Progress in the synthesis of the lituarines: Stereocontrol in sequential C-C bond formation on a spirobutenolide template

Article abstract of DOI:10.1021/ol0520018

(Chemical Equation Presented) We describe elaboration of a tricyclic spirobutenolide corresponding to the C(7-18) tricyclic substructure common to lituarines A-C. Conjugate addition, to install the C(16) methyl, is followed by construction of the crucial

Full text of DOI:10.1021/ol0520018

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5007-5010
Progress in the Synthesis of the
Lituarines: Stereocontrol in Sequential
C−C Bond Formation on a
Spirobutenolide Template
Jeremy Robertson* and Jonathan W. P. Dallimore
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K.
jeremy.robertson@chem.ox.ac.uk
Received August 18, 2005
ABSTRACT
We describe elaboration of a tricyclic spirobutenolide corresponding to the C(7
addition, to install the C(16) methyl, is followed by construction of the crucial C(18
spiroacetal C(18) O oxonium ion. Esterification with a C(1
−
18) tricyclic substructure common to lituarines A
−
C. Conjugate
−19) bond by silyl enol ether addition to the derived
−
−
6) acid, and selective ozonolysis to release the C(23) carbonyl, complete the
assembly of all the carbons present in the lituarine macrocyclic core.
We recently reported1 the preparation of two major structural
fragments of the lituarines, a group of cytotoxic, antifungal
spiroacetal macrolides isolated from Lituaria australasiae.2
Our plan for the union of these fragments and continuation
to the natural products is shown retrosynthetically in Scheme
1. Introduction of a C(19-24) hydroxydiketone equivalent
(4) at C(18) of tricycle 3, esterification with a C(1-6) acid
(5 or 6), release and elimination of the two protected primary
hydroxyl groups, olefin metathesis to close the macrocycle
at the C(6-7) bond, and epoxidation were expected to
provide the macrocyclic core; further studies would then
determine at which point in the route the C(24) N-acyl-
dienamine side chain would be installed. In parallel
studies, Smith’s group has described a fundamentally dif-
ferent synthesis of a C(7-19) fragment3 and its elabor-
ation by Horner-Wadsworth-Emmons extension at C(7)
and subsequent regioselective oxidation.4 In the Smith
approach, it is likely that macrocyclization will be achieved
by esterification after incorporation of a C(20-24) unit at
C(19).
In this paper, we focus on the introduction of the two new
C-C bonds at C(16) and C(18) in the tetrahydrofuran ring
since these are defining steps within the overall plan. Work
on the first of these goals was set to follow from our model
study in which we showed that conjugate addition of
(MeS)3CLi to spirobutenolide 7 (Scheme 2) proceeded
cleanly with high anti stereoselectivity (95:5 dr) with respect
to the tetrahydropyran ring oxygen;1b,5 furthermore, subse-
(1) (a) Robertson, J.; Dallimore, J. W. P.; Meo, P. Org. Lett. 2004, 6,
3857. (b) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.; Hoarau,
C. Org. Lett. 2004, 6, 3861.
(2) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-
M.; Aumelas, A. J. Org. Chem. 1992, 57, 5857.
(3) (a) Smith, A. B., III; Frohn, M. Org. Lett. 2001, 3, 3979. (b) Smith,
A. B., III; Frohn, M. Org. Lett. 2002, 4, 4183 (correction).
(4) Smith, A. B., III; Walsh, S. P.; Frohn, M.; Duffey, M. O. Org. Lett.
2005, 7, 139.
10.1021/ol0520018 CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/27/2005

Scheme 1. Lituarine Synthetic Strategy
quent Raney nickel desulfurization of adduct 8 did not
compromise this relative stereochemistry.
are well-known in the carbohydrate literature,6 the application
of such a method to the elaboration of spiroacetals has not
been described, to the best of our knowledge. In fact, the
use in synthesis of spirocyclic oxonium ions of this type is
surprisingly uncommon; for example, Mead7 and Brimble8
have described allylation of 1,7-dioxaspiro[5.5]undecanes,
and Hegedus has shown that 2-acetoxy-5-ethoxy tetrahydro-
furan derivatives undergo Lewis acid-mediated substitution
at the 2-position selectively with a variety of nucleophiles.9
Against this was evidence that these reactions could be
problematic with functionalized nucleophiles,10 and it was
with some trepidation that we embarked on the model study.
To work with a stereochemically simple system we chose
spirobutyrolactone 1111 (Scheme 3) as the starting point
which was prepared in a single step from 5-nitropentanol12
in an unoptimized cascade conjugate addition-Nef-cycliza-
tion sequence.13 Treatment of the derived acetoxy spiroacetal
12 with 3-methyl-2-(trimethylsilanyl)oxybutene (13)14 in the
Scheme 2. Conjugate Addition Model Study1b
With this result secured, attention turned to modeling the
formation of the C(18-19) bond since we were unable to
find an appropriate precedent for this step which we intended
to achieve through lactone reduction, acetylation, and
subsequent trapping of the derived oxonium ion (10) with a
silyl enol ether (Figure 1). While such bond constructions
Scheme 3. C(18-19) Bond Formation Model Study
Figure 1. Proposed construction of the C(18-19) bond.
5008
Org. Lett., Vol. 7, No. 22, 2005

Scheme 4. Elaboration of Butenolide 15 to an Advanced Lituarine B,C Intermediate
presence of SnBr4 resulted in the formation of a single
butenolide 1515 (Scheme 4) proved to be reliable and the
sequence was followed without incident to give intermediate
17 with a fully functionalized tetrahydrofuran ring. Both of
the key C-C bond-forming steps proceeded with high
stereocontrol. The C(16) stereochemistry, arising from the
conjugate addition, was established after complete assign-
compound, which we were delighted to find was the desired
ketone 14 obtained as an approximately 1:1 mixture of
diastereomers. Although we had not expected significant
diastereocontrol in this reaction, we were not able to rule
out the possibility that the addition had taken place to give
predominantly one stereoisomer and that loss of stereochem-
ical information had occurred subsequently by epimerisation
at the acetal center, e.g., by protic acid catalysis as illustrated
in Scheme 3. Since this mode of equilibration would be
accompanied by loss of anomeric stabilization in the (rigid)
lituarine system, we were confident that the results of high
stereocontrol in the analogous reaction in that system would
be retained during workup and purification.
1
ment of the H and 13C NMR spectra; from this, NOESY
correlations were established between the C(16) methyl and
both C(14) protons, and between H(16) and the C(12) methyl,
as illustrated in Figure 2. Second, in the reaction to form
The results of these model studies were then brought to
bear on the total synthesis. The chemistry from tricyclic
(5) Our working hypothesis is that a stabilizing interaction of the
incoming nucleophile, and then the forming C-C bond, with the tetra-
hydropyran [C(15)-O]σ* acts cooperatively with electrostatic and solvation
effects to favor attack anti to the six-membered ring oxygen. Cf. Corey, E.
J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063.
(6) Ogawa, T.; Pernet, A. G.; Hanessian, S. G. Tetrahedron Lett. 1973,
3543.
Figure 2. Diagnostic NOESY correlations.
(7) (a) Mead, K. T.; Zemribo, R. Synlett 1996, 1063. (b) Zemribo, R.;
Mead, K. T. Synlett 2000, 1569.
(8) Brimble, M. A.; Fares, F. A.; Turner, P. J. Chem. Soc., Perkin Trans.
1 1998, 677.
(9) Umbricht, G.; Hellman, M. D.; Hegedus, L. S. J. Org. Chem. 1998,
63, 3, 5173.
(10) Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K.
Org. Biomol. Chem. 2003, 104.
1
adduct 17, the H NMR spectrum of the crude product
indicated the presence of a single diastereomer only. As-
signment of the newly formed stereogenic center at C(18)
followed from a NOESY correlation between the C(16)
methyl and H(18), and the absence of a correlation between
H(16) and H(18).
(11) Fukuda, H.; Takeda, M.; Sato, Y.; Mitsunobu, O. Synthesis 1979,
368.
The sense of stereoselectivity in the formation of adduct
17 is accommodated by Woerpel’s “inside attack” model16
(12) Brewster, K.; Harrison, J. M.; Inch, T. D.; Williams, N. J. Chem.
Soc., Perkin Trans. 1 1987, 21.
(13) Cf. (a) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D. Synthesis
2002, 2725. (b) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D. Synthesis
2003, 316 (correction).
(14) Prepared in a standard procedure from methyl isopropyl ketone,
LDA, and TMSCl. Cf. Beutelman, H. P.; Xie, L.; Saunders, W. H., Jr. J.
Org. Chem. 1989, 54, 1703.
(15) Prepared on a multigram scale in a variant of the synthesis reported
in ref 1b; in particular, the absolute stereochemistry was established by
kinetic resolution through Sharpless epoxidation of (()-2-methylhepta-1,6-
dien-3-ol.
Org. Lett., Vol. 7, No. 22, 2005
5009

in which, discounting the influence of the counterion,
the oxonium ion is trapped, under stereoelectronic control,
from the upper face of envelope conformation A in prefer-
ence to the lower face of conformation B (Figure 3). This
From this point, we have progressed the synthesis fol-
lowing the route established by our earlier study,1a essentially
without modification. Some care was needed in the selective
desilylation of compound 17 in order to avoid epimerisation,
for example at C(21), and we prevented over-oxidation
during the ozonolysis of the methylene group in 18 by
keeping the reaction time down to an absolute minimum (6
s) in exposing the C(23) carbonyl group. These last three
steps remain unoptimized pending the production of more
material prior to completion of the synthesis as described in
the introductory paragraph.
Acknowledgment. We are grateful to the EPSRC for
funding (GR/R25842/01, GR/P01397/01) and to Dr. Paul
Meo for developing the synthesis of butenolide 15. We
particularly thank Drs. Barbara Odell and Tim Claridge for
NMR experiments.
Figure 3. Rationalization of stereocontrol in the addition of silyl
enol ether 4 to form 17.
reaction provides a further illustration17 of the importance
of a C(3) methyl substituent (furan numbering) in dictating
the stereochemical course of additions to C(5)-O oxonium
ions in these systems.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Larsen, C. H.; Ridgeway, B. H.; Shaw, J. T.; Woerpel, K. A. J.
Am. Chem. Soc. 1999, 121, 12208.
(17) For a survey of the stereoselectivity of silyl enol ether additions to
isomeric methyl γ-lactols in the presence of a variety of Lewis acids, see:
Schmitt, A.; Reiâig, H.-U. Eur. J. Org. Chem. 2001, 1169.
OL0520018
5010
Org. Lett., Vol. 7, No. 22, 2005