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Hydrophobically Directed Organic Synthesis.

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Highlights
DOI: 10.1002/anie.200502882
Synthetic Methods
Hydrophobically Directed Organic Synthesis
Ulf M. Lindstrm* and Fredrik Andersson
Keywords:
hydrophobic effect · solvent effects · synthetic
methods · water chemistry
The recent surge of interest, as well as
progress, in the use of water as a solvent
for synthetic chemistry holds great
promise for the future in terms of the
cheaper and less-hazardous production
of chemicals. Researchers in this area
are also discovering that water may offer
new possibilities in organic synthesis
because of its unique physical and
chemical properties that so clearly distinguishes it from other solvents.[1] Recently, significant advances have been
made towards directing the selectivity of
synthetic organic reactions in water
through the interaction of nonpolar, or
hydrophobic, regions of the reactants.
These forces are normally too weak to
compete with any steric and electronic
effects in organic solvents. In water, on
the other hand, hydrophobic surfaces
associate strongly as a result of the
tendency of water to exclude nonpolar
species and thus minimize the Gibbs
energy of solvation, a phenomenon
known as the hydrophobic effect. In
other words, reactions in water may be
predisposed to favor transition states
that optimize hydrophobic interactions.
Thus, it should in principle be possible to
use hydrophobic interactions as a nonbonding element of control for synthetic
reactions in water.
It has been known for some time
that hydrophobic interactions can have
a significant influence on organic reactions.[2] It was discovered in pioneering
studies on Diels–Alder reactions in
water by the research groups of Breslow
and Grieco in the early 1980s that such
[*] Dr. U. M. Lindstr=m, F. Andersson
Department of Organic Chemistry
Lund University
P.O. Box 124, 221 00 Lund (Sweden)
Fax: (+ 46) 46-222-8209
E-mail: ulf.lindstrom@organic.lu.se
548
phobic interactions to achieve selectivity.
Wang, Li, and co-workers described
aqueous RhI-catalyzed additions of aryl
bismuth and aryl lead reagents to alkyl
glyoxylates.[4] The addition of tris(2naphthyl)bismuth to ( )-menthyl glyoxylate in water led to only 13 % de, while
the reaction with ( )-8-phenylmenthyl
glyoxylate gave 85 % de (Table 1; cod =
cycloocta-1,5-diene). The higher de value was attributed to a p-stacking interaction leading to selective blocking of
one diastereotopic face of the aldehyde
(Figure 1). Previous studies suggest that
the hydrophobic effect may enforce
existing attractive interactions, and thus
it is not unlikely that water could add
additional stability to the p interaction
reactions often proceed with much higher rates than in organic solvents. The
accelerating effect of water has been
ascribed to a number of factors, including the hydrophobic effect as well as
hydrogen bonding between water molecules and reactants. In addition, the
endo/exo selectivities for many of the
Diels–Alder reactions studied were significantly higher in water than in organic
solvents, and favored the more compact
endo transition state. In view of the fact
that 25 years have passed since the first
ground-breaking observations, surprisingly little effort has gone into exploring
the potential of hydrophobic interactions in organic synthesis. This situation
has largely arisen because of the fact
that most chemists have not considered
water as being a useful solvent for
synthesis. Concerns about poor solubility and adverse reactivity of the solvent
with catalysts and functional groups
have hampered the wider implementation of water as a reaction medium.
However, as recent research in the area
has shown, these concerns may have
been overstated, and the many benefits
of using water call for it to be explored
to its fullest potential and scope.[3] Herein we highlight attempts to design reactions in water that make use of hydro-
Figure 1. Diastereoselectivity promoted by a
p-stacking interaction, which is enforced in
water through the hydrophobic effect. Copyright Elsevier Science.
Table 1: RhI-catalyzed reactions of chiral glyoxylate hydrates with tris(2-naphthyl)bismuth in water
and THF.[4]
Solvent
R
T [8C]
Yield [%]
de [%]
water
water
water/THF 4:1
THF
Me
Ph
Ph
Ph
50
50
40
40
68
81
73
71
13
85
46
36
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 548 – 551
Angewandte
Chemie
between the carbonyl group and the
phenyl ring.[5] In fact, diastereoselectivities were significantly lower for reactions in THF or dichloromethane than in
water, despite the aqueous reactions
being heterogeneous and run at higher
temperature (Table 1). This work gives a
hint to the untapped potential of designing reactions in which nonpolar, chiral
auxiliaries containing large hydrophobic
surfaces are used to achieve discrimination of diastereotopic faces.
Perhaps the most elaborate and
ambitious studies so far on hydrophobically directed synthetic reactions are
currently underway by Breslow and coworkers. For example, in 2002 they
showed that hydrophobic interactions
may determine the ratio of O versus
C alkylation in alkylations of phenoxide
ions in water.[6] Recognizing the potential of hydrophobically induced selectivity, Biscoe and Breslow explored the use
of hydrophobic reducing agents in reductions of ketones in water. They
performed competition reactions of the
quaternized b-ketoamines 1 and 2 with
differently substituted borohydrides to
give either 3 or 4 (Table 2).[7] As expected, the nonhydrophobic reducing
agent LiBH4 showed almost no selectivity between the two ketones (53:47). On
the other hand, a significant preference
(67:33) for reduction of the more hydrophobic ketone 1 was observed when
LiPhBH3 was employed. No such
change was observed in methanol, thus
reflecting the absence of the hydrophobic effect in methanol. The selectivity
observed in water could be enhanced
(72:28) by salting out the solution with
LiCl. Finally, performing the reduction
with lithium pentafluorophenyl borohydride (LiC6F5BH3) provided further improvement in selectivity (91:9), presumably as a result of an elevated hydrophobicity resulting from the fluorination. Again, addition of LiCl resulted in
better selectivity (95:5). An important
lesson from this study was that increased
hydrophobicity seems to be directly
related to increased reactivity for reductions in water. In another study, Breslow
and co-workers used hydrophobic borohydrides to control the regioselective
reduction of the sulfated naturally occurring steroid 5 (Table 3).[8] Reduction
proceeded with significant selectivity
(87:13) for the intrinsically more-reacAngew. Chem. Int. Ed. 2006, 45, 548 – 551
Table 2: Ratios of products (3:4) formed in the competition reactions of quaternized b-keto amines
1 and 2 with substituted borohydrides under different reaction conditions.[7]
R
D2O
LiCl/D2O
CD3OD
H
Ph
C6F5
53:47
67:33
91:9
58:42
72:28
95:5
35:65
38:62
54:46
Table 3: Ratios of products 6:7 formed in the reduction of 5 under different reaction conditions.[8]
R
D2O
4 m LiCl/D2O
1:1 CD3OD/D2O
H
Ph
C6F5
13:87
60:40
78:22
14:86
69:31
85:15
10:90
32:68
46:54
tive 17-keto group to give 7 when the
reaction was performed in water using
LiBH4. A remarkable reversal of selectivity was observed when the reduction
was performed instead with LiC6F5BH3
in 4 m LiCl/D2O. Under these conditions
optimized for “hydrophobic control”,
the reduction of the 6-keto group was
strongly favored (85:15) over the reduction of the 17-keto group to give 6. The
difference in selectivity between the
nonhydrophobic and hydrophobic conditions corresponds to a nearly 40-fold
increase in the relative rate. Both keto
groups in 5 are in hydrophobic environments and the large dependence of the
selectivity on the hydrophobicity of the
reducing agent is somewhat surprising.
Further experiments indicated that the
saturated framework surrounding the
17-keto group is less conducive to efficient hydrophobic packing than the
unsaturated, flat environment of the 6keto group.
Another important contribution was
the recent disclosure that epoxidations
of olefins can be selectively accelerated
by the use of a hydrophobic oxidizing
agent.[9] In this study, Biscoe and Breslow emphasized the importance of
having an accurate understanding of
the transition-state geometry when developing hydrophobic reagents. For example, the lack of acceleration of the
hydrophobic rate when various peracids
were screened was explained by invoking recently published computational
transition-state models of perbenzoic
acid epoxidation in which the hydrophobic phenyl ring is required to assume
a position highly unfavorable for hydrophobic interaction with the olefin (Figure 2 a). On the other hand, calculations
of transition states for dioxirane or
oxaziridinium cation epoxidations suggest a geometry that would be conducive
to hydrophobic interaction (Figure 2 b).
Indeed, by employing the hydrophobic
oxaziridinium salts 8 and 9 in competition experiments of cinnamic acid derivatives (10) and crotonic acid (11) it
was possible to effect relative rate
increases that were up to an order of
magnitude higher than the largest in-
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
549
Highlights
Table 4: Ratio of epoxide products (12/13) formed in the competition reactions of cinnamic acid
derivatives (10) and crotonic acid (11) with dioxirane and oxaziridinium epoxidizing reagents 8 and
9.[9]
Figure 2. Transition-state models of the epoxidation of styrene with a) perbenzoic acid and
b) the dioxirane derived from acetophenone.
Copyright American Chemical Society.
creases observed in hydride reductions.
Some of the results from this study are
shown in Table 4. Dimethyl dioxirane
(DMDO) was used as a nonhydrophobic
control. The epoxidations show a very
large increase in selectivity for the
hydrophobic cinnamic acid derivatives
10 when using either 8 or 9 instead of
DMDO. A striking example is the competition reaction of the 2-naphthyl olefin and crotonic acid, where changing
from DMDO to 9 leads to an increase in
selectivity for the more hydrophobic
olefin from 68:32 to 99.8:0.2, which
corresponds to a 240-fold increase in
the relative rate. However, the differences in selectivity on going from nonhydrophobic conditions (water/isopropyl alcohol 1:1) to pure water, while
significant enough to indicate a positive
influence of hydrophobic interactions,
are still modest and one should keep in
mind that other binding forces not so
affected by the nature of the solvent are
likely to be involved. A nice extension
of this study was the development of a
catalytic version using substoichiometric
amounts of the iminium precursor of the
oxaziridinium salt 8 and oxone as the cooxidant (Scheme 1).
In conclusion, organic synthesis in
water is a rapidly growing area of
research with an exciting future. Recent
findings presented herein suggest that
selective hydrophobic acceleration will
play an interesting and important part of
this development. However, the wider
applicability of this approach still remains to be established. The design of
stereoselective reactions based on hydrophobic interactions is an area of
great potential that is still largely unexplored. Early studies indicate that the
use of hydrophobic chiral auxiliaries is a
useful strategy worth pursuing. For all
intents and purposes, improved theoret-
550
www.angewandte.org
Ar
Solvent
DMDO
8
9
Ph
Ph
p-CF3C6H4
p-CF3C6H4
2-naphthyl
2-naphthyl
D2O
iPrOD/D2O 1:1
D2O
iPrOD/D2O 1:1
D2O
iPrOD/D2O 1:1
61:39
59:41
22:78
22:78
68:32
66:32
96.5:3.5
88:12
84:16
54:46
98.7:1.3
95.9:4.1
98.1:1.9
91.8:8.2
92.7:7.3
69:31
99.8:0.2
98.1:1.9
Scheme 1. Catalytic cycle using hydrophobic iminium salts. Copyright American Chemical
Society.
ical and experimental models are required to more effectively distinguish
hydrophobic interactions from other
nonbonding interactions and to reliably
and accurately quantify its contribution
to various synthetic reactions in water.
Published online: December 12, 2005
[1] For recent reviews on organic synthesis in
water, see: a) C. J. Li, Chem. Rev. 2005,
105, 3095 – 3166; b) U. M. LindstrFm,
Chem. Rev. 2002, 102, 2751; c) Organic
Synthesis in Water (Ed.: P. Grieco),
Blackie, London, 1998; d) C. J. Li, T. H.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chan, Organic Reactions in Aqueous
Media, Wiley, New York, 1997; see also
thematic issue: “Organic Reactions in
Water”, Adv. Synth. Catal. 2002, 344(3–
4).
[2] For reviews on hydrophobic interactions
and chemical reactivity, see: a) O. Sijbren, J. B. F. N. Engberts, Org. Biomol.
Chem. 2003, 1, 2809; b) R. Breslow, Acc.
Chem. Res. 2004, 37, 471; c) R. Breslow,
Acc. Chem. Res. 1991, 24, 159.
[3] For a recent study on the reactivity of
hydrophobic compounds in water, see: S.
Narayan, J. Muldoon, M. G. Finn, V. V.
Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem. 2005, 117, 3275; Angew.
Chem. Int. Ed. 2005, 44, 3339.
Angew. Chem. Int. Ed. 2006, 45, 548 – 551
Angewandte
Chemie
[4] R. Ding, C. S. Ge, Y. J. Chen, D. Wang,
C. J. Li, Tetrahedron Lett. 2002, 43, 7789.
[5] O. Sijbren, J. B. F. N. Engberts, J. Am.
Chem. Soc. 1999, 121, 6798, and references therein.
Angew. Chem. Int. Ed. 2006, 45, 548 – 551
[6] R. Breslow, K. Groves, M. U. Mayer, J.
Am. Chem. Soc. 2002, 124, 3622.
[7] M. Biscoe, R. Breslow, J. Am. Chem. Soc.
2003, 125, 12 718.
[8] M. R. Biscoe, C. Uyeda, R. Breslow, Org.
Lett. 2004, 6, 4331.
[9] M. R. Biscoe, R. Breslow, J. Am. Chem.
Soc. 2005, 127, 10 812.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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