Syntheses of the C(1-6) and C(19-24) fragments of lituarines A, B, and C

Article abstract of DOI:10.1021/ol048396x

(Chemical Equation Presented) Lituarines A-C are marine natural products comprising a tricyclic spiroacetal bridged at C(8) and C(18) by a functionalized ester linkage conceptually obtained from a C(19-24) alcohol and a C(1-6) carboxylic acid whose oxidat

Full text of DOI:10.1021/ol048396x

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3857-3859
Syntheses of the C(1−6) and C(19−24)
Fragments of Lituarines A, B, and C
Jeremy Robertson,* Jonathan W. P. Dallimore, and Paul Meo
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK
jeremy.robertson@chem.ox.ac.uk
Received August 12, 2004
ABSTRACT
Lituarines A
conceptually obtained from a C(19
routes are described to compounds 26 and 27, fully functionalized ester fragments of lituarine A and lituarines B and C, respectively.
−C are marine natural products comprising a tricyclic spiroacetal bridged at C(8) and C(18) by a functionalized ester linkage
−
24) alcohol and a C(1 6) carboxylic acid whose oxidation level varies at C(4) and C(5). Stereoselective
−
Lituarines A-C (1-3) were isolated from the New Cale-
donian sea pen, Lituaria australasiae, by Vidal and co-
workers in 1992.1 These compounds were found to inhibit
the growth of certain fungi and showed significant cytotox-
icity toward KB cells (1, IC50 ) 3.7-5.0 ng mL-1; 2, IC50
) 1.0-2.0 ng mL-1; 3, IC50 ) 5.0-6.0 ng mL-1). Because
the lituarines could not be obtained in a crystalline form,
their complex structures were determined mainly through
extensive NMR investigations and their absolute configura-
tions remain unknown.
and ring-closing metathesis will furnish the macrocycle. In
this Letter, we describe concise, stereoselective syntheses
of fully functionalized ester intermediates 26 and 27; our
approach to tricyclic lactone 4 is described in the ac-
companying paper.4
In our first approach (Scheme 2) to alcohol 5 (R ) H), a
terminal acetylene was chosen as a masked form of the
R-hydroxy ketone functionality. Pseudoephedrine amide 7
was alkylated under Myers’ optimized conditions5 with
trimethylsilylpropargyl iodide6 to give hexynone derivative
8 in good yield after treatment of the intermediate amide
with methyllithium. The trialkylsilyl group was found not
to interfere in Tamura’s protocol7 for oxidation of the triple
bond; however, the product obtained was not the expected
alcohol 5 (nor a cyclized variant thereof) but the trifluoro-
The synthetic challenge defined by the assemblage of bis-
(tetrahydropyran), spiroacetal, epoxide, and N-acyldien-amine
functionality, within a macrolactone ring, is not inconsider-
able, and, to date, only a single description of a synthetic
approach has been forthcoming.2 Our approach to the
macrolactone core, lacking the C(24) side-chain (Scheme 1),
is founded on key C-C bond-forming reactions at C(18-
19) and C(6-7). Thus, it is intended that esters formed by
hypothetical condensation of alcohol 5 with acids 6 will be
linked to tricyclic fragment 4 by nucleophilic addition of a
C(19-20) enolate equivalent to a C(18)-O oxonium ion,3
(3) Woerpel has developed a model for relative stereocontrol in nucleo-
philic additions to five-membered cyclic oxonium ions that predicts a 2,4-
anti relationship in related cases: Larsen, C. H.; Ridgway, B. H.; Shaw, J.
T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208-12209.
(4) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.; Hoarau,
C. Org. Lett. 2004, 6, 3861-3864.
(5) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511. (b) Myers,
A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116,
9361-9362.
(6) Rigby, J. H.; Cuisat, S. V. J. Org. Chem. 1993, 58, 6286-6291.
(7) Tamura, Y.; Yakura, T.; Haruta, J.-i.; Kita, Y. Tetrahedron Lett. 1985,
26, 3837-3840.
(1) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-
M.; Aumelas, A. J. Org. Chem. 1992, 57, 5857-5860.
(2) (a) Smith, A. B., III; Frohn, M. Org. Lett. 2001, 3, 3979-3982. (b)
Smith, A. B., III; Frohn, M. Org. Lett. 2002, 4, 4183 (correction).
10.1021/ol048396x CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/22/2004

Scheme 1. Synthetic Analysis of Lituarines A-C
Scheme 3. Synthesis of Alcohol 5 (R ) H) in Latent Form
from amide 7. Ketone 12 could be deprotected without
racemization under buffered TBAF conditions when the
reaction time was kept to a minimum (e3 h) in which case
some residual starting material remained. The ee of this
1
alcohol (91%) was determined on the basis of H NMR
analysis of its (R)-Mosher’s ester derivative.
Scheme 4. Synthesis of Acid 17 (cf. 6, R1 ) R2 ) H)
acetate derivative (9), a compound that proved to be
surprisingly stable and which could be passed through a silica
gel chromatography column without decomposition. At-
tempts to hydrolyze this ester to the corresponding alcohol
resulted in complex product mixtures, and this route was
discarded.
Identifying the C(23) (lituarine numbering) carbonyl group
as the most likely cause of problems in this route, we opted
for an alternative strategy in which this carbonyl would be
present in latent form as an alkene. To this end, iodide 11
was prepared8 in four efficient steps from triethyl phospho-
noacetate (Scheme 3) and used to alkylate the enolate derived
Separate routes (Schemes 4 and 5) to the variants of
carboxylic acid 6 were developed for the lituarine A synthesis
(R1 ) R2 ) H) and for the syntheses of lituarines B and C
(R1 ) OAc or OH, R2 ) OH). In the simpler case, the single
stereogenic center at C(4) was introduced, as before, using
Myers’ pseudoephedrine amide chemistry, this time in the
enantiomeric series. Thus, amide 14 was converted in two
high-yielding steps into ketone 15 and this ketone elaborated
by Horner-Wadsworth-Emmons olefination into ester 16,
Scheme 2. Attempted Synthesis of Alcohol 5 (R ) H)
1
obtained solely as the (E)-isomer as judged by H NMR.
Release of the free carboxylic acid 17 was achieved under
standard conditions and the ee (90%) assayed after reduction
(LiAlH4, Et2O) to the allylic alcohol and conversion to its
(R)-Mosher’s ester. Some loss of stereochemical integrity
(8) (a) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220-224. (b)
Danishefsky, S. J.; Mantlo, N. J. Am. Chem. Soc. 1988, 110, 8129-8133.
3858
Org. Lett., Vol. 6, No. 21, 2004

Scheme 5. Synthesis of Acid 23 (cf. 6, R1, R2 ) OCMe2O)
Scheme 6. Completion of Lituarine A-C Ester Linkages
omer in reasonable yield. Pleasingly, selective ozonolysis
of the methylene group provided diketoester 26; competitive
cleavage of the trisubstituted alkene was minimized by
keeping the reaction time within ca. 30-60 s. Following a
similar route, ester 27 was generated in two steps from acid
23, the dioxolane providing an increased steric impediment
and electronic deactivation toward competitive cleavage of
the enoate double bond (Scheme 6).
In our projected total synthesis of lituarines A-C, frag-
ments 4 and 5 will be united prior to esterification with acid
6; our progress on this coupling, subsequent macrocycliza-
tion, epoxidation, and incorporation of the C(24) side chain
will be reported in due course.
in this sequence may be attributable to the olefination
reaction that proved to be rather slow (16 h), even at ambient
temperature.
The more highly oxygenated analogues were prepared by
Sharpless asymmetric dihydroxylation. Aldehyde 189 was
olefinated10 to give enone 19 in good yield and with high
diastereocontrol in favor of the (E)-isomer (19:1; E- estab-
lished on basis of NOE data). Subjecting this compound to
standard AD conditions afforded diol 20, which was pro-
tected as the acetonide 21. The ee at this stage was
established as 94% after deprotection (DDQ) and esterifi-
cation with (R)-Mosher’s acid. From ketone 21, Horner-
Wadsworth-Emmons reaction afforded (E)-ester 22 as a
single diastereomer, and saponification completed the route
to acid 23 (Scheme 5).
Acknowledgment. We thank the EPSRC and the Uni-
versity of Oxford for funding (Grants GR/R25842/01, GR/
P01397/01). We are grateful to Ms. Jenna C. Jamal for
preliminary investigations.
To provide the complete ester linkages present in the
lituarines, alcohol 13 was condensed with acid 17 (as its acid
chloride) and the product (24) isolated as a single diastere-
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization for compounds
11-13, 15-17, and 19-27. This material is available free
of charge via the Internet at http://pubs.acs.org.
(9) Prepared in two steps from propane-1,3-diol by monoalkylation and
subsequent Swern oxidation: Oka, T.; Murai, A. Tetrahedron 1998, 54,
1-20.
(10) Corbel, B.; Medinger, L.; Haelters, J.-P.; Sturtz, G. Synthesis 1985,
1048-1051.
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3859