aldehyde 2a (1.1 equiv, 0.27 mmol) in solvent (1.0 mL) at 4 °C
was added (S)-proline (20 mol %), and the resulting reaction mixture was
stirred vigorously for the reported time. Next, the reaction mixture was
(pentane/EtOAc-mixtures or toluene/EtOAc-mixtures) furnished the
corresponding aldehyde. ent-3b: colorless oil. 1H NMR (400 MHz): d 9.73–
9.72 (m, 1H), 7.37–7.23 (m, 8H), 7.10–7.06 (m, 2H), 5.52 (br s, 1H), 5.24 (br s,
1H), 4.60 (d, J = 11.6 Hz, 1H), 4.39 (d, J = 11.6 Hz, 1H), 4.04 (br s, 1H), 1.40 (s,
9H); 13C NMR (100 MHz): 201.2, 155.2, 139.4, 136.7, 128.8, 128.7, 128.4, 128.3,
127.9, 126.8, 86.0, 80.3, 73.6, 54.3, 28.5; HRMS (ESI): calcd for [M+Na]
(C21H25NO4Na) requires m/z 378.1676, found 378.1671. The enantiomeric
excess was determined by HPLC with an AD column (n-hexane/i-PrOH =
90:10, k = 220 nm), 0.5 mL/min; major enantiomer tR = 15.9 min, minor
enantiomer = 28.2 min; ½a D25
ꢁ
+29.0 (c 1.0, CHCl3).
15. Preparation of acid 4b: To a solution of ent-3b (0.1 mmol) in chloroform (1 mL),
isobutene (0.1 mL), tert-butanol (0.4 mL), H2O (0.2 mL), KH2PO4 (54.4 mg,
4.0 mmol), and NaClO2 (36 mg, 4.0 mmol) were added sequentially at room
temperature. After 16 h, the crude product was purified by column
chromatography (pentane/EtOAc-mixtures) to afford 32 mg (85%) of the
desired acid 4b; colorless oil. 1H NMR (400 MHz, CDCl3): d 7.37–7.19 (m,
8H), 7.04–7.00 (m, 2H), 5.80 (d, J = 8 Hz, 1H), 5.30 (d, J = 8.8 Hz, 1H), 4.70 (d,
J = 10 Hz, 1H), 4.32 (d, J = 10 Hz, 1H), 4.20 (br s, 1H), 1.42 (s, 9H); 13C NMR
(100 MHz, CDCl3): 173.4, 155.9, 139.5, 136.6, 128.8, 128.6, 128.2, 128.0, 127.8,
126.9, 80.6, 80.1, 73.2, 56.0, 28.5; HRMS (ESI): calcd for [M+Na] (C21H25NO5Na)
directly loaded onto
a silica-gel column and immediate chromatography
(pentane/EtOAc-mixtures or toluene/EtOAc-mixtures) furnished the
corresponding aldehyde 3a: colorless oil. 1H NMR (400 MHz, CDCl3): d 9.70
(br s, 1H), 7.36–7.24 (m, 5H), 5.43 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 8.0 Hz, 1H),
4.22 (br s, 1H), 1.41 (s, 9H), 0.78 (s, 9H), ꢀ0.14 (s, 3H), ꢀ0.34 (s, 3H); 13C NMR
requires m/z 394.1625, found 394.1635. ½a D25
ꢁ
+19.0 (c 1.0, CHCl3).