Asymmetric synthesis of the tetrahydropyran ring, C32-C38 fragment, of phorboxazoles

Article abstract of DOI:10.1021/ol048099s

(Chemical Equation Presented) The asymmetric synthesis of a model aldehyde (2R,6R)-2 and the C32-C38 fragment of phorboxazoles, (2R,4R,6R)-1, is described using a sulfoxide as chiral auxiliary. Key advances include the stereoselective reductions of β-keto

Full text of DOI:10.1021/ol048099s

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4335-4338
Asymmetric Synthesis of the
Tetrahydropyran Ring, C32 C38
Fragment, of Phorboxazoles
−
Yasmin Brinkmann,†,‡ M. Carmen Carren˜o,*,† Antonio Urbano,†
Franc
¸
oise Colobert,*,‡ and Guy Solladie´*,‡
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid, Spain, and Laboratoire de Ste´re´ochimie associe´ au
CNRS, UniVersite´ Louis Pasteur, E.C.P.M., 25 rue Becquerel,
67087 Strasbourg Cedex 2, France
carmen.carrenno@uam.es
Received September 17, 2004
ABSTRACT
The asymmetric synthesis of a model aldehyde (2R,6R)-2 and the C32−C38 fragment of phorboxazoles, (2R,4R,6R)-1, is described using a
sulfoxide as chiral auxiliary. Key advances include the stereoselective reductions of
â
-keto- or -diketosulfoxides, the acid-catalyzed cyclization
â,γ
of enantiopure sulfinyl hydroxy ketone precursors to the tetrahydropyran ring, and the Pummerer reaction on the pendant sulfoxide to create
the formyl group.
Phorboxazoles A and B are unique tetrahydropyranoxazole-
based macrolides isolated in 1995 by Searle and Molinski
from a species of Indian Ocean sponge.1 Both compounds
were shown to inhibit growth of a wide range of different
tumoral cells.2 Their novel structure and potent biological
activity have combined to make the scarcely available
phorboxazoles attractive synthetic targets for the chemistry
community.3
Pattenden et al.7 in 2003. Phorboxazole B has been prepared
by Evans et al. in 2000.8
The phorboxazole skeleton consists of two 2,4-disubsti-
tuted oxazoles and four tetrahydropyrans, and 15 stereogenic
centers organized into a macrolide (C1-C26) and a side-
(4) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, Ch. S. J. Am. Chem.
Soc. 1998, 120, 5597-5598.
(5) (a) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M.
J. Am. Chem. Soc. 2001, 123, 4834-4836. (b) Smith, A. B., III; Minbiole,
K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942-
10953.
Phorboxazole A has been synthesized by Forsyth et al. in
1998,4 by Smith et al. in 2001,5 and by Williams et al.6 and
(6) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner,
M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258-1262.
(7) (a) Gonza´lez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003,
42, 1255-1258. (b) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan,
D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem 2003, 1,
4173-4208.
(8) (a) Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S.
Angew. Chem., Int. Ed. 2000, 39, 2533-2536. (b) Evans, D. A.; Fitch, D.
M.; Angew. Chem., Int. Ed. 2000, 39, 2536-2540. (c) Evans, D. A.; Fitch,
D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033-
10046.
† Universidad Auto´noma de Madrid.
‡ Universite´ Louis Pasteur.
(1) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126-
8131.
(2) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J.
Am. Chem. Soc. 1996, 118, 9422-9423. (b) Molinski, T. F. Tetrahedron
Lett. 1996, 37, 7879-7880.
(3) For a review on the total synthesis of the phorboxazoles, see:
Haustedt, L. O.; Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int.
Ed. 2003, 42, 2711-2716.
10.1021/ol048099s CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/08/2004

of phorboxazoles, illustrated with the asymmetric synthesis
of (2R,6R)-2, a model compound lacking the OMe group at
C-4, and (2R,4R,6R)-1, the enantiomer of the derivative
prepared by Molinski, bearing the three stereogenic centers
with the correct absolute configuration present in the natural
phorboxazoles.
The synthesis of the model compound (2R,6R)-2, depicted
in Scheme 1, began with the condensation of commercially
Scheme 1. Asymmetric Synthesis of Model Compound
(2R,6R)-2
chain substructure (C27-C46). Of the four THP rings, only
one, the C33-C37 fragment, possesses a hemiketal func-
tionality and three stereogenic centers. Besides the synthetic
efforts achieved for the stereoselective construction of this
portion in the total syntheses of phorboxazoles, several
groups have reported different strategies for the enantio-
selective assembly of this THP-hemiketal ring.9 Among them,
it is worth mentioning the first stereoselective approach to
this fragment published by Molinski et al. in 1996,2a where
derivative (2S,4S,6S)-1, bearing three stereogenic centers with
the configuration opposite to that present in the natural
phorboxazoles, was synthesized using malic acid as starting
material. This synthesis of a model compound and the use
of different NMR techniques served for the elucidation of
the absolute configuration of 14 out of the 15 stereocenters
in phorboxazoles.2a
In connection with a program devoted to asymmetric
synthesis mediated by sulfoxides,10 we have recently de-
scribed a highly stereoselective approach to different sized
cis-disubstituted oxygenated heterocycles (five-, six-, and
seven-membered rings) based on the reductive cyclization
of the corresponding enantiopure hydroxy sulfinyl ketones.11
In this communication, we report the synthesis of several
hydroxy sulfinylated intermediates and their use for the
enantioselective construction of the C32-C38 THP fragment
available glutaric anhydride (3) and the carbanion of (-)-
(SS)-methyl-p-tolyl sulfoxide (4)12 to give enantiopure â-ke-
tosulfoxide (SS)-5,13 in 84% yield. The transformation of
the carboxylic group of (SS)-5 into the Weinreb amide (SS)-6
was effected, in 98% yield, by treatment with N,O-dimeth-
ylhydroxylamine hydrochloride in the presence of diisopro-
(9) (a) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183-186.
(b) Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron Lett.
1998, 39, 6099-6102. (c) Wolbers, P.; Hoffmann, H. M. R. Synthesis 1999,
797-802. (d) Williams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A.
Org. Lett. 2000, 2, 3023-3026. (e) Marshall, J. A.; Yanik, M. M.
Tetrahedron Lett. 2000, 41, 4717-4721. (f) Li, R. D.; Tu, Y. Q.; Lin, G.-
Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 8729-8732. (g) Yadav, J. S.;
Rajaiah, G. Synlett 2004, 1743-1746.
(10) Overviews: (a) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´,
G. ARKIVOC 2003, 7, 328-401. (b) Carren˜o, M. C. Chem. ReV. 1995, 95,
1717-1760. Recent work: (c) Carren˜o, M. C.; Sanz-Cuesta, M. J.; Colobert,
F.; Solladie´, G. Org. Lett. 2004, 6, 3537-3540. (d) Bonini, C.; Chium-
miento, L.; Pullez, M.; Solladie, G.; Colobert, F. J. Org. Chem. 2004, 69,
5015-5022. (e) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem. Eur.
J. 2003, 9, 4118-4131. (f) Carren˜o, M. C.; Garcia-Cerrada, S.; Sanz-Cuesta,
M. J.; Urbano, A. J. Org. Chem. 2003, 68, 4315-4321.
(11) (a) Colobert, F.; Des Mazery, R.; Solladie´, G.; Carren˜o, M. C. Org.
Lett. 2002, 4, 1723-1725. (b) Carren˜o, M. C.; Des Mazery, R.; Urbano,
A.; Colobert, F.; Solladie´, G. J. Org. Chem. 2003, 68, 7779-7787. (c)
Carren˜o, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.; Solladie´, G.
Org. Lett. 2004, 6, 297-299.
(12) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173-175.
(13) (SR) enantiomer: Solladie´, G.; Maestro, M. C.; Rubio, A.; Pedregal,
C.; Carreno, M. C.; Garc´ıa Ruano, J. L. J. Org. Chem. 1991, 56, 2317-
2322.
4336
Org. Lett., Vol. 6, No. 23, 2004

pylethylamine (DIPEA) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI) and a catalytic
amount of DMAP.14 The stereoselective reduction of deriva-
tive (SS)-6 with diisobutylaluminum hydride (DIBALH)
afforded a 7:93 mixture of diastereoisomeric alcohols
(5S,SS)-7 and (5R,SS)-8, from which diastereoisomer (5R,SS)-8
was isolated pure after chromatographic separation in 75%
yield (based on recovered starting material). Without protec-
tion of the OH group, amide (5R,SS)-8 reacted with an excess
of methylmagnesium bromide in THF at room temperature,
affording enantiopure methyl ketone (6R,SS)-9 in 83% yield.
The cyclization of δ-hydroxy ketone (6R,SS)-9 into the
corresponding THP-ketal ring was carried out by treatment
with pyridinium p-toluenesulfonate (PPTS) in methanol
giving rise to a 13:87 mixture of cyclic derivatives (2S,6R,SS)-
10 and (2R,6R,SS)-11 from which the major diastereoisomer
(2R,6R,SS)-11 {[R]20D ) -270 (c 1.0, CHCl3)} was separated
in 77% yield after flash chromatography. Preferred formation
of the R-anomer 11 was expected on the basis of the higher
stability of the axially positioned OMe ketal group.15 The
structural assignment for 11 was verified by NOESY
experiments (interaction of H-6 with the OMe group and
not with the Me group). Finally, the treatment of sulfoxide
(2R,6R,SS)-11 under the typical Pummerer reaction condi-
tions16 [(i) trifluoroacetic anhydride (TFAA), 2,6-lutidine;
(ii) NaHCO3] gave rise, after flash chromatography on
deactivated silica gel (see Supporting Information), to
aldehyde (2R,6R)-2 {[R]20D ) -40 (c 0.36, CH2Cl2)} in 42%
yield, as an unstable colorless oil.
Scheme 2. Asymmetric Synthesis of Compound (2R,4R,6R)-1,
the C32-C38 Fragment of Phorboxazoles
Having demonstrated the feasibility of this strategy for
the stereoselective construction of the THP-hemiketal ring
of phorboxazoles, we turned our attention to enantioselective
synthesis of the C32-C38 fragment present in the natural
derivatives. The synthetic sequence leading to enantiomeri-
cally pure ketone (4R,6R,SS)-19, immediate precursor of the
tetrahydropyran moiety of (2R,4R,6R)-1, is outlined in
Scheme 2.
Methyl 3,5-diketohexanoate (12)17 was submitted to treat-
ment with sodium hydride (1 equiv) and tert-butyllithium
(2 equiv) to give the corresponding trianion intermediate,
whose sulfinylation at C-6 occurred in the presence of (+)-
menthyl-(SS)-(p-toluene)sulfinate (13).12 Under these condi-
tions, diketosulfoxide (SS)-14 was obtained in 70% yield,
showing the carbonyl group at C-3 totally enolized.18a The
reduction of (SS)-14 with DIBALH18b,c took place chemose-
lectively at the C-5 carbonyl group, probably as a conse-
quence of the aluminum atom of the DIBALH coordinating
the sulfinyl oxygen,19 affording the hydroxysulfoxide (5R,SS)-
15. This reaction was highly stereoselective, but the forma-
tion of two byproducts characterized as the starting material
12 and p-ditolyl disulfide could not be avoided. Purification
of 15 by flash chromatography led to further degradations.
Finally, a careful washing of the crude reduction mixture
with cold ether and recrystallization (CH2Cl2/ether) afforded
pure 15 in yields ranging from 42% to 60%. The remaining
ketone was stereoselectively reduced to the corresponding
anti-diol (3R,5R,SS)-16,18b in 80% yield, following the Evans
protocol using tetramethylammonium triacetoxyborohydride,
Me4NHB(OAc)3, as the reducing agent.20
The treatment of methyl ester (3R,5R,SS)-16 with N,O-
dimethylhydroxylamine hydrochloride in the presence of
trimethyl aluminum21 furnished the Weinreb amide (3R,5R,SS)-
17 in 82% yield (Scheme 2). Protection of the diol unit of
(14) Satoshi, S.; Mori, K. Eur. J. Org. Chem. 1999, 1679-1686.
(15) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, 1983; pp 5-20. (b) Smith, M. B.; March,
J. AdVanced Organic Chemistry. Reactions, Mechanisms and Structure, 5th
ed.; Wiley-Interscience: New York, 2001; p 176.
(16) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
(17) Batelaan, J. G. Synth. Commun. 1976, 6, 81-83.
(18) (a) Solladie´, G.; Bauder, C.; Rossi, L. J. Org. Chem. 1995, 60,
7774-7777. (b) Solladie´, G.; Colobert, F.; Denni, D. Tetrahedron:
Asymmetry 1998, 9, 3081-3094. (c) Solladie´, G.; Wilb, N.; Bauder, C.
Eur. J. Org. Chem. 1999, 3021-3026.
(19) Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Mart´ın, A.; Pedregal, C.;
Rodr´ıguez, J. H.; Rubio, A.; Sanchez, J.; Solladie´, G. J. Org. Chem. 1990,
55, 2120-2128.
(20) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 116, 3560-3578.
Org. Lett., Vol. 6, No. 23, 2004
4337

aldehyde (2R,4R,6R)-1 {[R]20 ) -66 (c 0.28, CHCl3)},
D
bearing the C32-C38 fragment of phorboxazoles, in 49%
yield. This transformation allowed the generation of the
formyl-substituted heterocycle in the last step by the
intermediacy of the sulfoxide. The three stereogenic centers
of 1 have the same absolute configuration as the correspond-
ing moiety in the natural enantiomers. Derivative (2R,4R,6R)-1
showed physical and spectroscopic parameters identical to
those described for the enantiomer (2S,4S,6S)-1 reported by
Molinski except in the sign of the optical rotation {[R]20
)
D
+52.5 (c 0.28, CHCl3)}.2a The stereoselective generation of
the carbinol group at C-38 of phorboxazoles with the correct
(R) absolute configuration has been achieved by Evans et
al.8c from an aldehyde similar to 1.
Figure 1. X-ray ORTEP for compound (2R,4R,6R,SS)-20.
In summary, our strategy, based on the stereoselective
reduction of several â-keto sufoxides and the acid-catalyzed
cyclization of the corresponding sulfinyl hydroxy ketones,
has been exemplified with an approach to the ketal THP ring
present in phorboxazoles. The asymmetric synthesis of model
compound (2R,6R)-2, lacking the oxygenated group at C-4,
has been achieved in six steps from commercially available
glutaric anhydride, and that of derivative 1, the C32-C38
fragment of natural phorboxazoles, in nine steps from methyl
3,5-diketohexanoate (12).
17 (2,2-dimethoxypropane, camphorsulfonic acid, acetone,
24 h, 84%), followed by reaction of the acetonide (3R,5R,SS)-
18 with methylmagnesium bromide, gave rise to sulfinyl
methyl ketone (4R,6R,SS)-19 in 75% yield. In this case, the
treatment of 19 with PPTS in MeOH afforded tetrahydro-
pyran (2R,4R,6R,SS)-20 {[R]20D ) -213 (c 2.4, CHCl3)} as
the unique diastereoisomer in optically pure form, after initial
deprotection of the acetonide of 19 and cyclization of the
4,6-dihydroxyketone intermediate. The structural assignment
of 20 was initially based on its NMR parameters, including
NOESY (interaction of H-4 and H-6 with the OMe group
and not with the Me group) and COSY experiments. The
(2R,4R,6R,SS) absolute configuration of all stereocenters
present in derivative 20 was later confirmed by X-ray
crystallography (Figure 1).
Acknowledgment. We thank Ministerio de Ciencia y
Tecnolog´ıa (Grant BQU2002-03371) and Centre Nationale
de la Recherche Scientifique (PICS 537) for financial
support. Y.B. also thanks Comunidad Auto´noma de Madrid
and Fundacio´n General de la Universidad Auto´noma de
Madrid for fellowships.
The free OH at C-4 on enantiopure derivative (2R,4R,6R,
SS)-20 (Scheme 2) was then methylated using NaH and MeI
to furnish in 59% yield (based on recovered starting material)
compound (2R,4R,6R,SS)-21 {[R]20 ) -320 (c 0.46,
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
for all new compounds and X-ray data for derivative
(2R,4R,6R,SS)-20. This material is available free of charge
via the Internet at http://pubs.acs.org.
D
CHCl3)}. Upon Pummerer reaction [(i) TFAA, 2,6-lutidine;
(ii) NaHCO3], sulfoxide 21 was transformed into the desired
(21) (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989-993. (b) Boukouvalas, J.; Fortier, G.; Radu, I. I. J. Org. Chem.
1998, 63, 916-917.
OL048099S
4338
Org. Lett., Vol. 6, No. 23, 2004