Chemo- and diastereoselective tandem dual oxidation of B(pin)-substituted allylic alcohols: Synthesis of B(pin)-substituted epoxy alcohols, 2-keto-anti-1,3-diols and dihydroxy-tetrahydrofuran-3-ones

Article abstract of DOI:10.1039/c3sc51616d

A novel retrosynthetic disconnection for the stereoselective preparation of α,α′-dioxygenated carbonyl compounds is disclosed. Herein we report a method to divert the oxidation of vinyl boronate esters from the B-C bond to the C=C bond, resulting in a new stereoselective class of oxidation products from vinyl boronate esters. Treatment of 2-B(pin)-substituted allylic alcohols with catalytic OV(acac)₂ and TBHP resulted in a highly chemo- and diastereoselective directed epoxidation to provide B(pin)-substituted epoxy alcohols (55-96% yield, dr > 20:1). In the case of B(pin)-substituted bis-allylic alcohols, highly substituted bis-epoxy alcohols with five contiguous stereocenters were obtained (dr > 20:1). Furthermore, the difference in reactivity between allylic alcohols and 2-B(pin)-substituted allylic alcohols towards epoxidation enabled the selective oxidation of the allylic alcohol in the presence of TBHP and VO(acac)₂. The reactivity difference between the two allylic alcohols suggests C=C B(pin) to be more electron deficient than C=C(alkyl). The B(pin)-substituted epoxy alcohols are also useful synthetic intermediates. Tandem vanadium catalyzed epoxidation of the 2-B(pin)-substituted allylic and bis-allylic alcohols with excess TBHP generated the intermediate epoxides and bis-epoxides, respectively. Subsequent addition of NaOH resulted in the oxidation of the B-C bond of the B(pin)-substituted epoxides to afford 2-keto-anti-1,3-diols (60-83% yield) and epoxide-substituted 2-keto-anti-1,3-diols (60-78% yield, dr > 20:1). The latter underwent a novel facile acid-mediated cyclization to furnish fully substituted dihydroxy-tetrahydrofuran-3-ones (65-91% yield, dr > 20:1). Such compounds are difficult to efficiently access via conventional synthetic methods.

Full text of DOI:10.1039/c3sc51616d

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EDGE ARTICLE
Chemo- and diastereoselective tandem dual oxidation
of B(pin)-substituted allylic alcohols: synthesis of B(pin)-
substituted epoxy alcohols, 2-keto-anti-1,3-diols and
dihydroxy-tetrahydrofuran-3-ones†
Cite this: Chem. Sci., 2013, 4, 3946
*
Nusrah Hussain, Mahmud M. Hussain, Patrick J. Carroll and Patrick J. Walsh
A novel retrosynthetic disconnection for the stereoselective preparation of a,a0-dioxygenated carbonyl
compounds is disclosed. Herein we report a method to divert the oxidation of vinyl boronate esters
from the B–C bond to the C]C bond, resulting in a new stereoselective class of oxidation products from
vinyl boronate esters. Treatment of 2-B(pin)-substituted allylic alcohols with catalytic OV(acac)2 and
TBHP resulted in a highly chemo- and diastereoselective directed epoxidation to provide B(pin)-
substituted epoxy alcohols (55–96% yield, dr > 20 : 1). In the case of B(pin)-substituted bis-allylic
alcohols, highly substituted bis-epoxy alcohols with five contiguous stereocenters were obtained
(dr > 20 : 1). Furthermore, the difference in reactivity between allylic alcohols and 2-B(pin)-substituted
allylic alcohols towards epoxidation enabled the selective oxidation of the allylic alcohol in the presence
of TBHP and VO(acac)2. The reactivity difference between the two allylic alcohols suggests C]CB(pin) to
be more electron deficient than C]C(alkyl). The B(pin)-substituted epoxy alcohols are also useful
synthetic intermediates. Tandem vanadium catalyzed epoxidation of the 2-B(pin)-substituted allylic and
bis-allylic alcohols with excess TBHP generated the intermediate epoxides and bis-epoxides, respectively.
Subsequent addition of NaOH resulted in the oxidation of the B–C bond of the B(pin)-substituted
epoxides to afford 2-keto-anti-1,3-diols (60–83% yield) and epoxide-substituted 2-keto-anti-1,3-diols
(60–78% yield, dr > 20 : 1). The latter underwent a novel facile acid-mediated cyclization to furnish fully
substituted dihydroxy-tetrahydrofuran-3-ones (65–91% yield, dr > 20 : 1). Such compounds are difficult
to efficiently access via conventional synthetic methods.
Received 9th June 2013
Accepted 4th July 2013
DOI: 10.1039/c3sc51616d
www.rsc.org/chemicalscience
1 Introduction
The diverse reactivity of the B–C bond has led to innumerable
applications in synthetic organic chemistry.1–3 One of the most
appreciated transformations of the B–C bond is its oxidation to
afford alcohols.4,5 In the case of vinyl boron derivatives, the
same oxidation affords ketones. In contrast to these oxidations,
there are very few examples demonstrating a reversal of che-
moselectivity in the oxidation of vinyl boron species leading to
the epoxidation of C]C. One strategy to reverse the oxidation
chemoselectivity of vinylboronates is to block oxidation at
boron by employing 4-coordinate boron species. Brauer and
Pawelke6 disclosed the epoxidation and oxidative cleavage of
(Me3N)B(CF3)2(CF]CF2) with ozone and dioxygen (Scheme 1A).
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104-6323, USA. E-mail:
pwalsh@sas.upenn.edu; Fax: +1 2155736743; Tel: +1 2155732875
† Electronic supplementary information (ESI) available: Data for new compounds,
experimental procedures, copies of 1H and 13C NMR spectra. CCDC
791005–791007 and 933549. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3sc51616d
Scheme 1 Oxidation of four-coordinate alkenyl boron derivatives.
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In 2003 Molander and Ribagorda7 demonstrated that vinyl tri-
uoroborates3 underwent epoxidation with DMDO to provide
epoxytriuoroborates (Scheme 1B). Uno, Gillis, and Burke8
showed that vinyl N-methyliminodiacetic acid (MIDA) boro-
nates also withstand epoxidation conditions with m-CPBA to
furnish the terminal epoxide (Scheme 1C). More recently, Burke
and Li9 extended this methodology to the highly diaster-
eoselective epoxidation of internal vinyl boronates bearing an
enantioenriched PIDA chiral auxiliary (Scheme 1D).
The results of Pawelke,6 Molander,7 Burke,8,9 and their co-
workers raise several interesting questions. These include: (1) is
the chemoselective epoxidation of alkenyl boron substrates
limited to 4-coordinate boron? and (2) Can the resulting boron-
substituted epoxides be useful intermediates in organic
synthesis? During our investigation into these questions, Pie-
truszka and co-workers10 reported that a 3-coordinate vinyl
boronate ester with a bulky chiral auxiliary could be epoxidized
(Scheme 2). Poor diastereoselectivity (<2 : 1) and low yields
(40–52%) were obtained with achiral epoxidizing agents such as
m-CPBA and VO(acac)2/TBHP. Use of 2 equiv. Ti(O-i-Pr)4, 2.4
equiv. (+)- or (ꢀ)-DET, and TBHP resulted in high diastereo-
meric ratios and moderate yields (46–65%) of the resulting
epoxy alcohols.10
En route to the current article, we reported the synthesis of
2-B(pin)-substituted allylic alcohols.11 Under basic conditions,
these intermediates underwent chemoselective oxidation of the
B–C bond in the presence of TBHP and base (Scheme 3A).11
Herein, we disclose an approach to reverse the chemoselectivity
in the oxidation of vinylboronate esters via a highly chemo- and
diastereoselective vanadium catalyzed epoxidation of readily
available 2-B(pin)-substituted allylic alcohols (Scheme 3B). We
probe, for the rst time, the relative rates of epoxidation of
allylic alcohols vs. B(pin)-substituted allylic alcohols using
substrates possessing two allylic double bonds (Scheme 3C and
D). A sequential diastereoselective epoxidation of the vinyl-
boronate ester followed by B–C bond oxidation to provide
2-keto-anti-1,3-diols is introduced (Scheme 3B). When alcohols
with both allylic and 2-B(pin)-substituted allylic double bonds
were subjected to the tandem oxidation, bis-epoxide interme-
diates generated via pathway E yielded epoxy-substituted 2-keto-
anti-1,3-diols with high diastereoselectivity (via F). Our work
here provides novel oxidation chemistry of vinyl boronate
esters, which can now be viewed as precursors to both ketones
and a-hydroxy ketones.12,13 Finally, we describe an acid-medi-
ated cyclization of four epoxide-substituted 2-keto-anti-1,3-diols
(synthesized via F, Scheme 3G) to provide fully substituted
dihydroxy-tetrahydrofuran-3-ones as single diastereomers. A
portion of this work has been previously communicated.12
Scheme 3 Known B–C bond oxidation of B(pin)-substituted allylic alcohols (A)
and a new class of stereoselective oxidation products via chemo- and diaster-
eoselective epoxidation or dual epoxidation/oxidation methodology (B); appli-
cation of these reactions to unsymmetrical dienols (C–F); an acid-mediated
cyclization to dihydroxy-tetrahydrofuran-3-ones (G).
2 Results and discussion
2.1 Synthesis of substrates
We recently reported11,12,14 a straightforward one-pot synthesis of
B(pin)-substituted allylic alcohols via functional group tolerant
1-alkenyl-1,1-bimetallic reagents15 (Scheme 4). Employing
air-stable B(pin)-substituted alkynes,11,14,16,17 hydroboration with
Scheme 2 Pietruszka and co-workers' epoxidation of vinyl boronate esters with
stoichiometric Sharpless–Katsuki catalyst.
Scheme 4 Generation and trapping of 1-alkenyl-1,1-bimetallic intermediates
with aldehydes.
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dicyclohexyl borane affords the intermediate 1,1-diboro
alkene.18 The Cy2B–C bond undergoes transmetallation
signicantly faster than the (pin)B–C bond,19,20 because in the
latter the p-orbital on boron is partially lled by resonance
donation from the adjacent oxygen lone pairs. Thus, trans-
metallation of the 1,1-diboro alkene with dialkylzinc reagents
leads exclusively to the (E)-1-alkenyl-1,1-heterobimetallic
intermediate, where the Zn–C bond exhibits much greater
reactivity than the (pin)B–C bond.11 Trapping the hetero-
bimetallics with aldehydes and work-up provides the 2-B(pin)-
substituted allylic alcohols in 55–92% yield (Scheme 4).12 The
additions in Scheme 4 work well with various aliphatic
and aromatic aldehydes as well as with diverse a,b-unsatu-
rated aldehydes. Table 1 contains new bis-allylic alcohol
substrates that were prepared for this study. It should be
noted that no conjugate addition products were observed.
Cinnamaldehyde derivatives typically gave excellent yields
(84–92%, entries 1, 2, 7 and 8) whereas aliphatic and cyclic
a,b-unsaturated aldehydes gave slightly lower yields (56–71%,
entries 4–6). The bis-allylic alcohol substrates in Table 1 were
all synthesized on the gram scale.
Scheme
5
Asymmetric addition of
a
1-alkenyl-1,1-heterobimetallic to
benzaldehyde.
2.2 Enantioselective addition of 1-alkenyl-1,1-heterobimetallic
reagents to aldehydes
Addition of 1,1-heterobimetallic borozinc intermediates to
prochiral aldehydes in the presence of enantioenriched cata-
lysts is expected to lead to optically active 2-B(pin)-substituted
allylic alcohols. We have previously demonstrated the utility
and versatility of these building blocks in a variety of highly
stereoselective transformations.11,12,14,17,21 Having developed a
robust method for alkenyl heterobimetallic additions to alde-
hydes, we next sought to introduce an asymmetric variant of
this reaction, as outlined below (Scheme 5).
b-Amino alcohols form highly enantioselective catalysts in
asymmetric additions of organozinc reagents to prochiral
aldehydes.22 One of the premier amino alcohol proligands is
Nugent's 2-(S)-(ꢀ)-3-exo-(morpholino)isoborneol [(ꢀ)-MIB] L1
(Table 2).23–25 In the presence of catalytic amounts of MIB,
organozinc reagents have been employed in the highly enan-
tioselective alkylation,23,24 vinylation,26–28 ethoxy vinylation,29
arylation,30 and heteroarylation31 of carbonyl compounds. We,
Table 1 Synthesis of 2-B(pin)-substituted bis-allylic alcohols
Entry
1
Aldehyde
Allylic alcohol
Yield (%)ab
92
1k
1l
Table 2 Enantioselective addition of a 1-alkenyl-1,1-heterobimetallic reagent to
2
3
4
5
6
7
84
60
67
56
71
92
benzaldehyde
1m
1n
1o
1p
1q
8
1r
92
a
Addition of aldehyde at ꢀ20 ꢁC, using 10 mol% L*. b Slow addition of
c
the aldehyde over 30 min at ꢀ30 ꢁC. Ligands screened with titanium
a
Isolated yields. b All substrates synthesized on the gram scale.
tetraisopropoxide.
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therefore, initiated our search for an enantioselective catalyst
for alkenyl borozinc heterobimetallic addition to aldehydes by
screening (ꢀ)-MIB and several other amino alcohols known to
afford high stereoinduction in carbonyl addition reactions.
Following hydroboration of the B(pin) alkyne (ALK-1) and
transmetallation to zinc (Scheme 5), the bimetallic intermediate
was added to benzaldehyde in the presence of 10 mol% (ꢀ)-MIB
at ꢀ20 ꢁC. Aer work-up, the 2-B(pin)-allylic alcohol 1j was
isolated in 65% yield with 62% ee (Table 2, entry 1). Slow
addition of the aldehyde over 30 min improved the product ee to
70% (entry 2). The low enantioselectivities in these additions
Scheme 6 Chemo- and diastereoselective epoxidation of B(pin)-substituted
allylic alcohols.
are surprising, because the MIB-based organozinc catalyst was that the chemoselectivity of the oxidation could be redir-
generally promotes the vinylation of benzaldehyde derivatives ected to favor epoxidation by employing transition metal-based
with >90% enantioselectivity. Given that B(pin)-substituted catalysts.
ꢁ
vinyl additions occur readily at ꢀ20 C in the absence of cata-
Optimization of the reaction parameters (catalyst, solvent,
lyst, and that the enantioselectivity was improved at higher temperature, stoichiometry, rate of addition, etc.) was per-
catalyst loading (80–82% ee with >40 mol% MIB), we speculate a formed for the OV(acac)2-catalyzed36 epoxidation of 2-B(pin)-
fast background reaction was responsible for the poor stereo- substituted allylic alcohols. The details are summarized in our
induction. Based on this hypothesis, we examined additional initial communication.12 In the presence of 10 mol% of OV-
catalysts in the addition of heterobimetallic reagents to (acac)2 and 3 equiv. of TBHP at ꢀ20 ꢁC in dichloromethane, the
benzaldehyde.
2-B(pin)-substituted allylic alcohols (1b–h) were rapidly con-
Ephedrine based amino alcohol ligands have been used in verted to 2-B(pin)-substituted epoxy alcohols (2b–h) as single
asymmetric vinylations of aldehydes to give allylic alcohols in diastereomers by 1H NMR spectroscopy (Scheme 6). Work-up
high enantioselectivity.20,32 Employing 10 mol% L2–L4, was performed by concentrating the reaction mixture under
however, imparted low enantioselectivities (entries 3–5). Next, reduced pressure and rapid purication on silica gel to furnish
we investigated L5, a binaphtho-azepine based amino alcohol the B(pin)-substituted epoxy alcohols as single diastereomers,
developed by Chan and co-workers for asymmetric alkynylation albeit in low yields (typically 30–40%). It was soon realized that
of aldehydes.33 In the presence of 10 mol% L5, the product was these 3-coordinate boron-substituted oxiranes readily decom-
obtained in 42% ee (entry 6). Ligand L6 bearing a tertiary pose in the presence of trace acid or Lewis acidic silica gel under
34
`
alcohol moiety, synthesized by Pericas and co-workers and air. Fortunately, the crude products were very clean and
known to form a highly enantioselective catalyst, generated the required only ltration through a small pad of silica gel or Celite
B(pin)-substituted allylic alcohol in 82% ee. Unfortunately the to remove the by-products.
best yield we could obtain at this ee was 50%. We nally
2.3.1 Substrate scope of the epoxidation of B(pin)-
investigated a class of bis-sulfonamides, L7–L9, which are substituted allylic alcohols. With the optimized conditions in
known to form highly enantioselective catalysts with organozinc hand, the scope of the epoxidation of B(pin)-substituted allylic
reagents in the presence of titanium tetraisopropoxide.35 In the alcohols was examined (Scheme 6). As anticipated from the
presence of 10 mol% of bis-sulfonamides L7–L9, 1.2 equiv. of results above, the B(pin)-substituted epoxides readily decom-
Ti(O-i-Pr)4 and 1.5 equiv. of Me2Zn, the resulting bis-sulfona- pose even when rapidly chromatographed on silica gel. To
mido-based catalysts failed to provide good enantioselectivities maximize the epoxide yields, upon consumption of the B(pin)-
(entries 8–10).
substituted allylic alcohols (as judged by TLC), the reaction
`
With promising results obtained with (ꢀ)-MIB and Pericas' mixtures were concentrated and the crude products quickly
ligand (entries 1, 2 and 7, Table 2), we attempted to further ltered through a pad of silica gel or Celite. This method
optimize several reaction parameters such as solvent (toluene, provided the epoxides in >90% purity (Scheme 6). In several
CH2Cl2, Et2O and hexanes) and nature of the alkyl zinc reagents. cases the allylic alcohol was converted to the epoxide product
Despite signicant effort, higher enantioselectivities and better without noticeable by-product formation (1H NMR), facilitating
yields were not obtained. Based on these results, we chose to isolation and purication of the B(pin)-substituted epoxides.12
proceed with the development of the methods outlined herein The anti-relationship between the hydroxyl and epoxide is
with racemic 2-B(pin)-substituted allylic alcohols.
expected due to minimization of A1,2-strain in the directed
diastereomeric epoxidation transition states.37,38 The predicted
relative stereochemistry was conrmed by single crystal X-ray
analysis of 2d (R1 ¼ CH2CH2Ph, R2 ¼ tBu).
2.3 Chemoselective epoxidation of vinyl boronate esters
With a series of racemic B(pin)-substituted allylic alcohol
2.3.2 Bis-epoxidation of B(pin)-substituted bis-allylic alco-
substrates prepared, we next focused on the chemoselective hols. Bis-epoxidation of dienols serves as a route to poly-
oxidation of vinyl boronate esters. As mentioned in the Intro- oxygenated compounds. With this in mind, we examined the
duction, we had previously shown that treatment of the inter- epoxidation of B(pin)-substituted bis-allylic alcohols using
mediate allylic zinc alkoxides with TBHP resulted in oxidation similar conditions as in Scheme 6. The results are depicted in
of the B–C bond to furnish a-hydroxy ketones.11 Our hypothesis Table 3. Thus, employing 10 mol% OV(acac)2 and 3 equiv. of
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Table 3 Chemo- and diastereoselective epoxidation of B(pin)-substituted bis-
vinyl groups in the bis-allylic alcohols 1k–q. Vinyl epoxy alco-
hols are versatile synthetic intermediates and have been widely
used in the synthesis of natural products, such as exo- and endo-
brevicomin,42 the anticancer agent EBC-23 found in Australian
tropical rainforests,43 isoaspinonene,44 and the potent immu-
nosuppressant antibiotic FK506.45
allylic alcohols
We hypothesized that the electrophilic nature of the oxova-
nadium(V) peroxide intermediate46 would enable the catalyst to
differentiate between the two vinyl groups based on electronics,
favoring epoxidation of the more electron rich vinyl group.
Despite the lower electronegativity of boron relative to carbon,
the B(pin) group was anticipated to act as a p-acid and remove
electron density from the double bond. Furthermore, the large
size of B(pin) is anticipated to slow epoxidation proximate to
boron. To explore our hypothesis, the relative barriers for
epoxidation of model alkenes bearing methyl and boron groups
were computed at the B3LYP/6-31G(d)47 level in the gas phase
and at the (M06-2X/6-311G(d,p))48,49 level in dichloromethane
(CPCM; UFF).50 These preliminary calculations indicate that the
epoxidation at the methyl-substituted alkene is more favorable
than the epoxidation at the boron-substituted alkene (see ESI†
for details). Consistent with the computational study, subject-
ing the bis-allylic alcohol 1k to 1.0 equiv. of TBHP in the pres-
ence of 10 mol% OV(acac)2 resulted in the chemoselective
oxidation of the C]C(alkyl) bond to afford the vinyl-B(pin)
substituted epoxy alcohol 3k with high diastereoselectivity
(Scheme 7, path a). No epoxidation of the C]CB(pin) bond was
observed. Increasing the amount of TBHP to 1.5 equiv. led to a
mixture of mono-epoxide 3k and bis-epoxide 2k. As outlined
above, further increasing the TBHP to 3.0 equiv. yielded exclu-
sively the bis-epoxide product 2k. Our optimal conditions
entailed slow addition of TBHP over 30 min using a syringe
pump to a solution of bis-allylic alcohol 1k and 10 mol%
a
b
Yields aer chromatographic purication. Reaction took 2 h for
completion. Yield determined by 1H NMR analysis of crude mixture
with internal standard CH2Br2; no chromatographic purication was
necessary.
c
TBHP at 0 ꢁC smoothly epoxidized B(pin)-substituted bis-allylic OV(acac)2 in dichloromethane solvent at 0 ꢁC. The reaction
alcohols to the corresponding B(pin)-substituted bis-epoxy required 40–60 min to reach completion.
alcohols. It is noteworthy that this bis-epoxidation generates
four new stereocenters and furnishes novel bis-epoxides in good
yields and excellent diastereoselectivity (dr > 20 : 1).39 We chose
a,b-unsaturated aldehydes with a-substituents that would lead
to a-substituted allylic alcohols (Table 3). It is known that
epoxidation of allylic alcohols lacking either A1,2 or A1,3 strain
leads to little or no diastereoselectivity.37,38,40,41 In fact, vana-
dium-catalyzed epoxidation of bis-allylic alcohol 1r (Table 1,
entry 8) gave a mixture of diastereomers (1.4 : 1) due to lack of
either A1,2 or A1,3 strain in the diastereomeric epoxidation
transition states. In contrast, the bis-epoxidations in Table 3 led
to single diastereomers in each case (1H NMR). The bis-epoxi-
dation reactions typically required 30 min to reach completion
with the exception of 1m, which required 2 h. The bis-epoxides
were obtained in 69–90% yield despite the purication chal-
lenges (Table 3).
2.3.3 Chemoselective
mono-epoxidation
of
B(pin)-
substituted bis-allylic alcohols. Chemoselectivity is one of the
most important challenges in synthetic organic chemistry. The
successful epoxidation of both the vinyl groups in B(pin)-
substituted bis-allylic alcohols positioned us to probe the che-
Scheme
7
Chemo-, diastereo- and regioselective epoxidation of B(pin)-
moselectivity in the vanadium-catalyzed epoxidation of the two substituted bis-allylic alcohols.
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Table 4 Chemo-, diastereo- and regioselective mono-epoxidation of bis-allylic
alcohols
Scheme 8 Chemoselective epoxidation at the vinyl boronate ester moiety of
a-bromo-vinyl substituted B(pin) bis-allylic alcohol.
redirect the oxidant towards the vinyl boronate ester moiety. We
envisioned that an electron decient vinyl group would steer the
reactivity toward the vinyl boronate ester p-system. Preliminary
calculations, performed as outlined above, were carried out to
predict the relative barriers for epoxidation of model alkenes
bearing the boro and bromo groups. The calculations indicated
that epoxidation at the boron-substituted alkene is more
favorable than epoxidation at the bromo-substituted alkene (see
ESI† for details). Therefore, 1q (Table 1, entry 7) was treated
with 3 equiv. of TBHP in the presence of catalytic OV(acac)2. The
reaction went to completion with the formation of 4q in 62%
isolated yield as a single diastereomer (Scheme 8).39
With reliable routes to form the B(pin)-substituted epoxides,
we then focused on the development of methods for stereo-
selective synthesis employing these epoxides as key intermediates.
2.4 Oxidation of B(pin)-substituted epoxides
a
b
Isolated yields based on TBHP amount used.
Yields aer
d
c
Boron-substituted epoxides are versatile intermediates
employed in a variety of novel transformations. They are formed
as transient intermediates upon quenching lithiated epoxides
with bis(pinacolato)diboron (Scheme 9A).51–53 The nal prod-
ucts of these reactions are olens,51,52 diols and triols.53 Shimizu
and Hiyama et al. quenched a lithiated epoxide with (pin)B(O-i-
Pr) and isolated the resulting divinyl B(pin)-substituted epoxide.
Upon heating, the epoxide underwent a Cope rearrangement to
form a seven membered oxacycle (Scheme 9B).54 Burke and Li
recently employed PIDA-boronate substituted epoxides in the
synthesis of small chiral medicinal building-blocks, such as a
glucagon receptor antagonist.9 These reports attest to the
diverse reactivity of boron-substituted epoxides.
chromatographic purication. 0.8 equiv. of TBHP used. 0.7 equiv.
of TBHP used. Yield determined by 1H NMR analysis of crude
e
mixture with internal standard CH2Br2; no chromatographic
purication was necessary.
Having developed a method for the selective epoxidation of
B(pin)-substituted bis-allylic alcohols, we set out to examine the
substrate scope of this reaction.
2.3.4 Substrate scope of the mono-epoxidation of B(pin)-
substituted bis-allylic alcohols. With the optimized conditions
for the mono-epoxidation of 2-B(pin)-substituted bis-allylic
alcohols in hand, the scope of the reaction was examined. The
epoxidation worked well with methyl and n-hexyl substituents at
the a-position (entries 1–5, Table 4). For the n-hexyl group (entry
3), 0.8 equiv. of TBHP was employed because use of 1 equiv. of
TBHP gave mixtures of mono- and bis-epoxy alcohols. Both
aromatic and aliphatic B(pin)-substituted bis-allylic alcohols
were good substrates. Yields were lower for product 3o and the
cyclohexenyl derivative 3p due to more challenging purica-
tions via silica gel chromatography. Substoichiometric amounts
of TBHP (0.7 equiv.) were used in entries 4–6 to avoid formation
of bis-epoxides. The anti-relationship between the hydroxyl and
epoxide is expected due to minimization of A1,2-strain in the
directed diastereomeric epoxidation transition states.37–39
2.3.5 Reversal of chemoselectivity with halide-substituted
allylic alcohols. The chemoselective epoxidation of vinyl groups
in the presence of vinyl boronate esters led us to ask whether we
2.4.1 Optimization of the oxidation of B(pin)-substituted
epoxy alcohols. With the successful epoxidation of B(pin)-
substituted allylic alcohols, we envisioned that further
could manipulate the electronics of the two vinyl groups to Scheme 9 Stereoselective synthesis of tetrasubstituted alkenyl boronates.
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Scheme 10 Oxidation of B(pin)-substituted allylic alcohols to form 2-keto-anti-
1,3-diols.
Scheme 11 Tandem C]C/B–C oxidation of B(pin)-substituted allylic alcohols to
keto diols.
oxidation of the B(pin)-substituted epoxides would provide
access to 2-keto-anti-1,3-diols. 2-Keto-anti-1,3-diols can be
precursors for polyoxygenated carbon chains that are common
structural motifs in natural products, such as sugars.55 Given
the high sensitivity of the B(pin) epoxides to silica gel, a tandem
diastereoselective epoxidation/B–C bond oxidation of 2-B(pin)-
substituted allylic alcohols was desired to circumvent the
isolation of the epoxide intermediates. Toward development of
this tandem reaction, we initially focused on oxidation of the B–
C bond in isolated B(pin)-substituted epoxides (Scheme 10).
Using 3 equiv. TBHP, the substrate 2f was treated with 2 M
NaOH in THF solvent at 0 ꢁC to cleanly provide the keto diol 5f
in 85% yield. Unfortunately, however, the tandem C]C/B–C
oxidation in THF solvent gave multiple products, probably due
to complications in the epoxidation step (Table 5, entry 1).
Switching to dichloromethane for the OV(acac)2/TBHP epoxi-
dation of 1f followed by addition of 2 M NaOH to the interme-
diate epoxide 2f generated the keto diol 5f. The oxidation of 2f,
however, was very slow and did not reach completion in 18 h
(entry 3). Conducting the epoxidation of 1f in dichloromethane
followed by addition of THF and 2 M NaOH to the intermediate
epoxide 2f resulted in consumption of the epoxide in 8 h and
generation of the keto diol 5f (entry 4). Other oxidants for the
B–C oxidation such as aqueous hydrogen peroxide and sodium
perborate5 were evaluated and performed comparably (entry
5–7). With these optimized conditions, we examined the scope
of the tandem epoxidation/B–C bond oxidation.
Scheme 12 Epoxidation of B(pin)-substituted allylic alcohols followed by
protection and oxidation.
aromatic substituents at the carbinol and in the vinylic posi-
tions (60–83% yield, Scheme 11). It is worthy of note that the
keto diols were formed as single diastereomers, suggesting that
epimerization of the a-carbons did not occur under our basic
reaction conditions. The oxidation of the B–C bond most likely
proceeds via attack of the deprotonated TBHP on the boron and
migration of the boron bound carbon to oxygen to form the C–O
bond. The strained ketal intermediate then opens with reten-
tion of conguration at the newly formed a-carbon. Consistent
with this mechanism, single crystal structure determinations of
5c (R1, R2 ¼ tBu) and 5f (R1 ¼ Cy, R2 ¼ Ph) exhibit an anti-
relationship between the hydroxyl groups.12 The results indicate
that using the same oxidant (TBHP) and directing the initial
oxidation to the B–C bond or the C]C bond, either a-hydroxy
ketones (Scheme 3A) or 2-keto-anti-1,3-diols (Scheme 11) can be
prepared with excellent chemoselectivity. The mechanistic
difference between the two oxidation reactions allowed us to
further couple the chemoselective dual oxidation to a hydroxyl
group protection transformation to furnish monoprotected 2-
keto-anti-1,3-diols (Scheme 12).12 It would be difficult to obtain
the same products via chemoselective protection of one of the
hydroxyl groups of 2-keto-anti-1,3-diol.
2.4.2 Substrate scope of the tandem epoxidation/B–C bond
oxidation. Using the optimized conditions in Table 5 (entries 4,
6 and 7) the tandem reaction afforded keto diols with good
yields. Keto diols were tolerant of large and small alkyl and
Table 5 Optimization of the tandem epoxidation/B–C bond oxidation
2.4.3 Oxidation of B(pin)-substituted bis-epoxides. With a
successful tandem epoxidation/B–C bond oxidation, we next
turned our attention towards the oxidation of more challenging
B(pin)-substituted bis-epoxides 2k–p, which would provide
access to epoxide-substituted 2-keto-anti-1,3-diols 5k–p. Epoxy-
keto-1,3-diols are important motifs in biologically active natural
products such as Chemomycin A, which possesses antitumor
activity against human cancer cells.56
For the synthesis of epoxy-keto-anti-1,3-diols, B(pin)-
substituted bis-epoxy alcohols were generated as shown in
Table 3. The crude products were quickly ltered through a pad
a
Isolated yields.
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Table 6 Two step oxidation of B(pin)-substituted allylic alcohols to form epoxy-2-keto-anti-1,3-diols
Entry
1
Bis-epoxide
Epoxide-1, 3-ketodiol
dr
Yield (%)a
78b
2k
2l
5k
5l
>20 : 1
2
3
4
>20 : 1
>20 : 1
>20 : 1
78b
64
2m
2o
5m
5o
60
5
2p
5p
>20 : 1
61
a
Isolated yields. b Oxidation with NaBO3$H2O, see ESI for details.
of silica gel, concentrated and re-dissolved in THF for the
subsequent B–C bond oxidation. We evaluated three reagents
for the oxidative B–C bond cleavage, namely basic TBHP,
sodium perborate and basic hydrogen peroxide. Treatment of
substrate 2k with NaBO3$H2O at rt cleanly provided the epoxy-
keto-anti-1,3-diol 5k in 78% yield (entry 1, Table 6). Similar
conditions smoothly furnished the bulky tert-butyl-substituted
epoxy-keto-diol 5l (entry 2, 78% yield). Using 3.3 equiv. of 30%
H2O2 and 1.1 equiv. of 5 M NaOH, epoxy-keto-diols 5o and 5p
were obtained in moderate yields (entries 4 and 5). Comparable
results were obtained when treated with basic TBHP (Section
2.4.1); however, the keto diols were obtained in slightly lower
yields. Tandem epoxidation/B–C bond oxidation of a B(pin)-
substituted bis-allylic alcohol was also examined. Conducting
the epoxidation of 1k in dichloromethane followed by addition
of THF, H2O2 and 5 M NaOH to the intermediate epoxide 2k
resulted in consumption of the epoxide in 2–3 h and generation
of the epoxy-keto-diol 5k in 49% isolated yield (Scheme 13). The
epoxy-keto-diols were again formed as single diastereomers,
suggesting that epimerization of the a-carbons did not occur
under the basic reaction conditions.39 Importantly, these epoxy-
keto-anti-1,3-diols containing bulky tert-butyl groups or aryl
Scheme 14 SN2-Type a-alkylation of dihydroxyacetone derivatives developed
by Enders and co-workers.
substituents (Table 6) cannot be accessed via the carbonyl a-
alkylation chemistry developed by Enders and co-workers
(Scheme 14).57
2.5 Diastereoselective synthesis of fully substituted
dihydroxy-tetrahydrofuran-3-ones
With reliable routes to synthesize the epoxy-2-keto-anti-1,3-diols
(Table 6), we then focused on the development of methods for
stereoselective synthesis employing these compounds as key
intermediates. We envisioned that intramolecular cyclization of
our epoxy-keto-diols would furnish fully substituted dihydroxy-
tetrahydrofuran-3-ones. Tetrahydrofuran-3-one motifs exist in a
variety of natural products, such as scabrolides and pecteno-
toxins (PTX), which exhibit strong cytotoxic activity against the
growth of human cancer cells.58 Tetrahydrofuran derivatives
have also been employed in the synthesis of nucleosides.59
Tetrahydrofurans and related compounds are typically synthe-
sized by intramolecular cyclization of epoxy alkanols, where the
5-exo mode of cyclization is favored due to the low ring strain of
the tetrahydrofuranyl alcohol products.60 Controlling the regio-
and diastereoselectivity of the cyclization can be a challenge,
Scheme 13 Tandem epoxidation/B–C bond oxidation of a B(pin)-substituted
bis-allylic alcohol.
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because it is inuenced by the nature of the epoxide substrate,
reagents and catalysts employed in the reaction.60 Few other
methods for the synthesis of fully substituted tetrahydrofuran-
3-ones have been developed. One well-known method of
synthesizing tetrahydrofuran-3-ones is the utilization of diazo
ketones in the presence of rhodium catalysts. This method
frequently gives low yields and mixtures of stereoisomers.61,62
Substituted tetrahydrofuran-3-ones were also synthesized by
singlet-oxygen-mediated reactions using 2-(b-hydroxyalkyl)
furans63 and by radical carbonylation/reductive cyclization
using organochalcogen precursors.62 Both these methods are
reported to give inseparable mixtures of diastereomeric fur-
anone products.
Fig. 1 ORTEP of dihydroxy-hydrofuran-3-one 6k illustrating the anti-relationship
of the hydroxyl groups.
We envisioned an acid-mediated cyclization of the epoxy-
keto-diols in Table 7 as a route to fully substituted tetrahydro-
furan-3-one cores with high dr. Treatment of the epoxy-keto-diol
5k with BF3$OEt2 at rt promoted cyclization to the dihydroxy-
tetrahydrofuran-3-one 6k as a single diastereomer in 90% iso-
lated yield. Compound 6k is exclusively formed via a 5-exo-tet
cyclization that involves attack of the benzylic alcohol at the
congested 3ꢁ carbon of the epoxide. Under acid catalysis, it is
known that epoxides open via attack of nucleophiles at the more
substituted carbon atom, and the 5-exo mode of cyclization is
favored due to the low ring strain of the tetrahydrofuranyl
alcohol products. The stereochemistry and regioselectivity of
the cyclization were conrmed by X-ray structure determination
of 6k (entry 1, Table 7). The structure exhibits a ve-membered
tetrahydrofuran-3-one core with inversion at the tertiary carbon
center of the epoxide and an anti-relationship between the
hydroxyl groups (Fig. 1). The acid p-TsOH gave similar results
(86% yield by 1H NMR), although higher temperature and
longer reaction times were required and minor side products
were produced. An a-hexyl substrate performed equally well,
furnishing the dihydroxy-tetrahydrofuran-3-one 6m in 91%
yield under BF3$OEt2 mediated conditions. Both BF3$OEt2 and
p-TsOH conditions were employed in the synthesis of dihydroxy
furan-3-ones 6o and 6p. In each case, the epoxy keto diols 5o
and 5p were smoothly transformed into the dihydroxy-tetrahy-
drofuran-3-ones 6o and 6p in 77 and 65% yield, respectively
(entries 3 and 4). Product 6p is interesting in that it contains a
spirocyclic ether unit that is found in a number of natural
products, including theaspirone isolated from tea,64 kuroyur-
inidine from the bulb of Fritillaria maximowiczii65 and
numerous others. These oxaspirodecane derivatives exhibit
biological activity, as exemplied by muscarinic cholinomi-
metics.66 It is reported that syntheses of oxaspirodecane systems
suffer from tedious and low-yielding synthetic methods.66,67 Our
approach for the diastereoselective synthesis of dihydroxy-tet-
rafuran-3-ones thus adds to the synthetic repertoire to access
these challenging structural motifs.
Table 7 Synthesis of fully substituted dihydroxy-tetrahydrofuran-3-ones from
epoxy-keto-diols
3 Summary and outlook
Chemoselectivity has been called the most challenging problem
facing synthetic organic chemists.68 In the oxidation of vinyl
boronate esters with peroxides under basic conditions, it is well
known that oxidation occurs preferentially at the B–C bond
rather than the C]C bond.1 We have developed a method to
reverse this chemoselectivity. The resulting products are
synthetically useful, opening a new manifold of chemistry for
vinyl boronate esters.
Outlined herein is the one-pot synthesis of a variety of
2-B(pin)-substituted allylic and bis-allylic alcohols using readily
generated 1-alkenyl-1,1-heterobimetallics. Highly chemo- and
diastereoselective oxidation of 2-B(pin)-substituted allylic alco-
hols and bis-allylic alcohols afforded B(pin)-substituted epoxy
alcohols and bis-epoxy alcohols respectively, with the latter
containing ve contiguous stereocenters. The epoxidations
were catalyzed by OV(acac)2 and proceeded under neutral
conditions with excellent diastereoselectivity (dr > 20 : 1) and
good to excellent yields.
a
Isolated yield. b BF3$OEt2 used. c p-TsOH in THF/H2O.
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We have also investigated the relative rate of epoxidation of
the two double bonds in B(pin)-substituted bis-allylic alcohols.
By variation of the electronic effect of the two vinyl groups, each
can be selectively epoxidized. To the best of our knowledge, this
is the rst study to probe the relative reactivity of vinyl B(pin) vs.
alkyl substituted vinyls in epoxidation reactions.
6 D. J. Brauer and G. Pawelke, J. Organomet. Chem., 2000, 604,
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3130.
We have also demonstrated that the B(pin)-substituted epoxy
9 J. Li and M. D. Burke, J. Am. Chem. Soc., 2011, 133, 13774.
alcohols are useful synthetic intermediates. Previously, vinyl 10 E. Fernandes, W. Frey and J. Pietruszka, Synlett, 2010, 1386.
boronate esters were precursors to ketones and 2-B(pin)- 11 H. Li, P. J. Carroll and P. J. Walsh, J. Am. Chem. Soc., 2008,
substituted allylic alcohols to a-hydroxy ketones. Employing the
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tion, vinylboronate esters can now serve as precursors to a,a0-
P. J. Walsh, Angew. Chem., Int. Ed., 2011, 50, 6337.
dihydroxy ketone motifs. Thus, 2-B(pin)-substituted allylic and 13 (a) A. S. Patil, D. L. Mo, H. Y. Wang, D. S. Mueller and
130, 3521.
bis-allylic alcohols could be transformed into 2-keto-anti-1,3-
diols and epoxy-2-keto-anti-1,3-diols, respectively, aer diaster-
eoselective C]C epoxidation/B–C bond oxidations. Given the
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~
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to a variety of polyoxygenated compounds that would be diffi-
cult to efficiently prepare by other methods.
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Acknowledgements
This work was nancially supported by the NSF (CHE-1152488).
We thank Dr Osvaldo Gutierrez for performing preliminary 17 M. M. Hussain and P. J. Walsh, Angew. Chem., Int. Ed., 2010,
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