Vicarious silylative mukaiyama aldol reaction: A vinylogous extension

Article abstract of DOI:10.1021/jo800741c

(Chemical Equation Presented) A vinylogous, silylative, and direct variant of the venerable Mukaiyama aldol reaction has been developed. Exploiting N-Boc-pyrrol-2(5H)-one as the conjugate donor, several aldehyde and ketone acceptors were scrutinized under

Full text of DOI:10.1021/jo800741c

Vicarious Silylative Mukaiyama Aldol Reaction: A Vinylogous
Extension
Claudio Curti,† Andrea Sartori,† Lucia Battistini,† Gloria Rassu,‡ Paola Burreddu,‡
Franca Zanardi,*,† and Giovanni Casiraghi*,†
Dipartimento Farmaceutico, UniVersita` di Parma, Viale G. P. Usberti 27A, I-43100 Parma, Italy, and
Istituto di Chimica Biomolecolare del CNR, TraVersa La Crucca 3, I-07040 Li Punti, Sassari, Italy
gioVanni.casiraghi@unipr.it; franca.zanardi@unipr.it
ReceiVed April 3, 2008
A vinylogous, silylative, and direct variant of the venerable Mukaiyama aldol reaction has been developed.
Exploiting N-Boc-pyrrol-2(5H)-one as the conjugate donor, several aldehyde and ketone acceptors were
scrutinized under the guidance of suitable dual Lewis acid-Lewis base activators to provide a varied
repertoire of functionality-rich R,ꢀ-unsaturated-γ-amino-δ-silyloxy carbonyl structures, in useful yields
and often with an exquisite level of diastereoselection.
SCHEME 1. Synthesis Itinerary to Carbacycles IV
Exploiting an Intramolecular Version of the Vicarious
Silylative Mukaiyama Aldol Reaction (VSMAR)a
Introduction
During work directed at the stereoselective synthesis of
densely substituted carbacycles of type IV, a stage was reached
where it was necessary to complete the ring construction by
connecting the carbon R to the ring carbonyl to the aldehyde
carbon within the precursor I.1 This was achieved by an
extremely productive protocol that constitutes a general method
for the assembly of a variety of bicyclo[x.2.1]alkane structures
III, and hence the carbacycles IV. Our approach, which is
summarized in Scheme 1 for a generic case with five-membered
rings, was based on a reaction cascade triggered by a dual silicon
* Corresponding author. Phone: +39-0521-905080 (G.C.); +39-0521-
905067 (F.Z.). Fax: +39-0521-905006.
† Dipartimento Farmaceutico.
a X ) NPG, O, S; L ) silicon leaving group; PG ) protecting group.
‡ Istituto di Chimica Biomolecolare.
(1) (a) Rassu, G.; Auzzas, L.; Pinna, L.; Battistini, L.; Zanardi, F.; Marzocchi,
L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2000, 65, 6307–6318. (b) Rassu,
G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Battistini, L.; Zanardi, F.; Marzocchi,
L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2001, 66, 8070–8075. (c) Zanardi,
F.; Battistini, L.; Marzocchi, L.; Acquotti, D.; Rassu, G.; Pinna, L.; Auzzas, L.;
Zambrano, V.; Casiraghi, G. Eur. J. Org. Chem. 2002, 1956–1964. (d) Rassu,
G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Marzocchi,
L.; Acquotti, D.; Casiraghi, G. J. Org. Chem. 2002, 67, 5338–5342. (e) Rassu,
G.; Auzzas, L.; Pinna, L.; Zambrano, V.; Zanardi, F.; Battistini, L.; Gaetani, E.;
Curti, C.; Casiraghi, G. J. Org. Chem. 2003, 68, 5881–5885. (f) Rassu, G.;
Auzzas, L.; Zambrano, V.; Burreddu, P.; Pinna, L.; Battistini, L.; Zanardi, F.;
Casiraghi, G. J. Org. Chem. 2004, 69, 1625–1628. See also: (g) Rassu, G.;
Auzzas, L.; Pinna, L.; Battistini, L.; Curti, C. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science B.V.: Amsterdam, The
Netherlands, 2003; Vol. 29 (Bioactive Natural Products (Part J)), pp 449-520.
(h) Rassu, G.; Auzzas, L.; Battistini, L.; Casiraghi, G. Mini-ReViews in Organic
Chemistry 2004, 1, 233–247. (i) Arjona, O.; Go´mez, A. M.; Lo´pez, J. C.; Plumet,
J. Chem. ReV. 2007, 107, 1919–2036.
Lewis acid/nitrogen Lewis base system, which encompasses two
main steps: (1) chemoselective deprotonation and enol-silylation
to ketene acetal II and (2) Mukaiyama aldol-type ring closure
with in situ aldolate silylation to III. There, the retrograde
fragmentation of the formed aldolate carbon-carbon bond, a
plague that often afflicts certain aldol-based maneuvers, was
hampered by prompt and irreversible aldolate silyl ether
formation.2 We suggest the name “vicarious silylative Mu-
kaiyama aldol reaction” (VSMAR) for such processes, a diction
(2) (a) Hatano, M.; Takagi, E.; Ishihara, K. Org. Lett. 2007, 9, 4527–4530.
See also: (b) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392–393.
5446 J. Org. Chem. 2008, 73, 5446–5451
10.1021/jo800741c CCC: $40.75 2008 American Chemical Society
Published on Web 06/13/2008

Vicarious SilylatiVe Mukaiyama Aldol Reaction
TABLE 1. Initial Screening of the Vicarious Silylative Mukaiyama Aldol Reaction (VSMAR) between Pyrrolinone 1 and Benzaldehyde (2) or
Acetophenone (3)a
entry
1e
2
3
4
5
6
7
8
acceptor
Lewis acid (equiv)
Lewis base (equiv)
solvent (v/v)
DCM
DCM
DCM
product(s)b
yield (%)c
anti/syn ratiod
f
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
TBSOTf (2.0)
TBSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TESOTf (2.0)
TBSOTf (2.0)
none
TMSOTf (2.0)
TMSOTf (2.0)
TMSOTf (2.0)
TESOTf (2.0)
TBSOTf (2.0)
TIPSOTf (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
Et3N (2.0)
Et3N (1.5)
2,6-lutidine (1.5)
DBU (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
-
4cg
4ag
4a
4a
4a
4a
4a
4a
4b
4c
48
62
40
67
70
95
45
<5
89
85
5.9:1
7.7:1
9.6:1
9.5:1
10.0:1
>12.0:1
7.2:1
nd
Et2O
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
Et2O/Hex (2:1)
DCM
9
10
11
12
13
14
15
16
17
18
4.5:1
5.9:1
h
-
i
-
5a
5a
5b
5c
92
95
90
95
>12.1:1
27.9:1
5.6:1
DCM/Et2O (9:1)
DCM/Et2O (9:1)
DCM/Et2O (9:1)
DCM/Et2O (9:1)
1.1:1
i
Et3N (1.5)
-
a Unless otherwise noted, the reactions were carried out in the presence of 1.3 equiv of acceptor at -78 °C for 5 h, and with a substrate concentration
of 0.027 M (0.27 mmol scale). b Racemic substances. c Isolated, combined yield. d Determined by 1H NMR analysis of crude reaction mixtures. e The
reaction was carried out at 22 °C. f Complicated reaction mixture obtained. g Dehydration products also formed. h 90% benzaldehyde recovered.
i Silyldienol ether from the donor solely recovered.
that evokes the cooperative role of the silicon/amine dual system
in triggering formation of the silyl enol ether in situ and
advancing the process by stabilizing the emerging aldolate by
silylation.3
tion of the aldolate by silylation.5 We evaluated several silicon
Lewis acid and amine base combinations, as well as various
solvents and reaction conditions, with the results displayed in
Table 1.
In this paper we disclose a vinylogous, intermolecular
extension of this direct Lewis acid-base comediated aldol
methodology in which nitrogen heterocycle 1 acts as the donor
and aldehydes 2 and 6-10 or ketones 3 and 11-15 act as the
acceptors.4
First of all, addition of pyrrolinone 1 to benzaldehyde (2)
was evaluated by using a combination of TBSOTf and DIPEA
(2.0 equiv each) in dichloromethane at room temperature (entry
1), one of the best conditions found during our previous
investigations with aldehydo-lactams and congeners.1a–f Actu-
ally, the reaction proceeded rapidly, with the starting materials
consumed within a few minutes; however, a complicated
reaction mixture was observed, with little if any aldol products
recovered. Lowering the reaction temperature to -78 °C (entry
2) or changing TBSOTf for TMSOTf at -78 °C (entry 3) was
only partially productive, giving rise to the expected aldol
products 4a in moderate yields, accompanied by marginal
amounts of dehydration compounds.
Results and Discussion
Synthesis. We initiated this investigation with benzaldehyde
(2) and acetophenone (3) as the acceptors. For an ideal promoter
system, we considered two criteria. One requirement was that
the promoter should contain a basic entity that selectively
deprotonates the R,ꢀ-unsaturated substrate at the γ-carbon while
increasing through association the electrophilicity of the silicon
reagent. The other criterion involved an electron-poor silicon
component that activates the carbonyl acceptor through
silicon-carbonyl association while participating in the stabiliza-
Reasoning that the use of ethereal, coordinative solvents in
lieu of DCM would decelerate the reaction while preserving
the integrity of the silylated aldol product, diethyl ether was
selected and, indeed, encouraging results were obtained with
neat diethyl ether (entry 4) or, better, with hexane/Et2O mixtures
(entry 5). In these instances, anti-configured (5R*,1′S*) and syn-
configured (5R*,1′R*) O-trimethylsilyl aldols anti-4a and syn-
4a formed exclusively, in moderate yield and with remarkable
margin of diastereoselectivity favoring, in all instances, the anti-
isomer anti-4a (∼10:1 dr).
(3) For recent examples of direct Mukaiyama aldol-type reactions triggered
by silyl triflate/tertiary amine dual systems see: (a) Downey, C. W.; Johnson,
M. W. Tetrahedron Lett. 2007, 48, 3559–3562. (b) Hoye, T. R.; Dvornikovs,
V.; Sizova, E. Org. Lett. 2006, 8, 5191–5194. (c) Takasu, K.; Ueno, M.; Ihara,
M. J. Org. Chem. 2001, 66, 4667–4672. (d) Downey, C. W.; Johnson, M. W.;
Tracy, K. J. J. Org. Chem. 2008, 73, 3299–3302. (e) Hoye, T. R.; Dvornikovs,
V.; Sizova, E. Org. Lett. 2006, 8, 5191–5194.
(4) Recent reviews on vinylogous aldol and related reactions: (a) Denmark,
S. E.; Heemstra, J. R., Jr J. Org. Chem. 2007, 72, 5668–5688. (b) Kalesse, M.
Top. Curr. Chem. 2005, 244, 43–76. (c) Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682–4698. (d) Soriente, A.;
De Rosa, M.; Villano, R.; Scettri, A. Curr. Org. Chem. 2004, 8, 993–1007. (e)
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100,
1929–1972.
The structural identity of compounds anti-4a and syn-4a was
quickly inferred by inspection of their 1H NMR characteristics
(5) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–
1638.
J. Org. Chem. Vol. 73, No. 14, 2008 5447

Curti et al.
3
where, as a general trend, a larger J5,1′ coupling constant (5.2
The structural identity of the tertiary carbinol TBS-ether anti-
5c (and hence of TMS- and TES-ethers anti-5a and anti-5b, by
analogy) was ascertained by single crystal X-ray analysis
showing a 5,1′-N,O-anti relative relationship, as recently
reported by ourselves.10
Hz) is indicative of a 5,1′-N,O-syn relative stereodisposition,
while a smaller J5,1′ value (2.1 Hz) denotes a 5,1′-N,O-anti
3
configuration.6,7
After further examination of several tertiary amine candidates
(e.g., entries 6-9 in Table 1), the optimum condition was found,
which was based on a slightly imbalanced combination of
TMSOTf (2.0 equiv) and triethylamine (1.5 equiv) in a 2:1
mixture of Et2O/hexane at -78 °C (entry 7 in Table 1), a
condition that revealed aldol anti-4a predominantly (>12.0:1
dr) in a pleasing 91% isolated yield after silica gel chromatog-
raphy. This reaction was clean on a 0.27 mmol scale (0.027
M), without significant side reactions, and it could be scaled
up to a 2.70 mmol scale with no erosion of the overall efficiency
and selectivity. Under such optimized reaction conditions,
TESOTf and TBSOTf equally served as Lewis acid candidates,
albeit the anti/syn diastereoisomeric ratio dropped down mark-
edly, when passing from TMSOTf to bulkier TES- and TBS-
counterparts (entry 7 vs entries 10 and 11 in Table 1). Here,
anti- and syn-configured O-triethylsilyl and O-tert-butyldim-
ethylsilyl carbinols 4b and 4c were isolated in 89% and 85%
combined yields, respectively.8 A blank experiment (entry 12
in Table 1), where the Lewis acid component was suppressed,
proved unproductive, emphasizing the crucial, cooperative role
of both the amine base and the silicon acid components in the
dual reaction promotion.9
Overall, these preliminary results establish a practical meth-
odology for the direct silylative, vinylogous Mukaiyama aldol-
type addition of 1 to both aromatic aldehyde 2 and ketone 3.
Interestingly, under standardized conditions, i.e., TMSOTf/Et3N
in proper solvent mixtures, the 5,1′-anti-configured silylated
aldols or ketols mainly formed, irrespective of the nature of
the acceptor component, thus suggesting a common diastereo-
selective mechanistic itinerary (vide infra).
With these successful results in terms of practicality and
diastereoselectivity, we turned our attention to the generality
of this silylative aldol technique, by scrutinizing a series of
enolizable and nonenolizable aldehyde and ketone acceptors in
coupling reactions to pyrrolinone 1. Assuming that our optimal
conditions might be equally operative with different carbonyl
electrophiles, five aldehyde and five ketone representatives
(6-10 and 11-15) were evaluated (Table 2).
With cinnamaldehyde 6 (entry 1 in Table 2), a totally
regioselective and highly diastereoselective reaction course was
observed, providing γ-substituted-5,1′-anti-configured silylated
lactam anti-16 predominantly, with no traces of any Michael-
type addition product (85% yield, ∼6:1 anti/syn ratio). Reaction
of (E)-crotonaldehyde 7, a γ-enolizable acceptor, mimicked the
cinnamaldehyde behavior, and when subjected to the same
coupling procedure, afforded doubly unsaturated 1,2-adduct anti-
17 in moderate isolated yield (3:1 dr, entry 2 in Table 2).
Addition to saturated aliphatic aldehydes 8 and 9 was next
examined (entries 3 and 4 in Table 2). Thus, with isobutyral-
dehyde 8, the aldol reaction again favored the formation of the
anti-aldol compound (anti-18, 5:1 dr), while with isovaleral-
dehyde 9, reversal of stereochemistry was observed, favoring
syn-disposed adduct syn-19 (0.8:1 anti/syn ratio). An attempt
to rationalize this anomalous, divergent outcome on a mecha-
nistic basis is given below.11 As observed for benzaldehyde-
derived compounds 4a-c, assignment of the relative 5,1′-
stereodisposition of aliphatic compounds 16-19 was preliminarily
based on the empirical “J-rule” (vide supra), whereupon small
values of J5,1′ coupling constants would indicate a 5,1′-anti
relationship (1.8-2.5 Hz), while large J5,1′ values (5.2-5.3 Hz)
would indicate 5,1′-syn isomers. This assumption was indisput-
Next, the silylative, vinylogous aldol addition of 1 to
acetophenone (3) was examined under the guidance of the
TMSOTf/Et3N system (2.0:1.5 molar ratio). Low temperature
reaction in Et2O/hexane mixture, the optimal solvent for
benzaldehyde, proved extremely sluggish, and returned 1-(tert-
butoxycarbonyl)-2-(trimethylsilyloxy)pyrrole solely, the product
of enolsilylation of the donor component (entry 13 in Table 1).
Actually, the intrinsic sluggish nature of the ketone acceptors,
vis-a`-vis the aldehyde relatives, forced us to accelerate the
process, by swapping the Et2O/hexane solvent mixture for
dichloromethane. As we had hoped, the reaction proceeded
smoothly (entry 14 in Table 1) giving rise to N,O-anti,
(5R*,1′S*)-configured TMS-ether anti-5a in high yield and with
appreciable diastereoselectivity (N,O-syn isomer syn-5a <8%).
A further improvement was reached when 10 vol % diethyl ether
was added to DCM, conditions that yielded compound anti-5a
in 92% isolated yield and exquisite diastereoselectivity (entry
15 in Table 1, ∼28:1 dr).
1
ably supported by in-depth H NMR structural analysis of a
As for the addition to benzaldehyde, screening of the Lewis
acid component revealed a strict dependence of the anti vs syn
diastereoselectivity upon the nature of the silicon species (entries
16-18 in Table 1), with the anti/syn ratio decreasing as the
bulkiness of the silicon substituents increases. Noteworthy, when
TIPSOTf was used, no reaction occurred, with complete
recovery of the triisopropylsilyl dienol ether of 1 (entry 18 in
Table 1).
bicyclic oxazolidinone compound, chemically derived from anti-
18 (Scheme S1 in the Supporting Information).
In view of our longstanding interest in Lewis acid-catalyzed
crossed Mukaiyama-aldol additions involving chiral nonrace-
mic glyceraldehyde 10 and pure, isolated dienoxypyrrole donors,
addition of 1 to 10 was especially evaluated.1d,12 Under the
standard silylative conditions of the present work, a nice 85%
combined yield of a nearly equimolar mixture of two diaste-
reoisomers, (5S,1′S,4′′R)-configured anti,anti-20 and (5R,1′S,4′′R)-
(6) Also, the H-4 proton resonance of syn-isomers is invariably downfield
as compared to the corresponding anti-isomeric protons.
(7) Uno, H.; Nishihara, Y.; Mizobe, N.; Ono, N. Bull. Chem. Soc. Jpn. 1999,
72, 1533–1539.
(10) Zanardi, F.; Curti, C.; Sartori, A.; Rassu, G.; Roggio, A.; Battistini, L.;
Burreddu, P.; Pinna, L.; Pelosi, G.; Casiraghi, G. Eur. J. Org. Chem. 2008, 2273–
2287.
(8) Compounds anti-4c and syn-4c are known substances (see ref 7) and
provided further confirmation for the relative stereodisposition of their strictly
related analogues anti-4a,b and syn-4a,b.
(11) Synthesis of anti-18 and syn-18 congeners has been reported (see ref
7).
(9) Actually, one example exists dealing with free tertiary amine-promoted
vinylogous aldol addition reactions involving activated furanone and pyrrolinone
donors: (a) Sarma, K. D.; Zhang, J.; Curran, T. T. J. Org. Chem. 2007, 72,
3311–3318. See also: (b) Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R.
J. Am. Chem. Soc. 2007, 129, 7258–7259.
(12) (a) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J. Org. Chem. 1992,
57, 3760–3763. (b) Rassu, G.; Casiraghi, G.; Spanu, P.; Pinna, L.; Gasparri Fava,
G.; Ferrari Belicchi, M.; Pelosi, G. Tetrahedron: Asymmetry 1992, 3, 1035–
1048. (c) Curti, C.; Zanardi, F.; Battistini, L.; Sartori, A.; Rassu, G.; Auzzas,
L.; Roggio, A.; Pinna, L.; Casiraghi, G. J. Org. Chem. 2006, 71, 225–230.
5448 J. Org. Chem. Vol. 73, No. 14, 2008

Vicarious SilylatiVe Mukaiyama Aldol Reaction
TABLE 2. TMSOTf/Et3N Comediated VSMAR with Pyrrolinone
1 as the Donor: Variation of the Acceptor Components
SCHEME 2. Proposed Reaction Itinerary for the
Vinylogous VSMAR between 1 and Carbonyl Acceptors
anti,anti-20,12a the stereodisposition was also corroborated by
clean Et3N-induced equilibration to syn,anti-20.13
In spite of their alleged recalcitrant nature as acceptor
substrates in aldol-type couplings, ketones proved to be pertinent
acceptors in the present VSMAR methodology, with no detri-
ment to the efficiency and diastereoselectivity of the transforma-
tion. Mirroring the optimum conditions for acetophenone (3)
(Table 1, entry 15), reactions of symmetrical ketones 11 and
12 went cleanly and efficiently, affording the expected racemic
silylated ketols 21 and 22 in 75% and 62% isolated yields,
respectively (entries 6 and 7). With ketoesters 13 and 14 the
reactions were less productive, affording the corresponding
hindered tertiary silyl ethers in low to moderate yields. As for
13, N,O-anti 2R*,2′R*-configured silyloxy ester anti-23 was
isolated in 18% yield and with good diastereoselectivity (>12:1
dr). When oxophenyl acetate 14 was employed, N,O-anti
2S*,2′R*-silylated ketol anti-24 was accessed in an acceptable
33% yield and appreciable diastereoselectivity (>15:1 dr).
Noteworthy, reacting 1 with D-glyceraldehyde-derived ketone
15 returned anti,syn-configured (5S,1′R,4′′R) adduct anti,syn-
25 as the sole stereoisomer (out of four), in an appreciable 68%
isolated yield.14
The structural assignment of compounds 23, 24, and 25 was
firmly ascertained by direct structural correlation to known
substances,10 as detailed in the Experimental Section.
Mechanistic Insights. As for the mechanistic itinerary of the
present vicarious silylative Mukaiyama aldol reaction, we
propose a tandem pathway (Scheme 2) involving first, Et3N/
Me3SiOTf-driven generation of a dienoxy silane intermediate
A that, in turn, couples to the appropriate carbonyl acceptor
under the assistance of the silicon Lewis acid in a strict
vinylogous and silylative manner. This direct approach involves
simultaneous addition of all reactants (donor, acceptor, solvent,
and the Lewis acid/Lewis base mixture) and markedly differs
from the classical Mukaiyama aldol reaction where preformed,
isolated, or in situ generated silyl enolates or dienolates react
with the acceptors under the guidance of Lewis acid catalysts
or promoters.15 A decisive asset of the method is that the
addition is simple to perform, direct, and reliable, and the
products are recovered in a quite stable silylated form.
During the crucial carbon-carbon bond-forming stage, when
prochiral carbonyl acceptors are involved (R1 * R2), two new
stereogenic centers generate, producing anti- and/or syn-
configured adducts B. The observed simple diastereoselection
with both aldehydes and ketones can be rationalized by
examining six generic transition state models: hetero-Diels-Alder-
like structures TS1 and TS4, open-chain antiperiplanar projec-
tions TS2 and TS5, and open-chain synclinal projections TS3
a All reactions were carried out in the presence of 1.3 equiv of
acceptor at -78 °C, and with a substrate concentration of 0.027 M (0.27
mmol scale). b Entries 1-5, Et2O/hexane (2:1); entries 6-10, DCM/
Et2O (9:1). c Only the major isomer is shown. d Except for 20 and 25,
all products are racemic substances. e Isolated, combined yield.
f
1
Determined by H NMR analysis of crude reaction mixtures.
(13) It is known that prolonged exposure of such γ-alkyl-substituted
pyrrolinone species to tertiary amine bases in DCM at room temperature results
in a thermodynamic equilibration between the 5,1′-syn and 5,1′-anti isomers.
See, for example, ref 12b
(14) During silica gel flash chromatographic purification, partial desilylation
and retrograde aldolization were observed, causing a small erosion of the isolated
yield.
configured syn,anti-20, was obtained, from which individual
isomers could be isolated and characterized. For syn,anti-20,
whose optical and spectral characteristics fully matched those
of a known substance,12 the relative and absolute configuration
was quickly assessed, while for its C5-epimeric counterpart
J. Org. Chem. Vol. 73, No. 14, 2008 5449

Curti et al.
aldol reaction applicable to both aldehyde and ketone acceptor
substrates. By using pyrrolinone 1 as a prototypical “vinylogous”
donor candidate, structurally and stereochemically diverse
γ-substituted-R,ꢀ-unsaturated lactam silyl ethers were obtained
in high yields and useful diastereoselectivities. Crucial to the
success of this practical transformation was the vicarious use
of a dual silicon Lewis acid/tertiary amine base promoter system
triggering a reaction cascade comprising in situ formation of
the actual dienoxysilane donor species, regioselective vinylogous
and diastereoselective donor-to-acceptor coupling, and aldol/
ketol O-silylation.
We are studying the applicability of the present methodology
to other “vinylogous” heterocyclic and alycyclic donors to
enlarge further the library of R,ꢀ-unsaturated-δ-hydroxycarbonyl
structures, a relevant class of synthetically useful multifunctional
compounds.4
FIGURE 1. Possible transition state models for the vinylogous VSMAR
of 1 to carbonyl compounds.
Experimental Section
Representative Procedure for the Vicarious Silylative
Mukaiyama Aldol Reaction (VSMAR) between Pyrrolinone
1 and Carbonyl Compounds: Preparation of (R*)-1-(tert-
Butoxycarbonyl)-5-[(S*)-trimethylsilanyloxy(phenyl)methyl]-
1H-pyrrol-2(5H)-one (anti-4a) (Table 1, entry 7). To a flame-
dried, two-necked, round-bottomed flask fitted with an argon
inlet adapter, magnetic stir bar, and septum was added triethy-
lamine (Et3N, 57 µL, 0.41 mmol) followed by anhydrous Et2O/
hexane (2:1 v/v) solvent mixture (6 mL) under argon atmosphere.
The solution was cooled to -78 °C for 5 min, and trimethyl-
silyloxytriflate (TMSOTf, 99 µL, 0.55 mmol) was added
dropwise. The resulting whitish suspension was vigorously stirred
at this temperature for 5 min. To this suspension was slowly
added a preformed solution of pyrrolinone 1 (50 mg, 0.27 mmol)
in 4 mL of anhydrous Et2O/hexane (2:1 v/v) solvent mixture.
After the mixture was stirred at -78 °C for 5 min, benzaldehyde
2 (36 µL, 0.35 mmol) was added dropwise and the resulting
whitish suspension was kept under vigorous stirring at the same
temperature for 5 h. Pyridine (44 µL, 0.55 mmol) was then added
at -78 °C and, after 10 min of stirring, brine (20 mL) was added.
The resulting mixture was allowed to warm to room temperature
(22 °C) and transferred to a separatory funnel. The aqueous layer
was separated and extracted with hexane (3 × 35 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure to give a yellowish oil that
FIGURE 2. The Newman projections of staggered transition state
conformers TS7, TS8, and TS9.
and TS6 (Figure 1). When π-donor groups are present within
the carbonyl substrates (e.g., R1 ) phenyl, styryl, propenyl,
carboxyethyl), endo hetero-Diels-Alder-like transition states
TS1 are strongly preferred, due to the beneficial orbital
overlapping of the donor and acceptor π systems, giving rise
to anti-configured adducts.16 When, instead, aliphatic substit-
uents are solely involved (e.g., R1 ) isopropyl, isobutyl,
dioxolanyl), concurring participation of several transition state
structures can be invoked accounting for the reduced and
variable anti-/syn-diastereoselectivity shown with such substrates.
As for the facial diastereoselectivity of reactions involving
nonracemic prochiral acceptors 10 and 15, a plausible rationale
explaining the 1′,4′′-syn vs anti preference relies on the
examination of the transition states from the Newman projec-
tions TS7, TS8, and TS9 (Figure 2). With aldehyde 10, a
classical polar Felkin-Anh model TS7 applies, accounting for
the exclusive formation of 1′,4′′-anti-configured aldols 20 via
si-face attack (Table 2, entry 5). However, a reverted outcome
was witnessed with ketone 15; in this case, 15 could not react
via the expected TS7-type geometry, but would have presumably
to adopt either an anti-Felkin-Anh transition state such as TS8
or a Felkin-Anh projection TS9, with the CH2O- group being
considered as the large substituent.17 In truth, the reaction
yielded 1′,4′′-syn-adduct 25 almost exclusively, via nucleophilic
attack at the re face of the carbonyl (Table 2, entry 10).
1
was directly subjected to H NMR analysis for determination
of the diastereomeric ratio (anti:syn ratio >12.0:1). The crude
residue was purified by silica gel flash chromatography (hexane/
EtOAc 85:15) to afford 92 mg (93%) of compound anti-4a. Data
for anti-4a: colorless oil; Rf 0.40 (hexane/EtOAc 9:1) [silica gel,
UV]; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H, Ph), 6.79
(dd, J ) 6.2, 2.0 Hz, 1H, H4), 6.08 (dd, J ) 6.2, 1.3 Hz, 1H,
H3), 5.52 (bd, J ) 2.2 Hz, 1H, H1′), 4.70 (ddd like a q, J ) 2.1
Hz, 1H, H5), 1.63 (s, 9H, t-Bu), 0.03 (s, 9H, TMS); 13C NMR
(75.4 MHz, CDCl3) δ 169.4 (Cq, C2), 149.7 (Cq, Boc), 146.4
(CH, C4), 140.8 (Cq, Ph), 128.4 (2C, CH, Ph), 127.9 (CH, Ph),
127.6 (CH, C3), 125.6 (2C, CH, Ph), 82.9 (Cq, t-Bu), 71.7 (CH,
C1′), 68.9 (CH, C5), 28.2 (3C, CH3, t-Bu), -0.4 (3C, CH3,
TMS). Anal. Calcd for C19H27NO4Si: C, 63.13; H, 7.53; N, 3.87.
Found: C, 62.97; H, 7.71; N, 3.75.
Conclusion
Treatment of compound anti-4a with catalytic hydrogen (H2,
Pd/C, EtOAc) followed by citric acid (3.0 mol equiv) in MeOH
quantitatively gave the corresponding known saturated and
In summary, we have developed a novel, direct, and viny-
logous variant of the classical Lewis acid-catalyzed Mukaiyama
(15) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503–7509. (b) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011–1014. (c) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004. (d) Heathcock, C. H. In ComprehensiVe Organic
Synthesis: Additions to C-X π-Bonds, Part 2; Heathcock, C. H., Ed.; Pergamon
Press: Oxford, UK, 1991; Chapter 1.5.
(16) With ketone acceptors, the syn/anti notation of the ketol products is
sometimes ambiguous, depending on the way the formulae are written. For a
uniform reading and clean rationalization of the stereochemical results, we opted
to positioning the R1 endo-directing group on the plane of the molecule (see
compounds 5a-c and 23-25 in Tables 1 and 2).
5450 J. Org. Chem. Vol. 73, No. 14, 2008

Vicarious SilylatiVe Mukaiyama Aldol Reaction
desilylated lactam:7 1H NMR (300 MHz, CDCl3) δ 7.3-7.5 (m,
5H, Ph), 5.38 (br s, 1H, H1′), 4.35 (ddd like a dt, J ) 9.4, 1.0
Hz, 1H, H5), 3.92 (br s, 1H, OH), 2.89 (ddd like a dt, J ) 17.9,
10.1 Hz, 1H, H3a), 2.30 (ddd, J ) 17.7, 10.1, 1.6 Hz, 1H, H3b),
2.02 (m, 1H, H4a), 1.70 (m, 1H, H4b), 1.63 (s, 9H, t-Bu).
“G. Casnati” (Universita` di Parma) for instrumental facilities.
A postdoctoral fellowship to P.B. from Centro Interdisciplinare
di Studi Bio-Molecolari e Applicazioni Industriali (CISI, Milano,
Italy) is gratefully acknowledged.
1
The presence of minor isomer syn-4a evidenced by H NMR
analysis of the crude reaction product could no longer be detected
Supporting Information Available: Experimental proce-
dures, compound characterization data, stereochemical assign-
ment of anti-18, and reproductions of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
after column chromatography purification. Data for syn-4a (taken
1
from the reaction mixture): H NMR (300 MHz, CDCl3) δ 7.40
(m, 5H, Ph), 7.35 (dd, J ) 6.1, 2.0 Hz, 1H, H4), 5.81 (dd, J ) 6.1,
1.6 Hz, 1H, H3), 5.51 (br d, J ) 5.2 Hz, 1H, H1′), 4.80 (ddd like
a dt, J ) 5.3, 2.0 Hz, 1H, H5), 1.54 (s, 9H, t-Bu), 0.10 (s, 9H,
TMS).
JO800741C
(17) For a related example involving nucleophilic addition to phenyl ketone
15, see: Roy, S.; Sharma, A.; Chattopadhyay, N.; Chattopadhyay, S. Tetrahedron
Lett. 2006, 47, 7067–7069.
Acknowledgment. This work was supported by the Univer-
sity of Parma. We thank the Centro Interdipartimentale Misure
J. Org. Chem. Vol. 73, No. 14, 2008 5451