Total synthesis of Neocosmosin A

Article abstract of DOI:10.1080/00397911.2021.1952435

An alternative synthetic route to (?)-Neocosmosin A has been synthesized from commercially available (R)-propylene oxide and 4-Methoxysalicylic acid as starting materials. The key steps involved in the synthesis are alkylation of 1,3-dithiane and Yamaguchi macrolactonization.

Full text of DOI:10.1080/00397911.2021.1952435

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Total synthesis of Neocosmosin A
Manmohan Reddy Depa, Suneetha Potla, Umesh C. Narkhede, Vinod D.
Jadhav, Gattu Sridhar & Siddaiah Vidavalur
To cite this article: Manmohan Reddy Depa, Suneetha Potla, Umesh C. Narkhede, Vinod D.
Jadhav, Gattu Sridhar & Siddaiah Vidavalur (2021): Total synthesis of Neocosmosin A, Synthetic
Communications, DOI: 10.1080/00397911.2021.1952435
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Published online: 15 Jul 2021.
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https://doi.org/10.1080/00397911.2021.1952435
Total synthesis of Neocosmosin A
Manmohan Reddy Depaa,b, Suneetha Potlaa,b, Umesh C. Narkhedea,
Vinod D. Jadhava, Gattu Sridharc, and Siddaiah Vidavalurb
b
aChemistry Services GVK Biosciences, Pvt. Ltd, IDA, Hyderabad, India; Department of Organic
c
Chemistry, Food, Drugs and Water, Andhra University, Visakhapatnam, India; Department of Chemistry,
Kakatiya Institute of Technology and Science, Warangal, India
ABSTRACT
ARTICLE HISTORY
Received 14 April 2021
An alternative synthetic route to (ꢀ)-Neocosmosin A has been syn-
thesized from commercially available (R)-propylene oxide and 4-
Methoxysalicylic acid as starting materials. The key steps involved in
the synthesis are alkylation of 1,3-dithiane and Yamaguchi macrolac-
tonization.
KEYWORDS
Resorcylic acid lactones;
Neocosmosin A; alkylation
of 1,3-dithiane and
Yamaguchi
GRAPHICAL ABSTRACT
macrolactonization
TBSO
O
OH
O
Br
O
O
OH
O
OBn
O
O
OH
OMe
S
S
(−)-Neocosmosin A
MeO
O
Introduction
Resorcylic acid lactones (RALs) have been known for decades, with the first isolation of
radicicol (monorden) in 1953,[1] followed by zearalenone,[2] LL-Z1640-2,[3] and hypoth-
emycin.[4] Todate, more than 130 RALs have been described, which were mainly
obtained from fungal species of genera Caryospora, Hamigera, Hypomyces,
Paecilomyces etc.[5] Many of them exhibit a diverse array of biological activities,
such as inhibition of heat shock protein 90 and kinases,[6,7] cytotoxic,[8] antiviral,[9]
anti-inflammatory,[10,11] estrogenic,[12] and nematocidal activities.[13] Several RAL com-
pounds are, in fact, currently under development for clinical applications.
Neocosmosin A is a 14 membered Resorcylic acid lactone, isolated with neocosmosins
B and C from the fungus Neocosmospora sp. (UM-031509) in 2012.[14,15] It exhibits a
strong binding affinity for human opioid and cannabinoid receptors.[16] The Structure
of neocosmosin A (1) was elucidated on the basis of extensive 1D and 2D NMR spec-
troscopic analysis, mass spectrometric (ESI-MS) data, and X-ray crystallography
(Figure 1).
CONTACT Siddaiah Vidavalur
siddaiah1chem@gmail.com
Department of Organic Chemistry, Food, Drugs and
Water, Andhra University, Visakhapatnam, Andhra Pradesh 530003, India.
ß 2021 Taylor & Francis Group, LLC

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M. R. DEPA ET AL.
OH
O
O
O
O
Neocosmosin A (1)
Figure 1. Structure of Neocosmosin A.
OH
O
OBn
OH
O
O
OH
O
O
S
O
S
1
2
OH
O
OBn O
TBSO
OH
O
OMe
S
S
+
Br
MeO
O
6
5
3
4
Scheme 1. Retro synthesis.
The first total synthesis of neocosmosin A was reported by Saibal Das and Coworkers
in 2014[17a]. Due to the promising biological activity and the impressive structural fea-
tures, neocosmosin A (1) appeared to be an attractive target for total synthesis[17b,c]. In
this communication, we herein, report an alternative synthetic strategy to achieve the
total synthesis of neocosmosin A (1) utilizing the alkylation of 1,3-dithiane and
Yamaguchi macrolactonization as the key steps.
Results and discussion
According to the retrosynthetic analysis of neocosmosin A (1) as shown in Scheme 1,
the target molecule 1 could be synthesized from seco-acid 2 via Yamaguchi macrolacto-
nization followed by removal of protecting groups. Hydroxy acid 2 could be accessible
by the coupling reaction of dithiane 3 and bromide 4. wherein, 3 could be envisaged
from the 4-Methoxysalicylic acid 5, while, bromide 4 could be achieved from the com-
mercially available chiral epoxide 6.
As discussed in retrosynthetic analysis, the synthesis of the dithiane 3 commenced
from known 4-Methoxysalicylic acid 7 (Scheme 2), which was subjected to esterification
using diazomethane to generate 4-Methoxy methyl salicylate 8 in quantitative yield
(Scheme 2). The hydroxyl group in compound 8 was protected with benzyl ether by
treating with benzyl bromide and K2CO3 to give 9 in 86% yield. Later, the ester group

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3
Scheme 2. Synthesis of fragment 3.
Synthesis of fragment 3; Reagents and conditions: (a) CH2N2, ether, 0 ꢁC, 15 min; (b) BnBr, K2CO3, DMF,
0 ꢁC to rt, 6h; (C) LiOH, THF:MeOH:H2O (3:1:1), rt, 4 h; (d) (i) sBuLi, TMEDA, allyl bromide, THF, –90 ꢁC,
4h; (ii) MeI, DBU, THF, 0 ꢁC to rt, 24h; (e) (i) O3, CH2Cl2, –78 ꢁC, 30 min; (ii) 1,3-propanedithiol, CAN,
CHCl3, 0 ꢁC to rt, 4 h.
Scheme 3. Synthesis of fragment 4.
Synthesis of fragment 4; Reagents and conditions: (a) lithium acetylide-ethylene diamine complex,
DMSO, rt, 24 h; (b) TBSCl, Imidazole, CH2Cl2, rt, 4 h; (c) n-BuLi, dry THF, –78 ꢁC, 13a, 3 h; (d) Red-Al,
dry ether, rt, 4 h; (e) i) p-TsCl, Et3N, CH2Cl2, rt, 4 h; ii) LAH, THF, rt to 25 ꢁC, 3h; (f) DDQ, aq. CH2Cl2,
0 ꢁC to rt, 1 h; (g) CBr4, Ph3P, CH2Cl2, 0 ꢁC to rt, 3 h.
in compound 9 was subjected to base (LiOH) hydrolysis in THF:MeOH:H2O (3:1:1) to
afford the corresponding acid 10, which was allylated[13] via the dianion followed by
esterification to afford compound 11 in 62% yield. Ozonolysis of 11 in CH2Cl2 at
ꢀ78 ꢁC for 30 min gave the corresponding aldehyde, which was transformed into 1,3-
dithiane 3 in 76% with 1,3-propanedithiol and ceric ammonium nitrate as a catalyst
in chloroform.
After successful synthesis of one key intermediate 3, we next turned our attention to
the synthesis of another key fragment 4 (Scheme 3). Accordingly, the synthesis was ini-
tiated with (R)-propylene oxide 6 as a chiral synthon, which was readily prepared from
racemic-propylene oxide through Jacobsen hydrolytic kinetic resolution.[18] Thus treat-
ment of (R)-propylene oxide 6 with lithium acetylideethylenediamine complex

4
M. R. DEPA ET AL.
Scheme 4. Synthesis of target compound 1.
Synthesis of target compound 1 Reagents and conditions: (a) n-BuLi, dry THF, –20 ꢁC, 3 h; (b) LiOH,
THF:MeOH:H2O (3:1:1), rt, 4 h; (c) TBAF, THF, 0 ꢁC to rt, 3 h; (d) i) 2,4,6-trichlorobenzoyl chloride, Et3N,
dry THF, rt, 2 h; ii) DMAP, toluene, 90 ꢁC, 10 h; (e) CaCO3, MeI, CH3CN:H2O (9:1), 45 ꢁC, 3 h; (f) TiCl4,
CH2Cl2, 0 ꢁC to rt, 2 h.
proceeded cleanly to afford the corresponding homopropargylic alcohol, in which the
secondary hydroxyl group was protected as its TBS ether 13 using TBSCl, imidazole in
CH2Cl2 in 84% yield.
Next, alkyne 13 was treated with n-BuLi in THF at ꢀ78 ꢁC and the resulting acety-
lenic anion was treated with known aldehyde 13a furnished alcohol 14 as a 1:1 mixture
of diastereomers in 72% yield. Reduction of 14 with Red-Al in dry ether at room tem-
perature for 4 h afforded 15 as a 1:1 mixture of diastereomers in 74% yield. The
hydroxyl group in 15 was transformed as tosylate 15a by treatment with p-TsCl in
CH2Cl2 at room temperature for 4 h, which on subsequent treatment with LAH in dry
THF to furnish compound 16 in 77% yield. The PMB protecting group in compound
16 was oxidatively removed upon treatment with DDQ in aq. CH2Cl2 afforded alcohol
17 in 84% yield. Finally, treatment of alcohol 17 with CBr4 in the presence of Ph3P in
CH2Cl2 gave the required bromo intermediate 4 in 80% yield.
Having synthesized both the desired fragments in a simple and efficient manner, we
turned our attention to couple the dithiane 3 and the bromide 4 toward the synthesis
of neocosmosin A. Accordingly, dithiane 3 was lithiated by n-BuLi at ꢀ20 ꢁC and then
coupled with bromide 4 to provide the desired product 19 in 84% yield (Scheme 4).
The ester functionality of 19 was hydrolyzed under basic conditions with LiOH in
THF:MeOH:H2O (3:1:1) to afford the corresponding acid 20, which on desilylation with
TBAF in THF at 0 ꢁC to room temperature for 3 h afforded hydroxy acid 2 in 91%

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5
yield. After successful synthesis of hydroxy acid fragment 2, which was subjected to
macrolactonisation under Yamaguchi high dilution conditions[19] to provide the lactone
21 in 66% yield. Next, the 1,3 dithaine group in compound 21 was successfully removed
with CaCO3 and MeI, in CH3CN:H2O for 3 h to afford the lactone 22 in 75% yield. In
the final step, deprotection of benzyl ether in lactone 22 was removed successfully using
TiCl4 at 0 ꢁC to rt to afford neocosmosin A (1) in 78% yield. The spectral data of 1 (1H
NMR, 13C NMR and HRMS) and optical rotation are in good agreement with the
reported values of natural neocosmosin A (1).
Experimental section
General
Solvents were dried over standard drying agents on freshly distilled prior to use.
Chemicals were purchased and used without further purification. All column chromato-
graphic separations were performed using silica gel (60–120 mesh). Organic solutions
1
were dried over anhydrous Na2SO4 and concentrated below 40 ꢁC in vacuo. H NMR
spectra were acquired at 300 MHz, 500 MHz and 600 MHz, while, 13C NMR at 75 MHz
and 125 MHz with TMS as internal standard for solutions in CDCl3. J values were given
in Hz. IR-spectra were recorded on FT IR spectrophotometer with NaCl optics. Optical
rotations were measured on digital polarimeter at 25 ꢁC. Mass spectra were recorded on
direct inlet system or LC by MSD trap SL, the HRMS data were obtained using Q-TOF
mass spectrometry.
Neocosmosin A (1)
To a stirred solution of 22 (0.10 g, 0.23 mmol) in dichloromethane (3 mL), TiCl4 (90 mg,
0.47 mmol) in dichloromethane was added at 0 ꢁC and stirred for 2 h. After completion
of reaction sat. aq. NaHCO3 solution (10 mL) was added and extracted with dichloro-
methane (3 ꢂ 10 mL). The combined organic layers were washed with water (15 mL),
brine (10 mL), dried (Na2SO4) and concentrated. The crude residue purified by column
chromatography (60–120 Silica gel, 20% EtOAc in pet. ether) to afford 1 (61 mg, 78%)
25
1
as a Pale yellow liquid. [a]D ꢀ43.1 (c 0.9, CHCl3); H NMR (400 MHz, CDCl3) d 12.1
(s. 1H), 6.42 (d, 1H, J ¼ 2.6 Hz), 6.22 (d, 1H, J ¼ 2.6 Hz), 5.49–5.40 (m, 2H), 5.37–5.29
(m, 1H), 4.37 (d, J ¼ 16.4 Hz, 1H), 3.81 (s, 3H) 3.49 (d, J ¼ 16.4 Hz, 1H), 2.63–2.50 (m,
2H), 2.41–2.34 (m, 1H), 2.29–2.21 (m, 1H), 2.17–2.07 (m, 2H), 1.67–1.51 (m, 3H),
1.44–1.39 (m, 1H), 1.36 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 208.2, 170.5,
166.1, 163.8, 139.1, 135.3, 124.6, 112.1, 105.7, 99.9, 73.0, 55.5, 50.3, 40.9, 37.7, 32.7, 25.3,
22.2, 18.8; HRMS (ESI): m/z calculated for C19H25O5 [M þ H]þ 333.1702,
found 333.1708.
Conclusions
Thus, In summary, we have demonstrated an efficient synthetic route for the total syn-
thesis of neocosmosin A in a stereoselective manner. The overall yield of longest linear
sequence in this synthesis i.e., From compound 6 to compound 1 (total number of steps

6
M. R. DEPA ET AL.
are 13) is 4.45%. The key steps involved in this synthesis are alkylation of 1,3-dithiane
and Yamaguchi macrolactonization.
Acknowledgments
The authors are thankful to Department of Organic Chemistry, Andhra University and GVK
Biosciences, Pvt. Ltd for providing facilities to carry out our research work.
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