Catalytic, asymmetric vinylogous Mukaiyama aldol reactions of pyrrole- and furan-based dienoxy silanes: How the diene heteroatom impacts stereocontrol

Article abstract of DOI:10.1002/adsc.201000189

Denmark's chiral bisphosphoramide/silicon tetrachloride system performs as an excellent Lewis base-Lewis acid catalyst for the vinylogous Mukaiyama aldol reaction of pyrrole- and furan-based dienoxy silanes with aromatic and heteroaromatic aldehydes. This asymmetric methodology provides a powerful synthetic entry to a variety of d-hydroxylated g-butenolide-type frameworks with high efficiency and valuable margins of regio-, diastereo-, and enantioselectivity. Notably, the nature of the heteroatom within the vinylogous dienoxy silane donor heavily impacts the diastereocontrol, with syn-configured aldol adducts emerging from pyrroles bearing electron- withdrawing N-protecting groups (Boc, Ts, and Cbz) and anti-configured adducts prevailing when furan- or N-alkyl/alkenylpyrrole donors are involved.

Full text of DOI:10.1002/adsc.201000189

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DOI: 10.1002/adsc.201000189
Catalytic, Asymmetric Vinylogous Mukaiyama Aldol Reactions
of Pyrrole- and Furan-Based Dienoxy Silanes: How the Diene
Heteroatom Impacts Stereocontrol
Claudio Curti,a,* Beatrice Ranieri,a Lucia Battistini,a Gloria Rassu,b
Vincenzo Zambrano,b Giorgio Pelosi,c Giovanni Casiraghi,a,*
and Franca Zanardia,*
a
Dipartimento Farmaceutico, Universitꢀ degli Studi di Parma, Viale G. P. Usberti 27A, 43124 Parma, Italy
Fax : (+39)-0521-90-5006; phone: (+39)-0521-90-5079 (C.C.), (+39)-0521-90-5080 (G.C.), (+39)-0521-90-5067 (F.Z.);
e-mail: claudio.curti@unipr.it, giovanni.casiraghi@unipr.it or franca.zanardi@unipr.it
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, 07100 Li Punti, Sassari, Italy
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Universitꢀ degli Studi di Parma,
b
c
Viale G. P. Usberti 17A, 43124 Parma, Italy
Received: March 10, 2010; Revised: June 8, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000189.
Abstract: Denmarkꢁs chiral bisphosphoramide/silicon within the vinylogous dienoxy silane donor heavily
tetrachloride system performs as an excellent Lewis impacts the diastereocontrol, with syn-configured
base-Lewis acid catalyst for the vinylogous Mukaiya- aldol adducts emerging from pyrroles bearing elec-
ma aldol reaction of pyrrole- and furan-based dien- tron-withdrawing N-protecting groups (Boc, Ts, and
oxy silanes with aromatic and heteroaromatic alde- Cbz) and anti-configured adducts prevailing when
hydes. This asymmetric methodology provides a furan- or N-alkyl/alkenylpyrrole donors are involved.
powerful synthetic entry to a variety of d-hydroxylat-
ed g-butenolide-type frameworks with high efficiency Keywords: asymmetric catalysis; asymmetric synthe-
and valuable margins of regio-, diastereo-, and enan- sis; diastereoselectivity; enantioselectivity; heterocy-
tioselectivity. Notably, the nature of the heteroatom clic dienoxy silanes; vinylogous aldol reaction
Introduction
carbon version [Eq. (2)]. In this scenario, unsaturated
heterocyclic adducts C and saturated open chain seg-
The asymmetric vinylogous aldol reaction, where the ments D, embedding a heteroatom substituent at the
immediate enantio-enriched adduct – an a,b-unsatu- g-carbon, clearly possess an improved functional com-
rated d-hydroxy carbonyl compound – often becomes plexity as compared to F and G, which emerge from
the substrate for targets of increasing molecular com- acyclic VMAR. The superior functionality asset of
plexity, has come to the fore as a chemical manoeuvre heterocyclic intermediary compounds of type C/D
that is now ranking amongst the most effective and has, in fact, been exploited by us and others to forge a
atom-conservative carbon-carbon bond-forming meth- variety of heteroatom-containing target structures
odologies.[1] For the past several years, we have been spanning from unusual amino acids and sugars to car-
active in this area by developing a triad of heterocy- basugars, alkaloids, and sophisticated secondary me-
clic dienoxy silanes based on furan, pyrrole, and thio- tabolites.[2]
phene rings (compounds A in Figure 1), which
As a continuation of our program aimed at the de-
emerged as a class of vinylogous donors rich in utility velopment of the heterocyclic VMAR in asymmetric
for the assembly of highly decorated carbon segments synthesis, we herein report a full study on the catalyt-
and privileged molecular scaffolds.[1a,h,2]
ic, enantioselective VMAR of pyrrole- and furan-
The example pictured in Figure 1 confronts a vinyl- based dienoxy silane donors with aromatic and heter-
ogous Mukaiyama-type aldol reaction (VMAR) in- oaromatic aldehydes, which resulted in the synthesis
volving heterocycles A [Eq. (1)] with an acyclic all- of a variety of butenolide-like frameworks with high
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Claudio Curti et al.
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Figure 1. Heterocyclic [Eq. (1)] vs. acyclic [Eq. (2)] VMAR, showing the improved functionality asset of segments C/D as
compared to F/G.
efficiency and valuable margins of regio-, diastereo- Results and Discussion
and enantioselectivity.[3]
Key to the success of this investigation was the ex- Synthesis
ploitation of Denmarkꢁs bisphosphoramide/silicon tet-
rachloride catalyst system, that had previously proven An initial catalyst screening was performed for the re-
to be highly performing in several asymmetric aldol[4] action between silyloxypyrrole 1a and benzaldehyde
and vinylogous aldol[5] reactions.
(2a), by employing a set of representative chiral
Variation of syn vs. anti selectivity by tuning the metal-based catalysts that had already proven to be
nature of the diene heteroatom component was also effective promoters during stereoselective simple and/
investigated, in order for these processes to reach a or vinylogous Mukaiyama aldol addition reactions
firm and faithful stereodivergence control.
(Figure 2). Of the investigated chiral catalysts, which
included oxazaborolidinone (S)-4a,[6] (R)-BINOL/(+)-
[a]
Figure 2. Chiral catalysts screened in VMAR between pyrrole 1a and benzaldehyde (2a).
Pyrrole 1a/aldehyde 2a (1.1/
1.0 mol equiv.), (S)-4a (50.0 mol%), i-PrOH (1.1 equiv.), with a substrate concentration of 0.25M (0.5 mmol scale) in n-
[b]
PrCN, at À788C, with a 20 h reaction time.
Pyrrole 1a/aldehyde 2a (1.5/1.0 mol equiv.), TiACTHNGUTRENU(NG O-i-Pr)4/(R)-BINOL/(+)-
TADDOL (1:1:1) (4b) (20.0 mol%), with a substrate concentration of 0.25M (0.5 mmol scale) in Et2O, at À208C, with a 20 h
[c]
reaction time. Pyrrole 1a/aldehyde 2a (2.0/1.0 mol equiv.), (R,R)-4c (3.0 mol%), SiCl4 (1.1 mol equiv., refluxed and redistil-
led under argon atmosphere), DIPEA (10.0 mol%), with a substrate concentration of 0.25M (0.5 mmol scale) in CH2Cl2, at
[d]
À788C, with a 20 h reaction time. Pyrrole 1a/aldehyde 2a (1.5/1.0 mol equiv.), (S,S)-4d (10.0 mol%), with a substrate con-
centration of 0.25M (0.5 mmol scale) in CH2Cl2, at À788C, with a 20 h reaction time.
2012
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Catalytic, Asymmetric Vinylogous Mukaiyama Aldol Reactions of Pyrrole- and Furan-Based Dienoxy Silanes
Table 1. Heterocyclic VMAR using different pyrrole donors.
Entry Donor R3
PG
Major product Yield [%][b,c] g:a[b]
dr (syn:anti)[b] ee [%] (syn)[d] ee [%] (anti)[d]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
1h
1i
t-BuMe2 Boc
syn-3aa
syn-3aa
syn-3aa
syn-3aa
syn-3aa
syn-3af
syn-3ag
anti-3ah
>99 (97)
99 (96)
80 (72)
>99 (96)
60 (56)
80 (75)
>99 (97)
60 (40)
80(50)
80 (65)
75 (50)
no reaction
8 (7)
>99:1 >99.5:0.5
>99
96
Me3
Et3
i-Pr3
Boc
Boc
Boc
>99:1 99.5:0.5
>99:1 99.6:0.4
>99:1 >99.5:0.5
>99:1 >99.5:0.5
>99:1 >99.5:0.5
>99:1 >99.5:0.5
>99:1 21.9:78.1
>99:1 17.0:83.0
>99:1 15.0:85.0
>99:1 9.1:90.9
>99
>99
>99
93.7
97
<10
<10
>10
racemic
t-BuPh2 Boc
t-BuMe2 Ts
t-BuMe2 Cbz
t-BuMe2 Bn
8[e]
9[e]
10[e]
11[e,f]
<10
<10
23
t-BuMe2 PMB anti-3ai
1j
1h
t-BuMe2 allyl
t-BuMe2 Bn
t-BuMe2 Bn
t-BuMe2 Boc
anti-3aj
anti-3ah
anti-3ah
syn-3aa
racemic
12[e,g] 1h
13[f]
1a
>99:1 90:10
racemic
racemic
[a]
Unless otherwise stated, the reactions were carried out in the presence of pyrroles 1/aldehyde 2a (2.0/1.0 mol equiv.),
(R,R)-4c (3.0 mol%), SiCl4 (1.1 mol equiv., refluxed and redistilled under argon atmosphere), DIPEA (10.0 mol%), with
a substrate concentration of 0.25M (0.5 mmol scale) in CH2Cl2, at À788C, with a 20 h reaction time. For details, see Ex-
perimental Section.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR analysis of the crude reaction product.
In parenthesis, combined yield of isolated products 3a after flash chromatography.
Determined by HPLC analysis with Chiralcel OD-H or Regis Welk-O1 columns.
Reaction time 3 h.
The reaction was carried out in the absence of (R,R)-4c.
The reaction was carried out in the absence of SiCl4.
[g]
TADDOL-based mixed Ti-complex 4b,[7] bisphosphor- actions with benzaldehyde (entries 1 vs. 6–10). Re-
amide (R,R)-4c/silicon tetrachloride complex, and markably, reactions involving pyrroles bearing elec-
copper-bisoxazoline catalyst (S,S)-4d,[8] only the dual tron-withdrawing – and possibly silicon-coordinating
Lewis base-Lewis acid 4c/SiCl4 system, discovered (vide infra) – N-protecting groups such as Ts and Cbz,
and rigorously exploited by Denmark and co-work- perfectly reflected the behaviour of the control reac-
ers,[4,5] catalyzed the asymmetric formation of the ex- tion with N-Boc-pyrrole 1a, with the respective ad-
pected lactam adducts 3aa with high levels of regio-, ducts syn-3af and syn-3ag obtained in 75% and 97%
diastereo- and enantioselectivity (>99:1 g:a ratio, isolated yields and no erosion in regio- and stereose-
>99.5:0.5 dr, and >99% ee for the syn-configured lectivity (entries 6 and 7).
5S,1’S-isomer 3aa).
Rather surprisingly, swapping the pyrrole N-pro-
Thus, having established that Denmarkꢁs catalyst tecting group to electron-donating substituents, such
pair ligand 4c/SiCl4 (3.0 mol% ligand for 1.1 mo- as for substrates 1h, 1i, and 1j, caused a dramatic re-
l equiv. SiCl4) in CH2Cl2 was the optimal system to versal of diastereoselectivity, with (5R,1’S) anti-config-
propel and govern the asymmetric VMAR process ured vinylogous adducts anti-3ah, anti-3ai, and anti-
between 1a and benzaldehyde (2a), the next task was 3aj being obtained as the major components, in mod-
to investigate the scope of the reaction with respect erate to good conversions.[9] Regrettably, in these in-
to the heterocyclic donor partner. Variation of the stances, the enantiopurity of the aldol products was
silyl component in the pyrrole from TBS to TMS, greatly affected, possibly due to acceleration of the
TES, TIPS, and TBDPS (Table 1, entries 1 vs. 2–5) competitive achiral background pathways (see control
did not perturb the overall selectivity of the VMARs, experiments in entries 11 and 12 vs. 13).[10]
with (5S,1’S)-configured syn-3aa being obtained
almost exclusively.
To assess the full scope of the procedure and fix the
issue of the N-protecting group-driven syn-anti dia-
Variation of the pyrrole N-protecting group in the stereodivergence, the scope of VMAR between sily-
series N-Boc 1a, N-Ts 1f, N-Cbz 1g, N-Bn 1h, N-PMB loxypyrroles 1a and 1h, 1j – emblems for both elec-
1i, and N-allyl 1j, was then scrutinized in standard re- tron-poor and electron-rich pyrrole donors – and a
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Table 2. Heterocyclic VMAR using different aldehyde acceptors.
Entry Donor PG Acceptor R
Major
product
Yield [%][b,c] g:a[b] dr
(syn:anti)[b]
ee [%] (syn)[d] ee [%] (anti)[d]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1h
1h
1j
Boc 2a
Boc 2b
Boc 2c
Boc 2d
Boc 2e
Boc 2f
Boc 2g
Boc 2h
Bn 2a
Bn 2b
allyl 2b
allyl 2i
Ph
syn-3aa >99 (97)
syn-3ba 99 (96)
syn-3ca 97 (92)
syn-3da 82 (77)
syn-3ea 92 (87)
syn-3fa 99 (93)
>99:1 >99.5:0.5 >99
>99:1 >99.5:0.5 >99
>99:1 >99.5:0.5 96.2
p-MeO-C6H4
p-F-C6H4
p-NO2-C6H4
2-furanyl
2-thiophenyl
2-naphthalenyl syn-3ga 99 (85)
2-styryl
Ph
>99:1 84.0:16.0
73.6
>99:1 >99.5:0.5 74.6
>99:1 >99.0:1.0 88.4
>99:1 >99.0:1.0 99.0
>99:1 >99.0:1.0 45.1
syn-3ha 99 (94)
anti-3ah 60 (40)
anti-3bh 65 (49)
anti-3bj 70 (55)
anti-3ij 60 (40)
9[e]
10[e]
11[e]
12[e]
>99:1 21.9:78.1
>99:1 20.0:80.0
>99:1 25.0:75.0
>99:1 15.0:85.0
<10.0
>10
12.5
40.0
<10
p-MeO-C6H4
p-MeO-C6H4
p-Br-C6H4
41.0
81.0
<10
1j
[a]
The reactions were carried out in the presence of pyrroles 1/aldehydes 2 (2.0/1.0 mol equiv.), (R,R)-4c (3.0 mol%), SiCl4
(1.1 mol equiv, refluxed and redistilled under argon atmosphere), DIPEA (10.0 mol%), with a substrate concentration of
0.25M (0.5 mmol scale) in CH2Cl2, at À788C, with a 20 h reaction time. For details, see Experimental Section.
[b]
[c]
[d]
[e]
1
Determined by H NMR analysis of the crude reaction product.
Combined yield of isolated products 3 after flash chromatography in parenthesis.
Determined by HPLC analysis with Chiralcel OD-H or Regis Welk-O1 columns.
Reaction time 3 h.
series of aromatic and heteroaromatic aldehydes was cused on catalytic, enantioselective VMARs of 2-(tri-
especially investigated (Table 2). Under the optimal methylsilyloxy)furan,[5g,7a,j,8e,f,11] exploiting different
conditions summarized in Table 1, VMARs involving catalyst systems and, in particular, the same Den-
1a and aldehydes 2a–h performed well, invariably markꢁs bisphosphoramide 4c/SiCl4 catalyst pair used
producing the expected 5,1’-syn (5S,1’S)-configured by us. In this last instance,[5g] the authors claimed that,
adducts syn-3aa-syn-3ha with outstanding margins of with a number of aromatic aldehydes, marked prefer-
regio-, diastereo-, and enantioselectivity. In truth, ence for 5,1’-anti butenolide products was assessed;
some enantioselectivity clouding was witnessed with and this emphasized the decisive, stereodirecting role
p-nitrobenzaldehyde (2d) and furan 2-carbaldehyde of the heteroatom embodied in the silyloxy substrate.
(2e) additions (entries 4 and 5) and, markedly, with
Since no definitive clues were supplied to support
cinnamaldehyde 2h (entry 8). In such instances, the the stereochemical identity of the butenolide products
improved reactivity of these substrates could have ac- (relative configuration assignment given by NMR
celerated the parasitic, competitive achiral back- comparison to literature data and absolute configura-
ground pathway, with detrimental effects to the tion assignment not given), we undertook a study to
chiral, bisphosphoramide-catalyzed process. En- clarify this delicate point. Here, 2-(tert-butyldimethyl-
tries 9–12, conversely, illustrate how benzyl- and allyl- silyloxy)furan (5) was employed as the donor, basical-
protected pyrroles 1h and 1j behaved. Actually, a dia- ly employing the reaction conditions in Table 1 and
stereoselectivity switch from syn- to anti-adducts was Table 2, with a slight variation in the solvent (CH2Cl2/
confirmed in all instances, with 3ah, 3bh, 3bj, and 3ij THF 9:1 en lieu of neat CH2Cl2).[12]
being isolated predominantly, in acceptable yields.
However, as expected, the enantioselectivity of the emerge: (1) the study confirmed the previously pub-
reactions declined considerably.
lished data[5g] with comparable efficiency and stereo-
From the data displayed in Table 3, several points
To investigate more precisely the correlation be- selectivity; (2) the 5,1’-anti relative configurations of
tween the stereochemical outcome of VMAR and the the major isomers indeed matched those argued by
inner stereoelectronic nature of the silyloxy diene het- Scettri et al.[5g] (vide infra); (3) the absolute configura-
eroatom, we finally moved to furan-based donors. We tions of both anti- and syn-isomers were definitely as-
were aware of notable precedents in this field, fo- signed as (5R,1’S) and (5S,1’S), respectively, by X-ray
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Catalytic, Asymmetric Vinylogous Mukaiyama Aldol Reactions of Pyrrole- and Furan-Based Dienoxy Silanes
Table 3. Heterocyclic VMAR between TBS-furan donor 5 and several aldehyde acceptors.
Entry Acceptor
R
Major product Yield [%][b,c] g:a[b]
dr (anti:syn)[b] ee [%] (anti)[d] ee [%] (syn)[d]
1
2
3
4
5
6
7
2a
2b
2d
2g
2h
2i
Ph
anti-6a
anti-6b
anti-6d
>99 (95)
83 (80)
55 (51)
>99 (95)
99 (95)
>99 (95)
90 (92)
>99:1 76.9:23.1
>99:1 73.7:26.3
>99:1 82.7:17.3
>99:1 76.6:23.4
>99:1 86.0:14.0
>99:1 80.4:19.6
>99:1 84.8:15.2
>99
>99
89.4
92.8
88.0
95.6
81.6
92.8
94.6
37.4
86.8
nd
p-MeO-C6H4
p-NO2-C6H4
2-naphthalenyl anti-6g
2-styryl
p-Br-C6H4
o-Me-C6H4
anti-6h
anti-6i
anti-6j
99
90
2j
[a]
The reactions were carried out in the presence of furan 5/aldehydes 2 (2.0/1.0 mol equiv.), (R,R)-4c (3.0 mol%), SiCl4
(1.1 mol equiv, refluxed and redistilled under argon atmosphere), DIPEA (10.0 mol%), with a substrate concentration of
0.25M (0.5 mmol scale) in CH2Cl2/THF 9:1 at À788C, with a 20 h reaction time. For details, see Experimental Section.
[b]
[c]
[d]
1
Determined by H NMR analysis of the crude reaction product.
In parenthesis, combined yield of isolated products 6 after flash chromatography.
Determined by HPLC analysis with a Chiralcel OD-H column.
analysis (vide infra); (4) the stereo-orienting role ex-
For the pyrrole series, with scant precedents in the
erted by the heteroatom in the silyloxy donor was literature,[13] stereochemical assignment of compound
firmly stated (vide infra).
syn-3aa – whose levorotatory [a]D value,[14] negative
CD molar ellipticity (p-p* Cotton effect),[15] and large
3J5,1’ 1H-1H NMR coupling constant[12,13c] were symp-
toms of a (5S,1’S)-syn configuration – was firstly car-
ried out by chemical correlation to a known substance
Stereochemical Assessment
In asymmetric catalysis and in natural product of certified structure (X-ray) (see Scheme S1 in Sup-
chemistry, unambiguous certification of the relative porting Information). In addition, derivatization of
and absolute stereochemistry of chiral non-racemic syn-3aa to crystalline menthyl compound 7 allowed us
compounds is often a decisive issue. Here, we did not to definitely confirm its three-dimensional disposition
escape adhering to this commandment, with a careful via single crystal X-ray analysis (Figure 3).
examination of literature data and further, definitive
analyses.
By analogy, the stereostructures of all levorotatory,
Boc-protected lactams syn-3ba/syn-3ha, as well as
tosyl- and carbobenzyloxy compounds syn-3af and
Figure 3. ORTEP representation of the X-ray structure of menthyl derivative 7.
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Claudio Curti et al.
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Finally, the stereostructures of the remaining lac-
tones 6a–6h and 6j were confidently attributed by
analogy, based on the above disclosed chiro-optical
and NMR speculations.
Scheme 1. Chemical correlation of N-Cbz-protected lactam
syn-3ag to syn-3aa.
Mechanistic Insights
Having established a viable asymmetric, catalytic
methodology to assemble a variety of synthetically
syn-3ag in Table 1 and Table 2, were attributed as useful butenolide-type platforms in a highly enantio-
5S,1’S.[16] Moreover, secure chemical correlation of enriched format and having assessed their relative
syn-3ag to syn-3aa via the intermediacy of compound and absolute stereostructure with a high level of relia-
8 supported this point (Scheme 1).
bility, we finally addressed the issue to formulate a
Base-promoted conversion (Et3N) of the major plausible rationale accounting for the observed global
isomer (5S,1’S) syn-3aa into the corresponding reaction governance.
(5R,1’S) anti-3aa counterpart, never detected in our
First, using (R,R)-bisphosphoramide ligand 4c, all
catalytic experiments, proved feasible, allowing us to the VMAR adducts in nitrogen and oxygen series
isolate pure anti-3aa which displayed a positive opti- emerged with a (1’S)-configuration,[16] via preferential
cal activity, positive CD molar ellipticity, and a small attack at the Re face of the aldehyde component, irre-
1
value of the 5,1’ H-1H NMR coupling constant. This, spective of the nature of both the donor and acceptor
once again, confirmed the reliability of the empirical substrates. This behaviour is consistent with the Den-
rule that correlates, for butenolide-type structures, the mark mechanistic insights on Mukaiyama-type aldol
sign of the optical rotation, CD ellipticity, and the and vinylogous aldol reactions catalyzed by chiral
value of NMR 5,1’ proton coupling constants to their phosphoramide Lewis bases.[5a]
stereostructure.[12,13c,14,15]
Second, using (R,R)-bisphosphoramide ligand 4c,
The relative configurational assignment of N-Bn- the 5,1’-syn vs. anti stereopreference heavily depend-
protected compound anti-3ah was unambiguously as- ed on the nature of the heteroatom within the donor
certained via single crystal X-ray analysis of its satu- component. Thus, (5S)-5,1’-syn aldol products exclu-
rated counterpart, namely racemic compound
(Figure 4).
9
sively formed using carbamate and sulfonylamide N-
protected silyloxypyrroles (preferential attack at the
As for the furan-derived butenolides 6, displayed in Re face of the nucleophile), and (5R)-5,1’-anti adducts
Table 3, suitable, high-quality crystals for X-ray analy- preferentially formed using N-alkyl/alkenyl-protected
ses were obtained for both brominated stereoisomers pyrroles or silyloxyfuran donors (preferential attack
syn-6i and anti-6i, and this allowed us to determine at the Si face of the nucleophile).
without ambiguity their relative and absolute configu-
Based on these experimental findings, a generalized
mechanistic rationale might be postulated, involving
possible transition state structures, TS-syn and TS-
rational arrangement (Figure 5).[17]
Figure 4. ORTEP representation of the X-ray structure of racemic N-benzyl derivative 9; the (R,S)-enantiomer is shown.
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Catalytic, Asymmetric Vinylogous Mukaiyama Aldol Reactions of Pyrrole- and Furan-Based Dienoxy Silanes
Figure 5. ORTEP representation of the X-ray structure of anti-6i and syn-6i.
anti-A–C (Figure 6). When an extra-binding around syn could be operative (Re-Re attack) leading to
the hypervalent silicon centre occurs, as in the case of (5S,1’S)-adducts. On the contrary, lacking supplemen-
Boc-, Cbz-, and Ts-pyrrole nitrogen protecting tary coordination at silicon, transition state structures
groups, an antiperiplanar bonding trajectory as in TS- TS-anti-A–C could be invoked (Si-Re trajectory),
giving rise to (5R,1’S)-configured adducts. In this last
instance, however, lacking key information on the
structure and conformation of the bisphosphoramide-
derived catalyst in complex with the aromatic alde-
hyde species, as well as in absence of extensive com-
putational modelling, it is not prudent to indicate
here which of the three possible TS-anti structures
(synclinal A vs. antiperiplanar B vs. endo-Diels Alder
C) actually prevails.[18]
Conclusions
Prompted by the rigorous, extended studies by Den-
mark on the evolution of Lewis base-induced hyper-
valent silicon species and their exploitation in the
context of enantioselective catalysis of Mukaiyama-
type aldol addition reactions, we have herein investi-
gated the catalytic, asymmetric vinylogous Mukaiya-
ma aldol reaction of pyrrole- and furan-based dienoxy
silane synthons by applying the appealing, chiral bi-
sphosphoramide/silicon tetrachloride 4c/SiCl4 catalyst
combination.
By using varied aromatic and heteroaromatic alde-
hyde acceptors, a wide panel of useful a,b-unsaturat-
ed g-hydroxyalkyl lactams and lactones has been di-
rectly accessed, with excellent efficiency and valuable
margins of regio-, diastereo-, and enantioselectivity.
From an analysis of the scope of the vinylogous
heterocyclic donors in these reactions, a clear trend
emerged, highlighting a striking impact of the nature
of the silyloxydiene heteroatom on the reaction dia-
stereocontrol, with syn-configured products exclusive-
ly emerging from pyrroles bearing chelating N-pro-
Figure 6. Proposed transition state models for the heterocy-
clic VMARs of this study.
Adv. Synth. Catal. 2010, 352, 2011 – 2022
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asc.wiley-vch.de
2017

Claudio Curti et al.
FULL PAPERS
Bisphosphoramide (R,R)-4c was fully recovered by wash-
tecting groups and anti-configured products preferen-
tially formed with non-chelating pyrrole and furan re-
agents.
ing the silica pad with 90:10 EtOAc/NH3-MeOH mixture.
1
syn-3aa: mp 132–1338C; H NMR (300 MHz, CDCl3): d=
7.2–7.4 (m, 5H, Ph), 7.05 (dd, J=6.1, 2.0 Hz, 1H, H4), 5.96
(dd, J=6.2, 1.6 Hz, 1H, H3), 5.23 (d, J=6.1 Hz, 1H, H1’),
4.96 (ddd, J=6.1, 1.9, 1.9 Hz, 1H, H5), 3.60 (bs, 1H, OH),
1.64 (s, 9H, tBu, Boc); 13C NMR (75 MHz, CDCl3): d=
168.8 (Cq, C2), 151.4 (Cq, Boc), 148.0 (CH, C4), 138.8 (Cq,
Ph), 128.7 (CH, Ph), 128.5 (2C, CH, Ph), 127.7 (CH, C3),
126.7 (2C, CH, Ph), 84.1 (Cq, t-Bu, Boc), 75.2 (CH, C1’),
67.2 (CH, C5), 28.3 (3C, CH3, t-Bu, Boc); Rf 0.27 (hexanes/
EtOAc, 60:40); Chiral HPLC [Regis (S,S)-Whelk-O1,
hexane/EtOH 85:15, 0.5 mLminÀ1, 254 nm]: (1’S,5S)-3aa, Rt
38.78 min (99.9%); (1’R,5R)-3aa, Rt 31.90 min (0.1%); MS
The stereostructures of the vinylogous aldol prod-
ucts in this work have been certified as rigorously as
possible by X-ray crystal structure analyses of four
representative candidates, syn-6i, anti-6i, 7, and 9, as
well as subsidiary chiro-optical and chemical correla-
tions.
Although a rigorous mechanistic rationale of the
studied reaction behaviours could not be drawn, pos-
sible transition state structures accounting for the ob-
served substrate-dependent stereocontrol were postu-
lated, by adapting the formulations evoked by Den-
mark for analogous reactions.[5a]
Future studies will include widening the synthetic
scope of the acceptor substrates in the asymmetric
VMAR domain (aliphatic achiral and chiral alde-
hydes) and exploiting the numerous enantiomerically
pure butenolide-type aldol products in our hands in
useful synthetic endeavours.
(ESI, 50 eV): m/z=290.1 (M+H)+; 312.2 (M+Na)+; [a]D20:
25
À347.5 (c 1.0, EtOH); [F] : À121303 degcm2 dmolÀ1 (c
215
2.0·10À3 M, MeOH); anal. calcd. for C16H19NO4 (289.33): C
66.42, H 6.62, N 4.84; found: C 66.38, H 6.53, N 4.95.
Preparation of (+)-(R)-5-[(S)-HydroxyACHTNUTRGNE(UNG phenyl)-
methyl]-furan-2(5H)-one (anti-6a) (Table 3, entry 1);
Representative Procedure E
Diisopropylethylamine (4.4 mL, 0.025 mmol, 10.0 mol%) was
added via syringe to a flame-dried, 20-mL, two-necked
round-bottomed flask containing 1.0 mL of a solution of bi-
sphosphoramide (R,R)-4c (6.4 mg, 0.007 mmol, 3.0 mol%) in
9:1 dry CH2Cl2/dry THF mixture, under an argon atmos-
phere. The resulting solution was cooled to À788C (bath
temperature) over 15 min, then freshly distilled SiCl4 (32 mL,
0.28 mmol) was added in one portion. After 10 min, benzal-
dehyde 2a (26 mL, 0.25 mmol) was added in one portion, fol-
lowed by slow dropwise addition (over 10 min) of a solution
of furan 5 (100 mg, 0.5 mmol) in 9:1 dry CH2Cl2/dry THF
mixture (1.0 mL). The resulting mixture was stirred at
À788C for 20 h, whereupon 3.0 mL of chilled CH2Cl2 were
added before the cold reaction mixture was poured into a
rapidly stirring 1:1 mixture of saturated aqueous NaHCO3/
saturated aqueous KF (25 mL) at 08C. This biphasic mixture
was stirred vigorously for 3 h, then the phases were separat-
ed and the aqueous phase was washed with CH2Cl2 (3ꢃ
20 mL). The organic layers were collected, dried over
MgSO4, filtered, and the filtrate was concentrated under
vacuum. The diastereomeric ratio and the conversion of the
Experimental Section
Preparation of (À)-(S)-N-(tert-Butoxycarbonyl)-5-
[(S)-hydroxyACHTUNGTRENNUNG(phenyl)methyl]-1H-pyrrol-2(5H)-one
(syn-3aa) (Table 1, entry 1; Table 2, entry 1);
Representative Procedure D
Diisopropylethylamine (4.4 mL, 0.025 mmol, 10.0 mol%) was
added via syringe to a flame-dried, 20-mL, two-necked
round-bottomed flask containing a solution of bisphosphora-
mide (R,R)-4c (6.4 mg, 0.007 mmol, 3.0 mol%) in anhydrous
CH2Cl2 (1.0 mL) under an argon atmosphere. The resulting
solution was cooled to À788C (bath temperature) over
15 min, then freshly distilled SiCl4 (32 mL, 0.28 mmol) was
added in one portion. After 10 min, benzaldehyde 2a
(26 mL, 0.25 mmol) was added in one portion followed by
slow dropwise addition (over 5 min) of a solution of pyrrole
1a (150 mg, 0.5 mmol) in anhydrous CH2Cl2 (1.0 mL). The
resulting mixture was stirred at À788C for 20 h, whereupon
3.0 mL of chilled CH2Cl2 were added before the cold reac-
tion mixture was poured into a rapidly stirring 1:1 mixture
of saturated aqueous solution NaHCO3/saturated aqueous
KF solution (25 mL) at 08C. This biphasic mixture was
stirred vigorously for 3 h, then the phases were separated
and the aqueous phase was washed with CH2Cl2 (3ꢃ20 mL).
The organic layers were collected, dried over MgSO4 and fil-
tered, and the filtrate was concentrated under vacuum. The
diastereomeric ratio of the addition products was deter-
mined to be >99.5/0.5 (>99% conversion) by 1H NMR
(300 MHz) analysis of the crude reaction mixture. The crude
residue, dissolved in EtOAc, was filtered through a short
pad of silica gel, and the filtrate was purified by semiprepar-
ative HPLC (CN-10 mm, 250ꢃ10 mm, hexane/anhydrous
EtOH 95:5, flow rate 5.0 mLminÀ1, detection at 254 nm,
Rt =31.50 min), affording (À)-syn-3aa as white crystals;
yield: 70 mg (97%).
1
reaction were determined by H NMR (300 MHz) analysis
of the crude and proved to be 76.9/23.1 (anti:syn) and
>99%, respectively. The crude residue, dissolved in EtOAc,
was filtered through a short pad of silica gel, and the filtrate
was purified by semipreparative HPLC (CN-10 mm, 250ꢃ
10 mm, hexane/anhydrous EtOH 97:3, flow rate
5.0 mLminÀ1, detection at 254 nm Rt anti-6a=26.76 min; Rt
syn-6a=31.67 min), affording (+)-anti-6a as white crystals;
yield: 35.6 mg (75%) and (À)-syn-6a as a colourless resin;
yield: 9.5 mg (20%).
Bisphosphoramide (R,R)-4c was fully recovered washing
the silica pad with 90:10 EtOAc/NH3-MeOH mixture.
1
anti-6a: mp 90–928C; H NMR: (300 MHz, CDCl3): d=
7.40 (m, 5H), 7.36 (dd, J=5.8, 1.5 Hz, 1H, H4), 6.19 (dd,
J=5.8, 2.0 Hz, 1H, H3), 5.20 (ddd, J=4.4, 1.7, 1.7 Hz, 1H,
H5), 5.12 (d, J=4.4 Hz, 1H, H1’), 3.25 (bs, 1H, OH);
13C NMR:(75 MHz, CDCl3): d=173.4 (Cq, C2), 153.2 (CH,
C4), 138.5 (Cq, Ph), 128.9 (2C, CH, Ph), 128.6 (CH, Ph),
2018
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2011 – 2022

Catalytic, Asymmetric Vinylogous Mukaiyama Aldol Reactions of Pyrrole- and Furan-Based Dienoxy Silanes
126.2 (2C, CH, Ph), 123.3 (CH, C3), 86.8 (CH, C5), 73.1
(CH, C1’); Rf 0.35 (hexane/EtOAc, 60:40); Chiral HPLC
[Regis Welk-O1, hexane/EtOH 90:10, 0.7 mLminÀ1,
(ddd, J=6.8, 1.9, 1.9 Hz, 1H, H5), 4.75 (d, J=6.8 Hz, 1H,
H1’), 2.07 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d=
172.0 (Cq, C2), 152.5 (CH, C4), 136.5 (Cq, Ph), 131.9 (2C,
CH, Ph), 128.4 (2C, CH, Ph), 123.3 (CH, C3), 122.0 (Cq,
Ph), 86.2 (CH, C5), 74.9 (CH, C1’); Rf 0.23 (hexanes/
EtOAc, 60:40); chiral HPLC: (Chiralcel OD-H, hexane/
EtOH 95:5, 1.0 mLminÀ1, 254 nm): (5S,1’S)-6i, Rt 27.91 min
(99.0%); (5R,1’R)-6i, Rt 29.18 min (1.0%); [a]2D0: À105.4 (c
0.4, EtOH); MS (ESI, 50 eV): m/z=270.1 (M+H)+; 292.2
(M+Na)+; anal. calcd. for C11H9BrO3 (269.09): C 49.10, H
3.37; found: C 49.12, H 3.43.
254 nm]: (5S,1’R)-6a, Rt 19.50 min (0.1%); (5R,1’S)-6a, Rt
25
217
21.16 min (99.9%); [a]2D0: +116.4 (c 1.0, MeOH); [F]
:
+116942 degcm2 dmolÀ1 (c 1.0·10À3 M, MeOH); MS (ESI,
50 eV): m/z=191.1 (M+H)+; 213.0 (M+Na)+; anal. calcd.
for C11H10O3 (190.20): C 69.46, H 5.30; found: C 69.40, H
5.36.
Preparation of (+)-(R)-5-[(S)-(4-Bromophenyl)-
hydroxylmethyl]furan-2(5H)-one (anti-6i) and (À)-
(S)-5-[(S)-(4-Bromophenyl)hydroxymethyl]furan-
2(5H)-one (syn-6i) (Table 3, entry 6)
Crystal data for syn-6i: C11H9BrO3, colourless crystals,
M=269.09, mp 128–1308C crystallized from petroleum
ether/CHCl3 9:1, monoclinic, P212121, a=5.9050(10) ꢄ, b=
9.084(2) ꢄ, c=19.169(4) ꢄ, b=92.137(4)8. CCDC 757776
contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Butenolides anti-6i and syn-6i were prepared according to
Representative Procedure E (reaction time 20 h), utilizing
4-bromobenzaldehyde 2i (46 mL, 0.25 mmol), bisphosphora-
mide (R,R)-4c (6.4 mg, 0.007 mmol, 3.0 mol%), diisopropy-
lethylamine (4.4 mL, 0.025 mmol, 10.0 mol%), SiCl4 (32 mL,
0.28 mmol) and furan 5 (100 mg, 0.5 mmol). The diastereo-
meric ratio and the conversion of the reaction were deter-
Determination of the Absolute and Relative
Configuration of (S)-N-(tert-Butoxycarbonyl)-5-[(S)-
1
mined by H NMR (300 MHz) analysis of the crude reaction
mixture and proved to be 80.4/19.6 (anti:syn) and >99%, re-
spectively. The crude residue, dissolved in EtOAC, was fil-
tered through a short pad of silica gel, and the filtrate was
purified by semipreparative HPLC (CN-10 mm, 250ꢃ10 mm,
hexane/anhydrous EtOH 97:3, flow rate 5.0 mLminÀ1, detec-
tion at 254 nm): Rt anti-6i=28.18 min; Rt syn-6i=
32.13 min), affording (+)-anti-6i as white crystals; yield: 54
mg (80%) and (À)-syn-6i as white crystals; yield: 10 mg
(15%). Recrystallization from petroleum ether/CHCl3 (9:1)
yielded X-ray quality crystals of anti-6i and syn-6i (vide
infra), whose structures established the (5R,1’S)-anti and
(5S,1’S)-syn relationship of the products.
hydroxyACTHNUTRGENUG(N phenyl)methyl]-1H-pyrrol-2(5H)-one (syn-
3aa) by Conversion to (S)-[(S)-N-(tert-Butoxy-
carbonyl)-2,5-dihydro-5-oxo-1H-pyrrol-2-
yl]ACTHNUTRGNEU(GN phenyl)methyl-(1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl Carbonate (7) (Figure 3)
To a 0 8C solution of lactam syn-3aa (55 mg, 0.19 mmol,
>99% ee) in anhydrous CH2Cl2 (3.0 mL), was added (À)-
(1R,2S,5R)-menthyl chloroformate (200 mL, 0.95 mmol),
DMAP (23 mg, 0.19 mmol), and pyridine (77 mL,
0.95 mmol). After stirring for 24 h at room temperature, the
reaction mixture was diluted with EtOAc (20 mL) and then
washed with 1N HCl (3ꢃ50 mL), 0.5N aqueous CuSO4 (2ꢃ
10 mL), saturated aqueous NaHCO3 (10 mL), and brine
(10 mL). The organic layer was dried over MgSO4, filtered
and concentrated. The crude residue was purified by silica
gel flash chromatography (hexanes/EtOAc, 75:25) to afford
the pure menthyl carbonate 7 as colourless crystals; yield:
67 mg (75%). Recrystallization from hexane containing
trace of benzene yielded X-ray quality crystals of (À)-7,
whose structure established the syn relationship as well as
the (5S,1’S) absolute stereochemistry of the product; mp
104–1058C. 1H NMR (300 MHz, CDCl3): d=7.34 (dd, J=
6.2, 2.1 Hz, 1H, H4), 7.28 (m, 3H, Ph), 7.11 (m, 2H, Ph),
6.39 (d, J=5.3 Hz, 1H, H1’), 5.96 (dd, J=6.1, 1.4 Hz, 1H,
H3), 5.06 (ddd, J=5.3, 1.8, 1.8 Hz, 1H, H5), 4.55 (ddd, J=
10.9, 10.9, 4.4 Hz, 1H, H1’’), 2.01 (m, 1H, H2’’), 1.87 (m,
1H, CH, i-Pr), 1.67 (m, 12H, H4’’, H5’’, t-Bu, Boc), 1.43 (m,
2H, H3’’, H6’’), 1.05 (m, 2H, H3’’, H6’’), 0.91 (d, J=6.7 Hz,
3H, CH3), 0.89 (d, J=6.3 Hz, 3H, CH3), 0.80 (d, J=6.7 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=168.6 (Cq, C2),
153.7 (Cq, OCO2), 149.6 (Cq, Boc), 146.4 (CH, C4), 133.6
(Cq, Ph), 129.0 (CH, Ph), 128.9 (CH, C3), 128.3 (2C, CH,
Ph), 126.8 (2C, CH, Ph), 83.9 (Cq, t-Bu, Boc), 79.5 (CH,
C1’), 63.9 (CH, C5), 47.2 (CH, C1’’), 40.8 (CH, C2’’), 34.2
(CH, C6’’), 31.5 (CH, C5’’), 28.3 (3C, CH3, t-Bu, Boc), 26.3
(CH, C4’’), 23.5 (CH, i-Pr), 22.0 (CH3, i-Pr), 20.9 (CH3, i-
Pr), 16.4 (CH3); Rf 0.46 (hexane/EtOAc, 70:30); [a]2D0:
À200.2 (c 0.8, CHCl3); MS (ESI, 50 eV); m/z=472.2 (M+
Bisphosphoramide (R,R)-4c was fully recovered washing
the silica pad with 90:10 EtOAc/NH3-MeOH mixture.
1
(+)-anti-6i: mp 134–1358C; H NMR: (300 MHz, CDCl3):
d=7.55 (m, 2H, Ph), 7.35–7.28 (m, 3H, H4 and Ph), 6.20
(dd, J=5.8, 1.9 Hz, 1H, H3), 5.16 (ddd, J=4.4, 1.6, 1.6 Hz,
1H, H5), 5.07 (d, J=4.4 Hz, 1H, H1’), 2.78 (bs, 1H, OH);
13C NMR: (75 MHz, CDCl3): d=172.7 (Cq, C2), 152.4 (CH,
C4), 137.2 (Cq, Ph), 131.9 (2C, CH, Ph), 127.7 (2C, CH,
Ph), 123.4 (CH, C3), 122.5 (Cq, Ph), 86.1 (CH, C5), 72.6
(CH, C1’); Rf 0.21 (hexanes/EtOAc, 60:40); chiral HPLC
(Chiralcel OD-H, hexane/EtOH 95:5, 1.0 mLminÀ1,
254 nm): (5S,1’R)-6i, tR 27.87 min (2.0%); (5R,1’S)-6i, tR
31.18 min (98.0%); [a]2D0: +111.5 (c 1.0, EtOH); MS (ESI,
50 eV): m/z=270.1 (M+H)+; 292.2 (M+Na)+; anal. calcd.
for C11H9BrO3 (269.09): C 49.10, H 3.37, found: C 49.09, H
3.41.
Crystal data for anti-6i: C11H9BrO3, colourless crystals,
M=269.09, mp 134–1358C crystallized from petroleum
ether/CHCl3 9:1, monoclinic, P21, a=12.957(3) ꢄ, b=
7.844(2) ꢄ, c=5.4290(10) ꢄ, b=92.137(4)8. CCDC 757775
contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
(À)-syn-6i: mp 128–1308C; H NMR (300 MHz, CDCl3):
d=7.55 (m, 2H, Ph), 7.28 (m, 2H, Ph), 7.20 (dd, J=5.7,
1.5 Hz, 1H, H4), 6.17 (dd, J=5.7, 1.9 Hz, 1H, H3), 5.16
Adv. Synth. Catal. 2010, 352, 2011 – 2022
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2019

Claudio Curti et al.
FULL PAPERS
H)+; 494.1 (M+Na)+; anal. calcd. for C27H37NO6 (471.59): C
68.77, H 7.91, N 2.97, found: C 68.75, H 7.90, N 2.96.
Crystal data for 7: C27H37NO6, colourless crystals, M=
471.59, mp 104–1058C crystallized from petroleum ether,
monoclinic, P21, a=8.9567(10) ꢄ, b=11.1045(10) ꢄ, c=
14.0568(10) ꢄ, b=94.411(2)8. CCDC 757774 contains the
supplementary crystallographic data for this compound.
These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Acknowledgements
Funding from Universitꢀ degli Studi di Parma is gratefully
acknowledged. The authors thank the Centro Interdiparti-
mentale Misure “G. Casnati” (Universitꢀ degli Studi di
Parma) for instrumental facilities.
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Determination of the Relative Configuration of (R*)-
N-(Benzyl)-5-[(S*)-hydroxyACTHUNTGRNEUNG(phenyl)methyl]-pyr-
rolidin-2-one (9) (Figure 4)
Palladium (10 wt% on activated carbon, 10 mg) was added
to solution of benzylated lactam anti-3ag (20 mg,
a
0.07 mmol) and NaOAc (10 mg) in anhydrous EtOAc
(8 mL) at room temperature. The reaction vessel was de-
gassed under vacuum and thoroughly purged with hydrogen
(three times). The resulting heterogeneous mixture was
stirred under hydrogen for 4 h, after which time the hydro-
gen was evacuated, the catalyst filtered off and the filtrate
concentrated under vacuum to give a crude residue which
was purified by silica gel flash chromatography (Et2O,
100%) to furnish saturated lactam 9 as a white solid;
yield:18.7 mg (95%). Recrystallization from petroleum
ether/CH2Cl2 (2:1) yielded X-ray quality crystals of 9, whose
structure established the anti relative configuration of the
product; mp 178–1808C. 1H NMR (400 MHz, CDCl3): d=
7.31–7.39 (m, 10H, CH2Ph, Ar), 5.05 (bs, 1H, H1’), 5.03 (1/
2ABq, J=14.6 Hz, 1H, CH2Ph), 4.25 (1/2ABq, J=14.6 Hz,
1H, CH2Ph), 3.68 (m, 1H, H5), 2.53 (ddd, J=17.0, 8.7,
8.7 Hz, 1H, H3a), 2.34 (ddd, J=16.7, 10.2, 4.1 Hz, 1H,
H3b), 2.05 (m, 1H, H4a), 1.64 (m, 1H, H4b); 13C NMR
(100 MHz, CDCl3): d=176.7 (Cq, C2), 137.0 (Cq, Bn), 129.1
(2C, CH, Bn), 128.9 (Cq, Ar), 128.6 (2C, CH, Bn), 128.4
(CH, Bn), 128.3 (2C, CH, Ar), 127.9 (CH, Ar), 125.9 (2C,
CH, Ar), 71.7 (CH, C1’), 63.3 (CH, C5), 45.2 (CH2, CH2Ph),
30.5 (CH2, C3), 18.0 (CH2, C4); Rf 0.39 (Et2O, 100%); MS
(ESI, 50 eV): m/z=282.33 (M+H)+; 304.1 (M+Na)+; anal.
calcd. for C18H19NO2 (281.14): C 76.84, H 6.81, N 4.98;
found: C 76.81, H 6.85, N 4.93
Crystal data for (Æ)-9: C18H19NO2, colourless crystals,
M=281.35, mp 178–1808C crystallized from petroleum
¯
ether/CH2Cl2 2:1, triclinic, P1, a=9.8560(12) ꢄ, b=
9.8843(18) ꢄ, c=10.392(2) ꢄ, a=115.039(5)8, b=
90.144(3)8, g=119.106(5)8. CCDC 763262 contains the sup-
plementary crystallographic data for this compound. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Supporting Information
Detailed description of experimental procedures, spectro-
scopic data, chiral HPLC traces, and NMR spectra of com-
pounds in Tables 1–3 are available as Supporting Informa-
tion.
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[17] Several publications exist dealing with racemic and
asymmetric syntheses of aromatic butenolides of type
6. As we searched through the reported data, we found
that all relative syn/anti configurational assignments
were consistent (complete matching of 1H and
Adv. Synth. Catal. 2010, 352, 2011 – 2022
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asc.wiley-vch.de
2021

Claudio Curti et al.
FULL PAPERS
13C NMR parameters), whereas the absolute configura-
tions were not. So, to the best of our knowledge, this is
the first report that unambiguously clarifies this point.
See, for example, refs.[5h,7a,7j] See also: a) G. Cafeo, M.
De Rosa, F. Kohnke, A. Soriente, C. Talotta, L. Valenti,
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[18] In the present VMAR processes, a generalized catalytic
cycle may apply, as recently postulated and experimen-
tally supported by Denmark. See: S. E. Denmark,
B. M. Eklov, P. J. Yao, M. D. Eastgate, J. Am. Chem.
Soc. 2009, 131, 11770–11787.
2022
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2011 – 2022