A divergent and stereoselective approach for the syntheses of (–)-zeylenol, (+)-6-O-benzoylzeylenol, (+)-uvarigranol E and (+)-uvarigranol F

Article abstract of DOI:10.1016/j.carres.2021.108432

A common, divergent, efficient, and stereoselective approach to the total syntheses of four carbasugars, namely, (–)-zeylenol, (+)-6-O-benzoylzeylenol, (+)-uvarigranol E and (+)-uvarigranol F from D-mannose derived key intermediate 14 is described. This intermediate was synthesized using mixed aldol condensation, Grignard reaction and ring closing metathesis as key steps by our previous method in nine steps from D-mannose. From this intermediate, we achieved the syntheses of (+)-6-O-benzoylzeylenol, (+)-uvarigranol F in three steps, (+)-uvarigranol E in four steps and improved synthesis of (–)-zeylenol.

Full text of DOI:10.1016/j.carres.2021.108432

Carbohydrate Research 509 (2021) 108432
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Carbohydrate Research
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A divergent and stereoselective approach for the syntheses of (–)-zeylenol,
(+)-6-O-benzoylzeylenol, (+)-uvarigranol E and (+)-uvarigranol F
Allam Vinaykumar, Batchu Venkateswara Rao*
Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Zeylenol
A common, divergent, efficient, and stereoselective approach to the total syntheses of four carbasugars, namely,
(–)-zeylenol, (+)-6-O-benzoylzeylenol, (+)-uvarigranol E and (+)-uvarigranol F from D-mannose derived key
intermediate 14 is described. This intermediate was synthesized using mixed aldol condensation, Grignard re-
action and ring closing metathesis as key steps by our previous method in nine steps from D-mannose. From this
Vinylation
RCM
Carbasugars
Benzoylation
intermediate, we achieved the syntheses of (+)-6-O-benzoylzeylenol, (+)-uvarigranol
(+)-uvarigranol E in four steps and improved synthesis of (–)-zeylenol.
F in three steps,
1. Introduction
(–)-zeylenol 1 show significant cytotoxicity against P388 cells [2d].
(+)-Uvarigranol F 8 also exhibited inhibition activities against both
PSN-1 and MDA-MB231 cell lines [5c]. (–)-Zeylenol 1 and (–)-zeylenone
Polyoxygenated cyclohexenes are common metabolites of the
Annonaceae family. These molecules have common structural features
where the polyoxygenated cyclohexene unit has benzoyloxymethyl or
hydroxymethyl or acetoxymethyl functionalities on a tertiary carbon.
The first example of this class is (–)-zeylenol 1. Numerous natural
products which are having zeylenol skeleton have been isolated from
different sources and are showing interesting biological activity [1–3].
3 (initially called as (–)-tonkinenin A) have shown
α-glucosidase
inhibitory activities better than acarbose [2e] (presently in the market
for the treatment of diabetes mellitus) and also showed plant root
growth inhibitory activity [1e]. In addition (–)-zeylenone 3 also shows
strong cytotoxic activity against various tumor cell lines and low toxicity
against normal cell lines [1a–d,2f,3e,8]. (–)-Zeylenone 3 is considered as
a potential candidate in cancer treatment.
(+)-Pipoxide 2, (–)-tonkinenin
A
3, (–)-6-O-benzoylzeylenol 4,
6, (+)-uvarigranol 7,
(–)-uvarigranol 5, (–)-uvarigranol
C
D
E
Interesting biological activity of zeylenol and its derivatives, where
some are in the developmental stage as drugs prompted us to develop a
common approach for this class of compounds. In this connection we are
presenting a common strategy for the synthesis of three natural carba-
sugars and enantiomer of natural product 4, viz. (–)-zeylenol 1,
(+)-uvarigranol E 7 and (+)-uvarigranol F 8, and (+)-6-O-benzoylzey-
lenol (ent-4). Synthesis of analogs of (–)-zeylenol and evaluation of their
biological activity is certainly an interesting area of research for finding
new leads.
(+)-uvarigranol F 8, (–)-uvarigranol G 9, and ferrudiol 10 (Fig. 1) are
some examples belong to this class which are isolated from natural
sources, whose absolute configuration has been established [1–3].
(–)-Zeylenol 1 was isolated by Cole and Bates [4], in 1981 from the plant
uvaria zeylanica. Recently, (–)-zeylenol was also isolated from uvaria
[2d–f,3a–c,5a,b], kaempferia [5c] and other species [1b]. Zeylenol
related compounds (–)-6-O-benzoylzeylenol 4 was isolated from the
same Kaempferia species [3d], (+)-uvarigranol E 7 and (+)-uvarigranol
F 8 isolated from the uvaria [5d] species. (–)-Zeylenol 1 shows anti-
cancer, antifeedant activity [5e] and anti-inflammatory activity (equally
active as phenylbutazone) [1b,5a]. For instance (–)-zeylenol 1 exhibits
moderate inhibition against PSN-1 [5c], MDA-MB231 (breast) [5a,c]
and HepG2 (liver) [5a] cell lines. (–)-Uvagranol C 5 (6-O- ethylzeylenol)
has shown significant activity as Nav1.7 inhibitor [6], which can be used
in the treatment of different pains and the molecule is in preclinical trials
at Protheragen [7] company, USA. (+)-Uvarigranol E 7 and also
Ogasawara et al. has reported both formal [9a] and total [9b,c]
enantiocontrolled synthesis of (–)-zeylenol 1 which has been utilized for
the synthesis of (+)-pipoxide 2, (–)-tonkinenin A 3, and (–)-uvarigranol
G 9 from meso ene diol. Palframan [10a] et al. synthesized (+)-zeylenol,
as well as its congeners (–)-6-O-benzoylzeylenol 4 and (–)-uvaribonol A
(ent-8) from ipso and ortho diols. Sharma [10b] et al. also synthesized
(–)-6-O-benzoylzeylenol 4 from diacetone glucose. There were no re-
ports on the synthesis of unnatural enantiomer (+)-6-O-benzoylzeylenol
* Corresponding author.,
E-mail addresses: venky@csiriict.in, drb.venky@gmail.com (B. Venkateswara Rao).
https://doi.org/10.1016/j.carres.2021.108432
Received 28 July 2021; Received in revised form 21 August 2021; Accepted 23 August 2021
Available online 2 September 2021
0008-6215/© 2021 Elsevier Ltd. All rights reserved.

A. Vinaykumar and B. Venkateswara Rao
Carbohydrate Research 509 (2021) 108432
(ent-4) and natural (+)-uvarigranol F 6. And also no report to date on the
synthesis of (+)- or (–)-uvarigranol E 7. We [11] synthesized (–)-zeyle-
nol 1 from D-mannose. (–)-Zeylenol 1 is a basic skeleton for the many
natural products of this class. Therefore we planned to synthesize target
molecules from the intermediate in our earlier (–)-zeylenol synthesis.
The reported synthesis of zeylenol and related structures so far suffer
from some drawbacks such as more number of steps, separation of iso-
mers, low yields and mainly lack of generality. Therefore, development
of a common approach which can give many of these molecules in good
yields and high optical purity will be helpful in generating library in a
short possible time.
(+)-6-O-benzoylzeylenol ent-4 in 80% yield (Scheme 3).
Both allylic hydroxyl groups in 14 were converted to benzoyl ester
17 with triethylamine, benzoyl chloride and DMAP (cat.). Cleavage of
TBDPS ether in 17 with TBAF in THF for a period of 4h at room tem-
perature gave regioisomers 18 and 19 in ratio of 1: 2 in 30% and 60%
yields respectively (Scheme 4). Compound 19 was a precursor in our
earlier synthesis of (–)-zeylenol 1, whose spectral data [11] matched
with the previously synthesized compound. This synthesis of compound
19 is shorter when compared to our previous one and can be obtained
from compound 14 in just three steps. Cleavage [13] of TBDPS ether in
17 was carried out using AcOH, TBAF in THF for a period of 1 h at 0 ◦C to
give compound 18 as a sole product in 80% yield. The primary hydroxyl
group in 18 was converted to acyl ester 20 with triethylamine, acetic
anhydride and DMAP (cat.). Finally, the deprotection of acetonide group
in ester 20 was carried out under acidic conditions with TFA/H2O to
give (+)-uvarigranol E 7 (Scheme 4).
In our approach, we used Grignard reaction, ring closing metathesis
[12], benzoylation and acylation reactions as key steps for the improved
synthesis of (–)-zeylenol 1 when compared to our previous synthesis and
other related natural products such as ent-4, 7 and 8 in good overall
yields.
To synthesize (+)-uvarigranol F 8, only the deprotection of acetonide
groups and TBDPS ether in 17 was needed. This can be achieved in a
single step under strongly acidic conditions but migration of benzoyl
groups from one hydroxyl position to another hydroxyl position was
previously observed with similar structures [3d,10a,14]. To minimize
the formation of undesired reaction products, It was thought to depro-
tect the acetonide group first then the TBDPS group in compound 17. For
this purpose, compound 17 was treated with TFA/H2O for a period of 1h
at 0 ◦C to give the diol 21 in 82% yield. Finally, the diol 21 was treated
with TBAF in presence of AcOH to remove the silyl group to give
(+)-uvarigranol F 8 as a sole product (Scheme 5). Deprotection of silyl
and other protecting groups, in cyclic poly hydroxyl acetates or benzo-
ates is tricky, under normal conditions, which results in migration of
acyl (benzoyl) groups, probably because of their close proximity. We
have really studied and optimized reaction conditions to prevent
migration, at the final stages of our synthesis.
2. Results and discussion
Based on the retrosynthetic analysis (Scheme 1) we have chosen D-
mannose as a starting material which is a cheap and commercially
available. D-Mannose was converted to lactol 11 using our previous
method [11]. To make the required diene compound for RCM in a better
way, we tried vinyl Grignard addition on lactol 11 at different condi-
tions. Interestingly, reversal in diastereoselectivity was observed at
different temperatures. Vinyl Grignard addition at room temperature for
6 h yielded the diol as diastereomers 12 and 13 in 1: 2.5 ratio, but at
ꢀ 78 ◦C it gave 3:1 ratio of 12 and 13 which were separated by column
chromatography (See Table 1) (Scheme 2).
Probably at higher temperatures less chelation might be occurring
and the nucleophilic addition is taking place via the Felkin-Anh model
giving rise to 13 as a major product (Fig. 2).
Ring closing metathesis [12] reaction was carried out on 12 using
Grubbs II generation catalyst (10 mol%) to give key intermediate 14
[11]. Synthesis of (+)-6-O-benzoylzeylenol ent-4, (+)-uvarigranol E 7
and (+)-uvarigranol F 8 can be obtained from 14 by benzoylation,
deprotection of the acetonide and silyl ether groups. For this, different
reactions were carried out on 14 to obtain ent-4, 7 and 8. All these
compounds differ only with number and position of the benzoyl groups,
whereas 7 has acetyl group also.
3. Conclusions
We have successfully developed a common strategy for the synthesis
of (–)-zeylenol 1 and their analogs ent-4, 7, and 8 using mixed aldol
condensation, Grignard addition, ring-closing metathesis, and benzoy-
lation reactions. This is the first report on synthesis of unnatural ent-4,
natural 7 and 8 isomers. Compound 1 is also a common intermediate for
making 2, 3 and 9. Therefore our approach is general in nature for the
synthesis of zeylenol and its related natural products and their analogs in
good yields and with high optical purity.
Cleavage of TBDPS ether in 14 with TBAF resulted in the formation
of triol 15 [11]. The triol compound 15 converted to tri benzoyl ester 16
[11] with triethylamine, benzoyl chloride and DMAP (cat.). Depro-
tection of acetonide under acidic conditions gave the target molecule
Fig. 1. Example of some naturally occurring compounds that belong to the zeylenol family.
2

A. Vinaykumar and B. Venkateswara Rao
Carbohydrate Research 509 (2021) 108432
Scheme 1. Retrosynthetic analysis of (–)-zeylenol 1, (+)-6-O-benzoylzeylenol ent-4, (+)-uvarigranol E 7 and (+)-uvarigranol F 8.
Perkin–Elmer RX-1and JASCO FT/IR-5300 FTIR system. NMR spectra
were recorded at 300, 400, 500 MHz (H) and 75, 100, 125, 176 MHz (C),
respectively. Chemical shifts (δ) are reported in ppm, using the residual
solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 77.16 ppm) as internal
standard, and coupling constants (J) are given in Hz. Optical rotations
were measured on JASCO P-2000 polarimeter at 20 ◦C using 50 mm cell
of 1 mL capacity. Accurate mass measurements were performed on a Q
STAR mass spectrometer (Applied Biosystems, USA).
Table 1
Vinyl Grignard addition on compounds 11.
Entry
Vinyl Grignard
(equivalents)
Temperature
Time
(h)
Yield (%)
(◦C)
1
2
4
rt
6
80% (dr: 1:
2.5)
4
ꢀ 78 ◦C-rt
12
75% (dr: 3: 1)
4. Experimental section
4.1. Procedures for the Grignard reaction
General Information: Moisture- and oxygen-sensitive reactions
were carried out under nitrogen. All solvents and reagents were purified
by standard techniques. All other reagents were obtained from com-
mercial sources and used without further purification. TLC was per-
formed on Merck Kiesel gel 60, F254 plates (layer thickness: 0.25 mm).
Column chromatography was performed on silica gel (Acme, 60–120
mesh) by using ethyl acetate, hexane, chloroform, and MeOH as eluents.
Organic solutions were dried over anhydrous Na2SO4 and concentrated
below 40 ◦C under reduced pressure. IR spectra were recorded on a
Procedure A: To the solution of lactol 11 (0.5 g, 2.17 mmol) in THF
(10 mL), 1.0 M THF solution of vinyl magnesium bromide (4.4 mL) was
added over 30 min at room temperature under nitrogen. After stirring
2.5 h at room temperature, the mixture was poured into saturated NH4Cl
(20 mL) and extracted with ethyl acetate (50 mL × 3). The collected
organic layers were combined, washed with water, brine, then dried
over Na2SO4, concentrated under reduced pressure and purified by
column chromatography (hexane: ethyl acetate = 12:1) to afford the
corresponding alcohols 12 (0.12 g, 23%) and 13 (0.3 g, 57%) as a yellow
Scheme 2. Synthesis of key intermediate 14.
3

A. Vinaykumar and B. Venkateswara Rao
Carbohydrate Research 509 (2021) 108432
afford the corresponding alcohols 12 (0.3 g, 56%) and 13 (0.1 g, 19%) as
a yellow oil in the ratio of 3: 1.
(S)-1-((4R,5S)-4-(((tert-Butyldiphenylsilyl)oxy)methyl)-5-((R)-
1-hydroxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol
28
(12): [11] [
α]
: +78.2 (c 1.5, CHCl3); IR (neat) νmax : 3391, 2932,
D
1716, 1427, 1216, 1108, 700 cmꢀ 1
;
1H NMR (500 MHz, CDCl3) : δ
7.73–7.60 (m, 4H), 7.46–7.36 (m, 6H), 6.06–5.95 (m, 1H), 5.89–5.78
(m, 1H), 5.38 (dt, 1H J = 17, 1.2 Hz), 5.28 (dt, 1H J = 17, 1.2 Hz), 5.23
(dt, 1H J = 10.5, 1.0 Hz), 5.16 (dd, 1H, J = 10.3, 1.0 Hz), 4.71–4.64 (m,
1H), 4.47 (d, 1H, J = 7.6 Hz), 4.27 (d, 1H, J = 2.1 Hz), 3.67 (d, 1H, J =
10.3 Hz), 3.51 (d, 3H, J = 10.3 Hz), 1.55 (s, 3H), 1.30 (s, 3H), 1.07 (s,
9H); 13C NMR (125 MHz, CDCl3) : δ 138.2, 135.6, 135.5, 132.5, 132.1,
129.9, 129.8, 127.8, 127.7, 118.3, 116.6, 108.5, 84.4, 83.8, 73.0, 70.0,
67.5, 29.6, 26.8, 26.1, 19.1; ESI-MS (m/z) : 505 (M+Na)+; HRMS calcd
for C28H38O5NaSi 505.2380 (M+Na)+, found 505.2389.
(1R,1′R)-1,1’-((4R,5S)-4-(((tert-Butyldiphenylsilyl)oxy)
methyl)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(prop-2-en-1-ol)
28
(13): [11] [
α]
D
: +38.2 (c 1.2, CHCl3); IR (neat) νmax : 3362, 2932,
1717, 1427, 1216, 1109, 701 cmꢀ 1
;
1H NMR (400 MHz, CDCl3) : δ
7.73–7.69 (m, 4H), 7.49–7.39 (m, 6H), 6.17–6.01 (m, 2H), 5.49–5.38
(m, 2H), 5.28–5.20 (m, 2H), 4.65 (d, 1H, J = 4.6 Hz), 4.56 (s, 1H), 4.30
(m, 1H, J = 2.1 Hz), 3.97 (d, 1H, J = 11.2 Hz), 3.76 (dd, 1H, J = 11.2,
2.5 Hz), 1.52 (s, 3H), 1.38 (s, 3H), 1.09 (s, 9H); 13C NMR (125 MHz,
CDCl3) : δ 138.1, 135.9, 135.5, 135.4, 134.7, 132.3, 132.2, 129.8, 129.7,
129.4, 127.6, 127.5, 115.8, 115.8, 107.6, 83.6, 80.4, 71.9, 69.1, 63.7,
28.1, 26.7, 26.3, 19.0; ESI-MS (m/z) : 505 (M+Na)+; HRMS calcd for
Fig. 2. Felkin-Anh model where nucleophile is vinyl Grignard.
oil in the ratio of 1: 2.5. Procedure B: To the solution of lactol 11 (0.5 g,
2.17 mmol) in THF (10 mL), 1.0 M THF solution of vinyl magnesium
bromide (4.4 mL) was added over 30 min at ꢀ 78 ◦C under nitrogen.
After stirring 12 h at room temperature, the mixture was poured into
saturated NH4Cl (20 mL) and extracted with ethyl acetate (50 mL × 3).
The collected organic layers were combined, washed with water, brine,
then dried over Na2SO4, concentrated under reduced pressure and pu-
rified by column chromatography (hexane: ethyl acetate = 12:1) to
C
28H38O5NaSi 505.2383 (M+Na)+, found 505.2380.
(3aR,4S,7R,7aS)-3a-(((tert-Butyldiphenylsilyl)oxy)methyl)-2,2-
dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-4,7-diol
(14): [11]
To the solution of diene 12 (1.0 g, 2.0 mmol) in toluene (80 mL),
Grubbs’ second-generation catalyst (0.176 g, 0.20 mmol) was added at
Scheme 3. Synthesis of (+)-6-O-benzoylzeylenol ent-4.
Scheme 4. First total synthesis of (+)-uvarigranol E 7.
4

A. Vinaykumar and B. Venkateswara Rao
Carbohydrate Research 509 (2021) 108432
Scheme 5. Synthesis of (+)-uvarigranol F 8.
room temperature. Refluxed the reaction mixture for 12 h. Toulene was
removed under vacuum, applied for column chromatography (hexane:
ethyl acetate = 1:4) to provide cyclohexenol 14 as an oily compound
temperature. The solution was stirred at room temperature for 2 h and
poured into saturated aqueous NH4Cl (10 mL). The aqueous phase was
extracted with CH2Cl2 (50 mL), and the combined organic extracts were
washed with brine (10 mL), dried (MgSO4), and filtered. The concen-
(0.75 g, 80%). [
α
]
28 : +45.6 (c 0.8, CHCl3); IR (neat) νmax : 3384, 2931,
2857, 1427, 1108Dcmꢀ 1
;
1H NMR (500 MHz, CDCl3) : δ 7.76–7.64 (m,
tration of the filtrate followed by flash chromatography (hexane: ethyl
23
4H), 7.48–7.37 (m, 6H), 6.14 (dd, 2H, J = 3.0, 1.6 Hz), 4.43 (s, 1H), 4.25
(s, 1H), 4.08 (d, 1H, J = 3.0 Hz), 4.01 (d, 1H, J = 11.2 Hz), 3.87 (d, 1H, J
= 11.2 Hz), 3.36 (bs 1H), 2.85 (bs 1H), 1.36 (s, 3H), 1.23 (s, 3H), 1.07 (s,
9H); 13C NMR (125 MHz, CDCl3) : δ 135.8, 135.5, 132.4, 132.2, 132.1,
131.8, 129.9, 127.8, 127.7, 109.6, 84.7, 81.3, 69.8, 68.0, 67.3, 28.0,
27.0, 26.8, 19.1; ESI-MS (m/z) : 477 (M+Na)+; HRMS calcd for
C26H38O5NSi 472.2513 (M+NH4)+, found 472.2515.
acetate = 10:1) provided 17 (1.19 g, 82%) as syrup. [
α
]
= +33.9 (c
0.41, CHCl3); IR (neat) νmax : 2930,1720, 1247, 1092,D703 cmꢀ 1
;
1H
NMR (500 MHz, CDCl3) : δ 8.07 (dd, J = 8.3, 1.2 Hz, 2H), 7.80 (dd, J =
8.3, 1.2 Hz, 2H), 7.69 (ddd, J = 8.0, 2.9, 1.3 Hz, 4H), 7.60–7.55 (m, 1H),
7.55–7.50 (m, 1H), 7.42–7.38 (m, 4H), 7.34–7.30 (m, 6H), 6.01–5.96
(m, 1H), 5.96–5.92 (m, 1H), 5.82–5.78 (m, 1H), 5.76 (dd, J = 4.1, 2.0
Hz, 1H), 4.86 (d, J = 1.4 Hz, 1H), 4.14 (d, J = 11.3 Hz, 1H), 3.89 (d, J =
11.3 Hz, 1H), 1.54 (s, 3H), 1.48 (s, 3H), 1.02 (s, 9H); 13C NMR (125
MHz, CDCl3) : δ 165.66, 165.64, 135.67, 133.21, 133.04, 130.04,
129.84, 129.72, 129.70, 128.36, 128.29, 127.70, 127.67, 126.89,
109.33, 82.84, 77.24, 73.02, 70.76, 63.23, 28.02, 27.12, 26.66, 19.17;
ESI-MS (m/z) : 685 [M+Na]+; HRMS calcd for C40H42O7NaSi [M+Na]+
685.2597, found 685.2581.
(3aR,4S,7R,7aS)-3a-((benzoyloxy)methyl)-2,2-dimethyl-
3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-4,7-diyl
dibenzoate
(16): To a solution of the triol 15 (0.1 g, 0.46 mmol), TEA (0.4 mL, 3
mmol), and a catalytic amount of DMAP in dry CH2Cl2 (10 mL) was
added benzoyl chloride (0.32 mL, 2.7 mmol) at room temperature. The
solution was stirred at room temperature for 2 h and poured into satu-
rated aqueous NH4Cl (10 mL). The aqueous phase was extracted with
CH2Cl2 (30 mL), and the combined organic extracts were washed with
brine (5 mL), dried (MgSO4), and filtered. Concentration of the filtrate
4.2. Procedures for the compounds 18 and 19
followed by flash chromatography (hexane: ethyl acetate = 10:1) pro-
Procedure A: To an ice cooled stirred solution of silyl compound 17
(0.5 g, 0.75 mmol) in THF (10 mL) was added TBAF (1.1 mL, 1 M so-
lution in THF, 1.13 mmol). The reaction mixture was allowed to warm to
room temperature and then stirred for 4 h. It was quenched with satu-
rated NaHCO3 solution (20 mL) and extracted with ethyl acetate (100
mL). The combined organic fractions were collected and washed with
water and brine, then dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column chroma-
tography (hexane: ethyl acetate = 10:1) to afford compound 18 (96 mg,
30%) & 19 [11] (192 mg, 60%) in overall 90% yield as a viscous liquid.
Procedure B: To a solution of compound 17 (100 mg, 0.15 mmol) and
23
vided 16 (0.183 g, 75%) as a syrup. [
α]
D
: -5.5 (c 0.97, CHCl3); IR
(neat) νmax : 2929, 1719, 1248, 1093, 707 cmꢀ 1
;
1H NMR (400 MHz,
CDCl3) : δ 8.13–7.95 (m, 6H), 7.61–7.31 (m, 9H), 6.08–6.00 (m, 2H),
5.95–5.92 (m, 1H), 5.84–5.82 (m, 1H), 4.85 (d, J = 12.1 Hz, 1H), 4.77
(d, J = 12.1 Hz, 1H), 4.65 (d, J = 2.0 Hz, 1H), 1.59 (s, 3H), 1.47 (s, 3H);
13C NMR (125 MHz, CDCl3) : δ 166.05, 165.67, 165.44, 133.36, 133.26,
133.18, 129.81, 129.75, 129.65, 129.61, 129.54, 129.49, 129.40,
128.48, 128.42, 128.34, 126.89, 109.98, 80.80, 78.32, 72.60, 69.75,
63.43, 27.86, 26.86; ESI-MS (m/z) : 551 (M+Na)+; HRMS calcd for
C
31H28O8Na [M+Na]+ 551.1682 found 551.1677.
(1R,4S,5S,6S)-5-((benzoyloxy)methyl)-5,6-dihydroxycyclohex-
acetic acid (25
μL, 0.45 mmol) in THF (1.4 mL) was added TBAF (1.0 M
2-ene-1,4-diyl dibenzoate (or) (þ)-6-O-benzoylzeylenol (4): [10a]
To the solution of tribenzoate 16 (0.1 g, 0.19 mmol) in TFA (2 mL) and
H2O (1 mL) was stirred at room temperature for 5 h. The reaction
mixture was concentrated under reduced pressure to give syrup which
was purified by column chromatography (hexane: ethyl acetate = 4:1) to
solution in THF, 450
μ
L, 0.45 mmol) at 0 ◦C. The mixture was stirred for
1 h. The reaction mixture was concentrated under reduced pressure to
give syrup which was purified by column chromatography (hexane:
ethyl acetate = 4:1) to give compound 18 in 80% yield (51 mg) as syrup.
(3aR,4S,7R,7aS)-3a-(hydroxymethyl)-2,2-dimethyl-3a,4,7,7a-
give (+)-6-O-benzoylzeylenol 4 in 80% yield (0.073 g) as a white solid.
28
tetrahydrobenzo[d][1,3]dioxole-4,7-diyl dibenzoate (18): [
α]
D
:
;
23
MP : 136-138 ◦C. {lit [10b]. MP 137-139}; [
α
]
: +58.3 (c 0.18,
-8.7 (c 1.35, CHCl3); IR (neat) νmax : 2927, 1720, 1259, 1097, 708 cmꢀ 1
CHCl3). {enantiomer lit [10a]. ꢀ 56 c 0.5, CHCl3)}; DIR (neat) νmax : 3464,
1H NMR (500 MHz, CDCl3) : δ 8.11–8.02 (m, 4H), 7.63–7.56 (m, 2H),
7.49–7.41 (m, 4H), 6.03–5.99 (m, 1H), 5.98–5.97 (m, 1H), 5.86 (dd, J =
4.1, 2.0 Hz, 1H), 5.77–5.75 (m, 1H), 4.64 (dd, J = 2.2, 0.7 Hz, 1H), 4.18
(d, J = 12.3 Hz, 1H), 3.82 (d, J = 12.3 Hz, 1H), 1.57 (s, 3H), 1.47 (s, 3H);
13C NMR (125 MHz, CDCl3) : δ 165.66, 165.57, 133.62, 133.33, 130.13,
129.83, 129.75, 129.62, 129.57, 129.44, 128.43, 127.32, 109.67, 82.74,
77.34, 72.25, 70.41, 60.86, 27.91, 26.96; ESI-MS (m/z) : 447 [M+Na]+;
HRMS calcd for C24H24O7Na [M+Na]+ 447.1420 found 447.1411.
((3aR,4S,7R,7aS)-7-(benzoyloxy)-4-hydroxy-2,2-dimethyl-7,7a-
2925, 1718, 1264, 1108, 709 cmꢀ 1
;
1H NMR (300 MHz, CDCl3) : δ
8.13–8.00 (m, 4H), 7.86 (d, J = 7.1 Hz, 2H), 7.63–7.30 (m, 9H),
6.14–5.99 (m, 2H), 5.84–5.76 (m, 2H), 4.92 (d, J = 12.2 Hz, 1H), 4.63
(d, J = 12.2 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3) : δ 167.19, 167.03, 165.78, 133.62, 133.50, 133.26, 129.86,
129.78, 129.68, 129.36, 129.33, 129.1, 128.54, 128.47, 128.44, 128.33,
126.69, 74.96, 73.40, 71.69, 71.33, 66.79; ESI-MS (m/z): 385 (M+H)+,
511 [M+Na]+; HRMS calcd for C28H24O8Na [M+Na]+ 511.1369 found
511.1351.
dihydrobenzo[d][1,3]dioxol-3a(4H)-yl)methyl benzoate (19):
(3aR,4S,7R,7aS)-3a-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-
dimethyl-3a,4,7,7a-tetrahydrobenzo[d][1,3]dioxole-4,7-diyl
dibenzoate (17): To a solution of the alcohol 14 (1 g, 2.2 mmol), TEA
(1.4 mL, 9.6 mmol), and a catalytic amount of DMAP in dry CH2Cl2 (10
mL) was added benzoyl chloride (0.64 mL, 5.5 mmol) at room
28
[11] [
α]
D
: +122 (c 1.6, CHCl3); IR (neat) νmax : 3392, 2926, 1714,
1249,1023, 709 cmꢀ 1; 1H NMR (300 MHz, CDCl3) : δ 8.07–7.98 (m, 4H),
7.58–7.51 (m, 2H), 7.42–7.35 (m, 4H), 6.03 (dt, 1H, J = 2.2, 10.2 Hz),
5.83 (dt, 1H, J = 2.2, 10.2 Hz), 5.73 (t, 1H, J = 2.2 Hz), 4.78 (d, 1H, J =
12.4 Hz), 4.52–4.48 (m, 2H), 4.45 (dd, J = 4.8, 2.4 Hz, 1H), 1.53 (s, 3H),
5

A. Vinaykumar and B. Venkateswara Rao
Carbohydrate Research 509 (2021) 108432
1.45 (s, 3H); 13C NMR (125 MHz, CDCl3) : δ 166.3, 165.5, 133.3, 133.1,
132.4, 129.7, 129.6, 129.2, 128.4, 125.7, 109.9, 82.6, 79.0, 71.6, 71.0,
63.4, 28.2, 26.8; ESI-MS (m/z) : 447 (M+Na)+; HRMS calcd for
mixture was concentrated under reduced pressure to give syrup which
was purified by column chromatography (hexane: ethyl acetate = 4:1) to
give (+)-uvarigranol F 8 in 80% yield (29 mg) as syrup. [
α
]
23 : +70.7 (c
C
24H24O7 (M+H)+ 424.3325, found 424.3320.
0.21, CHCl3) {lit [5d]. +58.2 (c 0.05, CHCl3)}; IR (neat)Dνmax : 3463,
2924, 1716, 1263, 1107, 710 cmꢀ 1; 1H NMR (400 MHz, CDCl3) : δ 8.11
(d, J = 7.2 Hz, 2H), 8.04 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.3 Hz, 2H),
7.47 (t, J = 7.7 Hz, 4H), 6.05 (m, 2H), 5.83 (d, J = 7.2 Hz, 1H), 5.52 (d, J
= 3.5 Hz, 1H), 4.23 (d, J = 7.4 Hz, 1H), 4.10 (d, J = 12.2 Hz, 1H), 3.67
(d, J = 12.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) : δ 167.77, 166.18,
133.68, 133.61, 130.24, 129.95, 129.84, 129.38, 129.17, 128.60,
128.51, 125.64, 74.79, 73.85, 73.34, 71.66, 64.79; ESI-MS (m/z) : 385
[M+H]+; HRMS calcd for C21H21O7 [M+H]+ 385.1281, found
385.1285.
(3aR,4S,7R,7aS)-3a-(acetoxymethyl)-2,2-dimethyl-3a,4,7,7a-
tetrahydrobenzo[d][1,3]dioxole-4,7-diyl dibenzoate (20): To
compound 18 (80 mg, 0.18 mmol) in DCM (2 mL) were added trie-
thylamine (78 μL, 0.56 mmol), acetic anhydride (26 μL, 0.28 mmol) and
a few crystals of DMAP (cat.) and the reaction mixture was stirred for 6 h
at room temperature. Then methanol (1 mL) was added, and stirring was
continued for 15 min. The solution was diluted with HCl (0.1 N, 0.1 mL),
the two layers were separated, and the organic layer was washed with
saturated aqueous NaHCO3. The aqueous layer was extracted twice with
DCM (10 mL). The total organic extracts were combined and dried using
anhydrous Na2SO4 and concentrated at reduced pressure to give a res-
Declaration of competing interest
idue. The residue was purified on column (hexane: ethyl acetate = 5:1)
28
to afford 20 (70 mg, 80%) as a colorless oil. [
α
]
: +128.8 (c 0.5,
CHCl3); IR (neat) νmax : 2923, 1723, 1252, 1096,D711 cmꢀ 1
;
1H NMR
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
(500 MHz, CDCl3) : δ 8.07–8.03 (m, 4H), 7.62–7.56 (m, 2H), 7.48–7.40
(m, 4H), 6.04–5.99 (m, 2H), 5.83–5.81 (m, 1H), 5.78–5.76 (m, 1H), 4.66
(d, J = 12.1 Hz, 1H), 4.52 (d, J = 2.3 Hz, 1H), 4.41 (d, J = 12.1 Hz, 1H),
2.03 (s, 3H), 1.55 (s, 3H), 1.46 (s, 3H); 13C NMR (125 MHz, CDCl3) : δ
170.49, 165.61, 165.44, 133.39, 129.79, 129.61, 129.54, 129.48,
128.48, 127.30, 110.06, 77.93, 77.56, 72.30, 69.93, 62.97, 27.87,
26.70, 20.79; ESI-MS (m/z) : 489 [M+H]+; HRMS calcd for C26H26O8Na
[M+H]+ 489.1525 found 489.1518.
Acknowledgments
AV thanks, the Council of Scientific and Industrial Research (CSIR),
New Delhi for research fellowship. Dr. BVRao, Emeritus Scientist, CSIR,
also thanks CSIR, New Delhi for financial support under CSIR-Emeritus
Scientist Scheme. The authors also thank Director, CSIR-IICT for the
constant support and encouragement. IICT Communication Number:
IICT/Pubs./2020/317.
(1R,4S,5S,6S)-5-(acetoxymethyl)-5,6-dihydroxycyclohex-2-ene-
1,4-diyl dibenzoate (or) (þ)-uvarigranol E (7): [5d] To compound 20
(50 mg, 0.107 mmol) in TFA (1 mL) and H2O (0.5 mL) was stirred at
room temperature for 5 h. The reaction mixture was concentrated under
reduced pressure to give syrup which was purified by column chroma-
tography (hexane: ethyl acetate = 4:1) to give (+)-uvarigranol E 7 in
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carres.2021.108432.
80% yield (36 mg) as a syrup. [
α
]
23 : +24.6 (c 0.1, CH3OH). {lit.5d + 23
D
c 0.5, CH3OH)}; IR (neat) νmax : 3464, 2924, 1718, 1261, 1096, 701
cmꢀ 1
;
1H NMR (500 MHz, CDCl3) : δ 8.11–8.02 (m, 4H), 7.60 (td, J =
References
7.3, 1.4 Hz, 2H), 7.47 (td, J = 7.9, 3.1 Hz, 4H), 6.06 (ddd, J = 10.1, 3.8,
1.5 Hz, 1H), 6.00 (dd, J = 10.1, 2.6 Hz, 1H), 5.79–5.75 (m, 1H), 5.68 (d,
J = 3.8 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.41 (d, J = 12.2 Hz, 1H),
4.24 (d, J = 6.1 Hz, 1H), 1.89 (s, 3H); 13C NMR (125 MHz, CDCl3) : δ
171.65, 167.02, 165.76, 133.56, 129.87, 129.74, 129.37, 128.64,
128.57, 128.51, 126.55, 74.72, 73.39, 71.64, 71.03, 66.44, 20.53;
ESI-MS (m/z) : 449 [M+Na]+; HRMS calcd for C23H22O8Na [M+Na]+
449.1212 found 449.1209.
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