Total synthesis of epothilone D by sixfold ring cleavage of cyclopropanol intermediates

Article abstract of DOI:10.1016/j.tetlet.2010.04.109

The ring-opening or ring fragmentation reactions of cyclopropanol intermediates are used in the total synthesis of epothilone D for the creation of trisubstituted double bonds, an ethyl ketone functionality, as well as for the protection of carboxylic and ester groups. Epothilone D is obtained in 1.6% overall yield (24 steps in the longest linear sequence) starting from (R)-methyl 2,3-O-isopropylideneglycerate. The key cyclopropanol intermediates are efficiently obtained by titanium(IV)-catalyzed reactions of readily available esters with Grignard reagents. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2010.04.109

Tetrahedron Letters 51 (2010) 3497–3500
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Tetrahedron Letters
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Total synthesis of epothilone D by sixfold ring cleavage of
cyclopropanol intermediates
*
Alaksiej L. Hurski, Oleg G. Kulinkovich
Department of Organic Chemistry, Belarusian State University, Nezavisimosty Av. 4, 220030 Minsk, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring-opening or ring fragmentation reactions of cyclopropanol intermediates are used in the total
synthesis of epothilone D for the creation of trisubstituted double bonds, an ethyl ketone functionality,
as well as for the protection of carboxylic and ester groups. Epothilone D is obtained in 1.6% overall yield
(24 steps in the longest linear sequence) starting from (R)-methyl 2,3-O-isopropylideneglycerate. The key
cyclopropanol intermediates are efficiently obtained by titanium(IV)-catalyzed reactions of readily avail-
able esters with Grignard reagents.
Received 3 March 2010
Revised 10 April 2010
Accepted 23 April 2010
Available online 28 April 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Ring-opening and ring fragmentation reactions have been
widely used in organic synthesis.1 For small-ring compounds hav-
ing ion-stabilizing substituents, these reactions usually proceed
under mild conditions with high regioselectivity. Such transforma-
tions are typical for cyclopropanols and their derivatives affording
carbonyl compounds, esters, allyl alcohols, allyl halides, and other
products.2 After finding that the reaction of esters with Grignard
reagents in the presence of titanium alkoxides leads to substituted
cyclopropanols,3 we started systematic studies on their use as syn-
thetically useful intermediates.4 In the present work we were
interested to apply cyclopropanol synthetic methodologies to the
total synthesis of the microtubule-stabilizing anticancer agent,
epothilone D (1),5 by sequential applications of cyclopropanation
and cyclopropanol ring-opening reactions for the preparation of
the appropriate synthetic intermediates. The choice of this target
molecule allowed us to study the synthesis of complex polyfunc-
tional compounds as well as to gauge the relative strength of the
elaborated cyclopropanol approach to the synthesis of epothilone
D in comparison with the many alternative routes described in
the literature.6
The C1–C6 subunit 2 was synthesized starting from ester 7,8
which was smoothly converted into the substituted cyclopropanol
8 by treatment with ethylmagnesium bromide in the presence of
titanium(IV) isopropoxide.3 The reaction of the magnesium alco-
holate of the product 8 with pivaloyl chloride gave the ester 9
and hydrolysis of the acetal group afforded aldehyde 4 (Scheme
Cyclopropyl sulfonate
C2-C3 ring opening
Cyclopropanol C1-C2 and
C1-C3 ring fragmentation
S
21
13
15
16
O
12
8
7
HO
6
N
17
3
1
5
OH O
O
Cyclopropanol
C1-C2 ring opening
Cyclopropanol C1-C2 and
C1-C3 ring fragmentation
1
In this work the frequently used macrolactonization strategy7
was applied to the synthesis of epothilone D (1). Cyclopropanol
ring fragmentation reactions were utilized to generate the corre-
sponding functionalities at C1, C7, and C12, whereas ring-opening
reactions were exploited for the generation of the carbonyl group
at C5 as well as for the creation of the C12–C13 and C16–C17 dou-
ble bonds (Scheme 1). Advanced cyclopropanol intermediates,
compounds 2 and 3, were, in turn, prepared via cyclopropanol
precursors 4–6.
12OH
S
21
1
3
5
15
THPO
+
N
OH O
O
7
OTBS
3
2
OH
12
3
5
O 15
OMs
7
+
PivO
O
17
OH
4
5
6
* Corresponding author. Fax: +375 17 2265609.
E-mail address: o.kulinkovich@gmail.com (O.G. Kulinkovich).
Scheme 1.
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.109

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A. L. Hurski, O. G. Kulinkovich / Tetrahedron Letters 51 (2010) 3497–3500
2). Condensation of the latter with trimethylsilyl ketene acetal 10
in the presence of N-tosyl-(S)-valine-derived oxazaborolidinone9
led to hydroxy ester 11 with 96% ee.10 The hydroxy group in com-
pound 11 was silylated and the resulting product 12 was subjected
to a titanium-catalyzed reaction with ethylmagnesium bromide in
ether at ꢀ35 °C. Site-selective cyclopropanation of the less-hin-
dered ester group was achieved under these conditions and the
bis-cyclopropanol 1311 was further converted into acetonide 14.
The pivaloyl-protecting group was removed by treatment of com-
pound 14 with lithium aluminum hydride and the resulting crude
cyclopropanol 2 was heated under reflux in methanol in the pres-
ence of potassium hydroxide. Cleavage of the C1–C2 cyclopropane
bond12 of the unprotected cyclopropanol moiety was observed un-
der these conditions affording ethyl ketone 15 bearing the oxycy-
clopropane fragment as a latent carboxylic group (see below).
The preparation of the cyclopropanol C7–C21 intermediate 3
was performed by cyclopropanation of ester 16 with the alkoxyti-
tanacyclopropane reagent generated by ligand exchange13 of TBS-
protected homoallyl alcohol 1714 and the alkoxytitanacyclopro-
pane precursor, generated from titanium(IV) isopropoxide and
cyclopentylmagnesium chloride (Scheme 3).15 Addition of the lat-
ter to the mixture of ester 16, olefin 17, and titanium(IV) isoprop-
oxide in THF provided disubstituted (E)-cyclopropanol 3 in 66%
yield based on ester 16 and 95% yield based on recovered alkene
17. The reaction proceeded with high (E)-diastereoselectivity to af-
ford compound 3 as the mixture of diastereomers (1.4:1) with
undetermined relative configuration of the chiral centers.16
OH
a
c
CO2Et
EtO2C
OPiv
OR2
OR1
5 R1=H
18
b
19 R1=Piv
O
O
d-f
OH
g
N
O
O
OPiv
O
Bn
20
22
HN
O
Bn
21
i
O
OR3
OH
OMe
j
25 R3=H
23 R2=Piv
24 R2=H
h
16 R3=THP
Scheme 4. Reagents and conditions: (a) EtMgBr (5 equiv), Ti(Oi-Pr)4 (0.2 equiv),
THF, 90%; (b) PivCl, Py, DMAP, 63%; (c) PhI(OAc)2, AcOH, H2O, 93%; (d) SOCl2, CHCl3;
(e) 21, BuLi, THF, hexane, 89% over two steps; (f) NaHMDS, MeI, THF, 92%; (g) LiBH4,
MeOH, THF, 89%; (h) LiAlH4, Et2O, 90%; (i) PhI(OAc)2, MeOH, 87%; (j) DHP, PPTS,
CH2Cl2, 99%.
Kirihara oxidative fragmentation of the unprotected cyclopropanol
moiety18 by treatment of pivalate 19 with phenyliodine(III) diace-
tate in acetic acid led to acid 20 along with its anhydride and the
mixed anhydride with acetic acid. Dilution of the reaction mixture
with aqueous THF and a short reflux enabled hydrolysis of the
anhydrides furnishing the acid 20 in 93% yield.19 Conversion of
the acid 20 into the acid chloride followed by coupling of the prod-
uct with the Evans chiral auxiliary 21 and diastereoselective meth-
ylation led to imide 22 in 92% yield. The chiral auxiliary of 22 was
removed by reduction with lithium borohydride, and the resulting
alcohol 23 was treated with lithium aluminum hydride to yield
cyclopropanol 24. Oxidative fragmentation of the latter with
phenyliodine(III) diacetate in methanol18 led to regeneration of
the ester group to form hydroxyester 25 with 88% ee.20,21 Protec-
tion of the hydroxy group in 25 furnished compound 16.
THP-protected hydroxy ester 16 was prepared from diethyl adi-
pate (18) via bis-cyclopropanol 5 (Scheme 4).17 Esterification of the
latter with 1 equiv of pivaloyl chloride and subsequent Rubottom–
OEt
OEtOR1
PivO O
a
c
CO2Et
EtO
EtO
8 R1=H
7
4
b
9 R1=Piv
The olefin subunit 17 was obtained, in turn, by silylation of the
homoallylic alcohol 26,14 whose preparation starting from the es-
ter 27 via cyclopropanol derivatives 6, 28, and allyl bromide 29
was described in our previous Letter (Scheme 5).22
The trisubstituted C12–C13 double bond of the target molecule
1 was formed by the cationic cyclopropyl-allyl rearrangement of
the cyclopropanol sulfonate 30 (Scheme 6).23 The latter was trea-
ted with magnesium bromide (3 equiv) in ether at room tempera-
ture to give a mixture of regioisomeric allyl bromides 31 and 32 in
an 87:13 ratio and with more than 99% stereoselectivity toward
the (E)-trisubstituted double bond in the primary allyl bromide
31. Reductive dehalogenation of the mixture of the compounds
PivO OR2OH
OTMS
OPh
PivO OR2
d
f
+
4
CO2Ph
11 R2=H
13 R2=TMS
10
e
12 R2=TMS
PivO
O
O
O
O
O
i
g
h
2
15
14
Scheme 2. Reagents and conditions: (a) EtMgBr (5 equiv), Ti(Oi-Pr)4 (0.5 equiv),
THF, 82%; (b) EtMgBr, Et2O, THF, then PivCl, 99%; (c) H2O, TsOH, acetone, 90%; (d) 10
(2 equiv), N-Ts-(S)-valine (1.25 equiv), BH3ꢁTHF (1.25 equiv), CH2Cl2, 58%; (e)
TMSCl, Et3N, THF, 88%; (f) EtMgBr (6 equiv), Ti(Oi-Pr)4 (2 equiv), Et2O, ꢀ35 °C,
74%; (g) 2,2-dimethoxypropane, PPTS, acetone, 99%; (h) LiAlH4, Et2O; (i) KOH,
MeOH, reflux, 78% over two steps.
ref.22
82%
ref.22
40 %
OAc
OMs
ref.22
78%
O
O
O
OMe
OMs
O
27
6
28
O
S
a
OMe
3
N
+
THPO
ref.22
68%
OH
OAc
a
OTBS
N
S
17
Br
17
16
Scheme 3. Reagents and conditions: (a) cyclopentylmagnesium chloride (4 equiv),
29
26
Ti(Oi-Pr)4 (1 equiv), THF, 66% yield based on 16 and 95% yield based on recovered
17.
Scheme 5. Reagents and conditions: (a) TBSCl, imidazole, DMF, 92%.

A. L. Hurski, O. G. Kulinkovich / Tetrahedron Letters 51 (2010) 3497–3500
3499
Br
S
THPO
N
OTBS
31, 87%
OR1
c
S
b
S
+
R2
N
THPO
a
N
OTBS
OTBS
33 R2=CH2OTHP
34 R2=CH2OH
35 R2=CHO
3 R1=H
30 R1=Ms
d
e
Br
S
THPO
N
OTBS
32, 13%
Scheme 6. Reagents and conditions: (a) MsCl, Et3N, Et2O, 99%; (b) MgBr2, Et2O, 99%, 87:13 31/32; (c) LiAlH4, Et2O, then KOAc, TEBA, DMF, 60%; (d) PPTS, i-PrOH, 94%; (e)
DMSO, (COCl)2, Et3N, CH2Cl2, 92%.
31 and 32 with lithium aluminum hydride led to Z-alkene 33 to-
gether with unreacted bromide 32. To facilitate chromatographic
purification of product 33, the secondary allyl halide 32 was con-
verted into the corresponding acetate by reaction with potassium
acetate in DMF in the presence of TEBA.23b The THP-protecting
group was removed by treatment of compound 33 with isopropyl
alcohol in the presence of PPTS to afford known alcohol 34,24 which
was further oxidized using the Swern method to give aldehyde
3514 in 51% overall yield (five steps).
The formation of the carbon backbone of the target epothilone
D (1) was accomplished in a similar way to earlier described pro-
cedures14,24 by syn-selective addition of the lithium enolate of
ethyl ketone 15 to aldehyde 35 to give product 36 in 80% yield
(Scheme 7). The acetonide-protecting group was removed from
compound 36 by treatment with a mixture of ether and 80% formic
acid (1:1) at room temperature over 6 h. The cyclopropanol group
of 37 was transformed into a carboxyl group, in excellent yield, by
treatment with phenyliodine(III) diacetate in aqueous THF18 and
standard manipulation of the protecting groups of the resulting
compound 38 was carried out to deliver hydroxy acid 39. The latter
was macrolactonized by Yamaguchi’s method,7,25 and after TBS
deprotection, epothilone D (1)26 was isolated in 34% overall yield
based on the cyclopropanol derivative 37.
In conclusion, the ring-opening reactions of the cyclopropanols
were successfully used in the total synthesis of epothilone D 1, for
the formation of the (Z)-C12–C13 and (E)-C16–C17 trisubstituted
double bonds in intermediates 17 and 33, the ethyl ketone frag-
ment in intermediate 15, and for the protection of the carboxylic
or ester groups in compounds 20, 25, and 38. The overall yield in
the longest linear sequence of 23 steps from diethyl adipate (18)
and 24 steps from isopropylideneglycerate 27 was 2% and 1.6%,
respectively. These values are close to the average number of steps
(22) and average overall yield (2.3%) in the previously reported to-
tal syntheses of epothilone D (1).6k,7b,c,14,27 At the same time, the
cyclopropanol approach is substantially longer than the most
efficient synthesis performed by Danishefsky (16 steps, 4.1%
yield).7b It is evident that one-step introduction of the desired
functionalities into a target molecule is more preferable in terms
of the man-hours costs of a synthesis than the corresponding
two or even multi-step sequences. Nevertheless, experimental
simplicity and efficiency of cyclopropanol preparation, along with
their ability to undergo smooth ring-opening or ring fragmentation
reactions on treatment with inexpensive reagents or catalysts,
could attach strategic importance to synthetic methods based on
such transformations.28
S
HO
b
a
N
15+35
OTBS
O
O
O
Acknowledgment
36
This work was carried out with support from the Ministry of
Education of the Republic of Belarus.
S
S
c
HO
HO
N
N
OTBS
CO2H
OTBS
References and notes
O
OH OH
O
OH
38
1. (a) Carreira, E. M.; Kvaerno, L. Classics in Stereoselective Synthesis; Wiley-VCH:
Weinheim, 2009; (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II;
Wiley-VCH: Weinheim, 2003; (c) Nicolaou, K. C.; Sorensen, E. J. Classics in Total
Synthesis; VCH: Weinheim, 1996; (d) Fuhrhop, J.; Penzlin, G. Organic Synthesis.
Concepts, Methods, Starting Material, 2nd ed.; VCH: Weinheim, 1994.
2. (a) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597; (b) Gibson, D. H.; De Puy, C. H.
Chem. Rev. 1974, 74, 605.
3. (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org.
Khim. 1989, 25, 2245. J. Org. Chem. USSR (Engl. Transl.) 1989, 25, 2027; (b)
Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Synthesis
1991, 234; (c) Sviridov, S. V.; Vasilevskii, D. A.; Kulinkovich, O. G. Zh. Org. Khim.
1991, 27, 1431. J. Org. Chem. USSR (Engl. Transl.) 1991, 27, 1251; For reviews,
see: (d) Kulinkovich, O. G. Izv. Akad. Nauk, Ser. Khim. 2004, 1022. Russ. Chem.
Bull., Int. Ed. (Engl. Transl.) 2004, 53, 1065; (e) Kulinkovich, O. G.; de Meijere, A.
Chem. Rev. 2000, 100, 2789.
37
S
f, g
d, e
TBSO
N
1
OH
CO2H
OTBS
O
39
Scheme 7. Reagents and conditions: (a) LDA, THF, 80%; (b) 80% HCO2H, Et2O, 77%;
(c) PhI(OAc)2, THF, H2O, 91%; (d) TBSOTf (4.5 equiv), 2,6-lutidine (7.5 equiv), CH2Cl2,
then AcOH, H2O, THF, 87%; (e) TBAF, THF, 69%; (f) 2,4,6-trichlorobenzoyl chloride,
Et3N, THF, then DMAP, toluene, 77%; (g) TFA, CH2Cl2, 80%.
4. Kulinkovich, O. G. Eur. J. Org. Chem. 2004, 4517.
5. (a) Höfle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. DE-4138042, 1993; Chem.
Abstr. 1994, 120, 52841.; (b) Washausen, G. P.; Höfle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560.

3500
A. L. Hurski, O. G. Kulinkovich / Tetrahedron Letters 51 (2010) 3497–3500
6. For reviews, see: (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew.
Chem. 1998, 110, 2120. Angew. Chem., Int. Ed. Engl. 1998, 37, 2014; (b) Harris, C.
R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434; (c) Mulzer, J.; Martin, H. J.;
Berger, M. J. Heterocycl. Chem. 1999, 36, 1421; (d) Nicolaou, K. C.; Ritzen, A.;
Namoto, K. Chem. Commun. 2001, 1523; (e) Altmann, K.-H. Org. Biomol. Chem.
2004, 2, 2137; (f) Watkins, E. B.; Chittiboyina, A. G.; Jung, J. C.; Avery, M. A. Curr.
Pharm. Des. 2005, 11, 1615; (g) Watkins, E. B.; Chittiboyina, A. G.; Avery, M. A.
Eur. J. Org. Chem. 2006, 4071; (h) Altmann, K.-H.; Pfeiffer, B.; Arseniyadis, S.;
Pratt, B. A.; Nicolaou, K. C. Chem. Med. Chem. 2007, 2, 396; (i) Feyen, F.; Cachoux,
F.; Gertsch, J.; Wartmann, M.; Altmann, K.-H. Acc. Chem. Res. 2008, 41, 21; (j)
Mulzer, J.; Altmann, K.-H.; Höfle, G.; Müller, R.; Prantz, K. C. R. Chimie 2008, 11,
1336; (k) Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org.
Chem. 2008, 73, 9675.
17. Kulinkovich, O. G.; Bagutskii, V. V. Zh. Org. Khim. 1997, 33, 898–901. Russ. J. Org.
Chem. (Engl. Transl.) 1997, 33, 830.
18. (a) Rubottom, G. M.; Marrero, R.; Krueger, D. S.; Schreiner, J. L. Tetrahedron Lett.
1977, 18, 4013; (b) Kirihara, M.; Yokoyama, S.; Kakuda, H.; Momose, T.
Tetrahedron Lett. 1995, 38, 6907; (c) Kirihara, M.; Yokoyama, S.; Kakuda, H.;
Momose, T. Tetrahedron 1998, 54, 13943.
19. PhI(OAc)2 (12.68 g, 39.4 mmol) was added portionwise over 20 min to a water
cooled solution of compound 19 (10.00 g, 39.4 mmol) in AcOH (50 ml). The
reaction mixture was stirred for 10 min, diluted with H2O (50 ml) and THF
(100 ml), and heated under reflux for 1 h. The reaction mixture was
concentrated under reduced pressure, and the residue was diluted with H2O
(50 ml) and extracted with Et2O. The organic layers were dried over MgSO4,
concentrated under reduced pressure, and the residue was chromatographed
on silica gel (petroleum ether/EtOAc) to give acid 20 (8.96 g, 93%). IR (CCl4)
7. (a) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem., Int. Ed. 1997,
36, 525; (b) Balog, A.; Harris, C.; Savin, K.; Zhang, X.-G.; Chou, T. C.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 1998, 37, 2675; (c) Schinzer, D.; Bauer, A.; Scieber, J.
Synlett 1998, 861.
m
max: 1739, 1712 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.61–0.64 (m, 2H), 0.75–
.
0.78 (m, 2H), 1.13 (s, 9H), 1.40–1.48 (m, 2H), 1.61–1.69 (m, 2H), 1.73–1.77 (m,
2H), 2.34 (t, J = 7.4 Hz, 2H), 10.13 (br s, 1H). 13C NMR (100 MHz, CDCl3) d 11.7
(2 ꢃ C), 24.3, 25.3, 26.9 (3 ꢃ C), 33.8, 34.0, 38.6, 59.1, 178.4, 179.7. Anal. Calcd
for C13H22O4: C, 64.44; H, 9.15. Found: C, 64.39; H, 9.11.
8. Deno, N. C. J. Am. Chem. Soc. 1947, 69, 2233.
9. Kiyooka, S.; Hena, M. A. J. Org. Chem. 1999, 64, 5511.
10. The ee value was determined by Mosher’s method30 from the integral
intensities of the signals of the protons at d = 5.83 and 5.85 ppm (CHOMTPA)
in the 1H NMR spectra of the (S)-MTPA esters.
20. Compound 25: ½a 2D0 max: 3640, 3534, 1742 cmꢀ1
ꢀ11 (c 2.2, CHCl3). IR (CCl4) m .
ꢂ
1H NMR (400 MHz, CDCl3): d 0.91 (dd, J = 6.7, 0.8 Hz, 3H), 1.09–1.19 (m, 1H),
1.38–1.47 (m, 1H), 1.54–1.75 (m, 3H), 2.31 (t, J = 7.3 Hz, 2H), 2.31 (br s, 1H),
3.44 (ddd, J = 10.8, 6.4, 1.0 Hz, 1H), 3.49 (ddd, J = 10.8, 6.1, 1.0 Hz, 1H), 3.66 (s,
3H). 13C NMR (100 MHz, CDCl3) d 16.4, 22.2, 32.5, 34.2, 35.4, 51.5, 67.9, 174.2.
Anal. Calcd for C8H16O3: C, 59.97; H, 10.07. Found: C, 59.85; H, 10.09.
21. The ee value was determined by Mosher’s method30 from the integral
intensities of the signals of the protons at d = 4.12 and 4.06 ppm
(CH2OMTPA) in the 1H NMR spectra of the (S)-MTPA esters of compound 23.
22. Hurski, A. L.; Sokolov, N. A.; Kulinkovich, O. G. Tetrahedron 2009, 65, 3518.
23. (a) Kozyrkov, Yu. Yu.; Kulinkovich, O. G. Synlett 2002, 443; (b) Kananovich, D.
G.; Hurski, A. L.; Kulinkovich, O. G. Tetrahedron Lett. 2007, 48, 8424.
11. To a solution of ester 12 (1.52 g, 3.62 mmol) and Ti(Oi-Pr)4 (2.2 ml, 7.40 mmol)
in Et2O (36 ml) at ꢀ35 °C was added a solution of EtMgBr (2 M in Et2O, 11 ml,
22 mmol) over 2 h. The reaction was quenched with H2O (2.6 ml), the reaction
mixture was filtered, and the filter cake was washed thoroughly with EtOAc.
The filtrate was concentrated under reduced pressure and the residue was
chromatographed on silica gel (petroleum ether/EtOAc) to give unreacted ester
12 (0.23 g, 15%) and cyclopropanol 13 (0.81 g, 63%, 74% based on recovered
starting material). ½a 2D0 max: 3542, 1723 cmꢀ1 1H
ꢀ18 (c 2.0, CHCl3). IR (CCl4) m .
ꢂ
NMR (400 MHz, CDCl3): d 0.15 (s, 9H), 0.29–0.34 (m, 1H), 0.50–0.67 (m, 3H),
0.58 (s, 3H), 0.70–1.06 (m, 4H), 1.10 (s, 3H), 1.12 (s, 9H), 1.45 (dd, J = 14.3,
10.2 Hz, 1H), 2.44 (dd, J = 14.3, 1.5 Hz, 1H), 2.90 (s, 1H), 3.96 (dd, J = 10.2,
1.5 Hz, 1H).13C NMR (100 MHz, CDCl3): d 1.2 (3 ꢃ C), 8.5, 11.7, 12.2, 14.1, 16.5,
25.6, 27.0 (3 ꢃ C), 39.0, 40.1, 42.1, 53.8, 65.0, 75.7, 178.5. Anal. Calcd for
C19H36O4Si: C, 64.00; H, 10.18. Found: C, 63.94; H, 10.35.
24. Schinzer, D.; Bauer, A.; Schieber, J. Chem. Eur. J. 1999, 5, 2492.
25. Iranaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989.
26. The NMR spectra of the obtained epothilone D (1) are in full agreement with those
reported earlier for this compound:14,6k 1H NMR (400 MHz, CDCl3) d 1.01 (d,
J = 6.9 Hz, 3H), 1.07 (s, 3H), 1.19 (d, J = 6.7 Hz, 3H), 1.24–1.32 (m, 3H), 1.34 (s,
3H), 1.66 (s, 3H), 1.69–1.77 (m, 2H), 1.85–1.91 (m, 1H), 2.06 (s, 3H), 2.24–2.35
(m, 3H), 2.46 (dd, J = 14.3, 11.3 Hz, 1H), 2.63 (dt, J = 14.8, 10.8 Hz, 1H), 2.69 (s,
3H), 3.08 (br s, 1H), 3.15 (q, J = 6.7 Hz, 1H), 3.64 (br s, 1H), 3.71–3.74 (m, 1H),
4.31 (d, J = 10.2 Hz, 1H), 5.14 (dd, J = 9.7, 4.6 Hz, 1H), 5.21 (d, J = 9.7 Hz, 1H),
6.59 (s, 1H), 6.96 (s, 1H). 13C NMR (100 MHz, CDCl3) d 13.4, 15.7, 15.8, 17.9,
18.9, 22.8, 22.9, 25.3, 31.5, 31.6, 32.4, 38.3, 39.6, 41.6, 53.5, 72.1, 74.1, 78.8,
115.5, 119.0, 120.8, 138.3, 139.1, 151.9, 165.0, 170.3, 220.6.
12. (a) Stahl, G. W.; Cottle, D. L. J. Am. Chem. Soc. 1943, 65, 1782; (b) De Puy, C. H.;
Breitbeil, F. W. J. Am. Chem. Soc. 1963, 85, 2176.
13. (a) Kulinkovich, O. G.; Savchenko, A. I.; Sviridov, S. V.; Vasilevski, D. A.
Mendeleev Commun. 1993, 230; (b) Epstein, O. L.; Savchenko, A. I.; Kulinkovich,
O. G. Tetrahedron Lett. 1999, 40, 5935; (c) Epstein, O. L.; Savchenko, A. I.;
Kulinkovich, O. G. Izv. Akad. Nauk. 2000, 376. Russ. Chem. Bull. (Engl. Transl.)
2000, 49, 378.
14. Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.;
Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974.
15. (a) Cha, J. K.; Kim, H.; Lee, J. J. Am. Chem. Soc. 1996, 118, 4198; (b) Lee, J.; Kim, Y.
G.; Bae, J. G.; Cha, J. K. J. Org. Chem. 1996, 61, 4878.
27. (a) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073; (b) May, S. A.; Grieco, P. A.
Chem. Commun. 1998, 1597; (c) White, J. D.; Carter, R. G.; Sundermann, K. F. J.
Org. Chem. 1999, 64, 684; (d) Mulzer, J.; Mantoulidis, A.; Öhler, E. J. Org. Chem.
2000, 65, 7456; (e) Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221; (f) Martin, N.;
Thomas, E. J. Tetrahedron Lett. 2001, 42, 8373; (g) Jung, J.-C.; Kache, R.; Vines, K.
K.; Zheng, Y.-S.; Bijoy, P.; Valluri, M.; Avery, M. A. J. Org. Chem. 2004, 69, 9269;
(h) Broadrup, R. L.; Sundar, H. M.; Swindell, C. S. Bioorg. Chem. 2005, 33, 116.
28. To support the validity of this statement, we roughly calculated the price29 of
the molar amounts of the chemicals used for the total syntheses of epothilone
16. A solution of cyclopentylmagnesium chloride (2 M in Et2O, 4.1 ml, 8.22 mmol)
was added over 40 min to a solution of ester 16 (0.50 g, 2.05 mmol), alkene 17
(1 g, 3.10 mmol), and Ti(Oi-Pr)4 (0.61 ml, 2.05 mmol) in THF (40 ml). The
reaction mixture was stirred for 10 min, the reaction was quenched with H2O
(1.1 ml), the reaction mixture was filtered, and the filter cake was washed
thoroughly with EtOAc. The filtrate was concentrated under reduced pressure
and the residue was chromatographed on silica gel (petroleum ether/EtOAc) to
give unreacted alkene 17 (0.54 g, 1.67 mmol) and cyclopropanol 3 (0.73 g, 66%
D.6k,7b,c,14,27 The average value of this sum (37 ꢃ 103 Euroꢁmolꢀ1
) is
based on ester 16, 95% based on alkene 17). IR (CCl4)
m
max: 3609, 3468 cmꢀ1
.
1H
substantially higher than the corresponding sum calculated for the synthesis
of epothilone D (1) by the cyclopropanol approach (11 ꢃ 103 Euroꢁmolꢀ1). The
latter value is almost twofold lower than the value for the leading approach7b
(21 ꢃ 103 Euroꢁmolꢀ1) and only slightly inferior to this one in obtaining the
same amount of the target molecule (1).
NMR (400 MHz, CDCl3): d 0.00 (s, 3H), 0.06 (s, 3H), 0.06–0.11 (m, 1H), 0.78–
0.89 (m, 3.5H), 0.88 (s, 9H), 0.92 (d, J = 7.7 Hz, 1.5H), 1.07–1.83 (m, 15H), 1.94
(s, 3H), 2.52 (br s, 1H), 2.68 (s, 3H), 3.14 (dd, J = 9.2, 6.5 Hz, 0.5H), 3.22 (dd,
J = 9.2, 5.9 Hz, 0.5H), 3.45–3.53 (m, 1.5H), 3.58 (dd, J = 9.2, 6.5 Hz, 0.5H), 3.80–
3.85 (m, 1H), 4.12–4.18 (m, 1H), 4.52–4.56 (m, 1H), 6.46 (s, 1H), 6.90 (s, 1H).
Anal. Calcd for C29H51O4NSSi: C, 64.76; H, 9.56. Found: C, 64.60; H, 9.45.
29. http://www.sigmaaldrich.com/european-export.html.
30. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.