Synthesis of 2-keto-anti-1,3-diols by chemoselective tandem oxidation of 2-B(pin)-substituted allylic alcohols

Article abstract of DOI:10.1002/anie.201005742

A new role for vinyl boronates: Vinyl boronate esters are well known as synthons for ketones and for their ability to participate in cross-coupling reactions. A tandem oxidation is introduced to convert 2-B(pin)-substituted allylic alcohols into 2-keto-anti-1,3-diols with high diastereoselectivity. Under these reaction conditions, the vinyl boronate ester is now a synthon for α-hydroxy ketones. Copyright

Full text of DOI:10.1002/anie.201005742

DOI: 10.1002/anie.201005742
Tandem Oxidations
Synthesis of 2-Keto-anti-1,3-diols by Chemoselective Tandem
Oxidation of 2-B(pin)-Substituted Allylic Alcohols**
Mahmud M. Hussain, Jorge Hernꢀndez Toribio, Patrick J. Carroll, and Patrick J. Walsh*
Polyoxygenated hydrocarbons are ubiquitous structural ele-
ments in nature.[1–4] An important structural motif within this
class is 2-keto-1,3-diols, which are present in numerous
natural products and synthetic intermediates.[5–7] Herein we
describe a novel stereoselective approach to the synthesis of
2-keto-anti-1,3-diols that are difficult or impossible to access
using known methods.[5–7] Our approach involves a tandem
Scheme 2. One-pot synthesis of 2-B(pin)-substituted allylic alcohols
oxidation of readily accessible 2-B(pin)-substituted allylic
alcohols (Scheme 1, right). This tandem oxidation demon-
strates that vinyl boronate esters can act as synthons for a-
hydroxy ketones, in addition to their well-known role as
synthons for ketones (Scheme 1, left).
through 1-alkenyl-1,1-heterobimetallic intermediates.
enantioenriched auxiliaries could be epoxidized with [OV-
(acac)2]/TBHP (tert-butyl hydroperoxide) (40% yield, 43:57
d.r.) or 200 mol% [Ti(OiPr)4]/DET (diethyl tartrate) (46–
65%, > 97:3 d.r.).[22]
Table 1: Chemo- and diastereoselective epoxidation of B(pin)-substituted allylic
alcohols.
Scheme 1. Known oxidation of B(pin)-substituted allylic alcohols to 2-
hydroxy ketones (left)[8, 9] and the diastereoselective oxidation to 2-keto-
anti-1,3-diols described herein (right).
No. Allylic
alcohol
Epoxide
d.r.
Yield
[%][b]
A crucial step in the development of new synthetic
methods is the introduction of reliable and scalable proce-
dures to prepare the substrates. Using our 1-alkenyl-1,1-
heterobimetallic reagents, (A, Scheme 2) nine new 2-B(pin)-
substituted allylic alcohols were prepared on gram-scale in
55–86% yield (Supporting Information, Table S1).[9–13]
Vinyl boronate esters, including derivatives of those in
1
2
3
4
5
6
7
1b
1c
1d
1e
1 f
2b >20:1 92[c]
2c >20:1 83[d](96[c])
2d >20:1 85[d,e](94[c])
2e >20:1 94[c]
À
Scheme 2, readily undergo oxidation at the B C bond to
provide ketones (Scheme 1, left).[8,9,14–18] In the last decade,
=
however, epoxidations of the C C bond of 4-coordinate vinyl
boron derivatives were disclosed[19–21] and, in 2010, Pietruszka
and co-workers[22] reported that boronate esters with bulky
[*] Dr. M. M. Hussain, Dr. J. Hernꢀndez Toribio, Dr. P. J. Carroll,
Prof. P. J. Walsh
2 f >20:1 96[c]
Department of Chemistry, University of Pennsylvania
231 S. 34th St., Philadelphia, PA 19104 (USA)
Fax: (+1)215-573-6743
E-mail: pwalsh@sas.upenn.edu
Homepage: http://titanium.chem.upenn.edu/walsh/index.html
1g
1h
2g
14:1 85[d]
[**] P.J.W. acknowledges the NIH (National Institute of General Medical
Sciences GM58101) and the NSF (CHE-0848467). Funds for
instrumentation were provided by the NIH for a MS
2h >20:1 55[d]
(1S10RR023444) and NSF for an X-ray diffractometer (CHE-
0840438). We thank Nusrah Hussain for assistance preparing
starting materials. B(pin)=pinacolyl boronate.
[a] 20 mol% V used for entries 2 and 3, rest 10 mol% V. [b] Yields of isolated
products. [c] Chromatographic purification was not necessary. [d] Yields after
chromatographic purification. [e] Single-crystal structure determination
performed.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005742.
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To perform the diastereoselective epoxidation of vinyl-
boronate esters, we initially subjected the allylic zinc alkoxide
intermediate (B, Scheme 2) to titanium tetraisopropoxide (30
mol%) and TBHP. Under these conditions, the a-hydroxy
ketones were isolated (Scheme 1, left) and no B(pin)-
substituted epoxides were detected. Two possible explana-
tions for the observed chemoselectivity are: 1) the back-
ground reaction of the zinc peroxide with the boron center is
too fast or 2) the titanium peroxide is too basic and
nucleophilic, resulting in attack on boron rather than
epoxidation. To circumvent these issues, we started with the
2-B(pin)-substituted allylic alcohols (1a–1j) and employed
the more electronegative vanadium complex, [OV(acac)2], to
catalyze the directed epoxidation.
Scheme 3. Proposed mechanism of oxidation of B(pin) epoxides.
Optimization of the [OV(acac)2]-catalyzed epoxidation of
2-B(pin) allylic alcohols was performed and the details are
outlined in Table S2. Under the optimized conditions, treat-
ment of the allylic alcohol 1a with [OV(acac)2] (10 mol%)
and 3 equiv TBHP[23] at À208C in dichloromethane formed
epoxide 2a as a single diastereomer by 1H NMR spectroscopy.
The B(pin)-substituted epoxides decomposed in the presence
of trace acid or Lewis acidic silica gel under air. Fortunately,
the epoxides formed cleanly and only required filtration
through a small pad of silica gel or Celite in most cases
(Table 1 and Supporting Information).
The scope of the epoxidation was next determined. When
both substituents on the allylic alcohol were aliphatic, the
B(pin)-substituted epoxides were isolated in 83–92% yields
as single diastereomers (Table 1, entries 1–3). With styryl
substrates, epoxides were formed in moderate to excellent
yields (55–96%) as single diastereomers (entries 4–7). The
yield in entry 7 is lower because chromatographic purification
was necessary and resulted in significant product loss due to
decomposition. The anti-relationship between the hydroxy
and epoxide was expected based on minimization of A1,2-
strain in the directed epoxidation transition states.[24,25] This
stereochemistry was confirmed by X-ray structural determi-
nation of 2d (Supporting Information).[26] Although boron-
substituted epoxides were generated from metallated epox-
ides, their reactions with oxidants have not been studied.[27–32]
We envisioned that further oxidation of the B(pin)
epoxides would provide access to valuable 2-keto-anti-1,3-
diols.[5–7] Given the sensitive nature of the B(pin)-substituted
epoxides in Table 1, a tandem diastereoselective epoxidation/
À
Table 2: Tandem vanadium-catalyzed epoxidation/B C bond oxidation to
yield 2-keto-1,3-anti-diols.
No. Allylic
alcohol
2-Keto-1,3-diol
d.r.
Yield
[%][a]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
1i
3a >20:1 68
3b >20:1 70
3c >20:1 83[b,c]
3d >20:1 81[d]
3e >20:1 60
3 f >20:1 75[b]
3i >20:1 60
À
B C bond oxidation was desired to circumvent their isolation.
Thus, after the completion of the epoxidation of B(pin)-
substituted allylic alcohols, THFand 2m NaOH were added to
perform the second oxidation (Scheme 3 and Table 2). The
mechanism of this oxidation likely proceeds through depro-
tonation of the TBHP by NaOH, followed by attack of the
peroxy species on the unsaturated boron center and migration
[a] Yields of isolated products. [b] Single-crystal structure obtained.
[c] Oxidation with NaBO3·H2O, see Supporting Information for details.
[d] Oxidation with 30% H2O2, see Supporting Information for details.
benzylic hydroxy groups (entries 5–7). The second oxidation
could also be performed with sodium perborate (entry 3) or
hydrogen peroxide (entry 4). Two features of the tandem
oxidation reaction in Table 2 should be emphasized; 1) the
keto diols were formed as single diastereomers, suggesting
that epimerization of the a-carbons did not occur under the
basic reaction conditions and 2) that 2-keto-anti-1,3-diols
containing bulky groups (entries 3 and 4) or aryl substituents
(entries 5–7) alpha to the carbonyl would not be accessible
À
of the B C bond. The strained ketal intermediate is expected
to undergo hydrolysis to furnish the keto diol.
We next examined the scope of the tandem epoxidation/
À
B C bond oxidation. The tandem oxidation afforded the 2-
keto-1,3-diols with good yields and was tolerant of large and
small alkyl substituents at the carbinol and on the vinyl group
(68–83% yield, Table 2, entries 1–4). Similar yields (60–75%)
were obtained with styryl analogues, which resulted in
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Table 3: Epoxidation of B(pin)-substituted allylic alcohols followed by protection and
oxidation.
using the carbonyl a-alkylation chemistry that
has been elegantly applied to the synthesis of 2-
keto-1,3-diols and natural products.[5,6] Consis-
tent with the mechanism proposed in Scheme 3,
the hydroxy groups of 3c and 3 f (entries 3 and 6)
are anti, as determined by X-ray crystallogra-
phy.[26]
Stereoselective elaboration of 2-keto-anti-
1,3-diol in Table 2 may require chemoselective
protection of one of the hydroxy groups, which
No. Allylic Protected
alcohol epoxide[b]
Yield
Monoprotected
1,3-ketodiol
Yield
[%][c,d]
[%][c,d]
would represent
a significant challenge. To
1
2
3
4
5
6
7
8
1 f
4 f 71
8 f
70
circumvent this issue, we conducted the diaste-
reoselective epoxidation of the B(pin)-substi-
tuted allylic alcohols as outlined in Table 1. The
resultant epoxy alcohols were then protected in
situ with TES, TBS, TIPS and Ac groups
(Table 3). With styryl substrates or sterically
bulky substrates (R’ = Ph, tBu), the protected
epoxides were formed in moderate to good yields
(71–84%) as single diastereomers (entries 1–4
and 7). When both substituents on the allylic
alcohol are aliphatic, the B(pin)-substituted
epoxides were isolated as single diastereomers
but in lower yields (41–50%) due to their
instability on silica during purification (entries 5
and 6). The acetate-protected B(pin)-epoxide
was isolated in 83% yield (entry 7). Careful
isolation of B(pin)-epoxide intermediates was
1d
1d
1d
1b
1b
1h
1g
5d 84
4d 72
6d 78
4b 41[e]
6b 50[e]
7h 83
9d 81
8d 77
10d 81
8b 64
10b 83
À
followed by oxidation of the B C bond with
–
–
sodium perborate leading to formation of the
selectively protected 2-keto-anti-1,3-diols in 64–
83% yield with > 20:1 diastereomeric ratio. Of
significance, monoprotection of the keto diol 3b
would not favor formation of 8b or 10b due to
unfavorable sterics. The sequence of epoxidation,
protection, and oxidation can also be performed
in a tandem fashion as shown in entry 9 (49%
yield over three steps).
not
isolated
4g
8g 49[f]
[a] See Supporting Information for detailed experimental procedures. [b] TBS=tert-butyl
dimethylsilyl, TES=triethylsilyl, TIPS=triisopropylsilyl, Ac=acetyl. [c] Yields of isolated
products. [d] >20:1 d.r. observed in all cases. [e] Epoxides readily decompose on silica
during chromatographic purification. [f] Yield for tandem reaction over three steps.
In summary, a variety of 2-B(pin)-substituted
allylic alcohols were prepared in one-pot procedures on gram
scale. Chemo- and diastereoselective oxidation of 2-(Bpin)
allylic alcohols affords anti-B(pin)-substituted epoxy alcohols.
The epoxidations are catalyzed by [OV(acac)2] and proceed
under neutral conditions with excellent diastereoselectivity
(> 20:1 d.r.) and good to excellent yields (55–96%). The
epoxidation can be followed by a base-induced TBHP
this method will be useful in the synthesis of polyoxygenated
natural products.
Received: September 14, 2010
Revised: March 15, 2011
Published online: May 26, 2011
Keywords: chemoselectivity · epoxidation · ketodiols ·
À
oxidation of the B C bond to afford 2-keto-anti-1,3-diols
.
oxidations · tandem reactions
with excellent control over the diastereoselectivity. The
epoxidation can also be followed by an in situ hydroxy
À
protection and B C bond oxidation sequence to provide
chemoselective monoprotected 2-keto-anti-1,3-diols in good
yields (64–83% yield, > 20:1 d.r.). Previously, vinyl boronate
esters were precursors to ketones and 2-B(pin)-substituted
allylic alcohols to a-hydroxy ketones.[8,9] Employing the
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