Biomimetic macrocycle-forming Diels-Alder reaction of an iminium dienophile: Synthetic studies directed toward gymnodimine

Article abstract of DOI:10.1021/ol051553n

(Chemical Equation Presented) The macrocyclic core of gymnodimine has been constructed via an intramolecular Diels-Alder reaction of an α,β-unsaturated iminium dienophile in water. The cycloaddition furnished a single exoproduct, along with two endo-produ

Full text of DOI:10.1021/ol051553n

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3997-4000
Biomimetic Macrocycle-Forming
Diels Alder Reaction of an Iminium
−
Dienophile: Synthetic Studies Directed
Toward Gymnodimine
Jeffrey W. Johannes, Steve Wenglowsky, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received July 1, 2005
ABSTRACT
The macrocyclic core of gymnodimine has been constructed via an intramolecular Diels
−Alder reaction of an
r,â-unsaturated iminium dienophile
in water. The cycloaddition furnished a single exo-product, along with two endo-products. Through X-ray analysis of a suitable derivative, the
stereochemistry of the exo-product was established, thereby demonstrating that its stereochemistry matches that of gymnodimine. In contrast,
macrocyclization of an analogous
r,â-unsaturated ketone dienophile gave only undesired endo-products. Interestingly, the imine dienophile
shows remarkable stability in water.
Gymnodimine (1) was first isolated from oysters collected
from the Foveaux Strait, South Island, New Zealand, by
Yasumoto and co-workers in 1995 (Figure 1).1 Blunt, Munro,
and co-workers established the relative and absolute stereo-
chemistry via single-crystal X-ray analysis.2 Subsequently,
Miles and co-workers isolated gymnodimines B and C.3
Gymnodimine is a member of a large class of natural
products bearing a cyclic imine fused to a cyclohexene ring
and a macrocarbocycle. Members of this class of natural
products include the pinnatoxins,4 the pteriatoxins,5 sym-
bioimine,6 the prorocentrolides,7 the spirolides,8 and spiro-
prorocentrimine.9
Upon isolation and structure elucidation of pinnaxtoxin
A, Uemura proposed that the macrocarbocycle of the natural
(1) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093-7096.
(2) Stewart, M.; Blunt, J. W.; Munro, M. H. G.; Robinson, W. T.;
Hannah, D. J. Tetrahedron Lett. 1997, 38, 4889-4890.
(3) Miles, C. O.; Wilkins, A. L.; Stirling, D. J.; MacKenzie, A. L. J.
Agric. Food Chem. 2003, 51, 4838-4840.
(4) (a) Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.;
Haino, T.; Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3491-
3494. (b) Chou, T.; Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37,
4023-4026. (c) Chou, T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetra-
hedron Lett. 1996, 37, 4027-4030. (d) Uemura, D.; Chou, T.; Haino, T.;
Nagatsu, A.; Fukuzawa, S.; Zheng, S. Z.; Chen, H. S. J. Am. Chem. Soc.
1995, 117, 1155-1156.
Figure 1. Structure of gymnodimine (1) and the hypothetical
biosynthetic precursor 2.
10.1021/ol051553n CCC: $30.25
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Published on Web 08/05/2005

product might be biosynthesized via an intramolecular
Diels-Alder reaction.4d Due to the structural similarities
within this class of natural products, this biosynthetic
hypothesis is applicable to gymnodimine and all other
members of this class. The hypothetical linear biosynthetic
precursor 2 of gymnodimine is depicted in Figure 1. In the
synthetic direction, conversion of 2 to 1 requires two discrete
steps: cyclic imine formation and a formal Diels-Alder
reaction. This process could involve direct macrocyclization
of ketone 2 followed by cyclic imine formation or, con-
versely, initial R,â-unsaturated imine formation (16, Scheme
3) followed by Diels-Alder macrocyclization. Close inspec-
tion of the stereochemistry of the resulting cyclohexene ring
reveals that the Diels-Alder reaction must occur through
the exo-mode, a common feature among most members of
this class of natural products.
In the synthesis of pinnatoxin A, we mimicked the
biosynthetic pathway suggested by Uemura.10 In that work,
the macrocarbocycle of pinnatoxin was constructed via an
intramolecular Diels-Alder reaction using an R,â-unsatur-
ated ketone as a dienophile followed by imine formation at
high temperature. The cycloaddition occurred with a 5:1 exo/
endo-selectivity at 70 °C. However, the facial selectivity of
the exo-mode was close to 1:1. Overriding the inherent endo-
selectivity known for Diels-Alder reactions and controlling
the diastereofacial selectivity of the exo process are signifi-
cant synthetic challenges. In the context of gymnodimine,
several potential solutions to this problem have been
disclosed.11
While the Diels-Alder motif appears quite often in nature,
this class of natural products is unique due to the intriguing
possibility that the macrocyclization may be facilitated
through the formation of an intramolecular R,â-unsaturated
imine. MacMillan and co-workers have shown that formation
of an R,â-unsaturated iminium ion formed via condensation
of a secondary amine with a ketone creates a potent
dienophile that is reactive toward a wide variety of dienes.14
In the gymnodimine system, intramolecular condensation of
the primary amine 2 with the ketone and subsequent
protonation could provide a similar dienophile, cf. 16 in
Scheme 3. In this letter, we report an intramolecular Diels-
Alder reaction of an R,â-unsaturated iminium dienophile that
allows us to construct the macrocyclic ring system of
gymnodimine.
Our experimental efforts began by exploring the feasibility
of intramolecular imine formation using compound 3 as a
model (Scheme 1). Deprotection of the Teoc group afforded
Scheme 1. Imine Formation
One might be tempted to hypothesize that an enzyme is
required to form the macrocarbocycle present in these natural
products. In recent years, several groups have reported
isolation of an enzyme that catalyzes a Diels-Alder pro-
cess.12 The mechanistic details have also been examined from
a theoretical perspective.13 Most of these works have centered
around R,â-unsaturated ketones as a dienophile.
amine salt 4. Treatment of this salt in D2O with Na2HPO4
furnished R,â-unsaturated imine 5. After standing for 24 h,
complete deuterium incorporation was observed at the
methylene R to the imine.15
Imine formation and stability were monitored by 1H NMR
(Figure 2). Spectrum a was taken 5 min after dissolving
(5) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron
Lett. 2001, 42, 3495-3497.
(6) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.; Matsumoto, T.; Lee,
K. H.; Woo, J. T.; Uemura, D. J. Am. Chem. Soc. 2004, 126, 4794-4795.
For a review of these macrocyclic iminium alkaloids, see: Kita, M.; Uemura,
D. Chem. Lett. 2005, 34, 454-459.
(7) (a) Torigoe, K.; Murata, M.; Yasumoto, T.; Iwashita, T. J. Am. Chem.
Soc. 1988, 110, 7876-7877. (b) Hu, T. M.; deFreitas, A. S. W.; Curtis, J.
M.; Oshima, Y.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 1996, 59,
1010-1014.
(8) (a) Hu, T. M.; Burton, I. W.; Cembella, A. D.; Curtis, J. M.; Quilliam,
M. A.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 2001, 64, 308-312. (b)
Falk, M.; Burton, I. W.; Hu, T.; Walter, J. A.; Wright, J. L. C. Tetrahedron
2001, 57, 8659-8665. (c) Hu, T. M.; Curtis, J. M.; Walter, J. A.; Wright,
J. L. C. Tetrahedron Lett. 1996, 37, 7671-7674.
(9) Lu, C. K.; Lee, G. H.; Huang, R.; Chou, H. N. Tetrahedron Lett.
2001, 42, 1713-1716.
(10) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-7648.
(11) (a) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett 2002,
399-402. (b) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-
766. (c) White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 5, 4983-
4986.
1
(12) (a) Auclair, K.; Sutherland, A.; Kennedy, J.; Witter, D. J.; Van den
Heever, J. P.; Hutchinson, C. R.; Vederas, J. C. J. Am. Chem. Soc. 2000,
122, 11519-11520. (b) Ose, T.; Watanabe, K.; Mie, T.; Honma, M.;
Watanabe, H.; Yao, M.; Oikawa, H.; Tanaka, I. Nature 2003, 422, 185-
189. (c) Oikawa, H.; Katayama, K.; Suzuki, Y.; Ichihara, A. Chem. Commun.
1995, 1321-1322.
Figure 2. Imine formation and stability followed by H NMR:
(a) primary amine trifluoroacetate salt 4 dissolved in neutral D2O,
t ) 5 min; (b) addition of Na2HPO4 to the NMR tube completed
imine cyclization, t ) 20 min; (c) acidification with trifluoroacetic
acid, t ) 16 h; (d) neutralization with Na2HPO4, t ) 30 h, and
observation of deuterium incorporation.
(13) Guimaraes, C. R. W.; Udier-Blagovic, M.; Jorgensen, W. L. J. Am.
Chem. Soc. 2005, 127, 3577-3588.
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Org. Lett., Vol. 7, No. 18, 2005

amine salt 4 in D2O. After addition of Na2HPO4, new
resonances corresponding to imine 5 were observed im-
mediately (spectrum b). To test the stability of this imine
toward hydrolysis, the solution was reacidified with TFA
and allowed to stand at room temperature for 16 h (spectrum
c). Then, the solution was made neutral again through the
addition of Na2HPO4 and allowed to stand for 24 h (spectrum
d). These results imply that the imine is stable in water at
acidic and neutral pH. Additionally, the reactivity of this
imine was tested against trans-2-methyl-1,3-pentadiene in
water at a slightly acidic pH. After approximately 4 h at
room temperature, a Diels-Alder reaction was complete.
The ease of formation of the R,â-unsaturated imine system
and its resistance to hydrolysis in water are remarkable. One
potential complication might be a 1,4-addition of the primary
amine to the unsaturated system; however, this has not been
observed in the model system or the functionalized system.
Once formed, imine 5 is surprisingly stable against hydroly-
sis.
Scheme 3. Diels-Alder Precursor Synthesisa
a Reagents and conditions: (a) 8, NiCl2, CrCl2, Ni(COD)2, THF,
DMF, t-BuPy, 50 °C, 70%, 1:1; (b) MnO2, CH2Cl2, 50%; (c) (R)-
2-methyl-CBS-oxazaborolidine, BH3‚DMS, tol, -10 °C, 80%, 6:1,
â: R; (d) TESCl, AgNO3, py, DMF, 99%; (e) DIBAL, CH2Cl2, -78
°C, 83%; (f) PCC, 4 Å MS, CH2Cl2, NaOAc, 71%; (g) 0.5% NiCl2/
CrCl2, DMF, 56%; (h) MnO2, CH2Cl2 reflux, 83%; (i) TBAF‚xH2O,
AcOH, THF, 78%; (j) (PPh3)4Pd, tol (0.1% AcOH).
Armed with this information, we designed and imple-
mented a synthesis of Diels-Alder precursor 16 (Scheme
3). The first synthetic hurdle was the formation of the highly
substituted tetrahydrofuran ring present in 16.16 To this end,
compound 7 was prepared (Scheme 2). Acid-catalyzed
using a THF/DMF/tert-butylpyridine solvent system.18 Oxi-
dation of the resulting 1:1 mixture of allylic alcohols using
MnO2 and subsequent reduction of the resulting ketone using
the CBS protocol19 gave allylic alcohol 10 as a 6:1 mixture
of diastereomers. The stereochemistry of the major product
was tentatively assigned on the basis of the known preference
of the CBS reduction and later proven through X-ray
analysis. Protection of the secondary alcohol using TESCl/
AgNO3 followed by reductive removal of the acetate with
DIBAL gave primary alcohol 12.
Scheme 2. Synthesis of the Tetrahydrofuran Moiety
cyclization of 7 occurred at room temperature to give a 9:1
mixture of cyclization products. The diastereomeric allylic
alcohols behave identically under the cyclization conditions,
supporting an SN1 mechanism. Through direct chemical
correlation and NOE analysis, the major product was shown
to be the desired syn-product.17 Under the acidic conditions
employed, the primary TBS group was also cleaved. Oxida-
tion of the resulting primary alcohol under Swern conditions
gave aldehyde 8.
The triene moiety present in 16 was introduced using a
Ni(II)/Cr(II)-mediated coupling between aldehyde 8 and
triene 9 (Scheme 3). Coupling of the trisubstituted vinyl
bromide occurred using elevated temperature and a stoichio-
metric amount of Ni(II). Homocoupling was suppressed by
Oxidation of this alcohol with PCC in the presence of
molecular sieves and sodium acetate gave aldehyde 13. Ni-
(II)/Cr(II)-mediated coupling of aldehyde 13 and vinyl iodide
14 and subsequent oxidation of the resulting mixture of
allylic alcohols using MnO2 gave enone 15. Treatment of
enone 15 with TBAF in the presence of 2 equiv of AcOH
(relative to substrate) in THF cleanly removed the primary
TIPS and secondary TES groups. Deprotection of the Alloc
carbamate using Pd(PPh3)4 gave R,â-unsaturated imine 16.
Diels-Alder macrocyclization of R,â-unsaturated imine
16 occurred in water at pH 6.5 under dilute conditions.20
No starting material was observed after 30 h at 36 °C. The
resulting cycloadducts were present as a mixture of one imine
product and two keto-amine diastereomers wherein the imine
(14) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 2458-2460.
(15) Deuterium incorporation was previously observed in a similar
system: Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett. 2001, 3,
751-754.
(16) For other approaches to the tetrahydrofuran system, see: (a) Ishihara,
J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997, 1417-1419. (b)
Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-766. (c) White,
J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 5, 4109-4112.
(17) Stereochemistry was assigned via an intermediate that had been
assigned by NOE analysis similar to that of Murai. See ref 16a.
(18) Stamos, D. P.; Sheng, X. C.; Chen, S. S.; Kishi, Y. Tetrahedron
Lett. 1997, 38, 6355-6358.
(19) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1987-
2012.
(20) For pioneering work on Diels-Alder reactions in water, see: (a)
Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816-7817. (b)
Breslow, R. Acc. Chem. Res. 1991, 24, 159-164. (c) Grieco, P. A.; Yoshida,
K.; Garner, P. J. Org. Chem. 1983, 48, 3137-3139. (d) Grieco, P. A.;
Garner, P.; He, Z. Tetrahedron Lett. 1983, 24, 1897-1900.
Org. Lett., Vol. 7, No. 18, 2005
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had been hydrolyzed. To simplify product analysis, the
imines were reformed by treatment of the entire mixture with
molecular sieves in benzene (Figure 3). The two major
Figure 5. Ketone Diels-Alder products formed via thermolysis
in benzene at 185 °C in the presence of 3 Å MS and Sumilizer for
48 h (60% yield, 2:1 selectivity).
Figure 3. Imine Diels-Alder products. Cyclization conditions: (i)
pH 6.5 sodium citrate/HCl buffer, H2O, 36 °C, 48 h, concn ) 60
µM; (ii) benzene, TEA, PivOH, 4 Å MS, 16 h. Derivatization
conditions: (i) NaCNBH3, MeOH, AcOH; (ii) p-bromobenzoyl
chloride, CH2Cl2, NaHCO3 (aq).
60% yield but no detectable exo-product (Figure 5).22
Interestingly, attempted macrocyclization of the intermediate
diol derived from TBAF deprotection of ketone 15 under
the aqueous conditions outlined in Figure 3 only resulted in
decomposition of the triene moiety.
In summary, we have observed significant differences in
rate and diastereoselectivity between the imine and ketone
dienophiles. Under identical conditions in water, the imine
dienophile reacts with the triene in 30 h, while the ketone
fails to react before decomposition of the triene. The imine
dienophile also allows access to the desired exo-product,
while the ketone dienophile produces only endo-products.
Moreover, in the exo manifold, the imine dienophile exhibits
excellent facial selectivity.
The imine system exhibits several interesting properties.
Cyclic imine formation from a linear carbon chain is facile
and selective, and the resulting imine is stable in an aqueous
environment. Moreover, the Diels-Alder reaction of the
imine dienophile has been shown to occur in water at
moderate temperatures. After cycloaddition under aqueous
conditions at pH 6.5, the unnatural Diels-Alder diastereo-
mers are hydrolyzed to keto-amines, while the natural
diastereomer resists hydrolysis. In this context, it is intriguing
to note that biologically inactive keto-amines have been
isolated in the case of the spirolides.8c These experimental
results suggest that the hypothetical biosynthesis outlined in
Figure 1, wherein Diels-Alder precursor 2 reacts to form
gymnodimine (1), could occur even without the aid of an
enzyme.
products thus isolated were exo-product 17 and endo-product
18 (about 1:1). A small amount of the second endo-product
was also observed (not shown). Interestingly, it was found
that the imine of the desired exo-product remained intact
during the reaction in water. In contrast, the endo-products
were observed as the keto-amines, which were presumably
formed through an iminium-catalyzed Diels-Alder reaction
followed by hydrolysis.
The structure of the exo-product 17 was established by
derivatization and single-crystal X-ray crystallography. Re-
duction of the imine using NaCNBH3 and acylation with
p-bromobenzoyl chloride gave benzamide 19. The X-ray
structure of this compound is presented in Figure 4.
Acknowledgment. J.W.J. thanks Eli Lilly and Co. for a
predoctoral fellowship, and S.W. thanks the NIH/NIGMS
for a postdoctoral fellowship (F32 NS10736). We also thank
Dr. Richard Staples for performing the X-ray analysis
experiments.
Figure 4. Crystal structure of compound 19.
In contrast to the imine Diels-Alder, an R,â-unsaturated
ketone dienophile gave only endo-products. Thermolysis of
an R,â-unsaturated ketone (15, R1, R2 ) TBS, R3 ) Teoc,
Scheme 3)21 at 185 °C in benzene in the presence of 4 Å
molecular sieves and 4,4′-thiobis-(6-tert-butyl-3-methyl-
phenol) (Sumilizer) gave two endo-products 20 and 21 in
Supporting Information Available: Experimental details
for the syntheses outlined in Schemes 1-3 and Figure 3,
and X-ray crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051553N
(21) This Diels-Alder precursor was prepared according to the synthetic
route outlined in Scheme 3 using different protecting groups.
(22) Stereochemistry of the ketone Diels-Alder products was assigned
via chemical correlation with the imine Diels-Alder products.
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