Asymmetric glycolate alkylation approach towards total synthesis of 8-O.6′ and 8-O.4′-neolignans

Article abstract of DOI:10.1016/j.tetlet.2016.11.087

The glycolate alkylation approach for the total synthesis of 8-O.6′ and 8-O.4′-neolignans has been optimized affording the natural products with high overall yields and excellent stereoselectivity. The developed approach can be further utilized towards the synthesis of many natural and unnatural neolignans. This is the first approach for the synthesis of neolignans using asymmetric glycolate alkylation approach.

Full text of DOI:10.1016/j.tetlet.2016.11.087

Accepted Manuscript
Asymmetric glycolate alkylation approach towards total synthesis of 8-O.6’and
8
-O.4’-neolignans
Mukesh Gangar, Mangilal Chouhan, Sandeep Goyal, M. Harikrishnan, R.
Chandran, Avinash Ittuveetil, Vipin A. Nair
PII:
S0040-4039(16)31568-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.087
TETL 48373
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 October 2016
15 November 2016
19 November 2016
Please cite this article as: Gangar, M., Chouhan, M., Goyal, S., Harikrishnan, M., Chandran, R., Ittuveetil, A., Nair,
V.A., Asymmetric glycolate alkylation approach towards total synthesis of 8-O.6’and 8-O.4’-neolignans,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.087
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Graphical Abstract
Asymmetric glycolate alkylation approach towards the
Leave this area blank for abstract info.
total synthesis of 8-O.6’ and 8-O.4’-neolignans
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Mukesh Gangar , Mangilal Chouhan , Sandeep Goyal , Harikrishnan M. , Chandran R , Avinash Ittuveetil , Vipin A. Nair

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Tetrahedron Letters
Asymmetric glycolate alkylation approach towards total synthesis of 8-O.6’and 8-O.4’-neolignans
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b
a
a
a
Mukesh Gangar , Mangilal Chouhan , Sandeep Goyal , Harikrishnan M. , Chandran R , Avinash
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Ittuveetil , Vipin A. Nair
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Punjab 160062, India
Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan 313001, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
.
©
2013 Elsevier Ltd. All rights reserved.
The glycolate alkylation approach for the total synthesis of 8-O.6’and 8-O.4’-neolignans has been
optimized affording the natural products with high overall yields and excellent stereoselectivity.
The developed approach can be further utilized towards the synthesis of many natural and
unnatural neolignans. This is the first approach for the synthesis of neolignans using asymmetric
glycolate alkylation approach.
Available online
Keywords:
Chiral auxiliary
Glycolate alkylation
Stereoselectivity
8
-O.4’-neolignans
Virolongin B
In eastern parts of the Madagaskar, Ocotea cymosa (Nees) Palacky The extensive literature survey related to synthesis of virolongin B
plant is widely distributed tree and the stems extracts of this plant and other structurally similar lignans, pointed out the major problem
1
yielded biologically active 8-O.6’ and 8-O.4’-neolignan derivatives.
associated with these natural products such as low stereoselectivety in
5
Further investigation of the bark extract demonstrated activity the construction of chiral centre, use of costly catalyst and low yield.
against drug resistant Plasmodium falciparum. In contrast to this To handle these issues, a retrosynthetic analysis (Scheme 1) of the
2
another plant such as Taxillus theifer from Loranthaceae family, is
intermediate 1 demonstrated the asymmetric glycolate alkylation and
Claisen rearrangent as key steps. For the construction of asymmetric
centre in the desired neolignans, the acetylated auxiliary could be
native to Taiwan and has been found to contain these types of
3
lignans with antihypertensive activity in Formosan folk medicine.
The new 8.O.6′-neolignan 1 (Figure 1), had in vitro activity against treated with corresponding substituted benzyl bromides to obtain the
2
Aedes aegypti, with ≥80% mortality at 4 mg/mL. Lignans and
enantiomerically pure alkylated adduct. In continuation of our work
on auxiliary mediated asymmetric transformations, we had recently
neolignans have been reported to have a wide range of bioactivities
such as antineoplastic, viral reverse transcriptase inhibitor, investigated some of the crucial factors which govern the
4
antimalarial, antileishmanial and others. The newly reported 8-O.6’ stereoselectivity of C-C bond formation in aldol reactions on various
6
and 8-O.4’-neolignan derivatives have shown good activity against
Plasmodium falciparum they also have shown antifungal and anti-
insecticidal activities also.
substrates.
2
Figure 1. Some biologically active 8-O.6’ and 8-O.4’-neolignans
Scheme 1. Retrosynthetic analysis of 1
—
——


Corresponding author. Tel.: +91-9646019319; e-mail: mukeshgangar88@gmail.com
Corresponding author. Tel.: +91-172-229-2045; fax: +91-172-221-4692; e-mail: vn74nr@yahoo.com

7
Recently we have explored an imidazolidinone based chiral
Next to get intermediate 9, the phenol group was first alkylated using
CO and allyl bromide under reflux conditions followed by
auxiliary for the glycolate alkylation reaction with high yields and
excellent stereoselectivity which motivated us to further explore the
usefulness of the chiral auxiliary in the chiral synthesis of various
neolignans.
K
2
3
thermal Claisen rearrangement to get intermediate 9. The phenolic
group in intermediate 9 was again alkylated using bromoacetylated
chiral auxiliary to give the intermediate 10. The key asymmetric
glycolate alkylation reaction was performed on the intermediate 10
via enolisation using LiHMDS/TMEDA in dry THF at -78°C
followed by addition of 3,4,5-trimethoxybenzyl bromide (6)
affording the alkylated intermediate 11 with 98:02 diastereo-
Result and Discussion:
The opted retrosynthetic route was applied for the synthesis of 8-
O.6’neolignan 1 (Scheme 2). The required 3,4,5-trimethoxybenzyl
bromide 6 was synthesized from commercially available 3,4,5-
1
selectivity deteremined by the H NMR spectra of the crude product.
4
Further treatment of intermediate 11 with NaBH in MeOH at rt
afforded intermediate 12 with 86% recovery of chiral auxiliary.
Finally the primary alcohol functionality in 12 was first tosylated and
complete removal of OTs group using LAH afforded the desired
natural 8-O.6’neolignan 1 with 17.3% overall yield and 98% ee, as
determined by HPLC . The absolute configuration of the 1 was
confirmed by correlating of the specific rotation value with the
trimethoxybenzaldehyde which reduced in the presence of NaBH
THF-H O afforded corresponding benzylalcohol intermediate 5. The
hydroxyl group was transformed into bromide in the presence of
PBr in Et O to give 3,4,5-trimethoxybenzyl bromide 6 in 90 %
yield. Further 3,4-dihydroxybenzaldehyde was converted to 7 in the
presence of DBU and diiodomethane. The transformation of
aldehyde group of 7 to phenol was performed via Baeyer-Villiger
reaction followed by hydrolysis using aq.KOH in MeOH to get
intermediate 8.
4
in
2
3
2
25
25
literature [observed [α]
D
+15.1 (c 0.1, MeOH) reported [α]
D
+23.0
2
(
c 0.1 in MeOH)], an S configuration was unambiguously assigned.
Next for the synthesis of Virolongin B (Scheme 3), the reaction
strategy starts with the O-alkylation of 2,6-dimethoxy phenol with
allyl bromide followed by thermal claisen rearrangement afford
intermediate 14. The O-alkylation of phenolic group with
2 3
bromoacetylated chiral auxiliary in the presence of K CO and
catalytic KI at rt in acetone afforded 15.
Scheme 3. Total synthesis of Virolongin B and Rhaphidecursinol A.
Once more the key glycolate alkylation reaction was performed on
the intermediate 15 through LiHMDS/TMEDA mediate enolate
generation folloed by reaction of intermediate 6 afforded alkylated
intermediate 16 with a 99:01 diastereoselectivity as deteremined by
1
the H NMR spectra of the crude product. Next reductive cleavage of
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the intermediate 16 using NaBH in MeOH at room temperature
afforded Rhaphidecursinol A 17 and with 84% recovery of the chiral
auxiliary back. Finally removal of the OH functionality in
intermediate 17 via OTs formation and treatment with LAH afforded
the Virolongin B 19 with 24.9% overall yield and 99% ee, as
Scheme 2. Total synthesis of (S)-5-allyl-6-((1-(3,4,5-trimethoxyphenyl)
propan-2-yl)oxy)benzo[d][1,3]dioxole 1

3
determined by HPLC.
Conclusion
To conclude, asymmetric glycolate alkylation and Claisen
rearrangement are used as key steps for the total synthesis of 8-
O.6’neolignan (1), Rhaphidecursinol A (17) and Virolongin B (19)
and the synthesis completed in 10, 5 and 7 steps respectively with
high overall yields and excellent enantioselectivity. The general
nature of scheme can be extrapolated toward the synthesis of various
other neolignans.
Acknowledgement
Financial assistance in the form of a Senior Research Fellowship
from CSIR to M.G. is gratefully acknowledged.
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Asymmetric glycolate alkylation approach
towards the total synthesis of 8-O.6’and
O.4’-neolignans
8-
a
b
a
Mukesh Gangar , Mangilal Chouhan , Sandeep Goyal ,
a
a
a
Harikrishnan M. , Chandran R , Avinash Ittuveetil ,
a
Vipin A. Nair
a
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, Sector 67, SAS
Nagar, Punjab 160062, India
b
Department of Pharmaceutical Sciences, Mohanlal Sukhadia
University, Udaipur, Rajasthan 313001, India
Highlights



Novel approach towards the synthesis of
neolignans using glycolate alkylation.
The yields and ee of neolignans were high
compared to the reported strategies.
The protocol could be extended to the
synthesis of various other neolignans.
—
——

Corresponding author. Tel.: +91-9646019319; e-mail:
mukeshgangar88@gmail.com

4
Corresponding author. Tel.: +91-172-229-2045; fax: +91-172-221-
692; e-mail: vn74nr@yahoo.com