Diversity-oriented synthesis of polyketide natural products via iterative chemo- and stereoselective functionalization of polyenoates: Development of a unified approach for the C(1-19) segments of lituarines A-C

Article abstract of DOI:10.1021/ol047792c

(Chemical Equation Presented) A unified, stereocontrolled synthesis of the C(1-19) segments of the lituarines A-C (1-3) has been achieved, highlighted by application of an iterative chemo- and stereoselective trienoate functionalization protocol, a strate

Full text of DOI:10.1021/ol047792c

ORGANIC
LETTERS
2005
Vol. 7, No. 1
139-142
Diversity-Oriented Synthesis of
Polyketide Natural Products via Iterative
Chemo- and Stereoselective
Functionalization of Polyenoates:
Development of a Unified Approach for
the C(1−19) Segments of Lituarines A−C
Amos B. Smith, III,* Shawn P. Walsh, Michael Frohn, and Matthew O. Duffey
Department of Chemistry, The Monell Chemical Senses Center,
and the Laboratory for Research on the Structure of Matter,
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 27, 2004
ABSTRACT
A unified, stereocontrolled synthesis of the C(1−19) segments of the lituarines A−C (1−3) has been achieved, highlighted by application of an
iterative chemo- and stereoselective trienoate functionalization protocol, a strategy that holds considerable promise for the diversity oriented
synthesis of polyketides.
In 1992, Vidal and co-workers reported the isolation,
structural elucidation, and biological activity of the lituarines
A-C (1-3, Scheme 1), 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 connectivities
and relative stereochemistries were secured via a combination
of multidimensional NMR techniques and chemical correla-
tion; their absolute configurations remain unknown.1 From
the biomedical perspective, the lituarines display significant
cytotoxicity toward KB cells [(1): IC50 ) 5.5-7.5 nM; (2):
IC50 ) 1-3 nM; (3): IC50 ) 7-9 nM].1
The unique C(8-18) tricyclic core, consisting of a [6,5]-
spiroketal and trans-fused tetrahydropyran rings, in conjunc-
tion with the highly functionalized C(1-7) fragment pos-
sessing four contiguous 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 challenge.
Given the structural complexity and biological activities
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, we recently initiated a program to construct these targets
in a stereocontrolled manner.2 An early achievement in this
area entailed the design and execution of an efficient,
(1) Vidal, J.-P.; Escale, R.; Girard, J.-P.; Rossi, J.-C.; Chantraine, J.-
M.; Aumelas, A. J. J. Org. Chem. 1992, 57, 5857.
10.1021/ol047792c CCC: $30.25
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C(19-20) bonds of the lituarines provides two C(1-19)
subtargets (Scheme 1): 4 corresponding to lituarine A and
5 corresponding to lituarines B and C, which we envisioned
to arise from a common C(1-19) trienoate. Iterative chemo-
and stereoselective oxidation, directed in each case to the
most electron rich olefin (i.e., distal to the ester), employing
reagent control, would install the requisite C(6,7) trans-
epoxide and C(4,5) functionality in a highly stereocontrolled
fashion, as required for any successful approach to the
lituarines. From the perspective of diversity-oriented syn-
thesis, extension of this iterative strategy, simply by varying
the chiral auxiliary required for each oxidation and/or
reduction step, would not only permit a unified approach to
both 4 and 5 but also provide access to a small library of
stereochemically diverse congeners at C(4-7).
Scheme 1
The iterative chemoselective epoxidation of a polyene
possessing a terminal electron-withdrawing group appears
to have been first exploited in complex molecule synthesis
by Pattenden and co-workers5 as a biomimetic approach for
the construction of the natural products aurovertin and
citreoveridinol. Shortly thereafter, Sharpless and co-workers7
reported high chemo- and enantioselectivities in the dihy-
droxylation of unfunctionalized dieneoates and trieneoates.
O’Doherty and co-workers6 later exploited the utility of the
Sharpless iterative chemo- and enantioselective dihydroxy-
lations for the elaboration of a simple trienoate in their
synthesis of colletodiol. Finally, Shi and co-workers, during
their development of chiral dioxiranes, demonstrated the
feasibility of electronically directed chemo- and enantiose-
lectivity in the enantioselective epoxidation of simple diene
systems.8
stereocontrolled synthesis of the common C(7-19) tricyclic
spiroketal fragment (+)-7, highlighted by a stereoselective
kinetic spiroketalization to establish the requisite C(16)
stereocenter.3,4 Herein we report the synthesis of the C(1-
19) segment of lituarines B and C (5), fully functionalized
for elaboration to the natural products, as well as the synthesis
of the remaining segment (17) bearing the requisite C(1-
19) stereocenters present in lituarine A.
Of considerable risk for the lituarine program was the
requisite chemoselectivity required for epoxidation of the
C(6,7)-disubstituted olefin [allylic to the C(8)-ether] versus
the trisubstituted C(4,5) olefin, as well as the effect that a
chiral substrate might exert on a reagent controlled process.9
Thus, the effect of reagent control (i.e., use of chiral reagents)
versus substrate control as a prospective tactic for future
diversity-oriented synthesis employing polyenoates was of
particular interest.
We began construction of 5 with removal of the PMB
moiety in spiroketal (+)-7, followed in turn by oxidation
and treatment of the resultant aldehyde (+)-8 with the sodium
ylide derived from dienyl phosphonate 9.10 A mixture of
trienes 6 (E/Z 2.5:1) at the C(6,7) olefin resulted (Scheme
2). Equilibration with catalytic iodine furnished the desired
all E-triene (>10:1 E/Z). Two methods were then explored
for installation of the C(6,7) epoxide.11 Application of the
Shi protocol8 to (+)-6, employing (-)-10 as catalyst,
In keeping with our longstanding interest in the develop-
ment of unified strategies, we selected a flexible approach
exploiting a seldom employed tactic: the iterative chemo-
and stereoselective functionalization of a polyenoate (6,
Scheme 1),5,6 a protocol that we believe holds considerable
potential for diversity oriented synthesis of polyketides.
Toward this end, disconnection at the macrolactone and the
(2) (a) Smith, A. B., III; Thompson, A. S. J. Org. Chem. 1984, 49, 1469.
(b) Smith, A. B., III; Fukui, M. J. Am. Chem. Soc. 1987, 109, 1269. (c)
Smith, A. B., III; Fukui, M.; Vaccaro, H. A.; Empfield, J. R. J. Am. Chem.
Soc. 1991, 113, 2071. (d) Smith, A. B., III; Rivero, R. A.; Hale, K. J.;
Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092. (e) Smith, A. B., III;
Hale, K. J.; Vaccaro, H. A.; Rivero, R. A. J. Am. Chem. Soc. 1991, 113,
2112. (f) Smith, A. B., III; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A.
J. Am. Chem. Soc. 1991, 113, 4037. (g) Smith, A. B., III; Friestad, G. K.;
Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima, M.; Qiu, Y.;
Bertounesque, E.; Spoors, P. G.; Salvatore, B. A. J. Org. Chem. 1998, 63,
7596. (h) 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. (i) 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. 2001,
40, 191. (j) 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. 2001, 40, 196 and references therein.
(7) (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7570. (b) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995,
51, 1345.
(3) Smith, A. B., III; Frohn, M. Org. Lett. 2001, 3, 3974; Org. Lett.
2002, 4, 4183.
(4) For an alternative approach to the lituarines, see: (a) Robertson, J.;
Meo, P.; Dallimore, J. W. P.; Doyle, B.; Hoarau, C. Org. Lett. 2004, 6,
3861. (b) Robertson, J.; Dallimore, J. W. P.; Meo, P. Org. Lett. 2004, 6,
3857.
(5) (a)Pattenden, G.; Forbes, J. Tetrahedron Lett. 1987, 28, 2771. (b)
Ebenezer, W.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4053.
(6) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447.
(8) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Frohn, M.; Shi, Y. Synthesis 2000, 1979.
(c) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (d) Frohn, M.; Dalkeiwicz, M.;
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 2948.
(9) For an investigation into substrate effects on the dihydroxylation
including a dieneoate system which favors reaction at the R,â-position,
see: Hermitage, S. A.; Murphy, A.; Nielsen, P.; Roberts, S. M. Tetrahedron
1998, 54, 13185.
(10) For the synthesis of phosphonate 9, see the Supporting Information.
140
Org. Lett., Vol. 7, No. 1, 2005

Scheme 2
provided the desired (6R,7S)-epoxide (+)-11 in moderate
smoothly with AD-mix-R to install the (4S,5S)-diol from the
face opposite to the C(6,7) epoxide [(+)-15]. For the
lituarines (B and C), however, we require installation of the
diol on the same face as the proximal epoxide.9
yield (57%) with excellent diastereoselectivity (>10:1),
accompanied by formation of the C(4,5)-epoxide (ca. 5%)
and over oxidation products (ca. 12%). The antipode (+)-
10 furnished a similar product mixture, featuring formation
of the diastereomeric epoxide (-)-12 (10:1 dr). Alternatively,
Sharpless dihydroxylation exploiting the AD-mix-â12 fur-
nished the (6R,7R)-diol (-)-13 as a single diastereomer in
good yield; the alternate AD-mix-R provided the diastere-
omer (+)-14 as the sole product. Epoxide formation by the
method of Sharpless13 converted diol (-)-13 to the same
epoxide [(+)-11] as obtained via the Shi protocol employing
ketone (-)-10 (67%; two steps). Dihydroxylation of the
C(4,5) olefin in (+)-11, the second electrophilic oxidation
required to functionalize the C(1-7) triene, proceeded
We therefore turned to the use of AD-mix-â; a mixture
of R,â and δ,γ diols (1:5) resulted, albeit the reaction proved
sluggish. Screening a series of ligands led to (DHDQ)2PYR;
at 0 °C the desired (4R,5R)-diol (+)-16 was obtained in high
yield with excellent chemo- and diastereoselectivity. Comple-
tion of the C(1-19) fragment for lituarines B and C then
only required protection of (+)-16 as the TBS-ether. Of
particular note in this synthetic sequence are the high chemo-
and diastereoselectivities obtained for both antipodes of the
chiral reagents. Assuming the generality of this synthetic
tactic, the iterative chemo- and diastereoselective function-
alization of polyenoates featuring a terminal electron-
withdrawing group should hold considerable promise for
diversity oriented synthesis.
(11) In an effort to correlate the stereochemistry of the C(6,7) epoxide
early in our program we discovered that a more conventional approach (i.e.,
Sharpless asymmetric epoxidation) for installing this functionality presented
a stereochemically mismatched/matched case.
To install the C(4) stereochemistry necessary for construc-
tion of fragment 4 required for lituarine A, we explored an
alternative iterative tactic (Scheme 3). Initially, direct reduc-
tion of the C(6,7)-epoxide (+)-11 proved problematic due
to low chemo- and diastereoselectivity, as well as over-
reduction. We reasoned that the C(6) hydroxyl might direct
both the chemo- and diastereoselectivity for the required
reduction; a variety of conditions were therefore explored.
Optimized conditions proved to be catalytic hydrogenation
employing the Lindlar catalyst; diol (-)-17, precursor to the
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(13) Kolb, H. C.; Sharpless, K. B Tetrahedron 1992, 48, 10515.
Org. Lett., Vol. 7, No. 1, 2005
141

variety of chiral substrates. Importantly, the stereogenicity
and functionality installed in the first iteration could be
employed to direct the second chemo- and diastereoselective
reduction in the absence of a chiral reagent. Progress toward
the total synthesis of the lituarines, as well as additional
applications of this iterative chemo- and stereocontrolled
polyenoate functionalization tactic for the diversity-oriented
synthesis of natural products and their stereochemical
congeners, will be reported in due course.
Scheme 3
Acknowledgment. Support was provided by the National
Institutes of Health (National Cancer Institute) through Grant
No. CA-19033. An American Cancer Society Postdoctoral
Fellowship to M.F. and an NIH Postdoctoral Fellowship to
M.O.D. are also gratefully acknowledged.
C(6,7) epoxide for lituarine A, was obtained in 79% yield
(7:1 dr).14
In summary, we have developed the iterative chemo- and
stereocontrolled functionalization of a trienoate substrate for
the unified construction of the C(1-19) segments for
lituarines A-C. High chemo- and stereoselectivities were
observed for both the Shi asymmetric epoxidation and
Sharpless asymmetric dihydroxylation protocols with a
Supporting Information Available: Spectroscopic data
as well as experimental procedures for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) The stereochemistry of the C(4)-methyl group has been established
via chemical correlation. For full details see the Supporting Information.
OL047792C
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Org. Lett., Vol. 7, No. 1, 2005