Total synthesis of enantiopure (+)-γ-lycorane using highly efficient Pd-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/ol060181v

A highly efficient short total synthesis of (+)-γ-lycorane (>99% ee, 41% overall yield) was achieved by using the asymmetric allylic alkylation in the key step catalyzed by palladium complexes with novel chiral biphenol-based monodentate phosphoramidite l

Full text of DOI:10.1021/ol060181v

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1395-1398
Total Synthesis of Enantiopure
)- -Lycorane Using Highly Efficient
Pd-Catalyzed Asymmetric Allylic
Alkylation
(+ γ
Bruno D. Chapsal and Iwao Ojima*
Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
iojima@notes.cc.sunysb.edu
Received January 22, 2006
ABSTRACT
A highly efficient short total synthesis of (
+)-γ-lycorane (>99% ee, 41% overall yield) was achieved by using the asymmetric allylic alkylation
in the key step catalyzed by palladium complexes with novel chiral biphenol-based monodentate phosphoramidite ligands.
Catalytic asymmetric allylic substitution serves as one of the
most powerful methods for the regio- and stereoselective
formation of C-C, C-N, and C-O bonds. The high
synthetic utility of this catalytic process is now well
established through numerous efficient syntheses of enan-
tiopure natural and unnatural products.1 Trost et al. pioneered
the asymmetric allylic alkylation using C2-symmetric di-
amine-based modular diphosphine ligands, which achieved
excellent enantioselectivity in various systems.1-2 The use
of chiral monodentate phosphorus ligands in catalytic asym-
metric allylic alkylation has been reported with an Ir-complex
precursor, which generally leads to the formation of branched
products with excellent regioselectivity.3 In contrast, the
corresponding Pd-catalyzed reactions with monodentate
phosphorus ligands remain poorly explored.4
We have reported a new class of monodentate phosphorus
ligands based on axially chiral biphenols.5 One of the salient
features of these ligands is their fine-tuning capability through
modification of the R1, R2, and R3 groups (Figure 1). Thus,
high catalytic activity and enantioselectivity have been
achieved in the hydrogenation of dimethyl itaconate (up to
99.6% ee), hydroformylation of allyl cyanide (up to 80%
(3) (a) For a review, see: Takeuchi, R. Synlett 2002, 1954-1965. For
recent publications, see: (b) Streiff, S.; Welter, C.; Schelwies, M.; Lipowsky,
G.; Miller, N.; Helmchen, G. Chem. Commun. 2005, 2957-2959. (c) Bartels,
B.; Garcia-Yebra, C.; Helmchen, G. Eur. J. Org. Chem. 2003, 1097-1103.
(d) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529-3532. (e) Polet, D.;
Alexakis, A. Org. Lett. 2005, 7, 1621-1624. (f) Leitner, A.; Shekhar, S.;
Pouy, M. J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506-15514.
(g) Leitner, A.; Shu, C. T.; Hartwig, J. F. Org. Lett. 2005, 7, 1093-1096.
(4) (a) Boele, M. D. K.; Kamer, P. C. J.; Lutz, M.; Spek, A. L.; de Vries,
J. G.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P. F. Chem. Eur. J.
2004, 10, 6232-6246. (b) Tsarev, V. N.; Lyubimov, S. E.; Shiryaev, A.
A.; Zheglov, S. V.; Bondarev, O. G.; Davankov, V. A.; Kabro, A. A.;
Moiseev, S. K.; Kalinin, V. N.; Gavrilov, K. N. Eur. J. Org. Chem. 2004,
2214-2222. (c) Edwards, C. W.; Shipton, M. R.; Alcock, N. W.; Clase,
H.; Wills, M. Tetrahedron 2003, 59, 6473-6480.
(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-
422. (b) Trost, B. M.; Lee, C. Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921-2943. (d) Trost, B. M. J. Org. Chem.
2004, 69, 5813-5837.
(2) (a) Trost, B. M.; Van Vranken, D. L.; Bingel, C.J. Am. Chem. Soc.
1992, 114, 9327-9343. (b) Trost, B.; Tanimori, S.; Dunn, P. T.; J. Am.
Chem. Soc. 1997, 119, 2735-2736. (c) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 1999, 121, 4545-4554.
(5) (a) Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831-3834.
(b) Hua, Z.; Vassar, V. C.; Choi, H.; Ojima, I. Proc. Nat. Acad. Sci. U.S.A.,
2004, 101, 5411-5416. (c) Choi, H.; Hua, Z.; Ojima, I. Org. Lett. 2004, 6,
2689-2691.
10.1021/ol060181v CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/10/2006

Scheme 1. Asymmetric Synthesis of (+)-γ-Lycorane
This short total synthesis appears to have a lot of room
for improvement. Thus, we decided to revisit this process
by applying a library of our new chiral monodentate
phosphoramidite ligands for optimization of the enantio-
selectivity and chemical yield and then accomplish a highly
efficient total synthesis of (+)-γ-lycorane.
First, we performed a model study on the desymmetriza-
tion of cis-1,4-dibenzoyloxycyclohex-2-ene (1) using diben-
zyl malonate as a nucleophile. The aim of this model study
was the preliminary screening of effective phosphoramidite
ligands. Results are summarized in Table 1.
Figure 1. Phosphoramidite ligands library.
Table 1. Desymmetrization of meso-Diester 1a
ee), and conjugate addition of diethylzinc to cycloalkenones
and nitroolefins (up to 99% ee).5
We describe here the application of these ligands to the
Pd-catalyzed asymmetric allylic alkylation reaction for the
total synthesis of (+)-γ-lycorane, an alkaloid isolated from
the plants of Amaryllidacae family. Because of its unique
pentacyclic structure, (+)-γ-lycorane has attracted substantial
attention for its total synthesis.6 However, very few ap-
proaches to the asymmetric synthesis of this alkaloid have
been reported so far.6a,7 In 1995, Mori and co-workers
reported the first asymmetric synthesis of (+)-γ-lycorane,
featuring a Pd-catalyzed asymmetric allylic alkylation in the
key step (Scheme 1).7 However, the best enantioselectivity
achieved in this key step (step 1 in Scheme 1) using (S)-
BINAPO was 54% ee, giving 7a in 30% yield (using 2.6
equiv of 6 and LDA). The yield and enantiopuiry of 7a was
dependent on the amounts of 6 and LDA used. Thus, 7a
was obtained in 66% yield and 40% ee on using 1.1 equiv
of 6 and LDA. This product (40% ee) was used to complete
the total synthesis in 17% overall yield. The expedited 5-step
total synthesis, incorporating one-pot protocol, gave (+)-γ-
lycorane with 46% ee in 23% overall yield.
entry
ligand
convb(%)
% eec
1
2
3
4
5
L1
L2
L3
L5a
L5b
80
82
70
82
50
28.7 (-)
48.1 (+)
68.4 (+)
81.3 (-)
10.8 (-)
a Reactions were run using [Pd(allyl)Cl]2 (1 mol %) with a monodentate
ligand (4 mol %) in THF at 0 °C for 2 h. b Determined by 1H NMR.
c Determined using Daicel Chiralpak AD.
As Table 1 shows, a substantial increase of enantioselec-
tivity for the formation of 7b is observed as the size of the
amine moiety of the ligand increases (entries 1 to 4). Thus,
L1 afforded 7b with 28.7% ee while 81.3% ee was obtained
with L5a. It is worthy of note that (i) (S)-biphenol-based
ligands give (+)-7b as the major product, while (R)-biphenol-
based ligands predominantly yield (-)-7b (i.e., the axial
chirality of the ligand dictates the direction of the enantio-
discrimination of the two benzoate groups) and (ii) introduc-
tion of methyl groups at the 3,3′-positions of the biphenol
moiety of L5a (i.e., L5b, R2 ) Me) causes a detrimental
effect on the enantioselectivity as well as conversion of the
(6) (a) Dong, L.; Xu, Y.-J.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Org. Lett. 2005, 7, 4285-4288. (b) Jin, Z. Nat. Prod. Rep.
2005, 22, 111-126. (c) Yasuhara, T.; Osafune, E.; Nishimura, K.;
Yamashita, M.; Yamada, K.-I.; Muraoka, O.; Tomioka, K. Tetrahedron Lett.
2004, 45, 3043-3045. (d) Shao, Z.-h.; Peng, F.-Z.; Tu, Y.-Q.; Zhang, H.-
b. Hecheng Huaxue 2004, 12, 111-114. (e) Shao, Z.; Chen, J.; Huang, R.;
Wang, C.; Li, L.; Zhang, H. Synlett 2003, (14), 2228-2230.
(7) Yoshizaki, H.; Satoh, H.; Sato, Y.; Nukui, S.; Shibasaki, M.; Mori,
M. J. Org. Chem. 1995, 60, 2016-2021.
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Org. Lett., Vol. 8, No. 7, 2006

reaction (entry 5). These preliminary results served as the
starting point for applying our ligands to the key step in the
total synthesis of enantiopure (+)-γ-lycorane.
Table 2. Pd-Catalyzed Allylic Alkylation Reaction:
Desymmetrization of 1 with 6a
According to our planned route to (+)-γ-lycorane by
revisiting Mori’s first asymmetric synthesis, it was necessary
to prepare the malonate half-amide 6. Since the synthesis of
6 was not reported in Mori’s paper nor anywhere else by
literature search, we synthesized 6 from commercially
available piperonal 2 through steps shown in Scheme 2.
entry
ligand
yieldb (%)
% eec
1
2
3
4
5
6
7
8
9
L5a
L5ad
L6e
L7
L8
93
27
63
86.2 (-)
92.6 (-)
89.5 (+)
ndg
85.5 (+)
83.0 (+)
99.7 (+)
ndg
ndg
ndg
Scheme 2. Synthesis of Nucleophile 6
conv <5%
92
85
L9
L10f
L11
L12
L13
L14f
76
conv 0%
conv <5%
conv <5%
83
10
11
99.4 (+)
a Reactions were run with 100 mg (0.31 mmol) of 1, [Pd(allyl)Cl]2 (2
mol %), a ligand (8 mol %), 6 (1.2 equiv), and LDA (1.2 equiv) in THF at
-60 °C for 15 h unless otherwised noted. b Isolated yield. c Estimated based
on the enantiopurity of 9 determined by chiral HPLC analysis using a Daicel
Chiralpak AD-RH column. d The reaction was run with 2.6 equiv of 6 and
LDA and was completed in 20 min. e The reaction run with 2.0 equiv of 6
and LDA. f The reaction time was 8 h. g nd ) not determined.
Next, the efficacy of phosphoramidite ligands L3, L5a,
and L5b was evaluated in the reaction of 1 with “real”
nucleophile 6 and LDA as base (6/LDA ) 1). Consistent
with the model study, L5a gave the best results among the
three ligands examined. Also, it was found the solvent and
the reaction temperature had critical effects on the reaction.
Thus, after basic optimization of the reaction conditions using
L5a as the ligand, the reactions in THF at -60 °C appeared
optimal. The reactions gave a 54/46 diastereomer mixture
of 7a due to epimerization of the acidic methine of the
malonate half amide moiety. Thus, it was necessary to
convert 7a to 9 in order to determine the enantioselectivity
of the reaction. The enantiopuriy of 9 was unambiguously
determined by chiral HPLC analysis using a Daicel Chiralpak
AD-RH column (Table 2).
Under these conditions, the reaction of 1 with 6 (1.2 equiv)
using L5a gave 7a in 93% yield and 86.2% ee (Table 2,
entry 1). We also examined the effects of the amounts of 6
and LDA on the reaction. The reactions with 2.0 and 2.6
equiv of 6 and LDA gave 7a with 89.5% ee (63% yield)
and 92.6% ee (27% yield), respectively (entries 2 and 3).
(Note: L6 is the enantiomer of L5a.) The results indicate
that the use of excess amounts of 6 and LDA increases the
enantioselectivity of the reaction. However, the observed
increase in enantioselectivity is accompanied by a significant
decrease in the yield of 7a. Thus, the use of 1.2 equiv of 6
and LDA appears optimal.
optimization library of phosphoramidite ligand L6 by
introducing various C2-symmetric, pseudo-C2-symmetric, and
nonsymmetrical N,N-bis(1-arylethyl)amine moieties bearing
different aryl groups, including those with an ortho substitu-
ent (ligands L7-14, Figure 1). For the introduction of ortho
substituents to the C2- and pseudo-C2-symmetric N,N-bis-
(1-arylethyl)amine moiety of BINOL-based phosphoramidite
ligands, Alexakis recently reported the markedly favorable
effects of such substituents on the enantioselectivity as well
as reaction rate in his Ir-catalyzed asymmetric allylic
substitution reactions.3e Thus, we set out to examine the ortho
substitution effect in our biphenol-based ligand-Pd-catalyst
system. In addition, we designed nonsymmetrical N,N-bis-
(1-arylethyl)amine moieties based on a combination of
different aryl groups, i.e., phenyl, o-tolyl, o-methoxyphenyl,
1-naphthyl, and 2-naphthyl groups.
The efficacy of L6 congeners was examined in the Pd-
catalyzed reaction of 1 with 6 using [Pd(allyl)Cl]2 and 1.2
equiv of 6 and LDA in THF at -60 °C for 15 h. Results are
summarized in Table 2. As Table 2 shows, a very interesting
and rather unanticipated substituent effect of the aryl groups
of the amine moiety on the enantioselectivity as well as
catalytic activity is observed. First of all, the markedly
contrasting results for the use of L7 (R3 ) R3′ ) 1-Np) and
L8 (R3 ) R3′ ) 2-Np) is worth mentioning (entries 4 and
5). The result for L8 (85.5% ee) is similar to that for L6
(entries 5 and 3), while the reaction with L7 almost did not
proceed under the same conditions and no change was
observed even when the reaction was forced at room
temperature. Use of even one 1-naphthyl group seems to kill
the Pd-catalyst activity. Thus, the reaction using L13 (R3 )
Although it was already a remarkable improvement at this
point that 7a was obtained in 93% isolated yield and 86.2%
ee as compared with Mori’s original work,7 we strongly felt
that more improvement would be possible through systematic
optimization of L6, which gives 7a that has the correct
absolute configuration for the total synthesis of (+)-γ-
lycorane. Accordingly, we designed and synthesized a new
Org. Lett., Vol. 8, No. 7, 2006
1397

rate. It is possible to hypothesize that the oxygen of
2-methoxyphenyl group interacts with the Pd metal to fix
the orientation of the phenyl ring, which has a crucial effect
on the enantio-differentiation (desymmetrization) of the two
benzoate groups in meso-1. Since the isolation of 7a from
the reaction mixture is very easy, the reaction with L14
provides a highly practical process for the total synthesis of
enantiopure (+)-γ-lycorane.
Scheme 3. Completion of the Total Synthesis of
(+)-γ-Lycorane from 7a
The total synthesis of (+)-γ-lycorane was completed
following Mori’s procedure with some modifications. As
Scheme 3 illustrates, (+)-7a (99.4% ee) was converted to
pentacyclic oxolycorane 8 in 61% yield through a one-pot,
tandem allylic amination-intramolecular Heck reaction.
Then, 8 was subjected to sequential demethoxycarbonylation,
hydrogenation, and LiAlH4 reduction to give the desired (+)-
γ-lycorane (>99% ee) in 41% overall yield (six steps) from
1.
In conclusion, highly efficient biphenol-based monodentate
phosphoramidite ligands have been developed for Pd-
catalyzed asymmetric allylic alkylation. The successful total
synthesis of (+)-γ-lycorane demonstrates the advantage of
the facile fine-tuning capability of our novel phosphoramidite
ligands in developing extremely efficient ligands for a
specific asymmetric transformation through rational modi-
fication of a lead ligand. Further studies on the expansion
of our monodentate chiral phosphorus ligand library and their
applications to various catalytic asymmetric transformations
are actively underway.
1-Np, R3′ ) 2-MeO-Ph) virtually did not proceed (entry 10).
To our surprise, ligands L11 and L12, bearing C2-symmetric
N,N-bis(1-arylethyl)amine moieties, behaved very poorly,
resulting in no conversion (entry 8) and <5% conversion
(entry 9), respectively, while L9 (R3 ) Ph, R3′ ) 2-tolyl)
gave 83.0% ee (entry 6).
These results are unanticipated since the same amine
moieties were reported to give excellent results in the Ir-
catalyzed reactions with BINOL-based ligands.3d,e Thus, this
reaction is found to be very sensitive to the bulkiness and
arrangement of the aryl moiety at the coordination site.
A breakthrough in the enantioselectivity was achieved with
ligands L10 (R3 ) Ph, R3′ ) 2-MeO-Ph) and L14 (R3 )
2-Np, R3′ ) 2-MeO-Ph), bearing nonsymmetrical N,N-bis-
(1-arylethyl)amine moieties wherein one of the aryl groups
is a 2-MeO-phenyl. The reaction with L10 and L14 gave
(+)-7a with 99.7% ee (76% yield) and 99.4% ee (83% yield),
respectively (entries 7 and 11). Both reactions reached 100%
conversion in 8 h. It appears that the 2-methoxyphenyl group
in the nonsymmetrical N,N-bis(1-arylethyl)amine moiety
exerts a profound effect on the enantioselectivity and reaction
Acknowledgment. This work was supported by grants
from the National Institutes of Health (NIGMS) and the
National Science Foundation. A generous contribution from
Mitsubishi Chemical Corp. is also gratefully aknowledged.
Supporting Information Available: Experimental pro-
cedures; characterization data for all new phosphoramidite
ligands as well as (+)-γ-lycorane and the intermediates in
its total synthesis. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL060181V
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Org. Lett., Vol. 8, No. 7, 2006