Total syntheses of lycopodium alkaloids (+)-fawcettimine, (+)-fawcettidine, and (-)-8-deoxyserratinine

Article abstract of DOI:10.1002/anie.201106753

A shared story: Three fawcettimine- and serratinine-type Lycopodium alkaloids are prepared from a common tetracyclic spirodiketone intermediate in concise total syntheses (see scheme). The intermediate was constructed by a remarkable biosynthesis-inspired

Full text of DOI:10.1002/anie.201106753

Angewandte
Chemie
DOI: 10.1002/anie.201106753
Natural Product Synthesis
Total Syntheses of Lycopodium Alkaloids (+)-Fawcettimine,
(+)-Fawcettidine, and (À)-8-Deoxyserratinine**
Houhua Li, Xiaoming Wang, and Xiaoguang Lei*
The Lycopodium alkaloids are a family of structurally
complex natural products,[1] which have provoked long-term
interests in their total syntheses because of their unique and
fascinating architectures and potential biological activities.[2]
In particular, fawcettimine-type Lycopodium alkaloids, such
as fawcettimine (1)[3] and fawcettidine (2)[3,4] (Scheme 1),
have attracted broad attention from the synthetic community
in recent years, and a number of impressive total syntheses
asymmetric total synthesis of (À)-8-deoxyserratinine (3) in
15 steps.[5i,7c]
According to the biogenetic pathway proposed by Inu-
bushi et al., both fawcettimine- and serratinine-type alkaloids
could be derived from lycopodine-type alkaloids through
rearrangement of the carbon-skeleton (Scheme 2).[8] The keto
Scheme 1. Structures of representative fawcettimine- and serratinine-
type Lycopodium alkaloids.
have been accomplished.[5] Serratinine-type Lycopodium
alkaloids, such as 8-deoxyserratinine (3),[6] serratinine (4),
serratine (5), and serratanidine (6), are structurally related to
the fawcettimine-type alkaloids, however, they possess a more
complex molecular architecture with two vicinal quaternary
stereogenic centers and a unique 6,5,6,5-tetracyclic frame-
work. In contrast to fawcettimine-type alkaloids, relatively
little progress and limited success have been made toward the
total synthesis of serratinine-type alkaloids.[7] In 1979, Inu-
bushi and co-workers reported the first total synthesis of (Æ)-
8-deoxyserratinine (3) in 23 steps with 0.29% overall yiel-
d.[7a,b] Very recently, Yang and co-workers achieved the first
Scheme 2. Proposed biogenetic pathway for fawcettimine- and serrati-
nine-type Lycopodium alkaloids.
amine form of fawcettimine (1) can epimerize to 4-epi-
fawcettimine, thus allowing a transannular N alkylation (SN2)
À
to construct the C4 N bond and furnish 8-deoxy-13-dehy-
droserratinine (8). Conceivably, the serratinine-type skeleton
could also be transformed to the fawcettimine-type frame-
[*] H. Li, Prof. Dr. X. Lei
À
work by selective C N bond cleavage. The following selective
National Institute of Biological Sciences, Beijing (NIBS)
Changping District, Beijing, 102206 (China)
E-mail: leixiaoguang@nibs.ac.cn
reduction of 8 would afford 8-deoxyserratinine (3). Despite
growing interest in the total synthesis of Lycopodium
alkaloids, biomimetic interconversions between fawcetti-
mine- and serratinine-type alkaloids have not been exten-
sively explored. Herein, we report a biosynthesis-inspired
strategy to accomplish the concise and collective total
syntheses of (+)-fawcettimine (1), (+)-fawcettidine (2), and
(À)-8-deoxyserratinine (3) from the common molecular
scaffold 8-deoxy-13-dehydroserratinine (8).[9]
Homepage: http://www.nibs.ac.cn/xlei/home.htm
X. Wang, Prof. Dr. X. Lei
School of Pharmaceutical Science and Technology
Tianjin University, Tianjin, 300072 (China)
[**] We thank Prof. David Zhigang Wang (Peking University Shenzhen
Graduate School) and Dr. Shaohui Wang for helpful discussions,
Mingyan Zhao and Rui Liu (NIBS) for NMR and HPLC-MS analysis,
and Dr. Jiang Zhou (Peking University) for HRMS analysis. Financial
support from the National High Technology Projects 863
(2008AA022317), the Program for New Century Excellent Talents in
University (NCET-10-0614), and the NSFC (20802050, 21072150) is
gratefully acknowledged.
According to our retrosynthetic analysis (Scheme 3), key
precursor 8 could be derived from compound 9 through a
biomimetic transannular N alkylation. The challenging qua-
ternary carbon center at C4 in 9 could be assembled by
Matsudaꢀs hydroxy-directed SmI2-mediated pinacol coupling
of aldehyde 10 to set up the correct relative stereochemis-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106753.
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With diketo mesylate 17 and diketo iodide 18 in hand, we
began to investigate the challenging intramolecular C alkyla-
tion to install the spiro-configured quaternary carbon center
at C12 (Scheme 5). Although the C alkylation of 1,3-dicar-
bonyl compounds with RX (R = alkyl; X = halide, tosylate,
Scheme 3. Retrosynthetic analysis. Boc=tert-butoxycarbonyl,
TBDPS=tert-butyldiphenylsilyl.
Scheme 5. Intramolecular C-alkylation reaction to give spirodiketone
11. Reagents and conditions: a) DBU, CH3CN (0.014m), RT.
DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene.
try.[10] The pinacol-coupling precursor 10 could be generated
from diketone 11 through selective reduction. The key spiro-
configured quaternary carbon center at C12 in diketone 11
could be installed by means of intramolecular C alkylation.
We envisioned that intermediate 12 could be efficiently
prepared through a tandem one-pot conjugate addition/aldol
reaction protocol by using readily available starting materials,
including optically active (5R)-5-methylcyclohex-2-enone
13,[11] allylmagnesium bromide 14, and aldehyde 15.
Our synthesis started with the tandem conjugate addition/
aldol reaction sequence (Scheme 4).[12] Enone 13 was treated
with allylcuprate (freshly prepared from allylmagnesium
bromide 14) at À788C, and the resulting enolate was trapped
with aldehyde 15[13] to afford alcohol 12 as a mixture of
diastereoisomers, which underwent desilylation to afford keto
diol 16. Selective mesylation of the primary alcohol following
Burkeꢀs protocol[14] and subsequent oxidation of the secon-
dary alcohol with Dess–Martin periodinane provided diketo
mesylate 17. Iodination of 17 gave another C-alkylation
precursor, diketo iodide 18.
mesylate, etc.) is a powerful method for the synthesis of a-
substituted 1,3-dicarbonyl compounds, previous examples of
intramolecular C alkylations of 1,3-dicarbonyl compounds
with RX to install spiro-configured quaternary carbon centers
for the synthesis of complex natural products are relatively
rare.[15] Through an extensive screening of reaction conditions
(base, solvent, temperature, and concentration), we found
that diketo mesylate 17 gave only O-alkylation product 19
(Scheme 5, entry 1), while the desired C-alkylation product 11
was generated in good yield (65%) by the treatment of diketo
iodide 18 with DBU under dilute conditions in CH3CN
(Scheme 5, entry 2). The quaternary carbon center at C12 was
correctly installed by this remarkable transformation. The
high stereoselectivity of 11 may be attributed to the steric
effect caused by the axial allylic group at C7 (see transition
state 20).[16]
After we established the spiro-configured quaternary
carbon center at C12 and the aza-cyclononane ring, we
attempted to synthesize the pinacol-coupling precursor alde-
hyde 10 (Scheme 6). We anticipated that the carbonyl group
at C4 in diketone 11 would be blocked because of the steric
hindrance of the axial allylic group at C7, thus the carbonyl
group at C13 could be selectively reduced to provide the 13-
hydroxy ketone. Gratifyingly, selective reduction of diketone
11 was realized by using NaBH4 in CH2Cl2/MeOH to afford 21
and 22 in 29% and 63% yield, respectively. The structure of
21 was confirmed by X-ray crystallographic analysis,[17] while
the stereochemistry of 22 was determined by NOE analysis.[18]
Lemieux–Johnson oxidation of 21 afforded 10a in 86% yield.
Compound 22 was also transformed into 10b in quantitative
yield.[19]
Scheme 4. Reagents and conditions: a) 1) 14, CuBr, Me2S, LiCl, THF,
À788C; 2) 15, À788C, 73%; b) Et3N·3HF, MeCN, RT, 94%; c) colli-
dine, MsCl, CH2Cl2, 48C; d) Dess–Martin periodinane, CH2Cl2, RT,
80% (two steps); e) NaI, acetone, RT, 84%. Ms=mesityl, THF=
tetrahydrofuran.
In order to set up the desired oxa-substituted quarternary
carbon center at C4, we initiated studies on the
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stereochemistry could be completely controlled by the
hydroxy group at C13 in starting material 10. Both 10a and
10b were used as coupling substrates in our investigation.
While 10a failed to afford any coupling products under
various conditions (Scheme 7, entry 1), we were pleased to
find that pinacol coupling of 10b occurred smoothly and
provided interesting stereochemical outcome under different
conditions. Specifically, treatment of 10b with SmI2 in THF at
RT afforded two coupling products, 4,5-cis diol 23 and 4,5-
trans diol 24 in 72% and 18% yield of isolated product,
respectively (Scheme 7, entry 2). However, 24 was isolated as
the sole product in 67% yield when the pinacol coupling was
carried out in the presence of HMPA (Scheme 7, entry 3). The
oxa-substituted quaternary stereocenters at C4 in 23 and 24
were confirmed by their subsequent oxidation to known
compound 9[5b] (see Scheme 8). Furthermore, acetylation of
23 and 24 afforded the two diacetate derivatives 25 and 26,
Scheme 6. Reagents and conditions: a) NaBH4, CH2Cl2/MeOH (10/1),
RT, 21, 29%, 22, 63%; b) OsO4, NaIO4, DABCO, dioxane/H2O (2/1),
RT, 10a (86%), 10b (quantitative). DABCO=1,4-diazabicyclo[2.2.2]-
octane.
SmI2-mediated pinacol coupling of 10 (Scheme 7).[20] Based
on Matsudaꢀs studies of hydroxy-directed SmI2-mediated
transformations,[10] we envisioned that formation of the
desired quaternary stereocenter at C4 with well-defined
Scheme 8. Reagents and conditions: a) TPAP, NMO·H2O, 4 ꢀ MS, RT,
for 23, 74%; for 24, 56%; b) TFA, CHCl3, RT, 92%; c) SOCl2/Et3N,
THF, À788C to 08C, 98%. NMO·H2O=N-methylmorpholine-N-oxide
monohydrate, M.S.=molecular sieves, TFA=trifluoroacetic acid,
TPAP=tetrapropylammonium perruthenate.
respectively. The stereochemistry at C5 in 25 and 26 were
determined by NOE experiments, which confirmed the
relative configurations of 23 and 24 as 4,5-cis and 4,5-trans,
respectively.[18] Substrate 29 (trimethylsilyl ether of 10b) was
synthesized for control experiments, and subjected to the
same coupling conditions.[18] The reaction of 29 with SmI2
both in the absence and presence of HMPA resulted in the
reduction of the aldehyde to form alcohol 30 instead of the
desired coupling products (Scheme 7, entry 4).[21]
Our results were consistent with previous reports by
Matsuda.[10] The observed stereochemical outcome could be
explained by two proposed chelation models, in which the
pinacol couplings are likely to proceed via different cyclic
ketyl radicals, depending on the absence or presence of
HMPA. In the absence of HMPA, only the aldehyde moiety
of 10b was reduced to the ketyl radical upon initial reduction
by SmI2. Chelation of the SmIII cation with the d hydroxy
group formed eight-membered ketyl radical 27, which
afforded 4,5-cis diol 23 as the major product. In the presence
of HMPA, a ketyl radical pair was generated through single-
electron transfer from SmI2, because HMPA could increase
the reducing ability of SmI2 by coordination to SmI2.[22] The
Scheme 7. Hydroxy-directed SmI2-mediated intramolecular pinacol cou-
pling. Ac=acetyl, HMPA=hexamethylphosphoramide, TMS=trime-
thylsilyl.
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six-membered ketyl radical 28 was formed by chelation of the
SmIII cation with the b hydroxy group. The pinacol coupling
occurred through the diketyl coupling pathway, in which the
4,5-trans diol 24 was generated as a single product, presum-
ably because of the strong dipole–dipole repulsion between
the two cationic SmIII complexes.
pleased to find that by the treatment of substrate 8 with SmI2
in THF at 08C, with 2.5 equivalents of water as a proton
source, we could obtain (+)-fawcettimine (1) in 51% yield.
The spectroscopic data of the synthetically obtained com-
pounds fully matched the data reported previously.[18]
In conclusion, we have demonstrated the feasibility of
collective total syntheses of both fawcettimine- and serrati-
nine-type Lycopodium alkaloids (+)-fawcettimine, (+)-faw-
cettidine, and (À)-8-deoxyserratinine from a common pre-
cursor based on a highly concise route (all syntheses were
accomplished in 12 steps). Our synthesis features: 1) an
intramolecular C alkylation to install the challenging spiro-
configured quaternary carbon center and the aza-cyclono-
nane ring; 2) a hydroxy-directed SmI2-mediated pinacol
coupling to establish the correct relative stereochemistry of
the oxa-substituted quaternary center; 3) most notably, the
unprecedented tandem transannular N alkylation and
removal of the Boc group to realize a biosynthesis-inspired
process to afford the desired tetracyclic skeleton. Total
syntheses of other related members of fawcettimine- and
serratinine-type Lycopodium alkaloids by using the strategies
highlighted herein are currently underway and will be
reported in due course.
After we installed the desired oxa-substituted quaternary
À
carbon center at C4, we examined the construction of the C4
N bond by using transannular N alkylation (Scheme 8).
Oxidation of triols 23 and 24 by Ley oxidation smoothly
furnished compound 9.[23] In initial attempts, we used a two-
step protocol: removal of the Boc group to give compound 31,
followed by transannular N alkylation.[24] However, further
efforts to use the free amine for the transannular N alkylation
failed, presumably because of intramolecular carbinolamine
formation.[5i]
The desired 8-deoxy-13-dehydroserratinine (8) was
obtained in nearly quantitative yield (98%) by the treatment
of compound 9 with SOCl2 and Et3N in THF. The remarkable
efficiency of this transformation suggests a mechanism
involving the transannular nucleophilic attack of the nitrogen
to afford the ionic acyl ammonium intermediate followed by
the base-triggered removal of the Boc group (Scheme 8).[25]
The key tetracyclic intermediate 8, which is obtained by this
biosynthesis-inspired N-alkylation protocol, was identical to
the previously reported 8-deoxy-13-dehydroserratinine.[5i,7c,26]
With key precursor 8 in hand, we were able to access both
fawcettimine- and serratinine-type Lycopodium alkaloids in a
collective manner (Scheme 9). Selective reduction of the
carbonyl group at C13 with NaBH4 at 08C provided (À)-8-
deoxyserratinine (3) in 98% yield. Furthermore, reductive
Received: September 23, 2011
Published online: November 23, 2011
Keywords: alkaloids · collective synthesis · natural products ·
.
samarium iodide · tandem reactions
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Scheme 9. Reagents and conditions: a) NaBH4, EtOH (dry), 08C,
98%; b) Zn, HOAc, 1408C, 95%; c) SmI2, H2O, THF, 08C, 51%.
À
cleavage of the C4 N bond of 8 occurred under harsh
reducing conditions (Zn/HOAc, 1408C, 8 h), the subsequent
dehydration formed the enamine moiety and furnished
(+)-fawcettidine (2) in excellent yield (95%).[27] Finally, we
À
attempted to selectively cleave the C4 N bond with SmI2
following Hondaꢀs protocol to give fawcettimine (1).[28] The
À
late-stage reductive carbon nitrogen bond cleavage proved
to be challenging because the two carbonyl groups at C5 and
C13 were likely to be reduced as well under these conditions.
After careful optimization of the reaction conditions, we were
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[21] We also used 33, the trimethylsilyl ether of 10a, in the pinacol
coupling reactions to obtain the desired coupling product in
good yield. However, without the stereo-induction of the C13-
hydroxy group, the stereochemistry of the coupling product was
controlled totally by the steric effect of the axial trimethylsilyl
ether group in 33, thus resulting in a completely opposite
stereochemical outcome at C4 and C5. Detailed studies will be
reported in a full paper in due course. During the preparation of
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À
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Angew. Chem. Int. Ed. 2012, 51, 491 –495
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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