Synthesis of a functionalized 7,6-bicyclic spiroimine ring fragment of the spirolides

Article abstract of DOI:10.1021/ol102525w

The asymmetric synthesis of a functionalized 7,6-spiroimine related to the spirolides is described. Intermolecular Diels-Alder cycloaddition of a chiral trisubstituted dienophile and Danishefsky's diene enabled simultaneous installation of the C7 and C29 stereocenters. Further transformations and late-stage aza-Wittig cyclization afforded the spiroimine in good yield. During this study, an unprecedented 14-membered dialdimine was also obtained.

Full text of DOI:10.1021/ol102525w

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5226-5229
Synthesis of a Functionalized
7,6-Bicyclic Spiroimine Ring Fragment
of the Spirolides
Ste´phanie M. Gue´ret, Daniel P. Furkert, and Margaret A. Brimble*
Department of Chemistry, UniVersity of Auckland, PriVate Bag 92019, Auckland, New Zealand
m.brimble@auckland.ac.nz
Received September 20, 2010
ABSTRACT
The asymmetric synthesis of a functionalized 7,6-spiroimine related to the spirolides is described. Intermolecular Diels-Alder cycloaddition
of a chiral trisubstituted dienophile and Danishefsky’s diene enabled simultaneous installation of the C7 and C29 stereocenters. Further
transformations and late-stage aza-Wittig cyclization afforded the spiroimine in good yield. During this study, an unprecedented 14-membered
dialdimine was also obtained.
Spirolides A-D (1-4) were first isolated from the digestive
glands of shellfish collected from the east coast of Nova
Scotia in Canada.1 These toxins are metabolites of the
dinoflagellates Alexandrium ostenfeldii and A. peruVianum.
To date, 14 members of this family have been identified from
around the world.2 The spirolides are considered as fast-
acting neurotoxins and are activators of L-type calcium
channels.3 They also represent the most potent nonpeptidic
nicotinic acetylcholine receptor antagonists as demonstrated
by a recently obtained X-ray structure of 13-desmethyl
spirolide C (5) bound to acetylcholine binding proteins
(AChBP).4
The remarkable biological activity of the spirolides renders
them attractive candidates for the development of lead
compounds for treatment of cardiovascular and neurological
diseases. However, total synthesis of these highly complex
marine biotoxins has not yet been reported. The proposed
relative stereochemistry5,6 bears a close resemblance to that
of pinnatoxin A7 whose absolute stereochemistry is known.
The structure of the spirolides can be divided into two parts
(Figure 1): the bis-spiroacetal unit previously synthesized
by the Ishihara8 and Brimble9 groups and the cyclic
spiroimine moiety known to be essential for biological
activity. Due to the presence of a seven-membered imine
ring, a quaternary stereocenter at the ring junction and the
(5) Falk, M.; Burton, I. W.; Hu, T. M.; Walter, J. A.; Wright, J. L. C.
(1) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun.
1995, 2159.
Tetrahedron 2001, 57, 8659.
(6) Ciminiello, P.; Catalanotti, B.; Dell’Aversano, C.; Fattorusso, C.;
Fattorusso, E.; Forino, M.; Grauso, L.; Leo, A.; Tartaglione, L. Org. Biomol.
(2) Gue´ret, S. M.; Brimble, M. A. Nat. Prod. Rep. 2010, 27, 1350.
(3) Gill, S.; Murphy, M.; Clausen, J.; Richard, D.; Quilliam, M.;
MacKinnon, S.; LaBlanc, P.; Mueller, R.; Pulido, O. Neurotoxicology 2003,
24, 593.
Chem. 2009, 7, 3674.
(7) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(8) Ishihara, J.; Ishizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahedron
Lett. 2004, 45, 7855.
(4) Bourne, Y.; Radic, Z.; Araoz, R.; Talley, T. T.; Benoit, E.; Servent,
D.; Taylor, P.; Molgo, J.; Marchot, P. Proc. Natl. Acad. Sci. 2010, 107,
6076.
(9) (a) Meilert, K.; Brimble, M. A. Org. Biomol. Chem. 2006, 4, 2184.
(b) Furkert, D. P.; Brimble, M. A. Org. Biomol. Chem. 2004, 2, 3573.
10.1021/ol102525w  2010 American Chemical Society
Published on Web 10/28/2010

to construct a cyclohexanone containing an R-substituted
quaternary center. Other research groups have employed
similar strategies with various (S)-dienophiles derived
from (R)-glyceraldehyde acetonide.12 However, to date,
the use of the (R)-trisubstituted dienophile derived from
(S)-glyceraldehyde acetonide in Diels-Alder reactions has
not been reported. In addition, synthetically useful asym-
metric Diels-Alder reactions of complex trisubstituted
dienophiles such as 10 possessing an acyclic R-substituent
larger than a methyl group remain relatively uncommon.13
Alkylated phosphonates 14a-c were obtained in high
yield by treatment of commercially available phosphonates
12a,b with O-protected iodides 13a,b. (S)-Glyceraldehyde
acetonide 1514 was obtained in three steps from com-
mercially available L-ascorbic acid and used immediately.
HWE reaction progress, E-selectivity, and acetonide
epimerization were monitored by RP-chiral-HPLC. Con-
densation of aldehyde 15 with phosphonate 14a in the
presence of LDA afforded 16a with racemization of the
stereocenter (Table 1, entry 1). HWE performed using
Figure 1. Relative stereochemistry of the spirolides.
presence of an R-stereocenter in an anti relationship to the
imine functionality, the synthesis of the spiroimine unit
presents a significant synthetic challenge. To date, synthetic
approaches to the related pinnatoxins have relied on difficult
late-stage imine formation within a macrocyclic framework.10
We were interested in investigating the possibility of
forming the imine at an earlier stage of the synthesis, to
allow a modular approach for assembly of the final
macrolide from component fragments. Our strategy aimed
to access model spiroimine 6 (Scheme 1) via aza-Wittig
Table 1. Synthesis of (R)-Dienophile via a
Horner-Wadsworth-Emmons Reaction
Scheme 1. Retrosynthetic Analysis
yield
entry R1
R2
conditions
(%) E/Z racemization
1
2
3
4
5
6
Et
Et
Et
Et
TBS LDA, -78 °C, DME
77 1.1:1
yes
no
no
no
no
no
TBS LiHMDS, -50 °C, DME 61 1:1.1
TBS DBU, LiCl, rt, MeCN
TBS t-BuOK, -78 °C, DME
34 1:1.1
78 5.7:1
i-Pr TBS t-BuOK, -78 °C, DME 77 7:1
Et
PMB t-BuOK, -78 °C, DME
90 4.9:1
cyclization of suitably functionalized keto-azide 7, derived
in turn from cyclohexenone 8. The required 7S,29S
configuration was envisioned to result from a stereose-
lective intermolecular Diels-Alder cycloaddition between
Danishefsky’s diene (9) and trisubstituted dienophile 10
prepared from phosphonate 11. Asano et al.11 have
reported the use of a Diels-Alder reaction between
Danishefsky’s diene and an (S)-trisubstituted dienophile
LiHMDS or under Masumune-Roush conditions gave 16a
without racemization but poor E/Z selectivity (entries 2
and 3). Finally, use of t-BuOK afforded the desired
dienophiles in high yield with good E/Z ratios in favor of
the E-isomer (entries 4-6).
(12) (a) Bunuel, E.; Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1996, 7, 1431. (b) Bunuel, E.; Gil, A. M.; Diaz-de-Villegas,
M. D.; Cativiela, C. Tetrahedron 2001, 57, 6417. (c) Ortuno, R. M.; Ibarzo,
J.; d’Angelo, J.; Dumas, F.; Alvarez-Larena, A.; Piniella, J. F. Tetrahedron:
Asymmetry 1996, 7, 127. (d) White, J. D.; Wang, G.; Quaranta, L. Org.
Lett. 2003, 5, 4983.
(10) Beaumont, S.; Ilardi, E.; Tappin, N.; Zakarian, A. Eur. J. Org.
Chem. 2010, 30, 5743.
(11) (a) Asano, M.; Inoue, M.; Katoh, T. Synlett 2005, 10, 1539. (b)
Asano, M.; Inoue, M.; Watanabe, K.; Abe, H.; Katoh, T. J. Org. Chem.
2006, 71, 6942.
(13) Baldovini, N.; Solladie´, G. Tetrahedron: Asymmetry 2002, 13, 885.
(14) Hubschwerlen, C. J. Org. Chem. 1991, 54, 4056.
Org. Lett., Vol. 12, No. 22, 2010
5227

The key Diels-Alder reaction between Danishefsky’s
diene15,16 (9) and 16a was first attempted using thermal
conditions (Table 2).11 Initial experiments afforded only
Scheme 2.
Conversion of Diels-Alder Adduct to Spiroimine 23a
Table 2. Diels-Alder Cycloaddition
entry
R
solvent
conditions
yield (%)a
1
2
3
4
5
6
TBS toluene sealed tube, 150 °C, 4 days
3
TBS toluene Yb(OTf)3,b rt, 48 h
0c
TBS CHCl3
Eu(fod)3,b 65 °C, 48 h
0c
14
65d
35
TBS toluene µν 150 °C, 18 h
TBS neat
PMB neat
µν 150 °C, 48 h
µν 150 °C, 48 h
a Yield of 17a-c or 18a-c after standard aqueous acid/DBU workup.
b 20 mol %. c sm recovered. ∼20% of E-dienophile recovered.
d
a 19b + c (27%) also isolated (see Scheme 3).
traces of the desired cycloadducts 17a-c (entry 1). Addition
of Lewis acids17,18 failed to give any improvement (entries
2 and 3). However, irradiation of the mixture in toluene19,20
resulted in a slight increase in yield (entry 4). Solvent-free
microwave-assisted conditions proved most successful, af-
fording cycloadducts 17a-c in 65% yield after acidic workup
and elimination of the methoxy group (entry 5). TBS proved
to be the most effective protecting group out of those tested
(entry 6). Importantly, the optimal conditions proved to be
reproducible and scalable, confirming the utility of trisub-
stituted dienophile 16a. Standard reduction of the enone
proceeded smoothly (Scheme 2). Protection of the ketone
as an exocyclic olefin by Wittig methylenation and LAH
reduction of the ester to the corresponding alcohol afforded
enantiomerically pure major diastereoisomer 19a, possessing
the correct absolute stereochemistry for the spirolides (vide
infra).
the natural product.21 Disappointingly, initial imine formation
attempts using 21 in the presence of triphenylphosphine
afforded only keto-amine hydrolysis product 22. All efforts
to cyclize this material using conditions reported for the
pteriatoxins22 and pinnatoxins23,24 returned only starting
material. Pelc and Zakarian25,26 have reported the successful
cyclization of a related keto-azide lacking substitution R to
the quaternary center. Accordingly keto-azide 21 was treated
with trimethylphosphine in toluene at room temperature then
at reflux to afford desired spiroketimine 23 in good yield.
23 proved to be stable in anhydrous toluene or deuterated
chloroform for several hours and could be stored for several
weeks in the freezer under argon without degradation. The
presence of an R-quaternary center and a side chain on
the six-membered ring appears to be sufficient to render the
imine functionality relatively stable.
To confirm the stereochemical assignment, adducts 17a-c
were converted to corresponding aldehydes 24a-c for
comparison of their respective NOE spectra (Scheme 3).
Oxidation with PCC and deprotection using TBAF gave
hydroxy aldehydes 24a-c in excellent yield that were
separable by chromatography. The NOESY spectra of the
major (24a) and minor (24c) diastereoisomers supported an
anti relationship between the aldehyde and the acetonide
Alcohol 19a was next advanced to azido methyl ketone
21 to investigate conditions for the required spiroketimine
formation. Previous work in this group has demonstrated the
feasibility of imine R-alkylation for later elaboration toward
(15) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807
.
(16) Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth., Coll. 1990,
7, 312
.
(17) Fringuelli, F.; Taticchi, A. The Diels-Alder Reaction: Selected
Pratical Methods; John Wiley & Sons, Ltd.: Chichester, U. K., 2002
.
(21) Brimble, M. A.; Gorsuch, S. Aust. J. Chem. 1999, 10, 965.
(22) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.; Kishi,
Y. J. Am. Chem. Soc. 2006, 128, 7463.
(18) Jorgensen, K. A. In Cycloaddition reactions in organic synthesis;
Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH Verlag GmbH: Wein-
heim, Germany, 2002; p 151.
(23) Matsuura, F.; Hao, J.; Reents, R.; Kishi, Y. Org. Lett. 2006, 8,
(19) Berlan, J.; Giboreau, P.; Lefeuvre, S.; Marchand, C. Tetrahedron
3327.
Lett. 1991, 32, 2363
.
(24) Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774
(25) Pelc, M. J.; Zakarian, A. Org. Lett. 2005, 7, 1629
(26) Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519
.
(20) Jankowski, C. K.; LeClair, G.; Belanger, J. M. R.; Pare, J. R. J.;
.
VanCalsteren, M.-R. Can. J. Chem. 2001, 79, 1906
.
.
5228
Org. Lett., Vol. 12, No. 22, 2010

Scheme 3
.
Stereochemical Determination of Diels-Alder
Scheme 4. Unexpected Formation of 14-Membered Dialdimines
Diastereoisomers (Key NOE Correlations Shown)
groups, both resulting from Diels-Alder reaction of the
E-isomer of dienophile 16a, with the diene preferentially
approaching from the less hindered Si face as expected. A
syn relationship between the aldehyde and acetonide in
diastereoisomer 24b resulted from reaction of the minor
Z-isomer component of dienophile 16a.27
Our earliest efforts to explore intramolecular imine forma-
tion had involved advanced azido aldehydes 25a and 25c,
obtained from primary alcohols 24a and 24c by tosylation
and nucleophilic displacement with sodium azide (Scheme
4). Attempted cyclizations using triphenylphosphine were
conducted in toluene-d8 to allow NMR monitoring. After
warming overnight at 55 °C, only the unexpected stable 14-
membered aldimine dimers 26a and 26c were isolated. The
minor diastereoisomer 26c proved to be crystalline with the
X-ray structure confirming all stereocenters to be R, opposite
to that required for the spirolides.28 This information, along
with additional NOESY studies,29 confirmed that major
dialdimine 26a, and therefore also spiroimine 23, possessed
the desired 7S,29S configuration necessary for the spiroimine
unit of the spirolides.
In conclusion, an efficient approach to enantiopure
spiroimine 23 containing both C7 and C29 stereocenters of
the spirolides has been developed. This approach also
resulted in the preparation of unprecedented stable 14-
membered dialdimines 26a,c that allowed unequivocal
confirmation of Diels-Alder selectivity by X-ray crystal-
lography. The successful preparation of the 7,6-bicyclic
spiroimine represents an important milestone in progress
toward the total synthesis of the spirolide family of marine
toxins. Further functionalization of the spiroimine unit is
currently under investigation.
Supporting Information Available: Experimental pro-
cedures, NMR spectra for new compounds, and NOESY
spectra for compounds 24a-c, 26a, and 26c. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(27) See Supporting Information for NOESY spectra of 24a-c.
(28) Gue´ret, S. M.; Boyd, P. D. W.; Brimble, M. A. Acta Crystallogr.,
Sect. E: Struct. Rep. Online 2010, E66, o1778.
(29) See Supporting Information for NOESY spectra of 26a and 26c.
OL102525W
Org. Lett., Vol. 12, No. 22, 2010
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