Synthesis of the lycopodium alkaloid (+)-lycoflexine

Article abstract of DOI:10.1021/ja107533m

The first total synthesis of (+)-lycoflexine (1), a constituent of Lycopodium clavatum var. inflexum, has been accomplished in eight steps with 13% overall yield. Our synthesis covers four one-pot reactions, including a tandem Sakurai/aldol sequence, a novel hydroboration/oxidation procedure, a deprotection/transannular Mannich reaction, and as a highlight, a tandem catalysis cascade combining an enynene ring-closing metathesis and a selective hydrogenation.

Full text of DOI:10.1021/ja107533m

Published on Web 09/24/2010
Synthesis of the Lycopodium Alkaloid (+)-Lycoflexine
Ju¨rgen Ramharter,* Harald Weinstabl, and Johann Mulzer
Institute of Organic Chemistry, UniVersity of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria
Received August 20, 2010; E-mail: juergen.ramharter@univie.ac.at
Our retrosynthetic analysis of lycoflexine (1) is outlined in
Abstract: The first total synthesis of (+)-lycoflexine (1), a con-
stituent of Lycopodium clavatum var. inflexum, has been ac-
complished in eight steps with 13% overall yield. Our synthesis
covers four one-pot reactions, including a tandem Sakurai/aldol
sequence, a novel hydroboration/oxidation procedure, a depro-
tection/transannular Mannich reaction, and as a highlight, a
tandem catalysis cascade combining an enynene ring-closing
metathesis and a selective hydrogenation.
Scheme 1. The final step of our synthesis refers to the biosynthetic
proposal of Ayer et al.5 As a suitable substrate for such a
conversion, we identified the tricyclic diketo compound 4, which
can be generated from substrate 5.6 The latter compound can be
accessed via an enynene ring-closing metathesis (RCM) reaction
of precursor 6, which is easily obtained from diketone 7 derived
from the well-known optically active enone 9.7
Scheme 2. Synthesis of Precursor 6a
Lycopodium alkaloids1 are a huge family of diverse but structur-
ally related compounds (see Figure 1 for some examples) with
impressive and challenging structures and interesting biological
activities, such as acetylcholinesterase inhibition [e.g., huperzine
A (2),2 lycojapodine A (3),3 or sieboldine A4].
Figure 1. Selected Lycopodium alkaloids.
a Conditions: (a) (i) TiCl4, allyltrimethylsilane, DCM, -78 °C; (ii)
acetaldehyde, 70%. (b) IBX, EtOAc, reflux. (c) Cs2CO3, 8, DMF, -15 °C,
68% (two steps). (d) Comins’ reagent, KHMDS, THF, -78 °C, 85%. (e)
Pyridine, 60 °C, 99%.
Lycoflexine (1) (also known as lycobergine) belongs to the class
of fawcettimine-related alkaloids and was isolated by Ayer et al.5
in the early 1970s by extraction of Lycopodium claVatum var.
inflexum collected in the Eastern Transvaal (Republic of South
Africa). Its structure consists of an exceptional tetracyclic
carbon-nitrogen skeleton including a spiro-annulated six-membered
ring and four stereogenic centers, of which two are adjacent
quaternary carbons. Despite the interesting, complex molecular
architecture of lycoflexine, no total synthesis has been reported to
date.
As is depicted in Scheme 2, the synthesis of key intermediate 6
started with a tandem Sakurai/aldol sequence that converted enone
9 into alcohol 10 as an inconsequential diastereomeric mixture.8
After mild oxidation with IBX,9 the resulting diketo compound 7
was alkylated with iodocarbamate 810 to provide compound 11 with
satisfying yield. After some optimization, triflation of the less-
hindered carbonyl moiety was achieved with Comins’ reagent.11
Treatment of the resulting vinyl triflate 12 with pyridine at elevated
temperature finally yielded dienyne 6.12
Scheme 1. Retrosynthetic Analysis
In our first attempts, the envisaged enynene RCM was carried
out under standard conditions with Grubbs’ second-generation
catalyst.13 Although the formation of the desired tricyclic diene 13
was observed, the yield was only slightly higher than 30%. As no
other byproducts could be isolated, we rationalized that the diene
is probably of moderate stability and prone to decomposition. On
the basis of Grubbs’ findings that metathesis catalysts can be
converted into active hydrogenation catalysts by treatment with
dihydrogen,14,15 we decided instead to attempt a tandem catalysis
sequence and selectively hydrogenate the less-substituted double
bond in situ. Gratifyingly, the desired tricyclic carbamate 5 was
formed in 52% yield from 6 (Scheme 3).
To complete our synthesis, only two steps were missing. Direct
oxidation of organoboranes to the corresponding ketones is known,
9
14338 J. AM. CHEM. SOC. 2010, 132, 14338–14339
10.1021/ja107533m  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Final Steps toward Lycoflexine (1)a
hydroboration/oxidation, N-Boc deprotection/transannular Mannich
cyclization) makes the sequence remarkably concise and efficient
(eight steps from 9 with an overall yield of 13%). It is flexible and
therefore should be suitable for the synthesis of several other
Lycopodium alkaloids as well.
Acknowledgment. We are very grateful to Professor Hiromitsu
Takayama of Chiba University for providing us spectroscopic data
for authentic lycoflexine. We thank S. Felsinger, L. Brecker, and
H. P. Ka¨hlig for NMR analysis, R. Konrat and G. Platzer for CD
spectra, and R. Schuecker for technical support, all at the University
of Vienna.
Supporting Information Available: Experimental procedures and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews of Lycopodium alkaloids, see: (a) Ayer, W. A.; Trifonov, L. S.
In The Alkaloids; Cordell, G. A., Brossi, A., Eds.; Academic Press: New
York, 1994; Vol. 45, pp 233-266. (b) Hirasawa, Y.; Kobayashi, J.; Morita,
H. Heterocycles 2009, 77, 679. (c) Ma, X.; Gang, D. R. Nat. Prod. Rep.
2004, 21, 752.
(2) Liu, J.-S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.; Wu, F.-W.;
Qi, B.-F. Can. J. Chem. 1986, 64, 837.
(3) He, J.; Chen, X.-Q.; Li, M.-M.; Zhao, Y.; Xu, G.; Cheng, X.; Peng, L.-Y.;
Xie, M.-J.; Zheng, Y.-T.; Wang, Y.-P.; Zhao, Q.-S. Org. Lett. 2009, 11,
1397.
(4) (a) Hirasawa, Y.; Morita, H.; Shiro, M.; Kobayashi, J. Org. Lett. 2003, 5,
3991. For a recently published total synthesis of sieboldine A, see: (b)
Canham, S. M.; France, D. J.; Overman, L. E. J. Am. Chem. Soc. 2010,
132, 7876.
(5) Ayer, W. A.; Fukazawa, Y.; Singer, P. P. Tetrahedron Lett. 1973, 14, 5045.
(6) Compound 5 has been synthesized by the Toste group via a totally different
route. See: Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2007, 46, 7671.
(7) (a) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem.
Commun. 2006, 4928. (b) Carpenter, R. D.; Fettinger, J. C.; Lam, K. S.;
Kurth, M. J. Angew. Chem., Int. Ed. 2008, 47, 6407. (c) Caine, D.; Procter,
K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647.
(8) Hosomi, A.; Hashimoto, H.; Kobayashi, H.; Sakurai, H. Chem. Lett. 1979,
245.
(9) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(10) Iodocarbamate 8 was prepared from N-Boc-protected allylamine in two
steps and 52% overall yield (see the Supporting Information for more
details).
(11) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(12) Hargrove, R. J.; Stang, P. J. J. Org. Chem. 1974, 39, 581.
(13) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem.
1996, 61, 1073.
(14) (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312. For another example of RCM/hydrogenation tandem catalysis,
see: (b) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308.
(15) Tandem catalysis in general has not found widespread application in
synthesis, despite the potential of such transformations. For a general review,
see: Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV.
2005, 105, 1001.
a Conditions: (a) (i) Grubbs’ second-generation (20 mol %), 1,2-
dichloroethane, reflux; (ii) H2, 10 atm, 70 °C, 52%. (b) (i) BH3 ·THF, THF,
50 °C; (ii) IBX, EtOAc, reflux. (c) HCHO(aq), 0.5 M HCl, EtOH, reflux,
64% (two steps).
though mostly based on rather aggressive and toxic chromium
reagents.16 We thus developed a novel protocol that allowed us to
oxidize the organoborane in situ with IBX to obtain an inconse-
quential diastereomeric mixture of diketo compounds 4. It is
noteworthy that both diastereomers also can be used to synthesize
fawcettimine (16), another prominent member of the Lycopodium
alkaloid family.17 Our total synthesis of lycoflexine was concluded
by a final tandem reaction. The N-Boc protecting group was
removed using dilute aqueous HCl, and by analogy to the
biomimetic conversion of fawcettimine to lycoflexine, excess
formaldehyde was used to generate an iminium species, which
smoothly underwent a transannular Mannich reaction to furnish (+)-
lycoflexine (1).18,19
(16) (a) Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1961, 83, 2951. (b) Brown,
H. C.; Kulkarni, S. U.; Rao, C. G. Synthesis 1980, 151.
(17) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989,
54, 1548.
The identity of our compound with authentic lycoflexine was
established by comparison with the spectroscopic data (1H and 13
C
NMR as well as CD) kindly provided by Professor Takayama, who
had reisolated and characterized the compound.20 In this way, the
absolute configuration of 1 also was confirmed by total synthesis.
In conclusion, we have achieved the first total synthesis of (+)-
lycoflexine. The extensive use of tandem and one-pot reactions
(Sakurai/aldol, enynene RCM/hydrogenation tandem catalysis,
(18) A similar reaction was applied by Ayer et al. in their isolation paper5 for
the conversion of fawcettimine to lycoflexine.
(19) For a review of the Mannich reaction, see: Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
(20) Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi, N.
Tetrahedron Lett. 2002, 43, 8307.
JA107533M
9
J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010 14339