A facile approach for the synthesis of C13-C24 fragments of maltepolides A, C and D

Article abstract of DOI:10.1039/c6ob01447j

A linear, chiron approach for the synthesis of C13-C24 fragments of cytostatic maltepolides A, C and D consisting of a tetrahydrofuran subunit and a chiral alkenyl/alkyl substituent is achieved from (+)-diethyl l-tartrate. The other chiral stereocenters were generated by employing key reactions such as Crimmins aldol, alkynylation and CeCl₃·7H₂O mediated Luche reduction reactions.

Full text of DOI:10.1039/c6ob01447j

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ARTICLE TYPE
A facile approach for the synthesis of C13-C24 fragment of maltepolides
A, C and D
a
a
P. Sankara Rao and P. Srihari*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A linear, chiron approach for the synthesis of C13ꢀC24 fragment for cytostatic maltepolides A, C and D
consisting of a tetrahydrofuran subunit and a chiral alkenyl/alkyl substituent is achieved from (+)ꢀdiethyl
Lꢀtartrate. The other chiral stereocenters were generated by employing key reactions such as Crimmins
aldol, alkynylation and CeCl 7H O mediated Luche reduction reactions.
3
.
2
herein we describe the synthesis of three independent C13ꢀC24
fragments useful for the total synthesis of maltepolides A, C and
D respectively starting from the readily available (+)ꢀdiethyl Lꢀ
tartrate in a linear fashion.
1
0
Introduction
The terrestrial and marine originated natural products continue to
attract significant attention because of their structural diversity
and broad spectrum of biological properties. There has been an
increased focus on the isolation of secondary metabolites towards
50
1
1
2
2
3
3
4
4
5
0
5
0
5
0
5
investigating their biological profiles. Maltepolides are the
recently isolated macrolides obtained from the fermentation broth
of myxobacterium Sorangium cellulosum So cel485 by Prusov et
2
al.
These remarkable novel structural class of compounds
characterised by either a tetrahydrofuran (THF) moiety for
maltepolide AꢀD and F 1ꢀ4, 6 or a vinylic epoxide functionality
for maltepolide E (5) (Figure 1) in the macrolactone ring were
found to exhibit moderate cytostatic activity. Further evaluation
by means of fluorescent microscopy revealed that maltepolide A
and E also cause unique morphological changes in the dividing
transformed PtK2 cells. The architectural novelty and potent
biological activity embeded with scarce availability of these
5
5
3
novel natural products make them the attractive targets for total
synthesis to further explore their biological activities.
Structurally, maltepolides AꢀD bear a similar macrolide skeleton
with a tetrahydrofuran moiety and 9 chiral centers. The
variations found in these molecules lies at C22ꢀC23 carbon where
in an epoxy functionality is present for maltepolide A, B and E
and diol functionality is present in maltepolide C and D. Also,
syn geometry at C14ꢀC17 tetrahydrofuran ring juncture for
maltepolide B and trans geometry at C14ꢀC17 for maltepolide A,
C and D. Maltepolide B also differs from other members by the
Figure 1: Structures of maltepolides AꢀE (1ꢀ5).
60
Results and Discussion
Retrosynthetically, it was envisioned that the target macrolides
maltepolides A, C and D can be synthesized by coupling the two
fragments 6 and 7 followed by functional group manipulations at
C22ꢀC23 carbons. Alternatively, we may also proceed with
presence of Zꢀgeometry at C2ꢀC3 olefin.
The structural 65 fragment 7 with appropriate functionalities at C22 and C23
elucidation of maltepolides was achieved by a combination of 2D
NMR experiments, molecular modelling and Xꢀray
crystallography studies. To our knowledge, so far there is only
carbons for coupling with fragment 6. Our initial focus was on
the tetrahydrofuran motif containing fragment 7 with seven
stereocenters. Accordingly, the fragment 7 was envisaged to be
synthesized from its precursor disubstituted alkyne 8 through
3
one contribution reported by Mohapatra et al, wherein they have
achieved the synthesis of C8ꢀC24 fragment of maltepolide C 70 partial reduction of triple bond to double bond. The alkyne 8 in
using a tandem dihyroxylation/S 2 cyclization sequence to build
turn could be accessed from 10 by means of an addition reaction
onto aldehyde 9 obtained from commercialy available (ꢀ)ꢀethyl Lꢀ
lactate. The compound 10 in turn can be accessed from 12
through acetonide deprotection followed by base mediated
N
up the tetrahydrofuran skeleton.
In continuation to our efforts on the synthesis of complex natural
4
products with an emphasis on lactone containing molecules,
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cyclization reaction to get the tetrahydrofuran skeleton. The
compound 12 can be synthesized from 13 by Luche reduction,
benzyl protection of the resulting propargyl alcohol and TBS
Compound 14 can be synthesized from aldehyde 15 via
Crimmins aldol reaction with auxiliary 16. The aldehyde 15 in
turn can be obtained from known alcohol 17 in three step
deprotection followed by mesyl protection. Compound 13 can be 10 sequence, i.e., oxidation, Wittig reaction followed by hydrolysis
5
obtained from 14 through auxillary cleavage followed by
of enol ether. The alcohol 17 was readily accessible from
trimethylsilylacetylide addition and oxidation reactions.
commercially available (+)ꢀdiethyl Lꢀtartrate.
1
2
2
5
0
Scheme 1. Retrosynthetic analysis for Maltepolide A, C and D.
5
Scheme 2. Synthesis of intermediate 23.
30
The synthesis began with the oxidation reaction of the known 35 nBuli to produce the enol ether which was further hydrolysed to
5
6
alcohol 17 (synthesized from (+)ꢀdiethyl Lꢀ tartrate in three steps
aldehyde 15 with mercuric acetate Hg(OAc) . Compound 15 was
2
with an overall 73% yield). The alcohol 17 was oxidized under
Swern conditions to the corresponding aldehyde and treated with
treated with (R)ꢀ1ꢀ(4ꢀbenzylꢀ2ꢀthioxothiazolidinꢀ3ꢀyl)propionone
16 in presence of TiCl4 using Crimmins protocol to yield the
7
(methoxymethyl)triphenylphosphonium chloride in presence of
synꢀaldol product 19 with good diastereoselectivity (98% de)
2
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(
Scheme 2). After protecting the secondary alcohol with
ketone 13 albeit in low yields (65% brsm). Alternatively, the
chiral auxiliary 14 was cleaved with DiBALꢀH to yield the
aldehyde 22, which was then subjected to an addition reaction
TBSOTf as the corresponding TBSꢀether 14, the chiral auxiliary
was treated with Nꢀmethyl methoxy aminohydrochloride salt in
presence of imidazole to yield the corresponding Weinreb amide 10 with lithiated trimethylsilyl acetylene to furnish the mixture of
5
5
20. Compound 20 when treated with lithiated trimethylsilyl
acetylene (generated by treating 21 with nBuLi) yielded the
diasteromeric alcohols 23 and 23a (4:6).
1
2
2
3
3
4
4
5
5
6
0
5
0
5
0
5
0
5
0
Scheme 3: Synthesis of tetrahydrofuran intermediate 10
Since, the diastereomeric selectivity was not observed, we 65 secondary alcohol was protected as the corresponding methyl
proceeded further for twoꢀstep sequence to get the desired
ether 10 with NaH and MeI in 75% yield as this protection was a
requisite for the natural product.
With the successful accomplishment of terahydrofuran motif
containing intermediate 10, we now focused our attention
diastereomer in major quantities. Thus, the mixture of 23 and
8
2
3a was oxidized under DessꢀMartin periodinane (DMP)
conditions to yield the ketone 13 and then subjected to Luche’s
9
reduction reaction with CeCl 7H O. Gratifyingly, high 70 towards extension of the carbon length (C21ꢀ24 carbons) with
3
.
2
1
2
diastereoselectivity (>98% de) for the product 23 was observed in
two chiral centers. Thus, the aldehyde 9 (obtained from
commercially available chiral lactic ester 11 in two step sequence
i.e., TBS protection to get silyl ether followed by DIBAL
treatment following known procedures) was subjected to addition
this reaction. The stereochemistry at the newly generated chiral
10
13
center was conformed following Rychnovsky’s protocol by
C
NMR analysis. Towards this, a small amount of the alcohol 23
was treated with TBAF to furnish 1,3ꢀdiol 24 with simultaneous 75 reaction with alkyne 10 in presence of nBuLi to yield alcohol 8 in
trimethylsilyl deprotection on the alkyne functionality.
Compound 24 was subjected to acetonide protection using 2,2ꢀ
dimethoxypropane and PTSA to give the corresponding
75% yield (Scheme 5). The geometry of the major isomer 8 was
conformed by Mosher analysis method
information). Since olefin functionality was a prerequisite for the
target natural product intermediate, our initial attempts for the
13
(See supporting
1
3
isopropylidene derivative 25. Based on the C NMR value for
the 1,3ꢀdiol acetonide carbons the geometry at the newly created 80 reduction of alkyne functionality with LiAlH4 at room
hydroxyl center was established as syn with respect to the other
free hydroxyl group. The ketal carbon resonated at 99.6 ppm
which is in accordance to the generalised value for syn 1,3ꢀdiol as
temperature or under heating conditions was not successful and
always lead to the deprotection of TBS moiety with the retention
of alkyne functionality. However, the challenge was overcome
1
0
14
demonstrated by Rychnovsky. After confirming the geometry,
with sodium bis(2ꢀmethoxyethoxy)aluminium hydride (Red Al)
compound 23 was treated with benzylbromide in presence of 85 to yield the olefin 7 in good yield. Thus the synthesis of key
1
1
NaH to yield the corresponding benzyl ether 26 in 80% yield
and then subjected to desilylation with TBAF to furnish the
alcohol 27. The alcohol 27 was further converted to mesylate 12
by treatment with methanesulfonyl chloride in presence of
fragment 7 required for the total synthesis of maltepolide D was
successfully accomplished.
With the key intermediate 7 in hand, we proceeded further for the
protection of allylic alcohol with MeI to furnish the
triethylamine and the stage was set to go further for acetonide 90 corresponding methyl ether 29 which is a key C13ꢀC24 fragment
deprotection and cyclization reaction to get the tetrahydrofuran
skeleton. Thus the compound 12 was treated with PTSA in
methanol to yield the diol and then subjected to cyclization
reaction by treating with NaH in THF to furnish the desired
(Scheme 4) that can be utilized for the total synthesis of
maltepolide C. Simultaneously, the alcohol 7 was masked as the
corresponding mesylate with methanesulphonyl chloride in
presence of triethyl amine (Et N) and was then treated with
3
cyclized product 28 (Scheme 3) in 50% yield. The resulting 95 TBAF for the oneꢀpot TBS deprotection and cyclization reaction
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to yield the epoxy intermediate 30,
a key fragment for 45 distilled from Na and benzophenone ketyl; MeOH from Mg and
maltepolide A. Thus the synthesis of three key fragments 7, 29
and 30 that can be utilized for the total synthesis of maltepolide
D, maltepolide C and maltepolide A respectively have been
accomplished.
I ; CH Cl from CaH . All air– or moisture–sensitive reactions
2 2 2 2
were conducted under a nitrogen or argon atmosphere in flame–
dried or oven–dried glassware with magnetic stirring. Column
chromatography was carried out using silica gel (100– 200 mesh)
packed in glass columns. Technical grade ethyl acetate and
petroleum ether used for column chromatography were distilled
prior to use.
5
5
5
6
6
7
7
8
8
9
9
0
5
0
5
0
5
0
5
0
5
((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)methanol (17) :-
A solution of (+)ꢀdiethyl Lꢀtartrate (50.0 g, 242.7 mmol, 1.0
equiv) and pꢀtoluenesulfonic acid (375 mg, 2.2 mmol, 0.01 equiv)
in benzene (500 mL) and 2,2ꢀdimethoxypropane (44.5 mL, 364.1
mmol, 2.5 equiv) was heated at reflux for 12 h. The mixture was
allowed to cool to ambient temperature, washed with an aq.
saturated sodium bicarbonate solution (150 mL) and then dried
over anhydrous Na SO . The solvent was evaporated and the
1
0
2
4
residue was purified by column chromatography (hexane/ EtOAc
:2) to give the acetonide protected product (55.0 g, 92%), as a
8
colorless liquid. The above prepared solution of acetonide
protected compound (55.0 g, 223.6 mmol, 1 equiv) in dry THF
(
3
300 mL) was slowly added to a suspension of LiAlH (12.1 g,
4
o
1
5
17.7 mmol, 1.8 equiv) in dry THF (200 mL) at 0 C over a
o
period of 30 min. The resulting mixture was heated at 45 C for 5
h to complete the reaction. The reaction was quenched carefully
Scheme 4 Completion of the synthesis of key fragments 7, 29 and 30 for
the total synthesis of maltepolide D, C and A respectively.
o
with a saturated aq Na
SO
solution (300 mL) at 0 C and the
2
4
resulting suspension was stirred for 3 h before it was filtered
through a pad of silica gel. The filtrate was dried over anhydrous
Conclusions
Na SO , the solvent was evaporated and the residue was purified
2 4
by column chromatography to give acetanoide protected diol
In conclusion, a facile strategy for the synthesis of C13ꢀC24
tetrahydrofuran motif containing fragments 7, 29 and 30 with
seven stereocenters for the total synthesis of maltepolides D, C
and A respectively have been demonstrated and the synthesis of
the same has been accomplished from the commercially available
(
6
27.8 g, 83%), as a colorless liquid; R = 0.30 (hexane/EtOAc,
0:40); [α]D = +10.8 (c 0.5, MeOH); H NMR (300 MHz,
f
2
0
20
1
CDCl ): δ 3.97–3.89 (m, 2H), 3.76–3.65 (m, 4H), 1.39 (s, 6H);
3
13
C NMR (75 MHz, CDCl ): δ 109.2, 78.3, 62.0, 26.8; IR (Neat):
3
3401, 2988, 2935, 2881, 1376, 1251, 1218, 1165, 1108, 1053,
(+)ꢀdiethyl Lꢀtartrate. Synthesis of other key fragment and
ꢀ1
8
44 cm ; ESIꢀMS: m/z 185.0
2
5
consequent coupling of these fragments for the total synthesis of
maltepolides A, C and D is being pursued in the laboratory.
A solution of the above obtained diol (30.0 g, 185.2 mmol, 1.0
equiv) in dry THF (200 mL) was slowly added to a suspension of
6
0% NaH (7.8 g, 194.5 mmol, 1.05 equiv) in dry THF (100 mL)
o
at 0 C over a period of 30 min. and the resulting mixture was
stirred at ambient temperature for 1 h until the evolution of gas
had ceased. To this mixture was added drop wise a solution of
benzyl bromide (21.9 mL, 185.2 mmol, 1.0 equiv) over 30 min
and the resulting mixture was stirred for 12 h. The reaction
Experimental Section
3
0
General Methods:
1
13
H NMR and C NMR spectra were recorded in CDCl or C D
6
o
3
6
mixture was then quenched with ice flakes at 0 C and extracted
as solvent on 300 MHz or 500 MHz spectrometer at ambient
temperature. The coupling constant J is given in Hz. The
chemical shifts are reported in ppm on scale downfield from TMS
as internal standard and signal patterns are indicated as follows: s
with EtOAc (2 x 200 mL). The organic layer was washed with
brine (200 mL), dried over anhydrous Na SO , filtered, and
2
4
concentrated under reduced pressure, purified with silica gel
3
5
column chromatography to give alcohol 17 (34.0 g, 73%) as a
=
singlet, d = doublet, t = triplet, q = quartet, sext = sextet, m =
20
yellowish liquid; R = 0.6 (hexane/EtOAc, 80:20); [α]
= +8:3
f
D
multiplet, br = broad. FTIR spectral values are reported in wave
1
(
c 1.0, CHCl ); H NMR (300 MHz, CDCl ): δ 7.38–7.28 (m,
3
3
–
1
number (cm ). Optical rotations were measured on digital
polarimeter using a 1 mL cell with a 1 dm path length. For low
(MS) and High (HRMS) resolution, m/z ratios are reported as
values in atomic mass units. Mass analysis was done in ESI
mode. All reagents were reagent grade and used without further
purification unless specified otherwise. Solvents for reactions
were distilled prior to use: THF, toluene and diethyl ether were
5
3
H), 4.56ꢀ4.54 (m, 2H), 4.02–3.96 (m, 1H), 3.92–3.86 (m, 1H),
.74–3.63 (m, 3H), 3.54–3.48 (m, 1 H), 2.18 (br s, 1H), 1.39 (s, 3
40
13
H), 1.38 (s, 3H); C NMR (75 MHz, CDCl ): δ 137.4, 128.3,
00 127.6, 127.5, 109.2, 79.4, 76.3, 73.4, 70.2, 62.2, 26.8, 26.7; IR
max (Neat): 3466, 2988, 2932, 2872, 1453, 1375, 1250, 1216,
1
3
1
ꢀ1
167, 1085, 847, 741, 699 cm ; ESIꢀMS: m/z 275.0
4
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DOI: 10.1039/C6OB01447J
dropwise, and the resulting orange slurry was stirred for 5 min.
2
4
-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-
-yl)acetaldehyde (15)
60 iPr NEt (4.8 mL, 28.39 mmol) was then added and the resultant
2
black solution was stirred for 15 min. Nꢀmethylꢀ2ꢀpyrrolidinone
(4.7 mL, 49.21 mmol) was added dropwise at 0 °C and stirred.
After 30 min, the reaction was cooled to ꢀ78 °C, and 15 (5.0 g,
18.93 mmol) was added dropwise stirred for 40min at ꢀ78 °C.
To the solution of dry DMSO (11.3 mL, 158.7 mmol, 4.0 equiv)
in dry CH Cl (50 mL) was added drop wise oxalyl chloride (6.9
mL, 79.4 mmol, 2.0 equiv) at ꢀ78 C over 15 min and stirred for
5
0
5
0
5
0
5
0
5
0
5
2
2
o
2
1
0 min at the same temperature. To this reaction mixture, alcohol 65 Upon completion of the reaction by TLC analysis, the reaction
7 (10.0 g, 39.7 mmol, 1.0 equiv) in dry CH Cl (60 mL) was
was then quenched by addition of a saturated aqueous NH Cl
2
2
4
o
added drop wise over 15 min at ꢀ78 C and the reaction mixture
was stirred at the same temperature for 2 h. The reaction was
quenched with Et N (33.0 mL, 238.1 mmol, 6.0 equiv) at ꢀ78 C,
and then allowed to warm to room temperature, after which water 70 which was purified by flash chromatography R = 0.4 (20%
solution. The layers were separated and the aqueous layer was
then extracted into CH Cl (2 x 200 mL). The organic extracts
1
1
2
2
3
3
4
4
5
5
2
2
o
were dried (Na SO ) and evaporated to give a crude yellow oil
2 4
3
f
2
0
(100 mL) was added, the organic layer was separated and the
EtOAc/Hexanes) to afford (10.2 g, 79%) of the product 19 [α]
D
= ꢀ124.9 (c 0.4, CHCl ); H NMR (500 MHz, CDCl ): δ 7.49–
1
aqueous layer was extracted with CH Cl (2 100 mL), the
combined organic layer was washed with brine (80 mL), dried
over anhydrous Na SO . The solvent was removed under reduced
pressure to give a crude aldehyde, which was utilized for the next 75 4.07 (td, J = 8.4, 3.3 Hz, 1H), 3.90 (dt, J = 8.3, 5.1 Hz, 1H), 3.63
reaction without further purification (8.5 g, 85%). To a cooled (ꢀ
2
2
3
3
7.16 (m, 10H), 5.28 (ddd, J = 10.7, 6.9, 4.0 Hz, 1H), 4.57 (q, J =
12.1 Hz, 2H), 4.50–4.44 (m, 1H), 4.17 (dt, J = 9.3, 3.0 Hz, 1H),
2
4
(dd, J = 10.2, 5.5 Hz, 1H), 3.56 (dd, J = 10.2, 4.8 Hz, 1H), 3.32
(dd, J = 11.5, 7.1 Hz, 1H), 3.19 (dd, J = 13.2, 3.8 Hz, 1H), 3.02
(dd, J = 13.2, 10.5 Hz, 1H), 2.84 (d, J = 11.5 Hz, 1H), 1.86 (ddd,
J = 13.9, 9.3, 3.3 Hz, 1H), 1.62 (ddd, J = 14.2, 8.5, 2.8 Hz, 1H),
o
1
0
C),
stirred
suspension
of
(methoxymethyl)triphenylphosphonium chloride (29.1 g, 85.0
mmol, 2.5 equiv) in 200 mL of dry THF under an N atmosphere
was added (79.9 mL, 2.35 equiv) 1.0
bis(trimethylsilyl) amide in THF. The reaction mixture was
stirred at the same temperature for 30 min. This solution was
transferred via cannula to a solution of the above aldehyde in
THF (100 mL). The resulting solution was then stirred at ꢀ10 C
for 2 h and then allowed to warm to room temperature, and 85 ESIꢀHRMS: m/z calcd for C H O NaS [M+Na] 552.1848,
stirred for 10 h. The reaction mixture was diluted with saturated
aq NaHCO (200 mL) and extracted with Et O (3 x 100). The
combined organic layer was washed with brine (100 mL), dried
over anhydrous Na SO , filtered, and concentrated under reduced
2
13
M
lithium 80 1.40 (d, J = 9.1 Hz, 6H), 1.27 (d, J = 6.8 Hz, 3H); C NMR (125
MHz, CDCl ): 200.8, 177.5, 137.4, 135.9, 129.0, 128.5, 128.0,
3
127.3, 127.2, 126.8, 108.6, 79.1, 76.3, 75.6, 73.1, 70.0, 69.2,
68.2, 43.1, 36.8, 36.3, 31.6, 26.8, 26.5, 10.8; IR (neat): 3493,
o
ꢀ1
2984, 2933, 1695, 1453, 1368, 1257, 1165, 1030, 857, 745 cm ;
+
28
35
5
2
found 552.1845.
3
2
(2R,3S)-1-((R)-4-Benzyl-2-thioxothiazolidin-3-yl)-4-((4S,5S)-5-
((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-((tert-
2
4
pressure to give a crude enol ether, which was purified by flash 90 butyldimethylsilyl)oxy)-2-methylbutan-1-one (14)
column chromatography to give a yellowish liquid (6.2 g, 65%).
This enol ether was dissolved in mixture of THF (70 mL) and
H O (14 mL), to which was added Hg(OAc) (10.7 g, 33.5 mmol,
2,6ꢀLutidine (1.3 mL, 11.34 mmol) was added to a solution of
secondary alcohol 19 (2.0 g, 7.56 mmol) in anhydrous CH Cl
2
2
(30 mL) and the mixture was stirred at 0 °C under N . After 15
min. TBSOTf (1.9 mL, 10.58 mmol) was added drop wise and
2
2
2
o
1
.5 equiv) at 0 C and then allowed to warm to room temperature.
The reaction mixture was stirred at same temperature for 30 min. 95 the mixture was stirred 20 min. The reaction was quenched with
To this mixture was added KI (8% w/v aq. saturated KI, 20 mL),
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 x 80 mL). The combined organic layer
was washed with brine, dried over anhydrous Na SO ,
concentrated under reduced pressure, and purified with column 100 acetate/hexane (5%) as eluent to give 14 as a yellow liquid (4.37
chromatography to give 15 (5.4 g, 91%) as a colorless liquid. R =
H O (8 mL) and the mixture was extracted with CH Cl (2 × 30
2 2 2
mL). The organic extract was washed with brine (20 mL), dried
(Na SO ), filtered, and concentrated under reduced pressure. The
2
4
residue was purified by column chromatography using ethyl
2
4
2
0
g, 90%). R = 0.5 (5% EtOAcꢀhexane). [α]
= ꢀ116.6 (c 0.4,
f
1
f
D
2
0
1
0
.5 (hexane/EtOAc, 20:80) [α]D = ꢀ5.7 (c 0.44, CHCl3);
H
CHCl ); H NMR (300 MHz, CDCl ): δ 7.38–7.24 (m, 10H), 5.18
3
3
NMR (300 MHz, CDCl ): δ 9.78 (t, J = 1.9 Hz, 1H), 7.47–7.18
(ddd, J = 10.4, 6.8, 3.6 Hz, 1H), 4.75–4.52 (m, 3H), 4.15–4.07
3
(m, 5H), 4.56 (s, 2H), 4.32 (ddd, J = 7.9, 6.9, 5.3 Hz, 1H), 3.89
(m, 1H), 3.97–3.80 (m, 2H), 3.60–3.56 (m, 2H), 3.32–3.24 (m,
(dt, J = 8.1, 5.2 Hz, 1H), 3.63 (ddd, J = 14.9, 10.0, 5.2 Hz, 2H), 105 2H), 3.03 (dd, J = 13.0, 10.9 Hz, 1H), 2.87 (d, J = 11.5 Hz, 1H),
1
3
2
1
.79–2.61 (m, 2H), 1.41 (s, 6H); C NMR (75 MHz, CDCl ): δ
1.93 (dd, J = 12.8, 9.2 Hz, 1H), 1.83–1.72 (m, 1H), 1.40 (d, J =
8.8 Hz, 6H), 1.22 (d, J = 6.9 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H),
3
99.8, 137.5, 128.3, 127.7, 127.6, 109.4, 79.0, 73.6, 73.5, 69.9,
13
46.6, 26.9, 26.7; IR (neat): 3451, 2986, 2867, 1727, 1454, 1373,
1
C H O Na [M+Na] 287.1253, found 287.1246.
0.03 (s, 3H); C NMR (75 MHz, CDCl ): δ 200.8, 176.4, 138.0,
3
ꢀ
1
218, 1087, 859, 741 cm .; ESIꢀHRMS: m/z calcd for
136.5, 129.4, 128.8, 128.2, 127.5, 127.0, 108.9, 80.1, 77.2, 74.5,
110 73.4, 72.2, 70.4, 69.2, 44.6, 37.7, 36.3, 31.8, 27.3, 26.9, 25.7,
+
1
5
20
4
2
5.7, 17.8, 12.8, ꢀ4.4, ꢀ4.8; IR (neat): 3384, 3029, 2931, 1705,
ꢀ
1
(2R,3S)-1-((R)-4-Benzyl-2-thioxothiazolidin-3-yl)-4-((4S,5S)-5-
1455, 1366, 1257, 1166, 1089, 1033, 837, 775, 700 cm ; ESIꢀ
HRMS: m/z calcd. for C H O NaS Si [M+Na] 666.2713, found
+
((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
hydroxy-2-methylbutan-1-one (19)
34
49
5
2
666.2710.
A solution of thione (6.5 g, 24.62 mmol) in 45 mL CH Cl was 115
2
2
cooled to 0 °C. Neat TiCl4 (2.9 mL, 26.50 mmol) was added
(2R,3S)-4-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
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DOI: 10.1039/C6OB01447J
dioxolan-4-yl)-3-((tert-butyldimethylsilyl)oxy)-2-
methylbutanal (22)
warm to room temperature and stirred for 4 h. The solution was
60 quenched with water and extracted with EtOAc. The organic
layer was washed with water, dried over anhydrous Na SO ,
The solution of aldol adduct 14 (2.0 g, 4.58 mmol) dissolved in
CH Cl (84 mL) was cooled to ꢀ78 °C. Diisoꢀbutylaluminum
2
4
filtered, concentrated under vacuum and purified by column
chromatography (10:90 Hexanes/EtOAc) to give pure propargylic
2
2
5
0
5
0
5
0
5
0
5
0
5
hydride (25% in hexanes, 6.5 mL, 11.4 mmol) was added
dropwise via syringe. After 10 minutes, the reaction was
monitored by TLC and then quenched by the dropwise addition 65 ꢀ38.6 (c 0.12, CHCl ); H NMR (500 MHz, CDCl ): δ 7.33–7.23
2
D
0
ketone 13 (0.85 g, 40%). R = 0.5 (20% EtOAcꢀhexane). [α]
=
f
1
3
3
of saturated aq. sodium potassium tartrate. After warming to
room temperature. The mixture was poured into brine and
extracted three times with CH Cl . The combined organic layers
(m, 5H), 4.55–4.50 (m, 3H), 3.92–3.87 (m, 1H), 3.78–3.73 (m,
1H), 3.57 (dd, J = 10.2, 5.3 Hz, 1H), 3.51 (dd, J = 10.2, 4.4 Hz,
1H), 2.66 (qd, J = 6.9, 3.0 Hz, 1H), 1.77 (ddd, J = 13.9, 8.3, 2.0
Hz, 1H), 1.62 (ddd, J = 14.2, 10.1, 4.5 Hz, 1H), 1.35 (d, J = 10.3
1
1
2
2
3
3
4
4
5
5
2
2
were dried over Na SO and concentrated in vacuo. Purification
2
4
through flash chromatography provided the aldehyde 22 (1.83 g, 70 Hz, 6H), 1.10 (d, J = 6.9 Hz, 3H), 0.81 (s, 9H), 0.02 (s, 3H), 0.01
13
7
5%), which was used immediately in the next reaction. R = 0.4
(s, 3H); C NMR (125 MHz, CDCl ): δ 190.1, 137.8, 128.3,
f
3
2
0
1
(85:15, hexane: EtOAc). [α]D = ꢀ47.53 (c 0.12, CHCl3);
H
127.5, 108.9, 102.1, 98.8, 79.9, 74.9, 73.5, 70.3, 54.1, 39.3, 27.3,
26.8, 25.8, 18.0, 8.9, ꢀ4.2, ꢀ4.6; IR (neat): 3679, 3331, 2986,
NMR (500 MHz, CDCl ): δ 9.80 (d, J = 0.6 Hz, 1H), 7.36–7.26
3
ꢀ
1
(m, 5H), 4.59–4.54 (m, 2H), 4.34 (dt, J = 8.6, 3.9 Hz, 1H), 3.96
2932, 1674, 1372, 1253, 1167, 1090, 847, 760 cm . ESIꢀHRMS:
+
(td, J = 9.7, 2.5 Hz, 1H), 3.80–3.76 (m, 1H), 3.60 (dd, J = 10.1, 75 m/z calcd for C H O NaSi [M+Na] 533.3113, found 533.3134.
29
49
5
2
5
.2 Hz, 1H), 3.53 (dd, J = 10.1, 4.7 Hz, 1H), 2.57 (qd, J = 7.0, 3.4
Hz, 1H), 1.73–1.60 (m, 2H), 1.38 (s, 3H), 1.37 (s, 3H), 1.06 (d, J
(3S,4S,5S)-6-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-5-((tert-butyldimethylsilyl)oxy)-4-methyl-1-
(trimethylsilyl)hex-1-yn-3-ol (23)
13
= 7.0 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); C NMR
(
125 MHz, CDCl ): δ 205.1, 137.8, 128.3, 127.6, 127.5, 109.0,
3
7
9.9, 74.8, 73.5, 70.2, 69.7, 52.3, 38.1, 27.3, 26.9, 25.7, 7.9, ꢀ4.4, 80 To the solution of propargylic ketone 13 (1.0 g, 1.87 mmol) in
EtOH (15 mL) at room temperature CeCl .7H O (905.7 mg, 2.43
ꢀ4.6; IR (neat): 2985, 2931, 2858, 1727, 1455, 1371, 1253, 1168,
3
2
ꢀ
1
1
096, 1030, 837, 777, 698 cm ; HRMS: m/z calcd. for
mmol, 1.3 equiv.) was added and the mixture was cooled to ꢀ78
+
C H O NaSi [M+Na] 459.253, found 459.2537.
°C. At the same temperature NaBH (213.3 mg, 5.63 mmol, 3.0
2
4
40
5
4
equiv.) was added in fractions over 1 h. The solution was allowed
(2R,3S)-4-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
85 to warm to ꢀ15 °C over 30min, then K CO3 (774.1 mg, 5.61
2
dioxolan-4-yl)-3-((tert-butyldimethylsilyl)oxy)-N-methoxy-
N,2-dimethylbutanamide (20)
mmol, 3.0 equiv.) was added at room temperature. The mixture
was stirred for 30 min. then quenched with water and extracted
with EtOAc. The organic layer was washed with water, dried
over anhydrous Na SO , filtered, and concentrated under vacuum
Adduct 14 (3.5 g, 5.4 mmol) was dissolved in CH Cl (20 mL).
2
2
Imidazole (1.46 g, 21.6 mol) and N,O–dimethylhydroxylamine •
HCl (1.05 g, 10.8 mol) was added at 0 °C. After stirring at rt for 6 90 and purified by column chromatography (Hexane/EtOAc, 20:80)
2
4
h, quenched with water and the mixture was extracted with
CH Cl (3 x 300 mL). The organic layers were combined, washed
to give pure propargylic alcohol 23 (998 mg, 99% yield, 98% ds).
20
D
1
R = 0.5 (20% EtOAcꢀhexane); [α] = ꢀ22.7 (c 0.4, CHCl ). H
2
2
f
3
with satd. brine (100 mL), dried with Na SO , and concentrated
NMR (300 MHz, CDCl ): δ 7.35–7.26 (m, 5H), 4.62–4.52 (m,
2
4
3
on a rotary evaporator. Flash chromatography with a gradient
1H), 4.42 (s, 1H), 4.14 (dt, J = 8.4, 3.6 Hz, 1H), 3.96–3.87 (m,
from (70:30 hexanes/EtOAc) afforded 20 (2.6 g, 85%). R = 0.5 95 1H), 3.83–3.76 (m, 1H), 3.62–3.51 (m, 1H), 2.72 (s, 1H), 1.91
f
2
0
1
(
30% EtOAcꢀhexane). [α]D = ꢀ15.4 (c 0.64, CHCl ); H NMR
(ddt, J = 14.2, 10.9, 4.6 Hz, 1H), 1.71 (ddd, J = 13.9, 9.7, 3.9 Hz,
1H), 1.39 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 7.0 Hz, 1H), 0.87 (s,
3
(
500 MHz, CDCl ): δ 7.28–7.20 (m, 5H), 4.51 (q, J = 12.1 Hz,
3
13
2H), 4.02 (ddd, J = 8.2, 5.5, 3.9 Hz, 1H), 3.95–3.89 (m, 1H),
9H), 0.07 (s, 3H), 0.06 (s, 3H); C NMR (75 MHz, CDCl ): δ
3
3
3
.82–3.77 (m, 1H), 3.65 (s, 3H), 3.56–3.54 (dd, J = 5.3, 1.8, 2H),
137.9, 128.3, 127.5, 127.5, 108.8, 106.6, 90.3, 80.2, 74.8, 73.5,
.16 (s, 3H), 1.80–1.70(m, 2H), 1.39 (s, 3H), 1.37 (s, 3H), 1.07 100 72.3, 70.2, 65.2, 44.5, 38.1, 27.3, 26.9, 25.8, 18.0, 9.9, ꢀ4.3, ꢀ4.6;
13
(d, J = 7.1 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H));
C
IR (neat): 3456, 2985, 2956, 2170, 1458, 1378, 1458, 1378, 1252,
ꢀ
1
NMR (125 MHz, CDCl ): δ 175.8, 138.0, 128.6, 127.5, 108.9,
1090, 841, 760 cm ; ESIꢀHRMS: m/z calcd for C H O NaSi
29 50 5 2
3
+
80.3, 74.6, 73.5, 71.3, 70.4, 61.1, 41.4, 39.0, 27.4, 27.0, 25.9,
[M+Na] 557.3089, found 557.3074.
1
1
8.0, 13.4, ꢀ4.2, ꢀ4.5; IR (neat): 2930, 2857, 1735, 1666, 1460,
ꢀ
1
377, 1254, 1091, 837, 775 cm ; ESIꢀHRMS: m/z calcd for 105 (((2S,3S,4S)-4-(Benzyloxy)-1-((4S,5S)-5-((benzyloxy)methyl)-
+
C H O NNaSi [M+Na] 518.2908, found 518.2893.
2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylhex-5-yn-2-
yl)oxy)(tert-butyl)dimethylsilane (26)
2
6
45
6
(4R,5S)-6-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-5-((tert-butyldimethylsilyl)oxy)-4-methyl-1-
To the mixture of sodium hydride (179 mg, 60% dispersion in
O
mineral oil, 4.49 mmol) in THF at 0 C was added alchol 23 (0.8
(trimethylsilyl)hex-1-yn-3-one (13)
110 g, 1.49 mmol) in THF (5 mL) was added dropwise and the
solution was stirred for 30 min. The mixture was then treated
with benzyl bromide (1.2 equiv.) at 0 °C and stirred further for 1
h allowing to warm to rt. The solution was poured into iceꢀwater
mixture and extracted with EtOAc. The organic phase were
To a solution of TMS acetylene (1.1 mL, 8 mmol, 2 equiv.) in
THF (15 mL), at ꢀ78 °C, was added a 1.6 M solution of nBuLi in
hexanes (4.5 mL, 7.2 mmol, 1.8 equiv.). The solution was stirred
3
0 min. at 0 °C, then recooled to ꢀ78 °C and to this a solution of
Weinreb amide 20 (2.0 g, 4.0 mmol, 1 equiv.) in THF (10 mL) 115 combined, dried over anhydrous Na SO and concentrated. The
2
4
was added. The light yellow reaction mixture was allowed to
residual oil was purified by column chromatography (10:90
6
|
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DOI: 10.1039/C6OB01447J
Hexane/EtOAc) to give the corresponding benzyl ether 26 (657
= 14.7, 8.6, 2.1 Hz, 1H), 1.89 (ddd, J = 14.7, 10.0, 4.6 Hz, 1H),
1
3
mg, 80%) as colorless liquid; R = 0.5 (10% EtOAcꢀhexane). 60 1.41–1.36 (d, J = 15.8 Hz, 6H), 1.16 (d, J = 7.0 Hz, 3H);
C
f
2
0
1
[
α]D = ꢀ63.7 (c 0.36, CHCl ); H NMR (500 MHz, CDCl ): δ
NMR (125 MHz, CDCl ): δ 137.7, 137.3, 128.3, 128.3, 128.0,
3
3
3
7
.35–7.26 (m, 10H), 4.77 (d, J = 11.6 Hz, 1H), 4.60–4.53 (q, J =
127.7, 127.6, 127.6, 109.3, 82.2, 81.2, 79.8, 75.4, 74.5, 73.5,
70.8, 70.0, 69.2, 42.4, 38.1, 35.8, 27.2, 26.8, 10.4; IR (neat):
3280, 3030, 2986, 2934, 1454, 1355, 1217, 1174, 1094, 910, 852,
5
0
5
0
5
0
5
0
5
0
5
11.2 Hz, 2H), 4.44 (d, J = 11.6 Hz, 1H), 4.17 (dd, J = 6.3, 2.0 Hz,
H), 4.12–4.08 (m, 1H), 3.88 (td, J = 8.4, 3.6 Hz, 1H), 3.80–3.76
1
ꢀ
1
+
(m, 1H), 3.57–3.50 (m, 2H), 2.46 (d, J = 2.0 Hz, 1H), 1.96 (m, 65 752 cm ; ESIꢀHRMS: m/z calcd for C H O NaS [M+Na]
28 36 7
1
6
H), 1.75–1.65 (m, 2H), 1.38 (s, 3H), 1.36 (s, 6H), 1.04 (d, J =
.9 Hz, 3H), 0.82 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). C NMR
539.2074, found 539.2065.
13
1
1
2
2
3
3
4
4
5
5
(125 MHz, CDCl ): δ 137.9, 137.7, 128.2, 128.0, 127.5, 108.7,
(2S,3S,5R)-2-((Benzyloxy)methyl)-5-((2R,3S)-3-
(benzyloxy)pent-4-yn-2-yl)tetrahydrofuran-3-ol (28)
6.9, 25.8, 17.9, 9.6, ꢀ4.4, ꢀ4.6; IR (neat): 3305, 3031, 2984, 70 To the compound 12 (600 mg, 1.0 mmol) dissolved in MeOH (5
3
8
2
2
2.7, 80.1, 74.8, 74.3, 73.3, 70.5, 70.3, 69.2, 44.3, 37.9, 27.3,
ꢀ
1
931, 2858, 1456, 1371, 1254, 1096, 839, 776, 698 cm ; ESIꢀ
mL) was added pTsOH (8 mg) and the reaction was stirred at rt
for 12 h. The solvent was removed under reduced pressure and
diluted with water and EtOAc. The layers were separated and the
aqueous layer was extracted with EtOAc. The combine organic
75 extracts were washed with brine, dried over Na SO , and
concentrated under reduced pressure to provide diol (402 mg,
73%) as a colourless oil. To the diol obtained above (300 mg,
0.73 mmol) in THF (5 mL) was added drop wise at 0 C to the
+
HRMS: m/z calcd for C H O NaSi [M+Na] 575.3163, found
575.3155.
3
3
48
5
(2S,3R,4S)-4-(Benzyloxy)-1-((4S,5S)-5-((benzyloxy)methyl)-
2
4
2
,2-dimethyl-1,3-dioxolan-4-yl)-3-methylhex-5-yn-2-ol (27)
To a stirred solution of silyl ether 26 (600 mg, 1.0 mmol) in THF
(5 mL) was added tetrabutylammonium fluoride (1M solution in
THF, 1.25 mmol, 1mL). Then the solution was stirred at rt for 2
h. THF was removed by rotary evaporator and the crude mixture 80 oil, 0.81 mmol) in THF (5 mL) and the mixture was stirred at that
was purified by column chromatography (20% EtOAcꢀhexane)
without extractive workꢀup to give the title 27 (452 mg, 95%) as
colorless liquid. R = 0.5 (20% EtOAcꢀhexane). [α] = ꢀ57.3 (c
0
1
1
1
o
solution of sodium hydride (32 mg, 60% dispersion in mineral
temperature for 4 h. The solution was poured into waterꢀice
mixture and extracted with EtOAc. The organic phase was
combined, dried over anhydrous Na SO and concentrated. The
2
D
0
f
2
4
1
.36, CHCl ); H NMR (300 MHz, CDCl ): δ 7.40 – 7.28 (m,
residual oil was purified by column chromatography (30:70
3
3
0H), 4.84 (d, J = 11.5 Hz, 1H), 4.63–4.53 (m, 2H), 4.47 (d, J = 85 Hexane/EtOAc) to give the corresponding 28 (138 mg, 50%) as
1.5 Hz, 1H), 4.28 (dd, J = 4.2, 2.1 Hz, 1H), 4.14 (d, J = 9.5 Hz,
H), 4.03 (td, J = 8.4, 3.3 Hz, 1H), 3.92–3.85 (m, 1H), 3.62–3.52
2
0
white low melting solid. R = 0.5 (30% EtOAcꢀhexane). [α] = ꢀ
f D
1
55.5 (c 0.12, CHCl ); H NMR (500 MHz, CDCl ): δ 7.30ꢀ7.34
3
3
(m, 2H), 3.02 (s, 1H), 2.55 (d, J = 2.1 Hz, 1H), 1.91–1.79 (m,
H), 1.65–1.55 (m, 2H), 1.41 (d, J = 3.1 Hz, 6H), 1.12 (d, J = 7.0
(m, 10H), 4.82 (d, J = 11.8 Hz, 1H), 4.60–4.54 (m, 2H), 4.48 (dd,
J = 9.7, 7.1 Hz, 3H), 4.35 (td, J = 9.4, 5.6 Hz, 1H), 4.02 (dd, J =
1
1
3
Hz, 3H). C NMR (75 MHz, CDCl ): δ 137.8, 137.2, 128.3, 90 9.9, 4.6 Hz, 1H), 3.73 (ddd, J = 10.1, 5.4 Hz, 2H), 2.91 (s, 1H),
1
7
26.8, 8.1. IR (neat): 3287, 2985, 2927, 1724, 1454, 1374, 1218,
1
4
3
28.2, 127.8, 127.7, 127.5, 127.5, 127.3, 126.7, 108.7, 81.1, 79.8,
5.8, 75.4, 73.3, 72.5, 70.7, 70.4, 70.4, 64.9, 42.9, 38.3, 27.1,
2.45 (d, J = 2.0 Hz, 1H), 2.06 (dd, J = 13.2, 5.6 Hz, 1H), 1.89–
1.82 (m, 1H), 1.74 (ddd, J = 13.3, 10.1, 5.0 Hz, 1H), 1.04 (d, J =
13
7.0 Hz, 3H); C NMR (125 MHz, CDCl ): δ 138.1, 137.5, 128.4,
3
ꢀ
1
+
090, 772 cm ; ESIꢀHRMS: m/z calcd for C H O Na [M+Na]
128.1, 127.8, 127.7, 127.6, 127.3, 82.3, 79.7, 78.1, 74.0, 73.7,
95 73.6, 70.8, 69.0, 69.0, 44.1, 39.6, 9.9; IR (neat): 3446, 3289,
2
7
34
5
16.2292, found 416.2298.
2
973, 2922, 2869, 1496, 1454, 1374, 1339, 1207, 1066, 985, 739
ꢀ
1
+
(2S,3S,4S)-4-(Benzyloxy)-1-((4S,5S)-5-((benzyloxy)methyl)-
cm ; ESIꢀHRMS: m/z calcd for C H O Na [M+Na] 403.1879,
24 28 4
2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylhex-5-yn-2-yl
methanesulfonate (12)
To the solution of alcohol 27 (400 mg, 0.91 mmol) in CH Cl (2 100 (2S,3S,5R)-2-((Benzyloxy)methyl)-5-((2R,3S)-3-
found 403.1872.
2
2
mL) was added Et N (0.17 mL. 1.26 mmol) followed by MsCl
(benzyloxy)pent-4-yn-2-yl)-3-methoxytetrahydrofuran (10)
To the solution of 28 (100 mg, 0.26 mmol) in THF (3 mL) at 0 °C
was added NaH (60% in oil, 16 mg, 0.40 mmol) and the
suspension stirred for 10 minutes. MeI (0.03 mL, 0.54 mmol) was
3
o
(0.8 mL, 1.0 mmol) at 0 C. The mixture was stirred for 1 h at rt
until the total consumption of the starting material occurred
monitored by TLC). Then, the reaction was quenched with a
(
saturated aqueous solution of NH Cl and extracted with CH Cl . 105 added dropwise and the reaction was warmed to room
The combined organic phase was washed with water, brine, dried
over anhydrous Na SO and concentrated. The residual oil was
purified by column chromatography (20:80 Hexane/EtOAc) to
give the product 12 (352 mg, 75%) as colorless liquid. R = 0.5
4
2
2
temperature. After one hour the reaction was quenched with
saturated aq NH Cl, partitioned between brine and EtOAc,
2
4
4
separated, and the aq. layer was extracted with EtOAc. The
combined organics were washed with brine, dried (Na SO ),
f
2
4
2
0
1
(20% EtOAcꢀhexane). [α]D = ꢀ32.4 (c 0.4, CHCl ); H NMR 110 filtered, and concentrated. The residue was purified by flash
3
(500 MHz, CDCl ): δ 7.38–7.26 (m, 10H), 5.06 (dt, J = 8.5, 4.2
chromatography (10:90, EtOAc/hexanes) to give the title product
3
2
0
Hz, 1H), 4.80 (d, J = 11.5 Hz, 1H), 4.55 (s, 2H), 4.43 (d, J = 11.5
Hz, 1H), 4.24 (dd, J = 5.4, 2.0 Hz, 1H), 3.93–3.89 (m, 1H), 3.80
10 (76 mg, 75%). R = 0.5 (10% EtOAcꢀhexane). [α] = ꢀ13.1 (c
f D
1
0.2, CHCl ); H NMR (400 MHz, CDCl ): δ 7.36–7.22 (m, 1H),
3
3
(
(
2
dt, J = 8.2, 5.0 Hz, 1H), 3.58 (dd, J = 10.2, 5.3 Hz, 1H), 3.51
dd, J = 10.1, 4.6 Hz, 1H), 2.97 (s, 1H), 2.97 (s, 3H), 2.55 (dd, J = 115 4.50 (d, J = 2.0 Hz, 1H), 4.47 (t, J = 2.6 Hz, 1H), 4.25–4.18 (m,
.0, 0.8 Hz, 1H), 2.34 (ddd, J = 7.0, 5.4, 4.0 Hz, 1H), 2.10 (ddd, J 1H), 4.10 (ddd, J = 6.6, 5.3, 4.0 Hz, 1H), 3.69 (dd, J = 10.1, 5.3
4.80 (d, J = 11.8 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.53 (s, 1H),
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DOI: 10.1039/C6OB01447J
Hz, 1H), 3.57 (dd, J = 10.1, 6.6 Hz, 1H), 3.30 (s, 1H), 2.43 (d, J =
Hz, 1H), 4.63–4.59 (d, J = 9.1 Hz, 1H), 4.53–4.45 (m, 3H), 4.32
2
1
.1 Hz, 1H), 2.17 (ddd, J = 13.3, 5.8, 1.0 Hz, 1H), 1.88 (ddd, J = 60 (s, 1H), 4.24–4.17 (m, J = 9.5, 5.8 Hz, 1H), 4.15–4.06 (m, 1H),
4.0, 7.0, 3.0 Hz, 1H), 1.58 (ddd, J = 13.5, 9.8, 4.6 Hz, 1H), 1.03
3.96–3.89 (m, 2H), 3.69 (dd, J = 10.1, 5.3 Hz, 1H), 3.57 (dd, J =
10.1, 6.6 Hz, 1H), 3.30 (s, 3H), 2.38 (d, J = 6.2 Hz, 1H), 2.19–
2.12 (m, 1H), 1.88 (ddd, J = 8.3, 6.9, 3.0 Hz, 1H), 1.66–1.54 (m,
1
3
(d, J = 7.0 Hz, 1H); C NMR (100 MHz, CDCl ): δ 138.4, 138.1,
3
5
0
5
0
5
0
5
0
5
0
5
128.2, 128.1, 127.6, 127.6, 127.4, 127.3, 82.5, 81.8, 80.6, 77.8,
7
2
4.0, 73.3, 70.8, 69.2, 68.8, 57.1, 44.1, 35.0, 9.9; IR (neat): 3287,
1H), 1.24–1.21 (d, J = 6.2 Hz, 6H), 1.02 (d, J = 7.0 Hz, 3H),
ꢀ
1
13
975, 2926, 1496, 1454, 1367, 1202, 1083, 772, 698 cm ; ESIꢀ 65 0.91–0.89 (s, 9H), 0.09 (d, J = 0.6 Hz, 6H). C NMR (100 MHz,
+
HRMS: m/z calcd for C H O Na [M+Na] 417.2036, found
4
CDCl ): δ 138.4, 138.4, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4,
2
5
30
4
3
17.2025.
127.2, 84.7, 83.8, 81.9, 80.6, 77.9, 73.3, 70.9, 70.8, 69.5, 68.8,
67.0, 57.1, 44.2, 35.0, 25.7, 20.0, 18.2, 10.1, ꢀ4.4, ꢀ4.8. IR (neat):
1
1
2
2
3
3
4
4
5
5
ꢀ
1
(
S)-2-((tert-Butyldimethylsilyl)oxy)propanal (9)
3440, 2926, 1454, 1258, 1084, 1026, 833, 777, 734, 696 cm ,
+
To the solution of (−)ꢀethyl lactate 11 (5 mL, 42.3 mmol) in 70 ESIꢀHRMS: m/z calcd forC H NaO Si [M+Na] 605.3269,
CH Cl (70 mL) was added imidazole (5.7 g, 84.6 mmol) and the
resultant solution was then cooled in an ice bath, and TBSCl
(11.8 g, 78 mmol) was subsequently added portion wise with
vigorous stirring. Over the course of the addition a white
34
50
6
found 605.3278.
2
2
(2S,3R,6R,7R,E)-6-(Benzyloxy)-7-((2R,4S,5S)-5-
((benzyloxy)methyl)-4-methoxytetrahydrofuran-2-yl)-2-((tert-
precipitate was formed. The ice bath was removed, and the 75 butyldimethylsilyl)oxy)oct-4-en-3-ol (7)
reaction mixture was allowed to warm to room temperature with
continuous stirring over 12 h. The reaction was quenched by
addition of saturated NaHCO3 The mixture was extracted with
The solution of propargylic alcohol 8 (20 mg, 0.034 mmol, 1.0
equiv.) dissolved in anhydrous Et O (7 mL) was added gradually
2
via syringe into the flask containing the mixture of RedꢀAl (60%
in toluene, 0.026 mL, 0.07 mmol). The reaction was stirred at ꢀ
.
.
CH Cl ; the combined organic layers were dried over Na SO and
2
2
2
4
evaporated. The residue was subjected to flash chromatography 80 40 °C for 2 h and quenched with water followed by saturated aq.
elution 5% EtOAc/Hexanes) to give silylated ester (8.8 g, 90%) NH Cl. The mixture was extracted with Et O and the combined
(
4
2
2
0
1
as colorless oil. [α]D = ꢀ32.0 (c 1.98, CHCl ); H NMR (400
MHz, CDCl ): δ 4.31 (q, J = 6.5 Hz, 1H), 4.24−4.14 (m, 2H),
1
0
6
2
To the solution of above silylated ester (5.0 g, 21.52 mmol) in 60
mL of CH Cl was added of DIBALꢀH (1.7 M in hexane, 22.6
mL, 22.6 mmol) at ꢀ78 C. The solution was stirred for 30min and 90 3H), 4.39 (d, J = 11.9 Hz, 1H), 4.19 (ddd, J = 9.9, 7.7, 5.7 Hz,
quenched with saturated potassium tartrate at 0 C . After the
mixture stirred for 1 h, the layers were separated and the aqueous
layer was extracted with ether. The combine organic extracts
were washed with brine, dried over Na SO , and concentrated
organic extracts were washed with saturated aq NH Cl and water,
3
4
dried over anhydrous Na SO , filtered, and concentrated by rotary
3
2
4
.40 (d, J = 6.5 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H,), 0.91 (s, 9H),
evaporation to afford the crude product, which was
1
3
1
.10 (s, 3H), 0.07 (s, 3H); C NMR (100 MHz, CDCl ): δ 174.4, 85 configurationally pure by HꢀNMR analysis. Purification by silica
3
8.7, 61.0, 26.0, 21.6, 18.6, −4.7, −5.0; IR (neat): 2943, 2897,
flash chromatography R = 0.4 (75:25 hexanes/EtOAc) yielded Eꢀ
f
ꢀ
1
20
D
852, 1759, 1255, 1145, 835, 778 cm .
allylic alcohol 7 (14 mg, 70%) as a light yellow oil. [α] = 30.1
(c 0.2, CHCl ); H NMR (500 MHz, CDCl ): δ 7.36–7.22 (m,
1
3
3
10H), 5.68 (qd, J = 15.8, 6.5 Hz, 2H), 4.58 (dt, J = 12.2 Hz, 8.2,
2
2
o
o
1H), 4.14–4.10 (m, 2H), 4.09–4.06 (m, 1H), 3.91 (t, J = 4.0 Hz,
1H), 3.87 (qd, J = 6.3, 3.5 Hz, 1H), 3.70 (dd, J = 10.1, 5.3 Hz,
1H), 3.60 (dd, J = 10.0, 6.7 Hz, 1H), 3.30 (s, 3H), 2.32 (d, J = 6.4
Hz, 1H), 2.09 (dd, J = 13.3, 5.7 Hz, 1H), 1.81–1.74 (m, 1H),
2
4
under reduced pressure to provide aldehyde 9 (3.2 g, 80%) as a 95 1.63–1.56 (m, 1H), 1.07 (d, J = 6.3 Hz, 1H), 0.91–0.88 (m, 1H),
colourless oil, which was used immediately for next reaction
without further purification.
13
0.09 (d, J = 3.3 Hz, 1H); C NMR (125 MHz, CDCl ): δ 139.1,
3
138.5, 131.8, 130.4, 128.2, 128.1, 127.7, 127.5, 127.1, 81.9, 80.6,
79.5, 78.6, 75.7, 73.3, 71.4, 70.8, 68.9, 57.2, 43.6, 34.5, 25.8,
17.7, 9.1, ꢀ4.4, ꢀ4.8; IR (neat): 3457, 2927, 1738, 1454, 1362,
(2S,3R,6S,7R)-6-(Benzyloxy)-7-((2R,4S,5S)-5-
ꢀ
1
((benzyloxy)methyl)-4-methoxytetrahydrofuran-2-yl)-2-((tert- 100 1252, 1083, 1005, 835, 776, 734, 697 cm ; ESIꢀHRMS: m/z calcd
+
butyldimethylsilyl)oxy)oct-4-yn-3-ol (8)
nꢀBuLi (0.06 mL, 1.6 M in hexane, 0.1 mmol) was added to a
solution of 10 (50 mg, 0.12 mmol) in dry ether (50 mL) stirred in
a dry ice–acetone bath under argon. After completion of the
addition the stirring was continued at ꢀ78 C for 15 min before a 105 ((benzyloxy)methyl)-4-methoxytetrahydrofuran-2-yl)-3-
solution of aldehyde 9 (37 mg, 0.25 mmol) in dry ether (5 mL)
was introduced via a syringe. The mixture was stirred at the same
temperature for 1 h. Saturated aq. NH Cl (5 mL) was added to
quench the reaction. The mixture was diluted with EtOAc (10
mL), washed with saturated aq. NaHCO (5 mL), and dried over 110 The reaction mixture was stirred at 0 C for 40 min. The reaction
anhydrous Na SO . Removal of the solvent and column
chromatography of the residue on silica gel (R = 0.4 (25:75,
Hexane/ EtOAc)) allowed the separation of the diastereoisomers
for C H NaO Si [M+Na] 607.3425,
34 52 6
found 605.3401.
(((2S,3R,6R,7R,E)-6-(Benzyloxy)-7-((2R,4S,5S)-5-
o
methoxyoct-4-en-2-yl)oxy)(tert-butyl)dimethylsilane (29)
To the solution of the alcohol 7 (10 mg, 0.011 mmol) in THF (1.5
o
mL) at 0 C was added NaH (60% oil dispersion, 3 mg, 0.11
4
mmol) in portion wise. After 20 min. MeI (7 µL, 0.11 mmol).
o
3
mixture was quenched by dropwise addition of saturated aqueous
2
4
NH Cl. Diethyl ether was added (10 mL), the layer was
f
4
separated. The organic layer was washed with water, and brine,
dried (Na SO ), filtered, and concentrated. The residue was
8
(55 mg) and 8a (2 mg) in 78% yield. (syn:anti = 92:8).
2
4
2
0
1
Analytical data for 8: [α]D = ꢀ20.3 (c 0.12, CHCl ); H NMR 115 purified by silica flash chromatography R = 0.6 (20% EtOAcꢀ
3
f
(
400 MHz, CDCl ): δ 7.35–7.21 (m, 10H), 4.80–4.75 (d, J = 11.8
hexane) (hexane : EtOAc =90:10) to afford the desired product 29
3
8
|
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DOI: 10.1039/C6OB01447J
2
0
1
(
7.6 mg, 75%) as colorless oil, [α]D = ꢀ2.5 (c 0.16, CHCl ); H
workꢀup to give the title compound 24 as colorless liquid (103
3
2
0
NMR (500 MHz, CDCl ): δ 7.37–7.22 (m, 10H), 5.61 (qd, J = 60 mg, 90%). R = 0.5 (40% EtOAcꢀhexane). [α] = ꢀ19.14 (c 0.35,
5.8, 6.5 Hz, 2H), 4.61 (t, J = 12.7 Hz, 2H), 4.53 (d, J = 12.2 Hz,
H), 4.40 (d, J = 11.8 Hz, 1H), 4.21 (ddd, J = 9.9, 7.7, 5.7 Hz,
1H), 4.13 (ddd, J = 9.5, 5.6, 3.8 Hz, 2H), 3.92 (t, J = 3.9 Hz, 1H),
3
f
D
1
1
1
CHCl ); H NMR (300 MHz, CDCl ): δ 7.38–7.28 (m, 5H), 4.63–
3 3
4.53 (m, 3H), 4.19–4.13 (m, 1H), 4.05 (td, J = 7.6, 4.2 Hz, 1H),
3.93 (dt, J = 8.2, 5.2 Hz, 1H), 3.65 (dd, J = 10.0, 5.3 Hz, 1H),
3.56 (dd, J = 10.0, 5.0 Hz, 1H), 3.33 (s, 1H), 2.48 (d, J = 2.2 Hz,
5
0
5
0
5
0
5
0
5
0
5
3
.83 (qd, J = 6.3, 4.1 Hz, 1H), 3.70 (dd, J = 10.1, 5.3 Hz, 1H),
3
3
1
.60 (dd, J = 10.0, 6.6 Hz, 1H), 3.41 (dd, J = 6.8, 4.0 Hz, 1H), 65 1H), 1.92 (ddd, J = 14.1, 9.9, 4.1 Hz, 1H), 1.77 (tdd, J = 10.0,
.30 (d, J = 3.1 Hz, 6H), 2.11 (dd, J = 13.2, 5.7 Hz, 1H), 1.84–
.76 (m, 1H), 1.62–1.57 (m, 1H), 1.11 (d, J = 6.3 Hz, 3H), 0.91
6.9, 3.1 Hz, 1H), 1.63 (ddd, J = 14.3, 7.2, 2.5 Hz, 1H), 1.40 (d, J
= 6.8 Hz, 6H), 1.09 (d, J = 7.1 Hz, 3H); C NMR (75 MHz,
13
13
1
1
2
2
3
3
4
4
5
5
(d, J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H);
NMR (125 MHz, CDCl ): δ 139.0, 138.5, 133.9, 129.9, 128.2,
1
7
C
CDCl ): δ 137.5, 128.3, 127.8, 127.7, 108.8, 83.7, 79.2, 76.6,
3
73.6, 73.5, 71.4, 70.5, 66.5, 43.2, 38.1, 27.1, 26.8, 6.9; IR (neat):
3
28.1, 127.7, 127.5, 127.4, 127.1, 86.7, 81.9, 80.6, 79.6, 78.6, 70 3424, 3290, 2984, 2928, 1722, 1455, 1377, 1249, 1218, 1092,
ꢀ
1
+
3.3, 70.9, 70.8, 68.9, 57.2, 56.7, 43.6, 34.4, 25.8, 19.7, 18.1, 9.1,
741 cm ; ESIꢀHRMS: m/z calcd for C H O Na [M+Na]
20 28 5
ꢀ4.5; IR (neat): 2955, 2923, 1461, 1340, 1259, 1083, 1051, 795,
371.1829, found 371.1828.
ꢀ
1
+
697 cm ; ESIꢀHRMS: m/z calcd for C H NaO Si [M+Na]
6
3
4
52
6
21.3553: found 621.3582.
75
(4S,5R,6S)-4-(((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)methyl)-6-ethynyl-2,2,5-trimethyl-1,3-
dioxane (25)
(2S,3S,5R)-5-((2R,3R,E)-3-(benzyloxy)-5-((2S,3S)-3-
methyloxiran-2-yl)pent-4-en-2-yl)-2-((benzyloxy)methyl)-3-
methoxytetrahydrofuran (30)
To the solution of alcohol 7 (10 mg, 0.017 mmol) in CH Cl (2
To a solution of 24 (70 mg, 0.2 mmol) in CH Cl (2 mL) was
2
2
added 2,2ꢀdimethoxypropane (0.1 mL, 1 mmol) and 4 mg PTSA.
2
2
mL) was added Et N (6.0 µL. 0.04 mmol) followed by MsCl (1 80 The solution was stirred for 4 h at rt prior to being quenched by
3
o
µL, 0.01 mmol) at 0 C. The reaction mixture was stirred for one
h at rt until total consumption of the starting material occured.
The reaction mixture was quenched with a saturated aqueous
solution of NH Cl (1 mL) and extracted with CH Cl . The
combined organic phase was washed with water, brine, dried over 85 (58 mg, 75%) as colorless oil. R = 0.5 (5% EtOAcꢀhexane);
anhydrous Na SO and concentrated to give mesylated product (8
mg, 71%), which was used immediately without further
purification for cyclization reaction. To a stirred solution of
mesylated compound (8 mg, 0.012 mmol) in THF (1.5 mL) was
addition of saturated NaHCO3 solution. The mixture was
extracted with CH Cl , the combined organic layers were dried
2
2
over Na SO4 and evaporated. The residue was subjected to
2
column chromatography (elution 5% EtOAc/Hexanes) to give 25
4
2
2
f
20
1
[α]D = ꢀ24.40 (c 0.25, CHCl ); H NMR (500 MHz, CDCl ): δ
3 3
2
4
7.36–7.27 (m, 5H), 4.79 (t, J = 2.3 Hz, 1H), 4.64–4.54 (m, 2H),
4.12 (dt, J = 9.0, 2.6 Hz, 1H), 3.93 (td, J = 8.8, 2.9 Hz, 1H), 3.86–
3.80 (m, 1H), 3.57 (d, J = 4.7 Hz, 2H), 2.49 (d, J = 2.1 Hz, 1H),
added tetrabutylammonium fluoride (1M solution in THF, 0.03 90 1.81–1.69 (m, 1H), 1.64–1.49 (m, 2H), 1.41 (dd, J = 7.4, 4.7 Hz,
13
mmol, 0.01mL). Then the solution was stirred at rt for 3 h. THF
was removed by rotary evaporator and the crude mixture was
purified by column chromatography (20% EtOAcꢀhexane)
without extractive workꢀup to give the title 30 (3 mg, 69%) as
colorless oil. R = 0.5 (20% EtOAcꢀhexane). [α] = 24.0 (c 0.1, 95 ESIꢀHRMS: m/z calcd for C H O Na [M+Na]
CHCl3); H NMR (500 MHz, CDCl ): δ 7.37–7.22 (m, 10H),
12H), 1.11 (d, J = 6.9 Hz, 3H); C NMR (125 MHz, CDCl ): δ
3
137.9, 128.3, 127.5, 108.7, 99.6, 81.5, 80.1, 75.0, 73.8, 73.4,
70.2, 69.2, 65.3, 37.2, 36.2, 29.8, 27.2, 26.9, 19.2, 6.3; IR (neat):
ꢀ
1
3287, 2988, 1455, 1381, 1218, 1169, 1100, 1010, 911, 772 cm ;
2
0
+
411.2142,
f
D
23 32
5
1
found 411.2132.
3
5
.90–5.84 (m, 1H), 5.41 (dd, J = 15.6, 7.9 Hz, 1H), 4.64–4.52 (m,
2H), 4.38 (d, J = 11.8 Hz, 1H), 4.21 (dd, J = 5.3, 3.1 Hz, 1H),
Acknowledgments
3
1
2
5
.92 ꢀ3.83 (m, 2H), 3.74 (dd, J = 10.3, 4.2 Hz, 1H), 3.60 (dd, J =
P. S. Thanks CSIR, New Delhi for financial assistance. P.S.
0.3, 6.3 Hz, 1H), 3.25 (s, 3H), 3.09 (d, J = 7.9 Hz, 1H), 2.93– 100 acknowledges funding from CSIR, New Delhi as a part of XII
.87 (m, 1H), 2.14 (td, J = 13.1, 6.5 Hz, 1H), 1.81 (dd, J = 10.0,
.1 Hz, 1H), 1.66–1.61 (m, 1H), 1.35 (dd, J = 5.1, 2.3 Hz, 3H),
Five year plan programme under title ORIGIN (CSCꢀ0108).
Notes and references
Division of Natural Products Chemistry, CSIR–Indian Institute
1
3
a
0.89–0.87 (m, 3H); C NMR (125 MHz, CDCl ): δ 139.0, 138.5,
1
7
IR (neat): 3853, 3734, 2360, 1683, 1558, 1507, 1457 cm ; ESIꢀ
HRMS: m/z calcd for C H O Na [M+Na] 475.2468: found
3
35.1, 129.3, 128.2, 128.1, 127.6, 127.4, 127.4, 127.2, 81.4, 80.6,
of Chemical Technology, Hyderabad–500 007, India. Fax: (+)
8.9, 78.7, 73.2, 71.1, 68.9, 59.1, 57.0, 56.5, 43.4, 35.1, 17.5, 9.5; 105 914027160512;
Tel:
(+)
914027191815;
E–mail:
ꢀ
1
srihari@iict.res.in
† Electronic Supplementary Information (ESI) available:
+
1
H
2
8
36
5
13
475.2455.
NMR and
C
NMR copies of new compounds,. See
DOI: 10.1039/b000000x/
2S,3R,4S)-1-((4S,5S)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3- 110 1.
(
(a) T. Zhung, F. Li, L.ꢀR. Huang, J.–Y. Liang and W. Qu,
Chem. and Biodivers., 2015, 12, 194–220. (b) S. Abolfazl,
I. Milad and I. Mehrdad, J. Asian Natu. Produ. Res., 2014,
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Algological studies, 2013, 143, 3ꢀ25. (d) M. E. Rateb and E.
Rainer, Nat. Prod. Rep. 2011, 28, 290–344. (e) Sterner, O.
Natural Products Isolation. Ed by Sarker, S. D.; Nahar, L.
dioxolan-4-yl)-3-methylhex-5-yne-2,4-diol (24)
To a stirred solution of 23 (180 mg, 0.33 mmol) in THF (5 mL)
was added tetrabutylammonium fluoride (1M solution in THF,
0
.67 mmol, 0.6 mL). Then the solution was stirred at rt for 2 h.
THF was evaporated and the crude mixture was purified by 115
column chromatography (40% EtOAcꢀhexane) without extractive
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

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DOI: 10.1039/C6OB01447J
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