Total synthesis and stereochemical revision of xiamenmycin A

Article abstract of DOI:10.1039/c5ob02476e

The relative and absolute configurations of xiamenmycin A, a benzopyran compound isolated from Streptomyces xiamenensis 318 with a highly potent anti-fibrotic activity, have been characterized through the total synthesis. The key steps include the constru

Full text of DOI:10.1039/c5ob02476e

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DOI: 10.1039/C5OB02476E
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ARTICLE
Total Synthesis and Stereochemical Revision of Xiamenmycin A
a
a
a
a
a
a
a
Xiaozhen Jiao, Yangyang Yao, Beibei Yang, Xiaoyu Liu, Xiaoyu Li, Hongguang Yang, Li Li, Jun
b
c
a
Xu, Minjuan Xu, *Ping Xie, *
Received 00th January 20xx,
Accepted 00th January 20xx
The relative and absolute configurations of xiamenmycin A, a benzopyran compound isolated from Streptomyces
xiamenensis 318 with a highly potent anti-fibrotic activity, have been characterized through the total synthesis. The key
steps include the construction of the 3-chromanol moiety via Sharpless epoxidation followed by regio- and diastereo-
selective cyclization and introduction of the threonine moiety at a later stage via Pd-catalysed aminocarbonylation in a
one-pot procedure. The stereochemical assignment of natural xiamenmycin A has been accordingly revised to be 2R, 3S,
DOI: 10.1039/x0xx00000x
www.rsc.org/
3
′S, 4′R.
correlations, its absolute configuration was established as (2S, 3S,
Introduction
3
3′S, 4′R) (Fig. 1).
Fibrotic diseases, which can occur in a variety of organs such as
pulmonary, liver, kidney and cardiovascular organs, are a serious
In our previous pharmacological studies, xiamenmycin A could
1
significantly inhibit cell proliferation and the activation of primary
human dermal fibroblasts as well as lung fibroblasts, by reducing
the contractile ability of the fibroblasts, indicating that the
threat to public health and life. It has been estimated that
approximately 45% of the mortalities in developed countries are
1
related to the fibrotic diseases of various organs. Therefore, more
3
compound may have an anti-fibrotic effect. Xiamenmycin A
and more attention has been paid to finding small bioactive
molecules that can be used to further dissect key pathways
implicated in the pathogenesis of tissue fibrosis, and there remains
a considerable need for continued research and drug discovery
+
attenuated hypertrophic scar formation by reducing CD4
lymphocyte and monocyte/macrophage retention in fibrotic foci
and blocked fibroblast adhesion with monocytes and had no
significant toxic effect on mice. Both in vivo and in vitro studies
found that xiamenmycin A inhibited the mechanical stress-induced
2
towards anti-fibrotic drugs.
Xiamenmycin A (1), a benzopyran derivative with a prenylated profibrotic effects by suppressing proliferation, activation, and
side chain, has been isolated from mangrove-derived Streptomyces fibroblast contraction as well as inactivating FAK, p38, and Rho
3
4
xiamenensis 318 in 2012. Its structure was elucidated by NMR and guanosine
triphosphatase
signalling.
Furthermore,
mass spectrometric analyses. Based on the analysis of the pharmacokinetic experiments showed that xiamenmycin A was
spectroscopic data, Mosher’s method, Marfey’s reagent and NOE rapidly absorbed into the blood and quickly eliminated in plasma.5
Therefore, xiamenmycin A is becoming a promising drug candidate
Fig. 1 The proposed structure of xiamenmycin A 1
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for treating excessive fibrotic diseases, and this has triggered our
Journal Name
Our first work was to prepare the key intermediatVeiewdAiortlic7le Ofrnolinme
DOI: 10.1039/C5OB02476E
efforts to establish a flexible and efficient method for the commercially available 2-hydroxyphenylacetic acid 2 (Scheme 2).
asymmetric total synthesis of xiamenmycin A to supply samples for Protection of 2 with a benzyl group followed by reduction with
9
further pharmaceutical development.
DIBAL-H afforded the aldehyde 3 in 78% yield. Horner-Wadsworth-
10
Emmons olefination of aldehyde 3 with the Ando’s reagent
Results and discussion
provided 4 (Z/E 20/1). Reduction of Z-4 with LiAlH afforded allyl
4
11
alcohol Z-5. Next, Sharpless epoxidation of allyl alcohol Z-5 with D-
-)-DIPT/titanium tetraisopropoxide/t-BuOOH gave the (2R, 3S)-
Although structure 1 might be expected to be obtained from the
(
corresponding molecule
D
and threonine (Scheme 1),
epoxide 6a as an oil but only in moderate ee (77% ee). Initial
attempts to promote the enantiomeric purity of 6a via reducing the
reaction temperature and increasing the catalyst load were
unsuccessful. However, the enantiomeric purity of 6a could be
improved to 94.5% by converting it to the corresponding 3, 5-
dinitrobenzoate 6b followed by recrystallization and hydrolysis.
enantioselective synthesis of the deceptively simple molecule D
with two adjacent cis stereocentres and a carboxyl group was
6
difficult. We felt that late stage introduction of the threonine
moiety and the unsaturated side chain would make the synthesis
more effective in terms of the number of steps. Specifically, our
retrosynthetic analysis of 1 is shown in Scheme 1. We envisioned
that the threonine moiety could be installed at a late stage via one-
After the removal of the benzyl group by hydrogenation, the acid
12
pot Pd-catalysed aminocarbonylation of the corresponding aryl catalytic cyclization was carried out under various conditions
7, 8
bromide A with methyl threonine. The homoprenyl carbon chain (Table 1). An inseparable mixture of 7 and 7’ was obtained, and the
might be elaborated from 10 via Wittig olefination. In addition, the best 7/7’ ratio, as determined by HPLC analysis, was approximately
key intermediate 10 in our strategy could later be amenable to 7.36:1 when the reaction was performed in the presence of 5% BF3-
analogue synthesis to probe biological activity, which in turn could Et O in CH Cl (entry 11).The pure isomer 7 could be obtained in 76%
2
2
2
be derived from allyl alcohol Z-5 via Sharpless epoxidation and yield using the optimized conditions after it was treated with NaIO4
subsequent deprotection along with regio- and diastereo- selective and then purified by column chromatography. As expected, a
cyclization.
pseudo-SN2 epoxide opening resulted in the trans orientation
13, 14
between 3-OH and 2-CH3 in compound 7,
which was
1
established on the basis of H-NMR spectra and NOE analyses. The
NOE correlation between the 4-Hax (δ 3.05 ppm) and 2-CH (δ 1.18
3
ppm) showed that the 2-CH group was in an axial orientation.
3
Moreover, analysis of the coupling constants of 3-H (δ 4.10 ppm,
pseudo t, 3.6Hz) shows that 3-H was in an equatorial orientation
(
Fig. 3). Based on the above analysis, the absolute configurations at
Scheme 1 The retrosynthetic analysis of 1
Fig. 2 The theoretical CD spectra and experimental CD spectra of 7
2
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ARTICLE
C-2 and C-3 in diol 7 were found to be 2S and 3S, which was also with the spectra calculated for the 2S, 3S configuration using TDDFT
15, 16
further confirmed by comparison of the experimental CD spectra method
(Fig. 2).
Scheme 2 Synthesis of diol 7.
a
Table 1 the optimization of the transformation of 6a to 7 and 7’
Entry
Catalytic
acid
2M HCl / Et O
solvent
CH CN
Temp.
conv
Ratio
With diol 7 in hand, we next embarked on introducing the
(%)
70
7 :7’
5.8:1
homoprenyl carbon chain and threonine moiety of xiamenmycin A
1
2
3
4
5
6
7
8
9
rt
2
3
17
1
(Scheme 3). Selective oxidation of the primary alcohol in diol 7
with BAIB in the presence of a catalytic amount of TEMPO
followed by Wittig olefination with methyl 2-
triphenylphosphoranylidene) acetate produced 8. Hydrogenation
of 8 in HOAc would be carried out to give the lactone 9. The
10% TsOH
20% TsOH
10%TFA
CH Cl
rt
93
90
91
94
82
86
94
94
94
94
2.42:1
2.38:1
1.68:1
6.51:1
9.19:1
5.8:1
2
2
2
2
2
CH Cl
rt
2
(
CH Cl
rt
2
18
bromine substitution reaction of lactone 9 with ZrCl and NBS
4
10% BF -Et O
CH Cl
rt
3
2
2
gave lactone 10. After reduction of lactone 10 with DIBAL-H, a
Wittig reaction with isopropyltriphenylphosphonium iodide
produced the chromanol 11 in THF. After esterification protection,
10% BF -Et O
CH CN
rt
3
2
3
10% BF -Et O
Toluene
CH Cl
rt
3
2
7
Pd-catalysed fluorocarbonylation with N-formylsaccharin and KF
20% BF -Et O
rt
6.96:1
6.47:1
6.67:1
7.36:1
3
2
2
2
2
2
2
8
in the presence of Xantphos and the subsequent one-pot coupling
10% BF -Et O
CH Cl
reflux
reflux
rt
with L-threonine methyl ester hydrochloride was used to give
amide 13. Finally, a basic hydrolysis would give xiamenmycin A 1.
Comparison of the data of 1 with those of the natural product
revealed that there were distinct differences in optical rotation
3
2
2
10
5% BF -Et O
CH Cl
3
2
2
11
5% BF -Et O
CH Cl
3
2
2
13
and C NMR spectra. The optical rotation of isolated xiamenmycin
a
General experimental conditions: 5 μmol of 6a, 1 mL of solvent, 1h.
22
A was *α+D = +39.5º (c 0.044, CH OH) and the optical rotation of
3
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25
synthetic xiamenmycin A was *α+D = +2.09º (c 0.438, CH OH). position methylene carbon atom (Δδ = 4.9ppm)V.iewThAerticlreeOsnulilntes
3
13
DOI: 10.1039/C5OB02476E
Specially, there were large deviations in the C NMR spectra for the suggested that the stereo-structure of the proposed xiamenmycin A
-position methyl carbon atom (Δδ = 3.3ppm) as well as the 2- was incorrect.
2
Scheme 3 The synthesis of 1
In our previous studies, the absolute configuration at C3 of
To fully elucidate the stereoconfiguration of C2, we further
xiamenmycin A was demonstrated by Mosher’s method, and the synthesized the epimer 24 of the proposed xiamenmycin A with an
absolute configuration at C2 of the natural product was determined R configuration at C2 using the same intermediate 3 (Scheme 4). A
through the relative configurations of C2 and C3 demonstrated by Wittig reaction of
3
with 2-(triphenylphosphoranylidene)
3
25
NOE correlations. However, the assignment of the absolute propanoate produced E-14. After reduction, the allyl alcohol E-15
configuration at C2 of this type of natural product still remained was formed. A Sharpless epoxidation reaction was carried out with
contentious. The relative configurations that were assigned for intermediate 15 and L-(+)-DET/titanium tetraisopropoxide/t-BuOOH
1
9
20
21
wittifurans, yojironin D, artopetelin F and 8-benzoyl-2-(4- in CH Cl to yield the (2S, 3S)-epoxide 16 with 90.5% ee. Following a
2
2
22
mehtylpenten-3-yl)chromane-3,5,7-triol
were based on NOE similar synthetic route, we successfully synthesized the C-2 epimer
correlations. Moreover, the absolute configurations of myrsinoic 24 of compound 1.
23
24
acid, and SMTP-0 were determined by the analysis of NOE cross
peaks in addition to derivation with Mosher’s reagent at 3-OH. In
addition, to our knowledge, the first unambiguous total synthesis of
the stereostructure of stachybotrin C was reported in 2013, and
subsequently, the stereostructure was fully elucidated revising the
1
13
The H and C NMR spectra as well as optical rotation of 24 were
3
identical to those reported for the previous isolated natural
product. The HPLC analyses on a chiral phase column also
confirmed that the retention time of compound 24 was the same as
that of the isolated xiamenmycin A. Thus, the absolute
configurations of the naturally occurred xiamenmycin A were
revised to be 2R, 3S, 3’S, 4’R rather than 2S, 3S, 3’S, 4’R (Fig. 4).
6
stereoconfiguration of C2 to be R. Therefore, the previous
interpretation of the NOE correlations seems inadequate and
misleading for the determination of the relative configuration of the
pyran ring due to the partial chair conformation of the six-
membered ring.
4
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Scheme 4 The synthesis of the C-2 epimer 24 of compound 1
Fig. 3 Stereochemical structure of 7 and 17
Fig. 4 The structure of the proposed xiamenmycin A 1 and the
corrected xiamenmycin A 24
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The organic phase was dried over Na SO and evaporated in vacuo.
Conclusions
2
4
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DOI: 10.1039/C5OB02476E
The residue was purified by column chromatography on silica gel (5%
In summary, the stereoconfiguration at C2 of xiamenmycin A was EtOAc in petroleum ether) to give 4 (270 mg, 94%) as a colourless
1
corrected through asymmetric total synthesis. Through the oil. R 0.5 (5:1 petrol -EtOAc). H NMR (400MHz, CDCl ): δ 7.43-7.31
f
3
comparison of physicochemical properties of the synthetic (m, 5H), 7.22-7.16 (m, 2H), 6.91 (d, J=8.0Hz, 2H), 6.09 (m, 1H), 5.09
counterpart with the natural isolated compound, we revised the (s, 2H),4.20 (q, J=7.2Hz, 2H), 3.88 (d, J=7.2Hz, 2H), 1.90 (s, 3H), 1.29
13
stereoconfigurations of the proposed xiamenmycin A to be 2R, 3S, (t, J=7.2Hz, 2H). C NMR (125MHz, CDCl ) : δ168.1, 156.4, 140.8,
3
3′S, 4′R. In addition, an asymmetric total synthesis of xiamenmycin 137.3, 130.1, 129.1, 128.4, 127.7, 127.4, 127.2, 127.0, 120.8, 111.7,
-1
A was achieved in 15 steps with an overall 11% yield from the 69.8, 60.1, 30.6, 20.6, 14.2. IR (film)νmax/cm 3064, 3032, 2978,
commercially available 2-hydroxyphenylacetic acid. The strategy 2929, 1711, 1600, 1588, 1493, 1453, 1378, 1240. HRMS (ESI): Calcd
+
developed here can be used for the synthesis of various isomers for C H O [M+H] 311.1640, found 311.1642.
20 23 3
and analogues of xiamenmycin A for finding new anti-fibrotic
compounds.
(
Z)-ethyl 4-(2-(benzyloxy)phenyl-2-methylbut-2-en-1-ol (5). To a
solution of enoate 4 (3.75 g, 12.67 mmol) in dry THF (50 mL), LiAlH4
1.44 g, 37.89 mmol) was added in three separate portions at 0°C ,
(
Experimental
and then the mixture was refluxed for 30 min. Upon completion,
the reaction was quenched with saturated Na SO and filtered. The
General
2
4
residue was washed with EtOAc (2 x 50 mL), and the combined
organic phase was washed with saturated brine (50 mL). The
organic phase was dried over Na SO and evaporated in vacuo. The
Solvents were dried according to standard procedures when
needed. All reagents and solvents were purchased from commercial
suppliers. Column chromatography was carried out on silica gel
2
4
residue was purified by column chromatography on silica gel
(
160–200 mesh). Melting points were measured on a microscope
(
CH Cl ) to give 5 (3.1 g, 91.2%) as a colourless oil. R 0.3 (5:1 petrol -
2
2
f
melting point apparatus. IR spectra were recorded on a Thermo
Nicolet 5700 FT-IR microscope Centaurμs spectrophotometer. NMR
spectra were recorded on a 400 or 600 MHz NMR spectrometer.
Chemical shifts are referenced to the residual solvent peak and
reported in ppm (δ scale), and all coupling constant (J) values are
given in Hz. The following multiplicity abbreviations are used: (s)
singlet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet, and (br)
broad. ESI-HRMS data were measured on an orbitrap mass
spectrometer.
1
EtOAc). H NMR (500MHz, CDCl ): δ 7.43-7.34 (m, 5H), 7.16 (m, 2H),
3
6
2
1
.92 (m, 2H), 5.45 (m, 1H), 5.08 (s, 2H), 4.13 (s, 2H), 3.43 (d, J=7.5Hz,
13
H), 1.80 (s, 3H). C NMR (125MHz, CDCl ) : δ 156.3, 137.0, 134.9,
3
28.6, 128.0, 127.4, 127.2, 120.9, 111.7, 70.0, 61.5, 28.7, 21.4. IR
-1
(
film)νmax/cm 3355, 3064, 3032, 2915, 2876, 1599, 1493, 1452,
+
1
2
380, 1240. HRMS (ESI): Calcd for C H O [M+H] 269.1536, found
18 21 2
69.1527.
(
(2R, 3S)-3-(2-(benzyloxy)benzyl)-2-methyloxiran-2-yl)methanol (6).
i
To a suspension of 4A sieve powder (454 mg) and Ti(O Pr) (317 mg,
4
(
Z)-ethyl 4-(2-(benzyloxy)phenyl-2-methylbut-2-enoate (4). To a
solution of ethyl 2-(diphenoxyphosphoryl) propanoate (650 mg,
.95 mmol) and 18-crown-6 ether (1.22 g, 4.64 mmol) in dry THF (5
1
1
.12 mmol) in dry CH Cl (20 mL), a solution of D-(-)-DIPT (312 mg,
2 2
.33 mmol) in dry CH Cl (0.5 mL) was added dropwise under an
2
2
1
argon atmosphere at -78°C . After 10 min, the solution of alcohol 5
1 g, 3.73 mmol) in dry CH Cl (1 mL) was added, and the mixture
mL), 1 M KHMDS (1.85 mL, 1.85 mmol) was added under an argon
atmosphere at -78°C , and then the mixture was stirred for 30 min.
Afterwards, a solution of 3 (209 mg, 0.93 mmol) in dry THF was
added and then the mixture was stirred for another 1 h. The
reaction mixture was quenched by the addition of a saturated
(
2
2
was stirred for 20 min at -78°C . After that, t-BuOOH (2.34 mL, 4 N in
toluene) was added. The reaction mixture was stirred for 8 h at -
20°C under an argon atmosphere. A solution of ferrous sulphate
(
2.34 g) and tartaric acid (936 mg) in water (10 mL) was added to
NH Cl solution and then stirred for 30 min at rt. The phase was
4
the mixture, which was stirred for 10 min at 0°C and then for 30
min at rt. The aqueous portion was extracted with ether (3 x 20 mL),
separated, the aqueous phase was extracted with EtOAc (3 x 10 mL)
and the combined organic layers were washed with brine (10 mL).
6
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and the combined organic solution was washed with brine (20 mL). ((2R,
ARTICLE
3S)-3-(2-(benzyloxy)benzyl)-2-methyloxiran-2Vi-eywl)AmrtiecltehOannlinoel
DOI: 10.1039/C5OB02476E
The organic phase was dried over Na SO and evaporated in vacuo. (6a). To a solution of 6b (500 mg, 1 mmol) in THF-CH OH (1:1, 10
2
4
3
The residue was dissolved in ether (20 mL), and a solution of NaOH mL), 1 N KOH (6 mL) was added at 0-5°C . The mixture was stirred
0.55 g) in brine (14 mL) was added, followed by stirring for 1 hr at for 15 min at 0-5°C and then poured into a saturated NaHCO3
°C . The aqueous phase was separated and extracted with ether (2 solution. The aqueous phase was extracted with CH Cl and the
(
0
2
2
x 20 mL). The combined organic phase was washed with water (10 combined organic layers was dried over Na SO followed by
2
4
mL) and saturated brine (10 mL). The organic phase was dried over evaporation in vacuo. The residue was purified by column
Na SO and evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in CH Cl ) to give 6a (250
2
4
2
2
25
column chromatography on silica gel (10% EtOAc in CH Cl ) to give mg, 87.7%, 95% ee) as an oil. R 0.3 (3:1 petrol -EtOAc). *α+ = -10º
2
2
f
D
1
(
-)-epoxide 6 (830 mg, 78%, 78%ee) as a colourless oil. R 0.3 (3:1 (c 1.14, CHCl ). H NMR (400 MHz, CDCl ): δ 7.41-7.34 (m, 5H), 7.22
f 3 3
27
1
petrol -EtOAc). *α+D = -4.4º (c 0.643, CHCl ). H NMR (400 MHz, (m, 2H), 6.96 (d, J = 6.0Hz, 2H), 5.11 (s, 2H), 3.69 (m, 2H), 3.12 (m,
3
13
CDCl ): δ 7.41-7.34 (m, 5H), 7.22 (m, 2H), 6.96 (d, J = 6.0Hz, 2H), 1H), 3.01 (m, 2H), 1.35 (s, 3H). C NMR (100 MHz, CDCl ) : δ 156.4,
3
3
5
.11 (s, 2H), 3.69 (m, 2H), 3.12 (m, 1H), 3.01 (m, 2H), 1.35 (s, 3H). 136.7, 128.5, 127.9, 127.4, 126.3, 121.1, 112.1, 70.3, 64.0, 63.9,
13
-1
C NMR (100 MHz, CDCl ) : δ 156.4, 136.7, 128.5, 127.9, 127.4, 61.3, 29.1, 20.0. IR (film)νmax/cm 3434, 3064, 3033, 2972, 2931,
3
1
26.3, 121.1, 112.1, 70.3, 64.0, 63.9, 61.3, 29.1, 20.0. IR 2876, 1741, 1601, 1589, 1495, 1453, 1380, 1242. HRMS (ESI): Calcd
-1
+
(
film)νmax/cm 3434, 3064, 3033, 2972, 2931, 2876, 1741, 1601, for C H O Na [M+H] 307.1305, found 307.1295.
18 20 3
1
589, 1495, 1453, 1380, 1242. HRMS (ESI): Calcd for C H O Na
18 20 3
(
2S, 3S)-2-(hydroxymethyl)-2-methylchroman-3-ol (7). To
solution of (-)-epoxide 6a (1.37 g, 4.82 mmol) in EtOAc (20 mL),
(2R,3S)-3-(2-(benzyloxy)benzyl)-2-methyloxiran-2-yl)methyl 3,5- Pd/C (10% w/w, 69 mg) was added, and the suspension was stirred
a
+
[
M+H] 307.1305, found 307.1295.
(
dinitrobenzonate (6b). To a solution of (-)-epoxide 6 (0.93 g, 3.27 for 24 h under an atmosphere of H . Then, the reaction mixture was
2
mmol) in CH Cl (20 mL), pyridine (3.6 mL) and 3,5-dinitrobenzyl filtered, and the filtrate was concentrated under reduced pressure.
2
2
chloride (1.065 g, 4.26 mmol) was added at 0-5°C , and then the The residue was dissolved in dry CH Cl (63.4 mL) without further
2
2
mixture was stirred for 30 min at 0-5°C . Afterwards, the mixture purification, and a catalytic amount of BF -Et O (31.6 μL, 48% BF -
3
2
3
was poured into ice-water. The organic layer was separated and the Et O in CH Cl v/v 1:9) was added under an argon atmosphere at rt.
2
2
2
water layer was extracted with CH Cl . The combined organic layer After the mixture was stirred for 1 h at rt, the reaction mixture was
2
2
was washed with water, a saturated CuSO solution, water and washed with water (20 mL) and saturated brine (20 mL). The
4
brine, dried over Na SO and evaporated in vacuo. The residue was organic phase was dried over Na SO and evaporated in vacuo. The
2
4
2
4
purified by column chromatography on silica gel (1% EtOAc in residue was dissolved in CH OH/H O (5 mL, v/v 10:1), and NaIO
4
3
2
petroleum) to give 6b (1.2 g, 74% ) as a white solid, which was (520 mg, 2.43 mmol) was added at rt. The mixture was stirred for 1
recrystallized twice from toluene to give 6b (800 mg). R 0.6 (5:1 h. Afterwards, the reaction mixture was diluted with EtOAc (50 mL)
f
25
1
petrol -EtOAc). m. p. 108-109°C ; *α+D = 0º (c 1.471, CHCl ). H NMR and washed with water (15 mL) as well as saturated brine (15 mL).
3
(
400 MHz, CDCl ) : δ 9.15 (complex, 2H), 7.43-7.29 (m, 5H), 7.21 (d, The organic phase was dried over Na SO and evaporated in vacuo.
3 2 4
J = 7.6Hz, 1H), 7.17 (d, J = 7.6Hz, 1H), 6.91 (m, 2H), 5.11 (s, 2H), 4.54 The residue was purified by column chromatography on silica gel
m, 2H), 3.26 (m, 1H), 3.11 (dd, J = 5.2 Hz, J = 10.8 Hz, 1H), 2.97 (dd, (10% EtOAc in CH Cl ) to give diol 7 (600 mg, 64% over 2 step) as a
(
1
2
2
2
13
26
J = 7.2 Hz, J = 14.8 Hz, 1H), 1.45 (s, 3H). C NMR (100 MHz, CDCl ) : colourless oil. R 0.3 (2:1 petrol -EtOAc). *α+ = -1.8º (c 1.17, CHCl3).
1
2
3
f
D
1
δ 162.1, 156.5, 148.6, 136.8, 133.4, 130.1, 129.4, 128.6, 128.1,
H NMR (600 MHz, CDCl ) : δ 7.13 (dt, J = 1.8Hz, J = 7.8 Hz, 1H),
3 1 2
1
2
1
28.0, 127.3, 125.7, 122.5, 121.0, 111.8, 70.1, 68.1, 63.4, 58.4, 29.6, 7.08 (d, J = 7.8 Hz, 1H), 6.90 (dt, J = 1.2 Hz, J =7.8 Hz, 1H), 6.85 (d, J
1 2
-1
0.3. IR (film)νmax / cm 3110, 3062, 2989, 2965, 2902, 2857, 1736, = 7.8 Hz, 1H), 4.10 (pseudo t, J = 3.6 Hz, 1H), 3.92 (d, J = 12.0 Hz, 1H),
628, 1549, 1495, 1451, 1381, 1346, 1278. HRMS (ESI): Calcd for 3.86 (d, J = 11.4 Hz, 1H), 3.05 (dd, J = 4.2 Hz, J = 16.8 Hz, 1H), 2.80
1
2
+
13
C H O N [M+H] 479.1449, found 479.1440.
(dd, J = 3.6 Hz, J = 16.8 Hz, 1H), 1.18 (s, 3H).. C NMR (100 MHz,
1 2
25
23
8
2
CDCl ) : δ 152.3, 130.4, 127.7, 120.9, 118.4, 117.1, 76.5, 69.0, 68.8,
3
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J. Name., 2013, 00, 1-3 | 7
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 8 of 12
ARTICLE
Journal Name
-1
+
4
1.0, 19.7. IR (film)νmax /cm 3390, 2978, 2935, 1612, 1584, 1489, 1230, 1200. HRMS (ESI): Calcd for C H O [M+H] 219.1016, found
13 15 3
View Article Online
+
DOI: 10.1039/C5OB02476E
1
457, 1237. HRMS (APCI): Calcd for C H O [M+H] 195.1016, 219.1008.
1
1 15 3
found 195.1004.
(4aS,
10aS)-8-bromo-4a-methyl-4,
4a,
10,
10a-
(E)-methyl 3-((2S, 3S)-3-hydroxy-2-methylchroman-2-yl)acrylate tetrahydropyrano[3,2-b]chromen-2(3H)-one (10). To a solution of
(
8). To a solution of 7 ( 300 mg, 1.55 mmol) in dry CH Cl (25 mL), N- bromosuccinimide (179.6 mg, 1.01 mmol) in dry CH Cl (10 mL),
2
2
2
2
indobenzene diacetate (793 mg, 2.46 mmol) and 2,2,6,6- ZrCl (10.7mg, 0.05 mmol ) was added under an argon atmosphere
4
tetramethylpiperidine 1-oxyl (33 mg, 0.21 mmol) were added under at -78°C , and then, the mixture was stirred for 15 min. Afterwards,
an argon atmosphere, and then the mixture was stirred for 6 h at rt. lactone 9 (200 mg, 0.92 mmol) in dry CH Cl (0.5 mL) was added,
2
2
Then, methyl 2-(triphenylphosphoranylidene) acetate (620 mg, 1.86 and the solution was warmed to room temperature slowly. The
mmol) was added. The reaction mixture was stirred for 4 h and then reaction mixture was stirred for 1 h at rt and then quenched with
evaporated in vacuo. The residue was purified by column saturated NaHCO . The phases were separated, the aqueous phase
3
chromatography on silica gel (15% EtOAc in petroleum ether) to was extracted with CH Cl (3 x 10 mL) and the combined organic
2
2
give 8 (300 mg, 78%) as a colorless oil. R 0.5 (3:1 petrol -EtOAc). layer was washed with brine (10 mL). The organic phase was dried
f
26
1
*
α+D = +77.9º (c 0.737, CHCl ). H NMR (400 MHz, CDCl ) : δ 7.13 (t, over Na SO and evaporated in vacuo. The residue was purified by
3 3 2 4
J = 7.2 Hz, 1H), 7.09 (d, J = 16 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.88 column chromatography on silica gel (20% EtOAc in petroleum
(
m, 2H), 6.09 (d, J = 16 Hz, 1H) , 3.94 (dd, J = 5.2 Hz, J = 7.6Hz, 1H), ether) to give 10 (240 mg, 88.2%) as a white solid. R 0.5 (2:1 petrol
1 2 f
27
1
3
.70 (s, 3H), 2.99 (dd, J = 5.2 Hz, J = 16.4 Hz, 1H), 2.69 (dd, J = 7.6 -EtOAc). m. p. 152-154°C ; *α+D = -119.8º (c 0.813, CHCl ); H NMR
1 2 1 3
13
Hz, J = 16.4 Hz, 1H), 1.48 (s, 3H). C NMR (100 MHz, CDCl ) : δ (400 MHz, CDCl ) : δ 7.22 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.55 (m,
2
3
3
1
6
1
66.7, 152.1, 147.3, 129.8, 127.9, 121.4, 120.9, 119.0, 116.7, 78.9, 1H), 3.11 (dd, J = 4.0 Hz, J = 18 Hz, 1H), 2.98 (d, J = 16.4 Hz, 1H),
1 2
-1
9.4, 51.6, 31.4, 23.8. IR (film)νmax /cm 3455, 2982, 2933, 2850, 2.82 (m, 1H), 2.62 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.31 (s, 3H).
13
722, 1658, 1585, 1488, 1456, 1437, 1311. HRMS (ESI): Calcd for
C NMR (100 MHz, CDCl ) : δ 170.2, 151.3, 132.3, 130.9, 119.1,
3
+
C H O [M+H] 249.1121, found 249.1115.
118.9, 113.2, 109.7, 75.9, 70.8, 32.3, 28.5, 26.3, 22.2. IR (film)νmax
1
4 17 4
-1
/
cm 2996, 2938, 1733, 1571, 1475, 1250, 1223, 1200. HRMS (ESI):
(
4aS, 10aS)-4a-methyl-4, 4a, 10, 10a-tetrahydropyrano[3,2-
+
Calcd for C H O Br [M+H] 297.0121, found 297.0108.
1
3 14 3
b]chromen-2(3H)-one (9). To a solution of 8 (260 mg, 1.04 mmol) in
HOAc (5 mL), Pd/C (10% w/w, 13 mg) was added, and the (2S, 3S)-6-bromo-2-methyl-2-(4-methylpent-3-en-1-yl) chroman-3-
suspension was stirred for 6 h under an atmosphere of H . Then, ol (11). To a solution of lactone 10 (130 mg, 0.439 mmol) in dry
2
the reaction mixture was filtered, and the filtrate was concentrated CH Cl (10 mL), 1 M DIBAL-H (0.527 mL, 0.527 mmol) was added
2
2
under reduced pressure. The residue was diluted with EtOAc (20 mL) dropwise under argon atmosphere at -78°C . The reaction mixture
and washed with saturated NaHCO (10 mL) as well as saturated was stirred for 1 h at -78°C and then quenched with a saturated
3
brine (10 mL). The organic phase was dried over Na SO4 and potassium sodium tartrate solution (2 mL). The phases were
2
evaporated in vacuo. The residue was purified by column separated, the aqueous phase was extracted with CH Cl (3 x 5 mL),
2
2
chromatography on silica gel (20% EtOAc in petroleum ether) to and the combined organic layer was washed with brine (10 mL). The
give 9 (210 mg, 91.7%) as a colourless oil. R 0.2 (3:1 petrol-EtOAc). organic phase was dried over Na SO and evaporated in vacuo. The
f
2
4
27
1
*
α+D = -53.5º (c 0.934, CHCl ). H NMR (500 MHz, CDCl ) : δ 7.13 (t, organic phase was residue was used immediately without further
3 3
J = 7.5 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.81 purification because the resulting residue is unstable. To a solution
(
d, J = 8.5 Hz, 1H),4.56 (m, 1H), 3.13 (dd, J = 3.5 Hz, J = 17.5 Hz, 1H), of isopropyltriphenylphosphonium iodide (928.5 mg, 2.195 mmol)
1 2
3
2
1
2
.01 (d, J = 17.5 Hz, 1H), 2.85 (m, 1H), 2.61 (m, 1H), 2.25 (m, 1H), in dry THF (5 mL), 1.6 M n-BuLi (1.234 mL, 1.976 mmol) was added
13
.03 (m, 1H), 1.33 (s, 3H). C NMR (125 MHz, CDCl ) : δ 170.6, dropwise under an argon atmosphere at 0°C . After the mixture was
3
52.1, 129.8, 127.8, 121.1, 117.2, 116.6, 76.6, 70.3, 32.3, 28.6, 26.4, stirred for 30 min, the colour of the solution turned to blood red.
-1
2.3. IR (film)νmax /cm 2978, 2938, 1739, 1585, 1490, 1360, 1296, The residue mentioned above in dry THF (0.5 mL) was added at 0°C ,
8
| J. Name., 2012, 00, 1-3
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Page 9 of 12
Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
and then the mixture was stirred for 30 min at 0°C . After saturated Et N (93 μL, 0.667 mmol) and L-threonine methyl ester
3
View Article Online
DOI: 10.1039/C5OB02476E
NH Cl (1 mL) was added at rt, the solution was extracted with EtOAc hydrochloride (48.5 mg, 0.286 mmol) were added, and then, the
4
(
3 x 6 mL). The combined organic phase was washed with saturated mixture was stirred for 2 h at rt. EtOAc (10 mL) and water (10 mL)
brine (3 mL), dried over Na SO and evaporated in vacuo. The were added, and the phases were separated. The aqueous phase
2
4
residue was purified by column chromatography on silica gel (20% was extracted with EtOAc (10 mL), and the combined organic layer
EtOAc in petroleum ether) to give 11 (90 mg, 72% over 2 steps) as a was washed with brine (10 mL). The organic phase was dried over
27
colorless oil. R 0.6 (3:1 petrol -EtOAc). *α+D = -14.6º (c 0.71, CHCl3). Na SO and evaporated in vacuo. The residue was purified by
f
2
4
1
H NMR (500 MHz, CDCl ): δ 7.20 (m, 2H), 6.71 (d, J = 8.5 Hz, 1H), column chromatography on silica gel (20% EtOAc in petroleum
3
5
2
1
1
2
1
3
.13 (m, 1H), 3.86 (brs., 1H), 3.03 (dd, J = 4.5 Hz, J = 17.5 Hz, 1H), ether) to give 13 (55 mg, 65%) as a colourless oil. R 0.2 (1:1 petrol -
1 2 f
28
1
.77 (dd, J = 4.5 Hz, J = 17.5 Hz, 1H), 2.10 (m, 2H), 1.74 (m, 5H), EtOAc). *α+D = +29.4º (c 0.605, CHCl ). H NMR (400 MHz, CDCl ): δ
1
2
3
3
13
.61 (s, 3H), 1.25 (s, 3H). C NMR (100 MHz, CDCl ) : δ151.8, 132.5, 7.61 (m, 2H), 7.16 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.8 Hz,
3
31.9, 130.5, 123.8, 121.3, 119.1, 112.5, 78.7, 68.1, 34.6, 30.8, 25.6, 1H), 5.09 (m, 2H), 4.81 (m, 1H), 4.45 (m, 1H), 3.80 (s, 3H), 3.15 (m,
-1
1.8, 21.2, 17.6. IR (film)νmax /cm 3360, 2973, 2925, 1573, 1480, 1H), 2.86 (m, 1H), 2.05 (m, 5H), 1.68 (m, 5H), 1.60 (s, 3H), 1.28 (m,
+
13
378, 1292, 1257, 1240. HRMS (ESI): Calcd for C H O Br [M+H]
6H). C NMR (100 MHz, CDCl ) : δ 171.9, 170.5, 167.4, 156.0, 132.3,
16
22
2
3
25.0798, found 325.0800.
2S, 3S)-6-bromo-2-methyl-2-(4-methylpent-3-en-1-yl) chroman-3-
129.5, 126.8, 123.5, 118.6, 117.3, 77.8, 69.6, 68.3, 57.5, 52.6, 35.5,
-1
2
2
8.0, 25.7, 21.7, 21.5, 21.1, 20.1, 17.6. IR (film)νmax /cm 3382,
(
974, 2928, 1742, 1643, 1581, 1491, 1376, 1245. HRMS (ESI): Calcd
yl acetate (12). To a solution of chroman 11 (80 mg, 0.246 mmol) in
pyridine (1 mL), acetyl chloride(28 μL, 0.369 mmol) was added at
+
for C H O N [M+H] 448.2330, found 448.2324.
2
4 34 7
0°C , and the suspension was stirred for 24 h at rt. Then, the (2S,3R)-3-hydroxy-2((2S,3S)-3-hydroxy-2-methyl-2-(4-methylpent-
reaction mixture was diluted with EtOAc (10 mL) and washed with 1 3-enyl)chroman-6-carboxamino)butanoic acid (1). To a solution of
M HCl (5 mL), water (5 mL) and saturated brine (5 mL). The organic 13 (14 mg, 0.031 mmol) in CH OH (1 mL), 4 M aq. NaOH (38 μL,
3
phase was dried over Na SO and evaporated in vacuo. The residue 0.152 mmol) was added, and the mixture was stirred for 6 h at rt.
2
4
was purified by column chromatography on silica gel (5% EtOAc in The pH of the mixture was adjusted to 7 with 1 M aq. HCl, and then,
petroleum ether) to give 12 (70 mg, 77.5%) as a colourless oil. R 0.5 EtOAc (15 mL) was added. The mixture was washed with water (5
f
27
1
(
10:1 petrol -EtOAc). *α+D = +29.9º (c 0.62, CHCl ). H NMR (400 mL) and saturated brine (5 mL). Then, it was dried over Na SO and
3 2 4
MHz, CDCl ) : δ 7.21 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 6.72 (d, J = 8.8 evaporated in vacuo. The residue was purified by column
3
Hz, 1H), 5.08 (m, 1H), 5.03 (m, 1H), 3.09 (dd, J = 5.2 Hz, J = 17.6 Hz, chromatography on silica gel (5% CH OH in CH Cl ) to give 1 (10 mg,
1
2
3
2
2
1
H), 2.77 (dd, J = 4.8 Hz, J = 18.0 Hz, 1H), 2.05 (m, 5H), 1.67 (m, 5H), 80%) as a white solid. R 0.3 (5:1 CH Cl -CH OH). m. p. 105-107°C ;
1 2 f 2 2 3
13
25
1
1
.59 (s, 3H), 1.26 (s, 3H). C NMR (100 MHz, CDCl ) : δ 170.2, 151.6, *α+D = +2.09º (c 0.438, CH OH). H NMR (600 MHz, DMSO) : δ7.75
3 3
1
31.9, 130.4, 123.5, 120.5, 118.9, 112.2, 76.6, 69.5, 35.1, 27.8, 25.5, (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.78 (d, J =
-1
2
1.6, 21.2, 20.9, 17.4. IR (film)νmax /cm 2973, 2929, 1740, 1481, 8.4 Hz, 1H), 5.13 (d, J = 4.2 Hz, 1H), 5.08 (t, J = 7.2 Hz, 1H), 4.38 (dd,
+
1
375, 1243. HRMS (ESI): Calcd for C H O Br [M+H] 367.0903, J = 3.6 Hz, J = 8.4 Hz, 1H), 4.17 (m, 1H), 3.74 (br., 1H), 2.96 (dd, J =
18
24
3
1
2
1
found 367.0898.
5.4 Hz, J = 16.8 Hz, 1H), 2.69 (dd, J = 7.2 Hz, J = 16.8 Hz, 1H), 2.05
2 1 2
(
m, 2H), 1.69-1.61 (complex, 4H), 1.59-1.45 (complex, 4H), 1.23 (s,
(
2S, 3R)-methyl 2-((2S, 3S)-3-acetoxy-2-methyl-2-(4-methylpent-3-
1
3
1
1
=
1
H), 1.11 (d, J = 6.6 Hz, 3H). H NMR (600 MHz, DMSO+D O): 7.62 (s,
2
en-1-yl) chroman-6-carboxamido)-3-hydroxybutanoate (13). To a
solution of 12 (70 mg, 0.19 mmol) in dry DMF (2 mL), N-
formylsaccharin (48.3 mg, 0.229 mmol), Xantphos (5 mg, 0.0086
H), 7.59 (d, J=9.0Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 5.05 (t, J = 7.2 Hz,
H), 4.37 (m, 1H), 4.16 (m, 1H), 3.73 (br., 1H), 2.95 (dd, J = 5.4 Hz, J
1
2
16.8 Hz, 1H), 2.66 (dd, J = 7.2 Hz, J = 16.8 Hz, 1H), 2.02 (m, 2H),
1
2
mmol), KF (27.7 mg, 0.476 mmol) and Pd(OAc) (1.28 mg, 0.0057
2
.64-1.59 (complex, 4H), 1.55-1.45 (complex, 4H), 1.21 (s, 3H), 1.10
mmol) was added under an argon atmosphere, and then the
mixture was stirred for 14h at 80°C and cooled to rt. Afterwards,
1
3
(
d, J = 6.6 Hz, 3H). C NMR (150 MHz, DMSO): δ 172.3, 166.3, 155.6,
1
30.7, 129.5, 126.7, 125.5, 124.4, 120.3, 116.2, 79.2, 67.2, 66.6,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
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ARTICLE
Journal Name
-
1
5
2
8.5, 33.1, 30.6, 25.4, 22.0, 21.3, 20.5, 17.4. IR (film)νmax /cm 3369, was washed with brine (20 mL). The organic phase wVaieswdArrtiieclde Oonvliener
DOI: 10.1039/C5OB02476E
925, 2855, 1726, 1640, 1611, 1538, 1491, 1262. HRMS (ESI): Calcd Na SO and evaporated in vacuo. The residue was dissolved in ether
2
4
+
for C H O N [M+H] 392.2068, found 392.2063.
(20 mL) and a solution of NaOH (1.1 g) in brine (28 mL) was added
followed by stirring for 1 h at 0°C . The aqueous phase was
separated and extracted with ether (2 x 20 mL). The combined
organic phase was washed with water (10 mL) and saturated brine
21 30 6
(
E)-methyl 4-(2-(benzyloxy)phenyl-2-methylbut-2-enoate (14). To a
solution of 2-(triphenylphosphoranylidene) propanoate (6.8 g, 19.6
mmol) in dry CH Cl (5 mL), 3 (2.95 g, 13 mmol) was added under an
2
2
(
10 mL). The organic phase was dried over Na SO and evaporated
2 4
an argon atmosphere at rt, and then, the mixture was refluxed for 4
h. The reaction mixture was evaporated in vacuo. The residue was
purified by column chromatography on silica gel (50% CH Cl in
in vacuo. The residue was purified by column chromatography on
silica gel (10% EtOAc in CH Cl ) to give (-)-epoxide 16 (1.86 g, 87.7%,
2
2
2
2
28
9
2
5
1
0.5%ee) as a colourless oil. R 0.3 (3:1 petrol -EtOAc). *α+ = -
f D
petroleum ether) to give 14 (3.57 g, 92.5%) as a colourless oil. R 0.5
f
1
1.2º (c 0.839, CHCl ). H NMR (400 MHz, CDCl ) : δ 7.42-7.33 (m,
3
3
1
(
5:1 petrol-EtOAc). H NMR (400 MHz, CDCl ): δ 7.41-7.38 (m, 5H),
3
H), 7.22 (m, 2H), 6.94 (m, 2H), 5.09 (s, 2H), 3.65 (dd, J = 4.8 Hz, J =
1
2
7
7
1
6
1
.22-7.14 (m, 2H), 6.93 (m, 3H), 5.09 (s, 2H), 3.72 (s, 3H), 3.55 (d, J =
2.4 Hz, 1H), 3.54 (m, 1H), 3.35 (m, 1H), 2.98 (m, 2H), 1.34 (s, 3H).
13
.2 Hz, 2H), 1.88 (s, 3H). C NMR (100 MHz, CDCl ) : δ168.6, 156.4,
3
13
C NMR (125 MHz, CDCl ) : δ 156.5, 137.0, 128.5, 127.9, 127.8,
3
40.5, 137.0, 129.8, 128.5, 127.8, 127.8, 127.7, 127.3, 120.8, 111.6,
1
27.3, 126.3, 120.9, 111.6, 67.0, 65.3, 61.4, 59.6, 29.1, 14.3. IR
-1
9.9, 51.6, 29.7, 12.4. IR (film)νmax /cm 3063, 3032, 2949, 2865,
714, 1600, 1494, 1453, 1245. HRMS (ESI): Calcd for C H O
-1
-1
(
film)νmax /cm IR (film)νmax/cm 3435, 3063, 3033, 2928, 2868,
19
21
3
1
741, 1601, 1589, 1495, 1453, 1383, 1242. HRMS (ESI): Calcd for
+
[
M+H] 297.1485, found 297.1475.
+
C H O Na [M+H] 307.1305, found 307.1297.
1
8 20 3
(
E)-ethyl 4-(2-(benzyloxy)phenyl-2-methylbut-2-en-1-ol (15). 15
(
2R, 3S)-2-(hydroxymethyl)-2-methylchroman-3-ol (17). 17 (373 mg)
(
3.1 g) was prepared from 14 (3.75 g, 12.7 mmol) following the
was prepared from 16 (650 mg, 2.29 mmol) following the procedure
1
procedure described for 5 in 90% yield. R 0.3 (5:1 petrol-EtOAc). H
f
22
described for 7 in 84% yield. R 0.3 (2:1 petrol-EtOAc). *α+
=
f
D
NMR (400 MHz, CDCl ): δ 7.44-7.33 (m, 5H), 7.16 (m, 2H), 6.91 (m,
3
1
+
25.1º (c 0.395, CHCl ). H NMR (600 MHz, CDCl ): δ 7.12 (t, J = 7.8
3
3
2
1
1
2
1
H), 5.61 (m, 1H), 5.09 (s, 2H), 4.02 (s, 3H), 3.43 (d, J = 7.2 Hz, 2H),
Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.88 (t, J = 7.8 Hz, 1H), 6.81 (d, J =
13
.72 (s, 3H). C NMR (125 MHz, CDCl ) : δ 156.4, 137.3, 135.4,
3
7
1
2
.8 Hz, 1H), 4.25 (dd, J = 6.0 Hz, J = 10.2 Hz, 1H), 3.83 (d, J = 10 Hz,
1 2
29.6, 128.5, 127.8, 127.2, 127.1, 124.4, 120.8, 111.6, 69.7, 69.0,
H), 3.75 (d, J = 10 Hz, 1H), 3.01 (dd, J = 6.0 Hz, J = 16.2 Hz, 1H),
1
2
-1
8.5, 13.7. IR (film)νmax /cm 3351, 3063, 3032, 2916, 2863, 1599,
589, 1494, 1452, 1381, 1241. HRMS (ESI): Calcd for C H O
2
13
.81 (dd, J = 10.2 Hz, J = 16.2 Hz, 1H), 1.19 (s, 3H). C NMR (150
1
2
18
21
MHz, CDCl ) : δ 152.4, 129.7, 127.8, 120.8, 120.0, 117.1, 78.8, 67.4,
3
+
[
M+H] 269.1536, found 269.1528
-1
6
5.6, 30.8, 14.6. IR (film)νmax /cm 3348, 2981, 2930, 1612, 1584,
+
1
486, 1457, 1232. HRMS (APCI): Calcd for C H O Na [M+Na]
1
1 14 3
(
(
(
(
(2S, 3S)-3-(2-(benzyloxy) benzyl)-2-methyloxiran-2-yl)methanol
i
217.0835, found 217.0842.
16). To a suspension of 4A sieve powder (906 mg) and Ti(O Pr)
4
646 mg, 2.24mmol) in dry CH Cl (45 mL), a solution of L-(+)-DET
2
2
(E)-methyl 3-((2R, 3S)-3-hydroxy-2-methylchroman-2-yl)acrylate
628 mg, 2.69 mmol) in dry CH Cl (1 mL) was added dropwise
2
2
(
18). 18 (287 mg) was prepared from 17 (300 mg, 1.55mmol)
under an argon atmosphere at -78°C . After 10 min, the solution of
following the procedure described for 8 in 75% yield. R 0.5 (3:1
f
the alcohol 15 (2 g, 7.46 mmol) in dry CH Cl (1 mL) was added and
2
2
25
1
petrol-EtOAc). *α+D = -75º (c 0.902, CH OH). H NMR (400 MHz,
3
the mixture was stirred for 20 min at -78°C . Afterwards, t-BuOOH
4.68 mL, 4 N in toluene) was added. The reaction mixture was
CDCl ): δ 7.16 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.98-6.88
3
(
(
m, 3H), 6.01 (d, J = 16.0 Hz, 1H) , 3.95 (brs., 1H), 3.70 (s, 3H), 2.95
dd, J = 4.0 Hz, J = 15.2 Hz, 1H), 2.81 (dd, J = 4.0 Hz, J = 16.8 Hz,
stirred for 8 h at -20°C under an argon atmosphere. A solution of
ferrous sulphate (4.68 g) and tartaric acid (1.87 g) in water (15 mL)
was added to the mixture, and it was stirred for 10 min at 0°C ,
followed by stirring for 30 min at rt. The aqueous phase was
extracted with ether (3 x 20 mL), and the combined organic solution
(
1
2
1
2
1
3
1
1
H), 1.50 (s, 3H). C NMR (100 MHz, CDCl ) : δ 166.7, 152.2, 148.5,
3
30.3, 128.0, 121.1, 120.3, 118.0, 116.7, 78.9, 67.6, 51.7, 31.5, 21.8.
-1
IR (film)νmax /cm 3445, 3024, 2986, 2949, 2846, 1723, 1658, 1585,
1
0 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 11 of 12
Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
+
1
2
489, 1457, 1436, 1311. HRMS (ESI): Calcd for C H O [M+H]
mmol) following the procedure described for 12 in 83% yield. R 0.5
1
4
17
4
f
View Article Online
25
DOI: 10.103 91 /C5OB02476E
49.1121, found 249.1115.
(10:1 petrol-EtOAc). *α+D = +63.5º (c 0.495, CHCl ). H NMR (500
3
MHz, CDCl ) : δ 7.24 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 6.78 (d, J = 8.5
3
(4aR, 10aS)-4a-methyl-4, 4a, 10, 10a-tetrahydropyrano[3,2-
Hz, 1H), 5.09 (m, 2H), 3.15 (dd, J = 5.0 Hz, J = 17.5 Hz, 1H), 2.79 (dd,
1
2
b]chromen-2(3H)-one (19). 19 (158 mg) was prepared from 18 (200
mg, 0.81 mmol) following the procedure described for 9 in 90%
J = 5.0 Hz, J = 17.5 Hz, 1H), 2.14 (m, 5H), 1.70 (s, 3H), 1.61 (m, 5H),
1
2
1
3
1
1
2
1
3
.34 (s, 3H). C NMR (125 MHz, CDCl ) : δ 170.5, 151.9, 132.3,
3
25
1
yield. R 0.2 (3:1 petrol-EtOAc). *α+ = -4.0º (c 0.63, CHCl ). H NMR
f
D
3
32.1, 130.6, 123.4, 120.6, 119.1, 112.4, 69.3, 36.9, 28.0, 25.7, 21.6,
(
400 MHz, CDCl ) : δ 7.18-7.11 (m, 2H), 6.93 (t, J = 7.2 Hz, 1H), 6.84
3
-1
1.1, 20.0, 17.6. IR (film)νmax /cm 2971, 2923, 1744, 1480, 1376,
(
d, J = 8.0 Hz, 1H), 4.52 (dd, J = 6.4 Hz, J = 11.2 Hz, 1H), 3.12 (dd, J
1
2
1
+
235. HRMS (ESI): Calcd for C H O Br [M+H] 367.0903, found
18 24 3
=
1
1
6.0 Hz, J = 16.0 Hz, 1H), 2.87 (m, 2H), 2.73 (m, 1H), 2.20 (m, 2H),
2
67.0903.
13
.29 (s, 3H). C NMR (100 MHz, CDCl ) : δ 169.9, 151.9, 129.8,
3
28.1, 121.1, 118.6, 117.1, 76.0, 71.9, 32.8, 28.2, 27.9, 16.2. IR (2S, 3R)-methyl 2-((2R, 3S)-3-acetoxy-2-methyl-2-(4-methylpent-3-
-1
(
film)νmax /cm 2976, 2916, 1733, 1609, 1581, 1490, 1458, 1305, en-1-yl) chroman-6-carboxamido)-3-hydroxybutanoate (23). 23 (35
+
1
2
251. HRMS (ESI): Calcd for C H O [M+H] 219.1016, found mg) was prepared from 22 (42 mg, 0.114mmol) following the
13 15 3
19.1006.
procedure described for 13 in 68% yield. R 0.2 (1:1 petrol-EtOAc).
f
26
1
*
α+D = +74.5º (c 0.52, CHCl ). H NMR (600 MHz, CDCl ): δ 7.62 (dd,
3 3
(
4aR,
10aS)-8-bromo-4a-methyl-4,
4a,
10,
10a-
J = 2.4 Hz, J = 8.4 Hz, 1H), 7.60 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.80
1
2
tetrahydropyrano[3,2-b]chromen-2(3H)-one (20). 20 (400 mg) was
(
d, J = 8.4 Hz, 1H), 5.11 (t, J = 4.8 Hz, 1H), 5.04 (m, 1H), 4.81 (dd, J1 =
.4 Hz, J = 9.0 Hz,, 1H), 4.44 (m, 1H), 3.80 (s, 3H), 3.16 (dd, J = 4.8
prepared from 19 (300 mg, 1.38mmol) following the procedure
2
2
1
25
described for 10 in 98.4% yield. R 0.5 (2:1 petrol-EtOAc). *α+D
=
f
Hz, J = 17.4 Hz,, 1H), 2.83 (dd, J = 4.8 Hz, J = 17.4 Hz,, 1H), 2.10 (m,
2
1
2
1
+
4.5º (c 0.662, CHCl ). H NMR (400 MHz, CDCl ) : δ 7.26 (br., 2H),
3
3
2
6
1
5
H), 2.07 (s, 3H), 1.66 (s, 3H), 1.60 (m, 5H), 1.33 (s, 3H), 1.26 (d, J =
6
.73 (d, J = 6.8 Hz, 1H), 4.48 (m, 1H), 3.08 (m, 1H), 2.89 (m, 2H), 2.72
13
.6 Hz, 3H). C NMR (150 MHz, CDCl ) : δ 171.8, 170.5, 167.2, 156.1,
3
13
(
m, 1H), 222-2.15 (m, 2H), 1.26 (s, 3H). C NMR (100 MHz, CDCl ) :
3
32.4, 129.5, 126.9, 125.8, 123.3, 118.6, 117.3, 77.9, 69.4, 68.3,
δ 169.6, 151.1, 132.2, 131.1, 120.8, 119.0, 113.2, 75.4, 72.2, 32.6,
7.5, 52.7, 37.1, 28.1, 25.7, 21.6, 21.1, 20.1, 20.1, 17.6. IR (film)νmax
-1
2
1
2
7.9, 27.8, 16.1. IR (film)νmax /cm 2981, 2931, 1873, 1725, 1572,
-1
/
cm 3434, 3391, 2969, 2934, 1750, 1638, 1613, 1546, 1494, 1377,
+
479, 1246, 1225. HRMS (ESI): Calcd for C H O Br [M+H]
13
14
3
+
1
4
251. HRMS (ESI): Calcd for C H O N [M+H] 448.2330, found
24 34 7
97.0121, found 297.0111.
48.2334.
(
2R, 3S)-6-bromo-2-methyl-2-(4-methylpent-3-en-1-yl) chroman-3-
(
2S, 3R)-3-hydroxy-2((2R,3S)-3-hydroxy-2-methyl-2-(4-methylpent-
ol (21). 21 (209 mg) was prepared from 20 (280 mg, 0.95 mmol)
3
-en-1-yl) chroman-6-carboxamino)butanoic acid (24). 24 (15 mg)
following the procedure described for 11 in 68.3% yield. R 0.6 (3:1
petrol -EtOAc). *α+D25 = +11.8º (c 0.509, CHCl ). H NMR (600 MHz,
f
was prepared from 23 (20 mg, 0.045 mmol) following the procedure
1
3
16
described for 1 in 90% yield. R 0.3 (5:1 CH Cl -CH OH). *α+
D
=
f
2
2
3
CDCl ): δ 7.21-7.18 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 5.07 (m, 1H),
3
1
+
8
1
8
38.7º (c 0.124, CH OH). H NMR (600 MHz, DMSO): δ7.77 (d, J =
3
3
.86 (t, J = 5.4 Hz, 1H), 3.02 (dd, J = 4.8 Hz, J = 16.8 Hz, 1H), 2.76
1 2
.4 Hz, 1H), 7.65 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz,
(
dd, J = 6.0 Hz, J = 16.8 Hz, 1H), 2.11 (m, 2H), 1.66 (s, 3H), 1.60 (m,
1 2
H), 5.19 (br., 1H), 5.10 (t, J = 6.6 Hz, 1H), 4.38 (dd, J = 3.6 Hz, J =
1
2
13
5
H), 1.32 (s, 3H). C NMR (100 MHz, CDCl ) : δ152.0, 132.5, 132.2,
3
.4 Hz, 1H), 4.17 (m, 1H), 3.74 (t, J = 5.4 Hz, 1H), 2.96 (dd, J = 5.4Hz,
1
1
30.6, 123.7, 121.3, 119.1, 112.5, 79.0, 67.8, 37.0, 31.0, 25.6, 21.6,
J = 16.8 Hz, 1H), 2.69 (dd, J = 7.8Hz, J = 16.8 Hz, 1H), 2.09 (m, 2H),
2
1
2
-1
1
9.2, 17.6. IR (film)νmax /cm 3382, 2972, 2925, 1574, 1479, 1378,
1
.62 (s, 3H), 1.59 (m, 2H), 1.55 (s, 3H), 1.16 (s, 3H), 1.11 (d, J = 6.6
+
1
291, 1260. HRMS (ESI): Calcd for C H O Br [M+H] 325.0798,
16
22
2
1
Hz, 3H). H NMR (600 MHz, DMSO+D O): 7.61 (s, 1H), 7.58 (d, J = 8.4
2
found 325.0784.
Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.05 (br., 1H), 4.36 (d, J = 3.0 Hz, 1H),
4
1
.17 (m, 1H), 3.72 (pesu t, J = 6.0Hz, 1H), 2.94 (dd, J = 4.8 Hz, J =
1 2
(
2R, 3S)-6-bromo-2-methyl-2-(4-methylpent-3-en-1-yl) chroman-3-
6.8 Hz, 1H), 2.67 (dd, J = 7.8 Hz, J = 16.8 Hz, 1H), 2.05 (m, 2H),
1
2
yl acetate (22). 22 (75 mg) was prepared from 21 (80 mg, 0.25
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 12 of 12
ARTICLE
.58 (s, 3H), 1.54 (t, J = 8.4 Hz, 2H), 1.50 (s, 3H), 1.15 (s, 3H), 1.09 (d, 21.
Journal Name
1
L. Chen, W. Jiang and A.-J. Hou, Helv Chim AVcietwa,A2rti0cl0e6O,n8lin9e,
1000-1007.
13
DOI: 10.1039/C5OB02476E
J = 6.6 Hz, 3H). C NMR (150 MHz, DMSO): δ 172.3, 166.2, 155.7,
22.
M. Pecchio, P. N. Solis, J. L. Lopez-Perez, Y. Vasquez, N.
Rodriguez, D. Olmedo, M. Correa, A. San Feliciano and M.
P. Gupta, J Nat Prod, 2006, 69, 410-413.
M. Hirota, S. Miyazaki, T. Minakuchi, T. Takagi and H.
Shibata, Bioscience, biotechnology, and biochemistry,
2002, 66, 655-659.
K. Hasumi, K. Hasegawa and Y. Kitano, The Journal of
antibiotics, 2007, 60, 463-468.
Y. Elemes and C. S. Foote, Journal of the American
Chemical Society, 1992, 114, 6044-6050.
1
5
2
30.8, 129.4, 126.8, 125.5, 124.3, 120.2, 116.2, 79.3, 66.6, 65.9,
-1
8.5, 37.5, 30.8, 25.4, 21.1, 20.5, 18.3, 17.4. IR (film)νmax /cm 3359,
23.
958, 2920, 2852, 1723, 1641, 1611, 1578, 1536, 1490, 1443. HRMS
+
(
ESI): Calcd for C H O N [M+H] 392.2068, found 392.2057.
2
1 30 6
2
4.
5.
2
Acknowledgements
We are grateful to the National Natural Science Foundation of China
(
No. 81102321, 81473105), PUMC Youth Fund and the Fundamental
Research Funds for the Central Universities (No. 33320140141) for
financial support.
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1
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins