Direct carbon-carbon bond formation via reductive soft enolization: A kinetically controlled syn-aldol addition of α-halo thioesters and enolizable aldehydes

Article abstract of DOI:10.1021/ja1057407

The direct addition of enolizable aldehydes and α-halo thioesters to produce β-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-se

Full text of DOI:10.1021/ja1057407

Published on Web 09/17/2010
Direct Carbon-Carbon Bond Formation via Reductive Soft Enolization: A
Kinetically Controlled syn-Aldol Addition of r-Halo Thioesters and Enolizable
Aldehydes
Scott J. Sauer, Michelle R. Garnsey, and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
Received July 10, 2010; E-mail: don.coltart@duke.edu
Scheme 1. Select Approaches to the Aldol Addition of Carboxylate
Derivatives and Enolizable Aldehydes
Abstract: The direct addition of enolizable aldehydes and R-halo
thioesters to produce ꢀ-hydroxy thioesters enabled by reductive
soft enolization is reported. The transformation is operationally
simple and efficient and has the unusual feature of giving high
syn-selectivity, which is the opposite of that produced for
(thio)esters under conventional conditions. Moreover, excellent
diastereoselectivity results when a chiral nonracemic R-hydroxy
aldehyde derivative is used.
The development of a generally applicable direct aldol addition1
in which a carboxylate derivative and enolizable aldehyde are
combined in the presence of a base (etc.) has been a long-standing
yet unrealized goal in the field of organic synthesis. Unfortunately,
side reactions between, for example, the base and electrophile
complicate this transformation. Introduced in 1951,2 prior enolate
formation3 (cf. Scheme 1a) provides a way of circumventing these
issues and has led to some of the most important reactions known.
While effective, the stepwise procedures used to generate the
enolates are time-consuming, particularly if trapping is involved,
and require that all manipulations be conducted under anhydrous
conditions and, when strong bases are used, at low temperature.
Given these factors along with the importance of the aldol reaction,4
a general, direct transformation applicable to enolizable aldehydes
remains highly desirable. In what follows, we describe the first
direct addition of enolizable aldehydes and R-halo thioesters to
produce simple ꢀ-hydroxy thioesters. Reductive soft enolization
provides access to the nucleophile in situ, thus obviating the need
for prior enolate formation. Moreover, this transformation has the
unusual feature of producing syn-selectivity, which is the opposite
of that produced for (thio)esters under conventional conditions. The
yield and diastereoselectivity are as good or better than these
traditional methods. In addition, the reactions proceed at room
temperature, open to the air in untreated solvents. The products of
these reactions are valuable and versatile intermediates that provide
access to a rich variety of carbonyl derivatives.
stereoselective direct aldol addition. To achieve this, readily
accessible and easily managed R-halo thioesters8 would be used in
combination with Ph3P and a Mg2+ salt to facilitate reductiVe soft
enolization.9 By analogy to our base mediated reactions,6 Mg2+
coordination (5 f 6) would polarize the thioester carbonyl, thus
allowing Ph3P to abstract X+ and generate the magnesium enolate
(6 f 7).10 Since a base would not be present, enolization of the
aldehyde should not compete, providing the required chemoselec-
tivity. Our expectation of kinetic control in the addition step (7 +
3 f 8) was based on the anticipated stability of magnesium aldolate
8 under the reaction conditions. In analogous amine mediated
reactions, retro-aldol addition (cf. 8 f 7 + 3) occurs,1i likely due
11
to participation of the amine through lone pair donation to Mg2+
.
In the proposed reductive aldol reaction, the related interaction with
Ph3P would be unlikely given its soft nature.12 Thus, the retro-
aldol reaction would not occur, resulting in a kinetic addition step.
When viewed in this way, R-halo thioesters represent a convenient
shelf-stable latent enolate,13 able to be liberated and utilized under
mild conditions.
We began our studies by testing the Ph3P-mediated reductive
aldol addition using different R-halo thioesters and magnesium salts.
Gratifyingly, the reaction proceeded under a range of conditions.8
However, our best results were obtained using a combination of
MgI2 and R-iodo thioester 10 (Scheme 2), so these conditions were
employed for the remainder of our studies.14
The main factor that must be controlled in a direct reaction
between an enolizable aldehyde and a carboxylate derivative to form
the corresponding ꢀ-hydroxy carboxylate system is the chemose-
lectivity of enolization. Since aldehydes are more susceptible to
deprotonation than simple carboxylate derivatives, a nonbasic means
of enolization is desirable. The second key factor is the stereose-
lectivity of the addition, which is most easily managed when the
reaction is kinetically controlled.
We have been studying the base mediated soft enolization5 of
Mg2+-activated thioesters in the development of direct versions of
certain fundamental carbon-carbon bond-forming reactions.6,7 It
occurred to us that a simple modification of this strategy could
provide both the chemoselectivity and kinetic control needed for a
With suitable conditions available, we examined the diastereo-
selectivity of the transformation with R-iodo propionoate thioester
13 (Table 1). Interestingly, the major product was the syn isomer,
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C O M M U N I C A T I O N S
Scheme 2. Aldol Addition via Reductive Soft Enolization
The transformation also proceeds in a highly diastereoselective
manner with aldehydes having an R-stereogenic center. As an initial
indication of this, when aldehyde 38 was subjected to the aldol
reaction with 16, only compound 39 was formed (Scheme 3).16
Scheme 3. Diastereoselective Aldol Addition to Aldehyde 38
which is the opposite of that normally obtained for the aldol addition
of (thio)esters under typical hard enolization conditions.3 However,
only a 3:1 ratio of diastereomers was produced. In pioneering work
on the development of an anti-selective aldol addition, Heathcock
and Pirrung showed that increasing the steric bulk of the ester
component led to an increase in diastereoselectivity.15 Thus, various
thioesters derived from more sterically demanding thiols were
examined. As with the previous study, an increase in steric bulk
did correlate to an increase in diastereoselectivity. However, in
contrast to that work, the syn-, not the anti-diastereomer, was
preferentially formed. In the case of 16 the selectivity was >20:1
in favor of the syn-product,8 so this thioester was used for the
remainder of our work.
To confirm our expectation of kinetic control in the addition step,
the reaction between 9 and 10 was carried out. However, after 18 h
rather than quenching the reaction with acid, p-tolualdehyde (41)
was added. The mixture was stirred for an additional 18 h and then
quenched. The sole product was 11 (Scheme 4). The lack of
incorporation of p-tolualdehyde confirms the predicted stability of
the aldolate intermediate (cf. 40) and supports the notion of a
kinetically controlled addition.
Table 1. Effect of Thioester on Diastereoselectivitya
Scheme 4. Kinetic Reactivity Studies
entry
thioester
aldol product
syn:anti
yield (%)
1
2
3
4
13 R ) Ph
17
18
19
20
3:1
3.7:1
15.3:1
>20:1
83
85
78
89
14 R ) t-Bu
15 R ) 2,6-(Me)2C6H3
16 R ) 2,4,6-(i-Pr)3C6H2
a 1.2 molar equiv of R-iodo thioester, 1.0 molar equiv of
benzaldehyde, 1.2 molar equiv of MgI2, 1.2 molar equiv of PPh3 in
CH2Cl2 (concn 0.2 M).
A model accounting for the observed stereoselectivity based on
a kinetically controlled addition step is shown in Scheme 5.
Enolization presumably occurs through an open transition state in
a manner analogous to LDA-mediated enolization in the presence
of chelating ligands.17 Alternatively, it is reversible and favors the
thermodynamically more stable Z-(O)-enolate (46). In either case,
a greater proportion of 46 forms as the steric bulk of the thioester
increases, which is consistent with the trend observed in Table 2.
Irreversible, kinetic addition of 4618 to the aldehyde through the
lower energy Zimmerman-Traxler transition state (47) then gives
the syn-aldol product via aldolate 48.
We next investigated the scope of the transformation using a
variety of aldehydes (Table 2). We were pleased to find that the
diastereoselectivity was excellent in all cases. As expected, the
transformation worked equally well with enolizable aldehydes
(entries 3-7). A particularly impressive example is seen in entry
7, where the aldol addition proceeded in high yield and selectivity
despite the presence of the strongly acidic R-protons of aldehyde
25. Aldehydes having other base-sensitive functionality were also
tested (entries 8-10) and underwent the reaction smoothly.
Table 2. Scope of the Reductive Soft Enolization Aldol Additiona
Scheme 5. Stereochemical Model
In summary, we have developed the first Mg2+ promoted direct
addition of R-halo thioesters and enolizable aldehydes to produce
ꢀ-hydroxy thioesters via reductive soft enolization. The syn-selective
nature of this reaction is the opposite of that obtained for simple
(thio)esters using amide bases (LDA, etc.) and so provides a
convenient complementary approach to this key transformation.
Moreover, the kinetic control exhibited in the addition step makes
a 1.2 molar equiv of 16, 1.0 molar equiv of aldehyde, 1.2 molar equiv
of MgI2, 1.2 molar equiv of PPh3 in CH2Cl2 (conc 0.2 M).
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C O M M U N I C A T I O N S
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: 1991; Vol. 2, pp 133-179. (d) Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press, 1991; Vol. 2, pp 181-238. (e) Kim, B. M.; Williams,
S. F.; Masamune, S. In ComprehensiVe Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: 1991; Vol. 2, pp 239-275.
(5) For pioneering examples of soft enolization, see: (a) Rathke, M. W.; Cowan,
P. J. J. Org. Chem. 1985, 50, 2622–2624. (b) Rathke, M. W.; Nowak, M.
J. Org. Chem. 1985, 50, 2624–2626. (c) Tirpak, R. E.; Olsen, R. S.; Rathke,
M. W. J. Org. Chem. 1985, 50, 4877–4879.
it ideal for the development of direct, stereocontrolled aldol
additions, as demonstrated by the preparation of 39. Further studies
of this reaction will focus on elucidating its mechanism and
extending the scope of the asymmetric process in a catalytic fashion.
Acknowledgment. S.J.S. and M.R.G. are grateful for support
from the Pharmacological Sciences Training Program (Duke
University). This work was supported by Duke University and
NCBC (2008-IDG-1010).
(6) For example, see: Zhou, G.; Lim, D.; Coltart, D. M. Org. Lett. 2008, 10,
3809–3812.
(7) For examples of thioesters in organocatalysis, see: (a) Alonso, D. A.;
Kitagaki, S.; Utsumi, N.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2008,
47, 4588–4591. (b) Utsumi, N.; Kitagaki, S.; Barbas, C. F., III. Org. Lett.
2008, 10, 3405–3408. For Malonic acid half-thioesters, see: (c) Lubkoll,
J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841–6844. (d) Ricci,
A.; Petterson, D.; Bernardi, L.; Fini, F.; Fochi, M.; Herrera, R. P.; Sgarzani,
V. AdV. Synth. Catal. 2007, 349, 1037–1040. (e) Kohler, M. C.; Yost, J. M.;
Garnsey, M. R.; Coltart, D. M. Org. Lett. 2010, 12, 3376–3379.
(8) See the Supporting Information for details.
Supporting Information Available: Experimental procedures and
analytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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