Enantioselective synthesis of amaryllidaceae alkaloids (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine

Article abstract of DOI:10.1002/asia.201300595

Cat. on a hot tin roof: Enantioselective catalytic Michael addition of α-cyanoketones to acrylates under bifunctional organocatalysis was used to construct the unique arylic all-carbon quaternary stereocenter, which is synthetically crucial in the chemical synthesis of optically pure cis-aryl hydroindole alkaloids. The protocol offers an asymmetric route to (+)-vittatine, (+)-epi-vittatine, and (+)-buphanisine. Copyright

Full text of DOI:10.1002/asia.201300595

COMMUNICATION
COMMUNICATION
Cat. on a hot tin roof: Enantioselective
catalytic Michael addition of a-cyano-
ketones to acrylates under bifunctional
organocatalysis was used to construct
the unique arylic all-carbon quaternary
stereocenter, which is synthetically cru-
cial in the chemical synthesis of opti-
cally pure cis-aryl hydroindole alka-
loids. The protocol offers an asymmet-
ric route to (+)-vittatine, (+)-epi-vitta-
tine, and (+)-buphanisine.
Asymmetric Synthesis
Meng-Xue Wei, Cheng-Tao Wang,
Ji-Yuan Du, Hu Qu, Pei-Rong Yin,
Xu Bao, Xiao-Yan Ma, Xian-He Zhao,
Guo-Biao Zhang,
Chun-An Fan*
&&&& — &&&&
Enantioselective Synthesis of Amaryl-
lidaceae Alkaloids (+)-Vittatine,
(+)-epi-Vittatine, and (+)-Buphanisine
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Chun-An Fan et al.
DOI: 10.1002/asia.201300595
Enantioselective Synthesis of Amaryllidaceae Alkaloids (+)-Vittatine,
(+)-epi-Vittatine, and (+)-Buphanisine
Meng-Xue Wei,[a] Cheng-Tao Wang,[a] Ji-Yuan Du,[a] Hu Qu,[a] Pei-Rong Yin,[a] Xu Bao,[a]
Xiao-Yan Ma,[a] Xian-He Zhao,[a] Guo-Biao Zhang,[a] and Chun-An Fan*[a, b]
The naturally occurring alkaloids having a cis-aryl hydro-
indole nucleus are widely distributed in the plants of the
Amaryllidaceae and Aizoaceae families (Figure 1),[1] and
such alkaloids have attracted considerable interest in the
chemistry community due to their intriguing molecular ar-
centers is one of the most challenging and dynamic research
areas in modern organic synthesis.[2] Encompassing the
asymmetric assembly of the quaternary stereocenters in cis-
aryl hydroindole alkaloids, various approaches for the direct
formation of a carbon–carbon bond centered on the sterical-
ly congested chiral quaternary carbon atom have been ex-
tensively developed over the past four decades, as mainly
exemplified by: 1) 3,3-sigmatropic rearrangement;[3] 2) semi-
pinacol rearrangement;[4] 3) a-alkylation of carbonyls or ad-
dition of enolates generated in situ by oxy-Cope rearrange-
ment;[5] 4) Mannich reaction initiated by aza-Cope rear-
rangement.[6] 5) cycloaddition reaction;[7] 6) Michael addi-
tion;[8] 7) epoxide ring opening;[9] 8) intramolecular Heck re-
action;[10]
9) intramolecular
carbene
insertion;[11]
10) intramolecular carbonyl–ene reaction;[12] 11) intramolec-
ular radical cyclization;[13] and 12) intramolecular zirconium-
mediated diene reductive cyclization.[14] Among them, how-
ever, asymmetric access to the vital quaternary centers was
entirely achieved by the diastereoselective induction of the
pre-existing stereocenters in chiral substrates or auxiliaries.
In addition, the diastereoselective and enantioselective de-
symmetrization strategies, which were based on lactonizatio-
n[15a,b] and intramolecular aza-Michael addition,[15c–f,16] have
also been elegantly utilized to indirectly access such quater-
nary stereocenters of cis-aryl hydroindole alkaloids from the
prochiral quaternary carbon atom. Despite the above-men-
tioned substantial progress in the construction of the related
chiral all-carbon quaternary centers, the exploration of alter-
native strategies, especially to create such stereocenters in
a catalytic enantioselective manner, is still of high demand
in the asymmetric synthesis of cis-aryl hydroindole alka-
loids.[3–16]
Figure 1. Selected representative Amaryllidaceae and Aizoaceae alka-
loids.
chitectures and broad range of biological activities.[1] Nota-
bly from a synthetic point of view, the asymmetric creation
of the arylic all-carbon quaternary stereocenter in the above
cis-aryl hydroindole nucleus constitutes one critical element
in the total synthesis of these bioactive alkaloids. The asym-
metric synthesis of chiral all-carbon quaternary stereogenic
To address this topic, three biologically interesting Amar-
yllidaceae alkaloids, (+)-vittatine, (+)-epi-vittatine, and
(+)-buphanisine (Figure 1), were selected as our synthetic
targets for developing a method-oriented strategy. These
structurally related molecules with a bridged polycyclic ring
system were originally found in some Amaryllidaceae plants
such as Hippeastrum vittatum, Nerine bowdenii, Crinum eru-
bescens, and Sternbergia sicula.[1a] It should be noted that
only one route to the asymmetric synthesis of (+)-vittatine
has been disclosed by Chida and co-workers,[3c,e] in which
the stereodefined construction of the key chiral quaternary
carbon center was successfully achieved by a diastereoselec-
tive Claisen rearrangement using chiral allylic alcohol pre-
[a] M.-X. Wei, C.-T. Wang, J.-Y. Du, H. Qu, P.-R. Yin, X. Bao, X.-Y. Ma,
X.-H. Zhao, G.-B. Zhang, Prof. Dr. C.-A. Fan
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University
222 Tianshui Nanlu, Lanzhou 730000 (China)
Fax : (+86)931-8915516
E-mail: fanchunan@lzu.edu.cn
[b] Prof. Dr. C.-A. Fan
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences
Peking University
38 Xueyuan Lu, Beijing 100191 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300595.
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Chun-An Fan et al.
cursor derived from chiral pool d-glucose. However, there
was no report on the asymmetric synthesis of (+)-epi-vitta-
tine[17] and (+)-buphanisine.[18] In connection with our
recent interest in the enantioselective synthesis of polycyclic
alkaloids with cis-hydrodibenzofuran cores,[19] we have pre-
viously demonstrated the synthetic potential of organocata-
lytic Michael addition of a-cyanoketones to acrylates in the
catalytic asymmetric establishment of highly functionalized
chiral all-carbon quaternary stereocenters. As a continuing
exploration of such organocatalysis in the arena of natural
product synthesis,[20] herein we report our results on the
enantioselective synthesis of some cis-aryl hydroindole alka-
loids.
Our retrosynthetic analysis of (+)-vittatine, (+)-epi-vitta-
Scheme 2. The key enantioselective organocatalytic Michael addition.
tine, and (+)-buphanisine (Scheme 1) commenced with the
À
À
disconnection of C6 C6a and C6 N in the hydroisoquino-
Scheme 1. Retrosynthetic analysis.
line ring B, giving a promising cis-aryl hydroindole synthon
I. Logically, the formation of pyrolidine ring D in I could be
envisioned by a diastereoselective intramolecular aza-Mi-
chael addition of enone synthon II, which could be chemi-
cally derived from the aldehyde synthon III through one-
carbon homologation at C11 and the carbonyl transposition
À
from C4a to C3. Subsequently, the scission of the C3 C4
bond in ring C of III could be conceived to deliver the func-
tionalized acyclic synthon 3 having the crucial quaternary
carbon center, which would be accessed by a novel enantio-
selective organocatalytic Michael addition as a key step.
According to the above synthetic considerations
(Scheme 1), the target-oriented model using a-cyanoketone
1 as Michael donor and the acrylate 2a as Michael acceptor
was then built for our synthetic study (Scheme 2), in which
two types of multifunctional organocatalysts (Cat. A and
Cat. B) were selected in the current Michael addition.
Based on our previous investigation on the Michael addition
of a-cyanoketones to acrylates,[19] several Cat. A-type chiral
tertiary amine thioureas 4a–4e (Figure 2),[21] which were de-
rived from the structural combinations of cyclic and acyclic
chiral diamines with nonchiral and chiral N-thiourea sub-
stituents, were firstly evaluated at 208C in the presence of
Figure 2. Evaluation of organocatalysts for the synthesis of 3a by Michael
addition of 1 to 2a. Ts=4-methylbenzenesulfonyl.
PhCl as solvent.[22] In the cases using 4a–4e as catalyst, the
desired Michael adduct 3a was afforded in 63–91% yields,
but with 56–75% ee, showing an appeal for the further im-
provement of enantioselectivity.
Following the above mode of acid–base catalysis, the Cat.
B-type chiral tertiary amine phenols 4g–4v (Figure 2),[23]
3
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Chun-An Fan et al.
Table 1. Effect of Michael acceptors on the enantioselectivity.[a,b]
which were grafted to the chiral 1,2-amino alcohol backbone
bearing a Brønsted acidic w-OH instead of the acidic thiour-
ea moiety in Cat. A, were then investigated. The presence
of the acidic w-OH in Cat. B proved to be pivotal for the re-
activity and stereoselectivity of this Michael addition, and
for example the quinidine-derived ether catalyst 4 f gave
a very low yield and ee (13% yield, 27% ee). Subsequently,
a series of R3 and R4 protecting groups, which included alkyl
(4g–4j), aryl (4k–4l), silyl (4m–4p), aryl-acyl (4q–4t) and
Entry
1
2
3
Yield [%][c]
94
ee [%][d]
alkyl-acyl (4u–4v), were installed on the CACTHNUTRGNEUNG
(sp3)-OH of cu-
(R)-3a[b]
85
preidine (O-demethylquinidine) to probe the potential influ-
ence on the reactivity and enantioselectivity. It is known
that the size and property of groups located on the aliphatic
secondary hydroxy group of Cinchona alkaloids can adjust
the spatial orientation of the appended isoquinoline motif
2
3
3b
3c
94
93
57
49
À
À
by rotation around the C4’ C9 and C9 C8 bonds (Figure 2),
which would consequently impact the stereocontrol in the
cinchona-related chiral catalysis. In comparison with the re-
sults by using the ester-type catalysts 4q–4v (68–76% ee),
generally the ether-type catalysts 4g–4l showed an inferior
asymmetric induction (27–64% ee). However, the silyl
ether-type catalyst 4o,[24] which was derived from the alco-
holic silylation of Cinchona alkaloid cupreidine, could give
an improved stereocontrol (85% ee) in the construction of
quaternary stereogenic center of the key building block 3a.
When other silyl ether-type catalysts bearing less sterically
bulky trimethylsilyl (4m) and triethylsilyl (4n) or more hin-
dered triisopropylsilyl (4p) were used, the enantioselectivity
of the model Michael addition of 1 to 2a was eroded (53–
67% ee), demonstrating the stereoselective influence of the
slight conformation change of the cupreidine skeleton on
this transformation.
4
5
6
3d
90
41
–
3e
trace
73
3 f[e]
74
7
3g[e]
94
60
[a] To an oven-dried 10 mL Schlenk tube were sequentially added 4o
(0.01 mmol), a-cyanoketone 1 (0.05 mmol), PhCl (0.25 mL), and acrylic
(thio)esters 2 (0.10 mmol). The reaction mixture was stirred for 2.5 days
at 208C (unless otherwise noted). [b] The (R) absolute configuration of
3a was determined by X-ray crystallographic analysis,[26] and then the
enantioselectivity for other cases was tentatively assigned by analogy.
[c] Yield of isolated product. [d] Determined by chiral HPLC analysis.
[e] Performed at À208C.
In addition to the optimization of catalysts mentioned
above, we also investigated the effect of Michael acceptors 2
in terms of our target-directed analysis (Scheme 1). As
shown in Table 1, some acrylates and thioacrylates were sub-
jected to the optimized conditions. Compared with 4-iodo-
phenyl acrylate 2a (Table 1, entry 1), either the bulky aryl
acrylates (2b,c) or the acrylate with additional hydrogen-
bonding site (2d) gave an obviously reduced induction (41–
57% ee; Table 1, entries 2–4). But surprisingly, the alkyl ac-
rylate 2e (Table 1, entry 5) was ineffective in current condi-
tions, probably due to the lower electrophilicity of the acry-
late double bond caused by the electron-donating nature of
access to the crucial chiral all-carbon quaternary stereocen-
ters in the designed asymmetric synthesis of cis-aryl hydroin-
dole alkaloids. Due to the importance of the requisite ste-
reochemistry depicted in our retrosynthetic analysis
(Scheme 1), the absolute configuration of crystal (R)-3a (>
99% ee), which was further obtained by a gradual recrystal-
lization of the resulting mother liquor (99% ee) from
a mixed solvent of CHCl3 and n-hexane, was unambiguously
determined by the X-ray crystallographic analysis
(Scheme 3).[26]
Accordingly, a bifunctional activation mode TS-1 for the
organocatalytic Michael addition of 1 to 2a was also pro-
posed for the observed stereocontrol under the catalysis of
4o, in which the preferential Si face attack of the energeti-
cally favorable (E)-enolate was involved.
the CACHTUNGTRENNUNG
(sp3)-hybridized alkyl substituent in the acceptor. Be-
sides, two more electrophilically reactive thioacrylates 2 f
and 2g were examined at À208C (Table 1, entries 6–7), and
unexpectedly the Michael addition did not exhibit the posi-
tive improvement of the enantioselectivity (60–74% ee).
In order to further enhance the enantiopurity of the cor-
responding Michael adduct (R)-3a (85% ee; Table 1,
entry 1), chiral enrichment by crystallization was employed.
Gratifyingly, the enantiomeric purity of the mother liquor
was readily enriched through an interesting heterochiral
crystallization[25] to deliver (R)-3a in 99% ee and 78% yield
after separation of the racemate crystals by filtration, pro-
viding an alternative opportunity for highly enantioselective
Based on the asymmetric establishment of the functional-
ized acyclic synthon (R)-3a (99% ee) having the crucial
chiral quaternary stereogenic center (Scheme 4), an intra-
molecular ketone–ester condensation and subsequent regio-
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Chun-An Fan et al.
ketal, the aldehyde 7 (99% ee)
was obtained by a subsequent
diisobutylaluminum hydride re-
duction of the cyano group in
80% yield over two steps. With
the aldehyde 7 in hand, one-
carbon
homologation
by
a Henry reaction was conduct-
ed, and the desired nitroolefin 8
(99% ee) was smoothly formed
through successive elimination
of the derived mesylate in 85%
overall yield. After a sequential
reduction of the conjugated ni-
Scheme 3. Stereochemical assignment of (R)-3a and proposed enantioselectivity mode. TBS=tert-butyldime-
thylsilyl.
troalkene 8 using NaBH4 and zinc powder, the primary
amine 9 was afforded in 91% overall yield. The removal of
ketal protection in 9 under acidic conditions resulted in the
in situ formation of enone intermediate, which rapidly un-
derwent a stereospecific intramolecular aza-Michael addi-
tion in one pot, followed by N-carbamation with di-tert-
butyl dicarbonate, to give the expected D ring containing
hydroindolone 10 (99% ee) in 77% yield over two steps.
Subsequently, a Saegusa–Ito oxidation protocol consisting of
the enol silylation and palladium-mediated oxidative dehy-
drogenation was adopted for the regioselective introduction
of the enone functionality, furnishing the desired functional-
ized hydroindolenone synthon 11 (99% ee) in 86% overall
yield.
After the stereocontrolled assembly of cis-aryl hydroin-
dole skeleton with rings C and D, the further elaboration di-
rected to the construction of ring B was then carried out.
Upon treatment of the synthon 11 with lithium tri-sec-butyl-
borohydride (l-selectride), as shown in Scheme 5, 1,2-reduc-
tion of the enone motif delivered two chromatographically
separable diastereoisomers 12-b (less polar) and 12-a (more
polar) in 40% yield and 58% yield, respectively, in which
the relative stereochemistry was confirmed by comparison
with the literature.[27] Accompanied by the acidic deprotec-
tion of the N-Boc group in 12-b and 12-a, the methylene
unit in ring B was readily installed via a Pictet–Spengler re-
action, leading to the completion of (+)-vittatine and
(+)-epi-vittatine in 92% yield and 88% yield, respectively.
As a continuing pursuit in the enantioselective synthesis of
cis-aryl hydroindole alkaloids, the stereoselective conversion
of the common building block 11 to the allyl methyl ether
13-b was achieved in 63% overall yield through a stepwise
protocol including the l-selectride reduction of the enone
moiety, the mesylation of an unpurified mixture of resulting
allylic alcohols, and the regio- and diastereoselective SN1-
like methanolysis of allylic mesylates.[28] Following the re-
moval of the N-Boc protecting group of 13-b under acidic
conditions, the incorporation of hydroisoquinoline ring B
was analogously accomplished by the Pictet–Spengler proto-
col, delivering the expected (+)-buphanisine in 73% overall
yield.
Scheme 4. Enantioselective synthesis of aryl hydroindole synthon 11.
a) tBuONa (2.5 equiv), tBuOH/THF (1:1), À208C; b) p-TsOH·H2O
(cat.), toluene/MeOH (10:1), 08C to rt; c) NaBH4, CeCl3, MeOH/THF
(3:1), À208C; d) MeSO3H, toluene, 08C; e) HO
ACHTUGNTRENUN(NG CH2)2OH, p-TsOH·Py
(cat.), benzene, reflux; f) iBu2AlH, CH2Cl2, À788C; g) MeNO2, NEt3, rt;
and then MsCl, NEt3, CH2Cl2, 08C to rt; h) NaBH4, EtOH, 08C to rt;
i) Zn (powder), aq. NH4Cl (sat.), EtOH, 508C; j) 2m HCl, THF, reflux;
k) Boc2O, NEt3, CH2Cl2, 08C to rt; l) TMSOTf, NEt3, CH2Cl2, À788C to
À408C; and then Pd
ACHTUNGTRENNUNG(OAc)2, MeCN, 08C to rt. Boc=tert-butoxycarbonyl,
Ms=methanesulfonyl, Py=pyridine, THF=tetrahydrofuran, Tf=tri-
fluoromethanesulfonyl, TMS=trimethylsilyl, p-TsOH=p-toluenesulfonic
acid.
selective etherification were used to construct the all-carbon
six-membered ring C, leading to the cyclic vinylogous ester
5 via 1,3-diketone intermediate 5-1 in 75% yield over two
steps. Then, the carbonyl transposition protocol involving
the Luche reduction of enone moiety of 5 and subsequent
acidic hydrolysis of enol ether group afforded the desired g-
quaternary cyclohexenone 6 (99% ee) in 90% overall yield.
Following the protection of enone carbonyl with cyclic
In conclusion, towards the catalytic asymmetric construc-
tion of the unique arylic all-carbon quaternary stereocenter,
5
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Keywords: alkaloids
· asymmetric synthesis · Michael
addition · organocatalysis · quaternary carbon
[1] a) Dictionary of Alkaloids, 2nd ed. (Eds.: J. Buckingham, K. H. Bag-
galey, A. D. Roberts, L. F. Szabꢁ), CRC Press, 2010; for selected re-
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[3] For examples using a diastereoselective 3,3-sigmatropic rearrange-
ment in the synthesis of (À)-mesembrine, (+)-mesembrine, (+)-vit-
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Bohno, K. Sugie, H. Imase, Y. B. Yusof, T. Oishi, N. Chida, Tetrahe-
dron 2007, 63, 6977; f) E. A. Ilardi, M. J. Isaacman, Y.-c. Qin, S. A.
Shelly, A. Zakarian, Tetrahedron 2009, 65, 3261; g) A. D. Findlay,
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[4] For examples using a diastereoselective semipinacol rearrangement
of chiral epoxides formed in situ in the synthesis of (À)-mesembrine,
see: a) H. Nemoto, T. Tanabe, K. Fukumoto, Tetrahedron Lett. 1994,
35, 6499; b) H. Nemoto, T. Tanabe, K. Fukumoto, J. Org. Chem.
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the synthesis of (À)-mesembrine, (+)-mesembrine, as well as the
chiral hydroindolone synthon, see: a) S. Takano, Y. Imamura, K.
Ogasawara, Tetrahedron Lett. 1981, 22, 4479; b) A. I. Meyers, R.
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riault, J. Org. Chem. 2007, 72, 9314.
Scheme 5. Asymmetric synthesis of (+)-vittatine, (+)-epi-vittatine, and
(CH2)2Cl,
08C to rt; and then 37% HCHO (aq.), 6m HCl, MeOH; c) NEt3, Ms2O,
THF; and then MeOH, 08C to rt. l-selectride=lithium tri-sec-butylboro-
hydride.
(+)-buphanisine. a) l-selectride, THF, À788C; b) CF3CO2H, Cl
ACHTUNGTRENNUNG
which synthetically crucial in the chemical synthesis of opti-
cally pure cis-aryl hydroindole alkaloids, an alternative strat-
egy featuring a key enantioselective organocatalytic Michael
addition of a-cyanoketones to acrylates was revealed. Im-
portantly, the catalytic efficiency of the axially chiral tertiary
amine-phenol 4o as a novel cupreidine-derived bifunctional
organocatalyst was unprecedentedly explored in our target-
oriented Michael addition, providing an opportunity to or-
ganocatalytically access the chiral quaternary carbon center
in high yield and good enantioselectivity. Based on the pre-
liminary investigation of such key conjugate addition and
combined with the further enantioenrichment by unusual
heterochiral crystallization, the enantioselective synthesis of
(+)-vittatine was presented, and also the first asymmetric
syntheses of (+)-epi-vittatine and (+)-buphanisine were di-
vergently achieved. Our current study not only enriches the
synthetic chemistry of cis-aryl hydroindole alkaloids, but
also extends the synthetic potential of organocatalytic Mi-
chael addition of a-cyanoketones to acrylates in the asym-
metric synthesis of natural products.[20]
Acknowledgements
We are grateful for financial support from the 973 Program of MOST
(2010CB833200), NSFC (21290180 and 21072082), the Fok Ying Tung
Education Foundation (121015), NCET (NCET-08-0254), the Major
New-Drug-Development Project of MOST (2012ZX09201101-003),
PCSIRT (IRT1138), FRFCU (lzujbky-2012-k39 and lzujbky-2013-ct02),
and the 111 Project of MOE (111-2-17).
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www.chemasianj.org
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Received: April 28, 2013
Published online: && &&, 0000
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These are not the final page numbers! ÞÞ