Biomimetic synthesis of hyperolactones

Article abstract of DOI:10.1021/jo102511x

Through a biomimetic pathway, hyperolactone D, 4-hydroxyhyperolactone D, and hyperolactone C were synthesized from methyl acetoacetate via Weilers dianion method, asymmetric allylic alkylation, biomimetic lactonization, oxidation, and cyclization. The stereochemistry of the quaternary carbon was controlled efficiently by Palladium-catalyzed asymmetric allylic alkylation. This strategy was also used for the synthesis of hyperolactone B.

Full text of DOI:10.1021/jo102511x

NOTE
pubs.acs.org/joc
Biomimetic Synthesis of Hyperolactones
Yingying Wu, Chao Du, Congcong Hu, Ying Li, and Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, 222
Tianshui South Road, Lanzhou, Gansu 730000, China
S Supporting Information
b
ABSTRACT: Through a biomimetic pathway, hyperolactone
D, 4-hydroxyhyperolactone D, and hyperolactone C were
synthesized from methyl acetoacetate via Weiler’s dianion
method, asymmetric allylic alkylation, biomimetic lactoniza-
tion, oxidation, and cyclization. The stereochemistry of the
quaternary carbon was controlled efficiently by Palladium-
catalyzed asymmetric allylic alkylation. This strategy was also
used for the synthesis of hyperolactone B.
he plant of Hypericum chinense L, which belongs to the
Guttiferae family, has been used as a folk medicine in Asian
which will be oxidized and cyclized to give hyperolactones as
indicated in Scheme 1 (path a).
T
countries for a long time. The pharmacological activity inspired
Tada and co-workers to investigate the secondary metabolites
from this plant. Their work resulted in the isolation of three
unique spiro-lactones, hyperolactones AꢀC, and related com-
pound hyperolactone D (Figure 1).1 Recently, two new spiro-
lactone-related derivatives, 4-hydroxyhyperolactone D (5) and
5,6-dihydrohyperolactone D (6), were discovered by Kashiwada
from the same species.2 On the basis of spectroscopic and mass
spectrometric analysis, the structure of 4-hydroxyhyperolactone
D was deduced. However, the structural ambiguity remained at
the tertiary-hydroxy-attached carbon (Figure 1).
Since the 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate
was discovered as a key intermediate for the second isoprenoid
biosynthetic pathway starting from 1-deoxy-D-xylulose
5-phosphate,10 we proposed that the hyperolactones’s biogenetic
synthesis might preferably start from polyketide (7) and 1-hy-
droxy-2-methyl-2-(E)-butenyl 4-diphosphate (9). We envi-
sioned that if nucleophilic β-ketoester 7 and electrophilic
1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (9) could be
merged together by an enzyme, a short and efficient synthesis of
hyperolactones could be realized after lactonization, selective
oxidation, and cyclization of the key intermediate polyketone 11.
(Scheme 1, path b)
These spiro-lactone compounds have become synthetic tar-
gets due to their unique structure and biological activity. The
total synthesis of (()-hyperolactone A was accomplished from
3-furoic acid and 2-methylbutanal by Kinoshita,3 and the (þ)-
hyperolactone B has been synthesized by the same group.4
Hyperolactone C has been synthesized by several groups.5 In
the course of our research for total synthesis of anti-HIV natural
products, we previously reported on the synthesis of hyperolac-
tone C and biyouyanagin A.6 We have now expanded this work to
related molecules, and in this paper we want to report the
biomimetic syntheses of 4-hydroxyhyperolactone D and hyper-
olactones BꢀD. Through our studies the absolute configuration
of 4-hydroxyhyperolactone D was determined.
Biomimetic synthesis of natural products can provide numer-
ous advantages,7 such as oxidative diversification of low-oxida-
tion-state precursors8 and exclusion of protecting groups.9 On
the basis of a common skeleton found in hyperolactones AꢀD,
Tada1b suggested that the common skeleton may be biosynthe-
sized from polyketide (7) and isopentenyl pyrophosphate (8). The
oxidation and cyclization of an intermediate polyketone (10) may
give hyperolactone D (R = benzene) and its acyl analogues (12),
With this view in mind, our synthesis of hyperolactone D
commenced with benzaldehyde. The δ-hydroxy-β-oxo-pentano-
ate 13a was prepared in 92% yield from methyl acetoacetate and
benzaldehyde as starting material.6 With β-ketoester 13a in hand,
the key palladium-catalyzed asymmetric allylic alkylation reac-
tion was investigated. When β-ketoester 13a was treated with 3
mol % of ligand (R,R)-L1 and 1 mol % of Pd2(dba)3 CHCl3 in
3
the presence of isoprene monoepoxide in CH2Cl2, the desired
branched product 14 and its linear isomer 15 were obtained in
40% and 44% yield, respectively (see Scheme 2). To increase the
desired branched product 14, β-ketoester 13b, which was pre-
pared from 13a in 79% yield, was used as the starting material.
However, the Pd-AAA reaction did not occur. The effectiveness
of the palladium-catalyzed AAA reaction was determined after
converting 14 to 16, and it was found that the enantioselectivity
was 89% ee. To improve the selectivity, ligand (R,R)-L2 was also
used. The desired product 14 was obtained with both better
Received: December 30, 2010
Published: April 01, 2011
r
2011 American Chemical Society
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|

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NOTE
The key intermediate 17 was then employed for the synthesis
and determination of the absolute configuration of 4-hydroxy-
hyperolactone D (Scheme 3). The key biomimetic oxidation was
first tried by using CeCl3 7H2O in i-PrOH.12 The oxidation of
3
lactone 17 generated 18a and 18b in the ratio of 3:1. We then
attempted the method reported by Jens’s13 using Mn(OAc)2 in
CH2Cl2. Unfortunately, the ratio of 18a and 18b was not
improved under this condition. Finally, we found that treatment
of the lactone 17 with m-CPBA in CH2Cl2 led to the formation of
18a and 18b in a ratio of 4.5:1 with overall yield of 84%, and the
use of FeCl3 6H2O and H2O2 in tert-amyl alcohol14 reversed the
3
ratio of 18a to 18b 1:2 in 65% yield. The alcohol 18a was oxidized
by DMP to compound 19, which was treated with HCl to give
4-epi-hyperolactone C (20). Compound 18b was oxidized in the
same procedure to give the 4-hydroxyhyperolactone D (5),
which by treatment of HCl was transformed to hyperolactone
C (3). The spectral data of our synthesized 4-hydroxyhypero-
lactone D (5) (1H, 13C NMR, IR, and HRMS) were consistent
with those of natural product,2 and thus the absolute stereo-
chemistry of 4-hydroxyhyperolactone D was assigned as 3S,4S-
4-hydroxyhyperolactone D.
The method for biomimetic synthesis of hyperolactone C and
4-epi-hyperolactone C could be used for synthesizing hypero-
lactone B (2). As shown in Scheme 4, the synthesis of hyper-
olactone B commenced with isobutyraldehyde and methyl
acetoacetate, which were converted to δ-hydroxy-β-oxo-pen-
tanoate 21 via Weiler’s dianion method.15 After the palladium-
catalyzed asymmetric allylic alkylation reaction of 21, the desired
branched product 23 and its linear isomer 22 were obtained in
the yields of 37% and 33%, respectively. The ee value of the
desired branched product 23 could be increased from 92% to
99% when (R,R)-L2 was used instead of (R,R)-L1 (determined
after conversion to the corresponding dihydrofuran 24). Expo-
sure of compound 23 to DBU and the oxidation of the
corresponding lactone 25 by m-CPBA provide 26a and 26b as
a 1:1.1 mixture. After separation by silica gel column chroma-
tography, the hydroxy 26a was smoothly transformed to hyper-
olactone B (2) in two steps. The spectral data of our fully
synthetic hyperolactone B (2) (1H, 13C NMR, IR, and HRMS)
were consistent with those of the natural product.1b
Figure 1. Structures of spiro-lactone hyperolactone AꢀC and its
related derivatives.
Scheme 1. Biosynthesis of Hyperolactones
In summary, we have developed a new biomimetic pathway
toward hyperolactone D, 4-hydroxyhyperolactone D, and hyperolac-
tone C from methyl acetoacetate. Through our studies the absolute
configuration of 4-hydroxyhyperolactone D was determined. The
stereochemistry of the quaternary carbon was controlled efficiently by
palladium-catalyzed asymmetric allylic alkylation. This strategy was
also successfully applied to the total syntheses of hyperolactone B and
the stereoisomers of hyperolactone C.
enantioselectivity (99% ee) and regioselectivity [14 (48%) and
15 (37%)]. Trost has shown that using tetra-n-butylammonium
triphenyldifluorosilicate (TBAT) as an additive would increase
the regioselectivity without sacrificing the ee in similar
reactions.11 However, in our case TBAT was not effective, and
with it the branched and linear product ratio was only 1:1.5. With
the desired product 14 in hand, the hyperolactone D was
obtained uneventfully after subsequent lactonization and oxida-
tion. Exposure of compound 14 to DBU in methylene chloride at
room temperature led to the formation of the corresponding
lactone 17 in 71% yield. The lactone 17 was smoothly trans-
formed into hyperolactone D as both diastereomers in the
presence of DessꢀMartin periodinane. The spectral data of
our fully synthetic hyperolactone D (4) (1H, 13C NMR, IR,
and HRMS) were consistent with those of the natural product.1b
’ EXPERIMENTAL SECTION
5-Hydroxy-5-aryl-3-oxo-pentanoates 13a. To a suspension
of sodium hydride (60%, 0.40 g, 10 mmol) in dry THF (5 mL) was added
acetoacetate (0.89 mL, 8.33 mmol) under nitrogen, then after 30 min at rt,
butyllithium (in hexane 2.4 M, 4.16 mL, 10 mmol) was added at ꢀ15 to
ꢀ10 °C (ice-salt bath). The mixture was kept at this temperature for 30
min, and then aldehydes (1.06 g, 10 mmol) were added at this temperature.
After the mixture was stirred for 1ꢀ2 h at low temperature, saturated
NH4Cl (30 mL) was added and the aqueous was extracted with ethyl
acetate (3 ꢁ 30 mL). The combined extracts was dried and evaporated
under vacuum. The residues were subjected to flash chromatography and
afforded 13a (1.70 g, 92%). Rf = 0.33 (silica gel, petroleum ether:ethyl
acetate 2:1); IR (thin film) 3494, 2955, 1746, 1713, 1494, 1439, 1405, 1326,
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NOTE
Scheme 2. Synthesis of Hyperolactone D
Scheme 3. Biomimetic Synthesis of 4-Hydroxyhyperolactone D (5), Hyperolactone C (3), and 4-epi-Hyperolactone C (20)
1
754, 702 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.32ꢀ7.34 (m, 4H),
7.25ꢀ7.28 (m, 1H), 5.14 (dd, J = 9.2, 3.2 Hz, 1H), 3.69 (s, 3H), 3.47 (s,
2H), 2.96 (dd, J = 17.2, 9.2 Hz, 1H), 2.84 (dd, J = 17.2, 3.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 202.7, 167.5, 142.8, 128.6, 128.6, 127.9, 125.7,
69.9, 52.5, 51.7, 49.7; MS (EI) m/z 222 (Mþ, 6), 204 (9), 162 (5), 149 (9),
145 (10), 131 (28), 116 (63), 107 (84), 84 (34), 77 (100).
pump) for 10 s and refilled with Ar; this purging procedure was repeated five
times to ensure no oxygen remained in the reaction vessel. After being placed
under an Ar atmosphere, freshly distilled CH2Cl2 (4 mL) was added and the
resulting dark purple solution was stirred at room temperature until it turned a
deep orange color. During this time, 13a (100 mg, 0.45 mmol) was added.
Finally, 2-methyl-2-vinyloxirane (53 μL, 0.54 mmol) was added to the
reaction mixture and the solution turned bright yellow. After 30 min, the
solvent was removed in vacuo. The crude product was purified by flash
column chromatography (silica gel, petroleum ether:ethyl acetate 6:1) to
afford compound 14 (67 mg, 49%) as a colorless oil and 15 (50 mg, 36%)
with a total yield of 85%.
(3R)-Methyl Tetrahydro-5-hydroxy-2-(2-hydroxy-2-phen-
ylethyl)-3-methyl-3-vinylfuran-4-carboxylate, 14, and Com-
pound 15. To an oven-dried round-bottomed flask were added Pd2dba3
CHCl3 (4.6 mg, 0.0045 mmol), (R,R)-L1 (10.6 mg, 0.0135 mmol) and a
stirring bar. The flask was then placed under reduced pressure (vacuum
3
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NOTE
Scheme 4. Total Synthesis of Hyperolactone B (2)
14: Rf = 0.5 (silica gel, petroleum ether:ethyl acetate 2:1); 1H NMR
(400 MHz,CDCI3) δ 7.32ꢀ7.4 (m, 4H), 7.27ꢀ7.28 (m, 1H), 6.14 (dd,
J = 10.8, 17.6 Hz, 1H), 5.98 (s, 1H), 5.17 (br s, 1H), 5.16 (d, J = 4.8 Hz,
1H), 5.12 (d, J = 11.2 Hz, 1H), 4.15 (d, J = 8.4 Hz, 1H), 3.74 (d, J = 8.8Hz,
1H), 3.71 (s, 3 H), 3.49 (br s, 1H), 2.81 (s, 1H), 2.20 (dd, J = 10.4, 14.4
Hz, 1H), 5.14 (dd, J = 1.6, 14.4 Hz, 1H), 1.41 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 173.0, 144.2, 141.2, 128.4, 127.4, 125.7, 114.3, 105.7,
77.7, 70.9, 62.2, 52.2, 48.5, 47.6, 24.8. MS m/z 306, 288, 270, 256, 241,
226, 221, 189, 182, 167, 150, 135, 127, 125, 106, 105, 104, 95, 81, 79, 77,
67, 55, 43; HRMS (ESI) calcd for C17H22O5Naþ [M þ Na]þ 329.1359,
found 329.1353.
equiv) in 2 mL of CH2Cl2 was added to the above mixture and the
solution was stirred overnight at room temperature. The mixture was
diluted with saturated NH4Cl, then dried over anhydrous Na2SO4. The
solvent was removed. The residue was purified by flash column
chromatography (silica gel, petroleum ether:ethyl acetate 6:1) to afford
16 (134 mg, 71%) as a red oil. Rf = 0.42 (silica gel, petroleum ether:ethyl
acetate 2:1); 1H NMR (400 MHz, CDCl3) δ 11.79ꢀ11.81, 3.44ꢀ3.64
and 4.38ꢀ4.44 (m, 1H), 7.28ꢀ7.36 (m, 5H), 5.11ꢀ5.28 (m, 1H),
5.66ꢀ5.94 (m, 3H), 3.94ꢀ4.12 (m, 2H), 2.95ꢀ3.08 (m, 2H),
2.56ꢀ2.76 (m, 1H), 1.20 and 1.38 and 1.39 and 1.27 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 204.2, 203.9, 203.3, 203.2, 176.4, 176.4,
172.4, 172.3, 171.9, 171.9, 170.2, 170.0, 143.2, 142.4, 142.4, 142.3, 142.2,
141.8, 139.9, 136.6, 128.6, 128.5, 127.9, 127.8, 127.8, 125.7, 125.6, 125.6,
125.6, 117.2,117.1, 116.0, 114.7, 105.0, 104.8, 78.9, 78.8, 77.3, 77.2, 77.0,
76.7, 76.6, 76.5, 76.4, 76.3, 71.2, 71.1, 69.8, 69.6, 69.4, 69.3, 64.2, 64.1,
61.2, 61.1, 53.5, 53.4, 53.3, 46.6, 43.4, 43.3, 41.2, 23.8, 23.7, 23.6, 23.5,
18.5, 18.4; MS m/z 256, 241, 225, 206, 188, 168, 153, 150, 137, 125, 111,
107, 105, 104, 95, 84, 81, 79, 77, 68, 67, 55, 44, 43; HRMS (ESI) calcd for
C16H18O4Naþ [M þ Na]þ 297.1097, found 297.1091.
15: Rf = 0.2 (silica gel, petroleum ether:ethyl acetate 2:1) 1H NMR
(400 MHz,CDCI3) δ 7.35 (m, 4H), 7.27 (m, 1H), 5.19 (m, 1H), 4.06
(m, 1H), 3.98 (s,1H), 3.69 (s, 1H), 3.40 (br s, 1H), 2.82ꢀ3.04 (m, 2H),
2.62 (m, 2H), 1.77 (s, 2H), 1.65 (s,1H); 13C NMR (100 MHz, CDCl3) δ
206.5, 204.9, 204.7, 171.9, 169.6, 169.4, 142.6, 138.9, 138.2, 138.1, 128.5,
127.8, 125.6, 122.7, 120.4, 120.2, 120.0, 69.8, 69.7, 69.6, 68.1, 68.0, 63.4,
61.1, 60.8, 60.7, 59.1, 58.8, 58.7, 52.7, 52.6, 52.5, 51.6, 51.4, 50.8, 48.2,
29.5, 29.3, 26.2, 21.6, 21.3, 13.7. HRMS (ESI) calcd for C17H22O5Naþ
[M þ Na]þ 329.1359, found 329.1362.
Hyperolactone D. To a solution of alcohol 17 (76 mg, 0.26 mmol)
in CH2Cl2 (4 mL) was added DMP (1.5 equiv). The heterogeneous
mixture was stirred at rt until the complete consumption of the starting
material was observed by TLC (1ꢀ3 h). The reaction mixture was
diluted with a 1:1 mixture of NaHCO3 (aq) and Na2S2O3 (aq). The
organic layer was separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried with Na2SO4 and the
solvent was removed in vacuo. The resulting crude residue was purified
by flash column chromatography on silica gel, using a mixture of ethyl
acetate and hexanes to afford hyperolactone D (66 mg, 88%). Rf = 0.63
(R,E)-Methyl 4-Methyl-2-styryl-4-vinyl-4,5-dihydrofuran-
3-carboxylate, 16. To a solution of compound 14 (36 mg) in
CH2Cl2 (2 mL) was added catalyzed PTSA, and the resulting mixture
was allowed to stir overnight at rt and then the solvent was removed in
vacuo. The crude product was purified by flash column chromatography
(silica gel, petroleum ether:ethyl acetate 10:1) to afford the product 16
(26 mg) with a yield of 83%. The ee value was 89% when (R R)-L1 was
used and it could be improved to more than 99% with use of (R,R)-L2
(Chiralcel OD-H, λ = 325.1 nm, hexane:isopropanol 99:1, flow rate =
0.5 mL/min). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 16.0 Hz, 1H),
7.53 (d, J = 7.2 Hz, 2H), 7.31ꢀ7.38 (m, 3H), 7.25 (d, J = 16.0 Hz, 1H),
6.06 (dd, J = 10.4, 17.6 Hz, 1H), 5.09 (dd, J = 10.8, 17.2 Hz, 2H), 4.35 (d,
J = 8.8 Hz, 1H), 4.15 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H), 1.46 (s, 3H); 13C
NMR (100 MHz, CDCl3,) δ 165.7, 164.1, 142.8, 137.1, 136.0, 129.1,
128.7, 127.6, 116.6, 112.8, 111.6, 81.6, 50.8, 49.3, 23.3; HRMS (ESI)
calcd for C17H18O3Naþ [M þ Na]þ 293.0784, found 293.0776.
(3R)-3-(3-Hydroxy-3-phenylpropanoyl)-3-methyl-3-vinyl-
dihydrofuran-5(3H)-one, 17. To a round-bottomed flask was
added 14 (215 mg, 0.70 mmol) in 18 mL of CH2Cl2, then DBU (6
1
(silica gel, petroleum ether:ethyl acetate 2:1); H NMR (300 MHz,
CDCl3) δ 7.86ꢀ7.92 (m, 2H), 7.54ꢀ7.59 (m, 1H), 7.45ꢀ7.49 (m, 2H),
6.36 and 6.29 (s, 1H), 6.01 and 5.91 (dd, J = 11.4, 17.6 Hz, 1H), 5.22 and
5.24 (d, J = 17.6 Hz, 1H), 5.23 and 5.28 (d, J = 11.4 Hz, 1H), 4.52 and
4.23 (d, J = 9.0 Hz, 1H), 4.05 and 4.09 (d, J = 9.0 Hz, 1H), 3.29 and 3.46
(s, 1H), 1.28 and 1.46 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 187.8,
187.2, 184.8, 184.6, 173.1, 172.7, 140.7, 136.9, 134.2 ꢁ 2, 133.0 ꢁ 2,
128.7 ꢁ 2, 127.4, 116.5, 115.2, 98.0, 97.8, 60.9, 58.6, 46.9, 46.8, 23.9,
18.8; MS m/z 272, 267, 257, 249, 241, 225, 209, 193, 183, 181, 167,
147,125, 111, 105, 97, 95, 85, 83, 81, 77, 71, 69, 67, 57, 55, 51, 43, 41;
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NOTE
HRMS (ESI) calcd for C16H16O4Naþ [M þ Na]þ 295.0941, found
295.0937.
solution was heated under reflux for 4 h. After cooling, the solution was
diluted with saturated NaHCO3 (aq) and extracted with ethyl acetate.
The combined organic layers were dried with Na2SO4 and the solvent
was removed in vacuo. The resulting crude residue was purified by flash
column chromatography on silica gel with use of a mixture of ethyl
acetate and hexanes to afford 4-epi-hperolactone C (20) (64 mg, 96%).
1H NMR (300 MHz, CDCl3) δ 7.84ꢀ7.86 (m, 2H), 7.60ꢀ7.63 (m,
1H), 7.50ꢀ7.54 (m, 2H), 6.06 (dd, J = 11.2, 17.6 Hz, 1H), 6.06 (s, 1 H),
5.35 (dd, J = 10.8, 17.6 Hz, 2H), 4.79 (d, J = 8.8 Hz, 1H), 4.39 (d, J = 8.8
Hz, 1H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.6, 187.4,
168.1, 136.7, 133.6, 129.0, 127.6, 127.4, 127.4, 116.2, 100.3, 92.3, 73.3,
48.8, 15.4; HRMS (ESI) calcd for C16H14O4Naþ [M þ Na]þ 293.0784,
found 293.0789.
(4R,3S)-4-Hydroxyl-4-(3-hydroxyl-3-phenylpropanoyl)-3-methyl-
3-vinyldihydrofuran-5-(3H)-one, 18a, and (4S,3S)-4-Hydro-
xyl-4-(3-hydroxyl-3-phenylpropanoyl)-3-methyl-3-vinyldihydrofur-
an-5(3H)-one, 18b. To a solution of 17 (274 mg, 1.0 mmol) in CH2Cl2
(25 mL) was added m-CPBA (245 mg, 85%, 1.2 equiv) and the resulting mixture
was stirred overnight at room temperature. The reaction mixture was quenched
with a mixture of saturated Na2S2O3 and saturated NaHCO3 and extracted with
EtOAc. Combined extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. Flash chromatography (petroleum ether:EtOAc 6:1) afforded 18b (44mg)
and 18a (199 mg) with a total yield of 84%.
18b: Rf = 0.70 (silica gel, petroleum ether:ethyl acetate 2:1); 1H NMR
(300 MHz, CDCl3) δ7.29ꢀ7.38 (m, 5H), 5.66 (dd, J = 11.1, 17.4 Hz, 1H),
5.21 (d, J = 10.8 Hz, 1H), 5.17 (d, J = 17.6 Hz, 1H), 5.05 (dd, J = 10.5, 3.0
Hz, 1H), 4.43 (d, J = 8.7 Hz, 1H), 4.02 (d, J = 8.7 Hz, 1H), 3.52 (br s, 1H,
OH), 3.39 (dd, J = 14.1, 11.1 Hz, 1H), 2.48 (dd, J = 13.5, 3.0 Hz, 1H), 1.31
(s, 3H); 13C (NMR 75 MHz, CDCl3) δ 209.3, 175.3, 142.3, 135.1, 128.7,
128.2, 125.5, 118.3, 87.1, 73.8, 72.3, 49.4, 48.2, 19.4; HRMS (ESI) calcd for
C16H18O5Naþ [M þ Na]þ 313.1046, found 313.1051.
Methyl 5-Hydroxy-6-methyl-3-oxoheptanoate, 21. n-Butyl-
lithium (3.8 mL, 2.5M, 2.2 equiv) was added to a solution of diisopro-
pylamine (1.4 mL, 2.4 equiv) in THF under Ar at ꢀ60 °C. The solution
was stirred at this temperature for 8 min and 3 min at room temperature.
Then acetoacetate (464 μL, 4.31 mmol, 1 equiv) was added to the above
solution at ꢀ60 °C. The solution was stirred at this temperature for 20
min and 5 min at room temperature, and then isobutyraldehyde was
added to the solution at ꢀ60 °C. With naturally elevating the tempera-
ture, the mixture was stirred for 4 h and then diluted with saturated
NH4Cl. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried with
Na2SO4 and the solvent was removed in vacuo. The resulting mixture
was purified by flash column chromatography (silica gel, petroleum
18a: Rf = 0.60 (silica gel, petroleum ether:ethyl acetate 2:1); 1H NMR
(300 MHz, CDCl3) δ 7.31ꢀ7.42 (m, 5 H), 5.99 (dd, J = 11.4, 17.4 Hz,
1H), 5.60 (b, 1 H), 5.30 (d, J = 11.2 Hz, 1H), 5.22 (d, J = 17.6 Hz, 1H),
5.12 (dd, J = 10.5, 3.0 Hz, 1H), 4.28 (d, J = 9.3 Hz, 1H), 4.17 (d, J = 9.3
Hz, 1H), 3.65 (b, 1H), 3.52 (dd, J = 13.5, 10.5 Hz, 1H), 2.59 (dd, J =
13.5, 3.0 Hz, 1H), 1.12 (s, 3H); 13C (NMR 75 MHz, CDCl3) δ 209.1,
175.1, 142.2, 136.6, 128.7, 128.2, 125.6, 116.0, 86.0, 73.7, 72.3, 49.0, 48.3,
16.0; MS m/z 290, 272, 257, 238, 205, 149, 142, 131, 127, 125, 107, 106,
105, 97, 96, 91, 85, 81, 77, 71, 69, 68, 67, 51, 50, 43, 40; HRMS (ESI)
calcd for C16H18O5Naþ [M þ Na]þ 313.1046, found 313.1059.
4-Hyproxyhyperolactone D. Following the procedure for hyper-
olactone D with 18b (76 mg, 0.26 mmol) gave a residue that was purified by
flash column chromatography (silica gel, petroleum ether:ethyl
acetate 6:1) to afford compound 4-hyproxyhyperolactone D (66 mg, 88%).
[R]20D ꢀ166 (c 1.0, CHCl3) [lit. [R]20D ꢀ118 (c 0.3, CHCl3)]; 1H NMR
(300 MHz, CDCl3) δ 15.59 (b, 1H), 7.88ꢀ7.90 (m, 2H), 7.54ꢀ7.58 (m,
1H), 7.45ꢀ7.48 (m, 2H), 6.63 (s, 1H), 5.80 (dd, J= 11.2, 17.6 Hz, 1H), 5.19
(dd, J= 10.8, 17.2 Hz, 2H), 4.68 (d, J= 8.8 Hz, 1H), 4.12 (d, J= 8.8 Hz, 1H),
3.60 (b, 1H), 1.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 195.6, 181.6,
175.6, 135.6, 133.3, 133.1, 128.8, 127.2, 117.6, 93.3, 84.0, 75.2, 49.8, 19.8; MS
m/z 288, 272, 257, 238, 205, 149, 142, 131, 127, 125, 107, 106, 105, 97, 96,
91, 85, 81, 77, 71, 69, 68, 67, 51, 50, 43, 41; HRMS (ESI) calcd for
C16H16O5Naþ [M þ Na]þ 311.0890, found 311.0888.
1
ether:ethyl acetate 6:1) to afford compound 21 (769 mg, 95%). H
NMR (400 MHz, CDCl3) δ 3.68 (m, 1H), 3.57 (s, 3H), 3.40 (s, 2H),
3.09 (br s, 1H), 2.50 (m, 2H), 1.52 (dd, J = 6.4, 12.8 Hz, 1H), 0.78 (d, J =
6.4 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
203.5, 167.4, 71.8, 51.9, 49.3, 46.6, 33.0, 18.0, 17.2; MS m/z 89, 171, 157,
155, 153, 145, 116, 113, 101, 97, 85, 71, 49, 43.
(4R)-Methyl 2-Hydroxy-2-(2-hydroxy-3-methylbutyl)-4-
methyl-4-vinyltetrahydrofuran-3-carboxylate, 22. Following
the procedure for 14 with 21 (370 mg, 1.97 mmol) as the starting
material gave a residue that was purified by flash column chromatogra-
phy (silica gel, petroleum ether:ethyl acetate 6:1) to afford compound
22 (177 mg, 33%) and 23 (198 mg, 37%) with a total yield of 70%.
23: 1H NMR (400 MHz, CDCl3) δ 5.76ꢀ6.13 (m, 1H), 5.03ꢀ5.11
(m, 2H), 3.84 (m, 2H), 3.65ꢀ3.74 (m, 3H), 2.76ꢀ2.92 (m, 1H),
1.60ꢀ1.87 (m, 3H), 1.22ꢀ1.37 (m, 3H), 0.87ꢀ0.89 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 172.9, 144.0 ꢁ 2, 141.0 ꢁ 2, 114.5, 114.1, 112.8,
112.5, 106.1 ꢁ 3, 72.9, 72.8, 72.9, 72.8, 72.0 ꢁ 2, 62.7, 62.1, 60.1, 59.8,
52.3, 52.1, 52.0, 47.5, 47.4, 43.5, 43.3, 43.0, 42.7, 33.9 ꢁ 2, 33.5 ꢁ 2, 24.8,
24.7, 20.4, 20.3, 18.2 ꢁ 2, 17.5 ꢁ 2, 17.3 ꢁ 2; MS m/z 255, 137, 211, 183,
179, 165, 152, 141, 127, 109, 95, 81, 73, 67, 55, 43; HRMS (ESI) calcd
for C14H24O5Na [M þ Na] 295.1516, found 295.1519.
(3R,4S,Z)-3-Hydroxy-3-(3-hydroxy-3-phenylacryloyl)-4-
methyl-4-vinyldihydrofuran-2(3H)-one, 19. To a solution of
alcohol 18a (92 mg, 0.32 mmol) in CH2Cl2 (4 mL) was added DMP
(1.5 equiv). The heterogeneous mixture was stirred at rt until the
complete consumption of the starting material was observed by TLC
(1ꢀ3 h). The reaction mixture was diluted with a 1:1 mixture of
NaHCO3 (aq) and Na2S2O3 (aq). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried with Na2SO4 and the solvent was removed
in vacuo. The resulting crude residue was purified by flash column
chromatography on silica gel with use of a mixture of ethyl acetate and
22: 1H NMR (400 MHz, CDCl3) δ 5.20 (m, 1H), 4.12 (dd, J = 13.4,
20 Hz, 2H), 3.89 (br s, 1H), 3.74 (s, 3H), 3.60 (dd, J = 7.6, 15.6 Hz, 1H),
2.70 (m, 4H), 2.24 (br s, 1H), 1.79 (s, 3H), 1.70 (m, 1H), 0.93 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 206.4, 206.1, 169.7, 138.4, 122.8, 72.1,
71.0, 61.2, 59.2, 59.0, 52.6, 46.8, 45.9, 33.0, 26.5, 21.7, 18.4, 18.3, 17.7,
17.6; HRMS (ESI) calcd for C14H24O5Naþ [M þ Na]þ 295.1516,
found 295.1508.
1
(4R)-3-(3-Hydroxy-4-methylpentanoyl)-4-methyl-4-vinyl-
dihydrofuran-2(3H)-one, 25. Following the procedure for 17 with
23 (323 mg, 1.19 mmol) as the starting material gave a residue that was
purified by flash column chromatography (silica gel, petroleum ether:
ethyl acetate 6:1) to afford compound 25 (205 mg, 72%). 1H NMR (400
hexanes to afford compound 19 (72 mg, 79%). H NMR (300 MHz,
CDCl3) δ 15.73 (br s, 1H), 7.89ꢀ7.92 (m, 2H), 7.54ꢀ7.59 (m, 1H),
7.36ꢀ7.48 (m, 2H), 6.74 (s, 1H), 5.98 (dd, J = 10.5, 17.7 Hz, 1H), 5.31
(dd, J = 10.8, 17.1 Hz, 2H), 4.44 (d, J = 8.7 Hz, 1H), 4.36 (d, J = 8.7 Hz,
1H), 3.57 (br s, 1H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
194.9, 182.1, 175.4, 137.1, 133.3, 133.1, 128.8, 127.3, 116.4, 93.6, 83.3,
74.5, 49.4, 16.6; HRMS (ESI) calcd for C16H16O5Naþ [M þ Na]þ
311.0890, found 311.0898.
MHz, CDCl3)
δ
5.83ꢀ5.98 (m, 1H), 5.17ꢀ5.30 (m, 2H),
4.08ꢀ4.15(m, 1H), 3.99ꢀ4.03 (m, 1H), 3.75ꢀ3.88 (br s, 1H),
3.48ꢀ3.69 (dd, J = 15.2 Hz, 1H), 2.65ꢀ2.79 (m, 2H), 2.28ꢀ2.41 (m,
1H), 1.67ꢀ1.74 (br s, 1H), 1.28ꢀ1.44 (m, 3H), 0.90ꢀ0.95 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 205.6, 205.1, 204.8, 204.4, 176.4, 176.3,
4-epi-Hyperolactone C. To a solution of 19 (72 mg, 0.25 mmol)
in THF (10 mL) was added several drops of 3 M HCl, and then the
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The Journal of Organic Chemistry
NOTE
172.6, 172.1, 172.0, 171.9, 141.9, 140.1, 136.7 ꢁ 2, 117.1, 115.8 ꢁ 2,
114.6, 104.5, 104.3, 78.9, 78.7, 73.7, 73.3, 72.3, 72.1, 71.8, 71.7, 64.4,
64.2, 61.4, 61.2, 48.9 ꢁ 2, 48.7, 48.5, 46.5, 46.4, 43.4, 36.1, 35.8, 33.7 ꢁ 2,
33.1 ꢁ 2, 33.0 ꢁ 2, 23.9, 23.8, 23.7, 23.6, 18.5, 18.3 ꢁ 3, 17.6, 17.5 ꢁ 2,
17.4; MS m/z 241, 223, 207, 197, 179, 168, 153, 150, 135, 125, 111, 109,
95, 81, 79, 77, 73, 67, 55, 43, 39; HRMS (ESI) calcd for C13H24O4Nþ
[M þ NH4]þ 258.1700, found 258.1707.
(R,E)-Methyl 4-Methyl-2-(3-methylbut-1-en-1-yl)-4-vinyl-
4,5-dihydrofuran-3-carboxylate, 24. Following the procedure
for preparing compound 16, compound 23 (100 mg) was used as star-
ting material to give a residue that was purified by flash column chro-
matography (silica gel, petroleum ether:ethyl acetate (10:1) to afford
product 24 (71 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 6.83 (dd, J =
1.6, 16 Hz, 1H), 6.42 (dd, J = 6.8, 16 Hz, 1H), 6.00 (dd, J = 10, 17.6 Hz,
1H), 5.04 (s, 1H), 5.00 (dd, J = 0.8, 6 Hz, 1H), 4.24 (d, J = 8.8 Hz, 1H),
4.03 (d, J = 8.8 Hz, 1H), 3.68 (s, 3H), 2.45 (m, 1H), 1.37 (d, J = 10 Hz,
3H), 1.03 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7,
164.4, 148.0, 142.9, 116.4, 112.5, 109.7, 81.4, 50.5, 49.1, 31.6, 23.2, 21.7;
C14H20O3Naþ [M þ Na]þ 259.1305, found 259.1299. The ee value was
92% when (R,R)-L1 was used and it could be improved to abpout 99%
with (R,R)-L2 (Chiralcel OD-H, λ = 290.6 nm, hexane:isopropanol
99:1, flow rate = 0.5 mL/min).
(3S,4S)-3-Hydroxy-3-(3-hydroxy-4-methylpentanoyl)-
4-methyl-4-vinyldihydrofuran-2(3H)-one, 26a, and (3S,4S)-3-
Hydroxy-3-(3-hydroxy-4-methylpentanoyl)-4-methyl-4-vinyldi-
hydrofuran-2(3H)-one 26b. Following the procedure for 18a and 18b
with 27 (111 mg) as the starting material gave a residue that was purified by
flash column chromatography (silica gel, petroleum ether:ethyl acetate 6:1) to
afford compound 26a (41 mg) and 26b (47 mg) with a total yield of 75%.
26a: 1H NMR (400 MHz, CDCl3) δ 5.71 (dd, J = 10.8, 17.6 Hz, 1H),
5.28 (d, J = 11.2 Hz, 1H), 5.18 (d, J = 17.6 Hz, 1H), 4.43 (d, J = 8.8 Hz,
1H), 4.00 (d, J = 8.8 Hz, 1H), 3.75ꢀ3.80 (br s, 1H), 3.09 (dd, J = 11.2,
12.8 Hz, 1H), 3.21 (d, J = 13.2 Hz, 1H), 1.70ꢀ1.78 (m, 1H), 1.31 (s,
3H), 0.92ꢀ0.98 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 211.2, 175.7,
135.3, 118.2, 87.1, 77.3, 77.0, 76.7, 75.3, 73.8, 49.4, 42.8, 34.2, 19.4, 17.9,
17.3; MS m/z 257, 239, 210, 195, 185, 171, 159, 155, 142, 127, 97, 81, 73,
69, 55, 43, 39; HRMS (ESI) calcd for C13H24O5Nþ [M þ NH4]þ
274.1649, found 274.1647.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra, and HPLC
S
b
for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
26b: 1H NMR (400 MHz, CDCl3) δ 6.01 (dd, J = 10.8, 17.2 Hz, 1H),
5.30 (d, J = 10.8 Hz, 1H), 5.23 (d, J = 17.6 Hz, 1H), 4.26 (d, J = 8.8 Hz,
1H), 4.14 (d, J = 8.8 Hz, 1H), 3.79ꢀ3.84 (br s, 1H), 3.20 (dd, J = 11.2,
12.8 Hz, 1H), 2.30 (d, J = 12.8 Hz, 1H), 1.73ꢀ1.78 (m, 1H), 1.14 (s,
3H), 0.92ꢀ0.94 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 211.0, 175.5,
136.8, 115.6, 86.1, 77.3, 77.0, 76.7, 75.2, 73.7, 48.9, 42.9, 34.1, 17.9, 17.3,
16.2; MS m/z 257, 239, 210, 195, 185, 171, 159, 155, 142, 127, 97, 81, 73,
69, 55, 43, 39; HRMS (ESI) calcd for C13H20O5Naþ [M þ Na]þ
279.1203, found 279.1209.
Corresponding Author
*E-mail: xiezx@lzu.edu.cn.
’ ACKNOWLEDGMENT
This work is financially supported by the 973 Program (Grant
2010CB833203), the National Natural Science Foundation of
China (Grant Nos. 20772050 and 21072083), and the Funda-
mental Research Funds for the Central Universities (Grant No.
lzujbky-2009-75). We sincerely thank Dr. Wei Yu (Lanzhou
University) for helpful discussions.
(3R,4S)-3-Hydroxy-3-((Z)-3-hydroxy-4-methylpent-2-en-
oyl)-4-methyl-4-vinyldihydrofuran-2(3H)-one, 27. Following
the procedure for hyperolactone D (4) with 26b (47 mg, 0.18 mmol)
as the starting material gave a residue that was purified by flash column
chromatography (silica gel, petroleum ether:ethyl acetate 6:1) to afford
compound 27 (26 mg, 55.8%) and it could also be directly used in the
next step without purification (there was only one product in this step,
but the yield was not very satisfiying after purification and the reason was
unclear). 1H NMR (400 MHz, CDCl3) δ 5.93 (dd, J = 10.8, 17.6 Hz,
1H), 5.43 (s, 1H), 5.30 (d, J = 9.2 Hz, 1H), 5.27 (d, J = 16.0 Hz, 1H),
4.70 (d, J = 8.8 Hz 1H), 4.31 (d, J = 8.4 Hz, 1H), 2.83 (dd, J = 6.8, 14.0
Hz, 1H), 1.58 (br s, 1H), 1.31 (d, J = 12 Hz, 3H), 1.29 (d, J = 2.4 Hz,
3H), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.2, 197.5, 168.1,
136.7, 116.0, 101.2, 73.2, 48.4, 37.0, 30.4, 19.7, 19.4, 15.4; MS m/z 254,
237, 211, 193, 153, 142, 125, 113, 97, 86, 71, 68, 53, 43, 41, 39;
C13H18O5 Naþ [M þ Na]þ 277.1046, found 277.1051.
Hyperolactone B. To a solution of 27 (8 mg) in THF was added
three drops of 3 M HCl, and the mixture was heated under reflux for 4 h.
The resulting solution was diluted with saturated NaHCO3 (aq) and
extrated with ethyl acetate. The combined organic layers were dried with
Na2SO4 and the solvent was removed in vacuo. The resulting crude residue
was purified by flash column chromatography on silica gel with a mixture of
ethyl acetate and hexanes to afford hyperolactone B (7.3 mg, 98%). HRMS
(ESI) calcd for C13H20O4Nþ [M þ NH4]þ 254.1387, found 254.1383.
[R]20D þ262.5(c 0.16, ethanol) [lit. [R]20D þ411 (c 0.018, ethanol)], mp
51 °C; 1H NMR (400 MHz, CDCl3) δ 5.93 (dd, J = 11.5, 18.0 Hz, 1H),
5.42 (s, 1H), 5.28 (dd, J = 1.2, 10.4 Hz, 2H), 4.69 (d, J = 9.0 Hz, 1H), 4.30
(d, J = 9.0 Hz, 1H), 2.83 (m, 1H), 1.26ꢀ1.28 (m, 6H), 1.22 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.2, 197.4, 168.1, 136.7, 116.0, 101.2, 91.8,
73.2, 48.4, 30.4, 19.7, 19.4, 15.4; MS m/z 136, 193, 177, 165, 153, 95, 81, 67,
53, 43, 39.
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