Divergent total syntheses of (-)-lycopladine D, (+)-fawcettidine, and (+)-lycoposerramine Q

Article abstract of DOI:10.1021/ol402906y

Enantioselective total syntheses of (+)-fawcettidine and (+)-lycoposerramine Q as well as the first total synthesis of (-)-lycopladine D from a common intermediate have been accomplished by a divergent path. The common intermediate was derived from a Hajos-Parrish-like diketone by a stereoselective Birch reduction and a Suzuki coupling. The synthesis of (-)-lycopladine D featured an allylic oxidation and a biomimetic aminoketalization while the route to (+)-fawcettidine and (+)-lycoposerramine Q highlighted an oxidative rearrangement.

Full text of DOI:10.1021/ol402906y

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5846–5849
Divergent Total Syntheses of
(ꢀ)-Lycopladine D, (þ)-Fawcettidine,
and (þ)-Lycoposerramine Q
Chen Zeng, Changwu Zheng, Jingyun Zhao, and Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
zhaog@mail.sioc.ac.cn
Received October 8, 2013
ABSTRACT
Enantioselective total syntheses of (þ)-fawcettidine and (þ)-lycoposerramine Q as well as the first total synthesis of (ꢀ)-lycopladine D from a
common intermediate have been accomplished by a divergent path. The common intermediate was derived from a HajosꢀParrish-like diketone by
a stereoselective Birch reduction and a Suzuki coupling. The synthesis of (ꢀ)-lycopladine D featured an allylic oxidation and a biomimetic
aminoketalization while the route to (þ)-fawcettidine and (þ)-lycoposerramine Q highlighted an oxidative rearrangement.
Since the first Lycopodium alkaloid lycopodine was
€
isolated and classified into four major groups to date.2
Members of this family are known to have cardiovascular
and neuromusculareffects.3 The uniquepolyfused/bridged
system and impressive biological activities of these com-
poundshavearousedgreat interestfrom syntheticchemists
in recent decades.4 One of the classes in the family named
fawcettimine-type Lycopodium alkaloids (Figure 1), which
usuallyfeature a tetracyclic skeleton including aR-oriented
methyl group at C-15 and account for nearly one-third of the
members, has particularly attracted the attention of several
groups in total synthesis. As the selected examples shown in
Figure 1, recently, several impressive total syntheses toward
fawcettidine (1),5 lycojapodine A,6 lycoflexine,7 huperzine
Q,8 and lycoposerramine Q (2)9 have been achieved.
separated by Bodeker in 1881 from clubmoss Lycopodium
complanatum,1 over 200 lycopodium alkaloids have been
€
(1) Bodeker, K. Justus Liebigs Ann. Chem. 1881, 208, 363.
(2) For recent reviews on Lycopodium alkaloids, see: (a) Ma, X.;
Gang, D.-R. Nat. Prod. Rep. 2004, 21, 752. (b) Hirasawa, Y.;Kobayashi, J.;
Morita, H. Heterocycles 2009, 77, 679. (c) Siengalewicz, P.; Mulzer, J.;
€
Rinner, U. In The Alkaloids; Knolker, H.-J., Ed.; Academic Press: New York,
2013; Vol. 72, pp 1ꢀ151.
(3) (a) Tang, X.-C.; Han, Y.-F.; Chen, X.-P.; Zhu, X.-D. Acta
Pharmacol. Sin. 1986, 7, 507. (b) Hirasawa, Y.; Morita, H.; Kobayashi,
J. Org. Lett. 2004, 6, 3389.
(4) For recent reports on the total syntheses of fawcettimine-class
Lycopodium alkaloids, see: (a) Linghu, X.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2007, 46, 7671. (b) Kozak, J. A.; Dake,
G. R. Angew. Chem., Int. Ed. 2008, 47, 4221. (c) Otsuka, Y.; Inagaki, F.;
Mukai, C. J. Org. Chem. 2010, 75, 3420. (d) Canham, S. M.; France,
D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876. (e) Ramharter,
J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132, 14338. (f)
Yang, Y.-R.; Shen, L.; Huang, J.-Z.; Xu, T.; Wei, K. J. Org. Chem. 2011,
76, 3684. (g) Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H.
Angew. Chem., Int. Ed. 2011, 50, 8025. (h) Zhang, X.-M.; Tu, Y.-Q.;
Zhang, F.-M.; Shao, H.; Meng, X. Angew. Chem., Int. Ed. 2011, 50,
3916. (i) Li, H.-H.; Wang, X.-M.; Lei, X.-G. Angew. Chem., Int. Ed.
2012, 51, 491. (j) Ge, H.-M.; Zhang, L.-D.; Tan, R.-X.; Yao, Z.-J. J. Am.
Chem. Soc. 2012, 134, 12323. (k) Pan, G.-J.; Williams, R. M. J. Org.
Chem. 2012, 77, 4801. (l) Shimada, N.; Abe, Y.; Yokoshima, S.;
Fukuyama, T. Angew. Chem., Int. Ed. 2012, 51, 11824. (m) Li, H.-H.;
Wang, X.-M.; Hong, B.-K.; Lei, X.-G. J. Org. Chem. 2013, 78, 800. (n)
Itoh, N.; Iwata, T.; Sugihara, H.; Inagaki, F.; Mukai, C. Chem.;Eur. J.
2013, 19, 8665. (o) Zaimoku, H.; Nishide, H.; Nishibata, A.; Goto, N.;
Taniguchi, T.; Ishibashi, H. Org. Lett. 2013, 15, 2140.
Meanwhile, many new fawcettimine-type Lycopodium
alkaloids with more diverse and novel architectures have
(5) For isolation, see: Burnell, R. H. J. Chem. Soc. 1959, 3091. For
total syntheses, see refs 4b, 4i, 4k, and 4n.
(6) For isolation, see: 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. For total synthesis, see ref 4m.
(7) For isolation, see: Ayer, W. A.; Fukazawa, Y.; Singer, P. P.
Tetrahedron Lett. 1973, 14, 5045. For total syntheses, see refs 4e, 4f, 4k,
and 4n.
(8) For isolation, see: Tan, C.-H.; Ma, X.-Q.; Chen, G.-F.; Zhu,
D.-Y. Helv. Chim. Acta 2002, 85, 1058. For total synthesis, see ref 4g.
r
10.1021/ol402906y
Published on Web 11/04/2013
2013 American Chemical Society

Scheme 1. Retrosynthetic Analysis
Figure 1. Selected fawcettimine-type Lycopodium alkaloids.
been identified. Lycopladine D (3), which was isolated from
Lycopodium complanatum by Kobayashi and co-workers
in 2006, exhibits a unique carbinolamine lactone, a fused
pentacyclic ring framework, and six stereogenic centers
including an all-carbon quaternary center.10 It is noteworthy
that the stereochemistry at C-4, C-5, and C-15 differs from
other fawcettimine class members, making it more interest-
ing in total synthesis. Although lycopladine D (3) was
isolated seven years ago, no total synthesis has been reported
to date probably due to its unique structure from others.
Interested by the fascinating structural diversities, here we
have discovered a route to accomplish its total synthese as
well as fawcettidine (1) and lycoposerramine Q (2) from a
common intermediate. As shown in Scheme 1 (top), the core
structure of fawcettimine-type Lycopodium alkaloids (I)
could be obtained from the secondary amine (II), which
was supposed to be the biomimetic pathway that has been
employed in the analogous synthesis.4 The intermediate II,
as we designed, could be generated from the HajosꢀParrish-
like diketone 9, a very popular and easily accessible starting
material in the synthetic chemistry. The other advantage of
this method is that the stereochemistry at C-4 and C-5 could
be modulated via the diastereoselective reduction and herein
fawcettidine (1), lycoposerramine Q (2), and lycopladine D
(3) can be synthesized via a divergent pathway.
all-carbon quaternary center, which was easily prepared
from 1,3-cyclopentadione by a three-step procedure.11 The
first challenge we faced was the selective 1,4-reduction of
the enone in the presence of the terminal alkene and
isolated carbonyl to construct the cis-fused 6,5-carbocyclic
ring. Direct reduction from the diketone(R)-9 proved tobe
problematic. The terminal alkene was also reduced by hydro-
genation of 9 catalyzed by Pd/C. Reduction by t-BuCuH
or NiCl2/NaBH4 gave a trans-fused bicycle ring as the
major product. The diastereoselectivity was almost 1:1
when 9 was subjected to lithium in liquid ammonia. Herein
the alternative hydroxyl-directed stereocontrolled Birch
redution developed by Corey and co-workers was em-
ployed.12 Selective reduction of the unconjugated carbonyl
group in 9 with NaBH4 at ꢀ78 °C afforded 10 with the
desired selectivity,13 which was then subjected to lithium in
liquid ammonia to give 11 in 8:1 diastereoselectivity. The
cis-fused isomer obtained as the major product was prob-
ably the result of intramolecular protonation of the radical
anion by internal proton transfer from the secondary
hydroxyl in the Birch reduction. With the cis-bicycle being
established, Dess-Martin oxidation of the hydroxyl group
followed by selective protection of the less sterically hin-
dered carbonyl provided 12 in one pot.14 Treatment of 12
with KHMDS followed by PhNTf2 afforded the triflate,
which coupled15 with the boron species generated in situ
from N-tosylallylamine and 9-BBN to furnish the common
intermediate 8 in high yield.
Our retrosynthetic strategy is detailed in Scheme 1 (bottom).
We envisioned that 1ꢀ2 or 3 could be respectively obtained
from precursor 4 or 6 through a dehydration condensation or
biomimetic aminoketalization transformation. The functional
groups at C-15 and C-13 in 4 or 6 were expected to be
constructed from carbonyl at C-15 in 5 or 7. We imagined
that both 5 and 7 could be assembled from a common
intermediate 8, which would be prepared from Hajosꢀ
Parrish-like diketone 9.
As outlined in Scheme 2, our syntheses commenced
with HajosꢀParrish-like diketone (R)-9, containing an
(9) For isolation, see: Takayama, H.; Katakawa, K.; Kitajima, M.;
Yamaguchi, K.; Aimi, N. Tetrahedron Lett. 2002, 43, 8307. For racemic
total synthesis, see ref 4n.
(10) Ishiuchi, K.; Kubota, T.; Hoshino, T.; Obara, Y.; Nakahata, N.;
Kobayashi, J. Bioorg. Med. Chem. 2006, 14, 5995.
(11) (a) Ruprah, P. K.; Cros, J.-P.; Pease, J. E.; Whittingham, W. G.;
Williams, J. M. J. Eur. J. Org. Chem. 2002, 3145. (b) Lacoste, E.; Vaique,
E.; Berlande, M.; Pianet, I.; Vincent, J.-M.; Landais, Y. Eur. J. Org.
Chem. 2007, 167. (c) Zhang, X.-M.; Wang, M.; Tu, Y.-Q.; Fan, C.-A.;
Jiang, Y.-J.; Zhang, S.-Y.; Zhang, F.-M. Synlett 2008, 2831.
(12) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873.
(13) Isaacs, R. C.; DiGrandi, M. J.; Danishefsky, S. J. J. Org. Chem.
1993, 58, 3938.
(14) Ciceri, P.; Joachim Demnitz, F. W. Tetrahedron Lett. 1997, 38,
389.
(15) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818.
Org. Lett., Vol. 15, No. 22, 2013
5847

Scheme 2. Synthesis of Common Intermediate 8
Scheme 3. Route to Fawcettidine (1) and Lycoposerramine Q (2)
With the common intermediate 8 in hand, the synthetic
routes toward fawcettidine (1) and lycoposerramine Q (2)
from 8 are illustrated in Scheme 3. Successive hydrobora-
tion of 8 was achieved with 9-BBN and a boraneꢀTHF
complex and subsequent oxidation by NaBO4 afforded a
diol,16 which was selectively transformed into O-tosyl
derivative 13 with p-toluenesulfonyl chloride at ꢀ10 °C.
The stereochemistry of 13 was determined by a NOESY
experiment. Simultaneous silylation of hydroxyl with
TBSOTf and deprotection of the ketal with 0.8 M HCl
in 13 afforded 14 in 90% yield. Treatment of compound
14 with Cs2CO3 provided 5 with an azonane ring by an
intramolecular SN2 reaction. 5 was then dehydrogenated
to 15 by IBX oxidation developed by Nicolaou and co-
workers.17 After nucleophilic addition of 15 with a methyl-
cerium reagent,18 the resulting tertiary allylic alcohol was
elaborated to 16 by a PDC-mediated oxidative rearrange-
ment.19 Reductive cleavage of the N-tosyl amide in 16
accompanied by 1,4-reduction of the conjugated double
bond with lithium in liquid ammonia provided the amino
ketone 4. Finally, treating 4 with oxalic acid in AcOH4k at
120 °C furnished lycoposerramine Q (2). Oxiation of2 with
PCC afforded fawcettidine (1).20
azonane ring of 18. 7 was then subjected to Tf2O using
Cy2NEt as a hindered base, and the resulting enol triflate
was further converted into the methyl ester compound 19
by a palladium catalyzed22 carbonylation reaction in
methanol.
The ensuing allylic oxidation of 19 proved to be difficult,
presumably due to the steric hindrance of the vicinal
quaternary carbon. After numerous conditions were eval-
uated, we observed that treatment of 19 with SeO2 fol-
lowed by oxidation with DMP produced 20 in 15% yield.23
The low yield resulted from the elimination of the hydroxyl
of the corresponding allyl alcohol intermediate and de-
composition of the TBS protecting group. To avoid the
side reactions, we hypothesized that the allyl alcohol
intermediate could be oxidized in situ by an appropriate
oxidant. After carefully screening, we found that in situ
oxidation using IBX with NaHCO3 as a buffer signifi-
cantly improved the yield to 35%.24 Finally, this yield
could be improved to 46% (66% b.r.s.m.) at 105 °C in 1 h
in a microwave reactor.25 Hydrogenation of 20 under
30 atm of hydrogen followed by removal of the
p-toluenesulfonyl group from nitrogen led to 6. The
final critical biomimetic aminoketalization was achieved
Encouraged by the successful syntheses of 1 and 2, we
next explored the synthesis of lycopladine D from the
common intermediate 8 (Scheme 4). Selective hydrobora-
tionof 8 wasachieved with9-BBN and followingoxidation
by NaBO4 afforded primary alcohol 17, which was trans-
formed into azonane ring 18 by a modified intramolecular
Mitsunobu reaction.21 The latter compound was elabo-
rated to 7 in a one-pot operation involving hydroboration/
oxidation with BH3 THF/NaBO4 and successive depro-
3
tection of the ketal by 4 M HCl followed by silylation with
TBSCl. The stereochemistry of 7 at C-4, C-5 was opposite
to that of 13 as a result of the steric hindrance of the
(22) Snider, B. B.; Vo, N. H.; Neil, S. V.; Foxman, B. M. J. Am.
Chem. Soc. 1996, 118, 7644.
(23) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.
(24) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2006, 128, 6312.
(25) For a review of microwave-assisted organic synthesis, see:
Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65, 3325.
(26) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K.
Science 2004, 305, 495.
(27) CCDC 936082 (3) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(16) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930.
(17) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.
J. Am. Chem. Soc. 2002, 124, 2245.
(18) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
(19) Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 683.
(20) Spectral data of the synthetic fawcettidine and lycoposerramine-Q
were consistent with the reported data; see: refs 4b, 4n.
(21) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34,
1639.
5848
Org. Lett., Vol. 15, No. 22, 2013

The synthetic compound was identical with the nat-
ural material, including 1H NMR, 13C NMR data, and
mass spectra. X-ray crystallographic analysis of single
crystal of 3 unambiguously confirmed the structure.27
The consistency of the optical rotation of the product
also determined the absolute configuration of the natu-
rally occurring 3.
Scheme 4. Approach to Lycopladine D (3)
In summary, we have achieved the syntheses of (þ)-
fawcettidineand (þ)-lycoposerramine Q, aswell asthe first
total synthesis of (ꢀ)-lycopladine D in 15, 14, and 15 steps
from known compound 9 by a divergent path.28 The
syntheses highlight the following: (1) a stereoselective
Birch reduction by way of intramolecular protonation
and a Suzuki coupling with in situ generated boron species
to afford the cis-fused intermediate 8; (2) 1ꢀ2 and 3 could
be respectively obtained from diastereoisomers 5 and 7,
both of which were produced from the common inter-
mediate 8 by changing the sequence of cyclization and
hydroboration oxidation of the double bond at C-4, C-5;
(3) an allylic oxidation with large steric hindrance and a
biomimetic aminoketalization. Due to the great efficiency
of this synthetic strategy, endeavors in achieving the total
syntheses of other fawcettimine-type alkaloids are being
pursued in our laboratory, and the results will be reported
in due course.
Acknowledgment. This work was financially supported
by the NSFC (20172064, 203900502, and 21032006), the
973 program (2010CB833204), and the Excellent Young
Scholars Foundation of National Natural Science Foun-
dation of China (No. 20525208).
Supporting Information Available. Experimental pro-
cedures, characterization data, and crystallographic data
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(28) For selected recent work on the divergent syntheses of natural
products, see: (a) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan,
D. W. C. Nature 2011, 475, 183. (b) Bian, M.; Wang, Z.; Xiong, X.; Sun, Y.;
Matera, C.; Nicolaou, K. C.; Li, A. J. Am. Chem. Soc. 2012, 134, 8078.
by treatment of 6 with aqueous TFA at 80 °C to produce
lycopladine D.26
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5849