Short synthesis of the C16-C28 polyketide fragment of apoptolidin A aglycone

Article abstract of DOI:10.1039/b701293d

Starting from (E,E)-1-[(1R)-(phenylethyl)oxy]-2-methylpenta-1,3-diene and triethylsilyl enol ether of butanone rapid access to Koert's advanced C ₁₀-C₂₈ polyketide fragment of apoptolidin A is now possible. The Royal Society of Chemi

Full text of DOI:10.1039/b701293d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Short synthesis of the C16–C28 polyketide fragment of apoptolidin A
aglycone{
Cotinica Craita,a Charles Didierb and Pierre Vogel*b
Received (in Cambridge, UK) 29th January 2007, Accepted 22nd February 2007
First published as an Advance Article on the web 12th March 2007
DOI: 10.1039/b701293d
mixture)18 were added to a premixed solution of (CF3SO2)2NH in
Starting from (E,E)-1-[(1R)-(phenylethyl)oxy]-2-methylpenta-
SO2–CH2Cl2 (5 : 1) cooled to 278 uC. After stirring overnight at
this temperature a b,c-unsaturated silyl sulfinate formed. The
reaction is believed to imply first a diastereoselective hetero-Diels–
Alder addition of SO2 to diene 4 giving a sultine intermediate, then
the latter is heterolyzed into a zwitterionic intermediate reacting
with enoxysilane 5 (see Scheme 1) that produces the b,c-unsatu-
rated silyl sulfinate. After recovery of the solvent (SO2 and
CH2Cl2) by evaporation at low temperature, in situ alcoholysis
liberated a b,c-unsaturated sulfinic acid that underwent stereo-
selective retro-ene elimination of SO2 affording the stereotriad 6
(a,b,c-syn,anti) and its anti/anti diastereoisomer as a 4 : 1 mixture.
a-Hydroxylation of methyl ketone 6 (crude 4 : 1 mixture) was
achieved by dimethyl(tert-butyl)silyl enol ether formation and
subsequent Rubottom oxidation19 giving 7. The a-silyloxyketone 7
underwent Mukaiyama aldol coupling with aldehyde 820 produ-
cing alkene 9 in 73% yield with 2,4,5-anti,syn relative configuration
as expected by the Evans polar model.21 Ozonolysis of alkene 9
provided the corresponding aldehyde which was treated under
Brown allylation conditions.22 The resulting homoallylic alcohol
was equilibrated with the hemiacetal 10. The relative configuration
1,3-diene and triethylsilyl enol ether of butanone rapid access
to Koert’s advanced C10–C28 polyketide fragment of apopto-
lidin A is now possible.
Apoptolidin A (1) isolated from Nocardiopsis sp.1 and natural
analogues B (2) and C(3)2 are among the most interesting leads for
cancer chemotherapy3 as they induce apoptosis selectively in
cancer cells (Fig. 1).4
Successful total synthesis of 1 has been achieved by the groups
of Nicolaou5 and Koert.6 Syntheses of apoptolidinone A, the
aglycone of 1, were reported by the groups of Sulikowsky,7
Crimmins,8 Nicolaou5 and Koert.9 In addition, several studies on
the synthesis of fragments of apoptolidinones have been
reported.10,11 Previously in our group, a very short synthesis of
Nicolaou’s intermediate C1–C11 fragment of 1 was published,12
applying our one-pot four-component synthesis of polyfunctional
sulfones.13 Recently, we demonstrated that polypropionate stereo-
triads can be generated in one-pot operations according to
Scheme 1.14 This method permitted the short synthesis of
rifamycin S15 and baconipyrones.16 We now present a short
synthesis of Koert’s C16–C28 fragment (13)6c of apoptolidinone A
applying our new organic chemistry of sulfur dioxide (Scheme 2).
The enantiomerically enriched (97% ee) diene 417 (derived from
inexpensive (R)-1-phenylethanol) and silyl ethers 5 (1 : 1 E : Z
1
of the tetrahydropyran moiety of 10 was confirmed by its 2D H
NMR NOESY spectrum and typical coupling constants between
vicinal protons.23 Acidic treatment of hemiacetal 10 (HCl–MeOH,
50 uC) led to desilylation, debenzylation and Fischer glycosidation
giving the corresponding methyl pyranoside which was not
isolated. Careful treatment of the resulting triol with Ac2O–
pyridine (0 to 20 uC) acetylated selectively the acyclic 1,2-diol
moiety affording diacetate 11. The cyclohexanol moiety was then
silylated into silyl ether 12 under standard conditions. Sharpless
asymmetric dihydroxylation24 of the terminal alkene moiety of 12
Fig. 1 Structure of apoptolidins.
aInstitute of Pharmaceutical Sciences, ETH Zu¨rich, Wolfgang-Pauli-
Strasse 10, CH, 8093, Zu¨rich, Switzerland
bLaboratory of Glycochemistry and Asymmetric Synthesis (LGSA),
Swiss Federal Institute of Technology (EPFL, ) Batochime, CH, 1015,
Lausanne, Switzerland. E-mail: pierre.vogel@epfl.ch;
Scheme 1 Reaction cascade involving C–C-bond formation between
electron-rich 1,3-dienes and alkenes via umpolung with sulfur dioxide, and
stereoselective retro-ene elimination of SO2: one-pot synthesis of
polyfunctional stereotriads.
Fax: 0041 21 693 93 75; Tel: 0041 21 693 93 71
{ Electronic supplementary information (ESI) available: Experimental and
characterization data, including NMR spectra, for compounds 6, 7, 9, 10,
11, 12 and 13 and the 20-epimer of 13. See DOI: 10.1039/b701293d
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2411–2413 | 2411

View Article Online
Notes and references
1 (a) J. W. Kim, H. Adachi, K. Shin-ya, Y. Hayakawa and H. Seto,
J. Antibiot., 1997, 50, 628–630; (b) Y. Hayakawa, J. W. Kim, H. Adachi,
K. Shin-ya, K. Fujita and H. Seto, J. Am. Chem. Soc., 1998, 120,
3524–3525.
2 P. A. Wender, M. Sukopp and K. Longcore, Org. Lett., 2005, 7,
3025–3525.
3 A. R. Salomon, D. W. Voehrigner, L. A. Herzenberg and C. Khosla,
Proc. Natl. Acad. Sci. USA, 2000, 97, 14766–14771.
4 (a) A. R. Salomon, D. W. Voehringer, L. A. Herzenberg and C. Khosla,
Chem. Biol., 2001, 8, 71–80; (b) A. R. Salomon, Y. Zhang, H. Seto and
C. Khosla, Org. Lett., 2001, 3, 57–59; (c) L. Benitez-Bribiesca, in When
Cells Die, ed. R. A. Lockshin, Z. Zakeri and J. L. Tilly, Wiley-Liss, New
York, 1998, p. 453.
5 (a) K. C. Nicolaou, Y. Li, K. C. Fylaktakidou, H. J. Mitchell, H. X. Wei
and B. Weyershausen, Angew. Chem., Int. Ed., 2001, 40, 3854–3857; (b)
K. C. Nicolaou, K. C. Fylaktakidou, H. Moneneschein, Y. Li,
B. Weyershausen, H. J. Mitchell, H. X. Wei, P. Guntupalli,
D. Hepworth and K. Sugita, J. Am. Chem. Soc., 2003, 125,
15433–15442; (c) K. C. Nicolaou, Y. Li, K. Sugita, H. Monenschein,
P. Guntupalli, H. J. Mitchell, K. C. Fylaktakidou, D. Vourloumis,
P. Giannakakou and A. O’Brate, J. Am. Chem. Soc., 2003, 125,
15443–15454.
6 (a) H. Wehlan, M. Dauber, M. T. M. Fernaud, J. Schuppan,
R. Mahrwald, B. Ziemer, M. E. J. Garc´ıa and U. Koert, Angew.
Chem., 2004, 116, 4698–4702, (Angew. Chem., Int. Ed., 2004, 43,
4597–4601); (b) J. Schuppan, H. Wehlan, S. Keiper and U. Koert,
Chem. Eur. J., 2006, 12, 7364–7377; (c) H. Wehlan, M. Dauber,
M. T. Mujica-Fernaud, J. Schuppan, S. Keiper, R. Mahrwald, M.-E.
Juarez Garc´ıa and U. Koert, Chem. Eur. J., 2006, 12, 7378–7397.
7 B. Wu, Q. Liu and G. A. Sulikowski, Angew. Chem., 2004, 116,
6841–6843, (Angew. Chem., Int. Ed., 2004, 43, 6673–6675).
8 M. T. Crimmins, H. S. Christie, K. Chaudhary and A. Long, J. Am.
Chem. Soc., 2005, 127, 13810–13812.
9 H. Wehlan, M. Dauber, M. T. M. Fernaud, J. Schuppan, R. Mahrwald,
B. Ziemer, M. E. Juarez-Garc´ıa and U. Koert, Angew. Chem., Int. Ed.,
2004, 43, 4597–4601.
10 (a) J. Schuppan, B. Ziemer and U. Koert, Tetrahedron Lett., 2000, 41,
621–624; (b) K. C. Nicolaou, Y. Li, B. Weyershausen and H.-X. Wei,
Chem. Commun., 2000, 307–308; (c) G. A. Sulikowski, W.-M. Lee, B. Jin
and B. Wu, Org. Lett., 2000, 2, 1439–1442; (d) K. Toshima, T. Arita,
K. Kato, D. Tanaka and S. Matsumura, Tetrahedron Lett., 2001, 42,
8873–8876; (e) Y. Chen, J. B. Evarts, E. Torres and P. L. Fuchs, Org.
Lett., 2002, 4, 3571–3574; (f) J. D. Pennington, H. J. Williams,
A. R. Salomon and G. A. Sulikowski, Org. Lett., 2002, 4, 3823–3825; (g)
P. A. Wender, O. D. Jankowski, E. A. Tabet and H. Seto, Org. Lett.,
2003, 5, 2299–2302; (h) K. Abe, K. Kato, T. Arai, M. A. Rahim,
I. Sultana, S. Matsumura and K. Toshima, Tetrahedron Lett., 2004, 45,
8849–8853; (i) W. D. Paquette and R. E. Taylor, Org. Lett., 2004, 6,
103–106; (j) M. T. Crimmins and A. Long, Org. Lett., 2005, 7,
4157–4160; (k) B. Jin, Q. Liu and G. A. Sulikowski, Tetrahedron, 2005,
61, 401–408.
11 For a review, see: P. T. Daniel, U. Koert and J. Schuppan, Angew.
Chem., 2006, 118, 886–908, (Angew. Chem., Int. Ed., 2006, 45, 872–893).
12 L. C. Bouchez and P. Vogel, Chem. Eur. J., 2005, 11, 4609–4620.
13 (a) X. Huang and P. Vogel, Synthesis, 2002, 232–236; (b) L. C. Bouchez,
M. Turks, S. R. Dubbaka, F. Fonquerne, C. Craita, S. Laclef and
P. Vogel, Tetrahedron, 2005, 61, 11473–11487.
14 (a) J.-M. Roulet, G. Puhr and P. Vogel, Tetrahedron Lett., 1997, 38,
6202–6204; (b) M. Turks, M. C. Murcia, R. Scopelliti and P. Vogel,
Org. Lett., 2004, 6, 1053–1057.
15 M. Turks, X. Huang and P. Vogel, Chem. Eur. J., 2005, 11, 465–476.
16 M. Turks, M. C. Murcia, R. Scopelliti and P. Vogel, Org. Lett., 2004, 6,
3031–3034.
17 V. Narkevitch, P. Vogel and K. Schenk, Helv. Chim. Acta, 2002, 85,
1674–1685.
18 (a) P. Cazeau, F. Duboudin, F. Moulines, O. Babot and J. Dunogues,
Tetrahedron, 1987, 43, 2088–2100; (b) I. Mamoru, S. Yuichi and
F. Takamasa, Tetrahedron Lett., 1999, 40, 711–714.
19 G. M. Rubottom, M. A. Vazquez and D. R. Pelegrina, Tetrahedron
Lett., 1974, 15, 4319–4322.
Scheme 2 Synthesis of Koert’s C16–C28 polyketide fragment.
using (DHQD)2PYR ligand25 furnished a 4.5 : 1 mixture of the
corresponding 1,2-diol. Selective monomethylation of the crude
mixture using MeI–Ag2O26 afforded a mixture (4.5 : 1) of alcohol
13 (68%) and its C27-epimer which can be separated by flash
column chromatography on silica gel. Pleasingly, spectral data of
alcohol 1327 were identical to those reported by Koert and co-
workers for this compound.6c
The rapid access of this advanced fragment of apoptolidin A is
made possible by the utilisation of our one-pot reaction cascade
giving rise to functionally rich stereotriads. These quickly accessible
intermediates contain both an alkyl ketone on one terminus,
allowing for aldol couplings, and an alkene on the other which can
readily be converted to other functionalities for chain expansion.
Our synthesis of the alcohol 13, key intermediate used for the total
synthesis of apoptolidin A,6c starts from inexpensive diene 4 and
enoxysilane 5 and requires only nine steps, thus making the
shortest synthesis of the C16–C28 fragment reported to date. The
method developed should enable us to prepare several analogues
of biological interest.
20 (a) C. Bonini, L. Chiummiento, M. Pullez, G. Solladie´ and F. Colobert,
J. Org. Chem., 2004, 15, 5015–5022; (b) I. V. Hartung, B. Niess,
L. O. Haustedt and H. M. Hoffmann, Org. Lett., 2002, 3239–3242; (c)
We thank the Roche Research Foundation (Basel) and the Swiss
National Science Foundation (Bern) for financial support.
2412 | Chem. Commun., 2007, 2411–2413
This journal is ß The Royal Society of Chemistry 2007

View Article Online
G. A. Sulikowski, L. Wai-Man, J. Bohan and W. Bin, Org. Lett., 2000,
2, 1439–1445.
21 (a) D. A. Evans, M. G. Yang, M. J. Dart, J. L. Duffy and A. S. Kim,
J. Am. Chem. Soc., 1995, 117, 9598–9599; (b) D. A. Evans, M. J. Dart,
J. L. Duffy and M. G. Yang, J. Am. Chem. Soc., 1996, 118,
4322–4343.
26 P. A. Clarke, R. L. Davie and S. Peace, Tetrahedron, 2005, 61,
2335–2351.
21
27 Data of 13: Rf (pentane–Et2O 1 : 2) = 0.24, [a]D = +42.6 (c = 0.85,
CHCl3), lit. [a]D = +45.1 (c = 0.85, CHCl3).6c 1H NMR (400 MHz,
24
CDCl3) dH: 0.59 (q, 6 H, J = 8.1), 0.99 (t, 5 H, J = 7.9), 1.17 (d, 3 H, J =
7.2), 1.25–1.34 (m, 1 H), 1.76, 1.79 (2 s, 6 H), 1.89–1.98 (m, 1 H), 2.18–
2.33 (m, 2 H), 2.93 (dd, 1 H, J = 8.8, 8.0), 3.03–3.07 (m, 1 H), 3.02, 3.33,
3.36 (3 s, 9 H), 3.34–3.46 (m, 3 H), 4.01–4.07 (m, 1 H), 4.09 (dd, 1 H), J =
10.2, 4.8), 4.27–4.36 (m, 3 H), 5.49 (d, 1 H, J = 5.3), 5.91–5.98 (m, 1 H),
7.06–7.30 (m, 5 H). 13C NMR (100.6 MHz, C6D6) dC: 5.4, 5.8, 7.2,
11.8, 20.55, 20.60, 36.8, 36.9, 37.6, 40.5, 48.1, 58.1, 58.6, 66.7, 66.1, 69.3,
72.6, 73.4, 73.6, 73.7, 77.1, 77.7, 101.4, 127.6, 127.7, 128.5, 139.1, 169.4,
169.7.
22 H. C. Brown, K. S. Bhat and R. S. Randad, J. Org. Chem., 1989, 54,
1571–1576.
23 Chair conformation (3C6): 3J(H4–H5) = 4.3 Hz, 3J(H5–H6) = 1.6 Hz.
24 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483–2547.
25 G. A. Crispino, K.-S. Jeong, H. C. Kolb, Z.-M. Wang, D. Xu and
K. B. Sharpless, J. Org. Chem., 1993, 58, 3785–3786.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 2411–2413 | 2413