Total synthesis of pikromycin

Article abstract of DOI:10.1021/jo201158q

The total synthesis of pikromycin (6), the first isolated macrolide antibiotic, was achieved. The target macrolide was retrosynthetically divided into two parts, pikronolide (6a) (aglycon) and d-desosamine. The aglycon was synthesized using key reactions

Full text of DOI:10.1021/jo201158q

Note
pubs.acs.org/joc
Total Synthesis of Pikromycin
Hong-Se Oh and Han-Young Kang*
Department of Chemistry, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea
S
* Supporting Information
ABSTRACT: The total synthesis of pikromycin (6), the first isolated macrolide
antibiotic, was achieved. The target macrolide was retrosynthetically divided into
two parts, pikronolide (6a) (aglycon) and D-desosamine. The aglycon was
synthesized using key reactions such as an asymmetric aldol reaction, Yamaguchi
esterification, and ring-closing metathesis. The aglycon was coupled successfully
with the trichloroacetimidate derivative of D-desosamine under Lewis acidic
conditions to afford pikromycin. Narbomycin (5) was also synthesized from
narbonolide (5a) under identical conditions.
acrolide antibiotics belong to a class of polyketide
natural products that exhibit clinically important bio-
neomethynolide (3a),10 novamethynolide (4a), 5a,11 and
pikronolide (6a)12 as well as macrolides such as 2. Surprisingly,
even though pikromycin is the representative molecule in this
series of macrolides that appear in the pikromycin biosynthetic
pathway in Streptomyces venezuelae and is important structurally
and historically, the total synthesis of pikromycin by chemical
means has not been reported.
We have been involved in the synthesis of the macrolides
that appear in the pikromycin pathway. We have successfully
reported the syntheses of aglycons of these macrolides, such as
1a and 5a,13 as well as macrolides such as 2,14 3, and 4.15 In this
paper, we report the first successful total synthesis of
pikromycin.
Our retrosynthetic analysis for pikromycin (6), which is
based on our previously reported synthetic experiences,13−15 is
shown in Figure 2. Pikromycin can be derived from 6a through
glycosylation. Pikronolide (6a) can, in turn, be retrosyntheti-
cally divided into three parts. Aldol reaction, Yamaguchi
esterification, and ring-closing metathesis could be used for the
construction of 6a. Our synthesis of 6a is summarized in
Scheme 1.
M
logical activities.1,2 They usually possess a macrolactone ring to
which are attached one or more sugars; these antibiotics are
usually produced by certain species of Streptomyces. Pikromycin
was the first known macrolide antibiotic that was isolated in
1950 and originally considered to be an isomer of methymycin,
which has a 12-membered lactone ring. The correct structure
was identified by Brockmann and co-workers in 1957 to be a
14-membered lactone attached with a sugar called D-desos-
amine.3 Streptomyces venezuelae produces a series of macrolides,
which belong to two families, methymycin and pikromycin. A
macrolide belonging to the methymycin family, such as
methymycin (2),4 has a 12-membered lactone ring, whereas a
macrolide belonging to the pikromycin family, such as
pikromycin (6), contains a 14-membered macrolactone ring
(Figure 1). Pikromycin polyketide synthase (Pik PKS) is a
gigantic enzyme that is responsible for producing many
macrolactones such as 10-deoxymethynolide (1a)5 and
narbonolide (5a). Glycosylation of these two macrolactones
with desosamine, which is the first post-PKS modification, is
catalyzed by enzymes encoded by the des genes to provide YC-
17 (1) and narbomycin (5), respectively. Hydroxylation,
another post-PKS modification, of these two macrolides by
cytochrome P450 oxygenase (Pik C), leads to the generation of
a variety of macrolides, depending upon the site of oxidation.
Hydroxylation of the C-10 and C-12 positions of 1 generates 2
and neomethymycin (3),4 respectively. YC-17 (1) is hydroxy-
lated at both C-10 and C-12 positions to afford novamethy-
mycin (4).6 Similarly, hydroxylation of 5 at C-12 or C-14
positions provides 6 and neopikromycin (7), respectively. The
oxidation of both C-12 and C-14 positions affords novapikro-
mycin (8).7 As a result, a total of eight macrolides, four with 12-
membered macrolactones and the other four with 14-
membered macrolactones, are produced with the involvement
of PKS, Des, and Pik C enzymes.
Carboxylic acid 913 was prepared according to a procedure
similar to that reported for the synthesis of 5a. Esterification
with the fragment 1014 through the Yamaguchi protocol
afforded an ester 11, which was subjected to the deprotection
of the TBS group under acidic conditions (CSA, MeOH) to
yield 12. Oxidation followed by Grignard addition and another
oxidation with DMP offered vinyl ketone 15 as a precursor for
the critical ring-closing metathesis (RCM). Cyclization of 15
with the second-generation Grubbs catalyst successfully
provided a 14-membered lactone 16 in good yield. Depro-
tection of the hydroxy group at C-3 with TBAF followed by the
Dess−Martin oxidation provided a PMB-protected ketone 18.
Deprotection of the PMB group to free the hydroxy group at
C-5 is the only remaining step for the completion of the total
synthesis of 6a. The usual deprotection condition employing
Chemical synthesis of these macrolides has attracted
considerable attention; as a result, synthetic studies have been
Received: June 18, 2011
Published: December 14, 2011
conducted on aglycons such as 1a,8 methynolide (2a),9
© 2011 American Chemical Society
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Figure 1. Methymycin and pikromycin families of macrolide antibiotics.
1: 1 by altering the solvent from CDCl3 to CD3OD. Although
Yonemitsu and co-workers who reported the synthesis of
pikronolide (6a) did not mention the formation of pikronolide-
5,9-hemiacetal (6b), possibility of the hemiacetal formation
through the reactions between the free hydroxy and the 9-keto
group had already been reported in erythromycin16 and
telithromycin cases.17
Having pikronolide in our hands, glycosylation of 6a with D-
desosamine is required in order to achieve our goal, the
synthesis of pikromycin. As a test for finding optimum
conditions for the desired glycosylation, we first performed
glycosylation of 5a. Narbonolide (5a), which was prepared
previously,13 did not suffer from the contamination of an
unidentified minor product and was also slightly more easily
accessible due to the absence of the C-12 hydroxy group. To
the best of our knowledge, total synthesis of narbomycin has
never been reported either.
Even though we had a successful test glycosylation with a
narbonolide derivative under the Lewis acidic conditions, we
could not achieve the desired glycosylation of 6a with a D-
desosamine trichloroacetimidate derivative18 under the Lewis
acidic conditions such as BF3 OEt or TMSOTf. Searching for a
better glycosylation method, we found that stereoselective
direct glycosylation developed by Kim,19 which includes
activation with phthalic anhydride and Tf2O, is effective for
the coupling of desosamine with 6a (Scheme 2).
Figure 2. Retrosynthetic analysis.
DDQ at 0 °C affords 6a (76%); the 1H NMR spectrum of thus
prepared 6a reasonably matched with that reported by
Yonemitsu and co-workers.12 Careful analysis of the NMR
spectrum shows that the deprotection provided a 4:1 mixture of
pikronolide (6a) and another compound which is identified as
the corresponding 5−9-hemiacetal 6b. Although this mixture
was inseparable, the structure of the hemiacetal 6b was strongly
supported by COSY and HSQC spectra. The 1H NMR
spectrum revealed that the ratio of the mixture was changed to
Scheme 1. Synthesis of Pikronolide (6a)
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Note
Scheme 2. Synthesis of Pikromycin (6)
EXPERIMENTAL SECTION
■
General Methods. 1H NMR spectra were recorded on a 300, 400,
or 500 MHz spectrometer at ambient temperature with CDCl3 as the
solvent unless otherwise stated. 13C NMR spectra were recorded on a
75, 100, or 125 MHz spectrometer (with complete proton decoupling)
at ambient temperature. High-resolution mass spectrometry (HRMS)
was performed using a FAB technique. Flash chromatography was
performed using 230−400 mesh silica gel.
(3S,4R)-3-Hydroxy-3-methylhex-1-en-4-yl (2R,3S,4R,
5S,6S,8R)-3,9-Bis-(tert-butyldimethylsilyloxy)-5-(4-methoxy-
benzyloxy)-2,4,6,8-tetramethylnonanoate (11). To a solution of
carboxylic acid 9 (611 mg, 1.00 mmol) in THF (10 mL) at room
temperature were added triethylamine (209 μL, 1.50 mmol) and 2,4,6-
trichlorobenzoyl chloride (203 μL, 1.30 mmol). The mixture was
stirred for 3 h at room temperature, and the solids were filtered off and
washed with hexane (2 × 5 mL). The combined solution was
concentrated under reduced pressure. The residue was dissolved in
benzene (5 mL), and to this solution a solution of alcohol 10 (196 mg,
1.50 mmol) and 4-(dimethlamino)pyridine (DMAP) (171 mg, 1.40
mmol) in benzene (2 mL) was added. After being stirred for 15 h, the
reaction mixture was diluted with ether (10 mL), washed with
saturated NaHCO3 (10 mL) and saturated NaCl (10 mL), dried
(MgSO4), and concentrated. Purification of the residue by flash
chromatography (hexane/EtOAc = 5:1) afforded the desired ester 11
In fact, glycosylation of 6a with Ac-protected desosamine
1914 was achieved through activation with phthalic anhydride
(phthalic anhydride, DBU, DTBMP, Tf2O, 4 Å MS, −78 °C) in
reasonable yield (33%). Deacetylation (MeOH, Et3N, H2O)
afforded the desired pikromycin in 79% yield. Encouraged with
this success in glycosylation via activation with phthalic
anhydride, we also applied this method to the synthesis of 5
from 5a. The phthalic anhydride method, however, resulted in
the decomposition of 5a. This was unexpected, since 6a seemed
to be more sensitive than narbonolide 5a owing to the existence
of an extra tertiary hydroxy group in 6a. After experimentation,
we finally found that the glycosylation of 5a with the
corresponding trichloroacetimidate 2114,15,18 using TfOH
effectively afforded the desired glycosylated product, which
was further subjected to deacetylation to yield 5. This
comprises the successful total synthesis of 5. Under this
glycosylation condition using TfOH we were also able to
perform the successful glycosylation of 6 (Scheme 3). The
(590 mg, 82%) as a colorless oil: [α]29 +8.12 (c 1.08, CHCl3); IR
D
(film) 3453, 2972, 2932, 1729, 1610, 1512, 1455, 1370, 1249, 1170,
1
1037 cm−1; H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), 0.05 (d, J =
3.4 Hz, 6H), 0.83 (m, 12H), 0.88 (m, 12H), 0.94 (d, J = 6.8 Hz, 6H),
1.19 (m, 6H), 1.34 (m, 1H), 1.48 (m, 1H), 1.63 (m, 2H), 1.84 (m,
3H), 2.80 (dddd, J = 7.0, 7.0, 7.0, 13.9 Hz, 1H), 3.23 (m, 2H), 3.56
(dd, J = 4.5, 9.8, Hz, 1H), 3.75 (s, 3H), 3.98 (dd, J = 4.2, 6.2 Hz, 1H),
4.43 (q, J = 10.8 Hz, 2H), 4.71 (dd, J = 2.9, 9.8 Hz, 1H), 5.06 (dd, J =
0.7, 10.9 Hz, 1H), 5.24 (d, J = 17.3 Hz, 1H), 5.81 (dd, J = 10.8, 17.3
Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 176.0, 158.9, 140.9, 131.3, 128.9, 114.1, 113.6,
83.8, 80.3, 74.8, 73.9, 73.6, 67.8, 55.2, 43.3, 40.4, 35.7, 33.2, 33.1, 26.2,
26.0, 24.9, 22.7, 19.0, 18.5, 18.3, 17.5, 17.2, 14.9, 10.8, 10.7, −3.7, −3.8,
−5.3; HRMS (FAB) calcd for C40H74O7Si2 + H 723.5051, found
723.5046.
(3S,4R)-3-Hydroxy-3-methylhex-1-en-4-yl (2R,3S,4R,
5S,6S,8R)-3-(tert-Butyldimethylsilyloxy)-9-hydroxy-5-(4-me-
thoxybenzyloxy)-2,4,6,8-tetramethylnonanoate (12). Ester 11
(590 mg, 0.82 mmol) was dissolved in MeOH (10 mL). To this
solution was added DL-10-camphorsulfonic acid (38 mg, 0.16 mmol).
The resulting solution was stirred at 0 °C for 1 h. The reaction was
terminated by addition of Et3N (114 μL, 0.82 mmol). After the
solution was concentrated, purification by flash chromatography
(hexane/EtOAc = 3:1) gave the desired primary alcohol 12 (385
Scheme 3. Synthesis of Narbomycin (5) and Pikromycin (6)
mg, 78%) as a colorless oil: [α]29 +7.59 (c 1.36, CHCl3); IR (film)
D
3480, 2932, 1745, 1695, 1613, 1514, 1460, 1379, 1299, 1249, 1193,
1
1080, 983, 823 cm−1; H NMR (300 MHz, CDCl3) δ 0.01 (d, J = 7.0
Hz, 6H), 0.74 (t, J = 7.3 Hz, 3H), 0.84 (m, 12H), 0.92 (d, J = 6.5 Hz,
3H), 0.94 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 7.8 Hz, 3H), 1.14 (s, 3H),
1.39 (m, 2H), 1.56 (m, 2H), 1.76 (m, 2H), 2.42 (bs, 1H), 2.68 (dddd,
J = 7.1, 7.1, 7.1, 14.3 Hz, 1H), 2.82 (bs, 1H), 3.12 (dd, J = 1.5, 9.0 Hz,
1H), 3.30 (dd, J = 4.2, 11.1 Hz, 1H), 3.54 (dd, J = 3.5, 11.1 Hz, 1H),
3.68 (s, 3H), 3.82 (d, J = 7.9 Hz, 1H), 4.38 (q, J = 10.8 Hz, 2H), 4.65
(dd, J = 2.6, 9.6 Hz, 1H), 5.03 (dd, J = 0.9, 10.8 Hz, 1H), 5.18 (dd, J =
1.0, 17.3 Hz, 1H), 5.75 (dd, J = 10.8, 17.4 Hz, 1H), 6.75 (d, J = 8.6 Hz,
2H), 7.15 (d, J = 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 177.0,
158.9, 140.4, 131.3, 128.9, 114.5, 113.6, 85.2, 80.6, 75.0, 74.3, 73.6,
65.9, 55.2, 44.6, 40.8, 33.0, 32.8, 32.6, 32.2, 26.2, 24.5, 22.6, 18.7, 18.6,
18.5, 16.3, 10.5, 9.8, −3.3, −3.4; HRMS (FAB) calcd for C34H60O7Si +
H 609.4187, found 609.4182.
(3S,4R)-3-Hydroxy-3-methylhex-1-en-4-yl (2R,3S,4R,
5S,6S,8R)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzy-
loxy)-2,4,6,8-tetramethyl-9-oxononanoate (13). The alcohol 12
(290 mg, 0.48 mmol) was dissolved in CH2Cl2 (8 mL). To this
solution was added Dess−Martin periodinane (DMP) (404 mg, 0.95
mmol). The resulting solution was stirred for 30 min at room
1
spectroscopic properties (both H NMR and 13C NMR) of 6
thus prepared are identical to those of 6 isolated from the cell
culture.
In conclusion, the first chemical total syntheses of
pikromycin (6) and narbomycin (5) have been achieved via
glycosylation of pikronolide (6a) and narbonolide (5a),
respectively, with the trichloroacetimidate derivative of D-
desosamine. Pikronolide was synthesized through the coupling
of the corresponding fragments using asymmetric aldol
reactions, Yamaguchi esterification, and ring-closing metathesis
using Grubbs' second-generation catalyst.
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Note
temperature. After the reaction was completed, aqueous saturated
NaHCO3 (10 mL) was added. The mixture was extracted with CH2Cl2
(3 × 10 mL). The organic layer was separated, dried (MgSO4), and
concentrated. Purification by flash chromatography (hexane/EtOAc =
5:1) offered the desired aldehyde 13 (271 mg, 94% yield) as a
(E)-(3R,4S,5R,6S,7S,9R,13S,14R)-4-(tert-Butyldimethylsily-
loxy)-14-ethyl-13-hydroxy-6-(4-methoxybenzyloxy)-
3,5,7,9,13-pentamethyloxacyclotetradec-11-ene-2,10-dione
(16). A flame-dried round-bottomed flask was charged with vinyl
ketone 15 (171 mg, 0.27 mmol) and CH2Cl2 (20 mL). Grubbs catalyst
(second generation) (46 mg, 0.054 mmol) was subsequently added as
a solid, producing a light brown solution which was stirred for 18 h at
room temperature. The mixture was then concentrated. Purification of
this residue by flash chromatography (hexane/EtOAc = 4:1) afforded
the lactone 16 (137 mg, 84%) as a yellow liquid: [α]25D +24.0 (c 1.00,
CHCl3); IR (film) 3346, 2925, 2853, 1739, 1673, 1544, 1462, 1378,
1246, 1161, 1078, 822 cm−1; 1H NMR (300 MHz, CDCl3) δ 0.02 (d, J
= 13.2 Hz, 6H), 0.80 (m, 3H), 0.86 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H),
1.05 (m, 9H), 1.16 (m, 2H), 1.25 (s, 3H), 1.48 (m, 3H), 1.74 (m, 2H),
2.11 (bs, 1H), 2.52 (m, 2H), 3.12 (d, J = 9.4 Hz, 1H), 3.72 (s, 3H),
3.87 (dd, J = 1.9, 3.7 Hz, 1H), 4.38 (q, J = 10.6 Hz, 2H), 4.73 (dd, J =
2.2, 10.9 Hz, 1H), 6.25 (d, J = 15.6 Hz, 1H), 6.79 (m, 3H), 7.17 (d, J =
8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 202.8, 177.1, 159.0, 148.1,
131.0, 129.0, 124.7, 113.7, 84.7, 80.0, 75.3, 74.6, 71.5, 55.3, 45.2, 45.0,
44.4, 34.7, 34.4, 26.2, 22.2, 18.6, 18.4, 17.4, 13.5, 10.7, 9.6, −3.1, −4.3;
HRMS (FAB) calcd for C34H56O7Si + H 605.3874, found 605.3868.
(E)-(3R,4S,5S,6S,7S,9R,13S,14R)-14-Ethyl-4,13-dihydroxy-6-
(4-methoxybenzyloxy)-3,5,7,9,13-pentamethyloxacyclotetra-
dec-11-ene-2,10-dione (17). To a stirred solution of lactone 16 (93
mg, 0.15 mmol) in dry THF (7 mL) at room temperature was added
1.0 M TBAF (460 μL, 0.46 mmol) via a syringe. After 2.5 h, the
reaction mixture was concentrated. Purification by flash chromatog-
raphy on a silica gel column (hexane/EtOAc = 2:1) afforded alcohol
colorless liquid: [α]32 +15.3 (c 1.10, CHCl3); IR (film) 3487, 2958,
D
2933, 2856, 1721, 1613, 1586, 1514, 1461, 1373, 1302, 1249, 1172,
1103, 1059 cm−1; 1H NMR (300 MHz, CDCl3): δ 0.09 (d, J = 2.6 Hz,
6H), 0.87 (t, J = 7.4 Hz, 3H), 0.93 (s, 9H), 1.03 (d, J = 6.8 Hz, 6H),
1.10 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 7.3 Hz, 3H), 1.25 (s, 3H), 1.53
(m, 2H), 1.70 (m, 1H), 1.84 (m, 3H), 2.07 (s, 1H), 2.43 (m, 1H), 2.79
(q, J = 7.2 Hz, 1H), 3.24 (dd, J = 2.5, 7.9 Hz, 1H), 3.80 (s, 3H), 3.95
(dd, J = 2.2, 7.6 Hz, 1H), 4.48 (q, J = 10.7 Hz, 2H), 4.78 (dd, J = 2.8,
10.2 Hz, 1H), 5.14 (d, J = 10.8 Hz, 1H), 5.30 (d, J = 17.3 Hz, 1H),
5.88 (dd, J = 10.8, 17.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 7.26 (d, J =
8.5 Hz, 2H), 9.59 (d, J = 3.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ
206.5, 175.9, 158.9, 140.7, 131.0, 128.9, 114.2, 113.6, 84.5, 80.2, 74.7,
74.6, 73.3, 55.2, 44.2, 44.1, 40.9, 33.0, 31.7, 26.2, 24.7, 22.6, 18.5, 17.7,
15.7, 15.0, 10.6, 10.2, −3.6, −3.7; HRMS (FAB) calcd for C34H58O7Si
+ Na 629.3850, found 629.3851.
(3S,4R)-3-Hydroxy-3-methylhex-1-en-4-yl (2R,3S,4R,5S,
6S,8R)-3-(tert-Butyldimethylsilyloxy)-9-hydroxy-5-(4-methoxy-
benzyloxy)-2,4,6,8-tetramethylundec-10-enoate (14). To a
stirred solution of the aldehdyde 13 (271 mg, 0.45 mmol) in THF
(6 mL) was added 1 M vinylmagnesium bromide (890 μL, 0.89 mmol)
at room temperature. After 20 min, the reaction mixture was diluted by
adding Et2O (10 mL), and then a saturated aqueous NH4Cl solution
(10 mL) was added. The organic solution was separated, and the
aqueous layer was extracted with ether (3 × 10 mL). The organic
solutions were combined, dried (MgSO4), and concentrated.
Purification of the residue by flash chromatography (hexane/EtOAc
= 4:1) afforded the desired vinyl alcohol 14 (231 mg, 82%, dr = 1:1) as
a colorless oil: IR (film) 3479, 2957, 2929, 2855, 1713, 1613, 1586,
17 (61 mg, 81%) as a colorless oil: [α]29 +26.8 (c 1.12, CHCl3); IR
D
(film) 3457, 2972, 2930, 1731, 1668, 1613, 1514, 1462, 1370, 1249,
1
1273 cm−1; H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H),
1.05 (m, 9H), 1.26 (d, J = 5.1 Hz, 3H), 1.31 (m, 6H), 1.54 (m, 1H),
1.73 (m, 1H), 1.92 (m, 1H), 2.14 (m, 2H), 2.64 (m, 1H), 2.78 (m,
1H), 3.05 (s, 1H), 3.59 (t, J = 3.4 Hz, 1H), 3.81 (s, 3H), 3.90 (d, J =
8.9 Hz, 1H), 4.37 (d, J = 10.8 Hz, 1H), 4.58 (d, J = 10.8 Hz, 1H), 4.85
(d, J = 10.9 Hz, 1H), 6.22 (d, J = 16.3 Hz, 1H), 6.79 (d, J = 16.3 Hz,
1H), 6.89 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 204.4, 176.2, 159.4, 149.1, 129.8, 129.5, 126.8, 114.0,
83.8 79.1, 73.6, 71.3, 55.3, 44.0, 40.0, 38.7, 37.9, 31.3, 29.7, 21.4, 21.4,
16.8, 14.8, 14.4, 10.4, 8.5; HRMS (FAB) calcd for C28H42O7 + Na
513.2828, found 513.2833.
1
1514, 1461, 1373, 1301, 1249, 1173, 1038, 957 cm−1; H NMR (400
MHz, CDCl3) δ 0.12 (m, 6H), 0.87 (m, 3H), 0.94 (m, 9H), 1.04 (m,
6H), 1.24 (m, 9H), 1.53 (m, 2H), 1.93 (m, 2H), 2.40 (m, 1H), 2.77
(m, 1H), 3.25 (m, 1H), 3.80 (s, 3H), 3.61−3.99 (m, 2H), 4.50 (q, J =
10.7 Hz, 2H), 4.79 (m, 1H), 5.14 (m, 2H), 5.29 (d, J = 17.5 Hz, 2H),
5.87 (m, 2H), 6.87 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 177.1, 176.7, 158.9, 140.4, 140.3, 140.2,
139.9, 131.4, 128.9, 128.6, 128.4, 128.0, 127.8, 127.7, 115.1, 114.7,
114.5, 114.0, 113.6, 85.4, 85.0, 80.7, 80.6, 77.8, 77.2, 75.2, 74.6, 74.5,
74.4, 73.7, 73.6, 72.4, 55.3, 44.8, 44.4, 40.8, 40.6, 37.3, 35.8, 34.2, 34.0,
32.5, 31.9, 29.7, 26.3, 24.8, 24.7, 22.8, 22.7, 18.6, 18.5, 18.5, 18.1, 16.5,
15.8, 14.9, 10.6, 10.5, 10.3, 9.8, −3.2, −3.3, −3.4, −3.5; HRMS (FAB)
calcd for C36H62O7Si + H 635.4343, found 635.4346.
(E)-(3R,5R,6S,7S,9R,13S,14R)-14-Ethyl-13-hydroxy-6-(4-me-
thoxybenzyloxy)-3,5,7,9,13-pentamethyloxacyclotetradec-11-
ene-2,4,10-trione (18). The alcohol 17 (61 mg, 0.12 mmol) was
dissolved in CH2Cl2 (5 mL). To this solution was added Dess−Martin
periodinane (DMP) (105 mg, 0.25 mmol). The resulting solution was
stirred for 30 min at room temperature. After the same workup as
described for the preparation of 13, purification by flash chromatog-
raphy (hexane/EtOAc = 2:1) offered the desired ketone 18 (54 mg,
89%) as a colorless oil: [α]25D −26.9 (c 0.32, CHCl3); IR (film) 3476,
2972, 2929, 1746, 1692, 1619, 1514, 1462, 1370, 1249, 1185, 1080
(3S,4R)-3-Hydroxy-3-methylhex-1-en-4-yl (2R,3S,4R,5S,
6S,8R)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-
2,4,6,8-tetramethyl-9-oxoundec-10-enoate (15). The vinyl alco-
hol 14 (231 mg, 0.36 mmol) was dissolved in CH2Cl2 (10 mL). To
this solution was added Dess−Martin periodinane (DMP) (305 mg,
0.72 mmol), and the resulting solution was stirred for 30 min at room
temperature. After the same workup procedure as described for the
preparation of 13, purification by flash chromatography (hexane/
EtOAc = 4:1) offered the desired vinyl ketone 15 (174 mg, 76%) as a
1
cm−1; H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.04
(m, 6H), 1.24 (d, J = 6.6 Hz, 3H), 1.45 (d, J = 7.3 Hz, 3H), 1.57 (s,
3H), 1.72 (m, 1H), 2.02 (m, 1H), 2.56 (m, 1H), 3.10 (dddd, J = 6.9,
6.9, 6.9, 6.9 Hz, 1H), 3.62 (s, 1H), 3.74 (m, 2H), 3.81 (s, 3H), 4.50 (s,
2H), 5.01 (dd, J = 1.7, 10.9 Hz, 1H), 6.28 (d, J = 15.7 Hz, 1H), 6.65
(d, J = 15.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H),7.26 (d, J = 8.1 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 212.5, 203.3, 170.3, 159.3, 145.6, 130.1,
129.4, 128.9, 113.8, 83.5, 77.2, 75.1, 72.9, 55.3, 53.2, 46.3, 43.2, 37.2,
34.7, 29.7, 23.2, 23.1, 17.9, 14.9, 14.8, 13.4, 10.8; HRMS (FAB) calcd
for C28H40O7 + Na 511.2672, found 511.2675.
yellow liquid: [α]26 +13.12 (c 1.35, CHCl3); IR (film) 3293, 2924,
D
1
2853, 1739, 1461, 1379, 1246, 1170, 1077, 983, 819 cm−1; H NMR
(300 MHz, CDCl3) δ 0.01 (d, J = 6.6 Hz, 6H), 0.81 (m, 12H), 0.94
(m, 6H), 1.05 (d, J = 6.9 Hz, 3H), 1.19 (m, 6H), 1.55 (m, 3H), 1.86
(m, 2H), 2.55 (bs, 1H), 2.71 (q, J = 6.8 Hz, 1H), 2.88 (m, 1H), 3.14
(dd, J = 2.7, 7.6 Hz, 1H), 3.72 (s, 3H), 3.88 (dd, J = 2.3, 6.9 Hz, 1H),
4.40 (q, J = 5.3 Hz, 2H), 4.74 (dd, J = 2.9, 9.8 Hz, 1H), 5.05 (d, J =
10.8 Hz, 1H), 5.24 (d, J = 17.3 Hz, 1H), 5.70 (d, J = 5.6 Hz, 1H), 5.81
(dd, J = 10.8, 17.3 Hz, 1H), 6.23 (d, J = 17.4 Hz, 1H), 6.48 (dd, J =
10.5, 17.4 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 204.9, 175.8, 158.9, 104.8, 135.0, 131.2,
128.8, 128.3, 114.0, 113.6, 84.7, 80.6, 74.6, 74.5, 73.4, 55.2, 44.6, 41.3,
40.8, 33.6, 33.1, 26.2, 25.0, 22.8, 18.5, 18.4, 17.4, 15.5, 10.8, 10.5, −3.6,
−3.8; HRMS (FAB) calcd for C36H60O7Si + Na 655.4006, found
655.4003.
Pikronolide (6a). To a solution of ketone 18 (54 mg, 0.11 mmol)
in CH2Cl2/H2O [10:1(v/v), 3 mL] was added dichlorodicynoquinone
(DDQ) (50 mg, 0.22 mmol) at 0 °C. The solution was stirred for 2 h.
After the reaction was completed, the solution was filtered through a
pad of Celite. The Celite pad was washed with CH2Cl2 (3 × 10 mL).
After the combined filtrate was concentrated, purification by flash
chromatography (hexane/EtOAc = 1:1) provided the desired product
as a white solid (31 mg, 76%) which turned out to be a 4:1 inseparable
1
mixture of pikronolide (6a) and its 5−9-hemiacetal 6b by H NMR
1128
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The Journal of Organic Chemistry
Note
(CDCl3): mp 136−139 °C; [α]26 +79.6 (c 0.25, CHCl3); IR (film)
1.32 (d, J = 7.2 Hz, 3H), 1.33 (s, 3H), 1.48 (d, J = 7.4 Hz, 3H), 1.55
(m, 2H), 1.68 (m, 2H), 1.73 (m, 1H), 2.17 (m, 1H), 2.28 (s, 6H), 2.49
(ddd, J = 3.9, 10.2, 12.3 Hz, 1H), 2.71 (m, 1H), 3.23 (m, 2H), 3.57
(m, 2H), 3.80 (m, 1H), 3.88 (m, 1H), 3.97 (bs, 1H), 4.37 (d, J = 7.3
Hz, 1H), 5.03 (dd, J = 2.4, 11.4 Hz, 1H), 6.33 (d, J = 15.7 Hz, 1H),
6.63 (d, J = 15.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 213.0,
203.8, 170.5, 145.2, 129.4, 105.1, 83.6, 75.2, 69.8, 67.0, 65.8, 53.5, 46.3,
40.3, 40.0, 37.7, 29.7, 28.2, 23.3, 23.1, 21.2, 17.5, 16.2, 15.1, 14.1, 13.2,
10.7; HRMS (FAB) calcd for C28H47NO8 + Na 548.3199, found
548.3196.
D
3345, 2972, 2782, 1743, 1632, 1456, 1373, 1241, 1163, 1112, 1055,
826 cm−1; HRMS (FAB) calcd for C20H32O6 + Na 391.2097, found
391.2094.
6a: 1H NMR (500 MHz, CDCl3) δ 0.91 (t, J = 7.4 Hz, 3H), 1.02 (d,
J = 7.1 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H), 1.23 (d, J = 7.2 Hz, 3H),
1.34 (s, 3H), 1.43 (d, J = 7.3 Hz, 3H), 1.47−1.54 (m, 3H), 1.79 (m,
1H), 1.94 (m, 1H), 2.83 (q, J = 6.6 Hz, 1H), 2.94 (m, 1H), 2.94 (bs,
1H), 3.78 (q, J = 7.3 Hz, 1H), 3.98 (m, 1H), 5.00 (dd, J = 2.4, 11.2 Hz,
1H), 6.30 (d, J = 15.9 Hz, 1H), 6.71 (d, J = 15.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 211.4, 204.0, 170.5, 146.9, 129.0, 83.0, 74.9,
73.6, 52.0, 48.5, 42.0, 37.0, 35.8, 23.1, 22.9, 17.7, 16.4, 13.7, 12.9, 10.6.
6b: 1H NMR (500 MHz, CDCl3) δ 0.84 (d, J = 6.6, 3H), 0.89 (m,
3H), 1.06 (d, J = 6.6, 3H), 1.37 (s, 3H), 1.38 (m, 3H), 1.72 (m, 1H),
1.88 (m, 1H), 2.58 (dd, J = 2.8, 6.7 Hz, 1H), 3.77 (m, 1H), 3.85 (dd, J
= 2.8, 10.2 Hz, 1H), 4.73 (dd, J = 1.9, 8.7 Hz, 1H), 5.98 (s, 1H), 5.99
(s, 1H); other protons are not assignable due to heavy overlap; 13C
NMR (100 MHz, CDCl3) δ 204.9, 169.3, 137.7, 126.9, 97.6, 78.1, 77.7,
74.6, 49.6, 47.5, 40.1, 38.3, 32.3, 29.7, 21.2, 19.0, 17.6, 16.5, 15.8, 10.9.
Ac-Protected Pikromycin 20. Method A:19 A solution of alcohol
1914 (36 mg, 0.17 mmol), phthalic anhydride (30 mg, 0.20 mmol),
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (28 μL, 0.015 mmol)
in CH2Cl2 (2 mL) in the presences of 4 A molecular sieves was stirred
for 15 min at room temperature. After 15 min the mixture was cooled
to −78 °C, di-tert-butylmethylpyridine (DTBMP) (75 mg, 0.36) and
Tf2O (1.3 μL, 0.015 mmol) were added sequentially at −78 °C, and
the resulting mixture was stirred for a further 15 min. After dropwise
addition of a solution of pikronolide (6a) (8.4 mg, 0.023 mmol) in
CH2Cl2 (2 mL) to the above solution via cannula, the reaction mixture
was stirred at −78 °C for 15 min before it was allowed to the warm
over 1 h to 0 °C. After additional stirring for 12 h at room temperature
NaHCO3 (20 mg) was added to the mixture. After filtration through a
pad of Celite with CH2Cl2 (3 × 10 mL), the solution was
concentrated. Purification of the residue by flash chromatography
(EtOAc/MeOH = 10:1) afforded the Ac-protected pikromycin 20 (4.3
mg, 33%) as a colorless oil.
Narbomycin (5). To a solution of trichloroacetimidate 21 (22 mg,
0.060 mmol) and narbonolide (5a)13(7.2 mg, 0.020 mmol) in CH2Cl2
(3 mL) was added 4 A molecular sieves (200 mg), and the resulting
solution was stirred at room temperature. After 30 min, the mixture
was cooled −20 °C, and then TfOH (3.0 μL, 0.026 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 Ac-protected
narbomycin 22 (6.5 mg, 59%) as a colorless oil: [α]27 +58.3 (c 0.68,
D
CHCl3); IR (film) 2924, 2851, 1739, 1712, 1624, 1460, 1378, 1259,
1
1164, 1110, 1078, 1031, 977 cm−1; H NMR (500 MHz, CDCl3) δ
0.89 (t, J = 7.4 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz,
3H), 1.11 (d, J = 6.6 Hz, 3H), 1.23 (d, J = 7.5 Hz, 3H), 1.24 (d, J = 6.2
Hz, 3H), 1.36 (d, J = 7.0 Hz, 3H), 1.58 (m, 1H), 1.73 (m, 3H), 2.02
(s, 3H), 2.07 (dd, J = 4.2, 11.5 Hz, 1H), 2.26 (s, 6H), 2.72 (m, 2H),
2.84 (m, 2H), 3.56 (m, 1H), 3.82 (q, J = 7.0 Hz, 1H), 4.27 (s, 1H),
4.46 (d, J = 7.7 Hz, 1H), 4.81 (dd, J = 7.6, 10.5 Hz, 1H), 4.89 (ddd, J =
3.6, 3.6, 9.9 Hz, 1H), 6.03 (d, J = 16.1 Hz, 1H), 6.60 (dd, J = 6.0, 16.1
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 208.5, 203.6, 169.8, 169.3,
146.7, 128.9, 102.9, 79.0, 71.2, 69.1, 63.3, 50.0, 48.3, 41.3, 40.6, 38.3,
37.1, 36.4, 30.7, 29.7, 22.2, 21.4, 21.1, 16.6, 14.9, 14.1, 12.9, 10.5;
HRMS (FAB) calcd for C30H49NO8 + Na 574.3356, found 574.3360.
To a stirred solution of Ac-protected narbomycin 22 (2.3 mg,
0.0042 mmol) in MeOH (1 mL) at room temperature was added H2O
(200 μL) and triethylamine (200 μL). After 3 h, the reaction mixture
was concentrated. Purification of the residue by flash chromatography
(EtOAc/MeOH = 10:1) afforded narbomycin (5) (2.0 mg, 94%) as a
Method B: To a solution of trichloroacetimidate 2114,15,18 (11 mg,
0.030 mmol) and pikronolide (6a) (3.5 mg, 0.010 mmol) in CH2Cl2
(2 mL) was added 4 A molecular sieves (200 mg), and the resulting
solution was stirred at room temperature. After 30 min, the mixture
was cooled −20 °C, and then TfOH (1.3 μL, 0.015 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 Ac-protected
colorless oil: [α]25 +61.3 (c 0.32, CHCl3); IR (film) 3397, 2962,
D
2924, 2852, 1739, 1704, 1632, 1461, 1377, 1261, 1164, 1078, 1031,
1
984 cm−1; H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 7.4 Hz, 3H),
1.02 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 6.6 Hz,
3H), 1.25 (m, 3H), 1.37 (d, J = 7.4 Hz, 6H), 1.51 (m, 2H), 1.58 (m,
2H), 1.67 (m, 2H), 1.85 (m, 1H), 2.29 (s, 6H), 2.51 (m, 2H), 2.74 (m,
2H), 2.94 (m, 1H), 3.26 (m, 1H), 3.55 (m, 1H), 3.86 (q, J = 7.1 Hz,
1H), 4.17 (bs, 1H), 4.32 (d, J = 7.4 Hz, 1H), 4.92 (ddd, J = 3.6, 3.6,
9.2 Hz, 1H), 6.13 (d, J = 15.8 Hz, 1H), 6.67 (d, J = 5.7, 15.8 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 208.7, 203.6, 169.4, 146.8, 123.2,
104.6, 78.7, 70.2, 69.6, 65.7, 50.8, 42.3, 40.3, 38.4, 36.7, 36.4, 29.7,
28.5, 25.6, 22.7, 21.2, 17.0, 14.3, 14.1, 13.8, 12.5, 10.5; HRMS (FAB)
calcd for C28H47NO7 + Na 532.3250, found 532.3254.
pikromycin 20 (4.2 mg, 43%) as a colorless oil: [α]27 +50.2 (c 0.17,
D
CHCl3); IR (film) 3346, 2972, 2934, 2861, 2776, 1743, 1668, 1631,
1457, 1373, 1240, 1163 cm−1; 1H NMR (500 MHz, CDCl3) δ 0.88 (t, J
= 7.3 Hz, 3H), 0.98 (d, J = 7.1 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 1.22
(d, J = 7.2 Hz, 3H), 1.25 (m, 3H), 1.33 (s, 3H), 1.47 (d, J = 7.4 Hz,
3H), 1.53 (m, 1H), 1.68−1.77 (m, 3H), 2.04 (s, 3H), 2.09 (m, 1H),
2.28 (s, 6H), 2.77 (m, 2H), 2.99 (m, 1H), 3.56 (s, 1H), 3.59 (m, 1H),
3.74 (q, J = 7.3 Hz, 1H), 4.15 (s, 1H), 4.51 (d, J = 7.6 Hz, 1H), 4.83
(dd, J = 7.7, 10.3 Hz, 1H), 5.01 (dd, J = 2.3, 11.4 Hz, 1H), 6.22 (d, J =
16.0 Hz, 1H), 6.56 (d, J = 16.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 212.2, 203.6, 170.2, 169.8, 145.5, 129.4, 103.5, 83.6, 75.3,
71.1, 69.3, 63.3, 61.2, 52.2, 46.3, 42.3, 40.6, 37.9, 36.4, 30.5, 23.2, 23.1,
21.3, 21.1, 16.9, 14.2, 14.1, 13.4, 10.7; HRMS (FAB) calcd for
C30H49NO9 + Na 590.3305, found 590.3301.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) for 5, 6, 6a, 11−18, 20, and 22;
COSY and HSQC spectra for 6a (and 6b). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hykang@chungbuk.ac.kr.
Pikromycin (6). To a stirred solution of Ac-protected pikromycin
20 (4.2 mg, 0.0082 mmol) in MeOH (1 mL) at room temperature was
added H2O (200 μL) and triethylamine (200 μL). After 3 h, the
reaction mixture was concentrated. Purification of the residue by flash
chromatography (EtOAc/MeOH = 10:1) afforded pikromycin (6)
■
ACKNOWLEDGMENTS
(3.5 mg, 91%) as a colorless oil: [α]27 −13.7 (c 0.34, CHCl3); IR
■
D
This work was supported by the Korea Research Foundation
(KRF) grant funded by the Korea Government (MEST)
(2009-0074078). The authentic sample of pikromycin with
(film) 3343, 2925, 2852, 1735, 1632, 1461, 1378, 1265, 1122, 1076
cm−1; 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H), 1.05 (d,
J = 7.1 Hz, 3H), 1.11 (d, J = 6.5 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H),
1129
dx.doi.org/10.1021/jo201158q | J. Org. Chem. 2012, 77, 1125−1130

The Journal of Organic Chemistry
Note
7811. (b) Ireland, R. E.; Daub, J. P.; Mandel, G. S.; Mandel, N. S. J.
Org. Chem. 1983, 48, 1312.
which NMR spectra was taken was isolated from the cell
culture provided by Prof. Yeo Joon Yoon (Ewha Womans
University, Seoul, Korea). The NMR spectra of pikromycin
were also kindly provided by Prof. David H. Sherman
(University of Michigan). We thank Professors Yoon and
Sherman.
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Yamaguchi, M. Chem. Lett. 1979, 1019. (b) Inanaga, J.; Katuski, T.;
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