Entropic factors provide unusual reactivity and selectivity
in epoxide-opening reactions promoted by water
The MIT Faculty has made this article openly available. Please share
how this access benefits you. Your story matters.
Citation
Byers, J. A., and T. F. Jamison. “Entropic Factors Provide
Unusual Reactivity and Selectivity in Epoxide-Opening Reactions
Promoted by Water.” Proceedings of the National Academy of
Sciences 110, no. 42 (October 15, 2013): 16724–16729.
As Published
http://dx.doi.org/10.1073/pnas.1311133110
Publisher
National Academy of Sciences (U.S.)
Version
Final published version
Accessed
Thu May 26 00:30:21 EDT 2016
Citable Link
http://hdl.handle.net/1721.1/87996
Terms of Use
Article is made available in accordance with the publisher's policy
and may be subject to US copyright law. Please refer to the
publisher's site for terms of use.
Detailed Terms
Entropic factors provide unusual reactivity and
selectivity in epoxide-opening reactions
promoted by water
Jeffery A. Byers1,2 and Timothy F. Jamison2
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139
Despite the myriad of selective enzymatic reactions that occur in
water, chemists have rarely capitalized on the unique properties of
this medium to govern selectivity in reactions. Here we report
detailed mechanistic investigations of a water-promoted reaction
that displays high selectivity for what is generally a disfavored
product. A combination of structural and kinetic data indicates
not only that synergy between substrate and water suppresses
undesired pathways but also that water promotes the desired
pathway by stabilizing charge in the transition state, facilitating
proton transfer, doubly activating the substrate for reaction, and
perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This
approach serves as an outline for a general strategy of exploiting
solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the
biosynthesis of the ladder polyether natural products, such as the
brevetoxins and ciguatoxins.
entropic control
| biomimetic
G
iven its simple structure and low molecular weight, water is
a remarkably complex substance. Several landmark investigations (1) have revealed the ability of water to self-assemble to
form sophisticated dynamic hydrogen bond networks, which
accounts for its unusual properties, such as its high boiling point
and high surface tension (2). Despite the unique properties that
it offers and that nature has exploited, water is generally
eschewed in synthetic chemistry largely because of chemical incompatibility with many commonly used reagents and the low
aqueous solubility of many organic molecules coupled with the
attendant assumption that homogeneity is required for reactivity.
Although several important examples of remarkable reactivity
have been documented for reactions carried out in water (3–5),
on the surface of water (6, 7), or in micelles suspended in water
(8, 9), utilization of the “biological solvent” in organic reactions
remains uncommon.
We became acutely aware of the remarkable properties of
water when we discovered that neutral aqueous solutions of
epoxy alcohol 1a underwent a spontaneous and selective “endo”
cyclization reaction to form 6,6-fused bicyclic product 2a (Fig. 1)
(10–12). Exceptional reactivity and selectivity were observed only
when two criteria were satisfied: The substrate contained a sixmembered tetrahydropyran ring, and the solvent used was water
at pH 7.0. These surprising results were counter to a set of
general empirical rules put forth by Baldwin for cyclization
reactions, which state that the smaller ring product resulting
from what is commonly called an exo cyclization is favored for
similar reactions (13). The tetrahydropyranol ring, therefore,
appeared to “template” the endo cyclization pathway to form the
larger ring product with water playing a critical yet heretofore
unknown role.
Moreover, 2a is a substructure found in a large family of
natural products commonly referred to as the ladder polyethers
(e.g., brevetoxin B, S) (14–16). These constituents of harmful
algal blooms (a.k.a., red tide) have attracted significant attention
www.pnas.org/cgi/doi/10.1073/pnas.1311133110
(17) because of the remarkable structural regularities that temper their apparent complexity. Several biogenetic pathways for
the construction of rings of these natural products have been
proposed and generally involve a cascade of cyclizations by way
of epoxide-opening reactions (Fig. 2) (18–23). However, this
hypothesis requires that all of the epoxide ring-opening events
proceed with atypical endo regioselectivity.
Our discovery that reactions of 1a in water preferentially lead
to the endo product 2a rather than exo product 3a provided
a possible means to overcome this obstacle. Further support was
provided when we demonstrated that cascade reactions akin to
those proposed for the biosynthesis of the natural products was
possible with the selective endo cyclization of di- and triepoxide
analogs, such as 4 and 6, respectively (Fig. 1). Once again selective reactions were only observed when reactions were carried
out in neutral water.
These striking results and their possible relevance to the biogenesis of the ladder polyether natural products prompted us to
investigate the mechanism of the cyclization reaction. Here we
report the culmination of these efforts. They reveal an intimate
connection between water and the tetrahydropyran ring (template) of 1a, provide support for the feasibility of the biosynthetic
proposal for the ladder polyether natural products, and demonstrate the importance of solvent–substrate interactions for
promoting selectivity. We believe that this last concept may have
broad implications and a different means for chemists to attain
unusual selectivity for a variety of chemical reactions.
Significance
Mechanistic studies of a water-promoted cyclization reaction
reveal that an unusual, multifaceted interaction between the
organic substrate and water causes an otherwise disfavored
chemical reaction. The combination of several factors leads to
the unusual selectivity and highlights the beneficial features of
water as a solvent in organic chemistry. Of particular importance is organization of the substrate, which is facilitated by
synergistic interactions between the surprisingly simple organic substrate and water. In addition to providing insight into
these important interactions, the results may be relevant to the
biosynthetic origins of the ladder polyether natural products.
These natural products are potent neurotoxins and are the
active constituents of harmful algae blooms commonly referred to as “red tide.”
Author contributions: J.A.B. and T.F.J. designed research; J.A.B. performed research; J.A.B.
and T.F.J. analyzed data; and J.A.B. and T.F.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1
Present address: Department of Chemistry, Boston College, Chestnut Hill, MA 02346.
2
To whom correspondence may be addressed. E-mail: Jeffery.Byers@bc.edu or tfj@
mit.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
1073/pnas.1311133110/-/DCSupplemental.
PNAS Early Edition | 1 of 6
CHEMISTRY
Edited by Larry E. Overman, University of California, Irvine, CA, and approved August 21, 2013 (received for review June 14, 2013)
Table 1. Endo:exo selectivity (2:3) for epoxy alcohol cyclizations
in water at 20 °C and pH 7.0 (0.1 M potassium phosphate buffer)
Entry
Label
1
1a
2
1b
Structure
2:3
10:1
HO
Me
H
1:1
O
H
HO
3
1c
<1:20
Me
H
O
HO
4
1d
Fig. 2. Biosynthetic proposal for the formation of the ladder polyether
natural product brevetoxin B, a potent neurotoxin.
2 of 6 | www.pnas.org/cgi/doi/10.1073/pnas.1311133110
O
H
Me O
1:3
HO
Fig. 1. Endo selective cyclization of epoxy alcohols templated by a tetrahydropyran ring(s) and promoted by water.
Results and Discussion
It is clear from the data in Table 1 that selectivity in the cyclization reactions under neutral aqueous conditions is very sensitive to the identity of the template and the size of the ring being
formed (10–12). We were particularly surprised to find that a 1:1
mixture of products resulted from the seemingly minor change
from 1a to 1b, which differ only by the replacement of an oxygen
atom with a CH2 group in the template (entries 1 and 2). Unfortunately, the combination of water and cyclic ether template
did not allow for the incorporation of larger rings either for
substrate 1c or for substrate 1d, the latter containing a sevenmembered oxepane ring as the purported template (entries 3
and 4, respectively). Nevertheless, some modifications of the
template did lead to enhanced selectivity. For example, 1e,
possessing a second fused tetrahydropyran ring, afforded the
highest levels of endo selectivity reported to date (entry 5) (24).
Our earlier mechanistic experiments (25) revealed that the
cyclization reactions are kinetically controlled, occur in water
H
5
1e
19:1
(rather than on its surface or in micelles), and at pH 7.0 occur in
a regime where neutral or “water-catalyzed” mechanisms prevail
(26), instead of acid or base-catalyzed mechanisms that are more
commonly invoked. Interestingly, kinetic studies revealed that
the carbocyclic analog 1b cyclized nearly 10 times faster (as well
as 10 times less selectively) than the original epoxy alcohol 1a.
The kinetic behavior of reactions in dimethyl sulfoxide/water
mixtures was most consistent with two additional water molecules required for the cyclization of 1a, but only one additional
water molecule being requisite for cyclization of 1b.
Uncovering the Specific Role of the Template. We hypothesized that
the additional water molecule required for 1a facilitates cyclization by forming a hydrogen-bonding network bridging the oxygen atom within the cyclic template and the oxygen atom of the
hydroxyl group attached to the template (25). This interaction
encourages reorganization of the epoxy alcohol from an energetically favorable chair conformation into a higher energy twist
conformation (Fig. 3). This structural change in turn alters the
trajectory of the nucleophile toward the epoxide electrophile, a
factor that computations suggest is most important for selectivity
in epoxide-opening reactions (27, 28). Because the template of
1b cannot participate in similar hydrogen-bonding interactions,
an unselective reaction proceeds with the template in the more
stable chair conformation.
However, we recognized that an alternative explanation for
the differences between 1a and 1b is that the electron-withdrawing element oxygen within its template encourages endo
cyclization of 1a by inductively disfavoring exo cyclization. Although this rationale accounts for the increased reaction rate
and decreased selectivity observed for 1b compared with 1a, it
does not explain why exo cyclization is observed for epoxy alcohol 1d, which has a different ring structure (oxepane) but
retains the oxygen atom in the same position from the epoxide
moiety. This would suggest that the different reactivity is due to
another major difference between 1a and 1d, such as the greater
conformational flexibility of the seven-membered oxepane ring.
Byers and Jamison
Fig. 3. Proposed transition state for the cyclization of 1a aided by two
water molecules in excess of those required for solvation.
Two additional pieces of evidence supported the importance
of substrate conformation upon selectivity in these reactions and
uncovered a unique role of the template. Determination of the
activation parameters for cyclizations of 1a and 1b from Eyring
plots revealed large and negative entropies of activation (ΔS‡) in
both cases (Table 2). This striking feature was somewhat surprising considering that the cyclization reactions are ostensibly
unimolecular, which is typically an entropically favorable situation characterized by small entropies of activation (SI Text).
Moreover, 1a displayed considerably more negative entropies of
activation compared with 1b, despite a seemingly minor structural difference between the template rings—O vs. CH2 (Table
2). These findings are completely consistent with cyclization
being assisted by additional water molecules and with the higher
kinetic order in water measured for 1a compared with 1b.
Comparing the activation parameters obtained for exo versus
endo cyclization for 1a and 1b led to the important realization
that entropy, not enthalpy, was most important in dictating selectivity in the cyclization of 1a—that is, jTΔΔS‡j ≥ jΔΔΗ‡j (Fig.
4). Hypothetically, if the reaction were governed entirely by
enthalpy (i.e., ΔΔH‡), then cyclization of 1a would exhibit slight
selectivity for the exo product rather than the 10:1 endo selectivity observed. Substitution of an oxygen atom in the template
ring apparently incurs a significant entropic penalty for exo cyclization of 1a that is completely absent in the case of 1b. This
finding is more consistent with the hypothesis that explains the
differences between 1a and 1b based on conformational differences rather than electronic differences because the former is
largely entropic (i.e., affecting the organization of the transition
state), whereas the latter is largely enthalpic (i.e., affecting bond
making/breaking in the transition state).
The second piece of evidence that supported the importance
of conformation to selectivity came from comparing the kinetic
behavior for a series of epoxy alcohols: 1a, 1d, and 1e. These
three epoxy alcohols contain templates that are virtually identical
electronically yet are conformationally very different. As Table 1
demonstrates, selectivity for cyclization of these substrates increased with the rigidity of the template (i.e., 1d > 1a > 1e).
Comparing the elementary rate constants for endo cyclization
(kendo) to exo cyclization (kexo) revealed that kendo was similar for
all three substrates, whereas kexo increased by a factor of 50 from
The Role of the Solvent (Water). Up to this point, the importance of
the template structure for selective endo cyclizations has been
emphasized, yet as noted above, water was also implicated (10).
Further investigation has revealed that selectivity is much less
sensitive to the identity of the solvent than is the reaction rate (Fig.
5B). The selectivities (kendo/kexo) measured for the cyclization of 1a
in various hydroxyllic solvents at room temperature are the
same within experimental uncertainty. In sharp contrast, however, the absolute rate constants (kendo and kexo) decrease by
more than two orders of magnitude among the solvents studied
in the order: 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) ∼ water >
2,2,2-trifluoroethanol (TFE) > methanol > ethanol. With the
exception of water, this order is roughly correlated to the acidity
of the solvent as indicated by solvent pKa, which increases in the
order: HFIP > TFE > methanol > water > ethanol. Even if
reactions in water are ignored, the correlation between solvent
acidity and cyclization are not consistent with typical acid/base
catalysis (Supporting Information). Nevertheless, it is noteworthy
that reaction rates in water are similar to solvents with acid dissociation constants that are over six orders of magnitude greater
than water at room temperature.
In addition to solvent pKa, virtually all other solvent properties, such as dielectric constant and polarizability, were poorly
correlated to reaction rate. However, a good correlation was
obtained with α, the Taft parameter that describes the hydrogenbond–donating ability of a solvent (Fig. 6A). In contrast, a poor
correlation was observed with β, the Taft parameter for hydrogen-bond–accepting ability of the solvent. An important step in
the reaction mechanism for these cyclization reactions is a proton transfer event that occurs before or in the rate-determining
step of the reaction, which is implicated by the small normal
solvent isotope effect observed for the cyclization of 1a (25).
That hydrogen-bond–accepting ability is better correlated than
Table 2. Activation parameters (ΔX‡) for the cyclizations of 1a
and 1b in D2O (pD 7.0, 0.1 M KPi buffer)
1a
ΔX
1b
‡
Endo
Exo
Endo
Exo
‡
16.4 ± 0.7
−27.2 ± 2.1
24.5
16.2 ± 0.8
−32.5 ± 2.5
25.9
16.3 ± 0.2
−23.4 ± 1
23.3
15.4 ± 0.2
−25.9 ± 1
23.1
ΔH
ΔS‡
ΔG‡
ΔH‡ in kcal/mol, ΔS‡ in cal/mol·K, and ΔG‡ in kcal/mol at 298 K. Error is
represented as average error.
Byers and Jamison
Fig. 4. Comparison of activation parameters determined for the cyclization
of epoxy alcohols 1a and 1b (T = 298 K).
PNAS Early Edition | 3 of 6
CHEMISTRY
the least (1e) to the most (1d) flexible epoxy alcohol (Fig. 5A).
These data suggest that an important role of the template is to
restrict conformational motion so that reaction pathways to the
normally favored exo cyclization products are limited. With
limited access to exo cyclization pathways, the reaction occurs via
a normally disfavored pathway to form endo products selectively.
Fig. 5. Rate constants and selectivities for cyclization of (A) a series of epoxy alcohols (1a, 1d, and 1e) that are electronically similar but decrease in conformational flexibility (reactions in neutral water at 70 °C) and (B) epoxy alcohol 1a at 25 °C in various hydroxyllic solvents (HFIP, 1,1,1,3,3,3-hexafluoroisopropanol; TFE, 2,2,2-trifluoroethanol). Most rate constants were determined from extrapolation of rate behavior at elevated temperatures (SI Text).
Error is represented as the average error.
hydrogen-bond–donating ability is consistent with the proton
transfer step being asynchronous for most solvents. In other
words, proton donation from the solvent is kinetically more important than proton accepting. Once again, water is the exception
to this trend. Reactions in water displayed unusually fast reaction
rates for a solvent with its hydrogen-bond–donating ability (Fig.
6A). This anomaly suggests that water, unlike any other solvent,
promotes a more synchronous proton transfer step (29).
A trend that includes all solvents (including water) is the linear
correlation observed between reaction rate and YOTs, the
Grunwald–Winstein parameter for solvent ionizing power (Fig.
6B). That this correlation is the best of all solvent properties
evaluated indicates that the primary role of the solvent is to
stabilize charged intermediates and transition states. Highlighting
the importance of this solvent property is the relatively large slope
(0.37) observed in Fig. 6B. A reaction that displays equal bond
making and bond breaking in the transition state (e.g., purely SN2
behavior) involves relatively small charge buildup. Consequently,
such reactions typically display smaller slopes of log(k) vs. YOTS
plots (m = 0.20–0.35) (30). The slopes observed in Fig. 6B are at
the upper limit of this range, which suggest that there is significant C–Oepox bond breaking in the transition state. Importantly,
water is the solvent that is best at stabilizing charge according to
the YOTs scale. It is likely that it is the ability of water to stabilize
charge coupled with its ability to donate and accept hydrogen
bonds that leads to the anomalously fast cyclization rates observed in water.
Implications for the Biogenisis of the Ladder Polyether Natural
Products. In addition to uncovering the specific details about
epoxy alcohol cyclization reactions, these mechanistic studies
are relevant to the biosynthetic proposal (18) for the formation of the ladder polyether natural products. The very slow
reaction rates observed for 1a and even slower rates for cascade reactions of multiple epoxides, such as 4 and 6 (12, 24),
are problematic for a biosynthetic proposal involving con4 of 6 | www.pnas.org/cgi/doi/10.1073/pnas.1311133110
secutive or concurrent epoxy alcohol cyclizations promoted by
neutral water. The data presented above suggest rate constants for endo cyclizations to be on the order of 10−5·s−1 at
300 K, which translates to a half-life of 16.6 h. These rates
seem unlikely under physiological conditions where metabolism or extrusion of intermediates during a cascade reaction
would compete. No such cascade intermediate has ever been
isolated along with the ladder polyether natural product.
Nevertheless, our results do not rule out the possibility that
the ladder polyether natural products are formed by enzymecatalyzed cyclizations of epoxy alcohols under conditions that are
similar to those in neutral water. This possibility stems from the
fact that the cyclization reactions in neutral water appear to
suffer severe entropic penalties with only modest enthalpic barriers to overcome. If the primary role of this hypothetical enzyme
is to organize the epoxy alcohol appropriately for cyclization or
alternatively organize the solvent molecules appropriately for
efficient proton transfer, then the entropic penalty incurred for
cyclization under neutral aqueous conditions would be significantly decreased. Our data show that if entropy is ignored, endo
cyclization rates would be on the order of 10 s−1 at 300 K or a
half-life of 70 ms. This translates into a theoretical reaction rate
that is seven orders of magnitude greater for reactions catalyzed
by enzymes whose primary function is to organize the substrate
(or solvent) appropriately for cyclization.
Supporting this notion is the seminal work from Janda, Shevlin,
and Lerner, who have developed a catalytic antibody that catalyzes
6-endo and 7-endo cyclizations of simple epoxy alcohols (i.e.,
without an appended tetrahydropyran ring) (27, 31, 32). Catalytic
rate constants measured for cyclizations leading to the 6-endo
product displayed half lives of 45 s (kcat = 1.5 × 10−2·s−1). If the
rate for 6-endo cyclization presented herein is similar to the
“uncatalyzed” rate for cyclization of the simple epoxy alcohols,
then a thousand-fold rate enhancement was observed as a result
of the catalytic antibody. Presumably, the rate increase observed
Byers and Jamison
is due in large part to entropic confinement of the epoxy alcohol that occurs upon binding to the antibody.
Perhaps more biologically relevant is the epoxide hydrolase
enzyme Lsd19 that has recently been reported to catalyze a
6-endo cyclization in the biosynthesis of lasolocid A (33). Although the class of natural products and the species that the enzyme originate from are different in this case compared with the
ladder polyether natural products, there is nonetheless a striking
parallelism between the role of the enzyme and the role that the
combination of water and substrate play in the reactions discussed above. We suggest that the enzyme, like the tetrahydropyran
template, serves to organize the substrate appropriately to limit the
otherwise favorable 5-exo cyclization, thereby allowing the less favored 6-endo cyclization reaction to occur.
Noteworthy is that the crystal structure of Lsd19 contains a
5-exo cyclization substrate in one of its catalytically active sites
rather than the expected 6-endo cyclization product (34). We
speculate that this cyclization product was observed due to the
conditions (pH < 4) that were necessary to provide X-ray quality
crystals of the enzyme. This implies that the neutral conditions
used in the catalytic reactions plays a role in dictating selectivity
for this enzyme. Although highly speculative, it is interesting to
consider the possibility that the enzyme works in concert with
neutral water to achieve the highly selective cyclization reaction
observed in this enzyme and for enzymes that may lead to the
ladder polyether natural products.
Conclusions
The mechanistic studies presented above have uncovered several
key features of epoxy alcohol cyclizations in neutral water (Fig.
7). First, an important role of the cyclic template is to prevent
the epoxy alcohol from undergoing exo cyclization rather than
promote endo cyclization. High levels of selectivity were also
observed only for substrates that can interact with water through
hydrogen bonding. These interactions likely cause conformational reorganization that alters the trajectory and consequently
selectivity of the chemical reaction. In addition to facilitating
reorganization of the template, a critical role of the solvent is to
stabilize charge in the transition state and/or intermediates
during the reaction. A secondary role for the solvent is to act as
a proton shuttle, which activates the epoxy alcohol for cyclization. This process appears to be asynchronous for reactions in
Fig. 7. Venn diagram illustrating the features of water, epoxy alcohol 1a, and their synergism to enhance endo selectivity in epoxy alcohol cyclization
reactions.
Byers and Jamison
PNAS Early Edition | 5 of 6
CHEMISTRY
Fig. 6. (A) Sensitivity of the rate of cyclization of 1a to the hydrogen-bond–donating ability of the solvent (α) at 25 °C. Linear regression displayed does not
include reactions in neutral water. (B) Sensitivity of the rate of cyclization of 1a to the ionizing power of the solvent (YOTs) at 25 °C. Error is represented as
average error.
by our findings bears a striking resemblance to enzymatic catalysis:
To maximize both rate and selectivity, use water to its maximum
enthalpic advantage and develop small organic molecules to supplant its entropic role. This strategy is under current investigation,
and we will report our results in due course.
most solvents except water, where reaction behavior is more
consistent with a synchronous proton transfer. Just as the equal
number of hydrogen-bond donors and acceptors present in a water
molecule engenders some of its unique properties, we surmise that
a similar bivalency is a very important feature of the promoter of
these reactions. As it can provide both Brønsted acids and Lewis
bases, water exerts upon the substrate multiple reinforcing interactions, some that orient it appropriately and others that initiate
the selective chemical transformation.
In closing, our investigations into the water-promoted epoxideopening reactions discussed here provide a vivid reminder of the
importance of entropic (rather than enthalpic) considerations in
catalytic reactions. It has been known for decades that substrate
organization is one of the major modes of assistance that enzymes
provide in accelerating selective catalysis. More recently similar
phenomena have been convincingly documented in reactions
catalyzed by synthetic organic molecules (35). Herein we have
shown that one of the at least five important roles of an even
smaller molecule, water, is organization of a substrate much
larger than itself. This effect is ultimately the source of selectivity
in these reactions, but it comes at a high entropic cost. Do these
results suggest that the proposed biogenesis of the ladder polyethers (epoxide-opening cascades) is indeed operative? Were the
cascades originally catalyzed by water? As intimated above, has
evolution subsequently provided enzymes to help catalyze these
reactions? The answers to these questions remain to be seen and
may never be known. However, in the meantime, a powerful and
general approach to catalysis by small molecules strongly suggested
Kinetic measurements were made using 1H NMR spectroscopy on a Varian
Inova 500 MHz spectrometer equipped with an inverse broadband gradient
probe (gHX). Efficient reactions (t1/2 ≤ 6 h) were carried out in the spectrometer, which was brought to the desired reaction temperature and
calibrated using an ethylene glycol external standard. Less efficient reactions
(t1/2 ≥ 6 h) were carried out in NMR tubes that were thermostated in an oil
bath. Periodic measurement of an NMR spectrum was carried out at regular
intervals at ambient temperatures. The pD of the buffer was measured at
the reaction temperature using a Symphony Posi-pHlo Ag/AgCl pH glass
electrode calibrated at the reaction temperature with standard solutions.
For reactions in D2O, a correction for the solvent isotope effect that is typical
for glass electrodes was applied ðpD = pHmeter + 0:4Þ (36). Synthetic procedures
and specific details about kinetic analysis appear in SI Text.
1. Engberts J (2007) Organic Reactions in Water: Principles, Strategies, and Applications,
Chapter 2, ed Lindström M (Blackwell Publishing, Oxford, UK).
2. Head-Gordon T, Hura G (2002) Water structure from scattering experiments and
simulation. Chem Rev 102(8):2651–2670.
3. Breslow R, Maitra U, Rideout D (1983) Selective Diels-Alder reactions in aqueous
solutions and suspensions. Tet Lett 24(18):1901–1904.
4. Greico PA, Yoshida K, Garner P (1983) Aqueous intermolecular Diels-Alder chemistry:
Reactions of diene carboxylate with dienophiles in water at ambient temperature.
J Org Chem 48(18):3137–3139.
5. Kool E, Breslow R (1988) Dichotomous salt effects in the hydrophobic acceleration of
the benzoin condensation. J Am Chem Soc 110(5):1596–1597.
6. Narayan S, et al. (2005) “On water”: Unique reactivity of organic compounds in
aqueous suspension. Angew Chem Int Ed Engl 44(21):3275–3279.
7. Jung Y, Marcus RA (2007) On the nature of organic catalysis “on water”. J Am Chem
Soc 129(17):5492–5502.
8. Dwars T, Paetzold E, Oehme G (2005) Reactions in micellar systems. Angew Chem Int
Ed Engl 44(44):7174–7199.
9. Tascioglu S (1996) Micellar solutions as reaction media. Tetrahedron 52(34):
11113–11152.
10. Vilotijevic I, Jamison TF (2007) Epoxide-opening cascades promoted by water. Science
317(5842):1189–1192.
11. Morten CJ, Jamison TF (2009) Water overcomes methyl group directing effects in
epoxide-opening cascades. J Am Chem Soc 131(19):6678–6679.
12. Morten CJ, Byers JA, Van Dyke AR, Vilotijevic I, Jamison TF (2009) The development of
endo-selective epoxide-opening cascades in water. Chem Soc Rev 38(11):3175–3192.
13. Baldwin JE (1976) Rules for ring closure. J Chem Soc Chem Commun 18:734–736.
14. Yasumoto T, Murata M (1993) Marine toxins. Chem Rev 93(5):1897–1909.
15. Poli MA, Mende TJ, Baden DG (1986) Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes. Mol Pharmacol
30(2):129–135.
16. Trainer VL, Baden DG, Catterall WA (1994) Identification of peptide components of
the brevetoxin receptor site of rat brain sodium channels. J Biol Chem 269(31):
19904–19909.
17. Nakata T (2005) Total synthesis of marine polycyclic ethers. Chem Rev 105(12):
4314–4347.
18. Nakanishi K (1985) The chemistry of brevetoxins: A review. Toxicon 23(3):473–479.
19. Shimizu Y (1986) in Natural Toxins: Animal, Plant, and Microbial, Chapter 8, ed Harris
JB (Oxford University Press, New York).
20. Nicolaou KC (1996) The total synthesis of Brevetoxin B: A twelve-year odyssey in organic synthesis. Angew Chem Int Ed Engl 35(6):588–607.
21. Lee MS, Qin GW, Nakanishi K, Zagorski MG (1989) Biosynthetic studies of brevetoxins,
potent neurotoxins produced by the dinoflagellate Gymnodinium breve. J Am Chem
111(16):6234–6241.
22. Chou HN, Shimizu Y (1987) Biosynthesis of brevetoxins. Evidence for the mixed origin
of the backbone carbon chain and possible involvement of dicarboxylic acids. J Am
Chem Soc 109(7):2184–2185.
23. Giner J-L (2005) Tetrahydropyran formation by rearrangement of an epoxy ester: A
model for the biosynthesis of marine polyether toxins. J Org Chem 70(2):721–724.
24. Morten CJ, Byers JA, Jamison TF (2011) Evidence that epoxide-opening cascades
promoted by water are stepwise and become faster and more selective after the first
cyclization. J Am Chem Soc 133(6):1902–1908.
25. Byers JA, Jamison TF (2009) On the synergism between H2O and a tetrahydropyran template
in the regioselective cyclization of an epoxy alcohol. J Am Chem Soc 131(18):6383–6385.
26. Pocker Y, Ronald BP, Anderson KW (1988) Epoxides in vicinal diol dehydration. 7. A
mechanistic characterization of the spontaneous ring opening process of epoxides in
aqueous solution: Kinetic and product studies. J Am Chem Soc 110(19):6492–6497.
27. Na J, Houk KN, Shevlin CG, Janda KD, Lerner RA (1993) The energetic advantage of
5-exo versus 6-endo epoxide openings: A preference overwhelmed by antibody catalysts. J Am Chem Soc 115(18):8453–8454.
28. Coxon JM, Thorpe AJ (1999) Ab initio study of intramolecular ring cyclization of
protonated and BF3-coordinated trans- and cis-4,5-epoxyhexan-1-ol. J Org Chem
64(15):5530–5541.
29. Gilli P, Pretto L, Bertolasi V, Gilli G (2009) Predicting hydrogen-bond strengths from
acid-base molecular properties. The pKa slide rule: Toward the solution of a longlasting problem. Accts Chem Res 42(1):33–44.
30. Reichardt C, Welton T (2011) Solvents and Solvent Effects in Organic Chemistry (Wiley-VCH, Weinheim, Germany), 4th Ed, pp 425–448.
31. Janda KD, Shevlin CG, Lerner RA (1993) Antibody catalysis of a disfavored chemical
transformation. Science 259(5094):490–493.
32. Janda KM, Shevlin CG, Lerner RA (1995) Oxepane synthesis along a disfavored
pathway: The rerouting of a chemical reaction using a catalytic antibody. J Am Chem
Soc 117(9):2659–2660.
33. Shichijo Y, et al. (2008) Epoxide hydrolase Lsd19 for polyether formation in the biosynthesis of lasalocid A: Direct experimental evidence on polyene-polyepoxide hypothesis in polyether biosynthesis. J Am Chem Soc 130(37):12230–12231.
34. Hotta K, et al. (2012) Enzymatic catalysis of anti-Baldwin ring closure in polyether
biosynthesis. Nature 483(7389):355–358.
35. Knowles RR, Jacobsen EN (2010) Attractive noncovalent interactions in asymmetric
catalysis: Links between enzymes and small molecule catalysts. Proc Natl Acad Sci USA
107(48):20678–20685.
36. Cook PA, Clelan WW (2007) Enzyme Kinetics and Mechanism (Garland, New York).
6 of 6 | www.pnas.org/cgi/doi/10.1073/pnas.1311133110
Materials and Methods
ACKNOWLEDGMENTS. We thank Li Li for mass spectral data collection and
analysis and Dr. Jeff Simpson for NMR assistance. We give special thanks to
Dr. Christopher J. Morten and Dr. Denise A. Colby for insightful discussions and to
Satapanawat Sittihan and Dr. Ivan Vilotijevic for assistance with the synthesis of
several compounds and for selected cyclization data. We also thank Prof. John E.
Bercaw and Prof. Ian Tonks for the gift of trifluoroethanol-d3. This work was
supported by the Petroleum Research Fund of the American Chemical Society
(47212-AC1) and the National Institute of General Medical Sciences (GM72566).
Byers and Jamison