Lituarine synthetic studies. An efficient, stereocontrolled construction of the common c(7-19) tricyclic spiroketal fragment.

Article abstract of DOI:10.1021/ol016948v

A highly efficient, stereocontrolled synthesis of (+)-4, the common C(7-19) tricyclic spiroketal fragment of the lituarines A, B, and C (1-3), has been achieved. Highlights of the synthesis include a remarkably facile 6-endo cyclization to access the C(8-

Full text of DOI:10.1021/ol016948v

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3979-3982
Lituarine Synthetic Studies. An Efficient,
Stereocontrolled Construction of the
Common C(7−19) Tricyclic Spiroketal
Fragment
Amos B. Smith, III* and Michael Frohn
Department of Chemistry, Monell Chemical Senses Center and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 22, 2001
ABSTRACT
A highly efficient, stereocontrolled synthesis of (+)-4, the common C(7−19) tricyclic spiroketal fragment of the lituarines A, B, and C (1−3),
has been achieved. Highlights of the synthesis include a remarkably facile 6-endo cyclization to access the C(8−12) pyran ring and a kinetically
controlled acid-catalyzed spiroketalization.
In 1992 Vidal and co-workers reported the isolation,
structural elucidation, and biological activity of the lituarines
A, B, and C (1-3), architecturally complex natural products,
isolated from the sea pen Lituaria australasaie endemic to
the western region of the New Caledonian Lagoon near the
“Baie de St. Vincent”.1 The connectivity and relative
stereochemistry were secured via a combination of multi-
dimensional NMR techniques and chemical correlation; the
absolute configurations remain unknown.1 Importantly, the
lituarines displayed significant cytotoxicity toward KB cells
stereogenic centers for lituarines B and C (2 and 3), and a
rare example of an acyclic conjugated dienamide, conspire
to make the synthesis of the lituarines a significant chal-
lenge.3 Given the structural complexity and potent cytotox-
icities of the lituarines, combined with their scarcity (12.5
kg of sea pen furnished less than 25 mg of each congener)
and our continuing interest in the synthesis of architecturally
complex spiroketals having important bioregulatory proper-
ties,4 we recently launched a program to construct these
targets in a stereocontrolled manner. In this Letter, we report
[1, IC50 ) 5.5-7.5 nmol; 2, IC50 ) 1-3 nmol; 3, IC50
)
7-9 nmol1].
(2) Okadaic acid contains a similar tricyclic fragment but is devoid of
the methyl substituents at C(12) and C(16), see: Tachibana, K.; Scheuer,
P. J.; Tsukitani, Y.; Kikuchi, H.; Engen, D. V.; Clardy, J.; Gopichand, Y.;
Schmitz, F. J. J. Am. Chem. Soc. 1981, 103, 2469-2471.
(3) For the construction of dienamides, see: (a) Oppolzer, W.; Frostl,
W. HelV. Chim. Acta 1975, 58, 587-589. (b) Overman, L. E.; Clizbe, L.
A. J. Am. Chem. Soc. 1976, 98, 2352-2354. (c) Overman, L. E.; Taylor,
G. F.; Jessup, P. J. Tetrahedron Lett. 1976, 3089-3092. (d) Katritzky, A.
R.; Ignatchenko, A. V.; Lang, H.; J. Org. Chem. 1995, 60, 4002-4005.
The unusual C(8-18) tricyclic core, consisting of a [6,5]
spiroketal and trans-fused tetrahydropyran rings,2 in conjunc-
tion with the C(1-7) fragment possessing four contiguous
(1) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-
M.; Aumelas, A. J. Org. Chem. 1992, 57, 5857-5860.
10.1021/ol016948v CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

an efficient, stereocontrolled synthesis of the common C(7-
19) tricyclic spiroketal fragment (+)-4.
From the retrosynthetic perspective, we envisioned 4 to
arise via an acid-catalyzed 6-endo cyclization of an epoxy-
ketone (5) to assemble the C(8-12) tetrahydropyran with
the required relative stereochemistry (Scheme 1); subsequent
the epoxide. Thus, unsaturation at C(13,14), as introduced
by Nicolaou,7 would serve to maximize the regioselectivity
in the ring formation. Reduction of the olefin would then be
followed by stereoselective spiroketalization; the requisite
stereogenicity of the C(15) spiroketal was anticipated on the
basis of the anomeric effect8 and previous experience in our
laboratory.4 Control of the relative configuration of the C(16)
methyl substituent however was far less certain.9 With this
as rationale, R,â-unsaturated ketone 5 was selected to be the
precursor for 4. Continuing with this analysis, ketone 5 would
arise via a Horner-Wadsworth-Emmons (HWE) condensa-
tion between phosphonate 6 and epoxy-aldehyde 7, followed
by removal of the silyl protecting groups.
Scheme 1
Our point of departure for the construction of 5 entailed
assembly of epoxy-aldehyde 7 (Scheme 2). Addition of
Scheme 2
allylmagnesium bromide to (R)-4-methoxybenzylglycidyl
ether10 catalyzed by CuI, followed by TBS protection of the
derived alcohol, readily furnished (-)-9 in 83% yield for
the two steps.11 Oxidative cleavage of the terminal olefin,
Wittig olefination with (carbethoxyethylidene)triphenyl-
phosphorane, and DIBAL reduction of the resulting ester then
reduction of the olefin and stereoselective spiroketalization
would then complete the tricyclic fragment.5 To overcome
the inherent stereoelectronic constraints of the initial tet-
rahydropyran construction (i.e., 6-endo vs 5-exo cyclization),6
we recognized the need for cationic stabilization adjacent to
(6) In general, 5-exo cyclization is favored geometrically over 6-endo
cyclization. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-
736.
(7) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K. J.
Chem. Soc., Chem. Commun. 1985, 1359-1362. (b) Nicolaou, K. C.; Prasad,
C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330-
5334.
(8) For reviews of the anomeric effect, see: (a) Deslongchamps, P.
Stereoelectronic Effects in Organic Chemistry; Pergamon Press: New York,
1983. (b) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer-Verlag: New York, 1983.
(4) (a) Smith, A. B., III; Hale, K. J.; Vaccaro, H. A.; Rivero, R. A. J.
Am. Chem. Soc. 1991, 113, 2112-2122 (b) Smith, A. B., III; Friestad, G.
K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima, M.; Qiu, Y.;
Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999,
121, 10468-10477. (c) Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang,
L.; McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama,
K.; Sobukawa, M. Angew. Chem., Int. Ed. Engl. 2001, 40, 191-195. (d)
Smith, A. B., III; Lin, Q.; Doughty, V. A.; Zhuang, L.; McBriar, M. D.;
Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem., Int.
Ed. Engl. 2001, 40, 196-199.
(5) For other methods for the construction of the fused tetrahydropyrans,
see: (a) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66,
1380-1386 and references therein. (b) Sakamoto, Y.; Matsuo, G.; Mat-
sukura, H.; Nakata, T. Org. Lett. 2001, 3, 2749-2752.
(9) Monte Carlo conformational searches using the MM2 force field
predicted the spiroketal epimeric to 4 at C(16) (i.e., â) to be more stable
by 0.99 kcal/mol (1.49:1 ratio at equilibrium). Both methyl isomers epimeric
at C(15) were predicted to be considerably less stable (ca. 7.7 kcal/mol).
(10) Smith, A. B., III; Zhuang, L.; Brook, C. S.; Boldi, A. M.; McBriar,
M. D.; Moser, W. H.; Murase, N.; Nakayama, K.; Verhoest, P. R.; Lin, Q.
Tetrahedron Lett. 1997, 38, 8667-8670.
(11) Interestingly, minor amounts (<10%) of regioisomeric products were
also observed.
3980
Org. Lett., Vol. 3, No. 24, 2001

led to the E allylic alcohol (-)-10 in nearly quantitative yield.
Subsequent Sharpless asymmetric epoxidation12 proceeded
both in high yield and with excellent diastereoselectivity
(90% yield, >20:1 dr). Completion of (-)-7 was achieved
by Swern oxidation;13 the overall yield for the seven-step
sequence was 58%.
Scheme 4
Construction of the HWE coupling partner, â-ketophos-
phonate 7, began with the alkylation of (S,S)-pseudoephe-
drine amide 11 employing (S)-benzylglycidyl ether14 accord-
ing to the Myers protocol15 to furnish, after acid-mediated
cyclization, lactone (-)-1315 (Scheme 3). Treatment of the
Scheme 3
latter with the lithium anion derived from dimethyl meth-
ylphosphonate, followed by in situ protection as the trieth-
ylsilyl ether,16 rapidly furnished (+)-6. The overall yield for
the three-step sequence was 57%.
Union of fragments (+)-6 and (-)-7 was next achieved
in excellent yield (92%) with exclusive E-selectivity (Scheme
4).17 Unfortunately, all attempts to effect cyclization of the
derived diol 5 (TBAF) proceeded with low regioselectivity,
presumably due to the electron poor nature of the olefin.18
We therefore explored conditions to effect 1,2-reduction of
the R,â-unsaturated ketone. Luche reduction19 employing 0.5
equiv of CeCl3‚7H2O at 0 °C in methanol furnished the
desired allylic alcohol in high yield, albeit as a mixture of
diastereomers (1:1). Removal of the silyl protecting groups
(TBAF) then led to 15, our second generation cyclization
precursor. Pleasingly, this mixture of triols displayed a high
propensity to undergo cyclization upon purification with
silica gel. Additional experimentation revealed that slow
elution of the mixture through silica gel consistently resulted
in triols 16 in high yield (90% yield; i.e., TBAF followed
by elution through silica gel). To the best of our knowledge
this is the first regioselective cyclization of a vinyl epoxide
reported to proceed by simple elution through silica gel.
Turning next to the requisite spiroketalization, selective
oxidation of 16 with manganese(IV) oxide, followed by
palladium(0)-catalyzed 1,4-reduction utilizing tributyltin hy-
dride as the stoichiometric reductant, proceeded to give
saturated ketone (+)-17,20 accompanied by minor amounts
of two cyclic hemiketals (ca. 10%). Unable to remove
completely all traces of tin impurities after single elution
through silica gel, the mixture of ketone (+)-17 and cyclic
hemiketals was used directly in the spiroketalization.
Of considerable risk vis-a`-vis the prospective spiroketal-
ization was loss of the C(16) stereogenicity.9 Notwithstanding
this concern, we were delighted to find that treatment of the
mixture of ketone and the cyclic hemiketals with a catalytic
amount of toluenesulfonic acid in CH2Cl2 at 0 °C (i.e., kinetic
conditions) furnished tricyclic spiroketal (+)-4 both in
excellent yield (87%) and with high stereochemical control
at the C(15) and C(16) stereogenic centers [C(15) > 18:1;
C(16) > 20:1]. The relative configurations at C(15) and
C(16), coinciding with those of the lituarines, were initially
confirmed by extensive 2D NOESY NMR experiments
(Figure 1).21 Single-crystal X-ray analysis of (+)-20, the
dibromobenzoate derived from (+)-4, confirmed this analy-
(12) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(13) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660.
(14) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 6776-6777.
(15) (a) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428-
2440. (b) Myers, A. G.; Yang, B. H. Org. Synth. 1999, 47, 22-28.
(16) Ditrich, K.; Hoffmann, R. W. Tetrahedron Lett. 1985, 26, 6325-
6328.
(17) Ley, S. V.; Meek, G. J. Chem. Soc., Perkin Trans. 1 1997, 1125-
1133.
(18) A mixture (ca. 1:1) of 6-endo/5-exo products was obtained in poor
yield.
(19) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-
5459.
(20) Keinan, E.; Gleize, P. A. Tetrahedron Lett. 1982, 23, 477-480.
Org. Lett., Vol. 3, No. 24, 2001
3981

Table 1. Spiroketalization Study
concentration
(M)
time
[(+)-4:(+)-18]
[dr at C(16)]
entry
(min)
(+)-19 (%)
Figure 1. 2D NOESY correlations for (+)-4, (+)-18, and (+)-19
and the ORTEP for (+)-20.
1
2
3
0.01
0.3
0.3
30
25
60
78 (18:1)
83 (>20:1)
83 (2.5:1)
10
<5
0
sis. When the spiroketalization was carried out on larger scale
(ca. 200 mg), a second spiroketal, (+)-19, was isolated (10%
yield), having the nonanomerically stabilized structure (Table
1, entry 1). Best results were obtained when the spiroketal-
ization was carried out at higher concentration (0.3 M) and
for a shorter reaction time (25 min) [83% yield, >20:1 dr at
C(16); entry 2]. Longer reaction times (60 min) significantly
erode the stereochemical integrity at C(16) (entry 3).
Aware of the possible future need for acidic protocols as
the lituarine synthetic venture unfolds, we thought it prudent
to define the minimal conditions that would lead to equili-
bration at C(16). To this end, treatment of (+)-4 with a
catalytic amount of toluenesulfonic acid, this time at room
temperature over a 15 h period, yielded a mixture of tricycles
(+)-4 and (+)-18, now with the undesired C(16) congener
(+)-18 as the major component (ca. 1.4:1; Figure 1).9 On
the basis of our MM2 calculations,9 this result presumably
represents the equilibrium mixture.
lituarines A, B, and C (1-3), has been achieved. The
cornerstone of the construction entailed a remarkably facile
6-endo cyclization of an epoxy-alcohol upon elution through
silica gel followed by a kinetically controlled, stereoselective
spiroketalization. Further progress toward the total syntheses
of the lituarines will be reported in due course.
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant
CA-19033. An American Cancer Society Postdoctoral Fel-
lowship to M.F. is also gratefully acknowledged.
Supporting Information Available: Spectroscopic and
analytical data for compounds (+)-4, (+)-6, (-)-7, (-)-9,
(-)-10, and (-)-14 through (+)-17 and selected experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, a highly efficient, stereocontrolled synthesis
of (+)-4, the C(7-19) tricyclic spiroketal fragment of the
(21) Tricycle (+)-4 has been characterized by 1H, 13C, DEPT; 2D COSY,
NOESY, HMQC, and HMBC NMR.
OL016948V
3982
Org. Lett., Vol. 3, No. 24, 2001