Highly enantioselective syntheses of functionalized α-methylene-γ-butyrolactones via Rh(I)-catalyzed intramolecular Alder ene reaction: Application to formal synthesis of (+)-pilocarpine

Article abstract of DOI:10.1021/ja020052j

A highly enantioselective Rh(I)-catalyzed intramolecular Alder ene reaction has been developed. The desired products, 3-vinyl, vinyl acetate, and vinyl ether-substitued α-methylene-γ-butyrolactones were formed in high yields. Aldehydes were produced with

Full text of DOI:10.1021/ja020052j

Published on Web 06/21/2002
Highly Enantioselective Syntheses of Functionalized
r-Methylene-γ-butyrolactones via Rh(I)-catalyzed Intramolecular Alder Ene
Reaction: Application to Formal Synthesis of (+)-Pilocarpine
Aiwen Lei, Minsheng He, and Xumu Zhang*
Department of Chemistry, 152 DaVey Laboratory, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
Received January 10, 2002
Scheme 1. Synthesis of (+)-Pilocarpine
The R-methylene-γ-butyrolactone unit is an important motif of
many natural products, such as (+)-pilocarpine, (+)-isopilocarpine,
and (+)-isopilosine.1 The exocyclic double bond is considered not
only to be responsible for the interesting biological properties of
γ-lactones but also to serve as a functional group for further
manipulations in organic synthesis.2 (+)-Pilocarpine, one of the
most important imidazole alkaloids, serves as the leading therapeutic
reagent in the treatment of narrow- or wide-angle glaucoma.3 Due
to its extensive pharmacological properties such as diaphoretic
effects, miotic action, and particular application in ophthalmology,4
considerable effort has been devoted to its synthetic studies.5 In
the synthesis of (+)-pilocarpine reported by Bu¨chi, the key
intermediate (4R)-(Z)-dehydrohomopilopic aldehyde was obtained
in five steps from 2-acetylbutyrolactone in 92% ee and 20% overall
yield (Scheme 1).5b
Several reviews on the synthesis of R-methylene-γ-butyrolactones
have been published.6 Most of them focus on the formation of the
C-O bond to construct the γ-lactone unit. Recently, palladium (II)-
catalyzed C-C formation via carbocyclization of enynes to form
γ-lactones has shown its potential efficiency.7 Extensive studies
on transition metal-catalyzed Alder ene reactions have also been
carried out.8 However, only a Rh(I) system has been used to make
γ-lactones.9 Furthermore, there are only few examples dealing with
the formation of chiral γ-lactones.10 Herein we report a highly
enantioselective Rh-catalyzed intramolecular Alder ene reaction for
the synthesis of functionalized γ-lactones.
Table 1. Rh-catalyzed Alder Ene Reaction of 1aa
entry
Rh(I)
temp
rt
65 °C AgSbF6
65 °C AgSbF6
additive
AgSbF6
time
1 h
conv.(%)b,c
1
2
3
4
5
6
7
8
9
[Rh(rac-BINAP)Cl]2
[Rh(rac-BINAP)Cl]2
[Rh(COD)Cl]2/rac-BINAP
[Rh(COD)Cl]2/rac-BINAP rt
Rh(COD)2SbF6/rac-BINAP rt
Rh(NBD)2SbF6/rac-BINAP rt
Rh(COD)2PF6/rac-BINAP
Rh(NBD)2BF4/rac-BINAP
[Rh(COD)Cl]2/rac-BINAP
0
12 h
100(65)
>99(90)
95(92)
10 min
10 min
10 min
10 min
10 min
10 min
10 min
AgSbF6
none
none
none
none
0
0
0
0
0
rt
rt
rt
100 mol %
COD AgSbF6
10
[Rh(COD)Cl]2/rac-BINAP rt
10 mol %
COD AgSbF6
10 min
<2
a All reactions were performed using 10 mol % Rh(I) and12 mol % rac-
BINAP in 0.2 mmol scale. b Conversion was detected by GC, and isolated
yield is in parentheses. c The stereochemistry of 2a was established by NOE.
We previously reported a novel procedure using [RhL2Cl]2 as
the catalyst precursor in a Rh-catalyzed Alder ene reaction.9,11 It
was found that the conversion is low when BINAP was used as
the ligand. To make γ-lactones, we investigated the Rh(I)-catalyzed
Alder ene reaction of 1a and found that the reactivity is low with
[Rh(rac-BINAP)Cl]2 as the precursor (Table 1, entry 1). However,
when the reaction was heated at 65 °C, 100% conversion and 65%
isolated yield were obtained (Table 1, entry 2). Furthermore, high
yields and reactivities were also achieved when the catalyst was
prepared in situ at 65 °C or room temperature (rt) (Table 1, entries
3-4). When other cationic rhodium precursors were used at rt, no
product was detected (Table 1, entries 5-8). Addition of cyclooc-
tadiene is found to inhibit the reaction (Table 1, entries 9-10).
The asymmetric Rh-catalyzed Alder ene reactions were carried
out in the presence of [Rh(COD)Cl]2, (R)- or (S)-BINAP, and
AgSbF6 at rt. Extraordinarily high enantioselectivity (>99% ee)
and high yields (90-98%) were obtained for a wide range of
substituents (Table 2, entries 1-8).
an acetyl group, the desired product is a vinyl acetate-substituted
γ-lactone. If R2 is an alkyl group, a vinyl ether is the corresponding
product. Due to the wide applications of vinyl acetates and vinyl
ethers, this transformation is particularly interesting and valuable
for organic synthesis. All of the reactions in Table 3 were completed
within 5 min at rt. Both vinyl acetate and vinyl ether-substituted
γ-lactone were formed in high yields (91-98%) with excellent
enantioselectivities (>99%) (Table 3, entries 1-11).
When the substrates with alcohol at allylic position 5 were used,
the resulting products 6 contained an aldehyde. Again, high yields
(91-99%) and enantioselectivities (>99%) were obtained (Table
4, entries 1-5). Further study shows the reaction of 5c takes place
smoothly with 2% catalyst loading without compromising the
enantioselectivity. The aldehyde (R)-(+)-6a is especially interesting
since it is the key intermediate in Bu¨chi’s synthesis of (+)-
pilocarpine.5b To determine the absolute configuration, we have
correlated the product 6a with the literature results by determining
the optical rotation [(+)-6a has R-configuration].5b
To further extend the utility of our methodology, we introduced
various functional groups at the allylic position (Table 3). If R2 is
A formal synthesis of (+)-pilocarpine is an excellent example
to demonstrate the synthetic utility of our method for making
* To whom correspondence should be addressed. E-mail: xumu@
chem.psu.edu.
functionalized γ-lactones. In comparison to Bu¨chi’s synthesis,5b
a
9
8198
J. AM. CHEM. SOC. 2002, 124, 8198-8199
10.1021/ja020052j CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Rh(I)-Catalyzed Intramolecular Alder Ene
Table 4. Asymmetric Rh(I)-Catalyzed Alder Ene Reactions of 5 to
Reactiona
Form Aldehyde Substituted Lactonesa
entry
R
5
BINAP
6d
yield(%)b
ee(%)c
substrate
product
yield(%)b ee (%)c
1
2
3
4
5
Me
Me
5a
5a
5b
5c
5c
R-BINAP
S-BINAP
S-BINAP
R-BINAP
S-BINAP
(R)-(+)-6a
(S)-(-)-6a
(S)-(-)-6b
(R)-(+)-6c
(S)-(-)-6c
99
98
95
92
91
>99
>99
>99
>99
>99
1
2
entry
1
R
R
BINAP
2d
1
2
3
4
5
6
7
8
1a Ph
1b Ph
1c Ph
1c Ph
1d Me
1e Me
Et
H
S-BINAP
R-BINAP (R)-(-)-2b
(S)-(+)-2a
93
>99
>99
>99
>99
>99
>99
>99
>99
n-C5H11
Ph
94
92
93
92
98
90
95
Me R-BINAP (R)-(-)-2c
Me S-BINAP (S)-(+)-2c
H R-BINAP (R)-(-)-2d
Ph
a All the reactions were carried out in 2 mL of ClCH2CH2Cl in 0.2 mmol
scale. The ratio of substrates/[Rh(COD)Cl]2/BINAP/AgSbF6 was 1: 0.05:
0.11:0.20. This reaction finished within 2-10 min. b Isolated yield. c ee
value was detected by GC. (R) and (S) were compared with known
compounds 6a.
Me R-BINAP (R)-(-)-2e
H
1f n-C5H11
S-BINAP
(S)-(+)-2f
(S)-(+)-2g
d
1g n-C5H11 Me S-BINAP
a All the reactions were carried out in 2 mL of ClCH2CH2Cl in 0.2 mmol
scale. The ratio of substrate/[Rh(COD)Cl]2/BINAP/AgSbF6 was 1:0.05:0.11:
0.20. This reaction finished within 2-10 min. b Isolated yield. c ee value
was detected by GC or HPLC. d (R) and (S) were compared with known
compounds 6a.
Supporting Information Available: Spectroscopic data, GC, HPLC
spectra, and experiments details (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
Table 3. Asymmetric Rh(I)-Catalyzed Alder Ene Reactions of 3 to
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1
2
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3a Ph
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3d Me
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Ac R-BINAP (R)-(-)-4a
Me S-BINAP (S)-(+)-4b
Bn S-BINAP (S)-(+)-4c
Ac R-BINAP (R)-(-)-4d
Ac S-BINAP (S)-(+)-4d
Me S-BINAP (S)-(-)-4e
Bn S-BINAP (S)-(+)-4f
96
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
96
92
93
98
95
91
97
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91
92
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3f
Me
3 g n-C5H11 Ac S-BINAP (S)-(+)-4g
3h n-C5H11 Me S-BINAP (S)-(-)-4h
10 3i
11 3i
n-C5H11 Bn R-BINAP (R)-(-)-4i
n-C5H11 Bn S-BINAP (S)-(+)-4i
a All the reactions were carried out in 2 mL of ClCH2CH2Cl in 0.2 mmol
scale. The ratio of substrate/[Rh(COD)Cl]2/BINAP/AgSbF6 was 1: 0.05:
0.11:0.20. This reaction finished within 2-10 min. b Isolated yield. c ee
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(Z)-2-buten-1,4-diol using our method provided the intermediate
(R)-(+)-6a in over 99% ee and 91% overall yield. (+)-Pilocarpine
can be prepared in two additional steps from (R)-(+)-6a according
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5b
to the literature method (Scheme 1).
In conclusion, we developed an atom-economic, highly efficient
Rh(I)-catalyzed intramolecular Alder ene reaction, by which various
functionalized R-methylene-γ-butyrolactones were formed in high
yields with over 99% ee. Highly enantioselective syntheses of
functionalized carbocycles and heterocycles such as lactams,
pyrroles, and tetra-H-furans are currently in progress.
(11) (a) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104-4106. (b)
Pd-catalyzed ene-type cyclization of a 1,6-enyne was reported using
BINAP as ligand, and ee value was up to 99% for one substrate. Hatano,
M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249-252.
Acknowledgment. This work was supported by NSF and NIH
grants.
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