A concise asymmetric synthesis of (-)- trans -aerangis lactone

Article abstract of DOI:10.1139/cjc-2018-0203

A concise stereoselective approach to functionalized δ-lactone skeleton from monosilylated ethylene glycol as a starting material and its application to the asymmetric total synthesis of (-)-trans-aerangis lactone have been demonstrated. The synthesis uti

Full text of DOI:10.1139/cjc-2018-0203

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A Concise Asymmetric Synthesis of (-)-trans-Aerangis Lactone
Rachana Pandey and Ranjana Prakash*
School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology,
Patiala 147 001, India.
*
Corresponding Author: Phone: +91-175-239-3832, Fax No. +91-175-236-4498
E-mail: rprakash@thapar.edu
Abstract:
1

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A concise stereoselective approach to functionalized δ-lactone skeleton from monosilylated
ethylene glycol as a starting material and its application to the asymmetric total synthesis of
(-)-trans-aerangis lactone have been demonstrated. The synthesis utilizes the organocatalyzed
MacMillan’s cross aldol reaction as key step.
Keywords: lactones, Wittig olefination, MacMillan’s cross aldol, fragrance, natural products
Introduction
Functionalized δ-lactone moiety is an ubiquitous motif possess intriguing biological activities
and are important building blocks to synthesize a variety of bioactive active natural products,1
some of which are displayed in Figure 1. These lactone-derived compounds are present in
nature as fragrance and pheromone compounds of various flowers, fruits and several other
2
natural products. In 1993, Kaiser reported the isolation of cis- and trans-aerangis lactones
(1a-d) as a 1:1 mixture from the African moth orchids Aerangis confusa and Aerangis kirkii
3
(
native to Kenya and Tanzania) as the main odoriferous components. In 1995, Kaiser and co-
workers isolated all four stereoisomers of aerangis lactone by chiral HPLC as enantiopure
4
compounds of distinct odour activities. The cis and trans-1 mixture is a perfume and
flavouring constituent which can increase the alpine herb, ylang-ylang and creamery notes of
5
various flavouring compounds and perfume. Various methods for the syntheses of cis- and
trans-aerangis lactones have been documented in the literature due to their unique structural
6
features and with an array of functionalities. Most of the synthesis described employed either
enzymatic hydrolysis or chiral auxiliary to establish the chirality. Herein, we are reporting a
simple, concise and flexible approach to the δ-lactone skeleton from monosilylated ethylene
glycol and its application to the short total synthesis of (-)-trans-aerangis lactone, employing
organocatalyzed MacMillan’s cross aldol reaction and Wittig olefination as key steps.
Results and discussion
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Our synthetic route for the synthesis of (-)-trans-aerangis lactone 1a was projected via the
retrosynthetic approach as displayed in Scheme 1. The olefinic ester compound 3 was
envisioned as a key synthetic intermediate from which functionalized hydroxyl δ-lactone 2
and aerangis lactone 1 could be synthesized via double bond reduction followed by silylether
deprotection and lactonization following standard organic functional group transformations.
The aerangis lactone 1 could be easily synthesised from δ-lactone 2 via oxidation followed by
4
C-Wittg olefination and hydrogenation. Subsequently, olefinic ester derivative 3 envisaged
from monosilylated ethylene glycol derivative 4 via organocatalyzed MacMillan’s cross aldol
reaction of aldehyde derived from 4 with propionaldehyde and Wittig homologation reaction.
The (R)- and (S)- configuration of the target compounds 1a-d could be manipulated by
changing organocatalyst under MacMillan’s cross aldol conditions.
Our asymmetric synthetic approach for the (-)-trans-aerangis lactone 1a is depicted in
Scheme 2. Synthesis of (-)-trans-aerangis lactone 1a began from readily available
monosilylated ethylene glycol derivative 7 which was subjected to a two-step sequence
including Swern oxidation followed by L-proline catalyzed MacMillan’s cross aldol reaction
to afford the diastereomeric
7
mixture of aldehyde 5 with >99% ee (anti/syn 9:1) and subsequent 2C-Wittig olefination
without separation with (ethoxycarbonylmethylene)triphenylphosphorane furnished
8
unsaturated ester 3a following a literature procedure. Subsequently, concomitant reduction
of olefin, TBDPS deprotection and δ-lactonization of compound 3a were carried out in
methanol and 3M HCl under one atmospheric hydrogenation condition in the presence of
catalytic amount of 10% Pd-C which afforded the δ-lactone derivative 2a in 91% yield. With
δ-lactone derivative 2a in hand, we then subjected it to oxidation under Swern conditions9
and subsequent treatment of aldehyde intermediate with phosphonium salt (butyltriphenyl-
phosphonium bromide) in presence of KHMDS furnished the olefin derivative 6 in 71%
3

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yield. In view of the fact that the incipient olefin would be ultimately hydrogenated to get the
target compound 1a we did not examine the olefin geometry of derivative 6. Accordingly, the
olefin derivative 6 on hydrogenation on one atmospheric pressure in the presence of 10%
Pd/C furnished the target compound (-)-trans-aerangis lactone 1a in 95% yield, [α]D25 -61.8
(
c 0.50, CHCl ). The spectroscopic and physical data of (-)-trans-aerangis lactone 1a were
3
consistent with literature data.
Conclusion
In summary, we have established a flexible, simple and convergent synthetic approach for δ-
lactones and its successful application to the total synthesis of (-)-trans-aerangis lactone 1a.
The synthetic approach demonstrated the application of organocatalyzed MacMillan’s cross-
aldol and Wittig olefination as the key steps. The (R)- and (S)-configuration of the target
compounds 1a-d could be manipulated by changing organocatalyst under MacMillan’s cross
aldol reaction conditions. The synthetic route described has noteworthy prospective for the
stereochemical variations and further extension to the total synthesis of other stereoisomer
and analogues.
Experimental
(5R,6R)-6-(hydroxymethyl)-5-methyltetrahydro-2H-pyran-2-one, 2a
A suspension of (4R,5R,E)-ethyl 6-(tert-butyldiphenylsilyloxy)-5-hydroxy-4-methylhex-2-
enoate 3a (500 mg, 1.17 mmol), 10% Pd/C catalyst in catalytic amount, and 3M HCl in
MeOH (10 mL) was hydrogenated under one atmospheric pressure and at rt for 5 hrs. Then
the catalyst was filtrated off and the solvent was evaporated. The residue was diluted with
CH Cl (20 mL) and washed with brine and dried over Na SO . Purification by silica gel
2
2
2
4
chromatography (EtOAc/hexane, 9:1) afforded 2a (154 mg, 91%) as a pale-yellow oil. [α]D25
-1 1
-
32.3 (c 1.0, CHCl ); IR (CH Cl ) ν: 3410, 2935, 1740, 1650, 1359, 1211 cm ; H NMR (400
3 2 2
MHz, CDCl ) δ: 4.03 (dq, J = 2.76, 4.60, 10.56 Hz, 1H), 3.88 (dd, J = 3.12, 12.84 Hz, 1H),
3
4

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3
1
2
1
.71 (dd, J = 5.04, 12.84 Hz, 1H), 2.84 (br, 1H), 2.68-2.45 (m, 2H), 2.03-1.89 (m, 2H), 1.64-
1
3
.52 (m, 1H), 1.04 (d, J = 6.84 Hz, 3H); C NMR (100 MHz, CDCl ) δ: 171.7, 86.7, 62.6,
3
+
9.6, 28.2, 27.5, 17.0; HRMS (ESI), m/z calcd for C H O Na [M + Na] 167.0678; found
7
12
3
67.0677.
-)-trans-Aerangis Lactone, 1a
To a solution of 6 (75 mg, 0.41 mmol) in MeOH (4 mL) was added a saptula tip of Pd-C
10%) and resulting reaction mixture was stirred at one atmospheric pressure of hydrogen for
hrs at rt. After completion of reaction, the catalyst was filtered over Celite and concentrated
in vacuo. Silica gel column chromatography furnished the (-)-trans-aerangis lactone 1a
(
(
3
(
EtOAc/hexane, 1:4) as a colourless oil with pleasent fragrance (72 mg, 95%). [α]D25 -61.8 (c
-1 1
0
.50, CHCl ), IR (CH Cl ) ν: 2925, 1738, 1445, 1364, 1257, 1129 cm ; H NMR (400 MHz,
3 2 2
CDCl ) δ: 3.97-3.91 (m, 1H), 2.67-2.43 (m, 2H), 1.92-1.87 (m, 1H), 1.77- 1.61 (m, 2H), 1.61-
3
1
3
1
.20 (m, 8H), 1.00 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.6 Hz, 3H), C NMR (100 MHz, CDCl )
3
δ: 172.1, 85.9, 36.6, 33.4, 32.3, 31.6, 29.5, 26.8, 22.6, 19.2, 14.1; HRMS (ESI), m/z calcd for
+
C H O Na [M + Na] 207.1355; found 207.1361.
1
1
20
2
Funding
The author (R.P.) acknowledge the research grant No. 02(0309)/17/EMR-II facilitated by the
CSIR (Council for Scientific and Industrial Research), New Delhi, India for the carrying out
the study. R. Pandey thanks Thapar Institute of Engineering and Technology for the teaching
associateship.
Supporting Information
1
13
Electronic supplementary information (ESI) available: copies of H and C NMR spectra of
compounds 1a, 2a, HRMS data of 2a and HPLC of diol derivative of intermediate 5. This
material can be found via the “Supplementary Content” section of this article’s webpage.
References
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1
. (a) Chiu, P.; Leung, L. T.; Ko, B. C. B. Nat. Prod. Rep. 2010, 27, 1066. (b) Florence,
G. J.; Gardner, N. M.; Paterson, I. Nat. Prod. Rep. 2008, 25, 342. (c) Boucard, V.;
Broustal, G.; Campagne, J. M. Eur. J. Org. Chem. 2007, 225. (d) Kaise, R. Chem.
Biodiversity 2004, 1, 13. (e) Galindo, J. C. G.; de Luque, A. P.; Jorrin, J.; Macias, F.
A. J. Agric. Food Chem. 2002, 50, 1911.
2
. (a) Mori, K. In Techniques in Pheromone Research; Hummel, H. H.; Miller, T., Eds.;
Springer: New York, 1989. (b) Silverstein, R. M. In Semiochemistry Flavours and
Pheromones; Acree, T.; Soderland, D. M., Eds.; Walter de Gruyter: Berlin, 1985.
. Kaiser, R. The Scent of Orchids, Olfactory and Chemical Investigations; Elsevier:
Amsterdam, 1993.
3
4
5
6
. Bartschat, D.; Lehmann, D.; Dietrich, A.; Mosandl, A.; Kaiser, R. Phytochem. Anal.
1
995, 6, 130.
. Kaiser, R. European Patent Application EP 513627 A1 19 Chem. Abstr. 1993,
18:66625.
1
. (a) Goswami, D.; Koli, M. R.; Chatterjee, S.; Chattopadhyay, S.; Sharma, A. Org.
Biomol. Chem. 2017, 15, 3756. (b) Watanabe, Y.; Shimada, N.; Anada, M.;
Hashimoto, S. Tetrahedron: Asymmetry 2014, 25, 63. (c) Fink, M. J.; Schoen, M.;
Rudroff, F.; Schnuerch, M.; Mihovilovic, M. D. ChemCatChem 2013, 5, 724. (d)
Kim, A.; Sharma, S.; Kwak, J. H.; Kim, I. S. Bull. Korean Chem. Soc. 2013, 34, 75.
(e) Winter, P.; Swatschek, J.; Willot, M.; Radtke, L.; Olbrisch, T.; Schäfer, A.;
Christmann, M. Chem. Commun. 2011, 47, 12200. (f) Yadav, J. S.; Rao, R. N.;
Kumar, B. P. R.; Ravindar, S. K.; Reddy, B. V. S.; Ghamdi, A. A. K. A. Synthesis
2
011, 3168. (g) Sabitha, G.; Bhikshapathi, M.; Yadav, J. S. Synth. Commun. 2007,
7, 559. (h ) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z.-L.; Hu, Q.; Shi, W. J. Org.
3
Chem. 2002, 67, 3802. (i) Wu, Y.; Shen, X.; Tang, C.-J.; Chen, Z.-L. Helv. Chim.
6

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Acta. 2001, 84, 3428. (j) Brenna, E.; Dei Negri, C.; Fuganti, C.; Serra, S.
Tetrahedron: Asymmetry 2001, 12, 1871.
7
. The enantiomeric excess of intermediate 5 was determined by in situ reduction with
o
NaBH at 0 C producing the corresponding diol. HPLC Chiralpak IB (250 x 4.6
4
mm), petether:EtOH (99:01) v/v, flow rate 1.0 ml/min, λmax = 220 nm, (2R, 3S) anti
isomer tr = 14.29 min, (2S, 3R) anti isomer t = 15.89 min, (2R, 3R) and (2S, 3S) syn
r
isomers t = 18.35, 19.88 min.
r
8
9
. (a) Northurp, A. B.; Mangoin I. K.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2
004, 43, 2152. (b) Smith III, Amos B.; Tomioka, T ; Risatti, C. A. ; Sperry, J. B.;
Sfouggatakis, C. Org. Lett. 2008, 10, 4359.
. (a) Tidwell, T. T. Synthesis 1990, 10, 857. (b) Tidwell, T. T. Org. React. 1990, 39,
2
97.
Figure and Scheme captions
Figure 1: Aerangis lactones
Scheme 1. Retrosynthetic route to asymmetric synthesis of δ-lactone motif and aerangis
lactones.
7

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Scheme 2. Reagents and conditions: (a)……..(e).
8

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Me
Me
Me
O
O
Me
O
O
1a (-)-trans-aerangis lactone 1b (+)-trans-aerangis lactone
Me
Me
Me
O
O
Me
O
O
1c (-)-cis-aerangis lactone
1d (+)-cis-aerangis lactone
Figure 1: Aerangis lactones

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O
*
O
*
OH
O
Me
O
*
O
*
TBDPSO
TBDPSO
*
OH
OEt
HO
*
4
1
2
3
Scheme 1. Retrosynthetic route to asymmetric synthesis of δ-lactone motif and aerangis
lactones.

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o
Scheme 2. Reagents and conditions: (a) i) (COCl) , Et N, DMSO, dry CH Cl , -78 C to rt, 3
2
3
2
2
o
h; ii) C
Ph PCHCOOEt, dry THF, rt, 24 h, 92%; (c) 10% Pd-C, H
1%; (d) i) (COCl) , Et N, DMSO, dry CH Cl
3 6
H O, 10 mol % L-Proline, dioxane, 4 C, 48 h, 84% (over two steps); (b)
3
2
(1 atm.), 3M HCl, MeOH, rt, 5h,
o
9
2
3
2
2
, -78 C to rt, 3 h; ii) KHMDS,
butyltriphenylphosphonium bromide, THF, -78 °C to rt, 3 h, 71%; (e) H
rt, 3 h, 95%.
2
, 10% Pd-C, MeOH,

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3
4x9mm (600 x 600 DPI)