Enantioselective total synthesis of β-zearalenol from (s)-propylene oxide

Article abstract of DOI:10.1080/00397911.2017.1383433

The total synthesis of 14-membered resorcylic acid macrolide, β-zearalenol, was accomplished starting from commercially available enantiomerically pure propylene oxide and methyl 2,4-dihydroxy-6-methylbenzoate using Grignard reaction, asymmetric dihydroxy

Full text of DOI:10.1080/00397911.2017.1383433

Synthetic Communications
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Enantioselective total synthesis of β-zearalenol
from (s)- propylene oxide
Ravindar Kotla, P. Aparna, Shobha Donthabakthuni, Radhakrishnamraju
Ruddarraju, Adharvana Chari Murugulla & Gattu Sridhar
To cite this article: Ravindar Kotla, P. Aparna, Shobha Donthabakthuni, Radhakrishnamraju
Ruddarraju, Adharvana Chari Murugulla & Gattu Sridhar (2017): Enantioselective total
synthesis of β-zearalenol from (s)- propylene oxide, Synthetic Communications, DOI:
10.1080/00397911.2017.1383433
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1383433
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Date: 17 November 2017, At: 08:17

Enantioselective total synthesis of β-zearalenol from (s)-
propylene oxide
Ravindar Kotla
Dr. MACS Bio-Pharma Pvt. Ltd, Pashamylaram, Patancheru, Medak (Dist), India
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad,
India
P. Aparna
Dr. MACS Bio-Pharma Pvt. Ltd, Pashamylaram, Patancheru, Medak (Dist), India
Shobha Donthabakthuni
Dr. MACS Bio-Pharma Pvt. Ltd, Pashamylaram, Patancheru, Medak (Dist), India
Radhakrishnamraju Ruddarraju
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad,
India
Adharvana Chari Murugulla
Dr. MACS Bio-Pharma Pvt. Ltd, Pashamylaram, Patancheru, Medak (Dist), India
Gattu Sridhar
1

Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
Address correspondence to Adharvana Chari Murugulla, Dr. MACS Bio-Pharma Pvt. Ltd,
Factory: Plot-79/B&C, Pashamylaram, Patancheru, Medak (Dist) 502307, India. E-mail:
rk1org@yahoo.com
ABSTRACT
The total synthesis of 14-membered resorcylic acid macrolide, β-Zearalenol was
accomplished starting from commercially available enantiomerically pure propylene oxide and
methyl 2,4-dihydroxy-6-methylbenzoate using Grignard reaction, Asymmetric dihydroxylation,
Yamaguchi macrolactonization and RCM as key steps.
Graphical Abstract
KEYWORDS: β-zearalenol, S-propylene oxide, Grignard reaction, Grubbs RCM, Yamaguchi
macrolactonization
Introduction
Resorcylic acid lactones (RALs) have been known for decades with the first isolation of
radicicol (monorden) in 1953[1] followed by zearalenone in 1962,[2] LL-Z1640-2in 1978[3] and
hypothemycin in 1980.[4] Particularly, in recent years, these lactones have attracted significant
interest among synthetic chemists and biologists due to their wide range of biological activities.
2

β-Zearalenol (2), a 14-membered resorcylic acid macrolide, is an estrogenic mycotoxin
produced by a species of the fungus Fusarium along with its natural isomer α-zearalenol (1).[5]
The hormonal activity of these compounds is linked to their close spatial similarity to 17β-
[
6]
[7]
estradiol, with the α-isomer 1 being three to four times as active as the β-isomer. Furthermore
this class of compounds has attracted attention due to their anabolic activity.
To date several synthetic routs have been reported towards enatioselective total synthesis
of α- and β-Zearalenols.[8] Herein we reported an alternative route for the synthesis of β-
Zearalenol. In this context, we would like to report an efficient and high yielding
enantioselective synthesis of β-Zearalenol employing an entirely different approach.
Retrosynthetic analysis of 2 (Scheme 1) revealed that bis-olefin 3 could be the late stage
intermediate, which on RCM protocol would generate the macrolide ring structure. Bis-olefin 3in
turn could be realized by esterfication of aromatic segment 4 with aliphatic segment 5, while 4
could be envisaged from commercially available methyl 2, 4-dihydroxy-6-methylbenzoate 14
and 5 from commercially available (S)-methyloxirane 6.
Synthesis of alcohol 5 began with commercially available (S)-methyloxirane 6 (Scheme
[
9]
2
). Accordingly, Asymmetric dihydroxylation of the known terminal olefin in 7 with AD-mix-
β afforded diol 8in 87% yields. (dr 9:1).[10] Protection of diol 8 with anisaldehyde dimethyl acetal
in the presence of PTSA (cat.) in dry CH
2
Cl at room temperature for 6h to resulted 9in 79%
2
yield. Regioselective reductive ring opening of 9 with DIBAL-H (2M solution in toluene) at 0 °C
to room temperature for 4h afforded primary alcohol 10in 84% yield. The alcohol 10 on
treatment with I
2
in the presence of PPh
3
and imidazole in dry THF afforded iodo-derivative[11]
1
1in 69% yield, which on subsequent treatment with homoallylmagnesium bromide in the
3

presence of CuI in dry THF at -40 C-rt for 2h afforded the required olefin 12in 78% yield.
Finally, deprotection of silyl ether in 12 TBAF in dry THF gave alcohol segment 5in 88% yields.
Having successfully synthesized the aliphatic segment 5, next it was aimed at the
synthesis aromatic fragment 4. Accordingly, commercially available 2,4-dihydroxy-6-
methylbenzoate 13, which was subjected to O-methylation with dimethyl sulfate in acetone at
reflex for 4h to afford 14 in 83% yield. Oxidation of benzylic methyl group in 14 to aldehyde
[12]
using TBHP, Co(acac)
methylene)triphenyl phosphonium iodide in THF gave olefin 16. Hydrolysis of 16 with LiOH in
THF: MeOH: H O (3:1:1) at room temperature for 4h afforded the acid 4in 81% yield.
2
yielded 15in 61% yield, which on Wittig olefination with
(
2
Having prepared both the intermediates, acid 4 and alcohol 5, next task was to couple
them through an ester bond (Scheme 4). Accordingly, acid 4 was treated with 2,4,6-
trichlorobenzoyl chloride (Yamaguchi reaction conditions)[13] and Et
N in dry THF to form a
3
mixed anhydride which on reaction with alcohol 5 afforded ester 17in 69% yield. Ester 17 on
treatment with Grubb’s[14] second generation catalyst in CH
2
Cl at reflux for 12h afforded 18in
2
7
1% yield. Finally, lactone 18 on global deprotection of PMB and methyl ethers at the same time
using the fresh prepared AlI in benzene for 1.5h afforded β-Zearalenol (2) in 77% yield, whose
3
spectral and optical rotation data were comparable with the data reported in the literature.[8]
In conclusion, we have reported an alternative route to the total synthesis of the 14-
membered resorcylic macrolide, β-Zearalenol in a regioselective manner from (S)-propylene
epoxide. This concise synthesis utilizes Grignard reaction, Asymmetric dihydroxylation,
Yamaguchi macrolactonization and RCM.
Experimental Section
4

General methods
(2S,6S )-6-(4-Methoxybenzyloxy)undec-10-en-2-ol (5)
To a cooled (0°C) solution of 12 (1.05g, 2.51 mmol) in dry THF (15mL ) under nitrogen
atmosphere, TBAF (3.75mL, 3.75 mmol) was added and stirred for 3h . After completion of
reaction, reaction mixture was diluted with water (5mL ) and extracted with ethyl acetate (2 x
5
0mL ). Organic layers were washed with water (2 x 10mL ), brine (10mL ), dried (Na
2
SO ),
4
evaporated and purified the residue by colomn chromatography (60–120 Silica gel, 55% EtOAc
1
in pet. ether) to give 5 (0.67g, 88%) as a liquid. []
D
-32.6 (c 1.0, CHCl
3
); H NMR (CDCl
3
,
3
1
1
00MHz ):  7.21 (d, 2H, J = 8.4Hz, ArH-PMB), 6.81 (d, 2H, J = 8.4Hz, ArH-PMB), 5.76 (m,
H, olefinic), 5.01–4.88 (m, 2H, olefinic), 4.51 (d, 1H, J = 11.1Hz, benzylic), 4.40 (d, 1H, J =
1.1Hz, benzylic), 3.78 (s, 3H, -OCH ), 3.74 (m, 1H, -OCH), 3.38 (m, 1H, -OCH), 2.06 (m, 2H,
), 1.16–1.06 (m, 2H, -CH ), 1.04 (d, 3H, J = 6.0Hz, -CH );
, 75MHz ):  172.6, 158.2, 146.4, 132.6, 128.9, 118.3, 113.6, 78.8, 72.4, 68.2,
3
-CH
2
), 1.54–1.23 (m, 8H, 4 x -CH
2
2
3
13C NMR (CDCl
3
5
6.4, 34.2, 29.8, 23.2; IR (neat): 3451, 2929, 2857, 2102, 1722, 1612, 1514, 1360, 1041, 777cm -
1;
HRMS (ESI): m/z calculated for C19
H
31
O [M + H] 307.2195, found 307.2197.
+
3
2
,4-Dimethoxy-6-vinylbenzoic acid (4)
To a solution of 16 (0.86g, 3.90 mmol) in THF: MeOH: water (3:1:1, 20mL ), LiOH
0.36g, 15.21 mmol) was added and stirred at room temperature for 4h . The pH of reaction
mixture was adjusted to acidic with 1N HCl solution and extracted with ethyl acetate (30mL ).
Organic layers were washed with water (15mL ), brine (15mL ), dried (Na SO ), evaporated
(
2
4
under reduced pressure and purified the residue by column chromatography (60–120 Silica gel,
¹
3
0% EtOAc in pet. ether) to give 4 (0.65g, 81%) as a white solid. m. p. 131–134°C; H NMR
5

(300MHz, CDCl
3
): δ 7.22 (dd, Jꢀ = ꢀ17.3, 10.8Hz, 1ꢀH, olefinic), 6.67 (s, 1ꢀH, ArH), 6.44 (s, 1ꢀH,
ArH), 5.63 (d, Jꢀ = ꢀ17.1ꢀHz, 1ꢀH, olefinic), 5.34 (d, Jꢀ = ꢀ10.9ꢀHz, 1ꢀH, olefinic), 3.91 (s, 3ꢀH, -
OCH
3
), 3.86 (s, 3ꢀH, -OCH
3
); 13C NMR (75MHz, CDCl
): 163.2, 159.4, 159.2, 139.2, 135,
3
-1
1
14.6, 114.2, 108, 98.5, 55.8, 55.5; IR (neat): 3450, 2986, 1721, 1638, 1194, 1057cm ; HRMS
+
(ESI): m/z calculated for C11
H
12
O Na [M + Na] 231.0736, found 231.0739.
4
β-Zearalenol (2)
Iodine (0.67g, 2.64 mmol) was added to a mixture of aluminum (101mg, 3.91 mmol) in
N I-
+
dry benzene. The mixture was heated at reflux for 1h, cooled to room temperature, n-Bu
4
(10mg, 0.026 mmol) and 18 (62mg, 0.13 mmol) in dry benzene (5mL ) were added. It was stirred
for 30min at room temperature and quenched with water (5mL ). After acidification with 2M
HCl (2mL ), the mixture was extracted with EtOAc (3 x 20mL ). The organic phase was washed
with brine (10mL ), dried, filtered and concentrated in vacuo . The residue was purified by
column chromatography (60–120 Silica gel, 50% EtOAc in pet. ether) to afford 2 (33mg, 77%)
1
9
as a white solid. []
D
-11.7 (c 0.14, acetone); lit. [α] -12.9 (c 1.00, acetone); m. p. 173–175°C;
D
1H NMR (500MHz, d6-acetone): δ 11.03 (br s, 1H, -OH), 9.02 (br s, 1H, -OH), 6.86 (d, 1H, J =
1
5
1
5.5Hz, ArH), 6.53 (d, 1H, J = 2.2Hz, ArH), 6.28 (d, 1H, J = 2.2Hz, ArH), 5.97 (m, 1H, -CH),
.14–5.07 (m, 1H, -CH), 3.81–3.71 (m, 1H, -CH), 3.40 (br s, 1H, -OH), 2.36–2.21 (m, 2H, -CH),
.96–1.61 (m, 6H, -CH), 1.59–1.37 (m, 3H, -CH), 1.34 (d, 3H, J = 6.1Hz ), 1.33–1.22 (m, 1H, -
1
3
CH); C NMR (75MHz, d6-acetone): δ 171.1, 163.6, 161.8, 142.3, 132.2, 131.4, 107.4, 105.2,
1
1
01.6, 73.4, 67.6, 36.3, 34.2, 22.5, 19.1, 18.0; IR (neat): 3390, 2926, 2850, 1644, 1608, 1584,
-1
456, 1448, 1380, 1352, 1312, 1259, 1197, 1165, 1110, 1024, 1018, 972cm ; HRMS (ESI): m/z
+
calculated for C18
H
24
O
5
Na [M + Na] 343.3802, found 343.3807.
6

Conclusion
In conclusion, enantioselective total synthesis of β-Zearalenol (2) has been accomplished
in a divergent way starting from commercially available inexpensive materials with 4.1% of
overall yield. In this approach Grignard reaction, Asymmetric dihydroxylation, Yamaguchi
esterification and ring-closing metathesis reactions (RCM) used as a key reactions.
Supporting Information
1
13
Full experimental details, spectral data of the products, H NMR and C NMR of all the
new compounds can be found via the Supplementary Content section of this article’s Web page.
Acknowledgements
The autohrs are thankful to GVK Bio sciences and CSIR, New Delhi for constant
encouragement in providing laboratory facilities and analytical data.
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8

Figure 1.
9

Scheme 1.
1
0

Scheme 2.
1
1

Scheme 3.
1
2

Scheme 4.
1
3