Synthesis of alkaloid (-)-205b via stereoselective reductive cross-coupling and intramolecular [3+2] cycloaddition

Article abstract of DOI:10.1021/ja306362m

An asymmetric synthesis of alkaloid (-)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol-imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (E)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselective-features which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry.

Full text of DOI:10.1021/ja306362m

Communication
pubs.acs.org/JACS
Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-
Coupling and Intramolecular [3+2] Cycloaddition
Dexi Yang and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States
*
S Supporting Information
reported syntheses of the natural antipode through chemical
pathways that have secured the utility of anion relay chemistry
and dihyropyridone-based functionalization processes to access
ABSTRACT: An asymmetric synthesis of alkaloid
−)-205B, a tricyclic member of the architecturally diverse
(
5
family of natural products isolated from the skin of
neotropical poison frogs, is described that proceeds
through two recently developed stereoselective synthetic
methods: (1) Ti-mediated allylic alcohol−imine reductive
cross-coupling and (2) intramolecular [3+2] cycloaddition
of a glyoxylate-based homoallylic nitrone. The utility of
this latter cycloaddition process for the assembly of the
stereochemically dense piperidine core of 205B is
noteworthy, as this method enables direct [3+2] cyclo-
addition of an intermediate homoallylic (E)-nitrone via a
pathway that is stereochemically unscathed by competitive
the heterocyclic core of this target. Here, we report a
conceptually unique synthesis of (−)-205B that proceeds by
two stereoselective synthetic methods that have recently
emerged from our laboratories: (1) Ti-mediated reductive
cross-coupling between an aldehyde and an allylic alcohol (via
6
the intermediacy of a TMS-imine) and (2) path-selective
intramolecular [3+2] cycloaddition of a glyoxylate-based
6
homoallylic nitrone. The current studies document the first
demonstrations of these reaction processes in natural product
synthesis.
While related to the structure of coccinelline (Figure 2A), the
stereochemically dense piperidine core of 205B presents a
challenge not easily addressed with the elegant two-directional
[
3,3]-sigmatropic rearrangement processes. Overall, the
synthesis is asymmetric, concise, and highly stereo-
selectivefeatures which point to the potential future
utility of these chemical methods in natural product
synthesis and medicinal chemistry.
7
synthesis that Stevens demonstrated for the former a
strategy undoubtedly inspired by Robinson’s classic tropinone
8
synthesis, and one that explored the stereochemical course of
an intermolecular Mannich reaction on a six-membered ring-
containing iminium ion (Figure 2B). We suspected that a
related approach to 205B, while potentially elegant, would
likely be substantially less effective for a number of reasons. As
illustrated in Figure 2C, the primary amine required for 205B is
not symmetric and can engage in iminium ion formation with
either of the terminal acetals (paths A and B)each path
presenting different obstacles. Adding to the mounting
uncertainty surrounding a coccinelline-inspired annulation en
route to 205B, the likely multistep nature of any modern
asymmetric synthesis of the requisite chiral primary amine
starting material dissuaded us from the pursuit of such an
annulation process.
ue to the pioneering and focused efforts of John Daly at
the National Institutes of Health, it has become clear that
D
neotropical frogs are a rich source of architecturally unique
1
alkaloids. To date, over 800 heterocycles spanning more than
2
0 structural classes have been discovered from anuran skin,
many of which are sequestered unchanged from dietary sources
ants, mites, beetles, and millipedes). Despite the rich structural
(
diversity associated with this class, the majority of these natural
products lack pharmacological characterization, due, in part, to
their low natural abundance. As a result, chemical synthesis
stands as an enabling tool for future evaluation of this
potentially important class of natural products. In this regard,
the azatricyclododecene (−)-205B, isolated from Dendrobates
Aiming to avoid these issues, we abandoned a strategy for
annulation that targets the simultaneous generation of the C2a
and C5a stereocenters, favoring a late stage annulation of the
relatively unfunctionalized indolizidine onto a pre-existing
2
pumilio, has risen as a target of interest due to its intriguing
structure and the synthesis-driven discovery that the unnatural
9
piperidine core (1→205B; Figure 2D). This piperidine was
enantiomer blocks the α7 nicotinic acetylcholine receptor in a
3
inturn envisioned to derive from functional group manipulation
of the 1-aza-7-oxabicyclo[2.2.1]heptane 2, itself generated by a
highly stereoselective [3+2] cycloaddition of an intermediate
homoallylic nitrone generated by condensation of 3 with
butylglyoxylate (4). In this manner, the C5a−C6 bond was
targeted as a key site for assembly of the densely functionalized
piperidine core, rather than relying on C5−C5a bond
construction via the intermediacy of a six-membered ring
selective fashion (Figure 1). Since Toyooka’s pioneering
4
synthesis of (+)-205B, Smith and Comins have independently
Figure 1. Structurally diverse alkaloids from the skin of the neotropical
poison frog Dendrobates pumilio.
Received: July 5, 2012
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ja306362m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
in situ), Ti(Oi-Pr) /s-BuLi (to form the azatitanacyclopropane
4
from the TMS-imine), and the allylic alcohol 8 (1 equiv). In
contrast to previous reports that employ the Li-alkoxide of the
allylic alcohol in Ti-mediated reductive cross-coupling reac-
tions, use of the free alcohol in this procedure avoided potential
13
Peterson elimination. Overall, the primary homoallylic amine
9
was produced as a single isomer in 57% yield, with complete
transfer of absolute stereochemical information.
The stereochemical course of this coupling reaction is
consistent with the empirical model depicted in Figure 4.
Directed carbometalation is proposed to occur through a boat-
like transition state geometry (A) that allows for alignment of
the σC−Ti bond with π
bond, where minimization of allylic-
CC
14
1
,3 strain (A1,3) and nonbonded steric interactions about the
developing C−C bond combine to define a highly stereo-
selective C−C bond-forming process. Subsequent syn-elimi-
15
nation of the oxatitanacyclobutane intermediate 17, and
hydrolysis of the resulting inorganic complex leads to the
homoallylic amine product 9. Competing transition state
geometries for this alkoxide-directed Ti-mediated coupling are
thought to be destabilized by substantial nonbonded steric
interactions (A1,3 and/or eclipsing interactions about the
developing C−C bond; highlighted in B−D of Figure 4).
Returning to the synthesis, oxidation of the primary
homoallylic amine 9 was straightforward by sequential exposure
to (BzO) and hydrazine. Heating a solution of this species
2
with butylglyoxylate resulted in a highly stereoselective
annulation process that likely proceeds by formation of the
(
E)-homoallylic nitrone and direct intramolecular [3+2]
cycloaddition to deliver the stereodefined 1-aza-7-
oxabicyclo[2.2.1]heptane 11 in 67% yield (dr ≥ 20:1). The
complexity of this annulation process deserves comment as this
glyoxylate-based nitrone annulation is rather unique among
related intramolecular cycloaddition processes. Homoallylic
nitrones are well known to undergo two competitive reaction
processes: (1) direct [3+2] cycloaddition with the pendant
alkene, or (2) sequential aza-Cope rearrangement/intra-
6,16
molecular [3+2] cycloaddition.
This latter pathway can
provide a stereochemically distinct product to that derived from
direct [3+2] cycloaddition. Unlike homoallylic nitrones
generated from aliphatic aldehydes, those derived from
glyoxylates have been observed to preferentially react by way
of a direct [3+2] cycloaddition through the (E)-isomer. Overall,
bicyclic products are typically observed with outstanding levels
of stereoselection, unscathed by potential competitive [3,3]-
sigmatropic rearrangement chemistry typical of aliphatic
Figure 2. Strategic considerations and retrosynthesis of (−)-205B.
iminium ion intermediate. Finally, the stereodefined acyclic
intermediate 3 could derive from enantioselective Ti-mediated
reductive cross-coupling of a TMS-imine (generated in situ
from the aliphatic aldehyde 5) with a simple chiral allylic
6
nitrones.
1
0
alcohol 6.
With the densely functionalized heterocycle 11 in hand, the
butyl ester was homologated by a simple three-step sequence to
the α-trimethylsilylmethyl-substituted enoate 13. Reduction to
Our pursuits began with attempted reductive cross-coupling
of aldehyde 5 with allylic alcohol 6 and quickly led to the
identification of a limitation in our Ti-mediated reductive cross-
the allylic alcohol and deoxygenation with allylic transposition
6
17
coupling technology. In short, allylic alcohol 6 is not a robust
(NBSH, PPh , DIAD, NMM) then delivered the allylic silane
3
substrate for Ti-mediated coupling, with all attempts leading to
low conversion and poor stereoselection (alkene geometry).
Given the documented success of related coupling reactions
with allylic alcohols that bear groups larger than Me- at the
14 in 55% yield (over the two-step sequence). Reductive
cleavage of the N−O bond (Zn, HOAc), followed by stirring in
3 N HCl/THF resulted in iminium ion formation (E) and
cyclization to deliver tricyclic product 15 in 82% yield.
While this acid-promoted cyclization reaction proved to be
an effective tandem process to establish the tricyclic core of the
natural product, the success of this sequence may speak to the
relative rates of aza-Sakurai ring closure and aza-Cope
rearrangement of the intermediate bicyclic iminium ion E. As
illustrated in Figure 5, direct aza-Sakurai-based ring closure
would lead to the observed product 15, while competitive aza-
6
,11
allylic position, we opted to pursue reductive cross-coupling
with an allylic alcohol that was functionally equivalent to 6 but
contained a suitable substituent at the allylic position to
facilitate reductive cross-coupling. As illustrated in Figure 3,
reaction of aldehyde 7 with the TMS-substituted allylic alcohol
1
2
8
proceeds effectively by sequential treatment of the aldehyde
(
2 equiv) with LiHMDS (2 equiv) (to generate the TMS-imine
B
dx.doi.org/10.1021/ja306362m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Figure 3. Asymmetric synthesis of (−)-205B via Ti-mediated reductive cross-coupling and stereoselective intramolecular [3+2] cycloaddition.
Figure 5. Success of the cationic annulation may reflect an increased
Figure 4. Stereochemical course of the reductive cross-coupling
rate for aza-Sakurai vs [3,3]-rearrangement and resulting competitive
fragmentation and epimerization pathways.
reaction between aldehyde 7 and allylic alcohol 8.
Cope rearrangement could deliver an isomeric iminium ion F
that has the potential to proceed through a variety of reaction
pathways capable of scrambling the C6 stereochemistry. For
example, loss of a proton would provide a means to generate an
enamine G that could be in equilibrium with the isomeric
iminium ion H. Alternatively, F could undergo thermodynamic
equilibration by retro aldol/aldol (F→I→J). While the lack of
an observed isomeric product in this cyclization does not
rigorously exclude the possibility of competitive aza-Cope
rearrangement of E, the results certainly support the conclusion
that the 1-aza-7-oxabicyclo[2.2.1]heptane 14 is a viable
intermediate en route to the azatricyclododecene core of
To complete the asymmetric synthesis of (−)-205B, a means
to remove the remaining TMS-substituent, accomplish
deoxygenation at C7, and selectively isomerize the alkene was
required. The first of these goals was met by treatment with
KOt-Bu/18-crown-6a procedure known to effect hydroxyl-
18
directed desilylation. Next, treatment with thiocarbonyldiimi-
dazole furnished the functionalized azatricyclododecene 16 in
59% yield (over two steps). Deoxygenation by treatment with
19
tributyltin hydride and AIBN was followed by acid-mediated
alkene isomerization to deliver (−)-205B in 61% yield.
In conclusion, we report a concise asymmetric synthesis of
(−)-205B that demonstrates the utility of two stereoselective
synthetic methods that have recently emerged from our
laboratory: (1) Ti-mediated reductive cross-coupling of allylic
2
05B, and that this cyclization process is not effected by the
potential pitfalls delineated in Figure 5.
C
dx.doi.org/10.1021/ja306362m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
alcohols with aldehydes through the intermediacy of a TMS-
imine and (2) path-selective intramolecular [3+2] cyclo-
addition of glyoxylate-based homoallylic nitrones. Overall,
the combined use of these methods defines a highly
stereoselective synthesis of a rare alkaloid that belongs to a
family of natural products that likely possess potent and diverse
neurological functions. We look forward to exploring the
pharmacological profile of synthetic (−)-205B and establishing
the scope and limitations of these powerful chemical methods
in stereoselective synthesis.
crotylsilanes for the synthesis of (E)-anti-homoallylic carbamates:
Schaus, J. V.; Jain, B.; Panek, J. S. Tetrahedron 2000, 56, 10263−10274.
(b) Asymmetric crotylation reactions (addition of a C4-unit) of
imines: Ramachandran, P. V.; Burghardt, T. E. Chem.Eur. J. 2005,
6
1
1, 4387−4395. It is well established that asymmetric crotylation of
oximes remains a challenging problem, so direct conversion to a
homoallylic hydroxylamine is not readily available. For a discussion,
see: (c) White, J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963−1977.
We note that the established asymmetric crotylation chemistry of
aldimines delivers products that contain a terminal alkene, not the
desired (E)-disubstituted olefin. Perhaps crossed olefin metathesis
with propylene could emerge as a solution for the conversion of such
terminal alkenes to the desired product, but we favored an approach
that would obviate the need for a chiral allylic organometallic reagent
and the use of olefin metathesis catalysts. Finally, imine propargylation
could serve as an entry to 3 but would suffer from moderate anti/syn
selectivities. See: (d) Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and tabulated spectroscopic data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
*
S
2
002, 43, 8635−8637. Additional functional group manipulations
would be required to access the desired primary homoallylic amine
product. Overall, the present solution that is based on Ti-mediated
reductive cross-coupling of a TMS-imine with a chiral allylic alcohol
offers a superbly enantio- and stereoselective alternative to chemistry
that may emerge from developments centered on controlling the
reactivity of allylic organometallic reagents and/or functional group
manipulation chemistry of the products that are known to be
accessible from such chemistry.
AUTHOR INFORMATION
Corresponding Author
micalizio@scripps.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(11) (a) Chen, M. Z.; McLaughlin, M.; Takahashi, M.; Tarselli, M.
A.; Yang, D.; Umemura, S.; Micalizio, G. C. J. Org. Chem. 2010, 75,
8048−8059. (b) Takahashi, M.; McLaughlin, M.; Micalizio, G. C.
Angew. Chem., Int. Ed. 2009, 48, 3648−3652.
We gratefully acknowledge financial support of this work by the
National Institutes of Health−NIGMS (GM80266 and
GM80266-04S1).
(12) Compound 8 was prepared by asymmetric reduction of the
corresponding enone: (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am.
Chem. Soc. 1987, 109, 5551−5553. (b) Corey, E. J. Angew. Chem., Int.
Ed. 2009, 48, 2100−2117.
REFERENCES
■
(
1
1) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
556−1575.
(
(
(
13) Ager, D. J. Org. React. 1990, 38, 1−223.
(
2) (a) Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.;
14) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841−1860.
15) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
Daly, J. W. Tetrahedron 1987, 43, 643−652. (b) Tokuyama, T.;
Garraffo, H. M.; Spande, T. F.; Daly, J. W. Anal. Asoc. Quim. Argentina
1
978, 100, 3611−3613. (b) Hartley, R. C.; Li, J.; Main, C. A.;
McKiernan, G. J. Tetrahedron 2007, 63, 4825−4864.
16) (a) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957−
965. (b) For a review of [3 + 2] nitrone cycloaddition reactions to
alkenes, see: Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1−
73.
17) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841−4844.
1
998, 86, 291−298. Notably, skins of 3620 frogs were required in the
original isolation paper to deliver only 13 mg of (−)-205B.
3) Tsuneki, H.; You, Y; Toyooka, N.; Kagawa, S.; Kobayashi, S.;
Sasaoka, T.; Nemoto, H.; Kimura, I.; Dani, J. A. Mol. Pharmacol. 2004,
6, 1061−1069.
4) Toyooka, N.; Fukutome, A.; Shinoda, H.; Nemoto, H. Angew.
Chem., Int. Ed. 2003, 42, 3808−3810.
5) (a) Smith, A. B.; Kim, D.-S. Org. Lett. 2005, 7, 3247−3250.
b) Tsukanov, S. V.; Comins, D. L. Angew. Chem., Int. Ed. 2011, 50,
626−8628.
6) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2011, 133, 9216−
219.
7) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032−
035.
(
1
(
6
(
1
(
In our hands, freshly prepared NBSH proved to be quite unstable after
drying under high vacuum for 48h. For example, in the presence of air,
a minor tap of the vial containing this material resulted in the
generation of red smoke followed immediately by an aggressive flame/
explosion. While the reported preparation of NBSH calls for drying
under vacuum at 23 °C for 14 h, in efforts to achieve a similar melting
point to that reported in the literature one batch of material was dried
under vacuum for 48 h. This was the only modification made to the
literature procedure.
(
(
8
(
9
(
7
(
(
5
1
1
8) Robinson, R. J. Chem. Soc., Trans. 1917, 111, 762−768.
9) (a) Grieco, P. A.; Fobare, W. F. Tetrahedron Lett. 1986, 27,
(18) (a) Hudrlik, P. F.; Holmes, P. E.; Hudrlik, A. M. Tetrahedron
067−5070. (b) Hosomi, A.; Sakurai, H. Tetrahdron Lett. 1976, 17,
295−1298. (c) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131,
7548−17549. A related ring closure based on an intramolecular
Lett. 1988, 29, 6395−6398. (b) Hudrlik, P. F.; Hudrlik, A. M.;
Kulkarni, A. K. J. Am. Chem. Soc. 1982, 104, 6809−6811. (c) Heitzman,
C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley, J. M.; Va, P.;
Roush, W. R. Org. Lett. 2005, 7, 2405−2408.
Mannich cyclization was a key reaction in Toyooka’s total synthesis of
(
+)-205B (see ref 4).
10) During review of this manuscript, it was suggested that modern
(19) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
(
Trans. 1 1975, 1574−1585. (b) For a review of radical chemistry
associated with thiocarbonyls, see: Crich, D.; Quintero, L. Chem. Rev.
asymmetric imine allylation chemistry may be suitable to afford direct
access to the stereodefined (E)-anti-homoallylic primary amine
precursor to 3. We recognize that a variety of alternative strategies
that embrace the reactivity of allylic and propargylic organometallic
reagents may be suitable to prepare the desired intermediate for
intramolecular nitrone cycloaddition. That said, we are unaware of any
synthetic method capable of delivering the desired (E)-anti-
homoallylic hydroxylamine (or primary amine) from the correspond-
ing aldimine or aldoxime. Related transformations include the
following. (a) Chelation-controlled addition reactions of chiral
1
989, 89, 1413−1432.
D
dx.doi.org/10.1021/ja306362m | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX