Total synthesis of apoptolidin: Part 2. Coupling of key building blocks and completion of the synthesis

Article abstract of DOI:10.1002/1521-3773(20011015)40:20<3854::AID-ANIE3854>3.0.CO;2-D

No less than 30 stereogenic elements, a highly unsaturated 20-membered macrocyclic system, four carbohydrate units, and unique biological activity, make the natural occurring apoptolidin (1) a challenging synthetic target. The retrosynthetic analysis reve

Full text of DOI:10.1002/1521-3773(20011015)40:20<3854::AID-ANIE3854>3.0.CO;2-D

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[25] K. C. Nicolaou, T. Ladduwahetty, J. L. Randall, A. Chucholowski, J.
Am. Chem. Soc. 1986, 108, 2466 ± 2467.
[26] K. C. Nicolaou, R. M. Rodriguez, H. J. Mitchell, H. Suzuki, K. C.
Fylaktakidou, O. Baudoin, F. L. van Delft, Chem. Eur. J. 2000, 6,
3095 ± 3115.
[27] This lower than expected yield was due to participation of the tertiary
C3 hydroxy group of 63 (despite its hindered nature) in the
glycosidation reaction leading to considerable amounts of the 3-O-
glycoside (ca. 26%).
According to the strategy delineated in the preceding
paper,[1] the first objective was the coupling of dithiane 2
(C21 ± C28 fragment) with aldehyde 3 (C12 ± C20 fragment),
a task that was accomplished as shown in Scheme 1. Thus,
generation of the anion from 2 followed by addition of
aldehyde 3 resulted in the formation of coupling products 4a
and 4b as a ca. 1.5:1 mixture of diastereoisomers at C20. Since
we had no direct way of knowing the stereochemistry of the
newly formed stereocenter, we decided to continue with each
of the two isomers 4a and 4b (after chromatographic
separation) expecting to be able to carry out the necessary
stereochemical assignment, and possibly correct the stereo-
chemistry of the wrong isomer, at a later stage. Thus, the bulky
silyl groups were removed from 4a and 4b (90% yield) to
generate tetraols 5a and 5b, from which the dithiane
protecting group was now easily removed by using PhI(CF3-
Total Synthesis of Apoptolidin: Part 2.
Coupling of Key Building Blocks and
Completion of the Synthesis**
[3]
CO2)2 to afford lactols 6a and 6b. Their resilylation with
TBSOTf in the presence of 2,6-lutidine proceeded smoothly
and regioselectively, and lead to the bis-silyl ethers 7a and 7b
(78% overall yield for two steps).
K. C. Nicolaou,* Yiwei Li,
Konstantina C. Fylaktakidou, Helen J. Mitchell, and
Kazuyuki Sugita
At this stage we attempted to assign the C20 stereo-
chemistry of the two stereoisomers by forming the corre-
sponding carbonates, 8a and 8b (triphosgene, py, 80% yield).
Indeed, NOE studies on 8a and 8b revealed 8a (major) as the
desired stereoisomer (see Scheme 2). Knowing that ways and
means had to be found soon to correct the stereochemistry of
the wrong isomer (7b), we took both compounds, 7a and 7b,
to the next stage. Originally, we envisioned that a methoxy
group at the anomeric center (C21) could allow the imple-
mentation of an oxidation ± reduction protocol for the inver-
sion of the C20 hydroxy group, but we were disappointed to
find out that this rather labile group was removed during the
hydrozirconation step that was required to convert the
acetylenic group to the vinyl iodide (see below). A solution
to this problem was provided by the use of an orthoester as a
protecting group for the C20 ± C21 diol system. Thus, treat-
ment of 7a and 7b with trimethyl orthoacetate in the presence
of PPTS led to orthoesters 9a and 9b (95% yield). Exposure
of 9a (ca. 5:1 mixture of orthoester diastereoisomers) and 9b
(single orthoester stereoisomer) to the hydrozirconation and
Zr± I exchange conditions[4] ([(Cp)2ZrClH]; I2) led to the
corresponding vinyl iodides (10a and 10b) as a ca. 6:1 mixture
with their regioisomers (90% combined yield).
The remarkable collapse of the methyl orthoester to the
methyl glycoside moiety at C21 in this reaction requires a
migration of the methoxy group from the orthoester moiety to
the anomeric position, an event presumably facilitated by the
pyranoside oxygen atom and initial complexation (presum-
ably by zirconium) at the departing orthoester oxygen atom.
The undesired methyl glycoside 10b was then conveniently
converted to the correct C20 stereoisomer (10a) by oxidation
(DMP, 88%) followed by reduction (NaBH4, 90% yield).
Removal of both the PMB and DMB groups from 10a was
achieved by a two-step procedure. Thus, upon exposure of 10a
to excess DDQ, the PMB group was cleaved off while the
DMB moiety at C20 became initially engaged with the free
hydroxy moiety at C21 as a benzylidene group, which finally
broke up as a mixture of C20 and C21 DMB esters. Exposure
of this mixture to LiOH then completed the deprotection
In the preceding communication[1] we described the con-
struction of five building blocks destined to provide the
molecular framework of apoptolidin (1).[2] In this communi-
cation we report the successful coupling of these intermedi-
ates in the proper manner and the completion of the total
synthesis of 1.
[*] Prof. Dr. K. C. Nicolaou, Y. Li, Dr. K. C. Fylaktakidou,
Dr. H. J. Mitchell, Dr. K. Sugita
Department of Chemistry and The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
[**] We thank Dr. C. Khosla and Dr. Y. Hayakawa for generous gifts of
apoptolidin, and Dr. D. H. Huang and Dr. G. Siuzdak for NMR
spectroscopic and mass spectrometric assistance, respectively. This
work was financially supported by the National Institutes of Health
(USA), the Skaggs Institute for Chemical Biology, American Bio-
sciences, a predoctoral fellowship from Boehringer Ingelheim (to
Y.L.), a postdoctoral fellowship the George Hewitt Foundation (to
K.C.F.), and grants from Abbott Laboratories, ArrayBiopharma,
Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche,
Merck, Novartis, Pfizer, and Schering Plough.
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Angew. Chem. Int. Ed. 2001, 40, No. 20

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Scheme 1. Synthesis of vinyliodide 14. a) dithiane 2 (3.0 equiv), tBuLi (2.95 equiv), THF, 788 !508C, 2 h; 3 (1.0 equiv), THF, 1008C, 2 h, 91%, ca. 1.5:1
mixture of diastereoisomers 4a:4b; b) nBu4NF (6.0 equiv), THF, 258C, 12 h, 90%; c) PhI(CF3CO2)2 (1.1 equiv), MeCN/pH 7.0 buffer (3:1), 08C, 5 min;
d) TBSOTf (2.5 equiv), 2,6-lutidine (5.0 equiv), CH2Cl2, 788C, 3 h, 78% over two steps; e) (CCl3O)2CO (5.0 equiv), py (20 equiv), CH2Cl2, 788C, 1 h,
88%; f) (MeO)3CMe (50 equiv), PPTS (0.5 equiv), CH2Cl2, 258C, 12 h, 95%; g) [(Cp)2ZrClH] (3.0 equiv), THF, 658C, 1.5 h; I2 (3.0 equiv), THF, 258C,
2 min, 90%; h) DMP (2.0 equiv), NaHCO3 (20 equiv), CH2Cl2, 08C, 1 h, 88%; i) NaBH4 (5.0 equiv), MeOH, 0 !258C, 4 h, 86%; j) DDQ (4.0 equiv),
CH2Cl2: buffer pH 7.0 (1:1), 0 !258C, 4 h; LiOH (2.0 equiv), MeOH, 258C, 12 h, 85% over two steps; k) (CCl3O)2CO (5.0 equiv), py (20 equiv), CH2Cl2,
788C, 1 h, 88%; l) TESOTf (1.5 equiv), 2,6-lutidine (3.0 equiv), CH2Cl2, 788C, 95%. DMP ˆ Dess ± Martin Periodianane; DMB ˆ 3,4-dimethoxybenzyl;
PPTS ˆ pyridinium p-toluene sulfonate; PMB ˆ p-methoxybenzyl; Tf ˆ trifluoromethane sulfonyl; DDQ ˆ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;
TBS ˆ tert-butyldimethylsilyl; TES ˆ triethylsilyl; py ˆ pyridine.
17[6] which lead to a-glycoside 18 (65% yield). The a
stereochemistry of this glycoside was confirmed by NMR
spectroscopy (J1,2 ˆ 3.5 Hz). Both the carbonate moiety and
methyl ester group were then cleaved from compound 18
upon exposure to KOH in dioxane/H2O at 608C to afford
dihydroxy carboxylic acid 19 (80% yield) which set the stage
for the planned Yamaguchi macrolactonization reaction.[7]
Reasoning that the C19 hydroxy group would be more
accessible than the sterically hindered C20 hydroxy group in
this ring closure, we proceeded to the next step without
protection. Indeed treatment of 19 with excess 2,4,6-trichloro-
benzoyl chloride and triethylamine in THF (0 ! 258C),
followed by addition of the resulting mixed anhydride to
excess 4-DMAP in dilute toluene solution at ambient temper-
ature resulted in the formation of macrolactone 20 in 63%
Scheme 2. NOE experiments with compounds 8a and 8b allowed stereo-
chemical assignment of C20 stereoisomers.
yield (for selected physical properties, see Table 1). The
remaining hydroxy group in 20 (C20) was then protected with
a chloroacetyl group (90% yield) to afford 21, from which the
TES group was selectively removed by exposure to PPTS in
process which lead to diol 12 (85% overall yield from 10a),
whose conversion to carbonate ± TES derivative 14 was
accomplished via 13 (for selected physical properties, see
Table 1) by sequential treatment with triphosgene/pyridine
(89% yield) and TESOTf/2,6-lutidine (95% yield).
With the C12 ± C28 advanced intermediate (14) appropri-
ately functionalized and protected, we then proceeded to
couple it to the vinyl stannane 15 (see Scheme 3). This was
accomplished by a Stille coupling reaction[5] in the presence of
[Pd(CH3CN)2Cl2] in DMF at ambient temperature which
furnished the desired C1 ± C28 segment 16 (86% yield).
Allylic alcohol 16 was then coupled with carbohydrate donor
MeOH at ambient temperature to afford hydroxy compound
22 (80% yield).
The last fragment, glycosyl fluoride 23 carrying the DE
disaccharide domain, was attached to the main frame 22 via
SnCl2-induced coupling to furnish protected apoptolidin 24 in
70% yield (for selected physical properties, see Table 1). The
desired a-glycoside bond in 24 connecting the DE carbohy-
drate domain to the rest of the molecule was formed
exclusively, as indicated by NMR spectroscopy (J1,2
ˆ
3.0 Hz). While intermediate 24 was stable, its global depro-
tection to apoptolidin (1) proved quite challenging due to its
chemical sensitivity. This was finally accomplished by employ-
Angew. Chem. Int. Ed. 2001, 40, No. 20
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Scheme 3. Completion of the total synthesis of apoptolidin (1). a) 15 (4.0 equiv), [Pd(MeCN)2Cl2] (0.05 equiv), DMF, 258C, 15 h, 86%; b) 17 (3.0 equiv),
Tf2O (2.5 equiv), DTBMP (5.0 equiv), Et2O, 788C, 1.5 h, 65%; c) KOH (20 equiv), dioxane/H2O (20:1), 608C, 12 h, 80%; d) 2,4,6-trichlorobenzoyl chloride
(20 equiv), Et3N (40 equiv), THF, 0 !258C, 7 h; 4-DMAP (80 equiv), toluene (0.01 mm), 258C, 12 h, 63%; e) (ClAc)2O (10 equiv), pyridine, 08C, 3 h, 90%;
f) PPTS (0.5 equiv), MeOH, 0 !258C, 15 min, 80%; g) 23 (2.0 equiv), SnCl2 (2.0 equiv), Et2O, 0 8C, 4 h, 70%; h) HF ´ py (50 equiv), THF, 258C, 48 h; Et3N
(100 equiv), MeOH, 258C, 36 h; TsOH (1 equiv), THF/H2O (5:1), 258C, 2.5 h, ca. 30%. 4-DMAP ˆ 4-dimethylaminopyridine; ClAc ˆ chloroacetyl;
DTBMP ˆ 2,6-di-tert-butyl-4-methylpyridine.
ing carefully controlled conditions involving sequential ex-
posure of 24 to HF ´ py in THF at 258C (to remove the silyl
groups), followed by Et3N in methanol (to remove the
chloroacetyl group) and TsOH in THF/H2O at room temper-
ature (to cleave the methyl glycoside) (ca. 30% overall yield
from 24). The chromatographic (TLC, HPLC), spectroscopic
(1H NMR, IR and UV), and high-resolution mass spectro-
metric properties of synthetic apoptolidin (1) matched those
of an authentic sample.[8, 9]
molecule toward a variety of reagents and conditions, the
specific protecting group combinations, and the collapse of
the anomeric orthoester to the corresponding methyl glyco-
side during the hydrozirconation step. Details will be given in
a full account of this work.
Received: August 22, 2001 [Z17774]
[1] K. C. Nicolaou, Y. Li, K. C. Fylaktakidou, H. J. Mitchell, H.-X. Wei, B.
Weyershausen, Angew. Chem. 2001, 113, 3968 ± 3972; Angew. Chem.
Int. Ed. 2001, 40, 3849 ± 3854.
[2] a) J. W. Kim, H. Adachi, K. Shin-ya, Y. Hayakawa, H. Seto, J. Antibiot.
1997, 50, 628 ± 630; b) Y. Hayakawa, J. W. Kim, H. Adachi, K. Shin-ya,
K. Fujita, H. Seto, J. Am. Chem. Soc. 1998, 120, 3524 ± 3525.
The described total synthesis of apoptolidin (1) in its
naturally occurring form is characterized by a highly con-
vergent strategy and considerable flexibility for the construc-
tion of simpler analogues. Of particular importance in this
synthesis are the noted chemical idiosyncrasies of the target
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Table 1. Selected physical properties of compounds 13, 20, and 24.
Carbonate 13: Colorless oil; Rf ˆ 0.20 (silica, 20% EtOAc in hexanes); IR
81.6, 77.7, 76.2, 75.2, 74.2, 73.7, 72.8, 70.9, 69.5, 69.4, 69.1, 68.2, 67.1, 63.9,
61.2, 61.1, 58.9, 47.8, 39.5, 38.7, 38.3, 37.9, 37.7, 36.2, 35.6, 30.4, 28.9, 26.4
(3C), 26.4 (3C), 26.2 (3C), 25.8 (3C), 25.1, 23.7, 23.0, 18.4, 18.3, 18.2, 18.1,
17.7, 16.4, 14.0, 11.7, 7.0, 5.3, 5.2, 3.0, 3.7, 4.1, 4.1, 4.2, 4.5, 4.9;
(thin film): nÄmax ˆ 3530, 2931, 2860, 1807, 1461, 1378, 1255, 1073, 832,
1
707 cm
;
1H NMR (600 MHz, CDCl3): d ˆ 6.15 (dd, J ˆ 3.9, 3.9 Hz, 1H,
H-13), 4.98 ± 4.92 (m, 1H, H-19), 4.33 (d, J ˆ 4.9 Hz, 1H, H-20), 4.06 (bd,
J ˆ 10.9 Hz, 1H, H-25), 4.01 ± 3.92 (m, 1H, H-27), 3.90 ± 3.79 (m, 1H,
H-16), 3.77 (dd, J ˆ 10.3, 4.6 Hz, 1H, H-23), 3.47 ± 3.34 (m, 2H, H-28,
H-17), 3.41 (s, 3H, OMe), 3.40 (s, 3H, OMe), 3.28 (s, 3H, OMe), 3.22 (dd,
J ˆ 8.6, 8.6 Hz, 1H, H-28), 2.37 (s, 3H, Me-12), 2.26 ± 2.17 (m, 1H, H-14),
2.10 ± 1.91 (m, 4H, H-22, H-18, H-15, H-14), 1.75 ± 1.67 (m, 1H, H-24),
1.66 ± 1.56 (m, 2H, H-26, H-18), 1.39 ± 1.20 (m, 2H, H-26, H-15), 0.99 (d,
J ˆ 6.5 Hz, 3H, Me-22), 0.89 (bs, 18H, tBuSi), 0.85 (d, J ˆ 7.0 Hz, 3H, Me-
24), 0.10, 0.08, 0.06, 0.03 (4 Â s, 4 Â 3H, MeSi); 13C NMR (150 MHz,
CDCl3): d ˆ 153.9, 140.7, 100.0, 93.9, 81.0, 79.3, 77.3, 75.2, 73.2, 70.0, 67.6,
66.8, 59.2, 58.5, 48.7, 39.3, 36.1, 35.4, 34.5, 30.3, 29.9, 27.5, 25.9 (6C), 18.1,
18.0, 11.6, 5.0, 4.2, 4.3, 4.7, 4.8; HRMS (MALDI-FT-MS): calcd for
‡
MS (ESI), calcd for C75H144O15Si5Na [M‡Na ]: 1448, found 1448
Fully protected apoptolidin 24: Colorless oil; Rf ˆ 0.19 (silica, 10% EtOAc
in hexanes); [a]D20
1737, 1707, 1455, 1378, 1249, 1096, 1020, 861, 832, 773, 732, 673 cm
ˆ
0.35 (c ˆ 0.02, CHCl3); IR (thin film): nÄmax ˆ 2931,
1
;
1H NMR (600 MHz, CDCl3): d ˆ 7.05 (s, 1H, H-3), 6.08 (d, J ˆ 15.8 Hz, 1H,
H-11), 6.01 (s, 1H, H-5), 5.47 ± 5.40 (m, 2H, H-13, H-19), 5.10 ± 5.03 (m, 2H,
H-10, H-7), 4.98 (d, J ˆ 7.4 Hz, 1H, H-20), 4.86 (d, J ˆ 3.0 Hz, 1H, H-1''),
4.76 (d, J ˆ 3.5 Hz, 1H, H-1'), 4.75 (dd, J ˆ 8.8, 1.8 Hz, 1H, H-1'''), 4.31 ±
4.27 (m, 1H, H-27), 4.11 ± 4.08 (m, 1H, H-25), 3.97, 3.80 (AB, J ˆ 14.9 Hz,
2H, ClCH2CO), 3.85 ± 3.78 (m, 2H, H-3', H-28), 3.77 ± 3.71 (m, 4H, H-9,
H-16, H-23, H-5''), 3.51 ± 3.42 (m, 3H, H-28, H-2', H-5'), 3.47 (s, 3H, OMe-
4'), 3.35 (s, 3H, OMe-17), 3.32 (s, 3H, OMe-28), 3.28 (s, 3H, OMe-21), 3.27
(s, 3H, OMe-3'''), 3.35 ± 3.28 (m, 1H, H-4''), 3.15 ± 3.05 (m, 2H, H-4''',
H-5'''), 3.00 ± 2.85 (m, 1H, H-3'''), 2.71 ± 2.60 (m, 3H, H-4', H-8, H-17),
2.40 ± 2.32 (m, 2H, H-2''', H-18), 2.08 (s, 3H, Me-4), 2.04 (s, 3H, Me-2),
2.07 ± 2.01 (m, 1H, H-22), 1.97 ± 1.87 (m, 1H, H-2''), 1.82 (s, 3H, Me-6),
1.82 ± 1.61 (m, 6H, H-15, H-14, H-18, H-24, H-26, H-2''), 1.54 (s, 3H, Me-
12), 1.47 ± 1.34 (m, 3H, H-26, H-14, H-15), 1.39 (s, 3H, Me-3''), 1.35 ± 1.20
(m, 10H, H-2''', Me-6''', Me-6'', Me-6'), 1.10 (d, J ˆ 6.6 Hz, 3H, Me-8), 1.03
(d, J ˆ 6.5 Hz, 3H, Me-22), 0.98 ± 0.85 (m, 57H, CH3CH2Si, tBuSi, Me-24),
0.64 ± 0.54 (m, 6H, CH2Si), 0.12, 0.10, 0.06, 0.06, 0.05, 0.05, 0.05, 0.03, 0.00,
0.01 (10  s, 10  3H, MeSi); 13C NMR (150 MHz, CDCl3): d ˆ 168.2,
166.5, 145.9, 144.8, 141.1, 140.1, 132.8, 132.4, 131.8, 131.5, 124.9, 122.5, 101.0,
101.0, 96.7, 95.1, 87.6, 85.7, 82.9, 82.3, 81.4, 81.0, 78.3, 76.0, 75.33, 75.26, 74.8,
74.4, 74.1, 73.7, 73.0, 72.8, 72.5, 69.5, 68.8, 67.1, 66.3, 61.23, 61.16, 59.1, 56.0,
47.8, 45.1, 43.2, 40.8, 39.2, 37.9, 36.3, 35.7, 35.6, 35.4, 35.0, 30.6, 26.41 (3C),
26.39 (3C), 26.1 (3C), 26.0 (3C), 25.8 (3C), 23.4, 23.1, 19.2, 18.5, 18.39,
18.37, 18.2, 18.09, 18.05, 17.7, 16.3, 15.3, 14.2, 13.9, 13.7, 7.1, 6.95, 6.85, 6.6,
3.0, 3.7, 3.9, 4.0, 4.1, 4.2, 4.2, 4.5, 4.8, 4.8; HRMS
‡
C36H69IO10Si2Na [M‡Na ]: 867.3366, found 867.3344
Macrolactone 20: Colorless oil; Rf ˆ 0.54 (silica, 30% Et2O in hexanes);
[a]2D2
ˆ
1.4 (c ˆ 0.05, CHCl3); IR (thin film): nÄmax ˆ 2934, 2856, 1722, 1700,
1
1459, 1380, 1246, 1095, 1072, 1027, 831, 775 cm
;
1H NMR (600 MHz,
CDCl3): d ˆ 7.12 (s, 1H, H-3), 6.09 (d, J ˆ 15.8 Hz, 1H, H-11), 6.04 (s, 1H,
H-5), 5.47 ± 5.46 (m, 2H, H-13, H-19), 5.10 (dd, J ˆ 15.8, 9.2 Hz, 1H, H-10),
5.07 (d, J ˆ 8.8 Hz, 1H, H-7), 4.79 (d, J ˆ 3.5 Hz, 1H, H-1'), 3.96 ± 3.92 (m,
1H, H-27), 3.86 ± 3.82 (m, 1H, H-25), 3.83 (dd, J ˆ 8.8, 8.8 Hz, 1H, H-3'),
3.77 ± 3.71 (m, 3H, H-9, H-16, H-23), 3.60 (bd, J ˆ 4.4 Hz, 1H, H-20), 3.51
(dd, J ˆ 9.2, 3.5 Hz, 1H, H-2'), 3.50 (s, 3H, OMe-4'), 3.41 (s, 3H, OMe-17),
3.37 (dd, J ˆ 9.7, 4.0 Hz, 1H, H-5'), 3.35 (s, 3H, OMe-28), 3.31 (dd, J ˆ 4.9,
1.3 Hz, 1H, H-28), 3.29 (d, J ˆ 5.7 Hz, 1H, H-28), 3.25 (s, 3H, OMe-21),
2.68 ± 2.62 (m, 3H, H-4', H-8, H-17), 2.47 ± 2.41 (m, 1H, H-14), 2.10 (s, 3H,
Me-4), 2.09 (s, 3H, Me-2), 1.84 (s, 3H, Me-6), 1.82 ± 1.78 (m, 4H, H-15,
H-18, H-22, H-26), 1.75 ± 1.64 (m, 2H, H-18, H-24), 1.58 (s, 3H, Me-12),
1.55 ± 1.45 (m, 3H, H-26, H-14, H-15), 1.30 (s, 3H, Me-8), 1.13 (d, J ˆ
6.5 Hz, 3H, Me-6'), 1.04 (d, J ˆ 6.5 Hz, 3H, Me-22), 0.96 (dd, J ˆ 8.0,
8.0 Hz, 9H, CH3CH2Si), 0.93, 0.93, 0.92 (3  s, 3  9H, tBuSi), 0.90 (d, J ˆ
6.5 Hz, 3H, Me-24), 0.88 (s, 9H, tBuSi), 0.64 ± 0.57 (m, 6H, CH2Si), 0.14,
0.13, 0.09, 0.08, 0.05, 0.04, 0.02, 0.02 (8 Â s, 8 Â 3H, MeSi); 13C NMR
(150 MHz, CDCl3): d ˆ 169.2, 145.1, 144.2, 140.5, 140.1, 132.8, 132.4, 130.9,
129.1, 125.0, 124.7, 101.6, 95.1, 87.6, 82.3,
‡
(MALDI-FTMS), calcd for C97H183ClO22Si6Na [M‡Na ]: 1926.1397, found
1926.1465
[3] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 287 ± 290.
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Chem. Soc. Jpn. 1979, 52, 1989 ± 1993; b) K. C. Nicolaou, M. R. V.
Finlay, S. Ninkovic, F. Sarabia, Tetrahedron 1998, 54, 7127 ± 7166.
[8] We thank Dr. C. Khosla and Dr. Y. Hayakawa for generous gifts of
natural apoptolidin.
[9] Apoptolidinꢁs rather labile nature proved challenging in the final
deprotection, purification, and characterization procedures. Specifi-
cally, upon standing at ambient temperature in solution or during
chromatographic manipulations, apoptolidin initially converted to an
isomer (presumably its C21 anomer) and, subsequently, to a number of
other unidentified products. The 1H NMR spectra of 1 (synthetic or
natural), therefore, included a number of additional signals due to these
contaminants. Characterization of these products is currently in
progress.
Angew. Chem. Int. Ed. 2001, 40, No. 20
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