Synthesis of the cyclobutylfuran sector of providencin via zirconium-mediated oxygen abstraction from a furanoside

Article abstract of DOI:10.1021/ol900152p

A portion of the macrocyclic cembrenoid diterpene providencin possessing conjoined cyclobutane and furancarboxylate units was synthesized from D-glucose using deoxygenative ring contraction methodology to construct the tetrasubstituted cyclobutane and a K

Full text of DOI:10.1021/ol900152p

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1433-1436
Synthesis of the Cyclobutylfuran Sector
of Providencin via Zirconium-mediated
Oxygen Abstraction from a Furanoside
James D. White* and Somnath Jana
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@oregonstate.edu
Received January 23, 2009
ABSTRACT
A portion of the macrocyclic cembrenoid diterpene providencin possessing conjoined cyclobutane and furancarboxylate units was synthesized
from D-glucose using deoxygenative ring contraction methodology to construct the tetrasubstituted cyclobutane and a Knoevenagel condensation
of glyceraldehyde to fabricate the trisubstituted furan.
Investigation of chemical constituents of the gorgonian
octoral Pseudoterogorgia kallos found in shallow waters of
the South West Caribbean has brought to light several new
cembrenoid diterpenes with interesting biological properties.1
Recently, Rodriguez et al. isolated a highly oxygenated
cembrenoid from this organism that they named providencin2
and for which X-ray crystallographic analysis revealed the
structure and relative configuration represented as 1.3 Provi-
dencin manifests a unique bicyclo[12.2.0]hexadecane scaf-
Figure 1. Structure of providencin (1).
fold incorporating a trisubstituted furan linked directly to a
tetrasubstituted cyclobutane as well as an unusual R,γ-
bridged ꢀ,γ-epoxy-γ-lactone. The 1,2,3,4-tetrasubstituted
cyclobutane of providencin presents a particularly intriguing
synthetic challenge, and it was this feature of the structure
that initially drew our interest toward a synthesis of 1.
Our plan for construction of the providencin skeleton
shown in Scheme 1 envisioned dissection of 2 at bonds
C9-C10 and C12-C13.4 For the linked furan-cyclobutane
component 3, we required a blueprint that would place three
of the four cyclobutane substituents in a firmly defined,
nonepimerizable configuration while leaving us a “handle”
from which the furan could be assembled. This premise led
to 4 as our cyclobutane template and to D-glucose (5) as the
progenitor of 4.5 The key transformation of 5 to 4 is
predicated upon zirconium-mediated deoxygenative ring
contraction of a furanoside, a process first described by
Taguchi6 and subsequently employed by Paquette as an entry
to enantiopure cyclobutanols.7
(1) Look, S. A; Burch, M. T.; Fenical, W. J. Org. Chem. 1985, 50,
5741.
(5) For a different approach to this segment of providencin, see: Bray,
C. D.; Pattenden, G. Tetrahedron Lett. 2006, 47, 3937.
(6) (a) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J. Am. Chem.
Soc. 1993, 115, 8835. (b) Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995,
229.
(2) Named for the isolation site near the island of Providencia.
(3) Marrero, J.; Rodr´ıguez, A. D.; Baran, P.; Raptis, R. G. Org. Lett.
2003, 5, 2551.
(4) Numbering conforms to the cembranoid convention.
10.1021/ol900152p CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society

toluene to give the 2-vinyltetrahydrofuran 9.11 Acid-catalyzed
methanolysis of 9 furnished tetrahydrofuranol 10, which was
protected as its silyl ether 11.
Scheme 1. Retrosynthetic Analysis of Providencin
Scheme 3
.
Oxygen Atom Abstraction from 11 and NOE
Correlations of 12
The zirconium reagent, nominally dicyclopentadienylzir-
conium(0), required for oxygen atom abstraction from 11
was generated by treatment of dicyclopentadienylzirconium
dichloride (2 equiv) with n-butyllithium in toluene (Scheme
3). Addition of tetrahydrofuran 11 to this mixture followed
by boron trifluoride etherate with work up in the presence
of dilute hydrochloric acid produced cyclobutane 12 in
excellent yield. That all four stereocenters of 11 had been
faithfully transcribed into 12 was confirmed by careful
Scheme 4. Synthesis of Cyclobutylfuran 20
The known alcohol 6,8 prepared in four steps from
D-glucose (5) via its diacetonide,9 was first protected as its
p-methoxybenzyl ether 7 (Scheme 2).10 Selective hydrolysis
of the exocyclic acetonide of 78 afforded diol 8 which was
treated with iodine, triphenylphosphine, and imidazole in hot
Scheme 2. Synthesis of Furanoside 11
1434
Org. Lett., Vol. 11, No. 6, 2009

Scheme 5. Synthesis of “Northern Sector” of Providencin
analysis of the 1H NMR spectrum of the cyclobutane which
showed NOE’s consistent with a cis relationship between
H1 and H4 and between H2 and H3.
the furan. Consequently, we turned to Horner-Wadsworth-
Emmons olefination of 20 with ethyl 2-(diethoxyphospho-
no)propionate (24)18 in order to extend this aldehyde
toward 3. This process gave (E)-R,ꢀ-unsaturated ester 25
in excellent yield. In anticipation that installation of the
After protection of cyclobutanol 12 as its TIPS ether 13,
Wacker oxidation of the vinyl substituent gave methyl ketone
14 with a trace of aldehyde resulting from the alternate
regiochemical oxidation12 (Scheme 4). Exposure of the
kinetic lithium enolate of 14 to methyl cyanoformate13
furnished ꢀ-keto ester 15 which was condensed with 2,3-
O-isopropylidene-D-glyceraldehyde (16)14 under acid cataly-
sis. The initially formed Knoevenagel product 17, detectable
by thin-layer chromatography, was converted slowly to a
mixture of 18 and desilylated alcohol 19.15 Oxidation of 18
with tetra-n-propyl perruthenate16 then yielded aldehyde 20.
Our first plan for 20 involved elaboration of this
aldehyde into an alkyne that could be used to set in place
the (E) trisubstituted alkene at C7-C9 of 2. To this end,
aldehyde 20 was reacted with dimethyl 1-diazo-2-oxo-
propylphosphonate (21)17 in the presence of base to
furnish terminal alkyne 22 (Scheme 5). The latter was
methylated to give disubstituted alkyne 23, but all attempts
to functionalize this alkyne through hydrozirconation or
hydrobromination returned starting material or destroyed
Scheme 6. Alternative Route to Northern Sector 27
(7) (a) Paquette, L. A.; Cunie`re, N. Org. Lett. 2002, 4, 1927. (b) Paquette,
L. A.; Zhang, Y. Org. Lett. 2005, 7, 511. (c) Paquette, L. A.; Zhang, Y. J.
Org. Chem. 2006, 71, 4353.
(8) Rosenthal, A.; Nguyen, L. J. Org. Chem. 1969, 34, 1029.
(9) Baker, C. D.; Horton, D.; Tindall, C. G., Jr. Carbohydr. Res. 1972,
24, 192.
(10) Nakajima, N.; Uoto, K.; Matasushima, T.; Yomemitus, H. G.;
Osawa, E. Chem. Pharm. Bull. Jpn. 1991, 39, 64.
(11) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 46, 9.
(12) Pellissier, H.; Michellys, P.-Y.; Sawtelli, M. Tetrahedron 1997, 53,
7577.
(13) Mander, L. N.; Sethis, S. P. Tetrahedron Lett. 1983, 24, 5425.
(14) Jackson, D. Y. Synth. Commun. 1988, 18, 337.
(15) Paquette, L. A.; Rayner, C. M.; Doherty, A. M. J. Am. Chem. Soc.
1990, 112, 4078.
(16) Ley, S. V.; Norman, J.; Griffith, W. D.; Marsden, S. D. Synthesis
1994, 639.
Org. Lett., Vol. 11, No. 6, 2009
1435

exo methylene function at C15 of providencin would
require a keto group at this site on the cyclobutane, the
TBS ether was selectively cleaved from 25 to liberate
alcohol 26 and the resulting alcohol was oxidized to
cyclobutanone 27.
Continuation of our route from 27 toward 1 requires
modification of the keto ester in a manner that permits
attachment of the γ-lactone unit comprising C10-C12(C20)
of providencin. Efforts along this line that change the
oxidation level at C9 and C13 are under way.
Subsequently, it was discovered that more direct access
to 27 could be realized through exhaustive oxidation of diol
19 with TPAP to furnish keto aldehyde 28 (Scheme 6).
Horner-Wadsworth-Emmons olefination of 28 with phos-
phonate 24 took place exclusively at the aldehyde but in this
case the result was a 2:1 E/Z mixture of 27 and 29,
respectively, which proved difficult to separate.
Acknowledgment. Financial support was provided by the
National Science Foundation (0413994-CHE).
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Ohira, S. Synth. Commun. 1989, 19, 561.
(18) Mayanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
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