Synthesis of the proposed structure of phaeosphaeride A

Article abstract of DOI:10.1039/c1ob05612c

The first total synthesis of the proposed structure of phaeosphaeride A has been achieved via six-membered-ring formation by means of an intramolecular vinyl-anion aldol reaction as the key step. This synthesis suggests a revised configurational assignment for phaeosphaeride A.

Full text of DOI:10.1039/c1ob05612c

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PAPER
Synthesis of the proposed structure of phaeosphaeride A†
Kenichi Kobayashi,a Iwao Okamoto,b Nobuyoshi Morita,b Tamiko Kiyotanib and Osamu Tamura*b
Received 16th April 2011, Accepted 19th May 2011
DOI: 10.1039/c1ob05612c
The first total synthesis of the proposed structure of phaeosphaeride A has been achieved via
six-membered-ring formation by means of an intramolecular vinyl-anion aldol reaction as the key step.
This synthesis suggests a revised configurational assignment for phaeosphaeride A.
Introduction
Results and discussion
Signal transducer and activator of transcription 3 (STAT3) is a
critical protein for cell proliferation and survival. Since STAT3 has
an important role in oncogenesis,1 it has been a novel target protein
for treating tumors, and small-molecule inhibitors of STAT3 are
considered to be candidate anti-cancer chemotherapeutic agents.2
Phaeosphaerides A (1) and B (2) are nitrogen-containing natural
products isolated from an endophytic fungus in 2006 by Clardy
and co-workers (Fig. 1).3 Phaeosphaeride A (1) inhibits the growth
of STAT3-dependent U266 multiple myeloma cells with an IC50
of 6.7 mM in vitro, whereas phaeosphaeride B (2) showed no
activity against STAT3. Although the relative stereochemistries
of phaeosphaerides A (1) and B (2) were deduced to be as
depicted in Fig. 1 on the basis of NOE experiments, the absolute
configurations remained unknown. Captivated by this unique
molecular structure and promising biological activity, we launched
a synthetic study of phaeosphaeride A. Here, we describe the first
total synthesis of the proposed structure 1 of phaeosphaeride A.
Our synthetic planning involved oxy-Michael reaction followed
by vinyl-anion aldol reaction as shown in the retrosynthetic
analysis (Scheme 1). Phaeosphaeride A (1) would be obtained
by regioselective methylenation of one of the two carbonyl groups
in maleimide 3. The maleimide moiety of 3 can be assembled
from diester 4 and methoxyamine (5). The dihydropyran ring
of 4 might then be constructed by vinyl-anion aldol reaction4
of the olefinic aldehyde 6, obtained by oxy-Michael reaction of
secondary alcohol 7 with acetylenedicarboxylate (8).
Fig. 1 Proposed structures of phaeosphaerides.
aDiscovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1,
Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan
bShowa Pharmaceutical University, 3-3165, Higashi-tamagawagakuen,
Machida, Tokyo 194-8543, Japan. E-mail: tamura@ac.shoyaku.ac.jp;
Fax: +81 (42) 721 1579
† Electronic supplementary information (ESI) available: CIF file of
compound 20 and 1H and 13C-NMR spectra. CCDC reference number
823955. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob05612c
Scheme 1 Retrosynthetic analysis of phaeosphaeride A (1).
Our investigation was initiated by preparation of alco-
hol 13, corresponding to 7, from hexanal (9) (Scheme 2).
Thus, Horner–Wadsworth–Emmons reaction of 9 afforded a,b-
unsaturated ester (E)-105 (77%) and (Z)-10 (8.5%). As expected,
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Scheme 2 Reagents and conditions: (i) (EtO)2P(O)CH(CH3)CO2Et, NaH,
DME, 77%; (ii) AD-mix-b, MeSO2NH2, t-BuOH, H2O, 99%; (iii) NaH,
BnBr, THF, 60%; (iv) MOMCl, i-Pr2NEt, CH2Cl2, 98%; (v) DIBALH,
THF, quant.; (vi) TIPSOTf, 2,6-lutidine, CH2Cl2, quant.; (vii) H2, Pd/C,
EtOH, 99%.
Scheme 3 Synthesis of aldehydes (E)-16 and (Z)-16.
Table 1 Oxy-Michael addition of alcohol 13 to 14
Yield (%)a
Sharpless dihydroxylation6 of (E)-10 provided the requisite a,b-
dihydroxyester 11 with high enantioselectivity (98% ee), as de-
termined by the modified Mosher’s method (Fig. 2).7 Benzyl
protection of the secondary hydroxy group, MOM protection
of the tertiary hydroxy group, and subsequent reduction of the
ester group using DIBALH gave primary alcohol 12. TIPS ether
formation of 12 followed by debenzylation provided oxy-Michael
precursor alcohol 13.
Entry Reagent (eq)
Solvent Temp
(E)-15 (Z)-15
1
2
3
4
5
6
DABCO (0.1)
DMAP (0.1)
AgOTf (0.05)
LHMDS (0.2) THF
KHMDS (0.2) THF
CH2Cl2
CH2Cl2
CH2Cl2
rt to 35 ◦
C
C
C
0
0
0
0
0
0
rt to 35 ◦
rt to 35 ◦
-78 ◦C to rt
-78 ◦C to rt
-78 ◦C to 0 ◦
22
43
76
0
0
18
n-BuLi (0.2)
THF
C
a Isolated yield.
The crucial construction of the six-membered-ring by means
of a vinyl-anion aldol reaction was next examined (Table 2).
First MHMDS (M = Li or Na or K) was examined as a base
(Table 2, entries 1–3). Treatment of (E)-16 with LiHMDS provided
the desired 17a (10%) and its diastereomer 17b (26%) (entry 1).
The use of NaHMDS was found to give 17a in the best yield
(43%) accompanied by 17b in 21% yield (entry 2). When KHMDS
was employed, the stereoselectivity and the chemical yield were
fairly low (entry 3). Furthermore, reaction of LDA surprisingly
afforded 18 as a major product (entry 4), and t-BuLi reacted with
the formyl group of (E)-16 to give mainly compound 19 (entry
5). In contrast to entry 2, treatment of (Z)-16 with NaHMDS
gave only trace amounts of 17a and 17b. When 17a or 17b was
independently treated with NaHMDS at -78 ◦C, no epimerization
at the C-6 stereogenic center occurred. From these results, the
present cyclization appears to be a kinetically controlled addition
reaction of an allenic enolate.10 A plausible transition state for the
Fig. 2 Modified Mosher’s method: differences of the chemical shifts (Dd =
(dS–dR), CDCl3) between (R)- and (S)-MTPA esters of 11.
Next we examined oxy-Michael addition of 13 to dimethyl
acetylenedicarboxylate (14) (Scheme 3, Table 1). After screening
several reaction conditions (Table 1, entries 1–5),8 the use of n-
BuLi at -78 ◦C to 0 ◦C was found to give a good yield of (E)-
15 (76%) and (Z)-15 (18%) (entry 6). The stereochemistries of
1
formation of 17a is depicted in Fig. 3. The H NMR spectrum
of 17a showed W-type long-range coupling between H-6 and H-8
(J = 1.3 Hz), whereas the corresponding long-range coupling was
not observed for diastereomer 17b. This observation suggested
a pseudo-diequatorial relationship of H-6 and H-8 of 17a, and
hence the stereochemistry of the resulting stereocenter C-6 in 17a
was deduced to be 6R.
1
these compounds were confirmed by H NMR analysis, which
indicated that the olefinic proton signal of (Z)-15 was shifted
downfield compared to that of (E)-15.9 Desilylation of (E)-15 and
(Z)-15 with HF·py followed by Dess–Martin oxidation gave the
cyclization precursors (E)-16 and (Z)-16, respectively.
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Table 2 Vinyl-anion aldol reaction of (E)-16 and (Z)-16
Yield (%)b
Entry
Substrate
Reagenta
Temp
17a
17b
1
2
3
4
5
6
(E)-16
(E)-16
(E)-16
(E)-16
(E)-16
(Z)-16
LiHMDS
NaHMDS
KHMDS
LDAc
-78 ◦
-78 ◦
-78 ◦
-78 ◦
-78 ◦
-78 ◦
C
10
43
12
trace
0
26
21
9
0
0
C
C
C
C
C
t-BuLid
NaHMDS
trace
0
a All reactions were performed with 1.5 equiv. of the reagent. b Isolated
yield. c Compound 18 was obtained as a major product. d Compound 19
was obtained as a major product.
Scheme 4 Reagents and conditions: (i) TBSOTf, 2,6-lutidine, CH2Cl2,
97%; (ii) 1 M NaOH, MeOH–H2O, 90%; (iii) MeONH2·HCl, Et3N,
WSC·HCl, HOBt, CH2Cl2, 89%; (iv) Et3N, DMF, 70%; (v) MeMgBr,
Et2O, quant.; (vi) HCl–dioxane, dioxane, 52%; (vii) 3HF·Et3N, THF, 90%.
Fig. 3 Plausible transition state for the formation of 17a.
Aldol adduct 17a has the correct stereochemistry for
phaeosphaeride A (1), and elaboration to 1 was now required
(Scheme 4). Silylation of alcohol 17a, regioselective hydrolysis,
and subsequent condensation with MeONH2 (5) gave the desired
amide 20 (78% in 3 steps), of which the structure, including stere-
ochemistry, was unambiguously determined by X-ray diffraction
(Fig. 4).† For the formation of the maleimide moiety, the use
of NaH11 or DIPEA as a base in THF proved to be ineffective,
and a significant amount of the starting material was recovered.
After experimentation, treatment of 20 with Et3N in DMF at
130 ◦C was found to afford the desired maleimide 21 in 70% yield.
Since direct methylenation of 21 with Tebbe reagent12 afforded a
complex mixture, a stepwise conversion had to be investigated. To
our delight, regioselective methylation with MeMgBr followed by
treatment with HCl in dioxane led to spontaneous dehydration and
removal of the MOM group at C-7 to provide the exo methylene
compound 22.13 Finally, removal of the remaining silyl group on
the C-6 hydroxy group with 3HF·Et3N furnished synthetic 1.
Surprisingly, the 1H and 13C NMR data for synthetic 1 were not
identical with those reported for the natural sample. In particular,
the observed chemical shifts of certain protons (H-6, H-8, and
H-15) and carbons (C-6, C-7, and C-8) of synthetic 1 signifi-
cantly deviated from those reported for natural phaeosphaeride
A. Since NOE correlations between H-6 and H-8 for the natural
sample were observed,3 one possibility for the correct structure
Fig. 4 ORTEP drawing of amide 20.
of phaeosphaeride A may be the C-7 epimer of the originally
proposed 1.
Conclusion
We have accomplished the first synthesis of the proposed structure
of phaeosphaeride A, featuring six-membered-ring formation by
means of a vinyl-anion aldol reaction. Although the spectral
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properties of synthetic phaeosphaeride A differed from those of
the natural product, the result obtained here would be a good
starting point for eventual proof of the structure of natural
phaeosphaeride A.
60.0, 31.5, 29.5, 29.1, 22.5, 20.6, 14.2, 14.0; MS (Fab+) m/z 185
(M+H)+; HRMS calcd for C11H21O2 185.1542, found 185.1545.
Ethyl (2S,3R)-2,3-dihydroxy-2-methyloctanoate (11). To a
stirred solution of AD-mix-b (59.5 g) and methanesulfonamide
(4.05 g, 42.6 mmol) in t-BuOH (200 mL) and H2O (200 mL) was
added (E)-10 (7.84 g, 42.5 mmol) in t-BuOH (10 mL) and H2O
(10 mL) at 0 ◦C. The reaction mixture was stirred at the same
temperature for 6 h. For workup, Na2SO3 (63.8 g) was added,
and the mixture was allowed to warm to room temperature, and
stirring was continued for 1 h. The whole was extracted with
AcOEt (200 mL ¥ 2). The combined extracts were washed with 1 M
aqueous NaOH (100 mL ¥ 2) and brine (100 mL), dried (Na2SO4),
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (hexane–AcOEt, 7 : 3) to
afford 11 (9.17 g, 99%) as a colorless oil. [a]2D5 +34.8 (c 0.50,
Experimental
General
Melting points were determined with a Yanagimoto micro melting
point apparatus and are uncorrected. Optical rotations were
measured with a JASCO P-1020 auto digital polarimeter. Infrared
1
spectra (IR) were recorded with PerkinElmer spectrum 100. H
NMR spectra were recorded on a JEOL JNM-AL300 (300 MHz)
or a Bruker AVANCE 500 (500 MHz) spectrometer. The chemical
shifts are expressed in ppm downfield from tetramethylsilane (d =
0) as an internal standard (CDCl3 solution). Splitting patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad peak. 13C NMR spectra were recorded on a
JEOL JNM-AL300 (75 MHz), a Bruker AVANCE 500 (125 MHz),
or a Bruker AVANCE 600 (150 MHz) spectrometer. The chemical
shifts are reported in ppm, relative to the central line of a triplet
at 77.0 ppm for CDCl3. Measurements of mass spectra (MS) and
high resolution MS (HRMS) were performed with a JEOL JMS
SX-102A or a JEOL JMS-T100LP mass spectrometer. Column
chromatography was carried out on silica gel (silica gel 40–50 mm
neutral, Kanto Chemical Co., Inc.). Merck precoated thin layer
chromatography (TLC) plates (silica gel 60 F254, 0.25 mm, Art
5715) were used for the TLC analysis. After extractive workup,
organic layers were dried over anhydrous sodium sulfate or
anhydrous magnesium sulfate and the solvent was removed by
rotary evaporation under reduced pressure.
1
CHCl3); IR (film) 3513, 2956, 1726, 1378, 1261 cm-1; H NMR
(300 MHz, CDCl3) d 4.28 (q, J = 7.1 Hz, 2H), 3.70 (dt, J = 1.8,
9.3 Hz, 1H), 3.39 (s, 1H), 1.86 (d, J = 9.3 Hz, 1H), 1.66–1.50 (m,
2H), 1.47–1.20 (m, 6H), 1.34 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 0.90
(t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 176.3, 77.3, 75.5,
62.1, 31.7, 30.3, 25.5, 22.6, 21.7, 14.1, 14.0; MS (Fab+) m/z 219
(M+H)+; HRMS calcd for C11H23O4 219.1596, found 219.1600.
Determination of stereochemistry at C-3 and estimation of the
optical purity of 11 were conducted by using modified Mosher’s
method. Derivatization of 11 to the corresponding (R)- or (S)-
MTPA ester was conducted according to a usual method using the
corresponding acid chlorides and pyridine. Since 1H NMR of each
crude product did not show the signals of the other diastereomer,
the optical purity of 11 was estimated to be more than 98% ee. (R)-
MTPA ester of 11: 1H NMR (300 MHz, CDCl3) d 7.62–7.53 (m,
2H), 7.46–7.32 (m, 3H), 5.34 (t, J = 6.6 Hz, 1H), 4.22 (dq, J = 10.5,
7.2 Hz, 1H), 4.12 (dq, J = 10.5, 7.2 Hz, 1H), 3.56 (d, J = 1.2 Hz,
3H), 3.22 (br s, 1H), 1.74–1.56 (m, 2H), 1.38 (s, 3H), 1.36–1.07 (m,
6H), 1.27 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 6.9 Hz, 3H). (S)-MTPA
Ethyl (E)-2-methyl-oct-2-enoate [(E)-10] and its (Z)-isomer [(Z)-
10]. To a stirred suspension of NaH (60% in mineral oil, 3.36 g,
84.0 mmol) in DME (120 mL) was added a solution of triethyl
2-phosphonopropionate (20.0 g, 84.0 mmol) in DME (10 mL)
at 0 ◦C. After being stirred at the same temperature for 5 min,
the reaction mixture was allowed to warm to room temperature,
and stirring was continued for 10 min. The resulting pale yellow
1
ester of 11: H NMR (300 MHz, CDCl3) d 7.61–7.53 (m, 2H),
7.46–7.32 (m, 3H), 5.32 (dd, J = 8.1, 4.2 Hz, 1H), 4.15 (dq, J =
10.8, 7.2 Hz, 1H), 4.03 (dq, J = 10.8, 7.2 Hz, 1H), 3.51 (d, J =
1.2 Hz, 3H), 3.22 (br s, 1H), 1.79–1.64 (m, 2H), 1.38–1.15 (m, 6H),
1.36 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 6.9 Hz, 3H). The
Dd values for these MTPA esters revealed that the configuration
of the secondary alcohol should be R (Fig. 2).
◦
solution was cooled to 0 C, a solution of hexanal (7.01 g, 70.0
mmol) in DME (10 mL) was added slowly, and stirring was
continued for 1 h. The reaction mixture was poured into H2O
(420 mL) and extracted with Et2O (100 mL ¥ 2). The combined
extracts were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexane–AcOEt, 49 : 1) to afford (E)-10 (9.95 g, 77%) as a colorless
oil and (Z)-10 (1.10 g, 8.5%) as a colorless oil. (E)-10: IR (film)
2930, 1700, 1648, 1458, 1260 cm-1; 1H NMR (500 MHz, CDCl3)
d = 6.76 (tq, J = 7.5, 1.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.16 (qq,
J = 7.6, 0.8 Hz, 2H), 1.84–1.82 (m, 3H), 1.49–1.39 (m, 2H), 1.37–
1.25 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 168.3, 142.4, 127.6, 60.3, 31.5,
28.6, 28.2, 22.5, 14.3, 14.0, 12.3; MS (Fab+) m/z 185 (M+H)+;
HRMS calcd for C11H21O2 185.1542, found 185.1545. (Z)-10: IR
Ethyl (2S,3R)-3-benzyloxy-2-hydroxy-2-methyloctanoate. To
a stirred suspension of NaH (60% in mineral oil, 201 mg, 5.01
mmol) in THF (10 mL) was added a solution of 11 (497 mg,
◦
2.28 mmol) in THF (3.0 mL) at 0 C. After stirring at the same
temperature for 1.5 h, BnBr (0.32 mL, 2.7 mmol) was added.
The reaction mixture was allowed to warm to room temperature,
and stirring was continued for 17 h. The mixture was poured into
saturated aqueous NH4Cl (20 mL) and extracted with Et2O (30 mL
¥ 2). The combined extracts were washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (hexane–
AcOEt, 19 : 1→9:1) to afford the title compound (423 mg, 60%)
as a colorless oil. [a]2D5 +10.0 (c 0.50, CHCl3); IR (film) 3566, 1732,
1
(film) 2928, 1703, 1647, 1457, 1210 cm-1; H NMR (500 MHz,
1
CDCl3) d 5.92 (tq, J = 7.5, 1.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H),
2.42 (qq, J = 7.5, 1.4 Hz, 2H), 1.89 (q, J = 1.4 Hz, 3H), 1.45–1.36
(m, 2H), 1.35–1.26 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H), 0.89 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 168.2, 143.1, 127.0,
1456, 1220 cm-1; H NMR (500 MHz, CDCl3) d 7.35–7.30 (m,
2H), 7.29–7.25 (m, 3H), 4.60 (d, J = 11.1 Hz, 1H), 4.46 (d, J =
11.1 Hz, 1H), 4.22 (dq, J = 10.8, 7.1 Hz, 1H), 4.12 (dq, J = 10.8,
7.1 Hz, 1H), 3.68 (dd, J = 7.4, 4.5 Hz, 1H), 3.24 (s, 1H), 1.72–1.62
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(m, 2H), 1.61–1.51 (m, 1H), 1.42–1.27 (m, 5H), 1.34 (s, 3H), 1.25
(t, J = 7.2 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 176.0, 138.2, 128.3 (2C), 127.6 (3C), 83.6, 77.6, 73.6,
61.6, 32.1, 29.1, 26.1, 22.6, 21.8, 14.1, 14.0; MS (Fab+) m/z 219
(M+H)+; HRMS calcd for C18H29O4 309.2066, found 309.2066.
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexane–AcOEt, 19 : 1) to afford the
title compound (5.61 g, quant.) as a colorless oil. [a]2D5 +0.4 (c
1
0.50, CHCl3); IR (film) 2945, 1464, 1096, 1037 cm-1; H NMR
(500 MHz, CDCl3) d 7.37–7.29 (m, 4H), 7.28–7.23 (m, 1H), 4.95
(d, J = 7.1 Hz, 1H), 4.78 (d, J = 7.1 Hz, 1H), 4.75 (d, J = 11.3 Hz,
1H), 4.60 (d, J = 11.3 Hz, 1H), 3.88 (d, J = 10.2 Hz, 1H), 3.73
(d, J = 10.2 Hz, 1H), 3.50 (dd, J = 9.5, 2.4 Hz, 1H), 3.37 (s, 3H),
1.68–1.43 (m, 3H), 1.35–1.21 (m, 5H), 1.28 (s, 3H), 1.16–1.00 (m,
21H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
139.2, 128.2 (2C), 127.7 (2C), 127.3, 91.9, 83.9, 81.9, 74.8, 67.2,
55.3, 32.2, 30.6, 26.8, 22.7, 18.0 (6C), 17.6, 14.1, 12.0 (3C); MS
(Fab+) m/z 467 (M+H)+; HRMS calcd for C27H51O4Si 467.3557,
found 467.3569.
Ethyl (2S,3R)-3-benzyloxy-2-methoxymethoxy-2-methylocta-
noate. To a stirred solution of the benzyl ether prepared above
(419 mg, 1.36 mmol) in CH2Cl2 (10 mL) were added i-Pr2NEt
(0.69 mL, 4.1 mmol) and MOMCl (0.26 mL, 3.5 mmol) at
0
◦C. The resultant mixture was allowed to warm to 40 ◦C,
and stirring was continued for 4 days. The mixture was diluted
with Et2O (30 mL) and washed with H2O (10 mL) and brine
(10 mL), dried (Na2SO4), and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(hexane–AcOEt, 9 : 1) to afford the title compound (472 mg,
98%) as a colorless oil. [a]D25 -3.0 (c 0.50, CHCl3); IR (film) 2956,
1730, 1455, 1265 cm-1; 1H NMR (500 MHz, CDCl3) d 7.35–7.29
(m, 4H), 7.29–7.24 (m, 1H), 4.86 (d, J = 7.2 Hz, 1H), 4.80 (d,
J = 11.3 Hz, 1H), 4.73 (d, J = 7.2 Hz, 1H), 4.62 (d, J = 11.3 Hz,
1H), 4.21 (dq, J = 10.8, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.1 Hz,
1H), 3.74 (dd, J = 9.4, 2.0 Hz, 1H), 3.40 (s, 3H), 1.58–1.48 (m,
2H), 1.46 (s, 3H), 1.37–1.19 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H),
0.87 (t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 173.1,
138.9, 128.2 (2C), 127.7 (2C), 127.4, 92.8, 84.3, 84.0, 74.9, 61.0,
56.1, 31.8, 30.5, 26.3, 22.5, 16.5, 14.1, 14.0; MS (Fab+) m/z 353
(M+H)+; HRMS calcd for C20H33O5 353.2328, found 353.2331.
(2R,3R)-2-Methoxymethoxy-2-methyl-1-triisopropylsilyl-oxyo-
ctan-3-ol (13). A mixture of the TIPS ether prepared above
(5.49 g, 11.8 mmol) and 10% Pd on charcoal (549 mg) in EtOH
(120 mL) was stirred at room temperature under hydrogen for
2 h. The mixture was filtered, and the filtrate was concentrated
in vacuo. The crude product was purified by column chromatog-
raphy on silica gel (hexane–AcOEt, 19 : 1) to afford 13 (4.39 g,
99%) as a colorless oil. [a]D25 +13.4 (c 0.50, CHCl3); IR (film) 3482,
2946, 1464, 1099 cm-1; 1H NMR (500 MHz, CDCl3) d 4.90 (d, J =
7.3 Hz, 1H), 4.78 (d, J = 7.3 Hz, 1H), 3.84 (d, J = 10.3 Hz, 1H),
3.73 (d, J = 10.3 Hz, 1H), 3.69–3.62 (m, 1H), 3.39 (s, 3H), 3.01
(dd, J = 5.9, 0.7 Hz, 1H), 1.71–1.60 (m, 1H), 1.60–1.49 (m, 1H),
1.42–1.23 (m, 6H), 1.21 (s, 3H), 1.16–1.02 (m, 21H), 0.89 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 91.6, 80.8, 74.6, 68.2,
55.4, 32.0, 31.4, 26.4, 22.7, 18.0 (6C), 17.2, 14.1, 11.8 (3C); MS
(Fab+) m/z 467 (M+H)+; HRMS calcd for C20H45O4Si 377.3087,
found 377.3088.
(2R,3R)-3-Benzyloxy-2-methoxymethoxy-2-methyloctan-1-ol
(12). To a stirred solution of the MOM ether prepared above
(4.33 g, 12.3 mmol) in THF (82 mL) was added DIBAL-H (1.02 M
solution in hexane, 36.1 mL, 36.8 mmol) at 0 ◦C. After being stirred
at the same temperature for 30 min, the mixture was allowed
to warm to room temperature, and stirring was continued for
2 h. To the reaction mixture was added 1 M aqueous Rochelle
salt (147 mL) at 0 ◦C, and the mixture was stirred at room
temperature for 1 h. The phases were separated, and the aqueous
phase was extracted with Et2O (50 mL). The organic phase and
the extract were combined and washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (hexane–AcOEt,
4 : 1) to afford 12 (3.81 g, quant.) as a colorless oil. [a]2D5 +27.4
(c 0.50, CHCl3); IR (film) 3465, 2956, 1455, 1029 cm-1; 1H NMR
(500 MHz, CDCl3) d 7.37–7.31 (m, 4H), 7.31–7.25 (m, 1H), 4.82
(d, J = 7.5 Hz, 1H), 4.77 (d, J = 7.5 Hz, 1H), 4.68 (d, J = 11.2 Hz,
1H), 4.61 (d, J = 11.2 Hz, 1H), 3.65 (dd, J = 12.4, 6.5 Hz, 1H),
3.57 (dd, J = 12.4, 7.3 Hz, 1H), 3.49 (dd, J = 9.3, 2.5 Hz, 1H),
3.43 (s, 3H), 3.12 (dd, J = 7.3, 6.5 Hz, 1H), 1.66–1.54 (m, 2H),
1.53–1.44 (m, 1H), 1.39–1.21 (m, 5H), 1.25 (s, 3H), 0.89 (t, J =
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 138.7, 128.3 (2C),
127.7 (2C), 127.5, 91.2, 84.3, 82.5, 74.9, 66.0, 55.5, 32.1, 30.8, 26.6,
22.6, 16.8, 14.0; MS (Fab+) m/z 311 (M+H)+; HRMS calcd for
C18H31O4 311.2222, found 311.2219.
Dimethyl (E)-2-{(1R)-1-[(1R)-1-methoxymethoxy-1-methyl-2-
triisopropylsilyloxyethyl]hexyloxy}but-2-enedioate [(E)-15] and its
(Z)-isomer [(Z)-15]. To a stirred solution of 13 (207 mg, 0.550
mmol) in THF (5.0 mL) was added n-BuLi (1.55 M solution in
hexane, 0.071 mL, 0.11 mmol) at -78 ◦C. After stirring at the
same temperature for 15 min, a solution of 14 (0.50 M, 1.7 mL,
0.85 mmol) in THF was added at -78 ◦C. The mixture was stirred
at the same temperature for 1 h, and then allowed to warm to 0 ◦C,
and stirring was continued for 1 h. The reaction was quenched with
saturated aqueous NH4Cl (10 mL). The phases were separated,
and the aqueous phase was extracted with Et2O (10 mL). The
organic phase and the extract were combined and washed with
brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by column chromatography on silica
gel (hexane–AcOEt, 19 : 1→9:1) to afford (E)-15 (216 mg, 76%) as
a colorless solid and (Z)-15 (52.6 mg, 18%) as a colorless oil. (E)-
◦
15: mp 36–37 C (hexane–AcOEt); [a]2D5 +4.8 (c 0.50, CHCl3);
IR (film) 2952, 1749, 1712, 1622, 1367, 1148 cm-1; 1H NMR
(500 MHz, CDCl3) d 5.37 (s, 1H), 4.81 (d, J = 7.5 Hz, 1H), 4.72 (d,
J = 7.5 Hz, 1H), 4.37 (dd, J = 9.9, 2.5 Hz, 1H), 3.87 (s, 3H), 3.80
(d, J = 10.5 Hz, 1H), 3.68 (s, 3H), 3.67 (d, J = 10.6 Hz, 1H), 3.35
(s, 3H), 1.76–1.67 (m, 1H), 1.66–1.55 (m, 1H), 1.54–1.44 (m, 1H),
1.36–1.22 (m, 5H), 1.25 (s, 3H), 1.16–1.00 (m, 21H), 0.88 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 167.1, 164.3, 163.2,
93.5, 91.5, 84.4, 80.6, 66.7, 55.3, 52.7, 51.4, 31.9, 29.8, 25.8, 22.4,
17.9 (6C), 16.6, 14.0, 11.9 (3C); MS (Fab+) m/z 519 (M+H)+;
HRMS calcd for C26H51O8Si 519.3353, found 519.3350. (Z)-15:
(2R,3R)-3-Benzyloxy-2-methoxymethoxy-2-methyl-1-triisopro-
pylsilyloxyoctane. To a stirred solution of 12 (3.74 g, 12.0 mmol)
in CH2Cl2 (120 mL) were added 2,6-lutidine (2.5 mL, 22 mmol)
and TIPSOTf (3.9 mL, 15 mmol) at 0 ◦C. The resulting mixture was
stirred at the same temperature for 1 h. The reaction mixture was
washed with H2O (60 mL) and brine (60 mL), dried (Na2SO4), and
This journal is
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Org. Biomol. Chem., 2011, 9, 5825–5832 | 5829
©

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[a]2D5 -28.8 (c 0.50, CHCl3); IR (film) 2952, 1735, 1716, 1626, 1463,
1267 cm-1; 1H NMR (500 MHz, CDCl3) d 5.61 (s, 1H), 4.82 (dd,
J = 9.2, 2.4 Hz, 1H), 4.65 (d, J = 7.5 Hz, 1H), 4.63 (d, J = 7.5 Hz,
1H), 3.80 (d, J = 11.2 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.63 (d, J =
11.2 Hz, 1H), 3.29 (s, 3H), 1.71–1.54 (m, 2H), 1.49–1.38 (m, 1H),
1.37–1.25 (m, 5H), 1.23 (s, 3H), 1.14–0.98 (m, 21H), 0.89 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 165.3, 163.4, 157.6,
101.7, 91.0, 85.3, 81.4, 66.6, 55.6, 52.2, 51.0, 32.0, 30.1, 26.1, 22.6,
18.0 (3C), 17.9 (3C), 14.2, 14.1, 12.0 (3C); MS (Fab+) m/z 519
(M+H)+; HRMS calcd for C26H51O8Si 519.3353, found 519.3348.
(5.0 mL), H2O (5.0 mL), and brine (5.0 mL), dried (Na2SO4),
and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (hexane–AcOEt, 4 : 1) to
afford (E)-16 (7.0 mg, quant.) as a colorless oil. [a]2D5 -11.0 (c 0.50,
1
CHCl3); IR (film) 2956, 1747, 1627, 1439, 1271, 1152 cm-1; H
NMR (500 MHz, CDCl3) d 9.62 (s, 1H), 5.37 (s, 1H), 4.82 (d, J =
7.4 Hz, 1H), 4.69 (d, J = 7.4 Hz, 1H), 4.31 (dd, J = 8.9, 3.6 Hz, 1H),
3.88 (s, 3H), 3.70 (s, 3H), 3.40 (s, 3H), 1.70–1.56 (m, 2H), 1.54–
1.41 (m, 1H), 1.36 (s, 3H), 1.34–1.20 (m, 5H), 0.88 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 201.3, 166.5, 163.8, 162.1,
94.8, 92.2, 83.9, 83.3, 56.0, 52.9, 51.6, 31.5, 29.7, 25.4, 22.3, 14.0,
13.9; MS (Fab+) m/z 361 (M+H)+; HRMS calcd for C17H29O8
361.1862, found 361.1846.
Dimethyl (E)-2-{(1R)-1-[(1R)-2-hydroxy-1-methoxy-methoxy-
1-methylethyl]hexyloxy}but-2-enedioate. A solution of (E)-15
(1.15 g, 2.21 mmol) in HF·pyr.–pyr.–THF (1 : 2 : 2) (20 mL) was
stirred at room temperature for 43 h. The reaction mixture was
poured into H2O (200 mL) and extracted with Et2O (40 mL
¥ 3). The combined extracts were washed successively with
0.1 M aqueous HCl (50 mL), H2O (50 mL), saturated aqueous
NaHCO3 (50 mL), and brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexane–AcOEt, 4 : 1→1:1) to afford
the title compound (751 mg, 94%) as a colorless oil. [a]2D5 +34.8
(c 0.50, CHCl3); IR (film) 3482, 2955, 1748, 1713, 1624, 1439,
1367, 1151 cm-1; 1H NMR (500 MHz, CDCl3) d 5.37 (s, 1H), 4.81
(d, J = 7.6 Hz, 1H), 4.67 (d, J = 7.6 Hz, 1H), 4.34 (dd, J = 9.9,
2.7 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 3.61–3.55 (m, 2H), 3.42 (s,
3H), 3.00 (t, J = 7.0 Hz, 1H), 1.72–1.54 (m, 2H), 1.54–1.41 (m,
Dimethyl (Z)-2-{(1R)-1-[(1S)-1-methoxymethoxy-1-methyl-2-
oxoethyl]hexyloxy}but-2-enedioate [(Z)-16]. Compound (Z)-16
(122 mg, 98%, colorless oil) was obtained from the alcohol
prepared above [(Z)-isomer, 125 mg, 0.344 mmol] by using a
procedure similar to that for the (E)-isomer. [a]2D5 -29.6 (c 0.50,
CHCl3); IR (film) 2955, 1735, 1632, 1436, 1266, 1208, 1032 cm-1;
1H NMR (500 MHz, CDCl3) d 9.51 (s, 1H), 5.82 (s, 1H), 4.88
(dd, J = 9.7, 1.9 Hz, 1H), 4.72 (d, J = 7.3 Hz, 1H), 4.52 (d, J =
7.3 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.33 (s, 3H), 1.69–1.52 (m,
2H), 1.44–1.19 (m, 6H), 1.42 (s, 3H), 0.87 (t, J = 6.9 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) d 200.7, 164.8, 163.0, 155.5, 104.9, 91.8,
84.9, 81.9, 55.9, 52.6, 51.3, 31.5, 30.0, 25.7, 22.4, 14.0, 11.4; MS
(Fab+) m/z 361 (M+H)+; HRMS calcd for C17H29O8 361.1862,
found 361.1848.
1H), 1.36–1.22 (m, 5H), 1.20 (s, 3H), 0.88 (t, J = 6.9 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) d 166.9, 164.2, 163.0, 93.8, 91.0, 84.2,
81.6, 65.5, 55.7, 52.8, 51.4, 31.7, 29.9, 25.6, 22.4, 15.5, 13.9; MS
(Fab+) m/z 363 (M+H)+; HRMS calcd for C17H31O8 363.2019,
found 363.2018.
Dimethyl (4R,5R,6R)-4-hydroxy-5-methoxymethoxy-5-methyl-
6-pentyl-5,6-dihydro-4H-pyran-2,3-dicarboxylate (17a) and its
(4S,5R,6R)-isomer (17b). To a stirred solution of NaHMDS
(1.0 M solution in THF, 0.63 mL, 0.63 mmol) in THF (1.0 mL) was
added a solution of (E)-16 (150 mg, 0.417 mmol) in THF (3.0 mL)
at -78 ◦C. The mixture was stirred at the same temperature for 1 h,
and the reaction was quenched by addition of silica gel (751 mg).
The resulting slurry was filtered, and the residue was washed with
AcOEt. The filtrate was concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (hexane–
AcOEt, 4 : 1→3:1→7:3) to afford 17a (64.7 mg, 43%) as a colorless
oil and 17b (31.1 mg, 21%) as a colorless solid. 17a: [a]2D5 +80.2
(c 0.50, CHCl3); IR (film) 3356, 2955, 1746, 1635, 1438, 1296,
Dimethyl (Z)-2-{(1R)-1-[(1R)-2-hydroxy-1-methoxy-methoxy-
1-methylethyl]hexyloxy}but-2-enedioate. The title compound
(176 mg, 70%, colorless solid) was obtained from (Z)-15 (362 mg,
0.698 mmol) by using a procedure similar to that for the (E)-
isomer. mp 44–45 ◦C (hexane–AcOEt); [a]D25 +13.6 (c 0.50, CHCl3);
IR (film) 3502, 2955, 1734, 1716, 1628, 1436, 1267, 1031 cm-1; 1H
NMR (500 MHz, CDCl3) d 5.74 (s, 1H), 4.74 (d, J = 7.6 Hz, 1H),
4.73 (dd, J = 9.5, 1.9 Hz, 1H), 4.59 (d, J = 7.6 Hz, 1H), 3.82 (s, 3H),
3.72 (s, 3H), 3.62 (dd, J = 12.4, 6.5 Hz, 1H), 3.47 (dd, J = 12.4,
7.7 Hz, 1H), 3.37 (s, 3H), 3.13 (dd, J = 7.7, 6.5 Hz, 1H), 1.73–1.52
(m, 2H), 1.46–1.37 (m, 1H), 1.36–1.25 (m, 5H), 1.27 (s, 3H), 0.89
(t, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 165.1, 163.2,
156.4, 103.8, 90.7, 84.6, 82.2, 65.9, 55.6, 52.5, 51.3, 31.7, 30.0, 26.1,
22.5, 14.5, 14.0; MS (Fab+) m/z 363 (M+H)+; HRMS calcd for
C17H31O8 363.2019, found 363.2014.
1
1031 cm-1; H NMR (500 MHz, CDCl3) d 4.91 (d, J = 7.5 Hz,
1H), 4.76 (d, J = 7.5 Hz, 1H), 4.31 (dd, J = 6.8, 1.3 Hz, 1H), 4.10
(d, J = 6.8 Hz, 1H), 3.94–3.90 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H),
3.44 (s, 3H), 2.02–1.90 (m, 1H), 1.76–1.53 (m, 2H), 1.39–1.21 (m,
5H), 1.32 (s, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 166.6, 163.1, 149.2, 110.5, 91.4, 83.3, 74.4, 68.4, 56.0,
52.7, 52.1, 31.5, 27.2, 25.9, 22.5, 18.6, 14.0; MS (Fab+) m/z 361
(M+H)+; HRMS calcd for C17H29O8 361.1862, found 361.1846.
Dimethyl (E)-2-{(1R)-1-[(1S)-1-methoxymethoxy-1-methyl-2-
oxoethyl]hexyloxy}but-2-enedioate [(E)-16]. To a stirred solution
of the alcohol prepared above [(E)-isomer, 7.0 mg, 0.019 mmol]
in CH2Cl2 (0.5 mL) was added a solution of Dess–Mar◦tin perio-
dinane (15%w/w, 62 mL, 0.029 mmol) in CH2Cl2 at 0 C. After
being stirred for 15 min, the mixture was allowed to warm to room
temperature, and stirring was continued for 1.5 h. Another 0.12 mL
(0.057 mmol) of a solution of Dess–Martin periodinane in CH2Cl2
was added, and the stirring was continued for another 1 h. The
mixture was diluted with Et2O (10 mL) and washed successively
with 5% aqueous Na2S2O3 (5.0 mL), saturated aqueous NaHCO3
◦
17b: mp 45–48 C (hexane–AcOEt); [a]2D5 +167 (c 0.50, CHCl3);
IR (film) 3502, 2955, 1748, 1706, 1636, 1439, 1283, 1036 cm-1; 1H
NMR (500 MHz, CDCl3) d 4.89 (d, J = 7.8 Hz, 1H), 4.61 (d, J =
7.8 Hz, 1H), 4.60 (br s, 1H), 3.99 (dd, J = 10.3, 2.4 Hz, 1H), 3.87 (s,
3H), 3.76 (s, 3H), 3.30 (s, 3H), 2.52 (br s, 1H), 1.89 (m, 1H), 1.69–
1.55 (m, 2H), 1.44–1.20 (m, 5H), 1.37 (s, 3H), 0.89 (t, J = 6.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 166.6, 163.9, 156.2, 105.3,
91.2, 79.8, 74.4, 65.8, 55.7, 52.8, 51.9, 31.7, 27.1, 25.4, 22.5, 17.0,
14.0; MS (Fab+) m/z 361 (M+H)+; HRMS calcd for C17H29O8
361.1862, found 361.1858.
5830 | Org. Biomol. Chem., 2011, 9, 5825–5832
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1
Dimethyl (4R,5S,6R)-4-(tert-butyldimethylsilyloxy)-5-methoxy-
methoxy-5-methyl-6-pentyl-5,6-dihydro-4H-pyran-2,3-dicarboxy-
late. To a stirred solution of 17a (674 mg, 1.87 mmol) in CH2Cl2
(19 mL) were added 2,6-lutidine (0.87 mL, 7.5 mmol) and TBSOTf
(0.86 mL, 3.7 mmol) at room temperature. The resulting mixture
was stirred at the same temperature for 1 h, and then was allowed
to warm to 35 ◦C, and stirring was continued for 2 h. The reaction
mixture was diluted with Et2O (50 mL) and washed successively
with 1 M aqueous HCl (20 mL), H2O (20 mL), saturated aqueous
NaHCO3 (20 mL), and brine (60 mL), dried (Na2SO4), and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexane–AcOEt, 9 : 1) to afford the
title compound (856 mg, 97%) as a colorless oil. [a]2D5 +80.2 (c 0.50,
CHCl3); IR (film) 2954, 1748, 1714, 1633, 1438, 1295, 1093 cm-1;
1H NMR (500 MHz, CDCl3) d 4.91 (d, J = 7.5 Hz, 1H), 4.65 (d,
J = 7.5 Hz, 1H), 4.33 (d, J = 1.8 Hz, 1H), 4.13 (dt, J = 11.1, 1.8 Hz,
1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.39 (s, 3H), 2.12–2.01 (m, 1H),
1.84–1.74 (m, 1H), 1.60–1.50 (m, 1H), 1.37–1.22 (m, 5H), 1.28 (s,
3H), 0.89 (t, J = 6.9 Hz, 3H), 0.84 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H);
13C NMR (125 MHz, CDCl3) d 166.5, 164.0, 150.8, 108.8, 91.4,
83.8, 74.6, 68.5, 56.0, 52.8, 51.7, 31.6, 27.8, 27.0, 25.8 (3C), 22.5,
21.1, 18.4, 14.0, -4.6, -5.2; MS (Fab+) m/z 475 (M+H)+; HRMS
calcd for C23H43O8Si 475.2727, found 475.2712.
3403, 2930, 1714, 1653, 1627, 1558, 1465, 1254, 1089 cm-1; H
NMR (500 MHz, CDCl3) d 8.67 (br s, 1H), 4.95 (d, J = 7.5 Hz, 1H),
4.64 (d, J = 7.5 Hz, 1H), 4.28 (br s, 1H), 4.05 (br d, J = 10.4 Hz, 1H),
3.82 (br s, 3H), 3.75 (s, 3H), 3.39 (s, 3H), 2.08–1.93 (m, 1H), 1.86–
1.71 (m, 1H), 1.55–1.40 (m, 1H), 1.38–1.21 (m, 5H), 1.28 (s, 3H),
0.90 (br t, J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.09 (s, 3H), 0.03 (s, 3H);
13C NMR (125 MHz, CDCl3) d 167.3, 160.2, 145.4, 113.6, 91.6,
83.3, 74.3, 70.0, 64.5, 56.1, 52.2, 31.6, 27.2, 27.2, 25.7 (3C), 22.6,
20.7, 18.3, 14.0, -4.4, -5.2; MS (Fab+) m/z 490 (M+H)+; HRMS
calcd for C23H44NO8Si 490.2836, found 490.2840. Crystal data† for
amide 20: C23H43NO8Si, Mw = 489.67, orthorhombic, P212121,
a = 9.0593(3), b = 15.3579(5), c = 19.9706(6), V = 2778.55(15), R =
0.0569, wR = 0.1255, S = 1.018
(2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-6-methoxy-3-metho-
xymethoxy-3-methyl-2-pentyl-3,4-dihydro-2H-pyrano[2,3-c]pyrro-
le-5,7-dione (21). A solution of 20 (403 mg, 0.822 mmol) and
Et3N (0.34 mL, 2.4 mmol) in DMF (10 mL) was stirred at
130 ◦C for 4 h. After being cooled to room temperature, the
mixture was diluted with Et2O (50 mL) and washed successively
with H2O (25 mL ¥ 3) and brine (25 mL), dried (Na2SO4), and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (hexane–AcOEt, 9 : 1) to afford 21
(262 mg, 70%) as a colorless solid. mp 54–55 ◦C (hexane–AcOEt);
[a]2D5 +29.4 (c 0.50, CHCl3); IR (film) 2931, 1738, 1663, 1417,
(4R,5S,6R)-4-(tert-Butyldimethylsilyloxy)-3-methoxy-carbonyl-
5-methoxymethoxy-5-methyl-6-pentyl-5,6-dihydro-4H-pyran-2-
carboxylic acid. To a stirred solution of the TBS ether prepared
above (805 mg, 1.70 mmol) in MeOH (20 mL) was added 1.0 M
aqueous NaOH (2.5 mL, 2.5 mmol) at room temperature. The
resulting mixture was stirred at the same temperature for 1 h, and
1120 cm-1; H NMR (500 MHz, CDCl3) d 4.99 (br s, 1H), 4.64
1
(d, J = 7.5 Hz, 1H), 4.26 (br s, 2H), 3.97 (s, 3H), 3.40 (s, 3H),
2.00–1.84 (m, 2H), 1.67–1.52 (m, 1H), 1.41–1.21 (m, 5H), 1.30 (s,
3H), 0.96–0.82 (m, 3H), 0.90 (s, 9H), 0.17 (br s, 3H), 0.15 (s, 3H);
13C NMR (150 MHz, CDCl3) d 165.0, 161.0, 152.0, 109.6, 92.0,
87.4, 75.2, 66.1, 65.0, 56.0, 31.6, 28.2, 26.6, 25.8 (3C), 22.5, 20.6,
18.2, 14.0, -4.7, -4.9; MS (Fab+) m/z 458 (M+H)+; HRMS calcd
for C22H40NO7Si 458.2574, found 458.2576.
◦
then was allowed to warm to 35 C, and stirring was continued
R
for 17 h. The reaction was quenched by addition of Amberliteꢀ
IR-120. After being stirred for 10 min, the mixture was filtered,
and the filtrate was concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (CHCl3–MeOH,
4 : 1) to afford the title compound (703 mg, 90%) as a pale yellow
syrup. [a]2D5 +20.6 (c 0.50, CHCl3); IR (film) 3525, 2955, 1715,
1625, 1295, 1094 cm-1; 1H NMR (500 MHz, DMSO-d6) d 4.81 (d,
J = 7.3 Hz, 1H), 4.68 (d, J = 7.3 Hz, 1H), 4.25 (d, J = 1.7 Hz,
1H), 4.08 (br d, J = 10.8 Hz, 1H), 3.55 (s, 3H), 3.29 (s, 3H), 1.98–
1.85 (m, 1H), 1.75–1.63 (m, 1H), 1.51–1.37 (m, 1H), 1.31–1.14 (m,
5H), 1.16 (s, 3H), 0.84 (t, J = 6.9 Hz, 3H), 0.80 (s, 9H), 0.07 (s,
3H), -0.01 (s, 3H). A signal due to one proton (COOH) was not
observed; 13C NMR (150 MHz, DMSO-d6) d 166.5, 164.8, 154.7,
104.4, 90.9, 81.7, 73.9, 68.5, 55.3, 51.1, 31.2, 27.3, 26.3, 25.7 (3C),
21.9, 20.7, 18.1, 13.8, -4.7, -5.2; MS (Fab+) m/z 483 (M+Na)+;
HRMS calcd for C22H40NaO8Si 483.2390, found 483.2391.
(2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-7-hydroxy-6-metho-
xy-3-methoxymethoxy-3,7-dimethyl-2-pentyl-3,4,6,7-tetrahydro-
2H-pyrano[2,3-c]pyrrol-5-one. To
a stirred solution of 21
(159 mg, 0.346 mmol) was added MeMgBr (3.0 M solution in
Et2O, 0.23 mL, 0.69 mmol) at -78 ◦C. The mixture was stirred at
the same temperature for 30 min, and then poured into saturated
aqueous NH4Cl (20 mL) and extracted with Et2O (30 mL).
The combined extracts were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (hexane–AcOEt,
3 : 1) to afford the title compound (164 mg, quant.) as a colorless
oil. [a]2D5 +2.2 (c 0.50, CHCl3); IR (film) 2930, 1727, 1669, 1416,
1219, 1030 cm-1; 1H NMR (300 MHz, CDCl3) d 4.93 [4.95] (d, J =
7.5 Hz, 1H), 4.67 [4.64] (d, J = 7.5 Hz, 1H), 4.25–4.12 (m, 2H),
3.94 [3.94] (s, 3H), 3.39 (s, 3H), 3.34 [2.09] (br s, 1H), 1.99–1.85 (m,
2H), 1.59–1.48 (m, 1H), 1.53 [1.60] (s, 3H), 1.38–1.23 (m, 5H), 1.25
[1.22] (s, 3H), 0.94–0.82 (m, 3H), 0.88 [0.87] (s, 9H), 0.16 [0.16 and
0.13] (s, 6H) (the minor counterpart of doubled signals in the ratios
of 1.2 : 1 are in brackets); 13C NMR (125 MHz, CDCl3) d 170.0
[169.4], 167.4 [167.1], 103.6, 91.8 [91.8], 86.7 [87.0], 86.4 [86.2], 77.2
[75.5], 65.9 [66.1], 64.5, 55.8, 31.6 [31.6], 28.1 [28.3], 26.9 [26.8],
25.8 [25.8] (3C), 22.4 [22.5], 21.3, 21.1 [20.1], 18.2, 14.0 [13.9], -4.7
[-4.7], -5.2 (the minor counterpart of doubled signals in the ratios
of 1.2 : 1 are in brackets); MS (Fab+) m/z 474 (M+H)+; HRMS
calcd for C23H44NO7Si 474.2887, found 474.2884.
Methyl (4R,5S,6R)-4-(tert-butyldimethylsilyloxy)-2-methoxy-
carbamoyl-5-methoxymethoxy-5-methyl-6-pentyl-5,6-dihydro-4H-
pyran-3-carboxylate (20). To a stirred solution of the carboxylic
acid prepared above (683 mg, 1.48 mmol) in CH2Cl2 (15 mL)
were added MeONH2·HCl (296 mg, 3.54 mmol), Et3N (0.79 mL,
5.7 mmol), 1-hydroxybenzotriazole monohydrate (434 mg, 2.83
mmol), and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hy-
drochloride (543 mg, 2.83 mmol) at room temperature, and the
mixture was stirred for 5 h. After concentration, the crude product
was purified by column chromatography on silica gel (hexane–
AcOEt, 7 : 3) to afford 20 (649 mg, 89%) as a colorless solid. mp
◦
89–90 C (hexane–AcOEt); [a]2D5 +8.4 (c 0.50, CHCl3); IR (film)
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Org. Biomol. Chem., 2011, 9, 5825–5832 | 5831
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(2R,3S,4R)-4-(tert-Butyldimethylsilyloxy)-3-hydroxy-6-metho-
xy-3-methyl-7-methylene-2-pentyl-3,4,6,7-tetrahydro-2H-pyrano-
[2,3-c]pyrrol-5-one (22). To a stirred solution of the hemiaminal
prepared above (142 mg, 0.299 mmol) in 1,4-dioxane (3.0 mL)
was added a solution of HCl (ca. 4 mol L-1, 3.0 mL) in 1,4-
dioxane at room temperature. The mixture was stirred at the same
temperature for 1 h. After concentration, the crude product was
purified by column chromatography on silica gel (hexane–AcOEt,
9 : 1→17:3→4:1→3:1) to afford 22 (63.5 mg, 52%) as a colorless
oil. [a]2D5 +59.8 (c 0.72, CHCl3); IR (film) 3526, 2931, 1738, 1666,
1421, 1221 cm-1; 1H NMR (500 MHz, CDCl3) d 5.05 (d, J = 1.7 Hz,
1H), 4.99 (d, J = 1.7 Hz, 1H), 4.12 (d, J = 1.2 Hz, 1H), 4.03 (dt,
J = 10.9, 1.4 Hz, 1H), 3.92 (s, 3H), 3.19 (s, 1H), 1.99–1.85 (m, 1H),
1.79–1.67 (m, 1H), 1.58–1.46 (m, 1H), 1.41–1.25 (m, 5H), 1.23 (s,
3H), 0.95–0.83 (m, 3H), 0.90 (s, 9H), 0.27 (s, 3H), 0.22 (s, 3H);
13C NMR (125 MHz, CDCl3) d 166.2, 156.4, 136.9, 103.3, 91.8,
86.1, 69.9, 65.6, 64.3, 31.5, 27.5, 26.7, 25.9 (3C), 24.0, 22.5, 18.2,
14.0, -4.5, -5.4; MS (Fab+) m/z 412 (M+H)+; HRMS calcd for
C21H38NO5Si 412.2519, found 412.22514.
1H), 3.79 (s, 3H), 1.82 (m, 1H), 1.51 (m, 1H), 1.44 (m, 2H), 1.28
(m, 2H), 1.27 (m, 2H), 1.18 (s, 3H), 0.85 (t, J = 6.7 Hz, 3H); 13
C
NMR (DMSO-d6) d 166.5, 155.2, 137.0, 104.7, 90.8, 86.2, 70.8,
64.1, 63.7, 30.8, 27.5, 25.9, 21.9, 20.5, 13.8.
Acknowledgements
We are grateful to Dr T. Ishizaki of Kyorin Pharmaceutical
Co., Ltd. for extensive support and Dr Y. Fukuda of Kyorin
Pharmaceutical Co., Ltd. for his encouragement and support of
this project.
References
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Proposed structure of phaeosphaeride A (1). A solution of 22
(61.5 mg, 0.149 mmol) and 3HF·Et3N (0.49 mL) in THF (2.0 mL)
was stirred at room temperature for 10 h. After concentration,
the crude product was purified by column chromatography on
silica gel (hexane–AcOEt, 1 : 1) to afford the proposed structure
of phaeo◦sphaeride A (1) (39.9 mg, 90%) as colorless crystals. mp
135–136 C (hexane–AcOEt); [a]2D5 +95.4 (c 0.50, CHCl3); IR (film)
1
3420, 2959, 1703, 1636, 1448, 1173 cm-1; H NMR (500 MHz,
DMSO-d6) d 5.17 (d, J = 7.0 Hz, 1H), 4.96 (d, J = 1.7 Hz, 1H),
4.94 (d, J = 1.7 Hz, 1H), 4.51 (br s, 1H), 4.02 (d, J = 7.0 Hz, 1H),
3.99 (dd, J = 10.7, 2.2 Hz, 1H), 3.76 (s, 3H), 1.86–1.75 (m, 1H),
1.75–1.64 (m, 1H), 1.57–1.45 (m, 1H), 1.38–1.21 (m, 5H), 1.07
(s, 3H), 0.86 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, DMSO-
d6) d 165.9, 156.4, 136.7, 104.9, 90.9, 85.0, 68.8, 64.7, 63.7, 31.1,
27.0, 25.2, 22.6, 22.0, 13.9; MS (Fab+) m/z 298 (M+H)+; HRMS
calcd for C15H24NO5 298.1654, found 298.1655. Reported data3 for
natural phaeosphaeride: 1H NMR (500 MHz, DMSO-d6) d 5.44
(d, J = 5.5 Hz, 1H), 4.97 (d, J = 1.8 Hz, 1H), 4.96 (d, J = 1.8 Hz,
1H), 4.92 (s, 1H), 4.07 (d, J = 11.5 Hz, 1H), 3.86 (d, J = 5.5 Hz,
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5832 | Org. Biomol. Chem., 2011, 9, 5825–5832
This journal is
The Royal Society of Chemistry 2011
©