Spirodiepoxide strategy to the C ring of pectenotoxin 4: Synthesis of the C1-C19 sector

Article abstract of DOI:10.1021/ol902984e

(Chemical Equetion Presentation) The synthesis of a C1-C19 precursor to pectenotoxin 4 is presented. The strategy employed the functionalized aliene shown. Key features include: olefin metathesis of two simple fragments to prepare the left portion of the

Full text of DOI:10.1021/ol902984e

ORGANIC
LETTERS
2010
Vol. 12, No. 5
988-991
Spirodiepoxide Strategy to the C Ring
of Pectenotoxin 4: Synthesis of the
C1-C19 Sector
Sipak Joyasawal,† Stephen D. Lotesta,† N. G. Akhmedov,‡ and
Lawrence J. Williams*,†
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854, and C. Eugene Bennett Department of
Chemistry, 406 Clark Hall, Prospect Street, West Virginia UniVersity,
Morgantown, West Virginia 26506
lawjw@rci.rutgers.edu
Received December 31, 2009
ABSTRACT
The synthesis of a C1-C19 precursor to pectenotoxin 4 is presented. The strategy employed the functionalized allene shown. Key features
include: olefin metathesis of two simple fragments to prepare the left portion of the allene-precursor, diastereoselective propargylation of an
epoxy aldehyde to form the right portion, use of the DMDO-stable m-fluorobenzyl ether, and an allene spirodiepoxidation/C-ring formation
cascade.
Here we report a short convergent route to a functionalized
fragment (C1-C19) of pectenotoxin 4 that relies upon the
use of spirodiepoxides1 to install the C-ring and function-
alized C10-C12 functionality. The pectenotoxins (PTX)
represent a significant challenge to chemical synthesis.2 For
example, pectenotoxin 4 (1) embodies a 34-membered
macrolide, 19 stereocenters, a spiroketal (AB), bicyclic ketal
(D) and hemiketal (G), and 3 functionalized tetrahydrofuran
rings (C, E, and F). One total synthesis of a pectenotoxin
has been achieved to date.2c,d Several new methods and
strategies have been developed through focused studies on
these targets.3
One set of related strategies is to fashion the AB spiroketal
and then the C-ring via a C10-C12 spirodiepoxide or to
(2) Isolation: (a) Sasaki, K.; Wright, J. L. C.; Yasumoto, T. J. Org. Chem.
1998, 63, 2475. (b) Yasumoto, T.; Murata, M.; Oshima, Y.; Sano, M.;
Matsumoto, G. K.; Clardy, J. Tetrahedron 1985, 41, 1019. Total synthesis:
(c) Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed.
2002, 41, 4569. (d) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp,
D. Angew. Chem., Int. Ed. 2002, 41, 4573.
† The State University of New Jersey.
(3) For lead references see: (a) Carley, S.; Brimble, M. A. Org. Lett.
2009, 11, 563. (b) Aho, J. E.; Salomaki, E.; Rissanen, K.; Pihko, P. M.
Org. Lett. 2008, 10, 4179. (c) Helmboldt, H.; Aho, J. E.; Pihko, P. M. Org.
Lett. 2008, 10, 4183. (d) Heapy, A. M.; Wagner, T. W.; Brimble, M. A.
Synlett 2007, 15, 2359. (e) Fujiwara, K.; Aki, Y.; Yamamoto, F.; Kawamura,
M.; Kobayashi, M.; Okano, A.; Awakura, D.; Shiga, S.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2007, 48, 4523. (f) Kolakowski, R. V.;
Williams, L. J. Tetrahedron Lett. 2007, 48, 4761. (g) Vellucci, D.;
Rychnovsky, S. D. Org. Lett. 2007, 9, 711. (h) O’Connor, P. D.; Knight,
C. K.; Friedrich, D.; Peng, X.; Paquette, L. A. J. Org. Chem. 2007, 72,
1747. (i) Halim, R.; Brimble, M. A.; Merten, J. Org. Lett. 2005, 7, 2659.
(j) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. See also, ref
1a.
‡ West Virginia University.
(1) (a) Lotesta, S. D.; Hou, Y.; Williams, L. J. Org. Lett. 2007, 9, 869.
(b) Ghosh, P.; Lotesta, S. D.; Williams, L. J. J. Am. Chem. Soc. 2007, 129,
2438. (c) Lotesta, S. D.; Kiren, S. K.; Sauers, R. R.; Williams, L. J. Angew.
Chem., Int. Ed. 2007, 46, 15. (d) Shangguan, N.; Kiren, S.; Williams, L. J.
Org. Lett. 2007, 9, 1093. (e) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.;
Williams, L. J. J. Am. Chem. Soc. 2004, 126, 15348. (f) Ghosh, P.; Cusick,
J. R.; Inghrim, J.; Williams, L. J. Org. Lett. 2009, 11, 4672. (g) Zhang, Y.;
Cusick, J. R.; Ghosh, P.; Shangguan, N.; Katukojvala, S.; Inghrim, J.; Emge,
T. J.; Williams, L. J. J. Org. Chem. 2009, 74, 7707. (h) Ghosh, P.; Zhang,
Y.; Emge, T. J.; Williams, L. J. Org. Lett. 2009, 11, 4402. (i) Wang, Z.;
Ning, S.; Cusick, J. R.; Williams, L. J. Synlett. 2008, 2, 213.
10.1021/ol902984e  2010 American Chemical Society
Published on Web 02/02/2010

form these rings in the reverse order,1a the difference being
that C10-C12 allenes of opposite configuration must be
used. For example, double epoxidation of an allene of type
3 would set into motion a spontaneous cascade of bond-
breaking and forming events to give the fully substituted C
ring system (Figure 1B). In this study we set out to scout
Scheme 1. C1-C10 Precursor Synthesis
conversion of 10 to amide 11 was also realized. Methylena-
tion of 10 followed by amide formation9 gave 11 in 62%
overall yield. This procedure avoids isolation of the volatile
methylenation product.
Union of the C1-C10 precursors 8 and 11 was ac-
complished with catalyst 1210 in refluxing DCM (f13, 85%
yield, single isomer, geometry not assigned, Scheme 2). The
use of bulk DCM11 proved superior to benzene and gave
substantially less homodimerization of 11. Only after treat-
ment of 13 under conditions designed to remove trace
ruthenium was hydrogenation efficient (f14, 97%).12 The
longest linear sequence to the C1-C10 sector required 6
steps from commercial materials.
Figure 1. C1-C19: Focus on a C9-C11 Spirodiepoxide.
this possibility,4 including an expanded cascade sequence
to directly convert allenes of type 2, to oxacycles of type 4
upon epoxidation. As with our earlier work, this strategy
takes advantage of copper-mediated stereospecific allene
assembly.1 Thus, we prepared 33, a specific target of type
4. Alkenes 8 and 11 were prepared and joined to give the
C1-C10 fragment (Schemes 1 and 2); the C11-C19
fragment 26 was also fashioned (Scheme 3). The C1-C10
and C11-C19 fragments were then fused to give the full
C1-C19 sector which was evaluated for ring formation
(Scheme 4).
The strategy to prepare the C11-C19 fragment was
guided, in part, by the desire to evaluate the compatibility
of asymmetric propargylation with epoxy aldehydes of type
23 (Scheme 3). The synthesis began with conversion of
commercially available diol 15 to mono-PMB ether, subse-
quent asymmetric epoxidation (16, >95:5 ee),13 and then silyl
ether formation (17, 71% over three steps). Addition of the
higher order vinyl cuprate generated from the vinyl Grignard
Scheme 2. C1-C10 Fragment Synthesis
The precursors to the C1-C10 fragment were prepared
as shown in Scheme 1. Known syn aldol5 product 5 was
converted to the TBS ether (90%) and then reduced with
LiBH4 to give 7 (70%). The resultant primary alcohol was
also masked (f8, 97%). The coupling partner for 8, amide
11, was synthesized from silyl enol ether 9 obtained from
the corresponding commercially available cyclohexanone
ketal (not shown).6 Ozonolysis7 and subsequent methylation
of the newly formed acid using TMSCHN28 in the presence
of methanol furnished ester aldehyde 10 in a single flask
from 9 (93%). A single flask procedure for the direct
Org. Lett., Vol. 12, No. 5, 2010
989

and subsequent epoxide ring-opening (not shown), as well
as formation of the diastereomeric epoxide. Dess-Martin
oxidation of 22 furnished the epoxy aldehyde 23 (80%).
Yamamoto propargylation15 effected conversion of 23 to
alkynol 25 in good yield and stereoselectivity (80%, >20:1
dr). Although we did not assign the configuration of this
center at this stage, based on NMR analysis of 33 (vide infra)
the stereochemistry is as drawn. This under-utilized method
is both simple and efficient. The procedure required allenyl
boronic acid and D-DIPT for in situ preparation of the chiral
allenyl boronate (24) and proved compatible with the
epoxide, silyl, and PMB protecting groups of 23. For reasons
described below, the hydroxyl group was masked as the
m-fluorobenzyl ether (m-FBn) to give the C11-C19 subunit.
The route to 26 required 11 steps from commercial materials.
Scheme 3. C11-C19 Fragment Synthesis
One of our key strategic interrogatives pertained to the
possible union of fragments 14 and 26. Although there is
do direct precedent, we were optimistic that the acetylide
derived from 26 could be formed with minimal damage to
the epoxide and used in a subsequent nucleophilic acyl
substitution reaction.16 Alkynylide addition to Weinreb
amides is slow in comparison to additions to ketones
and aldehydes and often requires temperatures near 0 °C.
Nevertheless, 26 was smoothly converted to the correspond-
ing epoxy acetylide at 0 °C, and addition of amide 14 to the
reaction mixture afforded epoxy alkynone 27 in 55% yield.17
The epoxide functionality posed no serious complicating
factor for alkynylation of the Weinreb amide or the subse-
quent steps up to the final sequence. Hence, Noyori reduc-
tion18 (86%, >20:1 dr) was followed by mesylation and then
copper-mediated allene formation 30 (85%). Although mild
oxidations were found to remove the PMB group and thereby
afford the corresponding epoxy alcohol (not shown), treat-
ment of 30 with DDQ effected cleavage of the PMB group
and spontaneous epoxide opening to furnish 31 (65%).
and CuBr•Me2S effected epoxide opening; immediate ex-
posure of the crude reaction mixture to silylation conditions
gave terminal olefin 18 in excellent yield (92% from 17).
Compound 18 was molded into 20 via a three step sequence
(69% yield) wherein the alkene was transformed into the
aldehyde, which was homologated with 19, and then reduced
to the alcohol. Shi epoxidation proved to be slow (f22, 60%)
but selective.14 This method was more efficient than Sharp-
less epoxidation, which was accompanied by PMB cleavage
It is remarkable that spirodiepoxides behave well in
complex structural contextssmore so even than in unfunc-
tionalized settings. We were anxious, therefore, to evaluate
the spirodiepoxides derived from 30 and 31. Our expectation
Scheme 4. C1-C19 Sector Synthesis
990
Org. Lett., Vol. 12, No. 5, 2010

was that allene oxidation would proceed along standard lines
and the major spirodiepoxide stereochemistry would cor-
respond to that shown for 32. Thus, the first oxygen would
be delivered to the more substituted π-bond, since this should
be the most nucleophilic portion of the allene. Approach
would be highly selective and occur from the most accessible
face. The second epoxidation would likely be less selective
but would also be governed by sterics.1g
establishing stereoselective inroads to the natural product,
several notable advances were realized, these include the:
(a) highly stereoselective propargylation of an epoxy alde-
hyde (f26), (b) alkynylation of amides with epoxy alky-
nylides (f27), (c) demonstration that the m-FBn ether is a
robust functional group stable to allene epoxidation condi-
tions (cf. 31 f 33), and (d) late-stage conversion of an allene
to an elaborated tetrahydrofuran via the spirodiepoxide
(f33). The insights these data provide will be used in further
studies toward this target and should be generalizable to other
targets as well.
PMB ethers are cleaved rapidly in the presence of DMDO
in chloroform.1a However, we found m-FBn ethers to be stable
to these conditions. Consequently, we masked the C14 hydroxyl
with this group and aimed to convert 30 to 33 directly (c.f. 2
f 4, Figure 1). The extended cascade would include in situ
PMB cleavage as part of the transformation from 30 f 31 f
33. There is an ill-defined distinction between functionality able
to open spirodiepoxides and that which cannot.1 Considerations
along this line identified a provocative possibility: the epoxide
might open the spirodiepoxide prior to, or in a concerted manner
with, epoxide opening by the hydroxyl group, as shown for 30
f 32 f 33. Treatment of 30 with excess DMDO under a
variety of conditions effected cleavage of the PMB group.
formation of the spirodiepoxide (assign as 32), and other
products, but not 33. The stepwise approach, however, was
successful, as exposure of allene 31 to DMDO smoothly
furnished 33 as a single isomer (54%).19 The C10 epimer, the
expected minor stereoisomer of this reaction, was not evident.
Minor related compounds that appear to be nonstereoisomeric
side products were observed by 500 MHz 1H NMR spectros-
copy in CDCl3.20 This transformation illustrates the facility of
the spirodiepoxide logic: oxidation converts the axial chirality
of the allene into three centers of chirality21 and also, in this
case, sets into motion subsequent conversion to the R-tetrahy-
drofuranyl-R′-hydroxy ketone.
Acknowledgment. Financial support from the NIH (GM-
078145) is gratefully acknowledged.
Supporting Information Available: Synthetic methods
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902984E
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This report establishes a concise route to the C1-C19
sector of pectenotoxin 4. From commercial reagents, the
longest linear sequence to 33 is 16 steps. Aside from
(16) Hoffmann-Roder, A.; Krause, N. HelV. Chim. Acta 2002, 85, 3176.
This report did not include nucleophilic acyl substitution, e.g. addition to
amide derivatives; however, it appears to be the only work on alkynylide
additions to carbonyl derivatives with epoxides in tow.
(4) There is precedent for related ring closing reactions in simple,
unfunctionalized, and stereochemically abbreviated systems. See: (a)
Crandall, J. K.; Batal, D. J. Tetrahedron Lett. 1988, 29, 4791. (b) Crandall,
J. K.; Batal, D. J.; Lin, F.; Riex, T.; Nadol, G. S.; Ng, R. A. Tetrahedron
1992, 48, 1427.
(17) The m-FBn appears to have compromized this yield. A TBS
analogue of 26 (instead of m-FB) under the conditions shown formed the
acetylide and added to the TIPS analogue of amide 14 (instead of TBS)
and gave the corresponding epoxy alkynone in 95% yield.
(18) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(5) Available in one step from the acyl oxazolidinone and acrolein, see:
Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 3425.
(6) Kerr, W. J.; McLaughlin, M.; Morrison, A. J.; Pauson, P. L. Org.
Lett. 2001, 3, 2945.
(19) A detailed stereochemical analysis (1D and 2D NMR) of 33 is
provided in the Supporting Information.
(20) Studies on these minor constutuents are ongoing.
(7) Oh, S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835.
(8) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475.
(21) The central carbon of this spirodiepoxide is stereogenic.
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