Total synthesis of apoptolidin: Part 1. Retrosynthetic analysis and construction of building blocks

Article abstract of DOI:10.1002/1521-3773(20011015)40:20<3849::AID-ANIE3849>3.0.CO;2-M

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<3849::AID-ANIE3849>3.0.CO;2-M

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[21] In this sense the (CH2)S(NtBu)3 dianion represents the framework of
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[8] For a general overview see: A. W. Johnson, Ylid Chemistry, Academic
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[22] D. Stalke, Chem. Soc. Rev. 1998, 27, 171.
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[23] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467.
[24] G. M. Sheldrick, SHELXL-97, Program for Crystal Structure Refine-
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[10] a) G. Boche, K. Marsch, K. Harms, G. M. Sheldrick, Angew. Chem.
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U. Dingerdissen, C. Krüger, K. Angermund, J. Am. Chem. Soc. 1987,
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logr. Sect. C 1997, 53, 419; d) J. F. K. Müller, M. Neuburger, M.
Zehnder, Helv. Chim. Acta 1997, 80, 2182.
[25] H. D. Flack, Acta Crystallogr. Sect. A 1983, 39, 876.
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Chem. Int. Ed. Engl. 1966, 5, 385.
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Hänssgen, R. Steffens, Z. Naturforsch.
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Hänssgen, R. Plum, Chem. Ber. 1987, 120, 1063.
Total Synthesis of Apoptolidin: Part 1.
Retrosynthetic Analysis and Construction of
Building Blocks**
[12] a) D. Hänssgen, H. Hupfer, M. Nieger, M. Pfendtner, R. Steffens, Z.
Anorg. Allg. Chem. 2001, 627, 17; b) B. Walfort, R. Bertermann, D.
Stalke, Chem. Eur. J. 2001, 7, 1424.
[13] B. Walfort, A. P. Leedham, C. A. Russell, D. Stalke, Inorg. Chem., in press.
[14] Crystal structure data for 1 and 2: The data were collected from shock-
cooled crystals on an BRUKER SMART-APEX CCD diffractometer
(graphite-monochromated MoKa radiation, l ˆ 71.073 pm) equipped
with a low-temperature device at 193(2) K.[22] The structures were
solved by direct methods (SHELXS-97)[23] and refined by full-matrix
least-squares methods against F 2 (SHELXL-97).[24] R values defined
K. C. Nicolaou,* Yiwei Li,
Konstantina C. Fylaktakidou, Helen J. Mitchell,
Heng-Xu Wei, and Bernd Weyershausen
From the many macrolide type structures recently isolated
from nature, that of apoptolidin (1, Scheme 1),[1] isolated from
Nocardiopsis sp., stands out. Its distinction as a synthetic
as R1 ˆ SjjFoj jF jj SjF j, wR2 ˆ [Sw(Fo2 F2†2 Sw(F 2†2]0.5
,
w ˆ
/
/
c
o
c
o
[s2(Fo2† ‡ (g1P)2 ‡ g2P] 1, P ˆ 1/3[max(Fo2,0) ‡ 2Fc2]. 1: C25H61Li2N7S,
Mr ˆ 505.75, orthorhombic, space group Pbca, a ˆ 1996.67(13),
b ˆ 1649.92(10), c ˆ 2027.39(14) pm, V ˆ 6.6789(8) nm3, Z ˆ 8,
1calcd ˆ 1.006 Mgm 3, m ˆ 0.120 mm 1, F(000) ˆ 2256, 26858 reflec-
tions measured, 4730 unique, R(int) ˆ 0.0931, wR2(all data) ˆ 0.1880,
R1(I > 2s(I)) ˆ 0.0657, g1 ˆ 0.1225, g2 ˆ 1.6000 for 341 parameters and
no restraints. 2: C18H43Li2N5OS, Mr ˆ 391.51, hexagonal, space group
P63, a ˆ b ˆ 1768.91(8), c ˆ 1506.06(10) pm, V ˆ 4.0812(4) nm3, Z ˆ 6,
1calcd ˆ 0.956 Mgm 3, m ˆ 0.132 mm 1, F(000) ˆ 1296, 16134 reflec-
tions measured, 3887 unique, R(int) ˆ 0.0647, wR2(all data) ˆ 0.1679,
R1(I > 2s(I)) ˆ 0.0627, g1 ˆ 0.0974, g2 ˆ 0.0 for 337 parameters and 289
restraints and a Flack x parameter of 0.2(2).[25] The hydrogen atoms at
the methylene atom C1 in 1 were located by difference Fourier syntheses
and refined freely. All other hydrogen atoms of the molecule were
refined by using a riding model. Compound 2 crystallized in the
noncentrosymmetric space group P63. An additional mirror plane in
the O3Li3 ring plane to give the higher symmetric space group P63/m is
precluded by the coordinated tmeda molecules and the N-bonded tert-
butyl groups. As the chirality is induced only in the periphery strictly
spoken the molecule is not planar chiral.[26] Crystallographic data
(excluding structure factors) for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos CCDC-164904 (1) and
CCDC-164905 (2). Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[*] Prof. Dr. K. C. Nicolaou, Y. Li, Dr. K. C. Fylaktakidou,
Dr. H. J. Mitchell, Dr. H.-X. Wei, Dr. B. Weyershausen
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. 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 Biosciences, a
pre-doctoral fellowship from Boehringer Ingelheim (Y.L.), a post-
doctoral fellowship the George Hewitt Foundation (K.C.F.), and
grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boeh-
ringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, No-
vartis, Pfizer, and Schering Plough.
Supporting information for this article (selected physical properties of
compounds 2, 3, 4, 51, and 69) is available on the WWW under
http://www.angewandte.com or from the author.
[15] a) R. Armstutz, T. Laube, W. B. Schweizer, D. Seebach, J. D. Dunitz,
Helv. Chim. Acta 1984, 67, 224; b) W. Zarges, M. Marsch, K. Harms, W.
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building blocks. The synthetic strategy for assembling these
intermediates into the apoptolidin framework envisioned, in
order of construction, the following key steps:
ꢀ1 A dithiane-based coupling reaction[6] to join building
blocks 3 (C12 ± C20 fragment) and 4 (C21 ± C28 fragment)
ꢀ2 A subsequent Stille coupling[7] reaction to introduce the
C1 ± C11 segment 2
ꢀ3 A glycosidation step incorporating carbohydrate unit 5
(ring A)
ꢀ4 A Yamaguchi macrolactonization[8] to close the 20-mem-
bered ring
ꢀ5 A final glycosidation step to attach the remaining
disaccharide system 6 (rings D and E)
The flexibility of this plan which, in principle, allows
changes in the order of steps in the construction sequence that
might be dictated by unforeseen events, was considered an
additional and decisive advantage.
The synthesis of the C1 ± C11 fragment 2 commenced with
acetylenic aldehyde 7[9] (Scheme 2). Thus, 7 was treated with
(Z)-(‡)-crotyldiisopinocampheyl borane[10] to afford alcohol
8 selectively and in 82% yield. Protection of this alcohol as a
TBS ether (9, 97% yield), followed by ozonolysis of the
olefinic bond, gave, upon reduction with PPh3, aldehyde 10
(90% yield). The latter compound was treated with Best-
mannꢁs reagent (MeC(O)C(N2)P(O)(OMe)2)[11] to afford the
diacetylene 11 (85% yield), which, upon methylation with
nBuLi and MeI, led to compound 12 (90% yield). Regio- and
stereoselective hydroboration of 12 with catecholborane and
catalytic amounts of 9-BBN, followed by hydrolysis, furnished
the vinyl boronic acid 13 in 60% yield. Finally, a Suzuki type
coupling[12] (81% yield) of 13 with vinyl bromide 19 (obtained
in 84% overall yield from the allylic alcohol 16[13] by one-pot
reaction[14] with MnO2 and MeC( PPh3)CO2Et, and subse-
Scheme 1. Molecular structure and retrosynthetic analysis of apoptolidin
(1). TBS ˆ tert-butyldimethylsilyl; TES ˆ triethylsilyl; DMB ˆ 3,4-dimeth-
oxybenzyl; PMB ˆ 4-methoxybenzyl.
ˆ
quent ester exchange, see Scheme 2), followed by desilylation
(TBAF, 98% yield) of the resulting product (14) and regio-
and stereoselective Pd-mediated hydrostannylation[15] (69%
yield), provided the desired vinyl stannane 2 via propargylic
alcohol 15.
target emanates from its molecular architecture which
includes no less than 30 stereogenic elements (25 stereo-
centers and 5 geometrical sites), a highly unsaturated 20-
membered macrocyclic system, and four carbohydrate units.
The appeal of apoptolidin (1) as a synthetic target is enhanced
by its unique biological activities, prominent among which are
the selective induction of apoptosis in rat glia cells trans-
formed with adenovirus E1A oncogene in the presence of
normal cells[2] and inhibition of the mitochondrial F0F1-
ATPase.[3] In this and the following communication,[4] we
report the first total synthesis of this fascinating natural
product.[5]
The retrosynthetic scheme for apoptolidin (1) outlined in
Scheme 1 was chosen on the basis of convergence and the
moleculeꢁs chemical sensitivity. The latter issue was of major
concern given the potentially labile nature of apoptolidinꢁs
conjugated systems, glycoside bonds, lactol moiety, and
macrocyclic ring. Specifically, the susceptibility of 1 to both
base and acid had to be addressed in any synthetic planning,
particularly regarding manipulation and final removal of
protecting groups.
Fragment 3 (C12 ± C20) was synthesized from commercially
available (‡)-glycidol (20) as outlined in Scheme 3. Thus, 20
was protected as its PMB ether 21 (90% yield) and reacted
with allenyl magnesium bromide[16] to afford acetylenic
alcohol 22 in 90% yield. The latter compound was then
protected as a TBS ether (23, 97% yield) and methylated
(nBuLi, MeI) to give acetylenic compound 24 in 95% yield.
Removal of the PMB group from 24 (DDQ, 97% yield),
followed by oxidation (TPAP, NMO) of the resulting alcohol
(25) furnished aldehyde 26 (90% yield). The subsequent
reaction of aldehyde 26 with (‡)-allyldiisopinocampheyl
borane[17] in diethyl ether at 1008C was both efficient
(85% yield) and stereoselective (ca. 10:1 ratio), and produced
the desired alcohol 27. Treatment of 27 with MeOTf in the
presence of 2,6-di-tert-butyl-4-methyl pyridine led to methyl
ether 28 in 85% yield. Asymmetric dihydroxylation of 28
under the Sharpless conditions[18] (AD-Mix-a) provided the
corresponding diol (29, 85% yield, ca. 6:1 ratio of diaster-
eoisomers) from which the benzylidene derivative 30 was
formed by exposure to 3,4-dimethoxy benzaldehyde and CSA
(99% yield). Regioselective opening of this acetal (30) with
Disconnection of the five strategic bonds ꢀ1 ± ꢀ5 as
indicated in Scheme 1 revealed intermediates 2 ± 6 as suitable
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Scheme 3. Synthesis of aldehyde 3. a) PMBCl (2.0 equiv), NaH
(2.0 equiv), nBu4NI (0.05 equiv), DMF, 0 !258C, 1 h, 90%; b) allenylmag-
nesium bromide (1.25 equiv), Et2O, 78 !258C, 1 h, 90%; c) TBSOTf
(2.5 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, 08C, 1 h, 97 %; d) nBuLi
(1.0 equiv), MeI (5.0 equiv), THF,
78 !258C, 2 h, 95%; e) DDQ
(2.0 equiv), CH2Cl2/H2O (18:1), 0 !258C, 97%; f) TPAP (0.05 equiv),
NMO (6.0 equiv), 4 Š MS, CH2Cl2, 0 !258C, 2 h, 90 %; g) B-(‡)-
allyldiisopinocampheylborane (4.0 equiv), Et2O, 1008C, 1 h; then Na-
BO3 ´ 4H2O (15 equiv), THF/H2O (1:1), 258C, 12 h, 85%, 27: diaster-
eoisomer ca. 10:1; h) MeOTf (3.0 equiv), 2,6-di-tert-butyl-4-methyl pyr-
idine (5.0 equiv), CH2Cl2, 408C, 24 h, 85%; i) K3[Fe(CN)6] (3.0 equiv),
K2CO3 (3.0 equiv), (DHQ)2-PYR (0.02 equiv), OsO4 (0.01 equiv, 2.5 wt%
in tBuOH), tBuOH/H2O (1:1), 08C, 12 h, 85%, diastereoisomer ca. 6:1;
j) DMBA (3.0 equiv), CSA (0.05 equiv), toluene, 1108C, 12 h; 99%;
Scheme 2. Synthesis of vinylstannane 2. a) (Z)-(‡)-crotyldiisopinocam-
pheyl borane (2.5 equiv), BF3 ´ Et2O (2.5 equiv), THF, 788C, 16 h; then
NaBO3 ´ 4H2O (15 equiv), THF/H2O (1:1), 258C, 12 h, 82%; b) TBSOTf
(1.5 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, 0 !258C, 2 h, 97%; c) O3,
k) DIBAL-H (3.0 equiv), CH2Cl2,
788C, 30 min, 70%; l) SO3 ´ py
Sudan red 7B (0.02 equiv), CH2Cl2,
788C; then PPh3 (1.5 equiv),
(5.0 equiv), Et3N (6.0 equiv), DMSO/CH2Cl2 (2:1), 0 !258C, 30 min,
95%. Tf ˆ trifluoromethane sulfonyl; DDQ ˆ 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; MS ˆ molecular sieves; (DHQ)2-PYR ˆ 2,5-diphenyl-
4,6-bis(9-O-dihydroquinyl) pyrimidine; DMBA ˆ 3,4-dimethoxybenzalde-
hyde; DIBAL-H ˆ diisobutylaluminum hydride; DMB ˆ 3,4-dimethoxy-
phenylmethyl; NMO ˆ 4-methylmorpholine N-oxide; CSA ˆ 10-camphor-
sulfonic acid.
78 !258C, 12 h, 90%; d) MeC(O)C(N2)P(O)(OMe)2 (4.0 equiv),
NaOMe (4.0 equiv), THF,
78 !258C, 1 h, 85%; e) MeI (7.0 equiv),
nBuLi (2.0 equiv), 78 !258C, 2 h, 98%; f) catecholborane (1.1 equiv),
9-BBN (0.1 equiv), 808C, 15 h; then H2O (pH 7), 258C, 2 h, 60%; g) 19
(1.0 equiv), [(Ph3P)2PdCl2] (0.05 equiv), NaOAc (5.0 equiv), MeOH, 708C,
5 h, 81%; h) TBAF (3.0 equiv), THF, 0 !258C, 1 h, 98%; i) nBu3SnH
(4.0 equiv), [(PPh3)2PdCl2] (0.05 equiv), THF, 08C, 30 min, 69%;
ˆ
j) Ph3P C(CH3)CO2Et (1.2 equiv), MnO2 (10.0 equiv), CH2Cl2, 258C,
42 h, 91%; k) LiOH (2.0 equiv), THF/H2O (2:1), 258C, 12 h, 93%;
l) MNNG (5.0 equiv), KOH (40 wt% in H2O), ether, 08C, 30 min, 99%.
TBAF ˆ tetra-n-butylammonium fluoride; 9-BBN ˆ 9-borabicyclo[3.3.1]-
nonane; MNNG ˆ 1-methyl-3-nitro-1-nitrosoguanidine.
yield),[20] was then treated with (Z)-(‡)-crotyldiisopinocam-
pheyl borane in the presence of BF3 ´ Et2O to afford hydroxy
olefin 36 in 98% yield as a single stereoisomer. The hydroxy
group of compound 36 was then protected as a TBS ether
(97% yield) and the terminal olefin of the resulting product
(37) was cleaved upon exposure to NaIO4 and catalytic
amounts of OsO4, to afford aldehyde 38 (94% yield).
Compound 38 then reacted with the boron enolate derived
from Evansꢁ chiral auxiliary 39[21] and nBu2BOTf, followed by
H2O2 workup, to furnish the corresponding syn-aldol product
40, which was then converted to Weinreb amide 41[22] upon
exposure to MeNH(OMe) ´ HCl and AlMe3 (90% yield).
Introduction of a TMS group in 41 and DIBAL-H reduction
led, via derivative 42, to aldehyde 43 in 89% overall yield.
Finally, conversion of the aldehyde functionality of 43 to the
desired dithiane moiety (78% yield) furnished compound 44
DIBAL-H,[19] then, led to primary alcohol 31 in 70% yield.
Subsequent oxidation of 31 with SO3 ´ py and DMSO furnish-
ed the targeted C12 ± C20 aldehyde 3 in 95% yield.
The opposite enantiomer of glycidol (from the one used
above) served as the starting material for the construction of
the C21 ± C28 fragment, dithiane 4 (Scheme 4). Thus, ( )-
glycidolꢁs methyl ether (32) was treated with the anion of 1,3-
dithiane to afford secondary alcohol 33 (91% yield), whose
protection with PMBCl in the presence of NaH and catalytic
amounts of nBu4NI led to PMB ether 34 (99% yield).
Aldehyde 35, generated by deprotection of dithiane 34 (92%
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The hydroxy thioglycoside 45[23] was also utilized for
the construction of the DE carbohydrate domain 6
(Scheme 6). Thus, a TBS group was installed on 45 by
treatment with TBSOTf and 2,6-lutidine (95% yield) to
furnish derivative 52. The acetonide group was then
removed (92% yield) to afford the corresponding 2,3-
diol system (53). Regioselective mono-allylation of diol
53 was effected through the tin acetal technology[24]
(nBu2SnO; allylbromide, 90% yield, ca. 3:1 ratio favor-
ing the desired 3-O derivative) which lead to hydroxy
compound 54. Protection of the C2 hydroxy group of
intermediate 54 as a PMB ether 55 (83% yield) was then
followed by cleavage of the allyl ether (92% yield) to
furnish hydroxy compound 56. Oxidation of the latter
with DMP afforded the corresponding ketone (57) in
96% yield. Stereoselective conversion of 57 to the
desired tertiary alcohol (58) was accomplished by treat-
ment of MeMgBr in diethyl ether at 788C (91% yield,
ca. 7.5:1 favoring the desired diastereoisomer). Protec-
tive group manipulations furnished intermediates 59 and
60, respectively. The 2-hydroxy phenylthioglycoside 60
was then subjected to a DAST-induced 1,2-migration
reaction[25, 26] to afford, quantitatively, the glycosyl
fluoride 61, which was subsequently reacted with benzyl
alcohol in the presence of SnCl2 in diethyl ether to
afford,[25] stereoselectively, the b-benzyl glycoside 62
(97% yield). Exposure of 62 to TBAF furnished the 3,4-
dihydroxy compound 63 (98% yield).
Coupling of acceptor 66 (obtained from the known
2,3-dihydroxy thioglycoside 64[26] by regioselective meth-
ylation followed by a DAST-induced 1,2-migration[25, 26]
in 83% yield as shown in Scheme 6) with glycosyl donor
63 in the presence of SnCl2 in diethyl ether gave disac-
charide 67 in 45% yield.[27] The tertiary hydroxy group
of derivative 67 was then protected as a TES ether (84%
yield) and the resulting disaccharide 68 was exposed to
Scheme 4. Synthesis of dithiane 4. a) 1,3-dithiane (1.5 equiv), nBuLi (1.5 equiv), THF,
78 !258C, 2 h, 91%; b) PMBCl (1.3 equiv), NaH (1.3 equiv), nBu4NI (0.1 equiv), DMF,
08C, 1 h, 99%; c) MeI (10.0 equiv), K2CO3 (2.0 equiv), CH3CN/H2O (10:1), 458C, 5 h,
92%; d) (Z)-(‡)-crotyldiisopinocampheyl borane (4.0 equiv), BF3 ´ Et2O (4.0 equiv),
THF, 788C, 2 h; then NaBO3 ´ 4H2O (15 equiv), THF/H2O (1:1), 258C, 12 h, 98%;
e) TBSOTf (2.5 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, 0 !258C, 2 h, 97%; f) OsO4
(0.03 equiv), NMO (2.0 equiv), tBuOH/H2O/THF (10:1:2); 258C, 12 h; then NaIO4
(5.0 equiv), pH 7.0 buffer, 258C, 2 h, 94%; g) 39 (1.15 equiv), nBu2BOTf (1.4 equiv),
Et3N (1.6 equiv), CH2Cl2, 78 !258C, 2 h; then H2O2 (15 equiv), 0 !258C, 2 h, 93%;
h) MeNH(OMe) ´ HCl (2.5 equiv), AlMe3 (2.5 equiv), CH2Cl2, 10 !258C, 12 h, 90%;
i) TMSOTf (2.5 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2,
358C, 1 h; j) DIBAL-H
(3.0 equiv), CH2Cl2, 788C, 2 h, 89% over two steps; k) HS(CH2)3SH (2.0 equiv),
BF3 ´ Et2O (1.0 equiv), CH2Cl2, 308C, 15 min, 78%; l) TBSOTf (2.5 equiv), 2,6-lutidine
(5.0 equiv), CH2Cl2, 0 !258C, 5 h, 97%. TMS ˆ trimethylsilyl.
whose free hydroxy group was protected as a TBS ether (97%
yield) to afford the targeted C21 ± C29 fragment 4.
The two carbohydrate domains (A and DE) were obtained
by stereoselective routes starting with readily available sugar
derivatives as depicted in Schemes 5 and 6. For fragment 5,
the readily available (from l-rhamnose) hydroxy thioglyco-
side 45[23] (Scheme 5) was first selectively methylated (NaH,
MeI, 92% yield) and the resulting methyl ether 46 was
exposed to TsOH in ethylene glycol to afford diol 47 (91%
yield). The C3 hydroxy group of compound 47 was selectively
protected as its TBS ether to furnish compound 48 in 95%
yield. The stereochemistry of the remaining C2 hydroxy group
of 48 was then inverted following a two-step sequence,
involving Swern oxidation and NaBH4 reduction, to afford the
l-glucose derivative 50 via ketone 49 in 70% overall yield.
Finally, silylation (100% yield) of 50 followed by S-oxidation
with mCPBA led to the desired sulfoxide 5 in 80% yield via
compound 51.
Scheme 5. Synthesis of carbohydrate building block
A (5). a) MeI
(5.0 equiv), NaH (2.5 equiv), DMF, 258C, 1.5 h, 92%; b) TsOH (0.1 equiv),
(CH2OH)2 (1.2 equiv), MeOH, 258C, 12 h, 91%; c) TBSOTf (1.05 equiv),
2,6-lutidine (1.5 equiv), CH2Cl2, 0 !258C, 3 h, 95%; d) (COCl)2
(2.0 equiv), DMSO (2.5 equiv), Et3N (4.0 equiv), CH2Cl2, 788C, 4.5 h,
100%; e) NaBH4 (1.2 equiv), MeOH, 08C, 5 min, 70%; f) TBSOTf
(2.0 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, 0 !258C, 1 h, 100%;
g) mCPBA (1.0 equiv), CH2Cl2, 788C, 5 h, 80%. mCPBA ˆ m-chloro-
perbenzoic acid; TsOH ˆ p-toluenesulfonic acid.
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Raney-Ni hydrogenolysis conditions which concomitantly
removed the phenylsulfanyl groups and caused cleavage of
the benzyl ether to furnish disaccharide lactol 69 (92% yield).
Lactol 69 was then converted to the desired glycosyl fluoride
building block 6 in quantitative yield by reaction with DAST.
The described sequences provided all five requisite building
blocks (2 ± 6) for the projected total synthesis of apoptolidin
(1) in large quantities and set the stage for the next phase of
the program directed at their coupling and elaboration to the
final target. The following communication[4] details the
successful accomplishment of this goal.
Received: August 22, 2001 [Z17773]
[1] Y. Hayakawa, J. W. Kim, H. Adachi, K. Shin-ya, K. Fujita, H. Seto, J.
Am. Chem. Soc. 1998, 120, 3524 ± 3525.
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L. A. Herzenberg, C. Khosla, Proc. Natl. Acad. Sci. USA 2000, 97,
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[4] K. C. Nicolaou, Y. Li, K. C. Fylaktakidou, H. J. Mitchell, K. Sugita,
Angew. Chem. 2001, 113, 3972 ± 3976; Angew. Chem. Int. Ed. 2001, 40,
3854 ± 3857.
[5] For previous synthetic studies towards apoptolidin, see: a) J. Schup-
pan, B. Ziemer, U. Koert, Tetrahedron Lett. 2000, 41, 621 ± 624;
b) K. C. Nicolaou, Y. Li, B. Weyershausen, H. Wei, Chem. Commun.
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Lett. 2000, 2, 1439 ± 1442; d) J. Schuppan, H. Wehlan, S. Keiper, U.
Koert, Angew. Chem. 2001, 113, 2125 ± 2128; Angew. Chem. Int. Ed.
2001, 40, 2063 ± 2066.
[6] E. J. Corey, D. Seebach, Angew. Chem. 1965, 77, 1134 ± 1135; Angew.
Chem. Int. Ed. Engl. 1965, 4, 1075 ± 1077.
[7] a) J. K. Stille, Angew. Chem. 1986, 98, 504 ± 519; Angew. Chem. Int.
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Chem. Soc. Jpn. 1979, 52, 1989 ± 1993; see also b) K. C. Nicolaou,
M. R. V. Finlay, S. Ninkovic, F. Sarabia, Tetrahedron 1998, 54, 7127 ±
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1996, 118, 4711 ± 4712.
Scheme 6. Synthesis of carbohydrate building block D (6). a) TBSOTf
(1.5 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, 788C, 0.5 h, 95%; b) BCl3 ´
SMe2 (0.5 equiv) (2.0m solution in CH2Cl2), CH2Cl2, 08C, 10 min, 92%;
c) nBu2SnO (1.3 equiv), toluene, reflux, 6 h; AllylBr (1.5 equiv), CeF
(1.2 equiv), DMF, 708C, 12 h, 90% (ca. 3:1 ratio); d) PMBCl (1.5 equiv),
nBu4NI (0.5 equiv), NaH (1.6 equiv), DMF, 08C, 1.5 h, 83%;
e) 1. [RhCl(PPh3)3] (0.05 equiv), DABCO (1.5 equiv), MeOH/H2O (10:1),
reflux, 1 h; 2. NMO (1.2 equiv), OsO4 (0.05 equiv), Me2CO/H2O (10:1),
258C, 12 h, 92%; f) DMP (1.5 equiv), NaHCO3 (2.0 equiv), CH2Cl2, 258C,
10 min, 96%; g) MeMgBr (2.0 equiv) (3m solution in Et2O), Et2O, 788C,
10 min, 91% (ca. 7.5:1 ratio); h) TBSOTf (2.0 equiv), 2,6-lutidine
(3.0 equiv), CH2Cl2, 0 !408C, 24 h, 93%; i) DDQ (1.5 equiv), CH2Cl2/
H2O (5:1) 08C, 1.5 h, 97%; j) DAST (1.5 equiv), CH2Cl2, 08C, 20 min,
100%, a:b ca. 1:10; k) BnOH (5.0 equiv), SnCl2 (1.0 equiv), Et2O,
0 !258C, 5 h, 97 %; l) nBu4NF (2.5 equiv), THF, 258C, 6 h, 98%;
m) nBu2SnO (1.2 equiv), toluene, reflux, 6 h; MeI (1.5 equiv), CsF
(1.2 equiv), DMF, 558C, 1 h, 83%; n) DAST (1.5 equiv), CH2Cl2, 08C,
0.5 h, 100%, a:b ca. 1:7; o) 63 (0.73 equiv), SnCl2 (1.0 equiv), Et2O,
0 !258C, 12 h, 45% of the 4-O glycoside, 26% of the 3-O glycoside;
p) TESOTf (1.5 equiv), 2,6-lutidine (2.0 equiv), CH2Cl2, 0 !258C, 6 h,
84%; q) Raney-Ni (ca. 4 equiv) (w/w), EtOH, 558C, 5 h, 92%; r) DAST
(1.5 equiv), CH2Cl2, 08C, 15 min, 100%, a:b ca. 15:1. Bn ˆ Benzyl;
DASTˆ (diethylamino)sulfur trifluoride; DABCO ˆ 1,4-diazabicyclo-
[2.2.2]octane; DMP ˆ Dess ± Martin Periodinane.
[14] X. Wei, R. J. K. Taylor, Tetrahedron Lett. 1998, 39, 3815 ± 3818.
Â
[15] H. X. Zhang, F. Guibe, G. Balavoine, J. Org. Chem. 1990, 55, 1857 ±
1867.
[16] L. Brandsma, H. Verkruijisse, Preparative Polar Organometallic
Chemistry I, Springer, Berlin, 1987, p. 63.
[17] U. S. Racherla, H. C. Brown, J. Org. Chem. 1991, 56, 401 ± 404.
[18] G. A. Crispino, K.-S. Jeong, H. C. Kolb, Z.-M. Wang, D. Xu, K. B.
Sharpless, J. Org. Chem. 1993, 58, 3785 ± 3786.
[19] A. B. Smith III, Q. Lin, K. Nakayama, A. M. Boldi, C. S. Brook, M. D.
McBriar, W. H. Moser, M. Sobukawa, L. Zhuang, Tetrahedron Lett.
1997, 38, 8675 ± 8678.
[20] S. Takano, S. Hatakeyama, K. Ogasawara, J. Chem. Soc. Chem.
Commun. 1977, 68.
[21] J. R. Gage, D. A. Evans, Org. Synth. 1999, 339 ± 343, collective issue 8.
[22] a) A. Basha, M. Lipton, S. M. Weinreb, Tetrahedron Lett. 1977, 4171 ±
4174; b) J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. 1982, 12,
989 ± 993.
[23] V. Pozsgay, Carbohydr. Res. 1992, 235, 295 ± 302.
[24] T. B. Grindley, Adv. Carbohydr. Chem. Biochem. 1998, 53, 17 ± 143.
Angew. Chem. Int. Ed. 2001, 40, No. 20
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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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