Highly diastereoselective total syntheses of (+)-7-epigoniodiol, (-)-8-epigoniodiol, and (+)-9-deoxygoniopypyrone

Article abstract of DOI:10.1002/hlca.201200368

An expedient concise total synthesis of (+)-7-epigoniodiol, (-)-8-epigoniodiol, and (+)-9-deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and base-mediated N-(acetyl)oxazolidinone addition reactions, which cou

Full text of DOI:10.1002/hlca.201200368

1366
Helvetica Chimica Acta – Vol. 96 (2013)
Highly Diastereoselective Total Syntheses of (þ)-7-Epigoniodiol, (ꢀ)-8-
Epigoniodiol, and (þ)-9-Deoxygoniopypyrone
by Gullapalli Kumaraswamy* and Rangaraju Satish Kumar
Organic & Biomolecular Division, Indian Institute of Chemical Technology, Hyderabad-500 607, India
(phone: þ 91-40-27193154; fax: þ 91-40-27193275; e-mail: gkswamy_iict@yahoo.co.in)
An expedient concise total synthesis of (þ)-7-epigoniodiol, (ꢀ)-8-epigoniodiol, and (þ)-9-
deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and
base-mediated N-(acetyl)oxazolidinone addition reactions, which could set the consecutive OH motif
that is either syn,syn or syn,anti with high diastereoselectivity. Moreover, this approach envisioned to
facilitate the synthesis of other representatives of the family with structural and stereochemical variation.
Introduction. – Bioactivity-guided studies on the constituents of the Asian trees of
the genus Goniothalamus led to the isolation of a number of therapeutic agents which
exhibited significant cytotoxicities against several solid tumor lines in addition to
antifungal, antibiotic properties [1]. The common sub-structural units found in these
bioactive compounds are depicted in Fig. 1 [2].
Fig. 1. Bioactive 6-(1,2-dihydroxy-2-phenylethyl)pyran-2-one, furano-2-pyrone, furo[3,2-b]furan-2-one,
and methano-1,5-dioxocan-2-one compounds
Among them, the most exploited natural products were (2-phenylethyl)pyran-2-
ones owing to their selective and remarkable cytotoxicities against human lung
carcinoma cell lines A-549 (ED50 0.122 mg mlꢀ1) [3], HL-60 cells [4], and P-388 murine
leukemia cells (IC50 4.56 mg mlꢀ1) [5]. Furthermore, it was established that the
biological profile of these pyran-2-ones profoundly depends on the relative config-
uration of contiguous stereogenic centers. By virtue of significant activities of these
molecules, impressive synthetic strategies have been reported. To date, most strategies
rely on generation of chirality resulting from chiral synthons [6], asymmetric
epoxidation [7], asymmetric alkoxyallylboration [8], proline-catalyzed aminoxylation
[9], and chemoenzymatic synthesis [10]. Analysis of existing synthetic strategies of (2-
phenylethyl)pyran-2-ones reveal that they lack in flexibility in terms of chemical
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 96 (2013)
1367
modification as well as suffer from moderate diastereoselectivities due to poor
stereocontrol of substrate or reagent.
Results and Discussion. – In the course of our program aiming at developing
flexible approaches for synthesizing different stereoisomers of biologically active small
molecules [11], herein, we report an alternative highly diastereoselective strategy for
the syntheses of (þ)-7-epigoniodiol, (ꢀ)-8-epigoniodiol, and (þ)-9-deoxygoniopypyr-
one by means of catalytic asymmetric hydroxylation, base-mediated chiral aldol
reaction and ring-closing metathesis [12] as key steps. Our retrosynthetic analysis is
delineated in Scheme 1.
Scheme 1. Retrosynthetic Analysis of Target Molecule
Initially, we envisaged to secure 5,6-dihydro-2H-pyran-2-one ring-closing meta-
thesis (RCM) of homoallylic tethered ester with acrylate 5. Then, two of three
stereogenic centers in 1a, the C(6) and C(7), were expected to arise from highly
diastereoselective base-mediated chiral aldol reaction of 1-acetyloxazolidin-2-one 8d
to duly protected aldehyde 7. The syn-dihydroxy moiety was anticipated to be
generated through a asymmetric hydroxylation of methyl cinnamate 9 employing a
respective chirality-inducing ligand (Scheme 1).
Accordingly, methyl cinnamate (9) was subjected to asymmetric hydroxylation with
hydroquinidine phthalazine-1,4-diyl diether (¼(DHQD)2PHAL) and subsequent
protection of the resulting diol with 2,2-dimethoxypropane under acidic conditions
leading to 10 in 80% yield with 99% enantiomer purity. A two-step sequence of
reduction, followed by oxidation, furnished aldehyde 7 in 56% yield [13] (Scheme 2).
With access to aldehyde 7, we intended to explore the asymmetric aldol addition
reaction. At the outset, we aimed at the evaluation of the stereochemical outcome of
substrate-induced diastereoselectivity employing lithium enolate of AcOEt, 8a. Thus,
the reaction with 7 at ꢀ 788 led to the desired product 6a with poor dr in 80% yield
(Table, Entry 1). On the other hand, considerable improvement in dr was observed

1368
Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 2. Synthesis of Chiral Aldehyde 7
replacing the enolate of 8a by the lithum enolate of 1-acetyloxazolidinone, 8b, under
similar conditions (Table, Entry 2). As well, employing the enolate of N,O-dimethyl-
hydroxylacetamide, 8c, in the reaction with 7 did not improve the dr of 6c (Table,
Entry 3).
Eventually, the addition of the lithium enolate of 1-acetyloxazolidinone, 8d, [14] to
aldehyde 7 resulted in the required compound 6d in > 99% diastereomeric purity with
good yield1) [15] (Table, Entry 4), whereas the enolate of sultam 8e led to a diminished
dr with 70% yield (Table, Entry 5).
The high diastereoselectivity of the formation of 6d could be rationalized on the
basis of a six-membered chelate of the closed transition state B* (Zimmermanꢀ
Traxler) in which the R and Xc groups are in antiperiplanar position, and the
diastereoface of the aldehyde efficiently shield by the benzyl moiety of the chiral
auxiliary. In the case of 6a, 6b, and 6c, due to the lower energy barrier between A* and
B* transition states (Fig. 2), the minor conformer also leads to product, hence the
lower diastereoselectivity was observed.
Fig. 2. Transition states of Li-enolate addition to aldehyde 7
1
)
The anti/syn diastereoisomers were separated by CC (SiO2; hexane/AcOEt). The enantioselectivity
and relative configuration of the major compounds 6d and 17 were determined on the basis of
optical rotation value of final products 1a and 1b, respectively.

Helvetica Chimica Acta – Vol. 96 (2013)
1369
Table. Additions of Various Acyl Enolates to Chiral Aldehyde 7
Entry
8
A*
Conditions
6b) drc)
Yield [%]
1
2
3
4
5
8a EtO
8b 2-Oxo-1,3-oxazolidin-3-yl
8c Methoxy(methyl)amino
LDAa), THF, ꢀ 788, 2 h 6a 3 : 2
80
80
75
LDA, THF, ꢀ 788, 4 h
LDA, THF, ꢀ 788, 3 h
6b 4 : 1
6c 4 : 1
8d (4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl LDA, THF, ꢀ 788, 4 h
6d > 99 80
6e > 4 : 1 70
8e (3aS,6S)-Tetrahydro-8,8-dimethyl-
2,2-dioxido-3a,6-methano-
LDA, THF, ꢀ 788, 4 h
2,1-benzothiazol-1(3H,4H)-yl
a) Lithium diisopropylamide (LiN(i-Pr)2). b) Yields of isolated products. c) Diastereoisomer ratio
determined by 1H-NMR.
Methanolysis of enantiomerically pure 6d with MeOLi (BuLi þ MeOH, 08, THF)
provided 12 in 82% yield, and subsequent protection of secondary alcohol (tBu(Me)2-
SiCl, 1H-imidazole, CH2Cl2, r.t.) led to 13 (90%). Next, the ester was converted to the
aldehyde, followed by olefination, resulting in the protected homoallylic alcohol 14
(90%). Fluoride ion induced deprotection of the silyl ether and subsequent reaction of
the resulting secondary alcohol with acryloyl chloride under basic conditions furnished
5 in 69% yield (Scheme 3).
Finally, RCM led to the target compound 1a in 71% yield. The spectroscopic data
and specific rotation of 1a are in full agreement with those reported in the literature
([a]2D0 ¼ þ85.0 (c ¼ 0.3, MeOH); [15]: [a]2D0 ¼ þ85.4 (c ¼ 0.3, MeOH)).
Under similar conditions, the reaction between ent-aldehyde 7 and 8d resulted in 17
(60% yield), but in low diastereoselectivity (8 :2)1). This could be rationalized on the
basis of mismatched effect as evident in enol additions to aldehydes. Further, the amide
was transformed to the methyl ester, followed by protection with TBDMSCl, to give 19
(70% over two steps). Reduction of the ester to the aldehyde, followed by Wittig
olefination, led to 20. Removal of the protecting group and subsequent reaction with
acryloyl chloride gave 22 in 71% yield. Exposure of 22 to RCM, followed by acid-
mediated isomerization, resulted in the isomer 8-epigoniodiol (1b) in 71% yield.
Finally, DBU-catalyzed intramolecular addition of 1b led 9-deoxygoniopypyrone (4) in
86% yield (Scheme 4). The analytical data of 1b and 4 were in full agreement with the
data reported for the natural product [3][5].
Conclusions. – We succeeded in developing a unified stereochemical diversity-
oriented synthesis for styryl lactones, a class of natural products. The consecutive OH
motif that is either syn,syn or syn,anti was generated with high stereocontrol and a

1370
Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 3. Synthesis of the Target Molecule. DIBAL-H, Diisobutylaluminium hydride; TBAB, Bu4NF.
predictable relative configuration through a catalytic hydroxylation and base-mediated
1-acetyloxazolidinone addition reactions. Employing the key reaction, followed by
application of established chemistry, could allow skeletal and stereogenic diversity,
which can generate a library of analogs. Research on further applications of this
strategy for the synthesis of biologically active compounds bearing a OH motif is
underway.
Experimental Part
General. All reactions were conducted under N2 (IOLAR Grade I). Glassware used for reactions
were oven-dried, and THF was distilled over sodium benzophenone ketyl before use. All other chemicals
used were commercially available. Progress of the reactions was monitored by TLC on precoated Silica
Gel 60 F-254 plates. Evaporation of solvents was performed at reduced pressure on a rotary evaporator.
Column chromatography (CC): silica gel, grade 60 – 120, or 100 – 200 mesh. Optical rotations: Horiba
high-sensitive polarimeter; 10-mm cell. IR Spectra: Thermo-Nicolet-FT/IR-5700 instrument; ˜n in cmꢀ1
.
1H- and 13C-NMR Spectra: Varian 200 and 500, Bruker 300 and 400, at 300, 400, and 500 MHz (1H), and
75 or 100 MHz (13C); in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. ESI- and HR-MS:
quadrupole time-of-flight (QTOF) mass spectrometer QSTAR XL (Applied Biosystems MDSSciex,
Foster City, USA); in m/z.
(4R)-4-Benzyl-3-{(3R)-3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]-3-hydroxypropanoyl}-
1,3-oxazolidin-2-one (6d). Anh. THF (24 ml) was introduced into a 250-ml flask under inert atmosphere,

Helvetica Chimica Acta – Vol. 96 (2013)
1371
Scheme 4. Synthesis of 9-Deoxygoniopypyrone (4). DBU, 1,8-Diazabicycloundec-7-ene.
and iPr2NH (4.8 mmol) and BuLi (1.6m/hexane, 4.4 mmol) were sequentially added at ꢀ 788. Thereafter,
a THF soln. (24 ml) of (4R)-3-acetyl-4-benzyl-1,3-oxazolidin-2-one (8d; 876 mg, 4.0 mmol) was added
over 30 min, and the resulting soln. was stirred for another 10 min. Then, a THF soln. (40 ml) of (4S,5R)-
2,2-dimethyl-5-phenyl-1,3-dioxolane-4-carbaldehyde (7; 865 mg, 4.4 mmol) was added during 2 h with
syringe pump at ꢀ 788. The resulting mixture was stirred further for 4 h at the same temp., followed by
quenching the reaction with sat. aq. NH4Cl soln. The aq. layer was extracted with CH2Cl2 (3 ꢁ 60 ml), and
the combined org. layers were dried (Na2SO4). Removal of the solvent under reduced pressure gave a
crude residue, which was purified by CC (hexane/AcOEt 7:3) to give 6d (1.5 g, 80%). Colorless liquid.
[a]2D4 ¼ þ3.0 (c ¼ 0.9, CHCl3). IR (KBr): 3420, 2969, 2924, 1739, 1452, 1368, 1215, 1058, 760, 700, 681.
1H-NMR (300 MHz, CDCl3): 7.54 – 7.13 (m, 10 H); 4.99 (d, J ¼ 7.9, 1 H); 4.62 – 4.53 (m, 1 H); 4.39 – 4.31
(m, 1 H); 4.22 – 4.02 (m, 3 H); 3.30 – 3.14 (m, 3 H); 2.98 (br. s, 1 H); 2.76 (dd, J ¼ 12.8, 9.8, 1 H); 1.56 (s,
3 H); 1.51 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 171.7; 153.2; 138.3; 134.9; 129.3; 129.0; 128.4; 128.2;
127.4; 109.5; 84.2; 80.4; 68.3; 66.2; 55.0; 39.0; 37.7; 29.6; 27.3; 27.0. ESI-MS: 448 ([M þ Na]þ). HR-ESI-
MS: 448.1715 ([M þ Na]þ, C24H27NNaO6þ ; calc. 448.1736).
Methyl (3R)-3-[(4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-3-hydroxypropanoate (12). BuLi
(1.6m/hexane, 4.4 mmol) and MeOH (2 ml) was added sequentially to anh. THF (16 ml) at 08. Then, a
THF (15 ml) soln. of 6d (1.25 g, 2.94 mmol) was added, and the resulting mixture was stirred for 1 h.
Then, the reaction was quenched with sat. aq. NH4Cl soln., and the resulting slurry was extracted with
CH2Cl2 (3 ꢁ 30 ml). The combined org. layers were dried (Na2SO4). The solvent was removed under
reduced pressure to give a crude residue, which was purified by CC (hexane/AcOEt 7:3) to yield 12

1372
Helvetica Chimica Acta – Vol. 96 (2013)
(674 mg, 82%). Colorless liquid. [a]2D4 ¼ ꢀ4.5 (c ¼ 0.9, CHCl3). IR (KBr): 3464, 2924, 253, 1738, 1439,
1215, 1165, 1062, 887, 758, 700. 1H-NMR (300 MHz, CDCl3): 7.41 – 7.20 (m, 5 H); 4.88 (d, J ¼ 8.1, 1 H);
4.19 – 4.11 (m, 1 H); 3.85 (dd, J ¼ 8.1, 5.6, 1 H); 3.59 (s, 3 H); 2.95 (br. s, 1 H); 2.53 – 2.38 (m, 2 H); 1.47 (s,
3 H); 1.41 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 172.8; 138.4; 128.5; 12.2; 127.2; 109.5; 84.4; 80.4; 68.5;
51.8; 37.3; 29.6; 27.2; 27.0. ESI-MS: 303 ([M þ Na]þ). HR-ESI-MS: 303.1219 ([M þ Na]þ, C15H20NaO5þ ;
calc. 303.1208).
Methyl (3R)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-3-[(4S,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-
yl]propanoate (13). To a stirred soln. of 12 (630 mg, 2.25 mmol) in CH2Cl2 (15 ml) at 08 was added
1H-imidazole (204 mg, 3 mmol) and 4-(dimethylamino)pyridine (DMAP; cat.). tBuMe2SiCl
(TBDMSCl; 3 mmol) dissolved in CH2Cl2 was added, and the resulting soln. was stirred at r.t. for 4 h.
Then, H2O (20 ml) was added to the mixture, and the aq. layer was extracted with AcOEt (3 ꢁ 30 ml),
dried, and filtered. The org. layer was evaporated under reduced pressure to give a crude residue, which
was purified by CC (hexane/AcOEt 9 :1) to give 13 (800 mg, 90%). Colorless liquid. [a]2D4 ¼ þ12.0
(c ¼ 0.9, CHCl3). IR (KBr): 3033, 2986, 2858, 2113, 1694, 1374, 1253, 1065, 836, 778. 1H-NMR (300 MHz,
CDCl3): 7.45 – 7.29 (m, 5 H); 4.86 (d, J ¼ 8.1, 1 H); 4.45 – 4.36 (m, 1 H); 3.98 (dd, J ¼ 8.1, 2.8, 1 H); 3.60 (s,
3 H); 2.48 – 2.27 (m, 2 H); 1.52 (s, 3 H); 1.49 (s, 3 H); 0.84 (s, 9 H); 0.02 (s, 3 H); 0.01 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 171.7; 138.2; 128.5; 128.3; 127.3; 109.1; 85.5; 79.0; 68.3; 51.5; 39.1; 27.2; 25.4; 17.9;
ꢀ 4.4; ꢀ 5.0. ESI-MS: 417 ([M þ Na]þ). HR-ESI-MS: 417.2075 ([M þ Na]þ, C21H34NaO5Siþ; calc.
417.2073).
(tert-Butyl)({(1R)-1-[(4S,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-yl}oxy)dimethyl-
silane (14). Compound 13 (680 mg, 1.72 mmol) was dissolved in toluene (15 ml), and the soln. was cooled
to ꢀ 788. Then, DIBAL-H (1.18 ml, 1.6m in toluene, 1.89 mmol) was added, and the resulting mixture was
stirred at the same temp. After 2 h, the reaction was quenched with sat. aq. potassium sodium tartarate.
The resulting mixture was diluted with AcOEt and stirred vigorously at r.t. until the layers became clear.
The org. layer was separated and washed with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure to give the crude aldehyde. To a separate flask, (methyl)(triphenyl)phosphonium
t
iodide (964 mg, 2.41 mmol) and BuOK (195 mg, 1.76 mmol) was added. To this, dry THF (10 ml) was
added while stirring, and stirring was continued further for 4 h at r.t. Stirring was stopped, and the solid
was allowed to settle, the clear supernant orange-yellow liquid was then cannulated into the THF (5 ml)
soln. of the above crude aldehyde (600 mg, 1.6 mmol) at 08. Then, the mixture was stirred at the same
temp. for 15 min. The reaction was quenched with aq. sat. NH4Cl, and the mixture was extracted with
AcOEt (3 ꢁ 30 ml). The org. layer was removed under reduced pressure to give a crude residue, which
was purified by CC (hexane/AcOEt 9 :1) to yield 14 (540 mg, 90%). Colorless liquid. [a]2D4 ¼ þ7.5 (c ¼
1
0.9, CHCl3). IR (KBr): 3074, 2934, 2860, 1637, 1447, 1374, 1246, 1063, 833, 769. H-NMR (300 MHz,
CDCl3): 7.44 – 7.22 (m, 5 H); 5.56 (m, 1 H); 4.98 – 4.83 (m, 2 H); 4.60 (d, J ¼ 17.1, 1 H); 3.99 – 3.87 (m,
2 H); 2.22 – 1.89 (m, 2 H); 1.49 (s, 3 H); 1.47 (s, 3 H); 0.91 (s, 9 H); 0.07 (s, 3 H); 0.06 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 134.0; 133.8; 133.6; 128.7; 128.5; 128.4; 128.2; 127.7; 117.4; 108.5; 84.2; 78.5; 71.0; 38.8;
27.4; 27.3; 25.9; 18.1; ꢀ 4.3; ꢀ 4.6. ESI-MS: 385 ([M þ Na]þ). HR-ESI-MS: 385.2175 ([M þ Na]þ,
C21H34NaO3Siþ; calc. 385.2175).
(1R)-1-[(4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-ol (15). To a cooled (08) soln.
of THF (10 ml) containing 14 (500 mg, 1.38 mmol), Bu4NF (1.51 ml, 1m in THF, 1.51 mmol) was added,
and the mixture was stirred for 2 h at r.t. The reaction was quenched with H2O (3 ml), and the mixture
was extracted with AcOEt (3 ꢁ 30 ml). The solvent was removed under reduced pressure to give a
residue, which was purified by CC (hexane/AcOEt 6 :4) to yield pure 15 (320 mg, 93%). Colorless liquid.
[a]2D4 ¼ þ2.0 (c ¼ 0.9, CHCl3). IR (KBr): 3457, 3035, 2985, 2929, 1640, 1375, 1236, 1058, 806, 757, 699.
1H-NMR (300 MHz, CDCl3): 7.45 – 7.24 (m, 5 H); 5.74 – 5.59 (m, 1 H); 4.97 – 4.95 (m, 2 H); 4.86 (dd, J ¼
17.1, 1.5, 1 H); 3.91 – 3.83 (m, 2 H); 2.17 – 2.12 (m, 2 H); 2.02 (br. s, 1 H); 1.54 (s, 3 H); 1.49 (s, 3 H).
13C-NMR (75 MHz, CDCl3): 133.8; 128.4; 128.3; 127.6; 126.8; 118.2; 109.0; 84.6; 79.3; 70.4; 37.2; 27.2; 27.0.
ESI-MS: 271 ([M þ Na]þ). HR-ESI-MS: 271.1312 ([M þ Na]þ, C15H20NaOþ3 ; calc. 271.1310).
(1R)-1-[(4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-yl Prop-2-enoate (5). To a
stirred CH2Cl2 (8 ml) soln. containing 15 (300 mg, 1.2 mmol) was added Et3N (0.186 ml, 1.34 mmol),
followed by acryloyl chloride (0.116 ml, 1.44 mmol) at 08, and the mixture was stirred for 2 h at the same
temp. Then, the reaction was quenched with sat. aq. NaHCO3 soln., and the mixture was extracted with

Helvetica Chimica Acta – Vol. 96 (2013)
1373
AcOEt (3 ꢁ 15 ml). The combined org. layers were washed with H2O, dried (Na2SO4), and filtered.
Solvent was removed under reduced pressure to give a crude residue, which was purified by CC (hexane/
AcOEt 8 :2) to give 5 (270 mg, 74%). Colorless liquid. [a]2D4 ¼ þ40.0 (c ¼ 0.9, CHCl3). IR (KBr): 2961,
2925, 1730, 1631, 1407, 1260, 1025, 802, 697. 1H-NMR (300 MHz, CDCl3): 7.36 – 7.23 (m, 5 H); 6.23 – 6.14
(m, 1 H); 5.95 – 5.83 (m, 1 H); 5.73 – 5.55 (m, 2 H); 5.26 – 5.17 (m, 1 H); 4.99 – 4.80 (m, 3 H); 3.99 (dd,
J ¼ 6.2, 8.1, 1 H); 2.46 – 2.21(m, 2 H); 1.50 (s, 3 H); 1.42 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 137.7;
132.7; 131.2; 128.5; 128.4; 127.9; 127.5; 118.2; 109.6; 82.8; 80.7; 72.5; 35.6; 29.7; 27.2; 26.8. ESI-MS: 325
([M þ Na]þ). HR-ESI-MS: 325.1419 ([M þ Na]þ, C18H22NaOþ4 ; calc. 325.1416).
(6R)-6-[(4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5,6-dihydro-2H-pyran-2-one (16). Com-
pound 5 (250 mg, 0.82 mmol) was dissolved in dry CH2Cl2 (8 ml), and Grubbs (second generation)
catalyst was added (reflux for 2 h). Then, the solvent was removed under reduced pressure to give a
residue, which was purified by CC (hexane/AcOEt 8 :2) to yield pure 16 (180 mg, 69%). Colorless liquid.
[a]2D4 ¼ þ58.2 (c ¼ 0.9, CHCl3). IR (KBr): 2922, 2854, 1728, 1629, 1458, 1378, 1248, 1075. 1H-NMR
(300 MHz, CDCl3): 7.48 – 7.30 (m, 5 H); 6.93 – 6.85 (m, 1 H); 6.04 – 5.97 (m, 1 H); 4.99 (d, J ¼ 7.7, 1 H ) ;
4.60 – 4.51 (m, 1 H); 4.12 (dd, J ¼ 7.7, 5.4, 1 H); 2.60 – 2.42 (m, 2 H); 1.58 (s, 3 H); 1.52 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 162.9; 144.6; 137.8; 128.6; 128.5; 127.0; 121.4; 110.2; 83.0; 80.5; 77.4; 27.2; 27.0; 25.6.
ESI-MS: 297 ([M þ Na]þ). HR-ESI-MS: 297.1103 ([M þ Na]þ, C16H18NaOþ4 ; calc. 297.1103).
(þ)-7-Epigoniodiol (¼(6R)-6-[(1S,2R)-1,2-Dihydroxy-2-phenylethyl]-5,6-dihydro-2H-pyran-2-one;
1a). Pyranone 16 (150 mg, 0.54 mmol) was dissolved in 50% aq. AcOH (10 ml) and heated at 808 for 1 h.
H2O (20 ml) was added, the mixture was extracted with AcOEt, and the org. layer washed with sat.
NaHCO3 soln. The org. solvent was removed under vacuum, and the resulting residue was purified by CC
(hexane/AcOEt 2 :8) to yield 1a (90 mg, 70%). Colorless liquid. [a]2D0 ¼ þ85.0 (c ¼ 0.3, MeOH); [15]:
[a]2D0 ¼ þ85.4 (c ¼ 0.3, MeOH). IR (KBr): 3448, 2924, 1704, 1629, 1391, 1261, 1081, 1029, 808, 710.
1H-NMR (300 MHz, CDCl3): 7.38 – 7.31 (m, 5 H); 6.93 – 6.91 (m, 1 H); 6.00 (dd, J ¼ 9.7, 1.0, 1 H); 4.90 (d,
J ¼ 4.1, 1 H); 4.42 – 4.38 (m, 1 H); 3.95 – 3.93 (m, 1 H); 2.83 (br. s, 1 H); 2.80 (br. s, 1 H); 2.61 – 2.59 (m,
1 H); 2.49 (ddd, J ¼ 18.8, 5.2, 4.9, 1 H). 13C-NMR (75 MHz, CDCl3): 163.8; 145.6; 140.1; 128.7; 126.4;
120.9; 77.3; 76;1; 71.9; 24.9. ESI-MS: 257 ([M þ Na]þ). HR-ESI-MS: 257.0796 ([M þ Na]þ, C13H14NaO4þ ;
calc. 257.0790).
(4R)-4-Benzyl-3-{(3R)-3-[(4S,5S)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]-3-hydroxypropanoyl}-
1,3-oxazolidin-2-one (17). Yield: 60%. Colorless liquid. [a]2D4 ¼ þ5.0 (c ¼ 0.9, CHCl3). IR (KBr): 3420,
2969, 2924, 1739, 1452, 1368, 1215, 1058, 760, 700, 681. 1H-NMR (300 MHz, CDCl3): 7.54 – 7.15 (m, 10 H);
5.00 (d, J ¼ 8.0, 1 H); 4.69 – 4.62 (m, 1 H); 4.40 – 4.33 (m, 1 H); 4.25 – 4.00 (m, 3 H); 3.30 – 3.12 (m, 3 H);
2.94 (br. s, 1 H); 2.69 (dd, J ¼ 13.0, 10.0, 1 H); 1.56 (s, 3 H); 1.51 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
171.8; 153.2; 138.5; 135.1; 129.3; 128.9; 128.5; 128.2; 127.3; 109.6; 84.5; 80.5; 77.4; 77.0; 76.5; 68.5; 66.3;
55.0; 38.9; 37.8; 27.3; 27.0. ESI-MS: 448 ([M þ Na]þ). HR-ESI-MS: 448.1715 ([M þ Na]þ, C24H27NNaO6þ ;
calc. 448.1736).
Methyl (3R)-3-[(4S,5S)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-3-hydroxypropanoate (18). Yield:
87%. Colorless liquid. [a]2D4 ¼ þ7.5 (c ¼ 0.9, CHCl3). IR (KBr): 3464, 2924, 253, 1738, 1439, 1215, 1165,
1062, 887, 758, 700. 1H-NMR (300 MHz, CDCl3): 7.25 – 7.15 (m, 5 H); 5.02 (d, J ¼ 7.7, 1 H); 4.29 – 4.23 (m,
1 H); 3.91 (dd, J ¼ 7.7, 5.8, 1 H); 3.53 (s, 3 H); 3.05 (br. s, 1 H); 2.37 – 2.27 (m, 2 H); 1.56 (s, 3 H); 1.54 (s,
3 H). 13C-NMR (75 MHz, CDCl3): 166.4; 136.7; 128.5; 126.8; 110.1; 84.3; 79.6; 65.1; 52.0; 29.6; 27.2; 26.9.
ESI-MS: 303 ([M þ Na]þ). HR-ESI-MS: 303.1219 ([M þ Na]þ, C15H20NaOþ5 ; calc. 303.1208).
Methyl (3R)-3-{[(tert-Butyl)(dimethyl)silyl]oxy}-3-[(4R,5S)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-
yl]propanoate (19). Yield: 85%. Colorless liquid. [a]2D4 ¼ þ11.1 (c ¼ 0.9, CHCl3). IR (KBr): 3033, 2986,
2858, 2113, 1694, 1374, 1253, 1065, 836, 778. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.27 (m, 5 H); 4.82 (d, J ¼
8.3, 1 H); 4.40 – 4.31 (m, 1 H); 3.90 (dd, J ¼ 8.3, 4.5, 1 H); 3.64 (s, 3 H); 2.57 (dd, J ¼ 15.8, 4.5, 1 H); 2.39
(dd, J ¼ 15.8, 7.5, 1 H); 1.52 (s, 3 H); 1.48 (s, 3 H); 0.78 (s, 9 H); 0.04 (s, 3 H); – 0.05 (s, 3 H). 13C-NMR
(75 MHz, CDCl3): 171.7; 138.1; 128.5; 128.2; 127.5; 109.0; 84.7; 79.1; 69.0; 51.4; 38.8; 29.7; 27.2; 27.0; 25.7;
18.0; ꢀ 4.5; ꢀ 5.1. ESI-MS: 417 ([M þ Na]þ). HR-ESI-MS: 417.2075 ([M þ Na]þ, C21H34NaO5Siþ; calc.
417.2073).
(tert-Butyl)({(1R)-1-[(4R,5S)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-yl}oxy)dimethyl-
silane (20). Yield: 87%. Colorless liquid. [a]D24 ¼ þ4.4 (c ¼ 0.9, CHCl3). IR (KBr): 3074, 2934, 2860, 1637,
1447, 1374, 1246, 1063, 833, 769. 1H-NMR (300 MHz, CDCl3): 7.38 – 7.23 (m, 5 H); 5.73 – 5.63 (m, 1 H);

1374
Helvetica Chimica Acta – Vol. 96 (2013)
4.97 – 4.83 (m, 3 H); 3.84 (dd, J ¼ 8.0, 4.0, 1 H); 3.80 – 3.75 (m, 1 H); 2.43 – 2.35 (m, 1 H); 2.21 – 2.13 (m,
1 H); 1.51 (s, 3 H); 1.48 (s, 3 H); 0.85 (s, 9 H); 0.07 (s, 3 H); 0.02 (s, 3 H). 13C-NMR (75 MHz, CDCl3):
138.3; 134.5; 128.4; 128.1; 127.4; 126.3;117.3; 108.7; 84.5; 79.0; 71.8; 38.5; 29.6; 27.3; 27.1; 25.9; 18.1; ꢀ 4.2;
ꢀ 4.3. ESI-MS: 385 ([M þ Na]þ). HR-ESI-MS: 385.2175 ([M þ Na]þ, C21H34NaO3Siþ; calc. 385.2175).
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-ol (21). Yield: 90%. Colorless
liquid. [a]2D4 ¼ þ7.2 (c ¼ 0.9, CHCl3). IR (KBr): 3457, 3035, 2985, 2929, 1640, 1375, 1236, 1058, 806, 757,
699. 1H-NMR (300 MHz, CDCl3): 7.40 – 7.24 (m, 5 H); 5.80 – 5.69 (m, 1 H); 5.06 – 4.98 (m, 3 H); 4.94 (d,
J ¼ 9.0, 1 H); 3.70 – 3.54 (m, 2 H); 2.33 – 2.17 (m, 2 H); 1.96 (d, J ¼ 9.0, 1 H); 1.55 (s, 3 H); 1.50 (s, 3 H).
13C-NMR (75 MHz, CDCl3): 137.6; 134.1; 128.6; 128.3; 126.9; 117.8; 109.3; 85.0; 79.3; 68.1; 39.6; 29.6;
27.3; 27.0. ESI-MS: 271 ([M þ Na]þ). HR-ESI-MS: 271.1312 ([M þ Na]þ, C15H20NaOþ3 ; calc. 271.1310).
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]but-3-en-1-yl Prop-2-enoate (22). Yield:
71%. Colorless liquid. [a]2D4 ¼ ꢀ76.5 (c ¼ 0.9, CHCl3). IR (KBr): 2961, 2925, 1730, 1631, 1407, 1260, 1025,
802, 697. 1H-NMR (300 MHz, CDCl3): 7.44 – 7.28 (m, 5 H); 6.50 – 6.46 (m, 1 H); 6.23 – 6.14 (m, 1 H); 5.88
(d, J ¼ 11.1, 1 H); 5.71 – 5.60 (m, 1 H); 5.17 – 4.98 (m, 3 H); 4.73 (d, J ¼ 8.8, 1 H); 3.90 (dd, J ¼ 8.8, 2.2,
1 H); 2.56 – 2.38 (m, 2 H); 1.58 (s, 3 H); 1.51 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 165.6; 137.3; 132.9;
131.4; 128.6; 128.3; 128.1; 126.7; 118.3; 109.4; 83.5; 78.8; 69.4; 36.3; 29.6; 27.1; 26.7. ESI-MS: 325 ([M þ
Na]þ). HR-ESI-MS: 325.1419 ([M þ Na]þ, C18H22NaOþ4 ; calc. 325.1416).
(6R)-6-[(4S,5S)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5,6-dihydro-2H-pyran-2-one (23). Yield:
65%. Colorless liquid. [a]2D4 ¼ ꢀ95.1 (c ¼ 0.9, CHCl3). IR (KBr): 2922, 2854, 1728, 1629, 1458, 1378, 1248,
1075. 1H-NMR (300 MHz, CDCl3): 7.50 – 7.30 (m, 5 H); 6.90 – 6.83 (m, 1 H); 6.03 (d, J ¼ 9.7, 1 H); 5.24 (d,
J ¼ 8.5, 1 H); 4.45 – 4.38 (m, 1 H); 3.82 (d, J ¼ 8.5, 1 H); 2.74 – 2.64 (m, 1 H); 2.25 (ddd, J ¼ 23.2, 9.7, 4.9,
1 H); 1.59 (s, 3 H); 1.55 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 163.6; 144.7; 137.1; 128.7; 128.6; 126.8;
121.7; 110.0. ESI-MS: 297 ([M þ Na]þ). HR-ESI-MS: 297.1103 ([M þ Na]þ, C16H18NaOþ4 ; calc.
297.1103).
(ꢀ)-8-Epigoniodiol (¼(6R)-6-[(1R,2S)-1,2-Dihydroxy-2-phenylethyl]-5,6-dihydro-2H-pyran-2-one;
1b). Yield: 71%. Colorless liquid. [a]D25 ¼ ꢀ13.7 (c ¼ 0.7, CHCl3) ([3][5]: [a]D25 ¼ ꢀ13.7 (c ¼ 0.7, CHCl3)).
IR (KBr): 3448, 2924, 1704, 1629, 1391, 1261, 1081, 1029, 808, 710. 1H-NMR (300 MHz, CDCl3): 7.47 – 7.28
(m, 5 H); 6.85 (ddd, J ¼ 8.4, 6.3, 2.0, 1 H); 5.95 (dd, J ¼ 9.8, 2.2, 1 H); 4.96 (d, J ¼ 6.2, 1 H); 4.20 (dd, J ¼
12.6, 3.8, 1 H); 3.89 – 3.10 (m, 3 H); 2.83 (ddt, J ¼ 18.6, 12.6, 2.7, 1 H); 2.09 (ddd, J ¼ 18.7, 6.3, 3.9, 1 H).
13C-NMR (75 MHz, CDCl3): 164.0; 146.0; 140.1; 128.7; 128.3; 126.9; 120.5; 77.0; 76.5; 74.1; 26.0. ESI-MS:
257 ([M þ Na]þ). HR-ESI-MS: 257.0796 ([M þ Na]þ, C13H14NaO4þ ; calc. 257.0790).
(þ)-9-Deoxygoniopypyrone (¼(1R,5R,7S,8S)-8-Hydroxy-2,6-dioxa-7-phenylbicyclo[3.3.1]nonan-3-
one; 4). DBU (0.008 ml, 0.06 mmol) was added to a soln. of 1b (70 mg, 0.29 mmol) in 0.5 ml of THF. The
mixture was stirred for 24 h at r.t., extracted with AcOEt, washed with H2O, dried (Na2SO4), and purified
by CC (hexane/AcOEt) to yield 4 (60 mg, 86%). Solid. [a]2D4 ¼ þ12.5 (c ¼ 0.2, EtOH) ([3][5]: [a]2D4
¼
þ12.5 (c ¼ 0.2, EtOH)). IR (KBr): 3448, 2930, 2859, 1733, 1631, 1461, 1253, 1074, 830, 772, 731.
1H-NMR (300 MHz, CDCl3): 7.43 – 7.31 (m, 5 H); 4.95 (br. s, 1 H); 4.86 (m, 1 H); 4.51 (m, 1 H); 3.94 (br.
s, 1 H); 3.02 – 2.82 (m, 2 H); 2.63 – 2.56 (ddd, J ¼ 14.1, 4.0, 1.1, 1 H); 1.84 (dd, J ¼ 13.5, 3.4, 1 H); 1.65 (d,
J ¼ 3.3, 1 H). 13C-NMR (75 MHz, CDCl3): 169.2; 136.7; 128.9; 18.4; 126.2; 74.2; 70.5; 68.3; 66.1; 36.3;
24.0. ESI-MS: 257 ([M þ Na]þ). HR-ESI-MS: 257.0756 ([M þ Na]þ, C13H14NaOþ4 ; calc. 257.0790).
We are grateful to Dr. J. S. Yadav, Director, IICT, for his constant encouragement. Financial support
was provided by the DST, New Delhi, India (Grant No. SR/S1/OC-08/2011), and the fellowship provided
to R. S. K. by UGC (New Delhi) is gratefully acknowledged. Thanks are also due to Dr. G. V. M. Sharma
for his support.
REFERENCES
[1] Y. C. Wu, C. Y. Duh, F. R. Chang, S. K. Wang, J. J. Chang, D. R. McPhail, A. T. McPhail, K. H. Lee,
J. Nat. Prod. 1991, 54, 1077; X. P. Fang, J. E. Anderson, X. Qui, J. F. Kozlowski, J. L. McLaughlin,
Tetrahedron 1993, 49, 1563; K. Jewers, J. B. Daivs, J. Dougan, A. H. Manchanda, G. Blunden, A. Kyi,
S. Wetchapinon, Phytochemistry 1972, 11, 2025; A. A. E. El-Zayat, N. R. Ferrighi, T. G. McKenzie,
S. R. Byrn, J. M. Cassady, C. J. Chang, J. L. McLaughlin, Tetrahedron Lett. 1985, 26, 955; S. Wang,

Helvetica Chimica Acta – Vol. 96 (2013)
1375
Y. J. Zhang, R. Y. Chen, D. Q. Yu, J. Nat. Prod. 2002, 65, 835; A. Bermejo, S. Leonce, N. Cabedo, I.
Andreu, D. H. Caignard, G. Atassi, D. Cortes, J. Nat. Prod. 1999, 62, 110; M. A. Blazquez, A.
Bermejo, M. C. Zafra-Polo, D. Cortes, Phytochem. Anal. 1999, 10, 161.
[2] J. P. Surivet, J. M. Vatele, Tetrahedron Lett. 1998, 39, 7299; H. B. Mereyala, M. Joe, Curr. Med. Chem.
Anticancer Agents 2001, 1, 293; Q. Mu, W. Tang, C. Li, Y. Lu, H. Sun, X. Zheng, N. Wu, B. Lou, B. Xu,
Heterocycles 1999, 51, 2969; Y. Yamashita, S. Saito, H. Ishitani, S. Kobayashi, J. Am. Chem. Soc.
2003, 125, 3793; M. Tsubiki, K. Kanai, T. Honda, J. Chem. Soc., Chem. Commun. 1992, 1640; C.
Mukai, S. Hirai, M. Hanaoka, J. Org. Chem. 1997, 62, 6619; K. Nakashima, N. Kikuchi, D. Shirayama,
T. Miki, K. Ando, M. Sono, S. Suzuki, M. Kawase, M. Kondoh, M. Sato, M. Tori, Bull. Chem. Soc.
Jpn. 2007, 80, 387; M. G. Banwell, M. J. Coster, O. P. Karunaratne, J. A. Smith, J. Chem. Soc., Perkin
Trans. 1 2002, 1622; J. P. Surivet, J. M. Vatele, Tetrahedron Lett. 1997, 37, 819.
[3] X. P. Fang, J. E. Anderson, C. J. Chang, J. L. Mc Laughlin, J. Nat. Prod. 1991, 54, 1034.
[4] M. Kondoh, M. Sato, M. Tori, Bull. Chem. Soc. Jpn. 2007, 80, 387.
[5] M. Tsubuki, K. Kanai, H. Nagase, T. Honda, Tetrahedron 1999, 55, 2493.
[6] J. P. Surivet, J. M. Vatele, Tetrahedron Lett. 1996, 37, 4373.
[7] J. P. Surivet, J. Gore, J. M. Vatele, Tetrahedron Lett. 1996, 37, 371; K. R. Prasad, S. L. Gholap,
Tetrahedron Lett. 2007, 48, 4679.
[8] P. V. Ramachandran, J. S. Chandra, M. V. Ram Reddy, J. Org. Chem. 2002, 67, 7547.
[9] G. Sabitha, T. R. Reddy, J. S. Yadav, Tetrahedron Lett. 2011, 52, 6550.
[10] T. Yoshida, S. Yamauchi, R. Tago, M. Maruyama, K. Akiyama, T. Sugahara, T. Kishida, Y. Koba,
Biosci., Biotechnol., Biochem. 2008, 72, 2342.
[11] G. Kumaraswamy, K. Sadaiah, Tetrahedron 2012, 68, 262; G. Kumaraswamy, G. Ramakrishna, P.
Naresh, B. Jagadeesh, B. Sridhar, J. Org. Chem. 2009, 74, 8468; G. Kumaraswamy, M. Padmaja, B.
Markondaiah, N. Jena, B. Sridhar, M. U. Kiran, J. Org. Chem. 2006, 71, 337; G. Kumaraswamy, G.
Ramakrishna, B. Sridhar, Tetrahedron Lett. 2011, 15, 1779; G. Kumaraswamy, N. J. Prakash,
Tetrahedron Lett. 2010, 51, 6500; G. Kumaraswamy, N. J. Prakash, B. Sridhar, J. Org. Chem. 2010, 75,
2745; G. Kumaraswamy, M. Padmaja, J. Org. Chem. 2008, 73, 5198.
[12] Z. W. You, X. Zhang, F. L. Qing, Synthesis 2006, 2535; K. R. Prasad, M. G. Dhaware, Synthesis 2007,
3697; M. G. Banwell, M. J. Coster, O. P. Karunaratne, J. A. Smith, J Chem. Soc., Perkin Trans. 1 2002,
1622; M. G. Banwell, M. J. Coster, A. J. Edwards, O. P. Karunaratne, J. A. Smith, L. L. Welling, A. C.
Willis, Aust. J. Chem. 2003, 56, 585; K. R. Prasad, M. G. Dhaware, Synlett 2007, 1112.
[13] P. Bianchi, G. Roda, S. Riva, B. Danieli, A. Zabelinskaja-Mackovac, H. Grienglc, Tetrahedron 2001,
57, 2213.
[14] Z. Ma, Y. Zhao, N. Jiang, X. Jin, J. Wang, Tetrahedron Lett. 2002, 43, 3209.
[15] Q. Mu, W. Tang, C. Li, Y. Lu, H. Sun, H. Zheng, X. Hao, Q. Zheng, N. Wu, L. Lou, B. Xu,
Heterocycles 1999, 51, 2969.
Received July 16, 2012