Divinylcarbinol Desymmetrization Strategy: A Concise and Reliable Approach to Chiral Hydroxylated Fatty Acid Derivatives

Article abstract of DOI:10.1021/acs.joc.0c02821

By the aid of the catalytic desymmetrization of divinylcarbinol as one-pot asymmetric induction and protection of olefin, asymmetric total syntheses of two chiral hydroxylated fatty acid derivatives were successfully achieved. The desired stereoisomers could be concisely prepared in mild conditions in a highly convergent manner. Thus, this novel strategy can help stereochemical elucidations of natural products, which have difficulties in spectroscopic stereochemical analyses due to their local symmetries in the vicinities of the stereogenic secondary hydroxyl units.

Full text of DOI:10.1021/acs.joc.0c02821

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Divinylcarbinol Desymmetrization Strategy: A Concise and Reliable
Approach to Chiral Hydroxylated Fatty Acid Derivatives
Kenji Sugimoto,* Ami Kobayashi, Aki Kohyama, Haruka Sakai, and Yuji Matsuya*
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ABSTRACT: By the aid of the catalytic desymmetrization of divinylcarbinol as one-pot asymmetric induction and protection of
olefin, asymmetric total syntheses of two chiral hydroxylated fatty acid derivatives were successfully achieved. The desired
stereoisomers could be concisely prepared in mild conditions in a highly convergent manner. Thus, this novel strategy can help
stereochemical elucidations of natural products, which have difficulties in spectroscopic stereochemical analyses due to their local
symmetries in the vicinities of the stereogenic secondary hydroxyl units.
strategies have been performed (Scheme 1). For example, a
synthesis of (−)-(S)-heptadec-1-en-6-ol, which is a precursor
for (−)-5-hexadecanolide, a pheromone of the wasp Vespa
orientalis, was established by the assistance of DIBALH·BHT
complex and chiral auxiliary (Scheme 1a).5a Optically active
(R)-2 could be prepared by hydrolysis of methyl (R)-9-
hydroxystearate obtained from Dimorphoteca sinuata seeds
through an extraction of methyl dimorphecolate and successive
hydrogenation (Scheme 1b).2c,d Although the enzymatic
resolution of ( )-2 was also examined, the enantiomeric
excess reached only 55% ee (Scheme 1c).5b Recently, (R)-2
and its acylated derivatives could be prepared through
nucleophilic installation of fatty chains on enantioenriched
(+)-(S)-epichlorohydrin ((+)-(S)-4) (Scheme 1d).5c How-
ever, the use of Grignard reagents as the nucleophiles would
arise the issue on the functional group acceptance and narrow
the product scope. Hence, there is still room for further
improvement on a flexible, catalytic enantioselective approach
for diverse chiral hydroxylated fatty acid derivatives.
INTRODUCTION
■
Recently, several hydroxylated fatty acids and their variants
have been reported as biologically active compounds (Figure
1). In 2012, 7′-multijuguinol (1) was isolated from senna
multijuga as an acetylcholinesterase inhibitor.1 However, it was
a racemic mixture and the biologically active enantiomer was
not determined. 9-Hydroxystearic acid (HSA) (2), which is a
member of endogeneous lipid peroxidation byproducts, has
been known as a sterically simple but competitive inhibitor of
histone deacetylase 1 (HDAC-1) isoform in cancerogenesis of
a human colon adenocarcinoma cell line, HT29.2 As suggested
by an in silico docking simulation study, (R)-2 demonstrated
higher HDAC-1 inhibitory activity than its antipode in vitro.
By extensive studies on the stem bark of Knema laurina
pursuing a neuroprotective constituent,3a (+)-2-hydroxy-6-
(10′-hydroxypentadec-8′(E)-enyl)benzoic acid ((+)-3) was
isolated as an acetylcholinesterase inhibitor.3b Apart from
structurally similar gingkolic acids,3c this compound was found
to be dextrorotary; however, its absolute configuration was not
indicated.
In these contexts, the stereoselective synthesis of the
secondary alcohols having quasi-symmetric long-chain sub-
stituents has been believed as important in the field of
synthetic organic chemistry. While several reliable methods for
asymmetric reduction of carbonyl compounds have been
developed,4 it would be obvious that such approach could not
be easily applicable for the discrimination between two alkyl
groups on quasi-symmetric carbonyl compounds. Hence,
alternative strategies have been applied and several synthetic
Our new concept to pave an easily accessible way to such
secondary alcohols is outlined in Scheme 1e. The divinylcarbi-
nol 7, which could be obtained from ethyl formate and vinyl
Received: November 25, 2020
Published: February 11, 2021
https://dx.doi.org/10.1021/acs.joc.0c02821
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 3970−3980
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Figure 1. Natural chiral hydroxylated fatty acids and derivatives.
Grignard reagent in a large scale,6 would be transformed into
optically active epoxy ether 8 via the Sharpless asymmetric
epoxidation (SAE),7 and subsequent introduction of one long-
chain unit onto the remained olefin could afford 9. After
deoxygenation of the epoxide 9, another long-chain fragment
would be installed on the olefin unmasked in 10 to give 11. For
the above synthetic strategy, catalytic desymmetrization of
divinylcarbinol 7 has two major strong points as follows: (1)
stereochemistry of generated chiral center can be reliable and,
in principle, the high enantiomeric excess can be secured; (2)
epoxide can be regarded as a small, one-atom protective group
of the olefin8 readily removable after the introduction of one
long-chain unit. Therefore, we expected that the SAE of
divinylcarbinol would realize one-pot “enantioselective pro-
tection of olefin”.9 Based on this strategy, we successfully
accomplished a concise, convergent total synthesis of
cryptchiral natural product containing local symmetry on
secondary alcohol unit and revealed an absolute stereo-
chemistry of a novel natural acetylcholine esterase inhibitor.
Therefore, we will describe herein the details of our work.
shifts of methyl group on the ester moiety are known to appear
at 3.671 ppm for the ester from (R)-22 and 3.668 ppm for the
ester from (S)-22, respectively, our derivative 23 shows a
corresponding signal only at 3.671 ppm (shown in the SI).
Thus, the absolute stereochemistry of 2 could be judged as “R”
unambiguously and the optical purity was elucidated to be
>98% ee. With these results, our concept was proved quite
promising for the production of quasi-symmetric secondary
alcohols.
With the concept proven in Schemes 2 and 3, we then
focused on the stereochemical elucidation of naturally
occurring AChE inhibitor 3 (Scheme 4) by asymmetric total
synthesis starting from 12. The right-hand fragment 25 was
prepared from triflate 2413 and 7-octenol through a modified
Larock’s procedure.14 The highly reactive Schrodi−Stewart−
Grubbs catalyst15 was found to be suitable for the cross-
metathesis of epoxide 12 with volatile 1-pentene. A hydro-
genation and deoxygenation sequence afforded known 2616
with a requisite alkyl chain. At this time, we confirmed again
that the stereocenter induced by SAE was retained through the
chemical transformations by comparison of optical rotations.
Then, the right-hand fragment benzodioxinone 25 was coupled
with 26 by cross-metathesis to give an inseparable mixture of
geometric isomers (trans/cis = 9:1); however, these isomers
could be separated after desilylation. Finally, hydrolysis of 27
under basic conditions followed by acidic workup gave the
RESULT AND DISCUSSION
■
To prove the concept, we initially applied our strategy to a
concise synthesis of (R)-2 (Scheme 2). SAE of divinylcarbinol
with (−)-DIPT followed by TBDPS protection of the hydroxyl
group afforded the epoxide 12 (≥99% ee).7d,9 A cross-
metathesis of 12 with 1-nonene provided 13 without undesired
olefin isomerization in the presence of 1,4-benzoquinone,10
and subsequent hydrogenation could afford 14. Deoxygenation
of 14 proceeded effectively with PPh3/Zn8b to give 15. Since
the specific rotation of allyl alcohol 16, which was obtained by
desilylation of 15, was comparable to the reported value for
>99% ee sample,11 its optical purity was proved to be
maintained at a high level and no racemization proceeded
through metathesis, hydrogenation, and deoxygenation se-
quence.
25
proposed structure of (R)-3 ([α]D −21.1 (c 0.080, CHCl3))
in a good yield. The sign of [α]D, which is found to be
antipodal to that for natural AChE inhibitor 3 ([α]D +23.2
(CHCl3)),3b revealed that the naturally occurring (+)-3 has “S”
absolute stereochemistry.
CONCLUSIONS
■
In conclusion, we could demonstrate a novel strategy for a
flexible production of optically active secondary alcohols
possessing quasi-symmetric alkyl side chains devising a
divinylcarbinol as a conjunctive chiral module via SAE. Since
our method provides a reliable stereoisomer and an adaptable
synthetic route due to excellent functional group compatibility,
this novel protocol can provide facile stereochemical
elucidations of naturally occurring compounds with their
concise asymmetric total syntheses. Furthermore, this strategy
enables a highly convergent synthesis of biologically active fatty
acid derivatives possessing chiral secondary hydroxyl group.
Thus, structure−activity relationship studies on similar
naturally occurring hydroxystearic acids such as 7-HSA and
8-HSA, whose precursors are less available from natural
sources than 9-HSA,17 can be accelerated by our strategy.
Further applications to complex molecules are now ongoing in
our laboratory.
From intermediate 15, we accomplished a total synthesis of
(R)-2, as depicted in Scheme 3. The right-hand segment of
(R)-2, methyl 7-heptenate (20) was prepared from dimethyl
malonate in a satisfactory yield (55% for five steps). After
alkylation with tosylate 17, hydrolysis followed by decarbox-
ylation afforded carboxylic acid 19. Fischer esterification gave
methyl 7-heptenate (20). With the right-hand fragment in
hand, seven carbon units were introduced by cross-metathesis
and subsequent hydrogenation to furnish 21. Finally,
desilylation followed by hydrolysis in one-pot procedure
established 2. For a definite stereochemical elucidation of
cryptchiral 2 ([α]D +0.4 in acetic acid),12 the precursor 21 was
delivered into 23, known as (R)-O-acetylmandelate ester of
22,2c and the reference rac-22/(R)-O-acetyl mandelic acid
ester was also prepared from rac-15. Although the chemical
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Scheme 1. Preparation of Chiral Hydroxylated Fatty Acids Having Local Symmetries in the Vicinity of the Hydroxyl Group
prepared by distillation over CaH2 or purchased from commercial
EXPERIMENTAL SECTION
■
1
suppliers. H and 13C NMR spectra were measured on a JEOL ECA
General. All nonaqueous reactions were carried out under an Ar
500 II, a JEOL ECX 400 or a Varian GEMINI 300 instrument, using
atmosphere unless otherwise noted. Reagents were purchased from
commercial suppliers and used as received. Anhydrous solvents were
1
tetramethylsilane (TMS) (0.00 ppm for H), CHCl3 (7.26 ppm for
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Scheme 2. Preparation of the Left-Hand Segment of (R)-2
1
1H), or CDCl3 (77.0 ppm for 13C) as an internal reference. The
following abbreviations are used for spin multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, and br = broad. J values
were in hertz. Mass spectra were measured on a JEOL JMS-GCmate
II or a JEOL JMS-AX 505 HAD mass spectrometer, and the
ionization method was electron impact (EI, 70 eV) and fast atom
bombardment (FAB). A magnetic sector mass analyzer was used for
high resolution mass spectrometry (HRMS) measurement. IR spectra
were recorded on a JASCO FT/IR-460Plus spectrometer. Optical
rotations were measured on a JASCO P-2100 digital polarimeter.
Column chromatography was carried out using Cica Silica Gel 60N
(spherical, neutral, 40−50 μm). Preparative thin-layer chromatog-
raphy was performed on precoated silica gel 60 F254 plates (Merck).
1,4-Pentadien-3-ol (7). To a stirred suspension of Mg turning (4.9
g, 200 mmol) in tetrahydrofuran (THF) (60 mL) were added
potionwise I2 (1.1 g, 4.33 mmol) and a solution of vinyl bromide (1.0
M in THF, 200 mL, 200 mmol) at 25 °C. After the mixture was
refluxed for 1.5 h, to the above Grignard reagent was added dropwise
ethyl formate (6.1 g, 82 mmol) at 0 °C. After the mixture was stirred
for 1 h at 25 °C, the reaction was quenched with saturated aqueous
NH4Cl. The aqueous phase was extracted with Et2O and the
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by vacuum distillation (45 °C/200 mmHg) to give divinylcarbinol (7)
(5.4 g, 78%) as a colorless oil. Rf 0.41 (n-hexane/AcOEt = 95:5). The
1H NMR spectrum was identical to that previously reported.7e 1H
NMR (500 MHz, CDCl3) δ 5.91 (2H, ddd, J = 17.2, 10.3, 5.7 Hz),
5.29 (2H, ddd, J = 17.2, 1.4, 1.4 Hz), 5.17 (2H, ddd, J = 10.3, 1.4, 1.4
Hz), 4.66−4.62 (1H, m), 1.63 (1H, br s).
(n-hexane/AcOEt = 90:10). The H NMR spectrum was identical to
that previously reported for its antipode.9 1H NMR (500 MHz,
CDCl3) δ 7.72−7.63 (4H, m), 7.45−7.35 (6H, m), 5.89 (1H, ddd, J =
17.1, 10.5, 6.6 Hz), 5.20 (1H, d, J = 17.1 Hz), 5.13 (1H, d, J = 10.5
Hz), 3.96−3.92 (1H, m), 2.91−2.87 (1H, m), 2.52−2.49 (1H, m),
2.18−2.16 (1H, m), 1.07 (9H, s). Separation of enantiomers by
Chiral HPLC (DAICEL, CHIRALCEL OD-H, heptane/iPrOH,
5000:1, flow rate = 0.8 mL min−1, t2S,3R = 12.7 min, t2R,3S = 14.4
min) provided the enantiomer ratio: (2S,3R):(2R,3S) ≥ 99:1 (≥98%
23
23
ee). [α]D −0.131 (c 1.85, CHCl3). [lit. [α]D +0.336 (c 1.95,
CHCl3) for ent-12].9
(2S,3R)-1,2-Epoxy-3-(tert-butyldiphenylsilyloxy)dodec-4-ene
(13). To a stirred solution of the epoxide 12 (269 mg, 0.795 mmol) in
toluene (3.7 mL) were added 1-nonene (197 mg, 1.56 mmol), 1,4-
benzoquinone (9.3 mg, 0.086 mmol), and Hoveyda−Grubbs second-
generation catalyst (24.0 mg, 0.038 mmol) at 25 °C. After the mixture
was stirred for 25 h in refluxing toluene (using a heating block), the
solvent was removed in vacuo. The residue was purified by flash
column chromatography on silica gel (eluent: gradient from n-hexane
only to n-hexane/AcOEt = 98:2) to afford olefin 13 (274 mg, 79%,
brsm 91%, colorless oil) with recovered epoxide 12 (33.9 mg). Rf 0.54
1
(n-hexane/AcOEt = 90:10); H NMR (500 MHz, CDCl3) δ 7.70−
7.64 (4H, m), 7.43−7.33 (6H, m), 5.49−5.41 (2H, m), 3.95−3.92
(1H, m), 2.93−2.88 (1H, m), 2.57−2.54 (1H, m), 2.30−2.27 (1H,
m), 1.96−1.92 (2H, m), 1.32−1.22 (10H, m), 1.06 (9H, s), 0.88 (3H,
t, J = 7.2 Hz); 13C{1H} NMR (100 MHz, CDCl3) δ 136.0, 135.9,
133.9, 133.8, 129.7, 129.6, 128.5, 127.5, 127.4, 73.9, 54.7, 45.2, 32.1,
31.8, 29.14, 29.07, 28.9, 26.9, 22.7, 19.3, 14.1; IR (neat) 1590, 1112
cm−1; MS (EI) m/z 436, (M+); HRMS (EI) m/z: [M]+ calcd for
22
C28H40O2Si 436.2798; Found 436.2773; [α]D −35.2 (c 0.18,
(2S,3R)-1,2-Epoxy-3-(tert-butyldiphenylsilyloxy)pent-4-ene (12).
According to a reported procedure for the antipode of 12,9 the
Sharpless asymmetric epoxidation of divinylcarbinol7d followed by
silylation was conducted. The epoxide 12 (1.72 g, 51% for two steps)
was prepared from divinylcarbinol (7) (841 mg, 10.0 mmol). Rf 0.51
CHCl3).
(2S,3R)-1,2-Epoxy-3-(tert-butyldiphenylsilyloxy)dodecane (14).
After a mixture of the olefin 13 (300 mg, 0.690 mmol) and 10%
Pd/C (74.0 mg, 0.0695 mmol) in AcOEt was vigorously stirred under
H2 gas (balloon) for 20 h at 25 °C, the mixture was filtered through a
3973
https://dx.doi.org/10.1021/acs.joc.0c02821
J. Org. Chem. 2021, 86, 3970−3980