Synthesis of enantiopure triols from racemic Baylis?Hillman adducts using a diastereoselective peroxidation reaction

Article abstract of DOI:10.1021/acs.orglett.0c03439

Using a chiral (?)-menthone auxiliary, enantiopure cyclic derivatives of Baylis?Hillman adducts were synthesized. A diastereoselective peroxidation reaction was used to introduce an oxygen atom and establish another stereocenter. The resulting products could be elaborated by employing a one-flask reduction?acetylation protocol followed by a diastereoselective nucleophilic substitution reaction. Removal of the (?)-menthone auxiliary provided an enantiopure triol with a structure related to naturally occurring polyols.

Full text of DOI:10.1021/acs.orglett.0c03439

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Letter
Synthesis of Enantiopure Triols from Racemic Baylis−Hillman
Adducts Using a Diastereoselective Peroxidation Reaction
Dylan S. Zuckerman and K. A. Woerpel*
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ABSTRACT: Using a chiral (−)-menthone auxiliary, enantiopure cyclic derivatives of
Baylis−Hillman adducts were synthesized. A diastereoselective peroxidation reaction was
used to introduce an oxygen atom and establish another stereocenter. The resulting
products could be elaborated by employing a one-flask reduction−acetylation protocol
followed by a diastereoselective nucleophilic substitution reaction. Removal of the
(−)-menthone auxiliary provided an enantiopure triol with a structure related to naturally
occurring polyols.
he structural motif consisting of a carbon chain bearing
hydroxyl groups on consecutive carbon atoms recurs in
many natural products. This motif, which defines carbohy-
drates, is also present in a number of biologically active
compounds, such as (9S)-dihydroerythronolide A (1), which is
a precursor to many common antibiotics, including eryth-
romycin,1 azithromycin,2 and clarithromycin (Figure 1).3
Scheme 1. General Transformation from Racemic Baylis−
Hillman Adducts to Enantiopure Triols
T
chain of carbon atoms and control the configuration of the
remaining stereocenter, leading to enantiopure triols12 with the
relative stereochemistry found in 1 and 2.
The alkene hydration reaction required optimization (Table
1). Initial studies were performed on lactone 6, which was
prepared by the route illustrated in Scheme 2 (vide infra). It
was anticipated that if the stereoselective peroxidation could be
developed, the resulting peroxide could be reduced to the
desired alcohol. Although the cobalt-catalyzed peroxidation of
alkenes is generally not diastereoselective in simple sys-
tems,17−22 similar cyclic Baylis−Hillman adduct derivatives
have been used in stereoselective radical reactions.23 With
trifluorotoluene (PhCF3) as the solvent and in the presence of
Et3SiH and molecular O2, diastereoselectivity improved as the
amount of PhSiH3 was increased, likely by selective
decomposition of the minor diastereomer of the silyl peroxide,
anti-7.15 The yield of the major silyl peroxide syn-7 also
decreased, however (entries 1−3). Switching the solvent to
acetonitrile (MeCN) increased the yield of the major silyl
Figure 1. Biologically active compounds bearing hydroxyl groups on
consecutive carbons.
Another natural product that contains this set of hydroxyl-
bearing stereocenters, altersolanol A (2), displayed anticancer
activity (Figure 1).4 The stereoselective synthesis of a tertiary
hydroxyl group positioned between two secondary hydroxyl
groups, as in compounds 1 and 2, has been particularly
difficult. For example, establishing this stereochemical array in
(9S)-dihydroerythronolide A (1) required lengthy synthetic
routes.5−9
In this Letter, we report a method for the synthesis of
enantiomerically pure triols with the motif highlighted in 1 and
2 using racemic Baylis−Hillman adducts as the key starting
materials (Scheme 1). The enantiomers of these adducts were
resolved by forming an acetal with (−)-menthone (5).10−14
The configuration at the tertiary hydroxyl group was
established with a diastereoselective cobalt-catalyzed perox-
idation reaction15 on the resulting acetal. A diastereoselective
nucleophilic substitution reaction16 was used to extend the
Received: October 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03439
© XXXX American Chemical Society
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Table 1. Optimization of the Diastereoselective
Peroxidation Reaction
Scheme 2. Representative Synthesis and Peroxidation of
Enantiopure Lactones
a
PhSiH3
(mol %)
yield syn-7
yield 7a
a
a
entry solvent
dr 7
(%)
(%)
1
2
3
4
5
PhCF3
PhCF3
PhCF3
MeCN
MeCN
0
5
10
0
5
94 : 6
97 : 3
98 : 2
98 : 2
99 : 1
63
66
57
73
68
10
11
12
8
7
a
1
Yields were obtained by H NMR spectroscopy with mesitylene as
the internal standard.
peroxide syn-7 while maintaining high diastereoselectivity, even
without PhSiH3. Because the addition of 5 mol % of PhSiH3
resulted in lower yields (entry 5), this additive was excluded
from the optimal conditions (entry 4).
The purification method also required optimization. The use
of Co(thd)2 in cobalt-mediated peroxidation reactions results
in the formation of significant quantities of cobalt-containing
impurities that are difficult to separate from the desired
product.24 The use of high surface-area silica (Davisil-grade)
was critical for the separation of the major silyl peroxide from
the cobalt-containing impurities. After one purification, the
product was isolated without residual cobalt-containing
a
Peroxidation reaction conditions: alkene (15 or 16, 1 equiv), Et3SiH
(2 equiv), and Co(thd)2 (10 mol %) in MeCN (0.3 M) under a
balloon of O2, 3 h.
1
impurities, as evidenced by H NMR spectroscopy and visual
inspection of the resulting white solid. Purification using
standard-grade silica gel caused significant decomposition of
the product,15 likely due to an acid-catalyzed25 degradation
pathway that formed methyl ketone 9 (Figure 2).26
The overall sequence employed for the preparation of
enantiomerically pure products from racemic Baylis−Hillman
adducts is demonstrated in Scheme 2 for a substrate that bears
a side chain similar to those found in peroxide-containing
natural products.27 Ester 12, which was prepared from 3,5,5-
trimethylhexanal (10) and methyl acrylate (11), was hydro-
lyzed to give the corresponding hydroxyacid 13 (dr 50:50).
After recrystallization, a single diastereomer of hydroxyacid 13
was obtained in 33% yield. Silylation of hydroxyacid 13 with
(Me3Si)2NH provided compound 14, which was immediately
coupled to (−)-menthone (5) with catalytic quantities of
trimethylsilyl trifluoromethanesulfonate (Me3SiOTf).10−13,28
The resulting diastereomeric lactones 15 and 16 were
separated by flash chromatography.
Although the sequence was generally continued with the
major diastereomer of each lactone, the minor diastereomeric
lactone can also be used to prepare enantiomerically pure
products. When lactones 15 and 16 were subjected separately
to the optimized peroxidation conditions, the corresponding
silyl peroxide products syn-17 and syn-18 were formed in
similar diastereomeric ratios (Scheme 2). X-ray crystallo-
Figure 2. Methyl ketone decomposition product.
graphic analysis was used to establish the configuration of the
major silyl peroxide product syn-18.29 Comparison of the H
1
NMR spectra of the silyl peroxide products syn-17 and syn-18
showed that they shared the same relative configuration.29
These experiments demonstrate that the configuration at the
allylic stereocenter, not the menthone auxiliary, controlled the
stereochemical outcome of the reaction. Torsional effects30
during the addition of molecular O2 to the planar, stabilized
radical31,32 likely dictate the stereochemical outcome.15
A range of Baylis−Hillman adduct-derived alkenes under-
went this peroxidation reaction with high diastereoselectivity
(Scheme 3). The diastereoselectivity of the peroxidation
depended upon the size of the alkyl side chain. The
peroxidations of β-branched substrates, such as 6 and 16,
occurred with the highest diastereomeric ratios (silyl peroxides
7 and 18, dr ≥ 98:2). The reactions of lactones with less
B
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Scheme 3. Substrate Scope of the Diastereoselective
Peroxidation Reaction
Scheme 4. Allylation of Reduced and Acetylated Acetal 26
and Expected Dioxanes 29
a
a
1
Yields were obtained by H NMR spectroscopy with mesitylene as
the internal standard.
consistent with this connectivity. Instead, the ring-contracted
product 28 was more consistent with the spectroscopic data.
The minor component of the reaction mixture was not the
diastereomer of 28. Its spectra indicate that it is the product of
an annulation reaction, cis-fused tetrahydrofuran 28a.35−40
The formation of the observed products can be explained by
considering the reaction mechanism (Scheme 5).41 Upon
Scheme 5. Proposed Reaction Mechanism of the Allylation
a
of Reduced and Acetylated Acetals
a
Reaction conditions: alkene (6, 16, 20−22, 1 equiv), Et3SiH (2
equiv), and Co(thd)2 (10 mol %) in MeCN (0.3 M) under a balloon
of O2, 3 h.
substituted side chains, including lactones 20 and 21, occurred
with slightly lower selectivity (silyl peroxides 23 and 24, dr =
94:6). The peroxidation of alkene 22, which bears an n-alkyl
group, was the least selective (silyl peroxide 25, dr = 89:11).
This trend suggests that the side chain may impede the
approach of molecular O2 to the radical intermediate.15
With two of the three stereogenic centers established, the
next stage of the synthesis involved a nucleophilic substitution
reaction. The success of this reaction was not assured because
the unprotected hydroxyl group could complicate the
substitution. One-flask reduction−acetylation33 of the major
silyl peroxylactone product (syn-7) with i-Bu2AlH and Ac2O
resulted in the dioxane acetal 26. This reduction also
converted the silylperoxy group into the desired hydroxyl
group. The resulting acetal underwent nucleophilic substitu-
tion using allyltrimethylsilane and BF3·OEt2 to yield two
products in a 91:9 ratio (Scheme 4). This result demonstrated
that the acetal substitution reaction could be achieved in the
presence of a free hydroxyl group.34 The major product was
initially assigned as the expected substitution product anti-29.
NOE and long-range 1H/13C correlation spectra (hetero-
nuclear multiple bond correlation, HMBC), however, were not
a
RM refers to the menthone auxiliary.
activation of the acetyl group, oxocarbenium ion 30 is formed.
The nucleophile preferentially attacks from the bottom face to
form the product in a chair conformer (33).30,42,43 A small
amount of attack from the other face of oxocarbenium ion 30
leads to the formation of an unfavorable twist-chair (31). The
β-silyl carbocation 31 is trapped by the hydroxyl group,
forming the cis-fused tetrahydrofuran 32.
C
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The major allylation product 34, however, is not stable to
the Lewis acid because it is destabilized by a 1,3-diaxial
interaction between the allyl group and the axial C−C bond of
the menthone auxiliary. To alleviate the syn-pentane-like
interaction, the Lewis acid activates the oxygen atom that is
farther from the isopropyl group on the menthone auxiliary
and is therefore less sterically hindered.10,11,44 Acetal exchange
leads to the favored ring-contracted product 36. Computa-
tional studies (ωB97X-D/6-31G*) support this hypothesis:
the dioxane with an axial allyl group, anti-29, was found to be
3.4 kcal/mol higher in energy than the diastereomer with an
equatorial allyl group, syn-29 (Scheme 4). This difference in
energy is comparable to the energy inherent to a syn-pentane
interaction, which is evident in the three-dimensional structure
of dioxane anti-29 (Scheme 4).45
Scheme 7. Substrate Scope of Nucleophilic Additions
The propensity to undergo rearrangement was even present
in the starting lactone. Upon standing in MeCN over several
weeks, alcohol 7a rearranged to acid 37 (Scheme 6). This
Scheme 6. Rearrangement of Alcohol Side Product 7a
rearrangement revealed that not only 1,3-diaxial interactions
contribute to the tendency for these substrates to undergo ring
contraction. This destabilizing effect may be stereoelectronic in
origin, considering that the hydrolysis of 1,3-dioxanes has been
shown to be about 40 times faster than the hydrolysis of 1,3-
dioxolanes due to improved orbital alignment during the
protonation/elimination step.46
The stereoselective addition and rearrangement reaction was
general for the other substrates. In each case, the major
product of the allylations of dioxanes 26 and 38−41 shared the
same overall structure as the product shown in Scheme 4 (28
and 43−46, Scheme 7). Methallyltrimethylsilane (42) also
reacted with the acetylated acetal 26 to form a single
diastereomer of 1,3-dioxolane 47 without formation of a side
product.
Scheme 8. Hydrolysis of the Menthone Auxiliary
The final step of the overall synthesis of triols involves a
hydrolysis reaction, which was demonstrated on allylated
dioxolanes 28 and 44.11 Removal of the menthone auxiliary in
acidic methanol yielded single stereoisomers of the triols 48
and 49 (Scheme 8).
In summary, racemic Baylis−Hillman adducts were con-
verted to enantiopure spirolactones using a (−)-menthone (5)
auxiliary. These lactones were peroxidized diastereoselectively.
The resulting silyl peroxides were subjected to a one-flask
reduction−acetylation reaction. Diastereoselective nucleophilic
substitution on the resulting acetylated spiroacetals, followed
by removal of the (−)-menthone (5) auxiliary, yielded
enantiopure triols that mirror substructures present in
biologically active compounds.
a
The low yield resulted from difficulty with purification. Details are
provided as Supporting Information.
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03439.
Experimental procedures, NMR spectra, and analytical
data for all new compounds (PDF)
D
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AUTHOR INFORMATION
Corresponding Author
■
K. A. Woerpel − Department of Chemistry, New York
University, New York, New York 10003, United States;
orcid.org/0000-0002-8515-0301; Email: kwoerpel@
nyu.edu
Author
Dylan S. Zuckerman − Department of Chemistry, New York
University, New York, New York 10003, United States;
orcid.org/0000-0002-2269-9372
Complete contact information is available at:
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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, Bruker Avance 400, and 500 NMR spectrometers
were supported by the National Institutes of Health
(OD016343) and the National Science Foundation (CHE-
01162222). The authors thank Dr. Chin Lin (NYU) for his
assistance with NMR spectroscopy and mass spectrometry.
The authors also thank the Molecular Design Institute of NYU
for purchasing a single-crystal diffractometer and Dr. Chunhua
Hu (NYU) for his assistance with data collection and structure
determination.
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