Formal Total Synthesis of Brevisamide by Using a Tandem Isomerization/C-O and C-C Bond Formation Reaction

Article abstract of DOI:10.1002/ejoc.201600142

A highly stereoselective formal total synthesis of brevisamide is described that proceeds through a convergent pathway and utilizes our own tandem isomerization/C-O and C-C bond formation reaction as the key step to construct the trans-2,6-disubstituted d

Full text of DOI:10.1002/ejoc.201600142

DOI: 10.1002/ejoc.201600142
Full Paper
Total Synthesis
Formal Total Synthesis of Brevisamide by Using a Tandem
Isomerization/C–O and C–C Bond Formation Reaction
[a]
[a]
[a]
[a]
Shivalal Banoth, Saurabh Maity, Sudheer R. Kumar, J. S. Yadav, and
Debendra K. Mohapatra*[
a]
Abstract: A highly stereoselective formal total synthesis of bre- 2,6-disubstituted dihydropyran ring system. Other significant
visamide is described that proceeds through a convergent path- reactions in this synthesis include an iodolactonization, a
way and utilizes our own tandem isomerization/C–O and C–C Crimmins-modified “non-Evans” syn aldol reaction, and a
bond formation reaction as the key step to construct the trans- Horner–Wadsworth–Emmons olefination.
Introduction
Marine polycyclic ether toxins produced by marine dinoflagel-
lates are interesting targets for synthetic chemists, as they are
unique and complex structures with potent biological activity.
The most characteristic toxins of dinoflagellates are polycyclic
ethers such as brevetoxin and brevenal, which contain ladder-
frame polyether fused rings or linear polycyclic ether rings. Bre-
visamide (1), a monocyclic ether alkaloid, was isolated from the
dinoflagellate Karenia brevis by Wright and co-workers. It con-
tains a complex functionalized tetrahydropyran core and a tri-
substituted (E,E)-diene as a side chain. The structural assign-
ment and the relative and absolute stereochemistry of brevis-
amide (1) was confirmed by its first total synthesis, which was
carried out by the Satake and Tachibana group. Because of its
interesting structural features and intriguing biological activity,
brevisamide has attracted the attention of synthetic as well as
medicinal chemists worldwide. As a part of our ongoing re-
search on the total synthesis of pyran ring containing biologi-
cally active natural products through the tandem isomeriza-
tion/C–O and C–C bond formation reaction developed by us,
we, herein, report the formal total synthesis of brevisamide (1),
which was carried out in a highly stereoselective and concise
manner.
6 by employing a 5-exo-trig iodolactonization reaction. Com-
pound 6, in turn, can be prepared from the δ-hydroxy-α,ꢀ-un-
saturated aldehyde 7 by using our own isomerization followed
by C–O and C–C bond formation strategy. Commercially avail-
able 1,4-butanediol can be used for the synthesis of 7, and
phosphonate coupling partner 4 can be easily synthesized from
commercially available 3-hydroxybutan-2-one.
[
1]
[
2]
[
3]
[
4]
[
5]
As shown in the retrosynthetic analysis (Scheme 1), brevis-
amide (1) can be obtained from ester 2 by using a previously
[
6]
known synthetic sequence that was adopted by Lindsley et al.
The conjugated (E,E)-diene ester 2 would then be accessible by
combining aldehyde 3 and phosphonate ester 4 under Horner–
Wadsworth–Emmons olefination conditions. The key fragment
3
can be synthesized from lactone 5 through a Curtius rear-
rangement, and the required lactone could be synthesized from
Scheme 1. Retrosynthetic analysis of brevisamide (1, TBS = tert-butyldimeth-
ylsilyl, PMB = para-methoxybenzyl).
[
a] Natural Products Chemistry Division, CSIR – Indian Institute of Chemical
Technology,
Hyderabad 500 007, India
E-mail: mohapatra@iict.res.in
www.iictindia.org
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600142.
Results and Discussion
The synthesis began from known aldehyde 9 (Scheme 2), which
was derived from commercially available 1,4-butanediol by us-
Eur. J. Org. Chem. 2016, 2300–2307
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ing a two-step sequence as reported in the literature.[7] The the synthesis of the C-21–C-29 fragment of sorangicin A. After
treatment of aldehyde 9 with Crimmins' chiral auxiliary 8 in the achieving the preparation of cis-iodolactone 15 as a single dia-
presence of TiCl (1.05 equiv.) followed by iPr NEt (1.1 equiv.) in stereomer in 86 % yield, the deiodination process was carried
4
2
CH Cl at –78 °C afforded the “non-Evans” syn aldol adduct 10 out by treating 15 with tri-n-butyltin hydride and a catalytic
2
2
[
8]
[14]
in 80 % yield [diastereomeric ratio (dr) 95:5]. This secondary amount of AIBN in toluene at reflux to obtain 5 in 92 % yield.
alcohol 10 was then protected by using TBSOTf (Tf = trifluoro- Under basic conditions, the hydrolysis of lactone 5 with aque-
methanesulfonyl) and 2,6-lutidine in CH Cl to obtain TBS ether ous LiOH (1.2 equiv.) in THF gave a product mixture that con-
2
[
2
9]
1
1 in 89 % yield. The reductive cleavage of chiral auxiliary 11 tained a hydroxyl Li-carboxylate intermediate. This mixture was
by treatment with diisobutylaluminum hydride furnished the concentrated under reduced pressure, and N,N-dimethylforma-
aldehyde, which was subsequently subjected to a two-carbon mide (DMF) was added. To this solution was added an excess
homologation with a Wittig ylide (Ph P=CHCO Et) to exclusively amount of TBSOTf in the presence of DMAP and imidazole to
3
2
obtain (E)-α,ꢀ-unsaturated ester 12 in 81 % yield over two steps. afford a bis(TBS)-protected intermediate. The addition of water
to the reaction mixture selectively removed the TBS group from
[
15]
the ester moiety to obtain 16 in 84 % yield (over two steps).
Scheme 2. Synthesis of trans-3-methyl-3,6-dihydropyran {DIBAL-H = diiso-
butylaluminum hydride, CSA = camphorsulfonic acid, TEMPO = (2,2,6,6-tetra-
Scheme 3. Synthesis of pyran-containing acid compound 16 [AIBN = azo-
bis(isobutyronitrile), DMAP = 4-(N,N-dimethylamino)pyridine].
methylpiperidin-1-yl)oxyl, BAIB
tetrahydrofuran}.
=
[bis(acetoxy)iodo]benzene, THF
=
The reduction of the ester functionality of 12 by treatment
Next, to synthesize key intermediate 3 (Scheme 4), methyla-
with DIBAL-H in CH Cl at –78 °C followed by the acid-mediated tion of acid 16 was carried out under neutral conditions with
2
2
removal of TBS group from the corresponding allylic alcohol diazomethane[16] to furnish methyl ester 17 in 91 % yield. The
produced the desired diol 13 in 81 % yield. The primary alcohol relative stereochemistry of 17 was assigned by NOE analysis.[17]
1
3 was chemoselectively oxidized in the presence of a catalytic The epimerization of the stereochemistry at C-12 through a
[
10]
amount of TEMPO and BAIB
to afford the required (E)-α,ꢀ- retro-oxa-Michael/oxa-Michael process with potassium tert-
unsaturated aldehyde 7 in 95 % yield. The tandem cyclization butoxide in THF at 0 °C proceeded smoothly in a stereoselective
[
18]
protocol was performed by subjecting 7 to our previous reac- manner to favor the desired C-12 ꢀ-epimer 18 in 92 % yield.
tion conditions (1.5 equiv. of allyltrimethylsilane and 0.25 equiv. The relative stereochemistry of 18 was assigned again by NOE
[
11]
of iodine), which allowed the allylation to occur stereoselect- analysis and was in good agreement with the structure re-
[
6]
ively and provide trans-3-methyl-3,6-dihydropyran 6 as the sole ported in the literature. The hydrolysis of the methyl ester
product in 96 % yield.
moiety in 18 by treatment with LiOH in THF/MeOH/H O (3:1:1)
2
Next, our attention turned to the synthesis of acid 16 as furnished seco acid 19 in 87 % yield. A Curtius rearrange-
depicted in Scheme 3. The selective oxidative cleavage of the ment[ of the resulting acid 19 by using (PhO) P(O)N (DPPA)
19]
2
3
terminal double bond in 6 was performed by using OsO , 2,6- afforded the corresponding primary amine 20 in 84 % yield.
4
[
12]
lutidine, and NaIO4 following by Jin's one-pot protocol
to Monoacylation of the primary amine 20 by treatment with ace-
obtain the corresponding aldehyde, which upon oxidation un- tic anhydride in the presence of pyridine afforded amide 21 in
[
13]
der Pinnick conditions
9 % yield over the two steps. The installation of the C-11 hy- benzoquinone (DDQ)[20] afforded primary alcohol 22 in 85 %
droxyl group with the (S) configuration was achieved by a cis- yield, which was subsequently oxidized under Parikh–Doering
gave the corresponding acid 14 in 96 % yield. The reaction of 21 with 2,3-dichloro-5,6-dicyano-
8
[
21]
selective 5-exo-trig iodolactonization reaction under our previ- reaction conditions
to provide the corresponding aldehyde
ously reported reaction conditions,[ which were employed for 3.
5a]
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Scheme 6. Formal total synthesis of brevisamide (NaHMDS = sodium hexa-
methyldisilazide).
Conclusions
In summary, we have described the efficient formal synthesis
of brevisamide. By using a convergent strategy, we utilized a
tandem isomerization/C–O and C–C bond formation reaction as
the key step to construct the trans-2,6-disubstituted dihydro-
pyran ring system. The synthesis involved other important reac-
tions such as an iodolactonization, a base-induced epimeriza-
tion, a Crimmins-modified “non-Evans” syn aldol reaction, and
a Horner–Wadsworth–Emmons olefination.
Scheme 4. Synthesis of tetrasubstituted pyran 3 (DPPA = diphenyl phosphor-
azidate, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMSO = di-
methyl sulfoxide).
Experimental Section
General Methods: The H and 13C NMR spectroscopic data were
recorded with a 300, 400, or 500 MHz spectrometer at ambient
1
The necessary phosphonate ester 4, the building block for
the western side chain (C-1–C-4) of brevisamide (1), was synthe-
sized from commercially available 3-hydroxybutan-2-one (23).
temperature, and CDCl was used as the solvent. The coupling con-
3
stants (J) are reported in hertz. The chemical shifts are reported in
Accordingly, 23 was subjected to two-carbon homologation by ppm on scale downfield from TMS as the internal standard, and
a Wittig reaction using a phosphorus ylide with the keto func- the abbreviations for the multiplicities are s (singlet), d (doublet), t
tionality (Ph P=CHCO Et) followed by the conversion of the hy- (triplet), q (quartet), sext (sextet), m (multiplet), and br. s (broad
3
2
singlet). FTIR spectra were recorded as KBr pellets, in CHCl , or neat
droxyl group to obtain the corresponding bromo ester 24 in
0 % yield over two steps (Scheme 5). An Arbuzov reaction of
3
(
[
as mentioned), and the bands are reported in wavenumbers
cm ]. Optical rotations were measured on a digital polarimeter
8
–
1
the resulting compound 24 by using triethyl phosphate pro-
vided the required phosphonate ester 4 in a good yield of
using a 1 mL cell with a 1 dm path length. For low (MS) and high
HRMS) resolution mass spectrometry, the m/z ratios are reported
(
[
22]
93 %.
in atomic mass units. Mass analysis was done in the ESI mode. All
reagents were reagent grade and used without further purification,
unless specified otherwise. Solvents for reactions were distilled prior
to use. THF and toluene were distilled from Na and benzophenone
ketyl. EtOH was distilled from Mg and I , and CH Cl was distilled
2
2
2
from CaH . All air- and moisture-sensitive reactions were conducted
2
under nitrogen or argon in oven- or flame-dried glassware. Mag-
netic stirring was used. Column chromatography was carried out
on silica gel (60–120 mesh) packed into a glass column.
(
[
2R,3S)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-hydroxy-6-
(4-methoxybenzyl)oxy]-2-methylhexan-1-one (10): To a stirred
yellow solution of N-propionyl thiazolidinethione 8 (8.0 g,
0.18 mmol) in CH Cl (75 mL) under argon was added TiCl (1
Scheme 5. Synthesis of phosponate ester 4 (DCM = dichloromethane).
3
M
2
2
4
in CH Cl , 31.7 mL, 31.7 mmol) dropwise at 0 °C, and the resulting
2
2
orange slurry was stirred for 5 min. iPr NEt (5.7 mL, 33.2 mmol) was
2
With the requisite compounds 3 and 4 in hand, our objective
was to couple the two fragments. The coupling reaction be-
tween C-1–C-4 fragment 4 and the C-5–C-15 fragment 3 pro-
ceeded well to obtain the corresponding dienoate 2 in 82 %
yield, which represents the formal total synthesis of brevis-
added dropwise to the viscous orange solution. The resulting
blood-red titanium enolate solution was stirred at 0 °C for 45 min
and then cooled to –78 °C. A solution of aldehyde 9 (6.9 g,
3
3.20 mmol) in CH Cl (30 mL) was added dropwise, and the result-
2 2
ing reaction mixture was stirred for 1 h. Upon completion (moni-
tored by TLC), the reaction was quenched by the addition of a
1
13
amide (Scheme 6). The spectroscopic ( H NMR, C NMR, and
MS spectra) and analytical data of 2 were in good agreement saturated aqueous NH Cl solution (70 mL). The layers were sepa-
4
[
6]
with the reported values.
rated, and the aqueous layer was then extracted with CH Cl (2 ×
2 2
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1
00 mL). The combined organic extracts were dried with anhydrous
(s, 3 H), 3.63 (m, 1 H), 3.45–3.37 (m, 2 H), 2.46 (m, 1 H), 1.65 (m, 1
Na SO and concentrated under reduced pressure to give a crude
yellow oil, which upon purification by silica gel column chromatog-
H), 1.59–1.48 (m, 2 H), 1.14 (m, 1 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.02
(d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.03 (s, 6 H) ppm. C NMR
2
4
1
3
raphy (EtOAc/hexane, 1:4) afforded 10 (11.5 g, 80 %, dr 95:5) as pale
(100 MHz, CDCl ): δ = 166.5, 158.9, 151.6, 130.5, 129.0, 120.7, 113.6,
3
2
0
yellow liquid. [α]D = +52.1 (c = 1.2, CHCl ). IR (neat): ν˜ = 3447, 2938, 74.8, 72.3, 69.8, 59.9, 55.0, 41.5, 30.4, 25.7, 25.5, 17.9, 14.1, 13.9, –4.4,
3
–
1
1
+
2
7
5
3
3
1
859, 1690, 1512, 1249, 1033 cm . H NMR (500 MHz, CDCl ): δ = –4.5 ppm. HRMS (ESI): calcd. for C25H43O Si [M + H] 451.2874;
.32 (d, J = 7.1 Hz, 2 H), 7.29–7.24 (m, 5 H), 6.85 (d, J = 8.6 Hz, 2 H),
3
5
found 451.2904.
.37 (m, 1 H), 4.69 (m, 1 H), 4.42 (s, 2 H), 4.06 (m, 1 H), 3.76 (s, 3 H),
.49 (t, J = 6.4 Hz, 2 H), 3.35 (q, J = 7.1 Hz, 1 H), 3.22 (dd, J = 13.2,
.9 Hz, 1 H), 3.02 (m, 1 H), 2.86 (d, J = 11.5 Hz, 1 H), 1.79 (m, 1 H),
(
(
4S,5S,E)-8-[(4-Methoxybenzyl)oxy]-4-methyloct-2-ene-1,5-diol
13): To a stirred solution of the α,ꢀ-unsaturated ester 12 (5.5 g,
1
2.22 mmol) in CH Cl (75 mL) was added diisobutylaluminum
2 2
.68 (m, 1 H), 1.62–1.53 (m, 2 H), 1.19 (d, J = 7.0 Hz, 3 H) ppm. 13
C
hydride (2.5
M hexane, 10.75 mL, 26.88 mmol) at –78 °C, and the
NMR (75 MHz, CDCl ): δ = 201.2, 177.8, 158.9, 136.3, 130.3, 129.3,
3
resulting mixture was stirred at –78 °C for 30 min. Upon completion
monitored by TLC), the reaction was quenched by the slow addi-
1
3
4
29.1, 128.7, 127.1, 113.6, 72.4, 70.8, 69.8, 68.7, 55.1, 42.9, 36.8, 31.6,
(
+
0.9, 26.2, 10.6 ppm. HRMS (ESI): calcd. for C H NO S [M + H]
2
5
32
4 2
tion of methanol (10 mL) followed by a saturated solution of Ro-
chelle salt (50 mL). The reaction mixture was warmed to room tem-
perature and then stirred vigorously until the resulting white slurry
was completely dissolved. The organic layer was separated, and the
aqueous layer was extracted with CH Cl (3 × 50 mL). The combined
74.1767; found 474.1799.
(
2R,3S)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3-[(tert-butyl-
dimethylsilyl)oxy]-6-[(4-methoxybenzyl)oxy]-2-methylhexan-1-
one (11): To a stirred solution of aldol adduct 10 (10.0 g,
2
2
2
1.14 mmol) in CH Cl (75 mL) at 0 °C were added 2,6-lutidine
organic extracts were washed with water and brine (50 mL), dried
with anhydrous Na SO , and concentrated under reduced pressure.
2
2
(
4.5 mL, 38.05 mmol) and then TBSOTf (8.3 mL, 31.7 mmol), and the
resulting mixture was stirred at 0 °C for 30 min. Upon completion
monitored by TLC), the reaction was quenched by the addition of
HCl (1 , 50 mL). The organic layer was separated, and the aqueous
layer was extracted with CH Cl (3 × 70 mL). The combined organic
2
4
The residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:4) to give the corresponding allylic alcohol (4.75 g,
(
2
0
N
95 %) as a colorless liquid. [α] = –15.7 (c = 0.8, CHCl ). IR (neat):
D
3
–
1
1
ν = 3423, 2954, 2930, 2856, 1612, 1513, 1093 cm . H NMR
(300 MHz, CDCl ): δ = 7.25 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz,
2
2
˜
extracts were dried with anhydrous Na SO and concentrated under
2
4
3
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane, 1:9) to give TBS-protected aldol
2 H), 5.72–5.55 (m, 2 H), 4.42 (s, 2 H), 4.07 (d, J = 5.0 Hz, 2 H), 3.79
(s, 3 H), 3.53 (dd, J = 10.9, 5.0 Hz, 1 H), 3.41 (t, J = 6.4 Hz, 2 H), 2.31
2
0
adduct 11 (11.1 g, 89 %) as a colorless liquid. [α]D = +8.2 (c = 3.1, (m, 1 H), 1.67 (m, 1 H), 1.56 (m, 1 H), 1.48–1.41 (m, 2 H), 0.97 (d, J =
CHCl ). IR (neat): ν˜ = 2930, 2859, 1694, 1512, 1458, 1251, 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR (100 MHz,
3
–1 1
1
7
1
3
098 cm . H NMR (500 MHz, CDCl ): δ = 7.32 (d, J = 6.8 Hz, 2 H), CDCl ): δ = 159.0, 135.4, 130.5, 129.1, 128.5, 113.6, 75.6, 72.3, 70.1,
.28–7.21 (m, 5 H), 6.82 (d, J = 8.6 Hz, 2 H), 5.33 (m, 1 H), 4.75 (m,
H), 4.41 (s, 2 H), 4.20 (m, 1 H), 3.76 (s, 3 H), 3.46–3.39 (m, 2 H),
.31 (q, J = 7.3 Hz, 1 H), 3.18 (dd, J = 13.1, 3.5 Hz, 1 H), 2.98 (dd,
3
3
63.8, 55.1, 41.4, 30.1, 25.8, 25.3, 18.0, 15.3, –4.3, –4.4 ppm. HRMS
+
(ESI): calcd. for C H O Si [M + H] 409.2769; found 409.2793. To a
2
3 41 4
stirred solution of the allylic alcohol (4.5 g, 11.02 mmol) in MeOH
(50 mL) was added camphorsulfonic acid (0.51 g, 2.2 mmol). The
resulting mixture was stirred until the starting material was com-
pletely consumed, and then the reaction was quenched by the ad-
dition of 10 drops of triethylamine. The solvent was removed under
reduced pressure, and the crude residue was directly purified by
J = 13.1, 10.8 Hz, 1 H), 2.84 (d, J = 11.4 Hz, 1 H), 1.73–1.60 (m, 4 H),
1
.21 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm.
1
3
C NMR (100 MHz, CDCl ): δ = 200.9, 176.6, 158.9, 136.5, 130.7,
3
1
3
29.3, 129.0, 128.8, 127.1, 113.6, 72.6, 72.2, 70.1, 69.0, 55.1, 43.4,
7.0, 32.1, 31.4, 25.9, 25.0, 18.1, 14.3, –4.0, –4.3 ppm. HRMS (ESI):
+
calcd. for C H NO S Si [M + H] 588.2632; found 588.2670.
column chromatography on silica gel (EtOAc/hexane, 1:1) to afford
31
46
4 2
diol 13 (2.75 g, 81 % over two steps) as a colorless liquid. [α]2
0
=
Ethyl (4S,5S,E)-5-[(tert-Butyldimethylsilyl)oxy]-8-[(4-methoxy-
benzyl)oxy]-4-methyloct-2-enoate (12): To a stirred solution of
silyl ether 11 (10.5 g, 17.88 mmol) in CH Cl (85 mL) at –78 °C,
D
–
1
2
10.34 (c = 1.7, CHCl ). IR (neat): ν˜ = 3389, 2930, 2860, 1730, 1612,
3
–
1 1
513, 1034 cm . H NMR (500 MHz, CDCl ): δ = 7.25 (d, J = 8.5 Hz,
3
2
2
H), 6.88 (d, J = 8.5 Hz, 2 H), 5.69–5.60 (m, 2 H), 4.44 (s, 2 H), 4.06
was added diisobutylaluminum hydride (2.5
M in hexane, 14.3 mL,
(d, J = 4.1 Hz, 2 H), 3.80 (s, 3 H), 3.49–3.44 (m, 3 H), 2.79 (br. s, 2 H),
3
5.77 mmol) dropwise until the yellow color disappeared. The reac-
2
3
1
.26 (m, 1 H), 1.80–1.58 (m, 3 H), 1.39 (m, 1 H), 1.01 (d, J = 6.8 Hz,
tion was immediately quenched by the addition of a saturated
aqueous sodium potassium tartrate solution and then warmed to
room temperature with vigorous stirring. After dispersion of the
emulsion, the layers were separated, and the aqueous layer was
extracted with CH Cl (3 × 75 mL). The combined organic extracts
H) ppm. 13C NMR (125 MHz, CDCl ): δ = 159.1, 135.0, 130.0, 129.4,
3
29.3, 113.7, 74.7, 72.5, 70.0, 63.3, 55.1, 42.1, 31.1, 26.4, 14.6 ppm.
+
HRMS (ESI): calcd. for C17H26NaO [M + Na] 317.1723; found
4
317.1741.
2
2
were dried with Na SO and concentrated under reduced pressure.
(4S,5S,E)-5-Hydroxy-8-[(4-methoxybenzyl)oxy]-4-methyloct-2-
enal (7): To a stirred solution of allylic alcohol 13 (2.7 g, 9.18 mmol)
in CH Cl (50 mL) were added iodobenzene diacetate (3.25 g,
2
4
The crude aldehyde (6.1 g) was used immediately in the next step
without purification. To a stirred solution of Ph P=CHCO Et (8.3 g,
3
2
2
2
2
(
1
3.8 mmol) in toluene (75 mL) was added the crude aldehyde
6.1 g) in one portion. The resulting mixture was stirred at 55 °C for
h and then heated at reflux for an additional 4 h. Upon comple-
10.10 mmol) and then TEMPO (0.35 g, 2.29 mmol) at 0 °C, and the
resulting mixture was stirred at ambient temperature for 3 h. Upon
complete conversion of the primary alcohol into the aldehyde
(monitored by TLC), the reaction was quenched by the addition
of a saturated solution of Na S O (40 mL). The organic layer was
tion of the reaction (monitored by TLC), the solvent was evaporated
under reduced pressure. The crude product was purified by column
2
2 3
chromatography on silica gel (EtOAc/hexane, 1:9) to give α,ꢀ-unsat- separated, and the aqueous layer was extracted with CH Cl (3 ×
2
2
urated ester 12 (6.5 g, 81 % over two steps) as a pale yellow oil. 40 mL). The combined organic layers were dried with anhydrous
2
0
[
1
α] = –2.2 (c = 3.0, CHCl ). IR (neat): ν˜ = 2955, 2932, 2857, 1719, Na SO and concentrated under reduced pressure. The crude alde-
D
3
2
4
–
1 1
651, 1513, 1250, 1096 cm . H NMR (500 MHz, CDCl ): δ = 7.24
hyde was purified by flash column chromatography on silica gel
3
(
2
d, J = 8.5 Hz, 2 H), 7.01 (dd, J = 15.8, 7.3 Hz, 1 H), 6.87 (d, J = 8.6 Hz,
H), 5.79 (d, J = 15.7 Hz, 1 H), 4.41 (s, 2 H), 4.21–4.14 (m, 2 H), 3.78
(EtOAc/hexane, 3:7) to obtain the corresponding aldehyde 7 (2.55 g,
2
0
95 %) as a colorless viscous liquid. [α] = –2.6 (c = 3.05, CHCl ). IR
D
3
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–
1 1
(
(
neat): ν˜ = 3426, 2936, 2862, 1688, 1612, 1513, 1248 cm . H NMR 4.43 (q, J = 11.7 Hz, 2 H), 3.79 (s, 3 H), 3.68 (m, 1 H), 3.51 (m, 1 H),
300 MHz, CDCl ): δ = 9.50 (d, J = 7.9 Hz, 1 H), 7.24 (d, J = 8.4 Hz,
3.44 (m, 1 H), 2.63 (dd, J = 15.1, 9.6 Hz, 1 H), 2.44 (dd, J = 15.1,
3
2
4
1
H), 6.91 (dd, J = 15.1, 7.3 Hz, 3 H), 6.13 (dd, J = 15.6, 7.9 Hz, 1 H),
.45 (s, 3 H), 3.80 (s, 3 H), 3.60 (m, 1 H), 3.53–3.43 (m, 2 H), 2.53 (m,
H), 1.79–1.58 (m, 3 H), 1.41 (m, 1 H), 1.11 (d, J = 6.7 Hz, 3 H) ppm.
4.4 Hz, 1 H), 2.04 (m, 1 H), 1.75 (m, 1 H), 1.67–1.44 (m, 3 H), 0.92 (d,
J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl ): δ = 175.6, 159.0,
3
132.5, 130.4, 129.2, 126.3, 113.7, 72.4, 71.0, 69.8, 69.5, 55.2, 38.6,
1
3
+
C NMR (100 MHz, CDCl ): δ = 194.1, 161.0, 159.2, 132.3, 129.7,
32.3, 28.2, 26.0, 13.1 ppm. HRMS (ESI): calcd. for C H O [M + H]
3
19 27 5
1
29.3, 113.7, 73.9, 72.7, 69.9, 55.1, 42.8, 31.9, 26.5, 13.9 ppm. HRMS
335.1853; found 335.1887.
+
(ESI): calcd. for C H NaO [M + Na] 315.1567; found 315.1581.
17
24
4
(
3aS,5S,6R,7R,7aR)-7-Iodo-5-{3-[(4-methoxybenzyl)oxy]propyl}-
(
2S,3S,6S)-6-Allyl-2-{3-[(4-methoxybenzyl)oxy]propyl}-3-
6-methylhexahydro-2H-furo[3,2-b]pyran-2-one (15): To a stirred
methyl-3,6-dihydro-2H-pyran (6): Iodine (0.54 g, 2.14 mmol) was
added at 0 °C to a stirred solution of δ-hydroxy-α,ꢀ-unsaturated
aldehyde 7 (2.5 g, 8.56 mmol) and allyltrimethylsilane (2.1 mL,
solution of acid 14 (2.2 g, 6.58 mmol) in THF (15 mL) was added a
solution of NaHCO (5.53 g, 65.86 mmol) in water (10 mL) at 0 °C.
3
The mixture was stirred at room temperature for 1 h, and to the
mixture was then added a solution of I (5.02 g, 19.76 mmol) and
1
2.84 mmol) in anhydrous THF (15 mL), and the resulting mixture
2
was allowed to come to room temperature and stirred for 45 min.
Upon completion (monitored by TLC), the reaction was quenched
by the addition of a saturated aqueous solution of Na S O (35 mL)
and then extracted with ethyl acetate (3 × 40 mL). The combined
organic extracts were washed with water and brine (30 mL), dried
with anhydrous Na SO , and concentrated under reduced pressure
to give a pale yellow oil, which was purified by column chromatog-
raphy on silica gel (EtOAc/hexane, 1:9) to give the cyclized product
6
KI (9.84 g, 59.28 mmol) dissolved in water (10 mL). After the mixture
was stirred at room temperature overnight, the reaction was
quenched by the addition of a saturated aqueous solution of
Na S O (25 mL) and then extracted with ethyl acetate (2 × 50 mL).
2
2 3
2
2 3
The combined organic extracts were washed with brine (50 mL),
dried with anhydrous Na SO , and concentrated under reduced
2
4
2
4
pressure. Purification by column chromatography on silica gel
EtOAc/hexane, 2:8) afforded iodo-lactone 15 (2.6 g, 86 %) as a light
(
(2.6 g, 96 %) as a colorless liquid. [α] D2 = +29.6 (c = 3.3, CHCl ). IR
0
20
3
yellow liquid. [α]D = –15.38 (c = 4.9, CHCl ). IR (neat): ν = 3552,
3
˜
–
1 1
(
neat): ν˜ = 3448, 2930, 2857, 1721, 1512, 1248, 1085 cm . H NMR
–1 1
2937, 2858, 1792, 1708, 1512, 1038 cm . H NMR (300 MHz, CDCl ):
3
(500 MHz, CDCl ): δ = 7.25 (d, J = 8.5 Hz, 2 H), 6.86 (d, J = 7.4 Hz,
3
δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.75 (dd, J =
2
(
3
H), 5.90–5.80 (m, 2 H), 5.62 (m, 1 H), 5.06 (t, J = 15.7 Hz, 2 H), 4.43
t, J = 13.4 Hz, 2 H), 4.16 (m, 1 H), 3.78 (s, 3 H), 3.68 (m, 1 H), 3.52–
.41 (m, 2 H), 2.37 (m, 1 H), 2.20 (m, 1 H), 2.01 (m, 1 H), 1.80 (m, 1
7
2
.5, 5.8 Hz, 1 H), 4.64 (dd, J = 13.0, 6.9 Hz, 1 H), 4.42 (q, J = 11.5 Hz,
H), 4.33 (m, 1 H), 3.81 (s, 3 H), 3.73 (m, 1 H), 3.45 (t, J = 5.8 Hz, 2
H), 2.69 (dd, J = 17.3, 7.3 Hz, 1 H), 2.50 (dd, J = 17.3, 6.9 Hz, 1 H),
.06–1.85 (m, 2 H), 1.73 (m, 1 H), 1.62–1.43 (m, 2 H), 1.11 (d, J =
13
H), 1.66–1.42 (m, 3 H), 0.91 (d, J = 7.0 Hz, 3 H) ppm. C NMR
75 MHz, CDCl ): δ = 158.9, 135.0, 131.2, 130.6, 129.0, 127.7, 116.6,
2
(
13
3
7.1 Hz, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 173.3, 159.0, 130.3,
3
1
13.6, 72.4, 72.3, 70.6, 69.8, 55.1, 38.4, 32.4, 28.1, 26.3, 13.3 ppm.
129.1, 113.6, 86.9, 77.9, 72.4, 69.1, 68.0, 55.1, 39.9, 33.9, 32.3, 29.0,
+
HRMS (ESI): calcd. for C20H28NaO [M + Na] 339.1931; found
+
3
25.9, 20.9 ppm. HRMS (ESI): calcd. for C19H25INaO [M + Na]
5
3
39.1949.
483.0639; found 483.0656.
2
-[(2S,5S,6S)-6-{3-[(4-Methoxybenzyl)oxy]propyl}-5-methyl-5,6-
(
3aS,5S,6S,7aS)-5-{3-[(4-Methoxybenzyl)oxy]propyl}-6-methyl-
dihydro-2H-pyran-2-yl]acetic Acid (14): To a stirred solution of
cyclized compound 6 (2.5 g, 7.91 mmol) in 1,4-dioxane (30 mL),
were added 2,6-lutidine (1.9 mL, 15.8 mmol), NaIO4 (6.3 g,
hexahydro-2H-furo[3,2-b]pyran-2-one (5): To a stirred solution of
iodo-lactone 15 (2.4 g, 5.21 mmol) in toluene (50 mL) under nitro-
gen was added a catalytic amount of AIBN (30 mg), and the result-
ing mixture was then heated at reflux. Tri-n-butyltin hydride (4.5 mL,
3
1.64 mmol) dissolved in distilled water (10 mL), and OsO (1 M in
4
toluene, 0.16 mL, 0.158 mmol). The reaction mixture was stirred at
room temperature for 6 h. Upon completion (monitored by TLC),
the reaction was quenched by the addition of solid NaHSO . The
1
5.65 mmol) was added to the reaction mixture under reflux condi-
tions, and the resulting mixture was then stirred for 30 min. Upon
completion of the reaction (monitored by TLC), the toluene was
removed under reduced pressure to afford the crude product,
which upon purification by column chromatography on silica gel
3
organic solvent was removed under reduced pressure, and water
(
20 mL) was added to the residue. The aqueous layer was extracted
with tert-butyl methyl ether (3 × 60 mL). The combined organic
layers were washed with 1 HCl (2 × 50 mL) to remove the excess
quantity of 2,6-lutidine, dried with anhydrous Na SO , and concen-
(EtOAc/hexane, 3:7) furnished the desired bicyclic lactone 5 (1.6 g,
N
2
0
9
2 %) as a colorless liquid. [α] = –14.9 (c = 3.6, CHCl ). IR (neat):
D
3
–1
2
4
1
ν˜ = 3448, 2954, 2923, 2855, 1772, 1559, 1035 cm . H NMR
trated under reduced pressure. The crude aldehyde (2.6 g) was used
immediately in the next step without further purification. To a
stirred solution of the resulting aldehyde (2.6 g, 8.17 mmol) in tert-
(300 MHz, CDCl ): δ = 7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.4 Hz,
3
2
H), 4.44 (s, 2 H), 4.36 (m, 1 H), 4.18 (t, J = 3.7 Hz, 1 H), 3.80 (s, 3
H), 3.65 (m, 1 H), 3.53–3.46 (m, 2 H), 2.64 (dd, J = 17.1, 4.3 Hz, 1 H),
2
1
NMR (125 MHz, CDCl ): δ = 175.9, 159.0, 130.4, 129.1, 113.6, 77.2,
7
butyl alcohol (30 mL) was added 2-methyl-2-butene (1
.17 mL, 8.17 mmol) at room temperature. Sodium dihydrogen
phosphate (3.8 g, 24.52 mmol) and sodium chlorite (1.1 g,
2.26 mmol) dissolved in water (10 mL) were added at 0 °C. The
M in THF,
.45 (d, J = 17.3 Hz, 1 H), 2.20 (m, 1 H), 2.05 (m, 1 H), 1.77 (m, 1 H),
8
1
3
.70–1.57 (m, 3 H), 1.38 (m, 1 H), 0.84 (d, J = 6.9 Hz, 3 H) ppm.
C
3
1
6.0, 72.5, 69.4, 65.6, 55.1, 38.4, 28.1, 26.4, 25.9, 20.0, 16.7 ppm.
resulting reaction mixture was stirred at room temperature for 3 h.
Upon completion (monitored by TLC), the reaction was diluted with
water (25 mL), and the aqueous layer was extracted with ethyl acet-
ate (3 × 50 mL). The combined organic extracts were washed with
brine (10 mL), dried with anhydrous Na SO , and concentrated un-
+
HRMS (ESI): calcd. for C19H26NaO [M + Na] 357.1672; found
3
5
57.1697.
2-{(2S,3S,5S,6S)-3-(tert-Butyldimethylsilyloxy)-6-[3-(4-methoxy-
benzyloxy)propyl]-5-methyltetrahydro-2H-pyran-2-yl}acetic
Acid (16): To a stirred solution of bicyclic lactone 5 (1.4 g,
2
4
der reduced pressure. The crude product was purified by column
chromatography on silica gel (EtOAc/hexane, 3:7) to afford acid 14
4.19 mmol) in THF (15 mL) was added a solution of LiOH·H O
2
2.35 g, 89 % over two steps) as a pale yellow liquid. [α]2 = +22.0 (0.19 g, 4.61 mmol) in water (2 mL), and the resulting mixture was
0
(
D
(
1
6
c = 1.1, CHCl ). IR (neat): ν˜ = 3029, 2958, 2933, 2872, 1731, 1611,
stirred at room temperature for 3 h. Upon completion of the reac-
087 cm . H NMR (500 MHz, CDCl ): δ = 7.25 (d, J = 8.5 Hz, 2 H), tion (monitored by TLC), the mixture was concentrated under re-
3
–1 1
3
.87 (d, J = 8.3 Hz, 2 H), 5.89 (m, 1 H), 5.60 (m, 1 H), 4.63 (m, 1 H),
duced pressure to give a lithium carboxylate salt as a yellow solid,
Eur. J. Org. Chem. 2016, 2300–2307
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2304
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
13
which was then dissolved in DMF (5 mL). To this solution were
C NMR (125 MHz, CDCl ): δ = 172.3, 159.0, 130.7, 129.2, 113.6,
3
added imidazole (1.14 g, 16.76 mmol), TBSOTf (3.3 mL, 12.57 mmol), 80.0, 79.7, 72.3, 69.7, 67.3, 55.2, 51.5, 41.1, 38.0, 32.9, 29.1, 26.3, 25.7,
and DMAP (0.25 g, 2.1 mmol) at room temperature, and the result- 17.8, 12.8, –4.0, –4.7 ppm. HRMS (ESI): calcd. for C H O Si [M +
26 45 6
+
ing mixture was stirred for 2 h. Water (10 mL) was then added, and
the mixture was then stirred for an additional 2 h. Upon completion
of the reaction (monitored by TLC), the mixture was diluted with
water and then extracted with CH Cl (3 × 50 mL). The combined
H] 481.2980; found 481.2998.
2
-{(2R,3S,5S,6S)-3-(tert-Butyldimethylsilyloxy)-6-[3-(4-methoxy-
benzyloxy)propyl]-5-methyltetrahydro-2H-pyran-2-yl}acetic
Acid (19): To a stirred solution of methyl ester 18 (0.5 g, 1.04 mmol)
in THF/MeOH/H O (3:1:1) was added LiOH (75 mg, 3.12 mmol), and
the resulting mixture was stirred at room temperature for 4 h. Upon
completion (monitored by TLC), the reaction was quenched by the
addition of a saturated aqueous solution of NH Cl (25 mL), diluted
2
2
organic extracts were washed with water and brine (25 mL), dried
with Na SO , and concentrated under reduced pressure. The residue
2
2
4
was purified by column chromatography on silica gel (EtOAc/hex-
ane, 2:8) to afford the desired acid 16 (1.65 g, 84 %) as a colorless
2
0
4
thick liquid. [α]D = –8.4 (c = 1.6, CHCl ). IR (neat): ν = 2954, 2932,
3
˜
with EtOAc, and carefully neutralized with 0.5
N HCl. The organic
–
1 1
2
858, 1712, 1612, 1513, 1250, 1100, 837, 775 cm
. H NMR
layer was separated, and the aqueous layer was extracted with ethyl
acetate (3 × 45 mL). The combined organic extracts were washed
with water and brine (30 mL), dried with anhydrous Na SO , and
(
500 MHz, CDCl ): δ = 7.25 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.6 Hz,
3
2
3
H), 4.42 (q, J = 11.7 Hz, 2 H), 4.01 (m, 1 H), 3.84 (m, 1 H), 3.80 (s,
H), 3.73 (m, 1 H), 3.51–3.40 (m, 2 H), 2.65 (dd, J = 15.7, 8.6 Hz, 1
2
4
concentrated under reduced pressure. The crude residue was puri-
H), 2.49 (dd, J = 15.7, 4.7 Hz, 1 H), 1.74 (m, 1 H), 1.66–1.52 (m, 3 H),
.35 (m, 1 H), 1.29–1.71 (m, 2 H), 0.89 (s, 9 H), 0.84 (d, J = 7.0 Hz, 3
fied by column chromatography on silica gel (EtOAc/hexane, 1:4) to
1
afford carboxylic acid 19 (0.42 g, 87 %) as a colorless liquid. [α]2
0
=
1
3
D
H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm. C NMR (125 MHz, CDCl ): δ =
3
+
6.6 (c = 1.5, CHCl ). IR (neat): ν˜ = 2932, 2857, 1715, 1611, 1513,
3
1
2
75.3, 159.0, 130.6, 129.2, 113.7, 75.2, 69.7, 66.4, 55.2, 35.1, 34.9,
–
1 1
1250, 1100 cm . H NMR (500 MHz, CDCl ): δ = 7.25 (d, J = 8.5 Hz,
3
9.6, 28.3, 25.8, 25.7, 23.0, 18.0, 15.6, –4.6, –4.9 ppm. HRMS (ESI):
2
H), 6.87 (d, J = 8.5 Hz, 2 H), 4.41 (s, 2 H), 3.80 (s, 3 H), 3.52–3.49
+
calcd. for C H O Si [M + H] 467.2823; found 467.2865.
25 43 6
(
1
(
m, 2 H), 3.47–3.43 (m, 2 H), 3.40 (m, 1 H), 2.80 (dd, J = 15.7, 2.1 Hz,
H), 2.35 (dd, J = 15.5, 8.0 Hz, 1 H), 1.88–1.80 (m, 2 H), 1.71–1.47
m, 4 H), 1.44–1.37 (m, 1 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H),
Methyl 2-[(2S,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-{3-[(4-
methoxybenzyl)oxy]propyl}-5-methyltetrahydro-2H-pyran-2-
yl]acetate (17): A freshly prepared and titrated ethereal solution of
13
0
1
2
.05 (s, 6 H) ppm. C NMR (75 MHz, CDCl ): δ = 175.2, 159.0, 130.7,
29.2, 113.7, 79.9, 79.8, 72.4, 69.8, 67.2, 55.2, 41.0, 38.3, 32.7, 29.1,
3
diazomethane (0.27 M, 0.4 mL, 2.57 mmol) was added to a cooled
suspension (0 °C) of sodium hydroxide (113 mg, 2.83 mmol) in dry
diethyl ether (25 mL). After 5 min, a solution of the corresponding
acid 16 (1.2 g, 2.57 mmol) in anhydrous diethyl ether (20 mL) was
added dropwise. Upon completion of the reaction (monitored by
TLC), the mixture was concentrated under reduced pressure, and
the resulting residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:9) to give methyl ester 17 (1.12 g, 91 %)
6.3, 25.7, 17.8, 12.7, –4.1, –4.7 ppm. HRMS (ESI): calcd. for
+
C H NaO Si [M + Na] 489.2643; found 489.2686.
25
42
6
[
(2R,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-{3-[(4-
methoxybenzyl)oxy]propyl}-5-methyltetrahydro-2H-pyran-2-
yl]methanamine (20): To a stirred solution of carboxylic acid 19
(350 mg, 0.75 mmol) in toluene (5 mL) were added Et N (0.32 mL,
3
2
0
2.25 mmol) and diphenyl phosphorazidate (0.34 mL, 1.50 mmol),
and the reaction mixture was stirred at room temperature for
as a colorless liquid. [α]D = –37.5 (c = 0.6, CHCl ). IR (neat): ν˜ =
3
–
1 1
3
448, 2959, 2857, 1740, 1512, 1095, 1031 cm . H NMR (500 MHz,
3
0 min and then at 80 °C for 4 h. The reaction mixture was concen-
trated, and the residue was dissolved in THF (5 mL) followed by the
addition of LiOH (4 aqueous solution, 3.9 mL). The resulting mix-
CDCl ): δ = 7.25 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.43
3
(
(
q, J = 11.5 Hz, 2 H), 4.04 (m, 1 H), 3.85 (m, 1 H), 3.80 (s, 3 H), 3.68
m, 1 H), 3.66 (s, 3 H), 3.51–3.41 (m, 2 H), 2.64 (dd, J = 15.2, 8.8 Hz,
N
ture was stirred at room temperature for 1 h. Upon completion of
the reaction (monitored by TLC), the mixture was diluted with water
and then extracted with ethyl acetate (3 × 35 mL). The combined
organic extracts were washed with water and brine (25 mL), dried
1
H), 2.48 (dd, J = 15.4, 4.8 Hz, 1 H), 1.76–1.68 (m, 2 H), 1.65–1.50
(
(
m, 4 H), 1.36 (m, 1 H), 0.89 (s, 9 H), 0.84 (d, J = 7.1 Hz, 3 H), 0.05
s, 3 H), 0.03 (s, 3 H) ppm. C NMR (100 MHz, CDCl ): δ = 172.4,
1
3
3
1
3
59.0, 130.7, 129.1, 113.6, 74.5, 72.3, 70.1, 69.7, 66.2, 55.2, 51.4, 35.1,
with anhydrous Na SO , and concentrated under reduced pressure.
4.9, 29.6, 28.5, 25.7, 23.2, 18.0, 15.5, –4.6, –5.0 ppm. HRMS (ESI):
2
4
+
The residue was purified by column chromatography on silica gel
calcd. for C H NaO Si [M + Na] 503.2799; found 503.2833.
26
44
6
(
(
(
(
MeOH/CH Cl , 1:9, containing 0.5 % of Et N) to give amine 20
2
2
3
Methyl 2-[(2R,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-{3-[(4-
methoxybenzyl)oxy]propyl}-5-methyltetrahydro-2H-pyran-2-
yl]acetate (18): To a stirred solution of methyl ester 17 (0.65 g,
2
0
270 mg, 84 %) as a colorless oil. [α] = +12.6 (c = 0.9, CHCl ). IR
D
3
–
1 1
neat): ν = 3414, 2926, 2855, 1712, 1608, 1512, 1252 cm . H NMR
500 MHz, CDCl ): δ = 7.25 (d, J = 7.9 Hz, 2 H), 6.87 (d, J = 8.6 Hz,
˜
3
1
.35 mmol) in THF (25 mL) was added tBuOK (151 mg, 1.35 mmol)
2
3
1
H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.52–3.42 (m, 3 H), 3.38 (m, 1 H),
.07–3.01 (m, 2 H), 2.62 (m, 1 H), 1.86–1.78 (m, 2 H), 1.72 (m, 1 H),
.64–1.49 (m, 3 H), 1.40 (m, 1 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.86 (s, 9
in one portion at 0 °C under nitrogen, and the resulting mixture
was stirred for 30 min. Upon completion (monitored by TLC), the
reaction was quenched by the addition of a saturated aqueous solu-
13
H), 0.05 (s, 3 H), 0.03 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ =
3
tion of NH Cl (10 mL) and then extracted with ethyl acetate (3 ×
4
1
3
H] .
59.0, 129.3, 129.2, 113.6, 83.9, 79.3, 72.4, 69.8, 65.8, 55.1, 43.7, 40.9,
2
0 mL). The combined organic extracts were washed with brine
2.6, 29.2, 26.5, 25.6, 12.6, –4.1, –4.8 ppm. MS (ESI): m/z = 438 [M +
(40 mL), dried with anhydrous Na SO , and concentrated under re-
2
4
+
duced pressure. The crude oil was purified by column chromatogra-
phy on silica gel (EtOAc/hexane, 1:9) to furnish 18 (0.6 g, 92 %) as
N-{[(2R,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-{3-[(4-
2
0
a colorless liquid. [α] = +6.6 (c = 0.7, CHCl ). IR (neat): ν˜ = 3448, methoxybenzyl)oxy]propyl}-5-methyltetrahydro-2H-pyran-2-
D
3
–
1 1
2
961, 2856, 1650, 1260, 1093, 1028 cm . H NMR (500 MHz, CDCl ): yl]methyl}acetamide (21): To a stirred solution of amine 20
3
δ = 7.25 (d, J = 9.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.41 (s, 2 H),
(220 mg, 0.50 mmol) in pyridine (5 mL) was added (CH CO) O
3 2
3
3
9
0
.80 (s, 3 H), 3.67 (s, 3 H), 3.53–3.49 (m, 2 H), 3.45 (m, 1 H), 3.41–
.37 (m, 2 H), 2.79 (dd, J = 14.8, 2.1 Hz, 1 H), 2.33 (dd, J = 15.1, completion of the reaction (monitored by TLC), the solvent was
.4 Hz, 1 H), 1.87–1.78 (m, 2 H), 1.70–1.44 (m, 4 H), 1.37 (m, 1 H),
.94 (d, J = 7.1 Hz, 3 H), 0.86 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm.
(3 mL), and the reaction mixture was warmed to 85 °C for 1 h. Upon
removed under reduced pressure. The residue was purified by col-
umn chromatography on silica gel (EtOAc/hexane, 2:3) to afford the
Eur. J. Org. Chem. 2016, 2300–2307
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2305
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
desired amide 21 (230 mg, 96 %) as a light yellow oil. [α] D2 0 = +12.6 addition of a saturated aqueous NH Cl solution (50 mL) and then
4
(
c = 1.4, CHCl ). IR (neat): ν˜ = 3316, 2955, 2930, 2856, 1656, 1254,
extracted with CH Cl (2 × 50 mL). The combined organic extracts
3
2 2
–1 1
1
6
3
3
1
0
1
3
098 cm . H NMR (500 MHz, CDCl ): δ = 7.26 (d, J = 9.3 Hz, 2 H), were washed with saturated aqueous NaHCO solution and brine
3
3
.88 (d, J = 8.3 Hz, 2 H), 5.86 (br. s, 1 H), 4.44 (s, 2 H), 3.80 (s, 3 H),
(50 mL), dried with anhydrous Na SO , and concentrated under re-
2
4
.76 (m, 1 H), 3.53 (m, 1 H), 3.49–3.42 (m, 2 H), 3.39 (m, 1 H), 3.13–
.06 (m, 2 H), 1.96 (s, 3 H), 1.89–1.80 (m, 2 H), 1.69 (m, 1 H), 1.64–
.51 (m, 3 H), 1.39 (m, 1 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.88 (s, 9 H),
duced pressure. The residue was purified by column chromatogra-
phy on silica gel (EtOAc/hexane, 1:4) to give bromide 24 (2.76 g,
86 %) as a colorless liquid. IR (neat): ν˜ = 3419, 2982, 2929, 1717,
1
3
–1 1
.07 (s, 3 H), 0.05 (s, 3 H) ppm. C NMR (125 MHz, CDCl ): δ = 169.8,
1646, 1376, 1225 cm . H NMR (500 MHz, CDCl ): δ = 5.91 (s, 1 H),
3
3
59.1, 130.4, 129.2, 113.7, 81.1, 79.5, 72.5, 69.7, 65.6, 55.2, 41.4, 40.8,
4.66 (q, J = 6.7 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 2.27 (d, J = 1.2 Hz,
1
3
2.5, 29.2, 26.5, 25.7, 23.2, 17.8, 12.6, –4.1, –4.8 ppm. HRMS (ESI):
3 H), 1.80 (d, J = 6.7 Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3 H) ppm. C NMR
+
calcd. for C H NO Si [M + H] 480.3140; found 480.3184.
(125 MHz, CDCl ): δ = 166.0, 156.6, 116.6, 59.9, 53.2, 23.6, 14.9,
26
46
5
3
1
4.1 ppm.
N-{[(2R,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-6-(3-hydroxy-
propyl)-5-methyltetrahydro-2H-pyran-2-yl]methyl}acetamide
(
Ethyl (E)-4-(Diethoxyphosphoryl)-3-methylpent-2-enoate (4): A
22): To a stirred solution of PMB ether 21 (180 mg, 0.37 mmol) in stirred solution of bromide 24 (650 mg, 2.95 mmol) in triethyl phos-
CH Cl /pH = 7.0 buffer (0.1
at 0 °C was added DDQ (0.17 g, 0.75 mmol). The reaction mixture
was stirred at room temperature for 45 min. Upon completion
M
NaOH, 0.1
M
KH PO ) (18:1; 2.1 mL)
phite (0.45 mL, 2.65 mmol) was heated to 140 °C, and the stirring
was continued at the same temperature overnight. The reaction
mixture was cooled to room temperature and purified by column
chromatography on silica gel (EtOAc/hexane, 2:1) to give phosphon-
ate ester 4 (760 mg, 93 %) as a colorless liquid. IR (neat): ν˜ = 3455,
2
2
2
4
(monitored by TLC), the reaction was quenched by the addition of
a saturated aqueous NaHCO solution. The layers were separated,
and the aqueous layer was extracted with CH Cl (3 × 30 mL). The
3
–
1 1
2983, 2937, 1715, 1643, 1278, 1024 cm . H NMR (500 MHz, CDCl ):
3
2
2
combined organic extracts were washed with brine (15 mL), dried
with anhydrous Na SO , and concentrated under reduced pressure.
δ = 5.82 (d, J = 4.2 Hz, 1 H), 4.20–4.05 (m, 6 H), 2.71 (dq, J = 24.0,
1
3
7.3 Hz, 1 H), 2.28 (d, J = 2.8 Hz, 3 H), 1.43–1.25 (m, 12 H) ppm.
C
2
4
The residue was purified by column chromatography on silica gel NMR (125 MHz, CDCl
): δ = 166.2, 155.5, 155.4, 118.7, 118.6, 62.3,
3
(
EtOAc/hexane, 1:4) to give alcohol 22 (110 mg, 85 %) as a viscous 62.2, 62.1, 62.1, 59.6, 42.8, 41.8, 18.2, 16.4, 16.3, 14.2, 13.7, 13.6 ppm.
2
0
+
oil. [α]D = +16.2 (c = 2.0, CHCl ). IR (neat): ν˜ = 3406, 2960, 1653, HRMS (ESI): calcd. for C12
H23NaO P [M + Na] 301.1175; found
5
3
–
1 1
1
560, 1379, 1260, 1097 cm . H NMR (500 MHz, CDCl ): δ = 6.02
301.1210.
3
(
br. s, 1 H), 3.83 (m, 1 H), 3.69–3.64 (m, 2 H), 3.54 (m, 1 H), 3.44 (m,
Ethyl (2E,4E)-7-{(2S,3S,5S,6R)-6-(Acetamidomethyl)-5-[(tert-
butyldimethylsilyl)oxy]-3-methyl-tetrahydro-2H-pyran-2-yl}-
1
1
0
H), 3.17 (dt, J = 8.2, 3.0 Hz, 1 H), 3.05 (m, 1 H), 2.34 (br. s, 1 H),
.98 (s, 3 H), 1.90–1.83 (m, 2 H), 1.69–1.54 (m, 4 H), 1.46 (m, 1 H),
.96 (d, J = 7.0 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm.
3
,4-dimethylhepta-2,4-dienoate (2): To a stirred solution of phos-
phonate 4 (20 mg, 0.071 mmol) in THF (1 mL) at –78 °C was added
NaHMDS (1.0 in THF, 0.064 mL, 0.064 mmol) dropwise. The reac-
1
3
C NMR (125 MHz, CDCl ): δ = 169.9, 81.5, 80.0, 65.5, 62.3, 41.3,
3
M
4
0.8, 33.0, 29.7, 29.1, 25.7, 23.2, 17.8, 12.6, –4.1, –4.8 ppm. HRMS
tion mixture was stirred at –78 °C for 10 min, warmed to 0 °C, and
then stirred for 50 min. The mixture was cooled to –78 °C, and a
precooled (–78 °C) solution of aldehyde 3 (23 mg, 0.064 mmol) in
THF (0.8 mL) was added dropwise. The mixture was warmed to
room temperature over 1 h and then stirred overnight. Upon com-
pletion (monitored by TLC), the reaction was quenched by the addi-
+
(ESI): calcd. for C H NNaO Si [M + Na] 382.2384; found 382.2418.
18
37
4
N-{[(2R,3S,5S,6S)-3-[(tert-Butyldimethylsilyl)oxy]-5-methyl-6-(3-
oxopropyl)tetrahydro-2H-pyran-2-yl]methyl}acetamide (3): To a
stirred solution of alcohol 22 (70 mg, 0.19 mmol) in CH Cl (10 mL)
2
2
were added DMSO (5 mL), Et N (0.14 mL, 0.97 mmol), and SO ·pyri-
3
3
tion of a saturated aqueous solution of NH Cl (10 mL) and then
dine (0.12 g, 0.76 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C for 1 h. Upon completion (monitored by TLC), the reaction
was quenched by the addition of a saturated aqueous solution of
NH Cl (10 mL) and then extracted with CH Cl (3 × 25 mL). The
combined organic extracts were washed with brine (10 mL), dried
with anhydrous Na SO , and concentrated under reduced pressure
4
extracted with ethyl acetate (3 × 15). The combined organic extracts
were washed with water and brine (25 mL), dried with anhydrous
Na SO , and concentrated under reduced pressure. The residue was
2
4
4
2
2
purified by column chromatography on silica gel (EtOAc/hexanes,
2
0
1
0
1
5
3
:1) to give ester 2 (28 mg, 82 %) as a colorless oil. [α] = +1.2 (c =
D
2
4
.8, CHCl ). IR (neat): ν˜ = 3439, 2985, 2930, 2854, 1724, 1646,
to give the crude aldehyde 3 (76 mg), which was used in next step
without further purification.
3
1 1
–
027 cm . H NMR (500 MHz, CDCl ): δ = 5.90 (t, J = 7.3 Hz, 1 H),
3
.84 (s, 1 H), 5.79 (br. s, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 3.74 (m, 1 H),
.55 (m, 1 H), 3.39 (m, 1 H), 3.18–3.07 (m, 2 H), 2.31 (s, 3 H), 2.24 (q,
Ethyl (E)-4-Bromo-3-methylpent-2-enoate (24): A stirred solution
of 3-hydroxy-2-butanone (23) (1.5 g, 17.04 mmol) and Ph P=
CHCO Et (7.1 g, 20.45 mmol) in toluene (15 mL) was heated at reflux
overnight. Upon completion of the reaction (monitored by TLC),
the solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel (EtOAc/hexane,
3
J = 7.4 Hz, 2 H), 1.97 (s, 3 H), 1.90–1.85 (m, 2 H), 1.82 (s, 3 H), 1.69–
2
1.58 (m, 2 H), 1.40 (m, 1 H), 1.29 (t, J = 7.0 Hz, 3 H), 0.95 (d, J =
13
7
.1 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H) ppm. C NMR
(
125 MHz, CDCl ): δ = 169.7, 167.4, 155.9, 136.6, 132.3, 114.7, 81.2,
3
7
1
8.9, 65.6, 59.6, 41.4, 40.8, 32.6, 32.1, 25.7, 25.5, 23.2, 17.9, 15.3, 14.3,
4.0, 12.7, –4.1, –4.7 ppm. HRMS (ESI): calcd. for C H NNaO Si [M
3
:2) to give the desired ester (2.5 g, 93 %) as yellow liquid. IR (neat):
26
47
5
–
1 1
ν = 3435, 2981, 1706, 1653, 1373, 1222, 1160 cm . H NMR
+
˜
+ Na] 504.3116; found 504.3146.
(
500 MHz, CDCl ): δ = 5.95 (d, J = 1.3 Hz, 1 H), 4.26 (q, J = 6.2 Hz,
3
Supporting Information (see footnote on the first page of this
1
1
1
H), 4.16 (q, J = 6.9 Hz, 2 H), 2.12 (s, 3 H), 1.32 (d, J = 6.6 Hz, 3 H),
1
13
1
3
article): Copies of the H and C NMR spectra for all new com-
pounds.
.28 (t, J = 7.1 Hz, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 167.0,
3
61.3, 113.8, 72.2, 59.7, 21.5, 14.8, 14.1 ppm. MS (EI): m/z = 159 [M
+
+
H] . To a stirred solution of the hydroxyl ester (2.3 g, 14.55 mmol)
in CH Cl (45 mL) at 0 °C were added imidazole (1.48 g, 21.83 mmol)
2
2
Acknowledgments
and PPh (6.9 g, 26.2 mmol) followed by CBr (7.2 g, 21.83 mmol).
3
4
The reaction mixture was stirred at room temperature for 1 h. Upon The authors thank the Council of Scientific and Industrial Re-
completion (monitored by TLC), the reaction was quenched by the search (CSIR), New Delhi for the financial support as part of XII
Eur. J. Org. Chem. 2016, 2300–2307
www.eurjoc.org
2306
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
f) D. K. Mohapatra, S. Maity, T. S. Rao, J. S. Yadav, B. Sridhar, Eur. J. Org.
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Five Year Plan Programme under title ORIGIN (CSC-0108).
D. K. M. thanks CSIR for a research grant [India National Science
Academy (INSA) Young Scientist Award Scheme]. S. B., S. M.,
and S. K. R. thank CSIR for the financial assistance in the form
of a research fellowship.
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Keywords: Natural products · Aldol reactions · Chiral
auxiliaries · Iodocyclization · Olefination
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Received: February 9, 2016
Published Online: April 4, 2016
Eur. J. Org. Chem. 2016, 2300–2307
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2307
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim