Synthesis of the macrocyclic core of apoptolidin

Article abstract of DOI:10.1039/b000424n

The convergent synthesis of the apoptolidin macrocyclic core is described.

Full text of DOI:10.1039/b000424n

Synthesis of the macrocyclic core of apoptolidin
K. C. Nicolaou,* Yiwei Li, Bernd Weyershausen and Heng-xu Wei
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037, USA and Chemistry and Biochemistry, University of California
San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. E-mail: kcn@scripps.edu
Received (in Cambridge, UK) 17th January 2000, Accepted 20th January 2000
The convergent synthesis of the apoptolidin macrocyclic
core is described.
ether (TBSOTf, 2,6-lutidine) to afford 7 (97% yield). Ozono-
lytic cleavage of the terminal olefin in 7 afforded 8, which
reacted with Ph3PNC(CH3)CO2Et (toluene, 100 °C) to afford 9
in 90% yield after chromatography. Reduction of this inter-
mediate using DIBAL-H (90% yield) followed by oxidation
(NMO/TPAP) afforded 11 via 10. Subsequent homologation
Apoptolidin (1) is a recently discovered natural product
possessing impressive biological properties, including the
employing
a
Horner–Wadsworth–Emmons
reaction8
[(EtO)2P(NO)–CH(CH3)CO2Et, NaH] provided 12 in 90%
overall yield from 10. After reduction of the ester moiety in 12
(DIBAL-H, 89%) and TBAF-mediated removal of both silyl
protecting groups (98% yield), it was found that upon exposure
of the resulting diol 14 to MnO2 in dilute CCl4 solution, the
primary hydroxy group was selectively oxidized to afford 15 in
97% yield. Use of a second Horner–Wadsworth–Emmons
olefination [(EtO)2P(NO)–CH(CH3)CO2TMSE, NaH, THF]
provided the desired all-trans 16 in 65% yield. In the final
transformation, Pd0-catalyzed hydrostannation [Bu3SnH,
Pd(Ph3P)2Cl2 cat., THF]9 provided a 4+1 mixture of b-(E) and
a-regioisomers, which were separated chromatographically to
afford the desired [b-(E)] vinylstannane 3 in 69% yield.
selective induction of apoptosis in rat glia cells transfected with
adenovirus E1A oncogene1 in the presence of normal cells.2
Originally isolated from cultures of Nocardiopsis sp by
Hayakawa and co-workers in 1997,3 this compound possesses a
novel molecular architecture whose central domain consists of
a 20-membered macrocyclic lactone containing independent
conjugated triene and diene systems. Because of its important
biological activity and novel molecular features, apoptolidin (1)
was deemed a prime target for total synthesis. Herein we report
a convergent construction of the apoptolidin macrocyclic core
(2) demonstrating a potential strategy for an eventual total
synthesis of the natural product.
The synthesis of the C12–C19 fragment (4) commenced with
PMB protection (PMBCl, NaH, 90%) of the commercially
available (S)-glycidol (17) leading to 18 (Scheme 3). Addition
In developing a synthetic strategy to access 2 (Scheme 1), we
envisaged union of key intermediates 3 and 4 via a Stille
coupling reaction4 followed by a Yamaguchi type macro-
lactonization5 process as a means to construct the 20-membered
macrocycle. Based on the expected conformational rigidity that
would be conferred to the backbone of the seco, open-chain
precursor of this macrocyclic system by the series of its double
bonds, we hypothesize that C1–C19 lactonization would be
highly preferred over C1–C16 or C1–C9 ring closures. To test
this hypothesis, the synthetic strategy was tailored so that all
three hydroxy groups (at C9, C16 and C19) would be free from
protection prior to lactonization. The successful execution of
this strategy is described below.
The construction of the C1–C11 fragment 3 began with 5 and
proceeded as shown in Scheme 2. Thus, the known 56 was
treated with Brown’s cis-crotylborane [(+)-Ipc2B(cis-crotyl)]7
to furnish 6 (82% yield), which was readily protected as a TBS
Scheme
2 Reagents and conditions: (a) (Z)-(+)-crotyldiisopinocam-
pheylborane (2.5 equiv.), THF, 278 °C; then NaBO3·4H2O (15 equiv.),
THF–H2O (1+1), 25 °C, 12 h, 82%; (b) TBSOTf (1.5 equiv.), 2,6-lutidine
(2.0 equiv.), CH2Cl2, 0 ? 25 °C, 12 h, 97%; (c) O3, Sudan red 7B (0.02
equiv.), CH2Cl2, 278 °C; then PPh3 (1.5 equiv.), 278 ? 25 °C, 12 h; (d)
Ph3PNC(CH3)CO2Et (10.0 equiv.), toluene, 100 °C, 12 h, 90% for 2 steps;
(e) DIBAL-H (2.5 equiv.), 278 °C, 2 h, 90%; (f) TPAP (0.05 equiv.), NMO
(6.0 equiv.), 4 Å MS, CH2Cl2, 25 °C, 30 min; (g) NaH (5.0 equiv.),
(EtO)2P(NO)CH(CH3)CO2Et (5.0 equiv.), THF, 0 ? 25 °C, 1 h, 81% for 2
steps; (h) DIBAL-H (2.5 equiv.), 278 °C, 2 h, 89%; (i) TBAF (3.0 equiv.),
THF, 0 ? 25 °C, 1 h, 98%; (j) MnO2 (20 equiv.), CCl4, 25 °C, 3 h, 97%;
(k) NaH (6.0 equiv.), (EtO)2P(NO)CH(CH3)CO2TMSE (6.0 equiv.), THF, 0
? 25 °C, 5 h, 65%; (l) Bu3SnH (4.0 equiv.). PdCl2(PPh3)2 (0.05 equiv.),
THF, 0 °C, 30 min, 69%. TPAP = Pr4NRuO4.
Scheme 1
Chem. Commun., 2000, 307–308
This journal is © The Royal Society of Chemistry 2000
307

Scheme 4 Reagents and conditions: (a) Pd(CH3CN)2Cl2 (0.05 equiv.),
DMF, 25 °C, 48 h, 60%; (b) TBAF (6.0 equiv.), THF, 25 °C, 12 h, 80%; (c)
Et3N (6.0 equiv.), 2,4,6-trichlorobenzoyl chloride (1.5 equiv.), THF, 1.5 h,
0 °C; then 4-DMAP (5.0 equiv.), benzene, 25 °C, 1 h, 60%.
Scheme 3 Reagents and conditions: (a) PMBCl (2.0 equiv.), NaH (2.0
equiv.), Bu4N+I2 (2.0 equiv.), DMF, 0 ? 25 °C, 1 h, 90%; (b)
Allenylmagnesium bromide (1.25 equiv.), Et2O, 278 ? 25 °C, 1 h, 90%;
(c) TBSOTf (2.5 equiv.), 2,6-lutidine (4.0 equiv.), CH2Cl2, 0 ? 25 °C,
97%; (d) BuLi (2.0 equiv.), MeI (5.0 equiv.), THF, 278 ? 25 °C, 2 h, 95%;
(e) DDQ (2.0 equiv.), CH2Cl2–H2O (18+1), 0 ? 25 °C, 97%; (f) TPAP
(0.05 equiv.), NMO (6.0 equiv.), 4 Å MS, CH2Cl2, 0 ? 25 °C, 2 h, 90%; (g)
B-(+)-allyldiisopinocampheylborane (4.0 equiv.), Et2O, 2100 °C, 1 h; then
NaBO3·4H2O (15 equiv.), THF–H2O (1+1), 25 °C, 12 h, 85%, 24:
diastereoisomer ca. 10+1; h) MeOTf (3.0 equiv.), 2,6-di-tert-butyl-
4-methylpyridine (5.0 equiv.), CH2Cl2, 40 °C, 24 h, 85%; (i) K3Fe(CN)6
(3.0 equiv.), K2CO3 (3.0 equiv.), (DHQ)2-PYR (0.02 equiv.), OsO4 (0.01
equiv. 2.5 wt% in ButOH), ButOH–H2O (1+1), 0 °C, 12 h, 85%, 26:
diastereoisomer ca. 6+1; (j) Bu2SnO (1.1 equiv.), toluene, 110 °C, 12 h; then
BnBr (1.2 equiv.), Bu4N+I2 (1.5 equiv.), toluene, 80 °C, 2 h, 85%; (k)
TBSOTf (2.5 equiv.), 2,6-lutidine (4.0 equiv.), CH2Cl2, 0 ? 25 °C, 97%; (l)
Cp2ZrHCl (2.0 equiv.), THF, 50 °C, 2 h; then I2 (2.0 equiv.), THF, 215 ?
compounds for biological screening purposes and paves the way
for an eventual total synthesis of apoptolidin itself. Alternative
strategies towards this macrocycle, including a palladium(0)-
catalysed coupling to form the C11–C12 single bond and an
olefin metathesis approach to form the C10–C11 double bond of
the construct are in progress.
We thank Drs G. Siuzdak and D. H. Huang for mass
spectrometric and NMR assistance, respectively. This work was
financially supported by The Skaggs Institute for Chemical
Biology, the National Institutes of Health (USA), a Feodor
Lynen Fellowship of the Alexander von Humboldt Stiftung (to
B. W.) and grants from Abbott, Amgen, Boehringer-Ingelheim,
Glaxo-Wellcome, Hoffmann-La Roche, Dupont, Merck, No-
vartis, Pfizer, Schering Plough, and Bristol-Myers Squibb.
25 °C, 0.5 h, 65%. (DHQ)2-PYR
= 2,5-diphenyl-4,6-bis(9-O-dihy-
droquinyl)pyrimidine.
Notes and references
† Selected data for 2: Rf = 0.40 (silica gel, EtOAc–hexane 1+1); [a]D20
250.0 (MeOH, c 0.42); nmax(film)/cm21 3419, 2925, 1696, 1453, 1381,
1243, 1104, 807, 712; dH(500 MHz, CDCl3) 7.35–7.20 (m, 5H, C6H5), 7.18
(s, 1H, H-3), 6.08 (d, J 15.4, 1H, H-11), 6.08 (s, 1H, H-5), 5.56 (br t, J 8.0,
1H, H-13), 5.35 (dd, J 15.4, 8.1, 1H, H-10), 5.22–5.20 (m, 1H, H-19), 5.13
(br d, J 9.9, 1H, H-7), 4.58 (d, J 12.1, 1H, OCH2C6H5), 4.51 (d, J 12.1, 1H,
OCH2C6H5), 3.90 (dd, J 8.4, 8.1, 1H, H-9), 3.60–3.46 (m, 3H), 3.42, (s, 3H,
OCH3), 3.44–3.40 (m, 1H), 2.90–2.87 (m, 1H), 2.55–2.43 (m, 2H),
2.30–2.24 (m, 1H), 2.13 (s, 3H), 2.07 (s, 3H), 1.97–1.89 (m, 1H), 1.87 (s,
3H), 1.85–1.78 (m, 1H), 1.68 (s, 3H), 1.65–1.52 (m, 2H), 1.13 (d, J 6.6, 3H,
8-CH3); dC(150 MHz, CDCl3) 168.7, 145.9, 145.1, 140.6, 138.0, 137.2,
136.5, 133.4, 132.5, 132.3, 131.7, 128.8 (2C), 127.6 (2C), 127.4, 123.2,
82.0, 79.7, 73.7, 73.2, 71.5, 71.0, 60.4, 39.5, 35.5, 34.6, 24.4, 17.5, 17.2,
16.2, 13.7, 12.0; HRMS (MALDI) calc. for C33H46NaO6 (M + Na+):
561.3192, found: 561.3216.
of allenylmagnesium bromide10 to 18 gave the desired hex-
5-yne-1,2-diol (19) in 90% yield. Silylation of the free hydroxy
group in 19 with TBSOTf–2,6-lutidine followed by methylation
of the terminal alkyne (BuLi, McI) afforded 21 in 95% yield.
Subsequent removal of the PMB group from 21 in the presence
of DDQ in CH2Cl2–H2O (18+1) (97% yield) followed by
TPAP–NMO mediated oxidation of the resulting alcohol 22
readily provided 23 (90% yield). Exposure of 23 to b-
(+)-allyldiisopinocampheylborane according to Brown et al.11
furnished a mixture of diastereomeric alcohols (ca. 10+1 ratio,
85% combined yield) from which the major and desired isomer
(24) was isolated chromatographically. Methylation of the
hydroxy group (MeOTf, 2,6-di-tert-butyl-4-methylpyridine,
40 °C, 85% yield)12 in 24 furnished 25 whose terminal olefin
underwent stereoselective dihydroxylation in the presence of
AD-mix-a13 to provide 26 together with its (minor) diastereoi-
somer (ca. 6+1 ratio) in 85% combined yield. The two
diastereoisomers could not be easily separated chromato-
graphically at this stage, but after protection of the primary
hydroxy group as a benzyl ether (Bu2SnO, BnBr, toluene),14 the
desired diastereoisomer 27 was readily isolated by flash
chromatography. Subsequent protection of the secondary
hydroxy group of 27 as a TBS ether (TBSOTf, 2,6-lutidine,
97%) followed by hydrozirconation–iodonation (Cp2ZHCl,
THF, 50 °C; then I2, 215 °C) generated the key intermediate 4
(65% overall yield) via 28.
1 M. Debbas and E. White, Genes Dev., 1993, 7, 546.
2 J. W. Kim, H. Adachi, K. Shin-ya, Y. Hayakawa and H. Seto,
J. Antibiot., 1997, 50, 628.
3 Y. Hayakawa, J. W. Kim, H. Adachi, K. Shin-ya, K. Fujita and H. Seto,
J. Am. Chem. Soc., 1998, 120, 3524.
4 J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508; J. Betzer, J.
Lallemand and A. Pancrazi, Synthesis, 1998, 522.
5 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi, Bull.
Chem. Soc. Jpn., 1979, 52, 1989; K. C. Nicolaou, M. R. V. Finlay, S.
Ninkovic and F. Sarabia, Tetrahedron, 1998, 54, 7127.
6 R. L. Danheiser, D. J. Carini, D. M. Fink and A. Basak, Tetrahedron,
1983, 39, 435.
7 H. C. Brown and K. S. Bhat, J. Am. Chem. Soc., 1986, 108, 293.
8 For reviews, see: W. S. Wadsworth Jr., Org. React., 1977, 25, 73; B. E.
Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863.
9 H. X. Zhang, F. Guibe and G. Balavoine, J. Org. Chem., 1990, 55,
1857.
10 L. Brandsma and H. Verkruijisse, Preparative Polar Organometallic
Chemistry I, Springer, Berlin, 1987, 63.
11 U. S. Racherla and H. C. Brown, J. Org. Chem., 1991, 56, 401.
12 D. M. Walba, W. N. Thurmes and R. C. Haltiwanger, J. Org. Chem.,
1988, 53, 1046.
With both key intermediates 3 and 4 in hand, the stage was set
for the crucial coupling and macrolactonization steps (see
Scheme 4). Thus, upon treatment with catalytic amounts of
Pd(CH3CN)2Cl2 (0.05 equiv.) in DMF, 3 and 4 readily coupled
to afford 29 in 60% yield. Subsequent exposure of 29 to TBAF
resulted in concomitant removal of all three silyl protecting
groups furnishing 30 in 80% yield. Finally, Yamaguchi
macrolactonization of seco-acid 30 (2,4,6-trichlorobenzoyl
chloride, DMAP, Et3N) resulted in the ring-selective formation
of macrocyclic core 2† in 60% yield.
13 G. A. Crispino, K.-S. Jeong, H. C. Kolb, Z.-M. Wang, D. Xu and K. B.
Sharpless, J. Org. Chem., 1993, 58, 3785.
14 T. B. Grindley, Adv. Carbohydr. Chem. Biochem., 1998, 53, 17.
The described chemistry demonstrates the feasibility of the
present strategy for the chemical synthesis of apoptolidin-like
Communication b000424n
308
Chem. Commun., 2000, 307–308