Exploring the original proposed biosynthesis of (+)-symbioimine: Remote exocyclic stereocontrol in a type i IMDA reaction

Article abstract of DOI:10.1021/ol101141a

(Figure Presented) The originally proposed biosynthesis of (+)-symbioimine was explored, resulting in the successful intramolecular Diels-Alder (IMDA) cyclization of an appropriate (E,E,E)-1,7,9-decatrien-3-one. In contrast to the originally proposed bios

Full text of DOI:10.1021/ol101141a

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3192-3195
Exploring the Original Proposed
Biosynthesis of (+)-Symbioimine:
Remote Exocyclic Stereocontrol in a
Type I IMDA Reaction
Jason P. Burke,† Michal Sabat,† Diana A. Iovan,‡ William H. Myers,‡ and
Jason J. Chruma*,†
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904, and
Department of Chemistry, UniVersity of Richmond, Richmond, Virginia 23173
jjc5p@Virginia.edu
Received May 18, 2010
ABSTRACT
The originally proposed biosynthesis of (+)-symbioimine was explored, resulting in the successful intramolecular Diels-Alder (IMDA) cyclization
of an appropriate (E,E,E)-1,7,9-decatrien-3-one. In contrast to the originally proposed biosynthesis, the IMDA reaction appears to proceed via
an endo transition state. Remarkably, a single exocyclic stereogenic center effectively controls the π-facial selectivity affording a highly
diastereoselective cycloaddition.
In 2004, Uemura and co-workers reported the isolation of
(+)-symbioimine (1) from a dinoflagellate Symbiodinium sp.
living symbiotically in the marine flatworm Amphiscolops
sp.1 In addition to its unique structural features (e.g., a
zwitterionic iminium sulfate and a compact tricyclic core
containing five contiguous stereocenters), (+)-1 demonstrated
promising inhibitory activity against the RANKL-induced
differentiation of murine RAW264 hematopoietic precursor
cells into osteoclasts without affecting overall cell viability.
This antiosteoclastogenic activity marked (+)-1 as a possible
entry point into a new small-molecule-based modality for
osteoporosis.2 Accordingly, several research groups have
reported efforts toward symbioimine3 and related com-
pounds,4 including both racemic3a,c and enantioselective total
syntheses.3e In the original isolation report, the authors
proposed a biosynthesis involving a tandem diastereoselective
exo intramolecular Diels-Alder (IMDA) cycloaddition/imine
condensation of (E)-enone 2 (Scheme 1).1a This proposed
type I IMDA cyclization is remarkable in at least two aspects.
First, the preponderance of literature precedents indicates that
(2) For other anti-osteoclastogenic natural products, see: (a) Hasegawa,
S.-i.; Yonezawa, T.; Ahn, J.-Y.; Cha, B.-Y.; Teruya, T.; Takami, M.;
Yagasaki, K.; Nagai, K.; Woo, J.-T. Biol. Pharm. Bull. 2010, 33, 487. (b)
Kawatani, M.; Okumura, H.; Honda, K.; Kanoh, N.; Muroi, M.; Dohmae,
N.; Takami, M.; Kitagawa, M.; Futamura, Y.; Imoto, M.; Osada, H. Proc.
Natl. Acad. Sci., U.S.A. 2008, 105, 11691. (c) Li, J.-F.; Chen, S.-J.; Zhao,
Y.; Li, J.-X. Carb. Res. 2009, 344, 599. (d) Cuong, N. X.; Minh, C. V.;
Kiem, P. V.; Huong, H. T.; Ban, N. K.; Nhiem, N. X.; Tung, N. H.; Jung,
J.-W.; Kim, H.-J.; Kim, S.-Y.; Kim, J.-A.; Kim, Y. H. J. Nat. Prod. 2009,
72, 1673. (e) Yoon, K. D.; Jeong, D. G.; Hwang, Y. H.; Ryu, J. M.; Kim,
J. J. Nat. Prod. 2007, 70, 2029. (f) Lee, S.-Y.; Choi, D.-Y.; Woo, E.-R.
Arch. Pharm. Res. 2005, 28, 909. (g) Park, C. K.; Kim, H. J.; Kwak, H. B.;
Lee, T. H.; Bang, M.-H.; Kim, C. M.; Lee, Y.; Chung, D. K.; Baek, N.-I.;
Kim, J.; Lee, Z. H.; Kim, H.-H. Int. Immunopharm. 2007, 7, 1507. (h)
Kwak, H. B.; Lee, B. K.; Oh, J.; Yeon, J.-T.; Choi, S.-W.; Cho, H. J.; Lee,
M. S.; Kim, J.-J.; Bae, J.-M.; Kim, S. H.; Kim, H. S. Bone 2010, 46, 724.
(i) Ichikawa, H.; Murakami, A.; Aggarwal, B. B. Mol. Cancer Res. 2006,
4, 275.
† University of Virginia.
‡ University of Richmond.
(1) (a) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.; Matsumoto, T.;
Lee, K.; Woo, J.; Uemura, D. J. Am. Chem. Soc. 2004, 125, 4794. (b) Kita,
M.; Ohishi, N.; Washida, K.; Kondo, M.; Koyama, T.; Yamada, K.; Uemura,
D. Bioorg. Med. Chem. 2005, 13, 5253.
10.1021/ol101141a  2010 American Chemical Society
Published on Web 06/15/2010

supposition that a freely rotating remote exocyclic stereo-
center can effectively control π-facial selectivity in a type I
IMDA process.
Scheme 1. Proposed Biosyntheses of (+)-Symbioimine (1)
Synthesis of the requisite IMDA precursor (()-5 began
with an efficient two-step conversion of 3,5-dimethoxy-
benzaldehyde (8) into (E)-vinyl bromide 9 (Scheme 2).8
Scheme 2. Synthesis of All-(E) Triene (()-5
IMDA cycloadditions of (E,E,E)-1,7,9-decatrien-3-ones pro-
ceed prefentially through an endo and not exo transition
state.5 Second, the nonconstrained exocyclic C-2 stereocenter,
which is decorated with two roughly equivalent substituents,6
is tasked with controlling the π-facial selectivity for the
cycloaddition. Perhaps in recognition of these unusual
requirements, Uemura and co-workers later proposed an
alternate biosynthesis involving a more traditional endo
IMDA cyclization of dihydropyridinium 3 followed by
epimerization of the relatively labile C-4 stereocenter to
afford (+)-1.1b Snider3c,d and Thomson3e have both provided
experimental support for this latter proposed biosynthetic
pathway, in which the rotationally constrained C-2 stereo-
center dictates the overall diastereoselectivity. Attempts to
validate the originally proposed biosynthetic pathway (2f1),
on the other hand, have not been successful. Maier reported
that N-Boc triene 5 failed to undergo IMDA cycloaddition
under thermal conditions (xylene, 180 °C).3a Similarly,
Kobayashi reported that N-Alloc triene 6 and E-enone 7 both
failed to undergo cyclization under either conventional
heating (xylene, reflux, 2 d) or Lewis acid catalysis
(MeAlCl2, CH2Cl2, -78 °C).3f,7 We report herein the first
successful IMDA cycloaddition of (E)-enone (()-5, resulting
in the exclusive production of a single diastereomer in high
yield. This product arises from an endo transition state, in
contrast to the originally proposed exo transition state. Our
results do lend support, however, to the unprecedented
Coupling of bromide 9 with known boronate 109 under
standard Suzuki-Miyaura cross-coupling conditions10 af-
forded diene 11 as an inseparable 10:1 ratio of (E,E) and
(E,Z) olefin isomers, respectively. Addition of lithiated
dimethyl methylphosphonate to methyl ester 11, followed
by Horner-Wadsworth-Emmons olefination11 of the result-
ant ꢀ-ketophosphonate ester with N-Boc-ꢀ-alanal (()-12
afforded the desired (E)-enone (()-5 in 62% isolated yield
over the two steps.
With (E,E,E)-triene (()-5 in hand, we next screened a
battery of reaction conditions to induce the desired cycload-
dition (Table 1). In agreement with previous reports,3a,f triene
(()-5 failed to undergo IMDA reaction under thermal
conditions (entry 1). Similarly, treatment with a substoichio-
metric amount of relatively mild Lewis acids (entries 2-5)
or an organocatalyst (entry 6) resulted in essentially no
conversion. One exception is the combination of 20 mol %
Sc(OTf)3 in THF, which afforded quantitative removal of
the tert-butyl carbamate group (5f13, entry 4). Treatment
with either strongly ionic conditions (entry 7) or harsher
Lewis acids (entries 8-14) resulted in either no conversion
or complete decomposition of starting material. Gratifyingly,
we discovered that treatment of (()-5 with a superstoichio-
(3) (a) Maier, M.; Varseev, G. Angew. Chem., Int. Ed. 2006, 45, 4767.
(b) Sakai, E.; Araki, K.; Takamura, H.; Uemura, D. Tetrahedron Lett. 2006,
47, 6343. (c) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 8, 5605. (d)
Snider, B. B.; Che, Q. Angew. Chem., Int. Ed. 2006, 45, 932. (e) Kim, J.;
Thomson, R. J. Angew. Chem., Int. Ed. 2007, 46, 3104. (f) Born, S.; Bacani,
G.; Olson, E. E.; Kobayashi, Y. Synlett 2008, 18, 2877. (g) Born, S.;
Kobayashi, Y. Synlett 2008, 2479.
(4) Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461.
(5) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1992; Vol. 5, pp 513-550.
(6) The A-values for a methyl (CH3) and an aminomethylene (CH2NH2)
group are expected to differ by e0.05 kcal/mol. Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1990;
pp 690-700.
(8) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron 2002, 58, 1491.
(9) Fujita, M.; Lee, H. J.; Okuyama, T. Org. Lett. 2006, 8, 1399.
(10) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(7) Microwave irradiation in methanol (160 °C) did affect the quantitative
conversion of (E)-enone 7 into a 3:1 ratio of the expected endo product
and the desired exo cycloadduct, respectively.
(11) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
Org. Lett., Vol. 12, No. 14, 2010
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discrete species on silica gel and in solution. X-ray crystal-
lographic analysis of a single crystal obtained from MeOH
unambiguously identified the major entity as the unsual
N-Boc hemiaminal (()-14a (Figure 1). With this lead, the
Table 1. IMDA Reaction Conditions
Figure 1. Product(s) from Me2AlCl-induced IMDA of (()-5,
including ORTEP diagram (50% probability ellipsoids) of (()-14a.
other species observed was deduced to be the corresponding
ketone (()-14b. With extended reaction times and/or when
>1.5 equiv of Lewis acid was employed, enamine (()-
15, resulting from dehydration of hemiaminal (()-14a,
also was isolated in relatively small quantities. Impor-
tantly, all of the products possess the same relative
stereochemistry, indicating that the exocyclic C-2 stereo-
center enforced a level of π-facial selectivity for the
[4 + 2] cycloaddition beyond the limits of detection for
TLC analysis and NMR spectroscopy. To the best of our
knowledge, this represents the first example of such
exquisite asymmetric induction by a single nonconstrained
exocyclic stereocenter in a type I IMDA cycloaddition.5,13
On the basis of the observed diastereomer 14, an endo-boat
transition state model14 can be proposed in which the C-2
stereocenter is oriented so as to minimize both intramolecular
steric interactions with the approaching diene and A1,3-strain
with the dienophile C-4 proton (Figure 2). An alternative
explanation to account for the remarkable π-facial selectivity
is chelation of the Lewis acid by the ketone and N-Boc
a Unless otherwise noted, 1 equiv of Lewis acid/catalyst was added.
b Determined by TLC and 1H NMR spectroscopic analysis of the unpurified
reaction mixture. c Solvent: PhCH3. d Solvent: CH2Cl2. e Solvent: THF.
f Solvent: CH3CN. g Solvent: Et2O. h 0.2 equiv. i 0.5 equiv. j 1.5 equiv.
metric amount (1.5 equiv) of either MeAlCl2 or Me2AlCl in
CH2Cl2 at -20 °C led to the formation of a single
cycloadduct (entries 15 and 16); less product decomposition
was obtained employing the milder Lewis acid Me2AlCl.
Under optimized reaction conditions,12 the resultant IMDA
product (()-14 was isolated in 88% yield. Importantly, no
reaction was observed when the mixture of (()-5 and
Me2AlCl was kept at -78 °C (entry 17), corroborating
previous reports.3f
Characterization of the resultant IMDA product was
complicated by its apparent interconversion between two
(12) 1.5 equiv Me2AlCl (1.0 M in hexanes) was added to (()-5 in
CH2Cl2 (0.1M) at -78 °C, held at that temperature for 1 h, and then stirred
at -20 °C for 18h; see Supporting Information.
(13) In their synthesis of dihydrocompactin, Sammakia et al. reported a
highly diastereoselective IMDA cyclization of a (Z,E,E)-1,7,9-decatrien-
3-one in which a single exocyclic stereocenter effectively controls π-facial
selectivity, but only after being constrained within a putative cyclic
vinyloxocarbeneium ion. Sammakia, T.; Johns, D. M.; Kim, G.; Berliner,
M. A. J. Am. Chem. Soc. 2005, 127, 6504.
(14) While it is impossible to distinguish between the endo-chair and
endo-boat transition states for our IMDA reaction, we favor the boat
conformation based on compelling related studies by Roush. (a) Coe, J. W.;
Roush, W. R. J. Org. Chem. 1989, 54, 915. (b) Dineen, T. A.; Roush, W. R.
Org. Lett. 2005, 7, 1355.
Figure 2
.
Model transition state for IMDA cyclization of 5.
Org. Lett., Vol. 12, No. 14, 2010
3194

carbonyls, thus constraining the C-2 stereocenter within a
strained 10-membered metallocycle.15
Scheme 4. Isomerization/IMDA Cyclization of (Z)-Enones 18
The resulting IMDA product (()-14 is doubly epimeric
(C-4 and C-3) with the exo-transition state product originally
proposed for the biosynthesis of (+)-1.1a Based on previous
studies with related substrates,3c-e cyclization of (Z)-enone
(()-1616 was expected to proceed via an endo transition state
to provide cis-decalin (()-17, which only differs from the
symbioimine framework at the relatively acidic C-4 stereo-
center (Scheme 3). Surprisingly, treatment of (Z,E,E)-triene
Scheme 3. Isomerization/IMDA Cyclization of (Z)-Enone 16
overall yield. Under no circumstances did we isolate products
arising from cyclization of the initial (Z)-enones 18a or 18b.
In both cases, the observed π-facial selectively was signifi-
cant but less than that observed for the cyclization of N-Boc-
(E)-enone (()-5. Notably, the relative stereochemistry of the
major isomers (+)-20a and 20b was identical to that present
in cycloadduct (()-14.
In summary, our studies confirm that the originally
proposed biosynthesis of (+)-1 involving an exo-IMDA
cyclization of (E)-enone 2 is counter to the inherent reactivity
of the all-E triene framework.1a When combined with
previous studies by Snider3c,d and Thomson,3e our results
also indicate the importance of constraining the correspond-
ing (Z)-enone as a dihydropyridinium or related species, a`
la 3, so as to increase the reactivity of the dienophile and to
prevent facile enone isomerization. Most importantly, these
studies provide compelling evidence that a single noncon-
strained exocyclic stereocenter can adequately control π-fa-
cial selectivity in a type I IMDA cyclization of (E,E,E)-1,7,9-
decatrien-3-ones. The resultant products (e.g., 14, 15, 20,
and 21) will serve as synthetic precursors to epimeric
analogues of (+)-1, valuable molecular tools for exploring
the structure-activity relationship of the anti-osteoclastogenic
alkaloid.
(()-16 with Me2AlCl produced cycloadduct (()-14 exclu-
sively, indicating that enone isomerization was faster than
IMDA cyclization. Indeed, (Z)-enone (()-16 completely
isomerized to (E)-enone (()-5 within 30 min at -78 °C upon
exposure to the Lewis acid.
To explore the role that the Boc-protected amine moiety
in 16 and 14 plays in both the (Z)-to-(E) enone isomerization
(e.g., 16f5) and the remarkable π-facial selectivity upon
IMDA cyclization, the corresponding TBDPS ether 18a and
pivalate ester 18b were subjected to analogous Lewis acidic
reaction conditions (Scheme 4).17 Exposing (Z)-enone 18a
to Me2AlCl at -78 °C resulted in no reaction after 7 days,
indicating that exchange of the Boc-protected amine in (()-
16 for a silyl ether significantly retards enone isomerization
without affecting IMDA cyclization. Warming the reaction
mixture to -20 °C, however, resulted in isomerization to
the corrsponding (E)-enone 19a,18 followed by endo-IMDA
cycloaddition to afford a 3:1 ratio of π-facial stereoisomers
(+)-20a and (-)-21a, respectively, in 76% combined yield.
The pivalate ester 18b behaved similarly, providing a slightly
improved ratio of diastereomers (4.5:1), albeit in lower
Acknowledgment. Partial financial support provided by
the UVA Institute on Aging (UVA) and the NSF [CHE-
0320669 (UR)]. J.P.B. was supported by a Presidential
Fellowship from the UVA GSA&S.
(15) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840.
(16) (Z)-Enone (()-16 was synthesized from methyl ester 11 using a
modified Ando olefination protocol; see Supporting Information. (a)
Touchard, F. P. Eur. J. Org. Chem. 2005, 9, 1790. (b) Ando, K. Tetrahedron
Lett. 1995, 36, 4105.
(17) Enantiopure (Z)-enones 18a and 18b were generated from methyl
ester 11 and a homochiral terminal alkyne derived from (S)-(+)-Roche ester;
see Supporting Information.
(18) The (E)-enones 19a and 19b were not isolated from the reaction
mixtures but represent necessary intermediates for the observed pro-
ducts.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101141A
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