The first total synthesis of (+)-goniothalesacetate and syntheses of (+)-altholactone, (+)-gonioheptolide A, and (-)-goniofupyrone by an asymmetric acetate aldol approach

Article abstract of DOI:10.1039/c5ob01598g

The first stereoselective total synthesis of (+)-goniothalesacetate and total synthesis of several bioactive styryl lactones, (+)-altholactone, (+)-gonioheptolide A, and (-)-goniofupyrone have been achieved from an advanced intermediate, which can be derived from l-(+)-DET.

Full text of DOI:10.1039/c5ob01598g

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Biomolecular Chemistry
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The first total synthesis of (+)-goniothalesacetate
and syntheses of (+)-altholactone, (+)-gonioheptolide
A, and (−)-goniofupyrone by an asymmetric
acetate aldol approach†
Cite this: DOI: 10.1039/c5ob01598g
Sandeep AnkiReddy, Praveen AnkiReddy and Gowravaram Sabitha*
Received 31st July 2015,
Accepted 21st August 2015
The first stereoselective total synthesis of (+)-goniothalesacetate and total synthesis of several bioactive
styryl lactones, (+)-altholactone, (+)-gonioheptolide A, and (−)-goniofupyrone have been achieved from
an advanced intermediate, which can be derived from L-(+)-DET.
DOI: 10.1039/c5ob01598g
www.rsc.org/obc
3
tism. The structure of the compound was determined on the
basis of standard spectroscopic methods and the absolute
Introduction
Styryl lactones, despite their restricted occurrence in the plant stereochemistry was established from the NOESY spectrum
kingdom, are reported to possess cytotoxic, anti-tumour, and by the preparation of R & S-MTPA esters. Goniothales-
1
pesticidal, teratogenic and embryotoxic activities. There- acetate has five contiguous stereocenters and its structure was
fore they make up an interesting group from a pharmaco- determined as (2R,3R,4S,5S,6R)methyl 3-(3-acetoxy-4-hydroxy-5-
logical point of view. (+)-Goniothalesacetate, (+)-altholactone, phenyloxolan-2-yl)-3-methoxypropanoate. (+)-Altholactone (2),
(+)-gonioheptolide A, and (−)-goniofupyrone are representa- a styryl lactone, tetrahydrofuro[3,2-b]pyran-5-one was first iso-
tives of the styryl lactones (1–4, Fig. 1). Goniothalesacetate (1) lated in 1977 from a Polyalthia species (Annonaceae) by Loder
4
was isolated along with other compounds from the stems of a and co-workers and later, in 1985 from the bark of Goniothala-
2
5
southern Taiwan tree Goniothalamus amuyon. The seeds were mus giganteus by El-Zayat et al. The flowers of this plant undu-
reported to be useful in the treatment of edema and rheuma- late like waves and their scent is sweet and very strong.
Altholactone has also been isolated from the Malaysian plant
G. malayanus and found to induce apoptosis via oxidative
6
a
stress in human HL-60 leukemia cells and displays promis-
6
b
ing antimicrobial activity. (+)-Altholactone (2) is a bicyclic
compound presenting an α,β-unsaturated δ-lactone (5-oxy-
genated-5,6-dihydro-2H-pyran-2-one) and a disubstituted furanic
motif with a bicyclic cis ring junction.
This natural product exhibits a very interesting cytotoxicity
to mice during the P388 in vivo antileukemic screening (toxic
at 45 mg kg− and 118% T/C at 25 mg kg ) and is lethal
1
−1
to brine shrimp, Artemia salina (LC = 234 μg mL− , 9KB
1
5
0
cytotoxicity ED50 = 2 μg mL− ). Additionally, it was known to
1 5
possess broad spectrum immune modulating activity by inhi-
biting the activation of pro-inflammatory cytokines in RAW
7
2
64.7 cell lines. Altholactone induces reactive oxygen species-
Fig. 1 Chemical structures of styryl lactones 1–4.
mediated apoptosis in bladder cancer T24 cells through mito-
chondrial dysfunction, MAPK-p38 activation and Akt suppres-
8
sion. Therefore, this lactone has been the target of synthetic
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 607, India. E-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in;
Fax: +91-40-27160512
9
efforts by several groups. In 1993, gonioheptolide A (3) was
10
isolated from the bark extract of Goniothalamus giganteus.
1
1
1
13
Later in 1999, the structure of gonioheptolide A was un-
†
Electronic supplementary information (ESI) available: H and C NMR spectra
of all compounds. See DOI: 10.1039/c5ob01598g
ambiguously revised as (1′R,2S,3S,4S,5R)-3,4-dihydroxy-2-[(19-
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Scheme 1 Retrosynthesis.
hydroxy-29-methoxycarbonyl)ethyl]-5-phenyltetrahydrofuran by
its racemic synthesis from (±)-goniofupyrone. The absolute
configuration of (+)-gonioheptolide A was established in
1
2
2
007 by its total synthesis. It showed marginal cytotoxicity to
1
3
certain human solid tumor cells in culture. Goniofupyrone
4) was also isolated from the stem bark of Goniothalamus
giganteus (Annonaceae) and is significantly cytotoxic to human
tumor cells. Its absolute stereochemistry was determined by
its synthesis.
Even though, several total syntheses of 2,
(
1
4
1
5
9
12
9,14
3
and 4
have been reported, to the best of our knowledge, no total syn-
thesis of goniothalesacetate 1 has been reported yet. As part of
our continuing efforts, in the preparation of biologically active
1
6
styryl lactones, we now disclose the first stereoselective
total synthesis of (+)-goniothalesacetate and total syntheses of
(+)-altholactone, (+)-gonioheptolide A and (−)-goniofupyrone
from L-(+)-DET via an advanced intermediate.
The retrosynthetic analysis of 1–4 is shown in Scheme 1. We
envisaged that the four target molecules (+)-goniothalesacetate,
altholactone, gonioheptolide A and goniofupyrone (1–4) could
be prepared from the common intermediate 5. C2 and C6
chiral centers in the intermediate 5 could be obtained from
Grignard and asymmetric acetate aldol reactions respectively.
Scheme 2 Synthesis of advanced intermediate 5.
2
1
Grignard reaction in the presence of MgBr ·OEt , afforded
2
2
1
9
,2-syn diol 10 in 82% yield and with a diastereomeric ratio of
Results and discussion
22
6 : 4 (determined by chiral HPLC). Following a modification
2
3
of the Mosher method, the newly created stereogenic center
in compound 10 bearing the hydroxyl group was assigned. The
syntheses of both the (S)- and (R)-MTPA esters of 10 were
achieved using MTPA acid with DCC as the coupling reagent.
The chemical shifts of both the (S)- and (R)-MTPA esters of 10
were assigned by H NMR. From the equation given in Fig. 2,
the Δδ values were calculated for as many protons as possible.
The synthesis of the key intermediate 5 is illustrated in
Scheme 2. The known allylic alcohol 6 prepared in 6 steps
1
7
from L-(+)-DET was subjected to Sharpless asymmetric epoxi-
1
8
dation using (+)-DET and TBHP to yield the required epoxy
alcohol 7 with good stereoselectivity in 85% yield. Iodination
under standard conditions followed by zinc reduction of the
derived iodo-epoxide afforded secondary allylic alcohol 8 in
1
1
9
8
6% yield for the two steps. The resulting secondary hydroxyl
was protected as its Bn ether to obtain 9 in 90% yield. Oxi-
dative cleavage of the olefin in compound 9 under Jin’s one-
2
0
pot conditions
using OsO
4
–NaIO
4
and 2,6-lutidine in
dioxane–water (3 : 1) furnished the corresponding aldehyde.
Due to its inherent lack of stability, aldehyde was used in the
next step without further purification. Treatment of the above
3
aldehyde with PhMgBr, generated from PhBr and Mg by the Fig. 2 Δδ = (δS − δR) × 10 for (S)- and (R)-MTPA esters of compound 10.
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The carbon chain bearing protons showing Δδ negative values occurred (TBS deprotection, β-methoxy elimination, cycli-
should be placed on the left hand side of the model (Fig. 2) zation) in a one-pot reaction by using TBAF in THF to furnish
whilst those where Δδ has positive values should be placed on a bicyclic compound 17, which can be later utilized in the syn-
the right hand side. From this the center was found to have thesis of altholactone (2). Alternatively, a silyl group removal in
the S-configuration which thus establishes the absolute stereo- compound 16 was achieved by treatment with PTSA in DCM :
chemistry of 10. Next, the hydroxyl group was tosylated in 10 MeOH (1 : 1) to afford the alcohol 18 in 82% yield, which was
and followed by the removal of acetonide under acidic con- subsequently acetylated with acetic anhydride and NEt
3
to give
ditions using PTSA in CH Cl : MeOH (1 : 1) resulted in the acetate compound 19. Benzyl ether deprotection in 19 could
2
2
4
desired 2,5-syn tetrahydrofuran 11 in 85% yield over two steps. not be achieved under TiCl conditions, which led to the com-
The secondary hydroxy group was protected as the corres- plete decomposition of the starting material. Finally, the clea-
ponding silyl ether 12 by treatment with tert-butyl(dimethyl)- vage of the Bn group occurred smoothly with SnCl (CH Cl ,
4
2
2
silyl triflate and 2,6-lutidine in 92% yield. Next, the removal of 40 °C) to furnish synthetic (+)-goniothalesacetate (1) in 90%
1
13
the PMB group with DDQ under buffer conditions obtained yield, whose spectroscopic properties ( H,
C NMR, IR,
the free alcohol 13. To extend the two carbon side chains with HRMS) as well as specific rotation ([α] ) were in full accord-
D
2
a chiral center, it was thought worthwhile to adopt a diastereo- ance with those reported for natural (+)-1.
selective asymmetric acetate aldol reaction.
The above bicyclic compound 17 formed during the syn-
Accordingly, oxidation of the alcohol using IBX furnished thesis of goniothalesacetate (refer Scheme 3) was converted
the corresponding aldehyde, which was immediately treated into the target compound 2. Accordingly, the removal of the
2
4
25
with (4S)-3-acetyl-4-benzyl-1,3-thiazolidine-2-thione 14 in the benzyl group with TiCl
4
in 17 led to the formation of altho-
9
presence of titanium(IV) chloride and ethyl(diisopropyl)amine, lactone (2) in 90% yield. The physical and spectroscopic data
yielding syn isomer 15 as the major diastereomer in a 97 : 3 of synthetic 2 were identical to the reported values of the
ratio (by crude H NMR analysis) (Scheme 2). The resulting natural product.
1
aldol adduct was immediately converted to methyl ester using
imidazole in methanol to obtain the pure compound 5 after
column chromatography. This advanced intermediate 5 can be
utilized for the synthesis of four styryl lactones.
Synthesis of (+)-gonioheptolide A (3) and synthesis of
−)-goniofupyrone (4)
(
With enough compound 5 in hand, we extended our work to
the synthesis of gonioheptolide 3, which was accomplished in
a single step (Scheme 4). Thus, global deprotection of
Bn and TBS groups in 5 was achieved with TiCl4 to afford
Synthesis of (+)-goniothalesacetate (1) and (+)-altholactone (2)
Synthesis of goniothalesacetate (1) was accomplished in 4
steps from an intermediate 5 (Scheme 3). Accordingly, the free
secondary hydroxyl group in 5 was methylated using Meerwein
salt to give O-methylated compound 16. Our next task was the
removal of the TBS group. However, a three step sequence
(
+)-gonioheptolide A (3) in 85% yield. The synthesis of gonio-
fupyrone 4 was accomplished in two steps from an intermediate
(Scheme 4). The treatment of 5 with PTSA/DCM deprotection
5
of the TBS group and cyclization occurred in one-pot to
furnish the lactone 20 in 90% yield. Finally, removal of
the benzyl group with TiCl in 20 led to the formation of
4
9
,14
(−)-goniofupyrone (4)
in 85% yield. The physical and spectro-
scopic data of synthetic 3 and 4 were identical to the reported
values of the natural products.
Scheme 3 Synthesis of goniothalesacetate (1) & altholactone (2).
Scheme 4 Synthesis of gonioheptolide A (3) & goniofupyrone (4).
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CDCl
3
): δ 7.27–7.23 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.50
Conclusion
(
s, 3H), 4.15–4.11 (m, 1H), 3.84 (dd, J = 12.9, 2.1 Hz, 1H), 3.81
We have reported the first stereoselective total synthesis of (s, 3H), 3.77 (dd, J = 8.2, 5.0 Hz, 1H), 3.66 (dd, J = 9.9, 4.8 Hz,
(
(
+)-goniothalesacetate and total syntheses of (+)-altholactone, 1H), 3.59–3.52 (m, 2H), 3.10–3.06 (m, 2H), 1.41 (s, 3H), 1.40
1
3
+)-gonioheptolide A and (−)-goniofupyrone using Grignard (s, 3H). C NMR (CDCl , 75 MHz): δ 159.3, 129.6, 129.5, 113.7,
3
and asymmetric acetate aldol reactions as the key steps.
110.0, 78.7, 76.4, 73.0, 69.7, 60.5, 55.6, 55.2, 54.5, 26.9, 26.5.
HRMS (ESI): m/z calcd for C17H O Na [M + Na] : 347.1450,
24 6
+
found = 347.1465.
Experimental section
(R)-1-((4S,5S)-5-((4-Methoxybenzyloxy)methyl)-2,2-dimethyl-
General
1,3-dioxolan-4-yl)prop-2-en-1-ol (8)
All reactions were performed under an inert atmosphere. All
glassware apparatus used for the reactions were perfectly oven/
flame dried. Anhydrous solvents were distilled prior to use:
To a stirred solution of 7 (5.1 g, 15.7 mmol) in Et
(
(
2
O–MeCN
3 : 1, 20 mL) were added TPP (6.2 g, 23.6 mmol) and imidazole
2.14 g, 31.5 mmol) at 0 °C and the mixture was stirred for
min. I (6.0 g, 23.6 mmol) was then added at 0 °C and the
2 2 2
THF from Na and benzophenone; CH Cl from CaH ; MeOH
5
2
from Mg cake. Commercial reagents were used without purifi-
cation. Column chromatography was carried out by using
silica gel (60–120 mesh). Analytical thin layer chromatography
mixture was stirred for 1 h. The reaction mixture was quenched
with sat. aq. Na S O (20 mL) and extracted with EtOAc
2
2 3
(
H
3 × 10 mL). The combined organic layers were washed with
O (10 mL), brine (10 mL), and dried (Na SO ). The solvent
(
(
TLC) was performed on silica gel 60 F254 pre-coated plates
2
2
4
2
5
250 μm thickness). Optical rotations [α]
D
were measured
was evaporated in vacuo to afford the crude iodo compound.
This was used for the next step without further purification.
To a stirred solution of the above iodo compound in EtOH
−
1
2
−1
using a polarimeter and given in 10 deg cm g . Infrared
spectra were recorded in CHCl /KBr (as mentioned) and
3
1
−
reported in wave number (cm ). Mass spectral data were
obtained using MS (EI) ESI, and HRMS mass spectrometers.
High resolution mass spectra (HRMS) [ESI+] were recorded
(
20 mL) was added activated Zn dust (3.66 g, 56.4 mmol) and
the mixture was stirred at reflux for 1–2 h. The mixture was
passed through a short pad of Celite. The filtrate was concen-
trated and the residue was purified by column chromatography
on silica gel (eluent: PE–EtOAc, 8 : 2) to afford 8 (4.16 g, 86%)
1
using either a TOF or a double focusing spectrometer. H NMR
1
3
spectra were recorded at 300, 400, 500 and C NMR spectra
were recorded at 75 and 125 MHz in CDCl3 solution unless
otherwise mentioned, chemical shifts are in ppm downfield
from tetramethylsilane and coupling constants (J) are reported
in hertz (Hz). The following abbreviations are used to design-
ate signal multiplicity: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad. The diastereomeric purity
was determined by HPLC.
2
5
as a colorless liquid. [α] = +10.7 (c 0.24, CHCl ); IR (neat):
D
3
1
1
3
454, 2987, 2867, 1612, 1513, 1248, 1081 cm−
;
H NMR
(
300 MHz, CDCl ): δ 7.27–7.23 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H),
3
5
1
7
3
.89–5.81 (m, 1H), 5.35 (dt, J = 17.2, 1.5 Hz, 1H), 5.22 (dt, J =
0.6, 1.5 Hz, 1H), 4.5 (s, 2H), 4.19–4.08 (m, 2H), 3.86 (dd, J =
.9, 4.4 Hz, 1H), 3.80 (s, 3H), 3.59 (dd, J = 10.0, 5.3 Hz, 1H),
.53 (dd, J = 10.0, 4.8 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 3H).
1
3
C NMR (CDCl , 75 MHz): δ 159.2, 136.7, 129.6, 129.3, 116.8,
3
((2S,3R)-3-((4R,5S)-5-((4-Methoxybenzyloxy)methyl)-
1
13.7, 109.5, 80.9, 76.0, 73.1, 72.0, 69.8, 55.2, 27.0 (2C). HRMS
2
,2-dimethyl-1,3-dioxolan-4-yl)oxiran-2-yl)methanol (7)
+
(
ESI): m/z calcd for C17
H
24
O
5
Na [M + Na] : 331.1504, found =
To a freshly flame dried double necked round bottom flask 331.1516.
equipped with activated molecular sieves (4 Å) (5 g) and dry
i
(4S,5S)-4-((R)-1-(Benzyloxy)allyl)-5-((4-methoxybenzyloxy)-
methyl)-2,2-dimethyl-1,3-dioxolane (9)
CH
3
2
Cl
2
4
(30 mL) at −20 °C were added Ti(O Pr) (1.14 mL,
.89 mmol) and D-(+)-diisopropyl tartrate (0.86 g, 3.89 mmol)
and the mixture was stirred for 30 min. To this reaction To a suspension of NaH (60%, 0.7 g, 28.4 mmol) in dry THF
mixture, allyl alcohol 6 (6.0 g, 19.4 mmol) after an interval of (20 mL) was added dropwise a solution of alcohol 8 (3.50 g,
3
0 min, TBHP (5.9 mL, 29.20 mmol, 5 M solution in CH Cl ) 11.3 mmol) in THF (20 mL) at 0 °C. To this reaction mixture
2 2
was then added and the stirring was continued till the com- TBAI (0.01 g) and benzyl bromide (1.94 mL, 11.3 mmol) were
pletion of the reaction (8 h). The reaction mixture was warmed added subsequently and stirring was continued for 2 h at the
to 0 °C and then filtered through Celite. The filtrate was same temperature and 6 h at room temperature. The reaction
quenched with water (1 mL) and 15% aqueous NaOH solution mixture was quenched by using crushed ice flakes until a clear
(
1 mL) and stirred vigorously for 1 h. The biphasic solution solution (biphasic) was formed. The reaction mixture was
was separated and the aqueous layer was extracted with extracted with ethyl acetate (2 × 30 mL). The organic extracts
CH Cl (3 × 20 mL). The combined organic extracts were dried were washed with water (1 × 50 mL), brine (1 × 50 mL) and
over anhydrous Na SO and concentrated under vacuum. The dried over anhydrous Na SO . Evaporation of the solvent fol-
crude residue was purified by column chromatography lowed by column chromatography (10% EtOAc/hexane)
2
2
2
4
2
4
(
7 : 3 hexane–EtOAc) to afford the pure epoxide 7 (5.36 g, 85%) afforded the pure product 9 (4.08 g, 90% yield) as a colorless
25
25
as a colorless oil. [α]
2
D
= −7.5 (c 0.18, CHCl
3
); IR (neat): 3452, liquid. [α]
D
3
= −22.7 (c 0.22, CHCl ); IR (neat): 2986, 2865,
−
1
1
−1 1
987, 2868, 1612, 1513, 1248, 1089 cm ; H NMR (300 MHz, 1611, 1513, 1086 cm ; H NMR (300 MHz, CDCl ): δ 7.38–7.21
3
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(
(
1
m, 7H), 6.86 (d, J = 8.6 Hz, 2H), 5.81–5.67 (m, 1H), 5.36–5.26 (R)-MTPA ester of compound 10
m, 2H), 4.67 (d, J = 12.2 Hz, 1H), 4.49 (s, 2H), 4.42 (d, J =
2.2 Hz, 1H), 4.16–4.08 (m, 1H), 3.94–3.84 (m, 2H), 3.80
s, 3H), 3.57 (dd, J = 10.5, 3.2 Hz, 1H), 3.46 (dd, J = 10.5,
1
H NMR (500 MHz, CDCl
3
): δ 7.45–7.41 (m, 1H), 7.40–7.35
(
m, 4H), 7.33–7.15 (m, 9H), 7.06 (d, J = 8.5 Hz, 2H), 6.83 (d, J =
(
8
4
1
.6 Hz, 2H), 6.23 (d, J = 9.1 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H),
.35 (d, J = 11.6 Hz, 1H), 4.31 (d, J = 7.9 Hz, 2H), 4.05 (td, J =
0.6,5.3 Hz, 1H), 3.81–3.77 (m, 4H), 3.40 (s, 3H), 3.30–3.26
1
3
6
7
1
2
4
.2 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3H). C NMR (CDCl3,
5 MHz): δ 159.0, 134.2, 129.2, 128.2 (2C), 127.5 (2C), 127.4,
19.7, 113.6, 109.6, 80.0, 79.0, 76.7, 72.9, 70.3, 70.2, 55.1, 27.1,
(
m, 2H), 3.13 (dd, J = 9.6, 5.8 Hz, 1H), 1.39 (s, 3H), 1.20 (s, 3H).
+
6.9. HRMS (ESI): m/z calcd for C H O N [M + NH ] :
2
4
34
5
4
16.2417, found = 416.2431.
(S)-MTPA ester of compound 10
1
(1S,2R)-2-(Benzyloxy)-2-((4R,5S)-5-((4-methoxybenzyloxy)-
H NMR (500 MHz, CDCl ): δ 7.37–7.34 (m, 1H), 7.34–7.26
3
methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-phenylethanol (10)
(m, 11H), 7.17–7.13 (m, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.80 (d,
J = 8.6 Hz, 2H), 6.15 (d, J = 9.3 Hz, 1H), 4.81 (d, J = 11.7 Hz,
To a solution of 9 (2.4 g, 5.52 mmol) in 1,4-dioxane/water
1
4
H), 4.57 (d, J = 11.6 Hz, 1H), 4.30 (ABq, J = 25.4, 11.9 Hz, 2H),
.12 (m, 1H), 3.82–3.78 (m, 4H), 3.37 (s, 3H), 3.33–3.27
(
(
3 : 1; 12 mL), 2,6-lutidine (1.7 mL, 16.58 mmol), and OsO4
2.82 mL, 0.05 mmol) followed by NaIO (5.20 g, 24.8 mmol)
4
(
m, 2H), 3.14 (dd, J = 9.7, 6.1 Hz, 1H), 1.45 (s, 3H), 1.24 (s, 3H).
were sequentially added at room temperature, and the mixture
was stirred for 2 h. After the completion of the reaction (moni-
tored by TLC), 1,4-dioxane was removed under reduced
(
2S,3R,4S,5R)-4-(Benzyloxy)-2-((4-methoxybenzyloxy)methyl)-
5-phenyltetrahydrofuran-3-ol (11)
pressure, and the residue was diluted with CH
The organic layer was separated and the aqueous layer
extracted with CH Cl (2 × 10 mL). The combined organic
2 2
Cl (20 mL).
To a stirred mixture of compound 10 (1.8 g, 3.76 mmol), tri-
ethylamine (1.04 mL, 7.53 mmol) and DMAP (cat, 10 mol%) in
2
2
2 2
CH Cl (20 mL) at 0 °C was added tosyl chloride (0.86 g,
layers were quickly washed with 1 N HCl (2 × 5 mL) to remove
excess 2,6-lutidine followed by brine (2 × 5 mL), dried with
4
.51 mmol) in CH Cl (2 mL) over 15 min. The reaction was
2
2
allowed to warm to room temperature and stirred for 2 h. The
reaction mixture was quenched with saturated NaHCO . The
organic layer was extracted with CH Cl (2 × 20 mL). The com-
2 4
anhydrous Na SO , and concentrated under reduced pressure
to give the crude aldehyde.
3
To a suspension of Mg (0.26 g, 11.0 mmol) in anhydrous
THF (10 mL) phenyl bromide (1.72 mL, 11.0 mmol) was
added dropwise under a nitrogen atmosphere at room temp-
erature. The suspension was stirred for half an hour at room
temperature.
2
2
bined organic layers were washed with H
solution (2 × 20 mL) and dried over Na
2
O (2 × 20 mL), brine
SO . Removal of the
2
4
solvent under reduced pressure gave the crude product which
was used for the next reaction without further purification.
To a stirred solution of compound 10a (2.1 g, 3.30 mmol)
in MeOH : DCM (1 : 1) 5 ml PTSA was added (10 mol%) and the
reaction mixture was stirred at r.t. for 3 h. MeOH and DCM
were removed under reduced pressure and the crude product
was purified by column chromatography on silica gel (eluent:
PE–EtOAc, 7 : 3) to afford the acid 11 (1.16 g, 72%) as a viscous
In another R.B. flask the crude aldehyde 9a (2.2 g,
5
.5 mmol) dissolved in CH Cl (10 mL) under nitrogen con-
2 2
ditions was added at 0 °C to a stirred suspension of
MgBr ·Et O (1.83 g, 7.15 mmol) in CH Cl . After stirring for
0 min, the flask was cooled to −78 °C and the phenyl
2
2
2
2
2
Grignard generated above was added slowly at −78 °C and the
reaction was stirred further at this temperature for 1 h. The
solvent was then removed in vacuo, after which the residue was
25
liquid; yield: [α]
611, 1511, 1247, 1032 cm−
δ 7.45–7.42 (m, 2H), 7.34–7.24 (m, 10H), 6.89 (d, J = 8.6 Hz,
D 3
= +3.4 (c 0.52, CHCl ); IR (neat): 3443, 2908,
1
1
1
;
H NMR (300 MHz, CDCl3):
diluted with CH
reaction mixture was quenched with saturated aq. NH
extracted with CH Cl (3 × 30 mL). The combined organic
2
Cl
2
and allowed to warm to 0 °C. Then, the
2
4
H), 4.79 (d, J = 4.7 Hz, 1H), 4.64–4.52 (m, 4H), 4.42 (dd, J =
.5, 2.3 Hz, 1H), 3.96 (dd, J = 10.5, 4.4 Hz, 1H), 3.94–3.89
4
Cl and
2
2
1
3
(
m, 3H), 3.81 (s, 3H). C NMR (CDCl
3
, 75 MHz): δ 159.3,
40.2, 137.7, 129.4, 128.3, 127.7, 127.6, 127.5, 126.3, 113.8,
2.0, 84.7, 79.2, 77.9, 73.6, 72.0, 68.6, 55.2. HRMS (ESI) m/z
2 4
layers were washed with brine, dried over Na SO , and the
1
9
solvent was removed under reduced pressure. The compound
was purified by silica gel column chromatography (20% EtOAc/
+
2
5
26 28 5
calcd for C H O Na [M + Na] : 443.1812, found = 443.1829.
hexane) to provide 10 (2.1 g, 82%) as yellow oil. [α]
D
= +24.3
(
3
c 0.27, CHCl ); IR (neat): 3474, 2987, 2932, 1611, 1513, 1248,
085 cm− ; H NMR (300 MHz, CDCl ): δ 7.43–7.24 (m, 9H),
1
1
((2S,3R,4R,5R)-4-(Benzyloxy)-2-((4-methoxybenzyloxy)methyl)-
-phenyltetrahydrofuran-3-yloxy)(tert-butyl)dimethylsilane (12)
1
7
4
5
3
3
3
5
.18–7.14 (m, 3H), 6.85 (d, J = 8.6 Hz, 2H), 4.92–4.89 (m, 1H),
.49 (d, J = 11.2 Hz, 1H), 4.44–4.39 (m, 3H), 4.23 (td, J = 10.5, A solution of compound 11 (0.72 g, 1.64 mmol) in CH Cl
2 2
.2 Hz, 1H), 3.82–3.79 (m, 4H), 3.60 (dd, J = 5.0, 3.0 Hz, 1H), (10 mL) was treated with 2,6-lutidine (0.57 mL, 4.93 mmol) at
.50 (dd, J = 10.0, 5.2 Hz, 1H), 3.41 (dd, J = 9.9, 5.2 Hz, 1H), 0 °C and stirred for 20 min. Next, TBSOTf (0.45 mL,
1
3
.09 (d, J = 3.9 Hz, 1H), 1.45 (s, 3H), 1.37 (s, 3H). C NMR 1.97 mmol) was added, and following the completion of the
(CDCl , 75 MHz): δ 159.1, 141.2, 137.6, 129.8, 129.2, 128.3, reaction as indicated by TLC, the mixture was quenched with
3
1
7
28.2, 128.1, 127.8, 127.5, 126.4, 113.7, 109.1, 81.6, 79.6, 75.5, sat. NH
4
Cl solution and extracted with CH
2
Cl
2
(3 × 50 mL).
SO
and evaporated under reduced pressure to yield a viscous
4.9, 74.2, 73.0, 69.9, 55.2, 26.9, 26.8. HRMS (ESI) m/z calcd for The combined organic layer was dried over anhydrous Na
2
4
,
+
C H O Na [M + Na] : 501.2220, found = 501.2247.
2
9
34 6
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liquid, which on purification by silica gel column chromato- 1H), 4.73–4.68 (m, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.52 (d, J =
graphy (EtOAc–hexane, 1 : 9) afforded the silyl-protected ether 11.7 Hz, 1H), 4.37 (dd, J = 4.1, 1.9 Hz, 1H), 3.91 (dd, J = 3.5,
2
5
1
2 (0.81 g, 92%) as a colorless liquid. [α]
CHCl
); IR (neat): 2929, 2858, 1611, 1513, 1250, 1093 cm−1
H NMR (300 MHz, CDCl ): δ 7.54–7.30 (m, 12H), 6.98 (d, J = (s, 3H), −0.15 (s, 3H). C NMR (CDCl , 75 MHz): δ 201.1,
D
= +31.2 (c 0.28, 2.1 Hz, 1H), 3.63–3.53 (m, 2H), 3.27–3.19 (m, 2H), 3.08–2.98
3
;
(m, 2H), 2.89 (dd, J = 16.4, 11.5 Hz, 2H), 0.78 (s, 9H), 0.07
1
13
3
3
8
4
0
1
9
.5 Hz, 2H), 5.0 (d, J = 2.3 Hz, 1H), 4.72–4.58 (m, 4H), 171.5, 140.5, 137.3, 136.4, 129.4, 129.2, 128.9, 128.8, 128.4,
.46–4.36 (m, 2H), 3.95–3.84 (m, 6H), 0.90 (s, 9H), 0.21 (s, 3H), 128.2, 127.9, 127.7, 127.5, 127.2, 127, 126.5, 113.9, 91.3, 85.1,
1
3
.12 (s, 3H). C NMR (CDCl , 75 MHz): δ 159.1, 140.9, 137.6, 83.2, 78, 72, 68.5, 67.2, 42.5, 36.5, 31.9, 25.5, 17.7, −4.5, −5.1.
3
+
46 5 2
30.3, 129.5, 128.4, 128.0, 127.7, 127.5, 127.2, 126.6, 113.7, HRMS (ESI): m/z calcd for C36H O NS Si [M + H] : 664.2564,
2.0, 86.2, 81.3, 77.0, 73.1, 71.8, 68.1, 55.2, 25.5, 17.9, −4.8, found = 664.2581.
+
−
5.3. HRMS (ESI): m/z calcd for C H O NSi [M + NH ] :
3
2
46
5
4
(R)-Methyl 3-((2S,3S,4R,5R)-4-(benzyloxy)-3-
5
52.3139, found = 552.3113.
(tert-butyldimethylsilyloxy)-5-phenyltetrahydrofuran-2-yl)-
((2S,3R,4R,5R)-4-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-
3-hydroxypropanoate (5)
5
-phenyltetrahydrofuran-2-yl)methanol (13)
Imidazole (0.41 g, 6.0 mmol) was added to a stirred solution of
To an ice-bath cooled solution of compound 12 (0.7 g, compound 15 (0.40 g, 0.60 mmol) in MeOH (10 mL). After stir-
.31 mmol) in 10 mL aq. CH Cl (CH Cl : H O, 9 : 1), DDQ ring overnight the yellow solution became colorless and then
1
2
2
2
2
2
(
0.32 g, 1.44 mmol) was added and the reaction mixture was EtOAc (10 mL) and saturated NaHCO
stirred for 1 h at 0 °C. The reaction mixture was washed with added. The layers were separated and the aqueous layer was
% aq. NaHCO solution (10 mL). The layers were separated extracted with EtOAc (3 × 5 mL). The combined organic layers
3
(10 mL) solutions were
5
3
and the aqueous layer was extracted twice with CH
2 2 4
Cl (2 × 10). were dried with MgSO , filtered, and concentrated in vacuo.
The combined organic extracts were washed with water, dried Flash chromatography (petroleum ether/EtOAc, 8 : 2) provided
2
5
over anhydrous Na SO and concentrated in vacuo. The crude methyl ester 5 (0.26 g, 90%) as a colorless oil. [α] = +4.1
2
4
D
product was purified by column chromatography (15% EtOAc/ (c 0.32, CHCl
3
); IR (neat): 3449, 2929, 2857, 1741, 1457, 1255,
hexane) to afford alcohol 13 (0.46 g, 85% yield) as a liquid. 1078 cm− ; H NMR (300 MHz, CDCl
1
1
): δ 7.48–7.44 (m, 2H),
3
2
5
[
α] = +29.0 (c 0.20, CHCl ); IR (neat): 3451, 2931, 2858, 1606, 7.35–7.24 (m, 8H), 4.89 (d, J = 3.9 Hz, 1H), 4.54 (d, J = 11.5 Hz,
D
3
1
460, 1072 cm−
1
;
1
3
H NMR (300 MHz, CDCl ): δ 7.46–7.44 1H), 4.51–4.46 (m, 2H), 4.39 (dd, J = 4.4, 2.7 Hz, 1H), 4.10–4.08
(
m, 2H), 7.35–7.24 (m, 8H), 4.88 (d, J = 3.9 Hz, 1H), 4.51 (ABq, (m, 1H), 3.91 (dd, J = 3.9, 2.4 Hz, 1H), 3.72 (s, 3H), 2.74–2.61
1
3
J = 20.2, 11.5 Hz, 2H), 4.38 (dd, J = 4.4, 2.3 Hz, 1H), 4.25–4.21 (m, 2H), 0.81 (s, 9H), 0.08 (s, 3H), −0.09 (s, 3H). C NMR
(
m, 1H), 4.01 (dd, J = 11.9, 5.7 Hz, 1H), 3.92–3.87 (m, 2H), 0.83 (CDCl
3
, 75 MHz): δ 172.0, 140.4, 137.3, 129.2, 128.8, 128.4,
1
3
(s, 9H), 0.07 (s, 3H), −0.04 (s, 3H). C NMR (CDCl
3
, 75 MHz): 128.3, 128.1, 127.9, 127.7, 127.6, 126.5, 126.4, 91.3, 84.6, 82.1,
δ 140.5, 137.4, 128.4, 128.3, 127.8, 127.6, 126.6, 91.8, 85.1, 78.3, 72.1, 67.7, 51.7, 37.9, 25.5, 17.7, −4.6, −4.2. HRMS (ESI)
+
8
1.5, 77.9, 72.1, 62.3, 25.5, 17.8, −4.8, −5.2. HRMS (ESI) m/z m/z calcd for C27
H
39
O
6
Si [M + H] : 487.2490, found = 487.2510.
+
calcd for C24
H
34
O
4
NaSi [M + Na] : 437.2096, found = 437.2118.
(
R)-Methyl 3-((2S,3S,4R,5R)-4-(benzyloxy)-
(R)-1-((S)-4-Benzyl-2-thioxothiazolidin-3-yl)-3-((2S,3S,4R,5R)-
3-(tert-butyldimethylsilyloxy)-5-phenyltetrahydrofuran-2-yl)-
4
-(benzyloxy)-3-(tert-butyldimethylsilyloxy)-5-
3-methoxypropanoate (16)
phenyltetrahydrofuran-2-yl)-3-hydroxypropan-1-one (15)
To a solution of alcohol 5 (0.1 g, 0.20 mmol) in DCM (5 mL) at
To a stirred solution of 13 (0.24 g, 1.04 mmol) in dry CH
2
Cl
2
0 °C was added Proton Sponge (0.13 g, 0.60 mmol) followed by
(
1
1
5 mL) at 0 °C under argon, freshly distilled TiCl
4
(0.11 mL, trimethyloxonium tetrafluoroborate (0.09 g, 0.60 mmol). The
.06 mmol) was added slowly. After 15 min, DIPEA (0.2 mL, reaction mixture was stirred for 6 h, before being quenched
.16 mmol) was added dropwise and the reaction mixture was with NaHCO (5 mL), filtered through Celite, and extracted
3
stirred for 1 h at 0 °C. The reaction mixture was cooled to with DCM (2 × 5 mL). The combined organic extracts were
78 °C and stirred for another 1 h before the addition of alde- washed with 1 N HCl (6 mL), dried (MgSO ) and concentrated
−
4
hyde 14 (0.43 g dissolved in 5 mL of dry CH
2 2
Cl , 1.04 mmol). in vacuo. Purification by flash chromatography (hexanes/
The reaction was continued for further 15 min at −78 °C prior EtOAc, 9 : 1) afforded methyl ether 16 (0.08 g, 78%) as a colour-
2
5
to quenching with saturated aqueous NH Cl (10 mL). The less oil. [α] = +8.2 (c 0.25, CHCl ); IR (neat): 2953, 1740, 1650,
4
D
3
mixture was extracted with EtOAc (2 × 50 mL), washed with 1076 cm− ; H NMR (300 MHz, CDCl
water and brine, dried over Na SO , and concentrated in vacuo. 7.35–7.21 (m, 8H), 4.95 (d, J = 3.2 Hz, 1H), 4.60 (d, J = 11.7 Hz,
Purification by column chromatography (SiO , 100–200 mesh, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.22 (dd, J = 3.5, 1.9 Hz, 1H),
1 1
): δ 7.45–7.42 (m, 2H),
3
2
4
2
2
0–30% EtOAc in hexane) of the crude residue resulted in 4.14–4.07 (m, 2H), 3.87 (dd, J = 3.0, 1.9 Hz, 1H), 3.71 (s, 3H),
aldol adduct 15 (0.41 g, 60% over 2 steps) as a white solid. 3.57 (s, 3H), 2.60–2.55 (m, 2H), 0.80 (s, 9H), 0.02 (s, 3H), −0.19
1
3
Attempts toward crystallization from 20% EtOAc/hexane gave a (s, 3H). C NMR (CDCl , 75 MHz): δ 171.6, 141, 137.5, 128.4,
3
2
5
yellow oil. [α]
856, 1695, 1456, 1255, 1042 cm− ; H NMR (300 MHz, CDCl
δ 7.47–7.44 (m, 2H), 7.37–7.25 (m, 13H), 4.96 (d, J = 3.3 Hz, calcd for C H O SiNa [M + Na] : 523.2481, found = 523.2481.
D
= +10.9 (c 0.45, CHCl
3
); IR (neat): 3455, 2928, 128.1, 127.9, 127.7, 127.3, 126.4, 90.7, 85.7, 84.3, 77.1, 76.8,
1
1
2
3
): 71.8, 59.3, 51.6, 36.7, 25.6, 17.8, −4.3, −5.2. HRMS (ESI) m/z
+
2
8
40 6
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1046 cm− ; H NMR (300 MHz, CDCl
1
1
): δ 7.45 (d, J = 7.1 Hz,
(R)-Methyl 3-((2R,3S,4S,5R)-4-(benzyloxy)-3-hydroxy-
3
5
-phenyltetrahydrofuran-2-yl)-3-methoxypropanoate (18)
2H), 7.38–7.28 (m, 3H), 5.0 (dd, J = 5.1, 2.6 Hz, 1H), 4.71 (d, J =
6
2
.1 Hz, 1H), 4.31 (dd, J = 6.9, 5.2 Hz, 1H), 4.08 (dd, J = 3.7,
.8 Hz, 1H), 4.05 (td, J = 6.9, 1.1 Hz, 1H), 3.72 (s, 3H), 3.55
To a stirred solution of compound 16 (0.052 g, 0.10 mmol) in
MeOH : DCM (1 : 2, 5 mL) was added PTSA (10 mol%) and the
reaction mixture was stirred at r.t. for 4 h. The MeOH was
removed under reduced pressure and the crude product was
purified by column chromatography on silica gel (eluent:
PE–EtOAc, 8 : 2) to afford the acid 18 (0.032, 82%) as a viscous
1
3
(
s, 3H), 2.60–2.58 (m, 2H), 2.08 (s, 3H). C NMR (CDCl3,
7
8
5 MHz): δ 171.5, 171.4, 139.4, 128.3, 127.8, 125.9, 84.9, 83.5,
1
3
1.9, 80.9, 77.2, 59.2, 51.8, 36.5. H NMR (300 MHz, CD OD):
δ 7.44 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H), 7.27 (tt, J =
6.5, 1.2 Hz, 1H), 5.08 (dd, J = 4.2, 2.4 Hz, 1H), 4.70 (d, J =
6.1 Hz, 1H), 4.26 (dd, J = 7.1, 4.2 Hz, 1H), 4.03 (dd, J = 4.4,
2
5
liquid; yield. [α]
2
D 3
= +25.0 (c 0.15, CHCl ); IR (neat): 3449, 2924,
854, 1738, 1636, 1215, 1098 cm−1; H NMR (300 MHz, CDCl ):
1
3
2.4 Hz, 1H), 3.99 (td, J = 7.3, 4.4 Hz, 1H), 3.69 (s, 3H), 3.51
δ 7.44–7.42 (m, 2H), 7.35–7.26 (m, 8H), 4.81 (d, J = 4.2 Hz, 1H),
.60 (ABq, J = 18.7, 11.7 Hz, 2H), 4.35–4.32 (m, 1H), 4.21–4.17
m, 1H), 4.13 (dd, J = 4.7, 3.9 Hz, 1H), 3.91 (dd, J = 4.1, 1.6 Hz,
(
(
s, 3H), 2.58 (d, J = 4.6 Hz, 1H), 2.56 (d, J = 7.6 Hz, 1H), 1.98
s, 3H). C NMR (CDCl
4
(
1
3
3
, 75 MHz): δ 173.2, 171.8, 141.7, 129.3,
1
27.1, 88.1, 83.3, 82.9, 81.2, 78.2, 59.3, 52.3, 37.5, 20.7. HRMS
1
H), 3.71 (s, 3H), 3.51 (s, 3H), 2.82 (dd, J = 18.3, 6.2 Hz, 2H).
+
1
3
(ESI): m/z calcd for C17
3
H
22
O
7
Na [M + Na] : 361.1257, found =
C NMR (CDCl , 75 MHz): δ 172.0, 140.2, 137.6, 128.4, 128.3,
3
61.1247.
1
27.8, 127.6, 126.2, 92.1, 84.9, 81.8, 77.1, 72.1, 58.0, 51.9, 35.9.
+
HRMS (ESI): m/z calcd for C22
found = 409.1621.
H
26
O
6
Na [M + Na] : 409.1606,
(
2R,3R,3aR,7aS)-3-(Benzyloxy)-2-phenyl-3,3a-dihydro-
H-furo[3,2-b]pyran-5(7aH)-one (17)
To a solution of 16 (30 mg, 0.06 mmol) in anhydrous THF
5 mL) was added TBAF (0.12 mL, 0.12 mmol, 1 M solution in
THF) dropwise at 0 °C, and the mixture was stirred for 2 h.
2
(
R)-Methyl 3-((2S,3S,4R,5R)-3-acetoxy-4-(benzyloxy)-
-phenyltetrahydrofuran-2-yl)-3-methoxypropanoate (19)
Anhydrous Et N (0.018 mL, 0.13 mmol), Ac O (0.006 mL,
.06 mmol), and DMAP (10 mg) were added to a solution of
alcohol 18 (20 mg, 0.05 mmol) in anhydrous CH Cl (5 mL)
5
(
3
2
H O (5 mL) was added, and the mixture was extracted with
ethyl acetate (2 × 5 mL). The org. extracts were washed with
0
2
2
2
brine (5 mL) and dried over anhydrous Na SO . After the
under a nitrogen atmosphere at room temperature. The
mixture was stirred at room temperature for 30 min. The reac-
2
4
evaporation of the solvent, the residue was purified by column
chromatography (30% EtOAc/hexane) to furnish the bicyclic
compound 17 (15 mg, 82% yield) as a colorless solid. M.P.
tion mixture was quenched with saturated NaHCO . The
3
2 2
organic layer was extracted with CH Cl (2 × 5 mL). The com-
2
5
8
1
9–91 °C; [α] = +11 2.7 (c 0.29, CHCl ); IR (neat): 2920, 1734,
D 3
bined organic layers were dried over Na SO . The solvent was
2
4
639, 1245, 1096 cm− ; H NMR (300 MHz, CDCl
1
1
): δ 7.35–7.26
removed under reduced pressure, and the mixture was purified
by silica gel column chromatography (10% EtOAc/hexane) to
3
(
5
(
1
1
7
3
m, 10H), 7.0 (dd, J = 9.9, 5.2 Hz, 1H), 6.25 (d, J = 9.9 Hz, 1H),
.01 (dd, J = 4.7, 1.3 Hz, 1H), 4.85 (d, J = 5.4 Hz, 1H), 4.68
d, J = 11.5 Hz, 1H), 4.62–4.57 (m, 2H), 4.24 (dd, J = 5.3, 1.3 Hz,
2
5
afford 19 (21 mg, 95%) as a colorless liquid. [α] = +30.4
D
−
1
(
c 0.12, CHCl ); IR (neat): 2927, 1741, 1646, 1231, 1097 cm ;
3
1
3
1
H). C NMR (CDCl , 75 MHz): δ 160.1, 139.4, 138.2, 136.8,
H NMR (300 MHz, CDCl
3
): δ 7.38–7.26 (m, 10H), 5.24 (dd, J =
3
28.6, 128.5, 128.3, 128.1, 127.7, 126.2, 124.2, 90.7, 85.3, 84.2,
3
1
4
3
7
1
3
4
.5, 1.1 Hz, 1H), 4.89 (d, J = 3.9 Hz, 1H), 4.77 (d, J = 11.9 Hz,
+
2.6, 68.7. HRMS (ESI): m/z calcd for C20
H
19
O
4
[M + H] :
H), 4.59 (d, J = 12.1 Hz, 1H), 4.27 (dd, J = 7.8, 3.5 Hz, 1H),
.14–4.08 (m, 1H), 3.84 (dd, J = 4.0, 1.1 Hz, 1H), 3.71 (s, 3H),
23.1270, found = 323.1277.
1
3
.56 (s, 3H), 2.55–2.51 (m, 2H), 2.02 (s, 3H). C NMR (CDCl3,
5 MHz): δ 171.4, 170.1, 140.0, 139.2, 128.4, 128.3, 127.8, (2R,3R,3aS,7aS)-3-Hydroxy-2-phenyl-3,3a-dihydro-
27.7, 127.6, 125.8, 89.9, 85.8, 82.4, 77.2, 76.5, 72.1, 59.3, 51.8, 2H-furo[3,2-b]pyran-5(7aH)-one (2)
+
6.8. HRMS (ESI): m/z calcd for C H O Na [M + Na] :
2
4
28 7
To a stirred solution of compound 17 (10 mg, 0.03 mmol) in
anhydrous CH Cl (5 mL) was added TiCl (1 M solution in
51.1711, found = 451.1727.
2
2
4
DCM, 0.06 mL, 0.06 mmol) at 0 °C and the reaction mixture
was stirred at the same temperature for 1 h. The reaction
(
5
R)-Methyl 3-((2S,3S,4R,5R)-3-acetoxy-4-hydroxy-
-phenyltetrahydrofuran-2-yl)-3-methoxypropanoate (1)
mixture was quenched with solid NaHCO
To a stirred solution of compound 19 (9 mg, 0.02 mmol) in tered, and the solvent was removed under reduced pressure.
anhydrous CH Cl (5 mL) was added SnCl (1 M solution in The residue was purified by silica gel column chromatography
DCM, 0.04 mL, 0.04 mmol) at 40 °C and the reaction mixture (40% EtOAc/hexane) to afford 2 (6.4 mg, 90%) as a colorless
3
(20 mg) and fil-
2
2
4
2
5
4
25
D
was stirred at the same temperature for 1 h. The reaction solid. M.p. 108–110 °C; [α] : +115.6 (c 0.52, CHCl ); lit. [α] :
D
3
mixture was quenched with solid NaHCO
and the solvent was removed under reduced pressure. The 1093 cm− ; H NMR (300 MHz, CDCl
residue was purified by silica gel column chromatography 6.99 (dd, J = 9.9, 5.0 Hz, 1H), 6.22 (d, J = 9.9 Hz, 1H), 4.92
3
(5 mg) and filtered, +118.6 (c 0.5, CHCl
3
); IR (neat): 3433, 2923, 1729, 1638, 1251,
1
1
3
): δ 7.36–7.28 (m, 5H),
(
70% EtOAc/hexane) to afford 1 (7 mg, 90%) as a colorless (dd, J = 5.0, 2.2 Hz, 1H), 4.73 (d, J = 5.6 Hz, 1H), 4.63 (t, J =
2
5
2
25
D 3 D
yellow oil. [α] : +3.02 (c 0.32, CH OH); lit [α] : +1.03 (c 0.39, 5.0 Hz, 1H), 4.44 (dd, J = 6.1, 2.2 Hz, 1H), 3.36 (Brs, 1H).
CH OH); IR (neat): 3451, 2923, 2853, 1740, 1632, 1237,
1
3
C NMR (CDCl , 75 MHz): δ 161.4, 140.4, 138.1, 128.6, 128.3,
3
3
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2
5
12
25
1
26.1, 123.5, 86.4, 85.9, 83.5, 68.1. HRMS (ESI): m/z calcd for oil. [α]
D
: −6.52 (c 0.34, CHCl
IR (neat): 3393, 2923, 1734, 1452, 1049 cm
300 MHz, CDCl ): δ 7.32–7.24 (m, 5H), 4.94 (dd, J = 5.0,
.3 Hz, 1H), 4.62 (d, J = 6.2 Hz, 1H), 4.33–4.24 (m, 2H), 4.17
dd, J = 6.2, 2.3 Hz, 1H), 3.91 (Brs, 1H), 2.79 (dd, J = 17, 3.5 Hz,
3
); lit. [α]
D
: −5.0 (c 0.3, CHCl
3
);
+
−1
1
C H O [M + H] : 233.0804, found = 233.0808.
;
H NMR
1
3
13 4
(
2
(
3
(
2
2R,3R,3aS,7R,7aS)-3-(Benzyloxy)-7-hydroxy-
-phenyltetrahydro-2H-furo[3,2-b]pyran-5(6H)-one (20)
A stirred solution of 5 (25 mg, 0.05 mmol) in DCM (5 mL) was 1H), 2.62 (dd, J = 16.7, 4.5 Hz, 1H). C NMR (CDCl
1
3
3
, 75 MHz):
treated with p-TSA (10%, 0.25 mmol) for 3 h at 40 °C. After the δ 170.6, 137.9, 128.6, 128.3, 125.9, 87, 85.4, 83.3, 75.8, 65.3,
+
completion of the reaction (indicated by TLC), the reaction 34.8. HRMS (ESI): m/z calcd for C H O [M + H] : 251.0908,
1
3
15 5
mixture was diluted with DCM (5 mL) and then solid NaHCO
0.34 g, 4.0 mmol) was added and stirred for further 15 min.
3
found = 233.0900.
(
The reaction mixture was then filtered through a short pad of
Celite and the Celite pad was washed with DCM (3 × 10 mL).
Evaporation of solvent followed by silica gel column chromato-
graphy of the resulting residue using EtOAc as the eluent
Acknowledgements
SA and PA thank CSIR, New Delhi for the award of fellowships.
All the authors thank CSIR, New Delhi, India for financial
support as part of XII Five Year Plan Programme under title
ORIGIN (CSC-0108).
2
5
yielded 20 (14 mg, 81%) as a colourless oil. [α]
c 0.19, CHCl
); IR (neat): 3432, 2922, 1741, 1496, 1055 cm−1
H NMR (300 MHz, CDCl ): δ 7.38–7.25 (m, 10H), 5.07 (dd, J =
D
= +38.35
(
3
;
1
3
4
1
4
1
.8, 1.8 Hz, 1H), 4.82 (d, J = 6.1 Hz, 1H), 4.68 (d, J = 11.5 Hz,
H), 4.55 (d, J = 11.5 Hz, 1H), 4.44 (dt, J = 7.6, 3.8 Hz, 1H),
.33–4.31 (m, 1H), 4.09 (dd, J = 6.1, 1.9 Hz, 1H), 2.91 (dd, J =
Notes and references
13
6.7, 3.6 Hz, 1H), 2.67 (dd, J = 16.1, 5.3 Hz, 1H). C NMR
, 75 MHz): δ 168.4, 138.1, 136.8, 128.6, 128.5, 128.3,
28.0, 127.7, 126, 90.4, 84.9, 84.2, 77.0, 72.6, 65.8, 35.2. HRMS
1 (a) X. P. Fang, J. E. Anderson, C. J. Chang, J. L. McLaughlin
and P. E. Fanwick, J. Nat. Prod., 1991, 54, 1034–1043;
(b) X. P. Fang, J. E. Anderson, C. J. Chang, J. L. McLaughlin
and P. E. Fanwick, Tetrahedron, 1991, 47, 9751–9758;
(c) T. W. Sam, C. Sew-Yeu, S. Matsjeh, E. K. Gan, D. Razak
and A. L. Mohamed, Tetrahedron Lett., 1987, 28, 2541–2544.
(CDCl
3
1
+
24 5 4
(ESI): m/z calcd for C20H O N [M + NH ] : 358.1641, found =
3
58.1649.
(
R)-Methyl 3-((2S,3S,4S,5R)-3,4-dihydroxy-
-phenyltetrahydrofuran-2-yl)-3-hydroxypropanoate (3)
To a stirred solution of compound 5 (11 mg, 0.02 mmol) in
anhydrous CH Cl (5 mL) was added TiCl (1 M solution in
2
Y.-H. Lan, F.-R. Chang, Y.-L. Yang and Y.-C. Wu, Chem.
Pharm. Bull., 2006, 54(7), 1040–1043.
5
3 W. S. Kan, Pharmaceutical Botany, National Research Insti-
tute of Chinese Medicine, Taipei, 1979, p. 247.
2
2
4
DCM, 0.04 mL, 0.044 mmol) at 0 °C and the reaction mixture
was stirred at the same temperature for 1 h. The reaction
mixture was quenched with solid NaHCO (20 mg) and fil-
3
tered, and the solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography
4 J. W. Loder and R. H. Nearn, Altholactone, a Novel from a
Polyalthia Species (Annonaceae), Heterocycles, 1977, 7, 113–118.
5 A. E. El-Zayat, N. R. Ferrigni, T. G. McCloud, A. T. McKenzie,
S. R. Byrn, J. M. Cassady, C. J. Chang and J. L. McLaughlin,
Tetrahedron Lett., 1985, 26, 955–956.
(
80% EtOAc/hexane) to afford 3 (5.4 mg, 85%) as a colorless
6 (a) S. H. Inayat-Hussain, A. B. Osman, L. B. Din and
N. Taniguchi, Toxicol. Lett., 2002, 131(3), 153–159;
(b) F. Al Momani, A. S. Alkofahi and N. M. Mhaidat,
Molecules, 2011, 16, 4560–4566.
7 T. A. Johnson, J. Sohn, A. E. Ward, T. L. Cohen, N. D. Lorig-
Roach, H. Chen, R. A. Pilli, E. A. Widjaja, M. Hanafi,
L. B. S. Kardono, P. D. Lotulung, K. Boundy-Mills and
L. F. Bjeldanes, Bioorg. Med. Chem., 2013, 21, 4358–4364.
8 B. Zhao and X. Li, Oncol. Rep., 2014, 2769–2775, DOI:
10.3892/or.2014.3126.
2
5
12
25
oil; [α]
D
: −2.80 (c 0.29, CHCl
3
); lit [α]
D
: −5.0 (c 0.3, CHCl
3
);
H NMR
): δ 7.48–7.44 (m, 1H), 7.37–7.27 (m, 4H), 4.58
d, J = 6.5 Hz, 1H), 4.45–4.38 (m, 1H), 4.35–4.30 (m, 1H),
−
1
1
IR (neat): 3405, 2924, 1727, 1440, 1044 cm
(
(
;
300 MHz, CDCl
3
4
2
.10–4.06 (m, 2H), 3.71 (s, 3H), 2.86 (dd, J = 16.4, 8.6 Hz, 1H),
1
3
3
.65 (dd, J = 16.6, 4.1 Hz, 1H). C NMR (CDCl , 75 MHz):
δ 173.2, 139.4, 128.5, 128, 126.4, 84.4, 83.8, 79.8, 67.8, 52.0,
3
3
+
7.6. HRMS (ESI): m/z calcd for C H O Na [M + Na] :
14 18 6
05.0985, found = 305.0995.
9
(a) A. Favre, F. Carreaux, M. Deligny and B. Carboni,
Eur. J. Org. Chem., 2008, 4900–4907; (b) D. Enders and
J. Barbion, Chem. – Eur. J., 2008, 14, 2842–2849; (c) S. Ho
Kang and W. Joo kim, Tetrahedron Lett., 1989, 30, 5915–
5918; (d) J. Gesson, J. Jacquesy and M. Mondon, Tetra-
hedron Lett., 1987, 28, 3949–3942.
(
2
2R,3R,3aS,7R,7aS)-3,7-Dihydroxy-2-phenyltetrahydro-
H-furo[3,2-b]pyran-5(6H)-one (4)
To a stirred solution of compound 20 (9 mg, 0.02 mmol) in
anhydrous CH Cl (5 mL) was added TiCl (1 M solution in
DCM, 0.05 mL, 0.05 mmol) at 0 °C and the reaction mixture
2
2
4
was stirred at the same temperature for 1 h. The reaction 10 X. P. Fang, J. E. Anderson, X. X. Qiu, J. F. Koxlowski,
mixture was quenched with solid NaHCO3 (20 mg) and fil-
tered, and the solvent was removed under reduced pressure.
C. J. Chang and J. L. McLaughlin, Tetrahedron, 1993, 49,
1563–1570.
The residue was purified by silica gel column chromatography 11 C. Mukai, H. Yamashita, S. Hirai, M. Hanaoka and
(50% EtOAc/hexane) to afford 4 (5.84 mg, 87%) as a colorless
J. L. McLaughlin, Chem. Pharm. Bull., 1999, 47, 131.
Org. Biomol. Chem.
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