Synthesis of the C7-C17 segment of epothilones by a 10-membered ring closing metathesis reaction

Article abstract of DOI:10.1055/s-1998-1870

The synthesis of the C7-C17 segment of epothilones employing a ring closing metathesis is described. Our approach utilizes the stereoselective methylation of the 10-membered lactone, generated by ring closing metathesis, for introducing the methyl group at C8 and provides an efficient access to strained epothilone derivatives, as well as to the C7-C17 segment of epothilones.

Full text of DOI:10.1055/s-1998-1870

1108
LETTERS
SYNLETT
Synthesis of the C7–C17 Segment of Epothilones by a 10-membered Ring Closing Metathesis
Reaction
Kai Gerlach, Monika Quitschalle and Markus Kalesse*
Institut für Organische Chemie, Universität Hannover, Schneiderberg 1b, 30167 Hannover (Germany)
FAX: +49-(0)511 762 4643; E-mail: Kalesse@mbox.oci.uni-hannover.de
Received 22 July 1998
Abstract: The synthesis of the C7-C17 segment of epothilones
employing a ring closing metathesis is described. Our approach utilizes
the stereoselective methylation of the 10-membered lactone, generated
by ring closing metathesis, for introducing the methyl group at C8 and
provides an efficient access to strained epothilone derivatives, as well as
to the C7-C17 segment of epothilones.
stereoselectivity and the hydroxyl group of (S)-ethyl lactate could later
be oxidized and used in the Wittig reaction for introducing the thiazole
moiety.
1
The fascinating biological activities of the epothilones, isolated and
2
characterized by Höfle, Reichenbach et al. at the GBF, have initiated a
variety of different projects throughout the scientific community
3
yielding in the total synthesis of epothilones and epothilone derivatives
4
as well as various partial solutions. Our strategy in the total synthesis of
epothilones employs the aldol reaction between C6 and C7 and a
macrolactonization for the ring closure (Scheme 1). With a practical
4b
synthesis for the ethyl ketone fragment 3 in our hands, we evaluated
different strategies in order to establish a short and efficient route to the
northern (C7-C17) segment, suitable for the aldol reaction.
Scheme 2
Here we report the synthesis of the C7-C17 segment of epothilone A,
starting from (S)-ethyl lactate (7) and employing the ring closing
metathesis reaction as the key step to generate the Z double bond of
epothilone in a rare 10-membered ring closing reaction. Subsequent
methylation establishes the desired carbon skeleton of the northern
hemisphere of epothilones (Scheme 3). (S)-Ethyl lactate (7) was
protected with PMB-trichloroacetimidate followed by reduction and
subsequent Swern oxidation generated aldehyde 8, which was
transformed into the secondary alcohol 9 by stereoselective addition (de
6
= 91%) of allyltrimethylsilane with SnCl as Lewis acid. Esterification
4
with 6-heptenoic acid under standard conditions provided diene 10
which was subjected to a ring closing metathesis reaction (RCM) using
7
Grubbs’ ruthenium-based catalyst (11). The choice of the solvent and
the reaction temperature had significant influence on the stereochemical
8
outcome of the metathesis reaction. High dilution technique in
refluxing CH Cl gave the best Z/E ratio (12:1), whereas reaction in
2
2
toluene only gave a 1:1 mixture of both stereoisomers.
In order to introduce the methyl group at C8 stereoselectively we
followed two strategies. The more straightforward approach was to
establish the methyl group right from the beginning by asymmetric
Scheme 1
We envisioned that the ring closure of compound 10 to generate the 10-
membered lactone 6 as the key step will provide an efficient access to
the C7-C17 segment of epothilones as well as to strained epothilone
derivatives (Scheme 2). The synthesis of this strained 10-membered
lactone could be a solution to the lack of stereocontrol observed in the
ring closing metathesis reaction utilized in the synthesis of the
epothilone backbone by other groups. Even though it was not obvious
whether such a ring closure metathesis reaction would be successful
since only three examples of a 10-membered ring closing metathesis
reaction had been published at that time, the results of Fürstner et al. on
synthesizing a 10-membered lactone by a ring closing metathesis
methylation of the 6-heptenoic acid according to Evans´ protocol
9
(Scheme 4). Cleavage of the chiral auxiliary with LiAlH followed by
4
oxidation with PDC provided 2-(S)-methyl-6-heptenoic acid (15) which
was esterified with alcohol 9 and subsequently subjected to a ring
closing metathesis reaction yielding lactone 5.
The second route made use of the conformation of the 10-membered
10
ring which was methylated stereoselectively without the need of any
additional chiral auxiliary as shown in Scheme 3. Both strategies were
employed in the synthesis of 5 and compound 5 derived from 2-methyl-
6-heptenoic acid (15) was used to assign the stereochemistry of the
methylation of 6. The alkylation of compound 6 gave only one
stereoisomer and both products gave identical NMR signals and the
5
indicated that this route can lead to the desired product. In order to
synthesize the desired precursor 10 we chose (S)-ethyl lactate (7)as the
starting material from the chiral pool. Addition of allyltrimethylsilane
should generate the desired stereochemistry at C15 in good
same optical rotation, indicating that the alkylation of 6 with NaHMDS
11
and CH I generated the desired compound.
3

October 1998
SYNLETT
1109
References and Notes
1.
Bollag, D.M.; McQueney, P.A.; Zhu, J.; Hensens, O.; Koupal, L.;
Liesch, J.; Goetz, M.E.; Lazarides, C.; Woods, M. Cancer Res.
1995, 55, 2325-2333.
2.
a) Höfle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. DE-4138042,
1993 [Chem. Abstr. 1993, 120, 52841]; b) Gerth, K.; Bedorf, N.;
Höfle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560-
563; c) Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.;
Gerth, K.; Reichenbach, H. Angew. Chem. 1996, 108, 1671-1673,
Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569; d) Schinzer, D.
Eur. Chem. Cron. 1996, 1, 7-10; e) Kalesse, M. Eur. Chem. Cron.
1997, 2, 7-11; f) Wessjohann, L. Angew. Chem. 1997, 109, 739-
742, Angew. Chem. Int. Ed. Engl. 1997, 36, 739-742.
3.
a) Balog, A.; Meng, D.; Kamencka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E.J.; Danishefsky, S.J. Angew. Chem. 1996, 108, 2976-
2978; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801.2803; b)
Nicolaou, K.C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z.
Angew. Chem. 1997, 109, 170-172; Angew. Chem. Int. Ed. Engl.
1997, 36, 166-168; c) Schinzer, D.; Limberg, A.; Bauer, A.;
Böhm, O.; Cordes, M. Angew. Chem. 1997, 109, 543-544; Angew.
Chem. Int. Ed. Engl. 1997, 36, 523-524; d) Nicolaou, K.C.;
Sarabia, F.; Nincovic, S.; Yang, Z. Angew. Chem. 1997, 109, 539-
540; Angew. Chem. Int. Ed. Engl. 1997, 36, 525-527; e) Su, D.-S.;
Meng; D.; Bertinanto, P.; Balog, A.; Sorensen, E.J.; Danishefsky,
S.J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horowitz, S.B. Angew.
Chem. 1997, 109, 775-777; Angew. Chem. Int. Ed. Engl. 1997, 36,
775-777; f) Nicolaou, K.C.; Winssinger, N.; Pastor, J.; Ninkovic,
S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.;
Giannakatou, P.; Hamel, E. Nature 1997, 387, 268-272.
4.
a) Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179-
9182; b) Claus, E.; Pahl, A.; Jones, P.G.; Meyer, H.H.; Kalesse,
M.; Tetrahedron Lett. 1997, 38, 1359-1362; c) Gabriel, T.;
Wessjohann, L.; Tetrahedron Lett. 1997, 38, 1363-1366; d) Taylor,
R.E.; Haley, J.D. Tetrahedron Lett. 1997, 38, 2061-2064; e) De
Brabander, J.; Rosset, S.; Bernardinelli, G. Synlett 1997, 824-826;
f) Chakraborty, T.K.; Dutta, S.; Tetrahedron Lett. 1998, 39, 101-
104; g) Bijoy, P.; Avery, M.A. Tetrahedron Lett. 1998, 39, 209-
212; h) Liu, Z.-Y.; Yu, C.-Z.; Yang, J.-D. Synlett 1997, 1383-1384;
i) Liu, Z.-Y.; Yu, C.-Z.; Wang, R.-F.; Li, G. Tetrahedron Lett.
1998, 39, 5261-5264.
5.
For ring closing metathesis reactions yielding 10-membered rings
see: a) Fürstner, A.; Müller, T. Synlett 1997, 1010-1012; b) Chang,
S.; Grubbs, R.H. Tetrahedron Lett. 1997, 38, 4757-4760; c) Oishi,
T.; Nagumo, Y.; Hirama, M. Chem. Commun. 1998, 1041-1042.
6.
7.
8.
Heathcock, C.H.; Kiyooka, S.-i.; Blumenkopf, T.A. J. Org. Chem.
1989, 49, 4214-4222.
Nguyen, S.T.; Grubbs, R.H.; Ziller, J.W. J. Am. Chem. Soc. 1993,
115, 9858-9859.
Experimental procedure for the ring closing metathesis reaction.
To a refluxing solution of RuCl (PCy ) CHC H (95 mg, 0.115
2
3 2
6 5
mmol, 20 mol%) in CH Cl (160 mL) is added a solution of diene
2
2
10 (200 mg, 0.577 mmol) in CH Cl (20 mL) over a period of 1 h.
2
2
After refluxing for 3 h the mixture is concentrated in vacuo. The
crude product is purified by column chromatography (pentane/
EtOAc 60:1) to provide the desired compound as a colourless oil
(99 mg, 0.312 mmol, 54%).
This strategy allows access to the northern fragment of epothilones
without the necessity of employing chiral auxiliaries for the introduction
of the C8-methyl group. Taking into account that the metathesis reaction
provides a rapid access to the C7-C17 segment of epothilones with the
Z-double bond in a very good Z/E ratio and no chiral auxiliary is
necessary for establishing the desired stereochemistry at C8, we now
have a convenient strategy for generating the northern hemisphere and
the carbon framework of strained epothilones.
Spectroscopic data for compound 6: IR (CHCl ): 2932, 2860,
3
-1
1
1720, 1612, 1512, 1444, 1248, 1172, 1032, 824 cm ; H-NMR
(400 MHz, CDCl ): δ (ppm) = 7.22-7.28, 2H, PMB), 6.84-6.89
3
(m, 2H, PMB), 5.38-5.50 (m, 2H, H-7, H-8), 4.90 (dd, J=10.67,
6.03 Hz, 1H, H-10), 4.57 (d, J=11.67 Hz, 1H, CH -p-MeOC H ),
2
6 4

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LETTERS
SYNLETT
4.47 (d, J=11.67 Hz, 1H, CH -p-MeOC H ), 3.65 (quin., J=6.35
temp. Extraction with MTB ether, drying over MgSO ,
2
6
4
4
Hz, 1H, H-11), 3.80 (s, 3H, MeO), 2.07-2.46 (m, 6H), 1.86-2.00
(m, 1H), 1.58-1.78 (m, 3H), 1.22 (d, J=6.4 Hz, 3H, H-12); C-
evaporation and column chromatography on silica gel (PE/EtOAc
13
80:1) provides 5 as a colourless oil (67 mg, 0.201 mmol, 82%).
20
NMR (100 MHz, DEPT, CDCl ): δ (ppm) = 174.44 (C, C-2),
[a]
= -11.3° (c=1, CHCl ); IR (CHCl ): 3000, 2972, 2936,
3 3
3
D
-1
159.08 (C, PMB), 134.57 (CH, PMB), 130.66 (C, PMB), 129.21
(CH, PMB), 124.07 (CH, C-7), 113.73 (CH, C-8), 75.58 (CH, C-
11), 74.38 (CH, C-10), 70.96 (CH , CH -p-MeO-C H ), 55.20
2856, 1720, 1612, 1512, 1460, 1248, 1172, 1068, 1036 cm ;
1
H-NMR (400 MHz, CDCl ): δ (ppm) = 7.22-7.28 (m, 2H, PMB),
3
6.84-6.89 (2H, PMB), 5.38-5.53 (m, 2H, H-7, H-8), 4.85 (dt,
2
2
6 4
(CH , MeO), 35.27 (CH , C-3), 28.54 (CH ), 26.72 (CH ), 25.25
3
2
2
2
J=7.15, 4.64 Hz, H-10), 4.54 (d, J=11.42 Hz, 1H, CH -p-MeO-
2
(CH , C-5), 23.49 (CH , C-4), 16.15 (CH , C-12); MS (EI, 70 eV,
RT) m/z : 318 (M , 3), 182 (8), 153 (1), 137 (58), 121 (100), 95
2
2
3
C H ), 4.50 (d, J=11.42 Hz, 1H, CH -p-MeO-C H ), 3.80 (s, 3H,
6
4
2
6 4
+
MeO), 3.69 (quin., J=6.35 Hz, 1H, H-11), 2.31-2.42 (m, 1H),
1.99-2.26 (m, 3H), 1.86-1.99 (m, 1H), 1.69-1.82 (m, 1H), 1.54-
1.68 (m, 2H), 1.45-1.54 (m, 1H), 1.23 (d, J=6.4 Hz, 3H, H-12),
(4), 80 (7); HR MS (C
318.18212.
H O ): calcd. 318.18311, found
19 26 4
13
9.
Limberg, A. 1998 Doktorarbeit Universität Braunschweig.
1.19 (d, J=7.02 Hz, 3H, H-13); C-NMR (100 MHz, DEPT,
CDCl ): δ (ppm) = 176.78 (C, C-2), 159.08 (C, PMB), 134.93
10. For the stereoselective alkylation of medium ring enolates see:
Still, W.C.; MacPherson, L.J.; Harada, T.; Callahan, J.F.;
Rheingold, A.L. Tetrahedron 1984, 40, 2275-2281.
3
(CH, PMB), 130.77 (C, PMB), 129.08 (CH, PMB), 123.44 (CH,
C-7), 113.71 (CH, C-8), 75.49 (CH, C-11), 74.58 (CH, C-10),
55.25 (CH , MeO), 42.20 (CH, C-3), 41.27 (CH , CH -p-MeO-
11. Experimental procedure for the synthesis of compound 5. To a
solution of lactone 6 (78 mg, 0.245 mmol) in THF (0.25 mL) is
added dropwise NaHMDS (0.35 mL, 1 M in THF, 0.35 mmol, 1.4
3
2
2
C H ), 32.10 (CH , C-6), 27.37 (CH , C-9), 26.07 (CH , C-5),
6
4
2
2
2
25.47 (CH , C-4), 18.93 (CH , C-13), 16.46 (CH , C-12); MS (EI,
2
3
3
+
+
70 eV, RT) m/z : 333 (M +1, 2), 332 (M , 12), 196 (8), 137 (69),
eq) at -78 °C. After stirring for 1 h at -78 °C CH I (0.1 mL, 1.6
3
121 (100), 95 (9), 85 (12), 68 (7); HR MS (C
332.19876, found: 332.19912.
H O ): calcd.
20 28 4
mmol, 6.5 eq) is added and stirring is continued for 5 h. After
addition of water at -78 °C the mixture is allowed to warm to room