Wittig Cyclization of ω-Hydroxy Hemiacetals: Synthesis of (+)-Aspicilin

Article abstract of DOI:10.1021/acs.joc.7b01702

The polyhydroxylated 18-membered lichen macrolide (+)-aspicilin was synthesized in 12 steps and 17% yield (longest linear sequence) starting from d-mannose and (S)-propylene oxide as the source of the stereogenic centers. Key steps were a palladium-catalyzed C^sp3X-C^sp3ZnX Negishi cross-coupling affording an ω-hydroxy hemiacetal which was macrocyclized via a domino addition-Wittig olefination reaction with the cumulated ylide Ph₃PCCO. This synthetic approach also allowed a regioselective glycosylation of 6-OH of aspicilin with d-desosamine, a quick entry to chimeric macrolides with potential antibiotic activity.

Full text of DOI:10.1021/acs.joc.7b01702

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Article
Wittig cyclization of #-hydroxy hemiacetals: Synthesis of (+)-aspicilin
René Schmidt, Michael Ostermeier, and Rainer Schobert
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01702 • Publication Date (Web): 27 Jul 2017
Downloaded from http://pubs.acs.org on July 27, 2017
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Page 1 of 22
The Journal of Organic Chemistry
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Wittig cyclization of !-hydroxy hemiacetals:
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Synthesis of (+)-aspicilin
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René Schmidt, Michael Ostermeier and Rainer Schobert*
Organic Chemistry Laboratory, University Bayreuth, 95440 Bayreuth, Germany
Rainer.Schobert@uni-bayreuth.de
The polyhydroxylated 18-membered lichen macrolide (+)-aspicilin was synthesized in 12 steps and 17%
yield (longest linear sequence) starting from D-mannose and (S)-propylene oxide as the source of the
stereogenic centers. Key steps were a palladium-catalyzed Csp3X–Csp3ZnX Negishi cross-coupling
affording an !-hydroxy hemiacetal which was macrocyclized via a domino addition–Wittig olefination
reaction with the cumulated ylide Ph3PCCO. This synthetic approach also allowed a regioselective
glycosylation of 6-OH of aspicilin with D-desosamine, a quick entry to chimeric macrolides with
potential antibiotic activity.
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Page 2 of 22
Introduction
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Previously, we reported the synthesis of the macrolide (+)-choriolide by a ring-closing Wittig
olefination of a phosphorus ester ylide bearing an !-hemiacetal, generated in situ by treating the
corresponding phosphonium salt with aqueous base.1 Though high-yielding, we intended to shorten this
sequence by preparing the reactive !-hemiacetal ester ylide directly from the corresponding !-hydroxy
hemiacetal. The 18-membered macrolactone (+)-aspicilin (1), first isolated in 1900 by Hesse2 from
lichen of the lecanoraceae family and structurally elucidated in 1973 by Huneck et al.,3 is an ideal target
molecule to try out this approach. It features a ring of accessible size, an E-configured ",#-unsaturated
lactone as obtained from Wittig reactions with stabilized ylides, and a contiguous triol potentially
competing for the intended glycosylation. The absolute configuration (2E,4R,5S,6R,17S) of 1 was
established in 1985 by Quinkert et al.4 by spectroscopic methods, single crystal X-ray analysis,
degradation and synthetic studies. The first total synthesis of 1 was described in 1987 by Zwanenburg et
al.5 applying a photolactonisation of diastereomeric o-quinol acetates as the key step. Many more
syntheses of 1 by other groups followed, differing mainly in the construction of the triol triad and the
cyclization method. In most cases macrocyclization was accomplished by RCM6 or Yamaguchi
esterification.7 Quinkert et al. also contributed a photochemical synthesis of 18 and Oppolzer et al.
achieved the macrocyclization by an intramolecular alkenylzinc/aldehyde addition.9 To the best of our
knowledge, the only Wittig-type macrocyclization leading to 1 was reported by Raghavan and
Sreekanth10 using an intramolecular Horner-Wadsworth-Emmons reaction under Masamune-Roush
conditions which required a separate preparation of a phosphonate ester and an oxidation of an !-
alcohol to the corresponding aldehyde. Biological properties of 1 were also reported. Reddy et al.7f
evaluated its antiproliferative effect against various cancer cell lines in 2012 by means of MTT assays
and found activities with IC50 (24 h) concentrations in the low double-digit micromolar range.
(+)-Aspicilin (1) exhibited neither antibacterial nor antifungal effects, probably due to its lack of a
glycoside required for effective binding to the 50S subunit of the bacterial peptidyl tranferase.11 In our
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The Journal of Organic Chemistry
new synthetic approach to (+)-aspicilin (1) we sought to make allowance for the regioselective
introduction of sugar residues such as desosamine12 at positions 4-O, 5-O, or 6-O, in order to open
access to potentially antimicrobial chimeric macrolides.
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Results and Discussion
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The retrosynthesis of (+)-aspicilin (1) is outlined in Scheme 1. It is accessible by hydrolysis of the
known 4,5-acetonide protected derivative 27a which, when glycosylated with D-desosamine prior to
hydrolysis, should optionally afford the 6-O-glycoconjugate 3. As a key step of the synthesis, the
macrocycle of 2 was to be closed by a domino addition–Wittig olefination reaction between the new
acetonide protected !-hydroxy hemiacetal 4 and the cumulated phosphorus ylide Ph3PCCO (5).13 The
latter does not enter directly into Wittig olefination reactions but adds OH-, NH-, SH-, and CH-acidic
compounds to give the corresponding stabilized phosphorus ylides which then undergo alkenation
reactions with aldehydes and ketones.14 Building block 4 was to be obtained by a Pd-PEPPSITM-IPr15
catalyzed Negishi cross-coupling of a new functionalized 2,3-acetonide protected (+)-D-mannose
derivative 6 with an organozinc reagent 7. The latter introduces the required spacer and the secondary
alcohol function masked as a TBS ether. It should be available by a cuprate catalyzed Grignard reaction
of (S)-propylene oxide (8) and commercially available 7-bromo-1-heptene (9), followed by silyl
protection,7e bromination16 of the olefin moiety and subsequent oxidative addition of zinc.17 Sugar
bromide 6 was to be prepared from D-(+)-mannose (10) via the corresponding alcohol 11 which had
already been prepared by Quinkert et al.7a
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SCHEME 1. Retrosynthesis of (+)-Aspicilin (1) and its Desosamine Glycoconjugate 3
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D-(+)-Mannose (10) was converted in six steps to alcohol 11, according to Quinkert’s protocol.7a
Alcohol 11 was then brominated with NBS and PPh3 to afford bromide 6 in excellent yield (Scheme 2,
top). For the synthesis of organozinc reagent 7, 7-bromo-1-heptene (9) was converted to its Grignard
derivative which was activated with CuCN and reacted with (S)-propylene oxide (8) to give the
corresponding alcohol,7e which was silylated right away to afford TBS ether 12 (Scheme 2, bottom). Its
hydroboration with BH3·THF and addition of bromine and NaOMe furnished bromide 13 in 63% yield.16
While bromide 13 had been prepared before,7a our sequence is distinctly shorter and allows for its multi-
gram scale preparation. Its reaction with zinc and catalytic amounts of iodine in 1,3-dimethyl-2-
imidazolidinone (DMI) at 80 °C in a sealed Carius tube, according to a modification of the method by
Huo,17 gave organozinc compound 7 in quantitative yield (GC).
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The Journal of Organic Chemistry
SCHEME 2.a Syntheses of Bromide 6 and Organozinc Reagent 7
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a Reagents and conditions: (i) NBS, PPh3, CH2Cl2, 0 °C to rt, 15 h; (ii) (a) Mg0, THF, rt, 1 h, then cat.
CuCN, (S)-propylene oxide (8), –78 °C to rt, 1 h; (b) TBSCl, imidazole, CH2Cl2, rt, 15 h; (iii) BH3·THF,
THF, 0 °C, 2 h, then Br2, NaOMe, 40 °C, 10 min; (iv) Zn0, cat. I2, DMI, sealed tube, 80 °C, 18 h.
DMI was chosen because a 2:1 mixture of THF and DMI was required for the subsequent Csp3X–
Csp3ZnX cross-coupling of 6 and 7 using the PEPPSITM-IPr catalyst15a which proceeded in 78% yield to
afford the known, fully protected cyclization precursor 14 in a more efficient and convenient way when
compared to the literature route7a (Scheme 3). Other solvent mixtures gave unsatisfactory yields or no
coupling reaction at all. Likewise, the use of stoichiometric amounts of LiBr was of the essence, in line
with the literature.15a Desilylation of the cross-coupling product 14 with HF·pyridine instead of TBAF,
as used in the literature,7a gave alcohol 15 in an immediately pure form. Catalytic debenzylation of 15
afforded the new !-hydroxy hemiacetal 4 in an ":# ratio of 3:1 as to NMR. Its cyclization with
Ph3PCCO (5) required some experimentation. When refluxed in toluene for 26 h, a stoichiometric
mixture of compounds 4 and 5 gave none of the desired aspicilin acetonide (2) but merely
decomposition products and an unexpected tricyclic product 16 in low yield. The latter originated from
an intramolecular Michael addition of 6-OH across the enoate of intermediate macrolactone 2.
Apparently, macrocyclization had taken place, yet under conditions that favor follow-up reactions and
decomposition.
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SCHEME 3. a Csp3X–Csp3ZnX Coupling and Unexpected Domino Wittig-Michael Cyclization
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Reagents and conditions: (i) PEPPSITM-IPr, LiBr, THF/DMI 2:1, rt, 2 h; (ii) HF·pyridine, THF, rt,
a
1.5 h; (iii) H2 (atmospheric pressure), Pd/C (10 wt%), EtOAc, rt, 2 h; (iv) Ph3PCCO (5), toluene, reflux,
26 h.
However, when carried out at a lower temperature of 70 °C for a shorter period of 12 h in a sealed
Carius tube, the reaction between compounds 4 and 5 afforded 40% of aspicilin acetonide (2) void of
tricyclic 16. These conditions seem to allow the formation of the intermediate ester ylide 17 and of its
Wittig product 2 while being insufficient for the furan ring formation (Scheme 4). The natural product
(+)-aspicilin (1) was eventually obtained in good yield as colorless crystalline platelets upon treating
acetonide 2 with TFA in a mixture of MeOH and H2O at 70 °C. Our synthetic (+)-aspicilin (1) showed
spectroscopic properties in keeping with those reported in the literature and it was diastereopure
according to NMR and GC.4-10
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The Journal of Organic Chemistry
SCHEME 4.a Wittig Macrocylization Leading to (+)-Aspicilin (1)
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a Reagents and conditions: (i) toluene, 70 °C, sealed tube, 12 h; (ii) TFA, MeOH/H2O 3:1, 70 °C, 2 h.
For the glycosylation of alcohol 2 with D-desosamine (19) according to a general protocol by
Woodward,12c the known thioglycoside 21 was prepared in three steps from commercially available
erythromycin (18) (Scheme 5). The usual acidic hydrolysis18 of the latter affords free D-desosamine (19)
which is difficult to extract and purify, though. The known chemical syntheses of 19 are no option,
either, to get access to larger amounts of the pure amino sugar since they are laborious or based on
costly reagents and starting materials.19 To improve the yield of D-desosamine (19), obtained by acidic
hydrolysis of the cheap antibiotic 18, we treated the crude hydrolysis product with Bz2O to get the 1,2-
dibenzoate 20 in an ":# ratio of 1:1.2 which was easy to extract and purify by chromatography. This
was then converted to thioglycoside 21 by reaction with 2-mercaptopyrimidine under Lewis acidic
conditions, according to a protocol by Zhang et al.19a
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SCHEME 5.a Improved Synthesis of Thioglycoside 21 from Erythromycin (18)
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Reagents and conditions: (i) 6 N HCl, EtOH, reflux, 4 h; (ii) Bz2O, NEt3, EtOAc, rt, 22 h; (iii)
2-mercaptopyrimidine, BF3·Et2O, dry Celite, 1,2-dichloroethane, 60 °C, 24 h.
The glycosylation of acetonide protected (+)-aspicilin 2 with thioglycoside 21 in the presence of
AgOTf, following a slightly modified Woodward protocol,12a gave the protected derivative 22 in over
90% yield (Scheme 6). Its deprotection turned out to be rather tricky. The desired product 3 could be
obtained only by first treating a solution of 22 in MeOH and H2O with TFA at 70 °C to cleave the
acetonide moiety and subsequently saponificating the benzoate with K2CO3 in MeOH. Saponification
with aqueous base led to rapid lactone ring opening while benzoyl deprotection proceeded sluggishly.
Glycoconjugate 3 is currently being tested for antimicrobial and other biological activities.
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The Journal of Organic Chemistry
SCHEME 6.a 6-O-Glycosylation of (+)-Aspicilin (1)
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a Reagents and conditions: (i) AgOTf, 21, 4 Å molecular sieves, CH2Cl2/toluene 2:1, rt, exclusion of
light, 16 h; (ii) TFA, MeOH/H2O 2:1, 70 °C, 2 h, then K2CO3, MeOH, rt, 20 h.
Conclusions
The 18-membered lichen macrolide (+)-aspicilin (1) was synthesized in 12 steps and 17% overall yield
starting from D-mannose (10), 7-bromo-1-heptene (9) and (S)-propylene oxide (8). This synthesis
comprises two unprecedented key steps, a Pd-catalyzed Csp3X–Csp3ZnX Negishi cross-coupling with
high functional group tolerance, and a one-pot Wittig-type macrocyclization of an !-hydroxy
hemiacetal with the cumulated phosphorus ylide Ph3PCCO (5) as the coupling reagent. It also introduces
a strategy for the regioselective attachment of D-desosamine (19), crucial for macrolide activity, at
specific positions on the aglycone.
Experimental Section
General Remarks. Melting points were determined with a Büchi M-565 melting point apparatus and
are uncorrected. IR spectra were recorded with an FT-IR spectrophotometer equipped with an ATR unit.
Chemical shifts of NMR signals are given in parts per million (!) using the residual solvent peak as an
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Page 10 of 22
internal standard20, i.e., 7.26 ppm (proton) and 77.16 ppm (carbon) for CDCl3. Mass spectra were
obtained under EI (70 eV) conditions. High resolution mass spectra were obtained with a
UPLC/Orbitrap MS system in ESI mode. GC-MS analyses were carried out on an Agilent 7890A GC
system equipped with aHP-5MS column (30 m " 0.32 mm x 0.25 µm) and a 5975C inert MSD detector.
Optical rotations were measured at 589 nm (Na-D line) using solutions in chloroform.
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Chemicals: All reagents were purchased from commercial sources and were used without further
purification. Alcohol 117a and thioglycoside 2119a were prepared according to literature. All anhydrous
solvents were used as supplied, except tetrahydrofuran and diethyl ether which were freshly distilled
over sodium-potassium alloy, and toluene, dimethyl formamide (DMF) and 1,3-dimethyl-2-
imidazolidinone (DMI) which were dried over molecular sieve (3 Å).21 Moisture or air sensitive
reactions were routinely carried out in oven-dried glassware under an argon atmosphere using standard
Schlenk technique.
Chromatography: Analytical thin layer chromatography was carried out using Merck silica gel
60GF254 pre-coated aluminium-backed plates and/or Merck 60 RP-18 F254S foil plates. Column
chromatography was performed at medium pressure using dry packed Marchery-Nagel silica gel 60,
pore size 40–63 $m with the eluent specified. Flash vacuum chromatography was performed using dry
packed Marchery-Nagel silica gel 60, pore size 25–40 $m with the eluent specified.
(+)-Aspicilin (1). According to literature7a macrolide 2 (10 mg, 0.027 mmol) was dissolved in a mixture
of methanol (3 mL) and H2O (1 mL), treated with TFA (0.1 mL, 1.38 mmol) and warmed under stirring
at 70 °C. After complete deprotection (TLC, 2 h) the reaction was quenched with sat. aqueous NaHCO3
(10 mL) and brine (10 mL), and extracted three times with methyl t-butyl ether (15 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. After recrystallization of the residue
from a mixture of n-hexane and ethyl acetate (+)-aspicilin (1) was obtained as colorless platelets (8 mg,
0.025 mmol, 91%) of mp 151–152 °C (lit6h mp 150–155 °C; lit7a mp 154–156 °C; lit7b mp 150–152 °C;
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The Journal of Organic Chemistry
lit7d mp 152–155 °C); Rf = 0.14 (50% ethyl acetate in n-hexane); ["]23D +37.5 (c 0.11, CHCl3) (lit6h ["]28
+35.0 (c 0.20 CHCl3); lit7b ["]23 +37.7 (c 0.22 CHCl3); lit7c ["]23 +38.5 (c 0.22 CHCl3); lit7d ["]22
D
D
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D
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+37.5 (c 0.55 CHCl3)); IR #max 3441, 3280, 2926, 2855, 1716, 1664, 1460, 1363, 1342, 1232, 1179,
7
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1072, 1035, 1009, 988, 951, 802, 762, 588 cm-1; H NMR (CDCl3, 300 MHz) ! 6.90 (dd, J = 15.9, 5.2
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Hz, 1 H), 6.12 (dd, J = 15.9, 1.6 Hz, 1 H), 5.05 (dqd, J = 6.3, 6.0, 5.8 Hz, 1 H), 4.53–4.62 (m, 1 H),
3.72–3.82 (m, 1 H), 3.54–3.62 (m, 1 H), 3.17–3.34 (m, 1 H), 2.99–3.13 (m, 1 H), 2.40–2.55 (m, 1 H),
13
1.16–1.64 (m, 23 H); C NMR (CDCl3,75 MHz) ! 165.6, 144.7, 123.3, 75.0, 73.4, 71.3, 70.1, 35.9,
32.3, 28.5, 27.9, 27.8, 27.4, 27.3, 26.6, 24.4, 23.8, 20.6; HRMS (+ESI) m/z [M +H]+ calcd for C18H33O5+
329.2323, found 329.2319.
(1R,2E,6S,17R,18S)-17-Hydroxy-6,20,20-trimethyl-5,19,21-trioxabicyclo[16.3.0]henicos-2-en-4-one
(2). A stirred solution of !-hydroxy hemiacetal 4 (198 mg, 0.58 mmol) and Ph3PCCO (5) (174 mg,
0.58 mmol) in dry toluene (8 mL) was heated in a sealed Carius tube for 12 h at 70 °C. The volatiles
were removed in vacuo and the residue was purified by column chromatography eluting with 10% ethyl
acetate in n-hexane to afford the macrolide 2 as a colorless crystalline solid (72 mg, 0.20 mmol, 40%) of
mp 112–114 °C (lit8b mp 114–115 °C); Rf = 0.82 (10% ethyl acetate in n-hexane); ["]23D +56.2 (c 0.18,
CHCl3) (lit8b ["]20 +56.9 (c 0.82 CHCl3)); IR #max 3463, 2925, 2857, 1706, 1659, 1461, 1370, 1252,
D
1183, 1129, 1086, 1034, 992, 858, 797, 596; 1H NMR (CDCl3, 300 MHz) ! 6.85 (dd, J = 15.6, 8.8 Hz, 1
H), 5.98 (d, J = 15.6 Hz, 1 H), 5.10 (dqd, J = 6.3, 6.0, 5.8 Hz, 1 H), 4.58 (dd, J = 8.8, 6.3 Hz, 1 H), 4.04
(dd, J = 8.6, 6.2 Hz, 1 H), 3.54–3.67 (m, 1 H), 2.19 (d, J = 1.4 Hz, 1 H), 1.19–1.59 (m, 29 H); 13C NMR
(CDCl3, 75 MHz) ! = 165.4, 142.7, 124.6, 109.8, 82.3, 76.9, 71.0, 69.2, 35.7, 32.7, 28.2, 28.1, 27.7,
27.6, 27.2, 27.1, 26.2, 25.7, 24.4, 23.5, 20.6; MS (EI, 70 eV) m/z 368 (M+), 353, 277, 157, 142, 114;
HRMS (+ESI) m/z [M +H]+ calcd for C21H37O5+ 369.2636, found 369.2630.
(3E,5R,6S,7R,18S)-7-O-[3’,4’,6’-trideoxy-(dimethylamino)-!-D-xylo-hexopyranosyl]-5,6-
dihydroxy-18-methyloxacyclooctadec-3-en-2-one (3). A stirred solution of protected glycosyl
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macrolide 22 (12 mg, 0.02 mmol) in a mixture of methanol (500 µL) and H2O (250 µL) was treated with
TFA (75 µL, 0.99 mmol) at ambient temperature and then stirred at 70 °C for 2 h. After deprotection of
the acetonide moiety (TLC) the reaction was quenched with sat. aqueous NaHCO3 (3 mL) and brine
(3 mL) and extracted three times with ethyl acetate (15 mL). The combined organic layers were dried
(MgSO4) and the volatiles were removed in vacuo. The residue was taken up in methanol (200 µL) and
treated with freshly ground K2CO3 (3 mg, 21 µmol) at ambient temperature. After stirring for 20 h the
reaction mixture was filtered over a plug of silica gel and washed with a mixture of acetone and 0.1%
NEt3 (20 mL). The filtrates were concentrated and purified by column chromatography eluting with
acetone and 0.1% NEt3 to give glycosyl macrolide 3 as a slightly yellowish and highly viscous oil
(3 mg, 0.006 mmol, 31%); Rf = 0.28 (0.1% NEt3 in acetone); IR #max 3395, 2926, 2854, 2218, 1727,
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1
1272, 1164, 1067, 716, 576, 569 cm-1; H NMR (CDCl3, 300 MHz) ! 7.15 (dd, J = 15.6, 4.2 Hz, 1 H),
6.18 (dd, J = 15.6, 1.9 Hz, 1 H), 4.89–5.03 (m, 2 H), 4.43 (d, J = 7.1 Hz, 1 H), 4.32–4.39 (m, 1 H),
3.99–4.12 (m, 1 H), 3.85–3.96 (m, 1 H), 3.56–3.68 (m, 3 H), 3.43–3.52 (m, 1 H), 3.32–3.40 (m, 1 H),
2.90 (br. s., 6 H), 2.24–2.41 (m, 1 H), 1.47–1.80 (m, 1 H), 1.21–1.44 (m, 23 H), 1.18 (d, J = 6.0 Hz, 3
H); HRMS (+ESI) m/z [M +H]+ calcd for C26H48O7N+ 486.3425, found 486.3418.
(10’S)-5-Deoxy-5-C-(10’-hydroxyundecyl)-2,3-O-isopropylidene-"-D-lyxofuranoside (4). A mixture
of palladium on charcoal (10wt%, 0.2 g), benzyl ether 15 (0.89 g, 2.1 mmol) and ethyl acetate (50 mL)
was hydrogenated at room temperature at 1 bar of H2 for 2 h (TLC control). The reaction mixture was
filtered over a plug of celite® 545 and the filtrate was washed with ethyl acetate (50 mL). The
combined organic phases were concentrated in vacuo to leave !-hydroxy hemiacetal 4 as a colorless
solid (0.72 g, 2.1 mmol, 99%) of mp 62-64 °C, consisting of a 3:1 mixture of " and # anomers as to 1H
NMR. Rf = 0.15 (30% ethyl acetate in n-hexane); ["]23 +14.5 (c 0.67, CHCl3); IR #max 3392, 2925,
D
2850, 1461, 1401, 1379, 1208, 1164, 1129, 1083, 1060, 1025, 1009, 973, 933, 903, 826, 737, 679 cm-1;
1H NMR (CDCl3, 300 MHz) mixture of anomers: ! 5.34 (d, J = 2.2 Hz, 1 H), 4.93 (dd, J = 12.1, 3.6 Hz,
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1 H), 4.65 (dd, J = 6.0, 3.6 Hz, 1 H), 4.54–4.62 (m, 2 H), 4.48 (dd, J = 6.0, 3.6 Hz, 1 H), 4.12 (td, J =
6.8, 3.4 Hz, 1 H), 3.73–3.87 (m, 2 H), 3.46 (ddd, J = 7.2, 6.3, 3.0 Hz, 1 H), 2.43 (d, J = 2.5 Hz, 1 H),
1.62–1.78 (m, 4 H), 1.22–1.59 (m, 32 H), 1.18 (d, J = 6.0 Hz, 4 H); 13C NMR (CDCl3, 75 MHz) mixture
of anomers: ! 101.0, 96.5, 85.9, 80.6, 80.5, 78.9, 76.1, 68.4, 41.0, 39.4, 29.8, 29.7, 29.7, 29.6, 29.6,
29.5, 29.5, 28.5, 28.3, 26.9, 26.3, 26.2, 26.1, 26.0, 25.9, 25.8, 25.4, 25.2, 25.1, 24.0, 23.6, 20.9, 17.4;
HRMS (+ESI) m/z [M +H]+ calcd for C19H37O5+ 345.2641, found 345.2650.
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Benzyl 6-bromo-5-deoxy-2,3-O-(1-methylethylidene)-"-D-lyxo-hexofuranoside (6). A solution of 5-
deoxy-2,3-O-(1-methylethylidene)-"-D-lyxo-hexofuranoside
(11)7a
(8.52 g,
28.9 mmol)
and
triphenylphosphane (19.00 g, 72.3 mmol) in dry CH2Cl2 (300 mL) was treated with
N-bromosuccinimide (12.89 g, 72.3 mmol) at 0 °C and the resulting mixture was stirred and allowed to
warm to room temperature. After 15 h, sat. aqueous NaHCO3 (100 mL) was added and the layers were
separated. The aqueous one was extracted twice with CH2Cl2 (200 mL) and the combined organic layers
were dried (anhydrous MgSO4). The volatiles were removed in vacuo and the resulting black oil was
purified by vacuum flash chromatography eluting with 10% ethyl acetate in n-hexane to give the title
compound after recrystallization from n-hexane as colorless needles (9.72 g, 27.2 mmol, 95%); Rf =
0.33 (5% ethyl acetate in n-hexane); mp 65-66 °C; ["]23 +93 (c 1.04, CHCl3); IR (neat) #max 2928,
D
1376, 1357, 1271, 1082, 1014, 862, 700, 652, 554 cm-1; 1H NMR (CDCl3, 300 MHz) ! 7.26–7.37 (m, 5
H), 5.07 (s, 1 H), 4.64–4.72 (m, 2 H), 4.69 (d, J = 11.8 Hz, 1 H), 4.49 (d, J = 11.8 Hz, 1 H), 4.24 (ddd, J
= 8.1, 4.9, 2.6 Hz, 1 H), 3.57 (dt, J = 6.6, 1.1 Hz, 1 H), 2.34 (ddt, J = 14.3, 8.5, 5.8 Hz, 1 H), 2.18 (dtd, J
= 14.2, 7.4, 4.8 Hz, 1 H), 1.45 (s, 3 H), 1.31 (s, 3 H); 13C NMR (CDCl3, 75 MHz) ! 137.5, 128.6, 128.3,
128.0, 112.6, 105.1, 85.5, 80.3, 77.8, 69.0, 31.8, 30.6, 26.2, 25.0; HRMS (+ESI) m/z [M +H]+ calcd for
C16H22BrO4+ 357.0704, found 357.0701.
(S)-t-Butyl(dec-9-en-2-yloxy)dimethylsilane (12). A Grignard solution was prepared from 7-bromo-1-
heptene (9) (19.78 g, 111.7 mmol), THF (200 mL) and magnesium turnings (2.85 g, 117.3 mmol) and
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added via cannula to a solution of (S)-propylene oxide (8) (7.8 mL, 111.7 mmol) and copper(I) cyanide
(0.50 g, 5.59 mmol) in THF (200 mL) at –78 °C. The mixture was allowed to warm to room temperature
and quenched after 1 h with conc. aqueous ammonia (100 mL) and sat. aqueous NH4Cl (100 mL). The
resulting mixture was extracted three times with methyl t-butyl ether (300 mL) and the combined
organic layers were dried (anhydrous MgSO4). After removing the volatiles in vacuo the crude alcohol
was obtained as a colorless oil. It was dissolved in dry CH2Cl2 (250 mL) and the resulting solution was
treated with t-butyldimethylsilyl chloride (17.68 g, 117.3 mmol), imidazole (9.13 g, 134.0 mmol) and
DMAP (1.37 g, 11.2 mmol) and the mixture was stirred at room temperature for 15 h. The volatiles
were removed in vacuo and the residue was taken up in n-hexane (100 mL), sat. aqueous NaHCO3
(100 mL) was added and the organic layer was separated. The aqueous layer was extracted three times
with n-hexane (150 mL) and the combined organic layers were dried (anhydrous MgSO4). After
removal of the volatiles in vacuo the title compound was obtained without further purification as a
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colorless oil (27.50 g, 101.6 mmol, 91%). Rf = 0.28 (n-hexane); ["]23 +9.6 (c 1.10, CHCl3); IR (neat)
D
1
#
2928, 2856, 1642, 1463, 1374, 1254, 1133, 1048, 993, 909, 833, 807, 772 cm-1; H NMR (CDCl3,
max
500 MHz) ! 5.81 (ddt, J = 17.1, 10.4, 6.7 Hz, 1 H), 4.99 (ddt, J = 17.1, 1.8, 1.5 Hz, 1 H), 4.93 (ddt, J =
10.2, 2.1, 1.2 Hz, 1 H), 3.76 (dq, J = 11.7, 6.1 Hz, 1 H), 2.04 (dtt, J = 7.4, 7.0, 1.2 Hz, 2 H), 1.19–1.48
13
(m, 10 H), 1.11 (d, J = 6.1 Hz, 3 H), 0.88 (s, 9 H), 0.04 (d, J = 1.2 Hz, 6 H); C NMR (CDCl3, 126
MHz) ! 139.4, 114.3, 68.8, 39.9, 34.0, 29.7, 29.3, 29.0, 26.1, 25.9, 24.0, –4.3, –4.6; HRMS (+ESI) m/z
[M +H]+ calcd for C16H35OSi+ 271.2457, found 271.2461.
(S)-(10-Bromodecan-2-yloxy)(t-butyl)dimethylsilane (13). A stirred solution of (S)-t-butyl(dec-9-en-
2-yloxy)dimethylsilane (12) (6.26 g, 23.1 mmol) in dry THF (10 mL) was treated with BH3·THF
complex (14.0 mL, 13.9 mmol, 1.0 M solution in THF) which was added by a syringe pump at 0 °C at a
rate of 1mL/min. The reaction mixture was allowed to warm to room temperature. After 2 h the mixture
was warmed to 40 °C and bromine (1.2 mL, 23.1 mmol) and sodium methoxide (5.8 mL, 25.4 mmol,
4.4 M in methanol) were added simultaneously, so that the mixture took on a persisting yellowish
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tinge. It was quenched by adding sat. aqueous K2CO3, extracted three times with n-hexane (150 mL) and
the combined organic layers were dried (anhydrous MgSO4). After removal of the volatiles in vacuo and
purifying the residue by filtration over a short plug of silica eluting with 10 % CH2Cl2 in n-hexane the
title compound was obtained as a colorless oil (5.12 g, 14.6 mmol, 63%); Rf = 0.79 (5% ethyl acetate in
n-hexane). ["]23D +8.7 (c 1.26, CHCl3) (lit7a ["]20D +8.7 (c 1,16 CHCl3)); IR (neat) #max 2928, 2856, 1463,
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1374, 1253, 1131, 1056, 1005, 833, 808, 772, 724 cm-1; 1H NMR (CDCl3, 300 MHz) ! 3.71–3.82 (m, 1
H), 3.40 (t, J = 6.9 Hz, 2 H), 1.85 (quin, J = 7.1 Hz, 2 H), 1.23–1.47 (m, 12 H), 1.11 (d, J = 6.0 Hz, 3
H), 0.88 (s, 9 H), 0.04 (d, J = 0.8 Hz, 6 H); 13C NMR (CDCl3, 75 MHz) ! 68.6, 39.7, 34.0, 32.8, 29.7,
29.6, 29.4, 28.7, 28.2, 25.9, 25.7, 23.8, –4.4, –4.7 ppm; HRMS (+ESI) m/z [M +H]+ calcd for
C16H36BrOSi+ 351.1719, found 351.1723.
(10’S)-Benzyl 5-C-{10’-[(t-butyl)dimethylsilyloxy]undecyl}-5-deoxy-2,3-O- isopropylidene-"-D-
lyxofuranoside (14). A Carius tube was charged under an argon atmosphere with a solution of bromide
13 (2.05 g, 5.8 mmol) in dry 1,3-dimethyl-1,2-imidazolidinone (4 mL), zinc dust (1.15 g, 17.5 mmol),
and iodine (46 mg, 0.18 mmol), and then sealed and heated at 80 °C for 18 h while stirring. After
cooling to room temperature the reaction mixture containing organozinc compound 7 was transferred
via cannula to a stirred solution of PEPPSITM-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-
chloropyridyl)palladium(II) dichloride) (50 mg, 0.072 mmol) and freshly dried LiBr (1.01 g,
11.7 mmol) in dry THF (16 mL) and dry 1,3-dimethyl-1,2-imidazolidinone (4 mL). A slow change of
color from yellowish to deep brown indicated the formation of the catalyst. Bromide 6 (1.30 g,
3.6 mmol) was added in one portion and stirring at room temperature was continued for 2 h. The
reaction was quenched by addition of an 0.5 M aqueous solution of Na3EDTA (50 mL) and extracted
three times with a mixture of n-hexane and Et2O (1:1, 100 mL). The organic layers were combined,
dried (anhydrous MgSO4), and concentrated in vacuo. Purification of the remainder by column
chromatography with 5% methyl t-butyl ether in n-hexane afforded product 14 as a colorless viscous oil
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(1.54 g, 2.8 mmol, 78%). Rf = 0.55 (50% ethyl acetate in n-hexane); ["]23 +47.9 (c 1.22, CHCl3) (lit7a
D
1
2
3
["]20 +49.5 (c 1,23 CHCl3)); IR #max 2927, 2856, 1463, 1372, 1255, 1209, 1085, 1016, 834, 807, 773,
D
4
5
6
1
697 cm-1; H NMR (CDCl3, 300 MHz) ! 7.27–7.38 (m, 5 H), 5.06 (s, 1 H), 4.67 (d, J = 11.8 Hz, 1 H),
7
8
9
4.60–4.64 (m, 2 H), 4.48 (d, J = 11.8 Hz, 1 H), 3.96 (td, J = 7.0, 1.8 Hz, 1 H), 3.78 (dqd, J = 6.3, 6.0,
5.8 Hz, 1 H), 1.71 (ddd, J = 14.1, 7.2, 6.4 Hz, 2 H), 1.24–1.48 (m, 26 H), 1.12 (d, J = 6.0 Hz, 3 H), 0.90
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13
(s, 9 H), 0.05 (s, 6 H); C NMR (CDCl3, 75 MHz) ! 137.8, 128.6, 128.2, 127.9, 112.3, 105.3, 85.5,
80.6, 80.3, 69.0, 68.8, 39.9, 29.9, 29.8, 29.8, 29.7, 28.5, 26.4, 26.3, 26.1, 26.0, 25.1, 24.0, 18.3, –4.2, –
4.6; HRMS (+ESI) m/z [M +H]+ calcd for C32H57O5Si+ 549.3975, found 549.3979.
(10’S)-Benzyl 5-Deoxy-5-C-(10’-hydroxyundecyl)-2,3-O-isopropylidene-"-D-lyxofuranoside (15). A
solution of silyl ether 14 (1.17, 2.1 mmol) in THF (10 mL) was treated with HF·pyridine (70wt%,
2.2 mL) at ambient temperature and the resulting mixture was stirred for 1.5 h. Water (10 mL) and sat.
aqueous K2CO3 (10 mL) were added and the mixture was extracted three times with methyl t-butyl ether
(50 mL). The combined organic layers were washed in turn with sat. aqueous CuSO4 (100 mL), H2O
(20 mL) and brine (50 mL). Drying the organic layer (anhydrous MgSO4) and removing the volatiles in
vacuo yielded product alcohol 15 as a colorless solid without further purification (0.89 g, 2.1 mmol,
97%). Rf = 0.27 (20% ethyl acetate in n-hexane); mp 41–42 °C (lit7a mp 41–41.5 °C); ["]23 +57.5 (c
D
1.05, CHCl3) (lit7a ["]20 +59.0 (c 1,05 CHCl3)); IR #max 2925, 2854, 1456, 1372, 1268, 1208, 1164,
D
1076, 1014, 873, 733, 698 cm-1; 1H NMR (CDCl3, 300 MHz) ! 7.27–7.38 (m, 5 H), 5.05 (s, 1 H), 4.66
(d, J = 11.8 Hz, 1 H), 4.60–4.63 (m, 2 H), 4.48 (d, J = 11.8 Hz, 1 H), 3.92–4.00 (m, 1 H), 3.78 (dqd, J =
13
6.3, 6.0, 5.8 Hz, 1 H), 1.63–1.78 (m, 2 H), 1.26–1.47 (m, 26 H), 1.18 (d, J = 6.0 Hz, 3 H); C NMR
(CDCl3, 75 MHz) ! 137.7, 128.6, 128.2, 127.9, 112.3, 105.3, 85.4, 80.6, 80.3, 68.9, 68.3, 39.5, 29.8,
29.8, 29.7, 29.7, 29.6, 28.5, 26.4, 26.3, 25.9, 25.1, 23.6; HRMS (+ESI) m/z [M +Na]+ calcd for
C26H42O5Na+ 457.2925, found 457.2914.
(1R,2R,6S,17R,18S)-6,20,20-trimethyl-5,19,21,22-tetraoxatricyclo[14,5,1,01,18]docosan-4-one (16).
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A stirred solution of !-hydroxy hemiacetal 4 (60 mg, 0.17 mmol) and Ph3PCCO (5) (52 mg,
0.17 mmol) in dry toluene (3 mL) was heated at reflux for 26 h. The volatiles were removed in vacuo
and the remainder was purified by column chromatography with 5% ethyl acetate in n-hexane to afford
the furan 16 as a colorless crystalline solid (8 mg, 0.021 mmol, 12%) of mp 95–97 °C. Rf = 0.82 (10%
1
2
3
4
5
6
7
8
9
ethyl acetate in n-hexane); ["]23 +37 (c 0.10, CHCl3); IR #max 2926, 2855, 1723, 1461, 1378, 1271,
10
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D
1
1234, 1208, 1165, 1068, 891, 860, 802 cm-1; H NMR (CDCl3, 300 MHz) ! 4.97–5.10 (m, 1 H), 4.54–
4.65 (m, 2 H), 4.48 (dd, J = 6.2, 1.2 Hz, 1 H), 3.82 (dt, J = 8.9, 3.4 Hz, 1 H), 2.49 (dd, J = 15.1, 11.8 Hz,
1 H), 2.29 (dd, J = 15.1, 2.5 Hz, 1 H), 1.75–1.88 (m, 1 H), 1.57–1.66 (m, 1 H), 1.22–1.57 (m, 24 H),
1.20 (d, J = 6.3 Hz, 3 H); 13C NMR (CDCl3, 75 MHz) ! 70.5, 112.8, 85.4, 82.4, 80.9, 79.3, 71.6, 36.5,
36.4, 28.7, 28.1, 27.6, 27.6, 27.5, 26.8, 26.6, 26.5, 25.9, 25.6, 24.6, 20.6; MS (EI, 70 eV) m/z 368 (M+),
353, 324, 293, 233, 114; HRMS (+ESI) m/z [M +H]+ calcd for C21H37O5+ 369.2636, found 369.2634.
D-Desosamine-1,2-dibenzoate (20). According to the literature18b a stirred solution of erythromycin
(18) (50 g, 68 mmol) in ethanol (300 mL) and 6 N HCl (800 mL) was heated to reflux for 4 h. The
aqueous acidic solution was cooled to ambient temperature and decanted from a black tar. The solution
was extracted 10 times with CHCl3 (2 L). The aqueous layer was then decolorised with charcoal (100 g)
and filtered over a plug of celite® 545. The volatiles were thoroughly removed in vacuo and the
resulting yellowish brown slurry of crude D-desosamine hydrochloride was dissolved in ethyl acetate
(250 mL) and treated with NEt3 (19.4 mL, 140 mmol), benzoic anhydride (33.9 g, 150 mmol), and
DMAP (3.7 g, 30 mmol). After stirring for 22 h, 5% aqueous NaHCO3 solution (150 mL) was added.
The mixture was stirred vigorously for another 30 min and then extracted three times with ethyl acetate
(300 mL). The combined organic layers were dried (MgSO4) and the volatiles were removed in vacuo.
The residue was partitioned between diethyl ether (200 mL) and 0.5 N HCl (200 mL), the ether layer
was separated and extracted two more times with 0.5 N HCl (200 mL). The combined acidic aqueous
layers were treated with 6 N NaOH to adjust pH 8 and the resulting milky aqueous suspension was
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extracted five times with CH2Cl2 (250 mL). The combined organic layers were dried (MgSO4), the
volatiles were removed in vacuo and the residue was purified by column chromatography with 10%
acetone and 0.1% NEt3 in n-hexane to afford the sugar 20 as a fawn foam (5.48 g, 14.3 mmol, 21%,
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1:1.2 mixture of " and # anomers as to H NMR).Rf = 0.51 (30% ethyl acetate in n-hexane) (lit19a Rf =
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0.47 (30% ethyl acetate in n-hexane)); H NMR (CDCl3, 300 MHz) !-anomer: ! 8.05–8.12 (m, 2 H),
7.89 - 8.03 (m, 2 H), 7.57–7.65 (m, 1 H), 7.44–7.53 (m, 5 H), 6.60 (d, J = 3.6 Hz, 1 H), 5.39–5.49 (m, 1
H), 4.23 (dqd, J = 11.6, 6.0, 2.1 Hz, 1 H), 3.44 (ddd, J = 12.3, 11.0, 4.1 Hz, 1 H), 2.37 (s, 6 H), 1.98
(ddd, J = 13.4, 4.3, 2.1 Hz, 1 H), 1.63 (dd, J = 12.8, 9.3 Hz, 1 H), 1.27 (d, J = 6.3 Hz, 3 H); "-anomer: !
7.89–8.03 (m, 4 H), 7.28–7.40 (m, 6 H), 5.97 (d, J = 8.0 Hz, 1 H), 5.39–5.49 (m, 1 H), 3.89 (dqd, J =
11.6, 6.0, 2.1 Hz, 1 H), 3.07 (ddd, J = 12.3, 10.5, 4.4 Hz, 1 H), 2.35 (s, 6 H), 1.90 (ddd, J = 13.4, 4.3,
2.1 Hz, 1 H), 1.55 (dd, J = 12.8, 9.3 Hz, 1 H), 1.34 (d, J = 6.0 Hz, 3 H).
(1R,2E,6S,17R,18S)-17-O-[3’,4’,6’-trideoxy-3’-(dimethylamino)-!-D-xylo-hexopyranosyl-2’-
benzoate]-6,20,20-trimethyl-5,19,21-trioxabicyclo[16.3.0]henicos-2-en-4-one (22). According to a
general protocol,12a a suspension of AgOTf (75 mg, 0.29 mmol) and powdered 4 Å molecular sieve
(200 mg) in dry CH2Cl2 (4 mL) and toluene (4 mL) at 0 °C was treated with a solution of 1-(2’-
pyrimidinethio)3,4,6,-trideoxy-2-O-benzoyl-3-(dimethylamino)-D-xylo-hexopyranoside (21) (91 mg,
0.24 mmol) in dry CH2Cl2 (2 mL) and with a solution of macrolide 2 (18 mg, 0.049 mmol) in dry
CH2Cl2 (2 mL). The resulting reaction mixture was stirred at ambient temperature in the dark for 16 h,
the molecular sieve was filtered off and sat. aqueous NaHCO3 (5 mL) was added. The resulting mixture
was extracted three times with ethyl acetate (30 mL), the combined organic layers were dried (MgSO4),
and the volatiles were removed in vacuo. After column chromatography with 10% acetone and 0.1%
NEt3 in n-hexane the desired product was obtained as a highly viscous colorless oil (28 mg,
0.046 mmol, 91%). Rf = 0.32 (20% acetone and 0.1% NEt3 in n-hexane); ["]23D +28 (c 1.51, CHCl3); IR
#
2929, 2858, 1718, 1452, 1369, 1268, 1249, 1164, 1123, 1105, 1056, 987, 859, 709, 638, 564 cm-1;
max
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The Journal of Organic Chemistry
1H NMR (CHCl3, 300 MHz) ! 8.01–8.08 (m, 2 H), 7.47–7.53 (m, 1 H), 7.37–7.45 (m, 2 H), 6.90 (dd, J
= 15.5, 8.9 Hz, 1 H), 5.92 (dd, J = 15.6, 0.8 Hz, 1 H), 5.03–5.15 (m, 2 H), 4.65 (d, J = 7.7 Hz, 1 H), 4.50
(ddd, J = 8.7, 5.8, 0.7 Hz, 1 H), 4.26 (dd, J = 8.4, 5.6 Hz, 1 H), 3.52–3.67 (m, 2 H), 2.89 (ddd, J = 12.3,
10.5, 4.4 Hz, 1 H), 2.28 (s, 6 H), 1.79 (ddd, J = 12.9, 4.4, 1.9 Hz, 1 H), 1.51 (s, 3 H), 1.37 (s, 3 H), 1.29
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(d, J = 6.1 Hz, 3 H), 1.22 (d, J = 6.3 Hz, 3 H), 0.67–1.57 (m, 33 H); C NMR (CDCl3, 75 MHz) !
165.7, 165.5, 143.1, 132.8, 130.8, 130.0, 128.4, 124.4, 109.7, 102.6, 81.2, 79.3, 77.4, 72.2, 70.9, 69.5,
64.0, 40.9, 35.6, 31.6, 29.9, 28.4, 27.8, 27.6, 27.3, 27.1, 26.7, 26.0, 25.9, 24.6, 23.4, 21.5, 20.5; HRMS
(+ESI) m/z [M +H]+ calcd for C36H56O8N+ 630.4000, found 630.3987.
1
Supporting Information Available: H and 13C NMR spectra of 1–4, 6, 12-16, 20 and 22. This
material is available free of charge via the Internet at http://pubs.acs.org.
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