A spirodiepoxide-based strategy to the A-B ring system of pectenotoxin 4

Article abstract of DOI:10.1021/ol063087n

(Chemical Equation Presented) A synthesis of a pectenotoxin 4 C1-C15 segment is reported. Suitable C1-C7 and C8-C15 segments were prepared, coupled, converted to I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.

Full text of DOI:10.1021/ol063087n

ORGANIC
LETTERS
2007
Vol. 9, No. 5
869-872
A Spirodiepoxide-Based Strategy to the
B Ring System of Pectenotoxin 4
A−
Stephen D. Lotesta, Yongquan Hou, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of
New Jersey, Piscataway, New Jersey 08854
ljw@rutchem.rutgers.edu
Received December 20, 2006
ABSTRACT
A synthesis of a pectenotoxin 4 C1−C15 segment is reported. Suitable C1−C7 and C8−C15 segments were prepared, coupled, converted to
I and the C3-hydroxy variant, and then cyclized. Key findings include the stereoselective conversion of the allene to the corresponding
spirodiepoxide, oxidative cleavage of the p-methoxybenzyl ether, and cyclization of the spirodiepoxide to spiroketal II.
Here we report studies that culminated in the preparation of
a C1-C15 segment of pectenotoxin 4 (PTX-4) using the
spirodiepoxide (SDE) functional group. Nucleophilic addition
to SDEs gives vicinal triads composed of hydroxyl, ketone,
and a syn-substituted substituent (e.g., 6f7, Figure 1B).1
Although addition of carbon nucleophiles to SDEs would
give densely functionalized R-hydroxy ketone motifs related
to polyketides (e.g., erythromycin1,2), intramolecular addition
of oxygen nucleophiles would give highly functionalized
cyclic ethers and related ring systems present in a myriad of
biomedically relevant substances, including the pectenotoxin
class of natural products.3
drofurans of PTX-4 flanked by oxygenated substituents and
thereby facilitate the synthesis of this and related targets.
Among the potential strategies for accessing the C1-C15
portion of PTX-4, we were intrigued by the possibility of
forming the A-B spiroketal ring system by way of an
intramolecular ketone addition to a SDE followed by trapping
the oxocarbenium ion with the resident alcohol (2f4f7,
Figure 1B). Alternatively, the A-B spiroketal could form
by lactol-initiated SDE opening (2f5f7).7 The stereochem-
ical outcome of each potential pathway notwithstanding, for
this study we were aware that isomerization to the more
The pectenotoxins (PTXs) have recently been the focus
of intense research,4 and one total synthesis has appeared.5,6
PTX-4 (Figure 1A) is a 34-membered macrolide that houses
seven oxygen-containing ring systems and 19 stereocenters.
This target represents a challenging problem to synthesis.
In principle, SDEs can provide access to the three tetrahy-
(3) (a) Friedrich, D.; Paquette, L. J. Nat. Prod. 2002, 65, 126. (b) Sheu,
J.; Wang, G.; Duh, C.; Soong, K. J. Nat. Prod. 2003, 66, 662. (c) Sakabe,
N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077. (d) Badder, A.; Garre,
C. Corresp.-Bl. Schweiz. Aerzte 1887, 17, 385. 1232. (e) Reategui, R. F.;
Gloer, J. B.; Campbell, J.; Shearer, C. A. J. Nat. Prod. 2005, 68, 701. (f)
Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem. 1998, 63, 2475.
(g) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.; Matsumoto, G. K.;
Clardy, J. Tetrahedron 1985, 41, 1019.
(4) For lead references, see: (a) Halim, R.; Brimble, M. A.; Merten, J.
Org. Lett. 2005, 7, 2659. (b) Bondar, D.; Liu, J.; Muller, T.; Paquette, L.
A. Org. Lett. 2005, 7, 1813. (c) Peng, X.; Bondar, D.; Paquette, L. A.
Tetrahedron 2004, 60, 9589. (d) Paquette, L. A.; Peng, X.; Bondar, D. Org.
Lett. 2002, 4, 937. (e) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3,
1949. (f) Amano, S.; Fujiwara, K.; Murai, A. Syn. Lett. 1997, 1300.
(5) PTX-4: (a) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew.
Chem., Int. Ed. 2002, 41, 4569. (b) Evans, D. A.; Rajapakse, H. A.; Chiu,
A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4573.
(1) (a) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.; Williams, L. J. J.
Am. Chem. Soc. 2004, 126, 15348 and references cited therein. (b) Ghosh,
P.; Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc., in press. (c) Lotesta,
S. D.; Kiren, S. K.; Sauers, R. R.; Williams, L. J., submitted.
(2) (a) Cane, D. E.; Walsh, C. T.; Khosla, C. Science 1998, 282, 63.
Katz, L. Chem. ReV. 1997, 97, 2557. (b) Aldridge, D. C.; Turner, W. B. J.
Antibiot. 1969, 22, 170. (c) Achenbach, H.; Muehlenfeld, A.; Fauth, U.;
Zaehner, H. Tetrahedron Lett. 1985, 26, 6167. (d) Kellner, M.; Wolf, G.;
Lee, Y. S.; Hansske, F.; Konetschny-Rapp, S.; Pessara, U.; Scheuer, W.;
Stockinger, H. J. Antibiot. 1993, 46, 1334. (e) Rinehart, K. L., Jr.; Martin,
P. K.; Coverdale, C. E. J. Am. Chem. Soc. 1966, 88, 3149.
(6) Natural PTX-4 can be converted into other PTXs (e.g., PTX-8).
See: ref 5b and references therein.
(7) Crandall, J. K.; Rambo, E. Tetrahedron Lett. 1994, 35, 1489.
10.1021/ol063087n CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/08/2007

Scheme 1. Synthesis of the C1-C7 Fragment
Weinreb amide 17 was synthesized from commercially
available â-hydroxy ester 16 by TBS protection and then
Scheme 2. Synthesis of the C8-C15 Fragment
Figure 1. Pectenotoxin 4.
stable spiroketal, which matches the structure of PTX-4,
would be readily achieved by the action of Brønsted acid.5b,8
Although the data presented do not allow one to discern the
operative pathway, the preparation of suitable target systems
and their oxidative cyclization is summarized in Schemes
1-4.
The C1-C7 fragment was prepared as shown in Scheme
1. Known syn-aldol product 89 was reduced with lithium
borohydride followed by PMP acetal formation, DIBAL
reduction, and then TBDPS protection to afford alkene 12
in 58% yield over four steps. Rigorous purification of 9-11
was hampered by the presence of inseparable byproducts.
However, 12 was readily purified and obtained in good
overall yield (87% average per step). Although ozonolysis
of related systems is documented,10 Lemieux-Johnson11
oxidation of 12 proved to be superior for this substrate and
furnished 13 (88%).
application of the Merck conditions13 (83%, two steps).
Alkynylation of 17 with 15 (90%) gave the expected
alkynone, which upon reduction14 gave the corresponding
alkynol 19 (99%, >95:5 ee by Mosher ester analysis).
The synthesis of the C8-C15 fragment (20, Scheme 2)
began with silyl protection of known alkyne diol 14.12
(12) 14 was prepared on a multigram scale following the known two-
step procedure. See: Findeis, R. A.; Gade, L. H. J. Chem. Soc., Dalton
Trans. 2002, 21, 3952.
(13) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(14) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738. Reaction employed 5 mol % of Ru(II) catalyst I.
(8) (a) Pihko, P. M.; Aho, J. E. Org. Lett. 2004, 6, 3849. (b) Miles, C.
O.; Wilkins, A. L.; Munday, R.; Dines, M. H.; Hawkes, A. D.; Briggs, L.
R.; Sandvik, M.; Jensen, D. J.; Cooney, J. M.; Holland, P. T.; Quilliam, M.
A.; MacKenzie, A. L.; Beuzenberg, V.; Towers, N. R. Toxicon 2004, 43,
1. See also ref 4a.
(9) 8 was prepared on a multigram scale in two steps from commercially
available 5-hexenol according to ref 5a.
(10) (a) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.;
Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583. (b)
Maurer, K. W.; Armstrong, R. W. J. Org. Chem. 1996, 61, 3106.
(11) Pappo, R.; Alen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
870
Org. Lett., Vol. 9, No. 5, 2007

Conversion of the propargyl alcohol to the mesylate and then
to allene 20 proceeded in excellent yield (96%).
At this stage, we turned our attention to the critical issue
of allene oxidation (Scheme 3). For 20, we expected the first
Scheme 4. Assembly of C1-C15 and Cyclization
Scheme 3. Stereoselectivity of Allene 20 Oxidation
oxidation to take place on the more highly substituted double
bond. The diastereoselectivity of this oxidation was expected
to be high for steric reasons (20f21). The increased
reactivity of the allene oxide relative to that of an allene
may render the second oxidation less selective than the first.
Consequently, we enlisted a bulky substituent at C-14 to
control the facial selectivity of allene oxide oxidation.15 We
reasoned that the allene oxide would avoid the destabilizing
syn-pentane interactions expected in conformers closely
related to 21 and would prefer to populate conformers
approximated by structure 22. The oxidant should prefer an
approach from the top face of the double bond because the
neopentyl group would disfavor attack from the bottom (22,
see arrows). In the event, exposure of 20 to a solution of
dimethyldioxirane (DMDO) in chloroform16 gave predomi-
nantly a single spirodiepoxide to which we assign structure
23 (>5:117).
from â-allenyl iodides are known to undergo cyclization,19
their potential addition to aldehydes seemed reasonable on
the basis of a recent report by Brummond.20 Accordingly,
lithium halogen exchange of 25 followed by addition of
aldehyde 13 under rigorously dry and oxygen-free conditions
gave γ-hydroxy allene 26 in 52% yield. Dess-Martin
oxidation (85%) and subsequent PMB removal with DDQ
(81%) gave 28.21
Upon DMDO oxidation in CHCl3, 28 gave a product
mixture that upon careful examination included the desired
bicycle as well as isomeric compounds. A separate experi-
ment established that oxidation of 28 followed by addition
of water in THF gave predominantly the corresponding diol
(not shown). Treatment of the diol with TsOH gave 29
(68%22). Upon further evaluation, we arrived at a single-
flask procedure for the conversion of 28 to 29, wherein
addition of MeOH to the DMDO oxidation, followed by
addition of acid at room temperature, smoothly converted
allene 28 to spiroketal 29 (89%, dr 7:1).
With routes to fragments 13 and 20 secured and with the
supportive evidence that allenes of type 20 would oxidize
selectively, we proceeded with the synthesis and study of
allene 28 (Scheme 4). The primary TBS group of 20 was
removed (f24, 94%), and the resultant hydroxyl was
converted to iodide 25 (91%).18 Although anions derived
(15) Of course, if the general strategy explored here was to be applied
in a total synthesis of PTX-4, this group, or its functional equivalent, would
have to also serve as a precursor to the keto group at C14 of the natural
product.
(16) Gibert, M.; Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetra-
hedron 1997, 53, 8643. See also ref 1b.
(19) Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993.
(20) Brummond, K. M.; Lu, J. J. Am. Chem. Soc. 1999, 121, 5087. See
also ref 9.
(21) Compound 28 exists as the δ-hydroxy ketone in CDCl3, and no
evidence for the lactol isomer was observed. 1H NMR analysis shows a
multiplet at 2.5 ppm corresponding to four protons, indicative of two
methylenes flanking a ketone. 13C shows no signals in the 100-110 ppm
region otherwise expected for a quaternary lactol carbon. Instead, a peak
at 210 ppm, indicative of a ketone, is observed.
(17) (a) The 1H NMR signals for the diastereomeric spirodiepoxides were
not baseline resolved. However, the signals that correspond to the erstwhile
allenic methyl groups approached baseline resolution. We conservatively
estimate spirodiepoxide 23 to be >5:1 dr. (b) The observation of two
isomers, instead of the four theoretically possible, is a strong indication
that the first oxidation is very highly selective (>20:1). See also refs 1
and: Crandall, J. K.; Batal, D. J.; Sebesta, D. P.; Ling, F. J. Org. Chem
1991, 56, 1153.
(18) Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801.
(22) Two isomers were apparent in a ratio of 7:1.
Org. Lett., Vol. 9, No. 5, 2007
871

The product ratio is consistent with our earlier observations
for the oxidation of allene 20 to 23. Thus, the first oxidation
at the more substituted double bond of the allene is highly
selective (>20:1) and the oxidation of the second bond is,
in this case, 7:1.17b,23 Acid-induced isomerization is known
to give the doubly anomeric spiroketal corresponding to 29
in acyclic PTX-type systems.5b,8 Comparison of key signals
in the 13C NMR with the PTXs and similar systems supports
this assignment.24
29 and found that treament of 27 under the conditions shown
effected its conversion to the targeted spiroketal in 72% yield,
which, as before, was obtained as a mixture of two isomers
(7:1). Thus, in an excellent overall yield, the following
occurred: the PMB group was removed, the allene was
selectively converted to a SDE (and thereby two stereocenters
were introduced), the SDE was opened to give the C12
tertiary hydroxyl and the C11 carbonyl, and the A-B
spiroketal was assembled.
Whereas the ability to control allene epoxidation and to
predict SDE cyclization has enabled a short synthesis of 29,
our final experiment constitutes an even more direct route
to the target. We noted previously the rapid cleavage of PMB
ethers in the presence of DMDO, particularly in chloroform.25
We therefore sought to effect the direct conversion of 27 to
Acknowledgment. Financial support from Merck & Co.,
Johnson & Johnson (Discovery Award), donors of the
American Chemical Society Petroleum Research Fund, and
Rutgers, The State University of New Jersey, is gratefully
acknowledged. We thank Kaneka America LLC for the
generous donation of compound 16.
(23) Trace quantities of a third compound were also observed. The A-B
spiroketal shown corresponds to the spiroketal of PTX-4 and related
compounds (see refs 5b, 9, and 24) which readily forms selectively under
acidic conditions. That the minor isomer is not the diastereomeric A-B
spiroketal cannot be ruled out. Hence, we conservatively estimate the
selectivity at this center as >10:1.
Supporting Information Available: Synthetic methods
and characterization data (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL063087N
(24) The 13C chemical shifts of C3 (72.3 ppm) and C7 (107.2 ppm) in
29 correlate well with PTX-4 and other reported PTX spiroketals with this
configuration (∆δ ) 0.2-1.2 ppm), whereas PTX-1 and related compounds
with the alternative spiroketal configuration do not (∆δ ) 2.3-3.9 ppm);
see refs 3f, 5b, and 8.
(25) For related substituted benzyl cleavage with DMDO, see: (a)
Marples, B. A.; Muxworthy, J. P.; Baggaley, K. H. Synlett 1992, 646. (b)
Csuk, R.; Do¨rr, P. Tetrahedron 1994, 50, 9983.
872
Org. Lett., Vol. 9, No. 5, 2007