Studies on the synthesis of apoptolidin A. 1. Synthesis of the C(1)-C(11) fragment

Article abstract of DOI:10.1021/jo702250z

(Chemical Equation Presented) A synthesis of the C(1)-C(11) fragment of apoptolidin A has been accomplished by a convergent route involving the stereoselective glycosidation of 9 and the Suzuki cross-coupling reaction of bromodienoate 7 and the vinylboran

Full text of DOI:10.1021/jo702250z

Studies on the Synthesis of Apoptolidin A. 1. Synthesis of the
C(1)-C(11) Fragment
Masaki Handa,† Karl A. Scheidt,‡ Martin Bossart,‡ Nan Zheng,‡ and William R. Roush*,†
Department of Chemistry, Scripps-Florida, Jupiter, Florida 33458, and Department of Chemistry,
UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@scripps.edu
ReceiVed October 17, 2007
A synthesis of the C(1)-C(11) fragment of apoptolidin A has been accomplished by a convergent route
involving the stereoselective glycosidation of 9 and the Suzuki cross-coupling reaction of bromodienoate
7 and the vinylborane generated via chemoselective hydroboration of diyne 6 with diisopinocamphey-
lborane.
Introduction
groups have reported ongoing studies directed toward the
synthesis of apoptolidin.6,7 We report herein an efficient
synthesis of the C(1)-C(11) fragment 1 containing the 6-deoxy-
4-O-methyl-L-glucoside moiety of apoptolidin A. In a subse-
quent paper we report a synthesis of the C-D disaccharide 3.8
Apoptolidin A is a glycosylated 20-membered macrolide that
was first isolated by Hayakawa and co-workers from an
actinomycete identified as Nocardiopsis sp.1a Apoptolidin A is
a potent and specific inhibitor of mitochondrial F0F1-ATPase
and ranks among the top 0.1% of the most selective cell line
cytotoxic agents known.1 In addition, apoptolidin A is of
considerable interest owing to its potent activity as an inducer
of apoptosis in cells transformed with the adenovirus E1A
oncogene.
(2) (a) Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Wei,
H.-X.; Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40, 3849. (b)
Nicolaou, K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K.
Angew. Chem., Int. Ed. 2001, 40, 3854. (c) Nicolaou, K. C.; Fylaktakidou,
K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.; Mitchell, H. J.; Wei,
H.-X.; Guntupalli, P.; Hepworth, D.; Sugita, K. J. Am. Chem. Soc. 2003,
125, 15433. (d) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.;
Guntupalli, P.; Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.;
Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443.
(3) (a) Schuppan, J.; Wehlan, H.; Keiper, S.; Koert, U. Angew. Chem.,
Int. Ed. 2001, 40, 2063. (b) Wehlan, H.; Dauber, M.; Mujica Fernaud, M.
T.; Schuppan, J.; Mahrwald, R.; Ziemer, B.; Juarez Garcia, M. E.; Koert,
U. Angew. Chem., Int. Ed. 2004, 43, 4597. (c) Schuppan, J.; Wehlan, H.;
Keiper, S.; Koert, U. Chem. Eur. J. 2006, 12, 7364. (d) Wehlan, H.; Dauber,
M.; Mujica Fernaud, M. T.; Schuppan, J.; Keiper, S.; Mahrwald, R.; Juarez
Garcia, M. E.; Koert, U. Chem. Eur. J. 2006, 12, 7378.
Total syntheses of apoptolidin A have been reported by the
Nicolaou2 and Koert3 groups. Apoptolidinone, the aglycon of
apoptolidin A, has also been synthesized in the laboratories of
Koert,3 Sulikowski,4 and Crimmins.5 Several other research
† Scripps-Florida.
‡ University of Michigan.
(1) (a) Kim, J. W.; Adachi, H.; Shin-ya, K.; Hayakawa, Y.; Seto, H. J.
Antibiot. 1997, 50, 628. (b) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-
ya, K.; Fujita, K.; Seto, H. J. Am. Chem. Soc. 1998, 120, 3524. (c) Salomon,
A. R.; Voehringer, D. W.; Herzenberg, L. A.; Khosla, C. Proc. Natl. Acad.
Sci. U.S.A. 2000, 97, 14766. (d) Salomon, A. R.; Voehringer, D. W.;
Herzenberg, L. A.; Khosla, C. Chem. Biol. 2001, 8, 71.
(4) Wu, B.; Liu, Q.; Sulikowski, G. A. Angew. Chem., Int. Ed. 2004,
43, 6673.
(5) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am.
Chem. Soc. 2005, 127, 13810.
(6) Daniel, P. T.; Koert, U.; Schuppan, J. Angew. Chem., Int. Ed. 2006,
45, 872.
10.1021/jo702250z CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/29/2007
J. Org. Chem. 2008, 73, 1031-1035
1031

Handa et al.
SCHEME 1. Global Retrosynthetic Analysis of Apoptolidin A
Retrosynthetic Analysis
SCHEME 2. Synthesis of Propargyl Alcohol 9
Our retrosynthetic analysis of apoptolidin A is outlined in
Scheme 1. Disconnection of the C(11)-C(12) bond and the
macrolactone C-O bond and cleavage of the disaccharide unit
gives the C(1)-C(11) fragment 1, the C(12)-C(28) fragment
2, and the activated disaccharide 3. We targeted the synthesis
of fragment 1 containing the requisite monosaccharide unit so
as to minimize use of protecting groups and to achieve optimal
synthetic efficiency. At the outset, we anticipated that 1 could
be assembled via a highly convergent Horner-Wadsworth-
Emmons coupling of aldehyde 4 and the bis-vinylogous HWE
reagent 5. However, despite considerable effort, all attempts to
effect this HWE coupling were unsuccessful.9,10 Consequently,
we have developed the alternative approach involving the Suzuki
cross-coupling of the vinylborane generated from 6 with vinyl
bromide 7. A similar cross-coupling sequence was employed
by Nicolaou for the synthesis of a non-glycosylated apoptolidin
intermediate.2
involved enantioselective reduction of propargyl ketone 12
(Scheme 2). Thus, treatment of the known Weinreb amide 1011
with p-methoxybenzyl trichloroacetimidate12 and catalytic triflic
acid provided the PMB ether 11. Subsequent treatment of 11
with the alkynyl lithium generated from tert-butyldimethylsi-
lylacetylene afforded the alkynyl ketone 12.13 Initially, use of
the CBS catalyst 13 was explored for the diastereoselective
reduction of 12.14 This reaction provided 9 in good yield but
with only 10:1 diastereoselectivity. Much better results were
obtained when the reduction of 12 was performed by using
Results and Discussion
Synthesis of Propargyl Alcohol 9. Of the various strategies
considered, the most efficient synthesis of propargyl alcohol 9
(7) For leading references to studies on the synthesis of apoptolidin,
see: (a) Toshima, K.; Arita, T.; Kato, K.; Tanaka, D.; Matsumura, S.
Tetrahedron Lett. 2001, 42, 8873. (b) Chen, Y.; Evarts, J. B., Jr.; Torres,
E.; Fuchs, P. L. Org. Lett. 2002, 4, 3571. (c) Chng, S.-S.; Xu, J.; Loh,
T.-P. Tetrahedron Lett. 2003, 44, 4997. (d) Abe, K.; Kato, K.; Arai, T.;
Rahim, M. A.; Sultana, I.; Matsumura, S.; Toshima, K. Tetrahedron Lett.
2004, 45, 8849. (e) Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6, 103.
(f) Bouchez, L. C.; Vogel, P. Chem. Eur. J. 2005, 11, 4609. (g) Li, X.;
Zeng, X. Tetrahedron Lett. 2006, 47, 6839. (h) Craita, C.; Didier, C.; Vogel,
P. Chem. Commun. 2007, 2411. (i) Kim, Y.; Fuchs, P. L. Org. Lett. 2007,
9, 2445.
(11) Correˆa, I. R., Jr.; Pilli, R. A. Angew. Chem., Int. Ed. 2003, 42, 3017.
(12) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139.
(8) Handa, M.; Smith, W. J., III; Roush, W. R. J. Org. Chem. 2008, 73,
1036.
(9) Scheidt, K. A. Ph.D. Dissertation, Indiana University, Bloomington,
1999.
(13) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(14) (a) For a review of CBS reductions: Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.
J. Am. Chem. Soc. 1987, 109, 5551. (c) Parker, K. A.; Ledeboer, M. W. J.
Org. Chem. 1996, 61, 3214.
(10) Zheng, N.; Roush, W. R. Unpublished research results.
1032 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of the C(1)-C(11) Segment of Apoptolidin A
SCHEME 3. Synthesis of Thioglycoside 8
SCHEME 5. Synthesis of the Apoptolidin C(1)-C(11)
Fragment 1
SCHEME 4. Synthesis of Bromodienoate 7
Noyori’s asymmetric transfer hydrogenation method.15 Thus,
treatment of 12 with the Noyori catalyst 14 in a mixture of
isopropanol and CH2Cl2 afforded the alcohol 9 in 87% yield as
a single diastereomer after column chromatographic purification.
Synthesis of Thioglycoside Donor 8. Thioglycoside 8 was
synthesized as summarized in Scheme 3. L-Di-O-acetyl-rhamnal
15 was prepared from L-rhamnose as described in the literature.16
Following deacetylation of 15 using NaOMe, the allylic alcohol
was protected as the TBS ether 16 prior to the formation of the
homoallylic (C(4)) methyl ether. This sequence provided a 16:1
mixture of regioisomeric products, with the minor product
resulting from 1,2-migration of the TBS group during the
methylation step. Stereoselective epoxidation of 17 using
dimethyl dioxirane (DMDO)17 followed by treatment with
thiophenol in the presence of K2CO3 and 18-crown-6 afforded
the â-thioglycoside 18.18 A small amount of 1,2-migration of
the TBS group was observed in this step. Protection of the
secondary alcohol of 18 produced the thioglycoside donor 8 in
99% yield.
Synthesis of Bromodienoate 7. Bromodienoate 7 was
synthesized by using minor modifications of Nicolaou’s syn-
thesis of this intermediate (Scheme 4).2c Thus, the known allylic
alcohol 20 (which was synthesized from methyl methacrylate
via bromination and subsequent LiAlH4 reduction)19 was
oxidized using MnO2 in the presence of stabilized ylid 21, which
provided 7 in 97% yield.20 Although Wittig reagent 21 is known,
it is not available commercially. Attempts to synthesize 21 by
using literature procedures invariably provided the ylid in low
yield.21 However, when the reaction of methyl R-bromopropi-
onate 22 with triphenylphosphine was performed in water at
70 °C, followed by addition of aqueous NaOH to the aqueous
suspension of phosphonium salt 23, the targeted ylid 21 was
obtained in 95% yield.
Synthesis of the C(1)-C(11) Fragment 1 of Apoptolidin
A. The C(1)-C(11) fragment 1 was assembled from building
blocks 7, 8, and 9 as summarized in Scheme 5. The glycosi-
dation of 8 and 9 was performed using NIS activation of 8 in
the presence of TfOH.22 The choice of solvent was quite critical
to the success of this glycosidation. When CH2Cl2 was used as
the solvent, a 3:1 ratio of R- and â-glycosides was obtained
with 24 as the major isomer, whereas no reaction occurred in
Et2O. However, a significant increase in stereoselectivity (R:â
) 8:1) was observed when the reaction was performed in
toluene. The diastereomeric glycosides were inseparable via
column chromatography; however, the anomers were separable
following deprotection of the PMB ether.23 In this way,
diastereomerically pure 25 was obtained following chromato-
graphic purification.
(15) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738. (b) Haack, K.-J.; Hashiguchi, S.; Fujii, A.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 285.
(16) Renneberg, B.; Li, Y.-M.; Laatsch, H.; Fiebig, H.-H. Carbohydr.
Res. 2000, 329, 861.
(17) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(b) Murray, R. W.; Singh, M. Organic Syntheses; Wiley: New York, 1998;
Collect. Vol. IX, p 288. (c) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem.
Soc. 1989, 111, 6661.
Oxidation of the primary hydroxyl group of 25 with the
(21) Elemes, Y.; Foote, C. S. J. Am. Chem. Soc. 1992, 114, 6044.
(22) (a) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H.
Tetrahedron Lett. 1990, 31, 1331. (b) Konradsson, P.; Udodong, U. E.;
Fraser-Reid, B. Tetrahedron Lett. 1990, 31, 4313.
(23) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(18) Gordon, D. M.; Danishefsky, S. J. Carbohydr. Res. 1990, 206, 361.
(19) Dzierba, C. D.; Zandi, K. S.; Mo¨llers, T.; Shea, K. J. J. Am. Chem.
Soc. 1996, 118, 4711.
(20) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815.
J. Org. Chem, Vol. 73, No. 3, 2008 1033

Handa et al.
Dess-Martin periodinane24 proceeded uneventfully and gave
the corresponding aldehyde, which was then subjected to
Corey-Fuchs dibromoolefination, in the presence of Zn metal,
which gave the dibromoolefin 26 in excellent yield.25 If the zinc
metal was omitted from this reaction, cleavage of the glycoside
bond was observed.26 Subsequent treatment of 26 with various
alkyllithium reagents including n-BuLi, in attempts to generate
the internal alkyne, led to a complex mixture or partially
epimerized products. Fortunately, use of an excess of LDA as
the base, a little used but known procedure for this conversion,27
followed by addition of methyl iodide converted 26 to the
methylated alkyne 6 in excellent yield.
Summary. An efficient and highly stereoselective synthesis
of 1 corresponding to the C(1)-C(11) fragment of apoptolidin
A has been completed. Key transformations of this synthesis
include the early stage stereoselective glycosidation of 9, the
use of LDA for the reductive elimination and methylation of
dibromoolefin 26 to give dialkyne 6, and the use of diisopi-
nocampheylborane as the hydroborating agent in the cross-
coupling of intermediates 6 and 7. Continued advancement of
these intermediates toward completion of a total synthesis of
apoptolidin A will be reported in due course.
Experimental Section34
The final key sequence in the synthesis of the apoptolidin
C(1)-C(11) fragment 1 is the reductive coupling of diacetylene
6 and bromodienoate 7. Attempted hydrostannylation of 6 using
n-Bu3SnH in the presence of a Pd catalyst [Pd(OAc)2-Chx3P,
(o-tol3P)2PdCl2, and (PPh3)2PdCl2 were tried]28 resulted in poor
regio- and stereoselectivity and low yields of the targeted
vinylstannane intermediate. Further, hydroboration of 6 using
pinacol borane, and catechol borane with a catalytic amount of
dicyclohexylborane also afforded unsatisfactory results.29 Treat-
ment of 6 with stoichiometric dicyclohexylborane led to
complete consumption of 6. The resultant dialkylvinylborane
was then directly subjected to Suzuki cross-coupling conditions
withbromodienoate7inthepresenceofTlOEtandPd(PPh3)4.30-32
This one-pot sequence provided the coupled product in 64%
yield as a ca. 2:1 mixture of regioisomers with the major isomer
being identified as 27. Although the alkynyl-TBS group proved
to be effective in protecting the C(10)-alkyne from undergoing
hydroboration with dicyclohexylborane, the regiochemistry of
the hydroboration of the less hindered C(6,7)-alkyne was poor.
Fortunately, treatment of 6 with the much more hindered
hydroborating agent33 lIpc2BH in THF at 0 °C followed by
addition of bromodienoate 7, Pd(PPh3)4, and TlOEt provided
the targeted cross-coupling product 27 in 83% yield with
significantly improved regioselectivity (>95:5).31,32 To the best
of our knowledge, use of di(isopinocampheyl)vinylboranes as
substrates for Suzuki cross-coupling reactions has not been
documented previously, although Suzuki reactions of other
vinyldialkylboranes are well-known.30 Finally, the acetylenic
TBS group was selectively removed by treatment of 27 with
TBAF in THF at 0 °C to afford the apoptolidin C(1)-C(11)
fragment 1.
(2R,3S,4R,5S,6S)-2-{(1S,2R)-1-[(tert-Butyl-dimethyl-silanyl)-
ethynyl]-2-methyl-pent-3-ynyloxy}-3,4-bis(tert-butyl-dimethyl-
silanyloxy)-5-methoxy-6-methyl-tetrahydro-pyran (6). To a so-
lution of diisopropylamine (1.22 mL, 8.72 mmol) in THF (43.6
mL) was added n-butyllithium in hexane (3.49 mL, 8.72 mmol,
2.5 M) at -20 °C. The resultant mixture was stirred for 20 min
and then cooled to -78 °C. Dibromoolefin 26 (672 mg, 872 µmol)
in THF (43.6 mL) was added, the mixture was stirred for 2 h at
-78 °C, and then iodomethane (1.09 mL, 17.4 mmol) was added.
The reaction mixture was allowed to warm to room temperature
gradually and stirred for 60 h. The mixture was then diluted with
saturated aqueous NH4Cl and extracted with Et2O. The organic
extracts were washed with brine, dried, and concentrated. The crude
product was purified by flash chromatography (hexane/EtOAc )
80:1 to 70:1) to give diacetylene 6 (498 mg, 798 µmol, 91%) as a
1
colorless solid: [R]23 ) -71.9° (c 1.24, CHCl3); mp 65 °C; H
D
NMR (400 MHz, CDCl3) δ 5.07 (d, J ) 3.4 Hz, 1H), 4.21 (d, J )
6.0 Hz, 1H), 3.80 (t, J ) 8.9 Hz, 1H), 3.64 (dq, J ) 9.7, 6.2 Hz,
1H), 3.56 (dd, J ) 9.1, 3.4 Hz, 1H), 3.46 (s, 3H), 2.72 (m, 1H),
2.64 (dd, J ) 9.2, 9.1 Hz, 1H), 1.76 (d, J ) 2.3 Hz, 3H), 1.26 (d,
J ) 6.6 Hz, 6H), 0.93 (s, 9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.11 (s,
3H), 0.10 (s, 6H), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
102.7, 95.2, 90.2, 87.2, 80.3, 77.4, 74.1, 73.7, 67.5, 67.4, 61.1, 32.3,
26.5 (3C), 26.3 (3C), 26.0 (3C), 18.2, 18.1 (2C), 16.9, 16.5, 3.42,
-3.26, -3.53, -3.80, -4.20, -4.66, -4.67; IR (neat) 2928, 2175,
1461, 1249, 1106, 1031, 836, 772, 673 cm-1; HRMS (ES+) m/z
for C33H64NaO5Si3 [M + Na]+ calcd 647.3959, found 647.3954.
(2E,4E,6E)-(8R,9S)-9-[(2R,3S,4R,5S,6S)-3,4-Bis(tert-butyl-
dimethyl-silanyloxy)-5-methoxy-6-methyl-tetrahydro-pyran-2-
yloxy]-11-(tert-butyl-dimethyl-silanyl)-2,4,6,8-tetramethyl-undeca-
2,4,6-trien-10-ynoic Acid Methyl Ester (27). In a glove box
lIpc2BH (21.1 mg, 74.0 µmol) was weighed into a round-bottom
flask containing a stir bar. The flask was capped with a rubber
septum, removed from the glove box, and placed in an ice bath.
To the flask was added diacetylene 6 (23.1 mg, 37.0 µmol) in THF
(500 µL), the mixture was stirred for 35 min at 0 °C, and then
methanol (6 µL) was added. After 2 h, to the resultant mixture
was added bromodienoate 7 (16.2 mg, 74.0 µmol) in THF (2.3 mL),
and the flask was allowed to warm to room temperature. To the
mixture were added Pd(PPh3)4 (4.2 mg, 3.70 µmol) and TlOEt (36.9
mg, 148 µmol) in H2O (900 µL). The reaction mixture was stirred
for 10 min at ambient temperature, and then the mixture was diluted
with 1 M aqueous NaHSO4. The mixture was filtered and extracted
with Et2O. The organic extracts were washed with brine, dried,
and concentrated. The crude product was purified by flash chro-
matography (first, hexane/EtOAc ) 30:1; second, hexane/EtOAc
) 60:1 to 40:1) to give the coupling product 27 (23.5 mg, 30.7
µmol, 83%) as a colorless syrup: [R]22D ) -58.2° (c 1.90, CHCl3);
(24) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(25) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(26) Wagner, A.; Heitz, M.-P.; Mioskowski, C. Tetrahedron Lett. 1989,
30, 557.
(27) (a) Suzuki, K.; Tomooka, K.; Katayama, E.; Matsumoto, T.;
Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 5221. (b) Simpkins, S. M.
E.; Kariuki, B. M.; Arico´, C. S.; Cox, L. R. Org. Lett. 2003, 5, 3971.
(28) (a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100,
3257. (b) Durham, T. B.; Blanchard, N.; Savall, B. M.; Powell, N. A.; Roush,
W. R. J. Am. Chem. Soc. 2004, 126, 9307. (c) Semmelhack, M. F.; Hooley,
R. J. Tetrahedron Lett. 2003, 44, 5737.
(29) (a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992,
57, 3482. (b) Arase, A.; Hoshi, M.; Mijin, A.; Nishi, K. Synth. Commun.
1995, 25, 1957.
(30) Reviews of the Suzuki reaction: (a) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(31) Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem.
Soc. 1987, 109, 4756.
(34) The spectroscopic and physical properties (e.g., 1H NMR, 13C NMR,
IR, mass spectrum, and/or C, H analysis) of all new compounds were fully
consistent with the assigned structures. Yields refer to chromatographically
and spectroscopically homogeneous materials (unless noted otherwise).
Experimental procedures and tabulated spectroscopic data for other new
compounds are provided in the Supporting Information.
(32) Frank, S. A.; Chen, H.; Kunz, R. K.; Schnaderbeck, M. J.; Roush,
W. R. Org. Lett. 2000, 2, 2691.
(33) Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki, A. Synth.
Commun. 1993, 23, 2851.
1034 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of the C(1)-C(11) Segment of Apoptolidin A
1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 5.98 (s, 1H), 5.41 (d,
J ) 9.6 Hz, 1H), 5.07 (d, J ) 3.3 Hz, 1H), 4.20 (d, J ) 5.4 Hz,
1H), 3.76 (m, 1H), 3.76 (s, 3H), 3.55 (dd, J ) 9.1, 3.3 Hz, 1H),
3.49 (dq, J ) 9.5, 6.2 Hz, 1H), 3.47 (s, 3H), 2.84 (m, 1H), 2.65
(dd, J ) 9.2, 9.0 Hz, 1H), 2.02 (s, 3H), 2.00 (s, 3H), 1.82 (s, 3H),
1.27 (d, J ) 6.2 Hz, 3H), 1.12 (d, J ) 6.8 Hz, 3H), 0.92 (s, 9H),
0.90 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 9H),
0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.7, 144.3, 138.7,
133.7, 132.9, 131.5, 125.4, 102.6, 95.3, 90.4, 87.2, 74.0, 73.8, 68.7,
67.5, 61.2, 51.9, 37.9, 26.5 (3C), 26.3 (3C), 26.1 (3C), 18.7, 18.3,
18.1, 18.0, 17.6, 17.2, 16.5, 14.2, -3.25, -3.49, -3.82, -4.15,
-4.60 (2C); IR (neat) 2931, 2170, 1713, 1463, 1254, 1107, 1026,
839, 775 cm-1; HRMS (ES+) m/z for C41H76NaO7Si3 [M + Na]+
calcd 787.4797, found 787.4813.
CDCl3) δ 7.16 (s, 1H), 6.01 (s, 1H), 5.40 (d, J ) 9.5 Hz, 1H), 5.07
(d, J ) 3.3 Hz, 1H), 4.21 (dd, J ) 5.3, 2.0 Hz, 1H), 3.76 (s, 3H),
3.76 (m, 1H), 3.55 (dd, J ) 9.1, 3.4 Hz, 1H), 3.50 (m, 1H), 3.47
(s, 3H), 2.86 (m, 1H), 2.66 (t, J ) 9.1 Hz, 1H), 2.37 (d, J ) 2.0
Hz, 1H), 2.03 (d, J ) 1.1 Hz, 3H), 2.01 (s, 3H), 1.82 (s, 3H), 1.26
(d, J ) 6.2 Hz, 3H), 1.13 (d, J ) 6.8 Hz, 3H), 0.92 (s, 9H), 0.89
(s, 9H), 0.10 (s, 3H), 0.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
169.7, 144.2, 138.8, 133.3, 133.0, 131.8, 125.5, 95.4, 87.2, 80.4,
75.4, 73.9, 73.7, 68.3, 67.7, 61.2, 51.9, 37.6, 26.4 (6C), 18.5, 18.3,
18.2, 18.0, 17.5, 16.9, 14.1, -3.25, -3.60, -4.12, -4.14; IR (neat)
3309, 2931, 1712, 1462, 1254, 1107, 1034, 839, 758 cm-1; HRMS
(ES+) m/z for C35H62NaO7Si2 [M + Na]+ calcd 673.3932, found
673.3939.
(2E,4E,6E)-(8R,9S)-9-[(2R,3S,4R,5S,6S)-3,4-Bis(tert-butyl-
dimethyl-silanyloxy)-5-methoxy-6-methyl-tetrahydro-pyran-2-
yloxy]-2,4,6,8-tetramethyl-undeca-2,4,6-trien-10-ynoic Acid Meth-
yl Ester (1). To a solution of 27 (20.6 mg, 26.9 µmol) in THF
(1.35 mL) was added tetrabutylammonium fluoride in THF (40 µL,
40.4 µmol, 1.0 M) at 0 °C. The resulting mixture was stirred for
10 min at 0 °C, and then H2O was added. The mixture was diluted
with Et2O, and the organic phase was washed with brine, dried,
and concentrated. The crude product was purified by flash chro-
matography (hexane/EtOAc ) 30:1 to 20:1) to give the apoptolidin
Acknowledgment. Financial support by the National Insti-
tutes of Health (GM038436) is gratefully acknowledged. M.H.
thanks the Uehara Memorial Foundation for a postdoctoral
fellowship, and M.B. thanks the Swiss National Science
Foundation for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures
and full spectroscopic data for additional new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
C(1)-C(11) fragment 1 (16.9 mg, 26 µmol, 96%) as a colorless
1
syrup: [R]23 ) -41.6° (c 0.38, CHCl3); H NMR (400 MHz,
JO702250Z
D
J. Org. Chem, Vol. 73, No. 3, 2008 1035