Construction of adjacent quaternary and tertiary stereocenters via an organocatalytic allylic alkylation of Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1002/adsc.200600467

Racemic Baylis-Hillman carbonates can be converted in densely functionalized products by reaction with cyano esters in the presence of a catalytic amount of a modified Cinchona alkaloid in high enantioselectivities and fair diastereoselectivities. A ratio

Full text of DOI:10.1002/adsc.200600467

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DOI: 10.1002/adsc.200600467
Construction of Adjacent Quaternary and Tertiary Stereocenters
via an Organocatalytic Allylic Alkylation of Morita–Baylis–Hill-
man Carbonates
Dirk Jan V. C. van Steenis,a Tommaso Marcelli,a Martin Lutz,b Anthony L. Spek,b
a,
Jan H. van Maarseveen,a andHenk Hiemstra *
a
Van ’t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam,
The Netherlands
Fax : (+31)-20-5252-5670; e-mail: hiemstra@science.uva.nl
Bijvoet Center for Biomolecular Research, Crystal andStructural Chemistry, Utrecht University, Padualaan 8, 3584 CH
b
Utrecht, The Netherlands
Received: September 12, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Racemic Baylis–Hillman carbonates can
be convertedin densely functionalizedproducts by
reaction with cyano esters in the presence of a cata-
lytic amount of a modified Cinchona alkaloidin
high enantioselectivities andfair diastereoselectivi-
ties. A rational for the observedstereoselectivity is
presented.
philic organocatalyst,[5] relying on a tandem SN2’/SN2’
substitution sequence (Scheme 1).
[7]
DABCO[6] andtriphenylphosphine were shown to
catalyze the allylic substitution of MBH adducts with
goodregioselectivity. Krische et al. reportedthat com-
mercially available Cl-OMe-BIPHEP promotes the
amination of MBH acetates with phthalimide in 56%
ee.[8] Cinchona derivatives were also employed as cat-
alysts for relatedtransformations: (DHQD) 2PHAL
was usedin the asymmetric hydrolysis of MBH ace-
tates with sodium bicarbonate, giving medium to high
levels of asymmetric induction (up to 84% ee).[9] Lu
andco-workers investigatedthe reaction of MBH car-
bonates with a variety of nucleophiles in the presence
of a catalytic amount of b-isocupreidine (b-ICPD),[10]
Keywords: allylic substitution; asymmetric catalysis;
Baylis–Hillman reaction; Cinchona alkaloids; hy-
drogen bond
The enantioselective construction of all-carbon qua- a strained quinidine derivative that was earlier used
ternary stereocenters still represents a major chal- by Hatakeyama et al. to achieve excellent levels of
lenge in synthetic organic chemistry.[1] The simultane- enantioselection in the parent MBH reaction of alde-
ous generation of two adjacent quaternary and terti- hydes and activated acrylates.[11] Remarkably, besides
ary stereocenters is even more problematic and, to
date, only few examples have been reported, all of
them relying on conjugate additions.[2]
The Morita–Baylis–Hillman (MBH) reaction has
attractedthe attention of many research groups, due
to the possibility of accessing densely functionalized
products in one step.[3] In the last decade, these efforts
have resultedin great progress being made in terms
of rate, scope andenantioselectivity. Upon conversion
of the alcohol to a leaving group, MBH adducts
become substrates for asymmetric allylic substitution.
Trost andco-workers successfully appliedthis strategy
to the synthesis of natural products employing chiral
palladium catalysts in the dynamic kinetic resolution
of MBH acetates.[4]
More recently, other groups investigatedthe feasi-
bility of this reaction with an (asymmetric) nucleo- tion.
Scheme 1. Organocatalytic vs. Pd-catalyzed allylic substitu-
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Dirk Jan V. C. van Steenis et al.
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Table 1. Substrate scope for the organocatalytic allylic alkylation.[a]
[b]
Entry
1
Product
T [8C]
À20
t [h]
Yield[%]
94
dr[c]
ee [%][d]
48
4:1
83
2
3
0
96
72
95
95
4:1
79
80
À20
1.4:1
4
5
À20
48
24
95
1.1:1
4:1
16
85
20
66[e]
6
À20
72
95[f]
3:1
80
[a]
Reaction conditions: 0.6 mmol 1, 0.3 mmol 2, 0.06 mmol b-ICPD in 6 mL toluene.
Isolatedyield(mixture of diastereomers).
[b]
[c]
[d]
[e]
[f]
Determinedby 1H NMR analysis of the crude reaction mixture.
The ee value of the major diastereoisomer was determined by chiral HPLC.
Compound 3e was obtainedas a pure diasteromer.
Reaction performedon 9.0 mmol of 1f
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Construction of Adjacent Quaternary and Tertiary Stereocenters
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Scheme 2. Reaction of an MBH carbonate with dimethyl
malonate.
nitrogen andoxygen nucleophiles, the authors report-
edthe reaction of an MBH carbonate with dimethyl
malonate. Although the enantioselectivity was moder-
ate (51% ee), Lu andco-workers establishedfor the
first time the possibility of using carbon nucleophiles
for an organocatalytic allylic alkylation. In this com-
munication we report our investigations on the same
reaction using prochiral tertiary nucleophiles thus
leading to products with two adjacent quaternary/ter-
tiary stereocenters.
Figure 1. Displacement ellipsoidplot of compound 3f in the
crystal, drawn at the 50% probability level.
In our preliminary experiments, we re-investigated
the reaction of carbonate 1a with dimethyl malonate
in the presence of b-ICPD: although screening of dif-
ferent reaction conditions (solvent, concentration,
temperature) did not improve the results reported by
Lu, we foundthat the employment of a methyl ester
as the electrophile resultedin slightly higher levels of
asymmetric induction (63 vs. 51% ee, Scheme 2).
Next, we examinedthe reaction of compound 1a
with highly reactive ethyl a,a-cyanophenylacetate
(2a) in toluene at room temperature. The reaction
Scheme 3. Kinetic resolution of MBH carbonate 1f.
As some adducts were obtained as crystalline solids
went to completion in less than 24 h with high regio- after chromatography, we ran a reaction on a gram
selectivity yet moderate stereoselectivity (dr 3:1, 68% scale with the aim to upgrade the optical purity of the
ee for the major diastereomer). Employment of an product via recrystallization. Hence, compound 1f
excess of compound 1a gave a strong rate enhance- (3.3 g, 9.0 mmol) was reactedwith cyanoacetate 2a
ment, probably due to a kinetic resolution effect (see (0.78 mL, 4.5 mmol) to afford, after chromatography,
later), allowing the reaction to be carriedout at a
lower temperature. Gratifyingly, performing the reac- single recrystallization from cyclohexane afforded
tion at À208C with 20 mol% of b-ICPD resultedin compound 3f (59% yield, calculated on cyanoacetate
full conversion to the adduct 3a in 83% ee (dr 4:1). 2a) with 98% ee as a pure diastereomer.[12] X-ray
We then examineddifferent combinations of reaction analysis of these crystals allowedan unambiguous as-
adduct 3f in 80% ee and95% yield(entry 7). A
partners (Table 1). In general, compounds 3 were ob- signment of the absolute andrelative configuration
tainedin high yielsd andgoodenantioselectivities.
Substrate 1d gave disappointing results, possibly due
(Figure 1).[13]
Interestingly, HPLC analysis of the recoveredstart-
to its high reactivity towards conjugate addition. Hin- ing material (1f) gave evidence for a kinetic resolu-
dered substrates (1b and 1e, entries 2 and5) required tion effect (Scheme 3). Compound 1f was isolated
slightly higher temperatures to obtain satisfying reac- from the crude mixture after column chromatography
tion rates; fortunately, the level of enantioselection in 90% ee. Recrystallization afforded enantiopure
was not negatively affected.
crystals (47% yieldbasedon 2a) whose absolute con-
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Dirk Jan V. C. van Steenis et al.
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Figure 2. Displacement ellipsoidplot of compound 1f in the
crystal, drawn at the 50% probability level.
figuration couldbe determinedwith X-ray spectrosco-
py (Figure 2).
[9]
As suggestedby Kim andco-workers,
who ob-
Scheme 4. Effects of the structure of catalyst andsubstrate.
serveda similar effect, this can be explainedin terms
of a kinetic resolution in the first step. This process,
however, does not affect the stereoselectivity of the protonates cyanoacetate 2a which, in turn, attacks the
À
second conjugate addition generating the C C bond. a,b-unsaturatedintermeidate
B, present as the E
[9]
To confirm that we examinedthe reaction of 1 equiv-
isomer, as previously shown by Kim andco-workers.
alent of 1a with 2 equivalents of 2a at room tempera- Probably, an intramolecular hydrogen bond between
ture (hence reversing the reagents ratio): after 24 h, the phenolic OH andthe ester moiety is responsible
1a was completely convertedto 3a with similar stereo- for the face shielding conferring stereoselectivity to
selectivity (68% ee, 3:1 dr), showing that both enan- the reaction; a DFT-minimizedstructure of B sup-
tiomers of the MBH carbonate undergo Michael addi- porting this hypothesis is depicted in Figure 3. Elimi-
tion although with different rates, followed by elimi- nation of the catalyst from intermediate C liberates
nation of the leaving group leading to the same inter- alkylatedproduct 3a, closing the catalytic cycle.
mediate.
In conclusion, we have developed a new methodol-
Next, we investigatedthe role of the C-6 ’-OH of b- ogy to access highly functionalizedcompounds featur-
ICPD, which was shown to be fundamental in the ing two adjacent stereocenters, one of them bearing
Baylis–Hillman reaction.[11] When b-isoquinidine (b- four carbon substituents. We also demonstrated for
IQD) was usedas the catalyst, less than 5% conver-
sion was observedafter two weeks. Furthermore, sub-
one example that the same reaction can be exploited
as a kinetic resolution to obtain highly enantioen-
strate 4, featuring a cyano group (a poorer hydrogen richedMBH carbonates.
bondacceptor) insteadof a methyl ester, underwent
allylic substitution giving adduct 5 in high yieldbut
no asymmetric induction was observed (Scheme 4).
On the basis of all these observations, we propose a
tentative hypothesis to rationalize our experimental
Experimental Section
General Procedure for the Asymmetric Allylic
results (Scheme 5). First, substrate 1a undergoes a
conjugate addition to form adduct A. Subsequently,
elimination of the OBoc group, leading to the forma-
tion of CO2 and tert-butoxide anion provides Michael
acceptor B. We believe that this irreversible reaction
step is responsible for the observedkinetic resolution.
As shown in the experiment with b-isoquinidine, the
presence of the C-6’-OH in the catalyst is requiredfor
activation of the ester prior to conjugate addition. As
Alkylation of MBH Carbonates (1a–f and 4)
b-ICPD (20 mol%) was added to the total volume of tolu-
ene andthe resulting suspension was heatedandstirred
until formation of a clear solution. Subsequently, the mix-
ture was allowedto cool to the indicatedtemperature. The
MBH carbonate (1a–f or 4) was added to the reaction mix-
ture andthe mixture was stirreduntil complete dissolution
(~5–10 min). Cyanoacetate (2a or b) was added in one por-
tion andthe mixture was kept at the indicatedtemperature
already proposed by Lu,[10] the tert-butoxide anion de- for the described reaction time. The experiments were stop-
284
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Construction of Adjacent Quaternary and Tertiary Stereocenters
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Scheme 5. Proposedmechanism.
Figure 3. Minimizedstructure of intermediate B (B3LYP/6-31G**).
pedby filtration of the reaction mixture over a short padof
Acknowledgements
silica gel andelution with Et O. Solvents were removedby
2
rotary evaporation andthe crude mixture was purifiedby
column chromatography.
The Dutch “National Research School Combination: Cataly-
sis” (NRSC-C) is gratefully acknowledged for financial sup-
port.
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285

Dirk Jan V. C. van Steenis et al.
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