An Easy Route to Enantiomerically Enriched 7- and 8-Hydroxy-stearic Acids by Olefin-Metathesis-Based Approach

Article abstract of DOI:10.1055/s-0035-1561570

The synthesis of enantiomerically enriched 7- and 8-hydroxy-stearic acids (7- and 8-HSA) has been successfully accomplished starting from chiral nonracemic 1-pentadecen-4-ol and 1-tetradecen-4-ol, respectively. Their Yamaguchi's esterification with 4-pentenoic and 5-hexenoic acids, respectively, afforded the suitable dienic esters which were submitted to ring-closing metathesis reaction. After hydrogenation and basic hydrolysis of the complex reaction mixture, chiral nonracemic 7- and 8-HSA were obtained in about 40% total yield.

Full text of DOI:10.1055/s-0035-1561570

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
C. Boga et al.
Letter
Synlett
An Easy Route to Enantiomerically Enriched 7- and 8-Hydroxy-
stearic Acids by Olefin-Metathesis-Based Approach
Carla Bogaa
Sara Driolib
Cristina Forzatob
Gabriele Michelettia
Patrizia Nitti*b
Fabio Pratic
O
( )
n
*
O
( )
( )
OH
n
( )
m
m
OH
O
40% total yield
n = 10, m = 2: (S) or (R) 98–97% ee
n = 9, m = 3: (S) or (R) 99–97% ee
(S)- or (R)-7-HSA
(S)- or (R)-8-HSA
a Dipartimento di Chimica Industriale ‘Toso Montanari’, Università di
Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
b Dipartimento di Scienze Chimiche e Farmaceutiche, Università di
Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy
pnitti@units.it
c Dipartimento di Scienze della Vita, Università di Modena e Reggio
Emilia, Via Giuseppe Campi 103, 41125 Modena, Italy
Received: 25.09.2015
Accepted after revision: 18.01.2016
Published online: 17.02.2016
production of HSAs in enantiopure forms seems an attrac-
tive challenge. Sometimes, the natural chiral pool is a valu-
able source of enantiopure precursors of these acids.9 For
example, a convenient route to (R)-9-HSA starts from 9-hy-
droxyoctadeca-trans-10,trans-12-dienoic acid [(S)-dimor-
phecolic acid] present in large amount in the seed oil of ge-
nus Dimorphotheca.9 Similarly, (R)-12-HSA10 can be ob-
tained from castor oil that contains up to 90% of D-ricinoleic
acid. Less accessible are enantiomerically pure natural pre-
cursors of 8-HSA, such as isanolic acid11 (from seed oils of
Santalaceae and Olacaceae) and laetisaric acid12 whereas, to
the best of our knowledge, no useful precursors of 7-HSA
are available. Recently, enantioenriched 7-, 8-, 9-, and
10-HSA have been obtained for the first time by enzymatic
kinetic resolution of their racemates but the best enantio-
meric excesses obtained were around 55%.13
DOI: 10.1055/s-0035-1561570; Art ID: st-2015-b0766-l
Abstract The synthesis of enantiomerically enriched 7- and 8-hydroxy-
stearic acids (7- and 8-HSA) has been successfully accomplished start-
ing from chiral nonracemic 1-pentadecen-4-ol and 1-tetradecen-4-ol,
respectively. Their Yamaguchi’s esterification with 4-pentenoic and 5-
hexenoic acids, respectively, afforded the suitable dienic esters which
were submitted to ring-closing metathesis reaction. After hydrogena-
tion and basic hydrolysis of the complex reaction mixture, chiral nonra-
cemic 7- and 8-HSA were obtained in about 40% total yield.
Key words hydroxystearic acid, ring closing metathesis, cross metath-
esis, homoallylic alcohols, lipase B from Candida antarctica, kinetic enzy-
matic resolution
Hydroxystearic acids (HSAs) and their derivatives are
interesting molecules whose presence is crucial in many bi-
ological processes.1 For instance, 9- and 10-hydroxystearic
acids (9- and 10-HSA) have shown a natural negative regu-
latory activity on tumor-cell proliferation.2 In HT29 cells, a
human colon adenocarcinoma cell line, both enantiomers
of 9-HSA were able to inhibit the enzymatic activity of
HDAC1, HDAC2, and HDAC3 histone deacetylases, the R iso-
mer resulting more active.3 Furthermore, HSAs have been
studied recently for a wide range of technological applica-
tions. For instance, in the material chemistry field, the crys-
talline symmetry of monolayers at the air–water interface
of some monohydroxystearic acid (namely, 2-, 7-, 9-, and
12-HSA) has shown a specific correlation with the position
of the secondary hydroxy group.4 In another application,
HSAs and their derivatives were studied as low-molecular-
weight organogelators (LMOGs).5,6 To underline that the
type of supramolecular architectures depends on the chi-
rality of the molecule, enantiopure (R)-12-HSA7 has been
found to form fibrillar networks, while racemic 12-HSA
forms platelets under the same conditions.8 Therefore, the
In this communication we propose an efficient enantio-
selective synthesis of 7-HSA (1a)13 and 8-HSA (1b)13
through a multistep approach starting from racemic pre-
cursors. An inspection of the molecules of HSAs would sug-
gest the ring-closing olefin metathesis substrates 4 as po-
tential key precursors to the target molecules, via a se-
quence of intermediates, as shown retrosynthetically in
Scheme 1. This approach was already successfully applied
to the synthesis of a analogues of Topsentolides by Bracher
and coworkers.14
Hydroxystearic acids 1 are equivalent to saturated mac-
rocyclic lactones 2, which would be obtained by reduction
of the unsaturated macrocyclic lactones 3. Intermediates 3
could be the products of ring-closing metathesis (RCM) of
α,ω-diene 4. Access to 4 would be possible via condensation
of terminally unsaturated carboxylic acids 5 and the appro-
priate homoallylic alcohols 6. Thus it is evident that the
configuration at the carbinol carbon atom in the final hy-
droxy stearic acids is determined by the chirality of the par-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
C. Boga et al.
Letter
Synlett
antarctica) that displayed high enantioselection (E21> 200).
It is worth noting that the same Novozym 435 displayed
much lower enantioselectivity in catalyzing the acylation of
alcohols 6a,b with vinyl acetate (E = 12 and 15, respective-
ly).
O
( )
( )
n
n
*
O
*
O
( )
*
( )
( )
n
OH
( )
m
m
m
OH
O
O
1
3
2
In this manner (S)-(–)-1-pentadecen-4-ol (6a)22,23 with
98% ee and (S)-(–)-1-tetradecen-4-ol (6b) with 99% ee were
isolated in about 30% yield. The moderate yields in the en-
zymatic resolution process might be due to the difficult
extraction process after significant degradation of the
supported enzyme. The unreacted esters (R)-(+)-7a and
(R)-(+)-7b, both in 97% ee, were then hydrolyzed with two
equivalents of K2CO3 in MeOH at room temperature for 24
hours to furnish the corresponding alcohols (R)-(+)-
6a15,16,22,24 and (R)-(+)-6b,without affecting their enantio-
meric composition.
For the RCM of α,ω-dienes 4a and 4b, first (cat1) and
second-generation Grubbs catalysts (cat2) were checked
(Figure 1). The more active catalyst25 cat2 well worked with
both dienes, whereas cat1 resulted active on 4b and inef-
fective on 4a, underlining the known26 ability of cat2 to
promote the formation of 16- and 18-membered dimeric
ring-closed products instead of unfavorable eight- and
nine-membered rings.14
RCM
( )
n
HO
( )
*
( )
*
m
n
O
+
( )
m
O
OH
O
6
5
4
Scheme 1 Retrosynthetic analysis of HSAs
ent homoallylic alcohol. According to this retrosynthetic
disconnection, we faced the synthesis of both enantiomers
of 7-HSA (1a, n = 10, m = 2) and of 8-HSA (1b, n = 9, m = 3).
Condensation of commercially available 4-pentenoic
acid (5a, m = 2) and 5-hexenoic acid (5b, m = 3) with chiral
nonracemic 1-pentadecen-4-ol (6a)15,16 (n = 10) and 1-tet-
radecen-4-ol (6b)17,18 (n = 9), respectively, was performed
by using the Yamaguchi’s esterification reaction19 and af-
forded the dienic esters 4a and 4b in good chemical yields
(Scheme 2). Yamaguchi’s esterification resulted a clean and
easy-to-perform reaction that gave higher yield than anoth-
er method reported in the literature for esterification of
long-chain homoallylic alcohols.14
N
N
P
Ru
P
Cl
Cl
( )
a) Et3N, TCBC,
n
*
O
Ru
P
HO
( )
THF, 0 °C
( )
*
m
n
Ph
Ph
Cl
Cl
+
( )
m
b) DMAP, rt
79–80%
O
OH
O
m = 2: 5a
m = 3: 5b
n = 10: (S)- or (R)-6a
n = 9: (S)- or (R)-6b
n = 10, m = 2: (S)- or (R)-4a
n = 9, m = 3: (S)- or (R)-4b
cat1
cat2
TCBC = 2,4,6-trichlorobenzoyl chloride
DMAP = 4-(dimethylamino)pyridine
Figure 1 First-generation (cat1) and second-generation (cat2) Grubbs
catalysts
Scheme 2 Synthesis of esters 4a and 4b
Access to enantiomerically enriched homoallylic alco-
hols 6a,b was possible via kinetic enzymatic resolution of
the corresponding racemic acetates 7a and 7b (Scheme 3),
which were in turn synthesized following a literature pro-
cedure20 by reaction of allylmagnesium chloride with do-
decanal and undecanal, respectively. Enzymatic hydrolyses
were catalyzed by Novozym 435 (Lipase B from Candida
The RCM of 4a and 4b was performed27 in refluxing di-
chloromethane using 6 mol% Grubbs catalyst, at low sub-
strate concentration (3 mM) and in the presence of three
equivalents of titanium isopropoxide28 (Scheme 4); in the
case of diene 4a other substrate concentrations (18 and 30
mM) were also investigated.
In all cases the crude reaction mixtures revealed the
presence of many species, such as configurational isomers
and double-bond regioisomers,29 as suggested by an analy-
sis of 1H NMR and 13C NMR spectra. In order to have a clear-
er view of the products formed in the RCM reactions, the
crudes were subjected to hydrogenation, thus decreasing
the number of species. Three main products were identi-
fied for each reaction, namely a small amount of the ex-
pected eight- and nine-membered lactones 2a,b (Scheme
4) along with 16- and 18-membered lactones 8a,b and 9a,b,
originated by cross metathesis (CM) and subsequent ring
closure; in addition, in the case of 4a, the larger macrocyclic
( )
Novozym 435
( )n
( )
n
n
+
OAc
buffer (pH 7.4)
8 days
OAc
OH
n = 10: 7a
n = 9: 7b
(R)-(+)-7a, 97% ee
(R)-(+)-7b, 97% ee
(S)-(–)-6a, 98% ee
(S)-(–)-6b, 99% ee
K2CO3
MeOH
(R)-(+)-6a, 97% ee
(R)-(+)-6b, 97% ee
Scheme 3 Kinetic enzymatic resolution of acetates 7a,b
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
C. Boga et al.
Letter
Synlett
587 [M + Na]+) and the trimer 10a (m/z = 869 [M + Na]+).
Since 8a and 9a are constitutional isomers, they could be
recognized only in the subsequent synthetic step, namely in
the hydrolysis reaction which gave different fragments for
the two isomers. In fact basic hydrolysis carried out on the
hydrogenated mixtures allowed the isolation of diols 11a
and 11b. On the contrary, of the two diacids formed from
9a and 9b only 12a could be isolated (Scheme 4). It is worth
noting that the main hydrolysis products were the target
molecules 1a and 1b, namely 7- and 8-HSA respectively, de-
rived from monomers 2a and 2b, from dimers 8a and 8b,
and, in the case of 7-HSA, from the trimer 10a. Total yields
are related to the substrate concentration adopted in the
metathetic process: when concentration of diene 4a,b was
3 mM, acids 1a,b were recovered in about 40% yield, which
gradually lowered to about 30% as concentration of 4a
raised up to 18 and 30 mM due to the increased formation
of the undesired adduct 9a.
The optical purity of 7- and 8-HSA 1a and 1b thus ob-
tained was determined by NMR spectrometry after their
esterification of the carboxylic moiety with diazomethane
and derivatization with both (R)-(–)-O-acetylmandelic ac-
id33 or enantiopure Mosher acid34 (derivatives 13a,b and
14a,b, respectively, Figure S1, Supporting Information). Di-
astereomeric ratios of 99:1 for (7R,2′R)-13a and (7S,2′R)-
13a, of 94:6 and 90:10 for (8R,2′R)-13b and (8S,2′R)-13b,
respectively, were calculated. These results were confirmed
also by treatment of the methyl ester of 1a with the (R)-(+)-
Mosher acid [(+)-MTPA] and of 1b with the (S)-(–)-Mosher
acid [(–)-MTPA] (see Supporting Information).
( )
RCM
complex mixture
of products
n
*
O
( )
m
O
H2, Pd/C
n = 10, m = 2: (S)- or (R)-4a
n = 9, m = 3: (S)- or (R)-4b
O
( )
n
( )
( )
n
O
m
+
O
( )
m
O
( )
( )
m
n
O
O
head-to-tail dimer
n = 10, m = 2: 2a
n = 9, m = 3: 2b
n = 10, m = 2: 8a
n = 9, m = 3: 8b
( )
O
n
( )
n
( )
O
m
( )
O
n
( )
( )
+
m
O
( )
( )
( )
O
m
m
O
O
n
O
O
( )
head-to-head dimer
m
n
n = 10, m = 2: 9a
n = 9, m = 3: 9b
O
n = 10, m = 2: 10a
KOH
MeOH
OH OH
HOOC
1a
1b
( )
+
+
( )
m
COOH
m
( )
( )
( )
n
n
4
n = 10: 11a
n = 9: 11b
m = 2: 12a
Scheme 4 Hydrogenation products of RCM reaction mixtures and sub-
The synthesis of both enantiomers of 7-HSA and 8-HSA,
not available from natural sources, was successfully accom-
plished starting from racemic homoallylic alcohols which
were efficiently resolved by enzymatic resolution with Li-
pase B from Candida antarctica. Their esterification with
suitable unsaturated acids furnished terminal dienes,
which underwent ring-closure metathesis. Hydrogenation
of the crude reaction mixtures, containing different types
of chiral nonracemic macrocyclic lactones, followed by hy-
drolysis under basic conditions allowed the isolation of the
desired R and S enantiomer of 7-HSA and 8-HSA in about
40% total yield. The outcome of the ring-closure metathesis
reaction was analyzed on the basis of the nature of the hy-
drogenation products, giving evidences of the formation of
undesired cross-metathesis byproducts.
sequent basic hydrolysis
10a was also detected. Therefore it is clear that in this me-
tathetic process the desired RCM product 3 (Scheme 1) was
only a minor product, the major products deriving from
CM–RCM. This outcome was expected, since formation of
eight- and nine-membered cyclic olefins from RCM is
known to be extremely difficult.30–32The formation of eight-
and nine-membered unsaturated lactones 3 could be in-
creased performing the metathesis reaction in very low
concentration (0.1 mM) at the expense of the use of a large
quantity of a not environmentally friendly solvent and stoi-
chiometric amount of catalyst.14
Of all products, only head-to-tail dimers 8a and 8b were
isolated by flash chromatography and characterized, while
monomers 2a and 2b were identified as main components
in mixtures of different composition. Essentially, identifica-
tion was made through 1H NMR, 13C NMR, and ESI-MS spec-
tra, this latter playing a decisive role in assignments. For in-
stance compound 2b (m/z = 305 [M + Na]+) was present in a
fraction also containing a mixture of symmetric dimers
(m/z = 587 [M + Na]+), whereas compound 2a was present
only in traces and the main products were 8a and 9a (m/z =
Acknowledgment
We are grateful to Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) (Project PRIN 2010FPTBSH_005 ‘NANO Molecular
Technologies for Drug Delivery – NANOMED’), to the University of Tri-
este (Fondo per la Ricerca d’Ateneo, FRA 2014), and Alma Mater Stud-
iorum – Università di Bologna [Fundamental Oriented Research (RFO)
funds] for financial supports.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
C. Boga et al.
Letter
Synlett
Supporting Information
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1982, 104, 72.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561570.
S
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(27) Typical Procedure
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To (–)-(S)-4a (0.143 g, 0.46 mmol) in anhydrous CH2Cl2 (14 mL),
Ti(Oi-Pr)4 (0.41 mL, 1.38 mmol) was added at room tempera-
ture. The stirred solution was refluxed under Ar for 30 min and
then left cooled for 15 min. Second-generation Grubbs catalyst
(0.0236 g, 0.027 mmol) dissolved in anhydrous CH2Cl2 (1 mL)
was added, the reaction was refluxed with stirring for 7 h in Ar
atmosphere then left at room temperature overnight. The solu-
tion was filtered on a SiO2 pad, and washed with CH2Cl2. The
solvent was evaporated, and to the crude reaction mixture
(0.095 g) MeOH (4.75 mL) and Pd/C (10%, 0.095 g) were added.
The reaction mixture was stirred under H2 atmosphere for 24 h,
then filtered on a short column of SiO2, and washed with
CH2Cl2. The solvent was evaporated, and the crude was treated
with 3.0 mL of 10% KOH/MeOH, the mixture was stirred at 46 °C
for 3 d. After removing the solvent, H2O (10 mL) was added and
repeatedly extracted with Et2O. The organic phase was dried on
anhydrous Na2SO4 and evaporated to afford diol 11a (0.0045 g,
0.01 mmol). Basic mother liquors were acidified to pH 1 and
extracted with Et2O. The organic phase was dried on anhydrous
Na2SO4 and evaporated to furnish the acid (S)-7-HSA (1a, 0.038
g, 0.12 mmol). Evaporation of acidic mother liquors furnished
diacid 12a. The same procedure was applied on (+)-(R)-4a.
(28) Mitchell, L.; Parkinson, J. A.; Percy, J. M.; Singh, K. J. Org. Chem.
2008, 73, 2389.
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related 1H NMR signals, see ref. 13. The diastereomeric ratio was
calculated on the crude for (R)-7- and (R)-8-HSA derivatives and
on the product purified by preparative TLC for (S)-7- and (S)-8-
HSA derivatives.
(34) General Procedure for Derivatization with Mosher Acid
(R)-(+)-α-Methoxy-α-trifluoromethylphenylacetic acid [(+)-MTPA,
for derivatization of 7-HSA methyl esters] (0.012 g), or (S)-(–)-
α-methoxy-α-trifluorophenylacetic acid [(–)-MTPA, for 8-HSA
methyl esters], and DMAP (0.003 g) were dissolved, under nitro-
gen atmosphere, in anhydrous CH2Cl2 (300 μL) and stirred at
0 °C (ice-bath). To this solution of methyl hydroxystearate
(0.008 g) and DCC (0.010 g) dissolved in anhydrous CH2Cl2 (500
μL) was added dropwise. After a few minutes, a white solid pre-
cipitated. The reaction was monitored by TLC (eluent: n-
hexane–EtOAc, 3:1) until completion (sometimes addition of a
further amount of DCC and DMAP was necessary to reach com-
pletion). The solvent was removed, and the crude was dissolved
(16) Kumar, R. S. C.; Sreedhar, E.; Reddy, G. V.; Babu, K. S.; Rao, J. M.
Tetrahedron: Asymmetry 2009, 20, 1160.
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J. Am. Chem. Soc. 2004, 126, 12250.
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Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Chatterjee, B.; Mondal,
D.; Bera, S. Tetrahedron: Asymmetry 2012, 23, 1170.
1
in CDCl3 and analyzed by H NMR and 19F NMR. The diastereo-
meric ratio was calculated by integration of the 19F NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
C. Boga et al.
Letter
Synlett
signals; hexafluorobenzene (δ = –163.0 ppm) was used as inter-
nal standard.
(R)-Methyl 7-{[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpro-
panoyl]oxy}octadecanoate [(7R,2′R)-14a]
(R)-Methyl 8-{[(S)-3,3,3-Trifluoro-2-methoxy-2-phenylpro-
panoyl]oxy}octadecanoate [(8R,2′S)-14b]
1H NMR (400 MHz, CDCl3): δ = 7.59–7.50 (m, 2 H, Ph), 7.45–7.36
(m, 3 H, Ph), 5.07 (quint, 1 H, J = 6.5 Hz, CHOH), 3.67 (s, 3 H,
COOCH3), 3.55 (br s, 3 H, OCH3), 2.27 (t, 2 H, J = 7.5 Hz, CH2CO),
1.82–1.40 (m, 6 H, CH2), 1.40–1.10 (m, 22 H, CH2), 0.87 (t, 3 H, J
= 7.0 Hz, CH3) ppm. 19F NMR (376 MHz, CDCl3): δ = –72.369
ppm.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.50 (m, 2 H, Ph), 7.42–7.37
(m, 3 H, Ph), 5.07 (quint, 1 H, J = 6.4 Hz, CHOH), 3.66 (s, 3 H,
COOCH3), 3.55 (br s, 3 H, OCH3), 2.28 (t, 2 H, J = 7.3 Hz, CH2CO),
1.80–1.40 (m, 6 H, CH2), 1.40–1.10 (m, 22 H, CH2), 0.88 (t, 3 H,
J = 6.2 Hz, CH3) ppm. 19F NMR (376 MHz, CDCl3): δ = –72.360 ppm.
(S)-Methyl 7-{[(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpro-
panoyl]oxy}octadecanoate [(7S,2′R)-14a]
(S)-Methyl 8-{[(S)-3,3,3-Trifluoro-2-methoxy-2-phenylpro-
panoyl]oxy}octadecanoate [(8S,2′S)-14b]
1H NMR signals are undiscernible from those of the 8R,2′S dia-
stereomer. 19F NMR (376 MHz, CDCl3): δ = –72.405 ppm.
1H NMR signals undiscernible from those of the 7R,2′R diaste-
reomer. 19F NMR (376 MHz, CDCl3): δ = –72.323 ppm.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E