Practical syntheses of the C12-C21 epothilone subunit via catalytic asymmetric reductions: Itsuno-Corey oxazaborolidine reduction and asymmetric Noyori hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2004.06.009

Two practical catalytic asymmetric reductions to introduce the epothilone C15 stereocenter are described (Itsuno-Corey reduction and Noyori hydrogenation).

Full text of DOI:10.1016/j.tetlet.2004.06.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5845–5847
Practical syntheses of the C12–C21 epothilone subunit via
catalytic asymmetric reductions: Itsuno–Corey oxazaborolidine
reduction and asymmetric Noyori hydrogenation
Emily A. Reiff, Sajiv K. Nair, B. S. Narayan Reddy, Jun Inagaki,
John T. Henri, Jack F. Greiner and Gunda I. Georg*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, University of Kansas, Lawrence, KS 66045-7582, USA
Received 11 April 2004; revised 31 May 2004; accepted 2 June 2004
Abstract—Two practical catalytic asymmetric reductions to introduce the epothilone C15 stereocenter are described (Itsuno–Corey
reduction and Noyori hydrogenation).
Ó 2004 Elsevier Ltd. All rights reserved.
The epothilones (1, Fig. 1) have proven to be the most
promising group of antimitotic agents among the new
classes of compounds that have activity similar to that
we targeted the total synthesis of these molecules and
analogues that could be used as biochemical tools.
1;2
of paclitaxel, that is microtubule stabilization. Their
interesting biological properties, especially their effec-
Herein we report two unique stereoselective syntheses of
key intermediates 2 and 3 that are important building
2–4
5–10
tiveness against multi-drug resistant cancer cell lines,
have inspired numerous synthetic and semisynthetic
blocks for the total syntheses of the epothilones.
The
stereochemistry at C15 of 2 was set by two different
asymmetric reductions utilizing ketones 4 and 5. Both
approaches rely on well precedented chemistry, known
to be amenable for large-scale enantioselective reduc-
4–9
efforts. The chemotherapeutic potential held by the
epothilones has sustained a continued interest in
the development of novel and practical synthetic routes
toward these promising antitumor macrolides.
11
tions. The Itsuno–Corey reduction utilizes oxazaboro-
lidines as chiral catalysts and Noyori asymmetric
hydrogenations are carried out in the presence of Bi-
As part of a program initiated to study the binding site
of the epothilones through affinity labeling on tubulin,
12
napRu-catalysts.
R1
O
OTBS
S
N
path A
S
1
5
S
Itsuno-
Corey
21
11
R3
1
5
OH
N
15
4
5
O
7
N
O
3
S
N
CO2Et
6
R2O
path B
Noyori
1
5
O
OH
O
epothilone A (1a): R1 = H
epothilone B (1b): R1 = Me
2 R2 = TBS, R3 = CHO
3 R2 = H, R3 = CH2OH
O
Figure 1. Structures of epothilones A and B and retrosynthetic analysis.
Keywords: Epothilones; Antitumor agents; Asymmetric catalysis; Itsuno–Corey reduction; Noyori reduction.
*
Corresponding author. Tel.: +1-7858644498; fax: +1-7858645836; e-mail: georg@ku.edu
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.009

5846
E. A. Reiff et al. / Tetrahedron Letters 45 (2004) 5845–5847
The asymmetric synthesis of aldehyde 2 from enone 4
via the Itsuno–Corey method is outlined in Scheme 1.
With a goal to create a useful handle to modify the
aryl region, we utilized a strategically functionalized b-
S
N
S
N
CO2Et
a
7
6%
CHO
9
(
+)-10
OH
13
–
keto-phosphonate 7 in a modified Horner–Wads-
14
S
worth–Emmons reaction with commercially available
aldehyde 6 to access enone 4 exclusively in 75% yield
CO Et
2
c
b
5
0%
9
1%
N
(Scheme 1). The C15 asymmetric center was then
introduced by the reduction of this enone using (R)-B-
8
3% ee
5
O
1
1
Me-CBS-oxazaborolidine,
which provided allylic
alcohol 8 in 98% yield and 95% ee (as determined by
S
N
CO2Et
d
15
chiral HPLC). Protection of 8 using TBSOTf provided
the corresponding bis-silyl ether in 94% yield. Selective
deprotection of the primary TBS ether functionality,
followed by Dess–Martin oxidation of the correspond-
3
7
0%
16;17
(-)-10
OH
18
Scheme 2. Reagents and conditions: (a) LDA, THF, )78 °C, EtOAc,
0 min; (b) MnO , CHCl )(S)-BINAP, H
, 0 °C, 2 h; (c) RuBr
MeOH, 50 psi, rt, 2 h; (d) DIBAL-H, CH Cl
, )78 °C, 1 h, then rt, 2 h.
ing alcohol, furnished aldehyde 2.
1
2
3
2
2
,
2
2
The optimized conditions for the Itsuno–Corey reduc-
tion involved removing toluene from the commercially
available catalyst and the addition of CH
2 2
Cl and
yielded over-reduced product that was difficult to sepa-
rate from the desired reaction product. The optimized
conditions yielded a 1:1 mixture of the starting material
and the product with only a trace of over-reduced
compound (reduction of the ketone and the double
bond). The product was easily separated from the
starting material by column chromatography. The
enantiomeric excess of ())-10 was 83% ee, as determined
BH ÆMe S at 0 °C. The optimum amount of catalyst was
3
2
found to be 50 mol %. The enone 4 was added to the
reaction mixture using a syringe pump. When the reac-
tion was scaled up to 33 mmol, the enone addition took
1
5 h. At that scale, the enantiomeric excess was 92%.
The second route toward the synthesis of building block
3 is shown in Scheme 2. Reaction of aldehyde 9 with
the lithium enolate of ethyl acetate furnished alcohol
19
15
by chiral HPLC. Reduction of the methyl ester of 5 to
the methyl ester of ())-10 under similar conditions gave
an ee of 80%. Conversion to the known diol 3 was
(
(
5
±)-10 in 76% yield. Oxidation with activated MnO
10 wt %) provided a 91% yield of the desired b-ketoester
, which was subjected to Noyori reduction.
2
10
accomplished with DIBAL-H in 70% yield.
We also investigated the Noyori reduction with epothi-
lone building blocks 11 in which the thiazole moiety was
replaced by a phenyl ring (Scheme 3). It is of interest to
note that the chemical yields (86–89%) and the enan-
tiomeric excesses (89–94%) of these reactions were sig-
nificantly improved compared to the reduction of 5.
We were able to increase the reaction times without
observing much of the double bond reduced products
The Noyori reduction needed to be optimized for reac-
tion time, temperature, pressure, and catalyst loading.
The best results were obtained at room temperature with
15 mol % catalyst, and a pressure range of 50.5–48.5 psi
for 2 h. Longer reaction times and higher temperatures
15
S
N
OTBS
(<5%). The results indicate that the presence of the
+
thiazole moiety is promoting the reduction of the enone
double bond and is also responsible for lowering the
enantiomeric excess of this reaction. This could be due
to the ability of the heteroatoms in the thiazole moiety
a
75%
CHO
(OEt)2(O)P
6
7
O
9
20
OTBS
to coordinate with the catalyst, promoting side reac-
tions.
S
b
8%
N
95% ee
4
8
O
R
CO2Me
a
OTBS
S
c
2
15
76%
three steps
N
O
1
1
OH
R
CO2Me
Scheme 1. Reagents and conditions: (a) Ba(OH)
vated), THF, 45 min, rt, then 6 in THF–H
O (40:1), 0 °C, 1 h, then rt,
5 min; (b) (R)-2-Me-CBS-oxazaborolidine (0.5 equiv), BH ÆMe
1.5 equiv), CH Cl
, 0 °C, then 4, 0 °C, 2 h, then ethanolamine, rt, 16 h;
c) i. TBSOTf, 2,6-lutidine, CH Cl
, )78 °C, 15 min, 94%, ii. HF (48%
O (1:1), 0 °C, 2 h, 82%, iii. Dess–Martin
Cl , rt, 1 h, 98%.
2
Æ8H
2
O (freshly acti-
12a R= H, 89%, 89% ee
2b R = F, 86%, 94% ee
2
1
4
3
2
S
(
(
2
2
OH
1
2
2
2
aq), glass splinters, MeCN–Et
periodinane (1.3 equiv), CH
2
Scheme 3. Reagents and conditions: (a) RuBr
MeOH, 50 psi, rt, R ¼ Ph, 5 h, R ¼ 4-FC , 3 h.
2
2
)(S)-BINAP, H ,
2
2
6 4
H

E. A. Reiff et al. / Tetrahedron Letters 45 (2004) 5845–5847
5847
Asymmetric ruthenium catalyzed reductions of b-keto-
esters, that also contain di- and tri-substituted double
7. Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su,
D.-S.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1996, 35, 2801–2803.
21;22
bonds in the molecule, have been described before.
The reductions were selective for the ketone moiety and
provided the alcohols in excellent yields and enantio-
8
. Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Yang, Z. Angew. Chem., Int. Ed. 1996, 35, 2399–2401.
. Schinzer, D.; Limberg, A.; Bauer, A.; B o€ hm, O. M.;
Cordes, M. Angew. Chem., Int. Ed. 1997, 36, 523–524.
9
21;22
meric excesses.
The Noyori reduction of c,d-unsat-
urated b-ketoesters such as 10–12 has apparently not
1
0. Niggemann, J.; Michaelis, K.; Frank, R.; Zander, N.;
H o€ fle, G. J. Chem. Soc., Perkin Trans. 1 2002, 2490–2503.
23
been investigated before. Our results suggest that
selective reduction of the ketone can be achieved in the
presence of a tri-substituted enone double bond unless
functional groups are present in the molecule, such as
the thiazole moiety, that promote side reactions.
11. Itsuno, S.; Ito, K. J. Org. Chem. 1984, 49, 555–557; For
review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed.
1998, 37, 1986–2012, and references cited therein; For an
example of the asymmetric reduction of an enone see:
Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am.
Chem. Soc. 1997, 119, 11769–11776.
2. Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.;
Sayo, N.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem.
Soc. 1987, 109, 5856–5858.
In summary, we have developed two asymmetric syn-
theses for the C12–C21 epothilone building block fea-
turing two highly versatile and enantioselective catalytic
asymmetric reductions, the Itsuno–Corey oxazaboroli-
dine-mediated reduction and the Noyori hydrogenation
1
1
3. Phosphonate 7 was synthesized in three steps from
commercially available b-propiolactone: (a) NaOH (cat.),
MeOH, 77%; (b) TBSCl, imidazole, CH Cl , 92%; (c)
24
to introduce the C15 epothilone stereocenter. The
strategies developed in this synthesis are currently being
applied toward the construction of analogues that
would assist in mapping the binding site of the epo-
thilones on tubulin protein.
2
2
EtP(O)(OEt) , n-BuLi, THF, 74%.
2
14. Paterson, I.; Yeung, K.-P.; Smaill, J. B. Synlett 1993, 774–
76.
7
1
5. HPLC data for 8 and 10 were obtained on a Chiracel OD-
H column using 90:10 hexanes/isopropanol with a flow
rate of 1 mL/min at 254 nm. The retention times for 8
were: minor: 7.5 min and major: 5.5 min and were com-
pared to the racemic alcohol for verification. The retention
times for 10 were: minor: 9.2 min and major: 12.0 min and
were compared to the racemic alcohol for verification. The
retention times for 12a were: minor: 11 min and major:
Acknowledgements
We gratefully acknowledge financial support from the
National Institutes of Health’s National Cancer Insti-
tute (NCI CA79641) and the General Research Fund at
the University of Kansas. E.A.R. acknowledges the
NIH training grant (NIH-GM-07775), and the Ame-
rican Foundation for Pharmaceutical Education for
fellowships. E.A.R. and J.I. acknowledge the Depart-
ment of Defense (DAMD 17-00-1-0303) for fellowship
support.
9.5 min and were compared to the racemic alcohol for
verification. The enantiomeric excess of 12b was deter-
mined by NMR after preparing the (S)-Mosher ester
derivative.
1
6. Pilcher, A. S.; Deshong, P. J. Org. Chem. 1993, 58, 5130–
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€
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