First asymmetric total syntheses of cernuane-type Lycopodium alkaloids cernuine, and cermizine D

Article abstract of DOI:10.1021/ol800574v

The first total syntheses of two cernuane-type Lycopodium alkaloids, (-)-cernuine and (+)-cermizine D, were accomplished starting from (+)-citronellal. The syntheses involved organocatalytic α-amination to afford oxazolidinone, which is used for diastereo

Full text of DOI:10.1021/ol800574v

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1987-1990
First Asymmetric Total Syntheses of
Cernuane-Type Lycopodium Alkaloids,
Cernuine, and Cermizine D
Yasuhiro Nishikawa, Mariko Kitajima, and Hiromitsu Takayama*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
takayama@p.chiba-u.ac.jp
Received March 12, 2008
ABSTRACT
The first total syntheses of two cernuane-type Lycopodium alkaloids, (-)-cernuine and (+)-cermizine D, were accomplished starting from
(+)-citronellal. The syntheses involved organocatalytic r-amination to afford oxazolidinone, which is used for diastereoselective allylation,
and asymmetric transfer aminoallylation followed by stereoselective construction of an aminal moiety as key steps.
Plants of the genus Lycopodium are known to produce a
number of alkaloids that often possess highly diverse,
complex structures and a variety of biological activities.1
Cernuine (1) and lycocernuine (2) are representatives of
cernuane-type Lycopodium alkaloids that consist of a fused
tetracyclic ring system containing an aminal moiety. Isolated
by Marion and Manske in 1948,2a their structures were
elucidated by Ayer et al. in 1967.2b–e However, while the
total syntheses of various types of Lycopodium alkaloids have
been reported,3 that of cernuane-type alkaloids has yet to be
established. In 2004, Kobayashi et al. reported the isolation
of cermizine D (3), a compound having an N-C9 seco-
cernuane skeleton and exhibiting cytotoxicity against murine
lymphoma L1210 cells with an IC50 of 7.5 µg/mL (Figure
1).4 Although the structure of cermizine D was proposed on
the basis of spectroscopic methods, its relative and absolute
configuration was not clarified. In relation to our chemical
(1) For recent reviews, see: (a) Kobayashi, J.; Morita, H. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2005; Vol. 61,
pp 1–57. (b) 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.
(c) Ma, X.; Gang, D. R. Nat. Prod. Rep 2004, 21, 752–772.
(3) For recent reports of the synthesis of Lycopodium alkaloids, see: (a)
Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H.
Org. Lett. 2007, 9, 4069–4073. (b) Linghu, X.; Kennedy-Smith, J. J.; Toste,
F. D. Angew. Chem., Int. Ed. 2007, 46, 7671–7673. (c) Beshore, D. C.;
Smith, A. B., III J. Am. Chem. Soc. 2007, 129, 4148–4149. (d) Snider,
B. B.; Grabowski, J. F. J. Org. Chem. 2007, 72, 1039–1042. (e) Staben,
S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.;
Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5995–5994.
(2) (a) Marion, L.; Manske, R. H. F. Can. J. Res. 1948, 26, 1–2. (b)
Ayer, W. A.; Jenkins, J. K.; Valverde-Lopez, S. Tetrahedron Lett. 1964,
32, 2201–2209. (c) Ayer, W. A.; Jenkins, J. K.; Valverde-Lopez, S.; Burnell,
R. H. Can. J. Chem. 1967, 45, 433–443. (d) Ayer, W. A.; Jenkins, J. K.;
Piers, K.; Valverde-Lopez, S. Can. J. Chem. 1967, 45, 445–450. (e) Ayer,
W. A.; Piers, K. Can. J. Chem. 1967, 45, 451–459.
(4) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015–7023.
10.1021/ol800574v CCC: $40.75
Published on Web 04/23/2008
2008 American Chemical Society

Table 1. Organocatalytic Oxazolidinone Synthesis
Figure 1. Cernuane-type Lycopodium alkaloids isolated from
Lycopodium cernuum.
studies on Lycopodium alkaloids,5 we planned the synthesis
of these cernuane-type alkaloids by which the structure,
including the absolute configuration, could be confirmed. In
this paper, we describe the first stereocontrolled total
syntheses of (-)-cernuine (1) and (+)-cermizine D (3).
Our retrosynthesis of cernuine (1) is outlined in Scheme
1. Construction of a characteristic aminal function in 1was
Scheme 1. Retrosynthetic Analysis of Cernuine (1)
a All reactions were carried out with 1.1 equiv of aldehyde and 1 equiv
of dibenzyl azodicarboxylate. b Isolated yield. c The de values were
determined by HPLC using CAPCELL PAK C18 MG.
R-amination was provided by (+)-citronellal (10) through
protection of aldehyde as an acetal function, followed by
oxidative cleavage of the residual olefin function.7 First, we
conducted amination of 9 with dibenzyl azodicarboxylate in
the presence of a catalytic amount of (S)-proline in CH2Cl2
at room temperature, followed by in situ reduction. The
resultant mixture was treated with K2CO3 in toluene to
furnish oxazolidinone 8 in 94% yield and 75% de (entry 1).
Selectivity could be improved by using catalyst A28,9 at room
temperature (entry 3), while lower temperature decreased the
selectivity (entry 4).
Next, reductive N-N bond cleavage in 8 was attempted
(Scheme 2). Whereas the direct reduction of 8 with Raney
Ni leading to 11 was not effective, we found that sequential
reduction involving removal of the Cbz group followed by
(5) (a) Takayama, H.; Katakawa, K.; Kitajima, M.; Seki, H.; Yamaguchi,
K.; Aimi, N. Org. Lett. 2001, 3, 4165–4167; 2002, 4, 1243. (b) Takayama,
H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi, N. Tetrahedron
Lett. 2002, 43, 8307–8311. (c) Takayama, H.; Katakawa, K.; Kitajima, M.;
Yamaguchi, K.; Aimi, N. Chem. Pharm. Bull. 2003, 51, 1163–1169. (d)
Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.; Furihata,
K.; Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658–663. (e)
Katakawa, K.; Nozoe, A.; Kogure, N.; Kitajima, M.; Hosokawa, M.;
expected by reductive cyclization of aminolactam 4 that would
be used as a common intermediate for the synthesis of cermizine
D (3). Homoallylamine 4 would be derived by stereoselective
installation of allyl and amino groups onto aldehyde 5 that could
be prepared by Wittig homologation from 6. The quinolizidine
moiety in 6 would be obtained through diastereoselective
allylation to aminoacetal 7 followed by RCM reaction. Oxazo-
lidinone 8 could be constructed via organocatalytic R-amination
of known aldehyde 9.
Takayama, H. J. Nat. Prod. 2007, 70, 1024–1028
.
(6) Shishido, K.; Irie, O.; Shibuya, M. Tetrahedron Lett. 1992, 33, 4589–
4592
.
(7) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814–4818
.
(8) (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N,; Zhuang, W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790–1793. (b) List, B.
J. Am. Chem. Soc. 2002, 124, 5656–5657. (c) Kumaragurubaran, N.; Juhl,
K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
Our synthesis began with the elaboration of oxazolidinone
8 (Table 1). Required aldehyde 96 for organocatalytic
124, 6254–6255
.
1988
Org. Lett., Vol. 10, No. 10, 2008

Scheme 2
.
Practical Synthesis of Key Intermediate 6
Scheme 3. Synthesis of Homoallylamine 4
hydrogenation of the resulting hydrazine with Raney Ni gave
oxazolidinone 11 efficiently. Upon treatment of 11 with a
catalytic amount of p-TsOH in refluxing MeOH, cyclization
occurred to give aminoacetal 7.10 Treatment of aminoacetal
Ph3PCH2(OMe)Cl and KHMDS in THF, followed by mild
acid hydrolysis to give aldehyde 5 in 62% yield over three
steps. Next, the simultaneous installation of an alkyl chain
and an amine function onto C-5 in 5 was examined. To our
delight, this transformation was stereoselectively accom-
plished by transfer aminoallylation developed by Kobayashi
et al.13 Thus, using 15 derived from (1R)-camphor quinone,
homoallylamine 4 was obtained in high yield and good
selectivity (92%, 94% de). The stereochemistry of the newly
generated chiral center was inferred from the reaction
mechanism shown in Scheme 3 and later confirmed by using
cyclic compound 18 (vide infra).
With cyclization precursor 4 in hand, we next investigated
the construction of an aminal moiety. We had envisioned
that reductive cyclization should lead to desired transforma-
tion, but exposure of amine 4 to several reductants (LiAlH4,
Red-Al, DIBAH, etc.) under various conditions mostly gave
over-reduction product 16. Accordingly, elaboration of 17
via amidine 18 was attempted as follows. Treatment of amine
4 with TiCl4 in refluxing xylene furnished amidine 18,14 the
stereochemistry of which, particularly of the chiral center at
C-5, was assigned by NOE experiment, as shown in Scheme
4. Stereoselective reduction was conducted with NaBH4 in
the presence of AcOH to give aminal 17, which was directly
acylated with acryloyl chloride and Et3N to provide acryl-
amide 19 in 62% yield (two steps). The stereochemistry at
C-9 was confirmed by NOE experiment. This stereoselec-
tivity can be explained by the attack of hydride from the
convex face on 18. Construction of the piperidone ring by
RCM with second-generation Grubbs catalyst and subsequent
11
7 with allyltrimethylsilane in the presence of TiCl4 gave
12 as the sole isomer at C-13, which would be formed by
stereoselective allylation of (axial attack to) the acyliminium
intermediate. At this stage, the stereochemistry of product
12 was determined by NOE experiments and the coupling
constants of the ꢀ-proton on C-14 (ddd, J ) 13.4, 12.2, 5.9
Hz), which indicated an all-syn relationship among the two
protons on C-7 and C-15 and the allyl group on C-13.
Hydrolysis of oxazolidinone in 12 and subsequent acryloy-
lation of the resultant amine gave acrylamide 13 in 56% yield
over six steps as a single diastereomer. The synthesis of
quinolizidinone 6 was accomplished in 99% yield by RCM12
with first-generation Grubbs catalyst, followed by hydroge-
nation of olefin. It is important to note that only two
purification steps were required throughout the conversion
of 8 into 6, which would serve as a key intermediate leading
to various quinolizidine alkaloids.
Having developed a practical and multigram scale route
to the key intermediate, we focused on the further transfor-
mation of 6 into cernuine (1) (Scheme 3). After oxidation
of the hydroxyl group in 6 with IBX in DMSO, the resulting
aldehyde was homologated to 14 by the Wittig reaction with
(9) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794–797. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212–4215. (c)
Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304.
(10) (a) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker,
H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005–4007. (b)
Botman, P. N. M.; Dommerholt, F. J.; Broxterman, Q. B.; Shoemaker, H. E.;
Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2004, 6, 4941–4944.
(11) Ciufolini, M. A.; Hermann, C. W.; Whitmire, K. H.; Byrne, N. E.
J. Am. Chem. Soc. 1989, 111, 3473–3475.
(13) Sugiura, M.; Mori, C.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128,
11038–11039.
(12) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
(b) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75–89.
(14) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186–
4194.
Org. Lett., Vol. 10, No. 10, 2008
1989

Scheme 4
.
Completion of Synthesis of Cernuine (1)
Scheme 5. Completion of Synthesis of Cermizine D (3)
to that of the natural product: synthetic free base, [R]25
D
+80.3 (c 0.06, MeOH), synthetic TFA salt, [R]20D +24.2 (c
0.50, MeOH); natural, [R]25 -33 (c 0.6, MeOH). The
D
absolute configuration of natural cermizine D remains a
question because the counteranion of the natural product has
not been reported so far.
In conclusion, we have achieved the first asymmetric total
syntheses of (-)-cernuine (1) (19 steps, 11.0% overall yield)
and (+)-cermizine D (3) (18 steps, 13.9% overall yield),
starting from known aldehyde 9. The highlights of the
syntheses are (1) organocatalytic R-amination to construct
oxazolidinone, which in turn is utilized for diastereoselective
allylation; (2) synthesis of homoallylamine by asymmetric
transfer aminoallylation; and (3) stereoselective construction
of the aminal ring system. The syntheses of other quinolizi-
dine-type alkaloids will be reported in due course.
hydrogenation completed the total synthesis of cernuine (1)
in good yield. Synthetic 1 was identical to the natural product
in all respects including optical property: synthetic, [R]25
D
-23.2 (c 0.46, MeOH); natural, [R]D -20.5 (c 1.0,
MeOH).2c,4 Therefore, the structure including the absolute
configuration was confirmed.
Next, we turned our attention toward the synthesis of
cermizine D (3) from homoallylamine 4, as shown in Scheme
5. Synthetic intermediate 4 was converted into piperidone
21 by a three-step sequence that included acryloylation,
RCM, and hydrogenation (78% in three steps). Reduction
of bisamide in 21 with LiAlH4 in THF gave target compound
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
1
3 in 60% yield. However, the H NMR data of synthetic 3
were not identical to that of reported data for natural
cermizine D,4 particularly the chemical shifts of protons on
the carbons neighboring the nitrogen atom. On the basis of
those data and its isolation procedure in literature, we
considered that the natural product might be isolated in its
protonated form. Indeed, 1H and 13C NMR data of the TFA
salt of synthetic 3 were in agreement with reported data. On
the other hand, its optical rotation showed an opposite sign
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectral data for
4-13, 18-21, synthetic cernuine (1), and (+)-cermizine D
(3) and its TFA salt. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800574V
1990
Org. Lett., Vol. 10, No. 10, 2008