Redox-triggered C-c coupling of alcohols and vinyl epoxides: Diastereo- and enantioselective formation of all-carbon quaternary centers via tert -(Hydroxy)-prenylation

Article abstract of DOI:10.1021/ja504625m

Iridium catalyzed primary alcohol oxidation triggers reductive C-O bond cleavage of isoprene oxide to form aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, a motif found in >2000 terpenoid natural products. Curtin-Hammett effects are exploited to enforce high levels of anti-diastereo- and enantioselectivity in the formation of an all-carbon quaternary center. The present redox-triggered carbonyl additions occur in the absence of stoichiometric byproducts, premetalated reagents, and discrete alcohol-to-aldehyde redox manipulations.

Full text of DOI:10.1021/ja504625m

Communication
pubs.acs.org/JACS
Redox-Triggered C−C Coupling of Alcohols and Vinyl Epoxides:
Diastereo- and Enantioselective Formation of All-Carbon
Quaternary Centers via tert-(Hydroxy)-Prenylation
Jiajie Feng, Victoria J. Garza, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: Iridium catalyzed primary alcohol oxidation
triggers reductive C−O bond cleavage of isoprene oxide
to form aldehyde-allyliridium pairs that combine to form
products of tert-(hydroxy)-prenylation, a motif found
in >2000 terpenoid natural products. Curtin−Hammett
effects are exploited to enforce high levels of anti-diastereo-
and enantioselectivity in the formation of an all-carbon
quaternary center. The present redox-triggered carbonyl
additions occur in the absence of stoichiometric by-
products, premetalated reagents, and discrete alcohol-to-
aldehyde redox manipulations.
ased on a pattern of reactivity wherein alcohol oxidation
B
triggers reductive C−C coupling,1 a suite of catalytic
enantioselective transformations for polyketide construction
were developed in our laboratory (alcohol C−H allylation,2
crotylation,3,4 and propargylation5). As illustrated in several
total syntheses, these merged “redox-construction” protocols
streamline polyketide construction, enabling the most concise
routes reported, to date, to members of several natural product
families.1 To access substructures evident in terpenoid natural
products, related protocols for alcohol C−H n-prenylation6a and
tert-prenylation6b were developed. Despite the ubiquity of the tert-
(hydroxy)-prenyl motif, which is found in over 2000 terpenoid
natural products, enantioselective carbonyl tert-(hydroxy)-
prenylation remains an unmet challenge (Figure 1).7,8 Here, we
disclose a catalytic protocol for direct regio-, diastereo-, and
enantioselective C−C coupling of primary alcohols and isoprene
oxide to form products of tert-(hydroxy)-prenylation, and related
aldehyde-isoprene oxide reductive couplings mediated by
isopropanol. These alcohol C−C couplings occur in the absence
of stoichiometric byproducts and represent the first enantio-
selective umpoled carbonyl allylations through the use of vinyl
epoxides.7−9
The prospect of utilizing vinyl epoxides in metal catalyzed
C−C couplings of primary alcohols is rendered uncertain
by competing epoxide ring opening to furnish products of
O-allylation,9−12 as well as the propensity of vinyl epoxides to
engage in metal catalyzed ring expansion.13 Remarkably,
exposure of p-bromobenzyl alcohol 1a to isoprene oxide 3a
in the presence of the chromatographically purified iridium−
SEGPHOS complex (R)-Ir-Ib in THF (0.5 M) at 60 °C led to
a promising 37% yield of the desired product of tert-(hydroxy)-
prenylation 4a as a single regioisomer with 2:1 anti-diastereo-
selectivity and 93% enantiomeric excess (Table 1, entry 1). Use of
Figure 1. The tert-(hydroxy)-prenyl motif is found in over 2000
terpenoid natural products, yet direct methods for its regio- and
stereoselective construction were hitherto unknown.
Received: May 8, 2014
Published: June 10, 2014
© 2014 American Chemical Society
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Table 1. Selected Optimization Experiments in the Iridium
Table 2. Regio-, Diastereo-, and Enantioselective Iridium
Catalyzed tert-(Hydroxy)-Prenylation of p-Bromobenzyl
Catalyzed tert-(Hydroxy)-Prenylation of Alcohols 1a−1i with
a
a
Alcohol 1a with Isoprene Oxide 3a
Isoprene Oxide 3a
a
b
Yields are of material isolated by silica gel chromatography. THF
c
d
e
(1.0 M). 3a (400 mol %). THF (0.33 M). 60 °C. See Supporting
Information for further details.
a
Yields are of material isolated by silica gel chromatography. Ir-Ia
Table 3. Regio-, Diastereo-, and Enantioselective Iridium
(ref 6b) and Ir-IIIa (ref 2a) are characterized by X-ray diffraction. See
Supporting Information for further details. K3PO4 was omitted. 48 h.
Catalyzed tert-(Hydroxy)-Prenylation of Aldehydes 2a−2i
b
c
a
with Isoprene Oxide 3a
K3PO4 (5 mol %) under these conditions improved conversion,
providing 4a in 90% yield with 4:1 anti-diastereoselectivity and 93%
enantiomeric excess (Table 1, entry 2). Although the reaction does
not proceed at ambient temperature, excellent conversion is
observed at 45 °C (Table 1, entries 3 and 4, respectively). Higher
temperatures erode conversion and enantiomeric enrichment
(Table 1, entry 5). At this stage, to identify optimal structural
features of the catalyst, a series of eight chromatographically purified
iridium complexes were evaluated (Table 1, entries 7−14). It
became evident that, to achieve optimal energetic partitioning
of the transient (E)- and (Z)-σ-allyliridium intermediates in the
transition state for aldehyde addition, use of a more electron-
deficient C,O-benzoate complex that embodies greater steric
demand is required. This ultimately led to the identification of
Ir-IVb, the (R)-Tol-BINAP modified C,O-benzoate complex
derived from 4-CN-3-NO2-benzoic acid, as the catalyst of
choice (Table 1, entry 7). Using Ir-IVb, adduct 4a was obtained
in 91% yield, 40:1 anti-diastereoselectivity, and 94% enantio-
meric excess.
Under optimized conditions that utilize Ir-IVb as the catalyst,
primary benzylic alcohols 1a−1c, allylic alcohols 1d−1f, and
aliphatic alcohols 1g−1i are converted to the corresponding
products of tert-(hydroxy)-prenylation 4a−4i (Table 2). Good
to excellent isolated yields were accompanied by uniformly high
levels of anti-diastereo- and enantioselectivity. Corresponding
reactions conducted from the aldehyde oxidation level were
achieved with isopropanol as a terminal reductant (Table 3).
Here, as shown in the tert-(hydroxy)-prenylation of aldehyde
a
b
Yields are of material isolated by silica gel chromatography. THF
c
d
e
f
g
(1.0 M). THF (0.33 M). 35 °C. THF (0.1 M). 60 °C. 70 °C.
See Supporting Information for further details.
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Scheme 1. Concentration Dependent anti-Diastereoselectivity As Illustrated in the Iridium Catalyzed tert-(Hydroxy)-
a
Prenylation of Aldehyde 2a with Isoprene Oxide 3a and General Catalytic Mechanism
a
Yields are of material isolated by silica gel chromatography.
2a (Scheme 1), anti-diastereoselectivity was found to increase
with decreasing concentration. This effect suggests a Curtin−
Hammett scenario is operative wherein the relative thermo-
dynamic stabilities of the (Z)- and (E)-σ-allyliridium intermediates
do not solely determine diastereoselectivity. Rather, rate-
determining carbonyl addition occurs more rapidly from the (E)-
σ-allyliridium intermediate, requiring lower concentrations to retard
the rate of carbonyl addition with respect to (E/Z)-isomerization
of the allyliridium intermediate, which is required to replenish
the (E)-σ-allyliridium intermediate from the unreacted (Z)-σ-
allyliridium isomer.14 This effect is especially pronounced in
reactions conducted from the aldehyde oxidation level, as the
delivers the product of tert-(hydroxy)-geranylation 5b in 94%
aldehyde concentration is higher throughout the course of the
yield, 40:1 anti-diastereoselectivity, and 87% enantiomeric
reaction, accelerating carbonyl addition. Concentration dependent
excess (eq 4).
kinetic resolution in the ionization of isoprene oxide 3a, a chiral
racemic material, can be excluded as recovered 3a displays low
levels of enantiomeric enrichment. Carbonyl addition by way of
the (E)-σ-allyliridium intermediate may be faster due to
minimization of dipole−dipole interactions. Reaction by way the
(Z)-σ-allyliridium intermediate may be slow due to internal
coordination of the hydroxyl group to iridium.
To further probe the scope of this process, the unprotected
malic acid derived diol 1j was reacted with isoprene oxide 3a.
As observed in related C−H allylations of glycols and higher
polyols,2f primary alcohol dehydrogenation is kinetically
preferred. Thus, using (R)-Ir-IVb and (S)-Ir-IVb as catalysts,
site-selective dehydrogenation enables tert-(hydroxy)-prenyl-
ation of 1j to form 4j and iso-4j, respectively, with excellent
levels of diastereoselectivity, as determined by 1H NMR
analysis (eqs 1 and 2).
Vinyl epoxides beyond isoprene oxide also participate in
redox-triggered C−C coupling. For example, the reaction of
butadiene oxide 3b with p-bromobenzyl alcohol 1a delivers the
product of (hydroxymethyl)-allylation 5a in 63% yield, 5:1 anti-
diastereoselectivity, and 94% enantiomeric excess (eq 3). The
reaction of myrcene oxide 3c15 with p-bromobenzyl alcohol 1a
In summary, we report the anti-diastereo- and enantio-
selective redox-triggered C−C coupling of vinyl epoxides and
alcohols to form products of carbonyl tert-(hydroxy)-
prenylation. This process enables formation of an all-carbon
quaternary center in the absence of stoichiometric byproducts
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Tanaka, J.; Hirashita, T.; Yamamura, H.; Kawai, M. J. Org. Chem. 2001,
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(9) For a recent review on vinyl epoxides in organic synthesis, see:
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to the >2000 terpenoid natural products incorporating the tert-
(hydroxy)-prenylation motif. Studies of this type are underway
and will reported in due course.
(10) For palladium catalyzed allylic alkylation with vinyl epoxides and
oxygen nucleophiles: (a) Trost, B. M.; McEachern, E. J.; Toste, F. D. J.
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(12) For selected recent examples of catalytic allylic alkylation with
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(a) Thies, S.; Kazmaier, U. Synlett 2010, 137. (b) Shaghafi, M. B.;
Grote, R. E.; Jarvo, E. R. Org. Lett. 2011, 13, 5188. (c) Liu, Z.; Feng,
X.; Du, H. Org. Lett. 2012, 14, 3154. (d) Zhang, Q.; Nguyen, H. M.
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(14) Such Curtin−Hammett effects are evident in the ruthenium
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McInturff, E. L.; Leung, J. C.; Krische, M. J. J. Am. Chem. Soc. 2011,
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for new compounds,
1
including scanned images of H and 13C NMR spectra. Single
crystal X-ray diffraction data for 4a-acetonide. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445), and the Center for Green Chemistry and
Catalysis are acknowledged for partial support of this research.
Yousef Okasheh is acknowledged for skillful technical
assistance.
(15) (a) Fauchet, V.; Arreguy-San Miguel, B.; Taran, M.; Delmond,
B. Synth. Commun. 1993, 23, 2503. (b) Lobermann, F.; Weisheit, L.;
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