Diastereoselective Titanium Enolate Aldol Reaction for the Total Synthesis of Epothilones

Article abstract of DOI:10.1021/ol026480b

(Matrix Presented) The development of a highly diastereoselective addition of the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient entry to the total synthesis of the epothilone family. The new aldol process is robust and tolerates

Full text of DOI:10.1021/ol026480b

ORGANIC
LETTERS
2
002
Vol. 4, No. 22
811-3814
Diastereoselective Titanium Enolate
Aldol Reaction for the Total Synthesis
of Epothilones
3
Guido Koch,* Olivier Loiseleur,* Daniel Fuentes, Andrea Jantsch, and
Karl-Heinz Altmann
NoVartis Pharma AG, Process R&D and BU Oncology,
Postfach CH-4002 Basel, Switzerland
guido.koch@pharma.noVartis.com
Received July 9, 2002
ABSTRACT
The development of a highly diastereoselective addition of the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient entry
to the total synthesis of the epothilone family. The new aldol process is robust and tolerates a wide range of functional groups.
The aldol approach for the total synthesis of epothilones has
been first reported by the groups of Mulzer and Nicolaou.
addition product are obtained. A significantly higher selectiv-
ity was obtained by Schinzer when using an acetonide
protected enolate (10:1). However, the cost to be paid for
the favorable selectivity is additional functional group
manipulations.
Our interest for the development of a highly convergent
large-scale synthesis of epothilone B prompted us to
reinvestigate the aldol approach. The basic concept of our
retrosynthetic analysis (Scheme 1) was the addition of the
sultam-derived fragment 1 to the aldehyde 2. Such a strategy
would allow us to make use of the chiral sultam auxiliary
as a carboxylate protecting group and therefore avoid
additional reduction and oxidation steps.
1
2
b,c
The disconnection of the C
6
-C
7
bond results in a significant
reduction of complexity. Many other groups closely studied
this key transformation in order to develop a highly
2
convergent synthesis of the epothilones. There are the
following most important lessons to be taken from these
extensive investigations: The most convergent route, the
aldol reaction of the free carboxylate ion enolate, is
2a
completely unselective. With protected analogues, stereo-
selectivities in the range of 3-5:1 in favor of the desired
(
1) (a) Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179.
b) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang. Z. Angew.
Chem., Int. Ed. Engl. 1997, 36, 166.
2) (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.,
(
Both building blocks were prepared according to literature
(
3
procedures.
Int. Ed. 1998, 37, 2014. (b) Schinzer, D.; Bauer, A.; B o¨ hm, O. M.; Limberg,
A.; Cordes, M. Chem.sEur. J. 1999, 5, 2483. (c) Schinzer, D.; Bauer, A.;
Schieber, J. Chem.sEur. J. 1999, 5, 2492. (d) Balog, A.; Harris, C.; Savin,
K.; Zhang, X. G.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int. Ed.
(3) (a) Preparation of the aldehyde 2: Nicolaou, K. C.; Ninkovic, S.;
Sarabia. F.; Vourloumis, D.; He. Y.; Vallberg, M. R.; Finlay, M. R. V.;
Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974. (b) Preparation of the
ketone 1: Altmann, K.-H.; Bold, G.; Caravatti, G.; Denni, D.; Fl o¨ rsheimer,
A.; Schmidt, A.; Rhis, G.; Wartmann, M. HelV. Chim. Acta 2002, 85,
in press.
1
998, 37, 2675. (e) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz,
P. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050. (f) Wu, Z.;
Zhang, F.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 4505. (g)
Mulzer, J.; Mantoulidis, A.; O¨ hler, E. J. Org. Chem. 2000, 65, 7456.
1
0.1021/ol026480b CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

6 7
Scheme 1. Key C -C Aldol in the Retrosynthetic Analysis for Epothilone B
In a first step, the ketone 1 was subjected to a variety of
enolization conditions (Table 1). The resulting enolates were
trapped with benzaldehyde in a model reaction.4
Table 1. Enolization Experiments with the Ketone 1
Figure 1. Formation of the silyl enol ethers 9a-c and X-ray
structure of the TMS-silyl enol ether 9a.
Treatment of 1 with silyl triflates in the presence of
triethylamine resulted in the selective formation of the
extraordinarily stable silyl enol ethers 9a-c (Figure 1) The
crystal structure of the TMS derivative 9a is shown.
a
THF; -78 to 0 °C. b CH2Cl2; -78 to 0 °C.
Scheme 2. Mukaiyama Aldol Reactions with Benzaldehyde
LDA favors deprotonation at the R position to the amide
entry 1), whereas the titanium enolate was selectively
(
formed at the ketone, most likely due to the higher acidity
of the proton R to the ketone (entry 2). With TiCl /Bu N,
the desired benzaldehyde addition product was formed in
6% yield with a diastereoselectivity of 3:1. Alternative
conditions examined including TiCl(OiPr) , TiCl (OiPr) , and
TiCl (OiPr)/i-Pr NEt did not result in the formation of
enolate. By treatment with TiCl(OiPr) /LDA (entry 3), the
4
3
8
3
2
2
3
2
3
cyclized product 7 was isolated along with cleaved sultam
auxiliary 8. The tin and the boron enolates of 1 could not be
obtained under standard conditions (Bu
cHex) BCl/Et N, and SnOTf /Et N).
2 2
BOTf/iPr NEt,
(
2
3
2
3
3812
Org. Lett., Vol. 4, No. 22, 2002

Having analytically pure silyl enol ethers in hand we tested
several Lewis acids (BF ‚OEt , MgBr , ZnCl , TiCl
TiCl (OiPr), TiCl (OiPr) , Ti(OiPr) , SnCl , EtAlCl , ScOTf
TMSOTf) for the Mukaiyama aldol reaction with benzalde-
hyde. The best results were obtained with BF ‚OEt and
TiCl (OiPr) (Scheme 2).
3
2
2
2
4
,
3
2
2
4
4
2
3
,
3
2
3
Compared to the titanium enolate of 1 (Table 1, entry 2)
lower diastereoselectivities and low yields were observed
when using the silyl enol ether 9a. We therefore decided to
focus on the titanium enolate addition. The model reaction
was carried out with ent-1 (Figure 2). Under optimized
conditions, the addition product ent-6 was obtained in 91%
yield and 3:1 diastereoselectivity. A following crystallization
afforded ent-6 with >95% diastereomeric purity. From the
X-ray data shown in Figure 2 and NMR analysis we
concluded that the major diastereoisomer formed has the
desired syn configuration.
Figure 3. ReactIR analysis of the lithium and titanium enolate
formation from ent-1 and addition to benzaldehyde.
Having defined optimized conditions for the direct utiliza-
tion of the sultam derived fragment 1 in a selective aldol
addition to benzaldehyde we then applied the reaction
conditions to a-branched aliphatic aldehydes. Whereas a
diastereoselectivity of 3:2 was observed when an R-config-
ured aldehyde (12) was utilized, excellent diastereoselec-
tivities of >20:1 were observed for the matched case (14a,b).
Figure 2. Ti-aldol with benzaldehyde and X-ray structure of the
aldol product ent-6.
Two model reactions carried out with ent-1 were moni-
tored by ReactIR (Figure 3). Treatment with LDA at -78
5
The results are summarized in Table 2.
°
1
C resulted in the generation of a lithium enolate band at
619 cm . The same band was generated in the deproton-
Finally, the titanium enolate aldol reaction between 1 and
the aldehyde 2 delivered in high yield and with excellent
diastereoselectivity the product 3 which is an intermediate
-
1
ation of the N-acetyl sultam 10. Addition of TiCl
4
to ent-1
at -78 °C shifted the amide and ketone carbonyl frequency
in the synthesis of epothilone B (Scheme 3). Compound 3
from 1694 cm-1 to lower wavenumbers at 1553 cm for
-1
2g,3a
was converted to the known carboxylic acid 17
steps (TBDMSOTf, 2,6-lutidine; LiO
in two
-
1
the amide-carbonyl and 1652 cm for the ketone-carbonyl
due to complexation with TiCl . After addition of base
triethylamine or tri-n-butylamine), only the complex-band
2
2
H, THF/H O 4:1).
4
Comparison of the analytical data of our sample of 17 with
the corresponding data reported in the literature showed that
the aldol product 3 with the desired stereochemistry had been
(
-
1
with the ketone-carbonyl (1652 cm ) disappeared whereas
-
1
the one with the amide-carbonyl (1553 cm ) remained,
indicating that the titanium enolate at the ketone group was
selectively formed under these conditions. After addition of
the electrophile (benzadehyde), the bands of the aldol product
ent-6 complexed with titanium chloride appeared.
6
obtained.
(5) Treatment of 2 with TiCl4 followed by trimethyl silyl enol ether 9a
at 0 °C resulted in the decomposition of the aldehyde with no formation of
aldol product.
(6) The sample 17 derived from the aldol product 3 was identical with
the corresponding compound described in the literature (refs 2g and 3a)
with respect to all reported properties.
(4) For the elucidation of the configuration of 6, vide infra.
Org. Lett., Vol. 4, No. 22, 2002
3813

Table 2. Diastereoselective Aldol Reaction with Chiral
Aliphatic Aldehydes
Scheme 3. Titanium Enolate Aldol Reaction with Aldehyde 2
and Conversion of 3 to Known 16
a
1
.1 equiv of TiCl4, 1.1 equiv of iPrNEt2, 1.1 equiv of aldehyde, CH2Cl2,
b
-
78 to 0 °C. 2.2 equiv of TiCl4, 2.5 equiv of iPrNEt2, 2.0 equiv of
aldehyde, CH2Cl2; -78 to 0 °C.
In conclusion, we have reported a highly diastereoselective
key aldol coupling for an efficient synthesis of epothilones.
This process is suitable for large quantity production of
intermediates and results in a significant shortcut for the total
synthesis of epothilones. In ongoing studies the methodology
will be applied to the synthesis of interesting epothilone
derivatives.
Rihs for the X-rays of ent-6 and 9a and Lukas Oberer and
Monique Ponelle for NMR analyses. We thank Novartis
Pharma AG for support.
Supporting Information Available: Complete experi-
mental procedures, spectral data, and structure correlation
for all relevant compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to Alfred Schmidt for
the preparation of substantial amounts of 1 and ent-1 and
Walter Prikoszovich for the ReactIR studies. We thank Grety
OL026480B
3814
Org. Lett., Vol. 4, No. 22, 2002