An Asymmetric Pathway to Dendrobine by a Transition-Metal-Catalyzed Cascade Process

Article abstract of DOI:10.1002/anie.201705713

An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one-pot, sequential palladium-catalyzed enyne cycloisomerization and rhodium-catalyzed diene-assisted pyrrolidine formation by allylic CH activation. The developed transition-metal-catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late-stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.

Full text of DOI:10.1002/anie.201705713

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Communications
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International Edition: DOI: 10.1002/anie.201705713
German Edition: DOI: 10.1002/ange.201705713
Natural Product Synthesis
An Asymmetric Pathway to Dendrobine by a Transition-Metal-
Catalyzed Cascade Process
Yujin Lee, Elise M. Rochette, Junyong Kim, and David Y.-K. Chen*
Abstract: An asymmetric pathway to the caged tetracyclic
pyrrolidine alkaloid, dendrobine, is reported. The successful
synthetic strategy features a one-pot, sequential palladium-
catalyzed enyne cycloisomerization and rhodium-catalyzed
diene-assisted pyrrolidine formation by allylic CH activation.
The developed transition-metal-catalyzed cascade process
permits rapid access to the dendrobine core structure and
circumvents the handling of labile intermediates. An intra-
molecular aldol condensation under carefully defined reaction
conditions takes place with a concomitant detosylation,
followed by reductive amine methylation, to afford a late-
stage intermediate (previously identified by several prior
dendrobine syntheses) in only 10 synthetic steps overall.
Synthetic organic chemistry has made significant strides in
terms of reducing the high step-count traditionally associated
with the total synthesis of complex architectures.[1] Synthetic
strategies that embrace redox[2] and protecting group[3]
economy are particularly attractive, together with complex-
ity-generating transformations in the context of cascade and
domino reactions.[4] In connection with the latter, there is
a growing interest in concurrent introduction of several non-
interfering reagents, either simultaneously or sequentially, to
a single reaction vessel.[5] In doing so, workup and purification
are significantly reduced, and the isolation of potentially
hazardous and/or labile intermediates is circumvented. How-
ever, realization of such one-pot operations are non-trivial,
and require in depth understanding of the individual reagents,
the anticipated byproduct(s) derived from each reagent, and
substrate/product compatibility with each reagent and its
byproduct(s). Furthermore, implementation of catalytic
transformations poses an even greater challenge, primarily
because of concerns over catalyst inhibition and turnover
efficiency. In spite of these challenges, several reports of
multimetal and multiligand catalytic transformations have
appeared recently,[6] most notably the contributions from the
Lautens laboratory.[7]
Scheme 1. a) Previously reported cascade enyne cycloisomerization/
intramolecular Diels–Alder reaction. b) Diene-assisted CH activation in
the synthesis of substituted pyrrolidines. c) Proposed dienyne cascade
reaction to access the core structure of dendrobine (1). Key: isopropyl
(iPr), tert-butyldimethylsilyl (TBS), cyclooctene (COE), para-toluene-
sulfonyl (Ts).
several transition-metal-mediated, conjugated diene-specific
transformations have been reported,[9] and more recently the
Yu laboratory demonstrated a serendipitous conjugated
diene-assisted CH-activation process in the synthesis of
substituted pyrrolidines together with its asymmetric variant
(Scheme 1b).[10] All facts considered, and mindful of the
structural framework of the anticipated cascade reaction
product, the polycyclic alkaloid dendrobine (1)[11] was
selected to showcase the newly developed synthetic technol-
ogy and as a significant advance in comparison with the prior
art (Scheme 1c).[12] Furthermore, realization of the proposed
synthetic strategy also represents a conceptually unique
approach that exploits an entirely acyclic starting material—
in stark contrast to the cyclic building blocks employed in all
past dendrobine syntheses.
As outlined in Scheme 2, our synthetic investigation
began with the preparation of the proposed cycloisomeriza-
tion precursor 8. Trans-1,4-dibromo-2-butene (2) was treated
with alkynyl Grignard reagent 3 in the presence of a catalytic
amount of CuBr·SMe2 (5 mol%) to afford the SN2’ product 4
exclusively. Subjecting homoallylic bromide 4 to a variety of
protected and unprotected aliphatic amines and ammonia
largely resulted in elimination; therefore, an azide displace-
ment (NaN3, 84% overall yield from 2) followed by reduction
(LiAlH4) was implemented to furnish amine 6. Reductive
amination between amine 6 and enal 7 (NaBH4), followed by
We have previously demonstrated an enyne cyclo-
isomerization/Diels–Alder cascade process to assemble the
core structure of the echinopines (Scheme 1a).[8] In connec-
tion with this study, we pondered whether an enyne cyclo-
isomerization product could further participate in other
conjugated diene-specific transformations. Specifically,
[*] Y. Lee, E. M. Rochette, J. Kim, Prof. Dr. D. Y.-K. Chen
Department of Chemistry, Seoul National University
Gwanak-1 Gwanak-ro, Gwanak-gu, Seoul 151-742 (South Korea)
E-mail: davidchen@snu.ac.kr
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.201705713.
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Scheme 2. Synthesis of dendrobine (1) via Kende Intermediate 13. Reagents and Conditions: a) 3 (1.5 equiv), CuBr·SMe2 (5.0 mol%), CH2Cl2,
À788C, 1 h; b) NaN3 (1.1 equiv), DMF, 238C, 16 h, 84% for two steps; c) LiAlH4 (1.5 equiv), Et2O, À78 to 238C, 2 h; d) 7 (1.0 equiv), MgSO4
(1.0 wt. equiv), Et2O, 238C, 2 h; then NaBH4 (0.8 equiv), MeOH, 238C, 1 h; e) Et3N (0.8 equiv), DMAP (0.17 equiv), TsCl (0.8 equiv), CH2Cl2,
238C, 16 h; followed by K2CO3 (1.7 equiv), MeOH, 238C, 16 h, 40% overall yield from 5; f) see Table 1; g) BH3·THF (10 equiv), THF, 08C, 2 h;
followed by NaOH (10% aq.)/H2O2 (35% aq.) (1:1), THF, 0 to 508C, 1 h, 87%; h) (COCl)2 (10 equiv), DMSO (20 equiv), CH2Cl2, À788C, 1 h;
followed by Et3N (30 equiv), À78 to 238C, 1 h, 86%; i) LiOH (0.1 equiv), iPrOH, 238C, 24 h, 80%; j) HCHO (37% aq., 20 equiv), NaCNBH3
(10 equiv), AcOH (3.0 equiv), MeOH, À78 to 238C, 5 h, 53%. Key: acetic acid (AcOH), N,N’-(dimethylamino)pyridine (DMAP), N,N’-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), isopropanol (iPrOH), para-toluenesulfonyl chloride (TsCl), trimethylsilyl (TMS).
Table 1: Transition-metal-mediated cycloisomerization of dienyne 8 and diene-assisted CH activation of
triene 9.
a one-pot tosylation (TsCl, Et3N,
DMAP) and desilylation (K2CO3,
MeOH) provided the targeted
dienyne 8 in 40% overall yield
from azide 5. In this manner,
every reaction along the estab-
lished pathway employed inexpen-
sive and easily handled reagents,
and required only two trivial chro-
matographic purifications (5 and 8)
over the entire synthetic sequence.
With dienyne 8 in hand, the
Entry
Substrate
Conditions
Yield [%][c]
1
2
3
4
5
6
7
8
8
8
8
8
8
8
8
8
8
9
9
9
9
8
Pd(OAc)2, benzene, 808C, 2 h
Pd(OAc)2, PPh3, benzene or DCE, 808C, 2 h
Pd(OAc)2, L1, benzene, 808C, 2 h
9+9a (35%), (9:9a 3:5)
9 (76% or 69%)
9+9a (24%), (9:9a 10:1)
9 (60%)
9+9a (41%), (9:9a 1:8)
9+9a (67%), (9:9a 10:1)
8 (72%)
stage was set to investigate the
proposed transition-metal-medi-
ated cascade process. To obtain
a clear picture of the individual
processes, cycloisomerization of
dienyne 8 was first examined.[13] In
this context, while the desired reac-
tion pathway involving the terminal
alkene and alkyne in 8 was antici-
pated based on both kinetic and
thermodynamic grounds, we were
conscious of potential side reac-
tions that might engage the pend-
ant trans-disubstituted alkene prior
to the desired cycloisomerization
event. Pleasingly, enyne cycloiso-
merization product 9 was obtained
from a variety of palladium cata-
lytic systems (Table 1). However,
certain conditions afforded varying
amounts of the enyne-cycloisome-
rization product 9a as a conse-
quence of alkyne moiety participa-
tion in an endo- rather than the
Pd(OAc)2(PPh3)2, benzene, 808C, 2 h
Pd2(dba)3, AcOH, benzene, RT, 12 h
Pd2(dba)3, P(o-tolyl)3, AcOH, benzene, RT, 12 h
Pd2(dba)3, P(o-tolyl)3, benzene, RT, 12 h
[Rh(COD)Cl2]2, AgSbF6, PPh3, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
[Rh(COD)Cl2]2, AgSbF6, PPh3, DCE, 808C, 3 h
RhCl(PPh3)3, AgOTf, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
Pd(OAc)2, PPh3, DCE, 808C, 2 h;
8 (50%)
8 (40%)
10 (43%)
10 (35%)
10 (67%)
10 (15%)
10 (60%)
9[a]
10[b]
11[b]
12[a]
13[b]
14[a]
then RhCl(PPh3)3, AgSbF6, DCE, 808C, 2 h
Pd(OAc)2, PPh3, DCE,
RhCl(PPh3)3, AgSbF6, DCE, 808C, 2 h
15[a]
8
9 (70%)
[a] Rhodium catalyst prepared by initially stirring at 808C for 1 h; [b] rhodium catalyst prepared by
initially stirring at 238C for 1 h; [c] chromatographically isolated yield and product ratio determined by
1H NMR analysis of the crude reaction mixture. Key: acetic acid (AcOH), acetate (OAc), 1,5-cyclo-
octadiene (COD), dibenzylideneacetone (dba), 1,2-dichloroethane (DCE), ortho-methylphenyl (o-tolyl).
desired
exo-mode
(Table 1,
Entries 1–6).[14] Trost had previ-
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ously suggested the Pd(OAc)2 catalytic system operates by a
different mechanistic pathway compared to the Pd0/HX
system (for example, X = acetate (OAc)); the latter process
is believed to involve the initial generation of a H-Pd-X
species followed by its hydropalladation of the terminal
alkyne.[14d] Trost and coworkers further demonstrated that the
cycloisomerization reaction under the Pd0/HX catalytic
system could be carried out in the presence or absence of
a phosphine ligand (P(o-tolyl)3) to yield an identical pro-
duct.[14d] However, in our studies the Pd0/acetic acid (AcOH)
system afforded the endo-enyne cycloisomerization product
9a preferentially in the absence of phosphine ligand (Table 1,
Entry 5), and more surprisingly, the exo-selectivity could be
restored by introduction of P(o-tolyl)3 (Table 1, Entry 6). We
speculate that the presence of phosphine ligand had a pro-
nounced effect on the electronic nature of the palladium
center and its coordinative ability with the proximal tosyla-
mide nitrogen, as depicted by the post-hydropalladation
transition states A and B leading to the corresponding
cycloisomerization products 9 and 9a, respectively. No
productive cycloisomerization was observed under the Pd0
system in the absence of AcOH (Table 1, Entry 7). During the
course of reaction optimization, we routinely observed that
the isolated yield of 9 was highly dependent on the storage
duration of the neat crude reaction mixture. Further inspec-
Scheme 3. a) Palladium-catalyzed cycloisomerization of dienyne 8a
and rhodium-catalyzed formation of pyrrolidine 10a; b) cycloisomer-
ization of dienynes 14 and 15, and attempted pyrrolidine formation;
c) transformations projected for diene 10 and selected oxidative trans-
formations (details in the Supporting Information). Key: meta-chloro-
perbenzoic acid (mCPBA), N-methylmorpholine N-oxide (NMO).
1
tion by thin layer chromatography and H NMR profiling of
the crude reaction mixture was revealing. The lability of
cycloisomerization product 9 was ultimately confirmed when
insoluble polymeric materials were isolated from purified 9
that had been stored neat; this phenomenon was more
pronounced for cycloisomerization product 9b (Scheme 3a;
Supporting Information). These counterproductive events
strengthened the impetus of our investigation and highlighted
the value of the synthetic technology described herein (see
proceeding text).
sequential introduction of the preformed catalyst blends, to
generate bicyclic diene 10 directly from dienyne 8 (Table 1,
Entry 14). The catalyst systems developed for the individual
processes could be applied directly without modifications,
while maintaining the low catalyst loading without increasing
the reaction time. Furthermore, the stability issue associated
with the cycloisomerization products 9 (and 9b) was com-
pletely avoided, and on a practical scale the one-pot method
afforded a slightly higher yield compared to the combined
individual processes. Interestingly, simultaneous introduction
of palladium and rhodium reagent blends to a solution of
dienyne 8 only afforded the cycloisomerization product 9
(Table 1, Entry 15), and introduction of additional rhodium
catalyst only marginally promoted the formation of
pyrrolidine 10.
Recognizing bicyclic pyrrolidine 10 harbors 15 of the 16
carbon atoms required for dendrobine (1), we pondered
whether a slightly revised substrate could provide the entire
carbon backbone of the target molecule. In this context,
dienynoate 14 was envisaged as a suitable candidate. While
the cycloisomerization of 14 proceeded smoothly, we were not
able to execute the subsequent allylic CH-functionalization
reaction (Scheme 3b). Although TMS–dienyne 15 was con-
sidered a more electronically compatible substrate, it shared
a similar fate as dienynoate 14. The precise reason(s) for these
observations are yet to be uncovered; however, preliminary
computational studies suggest dienoate 18 may suffer from
inefficient catalyst turnover, whereas the vinylsilane in 17
may be prohibitive to the post-CH-activation rhodium
With cycloisomerization product 9 secured (with care), its
participation in the proposed conjugated diene-assisted
CH-activation process was examined (Table 1, Entries 10–
13). In this instance, while the originally developed procedure
reported by Yu and Li was effective,[10a] we found the best
result was obtained with a preheated and aged catalyst
mixture containing RhCl(PPh3)3 and AgSbF6, followed by
introduction to a solution of freshly prepared triene 9. This
remarkable transformation required little fine-tuning com-
pared to the originally reported method, and generated highly
functionalized diene 10 (and 10a; Scheme 3a) reproducibly.
Bicyclic pyrrolidine 10 (and 10a) was obtained as a single
stereoisomer, and demonstrated excellent stability upon
storage in solution and neat, at low or ambient temperatures.
The success of the palladium-catalyzed cycloisomerization
and rhodium-catalyzed allylic CH functionalization as indi-
vidual processes was a prerequisite for the proposed tandem
process. We had already established that, under the palla-
dium-catalyzed cycloisomerization conditions, diene 10 was
not observed, and control experiments indicated that the
rhodium catalyst system developed for the allylic
CH-activation process was ineffective on dienyne 8 (Table 1,
Entries 8 and 9). Gratifyingly, merging the palladium and
rhodium catalyst systems as a one-pot process was realized by
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insertion. Furthermore, we also speculate that the initial
rhodium catalyst complexation may be disfavored in CO2Me
and TMS bearing dienes 16 and 17, respectively, compared to
the sterically less-demanding diene in 9 (and 9b).[15]
While the structural resemblance between bicyclic pyrro-
lidine 10 and dendrobine (1) was encouraging, we envisaged
the two olefins within 10 had to be differentiated for the
ensuing transformations (Scheme 3c).[16] In this regard, we
discovered under carefully controlled conditions that diene 10
could be epoxidized by meta-chloroperbenzoic acid or
dihydroxylated (OsO4, N-methylmorpholine N-oxide) selec-
tively at its 1,1-disubstituted olefin. However, upon contem-
plating the limited reaction scope and the number of synthetic
steps forecasted to reach dendrobine (1), epoxide 20 and
ketone 21 soon became less appealing. Continued redox
investigations eventually revealed diene 10 could undergo
a highly regio- and stereoselective hydroboration at both of its
olefins (BH3·SMe2) to afford the corresponding diol after
oxidative workup (H2O2, NaOH, 87% yield), and could be
further oxidized under Swern conditions (86% yield) to
furnish ketoaldehyde 11 (Scheme 2). We were excited by the
prospect of ketoaldehyde 11 participation in an intramolec-
ular aldol condensation reaction; thereby delivering an enone
structure closely resembling the Kende intermediate (13,
Scheme 2) intercepted by several of the past dendrobine
syntheses.[12c,h,n] However, we soon encountered uncertainty
and failure with a variety of conventional and unconventional
aldol condensation conditions.[17] Gratifyingly, continued
efforts ultimately uncovered LiOH/iPrOH as an uniquely
effective reagent system for the desired transformation,[18]
together with an unexpected but fortuitous detosylation by
b-elimination to afford enone 12 in a pleasing 80% yield. This
latter observation was particularly noteworthy because it
removed the need for the strong reducing conditions usually
associated with detosylation, and the so-obtained imine 12
was converted to the known Kende intermediate (13) under
reductive amination conditions (NaCNBH3, AcOH,
CH2Oaq)[19] (Scheme 2). Overall, the developed synthetic
sequence—comprising designed and serendipitously discov-
ered reactions—constituted one of the most efficient entries
to dendrobine (1) to date. Finally, this expedient synthesis was
streamlined through a related SN2’ reaction between allylic
bromide 22[20] and Grignard reagent 3 (Scheme 4), and
became asymmetric under the allylic alkylation condition
developed by Feringa and coworkers (TaniaPhos)[21] to afford
optically active bromide 4 and azide 5 (94:6 e.r.).[22]
Scheme 4. Alternative synthesis of dienyne 8 and synthesis of optically
active bromide 4 and azide 5 (details in the Supporting Information).
new tandem catalytic transformations, which are currently
under investigation in our laboratory.
Acknowledgements
This work was supported by Seoul National University
Foreign Faculty Fund, New Faculty Resettlement Fund,
National Research Foundation of Korea (NRF) grant
funded by the Korean government (MSIP; no.
2012R1A2A2A01002895, 2013R1A1A2057837, and 2014-
011165, Center for New Directions in Organic Synthesis),
and Novartis. E.M.R. and Y.L. were supported by the
BK21Plus Program, Ministry of Education. We thank Pro-
fessor Zhixiang Yu (Peking University) for preliminary
computational studies of palladium-catalyzed cycloisomeri-
zation and rhodium-catalyzed pyrrolidine formation, and
Hyunchang Park, Jurim Jang, and Jason Witek for preliminary
synthetic studies.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkaloids · cascade reactions ·
homogeneous catalysis · total synthesis · transition metals
In conclusion, an expedient transition-metal-catalyzed
synthetic pathway to dendrobine (1) was realized. Salient
features of the developed synthesis include a copper-cata-
lyzed asymmetric allylic alkylation, a palladium-catalyzed
enyne cycloisomerization, a rhodium-catalyzed diene-assisted
pyrrolidine formation by allylic CH activation, and a late-
stage intramolecular aldol condensation with concomitant
detosylation. Notably, the palladium and rhodium reagent
systems could be introduced sequentially to a single reaction
vessel, and in doing so reduced compound handling and
obviated the isolation of the sensitive triene intermediate 9
(and 9a). The mutual compatibility of the reagent systems
discussed herein opens up opportunities for the discovery of
[1] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40.
[2] T. Newhouse, P. S. Baran, R. W. Hoffmann, Chem. Soc. Rev.
2009, 38, 3010.
[3] I. S. Young, P. S. Baran, Nature 2009, 457, 193.
[4] For reviews of cascade reactions in total synthesis, see: a) K. C.
Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun. 2003,
551; b) L. F. Tietze, G. Brasche, K. M. Gericke, Domino
Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 2006,
p. 617; c) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew.
Chem. Int. Ed. 2006, 45, 7134; Angew. Chem. 2006, 118, 7292;
d) K. C. Nicolaou, J. S. Chen, Chem. Soc. Rev. 2009, 38, 2993;
e) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167.
4
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[5] a) C. Vaxelaire, P. Winter, M. Christmann, Angew. Chem. Int.
Mori, M. Shibasaki, K. Okamura, T. Date, J. Org. Chem. 1994,
59, 5633.
Ed. 2011, 50, 3605; Angew. Chem. 2011, 123, 3685; b) Y. Hayashi,
Chem. Sci. 2016, 7, 866.
[13] For a review on transition-metal-catalyzed cycloisomerization of
1,n-enynes, see: V. Michelet, P. Y. Toullec, J.-P. Genet, Angew.
Chem. Int. Ed. 2008, 47, 4268; Angew. Chem. 2008, 120, 4338.
[14] For pioneering examples and selected reaction conditions for
palladium-catalyzed enyne cycloisomerizations used herein, see:
a) B. M. Trost, G. J. Tanoury, M. Lautens, C. Chan, D. T.
MacPherson, J. Am. Chem. Soc. 1994, 116, 4255; b) B. Møller,
K. Undheim, Tetrahedron 1998, 54, 5789; c) S. E. Gibson, P. R.
Haycock, A. Miyazaki, Tetrahedron 2009, 65, 7498; d) B. M.
Trost, D. C. Lee, F. Rise, Tetrahedron Lett. 1989, 30, 651. For
a recent combined experimental and theoretical study, see: e) A.
Mekareeya, P. R. Walker, A. Couce-Rios, C. D. Campbell, A.
Steven, R. S. Paton, E. A. Anderson, J. Am. Chem. Soc. 2017,
139, 10104.
[15] A preliminary computational study was performed by Prof. Zhi-
Xiang Yu and coworkers, Peking University, and more detailed
studies are in progress.
[16] For selected synthetic investigations on the functionalization of
diene 10, epoxide 20, and ketone 21, see the Supporting
Information.
[17] See the Supporting Information for details. For examples and
conditions of intramolecular aldol condensation leading to the
formation of cyclohexenone, see: (KOH–EtOH) a) K. C. Nic-
olaou, G. S. Tria, D. J. Edmonds, M. Kar, J. Am. Chem. Soc. 2009,
131, 15909; (p-TsOH – toluene) b) S. Wang, Y. Zhang, G. Dong,
S. Wu, K. Fang, Z. Li, Z. Miao, J. Yao, H. Li, J. Li, W. Zhang, W.
Wang, C. Sheng, Org. Lett. 2014, 16, 692; (piperidine – AcOH)
c) A. Srikrishna, B. Beeraiah, Tetrahedron: Asymmetry 2007, 18,
2587; (K2CO3 – TBAB) d) D. F. Taber, T. D. Neubert, A. L.
Rheingold, J. Am. Chem. Soc. 2002, 124, 12416; (DBU – ben-
zene) e) N. Toyooka, M. Okumura, H. Takahata, H. Nemoto,
Tetrahedron 1999, 55, 10673.
[6] For recent examples and a review on dual-metal cascade
catalysis, see: a) Y. Nishibayashi, M. Yoshikawa, Y. Inada, M.
Hidai, S. Uemura, J. Am. Chem. Soc. 2004, 126, 16066; b) C.
Kammerer, G. Prestat, T. Gaillard, D. Madec, G. Poli, Org. Lett.
2008, 10, 405; c) M. Zhang, H.-F. Jiang, H. Neumann, M. Beller,
P. H. Dixneuf, Angew. Chem. Int. Ed. 2009, 48, 1681; Angew.
Chem. 2009, 121, 1709; d) T. A. Cernak, T. H. Lambert, J. Am.
Chem. Soc. 2009, 131, 3124; e) K. Yamamoto, T. Bruun, J. Y.
Kim, L. Zhang, M. Lautens, Org. Lett. 2016, 18, 2644. For
a review, see f) C. Bruneau, S. Derien, P. H. Dixneuf, Top.
Organomet. Chem. 2006, 19, 295.
[7] For seminal contributions from the Lautens group on multili-
gand, multimetal catalysis, see: a) J. Panteleev, L. Zhang, M.
Lautens, Angew. Chem. Int. Ed. 2011, 50, 9089; Angew. Chem.
2011, 123, 9255; b) A. A. Friedman, J. Panteleev, J. Tsoung, V.
Huynh, M. Lautens, Angew. Chem. Int. Ed. 2013, 52, 9755;
Angew. Chem. 2013, 125, 9937; c) L. Zhang, L. Sonaglia, J.
Stacey, M. Lautens, Org. Lett. 2013, 15, 2128; d) J. Tsoung, J.
Panteleev, M. Tesch, M. Lautens, Org. Lett. 2014, 16, 110; e) L.
Zhang, Z. Qureshi, L. Sonaglia, M. Lautens, Angew. Chem. Int.
Ed. 2014, 53, 13850; Angew. Chem. 2014, 126, 14070.
[8] P. A. Peixoto, R. Severin, C.-C. Tseng, D. Y.-K. Chen, Angew.
Chem. Int. Ed. 2011, 50, 3013; Angew. Chem. 2011, 123, 3069.
[9] For examples of the diene-effect in organic synthesis, see:
a) P. A. Wender, N. M. Deschamps, T. J. Williams, Angew. Chem.
Int. Ed. 2004, 43, 3076; Angew. Chem. 2004, 116, 3138; b) H. Du,
B. Zhao, Y. Shi, J. Am. Chem. Soc. 2007, 129, 762; c) M. Gulıas, J.
Duran, F. Lopez, L. Castedo, J. L. Mascarenas, J. Am. Chem. Soc.
2007, 129, 11026; d) S. W. Youn, J. I. Eom, J. Org. Chem. 2006,
71, 6705. For a review, see: e) M. P. Croatt, P. A. Wender, Eur. J.
Org. Chem. 2010, 19.
[10] a) Q. Li, Z.-X. Yu, J. Am. Chem. Soc. 2010, 132, 4542; b) Q. Li,
Z.-X. Yu, Angew. Chem. Int. Ed. 2011, 50, 2144; Angew. Chem.
2011, 123, 2192; c) Q. Li, Z.-X. Yu, Organometallics 2012, 31,
5185.
[11] a) H. Suzuki, I. Keimatsu, K. Ito, J. Pharm. Soc. Jpn. 1932, 52,
1049; b) H. Suzuki, I. Keimatsu, K. Ito, J. Pharm. Soc. Jpn. 1934,
54, 802; c) Y. Inubushi, Y. Sasaki, Y. Tsuda, B. Yasui, T. Konika,
J. Matsumoto, E. Katarao, J. Nakano, Tetrahedron 1964, 20, 2007;
d) Y. Inubushi, Y. Sasaki, Y. Tsuda, J. Nakano, Tetrahedron Lett.
1965, 6, 1519.
[12] For racemic total syntheses, see: a) K. Yamada, M. Suzuki, Y.
Hayakawa, K. Aoki, H. Nakamura, H. Nagase, Y. Hirata, J. Am.
Chem. Soc. 1972, 94, 8278; b) Y. Inubushi, T. Kikuchi, T. Ibuka,
T. Tanaka, I. Saji, K. Tokane, J. Chem. Soc. Chem. Commun.
1972, 1252; c) A. S. Kende, T. J. Bentley, R. A. Mader, D. Ridge,
J. Am. Chem. Soc. 1974, 96, 4332; d) W. R. Roush, J. Am. Chem.
Soc. 1978, 100, 3599; e) C. H. Lee, M. Westling, T. Livinghouse,
A. C. Williams, J. Am. Chem. Soc. 1992, 114, 4089. For racemic
formal syntheses, see: f) S. F. Martin, W. Li, J. Org. Chem. 1991,
56, 642; g) A. Padwa, M. Dimitroff, B. Liu, Org. Lett. 2000, 2,
3233; h) A. Padwa, M. A. Brodney, M. Dimitroff, B. Liu, T. Wu,
J. Org. Chem. 2001, 66, 3119. For asymmetric total syntheses, see:
i) C.-K. Sha, R.-T. Chiu, C.-F. Yang, N.-T. Yao, W.-H. Tseng, F.-L.
Liao, S.-L. Wang, J. Am. Chem. Soc. 1997, 119, 4130; j) J.
Cassayre, S. Z. Zard, J. Am. Chem. Soc. 1999, 121, 6072; k) L. M.
Kreis, E. M. Carreira, Angew. Chem. Int. Ed. 2012, 51, 3436;
Angew. Chem. 2012, 124, 3492. For asymmetric formal syntheses,
see: l) B. M. Trost, A. S. Tasker, G. Ruether, A. Brandes, J. Am.
Chem. Soc. 1991, 113, 670; m) Q.-Y. Hu, G. Zhou, E. J. Corey, J.
Am. Chem. Soc. 2004, 126, 13708; n) N. Uesaka, F. Saitoh, M.
[18] For use of the LiOH–iPrOH system in intramolecular aldol
condensation leading to the formation of cyclohexenone, see:
a) J. Dardenne, S. Desrat, F. Guꢀritte, F. Roussi, Eur. J. Org.
Chem. 2013, 2116; b) K. Chen, Y. Ishihara, M. M. Galan, P. S.
Baran, Tetrahedron 2010, 66, 4738.
[19] H. Satoh, H. Ueda, H. Tokuyama, Tetrahedron 2013, 69, 89.
[20] For synthesis of allylic bromide 22, see the Supporting Informa-
tion.
[21] For the use of the CuBr·SMe2–TaniaPhos combination in copper-
catalyzed asymmetric allylic alkylation reactions pioneered by
the Feringa group, see: a) F. Lꢁpez, A. W. van Zijl, A. J.
Minnaard, B. L. Feringa, Chem. Commun. 2006, 409; b) K.
Geurts, S. P. Fletcher, B. L. Feringa, J. Am. Chem. Soc. 2006, 128,
15572; c) J. F. Teichert, S. Zhang, A. W. van Zijl, J. W. Slaa, A. J.
Minnaard, B. L. Feringa, Org. Lett. 2010, 12, 4658; d) T.
den Hartog, B. Macia, A. J. Minnaard, B. L. Feringa, Adv.
Synth. Catal. 2010, 352, 999; e) M. FaÇanas-Mastral, B. ter Horst,
A. J. Minnaard, B. L. Feringa, Chem. Commun. 2011, 47, 5843;
f) Y. Huang, M. FaÇanas-Mastral, A. J. Minnaard, B. L. Feringa,
Chem. Commun. 2013, 49, 3309; g) B. Mao, M. FaÇanas-Mastral,
M. Lutz, B. L. Feringa, Chem. Eur. J. 2013, 19, 761; h) V.
Hornillos, M. Perez, M. FaÇanas-Mastral, B. L. Feringa, Chem.
Eur. J. 2013, 19, 5432.
[22] We synthesized TaniaPhos in 95% ee (chiral HPLC) by
following the literature procedure: T. Ireland, K. Tappe, G.
Grossheimann, P. Knochel, Chem. Eur. J. 2002, 8, 843.
Manuscript received: June 5, 2017
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Natural Product Synthesis
Y. Lee, E. M. Rochette, J. Kim,
D. Y.-K. Chen*
&&&& — &&&&
An Asymmetric Pathway to Dendrobine
by a Transition-Metal-Catalyzed Cascade
Process
An asymmetric pathway to polycyclic
alkaloid dendrobine was developed com-
prising a one-pot palladium-catalyzed
enyne cycloisomerization, and rhodium-
catalyzed diene-assisted pyrrolidine for-
mation by allylic CH activation. Intramo-
lecular aldol condensation with concom-
itant detosylation, followed by reductive
amination, afforded an advanced inter-
mediate in only 10 synthetic steps.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!