Chiron approach towards optically pure γ-valerolactone from alanine

Article abstract of DOI:10.1080/00397911.2018.1491993

A concise synthesis of both enantiomers of γ-valerolactone has been developed from commercially available Alanine. The key steps in the synthesis of these γ-Lactones are DIBAL-H reduction of ester (9) followed by in situ Wittig reaction with EtO₂CCH = PPh₃ ylide (13) (Z/E = 1: 3.5) and one pot lactonization triggered by deprotection of O-TBS ether (14).

Full text of DOI:10.1080/00397911.2018.1491993

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Chiron approach towards optically pure γ³-
valerolactone from alanine
Rajender Datrika, Srinivasa Reddy Kallam, Rambabu Katta, Vidavalur
Siddaiah & T. V. Pratap
To cite this article: Rajender Datrika, Srinivasa Reddy Kallam, Rambabu Katta, Vidavalur Siddaiah
& T. V. Pratap (2018): Chiron approach towards optically pure γ³-valerolactone from alanine,
Synthetic Communications, DOI: 10.1080/00397911.2018.1491993
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https://doi.org/10.1080/00397911.2018.1491993
Chiron approach towards optically pure c3-valerolactone
from alanine
Rajender Datrikaa,b, Srinivasa Reddy Kallama, Rambabu Kattaa,
Vidavalur Siddaiahb, and T. V. Pratapa
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd,
b
Hyderabad, India; Department of Organic Chemistry and FDW, Andhra University,
Visakhapatnam, India
ABSTRACT
ARTICLE HISTORY
Received 21 March 2018
A concise synthesis of both enantiomers of c-valerolactone has been
developed from commercially available Alanine. The key steps in the
synthesis of these c-Lactones are DIBAL-H reduction of ester (9)
followed by in situ Wittig reaction with EtO2CCH ¼ PPh3 ylide (13)
(Z/E ¼ 1: 3.5) and one pot lactonization triggered by deprotection of
O-TBS ether (14).
KEYWORDS
Alanine; diazotization;
lactonization; macrolides;
c-valerolactone
GRAPHICAL ABSTRACT
Introduction
c-Lactones are important structural motifs and valuable building blocks in the synthesis
of natural products and biologically active molecules such as pheromones, polyketides,
and prostaglandins.[1] The enantiopure c-valerolactone is used as a promising chiral
starting material for the synthesis of fine chemicals, valuable intermediates & natural
products. Few examples of intermediates are chiral pentane-1,4-diol, 5-methyl-3-methyl-
enedihydrofuran-2(3H)-one and its derivatives while Phoracantholide-I (Pheromone)
and Patulolide-C (Antifungal) being some of the examples of natural products[2]
(Fig. 1).
Considering the high stereoselectivity during Wittig reaction of the corresponding
lactol of optically pure c-valerolactone, the latter becomes a very good chiral synthon in
the synthesis of natural products.[2b,c,3] A variety of methods are in practice for the syn-
thesis of optically pure c-lactones starting from c-keto esters that either use stoichiomet-
ric or catalytic chiral reagent systems[4] or enzymes as part of a greener approach for
the asymmetric hydrogenation[5] of keto function. With a lot of progress being made in
CONTACT T. V. Pratap
tvpratap@drreddys.com
Technology Development Centre, Custom Pharmaceutical
Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

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R. DATRIKA ET AL.
Figure 1. Selected application of optically pure c-valerolactones.
Figure 2. Chiral synthons.
the field of asymmetric reduction of c-keto esters using enzymes[6] it has now become
quite facile to obtain the chiral alcohols that afford chirally pure c-valerolactones in
large quantities starting from commercially viable chiral synthons. (Fig. 2).
Though various protocols reported in the literature for the stereoselective synthesis of
S-(-)-c-valerolactone (1) & R-(þ)-c-valerolactone (2),[7] our approach involves the syn-
thesis of chiral c-lactone from readily available chiral intermediate Alanine (3) or
Methyl lactate (7) in a linear and high yielding approach. The retrosynthetic approach
for the stereoselective synthesis of S- (-)-c-valerolactone (1) & R-(þ)-c-valerolactone (2)
is outlined in Scheme 1.
S-(-)-c-valerolactone (1) is synthesized by one-pot lactonization of hydroxy ester (16)
under acidic conditions that lead to deprotection of O-TBS ether (14). O-TBS ether (14)
could be obtained from the hydrogenation of E &Z mixture of a,b-ethyl ester (11). The
E &Z mixture of a,b-unsaturated ethyl ester 11 could be traced to two carbon

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3
Scheme 1. Retrosynthetic approach for S-(-)-c-Valerolactone (1) & R-(þ)-c-Valerolactone (2).
homologation of a transient aldehyde with Wittig ylide (13) while the aldehyde is obtained
after DIBAL-H reduction of chirally pure TBS protected methyl lactate (9). The compound
9 was traced from corresponding chirally pure L-Alanine (3). Diazotization of L-Alanine 3
followed by hydration affords chirally pure lactic acid (5). Esterification of 5 lead to methyl
lactate (7). Silylation of the secondary alcohol affords compound (9). Similarly, the anti-
pode R-(þ)-c-valerolactone (2) was traced from D-Alanine (4).
Results and discussion
The synthesis of S-(-)-c-valerolactone (1) & R-(þ)-c-valerolactone (2) began using com-
mercially available L-Alanine (3) and its antipode (4). The L-Alanine (3) was subjected
to diazotization as per published report[8] to yield the corresponding chirally pure lactic
acid (5). Esterification in methanol of compound 5 afforded methyl lactate (7) as men-
tioned in Scheme 2. The secondary hydroxyl group of chirally pure methyl lactate (7)
was protected as silyl ether using TBDMSCl and imidazole in DCM at room tempera-
ture.[9] (Scheme 3). The silyl protected Methyl lactate (9) obtained in the previous step
was then subjected to reduction with DIBAL-H in DCM at -78 ꢀC to yield a transient
aldehyde which was then in situ converted to a,b-unsaturated ethyl ester (11) on treat-
ment with two carbon ylide EtO2CCH ¼ PPh3 (13) in DCM at room temperature by
using Wittig protcol.[10] The a,b-unsaturated ethyl ester (11) was obtained in 86% yield

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R. DATRIKA ET AL.
Scheme 2. Reagents and conditions: (a) NaNO2, H2SO4; (b) MeOH, H2SO4, rt, 24 h.
Scheme 3. Reagents and conditions: (a) TBDMSCl/Imidazole, DCM, rt, 24 h.
Scheme 4. Reagents and conditions: (a) (i) DIBAL-H, DCM, ꢁ78 ꢀC, 2 h; (ii) EtO2CCH ¼ PPh3 (13),
rt, 24 h.
with E & Z ratio (3.5: 1) as indicated by proton NMR which was found to be in line
with the literature[11] (Scheme 4). The cis and trans mixture of a,b-unsaturated ethyl
esters (11) was subjected to hydrogenation on 10% Pd/C in ethyl acetate to afford satu-
rated ethyl ester (14) in good yield (Scheme 5).
Finally, the lactonization to afford the title compound S-(-)-c-valerolactone (1) was
affected by one pot deprotection of silyl ether of saturated ethyl ester (14) with pTSA
in MeOH at rt for 24 h. Similarly, the antipode R-(þ)-c-valerolactone (2) was traced
from D-Alanine (4) following the same synthetic sequence (Scheme 6). An equilib-
rium between lactone (1) and c-hydroxy ester intermediate (16) was observed in
methanol under acidic conditions. It shifts towards lactone (1) by removal of
methanol (Fig. 3).
Further, we have compared the enantiomeric excess of S-(-)-c-valerolactone (1) & R-
(þ)-c-valerolactone (2) synthesized starting with ethyl levulinate (18) as shown in

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Scheme 5. Reagents and conditions: (a) H2, 40 psi, Pd/C, Ethyl acetate, rt, 2 h.
Scheme 6. Reagents and conditions: (a) pTSA/MeOH, 24 h, rt.
Figure 3. Lactonization triggered by pTSA in methanol.
Scheme 7. Thus ethyl levulinate (18) on reduction with NaBH4 gave a racemic mixture
of c-hydroxyl esters (16) & (17) in ratio (1:1) (Chromatographic conditions [GC condi-
tions: Column Betadex (30 m, ꢁ01.25 mm, 0.25 mm); Temp program: 100 ꢀC (5 min Hold)
to 200 ꢀC then Ramp 5 ꢀC min ; Injector temp: 200 ꢀC, Detector temp: 210 ꢀC, Carrier
gas: Helium 2.0 mL (constant flow); Injection volume: 1.0 mL, Split ratio: 50:1; Diluent:
DCM.]). This mixture was then further lactonized to corresponding racemic c-valerolac-
tone (1) & (2) in ratio (1:1). The corresponding S-(-)-c-valerolactone (1) & R-
(þ)-c-Valerolactone (2) synthesized was analyzed in comparison with the racemate and
found to have ee > 99.62% (S-Isomer)
&
99.66% (R-Isomer), respectively
(Chromatographic conditions [HPLC Column condition: Chiralpak AD-H 250 ꢂ 4.6 mm
ꢂ5 mm; Mobile phase: n-Hexane: EtOH: TFA (950:50:0.5) % v/v; Flow rate:
0.8 mL minꢁ1, inj. vol: 10 mL, Run time: 35 min, Column temp: 10 ꢀC, wavelength:
210 nm and diluent: Mobile Phase.])

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R. DATRIKA ET AL.
Scheme 7. Reagents and conditions: (a) NaBH4, THF/MeOH, 0–5 ꢀC, 2 h, 98% Yield; (b) pTSA/MeOH,
24 h, rt, 90% Yield.
Conclusions
In conclusion, a concise and highly stereoselective synthesis of S-(-)-c-valerolactone (1)
& R-(þ)-c-valerolactone (2) with high ee has been developed from readily accessible
starting materials in good yields. The route of synthesis developed for these c-Lactones
utilize fairly inexpensive reagents and operationally friendly processes. These c-Lactones
can be utilized for the stereoselective synthesis of macrolides. The application of this
methodology for the synthesis of biologically active and complex macrolides is cur-
rently underway.
Experimental
All reagents were used as received from commercial sources without further purification
or prepared as described in the literature. Reactions were stirred using Teflon-coated
magnetic stirring bars. TLC plates were visualized by ultraviolet light or by treatment
with a spray of KMNO4, Chromatographic purification of products was carried out by
flash column chromatography on silica gel (60–120 mesh, 100–200 mesh, and 230–400
mesh). Reactions were conducted under N2 in anhydrous solvents such as DCM, THF,
Toluene, and EtOAc. All reactions were monitored by TLC (silica-coated plates and
visualized under UV light, in case of non UV-active intermediates used suitable char-
ring solution). Yields refer to the isolation of compounds after chromatography and
spectroscopic (1 H and 13 C NMR) analysis of the homogeneous material. Air-sensitive
reagents were transferred by syringe or a double-ended needle. Evaporation of the sol-
vents was performed at reduced pressure on a Buchi rotary evaporator. 1 H and 13 C
NMR spectra were recorded in CDCl3 solution on a Varian Gemini 200 and Brucker
Avance 300 spectrometers. Chemical shifts (d) are reported relative to TMS (d ¼ 0.0) as

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7
an internal standard. Mass spectra were obtained on GC-Ms, HRMS mass spectrometers
of Agilent Technologies 1100 Series. Column chromatography was performed on silica
gel (60–120 mesh) supplied by Acme Chemical, India. TLC was performed on Merck
60 F-254 silica gel plates. IR (FT-IR) spectra were recorded either on KBr pellets or neat
as a thin film or in CHCl3. Optical rotations were recorded on a JASCO DIP–360
digital polarimeter.
Synthesis of (ethyl (S)-4-((tert-butyldimethylsilyl)oxy)pentanoate (14)
To a solution of 11 (13 g, 0.050 mole) in ethyl acetate (130 mL) was added 10% Pd/C
(50% wet) and hydrogenated for 2 h at rt with 40 psi, after completion of reaction as
indicated by TLC, the catalyst was separated by filtration and solvent was evaporated to
afford (14). Output: 12.35 g, Yield: 95%. Similarly, compound (15) was synthesized by
using above procedure from antipode (12), Output: 12.22 g, Yield: 94%.
25
Colorless oil; S-Isomer (14): [a]D ¼ þ19.63ꢀ (c 2.0, CHCl3); R-Isomer (15):
25
[a]D ¼ ꢁ19.93ꢀ (c 2.0, CHCl3); IR (Neat): 2957, 2934, 2859, 2894, 1738, 836,
1
776 cmꢁ1; H NMR (400 MHz, CDCl3): d 4.09 (q, J ¼ 6.9 & 14.2 Hz, 2H), 3.81 (m, 1H),
2.32–2.38 (m, 2H), 1.67–1.76 (m, 2H), 1.23 (t, J ¼ 6.9 Hz, 3H), 1.12 (d, J ¼ 5.9 Hz, 3H),
0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13 C NMR (100 MHz, CDCl3): d ꢁ 4.45, ꢁ4.89,
14.19, 18.00, 23.64, 25.81, 30.39, 34.35, 60.15, 67.40, 173.84. HRMS: Calcd. for
C13H29O3Si þ H: 261.1886, found: 261.1888.
Synthesis of S-(-)-c–valerolactone (1)
The (ethyl (S)-4-((tert-butyldimethylsilyl) oxy)pentanoate (14) (10 g, 0.038 mole) was
treated with pTSA (0.1g) in anhydrous methanol (100 mL) at rt for 24 h, solvent was
evaporated and codistilled with MTBE (50 mL). The crude residue obtained was diluted
with MTBE (100 mL) and washed with sat. NaHCO3 (240 mL), the solvent was removed
under reduced pressure and crude residue was further purified by fractional distillation
to afford S-(-)-c–Valerolactone (1) Output: 3.45 g yield: 90%. Similarly, R-
(þ)-c–Valerolactone (2) was synthesized by using above procedure, Output: 3.34 g,
Yield: 87%.
22
Colorless oil; S-Isomer (1): [a]D ¼ ꢁ37.79ꢀ (c 1.0, MeOH); R-Isomer (2):
22
[a]D ¼ þ37.05ꢀ (c 1.0, MeOH); IR (Neat): 2980, 2937, 1770, 1386, 1344, 1174, 1056,
1
942, 896 cmꢁ1; H NMR (400 MHz, CDCl3): d ¼ 1.41 (d, J ¼ 6.4 Hz, 3H), 1.78-1.88 (m,
1H), 2.09 ꢁ 2.40 (m, 1H), 2.53 ꢁ 2.57 (m, 2H), 4.62 (m, 1H) ppm; 13 C NMR (100 MHz,
CDCl3): d ¼ 20.79, 28.85, 29.44, 77.09, 177.14 ppm; GC-Ms: (100, Mþ).
Acknowledgments
The authors would like to thank Dr. H. Rama Mohan and Dr. Reddy’s Laboratories for the sup-
port and encouragement. They also would like to thank analytical department of Dr. Reddy’s
Laboratories Ltd. for providing analytical support.

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R. DATRIKA ET AL.
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