Catalytic enantioselective claisen rearrangements of O-allyl β-ketoesters

Article abstract of DOI:10.1002/anie.201005183

A chiral guanidinium ion is shown to catalyze enantioselective Claisen rearrangements of O-allyl β-ketoesters in 78-87 % ee (see scheme). The pericyclic nature of the process allows products containing vicinal stereogenic centers to be accessed with both enantio- and diastereocontrol. Copyright

Full text of DOI:10.1002/anie.201005183

Angewandte
Chemie
DOI: 10.1002/anie.201005183
Organocatalysis
Catalytic Enantioselective Claisen Rearrangements of O-Allyl
b-Ketoesters**
Christopher Uyeda, Andreas R. Rꢀtheli, and Eric N. Jacobsen*
The selective construction of contiguous quaternary stereo-
genic centers, a motif found in many complex natural
products, represents
rearrangement of b-ketoester derivative 3 to high levels of
conversion. Notably, the diastereoselectivity is also enhanced
under the guanidinium-catalyzed conditions (Scheme 1).
a
significant synthetic challenge.[1]
Among the limited number of approaches for the formation
of bonds between such sterically congested carbon atoms,
intramolecular processes such as polyene cyclizations,[2a,b]
intramolecular cycloadditions,[2c] and sigmatropic rearrange-
ments[2d,e] have been particularly effective. For addressing
vicinal quaternary carbons, these transformations have only
been applied in a diastereocontrolled manner using substrates
containing pre-existing stereogenic centers, either as part of
cleavable auxiliaries or structural features of the target
molecule. The development of catalytic asymmetric methods
for the direct and selective formation of such stereochemical
arrays represents a highly desirable and challenging goal.
Since its discovery in 1912,[3] the [3,3]-sigmatropic rear-
rangement of allyl vinyl ethers (the Claisen rearrangement)
has emerged as a proven strategy for the formation of carbon–
carbon bonds between vicinal stereogenic centers.[4] Diaste-
reoselectivity is generally predictable and high in these
Scheme 1. N,N’-Diphenylguanidinium-catalyzed rearrangement of
O-allyl b-ketoesters.
Here we report the discovery of chiral guanidinium-
catalyzed Claisen rearrangements of cyclic O-allyl b-ketoest-
ers as a method of broad scope for the formation of branched
allylation products with both enantio- and diastereocontrol.
While direct catalytic enantioselective allylations of b-
ketoester nucleophiles, such as by phase-transfer alkylatio-
n[7a,b] or p-allyl metal chemistry,[7c–e] are highly effective with
simple unsubstituted allyl electrophiles, regioselectivity for
branched allylation and diastereoselectivity using more sub-
stituted electrophiles have proven to be difficult to achieve
and highly dependent on the identity of the reaction
partners.[8]
An extensive catalyst optimization study for the Claisen
rearrangement was undertaken using representative 5- and 6-
membered ring substrates (Table 1, entries 1a and 2). As was
found previously in the rearrangement of O-allyl a-ketoest-
ers,[6] catalyst 2 proved optimal among all catalysts studied in
terms of both rate and enantioselectivity. Variation of the
catalyst diamine backbone, heterocyclic component, or aryl
substituent proved to be detrimental (see Supporting Infor-
mation). The highest enantioselectivities were obtained in
non-polar alkane solvents; however, toluene and dichloro-
methane also proved useful, affording products with only
slightly diminished enantiomeric excess (ee).
À
processes because of the concerted nature of the C O
À
bond-breaking and C C bond-forming events as well as the
large energetic preference for chair-like over boat-like
transition states. Furthermore, important examples of enan-
tioselective methods for Claisen rearrangements involving
Lewis acid catalysis[5] have been identified recently for select
substrates with chelating functional groups.
We reported recently that the achiral guanidinium ion 1,
bearing a non-coordinating tetraarylborate counterion, is a
viable catalyst for the [3,3]-sigmatropic rearrangement of a
wide range of substituted allyl vinyl ethers.[6] Rearrangements
that proceed through highly dipolar transition structures were
found to be particularly amenable to acceleration by hydro-
gen-bond donors. Substrates that meet this requirement
possess either electron-donating substituents on the allyl
group or electron-withdrawing substituents on the vinyl group
in order to stabilize developing charge. In accord with this
observation, the addition of 1 at 5 mol% loading induces
[*] C. Uyeda, A. R. Rꢀtheli, Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University
Awide range of cyclic b-ketoester-derived substrates were
synthesized and evaluated in order to determine the scope of
the reaction. Many of the vinyl ether substrates could be
prepared in modest yield by alkylation of the corresponding
potassium enolate with allyl sulfonates in the presence of
[18]crown-6. Mixtures of C- and O-allylated products were
formed under these conditions, generally favoring the former.
Higher selectivity for O-allylation was obtained under
12 Oxford St., Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-43214). We acknowledge
Matthew Rienzo for experimental assistance and Dr. Richard
Staples for X-ray analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005183.
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Communications
Table 1: Asymmetric rearrangements of cyclic O-allyl b-ketoesters.
and heteroatoms (entries 8–10). In all cases, the products
were isolated in high yield and enantiomeric excesses in the
range of 79% to 87%. The Meerwein–Eschenmoser–Claisen
rearrangement of a methallyloxyindole[10,5b] also proceeded
with similar enantioselectivity, providing the allylated oxin-
dole product (Table 1, entry 11). Indeed, the performance of
catalyst 2 across a broad range of substrates is remarkably
consistent, with the average enantioselectivity for all entries
in Table 1 expressed in terms of free energy (DDG°) being
1.38 kcalmolÀ1 with a relatively narrow standard deviation of
0.1 kcalmolÀ1. Although the degree of asymmetric induction
in these rearrangements is moderate, the broad substrate
scope suggests a general and common basis for enantio-
induction.
High conversion to product is observed for all rearrange-
ments at or near room temperature using 20 mol% loadings
of catalyst 2. For substrates that require extended reaction
times, higher rates can be obtained at higher temperatures
with a small loss of enantioselectivity. For example, the
cyclopentanone methyl ester substrate in entry 1a reached
full conversion after 48 h at 408C, and the product was
obtained in 80% ee.
Due to the pericyclic nature of the [3,3]-sigmatropic
rearrangement, substrates with substitution on the allyl
component undergo rearrangement with complete regiose-
lectivity for branched allylation. The scope for these sub-
strates is illustrated in Table 2. Products of either diastereo-
meric series could be accessed using substrates with (E)- or
(Z)-configured olefins (Table 2, entries 1 and 2). The relative
configuration of the products is consistent with the rearrange-
ment proceeding primarily through a chair-like transition
state.[11] In addition to alkyl substitution, substrates possessing
aryl groups were also effective (entries 3 and 7), providing
products with similar enantioselectivity and slightly dimin-
ished diastereoselectivity. Finally, trisubstituted alkenyl sub-
strates underwent rearrangement to generate products con-
taining vicinal quaternary stereogenic centers (entries 5–7).
For three representative examples in Table 2, the catalyst
loading was reduced to 10 mol% (see entries in parentheses).
Although lower reaction rates were observed, all of the
products were obtained in high yield and with only slightly
diminished ee.
This method holds potential utility for addressing complex
stereochemical relationships in natural product synthesis. A
0.5 mmol-scale rearrangement of the nerylated ethoxycyclo-
hexenone substrate 4 was run under the standard reaction
conditions (Scheme 2). After 72 h, 81% yield of the C-
allylated product 5 was isolated with a 7:1 diastereomeric
ratio and 81% ee for the major diastereomer. Upon
completion of the reaction, analytically pure catalyst (S,S)-2
was recovered in 95% yield. The particular stereochemical
array formed in this rearrangement corresponds directly to
the configuration of quaternary stereocenters found in hyper-
forin,[12] an important member of the polyprenylated phlor-
oglucinol family of natural products. To date, only one
enantioselective total synthesis has been reported.[13] The
rearrangement product 5 was readily elaborated to the
bicyclo[3.3.1]nonane core structure through an iodonium-
induced carbocyclization.[14]
Entry
Product
t, T
Yield
[%][a]
ee
[%][b]
1a[c]
1b
1c
6 days, 308C
6 days, 308C
6 days, 308C
81
82
90
84
83
85
2
3
4
5
6
7
8
6 days, 228C
5 days, 228C
4 days, 228C
72 h, 228C
81
98
94
96
92
92
80
81[d]
87[d]
79
86
48 h, 228C
82
36 h, 228C
82
6 days, 228C
80
9
5 days, 228C
48 h, 228C
72 h, 228C
91
96
90
80
10
11
82
80[d]
[a] Yields of isolated products were determined for rearrangements run
on a 0.1 mmol scale. [b] Enantiomeric excesses were determined by GC
and HPLC analysis using commercial chiral columns. [c] A full screen of
ester substituents was performed for the 5-membered ring substrate.
Details are included in the Supporting Information. [d] The absolute
configurations of the products in entries 2, 3, and 11 were determined by
comparing the optical rotation to values reported in the literature (see
Supporting Information).
Mitsunobu conditions using PPh3 in conjunction with either
diethyl azodicarboxylate (DEAD) or 1,1’-(azodicarbonyl)di-
piperidine (ADDP).[9] This protocol afforded substrates for
the enantioselective Claisen rearrangement in 40–52% iso-
lated yield in a single step from the precursor alcohol and b-
ketoester.
Simple carbocyclic substrates of a variety of ring sizes
(Table 1, entries 1–4) were effective as were those containing
unsaturation (entry 5), fused aromatic rings (entries 6 and 7),
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Chemie
Table 2: Asymmetric rearrangement of substituted O-allyl b-ketoesters.
developing negative charge on the
ether oxygen as well as alleviation
À
of steric hindrance by partial C O
bond-breaking contribute to this
change in geometry. This transition
state binding mode is remarkably
similar to that calculated for the
rearrangement of a model O-allyl
a-ketoester substrate,[6] and pro-
vides a rationale for the observation
that catalyst 2 is capable of high
levels of asymmetric induction for
both substrate classes.
The overall calculated effect of
the guanidinium ion is a 5.3 kcal
molÀ1 lowering of the activation
barrier for the rearrangement.
Additionally, binding of the product
b-ketoester is predicted to be
1.4 kcalmolÀ1 less favorable than
binding of the substrate, consistent
with the observation of catalyst
turnover.
Entry Substrate
Product[a]
t, T
Yield d.r.[c]
[%][b]
ee
[%][d]
48 h, 228C
99
16:1
83
(81)
1
2
3
4
(72 h, 228C)[e] (99) (15:1)
6 days, 408C
82
16:1
81
48 h, 48C
99
5:1
83
(80)
(72 h, 48C)[e]
(99) (5:1)
48 h, 408C
87
–
82
(81)
(72 h, 408C)[e] (99) (–)
5
6
6 days, 308C
6 days, 308C
99
99
10:1
82
Ongoing efforts are directed at
applying insights gleaned from this
system to other fundamental trans-
formations that are amenable to
asymmetric catalysis by hydrogen-
bond donors.
10:1
5:1
85
78
Experimental Section
5: 167.2 g of the substrate 4 (1.0 equiv,
0.5 mmol) was weighed into a 20 mL
screw-top vial and dissolved in 10 mL of
hexanes. 137.0 mg of (S,S)-2 (20 mol%,
7
4 days, 228C
48 h, 228C
99
98
8[11]
> 20:1 85
0.1 mmol) was added as a solid, and the
vial was sealed under air. The heteroge-
neous reaction was stirred in a temper-
ature-controlled aluminum heating
[a] Major diastereomer. [b] Yields of isolated products were determined for rearrangements run on a
0.1 mmol scale. [c] Diastereomer ratios were determined by H NMR spectroscopy. [d] Enantiomeric
1
excesses were determined by chiral GC and HPLC analysis using commercial chiral columns. [e] The
yield, d.r., and ee in parentheses were obtained using 10 mol% of the catalyst under the reactions
conditions shown.
block at 308C for 72 h. The crude
mixture was concentrated under re-
duced pressure and loaded directly
onto a silica gel column. The product
was eluted using a solvent gradient of 0–
50% Et2O in hexanes. The catalyst was
Computational studies were conducted in order to probe
the nature of the catalyst–substrate interaction and the basis
for the observed accelerations. Calculated lowest energy
structures for the substrate, product, and transition state for
both the uncatalyzed and N,N’-dimethylguanidinium-cata-
lyzed reaction pathways are depicted in Figure 1.
then recovered from the column by eluting with 4% MeOH in
CH2Cl2. 130.8 mg of (S,S)-2 (95% recovery) was isolated after drying
under reduced pressure (0.5 torr). 135.5 mg of the rearranged product
5 (0.41 mmol, 81% yield) was isolated as a 7:1 mixture of diastereo-
mers (determined by 1H NMR integration). The major diastereomer
was determined to be 81% ee by chiral HPLC analysis (OD-H,
1 mLminÀ1
, 2% isopropyl alcohol (IPA)/hexanes, tr(major) =
While a slight energetic preference for the s-trans
conformation of the a,b-unsaturated ester was calculated
for the uncatalyzed pathway, there is a large preference for
the s-cis conformation in the catalyzed pathway. This
geometry permits simultaneous interactions between the
catalyst and both the ester and vinyl ether oxygen atoms.
While the substrate is bound primarily through the more
Lewis basic ester group, binding is biased toward the ether
oxygen in the transition state. It is likely that both the
21.6 min, tr(minor) = 15.9 min), and the minor diastereomer was
determined to be 40% ee (OD-H, 1 mLminÀ1, 2% IPA/hexanes,
tr(major) = 23.9 min, tr(minor) = 18.0 min). [a]2D3 = À74.28 (c = 0.37,
1
CH2Cl2); H NMR (600 MHz, CDCl3): d = 6.25 (br. m, 1H), 5.30 (s,
1H), 5.10 (d, J = 11.0 Hz, 1H), 5.06 (t, J = 7.0 Hz, 1H), 4.92 (d, J =
17.1 Hz, 1H), 3.85 (q, J = 7.0 Hz, 2H), 3.65 (s, 3H), 2.48–2.30 (m, 2H),
2.30–2.21 (m, 1H), 2.20–1.71 (m, 4H), 1.64 (s, 3H), 1.55 (s, 3H), 1.46–
1.36 (m, 1H), 1.33 (t, J = 7.0 Hz, 3H), 1.16 ppm (s, 3H); 13C NMR
(126 MHz, CDCl3): d = 195.7, 175.3, 171.4, 143.8, 131.1, 125.0, 113.9,
104.6, 64.4, 62.2, 52.1, 46.1, 35.9, 27.9, 27.0, 25.8, 23.2, 17.7, 17.3,
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Scheme 2. Claisen rearrangement to establish the vicinal quaternary
stereogenic centers found in hyperforin and subsequent elaboration to
the bicyclo[3.3.1]nonane core structure.
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Figure 1. Calculated reaction coordinate for the uncatalyzed (top) and
N,N’-dimethylguanidinium-catalyzed (bottom) rearrangement at the
B3LYP/6-311+G(d,p) level of DFT. Relative energies are in kcalmolÀ1
,
and key hydrogen-bond distances are shown in Angstroms.
14.2 ppm; LRMS (APCI-ESI): 357.2 [M+Na]+; FTIR (neat): n˜ = 2980
(w), 1724 (m), 1660 (m), 1614 (s), 1431 (w), 1381 (m), 1314 (w), 1231
(m), 1189 (s), 1035 (w), 897 cmÀ1 (w).
Received: August 18, 2010
Published online: November 15, 2010
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Keywords: asymmetric catalysis · Claisen rearrangement ·
.
hydrogen bonding · keto esters · organocatalysis
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