Diastereoselective peroxidation of derivatives of Baylis–Hillman adducts

Article abstract of DOI:10.1016/j.tet.2019.05.008

Cyclic derivatives of Baylis–Hillman adducts were synthesized. Cobalt-catalyzed peroxidation of these cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.

Full text of DOI:10.1016/j.tet.2019.05.008

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective peroxidation of derivatives of BayliseHillman
adducts
Dylan S. Zuckerman, K.A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclic derivatives of BayliseHillman adducts were synthesized. Cobalt-catalyzed peroxidation of these
cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.
© 2019 Elsevier Ltd. All rights reserved.
Received 11 March 2019
Received in revised form
1 May 2019
Accepted 2 May 2019
Available online xxx
Keywords:
Peroxide
Diastereoselective
Radical
Cobalt
Catalysis
1. Introduction
compounds muqubilin (1) [1e3], artemisinin (2) [4], plakinic acid
B (3) [5], and (ꢀ)-FINO2 (4) [6] share a common structural motif: a
The peroxide moiety is present in a wide variety of biologically
active compounds. The biologically active, peroxide-containing
stereogenic center bearing a methyl group and a peroxide group
(Fig. 1). Methods for stereoselective introduction of this group are
underdeveloped, however. While both enantiomers of FINO2 are
formed during synthesis, the enantiomer shown displays more
anticancer activity, making clear the necessity of the stereoselective
synthesis of peroxide-containing compounds [7].
One of the most common peroxidation methods, developed by
Isayama and Mukaiyama, employs a cobalt catalyst, triethylsilane,
and triplet O2 to introduce a peroxide functional group at the most
substituted position of an alkene (Scheme 1) [8]. This reaction is
Fig. 1. Peroxide-containing compounds that display biological activity.
* Corresponding author.
Scheme 1. General conditions for the peroxidation of alkenes using the Isayama-
E-mail address: kwoerpel@nyu.edu (K.A. Woerpel).
Mukaiyama method.
https://doi.org/10.1016/j.tet.2019.05.008
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
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D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
general for most alkenes, it is regioselective, and it produces a
bench-stable, protected peroxide product.
2. Results/discussion
Mechanistic studies revealed that a planar, carbon-centered
radical intermediate, such as 6, is formed during the catalytic cy-
cle (Scheme 1) [9,10]. Unstabilized carbon-centered radicals are
known to react with molecular O2 at rates nearing the diffusion
limit [11], so it is likely that O2 will form a bond from either face of
the sp2-hybridized radical intermediate, resulting in a mixture of
diastereomers of the silyl peroxide product. The lack of selectivity
can complicate efforts to use this reaction in synthesis (Scheme 2)
[6,12e18]. While there are examples of diastereoselective peroxi-
dation reactions, they tend to involve conformationally con-
strained, multicyclic substrates [19].
We hypothesized that stabilizing the radical intermediate would
slow the addition of O2 below the diffusion limit, and facial selec-
tivity would be observed [10]. BayliseHillman adducts were the
ideal test compounds because the carbonyl group neighboring the
alkene provides stabilization to the resultant radical intermediate
[20], leading to slower trapping by O2 and therefore higher dia-
stereoselectivity [21e23]. While there have been reports of metal-
Initial studies demonstrate that acyclic BayliseHillman adduct
derivatives did not undergo peroxidation reactions selectively
(Table
1).
The
peroxidation
of
a
triethylsilyl-protected
56:44 mixture of di-
BayliseHillman adduct 19 yielded
astereomers (entry 1). The peroxidation of tert-butyldiphenylsilyl-
protected BayliseHillman adduct 20 gave a 61:39 mixture of di-
astereomers, which represents a small improvement despite the
marked increase in size of the protecting group (entry 2) [28,29].
The peroxidation of acyl-protected BayliseHillman adduct 21
yielded a 77:23 mixture of diastereomers (entry 3).
Higher selectivity was observed, however, with the cyclic ace-
tonide 25 (Scheme 3). The peroxidation of acetonide 25 yielded an
85:15 mixture of diastereomers of the expected silyl peroxide
product 26, as well as a small amount of a single diastereomer of
the alcohol side product 26a. The diastereomers of silyl peroxide 26
were easily separable by chromatography both from each other and
from the alcohol 26a.
The stereochemical configurations of the silyl peroxide and
alcohol products were determined by nOe and chemical correla-
tion. The nOe of the major diastereomer of the silyl peroxide, syn-
26, shows an interaction between Ha and the methyl groups
occupying the top face of the ring, Meb and Mec (Fig. 2). There was
no nOe with the other methyl group on the acetal carbon atom,
Med. The minor diastereomer, anti-26, shows an nOe between He
and Meg, but to no other methyl groups on the molecule. The ste-
reochemical configuration of the alcohol side product 26a was
catalyzed peroxidations and hydrations of enones and a,b-unsat-
urated esters, either no stereoselectivity has been observed, or it
has not been noted [24e27]. In this paper, we show that these
substrates can undergo peroxidation reactions diastereoselectively,
provided that they are constrained into a cyclic framework.
Table 1
Diastereomeric ratios of peroxidation reactions of protected BayliseHillman ad-
ducts.
Entry
Compound
R1
dr
Yield (%)
1
2
3
22
23
24
SiEt3
SiPh2t-Bu
Ac
56:44
61:39
77:23
72
47
68
Scheme 3. Peroxidation of the cyclic acetonide 25.
Scheme 2. Peroxidation reactions resulting in a mixture of diastereomers.
Fig. 2. Relevant nOe data for syn- and anti-26.
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Table 2
Optimization of peroxidation reaction conditions.
Scheme 4. Reduction of syn-26 to alcohol 27.
Entry
Catalyst
Solvent
PhSiH3
(mol %)
dr
Yield
Yield
determined by reducing the major diastereomer of the silyl
26 (%)a
26a (%)a
peroxide, syn-26, to its corresponding alcohol 27 (Scheme 4).
1
2
3
4
5
6
7
8
Co(acac)2
Co(dbm)2
Co(hfac)2
Co(thd)2
Co(thd)2
Co(thd)2
Co(thd)2
Co(thd)2
Co(thd)2
Co(thd)2
Co(thd)2
PhCF3
PhCF3
PhCF3
PhCF3
hexanes
THF
0
0
0
0
0
0
0
0
77:23
85:15
e
23
36
0
7
11
e
Because these two alcohol products are not identical by 1H and 13
C
NMR spectroscopy, it may be deduced that the alcohol side product
26a has the same overall stereochemical configuration as the minor
silyl peroxide, anti-26.
85:15
81:19
95:5
90:10
>97:3
87:13
92:8
60
53
48
55
29
61
65
63
4
4
14
10
8
7
11
15
The product syn-26 is the major product likely because of
torsional effects. As O2 attacks the carbon-centered radical in
pathway A, the atoms rehybridize to form the product in a stable
chair conformation, 29 (Fig. 3), just as it would for reactions of the
analogous oxocarbenium ion system [30]. In pathway B, however, a
twist-chair conformation, 31, would be formed. This unfavorable
intermediate is high enough in energy to drive the reaction toward
the syn-silyl peroxide 30, despite the fact that both large groups are
on the same side of the molecule, forcing one to occupy an axial
position.
DCE
MeCN
PhCF3
PhCF3
PhCF3
9
10
11
5
10
20
95:5
The conditions were varied to optimize the diastereoselectivity
and yield of the peroxidation reaction (Table 2). Of the catalysts
tested, Co(thd)2 gave the highest yield and the same diaster-
eoselectivity as Co(dbm)2 (entries 1e4). A solvent screen showed
that while peroxidation reactions in tetrahydrofuran (THF),
dichloroethane (DCE), and acetonitrile (MeCN) all resulted in
higher diastereomeric ratios than in trifluorotoluene (PhCF3), the
yield in PhCF3 made it the most suitable solvent (entries 4e8).
We hypothesized that if the pathway leading to alcohol 26a
could be accelerated, diastereoselectivity of the peroxide products
would increase because only the intermediate that leads to the
minor diastereomer of the silyl peroxide reacts to form an alcohol
(Scheme 5). The addition of a small amount of phenylsilane [31]
increased the amount of alcohol 26a that was produced, which
increased the diastereomeric ratio of the silyl peroxide products 26
(Table 2, entries 4, 9e11). The overall yield of major silyl peroxide
syn-26 also increased slightly with the addition of phenylsilane.
The scope of the reaction was examined with other acetonide-
protected substrates, which were prepared in three steps. For
example, the BayliseHillman adduct 38 was synthesized from
racemic 3,5,5-methylhexanal (36, Scheme 6). In this case, the
resulting BayliseHillman adduct 38 was obtained as a 50:50
a
Yields determined by 1H NMR spectroscopy with mesitylene as the internal
standard.
Scheme 5. Promotion of the pathway to alcohol 33 by phenylsilane.
mixture of diastereomers. The ester 38 was hydrolyzed using
lithium hydroxide to form hydroxyacid 39. Recrystallization of
hydroxyacid 39 from toluene yielded a single diastereomer of the
acid, which was treated with 2-methoxypropene (40) and catalytic
pyridinium para-toluenesulfonate (PPTS) to form a single diaste-
reomer of acetonide 41, which has a similar substitution pattern to
plakinic acid B (3, Fig. 1). The stereochemical configuration of the
product, however, has not been deduced.
The peroxidation conditions were applied to these substrates,
which all underwent peroxidation with high diastereoselectivity
(Table 3). The peroxidation of branched substrates, such as 25 and
41, resulted in the highest diastereomeric ratios. The slightly lower
diastereomeric ratio observed after the peroxidation of citronellal-
derived lactone 45 may be due to the increased amount of trie-
thylsilane that must be added to this reaction for it to reach
completion. Two peroxidations must occur, so the ratio of trie-
thylsilane to phenylsilane was different in this instance, and may
have affected the product ratio. In each case, the major products,
syn-26 and syn-46e50, were easily separated from their corre-
sponding minor diastereomers and alcohol byproducts by flash
chromatography.
The isolated yields of silyl peroxides 26 and 46e50 are dimin-
ished as compared to the yields determined by 1H NMR
Fig. 3. Explanation of stereochemical configuration.
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D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
Scheme 7. Degradation of silyl peroxide syn-26 on silica gel.
Scheme 6. Representative synthesis of acetonide 41.
Table 3
Substrate scope.
Scheme 8. Demonstration of the stability of syn- and anti-26.
stability of the silyl peroxide suggests that the alcohol is formed
along a different pathway at the same time as the silyl peroxide is
formed.
The alcohol side product may originate from its corresponding
hydroperoxide. When hydroperoxide 53, prepared by 2,3- dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ)-catalyzed removal of the
triethylsilyl group of minor silyl peroxide product anti-26 [14,34],
was subjected to the standard reaction conditions for 4 h, 35%
conversion of the starting material was observed (Scheme 9). While
the expected compound, alcohol 26a, was the major product, a
small amount of minor silyl peroxide anti-26 was also produced. So,
though it is likely that hydroperoxide 53 is along the pathway to
alcohol 26a, it may also lead to the minor silyl peroxide anti-26.
An experiment was devised to probe the degree of electronic
stabilization of the radical by the carbonyl group and its effect on
stereoselectivity. The acetonide 56, without the carbonyl moiety,
was synthesized by reduction of tert-butyldimethylsilyl-protected
BayliseHillman adduct 54, followed by deprotection of the tert-
butyldimethylsilyl (TBS) group to form diol 55, and cyclization to
the acetonide 56 (Scheme 10). Upon peroxidation, the diastereo-
meric ratio of silyl peroxide 57 was found to be 64:36, which is
a Yields in parentheses were obtained by 1H NMR spectroscopy with mesitylene as
the internal standard.
spectroscopy due to an acid-catalyzed removal of the acetonide
group followed by a Hock-type rearrangement on silica gel [32].
When silyl peroxide syn-26 was stirred with silica gel, which is
weakly acidic [33], in a mixture of ethyl acetate and hexanes for 4 h,
65% conversion to ketone 52 was observed (Scheme 7). Attempts to
avoid this degradation, such as using neutral alumina during pu-
rification, led to even lower yields.
Control experiments show that the alcohol side products are not
the result of degradation of the minor silyl peroxides. When both
major diastereomer syn-26 and minor diastereomer anti-26 were
resubjected to the reaction conditions for longer than the standard
reaction time, there was no appreciable formation of their corre-
sponding alcohols 27 and 26a, respectively (Scheme 8). The
Scheme 9. Degradation of hydroperoxide 53.
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5
flow (flash chromatography) of the indicated solvent system on
silica gel (SiO2) 60 (230e400 mesh). Due to difficulties in purifi-
cation for some substrates, diagnostic 1H and 13C resonances were
assigned. Infrared (IR) spectra were recorded using a Thermo
Nicolet AVATAR Fourier Transform IR spectrometer using attenu-
ated total reflectance (ATR). High-resolution mass spectra (HRMS)
were recorded using an Agilent 6224 Accurate-Mass time-of-flight
spectrometer with atmospheric pressure chemical ionization
(APCI) or electrospray ionization (ESI) ionization sources. Melting
points were reported uncorrected. THF and CH2Cl2 were dried and
degassed using a solvent purification system. PhCF3 was purified
via short-path distillation. All reactions were run under a nitrogen
atmosphere in glassware that had been flame-dried under vacuum
unless otherwise stated. All reagents were commercially available
unless otherwise noted. Co(thd)2, Co(dbm)2, and Co(hfac)2 were
prepared using procedures reported below.
TBSO
O
OH
1.DIBAL–H
CH2Cl2
-Pr
-Pr
OMe
OH
2. -Bu4NF
THF
40% over 2 steps
OMe
Me
PPTS
THF
Me Me
Me Me
O
O
O
O
Et3SiH, Co(thd)2
-Pr
-Pr
PhCF3, O2 (balloon)
Et3SiOO Me
dr 65:35
72%
49%
4.2. Reaction procedures and characterization data
Scheme 10. Formation and peroxidation of acetonide 56.
4.2.1. Representative procedure for silyl protections (methyl 5-
methyl-2-methylene-3-((triethylsilyl)oxy)hexanoate (19))
much lower than that of the peroxidation of the acetonide with the
carbonyl group (Scheme 2). The decrease in diastereomeric ratio
suggests that the carbonyl group may provide some stabilization to
the radical, lowering the rate of addition of O2 to below the diffu-
sion limit. Other factors may also be important, however. Incor-
porating an sp3 hybridized substituent to the radical center will
most likely increase the degree of pyramidalization of the radical
[35]. A change in the shape of the radical will change the geometry
of the transition state during the addition of oxygen and affect
diastereoselectivity, which may explain why the diastereomeric
ratio of this reaction is greater than 50:50. It is clear, however, that
the carbonyl moiety is essential for peroxidations of this type to
proceed diastereoselectively.
To a solution of BayliseHillman adduct methyl 3-hydroxy-5-
methyl-2-methylenehexanoate (0.11 g, 0.62 mmol) in CH2Cl2
(6 mL) was added DMAP (0.040 g, 0.33 mmol) and imidazole
(0.12 g, 1.8 mmol), and chlorotriethylsilane (0.30 mL, 1.8 mmol).
After 16 h, H2O (10 mL) was added and the product was extracted
with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were washed
with saturated aqueous NaHCO3 (1 ꢁ 10 mL) and concentrated in
vacuo. Purification by flash chromatography (2:98 EtOAc:hexanes)
afforded 19 as a colorless oil (0.12 g, 73%): 1H NMR (400 MHz,
CDCl3)
d
6.21 (dd, J ¼ 1.6, 1.0, 1H), 5.92 (t, J ¼ 1.6, 1H), 4.65 (dd,
J ¼ 7.7, 3.6, 1H), 3.75 (s, 3H), 1.80e1.70 (m, 1H), 1.43e1.31 (m, 2H),
0.96 (t, J ¼ 7.8, 9H), 0.93 (d, J ¼ 6.3, 3H), 0.89 (d, J ¼ 6.3, 3H), 0.58 (q,
J ¼ 7.8, 6H); 13C NMR (100 MHz, CDCl3)
d 167.0 (C), 145.2 (C), 124.2
(CH2), 69.0 (CH), 51.8 (CH3), 48.2 (CH2), 24.7 (CH), 23.9 (CH3), 21.9
(CH3), 7.0 (CH3), 5.0 (CH2); IR (ATR) 2929, 1733 cmꢀ1; HRMS (APCI)
m/z calcd for C15H30NaO3Si (M þ Na)þ 309.1856, found 309.1859.
Anal. Calcd for C15H30O3Si: C, 62.89; H, 10.56. Found: C, 63.18; H,
10.28.
3. Conclusion
A method for the diastereoselective peroxidation of alkenes was
devised by modifying the original IsayamaeMukaiyama conditions.
Cyclic acetonides derived from BayliseHillman adducts were syn-
thesized and peroxidized. The addition of phenylsilane to the
standard peroxidation conditions promoted a separate reaction
pathway that produced an alcohol-containing product rather than
a silyl peroxide. Only the intermediate that led to the minor dia-
stereomer of the silyl peroxide was funneled down this alternate
route, resulting in high diastereomeric ratios between the silyl
peroxide products.
4.2.1.1. Methyl 3-((tert-butyldiphenylsilyl)oxy)-5-methyl-2-
methylenehexanoate (20). Following the representative procedure
for silyl protections, protected BayliseHillman adduct 20 was pre-
pared using BayliseHillman adduct methyl 3-hydroxy-5-methyl-2-
methylenehexanoate (0.10 g, 0.58 mmol), DMAP (0.038 g,
0.31 mmol), imidazole (0.13 g, 1.8 mmol), tert-butyldiphenylsilyl
chloride (0.45 mL, 1.7 mmol), and CH2Cl2 (2 mL). Purification by
flash chromatography (1.5:98.5 EtOAc:hexanes) afforded 10 as a
4. Experimental section
colorless oil (0.22 g, 93%): 1H NMR (400 MHz, CDCl3)
d 7.68 (dd,
J ¼ 8.0, 1.5, 2H), 7.59 (dd, J ¼ 8.0, 1.5, 2H), 7.45e7.30 (m, 6H), 6.19 (d,
J ¼ 1.5, 1H), 5.93 (t, J ¼ 1.3, 1H), 4.70 (t, J ¼ 5.3, 1H), 3.63 (s, 3H),
1.52e1.45 (m, 2H), 1.41e1.34 (m, 1H), 1.06 (s, 9H), 0.69 (d, J ¼ 6.2,
4.1. General experimental
All 1H spectra were recorded at ambient temperature using
Bruker AVIII-400 (400 MHz), AV-500 (500 MHz), and AVIII-600
(600 MHz) spectrometers. All 13C spectra were recorded at
ambient temperature using Bruker AVIII-400 (100 MHz), AV-500
(125 MHz), and AVIII-600 (150 MHz) spectrometers. The data
were reported as follows: chemical shifts are reported in ppm from
residual solvent peaks (1H NMR: CDCl3 d 7.26; C6D6 d 7.16.13C NMR:
3H), 0.62 (d, J ¼ 6.2, 3H); 13C NMR (100 MHz, CDCl3)
d 166.7 (C),
144.3 (C), 136.1 (2 CH), 134.2 (C), 133.9 (C), 129.72 (CH), 129.68 (CH),
127.60 (CH), 127.58 (CH), 125.2 (CH2), 70.2 (CH), 51.7 (CH3), 47.9
(CH2), 27.2 (CH3), 24.3 (CH), 23.3 (CH3), 22.6 (CH3), 19.5 (C); IR (ATR)
2954, 1721, 1630, 1590 cmꢀ1; HRMS (APCI) m/z calcd for C25H35O3Si
(M þ H)þ 411.2350, found 411.2342.
CDCl3 d 77.16; C6D6 d 128.06) on the
d
scale, multiplicity (s ¼ singlet,
4.2.1.2. Methyl 3-((tert-butyldimethylsilyl)oxy)-5-methyl-2-
methylenehexanoate (54). Following the representative procedure
for silyl protections, protected BayliseHillman adduct 54 was pre-
pared using BayliseHillman adduct methyl 3-hydroxy-5-methyl-2-
methylenehexanoate (0.50 g, 2.9 mmol), DMAP (0.18 g, 1.5 mmol),
imidazole (1.3 g, 19 mmol), tert-butyldimethylsilyl chloride (1.3 g,
br ¼ broad, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet),
coupling constants (Hz), and integration. Diastereoselectivities
were calculated from the integrations of diagnostic 1H NMR reso-
nances. Multiplicities of carbon peaks were determined using HSQC
experiments. Liquid chromatography was performed using forced
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D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
8.8 mmol), and CH2Cl2 (15 mL). Purification by flash chromatog-
raphy (2:98 EtOAc:hexanes) afforded 54 as a colorless oil (0.71 g,
85%). The spectroscopic data are consistent with the data reported:
and silyl-containing materials as a green oil (0.041 g, 47%). The
product was characterized as a 65:35 mixture of diastereomers: 1H
NMR (400 MHz, C6D6, characteristic peaks)
d 4.72e4.69 (m, 0.6H),
[36] 1H NMR (400 MHz, CDCl3)
d
6.21 (d, J ¼ 1.6, 1H), 5.91 (t, J ¼ 1.6,
4.37 (dd, J ¼ 7.9, 1.4, 0.4H), 3.46 (s, 1.7H), 3.36 (s, 1.3H), 1.97 (s, 1.3H),
1.89 (1.7H), 1.67e1.65 (m, 0.6H), 1.58e1.52 (m, 1.6H), 1.50e1.49 (m,
0.4H), 1.25 (s, 1H), 1.24 (s, 0.4H), 1.21 (s, 3.6H), 1.13 (s, 5.4H); 13C
1H), 4.62 (dd, J ¼ 8.1, 3.1, 1H), 3.76 (s, 3H), 1.80e1.69 (m, 1H),
1.43e1.30 (m, 2H), 0.93 (d, J ¼ 6.7, 3H), 0.90 (s, 9H), 0.89 (d, J ¼ 6.7,
3H), 0.06 (s, 3H), ꢀ0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
167.0,
NMR (100 MHz, C6D6) d 171.9 (C), 171.5 (C), 136.7 (CH), 136.4 (CH),
145.1, 124.4, 69.0, 51.8, 48.2, 26.0, 24.6, 24.0, 21.9, 18.3, ꢀ4.3, ꢀ4.9;
HRMS (APCI) m/z calcd for C15H31O3Si (M þ H)þ 287.2034, found
287.2037.
136.33 (CH), 136.27 (CH), 134.9 (C), 134.7 (C), 133.7 (C), 133.2 (C),
130.1 (CH), 130.0 (CH), 129.9 (CH), 129.8 (CH), 128.6 (4 CH), 91.6 (C),
89.4 (C), 74.4 (CH), 73.3 (CH), 51.6 (CH3), 51.3 (CH3), 44.0 (CH2), 42.3
(CH2), 27.2 (CH3), 27.0 (CH3), 24.8 (CH), 24.6 (CH), 23.4 (CH3), 23.2
(CH3), 21.8 (CH3), 21.2 (CH3), 20.1 (C), 19.8 (C), 15.0 (CH3), 14.6 (CH3),
7.0 (CH3), 6.9 (CH3), 4.2 (CH2), 4.1 (CH2); IR (ATR) 2955, 1748,
1590 cmꢀ1; HRMS (ESI) m/z calcd for C31H50NaO5Si2 (M þ Na)þ
584.3118, found 584.3134.
4.2.1.3. Methyl 3-acetoxy-5-methyl-2-methylenehexanoate (21).
To a solution of BayliseHillman adduct methyl 3-hydroxy-5-
methyl-2-methylenehexanoate (0.10 g, 0.60 mmol) in CH2Cl2
(2 mL) was added DMAP (0.009 g, 0.07 mmol) and acetic anhydride
(0.083 mL, 0.88 mmol). After 10 h, H2O (5 mL) was added, and the
product was extracted with CH2Cl2 (3 ꢁ 5 mL). The combined
organic extracts were washed with saturated aqueous NaHCO3
(5 mL) and H2O (5 mL) and concentrated in vacuo to afford 21 as a
colorless oil which required no further purification (0.105 g, 84%).
The spectroscopic data are consistent with the data reported: [37]
4.2.2.2. Methyl 3-acetoxy-2,5-dimethyl-2-((triethylsilyl)peroxy)hex-
anoate (24). Following the representative procedure for perox-
idations A, using acyl-protected BayliseHillman adduct 21 (0.035 g,
0.16 mmol), triethylsilane (0.052 mL, 0.33 mmol), Co(thd)2 (0.007 g,
0.016 mmol), in PhCF3 (1.1 mL) afforded crude 24 as a 77:23 mixture
of diastereomers. Purification by flash chromatography (1:99e3:97
EtOAc:hexanes) yielded major-24 as a colorless oil (0.029 g, 49%)
and minor-24 as a colorless oil (0.011 g, 19%).
1H NMR (400 MHz, CDCl3)
d 6.26 (s, 1H), 5.76 (s, 1H), 5.68 (dd,
J ¼ 9.0, 3.6, 1H), 3.78 (s, 3H), 2.08 (s, 3H), 1.72e1.50 (m, 3H), 0.94 (t,
J ¼ 6.5, 6H); 13C NMR (100 MHz, CDCl3)
d 170.2, 165.9, 141.0, 124.9,
70.7, 52.1, 43.9, 25.1, 23.3, 21.9, 21.3; HRMS (APCI) m/z calcd for
C
11H18NaO4 (M þ Na)þ 237.1097, found 237.1079.1
Major-24: 1H NMR (400 MHz, C6D6)
d
5.84 (dd, J ¼ 10.4, 1.8, 1H),
3.41 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H), 1.65e1.58 (m, 2H), 1.24 (ddd,
J ¼ 14.9,10.7, 1.7, 1H),1.03 (t, J ¼ 7.9, 9H), 0.95 (d, J ¼ 6.5, 3H), 0.81 (d,
4.2.2. Representative procedure for peroxidations A (methyl 2,5-
dimethyl-3-((triethylsilyl)oxy)-2-((triethylsilyl)peroxy)hexanoate
(22))
J ¼ 6.5, 3H), 0.72 (q, J ¼ 7.9, 6H); 13C NMR (100 MHz, C6D6)
d 170.9
(C), 169.3 (C), 88.7 (C), 71.8 (CH), 51.7 (CH3), 39.6 (CH2), 25.0 (CH),
23.7 (CH3), 21.4 (CH3), 20.6 (CH3), 15.4 (CH3), 6.9 (CH3), 4.1 (CH2); IR
(ATR) 2956, 1749 cmꢀ1; HRMS (ESI) m/z calcd for C17H35O6Si
(M þ H)þ 363.2197, found 363.2207.
To a solution of protected BayliseHillman adduct 19 (0.050 g,
0.17 mmol) in PhCF3 (1.2 mL) was added triethylsilane (0.056 mL,
0.35 mmol) and Co(thd)2 (0.007, 0.018 mmol). The reaction vessel
was flushed with O2 for 30 s while the reaction mixture was stirred
vigorously. After 16 h, solvent was removed in vacuo, and the
resulting mixture was filtered through a 2-cm plug of silica with a
5:95 EtOAc:hexanes mixture. The filtrate was concentrated in vacuo
to afford crude 22 as a 56:44 mixture of diastereomers. Attempted
purification by flash chromatography (1:99e2:98 EtOAc:hexanes)
yielded silyl peroxide 22 contaminated with small amounts of
cobalt-containing materials and silyl-containing materials as a
green oil (0.054 g, 72%). The product was characterized as a 57:43
mixture of diastereomers: 1H NMR (400 MHz, C6D6, characteristic
Minor-24: 1H NMR (400 MHz, C6D6)
d
5.85 (dd, J ¼ 10.2, 2.1, 1H),
3.44 (s, 3H), 1.73 (s, 3H), 1.70e1.61 (m, 2H), 1.66 (s, 3H), 1.58e1.51
(m, 1H), 1.03 (t, J ¼ 7.9, 9H), 1.02 (d, J ¼ 6.5, 3H), 0.88 (d, J ¼ 6.5, 3H),
0.72 (q, J ¼ 7.9, 6H); 13C NMR (100 MHz, C6D6)
d 171.5 (C), 169.3 (C),
87.4 (C), 71.8 (CH), 51.7 (CH3), 38.8 (CH2), 24.9 (CH), 23.9 (CH3), 21.7
(CH3), 20.5 (CH3), 16.2 (CH3), 6.9 (CH3), 4.1 (CH2); IR (ATR) 2956,
1749 cmꢀ1; HRMS (ESI) m/z calcd for C17H34NaO6Si (M þ Na)þ
388.2050, found 388.2049.
peaks)
d
4.49 (dd, J ¼ 8.0, 3.9, 0.43H), 4.29 (dd, J ¼ 9.4, 1.6, 0.57H),
4.2.2.3. Triethyl((4-isobutyl-2,2,5-trimethyl-1,3-dioxan-5-yl)peroxy)
silane (57). Following the representative procedure for the syn-
thesis of silyl peroxides A, using acetonide-protected diol 56
(0.059 g, 0.33 mmol), triethylsilane (0.11 mL, 0.95 mmol), Co(thd)2
(0.013 g, 0.033 mmol), and PhCF3 (4.3 mL) afforded crude 57 as a
65:35 mixture of diastereomers. Attempted purification by flash
chromatography (2:98 hexanes:EtOAc) yielded 57 contaminated
with small amounts of cobalt-containing materials and silyl-
containing materials as a green oil (0.078 g, 72%). The product
was characterized as a 65:35 mixture of diastereomers: 1H NMR
3.51 (s, 1.29H), 3.41 (s, 1.71H), 1.98e1.84 (m, 1H), 1.82 (s, 1.71H), 1.73
(s, 1.29H), 0.91 (d, J ¼ 6.6, 1.71H), 0.90 (d, J ¼ 6.8, 1.29H), 0.88 (d,
J ¼ 6.6, 1.71H), 0.85e0.60 (m, 12H); 13C NMR (100 MHz, C6D6)
d
172.1 (C), 171.8 (C), 91.6 (C), 89.7 (C), 73.0 (CH), 72.5 (CH), 51.43
(CH3), 51.36 (CH3), 43.6 (CH2), 42.8 (CH2), 24.9 (CH), 24.7 (CH), 24.1
(CH3), 24.0 (CH3), 22.5 (CH3), 21.5 (CH3), 14.6 (CH3), 13.9 (CH3), 7.3
(CH3), 7.2 (CH3), 6.93 (CH3), 6.91 (CH3), 5.9 (CH2), 5.8 (CH2), 4.21
(CH2), 4.17 (CH2); IR (ATR) 2956, 1749 cmꢀ1; HRMS (APCI) m/z calcd
for C21H46NaO5Si2 (M þ Na)þ 457.2776, found 457.2775.
(400 MHz, C6D6, characteristic peaks)
d
4.32 (d, J ¼ 12.3, 0.65H),
4.2.2.1. Methyl
3-((tert-butyldiphenylsilyl)oxy)-2,5-dimethyl-2-
4.24e4.21 (m, 0.70H), 3.75 (d, J ¼ 11.4, 0.35H), 3.66 (dd, J ¼ 10.4, 1.6,
0.65H), 3.41 (d, J ¼ 12.3, 0.65H), 1.97e1.84 (m, 1.65H), 1.55e1.51 (m,
0.65H), 1.50 (s, 1.95H), 1.42 (s, 1.05H), 1.39 (s, 1.05H), 1.38 (s, 1.05H);
((triethylsilyl)peroxy)hexanoate (23). Following the representative
procedure for peroxidations A, protected BayliseHillman adduct 20
(0.065 g, 0.16 mmol), triethylsilane (0.051 mL, 0.32 mmol), Co(thd)2
(0.007 g, 0.016 mmol), in PhCF3 (1.1 mL) afforded crude 23 as a
61:39 mixture of diastereomers. Attempted purification by flash
chromatography (0.5:95.5e1:99 EtOAc:hexanes) yielded 23
contaminated with small amounts of cobalt-containing materials
13C NMR (100 MHz, C6D6)
d 99.3 (C), 98.6 (C), 81.1 (C), 78.9 (C), 73.8
(CH), 70.6 (CH), 67.6 (CH2), 64.4 (CH2), 38.5 (CH2), 36.9 (CH2), 28.7
(CH3), 28.1 (CH3), 25.0 (CH), 24.6 (CH), 24.0 (CH3), 23.9 (CH3), 22.1
(CH3), 21.3 (CH3), 20.4 (CH3), 19.5 (CH3), 18.0 (CH3), 16.0 (CH3), 7.2
(CH3), 7.0 (CH3), 4.3 (CH2), 4.2 (CH2); IR (ATR) 2955 cmꢀ1; HRMS
(APCI) m/z calcd for C17H35O3Si (M þ H e H2O)þ 315.2350, found
315.2353.
1
Corresponds to a 7.57 ppm difference.
Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
https://doi.org/10.1016/j.tet.2019.05.008

D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
7
4.2.3. Representative procedure for acetonide formation (6-
isobutyl-2,2-dimethyl-5-methylene-1,3-dioxan-4-one (25))
(m, 2H), 1.78e1.63 (m, 2H), 1.38 (s, 3H), 1.11 (s, 3H); 13C NMR
(100 MHz, C6D6) 161.9 (C),158.7 (C),137.0 (C),133.4 (C),129.7 (CH),
d
To
a
solution of carboxylic acid 3-hydroxy-5-methyl-2-
124.2 (CH2), 114.3 (CH), 103.9 (C), 70.7 (CH), 54.8 (CH3), 37.8 (CH2),
30.2 (CH2), 28.8 (CH3), 24.0 (CH3); IR (ATR) 2941, 1728, 1627,
1611 cmꢀ1; HRMS (ESI) m/z calcd for C16H20NaO4 (M þ Na)þ
299.1254, found 299.1267.
methylenehexanoic acid (0.50 g, 3.2 mmol) in THF (16 mL) was
added 2-methoxypropene (40, 1.5 mL, 16 mmol) and PPTS (0.079 g,
0.32 mmol). After 3 h, saturated aqueous NaHCO3 (10 mL) was
added to the reaction mixture, and the product was extracted with
Et2O (3 ꢁ 10 mL). The combined organic layers were concentrated
in vacuo. Purification by flash chromatography (5:95 EtOAc:hex-
anes) afforded 25 as a colorless oil (0.39 g, 62%): 1H NMR (400 MHz,
4.2.3.4. 6-Heptyl-2,2-dimethyl-5-methylene-1,3-dioxan-4-one (44).
Following the representative procedure for acetonide formation,
acetonide 44 was prepared using carboxylic acid 3-hydroxy-2-
methylenedecanoic acid (0.25 g, 1.2 mmol), 2-methoxypropene
(40, 0.45 mL, 6.2 mmol), and PPTS (0.031 g, 0.12 mmol), in THF
(6.2 mL). Purification by flash chromatography (5:95 EtOAc:hex-
anes) afforded 44 as a colorless oil (0.20 g, 68%): 1H NMR (400 MHz,
CDCl3)
d
6.49 (d, J ¼ 2.3, 1H), 5.57 (d, J ¼ 2.3, 1H), 4.75 (dd, J ¼ 9.8,
3.1, 1H), 1.95e1.85 (m, 1H), 1.72 (ddd, J ¼ 14.0, 9.8, 4.0, 1H), 1.61 (s,
3H), 1.58 (s, 3H), 1.48 (ddd, 14.0, 9.5, 4.0, 1H), 0.96 (d, J ¼ 6.7, 3H),
0.95 (d, J ¼ 6.7, 3H); 13C NMR (150 MHz, CDCl3)
d 163.4 (C), 137.0 (C),
124.9 (CH2), 104.9 (C), 69.8 (CH), 44.6 (CH2), 29.0 (CH3), 24.3 (CH),
24.1 (CH3), 23.7 (CH3), 21.5 (CH3); IR (ATR) 2958, 1720, 1610 cmꢀ1
;
CDCl3)
d
6.48 (d, J ¼ 2.2, 1H), 5.58 (d, J ¼ 2.2, 1H), 4.73e4.69 (m, 1H),
HRMS (APCI) m/z calcd for C11H17O2 (M þ H e H2O)þ181.1223,
found 181.1223. Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
66.78; H, 9.08.
1.81e1.64 (m, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 1.51e1.36 (m, 2H),
1.34e1.22 (m, 8H), 0.88 (t, J ¼ 6.9, 3H); 13C NMR (150 MHz, CDCl3)
d
163.5 (C), 136.6 (C), 125.1 (CH2), 104.8 (C), 71.8 (CH), 35.8 (CH2),
31.9 (CH2), 29.5 (CH2), 29.3 (CH2), 28.9 (CH3), 24.7 (CH2), 24.3 (CH3),
22.8 (CH2), 14.2 (CH3); IR (ATR) 2926, 1732, 1628 cmꢀ1; HRMS
(APCI) m/z calcd for C14H24NaO3 (M þ Na)þ 264.1652, found
264.1657. Anal. Calcd for C14H24O3: C, 69.96; H, 10.07. Found: C,
69.96; H, 10.00.
4.2.3.1. 2,2-Dimethyl-5-methylene-6-(2,4,4-trimethylpentyl)-1,3-
dioxan-4-one (41). Following the representative procedure for
acetonide formation, acetonide 41 was prepared using carboxylic
acid 39 (0.16 g, 0.75 mmol), 2-methoxypropene (40, 0.36 mL,
3.7 mmol), and PPTS (0.019 g, 0.075 mmol), in THF (3.7 mL). Puri-
fication by flash chromatography (5:95 EtOAc:hexanes) afforded a
single diastereomer of 41 as
a
white solid (0.13 g, 70%):
4.2.3.5. 6-(2,6-Dimethylhept-5-en-1-yl)-2,2-dimethyl-5-methylene-
1,3-dioxan-4-one (45). Following the representative procedure for
acetonide formation, acetonide 45 was prepared using carboxylic
acid 3-hydroxy-5,9-dimethyl-2-methylenedec-8-enoic acid (0.21 g,
0.93 mmol), 2-methoxypropene (40, 0.45 mL, 4.6 mmol), and PPTS
(0.026 g, 0.10 mmol), in THF (4.6 mL). Purification by flash chro-
matography (10:90 EtOAc:hexanes) afforded 45 as a colorless oil
(0.15 g, 60%). The product was characterized as a 50:50 mixture of
mp ¼ 40e41 ꢂC; 1H NMR (400 MHz, CDCl3)
d
6.48 (d, J ¼ 2.2, 1H),
5.56 (d, J ¼ 2.2, 1H), 4.75e4.71 (m, 1H), 1.89e1.76 (m, 2H), 1.61 (s,
3H), 1.59 (s, 3H), 1.48e1.40 (m, 1H), 1.20 (dd, J ¼ 13.9, 4.5, 1H), 1.13
(dd, J ¼ 13.9, 5.5, 1H), 0.97 (d, J ¼ 6.7, 3H), 0.90 (s, 9H); 13C NMR
(100 MHz, CDCl3)
d 163.4 (C), 137.1 (C), 124.9 (CH2), 104.9 (C), 69.7
(CH), 52.0 (CH2), 45.5 (CH2), 31.4 (C), 30.1 (CH3), 28.9 (CH3), 25.2
(CH), 24.3 (CH3), 21.8 (CH3); IR (ATR) 2952, 1733, 1628 cmꢀ1; HRMS
(APCI) m/z calcd for C15H25O2 (M þ H e H2O)þ 237.1849, found
237.1846. Anal. Calcd for C15H26O3: C, 70.83; H, 10.30. Found C,
71.08; H, 10.37.
diastereomers: 1H NMR (400 MHz, CDCl3)
d
6.48 (dd, J ¼ 4.5, 2.4,
1H), 5.56 (t, J ¼ 1.9, 1H), 5.12e5.07 (m, 1H), 4.78e4.75 (m, 1H),
2.09e1.92 (m, 2H), 1.83e1.71 (m, 1.5H), 1.69 (s, 3H), 1.64 (ddd,
J ¼ 8.0, 5.6, 1.7, 1H), 1.61 (s, 6H), 1.58 (s, 3H), 1.50e1.39 (m, 1H),
4.2.3.2. 2,2-Dimethyl-5-methylene-6-phenethyl-1,3-dioxan-4-one
(42). Following the representative procedure for acetonide for-
mation, acetonide 42 was prepared using carboxylic acid 3-hy-
droxy-2-methylene-5-phenylpentanoic acid (0.047 g, 0.23 mmol),
2-methoxypropene (40, 0.11 mL, 1.1 mmol), and PPTS (0.006 g,
0.023 mmol), in THF (1.1 mL). Attempted purification by flash
chromatography (10:90 EtOAc:hexanes) afforded 42 (0.036 g, 64%)
as a colorless oil with unknown minor impurities that can be
detected by 1H NMR spectroscopy: 1H NMR (400 MHz, CDCl3)
1.37e1.11 (m, 1.5H), 0.96 (d, J ¼ 5.8, 1.5H), 0.94 (d, J ¼ 5.8, 1.5H); 13
C
NMR (100 MHz, CDCl3)
d 163.40 (C), 163.37 (C), 137.05 (C), 137.03
(C), 131.7 (C), 131.6 (C), 125.0 (CH2), 124.9 (CH2), 124.7 (CH), 124.6
(CH), 104.9 (C), 104.8 (C), 69.9 (CH), 69.5 (CH), 43.0 (CH2), 42.8
(CH2), 38.0 (CH2), 36.0 (CH2), 29.0 (2 CH3), 28.8 (CH), 28.4 (CH), 25.9
(2 CH3), 25.5 (CH2), 25.3 (CH2), 24.3 (2 CH3), 20.5 (CH3), 19.0 (CH3),
17.83 (CH3), 17.82 (CH3); IR (ATR) 2916, 1733, 1628 cmꢀ1; HRMS
(ESI) m/z calcd for C16H26NaO3 (M þ Na)þ 290.1808, found
290.1806. Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C,
71.92; H, 9.94.
d
7.32e7.28 (m, 2H), 7.22e7.19 (m, 3H), 6.51 (d, J ¼ 2.2, 1H), 5.58 (d,
J ¼ 2.2, 1H), 4.68 (ddd, J ¼ 10.0, 5.9, 2.2, 1H), 2.86e2.70 (m, 2H),
2.13e1.98 (m, 2H), 1.63 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d
163.2 (C), 141.3 (C), 136.2 (C), 128.6 (2 CH), 126.3 (CH),125.4
4.2.3.6. 4-Isobutyl-2,2-dimethyl-5-methylene-1,3-dioxane
(56).
(CH2), 104.9 (C), 70.6 (CH), 37.4 (CH2), 30.8 (CH2), 28.9 (CH3), 24.4
Following the representative procedure for acetonide formation,
acetonide 56 was prepared using diol 55 (0.14 g, 0.94 mmol), 2-
methoxypropene (40, 0.45 mL, 4.7 mmol), and PPTS (0.052 g,
0.21 mmol) in THF (4.7 mL). Purification by flash chromatography
(4:96 Et2O:hexanes) and bulb-to-bulb distillation (0.3 torr, 75 ꢂC)
yielded acetonide 56 as a colorless oil (0.084 g, 49%): 1H NMR
(CH3); IR (ATR) 2996, 1729, 1628; HRMS (ESI) m/z calcd for
C
15H20NO2 (M þ NH4 e H2O)þ 246.1489, found 246.1478.
4.2.3.3. 6-(4-Methoxyphenethyl)-2,2-dimethyl-5-methylene-1,3-
dioxan-4-one (43). Following the representative procedure for
acetonide formation, acetonide 43 was prepared using carboxylic
acid 3-hydroxy-5-(4-methoxyphenyl)-2-methylenepentanoic acid
(0.24 g, 1.0 mmol), 2-methoxypropene (40, 0.51 mL, 5.1 mmol), and
PPTS (0.026 g, 0.10 mmol), in THF (5.0 mL). Purification by flash
chromatography (15:85 EtOAc:hexanes) afforded 43 as a white
(400 MHz, C6D6)
d
4.66 (d, J ¼ 1.4, 1H), 4.59 (d, J ¼ 1.4, 1H), 4.34 (d,
J ¼ 10.1, 1H), 4.20 (dd, J ¼ 13.5, 1.4, 1H), 4.11 (dd, J ¼ 13.5, 1.0, 1H),
2.07e1.94 (m, 1H), 1.69 (ddd, J ¼ 13.5, 10.1, 4.1, 1H), 1.42 (s, 3H),
1.41e1.35 (m, 1H), 1.36 (s, 3H), 0.92 (d, J ¼ 6.8, 3H), 0.88 (d, J ¼ 6.8,
3H); 13C NMR (100 MHz, C6D6)
d 148.3 (C),105.3 (CH2), 99.6 (C), 68.5
solid (0.12 g, 43%): mp ¼ 51e53 ꢂC; 1H NMR (400 MHz, C6D6)
d
6.95
(CH), 64.2 (CH2), 41.6 (CH2), 27.2 (CH3), 24.1 (CH3), 24.0 (CH), 22.1
(CH3), 21.5 (CH3); IR (ATR) 2956, 1657 cmꢀ1; HRMS (APCI) m/z calcd
for C11H19O (M þ H e H2O)þ 167.1430, found 167.1428.
(d, J ¼ 8.5, 2H), 6.81 (d, J ¼ 8.5, 2H), 6.41 (d, J ¼ 2.3, 1H), 4.89 (d,
J ¼ 2.3, 1H), 4.23 (ddd, J ¼ 10.1, 5.9, 2.3, 1H), 3.35 (s, 3H), 2.68e2.51
Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
https://doi.org/10.1016/j.tet.2019.05.008

8
D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
4.2.4. Representative procedure for peroxidation B (6-isobutyl-
2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-dioxan-4-one (26) and
(5R*,6R*)-5-hydroxy-6-isobutyl-2,2,5-trimethyl-1,3-dioxan-4-one
(26a))
(1:99e10:90 EtOAc:hexanes) yielded impure syn-46 as a green oil
(0.079 g), impure anti-46 as a green oil (0.010 g), and impure
alcohol 46a as a green oil (0.010 g), all of which were contaminated
with a small amount of cobalt-containing materials. Characteriza-
tion of syn-46 was obtained from a sample that was further purified
by flash chromatography (3:97 EtOAc:hexanes) to yield a colorless
oil (0.069 g, 38%). Characterization of anti-46 was obtained from a
sample that was further purified by flash chromatography (1:99) to
yield a colorless oil with minor impurities that can be detected by
1H NMR (0.003 g, 2%). Characterization of alcohol 46a was obtained
from a sample that was further purified by flash chromatography
(10:90 EtOAc:hexanes) to yield a white solid (0.007 g, 3%). The
stereochemical configurations of 46 and 46a were inferred by
comparison to the 1H NMR chemical shifts of 26 and 26a.
To a solution of acetonide 25 (0.11 g, 0.54 mmol) in PhCF3
(3.6 mL) was added triethylsilane (0.18 mL, 1.1 mmol), phenylsilane
(0.55 mL, 0.2 M in PhCF3, 0.11 mmol), and Co(thd)2 (0.019 g,
0.044 mmol). The reaction vessel was flushed with O2 for 30 s while
the reaction mixture was stirred vigorously. After 1.5 h, the solvent
was removed in vacuo, and the resulting mixture was filtered
through a 2-cm plug of silica with 10:90 EtOAc:hexanes. The filtrate
was concentrated in vacuo to afford a crude mixture of syn-26, anti-
26, and alcohol 26a in a 78:4:18 ratio (corresponding to a 95:5 ratio
of diastereomeric silyl peroxides). Separation of the products by
flash chromatography (2:98e10:90 EtOAc:hexanes) yielded impure
syn-26 as a green oil (0.077 g), anti-26 as a green oil (0.005 g, 3%),
and alcohol 26a as a green oil (0.018 g, 15%), all of which were
contaminated with a small amount of cobalt-containing materials.
Characterization of syn-26 was obtained from a sample that was
further purified by flash chromatography (1:99e3:97 EtOAc:hex-
anes) to yield a colorless oil (0.063 g, 33%). Characterization of anti-
26 was obtained from a sample from an unoptimized reaction that
maximized the amount of minor diastereomer produced. Charac-
terization of alcohol 26a was obtained from a sample that was
further purified by flash chromatography (10:90 EtOAc:hexanes) to
yield a colorless oil.
(5R*,6S*)-2,2,5-Trimethyl-5-((triethylsilyl)peroxy)-6-(2,4,4-
trimethylpentyl)-1,3-dioxan-4-one (syn-46): 1H NMR (400 MHz,
C6D6)
d
3.85 (dd, J ¼ 10.6, 2.1, 1H), 2.28 (ddd, J ¼ 14.3, 10.7, 3.5, 1H),
1.88e1.77 (m,1H),1.47 (s, 3H),1.26 (dd, J ¼ 14.0, 5.1,1H),1.27 (s, 3H),
1.25e1.21 (m, 1H), 1.20 (s, 3H), 1.13 (dd, J ¼ 14.0, 5.3, 1H), 1.08 (t,
J ¼ 7.9, 9H), 0.95 (s, 9H), 0.85 (d, ¼ 6.8, 3H), 0.80e0.74 (m, 6H); 13
C
NMR (100 MHz, C6D6) d 166.8 (C), 105.6 (C), 81.5 (C), 74.5 (CH), 52.2
(CH2), 37.1 (CH2), 31.3 (C), 30.2 (CH3), 29.4 (CH3), 25.6 (CH), 24.1
(CH3), 21.7 (CH3), 18.5 (CH3), 7.0 (CH3), 4.2 (CH2); IR (ATR) 2954,
1750 cmꢀ1; HRMS (APCI) m/z calcd for C21H42NaO5Si (M þ Na)þ
425.2694, found 425.2675.
(5R*,6S*)-2,2,5-Trimethyl-5-((triethylsilyl)peroxy)-6-(2,4,4-
(5R*,6S*)-6-Isobutyl-2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-
trimethylpentyl)-1,3-dioxan-4-one (anti-46): 1H NMR (400 MHz,
dioxan-4-one (syn-26): 1H NMR (400 MHz, C6D6)
d
3.82 (dd, J ¼ 10.2,
C6D6)
d
5.05 (d, J ¼ 10.2, 1H), 1.85e1.78 (m, 1H), 1.56 (ddd, J ¼ 13.9,
2.0, 1H), 2.13 (ddd, J ¼ 14.4, 10.3, 4.2, 1H), 1.84e1.74 (m, 1H), 1.48 (s,
3H), 1.28e1.21 (m, 1H), 1.25 (s, 3H), 1.18 (s, 3H), 1.07 (t, J ¼ 8.0, 9H),
0.90 (d, J ¼ 6.8, 3H), 0.84e0.71 (m, 9H); 13C NMR (150 MHz, C6D6)
10.5, 3.2,1H),1.48e1.42 (m,1H),1.46 (s, 3H),1.30 (s, 3H),1.28 (s, 3H),
1.25 (d, J ¼ 4.8, 1H), 1.18e1.15 (m, 1H), 1.12e1.08 (m, 12H), 0.93 (s,
9H), 0.81 (q, J ¼ 7.8, 6H); 13C NMR (100 MHz, C6D6)
d 168.7 (C), 105.4
d
166.7 (C), 105.6 (C), 81.6 (C), 74.7 (CH), 36.8 (CH2), 29.5 (CH3), 24.7
(C), 83.0 (C), 68.6 (CH), 52.0 (CH2), 37.7 (CH2), 31.3 (C), 30.2 (CH3),
29.3 (CH3), 26.3 (CH), 24.8 (CH3), 22.2 (CH3), 16.8 (CH3), 7.0 (CH3),
4.2 (CH2); IR (ATR) 2956, 1762 cmꢀ1; HRMS (APCI) m/z calcd for
(CH), 24.1 (CH3), 23.7 (CH3), 21.4 (CH3), 18.5 (CH3), 7.0 (CH3), 4.2
(CH2); IR (ATR) 2957, 1751 cmꢀ1; HRMS (APCI) m/z calcd for
C
C
20H35O5Si (M þ H)þ 387.2561, found 387.2561. Anal. Calcd for
C
21H43O5Si (M þ H)þ 403.2874, found 403.2878.
17H34O5Si: C, 58.92; H, 9.89. Found: C, 59.19; H, 9.98.
(5R*,6S*)-5-Hydroxy-2,2,5-trimethyl-6-(2,4,4-trimethylpentyl)-
(5R*,6R*)-6-Isobutyl-2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-
1,3-dioxan-4-one (46a): mp ¼ 94e96 ꢂC; 1H NMR (400 MHz, C6D6)
dioxan-4-one (anti-26): 1H NMR (400 MHz, C6D6)
d
5.00 (dd, J ¼ 6.1,
d
4.03 (dd, J ¼ 9.9, 1.9, 1H), 3.25 (s, 1H), 1.76e1.65 (m, 1H), 1.57 (ddd,
4.4, 1H), 1.85e1.74 (m, 1H), 1.44 (s, 3H), 1.41e1.37 (m, 2H), 1.31 (s,
3H), 1.25 (s, 3H), 1.08 (t, J ¼ 8.0, 9H), 0.97 (d, J ¼ 6.8, 3H), 0.93 (d,
J ¼ 13.9, 10.0, 3.8, 1H), 1.49 (ddd, J ¼ 13.9, 10.0, 2.1, 1H), 1.27 (s, 3H),
1.24 (s, 3H), 1.19 (dd, J ¼ 13.9, 4.6, 1H), 1.15 (s, 3H), 1.06 (dd, J ¼ 13.9,
5.7, 1H), 0.91 (d, J ¼ 6.7, 3H), 0.89 (s, 9H); 13C NMR (100 MHz, C6D6)
J ¼ 6.8, 3H), 0.82e0.76 (m, 6H); 13C NMR (125 MHz, C6D6)
d 169.0
(C), 105.3 (C), 83.0 (C), 68.6 (CH), 37.2 (CH2), 29.3 (CH3), 25.2 (CH),
24.7 (CH3), 23.8 (CH3), 22.0 (CH3), 16.8 (CH3), 7.0 (CH3), 4.2 (CH2); IR
(ATR) 2957, 1761 cmꢀ1; HRMS (ESI) m/z calcd for C17H35O5Si
(M þ H)þ 347.2248, found 347.2260. Anal. Calcd for C17H34O5Si: C,
58.92; H, 9.89. Found: C, 59.19; H, 9.86.
d 175.0 (C), 106.9 (C), 72.4 (CH), 71.1 (C), 51.8 (CH2), 37.2 (CH2), 31.2
(C), 30.2 (CH3), 28.8 (CH3), 25.9 (CH), 24.5 (CH3), 21.9 (CH3), 21.0
(CH3); IR (ATR) 3461, 2952, 1733 cmꢀ1; HRMS (APCI) m/z calcd for
C15H28NaO4 (M þ Na)þ 295.1880, found 295.1887.
(5R*,6R*)-5-Hydroxy-6-isobutyl-2,2,5-trimethyl-1,3-dioxan-4-one
4.2.4.2. 2,2,5-Trimethyl-6-phenethyl-5-((triethylsilyl)peroxy)-1,3-
dioxan-4-one (47) and (5R*,6R*)-5-hydroxy-2,2,5-trimethyl-6-
phenethyl-1,3-dioxan-4-one (47a). Following the representative
procedure for the synthesis of silyl peroxides B, using acetonide 42
(0.030 g, 0.12 mmol), triethylsilane (0.039 mL, 0.24 mmol), phenyl-
silane (0.12 mL, 0.2 M in PhCF3, 0.024 mmol), Co(thd)2 (0.005 g,
0.012 mmol), and PhCF3 (0.8 mL) afforded crude syn-47, anti-47, and
alcohol 47a as a 77:5:18 mixture (corresponding to a 94:6 ratio of
diastereomeric silyl peroxides). Separation of the products by flash
chromatography (2:98e15:85 EtOAc:hexanes) yielded impure syn-
47 as a green oil (0.019 g), impure anti-39 as a green oil (0.001 g, 2%)
from which characterization was obtained, and impure alcohol 47a
as a green oil (0.004 g), all of which were contaminated with a small
amount of cobaltecontaining materials. Characterization of syn-47
was obtained from a sample that was further purified by flash
chromatography (3:97e5:95 EtOAc:hexanes) to yield a colorless oil
(0.016 g, 33%). Characterization of alcohol 47a was obtained from a
sample that was further purified by flash chromatography (15:85
EtOAc:hexanes) as a colorless oil with minor impurities that can be
(26a): 1H NMR (400 MHz, C6D6)
d
3.99 (dd, J ¼ 9.7, 2.3, 1H), 3.24 (s,
1H), 1.74e1.60 (m, 1H), 1.53e1.39 (m, 2H), 1.24 (s, 6H), 1.13, (s, 3H),
0.85 (d, J ¼ 6.8, 3H), 0.81 (d, J ¼ 6.8, 3H); 13C NMR (100 MHz, C6D6)
d
175.0 (C), 106.9 (C), 72.6 (CH), 71.1 (C), 36.7 (CH2), 28.9 (CH3), 25.0
(CH), 24.4 (CH3), 23.6 (CH3), 21.8 (CH3), 21.0 (CH3); IR (ATR) 3458,
2957, 1736 cmꢀ1; HRMS (APCI) m/z calcd for C11H21O4 (M þ H)þ
217.1434, found 217.1432.
4.2.4.1. 2,2,5-Trimethyl-5-((triethylsilyl)peroxy)-6-(2,4,4-
trimethylpentyl)-1,3-dioxan-4-one (46) and (5R*,6S*)-5-hydroxy-
2,2,5-trimethyl-6-(2,4,4-trimethylpentyl)-1,3-dioxan-4-one
(46a).
Following the representative procedure for the synthesis of silyl
peroxides B, using acetonide 41 (0.12 g, 0.45 mmol), triethylsilane
(0.15 mL, 0.91 mmol), phenylsilane (0.45 mL, 0.2 M in PhCF3,
0.090 mmol), Co(thd)2 (0.019 g, 0.045 mmol), and PhCF3 (3.0 mL)
afforded crude syn-46, anti-46, and alcohol 46a as a 79:2:19
mixture (corresponding to a >97:3 ratio of diastereomeric silyl
peroxides). Separation of the products by flash chromatography
Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
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D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
9
detected by 1H spectroscopy (0.002 g, 6%). The relative stereo-
chemical configurations of 47 and 47a were inferred by comparison
to the 1H NMR chemical shifts of 26 and 26a.
114.3 (CH), 105.8 (C), 81.5 (C), 75.3 (CH), 54.8 (CH3), 31.3 (CH2), 29.9
(CH2), 29.5 (CH3), 24.3 (CH3), 18.5 (CH3), 7.0 (CH3), 4.2 (CH2); IR
(ATR) 2956, 1748, 1612, 1513 cmꢀ1; HRMS (APCI) m/z calcd for
(5R*,6S*)-2,2,5-Trimethyl-6-phenethyl-5-((triethylsilyl)peroxy)-
C
22H37O6Si (M þ H)þ 425.2354, found 425.2347.
1,3-dioxan-4-one (syn-47): 1H NMR (400 MHz, C6D6)
d
7.15e7.13 (m,
(5R*,6R*)-6-(4-Methoxyphenethyl)-2,2,5-trimethyl-5-((trie-
2H), 7.08e7.04 (m, 3H), 3.66 (dd, J ¼ 10.2, 2.2, 1H), 2.86e2.79 (m,
1H), 2.54e2.39 (m, 2H), 1.86e1.76 (m, 1H), 1.51 (s, 3H), 1.13 (s, 6H),
1.06 (t, J ¼ 7.9, 9H), 0.83e0.68 (m, 6H); 13C NMR (100 MHz, C6D6)
thylsilyl)peroxy)-1,3-dioxan-4-one (anti-48): 1H NMR (400 MHz,
C6D6)
d
7.05 (d, J ¼ 8.3, 2H), 6.82 (d, ¼ 8.7, 2H), 4.88 (dd, J ¼ 10.3, 1.8,
1H), 3.35 (s, 3H), 2.79 (ddd, J ¼ 13.8, 8.8, 4.8, 1H), 2.58 (dt, J ¼ 13.8,
8.3, 1H), 1.92e1.84 (m, 1H), 1.72e1.63 (m, 1H), 1.42 (s, 3H), 1.35 (s,
3H), 1.24 (s, 3H), 1.04 (t, J ¼ 8.0, 9H), 0.75 (q, J ¼ 8.0, 6H); 13C NMR
d
166.6 (C), 141.7 (C), 128.80 (CH), 128.77 (CH), 126.4 (CH), 105.7 (C),
81.4 (C), 75.3 (CH), 32.1 (CH2), 29.6 (CH2), 29.5 (CH3), 24.2 (CH3),
18.5 (CH3), 7.0 (CH3), 4.1 (CH2); IR (ATR) 2955, 1749, 1497 cmꢀ1
;
(100 MHz, C6D6) d 168.5 (C), 158.8 (C), 133.5 (C), 129.8 (CH), 114.3
HRMS (APCI) m/z calcd for C21H35O5Si (M þ H)þ 395.2248, found
(CH),105.5 (C), 82.9 (C), 69.4 (CH), 54.8 (CH3), 31.4 (CH2), 30.5 (CH2),
29.3 (CH3), 24.9 (CH3), 17.0 (CH3), 7.0 (CH3), 4.2 (CH2); IR (ATR)
2955, 1758, 1612, 1513 cmꢀ1; HRMS (APCI) m/z calcd for C22H37O6Si
(M þ H)þ 425.2354, found 425.2346.
395.2240.
(5R*,6R*)-2,2,5-Trimethyl-6-phenethyl-5-((triethylsilyl)peroxy)-
1,3-dioxan-4-one (anti-47): 1H NMR (600 MHz, C6D6)
d 7.12e7.03
(m, 5H), 4.86 (dd, J ¼ 10.3, 2.0, 1H), 2.79 (ddd, J ¼ 13.8, 8.9, 4.9, 1H),
2.59 (dt, J ¼ 13.8, 8.2, 1H), 1.91e1.86 (m, 1H), 1.69e1.63 (m, 1H), 1.39
(s, 3H), 1.33 (s, 3H), 1.21 (s, 3H), 1.04 (t, J ¼ 7.9, 9H), 0.77e0.72 (m,
(5R*,6R*)-5-Hydroxy-6-(4-methoxyphenethyl)-2,2,5-trimethyl-
1,3-dioxan-4-one (48a): The product was characterized as a 35:65
mixture with 3-hydroxy-5-(4- methoxyphenyl)pentan-2-one: 1H
6H); 13C NMR (150 MHz, C6D6)
d
168.5 (C), 141.6 (C), 128.9 (CH),
NMR (400 MHz, C6D6)
d
6.99 (d, J ¼ 8.6, 1.2H), 6.96 (d, J ¼ 8.6,
128.8 (CH), 126.4 (CH), 105.5 (C), 82.9 (C), 69.4 (CH), 32.3 (CH2), 30.2
(CH2), 29.3 (CH3), 24.8 (CH3), 17.0 (CH3), 7.0 (CH3), 4.2 (CH2); IR
(ATR) 2995, 1761, 1497 cmꢀ1; HRMS (APCI) m/z calcd for C21H35O5Si
(M þ H)þ 395.2248, found 395.2237.
0.78H), 6.81e6.77 (m, 2H), 3.89 (dd, J ¼ 10.0, 2.2, 0.35H), 3.77e3.72
(m, 0.65H), 3.54 (d, J ¼ 4.4, 0.66H), 3.34 (s, 0.99H), 3.33 (s, 1.89H),
3.13 (s, 0.35H), 2.74e2.59 (m, 1.7H), 2.45 (dt, J ¼ 13.8, 8.3, 0.36H),
2.04e1.96 (m, 0.37H), 1.77e1.65 (m, 1H), 1.49e1.40 (m, 0.65H), 1.44
(s, 2H), 1.27 (s, 1H), 1.22 (s, 1H), 1.10 (s, 1H); 13C NMR (100 MHz,
(5R*,6R*)-5-Hydroxy-2,2,5-trimethyl-6-phenethyl-1,3-dioxan-4-
one (47a): 1H NMR (400 MHz, C6D6)
d
7.14e7.12 (m, 2H), 7.08e7.04
C6D6) d 209.1 (C),174.8 (C),158.73 (C),158.70 (C),133.5 (C),133.3 (C),
(m, 3H), 3.84 (dd, J ¼ 10.1, 2.1, 1H), 3.04 (s, 1H), 2.69 (ddd, J ¼ 13.6,
9.2, 4.9, 1H), 2.48e2.40 (m, 1H), 2.02e1.94 (m, 1H), 1.71e1.62 (m,
1H), 1.25 (s, 3H), 1.19 (s, 3H), 1.07 (s, 3H); 13C NMR (100 MHz, C6D6)
129.9 (CH), 129.7 (CH), 129.6 (CH), 114.3 (CH), 107.0 (C), 75.8 (CH),
73.5 (CH), 71.1 (C), 54.81 (CH3), 54.80 (CH3), 35.9 (CH2), 31.3 (CH2),
30.6 (CH2), 30.0 (CH2), 28.8 (CH3), 24.6 (CH3), 24.3 (CH3), 21.1 (CH3);
IR (ATR) 3475, 2937, 1743, 1714, 1612, 1584 cmꢀ1; HRMS (APCI) m/z
calcd for alcohol 48a C16H21O4 (M þ H e H2O)þ 277.1434, found
277.1426; HRMS (APCI) m/z calcd for 3-hydroxy-5-(4-
methoxyphenyl)pentan-2-one C12H14NaO2 (M þ Na e H2O)þ
213.0886, found 213.0894.
d
174.7 (C), 141.5 (C), 128.79 (CH), 128.75 (CH), 126.4 (CH), 107.0 (C),
73.6 (CH), 71.1 (C), 32.2 (CH2), 29.8 (CH2), 28.8 (CH3), 24.5 (CH3),
21.1 (CH3); IR (ATR) 3471, 2941, 1738, 1497; HRMS (APCI) m/z calcd
for C15H19O3 (M þ H e H2O)þ 247.1329, found 247.1333.
4.2.4.3. 6-(4-Methoxyphenethyl)-2,2,5-trimethyl-5-((triethylsilyl)
peroxy)-1,3-dioxan-4-one (48) and (5R*,6R*)-5-hydroxy-6-(4-
4.2.4.4. 6-Heptyl-2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-
dioxan-4-one (49) and (5R*,6R*)-6-heptyl-5-hydroxy-2,2,5-
trimethyl-1,3-dioxan-4-one (49a). Following the representative
procedure for the synthesis of silyl peroxides B, using acetonide 44
(0.18 g, 0.77 mmol), triethylsilane (0.25 mL, 1.5 mmol), phenylsilane
(0.77 mL, 0.2 M in PhCF3, 0.15 mmol), Co(thd)2 (0.033 g,
0.077 mmol), and PhCF3 (5.1 mL) afforded crude syn-49, anti-49,
and alcohol 49a as a 70:7:23 mixture (corresponding to a 91:9 ratio
of diastereomeric silyl peroxides). Separation of the products by
flash chromatography (1:99e10:90 EtOAc:hexanes) yielded impure
syn-49 as a green oil (0.11 g), impure anti-49 as a green oil (0.013 g),
and impure alcohol 49a as a green oil (0.014 g), all of which were
contaminated with a small amount of cobalt-containing materials.
Characterization of syn-49 was obtained from a sample that was
further purified by flash chromatography (1:99e3:97 EtOAc:hex-
anes) to yield a colorless oil (0.060 g, 20%). Characterization of anti-
49 was obtained from a sample that was further purified by flash
chromatography (0:100e2:98 EtOAc:hexanes) to yield a colorless
oil with minor impurities that can be detected by 1H NMR (0.010 g,
3%). Characterization of alcohol 49a was obtained from a sample
that was further purified by flash chromatography (10:90 EtOA-
c:hexanes) to yield a colorless oil with minor impurities that can be
detected by 1H NMR (0.010 g, 4%). The stereochemical configura-
tions of 49 and 49a were inferred by comparison to the 1H NMR
chemical shifts of 26 and 26a.
methoxyphenethyl)-2,2,5-trimethyl-1,3-dioxan-4-one
(48a).
Following the representative procedure for the synthesis of silyl
peroxides B, using acetonide 43 (0.12 g, 0.42 mmol), triethylsilane
(0.13 mL, 0.83 mmol), phenylsilane (0.42 mL, 0.2 M in PhCF3,
0.084 mmol), Co(thd)2 (0.018 g, 0.042 mmol), and PhCF3 (2.8 mL)
afforded crude syn-48, anti-48, and alcohol 48a as a 77:4:19
mixture (corresponding to a 95:5 ratio of diastereomeric silyl per-
oxides). Separation of the products by flash chromatography
(3:97e25:75 EtOAc:hexanes) yielded impure syn-48 as a green oil
(0.080 g), impure anti-48 as a green oil (0.008 g), and impure
alcohol 48a as a green oil (0.016 g), all of which were contaminated
with a small amount of cobalt-containing materials. Characteriza-
tion of syn-48 was obtained from a sample that was further purified
by flash chromatography (5:95 EtOAc:hexanes) to yield a colorless
oil (0.063 g, 36%). Characterization of anti-48 was obtained from a
sample that was further purified by flash chromatography (3:97
EtOAc:hexanes) to yield a colorless oil with minor impurities that
can be detected by 1H NMR (0.005 g, 3%). Characterization of
alcohol 48a was obtained from a sample that was further purified
by flash chromatography (25:75 EtOAc:hexanes) to yield a colorless
oil that is contaminated with an oxidative decomposition product,
3-hydroxy-5-(4-methoxyphenyl)pentan-2-one (0.005 g, 2%). The
relative stereochemical configurations of 48 and 48a were inferred
by comparison to the 1H NMR chemical shifts of 26 and 26a.
(5R*,6S*)-6-(4-Methoxyphenethyl)-2,2,5-trimethyl-5-((trie-
(5R*,6S*)-6-Heptyl-2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-
thylsilyl)peroxy)-1,3-dioxan-4-one (syn-48): 1H NMR (400 MHz,
dioxan-4-one (syn-49): 1H NMR (400 MHz, C6D6)
d
3.70 (dd, J ¼ 10.1,
C6D6)
d
6.98 (d, J ¼ 8.7, 2H), 6.79 (d, J ¼ 8.7, 2H), 3.70 (dd, J ¼ 10.0,
1.9,1H), 2.14e2.06 (m,1H),1.70e1.50 (m, 2H),1.50 (s, 3H),1.32e1.22
(m, 12H), 1.19 (s, 3H), 1.09 (t, J ¼ 8.0, 9H), 0.90 (t, J ¼ 6.8, 3H),
2.1, 1H), 3.33 (s, 3H), 2.85 (m, 1H), 2.54e2.39 (m, 2H), 1.87e1.77 (m,
1H), 1.53 (s, 3H), 1.16 (s, 6H), 1.07 (t, J ¼ 7.9, 9H), 0.84e0.69 (m, 6H);
0.85e0.70 (m, 6H); 13C NMR (100 MHz, C6D6)
d 166.8 (C), 105.7 (C),
13C NMR (100 MHz, C6D6)
d
166.7 (C),158.7 (C),133.5 (C),129.7 (CH),
81.5 (C), 76.8 (CH), 32.2 (CH2), 29.9 (CH2), 29.7 (CH2), 29.5 (CH3),
Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
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10
D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
28.2 (CH2), 26.6 (CH2), 24.2 (CH3), 23.1 (CH2), 18.7 (CH3), 14.3 (CH3),
(CH2), 4.2 (CH2); IR (ATR) 2954,1751 cmꢀ1; HRMS (ESI) m/z calcd for
C
7.0 (CH3), 4.2 (CH2); IR (ATR) 2956, 1751; HRMS (APCI) m/z calcd for
28H58NaO7Si2 (M þ Na)þ 588.3641, found 588.3642.
C
C
20H40NaO5Si (M þ Na)þ 414.2572, found 414.2569. Anal. Calcd for
(5R*,6R*)-6-(2,6-Dimethyl-6-((triethylsilyl)peroxy)heptyl)-2,2,5-
20H40O5Si: C, 61.81; H, 10.38. Found: C, 62.11; H, 10.60.
trimethyl-5-((triethylsilyl)peroxy)-1,3-dioxan-4-one (anti-50): The
product was characterized as a 50:50 mixture of diastereomers at
the methyl-bearing stereocenter: 1H NMR (400 MHz, C6D6, char-
(5R*,6R*)-6-Heptyl-2,2,5-trimethyl-5-((triethylsilyl)peroxy)-1,3-
dioxan-4-one (anti-49): 1H NMR (400 MHz, C6D6, characteristic
peaks)
d
4.92 (dd, J ¼ 9.6, 2.1, 1H), 1.46 (s, 3H), 1.33 (s, 3H), 1.09 (t,
acteristic peaks)
d
5.07 (dd, J ¼ 10.2, 1.2, 0.5H), 5.06 (dd, J ¼ 9.4, 2.1,
J ¼ 7.8, 9H), 0.91 (t, J ¼ 6.8, 3H), 0.89e0.76 (m, 6H); 13C NMR
0.5H); 13C NMR (100 MHz, C6D6, characteristic peaks)
d
168.7 (2C),
(100 MHz, C6D6)
d
168.6 (C), 105.4 (C), 83.2 (C), 70.5 (CH), 32.2
105.4 (C), 105.3 (C), 83.2 (C), 83.0 (C), 82.52 (C), 82.48 (C), 68.8 (CH),
(CH2), 29.8 (CH2), 29.6 (CH2), 29.3 (CH3), 28.4 (CH2), 26.5 (CH2), 24.8
(CH3), 23.1 (CH2), 17.0 (CH3), 14.3 (CH3), 7.0 (CH3), 4.2 (CH2); IR
(ATR) 2996, 1762 cmꢀ1; HRMS (ESI) m/z calcd for C14H25O3 (M þ H
e H2O)þ 241.1798, found 241.1796.
68.3 (CH); IR (ATR) 2955, 1761 cmꢀ1; HRMS (ESI) m/z calcd for
C
28H59O7Si2 (M þ H)þ 563.3794, found 563.3802.
(5R*,6R*)-6-(2,6-Dimethyl-6-((triethylsilyl)peroxy)heptyl)-5-
hydroxy-2,2,5-trimethyl-1,3-dioxan-4-one (50a): The product was
characterized as a 50:50 mixture of diastereomers at the methyl-
bearing stereocenter: 1H NMR (400 MHz, C6D6, characteristic
(5R*,6R*)-6-Heptyl-5-hydroxy-2,2,5-trimethyl-1,3-dioxan-4-one
(49a): 1H NMR (400 MHz, C6D6)
d
3.89 (dd, J ¼ 9.8, 2.2, 1H), 3.26 (s,
1H), 1.73e1.67 (m, 1H), 1.50e1.39 (m, 2H), 1.28e1.25 (m, 1H), 1.27 (s,
peaks)
characteristic peaks)
d
4.05 (d, J ¼ 9.6, 1H), 3.19 (s, 1H); 13C NMR (100 MHz, C6D6,
6H), 1.24e1.20 (m, 8H), 1.15 (s, 3H), 0.89 (t, J ¼ 7.1, 3H); 13C NMR
d 175.0 (2C), 106.93 (C), 106.87 (C), 82.52 (C),
(100 MHz, C6D6)
d
175.0 (C), 107.0 (C), 74.6 (CH), 71.3 (C), 32.2 (CH2),
82.50 (C), 72.9 (CH), 72.2 (CH), 71.2 (C), 71.1 (C); IR (ATR) 3453,
29.7 (CH2), 29.6 (CH2), 28.9 (CH3), 28.1 (CH2), 26.4 (CH2), 24.5 (CH3),
2953, 1739 cmꢀ1
; HRMS (ESI) m/z calcd for C22H44NaO6Si2
23.0 (CH2), 21.1 (CH3), 14.3 (CH3); IR (ATR) 3453, 2924, 1735 cmꢀ1
;
(M þ Na)þ 455.2799, found 455.2794.
HRMS (ESI) m/z calcd for C14H26KO4 (M þ K)þ 297.1463, found
297.1453.
4.2.4.6. (5R*,6S*)-5-hydroxy-6-isobutyl-2,2,5-trimethyl-1,3-dioxan-
4-one (27). To
a solution of silyl peroxide syn-26 (0.045 g,
4.2.4.5. 6-(2,6-Dimethyl-6-((triethylsilyl)peroxy)heptyl)-2,2,5-
0.13 mmol) in THF (1.4 mL) was added Pd (0.003 g, 10% on carbon,
0.003 mmol). The solution was sparged with H2 for 2 min. After 5 h,
another portion of Pd (0.002 g,10% on carbon, 0.002 mmol) and THF
(0.5 mL) were added. The solution was sparged with H2 for 2 min.
After 11 h, another portion of Pd (0.004 g, 10% on carbon,
0.004 mmol) and THF (1 mL) were added. After 3 h, the reaction
mixture was filtered through a 2-cm plug of Celite (15:85 EtOA-
c:hexanes). The filtrate was concentrated in vacuo to yield 27 as a
white solid with 6% residual starting material remaining (0.014 g,
45%, unpurified yield due to instability on silica gel):
trimethyl-5-((triethylsilyl)peroxy)-1,3-dioxan-4-one
(50)
and
(5R*,6R*)-6-(2,6-Dimethyl-6-((triethylsilyl)peroxy)heptyl)-5-
hydroxy-2,2,5-trimethyl-1,3-dioxan-4-one (50a). Following the
representative procedure for the synthesis of silyl peroxides B,
using acetonide 45 (0.036 g, 0.14 mmol), triethylsilane (0.072 mL,
0.41 mmol), phenylsilane (0.14 mL, 0.2 M in PhCF3, 0.028 mmol),
Co(thd)2 (0.006 g, 0.014 mmol), and PhCF3 (0.9 mL) afforded crude
syn-50, anti-50, and alcohol 50a as a 78:7:15 mixture (corre-
sponding to a 92:8 ratio of diastereomeric silyl peroxides). Sepa-
ration of the products by flash chromatography (2:98e10:90
EtOAc:hexanes) yielded impure syn-50 as a green oil (0.056 g),
impure anti-50 as a green oil (0.011 g), and impure alcohol 50a as a
green oil (0.011 g), all of which were contaminated with a small
amount of cobalt-containing materials. Characterization of syn-50
was obtained from a sample that was further purified by flash
chromatography (3:97 EtOAc:hexanes) to yield a colorless oil
(0.046 g, 60%). Characterization of anti-50 was obtained from a
sample that was further purified by flash chromatography (1:99
EtOAc:hexanes) to yield a green oil with minor impurities that can
be detected by 1H NMR (0.006 g, 8%). Characterization of alcohol
50a was obtained from a sample that was further purified by flash
chromatography (10:90 EtOAc:hexanes) to yield a colorless oil
(0.007 g, 12%). The relative stereochemical configurations of 50 and
50a were inferred by comparison to the 1H NMR chemical shifts of
26 and 26a.
mp ¼ 75e80 ꢂC; 1H NMR (600 MHz, C6D6)
d
3.67 (dd, J ¼ 10.3, 2.1,
1H), 2.62 (br s, 1H), 1.78 (ddd, J ¼ 14.3, 10.3, 4.2, 1H), 1.71e1.64 (m,
1H), 1.30 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H), 1.10e1.06 (m, 1H), 0.84 (d,
J ¼ 6.7, 3H), 0.73 (d, J ¼ 6.7, 3H); 13C NMR (150 MHz, C6D6)
d 170.5
(C), 105.8 (C), 74.1 (CH), 71.6 (C), 36.2 (CH2), 29.4 (CH3), 24.4 (CH),
23.9 (CH3), 23.7 (CH3), 21.4 (CH3), 20.8 (CH3); IR (ATR) 3461, 2957,
1742 cmꢀ1; HRMS (ESI) m/z calcd for C11H19O3 (M þ H e H2O)þ
199.1329, found 199.1329.
4.2.4.7. Methyl 3-hydroxy-5,7,7-trimethyl-2-methyleneoctanoate
(38). Racemic 3,5,5-trimethylhexanal (36, 1.7 mL, 10 mmol),
methyl acrylate (37, 4.5 mL, 50 mmol), DABCO (0.56 g, 5.0 mmol),
and MeOH (1 mL) were combined. After 15 d, the reaction mixture
was diluted with H2O (10 mL) and the product was extracted with
CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were washed with
1 M HCl (20 mL) and concentrated in vacuo. Purification by flash
chromatography (10:90 EtOAc:hexanes) followed by removal of a
residual impurity by bulb-to-bulb distillation (0.3 torr, 175 ꢂC)
afforded 38 as a colorless oil (1.1 g, 50%). The product was charac-
terized as a 50:50 mixture of diastereomers: 1H NMR (400 MHz,
(5R*,6S*)-6-(2,6-Dimethyl-6-((triethylsilyl)peroxy)heptyl)-2,2,5-
trimethyl-5-((triethylsilyl)peroxy)-1,3-dioxan-4-one (cis-50): The
product was characterized as a 54:46 mixture of diastereomers at
the methyl-bearing stereocenter: 1H NMR (400 MHz, C6D6)
d
3.93e3.87 (m, 1H), 2.26 (ddd, J ¼ 14.2, 10.7, 3.5, 0.46H), 2.08 (ddd,
CDCl3) d 6.22e6.21 (m, 2H), 5.81e5.80 (m, 2H), 4.49e4.40 (m, 2H),
J ¼ 14.5, 9.7, 4.9, 0.54H), 1.68e1.48 (m, 3H), 1.51 (s, 1.62H), 1.49 (s,
1.38H), 1.47e1.41 (m, 1H), 1.41e1.35 (m, 1H), 1.35e1.29 (m, 1H), 1.31
(s,1.62H),1.27 (s,1.62H),1.26 (s,1.38H),1.25 (s, 6.48H),1.22e1.18 (m,
0.54H), 1.25 (s, 1.62H), 1.11e1.05 (m, 18.46H), 1.04e1.00 (m, 0.54H),
0.96 (d, J ¼ 6.8, 1.62H), 0.83e0.72 (m, 13.62H); 13C NMR (100 MHz,
3.78 (s, 6H), 2.46 (d, J ¼ 7.1, 1H), 2.41 (d, J ¼ 6.4, 1H), 1.87e1.76 (m,
1H), 1.68e1.60 (m, 2H), 1.58e1.54 (m, 1H), 1.50e1.43 (m, 1H), 1.37
(ddd, J ¼ 13.8, 10.3, 3.2, 1H), 1.31 (dd, J ¼ 13.8, 3.2, 1H), 1.21 (dd,
J ¼ 13.8, 3.9, 1H), 1.12 (dd, J ¼ 13.8, 6.0, 1H), 1.06 (dd, J ¼ 13.8, 6.4,
1H), 0.99 (d, J ¼ 7.1, 3H), 0.97 (d, J ¼ 7.1, 3H), 0.91 (s, 9H), 0.90 (s, 9H);
C6D6)
d
166.77 (C), 166.76 (C), 105.7 (C), 105.6 (C), 82.6 (C), 82.5 (C),
13C NMR (100 MHz, CDCl3)
d 167.11 (C), 167.10 (C), 143.2 (C), 142.7
81.7 (C), 81.6 (C), 74.9 (CH), 74.3 (CH), 39.6 (CH3), 39.5 (CH3), 38.8
(CH3), 36.6 (CH3), 35.3 (CH3), 35.1 (CH3), 30.0 (CH), 29.54 (CH3),
29.50 (CH), 29.1 (CH3), 24.6 (CH3), 24.51 (CH3), 24.49 (CH3), 24.47
(CH3), 24.2 (CH3), 24.1 (CH3), 21.9 (CH2), 21.5 (CH2), 20.6 (CH3), 18.8
(CH3), 18.6 (CH3), 18.5 (CH3), 7.2 (CH3), 7.03 (CH3), 7.02 (CH3), 4.4
(C), 124.9 (CH2), 124.5 (CH2), 70.3 (CH), 69.8 (CH), 51.9 (2 CH3 and
CH2), 50.7 (CH2), 46.14 (CH2), 46.12 (CH2), 31.3 (C), 31.0 (C), 30.1
(CH3), 30.0 (CH3), 26.2 (CH), 25.8 (CH), 23.5 (CH3), 21.8 (CH3); IR
(ATR) 3449, 2952, 1718, 1629 cmꢀ1; HRMS (APCI) m/z calcd for
C
13H23O2 (M þ H e H2O)þ 211.1693, found 211.1696. Anal. Calcd for
Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
https://doi.org/10.1016/j.tet.2019.05.008

D.S. Zuckerman, K.A. Woerpel / Tetrahedron xxx (xxxx) xxx
11
C13H24O3: C, 68.38; H, 10.60. Found: C, 68.61; H, 10.50.
112.5 (CH2), 73.1 (CH), 64.3 (CH2), 45.1 (CH2), 24.8 (CH), 23.3 (CH3),
22.3 (CH3); IR (ATR) 3324, 2928, 1654 cmꢀ1; HRMS (APCI) m/z calcd
for C8H15O (M þ H e H2O)þ 127.1117, found 127.1113.
4.2.4.8. 3-Hydroxy-5,7,7-trimethyl-2-methyleneoctanoic acid (39).
A solution of BayliseHillman adduct 38 (0.59 g, 2.6 mmol) in THF
(7.8 mL) was cooled to 0 ꢂC. LiOH (7.8 mL,1 M in H2O, 7.8 mmol) was
added. After 16 h, the reaction mixture was washed with Et2O
(10 mL) to remove organic impurities. The aqueous layer was
acidified to pH 1.5 with 1 M HCl. The acidified product was
extracted with Et2O (4 ꢁ 10 mL). The combined organic layers were
concentrated in vacuo. The resulting crude solid was recrystallized
from toluene to afford a single diastereomer of acid 39 as a white
solid (0.18 g, 33%): mp ¼ 122e123 ꢂC; 1H NMR (400 MHz, CDCl3)
4.2.4.12. Bis((2,2,6,6-tetramethyl-5-oxohept-3-en-3-yl)oxy)cobalt
(Co(thd)2). The synthesis of Co(thd)2 was modified from a reported
procedure [38,39]. To a solution of cobalt (II) chloride hexahydrate
(1.0 g, 4.2 mmol) in 50% aqueous ethanol (12 mL) was added
2,2,6,6-tetra-methyl-3,5-heptanedione (1.7 mL, 8.4 mmol). Ammo-
nium hydroxide (50% v/v aqueous solution, 0.63 mL, 8.4 mmol) was
added dropwise while the reaction mixture was stirred. After 1 h,
H2O (23 mL) was added and stirred. After 1 h, the resulting reaction
mixture was filtered, and the resulting solid was washed with H2O
(3 ꢁ 40 mL). The solid was dried at ambient temperature and
pressure for 18 h to yield Co(thd)2 as a pink solid (1.2 g, 66%) that
was used without further purification.
d
6.37 (s, 1H), 5.93 (s, 1H), 4.51 (dd, J ¼ 9.7, 3.2, 1H), 1.87e1.76 (m,
1H), 1.66 (ddd, J ¼ 13.9, 9.8, 4.1, 1H), 1.42 (ddd, J ¼ 13.9, 10.2, 3.5, 1H),
1.22 (dd, J ¼ 14.0, 4.1, 1H), 1.13 (dd, J ¼ 14.0, 6.0, 1H), 0.99 (d, J ¼ 6.6,
3H), 0.91 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 170.6 (C), 142.5 (C),
127.2 (CH2), 69.6 (CH), 52.0 (CH2), 46.2 (CH2), 31.4 (C), 30.2 (CH3),
26.0 (CH), 21.9 (CH3); IR (ATR) 3359, 2954, 1697, 1633 cmꢀ1; HRMS
(ESI) m/z calcd for C12H22NaO3 (M þ Na)þ 237.1461, found 237.1464.
4.2.5. Representative procedure for the synthesis of cobalt
complexes (Bis((3-oxo-1,3-diphenylprop-1-en-1-yl)oxy)cobalt
(Co(dbm)2))
4.2.4.9. 3-Hydroxy-5-methylhexan-2-one (52). To a solution of silyl
peroxide syn-26 (0.047 g, 0.14 mmol) in 5:95 EtOAc:hexanes
(2.0 mL) was added silica dioxide (1.0 g). After 16 h, the mixture was
filtered through a cotton plug using EtOAc (15 mL). The filtrate was
concentrated in vacuo to yield 52 as a colorless oil containing re-
sidual triethylsilanol (0.013 g, 69%): 1H NMR (400 MHz, C6D6)
126. The synthesis of Co(dbm)2 was modified from a reported
procedure [40]. To a solution of 1,3-diphenylpropane-1,3-dione
(0.10 g, 0.45 mmol) in MeOH (0.45 mL) was added NaOH (0.22 mL,
2 M in H2O, 0.44 mmol). Cobalt (II) chloride hexahydrate (0.22 mL,
1 M in H2O, 0.22 mmol) was added. After 2 h, the reaction mixture
was filtered, and the resulting solid was washed with H2O
(3 ꢁ 5 mL) and cold MeOH (3 ꢁ 5 mL). The solid was dried in vacuo
to yield Co(dbm)2 as an orange solid (0.085 g, 75%) that was used
without further purification.
d
3.80e3.77 (m, 1H), 3.41 (br s, 1H), 2.00e1.90 (m, 1H), 1.52 (s, 3H),
1.13e1.07 (m, 2H), 0.87 (d, J ¼ 6.6, 3H), 0.82 (d, J ¼ 6.6, 3H); 13C NMR
(100 MHz, C6D6)
d 209.5 (C), 75.5 (CH), 42.7 (CH2), 25.0 (CH), 24.4
(CH3), 23.7 (CH3), 21.4 (CH3); IR (ATR) 3478, 2917, 1716 cmꢀ1; HRMS
(APCI) m/z calcd for C7H13O (M þ H e H2O)þ 113.0961, found
113.0956.
4.2.5.1. Bis((1,1,1,5,5,5-hexafluoro-4-oxopent-2-en-2-yl)oxy)cobalt
(Co(hfac)2). Following the representative procedure for the syn-
thesis of cobalt complexes, using 1,1,1,5,5,5-hexafluoropentane-2,4-
dione (0.14 mL, 0.96 mmol), NaOH (0.48 mL, 2 M in H2O,
0.96 mmol), cobalt (II) chloride hexahydrate (0.48 mL, 1 M in H2O,
0.48 mmol) in MeOH (1.0 mL) yielded Co(hfac)2 as a yellow solid
(0.075 g, 33%) that was used without further purification.
4.2.4.10. (5R*,6R*)-5-Hydroperoxy-6-isobutyl-2,2,5-trimethyl-1,3-
dioxan-4-one (53). The synthesis of hydroperoxide 53 was modi-
fied from a reported procedure [14,34]. A solution of silyl peroxide
anti-26 (0.017 g, 0.049 mmol) in 50:50 THF:H2O (0.35 mL) was
cooled to 0 ꢂC. DDQ (0.10 mL, 0.2 M in 50:50 THF:H2O, 0.02 mmol)
was added. After 4 h, another portion of DDQ (0.10 mL, 0.2 M in
50:50 THF:H2O, 0.02 mmol) was added. After 1.5 h, the solution was
filtered through a 0.5-cm plug of Davisil using 10:90 EtOAc:hexanes
(10 mL). The filtrate was concentrated in vacuo to afford 53 as a
white solid containing silyl impurities which was characterized
without further purification (0.04 g, 35%): 1H NMR (400 MHz, C6D6)
Acknowledgements
This research was supported by the National Institute of General
Medical Sciences of the National Institutes of Health
(1R01GM118730). D.S.Z. thanks the NYU Department of Chemistry
for support in the form of a Margaret Strauss Kramer Fellowship.
NMR spectra acquired with the TCI cryoprobe and Bruker Avance
400 spectrometer were supported by the National Institutes of
Health (OD016343) and the National Science Foundation (CHE-
01162222), respectively. The authors thank Dr. Chin Lin for his
assistance with NMR spectroscopy and mass spectrometry, Jona-
than Oswald for synthesizing the cobalt catalysts, David Anthony
for obtaining preliminary data, and Ana Burris for technical
assistance.
d
9.18 (d, J ¼ 4.4, 1H), 4.65 (d, J ¼ 9.7, 1H), 1.75e1.63 (m, 1H),
1.45e1.37 (m, 1H), 1.31 (ddd, J ¼ 13.8, 9.4, 5.0, 1H), 1.27 (s, 3H), 1.24
(s, 3H), 1.21 (s, 3H), 0.85 (d, J ¼ 6.5, 6H); 13C NMR (100 MHz, C6D6)
d
170.9 (C), 106.5 (C), 83.3 (C), 69.0 (CH), 36.6 (CH2), 28.9 (CH3), 25.1
(CH), 24.6 (CH3), 23.5 (CH3), 21.8 (CH3), 16.3 (CH3); IR (ATR) 3334,
2957, 1732 cmꢀ1; HRMS (APCI) m/z calcd for C11H20NaO5 (M þ Na)þ
255.1203, found 255.1198.
4.2.4.11. 5-Methyl-2-methylenehexane-1,3-diol (55). To a solution of
protected
diol
3-((tert-butyldimethylsilyl)oxy)-5-methyl-2-
Appendix A. Supplementary data
methylenehexan-1-ol (0.49 g, 1.9 mmol) in THF (6.3 mL) was
added TBAF (3.8 mL, 1 M in THF, 3.8 mmol). After 16 h, reaction
mixture was diluted with H2O (10 mL). The product was extracted
with Et2O (3 ꢁ 10 mL). The combined organic layers were washed
with H2O (20 mL) and concentrated in vacuo. Purification by flash
chromatography (30:70 EtOAc:hexanes) followed by removal of a
residual impurity by bulb-to-bulb distillation (0.3 torr, 75 ꢂC) yiel-
ded diol 55 as a colorless oil (0.14 g, 52%): 1H NMR (400 MHz, CDCl3)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.05.008.
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Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
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Please cite this article as: D.S. Zuckerman, K.A. Woerpel, Diastereoselective peroxidation of derivatives of BayliseHillman adducts, Tetrahedron,
https://doi.org/10.1016/j.tet.2019.05.008