Studies on the synthesis of apoptolidin A. 2. Synthesis of the disaccharide unit

Article abstract of DOI:10.1021/jo7022526

(Chemical Equation Presented) Disaccharide 3 corresponding to the disaccharide unit of apoptolidin A has been synthesized via the regio- and stereoselective TBS-OTf-promoted β-glycosidation reaction of 2,6-dideoxy-2-iodo-β-glucopyranosyl acetate (5) and p

Full text of DOI:10.1021/jo7022526

Studies on the Synthesis of Apoptolidin A. 2. Synthesis of the
Disaccharide Unit
Masaki Handa,† William J. Smith, III,‡ 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
Disaccharide 3 correspoinding to the disaccharide unit of apoptolidin A has been synthesized via the
regio- and stereoselective TBS-OTf-promoted â-glycosidation reaction of 2,6-dideoxy-2-iodo-â-glucopy-
ranosyl acetate (5) and p-methoxybenzyl 2,6-dideoxy-2-iodo-3-C-methyl-R-mannopyranoside (11).
Introduction
As part of our efforts to complete a total synthesis of
apoptolidin A,9 we have developed and report herein a synthesis
of disaccharide 3, which we envisage will serve as the glycosyl
Apoptolidin A is a potent and specific inhibitor of the
mitochondrial F0F1-ATPase and is also able to induce apoptosis
in cells transformed with the adenovirus E1A oncogene.1 It ranks
among the top 0.1% of the most selective cell line cytotoxic
agents known and accordingly has attracted considerable interest
as a target for total synthesis and analog development.2 Several
groups have reported synthetic studies directed toward apop-
tolidin, the aglycone apoptolidinone, and its disaccharide
moiety.3,4 Total syntheses of apoptolidin A have been reported
by the Nicolaou5 and Koert6 groups. The aglycone, apoptoli-
dinone, has been synthesized by Koert,6 Sulikowski,7 and
Crimmins.8
(3) 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.
(4) Crimmins, M. T.; Long, A. Org. Lett. 2005, 7, 4157.
(5) (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.
(6) (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.
† 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.
(2) For structure activity studies of apoptolidin: (a) Salomon, A. R.;
Zhang, Y.; Seto, H.; Khosla, C. Org. Lett. 2001, 3, 57. (b) Wender, P. A.;
Jankowski, O. D.; Tabet, E. A.; Seto, H. Org. Lett. 2003, 5, 487. (c) Wender,
P. A.; Gulledge, A. V.; Jankowski, O. D.; Seto, H. Org. Lett. 2002, 4, 3819.
(d) Wender, P. A.; Jankowski, O. D.; Longcore, K.; Tabet, E. A.; Seto, H.;
Tomikawa, T. Org. Lett. 2006, 8, 589. (e) Wender, P. A.; Longcore, K. E.
Org. Lett. 2007, 9, 691.
10.1021/jo7022526 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/29/2007
1036
J. Org. Chem. 2008, 73, 1036-1039

Synthesis of the Disaccharide Unit of Apoptolidin A
SCHEME 1. Global Retrosynthetic Analysis of Apoptolidin A
SCHEME 2. Retrosynthetic Analysis of Disaccharide 3
donor for glycosidation of late stage intermediates en route to
completion of a total synthesis of apoptolidin A (Scheme 1).
4); glycosidation of very hindered secondary alcohols with
donors such as 5 have not yet been studied.
Strategy for Synthesis of Disaccharide 3
Results and Discussion
Disaccharide 3 contains a â-glycoside linkage and logically
disconnects into the precursor fragments 3-C-methyl-L-rhamnal
(4) and di-O-acetyl-D-rhamnal (6) (Scheme 2). We have
previously reported highly stereoselective syntheses of 2-deoxy-
â-glycosides,10-12 as well as 2-deoxy-R-glycosides,13,14 via the
TMS-OTf or TBS-OTf promoted glycosidation reactions of
2-deoxy-2-iodo-pyranosyl acetates10,13,14 and 2-deoxy-2-iodo-
pyranosyl trichloroacetimidates11 or the stannous chloride-silver
perchlorate promoted glycosidations of 2-deoxy-2-iodo-pyra-
nosyl fluorides.12 In this chemistry, an equatorial C(2)-iodide
on the glycoside donor directs the glycosidation with alcohols
to give the â-glycosidic linkage,10-12 whereas an axial C(2)-
iodide in the donor directs the glycosidation into the R-glycoside
product manifold.13,14 Thus, for the synthesis of 3, it is necessary
that di-O-acetyl-D-rhamnal (6) be functionalized with a C(2)-
equatorial iodide, as in 5. An axial C(2)-iodo unit is required
in the olivomycose unit of 3 (i.e., the residue deriving from
3-C-methyl-L-rhamnal, 4), since the glycosidic linkage between
the disaccharide and C(27)-OH of apoptolidinone is of the
R-configuration. The proposed coupling of 4 and 5 constitutes
a demanding application of the 2-deoxy-2-iodo-glycosidation
technology yet studied, owing to the very hindered nature of
the secondary hydroxyl group of the olivomycose unit (e.g.,
Synthesis of the suitably protected rhamnal derivative 8,
which we targeted as a precursor to the 2-iodo-rhamnosyl donor
5, commenced from the known diacetyl rhamnal 6, which was
prepared by Torii’s procedure.15 Deprotection of 6 using NaOMe
in MeOH followed by selective protection of the C(3)-OH and
silylation of C(4)-OH provided 7 (Scheme 3). Treatment of 7
with MeLi in THF at -78 °C followed by addition of MeOTf
and Et3N then provided 8.16 Treatment of 8 with N-iodosuc-
cinimide (NIS) and AcOH in toluene gave a mixture of the
2-deoxy-2-iodo- â-gluco (5) and 2-deoxy-2-iodo-R-manno (9)
glycosides in 97% yield but with virtually no diastereoselectivity
(ca. 1:1). It is possible to increase the â selectivity of such
5
reactions if one can access the H4 conformation of the glycal
partner using hindered protective groups such as TBDPS ethers,
as demonstrated by McDonald’s17 and our18 previous studies.
However, use of a TBDPS ether protecting group strategy was
not attractive for the purposes at hand. Fortunately, adding Ti-
(O-iPr)4 to the reaction of 8 with NIS and performing this
experiment at -20 to -30 °C led to a slight increase in reaction
selectivity (5:9 ) 59:41). The undesired R-manno isomer 9
could be effectively recycled to the starting rhamnal 8 by
treatment with LiI in toluene.10
With the glycoside donor 5 in hand, we attempted the
TMSOTf-promoted glycosidation reaction with the known 3-C-
methyl-L-rhamnal 419,20 as the acceptor. Unfortunately, numerous
(7) Wu, B.; Liu, Q.; Sulikowski, G. A. Angew. Chem., Int. Ed. 2004,
43, 6673.
(8) Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am.
Chem. Soc. 2005, 127, 13810.
(9) Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng, N.; Roush, W. R. J.
Org. Chem. 2008, 73, 1031.
(10) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(11) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891.
(12) Blanchard, N.; Roush, W. R. Org. Lett. 2003, 5, 81.
(13) Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993, 264.
(14) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899.
(15) Torii, S.; Inokuchi, T.; Masatsugu, Y. Bull. Chem. Soc. Jpn. 1985,
58, 3629.
(16) Barrett, A. G. M.; Miller, T. A. Tetrahedron Lett. 1988, 29, 1873.
(17) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304.
(18) Chong, P. Y.; Roush, W. R. Org. Lett. 2002, 4, 4523.
(19) Jung, G.; Klemer, A. Chem. Ber. 1981, 114, 740.
(20) Parker, K. A.; Meschwitz, S. M. Carbohydrate Res. 1988, 172, 319.
J. Org. Chem, Vol. 73, No. 3, 2008 1037

Handa et al.
SCHEME 3. Synthesis of Glycoside Donor 5
SCHEME 4. Stereoselective Synthesis of â-Disaccharide 12
SCHEME 5. Synthesis of Activated Disaccharide Donor 3
attempts to accomplish this glycosidation reaction using either
TMS-OTf or TBS-OTf at various temperatures and in the
presence of pyridine as a buffer were unsuccessful. Under all
conditions examined, Ferrier-type decomposition of the acceptor
4 occurred via ionization of the C(3) hydroxyl group, which is
both tertiary and allylic. Therefore, conversion of 4 to a suitably
protected 2,6-dideoxy-2-iodo-R-mannopyranoside was per-
formed prior to the glycosidation. Thus, treatment of 4 with
NIS and p-methoxybenzyl alcohol gave the R-manno glycoside
11 in 63% yield with excellent stereoselectivity (Scheme 4).
Dimers (or high oligomers) that potentially could result via
glycosidation of either of the hydroxyl groups of 4 were not
observed. Treatment of a mixture of donor 5 and acceptor 11
with a catalytic amount of TBS-OTf (0.3 equiv) at 0 °C then
gave the targeted â-disaccharide 12 but in only 12% yield. When
the amount of TBS-OTf was increased to 1.3 equiv, the yield
of 12 improved to 42% but an uncharacterized complex mixture
of other products was also observed. When the amount of TBS-
OTf was decreased to 1.1 or 1.0 equiv, disaccharide 12 was
obtained in 42% and 32% yields, respectively, again with an
uncharacterized mixture of byproducts also obtained. However,
when less than 1.0 equiv of TBS-OTf was used, only 12 and
unreacted starting materials were observed. After careful
optimization of reaction conditions, the optimal procedure was
determined to involve treatment of the mixture of 5 and 11 (1.3
equiv) with 1.0 equiv of TBS-OTf in the presence of 4 Å
molecular sieves at 0 °C for 1 h. Additional TBS-OTf was then
gradually added under careful monitoring until the donor 5 was
consumed. Gratifyingly, disaccharide 12 was obtained in 60%
yield (based on 5) without regio- or stereoisomers.
Finally, conversion of 12 to the activated disaccharide donor
3 was performed by a two-step procedure (Scheme 5). Treatment
of 12 with an excess amount of ceric ammonium nitrate
(CAN),21 followed by chemoselective acetylation of the resulting
pyranose using acetic anhydride and pyridine in the presence
of DMAP then provided the targeted disaccharide donor 3 in
87% yield as a ca. 6:4 mixture of anomeric acetates.
Summary. An efficient and highly â-selective synthesis of
3 corresponding to the disaccharide unit of apoptolidin A has
(21) Jacob, P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N., Jr. J.
Org. Chem. 1976, 41, 3627.
1038 J. Org. Chem., Vol. 73, No. 3, 2008

Synthesis of the Disaccharide Unit of Apoptolidin A
(40.8 mg, 51.5 µmol) in CH3CN (2.2 mL) and H2O (300 µL) was
added cerium ammonium nitrate (282 mg, 515 µmol). The resultant
mixture was stirred for 10 min, cooled to 0 °C, and diluted with
saturated aqueous NaHCO3. The organic layer was extracted with
CHCl3, the combined organic extracts were washed with brine,
dried, and concentrated. The crude product was used in the next
reaction without purification.
been completed. The key step of this synthesis is the regio-
and stereoselective â-glycosidation of the very hindered second-
ary alcohol in 11 using 5 as the glycosyl donor. Continued
advancement of these intermediates toward completion of a total
synthesis of apoptolidin A will be reported in due course.
Experimental Section22
To a solution of the above crude product in pyridine (1.0 mL)
were added DMAP (0.6 mg, 5.15 µmol) and Ac2O (15 µL, 154
µmol) at room temperature. The resultant mixture was stirred for
45 min at ambient temperature, cooled to 0 °C, and diluted with
saturated aqueous NaHCO3. The organic layer was extracted with
EtOAc, washed with brine, dried, and concentrated. The crude
product was purified by flash chromatography (hexane/EtOAc )
30:1 to 10:1) to give the activated glycoside 3 (32.2 mg, 45.1 µmol,
87%) as a colorless foamy solid: [R]24D ) +17.7° (c 1.15, CHCl3);
(2S,3S,4R,5R,6R)-3-[(2S,3R,4S,5R,6R)-5-(tert-Butyl-dimethyl-
silanyloxy)-3-iodo-4-methoxy-6-methyl-tetrahydropyran-2-yloxy]-
5-iodo-6-(4-methoxy-benzyloxy)-2,4-dimethyl-tetrahydropyran-
4-ol (12). A mixture of donor 5 (243 mg, 548 µmol), acceptor 11
(291 mg, 713 µmol), and 4 Å molecular sieves (550 mg) in CH2-
Cl2 (27.4 mL) was stirred for 20 min at room temperature and then
cooled to 0 °C. A solution of TBS-OTf in CH2Cl2 (2.74 mL, 548
µmol, 0.2 M) was added slowly. The resultant mixture was stirred
for 1 h at 0 °C. Additional TBS-OTf in CH2Cl2 (1.09 mL, 219
µmol, 0.2 M) was added portionwise during 1.5 h until the donor
was consumed, and then Et3N (300 µL) was added. The resultant
mixture was stirred for 5 min at 0 °C and filtered. The filtrate was
washed with saturated aqueous NaHCO3 and with brine, dried, and
concentrated. The crude product was purified by flash chromatog-
raphy (hexane/EtOAc ) 40:1 to 20:1) to give the â-disaccharide
1
mp 57-64 °C; H NMR data for R isomer (400 MHz, CDCl3) δ
6.39 (d, J ) 2.2 Hz, 1H), 4.79 (d, J ) 8.9 Hz, 1H), 4.33 (d, J )
2.3 Hz, 1H), 3.90 (dq, J ) 8.6, 6.3 Hz, 1H), 3.71-3.80 (m, 2H),
3.60 (s, 3H), 3.32 (m, 1H), 3.17-3.27 (m, 2H), 2.63 (s, 1H), 2.09
(s, 3H), 1.74 (s, 3H), 1.33 (d, J ) 6.2 Hz, 3H), 1.25 (d, J ) 6.1
Hz, 3H), 0.90 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR data
for R isomer (100 MHz, CDCl3) δ 168.6, 103.3, 95.6, 87.5, 82.3,
77.4, 72.6, 72.4, 70.8, 61.2, 41.1, 33.7, 25.8 (3C), 22.9, 21.1, 18.2,
12 (262 mg, 331 µmol, 60%) as a colorless foamy solid: [R]23
)
D
1
1
17.9 (2C), -4.08, -4.11; H NMR data for â isomer (400 MHz,
-15.1° (c 1.18, CHCl3); mp 45 °C; H NMR (400 MHz, CDCl3)
δ 7.24 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 5.31 (s, 1H),
4.79 (d, J ) 8.9 Hz, 1H), 4.61 (d, J ) 11.4 Hz, 1H), 4.41 (d, J )
11.4 Hz, 1H), 4.32 (s, 1H), 3.80 (s, 3H), 3.78 (m, 1H), 3.75 (m,
1H), 3.68 (d, J ) 9.1 Hz, 1H), 3.59 (s, 3H), 3.32 (m, 1H), 3.17-
3.26 (m, 2H), 2.66 (brs, 1H), 1.75 (s, 3H), 1.28 (d, J ) 6.2 Hz,
3H), 1.26 (d, J ) 6.1 Hz, 3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.09 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 129.5 (2C), 129.3, 113.8
(2C), 103.3, 101.8, 87.6, 83.0, 77.5, 72.6, 72.5, 69.4, 68.0, 61.2,
55.2, 43.2, 33.7, 25.8 (3C), 22.9, 18.3, 17.9 (2C), -4.09, -4.12;
IR (neat) 3522, 2931, 1613, 1514, 1462, 1381, 1248, 1084, 1006,
863, 836, 776, 708 cm-1; HRMS (ES+) m/z for C28H46I2NaO8Si
[M + Na]+ calcd 815.0949, found 815.0977.
CDCl3) δ 4.99 (d, J ) 1.6 Hz, 1H), 4.83 (d, J ) 8.9 Hz, 1H), 4.41
(d, J ) 1.5 Hz, 1H), 3.71-3.80 (m, 2H), 3.60 (s, 3H), 3.56 (m,
1H), 3.32 (m, 1H), 3.17-3.27 (m, 2H), 2.75 (s, 1H), 2.15 (s, 3H),
1.73 (s, 3H), 1.34 (d, J ) 6.1 Hz, 3H), 1.24 (d, J ) 6.1 Hz, 3H),
0.90 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR data for â isomer
(100 MHz, CDCl3) δ 168.7, 103.1, 90.2, 87.5, 82.6, 77.4, 72.8,
72.6, 72.4, 61.2, 47.2, 33.7, 25.8 (3C), 21.1, 21.0, 18.4, 17.9 (2C),
-4.08, -4.11; IR (neat) 3516, 2932, 1747, 1378, 1205, 1080, 1047,
1006, 930, 862, 836, 776, 708 cm-1; HRMS (ES+) m/z for C22H40I2-
NaO8Si [M + Na]+ calcd 737.0480, found 737.0504.
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.
Acetic Acid (2,3R,4R,5S,6S)-5-[(2S,3R,4S,5R,6R)-5-(tert-Butyl-
dimethyl-silanyloxy)-3-iodo-4-methoxy-6-methyl- tetrahydro-
pyran-2-yloxy]-4-hydroxy-3-iodo-4,6-dimethyl-tetrahydropyran-
2-yl Ester (3). To a room-temperature mixture of dissacharide 12
Supporting Information Available: Experimental procedures
for synthesis of 5 and 11, and full spectroscopic data for additional
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) 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 Supporting Information.
JO7022526
J. Org. Chem, Vol. 73, No. 3, 2008 1039