Prompt determination of absolute configuration for epoxy alcohols via exciton chirality protocol

Article abstract of DOI:10.1021/ja805058t

A microscale protocol for determination of absolute configurations of 2,3-epoxy alcohols is described. 2,3-Disubstituted (cis and trans), 2,2-disubstituted, 2,2,3-trisubstituted, and 2,3,3-trisubstituted epoxy alcohols rendered prominent ECCD signals upon complexing with a Lewis acidic porphyrin tweezer and consequently provide straightforward assignment of chirality for epoxy alcohols. This method proved to be rapid, simple, sensitive, and reliable for the class of molecules listed above. Copyright

Full text of DOI:10.1021/ja805058t

Published on Web 11/11/2008
Prompt Determination of Absolute Configuration for Epoxy Alcohols via
Exciton Chirality Protocol
Xiaoyong Li and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received July 1, 2008; E-mail: babak@chemistry.msu.edu
Table 1. ECCD Data of 2,3-Epoxy Alcohols in Hexanea
Chiral epoxy alcohols are invaluable building blocks in organic
synthesis and are encountered in many biologically active natural
products. Assignment of absolute configuration of chiral epoxy alcohols
relies heavily on Mosher ester analysis1,2 of the corresponding ring
opened diol or established empirical mnemonics developed for different
asymmetric epoxidation strategies.3-7 The former approach requires
derivatization, which is inconvenient especially when only a limited
amount of substrate is available. Moreover, in many cases the absolute
stereochemistry cannot be unambiguously assigned until several
diastereomers are synthesized.8,9 As important as chiral epoxy alcohols
are in synthetic organic chemistry, there is no direct method for the
assignment of their absolute stereochemistry. We describe here a
microscale, nonempirical, expedient protocol to determine the absolute
configuration of chiral epoxy alcohols without the need for any
derivatization.
It was envisaged that the use of the porphyrin tweezer, utilized
previously to assign the absolute stereochemistry of families of
different chiral organic molecules such as diamines and amino
alcohols, could also lead to a successful strategy for assignment of
chirality for epoxy alcohols.10,11 Central to the success of this route
would be the use of a porphyrin tweezer capable of efficient binding
with the epoxy alcohol. Recently, we have introduced the use of
the highly Lewis acidic porphyrin tweezer 111 featuring a strong
binding affinity for hydroxyl groups and demonstrated its ability
to bind 1,2,3,4-diepoxybutane. Indication of strong binding can be
demonstrated from the binding affinity of epoxy alcohols with Zn-
TPFP-tz 1 (Kassoc of 7 with 1 is 2.88 × 104 M-1, which is
comparable to that of vicinal diols;12 see Supporting Information,
SI). In light of the latter observations, Zn-TPFP-tz 1 was examined
for configurational assignment of epoxy alcohols via the Exciton
Coupled Circular Dichroism (ECCD) protocol.13-15 To our delight,
prominent bisignate CD signals (ECCD) at the Soret region were
observed upon complexation of Zn-TPFP-tz 1 with a large number
a Tweezer/substrate ratio - 1:40 unless otherwise indicated. b The
of chiral epoxy alcohols at micromolar concentrations.
As shown in Table 1, the (2S,3S) trans-disubstituted epoxy alcohols
(2, 4, and 6-8) resulted in negative ECCD spectra while positive
signals were observed for (2R,3R) substrates (9 and 10). The correlation
enantiomer showed mirror image CD spectrum. c Tweezer/substrate ratio
- 1:200. d Tweezer/substrate ratio - 1:100, 2 µM tweezer concentration at
0 °C was used for all measurements.
between substrate chirality and the sign of ECCD is illustrated in Figure
1a in which two binding interactions occur between the OH group
and the epoxide oxygen with the zincated porphyrins. It is assumed
that the binding of P1, the porphyrin bound to the epoxidic oxygen,
occurs opposite the largest substituent on the epoxide. Since P2 is
bound to the alcohol, invariably this will be the largest group such
that P1 and P2 avoid steric clash with each other. Since the lone pairs
on the epoxidic oxygen are geometrically fixed due to the rigid nature
of the epoxide ring, steric relief of P1 is through rotation/sliding of
the porphyrin ring to avoid the largest substituent on the epoxide that
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10.1021/ja805058t CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
clash. The resultant counterclockwise helicity results in a negative
ECCD spectrum for 2S,3S substrates (15, 18). Accordingly, positive
signals would reflect 2R,3R configuration (16, 19). It should be noted
that, with 2,3,3-trisubstituted olefins, the nature of R3 is inconsequential,
since P1 is bound away from R3 and undergoes steric differentiation
between R1 and the hydrogen atom (positioned at R2 in Figure 1a).
Conversely, with 2,2,3-trisubstituted olefins, both R1 and R2 face P1,
and thus steric differentiation is governed by their relative sizes. In
examples listed in Table 1 (18 and 19) R1 is larger than R2, thus leading
to the observed ECCD spectra.
2,2-Disubstituted epoxy alcohols (R1 ) R3 ) H), with R2 facing
P1 should also lead to predictable ECCD spectra based on the fact
that P1 would slide away from R2 toward the H atom (R1 in Figure
1a). This is indeed observed, as the anticipated sign of the ECCD
for 20 and 21 matches the experimentally observed data (20 and
21 bearing 2S configuration yield positive ECCD, resulting from
steric discrimination between R2 (n-octyl group or PhCH2CH2-)
and R1 (H)). In contrast, epoxy alcohol 22 did not yield an
observable ECCD. This is not surprising since there are no steric
determinants that orient P1 and P2 relative to each other.
In summary, we have demonstrated the facile determination of absolute
configurations for 2,3-epoxy alcohols with various substitution patterns
utilizing Zn-TPFP-tz 1 devoid of any derivatization in a microscale fashion
requiring only micrograms of substrate via the nonempirical ECCD
methodology. We are presently exploring the extension of this methodol-
ogy to epoxy alcohols bearing a chiral hydroxyl group.
Figure 1. (a) Proposed complexation pattern between tweezer 1 and epoxy
alcohol. Negative ECCD spectrum was obtained for compound 4; (b) enantiomeric
ECCD of 5 and ent-5 (40 equiv) in hexane exhibiting complex CD.
Acknowledgment. Generous support was provided by a NSF-
CAREER Grant (CHE-0094131).
Supporting Information Available: Synthesis of epoxy alcohols
and general procedures for CD measurements. Determination of Kassoc
for complexation of 7 with tweezer 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 2. Proposed complexation pattern between tweezer 1 and cis-epoxy
alcohol. Positive ECCD spectrum was obtained for 11.
References
faces P1. In case of trans-disubstituted epoxy alcohols (R2 ) R3 )
H) depicted in Figure 1a, P1 slides away from R1 in preference for
the smaller hydrogen atom, thus generating the energetically favored
complex in which the two chromophores are twisted in a counter-
clockwise fashion. Consequently, a negative ECCD spectrum is
observed for (2S,3S) trans-disubstituted substrates. Interestingly,
compounds 3 and 5 exhibited complex CD patterns with a fairly high
amplitude when 1-100 equiv of guests were added (Figure 1b).16 This
unique behavior was observed only in chiral epoxides with R-branched
aliphatic substituents (see SI for further discussion). Although the
following statement is based on observation and has no theoretical
basis, we have noticed that the sign of the first CE for the complex
CD spectra is the same as the sign of the anticipated ECCD.
With cis-disubstituted epoxy alcohols complexed with tweezer, P1
(assuming it also coordinates with the lone pair anti to the hydroxyl
bound P2) faces no steric bias since both R1 and R2 are hydrogen
atoms. The steric interaction between P2 and R3 would drive P2 away
from R3, leading to a clockwise twist of the two porphyrins relative to
each other (Figure 2), and hence a positive ECCD signal is expected
for (2S,3R) cis-disubstituted substrates. This was indeed observed
experimentally (11-14). It is instructive to note that 14 yields a strong
ECCD signal despite its fairly low optical purity (22% ee, see SI for
correlation of %ee with amplitude of ECCD).17
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(16) Similar ECCD signal was obtained for 5 in hexane, methylcyclohexane,
and isooctane while no CD was detected in benzene, toluene, CH3CN, and
CH2Cl2.
Next, we turned our attention to trisubstituted epoxy alcohols
(15-19), which upon complexation with Zn-TPFP-tz 1 resulted in
CD spectra that could be rationalized by the binding model depicted
in Figure 1a. For both 2,3,3 (R2 ) H) and 2,2,3 (R3 ) H) trisubstituted
substrates, P1 slides away from the bulky R1 group in a similar manner
as was described for trans-disubstituted substrates to minimize steric
(17) Substrates 11 (67% ee), 12 (56% ee), 13 (65% ee), and 21 (72% ee) with
low optical purity also rendered prominent ECCD.
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