Gram-scale carbasugar synthesis: Via intramolecular seleno -Michael/aldol reaction

Article abstract of DOI:10.1039/c9ra02002k

Carbasugars represent an important category of natural products possessing a broad spectrum of biological activities. Lots of effort has been done to develop gram scale synthesis. We are presenting a new approach to gram scale synthesis of the carbasugar skeleton via intramolecular seleno-Michael/aldol reaction. The proposed strategy gave gram amounts of 6-hydroxy shikimic ester in a tandem process in 36% overall yield starting from d-lyxose. We have attempted to demonstrate the synthetic utility of 6-hydroxyshikimic acid derivatives by covering the important synthetic modifications and related applications, namely synthesis of protected (-)-gabosine E, (-)-MK7606, (-)-valienamine and finally unprotected methyl (-)-shikimate.

Full text of DOI:10.1039/c9ra02002k

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Gram-scale carbasugar synthesis via intramolecular
seleno-Michael/aldol reaction†
Cite this: RSC Adv., 2019, 9, 12928
*
Piotr Banachowicz
and Szymon Buda
Carbasugars represent an important category of natural products possessing a broad spectrum of biological
activities. Lots of effort has been done to develop gram scale synthesis. We are presenting a new approach
to gram scale synthesis of the carbasugar skeleton via intramolecular seleno-Michael/aldol reaction. The
proposed strategy gave gram amounts of 6-hydroxy shikimic ester in a tandem process in 36% overall
yield starting from D-lyxose. We have attempted to demonstrate the synthetic utility of 6-
hydroxyshikimic acid derivatives by covering the important synthetic modifications and related
applications, namely synthesis of protected (ꢀ)-gabosine E, (ꢀ)-MK7606, (ꢀ)-valienamine and finally
unprotected methyl (ꢀ)-shikimate.
Received 15th March 2019
Accepted 17th April 2019
DOI: 10.1039/c9ra02002k
rsc.li/rsc-advances
high, prices are low and chemistry of carbohydrates is well
known. An application of monosaccharides to carbohydrate
mimetic synthesis seems to be a natural choice.12 General
synthesis of carbasugars moieties is employing Grubbs cross
metathesis reaction,13–16 aldol-type cyclization,17,18 Corey–Fuchs
reaction19 and others.3 Total synthesis of gabosines has been
recently reviewed by Mac and co-workers.20
Our proposal of shikimic-type esters synthesis and their
reduced analogues is based on modication of 6-hydroxy-
shikimic ester21,22 obtained via intramolecular seleno-Michael/
aldol reaction from D-lyxose (Scheme 1).
Introduction
Carbasugars are analogues of sugars that have attracted the
interest of medicinal chemists due to their potential application
as active pharmaceutical ingredients. These compounds are
structurally related to carbohydrates where the ring oxygen is
replaced with a methylene group.1,2 Carbasugar fragments have
been found in various natural products.3,4 The structural simi-
larity of carbasugar fragments to conventional mono-
saccharides suggests that they are likely to bind and inhibit the
same protein targets. The advantage of carbasugar containing
compounds is the lack of a glycosidic linkage resulting in the
increased stability toward enzymatic degradation.5,6 For
example, synthetic nucleotide analogues containing thiosugar
or carbasugars have been reported to be glycosyltransferase
inhibitors.7–9 The mechanism of glycosidase inhibition has
been studied and several carba-analogues, such as Sergliozin-
A10 or SL0101,11 have been introduced (Fig. 1). Growing interest
of carbasugar use is limited due to their low availability from
natural sources.
Results and discussion
First, we prepared oxo-a,b-unsaturated ester (8) according to the
literature method in multi-gram scale.23 Mixture of 2,3,4-tri-O-
benzyl-D-lyxopyranoses (6) have been reuxed with excess of
ylide over 12 h yielding mixture of E/Z isomers of 7. Alcohol 7
has been oxidized to corresponding aldehyde 8 using Swern
oxidation in 78% yield. Compound 8 has been subjected to
intramolecular seleno-Michael/aldol reaction with consecutive
oxidation-elimination process to afford a mixture of 6-hydrox-
yshikimic esters (5) in 56% yield for 7 h (Scheme 2).24
General strategies to obtain carbapyranoses can be broadly
classied into two groups: (i) synthetic methods that employ
non-carbohydrates as starting materials and (ii) protocols that
utilize carbohydrates as precursors. Multi gram synthesis of
carbasugar fragments is still challenging and extremely
important.
Aer short optimization, multistep tandem reaction gave the
carbocyclic products (6S)-5 and (6R)-5 in 76% yield over 3 steps
Carbohydrates, especially monosaccharides, are excellent
starting material for total synthesis of various natural and
valuable synthetic compounds. Their availability is usually very
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow,
Poland. E-mail: szym.buda@gmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra02002k
Fig. 1 Active carbasugars containing compounds.
12928 | RSC Adv., 2019, 9, 12928–12935
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
Scheme 3 Synthesis of protected (ꢀ)-valienamine.
Synthesis of protected (ꢀ)-MK7607
Scheme 1 General strategy of cyclitols synthesis.
Syn-isomer of compound 5 was transformed to partially protect
unnatural (ꢀ)-MK7607. Simple reduction with DIBAL-H gave
compound (6R)-9 in 33% yield which is surprising to the result
obtained for 6S-isomer (65%) at the same conditions (Scheme 4).
Synthesis of protected (ꢀ)-gabosine E
Starting from diastereomeric mixture of 5, ester fragment has
been reduced in the presence of DIBAL-H to give diol 9 in 48%
yield. Selective protection of primary hydroxyl group gave
mixture of isomers 13 in 64% yield. Oxidation with Dess–Martin
reagent in DCM to unsaturated ketone (14) and consecutive silyl
ether deprotection gave 2,3,4-tri-O-benzylated (ꢀ)-gabosine E
(15) in 84% yield in two steps (Scheme 5).
Scheme 2 Synthesis of key intermediate.
Synthesis of methyl (ꢀ)-shikimate
(ꢀ)-Shikimic acid is an important metabolite in plants and
microorganisms. This compound can be isolated from the
Japanese star anise or synthetized starting from chiral and
achiral substrates. Recently, Candeias et al.,25 summarized
as an 1 : 0.33 mixture of axial and equatorial alcohol (Table 1).
The 6S/R-isomers of 5 have been separated easily by column
chromatography (Experimental section). Having established the
optimized conditions for the cyclic core synthesis, further
functionalization has been achieved.
Synthesis of protected (ꢀ)-valienamine
The 6S-hydroxyshikimic ester (6S)-5 has been transformed to
non-natural valienamine derivative (11) with known protocol in
27% yield over 3 steps.16,24 Exposure of 10 to chlorosulfonyl
isocyanate in DCM afforded the desired product (11) in 51%
yield. Minor product has been assigned by NMR analysis as C3-
epimer of (ꢀ)-valienamine (12) (Scheme 3).
Scheme 4 Synthesis of unnatural (ꢀ)-MK7607.
Table 1 Scale optimizationa
Entry
Scale
Conditions
Yield
Anti/syn
1
2
174 mg (0.35 mmol)
1080 mg (2.21
mmol)
5600 mg
(11.45 mmol)
ꢀ20 ꢁC (6 h)
56%
76%
1 0.32
1 0.32
ꢀ78 ꢁC (30 min)
3
ꢀ78 ꢁC (30 min)
76%
1 0.33
a
Reaction conditions: THF, 1.2 equiv. n-BuSeLi to RT (30 min), 10 equiv.
H2O2, 5 equiv. py, 50 ꢁC (1 h).
Scheme 5 Synthesis of (ꢀ)-gabosine E derivative.
RSC Adv., 2019, 9, 12928–12935 | 12929
This journal is © The Royal Society of Chemistry 2019

View Article Online
RSC Advances
Paper
Table 2 Deoxygenation of 6-hydroxyshikimic acid
derivative enable access to selective modication of hydroxyl
groups. Deoxygenation of 6-hydroxyshikimic ester gave methyl
(ꢀ)-shikimate in 49% yield total.
Experimental
General experimental procedures
Entry
Conditions
Yield
All starting materials and reagents were purchased from
commercial sources and used without purication. Reactions
were controlled using TLC on silica [alu-plates (0.2 mm)]. Plates
were visualized with UV light (254 nm) and by treatment with:
aqueous cerium(IV) sulfate solution with molybdic and sulfuric
acid followed by heating. All organic solutions were dried over
anhydrous magnesium sulfate. Reaction products were puried
by column chromatography using silica gel 60 (240–400 mesh).
Optical rotations were measured at room temperature with
a digital polarimeter. CDCl3, D2O, CD3OD were used as NMR
solvents. 1H spectra were recorded with 600 and 300 MHz, and
referenced relative to: CDCl3 – solvent residual peak (d ¼ 7.26
ppm); D2O – solvent residual peak (d ¼ 4.79 ppm); CD3OD –
solvent residual peak (d ¼ 3.31 ppm). Data are reported as
follows: chemical shi in parts per million (ppm), multiplicity (s
¼ singlet, d ¼ doublet, t ¼ triplet, dd ¼ doublet of doublets, ddd
¼ doublet of doublet of doublets, dddd ¼ doublet of doublet of
doublet of doublets, m ¼ multiplet), coupling constants (in
hertz) and integration. 13C NMR spectra were measured at 150
and 75 MHz with complete proton decoupling. Chemical shis
were reported in ppm from the residual solvent as an internal
standard: CDCl3 (d ¼ 77.16 ppm); CD3OD (d ¼ 49.00 ppm).
High-resolution mass spectra were acquired using ESI-TOF
method.
1
2
3
Et3SiH, BF3$Et2O, DCM, rt, 1 h
nr
nr
nr
EtO3SiH, TFA, DCM, rt, up to 24 h
Tf2O, DCM ꢀ40 ꢁC, 30 min, 0 ꢁC,
30 min then NaBH4, EtOH
4
NaH, Im, 0 ꢁC, 30 min, THF then CS2,
30 min, rt, then MeI, 30 min, rt, 50 ꢁC, 1 h
nra
a
Xanthate not formed.
Scheme 6 Synthesis of methyl (ꢀ)-shikimate.
known methods of (ꢀ)-shikimic acid synthesis. Starting from
diastereomeric mixture of alcohols 5 several deoxygenation
methods have been tested (Table 2).
2,3,4-Tri-O-benzyl-D-lyxopyranose (6)
To methanolic solution of 1% HCl (50 mL) (prepared by dis-
solving 1 mL SOCl2 in anhydrous methanol) D-lyxose (5.0 g, 33.3
mmol) was added in one portion and resulting mixture was
reuxed for 5 h under argon (reaction was monitored by TLC
CH2Cl2/MeOH 2 : 1). The reaction mixture was allowed to cool
to room temperature, neutralized by addition of solid NaHCO3
and concentrated under reduced pressure. The residue was
dissolved in EtOH (40 mL) and concentrated to the half of the
original volume, toluene (25 mL) was added and the mixture
was concentrated to dryness. The residue crude mixture oil was
used without further purication in the next step. The viscous
oil from the previous step was dissolved in anhydrous DMF (50
mL) and anhydrous THF (50 mL) and in 5 portion was added to
60% NaH suspension in mineral oil (6.8 g, 170 mmol) cooled to
Finally, alcohol 5 was converted to mesylate 16. Unfortu-
nately, all of our attempts to displace the mesylate group with
hydride reagents resulted only in the 1,4-displacement. We
decided to change mesylate group to iodide (17) and we
found that halogenated compound (17) is unstable in the
presence of light. In the end, reduction of iodide crude
mixture carried out in the dark gave ethyl (ꢀ)-tri-O-benzyl-
shikimate (18) in 2 h in 73% yield over 3 steps. Ethyl ester
has been removed under basic conditions to give (ꢀ)-3,4,5-
tri-O-benzylshikimic acid in quantitative yield. Exposure of
19 to BCl3 gave methyl (ꢀ)-shikimate (20) in 67% yield
(Scheme 6).
ꢁ
0 C. Aer hydrogen evolution was complete the mixture was
Conclusions
treated with BnBr (14.8 mL, 122 mmol) and stirred for 30 min in
In summary, we have developed simple methods that provide 0 ꢁC and then 12 h in room temperature. The reaction mixture
a rapid entry into the synthesis of a series of shikimate ester and was carefully quenched with cold, 10% aqueous solution of
shikimate analogues, including (ꢀ)-gabosine
E
and NH4Cl (30 mL) followed by addition of water (75 mL). The
(ꢀ)-MK7606. Our synthesis of 6-hydroxy shikimates from D-lyx- aqueous layer was extracted with EtOAc (3 ꢂ 50 mL) and
ose has been efficiently achieved in six steps with a 35% overall combined organic layers were washed with water (2 ꢂ 60 mL)
yield. The strategies described take place through short, high- and brine (50 mL), then dried over anhydrous MgSO4 and
yield reaction sequences. Partial protection of D-lyxose concentrated under reduced pressure. Crude mixture of D-
12930 | RSC Adv., 2019, 9, 12928–12935
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
ꢁ
lyxosides from previous step was heated under reux for 15 h (below 35 C). Crude product was puried by column chroma-
with 1 M H2SO4 (42 mL), AcOH (48 mL) and 1,4-dioxane (44 mL). tography Hex/EtOAc (1 : 0) to (85 : 15) to give the title
Mixture was cooled to rt and extracted with EtOAc (2 ꢂ 100 mL). compound as a mixture of diastereoisomers (Z/E 1 : 0.5) as
Organic phase was washed twice with water (2 ꢂ 50 mL) and almost colorless oil (5.75 g, 11.8 mmol, 77%). 1H NMR (600
brine (50 mL) and dried over anhydrous MgSO4. Aer solvent MHz, CDCl3) d 9.73 (s, 1H), 9.61 (d, J ¼ 1.6 Hz, 0.5H), 7.34–7.26
evaporation residue was puried by column chromatography (m, 19.5H), 7.25–7.20 (m, 3H), 6.99 (dd, J ¼ 15.8, 6.7 Hz, 0.5H),
(Hex/EtOAc 2 : 1 to 3 : 2) to afford mixture of anomers of 2,3,4- 6.28 (dd, J ¼ 11.7, 8.7 Hz, 1H), 6.13 (dd, J ¼ 15.8, 1.0 Hz, 0.5H),
tri-O-benzyl-D-lyxopyranose as
a
colorless oil (10.97 g, 5.94 (dd, J ¼ 11.7, 1.2 Hz, 1H), 5.49 (dd, J ¼ 8.7, 3.5 Hz, 1H),
1
26.1 mmol, yield ¼ 78%). H and 13C spectra were compared 4.69–4.45 (m, 7.5H), 4.41 (d, J ¼ 11.8 Hz, 1H), 4.28–4.20 (m,
with lit.23
1.5H), 4.19–4.15 (m, 2.5H), 4.07 (dd, J ¼ 3.5, 1.6 Hz, 0.5H), 4.00–
3.97 (m, 2H), 3.87 (dd, J ¼ 7.6, 3.5 Hz, 0.5H), 1.31 (t, J ¼ 7.1 Hz,
1.5H), 1.27 (t, J ¼ 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d 202.7, 201.3, 165.9, 165.9, 147.2, 145.2, 138.0, 137.9, 137.3,
137.1, 137.0, 128.7, 128.6, 128.5, 128.5, 128.4, 128.4, 128.1,
128.1, 128.0, 128.0, 127.8, 127.7, 124.6, 122.5, 83.7, 83.3, 81.2,
74.6, 74.3, 73.6, 73.3, 73.2, 71.7, 71.3, 60.7, 60.5, 14.3, 14.3;
HRMS (ESI): calcd for C30H22O6Na [M + Na]+ 511.2091, found
511.2091.
Ethyl (4R,5R,6R)-4,5,6-tri-O-benzyl-7-hydroxyhept-2-enoate (7)
To a solution of 6 (10.0 g, 23.8 mmol) in anhydrous benzene
(200 mL), ethyl (triphenylphosphoranylidene)acetate (16.5 g,
47.6 mmol) was added in one portion and mixture was heated to
reux for 8 h. Aer that time next portion of ethyl (triphenyl-
phosphoranylidene)acetate (8.3 g, 23.8 mmol) was added and
heating to reux was continued for next 4 h. Reaction mixture
was cooled to room temperature and benzene was evaporated
under reduced pressure. Most of triphenylphosphine oxide was
precipitated from the mixture of Et2O/Hex 7 : 3 and ltered by
suction. Solvent was removed under reduced pressure and
crude product was puried by column chromatography (Hex/
EtOAc 3 : 1 to 7 : 3) to afford product as a colorless syrup
(8.95 g, 18.2 mmol, 77%, Z/E ¼ 1 : 0.6). 1H NMR (600 MHz,
CDCl3) d 7.36–7.26 (m, 24H), 7.06 (dd, J ¼ 15.9, 6.6 Hz, 1H), 6.40
(dd, J ¼ 11.8, 9.1 Hz, 0.6H), 6.14 (dd, J ¼ 15.8, 0.9 Hz, 0.6H), 5.97
(dd, J ¼ 11.8, 0.8 Hz, 1H), 5.48–5.44 (m, 1H), 4.80 (d, J ¼ 11.5 Hz,
1H), 4.68 (d, J ¼ 11.8 Hz, 1.6H), 4.63 (d, J ¼ 11.6 Hz, 1H), 4.60 (d,
J ¼ 5.1 Hz, 1H), 4.59–4.57 (m, Hz, 2.4H), 4.51 (d, J ¼ 11.6 Hz,
1H), 4.47 (d, J ¼ 11.7 Hz, 1H), 4.30 (d, J ¼ 11.5 Hz, 0.6H), 4.28–
4.25 (m, 0.6H), 4.22 (q, J ¼ 7.1 Hz, 1.2H), 4.17 (qd, J ¼ 7.1, 0.9 Hz,
2H), 3.89 (dd, J ¼ 6.0, 3.7 Hz, 1H), 3.80–3.68 (m, 3.8H), 3.66–3.61
Ethyl 3,4,5-tri-O-benzyl-6-hydroxyshikimate (5)
A suspension of elemental selenium (1.09 g, 13.75 mmol) in
anhydrous THF (250 mL) was cooled in an ice bath and n-BuLi
(1.6 M in hexanes, 8.6 mL, 13.75 mmol) was added dropwise (a
clear solution was produced) and the mixture was stirred for
15 min in 0 ꢁC. Aer that reaction mixture was cooled to ꢀ78 ꢁC,
solution of 8 (5.60 g, 11.46 mmol in 100 mL of anhydrous THF)
was added dropwise and stirring was continued through the
next 30 min and then cryo-bath was removed and mixture was
allowed to warm to room temperature and stirring was
continued for the next 1 h. Aer that time, reaction was cooled
to 0 ꢁC and hydrogen peroxide (35% v/v, 10.1 mL, 114.6 mmol)
and pyridine (4.6 mL, 57.3 mmol) were added. Ice bath was
removed and mixture was heated to 50 ꢁC for 1 h (solution
became clear and colorless). Aer solvent evaporation under
reduced pressure oily residue was dissolved in ethyl acetate (200
mL), washed twice with water (2 ꢂ 80 mL) and brine (100 mL)
and dried over anhydrous MgSO4. Solvent was evaporated under
reduced pressure and crude product was puried by column
chromatography (Hex/EtOAc 4 : 1 to 3 : 1) to give title product as
colorless syrup (4.22 g, 8.65 mmol, 76%, 6S(anti)/6R(syn)
1 : 0.33). 1 g sample of 5 was separated by column chromatog-
raphy (Hex/EtOAc 5 : 1 to 3 : 1) to give (6S)-5 (0.75 g) and (6R)-5
(m, 1.6H), 1.31 (t, J ¼ 7.1 Hz, 1.8H), 1.27 (t, J ¼ 7.1 Hz, 3H); 13
C
NMR (150 MHz, CDCl3) d 166.0, 146.5, 145.4, 138.6, 138.5, 138.3,
138.2, 137.8, 137.7, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4,
128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.8, 127.8,
127.7, 124.0, 122.5, 81.4, 81.1, 80.2, 79.2, 78.6, 74.8, 74.6, 73.7,
73.1, 73.1, 71.6, 71.5, 61.9, 61.9, 60.7, 60.5, 14.4, 14.3; HRMS
(ESI): calcd for C30H34O6Na [M + Na]+ 513.2248, found 513.2258.
Ethyl (4R,5R,6R)-4,5,6-tri-O-benzyl-7-oxohept-2-enoate (8)
A solution of oxalyl chloride (3.91 mL, 45.7 mmol) ꢁin anhydrous (0.24 g). Ethyl (6S)-3,4,5-tri-O-benzyl-6-hydroxyshikimate (6S-5):
methylene chloride (200 mL) was cooled to ꢀ78 C, aer that [a]2D0 ¼ ꢀ73.1 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) d 7.39–
DMSO (6.49 mL, 91.4 mmol) was added dropwise and stirred for 7.27 (m, 13H), 7.24–7.21 (m, 2H), 6.96 (dd, J ¼ 2.5, 0.9 Hz, 1H),
30 min. The 7 (7.47 g, 15.2 mmol) was dissolved in anhydrous 4.77 (d, J ¼ 11.9 Hz, 1H), 4.67 (dd, J ¼ 11.9, 6.3 Hz, 3H), 4.63 (d, J
methylene chloride (100 mL), slowly added to oxidative mixture ¼ 11.9 Hz, 1H), 4.56 (d, J ¼ 11.8 Hz, 1H), 4.50 (dd, J ¼ 9.4, 2.8 Hz,
ꢁ
and kept in ꢀ78 C for 30 min. The triethylamine (19.26 mL, 1H), 4.38 (t, J ¼ 2.8 Hz, 1H), 4.29–4.22 (m, 2H), 4.05 (dd, J ¼ 5.5,
137.0 mmol) was slowly added and stirring was continued for 2.9 Hz, 1H), 3.94–3.91 (m, 1H), 3.30 (d, J ¼ 9.3 Hz, 1H), 1.31 (t, J
next 30 min, aer that reaction mixture was allowed to slowly ¼ 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 166.0, 138.0, 137.9,
warm to 0 ꢁC. The reaction was quenched with addition of sat. 137.7, 137.4, 132.1, 128.6, 128.2, 128.1, 128.0, 127.8, 127.8, 77.4,
NH4Cl (100 mL), followed by addition of water (100 mL). The 74.3, 73.7, 73.7, 72.8, 71.9, 66.2, 61.0, 14.3; HRMS (ESI): calcd for
aqueous layer was extracted with methylene chloride (3 ꢂ 100
C
30H32O6Na [M + Na]+ 511.2091, found 511.2091; Ethyl (6R)-
mL), and combined organic layers were washed with water (2 ꢂ 3,4,5-tri-O-benzyl-6-hydroxyshikimate (6R-5): [a]2D0 ¼ ꢀ82.9 (c
1
100 mL), and brine (100 mL). The organic phase was dried over 1.0, CHCl3); H NMR (600 MHz, CDCl3) d 7.38–7.27 (m, 15H),
anhydrous MgSO4 and concentrated under reduced pressure 6.88 (d, J ¼ 3.7 Hz, 1H), 4.80 (t, J ¼ 3.2 Hz, 1H), 4.76 (d, J ¼
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 12928–12935 | 12931

View Article Online
RSC Advances
Paper
11.7 Hz, 1H), 4.73–4.66 (m, 4H), 4.62 (d, J ¼ 11.9 Hz, 1H), 4.30 (t,
J ¼ 3.3 Hz, 1H), 4.23 (qd, J ¼ 7.1, 1.0 Hz, 2H), 4.04 (dd, J ¼ 7.9,
4.1 Hz, 1H), 3.94 (dd, J ¼ 7.9, 3.7 Hz, 1H), 3.19 (d, J ¼ 3.3 Hz,
1H), 1.29 (t, J ¼ 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 166.3,
138.4, 138.2, 137.9, 132.1, 128.6, 128.6, 128.5, 128.1, 128.0,
128.0, 127.8, 76.3, 75.5, 73.9, 73.4, 72.5 (2C), 65.4, 61.2, 14.3;
HRMS (ESI): calcd for C30H32O6Na [M + Na]+ 511.2091, found
511.2091.
6-Epi-3,4,5,6,7-penta-O-benzyl-(ꢀ)-MK7607 (10)
To a stirred suspension of NaH (0.027 g, 0.67 mmol, 60% in
mineral oil) in anhydrous DMF (5 mL) was added a solution of 9
(0.130 g, 0.29 mmol) and BnBr (0.08 mL, 0.67 mmol) at 0 ꢁC
under argon. Aer 30 min of stirring, ice bath was removed and
stirring was continued for 12 h in room temperature. The
reaction mixture was carefully quenched with a cold, 10%
aqueous solution of NH4Cl (5 mL). The aqueous layer was
extracted with ethyl acetate (3 ꢂ 5 mL). The organic layer was
washed with H2O (5 mL) and brine (5 mL), dried over anhydrous
MgSO4, and concentrated under reduced pressure. The residue
was puried by column chromatography (Hex/EtOAc 9 : 1 to
7 : 1) to give title compound as a colorless syrup (0.117 g,
0.186 mmol, 83%). [a]D24 ¼ ꢀ150.3 (c 1.0, CHCl3); 1H NMR (600
MHz, CDCl3) d 7.41–7.27 (m, 25H), 5.92 (d, J ¼ 5.3 Hz, 1H), 5.05
(d, J ¼ 11.0 Hz, 1H), 4.85–4.66 (m, 7H), 4.49 (d, J ¼ 11.8 Hz, 1H),
4.45 (d, J ¼ 11.8 Hz, 1H), 4.32 (dd, J ¼ 10.0, 7.1 Hz, 1H), 4.24–
4.17 (m, 2H), 4.12–4.08 (m, 1H), 3.96 (d, J ¼ 12.5 Hz, 1H), 3.60
(dd, J ¼ 10.1, 3.5 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 140.2,
139.0, 138.9, 138.8, 138.6, 138.2, 128.5, 128.4, 128.4, 128.1,
128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6, 123.5, 80.6,
80.0, 79.8, 75.0, 73.8, 72.7, 72.6, 71.8, 71.0, 70.4; HRMS (ESI):
calcd for C42H42O5Na [M + Na]+ 649.2924, found 649.2927.
3,4,5-Tri-O-benzyl-(ꢀ)-MK7607 ((6R)-9)
A solution of compound (6R)-5 (0.10 g, 0.2 mmol) in anhydrous
ꢁ
methylene chloride (5 mL) was cooled to ꢀ30 C and solution of
DIBAL-H (1 M in methylene chloride, 1.2 mL, 1.2 mmol) was added
dropwise. When the addition was complete, the mixture was stir-
red at ꢀ10 ꢁC for 3 h. Aer that time, methanol (1 mL) was added
to quench the reaction, and mixture was stirred at ꢀ10 ꢁC for
30 min. Aer water addition (5 mL) and few drops of 1 M aqueous
HCl, water phase was extracted with methylene chloride (3 ꢂ 5
mL) and combined organic phases were washed with water (2 ꢂ 5
mL) and brine (10 mL) and dried over anhydrous MgSO4. Solvent
was evaporated under reduced pressure. Crude oil was puried by
column chromatography (Hex/EtOAc 2 : 1 to 1 : 1) to give title
compound as a colorless syrup (0.03 g, 0.067 mmol, 33%). [a]D20
¼
1
ꢀ78.5 (c 1.1, CHCl3); H NMR (600 MHz, CDCl3) d 7.36–7.27 (m,
15H), 5.83 (d, J ¼ 3.9 Hz, 1H), 4.75–4.68 (m, 4H), 4.65 (d, J ¼
11.5 Hz, 1H), 4.62 (d, J ¼ 12.1 Hz, 1H), 4.43 (s, 1H), 4.24 (d, J ¼
13.4 Hz, 1H), 4.18–4.13 (m, 2H), 4.02 (dd, J ¼ 8.2, 4.3 Hz, 1H), 3.92
4,5,6-Tri-O-benzyl-(ꢀ)-valienamine-N-benzyl carbamate (11)
and 4,5,6-tri-O-benzyl-(+)-b-valienamine-N-benzyl carbamate
(12)
(dd, J ¼ 8.2, 3.6 Hz, 1H), 2.83 (d, J ¼ 4.0 Hz, 1H); 13C NMR (150 To a stirred solution of 10 (0.69 g, 0.11 mmol) in anhydrous
MHz, CDCl3) d 139.7, 138.5, 137.8, 128.5, 128.4, 128.0, 127.8, 127.8, toluene (0.74 mL) was added Na2CO3 (0.132 g, 1.25 mmol) and
ꢁ
127.7, 123.8, 76.7, 75.6, 73.6, 73.2, 72.2, 72.0, 67.3, 64.9; HRMS chlorosulfonyl isocyanate (0.07 mL, 0.83 mmol) at 0 C under
(ESI): calcd for C28H30O5Na [M + Na]+ 469.1985, found 469.1987.
argon. The reaction mixture was stirred for 15 h at 0 ꢁC and
quenched carefully with addition H2O (1 mL). The aqueous
layer was extracted with ethyl acetate (2 ꢂ 2 mL). The organic
layer was added to a solution of aqueous 25% Na2SO3 (2 mL).
6-Epi-3,4,5-tri-O-benzyl-(ꢀ)-MK7607 ((6S)-9)
A solution of compound (6S)-5 (0.22 g, 0.45 mmol) in anhydrous The reaction mixture was stirred for 24 h at room temperature.
methylene chloride (10 mL) was cooled to ꢀ30 ꢁC and solution The organic layer was washed with H2O (ꢃ3 mL) and brine (ꢃ3
of DIBAL-H (1 M in methylene chloride, 2.7 mL, 2.7 mmol) was mL), dried over anhydrous MgSO4 and concentrated under
added dropwise. When the addition was complete, the mixture reduced pressure. The solid residue was puried by column
ꢁ
was stirred at ꢀ10 C for 3 h. Aer that time, methanol (2 mL) chromatography (Hex/EtOAc 7 : 1 to 4 : 1) to give title
was added to quench the reaction, and mixture was stirred at compounds 11 (0.038 g, 0.055 mmol, 51%), 12 (0.006 g,
ꢀ10 ꢁC for 30 min. Aer water addition (10 mL) and few drops 0.01 mmol, 9%) and substrate 10 (0.013 g, 0.021 mmol, 19%)
(0.5 mL) of 1 M aqueous HCl, water phase was extracted with was recovered. 4,5,6-Tri-O-benzyl-(ꢀ)-valienamine-N-benzyl
1
methylene chloride (3 ꢂ 10 mL) and combined organic phases carbamate (11): [a]2D0 ¼ ꢀ28.9 (c 1.0, CHCl3). H NMR and 13C
were washed with water (2 ꢂ 10 mL) and brine. (20 mL) and NMR spectra are identical as reported in lit. for enantiomer;16
dried over anhydrous MgSO4. Solvent was evaporated under 1H NMR (600 MHz, CDCl3) d 7.38–7.27 (m, 24H), 7.25 (s, 1H),
reduced pressure. Crude oil was puried by column chroma- 5.82 (s, 1H), 5.15–5.05 (m, 3H), 4.75 (d, J ¼ 11.4 Hz, 1H), 4.72–
tography (Hex/EtOAc 2 : 1 to 1 : 1) to give title compound as 4.55 (m, 6H), 4.48 (d, J ¼ 11.8 Hz, 1H), 4.40 (d, J ¼ 11.8 Hz, 1H),
20
ꢁ
a white solid (0.13 g, 0.29 mmol, 65%). Mp. 82–83 C; [a]D
¼
4.24 (d, J ¼ 12.1 Hz, 1H), 4.06 (d, J ¼ 3.4 Hz, 1H), 3.91 (d, J ¼
1
ꢀ48.5 (c 0.65, CHCl3); H NMR (600 MHz, CDCl3) d 7.38–7.27 12.1 Hz, 1H), 3.81 (dd, J ¼ 7.4, 4.8 Hz, 1H), 3.77–3.71 (m, 1H);
(m, 15H), 5.81 (d, J ¼ 1.7 Hz, 1H), 4.76 (d, J ¼ 11.9 Hz, 2H), 4.69– 13C NMR (150 MHz, CDCl3) d 156.2, 138.3, 138.2, 137.9, 137.2,
4.65 (m, 4H), 4.22 (s, 3H), 4.11 (dd, J ¼ 7.5, 4.8 Hz, 1H), 3.98 (dd, 136.6, 128.6, 128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9,
J ¼ 7.2, 4.7 Hz, 1H), 3.79 (dd, J ¼ 7.1, 3.6 Hz, 1H), 2.87 (d, J ¼ 127.7, 125.2, 76.3, 75.9, 74.4, 73.8, 72.2, 72.1, 70.6, 66.9, 47.2;
8.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 140.0, 138.4, 138.2, HRMS (ESI): calcd for C43H43NO6Na [M + Na]+ 692.2983, found
137.9, 128.5, 128.4, 128.4, 127.9, 127.9, 127.9, 127.8, 127.7, 692.2982. 4,5,6-Tri-O-benzyl-(+)-b-valienamine-N-benzyl carba-
127.7, 122.4, 78.9, 76.5, 73.5, 73.1, 72.7, 71.7, 70.1, 64.5; HRMS mate (12): 1H NMR and 13C NMR spectra are identical as we
(ESI): calcd for C28H30O5Na [M + Na]+ 469.1985, found 469.1981. previously reported;24 1H NMR (600 MHz, CDCl3) d 7.35–7.26 (m,
12932 | RSC Adv., 2019, 9, 12928–12935
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
25H), 5.65 (s, 1H), 5.13–5.06 (m, 2H), 4.83–4.62 (m, 7H), 4.47 (d,
J ¼ 11.8 Hz, 1H), 4.43 (d, J ¼ 11.8 Hz, 1H), 4.21 (d, J ¼ 8.0 Hz,
2H), 3.88 (d, J ¼ 12.3 Hz, 2H), 3.53 (t, J ¼ 7.7 Hz, 1H); 13C NMR
(150 MHz, CDCl3) d 155.9, 138.4, 138.3, 138.2, 136.6, 136.4,
128.6, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.9,
127.8, 127.8, 126.2, 82.3, 79.7, 77.9, 74.7, 74.3, 74.2, 72.6, 70.4,
66.8, 52.1.
3,4,5-Tri-O-benzyl-1-tert-butyldiphenylsilyl-(ꢀ)-gabosine E (14)
A solution of compound 13 (0.115 g, 0.17 mmol) in anhydrous
methylene chloride (3 mL) was cooled to 0 ꢁC and Dess–Martin
periodinane (0.214 g, 0.50 mmol) was added in one portion and
stirred in 0 ꢁC for 30 min. Aer that time ice bath was removed
and reaction mixture was stirred for 2 h in room temperature.
Reaction was quenched with 0.2 mL of saturated aqueous
solution of NaHCO3 and evaporated to dryness with silica gel
(<0.5 g). Aer column chromatography (Hex/EtOAc 7 : 1 to 6 : 1)
pure product was obtained as a clear syrup (0.108 g, 0.16 mmol,
94%). [a]2D3 ¼ ꢀ187.5 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3)
d 7.62 (ddd, J ¼ 10.4, 8.0, 1.3 Hz, 4H), 7.43–7.27 (m, 21H), 7.04
(dd, J ¼ 4.5, 2.1 Hz, 1H), 4.86 (d, J ¼ 11.4 Hz, 1H), 4.83–4.78 (m,
2H), 4.76–4.69 (m, 2H), 4.65 (d, J ¼ 11.4 Hz, 1H), 4.46–4.37 (m,
3H), 4.35 (d, J ¼ 8.2 Hz, 1H), 3.93 (dd, J ¼ 8.2, 3.3 Hz, 1H), 1.08
(s, 9H); 13C NMR (150 MHz, CDCl3) d 196.4, 138.8, 138.3, 138.2,
138.0, 135.6, 135.5, 133.2, 133.1, 129.9, 129.9, 128.6, 128.5,
128.4, 128.1, 128.0, 127.9, 127.9, 127.9, 80.4, 78.9, 74.1, 73.3,
72.6, 72.2, 60.5, 27.0, 19.4; HRMS (ESI): calcd for C44H46O5SiNa
[M + Na]+ 705.3007, found 705.3007.
3,4,5-Tri-O-benzyl-(ꢀ)-MK7607 and 6-epi-3,4,5-tri-O-benzyl-
(ꢀ)-MK7607 – mixture of diastereoisomers (9)
A solution of compound 5 (0.30 g, 0.61 mmol) in anhydrous
methylene chloride (10 mL) was cooled to ꢀ30 ꢁC and solution
of DIBAL-H (1 M in methylene chloride, 3.7 mL, 3.7 mmol) was
added dropwise. When the addition was complete, the mixture
ꢁ
was stirred at ꢀ10 C for 3 h. Aer that time, methanol (2 mL)
was added to quench the reaction, and mixture was stirred at
ꢀ10 ꢁC for 30 min. Aer water addition (10 mL) and few drops
(<1 mL) of 1 M aqueous HCl, water phase was extracted with
methylene chloride (3 ꢂ 15 mL) and combined organic phases
were washed with water (2 ꢂ 15 mL) and brine (20 mL) and
dried over anhydrous MgSO4. Solvent was evaporated under
reduced pressure. Crude oil was puried by column chroma-
tography (Hex/EtOAc 2 : 1 to 1 : 1) to give title mixture of dia-
stereoisomers as semi-solid residue (0.131 g, 0.29 mmol, 48%).
Products were characterized as pure diastereoisomers (6S)-9
and (6R)-9.
3,4,5-Tri-O-benzyl-(ꢀ)-gabosine E (15)
A solution of compound 14 (0.038 g, 0.056 mmol) in anhydrous
ꢁ
THF (1 mL) was cooled to 0 C and excess of HF$Py (0.05 mL)
complex was added dropwise and ice bath was removed and
stirring was continued for next 12 h in room temperature. Aer
that time reaction was quenched with water (2 mL) and product
was extracted with EtOAc (3 ꢂ 5 mL). Combined organic layers
were washed with water (5 mL), brine (10 mL) and dried over
anhydrous MgSO4. Solvent was evaporated under reduced
pressure. Crude product was puried by column chromatog-
raphy (Hex/EtOAc 4 : 1 to 1 : 1) to afford title compound as
a clear syrup (0.022 g, 0.05 mmol, 89%). [a]2D1 ¼ ꢀ120.5 (c 1.0,
CHCl3); 1H NMR (600 MHz, CDCl3) d 7.39–7.27 (m, 15H), 6.80 (d,
J ¼ 4.2 Hz, 1H), 4.86 (d, J ¼ 11.5 Hz, 1H), 4.78 (dd, J ¼ 12.0,
9.2 Hz, 2H), 4.71–4.65 (m, 3H), 4.45 (t, J ¼ 3.7 Hz, 1H), 4.35 (dt, J
¼ 14.3, 1.2 Hz, 1H), 4.32 (d, J ¼ 7.7 Hz, 1H), 4.23 (d, J ¼ 14.3 Hz,
1H), 3.99 (dd, J ¼ 7.7, 3.3 Hz, 1H); 13C NMR (150 MHz, CDCl3)
d 197.3, 140.9, 138.1, 138.0, 138.0, 137.7, 128.6, 128.5, 128.5,
128.1, 128.0, 128.0, 128.0, 127.9, 80.0, 78.5, 73.9, 73.4, 72.7, 72.5,
60.9; HRMS (ESI): calcd for C28H28O5Na [M + Na]+ 467.1829,
found 467.1829.
(4R,5R,6R/S)-4,5,6-Tri-O-benzyl-2-(((tert-butyldiphenylsilyl)oxy)
methyl)cyclohex-2-en-1-ol (13)
A solution of mixture of compounds 9 (0.120 g, 0.27 mmol) in
anhydrous methylene chloride (3 mL) was cooled to ꢀ20 ꢁC and
TBDPSCl (0.089 g, 0.32 mmol) was added in one portion fol-
lowed by dropwise addition of solution of imidazole (0.045 g,
0.65 mmol in 1 mL anhydrous DMF) and stirring was continued
ꢁ
in ꢀ20 C for 30 min. Ice bath was removed and mixture was
allowed to warm to room temperature. Aer addition of water (5
mL), product was extracted with EtOAc (3 ꢂ 10 mL) and
combined organic layers were washed with water (2 ꢂ 10 mL),
brine (15 mL) and dried over anhydrous MgSO4. Aer solvent
evaporation, oily residue was puried by column chromatog-
raphy (Hex/EtOAc 6 : 1 to 5 : 1) to give pure compound 13
(mixture of diastereoisomers) as a clear syrup (0.118 g,
1
0.17 mmol, 64%). H NMR (600 MHz, CDCl3) d 7.70–7.63 (m,
4.84H), 7.44–7.27 (m, 25.41H), 5.96 (d, J ¼ 4.5 Hz, 0.21H), 5.87
Ethyl (ꢀ)-3,4,5-tri-O-benzylshikimate (18)
(d, J ¼ 2.3 Hz, 1H), 4.82–4.63 (m, 7.26H), 4.35–4.27 (m, 2.42H),
4.20 (d, J ¼ 20.1 Hz, 1.21H), 4.16 (t, J ¼ 3.9 Hz, 0.21H), 4.07 (s, A solution of compound 5 (0.50 g, 1.02 mmol) in anhydrous
1H), 4.04 (dd, J ¼ 9.0, 4.2 Hz, 1H), 4.00 (dd, J ¼ 7.2, 4.7 Hz, 1H), methylene chloride (15 mL) was cooled to ꢀ20 ꢁC and meth-
3.94 (dd, J ¼ 9.0, 3.8 Hz, 0.21H), 3.77 (dd, J ¼ 7.2, 3.7 Hz, 1H), anesulfonyl chloride (0.238 mL, 3.07 mmol) was added in one
2.69 (s, 0.21H), 2.61 (d, J ¼ 5.6 Hz, 1H), 1.08–1.05 (m, 10.89H); portion followed by dropwise addition of triethylamine (0.427
13C NMR (150 MHz, CDCl3) d 140.4, 140.0, 138.9, 138.9, 138.7, mL, 3.07 mmol). Aer 30 min cryo-bath was removed and
138.6, 138.4, 138.3, 135.7, 135.7, 134.9, 133.5, 133.5, 133.4, reaction mixture was allowed to warm to room temperature.
129.8, 128.6, 128.5, 128.5, 128.0, 127.9, 127.9, 127.8, 127.8, Methylene chloride was evaporated under reduced pressure
127.7, 127.7, 127.6, 121.8, 120.8, 79.4, 77.0, 76.3, 73.6, 73.2, 73.1, (below 30 ꢁC) and crude yellow oil was puried by ash column
72.6, 72.1, 72.0, 71.5, 69.6, 66.6, 64.8, 64.4, 27.0, 19.4; HRMS chromatography (Hex/EtOAc 5 : 1 to 4 : 1) to afford mixture of
(ESI): calcd for C44H48O5SiNa [M + Na]+ 707.3163, found methanesulfonyl derivatives (16) as a clear syrup (0.545 g,
707.3165.
0.96 mmol, 95%). HRMS (ESI): calcd for C31H34O8SNa [M + Na]+
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 12928–12935 | 12933

View Article Online
RSC Advances
Paper
589.1867, found 589.1867. Compound 16 was dissolved in continued in ꢀ78 ꢁC for 1 h. Aer solvent evaporation under
anhydrous acetone (10 mL) and cooled to 0 ꢁC followed by reduced pressure (with 2 M NaOH trap) water was added (10
addition of NaI (1.44 g, 9.61 mmol). Reaction was stirred for mL), organic impurities were removed by washing water phase
ꢁ
ꢁ
15 min in 0 C and then heated to 40 C for 2 h (covered with with methylene chloride (3 ꢂ 5 mL). Water layer was acidied
aluminum foil to avoid light access). Solvent was evaporated with 1 M HCl (to pH ¼ 5) and solvent was evaporated under
under reduced pressure (below 35 ꢁC). Crude semi-solid residue reduced pressure. Title compound was crystallized from EtOAc
was puried by ash column chromatography (Hex/EtOAc 7 : 1 as white solid (0.060 g, 0.186 mmol, 67%). Mp 113–114 ꢁC;
to 6 : 1) to afford iodine intermediate (17) as a clear, colorless [a]2D1 ¼ ꢀ138.0 (c 0.5, MeOH); 1H NMR (600 MHz, CD3OD) d 6.80
syrup (0.560 g, 0.94 mmol, 97%). Crude mixture (17) was dis- (dq, J ¼ 1.8, 1.4 Hz, 1H), 4.40–4.37 (m, 1H), 4.01 (dt, J ¼ 7.1,
solved in ethanol (10 mL) and cooled to 0 ꢁC, followed by 5.2 Hz, 1H), 3.76 (s, 3H), 3.33 (dd, J ¼ 4.0, 2.4 Hz, 1H), 2.71 (ddt,
addition of sodium borohydride (0.071 g, 1.88 mmol) and J ¼ 18.2, 4.7, 1.9 Hz, 1H), 2.22 (ddt, J ¼ 18.2, 5.4, 1.7 Hz, 1H); 13
C
ꢁ
vigorously stirred in 0 C for 2 h (conversion of substrate was NMR (150 MHz, CD3OD) d 169.5, 139.9, 131.0, 73.4, 69.2, 68.1,
monitored by TLC). Reaction was quenched with diluted acetic 53.2, 32.3; 1H NMR and 13C NMR are identical as previously
acid (acetic acid/water v/v 1 : 10, 5 mL). Product was extracted reported.26
with EtOAc (3 ꢂ 5 mL). Combined organic layers were washed
with water (2 ꢂ 5 mL), brine (10 mL) and dried over anhydrous
Conflicts of interest
MgSO4. Aer solvent evaporation title compound was puried
by column chromatography (Hex/EtOAc 7 : 1 to 6 : 1) to afford
product as clear syrup (0.415 g, 0.88 mmol, 93% including 15%
There are no conicts to declare.
inseparable impurities), total yield aer 3 step ¼ 73% of pure
18. Ethyl (ꢀ)-3,4,5-tri-O-benzylshikimate (18): 1H NMR (600 Acknowledgements
MHz, CDCl3) d 7.39–7.22 (m, 15H), 6.92 (d, J ¼ 1.0 Hz, 1H), 4.75–
Financial support from the Polish National Science Centre
(Grant No. 2015/17/D/ST5/01334) is gratefully acknowledged.
The research was carried out with the equipment purchased
4.63 (m, 4H), 4.59 (d, J ¼ 11.9 Hz, 1H), 4.51 (d, J ¼ 11.9 Hz, 1H),
4.35 (s, 1H), 4.19 (qd, J ¼ 7.1, 1.4 Hz, 2H), 3.96 (dd, J ¼ 10.3,
4.3 Hz, 1H), 3.83 (dd, J ¼ 6.1, 3.7 Hz, 1H), 2.72 (ddt, J ¼ 18.5, 4.5,
thanks to the nancial support of the European Regional
2.2 Hz, 1H), 2.47–2.41 (m, 1H), 1.28 (t, J ¼ 7.1 Hz, 3H); 13C NMR
Development Fund in the framework of the Polish Innovation
(150 MHz, CDCl3) d 166.6, 138.6, 138.4, 136.1, 129.6, 128.5,
Economy Operational Program (contract no. POIG.02.01.00-12-
128.4, 127.9, 127.9, 127.8, 127.7, 127.7, 75.2, 73.9, 73.3, 73.1,
023/08).
71.8, 71.7, 60.7, 27.9, 14.3; HRMS (ESI): calcd for C30H32O5Na [M
+ Na]+ 495.2142, found 495.2142.
Notes and references
(ꢀ)-3,4,5-Tri-O-benzylshikimic acid (19)
1 G. E. Mccasland, S. Furuta and L. J. Durham, J. Org. Chem.,
18 (0.40 g, 0.85 mmol) was dissolved in THF (5 mL) followed by
1968, 33, 2835–2841.
addition of water (5 mL) and 1 M NaOH (1 mL) and reaction was
2 G. E. Mccasland, S. Furuta and L. J. Durham, J. Org. Chem.,
stirred for 48 h in room temperature. Aer that time reaction
1968, 33, 2841–2844.
mixture was treated with 1 M HCl (to pH ¼ 2) and product was
´
´
3 O. Arjona, A. M. Gomez, J. C. Lopez and J. Plumet, Chem.
extracted with Et2O (4 ꢂ 5 mL). Combined organic layers were
washed with water (10 mL), brine (10 mL) and dried over
anhydrous MgSO4. Solvent was evaporated in atmospheric
pressure. Product was puried by column chromatography
(PhMe/EtOH/EtOAc 5 : 1 : 1) to afford title compound as
Rev., 2007, 107, 1919–2036.
4 S. Roscales and J. Plumet, Int. J. Carbohydr. Chem., 2016,
2016, 1–42.
5 W. Ren, R. Pengelly, M. Farren-Dai, S. Shamsi Kazem Abadi,
V. Oehler, O. Akintola, J. Draper, M. Meanwell, S. Chakladar,
1
a colorless syrup (0.376 g, 0.846, quant., 88% NMR purity). H
´
K. Swiderek, V. Moliner, R. Britton, T. M. Gloster and
NMR (600 MHz, CDCl3) d 7.40–7.20 (m, 15H), 7.05 (s, 1H), 4.76–
4.61 (m, 4H), 4.57 (d, J ¼ 11.9 Hz, 1H), 4.49 (d, J ¼ 11.9 Hz, 1H),
4.35 (s, 1H), 3.95 (dd, J ¼ 9.9, 4.3 Hz, 1H), 3.82 (s, 1H), 2.73–2.67
(m, 1H), 2.48–2.40 (m, 1H); 13C NMR (150 MHz, CDCl3) d 171.4,
138.8, 138.6, 138.3, 138.3, 128.5, 128.4, 127.9, 127.9, 127.8,
127.8, 127.7, 75.0, 73.8, 73.3, 73.1, 71.8, 71.7, 27.6; HRMS (ESI):
calcd for C28H28O5Na [M + Na]+ 467.1829, found 467.1829.
A. J. Bennet, Nat. Commun., 2018, 9, 1–12.
6 S. Shamsi Kazem Abadi, M. Tran, A. K. Yadav,
P. J. P. Adabala, S. Chakladar and A. J. Bennet, J. Am.
Chem. Soc., 2017, 139, 10625–10628.
7 N. Tateda, K. Ajisaka, M. Ishiguro and T. Miyazaki, Bioorg.
Med. Chem., 2018, 1–23.
8 H. Yuasa, O. Hindsgaul and M. M. Palcic, J. Am. Chem. Soc.,
1992, 114, 5891–5892.
9 S. H. Yu and S. K. Chung, Tetrahedron: Asymmetry, 2005, 16,
2729–2747.
(ꢀ)-Methyl shikimate (20)
To a solution of 19 (0.210 g, 0.47 mmol) in anhydrous methylene
chloride (6 mL) cooled to ꢀ78 ꢁC boron trichloride (1 M in 10 T. K. M. Shing, W. L. Ng, J. Y. W. Chan and C. B. S. Lau,
methylene chloride, 9.5 mL, 9.50 mmol) was added dropwise
Angew. Chem., Int. Ed., 2013, 52, 8401–8405.
and stirring was continued for 12 h. Reaction was quenched by 11 M. Li, Y. Li, K. A. Ludwik, Z. M. Sandusky, D. A. Lannigan
addition of anhydrous methanol (2 mL) and intense stirring was
and G. A. O'Doherty, Org. Lett., 2017, 19, 2410–2413.
12934 | RSC Adv., 2019, 9, 12928–12935
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Advances
´
12 X. Yang, P. Yuan, F. Shui, Y. Zhou and X. Chen, Org. Biomol. 20 D. H. Mac, S. Chandrasekhar and R. Gree, Eur. J. Inorg.
Chem., DOI: 10.1039/c9ob00469f. Chem., 2012, 5881–5895.
13 D. C. Babu, C. B. Rao, K. Venkatesham, J. J. P. Selvam and 21 G. M. Whited, G. International, K. Way and S. S. Francisco,
Y. Venkateswarlu, Carbohydr. Res., 2014, 388, 130–137. Tetrahedron: Asymmetry, 1996, 7, 691–698.
14 J. P. Rao and B. V. Rao, Tetrahedron: Asymmetry, 2010, 21, 22 H. A. J. Carless and Y. Dove, Tetrahedron: Asymmetry, 1996, 7,
930–935. 649–652.
15 C. Muniraju, J. P. Rao and B. V. Rao, Tetrahedron: Asymmetry, 23 I. S. Kim, O. P. Zee and Y. H. Jung, Org. Lett., 2006, 8, 4101–
2012, 23, 86–93. 4104.
16 Q. R. Li, S. I. Kim, S. J. Park, H. R. Yang, A. R. Baek, I. S. Kim 24 P. Banachowicz, J. Mlynarski and S. Buda, J. Org. Chem.,
and Y. H. Jung, Tetrahedron, 2013, 26, 10384–10390. 2018, 83, 11269–11277.
17 P. Yuan, X. Liu, X. Yang, Y. Zhang and X. Chen, J. Org. Chem., 25 N. R. Candeias, B. Assoah and S. P. Simeonov, Chem. Rev.,
2017, 82, 3692–3701.
2018, 118, 10458–10550.
´
´
18 P. Wen and D. Crich, Tetrahedron, 2018, 74, 5183–5191.
19 J. Sardinha, A. P. Rauter and M. Sollogoub, Tetrahedron Lett.,
2008, 49, 5548–5550.
26 L. Sanchez-Abella, S. Fernandez, N. Armesto, M. Ferrero and
V. Gotor, J. Org. Chem., 2006, 71, 5396–5399.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 12928–12935 | 12935