Asymmetric synthesis of methylenetetrahydrofurans by palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane with aldehydes - A novel ligand design

Article abstract of DOI:10.1021/ja201181g

The palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane (TMM) with aldehydes is a direct and efficient route to methylenetetrahydrofurans. Herein we describe the first asymmetric synthesis of methylenetetrahydrofurans utilizing a palladium-TMM complex in the presence of a novel phosphoramidite ligand possessing a stereogenic phosphorus. The method allows for the formation of chiral disubstituted tetrahydrofurans in good yields and enantioselectivities.

Full text of DOI:10.1021/ja201181g

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Asymmetric Synthesis of Methylenetetrahydrofurans by
Palladium-Catalyzed [3 þ 2] Cycloaddition of Trimethylenemethane
with Aldehydes ꢀ A Novel Ligand Design
Barry M. Trost,* Dustin A. Bringley, and Steven M. Silverman
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
ABSTRACT: The palladium-catalyzed [3 þ 2] cycloaddi-
tion of trimethylenemethane (TMM) with aldehydes is a
direct and efficient route to methylenetetrahydrofurans.
Herein we describe the first asymmetric synthesis of methyl-
enetetrahydrofurans utilizing a palladiumꢀTMM complex
in the presence of a novel phosphoramidite ligand posses-
stereocontrol during ligand synthesis. Herein, we report our
sing a stereogenic phosphorus. The method allows for the
efforts to prepare such C1-symmetric ligands and their utilization
formation of chiral disubstituted tetrahydrofurans in good
in the palladium-catalyzed TMM cycloaddition with aldehydes,
yields and enantioselectivities.
allowing for the synthesis of methylenetetrahydrofurans in high
yield and enantiopurity.
We have previously demonstrated that the Pd-TMM cycload-
dition is a direct and efficient method for the generation of highly
he prevalence of tetrahydrofurans in natural and synthetic
products has stimulated a variety of efforts toward their
T
substituted tetrahydrofurans. A critical breakthrough in this
pioneering work was the discovery that Lewis acid cocatalysts
such as tin or indium salts facilitate cycloaddition.11,12 For example,
reaction of cinnamaldehyde in the absence of a Lewis acid affords
a mixture of the desired cycloadduct, an acyclic byproduct, and
oligomeric impurities in 65% yield (eq 2). In the presence of
catalytic Me3SnOAc, however, the desired product is formed in
95% yield (eq 3).11a We attributed the change in reactivity to
activation of the carbonyl group and coordination of the inter-
mediate alkoxide (III) by the Lewis acid, resulting in a softer
nucleophile that is more suitable for the intramolecular cycliza-
tion with the Pd-π-allyl.
construction.1 Among these methods, those that utilize cycload-
ditions offer a distinct advantage due to their ability to generate
multiple bonds in a single step.2 While enantioselective cycload-
ditions generating tetrahydrofurans are known,3 few reports
utilize aldehydes as a coupling partner despite the benefits of
these ubiquitous and readily available substrates.4 One such
strategy would involve the [3 þ 2] cycloaddition of aldehydes
with palladium-trimethylenemethane (TMM), generated in situ
from 3-acetoxy-2-trimethylsilylmethyl-1-propene (1) and cata-
lytic palladium, provided that a suitable chiral ligand could be
developed.
Recently, our group disclosed a new class of chiral phosphor-
amidites (I) that has led to the development of an asymmetric
version of the TMM cycloaddition. An advantage of modular
ligands such as I is their potential for steric and electronic
modification. Indeed, in our previous work we effectively ad-
justed the pyrrolidine of I in order to achieve highly enantiose-
lective syntheses of cyclopentanes (using Ar = phenyl),5
pyrrolidines (Ar = 2-naphthyl),6 and bicyclo[4.3.1]decadienes
(Ar = p-biphenyl).7 In related efforts, the Hayashi group has
described the analogous 1,4-zwitterion in enantioselective cy-
cloadditions with 1,1-dicyanocyclopropanes and N-tosyl aziri-
dines (Ar = phenyl),8 as well as cycloadditions using phosphor-
Our initial efforts to develop the asymmetric aldehyde cy-
cloaddition focused on the use of ligand L1 with 2-naphthalde-
hyde as a test substrate. In light of the above mechanistic dis-
cussion, we were surprised to see comparable yields of the
desired cycloadduct when the reaction was run with or without
In(acac)3 (Table 1, entries 1 and 2). When other substrates were
examined, however, yields were generally 20ꢀ30% lower without
In(acac)3. Based on these results, a survey of Lewis acids seemed
appropriate. To better evaluate potential Lewis acids, we switched to
ligand L2, which gave only a 33% yield in the absence of a
cocatalyst (entry 3). Indium (entry 4) or tin (entry 5) salts gave
amidites with acyclic amines.9
Despite these advances, extension of the TMM cycloaddition
toward the synthesis of tetrahydrofurans using these ligands has
remained a challenge, generally affording products with only
modest ee's (eq 1). Conspicuously absent from the previous
work, however, is any modification of the BINOL component of
the phosphoramidite. While 3,30-disubstituted BINOL deriva-
tives are common in chiral catalysis, monosubstituted derivatives
are rare.10 Additionally, such ligands possess added complexity in
that they bear a stereogenic phosphorus, mandating efficient
Received: February 7, 2011
Published: April 25, 2011
r
2011 American Chemical Society
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Table 1. Initial Reaction Optimizationa
Scheme 1. Selected BINOL Derivatization Resultsa
entry
Ligand
Additive
None
% yield
% ee
1
L1
L1
L2
L2
L2
L2
L2
L2
L3
L4
L5
63
67
33
61
60
76
55
69
75
81
25
79
67
56
51
50
52
46
52
47
39
6
2
In(acac)3
3
None
4
In(acac)3
5
n-Bu3Sn(OAc)
B-OMe-9-BBN
(S)-Me-CBS
(R)-Me-CBS
In(acac)3
6
7
8
9
10
In(acac)3
11
In(acac)3
a All reactions were conducted at 0.15 M in toluene at 50 °C, with
1.6 equiv of 1, 5% Pd(dba)2, 10% additive, and 10% ligand. Yields are
isolated values; ee’s were determined by chiral HPLC.
a All reactions were conducted at 0.15 M in toluene at 50 °C, with
1.6 equiv of 1, 5% Pd(dba)2, 10% In(acac)3, and 10% ligand. Yields are
isolated values; ee’s were determined by chiral HPLC.
conformation of the substituent are important factors affecting
the enantiocontrol of the ligand. We hypothesized that an ortho-
substituent tethered to the 4-position of BINOL would be
conformationally constrained and therefore might lead to
better ee's. Indeed, naphthofuran L10 led to a further improve-
ment and dihydrofuran L11 gave the best result with an 80%
yield and 87% ee.14
With optimized conditions in place, the reaction scope was
examined (Table 2). In most cases, the temperature could be
lowered to 23 °C, resulting in slight improvements in ee.
However, all attempts at 4 °C resulted in no reaction. Comparing
the optical rotation of the known benzaldehyde cycloadduct
(entry 2)15 allowed for the determination of absolute configura-
tion, and all other examples are proposed by analogy. In large-
scale experiments (1.0 mmol) using either 2-naphthaldehyde or
benzaldehyde, catalyst loading could be lowered to 2.5% without
erosion of yield or ee.16 Good to excellent yields and enantio-
selectivities were obtained with electron-rich benzaldehydes bear-
ing various substitution patterns, including mono- (entries 3ꢀ6)
and disubstituted (entry 7) substrates. While the reaction of
4-chlorobenzaldehyde proceeded with good yield and selectivity
(entry 8), p-nitrobenzaldehyde gave only 36% ee under the
optimized conditions (entry 9). Further testing with other Lewis
acids suggested that coordination of the nitro group was inter-
fering with the enantiodetermining event. However, employing
ligand L1 in this case resulted in a 78% ee. Heterocyclic aldehydes
also gave cycloadducts in good optical purity (entries 10ꢀ11).
Chemoselective cycloaddition with the carbonyl group of cinna-
maldehyde derivatives was also possible. While the reaction of
cinnamaldehyde shows a 3:1 mixture of aldehyde and olefin
cycloadducts with moderate ee for the oxacycle (entry 12),
R-alkylated cinnamaldehydes showed exclusive reaction with
the carbonyl group, giving methylenetetrahydrofurans in good
ee's (entries 13ꢀ14). At this time, the success of R,β-unsaturated
aldehydes as substrates allows them to serve as a surrogate for
saturated aliphatic aldehydes by simple hydrogenation of the
double bond.
significantly better yields, although the toxicity of the latter makes
this option unattractive. B-Methoxy-9-borabicyclo[3.3.1]nonane
gave the best yield with 2-naphthaldehyde (entry 6), but when
this additive was tested with other substrates the results were
comparable or worse than in the case of In(acac)3. We briefly
examined chiral boranes such as 2-methyl-CBS-oxazaborolidine
but were unable to improve the enantioselectivity (entries 7 and 8).
We therefore adopted a standard procedure employing 10 mol %
In(acac)3 for further optimization. Returning our attention to the
effect of the ligand, we explored bis-1-naphthyl L3 and the bis-p-
biphenyl L4, but neither was competitive with L1. Ligands
bearing acyclic amines such as Feringa ligand L5 resulted in a
near-racemic product.
Establishing the bis-2-naphthyl pyrrolidine as the optimal
amine for the phosphoramidite, we next examined the effect
of derivatizing the BINOL (Scheme 1). Surprisingly, bis-3,
30-methylated L6 resulted in a completely inactive catalyst.
However, monomethylated L7 gave not only excellent conver-
sion but also an increase in ee. Owing to the loss of C2 symmetry,
such ligands bear a stereogenic phosphorus center that is set
during the phosphoramidite synthesis. Interestingly, we observed
no change in enantioselectivity when using batches of ligands
with different diastereomeric ratios, although the yield did change.
This result, confirmed by selective preparation of both diaster-
eomers, indicates that only a single diastereomer of the phos-
phoramidite is catalytically active.13 While the ethyl analog L8
gave a comparable result to that of L7, use of the isopropyl ligand
L9 resulted in a substantial drop in both yield and selectivity.
Such a drastic change suggests that both the steric demands and
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Table 2. Palladium-Catalyzed [3 þ 2] Reactions of
absence of a Lewis acid, albeit only in the reaction of 2-naphthal-
dehyde. We hypothesize that the more electron-rich L11 may
enhance the nucleophilicity of the Pd-TMM intermediate (II)
and stabilize the resultant Pd-π-allyl intermediate (III) toward
cyclization. Furthermore, the increased steric bulk of ligand L11
may constrain the conformation to favor the desired intramole-
cular cyclization as well as inhibit the approach of an external
silylating agent.
Aldehydesa
In summary, we have developed a new phosphoramidite
ligand bearing a stereogenic center at phosphorus. Interestingly,
we find that only a single diastereomer of the ligand is catalyti-
cally active, allowing even mixtures diastereomeric at phosphorus
to function in the reaction. Furthermore, the high reactivity and
the steric demands of these ligands mitigate the need for the
Lewis acid cocatalysts that proved essential for the previous
achiral phosphite ligands employed for these cycloadditions.
Utilizing the novel phosphoramidites in the palladium-catalyzed
[3 þ 2] cycloaddition of TMM with aldehydes allows for the
formation of methylenetetrahydrofurans in good to excellent
yields and enantioselectivities. Investigations into the full scope
of this reaction, including the use of other carbonyl acceptors and
substituted TMM donors, are currently underway and will be
reported in due time.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and spec-
b
tral data for all unknown compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
’ ACKNOWLEDGMENT
We thank the NSF and the NIH (GM 033049) for their
generous support of our programs. Palladium salts were a generous
gift from Johnson-Matthey.
’ REFERENCES
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2009, 20, 2537. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261.
(2) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S.,
Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, Germany, 2002.
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a All reactions were conducted for 3ꢀ24 h at 0.15 M in toluene with
1.6 equiv of 1, 5% Pd(dba)2, 10% ligand, and 10% In(acac)3 unless noted
otherwise. Yields are isolated values; ee’s were determined by chiral HPLC.
b Reaction conducted without In(acac)3. c Used ligand L1. d Used
CpPd(η3-C3H5). e Isolated as a 3:1 mixture of carbonyl and olefin
cycloadducts; ee is for the methylenetetrahydrofuran only.
Interestingly, when several substrates were tested without
In(acac)3, the reaction still gave excellent yields of the desired
cycloadduct (entries 1, 3, 4, 7, 8, 12ꢀ14). In fact, of those
substrates tested without a Lewis acid, only in the case of
3-pyridinecarboxaldehyde did the absence of In(acac)3 lead to a
clear reduction in yield (54% vs 86% with In(acac)3). We note,
also, that ligand L1 was capable of facilitating cycloaddition in the
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Hayashi, T. J. Am. Chem. Soc. 2008, 130, 16174. (c) Shintani, R.;
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(13) Monoalkylated derivatives L7, L8, and L9 were obtained in
diastereomeric ratios of 9:1, 11:1, and 5:1, respectively, by coupling the
aminodichlorophosphine with the BINOL derivatives at ꢀ78 °C in
THF. Previous work suggests the active (major) diastereomer is the (RP,
R,R,R) ligand since the major signal in the 31P NMR spectrum is
downfield of the minor signal. See ref 10a.
(14) Ligands L10 and L11 were prepared as single diastereomers by
coupling the BINOL chlorophosphite with the pyrrolidine at ꢀ40 °C in
toluene. We tentatively assign the ligands as the (RP,R,R,R) diastereo-
mers by analogy to L7ꢀL9, despite a relative shift of the 31P NMR
signals wherein the isolated (active) diastereomer shows a 31P NMR
signal upfield of the other diastereomer (see refs 10a and 13). Efforts to
verify this stereochemistry are ongoing.
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(16) See Supporting Information for details.
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