Regio-and enantioselective catalytic monoepoxidation of conjugated dienes: Synthesis of chiral allylic cis-epoxides

Article abstract of DOI:10.1021/acs.orglett.5b00281

Ti(IV)-salan 4 catalyzes the diastereo-and enantioselective monoepoxidation of conjugated dienes using 30% H₂O₂ at rt or below even in the presence of other olefins and adjacent stereocenters. Its enantiomer, ent-4, provides access to the opposite diastereomer or enantiomer. The resultant chiral allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures present in many bioactive natural products. The epoxidation is highly specific for Z-olefins. For 1-acyl(silyl)oxypenta-2,4-dienes, epoxidation of the distal olefin is generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid, and other directed epoxidations of hydroxylated dienes.

Full text of DOI:10.1021/acs.orglett.5b00281

Letter
pubs.acs.org/OrgLett
Regio- and Enantioselective Catalytic Monoepoxidation of
Conjugated Dienes: Synthesis of Chiral Allylic cis-Epoxides
Jawahar L. Jat, Saroj Ranjan De, Ganesh Kumar, Adeniyi Michael Adebesin, Shyam K. Gandham,
and John R. Falck*
Division of Chemistry, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United
States
S
* Supporting Information
ABSTRACT: Ti(IV)-salan 4 catalyzes the diastereo- and
enantioselective monoepoxidation of conjugated dienes using
30% H2O2 at rt or below even in the presence of other olefins
and adjacent stereocenters. Its enantiomer, ent-4, provides
access to the opposite diastereomer or enantiomer. The
resultant chiral allylic epoxides, and the triols derived from them, are versatile synthetic intermediates as well as substructures
present in many bioactive natural products. The epoxidation is highly specific for Z-olefins. For 1-acyl(silyl)oxypenta-2,4-dienes,
epoxidation of the distal olefin is generally favored in contrast to the adjacent regioselectivity characteristic of Sharpless, peracid,
and other directed epoxidations of hydroxylated dienes.
llylic epoxides display a facile and diverse reaction manifold
that arises from the juxtaposition of the inherently strained
A
three-membered epoxide with an olefinic π-system.1 The rate of
nucleophilic addition, for instance, can be up to 104 times faster
than that for an isolated epoxide, proceeding via SN2 or SN2′
pathways.2 Due to their considerable synthetic appeal,1,3 a variety
of procedures have been introduced for the preparation of allylic
epoxides.1,4 One of the most popular and economic approaches
is catalytic monoepoxidation of 1,3-conjugated dienes,1a,5
including a smaller subset of asymmetric versions.6 However,
utilization of most extant protocols is constrained by one or more
restrictions including modest yields,5d,7 inadequate enantiose-
lectivity,8 polyoxidation,5c stereoisomerization,5e poor cis-/trans-
discrimination,5f,g and/or decomposition of the product under
the reaction conditions.5a A noteworthy exception is the Shi
fructose-based dioxirane reagents,6b,9 although the strict reaction
regimen and catalyst availability are potential deterrences to its
use.
Figure 1. Representative allylic epoxyol and triol natural products.
development of an operationally simple, catalytic, distal-selective
epoxidation of conjugated buta-1,3-dienes and penta-2,4-dien-1-
ols and to validate the utility of this method as a key
transformation in a biogenetically inspired17 total synthesis18 of
the potent antimitotic marine natural products nigricanosides A/
B19 and clinically useful mimetics.
An assortment of catalysts and oxidants were examined for
distal-selective epoxidation (Table 1). Diene 1 (R = H) was
selected as the model substrate because (i) it is readily prepared
in high stereochemical purity via multigram incubation14,20 of
linoleic acid with commercial soybean lipoxygenase, (ii) both
diastereomeric distal epoxide diastereomers 2 and 3 are
available,21 and (iii) it offers a stereochemical point of reference
and mechanistic probe of the reaction course.22 Initially,
epoxidations were conducted with the C(13)-hydroxyl un-
protected; in many cases, however, complex product mixtures
were obtained. Hence, most subsequent studies were conducted
with the hydroxyl blocked as the acetate, i.e., 1 (R = Ac).
The application of the catalytic monoepoxidation method to
the special case of 2,4-pentadiene-1-ols has been an area of long-
standing interest.10 The resultant allylic epoxyols are versatile
synthetic building blocks1 as well as key subunits,11 along with
their chemically or enzymatically derived triols, in numerous
bioactive natural products (Figure 1).12 Functional group
directed epoxidations, e.g., Sharpless,13 peracid,14 and others,15
have played a prominent role in achieving an acceptable level of
regio- and stereocontrol for substrates containing the 2,4-
pentadien-1-ol moiety. In most instances, however, epoxidation
occurs at the olefin adjacent to the hydroxyl and not the distal
olefin (eq 1).13−16 Our objective, consequently, was the
Received: January 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00281
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Letter
inductive deactivation with these reagents has been observed
previously.6,9 Titanium, sequestered within the salan-type ligands
pioneered by Katsuki and colleagues,34a afforded both high yield
and excellent control of diastereoselectivity (entry m). The yield
and selectivity toward erythro-epoxide 2 was further boosted
using (R,R)-Ti(salan) 4, created by introduction of an ortho-
methoxy onto the pendant phenyl (entry n).34b
Table 1. Survey of Catalytic Systems for Asymmetric, Distal-
Selective Epoxidation of 1
When treating 1 (R = Ac) with 4 and 30% H2O2, yields of 2
were optimum in CH2Cl2 (92%) and trended progressively lower
in THF (75%), Cl(CH2)2Cl (70%), CH3CN (65%), EtOAc
(60%), toluene (60%), DME (55%), and CH3NO2 (<10%).
Reaction rates were faster with 50% or 90% H2O2, but 30% H2O2
(1.5−2 equiv) was our preference for reasons of safety, cost, and
availability. Attempts to accelerate the rate by using a large excess
of 30% H2O2 (>6 equiv) were usually accompanied by minor, yet
noticeable, amounts (5−10%) of triol from hydrolysis of 2. For
convenience, most reactions with 4 were conducted at or near
room temperature.
To elucidate further the scope of monoepoxidation mediated
by 4 (and its enantiomer, ent-4), a panel of representative 2,4-
pentadien-1-ols and buta-1,3-dienes were oxidized under the
standard reaction conditions (Table 2). As with many other
reagents, epoxidation of 1 (R = H) with an unprotected hydroxyl
eroded the yield and diastereoselectivity (entry 1); however, the
regioselectivity was still entirely distal in sharp contrast to the
adjacent selectivity characteristic of Sharpless-type processes.
The corresponding benzyl ether 5, benzoate 7, pivaloate 9,
carbonate 11, and silyl ether 13, on the other hand, were all well
behaved and afforded the anticipated distal, erythro-allylic
epoxides in good yields and dr (entries 2, 3, 4, 5, and 6,
respectively). The nature of the hydroxyl protecting group (i.e.,
ether, ester, silyl ether) made no difference in the stereochemical
outcome (cf., Table 1, entries k and l). Despite having an
additional cis-olefin, linolenate-derived trienes 15 and 17
preferentially furnished 16 (entry 7) and 18 (entry 8),
respectively, and only minor amounts of additional epoxidation
at the Δ15,16-olefin, i.e., bis-epoxide, were detected. Significantly,
epoxidation of 17 mediated by ent-4 gave rise to allylic epoxide
19 (entry 9), the threo-diastereomer of 18, demonstrating that
the existing chiral center adjacent to the diene does not influence
epoxidation enantioselectivity. Triene 20 (entry 10), whose
olefinic pattern differs from 17, was also suitable as was the short
chain diene 22 from which 23 (entry 11) was obtained in
excellent yield and dr. An increase in the substitution level at the
acyloxy carbon, e.g., 24 → 25 (entry 12), had no effect on the
transformation, but it did for the distal olefin, e.g., 26 → 27 (entry
13), as revealed by a small decrease in the dr. For dienes 28, 30,
and 32 without an existing stereocenter, it was reassuring to find
epoxides 29 (entry 14), 31 (entry 15), and 33 (entry 16) were
generated with a high level of enantioselectivity. Exposure of
cholesta-4,6-diene 34 to ent-4 and 30% H2O2 under the usual
conditions culminated in α-epoxide 35 as the sole product (entry
17), yet 34 was completely immune to 4 even after prolonged
reaction times and was recovered unchanged. The epoxidation of
36, the methyl ester of natural conjugated linoleic acid (CLA),
was instructive (entry 18). Even absent the inductive influence of
an allylic oxygen substituent, epoxidation of the cis-olefin to give
37 predominated. While it might be tempting to attribute the
distal regioselectivity in the preceding examples to an inductive
deactivation of the adjacent olefin by the oxygen substituent, thus
redirecting epoxidation to the distal olefin, this example cogently
dispels this conjecture. This is an especially challenging example
since there is no functional group located closely enough to guide
a
Epoxidation procedures: entry a (ref 23), entry b (ref 24), entry c (ref
25), entry d (ref 26), entry e (ref 27), entry f (ref 28), entry g (ref 29),
entry h (ref 30), entry i (ref 32), entry j (ref 33), entry k (ref 6a), entry
b
l (ref 9), entries m and n (ref 34). Combined, isolated yield.
c
d
Determined by chiral HPLC. na = not applicable or not available.
Mainly recovered diene. Obtained as a 1:1 mixture with the 11,12-
e
f
monoepoxide regioisomers.
Many well established transition metal epoxidation cata-
lysts23,24 provided little, if any, of the desired epoxide 2 or 3
(entries a and b). Despite their utility with styrenes, chiral
complexes of Zr (entry c),25 Mo (entry d),26 and Fe (entry e)27
proved ineffective with 1 as the substrate. Ruthenium (entry f),28
tungsten (entry g),29 and bis-iron (entry h)30 salts displayed
more encouraging distal regioselectivities and, in some cases,
afforded good yields of distal epoxides. While a variety of reaction
conditions were evaluated using these catalysts, mixtures of 2 and
3 were always obtained;31 evidently, the chiral center had scant
influence upon the diastereoselectivities. Manganese (entry (i)32
and iron (entry j)33 coordinated by chiral tetradentate N2Py2
platforms were likewise marginally diastereoselective, but did
give acceptable yields. The Shi reagent (entry k)6a led to a
complex product mixture consisting of 2 and 3 (3:2 ratio) and an
equal amount of the 11,12-monoepoxides (3:2 ratio) when 1 was
protected as the silyl ether. The second generation oxazolidinone
reagent (entry l),9 developed by Shi for diene applications,
performed much better when applied to 1 (R = Ac) and afforded
only 2 and 3 (4:1 ratio). This is likely due, in part, to the inductive
deactivation of the adjacent olefin by the acetyloxy group;
B
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Letter
factors. In the case of 1 (R = H), H-bonding between the free
alcohol and peroxo-Ti intermediate could explain the erosion of
diastereoselectivity.
Table 2. Scope of Asymmetric, Monoepoxidation of
Representative 1,3-Dienes by Ti(salan) 4 and ent-4a
In summary, the Ti(IV)-salan catalyst 4 in combination with
environmentally friendly 30% H2O2 is an efficient, room
temperature catalytic system for the diastereo- and enantiose-
lective monoepoxidation of conjugated dienes even in the
presence of other olefins. Notably, the regioselectivity in some
systems, e.g., 2,4-pentadien-1-ols, is complementary to that
achievable using Sharpless and other directed epoxidations.
There is a strong preference for Z- vs E-olefins. Progress in the
development of a catalyst suitable for E,E-dienes will be reported
elsewhere.
ASSOCIATED CONTENT
* Supporting Information
The preparation and spectral characterization (1H/13C NMR) of
all new compounds and HPLC chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: j.falck@utsouthwestern.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by the Robert A. Welch Foundation
(I-0011) and USPHS NIH (HL111392, DK38226, HL034300).
Dr. Elaine R. Fogel (Tiferet Israel) and Prof. Mats Hamberg
(Karolinska Institutet) are thanked for guidance. Analyses
provided by the Shimadzu Center for Advanced Analytical
Chemistry at Univ. Texas-Arlington. Dedicated to the
accomplishments of Prof. Tsutomu Katsuki.
a
Reaction conditions: Ti(OiPr)4 (5 mol %), 4 or ent-4 (6 mol %), 30%
b
c
aq H2O2 (1.5−2 equiv), CH2Cl2, rt. Isolated yield. Determined by
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■
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