Stereoselective total synthesis of atpenins A4 and B, harzianopyridone, and NBRI23477 B

Article abstract of DOI:10.1248/cpb.c12-00266

The stereoselective total synthesis of atpenins A4 (2) and B (3), harzianopyridone (4), and NBRI23477 B (5) have been developed using a convergent approach involving the coupling reaction of a common iodopyridine with an aldehyde corresponding to the appropriate side chain of the desired compound. Furthermore, the absolute configurations of atpenin B (3), harzianopyridone (4), and NBRI23477 B (5) have been unambiguously determined.

Full text of DOI:10.1248/cpb.c12-00266

898
Regular Article
Chem. Pharm. Bull. 60(7) 898–906 (2012)
Vol. 60, No. 7
Stereoselective Total Synthesis of Atpenins A4 and B, Harzianopyridone,
and NBRI23477 B
Masaki Ohtawa,a Kouhei Sugiyama,a Tohru Hiura,a Shujiro Izawa,a Kazuro Shiomi,b
,b
,a
Satoshi Omura,* and Tohru Nagamitsu*
b
a Graduate School of Pharmaceutical Sciences, Kitasato University; and Kitasato Institute for Life Sciences and
Graduate School of Infection Control Sciences, Kitasato University; 5–9–1 Shirokane, Minato-ku, Tokyo 108–8641,
Japan. Received March 21, 2012; accepted April 11, 2012
The stereoselective total synthesis of atpenins A4 (2) and B (3), harzianopyridone (4), and NBRI23477 B
(5) have been developed using a convergent approach involving the coupling reaction of a common iodopyri-
dine with an aldehyde corresponding to the appropriate side chain of the desired compound. Furthermore,
the absolute configurations of atpenin B (3), harzianopyridone (4), and NBRI23477 B (5) have been unam-
biguously determined.
Key words total synthesis; complex II inhibitor; atpenin A4; atpenin B; harzianopyridone; NBRI23477 B
The atpenins, A5 (1), A4 (2), and B (3), contain a highly (1) has also been achieved.6) It is clear that atpenins and their
functionalized pyridine unit and were first isolated in 1988 analogues are useful chemical tools for elucidation of complex
from the fermentation broth of the atpenin producing strain II functionality and that they could act as lead compounds
Penicillium sp. FO-125 as growth inhibitors of both fatty for development of novel helminth complex II-specific inhibi-
acid synthase deficient (A-1) and acyl-CoA synthase I defi- tors. Recently, we successfully achieved a stereoselective total
cient (L-7) mutants of Candida lipolytica and 3 was shown synthesis of atpenin A5 (1) using a convergent approach10)
to inhibit the ATP-generating system of Raji cells.1,2) Har- and the synthetic strategy is amenable to the synthesis of a
zianopyridone (4) was originally isolated from Trichoderma variety of atpenin analogues. Herein we report the total syn-
harzianum in 1989, showing antifungal, antibacterial, and thesis of atpenins A4 (2) and B (3), harzianopyridone (4), and
herbicidal activities.3,4) NBRI23477 B (5) was isolated in 2005 NBRI23477 B (5) using the synthetic strategy developed for
from the culture broth of Penicillium atramentosum PF1420, the total synthesis of 1. Furthermore, the absolute structures
as a growth inhibitor of human prostate cancer cells5) (Fig. of 3, 4, and 5 have been determined.
1). The absolute configurations of atpenins A5 (1) and A4 (2)
have been confirmed by X-ray crystallographic analysis.6,7)
Results and Discussion
The total synthesis of ( )-atpenin B (3) was reported by the
Retrosynthetic Analysis of Atpenins A4 (2) and B (3),
Quéguiner group in 1994.8) In 2003, new interest developed Harzianopyridone (4), and NBRI23477 B (5) Retrosyn-
in atpenins A5 (1) and A4 (2) and harzianopyridone (4) when thesis of the target compounds is shown in Chart 1. We an-
the compounds were reported to provide high levels of inhi- ticipated that atpenins A4 (2) and B (3), harzianopyridone (4),
bition in a microbial screening assay against mitochondrial and NBRI23477 B (5) would possess the same configuration
complex II (succinate-ubiquinone oxidoreductase), which is as atpenin A5 (1), as shown in Fig. 1. It was envisaged that the
an attractive target for the treatment of helminthiasis.9) At- compounds could be synthesized by coupling of the common
penin A5 (1), in particular, proved to be much more potent iodopyridine 610) with the corresponding aldehydes 7, 8, and 9,
against bovine heart complex II than any known complex II which could in turn be derived from a common intermediate
inhibitors, although the inhibition of 1 was non-selective be- 10 or its equivalent 11, as was the case for compound 9.
tween helminthes and mammals. Crystal structure analysis of
Total Synthesis of Atpenin A4 (2) The synthesis of at-
Escherichia coli complex II co-crystallized with atpenin A5 penin A4 (2) started from compound 12, which was prepared
Fig. 1. Structures of Atpenins A5 (1), A4 (2), and B (3), Harzianopyridone (4), and NBRI23477 B (5)
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: omura-s@kitasato.or.jp;
nagamitsut@pharm.kitasato-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

July 2012
899
Chart 1. Retrosynthetic Analysis of Atpenins A4 (2) and B (3), Harzianopyridone (4), and NBRI23477 B (5)
°
°
Reagents and Conditions: (a) p-TsCl, Et3N, Me3N·HCl, CH2Cl2, rt, 85%; (b) n-BuLi, THF, 0 C, quant.; (c) DIBAL, CH2Cl2, −78 C, 97%; (d) NCS, PPh3, THF, rt;
°
°
(e) TBAF, THF, rt, 65% (2 steps); (f) TEMPO, PhI(OAc)2, CH2Cl2, rt, 75%; (g) 6, n-BuLi, THF, −78 C, 69%; (h) DMP, CH2Cl2, rt, 94%; (i) TFA, CH2Cl2, 0 C, 97%.
Chart 2
from 10 in four steps10) (Chart 2). Monotosylation of 12 un- thiocarbonyldiimidazole to give the corresponding cyclic thio-
der standard conditions followed by treatment with n-BuLi carbonate in 95% yield, which was subsequently converted to
11)
°
furnished epoxide 13 in 85% yield over the two steps. Regi- 18 in 74% yield by reaction with triethyl phosphite at 100 C.
oselective opening of the epoxide of 13 with bulky reducing Tetrabutylammonium fluoride (TBAF) mediated triisopro-
agents such as LiAl(Ot-Bu)3H proved unsuccessful, whereas pylsilyl (TIPS) deprotection of 18 gave the primary alcohol
reduction with diisobutylaluminium hydride (DIBAL) gave the 19. Compound 19 was found to have a high volatility and this
secondary alcohol 14 in 97% yield. Subsequent chlorination property was believed to be responsible for the low yields and
and desilylation furnished a primary alcohol 15 in 65% yield poor reproducibility observed in the subsequent oxidation re-
over the two steps. Oxidation of 15 with 2,2,6,6-tetramethylpi- action. To overcome this problem, an alternative strategy was
peridine 1-oxyl (TEMPO) gave the desired aldehyde 7 in 75% developed involving the construction of the terminal olefin fol-
yield. Halogen-lithium exchange of iodopyridine 6 with n- lowing the coupling reaction of the aldehyde with the pyridine
BuLi followed by a coupling reaction with aldehyde 7 afforded unit 6. Benzylation of diol 12 followed by TIPS deprotection
16 in 65% yield as a diastereomixture. Finally, oxidation of 16 gave 21 in 68% yield over the two steps. TEMPO mediated
with Dess–Martin periodinane (DMP) gave the ketone 17 in oxidation of 21 gave aldehyde 8 in 92% yield. Halogen-lithium
96% yield, which was subjected to acidic hydrolysis for depro- exchange of 6 with n-BuLi followed by a coupling reaction
tection of methoxymethyl (MOM) groups to afford the atpenin with the aldehyde 8 afforded 22 as a diastereomixture in 80%
A4 (2) in 97% yield. Synthetic atpenin A4 (2) was found to be yield. Oxidation of 22 with DMP followed by hydrogenolysis
1
analytically identical in all respects ([α]D, H- and 13C-NMR, with Pd(OH)2/C provided the keto-diol 23 in 74% yield over
IR, and FAB-MS) to an authentic sample.1)
the two steps. Diol 23 was then converted to the cyclic thio-
Total Synthesis of Atpenin B (3) and NBRI23477 B carbonate 24 in 75% yield as described above. Treatment with
°
(5) The synthesis of aldehyde 20 required for the cou- triethylphosphite at 110 C followed by trifluoroacetic acid
pling reaction with key intermediate 6 was initially explored (TFA) mediated deprotection of two MOM groups provided
as depicted (Chart 3). Diol 12 was heated in toluene with NBRI23477 B (5) in 47% yield over the two steps. Subsequent

900
Vol. 60, No. 7
°
°
°
Reagents and Conditions: (a) Thiocarbonyldiimidazole, toluene, 100 C, 95%; (b) P(OEt)3, 100 C, 74%; (c) TBAF, THF, rt; (d) BnBr, NaH, TBAI, THF, 40 C; (e)
°
TBAF, THF, rt, 68% (2 steps); (f) TEMPO, PhI(OAc)2, CH2Cl2, rt, 92%; (g) 6, n-BuLi, THF, −78 C, then 8, 80%; (h) DMP, CH2Cl2, rt, 94%; (i) H2, Pd(OH)2/C, EtOH,
°
°
rt, 79%; (j) Thiocarbonyldiimidazole, toluene, rt, 75%; (k) P(OEt)3, 110 C, (l) TFA, CH2Cl2, 0 C, 47% (2 steps); (m) H2, Pd/C, EtOH, rt, 92%.
Chart 3
°
°
Reagents and Conditions: (a) DIBAL, CH2Cl2, −78 C; (b) Ph3P=CHCO2Et, benzene, rt; (c) DIBAL, CH2Cl2, 0 C, 73% (3 steps); (d) TBDPSCl, imidazole, DMF, rt,
°
95%; (e) PPTS, EtOH, rt, 95%; (f) TEMPO, PhI(OAc)2, CH2Cl2, rt, 89%; (g) 6, n-BuLi, THF, −78 C, then 9, 72%; (h) DMP, CH2Cl2, rt, 90%; (i) TBAF, THF, rt, 93%;
(j) CBr4, (CH2PPh2)2, CH2Cl2, 0 C, 56%; (k) LiEt3BH, THF, –78 C, 86%.
°
°
Chart 4
hydrogenation of 5 provided atpenin B (3) in 92% yield. The described above to afford 26 in 72% yield as a diastereomix-
1
analytical properties ([α]D, H- and 13C-NMR, IR, and FAB- ture. Oxidation of 26 with DMP followed by TBAF mediated
MS) of synthetic atpenin B (3) and NBRI23477 B (5) were tert-butyldiphenylsilyl (TBDPS) deprotection afforded allylic
found to be identical in all respects to those reported for alcohol 27 in 84% yield over the two steps.
the natural materials,1,5) confirming that we had successfully
To complete the total synthesis of harzianopyridone (4),
achieved the total synthesis of atpenin B (3) and NBRI23477 removal of the allylic hydroxy group of 27 was required. Un-
B (5) and determined their absolute configurations. fortunately, our initial attempts to convert 27 to the required
Total Synthesis of Harzianopyridone (4) To avoid the allylic compounds by introducing a variety of leaving groups,
problem encountered above concerning the volatile aldehyde including mesylate, tosylate, bromide, and iodide under a vari-
19 (Chart 4), harzianopyridone (5) was synthesized according ety of reaction conditions, led only to no reaction or decompo-
to the same strategy used in the synthesis of compounds 3 sition. However, treatment of 27 with CBr4 and (CH2PPh2)213)
and 5. Allyl alcohol 11 was prepared from the known nitrile provided the required allyl bromide 28 in 56% yield, with
2512) in three steps, according to our total synthesis of 1.10)
A
concomitant removal of the two MOM groups. Subsequent re-
protection/deprotection sequence followed by TEMPO medi- duction of the allyl bromide 28 with LiEt3BH gave the desired
ated oxidation gave aldehyde 9 in 80% yield over the three product 4 in 86% yield without affecting the carbonyl group
steps. The coupling of the two key segments 6 and 9 was probably due to steric hindrance. The synthetic harzianopyri-
1
achieved according to the lithium-halogen exchange procedure done (4) was found to be analytically identical ([α]D, H- and

July 2012
901
13C-NMR, IR and MS) to the naturally occurring compound4) removal of the organic layer, the aqueous layer was extracted
in all respects and the absolute stereochemistry was deter- with EtOAc. The organic layer was combined, dried over
mined to be 2S.
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by frash silica gel column chromatography (100:1
hexanes/EtOAc) to afford 13 (348mg, quant.) as a colorless
Conclusion
The stereoselective total synthesis of atpenins A4 (2) and oil: [α]D27 −23.0 (c=1.0, CHCl3); IR (KBr) cm−1: 2942, 2865,
1
B (3), harzianopyridone (4), and NBRI23477 B (5) have been 1463, 1367, 1178, 1101, 883, 790, 680; H-NMR (400MHz,
achieved using a convergent strategy. Furthermore, the abso- CDCl3) δ: 3.51 (d, 2H, J=5.2Hz), 2.72 (dd, 2H, J=4.6, 2.7Hz),
lute stereochemistries of 3, 4, and 5 have been unambiguously 2.50 (dd, 1H, J=4.3, 3.4Hz), 1.81–1.72 (m, 1H), 1.47–1.38 (m,
determined. Evaluation of the associated biological activities 2H), 1.32–1.28 (m, 1H), 1.11–1.03 (m, 3H), 1.06 (brs, 18H),
and further studies focused on the structure-activity relation- 0.91 (d, 3H, J=6.6Hz), 0.88 (d, 3H, J=7.0Hz); 13C-NMR
ships of atpenin analogues are currently underway in our (100MHz, CDCl3) δ: 68.9, 57.4, 45.8, 37.7, 33.5, 33.2, 18.0,
laboratories for the development of novel anthelmintic and 16.4, 15.4, 12.0; HR-FAB-MS Calcd for C17H37O2Si: 301.2563,
anti-tumor agents.
Found: 301.2570.
(2R,3S,5S)-3,5-Dimethyl-6-(triisopropylsilyloxy)hexan-2-
ol (14) A solution of 13 (0.170g, 0.565mmol) in CH2Cl2
Experimental
General IR spectra were obtained using a Horiba FT-710 (6.0mL) was treated with DIBAL (1.03M in hexane, 2.74mL,
1
spectrophotometer. H- and 13C-NMR spectra were obtained 2.83mmol) at −78 C. After stirring for 0.5h at −78 C, MeOH
°
°
°
on JEOL JNM-EX-270, Agilent Technologies Mercury-300, was added dropwise at −78 C to the resulting solution until
UNITY-400 and INOVA-600 spectrometers, and chemical the evolution of gas ceased. The mixture was diluted with
shifts were reported on the δ scale and referenced to tetra- CH2Cl2, treated with Celite (1.0g) and Na2SO4·10H2O (1.5g),
methylsilane (TMS). Mass spectra were measured with JEOL and then stirred for 2h at room temperature. The resulting
JMS-700 and JEOL JMS-AX505HA spectrometers. Optical suspension was filtered through a pad of Celite and the filtrate
rotations were recorded on a JASCO DIP-1000 polarimeter. was concentrated in vacuo. The residue was purified by frash
Unless otherwise indicated, commercial reagents were used silica gel column chromatography (30:1 hexane/EtOAc) to
without further purification. Organic solvents were distilled afford 14 (169mg, 97%) as a colorless oil: [α]D27 −21.1 (c=1.0,
and dried over molecular sieves (3 or 4Å) prior to use. Reac- CHCl3); IR (KBr) cm−1: 3367, 2944, 2866, 1464, 1383, 1105,
1
tions were carried out in flame-dried glassware under a posi- 883, 796, 683; H-NMR (400MHz, CDCl3) δ: 3.67–3.59 (m,
tive pressure of argon with magnetic stirring, unless otherwise 1H), 3.48 (d, 2H, J=6.5Hz), 1.78–1.65 (m, 1H), 1.65–1.55
indicated. Flash column chromatography was carried out on (m, 1H), 1.31–1.16 (m, 2H), 1.13 (d, 3H, J=6.1Hz), 1.10–1.01
silica gel 60N (spherical, neutral, particle size 40–50µm). (m, 3H), 1.06 (brs, 18H), 0.87 (d, 3H, J=1.4Hz), 0.85 (d, 3H,
TLC was performed on 0.25mm Merck silica gel 60 F254 J=2.0Hz); 13C-NMR (100MHz, CDCl3) δ: 72.2, 69.4, 37.3,
plates. Plates were visualized by UV (254nm) and cerium am- 35.9, 33.4, 19.4, 18.0, 16.4, 14.6, 12.0; HR-ESI-MS Calcd for
monium molybdate staining.
C17H38O2SiNa: 325.2538, Found: 325.2578.
Triisopropyl-((2S,4S)-2-methyl-4-((S)-oxiran-2-yl)-
(2S,4S,5S)-5-Chloro-2,4-dimethylhexan-1-ol (15) To a
pentyloxy)silane (13) A solution of 1210) (1.03g, 3.23mmol) solution of 14 (0.270g, 0.890mmol) in THF (4.5mL) were
in CH2Cl2 (16mL) was treated with Et3N (1.34mL, 9.69mmol), added N-chlorosuccinimide (NCS) (0.180g, 1.34mmol) and
Me3N·HCl (30.6mg, 0.323mmol), and p-toluenesulfonyl chlo- PPh3 (0.350g, 1.34mmol). The reaction mixture was stirred
ride (p-TsCl) (674mg, 3.55mmol). The reaction mixture was at room temperature for 1h, quenched with water, and diluted
°
stirred at 0 C for 1h and quenched with water. After removal with EtOAc. After removal of the organic layer, the aque-
of the organic layer, the aqueous layer was extracted with ous layer was extracted with EtOAc. The organic layer was
CH2Cl2. The organic layer was combined, dried over Na2SO4, combined, dried over Na2SO4, filtered, and concentrated in
filtered, and concentrated in vacuo. The residue was purified vacuo. The residue was semi-purified by frash silica gel col-
by frash silica gel column chromatography (30:1 hexanes/ umn chromatography (hexane) to afford the crude chloride as
EtOAc) to afford the corresponding tosylate (1.29g, 85%) as a colorless oil.
a colorless oil: [α]D27 −3.94 (c=1.0, CHCl3); IR (KBr) cm−1:
To a solution of the crude chloride in THF (9.0mL) was
1
3531, 2917, 1469, 1361, 1247, 1172, 960, 775, 684; H-NMR added TBAF (1.0M THF, 1.68mL, 1.68mmol). The reaction
(400MHz, CDCl3) δ: 7.80 (d, 2H, J=10.7Hz), 7.35 (d, 2H, mixture was stirred at room temperature for 0.5h, quenched
J=8.4Hz), 4.12 (dd, 1H, J=10.4, 3.0Hz), 3.98 (dd, 1H, J=10.7, with a saturated aqueous NH4Cl solution, and diluted with
7.4Hz), 3.65–3.59 (m, 1H), 3.47 (dd, 1H, J=8.5, 4.5Hz), EtOAc. After removal of the organic layer, the aqueous layer
3.43 (dd, 1H, J=9.2, 5.1Hz), 2.41 (s, 3H), 1.75–1.62 (m, 2H), was extracted with EtOAc. The organic layer was combined,
1.32–1.16 (m, 2H), 1.10–1.01 (m, 3H), 1.06 (brs, 18H), 0.84 (d, dried over Na2SO4, filtered, and concentrated in vacuo. The
3H, J=7.0Hz), 0.82 (d, 3H, J=6.0Hz); 13C-NMR (100MHz, residue was purified by frash silica gel column chromatogra-
CDCl3) δ: 145.2, 133.0, 130.1, 128.2, 74.1, 72.9, 69.5, 35.9, 33.5, phy (30:1 hexane/EtOAc) to afford 15 (94.4mg, 65% over the
21.9, 18.2, 16.4, 15.4, 12.2; high resolution (HR)-FAB-MS two steps) as a colorless oil: [α]D27 −24.0 (c=1.0, CHCl3); IR
1
Calcd for C24H45O5SSi: 473.2757, Found: 473.2761.
(KBr) cm−1: 3352, 2967, 2927, 1458, 1381, 1038, 644; H-NMR
A solution of the tosylate (545mg, 1.15mmol) in tetrahy- (400MHz, CDCl3) δ: 4.16–4.04 (m, 1H), 3.52–3.42 (m, 2H),
drofuran (THF) (11mL) was treated with n-BuLi (1.38M in 1.87–1.78 (m, 1H), 1.75–1.66 (m, 1H), 1.47 (d, 3H, J=8.2Hz),
°
hexane, 2.74mL, 2.83mmol) at −78 C. After stirring for 1.42–1.33 (m, 1H), 1.27–1.21 (m, 1H), 0.95 (d, 3H, J=6.8Hz),
0.5h at 0 C, the reaction mixture was quenched with a satu- 0.91 (d, 3H, J=6.8Hz); 13C-NMR (100MHz, CDCl3) δ: 69.0,
°
rated aqueous NH4Cl solution and diluted with EtOAc. After 64.6, 37.6, 37.4, 33.2, 22.6, 16.4, 14.4.

902
Vol. 60, No. 7
1
(2S,4S,5S)-5-Chloro-2,4-dimethylhexanal (7) A solution 1699, 1585, 1459, 1389, 1114, 897; H-NMR (300MHz, CDCl3)
of 15 (22.0mg, 0.130mmol) in CH2Cl2 (1.3mL) was treated δ: 5.48 (s, 2H), 5.30 (s, 2H), 4.17 (ddd, 1H, J=13.4, 6.7, 3.1Hz),
with TEMPO (1.6mg, 10.0µmol) and PhI(OAc)2 (11.0mg, 3.97 (s, 3H), 3.77 (s, 3H), 3.49 (s, 3H), 3.48 (s, 3H), 3.25–3.12
0.330mmol). The reaction mixture was stirred at room tem- (m, 1H), 1.91–1.82 (m, 1H), 1.81–1.74 (m, 1H), 1.58–1.52 (m,
perature for 2h, quenched with a saturated aqueous Na2S2O3 1H), 1.47 (d, 3H, J=6.4Hz), 1.15 (d, 3H, J=7.1Hz), 0.95 (d,
solution, and diluted with CH2Cl2. After removal of the or- 3H, J=7.9Hz); 13C-NMR (100MHz, CDCl3) δ: 204.9, 157.0,
ganic layer, the aqueous layer was extracted with CH2Cl2. 156.0, 152.7, 129.8, 110.7, 98.9, 91.8, 63.3, 60.7, 57.6, 57.3,
The organic layer was combined, dried over Na2SO4, filtered, 53.9, 44.3, 37.4, 36.5, 22.6, 16.1, 14.0; HR-ESI-MS Calcd for
and concentrated in vacuo. The residue was purified by frash C19H30O7NClNa: 442.1608, Found: 442.1601.
silica gel column chromatography (100:1 hexanes/EtOAc) to
Atpenin A4 (2) A solution of 17 (96.0mg, 0.230mmol) in
afford 7 (15.9mg, 75%) as a colorless oil: [α]D27 +1.22 (c=1.0, CH2Cl2 (2.3mL) was treated with TFA (2.3mL) at 0 C, and
°
CHCl3); IR (KBr) cm−1: 3432, 2970, 2928, 1725, 1457, 1379, the mixture was stirred at 0 C for 0.5h. The reaction mix-
°
1
1256, 642, 451; H-NMR (400MHz, CDCl3) δ: 9.69 (d, 1H, ture was concentrated in vacuo. The residue was purified by
J=2.6Hz), 4.16–4.09 (m, 1H), 2.46–2.38 (m, 1H), 1.86–1.77 frash silica gel column chromatography (15:1 hexane/EtOAc)
(m, 1H), 1.77–1.66 (m, 1H), 1.48 (d, 3H, J=7.1Hz), 1.52–1.43 to afford atpenin A4 (2) (73.5mg, 97%) as a colorless solid:
(m, 1H), 1.11 (d, 3H, J=7.1Hz), 0.96 (d, 3H, J=6.3Hz); 13C- [α]D27 −8.5 (c=1.0, EtOH), (lit.1) [α]D22 −8.6 (c=1.0, EtOH)); IR
1
NMR (100MHz, CDCl3) δ: 204.8, 63.0, 43.9, 37.4, 34.5, 22.4, (KBr) cm−1: 1642, 1606, 1463, 1324, 1191, 1161, 997; H-NMR
14.0, 13.5; low resolution-electron ionization (LR-EI)-MS 163 (400MHz, CDCl3) δ: 4.13 (s, 3H), 4.20–4.11 (m, 1H), 4.10 (dq,
([M+H]+).
1H, J=2.8, 5.5Hz), 3.79 (s, 3H), 1.86–1.78 (m, 1H), 1.78–1.72
(2S,4S,5S)-5-Chloro-1-(5,6-dimethoxy-2,4-di(methoxy- (m, 1H), 1.52 (dt, 1H, J=6.4, 12.9Hz), 1.45 (d, 3H, J=5.7Hz),
methoxy)pyridin-3-yl)-2,4-dimethylhexan-1-ol (16) A so- 1.14 (3H, d, J=7.8Hz), 0.96 (d, 3H, J=6.9Hz); 13C-NMR
lution of n-BuLi (1.57M in hexane, 1.19mL, 1.88mmol) in (100MHz, CDCl3) δ: 210.5, 172.9, 162.2, 155.6, 121.1, 101.0,
THF (7.5mL) was treated with the solution of 6 (289mg, 63.3, 61.8, 58.4, 39.9, 37.9, 37.3, 23.0, 18.2, 14.4; HR-FAB-MS
°
0.750mmol) in THF (3.8mL) at –78 C, and then the solution Calcd for C15H23O5NCl: 332.1265, Found: 332.1274.
of 7 (0.110g, 0.681mmol) in THF (3.8mL) was added. The re- (2S,4S,5S)-5,6-Di(benzyloxy)-2,4-dimethylhexan-1-ol
°
action mixture was stirred for 5min at –78 C, quenched with (21) A solution of 12 (479mg, 1.50mmol) in THF (15mL)
a saturated aqueous NH4Cl solution, and diluted with EtOAc. was treated with NaH (192mg, 4.80mmol). After stirring for
°
Then the resulting mixture was allowed to warm to room 0.5h at 0 C, a resulting solution was treated with benzyl bro-
temperature. After removal of the organic layer, the aqueous mide (BnBr) (0.534mL, 4.50mmol) and tetrabutylammonium
layer was extracted with EtOAc, the organic layer was com- iodide (TBAI) (16.6mg, 45.0µmol). The reaction mixture was
°
bined, dried (Na2SO4), filtered, and concentrated in vacuo. stirred at 40 C for 8h, quenched with water, and diluted with
The residue was purified by frash silica gel column chroma- EtOAc. After removal of the organic layer, the aqueous layer
tography (10:1 hexane/EtOAc) to afford 16 (198mg, 69%) was extracted with EtOAc. The organic layer was combined,
as a colorless oil. This material was obtained as a mixture dried over Na2SO4, filtered, and concentrated in vacuo. The
of two diastereomers: [α]D27 −22.0 (c=1.0, CHCl3); IR (KBr) residue was semi-purified by frash silica gel column chroma-
1
cm−1: 3564, 2962, 1590, 1468, 1421, 1159, 1025, 902; H-NMR tography (60:1 hexane/EtOAc) to afford the crude dibenzyl
(300MHz, CDCl3) δ: 5.63–5.48 (m, 2H), 5.37–5.26 (m, 2H), ether as a colorless oil.
4.71–4.56 (m, 1H), 4.13–4.01 (m, 1H), 3.94, 3.94 (s, each 3H),
A solution of the crude dibenzyl ether in THF (15mL) was
3.75, 3.74 (s, each 3H), 3.57, 3.56 (s, each 3H), 3.52, 3.52 (s, treated with TBAF (1.0M THF, 2.25mL, 2.25mmol). The
each 3H), 2.17–1.97 (m, 1H), 1.85–1.69 (m, 1H), 1.51, 1.42 reaction mixture was stirred at room temperature for 0.5h,
(d, each 3H, J=7.1, 7.1Hz), 1.36–1.24 (m, 2H), 1.07 (d, 3H, quenched with a saturated aqueous NH4Cl solution, and di-
J=6.3Hz), 0.98 (d, 3H, J=5.5Hz), 0.83 (d, 3H, J=6.3Hz), 0.72 luted with EtOAc. After removal of the organic layer, the
(d, 3H, J=8.6Hz); 13C-NMR (100MHz, CDCl3) δ: 157.1, 157.0, aqueous layer was extracted with EtOAc. The organic layer
154.9, 153.0, 152.9, 129.8, 129.7, 110.0, 109.6, 99.2, 91.8, 72.2, was combined, dried over Na2SO4, filtered, and concentrated
72.0, 64.8, 64.3, 60.6, 60.5, 57.8, 57.4, 57.3, 53.6, 53.5, 38.0, in vacuo. The residue was purified by frash silica gel column
37.6, 37.4, 37.3, 36.6, 22.4, 22.2, 16.0, 15.8, 14.5, 13.9; HR- chromatography (3:1 hexane/EtOAc) to afford 21 (349mg,
electrospray ionization (ESI)-MS Calcd for C19H32O7NClNa: 68% over the two steps) as a colorless oil: [α]D27 –22.4 (c=1.0,
444.1765, Found: 444.1776.
CHCl3); IR (KBr) cm−1: 3423, 3063, 3030, 2924, 2869, 1455,
1
(2S,4S,5S)-5-Chloro-1-(5,6-dimethoxy-2,4-di(methoxy- 1369, 1097, 738, 698; H-NMR (400MHz, CDCl3) δ: 7.38–7.25
methoxy)pyridin-3-yl)-2,4-dimethylhexan-1-one
(17)
A
(m, 10H), 4.72 (d, 1H, J=12.7Hz), 4.56 (d, 1H, J=11.9Hz),
solution of 16 (131mg, 0.311mmol) in CH2Cl2 (3.1mL) was 4.53 (d, 2H, J=1.3Hz) 3.63–3.56 (m, 2H), 3.46–3.37 (m, 3H),
treated with Dess–Martin periodinane (198mg, 0.467mmol). 1.95–1.85 (m, 1H), 1.73–1.64 (m, 1H), 1.27–1.19 (m, 2H), 0.90
The reaction mixture was stirred at room temperature for (d, 3H, J=7.2Hz), 0.86 (d, 3H, J=7.2Hz); 13C-NMR (100MHz,
0.5h, quenched with a saturated aqueous Na2S2O3 solution CDCl3) δ: 139.0, 138.4, 128.4, 128.3, 128.0–127.7, 127.6, 127.5,
and a saturated aqueous NaHCO3 solution, and diluted with 83.1, 73.4, 72.7, 71.2, 68.9, 35.4, 33.3, 32.2, 16.0, 15.7; HR-ESI-
CH2Cl2. After removal of the organic layer, the aqueous layer MS Calcd for C22H30O3Na: 365.2093, Found: 365.2080.
was extracted with CH2Cl2. The organic layer was combined,
(2S,4S,5S)-5,6-Di(benzyloxy)-2,4-dimethylhexanal
(8)
dried over Na2SO4, filtered, and concentrated in vacuo. The To a solution of 21 (336mg, 0.982mmol) in CH2Cl2 (10mL)
residue was purified by frash silica gel column chromatog- were added TEMPO (15.0mg, 0.0982mmol) and PhI(OAc)2
raphy (20:1 hexane/EtOAc) to afford 17 (123mg, 94%) as a (788mg, 2.45mmol). The reaction mixture was stirred at room
colorless oil: [α]D27 –6.4 (c=1.0, CHCl3); IR (KBr) cm−1: 2969, temperature for 4.5h, quenched with a saturated aqueous

July 2012
903
Na2S2O3 solution, and diluted with CH2Cl2. After removal 5.43 (dd, 2H, J=8.9, 5.8Hz), 5.25 (dd, 2H, J=8.5, 5.5Hz),
of the organic layer, the aqueous layer was extracted with 4.67 (d, 1H, J=11.5Hz), 4.53 (d, 1H, J=7.4Hz), 4.52 (d, 2H,
CH2Cl2. The organic layer was combined, dried over Na2SO4, J=9.0Hz), 3.94 (s, 3H), 3.74 (s, 3H), 3.60–3.57 (m, 2H), 3.45
filtered, and concentrated in vacuo. The residue was purified (s, 3H), 3.45–3.43 (m, 1H), 3.43 (s, 3H), 3.15–3.08 (m, 1H),
by frash silica gel column chromatography (60:1 hexane/ 1.96–1.86 (m, 1H), 1.66–1.54 (m, 2H), 1.11 (d, 3H, J=8.8Hz),
EtOAc) to afford 8 (307mg, 92%) as a colorless oil: [α]D27 0.88 (d, 3H, J=5.2Hz); 13C-NMR (100MHz, CDCl3) δ: 204.9,
−14.4 (c=1.0, CHCl3); IR (KBr) cm−1: 2964, 2929, 2869, 1724, 157.1, 156.1, 154.7, 139.1, 138.4, 129.2, 128.4, 128.2, 127.6,
1
1456, 1369, 1206, 1097, 739, 699; H-NMR (400MHz, CDCl3) 127.5, 127.5, 109.8, 99.0, 91.7, 82.9, 73.4, 72.5, 71.1, 60.7, 57.6,
δ: 9.58 (d, 1H, J=2.5Hz), 7.35–7.25 (m, 10H), 4.70 (d, 1H, 57.2, 53.9, 44.8, 34.3, 32.7, 15.4, 15.1; HR-ESI-MS Calcd for
J=12.7Hz), 4.54 (d, 1H, J=7.2Hz), 4.52 (d, 2H, J=9.0Hz), C33H43O9NNa: 620.2835, Found: 620.2821.
3.63–3.56 (m, 2H), 3.45–3.41 (m, 1H), 2.43–2.33 (m, 1H),
A suspension of the ketone (16.1mg, 0.0269mmol) and 20%
1.96–1.86 (m, 1H), 1.63–1.55 (m, 1H), 1.49–1.41 (m, 1H), 1.04 Pd(OH)2/C (3.2mg) in EtOH (2.6mL) was vigorously stirred
(d, 3H, J=8.6Hz), 0.92 (d, 3H, J=6.2Hz); 13C-NMR (75MHz, under a H2 atmosphere at room temperature for 2h. The cata-
CDCl3) δ: 205.2, 139.0, 138.4, 128.5, 128.4, 127.9, 127.8, 127.6, lyst was filtered through a pad of celite, and the filtrate was
82.5, 73.5, 72.7, 70.7, 44.3, 32.6, 25.9, 15.8, 13.2; HR-ESI-MS concentrated in vacuo. The residue was purified by frash silica
Calcd for C22H28O3Na: 363.1936, Found: 363.1921.
gel column chromatography (1:2 hexane/EtOAc) to afford 23
(2S,4S,5S)-5,6-Di(benzyloxy)-1-(5,6-dimethoxy-2,4- (8.9mg, 79%) as a colorless oil: [α]D27 −6.9 (c=1.0, CHCl3);
di(methoxymethoxy)pyridin-3-yl)-2,4-dimethylhexan-1-ol IR (KBr) cm−1: 3479, 2933, 1695, 1587, 1468, 1389, 1212,
1
(22) A solution of n-BuLi (1.57M in hexane, 1.52mL, 1114, 756, 612, 428; H-NMR (400MHz, CDCl3) δ: 5.47 (dd,
2.40mmol) in THF (10mL) was treated with the solution of 2H, J=12.4, 5.8Hz), 5.28 (s, 2H), 3.95 (s, 3H), 3.76 (s, 3H),
°
6 (367mg, 0.960mmol) in THF (5.0mL) at −78 C, and then 3.71–3.67 (m, 1H), 3.48–3.45 (m, 2H), 3.47 (s, 6H), 3.25–3.17
the solution of 8 (297mg, 0.873mmol) in THF (5.0mL) was (m, 1H), 1.82–1.73 (m, 1H), 1.73–1.69 (m, 1H), 1.62–1.51 (m,
added. The reaction mixture was stirred for 5min at −78 C, 1H), 1.14 (d, 3H, J=7.8Hz), 0.88 (d, 3H, J=7.8Hz); 13C-NMR
°
quenched with a saturated aqueous NH4Cl solution, and di- (100MHz, CDCl3) δ: 210.8, 205.8, 157.0, 156.1, 152.7, 129.8,
luted with EtOAc. Then the resulting mixture was allowed 110.5, 99.0, 91.9, 75.8, 64.5, 60.8, 57.7, 57.4, 44.4, 34.5, 34.0,
to warm to room temperature. After removal of the organic 16.1, 15.3; HR-ESI-MS Calcd for C19H31O9NNa: 440.1896,
layer, the aqueous layer was extracted with EtOAc. The or- Found: 440.1874.
ganic layer was combined, dried (Na2SO4), filtered, and con-
(2S,4S)-1-(5,6-Dimethoxy-2,4-di(methoxymethoxy)-
centrated in vacuo. The residue was purified by frash silica pyridin-3-yl)-2-methyl-4-((S)-2-thioxo-1,3-dioxolan-4-yl)-
gel column chromatography (10:1 hexane/EtOAc) to afford 22 pentan-1-one (24) A solution of 23 (34.8mg, 0.0834mmol)
(0.420g, 80%) as a colorless oil. This material was obtained in toluene (1.6mL) was treated with thiocarbonyldiimidazole
as a mixture of two diastereomers: [α]D27 ‒31.4 (c=1.0, CHCl3); (17.8mg, 0.100mmol). The reaction mixture was stirred at
IR (KBr) cm−1: 3564, 2956, 1590, 1466, 1391, 1159, 905, room temperature for 4h, quenched with water, and diluted
1
738, 699; H-NMR (400MHz, CDCl3) δ: 7.38–7.21 (m, 10H), with EtOAc. After removal of the organic layer, the aqueous
5.58–5.43 (m, 2H), 5.34–5.22 (m, 2H), 4.74–4.47 (m, 5H), layer was extracted with EtOAc. The organic layer was com-
3.92, 3.92 (s, each 3H), 3.73, 3.68 (s, each 3H), 3.65–3.61 (m, bined, dried over Na2SO4, filtered, and concentrated in vacuo.
1H), 3.45–3.43 (m, 2H), 3.53, 3.51 (s, each 3H), 3.49, 3.46 (s, The residue was purified by frash silica gel column chroma-
each 3H), 2.14–2.04 (m, 1H), 1.93–1.81 (m, 1H), 1.39–1.27 (m, tography (3:1 hexane/EtOAc) to afford 24 (29.0mg, 75%) as a
1H), 1.05 (d, 3H, J=5.8Hz), 0.91 (d, 3H, J=7.2Hz), 0.97–0.81 colorless oil: [α]D27 −24.0 (c=1.0, CHCl3); IR (KBr) cm−1: 3467,
1
(m, 1H), 0.76 (d, 3H, J=8.4Hz), 0.67 (d, 3H, J=8.4Hz); 13C- 2931, 2360, 1584, 1458, 1288, 1158, 896; H-NMR (400MHz,
NMR (100MHz, CDCl3) δ: 157.2, 157.1, 154.9, 153.0, 139.2, CDCl3) δ: 5.50 (d, 1H, J=7.2Hz), 5.44 (d, 1H, J=5.6Hz), 5.28
138.5, 138.4, 129.8, 128.3, 128.1, 127.6, 127.5, 127.4, 127.2, (s, 2H), 4.78 (dd, 1H, J=15.7, 8.3Hz), 4.64 (t, 1H, J=8.8Hz),
110.0, 99.2, 99.1, 91.8, 83.4, 83.2, 73.3, 72.6, 72.5, 72.4, 72.2, 4.35 (t, 1H, J=8.2Hz), 3.95 (s, 3H), 3.75 (s, 3H), 3.46 (s,
71.2, 60.5, 57.8, 57.4, 53.5, 36.8, 36.7, 35.9, 35.6, 32.6, 32.5, 6H), 3.24–3.15 (m, 1H), 2.11–2.03 (m, 1H), 1.74–1.66 (m,
15.9, 15.8, 15.3, 15.1; HR-ESI-MS Calcd for C33H45O9NNa: 1H), 1.62–1.54 (m, 1H), 1.14 (d, 3H, J=7.6Hz), 0.95 (d, 3H,
622.2992, Found: 622.2962.
J=9.0Hz); 13C-NMR (100MHz, CDCl3) δ: 204.3, 191.9, 157.2,
(2S,4S,5S)-1-(5,6-Dimethoxy-2,4-bis(methoxymethoxy)- 152.7, 129.7, 110.2, 99.0, 93.2, 91.9, 86.1, 71.0, 60.9, 57.8,
pyridin-3-yl)-5,6-dihydroxy-2,4-dimethylhexan-1-one (23) 54.3, 44.3, 34.6, 34.0, 33.9, 15.7, 13.8; HR-ESI-MS Calcd for
A solution of 22 (0.420g, 0.701mmol) in CH2Cl2 (7.0mL) was C20H29O9NSNa: 482.1460, Found: 482.1458.
treated with Dess–Martin periodinane (445mg, 1.05mmol).
NBRI23477 B (5) A solution of 24 (28.9mg, 0.0631mmol)
°
The mixture was stirred at room temperature for 0.5h, in P(OEt)3 (1.2mL) was stirred at 110 C for 36h. The resulting
quenched with a saturated aqueous Na2S2O3 solution and a solution was semi-purified by frash silica gel column chroma-
saturated aqueous NaHCO3 solution, and diluted with CH2Cl2. tography (10:1 hexane/EtOAc) to afford a mixture of 5 and
After removal of the organic layer, the aqueous layer was MOM-protected 5.
extracted with CH2Cl2. The organic layer was combined,
To a solution of the mixture in CH2Cl2 (0.4mL) was added
°
dried over Na2SO4, filtered, and concentrated in vacuo. The TFA (0.350mL) at 0 C. The resulting mixture was stirred at
°
residue was purified by frash silica gel column chromatogra- 0 C for 15min and concentrated in vacuo. The residue was
phy (5:1 hexane/EtOAc) to afford the corresponding ketone purified by preparative TLC (2:1 hexane/EtOAc) to afford
(391mg, 94%) as a colorless oil: [α]D27 −17.7 (c=1.0, CHCl3); NBRI23477 B (5) (8.8mg, 47% over the two steps) as a white
IR (KBr) cm−1: 2934, 1698, 1585, 1457, 1389, 1158, 1029, 898, solid: [α]D27 −14.0 (c=0.2, EtOH), (lit.5) [α]D20 –39.0 (c=0.2,
1
741, 699; H-NMR (400MHz, CDCl3) δ: 7.33–7.24 (m, 10H), EtOH)); IR (KBr) cm−1: 2928, 1646, 1596, 1455, 1324, 1201,

904
Vol. 60, No. 7
1
1162, 996; H-NMR (400MHz, pyridine-d6) δ: 5.79 (ddd, 1H, 29.0mmol) and TBDPSCl (4.10mL, 16.0mmol). The reaction
J=17.4, 10.2, 7.5Hz), 4.99 (dd, 1H, J=17.2, 1.2Hz), 4.94 (dd, mixture was stirred at room temperature for 0.5h. The result-
1H, J=10.7, 1.3Hz), 4.45–4.40 (m, 1H), 3.89 (s, 3H), 3.83 (s, ing solution was diluted with water and EtOAc. After removal
3H), 2.35–2.31 (m, 1H), 2.13–2.07 (m, 1H), 1.46–1.39 (m, of the organic layer, the aqueous layer was extracted with
1H), 1.33 (d, 3H, J=6.9Hz), 1.07 (d, 3H, J=6.7Hz); 13C-NMR EtOAc. The organic layer was combined, dried over Na2SO4,
(100MHz, pyridine-d6) δ: 211.1, 165.6, 162.6, 159.9, 145.0, filtered, and concentrated in vacuo. The residue was purified
124.8, 113.0, 100.8, 60.5, 54.2, 42.1, 40.8, 36.4, 20.3, 18.0; HR- by frash silica gel column chromatography (70:1 hexane/
ESI-MS Calcd for C15H21O5NNa: 318.1317, Found: 318.1311.
EtOAc) to afford the corresponding TBDPS ether (7.01g, 95%)
Atpenin B (3) A suspension of 5 (3.8mg, 0.0128mmol) as a colorless oil: [α]D27 +4.88 (c=1.0, CHCl3); IR (KBr) cm−1:
1
and 5% Pd/C (1.0mg) in EtOH (1.2mL) was vigorously stirred 2955, 2931, 2858, 1468, 1254, 1108, 838, 704, 504; H-NMR
under a H2 atmosphere at room temperature for 4h. The (400MHz, CDCl3) δ: 7.73–7.67 (m, 4H), 7.46–7.34 (m, 6H),
catalyst was filtered through a pad of celite, and the filtrate 5.72–5.51 (m, 2H), 4.16 (dd, 2H, J=4.5, 1.0Hz), 3.47–3.36 (m,
was concentrated in vacuo. The residue was purified by pre- 2H), 2.21–2.11 (m, 1H), 1.88–1.78 (m, 1H), 1.72–1.60 (m, 1H),
parative TLC (2:1 hexane/EtOAc) to afford 3 (3.5mg, 92%) 1.06 (s, 9H), 0.90 (s, 9H), 0.86 (d, 3H, J=7.1Hz), 0.03 (s, 6H);
as a white solid: [α]D27 −14.5 (c=0.1, EtOH), (lit.1) [α]D22 −27.0 13C-NMR (75MHz, CDCl3) δ: 135.9, 134.3, 130.5, 129.9, 129.7,
(c=1.0, EtOH)); IR (KBr) cm−1: 1645, 1595, 1456, 1323, 1203, 127.9, 68.1, 64.9, 36.3, 36.2, 27.2, 26.3, 19.6, 18.7, 16.7; HR-
1
1159, 996; H-NMR (400MHz, pyridine-d6) δ: 4.35–4.27 (m, ESI-MS Calcd for C29H46O2Si2Na: 505.2934, Found: 505.2920.
1H), 3.78 (s, 3H), 3.72 (s, 3H), 1.73 (ddd, 1H, J=13.8, 7.8,
A solution of the TBDPS ether (50.0mg, 0.104mmol) in
5.0Hz), 1.43–1.36 (m, 1H), 1.34–1.29 (m, 1H), 1.28–1.20 (m, EtOH (1.0mL) was treated with pyridinium p-toluenesulfonate
1H), 1.20 (d, 3H, J=6.5Hz), 1.11–1,02 (m, 1H), 0.87 (d, 3H, (PPTS) (13.0mg, 0.0520mmol). The mixture was stirred at
J=7.2Hz), 0.72 (t, 3H, J=7.7Hz); 13C-NMR (100MHz, pyri- room temperature for 24h. The resulting solution was diluted
dine-d6) δ: 211.6, 165.7, 162.6, 159.9, 124.8, 100.6, 60.6, 54.2, with water and EtOAc. After removal of the organic layer,
41.9, 41.0, 30.6, 19.0, 17.0, 20.0, 11.7; HR-ESI-MS Calcd for the aqueous layer was extracted with EtOAc. The organic
C15H23O5NNa: 320.1473, Found: 320.1460.
layer was combined, dried over Na2SO4, filtered, and concen-
(S,E)-6-(tert-Butyldimethylsilyloxy)-5-methylhex-2-en-1- trated in vacuo. The residue was purified by frash silica gel
ol (11) A solution of 25 (4.26g, 20.0mmol) in CH2Cl2 column chromatography (15:1 hexane/EtOAc) to afford the
(100mL) was treated with DIBAL (1.02M in hexane, 45.0mL, corresponding alcohol (36.5mg, 95%) as a colorless oil: [α]D27
46.0mmol) at –78 C. After stirring for 1h at −78 C, 3N aque- +3.76 (c=1.0, CHCl3); IR (KBr) cm−1: 3378, 2932, 2859, 1964,
°
°
1
ous HCl solution was added dropwise to the resulting solution 1467, 1428, 1110, 702, 610, 503; H-NMR (400MHz, CDCl3) δ:
until the evolution of gas ceased. After removal of the organic 7.67–7.61 (m, 4H), 7.41–7.30 (m, 6H), 5.68–5.48 (m, 2H), 4.13
layer, the aqueous layer was extracted with CH2Cl2. The or- (dd, 2H, J=4.6, 1.1Hz), 3.49–3.36 (m, 2H), 2.15–2.06 (m, 1H),
ganic layer was combined, dried over Na2SO4, filtered, and 1.93–1.83 (m, 1H), 1.72–1.61 (m, 1H), 1.01 (s, 9H), 0.86 (d, 3H,
concentrated in vacuo.
J=7.7Hz); 13C-NMR (100MHz, CDCl3) δ: 135.6, 133.9, 130.5,
A solution of the residue in benzene (200mL) was treat- 129.7, 129.2, 127.7, 67.7, 64.6, 36.2, 35.9, 27.0, 19.3, 16.5; HR-
ed with (carbethoxymethylene)triphenylphosphorane (13.8g, ESI-MS Calcd for C23H32O2SiNa: 391.2069, Found: 391.2064.
40.0mmol). After stirring at room temperature for 12h, the
A solution of the alcohol (412mg, 1.12mmol) in CH2Cl2
resulting solution was concentrated in vacuo. The residue (11.2mL) was treated with TEMPO (17.4mg, 0.112mmol) and
was semi-purified by frash silica gel column chromatography PhI(OAc)2 (902mg, 2.80mmol). The reaction mixture was
(30:1 hexanes/EtOAc) to afford the crude α,β-unsaturated stirred at room temperature for 2h, quenched with a saturated
ester.
aqueous Na2S2O3 solution, and diluted with CH2Cl2. After
A solution of the crude ester in CH2Cl2 (182mL) was removal of the organic layer, the aqueous layer was extracted
treated with DIBAL (1.02M in hexane, 44.8mL, 45.7mmol) at with CH2Cl2. The organic layer was combined, dried over
°
°
0 C. After stirring for 1h at 0 C, MeOH was added dropwise Na2SO4, filtered, and concentrated in vacuo. The residue was
to the resulting solution until the evolution of gas ceased. The purified by frash silica gel column chromatography (60:1
mixture was diluted with CH2Cl2, treated with celite (13.4g) hexane/EtOAc) to afford 9 (367mg, 89%) as a colorless oil:
and Na2SO4·10H2O (15.8g), and then stirred for 2h at room [α]D27 +7.77 (c=1.0, CHCl3); IR (KBr) cm−1: 2932, 2858, 1727,
1
temperature. The resulting solution was filtered through a pad 1429, 1110, 822, 741, 704, 505; H-NMR (400MHz, CDCl3) δ:
of celite, the filtrate was concentrated in vacuo. The residue 9.60 (d, 1H, J=1.3Hz), 7.64–7.60 (m, 4H), 7.38–7.30 (m, 6H),
was purified by frash silica gel column chromatography (20:1 5.63–5.54 (m, 2H), 4.11 (dd, 2H, J=2.7, 1.6Hz), 2.44–2.39 (m,
hexane/EtOAc) to afford 11 (3.55g, 73% over the three steps) 2H), 2.12–2.02 (m, 1H), 1.04 (d, 3H, J=7.7Hz), 1.01 (s, 9H);
as a colorless oil: [α]D27 +1.74 (c=1.0, CHCl3); IR (KBr) cm−1: 13C-NMR (100MHz, CDCl3) δ: 204.6, 135.6, 133.8, 131.7,
3342, 2954, 2858, 1467, 1254, 1092, 1006, 972, 839, 776, 668; 129.7, 127.7, 126.8, 64.2, 46.1, 33.2, 26.8, 19.2, 13.0; HR-ESI-
1H-NMR (400MHz, CDCl3) δ: 5.70–5.64 (m, 2H), 4.10 (d, MS Calcd for C23H30O2SiNa: 389.1913, Found: 389.1903.
2H, J=4.1Hz), 3.41 (d, 2H, J=4.1Hz), 2.25–2.15 (m, 1H),
(2S, E)-6-(tert-Butyldiphenylsilyloxy)-1-(5,6-di-
1.89–1.80 (m, 1H), 1.72–1.63 (m, 1H), 0.89 (s, 9H), 0.87 (d, methoxy-2,4-di(methoxymethoxy)pyridin-3-yl)-2-methyl-
3H, J=6.6Hz), 0.03 (s, 6H); 13C-NMR (100MHz, CDCl3) δ: hex-4-en-1-ol (26) A solution of n-BuLi (1.57M in hexane,
131.9, 130.6, 68.0, 64.1, 36.2, 36.1, 26.2, 18.6, 16.6, −5.1; HR- 1.75mL, 2.75mmol) in THF (11mL) was treated with the solu-
°
tion of 6 (423mg, 1.10mmol) in THF (5.5mL) at −78 C, and
FAB-MS Calcd for C13H28O2SiNa: 267.1756, Found: 267.1761.
(S,E)-6-((tert-Butyldiphenylsilyl)oxy)-2-methylhex-4-enal then the solution of 9 (366mg, 1.00mmol) in THF (5.5mL)
(9) A solution of 11 (3.54g, 14.5mmol) in dimethylfor- was added. The reaction mixture was stirred for 5min at
°
mamide (DMF) (29mL) was treated with imidazole (1.98g, −78 C, quenched with a saturated aqueous NH4Cl solution,

July 2012
905
and diluted with EtOAc. Then the resulting mixture was al- 408.1620.
lowed to warm to room temperature. After removal of the or-
ganic layer, the aqueous layer was extracted with EtOAc. The 3-yl)-2-methylhex-4-en-1-one (28)
(S,E)-6-Bromo-1-(2,4-dihydroxy-5,6-dimethoxypyridin-
solution of the
A
organic layer was combined, dried over Na2SO4, filtered, and 27 (53.0mg, 0.138mmol) in CH2Cl2 (1.4mL) was treated
concentrated in vacuo. The residue was purified by frash silica with CBr4 (137mg, 0.414mmol) and (CH2PPh2)2 (165mg,
°
gel column chromatography (5:1 hexane/EtOAc) to afford 26 0.414mmol). The reaction was stirred at 0 C for 0.5h and
(449mg, 72%) as a colorless oil. This material was obtained concentrated in vacuo. The residue was purified by frash silica
as a mixture of two diastereomers: [α]D27 –5.0 (c=1.0, CHCl3); gel column chromatography (3:1 hexane/EtOAc) to afford 28
IR (KBr) cm−1: 3564, 2931, 1589, 1466, 1390, 1107, 903, 701; (27.9mg, 56%) as a colorless oil: [α]D27 −9.2 (c=1.0, CHCl3); IR
1H-NMR (400MHz, CDCl3) δ: 7.70–7.64 (m, 4H), 7.44–7.33 (KBr) cm−1: 3448, 2080, 1628, 1585, 1456, 1425, 1390, 1118,
1
(m, 6H), 5.78–5.43 (m, 3H), 5.35–5.24 (m, 2H), 4.68–4.60 (m, 919, 755; H-NMR (400MHz, CDCl3) δ: 5.85–5.65 (m, 2H),
1H), 4.18, 4.11 (d, each 2H, J=4.2, 4.9Hz), 3.93, 3.92 (s, each 4.18 (s, 3H) 4.06–3.95 (m, 1H), 3.92 (d, 2H, J=6.0Hz), 3.80
3H), 3.74, 3.73 (s, each 3H), 3.53, 3.53 (s, each 3H), 3.49, 3.49 (s, 3H), 2.58–2.50 (m, 1H), 2.19–2.11 (m, 1H), 1.15 (d, 3H,
(s, each 3H), 2.18–1.92 (m, 2H), 1.83–1.72 (m, 1H), 1.07 (d, J=7.8Hz); 13C-NMR (100MHz, CDCl3) δ: 209.0, 171.2, 161.7,
3H, J=8.2Hz), 1.04 (s, 9H), 0.70 (d, 3H, J=7.1Hz); 13C-NMR 155.6, 133.9, 128.4, 121.4, 100.3, 61.5, 57.5, 42.6, 35.5, 32.8,
(100MHz, CDCl3) δ: 157.2, 157.0, 155.0, 153.1, 135.5, 133.9, 16.3; HR-FAB-MS Calcd for C14H19O5NBr: 360.0477, Found:
133.8, 130.4, 130.1, 129.9, 129.8, 129.5, 127.6, 110.0, 109.9, 360.0432.
99.1, 91.7, 71.8, 71.4, 64.6, 64.5, 60.5, 57.8, 57.4, 57.3, 53.6,
53.5, 39.4, 39.3, 36.4, 36.1, 26.8, 26.7, 19.2, 16.1, 15.8; HR-ESI- 0.0705mmol) in THF (1.4mL) was treated with LiEt3BH
(−)-Harzianopyridone (4) A solution of 28 (25.3mg,
°
(323mL, 0.352mmol, 1.09M in THF) at −78 C. The mixture
MS Calcd for C34H47O8NSiNa: 648.2968, Found: 648.2963.
(S,E)-1-(5,6-Dimethoxy-2,4-bis(methoxymethoxy)- was stirred at −78 C for 12h, quenched with water, and di-
pyridin-3-yl)-6-hydroxy-2-methylhex-4-en-1-one (27) luted with CH2Cl2. Then the resulting mixture was allowed
°
A
solution of 26 (249mg, 0.398mmol) in CH2Cl2 (4mL) was to warm to room temperature. After removal of the organic
treated with Dess–Martin periodinane (0.250g, 0.598mmol). layer, the aqueous layer was extracted with CH2Cl2. The or-
The mixture was stirred at room temperature for 0.5h, ganic layer was combined, dried over Na2SO4, filtered, and
quenched with a saturated aqueous Na2S2O3 solution and a concentrated in vacuo. The residue was purified by preparative
saturated aqueous NaHCO3 solution, and diluted with CH2Cl2. TLC (1:5 hexane/EtOAc) to afford 4 (17.0mg, 86%) as a white
After removal of the organic layer, the aqueous layer was ex- solid: [α]D27 −8.4 (c=0.1, MeOH), (lit.4) [α]D22 −12.3 (c=0.1,
tracted with CH2Cl2. The organic layer was combined, dried MeOH)); IR (KBr) cm−1: 2925, 1645, 1598, 1458, 1375, 1324,
over Na2SO4, filtered, and concentrated in vacuo. The residue 1284, 1199, 1165, 1110, 996, 961, 804, 740, 623; 1H-NMR
was purified by frash silica gel column chromatography (20:1 (300MHz, CDCl3) δ: 5.50–5.35 (m, 2H), 4.15 (s, 3H), 3.96 (m,
hexane/EtOAc) to afford the corresponding ketone (224mg, 1H), 3.81 (s, 3H), 2.49–2.41 (m, 1H), 2.09–1.99 (m, 1H), 1.63
90%) as a colorless oil: [α]D27 −1.98 (c=1.0, CHCl3); IR (KBr) (d, 3H, J=5.0Hz), 1.13 (d, 3H, J=6.9Hz); 13C-NMR (100MHz,
1
cm−1: 2934, 1699, 1585, 1466, 1389, 1110, 898, 704, 504; H- CDCl3) δ: 210.0, 172.3, 161.9, 155.4, 128.7, 127.2, 121.3, 100.8,
NMR (400MHz, CDCl3) δ: 7.72–7.62 (m, 4H), 7.46–7.33 (m, 61.7, 58.0, 43.2, 36.1, 18.1, 16.4; HR-FAB-MS Calcd for
6H), 5.66–5.57 (m, 2H), 5.46 (d, 2H, J=1.1Hz), 5.26 (d, 2H, C14H20O5N: 282.1341, Found: 282.1353.
J=2.9Hz), 4.15 (d, 2H, J=3.15Hz), 3.95 (s, 3H), 3.75 (s, 3H),
3.46 (s, 3H), 3.44 (s, 3H), 3.14–3.07 (m, 1H), 2.57–2.50 (m,
Acknowledgements This research was partially supported
1H), 2.15–2.02 (m, 1H), 1.13 (d, 3H, J=5.8Hz), 1.04 (s, 9H); by a Grant-in-Aid for Young Scientists (to MO) from the Min-
13C-NMR (100MHz, CDCl3) δ: 204.6, 156.9, 156.1, 152.7, istry of Education, Culture, Sports, Science and Technology of
135.5, 133.8, 131.1, 129.9, 129.6, 128.3, 127.6, 110.8, 98.9, 91.7, Japan. MO also acknowledges a Kitasato University Research
64.4, 60.7, 57.6, 57.3, 53.9, 47.0, 35.0, 26.8, 19.2, 15.2; HR-ESI- Grant for young researchers. We thank Ms. N. Sato and Dr. K.
MS Calcd for C34H45O8NSiNa: 646.2812, Found: 646.2792.
Nagai (Kitasato University) for kindly measuring NMR and
To a solution of the ketone (224mg, 0.360mmol) in THF MS spectra.
(3.6mL) was added TBAF (1.0M THF, 0.540mL, 0.540mmol).
The reaction mixture was stirred at room temperature for
0.5h, quenched with water, and diluted with EtOAc. After
removal of the organic layer, the aqueous layer was extracted
with EtOAc. The organic layer was combined, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by frash silica gel column chromatography (3:1
hexane/EtOAc) to afford 27 (128mg, 93%) as a colorless oil:
[α]D27 −9.6 (c=1.0, CHCl3); IR (KBr) cm−1: 3448, 2080, 1628,
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