Total synthesis of deschlorocallipeltoside A [4]

Full text of DOI:10.1021/ja011424b

J. Am. Chem. Soc. 2001, 123, 9449-9450
9449
Total Synthesis of Deschlorocallipeltoside A
Barry M. Trost* and Janet L. Gunzner
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed June 11, 2001
Callipeltoside A (1) is a recently isolated cytotoxic agent from
a marine lithistida sponge (Callipelta sp.) with excellent prospects
for the study and treatment of cancer.1 It was found to inhibit in
vitro proliferation of NSCLC-N6 human bronchopulmonary
nonsmall-cell-lung carcinoma (11.26 µg/mL) and P388 (15.26 µg/
mL) cells. To study this fascinating molecule and its biological
activity, an efficient synthesis is required.2 Furthermore, there are
several unresolved stereochemical issues: (1) the relative con-
figuration of C-21 with respect to the macrolide and (2) the
absolute configuration of the natural product. Furthermore, the
relative configuration of the sugar with respect to the macrolide
rests only on two nOe’s.1a In this communication, we disclose a
facile synthesis of deschlorocallipeltoside (2) allowing for a
general entry to this structural type.
Figure 1. Structure of callipeltoside A 1 and 2.
Scheme 1a
Figure 1 illustrates a simplification of the synthetic target to
three building blocks: the core 3, the side chain 4, and the sugar
5. The three bond disconnections depicted facilitate the synthesis
of the core 3. The stereocenter at C-13 is envisioned to derive
from a palladium-catalyzed allylic alkylation and that at C-9 by
a diastereoselective reduction. The stereocenters at C-5, C-6, and
C-7 were conceived to derive from diastereoselective aldol-type
processes. The remaining stereocenter at C-8 came from the chiral
pool and thus was purchased.
Scheme 1 begins the journey with the synthesis of the C-7 to
C-11 fragment starting with the commerically available methyl
S-3-hydroxy-2-methylpropionate. The Weinreb amide 8 was made
by the Merck method3 using a magnesium reagent (98%) rather
than the more common aluminum reagents (best yield 65%).
Diastereoselective reduction of ketone 9 with achiral reducing
agents proved disappointing with threo:erythro ratios ranging from
0.5:1.0 to 1.8:1.0. Using 2-methyl (S)-CBS-oxazaborolidine,
borane reduction gave an excellent result.4
a Reagents and conditions: i.) TBDMSCl, imidazole, CH2Cl2, rt, 2h,
99%; ii.) MeNHOMe‚HCl, i-PrMgCl, THF, -20 °C, 1 h, 98%; iii.)
1-propynylmagnesium bromide, THF, 0 °C, 89%; iv.) 2-methyl (S)-CBS-
oxazaborolidine, BH3‚SMe2, THF, -30 °C, 1 h, 10:1 dr, 99%; v.) MeI,
Ag2 O, Et2O, rt, 4 h, 92%.
Scheme 2a
The extension of the C-7 to C-11 fragment to C-14 is outlined
in Scheme 2. The formation of the trisubstituted alkene requires
a regioselective Alder ene-type reaction. In the ideal situation,
the alcohol would already be activated for the subsequent allylic
alkylation. Neither of these two aspects had previously been
explored. Gratifyingly, this chain extension to form 12 proceeded
without any complications under our standard conditions for the
ruthenium-catalyzed alkene-alkyne coupling5 in 85% yield. The
use of chiral ligands was anticipated to control the regio- and
diastereoselectivity to set the C-13 stereocenter.6 Using the R,R-
ligand, ent-13, gave a matched pair to produce a 19:1 dr and a
3.0:1 branched-to-linear regioselectivity but with the configuration
opposite that of the natural product. Although this stereocenter
a Reagents and conditions: i.) CpRu(CH3CN)3PF6 (5 mol %), acetone,
rt, 20 min, 85%; ii.) p-methoxyphenol, 13 (7.5 mol %), Pd2dba3‚CHCl3
,
(2.5 mol %), tetrabutylammonium chloride, CH2Cl2 20:1 dr, 2:1
regioselectivity (2°:1°), 79%.
could subsequently be inverted by a Mitsunobu protocol, the
additional steps made that sequence unattractive. The S,S-ligand
13 provides a 20:1 dr and a somewhat reduced branched-to-linear
2:1 regioselectivity favoring the correct diastereomer which
allowed it to be isolated pure in 51% yield.
The completion of the synthesis of the core (23) of callipel-
toside A is displayed in Scheme 3. The kinetically formed E
lithium enolate of tert-butyl thiopropionate adds to aldehyde 16
to provide the Cram-type addition product 17 with 5:1 diaste-
reoselectivity.7 Felkin-Ahn type addition to aldehyde 18 of the
dienyl silyl ether 198 produced a single diastereomer 20 whose
silyl ether 21 was subjected to CAN to liberate the C-13 hydroxyl
group (22) for macrocyclization. The Boeckman thermal protocol
proceeded smoothly (82% yield) at high dilution to form the 14-
membered macrolide 23.9 The synthesis of the macrolide required
16 steps from commercially available 6 and proceeded in 11%
overall yield.
(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (b) Zampella, A.; D’Auria,
M. V.; Minale, L. Tetrahedron 1997, 53, 3243-3248.
(2) For synthetic work towards callipeltoside aglycon, see: (a) Hoye, T.
R.; Hongyu, Z. Org. Lett. 1999, 1, 169-171. (b) Velazquez, F.; Olivo, H. F.
Org. Lett. 2000, 2, 1931-1933. (c) Olivo, H. F.; Velazquez, F.; Trevisan, H.
C. Org. Lett. 2000, 2, 4055-4058. (d) Evans, D. A.; Burch, J. D. Org. Lett.
2001, 3, 503-505. (e) Paterson, I.; Davies, R. D. M.; Marquez, R. Angew.
Chem., Int. Ed. 2001, 40, 603-607. For synthetic work towards callipeltose,
see: (f) Smith, G. R.; Finley IV, J. J.; Giuliano, R. M. Carbohydrate Res.
1998, 308, 223-227. (g) Gurjar, M. K.; Reddy, R. Carbohydr. Lett. 1998, 3,
169-172. (h) Pihko, A. J.; Nicolaou, K. C.; Koskinen, A. M. P. Tetrahedon:
Asymmetry 2001, 12, 937-942.
(7) (a) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall, D. J. J. Am.
Chem. Soc. 1989, 111, 6247-6256. Akita, H. (b) Yamada, H.; Matsukura,
H.; Nakata, T.; Oishi, T. Tetrahedron Lett. 1988, 29, 6449-6452.
(8) Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.; Parlow,
J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.; Stevens, J. E. J. Org.
Chem. 1991, 56, 91-95.
(3) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461-5464.
(4) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214-3217.
(5) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739-7743.
(6) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545-4554.
10.1021/ja011424b CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/29/2001

9450 J. Am. Chem. Soc., Vol. 123, No. 38, 2001
Communications to the Editor
Scheme 3a
Scheme 5a
a Reagents and conditions: i.) CuI, pyrrolidine, THF, 0 °C to rt, 2 h,
38%; ii.) Red Al, THF, 0 °C, 1 h, 96%; iii: PPh3, CBr4, CH2Cl2, -40
°C, 1 h, 95%; iv.) P(OMe)3, 100 °C, 6 h, 97%.
Scheme 6a
a Reagents and conditions: i.) TBAF, THF, rt, 12 h, 96%; ii.) Dess-
Martin periodinane, NaHCO3, CH2Cl2, 0 °C, 84%; iii.) tert-butylthiopro-
pionate, LDA, THF, -108 °C, 3 h, 5:1 dr, 82%; iv.) TBDMSOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 2 h, 86%; v.) DIBAL, toluene, -78 °C, 3 h, 79%;
vi.) BF3‚OEt2 CH2Cl2 -78 °C, 45 min, 94%; vii.) TBDMSOTf, 2,6-
di-tert-butylpyridine, CH2Cl2, 0 °C, 1 h, 95%; viii.) CAN, acetone:H2O
(4:1), 0 °C, 5 min, 82%; ix.) 0.5 mM in toluene, 110 °C, 1 h, 82%.
a Reagents and conditions i.) OsO4, NMO, THF:H2O (4:1), 0 °C, 4 h;
NaIO4, THF:H2O, rt, 3 h, 80%; ii.) 4, LiHMDS, THF, -78 °C, 3 h, 4:1
(E:Z), 40%; iii.) HF‚pyr, MeOH, rt, 3 h; ppts, H2O, MeCN, rt, 1 h, 60%;
iv.) 5 , TMSOTf, dichloroethane, 4 Å MS, dichloroethane, rt, 30 min,
80%; v.) TBAF, acetic acid, THF, rt, 5 min, 95%.
,
,
Scheme 4a
1
zation to form the aglycone 27. Comparison of the H and 13C
NMR spectra of 27 to those reported by Paterson for the chloro
analogues2e showed a great likeness except for those regions
associated with the chloro side chain. The glycosylation proceeded
excellently to give a single diastereomer 2. Again, comparison
of the spectral data for 2 was virtually identical to that for
callipeltoside A (1) except in those regions associated with the
different side chains. The issue of the absolute configuration of
the natural product is unresolved. Unfortunately, Paterson’s data
indicates the chloro substituent can have an immense impact on
the sign of the rotation. Thus, although the sign of our rotation,
[R]D ) +45.0, is opposite that of the natural product,1a [R]D
)
a Reagents and conditions: i.) ref 2f; ii.) TBDMSOTf, 2,6-lutidine,
CH2Cl2, rt, 2 h, 55%; iii.) MeI, Ag2O, DMF, rt, 12 h, 69%, iv.) H2SO4,
PPTS, acetic anhydride, rt, 2 h, 81%; v.) K2CO3, MeOH, rt, 5 min, 89%;
vi.) Cl3CCN, NaH, CH2Cl2, rt, 10 min, 86%.
-17.6, it is still not possible to assign the absolute stereochem-
istry. The excellent agreement of our NMR spectra to that of the
natural product reinforces the correctness of the relative config-
uration of the sugar with respect to the macrolide.
This concise synthesis of deschloro callipeltoside is comprised
of 22 steps for the longest linear sequence with an additional five
steps for the enyne and 14 steps for the sugar, all starting with
commercially available materials. Either enantiomer of the core
macrolide can be readily accessed since it emanates from two
events: (1) the stereochemistry of methyl 3-hydroxy-2-methyl-
propionate (both enantiomers are commercially available) and (2)
the Pd AAA which can provide either epimer simply by choice
of ligand. Variation of the side chain including the naturally
occurring chloro analogues may also be accessed. Our route
highlights a new synthesis of geometrically defined trisubstituted
alkenes using Ru catalysis and regio- as well as diastereoselective
synthesis of an allyl ether via Pd AAA reactions that could not
be easily accomplished otherwise.
The timing for installation of the side chain was dictated by
the nature of the two-step oxidative cleavage of the alkene and
the Emmons-Wadsworth-Horner reaction. Best yields were
obtained by performing these transformations at the stage of the
macrolide 23. Scheme 4 outlines the synthesis of the trichloro-
acetimidate of the N-silyl derivative of callipeltose (15). Methyl
callipeltose (24) was synthesized starting from rhamnose as
previously reported.2f In our hands, the O-methylation was best
accomplished on the silylated oxazolidin-2-one. Scheme 5
provides a straightforward four-step approach to the deschloro
side chain.
Scheme 6 depicts the completion of the synthesis. Chemose-
lective cleavage was best accomplished by sequential dihydroxy-
lation followed by periodate cleavage. Emmons--Wadsworth-
Horner olefination produces a 4:1 E:Z mixture with the lithium
salt at -78 °C.10 Changing metal counterions to sodium or
potassium or performing the reaction at higher temperature erodes
the geometrical selectivity. Desilylation is accomplished by cycli-
Acknowledgment. We thank the National Institutes of Health for
their generous support of our programs. J.L.G. was supported by a
fellowship from the NIH (NCI). Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-San
Francisco, supported by the NIH Division of Research Resources.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Boeckman, R. K., Jr.; Pruitt, J. R., J. Am. Chem. Soc. 1989, 111, 8286-
8288. Chen, C.; Quinn, E. K.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem.
1993, 58, 5011-5014.
(10) Nicolaou, K. C.; Zipkin, R. E.; Dolle, R. E.; Harris, B. D. J. Am.
Chem. Soc. 1984, 106, 3748-3551.
JA011424B