Stereoselective Synthesis of C1–C7 and C6–C22 Fragments of Phostriecin, Goniothalamines, and Their Analogues

Article abstract of DOI:10.1002/ejoc.201800561

The stereoselective synthesis of two fragments (C1–C7 and C6–C22) of the anti-tumor agent phostriecin has been achieved. The chiral hydroxy-vinyl-δ-lactone building block (fragment C1–C7) was subsequently utilized for the synthesis of 5-hydroxygoniothalamin, 5-acetoxygoniothalamin, and their derivatives.

Full text of DOI:10.1002/ejoc.201800561

A Journal of
Accepted Article
Title: Stereoselective synthesis of C1-C7 and C6-C22 fragments of
phostriecin, goniothalamines and its analogs
Authors: Sabitha Gowravaram, Purushotham Reddy Karra, and
Vasudeva Reddy Dodda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800561
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10.1002/ejoc.201800561
European Journal of Organic Chemistry
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Stereoselective synthesis of C1-C7 and C6-C22 fragments of
phostriecin, goniothalamines and its analogs
K. Purushotham Reddy, D. Vasudeva Reddy and Gowravaram Sabitha*
Abstract: The stereoselective synthesis of the two reaction as the key step. Simultaneously various
fragments (C1-C7, C6-C22) of an antitumor analogs of these molecules were also prepared.
Phostriecin has been achieved. Chiral building block,
hydroxy vinyl δ-lactone was utilized to the synthesis of
5-hydroxygoniothalamin, 5-acetoxygoniothalamin and
their derivatives.
1. Introduction
Figure 1. Structures of Phostriecin and Sultriecin
Phostriecin (1) (originally referred to as Sultriecin (2))
2. Results and Discussion
was
isolated in 1992 from Streptomyces
roseiscleroticus no. L827-7 (Figure 1).1 Structurally
phostriecin consists of a 4-hydroxy unsaturated lactone,
a hydrophobic Z,Z,E-triene and a centered 1,3-diol unit.
It is a C9 phosphate-monoester. Later, studies with
authentic material established that phostriecin, but not
sultriecin, is an effective and selective inhibitor of
protein phosphatase 2A (PP2A) defining a mechanism
of action responsible for its antitumor activity. This
compound was identified as an antitumor antibiotic
when isolated from Streptomyces sp.44.2 Phostriecin
(renamed for Sultriecin) displayed moderate broad-
spectrum antifungal activity in vitro, moderate in vitro
cytotoxic activity against human and murine tumor cell
lines, and potent in vivo antitumor activity against
P388 leukemia and B16 melanoma.1 Dale L. Boger
reported the first and only total synthesis of natural
Phostriecin3 in 2010.
In continuation of our interest in the synthesis of
biologically active -lactone containing natural
products,4 we herein describe the synthetic studies
toward Phostriecin (1), Goniothalamins and their
derivatives.
Scheme 1. Retro Synthetic analysis of Phostriecin.
Our retrosynthesis is outlined in Scheme 1. It was
envisaged that Phostriecin (1) could be obtained by
cross metathesis of fragment 3 and fragment 4.
Fragment 3 could be synthesized from fragment 5 and
6 via Sonaghishra coupling. Fragment 5 could be
generated by readily available ally bromide 8 and
propargylic alcohol 9 by successive functional groups
Our study mainly aimed at developing suitable
methodology for the synthesis of 5-hydroxy vinyl
lactone (C1-C7 unit) and its application towards the
synthesis of several biologically active molecules such
as phostriecin including 5-hydroxygoniothalamin and
5-acetoxygoniothalamin using
a
cross-metathesis
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15 was obtained following di TBS protection of 7 and
selective removal of primary TBS group with PPTS in
ethanol9. The compound 15 was converted into a
mixture of alkynes (5, 5a) in two steps by oxidation
(IBX)10 followed by Grignard reaction with ethynyl
bromide. Conversion of 5a under Mitsunobu
manipulation which includes alkyne and allyl bromide
coupling, reduction, Sharpless epoxidation, Gilman’s
epoxide opening and Grignard reaction. Whereas
compound 6 obtained by Stork’s protocol from the
readily available Hexanal 10. The 5-hydroxy vinyl
lactone 4 could be obtained from readily available (+)-
DET diol (Scheme 1).
conditions11
yielded
alkyne
5.
2.2. Synthesis of C14-C22 fragment (6)
2.1. Synthesis of C6-C13 fragment 5
Z,E-iododiene fragment 6 (C14-C22) was produced
from 1-hexanal (10) in 3 steps. Accordingly, hexanal
was subjected to Wittig olefination with
triethylphosphono acetate to yield α,β-unsaturated
ester 16, that was reduced to the aldehyde by using
DIBAL-H and the key intermediate Z-vinyl iodide 5
was obtained from aldehyde using Stork’s protocol
(Scheme 3).12
The phostriecin molecule was initially divided into two
fragments (C1-C7, C6-C22). Our synthetic studies
started with the synthesis of C6-C13 fragment 5
(Scheme 2). Accordingly, synthesis of alkyne fragment
5 was initiated by reacting allyl bromide 8 with
propargyl alcohol 9 to give the compound 115.
Scheme 3: Synthesis of C14-C22 fragment (6)
2.2. Synthesis of the C6-C22 fragment of
Phostriecin (3)
The alkyne 5 was subjected to Sonogashira coupling13
with Z-vinyl iodide 6 in the presence of Pd(PPh3)4/CuI
in Et3N/dry THF to obtain 3 in 87% yield, thus
completing the synthesis of the C6-C22 fragment of
phostriecin (Scheme 4).
Scheme 2: Synthesis of C6-C13 fragment 5
Subsequently, triple bond was reduced to cis double
bond using Ni(OAc)2/NaBH4 to furnish compound 12.6
Sharpless asymmetric epoxidation7 of cis double bond
using (-)-DIPT gave an epoxide 13 in 88% yield.
Under Gilman reaction conditions,8 the epoxide 13
yielded syn 1,3-diol 7 along with undesired 1,2-diol.
The minor isomer 1,2-diol was eliminated by exposing
the crude reaction mixture (1,2- and 1,3-diol) to NaIO4
followed by column chromatography to afford the 1,3-
diol with 70% yield over two steps. Primary alcohol
Scheme 4: Synthesis of the C6-C22 fragment of
Phostriecin (3)
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Next, we turned our attention towards the synthesis of Subsequent regioselective reductive ring-opening of
o
hydroxy vinyl lactone unit (4). This was started from a the benzylidene acetals using DIBAL-H at -78 C led
known L-(+)-DET diol14 by protecting it as a mono- to a mixture of inseparable alcohols 23a, 23b.
benzyl ether 17. Oxidation of alcohol using IBX in Oxidation of the alcohol (mixture) with IBX followed
CH3CN yielded the corresponding aldehyde, which by Still-Gennari15,16 olefination of the resulting
was subjected to one carbon Wittig olefination using aldehyde gave an inseparable mixture of unsaturated
+
-
t
PPh3P CH3I salt in the presence of BuOK in one pot esters 24a, 24b in 80% over all yield. When this
to give terminal alkene 18. Acetonide deprotection of mixture was treated with PTSA at room temperature
compound 18 with PTSA resulted in diol 19, in which for 12 h, it gave a mixture of lactones 25a, 25b. These
allylic alcohol was selectively protected as TBS ether two lactones were readily separated by column
with TBSCl at 0 oC to give compound 20. chromatography. Treatment of 6-membered lactone
Subsequently, benzyl group was removed using 25a17 and 5-membered lactone 25b with TiCl4
Li/Naphthalene in THF to yield a diol 21. When 1,2- separately yielded 5-hydroxy vinyl lactone 418 and
diol functionality in compound 21 was protected as the lactone 26 (Scheme 5).19
benzylidene acetal using benzaldehyde dimethyl acetal Unfortunately, attempts to couple these two fragments
o
4 and 3 failed to give the cross-coupled product under
various Grubb’s conditions as shown scheme 6.20 First,
we attempted the reaction between 3 and 4 with Gr-I
cat. (10 mol%) in DCM at rt for 12 h the starting
materials were recovered (scheme 6, entry 1). Then we
have tried same reaction conditions in toluene (entry 2)
at rt for 10 h, also gave the same results as entry 1.
Then we moved to the catalyst Gr-II (10 mol%) in
DCM (30 oC) for 8 h, it gave a dimerised compound of
4 (entry 3). As it results in dimerisation we have
increased the eq. of compound 4 (0.08 mmol) and
changed the reaction conditions (entry 4) (Toluene/5
h), produced authentic results as entry 3. Other
conditions met with complete failure for example, “Gr-
II in Toluene at reflux for 3 h, results decomposition of
SM” (entry 5).
and catalytic PPTS in CH2Cl2 at 0 C to rt for 1 h, it
gave a mixture of 1,2 and 1,3-acetal as an inseparable
mixture 22a, 22b in 80:20 ratio in an overall yield of
86%.
2.3. Synthesis of 5-hydrxoy vinyl lactone (4) and
lactone (26)
Scheme 5. Synthesis of 5-hydroxy vinyl lactone (4)
and lactone (26)
Scheme 6: Cross-metathesis of fragment 3 and 4
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After failure to get the phostriecin, we turned our vinyl lactone 5 was achieved via an olefin cross-
attention towards the synthesis of other lactone natural metathesis reaction of styrene in the presence of
compounds such as 5-hydroxygoniothalamin and 5- Grubbs' second generation catalyst28 (10 mol%) in
acetoxygoniothalamin.
refluxing CH2Cl2 to give 5-hydroxygoniothalamin
The naturally occurring styryl lactones exhibit a wide (28). The spectroscopic and analytical data were
range of interesting biological activities such as comparable to the natural product.23a With the
cytotoxic,
anti-tumor,
pesticidal,
teratogenic, feasibility of synthetic route to the target molecule in
embryotoxic and immunosuppressive properties21. hand, we turned to synthesize the library of 5-
Many other members of this class of natural products hydroxygoniothalamin analogs 28a-28e by utilizing 5-
have been isolated from various plants and fungi that hydroxy vinyl lactone and a series of styrenes which
share the common 5-oxygenated-5,6-dihydro-2H- bear various substituents on the phenyl ring as starting
pyran-2-one structural motif, such as goniotriol, materials. It was found that a variety of polar
acetylphomalactone, and altholactone.22 These natural functional groups including electron donating group
products also have biological activity, including (Acetoxy, tert-Butyl) and electron withdrawing
antitumor,23a most notably antifungal properties,23b as
well as antibiotic potential.23b Due to the wide
substituents (Bromo, chloro) in the styrenes 28a－28e
were tolerated in this key cross-metathesis reaction.
distribution of 5,6-dihydro-2H-pyran-2-ones in plants
and fungi, many synthetic methodologies have been
employed to synthesize these structures.24,25 5-
Hydroxygoniothalamin (28), 5-acetoxygoniothalamin
(29) belongs to this group of lactones isolated23a
recently from the leaves and twigs of Goniothalamus
marcanii locally known as Khao Lam, grows widely in
the northern, northeastern and southern parts of
Thailand. Their anticancer activities were evaluated
using SRB assays. Styryllactones 28 and 29 showed
cytotoxicity to P-388, KB, MCF-7, A549, Hek 293 and
ASK cell lines; moreover, 29 also exhibited activity
against Col-2, Lu-1 and T24 cell line.
Compounds 28a－28e were obtained in good yields
(Scheme 7). The structures of the products were
established by spectral analysis.
Scheme 7: 5-hydroxygoniothalamin analogs
5-hydroxygoniothalamin when treated with acetic
anhydride in the presence of triethyl amine and DCM
Earlier 5-acetoxygoniothalamin26 has also been
isolated from various Goniothalamus Sp. To the best
of our knowledge, two total syntheses has been
reported toward the synthesis of 28. The first total
synthesis of 5-hydroxygoniothalamin was reported by
Doherty et al27a from furfural and the second synthesis
was reported from tri-O-acetyl-D-glucal. 27b
for
1
h
to produce naturally occurring 5-
acetoxygoniothalamin in 90% yield (Scheme 8).
Our studies were initiated with the reaction of hydroxy
vinyl lactone 5 with styrene. Coupling of 5-hydroxy
Scheme 8: Synthesis of 5-Acetoxy goniothalamin
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silica gel (60–120 mesh). Analytical thin layer
Similarly, several interesting 5-membered lactone chromatography (TLC) was run on silica gel 60 F254
analogs were also prepared from (S)-5-((S)-1- pre-coated plates (250 μm thickness). Optical rotations
hydroxyallyl)furan-2(5H)-one (24) with styrenes. [α]D were measured on a polarimeter and given in 10-1
Accordingly, the cross-metathesis reaction of 24 with deg cm2 g−1. Infrared spectra were recorded in
styrene in the presence of Grubb’s II catalyst (10%) CHCl3/KBr (as mentioned) and reported in wave
yielded cross-coupled product 30. Based on this number (cm−1). Mass spectral data were obtained using
success, we have prepared various analogs (Scheme 9). MS (EI) ESI, HRMS mass spectrometers. High
resolution mass spectra (HRMS) [ESI+] were obtained
using either a TOF or a double focusing spectrometer.
1H NMR spectra were recorded at 300, 400, 500 and
13C NMR spectra at 75, 100, 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 designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad.
Spectral data for all compounds
Hex-5-en-2-yn-1-ol (11): Propargyl alcohol 9 (0.68 g,
8.02 mmol) was treated with allyl bromide 8 (0.30 g,
Scheme 9: (S)-5-((S)-1-hydroxyallyl)furan-2(5H)-one 5.35 mmol) in presence of copper iodide (0.02 g, 0.10
analogs
mmol), sodium sulfite (0.33 g, 2.67 mmol) and K2CO3
(0.74 g, 5.35 mmol) in H2O (5mL) at rt for 2 h. After
stirring for 2 h reaction mixture was filtered through
Conclusions
In conclusion, we have developed a highly stereo Celite and extracted with ethyl acetate (2 x 5 mL). The
selective synthetic route for the C1-C7 and C6-C22 organic layer was evaporated and purified by column
fragments of Phostriecin (1), Goniothalamins and its chromatography to give allylated propargyl alcohol 11
analogs. The key features of the developed strategy are (0.44 g, 87%) as a colorless oil. IR (neat): 3525, 2920,
1
acid catalyzed epoxide opening, Gilman reaction, 2864, 1620, 1465, 835 cm-1; H-NMR (CDCl3, 400
Stereoselective synthesis, Stork’s protocol, cross- MHz): δ 5.86-5.77 (m, 1H), 5.31 (dq, J = 16.93, 1.67
metathesis, Sonogashira coupling. Total synthesis of Hz, 1H), 5.12 (dq, J = 9.91, 1.67 Hz, 1H), 4.29 (t, J =
Phostriecin is currently in progress in our group.
2.13 Hz, 2H), 3.01 (ddd, J = 7.32, 3.81, 1.83 Hz, 2H),
1.92 (brs, 1H) ppm; 13C-NMR (CDCl3, 100 MHz): δ
132.1, 116.2, 82.8, 80.6, 51.2, 22.9 ppm; HRMS (ESI):
calc. 119.3425 C6H8ONa, found 119.3420 [M+Na]+.
(Z)-hexa-2,5-dien-1-ol (12): 1M Solution of sodium
borohydride (0.22 g, 3.90 mmol) was added to nickel
acetate (0.97 g, 3.90 mmol) in EtOH at room
temperature under hydrogen atmosphere. After 30 min.
ethylenediamine (0.7 ml, 10.4 mmol) was added. After
15 minutes compound 11 (0.25 g, 2.60 mmol)
dissolved in EtOH was added. After stirred for
overnight at rt reaction mixture was filtered through
Experimental Section
General methods
All reactions were performed under inert atmosphere.
All glassware apparatus used for reactions are
perfectly oven/flame dried. Anhydrous solvents were
distilled prior to use: THF from Na and benzophenone;
CH2Cl2 from CaH2; MeOH from Mg cake.
Commercial reagents were used without purification.
Column chromatography was carried out by using
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celite and extracted with diethyl ether (2 x 10 mL). 1.6 M) in ether was added dropwise until it become
Organic layer was evaporated and purified by column clear solution. After 30 min at this temperature the
chromatography EtOAc: hexane (30:70) to obtain 12 solution was cooled to –40 °C, and then epoxy alcohol
(0.23 g, 89%). IR (neat): 3519, 2925, 2864, 1615, 1453, 13 (0.15 g, 1.07 mmol) in ether (2 mL) was added
935 cm-1; 1H-NMR (CDCl3, 400 MHz): δ 5.86-5.75 (m, dropwise. After being stirred for 2 h at –40 °C and
1H), 5.65-5.49 (m, 2H), 5.08-4.97 (m, 2H), 4.22-4.16 then for 30 min at –23 °C, the mixture was poured into
(m, 2H), 2.87-2.81 (m, 2H). 13C-NMR (CDCl3, 125 saturated aqueous NH4Cl (3 mL) and the blue aqueous
MHz): δ 136.2, 132.9, 128.4, 115.1, 58.5, 31.5.
layer was thoroughly extracted with CH2Cl2 (3 x 4
((2R,3S)-3-allyloxiran-2-yl)methanol (13): In a 25 mL). The combined organic layers were washed with
mL two neck round bottomed flask, 5 mL of brine (10 mL), dried over anhydrous Na2SO4 and
anhydrous CH2Cl2 was added to 4 Ao powdered concentrated
under
reduced
pressure.
The
activated molecular sieves and suspension mixture was contamination of the 1,2-diol was eliminated by
o
cooled to –20 C, Ti(OiPr)4 (1.2 mL, 0.40 mmol) and exposing the crude reaction mixture to NaIO4 followed
D-(-) DIPT (0.09 g, 0.40 mmol) in anhydrous CH2Cl2 by silicagel column chromatography (60:40
(5 mL) were added subsequently with stirring and the hexane/EtOAc) to afford the pure 1,3-diol 7 (0.12 g,
o
resulting mixture was stirred for 30 min at –20 C. 70% yield) as pale yellow oil. [α]25 = +1.00 (c = 0.1,
D
Compound 12 (0.20 g, 2.04 mmol) in anhydrous CHCl3); IR (neat): 3419, 2930, 2855, 1612, 1512, 1247,
1
CH2Cl2 (7 mL) was then added and the resulting 1035 cm-1; H-NMR (CDCl3, 400 MHz): δ 5.89-5.75
o
mixture was stirred for another 30 min at –20 C (m, 1H), 5.19-5.10 (m, 2H), 3.92-3.86 (m, 1H), 3.70 (d,
followed by addition of TBHP (0.61 mL, 3.06 mmol) J = 5.50 Hz, 2H), 2.28-2.23 (m, 2H), 1.89-1.79 (m,
and the resulting mixture was stirred at the same 1H), 0.94 (d, J = 7.09 Hz, 3H) ppm; 13C-NMR (CDCl3,
temperature for 24 h. The reaction mixture was 125 MHz): δ 135.0, 117.9, 73.2, 66.9, 38.6, 38.6, 10.1
warmed to 0 °C, filtered through Celite. The filtrate ppm; HRMS (ESI): calc. 153.1765 C7H14O2Na, found
was quenched with water (2 mL), 15% aqueous NaOH 153.1770 [M+Na]+.
solution (0.1 mL) and stirred vigorously for 1 h.The
organic phase was separated and the aqueous phase dioxa-3,9-disilaundecane (14):
(5S,6S)-5-allyl-2,2,3,3,6,9,9,10,10-nonamethyl-4,8-
A
solution of
was extracted with CH2Cl2. Combined organic phases compound 7 (0.10 g, 0.76 mmol) in CH2Cl2 (3 mL)
were washed with brine and dried over anhydrous was treated with 2,6-lutidine (0.18 mL, 1.52 mmol) at
Na2SO4. The solvent was removed under reduced 0 °C and stirred for 20 min. Next, TBSOTf (0.15 mL,
pressure and purified by silica gel column 0.91 mmol) was added and following completion of
chromatography (EtOAc/Hexane, 4:6) to afford 13 the reaction as indicated by TLC, the mixture was
(0.20 g, 88%) as a viscous liquid. [α]25 = -0.67 (c = quenched with sat.NH4Cl solution and extracted with
D
0.2, CHCl3); IR (neat): 3419, 2930, 2922, 2864, 1453, CH2Cl2 (3 × 5 mL). The combined organic layer was
1
1102, 935 cm-1; H-NMR (CDCl3, 500 MHz): δ 5.91- dried over anhydrous Na2SO4 and evaporated under
5.80 (m, 1H), 5.21-5.10 (m, 2H), 3.86 (dd, J = 12.20, reduced pressure to yield a viscous liquid, which on
4.27 Hz, 1H), 3.72 (dd, J = 12.20, 6.71 Hz, 1H), 3.23- purification by silica gel column chromatography
3.18 (m, 1H), 3.16-3.11 (m, 1H), 2.47-2.40 (m, 1H), (EtOAc-hexane, 1:9) afforded the silyl-protected ether
13
2.30-2.23 (m, 1H) ppm; C-NMR (CDCl3, 125 MHz): 14 (0.25 g, 92%) as a colorless liquid. [α]25D = -5.00 (c
δ 133.1, 117.3, 60.5, 56.6, 55.8, 32.3. ppm; HRMS = 0.1, CHCl3); IR (neat): 2956, 2930, 1610, 1472,
1
(ESI): calc. 137.1245 C6H10O2Na, found 137.1242 1253, 1095, 836 cm-1; H-NMR (CDCl3, 500 MHz): δ
[M+Na]+.
5.80-5.69 (m, 1H), 5.07-4.97 (m, 2H), 3.83 (ddd, J =
(2S,3S)-2-methylhex-5-ene-1,3-diol (7): To a cold (– 9.00, 6.10, 3.05 Hz, 1H), 3.52 (dd, J = 9.76, 7.01 Hz,
23 °C) suspension of copper(I)iodide (7.62 g, 40.0 1H), 3.40 (dd, J = 9.76, 6.71 Hz, 1H), 2.29-2.19 (m,
mmol) in dry ether (3 mL), MeLi (4.93 mL, 6.42 mmol, 2H), 1.69 (dd, J = 13.73, 6.86, 3.05 Hz, 2H), 0.89 (s,
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9H), 0.88 (s, 9H), 0.82 (d, J = 6.86 Hz, 3H), 0.04 (s, removed in vacuo, after which the residue was diluted
o
3H), 0.03 (s, 3H), 0.02 (s, 6H) ppm; 13C-NMR (CDCl3, with CH2Cl2 and allowed to warm to 0 C. Then, the
125 MHz): δ 128.2, 127.5, 72.9, 65.1, 40.8, 34.4 (2C), reaction mixture was quenched with saturated aq.
25.9 (3C), 25.6 (3C), 11.0, -4.4, -4.5, -4.3 (2C) ppm; NH4Cl and extracted with CH2Cl2 (3 × 10 mL). The
HRMS (ESI): calc. 359.1346 C19H42O2Si2, found combined organic layers were washed with brine, dried
359.1350 [M+H]+.
(2S,3S)-3-((tert-butyldimethylsilyl)oxy)-2-
over Na2SO4 and the solvent was removed under
reduced pressure. The compound was purified by silica
methylhex-5-en-1-ol (15): A solution of 14 (0.15 g, gel column chromatography (20%, EtOAc/Hexane) to
0.41 mmol) in 95 % ethanol (5 mL) was treated with provide 5 and 5a (0.046 g, 78%) as a colorless oil.
PPTS (0.010 g, 0.04 mmol). The reaction was Conversion of 5a under Mitsunobu conditions gave
monitored by TLC until all starting material had alkyne 5. [α]25 = +6.51 (c = 0.3, CHCl3); IR (neat):
D
disappeared. Then Et3N (0.1 mL) was added to 3223, 2630, 2260, 1612, 1512, 1247, 1005,830 cm-1;
neutralize the acid and the solution concentrated under 1H-NMR (CDCl3, 500 MHz): δ 5.78-5.68 (m, 1H),
reduced pressure. Purification of the residue by silica 5.13-5.03 (m, 2H), 4.37-4.31 (m, 1H), 3.31 (d, J = 5.03
gel chromatography (EtOAc/petroleum ether, 1:3) Hz, 1H), 2.47 (d, J = 2.13 Hz, 1H), 2.32-2.27 (m, 2H),
yielded 15 (0.084 g, 82%). [α]25 = +2.00 (c = 0.1, 1.93-1.86 (m, 1H), 1.00 (d, J = 7.01 Hz, 3H), 0.90 (s,
D
CHCl3); IR (neat): 3219, 2930, 2650, 1612, 1512, 1247, 9H), 0.12 (s, 3H), 0.09 (s, 3H) ppm; 13C-NMR (CDCl3,
1
1035, 835 cm-1; H-NMR (CDCl3, 400 MHz): δ 5.84- 100 MHz): δ 134.6, 117.3, 84.6, 73.3, 73.2, 65.2, 42.6,
5.71 (m, 1H), 5.13-5.01 (m, 2H), 3.88-3.82 (m, 1H), 38.2, 25.8 (3C), 17.9, 11.0, -4.5, -4.1 ppm; HRMS
3.74-3.65 (m, 1H), 3.54 (dd, J = 10.63, 5.25 Hz, 1H), (ESI): calc. 291.0526 C15H28O2NaSi, found 291.0530
2.31-2.25 (m, 2H), 2.00-1.90 (m, 2H), 0.90 (s, 9H), [M+Na]+.
0.85 (d, J = 6.96 Hz, 3H), 0.08 (s, 3H), 0.07 (s, 3H)
(3S,4S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-
ppm; 13C-NMR (CDCl3, 100 MHz): δ 135.4, 116.9, methyloct-7-en-1-yn-3-ol (5a): [α]25 = -10.23 (c =
D
1
74.7, 65.9, 39.4, 37.8, 25.8 (3C), 25.6, 11.4, -4.6, -4.2 0.1, CHCl3); H-NMR (CDCl3, 500 MHz): δ 5.89-5.65
ppm; HRMS (ESI): calc. 267.1100 C13H28O2NaSi, (m, 1H), 5.13-4.90 (m, 2H), 4.41 (dd, J = 5.86, 1.71
found 267.1105 [M+Na]+.
(3R,4S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-
Hz, 1H), 4.05-3.99 (m, 1H), 2.48 (d, J = 2.20 Hz, 1H),
2.36-2.28 (m, 2H), 1.88-1.79 (m, 1H), 1.05 (d, J = 6.96
methyloct-7-en-1-yn-3-ol (5): To an ice-cooled Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H) ppm;
solution of 2-(iodoxy) benzoic acid (0.074 g, 0.26 13C-NMR (CDCl3, 100 MHz): δ 134.4, 117.3, 84.3,
mmol) in anhydrous CH3CN (10 mL) was added a 74.2, 73.5, 65.7, 42.7, 39.6, 33.8, 25.8 (3C), 14.1, -4.7,
solution of alcohol 15 (0.054 g, 0.22 mmol). The -3.9 ppm; HRMS (ESI): calc. 291.2359 C15H28O2NaSi,
mixture was refluxed for 1 h, and then allowed to cool found 291.2354 [M+Na]+.
to RT. The solvent was removed under reduced
pressure and the unstable crude aldehyde product was methyloct-7-en-1-yn-3-yl 4-nitrobenzoate: To
used directly for the next step without further stirred solution of 5a (0.01 g, 0.03 mmol),
purification by column chromatography. triphenylphosphine (0.02 g, 0.06 mmol), and p-
(3R,4S,5S)-5-((tert-butyldimethylsilyl)oxy)-4-
a
The crude aldehyde (0.048 g, 0.19 mmol) dissolved in nitrobenzoic acid (0.01 g, 0.06 mmol) in dry THF (5
o
CH2Cl2 (10 mL) under nitrogen atmosphere was added mL) at 0 C was added diethyl azodicarboxylate (1.01
at 0 oC to a stirred suspension of MgBr2.Et2O (0.068 g, ml, 0.06 mmol) via syringe. After half an hour, the
0.26 mmol) in CH2Cl2. After stirring for 20 min, the reaction mixture was diluted with water (5 mL) and
flask was cooled to −78 oC and the alkyne extracted with ethyl acetate (2 x 5 mL). The solvent
(Ethynylmagnesium bromide) Grignard was added was evaporated followed by flash chromatography
slowly at −78 oC and the reaction was stirred further at (EtOAc-hexanes, 1:9) afforded PNB compound (0.01
1
this temperature for half an hour. The solvent was then g, 0.02 mmol, 87%) as a pale yellow oil. H-NMR
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10.1002/ejoc.201800561
European Journal of Organic Chemistry
FULL PAPER
(CDCl3, 400 MHz): δ 8.32-8.28 (m, 2H), 8.23-8.19 (m, vacuum to afford the crude aldehyde. This was used
2H), 5.84-5.69 (m, 1H), 5.47 (dd, J = 8.31, 2.07 Hz, for the next step without further purification.
1H), 5.17-5.09 (m, 2H), 3.93-3.88 (m, 1H), 2.53 (d, J = To a suspension of iodomethyl triphenylphosphonium
2.07 Hz, 1H), 2.37-2.32 (m, 2H), 2.22-2.13 (m, 1H), iodide (0.84 g, 1.57 mmol) in THF (15 mL) at 0 0C, a 1
1.15 (d, J = 6.84 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 3H), -
M
solution of sodium hexamethyldisilazane
0.10 (s, 3H) ppm; 13C-NMR (CDCl3, 100 MHz): δ (NaHMDS) (1.4 mL, 1.45 mmol) was slowly added,
163.4, 150.6, 135.2, 134.0, 130.7 (2C), 123.6 (2C), over a period of 10 min. After stirring for an additional
117.6, 79.9, 75.1, 70.4, 67.0, 40.9, 39.3, 25.7 (3C), 5 min, the solution was cooled to -78 °C and HMPA
18.0, 9.4, -4.9, -3.9 ppm; HRMS (ESI): calc. 418.1557 (0.3 mL) was added, followed by the addition of
C22H32NO5Si, found 418.1560 [M+H]+.
Ethyl (E)-oct-2-enoate (16):
aldehyde dissolved in THF (5 mL). The temperature
solution of was kept at -78 °C while the reaction mixture was
A
triethylphosphono acetate (0.58 g, 2.60 mmol) in THF stirred for 2 hours. Hexane (10 mL) was added and the
(5 mL) was added slowly to a stirred solution of NaH resulting slurry was filtrated over celite and washed
o
(0.10 g, 4.00 mmol) in THF (3 mL) at 0 C under N2. with additional hexane (10 mL). The filtrate was
The mixture was stirred at 0 °C for 30 min. Then the evaporated under reduced pressure and the resulting oil
mixture was cooled to 0 °C and the aldehyde 10 in was
purified
by
column
chromatography
THF (5 mL) was added dropwise over 5 min. The (hexane/EtOAc 100:0 to 20: 1) to afford (Z)-olefin
resulting mixture was stirred at 0 °C for 30 min. Then iodide 6 (0.14 g, 80% in two steps) as colorless oil. IR
the mixture was quenched with sat. NH4Cl (5 mL) and (neat): 2330, 2255, 1612, 1512, 1247, 1035,700 cm-1;
the product was extracted with EtOAc (2 × 5 mL) and 1H-NMR (CDCl3, 400 MHz): δ 6.68 (dd, J = 9.78, 7.58
dried over Na2SO4. The solvent was removed under Hz, 1H), 6.25-6.16 (m, 1H), 6.08 (d, J = 7.58 Hz, 1H),
reduced pressure and the crude product was purified by 6.04-5.95 (m, 1H), 2.17-2.10 (m, 2H), 1.47-136 (m,
using silica gel column chromatography (10% 2H), 1.36-1.23 (m, 4H), 0.90 (t, J = 6.96 Hz, 3H) ppm;
EtOAc/Hexane) to afford (E)-olefin ester 16 (0.3 g, 13C-NMR (CDCl3, 125 MHz): δ 140.4, 138.5, 130.3,
97%) as a colorless liquid. IR (neat): 2982, 1724, 1696, 79.2, 32.9, 31.3, 28.5, 22.4, 14.0 ppm; HRMS (ESI):
1
1289, 1173, 987, 845, 774 cm-1; H-NMR (CDCl3, 500 calc. 273.2670 C9H15INa, found 273.2679 [M+Na]+.
MHz): δ 7.00-6.93 (m, 1H), 5.81 (dt, J = 15.56 Hz,
(4S,5S,6R,9Z,11E)-4-((tert-butyldimethylsilyl)oxy)-
1H), 4.18 (qt, J = 7.17 Hz, 2H), 2.21-2.16 (m, 2H), 5-methylheptadeca-1,9,11-trien-7-yn-6-ol (3): To the
1.45 (m, 2H), 1.36-1.22 (m, 6H), 0.88 (t, J = 6.86 Hz, arm of a three-necked flask was charged Pd(PPh3)4
3H) ppm; 13C-NMR (CDCl3, 100 MHz): δ 166.7, 149.4, (0.008 g, 0.007 mmol) and CuI (0.02 g, 0.014 mmol)
121.1, 60.0, 32.1, 31.2, 27.6, 22.4, 13.9, 14.2 ppm; under Argon. A solution of alkyne 5 (0.020 g, 0.074
HRMS (ESI): calc. 193.13500 C10H18O2Na, found mmol), and the dienyl iodide 6 (0.027 g, 0.111 mmol)
193.13506 [M+Na]+.
and Et3N (0.1 mL, 0.74 mmol) in Dry-THF (2 mL)
(1Z,3E)-1-iodonona-1,3-diene (6): DIBAL-H (0.8 mL, was cannulated into the reaction vessel. The reaction
0.84 mmol) was added to a stirred solution of ester 16 flask was then freeze-thawed with liquid nitrogen three
(0.12 g, 0.70 mmol) in CH2Cl2 (10 mL) at -78 °C and times to remove oxygen. After removing any oxygen
the mixture was allowed to stir at the same temperature from the reaction flask the Pd(PPh3)4 and CuI was
for 30 mins. After monitoring with TLC, the reaction added and the reaction mixture was stirred overnight at
was quenched with aq. MeOH (5 mL) at -78 °C. Then room temperature. The reaction was worked up with
a saturated solution of sodium potassium tartrate (5 aqueous saturated NH4Cl (3 mL) and extracted with
mL) was added and extracted with CH2Cl2 (3 × 5 mL). Et2O (3 x 2 mL). The solvent was evaporated and the
The organic layer was washed with brine (2 × 5 mL) mixture was purified on silica gel using EtOAc-
and H2O (2 × 5 mL). The combined organic layer was hexanes (1:24) as the eluent to afford compound 3 as a
dried over anhydrous Na2SO4, concentrated under clear oil (0.025 g, 87%). [α]25 = +2.31 (c = 0.1,
D
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10.1002/ejoc.201800561
European Journal of Organic Chemistry
FULL PAPER
CHCl3); IR (neat): 3419, 2930, 2855, 2265, 1612, 1512, refluxed for 1 h, and then allowed to cool to RT. The
1
1247, 1045, 824 cm-1; H-NMR (CDCl3, 500 MHz): δ solvent was removed under reduced pressure and the
6.59-6.50 (m, 1H), 6.33 (t, J = 10.83 Hz, 1H), 5.92- unstable crude aldehyde product was used directly for
5.83 (m, 1H), 5.82-5.69 (m, 1H), 5.35 (d, J = 10.52 Hz, the next step without further purification by column
1H), 5.14-5.02 (m, 1H), 4.55-4.49 (m, 1H), 4.18-4.09 chromatography.
(m, 1H), 3.21-3.14 (m,1H), 2.35-2.27 (m, 2H), 2.14 (qt, To a suspension of methyltriphenylphosphonium
J = 7.17 Hz, 1H), 1.92 (ddd, J = 7.93, 7.17, 2.74 Hz, bromide (5.78 g, 16.20 mmol) in THF (15 mL) at 0 °C
1H), 1.46-1.36 (m, 1H), 1.34-1.22 (m, 5H), 1.03 (d, J = was added tBuO-K+ (1.51 g, 13.50 mmol). The mixture
7.01 Hz, 3H), 0.94-0.83 (m, 13H), 0.12 (s, 3H), 0.09 (s, was stirred vigorously for 30 min during which time a
13
3H) ppm; C-NMR (CDCl3, 75 MHz): δ 140.4, 139.0, clear yellow solution was formed. A solution of
134.7, 127.6, 117.2, 106.2, 95.4, 82.6, 73.1, 65.8, 43.0, aldehyde (1.35 g, 5.40 mmol) in THF (10 mL) was
38.5, 32.8, 31.4, 29.6, 28.7, 25.8 (3C), 22.5, 18.0, 14.0, added and the mixture was stirred at 0 °C for 4 h. The
11.0, -4.5, -4.1 ppm; HRMS (ESI): calc. 413.1689 reaction was quenched with aqueous NH4Cl and the
C24H42O2NaSi, found 413.1694 [M+Na]+.
((4R,5R)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-
separated aqueous layer was extracted with Et2O (3 x
10 mL). The combined extracts were dried (MgSO4)
dioxolan-4-yl)methanol (17): To a suspension of NaH and filtered, the filtrate was concentrated in vaccum to
(60%, 0.44 g, 18.50 mmol) in THF-DMF (10 mL, 1:1) leave a residue which was purified by flash
was added dropwise a solution of (+)-DET diol (1.5 g, chromatography (97:3, Hexane-EtOAc) to give
o
9.25 mmol) in THF (5 mL) at 0 C. To this reaction compound 18 as a colorless oil (0.98 g, 76%). [α]25
=
D
mixture TBAI (0.001 g) and benzyl bromide (1.04 mL, +4.00 (c = 0.2, CHCl3); IR (neat): 2930, 2855, 1712,
1
8.32 mmol) were added subsequently and stirring was 1512, 1247, 1035 cm-1; H-NMR (CDCl3, 500 MHz): δ
continued for 1 h at same temperature and 2 h at room 7.41-7.22 (m, 5H), 5.91-5.75 (m, 1H), 5.39-5.18 (m,
temperature. The reaction mixture was quenched by 2H), 4.59 (s, 2H), 4.27-4.18 (m, 1H), 3.96-3.86 (m,
crushed ice flakes until a clear solution (biphasic) 1H), 3.66-3.55 (m, 2H), 1.44 (s, 6H) ppm; 13C-NMR
formed. The reaction mixture was extracted with ethyl (CDCl3, 125 MHz): δ 137.8, 135.1, 128.2 (2C), 127.5
acetate (2 x 5 mL). Evaporation of the solvents (3C), 118.5, 109.3, 79.9, 79.3, 73.4, 69.3, 26.9, 26.8
followed by column chromatography (75:25, ppm; HRMS (ESI): calc. 271.2689 C15H20O3Na, found
hexane/EtOAc) afforded the pure product 17 (2.03 g, 271.2694 [M+Na]+.
87% yield) as a colorless liquid. [α]25D = +9.50 (c = 0.1, (2S,3S)-1-(benzyloxy)pent-4-ene-2,3-diol (19): To a
CHCl3); IR (neat): 3455, 2930, 1612, 1513, 1247, 1081 stirred solution of compound 18 (0.95 g, 3.83 mmol) in
cm-1; 1H-NMR (CDCl3, 500 MHz): δ 7.39-7.24 (m, 5H), MeOH (5 mL) was added p-toluenesulfonic acid (0.72
4.57 (s, 2H), 4.08-4.02 (m, 1H), 3.96-3.90 (m, 1H), g, 3.83 mmol) under nitrogen atmosphere. After
3.76 (dd, J = 11.74, 4.12 Hz, 1H), 3.70-3.62 (m, 2H), stirring for 2 h at room temperature, the reaction
3.56 (dd, J = 9.91, 5.49 Hz, 1H), 2.66-2.56 (brs, 1H), mixture was quenched with solid NaHCO3 (0.5 g) and
1.42 (s, 3H), 1.41 (s, 3H) ppm; 13C-NMR (CDCl3, 125 filtered off, the solvent was removed under reduced
MHz): δ 137.4, 128.3 (2C), 127.7, 127.6 (2C), 109.2, pressure and the residue was purified by silica gel
79.5, 76.4, 73.6, 70.2, 62.3, 26.9, 26.8 ppm; HRMS column chromatography (7:3 hexane/EtOAc) to afford
(ESI): calc. 275.1689 C14H20O4Na, found 275.1694 19 (0.73 g, 92% yield) as a yellow liquid. [α]25 = -
D
[M+Na]+.
1.54 (c = 0.1, CHCl3); IR (neat): 3500, 3419, 2930,
1
2855, 1612, 1512, 1347, 1024 cm-1; H-NMR (CDCl3,
(4R,5R)-4-((benzyloxy)methyl)-2,2-dimethyl-5-
vinyl-1,3-dioxolane (18): To an ice-cooled solution of 300 MHz): δ 7.39-7.22 (m, 5H), 5.91-5.76 (m, 1H),
2-(iodooxy) benzoic acid (2.26 g, 8.08 mmol) in 5.38-5.15 (m, 2H), 4.53 (qt, J = 11.89 Hz, 2H), 4.13 (t,
anhydrous CH3CN (15 mL) was added a solution of J = 5.48 Hz, 1H), 3.72-3.63 (brs, 1H), 3.63-3.47 (m,
alcohol 17 (1.7 g, 6.74 mmol). The mixture was 2H), 3.12-2.99 (brs, 1H) ppm; 13C-NMR (CDCl3, 100
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10.1002/ejoc.201800561
European Journal of Organic Chemistry
FULL PAPER
MHz): δ 137.5, 136.9, 128.4 (2C), 127.8, 127.7 (2C), J = 11.29, 3.50 Hz, 1H), 3.59-3.50 (m, 2H), 2.62 (s,
117.1, 73.5, 73.4, 72.7, 71.4 ppm; HRMS (ESI): calc. 1H), 0.90 (s, 9H), 0.07 (d, J = 15.41 Hz, 6H) ppm; 13C-
231.1095 C12H16O3Na, found 231.1087 [M+Na]+.
NMR (CDCl3, 125 MHz): δ 137.6, 117.3, 74.6 (2C),
62.9, 29.6, 25.7 (3C), -4.9, -4.1 ppm; HRMS (ESI):
(2S,3S)-1-(benzyloxy)-3-((tert-
butyldimethylsilyl)oxy)pent-4-en-2-ol (20): To an calc. 255.3689 C11H24O3SiNa, found 255.2694
ice-bath cooled solution of compound 19 (0.70 g, 3.36 [M+Na]+.
mmol), imidazole (0.57 g, 8.40 mmol) in anhydrous
CH2Cl2 (5 mL) was added solid tert-butyl yl)allyl)oxy)(tert-butyl)dimethylsilane (22a) and
dimethylsilyl chloride (0.45 g, 3.02 mmol). The
(((1S)-1-((4S)-2-benzyl-1,3-dioxolan-4-
(((4S,5S)-2-benzyl-4-vinyl-1,3-dioxan-5-yl)oxy)(tert-
mixture was stirred at 0 °C for 1 h, then diluted with butyl)dimethylsilane (22b): Benzaldehyde dimethyl
water (10 mL) and extracted with ether (3 × 5 mL). acetal (0.45 mL, 2.96 mmol) and catalytic PPTS (0.05
The combined organic phases were washed with brine g, 0.22 mmol) were added successively to a solution of
(10 mL) and dried over anhydrous Na2SO4 and diol 21 (0.53 g, 2.28 mmol) in CH2Cl2 (20 mL). The
concentrated. The residue was purified by flash solution was stirred at 0 °C - rt for 1 h, then quenched
column chromatography (97:3 hexane-EtOAc) to give with solid NaHCO3. The crude compound was
compound 20 (0.92 g, 85%) as a yellowish oil. [α]25
=
concentrated in vacuo and purified by column
chromatography (9:1, Hexane/EtOAc) to afford the
acetal compound mixture 22a and 22b (80:20%, 0.65 g,
D
-4.67 (c = 0.2, CHCl3); IR (neat): 3319, 2940, 2875,
1
1712, 1550, 1255, 1076, 838 cm-1; H-NMR (CDCl3,
86%) as a colorless liquid. [α]25 = -3.01 (c = 0.1,
500 MHz): δ 7.37-7.26 (m, 5H), 5.92-5.82 (m, 1H),
5.37-5.14 (m, 2H), 4.57-4.48 (m, 2H), 4.27-4.14 (m,
1H), 3.85-3.79 (m, 1H), 3.70-3.64 (m, 1H), 3.60-3.52
(m, 1H), 0.91-0.87 (m, 9H), 0.06-0.04 (m, 6H) ppm;
13C-NMR (CDCl3, 100 MHz): δ 138.2, 137.8, 128.3
(2C), 127.7, 127.67, 127.63, 115,7, 73.8, 72.9, 71.6,
70.5, 29.6, 25.7 (3C), -4.2, -4.4 ppm; HRMS (ESI):
calc. 345.1770 C18H30O3SiNa, found 345.1775
[M+Na]+.
D
CHCl3); IR (neat): 2830, 2855, 1612, 1512, 1247, 1025,
840 cm-1; 1H-NMR (CDCl3, 500 MHz): δ 7.57-7.46 (m,
2H), 7.41-7.34 (m, 3H), 6.05-5.89 (m, 1H), 5.41-5.22
(m, 2H), 4.41-4.34 (m, 2H), 4.28-4.21 (m, 1H), 4.17-
4.06 (m, 2H), 4.05-3.91 (m, 2H), 0.98-0.89 (m, 9H),
0.13-0.07 (m, 6H) ppm; HRMS (ESI): calc. 359.1023
C19H43O3SiNa, found 359.1020 [M+Na]+.
(5S,6S)-5-(benzyloxy)-6-vinyl-5,6-dihydro-2H-
(2S,3S)-3-((tert-butyldimethylsilyl)oxy)pent-4-ene-
1,2-diol (21): Lithium granules (0.15 g, 22.32 mmol)
were added, to a stirred solution of naphthalene (2.86 g,
22.32 mmol) in THF (10 mL) at rt and the solution
was stirred for 45 min to generate Lithium
naphthalenide. To the resulting dark green colour
solution, the compound 20 (0.90 g, 2.79 mmol) was
pyran-2-one
(25a)
and
(S)-5-((S)-1-
(benzyloxy)allyl)furan-2(5H)-one (25b): A stirred
solution of 24a and 24b (0.46 g, 1.22 mmol) in CH2Cl2
(10 mL) was treated with p-TSA.H2O (0.06 g, 0.36)
for 12 h at room temperature. After completion of the
reaction (indicated by TLC), reaction mixture was
diluted with CH2Cl2 (5 mL) and solid NaHCO3 was
added and stirred for further 15 min. The reaction
mixture was then filtered through a short pad of Celite
and the Celite pad was washed with CH2Cl2 (3 × 5
mL). Evaporation of solvent followed by silica gel
column chromatography (80:20; hexane-EtOAc) gave
compounds 25a (0.19 g, 85%) and 25b (0.048 g, 85%)
o
added at -20 C and allowed the mixture to stir at the
same temperature for 30 min then it was quenched
with aqueous NH4Cl, extracted into EtOAc (3 x 10
mL), dried over Na2SO4, concentrated in Rota vapor
and purified on silica gel column chromatography
(60% Hexane/ EtOAc) to provide diol 21 (0.55 g,
85%) as a colourless oil. [α]25 = +2.00 (c = 0.2,
D
as a colorless oil. 25a Compound Data: [α]25
=
D
CHCl3); IR (neat): 3415, 2931,1676, 1384, 1052, 772
cm-1; 1H-NMR (CDCl3, 500 MHz): δ 5.87-5.78 (m, 1H),
5.31-5.18 (m, 2H), 4.14 (t, J = 6.56 Hz, 1H), 3.67 (dd,
+62.50 (c = 0.2, CHCl3); IR (neat): 2924, 2855, 1715,
1
1630, 1460, 1247, 1081, 759 cm-1; H-NMR (CDCl3,
500 MHz): δ 7.42-7.27 (m, 5H), 6.83 (dd, J = 9.91,
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10.1002/ejoc.201800561
European Journal of Organic Chemistry
FULL PAPER
4.57 Hz, 1H), 6.15-6.07 (m, 2H), 5.50 (d, J = 17.24 Hz, residue was purified by silica gel column
1H), 5.42 (d, J = 10.68 Hz, 1H), 4.95-4.89 (m, 1H), chromatography (50% EtOAc-Hexane) to afford 26
13
4.62 (s, 2H), 4.16 (t, J = 4.12 Hz, 1H) ppm; C-NMR (0.02 g, 85%) as colorless oil. [α]25 = -27.00 (c = 0.2,
D
(CDCl3, 125 MHz): δ 162.5, 143.2, 137.0, 131.4, 128.5 CHCl3); IR (neat): 3452, 2925, 2854, 1722, 1650, 1633,
1
(2C), 128.1, 127.7 (2C), 122.9, 119.5, 80.1, 71.6, 69.0 1432, 1258, 825 cm-1; H-NMR (CDCl3, 500 MHz): δ
ppm; HRMS (ESI): calc. 253.2058 C14H14O3Na, found 7.46 (dd, J = 5.79, 1.52 Hz, 1H), 6.21 (dd, J = 5.79,
253.2051 [M+Na]+. 25b Compound Data: [α]25 = - 1.98 Hz, 1H), 5.91-5.83 (m, 1H), 5.47-5.41 (m, 1H),
D
2.50 (c = 0.2, CHCl3); IR (neat): 2930, 2855, 1715, 5.38-5.34 (m, 1H), 5.04 (tt, J = 5.79, 1.83 Hz, 1H),
1
13
1650, 1480, 1247, 1081, 759 cm-1; H-NMR (CDCl3, 4.33-4.27 (m, 1H), 2.67-2.59 (brs, 1H) ppm; C-NMR
500 MHz): δ 7.46 (dd, J = 5.74, 1.46 Hz, 1H), 7.39- (CDCl3, 125 MHz): δ 172.5, 153.0, 134.2, 123.1, 119.3,
7.30 (m, 5H), 6.17 (dd, J = 5.74, 1.95 Hz, 1H), 5.69- 85.4, 73.4 ppm; HRMS (ESI): calc. 141.10544 C7H8O3,
5.60 (m, 1H), 5.43-5.34 (m, 2H), 5.13-5.10 (m, 1H), found 141.10540 [M+H]+.
4.66 (d, J = 11.86 Hz, 1H), 4.46 (d, J = 11.86 Hz, 1H), 6-mem lactone derivatives: Second generation
4.10 (dd, J = 7.45, 5.62 Hz, 1H) ppm; 13C-NMR grubb’s catalyst (1.8 mg, 0.002 mmol) was dissolved
(CDCl3, 100 MHz): δ 172.6, 153.4, 137.4, 132.3, 128.4 in CH2Cl2 (1mL) and added dropwise to solution of the
(2C), 127.8, 127.7 (2C), 123.0, 121.6, 83.8, 79.5, 70.8 compound lactone 4 (0.03 g, 0.21 mL) and diffrent (4-
ppm; HRMS (ESI): calc. 253.1782 C14H14O3Na, found Acetyl,4-tButyl, 4-Bromo, 4-Chloro) Styrenes (33 mg,
253.1769 [M+Na]+.
(5S,6S)-5-hydroxy-6-vinyl-5,6-dihydro-2H-pyran-2-
0.31 mmol) in CH2Cl2 (1mL) at 40 oC. After
completion of addition, the reaction mixture was
one (4): To a stirred solution of compound 25a (0.18 g, allowed to reflux for few hrs. The solvent was
0.78 mmol) in anhydrous CH2Cl2 (5 mL), TiCl4 (0.1 removed under prressure and the crude product was
mL, 0.93 mmol) was added at 0 °C and the reaction purified by silica gel column chromatography
mixture was stirred at the same temperature for 45 min. (Hexane/EtOAc 7:3) to afford the pure products 28a,
The reaction mixture was quenched with solid 28b, 28c, 28d, 28e as a solid.
NaHCO3 and filtered. The solvent was removed under
(5S,6S)-5-hydroxy-6-((E)-styryl)-5,6-dihydro-2H-
o
reduced pressure. The residue was purified by silica pyran-2-one (28a): m.p. 145-148 C; [α]25 = +185.0
D
gel column chromatography (50% EtOAc-Hexane) to (c = 0.3, CHCl3); IR (neat): 3404, 2923, 1712, 1628,
1
afford 4 (0.09 g, 87%) as colorless oil. [α]25 = +31.05 1447, 1257, 1086, 750 cm-1; H-NMR (CDCl3, 500
D
(c = 0.1, CHCl3); IR (neat): 3452, 2925, 2854, 1722, MHz): δ 7.44-7.40 (m, 2H), 7.35-7.25 (m, 3H), 7.03
1
1650, 1633, 1432, 1258, 825 cm-1; H-NMR (CDCl3, (dd, J = 9.7, 5.5 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H),
500 MHz): δ 7.01 (dd, J = 9.82, 5.28 Hz, 1H), 6.14 (d, 6.39 (dd, J = 16.1, 6.7 Hz, 1H), 6.16 (d, J = 9.0 Hz,
J = 9.82 Hz, 1H), 6.11-5.97 (m, 1H), 5.63-5.54 (m, 1H), 5.05 (ddd, J = 6.7, 3.0, 1.3 Hz, 1H), 4.30 (dd, J =
1H), 5.53-5.46 (m, 1H), 4.93-4.87 (m, 1H), 4.29-4.20 5.0, 3.0 Hz, 1H), 2.47 (brs, 1H) ppm; 13C-NMR
(m, 1H), 2.58-2.37 (brs, 1H) ppm; 13C-NMR (CDCl3, (CDCl3, 125 MHz): δ 163.1, 144.6, 135.5, 135.2, 128.6
75 MHz): δ 163.1, 144.4, 131.0, 122.7, 120.1, 80.8, (2C), 128.4, 126.8 (2C), 122.8, 121.5, 81.0, 63.0 ppm;
62.6 ppm; HRMS (ESI): calc. 163.1627 C7H8O3Na, HRMS (ESI): calc. 217.1569 C13H12O3Na, found
found 163.1624 [M+Na]+.
217.1564 [M+Na]+.
(S)-5-((S)-1-hydroxyallyl)furan-2(5H)-one (26): To a
4-((E)-2-((2S,3S)-3-hydroxy-6-oxo-3,6-dihydro-2H-
stirred solution of compound 25b (0.04 g, 0.17 mmol) pyran-2-yl)vinyl)phenyl acetate (28b): m.p. 122-128
in anhydrous CH2Cl2 (4 mL), TiCl4 (0.02 mL, 0.20 oC; [α]25D = +104.30 (c = 0.4, CHCl3); IR (neat): 3427,
1
mmol) was added at 0 °C and the reaction mixture was 2925, 2855, 1744, 1610, 1164, 1021 cm-1; H-NMR
stirred at the same temperature for 1 h. The reaction (CDCl3, 500 MHz): δ 7.42 (d, J = 8.5 Hz, 2H), 7.05 (d,
mixture was quenched with solid NaHCO3 and filtered. J = 8.4 Hz, 2H), 7.01 (dd, J = 9.6, 5.3 Hz, 1H), 6.82 (d,
The solvent was removed under reduced pressure. The J = 16.0 Hz, 1H), 6.32 (dd, J = 16.0, 6.4 Hz, 1H), 6.14
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(d, J = 9.7 Hz, 1H), 5.02 (dd, J = 6.2, 2.6 Hz, 1H), 4.28
(dd, J = 4.8, 3.2 Hz, 1H), 2.29 (s, 3H) ppm; C-NMR
(2S,3S)-6-oxo-2-((E)-styryl)-3,6-dihydro-2H-pyran-
3-yl acetate (29):
13
(CDCl3, 125 MHz): δ 169.4, 163.2, 150.6, 144.7, 133.9, To a stirred solution of the lactone 28a (0.02 g, 0.09
133.4, 127.8 (2C), 122.6, 122.0, 121.8 (2C), 80.9, 62.9, mmol) in dry CH2Cl2 (3 mL) were added Et3N (0.026
21.1 ppm; HRMS (ESI): calc. 297.1009 C15H14O5Na, mL, 0.18 mmol) followed by acetic anhydride (0.014
found 297.1005 [M+Na]+.
mL, 0.13 mmol) and catalytic amount of DMAP at 0
oC. The reaction mixture was stirred for 1 hr and then
(5S,6S)-6-((E)-4-(tert-butyl)styryl)-5-hydroxy-5,6-
dihydro-2H-pyran-2-one (28c): m.p. 140-146 oC; diluted with CH2Cl2 (5 ml), the organic layer was
[α]25 = +145.80 (c = 0.6, CHCl3); IR (neat): 3408, washed with 5% NaHCO3 solution (2 x 4 mL), brine (2
D
2960, 2865, 1774, 1620, 1464, 1259, 1081 cm-1; H- x 4 mL) and dried over anhydrous Na2SO4. The
1
NMR (CDCl3, 300 MHz): δ 7.38 (s, 4H), 7.03 (dd, J = solvent was removed under reduced pressure and the
9.8, 5.2 Hz, 1H), 6.86 (dd, J = 15.8, 1.5 Hz, 1H), 6.34 crude residue was purified on silica gel column
(dd, J = 15.8, 6.0 Hz, 1H), 6.18 (d, J = 9.0 Hz, 1H), chromatography (40% EtOAC/Hexane) to provide the
5.06 (ddd, J = 6.7, 3.0, 1.5 Hz, 1H), 4.30 (brs, 1H), lactone 29 (20 mg, 90%) as acolorless oil. [α]25
=
D
1.32 (s, 9H) ppm; 13C-NMR (CDCl3, 125 MHz): δ +204.20 (c = 0.2, CHCl3); IR (neat): 2924, 2853, 1745,
1
163.4, 151.6, 144.7, 134.9, 132.8, 126.5 (2C), 125.5 1384, 1249, 1021, 759 cm-1; H-NMR (CDCl3, 300
(2C), 81.2, 63.0, 34.6, 31.2 (3C) ppm; HRMS (ESI): MHz): δ 7.43-.24 (m, 5H), 7.00 (dd, J = 9.82, 5.47 Hz,
calc. 295.1350 C17H20O3Na, found 295.1347 [M+Na]+. 1H), 6.83 (d, J = 16.05 Hz, 1H), 6.30-6.16 (m, 2H),
5.37 (dd, J = 5.47, 3.21 Hz, 1H), 5.22-5.16 (m, 1H),
(5S,6S)-6-((E)-4-bromostyryl)-5-hydroxy-5,6-
dihydro-2H-pyran-2-one (28d): m.p. 125-128 oC; 2.06 (s, 3H) ppm; 13C-NMR (CDCl3, 125 MHz): δ
[α]25D = +83.76 (c = 0.5, CHCl3); IR (neat): 3432, 2924, 169.9, 162.3, 140.6, 135.6, 134.8, 128.6, 126.7, 124.8,
1743, 1609, 1383, 1164 cm-1; H-NMR (CDCl3, 300 121.0, 79.0, 63.8, 20.5 ppm; HRMS (ESI): calc.
1
MHz): δ 7.46 (d, J = 8.3 Hz, 2H), 7.29 (d, J =8.3 Hz, 281.1189 C15H14O4Na, found 281.1191 [M+Na]+.
2H), 7.08-7.00 (m, 1H), 6,81 (d, J = 16.6 Hz, 1H), 6.38 5-mem lactone derivatives: Similar procedure
(dd, J = 15.8, 6.0 Hz, 1H), 6.18 (d, J = 9.8 Hz, 1H), followed as provided for 6-membered lactones
5.05 (dd, J = 6.0, 3.0 Hz, 1H), 4.31 (brs, 1H), 2.15 (d,
(S)-5-((S,E)-1-hydroxy-3-phenylallyl)furan-2(5H)-
o
J = 7.5 Hz, 1H) ppm; 13C-NMR (CDCl3, 125 MHz): δ one (30a): m.p. 121-124 C; [α]25 = -24.50 (c = 0.3,
D
162.9, 144.4, 133.9, 134.5, 128.3 (3C), 127.9 (2C), CHCl3); IR (neat): 3420, 2922, 1752, 1633, 1455, 1185,
1
122.9, 122.4, 80.8, 62.9 ppm; HRMS (ESI): calc. 1086, 769 cm-1; H-NMR (CDCl3, 400 MHz): δ 7.49
317.1243 C13H11BrO3Na, found 317.1249 [M+Na]+.
(dd, J = 5.86, 1.46 Hz, 1H), 7.42-7.27 (m, 5H), 6.73 (d,
J = 15.89 Hz, 1H), 6.24-6.16 (m, 2H), 5.10 (dt, J =
(5S,6S)-6-((E)-4-chlorostyryl)-5-hydroxy-5,6-
dihydro-2H-pyran-2-one (28e): m.p. 151-155 oC; 5.74 Hz, 1H), 4.44 (t, J = 6.23 Hz, 1H), 2.61 (brs, 1H)
[α]25 = +187.92 (c = 0.4, CHCl3); IR (neat): 3425, ppm; 13C-NMR (CDCl3, 125 MHz): δ 172.5, 153.1,
D
1
2927, 1703, 1405, 1254, 1038, 771 cm-1; H-NMR 135.6, 134.3, 128.6 (2C), 128.4, 126.7 (2C), 125.0,
(CDCl3, 500 MHz): δ 7.35-7.32 (m, 2H), 7.30-7.27 (m, 123.1, 85.8, 73.3 ppm; HRMS (ESI): calc. 239.1059
2H), 7.05 (dd, J = 9.7, 5.6 Hz, 1H), 6.81 (dd, J = 16.0, C13H12O3Na, found 239.1061 [M+Na]+.
0.9 Hz, 1H), 6.37 (dd, J = 16.0, 6.5 Hz, 1H), 6.17 (d, J
(S)-5-((S,E)-1-hydroxy-3-(4-
= 9.7 Hz, 1H), 5.04 (ddd, J = 6.5, 2.9, 1.3 Hz, 1H), methoxyphenyl)allyl)furan-2(5H)-one (30b): m.p.
13
o
4.29 (brs, 1H), 2.43 (brs, 1H) ppm; C-NMR (CDCl3, 135-137 C; [α]25 = -30.70 (c = 0.4, CHCl3); IR
D
125 MHz): δ 163.0, 144.5, 134.0, 134.2, 133.9, 128.8 (neat): 3447, 2925, 1772, 1665, 1461, 1220, 771 cm-1;
(2C), 128.0 (2C), 122.9, 80.9, 63.0 ppm; HRMS (ESI): 1H-NMR (CDCl3, 400 MHz): δ 7.48 (dd, J = 5.74, 1.46
calc. 251.1132 C13H11ClO3Na, found 251.1130 Hz, 1H), 7.42 (dd, J = 6.72, 2.07 Hz, 1H), 7.32 (dd, J =
[M+Na]+.
6.72, 1.95 Hz, 2H), 6.67 (d, J = 15.89 Hz, 1H), 6.21
(dd, J = 5.74, 1.95 Hz, 1H), 6.06 (dd, J = 15.89, 7.21
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10.1002/ejoc.201800561
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Hz, 1H), 5.09 (dt, J = 5.86 Hz, 1H), 4.40 (t, J = 6.48
Hz, 1H), 3.81 (s, 3H), 2.42 (brs, 1H). 13C-NMR
(CDCl3, 100 MHz): δ 172.5, 159.8, 153.2, 134.0, 30.4,
27.9, 127.3, 126.1, 123.0, 122.6, 114.0, 85.9, 73.6,
55.2 ppm; HRMS (ESI): calc. 269.2370 C14H14O4Na,
found 269.2367 [M+Na]+.
1. Ohkuma, H.; Naruse, N.; Nishiyama, Y.;
Tsunoda, T.; Hoshino, Y.; Sawada, Y.; Konishi,
M.; Oki, T. J. Antibiot. 1992, 45, 1239.
2. Sakai, Y.; Yoshida, T.; Ochiai, K.; Uosaki,
Y.; Saitoh,
Y.; Tanaka,
F.; Akiyama,
T.; Akinaga, S.; Mizukami, T. J. Antibiot. 2002,
55, 855.
(S)-5-((S,E)-3-(4-bromophenyl)-1-
hydroxyallyl)furan-2(5H)-one (30c): m.p. 163-166
oC; [α]25 = -15.0 (c = 0.2, CHCl3); IR (neat): 3380,
D
3. a) Christopher, P. B.; Nadia, H.; Boger, D. L. J.
Am. Chem. Soc. 2010, 132, 2157–2159. b)
Christopher, P. B.; Mark, R. S.; Richard, E. H.;
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7513.
1
2926, 1742, 1661, 1487, 1200, 1186, 746 cm-1; H-
NMR (CDCl3, 400 MHz): δ 7.49 (dd, J = 5.74, 1.46 Hz,
1H), 7.47-7.44 (m, 2H), 7.27-7.22 (m, 2H), 6.68 (d, J =
15.89 Hz, 1H), 6.23 (dd, J = 5.01, 2.07 Hz, 1H), 6.19
(dd, J = 15.89, 6.72 Hz, 1H), 5.10 (dt, J = 5.50 Hz,
1H), 4.45 (t, J = 5.86 Hz, 1H), 2.62 (brs, 1H) ppm;
13C-NMR (CDCl3, 100 MHz): δ 172.4, 153.0, 134.5,
133.0, 131.8 (2C), 128.1 (2C), 125.8, 123.2, 122.3,
85.6, 73.1 ppm; HRMS (ESI): calc. 317.1436
C13H11BrO3Na, found 317.1440 [M+Na]+.
4. a) Sabitha, G.; Fatima, N.; Gopal, P.; Reddy, C.
N.; Yadav, J. S. Tetrahedron Asymmetry. 2009,
20, 184. b) Sabitha, G.; S. Reddy, S. S. S.;
Yadav, J. S. Tetrahedron Lett. 2010, 51, 6259.
c) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.;
Yadav, J. S. Helv. Chim. Acta 2010, 93, 329. d)
Sabitha, G.; Shankaraiah, K.; Yadav, J. S. Eur.
J. Org. Chem. 2013, 4870.
(S)-5-((S,E)-1-hydroxy-3-
(perfluorophenyl)allyl)furan-2(5H)-one (30d): m.p.
o
127-130 C; [α]25 = -30.0 (c = 0.5, CHCl3); IR (neat):
D
3448, 2928, 1760, 1615, 1347, 1223, 1116, 771 cm-1;
1H-NMR (CDCl3, 300 MHz): δ 7.49 (dd, J = 5.86, 1.58
Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.23 (dd, J = 5.74,
1.34 Hz, 1H), 6.20 (dd, J = 16.2, 7.09 Hz, 1H), 5.11 (dt,
J = 5.86 Hz, 1H), 4.44 (t, J = 6.00 Hz, 1H) ppm; 13C-
NMR (CDCl3, 100 MHz): δ 168.2, 153.0, 135.5, 134.5,
128.7 (2C), 128.4, 126.7 (2C), 124.9, 123.2, 85.7, 73.5
ppm; HRMS (ESI): calc. 329.1149 C13H7F5O3Na,
found 329.1141 [M+Na]+.
5. Jeffery, T.; Gueugnot, S.; Linstrumelle, G.
Tetrahedron Lett. 1992, 33, 5757.
6. Radha Krishna, P.; Lopinto, K. Synlett. 2007,
12, 1742.
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Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
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Acknowledgements
8. Crimmins, M. T and De Baillie, A. C. J. Am.
Chem. Soc. 2006, 128, 4936-4937.
KPR and DVR thank CSIR, India 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).
9. (a) Prakash, C.; Saleh, S.; Blair, L. A.
Tetrahedron Lett. 1989, 30, 19. (b) Crouch, R.
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Keywords: Gilman; Stereoselective synthesis; Stork’s
protocol; Cross-metathesis; Sonogashira coupling;
Goniothalamins.
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Stereoselective synthesis of C1-C7 and C6-C22 fragments of phostriecin, goniothalamines and its analogs
K. Purushotham Reddy, D. vasudeva Reddy and Gowravaram Sabitha*
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad – 500 007,
India.
Corresponding author: Tel.: +91-40-27191629; fax: +91-40-27160512
e-mail: gowravaramsr@yahoo.com, sabitha@iict.res.in
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