A unified strategy for the synthesis of the C1-C14 fragment of marinolic acids, mupirocins, pseudomonic acids and thiomarinols: Total synthesis of pseudomonic acid methyl monate C

Article abstract of DOI:10.1039/c4ob00025k

A flexible stereoselective approach to the common C1-C14 skeleton present in natural products of the pseudomonic acid family is described. The strategy has been extended and the total synthesis of pseudomonic acid methyl monate C was achieved. The key synthetic reactions utilized include Achmatowicz rearrangement, Johnson-Claisen rearrangement, Julia-Kocienski olefination, and Horner-Wadsworth-Emmons olefination reaction. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00025k

Organic &
Biomolecular Chemistry
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PAPER
A unified strategy for the synthesis of the C1–C14
fragment of marinolic acids, mupirocins,
pseudomonic acids and thiomarinols: total
synthesis of pseudomonic acid methyl monate C†‡
Cite this: Org. Biomol. Chem., 2014,
12, 2950
Y. Sridhar and P. Srihari*
A flexible stereoselective approach to the common C1–C14 skeleton present in natural products of the
pseudomonic acid family is described. The strategy has been extended and the total synthesis of pseudo-
monic acid methyl monate C was achieved. The key synthetic reactions utilized include Achmatowicz
rearrangement, Johnson–Claisen rearrangement, Julia–Kocienski olefination, and Horner–Wadsworth–
Emmons olefination reaction.
Received 4th January 2014,
Accepted 27th February 2014
DOI: 10.1039/c4ob00025k
www.rsc.org/obc
Introduction
Pseudomonic acids isolated from the bacterium Pseudomonas
fluorescens NCIB 10586 species1 are strong inhibitors of Gram
positive bacteria and mycoplasmal pathogens. Mupirocin, a
mixture of pseudomonic acids comprised of 90% of pseudo-
monic acid A along with other pseudomonic acids B–D is used
as a clinical agent for bacterial skin infections. Mupirocin W
and H belong to another class of antibiotics isolated from
Pseudomonas fluorescens showing similar bioactivity to pseudo-
monic acids.2 A series of natural hybrids of pseudomonic
acids namely thiomarinols (TMs) were recently isolated from
marine bacterium Pseudoalteromonas sp. SANK 733903 and
found to display potent activity particularly against Staphylo-
coccus aureus including methicillin-resistant S. aureus (MRSA)
(MIC < 0.01 μg mL−1). Very recently another class of thiomari-
nols isolated from the same species Pseudoalteromonas SANK
73390 namely marinolic acids3d were found to be active
against Bacillus subtilis and MRSA. Structurally, all these
molecules bear a similar C1–C14 carbon frame (Fig. 1). The
structural architecture of pseudomonic acids along with the
impressive biological properties have stimulated many syn-
thetic groups and culminated in the synthesis of individual
members of this class.4 Our interest in the expedient synthesis
of 2,6-disubstituted di/tetra-hydropyran containing natural
products by elaborating the Achmatowicz rearrangement,5
Fig. 1 Structures of pseudomonic acids, thiomarinols, marinolic acids
and mupirocins.
prompted us to target pseudomonic acids for total synthesis.
Since all the pseudomonic acids have a similar C1–C14 carbon
frame (Fig. 1) with/without tetrahydropyran ring, our intention
was to construct this frame as the key intermediate involving a
common synthetic route which can be further elaborated for
the total synthesis of related natural products. Herein, we dis-
close the stereoselective synthesis of a common and advanced
precursor for the pseudomonic acid family of natural products
and its utility for the total synthesis of pseudomonic acid
methyl monate C 1.
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India. E-mail: srihari@iict.res.in;
We designed our strategy based on a diversity oriented
approach and anticipated that pseudomonic acids bearing a
similar C1–C14 framework (showed in red Fig. 1) can be syn-
thesized from a common intermediate 2 by further chemical
manipulations (Scheme 1). Intermediate 2 can be synthesized
Fax: (+)91 4027160512; Tel: (+)91 4027191815
†Dedicated to Dr. S. Chandrasekhar, CSIR-IICT on his 50th birthday.
‡Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra of new compounds. See DOI: 10.1039/c4ob00025k
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Scheme 2 Synthesis of 5. Reagents and conditions: (a) imidazole,
TBDMSCl, CH2Cl2, rt, 90%; (b) NBS, NaOAc·3H2O, NaHCO3, THF–H2O
(4 : 1), 0 °C, 5 min, 95%; (c) pyridine, Ac2O, CH2Cl2, 0 °C, 1 h, 90%; (d)
Et3SiH, BF3–OEt2, CH2Cl2, −78 °C, 1 h, 80%; (e) DIBAL-H, THF, −78 °C,
5 min, 95%, dr for 5 : 13 = 5 : 1.
Scheme 1 Retrosynthetic analysis of pseudomonic acids, thiomarinols
and mupirocins.
by coupling aldehyde 3 and sulfone 4 by means of an olefina-
tion reaction. Aldehyde 3 can be synthesized from allyl alcohol
5 utilizing a Johnson–Claisen rearrangement and syn dihydroxy-
lation. Allyl alcohol 5 can be prepared from chiral furyl alcohol
6 by means of an Achmatowicz rearrangement and further
functional group modifications of the derived pyranone-acetal.
The sulfone side arm 4 can be obtained from alcohol 7 which
in turn can be synthesized from propionoyl sultam 8 by an
aldol protocol.
Scheme 3 Reagents and conditions: (a) trimethyl orthoacetate, propio-
nic acid, 140 °C, 16 h, 90%; (b) (i) OsO4, NMO, acetone–H2O (1 : 1), rt,
24 h, 85%; (ii) 2,2-dimethoxypropane, pTsOH, EtOAc, 0 °C, 30 min, 95%;
(c) (i) LiAlH4, THF, 0 °C, 5 min, 96%, (ii) Dess–Martin periodinane, CH2Cl2,
rt, 2 h, 95%.
pTsOH to yield the corresponding isopropylidene derivative
15. A two-step process was required to transform ester func-
tionality in 15 to aldehyde 3, as the controlled reduction with
DIBAL-H resulted in a complex mixture. Treatment of ester 15
with LiAlH4 followed by oxidation with Dess–Martin periodi-
nane afforded aldehyde 3 in good yield.
The sulfone fragment 4 was synthesized by adoption of
Oppolzer’s aldol protocol10 wherein the propionoyl sultam 8
was converted to TBS enolate and was added to a mixture of
acetaldehyde and TiCl4 at −78 °C to afford aldol adduct 16
with 59% yield [98%, based on recovered starting material
(brsm)] (Scheme 4). Alcohol 16 was protected as the corres-
ponding MOM ether 17 and the sultam auxiliary was cleaved
with LiAlH4 to afford the alcohol 7. Under Mitsunobu con-
ditions, alcohol 7 was converted to sulfide, which upon oxi-
dation with H2O2 in presence of ammonium molybdate
afforded the required sulfone fragment 4.
Results and discussion
Our initial focus was towards the construction of the allyl
alcohol 5 in sufficient amounts for which we relied on Achma-
towicz oxidative rearrangement of furfuryl alcohol 9. Accord-
ingly, the diol 6 synthesized by following earlier known
methods6 was mono protected as the TBS ether to obtain the
secondary furfuryl alcohol 9. Under standard Achmatowicz
conditions,7 9 cleanly underwent the rearrangement to reveal
the acetal 10, which was further transformed to the corres-
ponding acetate 11. Anomeric acetate displacement was
achieved by hydride addition to the cyclic oxocarbenium ion
by exposure of 11 to BF3·OEt2 in presence of triethylsilane at
−78 °C to yield enone 12. Substrate controlled 1,2-syn
reduction of enone 12 was achieved with DIBAL-H in 95%
yield with 5 : 1 diastereoselectivity providing allyl alcohols 5
and 13 that were easily separable by silica gel column chrom-
atography (Scheme 2).8
Julia–Kocienski coupling11 of the two fragments 3 and 4
was optimized after screening several conditions by varying
base, temperature, stoichiometries and additives (solvating
agents) (see ESI‡). Finally, sulfone 4 was treated with two
equivalents of KHMDS and then with aldehyde 3 at −78 °C to
afford the coupled product 18 (Scheme 5) in 72% yield. The
geometry of the newly formed olefin was confirmed as the
Allyl alcohol 5 was subjected to Johnson–Claisen rearrange-
ment9 with trimethyl orthoacetate to afford the ester 14
(Scheme 3). Substrate controlled dihydroxylation4d of dihydro-
pyran 14 with OsO4 afforded β syn diol as a single diastereomer
which was masked with 2,2-dimethoxy propane in presence of
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Scheme 4 Reagents and conditions: (a) Et3N, TBSOTf, CH2Cl2, rt, 24 h;
(b) CH3CHO, TiCl4, CH2Cl2, −78 °C, 5 min, 59%, 98% (brsm); (c) MOMCl,
DIPEA, DMAP, CH2Cl2, 16 h, 96%; (d) LiAlH4, THF, 0 °C, 5 min, 90%; (e) (i)
PPh3, DIAD, 1-phenyl-1H-tetrazole-5-thiol, THF, 0 °C, 30 min, 90%; (ii)
(NH4)6Mo7O24·4H2O, H2O2, EtOH, rt, 6 h, 85%.
Scheme 6 Reagents and conditions: (a) (i) 2,6-lutidine, Tf2O, CH2Cl2,
−78 °C, 5 min; (ii) LDA, TMS-acetylene, HMPA, THF −78 °C–rt, 2 h; (iii)
K2CO3, MeOH, rt, 2 h, 76% from 2; (b) Hg(OAc)2, PPTS, THF, pH = 7
buffer, 50 °C, 30 min, 88%; (c) methyl diethylphosphanoacetate,
KHMDS, then ketone 24, rt, 16 h, 80%; (f) 2 N HCl, THF, rt, 2 h, 90%.
olefination4b with methyl diethylphosphanoacetate gave
α,β-unsaturated ester 23, the precursor for methyl monate
C. Finally, deprotection of acid sensitive groups (MOM and
acetonide) in 23 with aq. HCl afforded pseudomonic acid
methyl monate C 1. The analytical data of this synthetic com-
pound was found to be in good agreement with the data
reported earlier.4e
Intermediate 23 has a unique C1–C14 pseudomonic acid
family carbon skeleton with appropriate chirality and func-
tional groups for further manipulations towards other related
natural products: pseudomonic acids, marinolic acids and
thiomarinols. In addition, the retro oxy-Michael intermediate
21 forms a promising intermediate for the synthesis of
mupirocins.
Scheme 5 Reagents and conditions: (a) KHMDS, then 3, −78 °C, THF,
3 h, 72%; (b) TBAF, THF, rt, 6 h, 90%; (c) (i) Et3N, MsCl, CH2Cl2, 0 °C,
5 min; (ii) NaCN, 18-crown-6, DMSO, 90 °C, 1 h, 86% from 2; (d) MeLi,
Et2O, 0 °C, 1 h.
Conclusion
In conclusion, we have established a stereoselective strategy
for the synthesis of the advanced key intermediates 23 and 21
which can be used for the synthesis of thiomarinols and
mupirocins. The strategy has been successfully applied to the
total synthesis of pseudomonic acid methyl monate C (in 18
longest linear steps with an overall yield of 10.1% from known
diol 6). Functional group manipulations of 2/21/23 for further
elaboration towards the synthesis of thiomarinols and mupiro-
cins are currently being investigated.
E diastereomer (based on coupling constants 15.4 Hz and
15.3 Hz in 1H NMR) after cleavage of the silyl ether.
Having the required central tetrahydropyran nucleus along
with the side arm with required stereochemistry, we focussed
further on one carbon homologated ketone formation.
Towards this, we initially adopted the nitrile path, wherein the
alcohol 2 was converted to nitrile 19 in a two step process and
was then treated with MeLi to obtain the required ketone 20.
However, coincidentally when the nitrile was treated with
MeLi, a retro oxy-Michael product 21 was always formed predo-
minantly along with the desired ketone 20 in minor amounts.
To get better yields of the ketone, we chose an alternate
strategy i.e., an alkyne hydration sequence.12 Accordingly, the
alcohol 2 was converted to the corresponding triflate and then
coupled with trimethylsilyl acetylene and subjected to desilyla-
tion with K2CO3 to afford alkyne 22. Alkyne 22 was subjected
to Hg2+ catalyzed hydration to afford ketone 20 in 88% yield
(Scheme 6). Ketone 20 upon Horner–Wadsworth–Emmons
Experimental section
General methods
1H NMR and 13C NMR spectra were recorded in CDCl3 as
solvent on a 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 a scale downfield from
TMS as internal standard and signal patterns are indicated as
follows: s = singlet, d = doublet, t = triplet, q = quartet, sext =
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sextet, m = multiplet, br = broad. FTIR spectra were recorded 2858, 1700, 1466, 1367, 1124, 1030, 835, 779 cm−1; Major
on KBr pellets and reported in wave number (cm−1). Optical anomer: 1H NMR (CDCl3, 500 MHz) δ 6.94 (dd, J = 10.4, 3.1 Hz,
rotations were measured on a digital polarimeter using a 1 mL 1H), 6.16 (d, J = 10.5 Hz, 1H), 5.49–5.43 (m, 1H), 4.38 (t, J =
cell with a 1 dm path length. For low (MS) and high (HRMS) 2.1 Hz, 1H), 4.06 (dd, J = 11.1, 2.4 Hz, 1H), 4.04 (d, J = 3.7 Hz,
resolution, m/z ratios are reported as values in atomic mass 1H), 3.91 (dd, J = 11.1, 2.0 Hz, 1H), 0.85 (s, 9H), 0.07 (s, 3H),
units. Mass analysis was done in ESI mode. All reagents were 0.02 (s, 3H) ppm. Minor anomer δ 6.92 (dd, J = 10.2, 3.1 Hz,
reagent grade and used without further purification unless 1H), 6.14 (d, J = 10.7 Hz, 1H), 4.56 (t, J = 3.7 Hz, 1H) ppm;
specified otherwise. Solvents for reactions were distilled prior Major anomer: 13C NMR (CDCl3, 75 MHz) δ 194.7, 147.0,
to use: THF, and diethyl ether were distilled from Na and 127.2, 86.8, 79.6, 65.4, 25.5, 18.1, −5.9 ppm; Minor anomer
benzophenone ketyl; CH2Cl2 from CaH2. All air- or moisture- δ 145.7, 127.8, 87.8, 76.4, 63.2, 25.7, −5.5 ppm; HRMS (ESI) for
sensitive reactions were conducted under a nitrogen or argon C12H22O4SiNa [M + Na]+ found 281.11714, calcd 281.11796.
atmosphere in flame-dried or oven-dried glassware with mag-
(6S)-6-(((tert-Butyldimethylsilyl)oxy)methyl)-5-oxo-5,6-dihydro-
2H-pyran-2-yl acetate (11)
netic 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 To
chromatography were distilled prior to use.
a magnetically stirred solution of lactol 10 (3.0 g,
11.6 mmol) in CH2Cl2 (30 mL) pyridine (1.87 mL, 23.25 mmol)
was added at 0 °C followed by Ac2O (1.3 mL, 12.8 mmol) at the
same temperature. Within 1 h all the lactol was consumed and
(S)-2-((tert-Butyldimethylsilyl)oxy)-1-(furan-2-yl)ethanol (9)
To a magnetically stirred solution of diol 6 (4.00 g, 31.3 mmol) the reaction was then neutralized with 0.5 N HCl (51 mL) at
in CH2Cl2 (100 mL), imidazole (4.25 g, 62.5 mmol) was added 0 °C and extracted with CH2Cl2 (2 × 20 mL). The organic layer
at 0 °C temperature. After 5 min TBDMSCl (4.94 g, 32.8 mmol) was washed with water (30 mL) followed by sat. aq. NaHCO3
was added at the same temperature. Stirring was continued at (20 mL) and dried over anhydrous Na2SO4. Evaporation of
rt until complete consumption of starting material occurred CH2Cl2 in vacuo gave the crude product, which in turn was puri-
(monitored by TLC, ca. 16 h). The reaction mixture was diluted fied by column chromatography (hexane–EtOAc, 9 : 1) to give
with water (100 mL), the organic layer was separated and the desired acetate 11 (1 : 2 mixture of α, β anomers) as a yellow
aqueous layer extracted with CH2Cl2 (2 × 20 mL). The com- viscous oil (3.14 g, 90%); Rf = 0.50 (hexane–EtOAc 7 : 3). IR
bined organic layers were washed with brine (10 mL) and dried (KBr): 2930, 2857, 1757, 1701, 1467, 1217, 1133, 934, 836,
over anhydrous Na2SO4, filtered, and concentrated in vacuo to 778 cm−1; Major anomer: 1H NMR (CDCl3, 500 MHz) δ 6.91
give the crude product which upon column purification (dd, J = 10.3, 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 6.24 (d, J =
(hexane–EtOAc 9 : 1) gave alcohol 9 (6.80 g, 90%) as a colour- 10.3 Hz, 1H), 4.49 (dd, J = 4.3, 2.7 Hz, 1H), 4.08 (dd, J = 11.4,
less oil. Rf = 0.55 (hexane–EtOAc 7 : 3); [α]2D5 = −19.68 (c 1.20, 4.3 Hz, 1H), 4.02 (dd, J = 11.4, 2.3 Hz, 1H), 2.85 (s, 3H), 0.86 (s,
CHCl3), Lit6e [α]D22 = +20.8 (c 0.6, CHCl3) (for opposite enantio- 9H), 0.06 (s, 3H), 0.05 (s, 3H) ppm. Minor anomer: δ 6.85 (dd,
mer); IR (KBr): 3422, 2954, 2931, 2858, 1467, 1255, 119, 840, J = 10.3, 2.5 Hz, 1H), 6.58 (dd, J = 2.5, 1.1 Hz, 1H), 6.24 (dd, J =
778 cm−1 1H NMR (CDCl3, 500 MHz) δ 7.37 (dd, J = 1.5, 10.5, 1.4 Hz, 1H), 4.33 (dd, J = 6.4, 3.7 Hz, 1H), 3.96 (dd, J =
;
0.6 Hz, 1H), 6.34 (dd, J = 3.0, 2.2 Hz, 1H), 6.31 (d, J = 3.2, Hz, 11.2, 3.7 Hz, 1H), 2.14 (s, 3H) ppm; Major anomer: 13C NMR
1H), 4.77–4.74 (m, 1H), 3.90–3.82 (m, 2H), 2.85 (d, J = 4.0 Hz, (CDCl3, 75 MHz) δ 193.7, 169.4, 142.1, 129.1, 87.1, 77.9, 62.7,
1H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H) ppm; 13C NMR 25.7, 20.9, 18.2, −5.4 ppm; Minor anomer: δ 193.5, 143.0,
(CDCl3, 75 MHz) δ 153.7, 141.9, 110.1, 106.9, 68.3, 65.7, 25.8, 129.0, 87.1, 80.5, 64.0, 21.0 ppm; HRMS (ESI) for
18.2, −5.5 ppm; HRMS (ESI) for C12H22O3SiNa [M + Na]+ found C14H24O5SiNa [M + Na]+ found 323.1281, calcd 323.1285.
265.1229, calcd 265.1230.
(S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-2H-pyran-3(6H)-one
(2S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-hydroxy-2H-
pyran-3(6H)-one (10)
(12)
To a magnetically stirred solution of acetate 11 (1.5 g,
To a magnetically stirred solution of furfuryl alcohol 9 (3.00 g, 5.00 mmol) and triethylsilane (1.59 mL, 10.0 mmol) in CH2Cl2
12.4 mmol) in THF–H2O (4 : 1, 40 mL), solid NaHCO3 (2.08 g, (20 mL), BF3·OEt2 (0.18 mL, 1.25 mmol) was added at −78 °C,
24.8 mmol), NaOAc·3H2O (1.85 g, 13.6 mmol) and finally NBS stirring was continued until complete consumption of starting
(2.20 g, 12.4 mmol) were added at 0 °C temperature. Within material occurred (ca. 1 h). The reaction was quenched with
5 min all the starting material was consumed and the reaction sat. aq. NaHCO3 (10 mL) then extracted with CH2Cl2 (3 ×
was quenched with saturated aqueous NaHCO3 (20 mL) and 10 mL), washed with brine (20 mL), and dried over anhydrous
extracted with EtOAc (3 × 30 mL). The combined extracts were Na2SO4. Evaporation of CH2Cl2 in vacuo gave the crude
washed with sat. aq. Na2S2O3 (30 mL) followed by brine product, which was subjected to silica gel column chromato-
(30 mL). The organic layer was dried over anhydrous Na2SO4 graphy (hexane–EtOAc 19 : 1) to give desired enone 12 as a
and concentrated in vacuo. The residue obtained was purified light yellow oil (0.97 g, 80%). Rf = 0.60 (hexane–EtOAc 4 : 1);
by silica gel column chromatography (hexane–EtOAc 4 : 1) to [α]2D5 = +9.58 (c 0.95, CHCl3); IR (KBr): 2930, 2857, 1694, 1466,
1
give 10 (1 : 3 mixture of α, β anomers) as a yellow oil (3.04 g, 1255, 1130, 836, 777 cm−1; H NMR (CDCl3, 500 MHz) δ 7.08
95%); Rf = 0.55 (hexane–EtOAc 3 : 2); IR (KBr): 3387, 2931, (ddd, J = 18.5, 3.4, 1.8 Hz, 1H), 6.15 (dt, J = 10.4, 2.0 Hz, 1H),
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4.62 (ddd, J = 18.3, 3.6, 1.8 Hz, 1H), 4.40 (dddd, J = 18.5, 3.7, Methyl 2-((3aR,4S,7S,7aR)-4-(((tert-butyldimethylsilyl)oxy)-
2.4, 1.2 Hz, 1H), 4.11 (ddd, J = 5.3, 2.4, 1.4 Hz, 1H), 4.08 (dd, methyl)-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-
J = 11.3, 2.4 Hz, 1H), 3.99 (dd, J = 11.3, 5.3 Hz, 1H), 0.87 (s, 7-yl)acetate (15)
9H), 0.07 (s, 3H), 0.05 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz)
δ 194.7, 148.3, 126.9, 81.4, 64.0, 63.5, 25.8, 18.3, −5.5 ppm;
HRMS (ESI) for C12H23O3Si [M + H]+ found 243.14050, calcd
243.14110.
To
a magnetically stirred solution of ester 14 (2.5 g,
8.30 mmol) in acetone–H2O (1 : 1, 50 mL), N-methylmorpho-
line N-oxide (1.48 g, 12.5 mmol) followed by OsO4 (16.7 mL of
0.025 M solution in toluene, 0.416 mmol) were added at 0 °C,
stirring was continued at rt for 24 h by which time all the start-
ing material was consumed and the reaction was then
quenched with sat. aq. Na2SO3 (25 mL), and extracted with
EtOAc (4 × 20 mL), washed with brine (20 mL), and dried over
anhydrous Na2SO4. Evaporation of solvents in vacuo gave the
crude product, which was subjected to silica gel column
chromatography (hexane–EtOAc 3 : 2) to give diol 15a as a col-
(2S,3S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,6-dihydro-2H-
pyran-3-ol (5)
To a magnetically stirred solution of enone 12 (2.00 g,
8.20 mmol) in CH2Cl2 (20 mL), DIBAL-H (5.1 mL of 25% in
toluene, 9.00 mmol) was added at −78 °C temperature. Within
5 min all the enone was consumed (monitored by TLC) and
the reaction mixture was quenched with sat. aq. sodium pot-
assium tartrate (20 mL) then diluted with CH2Cl2 (20 mL) and
stirred at rt for 1 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com-
bined organic layers were washed with brine (20 mL) and dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give the crude product which upon
column purification (hexane–EtOAc 9 : 1) afforded anti alcohol
13 (319 mg, 15.8%) followed by syn alcohol 5 (1.59 g, 79.2%) as
a colourless oil. Rf = 0.55 (hexane–EtOAc 7 : 3); [α]2D5 = +135.07
(c 1.40, CHCl3) Lit.8a [α]D24 = −144.3 (c 2.84, CHCl3) for the
orless oil (2.37 g, 85%). Rf = 0.50 (hexane–EtOAc 1 : 1); [α]D25
+32.95 (c 1.2, CHCl3); IR (KBr): 3448, 2930, 2859, 1736, 1465,
1254, 1091, 836, 778 cm−1 1H NMR (CDCl3, 300 MHz)
δ 3.97–3.83 (m, 3H), 3.71–3.53 (m, 4H), 3.68 (s, 3H), 2.82 (br s,
1H), 2.58 (dd, J = 17.4, 10.5 Hz, 1H), 2.38 (dd, J = 17.3, 5.7 Hz,
1H), 2.41–2.35 (m, 1H), 1.67 (br s, 1H), 0.90 (s, 9H), 0.11 (s,
3H), 0.10 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz): δ 172.7,
74.0, 69.4, 69.2, 65.7, 64.9, 51.7, 37.2, 33.5, 25.7, 18.1, −5.6,
−5.7 ppm; HRMS (ESI) for C15H30O6SiNa [M + Na]+ found
357.17062, calcd 357.17039.
=
;
To a magnetically stirred suspension of diol 15a (2.00 g,
5.99 mmol) in EtOAc (10 mL), 2,2-dimethoxypropane (2.93 mL,
24.0 mmol), anhydrous Na2SO4 (5 g) and p-toluenesulfonic
acid (0.1 g, 0.6 mmol) were added at 0 °C. Stirring was contin-
ued until complete consumption of starting material was
observed (ca. 1 h) and then the reaction was quenched with
solid NaHCO3 (100 mg). The mixture was filtered and the fil-
trate was concentrated under reduced pressure to give the
crude product which upon column purification through a
short pad of silica gel (hexane–EtOAc 19 : 1) gave acetonide 15
(2.13 g, 95%) as a colourless oil. Rf = 0.50 (hexane–EtOAc 4 : 1);
[α]2D5 = −11.70 (c 1.00, CHCl3); IR (KBr): 2931, 2859, 1742, 1375,
opposite enantiomer; IR (KBr): cm−1
;
1H NMR (CDCl3,
500 MHz) δ 6.09–6.03 (m, 1H), 5.95 (ddd, J = 10.1, 5.0, 1.6 Hz,
1H), 4.26 (ddd, J = 16.9, 3.4, 1.7 Hz, 1H), 4.15 (ddd, J = 16.9,
4.0, 2.0 Hz, 1H), 3.97 (br s, 1H), 3.87 (dd, J = 10.6, 6.6 Hz, 1H),
3.81 (dd, J = 9.6, 5.1 Hz, 1H), 3.54 (dt, J = 6.3, 2.0 Hz, 1H), 0.90
(s, 9H), 0.10 (s, 3H), 0.09 (s, 3H) ppm; 13C NMR (CDCl3,
75 MHz) δ 130.1, 126.6, 78.2, 66.0, 62.7, 62.4, 25.8, 18.2, −5.4,
−5.5 ppm; HRMS (ESI) for C12H25O3Si [M + H]+ found
245.15611, calcd 245.15675.
Methyl 2-((3R,6R)-6-(((tert-butyldimethylsilyl)oxy)methyl)-
3,6-dihydro-2H-pyran-3-yl)acetate (14)
1252, 1220, 1061, 837, 777 cm−1; H NMR (CDCl3, 300 MHz) δ
1
4.10 (dd, J = 5.0, 1.6 Hz, 1H), 3.92 (dd, J = 8.7, 5.0 Hz, 1H), 3.82
(dd J = 11.5, 2.2 Hz, 1H), 3.80–3.76 (m, 1H), 3.70–3.62 (m, 2H),
3.69 (s, 3H), 3.34 (ddd, J = 8.7, 5.6, 2.2 Hz, 1H), 2.57 (dd, J =
13.4, 7.1 Hz, 1H), 2.53–2.47 (m, 1H), 2.42 (dd, J = 13.3, 4.6 Hz,
1H), 1.50 (s, 3H), 1.36 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H) ppm;
13C NMR (CDCl3, 75 MHz) δ 172.4, 108.9, 79.1, 75.2, 69.7, 65.9,
63.7, 51.7, 34.7, 33.7, 28.2, 26.4, 25.9, 18.4, −5.3 ppm; HRMS
(ESI) for C18H34O6SiNa [M + Na]+ found 397.20175, calcd
397.20169.
To a magnetically stirred solution of alcohol 5 (4.00 g,
16.4 mmol) in trimethyl orthoacetate (10 mL), propionic acid
(0.12 mL, 1.64 mmol) was added at rt and the reaction mixture
was heated up to 140 °C while continuing the stirring until
complete consumption of starting material occurred (ca. 6 h).
The reaction mixture was quenched by the addition of solid
NaHCO3 (100 mg) and filtered. The filtrate was concentrated
under reduced pressure to give the crude product which upon
flash column purification (hexane–EtOAc 49 : 1) gave ester 14
(4.42 g, 90%) as a colourless oil. Rf = 0.55 (hexane–EtOAc
19 : 1); [α]2D5 = +11.67 (c 0.60, CHCl3); IR (KBr): 2927, 2856,
2-((3aR,4S,7S,7aR)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-
2,2-dimethyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-7-yl)-
acetaldehyde (3)
1
1739, 1253, 1096, 838, 778 cm−1; H NMR (CDCl3, 300 MHz) δ
5.94–5.86 (m, 1H), 5.76 (d, J = 10.4 Hz, 1H), 4.16–4.08 (m, 1H),
3.78–3.69 (m, 3H), 3.68 (s, 3H), 3.55 (dd, J = 10.2, 5.7 Hz, 1H), To a magnetically stirred suspension of LiAlH4 (0.41 g,
2.57–2.38 (m, 3H), 0.90 (s, 9H), 0.07 (s, 6H) ppm; 13C NMR 10.7 mmol) in THF (20 mL) ester 15 (4.00 g, 10.7 mmol) was
(CDCl3, 75 MHz): δ 172.8, 128.7, 128.3, 75.1, 67.0, 65.7, 51.5, added at 0 °C. Within 5 min all the starting material was con-
37.3, 31.4, 25.9, 18.4, −5.4 ppm; HRMS (ESI) for C15H28O4SiNa sumed and the reaction mixture was then quenched with sat.
[M + H]+ found 323.16384, calcd 323.16491.
aq. Na2SO4 (5 mL). Silica gel (5.00 g) was added and the result-
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ing white suspension was stirred at rt for 30 min and filtered. white solid (mp = 119–120). Rf = 0.45 (hexane–EtOAc 7 : 3); [α]D25
The filtrate was concentrated under reduced pressure to give = −46.17 (c 1.2, CHCl3); IR (KBr): 3526, 2959, 1698, 1683, 1307,
the crude product which upon column purification through a 1216, 1062 cm−1; 1H NMR (CDCl3, 300 MHz) δ 3.90 (dd, J = 7.6,
short pad of silica gel (hexane–EtOAc 4 : 1) gave alcohol 3a 5.1 Hz, 1H), 3.88–3.79 (m, 1H), 3.54 (d, J = 13.9 Hz, 1H), 3.45
(3.55 g, 96%) as a colourless oil. Rf = 0.50 (hexane–EtOAc 3 : 2); (d, J = 13.9 Hz, 1H), 3.16–3.07 (m, 1H), 2.40–2.24 (m, 1H),
[α]2D5 = +18.40 (c 0.80, CHCl3); IR (KBr): 3447, 2930, 2859, 1382, 2.22–2.03 (m, 2H), 1.98–1.81 (m, 2H), 1.47–1.32 (m, 2H), 1.25
1251, 1058, 836, 776 cm−1 1H NMR (CDCl3, 300 MHz) (d, J = 6.2 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.18 (s, 3H), 0.97 (s,
;
δ 4.14–4.11 (m, 1H), 4.02 (dd, J = 8.1, 5.5 Hz, 1H), 3.85 (dd, J = 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 175.1, 71.5, 65.3,
11.3, 2.3 Hz, 1H), 3.78–3.66 (m, 5H), 3.48 (ddd J = 7.7, 5.1, 53.1, 48.2, 47.6, 46.9, 44.6, 38.4, 32.8, 26.3, 21.8, 20.7, 19.8,
2.3 Hz, 1H), 2.35 (br s, 1H), 2.19–2.11 (m, 1H), 1.82–1.63 (m, 14.0 ppm; HRMS (ESI) for C15H26O4NS [M + H]+ found
2H), 1.50 (s, 3H), 1.37 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H) ppm; 316.15682, calcd 316.15771.
13C NMR (CDCl3, 75 MHz) δ 108.4, 78.3, 76.3, 70.3, 66.1, 63.8,
(2S,3S)-1-((6R,7aR)-8,8-Dimethyl-2,2-dioxidohexahydro-
1H-3a,6-methanobenzo[c]isothiazol-1-yl)-3-(methoxymethoxy)-
2-methylbutan-1-one (17)
60.2, 34.4, 33.8, 28.1, 26.2, 25.9, 18.4, −5.4 ppm; HRMS (ESI)
for C17H34O5SiNa [M + Na]+ found 369.20703, calcd 369.20677.
To a magnetically stirred solution of alcohol 3a (1.00 g,
2.90 mmol) in CH2Cl2 (20 mL), Dess–Martin periodinane To a stirred solution of alcohol 16 (4.00 g, 12.70 mmol) in
(1.46 g, 3.48 mmol) was added at 0 °C temperature. Stirring CH2Cl2 (40 mL), MOMCl (4.06 mL of 50% solution in MeOAc,
was continued until complete consumption of starting 25.4 mmol) followed by N,N-diisopropylethylamine (4.4 mL,
material was observed (ca. 2 h). The reaction mixture was fil- 25.4 mmol) were added at 0 °C. Stirring was continued for
tered through a pad of celite and the filtrate was washed with 16 h by which time all the starting material was consumed.
sat. aq. NaHCO3 (20 mL), dried over anhydrous Na2SO4, fil- Sat. aq. NH4Cl (10 mL) was added and the reaction was further
tered, and concentrated under reduced pressure to give the diluted with water (30 mL). The organic layer was separated
crude product which upon column purification (hexane–EtOAc and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL).
9 : 1) gave aldehyde 3 (0.94 g, 95%) as a colourless oil. Rf = 0.55 The combined organic layer was washed with brine (20 mL)
(hexane–EtOAc 5 : 1); [α]2D5 = −24.50 (c 0.90, CHCl3); IR (KBr): and dried over anhydrous Na2SO4, filtered, and concentrated
2930, 2858, 1727, 1375, 1253, 1060 cm−1 1H NMR (CDCl3, under reduced pressure to give the crude product which upon
;
300 MHz) δ 9.81 (t, J = 1.3 Hz, 1H), 4.06 (dd, J = 5.2, 2.5 Hz, column purification (hexane–EtOAc 9 : 1) gave MOM ether 17
1H), 3.93 (dd, J = 8.7, 5.1 Hz, 1H), 3.81 (td, J = 11.4, 2.2 Hz, (4.38 g, 96%) as a white solid (mp = 110–111). Rf = 0.65
2H), 3.66 (dd, J = 11.6, 5.3 Hz, 1H), 3.63 (ddd, J = 11.9, 2.3, (hexane–EtOAc 7 : 3); [α]2D5 = −31.64 (c 1.1, CHCl3); IR (KBr):
0.8 Hz, 1H), 3.35 (ddd, J = 8.6, 5.3, 2.2 Hz, 1H), 2.75 (ddd, J = 2989, 2960, 1684, 1460, 1334, 1233, 1133, 1035, 539 cm−1
;
16.4, 6.9, 1.0 Hz, 1H), 2.66–2.59 (m, 1H), 2.42 (dd, J = 16.5, 1H NMR (CDCl3, 300 MHz) δ 4.62 (d, J = 6.8 Hz, 1H), 4.58 (d,
5.7 Hz, 1H), 1.50 (s, 3H), 1.35 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H) J = 6.8 Hz, 1H), 3.97–3.87 (m, 2H), 3.51 (d, J = 13.8 Hz, 1H),
ppm; 13C NMR (CDCl3, 75 MHz) δ 200.2, 108.9, 79.0, 75.3, 3.42 (d, J = 13.8 Hz, 1H), 3.33 (s, 3H), 3.27–3.18 (m, 1H),
69.7, 65.9, 63.6, 44.5, 31.4, 28.2, 26.3, 25.9, 18.4, −5.3 ppm; 2.10–1.97 (m, 2H), 1.95–1.80 (m, 3H), 1.44–1.28 (m, 2H), 1.21
HRMS (ESI) for C17H32O5SiNa [M + Na]+ found 367.19162, (d, J = 6.3 Hz, 3H), 1.19 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.18 (s,
calcd 367.19112.
3H), 0.97 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 174.4, 95.2,
75.9, 65.0, 55.5, 53.0, 48.1, 47.6, 46.1, 44.6, 38.4, 32.7, 26.3,
20.6, 19.8, 17.2, 12.8 ppm; HRMS (ESI) for C17H29O5NSNa
[M + Na]+ found 382.16627, calcd 382.16586.
(2S,3S)-1-((6R,7aR)-8,8-Dimethyl-2,2-dioxidohexahydro-
1H-3a,6-methanobenzo[c]isothiazol-1-yl)-3-hydroxy-
2-methylbutan-1-one (16)
(2R,3S)-3-(Methoxymethoxy)-2-methylbutan-1-ol (7)
To a magnetically stirred solution of propionate 8 (5.00 g,
18.5 mmol) in CH2Cl2 (40 mL), triethylamine (2.82 mL, To a magnetically stirred suspension of LiAlH4 (0.42 g,
20.3 mmol) followed by tert-butyldimethylsilyl-O-triflate 11.1 mmol) in THF (20 mL) amide 17 (2.00 g, 5.57 mmol) was
(4.66 mL, 20.3 mL) were added at room temperature. Stirring added at 0 °C. Within 5 min all the starting material was con-
was continued for 24 h and then the resulting solution was sumed and the reaction was quenched with sat. aq. Na2SO4
added to a solution of acetaldehyde (1.14 mL, 20.3 mmol) and (5 mL) and then silica gel (5.00 g) was added and the resulting
TiCl4 (2.23 mL, 20.3 mmol) in CH2Cl2 (30 mL) at −78 °C. After white suspension was further stirred at room temperature
5 min the reaction was quenched with sat. aq. NH4Cl (20 mL), for 30 min and filtered. The filtrate was concentrated under
diluted with water (50 mL) and stirred at room temperature for reduced pressure to give the crude product which upon
15 min. The organic layer was separated and the aqueous layer column purification through a short pad of silica gel (hexane–
was extracted with CH2Cl2 (2 × 20 mL) and the combined EtOAc 9 : 1 to 5 : 1) gave free sultam auxiliary (1.17 g, 98%) and
organic layers were washed with brine (20 mL) and dried over alcohol 7 (0.74 g, 90%) as a colourless oil. Data for 7: Rf = 0.30
anhydrous Na2SO4, filtered, and concentrated under reduced (hexane–EtOAc 7 : 3); [α]2D5 = +58.4 (c 0.55, CHCl3); IR (KBr):
1
pressure to give the crude product which upon column purifi- 3446, 2931, 1036 cm−1; H NMR (CDCl3, 500 MHz) δ 4.74 (d,
cation (hexane–EtOAc 5 : 1) gave unreacted propionate
8
J = 6.9 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 3.72 (dd, J = 11.0,
(2.00 g) and finally alcohol 16 (3.42 g, 59%, (98% brsm)) as a 3.7 Hz, 1H), 3.69–3.63 (m, 1H), 3.57 (dd, J = 11.1, 6.1 Hz, 1H),
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3.41 (s, 3H), 1.78–1.70 (m, 1H), 1.21 (d, J = 6.1 Hz, 3H), 0.95 starting material. Solvents were removed under reduced
(d, J = 7.0 Hz, 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 94.9, 77.0, pressure to give the crude product which upon column purifi-
65.7, 55.5, 40.9, 17.6, 13.5 ppm; HRMS (ESI) for C7H16O3Na cation (hexane–EtOAc 19 : 1) gave alkene 18 (0.97 g, 72%) as a
[M + Na]+ found 171.0991, calcd 171.0992.
colourless oil. Rf = 0.55 (hexane–EtOAc 9 : 1); [α]2D5 = −7.1 (c 1.4,
CHCl3); IR (KBr): 2929, 2858, 1459, 1375, 1250, 1041, 836,
5-(((2S,3S)-3-(Methoxymethoxy)-2-methylbutyl)sulfonyl)-
1-phenyl-1H-tetrazole (4)
1
cm−1; H NMR (CDCl3, 300 MHz) δ 5.50–5.37 (m, 2H), 4.67 (d,
J = 7.0 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 4.13 (dd, J = 4.7,
To a magnetically stirred solution of alcohol 7 (0.50 g, 2.1 Hz, 1H), 3.90 (dd, J = 8.9, 5.1 Hz, 1H), 3.82 (dd, J = 11.5,
3.38 mmol) in THF (20 mL), PPh3 (1.33 g, 5.07 mmol), 1.9 Hz, 1H), 3.73–3.55 (m, 4H), 3.36 (s, 3H), 3.33–3.28 (m, 1H),
1-phenyl-1H-tetrazole-5-thiol (0.90 g, 5.07 mmol) and finally 2.35–2.09 (m, 3H), 2.00–1.91 (m, 1H), 1.49 (s, 3H), 1.35 (s, 3H),
diisopropyl azodicarboxylate (1.02 mL, 5.07 mmol) were added 1.09 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H),
at 0 °C. Within 30 min all the starting material was consumed. 0.07 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz) δ 135.0, 127.8,
THF was evaporated under reduced pressure and the crude 108.5, 95.1, 79.1, 76.5, 75.4, 69.8, 65.8, 63.8, 55.3, 42.1, 36.8,
mass was purified by silica gel column chromatography 33.7, 28.3, 26.3, 25.9, 18.4, 16.9, 15.7, −5.3 ppm; HRMS
(hexane–EtOAc 19 : 1) to give the sulfide 4a (0.94 g, 90%) as (ESI) for C24H46O6SiNa [M + Na]+ found 481.29590, calcd
a colourless oil. Rf = 0.55 (hexane–EtOAc 5 : 1); [α]2D5 = +26.91 481.29559.
(c 0.55, CHCl3); IR (KBr): 2930, 1633, 1597, 1498, 1385, 1097,
((3aR,4S,7S,7aR)-7-((4R,5S,E)-5-(Methoxymethoxy)-
1036 cm−1 1H NMR (CDCl3, 300 MHz) δ 7.60–7.51 (m, 5H),
;
4.70 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 3.71–3.63 (m,
2H), 3.37 (s, 3H), 3.31 (dd, J = 12.7, 8.1 Hz, 1H), 2.14–2.03 (m,
4-methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-4-yl)methanol (2)
1H), 1.21 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.9 Hz, 3H) ppm; TBAF (2.62 mL of 1 M solution in THF, 2.62 mmol) was added
13C NMR (CDCl3, 75 MHz) δ 154.6, 133.7, 130.0, 129.7, 123.8, dropwise to a magnetically stirred solution of TBS ether 18
95.2, 75.8, 55.5, 38.6, 36.6, 16.9, 15.2 ppm; HRMS (ESI) for (0.80 g, 1.75 mmol) in THF (10 mL) at 0 °C. Stirring was con-
C14H21O2N4S [M + H]+ found 309.13715, calcd 309.13797.
tinued at rt until complete consumption of starting material
To a magnetically stirred solution of sulfide 4a (0.90 g, occurred (ca. 2 h). THF was removed in vacuo to give the crude
2.92 mmol) in EtOH (10 mL), a precooled solution of product which upon column purification (hexane–EtOAc 4 : 1)
ammonium molybdate tetrahydrate (1.08 g, 0.88 mmol) in gave alcohol 2 (540 mg, 90%) as a colourless oil. Rf = 0.55
30% H2O2 (4 mL) was added at 0 °C. Stirring was continued (hexane–EtOAc 3 : 2); [α]2D5 = −5.18 (c 1.1, CHCl3); IR (KBr):
until complete consumption of starting material occurred 3454, 2930, 1456, 1244, 1050, 758 cm−1 1H NMR (CDCl3,
;
(ca. 12 h). Saturated aq. NaCl (10 mL) was added and the 500 MHz) δ 5.47 (dd, J = 15.4, 6.6 Hz, 1H), 5.42 (dd, J = 15.3,
organic layer was extracted with CH2Cl2 (4 × 10 mL). The com- 6.1 Hz, 1H), 4.67 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H),
bined organic layers were dried over anhydrous Na2SO4, fil- 4.14 (dd, J = 5.2, 2.1 Hz, 1H), 3.87 (dd, J = 9.2, 5.0 Hz, 1H), 3.81
tered, concentrated under reduced pressure to give the crude (dd, J = 11.7, 2.9 Hz, 1H), 3.75 (dd, J = 11.4, 2.9 Hz, 1H), 3.68
product which upon column purification (hexane–EtOAc 9 : 1) (d, J = 11.6 Hz, 1H), 3.62–3.55 (m, 2H), 3.36 (s, 3H), 3.37–3.33
gave sulfone 4 (0.84 g, 85%) as a colourless oil. Rf = 0.50 (m, 1H), 2.34–2.27 (m, 1H), 2.25–2.14 (m, 2H), 2.06–1.98 (m,
(hexane–EtOAc 5 : 1); [α]D25 = +21.38 (c 0.75, CHCl3); IR (KBr): 1H), 1.49 (s, 3H), 1.34 (s, 3H), 1.09 (d, J = 6.3 Hz, 3H), 1.01 (d,
1
2932, 1343, 1153, 1038, 765 cm−1; H NMR (CDCl3, 300 MHz) J = 6.9 Hz, 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 135.2, 127.6,
δ 7.70–7.58 (m, 5H), 4.68 (d, J = 6.9 Hz, 1H), 4.58 (d, J = 6.8 Hz, 108.8, 95.1, 78.4, 76.5, 75.2, 70.1, 66.0, 63.3, 55.3, 42.2, 36.7,
1H), 4.10 (dd, J = 14.6, 2.9 Hz, 1H), 3.68–3.63 (m, 1H), 3.55 (dd, 33.8, 28.2, 26.3, 17.1, 15.8 ppm; HRMS (ESI) for C18H32O6Na
J = 14.7, 9.2 Hz, 1H), 3.38 (s, 3H), 2.44–2.35 (m, 1H), 1.22 (d, [M + Na]+ found 367.20954, calcd 367.20911.
J = 6.8 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (CDCl3,
2-((3aS,4S,7S,7aR)-7-((4R,5S,E)-5-(Methoxymethoxy)-
4-methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-4-yl)acetonitrile (19)
75 MHz) δ 154.0, 133.0, 131.4, 129.6, 125.1, 95.1, 75.7, 58.2,
55.7, 33.9, 17.2, 16.6 ppm; HRMS (ESI) for C14H20O4N4NaS
[M + Na]+ found 363.11041, calcd 363.10975.
To a stirred solution of alcohol 2 (0.35 g, 1.01 mmol) in
CH2Cl2 (5 mL), Et3N (0.42 mL, 3.05 mmol) followed by metha-
nesulfonyl chloride (0.12 mL, 1.52 mmol) were added at 0 °C.
Within 5 min all the starting material was consumed, the reac-
tert-Butyl(((3aR,4S,7S,7aR)-7-((4R,5S,E)-5-(methoxymethoxy)-
4-methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-4-yl)methoxy)dimethylsilane (18)
To a magnetically stirred solution of sulfone 4 (1.00 g, tion mixture was quenched with sat. aq. NH4Cl (5 mL) and
2.94 mmol) in THF (20 mL), KHMDS (11.8 mL of 0.5 M solu- extracted with CH2Cl2 (2 × 10 mL). The combined organic
tion in toluene, 5.88 mmol) was added at −78 °C. After stirring layers were dried over anhydrous Na2SO4, filtered, and concen-
for 1 h, aldehyde 3 (1.01 g, 2.94 mmol) was added (5 mL THF) trated under reduced pressure to give the mesylate which was
at the same temperature and stirred for 1 h. The mixture was directly used for the next step. To a stirred solution of mesylate
allowed to warm to room temperature over 1 h by which time in DMSO (5 mL) were added 18-crown-6 (66 mg, 0.25 mmol)
the reaction mixture turned into white cloudy suspension and NaCN (0.25 g, 5.05 mmol) and the mixture was heated up
and the TLC analysis indicated complete consumption of the to 90 °C. Within 1 h all the starting material was consumed
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and the reaction mixture was then diluted with ice cold water (hexane–EtOAc 19 : 1) through a short pad of silica gel afforded
(20 mL), and extracted with Et2O (3 × 10 mL). The combined alkyne 22 (0.39 g, 76%). Rf = 0.50 (hexane–EtOAc 5 : 1); [α]D25
extracts were washed with brine (10 mL), dried over anhydrous −8.00 (c 0.25, CHCl3); IR (KBr): 2927, 2125, 1459, 1374, 1217,
Na2SO4, filtered, concentrated under reduced pressure to give 1105, 1040 cm−1 1H NMR (CDCl3, 500 MHz) δ 5.48 (dd, J =
=
;
crude product, which upon column purification (hexane– 15.4, 6.4 Hz, 1H), 5.44 (dd, J = 15.3, 5.9 Hz, 1H), 4.67 (d, J =
EtOAc 9 : 1) gave cyanide 19 (0.31 g, 86%) as a colourless oil. 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.15 (dd, J = 4.8, 2.0 Hz,
Rf = 0.55 (hexane–EtOAc 7 : 3); [α]2D5 = −10.00 (c 0.7, CHCl3); IR 1H), 3.89 (dd, J = 9.0, 5.1 Hz, 1H), 3.76 (dd, J = 11.6, 3.0 Hz,
(KBr): 2974, 2930, 2251, 1456, 1376, 1218, 1040, 977 cm−1
;
1H), 3.72 (dd, J = 11.6, 1.1 Hz, 1H), 3.62–3.53 (m, 1H),
1H NMR (CDCl3, 300 MHz) δ 5.53–5.37 (m, 2H), 4.68 (d, J = 3.40–3.35 (m, 1H), 3.36 (s, 3H), 2.63–2.59 (m, 1H), 2.40 (ddd,
7.0 Hz, 1H), 4.60 (d, J = 7.0 Hz, 1H), 4.16 (dd, J = 4.9, 1.9 Hz, J = 17.0, 6.7, 2.6 Hz, 1H), 2.34–2.17 (m, 3H), 2.04–1.97 (m, 1H),
1H), 3.79 (dd, J = 9.3, 4.9 Hz, 1H), 3.73 (d, J = 2.1 Hz, 2H), 2.02 (t, J = 2.6 Hz, 1H), 1.49 (s, 3H), 1.35 (s, 3H), 1.09 (d, J =
3.63–3.55 (m, 1H), 3.47–3.40 (m, 1H), 3.37 (s, 3H), 2.72 (dd, J = 6.3 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (CDCl3,
16.8, 3.6 Hz, 1H), 2.52 (dd, J = 16.8, 6.8 Hz, 1H), 2.36–2.14 (m, 125 MHz) δ 135.2, 127.7, 108.8, 95.2, 80.6, 76.5, 76.2, 75.4,
3H), 2.07–1.98 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 1.09 (d, J = 72.9, 69.7, 66.6, 55.4, 42.2, 36.7, 33.9, 28.3, 26.3, 22.7, 17.0,
6.4 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H) ppm; 13C NMR (CDCl3, 15.8 ppm; HRMS (ESI) for C20H32O5Na [M + Na]+ found
75 MHz) δ 135.6, 127.2, 117.0, 109.2, 95.0, 76.4, 75.3, 74.0, 375.21182, calcd 375.21420.
72.7, 66.5, 55.3, 42.2, 36.3, 33.8, 28.2, 26.9, 21.74, 17.0,
15.8 ppm; HRMS (ESI) for C19H31O5NNa [M + Na]+ found
376.21008, calcd 376.20944.
1-((3aS,4S,7S,7aR)-7-((4R,5S,E)-5-(Methoxymethoxy)-
4-methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]-
(3aS,4S,7S,7aR)-7-((4R,5S,E)-5-(Methoxymethoxy)-4-methylhex-
2-en-1-yl)-2,2-dimethyl-4-(prop-2-yn-1-yl)tetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran (22)
dioxolo[4,5-c]pyran-4-yl)propan-2-one (20)
From 19: MeLi (0.27 mL of 1.6 M solution in Et2O, 0.42 mmol)
was added dropwise to a magnetically stirred solution of
To a stirred solution of alcohol 2 (0.50 g, 1.453 mmol) in nitrile 19 (0.10 g, 0.28 mmol) in Et2O (5 mL) at 0 °C. Stirring
CH2Cl2 (10 mL), 2,6-lutidine (0.34 mL, 2.90 mmol) was added was continued at room temperature until complete consump-
followed by trifluoromethanesulfonic anhydride (0.37 mL, tion of starting material occurred (ca. 30 min). The reaction
2.18 mmol) at −78 °C. After 10 min all the starting material mixture was quenched with sat. aq. NH4Cl (5 mL) and
was consumed and the reaction was quenched with sat. aq. extracted with Et2O (2 × 10 mL) and the combined organic
NH4Cl (5 mL) while allowing the reaction mixture to attain layers were dried over anhydrous Na2SO4, filtered, and concen-
room temperature. The reaction mixture was extracted with trated under reduced pressure to give the crude product which
CH2Cl2 (2 × 10 mL) and the combined organic extracts were upon column purification (hexane–EtOAc 9 : 1) gave ketone 20
washed with brine (10 mL), dried over anhydrous Na2SO4, fil- (30 mg, 30%) as a colourless oil and retro oxy-Michael product
tered, and concentrated under reduced pressure to give crude 21 (66 mg, 66%) as a colourless oil.
product which upon column purification (hexane–EtOAc 19 : 1)
through a short pad of silica gel gave the corresponding triflate (0.40 g, 1.14 mmol) in THF pH = 7 buffer (9 : 1, 8 mL), TsOH
(0.68 g, 98%) which was directly utilized for the next step. (0.43 g, 1.71 mmol) followed by Hg(OAc)2 (0.11 g, 0.342 mmol)
From 22: To a magnetically stirred solution of alkyne 22
HMPA (2.55 mL, 14.5 mmol) was added to the freshly gen- were added at 0 °C and the reaction mixture was stirred
erated lithium diisopropylamide (0.78 g, 7.27 mmol) in THF at 50 °C until complete consumption of starting material
(20 mL) at −78 °C. After 5 min trimethylsilyl acetylene (ca. 30 min), the reaction was quenched with sat. aq. NaHCO3
(1.03 mL, 7.27 mmol) was added at the same temperature, (10 mL), extracted with EtOAc (2 × 10 mL) and the combined
stirred for 30 min and a solution of the above prepared triflate organic layers were dried over anhydrous Na2SO4, filtered, and
in THF (5 mL) was added slowly. Stirring was continued for concentrated under reduced pressure to give the crude product
1 h then the reaction mixture was warmed to rt during 1 h which upon column purification through a short pad of silica
whereupon TLC analysis showed clean conversion of triflate gel (hexane–EtOAc 9 : 1) gave ketone 20 (370 mg, 88%) as a
to alkyne. The reaction was quenched with sat. aq. NH4Cl colourless oil. Rf = 0.50 (hexane–EtOAc 7 : 3); [α]2D5 = −4.0 (c 0.2,
(10 mL) and extracted with EtOAc (2 × 20 mL). The combined CHCl3); IR (KBr): 2926, 2856, 1739, 1456, 1375, 1225, 1044,
1
organic extracts were washed with brine (20 mL), dried over cm−1; H NMR (CDCl3, 500 MHz) δ 5.48–5.39 (m, 2H), 4.67 (d,
anhydrous Na2SO4, filtered, and concentrated under reduced J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.13–4.11 (br m, 1H),
pressure to give the crude product which was dissolved in 3.78–3.68 (m, 3H), 3.63–3.54 (m, 2H), 3.36 (s, 3H), 2.69–2.65
MeOH (5 mL) and K2CO3 (0.30 g, 2.18 mmol) was added at (m, 1H), 2.59–2.53 (m, 1H), 2.33–2.15 (m, 3H), 2.19 (s, 3H),
0 °C and stirring continued until complete consumption of 2.02–1.97 (m, 1H), 1.50 (s, 3H), 1.34 (s, 3H), 1.09 (d, J = 6.3 Hz,
starting material was observed (ca. 2 h). Brine (10 mL) was 3H), 1.01 (d, J = 6.9 Hz, 3H) ppm; 13C NMR (CDCl3, 75 MHz)
added and the reaction mixture was extracted with Et2O (3 × δ 206.8, 135.2, 127.6, 108.8, 95.1, 76.4, 75.3, 74.5, 73.6, 66.5,
10 mL). The combined extracts were dried over anhydrous 55.3, 46.9, 42.2, 36.6, 34.0, 30.8, 28.2, 26.3, 17.0, 15.8 ppm;
Na2SO4, filtered, and concentrated under reduced pressure to HRMS (ESI) for C20H34O6Na [M + Na]+ found 393.22577, calcd
give the crude product which upon column purification 393.22476.
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Organic & Biomolecular Chemistry
(E)-3-((4S,5R)-5-((2S,6R,7S,E)-1-Hydroxy-7-(methoxymethoxy)-
6-methyloct-4-en-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
acrylonitrile (21)
oil. Rf = 0.55 (EtOAc); [α]2D5 = +9.60 (c 0.2, CHCl3); IR (KBr):
3424, 2924, 2854, 1714, 1645, 1440, 1379, 1229, 1154
1
1052 cm−1; H NMR (CDCl3, 500 MHz) δ 5.75 (br s, 1H), 5.47
(dt, J = 15.3, 6.7 Hz, 1H), 5.38 (dd, J = 15.4, 8.1 Hz, 1H), 3.88
(m, 1H), 3.77 (dd, J = 11.7, 2.9 Hz, 1H), 3.70–3.67 (m, 1H), 3.66
(s, 3H), 3.54–3.46 (m, 2H), 3.44–3.39 (m, 1H), 2.60 (br d, J =
14.6 Hz, 1H), 2.28–2.22 (m, 2H), 2.19 (s, 3H), 2.16–2.00 (m,
3H), 1.13 (d, J = 6.3 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H) ppm; 13C
NMR (CDCl3, 75 MHz) δ 167.0, 157.2, 134.5, 129.4, 117.1, 74.6,
71.1, 70.4, 68.9, 64.8, 50.8, 44.8, 43.1, 41.9, 32.3, 20.3, 19.1,
16.7 ppm; HRMS (ESI) for C23H38O7Na [M + Na]+ found
365.19316, calcd 365.19346.
Rf = 0.40 (hexane–EtOAc 7 : 3); [α]2D5 = +1.6 (c 0.65, CHCl3);
IR (KBr): 3468, 2931, 2226, 1634, 1454, 1377, 1217, 1038 cm−1
;
1H NMR (CDCl3, 500 MHz) δ 6.87 (dd, J = 16.2, 5.2 Hz, 1H),
5.67 (dd, J = 16.3, 1.8 Hz, 1H), 5.49–5.39 (m, 2H), 4.73–4.70 (m,
1H), 4.67 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 6.9 Hz, 1H), 4.22 (dd,
J = 9.0, 6.3 Hz, 1H), 3.67 (dd, J = 11.0, 4.4 Hz, 1H), 3.61–3.48
(m, 2H), 3.37 (s, 3H), 2.36–2.31 (m, 1H), 2.30–2.24 (m, 1H),
2.12–2.04 (m, 1H), 1.83–1.76 (m, 1H), 1.50 (s, 3H), 1.38 (s, 3H),
1.11 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H) ppm; 13C NMR
(CDCl3, 75 MHz) δ 152.0, 135.1, 127.2, 117.1, 108.5, 101.4,
95.1, 79.2, 77.2, 76.7, 63.2, 55.4, 42.4, 40.3, 31.8, 27.6, 25.2,
17.3, 16.1 ppm; HRMS (ESI) for C19H31O5NNa [M + Na]+ found
376.20941, calcd 376.20944.
Acknowledgements
Y. S. thanks CSIR, New Delhi for financial assistance in the
form of fellowship. P. S. acknowledges funding from CSIR,
New Delhi as a part of XII Five year plan programme under
title ORIGIN (CSC-0108) and from research grant (P-81-113)
from the Human Resources Research Group-New Delhi
through the Council of Scientific & Industrial Research (CSIR)
Young Scientist Award Scheme.
(E)-Methyl 4-((3aS,4S,7S,7aR)-7-((4R,5S,E)-5-(methoxymethoxy)-
4-methylhex-2-en-1-yl)-2,2-dimethyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-4-yl)-3-methylbut-2-enoate (23)
To a magnetically stirred solution of methyl diethyl phospho-
noacetate (0.28 g, 1.35 mmol) in THF (10 mL), KHMDS
(2.70 mL of 0.5 M solution in toluene, 1.35 mmol) was added
at rt. After 1 h, ketone 20 (0.10 g, 0.270 mmol) was added
(2 mL, THF) at room temperature while stirring was continued
until complete consumption of starting material occurred
(ca. 16 h). Solvents were removed under reduced pressure and
the residue was column chromatographed (hexane–EtOAc
19 : 1) through a short pad of silica gel to give ester 23 (92 mg,
Notes and references
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K. D. Barrow and E. B. Chain, Nature, 1971, 234, 416;
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J. Hothersall, W. Laosripaiboon, T. J. Simpson and
C. M. Thomas, Chem. Commun., 2005, 1179; (b) J. Wu,
S. M. Cooper, R. J. Cox, J. Crosby, M. P. Crump,
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Chem. Commun., 2007, 2040.
3 (a) H. Shiozawa, T. Kagasaki, T. Kinoshita, H. Haruyama,
H. Domon, Y. Utsui, K. Kodama and S. Takahashi, J. Anti-
biot., 1993, 46, 1834; (b) H. Shiozawa, T. Kagasaki,
A. Torikata, N. Tanaka, K. Fujimoto, T. Hata, Y. Furukawa
and S. Takahashi, J. Antibiot., 1995, 48, 907;
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1997, 50, 449; (d) A. C. Murphy, D. Fukuda, Z. Song,
J. Hothersall, R. J. Cox, C. L. Willis, C. M. Thomas and
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4 (a) Y. J. Class and P. DeShong, Chem. Rev., 1995, 95, 1843
and references cited therein; (b) C. McKay, T. J. Simpson,
C. L. Willis, A. K. Forrest and P. J. O’Hanlon, Chem.
Commun., 2000, 1109; (c) T. Honda and N. Kimura, Org.
Lett., 2002, 4, 4567; (d) X. Gao and D. G. Hall, J. Am. Chem.
Soc., 2005, 127, 1628; (e) L. van Innis, J. M. Plancher and
I. E. Marko, Org. Lett., 2006, 8, 6111; (f) R. F. de la Pradilla
80%) as a colourless oil. Rf = 0.65 (hexane–EtOAc 5 : 1); [α]D25
=
−12.40 (c 0.25, CHCl3); IR (KBr): 2925, 2854, 1718, 1648, 1459,
1376, 1220, 1150, 1040 cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.75
(br s, 1H), 5.50–5.37 (m, 2H), 4.67 (d, J = 6.8 Hz, 1H), 4.60 (d,
J = 6.8 Hz, 1H), 4.12 (dd, J = 4.5, 1.7 Hz, 1H), 3.79–3.48 (m,
4H), 3.68 (s, 3H), 3.44–3.34 (m, 1H), 3.36 (s, 3H), 2.49 (br d, J =
14.2 Hz, 1H), 2.35–2.10 (m, 3H), 2.20 (s, 3H), 2.08–1.85 (m,
2H), 1.49 (s, 3H), 1.35 (s, 3H), 1.09 (d, J = 6.2 Hz, 3H), 1.00 (d,
J = 6.8 Hz, 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 167.0, 156.8,
135.2, 127.7, 117.1, 108.6, 95.1, 76.5, 76.4, 75.4, 74.1, 66.5,
55.4, 50.8, 44.0, 42.2, 36.7, 34.1, 28.3, 26.3, 19.1, 17.0,
15.8 ppm; HRMS (ESI) for C23H38O7Na [M + Na]+ found
449.24763, calcd 449.25097.
Pseudomonic acid methyl monate C (1)
To a magnetically stirred solution of ester 23 (20 mg,
47.0 μmol) in THF (2 mL), 2 N HCl (2 mL) was added at
0 °C. Stirring was continued until complete consumption of
starting material (ca.
4 h) was observed. The reaction
mixture was neutralized with solid NaHCO3 and extracted
with EtOAc (3 × 5 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product which
upon column purification (hexane–EtOAc 1 : 1) gave pseudo-
monic acid methyl monate C 1 (14.4 mg, 90%) as a colourless
2958 | Org. Biomol. Chem., 2014, 12, 2950–2959
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Paper
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This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2950–2959 | 2959