Direct and highly regioselective and enantioselective allylation of β-diketones

Article abstract of DOI:10.1038/nature11189

The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Bronsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones.

Full text of DOI:10.1038/nature11189

LETTER
doi:10.1038/nature11189
Direct and highly regioselective and enantioselective
allylation of b-diketones
Wesley A. Chalifoux1, Samuel K. Reznik1 & James L. Leighton1
The enantioselective allylation of ketones is a problem of fun- acetylacetone seemed a worthy enough aim, but the ultimate goal of
damental importance in asymmetric reaction design, especially this study became the generalization of such a method to a broad range
given that only a very small number of methods can generate
tertiary carbinols. Despite the vast amount of attention that syn-
thetic chemists have given to this problem1–8, success has generally
been limited to just a few simple ketone types. A method for the
selective allylation of functionally complex ketones would greatly
increase the utility of ketone allylation methods in the chemical
synthesis of important targets. Here we describe the operationally
simple, direct, regioselective and enantioselective allylation of
b-diketones. The strong tendency of b-diketones to act as nucleo-
philic species was overcome by using their enol form to provide the
necessary Brønsted-acid activation. This reaction significantly
expands the pool of enantiomerically enriched and functionally
complex tertiary carbinols that may be easily accessed. It also
overturns more than a century of received wisdom regarding the
reactivity of b-diketones.
Chiral non-racemic tertiary carbinols are common in important
natural products and in medicinal-chemistry research programmes.
Asymmetric ketone allylation is one of the few methods available for
their direct synthesis, and over the past 15 years there have been several
seminal reports that describe important and significant progress
towards the development of efficient, practical and highly enantioselec-
tive techniques1–8. With only a few exceptions, however, these methods
are limited in scope to aryl methyl ketones and aryl linear alkyl ketones
(that is, ArCOCH2R, where Ar is an aryl group and R is hydrogen, an
alkyl group or an aryl group). Thus, although efficiency and practicality
rightly constitute one major focus in asymmetric reaction design, scope,
generality, reliability and applicability in complex settings are equally
vital totherealizationofmethods with trulybroad utilityand thatwillbe
widely adopted9.
of b-diketones, including unsymmetrical b-diketones. Far from repre-
senting a straightforward extension of the proposed method, however,
the allylation of unsymmetrical b-diketones poses a further distinct
and formidable challenge: the control of regioselectivity (Fig. 1c).
Intrigued by these challenges and by the almost total dearth of useful
precedent, we have pursued a general, practical and highly regioselec-
tive and enantioselective allylation of b-diketones. We report its suc-
cessful development and mechanistic elucidation.
Rather than attempting to mask the enol tautomer of the b-diketone
in situ, preclude its formation or otherwise render it innocuous, our
approach centred on the idea that we might instead react it with an
allylchlorosilane to generate b-silyloxyenone 2, which would sub-
sequently undergo intramolecular allylation (Fig. 2a). However,
this otherwise beneficial tethering strategy would in this case also lead
to deactivation of the ketone electrophile by converting it into a
vinylogous silyl ester, raising concerns about whether the desired
reaction might be impractically slow and allow competing side
reactions (for example, Knoevenagel condensation between 2 and
unreacted diketone, or intermolecular diketone allylation by the
allylsilane or by 2). Ideally, then, to favour the desired pathway, the
complexation should be very fast, so that no unreacted diketone is
available for such side reactions, and the allylsilane should become
strongly activated upon complexation. Allylsilane 3 and other related
aminosilanes are strongly activated by protonation with Brønsted
acids17,18. Given that the proposed enol silylation reaction would
produce an equivalent of hydrochloric acid, it seemed possible that
a
Me OH
O
Me OH
AcO
These thoughts were triggered by our retrosynthesis of the AB
spiroketal portion of the potent and precious anti-mitotic marine
macrolide spongistatin 110–12—which bears a tertiary carbinol —to
b-hydroxyketone 1 (Fig. 1a). It seemed that the ideal13 synthesis of 1
should involve a direct asymmetric allylation of acetylacetone (Fig. 1b).
However, although a few sporadic examples of the non-asymmetric
allylation of acetylactone have been reported14–16, there are no
known examples of an enantioselective addition of a nucleophile to a
b-diketone. In fact, there are simply no general methods that use
b-diketones as electrophiles in reactions to form carbon–carbon bonds.
This is unsurprising given that b-diketones are not simply compounds
with two ketones, but rather are distinct chemical entities that exist
primarily in their enol tautomer form. They are rarely used
in organic chemical synthesis, and when they are, it is typically as
nucleophiles in reactions such as simple alkylations or Knoevenagel
condensations. As a result, the synthesis of 1 by means of an asymmetric-
allylationapproachusingknown methodswouldrequire protectionor
masking of one of the ketones, thus turning what is in principle an
ideal synthesis into a multi-step process that would in practice involve
protecting-group manipulations and/or oxidation-state adjustments.
R2
Me
O
1
O
H
H
The AB spiroketal
of spongistatin 1
R1O2C
O
b
c
O
OH
O
O
Me OH
?
Me
Me
Me
Me
Me
1
Direct asymmetric allylation of acetylacetone?
O
OH
R2
OH
O
O
O
HO
OH
?
or
R1
R1
R2
R1
R2
R1
R2
Regioselective direct asymmetric allylation of β-diketones?
Figure 1
|
Origin and evolution of a proposal for a direct, enantioselective
and regioselective allylation of b-diketones. a, Retrosynthesis of the AB
spiroketal of spongistatin 1 to b-hydroxyketone 1. Me, methyl group; Ac, acetyl
group; R, unspecified group. b, A direct asymmetric allylation of acetylacetone
would have to contend with the enol form of the diketone. c, The generalization
The development of a method for the direct asymmetric allylation of of a direct method would require control of regioselectivity.
1Department of Chemistry, Columbia University, New York, New York 10027, USA.
8 6
| N A T U R E | V O L 4 8 7 | 5 J U L Y 2 0 1 2
Macmillan Publishers Limited. All rights reserved
©2012

LETTER RESEARCH
a
a
Regio- and enantioselective allylation of β-diketones
p-BrC6H4
O
O
O
R
R
R
R
R
R
N
N
O
O
O
Si
HO
Si
Me
Me
Me
CHCl3
Si
Si
O
O
O
O
slow?
Me
+
Cl
R1
R2
R1
R2
Me
Cl
23 °C, 13–27 h
(S,S)-3
(1.2 equiv.)
(–HCl)
Me
Me
2
p-BrC6H4
HO
deactivated
fast?
Me
b
Symmetric dialkyl and diaryl β-diketones
‡
O
HO
O
O
HO
HO
p-BrC6H4
Ar
9
N
–
Cl
N
t-Bu
83%, 87% e.e.
t-Bu
Ph
Ph
8
7
+
N
N
H
+
Ar
–
Cl
N
80%, 96% e.e.
Br
68%, 95% e.e.
Br
Si
H N
Si
Si
Cl
O
O
O
O
Ar
Me
c
Unsymmetrical aryl,alkyl β-diketones
(S,S)-3
4
Ar
p-BrC6H4
activated Me
Me
Me
unactivated
O
HO
11
O
HO
O
Me
Ph
Me
b
10
No allylation observed with:
68%, >20:1 r.r., 95% e.e.
O
O
O
81%, 19:1 r.r., 97% e.e.
Me OH
O
O
O
O
(S,S)-3
O
O
CHCl3
23 °C, 1 h
HO
12
HO
Me
6
Me Me
Me
Me
Me
Me
1
5
72%, 89% e.e.
Ph
Me
Ph
t-Bu
13
79%, 16:1 r.r., 98% e.e.
Figure 2
|
Reaction design and proof of concept. a, The reaction design
75%, >20:1 r.r., 97% e.e.
entails tethering theallylsilane to theenol form of thediketone and activation of
the silane by the liberated hydrochloric acid (HCl). Ar, aryl group. b, First
demonstration of the asymmetric allylation of acetylacetone.
d
Unsymmetrical diaryl β-diketones
Br
O
Br
Br
O
O
HO
HO
80%,
77%,
3, which is wholly incapable of allylating ketones, might be perfectly
configured to react with b-diketones by way of activated silane com-
plex 4 (Fig. 2a). Indeed, it transpired that allylsilane 3 smoothly
allylated acetylacetone, and, on optimization of the reaction conditions
(CHCl3, 23 uC, 1 h), produced 1 in 72% yield and 89% enantiomeric
excess (e.e.) (Fig. 2b). This operationally simple reaction provides
direct and scalable access to 1 from two commercially available com-
pounds, and neither 5 nor 6 was allylated by 3 (Supplementary Fig. 1
and 2), which strongly implies that the underlying mechanistic pro-
posal is sound. The enol form of the diketone, which usually represents
a serious functional-group incompatibility, has thus been co-opted as
the very functionality responsible for the success of the reaction.
With this proof of concept in hand, we examined the scope of
the reaction (Fig. 3a). We began with three further symmetrical
b-diketones; as shown (Fig. 3b), products 7, 8 and 9 were all obtained
in good yields and with good to excellent enantioselectivity, establish-
ing that both t-butyl and aryl ketones are well tolerated. We next
examined a series of unsymmetrical b-diketones, in an effort to estab-
lish whether and under what circumstances useful levels of regioselec-
tivity could be realized. Whereas substrates that pitted two alkyl
ketones against each other led to little or no regioselectivity, we quickly
discovered that substrates that pitted a conjugated ketone against an
alkyl ketone consistently reacted such that the allyl group was added to
the alkyl ketone with excellent regio- and enantioselectivity (Fig. 3c).
This preference not only led to the efficient and selective production of
10–12, but also operated even when the alkyl group is a t-butyl group
(as in 13). Next, we examined 1,3-diphenylpropane-1,3-diones with
varying substitutions. We were disappointed at first to find that the
para-bromo, para-methoxy derivative was completely non-selective.
When we interrogated the impact of ortho substitution, however,
subtle effects were revealed (Fig. 3d). Thus, whereas an ortho-bromo
group regioselectively directs theallylation to the distalketone (asin 14
and 15), an ortho-methoxy group has the opposite effect (as in 16)
albeit with only moderate (4:1) regioselectivity. These effects are
mutually reinforcing, as demonstrated by the reaction of the ortho-
bromo, ortho-methoxy analogue to give 17 as a single regioisomer in
89% yield and 95% e.e., a result that is particularly striking in light of
the complete lack of regioselectivity in the reaction of the para, para
18:1 r.r.,
94% e.e.
>20:1 r.r.,
92% e.e.
14
15
OMe
Br
O
O
OMe
OMe
HO
HO
63%,
89%,
>20:1 r.r.,
95% e.e.
4:1 r.r.,
95% e.e.
16
17
Br
Me
O
HO
HO
94%,
>20:1 r.r.,
83% e.e.
62%,
5:1 r.r.,
84% e.e.
18
19
Me
Me
N
Cl
Figure 3
|
Scope of the regio- and enantioselective allylation of b-diketones.
a, The b-diketone was treated with 1.2 equiv. of (S,S)-3 in chloroform (CHCl3)
and the resultant mixture was stirred at ambient temperature for 13–27 h. In all
cases, the reported yield refers to the yield of isolated (greater than or equal to
20:1 regioisomericpurity) major product after workup and purification by flash
chromatography, and the enantiomeric excess (e.e.) was determined by chiral
high-performance liquid chromatography. d.r., diastereomer ratio.
b, Enantioselective allylation of symmetrical b-diketones. Ph, phenyl group.
c, Regio- and enantioselective allylation of unsymmetrical aryl, alkyl
b-diketones (r.r., regioisomer ratio). d, Regio- and enantioselective allylation of
unsymmetrical diaryl b-diketones.
In principle, the extension of this reaction methodology to crotyla-
tion reactions would allow the establishment of a second stereocentre
intheallylic positionof the homoallylic alcoholproducts, butexamples
of highly diastereo- and enantioselective ketone crotylation reactions
are rare5,7,8,19. We therefore decided to interrogate the ability of
crotylsilanes 20 and 21 (ref. 20) to crotylate b-diketones, and found
that treatment of acetylacetone and benzoylacetone with trans-
crotylsilane 20 led to the isolation of 22 (69%, 89% e.e.) and
23 (75%, 97% e.e.) respectively (Fig. 4a). However, treatment of
benzoylacetone with cis-crotylsilane 21 resulted in a much slower
reaction that provided the desired product in very low yield (less than
15%), along with significant amounts of a by-product that we have
tentatively identified as 24. The formation of 24 is readily rationalized
as the result of a Knoevenagel condensation cascade that presumably
isomer. Two final examples (18 and 19) show that this ortho-effect begins with attack of the silyl enol ether complex on unreacted
extends to groups other than bromide, and establish that the methoxy b-diketone. This hypothesis implied that the complexation event is
group is the outlier (as in 16).
slow in these reactions in general, and that the desired carbon–carbon
5
J U L Y 2 0 1 2 | V O L 4 8 7 | N A T U R E | 8 7
Macmillan Publishers Limited. All rights reserved
©2012

RESEARCH LETTER
a
b-silyloxyenones (31E, 31Z, 32E and 32Z), which may be considered
as two regioisomeric pairs of E and Z isomers. Once it has been estab-
lished that the E and Z isomers in each pair interconvert quickly
(Supplementary Fig. 3), there are two readily apparent possibilities.
Thefirst is that there is no (fast)interconversionbetween 31Z and 32Z,
and the regioselectivity is determined by the relative rates of formation
of 31 and 32. The second is that interconversion of 31Z and 32Z,
presumably by way of 33, is fast and the regioselectivity is determined
by the relative energies of transition states 34 and 35. To distinguish
between these possibilities, we repeated the reaction of 27 with 21
p-BrC6H4
p-BrC6H4
Me
O
OH
Me
N
N
N
N
Si
Si
Ph
24
Cl
Cl
Me
Ph
(S,S)-20
p-BrC6H4
(S,S)-21
p-BrC6H4
O
O
O
O
Me OH
22 R = Me:
69%, 89% e.e.
1.3 equiv. (S,S)-20
R
Me CHCl3, 23 °C, 40 h
R
R
23 R = Ph:
75%, >20:1 r.r., 97% e.e.
Me
O
Me OH
(All reactions: >20:1 d.r.)
1.3 equiv. (S,S)-21
1.3 equiv AgOTf
O
1
25 R = Me:
91%, 91% e.e.
(Fig. 4b) in deuterated chloroform, and monitored it by H NMR
spectroscopy (Supplementary Fig. 4). After one hour, the singlet for
the methyl group in 27 disappeared and three new singlets appeared at
2.53, 2.11 and 1.97 p.p.m. in a roughly 2:3.4:1 ratio. We have assigned
these peaks to the three possible silyl enol ether complexes. Given that
the peaks all disappear at the same rate and that this reaction is com-
pletely regioselective despite only one of these silyl enol ethers being
R
Me CHCl3, 23 °C, 64 h
26 R = Ph:
71%, 7:1 r.r., 96% e.e.
Me
b
O
O
O
Me OH
i. 1.3 equiv. (S,S)-20
CHCl3, 23 °C, 43 h
69%,
>20:1 r.r.,
94:6 d.r.,
98% e.e.
Me
ii. n-Bu4NF, –40 °C
27
29 Me
a
O
O
Si
28
+
R2
(S,S)-3
Si
Si
O
O
i
i
ii
ii
O
R1
O
Me
Me
R2
R1
32E
31E
R2
O
O
R1
i. 1.3 equiv. (S,S)-21
1.3 equiv. AgOTf
CHCl3, 23 °C, 48 h
O
O
O
Me OH
Si
59%,
O
O
Si
Si
>20:1 r.r.,
88:12 d.r.,
96% e.e.
33
Me
O
O
O
O
27
ii. n-Bu4NF, –40 °C
R1
R2
30
Me
R1
R2
R1
R2
31Z
Figure 4
|
Regio-, diastereo- andenantioselective crotylation of b-diketones.
Fast
32Z
a, The crotylation of b-diketones allows the establishment of a second
stereocentre in the homoallylic alcohol products. OTf, triflate. b, a-Substitution
on the b-diketone substrate may be parlayed into reactions that establish three
stereocentres from simple starting materials.
‡
‡
R2
R1
R2 OH
O
O
O
–
–
R1
Cl
Cl
R1
R2
O
Si
O
Si
Ar
Ar
H
H
bond-forming step is especially slow in this particular reaction. In this
way, the silyl enol ether complex and the starting diketone would both
be present in significant concentrations for long periods of time. One
way to avoid this could be to accelerate the complexation so that no
unreacted diketone would be available to the silyl enol ether complex,
and it seemed plausible that replacement of the chloride on the silane
with a triflate (2OSO2CF3) might accomplish this. Indeed, pre-
treatment of 21 with AgOSO2CF3 before the addition of acetylacetone
and benzoylacetone led to vastly improved results, giving 25 and 26
respectively, in excellent yields and enantioselectivities.
Havingworked outeffectiveconditionsfor thecrotylationreactions,
we next examined 2-acetyltetralone 27 to probe the effect of substi-
tution on the a-carbon (Fig. 4b). It will be noted that the initial pro-
ducts in these reactions are silyl enol ethers (such as 28), which are
converted to enols that tautomerize to ketones on quench and workup.
When the a-carbon is substituted, as in 28, the tautomerization has
stereochemical consequences, and we have demonstrated in similar
systems that good to excellent diastereocontrol may be realized with
proper choice of quench/workup conditions21. The standard quench
for the present method entails cooling the reaction mixtures to 240 uC
and adding n-Bu4NF (where Bu is a butyl group), followed by an
aqueous workup. When we quenched and worked up the crotylation
reactions of 27 with 20 and 21 using these conditions, good to excellent
diastereoselectivity was realized, resulting in the isolation of 29 and
30 in 69% and 59% yield, respectively, with excellent regio- and
enantioselectivity. The result is an operationally simple single-step
and protecting-group-free synthesis of complex polyketide-like arrays
of three stereocentres (including a tertiary carbinol) from simple and
readily available starting materials with exceedingly high levels of
enantioselectivity.
N
N
+
+
O
H
H
N
H
HO R1
N
H
Ar
Ar
R2
34
35
b
Case 1: R1 = conjugating group, R2= alkyl group
‡
‡
Ralk
Rconj
O
O
–
–
Cl
Cl
Rconj
Ralk
O
Si
O
Si
Ar
Ar
H
N
<
H
N
+
+
H
H
N
H
N
Ar
34a
Ar
35a
H
Conjugation maintained
in transition state 34a
Cross conjugation lost
in transition state 35a
Case 2: R1 = o-Br-C6H4, R2 = o-MeO-C6H4
‡
‡
Steric
clash
MeO
Br
H
OMe
O
Si
O
<
–
–
H
Cl
Cl
O
O
Si
Ar
Ar
H
N
H
N
Br
+
+
H
H
N
H
N
H
Ar
Ar
34b
35b
Figure 5
|
General mechanism and origin of regioselectivity. a, A general
mechanistic scheme for the allylation of b-diketones wherein the product
distribution is determined by Curtin–Hammett kinetics. b, Models for the
We next tried to elucidate the mechanistic basis for the remarkable
regioselectivity of the reaction. The reaction of an unsymmetrical
b-diketone with (S,S)-3 (Fig. 5a) may produce four different observed regioselectivity.
8 8
| N A T U R E | V O L 4 8 7 | 5 J U L Y 2 0 1 2
Macmillan Publishers Limited. All rights reserved
©2012

LETTER RESEARCH
7. Barnett, D. S., Moquist, P. N. & Schaus, S. E. The mechanism and an improved
asymmetric allylboration of ketones catalyzed by chiral biphenols. Angew. Chem.
Int. Edn 48, 8679–8682 (2009).
8. Shi, S.-L., Xu, L.-W., Oisaki, K., Kanai, M. & Shibasaki, M. Identification of modular
chiral bisphosphines effective for Cu(I)-catalyzed asymmetric allylation and
propargylation of ketones. J. Am. Chem. Soc. 132, 6638–6639 (2010).
9. Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-
butanesulfinimide. Chem. Rev. 110, 3600–3740 (2010).
able to react directly to give the product, we conclude that in these
reactions, the interconversion between 31Z and 32Z is fast22–25 and the
regioselectivity is determined by the relative energies of transition
states 34 and 35: that is, the reaction is governed by Curtin–
Hammett kinetics26.
The regioselectivity observed with substrates wherein R1 5 aryl/
alkenyl and R2 5 alkyl (as in Fig. 3c) is difficult to attribute to a simple
steric effect, given the regioselective production of 13. Rather, we pro-
pose that the energy of transition state 34a is lower than that for 35a
because conjugation is maintained in the former pathway but lost
completely in the latter (Fig. 5b, case 1). Conversely, we propose that
the regioselectivity observed with substrates wherein both R1 and R2
are aryl groups and at least one bears ortho-substitution (as in Fig. 3d)
is the result of steric effects (Fig. 5b, case 2). We expect 2-bromophenyl,
mesityland2-chloro-3-pyridylgroupstoberotatedsubstantiallyoutof
conjugation with the ketones to which they are attached27–29, rendering
them highly sterically hindered towards nucleophilic attack, as shown
in transition state 35b. By contrast, 2-methoxybenzoyl and ortho-
unsubstituted phenyl groups are conjugated30, allowing an unhindered
approach of the allyl group as in transition state 34b. Thus, in this
context, an ortho-bromophenyl group is effectively large and an ortho-
methoxyphenyl group is effectively small. We believe that this steric
effect is large enough to overwhelm the complete loss of conjugation in
transition state 34b. The moderate regioselectivity for product 16 is
more difficult to rationalize, but it may be that the activation energies
for the competing carbon–carbon bond-forming steps are nearly equi-
valent and the selectivity derives from a modest shifting of the equi-
librium constant K towards 31Z owing to the silane’s preference for
residing away from the larger ortho-methoxyphenyl group.
10. Pettit, G. R. et al. Isolation and structure of spongistatin 1. J. Org. Chem. 58,
1302–1304 (1993).
11. Fusetani, N., Shinoda, K. & Matsunaga, S. Cinachyrolide A: a potent cytotoxic
macrolide possessing two spiro ketals from marine sponge Cinachyra sp.
J. Am. Chem. Soc. 115, 3977–3981 (1993).
12. Kobayashi, M. et al. Altohyrtin A, a potent anti-tumor macrolide from the Okinawan
marine sponge Hyrtios altum. Tetrahedr. Lett. 34, 2795–2798 (1993).
13. Gaich, T. & Baran, P. S. Aiming for the ideal synthesis. J. Org. Chem. 75, 4657–4673
(2010).
14. Deng, D.-L. & Lu, Z.-H. Monoallylation of symmetric diketones in the presence of
water by allylic bromide and metallic zinc. Chin. Chem. Lett. 5, 173–176 (1994).
15. Kira, M., Sato, K., Sekimoto, K., Gewald, R. & Sakurai, H. Stereoselective allylation of
b-hydroxy- and b-amino-a,b-enones with allyltrifluorosilane/triethylamine
systems. Chem. Lett. 1995, 281–282 (1995).
16. Marton, D., Stivanello, D. & Tagliavini, G. Allylstannation of a-, b- and c-diketones
mediated by allylbutyltin halides: Bu2(CH25CHCH2)SnCl and
Bu(CH25CHCH2)SnCl2. J. Organomet. Chem. 540, 77–81 (1997).
17. Leighton, J. L. Powerful and versatile silicon Lewis acids for asymmetric chemical
synthesis. Aldrichim. Acta 43, 3–12 (2010).
18. Kim, H., Ho, S. & Leighton, J. L. A more comprehensive and highly practical solution
toenantioselectivealdehydecrotylation.J.Am. Chem. Soc.133, 6517–6520 (2011).
19. Burns, N. Z., Hackman, B. M., Ng, P. Y., Powelson, I. A. & Leighton, J. L. The
enantioselective allylationand crotylationofstericallyhinderedandfunctionalized
aryl ketones: convenient access to unusual tertiary carbinol structures. Angew.
Chem. Int. Edn 45, 3811–3813 (2006).
20. Hackman, B. M., Lombardi, P. J. & Leighton, J. L. Highly diastereo- and
enantioselective reagents for aldehyde crotylation. Org. Lett. 6, 4375–4377 (2004).
21. Spletstoser, J. T., Zacuto, M. J. & Leighton, J. L. Tandem silylformylation–
crotylsilylation/Tamao oxidation of internal alkynes: a remarkable example of
generating complexity from simplicity. Org. Lett. 10, 5593–5596 (2008).
22. Pinnavaia, T. J., Collins, W. T. & Howe, J. J. Triorganosilicon acetylacetonates. Enol
ether isomerism and stereochemical lability. J. Am. Chem. Soc. 92, 4544–4550
(1970).
23. Reich, H. J. & Murcia, D. A. Stereochemical studies of degenerate silyl
rearrangements. Stereospecificity of the tropolone and acetylacetone trialkylsilyl
ether rearrangements. J. Am. Chem. Soc. 95, 3418–3420 (1973).
24. Pinnavaia, T. J. & McClarin, J. A. Rearrangements of1-acetylacetonato-1-methyl-1-
silacyclobutane via internal nucleophilic displacement. J. Am. Chem. Soc. 96,
3012–3013 (1974).
We have demonstrated that it is possible to achieve not only the
highly enantioselective allylation and crotylation of b-diketones, but
also the highly regioselective allylation and crotylation of unsymmet-
rical b-diketones. The method allows the protecting-group-free, sin-
gle-step (that is, ideal) synthesis of functionally and stereochemically
complex products from readily available—and undifferentiated—
b-diketone starting materials. We have elucidated important aspects
of the mechanism and found that the regioselectivity is governed by
Curtin–Hammett kinetics. This may have important implications for
the extension of this methodology to other dicarbonyl substrate types;
experiments along these lines are in progress.
25. McClarin, J. A., Schwartz, A. & Pinnavaia, T. J. 1,5-Migrations of silicon between
oxygen centers in silyl b-diketones. J. Organomet. Chem. 188, 129–139 (1980).
26. Seeman, J. I. Effect of conformational change on reactivity in organic chemistry.
Evaluations, applications, and extensions of Curtin–Hammett Winstein–Holness
kinetics. Chem. Rev. 83, 83–134 (1983).
27. Mirarchi, D. & Ritchie, G. L. D. Solution-state conformations of 2-fluoro-, 2-chloro-
and 2-bromo-acetophenone: a diploe moment and Kerr effect study. J. Mol. Struct.
118, 303–310 (1984).
METHODS SUMMARY
The general procedure for the allylation reactions described in Fig. 3 is as follows.
To a 0.10 M solution of b-diketone(1.0 equiv.) in anhydrous CHCl3 is added (S,S)-
3 (1.2 equiv.). The resulting mixture is stirred at ambient temperature (roughly
23 uC) for between 12 and 27 h. The mixture is cooled to 240 uC, n-Bu4NF
(4.0 equiv., 1 M in tetrahydrofuran) is added, and the resulting mixture is main-
tained at 240 uC for 1 h. Saturated aqueous NH4Cl is added and the mixture is
allowed to warm to ambient temperature. The mixture is extracted three times
with CH2Cl2. The combined organic layers are washed with water and brine, dried
over MgSO4, filtered and concentrated. The residue is purified by flash chromato-
graphy on silica gel. For complete experimental details and compound character-
ization, see Supplementary Information.
´
¨
´
28. Kulhanek, J., Bohm, S., Palat, K. Jr & Exner, O. Steric inhibition of resonance:
revision of the principle on the electronic spectra of methyl-substituted
acetophenones. J. Phys. Org. Chem. 17, 686–693 (2004).
29. Cheng, C. L. & Ritchie, G. L. D. Conformations of the formyl-, acetyl-, and benzoyl-
pyridines. J. Chem. Soc. 2, 1461–1465 (1973).
30. Ramachandran, P. V., Gong, B., Brown, H. C. & Francisco, J. S. Relationship between
the structure and enantioselectivity in the asymmetric reduction of 2’,6’-
disubstituted acetophenones with DIP-chlorideTM. An ab initio study. Tetrahedr.
Lett. 45, 2603–2605 (2004).
Supplementary Information is linked to the online version of the paper at
www.nature.com/nature.
Acknowledgements This work was supported by a grant from the National Institute of
General Medical Sciences (GM58133). W.A.C. was supported by a Natural Sciences
and Engineering Research Council of Canada Postdoctoral Fellowship. We thank the
US National Science Foundation (CRIF-0840451) for acquisition of a 400 MHz NMR
spectrometer. We thank our colleagues G. Parkin and W. Sattler for an X-ray structure
analysis (see the Supplementary Information), and the US National Science
Foundation (CHE-0619638) for acquisition of an X-ray diffractometer.
Received 5 April; accepted 4 May 2012.
Published online 27 June 2012.
1. Nakamura, M., Hirai, A., Sogi, M. & Nakamura, E. Enantioselective addition of
allylzinc reagent to alkynyl ketones. J. Am. Chem. Soc. 120, 5846–5847 (1998).
2. Waltz, K. M., Gavenonis, J. & Walsh, P. J. A simple, reliable, catalytic asymmetric
allylation of ketones. Angew. Chem. Int. Edn 41, 3697–3699 (2002).
3. Wu, T. R., Shen, L. & Chong, J. M. Asymmetric allylboration of aldehydes and
ketones using 3,39-disubstitutedbinaphthol-modified boronates. Org. Lett. 6,
2701–2704 (2004).
Author Contributions W.A.C. planned and did the vast majority of the experimental
work. S.K.R. did the experiments that established the validity of the idea and optimized
the allylation of acetylacetone. J.L.L. conceived and directed the project and wrote the
manuscript.
4. Canales, E., Prasad, K. G. & Soderquist, J. A. B-Allyl-10-Ph-9-
borabicyclo[3.3.2]decanes: strategically designed for the asymmetric
allylboration of ketones. J. Am. Chem. Soc. 127, 11572–11573 (2005).
5. Wadamoto, M. & Yamamoto, H. Silver-catalyzed asymmetric Sakurai–Hosomi
allylation of ketones. J. Am. Chem. Soc. 127, 14556–14557 (2005).
6. Miller, J. J. & Sigman, M. S. Design and synthesis of modular oxazoline ligands for
the enantioselective chromium-catalyzed addition of allyl bromide to ketones.
J. Am. Chem. Soc. 129, 2752–2753 (2007).
Author Information X-ray crystallographic data have been deposited in the Cambridge
Crystallographic Data Centre database (http://www.ccdc.cam.ac.uk/) under accession
code CCDC 874744. Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of this article at www.nature.
com/nature. Correspondence and requests for materials should be addressed to J.L.L.
(leighton@chem.columbia.edu).
5
J U L Y 2 0 1 2 | V O L 4 8 7 | N A T U R E | 8 9
Macmillan Publishers Limited. All rights reserved
©2012