Stereoselective synthesis of the lituarine tricyclic spiroacetal

Article abstract of DOI:10.1021/ol0483955

(Chemical Equation Presented) Oxidative cyclizations of 2-(4-hydroxybutyl)furan derivatives provide spirobutenolide acetals directly; on the basis of this methodology, we describe an asymmetric synthesis of a tricyclic spirobutenolide precursor to the C(7

Full text of DOI:10.1021/ol0483955

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3861-3863
Stereoselective Synthesis of the
Lituarine Tricyclic Spiroacetal
Jeremy Robertson,* Paul Meo, Jonathan W. P. Dallimore, Bryan M. Doyle, and
Christophe Hoarau†
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
Oxidative cyclizations of 2-(4-hydroxybutyl)furan derivatives provide spirobutenolide acetals directly; on the basis of this methodology, we
describe an asymmetric synthesis of a tricyclic spirobutenolide precursor to the C(7 18) fragment common to lituarines A C.
−
−
In the accompanying paper,1 we introduced our strategy for
the synthesis of lituarines A-C (1-3, Scheme 1), a small
class of cytotoxic, antifungal marine natural products isolated
from Lituaria australasiae,2 and described a route to the
C(1-6) and C(19-24) fragments of the natural products.
Prior to this report, Smith’s highly efficient synthesis of the
C(7-19) tricyclic spiroacetal domain, starting from antipodal
glycidyl ethers, stood as the only published synthetic work
in this area.3
furans to give enediones5 could be used as the key step in a
direct synthesis of spirobutenolide 6 (Scheme 2) from which
the C(16) methyl group could be introduced under kinetic
Scheme 1. Synthetic Analysis of Lituarines A-C
In this Letter, we describe a conceptually very different
route to the lituarine C(7-18) spiroacetal, in which the
absolute stereochemistry originates in an oxazaborolidine-
mediated asymmetric reduction of 2-methylcyclopentenone.
In our original analysis of the synthesis,4 we were concerned
that the C(16) stereogenic center would be prone to epimer-
ization under the equilibrating acidic conditions typically
employed for spiroacetal formation by ketodiol condensation,
and this classical approach was rejected. Instead, we realized
that a variant of the peracid oxidation of 2,5-disubstituted
† Current address: IRCOF-INSA Laboratoire de Chimie Organique Fine
et He´te´rocyclique, UMR 6014, B. P. 08, 76131 Mont St. Aignan Cedex,
France.
(1) Robertson, J.; Dallimore, J. W. P.; Meo, P. Org. Lett. 2004, 6, 3857-
3860.
(2) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-
M.; Aumelas, A. J. Org. Chem. 1992, 57, 5857-5860.
(3) (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).
(4) Yanase, M. Part II Thesis, University of Oxford, Oxford, UK, 2001.
10.1021/ol0483955 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/22/2004

Scheme 2. Route to Tricycle 4 Based on Furan Oxidation
Scheme 4. Asymmetric Reduction and Elaboration
conditions by conjugate addition. This proposal6 required
stereocontrolled access to functionalized 2-(4-hydroxybutyl)-
furan precursors of general structure 5; before embarking
on that synthesis, a model study was undertaken in order to
establish the viability of the methodology.
Treatment of 2-(4-hydroxybutyl)furan7 with MCPBA in
dichloromethane for 2 h at 0 °C provided spirolactol 7 (82%),
which was oxidized without complication to give multigram
quantities of the spirobutenolide 88 (75%). Butenolide 8 could
be obtained directly from the furan in comparable overall
yield (65%) using 2.0 equiv of MCPBA at 20 °C. Pleasingly,
subsequent 1,4-addition9 of (MeS)3CLi afforded the conju-
gate adduct as essentially one diastereomer.10 Raney nickel
desulfurization of this adduct gave spirolactone 9, the
stereochemistry (dr ) 19:1) being established by NOE
experiments (Scheme 3).11 We also briefly investigated
Following this success, the synthesis of the more complex
oxidation precursor 5 (R ) CH2CH2OTBDPS) was under-
taken, beginning with asymmetric reduction13 of 2-methyl-
cyclopentenone (Scheme 4). Use of BH3‚THF in this reduc-
tion14 provided an 85:15 mixture of inseparable alcohols 10
and 11 in mediocre yield and with only a moderate ee (82%)-
15
.
In contrast, application of Corey’s modification,16 using
catecholborane at low temperature, resulted in an improved
ee (92%)15 and avoided competing over-reduction.17 Later
work showed that the most reproducible results (90% yield,
94% ee) could be obtained using a stoichiometric quantity
of (S)-2-methyl-CBS-oxazaborolidine‚BH3 complex.18
The crude alcohol (10) was immediately protected and the
alkene cleaved to provide keto aldehyde 12. Interestingly,
the intermediate ozonide19 precursor to keto aldehyde 12
proved to be relatively stable in the presence of a large excess
of dimethyl sulfide and was isolated after silica gel chro-
matography. Fortunately, triphenylphosphine effected com-
plete reduction of this ozonide at -78 °C. Selective Horner-
Wadsworth-Emmons olefination of aldehyde 12 proceeded
in good yield at low temperature20 with high (E)-stereo-
selectivity and with no significant loss of stereochemical
Scheme 3. Oxidative Spiroacetalization and Stereoselective
Conjugate Addition; Diagnostic NOE Data for 9
(7) Sun, M.; Deng, Y.; Batyreva, E.; Sha, W.; Salomon, R. G. J. Org.
Chem. 2002, 67, 3575-3584.
(8) Fukuda, H.; Takeda, M.; Sato, Y.; Mitsunobu, O. Synthesis 1979,
368-370.
(9) Damon, R. E.; Schlessinger, R. H. Tetrahedron Lett. 1976, 1561-
1564.
(10) Cf.: Reed, A. D.; Hegedus, L. S. J. Org. Chem. 1995, 60, 3787-
3794.
(11) This was confirmed by X-ray crystallography, details of which will
be provided in a full description of this work.
(12) Asao, N.; Lee, S.; Yamamoto, Y. Tetrahedron Lett. 2003, 44, 4265-
4266.
(13) (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3,
1475-1504. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37
(7), 1986-2012.
(14) Corey, E. J.; Gavai, A. V. Tetrahedron Lett. 1988, 29, 3201-3204.
(15) Enantiomeric excess was determined by Mosher’s ester derivatiza-
tion.
Yamamoto’s system12 for delivery of methyl in a conjugate
sense; under the recommended conditions (Me2CuLi‚TMSCl,
CH2Cl2, 0 f 20 °C), 1,4-addition proceeded cleanly, but
the adduct was obtained as a roughly equimolar mixture of
diastereomers.
(5) (a) First report: Clauson-Kaas, N.; Fakstorp, J. Acta Chem. Scand.
1947, 1, 415-421. (b) For an early synthetic application: Williams, P. D.;
LeGoff, E. J. Org. Chem. 1981, 46, 4143-4147.
(6) Recently, Nelson reported such a process during a study of the
Sharpless kinetic resolution of difuryl diols: (a) Harding, M.; Hodgson,
R.; Nelson, A. J. Chem. Soc., Perkin Trans. 1 2002, 2403-2413. (b) Bartlett,
S.; Hodgson, R.; Holland, J. M.; Jones, M.; Kilner, C.; Nelson, A.; Warriner,
S. Org. Biomol. Chem. 2003, 1, 2393-2402.
(16) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
1
(17) On the basis of the H NMR spectrum of the crude material.
(18) Simpson, A. F.; Szeto, P.; Lathbury, D. C.; Gallagher, T. Tetrahe-
dron: Asymmetry 1997, 8, 673-676.
(19) Bunnelle, W. H.; Isbell, T. A. J. Org. Chem. 1992, 57, 729-740.
(20) Hammond, G. B.; Cox M. B.; Wiemer D. F. J. Org. Chem. 1990,
55, 128-132.
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Org. Lett., Vol. 6, No. 21, 2004

integrity at C(11), as inferred by Mosher’s ester analysis at
a later stage (compound 18).
Scheme 5. Assembly of the C(8-12) Tetrahydropyran Ring
Two key aspects of stereocontrol then had to be faced:
(1) the level of stereochemical induction during addition of
a furan-containing organometallic to the R-(silyloxy)ketone
and (2) the level and sense of stereoselectivity during
and Oxidative Spirocyclization
conjugate cyclization to form the tetrahydropyran ring.21
A
screen of unfunctionalized organometallic reagents soon
showed Grignard reagents to be preferential; addition of 2-(2-
furyl)ethylmagnesium bromide (14)22 to ketone 13 proceeded
in moderate yield (f 16) and with good (10:1) stereocontrol
in accord with a nonchelated Felkin-Anh approach (15).
This Grignard reaction was particularly sensitive to oxidation,
careful degassing of the solvents23 being necessary in order
to obtain consistent results.
Anticipating the stereochemical outcome of the tetrahy-
dropyran ring closure, we expected the desired product (17)
to be the more stable of the two diastereomers, but predicting
the outcome under kinetic conditions was difficult given the
absence of a close literature precedent.24 Therefore, a small
range of bases was screened in this reaction (full details will
be reported elsewhere) and it was found that the diastereo-
selectivity was influenced by the reaction temperature as well
as the nature of the metal counterion; with LHMDS as the
base, and maintaining the reaction temperature below -40
°C, the desired diastereomer 17 was obtained exclusively,
albeit with some recovery of starting material (Scheme 5).
1
In the H NMR spectrum of this compound, both CHOR
resonances exhibited a coupling constant of a magnitude
consistent with a diaxial relationship between the vicinal
protons in support of the desired relative stereochemistry.
To prevent competitive addition of the nucleophilic methyl
equivalent later in the synthesis, and to set up a double-
deprotection/double-elimination sequence prior to eventual
ring-closing metathesis,1 the ester in 17 was reduced and
the primary hydroxyl protected (f 19). The furan oxidation
method worked particularly well in this case, and spirobuteno-
lide 20 was obtained as a single diastereomer in 77% overall
yield.
Investigations of the conjugate addition chemistry of
spirobutenolide 20 and its elaboration toward the lituarines
are currently underway.
Acknowledgment. We thank the EPSRC (Grants GR/
R25842/01, GR/P01397/01) and the University of Oxford
for funding. We are grateful to Ms. Midori Yanase4 for
preliminary investigations.
(21) For a discussion of the origins of stereocontrol in related cyclizations,
see: (a) Betancort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.;
Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570-4583. (b)
Ram´ırez, M. A.; Padro´n J. M.; Palazo´n, J. M.; Mart´ın, V. S. J. Org. Chem.
1997, 62, 4584-4590.
(22) Grignard reagent was generated from 2-(2-bromoethyl)furan, pre-
pared in a three-step sequence from furan in 87% overall yield: (a) BuLi,
ethylene oxide, THF; (b) MsCl, Et3N, Et2O; (c) LiBr, THF; see: Jung, M.
E.; Miller, S. J. Heterocycles 1990, 30, 839-853.
(23) Cf.: Sperry, J. B.; Whitehead, C. R.; Ghiviriga, I.; Walczak, R.
M.; Wright, D. L. J. Org. Chem. 2004, 69, 3726-3734.
(24) For a related example of cyclization of a 3°-alkoxide, see: Nicolaou,
K. C.; Hwang, C.-K.; Duggan, M. E. J. Am. Chem. Soc. 1989, 111, 6682-
6690.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization are provided for
compounds 8, 9, 12, 13, and 16-20. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0483955
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