Studies toward (-)-Gymnodimine: concise routes to the spirocyclic and tetrahydrofuran moieties

Article abstract of DOI:10.1021/ol005510c

(formula presented) (-)-Gymnodimine is a member of a unique class of potent marine toxins possessing imines within a spirocylic array. Herein we report the synthesis of the tetrahydrofuran fragment and a strategy toward the spirocyclic imine fragment of this family of toxins. Key reactions include an asymmetric anti-aldol reaction to set the stereochemistry of the tetrahydrofuran and a formal, intermolecular Diels-Alder reaction involving an α-methylene-δ-lactam and a dienyne.

Full text of DOI:10.1021/ol005510c

ORGANIC
LETTERS
2000
Vol. 2, No. 6
763-766
Studies toward (−)-Gymnodimine:
Concise Routes to the Spirocyclic and
Tetrahydrofuran Moieties
Ju Yang, Stephen T. Cohn, and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77843-3012
romo@mail.chem.tamu.edu
Received January 4, 2000
ABSTRACT
(−)-Gymnodimine is a member of a unique class of potent marine toxins possessing imines within a spirocylic array. Herein we report the
synthesis of the tetrahydrofuran fragment and a strategy toward the spirocyclic imine fragment of this family of toxins. Key reactions include
an asymmetric anti-aldol reaction to set the stereochemistry of the tetrahydrofuran and a formal, intermolecular Diels−Alder reaction involving
an r-methylene-δ-lactam and a dienyne.
Marine toxins have proven to be useful biochemical probes
for the study of a variety of biological systems. Examples
include the use of tetrodotoxin and brevetoxin in studies of
sodium channels,1 okadaic acid in studies of protein phos-
phatases,2 and domoic acid in studies of neuronal receptors.3
Gymnodimine (1) is a member of a class of recently isolated
marine toxins that possess unusual spirocyclic imines within
macrocycles that also contain an ether or polyether subunit.4
Other members of this family include the spirolides5 and
pinnatoxins.6 These natural products have attracted much
synthetic interest,7 culminating recently in an elegant syn-
thesis of pinnatoxin A by Kishi employing an intramolecular
Diels-Alder reaction.7g Recently, Munro and Blunt disclosed
the relative and absolute stereochemistry of gymnodimine
as determined by X-ray analysis of the p-bromobenzamide
3 of gymnodamine (2), the reduction product of gymnodi-
mine.8 A new analogue of gymnodimine, gymnodimine B,
has recently been isolated.9
As a means to explore concise synthetic strategies to the
interesting spirocyclic imines found in these toxins and to
(1) Catterall, W. A. Physiol. ReV. 1992, 72, S15-S48.
(2) (a) Bialojan, C.; Takai, A.; Biochem. J. 1988, 256, 283-290. (b)
Haystead, T. A. J.; Sim, A. T. R.; Carling, D.; Honnor, R. C.; Tsukitani,
Y.; Cohen, P.; Hardie, D. G. Nature 1989, 337, 78-81.
(3) Wenthold, R. J.; Hampson, D. R. J. Biol. Chem. 1988, 263, 2500-
2505.
(4) Seki, T.; Masayuki, S.; Mackenzie, L.; Kaspar, H. F.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093-7096.
(5) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995,
2159-2161.
(6) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155-1156.
(7) For other synthetic studies toward gymnodimine, see: (a) Ishihara,
J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997, 1417-1419. (b)
Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27-29. For synthetic studies of
pinnatoxin, see: (c) Ishihara, J.; Sugimoto, T.; Murai, A. Synlett 1998, 603-
606. (d) Ishiwata, A.; Sakamoto, S.; Noda, T.; Hirama, M. Synlett 1999,
692-694. (e) Nitta, A.; Ishiwata, A.; Noda, T.; Hirama, M. Synlett 1999,
695-696. (f) Sugimoto, T.; Ishihara, J.; Murai, A. Synlett 1999, 541-544.
(g) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones
M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-7648.
10.1021/ol005510c CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/25/2000

study their mode of action, we initiated a total synthesis of
(-)-gymnodimine. In our retrosynthetic analysis, we envi-
sioned the coupling of three fragments to provide the most
convergency and the most flexibility in preparing derivatives
for biomechanistic studies (Figure 1). Coupling the tetrahy-
fragment 4. Toward these goals, we have developed a concise
formal Diels-Alder strategy to the spirocyclic moiety of
gymnodimine that may also be applicable to other members
of this family of toxins. In addition, we have completed an
asymmetric synthesis of the tetrahydrofuran moiety.
Acylation (TCBoc-Cl) or tosylation (TsCl) of the known
δ-lactam 1312 provided the R-methylene lactams required for
the Diels-Alder strategy (Scheme 1). This lactam is
Scheme 1. Synthesis of Dienophiles 8 and 14a
a (a) EtOH, 80 °C, 1000 psi H2, 8 h; (b) MeOH, 0 f 23 °C, 12
h; (c) PhMe, reflux, 25 min; (d) THF, -78 °C, 1 h; (e) THF, -78
°C, 1 h.
ultimately derived from diester 10, readily available in >100
g quantities by Michael addition of diethylmalonate to
acrylonitrile by a known procedure.13 Although lactam 11
is commercially available, it is somewhat expensive. There-
fore, it was prepared on a large scale by Raney nickel
reduction of the nitrile 10.13 Subsequent reduction and
dehydration gave the known R-methylene lactam 13.12
Lactam 13 is a pivotal intermediate as several nitrogen
protecting groups could be appended and studied in the
Diels-Alder reaction. Initially, the trichloro-tert-butoxy
carbamate (TCBoc) protected dienophile 14 and the tosylated
dienophile 8 were prepared.
Figure 1. Retrosynthetic analysis of gymnodimine and structures
of derivatives.
drofuran fragment 4, the spirocyclic lactam 5, and the
dihydrofuran 6 would deliver the target molecule.
The required (Z)-diene for the Diels-Alder strategy was
prepared in a concise fashion from propyne using tellurium
chemistry as outlined in Scheme 2. Highly selective hydro-
telluration of hexa-2,4-diyne14 (16) by the method of
Comasseto15 gave vinyl tellurium 17 (>19:1 Z:E, 300 MHz
1H NMR). Metalation of vinyl tellurium 17 and addition of
Weinreb amide16 18 gave ketone 19. Silylation leading to
enol ether 7 proceeded without isomerization under carefully
We envisioned the use of a Diels-Alder strategy to access
the spirocyclic moiety of gymnodimine and related toxins.
Initially, we recognized that application of a Diels-Alder
strategy would dictate the use of either an intramolecular
process to enforce exo selectivity or the use of a (Z)-diene
as a means to access the relative stereochemistry found in
gymnodimine. We chose the latter approach and thus the
(Z)-diene 7 and R-methylene lactam 8 as our Diels-Alder
substrates. The recent compilation by Roush10 of acyclic (Z)-
dienes that participate in Diels-Alder reactions suggested
that the proposed (Z)-diene would participate in an inter-
molecular Diels-Alder reaction. A Heathcock anti-aldol11
reaction and a stereoselective allylation would be utilized
for introduction of stereochemistry in the tetrahydrofuran
(11) (a) Walker, M.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-
5750. (b) Raimundo, B. C.; Heathcock, C. H. Synlett 1995, 1213-1214.
(c) Hansen, M. M.; Danda, H.; Heathcock, C. H. J. Org. Chem. 1990, 55,
173-181.
(12) Klutchko, S.; Hoefle, M. L. J. Med. Chem. 1981, 24, 104-109.
(13) (a) Koelsch, C. F. J. Am. Chem. Soc. 1943, 65, 2458-2459. (b)
Hesse, G.; Bu¨cking, E. Justus Liebigs Ann. Chem. 1949, 563, 31-37. (c)
Albertson, N. F.; Fillman, J. L. J. Am. Chem. Soc. 1949, 71, 2818-2820.
(14) Brandsma, L.; Verkruijsse, H. D.; Walda, B. Synth. Commun. 1991,
21, 137-139.
(15) (a) Dabdoub, M. J.; Dabdoub, V. B.; Comasseto, J. V. Tetrahedron
Lett. 1992, 33, 2261-2264. (b) Tucci, F. C.; Chieffi, A.; Comasseto, J. V.;
Marino, J. P. J. Org. Chem. 1996, 61, 4975-4989.
(16) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818. (b) Oster, T. A.; Harris, T. M. Tetrahedron Lett. 1983, 24, 1851-
1854.
(8) Stewart, M.; Blunt, J. W.; Munro, M. H. G.; Robinson, W. T.;
Hannah, D. J. Tetrahedron Lett. 1997, 38, 4889-4890.
(9) Miles, C. O.; Wilkins, A. L.; Stirling, D. J.; MacKenzie, A. L. In
Proceedings of the Marine Biotoxin Science, Workshop No. 11, Wellington,
New Zealand, 1999; Ministry of Agriculture and Forestry, pp 103-106.
(10) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402-
7403.
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Org. Lett., Vol. 2, No. 6, 2000

Scheme 2. Synthesis of Diene (Z)-7a
Figure 2. Chem 3D representation of the X-ray crystal structure
of the formal Diels-Alder adduct 5.
a (a) DBU, py, DMF, -42 f 35 °C, 3 h; (b) absolute EtOH,
reflux, 3 h; (c) THF, -78 °C, 1 h then 18, -78 °C, 0.75 h; (d)
THF, -78 °C, 0.5 h.
accomplished using sodium naphthalenide in 83% yield
(Scheme 3).18
The excellent diastereoselectivity observed in this net
cycloaddition deserves comment. We suggest that this
reaction is, in fact, a formal Diels-Alder reaction proceeding
through a stepwise process involving two sequential Michael
reactions and passing through highly stabilized carbocation
intermediates (i.e., 21 and 22, Figure 3). Two of four possible
controlled conditions; however, silica gel chromatography
of this intermediate led to varying degrees of isomerization.
Diene 7 could be readily prepared on a large scale (∼5 g),
but due to the instability of the silyl enol ether, material was
typically advanced and stored at the stage of ketone 19.
Attempted Lewis acid-promoted Diels-Alder reactions
with the TCBoc-protected lactam 14 failed under a variety
of conditions. We reasoned that further activation of the
dienophile was required, and tosylation of lactam dienophiles
had previously been employed to increase their reactivity in
Diels-Alder reactions.17 Gratifyingly, the Diels-Alder reac-
tion of tosylated dienophile 8 and diene 7 was found to
proceed efficiently with Et2AlCl at -30 °C to give a single
diastereomer of crystalline cycloadduct 5 (67%) (Scheme 3).
Figure 3. Two possible transition state arrangements leading to
the formal Diels-Alder adduct.
Scheme 3. Synthesis of Spirocycle Moiety 5
transition state arrangements are shown, and these both lead
to the observed cycloadduct 5; however, transition state
arrangement 22 should be preferred as it avoids nonbonded
interactions present in 21.
The synthesis of the tetrahydrofuran fragment commenced
with a Heathcock anti-aldol reaction11 employing the ephe-
drine-derived auxiliary 2319 and the known aldehyde 24
(Scheme 4).20 This provided a mixture of three diastereomers
(dr, 5:1:0.5) from which the major diastereomer 25 could
be isolated in 68% yield. The stereochemistry of the major
diastereomer was determined to be anti by 1H-1H coupling
constant analysis which showed the coupling constant JHR,Hâ
) 8.7-9.3 Hz (typical values: syn, J ) 3.2-6.4 Hz; anti,
J ) 7.2-9.6 Hz).11 This aldol reaction set the stereochemistry
corresponding to the C15 and C16 stereocenters of gymn-
odimine, and what was now required was homologation to
the furanose. After extensive experimentation, it was deter-
mined that removal of the chiral auxiliary could best be
achieved by methanolysis which gave the ester 26 in 80%
This spirocyclic lactam was found to possess the correct
regio- and relative stereochemistry required for the synthesis
of gymnodimine as determined by single-crystal X-ray
analysis (Figure 2). Interestingly, we found that the same
diastereomer is obtained regardless of the geometry of the
diene 7, suggestiVe of a stepwise, net Diels-Alder process.
Deprotection of the tosyl lactam 5 to give lactam 20 was
(17) (a) Torisawa, Y.; Hosaka, T.; Tanabe, K.; Suzuki, N.; Motohashi,
Y.; Hino, T.; Nakagawa, M. Tetrahedron 1996, 52, 10597-10608. (b)
Casamitjana, N.; Jorge, A.; Perez, C. G.; Bosch, J.; Espinosa, E.; Molins,
E. Tetrahedron Lett. 1997, 38, 2295-2298. (c) Torisawa, Y.; Nakagawa,
M.; Takami, H.; Nagata, T.; Ali, M. A.; Hino, T. Heterocycles 1994, 39,
277-292. (d) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. HelV. Chim.
Acta 1984, 67, 1397-1401.
(18) (a) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311-5312. (b) Alonso,
D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455-9461.
(19) Evans, D. A.; Mathre, D. J.; Scott, W. L. J. Org. Chem. 1985, 50,
1830-1835.
Org. Lett., Vol. 2, No. 6, 2000
765

to 0 °C and delivered a 4:1 mixture of diastereomers.23 The
stereochemistry of the major diastereomer was determined
to be R on the basis of a ROESY experiment that showed a
cross-peak for Ha and Hb for the major diastereomer of
tetrahydrofuran 33. The moderate diastereoselectivity is
surprising in light of an allylation by Murai on a related
substrate that differs only by the nature of the substituent at
C4 (ribose numbering).7a,24 With the hope of performing the
allylation at lower temperature, acetoxyfuranoses 32 were
prepared. While allylation of these substrates did proceed at
-78 °C, the ratio of epimers did not improve. The diaster-
eomeric tetrahydrofurans 33 were inseparable at this stage,
so they were converted to silyl ethers 4 by a hydroboration/
oxidation sequence followed by silylation.
Scheme 4. Synthesis of Tetrahydrofuran Moiety 4a
This overall sequence provides a concise entry into the
spirocyclic array of gymnodimine that is functionalized
appropriately for elaboration to the complete spirocyclic
fragment. Asymmetric versions of this process are being
explored. Importantly, this approach would also appear to
be applicable to the synthesis of the related spirolides. We
have also developed an asymmetric route to the tetrahydro-
furan fragment of gymnodimine. However, the allylation step
suffers from moderate selectivity and current studies are
focused on alternative methods for introduction of the final
three carbons on this fragment with the goal of improving
stereoselectivity while also increasing convergency.
Acknowledgment. We thank the NIH (GM 52964-01)
and Zeneca Pharmaceuticals for support of these investiga-
tions. D.R. is an Alfred P. Sloan Fellow and a Camille-Henry
Dreyfus Teacher-Scholar. We thank Profs. Murray M. H.
G. Munro and John W. Blunt (University of Canterbury, NZ)
for informative discussions regarding the relative and
absolute stereochemistry of gymnodimine. We thank Aaron
Reuland for expert technical assistance. We thank Dr. Joe
Reibenspies for obtaining the X-ray structure of 5 using
instruments obtained with funds from the NSF (CHE-
9807975) and Dr. Lloyd Sumner of the Texas A&M Center
for characterization for mass spectral analyses obtained on
instruments acquired by generous funding from the NSF
(CHE-8705697) and the TAMU Board of Regents Research
Program.
a (a) i-Pr2NEt, Et2O, 0 °C, 45 min, -78 °C, then 24, Et2O, -78
°C, 6 h; (b) MeOH, -78 f -10 °C, 2 h; (c) 2,6-lutidine, CH2Cl2,
-78 °C, 10 min; (d) CH2Cl2, -78 °C, 30 min; (e) DMSO, (COCl)2,
CH2Cl2, -78 °C, 10 min, then 28, Et3N, -78 °C, 1 h; (f) K-O-t-
Bu, THF, 0 f 22 °C, 2 h; (g) MeOH, 25 °C (for 30), or THF,
H2O, 25 °C (for 31); (h) Et3N, CH2Cl2, catalytic DMAP, 22 °C, 2
h; (i) Et2O, 0 °C (for 30) or Et2O, -78 °C (for 32); (j) THF, 0 °C,
24 h; NaOH; (k) 2,6-lutidine, CH2Cl2, -78 °C, 40 min.
yield.21 Silylation followed by a reduction-oxidation se-
quence provided aldehyde 9 in good overall yield. Wittig
olefination proceeded smoothly to give methoxy olefins 29
as a 3:1 mixture (300 MHz 1H NMR) of geometrical isomers
in 97% yield.22 Acid-promoted desilylation and cylization
in MeOH provided epimeric furanoses 30.
Supporting Information Available: Experimental pro-
1
cedures and full characterization data (including IR and H
and 13C NMR spectra) for compounds 4, 5, 7, 8, 25, 28, 30,
and 33. This material is available free of charge via the
Internet at http://pubs.acs.org.
Allylation of furanose 30 was employed for setting the
remaining stereocenter at C13. Allylation with BF3‚OEt2 and
allylsilane did not proceed at -78 °C but required warming
OL005510C
(23) Kozikowski, A. P.; Sorgi, K. L.; Wang, B. C.; Xu, Z. Tetrahedron
Lett. 1983, 24, 1563-1566.
(20) Hirama, M.; Noda, T.; Takeishi, S.; Itoˆ, S. Bull. Chem. Soc. Jpn.
1988, 61, 2645-2646.
(21) For a related deprotection/cyclization, see: Walba, D. M.; Thurmes,
W. N.; Haltiwanger, R. C. J. Org. Chem. 1988, 53, 1046-1056.
(22) For a detailed procedure of this Wittig reaction, see: Pyne, S. G.;
Hensel, M. J.; Fuchs, P. L. J. Am. Chem. Soc. 1982, 104, 5719-5728.
(24) Due to space limitations, a possible rationalization for the moderate
selectivity will be described in a full account of this work. For a recently
proposed stereoelectronic model rationalizing nucleophilic additions to five-
membered-ring oxocarbeniums and applicable to the present system, see:
Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208-12209.
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