Catalytic asymmetric synthesis of acyclic arrays by tandem 1,4-addition-aldol reactions

Article abstract of DOI:10.1021/ja0651862

Herein, we report efficient acyclic stereocontrol in tandem 1,4-addition-aldol reactions triggered by catalytic asymmetric organometallic addition. Grignard reagents add to α,β-unsaturated thioesters in a 1,4-fashion and the resulting magnesium enolates are trapped with aromatic or aliphatic aldehydes. The process provides a range of tandem products bearing three contiguous stereocenters with excellent control of relative and absolute stereochemistry. The various diastereomeric products have been fully characterized using single-crystal X-ray analysis and the origins of stereocontrol in this tandem protocol are discussed. The versatility and efficiency of this methodology are demonstrated in the first catalytic asymmetric synthesis of (-)-phaseolinic acid with 54% overall yield via a short and concise route.

Full text of DOI:10.1021/ja0651862

Published on Web 11/01/2006
Catalytic Asymmetric Synthesis of Acyclic Arrays by Tandem
1,4-Addition-Aldol Reactions
Gareth P. Howell, Stephen P. Fletcher, Koen Geurts, Bjorn ter Horst, and
Ben L. Feringa*
Contribution from the Department of Organic & Molecular Inorganic Chemistry,
Stratingh Institute, UniVersity of Groningen, Nijenborgh 4, 9747 AG,
Groningen, The Netherlands
Received July 31, 2006; E-mail: b.l.feringa@rug.nl
Abstract: Herein, we report efficient acyclic stereocontrol in tandem 1,4-addition-aldol reactions triggered
by catalytic asymmetric organometallic addition. Grignard reagents add to R,â-unsaturated thioesters in a
1,4-fashion and the resulting magnesium enolates are trapped with aromatic or aliphatic aldehydes. The
process provides a range of tandem products bearing three contiguous stereocenters with excellent control
of relative and absolute stereochemistry. The various diastereomeric products have been fully characterized
using single-crystal X-ray analysis and the origins of stereocontrol in this tandem protocol are discussed.
The versatility and efficiency of this methodology are demonstrated in the first catalytic asymmetric synthesis
of (-)-phaseolinic acid with 54% overall yield via a short and concise route.
Scheme 1. Catalytic Tandem 1,4-Addition-Aldol Reactions
Introduction
The generous amount of research invested into C-C bond
formation via the addition of organometallic species to R,â-
unsaturated carbonyl compounds now allows for this transfor-
mation to be achieved in a catalytic asymmetric manner using
a range of nucleophilic and electrophilic partners (Scheme 1).1
The initial product of reaction is the metal enolate 1 and, in the
presence of a suitable carbonyl electrophile, enolate 1 can be
intercepted to yield aldol type products 2 bearing up to three
contiguous stereocenters. Tandem reactions attract significant
research interest2 as they can effect a rapid increase in structural
and stereochemical complexity using only catalytic sources of
chirality.
The reported intramolecular examples of catalytic asymmetric
1,4-addition-aldol reactions utilize organometallic nucleophiles
in combination with substrates which contain both activated
olefin and aldehyde functions.3 The intermolecular 1,4-addition-
aldol reactions described so far require the use of cyclic
substrates to enforce geometrical constraints on any intermediate
enolate and promote stereocontrol.4-7 In 2001, we reported a
concise synthesis of prostaglandin E1 utilizing a tandem 1,4-
addition-aldol reaction as the key transformation (A, Scheme
2).4c More recently, Nicolaou et al. described highly enantiose-
lective 1,4-addition-aldol coupling using vinylzirconium nu-
cleophiles and cyclic enones 3 (B, Scheme 2).5 Hoveyda et al.
have achieved highly enantio- and diastereoselective 1,4-
addition-aldol coupling using organozinc reagents and chrome-
nones 6 (C, Scheme 2).6 Hayashi et al. used a chiral rhodium
catalyst to achieve an intermolecular 1,4-addition-aldol reac-
tion involving an organoboron addition to an R,â-unsaturated
ketone.7 The racemic version of the reaction proceeded smoothly
with excellent control of relative stereochemistry. Attempts to
control the absolute stereochemistry of the reaction using chiral
ligands gave high enantioselectivity but the chemical yield and
(4) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H.
M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623. (b) Keller, E.;
Maurer, J.; Naasz, R.; Schrader, T.; Meetsma, A.; Feringa, B. L.
Tetrahedron: Asymmetry 1998, 9, 2409-2411. (c) Arnold, L. A.; Naasz,
R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841-
5842. (d) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2002, 67, 7244-7254. (e) Alexakis, A.; Trevitt, G. P.; Bernardinelli,
G. J. Am. Chem. Soc. 2001, 123, 4358-4360.
(5) Nicolaou, K. C.; Tang, W.; Dagneau, P.; Faraoni, R. Angew. Chem., Int.
Ed. 2005, 44, 3874-3879. Control of the relative stereochemistry proved
challenging but this was not of great importance as two of the three new
stereogenic centers were removed via dehydration to reform the R,â-
unsaturated system.
(1) For reviews, see: (a) Woodward, S. Angew. Chem., Int. Ed. 2005, 44,
5560-5562. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-
196; (c) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. in Modern
Organocopper Chemistry; Krause, N., Ed.; VCH: Weinheim, Germany,
2002, pp 224-258. (d) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-
353. (e) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236.
(f) Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999, Vol. 3, pp 1105-1120. (g) Yamasaki, K.; Hayashi, T. Chem. ReV.
2003, 103, 2829-2844.
(2) For a recent review, see Guo, H. C.; Ma, J. A. Angew. Chem., Int. Ed.
2006, 45, 354-366.
(3) (a) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003,
125, 1110-1111. (b) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am.
Chem. Soc. 2004, 126, 4528-4529. (c) Bocknack, B. M.; Wang, L. C.;
Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421-2425.
(6) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2005, 44, 5306-5310.
(7) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 2002, 124,
10984-10985.
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J. AM. CHEM. SOC. 2006, 128, 14977-14985
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A R T I C L E S
Howell et al.
Scheme 2. Applications of Tandem 1,4-Addition-Aldol Coupling
Scheme 3. Tandem 1,4-Addition-Aldol Coupling of Thioester Substrates
(a) CuBr‚SMe2 (0.05 equiv), (R,S)-JOSIPHOS (0.06 equiv), MeMgBr (1.2 equiv), TBME, -75 °C, 16 h; (b) PhCHO (2 equiv), -75 °C, 1 min; (c)
K2CO3, MeOH, room temperature, 3 h.
diastereoselectivity were limited. To the best of our knowledge,
this is the only acyclic example of a catalytic asymmetric,
intermolecular 1,4-addition-aldol coupling via organometallic
addition. On the basis of the notion that acyclic stereocontrol
via catalytic asymmetric tandem 1,4-addition-aldol coupling
remains a major challenge and that the products of such
transformations are particularly valuable for natural product
synthesis, we wished to develop a method to achieve this goal.
Recently, we have developed a number of protocols for the
catalytic asymmetric 1,4-addition of Grignard nucleophiles to
R,â-unsaturated carbonyl compounds.8 We have found R,â-
unsaturated thioester substrates to be of great utility; a wide
range of alkyl and aryl groups are tolerated at the termini of
the olefinic bond and various Grignard species can be added
with high yield and enantioselectivity. We envisioned that this
methodology might be utilized to achieve 1,4-addition-aldol
reactions on the basis of the premise that magnesium enolates
have been shown to display high reactivity toward aldol
coupling,9 and furthermore sulfur containing enolates have been
successfully employed in a range of diastereoselective aldol
reactions.10 Accordingly, we have developed a powerful and
efficient protocol for the catalytic asymmetric construction of
acyclic stereochemical triads using R,â-unsaturated thioester
substrates, methyl Grignard nucleophiles, and aromatic or
aliphatic aldehydes. The tandem reaction products are formed
in good yield with excellent control of relative and absolute
stereochemistry across the three newly formed stereogenic
centers. We also demonstrate the utility and efficiency of this
new methodology by achieving the first catalytic asymmetric
synthesis of (-)-phaseolinic acid using a short and concise route.
Results and Discussion
Our initial hypothesis was that the diastereoselectivity of the
aldol coupling ought to be strongly influenced by the steric
properties of the substituents at the γ-position of the intermediate
enolate 9 (Scheme 3). With this in mind, we elected to use
thioester 8 in conjunction with a methyl Grignard nucleophile
in order to explore the potential for tandem 1,4-addition-aldol
reactions. Thus, the intermediate enolate 9 will feature (in
relative terms) “large” (Ph, “A” value ) 3.0 kcal)11 and “small”
(Me, “A” value ) 1.7 kcal) substituents at the γ-position. This
steric discrepancy ought to provide the best opportunity for
diastereoselective attack on the carbonyl electrophile in the aldol
coupling step.
(8) (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.; Minnaard,
A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b) Lo´pez, F.;
Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc.
2004, 126, 12784-12785. (c) Lo´pez, F.; Harutyunyan, S. R.; Meetsma,
A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-
2756. (d) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966-9967.
(9) For key examples of magnesium mediated aldol chemistry, see (a) Evans,
D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002,
124, 392-393. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J.
S. Org. Lett. 2002, 4, 1127-1130.
(10) (a) Masamune, S.; Sato, T.; Kim, B.; Wollmann, T. A. J. Am. Chem. Soc.
1986, 108, 8279-8281. (b) Mukaiyama, T.; Uchiro, H.; Kobayashi, S.
Chem. Lett. 1986, 6, 1001-1004. (c) Evans, D. A.; Downey, C. W.; Hubbs,
J. L. J. Am. Chem. Soc. 2003, 125, 8706-8707. (d) Zhang, Y. C.; Phillips,
A. J.; Sammakia, T. Org. Lett. 2004, 6, 23-25.
(11) Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G. A. In Conforma-
tional Analysis; Interscience: New York, 1965.
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Tandem 1,4-Addition-Aldol Reactions
A R T I C L E S
Table 1. Substrate Screening for Tandem 1,4-Addition-Aldol Coupling
a Determined by 1H NMR. b Measured by HPLC/GC of corresponding 1,4-addition product (10, 20, or 21) prior to aldol coupling. c Isolated yield
after chromatography and/or crystallization. d Stereochemistry assigned via single-crystal X-ray analysis. e Compound 12b was isolated as the thioester
to allow for determination of absolute stereochemistry by X-ray analysis employing heavy atom effect. f Stereochemistry assigned by comparison to
products 11a and 11e. g Stereochemistry assigned via subsequent derivatization. h Absolute configuration assigned via subsequent derivatization
studies; relative configuration assigned by comparison to compounds 11a and 11e; diastereomers separated as thioesters (without methanolysis) by
chromatography.
The initial 1,4-addition proceeded smoothly using the
Cu/JOSIPHOS catalyst we have utilized previously8d and it was
quickly found that the intermediate magnesium enolate 9 readily
underwent aldol coupling with benzaldehyde, with complete
conversion after 1 min at -75 °C. This is in direct contrast to
the extended reaction times we have found necessary for aldol
coupling of the corresponding zinc enolates.4 This sequence
provides products with three contiguous stereocenters and, while
four diastereomeric aldol products (11-13) are possible, we
observed a ratio of 85:10:5 (11a/12a/13a) by 1H NMR. Attempts
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A R T I C L E S
Howell et al.
Numerous studies have been made concerning stereochemistry
in the direct aldol reaction12 and accordingly, a chair like
Zimmerman-Traxler transition state model (Scheme 4) would
seem pertinent for this magnesium mediated aldol reaction. It
would also seem logical that (1) both enolate and aldehyde are
monodentate ligands; (2) the large phenyl substituent on the
aldehyde occupies a pseudoequatorial site to minimize unfavor-
able diaxial interactions. The observed ratio of syn- (11a + 12a)
to anti- (13a) aldol products is high (g20:1 by 1H NMR), and
it can be seen from Scheme 4 that if high energy boat
conformations are ignored, only the Z-enolate 14 can give rise
to the observed syn-aldol products 11a and 12a. This indicates
that the initial 1,4-addition reaction furnishes the magnesium
enolate 9 with high Z-selectivity. To investigate this hypothesis
further, we attempted to isolate the intermediate enolate 9
(Scheme 4) as the corresponding trimethylsilyl thioketene acetal
9a directly from the 1,4-addition reaction mixture. This proved
unsuccessful and we were unable to detect silylated products
under these conditions.13 However, treatment of 1,4-addition
product 10 (Scheme 4) with lithium diisopropylamide and
trimethylsilyl chloride afforded the thioketene acetal 9a with
high Z/E selectivity (88:12 by 1H NMR). Enolate geometry was
assigned based on the observed “weak” NOE interaction
(Scheme 4) in the major enolate product (Z) and a much more
(∼15 times) intense interaction in the minor enolate product
(E). Reaction between lithium enolate 9 and PhCHO generated
the syn-aldol product with high diastereoselectivity. These
observations indicate that our tandem reaction (Scheme 3) and
the lithium mediated aldol reaction (Scheme 4) proceed via the
same enolate intermediate 9 with a high preponderance of the
Z-geometry.
Figure 1. Crystal structure representations of 11a (top) and 12b (bottom).
to increase the diastereoselectivity further by varying solvent,
substrate addition order/addition time and quenching conditions
were ineffective. The observed level of stereocontrol with this
acyclic substrate is comparable to that obtained by Hoveyda et
al. using cyclic chromenone substrates.6 We found that the
crude aldol product could be easily converted to the corre-
sponding oxygen ester affording higher stability to chro-
matography and, crucially, allowing the diastereomeric aldol
products to be readily separated by crystallization. We were
able to isolate the major diastereomer 11a as a single compound
in 64% yield.
To rationalize the selectivity observed between the two syn-
aldol products 11a and 12a, we might consider two more
detailed transition state models (Figure 2). Minimization of the
A
1,3-strain (16) in the enolate would promote Re-facial attack
Determination and Origin of Stereochemistry. The enan-
tiomeric excess (95% ee) of the tandem 1,4-addition-aldol
reaction above was determined by HPLC analysis of the 1,4-
addition product 10 prior to aldol coupling. While we were
unable to isolate the second diastereomer 12a, we could isolate
a pure sample of the corresponding diastereomer from a
subsequent, analogous reaction (thioester 12b, Scheme 5, Table
1, entry 2). With pure, crystalline samples of the first (11a)
and second (12b) diastereomers in hand, we were able to assign
relative (11a) and absolute (12b, using sulfur as a “heavy atom”)
configurations using single-crystal X-ray analysis. Crystal
structure representations can be seen in Figure 1. Since all of
the diastereomeric products discussed thus far are formed from
the same enantio-enriched enolate 9, both 11a and 12b must
possess like configuration (3S) at the benzylic stereocenter. On
the basis of this observation and our crystal structure analy-
ses, we have assigned the first diastereomer as (2S,3S,1′R)-11a
and the second diastereomer as (2R,3S,1′S)-12a. The assign-
ment of (2S,3S,1′R) for the major diastereomeric product
was confirmed in subsequent studies where an analogous
major product 11e (Scheme 5, Table 1, entry 5) was deriva-
tized to natural (-)-phaseolinic acid (2S,3S,4S)-22 (vide infra,
Scheme 6).
on the enolate, as the phenyl substituent is more sterically
demanding than the methyl group. This transition state would
predict the anti,syn diastereomer 12a to be the major product.
This is in direct disagreement with our findings and is therefore
disregarded. Alternatively, minimization of the inherent syn-
pentane interaction (17)12a,c in the transition state would promote
Si-facial attack on the enolate giving rise to syn,syn-11a as the
major diastereomer. This is supported by our findings, and we
would suggest 17 to be a likely transition state model for this
reaction. This analysis would suggest that the high level of
diastereoselectivity is reliant on the steric differential between
the two groups (Ph and Me) at the γ-stereogenic center present
in the intermediate enolate.
Scope and Applications. To further probe this mechanism
for stereocontrol and to investigate the scope of the reaction
we screened other thioester and carbonyl partners (Scheme 5,
Table 1). Substrate 8 reacted smoothly and in a stereoselective
manner with aromatic and aliphatic aldehydes displaying
excellent conversions in all cases. Diastereoselectivity was
(12) (a) Evans, D. A.; Nelson, J. V.; Taber, T. Top. Stereochem. 1982, 13, 1-115.
(b) Arya, P.; Qin, H. P. Tetrahedron 2000, 56, 917-947. (c) Roush, W. R.
J. Org. Chem. 1991, 56, 4151-4157. (d) Van Draanen, N. A.; Arseniyadis,
S.; Crimmins, M. T.; Heathcock, C. H. J. Org. Chem. 1991, 56, 2499-
2506.
(13) It is likely that the presence of stoichiometric amounts of magnesium(II)
halides either precludes the silylation of enolate 9 or causes degradation
of the desired product 9a.
The second step in the process outlined in Scheme 3 is, in
essence, a diastereoselective aldol reaction using a chiral
nucleophile (enolate) and a prochiral electrophile (aldehyde).
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Tandem 1,4-Addition-Aldol Reactions
A R T I C L E S
Scheme 4. Enolate Selectivity
(a) Diisopropylamine (1.1 equiv), n-BuLi (1.1 equiv), TBME, -50 °C, 2 h; (b) trimethylsilyl chloride (1.1 equiv), -50 °C to room temperature, 1 h; (c)
PhCHO (2 equiv), -75 °C to room temperature, 1 h.
Figure 2. Model for anti,syn/syn,syn selectivity.
Scheme 5. Substrate Screening
(a) CuBr‚SMe2 (0.05 equiv), JOSIPHOS (0.06 equiv), MeMgBr (1.2 equiv), TBME, -75°, 16 h; (b) R′CHO (2 equiv), -75°, 1 min; (c) K2CO3, MeOH,
room temperature, 3 h.
typically high for the aromatic aldehydes (entries 1-4) and very
high for the aliphatic aldehydes (entries 5-7). Removal of the
minor diastereomeric products was readily achieved in all cases
by column chromatography and/or crystallization. Diastereo-
merically pure products 11a-h (with g95% ee) were obtained
in moderate to good overall yields based on the starting thioester
substrates. Aryl substituted thioester 18 yielded similar results
to 8 (entry 8), while substrate 19 (entry 9), bearing a protected
hydroxy function, reacted smoothly but in a nondiastereo-
selective manner. While we were able to separate the two
diastereomeric products 11j/12j, the stereochemical assignment
(syn,syn or syn,anti) based on NMR data was not successful.
As we proposed earlier, the diastereoselectivity of this reaction
is likely controlled by the steric differential between the two
substituents at the γ-position in the intermediate enolate.
Considering substrate 19, the two γ-substituents are methyl (A
value ) 1.7 kcal) and CH2OTBDMS (A value ≈ 1.8 kcal).11
These two groups have almost equivalent steric parameters and
so the lack of diastereoselectivity in the ensuing aldol reaction
is, perhaps, not surprising.
carboxylic acid. This would greatly expand the scope of our
tandem 1,4-addition-aldol methodology and allow access to
important families of biologically active products (Scheme 6).
The three natural products shown belong to the paraconic acid
family14 and have been isolated from various lichens, mosses,
and fungi. These compounds, displaying useful antifungal,
antitumor, and antibacterial properties, have attracted significant
interest from the synthetic-organic community.15 The three
specific paraconic acids shown below each display trans-cis
stereochemistry and are often described as the most challenging
of the paraconic acids from a synthetic viewpoint.15e Using our
tandem 1,4-addition-aldol pathway, we might provide access
to the paraconic acid skeleton in as little as four synthetic
transformations, with the sequence relying on a key oxidation
of the aromatic ring.
With the simplest pentyl-substituted paraconic acid (phase-
olinic acid 22)15 as our target, the tandem product 11e was
synthesized as a single diastereomer in 72% yield and 95% ee
(Table 1, entry 5) using our 1,4-addition-aldol methodology with
(14) Bandichhor, R.; Nosse, B.; Reiser, O. Top. Curr. Chem. 2005, 243, 43-
72.
The products 11a-j show how this tandem methodology can
be used to create structurally complex, acyclic stereochemical
triads both rapidly and efficiently. In the majority of cases above,
a phenyl group appears to serve as a “bulky” substituent at the
γ-position of the enolate to promote diastereoselectivity in the
ensuing aldol transformation. We were hopeful that this phenyl
function might be utilized as a synthetic handle for further
transformations via exhaustive oxidation to the corresponding
(15) For isolation and asymmetric syntheses, see (a) Mahato, S. B.; Siddiqui,
K. A. I.; Bhattacharya, G.; Ghosal, T.; Miyahara, K.; Sholichin, M.;
Kawasaki, T. J. Nat. Prod. 1987, 50, 245-247. (b) Jacobi, P. A.; Herradura,
P. Tetrahedron Lett. 1996, 37, 8297-8930. (c) Drioli, S.; Felluga, F.;
Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E. J. Org. Chem. 1998, 63,
2385-2388. (d) Ariza, X.; Garcia, J.; Lopez, M.; Montserrat, L. Synlett
2001, 120-122. (e) Brecht-Forster, A.; Fitremann, J.; Renaud, P. HelV.
Chim. Acta 2002, 85, 3965-3974. (f) Zhang, Z.; Xiyan, L. Tetrahedron:
Asymmetry 1996, 7, 1923-1928. (g) Amador, M.; Ariza, X.; Garcia, J.;
Ortiz, J. J. Org. Chem. 2004, 69, 8172-8175.
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Howell et al.
Scheme 6. Catalytic Asymmetric Synthesis of Phaseolinic Acid
(a) CuBr‚SMe2 (0.05 equiv), JOSIPHOS (0.06 equiv), MeMgBr (1.2 equiv), TBME, -75°, 16 h; (b) PhCHO (2 equiv), -75°, 1 min; (c) K2CO3, MeOH,
room temperature, 3 h; (d) TBDMSOTf (1.20 equiv), 2,6-lutidine (1.20 equiv), THF, room temperature, 3 h; (e) RuCl3 (0.10 equiv), NaIO4 (50 equiv),
MeCN/EtOAc/H2O, room temperature, 16 h; (f) HBr (48%), reflux, 3 h.
Experimental Section
hexanal as the carbonyl component. With the ensuing aromatic
oxidation in mind, we elected to protect the free hydroxyl
function in 11e. Coupling of the secondary alcohol with tert-
butyldimethylsilyl triflate proceeded efficiently affording com-
pound 23 which was used to test exhaustive oxidation of the
aromatic system. We desired a pH-neutral procedure for
oxidation to avoid any potential epimerisation or desilylation
and inspection of the literature revealed a simple procedure using
catalytic RuCl3 and NaIO4 as the stoichiometric oxidant.16 In
our hands this method could be used without any modification,
and we were able to isolate the carboxylic acid 24 in high yield
without any loss of stereochemical integrity (1H NMR). The
remaining synthetic transformations included ester hydrolysis,
alcohol deprotection, and lactonization. We postulated that these
three transformations might be effected simultaneously under
acidic conditions. Exposure of 24 to 1 M HCl in THF yielded
only starting material after 16 h, indicating that more vigorous
conditions were required. Refluxing compound 24 in aqueous
(48%) HBr for 3 h resulted in clean alcohol deprotection, ester
hydrolysis, and lactonization to give the desired phaseolinic acid
22 in 91% yield after chromatography. The physical (melting
point, optical rotation) and spectroscopic (1H and 13C NMR)
data were in agreement with literature values.14 On the basis of
our assignment of the absolute stereochemistry for the tandem
product 11e, we can confirm the revised stereochemistry for
(-)-phaseolinic acid [(2S,3S,4S)-22] reported by Drioli et al.
in 1998.15c Our concise, catalytic asymmetric synthesis of
phaseolinic acid was achieved with an overall yield of 54%.
The route, while short and efficient, is also the first to employ
a catalytic asymmetric approach. Moreover, it is a clear
demonstration of the potential and efficiency of the tandem 1,4-
addition-aldol methodology described here.
1
General. H NMR spectra were recorded at 400 or 500 MHz with
CDCl3 (referenced to 7.26 ppm) as solvent. 13C NMR spectra were
recorded at 100 or 125 MHz with CDCl3 (referenced to 77.1 ppm)
as solvent. Coupling constants (J) are given in Hz. Varian Gemini
200, VXR300, AMX400 and Inova 500 spectrometers were used
throughout. HRMS data were obtained using a JEOL JMS-600H
spectrometer. A Shimadzu 10A system was used for HPLC and
Hewlett-Packard HP6890 for GC analysis. Optical rotations were
measured at 254 µm using a Schmidt & Haendsch polarimeter
(Polartronic MH8) with a 10 cm cell (c given in g/100 mL and
measurements are given in 10-1 deg cm2 g-1). Thin-layer chromatog-
raphy was performed on commercial Kieselgel 60F254 silica gel plates;
KMnO4 and H3[P(Mo3O10)4]‚H2O were used for visualization. Flash
chromatography was performed using silica gel. Reagents were obtained
from Sigma Aldrich Chemie BV, solvents were purified according to
standard methods, and the JOSIPHOS ligand was obtained as a gift
from Solvias (Basel).
Synthesis of Thioester Substrates. 3-Phenyl-thioacrylic Acid
S-Methyl Ester (8). AlCl3 (6 g, 45 mmol) and Me3Si-SMe (6.78 mL,
48 mmol) were added to a stirred solution of methyl trans-cinnamate
(6 g, 36.9 mmol) in dry THF (100 mL) under a nitrogen atmosphere at
room temperature. The reaction mixture was heated to reflux for 4 h
and subsequently quenched at room temperature by the addition of
aqueous phosphate buffer (pH 7). The mixture was partitioned between
Et2O (50 mL) and water, and the aqueous layer extracted with Et2O (3
× 50 mL). The combined organic layers were washed with brine, dried
(MgSO4) and filtered, and the solvent was evaporated. Flash chroma-
tography of the yellow residue over silica gel, using pentane-Et2O
(50:1) gave title compound 8 (6.0 g, 91%) as a clear oil that crystallized
1
upon standing: mp 49.2-50.1 °C. H NMR δ 7.62 (1H, d, J ) 15.8
Hz): 7.56-7.50 (2H, m), 7.40 (3H, dd, J ) 6.4, 3.6 Hz), 6.74 (1H, d,
J ) 15.8 Hz), 2.43 (3H, s). 13C NMR: δ 189.9, 140.0, 133.9, 130.3,
128.7, 128.2, 124.6, 11.5. HRMS: calcd for C10H10OS, 178.04523;
found, 178.04589.
Summary
3-(4-Chloro-phenyl)-thioacrylic Acid S-Methyl Ester (18). AlCl3
(1.63 g, 12.20 mmol) and Me3Si-SMe (1.87 mL, 13.22 mmol) were
added to a stirred solution of (E)-methyl 3-(4-chlorophenyl)acry-
late (2.0 g, 10.17 mmol) in dry THF (40 mL) under a nitrogen
atmosphere at room temperature. The reaction mixture was heated to
reflux for 90 min. The reaction mixture was then quenched at room
temperature by the addition of aqueous phosphate buffer (pH 7). The
mixture was partitioned between Et2O (20 mL) and water, and the
aqueous layer was extracted with Et2O (3 × 25 mL). The combined
organic layers were washed with brine, dried (MgSO4) and filtered,
and the solvent was evaporated. Triturating the yellow residue with
cold pentane gave title compound 18 (1.90 g, 88%) as opaque white
needles: mp 99.7-100.1 °C. 1H NMR: δ 7.56 (1H, d, J ) 15.8 Hz),
7.50-7.45 (2H, m), 7.39-7.34 (2H, m), 6.70 (1H, d, J ) 15.8 Hz),
We have developed the first catalytic asymmetric protocol
for acyclic 1,4-addition-aldol coupling using organometallic
nucleophiles. Using R,â-unsaturated thioesters and methyl
Grignard reagents, the chemical yields and levels of stereocon-
trol displayed in the tandem products are comparable to recent
reports using cyclic systems and are well in excess of any
reported results for acyclic systems. The utility of this tandem
protocol is exemplified by the first catalytic asymmetric
synthesis of phaseolinic acid, accomplished with an overall yield
of 54%, via an exceptionally short and efficient route.
(16) Nunez, M. T.; Martin, V. S. J. Org. Chem. 1990, 55, 1928-1932.
9
14982 J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006

Tandem 1,4-Addition-Aldol Reactions
A R T I C L E S
2.43 (3H, s). 13C NMR: δ 189.8, 138.5, 136.3, 132.5, 129.4, 129.1,
125.1, 11.6. HRMS: calcd for C10H9ClOS, 212.00626; found, 212.00547.
(3S)-3-Phenyl-thiobutyric Acid S-Methyl Ester (10). The com-
pound was used to determine enantiomeric excess of tandem 1,4-
addition-aldol reactions using thioester 8 as substrate (products
11a-g). It was prepared using general procedure A and isolated from
a sample of the reaction mixture prior to aldehyde addition (aldol
coupling). Title compound 10 was obtained as a clear oil: [R]D ) +45.1
(c 0.27, CHCl3). 1H NMR: δ 7.35-7.17 (5H, m), 3.43-3.29 (1H, m),
2.84 (2H, dq, J ) 14.8, 7.4 Hz), 2.27 (3H, s), 1.31 (3H, d, J ) 6.9
Hz). 13C NMR: δ 198.6, 145.3, 128.4, 126.7, 126.4, 52.0, 36.9, 21.4,
11.5. HRMS: calcd for C11H14OS, 194.07653; found, 194.07651. HPLC
analysis indicated an enantiomeric excess of 97% [Chiralcel OD-H
column; flow, 0.5 mL/min; heptane/i-PrOH, 99:1, 210 nm; minor
4-(tert-Butyl-diphenyl-silanyloxy)-but-2-enethioic Acid S-Methyl
Ester (19). tert-Butyl-chlorodiphenylsilane (10 mL, 38.5 mmol) was
added to a stirred solution of ethane-1,2-diol (12 mL, 231 mmol) and
imidazole (2.88 g, 42.4 mmol) in THF (200 mL) under nitrogen
atmosphere. The resulting mixture was stirred for 24 h at room
temperature and quenched with 200 mL water followed by the addition
of 200 mL Et2O. After phase separation and extraction of the aqueous
phase with Et2O (3 × 200 mL), the combined organic phases were
dried (MgSO4), concentrated, and purified by flash chromatography
(eluent pentane/EtOAc 4:1) to afford monosilyl alcohol A as a colorless
oil (9.140 g, 79% yield). A solution of A (9.14 g, 30.5 mmol) and IBX
(11.09 g, 39.6 mmol) in EtOAc (200 mL) was refluxed for 24 h and
cooled to room temperature. The IBX and benzoic acid were removed
via filtration (Celite pad) and washed with EtOAc. The filtrate was
concentrated under reduced pressure to give aldehyde B, which was
used in the next step without any purification (8.81 g, 97% yield). A
solution of aldehyde B (8.81 g, 29.6 mmol) and Ph3PCHCOSEt (13.99
g, 38.4 mmol) in CH2Cl2 (150 mL) was refluxed for 24 h. The solution
was concentrated under reduced pressure and purified by flash
chromatography (eluent pentane/ether 40:1) to afford title compound
19 as a colorless oil (9.08 g, 80% yield). 1H NMR: δ 7.67 (4H, dd, J
) 7.60, 1.20 Hz), 7.42 (6H, m), 6.90 (1H, dt, J ) 15.20, 3.20 Hz),
6.55 (1H, dt, J ) 14.80, 2.40 Hz), 4.35 (2H, m), 2.98 (2H, q, J ) 7.60
Hz), 1.31 (3H, t, J ) 7.20 Hz), 1.09 (9H, s). 13C NMR: 190.1, 142.7,
135.4, 132.9, 129.9, 127.8, 126.7, 62.8, 26.7, 23.2, 19.2, 14.8. MS
(EI): 327 (71%, M+ - tert-butyl), 384 (100%, M+).
Protocol for Tandem 1,4-Addition-Aldol Coupling. General
Procedure A. A Schlenk flask fitted with a magnetic stirrer was flame-
dried under vacuum and cooled before CuBr‚SMe2 (4.8 mg, 0.04 equiv)
and JOSIPHOS (16.4 mg, 0.05 equiv) were added. A triple evacuation-
N2 purge was carried out and TBME (2.5 mL) was added. Stirring at
room temperature for 15 min gave an orange solution which was cooled
to -75 °C. A 3 M solution of MeMgBr in Et2O (0.20 mL, 1.20 equiv)
was added dropwise over 2 min to give a yellow solution. The thioester
substrate (0.50 mmol, 1.00 equiv) was dissolved in TBME (1 mL) and
added to the reaction flask at -75 °C over 2 min. The mixture was
left to stir for 16 h then warmed to room temperature over 30 min. A
sample of the mixture was removed and passed through a short silica
plug using hexane/TBME (5:1) as eluent to provide a purified sample
of the 1,4-addition product (10, 20, or 21) for chiral HPLC analysis.
The reaction flask was recooled to -75 °C before dropwise addition
of the aldehyde (1.00 mmol, 2.00 equiv) over 2 min. A 2:1 mixture of
THF/H2O (2 mL) was added, and the mixture was warmed to room
temperature over 30 min. Saturated NH4Cl (aq, 5 mL) was added, and
the mixture was stirred for 30 min. After addition of Et2O (10 mL),
the aqueous phase was separated and extracted with Et2O (3 × 10 mL).
The combined organic phases were washed (brine) and dried (MgSO4),
and the solvent was evaporated to give an orange oil. This was dissolved
in MeOH (10 mL), and K2CO3 (1 g) was added before stirring at room
temperature for 3 h. After addition of Et2O (10 mL) and aqueous 1 M
HCl (to ∼ pH 1), the aqueous phase was separated and extracted with
Et2O (3 × 10 mL). The combined organic phases were washed (brine)
and dried (MgSO4), and the solvent was evaporated to give an orange
oil. Flash column chromatography (10:1 hexane/EtOAc) afforded the
purified tandem 1,4-addition-aldol product as a mixture of diastereo-
mers. Crystallization (i-Pr2O) afforded the purified product as a single
diastereomer.
enantiomer (-)-10, tR ) 10.76 min; major enantiomer (+)-10, tR
)
12.08 min].
(2S,3S,1′R)-2-(Hydroxy-phenyl-methyl)-3-phenyl-butyric Acid
Methyl Ester (11a). The compound was obtained using general
procedure A from thioester 8 (0.50 mmol, 90 mg) and benzaldehyde
(1.00 mmol, 106 mg). After purification, title compound 11a was
isolated as a white solid (94 mg, 66%, >20:1 dr, 95% ee based on
analysis of 1,4-addition product 10 prior to aldol coupling): mp
1
133.5-134.5 °C; [R]D +5.4 (c 1.0, CHCl3). H NMR: δ ppm 7.43-
7.08 (10 H, m), 4.45 (1 H, dd, J ) 9.49, 3.44 Hz), 3.69 (1 H, d, J )
9.55 Hz), 3.53 (3 H, s), 3.42-3.32 (1 H, m), 2.93 (1 H, dd, J ) 10.58,
3.46 Hz), 1.28 (3 H, d, J ) 7.04 Hz). 13C NMR: δ ppm 175.5, 144.0,
142.8, 129.0, 128.5, 127.7, 127.5, 127.1, 125.3, 72.2, 59.7, 51.8, 39.7,
20.3. HRMS: calcd for C18H20O3Na (M + Na+), 307.1304; found,
307.1297.
(2S,3S,1′R)-2-[(4-Nitro-phenyl)-hydroxy-methyl]-3-phenyl-bu-
tyric Acid Methyl Ester (11b). Compound 11b was obtained using
general procedure A from thioester 8 (0.50 mmol, 90 mg) and 4-nitro-
benzaldehyde (1.00 mmol, 151 mg). After purification, title compound
11b was isolated as a white solid (102 mg, 62%, >20:1 dr, 95% ee
based on analysis of 1,4-addition product 10 prior to aldol coupling):
1
mp 150.5-151.5 °C; [R]D -26.4 (c 0.8, CHCl3). H NMR: δ ppm
8.16 (2 H, dd, J ) 8.78, 2.37 Hz), 7.62-7.16 (7 H, m), 4.51 (1 H, d,
J ) 9.75 Hz), 4.05 (1 H, dd, J ) 9.76, 2.42 Hz), 3.76-3.31 (4 H, m),
2.94 (1 H, td, J ) 11.07, 2.62 Hz), 1.32 (3 H, d, J ) 9.44 Hz). 13C
NMR: δ ppm 175.0, 150.3, 147.2, 143.1, 129.0, 127.4, 127.2, 126.0,
123.5, 71.4, 59.0, 51.9, 39.7, 20.4. HRMS calcd for C18H19NO5Na (M
+ Na+), 352.1155; found, 352.1109.
(2R,3S,1′S)-2-[Hydroxy-(4-nitro-phenyl)-methyl]-3-phenyl-thiobu-
tyric Acid S-Methyl Ester (12b). Compound 12b was obtained as
the second (minor) diastereomer from the synthesis of compound 11b
(see above) using general procedure A, and was crystallized preferen-
tially (i-Pr2O) from the reaction mixture prior to methanolysis. It was
obtained as clear needles (6%) suitable for single-crystal X-ray analysis.
1H NMR: δ ppm 8.21 (2H, d, J ) 8.71 Hz), 7.52-7.43 (3H, m), 7.34-
7.26 (2H, m), 7.26-7.17 (2H, m), 5.23 (1H, dd, J ) 9.79, 2.38 Hz),
4.13 (1H, d, J ) 10.08 Hz), 3.52 (1H, qd, J ) 10.46, 7.00 Hz), 3.07
(1H, dd, J ) 10.30, 2.91 Hz), 1.86 (3H, s), 1.59 (3H, d, J ) 6.91 Hz).;
13C NMR: δ ppm 167.4, 150.2, 147.5, 143.4, 128.8, 127.8, 127.2, 126.5,
123.8, 72.3, 66.8, 40.4, 19.3, 12.0.
(2S,3S,1′R)-2-[(4-Bromo-phenyl)-hydroxy-methyl]-3-phenyl-bu-
tyric Acid Methyl Ester (11c). The compound was obtained using
general procedure A from thioester 8 (0.50 mmol, 90 mg) and
4-bromobenzaldehyde (1.00 mmol, 185 mg). After purification, title
compound 11c was isolated as a white solid (123 mg, 68%, >20:1 dr,
95% ee based on analysis of 1,4-addition product 10 prior to aldol
coupling): mp 118.5-120.0 °C; [R]D -14.4 (c 0.5, CHCl3). 1H NMR:
δ ppm 7.44-7.21 (6 H, m), 7.02 (2 H, d, J ) 8.58 Hz), 4.38 (1 H, dd,
J ) 9.64, 3.14 Hz), 3.77 (1 H, d, J ) 9.62 Hz), 3.56 (3 H, s), 3.37 (1
H, qd, J ) 10.86, 6.93 Hz), 2.88 (1 H, dd, J ) 10.83, 3.15 Hz), 1.28
(3 H, d, J ) 7.00 Hz), 1.13 (3 H, d, J ) 6.86 Hz). 13C NMR: δ ppm
175.2, 143.4, 141.7, 131.3, 128.8, 127.4, 127.0, 126.8, 121.1, 71.33,
59.2, 51.7, 39.5, 20.2. HRMS: calcd for C18H19O3BrNa (M + Na+),
385.0415; found, 385.0380.
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14983

A R T I C L E S
Howell et al.
(2S,3S,1′R)-2-[(4-Methoxy-phenyl)-hydroxy-methyl]-3-phenyl-bu-
tyric Acid Methyl Ester (11d). The compound was obtained using
general procedure A from thioester 8 (0.50 mmol, 90 mg) and
4-methoxybenzaldehyde (1.00 mmol, 136 mg). After purification, title
compound 11d was isolated as a white, semisolid (85 mg, 54%, >20:1
dr, 95% ee based on analysis of 1,4-addition product 10 prior to aldol
general procedure A from thioester 18 (0.50 mmol, 106 mg) and
benzaldehyde (1.00 mmol, 100 mg). After purification, title compound
11h was isolated as a white solid (78 mg, 49%, >20:1 dr, >99% ee
based on analysis of 1,4-addition product 20 prior to aldol coupling):
mp 78.5-80.4 °C; [R]D -9.9 (c 1.4, CHCl3). 1H NMR δ 7.39-7.22 (7
H, m), 7.17 (2 H, d, J ) 7.60 Hz), 4.47 (1 H, dd, J ) 9.27, 3.53 Hz),
3.66 (1 H, d, J ) 9.39 Hz), 3.56 (3 H, s), 3.37 (1 H, qd, J ) 10.67,
7.02 Hz), 2.91 (1 H, dd, J ) 10.48, 3.73 Hz), 1.29 (3 H, d, J ) 7.04
Hz). 13C NMR: δ 175.0, 142.3, 132.5, 129.0, 128.8, 128.4, 128.3, 127.4,
125.0, 72.0, 59.5, 51.7, 38.8, 19.8. HRMS: calcd for C18H19ClO3Na
(M + Na+), 341.0914; found, 341.0918.
1
coupling): [R]D -2.4 (c 0.5, CHCl3). H NMR: δ ppm 7.40-7.24
(5H, m), 7.10 (2H, d, J ) 8.74 Hz), 6.83 (2H, d, J ) 8.79 Hz), 4.46
(1H, dd, J ) 9.13, 3.78 Hz), 3.80 (3H, s), 3.66-3.50 (4H, m), 3.36
(1H, qd, J ) 10.37, 7.06 Hz), 2.94 (1H, dd, J ) 10.38, 3.81 Hz), 1.30
(3H, d, J ) 7.05 Hz). 13C NMR: δ 175.3, 158.8, 143.8, 134.7, 128.7,
127.5, 126.8, 126.3, 113.7, 71.6, 59.5, 55.2, 51.5, 39.4, 19.8. HRMS:
calcd for C19H22O4Na (M + Na+), 337.1410; found, 337.1398.
(2S,3S,1′S)-3-Hydroxy-2-(1-phenyl-ethyl)-octanoic Acid Methyl
Ester (11e). The compound was obtained using general procedure A
from thioester 8 (0.50 mmol, 90 mg) and hexanal (1.00 mmol, 100
mg). After purification, title compound 11e was isolated as a clear oil
(103 mg, 74%, >20:1 dr, 95% ee based on analysis of 1,4-addition
product 10 prior to aldol coupling): [R]D +1.2 (c 1.0, CHCl3). 1H
NMR: δ ppm 7.58-7.11 (5H, m), 3.81 (3H, s), 3.37 (1H, qd, J )
11.06, 7.00 Hz), 3.20 (1H, s), 2.68 (1H, s), 2.61 (1H, dd, J ) 11.11,
2.58 Hz), 1.51-1.04 (11H, m), 0.85 (3H, t, J ) 7.20 Hz). 13C NMR:
δ 175.8, 144.0, 128.7, 127.5, 126.7, 70.1, 57.2, 51.7, 39.1, 36.6, 31.6,
25.7, 22.5, 20.5, 14.0. HRMS: calcd for C17H26O3Na (M + Na+),
301.1774; found, 301.1760.
(2S,3S,1′R)-2-(Cyclohexyl-hydroxy-methyl)-3-phenyl-butyric Acid
Methyl Ester (11f). The compound was obtained using general
procedure A from thioester 8 (0.50 mmol, 90 mg) and cyclohexane
carboxaldehyde (1.00 mmol, 112 mg). After purification, title compound
11f was isolated as a white semisolid (110 mg, 76%, >20:1 dr, 95%
ee based on analysis of 1,4-addition product 10 prior to aldol
coupling): [R]D +3.5 (c 1.0, CHCl3). 1H NMR: δ ppm 7.41-7.12 (5
H, m), 3.78 (3 H, s), 3.35 (1 H, qd, J ) 13.98, 7.01 Hz), 2.99-2.59 (3
H, m), 1.92 (1 H, d, J ) 12.78 Hz), 1.79-1.40 (2 H, m), 1.37-0.88
(9 H, m), 0.86-0.55 (2 H, m). 13C NMR: δ ppm 176.1, 144.0, 128.6,
127.4, 126.6, 74.6, 53.9, 51.7, 43.0, 39.3, 29.4, 29.0, 26.2, 25.9, 25.7,
20.7. HRMS calcd for C18H26O3Na (M + Na+), 313.1774; found,
313.1786.
(3S)-4-(tert-Butyl-diphenyl-silanyloxy)-3-methyl-thiobutyric Acid S-
Methyl Ester (21). Used to determine enantiomeric excess of tandem
1,4-addition-aldol reactions using thioester 19 as substrate (product 11j).
Prepared using general procedure A and isolated from a sample of the
reaction mixture prior to aldehyde addition (aldol coupling). Title
1
compound 21 obtained as a clear oil: [R]D +8.0 (c 1.2, CHCl3). H
NMR: δ 7.66 (4H, dd, J ) 6.76, 1.37 Hz), 7.41 (6H, m), 3.55 (1H,
dd, J ) 9.95, 5.27 Hz), 3.46 (1H, dd, J ) 9.94, 6.27 Hz), 2.88 (2H, q,
J ) 7.43 Hz), 2.83 (1H, dd, J ) 14.46, 5.27 Hz), 2.38 (1H, dd, J )
14.47, 8.43 Hz), 2.28 (1H, m), 1.25 (3H, t, J ) 7.43 Hz), 1.15 (9H, s),
0.98 (3H, d, J ) 6.63 Hz). 13C NMR: δ 199.1, 135.6, 133.6, 129.6,
127.5, 67.90, 47.8, 33.8, 26.8, 23.3, 19.3, 16.4, 14.8. For determination
of enantiomeric excess, compound 21 was treated with TBAF to yield
a pure sample of (R)-4-methyl-dihydrofuran-2-one: [R]D ) +21.6 (c
0.5, MeOH), lit. [for (S)-4-methyl-dihydrofuran-2-one] ) -24.7 (c 1.7,
MeOH).17 Determination of enantiomeric excess was achieved by GC
analysis [Chiraldex AT-A (30.0 m × 0.25 mm), 1.0 mL min-1, initial
temp is 50 °C then 5 °C min-1 to final temp of 170 °C, 19.7 min
(minor), 19.9 min (major) shows 98% ee].
4-(2,2-Dimethyl-1,1-diphenyl-propoxy)-2-(hydroxy-phenyl-meth-
yl)-3-methyl-thiobutyric Acid S-Methyl Ester (11j). The compound
was obtained using general procedure A from thioester 19 (0.72 mmol,
330 mg) and benzaldehyde (1.40 mmol, 148 mg). Flash column
chromatography gave the title compound 11j (184 mg, 50%, ∼1:1 dr,
98% ee based on analysis of 1,4-addition product 21 prior to aldol
coupling). Repeated chromatography (20:1 Et2O/pentane) allowed
separation of diastereomers. First diastereomer: [R]D -63.3 (c 4.2,
(2S,3R,1′S)-3-Hydroxy-4,4-dimethyl-2-(1-phenyl-ethyl)-pentano-
ic Acid Methyl Ester (11 g). The compound was obtained using general
procedure A from thioester 8 (0.50 mmol, 90 mg) and pivalinaldehyde
(1.00 mmol, 86 mg). After purification, title compound 11g was isolated
as a clear oil (95 mg, 72%, >20:1 dr, 95% ee based on analysis of
1,4-addition product 10 prior to aldol coupling): [R]D +9.4 (c 1.0,
1
CHCl3). H NMR: δ ppm 7.71-7.64 (4H, m), 7.50-7.24 (11H, m),
1
CHCl3). H NMR: δ ppm 7.41-7.10 (5 H, m), 3.76 (3 H, s), 3.64 (1
5.04 (1H, dd, J ) 4.2, 8.8 Hz), 3.61 (1H, dd J ) 4.7, 10.3 Hz), 3.58-
3.52 (2H, m), 3.09 (1H, dd, J ) 4.2, 8.4 Hz), 2.74-2.60 (2H, m),
2.38-2.28 (1H, m), 1.20 (3H, m), 1.08 (9H, s), 1.00 (3H, t, J ) 7.4
Hz). 13C NMR: δ 203.8, 142.3, 135.6, 135.6, 133.5, 133.4, 129.5, 128.1,
127.5, 127.5, 127.2, 125.6, 72.6, 72.5, 66.3, 66.3, 66.3, 61.9, 61.9, 36.7,
H, d, J ) 10.04 Hz), 3.29 (1 H, qd, J ) 11.27, 7.00 Hz), 2.82 (1 H,
ddd, J ) 12.57, 10.60, 1.44 Hz), 1.20 (3 H, d, J ) 7.01 Hz), 0.74 (9
H, s). 13C NMR: δ ppm 177.0, 144.1, 128.6, 127.4, 126.7, 78.0, 51.7,
50.8, 40.8, 35.5, 25.6, 20.6. HRMS: calcd for C16H24O3Na (M + Na+),
287.1617; found, 287.1610.
26.9, 26.9, 23.2, 19.2, 15.2, 14.3, 14.2. HRMS: C26H29O3SSi (M+
-
(3S)-3-(4-Chloro-phenyl)-thiobutyric Acid S-Methyl Ester (20).
Compound 20 was used to determine enantiomeric excess of tandem
1,4-addition-aldol reactions using thioester 18 as substrate (product 11h).
The compound was prepared using general procedure A and isolated
from the reaction mixture prior to aldehyde addition (aldol coupling).
Title compound 20 was obtained as a clear oil: [R]D +59.3 (c 0.3,
t-Bu): calcd, 449.16066; found, 449.15948. Second diastereomer:
[R]D +10.6 (c 3.9, CHCl3). 1H NMR: δ ppm 7.66 (2H, m), 7.59 (2H,
m), 7.50-7.23 (11H, m), 5.07 (1H, t, J ) 6.6 Hz), 3.70 (1H, dd, J )
4.6, 10.4 Hz), 3.64 (1H, dd, J ) 6.2, 10.4 Hz), 3.36 (1H, t, J ) 6.4
Hz), 3.15 (1H, d, J ) 7.2 Hz), 2.79 (2H, dq, J ) 1.9, 7.4 Hz), 2.04
(1H, dq, J ) 4.8, 6.6 Hz), 1.13 (3H, t, J ) 7.4 Hz), 1.09 (9H, s), 0.94
(3H, d, J ) 7.0 Hz). 13C NMR: δ 203.0, 142.2, 135.9, 135.7, 133.7,
133.6, 129.9, 128.6, 127.9, 126.3, 73.7, 73.7, 66.3, 61.5, 35.8, 27.1,
27.1, 23.7, 19.6, 14.8, 14.7, 14.7. HRMS: C26H29O3SSi (M+ - t-Bu):
calcd, 449.16066; found, 449.15927.
1
CHCl3). H NMR: δ 7.28-7.22 (2H, m), 7.17-7.10 (2H, m), 3.32
(1H, sext, J ) 7.1 Hz), 2.88-2.70 (2H, m), 2.25 (3H, s), 1.27 (3H, d,
J ) 7.0 Hz). 13C NMR: δ 198.1, 143.7, 132.0, 128.5, 128.0, 51.7,
36.3, 21.4, 11.5. HRMS: calcd for C11H13ClOS, 228.03756; found,
228.03834. HPLC analysis indicated an enantiomeric excess of >99%
[Chiralcel OD-H column; flow, 0.5 mL/min; heptane/i-PrOH, 99.5/
0.5; 210 nm; minor enantiomer (-)-20, tR ) 10.9; major enantiomer
(+)-20, tR ) 12.3 min].
(2S,3S,4S)-4-Methyl-5-oxo-2-pentyl-tetrahydro-furan-3-carboxy-
lic Acid [(-)-Phaseolinic Acid (22)]. Succinic acid derivative 24 (75
(17) (a) Leuenberg, H. G. W.; Boguth, W.; Barner, R.; Schmid, M.; Zell, R.
HelV. Chem. Acta 1979, 62, 455-463. (b) Mukayama, T.; Fujimoto, K.;
Hirose, T.; Takeda, T. Chem. Lett. 1980, 635. (c) Mori, K. Tetrahedron
1983, 39, 3107-3109.
(2S,3S,1′R)-3-(4-Chloro-phenyl)-2-(hydroxy-phenyl-methyl)-bu-
tyric Acid Methyl Ester (11h). The compound was obtained using
9
14984 J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006

Tandem 1,4-Addition-Aldol Reactions
A R T I C L E S
mg, 0.21 mmol, 1.00 equiv) was dissolved in aqueous HBr (48%, 15
mL) and heated to reflux with stirring for 3 h. The mixture was cooled
and water (10 mL) was added. The mixture was extracted with EtOAc
(4 × 15 mL), and the combined organic phases were washed (brine)
and dried (MgSO4), and the solvent evaporated to give a pale brown
solid. Crystallization (hexane/EtOAc) gave title compound 22 (38 mg,
91%) as a white solid: mp 142.0-144.0 °C (lit. 138-140 °C,15f 137-
138 °C15b); [R]D -145.4 (c 0.5, CHCl3) [lit. -142 (0.22, CHCl3),15f
mL), and water (15 mL) and stirred at room temperature for 5 min. To
the flask was added NaIO4 (3.90 g, 18.0 mmol, 55.0 equiv) followed
by RuCl3‚xH2O (8 mg, 0.04 mmol, 0.09 equiv). The mixture was stirred
and became brown over ∼5 min, then a white suspension formed over
∼16 h. After this time, water (20 mL) was added, and the mixture was
extracted with EtOAc (3 × 25 mL). The combined organic phases were
washed (brine) and dried (MgSO4), and the solvent evaporated to give
a brown/black oil which was purified by column chromatography (5:1
hexane/EtOAc) directly to give title compound 24 (105 mg, 88%) as
a clear oil. 1H NMR δ ppm 4.02-3.89 (1 H, m), 3.71 (1 H, s), 3.02-
2.89 (2 H, m), 1.72-1.16 (11 H, m), 1.01-0.79 (12 H, m), 0.07 (6 H,
s). 13C NMR: δ ppm 180.9, 171.9, 71.9, 52.5, 51.4, 38.5, 35.0,
31.9, 25.8, 24.2, 22.6, 18.0, 15.5, 14.0, -4.2. HRMS calcd for
C18H36O5SiNa (M + Na+), 383.2224; found, 383.2228.
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-147 (0.37, CHCl3)15b]. H NMR: δ ppm 4.87-4.62 (1 H, m), 3.25
(1 H, t, J ) 8.94 Hz), 3.07 (1 H, qd, J ) 14.24 Hz), 1.71-1.16 (11 H,
m), 0.91 (1 H, t, J ) 6.53 Hz), 13C NMR: δ 177.4, 174.8, 77.3, 51.6,
36.4, 31.3, 31.1, 25.3, 22.4, 14.4, 13.9.
(2S,3S,1′S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-(1-phenyl-ethyl)-
octanoic Acid Methyl Ester (23). Tandem product 11e (170 mg, 0.61
mmol, 1.00 equiv) was dissolved in dry THF (10 mL) and stirred under
N2. To this solution was added 2,6-lutidine (90 µL, 0.70 mmol, 1.20
equiv) and TBDMS-OTf (175 µL, 0.70 mmol, 1.20 equiv). The
mixture was stirred at room temperature for 3 h before addition of
aqueous NH4Cl (saturated) and Et2O (10 mL). The organic phase was
separated and washed with brine, dried (MgSO4), and evaporated to
give a clear oil. Flash column chromatography (25:1 hexane/EtOAc)
Acknowledgment. We thank The Leverhulme Trust for a
European Fellowship to G.P.H., The Natural Science and
Engineering Research Council of Canada for a fellowship to
S.P.F. and The Netherlands Research School on Catalysis
(NRSC-C) for financial support. We also thank Auke Meetsma
for conducting the single crystal X-ray analyses. Generous
support (chiral ligands) from Solvias, Basel, is gratefully
acknowledged.
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gave title compound 23 (225 mg, 94%) as a clear oil. H NMR: δ
ppm 7.38-7.13 (5 H, m), 3.86-3.77 (1 H, m), 3.68 (3 H, s), 3.22 (1
H, qd, J ) 14.01, 6.95 Hz), 2.90 (1 H, dd, J ) 8.95, 5.61 Hz), 1.69-
1.03 (14 H, m), 0.95 (9 H, s), 0.06 (3 H, s), 0.05 (3 H, s). 13C NMR:
δ ppm 173.2, 144.9, 128.4, 127.4, 126.4, 71.7, 56.4, 51.0, 38.9, 35.0,
31.9, 25.8, 23.4, 22.6, 19.4, 18.1, 14.0, -3.9. HRMS: calcd for
C23H41O3Si, 393.2819; found, 393.2828.
(2S,3S,1′S)-2-[1-(tert-Butyl-dimethyl-silanyloxy)-hexyl]-3-methyl-
succinic Acid 1-Methyl Ester (24). Methyl ester 23 (130 mg, 0.33
mmol, 1.00 equiv) was dissolved in MeCN (1.50 mL), EtOAc (1.50
Supporting Information Available: NMR spectra (1H and
13C NMR) and HPLC chromatograms are available for all novel
compounds along with crystallographic data for structures 11a
and 12b. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA0651862
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J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14985