Total synthesis of methymycin

Article abstract of DOI:10.1039/b911200f

Methynolide and 10-epi-methynolide were synthesized from the necessary segments, which were prepared by the addition of Grignard reagents to the corresponding α-alkoxyketones utilizing 1,2-stereochemical selection based on Cram chelation control. Ring-clo

Full text of DOI:10.1039/b911200f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of methymycin†
Hong-Se Oh, Richeng Xuan and Han-Young Kang*
Received 8th June 2009, Accepted 20th July 2009
First published as an Advance Article on the web 18th August 2009
DOI: 10.1039/b911200f
Methynolide and 10-epi-methynolide were synthesized from the necessary segments, which were
prepared by the addition of Grignard reagents to the corresponding a-alkoxyketones utilizing
1,2-stereochemical selection based on Cram chelation control. Ring-closing metathesis, as the key
reaction, was carried out to combine the segments for the synthesis of methynolide and
10-epi-methynolide. The total synthesis of methymycin was also achieved by the glycosylation of
methynolide with the trichloroimidate derivative of D-desosamine.
narbonolide, have already been reported.7 Success in the syntheses
Introduction
of these macrolactones encouraged us to investigate the synthesis
of related macrolide antibiotics. Methymycin was chosen as a
synthetic target because it is one of the most abundant macrolides
that belongs to the methymycin family of macrolides, and no
total synthesis of this macrolide antibiotic has been reported since
Masamune et al. reported their synthesis in 1975.5 The synthesis
of methymycin would provide a good opportunity to facilitate
biosynthetic research as well as to evaluate the efficiency of modern
synthetic methods.
Macrolide antibiotics have attracted the attention of synthetic
chemists not only for the complex stereochemical relationship
around the macrocylic ring skeleton but also for their significant
biological activities.1 The pikromycin biosynthetic pathway in-
volves a series of macrolide antibiotics, such as methymycin and
pikromycin, which contain 12- and 14-membered macrolactones
as the core structures, respectively.2
Pikromycin polyketide synthase (Pik PKS) from Streptomyces
venezulae is a gigantic enzyme that is responsible for producing
these macrolide lactones. Pik PKS produces two macrolactones,
that is, 10-deoxymethynolide and narbonolide, which undergo
post-PKS modifications to produce methymycin and pikromycin
macrolactone antibiotics. The post-PKS modifications include
glycosylation followed by regiospecific oxidations which are
caused by Des VII and cytochrome P450 hydroxylase (PikC).
Among the macrolides formed from the pikromycin biosyn-
thetic pathway, methymycin and pikromycin are two of the
major macrolides. Methymycin contains a macrolactone called
methynolide as an aglycone. A great deal of effort has been
directed towards the total synthesis of methynolide3 and its seco-
derivative.4 The first and only total synthesis of methymycin
was reported by Masamune and co-workers.5 We have been
interested in the pikromycin biosynthetic pathways in connection
with the possibility of generating a wide variety of biologically
active derivatives through a combination of genetic and chemical
methods.6 In order to facilitate the investigation of the biosynthetic
mechanisms and explore macrolactone derivatives with new
chemical structures using these techniques, it is important to
identify and secure the expected macrolides. This requirement for
biosynthetic studies, as well as interest in structural complexity,
prompted this study of the synthesis of macrolides that appear in
the pikromycin biosynthetic pathway.
Results and discussion
Fig. 1 shows the retrosynthetic analysis of methymycin (1).
Methymycin could be synthesized by combining methynolide
(2a), the corresponding aglycone part, and D-desosamine, the
sugar moiety. Following the successful synthetic route devel-
oped for 10-deoxymethynolide,7 methynolide was disassembled
retrosynthetically into the parts shown in Fig. 1 ensuring that
the implementation of segment A would lead to the synthesis of
methynolide (2a), and eventually to methymycin (1).
Successful synthetic routes for the total synthesis of typical
12- and 14-membered macrolactones, 10-deoxymethynolide and
Department of Chemistry, Chungbuk National University, Cheongju 361-
763, Republic of Korea. E-mail: hykang@chungbuk.ac.kr; Fax: +82-43-
267-2279; Tel: +82-43-261-2305
Fig. 1 Retrosynthesis of methymycin (1).
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization of compounds 2b, 4–12, 14b–16b, 18–
22, and 1H NMR and 13C NMR spectra for the prepared compounds. See
DOI: 10.1039/b911200f
Our synthetic efforts towards methymycin started with the
preparation of segment A. Scheme 1 summarizes the synthesis
of segment A. The synthesis started from benzyl-protected diol 3
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1,2-stereochemical selection by chelation control resulted in the
successful implementation of the required diol stereochemistry
for the synthesis of the segment.
The synthesis of methynolide was then achieved based
on the route developed previously for the synthesis of 10-
deoxymethynolide (Scheme 2). Carboxylic acid 137 was subjected
to esterification with 9 (a series) using the Yamaguchi protocol.
Removal of the protecting group (DDQ) followed by the Dess-
Martin oxidation provided an aldehyde, which was further sub-
jected to a Grignard reaction with vinyl Grignard reagent. The
resulting alcohol was oxidized to furnish vinyl ketone 15a. The
successful synthesis of vinyl ketone 15a set the stage for testing
the key ring-closing metathesis (RCM) reaction. There were two
issues regarding the key RCM reaction with compound 15a. The
bulkiness of the quaternary carbon center next to the vinyl group
and the instability of the unprotected allylic hydroxy group raised
concern for the success of the RCM reaction. The inability to
protect the tertiary allylic hydroxyl group (e.g. benzylation) led us
to examine the RCM reaction of compound 15a with the hydroxy
group intact. The critical RCM reaction with Grubbs’ second-
generation catalyst was carried out uneventfully in good yield.
Masamune et al. used the protection of the corresponding tertiary
hydroxy group with a benzyl group during their total synthesis of
methynolide.5 This presents another example of the mildness and
superiority of the RCM reaction with Grubbs’ catalyst. The total
synthesis of methynolide (2a) was achieved after deprotection. The
successful synthesis of methynolide demonstrated the efficiency
and generality of the synthetic strategy reported previously for the
synthesis of 12-membered macrolactones.
Scheme 1 Synthesis of the segment A.
which was prepared from (S)-glycidol according to the procedure
reported in the literature.8 After the secondary hydroxy group
was protected with MOM group, the primary alcohol 5 was
synthesized by debenzylation (Pd/C, H2). Cram chelation control
is the key to implementing the necessary stereochemistry at the
carbon that contains a tertiary hydroxy group. Oxidation of alco-
hol 5 provided the aldehyde 6, which was used for the chelation-
controlled nucleophilic addition for the implementation of the
1,2-stereochemical relationship. It is well known in the literature
that highly effective asymmetric induction can be achieved by the
reaction of organometallic compounds, such as Grignard reagents,
with a-alkoxyketones.9
Changing the order of addition of the nucleophiles that attack
the carbonyl group can allow preparation of the desired segment A
with the correct stereochemistry for the synthesis of methynolide
as well as the segment with the epimeric stereochemistry for
preparing 10-epi-methynolide. Therefore, the addition of vinyl
Grignard reagent to the aldehyde 6 first provided a sec-alcohol
as a diastereomeric mixture, which was then oxidized without
separation to give the vinyl ketone 7. Methyl Grignard (MeMgBr)
addition to this vinyl ketone occurred in a chelation-controlled
manner to produce the desired diol derivative 8 with excellent
selectivity. The addition occurred in an almost completely con-
trolled manner and with no formation of the corresponding
diastereomeric diol derivative 11. After acid hydrolysis, the desired
diol 9 possessing the correct stereochemistry for the synthesis
of methynolide (1) was synthesized. Alternatively, the aldehyde
6 was subjected to an addition reaction with methyl Grignard
reagent (MeMgBr) to provide the corresponding MOM-protected
diol. Oxidation followed by vinyl Grignard (vinylMgBr) addition
under the chelation-controlled conditions provided the MOM-
protected diol 11 exclusively. No formation of the diastereomeric
diol derivative 8 was observed. The diastereomeric diol segment
12 was obtained by the deprotection of compound 11 by hy-
drolysis under acidic conditions. In summary, the utilization of
Scheme 2 Synthesis of methynolide and 10-epi-methynolide.
10-epi-Methynolide (2b) was also prepared successfully through
the same reaction sequences, using compound 12 as the cor-
responding segment A (b series) for the esterification of car-
boxylic acid 13. The structure was confirmed by a comparison
with the NMR data reported in the literature for racemic
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10-epi-methynolide (2b).10 The synthesis of methynolide and
10-epi-methynolide assures our assignment of the correct stere-
ochemistry for the chelation-controlled attack of the Grignard
reagents during the synthesis of segment A, as shown in Scheme 1.
After the synthesis of methynolide, we then turned our atten-
tion to methymycin. In order to pursue the total synthesis of
methymycin, it is important to secure the corresponding sugar,
D-desosamine. During their synthesis of methymycin, the
Masamune group exploited the sugar part derived from the
degradation of the natural product.11 In the present study,
we decided to prepare the D-desosamine derivative required
for the glycosylation of methynolide by chemical synthesis.12
D-Desosamine belongs to a class of naturally occurring deoxy
amino sugars which frequently show a variety of biological activ-
ities and are found in several important macrolide antibiotics.13
The synthesis started with compound 17 that was prepared from
commercially available methyl a-D-glycopyranoside (Scheme 3).14
The epoxide18 was prepared from compound17 by the Mitsunobu
reaction, and it was opened with dimethylamine to provide methyl
a-D-desosamine 19. From compound 19, the diacetate derivative
21 was synthesized in a two-step sequence ((a) Ac2O, Et3N; (b)
Ac2O, H2SO4). Deacetylation was achieved by a treatment with
benzylamine to provide compound 22.15
Scheme 4 Total synthesis of methymycin.
segment due to the modular nature of the approach. The key
segment for the synthesis of methynolide was prepared utilizing
1,2-stereochemical selection based on Cram chelation control,
which allowed adjustment of the stereochemical relationship
by variation of the order of addition of the nucleophiles to the
carbonyl group. As a result, the corresponding segments for both
the synthesis of methynolide and 10-epi-methynolide could be
prepared. The stereoselective preparation of methynolide as well
as 10-epi-methynolide is a strong advantage of this synthetic route.
D-Desosamine, which is the sugar part of various natural products,
was synthesized and used for the glycosylation of methynolide,
which led to the successful synthesis of methymycin (1). The
modular approach for the synthesis of macrolactones, and the
glycosylation method developed in this study, will be useful for
synthesizing other polyketide macrolides in the methymycin
family.
Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker
DPX-300 and Brucker Avance 500 NMR spectrometer. The
chemical shifts are reported in ppm on a scale downfield from
TMS, and signal patterns are indicated as follows: s, singlet;
d, doublet; t, triplet; m, multiplet; br, broad peak. IR spectra
were recorded on JASCO FT/IR-300E. Optical rotations were
measured by a JASCO DIP-1000 digital polarimeter in solution
in a 1 dm cell. High resolution mass spectra were recorded on
a Jeol JMS700 by using FAB method. All reagents and solvents
were reagent grade and used without further purification unless
specified otherwise. Technical grade ethyl acetate, hexane, and
pentane used for column chromatography were distilled prior
to use. Tetrahydrofuran (THF) and diethyl ether, when used
as solvents for reactions, were freshly distilled from sodium-
benzophenone ketyl. Dimethylformamide (DMF) was stored over
Scheme 3 Synthesis of the D-desosamine derivative.
The remaining task for the total synthesis of methymycin was
glycosylation. Careful selection of the glycosylation conditions
was needed due to the potential instability of methynolide,
particularly under acidic glycosylation conditions because it has a
tertiary allylic hydroxy group. After considerable experimentation,
we decided to use the trichloroimidate method for glycosylation
(Scheme 4).16 Acetylated desosamine 22 was converted to the
corresponding trichloroimidate 23. The critical glycosylation of
methynolide (2) with compound 23 was carried out successfully
in the presence of BF3·OEt2 to offer compound 24. Final
deacetylation completed the total synthesis of methymycin (1).
The spectral data matched with those reported in the literature.17
˚
4 A molecular sieves, and diethylamide was distilled before use.
Flash chromatography was carried out on Woelm 32–64 mm silica
packed in glass columns.
Conclusion
(1R,2S)-1-Ethyl-2-hydroxy-2-methylbut-3-enyl
(2R,3S,4S,6R)-3-(tert-butyldimethylsilanyloxy)-7-(4-
methoxybenzyloxy)-2,4,6-trimethylheptanoate (14a)
A total synthesis of methymycin has been achieved, which is the
only synthesis reported since the Masamune group reported their
result.5 Methynolide, the aglycone, was synthesized by combining
segments based on the route developed previously by us. In
principle, all the polyketide macrolactones in the pikromycin
biosynthetic pathway can be synthesized by switching the key
To a solution of carboxylic acid 13 (45 mg, 0.10 mmol) in
THF (1.5 mL) at room temperature were added triethylamine
(19 mL, 0.13 mmol) and 2,4,6-trichlorobenzoyl chloride (20 mL,
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0.12 mmol). The mixture was stirred for 3 h at room temperature,
and the solids were filtered off and washed with hexane (3 mL).
The combined solution was concentrated under reduced pressure.
The residue was dissolved in benzene (1 mL), and to this solution
a solution of alcohol 9 (21 mg, 0.16 mmol) and DMAP (17 mg,
0.14 mmol) in benzene (2 mL) was added. After being stirred
for 13 h, the reaction mixture was diluted with ether (10 mL),
and washed with saturated NaHCO3 (10 mL) and saturated NaCl
(10 mL), dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography (hexane/EtOAc = 4:1) afforded
aqueous saturated NaHCO3 (10 mL) and aqueous saturated
Na2S2O3 (5 mL) were added. The resulting mixture was stirred
and the organic layer was extracted and washed with saturated
aqueous NaHCO3 (10 mL), water (10 mL), dried (MgSO4), and
concentrated. Purification of the residue by flash chromatography
(hexane:EtOAc = 5:1) afforded the desired aldehyde (55 mg, 91%):
[a]D27.3 +32.7 (c 1.25, CHCl3); 1H NMR (300 MHz, CDCl3): d 0.06
(s, 3H), 0.07 (s, 3H), 0.85 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.93
(d, J = 6.8 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.05–1.16 (m, 1H),
1.20 (d, J = 7.1 Hz, 3H), 1.24 (s, 3H), 1.42–1.75 (m, 3H), 1.86
(ddd, J = 13.7, 9.6, 3.6 Hz, 1H), 2.38–3.50 (m, 1H), 2.63 (bs, 1H),
2.74 (quintet, J = 7.3 Hz, 1H), 3.86 (dd, J = 7.8, 2.2 Hz, 1H),
4.79 (dd, J = 10.0, 2.9 Hz, 1H), 5.16 (dd, J = 10.8, 1.0 Hz, 1H),
5.32 (dd, J = 17.3, 1.0 Hz, 1H), 5.90 (dd, J = 17.3, 10.8 Hz, 1H),
9.54 (d, J = 2.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 205.7,
176.1, 140.6, 114.0, 80.6, 76.3, 74.6, 44.0, 43.4, 36.3, 32.3, 26.0,
25.0, 22.8, 18.3, 17.2, 15.5, 14.8, 10.6, -3.8, -3.9.
To a stirred solution of the aldehyde (36.1 mg, 0.084 mmol)
prepared as described in the previous procedure and THF (2 mL)
was added vinylmagnesium bromide (1 M, 420 mL, 0.420 mmol)
at 0 ◦C. After stirring for 20 min, the reaction mixture was
diluted with Et2O (5 mL) and saturated aqueous NH4Cl solution
(5 mL). The organic layer was separated, and the aqueous layer
was extracted with ether (3 ¥ 5 mL). The organic solutions were
combined, dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography (hexane:EtOAc = 3:1) afforded
the desired vinyl alcohol (32 mg, 76%) as a colorless oil.
25.8
the desired ester 14a (40 mg, 72%) as a colorless oil: [a]D +10.5
(c 1.32, CHCl3); IR (film): 3486.7, 2954.4, 2858.0, 1727.9, 1612.2,
1511.9, 1461.8, 1369.2, 1299.8, 1172.5, 1056.8 cm-1; 1H NMR
(300 MHz, CDCl3): d 0.05 (s, 6H), 0.85 (t, J = 7. 6 Hz, 3H),
0.89 (s, 9H), 0.92 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H),
0.90–1.10 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 1.23 (s, 3H), 1.40–1.90
(m, 5H), 2.18 (s, 1H), 2.65 (quintet, J = 7.0 Hz, 1H), 3.14 (dd, J =
9.0, 6.8 Hz, 1H), 3.28 (dd, J = 9.0, 5.3 Hz, 1H), 3.80 (s, 3H), 3.92
(dd, J = 6.0, 2.1 Hz, 1H), 4.41 (s, 2H), 4.76 (dd, J = 10.0, 2.9 Hz,
1H), 5.13 (dd, J = 10.8, 1.2 Hz, 1H), 5.30 (dd, J = 17.3, 1.2 Hz,
1H), 5.87 (dd, J = 17.3, 10.8 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H),
7.25 (d, J = 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 176.2,
159.0, 140.8, 130.7, 129.1, 114.0, 113.6, 80.3, 75.4, 75.3, 74.8, 72.6,
55.2, 42.3, 36.9, 36.2, 31.1, 26.0, 25.1, 22.7, 18.3, 16.6, 14.7, 10.7,
-4.1, -4.2; HRMS: m/z calcd for C31H54O6Si, 550.3690; found,
550.3677.
To a stirred solution of the alcohol (16.7 mg, 0.0365 mmol)
prepared as described in the previous procedure in CH2Cl2 (2 mL)
was added Dess-Martin periodinane (31 mg, 0.073 mmol) at
(1R,2S)-1-Ethyl-2-hydroxy-2-methylbut-3-enyl (2R,3S,4S,6R)-3-
(tert-butyldimethylsilanyloxy)-2,4,6-trimethyl-7-oxonon-8-
enoate (15a)
0
◦C. The resulting solution was stirred for 5 h and diluted
To a stirred solution of ester 14a (102 mg, 0.185 mmol) in H2O
(0.2 mL) and CH2Cl2 (2 mL) was added DDQ (84 mg, 0.370 mmol)
at 0 ◦C. After 2.5 h, the reaction mixture was diluted with CH2Cl2
(5 mL). Then, aqueous saturated NaHCO3 (5 mL) was added
to the mixture. The layers were then separated and the aqueous
layer was extracted with CH2Cl2 (3 ¥ 5 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (5 mL), water
(5 mL), and dried (MgSO4). After being concentrated, purification
of the residue by flash chromatography (hexane:EtOAc = 3:1)
afforded the desired primary alcohol (64 mg, 80%) as a colorless
oil: [a]D25.7 +19.2 (c 1.41, CHCl3); IR (film): 3401.8, 2958.3, 1724.1,
1461.8, 1376.9, 1257.4, 1180.2, 1052.9, 929.5, 837.0 cm-1; 1H NMR
(300 MHz, CDCl3): d 0.07 (s, 3H), 0.08 (s, 3H), 0.85 (t, J = 7.4 Hz,
3H), 0.90 (s, 9H), 0.93 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.8 Hz,
3H), 0.90–1.00 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 1.27 (s, 3H),
1.40–1.80 (m, 5H), 2.25 (bs, 2H), 2.73 (quintet, J = 7.1, 1H), 3.37
(dd, J = 10.8, 5.1 Hz, 1H), 3.48 (dd, J = 10.8, 4.6 Hz, 1H), 3.88
(dd, J = 7.3, 2.4 Hz, 1H), 4.80 (dd, J = 10.0, 2.9 Hz, 1H), 5.16
(dd, J = 10.8, 1.0 Hz, 1H), 5.30 (dd, J = 17.3, 1.0 Hz, 1H), 5.90
(dd, J = 17.3, 10.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 176.7,
140.4, 114.2, 80.6, 76.1, 74.7, 66.8, 42.9, 36.0, 34.5, 32.6, 26.0, 25.0,
22.8, 18.3, 18.0, 17.2, 15.5, 10.6, -3.9, -4.0; HRMS: m/z calcd for
C23H47O5Si (M + H)+, 431.3193; found, 431.3196.
with CH2Cl2 (5 mL). After the reaction was completed, aqueous
saturated NaHCO3 (10 mL) and aqueous saturated Na2S2O3
(5 mL) were added. The resulting mixture was stirred and the
organic layer was separated and washed with saturated aqueous
NaHCO3 (5 mL), water (5 mL), and finally dried (MgSO4).
Concentration followed by purification of the residue by flash
chromatography (hexane:EtOAc = 10:1) afforded the desired vinyl
ketone 15a as a colorless oil (13.2 mg, 79%): [a]D25.6 +25.9 (c 1.50,
CHCl3); IR (film): 3506.0, 2962.1, 1727.9, 1616.1, 1401.8, 1376.9,
1253.5, 1176.4, 1052.9 cm-1; 1H NMR (300 MHz, CDCl3): d 0.07
(s, 6H), 0.87 (t, J = 7.4 Hz, 3H), 0.90 (s, 9H), 0.93 (d, J = 7.1 Hz,
3H), 1.20 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.30–1.50 (m, 1H),
1.50–1.70 (m, 2H), 1.97 (ddd, J = 13.7, 10.8, 2.8 Hz, 1H), 2.82–
3.10 (m, 1H), 3.36 (s, 1H), 3.84 (dd, J = 8.5, 1.5 Hz, 1H), 4.79 (dd,
J = 9.6, 3.5 Hz, 1H), 5.16 (dd, J = 10.8, 1.3 Hz, 1H), 5.36 (dd, J =
17.3, 1.3 Hz, 1H), 5.82 (dd, J = 10.1, 1.6 Hz, 1H), 5.97 (dd, J =
17.3, 10.8 Hz, 1H), 6.29 (dd, J = 17.6, 1.5 Hz, 1H), 6.41 (dd, J =
17.6, 10.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 205.1, 176.4,
140.7, 135.4, 128.9, 113.9, 80.9, 76.5, 74.5, 43.3, 40.6, 36.4, 33.8,
26.1, 25.1, 23.1, 18.8, 18.4, 17.8, 16.0, 10.7, -3.7, -3.8.; HRMS:
m/z calcd for C25H47O5Si (M + H)+, 455.3193; found, 455.3193.
(E)-(3R,4S,5S,7R,11S,12R)-4-(tert-Butyldimethylsilanyloxy)-12-
ethyl-3,5,7,11-tetramethyloxacyclododec-9-ene-2,8-dione (16a)
To a solution of the primary alcohol (61.4 mg, 0.142 mmol) ob-
tained as described in the previous procedure and CH2Cl2 (5 mL)
was added the Dess-Martin periodinane (121 mg, 0.285 mmol)
at 0 ◦C. The resulting solution was stirred for 1.5 h and was
diluted with CH2Cl2 (10 mL). After the reaction was completed,
A flame-dried round-bottomed flask was charged with a solution
of vinyl ketone 15a (16.0 mg, 35.2 mmol) in CH2Cl2 (7 mL).
Grubbs’ Catalyst (2nd-Generation) (3.0 mg, 3.52 mmol) was
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subsequently added as a solid, producing a light brown solution,
which was stirred for 12 h at room temperature. The mixture
was then concentrated to give a dark brown oil. Purification
of this residue by flash chromatography (hexane:EtOAc = 7:1)
afforded the◦lactone 16a (13.6 mg, 90%) as a white solid: mp
added molecular sieves (200 mg), and the reaction was stirred
for 30 min at room temperature. After 30 min the mixture was
cooled to -20 ◦C and then BF3·OEt2 (3.5 mL, 0.0247 mmol) was
added. The resulting mixture was stirred for 2 h at -20 ◦C before
it was warmed to room temperature. After additional stirring for
12 h at room temperature NaHCO3 (10 mg) was added to the
mixture. After filtration through a pad of Celite with CH2Cl2
(3 ¥ 5 mL), the solution was concentrated. Purification of the
residue by flash chromatography (EtOAc:MeOH = 10:1) afforded
the protected methymycin 24 (4.2 mg, 43%) as a colorless oil.
23.7
184.2–186.5 C; [a]D +75.5 (c 1.45, CHCl3); IR (film): 3397.0,
2969.8, 1727.9, 1681.6, 1630.5, 1461.8, 1251.6, 1088.6, 1056.8,
1
973.9, 836.0, 774.3 cm-1; H NMR (300 MHz, CDCl3): d 0.07
(s, 3H), 0.08 (s, 3H), 0.85–1.00 (ovlp m, 15H), 1.20 (d, J = 6.9 Hz,
3H), 1.24 (d, J = 7.0 Hz, 3H), 1.34 (s, 3H), 1.28–1.36 (m, 1H),
1.40–1.70 (m, 3H), 1.89–1.97 (m, 1H), 2.11 (s, 1H), 2.50–2.67 (ovlp
m, 2H), 3.64 (d, J = 10.0 Hz, 1H), 4.75 (dd, J = 2.0, 10.7 Hz, 1H),
6.34 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d 204.2, 175.4, 148.7, 125.6, 79.0, 76.5, 76.1,
74.4, 45.0, 44.4, 34.4, 33.4, 26.2, 21.2, 19.4, 18.5, 18.4, 17.7, 17.3,
10.6, -3.1, -3.3; HRMS: m/z calcd for C23H43O5Si (M + H)+,
427.2880; found, 427.2878.
27.0
[a]D +50.2 (c 0.17, CHCl3); IR (film): 3453.9, 2925.9, 2854.1,
1731.8, 1692.2, 1628.6, 1459.9, 1373.1, 1238.1, 1162.9, 1109.8,
1
1059.7, 989.3, 903.5 cm-1; H NMR (500 MHz, CDCl3): d 0.90
(t, J = 7.4 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 7.0 Hz,
3H), 1.23 (d, J = 6.1 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.37 (s,
3H) 1.43 (m, 1H), 1.73 (bd, J = 11.4 Hz, 1H), 1.93 (ddd, J = 14.1,
7.6, 2.3 Hz, 1H), 2.03 (s, 1H), 2.08 (s, 3H), 2.26 (s, 6H), 2.55 (m,
1H), 2.71 (m, 2H), 3.47 (m, 1H), 3.55 (d, J = 10.3 Hz, 1H), 4.31 (d,
J = 7.6 Hz, 1H), 4.77 (m, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.57 (d,
J = 16.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 204.3, 174.9,
169.9, 148.3, 125.9, 102.9, 85.3, 74.5, 71.6, 69.1, 63.5, 45.1, 44.1,
40.6, 33.7, 33.5, 30.4, 29.7, 21.4, 21.0, 19.5, 17.6, 17.3, 16.0, 10.7;
HRMS: m/z calcd for C27H46NO8 (M + H)+, 512.3223; found,
512.3226.
Methynolide (2a)
To a stirred solution of lactone 16a (3.4 mg, 0.0079 mmol) in
dry THF (1 mL) at room temperature was added 1.0 M TBAF
(200 mL, 0.200 mmol) via a syringe. After 2.5 h, the reaction
mixture was concentrated. Purification by flash chromatography
(hexane:EtOAc = 1:2) afforded methynolide (2a) (1.9 mg, 77%) as
To a stirred solution of 24 (4.2 mg, 0.0082 mmol) in MeOH
(1 mL) at room temperature was added H2O (200 mL) and
triethylamine (200 mL). After 3 h, the reaction mixture was
concentrated. Purification of the residue by flash chromatography
(EtOAc:MeOH = 10:1) afforded methymycin (1) (3.5 mg, 91%) as
◦
21.7
a white solid: mp 164.0–167.2 C; [a]D +74.9 (c 0.07, CHCl3);
IR (film): 3428.8, 2966.0, 1724.1, 1627.6, 1457.9, 1373.1, 1272.8,
1160.9, 987.4 cm-1: 3428.8, 2965.0, 1724.1, 1627.6, 1457.9, 1373.1,
1272.8, 1160.9 cm-1; 1H NMR (500 MHz, CDCl3): d 0.91 (t, J =
7.4 Hz, 3H), 1.01 (d, J = 5.9 Hz, 3H), 1.25–1.40 (m, 1H), 1.21 (d,
J = 7.0 Hz, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.38 (s, 3H), 1.46–1.67
(m, 3H), 1.94 (s, broad, 1H), 1.94 (ddq, J = 14.0, 7.5, 2.0 Hz, 1H),
2.50–2.66 (m, 2H), 3.58 (brd, J = 10.5 Hz, 1H), 4.78 (dd, J = 11.0,
2.0 Hz, 1H), 6.34 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H);
13C NMR (125 MHz, CDCl3): d 203.9, 174.8, 148.6, 125.5, 78.0,
76.5, 74.5, 45.2, 43.5, 33.4, 33.1, 21.2, 19.5, 17.6, 17.4, 16.5, 10.7;
HRMS: m/z calcd for C17H28O5, 312.1937; found, 312.1937.
24.9
a colorless oil. [a]D +79.7 (c 0.11, CHCl3); IR (film): 3432.7,
2924.5, 2852.2, 2345.0, 2081.8, 1729.8, 1686.4, 1631.5, 1461.8,
1376.9, 1268.0, 1161.9 cm-1; 1H NMR (500 MHz, CDCl3): d 0.92
(t, J = 7.4 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 7.0 Hz,
3H), 1.23 (d, J = 6.1 Hz, 3H), 1.37 (s, 3H), 1.44 (d, J = 6.9 Hz,
3H), 1.51 (m, 2H), 1.67 (m, 1H), 1.92 (ddd, J = 14.1, 7.6, 2.2 Hz,
1H), 2.28 (s, 6H), 2.50 (m, 1H), 2.56 (m, 1H), 2.87 (m, 1H), 3.22
(dd, J = 10.2, 7.4 Hz, 1H), 3.48 (m, 1H), 3.61 (d, J = 10.4 Hz,
1H), 4.24 (d, J = 7.3 Hz, 1H), 4.75 (dd, J = 10.8, 2.2 Hz, 1H),
6.35 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 15.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d 204.4, 175.2, 148.4, 125.8, 105.0, 85.5, 76.2,
74.5, 70.3, 69.5, 65.9, 45.1, 44.2, 40.2, 33.9, 33.6, 29.7, 21.3, 21.1,
19.5, 17.6, 17.4, 16.2, 10.7; HRMS: m/z calcd for C25H44NO7 (M +
H)+, 470.3118; found, 470.3121.
2-O-Acetyl-3-dimethylamino-3,4,6-trideoxy-a-D-
xylohexopyranosyl trichloroacetimidate (23)
To a solution of 22 (27 mg, 0.12 mmol) in CH2Cl2 (5 mL)
at 0 ◦C were added Cl3CCN (149 mL, 1.49 mmol) and DBU
(5.00 mL, 0.036 mmol). After stirring for 1 h at 0 ◦C, the reaction
mixture was concentrated. Purification by flash chromatography
(EtOAc:MeOH = 10:1) afforded the desired trichloroacetimidate
23 (a:b = 1:1, 24 mg, 56%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d 1.21 (d, J = 6.2 Hz, 3H), 1.29 (d, J = 6.1 Hz, 3H), 1.46
(m, 2H), 1.82 (m, 3H), 2.00 (s, 3H), 2.01 (s, 3H), 2.10 (m, 1H),
2.28 (s, 6H), 2.29 (s, 6H), 2.83 (m, 1H), 3.24 (m, 1H), 3.76 (dddd,
J = 10.8, 6.2, 6.2, 6.2 Hz, 1H), 4.11 (m, 1H), 5.06 (m, 2H), 5.70
(d, J = 7.7 Hz, 1H), 6.38 (d, J = 3.4 Hz, 1H), 8.49 (s, 1H), 8.57
(s, 1H); 13C NMR (75 MHz, CDCl3): d 170.4, 169.6, 161.4, 161.3,
97.7, 94.9, 91.3, 90.8, 70.6, 69.6, 69.4, 67.6, 62.9, 57.6, 40.6, 40.4,
31.7, 30.4, 21.1, 21.0, 21.0.
Acknowledgements
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-
2007–521-C00152). The authors are grateful to Prof. Yeo Joon
Yoon (Ewha Womans University) for supplying the cell culture
from which the authentic sample of methymycin was isolated.
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