Concise total synthesis of (-)-erinapyrone b from d-(+)-malic acid

Article abstract of DOI:10.1080/00397911.2013.817017

A convenient and facile enantioselective synthesis of (-)-erinapyrone B from commercially available D-(+)-malic acid has been achieved in seven steps. One of the key steps in this synthesis was the one-pot reaction of palladium(II)-mediated Wacker-type oxidative cyclization in the presence of a catalytic amount of p-toluenesulphonic acid (p-TsOH) which has been found to be effective for the preparation of enantiopure 2,3-dihydro-4H-pyran-4-one from the corresponding enantiopure β-hydroxyenone via enantio-enriched diketohydroxy intermediate.

Full text of DOI:10.1080/00397911.2013.817017

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Concise Total Synthesis of (-)-
Erinapyrone B from D-(+)-Malic Acid
Ramakrishna Samala a b , Venkateshwarlu Gurram a b , Balaram Patro
a , Narender Pottabathini a & K. Mukkanti b
a Medicinal Chemistry Division , GVK Biosciences Pvt. Ltd. ,
Hyderabad , India
b Chemistry Division , IST, Jawaharlal Nehru Technological
University , Hyderabad , India
Published online: 27 Dec 2013.
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To cite this article: Ramakrishna Samala , Venkateshwarlu Gurram , Balaram Patro , Narender
Pottabathini & K. Mukkanti (2014) Concise Total Synthesis of (-)-Erinapyrone B from D-(+)-Malic Acid,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:4, 500-506, DOI: 10.1080/00397911.2013.817017
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Synthetic Communications1, 44: 500–506, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.817017
CONCISE TOTAL SYNTHESIS OF (ꢀ)-ERINAPYRONE
B FROM D-(þ)-MALIC ACID
Ramakrishna Samala,1,2 Venkateshwarlu Gurram,1,2
Balaram Patro,1 Narender Pottabathini,1 and K. Mukkanti2
1Medicinal Chemistry Division, GVK Biosciences Pvt. Ltd.,
Hyderabad, India
2Chemistry Division, IST, Jawaharlal Nehru Technological University,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A convenient and facile enantioselective synthesis of (ꢀ)-erinapyrone B from
commercially available D-(þ)-malic acid has been achieved in seven steps. One of the
key steps in this synthesis was the one-pot reaction of palladium(II)-mediated Wacker-type
oxidative cyclization in the presence of a catalytic amount of p-toluenesulphonic acid (p-
TsOH) which has been found to be effective for the preparation of enantiopure
2,3-dihydro-4H-pyran-4-one from the corresponding enantiopure b-hydroxyenone via
enantio-enriched diketohydroxy intermediate.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2,3-Dihydro-4H-pyran-4-one; b-hydroxyenone; oxidative cyclization;
Pd-catalyzed; p-TsOH
INTRODUCTION
2,6-Disubstituted dihydropyrones are seemingly present in many natural pro-
ducts. These compounds are also important synthetic intermediates in the syntheses
of biologically active molecules.[1] Their syntheses have been well established in the
literature. For example, hetero-Diels–Alder reactions have been used to synthesize
this type of compound.[2] New strategies that have been recently developed include
the tandem aldol reaction = conjugate addition[3]and the oxidative cyclization of b-
hydroxyenenoneswith palladium(II).[4] Erinapyrone A (1) and erinapyrone B (2)
Received April 5, 2013.
Address correspondence to Balaram Patro, GVK Biosciences Pvt. Ltd., 28A, IDA, Nacharam,
Hyderabad 500076, India. E-mail: balaram.patro@gvkbio.com, b_patro30@hotmail.com
500

ERINAPYRONE-B
501
Figure 1. Natural products from Hericium erinaceummycelia.
belong to the class of 2,6-dihydroxy dihydropyrones isolated from the culture broth
of Hericium erinaceummycelia (Fig. 1) reported by Kawagishi et al., which possess
cytotoxicity toward HeLa cells.[5] The first total syntheses of optically active (ꢀ)-1
and (ꢀ)-2 were reported by Noda et al.[6] in a short route from bis-2-(1,3-
dithianyl)methane, (S)-propylene oxide, (R)-benzyl glycidyl ether, and HgCl2.[7,8]
In early 1999, Jacobsen et al. developed a palladium-mediated route for
structurally diverse 2,3-dihydro-4H-pyran-4-ones using a concerted or stepwise
hetero-Diels–Alder (HAD) reaction of aldehydes with Danishefsky’sdienes catalyzed
by various Lewis acids that led to b-hydroxyenenones. These are common precursors
for the preparation of 2,3-dihydro-4H-pyran-4-ones via Wacker-type oxidative
palladium(II)-mediated cyclization.[9] See Scheme 1.
Based on these strategies, Reiter et al. reported the synthesis of 2,3-dihydro-4-
H-pyran-4-ones using the common precursor of b-hydroxyenenones from the corre-
sponding Grignard reagent and Weinreb amide.[4] The crotyl-b-hydroxyenenones
were converted to the corresponding 2,3-dihydro-4H-pyran-4-ones via Wacker-type
oxidative palladium(II)-mediated cyclization. We are interested in a facile synthesis
of stereospecific (ꢀ)-erynopyrone B (2).We outline in this communication a versatile
Scheme 1. Methods available for the synthesis of dihydro-4H-pyran-4-ones.

502
R. SAMALA ET AL.
Scheme 2. Approaches toward the synthesis of b-hydroxyenenone via Grignard reactions. (Figure is
provided in color online.)
synthetic route of chiral erinapyrone B in seven steps from commercially available
D-(þ)-malic acid. Our approach is inspired by Reiter’s method using the formation
of b-hydroxyenenone as a key intermediate (Scheme 2). In Scheme 2, Gouverneur
and colleagues[4] reported the synthesis of crotyl-b-hydroxyenenones using crotyl-
magnesium bromide as the Grignard reagent and performed the reactions at
ꢀ40ꢁC to 0ꢁC and then achieved the 6-hydroxyheptane-2,4-diones with an ee > 97%
by Wacker oxidation using PdCl2=CuCl under oxygen atmosphere in a DME
solvent. Based on the above information, we tried to use commercially available
allylmagnesium bromide as the cost effective Grignard reagent than the crotylmag-
nesium bromide, performed the various reactions at ambient temperatures and
optimized the reaction conditions successfully to achieve the allyl-b-hydroxyene-
nones in 69% yield with an ee of 99%, which proceeded for Wacker oxidation using
PdCl2=CuCl under oxygen atmosphere in a DMF solvent. The reaction was carried
out overnight and afforded the 6-hydroxyheptane-2,4-dione (11) and was confirmed
1
by H NMR and mass spectrum analysis.
Our aim is to cyclize the 6-hydroxyheptane-2,4-dione (11) to the corresponding
dihydropyranone (10) without isolation of hydroxydiketones. We carried out the
reaction mixture to next cyclisation with the addition of p-TsOH(cat.) and contin-
ued the reaction at room temperature for 3 h. After workup, silica gel column chro-
matography afforded the erinapyrone B with an ee of 99%.
RESULTS AND DISCUSSIONS
We began with the esterification of D-(þ)-malic acid by treatment of thionyl
chloride in methanol. This resulted its dimethyl ester 5 in 90% yield.[10] The selective
reduction of 5 in presence of BH3 ꢂ Me2S and sodium borohydride in tetrahydrofuran
(THF) at rt for 3 h afforded 6 in excellent yield (90%).[11] The selective protection of 6
happened by the treatment of 1 equiv of tert-butyldiphenylsilylchloride and imidaz-
ole in dimethylformanide (DMF) resulting in ester 7 in 90% yield.[12] Reaction of 7
with N,O-dimethylhydroxylamine hydrochloride in the presence of trimethylalumi-
num provided the crystalline N-methoxy-N-methylamide 8 (70%), which on treat-
ment with exposure to allyl magnesium bromide provided the novel enone 9 in
85% yield[13] (Scheme 3).
One-pot conversion from 9 to 10 happened by oxidation of eneone 9 using
palladium(II) chloride = copper(I) chloride=oxygen in aqueous DMF[14] followed
by the treatment with p-toluenesulfonic acid (p-TsOH)[8] at room temperature for

ERINAPYRONE-B
503
Scheme 3. Synthesis of (ꢀ)-erinapyrone B. Reagents and conditions: (a) SOCl2, MeOH, rt, 18 h (95%); (b)
BH3 ꢂ Me2S, NaBH4, THF, rt, 3 h (90%); (c) TBDPSCl, imidazole, DMF, rt, 18 h (90%); (d) (MeO)-
MeNH ꢂ HCl, Al(CH3)3,CH2Cl2, reflux, 18 h (75%); (e) CH2¼CH-CH2MgBr, THF, 0 ꢁC, 2 h (85%); (f)
PdCl2, CuCl, O2, DMF=H2O, rt, 18 h; p-TsOH, rt, 3 h (60%); and (g) TBAF, THF, rt, 3 h (80%).
Scheme 4. One-pot reaction of b-hydroxyenone (9) to 2,3-dihydro-4H-pyran-4-one (10).
3 h affords dihydropyranone 10 in 60% yield with an enantiomeric excess of 99%
(Scheme 4).
Deprotection of the TBDPS group[15] of 10 with tetrabutylammonium fluoride
1
(TBAF) furnished (ꢀ)-erinapyrone B in 80% yield. H, and 13C NMR spectra of
(ꢀ)-erinapyrone B matched with the literature reported values.[5]
CONCLUSION
In conclusion, we have developed a convenient, operationally simple, and
efficient synthesis of erinapyrone B from commercially available D-(þ)-malic acid
in seven steps with 82% overall yield. The efforts to expand this work to the synthesis
of other heterocyclic compounds are under way in our laboratory.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Varian Unity instrument at rt at
400 MHz. Chemical shifts are reported in d parts per million (ppm) downfield from
tetramethylsilane (TMS) with reference to internal solvent and coupling constants in
hertz. Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR spectrometer.
Mass spectra were obtained on a high resolution Micromass QuattroMicroTM
API-autospectrometer using electraspray ionization techniques (ESI). High-
resolution mass spectrometry (HRMS) TOF ES mass spectra were recorded on a
Waters-Alliance 2695 Separation Module=Q-TOF Micromass. Optical rotations
were obtained on an automated Jasco P-1030 Polari meter. Chiral high-performance

504
R. SAMALA ET AL.
liquid chromatography (HPLC) analysis was performed by Chiralcel OJH (4.6 ꢃ
250 mm), 5 mm, and Chiralpak-IC (250 ꢃ 4.6 mm), 5 mm, columns.
General Procedure for the Synthesis of (R)-7-(tert-
Butyldiphenylsilyloxy)-6-hydroxyhept-1-en-4-one (9)
A solution of Weinreb amide 8 (1.0 g, 3.61 mmol) in 20 mL of THF was added
dropwise to a solution of ally magnesium bromide (1 M solution in THF; 9.1 mL,
9.11 mmol) at 0 ꢁC under a nitrogen atmosphere. The reaction mixture was stirred
for 2 h at room temperature, then added to aqueous 20% NH4Cl solution (10 mL)
at 0 ꢁC, and extracted with ether (2 ꢃ 25 mL). The combined organic layer was
washed with brine (10 mL), dried (MgSO4), and concentrated under reduced press-
ure. The crude product was purified by column chromatography over silica gel
(20% EtOAc in hexanes) to afford the title compound.
General Procedure for the Synthesis of (R)-7-(tert-
Butyldiphenylsilyloxy)-6-hydroxyheptane-2,4-dione (11)
A 25-mL, three-necked, round-bottomed flask was charged with a mixture of
palladium (II) chloride (35 mg, 0.2 mmol), cuprous chloride (99 mg, 1 mmol), and
aqueous DMF (DMF=H2O ¼ 7:1, 23 mL), and the reaction mixture was purged with
oxygen for 10 min. The reaction was continued under oxygen for 1 h and then
substrate 9 (0.38 g, 1 mmol) was added in DMF (2 mL) to the reaction mixture at
the same temperature. The resulting reaction mixture was stirred at room tempera-
ture for 18 h under an oxygen atmosphere, which was used for next step without
isolation. For the confirmation of compound 11, 0.2 mL of this reaction mixture
was concentrated and purified by preparative thin-layer chromatography (TLC)
using 15% EtOAc in hexanes as an eluent to afford the title compound, which was
1
confirmed by H NMR and MS.
General Procedure for the Synthesis of (R)-2-((tert-
Butyldiphenylsilyloxy)methyl)-6-methyl-2H-Pyran-4(3H)-one(10)
To this reaction mixture, p-TsOH (18 mg, 10% mol) was added and stirring was
continued at room temperature for 3 h. The reaction mixture was diluted with water
(10 mL) and extracted with ether (3 ꢃ 25 mL). The combined organic layer was
washed with brine (10 mL), dried (MgSO4), and concentrated under reduced press-
ure. The crude product was purified by column chromatography over silica gel
(15% EtOAc in hexanes) to afford the title compound.
Spectral Data for New Compounds
(R)-7-(tert-Butyldiphenylsilyloxy)-6-hydroxyhept-1-en-4-one
(9). Yield 0.79 g (85%), light yellow oil; Rf 0.5 (30% EtOAc=hexanes); IR (DCM
film) 3445, 3304, 2956, 2929, 2857, 1714, 1463, 1427, 1393, 1260, 1187, 1112, 923,
27
1
823, 741, 703 cmꢀ1; ½aꢄD þ10.91ꢁ (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) d
7.68 (m, 4H), 7.38 (m, 6H), 5.83 (m, 1H), 5.28 (m, 2H), 4.31 (s, 1H), 3.62 (d, 2H);

ERINAPYRONE-B
505
3.23 (d, 2H), 2.84 (s, 1H), 2.64 (d, 2H); 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3): d
208.2, 135.4, 133.0, 133.0, 130.0, 129.8, 127.7, 119.1, 68.1, 66.9, 48.4, 45.0, 26.8,
19.2;MS (ESI) m=z 406.12 (M þ Na)þ. HRMS calculated for C23H31O3Si [M þ Na]þ
405.1862; found 408.1877.
(R)-7-(tert-Butyldiphenylsilyloxy)-6-hydroxyheptane-2,4-dione (11). Gummy
1
liquid; Rf 0.6 (30% EtOAc=hexanes); H NMR (400 MHz, CDCl3) d 7.67 (m, 4H),
7.45 (m, 6H), 4.43 (m, 1H), 3.96 (m, 2H), 2.68 (m,1H), 2.41 (m, 1H), 2.01 (s, 3H),
1.09 (s, 9H); MS (ESI) m=z 397.26 (M þ H)þ.
(R)-2-((tert-Butyldiphenylsilyloxy)methyl)-6-methyl-2h-pyran-4(3H)-one
(10). Yield 0.22 g (60%), light yellow oil; Rf 0.35 (20% EtOAc=hexanes); IR (DCM
film) 3464, 3071, 2957, 2858, 1896, 1667, 1613, 1461, 1427, 1397, 1335, 1240, 1112,
25
1041, 903, 822, 703 cmꢀ1; ½aꢄD ꢀ91.22ꢁ (c 1.02, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.68 (m, 4H), 7.38 (m, 6H), 5.36 (s, 1H), 4.46 (m, 1H), 3.93 (m, 2H),
2.62 (m,1H); 2.36 (m, 1H), 1.95 (s, 3H); 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 192.7, 174.1, 135.5, 132.5, 132.9, 129.8, 127.7, 127.7, 116.0, 104.6, 79.2, 64.9, 37.1,
29.6, 26.7, 20.9, 19.2; MS (ESI) m=z 381.4 (M þ H)þ. HRMS calculated for
C23H29O3Si [M þ H]þ 381.1886; found 381.1891.
Supporting Information
Full experimental details, 1H and 13C NMR spectra, and chiral HPLC chroma-
tograms of all the important compounds associated with this article can be found via
the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
The authors are grateful to GVK Biosciences Pvt. Ltd. for the financial support
and encouragement. We thank Subhabrata Sen for his immense assistance.
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