Stereocontrolled synthesis of 1,3-diols from enones: Cooperative lewis base-mediated intramolecular carbonyl hydrosilylations

Article abstract of DOI:10.1021/jo401293a

A streamlined synthesis of β-hydroxy ketone substrates has been developed to further investigate a recently discovered cooperative Lewis base-mediated intramolecular carbonyl hydrosilylation reaction. The synthesis features an enone β-borylation/oxidation

Full text of DOI:10.1021/jo401293a

Article
pubs.acs.org/joc
Stereocontrolled Synthesis of 1,3-Diols from Enones: Cooperative
Lewis Base-Mediated Intramolecular Carbonyl Hydrosilylations
Casey Medina,† Kyle P. Carter,† Michael Miller,† Timothy B. Clark,‡ and Gregory W. O’Neil*,†
†Department of Chemistry, Western Washington University, Bellingham, Washington 98225, United States
‡Department of Chemistry, University of San Diego, San Diego, California 92110, United States
S
* Supporting Information
ABSTRACT: A streamlined synthesis of β-hydroxy ketone
substrates has been developed to further investigate a recently
discovered cooperative Lewis base-mediated intramolecular
carbonyl hydrosilylation reaction. The synthesis features an
enone β-borylation/oxidation sequence that has proven to be
quite general and high-yielding. This has allowed for additional
investigations into the diastereoselectivity of the hydro-
silylation reaction through the preparation of important poly-
ketide fragments.
diphenylchlorosilane, imidazole, and triethylamine (Scheme
2). The proposed mechanism is as illustrated with nucleophilic
activation at silicon by imidazole to generate a transient hydro-
silanide.8,9 The developing negative charge on silicon can be
stabilized by each phenyl substituent and the positively charged
imidazolium by hydrogen bonding/abstraction with triethyl-
amine.10,11 Hydride is then delivered from silicon via a six-
membered chairlike transition state, which leads to useful
INTRODUCTION
■
Hydridosilanes, or organosilicon compounds containing at least
one Si−H group, have the ability to serve as a formal hydride
source in part because this bond is polarized as Siδ+−Hδ−. A
range of reductions involving hydridosilanes are known, and
there are several excellent reviews dedicated to reactions of
organosilicon hydrides.1−4 One of the earliest reports by
Anderson 55 years ago described spontaneous reactions of
triethylsilane with inorganic halides and acids to generate the
corresponding free metals and hydrogen gas, respectively.5
Reductions of carbonyls by hydridosilanes, however, most often
require an activation event.1 This can be either Lewis acid acti-
vation of the carbonyl compound to increase its electrophilicity
or nucleophilic activation at the silicon center to create a
valence-expanded pentacoordinate hydrosilanide (Scheme 1).6
Our group recently reported a new twist on this well-known
reaction with the discovery of a novel intramolecular carbonyl
hydrosilylation process.7 β-Hydroxy ketones can be converted
directly to cyclic siloxane products by the action of
Scheme 2. Cooperative Lewis Base-Mediated Intramolecular
a
Hydrosilylations
Scheme 1. Activation Modes for Carbonyl Hydrosilylation
a
Isolated yields after desilylation with TBAF. Ratios were determined
1
by H NMR spectroscopy.
Received: June 14, 2013
© XXXX American Chemical Society
A
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diastereoselectivities.12 For instance, placement of a methyl
substituent between the hydroxyl group and the ketone forces
this group into a preferred equatorial position, thus directing
the face of the carbonyl to which the hydride is then added,
leading in each case to the syn-propionate product.
Herein we describe an optimization of this reaction as a
general method for the direct conversion of β-hydroxy ketones
to cyclic siloxanes. An efficient enone β-borylation/oxidation
sequence was employed to synthesize the β-hydroxy ketone
substrates, which allowed for further investigations into the
diastereoselectivity of the hydrosilylation reaction. The utility of
the hydrosilylation reaction was then highlighted through the
preparation of several important polyketide fragments.
reagent.14 Careful analysis of these methods, however, revealed
only a select number of examples involving terminal α,β-
unsaturated ketones (enones).15 This is likely a reflection of
the challenge associated with terminal enone transformations
due to their decreased stability relative to their ester- or di-
substituted counterparts.16 For instance, while Bonet et al.17
reported the successful β-borylation of a variety of conjugated
esters using Ph3P and CsCO3, we found that this system
resulted in rapid decomposition of terminal enones. Chea et
al.18 included methyl vinyl ketone as a single terminal enone
substrate in their report on the scope of a copper-catalyzed β-
borylation. When we applied these conditions to phenyl vinyl
ketone using the prescribed 1:1.1 stoichiometric ratio of enone
to bis(pinacolato)diboron (B2pin2), the boronate ester product
1 was obtained in only 38% yield (Table 1, entry 1). It was
suspected that the inherent instability of terminal enones was in
part responsible for the low yield. When the reaction was
instead performed using a 1:0.8 enone:diboron molar ratio, the
yield of 1 was 64% (51% based on enone; entry 2). Increasing
the equivalents to 2:1 in favor of the enone further improved
the yield to 82% (entry 3). Importantly, no starting phenyl
vinyl ketone was recovered from this mixture, supportive of a
competing decomposition during the course of the reaction for
these particular substrates. The terminal enones for entries 4, 5,
and 6 proved similarly sensitive and were thus used in slight
excess (1.2 equiv) to obtain good yields of the corresponding
boronate ester products 2, 3, and 4 without sacrificing a large
excess of the enone.
RESULTS AND DISCUSSION
■
β-Hydroxy ketone substrates for our previous work were typi-
cally prepared according to the method of Martin et al.13 via a
five-step sequence from various commercial aldehydes as outlined
in Scheme 3, with overall yields of 30−40%. As an alternative, we
envisioned a shorter and more versatile β-borylation/oxidation
sequence from readily available terminal enones.
Many reagents have been described to promote the con-
jugate or 1,4-addition of a boronate ester from a diboron
Scheme 3. Previous β-Hydroxy Ketone Synthesis and
Potential β-Borylation/Oxidation Alternative
Interestingly, when the reaction was performed using PMB-
protected Roche ester-derived enone 5 with a 1:1.1 enone:diboron
ratio (Table 2, entry 1), the product was obtained in 91% yield.
Along with the corresponding boronate ester 9, a small amount
of starting enone was observed, indicating an increased stability
for this particular substrate. TBS-protected Roche ester enone 6
Table 1. Optimization of a Copper-Catalyzed Terminal Enone β-Borylation
a
b
Yield based on enone starting material. Yield based on bis(pinacolato)diboron.
B
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dienone 14, however, was unaffected by the reaction con-
ditions, providing the corresponding boronate ester 15 in 79%
isolated yield with complete chemoselectivity.
Table 2. β-Borylation of Chiral Enone Substrates Using
Excess Diboron
Completion of the synthesis by oxidative cleavage of the
boronate ester was best accomplished using sodium perborate
(Scheme 5).21 Yields ranged from good to quantitative. The se-
quence could also be performed without isolation and
purification of the intermediate boronate ester, taking the
crude product from the copper-catalyzed β-borylation directly
into the perborate oxidation. This resulted in an overall enhanc-
ement of the yield, presumably due to the decreased handling
of the intermediate boronate esters, which are susceptible to
hydrolysis.22
Convenient access to β-hydroxy ketone substrates 16−20
allowed for further explorations of the diastereoselectivity of
the intramolecular hydrosilylation reaction complementary to
those previously reported (Scheme 2).7 For instance, treatment
of 16 with our optimized hydrosilylation conditions followed by
desilylation with TBAF gave diol 21 in 68% yield as a 10:1
1
mixture of diastereomers, as determined by H NMR spec-
troscopy (Scheme 6). Comparison to literature data allowed
Scheme 6. Felkin-Controlled Intramolecular Hydrosilylation
and lactate-derived substrates 719 and 8 (entries 2−4) proved
similarly robust, allowing for the chiral enone and arguably
more precious substrates to serve as the limiting reactants and
giving the corresponding ketoboronate esters 10, 11, and 12 in
high yield.
The chemoselectivity of the β-borylation reaction was also ex-
plored (Scheme 4). β-Borylation of a cinnamaldehyde-derived
Scheme 4. Chemoselective Enone β-Borylation
for assignment of the major stereoisomer as the anti-propionate
product.23 This can be rationalized as a Felkin-controlled ad-
dition,24 in which the phenyl group as the largest substituent is
projected away from the incoming nucleophilic hydride.
Results from additional hydrosilylations of substrates con-
taining α′-stereocenters are outlined in Scheme 7. The TBS-
protected lactate derivative 19 proved unreactive, consistent
with previous observations when using sterically demanding
compounds.7 Switching to the smaller PMB-protected lactate-
derived substrate 20 then allowed the reaction to proceed to
22, albeit with no selectivity. Neither the PMB- nor TBS-Roche
ester-derived substrate 17 or 18, respectively, reacted with an
appreciable level of selectivity. The major stereoisomer in each
dienone20 proved only moderately selective, giving boronate
ester 13 in 42% yield as a mixture along with what have been
tentatively assigned as internally borylated and bis-β-borylated
adducts. The trisubstituted conjugated alkene of nerol-derived
a
Scheme 5. Boronate Ester Oxidation
a
Yields in parentheses are from the starting enone without isolation/purification of the boronate ester intermediate.
C
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which to build up extended polypropionate systems. For
instance, compound 28 maps onto the C10−C12 region of
(−)-discodermolide, and a similar substrate served as a key
intermediate for multiple fragment syntheses in the preparation
of this compound by the Smith group.32 As a demonstration,
the primary alcohol of 28 was oxidized with TEMPO, and
the resulting aldehyde underwent an Evans syn-aldol reaction33
to generate 30 containing the C16−C20 stereopentad of
discodermolide (Scheme 9).
Scheme 7. Effect of α′-Stereocenters on the Intramolecular
Carbonyl Hydrosilylation
Scheme 9. Synthesis of the C16−C20 Stereopentad of
(−)-Discodermolide from Hydrosilylation Adduct 30
case was the anti-propionate product (2325 or 24,26 respec-
tively), consistent with a Felkin-control model.
The nominal influence of the α′-stereocenter on the ste-
reoselectivities in Scheme 7 suggested that both syn,syn- and
anti,syn-stereotriads could be prepared by intramolecular
hydrosilylation with high levels of stereocontrol. To that end,
enolization of ethyl ketone 2527 with chlorodicyclohexylborane
and triethylamine or trichlorotitanium isopropoxide and
Hunig’s base followed by reaction with formaldehyde gave
̈
hydroxy ketone 26 or 27, respectively, as previously described
(Scheme 8).28,29 Intramolecular hydrosilylation of the matched
substrate 26 gave the expected anti,syn-stereotriad 28 in 68%
1
yield as a single diastereomer, as determined by H NMR
spectroscopy.30 Importantly, hydrosilylation of 27 proceeded
with similarly high levels of selectivity, with the methyl group
within the six-membered cyclic transition state proving to be
the dominant stereocontrolling element, affording the syn,syn-
stereotriad 29 in 72% yield (dr >10:1).31
CONCLUSION
■
In summary, a novel intramolecular carbonyl hydrosilylation
protocol promoted by the combined action of imidazole and
triethylamine bases has been developed. The reaction proceeds
via a six-membered chairlike transition state, leading to useful
and predictable diastereoselectivities. Access to β-hydroxy ke-
tone substrates was streamlined through the use of a terminal
enone β-borylation/oxidation sequence. This then allowed for
further investigations into the stereoselectivity of the hydro-
silylation reaction. Ultimately these results revealed the ver-
satility of the protocol, which has the ability to generate both
syn,syn- and syn,anti-stereotriads in high yield with similar ste-
reocontrol. Products of this type represent important building
blocks with which to prepare more complex polyketide targets,
including discodermolide.
Stereotriads themselves are common to a number of impor-
tant natural products and can serve as a starting point from
Scheme 8. Stereotriad Synthesis by Diastereoselective
Intramolecular Hydrosilylation
EXPERIMENTAL SECTION
■
General Procedure for β-Borylation of Terminal Enones
(Compounds 1−4, 9−12, and 15). To a solution of copper(I)
chloride (20 mol %) in THF (2 mL) was added NaOtBu (20 mol %),
and the mixture was allowed to stir at room temperature for 10 min.
Bis(pinacoloto)diboron (0.5−1.1 equiv; see Tables 1 and 2) was then
added, and the resulting black solution was stirred for 10 min before
addition of the appropriate enone and H2O (1 mL), after which the
mixture was stirred for 3 h. The reaction was then quenched with
saturated aq. NaCl (10 mL), and the mixture was extracted with ethyl
acetate (2 × 15 mL). The combined organic extracts were dried over
MgSO4, filtered, and concentrated in vacuo. The resulting residue was
purified by flash chromatography on silica (10:1 hexanes/ethyl
acetate).
1-Phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-
1-one (1). (0.166 g, 64%). IR (neat): 2977, 2933, 1685, 1379, 1371,
D
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1316, 1221, 1144, 690 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.97 (d,
J = 7.0 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 3.16
(t, J = 7.0 Hz, 2H), 1.25 (s, 12H), 1.07 (t, J = 7.0 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 200.8, 137.1, 133.0, 128.7, 128.2, 83.3, 33.9,
25.0.34 11B NMR (160 MHz, CDCl3): δ 33.6. HRMS (TOF ESI+)
calcd for [C15H21BO3 + Na]+ 283.1484, found 283.1490.
(S)-4-((tert-Butyldimethylsilyl)oxy)pent-1-en-3-one (7). To a sol-
ution of (S)-2-((tert-butyldimethylsilyl)oxy)-N-methoxy-N-methylpro-
panamide37 (1.50 g, 2.07 mmol, 1 equiv) in THF (50 mL) at 0 °C was
added a freshly made solution of vinylmagnesium bromide (8.0 mL,
1.5 M, 2.0 equiv), and the mixture was stirred for 1 h. The reaction was
quenched with aq. NH4Cl, and the mixture was extracted with MTBE
(3 × 25 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica (10:1 hexanes/EtOAc) provided compound 7 as a clear
colorless oil (0.812 g, 66%). [α]2D0 = −1.48 (c = 1.2, CH2Cl2). IR
(neat): 2956, 2930, 2887, 2858, 1703, 1612, 1473, 1402, 1253, 1118,
1091, 935, 831, 814, 777 cm−1. The NMR spectral data matched those
previously reported in the literature:19 1H NMR (500 MHz, CDCl3): δ
6.87 (dd, J = 11.0, 18.0 Hz, 1H), 6.40 (dd, J = 2.0, 17.5 Hz, 1H), 5.77
(dd, J = 2.0, 11.0 Hz, 1H), 4.29 (q, J = 6.5 Hz, 1H), 1.31 (d, J = 7.0 Hz,
3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 201.9, 130.6, 129.5, 74.3, 25.7, 20.9, 18.1, −4.8, −5.0.
1-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)octan-3-one (2).
(0.163 g, 64%). IR (neat): 2931, 1712, 1378, 1313, 1145, 968, 841
1
cm−1. H NMR (500 MHz, CDCl3): δ 2.55 (t, J = 7.0 Hz, 2H), 2.37
(t, J = 7.5 Hz, 2H), 1.56 (quin, J = 7.5 Hz, 2H), 1.33−1.23 (m, 4H),
1.23 (s, 12H), 0.90 (t, J = 7.0 Hz, 2H), 0.87 (t, J = 7.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 212.0, 83.3, 42.4, 37.7, 31.6, 25.0, 24.0,
22.7, 14.1. 11B NMR (160 MHz, CDCl3): δ 34.4. HRMS (TOF ESI+)
calcd for [C14H27BO3 + Na]+ 277.1954, found 277.1943.
5-Methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexan-
3-one (3). (0.284 g, 79%). IR (neat): 2957, 1711, 1414, 1379, 1370,
1313, 1144, 968, 872, 844 cm−1. 1H NMR (500 MHz, CDCl3): δ 2.54
(t, J = 7.0 Hz, 2H), 2.26 (d, J = 6.5 Hz, 2H), 2.12 (m, 1H), 1.23 (s,
12H), 0.90 (d, J = 6.5 Hz, 6H), 0.88 (t, J = 6.5 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 211.5, 83.2, 51.5, 38.4, 25.2, 25.0, 22.8. 11B
NMR (160 MHz, CDCl3): δ 34.4. HRMS (TOF ESI+) calcd for
[C13H25BO3 + Na]+ 263.1797, found 263.1791.
(S)-4-((4-Methoxybenzyl)oxy)pent-1-en-3-one (8). To a solution
of (S)-N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylpropanamide38
(0.585 g, 2.31 mmol, 1 equiv) in THF (50 mL) at −15 °C was added a
freshly made solution of vinylmagnesium bromide (2.88 mL, 2.0 M,
2.5 equiv), and the mixture was stirred for 1 h. The reaction was
quenched with aq. NH4Cl, and the mixture was extracted with MTBE
(3 × 25 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica (4:1 hexanes/EtOAc) provided compound 8 as a clear
colorless oil (0.329 g, 65%). [α]2D0 = −18.4 (c 1.2, CH2Cl2). IR (neat):
2916, 2849, 1699, 1611, 1513, 1402, 1246, 1173, 1092, 1032, 988, 968,
4-Phenyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pentan-
3-one (4). (0.197 g, 68%). IR (neat): 2976, 2930, 1712, 1371, 1315,
1
1144, 699 cm−1. H NMR (500 MHz, CDCl3): δ 7.31 (t, J = 7.5 Hz,
2H), 7.25−7.2 (m, 3H), 3.77 (q, J = 7.0 Hz, 1H), 2.52 (m, 2H),
1.38 (d, J = 7.0 Hz, 3H), 1.21 (s, 12H), 0.85 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ 211.6, 141.2, 129.0, 128.1, 127.1, 83.2, 52.5,
36.3, 25.0, 17.9. 11B NMR (160 MHz, CDCl3): δ 34.3. HRMS (TOF
ESI+) calcd for [C17H25BO3 + Na]+ 311.1798, found 311.1799.
(R)-5-((4-Methoxybenzyl)oxy)-4-methylpent-1-en-3-one (5). To a
solution of (R)-N-methoxy-3-((4-methoxybenzyl)oxy)-N,2-dimethyl-
propanamide35 (0.649 g, 2.43 mmol, 1 equiv) in THF (13 mL) at
−15 °C was added a freshly made solution of vinylmagnesium bro-
mide (8.2 mL, 1.0 M, 3.2 equiv), and the mixture was stirred and
allowed to warm to room temperature over 5 h. The reaction was
quenched with aq. NH4Cl, and the mixture was extracted with MTBE
(3 × 25 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica (4:1 hexanes/EtOAc) provided compound 5 as a clear
colorless oil (0.350 g, 62%). [α]2D0 = −9.3 (c 1.0, CH2Cl2). IR (neat):
2935, 2857, 1697, 1676, 1611, 1512, 1245, 1093, 1033, 972, 818 cm−1.
1H NMR (500 MHz, CDCl3): δ 7.22 (d, J = 9.0 Hz, 2H), 6.87 (d, J =
9.0 Hz, 2H), 6.44 (dd, J = 11.0, 18.0 Hz, 1H), 6.28 (dd, J = 1.5,
18.0 Hz, 1H), 5.80 (dd, J = 1.5, 10.5 Hz, 1H), 4.44 (d, J = 11.0 Hz,
1H), 4.40 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.67 (dd, J = 9.5, 2.0 Hz,
1H), 3.44 (dd, J = 8.5, 3.0 Hz, 1H), 3.17 (sextet, J = 6.0 Hz, 1H), 1.11
(d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 202.7, 159.4,
135.7, 130.4, 129.4, 128.6, 113.9, 73.1, 71.9, 55.5, 43.9, 14.1. HRMS
(TOF ESI+) calcd for [C14H18O3 + Na]+ 257.1154, found 257.1152.
(R)-5-((tert-Butyldimethylsilyl)oxy)-4-methylpent-1-en-3-one (6).
To a solution of (R)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2-
dimethylpropanamide36 (0.965 g, 3.74 mmol, 1 equiv) in THF (19 mL)
at −15 °C was added a freshly made solution of vinylmagnesium
bromide (12.0 mL, 1.0 M, 3.2 equiv), and the mixture was stirred and
allowed to warm to room temperature over 5 h. The reaction was
quenched with aq. NH4Cl, and the mixture was extracted with MTBE
(3 × 25 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy on silica (10:1 hexanes/EtOAc) provided compound 6 as a clear
colorless oil (0.455 g, 53%). [α]2D0 = −36.2 (c 1.0, CH2Cl2). IR (neat):
1
820 cm−1. H NMR (500 MHz, CDCl3): δ 7.26 (d, J = 9.0 Hz, 2H),
6.88 (d, J = 9.0 Hz, 2H), 6.79 (dd, J = 10.0, 17.0 Hz, 1H), 6.43 (dd, J =
2.0, 17.5 Hz, 1H), 5.80 (dd, J = 2.0, 11.0 Hz, 1H), 4.49 (d, J = 11.0 Hz,
1H), 4.38 (d, J = 11.0 Hz, 1H), 4.09 (q, J = 7.0 Hz, 1H), 3.81 (s, 3H),
1.36 (d, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 201.6,
159.4, 130.9, 129.8, 129.6, 129.5, 113.9, 79.5, 71.5, 55.3, 17.8. HRMS
(TOF ESI+) calcd for [C13H16O3 + Na]+ 243.0997, found 243.1002.
(R)-1-((4-Methoxybenzyl)oxy)-2-methyl-5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)pentan-3-one (9). Prepared according to the
general procedure for β-borylation. (0.197 g, 91%). [α]2D0 = −20.3 (c =
1.2, CH2Cl2). IR (neat): 2976, 2933, 1711, 1612, 1513, 1371, 1245,
1
1144, 819 cm−1. H NMR (500 MHz, CDCl3): δ 7.22 (d, J = 9.0 Hz,
2H), 6.86 (d, J = 8.5 Hz, 2H), 4.42 (d, J = 11.0 Hz, 1H), 4.38 (d,
J = 11.0 Hz, 1H), 3.80 (s, 3H), 3.60 (dd, J = 8.0, 9.5 Hz, 1H), 3.40
(dd, J = 5.5, 9.0 Hz, 1H), 2.86 (m, 1H), 2.64 (dt, J = 1.5, 7.0 Hz, 2H),
1.22 (s, 12H), 1.06 (d, J = 6.5 Hz, 3H), 0.90 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ 213.8, 159.3, 130.5, 129.4, 113.9, 83.2, 73.1,
72.3, 55.5, 46.2, 37.3, 31.8, 25.2, 25.0, 24.9, 13.9. 11B NMR (160 MHz,
CDCl3): δ 34.2. HRMS (TOF ESI+) calcd for [C20H31BO5 + Na]+
385.2166, found 385.2156.
(R)-1-((tert-Butyldimethylsilyl)oxy)-2-methyl-5-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)pentan-3-one (10). Prepared ac-
cording to the general procedure for β-borylation. (0.367 g, 94%).
[α]2D0 = −21.1 (c 1.0, CH2Cl2). IR (neat): 2929, 2858, 1714, 1379,
1371, 1313, 1145, 1097, 835, 775 cm−1. 1H NMR (500 MHz, CDCl3):
δ 3.72 (dd, J = 10.0, 2.0 Hz, 1H), 3.56 (dd, J = 10.0, 4.0 Hz, 1H), 2.75
(m, 1H), 2.64 (t, J = 7.0 Hz, 2H), 1.23 (s, 6H), 1.22 (s, 6H), 1.02 (d,
J = 6.5 Hz, 3H), 0.89 (m, 2H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 214.3, 83.2, 65.7, 48.5, 37.8, 26.0,
25.0, 24.9, 18.4, 13.4, −5.3. 11B NMR (160 MHz, CDCl3): δ 33.7.
HRMS (TOF ESI+) calcd for [C18H37BO4Si + Na]+ 379.2456, found
379.2461.
(S)-4-((tert-Butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pentan-3-one (11). Prepared according to the
general procedure for β-borylation. (0.270 g, 82%). [α]2D0 = −6.8 (c
1.1, CH2Cl2). IR (neat): 2955, 2931, 2858, 1716, 1379, 1371, 1314,
1251, 1145, 834, 776 cm−1. 11H NMR (500 MHz, CDCl3): δ 4.15 (q,
J = 6.5 Hz, 1H), 2.78 (ddd, J = 6.5, 6.5, 19.5 Hz, 1H), 2.69 (ddd, J =
7.0, 7.0, 19.5 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H), 1.22 (s, 6H), 1.22 (s,
6H), 0.91 (s, 9H), 0.88 (m, 2H), 0.7 (s, 3H), 0.6 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 215.1, 83.2, 74.9, 32.3, 26.0, 25.0, 24.9, 21.3,
1
2956, 2929, 2857, 1700, 1680, 1463, 1252, 1099, 834, 775 cm−1. H
NMR (500 MHz, CDCl3): δ 6.45 (dd, J = 10.0, 17.5 Hz, 1H), 6.26
(dd, J = 1.5, 17.5 Hz, 1H), 5.79 (dd, J = 1.5, 10.5 Hz, 1H), 3.80 (dd,
J = 7.5, 10.0 Hz, 1H), 3.62 (dd, J = 6.0, 9.5 Hz, 1H), 3.09 (sextet, J =
6.5 Hz, 1H), 1.07 (d, J = 7.0 Hz, 3H), 0.85 (s, 9H), 0.3 (s, 3H), 0.1 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 203.5, 136.3, 128.3, 65.6, 46.0,
26.0, 18.4, 13.6, −5.3. HRMS (TOF ESI+) calcd for [C12H24O2Si +
Na]+ 251.1443, found 251.1443.
E
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18.3, −4.5, −4.9. 11B NMR (160 MHz, CDCl3): δ 33.4. HRMS (TOF
ESI+) calcd for [C17H35BO4Si + Na]+ 365.2299, found 365.2307.
(S)-4-((4-Methoxybenzyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)pentan-3-one (12). Prepared according to the general
procedure for β-borylation. (0.447 g, 89%). [α]2D0 = −6.2 (c 1.0,
CH2Cl2). IR (neat): 2977, 2934, 1714, 1612, 1513, 1379, 1370, 1314,
1244, 1144, 1034, 822 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.28 (d,
J = 8.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.51 (d, J = 11.0 Hz, 1H),
4.38 (d, J = 11.5 Hz, 1H), 3.93 (q, J = 7.0 Hz, 1H), 3.81 (s, 3H), 2.72
(t, J = 6.5 Hz, 2H), 1.32 (d, J = 7.0 Hz, 3H), 1.23 (s, 12H), 0.93 (t, J =
6.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 213.7, 159.2, 129.8,
129.5, 113.9, 83.1, 80.0, 71.4, 55.3, 32.4, 24.8, 24.8, 17.9. 11B NMR
(160 MHz, CDCl3): δ 34.6. HRMS (TOF ESI+) calcd for
[C19H29O5B + Na]+ 371.2009, found 371.1998.
3.47 (dd, J = 7.0, 9.0 Hz, 1H), 2.89 (m, 1H), 2.76 (ddd, J = 4.0, 6.5,
17.5 Hz, 1H) 2.71 (ddd, J = 4.0, 6.0, 17.5 Hz, 1H), 2.56 (bt, J =
6.5 Hz, O−H), 1.07 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 214.4, 159.3, 129.8, 129.3, 113.8, 73.0, 71.9, 58.1, 55.3, 46.7,
44.0, 24.9, 13.2. HRMS (TOF ESI+) calcd for [C14H20O4 + Na]+
275.1259, found 275.1251.
(R)-1-((tert-Butyldimethylsilyl)oxy)-5-hydroxy-2-methylpentan-3-
one (18). (0.099 g, 100%). [α]2D0 = −34.5 (c 0.8, CH2Cl2). IR (neat):
3399, 2955, 2929, 2857, 1707, 1472, 1388, 1253, 1078, 834, 775 cm−1.
1H NMR (500 MHz, CDCl3): δ 3.90−3.78 (m, 2H), 3.74 (dd, J = 7.5,
9.5 Hz, 1H), 3.66 (dd, J = 5.0, 9.5 Hz, 1H), 2.83−2.68 (m, 3H), 2.57
(t, J = 6.5 Hz, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.86 (s, 9H), 0.04 (s,
3H), 0.03 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 215.2, 65.8, 58.3,
49.1, 44.6, 26.0, 18.4, 13.0, −5.4, −5.4. HRMS (TOF ESI+) calcd for
[C12H26O3Si + Na]+ 269.1549, found 269.1549.
(Z)-5,9-Dimethyldeca-1,4,8-trien-3-one (14). To a solution of
neral (0.3 g, 2.0 mmol, 1.0 equiv) in THF (5.5 mL) at 0 °C was added
freshly prepared vinylmagnesium bromide (2.6 mL, 1.5 M, 4.0 mmol,
2.0 equiv), and the mixture was allowed to stir for 30 min. The
reaction was quenched with saturated aq. NH4Cl (25 mL), and the
mixture was extracted with MTBE (3 × 25 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. The crude allylic alcohol was redissolved in DCM (13 mL) and
acetonitrile (1.3 mL) with 4 Å molecular sieves. N-Methylmorpholine-
N-oxide (0.352 g, 3.0 mmol, 1.5 equiv) was added, and the mixture
was stirred for 5 min before the addition of tetrapropylammonium
perruthenate (0.070 g, 0.20 mmol, 0.1 equiv). The mixture was stirred
for 15 h, filtered through a plug of silica with EtOAc, and concentrated
in vacuo. Purification by flash chromatography on silica provided
compound 14 as a clear pale-yellow oil (0.236 g, 66%). IR (neat):
2968, 2915, 2856, 1724, 1661, 1674, 1622, 1601, 1447, 1400, 1376,
1243, 1117, 983, 959, 853, 713 cm−1. 1H NMR (500 MHz, CDCl3): δ
6.40 (dd, J = 9.5, 18.0 Hz, 1H), 6.25 (d, J = 1.5 Hz, 1H), 6.21 (dd, J =
1.0, 17.0 Hz, 1H), 5.73 (dd, J = 1.5, 11.0 Hz, 1H), 5.15 (tq, J = 1.5,
9.0 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.16 (q, J = 7.0 Hz, 2H), 1.93
(d, J = 1.5 Hz, 3H), 1.67 (d, J = 1.0 Hz, 3H), 1.63 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 190.1, 161.0, 138.3, 132.2, 127, 123.7, 122.3,
34.2, 26.8, 25.9, 25.7, 17.6. HRMS (TOF CI+) calcd for [C12H18O +
H]+ 179.1436, found 179.1430.
(Z)-5,9-Dimethyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
deca-4,8-dien-3-one (15). Prepared according to the general
procedure for β-borylation. (0.048 g, 79%). IR (neat): 2975, 2927,
1687, 1620, 1443, 1414, 1371, 1310, 1243, 1145, 1093, 968, 842 cm−1.
1H NMR (500 MHz, CDCl3): δ 6.03 (d, J = 1.5 Hz, 1H), 5.13 (tq, J =
1.5, 7.5 Hz, 1H), 2.57 (q, J = 7.0 Hz, 4H), 2.12 (q, J = 8.5 Hz, 2H),
1.85 (d, J = 1.5 Hz, 3H), 1.67 (d, J = 1.0 Hz, 3H), 1.61 (s, 3H), 1.24
(s, 12H), 0.90 (t, J = 7.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ
200.6, 157.9, 131.9, 123.9, 123.6, 83.0, 39.0, 33.8, 26.8, 25.7, 25.6, 24.8,
17.7. HRMS (TOF ESI+) calcd for [C18H31O3B + Na]+ 329.2267,
found 329.2256.
General C−B Oxidation Procedure (Compounds 16−20). To
a solution of the boronate ester (1.0 equiv) in THF/H2O (1:1, 0.1 M
relative to boronate ester substrate) at room temperature open to air
was added NaBO3·4H2O (5 equiv), and the mixture was stirred
vigorously for 3 h. H2O was then added (10 mL), and the reaction
mixture was extracted with ethyl acetate (3 × 15 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on silica
(4:1 to 1:1 hexanes/ethyl acetate).
1-Hydroxy-4-phenylpentan-3-one (16). (0.097 g, 89%). The NMR
spectral data matched those previously reported in the literature:39 1H
NMR (500 MHz, CDCl3): δ 7.34 (t, J = 7.0 Hz, 2H), 7.28 (d, J =
7.0 Hz, 1H), 7.21 (d, J = 7.0 Hz, 2H), 3.79−3.73 (m, 3H), 2.61 (t, J =
5.0 Hz, 2H), 1.41 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 211.8, 140.1, 129.1, 127.9, 127.4, 58.1, 53.4, 42.7, 17.1.
(S)-4-((tert-Butyldimethylsilyl)oxy)-1-hydroxypentan-3-one (19).
(0.173 g, 98%). [α]2D0 = −3.6 (c 1.0, CH2Cl2). IR (neat): 3429,
1256, 2930, 2886, 2858, 1715, 1473, 1362, 1252, 1118, 832, 776 cm−1.
1H NMR (500 MHz, CDCl3): δ 4.15 (q, J = 7.0 Hz, 1H), 3.86 (s, 2H),
2.90 (ddd, J = 5.0, 6.0, 19.0 Hz, 1H), 2.79 (ddd, J = 5.0, 5.0, 18.5 Hz,
1H), 2.42 (bs, O−H), 1.29 (d, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.09 (s,
6H). 13C NMR (125 MHz, CDCl3): δ 215.5, 75.0, 57.9, 39.4, 25.9,
20.9, 18.2, −4.5, −4.9. HRMS (TOF ESI+) calcd for [C11H24O3Si +
Na]+ 255.1392, found 255.1386.
(S)-1-Hydroxy-4-((4-methoxybenzyl)oxy)pentan-3-one (20).
(0.271 g, 91%). [α]2D0 = −30.7 (c 0.8, CH2Cl2). IR (neat): 3429,
1
2937, 1713, 1612, 1513, 1245, 1091, 1030, 818 cm−1. H NMR (500
MHz, CDCl3): δ 7.27 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H),
4.48 (s, 2H), 3.92 (q, J = 7.0 Hz, 1H), 3.86 (t, J = 5.5 Hz, 2H), 3.81 (s,
3H), 2.83 (ddd, J = 5.5, 5.5, 18.0 Hz, 1H), 2.78 (ddd, J = 4.5, 5.5,
18.5 Hz, 1H), 1.33 (d, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 214.0, 159.5, 129.5, 129.4, 113.9, 80.2, 71.6, 57.7, 55.3, 39.5, 17.2.
HRMS (TOF CI+) calcd for [C13H18O4 + NH4]+ 256.1549, found
256.1540.
General Intramolecular Hydrosilylation Procedure (Com-
pounds 21−24, 28, and 29). To a solution of the β-hydroxy ketone
(1 equiv) in DCM (0.1 M relative to the hydroxy ketone substrate) at
0 °C were added triethylamine (6.0 equiv), imidazole (3.0 equiv), and
diphenylchlorosilane (3.0 equiv), and the resulting homogeneous
mixture was allowed to warm to room temperature slowly and stirred
for 15 h. The reaction mixture was transferred to a round-bottom flask
with hexanes (15 mL) and placed in a freezer (0 °C) for 2 h. The
resulting ammonium salts were removed by filtration through Celite,
and the filtrate was concentrated in vacuo. The crude product was
redissolved in THF (0.2 M relative to the hydroxy ketone substrate) at
0 °C. A solution of TBAF (1.0 M, 9.0 equiv) was then added, and the
mixture was warmed to room temperature for 1 h. The reaction was
quenched with aq. NH4Cl (15 mL), and the mixture was extracted
with ethyl acetate (3 × 15 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica (1:1 hexanes/ethyl
acetate).
(3R,4S)-4-Phenylpentane-1,3-diol/(3S,4R)-4-Phenylpentane-1,3-
diol (21). (0.060 g, 68%, dr >10:1 in favor of the anti-propionate
23
1
product by comparison to literature data ). H NMR (500 MHz,
CDCl3): δ 7.38−7.30 (m, 2H), 7.26−7.19 (m, 3H), 3.95−3.80 (m,
3H), 2.79 (quin, J = 7.0 Hz, 1H), 2.58 (bs, 1H), 2.02 (m, 1H), 1.91−
1.85 (m, 1H), 1.70−1.62 (m, 1H), 1.28 (d, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 143.2, 128.9, 128.8, 128.3, 128.0, 127.1, 62.0,
46.8, 35.8, 17.8 cm−1.
(3R,4S)/(3S,4S)-4-((4-Methoxybenzyl)oxy)pentane-1,3-diol (22).
(0.038 g, 83%, dr ∼1:1). Spectral data for the mixture of
stereoisomers: IR (neat): 3378, 2935, 1612, 1513, 1245, 1092, 1032,
1
821, 730 cm−1. H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 9.0 Hz,
4H), 6.88 (d, J = 9.0 Hz, 4H), 4.60 (d, J = 11.0 Hz, 2H), 4.55 (d, J =
11.0 Hz, 1H), 4.42 (d, J = 11.0 Hz, 1H), 4.36 (d, J = 11.5 Hz, 2H),
3.90 (m, 1H), 3.80 (s, 6H), 3.67 (m, 2H), 3.50 (m, 1H), 3.40 (q, J =
5.5 Hz, 2H), 1.75−1.62 (m, 4H), 1.17 (d, J = 6.5 Hz, 6H). 13C NMR
(125 MHz, CDCl3): δ 159.3, 159.2, 130.4, 130.2, 129.5, 129.3, 78.1,
76.8, 75.0, 73.3, 70.7, 70.4, 61.4, 61.2, 55.3, 34.3, 33.7, 15.3, 14.0.
(R)-5-Hydroxy-1-((4-methoxybenzyl)oxy)-2-methylpentan-3-one
(17). (0.098 g, 91%). [α]D20 = −2.03 (c 1.1, CH2Cl2). IR (neat): 3430,
2937, 1707, 1612, 1512, 1459, 1364, 1302, 1245, 1173, 1076, 1032,
1
818 cm−1. H NMR (500 MHz, CDCl3): δ 7.21 (d, J = 9.0 Hz, 2H),
6.87 (d, J = 9.0 Hz, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz,
1H), 3.90−3.80 (m, 2H), 3.80 (s, 3H), 3.59 (dd, J = 8.5, 9.5 Hz, 1H),
F
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HRMS (TOF ESI+) calcd for [C13H20O4 + Na]+ 263.1259, found
263.1267.
3398, 2972, 2936, 2877, 1707, 1612, 1512, 1245, 1173, 1085, 1030,
1
818 cm−1. H NMR (500 MHz, CDCl3): δ 7.20 (d, J = 8.5 Hz, 2H),
(3S,4R)-5-((4-Methoxybenzyl)oxy)-4-methylpentane-1,3-diol (23).
(0.085 g, 90%, dr 1.4:1 in favor of the (3S,4R) product by comparison
to literature data25). Spectral data for the mixture of stereoisomers: IR
6.87 (d, J = 9.0 Hz, 2H), 4.42 (d, J = 11.5 Hz, 1H), 4.38 (d, J =
11.0 Hz, 1H), 3.80 (s, 3H), 3.77 (m, 1H), 3.69−3.62 (m, 2H), 3.42
(dd, J = 5.0, 9.0 Hz, 1H), 3.12 (m, 1H), 2.88 (m, 1H), 2.52 (t, J =
6.5 Hz, O−H), 1.10 (d, J = 7.5 Hz, 3H), 1.04 (d, J = 7.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ 217.4, 159.3, 129.7, 129.3, 113.8, 73.1,
72.2, 64.6, 55.3, 48.5, 44.1, 13.9, 12.7. HRMS (TOF ESI+) calcd for
[C15H22O4 + Na]+ 289.1416, found 289.1407.
1
(neat): 3378, 2935, 1612, 1513, 1245, 1092, 1032, 821, 730 cm−1. H
NMR (500 MHz, CDCl3): δ 7.24 (d, J = 7.5 Hz, 4H), 6.88 (d, J =
8.0 Hz, 4H), 4.44 (s, 2H), 4.43 (s, 2H), 3.98 (d, J = 10.0 Hz, 1H),
3.85−3.80 (m, 4H), 3.80 (s, 6H), 3.76 (m, 1H), 3.60 (dd, J = 3.5,
9.0 Hz, 1H), 3.50 (q, J = 7.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 1H), 3.33
(bs, OH), 3.18 (bs, OH), 2.93 (bs, OH), 1.94−1.86 (m, 2H), 1.80−
1.63 (m, 4H), 1.56−1.51 (m, 1H), 0.92 (d, J = 7.0 Hz, 3H), 0.85 (d,
J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 159.6, 159.5, 130.1,
129.8, 129.6, 129.5, 114.1, 114.1, 77.6, 75.4, 75.2, 74.3, 73.4, 73.4, 62.4,
61.9, 55.5, 38.7, 38.5, 36.2, 35.2, 29.9, 13.8, 11.6.
(2S,4R)-1-Hydroxy-5-((4-methoxybenzyl)oxy)-2,4-dimethylpen-
tan-3-one (27). To a solution of TiCl4 (3.36 mL, 1.0 M, 3.36 mmol,
0.84 equiv) in DCM (4 mL) at 0 °C was added dropwise freshly
distilled Ti(i-PrO)4 (0.331 mL, 1.12 mmol, 0.28 equiv), and the mix-
ture was stirred for 10 min followed by 10 min at room temperature.
This mixture was then added via cannula to a solution of compound
25 (0.944 g, 4.0 mmol, 1.0 equiv) in DCM (8 mL) at −78 °C. The re-
sulting mixture was stirred for 2 min, after which i-Pr2NEt (0.766 mL,
4.4 mmol, 1.1 equiv) was added and the reaction was stirred for
30 min. Formaldehyde [obtained by pyrolysis of dry paraformaldehyde
(1.20 g, 40 mmol, 10.0 equiv)] as a precooled solution in diethyl ether
(5 mL) was then added via cannula, and the mixture was stirred for
1.5 h at −78 °C. The reaction was quenched with aq. NH4Cl (20 mL),
and the mixture was stirred vigorously at room temperature for 5 min.
MTBE (40 mL) was added along with H2O (20 mL), saturated
NaHCO3 (20 mL), and brine (20 mL). The layers were separated, and
the aqueous phase was extracted with MTBE (3 × 50 mL). The com-
bined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography on silica
(10:1 to 1:1 hexanes/EtOAc) provided compound 27 as a clear
colorless oil (0.620 g, 56%) as a 4:1 mixture of diastereomers in favor
of the (2S,4R) stereoisomer by comparison to literature data.41 Char-
acteristic signals for the major stereoisomer: IR (neat): 3447, 2970,
2934, 2877, 1707, 1612, 1513, 1458, 1362, 1302, 1245, 1087, 1032,
(3S,4R)-5-((tert-Butyldimethylsilyl)oxy)-4-methylpentane-1,3-diol
(24). (0.041 g, 83%, dr 2:1 in favor of the (3S,4R) stereoisomer26).
Spectral data for the mixture of stereoisomers: IR (neat): 3334, 2954,
1
2928, 2884, 2857, 1472, 1463, 1525, 1053, 8333, 774 cm−1. H NMR
(500 MHz, CDCl3): δ 4.49 (bs, 2H), 4.03 (d, J = 11.0 Hz, 1H), 3.90−
3.75 (m, 7H), 3.67 (dd, J = 6.0, 10.5 Hz, 1H), 3.57 (dd, J = 6.0, 9.5 Hz,
2H), 1.82−1.65 (m, 6H), 1.48 (m, 1H), 0.92 (d, J = 7.5 Hz, 3H), 0.89
(s, 18H), 0.82 (d, J = 6.5 Hz, 3H), 0.08 (s, 6H), 0.07 (s, 6H). 13C
NMR (125 MHz, CDCl3): δ 78.2, 75.9, 69.1, 69.3, 62.4, 61.9, 39.8,
39.4, 36.4, 35.4, 26.0, 26.0, 18.3, 18.3, 13.5, 11.1, −5.4, −5.5, −5.5.
HRMS (TOF ESI+) calcd for [C12H28O3Si + Na]+ 271.1705, found
271.1703.
(R)-1-((4-Methoxybenzyl)oxy)-2-methylpentan-3-one (25). To a
solution of (R)-methyl 3-((4-methoxybenzyl)oxy)-2-methylpropa-
noate40 (4.8 g, 20.0 mmol, 1.0 equiv) and N,O-dimethylhydroxylamine
(4.1 g, 42.0 mmol, 2.1 equiv) in THF (44 mL) at −20 °C was added
freshly prepared isopropylmagnesium chloride (28.0 mL, 3.0 M,
4.2 equiv) over 20 min, and the mixture was slowly warmed to 0 °C
and stirred for 1 h. The reaction was quenched with aq. NH4Cl
(40 mL), and the mixture was extracted with MTBE (4 × 40 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo, and the crude product was redissolved in
THF (140 mL) at 0 °C. Ethylmagnesium bromide (13.3 mL, 3.0M,
2.0 equiv) was added slowly over 5 min, and the mixture was stirred
for 45 min. The reaction was quenched with aq. NH4Cl (50 mL), and
the mixture was extracted with MTBE (3 × 50 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on silica provided com-
pound 25 as a clear pale-yellow oil (4.06 g, 86% over two steps). NMR
spectral data matched those reported in the literature:27 1H NMR
(500 MHz, CDCl3): δ 7.21 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0 Hz,
2H), 4.4 (d, J = 11.0 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H),
3.59 (dd, J = 8.0, 9.5 Hz, 1H), 3.42 (dd, J = 5.5, 9.5 Hz, 1H), 2.85 (m,
1H), 2.50 (q, J = 7.5 Hz, 2H), 1.06 (d, J = 7.5 Hz, 3H), 1.03 (t, J =
7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 213.9, 159.2, 130.2,
129.2, 113.7, 72.9, 72.1, 55.3, 49.2, 46.2, 35.3, 13.7, 7.6.
(2R,4R)-1-Hydroxy-5-((4-methoxybenzyl)oxy)-2,4-dimethylpen-
tan-3-one (26). To a solution of dicyclohexylboron chloride (5.2 mL,
1.0 M, 1.3 equiv) in diethyl ether (16 mL) at 0 °C was added
triethylamine (0.892 mL, 6.4 mmol, 1.6 equiv) followed by the drop-
wise addition of compound 25 (0.944 g, 4.0 mmol, 1.0 equiv) as a
solution in diethyl ether (8 mL). The mixture was stirred for 2 h and
then cooled to −78 °C, and formaldehyde [obtained by pyrolysis of
dry paraformaldehyde (1.20 g, 40 mmol, 10.0 equiv)] as a precooled
solution in diethyl ether (5 mL) was added via cannula. After 1 h, the
solution was warmed to 0 °C, and the reaction was quenched with
MeOH (16 mL) and pH 7.0 buffer (16 mL). Hydrogen peroxide
(3.0 mL, 30% aq.) was added dropwise, and the mixture was stirred
and allowed to warm to room temperature for 1 h. The reaction
mixture was extracted with DCM (3 × 50 mL), and the combined
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on silica (10:1 to 1:1
hexanes/EtOAc) provided compound 26 as a clear colorless oil (1.10 g,
100%) with approximately 20:1 diastereoseletivity in favor of the
(2R,4R) stereoisomer by comparison to literature data:41 IR (neat):
1
818 cm−1. H NMR (500 MHz, CDCl3): δ 7.20 (d, J = 8.5 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 4.41 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 12.0
Hz, 1H), 3.80 (s, 3H), 3.77 (m, 1H), 3.69−3.62 (m, 2H), 3.45 (dd, J =
4.5, 8.0 Hz, 1H), 3.19 (m, 1H), 2.90 (m, 1H), 2.71 (t, J = 7.0 Hz, 1H),
1.08 (d, J = 7.5 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 217.6, 159.4, 129.5, 129.4, 113.9, 73.2, 73.0,
65.0, 55.2, 48.9, 45.1, 13.4, 12.7. HRMS (TOF ESI+) calcd for
[C15H22O4 + Na]+ 289.1416, found 289.1407.
(2R,3S,4R)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentane-1,3-
diol (28). Prepared according to the general intramolecular hydro-
silylation procedure. (0.036 g, 68%, dr >10:1 in favor of the (2R,3S,4R)
stereoisomer by comparison to literature data42). IR (neat): 3264,
2969, 2935, 2890, 2870, 2839, 1612, 1514, 1299, 1247, 1058, 1039,
1025, 990, 817, 697 cm−1. 1H NMR (500 MHz, CDCl3): δ 7.24 (d, J =
8.5 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 4.46 (s, 1H), 3.81 (s, 3H),
3.80−3.73 (m, 2H), 3.69−3.64 (m, 1H), 3.59 (dd, J = 4.0, 9.5 Hz,
1H), 3.45 (t, J = 9.0 Hz, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 0.98 (d, J =
6.5 Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 159.4, 129.4, 113.9, 76.5, 73.3, 55.3, 36.3, 35.8, 13.1, 8.7.
(2S,3R,4R)-5-((4-Methoxybenzyl)oxy)-2,4-dimethylpentane-1,3-
diol (29). Prepared according to the general intramolecular hydro-
silylation procedure. (0.038 g, 72%, dr >10:1 in favor of the (2S,3R,4R)
stereoisomer43). IR (neat): 3384, 2963, 2932, 2876, 1612, 1513, 1459,
1
1245, 1078, 1032, 972, 819 cm−1. H NMR (500 MHz, CDCl3): δ
7.23 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 4.42 (s, 2H), 3.80
(s, 3H), 3.78−3.70 (m, 2H), 3.64 (d, J = 5.0 Hz, 2H), 3.44 (d, J =
5.5 Hz, 2H), 1.93 (m, 1H), 1.81 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H),
1.01 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 159.2,
130.2, 129.4, 113.8, 74.4, 73.0, 67.2, 55.3, 37.7, 36.3, 12.3, 11.6. HRMS
(TOF ESI+) calcd for [C15H24O4 + Na]+ 291.1572, found 291.1579.
(4S,5S)-4-((R)-1-((4-Methoxybenzyl)oxy)propan-2-yl)-5-methyl-
1,3-dioxan-2-one (29-carbonate). To a flask containing compound
29 (0.034 g, 0.127 mmol, 1.0 equiv) in toluene (2.0 mL) was added
carbonyldiimidazole (0.023 g, 0.14 mmol, 1.1 equiv), and the mixture
was heated to 115 °C for 18 h, cooled to room temperature, and con-
centrated in vacuo. Purification by flash column chromatography on
silica gel (4:1 to 1:1 hexanes/EtOAc) provided 29-carbonate (0.026 g,
G
dx.doi.org/10.1021/jo401293a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
75%) as a clear colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.21 (d,
J = 8.5 Hz, 1H, C(2)), 6.88 (d, J = 9.0 Hz, 1H, C(3)), 4.43 (dd, J = 3,
11 Hz, 1H, C(9)), 4.41 (d, J = 12.0 Hz, 1H, C(4)), 4.38 (d, J = 12.0
Hz, 1H, C(4)), 4.33 (dd, J = 2.5, 9.5 Hz, 1H, C(7)), 4.15 (dd, J =
1.5, 10.5 Hz, 1H, C(9)), 3.81 (s, 3H, C(1)), 3.41 (dd, J = 3.5, 9.5 Hz,
1H, C(5)), 3.34 (dd, J = 5.5, 9.5 Hz, 1H, C(5)), 2.17 (m, 1H, C(8)),
2.00 (m, 1H, C(6)), 1.15 (d, J = 7.0 Hz, 3H, C(10)), 1.11 (d, J =
7.5 Hz, 3H, C(11)). 13C NMR (125 MHz, CDCl3): δ 228.6, 159.3,
148.9, 129.9, 113.8, 84.4, 74.4, 73.0, 71.2, 55.3, 35.9, 35.7, 35.3, 27.7,
14.1, 10.1.
ACKNOWLEDGMENTS
■
Financial support from the Research Corporation (Cottrell
College Science Award ID7864), the National Science
Foundation (CHE-1151492), and the National Institutes of
Health (7R15GM093891-02) is gratefully acknowledged.
REFERENCES
■
(1) Larson, G. L.; Fry, J. L. Ionic and Organometallic-Catalyzed
Organosilane Reductions. In Organic Reactions, Vol. 71; Denmark, S.
E., Ed.; Wiley: Hoboken, NJ, 2008.
(2) Fry, J. L.; Orfanopoulos, M.; Adlington, M. G.; Dittman, W. R.,
Jr.; Silverman, S. B. J. Org. Chem. 1978, 43, 374.
(3) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633.
(4) Nagai, Y. Org. Prep. Proced. Int. 1980, 12, 13.
(5) Anderson, H. H. J. Am. Chem. Soc. 1958, 80, 5083.
(6) For selected examples of Lewis basic activation of silanes as
reducing agents, see: (a) Gan, L.; Brook, M. Can. J. Chem. 2006, 84,
(S)-4-Benzyl-3-((2S,3R,4S,5R,6R)-3,5-dihydroxy-7-((4-
methoxybenzyl)oxy)-2,4,6-trimethylheptanoyl)oxazolidin-2-one
(30). In an open-air atmosphere, compound 28 (0.054 g, 0.2 mmol,
1.0 equiv) was dissolved in DCM (2 mL) at 0 °C. Saturated aqueous
NaHCO3 (1.5 mL) was added, and the mixture was stirred vigorously.
Potassium bromide (0.0095 g, 0.08 mmol, 0.4 equiv), TEMPO
(0.0031 g, 0.02 mmol, 0.1 equiv), and NaOCl (0.4 mL, 6% aq.,
0.4 mmol, 2.0 equiv) were then added, and the mixture was stirred for
20 min. The reaction was quenched with H2O (10 mL), and the
mixture was extracted with DCM (3 × 10 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated in vacuo
to provide (2S,3R,4R)-3-hydroxy-5-((4-methoxybenzyl)oxy)-2,4-
dimethylpentanal, which was taken directly into the next reaction.
To a solution of (S)-4-benzyl-3-propionyloxazolidin-2-one (0.114 g,
0.5 mmol, 2.5 equiv) in DCM (3 mL) at 0 °C was added TiCl4
(0.55 mL, 1.0 M, 2.75 equiv), and the mixture was stirred for 5 min.
i-Pr2NEt (0.087 mL, 0.5 mmol, 2.5 equiv) was then added dropwise,
and the mixture was stirred for 20 min and then cooled to −78 °C.
N-Methyl-2-pyrrolidone (0.048 mL, 0.5 mmol, 2.5 equiv) was added,
and the mixture was stirred for 10 min. (2S,3R,4R)-3-Hydroxy-5-((4-
methoxybenzyl)oxy)-2,4-dimethylpentanal (0.046 g, 0.017 mmol,
1.0 equiv) was then added as a solution in DCM (3 mL), and the
mixture was stirred for 1 h at −78 °C before warming to 0 °C and
stirring for 2 h. The reaction was quenched with aq. NH4Cl (10 mL),
and the mixture was extracted with DCM (3 × 15 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography on silica (4:1 to 1:1
hexanes/EtOAc) provided compound 30 as a clear colorless oil (0.072
g, 85%) as a 4:1 mixture of diastereomers. IR (neat): 3446, 2968, 1775,
1697, 1612, 1513, 1454, 1382, 1363, 1245, 1209, 1100, 1077, 1032,
1416. (b) Malkov, A. V.; Liddon, A. J. S.; Ramírez-Lop
́ ́
ez, P.; Bendova,
L.; Haigh, D.; Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432.
̌
́
(c) Tan, M.; Zhang, Y.; Ying, J. Y. Adv. Synth. Catal. 2009, 351, 1390.
(d) Riduan, S. N.; Zhang, Y. G.; Ying, J. Y. Angew. Chem., Int. Ed. 2009,
48, 3322. For a review, see: Chuit, C.; Corriu, R. J. P.; Reye, C.; Young,
J. C. Chem. Rev. 1993, 93, 1371.
(7) O’Neil, G. W.; Miller, M. M.; Carter, K. P. Org. Lett. 2010, 12,
5350.
(8) Gronert, S.; Glaser, R.; Streitwieser, A. J. Am. Chem. Soc. 1989,
111, 3111.
(9) For examples of imidazolium silicates, see: (a) Boyer, J.; Corriu,
R. J. P.; Kopton, A.; Mazhar, M.; Poirier, M.; Royo, G. J. Organomet.
Chem. 1986, 301, 131. (b) Brelier
Poirier, M.; Royo, G. Organometallics 1986, 5, 388. (c) Boyer, J.;
Breliere, C.; Corriu, R. J. P.; Kopton, A.; Poirier, M.; Royo, G. J.
̀ ̀
e, C.; Carre, F.; Corriu, R. J. P.;
̀
Organomet. Chem. 1986, 311, C39−C43.
(10) For an example of coordinated imidazole stabilization by
amines, see: Balch, A. L.; Watkins, J. J.; Doonan, D. J. Inorg. Chem.
1979, 18, 1228.
(11) For a recent example of reductions involving a phenylsilane and
triethylamine, see: Frost, C. G.; Hartley, B. C. J. Org. Chem. 2009, 74,
3599.
1
970, 910, 824, 760, 729, 701 cm−1. H NMR (500 MHz, CDCl3): δ
(12) For a similar acid-promoted intramolecular carbonyl hydro-
silylation, see: (a) Anwar, S.; Davis, A. P. J. Chem. Soc., Chem. Commun.
1986, 831. (b) Davis, A. P.; Anwar, S. Tetrahedron 1988, 44, 3761.
(13) Martin, V. A.; Murray, D. H.; Pratt, N. E.; Zhao, Y. B.; Albizati,
K. F. J. Am. Chem. Soc. 1990, 112, 6965.
7.33 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 9.0 Hz,
2H), 7.21 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 4.69−4.65 (m,
1H), 4.49 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.22−4.16
(m, 2H), 4.14 (dd, J = 3.0, 9.5 Hz, 1H), 4.09 (q, J = 5.5 Hz, 1H),
4.02−3.95 (m, 2H), 3.80 (s, 3H), 3.62 (d, J = 5.5 Hz, 1H), 3.59 (dd,
J = 4.0, 9.0 Hz, 1H), 3.48 (t, J = 9.0 Hz, 1H), 3.31 (dd, J = 3.5,
13.0 Hz, 1H), 2.63 (dd, J = 10.0, 13.0 Hz, 1H), 2.02 (m, 1H), 1.76
(qd, J = 2.0, 7.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz,
3H), 0.73 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 177.2,
159.4, 153.0, 135.3, 129.5, 129.4, 129.0, 127.4, 113.9, 76.6, 74.9, 73.3,
66.0, 40.5, 38.2, 36.5, 35.7, 13.0, 12.2, 9.7. HRMS (TOF ESI+) calcd
for [C28H37O7N + Na]+ 522.2468, found 522.2460.
(14) For a recent review, see: Calow, A. D. J.; Whiting, A. Org.
Biomol. Chem. 2012, 10, 5485.
(15) For examples of terminal enone β-borylation reactions, see:
(a) Gao, M.; Thorpe, S. B.; Kleeberg, K.; Slebodnick, C.; Marder, T.
B.; Santos, W. L. J. Org. Chem. 2011, 76, 3997. (b) Thorpe, S. B.;
Calderone, J. A.; Santos, W. L. Org. Lett. 2012, 14, 1918.
(16) Some of the terminal enone substrates used in our studies
decomposed upon storage even at low temperatures (−18 °C) after
roughly 1 week.
(17) Bonet, A.; Guylas, H.; Fernandez, E. Angew. Chem., Int. Ed.
2010, 49, 5130.
(18) Chea, H.; Sim, H.; Yun, J. Bull. Korean Chem. Soc. 2010, 31, 551.
(19) Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513.
(20) Brozek, L. A.; Sieber, J. D.; Morken, J. P. Org. Lett. 2011, 13,
995.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental procedures and H and 13C NMR data
1
for compounds 1−12 and 14−30. This material is available free
of charge via the Internet at http://pubs.acs.org.
(21) Moure, A. L.; Arrayas, R. G.; Carretero, J. C. Chem. Commun.
2011, 47, 6701.
(22) Matteson, D. S. J. Organomet. Chem. 1999, 581, 51.
(23) Fordred, P. S.; Bull, S. D. Tetrahedron Lett. 2013, 54, 27.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: oneil@chem.wwu.edu.
(24) (a) Cher
9, 2199. (b) Cher
́
est, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
́
est, M.; Felkin, H. Tetrahedron Lett. 1968, 9, 2205.
Notes
(25) Ehrlich, G.; Hassfeld, J.; Eggert, U.; Kalesse, M. ChemEur. J.
The authors declare no competing financial interest.
2007, 14, 2232.
H
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(26) To determine the stereochemistries of the major and minor
isomers for 24, they were converted to the corresponding mono-PMB
1
derivatives: The H NMR data were then compared to those for the
two isomers given in the following reference: Phukan, P.; Sasmal, S.;
Maier, M. E. Eur. J. Org. Chem. 2003, 9, 1733.
(27) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
(28) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien,
M.; Scott, J. P.; Sereinig, N. Org. Lett. 2003, 5, 35.
(29) Solsona, J. G.; Nebot, J.; Romea, P.; Urpi, F. J. Org. Chem. 2005,
70, 6533−6535.
(30) Reduction of compound 26 using NaBH(OAc)3 gave 28 with
90:10 dr (see ref 28).
(31) For comparison, reduction of 27 using NaBH4 proceeded with
∼1:1 ds:
(32) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am.
Chem. Soc. 1995, 117, 12011.
(33) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883.
(34) A signal for the carbon directly attached to the boron atom was
not observed for compounds of this type as described in the following
reference: Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.;
Sawamura, M. J. Am. Chem. Soc. 2011, 133, 19310.
(35) Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891.
(36) O’Sullivan, P. T.; Buhr, W.; Fuhry, M. A. M.; Harrison, J. R.;
Davies, J. E.; Feeder, N.; Marshall, D. R.; Burton, J. W.; Holmes, A. B.
J. Am. Chem. Soc. 2004, 126, 2194.
(37) Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513.
(38) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee, Y.-S.; Jung,
J.-K.; Suh, Y.-G. Org. Lett. 2005, 7, 3159.
(39) Deagostino, A.; Prandi, C.; Venturello, P. Tetrahedron 1996, 52,
1433.
(40) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945.
(41) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien,
M.; Scott, J. P.; Sereinig, N. J. Org. Chem. 2005, 70, 150.
(42) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K.
G. Angew. Chem., Int. Ed. 2004, 43, 4629.
(43) The stereochemistry of the major product was determined by
detailed NMR analysis after its conversion to a cyclic carbonate:
I
dx.doi.org/10.1021/jo401293a | J. Org. Chem. XXXX, XXX, XXX−XXX