Protecting group-free total synthesis of (-)-lannotinidine B

Article abstract of DOI:10.1021/ja305261h

The first total synthesis of (-)-lannotinidine B, a unique tetracyclic constitutent of Lycopodium annotinum, has been accomplished in 10 steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly chemo- and/or stereoselective reductive-amination steps to furnish the desired trans-fused 6/6 bicycle and the aza seven-membered ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful application of a protecting group-free strategy and an optimal redox order.

Full text of DOI:10.1021/ja305261h

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Communication
Protecting Group-free Total Synthesis of (-)-Lannotinidine B
Hui Ming Ge, Lan-De Zhang, Ren Xiang Tan, and Zhu-Jun Yao
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Jul 2012
Downloaded from http://pubs.acs.org on July 16, 2012
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Protecting Group-free Total Synthesis of (-)-Lannotinidine B
Hui Ming Ge,†,‡ Lan-De Zhang,† Ren Xiang Tan,‡ Zhu-Jun Yao†,*
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†State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of Microstructures, Institute of Chemical
Biology and Drug Innovation, School of Chemistry and Chemical Engineering; ‡Institute of Functional Biomolecules, State
Key Laboratory of Pharmaceutical Biotechnology, School of Life sciences, Nanjing University, 22 Hankou Road, Nanjing
210093, China
Supporting Information Placeholder
ABSTRACT: The first total synthesis of (-)-lannotinidine B, a unique tetracyclic constitutent of Lycopodium annotinum, has been
accomplished in ten steps with 23% overall yield. The completed short and efficient synthesis is characterized with three highly
chemo- and/or stereoselective reductive-amination steps to furnish the desired trans-fused 6/6 bicycle and the aza seven-membered
ring system, and a direct intramolecular acyloin condensation to deliver the cyclopentanone moiety, as well as successful applica-
tion of a protecting group-free strategy and an optimal redox order.
The Lycopodium alkaloids are a diverse group of structural-
ly complex compounds with impressive biological activities,1
and they have attracted significant synthetic interests for sev-
eral decades.2 Recently, the isolation and characterization of a
group of closely related polycyclic alkaloids, lannnotinidine
B,3 lycovatine A4 and lacopladine D3 (Figure 1), were reported
by Kobayashi and co-workers. Among these, lannotinidine B
(1) is a unique tetracyclic C16N-type alkaloid, whose structure
consists of an exceptional tetracyclic carbon-nitrogen skeleton
including five stereogenic centers and a rare N-oxide function-
ality. It was found to effectively improve mRNA expression of
neurotrophic growth factor (NGF) in 1321N1 human astrocy-
toma cells. Owing to the intriguing structural features of
fused/spiro multiring system and continuous stereogenic cen-
ters, synthesis of these compounds remains a formidable chal-
lenge. Herein, we report the first asymmetric total synthesis of
(-)-lannotinidine B in a short and efficient route using a pro-
tecting group-free strategy.5,6
signed as a key step-economic (protecting group-free) strategy
in this synthesis. To achieve such a goal, establishment of the
correct chemo- and stereoselectivities to form the trans 6/6
bicyclic core would be a major challenge in the synthesis. We
believed that the C4 ketone of 8 was the most hindered and
insufficiently reactive, and the C9 aldehyde should be a suita-
ble position to accept the first reductive amination and intro-
duce the nitrogen atom. To establish the correct stereochemis-
try of C13-N bond, two possible sequences (formation of C1-
N and C13-N bonds in different orders) were theoretically
compared, indicating that the C13-N cyclization would be
more favorable as the second reductive amination with correct
stereoselectivity. Formation of C1-N bond was thus arranged
as the last one. A terminal olefin was accordingly devised in 8
as the equivalent of the C1 aldehyde, so that we could avoid
insurmountable problem of chemoselectivity. With these con-
siderations, the tri-carbonyl compound 8 was then identified as
the key intermediate for successive reductive aminations in a
well-organized order. The chiral quaternary-carbon of 8 could
be established by two Michael additions to the activated
Figure 1. Three polycyclic C16N-type Lycopodium alkaloids.
As outlined in Figure 2, we envisaged that the
cyclopentanone moiety of lannotinidine B (1) could be assem-
bled from an ester-ketone precursor 11 through an
intramolecular reductive C4-C5 bond formation. To achieve
quick and efficient formation of the tertiary amine functionali-
ty (C1,C9,C13/N) of 11, successive order-controlled reductive
aminations upon a multi-carbonyl intermediate 8 were de-
Figure 2. Retrosynthetic analysis of (-)-lannotinidine B (1).
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enone 6, which could be further synthesized from the easily
be predominantly attacked by the newly introduced secondary
5
6
7
8
available chiral building block 47 by a Morita-Baylis-Hillman
amine at C9 intramolecularly with assistance of the steric hin-
drance between the C5 ester and the C4 ketone.2h Further in-
spection of the transition state models suggested that hydride
approach to 8b might be less hindered from the -face. Such
hypothesis was proven to accord with the facts because the
bicycle 9 was obtained as the sole product (87% yield, >99%
ee by chiral HPLC analysis). The relative stereochemistry of 9
was subsequently confirmed by the NOE experiment and X-
ray analysis of rac-11 (See Supporting Information for the
details).9 Exposure of olefin 9 to K2OsO2(OH)4/NMO fol-
lowed by oxidative cleavage with NaIO4 gave aldehyde 10,
which was perfectly applied to the third reductive amination to
construct the seven-membered ring intramolecularly (Scheme
3).10 Hydrogenolysis of the N-benzyl group of 10 followed by
reductive amination with C1 aldehyde was completed in one
pot in an optimized high temperature (110 °C) and high pres-
sure (3.5 atm), delivering the tricycle 11 in good yield (73%).
reaction.
Scheme 1. Synthesis of enantiopure cyclohexanone precursor 8.a
9
COOMe
10
11
12
13
14
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a
b
c
4
O
OH
O
O
O
O
5
6
7
d
COOMe
OMe
12
OTBS
O
O
O
14
15
8
O
a
Reagents and conditions: a) n-Bu3P, 1,1’-2-naphthol, 14, THF, rt, 96h,
83%; b) Dess-Martin periodinane, NaHCO3, CH2Cl2, 0°C→RT, 2h, 100%;
c) 15, LiClO4, DCM, 0°C→RT; then 2N HCl, THF, 90%; d) acrolein,
DMF, Et3N, rt, 12h, 81%.
Conversion of ester 11 into the corresponding
hydroxylketone 12 usually needs four sluggish redox steps
(reduction of the ester group to primary alcohol, then oxida-
tion to aldehyde, reductive pinacol coupling to form a new C-
C bond, and oxidation of the newly born secondary alcohol to
ketone).2g,2h To achieve a step-economic transformation, we
decided to explore a direct reductive ketyl radical anion cou-
pling11,12 between C4-ketone and C5-ester. After many exper-
imental trials, our attempt was fortunately achieved with lithi-
As depicted in Scheme 1, our synthesis commenced with
chiral enone 4. Treatment of the mixture of enone 4 and alde-
hyde 14 with n-Bu3P and 1,1’-2-naphthol in THF under
Ikegama conditions8 afforded -hydroxyl ketone 5 as an in-
separable mixture of diastereomers in 83% yield. Dess-Martin
oxidation of the newly born hydroxyl group gave 6 in almost
quantitative yield. Subsequent Mukaiyama-Michael addition
of tert-butyl(1-methoxyvinyloxy)dimethylsilane 15 to ,-
unsaturated diketone 6, followed by treatment with 2N HCl,
furnished 7 as an inseparable tautomer mixture of 1,3-diketone
o
um naphthalide in THF for 15 min at -78 C under Gössinger
conditions13 to provide -hydroxyketone 12 (63% yield) and
cyclopentanone 13 (17% yield).14 Further treatment of 12 with
SmI2 smoothly gave 13, whose structure was confirmed by the
X-ray analysis of a single crystal of its HCl salt (See Support-
ing Information for the details). Finally, the bridged tertiary
amine 13 was smoothly transformed to the natural N-oxide 1
(91% yield) upon exposure to mCPBA in dichloromethane at
room temperature. The NMR spectroscopic data of the syn-
thetic lannotinide B (1) well agree with those reported for the
natural product.3 The optical rotation {[]D -54 (c 0.8 MeOH)}
was also consistent with the literature value {[]D -62 (c 1.0
MeOH)},3 thereby providing further confirmation of the abso-
lute configuration.
1
and enone (~3/7 ratio judged by H NMR) in 90% yield. The
all functionality-equipped cyclohexanone 8 with C12 quater-
nary carbon was finally established by the second Michael
addition of 7 to acrolein in the presence of Et3N.
Scheme 2. Chemo- and stereoselective sequential reductive
aminations.a
Scheme 3. Completion of the total synthesis.a
a
Reagents and conditions: a) Lithium naphthalide, THF, -78 °C, 15 min,
12 (63%) + 13 (17%); b) SmI2, THF/t-BuOH, rt, 10 min, 94%; c) mCPBA,
DCM, 0 °C→RT, 1h, 91%. mCPBA = meta-chloroperbenzoic acid.
a
Reagents and conditions: a) Benzylamine, NaBH(OAc)3, AcOH,
ClCH2CH2Cl, -30 °C→RT, 48 hours, 87%; b) K2OsO2(OH)4, NMO, ace-
tone/H2O, 12h; c) NaIO4, THF/H2O, 3h, 87% (2 steps); d) H2 (3.5 atm),
10% Pd/C, MeOH, 110 °C, 5h, 73%. NMO = N-methylmorpholine-N-
oxide.
In summary, we have accomplished the first total synthesis
of (-)-lannotinidine B in ten steps and 23% yield with excel-
lent chemo- and stereoselectivities. The short and efficient
synthesis features a successful protecting group-free strategy
and careful considerations on step- and redox-economy, and
therefore demonstrated the pursuing values of modern organic
synthesis. The strategy and methodologies applied in this syn-
With the tri-carbonyl compound 8 in hand, cascade reduc-
tive aminations were conducted as shown in Scheme 2. As
mentioned above, we hypothesized that the C13 ketone could
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(4) Kubota, T.; Sunaura, T.; Morita, H.; Mikami, Y.; Hoshino, T.;
thesis are also flexible and capable to expand to the synthesis
of other Lycopodium alkaloids.
Obara, Y.; Nakahata, N.; Kobayashi, J. Heterocycles, 2006,
46, 469.
(5) Recent reviews on the protecting group-free syntheses, see: (a)
Emmanuel, R. Angew. Chem. Int. Ed., 2011, 50, 1226; (b)
Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193; (c) Hoff-
mann R. W. Synthesis-Stuttgart, 2006, 3531.
(6) Representative recent syntheses using a protecting group-free
strategy, see: (a) Fañanás, F. J.; Mendoza, A.; Arto, T.;
Temelli, B.; Rodríguez, F. Angew. Chem. Int. Ed. 2012, 51,
4930; (b) Gerfaud, T.; Xie, C. S.; Neuville, L.; Zhu, J. P.
Angew. Chem. Int. Ed. 2011, 50, 3954; (c) Hickmann, V.;
Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2010, 132,
11042; (d) Chen, P.; Cao, L.; Li, C. J. Org. Chem. 2009, 74,
7533; (e) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield,
B. W.; Llamas, T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 17938. (f) Li, X. H.; Yudin A. K. J. Am.
Chem. Soc. 2007, 129, 14152; (g) Baran, P. S.; Maimone, T.
J.; Richter, J. M. Nature 2007, 446, 404; (h) McFadden, R. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738.
(7) Fleming, I.; Maiti, P.; Ramarao, C. Org. Biomol. Chem. 2003,
1, 3989.
(8) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41,
2165.
(9) A sample of rac-11 was obtained from our initial methodolo-
gy study using rac-4 as the starting material.
(10) When repeating the procedures, we found only one silica-gel
column chromatography was needed from 5 to 10 with 62%
isolated yield.
ASSOCIATED CONTENT
Supporting Information Available. Experimental details and
characterizations of new compounds, and NMR spectra of new
compounds (PDF); X-ray single crystal data for rac-11 and (-)-13
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
yaoz@nju.edu.cn
ACKNOWLEDGMENT
We are grateful to MOST (2010CB833200), and Natural Science
Foundation of China (21032002, 81121062 & 81172948) for the
financial support. We also appreciate Prof. S. W. Ng (University
of Malaya, Malaysia) for kind assistance in X-ray data analysis.
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(14) With ~3.0 equiv. of lithium naphthalide in THF at -78°C, the
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