Enantioselective total synthesis of (+)-amabiline

Article abstract of DOI:10.1021/ol300466a

The first total synthesis of (+)-amabiline, an unsaturated pyrrolizidine alkaloid from Cynoglossum amabile, is reported. This convergent, enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features

Full text of DOI:10.1021/ol300466a

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1869–1871
Enantioselective Total Synthesis
of (þ)-Amabiline
Timothy J. Senter, Olugbeminiyi O. Fadeyi, and Craig W. Lindsley*
Departments of Chemistry and Pharmacology, Vanderbilt University, Nashville,
Tennessee 37232, United States
craig.lindsley@vanderbilt.edu
Received February 24, 2012
ABSTRACT
The first total synthesis of (þ)-amabiline, an unsaturated pyrrolizidine alkaloid from Cynoglossum amabile, is reported. This convergent,
enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features novel methodology to
construct the unsaturated pyrrolizidine or (ꢀ)-supinidine core.
Pyrrolizidine alkaloids (1), historically referred to as
necine bases, share a common azabicyclo[3.3.0]octane core
but differ based on the oxygenation patternand whether or
not C1ꢀC2 is saturated (Figure 1).1 While the amine bases
themselves are rarely isolated in nature, the corresponding
mono- and diesters are more common, as either the tertiary
amine or the N-oxide, 2ꢀ5.1 Members of this family of
alkaloids possess a wide range of biological activities
including antitumor, antibacterial, anti-inflammatory,
carcinogenic, and hepatotoxic activity, with several mem-
bers entering human clinical trials.1ꢀ5 Plants containing
pyrrolizidine alkaloids are toxic to humans and animals,
but several insect species have evolved to employ them for
their own chemical defense.6 Interestingly, the toxicity
has been attributed to liver metabolism of the C1ꢀC2
unsaturated congeners leading to the generation of highly
reactive alkylating agents.7
(1) For reviews on the pyrrolizidine alkaolids, see: (a) Robins, D. J.
J. Nat. Prod. Rep. 1989, 6, 221. (b) Ikeda, M.; Sato, T.; Ishibashi, H.
Heterocycles 1988, 27, 1465. (c) Dai, W.-M.; Nagao., Y. Heterocycles
1990, 30, 1231–1261.
(2) Culvenor, C. C. J.; Dowling, D. T.; Edgar, J. A.; Jago, M. V. Ann.
N.Y. Acad. Sci. 1969, 163, 837.
Figure 1. Structures and numbering convention of pyrrolizidine
alkaloids 1, and representative examples 2ꢀ4.
(3) Zalkow, L. H.; Glinski, J. A.; Gelbaum, L. T.; Fleischmann, T. J.;
McGowan, L. S.; Gordon, M. M. J. Med. Chem. 1985, 28, 687.
(4) Suffness, M.; Cordell, G. A. The Alkaloids: Chemistry and
Pharmacology, Vol. 25; Brossi, A., Ed.; Academic Press: NY, 1985.
(5) Cheeke, P. R. Toxicants of Plant Origins, Vol. 1; Cheeke, P. R.,
Ed.; CRC Press: FL, 1989.
(6) Hartmann, T.; Biller, A.; Witte, L.; Ernst, L.; Boppre, M.
Biochem. Syst. Ecol. 1990, 18, 549–556.
(7) White, L.; Rubiolo, P.; Bicchi, C.; Hartmann, T. Phytochemistry
1993, 32, 187–196.
A number of racemic routes to the pyrrolizidine alkaloid
core (1) have been developed, but recent efforts have
focused on asymmetric approaches.1ꢀ5 The majority of
these approaches rely on the chiral pool, employing
L-proline, malic acid, or carbohydrates as chiral starting
materials.1 Based on the synthetic challenge, the diverse
r
10.1021/ol300466a
2012 American Chemical Society
Published on Web 03/20/2012

biological activity, and our recently reported methodology
to construct multiple bicyclic azacine systems,8 we decided
to apply our methodology toward the enantioselective syn-
thesis of (þ)-amabiline (3), an unsaturated pyrrolizidine
alkaloid, isolated in 1967 from Cynoglossum amabile, that
has yet to be the subject of a total synthesis.7,9ꢀ12
afford (S,S)-diol 16 in >8:1 dr. Ester hydrolysis gave
the (ꢀ)-viridifloric acid (7), idenitical in all respects to the
natural acid, which was then protected as the dioxolane
congener 9. Thus, the synthesis of 9 required five steps and
proceeded in 48% overall yield.
Scheme 2. Synthesis of protected (ꢀ)-viridifloric acid (9)
Scheme 1. Retrosynthetic Analysis of (þ)-Amabiline (3)
With 7 in hand, attention was now directed to the
synthesis of key intermediate 8 (Scheme 3). Commercial
diol 10 was monosilylated. MnO2 oxidation of the allylic
Scheme 3. Synthesis of Key Intermediate 8 and Attempted
Synthesis of 6
Our retrosynthesis first cleaved the ester bond to liberate
the necine base (ꢀ)-supinidine (6) and (ꢀ)-viridifloric acid
(7) (Scheme 1). 6 has been synthesized previously, but
the most expedient route required 18 steps.13 By employ-
ing a novel extension of our newly developed azacine
methodology,8 6 would be accessed from 8, which would
be derived from commercial diol 10 and (S)-tert-butyl
sulfinimine 11. (ꢀ)-Viridifloric acid (7) would be pre-
pared as prescribed by Schulz,14 via 9, from commercial
12 and 13.
Efforts initially focused on the synthesis of
7
(Scheme 2).14 Alkylation of phosphonate ester 12 with 13
provided 14 in 93% yield. A HornerꢀWadsworthꢀ
Emmons reaction with acetaldehyde provided alkene 15,
which then underwent a Sharpless dihydroxylation to
(8) Faedyi, O. O.; Senter, T. J.; Hahn, K. N.; Lindsley, C. W. Chem.
Eur. J., DOI: 10.1002/chem.201200629.
(9) Culvenor, C. C. J.; Smith, L. W. Aust. J. Chem. 1967, 20, 2499–
2503.
(10) El-Shazy, A.; Sarg, T.; Ateya, A.; Aziz, E. A.; Witte, L.; Wink,
M. Biochem. Syst. Ecol. 1996, 24, 415–421.
alcohol then delivered aldehyde 17 in 84% yield for the two
steps. Condensation of 17 with (S)-tert-butyl sulfinimine
11 gave 18 in 79% yield.8,15ꢀ17 Addition of Grignard
reagent 19 provides 20 in >9:1 dr,8,15ꢀ21 which is
(11) Roeder, E.; Breitmaier, E.; Birecka, H.; Frohlich, M. W.;
Badzies-Crombach, A. Phytochemistry 1991, 30, 1703–1706.
(12) In 1993, a strucuturally unrelated Amaryllidaceae alkaloid was
isolated and also named amabiline. However, the moniker of amabiline
has been applied to 3 in multiple manuscripts over the past 45 years. For
the isolation and synthesis of the Amaryllidaceae alkaloid also named
amabiline, see: (a) Likhitwitayawuid, K.; Angerhofer, C. K.; Pezzuto,
J. M.; Cordell, G. A.; Ruangrungsi, N. J. Nat. Prod. 1993, 56, 1331. (b)
Findlay, A. D.; Banwell, M. G. Org. Lett. 2009, 11, 3160–3162.
(13) Takahata, Banba, Y.; Momose, T. Tetrahedron 1991, 47, 7635–
7644.
(15) Brinner, K. M.; Ellman, J. A. Org. Biomol. Chem. 2005, 3, 2109–
2113.
(16) Schulte, M. L.; Lindsley, C. W. Org. Lett. 2011, 13, 5684–5687.
(17) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, T. P.
J. Org. Chem. 1999, 64, 1278–1284.
(18) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819–7832.
(19) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092–1093.
(20) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850–3851.
(21) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883–
8904.
(14) Stritzke, K.; Schulz, S.; Nishida, R. Eur. J. Chem. 2002, 3884–
3892.
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Org. Lett., Vol. 14, No. 7, 2012

subsequently allylated to deliver 21 in 77% yield for the
two steps. A ring closing metathasis reaction employing
Grubbs II22 smoothly led to pyrrolidine 22, and a TBAF
deprotection generated the key intermediate 8. Single
X-ray crystallography (Figure 2) confirmed the absolute
stereochemistry of 8 as (S,S).23 Here, we anticipated that
deprotection of the acetal and the sulfinamine would
liberate the free aldehyde and amine, respectively, followed
by an intramolecular condensation to form the imine that
would then be reduced in situ to provide (ꢀ)-supinidine (6).
However, classical Ellman conditions and a number of
other variants failed to facilitate this transformation,
affording complex mixtures of polar species.
Scheme 4. Synthesis of (þ)-Amabiline (3)
yield/transformation). Thus, thefirst total synthesis of(þ)-
amabiline (3) was completed in 15 synthetic steps (10-step
longest linear sequence) and in 6.2% overall yield. Our
synthetic amabiline was identical in all respects to the data
reported for natural 3. Moreover, this represents a notable
improvement, as previous efforts have required up to 18
steps todeliver(ꢀ)-supinidine (6), the parent necine base.13
Based on the strucutral similarity of 3to other pyrrolizidine
alklaoids with anticholinergic activity,1ꢀ5 we evaluated
our synthetic 3 against all five human mAChR receptors
(hM1ꢀM5). Interestingly, 3 possessed no activity at any of
the mAChRs (IC50 >10 μM), as well as a larger collection of
GPCRs, ion channels, and transporters.
In summary, we have completed the first total synthesis
of (þ)-amabiline (3), requiring only 15 synthetic steps (10-
step longest linear sequence) in 6.2% overall yield. This
highly convergent and concise synthesis will enable the
preparation of unnatural, unsaturated pyrrolizidine alka-
loids for additional biological evaluation. Further refine-
ments are in progress and will be reported in due course.
Figure 2. X-ray structure (ORTEP) of key intermediate 8,
confirming the correct (S,S)-stereochemistry.
Therefore, we elected to first couple 8 and 9, followed by
global deprotection and intramolecular reductive amina-
tion. However, this too proved difficult, due to the steri-
cally hindered acid 9. We evaluated several coupling
reagents (EDCI/DMAP, TBTU/DBU, DCC/DMAP,
HATU/DIEA) and protocols, butnoneprovidedanytrace
of the ester product. Therefore, we decided to convert the
hydroxyl of 8 into a leaving group and attempt to install
the ester linkage by emloying the acid as a nucleophile. A
mesylate derivative afforded a 45% conversion to the
desired ester, but 23, a tosylate variant, afforded the
desired ester in 82% yield (Scheme 4). A final acid-
mediated global deprotection of the acetal, the dioxolane,
and the sulfinamine enabled the intramolecular condensa-
tion to form the imine, which was then reduced in situ by
MP-BH(OAc)3 to deliver amabiline (3) in 37% yield in a
five-step, one-pot reaction cascade (an average of 82%
Acknowledgment. This work was supported, in part, by
the Department of Pharmacology and Vanderbilt Univer-
sity. Funding for the NMR instrumentation was provided
in part by a grant from the NIH (S10 RR019022).
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Note Added after ASAP Publication. This manuscript
was published ASAP on March 20, 2011. Due to a
production error, Scheme 3 was not updated. The
corrected version was posted on March 23, 2012.
(22) Kuhn, K. M.; Champange, T. M.; Hong, S. H.; Wei, W.-H.;
Nickel, A.; Lee, C. W.; Virgil, S. C.; Grubbs, R. H.; Pederson, R. L. Org.
Lett. 2010, 125, 984–987.
The authors declare no competing financial interest.
(23) See the Supporting Information for full details.
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